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HK1086559A - Benzopyran compounds useful for treating inflammatory conditions - Google Patents

Benzopyran compounds useful for treating inflammatory conditions Download PDF

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Publication number
HK1086559A
HK1086559A HK06106482.6A HK06106482A HK1086559A HK 1086559 A HK1086559 A HK 1086559A HK 06106482 A HK06106482 A HK 06106482A HK 1086559 A HK1086559 A HK 1086559A
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HK
Hong Kong
Prior art keywords
trifluoromethyl
chromene
carboxylic acid
chloro
methyl
Prior art date
Application number
HK06106482.6A
Other languages
Chinese (zh)
Inventor
J．S．卡特
K．W．阿斯顿
D.L.布朗
A．德普罗
T．弗莱彻
E．A．哈利南
B．C．汉普尔
R．赫夫
J．R．小基弗
F．科茨耶克
S.克雷默
廖速波
D．C．林博格
C.路德维格
J．M．麦考尔
J．R．斯普林格
J．J．塔利
L.J.王
邢莉
Y.于
Original Assignee
法玛西雅公司
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Publication of HK1086559A publication Critical patent/HK1086559A/en

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Description

Benzopyran compounds for the treatment of inflammation
no marking
Technical Field
The present invention is in the field of anti-inflammatory agents, and in particular, relates to compounds, compositions and methods for treating cyclooxygenase-2 mediated disorders, such as inflammation and inflammation-related disorders.
Background
Prostaglandins play an important role in the inflammatory process; inhibiting the production of prostaglandins, particularly PGG2、PGH2With PGE2Has been a common goal of research and development work on anti-inflammatory drugs. However, the common non-steroidal anti-inflammatory drugs (NSAIDs), which have the activity of reducing prostaglandin-induced pain and swelling associated with inflammatory processes, also have the activity of affecting other prostaglandin-mediated processes unrelated to inflammatory processes. Thus, the use of high doses of the most common non-steroidal anti-inflammatory drugs can produce serious side effects, including ulcers with a fatal risk, and their therapeutic potential is therefore limited. An alternative to non-steroidal anti-inflammatory drugs is the use of corticosteroids, which have even more serious side effects, especially when long-term treatment is involved.
Previous non-steroidal anti-inflammatory drugs have been found to inhibit the production of prostaglandins by inhibiting enzymes in the human arachidonic acid/prostaglandin pathway, including Cyclooxygenase (COX). A recently discovered induction enzyme associated with inflammation, known as "cyclooxygenase-2 (COX-2)" or "prostaglandin G/H synthase II", provides a viable target for inhibition that is more effective in reducing inflammation and produces fewer and less severe side effects.
U.S. patent No. 6,034,256 describes certain benzopyran compounds that are useful for treating inflammatory conditions. U.S. patent No. 6,077,850 further describes benzopyran compounds useful in the treatment of inflammatory conditions. Some other benzopyran compounds useful in the treatment of inflammatory conditions are also described in U.S. patent No. 6,271,253.
Disclosure of Invention
Novel benzopyran derivatives are safe and effective anti-inflammatory agents. The substituted benzopyran derivatives disclosed herein, preferably selectively inhibit cyclooxygenase-2 rather than cyclooxygenase-1.
The compounds of the present invention have never been described as anti-inflammatory cyclooxygenase inhibitors.
The following description is provided to assist those skilled in the art in carrying out the invention. Even so, this detailed description should not be taken as commensurately limiting the invention, as modifications or variations in the embodiments described herein may be made by those of ordinary skill in the art without departing from the spirit or scope of the inventive discoveries herein.
The contents of each of the references cited herein, including the contents of the references cited within their original references, are hereby incorporated by reference in their entirety.
In various embodiments of the present invention, there is provided a compound of formula 1, or a pharmaceutically acceptable salt thereof,
wherein: x is selected from the group consisting of: hydrogen, alkyl and a pharmaceutically acceptable cation; z is selected from the group consisting of: oxygen, sulfur and NH; wherein R is1、R2、R3And R4Each independently selected from the group consisting of: hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonylalkyl, alkylthio, alkynyl, aminocarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkylamino, arylalkynyl, arylcarbonyl, aryloxy, cyano, dialkylamino, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkoxy, heteroarylcarbonyl, hydroxy and hydroxyalkyl; wherein each aryl group, at any position, is independently substituted with 1 to 5 substituents selected from the group consisting of: alkyl, alkoxy,Alkylamino, cyano, halo, haloalkyl, hydroxy and nitro.
The present invention further provides a pharmaceutical composition comprising a compound having structural formula 1 or a pharmaceutically acceptable salt thereof, wherein Z, X, R 1、R2、R3And R4Each independently as described above; and includes a pharmaceutically acceptable excipient.
The present invention further provides a method for treating or preventing cyclooxygenase-2 mediated disorders in a patient in need of such treatment or prevention, wherein said method comprises administering to said patient an amount of a compound of formula 1 or a pharmaceutically acceptable salt thereof, wherein Z, X, R1、R2、R3And R4Each independently as described above; and wherein the amount of the compound is effective to treat or prevent a cyclooxygenase-2 mediated condition.
The compounds of the invention are useful for, but not limited to, treating inflammation in a patient, and are useful for treating cyclooxygenase-2 mediated other disorders, such as analgesics for treating pain and headaches, including migraine, or as antipyretics for treating fever. For example, the compounds of the present invention are useful in the treatment of arthritis, including but not limited to rheumatoid arthritis, spondyloarthropathies, gouty arthritis, osteoarthritis, systemic lupus erythematosus and juvenile arthritis. The compounds of the invention will be useful in the treatment of asthma, bronchitis, menstrual cramps, premature labour, tendonitis, bursitis, allergic neuritis, cytomegalovirus infectivity, apoptosis including HIV-induced apoptosis, lumbago, liver diseases including hepatitis, skin-related conditions such as psoriasis, eczema, acne, uv damage, burns and dermatitis. The compounds of the invention will also be useful in the treatment of gastrointestinal conditions such as inflammatory bowel disease, Crohn's disease, gastritis, irritable bowel syndrome and ulcerative colitis. The compounds of the present invention will be useful in the treatment of inflammatory phenomena in the following diseases: migraine, periarteritis nodosa, thyroiditis, aplastic anemia, Hodgkin's (Hodgkin) disease, dermatosclerosis, rheumatic fever, type I diabetes, neuromuscular junction diseases including myasthenia gravis, white matter diseases including multiple sclerosis, sarcoidosis, nephrotic syndrome, Bechet's (Bechet) syndrome, polymyositis, gingivitis, nephritis, hypersensitivity reactions, swelling phenomena occurring after surgery including cerebral edema, myocardial ischemia, etc. The compounds of the invention will also be useful in the treatment of ocular diseases such as retinitis, conjunctivitis, retinopathies (including diabetic retinopathy), uveitis, ocular photophobia, conditions involving elevated intraocular pressure (including glaucoma), sarcoidosis, macular degeneration (including wet and dry macular degeneration), ocular neovascularization, retinal neovascularization (including neovascularization following injury or infection), rejection of transplanted corneas, retrolental fibroplasia, inflammation after eye surgery (including cataract surgery, retinal detachment surgery, lens implantation surgery, corneal transplantation surgery, and refractive surgery), blepharitis, endophthalmitis, episcleritis, keratitis, keratoconjunctivitis, dry eye, moren's (Mooren) ulcer, macular edema, miosis during surgery, eye pain, and acute injury to eye tissue. The compounds of the invention will also be useful in the treatment of pulmonary inflammation, such as diseases associated with viral infection and cystic fibrosis; and for the treatment of bone resorption such as diseases associated with osteoporosis.
The compounds of the invention will also be useful in the treatment of central nervous system disorders such as cortical dementias including Alzheimer's disease, schizophrenia, neurodegeneration and central nervous system injury from stroke, ischemia and trauma. The term "treating" includes the partial or complete inhibition of dementia, including Alzheimer's disease, vascular dementia, multi-infarct dementia, Alzheimer's disease, alcoholic dementia and senile dementia.
The compounds of the invention are suitable as anti-inflammatory agents, such as for the treatment of arthritis, and have the additional advantage of being significantly less harmful for side effects. These compounds would also be useful in the treatment of allergic rhinitis, respiratory distress syndrome, endotoxic shock syndrome and liver disease. The compounds of the invention will also be useful in the treatment of pain, but are not limited to post-operative pain, dental pain, muscle pain and pain from cancer.
The above methods would also be suitable for treating and preventing inflammation-related cardiovascular disorders in a patient. The method will be suitable for the treatment and prevention of vascular disease; coronary artery disease; hemangioma; vascular rejection; atherosclerosis; atherosclerosis, including heart transplant atherosclerosis; myocardial infarction; arterial thrombosis; stroke; thrombosis, including venous thrombosis; angina pectoris, including unstable angina; inflammation of coronary plaque; bacterial-induced inflammation, including induced inflammation; viral-induced inflammation; and inflammation associated with surgical procedures, such as vascular anastomosis procedures including coronary artery bypass surgery; revascularization procedures include angioplasty, stent placement, endarterectomy, or other invasive surgical procedures involving arteries, veins, and capillaries.
The compounds will be suitable for, but not limited to, the treatment of disorders associated with angiogenesis in a patient. The compounds may be administered as described herein to a patient in need of angiogenesis inhibition. The method will be useful for treating neoplasia, including metastasis; ophthalmic conditions include corneal graft rejection, ocular neovascularization, retinal neovascularization including neovascularization following injury or infection, diabetic retinopathy, macular degeneration, retrolental fibroplasia, and neovascular glaucoma; ulcerative diseases such as gastric ulcer; pathological but non-malignant conditions such as hemangiomas, including infantile hemangiomas, angiofibromas of the nasopharynx, and avascular necrosis of the bone; and disorders of the female reproductive system such as endometriosis.
The compounds of the invention will be useful in the prevention or treatment of benign and malignant tumors/neoplasia, including cancers such as colorectal cancer; brain cancer; bone cancer; epidermal cell-derived tumors (epithelial cancers) such as basal cell carcinoma; adenocarcinoma; gastrointestinal cancer such as lip cancer, oral cancer, esophageal cancer, small intestine cancer, and stomach cancer; colon cancer; liver cancer; bladder cancer; pancreatic cancer; ovarian cancer; cervical cancer; lung cancer; breast and skin cancers, such as squamous cell and basal cell carcinoma; prostate cancer; renal cell carcinoma; and other cancers known to affect epithelial cells of the body. Preferably, the craving organism formation is selected from gastrointestinal cancer, Barrett's esophageal cancer, liver cancer, bladder cancer, pancreatic cancer, ovarian cancer, prostate cancer, cervical cancer, lung cancer, breast cancer and skin cancers such as squamous cell and basal cell carcinoma. The compounds are also useful in the treatment of fibrosis due to radiation therapy. The method may also be used to treat patients with adenomatous polyps, including those with Familial Adenomatous Polyposis (FAP). In addition, the method can prevent polyps in patients at risk for FAP. Further, the compounds of the present invention may be used for the treatment or prevention of side effects resulting from oncology related therapies such as radiation therapy or chemotherapy. For example, the compounds of the invention will be useful in reducing diarrhea caused by chemotherapy with a topoisomerase such as irinotecan.
In addition to being useful in the treatment of humans, these compounds are also suitable for veterinary use in the treatment of companion animals, foreign animals and farm animals, including mammals, rodents, and the like. More preferred animals include horses, dogs and cats.
Definition of
The term "preventing" includes preventing the onset of a clinically significant cardiovascular disorder in a patient in general, or preventing the onset of a pre-clinically significant phase of a cardiovascular disorder. It includes prophylactic treatment of those at risk of developing diseases such as cardiovascular disorders, dementia or cancer.
The term "therapeutically effective" is intended to quantify the amount of each agent that achieves the goal of improving the severity and frequency of the condition itself during treatment, while avoiding the severe side effects typically associated with alternative therapies.
As used herein, "COX-2 selective" -)The term means that a compound has a better ability to inhibit COX-2 than COX-1 in an in vitro assay. The present invention includes compounds that are COX-2 selective. Compounds with COX-2 selectivity preferably have less than about 0.5 micromolar COX-2 IC in vitro50. The selectivity ratio of a COX-2 selective compound over a COX-1 inhibitory effect for COX-2 inhibition is preferably at least 2, preferably at least 5, more preferably at least 10, more preferably at least 20, more preferably at least 50, and more preferably at least 100. It is even more preferred that the COX-2 selective compound have a COX-1 IC greater than about 5 micromolar 50. These preferred selectivities show the ability to reduce the frequency of side effects caused by common non-steroidal anti-inflammatory drugs.
As used herein, the term "COX-1 selective" means that a compound inhibits COX-1 better than COX-2 in an in vitro assay. The invention also includes compounds that are COX-1 selective. Compounds with COX-1 selectivity preferably have less than about 0.5 micromolar COX-1 IC in vitro50. The selectivity ratio of a COX-1 selective compound over a COX-2 inhibitory effect for COX-1 inhibition is preferably at least 2, preferably at least 5, more preferably at least 10, more preferably at least 20, more preferably at least 50, and more preferably at least 100. Even more preferably, COX-1 selective compounds have COX-2IC greater than about 5 micromolar50. These preferred selectivities will have utility in tissues where the COX-1 enzyme product produces effects that are adverse to the patient.
The terms "benzopyran" and "chromene" and the like are used interchangeably.
Unless otherwise mentioned, "alkyl", "alkenyl" and "alkynyl" as used herein are each straight or branched chain hydrocarbon radicals, the alkyl radicals of the present invention having from 1 to 20 carbon atoms, and the alkenyl and alkynyl radicals having from 2 to 20 carbon atoms, and thus refer to, for example, methyl, ethyl, propyl, butyl, pentyl or hexyl, respectively; ethenyl, propenyl, butenyl, pentenyl or hexenyl; and ethynyl, propynyl, butynyl, pentynyl or hexynyl; and isomers thereof.
"aryl" refers to a fully unsaturated monocyclic or polycyclic carbocyclic ring including, but not limited to, substituted or unsubstituted phenyl, naphthyl, or anthracenyl. "heterocycle" refers to a saturated or unsaturated monocyclic or polycyclic carbocyclic ring in which one or more carbon atoms may be replaced by nitrogen, sulfur, phosphorus, or oxygen. It includes, for example, the following structures:
or
Z, Z therein1、Z2Or Z3Carbon, sulfur, phosphorus, oxygen or nitrogen, with the proviso that Z, Z1、Z2Or Z3One of which is not carbon; and is not oxygen or sulfur when linked to another Z atom in a double bond or when linked to another oxygen or sulfur atom. Furthermore, it is understood that only when each is carbon, is an optional substituent attached to Z, Z1、Z2Or Z3。
The term "heteroaryl" refers to a fully unsaturated heterocyclic ring.
In "heterocycle" or "heteroaryl", the point of attachment to the molecule of interest may be a heteroatom or elsewhere within the ring.
The term "hydroxy" refers to a group having the structure-OH.
The term "halogen" or "halo" refers to fluoro, chloro, bromo, or iodo.
The term "haloalkyl" refers to an alkyl group substituted with one or more halogens.
The term "cycloalkyl" refers to a monocyclic or polycyclic carbocyclic ring wherein each ring contains from 3 to 10 carbon atoms and wherein any ring may contain one or more double or triple bonds. Examples include radicals such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloalkenyl, and cycloheptyl. "cycloalkyl" additionally encompasses spiro systems in which one carbon ring atom of the cycloalkyl ring is shared with a 7-membered heterocycle of benzothiepine.
The term "oxo" refers to a double bond bonded oxygen.
The term "cycloalkylene" refers to a monocyclic or polycyclic carbocyclic ring in which one carbon of the ring structure is bonded to an atomic double bond that is not located within the ring structure.
The term "nitro" refers to a compound of the formula-NO2A group of (1).
The term "sulfo" refers to a sulfo group-SO3H or a salt thereof.
The term "thio" refers to a group of the formula-SH.
The term "sulfoalkyl" refers to an alkyl group bonded to a sulfonate group, wherein the alkyl group is bonded to the molecule in question.
The term "aminosulfonyl" refers to compounds having the formula-SO2NH2A group of (1).
The term "alkylthio" refers to a radical containing a moiety with an alkyl radical attached to a sulfur atom, such as a methylthio radical. The alkylthio moiety is bonded to the molecule of interest at the sulfur atom position of the alkylthio group.
The term "aryloxy" refers to a moiety containing an aryl radical attached to an oxygen atom, such as a phenoxy radical. The aryloxy moiety is bonded to the molecule in question at the position of the oxygen atom of the aryloxy group.
The term "alkenyloxy" refers to a moiety containing an alkenyl radical attached to an oxygen atom, such as a 3-propenyloxy radical. The alkenyloxy moiety is bonded to the molecule in question at the oxygen atom position of the alkenyloxy group.
The term "arylalkyl" refers to an alkyl radical substituted with an aryl group, such as benzyl. The term "alkylarylalkyl" refers to an arylalkyl radical substituted on the aryl with one or more alkyl groups.
The term "amino" refers to a compound having the formula-NH2A group of (1). Alternatively, the amino group may be substituted with, for example, one, two or three substituents such as alkyl, alkenyl, alkynyl, aryl, and the like.
The term "cyano" refers to a group having the formula-CN.
The term "heterocyclylalkyl" refers to an alkyl radical substituted with one or more heterocyclyl groups.
The term "heteroarylalkyl" refers to an alkyl radical substituted with one or more alkyl groups.
The term "alkylheteroarylalkyl" refers to a heteroarylalkyl radical substituted with one or more heteroaryl groups.
The term "alkoxy" refers to a moiety containing an alkyl radical attached to an oxygen atom, such as a methoxy radical. The alkoxy moiety is bonded to the molecule in question at the position of the oxygen atom of the alkoxy group. Examples of the radical include methoxy, ethoxy, propoxy, isopropoxy, butoxy and tert-butoxy.
The term "carboxy" refers to a carboxy group-CO 2H or a salt thereof.
The term "carbonyl", whether used alone or in combination with other terms, such as "alkoxycarbonyl", denotes- (C ═ O) -.
"alkanoyl" means a-C (═ O) H group, and examples of such alkanoyl radicals include formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, pivaloyl, hexanoyl, and radicals derived from succinic acid, glycolic acid, gluconic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, glucuronic acid, maleic acid, fumaric acid, pyruvic acid, mandelic acid, pantothenic acid, β -hydroxybutyric acid, galactaric acid, galacturonic acid.
The term "carboxyalkyl" refers to an alkyl radical substituted with one or more carboxyl groups. The carboxyalkyl radical is preferably a "lower carboxyalkyl" radical having one or more carboxyl groups attached to one alkyl radical containing 1 to 6 carbon atoms.
The term "carboxyheterocyclyl" refers to a heterocyclyl radical substituted with one or more carboxyl groups.
The term "carboxyheteroaryl" refers to a heteroaryl radical substituted with one or more carboxyl groups.
The term "alkoxycarbonylalkyl" refers to an alkyl radical substituted with one or more alkoxycarbonyl groups. The carbalkoxyalkyl radical is preferably a "lower carbalkoxyalkyl" radical having one or more alkoxycarbonyl groups attached to one alkyl radical containing from 1 to 6 carbon atoms.
The term "carboxyalkylamino" refers to an amino radical that is mono-or di-substituted with a carboxyalkyl group. The carboxyalkyl substituent is preferably a "lower carboxyalkyl" radical in which the carboxyl group is attached to an alkyl radical having 1 to 6 carbon atoms.
When used in combination, for example, "alkylaryl" or "arylalkyl," each of the above terms has the meaning set forth above.
Description of the invention
In many embodiments of the present invention, there are provided compounds having structural formula 1:
or a pharmaceutically acceptable salt thereof, wherein: x is selected from the group consisting of: hydrogen, alkyl and a pharmaceutically acceptable cation; z is selected from the group consisting of: oxygen, sulfur and NH; wherein R is1、R2、R3And R4Each independently selected from the group consisting of: hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonylalkyl, alkylthio, alkynyl, aminocarbonylalkyl, aryl, arylalkenyl, arylAlkoxy, arylalkyl, arylalkylamino, arylalkynyl, arylcarbonyl, aryloxy, cyano, dialkylamino, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkoxy, heteroarylcarbonyl, hydroxy, and hydroxyalkyl; wherein each aryl group, at any position, is independently substituted with 1 to 5 substituents selected from the group consisting of: alkyl, alkoxy, alkylamino, cyano, halo, haloalkyl, hydroxy and nitro.
Z is preferably oxygen.
R1、R2、R3And R4Preferably each is independently selected from the group consisting of: hydrogen, (C)2-C10) -alkenyl, (C)1-C10) -alkoxy, (C)1-C10) -alkoxy- (C)1-C10) Alkyl radicals, (C)1-C10) -alkoxycarbonyl- (C)1-C10) Alkyl radicals, (C)1-C10) Alkyl radicals, (C)1-C10) -alkylamino, (C)1-C10) -alkylcarbonyl, (C)1-C10) -alkylheteroaryl, (C)1-C10) -alkylsulfonyl- (C)1-C10) Alkyl radicals, (C)1-C10) Alkylthio group(s), (C)2-C10) -alkynyl, aminocarbonyl- (C)1-C10) Alkyl, aryl- (C)2-C10) -alkenyl, aryl- (C)1-C10) Alkoxy, aryl- (C)1-C10) Alkyl, aryl- (C)1-C10) -alkylamino, aryl- (C)2-C10) -alkynyl, arylcarbonyl, aryloxy, cyano, di- (C)1-C10) Alkylamino, halogeno- (C)1-C10) -alkoxy, halo- (C)1-C10) Alkyl, heteroaryl- (C)1-C10) Alkoxy, heteroarylcarbonyl, hydroxy and hydroxy- (C)1-C10) -an alkyl group; wherein each aryl group, at any position, is independently substituted with 1 to 5 substituents selected from the group consisting of: (C)1-C10) Alkyl radicals, (C)1-C10) -alkoxy, (C)1-C10) Alkylamino, cyano, halo- (C)1-C10) Alkyl, hydroxyl and nitro.
R1、R2、R3And R4More preferably each independently selected from the group consisting of: hydrogen, (C)2-C10) -alkenyl, (C)1-C10) -alkoxy, (C)1-C10) Alkyl radicals, (C)1-C10) -alkylamino, (C)1-C10) -alkylcarbonyl, (C)1-C10) -alkylheteroaryl, (C) 1-C10) -alkylsulfonyl- (C)1-C10) Alkyl radicals, (C)1-C10) Alkylthio group(s), (C)2-C10) -alkynyl, aryl- (C)1-C10) Alkyl, aryl- (C)2-C10) -alkynyl, arylcarbonyl, aryloxy, di- (C)1-C10) Alkylamino, halogeno- (C)1-C10) Alkoxy, heteroaryl and heteroaryl- (C)1-C10) -an alkoxy group; wherein each aryl group, at any position, is independently substituted with 1 to 5 substituents selected from the group consisting of: (C)1-C10) Alkyl radicals, (C)1-C10) -alkoxy, (C)1-C10) Alkylamino, cyano, halo- (C)1-C10) Alkyl, hydroxyl and nitro.
R1、R2、R3And R4Even more preferably each is independently selected from the group consisting of: hydrogen, (C)2-C10) -alkenyl, (C)1-C10) -alkoxy, (C)1-C10) Alkyl radicals, (C)1-C10) -alkylamino, (C)1-C10) -alkylsulfonyl- (C)1-C10) Alkyl radicals, (C)1-C10) Alkylthio group(s), (C)2-C10) -alkynyl, aryl- (C)1-C10) Alkyl, aryl- (C)2-C10) -alkynyl, arylcarbonyl, di- (C)1-C10) -alkylamino, haloSubstituted, halo- (C)1-C10) -alkoxy and heteroaryl; wherein each aryl group, at any position, is independently substituted with 1 to 5 substituents selected from the group consisting of: (C)1-C10) Alkyl radicals, (C)1-C10) Alkoxy and halo.
R1、R2、R3And R4Still more preferably each is independently selected from the group consisting of: hydrogen, (C)1-C10) -alkoxy, (C)1-C10) Alkyl radicals, (C)1-C10) Alkylthio group(s), (C) 2-C10) -alkynyl, aryl- (C)1-C10) Alkyl, aryl- (C)2-C10) -alkynyl, arylcarbonyl, halo and halo- (C)1-C10) -an alkoxy group; wherein each aryl group, at any position, is independently substituted with 1 to 5 substituents selected from the group consisting of: (C)1-C10) -alkyl and halo.
R1、R2、R3And R4Further preferred are each independently selected from the group consisting of: hydrogen, (C)1-C8) -alkoxy, (C)1-C8) Alkyl radicals, (C)1-C8) -alkylsulfonyl- (C)1-C8) Alkyl radicals, (C)1-C8) Alkylthio group(s), (C)2-C8) -alkynyl, aryl- (C)1-C8) Alkyl, aryl- (C)2-C8) -alkynyl, arylcarbonyl, halo and halo- (C)1-C8) -an alkoxy group; wherein each aryl group, at any position, is independently substituted with 1 to 5 substituents selected from the group consisting of: (C)1-C8) -alkyl and halo.
R1、R2、R3And R4Even further preferred are each independently selected from the group consisting of: hydrogen, (C)1-C5) -alkoxy, (C)1-C5) -alkyl, methyl alkylsulfonyl- (C)1-C8) Alkyl radicals, (C)1-C5) Alkylthio group(s), (C)2-C5) -alkynyl, aryl- (C)1-C5) Alkyl, aryl- (C)2-C5) -alkynyl, arylcarbonyl, halo and halo- (C)1-C5) -an alkoxy group; wherein each aryl group, at any position, is independently substituted with 1 to 5 substituents selected from the group consisting of: (C)1-C5) -alkyl and halo.
In one embodiment of the invention, the compound has S-absolute configuration, R-absolute configuration, or a mixture of S-and R-absolute configurations at the 2-carbon position of formula 1. The compound preferably has an S-absolute configuration at the 2-carbon position. Optionally, the compound has the R-absolute configuration at the 2-carbon position. In another alternative, the compound has a mixture of S-and R-absolute configurations at the 2-carbon position. In another embodiment, the compound is racemic.
In another embodiment, the present invention provides a compound having structural formula 1, wherein X is hydrogen. Optionally, X may be a pharmaceutically acceptable cation. For non-limiting examples, X can be an ammonium cation, an alkylammonium cation, a dialkylammonium cation, a trialkylammonium cation, a tetraalkylammonium cation, an alkali metal cation, or an alkaline earth metal cation. The pharmaceutically acceptable cation may be an alkali metal cation. The alkali metal cation is preferably selected from the group consisting of: sodium and potassium. More preferably, the alkali metal cation is sodium. Alternatively, the alkali metal cation may be potassium.
In another embodiment, the pharmaceutically acceptable cation can be an alkaline earth metal cation. For example, the alkaline earth metal cation may be calcium. In another example, the alkaline earth metal cation is magnesium.
The compound is preferably selected from the following group:
(2R) -6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-butoxy-6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-bromo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-butyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-methyl-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-ethylbutoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (isopentyloxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7-isobutoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (sec-butylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-chloro-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-bromo-6, 7-dichloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzoyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-pent-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-bromo-5, 7-dichloro-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (3, 3-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (methylthio) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 7-dichloro-8-methoxy-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-methyl 7- (neopentyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (phenylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-chloro-6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-5, 6-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid; and
(2S) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
or isomers and pharmaceutically acceptable salts thereof.
In a more preferred embodiment, the compounds of the invention are selected from the following group:
(2R) -6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-butoxy-6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-bromo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-butyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-methyl-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-ethylbutoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (isopentyloxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7-isobutoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (sec-butylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-chloro-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-bromo-6, 7-dichloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid; and
(2S) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
or isomers and pharmaceutically acceptable salts thereof.
In one embodiment, the compound is selected from the group consisting of:
7-benzoyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (pyridin-3-ylcarbonyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt;
7- (2-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-5, 6-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (2, 2, 2-trifluoroethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (benzyloxy) -8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (hexyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 8-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7, 8-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7- (3, 3-dimethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7-isobutoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (benzyloxy) -6, 8-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-tert-butoxy-6, 8-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-tert-amyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-tert-amyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (1, 1-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (1, 1-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-tert-butyl-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-isopropenyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-methoxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-tert-butyl-5-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-tert-butyl-5, 8-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-hydroxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid;
(2R) -6-chloro-7- (2-hydroxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (2-hydroxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 8-dichloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-chloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (dipropylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-8-propyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-isopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-isopropyl-7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (ethoxymethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-tert-butyl-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-diethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- [3, 5-bis (trifluoromethyl) phenyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (4-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-thiophen-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (2-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (4-methylthiophen-2-yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (3-nitrophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (1, 3-benzodioxol-5-yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-pyridin-4-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (3-isopropylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (2-naphthyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-pyridin-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (1H-indol-6-yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-quinolin-8-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (3, 4-dimethoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
2- (trifluoromethyl) -6- [4- (trifluoromethyl) phenyl ] -2H-chromene-3-carboxylic acid;
2- (trifluoromethyl) -6- [3- (trifluoromethyl) phenyl ] -2H-chromene-3-carboxylic acid;
8-chloro-6-phenyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (4-chlorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (2-chlorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (4-fluorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-thiophen-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (2-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (3-nitrophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (1, 3-benzodioxol-5-yl) -8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (4-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (3-isopropylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (2-naphthyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-pyridin-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (1H-indol-5-yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-quinolin-8-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (3, 4-dimethoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-2- (trifluoromethyl) -6- [4- (trifluoromethyl) phenyl ] -2H-chromene-3-carboxylic acid;
8-chloro-2- (trifluoromethyl) -6- [3- (trifluoromethyl) phenyl ] -2H-chromene-3-carboxylic acid;
8-chloro-6- (3-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (3-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-butyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-butyl-8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-2- (trifluoromethyl) -6-vinyl-2H-chromene-3-carboxylic acid;
8-chloro-6- (phenylethynyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-cyano-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-acetyl-8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-allyl-8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-prop-1-ynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-methylbut-1-ynyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-prop-1-ynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-but-1-ynyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-fluorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-chloro-4-fluorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3, 5-dichlorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3, 4-dichlorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-fluorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-chlorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (2-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-2- (trifluoromethyl) -8- [3- (trifluoromethyl) phenyl ] -2H-chromene-3-carboxylic acid;
6-chloro-2- (trifluoromethyl) -8- [4- (trifluoromethyl) phenyl ] -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-ethoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-cyanophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-ethoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (2-ethoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- [3, 5-bis (trifluoromethyl) phenyl ] -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-pyridin-4-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-2- (trifluoromethyl) -8- [2- (trifluoromethyl) phenyl ] -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-cyanophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-pyridin-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3, 5-difluorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3, 5-dimethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-isopropylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (4-tert-butylphenyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (2, 4-dimethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-methyl-3-nitrophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (4-butylphenyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (5-chloro-2-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (4-acetylphenyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3, 4-dimethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-hydroxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-chloro-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-fluoro-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-2- (trifluoromethyl) -8- (3, 4, 5-trimethoxyphenyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-fluoro-4-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-methoxy-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-isobutylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-methoxy-3, 5-dimethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-thiophen-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-nitrophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- [4- (dimethylamino) phenyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6-phenyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6-thiophen-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6- (4-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-2- (trifluoromethyl) -6- [4- (trifluoromethyl) phenyl ] -2H-chromene-3-carboxylic acid;
7-methoxy-2- (trifluoromethyl) -6- [3- (trifluoromethyl) phenyl ] -2H-chromene-3-carboxylic acid;
6- (3-furyl) -7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6- (3-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (2-furyl) -7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6- (3-nitrophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (1, 3-benzodioxol-5-yl) -7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (3-isopropylphenyl) -7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6- (2-naphthyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6-pyridin-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (3, 4-dimethoxyphenyl) -7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6-quinolin-8-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (4-chlorophenyl) -7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (2-chlorophenyl) -7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (4-fluorophenyl) -7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-iodo-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-2- (trifluoromethyl) -6-vinyl-2H-chromene-3-carboxylic acid;
6-ethynyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-acetyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6-prop-1-ynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-ethoxy-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-7- (pyridin-3-ylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-7- (pyridin-4-ylmethoxy) -2-trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-iodo-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-ethyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 7-dichloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 7-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 7-dichloro-6-isopropoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
sodium 8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
8-but-1-ynyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
sodium 6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-chloro-8- (4-chloro-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-chloro-8- (4-methoxy-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-ethyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
Sodium 6-chloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
5, 7, 8-trichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (phenylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-prop-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-pent-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-ethynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-isobutyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-pentyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (trifluoromethoxy) -2- (trifluoromethyl) -8-vinyl-2H-chromene-3-carboxylic acid;
8- (2-phenylethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-cyano-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-but-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-butyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-allyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-chloro-8-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-chloro-8- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (benzyloxy) -5-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-chloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 6-dichloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 7-dichloro-8-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-bromo-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-bromo-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-butoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (benzyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (3-furylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-bromo-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-bromo-5, 7-dichloro-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 6, 7-trichloro-8-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-butoxy-5, 6, 7-trichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 6, 7-trichloro-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 7-dichloro-8-methoxy-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (3, 3-dimethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (benzyloxy) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-tert-butoxy-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-bromo-6, 7-dichloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-ethoxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid compound with (1S) -1-phenylethylamine (1: 1);
(2R) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid compound with (1R) -1-phenylethylamine (1: 1);
5-chloro-6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (1, 1-difluoroethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-tert-butyl-8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (1-phenylvinyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (1-phenylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7- (methylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-methoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-ethylbutoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-methyl-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-isobutoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-butoxy-6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-methyl-7- (neopentyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (isopentyloxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
sodium 6, 8-dichloro-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
8-ethoxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
sodium 6-chloro-7- (2-ethylbutoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2S) sodium 6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2R) sodium 6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium (2S) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 7- (sec-butylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
2- (trifluoromethyl) -8-propyl-6- (trifluoromethoxy) -2H-chromene-3-carboxylic acid sodium salt;
(S) -8-ethyl-2- (trifluoromethyl) -6- (trifluoromethoxy) -2H-chromene-3-carboxylic acid sodium salt;
(2S) -8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
sodium 6-chloro-7- (3, 6-dihydropyridin-1 (2H) -yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
2- (trifluoromethyl) -8-phenethyl-6- (trifluoromethoxy) -2H-chromene-3-carboxylic acid sodium salt;
6-chloro-8-methyl-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
sodium 6-chloro-8-methyl-7- (neopentyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium (2S) -6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 8-allyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
7-benzyl-6-bromo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-propyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-butyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7, 8-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7, 8-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-tert-butoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-ethylbutoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-furylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-isopropyl-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (ethylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (isopentylthio) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (propylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (butylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (sec-butylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (3, 6-dihydropyridin-1 (2H) -yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- [ ethyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- [ butyl (ethyl) amino ] -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- [ benzyl (methyl) amino ] -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (benzylamino) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (diethylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-butyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (3, 3-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-isopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
4, 6-dichloro-7-isopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-propyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid compound with (1R) -1-phenylethylamine (1: 1);
6, 8-dibromo-2- (trifluoro-methyl) -1, 2-dihydroquinoline-3-carboxylic acid;
8-bromo-6-methyl-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid;
6-chloro-8-methyl-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid;
6- (4-fluorophenyl) -2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid;
6-chloro-7- (2-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2, 3-dimethoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2, 6-dimethoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-propylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-propylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 3-dimethoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 6-dimethoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-propylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (5-isopropyl-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 6-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (-) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 4-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-chloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-bromo-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 5-difluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-fluoro-5-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-chloro-4-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-ethoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 4-difluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-fluoro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-bromo-5-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-bromo-4, 5-difluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 4-dibromophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-bromo-2-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-bromo-4-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-chloro-4-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-iodo-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-chloro-2-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-bromo-2-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-methoxy-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylic acid;
7- (2, 3-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (3-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2, 3-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (3-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2, 4-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (4-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (4-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (3, 4-dichlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2-naphthoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (1-naphthoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (4-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
2- (trifluoromethyl) -5- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylic acid;
5- (4-chloro-3, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2-methoxy-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2, 6-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (4-propylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2, 5-difluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2-chloro-4-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (2, 3-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (3-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (2-chloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (4-chloro-2-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (4-fluoro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (2-methoxy-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (4-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (2, 4-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (2-fluoro-5-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (4-ethoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (2-chloro-4-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2, 3-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (3-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2-chloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (4-chloro-2-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (4-fluoro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2-methoxy-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (4-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2, 4-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2-fluoro-5-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (4-ethoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2-chloro-4-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5-thiophen-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (3-isopropylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5-phenyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-fluoro-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-chloro-2-methylphenoxy) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-ethyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-butyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 3-dimethylphenyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-isobutyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-ethylphenyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-ethylphenoxy) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-chloro-4-methoxyphenoxy) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-fluoro-2-methylphenoxy) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-fluoro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methyl-7-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 4-difluorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 5-difluorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-chlorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (3-chlorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-methoxyphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-chloro-4-methylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methyl-7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-ethylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methyl-7- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 4-dimethylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methyl-2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylic acid;
7- (2, 6-dimethylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (_ oxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (3, 4-dichlorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-fluorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-fluorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methyl-7- (4-propylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-methoxy-4-methylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-ethoxyphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-chloro-2-fluorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-bromo-2-fluorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-chloro-4, 5-dimethylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-chloro-4-fluorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-fluoro-5-methylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-bromo-5-fluorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-chloro-2-methylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methyl-7- (1-naphthyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (2, 4-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (2, 4-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (3, 5-dichloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (3, 5-dichloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (2-chloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (2-chloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylic acid;
(2S) -2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylic acid;
(2R) -7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -7- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -7- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (2-chloro-4-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (2-chloro-4-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (4-fluoro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (4-fluoro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (2-methoxy-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (2-methoxy-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 7-dichloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 7-dichloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 7-dichloro-6-isopropoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 7-dichloro-6-isopropoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-8- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-8- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-8- (4-methoxy-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-8- (4-methoxy-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
sodium 7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 5- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2S) -5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
(2S) -8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
sodium (2R) -7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
Sodium (2R) -2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylate;
sodium 7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylate;
sodium 6-chloro-7- (2-propylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-chloro-5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2S) -8-but-1-ynyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
sodium (2S) -6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium (2S) -6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 7- (4-ethylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2R) -6, 8-dichloro-7-isobutoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6, 8-dichloro-7-isobutoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- { [ isopropyl (methyl) amino ] methyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate;
6-chloro-7- [ (diisopropylamino) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt;
6-chloro-7- { [ ethyl (methyl) amino ] methyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt;
(2R) -6-chloro-8-methyl-7- (3-methylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-8-methyl-7- (3-methylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (4-cyanobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (hydroxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (methoxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (ethoxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-methyl-2- (trifluoromethyl) -2H-chromene-3, 8-dicarboxylic acid;
8-benzyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (1-hydroxyethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-methyl-8- (2, 2, 2-trifluoroethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-ethyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methoxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5-isopropyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (2R) -6-chloro-8-isopropyl-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-8-isopropyl-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (propylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (butylamino) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (isopentylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- [ (3, 3-dimethylbutyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (neopentylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (sec-butylamino) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-chlorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-chlorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 4-dimethylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -7-butyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -7-butyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (3, 3-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (3, 3-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (3-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (3-hydroxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (3-hydroxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (5-bromo-3-chloro-2-methoxybenzyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (5-bromo-2-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (3-chloro-2-methoxy-5-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-bromo-7- (2-bromobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (3-methylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (5-bromo-2-methoxybenzyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7- (propylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -7-benzyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -7-benzyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (benzyloxy) -7-bromo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6- (benzyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-methyl-7- (2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-butoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6- (pentyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-hexyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-bromo-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6- (hexyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (neopentyl amino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-bromo-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-methoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- [ isobutyl (methyl) amino ] -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (isobutylamino) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-tert-butyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (hydroxymethyl) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-methoxy-8- (methoxymethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-benzyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-acetyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-phenyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (2-hydroxyethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (1-hydroxy-1-methylethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-isopropyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-hydroxy-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methoxy-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-ethoxy-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-methoxy-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
sodium 6- (benzyloxy) -8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2R) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
sodium 6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-chloro-7- (2, 4-dimethylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2R) -8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
Sodium 6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-chloro-7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
8-acetyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
(2S) -8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
(2R) -6-chloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
(2R) -6-chloro-7- (3, 3-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
(2S) -8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
(2S) -6-chloro-8-isopropyl-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
(2R) -6-chloro-7- (4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
sodium (2S) -6-chloro-8-methyl-7- (3-methylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-methyl-7- (2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2R) -6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
sodium 5, 8-dichloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-chloro-7- (4-chlorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
Sodium 6-isopropyl-7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2R) -6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
6-ethyl-8-propyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-diethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
sodium 6, 8-diethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2R) -6-chloro-7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
5-chloro-6-ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (ethoxymethyl) -5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (hydroxymethyl) -7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (hydroxymethyl) -5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (3-fluoro-4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-ethylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-ethylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
sodium 6-chloro-7- (2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
6-ethyl-8-thiophen-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6, 8-diethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-ethyl-8-propyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
sodium 6-chloro-7- (2-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
6- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (ethoxymethyl) -7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5, 7-bis (ethoxymethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
and sodium (2R) -6, 8-diethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
or isomers and pharmaceutically acceptable salts thereof.
The invention further includes tautomers of said compounds.
In another embodiment, the invention includes a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula 1 and a pharmaceutically acceptable excipient. The excipient may include, for example, a carrier, adjuvant or diluent.
The invention also includes a method for treating a cyclooxygenase-2 mediated disorder, such as inflammation, in a subject, wherein the method comprises treating a subject having or susceptible to the disorder with a therapeutically effective amount of a compound having formula 1.
Within the family of compounds having structural formula 1, stereoisomers thereof are also included. The compounds of the invention may have one or more asymmetric carbon atoms and may thus exist in the form of optical isomers and in the form of their racemic or non-racemic mixtures. Thus, some of the compounds of the present invention can exist as racemic mixtures, which are also encompassed by the present invention. Optical isomers can be prepared by resolution of racemic mixtures according to known methods; for example, by treatment with an optically active base followed by separation of the mixture of diastereomers by crystallization to form diastereomeric salts, followed by liberation of the optically active base from these salts. Suitable examples of bases include brucine, strychnine, dehydroabietylamine, quinine, cinchonidine (cincinnidine), ephedrine, α -methylbenzylamine, amphetamine, the deoxyephedrine chloramphenicol intermediate, 2-amino-1-butanol and 1- (1-naphthyl) ethylamine. Another method of separating different optical isomers involves the use of a chiral chromatographic column that is optimally selected to maximize the separation of the enantiomers. Another method that may be used involves the synthesis of covalent diastereomeric molecules. The diastereoisomers synthesized may be separated by known means such as chromatography, distillation, crystallization or sublimation and then hydrolyzed to give enantiomerically pure compounds. Similarly, the optically inactive compound of formula 1 can be prepared by using an optically active starting material. These isomers may be in the form of a free acid, a free base, an ester or a salt. Other methods for resolving optical isomers are well known to those skilled in the art.
Within the family of compounds having formula 1, protected acids such as esters, hydroxyamino derivatives, amides and sulfonamides are also included. Thus, mono-and diamines may be reacted with chromene-3-carboxylic acids of formula 1 to form amides useful as prodrugs. Preferred amines are heterocyclic amines including optionally substituted aminothiazoles, optionally substituted aminoisoxazoles and optionally substituted aminopyridines; an aniline derivative; a sulfonamide; aminocarboxylic acids, and the like. In addition, 1-acyl dihydroquinolines can function as prodrugs for 1-dihydroquinolines. Esters, hydroxy amino derivatives and sulfonamides can be prepared from acids by methods known to those skilled in the art.
The compounds of the present invention may be used in the prevention or treatment of cyclooxygenase-related (e.g., COX-1-related or COX-2-related) disorders or conditions by administration, preferably orally, of any form that brings the compound into contact with its site of action in vivo. For the prevention or treatment of the above conditions, the compounds of the present invention can be used as the compounds themselves. Pharmaceutically acceptable salts are particularly useful for medical purposes because they are more water soluble than the parent compound. These salts must clearly possess pharmaceutically acceptable anions or cations. A suitable pharmaceutically acceptable acid addition salt of the compound of formula 1 may be prepared from an inorganic or organic acid. Examples of such inorganic acids are hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, carbonic acid, sulfuric acid, and phosphoric acid. Suitable organic acids may be selected from fatty acids, cyclic fatty acids, aromatic fatty acids, heterocyclic carboxylic and sulfonic types of organic acids, examples of which are formic, acetic, propionic, succinic, glycolic, gluconic, lactic, malic, tartaric, citric, ascorbic, glucuronic, cis-butenedioic, trans-butenedioic, pyruvic, aspartic, glutamic, benzoic, anthranilic, methanesulfonic, salicylic, 4-hydroxybenzoic, phenylacetic, hydroxyphenylacetic, dinaphthylsalicylic (pamoic), methanesulfonic, ethanesulfonic, benzenesulfonic, pantothenic, 2-hydroxyethanesulfonic, toluenesulfonic, sulfanilic, cyclohexylsulfamic, stearic, alginic, β -hydroxybutyric, galactaric and galacturonic. Suitable pharmaceutically acceptable base addition salts of the compound of formula 1 include metal salts such as those made from aluminium, calcium, lithium, magnesium, potassium, sodium and zinc; or salts prepared from organic bases including mono-, di-and tri-amines, substituted amines including cyclic amines such as caffeine, arginine, diethylamine, N-ethylpiperidine, histidine, glucosamine, isopropylamine, lysine, morpholine, N-ethylmorpholine, piperazine, piperidine, triethylamine, trimethylamine. All of these salts can be prepared from the corresponding compounds of the invention by known methods, for example by reacting the appropriate acid or base with a compound of formula 1.
Optionally, the pharmaceutically acceptable salt may comprise an anionic counterion, for example when the molecule contains a cationic functional group such as an ammonium group. Of course, the anion must also be pharmaceutically acceptable and is also selected from the above list.
The compounds of the invention can be administered to a patient as the pure compound itself. Optionally, the compounds of the present invention may be presented in the form of a pharmaceutical composition together with one or more pharmaceutically acceptable excipients. Suitable excipients may be, for example, carriers. Of course, the carrier must be acceptable in the sense of being compatible with the other ingredients of the composition and must not harm the user. The carrier may be solid or liquid or both and is preferably formulated with the compound as a unit dosage composition, e.g., a tablet, which may contain from 0.05% to 95% by weight of the active compound. Other pharmaceutically active substances may also be present, including other compounds of the invention. The pharmaceutical compositions of the present invention may be prepared by well-known pharmaceutical techniques, which essentially comprise admixing the components.
These compounds may be administered by any known means suitable for co-administration with a drug, either as individual therapeutic compounds, or as a combination of therapeutic compounds.
The amount of compound required to achieve the desired biological effect will, of course, depend on several factors, such as the particular compound selected, its intended use, the mode of administration and the clinical condition of the subject.
In general, the daily dose will be in the range of about 0.01 to about 100 mg/kg body weight/day, preferably about 0.05 mg to about 50 mg/kg body weight/day, more preferably about 0.01 mg to about 20 mg/kg body weight/day. Even more preferably from about 0.01 mg to about 10 mg per kg of body weight per day. The total daily dose can be administered to a patient as a single dose or as proportionately multiple sub-doses. Sub-doses may be administered from 2 to 6 times daily. The dosage may be in a sustained release form effective to achieve the desired result.
An orally administrable unit dosage formulation, such as a tablet or capsule, may contain, for example, from about 0.1 mg to about 1000 mg of the compound, preferably from about 1.0 mg to about 500 mg of the compound, more preferably from about 2.0 mg to about 400.0 mg of the compound, even more preferably from about 2.0 mg to about 200.0 mg of the compound, even more preferably from about 2.0 mg to about 100.0 mg of the compound, and even more preferably from about 2.0 mg to about 50.0 mg of the compound. In the case of pharmaceutically acceptable salts, the above weights refer to the weight of the ion derived from the salt.
As is well known to those skilled in the art, oral delivery of the compounds of the present invention may encompass formulations to provide prolonged or sustained delivery of the drug to the gastrointestinal tract by any number of mechanisms. They include, but are not limited to, pH-sensitive release from dosage forms based on changes in small intestinal pH; slow erosion of tablets or capsules; stay in the stomach based on the physical properties of the formulation; the preparation has biological adhesion with small intestine mucosa layer; or enzymatic release of the active agent from the dosage form. By manipulating the dosage form, the predetermined effect is extended beyond the period of time during which the active drug molecule is delivered to the site of action. Thus, enteric coated formulations and controlled release enteric coated formulations are contemplated within the scope of the present invention. Suitable enteric coatings include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate and anionic polymers of methacrylic acid and methyl methacrylate.
When administered intravenously, the daily dose can range, for example, from about 0.1 mg/kg body weight to about 20 mg/kg body weight, preferably from about 0.25 mg/kg body weight to about 10 mg/kg body weight, more preferably from about 0.4 mg/kg body weight to about 5 mg/kg body weight. The dose may conveniently be administered as an infusion of from about 10 ng/kg body weight to about 2000 ng/kg body weight per minute. Infusions suitable for this purpose may contain, for example, from about 0.1 grams to about 10 milligrams per milliliter, preferably from about 1 nanogram to about 200 milligrams per milliliter. A unit dose, for example, may contain from about 1 mg to about 200 g of a compound of the invention. Thus, for example, an ampoule for injection may contain from about 1 mg to about 200 mg.
Pharmaceutical compositions according to the invention may include those suitable for oral, rectal, buccal (e.g. sublingual) and parenteral (e.g. subcutaneous, intramuscular, intradermal or intravenous) administration, although the most suitable route in any case will depend on the nature and severity of the condition being treated and on the nature of the particular compound used. Oral administration is the preferred route of administration for the majority of cases.
Formulations suitable for topical administration to the eye also include eye drops wherein the active ingredient is dissolved or suspended in a suitable carrier, particularly an aqueous solvent for the active ingredient. The anti-inflammatory active ingredients are preferably present in these formulations in concentrations of from 0.1 to 25%, advantageously from 0.5 to 10% and in particular about 1.5% w/w.
Pharmaceutical compositions suitable for oral administration may be presented as discrete units such as capsules, cachets, brittle hard candy or tablets, each containing a predetermined amount of at least one compound of the invention; such as powder or granules; such as a solution or suspension in an aqueous or non-aqueous liquid; or as an oil-in-water or water-in-oil emulsion. As indicated, these compositions may be prepared by any suitable pharmaceutical method which includes the step of bringing into association the active compound with the carrier, which may constitute one or more required ingredients. In general, the compositions are prepared by uniformly and intimately admixing the active compounds with a liquid or finely divided solid carrier or both, and then, if necessary, shaping the product. For example, tablets may be prepared by compression or molding of a powder or granules of the compound, optionally with one or more essential ingredients. Compressed tablets may be prepared by compressing in a suitable machine the compound in a free-flowing form such as a powder or granules, optionally mixed with a binder, lubricant, inert diluent and/or surface active/dispersing agent. Molded tablets may be made by molding in a suitable machine the powdered compound moistened with an inert liquid diluent.
Pharmaceutical compositions suitable for buccal (sublingual) administration include brittle hard candies comprising a compound of the invention in a flavored base, usually sucrose and acacia or tragacanth; and soft tablets comprising the compounds in an inert base such as gelatin and glycerin or sucrose and acacia.
Pharmaceutical compositions suitable for parenteral administration conveniently comprise sterile aqueous preparations of a compound of the invention. These formulations are preferably administered intravenously, although administration by subcutaneous, intramuscular or intradermal injection is also possible. These formulations are conveniently prepared by admixing the compound with water, and disinfecting and rendering the resulting solution isotonic with blood. Such as the injectable compositions of the present invention. Typically containing 0.1 to 5% w/w of a compound disclosed herein.
Pharmaceutical compositions suitable for rectal administration are preferably presented as unit dose suppositories. They may be prepared by blending a compound of the invention with one or more known solid carriers, such as cocoa butter, and then shaping the resulting mixture.
Pharmaceutical compositions suitable for topical application to the skin, preferably in the form of ointments, creams, lotions, paste-like gels, sprays, aerosols or oils. Suitable carriers include petrolatum, lanolin, polyethylene glycols, alcohols and combinations of two or more thereof. The active compound is generally present in a concentration of 0.1 to 15% w/w, for example from 0.5 to 2%.
Transdermal administration is also possible. Pharmaceutical compositions suitable for transdermal administration can be presented in the form of individual patches which are maintained in intimate contact with the epidermis of the user for an extended period of time. These patches suitably contain a compound of the invention in an optionally buffered aqueous solution, which is dissolved and/or dispersed in an adhesive or dispersed in a polymer. Suitable concentrations of the active compound are about 1% to about 35%, preferably about 3% to about 15%. As another particular possibility, the compound may be delivered from the patch by electrotransport or iontophoresis, as described in Pharmaceutical Research, 3(6), page 318 (1986).
In either case, the amount of active ingredient that can be combined with the carrier materials to produce a single dosage form for administration will depend upon the host treated and the particular mode of administration.
Solid dosage forms for oral administration include capsules, tablets, pills, powders and granules as described above which comprise one or more compounds of the invention in admixture with at least one inert diluent, such as sucrose, lactose or starch. As is conventional, these dosage forms may also include additional substances other than inert diluents, such as lubricating agents, for example, magnesium stearate. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. Tablets and pills can additionally be prepared with enteric coatings.
Liquid dosage forms for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups and elixirs containing inert diluents commonly used in the art, such as water. These compositions may also include adjuvants such as wetting agents, emulsifying and suspending agents, and sweetening, flavoring, and perfuming agents.
Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, may be prepared according to the known art using suitable dispersing or suspending agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a parenterally-acceptable non-toxic diluent or solvent, for example as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents, water, Ringer's solution and isotonic sodium chloride solution may be used. In addition, it is known to use sterile fixed oils as a solvent or suspending base. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
Pharmaceutically acceptable carriers encompass the foregoing owners and the like.
Mode of treatment
The dosage regimen for preventing, alleviating or ameliorating a disease condition using the compounds and/or compositions of the invention is selected based on a number of factors. They include the type, age, weight, sex, diet and medical condition of the patient; the severity of the disease; the route of administration; pharmacological considerations such as the activity, potency, pharmacokinetics, and mode of toxic action of the particular compound employed; whether a drug delivery system is used; and whether the compound is administered as part of a pharmaceutical composition. Thus, the dosage regimen actually employed will vary widely and thus differ from the preferred dosage regimen described above.
Initial treatment of a patient suffering from a therapeutic condition may begin with the dosages described above. Treatment should generally be continued for a period of weeks to months to years, as necessary, until the disease condition is controlled or eliminated. Patients treated with the compounds or compositions disclosed herein should be routinely monitored, for example, by measuring serum cholesterol levels by any method known in the art, to determine the efficacy of the treatment. Continued analysis of these data will allow for modification of the treatment regimen during the treatment period, whereby the optimal effective amount of the compound of the invention can be administered at any point in time, and whereby the treatment period can be determined. In this manner, the treatment regimen/dosage regimen can be reasonably modified during the course of treatment, whereby the minimum amount of the compound of the invention is administered with satisfactory utility, and whereby administration is continued only as needed for successful treatment of the condition.
The compounds of the invention may be administered alone or in combination with other therapies known to those skilled in the art of preventing or treating tumors. Optionally, the compounds may be used in combination therapy. For example, these compounds may be administered alone or in combination with other antineoplastic agents or other growth inhibitory agents or other drugs or nutrients.
In commercial applications, clinical assessments, or preclinical development, a wide variety of antineoplastic agents are available that can be selected for treatment of neoplasia using combinatorial drug chemotherapy. These antineoplastic agents can be divided into several major classes, namely antibiotic-type agents, alkylating agents, antimetabolite agents, hormonal agents, immunological agents, interferon-type agents, and others. Optionally, other anti-tumor agents may be used, such as Metal Matrix Proteases (MMPs), SOD mimetics or alphav-β3And (3) an inhibitor.
A first family of antineoplastic agents which may be used in combination with the compounds of the present invention includes antimetabolite type antineoplastic agents. Suitable antimetabolite antineoplastic agents may be selected from the following group: 5-FU-fibrinogen, acarboxic acid (acarboxic acid), aminothiadiazole, brucidina sodium, carmofur (carmofur), Ciba-Geigy CGP-30694, cyclopentylcytosine, cytarabine phosphate stearate, cytarabine conjugate, Lilly DATHF, Merrel Dow DDFC, dizoguanine, dideoxycytidine, dideoxy-cornuridine, didaxx, Yoshitomi DMDC, desfluridine (deoxyfluridine), Weikang EHNA, Merck & Co., EX-015, Fazabinia-Fluoroxyline, flucloxacin 152, 5-Dafelicine 2-5- (Dakifuil) -5-Dakifuil phosphate, Isopropylpyrrolizine, LY-188011 from Lilly, LY-264618 from Lilly, mobenzamide, methoprene, MZPES from Wellcome, norspermidine, NCI NSC-127716, NCI NSC-264880, NCI C-39661, NCI NSC-612567, PALA from Warner-Lambert, glutaredom, piritertrixin (piritrexim), plicamycin (plicamycin), PL-AC from Asahi chemical, TAC-788 from Takeda, thioguanine, tezofurin (tiazofurin), TIF from bermant, erbaunt, tyrosine, protein inhibitors from Trimethyltyrosine, and Taichin (Taurocidin).
A second family of antineoplastic agents that can be used in combination with the compounds of the present invention includes the alkylating type of antineoplastic agents. Suitable alkylating-type antineoplastic agents may be selected from the following group: 254-S from Shionogi, aldehyde-phosphoramide analogues, alutamide (altreamine), Ananoxiron (analtron), BBR-2207 from Boehringer Mannheim, Youbkul (Bestruucil), buditamide (budotitane), CA-102 from Wakunaga, Carboplatin (carboplatin), nitrosourea mustard, Johnonene (Chinoin) -139, Johnonene (Chinoin) -153, chlorambucil, cisplatin, cyclophosphamide, CL-286558 from American cyanamide (American Cyanamid), CY-233 from Sanofi, Cybrene (cyoplatate), D-19-384 from Degussa, Metallosa (Chemimoto), Chdamycin P2 from CHmimoto, Spirosin (Biopsis), derivatives of Adriamide (Biopsis), DWARA-2114, DWARE-A, DWARE-102 from Boehringer Mannheim, Gerni, Geranine (Chinoin-233, Geranine) from Wakumsonian, Ciba (Chimonarda-b) from Wakumsoni, Ciba, Althazine (elmustine), Erbamont (Erbamont) FCE-24517, estramustine sodium phosphate, Fertuzine (fotemustine), Yonimide (Unimed) G-6-M, Chenomin (Chinoin) GYKI-17230, heptylsulfonyl (hepsulfam), ifosfamide, ipropamine, lomustine (lomustine), mofsfamide (mafosfamide), dibromodulcitol (mitolactocton), Nippon Kayaku (Nippon Kayaku) NK-121, NCI NSC-264395, NCI NSC-342215, chloroplatinum, Upjohn (Upjohn), prednimustine (prednimustine), Rhost (Protamine) PTT-119, Yamustine (Histigman), Kliman-101772, Kliman-7 (Hemochamine), Kliman-35sk-7, Klimazethazine & S-7, Klimazepinochine & S-264395, Nakayaku (Nakayaku), Taurochlorethamine (tauromustine), tomozolamide (temozolomide), epoxytriazone, cisplatin and trimethanol.
A third family of antineoplastic agents that can be used in combination with the compounds of the present invention includes antibiotic-type antineoplastic agents. Suitable antibiotic-type antineoplastic agents may be selected from the following group: 4181-A of Dabao (Taiho), aclarubicin (aclarubicin), actinomycin D, amrinone, ADR-456 of Erbamont (Erbamont), Aeroprisin derivatives, AN-201-II of Ajinomoto, anisomycin of Ajinomoto AN-3 Japan Soda (Nippon Soda), anthracycline, azino-mycin-A, refusa-kaurin (bisucaberin), BL-6859 of Bristol-Myers, BMY-67 of Bituo, BMY-25551 of Bituo, BMY-26605 of Bituo, BMY-27557 of Bituo, BMY-28438 of Bituo, sulphate of Blattin (Bristol-Myers), BMY-25078 of Bituo, BMY-26605 of Bituo, BMY-27557 of Bituo, BMY-28438 of Bituo, Bristol-Brukin, Bristoc-1 of Epstein, Epsilomycin-7 of Tachomycin C, Tachomycin C (Tachomoto-myc), Adamandomycin of Eremomycin of Tachot, Adamando, Adenomycin of Eremomycin of Katsunamino, Adenomycin of Katsunami, Dactinomycin, daunorubicin, Kyowa Hakko Co.DC-102, Coflukuwa fermentation Co.DC-79, Coflukuwa fermentation Co.DC-88A, Coflukuwa fermentation Co.DC 89-A1, Coflukuwa fermentation Co.DC 92-B, desacetylene B (ditrusubicin B), Salinogi (Shionogi) Co.DOB-41, Adriamycin-fibrinogen, Isamycin (elsamicin-A), Epdaunomycin, Erbostatin (erbstatin), Nevadamycin, Insectamycin-A1 (esperamicin-A1), Insamycin-Alb (esperamicin-A1B), Bermont (Erbamont) Co.FCE-21954, Takaze (jisawa) Co.FK-973, Futiamicin (Fuegawa), Fuigrain-A9003, Fuigrain-Saigamycin (Fuigwa), Fuigrain-Saigra-A, Fugewa-Saigraingin (Fugega-A), Fugewa) Farff (Fuga-A, Fugega-A, Saigraingin, Fugega-R (Fuga-FR, Sago-A-41, Shisago-A, Shinagcin, Shi, Grincamycin (grincamycin), herbimycin, idarubicin (idarubicin), cryptobrevicin, calicheamicin (kuzasamycin), kasugamycin (keshimycin), kasugamycin (kesarginins), Kyowa Hakko KM-5539, Kirin BreweryKRN-8602, Kyowa Hakko KT-5432, KT-5594 of Kyowa Hakko, KT-6149 of Kyowa fermentation company, LL-D49194 of American Cyanamid, ME 2303 of Meiji Seika, Melalel (melanogaril), mitomycin, mitoxantrone (mitoxantrone), M-yamycin of Smithcine (Smithcine), Klenoxin (neomycin), gentamycin (SRn-313), Nippomycin of Japan-357704, Nippomycin of Nippon Hakko, Nippon K-78 of Nippon Hakko, Nippon-K, Kyowa Hakko K-5539, Kirin Brewer KRN-8602, Kyowa Hakko K-5432, Kyowa Hakko, Kyowa Kogyo-K, Kyoto, Kyowa, K-K, pirarubicin (pirarubicin), puromycin (porramycin), refudamycin A (pyrindamycin A), Toblin (Tobisi) RA-I, rapamycin (rapamyin), capsoxin (rhizoxin), rodomamycin (rodorubicin), sibanomycin (sibanomicin), siwenmycin (siwenmycin), Sumitomo (SW-5887), Snow print (Snow Brand) SN-706, Snow print (SN-07, Pamulin-A, sparsomycin, SS-21020, SS-7313B, SS, SS-9816B, steganomycin B, Taiho (Taiho) 4181-2, merisulosin, Tatian (Takeda) N-868, fermented soy (Kyomycin A), fermented soy (Uthromycin A-36868), fermented soy (Uthromycin A-73975), fermented soy (Uthromycin A-36868), fermented soy (Uthromycin A), fermented soy (Tokyo) and Sauromycin (Uthromycin) WF-3405 from Tenze (Fujisawa), Y-25024 from Yoshitomi, and benzoylhydrazone daunorubicin.
A fourth family of antineoplastic agents useful in combination with the compounds of the present invention, comprising a miscellaneous family of antineoplastic agents selected from the group consisting of: alpha-carotene, alpha-difluoromethyl-arginine, Avermectin (acitretin), AD-5 from Biotec (Biotec), AHC-52 from apricot (Kyorin), piceid, amonafide (amonafide), amphetamine (amphetamine), amsacrine (amsacrine), angiostatin (angiostatin), amkinomycin (ankyrin), antineoplastic agent (antineoplaston) A-10-antineoplaston A2, A3, A5, AS2-1, APD from Henkel, aphidicolin glycinate, aspartyl amidase, alfarol, canthrin, belief (rapecilin), freron (benflurron), formyl-valine (benzoyl arginine), eosin (eosin), beta-6, beta-E, Bysaruron (balsamin), Begonin (bern), Begonin-4040409), Britisol (Britisol-10), Bestaurin (Bestaurin), Bestaurin (Bestan-10, Bestaurin), Bestan (Bestan) A-10, Bestaurin (B-10, Bestan), Bestan (Bystone, Bystein, Bystone, Bystein, Cyclophosphamide bromide, Weikang (Wellcome) BW-502, Weikang BW-773, Carlacamide (caramoemide), Carmetoxazole hydrochloride, Ajinomoto (Ajinomoto) CDAF, Chloroquinoxalone, Cammins (Chemes) CHX-2053, Camumx (Chemex) CHX-100, Warner-Lambert (Warner-Lambert) CI-921, Warner-Lambert CI-937, Warner-Lambert CI-941, Warner-Lambert CI-958, Klineweizone (clandinen), Cliviridone (Cliviridone), ICN 1259, ICN 4711, Comercrast (Camarac), Yanglet Hokulare (Yakloth) Hovenin), Cytara-11, Cytara-Cytara (Cytara), Cytarda (Cytara-B), Cytara-Cytarda (Cytara, Cytara-Cytarda), Cyclams (Cyclams B, Cyclams (Cyclams) and Cyclams (Cyclams) C-B, Cyclams (Cyclams) C-C, D-609 from Meiweizi (Merz), DABIS cis-butenedioate, azoimidazole amine (dacarbazine), dexelidinium (datelliptinium), ecteinascidin-B (didemnin-B), dichlorescensin, dihydroterpenone (dihydroterpenone), dinaline (dinaline), distamycin, DM-341 from Toyo (Toyo) pharmaceuticals, DM-75 from Toyo medicine, DN-9693 from Daiichi Seiyaku (Daiichi Seiyaku) for first-drug manufacturing, illipopine (ellipramin), illicium acetate (ellovitinate), EPTMC from Tsuura (Tsukura), ergotamine, etoposide (etoposide), abamectin-acetate (etheine), fenretinide (fenretinide), fujiwawa-57704 from Teng, gallium nitrate (Genkwan-63178), Glaucaine (Genkwan-32), Glauca-K (Genkwa-32), Gluconus-A (Genkwa-32), Glycine (Genkwa-K) for first-K, and Glycine (Genkwa-K, HO-221 of Green crosses (Green Gross), homoharringtonine, hydroxyurea, BTG ICRF-187, imofortine (ilmofosine), isoglutamine, retinoic acid, JI-36 of Tsukamur (Otsuka), K-477 of Ramot (Ramot), K-76COONa of Tsukawa, K-AM of Wuyu (Kureha) Chemicals, KI-8110 of MECT Corp, L-623 of American cyanamide (American Cyanamid), leukocyte regulator (leukaregulin), lonidamine (lonidamine), LU-23-112 of Benkunck (Lundbeck), LU-186641 of Li (Lilly), MAP of NCI, Merrolone (Merrolone), DR-340 of Mermocarpus (Mermocarpus), Mermonine (Mermarone) 340, Mermocarb-d derivatives of Mermocarb, and so on, Methylanilinoacridine, MGI-136 from molecular genetics (molecular genetics), Minacitvine (minicactivin), mitonaphthylamine (mitonafide), mitoquinolones (mitoquinolone), Mopidamol (mopidamol), motrethinide (motretetinide), MST-16 from Zenyaku Kogyo, N- (retinoyl) amino acids, N-021 from Nisshin flour milling, N-acylated dehydroalanine, naphthoxazolone, NCU-190 from Taisho (Taisho), pyridazone derivatives, Normousing, NSC-145813 from NCI, NSC-361456 from NCI, NSC-604782 from NCI, NSC-95580 from NCI, somatostatin peptides (normotitide), Small woollatin (101112), Oncolanzolazine-72 from Warnozolazine, Van-72 from Warnolanzolazine, Van-111707 from Warnolazine, Van-6326 from Taisho, and so on-pazinone, PD-115934 from Huana-Lambert, PD-131141 from Huana-Lambert, PE-1001 from Pierre Fabre, peptide D from ICRT, piroxantrone, polymethine, polypreoic acid, viologen from Efamol, Probimane, procarbazine, proglumide, Inviniferin (Invitron), RA-700 from Tobishi, propinimine, RBS from Sapporo brewing, Restricin-P, Ritepptin, retinoic acid, RP-532 from Rhone-Poulenc, RP-4983 from Sarakr-4983, Klomr-S from SMRamity & S & 35 from SMomr & S &, SP-10094 of SeaPharm, Steatol, Spiropropane derivatives, Spirogermanium, Yonimedi (Unimed) SS-554 of Pharmacology, Stapydinone, Staphyndione, SUN 0237 of Suntory, SUN 2071 of Sanderry, superoxide dismutase, T-506 of Fushan (Toyama), T-680 of Fushan, paclitaxel, TEI-0303 of Teijin, Podophyllotoxin, Litliptin (thablintine), TJB-29 of Eastman Kodak, tocotrienol, Totopostin, topoisomerase inhibitors including Etinoxynine and Iridoxytin (Iridothic), fermentation broth of Kitazian, fermentation broth of Kuntzian, Kuntzian 82 of Kuntzian, and fermentation broth of Kuntzin 82 of Kuntzian, Chelidonine (ukrain), USB-006 from Istmann Kodak, vinblastine sulfate, aldehydic vinblastine, vinblastine amide, vinetramide, vinorelbine (vinestramide), vinorelbine (vinorelbine), vintriptol (vintriptol), vinzolidine (vinzolidine), withanolides, and YM-534 from Yamanouchi.
Examples of radioprotectors that may be used in combination with the compounds of the invention are AD-5, Adechon, amifostine analogs, Detos, damansna (dimesna), 1-102, MM-159, N-acylated dehydroalanine, TGF-Genentech, Dipupimod, amifostine (amifostine), WR-151327, FUT-187, ketoprofen, nabumetone (nabumetone), superoxide dismutase (Chiron corporation) and superoxide dismutase (Enzon corporation).
The compounds of the present invention are also suitable for use in combination with radiation therapy for the treatment of tumors, including malignancies.
The compounds of the invention may also be used in partial or complete co-therapy, in addition to other anti-inflammatory agents, in combination with: steroids, non-steroidal anti-inflammatory drugs (NSAIDs), nitric oxide synthase inhibitors (NOS inhibitors include iNOS inhibitors), kinase inhibitors (including IKK inhibitors and MK-2 inhibitors), p-38 inhibitors, TNF inhibitors, 5-lipoxygenase inhibitors, LTB4Receptor antagonists and LTA4Inhibitors of hydrolytic enzymes. Suitable LTA4The hydrolase inhibitors include RP-64966, (S, S) -3-amino-4- (4-benzyloxyphenyl) -2-hydroxybutyric acid benzyl ester (Shikurpu (Scripps) research institute), N- (2R) - (cyclohexylmethyl) -3- (hydroxycarbamoyl) propionyl) -L-alanine (Searle), 7- (4- (4-ureidobenzyl) phenyl) heptanoic acid (Rhone-Poulenc Rorer) and lithium 3- (3- (1E, 3E-tetradecadienyl) -2-oxacyclopropanyl) benzoate (Searle). Suitable LTB 4-receptor antagonists include ebselen (ebselen); linazolala (linazolast), antazolala (ontazolast); bayer (Bayer) Bayer Process Bayer; compound CGS-25019C from Ciba-Geigy; compound ETH-615 from Ondodema (Leo Denmark) Inc.; merck (Merck) corporationCompound MAFP; compound TMK-688 of Terumo (Terumo); compound T-0757 from Border (Tanabe); compounds LY-213024, LY-210073, LY223982, LY233469 and LY255283, LY-293111, 264086 and 292728 from the company Lilly (Lilly); the compounds ONO-KB457, ONO-4057 and ONO-LB-448 from Small wild (Ono) Inc.; compound S-2474 of Shionogi, Inc.; calcitriol (calcerol); compounds SC-53228, SC-41930, SC-50605 and SC-51146 of Searle, Compound of Lilly (Lilly); compound BPC-15 from the company Huaner-Lambert (Warner-Lambert); compound SB-209247 from smith becker bechaman (SmithKline Beecham); and SK&Compound SKF-104493 of company F. LTB4The receptor antagonist is preferably selected from calcitriol, ebselen, Bay-x-1005 of Bayer (Bayer), compound CGS-25019C of Ciba-Geigy, compound ETH-615 of Leo Denmark, Compound LY-293111 of Lilly (Lilly), Compound ONO-4057 of Nanye (Ono), and Compound TMK-688 of Tello (Terumo). Suitable 5-LO inhibitors include Compounds A-76745, 78773 and ABT761 from Abbott corporation; bayer (Bayer) Bayer Process Bayer; CMI-392 from Setosomed (Cytomed); e-3040, manufactured by Eisai corporation; EF-40 from pharmaceutical company of Scotia (Scotia); f-1322 by Fujirebio corporation; ML-3000 of Merckle (Merckle); RF-5901 by Purdue Frederick, Inc.; r-840 from 3M pharmaceuticals; rilopirox (rilopirox); flurbipen (flobufen); linnazola; lonapolene (lonapolene); masoprocol (masoprocol); antazotala; tenidap (teidap); jiluton (zileuton); prussian virtual kast (pranlukast); tazaralin (tepoxalin); rilopirox fezaratidine (flezelastine) hydrochloride; imazamide (enazadrem) phosphate; and bunaprost (bunaprolast).
The compounds of the present invention may also be used in combination therapy with opioids and other analgesics, including narcotic analgesics, Mu receptor antagonists, Kappa receptor antagonists, non-narcotic (i.e., non-addictive) analgesics, monoamine uptake inhibitors, adenosine modulators, cannabinoid derivatives, substance P antagonists, neurokinin-1 receptor antagonists, sodium channel blockers, and the like. More preferred would be combinations having compounds selected from the following group: morphine, cinnidine, codeine, tebuconazole, buprenorphine, cyclobutyline, tranexamine, diazoxan (dezocine), meptazinol (meptazinol), dihydrocodeinone, oxycodone, methadone, Tramadol (Tramadol) [ (+) enantiomer ], DuP 747, dinophene (Dynophine) A, ennadoline (Enadoline), RP-60180, HN-11608, E-2078, ICI-204448, acetominophen (acetominophen) (4-acetaminophen), propoxyphene, cyclobutyloxymorphone, E-4018, phenadol (filnadiol), mefenetaline (mirtranilil), amitriptyline (Duamitriptyline), Tramadol (Tradel) (-) 631), alexan (Tramadol) (-) -403531), AKE-35I-3569, GP-3, GP-3269, G-3, enantiomer GP-3269, G-3, G-3269, and E-D2, E-2078, AXC3742, SNX-111, ADL2-1294, CT-3 and CP-99, 994.
The compounds of the present invention may also be used in therapeutic compositions with lipid lowering agents including HMG Co-a reductase inhibitors including pravastatin (pravastatin), simvastatin (simvastatin), romanstatin (lovastatin), ZD4522, atorvastatin (cerivastatin) and frevastatin (fluvastatin), bile acid sequestrants including cholestyramine and cholecystenol (cholestipol), basic acid derivatives including basic acid, phenoxyisobutyric acid derivatives including p-chlorophenoxyisobutyric acid, gefibrazil (gemfibrozil), phenoxyphenylbutyl, cumylbutyl, benzylphenylbutyl, MTP inhibitors, ACAT inhibitors and CETP inhibitors.
These compounds are also useful in therapeutic compositions with anti-muscarinic agents such as tolterodine (tolterodine), thiometamol, isopropyldiazepine, cinnodipine, homoprotosol, hyoscyamine and atropine to control urinary conditions and other conditions associated with the muscarinic receptor.
These compounds are also useful in therapeutic compositions with sex steroids for the treatment or prevention of menstrual cramps.
These compounds may also be used alone or in combination with other therapeutic agents to treat or prevent migraine. These combination therapies include caffeine, an ergot alkaloid (such as ergotamine or dihydroergotamine), a 5H 1B/1DReceptor antagonists such as sumatriptan and a GABA-analogue such as carboplatin.
These compounds may be used in combination with one or more antihistamines, decongestants, diuretics, cough suppressants, or other agents previously known to be effective in combination with anti-inflammatory agents in replacement of other anti-inflammatory agents in co-therapy.
General synthetic procedure
Compounds of the present invention can be synthesized according to the following procedures in schemes 1 through 16, wherein the R1-R6 substituents are as defined above for structures I and II, unless otherwise indicated.
1 flow chart
The synthesis scheme 1 illustrates a general procedure for the preparation of a wide variety of substituted 2H-1-benzopyran derivatives 3 and 4. In step 1, a representative o-hydroxybenzaldehyde (salicylaldehyde) derivative 1 is condensed with an acrylate derivative 2 in a solvent such as dimethylformamide in the presence of a base such as potassium carbonate to give the desired 2H-1-benzopyran ester 3. Optional base-solvent compositions for the condensation include an organic base such as triethylamine, diazobicyclononane, with or without a solvent such as dimethyl sulfoxide. Mixtures of different stoichiometric amounts of organic and inorganic bases, with or without added solvent, may also be used. In step 2, the ester is hydrolyzed to the corresponding acid, such as by treatment with aqueous base (sodium hydroxide) in a suitable solvent such as ethanol or a THF-alcohol mixture, to produce the substituted 2H-1-benzopyran-3-carboxylic acid 4 after acidification.
2 flow chart
E, E ═ halogen, acyl, sulfonyl
The 2 nd synthetic scheme shows a general procedure for functionalizing a selected 2H-1-benzopyran. Treatment of 2H-1-benzopyran-3-carboxylic acid 4 or 2H-1-benzopyran ester 3 with an electrophile produces 6-substituted 2H-1-benzopyrans 5. A wide variety of electrophiles selectively react with 2H-1-benzopyran 4 at position 6, providing novel analogs in high yields. Electrophiles such as halogen (chlorine or bromine) can yield 6-halo derivatives. Chlorosulfonic acid reacts to give sulfonyl chloride at position 6, which can be further converted to a sulfonamide or sulfone. Friedel-Crafts acylation of Compound 4 provides 6-acylated 2H-1-benzopyran in good to excellent high yields. Several other electrophiles can be used to selectively react with these 2H-1-benzopyrans in a similar manner. The 2H-1-benzopyran substituted at the 6 position may be reacted with an electrophile at the 8 position using chemistry similar to the electrophilic substitution at the 6 position. Which produces a 2H-1-benzopyran substituted in both the 6 th and 8 th positions.
If R2 is part of an activation of the aryl group towards electrophilic substitution, the substitution may occur at the 5, 6, 7 or 8 position of the benzopyran nucleus. Thus, a 6-methoxy substituent may lead to electrophilic substitution at the 5 or 7 position. The ortho/para director at a different position from the 5, 6, 7 or 8 position of the benzopyran, when possible, activates the ortho or para position (relative to the substituent) toward substitution.
3 flow chart
The 3 rd synthetic scheme illustrates a second general synthesis of substituted 2H-1-benzopyran derivatives-3-carboxylic acids, which allows substitution at the 4 th position of 2H-1-benzopyran. In this case, a commercially available or synthetically obtained substituted o-hydroxyacetophenone 6 is reacted with two or more equivalents of a strong base such as lithium bis (trimethylsilyl) amide in a solvent such as Tetrahydrofuran (THF) followed by reaction with diethyl carbonate to obtain the β -keto ester 7. The ester 7 is condensed with an acid chloride or anhydride in a solvent such as toluene and with heating in the presence of a base such as potassium carbonate to give 4-oxo-4H-1-benzopyran 8. A variety of reagents can be employed including sodium borohydride (NaBH) in a solvent mixture such as ethanol and tetrahydrofuran4) Or by using triethylsilane in a solvent such as trifluoroacetic acid; or catalytic reduction using palladium on charcoal and hydrogen in a solvent such as ethanol to obtain beta-ketoester 9 (showing two tautomeric structures). Acylation of the oxygen in the keto-enolate is carried out in the presence of a base such as 2, 6-di-tert-butyl-4-methylpyridine and an acylating agent such as trifluoromethanesulfonic anhydride and using a solvent such as dichloromethane to produce enol-trifluoromethanesulfonate 10. Trifluoromethanesulfonate 10 can be prepared in a solvent such as tetrahydrofuran with reagents such as tri-n-butyltin hydride, lithium chloride, and a palladium (O) catalyst such as tetrakis (triphenylphosphine) palladium (O) to yield 2H-1-benzopyran ester 11, where R "is hydrogen. The ester 11 can be saponified in a mixed solvent such as tetrahydrofuran-ethanol-water (7: 2: 1) with a base such as 2.5N sodium hydroxide to give the desired substituted 2H-1-benzopyran-3-carboxylic acid.
To incorporate a carbon fragment R3The triflate 10 can be treated in a solvent such as tetrahydrofuran to obtain 2H-1-benzene using reagents known to perform "cross-linking" chemistry such as tributylvinyltin, lithium chloride and a palladium (O) catalyst such as tetrakis (triphenylphosphine) palladium (O)And pyranyl ester 11, wherein R3Is a vinyl moiety. The ester 6 can be saponified in a mixed solvent such as tetrahydrofuran-ethanol-water (7: 2: 1) with a base such as 2.5N sodium hydroxide to give the desired 4-vinyl-2H-1-benzopyran-3-carboxylic acid (12, R' -CH)2CH-). Similarly, triflate 10 can be converted to 2H-1-benzopyran using tri-n-butylphenyl tin under similar conditions, wherein R is3Is phenyl; and conversion to carboxylic acid 12 by hydrolysis of the ester, wherein R3Is phenyl. Using a similar strategy, are included as substituents R3The substituent(s) may be substituted alkenes, substituted aromatics, substituted heteroaryls, ethynyls and substituted ethynyls.
If R in formula 8 is1For hydrogen, CF is used3Si(CH3)3(or similar CF)3Silyl reagent) and concomitant fluoride (F-) treatment, can yield structure 9, wherein R 1Is CF3。
4 flow chart
Synthetic scheme 4 shows an alternative general procedure for the preparation of 4-oxo-4H-1-benzopyran 8. Treatment of o-fluorobenzoyl chloride with a suitably substituted beta-keto ester 14 with a base such as potassium carbonate in a solvent such as toluene affords 4-oxo-4H-1-benzopyran 8. 4-oxo-4H-1-benzopyran 8 can be converted to 2H-1-benzopyran as depicted in scheme 3.
5 flow chart
Y＝Br，I，CF3SO3
FIG. 5 shows a general scheme for the substitution of the aromatic ring of 2H-1-benzopyran. This is accomplished using an organopalladium mediated "cross-linking" chemistry using a palladium (O) catalyst to couple position Y of benzopyran 15 (where Y is iodide, bromide, boronic acid and ester, substituted borane, zinc species, magnesium species, or triflate) with an alkyl, ethynyl, alkene, nitrile (cyanide) or aryl coupler. Suitable coupling agents may include functionalized alkyl, alkenyl, aryl groups substituted with borane, boronic acid, dicarboxyboronic acid ester, zinc, tin, copper or magnesium species. Palladium coupling strategies using alcohols, phenols, anilines or amines can also be carried out to couple at position Y of the benzopyran 15. Furthermore, the corresponding ketones can be generated using acid chlorides or suitable coupling agents and carbon monoxide. Some of these suitable coupling agents may be generated in situ using suitable metals and reactive organic precursors. Substituted acetylenes as coupling agents will give the corresponding substituted acetylenes. With the use of arylboronic acids or esters, substituted aryl moieties may be incorporated; with the use of zinc (II) cyanide, nitriles can be incorporated. The ester 16 produced can be converted to carboxylic acid 17 as described in scheme 1.
Another aspect for substituting the aryl moiety of benzopyran 15 is the conversion of Y (where Y is iodide or bromide) to a perfluoroalkyl moiety. An example of such a conversion is the use of potassium pentafluoropropionate with copper (I) iodide in Hexamethylphosphoramide (HMPA) to convert 15(Y is iodide) to 16 (R)2’Is pentafluoroethyl). The ester 16 produced can be converted to carboxylic acid 15 as described in scheme 1.
A similar approach is to add substitution of aromatic rings to dihydroquinoline-3-carboxylic acid esters. This can be accomplished by coupling of the organopalladium with aryl iodides, bromides or triflates and various coupling agents (R.F. heck, "palladium reagents in organic Synthesis", academic Press, 1985). When a suitable palladium catalyst such as tetrakis (triphenylphosphine) palladium (O) is used in the reaction, a coupling agent such as an alkyne provides the disubstituted alkyne, phenylboronic acid provides the biphenyl compound, and cyanide produces the aryl cyano compound. A wide variety of other palladium catalysts and coupling agents can be used to selectively react with the appropriately substituted dihydroquinoline-3-carboxylic acid esters in a fashion.
6 th flow chart
The 6 th synthetic scheme shows a general synthetic pathway for converting a commercially available or synthetically derived substituted phenol to a substituted salicylaldehyde. Several different methods of using formaldehyde or a chemically equivalent reagent are detailed later.
In a basic matrix, reaction of a suitably substituted phenol 18 with formaldehyde (or a chemical equivalent) will yield the corresponding salicylaldehyde 1. Under suitable reaction conditions, the intermediate o-hydroxymethylphenol 19 will be oxidized in situ to salicylaldehyde 1. The reaction generally uses ethylmagnesium bromide or magnesium methoxide (1 eq) as the base, toluene as the solvent, paraformaldehyde (2 eq or more) as the formaldehyde source, and Hexamethylphosphoramide (HMPA), N, N, N ', N' -Tetramethylethylenediamine (TMEDA) (Casiraghi, G., et al, J.C.S.Perkin I (1978) p.318-321). A related approach is to use magnesium chloride with formaldehyde (or chemical equivalent) and phenol 18 to produce salicylaldehyde 1.
Alternatively, a suitably substituted phenol 18 may be reacted with formaldehyde under aqueous alkaline conditions to form a substituted o-hydroxybenzyl alcohol 19 (see (a) J.Leroy and C.Waselman, J.Fluorine chem., pp.40, 23-32 (1988); (b) A.A.Moshfegh et al, Helv.Chim.acta. 65, pp.1229-1232 (1982)). Common bases include aqueous potassium hydroxide or sodium hydroxide. Formalin (Formalin) (38% formaldehyde in water) is typically used as the formaldehyde source. The o-hydroxybenzyl alcohol 19 produced can be converted to salicylaldehyde 1 using an oxidizing agent such as manganese dioxide (IV) in a solvent such as dichloromethane or chloroform (R-GXie et al, Synthetic Commun. 24, pp.53-58 (1994)).
A suitably substituted phenol 18 can be treated with Hexamethylenetetramine (HMTA) under acidic conditions to prepare salicylaldehyde 1 (Duff reaction; see Y.Suzuki and H.Takahashi in chem.Pharm.Bull. 31, page 1751-1753 (1983)). Acids such as acetic acid, boric acid, methanesulfonic acid or trifluoromethanesulfonic acid are typically used for this reaction. A common formaldehyde source is hexamethylenetetramine. A related procedure uses magnesium chloride (anhydrous) with paraformaldehyde and a suitably substituted phenol 18 to prepare salicylaldehyde 1.
7 th flow chart
FIG. 7 shows a Reimer-Dermann reaction in which a commercially available or synthetically obtained, suitably substituted phenol 18 is reacted with chloroform under basic conditions to produce a substituted salicylaldehyde 1 (see Gragoe, E.J.; Schultz, E.M. U.S. Pat. No. 3,794,734 (1974)).
8 th flow chart
Scheme 8 shows a conversion of a commercially available or synthetically derived, suitably substituted salicylic acid 21 to its corresponding salicylaldehyde 1 via an intermediate 2-hydroxybenzyl alcohol 19. Reduction of salicylic acid 21 may be accomplished using a hydride reducing agent such as borane in a solvent such as tetrahydrofuran. Salicylaldehyde 1 is prepared by treating intermediate 2-hydroxybenzyl alcohol 19 with an oxidizing agent such as manganese (IV) oxide in a solvent such as dichloromethane or chloroform.
9 th flow chart
The 9 th synthetic scheme illustrates a general procedure for the preparation of a wide variety of substituted 2- (trifluoromethyl) -2H-1-thiochroman-3-carboxylic acids (25). In step 1, ortho-metallation of a commercially or synthetically obtained substituted thiophenol 22 using TMEDA (N, N' -tetramethylethylenediamine) with a base such as N-butyllithium followed by treatment with dimethylformamide affords 2-mercaptobenzaldehyde 23. Condensation of 2-mercaptobenzaldehyde 23 with an acrylate 2 in the presence of a base produces an ester 24 which can be saponified in the presence of an aqueous base to yield substituted 2H-1-thiochroman-3-carboxylic acid 25.
10 th flow chart
The 10 th synthetic scheme shows a general method for preparing a substituted 2-mercaptobenzaldehyde from a suitable commercially available or synthetically obtained substituted salicylaldehyde. In step 1, the phenolic hydroxyl group of salicylaldehyde 1 is converted to the corresponding O-arylthiocarbamate 26 by acylation with a suitably substituted thiocarbamoyl chloride such as N, N-dimethylthiocarbamoyl chloride using a base such as triethylamine in a solvent such as dimethylformamide. In step 2, when the O-arylthiocarbamate 26 is heated sufficiently, such as to 200 ℃, without or with a solvent such as N, N-dimethylaniline, the molecule rearranges to the S-arylthiocarbamate 27 (see A. Levai and P. Sebok, Synth. Commun. No. 22, page 1735-1750 (1992)). Hydrolysis of the S-arylthiocarbamate 27 with a base such as 2.5N sodium hydroxide in a solvent mixture such as tetrahydrofuran and ethanol produces a substituted 2-mercaptobenzaldehyde 23 which can be converted to a substituted 2H-1-benzothiopyran-3-carboxylic acid 25 as depicted in scheme 9.
11 th flow chart
The 11 th synthetic scheme illustrates a general method for preparing a wide variety of dihydroquinoline-3-carboxylic acid derivatives 30. R2Represents the aromatic substitution of the commercially or synthetically obtained 2-aminobenzaldehyde 28. In a base such as potassium carbonate, triethylamine or diazabicyclo [2.2.2.]In the presence of undec-7-enes and in a solvent such as dimethylformamide, wherein R22-aminobenzaldehyde derivatives 28, representing various substitutions, are condensed with an acrylate derivative 2 to obtain dihydroquinoline-3-carboxylic acid esters 29. The ester 29 may be saponified to the corresponding acid by treatment with an aqueous inorganic base such as 2.5N sodium hydroxide in a suitable solvent mixture such as ethanol; and obtaining the desired dihydroquinoline-3-carboxylic acid 30 after acidification.
12 th flow chart
The 12 th synthetic scheme illustrates a general procedure for the preparation of dihydroquinoline-3-carboxylic acid 30 from 2-aminobenzoic acid 31. R2Represents the aromatic substitution of commercially or synthetically obtained 2-aminobenzoic acid 31. The reduction of representative 2-aminobenzoic acid 31 to the desired 2-aminobenzyl alcohol 32 is accomplished in a solvent such as tetrahydrofuran with a hydride reducing agent such as borane. The desired 2-aminobenzyl alcohol 32 is treated with an oxidizing agent such as manganese (IV) oxide in a solvent such as methylene chloride to produce the representative 2-aminobenzaldehyde 28 (see C.T. Alabaster et al J.Med.chem. 31, pages 2048-2056 (1988)). 2-Ammonia as described in scheme 11 The benzaldehyde 28 is converted to the desired dihydroquinoline-3-carboxylic acid 30.
13 th flow chart
The 13 th synthetic scheme illustrates a general method for preparing a wide variety of dihydroquinoline-3-carboxylic acid derivatives 30 from isatin 33. R2Represents aromatic substitution of commercially or synthetically obtained isatin 33. A representative isatin 33 is treated with an alkaline peroxide generated from hydrogen peroxide and a base such as sodium hydroxide to produce the desired representative 2-aminobenzoic acid 31 (see m.s. newman and m.w. lougue at j.org.chem. 36, pages 1398-1401 (1971)). 2-aminobenzoic acid 31 is then converted to the desired dihydroquinoline-3-carboxylic acid derivative 30 as depicted in scheme 12.
14 th flow chart
FIG. 14 is a synthesis scheme of another general method for preparing dihydroquinoline-3-carboxylic acid derivative 30. In step 1, a suitable commercially available or synthetically derived substituted aniline 34 may be treated with an acylating agent such as pivaloyl chloride to obtain an amide 35. The o-dianion of amide 35 is prepared by treating amide 35 with an organolithium base such as n-butyllithium or t-butyllithium in tetrahydrofuran at low temperature. The dianion is quenched with dimethylformamide to give acylated-2-amino-benzaldehyde 36 (see J.Turner in J.org.chem. No. 48, 3401-3408 (1983)). These aldehydes are reacted with an acrylate in the presence of a base such as lithium hydride, followed by treatment with an aqueous inorganic base and hydrolysis, such as treatment with an aqueous base (sodium hydroxide) in a suitable solvent such as ethanol, to produce dihydroquinoline-3-carboxylic acid 30 after acidification.
Flow chart of 15
The 15 th synthesis scheme shows a general procedure for alkylating the nitrogen of dihydroquinoline-3-carboxylic acid ester derivative 29. This step involves treating dihydroquinoline-3-carboxylic acid ester derivative 29 with an alkyl halide such as ethyl iodide in a solvent such as methylene chloride in the presence of a phase transfer catalyst such as tetrabutylammonium iodide and a base such as caustic (50% aqueous sodium hydroxide). These conditions produce an N-alkylated dihydroquinoline-3-carboxylic acid ester 37. This compound 37 is saponified with an aqueous base to obtain an N-alkylated-dihydroquinoline-3-carboxylic acid derivative 38.
16 th flow chart
Scheme 16 shows the scheme for the preparation of 5 or 7-ethers (Z)1Is oxygen), a thioether (Z)1Is sulfur) or an amine (Z)1NH or NR) substituted benzopyran-3-carboxylic acid esters. A suitably substituted phenol, thiophenol, hydroxy-heterocycle, mercaptoheterocycle, alcohol, alkylthiol, amine (mono-or di-substituted) can be condensed with a suitably substituted 7-fluorophenylpyran derivative 30 in a solvent such as dimethyl sulfoxide at a temperature above room temperature such as 100 ℃ under basic conditions using a base such as potassium carbonate to produce the corresponding ether or thioether. Hydrolysis of the esters with an aqueous base such as lithium hydroxide or sodium hydroxide in a solvent mixture such as tetrahydrofuran-ethanol-water produces the acid 40. Where appropriate, a thioether (Z) may be reacted with an oxidizing agent such as OXONE or m-CPBA before or after hydrolysis of the ester 2Is sulfur) to sulfoxide (Z)2Is SO) or a sulfone (Z)2Is SO2). In this chemistry, RdCan include aryl, heteroarylA group, a heterocyclic group, an alicyclic group, a branched or straight aliphatic, a branched or straight perfluoroaliphatic moiety.
An alternative process for preparing salicylaldehyde precursors is shown in scheme 17. A phenol 21 is O-alkylated with a suitable protecting group (P) which may include any ortho-oriented protecting group (DoM). These groups may include methyl, methoxymethyl, methoxyethoxymethyl, Tetrahydropyranyl (THP) or other ethers. The C-deprotonation of the protected phenols can be carried out with a suitable base such as an alkyl lithium including butyl lithium, or with a lithium amide such as lithium diisopropanolyamide or lithium bis (trimethylsilyl) amide. The anion can be formylated directly with a formylating agent such as DMF (dimethylformamide). The treatment with phenol and deprotection yields salicylaldehyde 1. The deprotection of the phenol alkyl ether can be completed under acidic conditions. Optionally, the ortho-anion generated may be reacted with a reactive electrophile (R)e) And (4) reacting. They may include haloalkyl, alkyl or aryl esters, alkyl or aryl aldehydes, halosilyl groups, or halogenating agents. The resulting protected (additionally substituted) phenol may, where appropriate, be deprotonated again and formylated using DMF or other formylating agents. The treatment and deprotection of phenol produces substituted salicylaldehyde 44.
17 th flow chart
The foregoing chemistry may be applied to a solid phase method as shown in scheme 18. An example of this strategy is the covalent attachment of carboxylic acids to a polymer (45). The compound may be attached via an ester linkage, but is not limited to the functional group. The X functionality of the resin may be a halogenated alkyl group, an alcohol, or other functional group. Following this linkage, additional chemical transformations may be performed to displace substituents to form a differently substituted product 46, or to add additional functionality to form a product 48. The separate cleavage of product 46 and product 48 produces free carboxylic acids 47 and 49, respectively. The cleavage can be accomplished using a variety of conditions employing acid, base, Lewis acid or base, nucleophilic agents, and solvolysis.
18 th flow chart
Detailed Description
Detailed preparation method
The following abbreviations or expressions are used:
α-alpha
ACN: acetonitrile
BBr3: boron tribromide
Acetone: acetone (II)
For: calculated value
Found: measured value
High resolution: high resolution
And (3) Purity: purity of
Minor peak: small peak
Enantiomer: enantiomers
Non-equality with: is not equivalent to
Texture of the (R) and (S) enatiomer: mixtures of the (R) and (S) enantiomers
(1-naphthyl) ethyl amine: (1-naphthyl) ethylamine
negative: negative pole
9-BBN: 9-borabicyclo [3.3.1] nonanes
Br2: bromine compound
n-BuLi: n-butyl lithium
(BzO)2: benzoyl peroxide
Calc'd: is calculated by
CH2Cl2Or DCM: methylene chloride or methylene chloride
CD: circular dichroism
CDCl3: deuterated chloroform
CD3OD: deuterated methanol
Cl2: chlorine gas
CCl4: carbon tetrachloride
con, conc'd: concentrated
And (2) CuI: copper iodide (I)
DMAP: n, N-dimethylaminopyridine
DMF: dimethyl formamide
DMSO, DMSO: dimethyl sulfoxide
And (3) DPPP: 1, 3-bis-diphenylphosphinopropane
Et2O: diethyl ether
EtAOc: ethyl acetate
EtOH: ethanol
Et3SiH: triethylsilane
ESHRMS: electrospray high-resolution mass spectrometry
h: hour(s)
HBr: hydrobromic acid
HCl: hydrochloric acid
HF: hydrogen fluoride
HMPA: hexamethylphosphoric triamide
HMTA: hexamethylenetetramine, hexamethylenetetramine
H2O: water (W)
HOAc: acetic acid
IPA: isopropanol (I-propanol)
KCN: potassium cyanide
K2CO3: potassium carbonate
KHSO4: potassium sulfate
K3PO4: potassium phosphate
LCMS: liquid chromatography mass spectrometry
LiOH: lithium hydroxide
MeOH: methanol
MgSO4: magnesium sulfate
MTBE: methyl tert-butyl ether
M+H：M+1
M-H：M-1
m/z: mass/charge
NaBH4: sodium borohydride
NBS: n-bromosuccinimide
NaHCO3: sodium bicarbonate
NH4Cl: ammonium chloride
NH4F: ammonium fluoride
NaN3: sodium azide
NaOH: sodium hydroxide
NaOD: deuterated sodium hydroxide
Na2SO4: sodium sulfate
OXONE: potassium peroxymonosulfate
Pd(dba)2: bis (dibenzylideneacetone) palladium
PdCl2(PPh3)2: bis (triphenylphosphine) palladium chloride (II)
Pd(dppf)C·CH2Cl2: [1, 1' -bis (diphenylphosphino) ferrocene]Palladium chloride complex and dichloromethane
Pd(PPh3)4: tetrakis-triphenylphosphine palladium
[(t-Bu3P)PdBr]2: tri-tert-butylphosphine palladium (I) bromide dimer
PPh3: triphenylphosphine
P2O5: phosphorus pentoxide
psi: pounds per square inch
RPHPLC: reversed phase high pressure liquid chromatography
Sat, sat'd, and satd: saturated
TBAF: tetrabutylammonium fluoride
TEA: triethylamine
TFA: trifluoroacetic acid
THF: tetrahydrofuran (THF)
TiCl4: tin chloride (IV)
TMAF: tetramethyl ammonium fluoride
TMEDA: tetramethyl ethylene diamine
TMSCF3: trimethyl (trifluoromethyl) silane
Tfp: trifuranylphosphine
μ: micro (e.g., μ L or μ M)
Zn: zinc powder
(ZnCl2: zinc chloride)
In the following examples, the NMR chemical shift digital shift (δ) is a high magnetic field shift from TMS, shown in ppm.
In the following examples, specific numbers assigned to each compound are not meaningful, and they are only numbers assigned by the inventors. A gap in the order does not imply that any embodiment has not been disclosed.
Example 1a
6, 8-dichloro-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of ethyl 7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Prepare for
2, 4-dihydroxybenzaldehyde (20.0 g, 0.145 mol) and ethyl 4, 4, 4-trifluorocrotonate (36.58 g, 0.217 mol) were dissolved in anhydrous DMF (40 mL). The solution was warmed to 60 ℃, treated with anhydrous potassium carbonate (40.0 g, 0.290 mol), and maintained at 80 ℃ for 48 hours. The reaction was cooled to room temperature, diluted with 3N hydrochloric acid, and extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give an oil. The oil was passed through a plug of silica and the plug was washed with 20% ethyl acetate in hexane to give a yellow solid (13.22 g, 31.6%):
LCMS m/z 311.05(M+Na).1H NMR(CDCl3/400MHz)7.67(s，1H)，7.09(d，1H，J＝8.8Hz)，6.46(m，2H)，5.67(q，1H，J＝6Hz)，4.29(q，2H，J＝7.2Hz)，1.33(t，3H，J＝7.2Hz).
step 2: ethyl 6, 8-dichloro-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
A solution of the ester from step 1 (2.1 g, 7.29 mmol) in acetic acid (30 ml) was stirred at 10 ℃. A solution of chlorine gas prepared beforehand in acetic acid (31 ml, 8.7 mmol) was added to the above solution. The mixture was stirred for 2 hours. After chlorine gas was blown off, zinc powder (5 equivalents) was added to the mixture, and the mixture was stirred for 10 minutes. The zinc salt was removed and the filtrate was evaporated to dryness. The residue was purified by normal phase silica chromatography eluting with 20% ethyl acetate in hexane to give a white solid as the dichloro compound (0.22 g, 8%):
LCMS m/z 356.95(M+H).1HNMR(CDCl3/400MHz)7.60(s，1H)，7.16(s，1H)，5.80(q，1H，J＝6.8Hz)，4.30(q，2H，J＝7.2Hz)，1.33(t，3H，J＝7.2Hz).
Step 3: preparation of 6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The solution of the ester from step 2 (0.20 g, 0.56 mmol) was dissolved in 3 ml of 1/1/1 methanol/acetonitrile/water mixture, treated with lithium hydroxide (81 mg, 3.36 mmol) and stirred at room temperature for 2 days. The reaction mixture was acidified to pH 1 with 1.0N hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated and dried in vacuo to afford the title compound as a yellow solid (0.11 g, 60%): ESHRMS M/z 326.9438(M-H, C)11H4O4F3Cl2Calculated 326.9433).1HNMR(acetone-d6/400MHz)7.82(s，1H)，7.46(s，1H)，6.00(q，1H，J＝7.0Hz).
Example 1b
6, 8-dichloro-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acid esters
The polymer bound triphenylphosphine was suspended in THF for 15 min. To the above thick slurry were added ethyl 7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (2.0 g, 6.94 mmol) from step 1 of example 1a and 2-ethyl-1-butanol (1.3 ml, 10.35 mmol) and the mixture was stirred at room temperature for 15 min. Ethyl azodicarboxylate (1.6 ml, 10.35 mmol) was added dropwise to the above mixture, and the mixture was stirred at room temperature over liquid. LCMS showed product formation and minor amounts of starting material were still present. The polymer was filtered off through a pad of celite and the pad was cleaned with ether. The filtrate was concentrated and the product mixture was suspended in hexane. The suspension was filtered, the filtrate was evaporated and dried in vacuo to afford a yellow oil (2.37 g, 92%): LCMS M/z 394.95(M + Na). The ester has a suitable purity and can be used without further purification.
Step 2: ethyl 6, 8-dichloro-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
To a solution of the ester from step 1 (1.2 g, 3.2 mmol) in acetic acid (40 ml) was added sodium acetate (1.0 g, 12.1 mmol). Chlorine gas was bubbled through the solution until a precipitate was observed. The mixture was stirred for 2 hours. After chlorine gas was blown off, zinc powder (5 equivalents) was added to the mixture, and stirred for 30 minutes. The zinc salts were removed by filtration and the filtrate was evaporated to dryness. The residue was purified by flash chromatography eluting with 10% ethyl acetate in hexane to give a clear oil (0.77 g, 49%) which was found to contain a mixture of dichloro (84%) and monochloro (16%) by NMR analysis. The ester has a suitable purity and can be used without further purification.
Step 3: 6, 8-dichloro-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid
The ester from step 2 (0.75 g, 1.70 mmol) was dissolved in 4 ml of methanol and 4 ml of tetrahydrofuran. To the above solution was added sodium hydroxide (2.5N) (1.6 ml, 4 mmol), and the solution was stirred at room temperature for 5 hours. The reaction mixture was acidified with 1.5N hydrochloric acid to pH 1. The compound was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated and dried in vacuo to afford a crude yellow solid (0.61 g, 85%). The solid was purified by RPHPLC to give the title compound as a white solid (0.16 g, 28.4%): ESHRMS M/z 411.0343(M-H, C) 14H16O4F3Cl2Calculated 411.0372).1HNMR(acetone-d6/400MHz)7.89(s，1H)，7.62(s，1H)，5.98(q，1H，J＝7.0Hz)，4.01(d，1H，J＝5.6Hz)，1.71(m，1H)，1.61(m，2H)，1.53(m，2H)，0.971(t，6H，J＝7.2Hz).
Example 1c
6, 8-dichloro-7- (cyclopentylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 1b, 6, 8-dichloro-7- (cyclopentylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared using ethyl 7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1, example 1a as the starting material. ESHRMS M/z 409.0187(M-H, C)17H14O4F3Cl2Calculated 409.0216).
1H NMR(acetone-d6/400MHz)7.87(s，1H) 7.60(s，1H)，5.98(q，1H，J＝7.0Hz)，3.96(d，1H，J＝5.6Hz)，2.45(m，1H)，1.85(m，2H)，1.(m，2H)，1.84(m，3H)，1.57(m，3H).
Example 1d
6, 8-dichloro-7- (3, 3-dimethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 1b, 6, 8-dichloro-7- (3, 3-dimethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared using ethyl 7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 of example 1a as the starting material. ESHRMS M/z 411.0414(M-H, C)17H16O4F3Cl2Calculated 411.0372).
1H NMR(acetone-d6/400MHz)7.92(s，1H)，7.66(s，1H)，6.13(q，1H，J＝7.0Hz)，4.19(t，1H，J＝5.6Hz)，1.89(t，2H)，1.05(s，9H).
Example 1e
6, 8-dichloro-7-isobutoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 1b, 6, 8-dichloro-7-isobutoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared using ethyl 7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1, example 1a as starting material. ESHRMS M/z 383.0016(M-H, C) 15H12O4F3Cl2Calculated 383.0059).
1H NMR(acetone-d6/400MHz)7.87(s，1H)，7.60(s，1H)，5.97(q，1H，J＝7.2Hz)，3.86(d，1H，J＝6.4Hz)，2.15(m，1H)，1.07(d， 6H，J＝6.4Hz).
Example 1f
6, 8-dichloro-7- (cyclohexylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 1b, 6, 8-dichloro-7- (cyclohexylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared using ethyl 7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 of example 1a as starting material. ESHRMS M/z 423.0324(M-H, C)18H16O4F3Cl2Calculated 423.0372).
1H NMR(acetone-d6/400MHz)7.89(s，1H)，7.61(s，1H)，5.98(q，1H，J＝7.0Hz)，3.88(d，2H，J＝5.6Hz)，1.77(m，3H)，1.68(m，3H)，1.29(m，2H)，1.22(m，3H).
Example 1g
7- (benzyloxy) -6, 8-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 1b, 7- (benzyloxy) -6, 8-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared using ethyl 7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 of example 1a as starting material. ESHRMS M/z 416.9899(M-H, C)18H10O4F3Cl2Calculated 416.9903).1H
NMR(acetone-d6/400MHz)7.90(s，1H)，7.64(s，1H)，7.57(m，2H)，7.40(m，3H)，5.99(q，1H，J＝7.0Hz)，5.14(s，2H).
Example 1h
7-tert-butoxy-6, 8-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of ethyl 7-tert-butoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (2.0 g, 6.94 mmol) from step 1 of example 1a was treated with t-butyl trichloroacetimidate (acetaimidate) at room temperature in cyclohexane. After addition of a catalytic amount of boron trifluoride etherate (139. mu.l), the mixture (orange solid precipitate) is stirred over at room temperature. To the mixture was added solid sodium bicarbonate (2.33 g, 27.76 mmol). The mixture was passed through a plug of silica and washed with 6% ethyl acetate in hexane. The filtrate containing the product was evaporated to obtain a yellow oil with a purity higher than 90% (1.34 g, 56%): LCMS M/z 367.00(M + Na).
1H NMR(CDCl3/400MHz)7.70(s，1H)，7.121(m，1H)，6.63(s，1H)，6.61(m，1H)，5.68(q，1H，J＝7.2Hz)，4.30(q，2H，J＝7.2Hz)，1.33(t，3H，J＝7.2Hz).
The ester has a suitable purity and can be used without further purification.
Step 2: ethyl 7-tert-butoxy-6, 8-dichloro-2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
To a solution of the ester from step 1 (0.60 g, 1.74 mmol) in acetic acid (30 ml) was added sodium acetate (0.71 g, 8.72 mmol). Chlorine gas was bubbled through the above solution until a precipitate formed. The mixture was stirred for 2 hours. After chlorine gas was blown off, zinc powder (5 equivalents) was added to the mixture, and the mixture was stirred for 15 minutes. The zinc salts were removed by filtration and the filtrate was evaporated to dryness. The residue was purified by chromatography on Biotage silica eluted with 10% ethyl acetate in hexane to give a clear oil (0.12 g) as a mixture of monochloro and dichloro products, some of which had no tert-butyl groups.
Step 3: process for preparing 7-tert-butoxy-6, 8-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
The monochloro and dichloro esters from step 2 (0.11 g, 0.28 mmol) were dissolved in 0.75 ml of methanol and 0.75 ml of tetrahydrofuran. To the above solution was added sodium hydroxide (2.5N) (0.3 ml, 0.75 mmol), and the solution was stirred at room temperature. The reaction mixture was acidified to pH 2 with 1.5N hydrochloric acid. The compound was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The filtrate was evaporated and dried in vacuo to give a yellow solid. The mixture was purified by RPHPLC to obtain 6, 8-dichloro product as a white solid (29 mg, about 28% yield). ESHRMS M/z 383.0082(M-H, C) 15H126O4F3Cl2Calculated 383.0059).1H NMR(acetone-d6400MHz)7.88(s, 1H), 7.60(s, 1H), 5.97(q, 1H, J ═ 6.8Hz), 1.51(s, 9H) furthermore, 29 mg of 6-monochloro product were obtained in the form of a white solid (about 28% yield).
Example 2a
7- (4-amino-2-fluorophenoxy) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1The method comprises the following steps: ethyl 7- (2-fluoro-4-nitrophenoxy) -2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid esters
Ethyl 7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.50 g, 1.73 mmol), 1, 2-difluoro-4-nitrobenzene (0.30 g, 1.91 mmol) from step 1, example 1a were mixed with cesium carbonate (0.62 g, 1.91 mmol) in DMF (2 ml). To the above mixture was added copper (I) trifluoromethanesulfonate benzene complex (5 mg). The mixture was heated to 90 ℃ for 6 hours. LCMS showed formation of product and no starting material was present. The reaction was quenched with sodium bicarbonate (saturated) and extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous magnesium sulfate. The filtrate was evaporated and dried in vacuo to give a brown oil which was purified by chromatography on Biotage silica eluted with 20% ethyl acetate in hexane to give a pale yellow oil (0.62 g, 84%): LCMS M/z 449.65(M + Na).
1H NMR(CDCl3/400MHz)8.05(m，2H)，7.70(s，1H)，7.24(m，1H)，7.17(dd，1H，J＝8.8，8Hz)，6.66(m，1H)，665(s，1H)，5.69(q，1H，J＝6.8Hz)，4.30(q，2H，J＝7.2Hz)，1.33(t，3H，J＝7.2Hz).
Step 2: ethyl 7- (4-amino-2-fluorophenoxy) -6-chloro-2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
A solution of the ester from step 1 (0.5 g, 1.17 mmol) in acetic acid was stirred at 10 ℃. A solution of chlorine gas prepared in advance in acetic acid (10 ml, 4.0 mmol) was added to the above solution. The mixture was stirred for 2 hours. After chlorine gas was blown off, zinc powder (5 equivalents) was added to the mixture, and stirred for 30 minutes. The zinc salts were removed by filtration and the filtrate was evaporated to dryness. The residue was purified by normal phase silica chromatography eluting with 20% ethyl acetate in hexanes to afford the ester as a yellow oil which solidified upon standing (0.43 g, 85%): LCMS M/z 431.75(M + H).
1H NMR(CDCl3/400MHz)7.61(s，1H)，7.27(s，1H)，6.95(dd，1H，J＝8.4Hz)，6.50(dd，1H，J＝12，2.4Hz)，6.42(m，1H)，5.61(q，1H，J＝6.8Hz)，4.30(q，2H，J＝7.2Hz)，1.33(t，3H，J＝7.2Hz).
Step 3: 7- (4-amino-2-fluorophenoxy) -6-chloro-2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid
The ester from step 2 (0.10 g, 0.23 mmol) was dissolved in 0.5 ml methanol and 0.5 ml tetrahydrofuran. To the above solution was added sodium hydroxide (2.5N) (0.2 ml, 0.46 mmol), and the solution was stirred at room temperature. The reaction mixture was acidified with 0.5N hydrochloric acid. The compound was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The filtrate was evaporated and dried in vacuo to afford the title compound as a yellow solid (0.07 g, 75%): LCMS M/z 402.85(M + H).
1H NMR(acetone-d6/400MHz)7.89(s，1H)，7.73(s，1H)，7.67(dd，1H，J＝10.8，2.4Hz)，7.53(dd，1H，J＝10，1.6Hz)，7.47(m，1H)，5.81(q，1H，J＝7.0Hz).
Example 2b
6-chloro-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of ethyl 7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared using a procedure analogous to the method described in step 1 of example 1b, using ethyl 7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 of example 1a as the starting material. LCMS M/z 331.05(M + H). The ester has a suitable purity and can be used without further purification.
Step 2: ethyl 6-chloro-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
A solution of the ester from step 1 (0.4 g, 1.2 mmol) in acetic acid (10 ml) was treated with a solution of chlorine in acetic acid (0.5M prepared beforehand) (7.3 ml, 3.6 mmol). The mixture was stirred for 3 hours. After chlorine gas was blown off, zinc powder (3 equivalents) was added to the mixture, and stirred for 30 minutes. The zinc salts were removed by filtration and the filtrate was evaporated to dryness. The residue was purified by flash chromatography eluting with 10% ethyl acetate in hexane to give a clear oil (0.33 g, 69%). The ester has a suitable purity and can be used without further purification.
Step 3: preparation of 6-chloro-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in step 3 of example 2a, 6-chloro-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 335.0334(M-H, C)14H11O4F3Cl calculated 335.0292).1H NMR(acetone-d6/400MHz)7.81(s，1H)，7.51(s，1H)，6.78(s，1H)，5.80(q，1H，J＝7.0Hz)，4.10(m，2H)，1.85(m，2H)，1.05(q，3H，J＝7.0Hz).
Example 2c
6-chloro-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
In a manner analogous to that described in example 1bUsing ethyl 7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 of example 1a as starting material, to prepare 6-chloro-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. ESHRMS M/z 423.0585(M-H +2Na, C)17H17O4F3ClNa2Calculated 423.0557).
1H NMR(acetone-d6/400MHz)7.83(s，1H)，7.53(s，1H)，6.84(s，1H)，5.79(q，1H，J＝7.2Hz)，4.08(m，2H)，1.72(m，1H)，1.53(m，4H)，0.95(t，6H，J＝6.8Hz).
Example 2d
6-chloro-7- (cyclopentylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-chloro-7- (cyclopentylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared using a procedure analogous to the method described in example 1c, using ethyl 7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1, example 1a, as starting material. ESHRMS M/z 375.0595(M-H, C) 17H17O4F3Cl calculated 375.0605).
1H NMR(acetone-d6/400MHz)7.83(s，1H)，7.53(s，1H)，6.81(s，1H)，5.79(q，1H，J＝7.2Hz)，4.08(d，2H，J＝6.8Hz)，2.42(m，1H)，1.67(m，2H)，1.63(m，2H)，1.59(m，2H)，1.47(m，2H).
Example 2e
6-chloro-7- (3, 3-dimethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-chloro-7- (3, 3-dimethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared using a procedure analogous to the method described in example 1d, using ethyl 7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 of example 1a as starting material. ESHRMS M/z 377.0750(M-H, C)17H17O4F3Cl calculated 377.0762).
1H NMR(acetone-d6/400MHz)7.87(s，1H)，7.59(s，1H)，6.92(s，1H)，5.88(q，1H，J＝7.0Hz)，4.24(t，1H，J＝5.6Hz)，4.30(m，2H)，1.89(t，2H)，1.05(s，9H).
Example 2f
7- (benzyloxy) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
7- (benzyloxy) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared using a procedure analogous to the method described in example 1g, using ethyl 7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 of example 1a as starting material. ESHRMS M/z 383.0277(M-H, C)18H11O4F3Cl calculated 383.0292).1HNMR(acetone-d6/400MHz)7.89(s，1H)，7.62(s，1H)，7.58(m，2H)，7.46(m，3H)，6.98(s，1H)，5.87(q，1H，J＝7.0Hz)，5.37(s，2H).
Example 2g
7-tert-butoxy-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 1h, the ethyl 7-hydroxy radical from step 1 of example 1a is used1-Yl-2- (trifluoromethyl) -2H-chromene-3-carboxylate as starting material to prepare 7-tert-butoxy-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. ESHRMSm/z 349.0480(M-H, C) 15H13O4F3Cl calculated 349.0449).1HNMR(acetone-d6/400MHz)7.84(s，1H)，7.56(s，1H)，6.89(s，1H)，5.80(q，1H，J＝6.8Hz)，1.46(s，9H).
Example 2h
6-chloro-7- (2-methoxyethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7- (2-methoxyethoxy) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
Methyl 7- (2-methoxyethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared using a procedure analogous to the method described in example 1b, using ethyl 7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 of example 1a as starting material. The residue was purified by flash chromatography (silica gel) eluting with 10-30% ethyl acetate in hexanes to give a clear oil (2.0 g, 83%). LCMS M/z333.10(M + H). The ester was of suitable purity and was used without further purification.
Step 2: ethyl 6-chloro-7- (2-methoxyethoxy) -2- (trifluoromethyl) -2H-color Preparation of alkene-3-carboxylic acid esters
A solution of the ester from step 1 (1.0 g, 3.0 mmol) in acetic acid (100 ml) was treated with a solution of chlorine in acetic acid (0.5M prepared beforehand) (8.0 ml, 4.0 mmol). The mixture was stirred for 18 hours. After chlorine gas was blown off, zinc powder (3 equivalents) was added to the mixture, and stirred for 30 minutes. The zinc salt was removed and the filtrate was evaporated to dryness. The residue was purified by flash chromatography (silica gel) eluting with 10-15% ethyl acetate in hexanes to give a white solid (0.82 g, 75%). LCMSM/z 367.00(M + H). The ester was of suitable purity and was used without further purification.
Step 3: 6-chloro-7- (2-methoxyethoxy) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
Using a procedure analogous to the method described in step 3 of example 2a, 6-chloro-7- (2-methoxyethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z351.0280(M-H, C)14H11O5F3Cl calculated 351.0242).1H NMR(CDCl3/300MHz)7.73(s，1H)，7.25(s，1H)，6.60(s，1H)，5.65(q，1H，J＝7.0Hz)，4.20(m，2H)，3.82(m，2H)，3.48(s，3H).
Example 2i
6-chloro-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of ethyl 7-methoxy-2- (trifluoromethyl) -2H-chromen-3-stearate
A mixture of 2-hydroxy-4-methoxybenzaldehyde (50.1 g, 329 mmol), ethyl 4, 4, 4-trifluorocrotonate (58.7 ml, 394 mmol) and potassium carbonate (49.9 g, 361 mmol) in DMF (155 ml) was stirred under nitrogen at 80 ℃ for 2 h. Water was added and the mixture was extracted with ethyl acetate. The crude product was purified by filtration through a plug of silica gel and recrystallized to give a yellow crystalline solid: ESHRMS M/z302.0748(M +, C)14H13ClF3O4Calculated 302.0766).
Step 2: second step6-chloro-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
To a solution of the ester from step 1 (5.04 g, 16.7 mmol) in glacial acetic acid was slowly added chlorine for 3 minutes. After standing for 8 minutes, powdered zinc (2.25 g, 34.4 mmol) was added and the mixture was warmed slightly. The mixture was stirred until GCMS indicated removal of the polychlorinated byproducts. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with aqueous sodium bicarbonate, water, aqueous ammonium chloride, dried in vacuo and concentrated. The crude product was purified by silica chromatography (elution with 9: 1 hexane: ethyl acetate) to obtain the product as an impure mixture which was subjected to subsequent steps without further purification: ESHRMS M/z 336.0376(M +, C) 14H12ClF3O4Calculated 336.0376).
Step 3: preparation of 6-chloro-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The solution of the ester from step 2 (4 g, 12 mmol) was dissolved in a mixture of tetrahydrofuran: methanol: water, lithium hydroxide hydrate (4 g, 95 mmol) was added and the mixture was stirred at room temperature for 2 hours and then concentrated in vacuo. The mixture was acidified with 10% hydrochloric acid and extracted with ethyl acetate. The ethyl acetate layer was washed twice with water, aqueous ammonium chloride, dried over anhydrous sodium sulfate and dried in vacuo to give 1.3 g (36% yield) of the product:1H NMR(CDCl3/300MHz)7.48(s，1)，7.09(s，1H)，6.47(s，1H)，5.56(q，1H，J＝6.9Hz)，3.79(s，3H)；
ESHRMS m/z 307.0012(M-H，C12H7ClF3O4calculated 306.9985).
Example 3a
6-chloro-7-methoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 2-hydroxy-4-methoxy-3-methylbenzaldehyde
A mixture of 2, 4-dimethoxy-3-methylbenzaldehyde (3.75 g, 20.8 mmol) and beryllium chloride (5.0 g, 62.5 mmol) in dry toluene (50 ml) was heated to reflux for 3.5 hours. The solvent was removed by evaporation under reduced pressure to give an orange residue, which was treated with 2N hydrochloric acid. The compound was extracted with dichloromethane, and the organic layer was dried over magnesium sulfate. The filtrate was evaporated and dried in vacuo to afford an orange solid (3.4 g, 99%): LCMS M/z168.05(M + H). 1H NMR(CDCl3/300MHz)11.45(s，1H)，9.72(s，1H)，7.37(d，1H，J＝8.7Hz)，6.57(d，1H，J＝8.7Hz)，3.92(s，3H)，2.10(s，3H).
Step 2: ethyl 7-methoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
A mixture of benzaldehyde from step 1 (3.0 g, 18.07 mmol) and ethyl 4, 4, 4-trifluorocrotonate (4.5 g, 27.11 mmol) was dissolved in anhydrous DMF (20 ml), warmed to 60 ℃ and treated with anhydrous potassium carbonate (4.99 g, 36.14 mmol). The solution was maintained at 90 ℃ for 24 hours. LCMS analysis showed the reaction was complete. After the reaction was cooled to room temperature, the solution was extracted with ethyl acetate. The extract of the mixture was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a brown solid, which was dissolved in methanol (40 ml) and precipitated upon addition of 13 ml of water. The suspension was filtered and dried under vacuum to give a pale brown crystalline solid (4.37 g, 76.6%): LCMS M/z 339.10(M + Na).1HNMR(CDCl3/400MHz)7.68(s，1H)，7.03(d，1H，J＝8.7Hz)，6.50(d，1H，J＝8.7Hz)，5.70(q，1H，J＝6Hz)，4.29(q，2H，J＝7.2Hz)，3.84(s，3H)，2.09(s，3H)，1.33(t，3H，J＝7.2Hz).
Step 3: ethyl 6-chloro-7-methoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
To a solution of the ester from step 2 (0.50 g, 1.58 mmol) in acetic acid (30 ml) was added sodium acetate (0.65 g, 7.9 mmol). Chlorine gas was bubbled through the solution until a precipitate was observed. The mixture was stirred for 0.5 hour. After chlorine gas was blown off, zinc powder (5 equivalents) was added to the mixture, and stirred for 30 minutes. The zinc salts were removed by filtration and the filtrate was evaporated to dryness to give a brown oil (0.54 g, 97%):
1H NMR(CDCl3/300MHz)7.64(s，1H)，7.13(s，1H)，5.75(q，1H，J＝6Hz)，4.33(q，2H，J＝7.2Hz)，3.86(s，3H)，2.22(s，3H)，1.37(t，3H，J＝7.2Hz).
Step 4: 6-chloro-7-methoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
The ester from step 3 (0.50 g, 1.43 mmol) was dissolved in 3.5 ml of methanol and 4 ml of tetrahydrofuran. To the above solution was added sodium hydroxide (2.5N) (1.7 ml, 4.28 mmol) and stirred at room temperature overnight. The reaction mixture was acidified with 1.5N hydrochloric acid. The compound was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was evaporated and dried in vacuo to give a pale brown solid (0.4 g, 87%) containing about 20% of 6-monochloro compound. The mixture was purified by RPHPLC to obtain the title compound as a white solid (0.16 g, 28.4%): ESHRMS M/z321.0129(M-H, C)13H9C4F3Cl calculated 321.0136).1HNMR(acetone-d6/400MHz)7.83(s，1H)，7.43(s，1H)，5.85(q，1H，J＝7.0Hz)，3.83(s，3H)，2.18(s，3H).
Example 3b
6-chloro-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: methyl 7-hydroxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
Ethyl 7-methoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (3.0 g, 9.49 mmol) from step 2, example 3a was dissolved in dichloromethane (120 ml). The solution was cooled to-78 ℃ and boron tribromide (94.9 ml of a 1M solution in water) was added slowly to the above solution. The reaction was slowly warmed to room temperature and stirred overnight. The reaction was cooled to-78 ℃ and methanol (30 ml) was added. Thereafter, the solution was stirred at room temperature for 2 hours, the reaction was evaporated to dryness to obtain a brownish solid with a purity of about 90% the crude product was further purified by silica plug to give a yellow solid (2.7 g, 80%): LCMS M/z 311.05(M + Na).
1H NMR(acetone-d6/400MHz)9.11(s，1H)，7.75(s，1H)，7.11(d，1H，J＝8.4Hz)，6.59(d，1H，J＝8.4Hz)，5.78(q，1H，J＝6Hz)，3.79(s，3H)，2.09(s，3H).
Step 2: methyl 7- (2-ethylbutoxy) -8-methyl-2- (trifluoromethyl) -2H-color Preparation of alkene-3-carboxylic acid esters
The polymer bound triphenylphosphine was suspended in THF for 15 min. To the above thick slurry was added methyl 7-hydroxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.5 g, 5.21 mmol) from step 1 and 2-ethylbutanol (0.96 ml, 7.81 mmol) and stirred for 15 min. Ethyl azodicarboxylate (1.23 ml, 7.81 mmol) was added dropwise to the above mixture, and the mixture was stirred at room temperature overnight. LCMS showed formation of product and no starting material was present. The polymer was filtered off through a pad of celite and the pad was cleaned with ether. The filtrate was concentrated and the product mixture was suspended in hexane. The insoluble solids were removed by filtration, and the filtrate was evaporated and dried in vacuo to afford a yellow solid (1.76 g, 98%): LCMS M/z 395.15(M + Na).
1H NMR(CDCl3/400MHz)7.68(s，1H)，7.00(d，1H，J＝8.4Hz)，6.48(d，1H，J＝8.4Hz)，5.68(q，1H，J＝7.2Hz)，3.89(m，2H)，3.82(s，3H)，2.09(s，3H)，1.72(m，1H)，1.53(m，4H)，0.95(m，6H).
The ester is of suitable purity and can be used without further purification.
Step 3: methyl 6-chloro-7- (2-ethylbutoxy) -8-methyl-2- (trifluoromethyl) Preparation of (E) -2H-chromene-3-carboxylic acid esters
To a solution of the ester from step 2 (1.2 g, 3.22 mmol) in acetic acid (100 ml) was added sodium acetate (2.1 g, 25.8 mmol). Chlorine gas was bubbled through the solution until a precipitate was observed. The mixture was stirred for 1 hour. After chlorine gas was blown off, zinc powder (5 equivalents) was added to the mixture, and stirred for 30 minutes. The salt was removed by filtration and the filtrate was evaporated to dryness. The residue was purified by Biotage silica chromatography eluting with 10% ethyl acetate in hexanes to give a clear oil (0.60 g, 49%): LCMS M/z 407.15(M + H).
1H NMR(CDCl3/400MHz)7.63(s，1H)，7.08(s，1H)，5.70(q，1H，J＝7.2Hz)，3.84(s，3H)，3.80(m，2H)，2.17(s，3H)，1.68(m，1H)，1.53(m，4H)，0.95(m，6H).
Step 4: 6-chloro-7- (2-ethylbutoxy) -8-methyl-2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid
The ester from step 3 (0.55 g, 1.35 mmol) was dissolved in 3.5 ml methanol and 3.5 ml tetrahydrofuran. To the above solution was added sodium hydroxide (2.5N) (1.6 ml, 4 mmol) and stirred at room temperature overnight. The reaction mixture was acidified with 1.5N hydrochloric acid. The compound was extracted with ethyl acetate. The organic layer was washed with water and dried over anhydrous magnesium sulfate. The filtrate was evaporated and dried in vacuo to afford a yellow solid (0.31 g, 59%) after recrystallization from ethanol and water: ESHRMS M/z 391.0884(M-H, C)18H19O4F3Cl calculated 391.0918).1H NMR(acetone-d6/400MHz)7.84(s，1H)，7.45(s，1H)，5.88(q，1H，J＝7.0Hz)，3.92(m，2H)，2.17(s，3H)，1.71(m，1H)，1.61(m，2H)，1.53(m，2H)，0.971(t，6H，J＝7.2Hz).
Example 3c
6-chloro-8-methyl-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 3b, 6-chloro-8-methyl-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 349.0477(M-H, C)15H13O4F3Cl calculated 349.0449).1H NMR(acetone-d6/300MHz)7.85(s，1H)，7.45(s，1H)，5.88(q，1H，J＝7.0Hz)，3.92(m，2H)，2.21(s，3H)，1.84(m，2H)，1.07(t，6H，J＝7.2Hz).
Example 3d
6-chloro-7- (cyclopropylmethoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 3b, 6-chloro-7- (cyclopropylmethoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z361.0455(M-H, C)16H13O4F3Cl calculated 361.0449).1H NMR(acetone-d6/300MHz)7.84(s，1H)，7.45(s，1H)，5.88(q，1H，J＝7.0Hz)，3.86(m，2H)，2.21(s，3H)，1.31(m，1H)，0.59(m，2H)，0.35(m，2H).
Example 3e
6-chloro-7-isobutoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 3b, 6-chloro-7-isobutoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 363.0636(M-H, C)16H15O4F3Cl calculated 363.0605).1H NMR(acetone-d6/300MHz)7.84(s，1H)，7.45(s，1H)，5.88(q，1H，J＝7.0Hz)，3.75(m，2H)，2.21(s，3H)，2.13(m，1H)，1.08(d，6H，J＝6.9Hz).
Example 3f
7-butoxy-6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 3b, 7-butoxy-6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 363.0631(M-H, C)16H15O4F3Cl calculated 363.0605).1H NMR(acetone-d6/300MHz)7.84(s，1H)，7.45(s，1H)，5.88(q，1H，J＝7.0Hz)，3.75(m，2H)，2.21(s，3H)，1.86(m，2H)，1.58(m，2H)，0.98(t，3H，J＝7.2Hz).
Example 3g
6-chloro-8-methyl-7- (neopentyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 3b, 6-chloro-8-methyl-7- (neopentyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 377.0758(M-H, C) 17H17O4F3Cl calculated 377.0762).
1H NMR(acetone-d6/300MHz)7.84(s，1H)，7.45(s，1H)，5.88(q，1H，J＝7.0Hz)，3.65(d，1H，J＝8.3Hz)，3.61(d，1H，J＝8.3Hz)，2.21(s，3H)，1.12(s，9H).
Example 3h
6-chloro-7- (isopentyloxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the one described in example 3b, 6-chloro-7- (isopentyloxy) -8-methyl-2- (trifluoromethyl) -2H-chromene was prepared-3-carboxylic acid. ESHRMS M/z 377.0765(M-H, C)17H17O4F3Cl calculated 377.0762).1H NMR(acetone-d6/300MHz)7.84(s，1H)，7.45(s，1H)，5.88(q，1H，J＝7.0Hz)，3.62(t，2H，J＝6.6Hz)，2.21(s，3H)，1.96(m，1H)，1.75(m，2H)，1.12(s，6H，J＝6.3Hz).
Example 3i
6-chloro-7-hydroxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 3b, 6-chloro-7-hydroxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 306.9996(M-H, C)12H7O4F3Cl calculated 306.9979).1H NMR(acetone-d6/300MHz)7.84(s，1H)，7.45(s，1H)，5.88(q，1H，J＝7.0Hz)，2.21(s，3H).
Example 4a
7, 8-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: process for preparation of ethyl 7, 8-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
To a solution of 3, 4-bis-methoxysalicylaldehyde (5 g, 27 mmol) in DMF (50 ml) was added potassium carbonate (3.79 g, 27.5 mmol) and ethyl 4, 4, 4-trifluorocrotonate (5.08 g, 30 mmol). The mixture was heated to 65 ℃ for 4 hours. The reaction was cooled to room temperature, poured into water (150 ml) and extracted with ethyl acetate (2 × 150 ml). The combined organic layers were washed with aqueous sodium bicarbonate (2 × 50 ml), aqueous 3N hydrochloric acid (2 × 50 ml) and brine (2 × 50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford ethyl ester as an amber oil (6.3 g, 70%). The ester has a suitable purity and can be used without further purification.
1HNMR(DMSO-d6/400MHz)7.86(s，1H)，7.23(d，1H，J＝8.6Hz)，6.75(d，1H，J＝8.6Hz)，5.95(q，1H，J＝7.1Hz)，4.23(m，2H，J＝3.4Hz)，3.81(s，3H)，3.67(s，3H)，1.24(t，3H，J＝7.1Hz).
Step 2: preparation of 7, 8-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Tetrahydrofuran (7), ethanol (2) and water (1) were added to the ester (step 1), followed by lithium hydroxide (1.5 equivalents) and heated to 40 ℃ for 4 hours. The reaction was cooled to room temperature, concentrated in vacuo, and the solid was filtered by acidification with hcl to pH 1 and subjected to preparative reverse phase chromatography to give the title compound (350 mg, 99%): ESHRMSm/z 303.0435(M-H, C)13H10F3O5Calculated 303.0475).
1HNMR(DMSO-d6/400MHz)13.23(s，1H)，7.86(s，1H)，7.23(d，1H，J＝8.6Hz)，6.75(d，1H，J＝8.6Hz)，5.95(q，1H，J＝7.1Hz)，3.81(s，3H)，3.67(s，3H)，1.24.
Example 4b
6-chloro-7, 8-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-7, 8-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acid esters
The ester from step 1 of example 4a (365 mg, 1 mmol) was dissolved in acetic acid (25 ml). Chlorine gas was passed through the solution for 15 minutes. The solution was allowed to stand at room temperature for 30 minutes. The reaction was cooled to room temperature, poured into water (150 ml) and extracted with ethyl acetate (2 × 150 ml). The combined organic layers were washed with aqueous sodium bicarbonate (2 × 50 ml), aqueous 3N hydrochloric acid (2 × 50 ml) and brine (2 × 150 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford ethyl ester (385 mg, 95%) as a amber oil. The ester has a suitable purity and can be used without further purification. ESHRMSm/z 367 (M-H).
Step 2: preparation of 6-chloro-7, 8-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Prepare for
The ester (step 1) was hydrolyzed via a similar procedure as described in step 2 of example 4a to form the carboxylic acid (317 mg, 99%): ESHRMS M/z 337.0037(M-H, C)13H9ClF3O5Calculated 337.0055).1HNMR(DMSO-d6/400MHz)13.33(brs，1H)，7.79(s，1H)，7.44(s，1H)，6.00(q，1H，J＝7.1Hz)，3.80(s，3H)，3.70(s，3H).
Example 5a
7- (2-fluoro-4-nitrophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure similar to that described in step 3 of example 2a, the ethyl 7- (2-) -phase from step 1 of example 2a was usedHydrolysis of fluoro-4-nitrophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate to produce 7- (2-fluoro-4-nitrophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. ESHRMS M/z 398.0242(M-H, C)17H18F4O6Calculated N is 398.0282).
1H NMR(acetone-d6/400MHz)8.20(m，1H)，8.16(m，1H)，7.89(s，1H)，7.45(m，1H)，7.31(m，1H)，6.81(m，2H)，5.69(q，1H，J＝6.8Hz).
Example 5b
7-tert-butoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
7-tert-butoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared using a procedure analogous to the method described in example 1H, step 3, using hydrolysis of ethyl 7-tert-butoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from example 1H, step 1. ESHRMS M/z 315.0840(M-H, C) 15H14O4F3Calculated 315.0839).1HNMR(acetone-d6/400MHz)7.84(s，1H)，7.35(d，1H，J＝8.4Hz)，7.35(dd，1H，J＝8.4，2.4Hz)，6.62(d，J＝2 1H)，5.75(q，1H，J＝6.8Hz)，1.39(s，9H).
Example 5c
7-methoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Preparation of 7-Methoxyphenoxy-2H-chromene-3-carboxylate ester Using a procedure analogous to the procedure described in example 1H, step 3, step 2, hydrolysis of ethyl 7-methoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate ester from example 3aYl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. ESHRMS M/z 287.0502(M-H, C)13H10O4F3Calculated 287.0526).
1HNMR(acetone-d6/300MHz)7.82(s，1H)，7.29(d，1H，J＝8.4Hz)，6.72(d，1H，J＝8.4Hz)，5.80(q，1H，J＝6.8Hz)，3.90(s，3H)，2.08(s，3H).
Example 5d
7- (2-ethylbutoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
7- (2-ethylbutoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared using a procedure analogous to the procedure described in example 1H, step 3, using hydrolysis of methyl 7- (2-ethylbutoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 2 of example 3 b. ESHRMS M/z 357.1325(M-H, C)18H20O4F3Calculated 357.1308).
1H NMR(acetone-d6/400MHz)7.81(s，1H)，7.26(d，1H，J＝8.4Hz)，6.71(d，1H，J＝8.4Hz)，5.80(q，1H，J＝6.8Hz)，3.99(m，2H)，2.09(s，3H)，1.07(m，1H)，1.51(m，4H)，0.94(t，6H，J＝6.8Hz).
Examples of all 5e
7- (2-methoxyethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7- (2-methoxyethoxy) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
Ethyl 7- (2-methoxyethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared using a procedure analogous to the method described in step 1 of example 1b, using ethyl 7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 of example 1a as starting material. The residue was purified by flash chromatography (silica gel) eluting with 10-30% ethyl acetate in hexanes to give a clear oil (2.0 g, 83%). LCMSM/z 333.1(M + H). The ester has a suitable purity and can be used without further purification.
Step 2: 7- (2-methoxyethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
Using a procedure analogous to the method described in step 3 of example 2a, 7- (2-methoxyethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 317.0648(M-H, C)14H12F3O4Calculated 317.0631).1H NMR(CDCl3/400MHz)7.78(s，1H)，7.14(d，1H，J＝8.4Hz)，6.52(m，2H)，5.63(q，1H，J＝7.0Hz)，4.12(m，2H)，3.74(m，2H)，3.44(s，3H).
Example 5f
7- (2-Furanylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 5e, 7- (2-furylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 339.0461(M-H, C)16H10P3O5Calculated 339.0475).1H NMR(CDCl3/300MHz)7.82(s，1H)，7.45(s，1H)，7.14(d，1H，J＝8.4Hz)，6.64(m，2H)，6.42(m，2H)，5.65(q，1H，J＝7.0Hz)，5.02(m，2H).
Example 5g
7- (carboxymethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 5e, 7- (carboxymethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 317.0247(M-H, C)13H8F3O6Calculated 317.0267).1H NMR(DMSO/300MHz)13.05(brs，2H)，7.79(s，1H)，7.39(d，1H，J＝8.4Hz)，6.60(m，2H)，5.84(q，1H，J＝7.0Hz)，4.73(s，2H).
Example 6
6-chloro-8-isopropyl-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 3-chloro-6-hydroxy-5-isopropyl-2-methylbenzaldehyde
To a solution of 4-chloro-2-isopropyl-5-methylphenol (5.00 g, 27.08 mmol) in anhydrous acetonitrile (150 ml) were added magnesium chloride (3.87 g, 40.61 mmol), TEA (10.28 ml, 101.55 mmol) and paraformaldehyde (5.48 g, 182.79 mmol), and the resulting mixture was refluxed under a dry nitrogen atmosphere for 18 hours. The mixture was then cooled, acidified with 2.4N hydrochloric acid and extracted with ethyl acetate (2 × 250 ml). The combined extracts were washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give a dark orange oil which was flash chromatographed (silica gel) and eluted with 25% hexane/dichloromethane to give 5.8 g (99% yield) of the product as a pale yellow oil. GCMS M/z 212.0(M +). The ester has a suitable purity and can be used without further purification.
Step 2: ethyl 6-chloro-8-isopropyl-5-methyl-2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
A mixture of 3-chloro-6-hydroxy-5-isopropyl-2-methylbenzaldehyde (5.21 g, 24.56 mmol), potassium carbonate (6.78 g, 49.12 mmol) and ethyl 4, 4, 4-trifluorocrotonate (6.19 g, 36.84 mmol) prepared as in step 1 in anhydrous DMF (30.0 ml) was heated to 90 ℃ under a dry nitrogen atmosphere for 18 hours. The mixture was then cooled, poured into 1.2N hydrochloric acid (100 ml) and extracted with ethyl acetate (2 × 100 ml). The combined extracts were washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give a dark orange oil which was flash chromatographed (silica gel) and eluted with 50% hexane/dichloromethane to give the product as 3.94 g (44%) of an orange oil. GCMS M/z 362.0(M +).
1H NMR(CDCl3/400MHz)7.98(s，1H)，7.26(s，1H)，5.75(q，1H，J＝7.0Hz)，4.36(m，2H)，3.28(m，1H)，2.45(s，3H)，1.39(m，3H)，1.23(m，6H).
Step 3: 6-chloro-8-isopropyl-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
Using a procedure analogous to the method described in step 3 of example 2a, 6-chloro-8-isopropyl-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 333.0538(M-H, C)15H13F3O3Calculated Cl 333.05001H NMR(CDCl3/400MHz)8.08(s，1H)，7.34(s，1H)，5.87(q，1H，J＝7.0Hz)，3.28(m，1H)，2.46(s，3H)，1.22(m，6H).
Example 7a
6-chloro-7- (ethylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 5-chloro-4-fluoro-2-hydroxybenzaldehyde
To 4-chloro-3-fluorophenol (25 g, 171 mmol), methanesulfonic acid (130 ml) was added, and the mixture was stirred at room temperature. The temperature of the stirred reaction mixture was cooled to 10 ℃ using an ice water bath. Hexamethylene tetramine (47.8 g, 341 mmol) was added portionwise in 3 g portions of one spoon to dissolve the solid and maintain the temperature below 40 ℃. The addition was complete after 90 minutes. Attention is paid to: if added too quickly, the solid will react with the acid and decompose in an exothermic manner. The mixture was heated to 100 ℃. At 70 ℃ a change in the color of the reaction mixture and the formation of a solid were observed. Once the temperature reached 100 ℃, the heating mantle was removed and the mixture was allowed to cool to room temperature. The reaction mixture was poured into 1 liter of ice water and extracted 3 times with dichloromethane. The combined extracts were filtered through a plug of silica (4.5X 9 cm), washed with additional dichloromethane, and concentrated to give a crude yellow solid. Kugelrohr distillation (100 mTorr, 60 ℃ C.) was carried out to obtain 18.06 g (60.6%) of a white solid. NMR showed purity higher than 95%.
1H NMR(CDCl3)6.79(d，1H，J＝10.3Hz)，7.62(d，1H，J＝7.9Hz)，9.80(s，1H)，11.23(d，1H，J＝1.5Hz).
Step 2: preparation of ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate Prepare for
Aldehyde from step 1 (17.46 g, 100 mmol) in DMF (25 mL)) To (5), potassium carbonate (15.2 g, 110 mmol) was added. The mixture was stirred, heated to 70 ℃ and treated with ethyl-trifluorocrotonate (22.4 ml, 150 mmol). After 2 hours, the mixture was heated to 95 ℃. After a total of 4 hours, an additional 16 ml of crotonate are added and the mixture is stirred at 95 ℃ for 4 hours and at room temperature for 12 hours. LCMS showed reaction completion. The mixture was treated with 300 ml of 1N hydrochloric acid and extracted 4 times with ethyl acetate. The combined extracts were filtered through a plug of silica (4.5X 6 cm) and the plug was rinsed with additional dichloromethane. The extract was concentrated, the crude product triturated with cold methanol, the solid collected and air dried to give 19.1 g of a tan solid. The mother liquor was concentrated, dissolved in dichloromethane and filtered through a fresh plug of silica following the same procedure described above to give a second 4.1 g of solid material. The mother liquor was diluted with water and the solids were collected to give a third batch of 3.16 g solids. The total yield was 26.36 g (81.2%). By using 1H NMR analysis showed: the purity of the first and second batches was higher than 95%, while the purity of the third batch was higher than 90%.
1HNMR(CDCl3)1.35(t，3H，J＝7.1Hz)，4.33(m，2H)，5.71(q，1H，J＝6.7Hz)，6.82(d，1H，J＝9.4hz)，7.28(d，1H，7.9Hz)，7.63(s，1H).19FNMR(CDCl3)-78.9(d，3F，J＝6.7Hz)，-106.7(t，1F，J＝8.7Hz).13CNMR(CDCl3)14.2，61.7，70.9(q，C2，J＝33.3Hz)，105.5(d，C8，J＝25.5Hz)，114.9(d，J＝18.7Hz)，116.4，117.1，123.1(q，CF3，J＝287.2Hz)，130.4(d，J＝1.5Hz)，134.9(d，J＝1.9Hz)，152.9(d，J＝11.4Hz)，160.1(d，C7，J＝255.2Hz)，163.4(C＝O)
Step 3: ethyl 6-chloro-7- (ethylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acid esters
A mixture of ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (step 2) (0.5 g, 1.54 mmol) and ethanethiol (0.1 g, 1.54 mmol) was dissolved in anhydrous DMF (5 ml), warmed to 90 ℃ and treated with potassium carbonate (0.25 g, 1.84 mmol). The solution was maintained at 90 ℃ for 48 hours, cooled to room temperature, filtered through celite and concentrated to a viscous oil. The oil was purified by flash chromatography (silica gel) eluting with 10-40% ethyl acetate in hexane to give a pale yellow solid (0.24 g, 43%): GCMS 366.00(M +).
1H NMR(CDCl3/400MHz)7.60(s，1H)，7.27(s，1H)，6.77(s，1H)，5.67(q，1H，J＝7.0Hz)，4.29(m，2H)，2.96(m，2H)，1.40(m，3H)，1.35(m，3H).
Step 4: preparation of 6-chloro-7- (ethylthio) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Prepare for
Using a procedure analogous to the method described in example 1H, step 3, 6-chloro-7- (ethylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 336.9866(M-H, C)13H9O3F3Calculated CIS 336.9908).
1H NMR(acetone-d6/300MHz)7.86(s，1H)，7.54(s，1H)，6.98(s，1H)，5.84(q，1H，J＝7.0Hz)，3.12(q，2H，J＝7.2Hz)，1.39(t，3H，J＝7.2Hz).
Example 7b
6-chloro-7- (isopentylthio) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 7a, 6-chloro-7- (isopentylthio) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 390.0420(M-H, C)16H15O3F3Calculated CIS 379.0377).1H NMR(acetone-d6/400MHz)7.85(s，1H)，7.52(s，1H)，6.99(s，1H)，5.82(q，1H，J＝7.0Hz)，3.10(t，2H，J＝8.0Hz)，1.84(m，1H)，1.64(m，2H)，1.59(m，3H)，0.93(m，3H).
Example 7c
6-chloro-7- (propylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 7a, 6-chloro-7- (propylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 351.0076(M-H, C)14H11O3-F3Calculated CIS 351.0064).
1H NMR(acetone-d6/400MHz)7.86(s，1H)，7.54(s，1H)，6.99(s，1H)，5.83(q，1H，J＝7.0Hz)，3.09(t，2H，J＝8.0Hz)，1.76(m，2H)，1.12(m，3H).
Example 7d
6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 7a, 6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. LCMS 367.10(M + H).
1H NMR(acetone-d6/300MHz)7.86(s，1H)，7.54(s，1H)，6.99(s，1H)，5.83(q，1H，J＝7.0Hz)，2.99(m，2H)，1.99(m，1H)，1.10(m，6H).
Example 7e
7- (benzylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 7a, 7- (benzylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 399.0036(M-H, C)18H11O3F3CIS calculated value 399.0064)
1H NMR(acetone-d6/300MHz)7.86(s，1H)，7.54(m，3H)，7.32(m，3H)，7.08(s，1H)，5.83(q，1H，J＝7.0Hz)，4.40(s，2H).
Example 7f
7- (butylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 7a, 7- (butylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 365.0208(M-H, C) 15H13O3F3Calculated CIS 365.0221).1H NMR(acetone-d6/300MHz)7.85(s，1H)，7.53(s，1H)，6.98(s，1H)，5.82(q，1H，J＝7.0Hz)，3.10(m，2H)，1.72(m，2H)，1.53(m，2H)，0.96(m，3H).
Example 7g
7- (sec-butylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 7a, 7- (sec-butylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 365.0226(M-H, C)15H13O3F3Calculated CIS 365.0221).
1H NMR(acetone-d6/300MHz)7.86(s，1H)，7.54(s，1H)，7.04(s，1H)，5.82(q，1H，J＝7.0Hz)，3.57(m，1H)，1.72(m，2H)，1.37(m，3H)，1.05(m，3H).
Example 8a
6-chloro-7- (3, 5-dimethylpiperidin-1-yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: 6-chloro-7- (3, 5-dimethylpiperidin-1-yl) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
A mixture of ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (from step 2 of example 7 a) (0.5 g, 1.54 mmol) and 3, 5-dimethylpiperidine (0.17 g, 1.54 mmol) is dissolved in anhydrous DMF (5 ml), warmed to 90 ℃ and treated with potassium carbonate (0.25 g, 1.84 mmol). The solution was maintained at 90 ℃ for 48 hours, cooled to room temperature, filtered through celite and concentrated to a viscous oil. The oil was purified by chromatography on Biotage silica gel eluted with 30% dichloromethane in hexane to afford a pale yellow oil (0.6 g, 93%): GCMS 417.00(M +).
1H NMR(CDCl3/300MHz)7.61(s，1H)，7.18(s，1H)，6.60(s，1H)，5.67(q，1H，J＝7.0Hz)，4.67(m，2H)，3.40(m，2H)，2.18(m，2H)，1.86(m，2H)，1.31(m，3H)，1.04(m，1H)，0.90(m，6H)，0.68(m，1H).
Step 2: 6-chloro-7- (3, 5-dimethylpiperidin-1-yl) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid
Using a procedure analogous to the method described in step 3 of example 2a, 6-chloro-7- (3, 5-dimethylpiperidin-1-yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMSm/z 390.1048(M + H, C)18H20O3F3Calculated CIN of 390.1078).1H NMR(acetone-d6/400MHz)7.80(s，1H)，7.47(s，1H)，6.71(s，1H)，5.78(q，1H，J＝7.0Hz)，3.38(m，2H)，2.27(m，2H)，1.84(m，2H)，1.04(m，1H)，0.92(m，6H)，0.76(m，1H).
Example 8b
6-chloro-7- (3-methylpiperidin-1-yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 8a, 6-chloro-7- (3-methylpiperidin-1-yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 376.0931(M + H, C)17H18O3F3Calculated CIN of 376.0922).1H NMR(acetone-d6/400MHz)7.82(s，1H)，7.48(s，1H)，6.71(s，1H)，5.78(q，1H，J＝7.0Hz)，3.41(m，2H)，2.38(m，1H)，1.75(m，5H)，1.10(m，1H)，0.93(m，3H).
Example 8c
6-chloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the one described in example 8a, 6-chloro-7- [ isobutyl (methyl) amino]-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. ESHRMS M/z 364.0897(M + H, C)16H18O3F3Calculated CIN of 364.0922).1H NMR(acetone-d6/400MHz)7.81(s，1H)，7.46(s，1H)，6.76(s，1H)，5.78(q，1H，J＝7.0Hz)，3.04(m，2H)，2.95(s，3H)，1.96(m，1H)，0.96(m，6H).
Example 8d
6-chloro-7- (4-methylpiperidin-1-yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 8a, 6-chloro-7- (4-methylpiperidin-1-yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. Ehrms M/z 376.0924(M + H, C) 17H18O3F3Calculated CIN of 376.0922).
1H NMR(acetone-d6/300MHz)7.81(s，1H)，7.48(s，1H)，6.72(s，1H)，5.79(q，1H，J＝7.0Hz)，3.48(m，2H)，2.72(m，2H)，1.75(m，2H)，1.58(m，1H)，1.38(m，2H)，0.98(m，3H).
Example 8e
6-chloro-7- (3, 6-dihydropyridin-1 (2H) -yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 8a, 6-chloro-7- (3, 6-dihydropyridin-1 (2H) -yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z360.0592(M + H, C)16H14O3F3Calculated CIN of 360.0609).1HNMR(acetone-d6/400MHz)7.81(s，1H)，7.49(s，1H)，6.74(s，1H)，5.79(m，3H)，3.68(m，2H)，3.39(m，1H)，3.22(m，1H)，2.30(m，2H).
Example 8f
6-chloro-7- [ ethyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the one described in example 8a, 6-chloro-7- [ ethyl (methyl) amino]-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. ESHRMS M/z 336.0574(M + H, C)14H14O3F3Calculated ClN 336.0609).
1H NMR(acetone-d6/400MHz)7.81(s，1H)，7.46(s，1H)，6.71(s，1H)，5.77(q，1H，J＝7.0Hz)，3.21(m，2H)，2.84(s，3H)，0.96(m，3H).
Example 8g
6-chloro-7- [ (cyclopropylmethyl) (propyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to that described in example 8a, 6-chloro-7- [ (cyclopropylmethyl) (propyl) amino]-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. ESHRMS M/z390.1040(M + H, C)13H20O3F3Calculated ClN 390.1078).1HNMR(acetone-d6/300MHz)7.83(s，1H)，7.48(s，1H)，6.84(s，1H)，5.79(q，1H，J＝7.0Hz)，3.33(m，2H)，3.11(m，2H)，1.53(m，2H)，1.00(m，1H)，0.90(m，3H)，0.45，(m，2H)，0.10(m，2H).
Example 8h
7- [ butyl (ethyl) amino ] -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the one described in example 8a, 7- [ butyl (ethyl) amino]-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. ESHRMS M/z 378.1058(M + H, C)17H20O3F3Calculated ClN 378.1078).1H NMR(acetone-d6/300MHz)7.83(s，1H)，7.49(s，1H)，6.79(s，1H)，5.79(q，1H，J＝7.0Hz)，3.24(m，4H)，1.51(m，2H)，1.31(m，2H)，1.10(m，3H)，0.91(m，3H).
Example 8i
7- [ benzyl (methyl) amino ] -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the one described in example 8a, 7- [ benzyl (methyl) amino group]-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. ESHRMS M/z 398.0788(M + H, C)19H16O3F3Calculated ClN 398.0765).1H NMR(acetone-d6/300MHz)7.84(s，1H)，7.53(s，1H)，7.36(m，5H)，6.77(s，1H)，5.79(q，1H，J＝7.0Hz)，4.36(m，2H)，2.77(s，3H).
Example 8j
7-azetidin-1-yl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 8a, 7-azetidin-1-yl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 334.0441(M + H, C)14H12O3F3Calculated ClN 334.0452).1H NMR(acetone-d6/300MHz)7.75(s，1H)，7.28(s，1H)，6.09(s，1H)，5.72(q，1H，J＝7.0Hz)，4.23(m，4H)，
2.35(m，2H).
Example 8k
7- (benzylamino) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 8a, 7- (benzylamino) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 384.0583(M + H, C) 18H14O3F3Calculated ClN 384.0609).1H NMR(acetone-d6/400MHz)7.73(s，1H)，7.40(m，6H)，6.28(s，1H)，5.66(q，1H，J＝7.0Hz)，4.58(m，2H).
Example 8l
6-chloro-7- (diethylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7- (diethylamino) -2- (trifluoromethyl) -2H-chromen-3-U acid Preparation of esters
Ethyl 7- (diethylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared using a procedure analogous to the method described in step 1 of example 1 a. GCMS M/z 343.0(M +). The ester has a suitable purity and can be used without further purification.
Step 2: ethyl 6-chloro-7- (diethylamino) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
Ethyl 6-chloro-7- (diethylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared using a procedure analogous to the method described in example 1H, step 2. GCMS M/z377.0(M +).
1H NMR(CDCl3/400MHz)7.59(s，1H)，7.17(s，1H)，6.59(s，1H)，5.65(q，1H，J＝70Hz)，4.28(m，2H)，3.19(m，4H)，1.32(m，3H)，1.09(m，6H).
Has suitable purity, and can be used without further purification.
Step 3: 6-chloro-7- (diethylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
Preparation of 6-chloro-7- (diethylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid using a procedure analogous to the one described in step 3 of example 2a。ESHRMS m/z 350.0774(M+H，C15H16O3F3Calculated ClN 350.0765). 1H NMR(CDCl3/400MHz)7.73(s，1H)，7.20(s，1H)，6.59(s，1H)，5.63(q，1H，J＝7.0Hz)，3.23(m，4H)，1.10(m，6H).
Example 9a
7-butyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 2-hydroxy-4-iodobenzaldehyde
To a cooled solution of commercially available 2-iodophenol (30 g, 136 mmol) in acetonitrile was added magnesium chloride (19.5 g, 204 mmol) in portions while maintaining the temperature below 10 ℃, followed by paraformaldehyde (28.6 g, 954 mmol) and TEA (76 ml, 545 mol) to give a 15 ℃ exotherm. The solution was heated to 72 ℃ for 2 hours. The reaction was cooled to room temperature and poured into saturated aqueous ammonium chloride (500 ml) and extracted with ethyl acetate (2 × 150 ml). The combined organic layers were washed with aqueous sodium bicarbonate (2 × 150 ml), aqueous 1N hydrochloric acid (2 × 150 ml) and brine (2 × 150 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was subjected to flash chromatography (silica gel, 5% ethyl acetate/hexane). The desired fractions were collected and mixed and the solvent was removed in vacuo to yield ethyl ester as a yellow solid (27 g, 79%). The salicylaldehyde has a suitable purity and can be used without further purification.1HNMR(DMSO-d6/400MHz)10.95(s，1H)，10.19(s，1H)，7.33(m，3H)，4.31(m，1H).
Step 2: preparation of ethyl 7-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate
The aldehyde from step 1 (25 g, 114 mmol) was condensed in a similar manner to that described in step 1 of example 4 a. (15 g, 52%). The ester has a suitable purity and can be used without further purification. ESHRMS M/z 361.1040(M + H, C)13H9IF3O3Calculated 361.1046).
Step 3: preparation of ethyl 7-butyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
1-butene was bubbled through 9-BBN in tetrahydrofuran (6.53 mL, 6.5 mmol) for 15 min, and the resulting solution was stirred at room temperature overnight. To this solution were added the ester (step 2) (2.0 g, 5 mmol) dissolved in tetrahydrofuran (25 ml), Pd (dppf) Cl. CH2Cl2(0.133 g, 5 mmol%), aqueous potassium phosphate (3.5 ml, 7.1 mmol). The reaction was heated to 60 ℃ for 4 hours. The reaction was cooled to room temperature, poured into water (150 ml) and extracted with ethyl acetate (2 × 150 ml). The combined organic layers were washed with aqueous sodium bicarbonate (2 × 50 ml), aqueous 3N hydrochloric acid (2 × 50 ml) and brine (2 × 50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was subjected to flash chromatography (silica gel, 2% ethyl acetate/hexane). The desired fractions were collected and mixed and the solvent was removed in vacuo to yield ethyl ester as an amber oil (600 mg, 56%). The ester has a suitable purity and can be used without further purification. ESLRMS M/z 329(M + H).
Step 4: process for preparation of ethyl 7-butyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
The ester from step 1 was chlorinated (91%) via a similar method as described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification.
1HNMR(DMSO-d6/400MHz)，7.88(s，1H)，7.60(s，1H)，7.02(s，1H)，5.92(q，1H，J＝7.1Hz)，2.62(m，2H)，1.49(m，2H)，1.25(m，2H)，0.866(t，3H，J＝7.3Hz).
Step 5: preparation of 7-butyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester (step 4) was hydrolyzed to form the title carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 333.0497(M-H, C)15H13ClF3O3Calculated 333.0500).1HNMR(DMSO-d6/400MHz)，13.13(s，1H)，7.79(s，1H)，7.56(s，1H)，7.00(s，1H)，5.89(q，1H，J＝7.1Hz)，2.62(t，2H，J＝7.5Hz)，1.50(m，2H)，1.30(m，2H)，0.860(t，3H，J＝7.3Hz).
Example 9b
6-chloro-7- (3, 3-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7- (3, 3-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
To a solution of 9-BBN in tetrahydrofuran (6.53 mL, 6.5 mmol) was added neohexene, and the resulting solution was stirred at room temperature overnight. To this solution was added the ester of step 2 of example 9a (2.0 g, 5 mmol), Pd (dppf) Cl. CH in tetrahydrofuran (25 ml)2Cl2(0.133 g, 5 mmol%), aqueous potassium phosphate (3.5 ml, 7.1 mmol). The reaction was heated to 60 ℃ for 4 hours. Work-up and purification of the reaction was carried out according to example 9a, step 1 to give ethyl ester as amber oil (720 mg, 62%). The ester has a suitable purity and can be used without further purification. ESLRMSm/z 357(M + H).
Step 2: ethyl 6-chloro-7- (3,3-dimethylbutyl) -2- (trifluoromethyl) -2H-color Preparation of alkene-3-carboxylic acid esters
The ester (step 1) was chlorinated (87%) via a similar method as described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification. ESLRMSm/z 376(M + H).
Step 3: 6-chloro-7- (3, 3-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
The ester (step 2) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 361.0801(M-H, C)17H17ClF3O3Calculated 361.1813).1HNMR(DMSO-d6/400MHz)13.23(brs，1H)，7.80(s，1H)，7.55(s，1H)，7.01(s，1H)，5.89(q，1H，J＝7.1Hz)，3.30(m，2H)，2.56-2.60(m，2H)，1.31-1.37(m，2H)，0.91(s，9H).
Example 9c
6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of ethyl 7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
This compound was prepared and purified by analogous methods to those described in step 3, example 9a, substituting with the appropriate isobutylene to give the ethyl ester as a amber oil (720 mg, 58%). The ester has a suitable purity and can be used without further purification. EILRMSm/z 328(M +).
Step 2: ethyl 6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
The ester (step 1) was chlorinated (92%) via a similar method as described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification. ESLRMSm/z 363(M + H).1HNMR(DMSO-d6/400MHz)7.88(s，1H)，7.61(s，1H)，5.96(q，1H，J＝7.1Hz)，4.18-4.27(m，2H)，2.51-2.53(d，2H，J＝7.2Hz)，1.84-1.91(m，2H)，1.240(t，1H，J＝7.1Hz)，0.842(m，6H).
Step 3: preparation of 6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester (step 2) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 333.0496(M-H, C)15H13ClF3O3Calculated 333.0500).1HNMR(DMSO-d6/400MHz)13.31(brs，1H)，7.81(s，1H)，7.5(s，1H)，6.97(s，1H)，5.89(q，1H，J＝7.1Hz)，2.51(d，2H，J＝6.7Hz)，1.85-1.89(m，1H)，0.843(m，6H).
Example 9d
(2S) -6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The racemic mixture of the compound prepared in step 3 of example 9c was resolved using a manual chromatography using a kewsel (chiralel) OJ column and eluted with ethanol/heptane/TFA of 5/95/0.1, with the first peak detected at 254nm with a retention time of 6.60 minutes. ESHRMS M/z 333.0496(M-H, C)15H13ClF3O3Calculated 333.0500). 1HNMR(DMSO-d6/400MHz)13.31(brs，1H)，7.81(s，1H)，7.5(s，1H)，6.97(s，1H)，5.89(q，1H，J＝7.1Hz)，2.51(d，2H，J＝6.7Hz)，1.85-1.89(m，1H)，0.843(m，6H).
Example 9e
(2R) -6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The racemic mixture of the compound prepared in step 3 of example 9c was resolved using a chiral separation using a kewsel (chiralel) OJ column and elution with ethanol/heptane/TFA 5/95/0.1, with a second peak detected at 254nm with a retention time of 9.77 minutes. ESHRMS M/z 333.0496(M-H, C)15H13ClF3O3Calculated 333.0500).
1HNMR(DMSO-d6/400MHz)13.31(brs，1H)，7.81(s，1H)，7.5(s，1H)，6.97(s，1H)，5.89(q，1H，J＝7.1Hz)，2.51(d，2H，J＝6.7Hz)，1.85-1.89(m，1H)，0.843(m，6H).
Example 9f
6-chloro-7-isopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 2-hydroxy-4-isopropylbenzaldehyde
To a cooled solution of commercially available 3-isopropylphenol (5 g, 36.7 mmol) in acetonitrile was added magnesium chloride (5.24 g, 55 mmol) in portions while maintaining the temperature below 10 ℃ C, followed by 15 ℃ exotherm using paraformaldehyde (7.72 g, 257 mmol) and TEA (20.47 ml, 146 mol). The solution was heated to 72 ℃ for 2 hours. The reaction was cooled to room temperature and poured into saturated aqueous ammonium chloride (200 ml) and extracted with ethyl acetate (2 × 50 ml). The combined organic layers were washed with aqueous sodium bicarbonate (2 × 50 ml), aqueous 1N hydrochloric acid (2 × 50 ml) and brine (2 × 50 ml), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The crude product was subjected to flash chromatography (silica gel, 5% ethyl acetate/hexane). The desired fractions were collected and mixed and the solvent was removed in vacuo to yield ethyl ester as a yellow solid (4.6 g, 76%). The salicylaldehyde has a suitable purity and can be used without further purification. EILRMS M/z 164(M +).
Step 2: preparation of ethyl 7-isopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Salicylaldehyde (step 1) was condensed with ethyl 4, 4, 4-trifluorocrotonate via a similar procedure as step 1 of example 4a to yield ethyl acetate (8.21 g, 84%) as a yellow solid. The ester has a suitable purity and can be used without further purification. ESLRMS M/z315(M + H).
Step 3: ethyl 6-chloro-7-isopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
The ester (step 2) was chlorinated (82%) via a similar method as described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification. ESLRMS M/z349(M + H).
Step 4: process for preparation of (2R) -6-chloro-7-isopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
The ester (step 3) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 319.0309(M-H, C)14H11ClF3O3Calculated 319.0343). 1HNMR(DMSO-d6/400MHz)13.26(brs，1H)，7.81(s，1H)，7.57(s，1H)，7.01(s，1H)，5.90(q，1H，J＝7.1Hz)，3.29(m，1H)，1.14-1.17(m，6H).
Example 9g
4, 6-dichloro-7-isopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 4, 6-dichloro-7-isopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acid esters
The ester (example 9f step 3) was chlorinated (29%) via a similar method to that described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification. ESLRMS M/z 383(M + H).
Step 2: preparation of 4, 6-dichloro-7-isopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Prepare for
The ester (step 1) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 352.9934(M-H, C)14H10Cl2F3O3Calculated 352.9954).1HNMR(DMSO-d6/400MHz)14.1(brs，1H)，7.64(s，1H)，7.11(s，1H)，6.15(q，1H，J＝7.1Hz)，3.27(m，1H)，1.175(m，6H).
Example 9h
6-chloro-7-propyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7-propyl radicalPreparation of (E) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid ester
This compound was prepared and purified by analogous methods to those described in example 9a, step 3, substituting the appropriate propylene to yield ethyl ester as a amber oil (1.24 g, 78%). The ester has a suitable purity and can be used without further purification. ESLRMS M/z315(M + H).
Step 2: process for preparation of ethyl 6-chloro-7-propyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
The ester (step 1) was chlorinated via a similar method as described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification. ESLRMS M/z 349(M + H).
Step 3: preparation of 6-chloro-7-propyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester (step 2) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 319.0326(M-H, C) 14H11ClF3O3Calculated 319.0343).1HNMR(DMSO-d6/400MHz)13.35(brs，1H)，7.80(s，1H)，7.56(s，1H)，7.00(s，1H)，5.89(q，1H，J＝7.1Hz)，2.59(m，2H)，1.52(m，2H)，0.873(m，3H).
Example 9i
6-chloro-7- (2-cyclohexylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7- (2-cyclohexylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acid esters
This compound was prepared and purified by analogous methods to those described in example 9a, step 1, substituting the appropriate propylene to yield the ethyl ester as a tan solid (1.21 g, 63%). The ester has a suitable purity and can be used without further purification. ESLRMS M/z383(M + H).
Step 2: ethyl 6-chloro-7- (2-cyclohexylethyl) -2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid esters
The ester (step 1) was chlorinated (85%) via a similar method as described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification. ESLRMS M/z417(M + H).
Step 3: 6-chloro-7- (2-cyclohexylethyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
The ester (step 2) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 387.0969(M-H, C)19H19ClF3O3Calculated 387.0996).
1HNMR(DMSO-d6/400MHz)13.20(brs 1H)，7.77(s，1H)，7.54(s，1H)，6.98(s，1H)，5.88(q，1H，J＝7.1Hz)，2.61(m，2H)，1.55-1.70(m，5H)，1.38(m，2H)，1.09-1.20(m，4H)，0.860-0.917(m，2H).
Example 9j
6-chloro-7- [2- (4-chlorophenyl) ethyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7- [2- (4-chlorophenyl) ethyl]-2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid esters
This compound was prepared and purified by analogous methods to those described in example 9a, step 1, substituting with the appropriate p-chlorostyrene to yield the ethyl ester as a yellow solid (1.15 g, 55%). The ester has a suitable purity and can be used without further purification. ESLRMS M/z 397(M + H).
Step 2: ethyl 6-chloro-7- [2- (4-chlorophenyl) ethyl]-2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
The ester (step 1) was chlorinated (82%) via a similar method as described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification. ESLRMS M/z431(M + H).
Step 3: 6-chloro-7- [2- (4-chlorophenyl) ethyl]-2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid
The ester (step 2) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 415.0110(M-H, C)19H12Cl2F3O3Calculated 415.0098). 1HNMR(DMSO-d6/400MHz)13.25(brs，1H)，7.82(s，1H)，7.61(s，1H)，7.33(d，2H，J＝8.3)，7.20(d，2H，J＝8.3Hz)，7.03(s，1H)，5.91(q，1H，J＝7.1Hz)，4.00(s，2H).
Example 9k
7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of ethyl 7-benzyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Beta-benzyl 9-BBN (20 mL, 10 mmol) in tetrahydrofuran (20Ml) of the solution of the ester of step 3 of example 9a, Pd (dppf) Cl. CH in tetrahydrofuran (25 ml) was added2Cl2(0.133 g, 5 mmol%), aqueous potassium phosphate (3.5 ml, 7.1 mmol). The reaction was heated to 60 ℃ for 4 hours. Work-up and purification of the reaction was carried out according to example 9a, step 1 to yield ethyl ester as a pale yellow solid (1.4 g, 76%). The ester has a suitable purity and can be used without further purification. ESLRMS M/z 363(M + H).
Step 2: process for preparation of ethyl 7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
The ester (step 1) was chlorinated (80%) via a similar method as described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification. ESLRMS M/z397(M + H).
Step 3: preparation of 7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester (step 2) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 367.0343(M-H, C) 18H11ClF3O3Calculated 367.0329).1HNMR(DMSO-d6/400MHz)13.34(brs，1H)，7.81(s，1H)，7.61(s，1H)，7.25-7.29(m，2H)，7.17-7.19(m，3H)，6.99(s，1H)，5.89(q，1H，J＝7.1Hz)，4.00(s，2H).
Example 9l
(2R) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Chiral resolution of the compound prepared in step 3 of example 9k using the same procedure as in step 1 of example 9dThe racemic mixture was the second peak with a retention time of 5.76 minutes. ESHRMS M/z 367.0343(M-H, C)18H11ClF3O3Calculated 367.0329).1HNMR(DMSO-d6/400MHz)13.34(brs，1H)，7.81(s，1H)，7.61(s，1H)，7.25-7.29(m，2H)，7.17-7.19(m，3H)，6.99(s，1H)，5.89(q，1H，J＝7.1Hz)，4.00(s，2H).[□]25 589＝+2.0 inMeOH.
Example 9m
(2S) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The racemic mixture of the compound prepared in example 9k, step 3 was resolved chirally as a first peak with a retention time of 4.27 minutes using the same method as example 9d, step 1. ESHRMS M/z 367.0343(M-H, C)18H11ClF3O3Calculated 367.0329).1HNMR(DMSO-d6/400MHz)13.34(brs，1H)，7.81(s，1H)，7.61(s，1H)，7.25-7.29(m，2H)，7.17-7.19(m，3H)，6.99(s，1H)，5.89(q，1H，J＝7.1Hz)，4.00(s，2H).[a]25 589＝-1.4 degrees(in MeOH).
Example 9n
6-chloro-7- (2-chlorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1 : ethyl 7- (2-chlorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
To a solution of the ester of step 2 of example 9a (2.0 g, 5 mmol) in tetrahydrofuran (25 ml) was added Pd (dba)2(58 mg, 2 mmol%), trifuranylphosphine (47 mg, 4 mmol%), followed by 2-chlorobenzylzinc chloride via syringe. The reaction was heated to 65 ℃ for 6 hours. Work-up and purification of the reaction was carried out according to example 9a, step 1 to yield ethyl ester as a yellow solid (1.4 g, 70%). The ester has a suitable purity and can be used without further purification. ESLRMS M/z 397(M + H).
Step 2: ethyl 6-chloro-7- (2-chlorobenzyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
The ester (step 1) was chlorinated (78%) via a similar method as described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification. ESLRMS M/z431(M + H).
1HNMR(DMSO-d6/400MHz)1.98(brs，1H)，7.91(s，1H)，7.70(s，1H)，7.47(m，1H)，7.29(m，2H)，7.11(m，1H)，6.68(s，！H)，5.95(q，1H，J＝7.1Hz)，4.23(m，2H)，4.11(d，2H，J＝6.3Hz)，1.24(t，3H，J＝7.1Hz).
Step 3: process for preparing 6-chloro-7- (2-chlorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
The ester (step 2) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 400.9984(M-H, C) 18H10Cl2F3O3Calculated 400.9954).1HNMR(DMSO-d6/400MHz)13.34(brs，1H)，7.79(s，1H)，7.64(s，1H)，7.27(m，2H)，7.11(m，1H)，6.66(s，1H)，5.88(q，1H，J＝7.1Hz)，4.1(d，2H，J＝6.3Hz).
Example 9o
6-chloro-7- (4-chlorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7- (4-chlorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
This compound was prepared and purified by analogy to the methods described in example 9n, step 1, substitution with the appropriate 4-chlorobenzyl zinc chloride to yield ethyl ester as a yellow solid (1.4 g, 70%). The ester has a suitable purity and can be used without further purification. ESLRMS M/z 397(M + H) _ based on the total mass of cells
Step 2: ethyl 6-chloro-7- (4-chlorobenzyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
The ester (step 1) was chlorinated (81%) via a similar method as described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification. EILRMS M/z430(M +).
Step 3: process for preparing 6-chloro-7- (4-chlorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
The ester (step 2) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 400.9993(M-H, C)18H10Cl2F3O3Calculated 400.9954). 1HNMR(DMSO-d6/400MHz)13.21(brs，1H)，7.82(s，1H)，7.61(s，1H)，7.33(d，2H，J＝8.3Hz)，7.20(d，2H，J＝8.3Hz)，7.03(s，1H)，5.91(q，1H，J＝7.1Hz)，4.00(s，2H).
Example 9p
6-chloro-7- (4-chloro-2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of (4-chloro-2-methylbenzyl) (3-methoxyphenyl) methanone
To a cooled stirred solution of 3-methoxybenzoyl chloride (5.0 g, 29.3 mmol) in acetone/water (3: 1) was added 4-chloro-2-methylphenylboronic acid (5.0 g, 29.3 mmol), followed by palladium chloride (0.259 g, 5 mmol%) and sodium carbonate (23.87 ml, 47 mmol). The solution was allowed to stir at room temperature overnight. Work-up and purification of the reaction was carried out according to example 9a, step 1, to give the title compound (5.8 g, 76%) which was of suitable purity and was used without further purification. ESLRMS M/z 261.1(M + H).
Step 2: preparation of 3- (4-chloro-2-methylbenzyl) phenyl methyl ether
To a solution of methyl ether (5.8 g, 22 mmol) in dichloromethane (15 ml) from step 1 was added triethylsilane (14.2 ml, 88.9 mmol) followed by TFA (25.36 ml, 222 mmol). The solution was stirred at room temperature overnight. The reaction was quenched in saturated aqueous ammonium chloride and extracted with dichloromethane (2 × 150 ml). The combined organic layers were washed with aqueous sodium bicarbonate (2 × 50 ml), aqueous 3N hydrochloric acid (2 × 50 ml) and brine (2 × 50 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was subjected to flash chromatography (silica gel, 5% ethyl acetate/hexane). The desired fractions were collected and mixed, and the solvent was removed in vacuo to yield the title compound as a clear oil (4.5 g, 82%). The methyl ether has a suitable purity and can be used without further purification. ESLRMS M/z 274.1(M + H).
Step 3: preparation of 3- (4-chloro-2-methylbenzyl) phenol
To a cooled (-20 ℃) stirred solution of methyl ether (3.01 g, 12 mmol) from step 2 was added 1M boron tribromide (121.99 ml, 121 mmol) in dichloromethane. The reaction was cooled (-20 ℃) and methanol was added via syringe. The solvent was removed in vacuo and the crude product was flash chromatographed (silica gel, 10% ethyl acetate/hexanes). The desired fractions were collected and mixed, and the solvent was removed in vacuo to yield the title compound as a clear oil (2.18 g, 77%). The methyl ether has a suitable purity and can be used without further purification. EILRMS M/z 232(M +).
Step 4: preparation of 4- (4-chloro-2-methylbenzyl) -2-hydroxybenzaldehyde
Phenol (step 3) was formylated via a similar process to that described in step 1 of example 9 f. ESLRMS M/z 261.1(M + H).
Step 5: ethyl 7- (4-chloro-2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
The aldehyde (step 4) was condensed via a similar method as described in step 1 of example 4 a. The aldehyde has a suitable purity and can be used without further purification. ESHRMS M/z409.0862(M-H, C) 19H13ClF3O3Calculated 409.0813).
Step 6: ethyl 6-chloro-7- (4-chloro-2-methylbenzyl) -2- (trichloromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
The ester (step 5) was chlorinated (68%) via a similar method as described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification. ESLRMS M/z445.2(M + H).
And 7, a step: 6-chloro-7- (4-chloro-2-methylbenzyl) -2-(trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
The ester (step 6) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 415.0119(M-H, C)19H12Cl2F3O3Calculated 415.0110).1HNMR(DMSO-d6/400MHz)13.35(brs，1H)，7.81(s，1H)，7.65(s，1H)，7.27(s，1H)，7.17(d，1H，J＝10.4Hz)，6.9(d，1H，J＝10.4Hz)，6.65(s，1H)，5.88(q，1H，J＝7.1Hz)，3.96(m，2H)，2.17(s，3H).
Example 9q
6-fluoro-7- (4-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7- (4-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acid esters
This compound was prepared and purified by analogy to the methods described in example 9n, step 1, substitution with the appropriate 4-chloro-2-methylbenzylzinc chloride to give the ethyl ester as a yellow solid (2.95 g, 81%). The ester has a suitable purity and can be used without further purification. ESLRMS M/z 393.2(M + H).
Step 2: ethyl 6-chloro-7- (4-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid esters
The ester (step 1) was chlorinated (62%) via a similar method as described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification. ESLRMS M/z427(M + H).
Step 3: 6-chloro-7- (4-methoxybenzyl) -2- (2: (A)Trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
The ester (step 2) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 397.0452(M-H, C)19H13ClF3O4Calculated 397.0449).1HNMR(DMSO-d6/400MHz)13.16(brs，1H)，7.78(s，1H)，7.35(d，1H，J＝7.6Hz)，7.29(s，1H)，7.15(d，1H，J＝8.3Hz)，7.03(d，1H，J＝8.3Hz)，6.89(m，2H)，5.83(q，1H，J＝7.1Hz)，3.83(s，2H)，3.67(s，3H).
Example 9r
6-chloro-7- (3-chloro-4-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-7- (3-chloro-4-methoxybenzyl) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
The ester (example 9q step 2) was chlorinated (23%) via a similar method to that described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification. ESLRMS M/z 461(M + H).
Step 2: 6-chloro-7- (3-chloro-4-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid
The ester (step 1) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 431.0079(M-H, C)19H12Cl2F3O4Calculated 431.0059).1HNMR(DMSO-d6/400MHz)13.32(brs，1H)，7.81(s，1H)，7.61(s，1H)，7.39(s，1H)，7.24(d，1H，J＝2.0Hz)，7.12(d，1H，J＝2.0Hz)，7.10(d，1H，J＝2.0Hz)，7.04(t，1H，J＝8.0Hz)，5.86(q，1H，J＝7.1Hz)，3.94(s，2H)，3.78(s，3H).
Example 9s
6-chloro-7- (2, 4-dimethylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of (2, 4-dimethylbenzyl) (3-methoxyphenyl) methanone
The title compound (89%) was coupled via a method analogous to that described in example 9p, step 1. The ketone has a suitable purity and can be used without further purification. ESLRMS M/z241(M + H).
Step 2: preparation of 3- (2, 4-dimethylbenzyl) phenyl methyl ether
The ketone (step 1) was reduced (92%) via a similar method to that described in example 9p, step 2. The methyl ether has a suitable purity and can be used without further purification. EILRMS M/z 226(M +).
Step 3: preparation of 3- (2, 4-dimethylbenzyl) phenol
The methyl ether (step 2) was deprotected (98%) via a similar procedure as described in example 9p, step 3. The phenol has a suitable purity and can be used without further purification. EILRMS M/z 212(M +).
Step 4: preparation of 4- (2, 4-dimethylbenzyl) -2-hydroxybenzaldehyde
Phenol (step 3) was formylated (78%) via a similar procedure as described in step 1 of example 9 f. The aldehyde has a suitable purity and can be used without further purification. ESLRMSm/z 241(M + H).
Step 5: ethyl 7- (2, 4-dimethylbenzyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
The aldehyde (step 4) was condensed via a similar method as described via step 1 of example 4 a. The ester has a suitable purity and can be used without further purification. ESLRMS M/z 391(M + H).
Step 6: ethyl 6-chloro-7- (2, 4-dimethylbenzyl) -2- (trifluoromethyl) -2H-color Preparation of alkene-3-carboxylic acid esters
The ester (step 5) was chlorinated (83%) via a similar method as described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification. ESLRMS M/z425(M + H).
And 7, a step: 6-chloro-7- (2, 4-dimethylbenzyl) -2- (trifluoromethyl) -2H-chromagen diluent Preparation of (E) -3-carboxylic acid
The ester (step 6) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 395.0676(M-H, C)20H15ClF3O3Calculated 395.0656). 1HNMR(DMSO-d6/400MHz)13.25(s，1H)，7.81(s，1H)，7.64(s，1H)，7.00(s，1H)，6.92(d，1H，J＝8.0Hz)，6.81(d，1H，J＝7.7Hz)，6.53(s，1H)，5.86(q，1H，J＝7.1Hz)，3.91(s，2H)，2.22(s，3H)，2.10(s，3H).
Example 9t
6-chloro-7- (5-chloro-2, 4-dimethylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-7- (5-chloro-2, 4-dimethylbenzyl) -2- (trifluoromethyl) -2H-chromenePreparation of (E) -3-carboxylic acid esters
The ester (example 9s, step 4) was chlorinated (18%) via a similar method to that described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification. ESLRMS M/z 459(M + H).
Step 2: 6-chloro-7- (5-chloro-2, 4-dimethylbenzyl) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid
The ester (step 1) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 429.0290(M-H, C)20H14Cl2F3O4Calculated 429.0267).1HNMR(DMSO-d6/400MHz)，13.25(s，1H)，7.82(s，1H)，7.66(s，1H)，7.17(s，1H)，6.91(s，1H)，6.64(s，1H)，5.89(q，1H，J＝7.1Hz)，3.93(s，2H)，2.23(s，3H)，2.10(s，3H).
Example 9u
6-chloro-7- (3-chloro-2, 4-dimethylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-7- (3-chloro-2, 4-dimethylbenzyl) -2- (trifluoromethyl) Preparation of (E) -2H-chromene-3-carboxylic acid esters
The ester (example 9s, step 4) was chlorinated (23%) via a similar method to that described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification. ESLRMS M/z 459(M + H).
Step 2: 6-chloro-7- (3-chloro-2, 4-dimethylbenzyl) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid
The ester (step 1) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 429.0259(M-H, C)20H14Cl2F3O4Calculated 429.0267).
1HNMR(DMSO-d6/400MHz)13.39(sbrs，1H)，7.82(s，1H)，7.66(s，1H)，7.17(s，1H)，6.91(s，1H)，6.94(s，1H)，5.88(q，1H，J＝7.1Hz)，3.98(s，2H)，2.23(s，1H)，2.10(s，1H).
Example 9v
(2R) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid compound with (1R) -phenylethylamine (1: 1)
(2R) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from example 91 (50 mg, 0.135 mmol) was dissolved in 1% ethyl acetate/hexane (2 mL). (R) - (+) - α -methylbenzylamine (0.017 mL, 0.135 mmol) was added and the solution was allowed to stand at room temperature for 1 week until crystallization occurred. The absolute configuration was determined by small molecule X-ray diffraction.
Example 9w
7- (3-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7- (3-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acid esters
This compound was prepared and purified by analogy to the methods described in example 9n, step 1, substitution with the appropriate 3-methoxybenzylzinc chloride to yield ethyl ester as a yellow solid (2.95 g, 81%). The ester has a suitable purity and can be used without further purification. ESLRMS M/z 393(M + H).
Step 2: process for preparation of 7- (3-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
The ester (step 1) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 363.0827(M-H, C)19H14F3O4Calculated 363.0839).
1HNMR(DMSO-d6/400MHz)13.17(brs，1H)，7.78(s，1H)，7.35(d，1H，J＝7.7Hz)，7.17(t，1H，J＝7.9Hz)，6.89(m，2H)，6.74(m，3H)，(q，1H，J＝7.1Hz)，3.86(s，2H)，3.68(s，3H).
Example 9x
6-chloro-7- (4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7- (4-methylbenzoyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
In a silver vessel (sterling bombb), ethyl 7-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate (3.0 g, 7.53 mmol), 4-methylphenylboronic acid (1.11 g, 8.26 mmol), potassium carbonate (3.12 g, 22.59 mmol) and PdCl from step 2 of example 9a were charged2(PPh3)2(159 mg, 0.225 mmol) was mixed in dioxane (30 ml). Carbon monoxide was passed to 40 psi. The reaction was heated to 80 ℃ for 5 hours. After filtration, the reaction was quenched with ammonium chloride and extracted with ethyl acetate. Medicine for treating acute respiratory syndromeThe organic layer was washed and dried over magnesium sulfate. The filtrate was evaporated and dried in vacuo to afford a yellow solid (1.2 g, 41%). LCMS M/z 391.10(M + H).
1H NMR(CDCl3/400MHz)7.75(s，1H)，7.69(d，2H，J＝8.0Hz)，7.39(d，1H，J＝8.0Hz)，7.36(s，1H)，7.31(d，1H，J＝8.0Hz)，7.28(d，2H，J＝8.0Hz)，7.25(8，1H)，5.78(q，1H，J＝6Hz)，4.33(m，2H)，2.43(s，3H)，1.35(t，3H，J＝7.2Hz).
Step 2: ethyl 7- (4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
The ester from step 1 was dissolved in TFA (18 ml). Triethylsilane was added dropwise at room temperature. The reaction was stirred at room temperature overnight. The reaction was quenched with sodium bicarbonate and extracted with diethyl ether. The organic layer was dried over magnesium sulfate. The filtrate was concentrated to give a yellow oil which was purified by Biotage chromatography eluting with 3-5% ethyl acetate in hexane to give a clear oil. LCMS M/z 377.15(M + H).
1H NMR(CDCl3/400MHz)7.68(s，1H)，7.08(m，4H)，6.79(d，1H，J＝6.4Hz)，5.68(q，1H，J＝7.2Hz)，4.29(m，2H)，3.89(s，2H)，2.31(s，3H)，1.35(t，3H，J＝7.2Hz).
Step 3: ethyl 6-chloro-7- (4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
To a solution of the ester from step 2 (0.95 g, 2.53 mmol) in acetic acid (30 ml) was added sodium acetate (1.03 g, 12.6 mmol). Chlorine gas was bubbled through the solution until a precipitate was observed. The mixture was stirred for 2 hours. After chlorine gas was blown off, zinc powder (5 equivalents) was added to the mixture, and stirred for 30 minutes. The zinc salt was removed and the filtrate was evaporated to give a yellow oil (1.0 g, 97%): monochloro C21H18O3F3LCMS for Cl was 409.10(M + H),dichloro C21H17O3F3Cl2The LCMS of (A) is 443.05(M + H). The ester has a suitable purity and can be used without further purification.
Step 4: 6-chloro-7- (4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
The ester from step 3 (1.0 g, 2.44 mmol) was dissolved in 4.0 ml methanol and 4.0 ml tetrahydrofuran. To the above solution was added sodium hydroxide (2.5N) (2.4 ml, 6.1 mmol) and stirred at 50 ℃ for 6 hours. The crude product was purified by RPHPLC eluted with 60% acetonitrile in water to afford an off-white solid (0.324 g, 35%): ESHRMSm/z 391.0474(M-H, C)19H13F3O3Cl calculated 381.0500).
1H NMR(acetone-d6/400MHz)7.87(s，1H)，7.56(s，1H)，7.13(m 4H)，6.91(s，1H)，5.80(q，1H，J＝7.0Hz)，4.07(d，1H，J＝14.7Hz)，4.01(d，1H，J＝14.7Hz)，2.27(s，3H).
Example 9y
6-chloro-7- (3-chloro-4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using the same procedure as step 4 of example 9p, 6-chloro-7- (3-chloro-4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared: ESHRMS M/z 415.0087(M-H, C)19H12O3F3Cl2Calculated 415.0110).
1H NMR(acetone-d6/400MHz)7.87(s，1H)，7.57(s，1H)，7.28(m 2H)，7.13(m，1H)，6.99(s，1H)，5.83(q，1H，J＝7.0Hz)，4.08(m，2H)，2.30(s，3H).
Example 9z
6-chloro-7- (3, 4-difluorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7- (3, 4-difluorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acid esters
Pd(dba)2(57.5 mg, 0.100 mmol) and a solution of trifuranylphosphine (46.7 mg, 0.21 mmol) in dry tetrahydrofuran (10.0 ml) were stirred at room temperature for 20 minutes and then cooled to 0 ℃. Ethyl 7-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate (2.00 g, 5.02 mmol), prepared as in step 2 of example 9a, was added as a solid, followed by dropwise addition of a solution of 3, 4-difluorobenzylzinc bromide in anhydrous tetrahydrofuran (20.0 ml-0.5M, 0.100 mmol) over a period of 5 minutes. The mixture was stirred at 0 ℃ C for 0.5 h, then at room temperature for 24 h, then poured into saturated ammonium chloride (100 ml) and extracted with ethyl acetate (2X 200 ml). The combined extracts were washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give 3.45 g of an orange oil. The crude product was purified by silica chromatography (eluting with 92.5: 7.5 hexanes: ethyl acetate) to afford 1.81 g (91% yield) of the product as a yellow oil: ESHRMS M/z 398.0955(M +, C) 20H15F5O3Calculated 398.0941).
Step 2: ethyl 6-chloro-7- (3, 4-difluorobenzyl) -2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid esters
In a solution of the ester from step 1 (0.920 g, 2.31 mmol) in glacial acetic acid (50 ml), slowlyChlorine gas was added for 1 minute. After standing at room temperature for 25 minutes, the solvent was removed in vacuo and the residue was redissolved in glacial acetic acid (50 ml). Powdered zinc (0.250 g, 3.82 mmol) was added and the mixture was stirred for 20 minutes. The solids were removed by filtration and the filtrate was concentrated in vacuo to give a crystalline solid. The crude product was recrystallized from ethyl acetate-hexane to yield 0.95 g (95% yield) of colorless needles: ESHRMS M/z 432.0573(M +, C)20H14ClF5O3Calculated 432.0552).
Step 3: 6-chloro-7- (3, 4-difluorobenzyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
To a solution of the ester from step 2 (0.84 g, 1.94 mmol) in 7: 2: 1 tetrahydrofuran: ethanol: water was added lithium hydroxide hydrate (0.122 g, 2.91 mmol), the mixture was stirred at 50 ℃ for 75 minutes and the solvent was removed in vacuo. The residue was redissolved in water, filtered and acidified with 1N hydrochloric acid and the resulting solid filtered off, washed with water and dried in vacuo to yield 763 mg (97% yield) of the product as an off-white solid:
1H NMR(dmso-d6/300MHz)13.40(brs，1H)，7.80(s，1H)，7.62(s，1H)，7.24-7.39(m，2H)，7.00-7.05(m，2H)，5.92(q，1H，J＝7.3Hz)，4.01(s，2H)；ESHRMS m/z 403.0140(M-H，C18H9ClF5O3，Calc’d 403.0155).
Example 9aa
7- (3, 4-difluorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using an analogous method to that described in example 9z, step 3, using the ester from example 9z, step 1 as starting material, 7- (3, 4-difluorobenzyl) -2- (trifluorotetrayl) -2H-chromene-3-carboxylic acid was prepared as a yellow solid.
1H NMR(dmso-d6/300MHz)13.18(brs，1H)，7.28-7.80(m，3H)，7.06-7.10(m，1H)，6.91-6.93(m，2H)，5.85(q，1H，J＝7.3Hz)，3.91(s，1H)；ESHRMS m/z369.0545(M-H，C18H10F5O3，Calc’d 369.0516).
Example 9bb
7- (4-Fluorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7- (4-fluorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
Pd(dba)2(53.7 mg, 0.0934 mmol) and a solution of trifuranylphosphine (43.3 mg, 0.187 mmol) in dry tetrahydrofuran (8.0 ml) were stirred at room temperature for 5 minutes and then cooled to 0 ℃. Ethyl 7-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.86 g, 4.67 mmol), prepared as in step 2 of example 9a, was added as a solution in anhydrous tetrahydrofuran (7.0 ml) followed by a solution of 4-fluorobenzylzinc chloride in anhydrous tetrahydrofuran (14.0 ml-0.5M, 0.700 mmol). The mixture was allowed to warm to room temperature. After stirring for 17.5 hours, additional 4-fluorobenzylzinc chloride (10.0 ml-0.5M/THF, 0.500 mmol) was added at room temperature and stirring was continued for 45 minutes. Additional 4-fluorobenzylzinc chloride (5.0 ml-0.5M/THF, 0.250 mmol) was added at room temperature and stirring was continued until the starting material disappeared. The mixture was then poured into saturated ammonium chloride (100 ml) and extracted with ethyl acetate (2 × 200 ml). The combined extracts were washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give 2.41 g of a red-brown oil. Crude product recovery Purification by silica chromatography (9: 1 hexanes: ethyl acetate elution) gave 1.58 g (89% yield) of the product as a yellow oil: ESHRMS M/z 380.0999(M +, C)20H16F4O3Calculated 380.1036).
Step 2: preparation of 7- (4-fluorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester of step 1 was hydrolyzed via a similar method as described in example 9x step 3 to obtain the product as a white crystalline solid.
1H NMR(dmso-d6/300MHz)13.18(brs，1H)，7.80(s，1H)，7.37(d，1H，J＝7.7Hz)，7.24-7.29(m，2H)，7.07-7.14(m，2H)，6.88-6.91(m，2H)，5.85(q，1H，J＝7.3Hz)，3.91(s，1H)；ESHRMS m/z 351.0623(M-H，C18H11F4O3，Calc’d 351.0639).
Example 10
7-benzoyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 7-benzoyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The acid from example 9k, step 3 (100 mg, 0.271 mmol) was dissolved in acetic acid (glacial acetic acid) (10 ml). Chromic anhydride (5 equivalents) was added in the solid state. The reaction was heated to 90 ℃ for 1 hour, cooled to 0 ℃ and diluted with water (100 ml), extracted with ethyl acetate (2 × 50 ml), the organic layers were mixed and washed sequentially with brine (2 × 25 ml) and sodium bicarbonate (2 × 50 ml). The organics were dried over sodium sulfate, filtered and concentrated under vacuumConcentrating. The solid was treated by reverse phase chromatography eluting with acetonitrile/water (gradient 5 to 95 acetonitrile). The desired fractions were collected, mixed and concentrated in vacuo to afford the benzyl ketone (22 mg, 21%): ESHRMS M/z 381.0138(M-H, C) 18H19ClF3O4Calculated 381.0136).
Example 11
7- (pyridin-3 ylcarbonyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7- (pyridin-3-ylcarbonyl) -2- (trifluoromethyl) -2H-chromen-3- Preparation of carboxylic acid esters
Ethyl 7-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.0 g, 2.51 mmol), pyridin-3-ylboronic acid (0.34 g, 2.76 mmol), potassium carbonate (1.04 g, 7.53 mmol) and PdCl from step 2 of example 9a were charged in a reliable high pressure vessel2(PPh3)2(53 mg, 0.075 mmol) was mixed in dioxane (10 ml). The reactor was charged with carbon monoxide (40 psi). The reaction was heated to 80 ℃ for 6 hours and then at room temperature overnight. After filtration, the reaction was quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was washed and dried over magnesium sulfate. The filtrate was evaporated and dried in vacuo to give the crude product, which was purified by RPHPLC eluting with 50 to 95% acetonitrile in water to give a yellow solid (39 mg, 4%). LCMS M/z 378.10(M + H).
1H NMR(CDCl3/400MHz)9.08(s，1H)，8.97(d，1H，J＝5.2Hz)，8.48(d，1H，J＝8.0Hz)，7.81(dd，1H，J＝7.6，5.2Hz)，7.75(s，1H)，7.40(m，3H)，5.76(q，1H，J＝6Hz)，4.34(m，2H)，1.36(t，3H，J＝7.2Hz).
Step 2: process for preparation of 7- (pyridin-3-ylcarbonyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
The ester from step 1 (38 mg, 0.08 mmol) was dissolved in 0.5 ml methanol and 0.5 ml tetrahydrofuran. To the above solution was added sodium hydroxide (2.5N) (0.2 ml, 0.5 mmol) and stirred at 50 ℃ for 4 hours. The crude product was purified by RPHPLC eluted with 45% acetonitrile in water to afford a white solid (15 mg, 41%): LCMS M/z350.05(M + H). 1H NMR(DMSO-d6/400MHz)8.87(s，1H)，8.83(d，1H，J＝6.8Hz)，8.11(d，1H，J＝10.4Hz)，7.94(s，1H)，7.69(d，1H，J＝14Hz)，7.60(m，1H)，7.42(d，1H，J＝10.4Hz)，7.34(s，1H)，6.03(q，1H，J＝9.6Hz).
Example 12
7- (2-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7- (2-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
7-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate (2.0 g, 5.02 mmol), 2-furandicarboxyboronic acid (0.62 g, 5.52 mmol), potassium carbonate (2.08 g, 15.06 mmol) and PdCl from step 2, Exactly 9a, were charged in a reliable high pressure vessel2(PPh3)2(106 mg, 0.15 mmol) was mixed in dioxane (20 ml). Carbon monoxide was passed to 40 psi. The reaction was heated to 80 ℃ for 12 hours, after filtration, quenched with ammonium chloride and extracted with ethyl acetate. The organic layer was washed and dried over magnesium sulfate. The filtrate was evaporated and dried in vacuo to give the crude product, which was washed with 10-20% ethyl acetonitrile in hexaneThe extracted Biotage chromatography was purified to yield a yellow solid (350 mg, 21%). LCMS M/z 339.05(M + H).1HNMR(CDCl3/300MHz)7.74(s，1H)，7.51(s，1H)，8.97(m，3H)，6.76(d，1H，J＝3.3Hz)，6.51(m，1H)，5.73(q，1H，J＝6.9Hz)，4.34(m，2H)，1.36(t，3H，J＝7.2Hz).
Step 2: preparation of 7- (2-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from step 1 (340 mg, 1.0 mmol) was dissolved in 2.5 ml methanol and 2.5 ml tetrahydrofuran. To the above solution was added sodium hydroxide (2.5N) (1.0 ml, 2.5 mmol) and stirred at 50 ℃ for 4 hours. The crude product was purified by RPHPLC eluted with 45% acetonitrile in water to afford a white solid (293 mg, 95%): ESHRMSm/z 309.0320(M-H, C) 15H8F4C3Calculated N is 309.0369).
1H NMR(DMSO-d6/400MHz)7.88(s，1H)，7.69(d，1H，J＝1.6Hz)，7.50(d，1H，J＝8.0Hz)，7.44(dd，1H，J＝8.0，1.3Hz)，7.34(s，1H)，7.05(d，1H，J＝2.4Hz)，6.59(m，1H)，7.34(s，1H)，5.82(q，1H，J＝7.2Hz).
Example 13
7-benzyl-5, 6-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7-benzyl-5, 6-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
The ester (example 9k, step 2) was chlorinated (18%) via a method analogous to that described in example 4b, step 1. The ester has a suitable purity and can be used without further purification. ESLRMS M/z 431(M + H).
Step 2: preparation of 7-benzyl-5, 6-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester (step 1) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESHRMS M/z 400.9947(M-H, C)18H10Cl2F3O3Calculated 400.9954).
1HNMR(DMSO-d6/400MHz)13.12(brs 1H)，7.67(s，1H)，7.25(m，2H)，7.18(m，3H)，7.09(s，1H)，6.14(q，1H，J＝7.1Hz)，4.04(s，2H).
Example 14a
7-benzyl-6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 3-benzoyl-2-methylphenyl acetate
A mixture of 3- (chlorocarbonyl) -2-methylphenyl acetate (10.0 g, 47.0 mmol), palladium chloride (83.4 mg, 0.470 mmol), sodium carbonate (8.13 g, 76.77 mmol) and phenylboronic acid (6.02 g, 49.4 mmol) in a 3: 1 acetone/water mixture was stirred at room temperature for 5 days. The acetone was removed in vacuo and the aqueous mixture was extracted with ethyl acetate (2 × 200 ml). The combined extracts were washed with brine (100 ml), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to afford 7.68 g (64% yield) of the product as a white crystalline solid. ESHRMS M/z 254.0939(M +, C) 16H14O3Calculated 254.0943).
Step 2: (3-hydroxy-2-methylbenzene)Preparation of phenyl ketone
A mixture of 3-benzoyl-2-methylphenyl acetate (6.85 g, 26.9 mmol) prepared in example 1 and potassium hydroxide (15.0 g, 267 mmol) in water (100ml) was stirred at room temperature for 18 hours. The aqueous mixture was then washed with ethyl ether (3 × 200 ml), cooled to 0 ℃, and acidified with concentrated hydrochloric acid. The resulting solid was filtered off, washed with water and dried in vacuo to yield 0.99 g (17% yield) of the product as an off-white crystalline solid. ESHRMS M/z 212.0829(M +, C)14H12O2Calculated 212.0837).
Step 3: preparation of 3-benzyl-2-methylphenol
A solution of (3-carboxy-2-methylphenyl) (phenyl) methanone prepared in step 2 (1.60 g, 7.54 mmol) in dry dichloromethane (70 ml) was cooled to 0 ℃. Triethylsilane (32.5 ml, 203 mmol) and TFA (52.3 ml, 679 mmol) were added in portions over a period of 3 days at 0 ℃, and the mixture was returned to reflux after each addition. After 3 days, the mixture was cooled, poured into saturated ammonium chloride (200 ml) and extracted with dichloromethane (3 × 200 ml). The combined extracts were washed with water (200 ml) and brine (100ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil. The crude product was purified by silica chromatography (95: 5 hexanes: ethyl acetate elution) to yield 1.19 g (80% yield) of the product as a pale yellow oil: ESHRMSm/z 198.1072(M +, C) 14H14O calculated 198.1045).
Step 4: preparation of 4-benzyl-2-hydroxy-3-methylbenzaldehyde
To a solution of 3-benzyl-2-methylphenol (1.06 g, 5.36 mmol) prepared in step 3 in anhydrous acetonitrile (25 ml) were added magnesium chloride (0.776 g, 8.04 mmol), TEA (2.80 ml, 20.1 mmol) and paraformaldehyde (1.09 g, 36.2 mmol), and the resulting mixture was driedWas refluxed for 3 hours under a nitrogen atmosphere. The mixture was then cooled, acidified with 1N hydrochloric acid and extracted with ethyl acetate (2 × 100 ml). The combined extracts were washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to afford 1.10 g (91% yield) of the product as a pale yellow oil: ESHRMSm/z 226.1008(M +, C)15H14O2Calculated 226.0994).
Step 5: ethyl 7-benzyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
A mixture of 4-benzyl-2-hydroxy-3-methylbenzaldehyde (1.07 g, 4.73 mmol), potassium carbonate (0.654 g, 4.73 mmol) and ethyl 4, 4, 4-trifluorocrotonate (484 μ l, 5.67 mmol) prepared as in step 4 in dry DMF (5.0 ml) was heated to 85 ℃ under a dry nitrogen atmosphere for 2.75 hours. The mixture was then cooled, poured into 1N hydrochloric acid (100 ml) and extracted with ethyl acetate (2 × 100 ml). The combined extracts were washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give 1.86 g of a yellow oil. The crude product was purified by silica chromatography (95: 5 hexanes: ethyl acetate elution) to yield 1.04 g (59% yield) of the product as a pale yellow oil. ESHRMS M/z 376.1310(M +, C) 21H19F3O3Calculated 376.1268).
Step 6: ethyl 7-benzyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
The ester prepared in step 5 was chlorinated via a method similar to that described in step 2 of example 9z to obtain the product as a pale yellow crystalline solid. ESHRMS M/z 410.0928(M +, C)15H14O2Calculated 410.0897).
And 7, a step: process for preparation of 7-benzyl-6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
The ester prepared in step 6 was hydrolyzed via a method similar to that described in step 3 of example 9z to obtain a white solid. Recrystallization from isopropanol-ethanol-dichloromethane-hexane gave the product as a light yellow solid. ESHRMS M/z 381.0545(M-H, C)19H13Cl2F3O3Calculated 381.0500).
1H NMR(dmso-d6/300MHz)13.35(brs，1H)，7.84(s，1H)，7.57(s，1H)，7.14-7.28(m，3H)，7.02-7.04(m，2H)，5.96(q，1H，J＝7.3Hz)，4.17(m，2H)，2.10(s，3H).
Example 14b
7-benzyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ethyl 7-benzyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate prepared in step 5 of example 14a was hydrolyzed via a method analogous to that described in step 2 of example 18a to give the product as an off-white solid. ESHRMS M/z 347.0879(M-H, C)19H14F3O2Calculated 347.0890). 1H NMR(dmso-d6/300MHz)13.15(brs，1H)，7.80(s，1H)，7.10-7.29(m，6H)，6.85(d，1H，J＝7.7Hz)，5.89(q，1H，J＝7.3Hz)，3.97(s，2H)，2.07(s，3H).
Example 16
7- [ (butyrylamino) methyl group]-6-chloro-2- (trifluoromethyl) -2H-chromen-3-carboxylic acids
Step 1: preparation of ethyl 7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
A mixture of 2-hydroxy-4-methylbenzaldehyde (50.0 g, 0.367 mol) and ethyl 4, 4, 4-trifluorocrotonate (308.8 g, 1.84 mol) was dissolved in anhydrous DMF (10 ml) and triethylamine (20 ml). Warmed to 60 ℃ and treated with anhydrous potassium carbonate (81 g, 0.58 mol). The solution was maintained at 90 ℃ for 2 hours. LCMS analysis showed 60% conversion. Additional triethylamine (10 ml) was added to the mixture and the reaction was heated for an additional 2 hours. The reaction was cooled to room temperature and diluted with water. The solution was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give a brown oil which solidified upon standing. The crystalline solid was collected, washed with hexane and dried to give 40.2 g of an off-white crystalline solid. The mother liquor was concentrated to give the crude product, which was recrystallized from ethanol and water to give 48.5 g of an off-white solid (84% total yield) LCMS M/z 287.15(M + H).
1H NMR(CDCl3/300MHz)7.70(s，1H)，7.11(d，1H，J＝8.1Hz)，6.80(m，2H)，5.67(q，1H，J＝6Hz)，4.29(m，2H)，1.33(t，3H，J＝7.2Hz).
Step 2: process for preparation of ethyl 6-chloro-7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
Ethyl 6-chloro-7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate prepared using a procedure similar to that described in step 2, example 1 a. Recrystallization from ethanol gave a white crystalline compound (3.6 g, 80%): ESHRMS M/z 321.25(M + H)
1H NMR(CDCl3/400MHz)7.62(s，1H)，7.18(s，1H)，6.85(s，1H)，5.67(q，1H，J＝6.8Hz)，4.30(q，2H，J＝7.2Hz)，1.33(t，3H，J＝7.2Hz).
Step 3: ethyl 7- (bromomethyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acid esters
The ester from step 2 (2.0 g, 6.24 mmol) was dissolved in carbon tetrachloride (10 ml) and the solution was heated. Adding NBS and (BzO) to the heated solution2And the reaction was heated to reflux overnight, the reaction was cooled, and the solid was filtered off. The filtrate was washed with sodium bicarbonate and brine. The organic layer was dried over magnesium sulfate and evaporated to dryness. The crude product was purified by flash chromatography eluting with 10% ethyl acetate in hexane to afford a white solid (2.11 g, 85%): LCMS M/z 397.05(M + H).
1H NMR(acetone-d6/400MHz)7.62(s，1H)，7.25(s，1H)，7.06(s，1H)，5.66(q，1H，J＝7.0Hz)，4.47(m，2H)，4.31(m，2H)，1.34(m，3H).
Step 4: ethyl 7- (azidomethyl) -6-chloro-2- (trifluoromethyl) -2-H-chromene-3- Preparation of carboxylic acid esters
The ester from step 3 (2.2 g, 5.5 mmol) was dissolved with sodium azide (1.79 g, 27.5 mmol) in DMF (15 ml). The mixture was heated at 50 ℃ overnight under nitrogen. The solid was filtered off and washed with ethyl acetate. The organic layer was washed with water and dried over magnesium sulfate. After concentration, the ester is of suitable purity and can be used without further purification.
Step 5: ethyl 7- (aminomethyl) -6-chloro-2- (trifluoromethyl) -2-H-chromene-3- Preparation of carboxylic acid esters
The ester from step 4 (0.93 g, 2.57 mmol) was dissolved in ethanol (30 ml). After flushing with nitrogen, 10% palladium-carbon (0.11 g, 11 wt%) was added to the solution. The mixture was stirred under hydrogen atmosphere overnight. Pd was filtered off and the filtrate was concentrated to give a yellow oil (0.9 g, 100%): LCMS M/z 336.05(M + H). The ester has a suitable purity and can be used without further purification.
Step 6: ethyl 7- [ (butyrylamino) methyl group]-6-chloro-2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
The amine from step 4 (0.9 g, 2.68 mmol) was dissolved in DMF (10 ml) at room temperature and butyryl chloride (0.39 ml, 3.76 mmol) was added to the above solution. After triethylamine (0.52 ml, 7.08 mmol) was added to the solution, it was stirred at room temperature overnight. The reaction was quenched with ammonium chloride and the compound was extracted with ethyl acetate. The organic layer was washed with brine and dried over magnesium sulfate. The crude product was purified by Biotage silica flash chromatography eluting with 20 to 30% ethyl acetate in hexanes to give a yellow solid (0.70 g, 64.5%). LCMS M/z 406.10(M + H).
1H NMR(acetone-d6/300MHz)7.62(s，1H)，7.25(s，1H)，6.98(s，1H)，5.83(bs，1H)，5.68(q，1H，J＝6.6Hz)，4.47(m，2H)，4.31(m，2H)，2.20(m，2H)，1.68(m，2H)，1.32(m，3H)，0.97(m，3H).
And 7, a step: 7- [ (butyrylamino) methyl group]-6-chloro-2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid
Preparation of 7- [ (butyrylamino) methyl ] amino using a procedure analogous to the one described in step 3 of example 1a]-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid: ESHRMS M/z376.0598(M-H, C)16H14F3O4Calculated ClN 376.0558).1HNMR(acetone-d6/300MHz)7.85(s，1H)，7.66(bs，1H)，7.53(s，1H)，7.04(s，1H)，5.84(q，1H，J＝7.0Hz)，4.45(m，2H)，2.28(t，2H，J＝7.3Hz)1.67(m，2H)，0.931(t，3H，J＝7.3Hz).
Example 17a
8-chloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 3-chloro-2-hydroxy-5-methoxybenzaldehyde
To a solution of 2-chloro-4-methoxyphenol (25.0 g, 158 mmol) in anhydrous acetonitrile (625 ml) under nitrogen was added magnesium chloride (22.5 g, 236 mmol) and TEA (82.3 ml, 591 mmol). When magnesium chloride was added, the mixture warmed slightly. Paraformaldehyde (32.0 g, 1.06 mol) was then added and the mixture was refluxed for 4.5 hours and allowed to stand overnight at room temperature. Additional paraformaldehyde (14.2 g, 474 mmol) was added and the reflux was restored. After 4 hours, the mixture was cooled, additional paraformaldehyde (32.0 g, 1.06 mol) was added, and reflux was again carried out for 2.5 hours. The mixture was then cooled to room temperature, acidified with 1N hydrochloric acid and extracted with ethyl ether (4 × 500 ml). The combined extracts were washed with brine (250 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give 30.3 g of a yellow crystalline solid. Recrystallization from isopropanol-water gave 11.9 g (41% yield) of the product as a yellow crystalline solid.
1H NMR(dmso-d6/300MHz)10.47(brs，1H，10.11(s，1H)，7.36(d，1H，J＝3.0Hz)，7.19(d，1H，J＝3.0Hz)，3.73(s，3H).
Step 2: ethyl 8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
A mixture of 3-chloro-2-hydroxy-5-methoxybenzaldehyde (9.00 g, 48.2 mmol), potassium carbonate (6.67 g, 48.2 mmol) and ethyl 4, 4, 4-trifluorocrotonate (8.65 ml, 57.9 mmol) prepared as step 1 in dry DMF (20 ml) was stirred at room temperature for 30 min and heated to 85 ℃ for 3 h under a dry nitrogen atmosphere. Additional ethyl 4, 4, 4-trifluorocrotonate (3.00 ml, 20.1 mmol) was then added and the mixture was stirred at 85 ℃ overnight. The mixture was then cooled and poured into 1N hydrochloric acid (200 ml). After extraction with ethyl acetate (3 × 200 ml), the combined extracts were washed with 0.25N sodium hydroxide until the wash was basic, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was recrystallized from ethanol to yield 11.0 g (68% yield) of the product as a yellow crystalline solid.
1H NMR(dmso-d6/300MHz)7.92(s，1H)，7.18(d，1H，J＝2.8Hz)，7.13(d，1H，J＝2.8Hz)，6.05(q，1H，J＝7.3Hz)，4.21-4.29(m，2H)，3.73(s，3H)，1.26(t，3H，J＝7.1Hz).
Step 3: process for preparation of ethyl 8-chloro-6-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
A solution of ethyl 8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.41 g, 4.19 mmol) prepared in step 2 in dry dichloromethane (80 ml) was cooled to-78 ℃ and a solution of boron tribromide in dichloromethane (42 ml-1.0M, 42.0 mmol) was added dropwise to the above solution under dry nitrogen. The dry ice bath was removed and the mixture was allowed to warm to room temperature. After 3 hours, the mixture was cooled to-78 ℃ and quenched with the addition of anhydrous methanol (20 ml). The solvent was removed in vacuo and the residue was extracted with ethyl acetate (200 ml). The extract was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a light brown solid. Purification by silica chromatography (eluting with 98: 2 dichloromethane: methanol) gave 1.10 g (82% yield) of the product as a dark yellow solid: ESHRMS M/z 322.0215(M +, C1) 3H10ClF3O4Calculated value is 322.0220)。
1H NMR(dmso-d6/300MHz)9.79(s，1H)，7.89(s，1H)，6.78-6.91(m，2H)，5.99(q，1H，J＝7.3Hz)，4.17-4.32(m，2H)，1.26(t，3H，J＝7.05Hz)；
Step 4: ethyl 8-chloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
To a solution of ethyl 8-chloro-6-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.500 g, 1.55 mmol) prepared in step 3 in anhydrous DMF (5.0 ml) under dry nitrogen atmosphere was added potassium iodide (26 mg, 0.155 mmol), potassium carbonate (0.643 g, 4.65 mmol) and ethyl iodide (272 μ l, 4.65 mmol). After stirring overnight at room temperature, the mixture was poured into water (150 ml) saturated with solid sodium chloride and extracted with ethyl acetate (200 ml). The extract was washed with brine (2 × 200 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to yield the product as a tan solid in quantitative yield: ESHRMS M/z 350.0564(M +, C)15H14ClF3O4Calculated 350.0533).
1H NMR(dmso-d6/300MHz)7.93(s，1H)，7.18(d，1H，J＝3.0Hz)，7.13(d，1H，J＝2.8Hz)，6.06(q，1H，J＝7.3Hz)，4.23-4.31(m，2H)，4.01(q，2H，7.0Hz)，1.29(q，6H，J＝7.0Hz).
Step 5: preparation of 8-chloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a solution of the ester from step 4 (250 mg, 0.713 mmol) in a 7: 2: 1 mixture of tetrahydrofuran, ethanol and water (10 mL) was added hydrogenLithium oxide hydrate (44.9 mg, 1.07 mmol), and the mixture was stirred at room temperature for 15 minutes and then at 50 ℃ for 75 minutes. After standing at room temperature for 2.75 days, the solvent was removed in vacuo. The residue was redissolved in water (20 ml) and washed with ethyl ether (20 ml). The volume of the aqueous layer was concentrated to 5 ml and acidified with 1N hydrochloric acid. The resulting solid was filtered off, washed with water and dried in vacuo to yield 216 mg (94% yield) of the product as a yellow crystalline solid: ESHRMS M/z 321.0135(M-H, C) 13H9ClF3O4Calculated 321.0136).1H NMR(dmso-d6/300MHz)13.45(brs，1H)，7.88(s，1H)，7.13-7.16(m，2H)，6.02(q，1H，J＝7.3Hz)，4.03(q，2H，J＝6.9Hz)，1.32(t，3H，J＝6.9Hz).
Example 17b
8-chloro-6-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from step 3 of example 17a was hydrolyzed via a similar procedure as described in step 5 of example 17a to give the product as a yellow crystalline solid. ESHRMS M/z292.9848(M-H, C)15H5ClF3O3Calculated 292.9823).
1H NMR(dmso-d6/300MHz)13.40(brs，1H)，9.80(s，1H)，7.86(s，1H)，6.90-6.92(m，2H)，5.97(q，1H，J＝7.2Hz).
Example 17c
8-chloro-6- (2, 2, 2-trifluoroethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 8-chloro-6- (2, 2, 2-trifluoroethoxy) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
To a solution of ethyl 8-chloro-6-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.500 g, 1.55 mmol) prepared in step 3 of example 17a in anhydrous DMF (5.0 ml) under dry nitrogen atmosphere were added potassium iodide (26 mg, 0.155 mmol), potassium carbonate (0.321 g, 2.33 mmol) and 2, 2, 2-trifluoroethyl iodide (0.458 ml, 4.65 mmol), and the mixture was stirred at room temperature for 1 hour and then at 40 ℃ for 1 hour. After addition of additional potassium carbonate (0.467 g, 4.65 mmol) and 2, 2, 2-trifluoroethyl iodide (0.458 ml, 4.65 mmol) to the mixture, the temperature was raised to 50 ℃ overnight. After addition of additional 2, 2, 2-trifluoroethyl iodide (0.458 ml, 4.65 mmol), the temperature was raised to 85 ℃ for 18.5 hours. The mixture was poured into saturated sodium bicarbonate (100 ml) and extracted with ethyl acetate (2 × 200 ml). The combined extracts were then washed with brine (2 × 200 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give a brown oil. The purified product was purified by silica chromatography (eluting with 6: 1 hexane: ethyl ethane) to yield 0.237 g (41% yield) of the product as a pale yellow crystalline solid: ESHRMS M/z 404.0246(M +, C) 15H11ClF6O4Calculated 404.0250).
Step 2: 8-chloro-6- (2, 2, 2-trifluoroethoxy) -2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid
The ester from step 1 was hydrolyzed via a similar procedure as described in step 3 of example 9z to give the product as a yellow crystalline solid. ESHRMS M/z 374.9855(M-H, C)13H6ClF6O4Calculated 374.9853).1H NMR(dmso-d6/300MHz)13.54(brs，1H)，7.88(s，1H)，7.37(d，1H，J＝2.7Hz)，7.32(d，1H，J＝2.8Hz)，6.09(q，1H，J＝7.1Hz)，4.81(q，2H，J＝8.9Hz).
Example 17d
6- (benzyloxy) -8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6- (benzyloxy) -8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acid esters
To a solution of ethyl 8-chloro-6-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.00 g, 3.10 mmol) prepared in step 3 of example 17a in anhydrous DMF (10.0 ml) was added potassium iodide (51.5 mg, 0.310 mmol), potassium carbonate (1.29 g, 9.3 mmol) and benzyl bromide (1.11 ml, 9.30 mmol). The suspension was stirred at room temperature for 2 hours and poured into water (150 ml) and extracted with ethyl acetate (3 × 100 ml). The combined extracts were washed with brine (2 × 100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow oil. Purification by silica chromatography (6: 1 hexanes: ethyl acetate elution) gave 1.12 g (87.5% yield) of the product as a yellow crystalline solid: ESHRMS M/z 412.0689(M +, C) 20H16ClF3O4Calculated 412.0680).
Step 2: preparation of 6- (benzyloxy) -8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Prepare for
The ester from step 1 was hydrolyzed via a similar procedure as described in step 3 of example 9z to obtain a crude product in the form of a viscous solid. Brine was added and the mixture was extracted with ethyl acetate (20 ml). The ethyl acetate solution was dried over magnesium sulfate, filtered and concentrated in vacuo to yield a quantitative yield of product in the form of a yellow crystalline solidAn object: ESHRMSm/z 383.0311(M-H, C)18H11ClF3O4Calculated 383.0292).1HNMR(dmso-d6/300MHz)13.49(brs，1H)，7.90(s，1H)，7.34-7.50(m，5H)，7.27(s，2H)，6.05(q，1H，J＝7.2Hz)，5.12(s，2H).
Example 17e
8-chloro-6- (hexyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 8-chloro-6- (hexyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acid esters
The ester was prepared by a method analogous to that described in example 17d, step 1. The crude product was purified by silica chromatography (eluting with 6: 1 hexane: ethyl acetate) to obtain the product as a yellow oil: ESHRMS M/z 404.1147(M +, C)19H22ClF3O4Calculated 404.1159).
Step 2: preparation of 8-chloro-6- (hexyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Prepare for
The ester from step 1 was hydrolyzed via a similar procedure as described in step 3 of example 9z to give the product as a yellow solid: ESHRMS M/z 377.0771(M-H, C)17H17ClF3O4Calculated 377.0762).
1H NMR(dmso-d6，300MHz)13.47(brs，1H)，7.89(s，1H)，7.15-7.18(m，2H)，6.04(q，1H，J＝7.25Hz)，3.98(t，2H，J＝6.2Hz)，1.69-1.74(m，2H)，1.32-1.43(m，6H)，0.89-0.91(m，3H).
Example 17f
8-chloro-6-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 8-chloro-6-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
The ester was prepared by a similar method as described in example 17d, step 1. The crude product was recrystallized from ethyl acetate-hexane to obtain the product as a tan solid: ESHRMSm/z 364.0711(M +, C)16H16ClF3O4Calculated 364.0689).
Step 2: preparation of 8-chloro-6-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from step 1 was hydrolyzed at 70 ℃ via a similar procedure as described in step 3 of example 9z to give the product as a yellow solid: ESHRMS M/z 335.0263(M-H, C)14H11ClF3O4Calculated 335.0292).
1H NMR(dmso-d6，300MHz)13.48(brs，1H)，7.90(s，1H)，7.16-7.18(m，2H)，6.04(q，1H，J＝7.3Hz)，3.95(t，2H，J＝6.4Hz)，1.71-1.78(m，2H)，1.00(t，3H，J＝7.3Hz).
Example 17g
8-chloro-6- (cyclohexyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1:ethyl 8-chloro-6- (cyclohexyloxy) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
To a solution of ethyl 8-chloro-6-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.00 g, 3.10 mmol) prepared in step 3 of example 17a in anhydrous DMF (10.0 ml) were added potassium iodide (51.5 mg, 0.310 mmol), potassium carbonate (1.29 g, 9.3 mmol) and cyclohexyl iodide (1.20 ml, 9.30 mmol). The suspension was heated at 50 ℃ for 17 hours, then the temperature was slowly raised to 80 ℃ and stirred overnight. Additional cyclohexyliodide (1.20 mL, 9.30 mmol) was added and the temperature was maintained at 100 ℃ and 120 ℃ for 3 days. The mixture was then cooled and poured into water (200 ml) saturated with solid sodium chloride. After extraction with ethyl acetate (2 × 100 ml), the combined extracts were washed with brine (3 × 100 ml) and concentrated in vacuo. Purification by silica chromatography (eluting with 6: 1 hexanes: ethyl acetate) gave 45 mg (3.5% yield) of the product: ESHRMS M/z 404.0999(M +, C) 19H20ClF3O4Calculated 404.1002).
Step 2: process for preparing 8-chloro-6- (cyclohexyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
The ester from step 1 was hydrolyzed via a similar procedure as described in step 3 of example 9z to give the product as a yellow crystalline solid: ESHRMS M/z 375.0642(M-H, C)18H11ClF3O4Calculated 375.0605).1H NMR(dmso-d6，300MHz)13.39(brs，1H)，7.84(s，1H)，7.15(d，1H，J＝2.8Hz)，7.10(d，1H，J＝2.8Hz)，5.98(q，1H，J＝7.3Hz)，4.20-4.35(m，1H)，1.14-1.87(m，10H).
Example 17h
(2R) -8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
(2R) -8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was resolved using a Chialpak AD column eluted with 5/95/0.1 ethanol/heptane/TFA using chiral separation of racemic 8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from U.S. Pat. No. 6,271,253B1, with the first peak detected at 254nm with a retention time of 8.55 minutes. ESHRMS M/z 306.9953(M-H, C)12H8F3O4Cl calculated 306.9979).
1H NMR(acetone-d6/400MHz)7.87(s，1H)，7.08(m，2H)，5.87(q，1H，J＝7.0hz)，3.82(s，3H).
Example 17i
(2S) -8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
(2S) -8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was resolved using a Chialpak AD column eluted with 5/95/0.1 ethanol/heptane/TFA using chiral separation of racemic 8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from U.S. Pat. No. 6,271,253B1, with a second peak detected at 254nm with a retention time of 10.58 minutes. ESHRMS M/z 306.9953(M-H, C) 12H7F3O4Cl calculated 306.9979).
1H NMR(acetone-d6/400MHz)7.87(s，1H)，7.08(m，2H)，5.87(q，1H，J＝7.0Hz)，3.82(s，3H).
Example 18a
5, 8-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 5, 8-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acid esters
To a solution of ethyl 8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (2.32 g, 6.89 mmol) prepared in U.S. patent No. 6,271,253B 1, example 40 in glacial acetic acid (100 ml) was added chlorine gas for 0.5 min. After standing for 20 minutes, the solvent was removed in vacuo and the remaining acetic acid was azeotroped with hexane to obtain a crystalline solid containing a mixture of alignment isomers. The crude product was recrystallized from ethyl acetate-hexane to yield 189 mg (7.4% yield) of the product as colorless needles: ESHRMS M/z 369.9986(M +, C)14H11Cl2F3O4Calculated 369.9986).
Step 2: preparation of 5, 8-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Prepare for
The ester from step 1 (0.174 g, 0.469 mmol) was dissolved in 7: 2: 1 tetrahydrofuran: ethanol; to a mixture of water (10 ml), lithium hydroxide hydrate (29.5 mg, 0.704 mmol) was added. The mixture was stirred at room temperature overnight and the solvent was removed in vacuo. The residue was dissolved in water, filtered (0.45, PTFE) and acidified with 1N hydrochloric acid. The resulting solid was filtered off, washed with water and dried in vacuo to give 134 mg (83% yield) of the product as a yellow solid: ESHRMS M/z 340.9607(M-H, C) 12H6Cl-2F3O4Calculated 340.9590).
1H NMR(dmso-d6，300MHz)13.70(brs，1H)，7.90(s，1H)，7.41(s，1H)，6.10(q，1H，J＝7.1Hz)，3.86(s，3H).
Example 19
7, 8-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7, 8-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acid esters
The ester was prepared as described in example 18a, step 1, and by recrystallization from ethyl acetate-hexane followed by silica chromatography (eluting with 3: 1 hexane: ethyl acetate) 0.292 g (11% yield) of the product was obtained as a yellow crystalline solid: ESHRMS M/z369.9986(M +, C)14H11Cl2F3O4Calculated 369.9986).
Step 2: preparation of 7, 8-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Prepare for
The ester from step 1 was hydrolyzed via a similar procedure as described in step 2 of example 18a to obtain the product as a light yellow solid: ESHRMS M/z 340.9567(M-H, C)12H6Cl2F3O4Calculated 340.9590).1H NMR(dmso-d6，300MHz)13.45(brs，1H)，7.89(s，1H)，7.42(s，1H)，6.07(q，1H，J＝7.1Hz)，3.87(s，3H)；
Example 20a
5, 7, 8-trichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 5, 7, 8-trichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3- Process for preparation of carboxylic acid estersPreparation of
A solution of ethyl 8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.500 g, 1.49 mmol) prepared as in U.S. Pat. No. 6,271,253B1, example 40 in glacial acetic acid (25 mL) was saturated with chlorine. After standing overnight at room temperature, the solvent was removed in vacuo and the remaining acetic acid was azeotroped with hexane. The crude product was purified by silica chromatography (9: 1 ethyl acetate: hexanes elution) followed by recrystallization from hexanes to yield 0.244 g (41% yield) of the colorless needle product: ESHRMS M/z403.9564(M +, C) 14H10Cl3F3O4Calculated 403.9597).
Step 2: process for preparing 5, 7, 8-trichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
The ester from step 1 was hydrolyzed via a similar method as described in step 5 of example 17a to obtain the product as a white crystalline solid: ESHRMS M/z 374.9178(M-H, C)12H5F3O4Cl3Calculated 374.9200).1H NMR(dmso-d6，300MHz)13.86(brs，1H)，7.90(s，1H)，6.28(q，1H，J＝7.1Hz)3.86(s，3H).
Example 21a
8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 2-hydroxy-3-iodo-5- (trifluoromethoxy) benzaldehyde
A mixture of 2-hydroxy-5- (trifluoromethoxy) benzaldehyde (5.09 g, 24.7 mmol) and N-iodosuccinimide (13.9 g, 61.8 mmol) in anhydrous DMF (50 ml) was stirred at room temperature under dry nitrogen atmosphere for 2 days. The solvent was removed in vacuo and the mixture was,the residue was dissolved in ethyl acetate (200 ml), washed with 0.5N hydrochloric acid (200 ml), water (200 ml), aqueous sodium thiosulfate (100 ml), brine (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give a yellow solid. Purification was carried out in vacuo using sublimation at 85 ℃ to yield 7.97 g (97% yield) of the product as a white solid. ESHRMS M/z 331.9159(M +, C) 8H8F3IO4Calculated 331.9157).
Step 2: ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
A mixture of 2-hydroxy-3-iodo-5- (trifluoromethoxy) benzaldehyde (60.0 g, 181 mmol), ethyl 4, 4, 4-trifluorocrotonate (108 ml, 723 mmol), prepared in step 1, and TEA (50.4 ml, 361 mmol) was heated to 85 ℃ for 66 hours. The mixture was concentrated in vacuo and the product crystallized from ethanol-water to yield 78.0 g (90% yield) of a light yellow needle product.
1H NMR(dmso-d6，300MHz)7.95(s，1H)，7.86(d，1H，J＝2.4Hz)，7.70(d，1H，J＝1.8Hz)，6.17(q，1H，J＝7.0Hz)，4.18-4.34(m，2H)，1.26(t，3H，J＝7.0Hz).
Step 3: 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
By a similar method to that described in example 17d, step 2, the ester from step 2 was hydrolyzed at 60 ℃ to give the product as a pale yellow crystalline solid: ESHRMS M/z452.9012(M-H, C)12H14F6O4Calculated 452.9053).1H NMR(dmso-d6，300MHz)13.51(brs，1H)，7.87(s，1H)，7.84(1，1H，J＝2.2Hz)，7.76(d，1H，J＝1.8Hz)，6.10(q，1H，J＝7.1Hz).
Example 21b
8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid esters
Ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.500 g, 1.04 mmol), trimethylboroxine (145. mu.l, 1.04 mmol), PdCl, prepared as per 2 nd step of example 21a, were combined under dry nitrogen atmosphere 2(dppf)2·CH2Cl2A mixture of (0.087 mg, 0.104 mmol) and cesium carbonate (1.01 g, 3.11 mmol) in 10% aqueous dioxane (2.5 ml) was heated to 110 ℃ for 6 hours. The mixture was poured into ethyl acetate (100 ml), washed with brine (2 × 50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give an oily yellow solid. Purification by silica chromatography (9: 1 hexanes: ethyl acetate elution) gave 0.320 g (83% yield) of the product as a yellow crystalline solid: ESHRMS M/z 370.0650(M +, C)15H1F6O4Calculated 370.0640).
Step 2: 8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
The ester from step 1 was hydrolyzed via a similar method as described in step 3 of example 9z to obtain the product as a white solid: ESHRMS M/z 341.0268(M-H, C)13H7F6O4Calculated 341.0243).1H NMR(dmso-d6，300MHz)13.40(brs，1H)，7.87(s，1H)，7.43(s，1H)，7.31(s，1H)，5.99(q，1H，J＝7.3Hz)，2.20(s，3H).
Example 21c
8- (Phenylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 8- (phenylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) Preparation of (E) -2H-chromene-3-carboxylic acid esters
Ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate prepared in step 2 of example 21a (1.00 g, 2.07 mmol), phenylacetylene (0.445 ml, 4.15 mmol), iodinated steel (39.5 mg, 0.207 mmol), PdCl 2(dppf)2·CH2Cl2A mixture of (169 mg, 0.207 mmol) and TEA (0.867 mg, 6.22 mmol) in dry toluene (10 ml) was stirred at room temperature for 18.5 h. The mixture was then poured into brine (100 ml) and extracted with ethyl acetate. The ethyl acetate layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica chromatography (eluting with 9: 1 hexanes: ethyl acetate) to afford 0.802 g (85% yield) of the product as a yellow crystalline solid: ESHRMS M/z456.0781(M +, C)14H14F6O4Calculated 456.0796).
Step 2: 8- (Phenylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) Preparation of (E) -2H-chromene-3-carboxylic acid
The ester from step 1 was hydrolyzed via a similar procedure as described in step 2 of example 18a to obtain the product as a yellow solid: ESHRMS M/z 427.0350(M-H, C)20H9F6O4Calculated 427.0400).
1H NMR(dmso-d6，300MHz)13.53(brs，1H)，7.92(s，1H)，7.44-7.87(m，7H)，6.15(q，1H，J＝7.1Hz).
Example 21d
8-prop-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 8-prop-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
Ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate prepared as in step 2 of example 21a (0.500 g, 1.04 mmol), copper iodide (20 mg, 0.104 mmol), PdCl in a Parr bottle 2(dppf)2CH2Cl2(84.5 mg, 0.104 mmol) and TEA (434. mu.l, 3.11 mmol) in dry toluene (10 ml) were added propyne (2 ml) at-78 ℃ and the bottle was sealed. After stirring at room temperature for 23 hours, additional propyne (5 ml) was added and the mixture was stirred at room temperature for an additional 23 hours. Addition of additional PdCl2(dppf)2·CH2Cl2(120 mg, 0.147 mmol) and the mixture is stirred at room temperature for a further 24 hours. The mixture was then poured into brine (100 ml) and extracted with ethyl acetate (200 ml). The ethyl acetate layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica chromatography (eluting with 9: 1 hexanes: ethyl acetate) to afford 0.363 g (89% yield) of the product as a yellow crystalline solid: ESHRMS M/z 394.0644(M +, C)17H12F6O4Calculated 394.0640).
Step 2: 8-prop-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid
Via a corresponding to the class described in step 2 of example 17dAnalogously, the ester from step 1 is hydrolyzed to obtain the product in the form of a tan crystalline solid: ESHRMS M/z 365.0275(M-H, C)15H7F6O4Calculated 365.0243). 1H NMR(dmso-d6，300MHz)13.49(brs，1H)，7.88(s，1H)，7.59(s，1H)，7.42(d，1H，J＝2.2Hz)，6.09(q，1H，J＝7.2Hz)，2.08(s，3H).
Example 21e
8-pent-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 8-pent-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
Ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate prepared as step 2 of example 21a (0.500 g, 1.04 mmol), 1-pentyne (0.205 ml, 2.08 mmol), copper iodide (20 mg, 0.104 mmol), PdCl2(dppf)2·CH2Cl2A mixture of (84.5 mg, 0.104 mmol) and TEA (0.434 ml, 3.11 mmol) in dry toluene (5 ml) was stirred at room temperature for 23 hours, then additional 1-pentyne (2.0 ml, 20.3 mmol) was added and the mixture was stirred at room temperature for an additional 24 hours. Then add additional PdCl2(dppf)2·CH2Cl2(120 mg, 0.147 mmol) and the mixture is stirred at room temperature for a further 24 hours. The mixture was then poured into brine (100 ml) and extracted with ethyl acetate (200 ml). The ethyl acetate layer was separated, dried over magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica chromatography (elution with 9: 1 hexane: ethyl acetate) to yield 0.41 g (93% yield) of the product as a yellow crystalline solid: ES (ES) HRMS m/z 422.0946(M+，C19H16F6O4Calculated 422.0953).
Step 2: 8-pent-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid
The product was obtained by hydrolysis of the ester from step 1 via a similar method to that described in step 2 of example 17 d: ESHRMS M/z 393.0566(M-H, C)17H11F6O4Calculated 393.0556).1HNMR(dmso-d6，300MHz)13.48(brs，1H)，7.88(s，1H)，7.59(d，1H，J-2.2Hz)，7.41(d，1H，J＝2.4Hz)，6.06(q，1H，J＝7.0Hz)，2.43(1，2H，J＝6.9Hz)，1.48-1.90(m，2H)，0.99(t，3H，J＝7.5Hz).
Example 21f
8-ethynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6- (trifluoromethoxy) -2- (trifluoromethyl) -8- [ (trimethylmethyl) methyl Silyl) ethynyl]Preparation of (E) -2H-chromene-3-carboxylic acid esters
Ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate prepared in step 2 of example 21a (25.0 g, 51.9 mmol), acetylene (trimethyl) silane (36.6 mL, 256 mmol), copper iodide (0.988 g, 5.19 mmol), Pd (PPh)3)4A mixture of (5.99 g, 5.19 mmol) and TEA (21.7 ml, 156 mmol) in dry toluene (200 ml) was stirred at room temperature for 2 days. Additional copper iodide (0.99 g, 5.19 mmol) was added and stirring continued for an additional 1 day. Additional copper iodide (2.0 g, 10.5 mmol) was added again and stirring was continued for an additional 3 days. The mixture was then poured into brine (500 ml) and extracted with ethyl acetate (500 ml) . The ethyl acetate layer was separated, dried over magnesium sulfate and filtered through a plug of silica gel (eluting with 95: 5 hexane: ethyl acetate) to yield 24 g (quantitative yield) of the product as a tan solid: ESHRMS M/z 452.0853(M +, C)19H18F6O4Calculated Si 452.0879).
Step 2: ethyl 8-ethynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-color Preparation of alkene-3-carboxylic acid esters
Ethyl 6- (trifluoromethoxy) -2- (trifluoromethyl) -8- [ (trimethylsilyl) ethynyl prepared in step 1 under a dry nitrogen atmosphere]To a solution of-2H-chromene-3-carboxylate (22.8 g, 50.3 mmol) in anhydrous dichloromethane (200 ml) was added a TBAF solution (32.9 ml, 1.0M solution in THF, 62.9 mmol). The mixture was stirred for 10 minutes, then poured into saturated ammonium chloride (200 ml) and extracted with ethyl acetate (500 ml). The ethyl acetate extract was washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to yield 40 g of a light brown oil. The crude product was purified by silica chromatography (eluting with 98: 2 hexane: dichloromethane) to yield 13.9 g (79% yield) of the product as a yellow crystalline solid: ESHRMS M/z 380.0505(M +, C) 16H10F6O4Calculated 380.0483).
Step 3: 8-ethynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
The ester from step 2 was hydrolyzed via a similar procedure as described in example 17d, step 2 to give the product as a yellow oil: ESHRMS M/z 351.0110(M-H, C)14H5F6O4Calculated 351.0087).
1H NMR(dmso-d6，300MHz)13.52(brs，1H)，7.90(s，1H)，7.68(s，1H)，7.54(s，1H，J＝2.6Hz)，6.11(q，1H，J＝7.1Hz)，4.57(s，1H).
Example 21g
8-Ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid esters
A mixture of ethyl 8-ethynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (12.2 g, 32.0 mmol) prepared in step 2 of example 21f and 10% palladium on carbon (1.22 g) in absolute ethanol (250 ml) was hydrogenated at 30psi for 3H. The catalyst was then removed by filtration and the solution was concentrated in vacuo to yield the product as an off-white solid in theoretical quantitative yield. The solid was used without further purification: ESHRMS M/z 348.0759(M +, C)16H14F6O4Calculated 348.0796).
Step 2: 8-Ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
The ester from step 1 was hydrolyzed via a similar procedure as described in step 2 of example 17d to obtain the product as a light yellow crystalline solid: ESHRMS M/z 355.0389(M-H, C) 14H9F6O4Calculated 355.0400).1H NMR(dmso-d6，300MHz)13.39(brs，1H)，7.88(s，1H)，7.44(d，1H，J＝2.2Hz)，7.28(d，1H，J＝2.4Hz)，6.00(q，1H，J＝7.3Hz)，2.54-2.68(m，2H)，1.12(t，3H，J＝7.5Hz).
Example 21h
8-isobutyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 8-isobutyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-color Preparation of alkene-3-carboxylic acid esters
Isobutylene was bubbled through a solution of 9-BBN (3.32 mL, 1.0M solution in THF, 1.66 mmol) at 0 ℃ for 15 minutes, and the mixture was stirred for 15 minutes, maintaining the temperature at 0 ℃. Isobutene was again passed through the solution for 15 minutes and the mixture was stirred at room temperature for 1 hour. To this mixture was added the solution of ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.400 g, 0.830 mmol) prepared in step 2 of example 21a in anhydrous THF (3.0 ml), PdCl2(dPPf)2·CH2Cl2(33.9 mg, 0.0415 mmol) and potassium phosphate solution (0.943 ml, 2.0M, 1.87 mmol). The resulting mixture was stirred at room temperature for 45 minutes, poured into saturated sodium bicarbonate (100 ml), and extracted with ethyl acetate (100 ml). The ethyl acetate solution was washed with 1N hydrochloric acid (100 ml), brine (50 ml), dried over magnesium sulfate, and concentrated in vacuo. Purification by silica chromatography (elution with 9: 1 hexane: ethyl acetate) followed by reverse phase chromatography (elution with acetonitrile: 0.5% TFA-water) afforded 110 mg (32% yield) of the product as a white crystalline solid: ESHRMS M/z411.1109(M +, C) 18H18F6O4Calculated 411.1140).
Step 2: 8-isobutyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
The ester from step 1 was hydrolyzed via a similar procedure as described in step 2 of example 17d to obtain the product as a yellow crystalline solid: ESHRMS M/z 383.0710(M-H, C)17H11F6O4Calculated 383.0713)。 1H NMR(dmso-d6，300MHz)13.37(brs，1H)，7.88(s，1H)，7.45(d，1H，J＝2.4Hz)，7.24(d，1H，J＝2.4Hz)，5.98(q，1H，J＝7.1Hz)，2.36-2.58(m，2H)，1.84-1.93(m，1H)，0.85(d，3H，J＝3.2Hz)，0.83(d，3H，J＝3.0Hz).
Example 21i
8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
In a parr (Paar) bottle, 8-prop-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared in example 21d, 2 (150 mg, 0.409 mmol), 10% palladium on carbon (75 mg) and absolute ethanol (10 ml) were added. The mixture was hydrogenated at 30psi for 2 hours. The catalyst was filtered off, the solvent was removed in vacuo and the resulting oily solid was triturated with hexane to yield 76 mg (50% yield) of the product as an off-white solid: ESHRMS M/z 369.0559(M-H, C)15H11F6O4Calculated 369.0556).1HNMR(dmso-d6，300MHz)13.38(brs，1H)，7.87(s，1H)，7.43(s，1H)，7.26(s，1H)，5.99(q，1H，J＝7.3Hz)，2.51-2.66(m，2H)，1.48-1.60(m，2H)，0.86(t，3H，J＝7.3Hz).
Example 21j
8-pentyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Example 21e, step 1, as described in example 21i2 step preparation of 8-pent-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. Purification by phase chromatography (elution with acetonitrile: 0.5% TFA-water) afforded the product as a brown oil: ESHRMS M/z 397.0846(M-H, C)17H15F6O4Calculated 397.0869).
1H NMR(dmso-d6，300MHz)13.39(brs，1H)，7.87(s，1H)，7.42(d，1H，J＝2.2Hz)，7.25(s，1H，J＝2.4Hz)，5.98(q，1H，J＝7.3Hz)，2.46-2.65(m，2H)，1.47-1.57(m，2H)，1.21-1.33(m，4H)，0.83(t，3H，J＝6.8Hz).
Example 21k
(2S) -8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid compound and (1R) -1-phenylethylamine
Racemic 8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (10.1 g) prepared as in example 21g, step 2 was resolved by chiral separation using a kessell (chiralel) OJ column and elution with ethanol/heptane/TFA ═ 5/95/0.1, with a first peak detected at 254nm with a retention time of 5.03 min to give 4.65 g (46% yield) of the product as an off-white solid. ESHRMS M/z357.1(M + H, C)14H11F6O4Calculated 357.1).1HNMR(dmso-d6，400MHz)13.39(brs，1H)，7.87(s，1H)，7.43(d，1H，J＝2.4Hz)，7.27(d，1H，J＝2.7Hz)，5.99(q，1H，J＝7.3Hz)，2.50-2.67(m，2H)，1.11(t，3H，J＝7.5Hz).
Example 21l
(2R) -8-Ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Racemic 8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (10.1 g) prepared as in example 21g, step 2 was resolved by chiral separation using a kessell (chiralel) OJ column and elution with ethanol/heptane/TFA ═ 5/95/0.1, whereas the second peak was detected at 254nm with a retention time of 5.55 min, yielding 4.41 g (44% yield) of the product as a pale yellow solid. ESHRMS M/z357.1(M + H, C) 14H11F6O4Calculated 357.1).1HNMR(dmso-d6，300MHz)13.39(brs，1H)，7.88(s，1H)，7.44(d，1H，J＝2.2Hz)，7.27(d，1H，J＝2.4Hz)，6.00(q，1H，J＝7.3Hz)，2.54-2.67(m，2H)，1.12(t，3H，J＝7.5Hz).
Example 21m
(2S) -8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid compound and (1R) -1-phenylethylamine
To (S) -8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared in example 21k (17.8 mg, 0.0500 mmol) and (1R) -1-phenylethylamine (12.7 μ l, 0.0500 mmol) was added several drops of isopropanol. Heptane (0.30 ml) was then added and the solvent was allowed to slowly evaporate from the loosely capped vial. After standing at room temperature for 1 day, crystals formed in the solution. The title compound was confirmed to be the (S) -enantiomer by X-ray crystal structure analysis.
Example 21n
6- (trifluoromethoxy) -2- (trifluoromethyl) -8-vinyl-2H-chromene-3-carboxylic acid
Step 1: ethyl 6- (trifluoromethoxy) -2- (trifluoromethyl) -8-vinyl-2H-color Preparation of alkene-3-carboxylic acid esters
Ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate prepared in step 2 of example 21a (1.00 g, 2.07 mmol) with Pd (PPh) under dry nitrogen atmosphere3)4To a mixture of (0.239 g, 0.207 mmol) in dry toluene (50 ml) was added tributylvinyltin (0.665 ml, 2.28 mmol). The mixture was refluxed for 3 hours and stirred at room temperature for 18 hours. After refluxing for an additional 21 hours, a saturated ammonium fluoride solution (50 ml) was added, the mixture was stirred for 30 minutes, and extracted with ethyl acetate (200 ml). The extract was washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica chromatography (95: 5 hexanes: ethyl acetate elution) gave 0.510 g (64% yield) of the product as a crystalline solid: ESHRMS M/z 382.0620(M +, C) 16H12F6O4Calculated Si 382.0640).
Step 2: 6- (trifluoromethoxy) -2- (trifluoromethyl) -8-vinyl-2H-chromene-3- Preparation of carboxylic acids
The ester from step 1 was hydrolyzed via a similar procedure as described in step 2 of example 17d to obtain the product as a yellow crystalline solid: ESHRMS M/z 353.0246(M-H, C)14H7F3O3Calculated 353.0243).
1H NMR(dmso-d6，300MHz)13.45(brs，1H)，7.89(s，1H)，7.63(d，1H，J＝2.7Hz)，7.54(2，1H)，6.84(dd，1H，J＝11.3，18.0Hz)，6.04(q，1H，J＝7.0Hz)，6.03(d，1H，J＝17.2Hz)，5.47(d，1H，J＝11.7Hz).
Example 21o
8- (2-phenylethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Via a similar process to that described in example 21j, 8- (phenylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid, prepared as step 2 of example 21c, was hydrogenated to give the product as a pale tan crystalline solid: ESHRMS M/z431.0698(M-H, C)20H13F6O4Calculated 431.0713).1H NMR(dmso-d6，300MHz)13.41(brs，1H)，7.89(s，1H)，7.44(d，1H，J＝2.4Hz)，7.23-7.28(m，2H)，7.14-7.18(m，4H)，6.04(q，1H，J＝7.3Hz)，2.80-2.96(m，4H).
Example 21p
8-cyano-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 8-cyano-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid esters
Ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate prepared in step 2 of example 21a (2.00 g, 4.15 mmol), copper iodide (158 mg, 0.830 mmol), potassium cyanide (1.08 g, 16.6 mmol) and Pd (PPh) 3)4A mixture (480 mg, 0.415 mmol) in THF (5.0 ml) was refluxed under dry nitrogen for 2.5 days. The mixture was poured into brine (100 ml)Extracted with ethyl acetate (100 ml), dried over magnesium sulfate and concentrated in vacuo. Purification by silica chromatography followed by ethyl-acetoacetate-hexane recrystallization gave 1.30 g (82% yield) of the product as a yellow crystalline solid: ESHRMS M/z399.0812(M + HH)4，C15H9NO4F6NH4Calculated 399.0774).
Step 2: 8-cyano-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
The ester from step 1 was hydrolyzed via a similar procedure as described in step 2 of example 18a to obtain the crude product as an off-white solid:
1H NMR(dmso-d6，300MHz)13.69(brs，1H)，8.05(d，1H，J＝2.2Hz)，7.99(d，1H，J＝2.0Hz)，6.29(q，1H，J＝7.0Hz)，4.16(q，1H，J＝7.3Hz)，1.56(d，3H，J＝7.3Hz)；ESHRMS m/z 352.0048(M-H，C13H4F6O4，Calc’d 352.0039).
example 21q
8-but-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 8-but-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
In the presence of ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.00 g, 2.07 mmol), copper iodide (39 mg, 0.207 mmol), PdCl, prepared as step 2 in example 21a 2(dppf)2·CH2Cl2(167 mg, 0.207 mmol) and TEA (867. mu.l, 6.22 mmol) in dry toluene (10 ml) in a Paar (Paar) bottle, 1-butyne (5 ml) was added at-78 ℃ and the bottle was sealed. After stirring overnight at room temperature, additional copper iodide (390 mg, 2.07 mmol) and PdCl were added2(dppf)2·CH2Cl2(1.67 g, 2.07 mmol) and the vessel is sealed again. After stirring for 2.5 days, the mixture was cooled to-78 ℃ and additional copper iodide (200 mg, 1.05 mmol) and PdCl were added2(dppf)2·CH2Cl2(0.500 g, 0.613 mmol), dry toluene (10 ml) and 1-butyne (5 ml) and the vessel was sealed again. After stirring for 4 days at room temperature, additional copper iodide (390 mg, 2.07 mmol) and PdCl were added2(dppf)2·CH2Cl2(0.500 g, 0.613 mmol), the vessel is sealed again and stirred at room temperature overnight. The mixture was poured into brine (100 ml) and extracted with ethyl acetate (200 ml). The extract was dried over magnesium sulfate, filtered and concentrated in vacuo. Purification by silica chromatography (95: 5 ethyl acetate: hexane elution) afforded the product as a crystalline solid: ESHRMS M/z 408.0773(M +, C)18H14F6O4Calculated 408.0796).
Step 2: 8-but-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid
The ester from step 1 was hydrolyzed via a similar procedure as described in example 17d, step 2 to obtain the crude product as a yellow solid:1H NMR(dmso-d6，300MHz)13.48(brs，1H)，7.89(s，1H)，7.60(d，1H，J＝2.2Hz)，7.41(d，1H，J＝2.4Hz)，6.08(q，1H，J＝7.0Hz)，2.45(q，2H，J＝7.5Hz)，1.16(t，3H，J＝7.5Hz)；ESHRMS m/z379.0389(M-H，C16H9F6O4，Calc’d 379.0400).
example 21r
8-butyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 8-butyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid esters
A mixture of ethyl 8-but-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (450 mg, 1.10 mmol), prepared as in step 1, example 21q, and 10% palladium on carbon (45 mg) in absolute ethanol was hydrogenated at 30psi for 1.5H. The catalyst was removed by filtration and the solvent was removed in vacuo to yield 310 mg (68% yield) of the product as a yellow crystalline solid: ESHRMS M/z 412.1099(M +, C)18H18F6O4Calculated 412.1109).
Step 2: 8-butyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
The ester from step 1 was hydrolyzed via a similar procedure as described in example 17d, step 2 to obtain the crude product as a yellow solid:
1H NMR(dmso-d6，300MHz)13.39(brs，1H)，7.88(s，1H)，7.43(d，1H，J＝2.3Hz)，7.26(d，1H，J＝2.4Hz)，5.99(q，1H，J＝7.3Hz)，2.49-2.68(m，2H)，1.45-1.55(m，2H)，1.21-1.33(m，2H)，0.86(t，3H，J＝7.5Hz)；ESHRMS m/z 383.0742(M-H，C16H13F6O4，Calc’d 383.0713).
Example 21s
8-allyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 8-allyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-color Preparation of alkene-3-carboxylic acid esters
Ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate prepared in step 2 of example 21a (1.00 g, 2.07 mmol) with Pd (PPh) under dry nitrogen atmosphere3)4(0.239 g, 0.207 mmol) in dry toluene (50 ml) was added tributylallyltin (0.707 ml, 2.28 mmol). The mixture was refluxed for 16 hours and 20% ammonium fluoride solution (50 ml) was added. The mixture was stirred for 1 hour and extracted with ethyl acetate (200 ml). The extract was washed with brine (100 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Purification by silica chromatography (9: 1 hexanes: ethyl acetate elution) gave 0.770 g (94% yield) of the product as a yellow oil: ESHRMS M/z 396.0769(M +, C)17H14F6O4Calculated 396.0796).
Step 2: 8-allyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
The ester from step 1 was hydrolyzed via a similar method as described in example 9x step 3 to obtain the product in the form of a yellow crystalline polymorph. Purification by reverse phase chromatography (elution with acetonitrile: 0.5% TFA-water) afforded 439mg (68% yield) of the product as an off-white solid:
1H NMR(dmso-d6，300MHz)13.43(brs，1H)，7.90(s，1H)，7.50(s，1H)，7.27(s，1H)，5.86-6.05(m，2H)，5.02-5.08(m，2H)，3.29-3.45(m，2H)；ESHRMS m/z 367.0437(M-H，C15H9F6O3，Calc’d 367.0400).
Example 21t
(2S) -6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Racemic 6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (10.0 g) prepared in U.S. patent No. 6,271,253B 1 was resolved by chiral separation using a kessel (chiralel) OJ column and elution with ethanol/heptane/TFA ═ 5/95/0.1, with a first peak detected at 254nm with a retention time of 6.05 min to give 4.94 g (49% yield) of the product as a solid. The title compound was confirmed to be the (S) -enantiomer by X-ray crystal structure analysis.1HNMR(dmso-d6，300MHz)13.36(brs，1H)，7.82(s，1H)，7.44(d，1H，J＝2.7Hz)，7.33(d，1H，J＝2.0Hz)，5.95(q，1H，J＝7.3Hz)，2.16(s，3H)；ESLRMS m/z 293(M+H，C12H9Cl1F3O3，Calc’d 293).
Example 21u
(2R) -6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Racemic 6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (10.0 g) prepared in U.S. Pat. No. 6,271,253B 1 was resolved by chiral separation using a kessel (chiralel) OJ column and elution with ethanol/heptane/TFA ═ 5/95/0.1, whereas the second peak was detected at 254nm with a retention time of 7.68 min to yield 3.99 g (40% yield) of solidProduct in bulk form: ESHRMS M/z 293(M + H, C) 12H9ClF3O3Calculated value 293).
Example 22
6, 8-dichloro-7-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 2-hydroxy-4-iodobenzaldehyde
The formylation of commercially available 3-iodophenol was carried out via a similar procedure as described in step 1 of example 9 f:1HNMR(DMSO-d6/300MHz)10.95(s，1H)，10.19(s，1H)，7.33(m，3H)，4.31(m，1H).
step 2: ethyl 6, 8-dichloro-7-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
Salicylaldehyde (step 1) (6.05 g, 24.4 mmol) was chlorinated (3.91 g, 51%) via a similar method as described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification.1HNMR(CDCl3/300MHz)11.55(s，1H)，9.84(s，1H)，7.6(s，1H).
Step 3: preparation of ethyl 7-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester (step 2) (3.85 g, 12.1 mmol) was condensed (2.83 g, 50%) via a similar method to that described in step 1 of example 4 a. The ester has a suitable purity and can be used without further purification.
1HNMR(CDCl3-/300MHz)7.64(s，1H)，7.30(d，1H，J＝9.2Hz)，5.83(q，1H，J＝7.1Hz)，4.32-4.40(m，2H)，1.36-1.57(m，3H).
Step 4: preparation of 6, 8-dichloro-7-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester (step 3) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a.1HNMR(CDCl3-d6/300MHz)7.95(s，1H)，7.78(s，1H)，6.05(q，1H，J＝7.1Hz).
Example 23a
5-chloro-8-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of ethyl 8-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared using a procedure similar to that described in step 1, example 1a, using 2, 3-dihydroxybenzaldehyde as starting material: LCMS M/z 289.15(M + H).1H NMR(CDCl3/400MHz)7.72(s，1H)，6.98(dd，1H，J＝1.6，8.0Hz)，6.88(m，1H)，6.79(dd，1H，J＝1.6，7.6Hz)，5.76(q，1H，J＝6Hz)，4.29(m，2H)，1.33(t，3H，J＝7.2Hz).
Step 2: preparation of 5-chloro-8-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure similar to that described in example 2b, 5-chloro-8-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared using ethyl 8-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 as the starting material: ESHRMS M/z 335.0253(M-H, C)14H11O4F3Calculated 335.0292).1H NMR(acetone-d6/400MHz)8.02(s，1H)，7.14(d，1H，J＝8.8Hz)，7.10(d，1H，J＝8.8Hz)，5.90(q，1H，J＝7.0Hz)，4.03(m，2H)，1.78(m，2H)，1.07(t，3H，J＝7.2Hz).
Example 23b
5-chloro-8- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the one described in example 23a, 5-chloro-8- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared: ESHRMS M/z 377.0761(M-H, C)17H17O4F3Cl calculated 377.0762).
1H NMR(acetone-d6/400MHz)8.02(s，1H)，7.14(d，1H，J＝8.8Hz)，7.10(d，1H，J＝8.8Hz)，5.90(q，1H，J＝7.0Hz)，4.03(m，2H)，1.66(m，1H)，1.49(m，4H)，0.93(t，6H，J＝7.2Hz).
Example 23c
8- (benzyloxy) -5-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the one described in example 23a, 8- (benzyloxy) -5-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared: ESHRMS M/z 383.0326(M-H, C) 18H11O4F3Cl calculated 383.0303).
1H NMR(CDCl3/300MHz)8.17(s，1H)，7.34(m，5H)，6.92(d，1H，J＝8.8Hz)，6.92(d，1H，J＝8.8Hz)，5.79(q，1H，J＝7.0Hz)，5.16(d，1H，J＝12Hz)，5.14(d，1H，J＝12Hz).
Example 23d
5-chloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of ethyl 8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
2-hydroxy-3-methoxybenzaldehyde (3.05 g, 20 mmol) was dissolved in DMSO (9 ml). To the above solution was added TEA (4.09 g, 40 mmol) and ethyl 4, 4, 4-trifluorocrotonate (6.93 g, 40 mmol). The reaction was heated to 70 ℃ and monitored by TLC and GCMS until completion. The reaction was quenched with 10% hydrochloric acid. The compound was extracted with ethyl acetate and washed with water and ammonium chloride. The organics were dried over magnesium sulfate. After concentration, the crude product was purified using a flash column eluting with 20% ethyl acetate in hexane. The ester has a suitable purity and can be used without further purification.
Step 2: preparation of 5-chloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Via a procedure analogous to the method described in example 2b, steps 2 and 3, 5-chloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared: ESHRMS M/z 307.0006(M-H, C)12H7O4F3Cl calculated 306.9979). 1H NMR(CDCl3/300MHz)8.17(s，1H)，7.02(d，1H，J＝8.7Hz)，6.91(d，1H，J＝8.7Hz)，5.77(q，1H，J＝7.0Hz)，3.89(s，3H)C12H8ClF3O4The calculation analysis shows that: carbon 46.70; hydrogen 2.61. And (3) measuring: 46.40 parts of carbon; hydrogen 2.71.
Example 23e
5, 6-dichloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 1b, step 2, using ethyl 8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 of example 23d as starting material, 5, 6-dichloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared: ESHRMS M/z 340.9600(M-H, C)12H6O4F3Cl2Calculated 340.9590).
1H NMR(CDCl3/300MHz)7.93(s，1H)，6.92(s，1H)，5.67(q，1H，J＝7.0Hz)，3.78(s，3H).
Example 23f
5, 7-dichloro-8-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 2b, using ethyl 8-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 of example 23a as starting material, 5, 7-dichloro-8-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared: ESHRMS M/z368.9950(M-H, C)14H10O4F3Cl2Calculated 368.9903).1HNMR(acetone-d6/400MHz)8.02(s，1H)，7.30(s，1H)，5.90(q，1H，J＝7.0Hz)，4.03(m，2H)，1.78(m，2H)，1.07(t，3H，J＝7.2Hz).
Example 24a
5-bromo-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 5-bromo-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
Ethyl 5-bromo-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared via a procedure analogous to the method described in step 1, example 23 d: 1HNMR(CDCl3/300MHz)7.98(s，1H)，7.18(d，1H，J＝8.7Hz)，6.83(d，1H，J＝8.7Hz)，5.78(q，1H，J＝7.0Hz)，4.39(m，2H)，1.37(m，3H).
Step 2: preparation of 5-bromo-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Via a procedure analogous to the method described in step 3 of example 2a, 5-bromo-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared: ESHRMS M/z 350.9495(M-H, C)12H8O4F3Calculated Br 350.9474).1H NMR(CDCl3/300MHz)7.85(s，1H)，7.05(d，1H，J＝8.8Hz)，6.71(d，1H，J＝8.8Hz)，5.65(q，1H，J＝7.0Hz)，3.75(s，3H).
Example 24b
5-bromo-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 5-bromo-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
The ester (example 28d, step 2) was brominated (76%) via a method similar to that described in step 1 of example 41. ESHRMS M/z 394.0028(M-H, C)15H14ClF3O4Calculated 393.9979).
Step 2: preparation of 5-bromo-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester (step 1) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a:1HNMR(CDCl3-d6/400MHz)，8.13(s，1H)，7.16(d，1H，J＝8.6Hz)，6.86(d，1H，J＝8.6Hz)，5.77(q，1H，J＝7.1Hz)，4.07-4.14(m，2H)，1.41-1.46(m，3H)
example 25a
8- (2-fluoro-4-nitrophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure similar to that described in example 5a, using ethyl 8-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 of example 23a as starting material, 8- (2-fluoro-4-nitrophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared: ESHRMS M/z 398.0264(M-H, C) 17H8O6F4Calculated N is 398.0282).1HNMR(acetone-d6/400MHz)7.85(dd，1H，J＝10.8，2.8Hz)，8.07(m，1H)，7.96(s，1H)，7.50(dd，1H，J＝8.0，1.6Hz)，7.40(dd，1H，J＝8.0，1.6Hz)，7.21(t，1H，J＝8.0)，7.02(t，1H，J＝8.0Hz)5.84(q，1H，J＝7.0Hz).
Example 25b
8- (4-amino-2-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 2a, using ethyl 8-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 of example 23a as starting material, 8- (4-amino-2-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared: ESHRMS M/z 368.0560(M-H, C)17H10O4F4Calculated N is 368.0540).
1H NMR(acetone-d6/400MHz)7.98(s，1H)，7.37(m，1H)，7.25(m，1H)，7.14(m，1H)，7.05(m，2H)，6.87(m，1H)，6.62(m，1H)，5.84(q，1H，J＝7.0Hz).
Example 25c
8- (4-amino-2-fluorophenoxy) -4-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 2a, using ethyl 8-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 of example 23a as starting material, 8- (4-amino-2-fluorophenoxy) -4-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (TFA salt): ESHRMS M/z 402.0158(M-H, C)17H9O4F4NCL calculated 402.0151).1H NMR(acetone-d6/400MHz)7.75(dd，1H，J＝8.0，1.0Hz)，7.59(dd，1H，J＝10.6，2.3Hz)，7.39(dd，1H，J＝8.3，1.5)，7.37(m，1H)，7.25(m，1H)，7.10(m，1H)，5.98(q，1H，J＝7.0Hz).
Example 25d
8- (4-amino-3, 5-dichloro-2-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the procedure described in step 2 of example 2a, 8- (4-amino-3, 5-dichloro-2-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared using chlorination of 8- (4-amino-2-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from example 25 b: ESHRMS M/z 436.9560(M-H, C) 17H7O5F4Cl2Calculated 436.9601).1HNMR(acetone-d6/300MHz)7.93(s，1H)，7.35(dd，1H，J＝7.2，1.2Hz)，7.21(dd，1H，J＝8.1，1.5Hz)，7.08(m，2H)，7.05(m，2H)，5.84(q，1H，J＝7.0Hz).
Example 25e
8-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 5e, using ethyl 8-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 of example 23a as starting material, 8-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared: ESHRMS M/z301.0691(M-H, C)14H12O4F3Calculated 301.0682).1H NMR(CDCl3/300MHz)7.89(s，1H)，6.98(m，3H)，5.80(q，1H，J＝7.0Hz)，4.05(m，2H)，1.88(m，2H)，1.08(t，3H，J＝7.4Hz).
Example 25f
8-butoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 5e, using ethyl 8-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 of example 23a as starting material, 8-butoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared: ESHRMS M/z315.0815(M-H, C)15H14O4F3Calculated 368.0540).
1H NMR(CDCl3/300MHz)7.85(s，1H)，6.98(m，3H)，5.76(q，1H，J＝7.0Hz)，4.06(m，2H)，1.82(m，2H)，1.50(m，2H)，0.97(t，3H，J＝7.4Hz).
Example 25g
8- (benzyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in example 5e, using ethyl 8-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 of example 23a as starting material, 8- (benzyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared: ESHRMS M/z349.0710(M-H, C) 18H12O4F3Calculated 349.0682). 1H NMR (CDCl)3/300MHz)7.86(s，1H)，7.34(m，5H)，7.00(m，1H)，6.89(m，1H)，5.80(q，1H，J＝7.0Hz)，5.22(d，1H，J＝12.3Hz)，5.19(d，1H，J＝12.3Hz).
Example 25h
8- (3-Furanylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
By mixing with fruitAnalogously to the procedure described in example 5e, 8- (3-furylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared using ethyl 8-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 of example 23a as starting material: ESHRMS M/z 339.0510(M-H, C)16H10O5F3Calculated 339.0457).1H NMR(CDCl3/300MHz)7.85(s，1H)，7.47(s，1H)，7.41(m，1H)，7.02(m，1H)，6.90(m，2H)，6.48(s，1H)，5.84(q，1H，J＝7.0Hz)，5.07(q，1H，J＝11.7Hz)，5.01(q，1H，J＝11.7Hz).
Example 26
6-bromo-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 5-bromo-3-ethoxy-2-hydroxybenzaldehyde
To a stirring solution of ethoxy-2-hydroxybenzaldehyde (5.30 g, 31.9 mmol) in 30% hydrobromic acid/acetic acid was added bromine (2.95 g, 15.95 mmol). The solution was stirred at room temperature for 1.5 hours. The reaction was quenched with water and extracted with ethyl acetate. The organic layer was washed with saturated ammonium chloride and dried over anhydrous sodium sulfate. Upon filtration, the filtrate was concentrated in vacuo and purified by flash chromatography (silica gel) eluting with 5% ethyl acetate/hexanes to give 1.56 g (20%) of the title compound as a colorless oil. ESHRMSm/z 242.9657(M-H, C) 9H9O3Calculated Br 242.9662).
Step 2: ethyl 6-bromo-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
Using a procedure analogous to the method described in example 23d, step 1, using the aldehyde from step 1 as starting material, ethyl 6-bromo-8-ethoxy-2- (tris)Fluoromethyl) -2H-chromene-3-carboxylate. GCMS M/z 394.0(M +).1H NMR(CDCl3/400MHz)7.63(s，1H)，7.06(s，1H)，6.99(s，1H)，5.78(q，1H，J＝7.0Hz)，4.34(m，2H)，4.11(m，2H)，1.45(m，3H)，1.37(m，3H).
Step 3: preparation of 6-bromo-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Via a procedure analogous to that described in step 3 of example 2a, 6-bromo-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared: ESHRMS M/z 364.9637(M-H, C)13H9O4F3Calculated Br 334.9631).1H NMR(CDCl3/400MHz)7.74(s，1H)，7.07(s，1H)，7.00(s，1H)，5.74(q，1H，J＝7.0Hz)，4.10(m，2H，J＝7.0Hz)，1.43(q，3H，J＝7.0Hz).
Example 27
6-bromo-5, 7-dichloro-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-bromo-5, 7-dichloro-8-ethoxy-2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid esters
Ethyl 6-bromo-5, 7-dichloro-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared using a procedure analogous to the method described in example 1H, step 2, using ethyl 6-bromo-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 2 of example 26 as starting material. GCMS M/z 464.0(M +). 1HNMR(CDCl3/400MHz)8.03(s，1H)，5.80(q，1H，J＝7.0Hz)，4.34(m，2H)，4.10(m，2H)，1.42(m，3H)，1.37(m，3H).
Step 2: 6-bromo-5, 7-dichloro-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acids
Via a procedure analogous to the method described in step 3 of example 2a, 6-bromo-5, 7-dichloro-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared: ESHRMS M/z432.8829(M-H, C)13H7O4F3BrCl2Calculated 432.8851).1H NMR(CDCl3/400MHz)8.18(s，1H)，5.78(q，1H，J＝7.0Hz)，4.12(m，2H)，1.43(m，3H).
Example 28a
5, 6, 7-trichloro-8-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
5, 6, 7-trichloro-8-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared using a procedure similar to the procedure described in example 2b, using ethyl 8-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1, example 23a as the starting material. ESHRMS M/z 402.9490(M-H, C)14H19O4F3Cl3Calculated 402.9513).1HNMR(CDCl3/300MHz)8.19(s，1H)，5.79(q，1H，J＝7.0Hz)，4.02(m，2H)，1.83(m，2H)，1.07(t，3H，J＝7.2Hz).
Example 28b
8-butoxy-5, 6, 7-trichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure similar to the one described in example 2b, using a procedure from the implementationEXAMPLE 23a Ethyl 8-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 1 as the starting material 8-butoxy-5, 6, 7-trichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 416.9670(M-H, C) 15H11O4F3Cl3Calculated 416.9649).1HNMR(acetone-d6/400MHz)8.04(s，1H)，6.06(q，1H，J＝6.8Hz)，4.10(m，2H)，1.83(m，2H)，1.54(m，2H)，0.96(t，3H，J＝7.6Hz).
Example 28d
5, 6, 7-trichloro-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of ethyl 8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Commercially available 3-ethoxysalicylaldehyde was condensed (15g, 90.26mmol) (18 g, 64%) in a similar manner as described in step 1 of example 4 a. The ester has a suitable purity and can be used without further purification. ESHRMS M/z 316.0887(M-H, C)15H15ClF3O4Calculated 316.0922).
Step 2: ethyl 5, 6, 7-trichloro-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
The ester (step 1) was chlorinated (98%) via a similar method as described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification. ESHRMSm/z 417.9753(M-H, C)15H12Cl3F3O4Calculated 417.9785).
Step 3: process for preparing 5, 6, 7-trichloro-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
The ester (step 2) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a: ESHRMS M/z 388.9384(M-H, C)13H7Cl3F3O4Calculated 388.9357). 1H NMR(DMSO-d6/400MHz)，13.89(brs，1H)，7.84(s，1H)，6.20(q，1H，J＝7.1Hz)，4.07-4.14(m，2H)，1.41-1.46(m，3H).
Example 29
6, 7-dichloro-8-methoxy-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 5-bromo-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
Using a procedure analogous to the method described in step 1, example 24a, ethyl 5-bromo-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared:1HNMR(CDCl3/300MHz)7.98(s，1H)，7.18(d，1H，J＝8.7Hz)，6.83(d，1H，J＝8.7Hz)，5.78(q，1H，J＝7.0Hz)，4.39(m，2H)，1.37(m，3H).
step 2: ethyl 5-bromo-6, 7-dichloro-8-methoxy-2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid esters
Using a procedure analogous to the method described in example 1H, step 2, ethyl 5-bromo-6, 7-dichloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared:1HNMR(CD3OD/300MHz)8.02(s，1H)，7.25(s，1H)，5.80(q，1H，J＝7.0Hz)，4.34(m，2H)，3.91(s，3H)，1.37(m，3H).
step 3: ethyl 6, 7-dichloro-8-methoxy-5-methyl-2- (trifluoromethyl) -2H-color Preparation of alkene-3-carboxylic acid esters
To a stirred solution of ethyl 5-bromo-6, 7-dichloro-8-methylchloroyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.38 g, 0.85 mmol) in 1, 4-dioxane was added Pd (PPh)3)4(0.13 g, 0.85 mmol), potassium carbonate (0.34 g, 0.85 mmol) and trimethylboroxine (0.14 g, 0.85 mmol), and heated to reflux for 24 hours. It was allowed to cool to room temperature, filtered through celite, and washed with ethyl acetate. The resulting solution was concentrated in vacuo and purified by flash chromatography (silica gel) eluting with 10% ethyl acetate/hexanes to give 0.18 g (56%) of the title compound as an amorphous solid. GCMS M/z 384.0(M +). 1H NMR(CDCl3/300MHz)7.92(s，1H)，5.80(q，1H，J＝7.0Hz)，4.35(m，2H)，3.89(s，3H)，2.47(s，3H)，1.36(m，3H).
Step 4: 6, 7-dichloro-8-methoxy-5-methyl-2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
Using a procedure analogous to the method described in step 3 of example 2a, 6, 7-dichloro-8-methoxy-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared: ESHRMS M/z354.9782(M-H, C)13H8O4F3Cl2Calculated 354.9746).1H NMR(CDCl3/300MHz)8.08(s，1H)，5.78(q，1H，Y＝7.0Hz)，3.90(s，3H)，2.49(s，3H).
Example 30
5-bromo-6, 7-dichloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 5-bromo-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
Using a procedure analogous to the method described in step 1 of example 1a, ethyl 5-bromo-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared:1HNMR(CDCl3/300MHz)7.98(s，1H)，7.18(d，1H，J＝8.7Hz)，6.83(d，1H，J＝8.7Hz)，5.78(q，1H，Y＝7.0Hz)，4.39(m，2H)，1.37(m，3H).
step 2: ethyl 5-bromo-6, 7-dichloro-8-methoxy-2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid esters
Using a procedure analogous to the method described in example 1H, step 2, ethyl 5-bromo-6, 7-dichloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared:1HNMR(CD3OD/300MHz)8.02(s，1H)，7.25(s，1H)，5.80(q，1H，J＝7.0Hz)，4.34(m，2H)，3.91(s，3H)，1.37(m，3H).
step 3: 5-bromo-6, 7-dichloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acids
Using a procedure analogous to the method described in step 3 of example 2a, 5-bromo-6, 7-dichloro-8-methoxy-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared: ESHRMS M/z420.8657(M-H, C)12H5O4F3Cl2Calculated Br 402.8672).1H NMR(CDCl3/300MHz)7.87(s，1H)，5.67(q，1H，J＝7.0Hz)，3.77(s，3H).
Example 31
8-ethoxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-bromo-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
Ethyl 6-bromo-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared using a procedure analogous to the method described in step 2 of example 26: GCMS M/z 394.0(M +).
1H NMR(CDCl3/400MHz)7.63(s，1H)，7.06(s，1H)，6.99(s，1H)，5.78(q，1H，J＝7.0Hz)，4.34(m，2H)，4.11(m，2H)，1.45(m，3H)，1.37(m，3H).
Step 2: ethyl 8-ethoxy-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
Using a procedure analogous to the method described in step 3 of example 29, ethyl 8-ethoxy-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared:1HNMR(CDCl3/300MHz)7.66(s，1H)，6.78(s，1H)，6.65(s，1H)，5.74(q，1H，J＝7.0Hz)，4.31(m，2H)，4.11(m，2H)，2.27(s，3H)，1.42(m，3H)，1.34(m，3H).
step 3: preparation of 8-ethoxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a procedure analogous to the method described in step 3 of example 2a, 8-ethoxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared: ESHRMS M/z 301.0667(M-H, C) 14H12O4F3Calculated 301.0682).1H NMR(CDCl3/300MHz)7.80(s，1H)，6.81(s，1H)，6.68(s，1H)，5.73(q，1H，J＝7.0Hz)，4.11(m，2H)，2.28(s，3H)，1.43(m，3H).
Example 32a
6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 2-hydroxy-3, 5-dimethylbenzaldehyde
To a solution of 2.4-dimethylphenol (24.9 g, 204 mmol) in dry toluene (75 ml) at 0 ℃, HMPA (35 ml) was added followed by an ethyl magnesium bromide solution (61 ml, 3M solution in ethyl ether, 0.183 mmol) and the temperature was maintained below 10 ℃. Paraformaldehyde (13 g, 0.43 mol) was then added and the cooling was removed. The ethyl ether was distilled off and the mixture was refluxed. The mixture was quenched with 10% hydrochloric acid and ethyl acetate was added. The ethyl acetate solution was washed 2 times with water, 2 times with aqueous ammonium chloride solution, dried over sodium sulfate and concentrated in vacuo. Purification by silica chromatography (eluting with 98: 2 hexane: ethyl acetate) gave 17.9 g (59% yield) of the product as a yellow oil. ESHRMS M/z 147.0619(M-H, C)9H9O2Calculated 147.0603).
Step 2: preparation of ethyl 6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Prepare for
A mixture of 2-hydroxy-3, 5-dimethylbenzaldehyde (6.16 g, 0.411 mol), ethyl 4, 4, 4-trifluorocrotonate (13.4 g, 0.970 mol) and TEA (8.3 g, 0.82 mol) prepared in step 1 in DMSO (10 ml) was heated at 90 ℃. The reaction rate was slow as shown by GCMS. Potassium carbonate was then added and when the reaction was mostly complete, 10% hydrochloric acid was added followed by ethyl acetate. The layers were separated and the ethyl acetate layer was washed 2 times with water, 2 times with aqueous ammonium chloride, dried over sodium sulfate and concentrated in vacuo to give an orange oil. The crude product was purified by silica chromatography (elution with 9: 1 hexane: ethyl acetate) to yield 5.47 g (44% Yield) of the product. ESHRMS M/z 330.0938(M +, C)15H15F3O3Calculated 300.0973).
No. 3The method comprises the following steps: preparation of 6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The product was obtained by hydrolysis of the ester from step 2 via a similar method to that described in step 2 of example 17 d:1H NMR(CDCl3/400MHz)7.79(s，1H)，7.01(s，1H)，6.88(s，1H)，5.68(q，1H，J＝6.9Hz)，2.24(s，3H)，2.20(s，3H)；ESHRMS m/z 271.0575(M-H，C13H10F3O3，Calc’d 271.0582).
example 32b
(2S) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a kessel (chiralel) OJ column eluting with ethanol/heptane/TFA ═ 5/95/0.1, (2S) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from example 32a for chiral separation using racemic 6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid, whereas the second peak was detected at 254nm with a retention time of 6.36 min:
1H NMR(acetone-d6/300MHz)7.81(s，1H)，7.09(s，2H)，5.80(q，1H，J＝7.2Hz)，2.25(s，3H)，2.21(s，1H).[a]25 589＝+3.2 degrees(MeOH)and[a]25 436＝+37.8 degrees(MeOH).
example 32c
(2R) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
(2R) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was resolved using a chiral separation of racemic 6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from example 32a using a kessel (chiralel) OJ column eluted with ethanol/heptane/TFA-5/95/0.1, with a first peak detected at 254nm with a retention time of 4.38 min:
1H NMR(acetone-d6/300MHz)7.81(s，1H)，7.09(s，2H)，5.80(q，1H，J＝7.2Hz)，2.25(s，3H)，2.21(s，1H).[a]25 589＝-7.6 degrees(MeOH)and[a]25 436＝40.4 degrees(MeOH).
Example 32d
(2R) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid compound with (1S) -1-phenylethylamine (1: 1)
(2R) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from example 32c (138.5 mg, 0.51 mmol) was dissolved in ethyl acetate (2 mL) and IPA (2 mL). To this solution was added (S) - (+) - α -methylbenzylamine (61.6 mg, 0.51 mmol). While the solution was stirred, hexane (12 ml) was added. The uncapped solution was allowed to stand until crystallization occurred. And (3) determining the absolute configuration of the complex by using small molecule X-ray diffraction.1H NMR(acetone-d6/400MHz)7.76(s，1H)，7.39(d，2H，J＝7.2Hz)，7.27(t，2H，J＝7.2Hz)，7.17(t，1H，J＝6.8Hz)，7.06(s，2H)，5.80(q，1H，J＝7.2Hz)，2.23(s，3H)，2.19(s，1H).
Example 32e
(2R) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid compound with (1R) -1-phenylethylamine (1: 1)
Using a procedure analogous to the method described in example 32d, the (2R) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid compound was prepared with (1R) -1-phenylethylamine (1: 1):1H NMR(acetone-d6/400MHz)7.76(s，1H)，7.39(d，2H，J＝7.2Hz)，7.27(t，2H，J＝7.2Hz)，7.17(t，1H，J＝6.8Hz)，7.06(s，2H)，5.80(q，1H，J＝7.2Hz)，2.23(s，3H)，2.19(s，1H).
example 32f
(2S) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid compound with (1R) -1-phenylethylamine (1: 1)
Using a procedure analogous to the method described in example 32d, the (2S) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid compound was prepared with (1R) -1-phenylethylamine (1: 1):
1H NMR(acetone-d6/400MHz)7.76(s，1H)，7.39(d，2H，J＝7.2Hz)，7.27(t，2H，J＝7.2Hz)，7.17(t，1H，J＝6.8Hz)，7.06(s，2H)，5.80(q，1H，J＝7.2Hz)，2.23(s，3H)，2.19(s，1H).
example 33
5-chloro-6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 5-chloro-6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
The ester (example 32a, step 2) was chlorinated (91%) in a similar manner as described in step 1 of example 4 b. The ester has a suitable purity and can be used without further purification.
1H NMR(Chloroform-d6/400MHz)，8.09(s，1H)，7.02(s，1H)，5.71(q，1H，J＝7.1Hz)，4.28-4.35(m，2H)，2.27(s 3H)，2.17(s，3H)，1.33-1.37(m，3H).
Step 2: preparation of 5-chloro-6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester (step 1) was hydrolyzed to form the carboxylic acid (132 mg, 99%) via a similar procedure as described in step 2 of example 4 a: ESHRMS M/z 305.0171(M-H, C)13H9ClF3O3Calculated 305.0187).1HNMR(Chloroform-d6/400MHz)7.86(s，1H)，6.83(s，1H)，5.49(q，1H，J＝7.1Hz)，2.06(s，3H)，1.96(s，3H).
Example 34a
6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of ethyl 2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylate
In a three-neck flask equipped with an overhead mechanical stirrer, condenser, thermocouple/heating mantle and nitrogen inlet was charged salicylaldehyde (56.03 g, 4581.81 mmol) and DMF (200 ml). Potassium carbonate (63.41 g, 458.81 mmol) was added with stirring to give a yellow suspension. Ethyl 4, 4, 4-trifluorocrotonate was added with warming. The temperature is initially raised to 106 ℃ and then maintained at 90 ℃ for 20 hours with heating. The reaction was allowed to cool to room temperature, diluted with water, and transferred to a separatory funnel. The mixture was extracted with diethyl ether and the organic layers were mixed. The ether layer was washed with water, saturated sodium bicarbonate, brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford a clear brown oil: boiling point 116 deg.C, about 2 mm.
1HNMR(acetone-d6/300MHz)7.89(s，1H)，7.52-7.38(m，2H)，7.09(dt，1J＝1.0，7.7Hz)，7.03(d，1H，J＝8.3Hz)，5.84(q，1H，J＝7.3Hz)，4.39-4.23(m，2H)，1.33(t，3H，J＝7.0Hz).GCMS m/z 272(M+).
Step 2: preparation of ethyl 6-acetyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
A 500 ml three-neck round bottom flask equipped with a stir bar, thermocouple and heating mantle, condenser and nitrogen inlet was charged with dichloromethane (150 ml), ethyl 2-trifluoromethyl-2H-chromene-3-carboxylate (14.94 g, 54.882 mmol) and aluminum chloride (18.29 g, 137.21 mmol). The reaction was cooled to 0 ℃ with stirring, followed by the addition of acetyl chloride (5.85 ml, 6.46 g, 82.32 mmol). The reaction was stirred at room temperature for 3 days, and then refluxed for 6 days. The reaction was poured onto ice and extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo to give a solid. The solid was triturated with hexane to obtain a slurry. The thick slurry was filtered under vacuum to obtain the title compound as a white solid (11.78 g, 68.3%): melting point 101-.
1H NMR(acetone-d6/300MHz)8.14(s，1H)，8.04(dd，1H，J＝8.7，2.2Hz)，7.98(s，1H)，7.13(d，1H，J＝8.6Hz)，5.95(q，1H，J＝6.8Hz)，4.38-4.23(m，2H)，2.57(s，3H)，1.33(t，3H，J＝7.0Hz).GCMS m/z 314(M+).
Step 3: preparation of ethyl 6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
In a 50 ml single neck round bottom flask, ethyl 6-acetyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.465 g, 4.662 mmol), dichloromethane (4 ml) and triethylsilane (1.71 ml, 1.25 g, 10.72 mmol) were charged and stirred at room temperature overnight. The crude reaction was poured into water and extracted several times with dichloromethane. The combined organics were washed sequentially with water, 10% aqueous sodium carbonate, dried over magnesium sulfate, filtered and concentrated in vacuo to give a colorless oil. The oil was purified by silica chromatography (eluting with 9 hexanes: 1 ethyl acetate) to give the title compound as a clear, colorless oil (1.25 g, 89%):
1H NMR(acetone-d6/300MHz)7.84(s，1H)，7.30(d，1H，J＝2.0Hz)，7.26(dd，1H，J＝8.3，2.0Hz)，6.93(d，1H，J＝8.3Hz)，5.79(q，1H，J＝7.3Hz)，4.37-4.24(m，2H)，2.60(q，2H，J＝7.6Hz)，1.32(t，3H，J＝7.3Hz)，1.20(t，3H，J＝7.6Hz).GCMS m/z 300(M+).
Step 4: preparation of 6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
A15 mL, single-neck round bottom flask was charged with ethyl 6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.238 g, 0.932 mmol), tetrahydrofuran: ethanol: water (7: 2: 1, 3 mL in volume), and aqueous sodium hydroxide (0.41 mL of 2.5N in water, 1.026 mmol). The reaction was stirred at room temperature under nitrogen for 3 days and concentrated in vacuo (high vacuum) to give a semi-solid. The semi-solid was dissolved in water, washed with diethyl ether, purged with nitrogen and gently heated. Under stirring, the resulting organic solvent-free aqueous layer is acidified with concentrated hydrochloric acid while stirring to give a thick layerAnd (4) pulping. The thick slurry was vacuum filtered to obtain a white solid. The solid was dried under high vacuum to give the title compound as a white powder (0.178 g, 70%): melting point 145-149 ℃. HRMS M/z271.0600(M-H, C)13H10F3O calculated 271.0577).1HNMR(acetone-d6/300MHz)7.86(s，1H)，7.30(d，1H，J＝2.0Hz)，7.27(d，1H，J＝8.3Hz)，6.94(d，1H，J＝8.3Hz)，5.77(q，1H，J＝7.0Hz)，2.61(q，2H，J＝7.5Hz)，1.21(t，3H，J＝7.5Hz).
Example 34b
(2S) -6-Ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using a kessel (chiralcel) OJ column eluted with ethanol/heptane/TFA ═ 5/95/0.1, (2S) -6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was resolved using chiral separation of racemic 6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from example 34a, and a second peak was detected at 254nm with a retention time of 6.50 minutes:
1H NMR(acetone-d6/400MHz)7.84(s，1H)，7.29(d，1H，J＝2.0Hz)，7.24(dd，1H，J＝8.4，2.4Hz)，6.92(d，1H，J＝8.4Hz)，5.90(q，1H，J＝7.0Hz)，2.59(q，2H，J＝7.6Hz)，1.19(t，3H，J＝7.6Hz).
[α]25 589α is neutralized in methanol at +32.3 °]25 436At +146.5 degrees in methanol.
Example 34c
(2R) -6-Ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
(2R) -6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was resolved using chiral separation of racemic 6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from example 34a using a Kelvier (Chiracel) OJ column eluted with ethanol/heptane/TFA-5/95/0.1, with a peak detected at 254nm with a retention time of 5.16 min:
1H NMR(acetone-d6/400MHz)7.84(s，1H)，7.29(d，1H，J＝2.0Hz)，7.24(dd，1H，J＝8.4，2.4Hz)，6.92(d，1H，J＝8.4Hz)，5.90(q，1H，J＝7.0Hz)，2.59(q，2H，J＝7.6Hz)，1.19(t，3H，J＝7.6Hz).
[α]25 589-33.9 degrees (methanol) and [ alpha ]]25 436-134.9 degrees (methanol).
Example 34d
6- (1, 1-difluoroethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6- (1, 1-difluoroethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acid esters
A15 mL, three-necked, round-bottomed flask equipped with a nitrogen inlet, thermocouple and heating mantle and stopper was charged with ethyl 6-acetyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.997 g, 3.173 mmol) and deoxoflur from step 2 of example 34a_(2 ml, 2.4 g, 10.8 mmol), stirred at 65 ℃ for 24 h and then at 75 ℃ for 5 h, the reaction was allowed to cool to room temperature, diluted with ethyl acetate and washed with water. The resultant ethyl acetate layer was washed with a 2N hydrochloric acid solution, water, a 10% sodium carbonate solution and brine, and dried over magnesium sulfate. The resulting suspension was filtered and the solution was concentrated in vacuo to give a brown pigment And (5) obtaining oil. The oil was purified by silica chromatography (eluting with 9: 1 hexanes: ethyl acetate) to afford the title product as an oily, white crystalline solid (0.410 g, 38%): the melting point is 48-51 ℃.1H NMR(acetone-d6/300MHz)7.95(s，1H)，7.72(s，1H)，7.61(d，1H，J＝8.5Hz)，7.13(d，1H，J＝8.5Hz)，5.91(q，1H，J＝7.1Hz)，4.41-4.2(m，2H)，1.96(t，3H，J＝18.4Hz)，1.33(t，1H，J＝7.1Hz).GCMS m/z 336(M+).
Step 2: process for preparing 6- (1, 1-difluoroethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
A500 mL round bottom flask was charged with ethyl 6- (1, 1-difluoroethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.385 g, 1.145 mmol) THF: EtOH: H from step 12O (7: 2: 1 by volume, 3ml) and aqueous sodium hydroxide (0.55 ml, 1.374 mmol) and stirred at room temperature for 2 days. The reaction was concentrated in vacuo to give a semi-solid. The semisolid was dissolved in water, washed with diethyl ether, and the resultant water layer was purged with nitrogen and warmed. The resulting organic solvent-free aqueous layer was acidified (to pH 1) with concentrated hydrochloric acid to give a gummy solid. The mixture was extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, diluted with isooctane and concentrated in vacuo to give an oil. After standing, the mixture formed a white powder (0.159 g, 45%): melting point 156 ℃ and 158 ℃ (w/decomposition). LCMS M/z 309(M + H). HRMS M/z 307.0408(M-H, C) 13H8F5O3Calculated 307.0388).1HNMR(acetone-d6/300MHz)12.2-11.2(br s，～0.5H(1H exch)，7.97(s，1H)，7.72(s，1H)，7.61(dd，1H，J＝8.5，2.2Hz)，7.13(d，1H，J＝8.7Hz)，5.89(q，1H，J＝7.0Hz)，1.97(t，3H，J＝18.3Hz).
Example 34e
6- (2, 2, 2-trifluoroethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-formyl-2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylate Preparation of
In a 50 ml round bottom flask, 5-formyl salicylaldehyde (3.21 g, 21.39 mmol), ethyl 4, 4, 4-trifluorocrotonate (3.50 ml, 3.96 g, 23.53 mmol), dimethylformamide (15 ml), and potassium carbonate (2.95 g, 21.39 mmol) were charged and heated to 60 ℃ for 12 hours. Additional ethyl 4, 4, 4-trifluorocrotonate (3.50 ml, 3.96 g, 23.53 mmol) was added. And the reaction was heated at 75 ℃ for 16 hours. After cooling to room temperature, the reaction was partitioned between water and diethyl ether. The organic layer was washed with saturated sodium bicarbonate solution, potassium hydrogen sulfate solution (0.25M), brine, and treated with decolorizing carbon (and gently warmed). The resulting black suspension was dried over magnesium sulfate, vacuum filtered through celite, and concentrated in vacuo to give an orange crystalline material. The material was recrystallized from hot hexane to obtain the ester as orange crystals (1.51 g, 24%): the melting point is 84.3-86.2 ℃. 1H NMR(acetone-d6/300MHz)9.96(s，1H)，8.06(d，1H，J＝2Hz)，8.02(s，1H)，7.99(dd，1H，J＝8.5，2.0Hz)，7.24(d，1H，J＝8.5Hz)，5.99(q，1H，J＝7.1Hz)，4.43-4.25(m，2H)，1.34(t，3H，J＝7.3Hz).
FABLRMS M/z 301(M + H). EIHRMS M/z 300.0605(M +, calculated 300.0609) C14H11F3O4The calculation analysis shows that: carbon 56.01; hydrogen 3.69. And (3) measuring: 56.11 carbon; hydrogen 3.77).
Step 2: ethyl 6- (1-hydroxy-2, 2, 2-trifluoroethyl) -2- (trifluoromethyl) -2H-1- Benzopyran-3-carboxylic acid estersPreparation of
The aldehyde from step 1 (0.89 g, 3.0 mmol) was cooled to 0 ℃, treated with a 0.5M solution of trimethyl (trifluoromethyl) silane (8.4 ml, 4.2 mmol), and 4 drops of a 1.0M solution of tetrabutylammonium fluoride were added. The reaction was allowed to warm to room temperature and stirred for 21.1 hours. The reaction was quenched with 3N hydrochloric acid, extracted with ethyl acetate, washed with water, brine, dried over magnesium sulfate and concentrated in vacuo to afford a brown oil (1.02 g). The oil was purified by flash chromatography on silica gel eluted with 10% ethyl acetate/hexane to give a brown oil (0.77 g, 58%):
1H NMR(CDCl3/300MHz)7.72(d，1H，J＝3.4Hz)，7.34(m，2H)，6.99(d，1H，J＝8.5Hz)，5.71(q，1H，J＝6.8Hz)，4.83(q，1H，J＝6.4Hz)，4.33(m，2H)，1.35(t，3H，J＝7.1Hz)，0.11(s，9H).FABLRMS m/z 443(M+H).
step 3: ethyl 6- {2, 2, 2-trifluoro-1- [ (1H-imidazole-1-carbo-thioyl) oxy]Second step Preparation of yl } -2- (trifluoromethyl) -2H-benzopyran-3-carboxylic acid esters
The alcohol from step 2 (1 g, 2.7 mmol) was dissolved in dichloromethane. To the above solution was added thiocarbonyldiimidazole (0.72 g, 4.05 mmol), followed by DMAP (105 mg, 0.86 mmol). The mixture was stirred at room temperature for 2 hours. The mixture was filtered through a plug of silica, which was washed with 15 to 30% ethyl acetate in hexane to give a pale yellow oil (2.5 g, 59%). LCMS M/z 418.05(M + H).
1H NMR(CDCl3/400MHz)8.37(s，1H)，7.72(d，1H，J＝6.4Hz)，7.65(s，1H)，7.45(m，1H)，7.34(m，1H)，7.08(s，1H)，7.04(d，1H，J＝8.4Hz)，6.66(m，1H)，5.71(q，1H，J＝6.8Hz)，4.33(m，2H)，1.35(t，3H，J＝7.1Hz).
Step 4: preparation of ethyl 6- (2, 2, 2-trifluoroethyl) -2H-chromene-3-carboxylate
The ester from step 3 (2.4 g, 5 mmol) was dissolved in toluene (15 ml). Triethylsilane (30 ml, 0.18 mmol) was added to the above solution. The mixture was heated to reflux. Benzoyl peroxide (1.21 g, 5 mmol) in toluene (15 ml) was added in four portions at 15 minute intervals. The mixture was heated to reflux for 2 hours. The mixture was filtered through a plug of silica, which was washed with 10 to 20% ethyl acetate in hexane to obtain a pale yellow oil. The ester has a suitable purity and can be used without further purification.
Step 5: 6- (2, 2, 2-trifluoroethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
Using a procedure analogous to the method described in example 1a, step 3, 6- (2, 2, 2-trifluoroethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z325.0294(M-H, C)13H7F6O3Calculated 325.0251).1H NMR(acetone-d6/400MHz)7.88(s，1H)，7.47(s，1H)，7.41(d，1H，J＝5.6Hz)，7.04(d，1H，J＝8.4Hz)，5.84(q，1H，J＝7.0Hz)，3.54(t，2H，J＝11.2Hz).
Example 35
6-tert-butyl-8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 5-tert-butyl-3-chloro-2-hydroxybenzaldehyde
5-tert-butyl-3-chloro-2-hydroxybenzaldehyde was prepared using a procedure analogous to the method described in step 2 of example 1a, using 5-tert-butyl-2-hydroxybenzaldehyde as starting material. The ester has a suitable purity and can be used without further purification.
Step 2: ethyl 6-tert-butyl-8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
Ethyl 6-tert-butyl-8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared using a procedure analogous to the method described in step 1 of example 1a, using 5-tert-butyl-3-chloro-2-hydroxybenzaldehyde from step 1 as starting material. The ester has a suitable purity and can be used without further purification.
Step 3: preparation of 6-tert-butyl-8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-tert-butyl-8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared via a procedure analogous to the method described in step 3 of example 1a, using ethyl 6-tert-butyl-8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 2 as starting material. ESHRMS M/z 333.0485(M-H, C)15H13O3F3Cl calculated 333.0500).
1H NMR(acetone-d6/300MHz)7.93(s，1H)，7.52(m，2H)，5.90(q，1H，J＝7.0Hz)，1.33(s，9H).
Example 36
6-chloro-8- (3-methylbut-3-en-1-ynyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-8- (3-methylbut-3-en-1-ynyl) -2- (trifluoromethyl) Preparation of (E) -2H-chromene-3-carboxylic acid esters
Ethyl 6-chloro-8-iodo-2- (trifluoromethyl) -2H-chromene prepared as step 2 of U.S. Pat. No. 73, 6,271,253B 1 To a solution of-3-carboxylic acid ester (0.342 g, 0.790 mmol) in degassed anhydrous toluene was added Pd (PPh)3)3(54 mg, 0.47 mmol), copper iodide (15 mg, 0.079 mmol), TEA (0.275 mg, 2.72 mmol) and 2-methylbut-1-en-3-yne (0.247 g, 3.74 mmol), and the mixture was stirred under a dry nitrogen atmosphere. When the reaction was judged to be complete using GCMS, water and ethyl acetate were added and the layers were separated. The ethyl acetate layer was washed with 10% hydrochloric acid, twice with water and twice with aqueous ammonium chloride, dried over sodium sulfate and concentrated in vacuo. The crude product was purified by silica chromatography (95: 5 hexanes: ethyl acetate elution) to yield 155 mg (53% yield) of the product as a white crystalline solid:
1H NMR(CDCl3/300MHz)7.62(s，1H)，7.37(d，1H，J＝2.4Hz)，7.14(d，1H，J＝2.4Hz)，5.80(q，1H，J＝6.6Hz)，5.44(m，1H)，5.35-5.36(m，1H)，4.31-4.34(m，2H)，1.99(s，3H)，1.36(t，3H，J＝7.1Hz).
step 2: 6-chloro-8- (3-methylbut-3-en-1-ynyl) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid
The ester from step 1 was hydrolyzed and recrystallized from hot hexane via a similar procedure as described in step 2 of example 17d to give the product:
1H NMR(CDCl3/400MHz 7.76(s，1H)，7.41(d，1H，J＝2.4Hz)，7.19(d，1H，J＝2.4Hz)，5.79(q，1H，J＝6.6Hz)，2.00(s，3H)；ESHRMS m/z 341.0197(M-H，C16H9ClF3O3，Calc’d 341.0187).
example 37a
7- (1-phenylethenyl) -2- (trifluoromethyl) -2H-chromene 3-carboxylic acid
Step 1: phenyl (3- { [2- (trimethylsilyl) ethoxy ]Methoxy } phenyl group) Preparation of ketones
To a solution of (3-hydroxyphenyl) (phenyl) methanone (30.0 g, 151 mmol) in anhydrous tetrahydrofuran (300 ml) at 0 ℃, potassium tert-butoxide solution (200 ml of a 1M solution in tetrahydrofuran, 0.200 mmol) was added slowly followed by [2- (chloromethoxy) ethyl](trimethyl) silane (32.1 ml, 182 mmol). After stirring the mixture for 2 hours, the solvent was removed in vacuo and the residue was dissolved in a mixture of water (200 ml) and ethyl acetate (200 ml). The aqueous layer was further extracted with ethyl acetate (2 × 100 ml). The extract of the mixture was washed with water (200 ml), 0.1N hydrochloric acid (500 ml) and brine (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo to give an orange oil. The crude product was redissolved in hexane and filtered through a plug of silica gel to obtain the product as an impure pale yellow oil which was used subsequently without further purification. ESHRMS M/z 329.1586(M + H, C)19H25O3Calculated Si 329.1567).
Step 2: preparation of 3- (1-phenylvinyl) phenol
To a solution of titanium chloride (4.01 ml, 36.5 mmol) in dry dichloromethane (100 ml) under dry nitrogen was added a 0 ℃ solution of trimethylaluminum (36.5 ml of a 2.0M solution in toluene, 73.0 mmol). The mixture was stirred for 30 minutes, cooled to-40 to-50 ℃ and phenyl (3- { [2- (trimethylsilyl) ethoxy ] was added ]A solution of methoxy } phenyl) methanone (13.33 g-75 wt%, 36.5 mmol) in dry dichloromethane (20 ml) was allowed to warm to room temperature while stirring overnight. The mixture was then cooled to 0 ℃ and water was added dropwise. It was then acidified to pH 1 with 1N hydrochloric acid and the mixture was extracted with ethyl acetate (2 × 300 ml). The mixed extracts were washed with brine (100 ml),dried over magnesium sulfate, filtered and concentrated in vacuo to yield 4.22 g (71% yield) of the product as a yellow oil: EIHRMS M/z 196.0894(M +, C)14H12O calculated 196.0888).
Step 3: preparation of 2-hydroxy-4- (1-phenylvinyl) benzaldehyde
A mixture of phenol (4.15 g, 21.1 mmol), magnesium chloride (3.02 g, 31.7 mmol), TEA (11.1 ml, 79.3 mmol) and paraformaldehyde (4.29 g, 143 mmol) from step 2 in dry acetonitrile (100 ml) was refluxed for 17 hours. Additional magnesium chloride (1.5 g, 15.8 mmol), TEA (5.6 ml, 40 mmol) and paraformaldehyde (2.23 g, 74 mmol) were then added and reflux continued for 2 hours. The mixture was then cooled, acidified with 1N hydrochloric acid and extracted with ethyl acetate (2 × 200 ml). The combined extracts were washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by passage through a silica gel plug (elution with 9: 1 hexane: ethyl acetate) to yield 4.28 g (91% yield) of the product as a yellow oil. EIHRMS M/z 224.0837(M-H, C) 15H12O2Calculated 224.0837).
Step 4: ethyl 7- (1-phenylethenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acid esters
A mixture of 2-hydroxy-4- (1-phenylvinyl) benzaldehyde (4.17 g, 18.6 mmol) prepared in step 3, potassium carbonate (2.57 g, 18.6 mmol) and ethyl 4, 4, 4-trifluorocrotonate (3.34 ml, 22.3 mmol) in anhydrous DMF (20 ml) was heated to 85 ℃ for 16.5 hours under a dry nitrogen atmosphere. The mixture was then cooled, poured into 1N hydrochloric acid (100 ml) and extracted with ethyl acetate (2 × 100 ml). The combined extracts were washed with brine (50 ml), dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purified by silica chromatography (eluting with 3: 1 dichloromethane: hexane) to yield 2.33 g(33% yield) product as a pale yellow oil. EIHRMS M/z 374.1120(M +, C)21H17F3O3Calculated 374.1130).
Step 5: process for preparing 7- (1-phenylvinyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
The ester from step 4 was hydrolyzed via a similar procedure as described in step 2 of example 18a to obtain the product as a white crystalline solid:
1H NMR(dmso-d6，300MHz)13.26(brs，1H)，7.87(s，1H)，7.46(d，1H，J＝2.9Hz)，7.34-7.40(m，3H)，7.25-7.28(m，2H)，6.96(dd，1H，J＝1.6，7.9Hz)，6.89(s，1H)，5.99(q，1H，J＝7.3Hz)，5.63(s，1H)，5.51(s，1H)；
ESHRMS m/z 345.0722(M-H，C19H12F3O2Calculated 345.0733).
Example 37b
7- (1-phenylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7- (1-phenylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
A mixture of ethyl 7- (1-phenylvinyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (2.13 g, 5.69 mmol), prepared as in step 4 of example 50, and 10% palladium on carbon (150 mg) in dry ethanol (30 mL) was hydrogenated at 30psi for 3H. The catalyst was removed by filtration and the filtrate was concentrated in vacuo. The crude product was purified by silica chromatography (eluting with 92.5 hexanes: ethyl acetate) to afford 1.62 g (75% yield) of the product in the form of a colorless oil: EIHRMS M/z 376.1279(M +, C)21H19F3O2Calculated 376.1286).
Step 2: preparation of 7- (1-phenylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Prepare for
The ester from step 1 was hydrolyzed via a similar procedure as described in step 2 of example 18 a. Purification by reverse phase chromatography (elution with acetonitrile: 0.5% TFA-water) afforded the product as an off-white crystalline solid:
1H NMR(dmso-d6，300MHz)13.20(brs，1H)，7.81(s，1H)，7.36-7.40(m，1H)，7.28-7.30(m，4H)，7.16-7.23(m，1H)，6.92-7.00(m，2H)，5.87(q，1H，J＝7.3Hz)，4.16(q，1H，J＝7.3Hz)，1.56(d，3H，J＝7.3Hz)；
ESHRMS m/z 347.0864(M-H，C19H14F3O3calculated 347.0890).
Example 38a
6, 8-dichloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1; ethyl 6-chloro-7- [ isobutyl (methyl) amino]-2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
Ethyl 6-chloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared using a procedure analogous to the procedure described in step 1, example 8 a. GCMSm/z 391.0(M +).
1H NMR(acetone-d6/400MHz)7.61(s，1H)，7.19(s，1H)，6.60(s，1H)，5.66(q，1H，J＝7.0Hz)，4.30(m，2H)，2.96(m，2H)，2.93(s，3H)，1.96(m，1H)，1.33(m，3H)，0.96(m，6H).
Step 2: ethyl 6, 8-dichloro-7- [ isobutyl (methyl) amino]-2- (trifluoromethyl) Preparation of (E) -2H-chromene-3-carboxylic acid esters
Ethyl 6, 8-dichloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared using a procedure analogous to the procedure described in step 2 of example 1 a. GCMS M/z 425.0(M +).
1H NMR(CDCl3/400MHz)7.57(s，1H)，7.06(s，1H)，5.78(q，1H，J＝7.0Hz)，4.28(m，2H)，3.38(m，2H)，3.21(s，3H)，1.85(m，1H)，1.32(m，3H)，0.96(m，6H).
Step 3: 6, 8-dichloro-7- [ isobutyl (methylamino) amino]-2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid
Preparation of 6, 8-dichloro-7- [ isobutyl (methyl) amino ] via a procedure analogous to the procedure described in step 2 of example 8a]-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. ESHRMSm/z 396.0371(M + H, C)16H17O3F3Cl2Calculated N is 396.0376).1HNMR(acetone-d6/400MHz)7.86(s，1H)，7.53(s，1H)，5.78(q，1H，J＝7.0Hz)，3.02(m，2H)，2.86(m，3H)，1.82(m，1H)，0.90(m，6H).
Example 38b
6, 8-dichloro-7- (methylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-7- [ isobutyl ] etherRadical (methyl) amino]-2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
Ethyl 6-chloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared using a procedure analogous to the procedure described in step 1, example 8 a. GCMSm/z 391.0(M +).
1H NMR(acetone-d6/400MHz)7.61(s，1H)，7.19(s，1H)，6.60(s，1H)，5.66(q，1H，J＝7.0Hz)，4.30(m，2H)，2.96(m，2H)，2.93(s，3H)，1.96(m，1H)，1.33(m，3H)，0.96(m，6H).
Step 2: ethyl 6, 8-dichloro-7- (methylamino) -2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid esters
Ethyl 6, 8-dichloro-7- (methylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared using a procedure analogous to the method described in step 2 of example 1 b. GCMS M/z425.0(M +).
1H NMR(CDCl3/400MHz)7.57(s，1H)，7.06(s，1H)，5.78(q，1H，J＝7.0Hz)，4.28(m，2H)，3.21(s，3H)，1.32(m，3H).
Step 3: 6, 8-dichloro-7- (methylamino) -2- (trifluoromethyl) -2H-chromen-3- Preparation of carboxylic acids
Via a procedure analogous to the method described in example 8a, step 2, 6, 8-dichloro-7- (methylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z339.9777(M + H, C)12H9O3F3Cl2Calculated N is 339.9750).1H NMR(acetone-d6/400MHz)7.80(s，1H)，7.41(s，1H)，5.89(q，1H，J＝7.0Hz)，3.25(m，3H).
Example 38c
6, 8-dichloro-7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Via a procedure analogous to the method described in example 38b, 6, 8-dichloro-7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared. ESHRMS M/z 382.0242(M + H, C)15H15O3Cl2Calculated N is 382.0219). 1H NMR(acetone-d6/400MHz)7.82(s，1H)，7.45(s，1H)，5.91(q，1H，J＝7.0Hz)，3.45(m，2H)，1.86(m，1H)，0.95(m，6H).
Example 39a
8- [4- (aminosulfonyl) phenyl ] -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Chlorosulfonic acid (5 ml) was cooled to-20 ℃ and 6-chloro-8-phenyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (61.7 mg, 0.174 mmol), prepared as in step 2 of U.S. Pat. No. 6,271,253B1, was added as a solid. The bright orange mixture was then added dropwise to the cold ammonium hydroxide solution, ethyl acetate was added, and the mixture was stirred for 1 hour. The ethyl acetate layer was separated, washed twice with water, aqueous ammonium chloride, dried over sodium sulfate and concentrated in vacuo, and triturated with hexane to give the product:
1H NMR(CD3OD/400MHz)7.95(d，2H，J＝8.6Hz)，7.81(s，1H)，7.66(d，2H，J＝8.6Hz)，7.46(d，1H，J＝2.6Hz)，7.42(d，1H，J＝2.6Hz)，5.80(q，1H，J＝7.0Hz)；ESHRMS m/z 431.9945(M-H，C17H10ClF3NO5calculated S is 431.9915).
Example 39b
8- { [4- (aminosulfonyl) phenyl ] ethynyl } -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: 4- [ (trimethylsilyl) ethynyl group]Preparation of benzenesulfonamides
To a solution of 4-bromobenzenesulfonamide (4.51 g, 19.1 mmol) in toluene (900 ml) at 75 ℃ was added ethynyl (trimethyl) silane (4 g, 40 mmol), Pd (PPh)3)4(1.3 g, 1.1 mmol), copper iodide (0.46 g, 2.42 mmol) and TEA (5.7 g, 56 mmol) and the mixture was allowed to cool to room temperature with stirring. Addition of additional Pd (PPh) 3)4(1 g, 0.9 mmol), and the mixture is stirred at room temperature. After 5 days, ethyl ether was added and the mixture was washed with 10% hydrochloric acid, water and saturated aqueous ammonium chloride, dried over sodium sulfate and concentrated in vacuo to yield 2.93 g (61% yield) of the product: ESHRMS M/z 271.0935(M + NH)4，C11H15NO2SSiNH4Calculated 271.0937).
Step 2: preparation of 4-ethynylbenzenesulfonamide
4- [ (trimethylsilyl) ethynyl prepared in step 1 under a dry nitrogen atmosphere]To a solution of benzenesulfonamide (1.69 g, 3.13 mmol) in anhydrous tetrahydrofuran was added TBAF (10 ml of a 1.0M solution in tetrahydrofuran, 10 mmol), and the resulting mixture was stirred at room temperature. When silica TLC (elution with 1: 1 hexane: ethyl acetate) showed the reaction was complete, 10% hydrochloric acid and ethyl acetate were added. The ethyl acetate layer was separated, washed twice with water and aqueous ammonium chloride, dried over sodium sulfate and placed under vacuumConcentration gave 0.748 g (62% yield) of product: ESHRMS M/z 199.0506(M + NH)4，C8H7NO2SNH4Calculated 199.0541).
Step 3: ethyl 8- { [4- (aminosulfonyl) phenyl]Ethynyl } -6-chloro-2- (trifluoro-phenyl) phosphonium chloride Preparation of methyl) -2H-chromene-3-carboxylic acid esters
Ethyl 6-chloro-8-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate, prepared as in step 2 of U.S. patent No. 6,271,253B1, was reacted with 4-ethynylbenzenesulfonamide, prepared in step 2, via a similar procedure as described in step 1 of example 21f to give the product: ESHRMS M/z 503.0686(M + NH)4，C21H15ClF3O5SNH4Calculated 503.0655).
Step 4: 8- { [4- (aminosulfonyl) phenyl]Ethynyl } -6-chloro-2- (trifluoromethyl) Preparation of (E) -2H-chromene-3-carboxylic acid
The ester from step 3 was hydrolyzed via a similar procedure as described in example 17d, step 2, to yield the product:1H NMR(CD3OD/400MHz)7.88(d，2H，J＝8.6Hz)，7.64(d，2H，J＝8.6Hz)，7.45(s，1H)，7.39(d，1H，J＝2.4Hz)，7.26(d，1H，J＝2.6Hz)，5.98(q，1H，J＝7.0Hz)；
ESHRMS m/z 455.9885(M-H，C19H10ClF3O5calculated S is 455.9915).
Example 40a
6.8-dichloro-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
6, 8-dichloro-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from example 1b was dissolved in a minimum of ethanol. Sodium hydroxide (0.5016N from Aldrich) was added dropwise (1 equivalent relative to the free acid) to the above solution via a titration tube. The solvent was removed in vacuo and the resulting solid redissolved in water. The solvent was removed in vacuo and the residue was dried in high vacuum to give the sodium salt.
1H NMR(acetone-d6/400MHz)7.58(s，1H)，7.10(s，1H)，6.20(q，1H，J＝7.0Hz)，3.95(m，2H)，1.65(m，1H)，1.51(m，4H)，0.971(m，6H).
Example 40b
6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
To a stirred solution of the acid (example 9c, step 3) in 10 ml ethanol (anhydrous) was added sodium hydroxide (0.5006N). The resulting solution was stirred at room temperature for 1 hour. The solvent was removed in vacuo to give the sodium salt (99%).
1H NMR(DMSO-d6/400MHz)7.81(s，1H)，7.5(s，1H)，6.97(s，1H)，5.89(q，1H，J＝7.1Hz)，2.51(d，2H，J＝6.7Hz)，1.85-1.89(m，1H)，0.843(m，6H).
Example 40c
8-ethoxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Sodium 8-ethoxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by a similar procedure as described in example 40a, using the carboxylic acid from example 31.
1H NMR(D2O/300MHz)7.26(s，1H)，6.83(d，1H，J＝1.2Hz)，6.68(d，1H，J＝1.2Hz)，5.67(q，1H，J＝7.2Hz)，4.02(q，2H，J＝6.9Hz，2.13(s，3H)，1.24(t，3H，J＝7.0Hz).
Example 40d
Sodium 6-chloro-7- (2-ethylbutoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Sodium 6-chloro-7- (2-ethylbutoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by a similar procedure as described in example 40a using the carboxylic acid from example 3 b.
1H NMR(acetone-d6/300MHz)7.54(s，1H)，7.01(s，1H)，6.18(q，1H，J＝7.0Hz)，3.78(m，2H)，2.07(s，3H)，1.61(m，5H)，1.51(m，4H)，0.971(m，6H).
Example 40e
(2s) sodium 6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Sodium (2S) 6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by a similar procedure as described in example 40a, using the carboxylic acid from example 34 b.
1H NMR(acetone-d6/400MHz)7.54(s，1H)，6.99(dd，1H，J＝8.0，2.0Hz)，6.94(d，1H，J＝1.6Hz)，6.73(d，1H，J＝8.4Hz)，5.95(q，1H，J＝7.0Hz)，2.46(q，2H，J＝7.6Hz)，1.10(t，3H，J＝7.6Hz).
Example 40f
(2R) sodium 6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Sodium (2R) 6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by a similar procedure as described in example 40a, using the carboxylic acid from example 34 c.
1H NMR(acetone-d6/400MHz)7.54(s，1H)，6.99(dd，1H，J＝8.0，2.0Hz)，6.94(d，1H，J＝1.6Hz)，6.73(d，1H，J＝8.4Hz)，5.95(q，1H，J＝7.0Hz)，2.46(q，2H，J＝7.6Hz)，1.10(t，3H，J＝7.6Hz).
Example 40g
8-Ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
To a solution of example 21g of the carboxylic acid prepared in step 2 (85 mg, 0.239 mmol) in ethanol was added aqueous sodium hydroxide (0.4756 ml of 0.5017N solution, 0.239 mmol). The solvent was removed in vacuo to yield 81.5 mg (90% yield) of the product as an off-white crystalline solid. ESLRMS M/z357.1(M + H, C)14H10F6O4Calculated 357.1).
Example 40h
(2S) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Sodium (2S) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by a similar procedure as described in example 40a, using the carboxylic acid from example 32 b.
1H NMR(D2O/300MHz)7.18(s，1H)，6.87(8，1H)，6.78(s，1H)，5.60(q，1H，J＝7.5Hz)，2.07(s，3H)，2.03(s，3H).
Example 40i
6-chloro-7- (4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Sodium 6-chloro-7- (4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by a similar procedure as described in example 40a, using the carboxylic acid from example 9x as the starting material.
1H NMR(D2O/300MHz)7.09(s，1H)，6.88(s，1H)，6.66(m，4H)，6.36(s，1H)，5.53(q，1H，J＝6.3Hz)，3.47(q，2H，J＝14Hz)，1.87(s，3H).
Example 40j
7- (sec-butylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
From 7- (sec-butylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (example 7g) by a procedure similar to the method described in example 40a, sodium 7- (sec-butylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate:
ESHRMS m/z 365.0221(M-H，C15H14F3O3ClS，Calc’d365.0222).1H NMR(CD3OD/400MHz)7.34(s，1H)，7.25(s，1H)，6.90(s，1H)，5.82(q，1H，J＝7.0Hz)，3.36(m，1H)，1.65(m，2H)，1.30(m，3H)，1.03(m，3H).
example 40k
8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
The product sodium 8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared in the form of an off-white solid by a similar method to that described in example 40g, using the carboxylic acid from example 21 i. ESLRMS M/z 371.0(M + N, C)15H12F6O4Calculated 371.1).
Example 40l
(2S) -8-Ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
The product sodium (2S) -8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared in the form of a white solid using the carboxylic acid from example 21k by a method analogous to that described in example 40 g: ESLRMS M/z 357.1(M + H, C)14H10F6O4Calculated 357.1).
Example 40m
(2S) -8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
From (2S) -8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (example 17i), by a procedure analogous to the method described in example 40a, sodium (2S) -8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate: ESHRMS M/z307.0004(M-H, C) 12H7F3O4Cl calculated 306.9979).1H NMR(D2O/300MHz)7.16(s，1H)，6.83(s，1H)，6.68(s，1H)，5.66(q，1H，J＝7.0Hz)，3.64(s，3H).
Example 40n
6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
From 6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (example 7d), by a procedure similar to the one described in example 40a, sodium 6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate:
1H NMR(CD3OD/300MHz)7.33(s，1H)，7.22(s，1H)，6.82(s，1H)，5.79(q，1H，J＝7.0Hz)，2.83(m，2H)，1.94(m，1H)，0.84(m，6H).
example 40o
6-chloro-7- (3, 6-dihydropyridin-1 (2H) -yl) -2- (trifluoromethyl) -2H-chromogen-3-carboxylic acid sodium salt
From 6-chloro-7- (3, 6-dichloropyridin-1 (2H) -yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (example 8e) by a procedure similar to the method described in example 40a, sodium 6-chloro-7- (3, 6-dichloropyridin-1 (2H) -yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared:
1H NMR(D2O/400MHz)7.18(m，2H)，6.69(s，1H)，5.68(m，3H)，3.36(m，2H)，3.04(m，2H)，2.13(m，2H).
example 40p
6-chloro-7- [ (cyclopropylmethyl) (propyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Prepared by a procedure analogous to the one described in example 40a from 6-chloro-7- [ (cyclopropylmethyl) (propyl) amino]-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (example 8g) preparation of 6-chloro-7- [ (cyclopropylmethyl) (propyl) amino]-sodium 2- (trifluoromethyl) -2H-chromene-3-carboxylate: ESHRMS M/z 390.1066(M + H, C) 18H19F3O3Calculated ClN 390.1078).
1H NMR(CD3OD/300MHz)7.38(s，1H)，7.19(s，1H)，6.70(s，1H)，5.73(q，1H，J＝7.0Hz)，3.18(m，2H)，2.97(m，2H)，1.47(m，2H)，1.00(m，4H)，0.45，(m，2H)，0.10(m，2H).
Example 40q
8- (2-phenylethyl) -6- (trifluoromethoxy) chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
To a solution of the carboxylic acid prepared in example 21o (43.2 mg, 0.0999 mmol) in ethanol (1.0 ml) was added aqueous sodium hydroxide (199.6 μ l of 0.5006N solution, 0.0999 mmol). The solvent was removed in vacuo, the residue dissolved in water and lyophilized to give 40.3 mg (89% yield) of the product as a solid: ESLRMS M/z 433.3(M + h, C)20H14F6O4Calculated 433.1).
Example 40r
6-chloro-8-methyl-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Using the carboxylic acid from example 3c, sodium 6-chloro-8-methyl-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared using a procedure similar to that described in example 40 a.
1H NMR(D2O/400MHz)7.12(s，1H)，6.98(s，1H)，5.63(q，1H，J＝7.2Hz)，3.70(m，2H)，1.94(s，3H)，1.65(m，2H)，0.86(t，3H，J＝7.6Hz).
Example 40s
6-chloro-8-methyl-7- (neopentyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Sodium 6-chloro-8-methyl-7- (neopentyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by a similar procedure as described in example 40a, using the carboxylic acid from example 3 g.
1H NMR(D2O/400MHz)7.11(s，1H)，6.89(s，1H)，5.60(q，1H，J＝7.2Hz)，3.27(s，2H)，1.88(s，3H)，0.83(s，9H).
Example 40t
(2S) -6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
The product sodium (2S) -6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared in the form of a pale yellow solid by a similar method to that described in example 40g, using the carboxylic acid from example 21t as starting material: ESLRMS M/z 293.0(M + H, C)12H9F3O3Calculated 293.0).
Example 40v
8-allyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
The product sodium 8-allyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by an analogous method to that described in example 40g, using the carboxylic acid from step 2 of example 21s as starting material, as an off-white solid: ESLRMS M/z 369.4(M + H, C)15H11F6O4Calculated 369.1).
EXAMPLE 41
7-benzyl-6-bromo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: process for preparation of ethyl 7-benzyl-6-bromo-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
The ester (example 9k step 1) was dissolved in acetic acid (glacial acetic acid) (20 ml). Bromine was added and the solution was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo. Water (50 ml) was added to the residue, and the reaction was extracted with ethyl acetate (2 × 50 ml). The organic layers were mixed and washed with brine (2 × 50 ml), dried over sodium sulfate, filtered and concentrated in vacuo to afford the bromo ester (93%): ESLRMS M/z 441(M + H).
Step 2: preparation of 7-benzyl-6-bromo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester (step 1) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a: ESLRMS M/z 410.9841(M + H, C)18H11GBrF3O3Calculated 410.9838).
1HNMR(DMSO-d6/400MHz)13.34(brs，1H)，7.91(s，1H)，7.71(s，1H)，7.42-7.54(m，2H)，7.28-7.39(m，3H)，6.99(s，1H)，5.89(q，1H，J＝7.1Hz)，4.00(s，2H).
Example 42a
7-benzyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7-benzyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
To a stirred DMF solution (15 ml) was added the ester (example 41, step 1) (1.0 g, 2.2 mmol). Trimethylboroxine (0.316 ml, 2.2 mmol) was added toAnd Pd (PPh)3)4(0.261 g, 10 mol%) followed by the addition of potassium carbonate. The solution was heated to 100 ℃ for 8 hours. The solution was poured into water (50 ml), extracted with ethyl acetate (2 × 50 ml), the organic layers were mixed and washed sequentially with 1N hydrochloric acid (2 × 50 ml) and brine (2 × 50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo to afford the ester (67%):
ESLRMS m/z377(M+H)。
step 2: preparation of 7-benzyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester (step 1) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a: ESLRMS M/z 347.0896(M-H, C) 19H14F3O3Calculated 347.0890).
1HNMR(DMSO-d6/400MHz)13.19(brs，1H)，7.74(s，1H)，7.11-7.27(m，6H)，6.74(q，1H，J＝7.1Hz)，3.91(s，2H)，2.11(s，3H).
Example 42b
7-benzyl-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7-benzyl-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
To a stirred solution of THF (20 ml) containing triethylborane (4.53 ml, 4.5 mmol) was added the ester (example 41, step 1) (1.0 g, 2.2 mmol). Addition of Pd (dppf) Cl2·CH2Cl2(0.092 g, 5 mol%) followed by the addition of 2M aqueous potassium phosphate solution (2.49 ml, 4.9 mmol). The solution was heated to 70 ℃ for 4 hours. Pouring the solution into waterTo (50 ml), extracted with ethyl acetate (2 × 50 ml), the organic layers were mixed and washed sequentially with 1N hydrochloric acid (2 × 50 ml) and brine (2 × 50 ml). The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was analyzed by flash chromatography (silica, ethyl acetate/hexane), the desired fractions were collected and mixed and concentrated in vacuo to give the ester (325 mg, 37%). The ester was of suitable purity and was used without further purification. ESLRMS M/z 391(M + H).
Step 2: preparation of 7-benzyl-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester (step 1) was hydrolyzed to form the carboxylic acid via a similar procedure as described in step 2 of example 4 a. ESLRMS M/z 361.1056(M-H, C) 20H16F3O3Calculated 361.1046).
1HNMR(DMSO-d6/400MHz)13.18(brs，1H)，7.79(s，1H)，7.10-7.28(m，6H)，6.73(s，1H)，5.79(q，1H，J＝7.1Hz)，3.94(s，2H)，2.61(m，2H)，1.03(t，3H，J＝7.1Hz).
Example 42c
7-benzyl-6-propyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of ethyl 7-benzyl-6-propyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Prepare for
The compound was prepared and purified by analogous methods as described in example 9a, step 3, substituting the appropriate propene to give the ester (425 mg, 45%). The ester was of suitable purity and was used without further purification. ESLRMS M/z 405(M + H).
Step 2: 7-benzylPreparation of 6-propyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester (step 1) was hydrolyzed to form the carboxylic acid (99%) via a similar procedure as described in step 2 of example 4 a. ESLRMS M/z 375.1195(M-H, C)21H18F3O3Calculated 375.1203).
1HNMR(DMSO-d6/400MHz)13.15(brs，1H)，7.77(s，1H)，7.10-7.28(m，6H)，6.72(s，1H)，5.79(q，1H，J＝7.1Hz)，3.94(s，2H)，2.38-2.44(m，2H)，1.32-1.44(m，2H)，0.835(t，3H，J＝7.2Hz).
Example 42d
7-benzyl-6-butyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7-benzyl-6-butyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
The compound was prepared and purified by analogy to the methods described in example 42b, step 1, and substitution with the appropriate tributylborane gave the ester (423 mg, 45%). ESLRMSm/z 419(M + H).
Step 2: preparation of 7-benzyl-6-butyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester (step 1) was hydrolyzed to form the carboxylic acid via a similar procedure as described in step 2 of example 4 a. ESLRMS M/z 389.1372(M + H, C)22H20F3O3Calculated 389.1359).
1HNMR(DMSO-d6/400MHz)13.14(s，1H)，7.77(s，1H)，7.09-7.28(m，6H)，6.73(s，1H)，5.80(q，1H，J＝7.1Hz)，3.94(s，2H)，2.61(t，2H，J＝7.0Hz)，1.20-1.29(m，2H)，1.30-1.37(m，2H)，0.810(t，3H，J＝7.1Hz).
Example 44
6-chloro-8- (methylthio) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of ethyl 6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate
5-chlorosalicylaldehyde (20.02 g, 0.128 mol) and ethyl 4, 4, 4-trifluorocrotonate (23.68 g, 0.14 mol) were dissolved in anhydrous DMF, warmed to 60 ℃ and treated with anhydrous potassium carbonate (17.75 g, 0.128 mol). The solution was maintained at 60 ℃ for 20 hours, cooled to room temperature and diluted with water. The solution was extracted with ethyl acetate. The combined extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo to give 54.32 g of oil. The oil was dissolved in 250 ml of methanol and 100 ml of water, whereupon a white solid formed, which was isolated by filtration. The resulting solid was washed with water and dried in vacuo to give a yellow solid (24.31 g, 62%): the melting point is 62-64 ℃.
1H NMR(CDCl3/90MHz)7.64(s，1H)，7.30-7.21(m，2H)，6.96(d，1H，J＝Hz)，5.70(q，1H，J＝Hz)，4.30(q，2H，J＝7.2Hz)，1.35(t，3H，J＝7.2Hz).
Step 2: ethyl 6-chloro-8- (chlorosulfonyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
To ice-cooled, stirred chlorosulfonic acid (15 ml), ethyl 6-chloro-2- (trifluoromethyl) -2H-benzopyran-3-carboxylate (step 1, 2.0 g, 6.5 mmol) was added in portions, allowed to warm to room temperature and stirred for 60 hours. The resulting dark brown homogeneous solution was added dropwise to stirred ice/water (200 ml) to form a suspension. The resulting precipitate was collected by vacuum filtration. The product was purified by silica chromatography. The resulting mixture was dissolved in ethyl acetate, washed with sodium bicarbonate solution and brine, dried over magnesium sulfate, filtered and concentrated in vacuo to afford the title compound as a solid. The solids were sufficiently pure for subsequent steps.
Step 3: ethyl 6-chloro-8- (methylthio) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
To benzene (solvent) was added 6-fluoro-8- (chlorosulfonyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (step 2, 0.68 g, 1.68 mmol), iodine (0.11 g, 0.84 mmol), and triphenylphosphine (4.41 g, 1.68 mmol), and the resulting mixture was heated to reflux for 4 hours, allowed to cool to room temperature, and left to stand for 48 hours. Et was added to the crude reaction 3N (0.58 ml, 0.424 g, 4.20 mmol) and methyl iodide (0.06 ml, 0.13 g, 0.92 mmol). After extractive workup and silica chromatography, the title compound was obtained as a yellow crystalline solid (0.215 g, 36%).
1HNMR(CDCl3-d6/300MHz)7.59(s，1H)，7.07(d，J＝2.4Hz，1H)，6.98(d，J＝2.4Hz，1H)，5.78(q，1H，J＝6.8Hz)，4.20-4.40(m，3H)，2.42(s，3H)，1.33(t，3H，J＝7.3Hz).
Step 4: process for preparing 6-chloro-8- (methylthio) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
To a stirred solution of ethyl 6-chloro-8- (methylthio) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (step 3, 0.203 g, 0.575 mmol) in tetrahydrofuran: ethanol: water (7: 2: 1, 5 ml) was added aqueous sodium hydroxide (0.63 mmol, 0.25 ml of 2.5N solution) and stirred for 2 days. The resulting clear yellow solution was concentrated in vacuo, diluted with water (35 ml) and acidified with concentrated hydrochloric acid to form a yellow suspension. Vacuum filtration of the suspension was carried out to obtain the title compound (0.132 g, 71%) as a yellow powder.
1HNMR(acetone-d6/300MHz)7.87(s，1H)，7.34(d，J＝2.2Hz，1H)，7.25(d，J＝2.2Hz，1H)，5.93(q，1H，J＝7.05Hz)，2.53(s，3H).LRMS m/z323(M-H)；
ESHRMS m/z 322.9782(M-H，C12H7F3O3ClS calculated 322.9757). C12H8F3O3ClS is calculated as: carbon 44.39; and 2.48 of hydrogen. And (3) measuring: carbon 44.63; hydrogen 2.52.
Example 45
6, 8-dibromo-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid
Step 1: preparation of ethyl 6, 8-dibromo-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid ester Prepare for
2-amino-3, 5-dibromobenzaldehyde (6.50 g, 23.3 g mol), triethylamine (6.96 g, 69.9 mmol) and ethyl 4, 4, 4-trifluorocrotonate (7.85 g, 46.6 mol) were mixed in dimethyl sulfoxide (12.0 ml) at 90 ℃ for 48 hours. The solution was cooled to room temperature, and the solution was poured into ethyl acetate (100 ml). The solution was extracted with saturated aqueous ammonium chloride (2 × 100 ml), dried over sodium sulfate, filtered and concentrated in vacuo. Ethyl 6, 8-dibromo-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid ester (4.3 g, 10.0 mmol) was isolated as a yellow solid (43% yield) by flash silica chromatography: MS M/z428(M-H, calculated 428).
Step 2: preparation of 6, 8-dibromo-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid
Ethyl 6, 8-dibromo-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylate (732.0 mg, 1.70 mmol) was suspended in methanol-tetrahydrofuran-water (5 mL, 7: 2: 1). Lithium hydroxide (214 mg, 5.108 mmol) was added and the mixture was gently heated to reflux for 2 hours. The reaction was cooled to room temperature and 1N aqueous hydrochloric acid was added until the pH was 1. The organic solvent was removed in vacuo to give a suspension of crude yellow solid. Diethyl ether (50 ml) was added, and the solution was washed with water (2 × 50 ml), saturated ammonium chloride (2 × 50 ml), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford 6, 8-dibromo-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid (633.0 mg, 1.52 mmol) as a yellow solid (89% yield):
1H NMR(CD3OD3，300MHz)7.07(s，1H)，7.57(d，1H，J＝2.0Hz)，7.39(d，1H，J＝2.0Hz)，5.26(m，1H).
C11H6Br2F3NO3The calculation analysis shows that: 32.95 parts of carbon; hydrogen 1.51; and 3.49 of nitrogen. And (3) measuring: 32.88 carbon; hydrogen 1.51; and 3.46 of nitrogen.
Example 46
8-bromo-6-methyl-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid
Step 1: preparation of (2-amino-3-bromo-5-methylphenyl) methanol
2-amino-3-bromo-5-methylbenzoic acid (20.0 g, 86.0 mmol) was dissolved in tetrahydrofuran (200 ml) and cooled to 0 ℃. A solution of borane dimethyl sulfide complex (15.6 ml, 156.0 mmol) was dissolved in tetrahydrofuran (40 ml) and added gradually. The solution was maintained at 0 ℃ for a further 30 minutes, warmed to room temperature for 2 hours and finally refluxed for 16 hours. The solution was cooled to room temperature and methanol (10 ml) was added slowly to control evolution of gas. The solution was stirred at room temperature for 30 minutes and 1N hydrochloric acid was added. The solution was stirred for 3 hours and the solvent was removed until the volume was about 100 ml. Water (200 ml) was added and the solution was extracted with diethyl ether (200 ml). The water layer was collected and the pH adjusted to 12 with 1N sodium hydroxide to form a solid in solution. The solid was collected, dissolved in ethyl acetate (100 ml), dried over sodium sulfate, and the solvent was removed under reduced pressure. (2-amino-3-bromo-5-methylphenyl) methanol (9.5 g, 43.9 mmol) was obtained as an off-white solid (51% yield): HRMS m/z 216.0047; and M + X calculated 216.0024.
Step 2: preparation of 2-amino-3-bromo-5-methylbenzaldehyde
(2-amino-3-bromo-5-methylphenyl) methanol (7.80 g, 36.1 mmol) was dissolved in tetrahydrofuran (20 ml). Dichloromethane (50 ml) and activated carbon (16.3 g) were added. Manganese dioxide (9.40 g, 108 mmol) was added and the solution was stirred at 40 ℃ for 16 h. The solution was cooled to room temperature and vacuum filtered through celite. The solvent was removed under reduced pressure and 2-amino-3-bromo-5-methylbenzaldehyde (6.10 g, 28.5 mmol) was obtained by recrystallization from diethyl ether/hexane (1: 10, 100 ml) (78% yield): the melting point is 99.6-101.2 ℃.1H NMR(300MHz，CDCL3)9.77(s，1H)，7.46(s，1H)，7.26(s，1H)，6.48(bs，2H)，2.76(s，3H).HRMS m/z 213.9902；
And M + H calculated 213.9962.
Step 3: ethyl 8-bromo-6-methyl-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid ester Preparation of
2-amino-3-bromo-5-methylbenzaldehyde (5.60 g, 26.2 mmol), diazabicyclo [2.2.2] undec-7-ene (9.2 g, 61.3 mmol) and ethyl 4, 4, 4-trifluorocrotonate (10.9 g, 65.4 mol) were mixed at 60 ℃ in 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone (12.0 ml) for 8 hours. The solution was cooled to room temperature. And the solution was poured into ethyl acetate-hexane (1: 1, 100 ml). The solution was extracted with 2.5N aqueous hydrochloric acid (2 × 50 ml), saturated aqueous ammonium chloride (2 × 50 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting dark yellow oil was dissolved in hexane (30 ml) and upon standing, yellow powder crystals formed. Ethyl 8-bromo-6-methyl-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylate (7.2 g, 19.9 mmol) was collected by vacuum filtration (75% yield). The melting point is 122.2-123.6 ℃. HRMS m/z 364.0142; and M + H calculated 364.0155.
Step 4: process for preparing 8-bromo-6-methyl-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid Preparation of
Ethyl 8-bromo-6-methyl-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylate (1.8 g, 4.95 mmol) was suspended in methanol-tetrahydrofuran-water (20 mL, 7: 2: 1). Lithium hydroxide (414 mg, 9.88 mmol) was added and the mixture was gently heated to reflux for 2 hours. The reaction was cooled to room temperature and 1N aqueous hydrochloric acid was added until the pH was 1. The organic solvent was removed in vacuo to give a suspension of crude yellow solid. Diethyl ether (50 ml) was added, and the solution was washed with water (2 × 50 ml), saturated ammonium sulfate (2 × 50 ml), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford 8-bromo-6-methyl-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid (1.3 g, 4.05 mmol) as a yellow solid (82% yield):
1H NMR(300MHz，CDCL3)7.78(s，1H)，7.82(s，1H)，6.59(s，1H)，5.20(m，2H)，5.13(bs，1H)，2.34(s，1H).HRMS m/z 334.9763；(M+，C12H9BrF3NO2calcd 334.9769).
example 47
6-chloro-8-methyl-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid
Step 1: preparation of 2-amino-5-chloro-3-methylbenzoic acid
5-chloro-7-methyl-1H-indole-2, 3-dione (25.0 g, 0.13 mmol), potassium hydroxide (8.4 g, 0.15 mmol) and 30% hydrogen peroxide (21.6 g, 0.18 mmol) were mixed in methanol (300 mL) at 0 ℃ for 2 hours, followed by mixing at room temperature for 16 hours. The solution was poured into ethyl acetate (500 ml) and extracted sequentially with 1N hydrochloric acid (3 × 200 ml) and brine (1 × 50 ml). The solution was dried over sodium sulfate and the solvent was removed under reduced pressure. 2-amino-5-chloro-3-methylbenzoic acid (18.0 g, 0.10 mmol) was isolated as a yellow solid (75% yield): HRMS m/z 185.0238; the calculated value was 185.0244.
Step 2: preparation of (2-amino-5-chloro-3-methylphenyl) methanol
2-amino-5-chloro-3-methylbenzoic acid (15.6 g, 84.3 mmol) was dissolved in tetrahydrofuran (200 ml) and cooled to 0 ℃. A solution of borane dimethyl sulfide complex (16.8 ml, 16.8 mmol) was dissolved in tetrahydrofuran (40 ml) and added dropwise. The solution was maintained at 0 ℃ for an additional 30 minutes, warmed to room temperature for 2 hours, and finally refluxed for 16 hours. The solution was cooled to room temperature and methanol (10 ml) was added slowly to control evolution of gas. The solution was stirred at room temperature for 30 minutes. And 1N hydrochloric acid was added. The solution was stirred for 3 hours and the solvent was removed until the volume was about 100 ml. Water (200 ml) was added and the solution was extracted with diethyl ether (200 ml). The water layer was collected and the pH adjusted to 12 with 1N sodium hydroxide to form a solid in solution. The solid was collected, dissolved in ethyl acetate (100 ml), dried over sodium sulfate, and the solvent was removed under reduced pressure. (2-amino-5-chloro-3-methylphenyl) methanol (10.8 g, 63.1 mmol) was obtained as a pale yellow solid (75% yield): HRMS m/z 172.0544; and M + X calculated 172.0524.
Step 3: preparation of 2-amino-5-chloro-3-methylbenzaldehyde
(2-amino-5-chloro-3-methylphenyl) methanol (10.8 g, 63.1 mmol) was dissolved in tetrahydrofuran (20 ml). Dichloromethane (50 ml) and activated carbon (16.3 g) were added. Manganese dioxide (16.8 g, 189 mmol) was added and the solution was stirred at 40 ℃ for 16 h. The solution was cooled to room temperature and vacuum filtered through celite. The solvent was removed under reduced pressure and 2-amino-5-chloro-3-methylbenzaldehyde (7.90 g, 46.0 mmol) was obtained by recrystallization from diethyl ether/hexane (1: 10, 100 ml). HRMS m/z 169.0280; and M + H calculated 169.0294.
Step 4: ethyl 6-chloro-8-methyl-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid ester Preparation of
2-amino-5-chloro-3-methylbenzaldehyde (5.60 g, 33.1 mmol), diazabicyclo [2.2.2] undec-7-ene (12.1 g, 82.0 mmol) and ethyl 4, 4, 4-trifluorocrotonate (13.9 g, 82.7 mol) were mixed at 60 ℃ in 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone (12.0 ml) for 8 hours. The solution was cooled to room temperature, and the solution was poured into ethyl acetate-hexane (1: 1, 100 ml). The solution was extracted with 2.5N aqueous hydrochloric acid (2 × 50 ml), saturated aqueous ammonium chloride (2 × 50 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting dark yellow oil was dissolved in hexane (30 ml) and upon standing, yellow powder crystals formed. Ethyl 6-chloro-8-methyl-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylate (6.6 g, 20.7 mmol) was collected by vacuum filtration (60% yield). Melting point 154-. HRMS m/z 216.0047; and M + H calculated 216.0024.
Step 5 preparation of 6-chloro-8-methyl-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid
Ethyl 6-chloro-8-methyl-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylate (4.5 g, 0.51 mmol) was suspended in methanol-tetrahydrofuran-water (50 mL, 7: 2: 1). Lithium hydroxide (1.70 g, 42.3 mmol) was added and the mixture was gently heated to reflux for up to 2 hours. The reaction was cooled to room temperature and 1N aqueous hydrochloric acid was added until the pH was 1. The organic solvent was removed in vacuo to obtain a suspension of crude yellow solid. Diethyl ether (200 ml) was added, and the solution was washed with water (2 × 200 ml), saturated ammonium sulfate (2 × 200 ml), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford 6-chloro-8-methyl-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid (3.8 g, 13.4 mmol) as a yellow solid (95% yield):
(CDCl3，300MHz)7.56(s，1H)，6.93(s，1H)，6.90(s，1H)，5.11(q，1H，J＝7.2Hz)，4.78(bs，1H)，2.08(s，3H).HRMS m/z 291.0286(M+，C12H9ClF3NO2，calcd 291.0274).
example 48
6- (4-fluorophenyl) -2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid
Step 1: preparation of ethyl 6-iodo-1, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylate
5-iodo-2-aminobenzaldehyde was prepared from commercially available 5-iodo-2-aminobenzoic acid using the aforementioned literature procedure (Alabaster, C.J.Med.chem. (1988) pp.2018-2056). 5-iodo-2-aminobenzaldehyde (24.0 g, 96.7 mmol), diazabicyclo [2.2.2] undec-7-ene (32.2 g, 212.0 mmol) and ethyl 4, 4, 4-trifluorocrotonate (37.5 g, 212.0 mol) were mixed with 1, 3-dimethyl-3, 4, 5, 6-tetrahydro-2 (1H) -pyrimidinone (48 mL) at 60 ℃ for 8 hours. The solution was cooled to room temperature, and the solution was poured into ethyl acetate-hexane (1: 1, 500 ml). The solution was extracted with 2.5N aqueous hydrochloric acid (2 × 200 ml), saturated aqueous ammonium chloride (2 × 200 ml), dried over sodium sulfate, filtered and concentrated in vacuo. The resulting dark yellow oil was dissolved in hexane (100 ml) and upon standing, yellow powder crystals formed. Ethyl 6-iodo-1, 2-dihydro-2- (trifluoromethyl) -3-quinolinecarboxylate (19.3 g, 48.8 mmol) was collected by vacuum filtration (50% yield). Melting point 137-.
1H NMR(CDCl3，300MHz)7.62(s，1H)，7.36-7.48(m，2H)，6.43(d，J＝8.2Hz)，5.36(brs，1H)，5.11(q，1H，J＝7.1Hz)，4.25-4.35(m，2H)，1.34(t，3H，J＝7.0Hz).HRMS m/z 395.9716；Calcd for M-H，395.9708.
Step 2: ethyl 6- (4-fluorophenyl) -2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid Preparation of esters
Ethyl 6- (4-fluorophenyl) -2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylate (700 mg, 1.76 mmol), p-fluorophenylboronic acid (257 mg, 1.85 mmol), palladium acetate I I (3.48 mg, 0.015 mmol), triphenylphosphine (12.2 mg, 0.045 mmol) and sodium bicarbonate (222 mg, 2.11 mmol) were refluxed in n-propanol/water (5.0 ml, 9: 1) for 1 hour. The solution was poured into ethyl acetate (50 ml) and extracted with water (2 × 25 ml), 1N hydrochloric acid (2 × 25 ml) and saturated aqueous ammonium chloride solution (2 × 25 ml). The organic layer was dried over sodium sulfate, the solvent was removed under reduced pressure, and the ester was isolated by flash silica chromatography (eluting with 0-25% ethyl acetate in hexanes). Trituration from hexane gave ethyl 6- (4-fluorophenyl) -2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylate (243 mg, 0.66 mmol) as a yellow solid (26% yield). HRMS m/z 364.0989; and M-H was calculated as 394.0960.
Step 3: preparation of 6- (4-fluorophenyl) -2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid Prepare for
Ethyl 6- (4-fluorophenyl) -2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylate (189 mg, 0.51 mmol) was suspended in methanol-tetrahydrofuran-water (10 ml, 7: 2: 1). Lithium hydroxide (42 mg, 0.1.53 mmol) was added and the mixture was heated to reflux with mixing for 2 hours. The reaction was cooled to room temperature and 1N aqueous hydrochloric acid was added until the pH was 1. The organic solvent was removed in vacuo to obtain a suspension of crude yellow solid. Diethyl ether (20 ml) was added, and the solution was washed with water (2 × 20 ml), saturated ammonium sulfate (2 × 20 ml), dried over sodium sulfate and filtered. The filtrate was concentrated in vacuo to afford 6- (4-fluorophenyl) -2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid (152 mg, 0.45 mmol) as a yellow solid (88% yield):
1H NMR(CD3OD3，300MHz)7.81(s，1H)，7.40-7.56(m，4H)，7.10(t，1H，J＝9.1Hz)，6.78(d，1H，J＝8.3Mz)，5.12(m，1H).HRMS m/z337.0732；calcd 337.0726.
Example 100
6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 3-chloro-6-hydroxy-2, 4-dimethylbenzaldehyde
To a solution of 4-chloro-3, 5-dimethyl-phenol (10.0 g, 63.9 mmol) in 400 ml of acetonitrile were added magnesium chloride (9.12 g, 95.8 mmol), TEA (23.9 g, 32.9 ml, 236 mmol) and (CH)2O)n(13.4 g, 304 mmol). The reaction is carried outThe fluid state was heated for 4 hours. After cooling to room temperature, 2N hydrochloric acid was added until the pH of the reaction was 3. The aqueous layer was extracted twice with 300 ml of diethyl ether. The organic layer was filtered, and the filtrate was washed once with saturated brine, then dried over magnesium sulfate, and concentrated in vacuo. The desired crude product (12.6 g) was isolated. Under flash chromatography conditions, 6.9 g (59%) of the pure compound were isolated.
Step 2: process for preparation of ethyl 6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
To a solution of 3-chloro-6-hydroxy-2, 4-dimethylbenzaldehyde (6.9 g, 37.4 mmol) in 80 ml of DMF was added potassium carbonate (11.36 g, 82.2 mmol) as a dry fine powder. The reaction was heated to 65 ℃ with mechanical stirring. To this suspension was added ethyl trifluorocrotonate (7.54 g, 44.9 mol) dropwise. The reaction was heated at 90 ℃ for 1.5 hours while stirring. The potassium carbonate was filtered off from the reaction after cooling. DMF was removed from the reaction under vacuum. The resulting residue was dissolved in 400 ml of ethyl acetate. The organic solution was washed with 100 ml of 1M potassium hydrogen sulfate, 70 ml of saturated potassium hydrogen carbonate, 100 ml of brine, then dried over magnesium sulfate and concentrated in vacuo. The desired crude product (13.8 g) was isolated. After analysis of the conditions by flash chromatography, the pure compound was isolated (9.8 g, 78%) and its structure was confirmed by NMR and LC-MS.
Step 3: preparation of 6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Prepare for
To a suspension of ethyl 6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (4.00 g, 11.9 mmol) in 40 ml ethanol was added a solution of sodium hydroxide (1.2 g, 30 mmol) in 18 ml water. The reaction was heated at reflux for 1.5 hours. Once cooled, the reaction was neutralized with 2N hydrochloric acid. The product precipitated from the solution was filtered off and washed with water. After drying in a vacuum oven at 50 ℃, 6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was isolated as a pale yellow solid (3.46 g, 95%):
1H NMR(MeOH-d4)7.93(s，1H)，6.76(s，1H)，5.65(q，1H，J＝7.15Hz)，2.39(s，3H)，2.31(s，3H).DSC 203.59℃.
example 101
(2R) -6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
(2R) -6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Isomers of 6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid were isolated by chiral chromatography using koroseal (chirale) AS or AD. (2R) -6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid has a negative specific optical rotation. Chiral HPLC analysis on a Chirobiotic T-column (eluted with methanol/water/acetic acid/TEA) showed a retention time of 6.03 minutes for (2R) -6-chloro-5, 7-dimethyl-2- (3 fluoromethyl) -2H-chromene-3-carboxylic acid.
Example 102
(2S) -6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Isolation of (2S) -6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
See example 101. (2S) -6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid has a positive specific optical rotation. Chiral HPLC analysis on a Chirobiotic T-column (eluted with methanol/water/acetic acid/TEA) showed a retention time of 8.02 min for (2S) -6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid.
Example 103
6-chloro-7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 2-hydroxy-3, 4-dimethylbenzaldehyde
2-hydroxy-3, 4-dimethylbenzaldehyde was prepared in the same manner as described in step 1 of example 100, except that the starting material was 2, 3-dimethylphenol.
Step 2: preparation of ethyl 7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared in the same manner as described in step 2 of example 100, except that the starting material was 6-hydroxy-2, 4-dimethylbenzaldehyde.
Step 3: process for preparation of ethyl 6-chloro-7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
To a solution of ethyl 7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (4.0 g, 13.3 mmol) in 75 ml of acetic acid was added chlorine until saturation of the solvent by a green cloud of chlorine above the solvent. After 2 hours, the reaction was flushed with nitrogen, followed by treatment with excess zinc dust for 1.5 hours. The reaction mixture was decanted from the zinc and concentrated in vacuo. The resulting residue was dissolved in 300 ml of ethyl acetate and washed with 100 ml of 1M potassium hydrogensulfate and 100 ml of brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. The yield of ethyl 6-chloro-7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was 5.2 g.
Step 4: preparation of 6-chloro-7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-chloro-7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared in the same manner as described in step 3 of example 100, except that the starting material was ethyl 6-chloro-7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate.1HNMR(MeOH-d4)7.68(s，1H)，7.20(s，1H)，5.78(q，1H，J＝7.08Hz)，2.36(s，3H)，2.23(s，3H).DSC 216.32℃。
Example 104
6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 6-hydroxy-2, 4, 5-trimethylbenzaldehyde
To a solution of 2, 3, 5-trimethylphenol (11.2 g, 82.0 mmol) in 400 ml of acetonitrile was added paraformaldehyde (17.2 g, 574 mmol), anhydrous magnesium chloride (11.7 g, 123 mmol) and TEA (43 ml, 31 g, 308 mmol). The mixture was refluxed for 6 hours with stirring. After cooling, the mixture was partially concentrated, water was added, and the mixture was acidified with dilute aqueous hydrochloric acid. The mixture was extracted three times with diethyl ether, and the combined extracts were washed with brine, dried over sodium sulfate, filtered and concentrated. Chromatography of the residue on silica gel using DCM as eluent gave 8.8 g of 6-hydroxy-2, 4, 5-trimethylbenzaldehyde in the form of an oil.
Step 2: preparation of ethyl 5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Prepare for
To a solution of 6-hydroxy-2, 4, 5-trimethylbenzaldehyde (2.77 g, 17.1 mmol) in 50 ml of anhydrous DMF was added anhydrous potassium carbonate (5.19 g, 37.6 mmol) and ethyl 4, 4, 4-trifluorocrotonate (3.16 g, 18.8 mol). The mixture was rapidly stirred in a drying tube at 100 ℃ for 3 hours. After cooling, the mixture was diluted with DMF, filtered and evaporated. Chromatography of the residue was performed on silica gel using DCM as eluent. 3.75 g of ethyl 5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate are obtained in the form of an oil.
Step 3: ethyl 6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
In a solution of ethyl 5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 50 ml of acetic acid, a stream of monochloro gas is passed until a continuous appearance of chlorine is observed above the solution. The mixture was stirred for 1 hour, after which nitrogen was bubbled in to drive off excess chlorine. Zinc powder (731 mg, 11.2 mg-atm) was added, the mixture was stirred for 30 minutes, and evaporated. Chromatography of the residue on silica gel using DCM as eluent gave 3.01 g of ethyl 6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate in the form of an oil.
Step 4: preparation of 6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
A solution of 3.01 g of ethyl 6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (8.62 mmol) was treated in the same manner as described in step 3 of example 100. 2.52 g of 6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid are obtained in the form of a white solid.
1H NMR(acetone-d6)8.07(s，1H)，5.85(q，1H，J＝7.2Hz)，2.50(s，3H)，2.40(s，3H)，2，24(s，3H).
Example 105
6-fluoro-5, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 6-hydroxy-2, 5-dimethylbenzaldehyde
By the method of step 1 of example 104, 6-hydroxy-2, 5-dimethylbenzaldehyde was prepared, except that 2, 5-dimethylphenol was used as a starting phenol.
Step 2: preparation of ethyl 5, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 5, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by the method of step 2 of example 104, except that 6-hydroxy-2, 5-dimethylbenzaldehyde was used instead of 6-hydroxy-2, 4, 5-trimethylbenzaldehyde.
Step 3: process for preparation of ethyl 6-chloro-5, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
Ethyl 6-chloro-5, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by the method of step 3 of example 104, except that ethyl 5, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was used instead of ethyl 6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate.
Step 4: preparation of 6-chloro-5, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The procedure of example 104, step 4 was followed, except for using ethyl 6-chloro 5, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate instead of ethyl 6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate. Preparation of 6-chloro-5, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. 1HNMR(acetone-d6)8.06(s，1H)，7.34(s，1H)，5.87(q，1H，J＝7.2Hz)，2.48(s，3H)，2.23(s，3H).
Example 106
7-neo-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 2- (3-methoxyphenyl) -2-methylpropanenitrile
In 190 ml of DMSO, 55 ml of 50% aqueous sodium hydroxide solution were added to form a stirrable paste. A solution of 3-methoxyphenylacetonitrile (25.0 g, 270 mmol) in 25 ml DMSO was added slowly with stirring. After a few minutes, 32 ml of methyl iodide was added, causing an exotherm. Another portion of methyl iodide was added, stirring was continued until the mixture was cooled, and the mixture was maintained at room temperature. Ice was added and the mixture was extracted with several portions of diethyl ether. The combined organic extracts were washed twice with water, once with brine, dried over sodium sulfate, filtered and evaporated to yield 27.7 g of the title compound as an oil.
Step 2: preparation of 2- (3-methoxyphenyl) -2-methylpropanal
To a solution of 2- (3-methoxyphenyl) -2-methylpropanenitrile (27.7 g, 158 mmol) in 250 ml THF was added dropwise diisobutylaluminum hydride in heptane (202 ml, 1.0M solution). The mixture was allowed to warm to room temperature over an overnight period. After cooling, a solution of sulfuric acid (21.5 ml) in 85 ml of water was carefully added in small amounts. The resulting solution was dissolved between diethyl ether and water, the aqueous layer was further extracted, and the combined organic extracts were dried over sodium sulfate, filtered and evaporated to give 21.7 g of 2- (3-methoxyphenyl) -2-methylpropionaldehyde as an oil.
Step 3: preparation of 1- (1, 1-dimethylprop-2-enyl) -3-methoxybenzene
A sodium dimesylate solution was prepared by dissolving 60% sodium hydride in mineral oil (4.89 g, 122 mmol) washed with hexane in 120 ml of DMCO and heating to 60 ℃. To 40 ml of this solution, methyltriphenylphosphonium bromide (14.5 g, 40.7 mmol) was added in solid form to form a thick paste. A solution of 2- (3-methoxyphenyl) -2-methylpropionaldehyde (5.00 g, 28.1 mmol) in 6 ml of DMSO was added and the mixture was stirred overnight. The mixture was dissolved between diethyl ether and water, and the aqueous layer was further extracted with diethyl ether. The combined extracts were washed with water and brine, dried over sodium sulfate, filtered and evaporated. Chromatography of the residue on silica gel using DCM as eluent gave 4.25 g of 1- (1, 1-dimethylprop-2-enyl) -3-methoxybenzene as an oil.
Step 4: preparation of 1-methoxy-3-neo-pentylbenzene
Hydrogenation of 1- (1, 1-dimethylprop-2-enyl) -3-methoxybenzene was carried out under 5psi of hydrogen using 5% palladium on carbon to yield 3.27 g of 1-methoxy-3-neo-pentylbenzene.
Step 5: preparation of 3-neo-pentylphenol
To a solution of 1-methoxy 3-neo-pentylbenzene (3.22 g, 18.1 mmol) in 100 ml of DCM was added 2.14 ml (5.68 g) of boron tribromide dropwise with stirring in a-78 ℃ bath. The mixture was stirred while warming to room temperature. After 3 hours, ice was added and the organic layer was separated, dried over sodium sulfate, filtered and evaporated to give 2.77 g of 3-neo-pentylphenol as an oil.
Step 6: preparation of 2-hydroxy-4-neo-pentylbenzaldehyde
2-hydroxy-4-neo-pentylbenzaldehyde was prepared by the method of step 1 of example 104, except that 3-neo-pentylphenol was used instead of 2, 3, 5-trimethylphenol.
And 7, a step: preparation of ethyl 7-neo-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 7-neo-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by the method of step 2 of example 104, except that 2-hydroxy-4-neo-pentylbenzaldehyde was used instead of 6-hydroxy-2, 4, 5-trimethylbenzaldehyde.
Step 8: preparation of 7-neo-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
7-neo-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by the method of example 104 step 3, except that ethyl 7-neo-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was used in place of ethyl 5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate. 1H NMR(acetone-d6)7.98(s，1H)，7.41(d，1H，J＝8.0Hz)，7.11(dd，J＝8.0Hz，J＝1.8Hz)，7.01(d，J＝1.8Hz)，5.80(q，1H，J＝7.2Hz)，1.68(q，2H，J＝5.5Hz)，1.30(s，6H)，0.69(t，3H，J＝5.5Hz).
Example 107
6-chloro-7-neo-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: process for preparation of ethyl 6-chloro-7-neo-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
Ethyl 6-chloro-7-neo-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by the method of step 3 of example 104, except that ethyl 7-neo-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was used to take ethyl 5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate.
Step 2: preparation of 6-chloro-7-neo-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Except that ethyl 6-chloro-7-neo-pentyl-2- (trifluoromethyl)6-chloro-7-neo-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by the method of example 104 step 4, except for substituting ethyl 6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate.1H NMR(CDCl3)7.76(s，1H)，7.23(s，1H)，7.02(s，1H)，5.67(q，1H，J＝7.2Hz)，2.00(m，1H)，1.94(m，1H)，1.42(s，3H)，1.41(S，3h)，0.66(t，3H，J＝7.5Hz).
Example 108
7- (1, 1-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: 3- [ (2Z) -1, 1-dimethylbut-2-enyl)]Preparation of phenyl methyl ether
3- [1, 1-Dimethylbut-2-enyl ] phenylmethyl ether is prepared by the method of step 3 of example 106, except that ethyltriphenylphosphonium bromide is used instead of methyltriphenylphosphonium bromide.
Step 2: preparation of 3- (1, 1-dimethylbutyl) phenylmethyl ether
3- (1, 1-dimethylbutyl) phenylmethyl ether was prepared by the method of example 106 step 4, except that 3- [1, 1-dimethylbut-2-enyl ] phenylmethyl ether was used in place of 1- (1, 1-dimethylprop-2-enyl) -3-methoxybenzene.
Step 3: preparation of 3- (1, 1-dimethylbutyl) phenol
By the method of example 106, step 5, 3- (1, 1-dimethylbutyl) phenol was prepared, except that 3- (1, 1-dimethylbutyl) phenylmethyl ether was used in place of 1-methoxy-3-neo-pentylbenzene.
Step 4: preparation of 4- (1, 1-dimethylbutyl) -2-hydroxybenzaldehyde
The title benzaldehyde was prepared by the method of example 106, step 6, except that 3- (1, 1-dimethylbutyl) phenol was used in place of 3-neo-pentylphenol.
Step 5: ethyl 7- (1, 1-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acid esters
Ethyl 7- (1, 1-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by the method of example 106, step 7, except that 4- (1, 1-dimethylbutyl) -2-hydroxybenzaldehyde was used in place of 2-hydroxy-4-neo-pentylbenzaldehyde.
Step 6: process for preparation of 7- (1, 1-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
7- (1, 1-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by the method of example 106 step 8, except that ethyl 7- (1, 1-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was used in place of ethyl 7-neo-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate.
1H NMR(acetone-d6)7.85(s，1H)，7.39(2H，J＝8Hz)，7.06(dd，J＝8Hz，J＝1.8Hz)，7.00(d，1H，J＝1.8Hz)，5.79(q，1H，J＝7.2Hz)，1.61(m，2H)，1.30(s，6H)，1.08(m，2H)，0.83(t，3H，J＝5.5Hz).
Example 109
7- (1, 1-dimethylpentyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: 1- [ (2Z) -1, 1-dimethylpent-2-enyl]Preparation of (E) -3-methoxybenzene
The title compound was prepared by the method of example 106 step 3, except that propyltriphenylphosphonium bromide was used instead of methyltriphenylphosphonium bromide.
Step 2: preparation of 1- (1, 1-dimethylpentyl) -3-methoxybenzene
The title compound was prepared by the method of example 106 step 4, except that 1- [ (2Z) -1, 1-dimethylpent-2-enyl ] -3-methoxybenzene was used in place of 1- (1, 1-dimethylprop-2-enyl) -3-methoxybenzene.
Step 3: preparation of 3- (1, 1-dimethylpentyl) phenol
With the exception of using 1- (1, 1-dimethylpentyl) -3-methoxybenzene in place of 1-methoxy-3-neo-pentylbenzene, 3- (1, 1-dimethylpentyl) phenol was prepared by the method of step 5 of example 106.
Step 4: preparation of 4- (1, 1-dimethylpentyl) -2-hydroxybenzaldehyde
4- (1, 1-dimethylpentyl) -2-hydroxybenzaldehyde was prepared by the method of example 106, step 6, except that 3- (1, 1-dimethylpentyl) phenol was used instead of 3-neo-pentylphenol.
Step 5: ethyl 7- (1, 1-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
Ethyl 7- (1, 1-dimethylpentyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by the method of example 106, step 7, except that 4- (1, 1-dimethylpentyl) -2-hydroxybenzaldehyde was used in place of 2-hydroxy-4-neo-pentylbenzaldehyde.
Step 6: preparation of 7- (1, 1-dimethylpentyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Except that ethyl 7- (1, 1-dimethylpentyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was used instead of ethyl 7-neo-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate7- (1, 1-Dimethylpentyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by the method of step 8 of example 106.1H NMR(acetone-d6)7.88(s，1H)，7.40(d，1H，J＝8Hz)，7.11(dd，J＝8Hz，J＝1.8Hz)，7.01(d，1H，J＝1.8Hz)，5.80(q，1H，J＝7.2Hz)，1.65(m，2H)，1.31(s，6H)，1.23(m，2H)，1.07(m，2H)，0.83(t，J＝5.5Hz).LCMSm/z＝343.2(M+H)
Example 110
6-chloro-7- (1, 1-dimethylpentyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-7- (1, 1-dimethylpentyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
Ethyl 6-chloro-7- (1, 1-dimethylpentyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by the method of example 104, step 3, except that ethyl 7- (1, 1-dimethylpentyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was used in place of ethyl 5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate.
Step 2: 6-chloro-7- (1, 1-dimethylpentyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
6-chloro-7- (1, 1-dimethylpentyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by the method of step 4 of example 104, except for using ethyl 6-chloro-7- (1, 1-dimethylpentyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate instead of ethyl 6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate.1H NMR(acetone-d6)7.87(s，1H)，7.51(s，1H)，7.07(s，1H)，5.84(q，1H，J＝7.2Hz)，1.95(m，2H)，1.46(s，6H)，1.25(m，2H)，1.02(m，2H)，0.83(t，3H，J＝5.5Hz).
Example 111
6-chloro-7- (1, 1-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-7- (1, 1-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
Ethyl 6-chloro-7- (1, 1-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by the method of step 3 of example 104, except that ethyl 7- (1, 1-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was used in place of ethyl 5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate.
Step 2: 6-chloro-7- (1, 1-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acids
6-chloro-7- (1, 1-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by the method of step 4 of example 104, except that ethyl 6-chloro-7- (1, 1-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was used in place of ethyl 6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate.1H NMR(acetone-d6)7.83(s，1H)，7.47(s，1H)，7.03(s，1H)，5.80(q，1H，J＝7.2Hz)，1.92(m，2H)，1.41(s，6H)，0.99(m，2H)，0.80(t，3H，J＝5.5Hz).
Example 112
7-tert-butyl-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: 4-tert-butyl-2-hydroxy-5-methoxybenzaldehydePreparation of
4-tert-butyl-2-hydroxy-5-methoxybenzaldehyde was prepared by the method of step 1 of example 104, except that 3-tert-butyl-4-methoxyphenol was used instead of 2, 3, 5-trimethylphenol.
Step 2: ethyl 7-tert-butyl-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
Ethyl 7-tert-butyl-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by the method of step 2 of example 104, except that 4-tert-butyl-2-hydroxy-5-methoxybenzaldehyde was used instead of 6-hydroxy-2, 4, 5-trimethylbenzaldehyde.
Step 3: preparation of 7-tert-butyl-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
7-tert-butyl-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by the method of step 4 of example 104, except that ethyl 7-tert-butyl-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate was used in place of ethyl 6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate.
Example 113
6-chloro-7-isopropenyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 2- (3-hydroxyphenyl) -2-methylpropanal
To a solution of 2- (3-methoxyphenyl) -2-methylpropionaldehyde (20.0 g, 112 mmol) in 90 ml of N-methylpyrrolidone were added thiophenol (11.5 ml, 112 mmol) and anhydrous potassium carbonate (1.55 g, 11.2 mmol). The mixture was stirred at 210 ℃ and 215 ℃ for 3 hours. After cooling, the mixture was partitioned between diethyl ether and 5% aqueous sodium hydroxide. The aqueous layer was acidified with dilute hydrochloric acid and extracted with DCM. The combined extracts were dried over sodium sulfate, filtered and evaporated. Chromatography of the residue was performed using 25% ethyl acetate-hexane as an eluent, to obtain 10.3 g of the title compound as a pale yellow oil.
Step 2: preparation of 4- (1, 1-dimethyl-2-oxyethyl) -2-hydroxybenzaldehyde
4- (1, 1-dimethyl-2-oxoethyl) -2-hydroxybenzaldehyde was prepared by the method of step 1 of example 104, except that 2- (3-hydroxyphenyl) -2-methylpropionaldehyde was used in place of 2, 3, 5-trimethylphenol.
Step 3: ethyl 7- (1, 1-dimethyl-2-oxoethyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
Ethyl 7- (1, 1-dimethyl-2-oxoethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by the method of step 2 of example 104, except that 4- (1, 1-dimethyl-2-oxoethyl) -2-hydroxybenzaldehyde was used instead of 6-hydroxy-2, 4, 5-trimethylbenzaldehyde.
Step 4: process for preparation of ethyl 6-chloro-7-isopropenyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
The title compound was prepared by the method of example 104 step 3, except using ethyl 7- (1, 1-dimethyl-2-oxoethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate instead of ethyl 5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate.
Step 5: preparation of 6-chloro-7-isopropenyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The title compound was prepared by the method of example 104 step 4, except using ethyl 6-chloro-7-isopropenyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate instead of ethyl 6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate.
1H NMR(acetone-d6)，7.82(s，1H)，7.50(s，1H)，6.87(s，1H)，5.78(q，1H，J＝7.2Hz)，5.23(br s，1H)，4.94(br s，1H)，2.02(br s，3H).
Example 114
7- (1, 1-dimethyl-2-oxyethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: 7- (1, 1-dimethyl-2-oxyethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
By the method of example 104 step 4, 7- (1, 1-dimethyl-2-oxoethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared, except that ethyl 7- (1, 1-dimethyl-2-oxoethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was used in place of ethyl 6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate.1H NMR(CDCl3)9.50(s，1H)，7.83(s，1H)，7.25(d，1H，J＝8.0Hz)，6.94(br s，1H)，6.91(dd，J＝8.0Hz，J＝7.2Hz)，5.70(q，1H，J＝7.2Hz)，1.46(s，6H).
Example 115
7- (1-carboxy-1-methylethyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: 2- [3- (ethoxycarbonyl) -2- (trifluoromethyl) -2H-chromen-7-yl]-2-methyl Preparation of propionic acid
In a solution of ethyl 7- (1, 1-dimethyl-2-oxoethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (500 mg, 1.46 mmol) in 20 ml dioxaneTo the solution, 80% NaClO in 5 ml of water was added2(707 mg, (582 mg), 6.43 mmol) of the solution. The resulting mixture was stirred in an oil bath at 90 ℃ for 1.5 hours and cooled. The mixture was partitioned between DCM and water, extracted further, and the combined extracts were dried over sodium sulfate, filtered and evaporated. Chromatography of the residue was performed using 30% ethyl acetate-hexane-1% acetic acid as eluent to obtain 400 mg of the title compound as an oil.
Step 2: 7- (1-1-carboxy-1-methylethyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3- Carboxylic acid preparation
A solution of the title product of step 1 of example 115 (400 mg, 1.12 mmol) in 20 ml of acetic acid was purged with chlorine while protecting the mixture from light. After 3 minutes, the mixture was stirred for 30 minutes, nitrogen was briefly purged, zinc powder (500 mg, 7.6 mg-atm) was added, and the mixture was stirred for 30 minutes. After chromatographic analysis of the residue with 30% ethyl acetate-hexane-1% acetic acid as eluent, the appropriate fractions were mixed and evaporated to give a mixture of chlorinated product and starting material. The residue was worked up again as described above and then chromatographed to give 241 mg of an 85: 15 mixture of product and starting material for the next step.
A solution of 241 mg of the above mixture (0.613 mmol) in 15 ml of ethanol was treated with 366 mg of 50% aqueous sodium hydroxide in 3 ml of water. The mixture was refluxed and cooled. After acidification to pH 1 with dilute aqueous hydrochloric acid, the mixture is partially concentrated to give a pure white solid which is isolated by filtration, e.g. by washing and drying, to give an 85: 15 mixture of chlorinated and unchlorinated diacids which is used in the next step.
The acid (85: 15) was dissolved in 10 ml of acetic acid and chlorine was passed through. The resulting mixture was stirred for 5 hours and briefly purged with nitrogen. Zinc powder (200 mg, 3.1 mg-atm) was added, and the mixture was stirred for 1 hour and concentrated. Chromatography of the residue with 1% acetic acid-ethyl acetate as eluent gave 125 mg of the title compound as a white crystalline solid.
1H NMR(CDCl3)7.76(s，1H)，7.07(s，1H)，5.69(q，1H，J＝7.2Hz)，1.66(s，6H).
Example 116
6-chloro-7- (2-methoxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7- (2-hydroxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-color Preparation of alkene-3-carboxylic acid esters
To a stirred solution of ethyl 7- (1, 1-dimethyl-2-oxoethyl) -2- (trifluoromethyl) -2H-chromene 3-carboxylate (6.90 g, 20.2 mmol) in 200 ml of methanol in an ice bath was added NaBH as a solid in portions4(763 mg, 20.2 mmol). After 25 minutes, acetic acid was carefully added and the solution was concentrated. The residue was partitioned between DCM and water and the organic extracts were dried over sodium sulfate, filtered and evaporated. Chromatography of the residue was carried out using 0-10% ethyl acetate-DCM as eluent to yield 5.4 g of the title compound as a very light yellow oil.
Step 2: ethyl 6-chloro-7- (2-hydroxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
Ethyl 7- (2-hydroxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (5.4 g, 16 mmol) was treated as in example 115, step 2, in a single pass with chlorine. Chromatography of the residue was performed using 0-10% ethyl acetate-DCM as eluent to yield 3.7 g of the title compound as a nearly colourless oil.
Step 3: ethyl 6-chloro-7- (2-methoxy-1, 1-dimethylethyl) -2- (trifluoromethyl) Preparation of (E) -2H-chromene-3-carboxylic acid esters
To a solution of ethyl 6-chloro-7- (2-hydroxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (205 mg, 0.584 mmol) in 8 ml of anhydrous DMF was added 86 mg of 60% sodium hydride and 0.5 ml of methyl iodide. The mixture was stirred at room temperature overnight. Water was added, the mixture was extracted with DCM, and the combined organic extracts were dried over sodium sulfate, filtered and evaporated. Chromatography of the residue using DCM as eluent gave 49 mg of the title compound as an oil.
Step 4: 6-chloro-7- (2-methoxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid
The title compound was prepared by the method of example 104 step 4, except using ethyl 6-chloro-7- (2-methoxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate in place of ethyl 6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate.
1H NMR(CDCl3)7.64(s，1H)，7.20(s，1H)，7.05(s.1H)，5.64(q，1H，J＝7.2Hz)，3.97(d，1H，J＝9Hz)，3.56(d，1H，J＝9Hz)，3.35(s，3H)，1.47(s，3H)，1.46(s，3H).
Example 117
7-tert-butyl-5-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid and 7-tert-butyl-5, 8-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7-tert-butyl-5-chloro-6-methoxy-2- (trifluoromethyl)) -2H-chromene-3- Carboxylate and ethyl 7-tert-butyl-5, 8-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
A single chlorination of ethyl 7-tert-butyl-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (500 mg, 1.40 mmol) was performed as described in example 115. Chromatography of the residue was performed using 25% ethyl acetate-hexane as an eluent to obtain a mixture of monochloro and dichloro products, which was used in the next reaction.
Step 2: 7-tert-butyl-5-chloro-6-methoxy-2- (trichloromethyl) -2H-chromene-3- Carboxylic acids and 7-tert-butyl-5, 8-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
A mixture of ethyl 7-tert-butyl-5-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate and ethyl 7-tert-butyl-5, 8-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (330mg) was hydrolyzed as described in example 104, step 4. Chromatography of the residue was performed on silica gel using 40% ethyl acetate-hexane-1% acetic acid as eluent to obtain the title compound as a white solid.
Isomer 117-1: (7-tert-butyl-5-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid): 16 mg:
1H NMR(acetone-d6)8.02(s，1H)，6.94(s，1H)，5.80(q，1H，J＝7.2Hz)，3.89(s，3H)，1.37(s，9H).LCMS m/z＝365(M+H)
isomer 117-2: (7-tert-butyl-5, 8-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid): 18 mg;
1H NMR(acetone-d6)8.07(s，1H)，6.02(q，1H，J＝7.2Hz)，3.78(s，3H)，1.66(s，9H).LCMS m/z＝399，400，401(M，M+H，M+2H)
example 118
6-chloro-7- (1-cyano-1-methylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 2- (3-hydroxyphenyl) -2-methylpropanenitrile
A mixture of the title product of example 106 step 1 (520 mg, 2.97 mmol) and pyridinium hydrochloride (2 g, 17.3 mmol) was stirred under a dry tube in an oil bath at 200-220 ℃ and maintained in this manner for 3 hours. After cooling, the mixture was dissolved separately in DCM and water, extracted further and the combined extracts dried over sodium sulphate, filtered and evaporated to give 416 mg of the title compound as a brown oil.
Step 2: preparation of 2- (4-formyl-3-hydroxyphenyl) -2-methylpropanenitrile
The title benzaldehyde was prepared by the method of example 104 step 1, except that the phenol of example 118 step 1 was used instead of 2, 3, 5-trimethylphenol.
Step 3: ethyl 7- (1-cyano-1-methylethyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
The title benzopyran was prepared by the method of example 104 step 2, except that the title product from example 118 step 2 was used instead of the title product of example 104 a.
Step 4: ethyl 6-chloro-7- (1-cyano-1-methylethyl) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
The title product of example 118, step 3, was processed in a single pass in the manner described in step 2, 115. Chromatography of the residue on silica gel using DCM as eluent gave the title compound as a 3: 1 mixture with the starting material, which was used in the next reaction.
Step 5: 6-chloro-7- (1-cyano-1-methylethyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
The mixture described in example 118, step 4 (111 mg) was stirred in 8 ml of methanol with 127 mg of 50% sodium hydroxide in 0.5 ml of water at room temperature for 4 hours. The mixture was acidified with aqueous hydrochloric acid and extracted twice with DCM. The combined extracts were dried over sodium sulfate, filtered and evaporated. The residue was dissolved in hexane-ethyl acetate and allowed to crystallize. The title compound was isolated by filtration as 44 mg of a pure white crystalline solid.
1H NMR(CDCl3)7.77(s，1H)，7.35(s，1H)，7.13(s，1H)，5.71(q，1H，J＝7.2Hz)，1.87(s，6H).LCMS m/z＝346.0(M+H).
Example 119
9-chloro-6- (trifluoromethyl) -6H- [1, 3] dioxa-cyclopenta [4, 5-g ] chromene-7-carboxylic acid
Step 1: preparation of 6-hydroxy-1, 3-benzodioxole-5-carboxaldehyde
The title compound was prepared by the method of example 104, step 1, except that sesamol was used instead of 2, 3, 5-trimethylphenol.
Step 2: ethyl 6- (trifluoromethyl) -6H- [1, 3]Dioxacyclopenta [4, 5-g]Chromene-7-carboxylic acid Preparation of esters
The title benzopyran was prepared by the method of example 104 step 2, except that the title benzaldehyde of example 119 step 1 was used instead of the title benzaldehyde of example 104 step 1.
Step 3: ethyl 9-chloro-6- (trifluoromethyl) -6H- [1, 3]-dioxacyclopenta [4, 5-g]Chromenes and derivatives thereof Preparation of (E) -7-carboxylic acid esters
To a solution of ethyl 6- (trifluoromethyl) -6H- [1, 3] -dioxano [4, 5-g ] -7-carboxylate (500 mg, 1.58 mmol) in 6 ml TFA was added a solution of chlorine in TFA (6 ml, 0.28M). After 30 minutes, a further 6 ml of chlorine solution were added and stirring was continued. Zinc powder (1.00 g, 15.3 mg-atm) was added and stirred overnight. After concentration, chromatography of the residue on silica gel with 20% ethyl acetate-hexane as eluent gave 460 mg of the title compound as a yellow solid.
Step 4: 9-chloro-6- (trifluoromethyl) -6H- [1, 3]Dioxacyclopenta [4, 5-g]Chromene-7-carboxylic acid Preparation of acids
The title compound was prepared by the method of example 104 step 4, except using the title product of example 119 step 3 to take the product of step 3 of example 104. The title compound was a yellow solid.
1H NMR(acetone-d6)7.98(s，1H)，6.73(s，1H)，6.24(s，2H)6.02(q，1H，J＝7.2Hz).LCMS m/z＝323.0，325.0(M+H，M+2H)).
Example 120
7- {2- [ (tert-Butoxycarbonyl) amino ] -1, 1-dimethylethyl } -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 3- (2-amino-1, 1-dimethylethyl) phenol
At room temperature under 60psi hydrogen using PtO2Catalyst, examples carried out in acetic acid118 step 1 reduction of the title product (19.9 g, 121 mmol) for 24 h. After filtration, the solution was concentrated, and the resulting title compound was used for the next reaction.
Step 2: preparation of tert-butyl 2- (3-hydroxyphenyl) -2-methylpropylcarbamate
To a solution of the product of step 1 of example 120 (about 121 mmol), sodium bicarbonate (37 g, 440 mmol) in 250 ml of ethyl acetate and 250 ml of water was added di-tert-butyl dicarbonate (33 g, 151 mmol). The mixture was stirred rapidly for 3 days. The organic layer was separated, dried over sodium sulfate, filtered and evaporated to yield 36 g of the title compound as a brown oil.
Step 3: process for preparing tert-butyl 2- (4-formyl-3-hydroxyphenyl) -2-methylpropylcarbamate Preparation of
The title benzaldehyde was prepared by the method of example 104, step 1, except that the title product of example 120, step 2 was used in place of 2, 3, 5-trimethylphenol.
Step 4: ethyl 7- {2[ (tert-butoxycarbonyl) amino group]-1, 1-dimethylethyl } -2- (trifluoro-1-ethyl ester) Preparation of methyl) -2H-chromene-3-carboxylic acid esters
The title benzopyran was prepared by the method of example 104 step 2, except that the title product of example 120 step 3 was used instead of the title product of example 104 step 2.
Step 5: 7- {2- [ (tert-Butoxycarbonyl) amino group]-1, 1-dimethylethyl } -2- (trifluoromethyl) Preparation of yl) -2H-chromene-3-carboxylic acid
The title compound was prepared by the method of example 104 step 4, except that the title product of example 120 step 4 was used instead of the title product of example 104 step 3.
1H NMR(CDCl3-DMSO-d6)7.69(s，1H)，7.18(d，1H，J＝8.0Hz)，6.99(d，1H，J＝8.0Hz)，6.95(br s，1H)，5.72(q，1H，J＝7.2Hz)，4.67(t，1H，J＝6.0Hz)，3.28(d，2H，J＝6.0Hz)，1.39(s，9H)，1.29(s，6H).LCMS m/z＝360，361(M+H，M+2H)
Example 121
7- [1, 1-dimethyl-2- (propylamino) ethyl ] -2- (trifluoromethyl) -2H-chromen-3-carboxylate
Step 1: ethyl 7- [1, 1-dimethyl-2- (propylamino) ethyl group]-2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
To a solution of the title product of step 3 of example 113 (198 mg, 0.579 mmol) in 8 ml of methanol and 1 ml of acetic acid was added n-propylamine (68 mg, 1.2 mmol), 0.9 ml of a 1M solution of sodium cyanoborohydride in THF and 1 g of activated 4. ANG. molecular sieve. The resulting mixture was stirred at room temperature overnight. The mixture was diluted with methanol, filtered through celite, concentrated, and azeotropically distilled with toluene. Chromatography of the residue on silica eluted with 10% methanol-DCM gave 220 mg of the title compound as a colourless oil.
Step 2: 7- [1, 1-dimethyl-2- (propylamino) ethyl group]-2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid
To a solution of the title product of step 1 of example 121 (88 mg, 0.23 mmol) in 5 ml of methanol was added 243 mg of a solution of 50% aqueous sodium hydroxide in 1 ml of water. The mixture was refluxed for 1 hour, cooled and acidified to pH 1. The reaction was concentrated and the remaining solvent was freeze dried. The white solid produced was triturated with water and the solid was separated by filtration. Washed with water and dried to give 23 mg of the title compound as a white solid.
1H NMR(DMSO-d6)7.74(s，1H)，7.42(d，1H，J＝8Hz)，7.12(dd，1H，J＝8Hz，J＝1.6Hz)，7.10(br s，1H)，5.88(q，1H，J＝7.2Hz)，3.13(dd，2H，J＝13Hz，J＝6Hz)，2.73(dd，2H，J＝8Hz)，J＝8Hz)，1.58(m，2H)，1.36(s，3H)，1.34(s，3H)，0.83(t，3H，J＝8Hz).
Example 122
6-chloro-7- [1, 1-dimethyl-2- (propylamino) ethyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Step 1: ethyl 6-chloro-7- [1, 1-dimethyl-2- (propylamino) ethyl]-2- (trifluoromethyl) Preparation of 2H-chromene-3-carboxylic acid esters
The title compound was prepared by the method of example 104 step 3, except that the title product of example 121 step 1 was used instead of the title product of example 104 step 2.
Step 2: 6-chloro-7- [1, 1-dimethyl-2- (propylamino) ethyl]-2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid hydrochloride
The title compound was prepared by the method of example 121 step 2, except that the title product of example 122 step 1 was used instead of the title product of example 121 step 1.
1H NMR(DMSO-d6)7.68(s，1H)，7.56(s，1H)，7.01(s，1H)，5.92(q，1H，J＝7.2Hz)，2.78(m，2H)，2.51(m，2H)，1.58(m，2H)，1.50(s，6H)，0.84(t，3H，J＝5.5Hz).LCMS m/z＝392.0，394.0(M+H).
Example 123
Ethyl (2S) -6-chloro-7- (1, 1-dimethylpentyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl (2S) -6-chloro-7- (1, 1-dimethylpentyl) -2- (trifluoromethyl) -2H-color Preparation of alkene-3-carboxylic acid esters
The title product of example 110, step 1 was separated into the S and R enantiomers using Chiral preparative scale chromatography on a Chiral Pak AD column using 2: 98 isopropanol-heptane as eluent to afford the title compounds of examples 123 and 124.
Example 124
Ethyl (2R) -6-chloro-7- (1, 1-dimethylpentyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
See example 123.
Example 125
(2S) -6-chloro-7- (1, 1-dimethylpentyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Step 1: (2S) -6-chloro-7- (1, 1-dimethylpentyl) -2- (trifluoromethyl) -2H-color Preparation of alkene-3-carboxylic acids
To a solution of the title compound of example 123 (123 mg, 0.304 mmol) in 8 ml of methanol was added 163 mg of a solution of 50% aqueous sodium hydroxide in 1.5 ml of water. After stirring for 4 hours, the mixture was acidified with dilute aqueous hydrochloric acid and extracted with DCM. The combined organic extracts were dried over sodium sulfate, filtered and evaporated to give 99 mg of the title compound as a pale yellow solid.
1H NMR(CDCl3)7.76(s，1H)，7.22(s，1H)，7.01(s，1H)，5.67(q，1H，J＝7.2Hz)，1.99(m，1H)，1.87(m，1H)，1.43(s，3H)，1.42(s，3H)，1.25(m，2H)，0.98(m，2H)，0.83(t，3H，J＝7.0Hz).
Example 126
(2R) -6-chloro-7- (1, 1-dimethylpentyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: (2R) -6-chloro-7- (1, 1-dimethylpentyl) -2- (trifluoromethyl) -2H-chromen-3-one Preparation of carboxylic acids
The title product was prepared by the method of example 125, step 1, except that the title compound of example 124 was used instead of the title product of example 123.
1H NMR(CDCl3)7.76(s，1H)，7.22(s，1H)，7.01(s，1H)，5.67(q，1H，J＝7.2Hz)，1.99(m，1H)，1.87(m，1H)，1.43(s，3H)，1.42(s，3H)，1.25(m，2H)，0.98(m，2H)，0.83(t，3H，J＝7.0Hz).
Example 127
6-chloro-7- (2-hydroxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid.
Step 1: 6-chloro-7- (2-hydroxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-color Preparation of alkene-3-carboxylic acids
The title compound was prepared as a racemic mixture by the method of example 104, step 4, except that the title product of example 116, step 2, was used instead of the title product of example 104, step 3.
Example 128
(2R) -6-chloro-7- (2-hydroxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: (2R) -6-chloro-7- (2-hydroxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid
The title compound of example 127 was isolated as its enantiomer by Chiral preparative chromatography on a Chiral Pak AD column using isopropanol-heptane-TFA 20: 80: 1 as eluent. The title product of example 128 was prepared as a single isomer.
1H NMR(CDCl3)7.61(s，1H)，7.23(s，1H)，7.09(s，1H)，5.66(q，1H，J＝7.2Hz)，4.23(d，1H，J＝11Hz)，3.87(d，1H，J＝11Hz)，1.48(s，3H)，1.47(s，3H).
Example 129
(2S) -6-chloro-7- (2-hydroxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: (2S) -6-chloro-7- (2-hydroxy-1, 1-dimethylethyl) -2- (trifluoromethyl) Preparation of (E) -2H-chromene-3-carboxylic acid
The mixture of the hydroxy compound and trifluoroacetate was prepared from chiral chromatography. To a solution of 113 mg of this mixture in 5 ml of methanol, 0.5 ml of triethylamine was added, and the resulting mixture was stirred at room temperature overnight. After concentration, the mixture was dissolved in DCM, washed with aqueous hydrochloric acid, dried over sodium sulfate, filtered and evaporated to give 59 mg of the title compound as an off-white solid.
1H NMR(CDCl3)7.61(s，1H)，7.23(s，1H)，7.09(s，1H)，5.66(q，1H，J＝7.2Hz)，4.23(d，1H，J＝11Hz)，3.87(d，1H，J＝11Hz)，1.48(s，3H)，1.47(s，3H).
Example 130
6-chloro-7- {2- [ (4-chlorobenzoyl) amino ] -1, 1-dimethylethyl } -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-7- {2- [ amino]-1, 1-dimethylethyl } -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylate hydrochloride
In a solution of the title product of example 120 step 4 (3.47 g, 7.83 mmol) in 50 ml of acetic acid, chlorine was passed through. After 4 hours, nitrogen was purged, zinc powder (2.1 g, 32.1 mg-atm) was added, and the mixture was stirred for 1 hour. The mixture was concentrated. The residue was chromatographed on silica gel using 10% methanol-DCM as eluent to give 3.61 g of the title compound as a white foam.
Step 2: ethyl 6-chloro-7- {2- [ (4-chlorobenzoyl) amino]-1, 1-dimethylethyl } -2- (trifluoromethyl)Preparation of (E) -2H-chromene-3-carboxylic acid esters
To a solution of the title product of example 130 step 1 (150 mg, 0.397 mmol) in 5 ml of pyridine was added a solution of 4-chlorobenzoyl chloride (90 mg, 0.51 mmol) in 1 ml of DCM. The mixture was stirred for 2 hours and 750 mg of Tris resin was added. After stirring overnight, the mixture was filtered and concentrated to give the title compound, which was used in the next step.
Step 3: 6-chloro-7- {2- [ (4-chlorobenzoyl) amino]-1, 1-dimethylethyl } -2- (tris) Preparation of fluoromethyl) -2H-chromene-3-carboxylic acid
The title compound of example 130, step 2, was dissolved in 5 ml of methanol and a solution of 244 mg of 50% aqueous sodium hydroxide in 1 ml of water was added. After stirring for 2 hours, the mixture was acidified, extracted with DCM, and the combined organic extracts were dried over sodium sulfate, filtered and evaporated. Chromatography of the residue on silica gel eluted with 25% ethyl acetate-heptane-1% acetic acid gave 65 mg of the title compound as a pure white crystalline solid.
1H NMR(DMSO-d6)8.34(t，1H，J＝4.6Hz)，7.86(s，1H)，7.72(d，2H，J＝8.8Hz)，7.60(s，1H)，7.48(d，2H，J＝8.8Hz)，7.03(s，1H)，5.93(q，1H，J＝7.2Hz)，3.78(m，2H)，1.44(s，6H).LCMS m/z＝488.0.
Example 131
6, 8-dichloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 3-chloro-2-hydroxy-6-methylbenzaldehyde
Example 100 No1 procedure 3-chloro-6-methylsalicylaldehyde (0.96 g, 5.6 mmol) was prepared from 2-chloro-5-methylphenol (2.85 g, 20 mmol). The structure of the product and1h and13c NMR analysis was consistent.
Step 2: preparation of ethyl 8-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.47 g, 1.46 mmol) was prepared by the method of example 100, step 2, from salicylaldehyde (0.86 g, 5 mmol) from example 131, step 1. The structure of the product and 1H and13c NMR analysis was consistent.
Step 3: preparation of ethyl 6, 8-dichloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Prepare for
A solution of the monochloro ester of example 131, step 2 (0.47 g, 1.46 mmol) in 10 ml of acetic acid was purged with chlorine for about 12 minutes until a persistent greenish yellow color was observed and stirred at room temperature for 1 hour. The mixture was treated with several parts of zinc powder until zinc remained in the reaction for more than 10 minutes. The mixture was stirred at room temperature overnight. Unreacted zinc was filtered off and the solid was washed with ethyl acetate. The filtrate was concentrated in vacuo and again azeotropically concentrated with heptane. While 0.63 g of an off-white (crude) solid remained, according to1H、19F and13c NMR analysis, which corresponds to the desired dichloro ester.
Step 4: preparation of 6, 8-dichloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The title product of example 131, step 4 (0.12g, 0.37mmol) was prepared by the method of example 100, step 3 from ethyl 6, 8-dichloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.61 g, 1.46 mmol).
1H NMR(MeOH-d4)8.00(s，1H)，7.50(s，1H)，5.88(q，1H，J＝7.1Hz)，2.45(s，3H)，19F NMR(MeOH-d4)-78.49.
Example 132
6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 2-hydroxy-4, 5-dimethoxybenzaldehyde
By the method of step 3 of example 100, from 3, 4-dimethoxyphenol (7.71 g, 50 mmol). Preparation of 2-hydroxy-4, 5-dimethoxybenzaldehyde (5.72g, 31.8mmol) the structure and1h and13c NMR analysis was consistent.
Step 2: preparation of ethyl 6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Prepare for
Ethyl 6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (8.32 g, 25.0 mmol) was prepared by the method of step 2 of example 100 from 2-hydroxy-4, 5-dimethoxybenzaldehyde (5.50 g, 30.2 mmol). The structure of the product and1h and19f NMR analysis is in agreement.
First, the3, step (3): preparation of 6, 7-dimethyloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The title compound (1.73 g, 5.7 mmol) was prepared by the method of example 100, step 3, from the ester of example 132, step 2 (2.0 g.6 mmol).
1H NMR(MeOH-d4)7.74(s，1H)，6.87(s，1H)，6.63(s，1H)，5.67(q，1H，J＝7.0Hz)，3.88(s，3H)，8.83(s，3H)19F NMR(MeOH-d4)-78.34.
Example 133
5, 8-dichloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 5, 8-dichloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
Ethyl 5, 8-dichloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.48 g, 1.19 mmol) was prepared from ethyl 6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (2.0 g, 6 mmol) by the method of step 3 of example 131, followed by purification by chromatography. The structure of the product and 1H、19F and13c NMR analysis was consistent.
Step 2: 5, 8-dichloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
5, 8-dichloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (0.36 g, 0.95 mmol) was prepared from ethyl 5, 8-dichloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.48 g, 1.2 mmol) by the method of step 3 of example 100.
1H NMR(MeOH-d4)8.00(s，1H)，5.90(q，1H，J＝7.1Hz)，3.99(s，3H)，3.87(s，3H).19FNMR(MeOH-d4)-78.55.
Example 134
5-chloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 5-chloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate With 8-chloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.67, 2 mmol) was dissolved in 4 ml of TFA and cooled to 0 ℃ followed by treatment with a total of 13 ml of saturated chlorine solution in TFA (0.28M). After stirring at 0 ℃ for 15 minutes, it was stirred at room temperature for a further 45 minutes. The zinc powder was slowly added in several portions until the solids persisted for 10 minutes. The mixture was stirred overnight. The mixture was filtered, concentrated in vacuo, diluted with MTBE, washed twice with dilute brine, followed by washing with saturated brine and dried. After removal of the solvent, the residue was chromatographed to give ethyl 5-chloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.35 g, 1.03 mmol) and ethyl 8-chloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.09 g, 0.26 mmol). The structures of these products are all the same as 1H、19F and13c NMR analysis was consistent.
Step 2: preparation of 5-chloro-6, 7-dimethyloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Prepare for
5-chloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (0.24 g, 0.71 mmol) was prepared by the method of example 100, step 3, 5-chloro ester from step 1, 134 (0.30 g, 0.82 mmol).
1H NMR(CDCl3)8.03(s，1H)，6.53(s，1H)，5.68(q，1H，J＝6.9Hz)，3.91(s，3H)，3.82(s，3H)19F NMR(CDCl3)-77.24.M+1，2：339，340
Example 135
8-chloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 8-chloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The title chromene (0.08 g, 0.24 mmol) was prepared by the method of example 100, step 3, from 8-chloro ester of example 134, step 1 (0.09 g, 0.27 mmol).
1H NMR(CDCl3)7.69(s，1H)，6.73(s，1H)，5.76(q，1H，J＝6.8Hz)，3.93(s，3H)，3.86(s，3H)19F NMR(CDCl3)-77.32.LCMS m/z＝339，340
Example 136
6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 2-hydroxy-6-methylbenzaldehyde
2-hydroxy-6-methylbenzaldehyde was prepared by the method of Noguchi, Satoshi et al, biosci.Biotechnol.biochem. (1997) at page 61, page 1546-1547.
Step 2: preparation of ethyl 5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.28 g, 4.47 mmol) was prepared by the method of example 100, step 2, from the benzaldehyde (1.56 g, 6.9 mmol) of example 136, step 1. The structure of the product and 1H and19f NMR analysis is in agreement.
Step 3: preparation of ethyl 6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.94 g, 2.9 mmol) was prepared from ethyl 5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.26 g, 4.4 mmol) by the method of step 3 of example 103. The structure of the product and1H、19f and13c NMR analysis was consistent.
Step 4: preparation of 6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared from ethyl 6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.60 g, 1.9 mmol) by the method of example 100, step 3.
1H NMR(MeOH-d4)8.02(s，1H)，7.37(d，1H J＝8.6Hz)，6.85(d，1H J＝8.6Hz)5.74(q，1H，J＝7.1Hz)，2.43(s，3H).19F NMR(MeOH-d4)-78.36.
Example 137
5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The title compound was prepared by the method of example 100, step 3, from the ester described in example 136, step 2.
1H NMR(MeOH-d4)7.74(s，1H)，7.12(t，1H J＝7.9Hz)，6.82(d，1H J＝7.6Hz)，6.75(d，1H J＝8.1Hz)，5.80(q，1H，J＝7.4Hz)，2.41(s，3H).
Example 138
(2S) -6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: chiral 6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Separation action
The ester isomer from step 3 of example 136 was isolated by Chiral chromatography using Chiral Pak AD support. Chiral GC analysis was performed on a Restek Rt-BDEX _ sm column (30 meters, 0.32 mm id, 0.25 μm film) with a temperature program of 175 to 215 ℃ at 2.5 ℃/min-helium carrier to obtain the following retention times: a first isomer: 7.19 minutes; a second isomer: 7.35 minutes.
Step 2: preparation of (2S) -6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The first isomer (0.10 g, 0.32 mmol) from step 1 of example 138 was converted to the corresponding acid (0.09 g, 0.31 mmol) by the method of step 3 of example 100. Step 2 of 138 has a positive specific rotation. Chiral HPLC analysis was performed on a Chirobiotic T-column (eluting with methanol/water/acetic acid/TEA) to obtain a retention time of 5.76 min.
1H NMR(CDCl3)8.11(s，1H)，7.33(d，1H J＝8.6Hz)，6.83(d，1H J＝8.6Hz)，5.65(q，1H，J＝7.1Hz)，2.47(s，3H).19F NMR(CDCl3)-76.83.
Example 139
(2R) -6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: (2R) -6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromen-3Preparation of carboxylic acids
The second isomer (1.03 g, 3.2 mmol) from step 1 of example 138 was converted to the corresponding acid (0.89 g, 3.04 mmol) by the method of step 3 of example 100. Example 139 has a negative specific rotation. Chiral HPLC analysis on a Chirobiotic T-column (eluting with methanol/water/acetic acid/TEA) gave a retention time of 5.33 min.
1H NMR(CDCl3)8.11(s，1H)，7.33(d，1H J＝8.6Hz)，6.83(d，1H J＝8.6Hz)，5.65(q，1H，J＝7.1Hz)，2.47(s，3H).19F NMR(CDCl3)-76.82.
Example 140
7-pyrrolidin-1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of ethyl 7-pyrrolidin-1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Prepare for
In a sealed tube flushed with argon, ethyl 7-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.40 g, 1.0 mmol) was dissolved in 3 mL of toluene, followed by addition of Pd (OAc) 2(23 mg), 10% by weight of P (t-Bu) in hexane3(0.21 g), cesium carbonate (0.56 g, 1.7 mmol) and pyrrolidine (0.10 g, 1.4 mmol), stirred vigorously while heating to 75 ℃ for 21 hours. The reaction was cooled, filtered and solubilized, leaving a dark reddish orange oil which was purified by flash chromatography to afford ethyl 7-pyrrolidin-1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.27 g, 0.79 mmol) as a yellow solid. The structure of the product and1H、19f and13c NMR analysis was consistent.
Step 2: 7-pyrrolidin-1-yl-2- (trifluoromethyl)) Preparation of (E) -2H-chromene-3-carboxylic acid
7-pyrrolidin-1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by the procedure 3 of example 100, the ester from procedure 1 of example 138 (0.21 g, 0.60 mmol).
1H NMR(MeOH-d4)7.68(s，1H)，7.1(d，1H J＝8.2Hz)，6.22(dd，1H J＝8.2，2.1Hz)，6.11(d，1H J＝2.1Hz)，5.61(q，1H，J＝7.2Hz)，3.31(m，4H)，2.01(m，4H).
19F NMR(MeOH-d4)-78.66.
Example 141
6, 8-dichloro-7-pyrrolidin-1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-7-pyrrolidin-1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Esters with ethyl 6, 8-dichloro-7-pyrrolidin-1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
The ester from step 1 of example 140 (0.35 g, 1.0 mmol) was treated with chlorine gas according to the procedure in step 3 of example 103, followed by chromatography to afford the fast eluting 6, 8-dichloro ester (0.11 g, 0.27 mmol) and the 6-chloro ester derivative (0.14 g, 0.37 mmol). The structures of these products are all the same as 1H、19F and13c NMR analysis was consistent.
Step 2: 6, 8-dichloro-7-pyrrolidin-1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
Example 141, step 1, 6, 8-dichloro ester (0.10 g, 0.25 mmol) was converted to 6, 8-dichloro-7-pyrrolidin-1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (0.09 g, 0.24 mmol) by example 100, step 3.
1H NMR(CDCl3)7.64(s，1H)，7.15(s，1H)，5.78(q，1H，J＝7.0Hz)，3.33-3.68(m，4H)，1.95-1.99(m，4H)，19F NMR(CDCl3)-73.35.LCMS m/z＝383，384(M+H，M+2H).
Example 142
6-chloro-7-pyrrolidin-1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 6-chloro-7-pyrrolidin-1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Prepare for
The 6-chloro ester of example 141, step 2 (0.13 g, 0.35 mmol) was converted by example 100, step 3, to 6-chloro-pyrrolidin-1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (0.11 g, 0.32 mmol).
1H NMR(MeOH-d4)7.66(s，1H)，7.22(s，1H)，6.42(s，1H)，5.68(q，1H，J＝7.1Hz)，3.58(m，4H)，1.99(m，4H)，19F NMR(MeOH-d4)-78.60.LCMS m/z＝348，349(M+H，M+2H).
Example 143
6-chloro-7-piperidin-1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of ethyl 7-piperidin-1-yl-2- (trifluoromethyl) -2H-chromen-3-carboxylate
Following the procedure of step 1 of example 138, ethyl 7-iodo-2- (tris)Fluoromethyl) -2H-chromene-3-carboxylate (0.60 g, 1.5 mmol) was converted to ethyl 7-piperidin-1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.38 g, 1.06 mmol). Structure of the product and 1H、19F and13c NMR analysis was consistent.
Step 2: ethyl 6-chloro-7-piperidin-1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
The ester obtained in step 1 of example 143 (0.38 g, 1.06 mmol) was treated with chlorine gas according to the procedure in step 3 of example 103 to give ethyl 6-chloro-7-piperidin-1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.16 g, 0.41 mmol). Structure of the product and1H、19f and13c NMR analysis was consistent.
Step 3: preparation of 6-chloro-7-piperidin-1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The 6-chloro ester of example 143, step 2 (0.16 g, 0.41 mmol) was converted by example 100, step 3, to 6-chloro-7-piperidin-1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (0.13 g, 0.36 mmol).
1H NMR(CDCl3)7.74(s，1H)，7.21(s，1H)，6.61(s，1H)，5.65(q，1H，J＝6.9Hz)，3.10-3.16(m，2H)，3.00-3.05(m，2H)，1.71-1.76(m，4H)，1.59-1.64(m，2H)，
19F NMR(CDCl3)-77.14.LCMS m/z＝362，363(M+H，M+2H).
Example 144
6-chloro-7- (dipropylamino) -1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7- (dipropylamino) -1-yl-2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
According to the method of step 1 of example 140, ethyl 7-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.60 g, 1.5 mmol) is converted to ethyl 7- (dipropylamino) -1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.38 g, 1.06 mmol). Structure of the product and 1H、19F and13c NMR analysis was consistent.
Step 2: ethyl 6-chloro-7- (dipropylamino) -1-yl-2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid esters
Ethyl 7- (dipropylamino) -1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.38 g, 1.06 mmol) was treated with chlorine according to the procedure in step 3 of example 131 to give ethyl 6-chloro-7- (dipropylamino) -1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.16 g, 0.41 mmol). Structure of the product and1H、19f and13c NMR analysis was consistent.
Step 3: 6-chloro-7- (dipropylamino) -1-yl-2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
Ethyl 6-chloro-7- (dipropylamino) -1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.16 g, 0.40 mmol) was converted to 6-chloro-7- (dipropylamino) -1-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (0.13 g, 0.35 mmol) by the 3 rd step of example 100.
1H NMR(CDCl3)7.74(s，1H)，7.20(s，1H)，6.60(s，1H)，5.65(q，1H，J＝6.9Hz)，3.11-3.19(m，4H)，1.25-1.58(m，4H)，0.85-0.89(m，6H)19F NMR(CDCl3)-77.08.LCMSm/z＝378，379(M+H，M+2H)：
Example 145
6-chloro-8- (2-phenylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-8- (2-phenylethyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
Ethyl 6-chloro-8- (2-phenylethynyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.30 g, 0.74 mmol) was dissolved in ethanol and combined with Pt2O catalyst. And reduction was carried out at room temperature under 20psi hydrogen for 4 hours. The mixture was filtered, extracted and purified by flash chromatography on silica gel to give ethyl 6-chloro-8- (2-phenylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.21 g, 0.51 mmol). Structure of the product and 1H、19F and13c NMR analysis was consistent.
Step 2: 6-chloro-8- (2-phenylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acids
The 6-chloro ester of step 1, example 145 (0.20 g, 0.49 mmol) was converted to 6-chloro 8- (2-phenylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (0.16 g, 0.42 mmol) by the 3 rd step of example 100.
1H NMR(CDCl3)7.17-7.32(m，5H)，7.11(d，1H，J＝2.5Hz)，7.08(d，1H，J＝2.5Hz)5.76(q，1H，J＝6.8Hz)，2.83-2.97(m，4H).19F NMR(CDCl3)-76.97.LCMS m/z＝384，385(M+H，M+2H).
Example 146
7-cyclopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: 7-iodo-2- (trifluoromethyl) -2H-chromenePreparation of (E) -3-carboxylic acid
To a suspension of ethyl 7-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.50 g, 3.9 mmol) in 5 ml ethanol was added sodium hydroxide (0.46 g, 11.6 mmol) in 2.5 ml water. After heating for 1.5 hours, the solvent was removed in vacuo. The resulting sodium salt was used immediately.
Step 2: preparation of 7-cyclopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
In (9-BBN)2To a suspension of (1.96 g, 8.7 mmol) in 10 ml THF was added propargyl bromide (0.53 g, 4.4 mmol). After heating for 2 hours and cooling to room temperature, sodium hydroxide (0.52 g, 13 mmol) in 4.3 ml of water was added and the reaction was stirred for 1 hour. In a separate flask, the title product of step 1 of example 146 in 5 mL THF and Pd (PPh) were added under argon 3)4. The reaction in the original flask was transferred to the second flask via cannula. After refluxing for 18 hours and cooling to room temperature, 25 ml of water was added. The organic solvent was removed from the reaction in vacuo. The aqueous layer was extracted three times with 70 ml of ethyl acetate. The combined organic extracts were washed once with 50 ml of 1N hydrochloric acid and once with 50 ml of saturated brine. After drying over sodium sulfate and concentration in vacuo, the product was purified by flash column chromatography and reverse phase chromatography on YMC ODS-AQ in methanol/water to give the desired product (0.40 g, 40%).
Example 147
6-chloro-7-cyclopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 6-chloro-7-cyclopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a solution of the product of step 2 of example 146 (0.28 g, 1.0 mmol) in 5 ml of acetic acid was added chlorine in acetic acid (3.0 ml, ca. 1.5 mmol). After 0.75 hours, the reaction was treated with zinc dust for 1.5 hours. The reaction mixture was decanted from the zinc and concentrated in vacuo. The residue obtained is triturated with water, filtered and washed with water. After drying overnight in a vacuum oven at 50 ℃, the yield of 6-chloro-7-cyclopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was 0.26 g (82%).
1H NMR(MeOH-d4)7.74(s，1H)，6.57(s，1H)，5.73(q，1H，J＝7.06Hz)，2.21(dd，2H，J＝2.0，8.5Hz)，0.75(m，2H).
Example 148
6, 8-dichloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 2-hydroxy-4, 6-dimethylbenzaldehyde
The title product of example 148, step 1, was prepared by the same manner as described in example 100, step 1, starting from 3, 5-dimethylphenol.
Step 2: preparation of ethyl 5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
The title product of example 148, step 2, was prepared by the same procedures as described for example 100, step 2, starting from the title product of example 148, step 1.
Step 3: ethyl 6, 8-dichloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
The title product of example 148, step 3, was prepared by the same manner as described in example 100, step 3, starting from ethyl 5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate.
Step 4: preparation of 6, 8-dichloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Prepare for
6, 8-dichloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by the same manner as described in step 3 of example 100, starting from ethyl 6, 8-dichloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate. 1H NMR(MeOH-d4)7.93(s，1H)，5.81(q，1H，J＝6.98Hz)，2.49(s，3H)，2.43(s，3H)
Example 149
5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid is prepared by the same procedure as described in step 3 of example 100, starting from ethyl 5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate.
1H NMR(MeOH-d4)7.95(s，1H)，6.72(bs，1H)，6.65(s，1H)，5.67(q，1H，J＝7.18Hz)，2.39(s，3H)，2.31(s，3H)
Example 150
6-Ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 4-ethyl-2-methylphenol
A mixture of 3-methyl-4-hydroxyacetophenone (12.0 g, 79.9 mmol), 20% palladium hydroxide in acetic acid/carbon was hydrogenated at 25 ℃ and 60 psi. After 16 hours, the catalyst was filtered off from the reaction. The filtrate was concentrated. The product was dried under high vacuum for 18 hours to yield a clear oil (10.1 g, 93%).
Step 2: preparation of 5-ethyl-2-hydroxy-3-methylbenzaldehyde
To a solution of the phenol of example 150, step 1 (5.0 g, 36.7 mmol) in 200 ml of acetonitrile were added magnesium chloride (5.25 g, 55.1 mmol), TEA (13.9 g, 19.2 ml, 137.6 mmol) and paraformaldehyde (8.3 g, 280 mmol). The solution was heated to reflux for 3 hours. After cooling, the reaction was diluted with ethyl acetate (500 ml) and acidified with 2N aqueous hydrochloric acid until the pH of the reaction was 4. The reaction was diluted with 300 ml of water. The organic layer was washed with water, brine, dried over magnesium sulfate, and concentrated. The residue was purified by flash chromatography (on silica, eluting with 94/6 hexanes/ethyl acetate) to afford 3.2 g (53%) of the desired product as a clear oil.
Step 3: ethyl 6-ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
To a solution of benzaldehyde (1.8 g, 11.0 mmol) and finely powdered potassium carbonate (3.34 g, 24.2 mmol) in DMF (20 ml) of example 150, step 2 was added ethyl 4, 4, 4-trifluorocrotonate (2.2 g, 13.2 mol). The reaction was heated to 85 ℃. After 2 hours, the reaction was cooled to 25 ℃ and diluted with ethyl acetate (200 ml) and water (200 ml). The organic layer was washed with saturated sodium bicarbonate (150 ml), water (100 ml) and brine (150 ml), dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a brown residue. The residue was dried under high vacuum to yield 2.7 g (78%) of a brown crystalline solid.
Step 4: preparation of 6-ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a solution of ethyl 6-ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (2.6 g, 8.3 mmol) in ethanol (90 ml) was added 1N sodium hydroxide (24.8 ml, 24.8 mmol). The reaction was stirred at 25 ℃ for 18 hours. Ethanol was removed from the reaction under reduced pressure. The residue was acidified with 2N hydrochloric acid. The product was extracted into ethyl acetate (300 ml) and then washed with brine (100 ml), dried over magnesium sulfate, filtered and concentrated. The crude product was dissolved in 20 ml of ethyl acetate and then diluted with 150 ml of hexane. The resulting solution was cooled at 0 ℃ for 30 minutes. The product precipitated from the solution was collected by filtration. The desired product was isolated in the form of an off-white solid in an amount of 1.6 g (68%).
1H NMR(DMSO-d6)1.15(t，3H，J＝7.56Hz)，2.16(s，3H)，2.51(q，2H，J＝7.6Hz)，5.89(q，1H，J＝7.4Hz)，7.11(d，1H，J＝2.1Hz)，7.14(d，1H，J＝2.1Hz)，7.79(s，1H).
Example 151
(2S) -6-ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: (+) -6-ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
The product of example 150, step 4 (isomer) was isolated by Chiral chromatography on a chiralpak AD column using isopropanol/heptane/TFA (5/95/0.1) as mobile phase. The product of step 1 of example 151 had a residence time of 5.58 minutes and a positive specific rotation.
1H NMR(DMSO-d6)1.15(t，3H，J＝7.56Hz)，2.16(s，3H)，2.51(q，2H，J＝7.6Hz)，5.89(q，1H，J＝7.4Hz)，7.11(d，1H，J＝2.1Hz)，7.14(d，1H，J＝2.1Hz)，7.79(s，1H).
Example 152
(2R) -6-Ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: (-) -6-ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
See example 151, step 1. Example 152 had a residence time of 45.58 minutes and a negative specific rotation.
1H NMR(DMSO-d6)1.15(t，3H，J＝7.56Hz)，2.16(s，3H)，2.51(q，2H，J＝7.6Hz)，5.89(q，1H，J＝7.4Hz)，7.11(d，1H，J＝2.1Hz)，7.14(d，1H，J＝2.1Hz)，7.79(s，1H).
Example 153
6-Ethyl-7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 6-ethyl-7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Prepare for
6-Ethyl-7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was synthesized in the same manner as described in the procedure of example 150, using 2-methyl-4-hydroxyacetophenone as a starting material.
1H NMR(DMSO-d6)1.14(t，3H，J＝7.5Hz)，2.25(s，3H)，2.51(q，2H，J＝7.5Hz)，5.83(dd，1H，J＝7.4Hz)，6.84(s，1H)，7.24(s，1H)，7.80(s，1H).
Example 154
6-Ethyl-8-propyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-Ethyl-8-propyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was synthesized in the same manner as described in the procedure of example 150, using 3 '-allyl-4' -hydroxyacetophenone as the starting material.
1H NMR(MeOH-d4)0.93(t，3H，J＝7.3Hz)，1.20(t，3H，J＝7.6Hz)，1.60(hextet，2H，J＝7.5Hz)，2.45-2.65(m，4H)，5.73(q，1H，J＝7.2Hz).6.96(d，1H，J＝2.1Hz)，7.03(d，1H，J＝2.1Hz).7.73(s，1H).
Example 155
6-isopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 2-hydroxy-5-isopropylbenzaldehyde
The formylation reaction was carried out in the same manner as described in step 2 of example 150 using 4-isopropylphenol (5.0 g, 36.7 mmol). The purified product was isolated in the form of a golden yellow oil in an amount of 5.2 g (86%).
Step 2: process for preparing ethyl 6-isopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
The cyclization reaction was carried out in the same manner as described in step 3 of example 150 using the product of step 1 of example 155 (3.0 g, 18.3 mmol). The crude product was purified by flash chromatography (eluting with 9/1 hexane/ethyl acetate) to yield a purified product in an amount of 4.54 g (79%).
Step 3: preparation of 6-isopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The product of step 2, example 155 (2.1 g, 6.7 mmol) was converted to the acid in the same manner as described in step 4 of example 150. The product was isolated in the form of an off-white solid in an amount of 1.6 g (68%).
1H NMR(DMSO-d6)1.17(s，3H)，1.19(s，3H)，2.79-2.88(m，1H)，5.86(q，1H，J＝7.3Hz)，6.94(d，2H，J＝8.4Hz)，7.25(dd，1H，J＝6.3Hz，J＝2.2Hz)，7.37(d，1H，J＝2.2)，7.83(s，1H).
Example 156
6-isopropyl-7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: process for preparing 6-isopropyl-7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
6-isopropyl-7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was synthesized by the same procedure as described for the procedure of example 155, starting from 4-isopropyl-3-methylphenol.
1H NMR(DMSO-d6)1.14(s，3H)，1.16(s，3H)，2.26(s，1H)，2.95-3.06(m，1H)，5.81(q，1H，J＝7.5Hz)，6.76(s，1H)，7.24(s，1H)，7.58(s，1H).
Example 157
6-chloro-7- [ (2-propyl-1H-imidazol-1-yl) methyl ] -2- (trifluoromethyl) -2H-chromen-3-carboxylate
Step 1: preparation of 5-chloro-2-hydroxy-4-methylbenzaldehyde
4-chloro-3-methylphenol (10.0 g, 70.1 mmol) was converted to the aldehyde using the procedure described in step 2 of example 150. The desired product was isolated in the form of a pale yellow solid in an amount of 8.8 g (74%).
Step 2: ethyl 6-chloro-7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
The product of step 1, example 157 (8.9 g, 52.2 mmol) was converted to chromene using the procedure described in step 3, example 150. The desired product was isolated in the form of a yellow solid in an amount of 9.9 g (59%).
Step 3: ethyl 7- (bromomethyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
To a mixture of the product of step 2 of example 157 (4.0 g, 12.5 mmol), N-bromosuccinimide (2.3 g, 13.1 mmol) and 21 ml of benzene was added benzoyl peroxide (145 mg, 0.6 mmol). The reaction was heated to 84 ℃. After 5 hours, the reaction was cooled to 25 ℃ and stored overnight. The solid material in the reaction was removed by filtration and washed with 4 ml of benzene. To the filtrate was added N-bromosuccinimide (1.0 g, 5.7 mmol) and benzoyl peroxide (145 mg, 0.6 mmol). The reaction was heated to 84 ℃. After 2.5 hours, the reaction was cooled to 25 ℃. The solid in the reaction was removed by filtration, and the filtrate was concentrated. The residue was purified by flash chromatography (eluting with 9/1 of toluene/ethyl acetate) to give 3.9 g of a yellow solid which was of suitable purity for use without further purification.
Step 4: ethyl 6-chloro-7- [ (2-propyl-1H-imidazol-1-yl) methyl]-2- (III) Preparation of fluoromethyl) -2H-chromene-3-carboxylic acid esters
A solution of 2-propylimidazole (76 mg, 0.69 mmol) in 1 ml DMF was added to a mixture of sodium hydride (32 mg, 0.81 mmol, 60% suspension in mineral oil) at 0 ℃ under argon. After 20 minutes, a solution of the product of step 3 of example 157 (250 mg, 0.62 mmol) in 2 ml of DMF was added at 0 ℃. The reaction was warmed to 25 ℃. After 1.5 hours, the reaction was filtered through a pad of celite (1 inch) and washed with ethyl acetate (20 ml). The filtrate was concentrated to yield 0.21 g (80%) of a light brown oil.
First, the5, step (2): 6-chloro-7- [ (2-propyl-1H-imidazol-1-yl) methyl]-2- (trifluoromethyl) Preparation of yl) -2H-chromene-3-carboxylic acid
The product of step 4 (0.21 g, 0.5 mmol) of example 157 was converted to the acid according to the procedure of step 4 of example 150. The crude product was purified by HPLC (column: Delta Pak 300 × 50 mm i.d., C18, 15 μ M) using a water-acetonitrile gradient (conditions: acetonitrile-water 10-50% over 30 minutes) to obtain the purified product. The yield of an off-white solid was 66 mg (30%).
1H NMR(MeOH-d4)0.99(t，3H，J＝7.41Hz)，1.73(hextet，2H，J＝7.8Hz)，3.00(t，2H，J＝7.8Hz)，5.51(s，2H)，5.83(q，1H，J＝7.0Hz)，6.86(s，1H)，7.46(d，1H，J＝2.1Hz)，7.54(d，1H，J＝2.1Hz)，7.81(s，1H)，7.89(s，1H).
Example 158
6-chloro-7- (1H-imidazol-1-ylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate salt
6-chloro-7- (1H-imidazol-1-ylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid hydrochloride was synthesized according to the procedure described in example 157, using imidazole as the starting amine. 158:1H NMR(MeOH-d4)5.44-5.52(m，2H)，5.76(q，1H，J＝6.94Hz)，7.02(s，1H)，7.53(s，1H)，7.56(s，1H)，7.73(s，1H)，9.00(s，1H).
example 159
6-chloro-7- [ (2-methyl-1H-imidazol-1-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate hydrochloride
6-chloro-7- [ (2-methyl-1H-imidazol-1-yl) methyl was synthesized according to the procedure described in example 157, using 2-methylimidazole as the starting amine]-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate hydrochloride.1HNMR(MeOH-d4)2.66(s，3H)，5.41-5.51(m，2H)，5.83(q，1H，J＝7.0Hz)，6.90(s，1H)，7.42(d，1H，J＝2.2Hz)，7.49(d，1H，J＝2.2Hz)，7.59(s，1H)，7.81(s，1H).
Example 160
6-chloro-7- [ (2-isopropyl-1H-imidazol-1-yl) methyl ] -2- (trifluoromethyl) -2H-chromen-3-carboxylate
6-chloro-7- [ (2-isopropyl-1H-imidazol-1-yl) methyl was synthesized according to the procedure described in example 157, using 2-isopropylimidazole as the starting amine]-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid hydrochloride.1H NMR(MeOH-d4)1.35(s，3H)，1.37(s，3H)，3.45-3.54(m，1H)，5.54(s，2H)，5.83(q，1H，J＝7.0Hz)，6.82(s，1H)，7.44(d，1H，J＝2.1Hz)，7.55(d，1H，J＝2.1Hz)，7.59(s，1H)，7.80(s，1H).
Example 161
7- (1H-benzimidazol-1-ylmethyl) -6-chloro-2- (trifluoromethyl) -2H-chromen-3-carboxylate
7- (1H-benzimidazol-1-ylmethyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid hydrochloride was synthesized according to the procedure described in example 157, using benzimidazole as the starting amine.
1H NMR(DMSO-d6)5.80(s，2H)，5.98(q，1H，J＝7.1Hz)，7.05(s，1H)，7.55-7.59(m，2H)，7.77-7.80(m，2H)，7.88-7.90(m，2H).
Examples 162a and 162b
6-chloro-7- [ (2-ethyl-1H-imidazol-1-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate hydrochloride with 6-chloro-5- [ (2-ethyl-1H-imidazol-1-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid hydrochloride.
Step 1: 5-chloro-2-hydroxy-4-methylbenzaldehyde and 5-chloro-2-hydroxy-6-methylbenzene Preparation of formaldehyde
4-chloro-3-methylphenol (10.0 g, 70.1 mmol) was converted to the aldehyde using the procedure described in step 2 of example 150. The impurities were removed by flash chromatography (eluting with 9/1 hexanes/ethyl acetate). A94: 6 mixture of aligned isomeric aldehydes was prepared and a pale yellow solid was isolated in an amount of 8.8 g (74%).
Step 2: ethyl 6-chloro-7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters with ethyl 6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
The product of step 1, example 162 (8.9 g, 52.2 mmol) was converted to chromene using the procedure described in step 3, example 150. The crude product was purified by flash chromatography (eluting with 8/2 of heptane/ethyl acetate) to yield a mixture of chromenes as a yellow solid in an amount of 9.9 g (59%).
Step 3: ethyl 7- (bromomethyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3- Carboxylic acid esters and ethyl 5- (bromomethyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
The product of step 2, example 162 (4.0 g, 12.5 mmol) was converted to bromide using the procedure described in step 3, example 157. The residue was purified by flash chromatography (eluting with 9/1 of toluene/ethyl acetate) to give the product mixture as a yellow solid (3.9 g, 78%).
Step 4: ethyl 6-chloro-7- [ (2-ethyl-1H-imidazol-1-yl) methyl]-2- (III) Fluoromethyl) -2H-chromene-3-carboxylate with ethyl 6-chloro-5- [ (2-ethyl-1H-imidazol-1-yl) Methyl radical]Preparation of (E) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid ester
The product of step 3, example 162 (300 mg, 0.75 mmol) was converted to 2-ethylimidazole using the procedure described in step 4, example 157. The product was a light brown oil (320 mg, 70%).
Step 5: 6-chloro-7- [ (2-ethyl-1H-imidazol-1-yl) methyl]-2- (trifluoromethyl) Yl) -2H-chromene-3-carboxylic acid with 6-chloro-5- [ (2-ethyl-1H-imidazol-1-yl) methyl]-2- Preparation of (trifluoromethyl) -2H-chromene-3-carboxylic acid
The products of step 4 of example 162 were converted to their acids according to the procedure of step 4 of example 150. The crude product was purified by reverse phase HPLC (column: Delta Pak 300 × 50 mm i.d., C18, 15 μ M) using a water-acetonitrile gradient (conditions: acetonitrile-water-10-50% over 30 minutes) to obtain the purified product. The product 162-1 was isolated in the form of a light yellow solid in an amount of 100 mg. Product 162-2 was isolated in the form of a yellowish solid in an amount of 15 mg.
162-1 1H NMR(MeOH-d4)1.37(t，2H，J＝7.4Hz)，3.08(q，2H，J＝7.6Hz)，5.48-5.56(m，2H)，5.88(q，1H，J＝7.0Hz)，6.90(s，1H)，7.47(d，1H，J＝2.1Hz)，7.55(d，1H，J＝2.1Hz)，7.62(s，1H)，7.85(s，1H).
162-2 1H NMR(MeOH-d4)1.44(t，2H，J＝7.5Hz)，3.17(q，2H，J＝7.7Hz)，5.68-5.74(m，2H)，5.89(q，1H，J＝7.0Hz)，6.98(d，1H，J＝2.1Hz)，7.22(d，1H，J＝8.8Hz)，7.45(d，1H，J＝2.1Hz)，7.59(d，1H，J＝8.8Hz)，8.05(s，1H).
Examples 163a and 163b
6-chloro-7- [ (4, 5-dichloro-1H-imidazol-1-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate and 6-chloro-5- [ (4, 5-dichloro-1H-imidazol-1-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: 6-chloro-7- [ (4, 5-dichloro-1H-imidazol-1-yl) methyl]-2- (III) Fluoromethyl) -2H-chromene-3-carboxylate with 6-chloro-5- [ (4, 5-dichloro-1H-imidazole-1- Radical) methyl]Preparation of (E) -2- (trifluoromethyl) -2H-chromene-carboxylic acid hydrochloride
6-chloro-7- [ (4, 5-dichloro-1H-imidazol-1-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate salt and 6-chloro-5- [ (4, 5-dichloro-1H-imidazol-1-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid hydrochloride salt were synthesized in the same manner as described in example 162 using 4, 5-dichloroimidazole in the alkylation reaction.
163-1 1H NMR(DMSO-d6)5.27-5.37(m，2H)，5.97(q，1H，J＝7.2Hz)，6.55(s，1H)，7.75(s，1H)，7.87(s，1H)，7.93(s，1H).
163-2 1H NMR(DMSO-d6)5.47-5.56(m，2H)，5.85(q，1H，J＝7.0Hz)，7.16(d，1H，J＝8.83Hz)，7.40(s，1H)，7.55(d，1H，J＝8.8Hz)，8.07(s，1H).
Example 164
6-chloro-7- (phenoxymethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-7- (phenoxymethyl) -2- (trifluoromethyl) -2H-color Preparation of alkene-3-carboxylic acid esters
A solution of phenol (117 mg, 0.69 mmol) in 1 ml of DMF was added to a mixture of sodium hydride (30 mg, 0.75 mmol) in 1 ml of DMF at 0 ℃ under argon. After 30 minutes, a solution of ethyl 7- (bromomethyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (250 mg, 0.62 mmol) described in step 3 of example 157 in 2 ml of DMF was added dropwise. The reaction was warmed to 25 ℃. After 18 hours, the reaction was filtered through a pad of celite (1 inch) and washed with ethyl acetate (20 ml). The filtrate was concentrated to obtain 230 mg of a pale yellow solid.
Step 2: 6-chloro-7- (phenoxymethyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
The product of step 1, example 164 (0.22 g, 0.53 mmol) was converted to the acid according to the procedure of step 4, example 150 and purified by reverse phase HPLC (column: Delta Pak 300 × 50 mm i.d., C18, 15 μ M) using an acetonitrile-water gradient 10-50% over 30 minutes to give 80 mg (40%) of a light yellow solid.
1H NMR(DMSO-d6)5.12(s，2H)，5.98(q，1H，J＝7.3Hz)，6.98(t，1H，J＝7.4Hz)，7.04(d，2H，J＝7.8Hz)，7.26(s，1H)，7.32(dt，2H，J＝2.0Hz，J＝7.4Hz)，7.72(s，1H)，7.89(s，1H).
Example 165
6-chloro-7- (ethoxymethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-7- (ethoxymethyl) -2- (trifluoromethyl) -2H-color Preparation of alkene-3-carboxylic acid esters
A solution of pyrrole (55 mg, 0.75 mmol) in 1.5 ml DMF was added to a mixture of sodium hydride (38 mg, 0.83 mmol) in 1 ml DMF at 0 ℃ under argon. The mixture was stirred at 0 ℃ for 10 minutes and then warmed to 25 ℃. After 30 minutes, a solution of ethyl 7- (bromomethyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (300 mg, 0.75 mmol) from step 3 of example 162 in 2.5 ml of DMF was added dropwise. After 3 hours, the reaction was filtered through a pad of celite (1 inch) and washed with ethyl acetate (10 ml). The filtrate was concentrated to give 350 mg (100%) of a brown oil.
Step 2: 6-chloro-7- (ethoxymethyl) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
The product of example 165a (350 mg, 0.75 mmol) was converted to the acid according to the procedure of example 150d and purified using reverse phase HPLC (column: Delta Pak 300 × 50 mm i.d., C18, 15 μ M) with an acetonitrile-water gradient over 30 minutes to give 60 mg of the title product as a pale brown solid.
1H NMR(MeOH-d4)1.27(t，3H，J＝7.0Hz)，3.63(q，2H，J＝7.0Hz)，4.54(s，1H)，5.78(q，1H，J＝7.0Hz)，7.12(s，1H) 7.39(s，1H)，7.77(s，1H).
Example 166
6-Ethyl-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 2- (4-ethyl-2-methoxyphenoxy) tetrahydro-2H-pyran
Ethyl guaiacol (10 g, 65 mmol) was dissolved in 100 ml of ethyl acetate and to this solution was added 8.9 ml of 3, 4-dihydro-2H-pyran (97.5 mmol, 8.2 g) followed by a catalytic amount of 4.0M hydrochloric acid/dioxane solution. The reaction was stirred at 25 ℃ overnight. The next day, the solution was washed with 1N aqueous sodium hydroxide solution and evaporated to dryness. The crude mixture was redissolved in ether and then stirred with 1N aqueous sodium hydroxide for a short period, the stirring was stopped and allowed to stand overnight. The organic layer was washed with water and brine. The resulting solution was dried (sodium sulfate). The solution was filtered and evaporated to dryness to yield 9.9 g of a colorless oil (64%). This material was used without further purification.
Step 2: 5-ethyl-3-methoxy-2- (tetrahydro-2H-pyran-2-yloxy) benzaldehyde Preparation of
A solution of the product from step 1 of example 166 (1.0 g, 4.2 mmol) in 7.0 ml hexane and 0.70 ml TMEDA (4.6 mmol, 543.2 mg) was cooled to-78 ℃ and n-butyllithium (2.9 ml of a 1.6M solution in hexane) was added. After addition, the reaction was warmed to 25 ℃. After 5 hours, DMF in 3 ml hexane (0.5 ml) was added. The reverse reactionThe solution should be quenched with water and the resulting solution washed with water. The organic extract was dried over magnesium sulfate, filtered and evaporated to give 1.1 g of a golden yellow oil (100%) which was obtained by1H NMR was judged to be of suitable purity and used without further purification.
Step 3: preparation of 5-ethyl-2-hydroxy-3-methoxybenzaldehyde
The title product of step 2 of example 166 (1.1 g, 4.1 mmol) was dissolved in 10 ml of methanol and 10 ml of 2N hydrochloric acid was added to the solution. The reaction was stirred at 25 ℃ overnight. The reaction was diluted with 25 ml of ethyl acetate and washed with saturated aqueous sodium bicarbonate. The organic extract was dried over magnesium sulfate, filtered and concentrated under reduced pressure to give 660 mg (85%) of the filtrate 1The H NMR was judged as a highly purified product, which was used without further purification.
Step 4: ethyl 6-ethyl-8-methoxy-2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
To the product of step 3 of example 166 (410 mg, 2.27 mmol) dissolved in 4.1 ml of anhydrous DMF was added anhydrous potassium carbonate (658.8 mg, 4.76 mmol) and 80 mg of powdered 4 angstrom molecular sieve, followed by ethyl 4, 4, 4-trifluorocrotonate (450.5 mg, 0.40 ml, 2.68 mol). The reaction was heated to 80-85 ℃ for 2 hours. Another portion of ethyl 4, 4, 4-trifluorocrotonate (0.17 ml) was added and the resulting solution was heated overnight. The next day, the reaction was diluted with ethyl acetate (200 ml) and water (200 ml). More ethyl acetate was added until the layers were resolved. The organic layer was washed with saturated sodium bicarbonate (50 ml), water (100 ml) and brine (50 ml), dried over magnesium sulfate, filtered and evaporated under reduced pressure to give a dark brown oil which was purified by flash chromatography (eluting with 25% ethyl acetate/hexane) to give 450 mg (38%) of the desired product which crystallized on standing.
Step 5: 6-Ethyl radicalProcess for preparing (E) -8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
The product from example 166, step 4 (167.1 mg, 0.50 mmol) was converted to the acid according to the procedure of example 150, step 4 to give 137 mg (90%) of 6-ethyl-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid as a yellow solid.
1H NMR(MeOH-d4)7.75(s，1H)，6.94(d，1H，J＝1.8Hz)，6.79(d，1H，J＝1.9Hz)，5.77(q，1H，J＝7.1Hz)，3.87(s，3H)，2.61(q，2H，J＝7.6Hz)，1.25(t，3H，J＝7.6Hz).
Examples 167a and 167b
6-chloro-7- [ (2-oxopyridin-1 (2H) -yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid with 6-chloro-5- [ (2-oxopyridin-1 (2H) -yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-7- [ (2-oxopyridin-1 (2H) -yl) methyl]-2- (trifluoromethyl) -2H-chromene-3-carboxylate with ethyl 6-chloro-5- [ (2-oxopyridine-1 (2H) -radical) methyl group]Preparation of (E) -2- (trifluoromethyl) -2H-chromene-2-carboxylate
Using 2-hydroxypyridine (140.3 mg, 1.4 mmol) and bromide from step 3 of example 157 (592.3 mg, 1.4 mmol), a reaction was carried out in the same manner as described in step 4 of example 157. The crude product was purified by flash chromatography (eluting with toluene-ethyl acetate from 10/90 to 50/50) to yield 209 mg (35%) of a yellow oil.
Step 2: 6-chloro-7- [ (2-oxopyridin-1 (2H) -yl) methyl ]-2- (trifluoro benzene) Methyl) -2H-chromene-3-carboxylic acid and 6-chloro-5- [ (2-oxopyridin-1 (2H) -yl) methyl]-2- (trifluoromethyl) -2H-chromen-3Preparation of carboxylic acids
The ester from step 1 of example 167 was converted to the acid following the procedure of step 4 of example 150. The crude product was purified by reverse phase HPLC (column: Delta Pak 300 × 50 mm i.d., C18, 15 μ M) using a water-acetonitrile gradient 90/10 to 50/50 over 30 minutes to obtain two products 167-1 and 167-2.
1H NMR 167-1：(DMSO-d6)7.90(s，1H)，7.75(d，d，1H，J＝6.8Hz，1.9Hz)7.72(s，1H)，7.52(d，d，d，1H，J＝9.1Hz，7.4Hz，2.2Hz)，6.47(d，1H，J＝9.2Hz)，6.38(s，1H)，6.32(t，d，1H，J＝6.6Hz，1.3Hz)，5.94(q，1H，J＝7.2Hz)，5.16(d，1H，J＝15.9Hz)，5.10(d，1H，J＝16.0Hz).
167-2(DMSO-d6)8.16(s，1H)，7.54(d，1H，J＝8.8Hz)，7.39(d，d，d，1H，J＝9.0Hz，6.7Hz，2.0Hz)，7.33(d，d，1H，J＝6.8Hz，1.7Hz)，7.15(d，1H，J＝8.8Hz)，6.39(d，1H，J＝8.8Hz)，619(t，d，1H，J＝6.6Hz，1.3Hz)5.95(q，1H，J＝7.2Hz)5.39(d，1H，J＝15.0Hz)5.24(d，1H，J＝15.0Hz).
Examples 168a and 168b
6-chloro-7- (1H-pyrazol-1-ylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid and 6-chloro-5- (1H-pyrazol-1-ylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-7- (1H-pyrazol-1-ylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate with ethyl 6-chloro-5- (1H-pyrazol-1-ylmethyl) -2- (trifluoro-methyl) Preparation of methyl) -2H-chromene-3-carboxylic acid esters
Using pyrazole (76.0 mg, 1.11 mmol) and bromide from step 3 of example 157 (592.3 mg, 1.4 mmol), a reaction was carried out in the same manner as described in step 4 of example 157. The crude oil product was purified by flash chromatography (eluting with 90/10 toluene-ethyl acetate) to yield 144 mg (33%) of the desired material.
Step 2: 6-chloro-7 (1H-pyrazol-1-ylmethyl) -2- (trifluoromethyl) 2H-color Alkene-3-carboxylic acid with 6-chloro-5- (1H-pyrazol-1-ylmethyl) -2- (trifluoromethyl) -2H-chrolol Preparation of alkene-3-carboxylic acids
The ester from step 1 of example 168 (106 mg) was converted to the acid according to the procedure of step 5 of example 166 to give two products 168-1 and 168-2.
1H NMR(MeOH-d4)7.79(2H)，7.62(d，1H，J＝1.7Hz)，7.49(s，1H)，6.42(t，1H，J＝2.1Hz)，6.36(s，1H)，5.77(q，1H，J＝7.0Hz)，5.52(d，1H，J＝16.8Hz)，5.46(d，1H，J＝16.8Hz).
1H NMR(MeOH-d4)8.22(s，1H)，7.56(d，1H，J＝2.0Hz)，7.51-7.48(3H)，7.07(d，d，1H，J＝8.2Hz，0.6Hz)，6.30(t，1H，J＝2.1Hz)，5.80(q，1H，J＝7.1Hz)，5.66(d，1H，J＝15.3Hz)，5.63(d，1H，J＝15.2Hz).
Example 169
6-chloro-7- [ (5-chloro-2-oxopyridin-1 (2H) -yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-7- [ (5-chloro-2-oxopyridin-1 (2H) -yl) methyl]-2- Preparation of (trifluoromethyl) -2H-chromene-3-carboxylic acid esters
Ester formation was carried out according to the procedure described in example 157, step 4, starting from 97 mg of 5-chloro-2-pyridinol, 20.7 mg of sodium hydride (60% dispersion in mineral oil) and 300 mg of bromide from example 157, step 3. The compound was purified by a FlashMaster eluting with 25% EA/hexane and 50% EA/hexane in this order_The chromatography system was purified to give 128 mg (38%) of the desired compound.
Step 2: 6-chloro-7- [ (5-chloro-2-oxopyridin-1 (2H) -yl) methyl]-2- Preparation of (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from step 1 of example 169 was converted to the acid according to the procedure for example 150 to give 75 mg (60%) of the desired acid 169. 1H NMR(DMSO-d6)8.05(d，1H，J＝2.8Hz)，7.87(s，1H)，7.72(s，1H)，7.59(d，d，1H，J＝9.7Hz，2.9Hz)，6.53(d，1H，J＝9.8Hz)，6.47(s，1H)，5.95(q，1H，J＝7.2Hz)，5.12(d，1H，J＝16.0Hz)，5.07(d，1H，J＝16.2Hz).
Example 170
6-chloro-7- (thiophen-2-ylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-7-formyl-2- (trifluoromethyl) -2H-chromen-3-carboxylic acid Preparation of acid esters
Crude bromide (1.6 g, 4.0 mmol) from example 157c was dissolved in 9 ml of anhydrous DMSO and to this solution was added solid sodium bicarbonate (383.4 mg, 4.5 mmol). The solution was heated to 100 ℃ for 1.5 hours. The reaction was removed from the heat source and left overnight at 25 ℃. The next day, the reaction was poured into 300mL of brine and washed with ethyl acetate (3 × 200 mL). The organic extracts were washed with brine, dried over magnesium sulfate, and filtered to give a tan solid which was purified by flash chromatography (eluting with 97/3 toluene-ethyl acetate). All fractions containing the desired product were collected to yield a yellow solid. The solid was washed with hexane to give 382 mg of the desired product.
Step 2: ethyl 6-chloro-7- [ hydroxy (thiophen-2-yl) methyl]-2- (trifluoromethyl) Preparation of 2H-chromene-3-carboxylic acid esters
The title product from example 170, step 1 (100 mg, 0.31 mmol) was dissolved in 1.0 ml of diethyl ether and cooled to-30 ℃. To this solution was added 0.31 ml of thien-2-ylmagnesium bromide (1.0M solution in THF). After 10 minutes, the reaction mixture was pipetted onto ice and diluted with ether and dilute sulfuric acid solution. The organic extracts were washed with saturated sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated to dryness under reduced pressure to yield 112 mg of a yellow oil. The oil was used without further purification.
Step 3: ethyl 6-chloro-7- (thien-2-ylmethyl) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
The crude oil from step 2 of example 170 was dissolved in 1 ml of DCM. To this solution was added triethylsilane (41 μ l, 0.26 mmol) and 20 μ l TFA, and stirred at 25 ℃. After 24 hours, the solution was vigorously stirred with solid sodium bicarbonate and water to quench the reaction. After 5 minutes the stirring was stopped and the solution was allowed to separate into layers. The solution was allowed to stand in this state for 1 day before treatment. The organic layer was dried over magnesium sulfate, filtered and evaporated under reduced pressure to give an orange oil. The crude product was purified by flash chromatography to obtain the compound with reasonable purity.
Step 4: 6-chloro-7- (thien-2-ylmethyl) -2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid
The acid from step 3 of example 170 was converted to the acid according to the procedure of step 4 of example 150. The product (20 mg) contained a significant amount of impurities up to 14%, determined as 7-methyl-6-chlorothromene, which could be removed by reverse phase HPLC (column: Delta Pak 300 × 50 mm i.d., C18, 15 μ M) using a water-acetonitrile gradient (conditions: from 90/10 to 50/50 over 30 min) to give a pure product.
1H NMR(MeOH-d4)7.54(s，1H)，7.14(s，1H)，7.07(d，1H，J＝4.3Hz)，6.76-6.73(3H)，5.55(q，1H，J＝6.9Hz)，4.15(d，1H，J＝16.7Hz)，4.05(d，1H，J＝16.1Hz).
Example 171
8-tert-butyl-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
8-tert-butyl-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was synthesized by the same procedure as described in example 155, using 2-tert-butyl-4-ethylphenol as starting material.
1H NMR(DMSO-d6)1.16(t，3H，J＝7.6Hz)，1.34(s，9H)，2.54(q，2H，J＝7.6Hz)，5.96(q，1H，J＝7，4Hz)，7.17(d，1H，J＝2.2Hz)，7.18(d，1H，J＝2.0Hz)，7.78(s，1H).
Example 172
6, 8-diethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6, 8-diethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was synthesized by the procedure described for example 150, using 5-ethyl-2-hydroxyacetophenone as starting material.
1H NMR(DMSO-d6)1.20(t，3H，J＝7.5Hz)，1.22(t，3H，J＝7.6Hz)，2.54-2.66(m，4H)，5.70(q，1H，J＝7.0Hz)，6.92(d，1H，J＝2.1Hz)，7.06(d，1H，J＝2.1)，7.84(s，1H).
Example 173
7, 7-dimethyl-2- (trifluoromethyl) -7, 8, 9, 10-tetrahydro-2H-benzo [ H ] chromene-3-carboxylic acid
The title compound of example 173 was synthesized by the procedure described for example 100 using 5, 5-dimethyl-5, 6, 7, 8-tetrahydronaphthalen-1-ol as starting material.
1H NMR
(MeOH-d4)7.75(s，1H)，7.10(q，2H，J＝8.1Hz)，5.77(q，1H，J＝7.2Hz)，2.66(m，2H)，1.82(m，2H)，1.68(m，2H)，1.31(s，3H)，1.30(s，3H).
Example 174
6-chloro-7, 7-dimethyl-2- (trifluoromethyl) -7, 8, 9, 10-tetrahydro-2H-benzo [ H ] chromene-3-carboxylic acid
The title compound of example 174 was prepared in the same manner as described in step 3 and 4 of example 103 except that the starting material was 173 ethyl 7, 7-dimethyl-2- (trifluoromethyl) -7, 8, 9, 10-tetrahydro-2H-benzo [ H ] chromene-3-carboxylate, an intermediate in the preparation of the title compound.
1H NMR(MeOH-d4)7.63(s，1H)，7.13(s，1H)，5.72(q，1H，J＝7.1Hz)，2.61(m，2H)，1.67(m，2H)，1.62(m，2H)，1.44(s，3H)，1.43(s，3H).
Example 175
6-chloro-7- [ (2-phenyl-1H-imidazol-1-yl) methyl ] -2- (trifluoromethyl) -2H-chromen-3-carboxylate
6-chloro-7- [ (2-phenyl-1H-imidazol-1-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid hydrochloride was synthesized by the procedure described for example 157 using 2-phenylimidazole.
1H NMR(DMSO-d6)5.47-5.56(m，2H)，5.98(q，1H，J＝7.2Hz)，6.84(s，1H)，7.60-7.71(m，6H)，7.83-7.87(m，3H).
Table 1
Example numbering Formula (II) Theoretical value Measured value
Example 100 C13H10ClF3O3·0.15H2O C，50.47，H，3.29 C，50.25，H，3.12
Example 101 C13H10ClF3O3 C，50.92，H，3.29 C，50.85，H，3.40
Example 102 C13H10ClF3O3 C，50.92，H，3.29 C，50.92，H，3.29
Example 103 C13H10ClF3O3 C，50.92，H，3.29Cl，11.56 C，50.81，H，3.10Cl，11.86
Example 104 C14H12ClF3O3 C，52.43，H，3.77 C，52.59，H，3.80
Example 105 C13H10ClF3O3 C，50.92，H，3.29 C，50.85，H，3.20
Example 106 C16H17F3O3 C，61.14，H，5.45 C，61.11，H，5.45
Example 107 C16H16ClF3O3 C，55.10，H，4.62 C，55.05，H，4.64
Example 108 C17H19F3O3 C，62.19，H，5.83 C，62.11，H，5.68
Example 110 C18H20ClF3O3 C，57.38，H，5.35. C，57.44，H，5.12.
Example 111 C17H18ClF3O3·0.25H2O C，55.59，H，4.94 C，55.20，H，4.86
Example 112 C16H17ClF3O4 C，58.16，H，5.19 C，58.06，H，4.93
Example 114 C15H13F3O4·0.25H2O C，56.52，H，4.11 C，56.40，H，4.68
Example 115 C15H12ClF3O5·2H2O C，44.96，H，3.94 C，44.96H，3.02
Example numbering Formula (II) Theoretical value Measured value
Example 116 C16H16ClF3O4 C，52.69，H，4.42 C，52.31，H，4.68
Example 121 C18H22F3NO4·HCl C，54.90，H，5.89，N，3.56 C，54.61，H，6.49，N，3.20
Example 125 C18H20ClF3O3 C，57.38，H，5.35 C，56.98，H，5.62
Example 126 C18H20ClF3O3·0.25H2O C，56.70，H，5.29 C，56.63，H，5.49
Example 128 C15H14ClF3O4·0.125H2O C，51.04，H，4.00 C，50.64，H，4.40
Example 129 C15H14ClF3O4·0.75H2O C，49.46，H，3.87 C，49.46，H，4.32
Example 132 C13H11F3O5 C 51.33％，H 3.64％ C 51.11％，H 3.63％
Example 133 C13H9Cl2F3O5 C 41.85％，H 2.43％，Cl 19.00％ C 41.92％，H 2.34％，Cl 18.96％
Example 136 C12H8ClF3O3 C 49.25％，H 2.76％，Cl 12.11％ C 48.91％，H 2.61％，Cl 11.94％
Example 138 C12H8ClF3O3·0.3H2O C 48.36％，H 2.91％ C 48.38％，H 2.99％
Example 139 C12H8ClF3O3 C 49.25％，H 2.76％，Cl 12.11％ C 49.03％，H 2.99％，Cl 12.44％
Example 140 C15H14F3NO3 C 57.51％，H 4.50％，N 4.47％ C 57.47％，H 4.70％，N 4.39％
Examples C14H11lF3O3·0.25 C，58.24 C，58.55
Example numbering Formula (II) Theoretical value Measured value
146 H2O H，4.01 H，4.08
Example 147 C14H10ClF3O3·0.25H2O C，52.03H，3.27 C，51.32H，3.47
Example 148 C13H9Cl2F3O3 C，45.77；H，2.66；Cl，20.79. C，45.95；H，2.53；Cl，20.27.
Example 149 C13H11F3O3 C，57.36％，H，4.07％ C，57.23％，H，3.95％
Example 150 C14H13O3F3 C，58.74；H，4.58 C，58.75；H，4.45.
Example 153 C14H13O3F3 C，58.74；H，4.58. C，58.50；H，4.62.
Example 154 C16H17O3F3 C，61.14；H，5.45. C，61.09；H，5.61.
Example 155 C14H13O3F3 C，58.74；H，4.58. C，58.65；H，4.88.
Example 156 C15H15O3F3·1.1H2O C，56.28；H，5.42. C，56.13；H，5.07.
Example 157 C18H16N2O3ClF3·HCl. C，48.45；H，4.07；N，6.28. C，48.18；H，4.19；N，6.19.
Example 158 C15H10N2O3ClF3·1.0HCl. C，45.59；H，2.81；N，7.81. C，45.39；H，2.95；N，6.98.
Example 159 C16H12N2O3ClF3·1.5HCl·0.5CF3COOH C，42.15；H，2.91；N，5.78. C，42.36；H，2.95；N，5.34.
Examples C18H16N2O3ClF3· C，46.57； C，46.87；
Example numbering Formula (II) Theoretical value Measured value
160 HCl·1.5H2O H，4.34；N，6.03. H，4.49；N，6.19.
Example 161 C19H12N2O3ClF3·1.5HCl C，49.24；H，2.94；N，6.04. C，49.34；H，3.32；N，5.87.
Example 162-1 C17H14N2O3ClF3·1.5HCl·0.25H2O C，45.79；H，3.62；N，6.28. C，45.90；H，4.05；N，6.32
Example 162-2 C17H14N2O3ClF31.75HCl C，45.32；H，3.52；N，6.22. C，45.11；H，3.81；N，6.19.
Example 163-1 C15H8N2O3ClF3·0.25HCl C，41.26；H，1.90；N，6.41. C，41.40；H，2.03；N，6.32.
Example 163-2 C15H8N2O3ClF3·H2O C，40.43；H，2.26；N，6.29. C，40.99；H，2.76；N，5.96.
Example 164 C18H12O4ClF3 C，56.19；H，3.14. C，55.96；H，3.23.
Example 165 C14H12O4ClF3·0.2H2O C，49.41；H，3.67. C，49.11；H，3.74.
Example 166 C14H13O4F3 C，55.63；H，4.34. C，55.60；H，4.79.
Example 167-1 C17H11NO4ClF3·0.5H2O C，51.94；H，3.03；N，3.48. C，51.73；H，3.06；N，3.55.
Example 167-2 C17H11NO4ClF3·0.5H2O·0.5TFA C，47.86；H，2.79；N，3.10. C，47.69；H，2.75；N，3.08.
Example numbering Formula (II) Theoretical value Measured value
Example 168-1 C15H10N2O3ClF3·0.5HCl·0.6TFA C，40.38；H，2.53；N，5.81. C，40.05；H，2.30；N，6.00.
Example 168-2 C15H10N2O3ClF3·1.5HCl C，43.58；H，2.80；N，6.78. C，43.34；H，2.78；N，7.58.
Example 169 C17H10NO4Cl2F3·0.2H2O C，48.31；H，2.61；N，3.24 C，48.39；H，2.56；N，3.12
Example 170 C16H10O3ClF3S·0.9H2O C，49.15；H，3.04. C，49.13；H，2.79.
Example 171 C17H19O3F3 C，62.19；H，5.83. C，62.08；H，6.06.
Example 172 C15H15O3F3 C，60.00；H，5.04. C，59.82；H，5.20.
Example 173 C17H17O3F3 C，62.57；H，5.25. C，62.56；H，5.50.
Example 174 C17H16ClO3F3 C，56.60；H，4.47，Cl，9.83. C，56.50；H，4.39，Cl，10.07
Example 175 C21H14N2O3ClF3·HCl C，52.52；H，3.36；N，5.83.. C，52.24；H，3.72，N，5.63
General description of parallel formula
Analytical LCMS reverse phase chromatography was performed using a C18 column (2.1 mm x 30 mm id.) with a linear gradient of 1 mm/min flow rate from 5% acetonitrile in 0.1% TFA/water to 95% acetonitrile in 0.1% TFA/water over 4.5 min. The eluent composition was maintained in 0.1% TFA/water containing 95% acetonitrile for 4.5 to 5 minutes. The LCMS is equipped with a diode array detector, a Mass Spectrometry Detector (MSD) and an evaporative light scattering detector. A flow splitter is connected after the UV diode array detector to allow flow to the Mass Spectrometer Detector (MSD) and ELS. Mass spectra were obtained using an Agilent (Agilent) MSD in electrospray positive mode. Preparative scale reverse phase chromatography was performed using a 41.4 mm internal diameter C18 column and a length of 50 mm 100 mm or 300 mm.
The compounds prepared by the parallel synthesis are recorded in an appropriate table and characterized by determining purity, confirming molecular weight, determining retention time (LC, min) of analytical HPLC and gravimetrically determining yield. HPLC retention time was determined using analytical LCMS reverse phase analysis and represents the time obtained in the case of compounds with the desired molecular ion. The residence time is based on the time observed in the uv chromatograph. The molecular ions listed in the table are baseline (100%) spikes unless otherwise noted. The purity of the compounds prepared by the parallel synthesis was determined by detection of a peak of the desired molecular ion and by integration of the corresponding peak detected at 250nm uv or by ELS. Purity is expressed as a percentage, which is the ratio of the peak of interest to the total area of all peaks in the chromatogram. The percentage yield is based on the gravimetric determination of the final product after suitable purification.
Parallel synthesis of libraries of compounds with 6-and 8-position substitution
X is hydrogen or chlorine
R is as described
(intermediate preparation and preparation of example 201-261)
Preparation of ethyl 6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Step 1: preparation of 2-hydroxy 5-iodobenzaldehyde
To a mixture of 20 g (91 mmol) of 4-iodophenol and 25.1 g (264 mmol) of anhydrous magnesium dichloride in 455 ml of anhydrous acetonitrile, triethylamine and paraformaldehyde are added. The mixture was heated to reflux for 4 hours, allowed to cool to room temperature, and treated with 500 ml of 50% hydrochloric acid. The solution was extracted three times with ethyl acetate. The combined organic extracts were washed three times with brine and dried over anhydrous magnesium sulfate. The dried organic solution was evaporated to give an oil which was purified by chromatography on silica eluting with ethyl acetate/hexane (2: 8). The desired fractions were concentrated to yield 15 g (66%) of a yellow solid which was used directly in the next step without further purification.
Step 2: preparation of ethyl 6-iodo-2 (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of 6.0 g (24 mmol) of 2-hydroxy 5-iodobenzaldehyde and 5 ml (33.3 mmol) of ethyl 4, 4, 4-trifluorocrotonate in 20 ml of anhydrous DMF at 60 ℃ is added potassium carbonate in one portion. The mixture was stirred at 60 ℃ overnight. After cooling to room temperature, the solid was filtered off and washed with ethyl acetate. The mixed solution was diluted by adding 300 ml of ethyl acetate and washed with brine. The organic layer was dried over anhydrous magnesium sulfate and evaporated to give an oil which was further purified by chromatography on silica eluting with ethyl acetate/hexane (1: 9). The desired fractions were concentrated to give 4.7 g (49%) of a light yellow solid:
1H NMR(CDCl3/300MHz)7.65-7.55(m，3H)，6.78(d，J＝8.4Hz，1H)，5.72(q，J＝6.6Hz，1H)，4.34(m，2H)，1.37(t，J＝6.9Hz，3H).MS(ES+)398.9(M+H，100).
Preparation of ethyl 8-chloro-6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Step 1: preparation of 3-chloro-2-hydroxy-5-iodobenzaldehyde
To 24 g (96.8 mmol) of 5-iodosalicylaldehyde in 320 ml of acetic acid, an excess of chlorine gas is added. After the addition of about 10 grams of chlorine, a white solid appeared in the solution. The mixture was heated to 70 ℃ and stirred for 3 hours. The heated solution is a homogeneous solution, which remains so after cooling to room temperature. The mixture was added to 1200 ml of water and stirred for 1 hour. The resulting solid was collected by filtration, washed with water, filtered and allowed to air dry to give 27.3 g of a yellow solid. Recrystallization of the solid was carried out by dissolving the material in 250 ml of hot methanol and adding 80 ml of water. After standing overnight, the crystalline solid was collected and air dried to give 23.0 g (74.2%) of a yellow solid. The product contains small amounts of impurities (by passing through)1H NMR measurement about 9%) and was used directly in the next step without further purification.
1H NMR(CDCl3/400MHz)7.78(d，1H，J＝2.1Hz)，7.88(d，1H，J＝1.8Hz)，9.83(s，1H)，11.40(s，1H)；13C NMR(CDCl3/100MHz)79.5，122.8，123.7，140.3，144.4，156.9，194.8；MS(ESI+)283(M+1，100)；HRMS(EI)m/z calcd for(C7H4O2ICl)281.8945，found 281.8899.
Step 2: ethyl 8-chloro-6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
To 18 g (63.7 mmol) of 3-chloro-2-hydroxy-5-iodobenzaldehyde in 16 ml of DMF were added 14.3 ml (16.1 g, 95.6 mmol) of ethyltrifluorocrotonate and 9.69 g (70 mmol) of potassium carbonate. The mixture was heated to 100 ℃ for 2 hours. The mixture was allowed to cool, treated with 300 ml of water and extracted three times with diethyl ether. The combined extracts were washed with water and filtered through a plug of silica (4.5X 6 cm). The silica plug was washed with dichloromethane and the combined filtrates were concentrated to yield 10.39 g of a yellow solid. Recrystallization from hexane afforded 6.64 g (24.1%) of this crystalline yellow solid:
1H NMR(CDCl3/400MHz)1.35(t，3H，J＝7.1Hz)，4.33(m，2H)，5.81(q，1H，J＝6.6Hz)，7.44(d，1H，J＝2.0Hz)，7.62(s，1H)，7.66(d，1H，J＝2.0Hz)；19F NMR(CDCl3/400MHz)-79.0(d，3F，J＝6.8Hz)；13C NMR(CDCl3100MHz)13.1, 60.8, 70.4(q, J ═ 33.7Hz), 82.6(C-I), 117.7, 121.2, 121.8, 121.9(q, J ═ 287.2Hz), 133.6, 134.9, 139.9, 147.9, 162.0; MS (ESI +)433(M +1, 100); HRMS (EI) m/z calculation (C)13H9O3IClF3)431.9237, found 431.9221.
Preparation of ethyl 6-bromo-8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate.Preparation of Ethyl 6-bromo-8-chloro-2- (trifluoro-methyl) -6-bromo-8-chloro-2- (trifluoromethyl) benzaldehyde from 5-bromo-3-chloro-2-hydroxybenzaldehyde in a manner analogous to the preparation of Ethyl 8-chloro-6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate step 2Methyl) -2H-chromene-3-carboxylate.
Example 201
8-chloro-6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To 180 mg (0.42 mmol) of ethyl 8-chloro-6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate, 100 mg of lithium hydroxide-water and 5 ml of a solvent mixture of THF/methanol/water (7: 2: 1) were added. The mixture was heated to reflux for 30 minutes and allowed to cool to room temperature. After standing overnight, the mixture was concentrated in vacuo, treated with 20 ml of 1N hydrochloric acid and stirred. The mixture was extracted three times with diethyl ether, and the combined extracts were dried and concentrated in vacuo to yield 150 mg (88.3%) of an off-white solid: 1H NMR(CDCl3/d6-acetone/400MHz)5.86(q，1H，J＝6.7Hz)，7.60(s，1H)，7.70(s，1H)，7.75(s，1H)；19F NMR(CDCl3/d6-acetone/400MHz) -79.2(d, 3F, J ═ 6.8 Hz); MS (ESI +)405(M +1, 100, one Cl pattern); HRMS (ES-) m/z calculation (C)11H4O3IClF3)402.8840, found 402.8850.
Preparation of 6-aryl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
X1＝I，Br
X2＝H，Cl
Example 202
6- [3, 5-bis (trifluoromethyl) phenyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6- [3, 5-bis (trifluoromethyl) phenyl]-2- (trifluoromethyl) Preparation of (E) -2H-chromene-3-carboxylic acid esters
To a solution of 0.3 g (0.75 mmol) of ethyl 6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 10 ml of dimethylacetamide under nitrogen atmosphere were added 87 mg (0.0075 mmol) of tetrakis (triphenylphosphine), 0.29 g (1.13 mmol) of 3, 5-bis (trifluoromethyl) phenylboronic acid and 1.0 ml of 2.0M aqueous sodium carbonate. The mixture was purged with nitrogen for 2 minutes, and then heated to 95 ℃ overnight. After cooling to room temperature, 50 ml of a 4: 1 mixture of ethyl acetate/methanol was added. To the resulting mixture was added 50 ml of brine. The product was extracted three times with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removal of the volatile substances, the residue was purified on a silica column eluted with ethyl acetate/hexane (1: 9) to give 0.20 g (56%) of a pale gray solid:
1H NMR(CDCl3400MHz)7.94(s, 2H), 7.83(s, 1H), 7.80(s, 1H), 7.55(dd, J ═ 2.4Hz, 8.4Hz, 1H), 7.46(s, J ═ 2.4Hz, 1H), 7.31(s, 1H), 7.10(d, J ═ 8.4Hz, 1H), 5.75(q, J ═ 6.4Hz, 1H), 4.32(M, 2H), 1.35(t, J ═ 7.2Hz), MS (ES +)485.0(M +1, 100), hrms (ei) (calculated value of M/z (C ei) (C, ei)21H13F9O3)484.0721，found 484.0687.
Step 2: 6- [3, 5-bis (trifluoromethyl) phenyl]-2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid
In the presence of 150 mg (0.31 mmol) of ethyl 6- [3, 5-bis (trifluoromethyl) phenyl]-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 5 ml tetrahydrofuranTo the solution in (1) was added 51 mg (1.24 mmol) of lithium hydroxide (LiOH 2H)2O) solution in 5 ml of water. The resulting mixture was heated to reflux for 1 hour. After cooling to room temperature, the volatile substances were removed. The residue was diluted with water and then acidified to pH 1.5 with dilute hydrochloric acid at 0 ℃. The product was then extracted with ethyl ether. The mixed extracts were dried over anhydrous magnesium sulfate. The dried organic solution was evaporated to yield 0.13 g (92%) of a light yellow solid:
1H NMR(CDCl3/400MHz)7.89(s，2H)，7.78(s，1H)，7.77(s，1H)，7.51(dd，J＝2.4Hz，8.4Hz，1H)，7.41(d，J＝2.4Hz，1H)，7.06(d，J＝8.4Hz，1H)，5.69(m，1H).MS(ES+)457.0(M+1，100).
6-aryl-2- (trifluoromethyl) -2H-chromene-2-carboxylic acids by parallel synthesis Preparation of acids
Example 203
6- (4-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6- (4-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid esters
All reactions were carried out in an aluminum reactor zone (Prep reactor, san Louis J-Kem, Mo., USA) equipped with a condenser, inert gas atmosphere and space for 24 vessels. A solution of 0.20 g (0.5 mmol) of ethyl 6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 3 ml of anhydrous dimethylacetamide was prepared in a 50 ml glass centrifuge tube equipped with a septal screw cap. The solution was degassed by passing nitrogen through the mixture for 10 minutes. The solution was treated with 0.11 ml (0.75 mmol) of 4-methoxyphenylboronic acid, 58 mg (0.1 eq, 0.05 mmol) of tetrakis (triphenylphosphine) -palladium (0) and 2.0 ml of degassed aqueous 2.0M sodium carbonate (4.0 eq, 2.0 mmol). The solution was flushed with nitrogen, capped, heated to 95 ℃ in an aluminum reactor block equipped with a condenser for 16 hours, and placed under a nitrogen atmosphere. After cooling to room temperature, brine was added and extracted four times with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and dried under a stream of nitrogen. The product was used in the next step without further purification.
Step 2: 6- (4-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acids
The product of step 1 was dissolved in a mixture of 5 ml ethanol and 1 ml THF. A solution of 165 mg of lithium hydride monohydrate in 6 ml of water was prepared and added to the ester solution. The vessel was capped and heated to 80 ℃ for 1 hour. After cooling to room temperature, the mixture was concentrated using a stream of nitrogen. The basic solution was acidified with 3N hydrochloric acid to pH 2 and extracted four times with ethyl ether. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The sample was purified by reverse phase chromatography analysis system to obtain 63.2 mg (36%) of a yellow solid:
1H NMR(CDCl3，CD3OD/400MHz)3.78(s，3H)，5.64(q，1H，J＝6.8Hz)，6.89(d，2H，J＝8.8Hz)，6.95(d，1H，J＝8.8Hz)，7.32(s，1H)，7.40-7.44(m，3H)，7.72(s，1H)；MS(ES+)351(M+1，100)；LC-MS purity 100％(UV and ELSD)；HRMS(ES-)m/z calcd for(M-1；C18H12O4F3)349.0682，found 349.0678.
6-aryl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acids by parallel synthesis Preparation of acids
The following examples in table 2 were prepared as described in the 6- (4-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid moiety above using a parallel synthesis setup with ethyl 6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate or ethyl 8-chloro-6-bromo-2- (trifluoromethyl) -2H-chromene-3-carboxylate as starting materials.
Table 2: by parallel synthesis1Yield, purity and mass spectral data of the prepared 6-aryl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid.
Table 2
Examples LC (residence time) MS(ES+) % purity % yield
X2＝H
204 3.004 327 99 33
205 2.849 311 99 39
206 1.838 336 95 48
207 3.213 341 97 43
208 3.039 365 99 44
209 2.971 365 99 37
203 3.024 351 99 36
210 3.273 335 99 36
211 1.537 322 95 19
212 3.554 363 97 35
Examples LC (residence time) MS(ES+) % purity % yield
213 2.657 352 97 39
214 3.431 371 95 46
215 3.241 366 95 46
216 1.470 322 99 29
217 2.776 360 95 57
218 2.114 372 99 43
219 2.786 381 95 43
220 2.745 383 95 23
221 3.379 389 95 38
222 3.368 389 95 32
X2＝Cl
223 3.278 355 99 65
224 3.502 390 99 41
225 3.353 390 100 42
226 3.272 373 100 67
227 3.129 361 99 66
228 3.059 345 97 73
229 2.119 370 95 53
230 3.138 400 95 52
231 3.132 399 88 62
232 3.208 385 100 75
233 3.448 369 99 74
234 3.734 397 100 74
235 2.928 386 100 35
236 3.593 405 100 53
237 3.437 401 95 77
238 1.840 356 95 10
239 2.996 394 95 53
240 2.502 406 100 7
241 3.007 415 100 37
Examples LC (residence time) MS(ES+) % purity % yield
242 2.740 417 95 44
243 3.651 423 100 75
244 3.323 423 100 77
245 2.983 345 98 75
246 3.256 385 95 77
1See general experimental section for description of recorded data. LC represents chromatographic retention time in minutes. The% purity was determined by UV at 254 nm.
Example 232
8-chloro-6- (4-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The sample obtained from the parallel synthesis was purified by reverse phase chromatography to yield 150.6 mg (75%) of a yellow solid:1H NMR(CDCl3，CD3OD/300MHz)3.87(s，3H)，5.85(q，1H，J＝6.3Hz)，7.0(d，1H，J＝8.1Hz)，7.36(s，1H)，7.48(d，2H，J＝8.7Hz)，7.58(s，1H)，7.82(s，1H)；MS(ES+)385(M+1，100)
preparation of 6-alkyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
X1Iodine and bromine
X2Hydrogen,Chlorine
Example 247
8-chloro-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 8-chloro-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
To a solution of 500 mg (1.16 mmol) of ethyl 8-chloro-6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 3 ml of anhydrous DMF were added 0.481 g (3.48 mmol, 3.0 equivalents) of potassium carbonate, 0.134 mg (0.116 mmol, 0.1 equivalents) of tetrakis (triphenylphosphine) -palladium (O) and 1.74 ml (1.75 mmol, 1.5 equivalents) of a 1M solution of triethylborane in THF. The vessel was heated to 110 ℃ for 5 hours under nitrogen. After cooling to room temperature, the mixture was treated with water and extracted with ethyl acetate. The organic layer was washed 4 times with water and 2 times with brine, dried over sodium sulfate, filtered and concentrated in vacuo. The product was taken to the next step without further purification.
Step 2: preparation of 8-chloro-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from step 1 was dissolved in 5 ml ethanol and 1 ml TFH. A solution of 165 mg of lithium hydroxide monohydrate in 6 ml of water was prepared and added to the ester solution. The vessel was capped and heated to 80 ℃ for 1 hour. After cooling to room temperature, the ethanol and tetrahydrofuran were removed using a stream of nitrogen. The basic solution was then acidified to pH 2 with 3N hydrochloric acid and extracted four times with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and the solvent removed. This sample was purified by reverse phase chromatography analysis system to obtain 153 mg (70%) of a light brown solid:1H NMR(CDCl3，CD3OD/400MHz)1.22(t，3H，J＝7.6Hz)，2.58(q，2H，J＝7.6Hz)，5.78(q，1H，J＝6.8Hz)，6.97(s，1H)，7.21(s，1H)，7.70(s，1H)；MS(ES+)307(M+1，50)；LC-MS purity 95％at 3.026min.(UV)，100％(ELSD)；HRMS(ES-)m/z calcd for(M-1；C13H9O3ClF3)305.0187，found 305.0210.
example 248
6-butyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using the procedure as described for the 8-chloro-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid moiety, a tan solid (10.2 mg, 12%) was prepared:1H NMR(CDCl3，CD3OD/400MHz)0.85(t，3H，J＝7.2Hz)，1.26(m，2H)，1.49(m，2H)，2.47(t，2H，J＝7.6Hz)，5.58(m，1H)，6.80(d，1H，J＝8Hz)，6.95(s，1H)，7.05(d，1H，J＝8Hz)，7.65(s，1H)；MS(ES+)301(M+1，100)；LC-MS purity 100％(ELSD)，95％(UV)at 3.263min.
example 249
6-butyl-8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using the procedure as described for the 8-chloro-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid moiety, a tan solid (232.9 mg, 50%) was prepared: 1H NMR(CDCl3，CD3OD/300MHz)0.93(t，3H，J＝7.2Hz)，1.37(m，2H)，1.59(m，2H)，2.53(t，2H，J＝7.8Hz)，5.29(q，1H，J＝6.9Hz)，6.95(d，1H，J＝2.1Hz)，7.19(d，1H，J＝1.8Hz)，7.71(s，1H)；MS(ES+)335(M+1，100)；LC-MS purity 95％ at 3.430min.(UV)，100％(ELSD)；HRMS(ES-)m/z calcd for(M-1；C15H13O3ClF3)333.0500，found 333.0491.
Preparation of 6-substituted 2- (trifluoromethyl) -2H-chromene-3-carboxylic acids
Example 250
8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromen-3-carboxylic acid Preparation of acid esters
To 0.86 g (2.0 mmol) of ethyl 8-chloro-6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate were added 46 mg (0.040 mmol) of tetrakis (triphenylphosphine) -palladium (0), 6 ml of degassed toluene and 0.64 ml (0.69 g, 2.2 mmol) of tributyl (ethynyl) tin. The stirred mixture was heated to reflux for 3 hours. After allowing the reaction to cool, the mixture was washed with 20% aqueous ammonium fluoride solution, and the aqueous layer was extracted three times with diethyl ether. The combined extracts were filtered through silica and the silica was washed with diethyl ether and the organic layer was concentrated in vacuo. Purification by chromatography (70 g silica, 5% ethyl acetate/hexane) afforded a solid which was triturated with hexane to give 0.50 g (75.6%) of a crystalline solid:1HNMR(d6-acetone/400MHz)1.32(t，3H，J＝7.1Hz)，3.73(s，1H)，4.32(m，2H)，6.04(q，1H，J＝6.9Hz)，7.60(m，2H)，7.90(s，1H)；19F NMR(d6-acetone/400MHz)-79.6(d，3F，J＝6.8Hz)；MS(ESI+)331(M+1，100，one Cl pattern).
step 2: preparation of 8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Prepare for
To 450 mg (0.36 mmol) of ethyl 8-chloro-6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate was added 9 ml of a solvent mixture of THF/methanol (7: 2), followed by 172 mg of lithium hydroxide-water in 1 ml of water. The mixture was stirred at room temperature for 30 minutes. The mixture was concentrated, treated with 10 ml of water and acidified with concentrated hydrochloric acid (ca. 0.4 ml). The product was drained from the solution and extracted three times with diethyl ether. The combined extracts were dried and concentrated to yield 0.32 g of a crude yellow solid. Chromatography (C18, Gilson (Gilson)10 × 4 cm, 50 mg each and 7 coinjection) afforded 0.18 g (43.7%) of a white solid:
1H NMR(d6-acetone/400MHz)3.74(s，1H)，6.03(q，1H，6.8Hz)，7.61(m，2H)，7.92(s，1H)；13C NMR(d6-acetone/400MHz)72.0(q，J＝33.2Hz)，80.0，81.6，118.3，119.6，121.7，121.8(q，J＝0.7Hz)，124.2(q，J＝286.6Hz)，132.5，136.1，136.7，149.9，164.6；19F NMR(d6-acetone/400MHz)-79.6(d，3F，J＝6.5Hz)；MS(ES+)303(M+1，27)，291(65)，289(51)，235(100)，233(79)；MS(ES-)301(M-1，100)，303(35)；HRMS(EI-)m/z calcd for(C13H5O3ClF3)300.9874，found 300.9837.
8-chloro-6-substituted-2- (trifluoromethyl) -2H-substituted compounds by parallel synthesis Preparation of chromene-3-carboxylic acid
The following examples in table 3 were prepared as described above for ethyl 8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate moiety using a parallel synthesis setup and each reaction performed on a 1.0 millimolar scale.
Table 3: yield, purity and mass spectral data for 8-chloro-6-substituted-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared by the parallel synthesis of synthesis 1.
No. 3 table
Examples LC (residence time) MS(ES+) % purity % yield
251 3.54 305 98.7 23
252 4.20 379 ＞99 13.4
253 2.91 304 77.4 -
254 3.09 321 ＞99 12.4
255 3.69/3.772 319 ＞99 3.1
256 3.65 317 ＞99 28.9
1: see general experimental section for description of recorded data. LC represents chromatographic retention time in minutes. The% purity was determined by UV at 254 nm.
2: a1: 1 mixture of E and Z isomers (as determined by HNMR and LCMS) was obtained with a 3.1% combined yield.
Preparation of 6-substituted-2- (trifluoromethyl) -2H-chromene-3-carboxylic acids
Example 257
6- [ (1E) -3-amino-3-oxoprop-1-enyl ] -8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6- [ (1E) -3-amino-3-oxoprop-1-enyl]-8-chloro-2- Preparation of (trifluoromethyl) -2H-chromene-3-carboxylic acid esters
To a mixture of 0.4 g (1.0 mmol) ethyl 6-bromo-8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate, 45 mg (0.2 mmol) palladium acetate, 122 mg (0.4 mmol) tri-o-tolylphosphine, 451 mg (5.5 mmol) sodium acetate under nitrogen atmosphere was added 6 ml of anhydrous dimethylformamide followed by 107 mg (1.5 mmol) acrylamide. The resulting mixture was shaken at 110 ℃ for 85 hours. LC-MS showed the reaction was complete. To the reaction was added 50 mg of ethyl acetate. The resulting organic solution was washed with brine and dried over anhydrous magnesium sulfate. After removal of the volatile substances, the purification residue was analyzed by reverse phase chromatography to obtain 0.23 g of an off-white solid which was used continuously in the next step.
Step 2: 6- [ (1E) -3-amino-3-oxoprop-1-enyl]-8-chloro-2- (trifluoro) Preparation of methyl) -2H-chromene-3-carboxylic acid
The product from step 1 was dissolved in 3 ml of THF and treated with 0.13 g (2.55 mmol) of lithium hydroxide hydrate in 3 ml of water. The mixture was treated with 3 ml of ethanol and heated to 80 ℃ for 2 hours. Removing the volatile substance; the residue was acidified to pH 1.0 with dilute hydrochloric acid at 0 ℃. The product was extracted with ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. The organic fraction was concentrated to yield 0.169 g (48.6%) of an off-white solid:
1H NMR(DMSO/300MHz)7.87(s，1H)，7.70(d，J＝2.1HZ，1H)，7.55(d，J＝2.1Hz，1H)，7.48(d，J＝15.9Hz，1H)，6.63(d，J＝15.9，1H)，5.96(q，J＝6.6Hz，1H).MS(ESI+)348.0(M+1，100).MS(ES-)346.0(M-1，100).HRMS(ES-)m/z calcd for(M-H；C14H8ClF3NO4)：346.0088，found 346.0078.
Example 258
8-chloro-6- [ (1E) -oct-1-enyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
8-chloro-6- [ (1E) -oct-1-enyl)]Process for preparing (E) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
By passing6- [ (1E) - -3-amino-3-oxoprop-1-enyl]Method for the preparation of (E) -8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid this example was prepared. 55 mg of a yellow solid are obtained in 14.1% yield and 100% purity.1H NMR(CDCl3/300MHz)7.70(s，1H)，7.26(d，J＝1.8Hz，1H)，6.98(s，J＝1.8Hz，1H)，6.16-5.98(m，2H)，5.65(q，J＝6.6Hz，1H，)，2.06(m，2H)，1.34-1.16(m，8H)，0.76(m，3H).MS(ESI+)389.1(M+1，100).MS(ES-)387.1(m-1，100).HRMS(ES-)m/z calcd for(M-H；C19H19ClF3O3)：387.0969，found387.0963.
Example 259
8-chloro-6- [ (E) -2- (4-methoxyphenyl) vinyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
8-chloro-6- [ (E) -2- (4-methoxyphenyl) vinyl]-2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid
This example was prepared by the method used for the preparation of 6- [ (1E) -3-amino-3-oxoprop-1-enyl ] -8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. 140 mg of a yellow solid were obtained in 34.1% yield and 100% purity.
1H NMR(CDCl3/300MHz)7.73(s，1H)，7.49(s，1H)，7.42-7.40(m，2H)，7.23(s，1H)，6.98-6.77(m，4H)，5.79(q，J＝6.6Hz，1H)，3.82(s，3H).MS(ESI+)411.0(M+1，100).MS(ES-)409.0(M-1)，HRMS(ES-)m/zcalcd for(M-H；C20H13ClF3O4)：409.0449，found 409.0428.
Example 260
8-chloro-6- [ (E) -2- (1H-imidazol-1-yl) vinyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
8-chloro-6- [ (E) -2- (1H-imidazol-1-yl) ethenyl]-2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid
This example was prepared by the method used for the preparation of 6- [ (1E) -3-amino-3-oxoprop-1-enyl ] -8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. 130 mg of a white solid were obtained in 35% yield and 94% purity.
1H NMR(CD3OD/300MHz)8.84(s，1H)，7.61(s，2H)，7.52-7.22(m，4H)，7.21(s，1H)，6.93(d，J＝14.7Hz 1H)，5.70(q，J＝6.6Hz，1H).MS(ESI+)371.0(M+1，100).
Example 261
8-chloro-6- (3-oxo-butyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Preparation of 8-chloro-6- (3-oxo-butyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Prepare for
This example was prepared by the method used for the preparation of 6- [ (1E) -3-amino-3-oxoprop-1-enyl ] -8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. 130 mg of an off-white solid were obtained in 37.3% yield and 95% purity.
1H NMR(CDCl3/300MHz)7.84(s，1H)，7.28(s，1H)，7.05(s，1H)，5.81(q，J＝6.6Hz，1H)，2.83(m，4H)，2.20(s，3H).MS(ESI+)291.0(M-58，100)，371.0(M+23，52)，349.0(M+1，40).MS(ES-)347.0(M-1，100).HRMS(ES-)m/z calcd for(M-H；C15H11ClF3O4)：347.0292，found 347.0296.
Parallel synthesis of libraries of compounds with 6-and 8-position substitution
R is as described
(intermediate preparation and preparation of example 262-356)
6-chloro-8-alkynyl-2- (trifluoromethyl) -2H-substituted benzene by Sonagashira coupling Preparation of chromene-3-carboxylic acid
Example 262
6-chloro-8- [ (4-methylphenyl) ethynyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-8- [ (4-methylphenyl) ethynyl group]-2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
To 0.150 g (0.347 mmol) of ethyl 6-chloro-8-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate were added 20 mg (0.017 mmol) of tetrakis (triphenylphosphine) palladium (0), 6.6 mg (0.035 mmol) of copper (I) iodide, 3 ml of degassed toluene, 0.15 ml (1.041 mmol) of degassed TEA and 0.066 ml (0.521 mmol) of 4-ethynyltoluene. The mixture was stirred at room temperature overnight. The mixture was concentrated and the resulting oil was filtered through silica. The silica was washed with hexane, ethyl acetate and dichloromethane, and the clear liquid fractions were mixed to obtain 0.114 g of a crystalline solid: MS (ES +)421(M +1, 100).
Step 2: 6-chloro-8- [ (4-methylphenyl) ethynyl group]-2- (trifluoromethyl) -2H-color Preparation of alkene-3-carboxylic acids
To 0.114 g (0.271 mmol) of ethyl 6-chloro-8- [ (4-methylphenyl) ethynyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate was added 1.5 ml of a solvent mixture of THS/ethanol/water (7: 2: 1), followed by 22 mg (0.524 mmol) of lithium hydroxide-water. The mixture was stirred at room temperature overnight. The mixture was concentrated, treated with 2 ml of water and acidified with 0.5N hydrochloric acid. The product precipitated out of solution and was washed three times. The resulting solid was dried to yield 0.103 g (76% yield in two steps) of a crude green solid:
1H NMR(d4-DMF/400MHz)2.36(s，3H)，6.11(q，1H，J＝7.2Hz)，7.30(d，2H，J＝8.4Hz)，7.48(d，2H，J＝8.0Hz)，7.66(d，1H，J＝2.4Hz)，7.74(d，1H，J＝2.4Hz)，7.98(s，1H)；MS(ES+)393(M+1，100)；HRMS(ES-)m/z calcd for(C20H12O3ClF3)391.0343，found 391.0294.
the calculated value was 391.0343 and the measured value was 391.0294.
The preparation of 6-chloro-8-alkynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by a parallel procedure as described in the 6-chloro-8- [ (4-methylphenyl) ethynyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid section, using a parallel synthesis setup and optionally purification by filtration, extraction or reverse phase chromatography to prepare the following examples in table 4.
Table 4: yield, purity and mass spectra data for 6-chloro-8-alkynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared by parallel synthesis method 1.
4 th table
Examples LC (minutes) MS(ES+) HRMS % purity % yield
262 4.160 393 391.0294 100 76
263 2.832 347 345.0132 100 50
264 3.323 387 385.0454 100 23
265 2.260 360 360.06452 97 43
266 2.242 346 346.04962 100 25
267 2.597 388 371.06667 100 38
268 3.110 394 412.05903 100 16
269 3.956 409 407.0303 100 66
270 2.725 333 330.9957 99 67
271 2.133 332 332.03242 736 72
272 3.419 395 393.0154 97 38
273 2.970 361 359.0311 98 70
274 3.266 347 345.0139 99 25
275 2.732 347 344.9741 ＞95 17
276 2.5414 345 343.0314 100 70
277 2.9604 393 391.0338 100 40
278 3.0944 447 445.0100 100 54
279 1.5854 394 394.04382 100 53
280 3.1954 385 383.0675 100 66
281 2.7844 407 405.0526 100 76
282 2.4764 409 407.0296 100 72
283 1.7644 373 371.0281 100 8
284 1.6714 380 380.02912 96 50
Examples LC (minutes) MS(ES+) HRMS % purity % yield
285 2.7214 397 395.0100 100 43
286 2.8404 413 410.9804 100 58
287 3.1384 475 474.9208 100 22
288 1.9364 411 411.0736 100 13
289 1.8624 370 387.06885 100 24
1: see general experimental section for description of recorded data. LC represents chromatographic retention time in minutes. HRMS refers to the molecular ion (M-H) observed in high resolution mass spectroscopy in electron spray negative mode. % purity is determined using the ELS assay.
2: electron spray positive mode, M +1 ions.
3: positive mode of electron spray, M + H2And (4) O ions.
4: the residence time was determined as a linear gradient from 0 min 40% acetonitrile in 0.1% TFA/water to 4.5 min 95% ethylene.
5: positive mode of electron spray, M + NH4Ions.
6: 100% purity was measured using UV rays at 254 nm.
7: positive mode of electron spray, M-NH3Ions.
Example 290
6-chloro-8-prop-1-ynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-8-prop-1-ynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
A mixture of 0.50 g (1.160 mmol) ethyl 6-chloro-8-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate, 67 mg (0.058 mmol) tetrakis (triphenylphosphine) palladium (0), 22 mg (0.116 mmol) copper (I) iodide, 10 ml degassed toluene and 0.484 ml (3.48 mmol) degassed TEA was cooled to-78 ℃ and treated with excess condensed gaseous propyne. The mixture was stirred at-78 ℃ for 30 minutes and allowed to warm to room temperature. The mixture was then stirred overnight. The reaction mixture was concentrated and the resulting oil was filtered through silica. The silica was washed with hexane and dichloromethane and the clear fractions were mixed to obtain 0.320 g (80%) of a crystalline solid: 1H NMR(CDCl3/400MHz)1.33(t，3H，J＝7.2Hz)，2.09(s，3H)，4.27-4.35(m，2H)，5.77(q，1H，J＝6.8Hz)，7.10(d，1H J＝2.4Hz)，7.31(d，1H，J＝2.4Hz)，7.59(s，1H)；MS(ES+)345(M+1，100).
Step 2: preparation of 6-chloro-8-prop-1-ynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Prepare for
To 0.320 g (1.01 mmol) of ethyl 6-chloro-8-prop-1-ynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was added 5 ml of a solvent mixture of THF/ethanol/water (7: 2: 1) followed by 64 mg (1.52 mmol) of lithium hydroxide-water. The mixture was stirred at 60 ℃ for 2 hours. The mixture was concentrated, treated with water and acidified with 0.5N hydrochloric acid. The product precipitated out of solution and was washed three times with water. The resulting solid was dried to yield 0.050 g (16%) of a brown solid:
1H NMR(CDCl3/400MHz)1.83(s，3H)，5.77(q，1H，J＝6.8Hz)，6.89(d，1H J＝2.4Hz)，7.03(d，1H，J＝2.4Hz)，7.35(s，1H)；MS(ES-)315(M-1，100).HRMS(ES-)m/z calcd for(C14H8O3ClF3)315.0030，found315.0048.
the calculated value was 315.0030 and the measured value was 315.0048.
Example 285
6-chloro-8- [ (4-fluorophenyl) ethynyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-8- [ (4-fluorophenyl) ethynyl group]-2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
To 0.350 g (0.809 mmol) of ethyl 6-chloro-8-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate were added 47 mg (0.040 mmol) of tetrakis (triphenylphosphine) palladium (0), 15 mg (0.081 mmol) of copper (I) iodide, 5 ml of degassed toluene, 0.338 ml (2.43 mmol) of degassed TEA and 0.139 ml (1.21 mmol) of 1-ethynyl-4-fluorobenzene. The mixture was stirred at room temperature overnight. The mixture was concentrated and the resulting oil was purified by reverse phase chromatography to obtain a crystalline solid: MS (ES +)425(M +1, 100)
Step 2: 6-chloro-8- [ (4-fluorophenyl) ethynyl group]-2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid
At 0.344 g (0.809 mmol) of ethyl 6-chloro-8- [ (4-fluorophenyl) ethynyl]To (E) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was added 5.0 ml of a solvent mixture of THF/ethanol/water (7: 2: 1), followed by 51 mg (1.21 mmol) of lithium hydroxide-water. The mixture was stirred at 60 ℃ for 2 hours. The mixture was concentrated, diluted with water and acidified with 0.5N hydrochloric acid. The crude material was purified by reverse phase chromatography to afford 0.138 g of a yellow crystalline solid (43% yield in 2 steps):1H NMR(d4-DMF/400MHz)6.11(q，1H，J＝7.2Hz)，7.31-7.36(m，2H)，7.64-7.69(m，3H)，7.75(d，1H，J＝2.4Hz)，7.98(s，1H)；MS(ES-)395(M-1，100)；HRMS(ES-)m/z calcd for(C19H9O3ClF4)395.0093，found395.0100.
the calculated value was 395.0093 and the measured value was 395.0100.
Example 291
8-but-1-ynyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 8-but-1-ynyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
A mixture of 1.00 g (2.31 mmol) ethylene 6-chloro-8-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate, 134 mg (0.116 mmol) tetrakis (triphenylphosphine) palladium (0), 44 mg (0.231 mmol) copper (I) iodide, 20 ml degassed toluene and 0.965 ml (6.94 mmol) degassed TEA was cooled to-78 ℃ and treated with excess condensed gaseous 1-butyne. The mixture was stirred at-78 ℃ for 30 minutes, allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated and the resulting oil was purified by reverse phase chromatography to yield 0.768 g (93%) of a crystalline solid:
1H NMR(CDCl3/400MHz)1.24(t，3H，J＝7.2Hz)，1.34(t，3H，J＝7.2Hz)，2.45(q，2H，J＝7.6Hz)，4.27-4.35(m，2H)，5.78(q，1H，J＝6.8Hz)，7.10(d，1H，J＝2.4Hz)，7.32(d，1H，J＝2.4Hz)，7.59(s，1H)；MS(ES+)359(M+1，100).
Step 2: preparation of 8-but-1-alkynyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Prepare for
To 0.768 g (2.14 mmol) of ethyl 8-but-1-ynyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate was added 11 ml of a solvent mixture of THF/ethanol/water (7: 2: 1) followed by 135 mg (3.22 mmol) of lithium hydroxide-water. The mixture was stirred at 60 ℃ for 2 hours. The mixture was concentrated, treated with water and acidified with 0.5N hydrochloric acid. The crude material was purified by reverse phase chromatography to yield 0.575 g (81%) of a yellow crystalline solid:1H NMR(CDCl3/400MHz)1.24(t，3H，J＝7.2Hz)，2.46(q，2H，J＝7.6Hz)，5.74(q，1H J＝6.8Hz)，7.16(d，1H，J＝2.8Hz)，7.39(d，1H，J＝2.4Hz)，7.81(s，1H)；MS(ES+)331(M+1，100)；HRMS(ES-)m/z calcd for(C15H10O3ClF3)329.0187，found329.0202.
the calculated value was 329.0187 and the measured value was 329.0202.
Example 292
6-chloro-8- [ (2-fluorophenyl) ethynyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-8- [ (2-fluorophenyl) ethynyl group]-2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
To 0.502 g (1.161 mmol) of ethyl 6-chloro-8-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate, 67 mg (0.060 mmol) of tetrakis (triphenylphosphine) palladium (0), 22 mg (0.116 mmol) of copper (I) iodide, 10 ml of degassed toluene, 0.484 ml (3.48 mmol) of degassed TEA and 0.199 ml (1.74 mmol) of 2-chlorophenylacetylene were added. The mixture was stirred at room temperature overnight. The mixture was concentrated and the resulting oil was purified by reverse phase chromatography to yield 0.440 g (89%) of a crystalline solid:
1H NMR(CDCl3/400MHz)1.35(t，3H，J＝6.8Hz)，4.26-4.38(m，2H)，5.83(q，1H，J＝6.8Hz)，7.08-7.15(m，2H)，7.18(d，1H J＝2.4Hz)，7.31-7.37(m，1H)，7.45(d，1H，J＝2.4Hz)，7.49-7.53(m，1H)，7.63(s，1H)；(ES+)425(M+1，100).
Step 2: 6-chloro-8- [ (2-fluorophenyl) ethynyl group]-2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid
To 0.387 g (0.911 mmol) of ethyl 6-chloro-8- [ (2-fluorophenyl) ethynyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate was added 5.0 ml of a THF/ethanol/water (7: 2: 1) solvent mixture, followed by 57 mg (1.37 mmol) of lithium hydroxide-water. The mixture was stirred at 60 ℃ for 2 hours. The mixture was concentrated, diluted with water and acidified with 0.5N hydrochloric acid. The crude material was purified by reverse phase chromatography to yield 0.289 g (80%) of a yellow crystalline solid:
1H NMR(CDCl3/400MHz)5.80(q，1H，J＝6.4Hz)，7.09-7.16(m，2H)，7.24(d，1H，J＝2.4Hz)，7.32-7.38(m，1H)，7.50-7.54(m，2H)，7.83(s，1H)；MS(ES+)397(M+1，100)；HRMS(ES-)m/z calcd for(C19H9O3ClF4)395.0093，found 395.0094.
the calculated value was 395.0093 and the measured value was 395.0094.
Example 293
6-chloro-8- [ (3-fluorophenyl) ethynyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The first step is as follows: ethyl 6-chloro-8- [ (3-fluorophenyl) ethynyl group]-2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
To 0.502 g (1.161 mmol) of ethyl 6-chloro-8-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate, 67 mg (0.060 mmol) of tetrakis (triphenylphosphine) palladium (0), 22 mg (0.116 mmol) of copper (I) iodide, 10 ml of degassed toluene, 0.484 ml (3.48 mmol) of degassed TEA and 0.199 ml (1.74 mmol) of 3-fluorophenylacetylene were added. The mixture was stirred at room temperature overnight. The mixture was concentrated and the resulting oil was purified by reverse phase chromatography to yield 0.440 g (89%) of a crystalline solid:
1H NMR(CDCl3/400MHz)1.35(t，3H，J＝6.8Hz)，4.28-4.37(m，2H)，5.83(q，1H，J＝6.8Hz)，7.04-7.09(m，1H)，7.18(d，1H，J＝2.4Hz)，7.20-7.23(m，1H)，7.30-7.33(m，2H)，7.44(d，1H，J＝2.8Hz)，7.63(s，1H)；MS(ES+)425(M+1，100).
Step 2: 6-chloro-8- [ (3-fluorophenyl) ethynyl group]-2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid
To 0.440 g (1.036 mmol) of ethyl 6-chloro-8- [ (3-fluorophenyl) ethynyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate was added 5.2 ml of a THF/ethanol/water (7: 2: 1) solvent mixture followed by 65 mg (1.55 mmol) of lithium hydroxide-water. The mixture was stirred at 60 ℃ for 2 hours. The mixture was concentrated, diluted with water and acidified with 0.5N hydrochloric acid. The crude material was purified by reverse phase chromatography to give 0.387 g (94%) of a yellow crystalline solid:
1H NMR(CDCl3/400MHz)5.79(q，1H，J＝6.4Hz)，7.04-7.09(m，1H)，7.21-7.23(m，2H)，7.31-7.33(m，2H)，7.50(d，1H，J＝2.4Hz)，7.84(s，1H)；MS(ES+)397(M+1，100)；HRMS (ES-)m/z calcd for(C19H9O3ClF4)395.0093，found 395.0092.
the calculated value was 395.0093 and the measured value was 395.0092.
Example 294
Ethyl 6-chloro-8- (phenylethynyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
To 2.000 g (4.624 mmol) of ethyl 6-chloro-8-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate was added 267 mg (0.231 mmol) of tetrakis (triphenylphosphine) palladium (0), 88 mg (0.462 mmol) of copper (I) iodide, 40 ml of degassed toluene, 1.930 ml (13.87 mmol) of degassed TEA and 0.762 ml (6.94 mmol) of phenylacetylene. The mixture was stirred at room temperature overnight. The mixture was concentrated and the resulting oil was purified by reverse phase chromatography to yield 1.648 g (88%) of a yellow crystalline solid:
1H NMR(CDCl3/400MHz)1.35(t，3H，J＝7.2Hz)，4.27-4.39(m，2H)，5.83(q，1H，J＝6.4Hz)，7.17(d，1H，J＝2.4Hz)，7.34-7.37(m，3H)，7.45(d，1H，J＝2.4Hz)，7.51-7.55(m，2H)，7.63(s，1H)；MS(ES+)407(M+1，100)；MS(EI)406(M+，39)，337(100)，309(45).
Example 295
Ethyl 6-chloro-8- [ (4-methylphenyl) ethynyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate
To 2.000 g (4.624 mmol) of ethyl 6-chloro-8-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate was added 267 mg (0.231 mmol) of tetrakis (triphenylphosphine) palladium (0), 88 mg (0.462 mmol) of copper (I) iodide, 40 ml of degassed toluene, 1.930 ml (13.87 mmol) of degassed TEA and 0.880 ml (6.94 mmol) of 4-ethynyltoluene. The mixture was stirred at room temperature overnight. The mixture was concentrated and the resulting oil was purified by reverse phase chromatography to yield 1.193 g (61%) of a yellow crystalline solid:
1H NMR(CDCl3/400MHz)1.35(t，3H，J＝7.2Hz)，2.36(s，3H)，4.28-4.37(m，2H)，5.82(q，1H，J＝6.8Hz)，7.14-7.17(m，3H)，7.41-7.43(m，3H)，7.62(s，1H)；MS(ES+)421(M+1，100)；MS(EI)420(M+，42)，351(100)，323(49).
example 296
Ethyl 6-chloro-8- [ (4-fluorophenyl) ethynyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate
To 2.000 g (4.624 mmol) of ethyl 6-chloro-8-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate was added 267 mg (0.231 mmol) of tetrakis (triphenylphosphine) palladium (0), 88 mg (0.462 mmol) of copper (I) iodide, 40 ml of degassed toluene, 1.930 ml (13.87) of degassed TEA and 0.833 g (6.94 mmol) of 1-ethynyl-4-fluorobenzene. The mixture was stirred at room temperature overnight. The mixture was concentrated and the resulting oil was purified by reverse phase chromatography to yield 1.804 g (92%) of a tan crystalline solid:
1H NMR(CDCl3/400MHz)1.35(t，3H，J＝7.2Hz)，4.27-4.39(m，2H)，5.82(q，1H，J＝6.8Hz)，7.02-7.08(m，2H)，7.17(d，1H，J＝2.4Hz)，7.43(d，1H，J＝2.4Hz)，7.49-7.53(m，2H)，7.63(s，1H)；MS(ES+)425(M+1，100)；MS(EI)424(M+，34)，355(100)，327(55).
Example 297
Ethyl 6-chloro-8- (3-methylbut-1-ynyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
To 2.000 g (4.624 mmol) of ethyl 6-chloro-8-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate was added 267 mg (0.231 mmol) of tetrakis (triphenylphosphine) palladium (0), 88 mg (0.462 mmol) of copper (I) iodide, 40 ml of degassed toluene, 1.930 ml (13.87 mmol) of degassed TEA and 0.473 g (6.94 mmol) of 3-methyl-1-butyne. The mixture was stirred at room temperature overnight. The mixture was concentrated and the resulting oil was purified by reverse phase chromatography to yield 1.573 g (91%) of a yellow crystalline solid:
1H NMR(CDCl3/400MHz)1.26(d，6H，J＝6.8Hz)，1.34(t，3H，J＝7.2Hz)，2.80(septet，1H，J＝6.8Hz)，4.27-4.35(m，2H)，5.78(q，1H，J＝6.8Hz)，7.09(d，1H，J＝2.4Hz)，7.31(d，1H，J＝2.4Hz)，7.59(s，1H)；MS(ES+)373(M+1，100)；MS(EI)372(M+，22)，303(100)，275(35).
process for preparation of Wang (Wang) resin 6-chloro-8-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
To a thick slurry of 53 g (63.6 mmol) of bromo-Wang (Wang) resin (4- (bromomethyl) phenoxymethyl polystyrene, NovaBiochem, model #01-64-0186, 1.20 meq/g) in 1 l of anhydrous dimethylacetamide was added 31.1 g (95.5 mmol) of cesium carbonate and 38.62 g (95.5 mmol) of 6-chloro-8-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. The thick slurry was stirred at room temperature overnight. The mixture was filtered and the resin was washed three times with each of DMF, methanol and dichloromethane. Blowing the collected resin Dry to yield 73.75 grams of an off-white resin. 1.00 ml of hexamethyldisiloxane in CDCl3A5.85M solution in/TFA (1: 1) was used to treat 73.4 mg of resin and direct dissociation NMR was used to determine the amount of resin adsorbed. After 1 hour, the filtrate was collected and a small amount of CDCl was added3The resin was washed three times. The mixed filtrate was analyzed by NMR to provide the adsorption and resin analysis: direct dissociation1H NMR loading＝1.071meq/g；
1H NMR(CDCl3+TFA/400MHz)5.79(q，1H，J＝6.6Hz)，7.27(d，1H，J＝2.2Hz)，7.81(m，2H).
6-chloro-8-aryl-2- (trifluoromethyl) -2H-substituted derivatives using Suzuki coupling Preparation of chromene-3-carboxylic acid
Example 298
6-chloro-8- (4-fluorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Preparation of 6-chloro-8- (4-fluorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To 0.400 g (0.428 mmol) of Wang (Wang) resin 6-chloro-8-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate were added 50 mg (0.043 mmol) of tetrakis (triphenylphosphine) palladium (0), 0.180 g (1.285 mmol) of 4-fluorophenylboronic acid, 0.857 ml of potassium carbonate (degassed 2M solution) and 4 ml of degassed DMF. The reaction mixture was heated to 100 ℃ for 18 hours. The reaction mixture was transferred and washed as follows: DMF (5 times), water (5 times), methanol (5 times) and dichloromethane (5 times). The resin was treated with 2 ml of 1: 1 TFA: dichloromethane for 30 minutes. Collecting filter And repeating the process. The resin was washed with dichloromethane (2 times), all filtrates were combined and concentrated. The resulting oil was purified by reverse phase chromatography to yield 0.055 g (34%) of a yellow crystalline solid:1H NMR(CDCl3/400MHz)5.66(q，1H，J＝6.8Hz)，7.10-7.15(m，2H)，7.26(d，1H，J＝2.4Hz)，7.37(d，1H，J＝2.4Hz)，7.42-7.47(m，2H)，7.90(s，1H)；MS(ES+)373(M+1，100)；HRMS(ES-)m/z calcd for(C17H9O3ClF4)371.0093，found 371.0067.
6-chloro-8-aryl-2- (trifluoromethyl) -2H-chromen-3-one by parallel synthesis Preparation of carboxylic acids
The following examples in Table 5 were prepared as described above for 6-chloro-8- (4-fluorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid moiety using a parallel synthesis setup and optionally purified by reverse phase chromatography.
Table 5: yield, purity and mass spectra data for 6-chloro-8-aryl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared by parallel synthesis.
5 th table
Examples LC (minutes) MS(ES+) HRMS % purity % yield
298 2.391 373 371.0067 100 34
299 2.705 407 404.9710 100 25
300 3.055 423 420.9372 100 44
301 2.960 423 420.9399 100 38
302 2.389 373 371.0084 100 34
303 2.631 389 386.9831 100 37
304 2.478 369 367.0361 100 36
305 2.594 369 367.0321 100 38
306 2.604 369 367.0303 100 33
307 2.674 423 421.0025 100 40
308 2.742 423 421.0016 100 43
309 2.582 399 397.0485 100 18
310 2.809 439 437.0014 100 37
311 2.070 380 378.0154 100 24
312 2.051 383 381.0119 100 14
313 2.585 399 397.0439 100 4
314 3.3552 399 397.0470 100 11
315 2.040 383 381.0160 100 15
316 3.059 491 489.0095 100 32
317 2.1682 356 354.0106 100 6
318 2.448 423 421.0026 100 11
319 2.860 415 - 100 22
320 2.389 401 399.0082 100 19
321 2.100 380 378.0138 100 23
322 1.215 356 354.0174 100 18
323 2.501 391 388.9970 100 39
324 1.718 399 397.0072 99 3
325 2.860 383 381.0519 100 28
326 3.030 397 395.0640 100 15
327 3.239 411 409.0766 100 38
Examples LC (minutes) MS(ES+) HRMS % purity % yield
328 3.5822 383 381.0549 100 38
329 3.3292 414 412.0220 100 43
330 3.808 431 429.0453 100 36
331 4.0552 411 409.0775 100 41
332 3.382 419 416.9866 100 20
333 3.0062 397 395.0312 100 34
334 3.6612 383 381.0509 100 42
335 3.519 387 385.0288 100 38
336 2.3272 384 384.06433 100 20
337 3.2102 413 411.0242 100 18
338 3.6192 383 381.0498 100 40
339 2.5292 428 428.04973 100 13
340 2.6402 385 383.0324 100 17
341 1.295 384 384.06433 92 5
342 1.7552 371 369.0152 100 4
343 2.461 439 437.0397 100 22
344 2.0072 394 392.0304 100 1
345 3.0832 413 411.0199 100 30
346 3.9032 403 400.9926 100 39
347 2.8582 425 423.0201 100 9
348 2.6562 399 397.0095 100 4
349 3.6432 387 382.0242 100 31
350 3.0992 445 443.0473 100 4
351 2.6092 412 412.05533 100 12
352 3.7992 439 436.9999 100 4
353 2.8242 427 425.0346 100 5
354 3.0692 397 395.0280 100 11
355 3.3222 403 - 100 27
356 3.6232 399 397.0442 99 58
357 4.2292 411 409.0797 100 35
Examples LC (minutes) MS(ES+) HRMS % purity % yield
358 2.6702 448 465.04914 100 13
359 3.4952 427 425.0360 100 33
360 2.5902 412 425.0588 100 18
361 3.9712 447 445.0463 100 18
362 3.6712 413 411.0573 100 23
363 1.8952 370 368.0321 100 15
364 3.2682 361 358.9743 100 3
365 3.2602 400 398.0000 100 39
366 1.9422 370 370.04623 100 25
367 2.4932 398 398.08033 100 34
368 3.5532 427 425.0385 100 30
369 2.4882 428 428.05303 100 16
1: see general experimental section for description of recorded data. LC refers to the chromatographic retention time determined as a linear gradient from 0 min 40% acetonitrile in 0.1% TFA/water to 4.5 min 95% acetonitrile. HRMS refers to the molecular ion (M-H) observed in high resolution mass spectroscopy in electron spray negative mode. % purity is determined by LS detection method.
2: LC refers to the chromatographic retention time determined as a linear gradient from 0 min 5% acetonitrile in 0.1% TFA/water to 4.5 min 95% acetonitrile.
3: electron spray positive mode, M +1 ions.
4: positive mode of electron spray, M + NH4Ions.
Example 319
6-chloro-8- [4- (ethylthio) phenyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Preparation of 6-chloro-8- [4- (ethylthio) phenyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. The sample obtained by the parallel synthesis was purified by reverse phase chromatography to obtain 0.039 g (22%) of a yellow crystalline solid.
1H NMR(CDCl3/400MHz)1.36(t，3H，J＝7.2Hz)，3.00(q，2H，J＝7.2Hz)，5.68(q，1H，J＝6.8Hz)，7.22(d，1H，J＝2.4Hz)，7.34-7.41(m，5H)，7.81(s，1H)；MS(ES+)415(M+1，100).
Example 323
6-chloro-8- (3, 5-difluorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Preparation of 6-chloro-8- (3, 5-difluorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. From the sample obtained by the parallel synthesis method, it was purified by reverse phase chromatography to obtain 0.066 g (39%) of a yellow crystalline solid.
1H NMR(CDCl3/400MHz)5.69(q，1H，J＝6.8Hz)，6.82-6.87(m，1H)，6.99-7.05(m，2H)，7.31(d，1H，J＝2.4Hz)，7.38(d，1H，J＝2.8Hz)，7.91(s，1H)；MS(ES-)389(M-1，100)；HRMS(ES-)m/z calcd for(C17H8O3ClF5)388.9998，found 388.9970.
Example 335
6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Preparation of 6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. From a sample prepared by the parallel synthesis (0.536 mmol scale), purified using reverse phase chromatography to yield 0.079 g (38%) of a yellow crystalline solid.
1H NMR(CDCl3/400MHz)2.32(d，3H，J＝1.6Hz)，5.66(q，1H，J＝6.8Hz)，7.13-7.16(m，2H)，7.25-7.27(m，2H)，7.37(d，1H，J＝2.4Hz)，7.89(s，1H)；MS(ES+)387(M+1，100)；HRMS(ES-)m/z calcd for(C18H11O3ClF4)385.0249，found 385.0288.
The calculated value was 385.0249 and the measured value was 385.0288.
Example 334
6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Preparation of 6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. From a sample prepared by the parallel synthesis method (0.536 mmol scale), purified using reverse phase chromatography to yield 0.087 g (42%) of a yellow crystalline solid.
1H NMR(CDCl3/400MHz)1.28(t，3H，J＝7.6Hz)，2.70(q，2H，J＝7.6Hz)，5.68(q，1H，J＝6.8Hz)，7.21(d，1H，J＝2.8Hz)，7.27-7.29(m，2H)，7.36(d，1H，J＝2.4Hz)，7.39-7.41(m，2H)，7.82(s，1H)；MS(ES+)383(M+1，100)；HRMS(ES-)m/zcalcd for(C19H14O3ClF3)381.0500，found 381.0509.
The calculated value was 381.0500 and the measured value was 381.0509.
Example 346
6-chloro-8- (4-chloro-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Preparation of 6-chloro-8- (4-chloro-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. From a sample prepared by the parallel synthesis method (0.536 mmol scale), purified using reverse phase chromatography to yield 0.085 g (39%) of a yellow crystalline solid.
1H NMR(CD3OD/400MHz)2.36(s，3H)，5.73(q，1H，J＝6.8Hz)，7.21-7.23(m，1H)，7.28-7.29(m，1H)，7.32-7.35(m，3H)，7.75(s，1H)；MS(ES-)401(M-1，100)；HRMS(ES-)m/z calcd for(C18H11O3Cl3F3)400.9954，found400.9926.
The calculated value was 400.9954 and the measured value was 400.9926.
Example 356
6-chloro-8- (4-methoxy-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Preparation of 6-chloro-8- (4-methoxy-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. From a sample prepared by the parallel synthesis (0.536 mmol scale), purified using reverse phase chromatography to yield 0.124 g (58%) of a yellow crystalline solid.
1H NMR(CD3OD/400MHz)2.20(s，3H)，3.84(s，3H)，5.74(q，1H，J＝6.8Hz)，6.92(d，1H，J＝8.0Hz)，7.25-7.29(m，4H)，7.76(s，1H)；MS(ES+)399(M+1，100)；HRMS(ES-)m/z calcd for(C19H14O4ClF3)397.0449，found397.0442.
The calculated value was 397.0449 and the measured value was 397.0442.
Parallel synthesis of libraries of compounds with 6-and 7-position substitution
X is hydrogen or chlorine
R is as described
(preparation of intermediate and Synthesis of example 370-483)
Preparation of ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Step 1: preparation of 5-chloro-4-fluoro-2-hydroxybenzaldehyde
To 4-chloro-3-fluorophenol (25 g, 171 mmol), methanesulfonic acid (130 ml) was added, andthe mixture was stirred at room temperature. An ice water bath was used to reduce the temperature of the stirred mixture to 10 ℃. Hexamethylene tetramine (47.8 g, 341 mmol) was added portionwise in 3 g portions of one spoon to dissolve the solid and maintain the temperature below 40 ℃. The addition was complete after 90 minutes. Attention is paid to: if added too quickly, the solid will react with the acid and decompose in an exothermic manner. The mixture was heated to 100 ℃. At 70 ℃ a change in the color of the reaction mixture and the formation of a solid was observed. Once the temperature reached 100 ℃, the heating mantle was removed and the mixture was allowed to cool to room temperature. The reaction mixture was poured into 1 liter of ice water and extracted 3 times with dichloromethane. The combined extracts were filtered through a plug of silica (4.5X 9 cm), washed with additional dichloromethane, and concentrated to give a crude yellow solid. Kugelrohr distillation (100 mTorr, 60 ℃ C.) gave 18.06 g (60.6%) of a white solid 1H NMR(CDCl3)6.79(d，1H，J＝10.3Hz)，7.62(d，1H，J＝7.9Hz)，9.80(s，1H)，11.23(d，1H，J＝1.5Hz).
Step 2: preparation of ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate Prepare for
To the aldehyde from step 1 (17.46 g, 100 mmol) in 25 ml DMF was added potassium carbonate (15.2 g, 110 mmol). The mixture was stirred, heated to 70 ℃ and treated with ethyl-trifluorocrotonate (22.4 ml, 150 mmol). After 2 hours, the mixture was heated to 95 ℃. After a total of 4 hours, an additional 16 ml of ethyltrifluorocrotonate are added and the mixture is stirred at 95 ℃ for 4 hours and at room temperature for 12 hours. LCMS showed reaction completion. The mixture was treated with 300 ml of 1N hydrochloric acid and extracted 4 times with ethyl acetate. The combined extracts were filtered through a plug of silica (4.5X 6 cm) and the plug was rinsed with additional dichloromethane. The extract was concentrated, the crude product triturated with cold methanol, the solid collected and air dried to give 19.1 g of a tan solid. The mother liquor was concentrated, dissolved in dichloromethane and the same procedure as described above was followedThe second batch was obtained as a 4.1 g solid by filtration through a new plug of silica. The mother liquor was diluted with water and the solids were collected to give a third batch of 3.16 g solids. The total yield was 26.36 g (81.2%). By using 1H NMR analysis showed: the purity of the first and second batches was higher than 95%, while the purity of the third batch was higher than 90%.
1H NMR(CDCl3)1.35(t，3H，J＝7.1Hz)，4.33(m，2H)，5.71(q，1H，J＝6.7Hz)，6.82(d，1H，J＝9.4Hz)，7.28(d，1H，7.9Hz)，7.63(s，1H).19FNMR(CDCl3)-78.9(d，3F，J＝6.7Hz)，-106.7(t，1F，J＝8.7Hz).13CNMR(CDCl3)14.2，61.7，70.9(q，C2，J＝33.3Hz)，105.5(d，C8，J＝25.5Hz)，114.9(d，J＝18.7Hz)，116.4，117.1，123.1(q，CF3，J＝287.2Hz)，130.4(d，J＝1.5Hz)，134.9(d，J＝1.9Hz)，152.9(d，J＝11.4Hz)，160.1(d，C7，J＝255.2Hz)，163.4(C＝O)；MS(ES+)325(M+1，100).
Preparation of 6-chloro-7-aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Example 370
6-chloro-7- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-7- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) Preparation of (E) -2H-chromene-3-carboxylic acid esters
To 325 mg (1.0 mmol) of ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 2.5 ml of DMF were added 172 mg (1.1 mmol) of 2-chloro-4, 5-dimethylphenol and 193.5 mg (1.4 mmol) of potassium carbonate. The suspension was prepared in a capped vial and placed in an aluminum heating zone equipped with a shaker. The aluminum heating zone was heated to 110 ℃ for 16 hours. After the vial was cooled, the mixture was treated with 10 ml of water and 2 ml of diethyl ether. The organic layer was removed and the aqueous layer was extracted 2 times with diethyl ether. The combined organic extracts were filtered through 5 g of silica, which was washed with 10 ml of diethyl ether. The filtrate was concentrated under a stream of nitrogen to give an off-white solid which was used in the next step without further purification.
1H NMR(CDCl3/300MHz)1.36(t，3H，J＝7.2Hz)，2.25，(s，3H)，2.27(s，3H)，4.32(m，2H)，5.66(q，1H，J＝6.8Hz)，6.27(s，1H)，6.93(2，1H)，7.25(s，1H)，7.33(s，1H)，7.66(s，1H)；19F NMR(CDCl3/300MHz)-78.9(d，3F，J＝6.2Hz).
Step 2: 6-chloro-7- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid
To the concentrated product of step 1 in a suitable vial, 400 ml (mmol) of lithium hydroxide monohydrate, 1 ml of water, 2 ml of methanol and 7 ml of THF are added. The vial was capped and placed in an aluminum heating zone, which was heated to 100 ℃ for 30 minutes. After the vial was cooled to room temperature, the mixture was treated with 5 ml of 1N hydrochloric acid and 2 ml of diethyl ether. The solvent was removed by evaporation under a stream of nitrogen and the combined organic extracts were concentrated, followed by concentration in vacuo to yield 150 mg (34.6%) of a yellow solid:
1H
NMR(CDCl3/300MHz)2.26(s，3H)，5.64(q，1H，J＝6.8Hz)，6.27(s，1H)，6.94(s，1H)，7.26(s，1H)，7.3H(s，1H)，11.28(hs，1H)；MS(ES-)431(M-1，100)；HRMS(ES-)m/zcalcd for(M-H；C19H12Cl2F3O4)431.0059，found 431.0048.
the calculated value was 431.0059 and the measured value was 431.0048.
6-chloro-7-aryloxy-2- (trifluoromethyl) -2H-chromen-3-one prepared by parallel synthesis Preparation of carboxylic acids
The following examples in table 6 were prepared as described above for the-chloro-7- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid moiety using a parallel synthesis setup and each reaction on a 1.0 or 0.5 millimolar scale. The product was optionally purified by reverse phase chromatography (C18 column, 40 mm I.D.. times.100 mm, gradient acetonitrile in water/0.1% TFA).
Table 6: by parallel synthesis1Yield, purity, mass spectral data and HPLC residence time of the prepared 6-chloro-7-aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid.
6 th table
Examples LC (residence time) MS(ES+) % purity % yield
370 4.304 433 95 34.6
371 3.581 399 89 76.1
372 3.377 417 99 79.1
373 3.636 419 99 78.0
374 3.793 453 99 79.1
375 3.704 413 83 71.7
376 3.555 399 95 82.5
377 3.38 385 99 80.2
378 3.587 399 94 77.2
379 3.363 385 99 68.8
380 2.295 414 94 68.7
381 3.888 445 99 40.3
382 3.837 425 94 82.1
383 3.768 413 91 81.9
384 3.748 4532 85 62.2
385 3.712 413 94 70.1
Examples LC (residence time) MS(ES+) % purity % yield
386 3.736 413 94 82.6
387 3.829 427 94 75.9
388 3.525 4633 99 76.9
389 3.868 427 96 85.1
390 3.666 411 96 76.3
391 3.111 389 99 67.0
392 3.347 385 94 70.5
393 2.216 436 99 13.1
394 2.996 406 91 49.8
395 3.305 415 99 68.3
396 2.801 386 93 45.8
397 1.895 386 99 48.7
398 3.812 443 99 68.6
399 3.151 389 97 60.6
400 2.964 415 99 64.3
401 3.024 389 99 62.1
402 2.811 431 99 63.0
403 3.669 477 99 58.6
404 3.227 435 99 61.1
405 3.376 403 99 69.9
406 3.558 451 97 54.6
407 3.825 433 92 72.5
408 3.631 419 95 66.7
409 3.345 403 95 68.3
410 2.717 4503 99 52.4
411 3.099 407 99 67.9
412 3.893 433 99 70.4
413 3.501 439 99 62.2
414 3.956 6052 99 67.8
415 3.691 5274 93 71.1
Examples LC (residence time) MS(ES+) % purity % yield
416 3.25 4493 99 61.3
417 3.809 475 99 53.6
418 3.651 439 99 64.3
419 3.71 4993 99 59.5
420 3.328 4673 99 70.2
421 3.317 4673 99 53.9
422 3.317 4853 91 74.6
423 3.587 4532 99 0.0
424 2.78 426 99 0.0
425 3.069 430 99 0.0
426 3.893 422 77 2.7
427 3.878 436 74 1.7
428 3.506 512 95 7.4
429 3.319 421 91 2.0
430 2.838 406 89 17.3
431 3.312 4503 95 16.0
432 3.836 490 92 4.8
433 3.33 423 99 36.9
434 3.993 427 99 21.6
435 3.885 413 99 27.2
436 3.516 473 74 27.0
437 3.469 423 99 33.6
438 3.136 407 99 41.7
439 3.445 457 99 40.7
440 3.334 403 99 34.5
441 3.651 399 99 28.5
442 3.674 419 99 23.6
443 3.582 4673 99 37.7
444 3.433 403 99 36.1
445 3.74 473 99 18.4
Examples LC (residence time) MS(ES+) % purity % yield
446 3.858 461 99 31.5
447 3.957 481 99 28.7
448 3.151 4295 99 33.6
449 3.88 511 99 31.5
450 3.739 4836 99 38.6
451 3.837 413 99 21.1
452 3.981 4633 99 38.3
453 3.778 419 99 35.1
454 3.86 399 99 31.7
455 4.379 489 99 37.9
456 4.308 481 99 33.0
457 4.37 439 99 30.5
458 3.817 441 99 27.8
459 4.056 413 99 38.1
460 3.54 415 99 26.8
461 2.815 415 99 37.4
462 4.267 427 99 26.9
463 4.379 441 99 33.7
464 3.772 441 99 31.7
465 2.97 449 99 31.1
466 3.606 4493 99 40.8
467 3.151 3837 99 41.7
468 2.516 3838 99 29.6
1See general experimental section for description of recorded data. The% purity was determined by UV light at 254 nm.
2The ion listed is a Cl3M +1 of the population; (M +1, 100; M +3, 97).
3The listed ions are M +1 of one ClBr population; (M +1, 77; M +3, 100).
4The ion listed is a ClBr2M +1 of the population; (M +1, 44; M +3, 100).
5.429(M+1，65)；197(100)。
6The ion listed is a Cl2M +1 of Br population; (M +1, 61; M +3, 100).
7.383(M-OCH3100), using ES-),1H NMR and HRMS (described later) were subjected to detailed characteristic analysis.
8383(M-OH, 100), detailed characterization was obtained using ES-, 1H NMR and HRMS (see below).
Example 395
6-chloro-7- (4-ethoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The sample (Table 2) obtained by the parallel synthesis was concentrated to obtain 141.8 mmG (68.3%) of an off-white solid.1H NMR(d6-acetone/400MHz)1.37(t，3H，J＝7.0Hz)，4.06(q，2H，J＝7.0Hz)，5.77(q，1H，J＝7.1Hz)，6.38(s，1H)，7.01(d，2H，J＝6.8Hz)，7.09(d，2H，J＝6.8Hz)，7.64(s，1H)，7.85(s，1H)；19F NMR(d6-acetone/400MHz)-79.4(d，3F，J＝7.7Hz)；13C NMR(d6-acetone/100MHz)15.0，64.4，71.5(q，J＝32.7Hz)，105.3，115.5，116.6，117.5，122.2，124.5(q，J＝287.1Hz)，131.6，136.1，148.8，153.7，157.5，158.6，163.3；MS(ES-)413(M-1，100)；HRMS(ES-)m/z calcd for(C19H13ClF3O5)413.0398，found 413.0396.
Example 432
6-chloro-2- (trifluoromethyl) -7- { [8- (trifluoromethyl) quinolin-4-yl ] oxy } -2H-chromene-3-carboxylic acid
The sample prepared by the parallel synthesis (Table 2) was concentrated to yield 11.7 mg (4.8%) of an off-white solid.
1H NMR(d6-acetone/400MHz)5.93(q，1H，J＝7.0Hz)，6.86(d，1H，J＝5.1Hz)，7.24(s，1H)，7.82(m，2H)，7.98(d，1H，J＝7.4Hz)，8.25(d，1H，J＝7.2Hz)，8.65(d，1H，J＝8.5Hz)，8.88(d，1H，J＝5.1Hz)；19F NMR(d6-acetone/400MHz)-60.9(s，3F)，-79.3(d，3F，J＝7.7Hz)；MS(ES-)488(M+1，100)；HRMS(ES-)m/z calcd for(C21H9ClF6NO4)488.0119，found 488.0112.
Example 443
6-chloro-7- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromen-3-enoic acid
The sample prepared by the parallel synthesis (Table 2) was concentrated to give 56.8 mg (28.5%) of an off-white solid.
1H NMR(d6-acetone/400MHz)1.22(t，3H，J＝7.6Hz)，2.66(q，2H，J＝7.6Hz)，5.78(q，1H，J＝7.1Hz)，6.45(s，1H)，7.04(d，2H，J＝8.4Hz)，7.31(d，2H，J＝8.5Hz)，7.67(s，1H)，7.88(s，1H)；MS(ES-)397(M-1，100)；HRMS(ES-)m/z calcd for(C19H13ClF3O4)397.0449，found 397.0484.
Example 444
6-chloro-7- (5-fluoro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The sample prepared by the parallel synthesis (Table 2) was concentrated to yield 72.7 mg (36.1%) of an off-white solid.1H NMR(d6-acetone/300MHz)2.22(s，3H)，5.85(q，1H，J＝7.0Hz)，6.53(s，1H)，6.88(dd，1H)，7.02(dt，1H)，7.43(t，1H)，7.75(s，1H)，7.94(s，1H)；MS(ES-)401(M-1，100)；HRMS(ES-)m/z calcd for(M-1；C18H10ClF4O4)401.0198，found 401.0187.
The calculated value was 401.0198 and the measured value was 401.0187.
Example 454
6-chloro-7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The sample prepared by the parallel synthesis (Table 2) was concentrated to give 63.2 mg (31.7%) of an off-white solid.1H NMR(CD3OD/300MHz)2.13(s，3H)，2.35(s，3H)，5.73(q，1H，J＝7.0Hz)，6.18(s，1H)，6.83(s，1H)，7.05(d，1H，J＝7.8Hz)，7.24(d，1H，J＝7.7Hz)，7.54(s，1H)，7.79(s，1H)；MS(ES-)397(M-1，100)；HRMS(ES-)m/z calcd for(C19H13ClF3O4)397.0449，found 397.0419.
The calculated value was 397.0449 and the measured value was 397.0419.
Example 467
6-chloro-7- [4- (methoxymethyl) phenoxy ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The sample prepared by the parallel synthesis (Table 2) was concentrated to yield 86.3 mg (41.7%) of an off-white solid.
1H NMR(d6-acetone/300MHz)3.39(s，3H)，4.49(s，2H)，5.84(q，1H，J＝7.0Hz)，6.57(s，1H)，7.14(d，2H，J＝6.6Hz)，7.48(d，2H，J＝8.6Hz)，7.72(s，1H)，7.93(s，1H)；MS(ES-)413(M-1，100)；HRMS(ES-)m/z calcd for(M-1；C19H13ClF3O5)413.0398，found 413.0443.
The calculated value was 413.0398 and the measured value was 413.0443.
Example 468
6-chloro-7- [4- (hydroxymethyl) phenoxy ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The sample prepared by the parallel synthesis (Table 2) was concentrated to give 59.2 mg (29.6%) of an off-white solid.1H NMR(d6-acetone/300MHz)2.67(s，1H)，4.71(s，2H)，5.83(q，1H，J＝7.0Hz)，6.52(s，1H)，7.13(d，2H，J＝6.6Hz)，7.51(d，2H，J＝8.6Hz)，7.72(s，1H)，7.92(s，1H)；MS(ES-)399(M-1，100)；HRMS(ES-)m/z calcd for(M-1；C18H11ClF3O5)399.0242，found 399.0267.
The calculated value was 399.0242 and the measured value was 399.0267.
Example 469
7- [4- (2-carboxyethyl) phenoxy ] -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
A two-component mixture was prepared from ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate and methyl 3- (4-hydroxyphenyl) propionate using a two-step parallel synthetic route. The two products were separated by reverse phase chromatography (C18 column, 4 cm id. times.10 cm, 5% to 95% gradient acetonitrile/water/0.1% TFA). The shorter residence time component (analytical LC residence time 3.40 minutes, ELS purity greater than 99%) was concentrated in vacuo to yield 61.1 mg (27.6%) of a white solid.1HNMR(d6-acetone/400MHz)2.59(t，2H，J＝7.6Hz)，2.92(t，2H，J＝7.6Hz)，5.78(q，1H，J＝7.1Hz)，7.04(d，2H，J＝8.6Hz)，7.36(d，2H，J＝8.6Hz)，7.66(s，1H)，7.82(s，1H)；19FNMR(d6-acetone/100MHz)-79.2(d，3F，J＝6.8Hz)；MS(ES+)443(75％，M+1)，465(100％，M+Na)；MS(ES-)441(M-1，100)；HRMS(ES-)m/z calcd for(M-1；C20H13O6ClF3)441.0347，found 441.0347.
The calculated value was 441.0347 and the measured value was 441.0347.
Example 470
6-chloro-7- [4- (3-methoxy-3-oxopropyl) phenoxy ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
A two-component composition was prepared from ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate and methyl 3- (4-hydroxyphenyl) propionate using a two-step parallel synthetic route. The two products were separated by reverse phase chromatography (C18 column, 4 cm id. times.10 cm, 5% to 95% gradient acetonitrile/water/0.1% TFA). The longer-lived component (analytical LC residence time 3.83 minutes, ELS purity greater than 99%) was concentrated in vacuo to yield 66.0 mg (29.0%) of a white solid.
1H NMR(d6-acetone/400MHz)2.64(t，2H，J＝7.6Hz)，2.94(t，2H，J＝7.6Hz)，3.82(s，3H)，5.80(q，1H，J＝7.0Hz)，7.04(d，2H，J＝8.6Hz)，7.36(d，2H，J＝8.6Hz)，7.67(s，1H)，7.86(s，1H)；19F NMR(d6-acetone/100MHz)-79.5(d，3F，J＝7.7Hz)；MS(ES+)457(M+1，100)；MS(ES-)455(M-1，100)；HRMS(ES-)m/z calcd for(M-1；C21H16O6ClF3)455.0504，found 455.0490.
The calculated value was 455.0504 and the measured value was 455.0490.
Example 471
5, 6-dichloro-7- (3-chloro-4-ethoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To 135 mg (0.32 mmol) of 6-chloro-7- (4-ethoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid in 3 ml of glacial acetic acid was added an excess (ca.1 g) of chlorine. After stirring overnight, the mixture was added to 20 ml of water. The reaction mixture was extracted three times with diethyl ether, dried and concentrated. Preparative reverse phase chromatography gave 38 mg (24%) of an off-white solid.1H NMR(d6-acetone/400MHz)1.41(t，3H，J＝7.0Hz)，4.15(q，2H，J＝7.0Hz)，5.44(q，1H，J＝6.6Hz)，6.50(s，1H)，7.05(dd，1H，J＝3.0Hz，J＝8.9Hz)，7.17(d，1H，J＝9.0Hz，7.21(d，1H，J＝2.8Hz)，7.66(s，1H)；13C NMR(d6-acetone/100MHz)14.9，65.8，77.7(q，J＝31.5Hz)，106.6，115.5，117.1，118.3，120.1，122.5，123.3(q，J＝283.6Hz)，124.0，131.6，149.4，151.6，152.8，155.7，164.4；MS(ES+)483(M+1，100)；HRMS(ES-)m/z calcd for(C19H13O6Cl3F3)498.9724，found 498.9712(M-H+H2O).
Calculated value is 498.9724, found 498.9712(M-H + H)2O)。
Ethyl 6-chloro-7- (2-chloro-4-bromophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
To a mixture of 1.5 g (4.61 mmol) ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate, 1.04 g (6.44 mmol) 2-chloro-4-bromophenol and 0.89 g (8.76 mmol) potassium carbonate was added 10 ml anhydrous DMF. The resulting mixture was heated to 110 ℃ for 5 hours. After cooling to room temperature, the reaction was treated with 150 ml of ethyl acetate. The organic layer was washed three times with saturated sodium bicarbonate, three times with brine, and dried over anhydrous magnesium sulfate. After removal of the volatiles, the residue was purified on a silica gel column eluting with ethyl acetate/hexane (1: 9) to yield 1.8 g (76.3%) of a light yellow solid.
1H NMR(CDCl3/400MHz)7.69(s，1H)，7.68(s，1H)，7.47(dd，1H，J＝2.4Hz，8.7Hz)，7.37(s，1H)，7.00(d，J＝8.7Hz，1H)，6.38(s，1H)，5.70(q，1H，J＝6.6Hz)，4.35(m，2H)，1.38(t，3H，J＝7.2Hz).MS(ESI+)511(M+1，60)，513(M+3，100)；HRMS(EI)m/z calcd for(C19H12BrCl2F3O4)509.9248，found 509.9274.
The calculated value was 509.9248 and the measured value was 509.9274.
Ethyl 6-chloro-7- (2-chloro-4-bromophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
The desired compound was prepared in 79% yield as a yellow solid according to the general procedure for ethyl 6-chloro-7-aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate.
1H NMR(CDCl3/400MHz)7.63(s，1H)，7.39(dd，J＝2.4Hz，10Hz，1H)，7.32-7.29(m，2H)，7.00(t，J＝8.4Hz，1H)，6.38(s，1H)，5.65(q，J＝6.8Hz，1H)，4.30(m，2H)，1.33(t，J＝7.2Hz，3H)；LC-MS(ES+)496.9(+2，100)，494.9(M+1，73)；HRMS(EI+)m/z calcd for(C19H12ClBrF4O4)493.9544，found 493.9551.
The calculated value was 493.9544 and the measured value was 493.9551.
Ethyl 6-chloro-7- (2-methyl-4-iodophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acid esters
The desired compound was prepared in 56% yield as a pale yellow solid according to the general procedure for ethyl 6-chloro-7-aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate.
1H NMR(CDCl3/400MHz)7.63(s，1H)，7.61(d，J＝1.2Hz，1H)，7.52(dd，J＝1.6Hz，8.8Hz，1H)，7.30(s，1H)，6.68(d，J＝8.4Hz，1H)，6.28(s，1H)，5.63(q，J＝7.2Hz，1H)，4.30(m，2H)，2.15(s，3H)，1.33(t，J＝7.2Hz，3H)；LC-MS(ES+)538.9(M+1，100).HRMS(EI)m/z calcd for(C20H15ClF3IO4)537.9656，found 537.9634.
The calculated value was 537.9656 and the measured value was 537.9634.
Ethyl 6-chloro-7- (2, 5-difluoro-4-bromophenoxy) -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
The desired compound was prepared in 56% yield as a pale yellow solid according to the general procedure for ethyl 6-chloro-7-aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate.
1H NMR(CDCl3/300MHz)7.63(s，1H)，7.44(dd，J＝9.6Hz，J＝6.2Hz，1H)，7.32(s，1H)，6.88(dd，J＝8Hz，J＝6.8Hz，1H)，6.47(s，1H)，5.66(q，J＝6.4Hz，1H)，4.31(m，1H)，1.34(t，J＝6.8Hz，3H).
6-chloro-7- (substituted) phenoxy-2- (trichloromethyl) -2H-substituted carboxylic acids using palladium coupling Preparation of chromene-3-carboxylic acid
X is iodine or bromine
R1、R3Hydrogen, fluorine, chlorine, methyl
Example 472
6-chloro-7- (2-chloro-4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-7- (2-chloro-4-ethylphenoxy) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid esters
To a mixture of 0.3 g (0.59 mmol, 1.0 eq) of ethyl 6-chloro-7- (2-chloro-4-bromophenyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate, 0.32 g (2.3 mmol) of potassium carbonate, 68 mg (0.059 mmol) of tetrakis (triphenylphosphine) palladium (0) and 2.5 ml of anhydrous DMF under nitrogen was added 0.83 ml (0.83 mmol, 1.0M solution in THF) of triethylborane. The mixture was heated to 110 ℃ and shaken for 5 hours. LC-MS showed the reaction was complete. After cooling to room temperature, the reaction was added to 50 ml of ethyl acetate. The resultant organic layer was washed three times with brine and dried over anhydrous magnesium sulfate. After removal of the volatiles, the residue was purified on a silica gel column eluting with 1: 9 ethyl acetate/hexane to yield 0.23 g (84.7%) of a light yellow solid. The product was used directly in the next step.
Step 2: 6-chloro-7- (2-chloro-4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene Preparation of (E) -3-carboxylic acid
The isolated pale yellow solid (230 mg, 0.5 mmol) was dissolved in 3 ml of tetrahydrofuran. To the resulting solution was added 104 mg (2.5 mmol) of lithium hydroxide (LiOH 2H)2O) in 3 mlSolution in water, followed by 3 ml of ethanol. The resulting solution was heated at 80 ℃ for 1 hour. LC-MS showed the reaction was complete. The volatiles were removed and the aqueous residue was diluted with water and then acidified to pH 1.0 with dilute hydrochloric acid at 0 ℃. The product was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After removal of the volatiles, the residue was purified by reverse phase HPLC to give 90 mg (41%) of a light yellow solid:
1H NMR(CDCl3/300MHz)7.83(s，1H)，7.40(s，1H)，7.37(s，1H)，7.19(d，J＝8.1Hz，1H)，7.10(d，J＝8.1Hz，1H)，6.32(s，1H)，5.65(m，1H)，2.71(q，J＝7.5Hz，2H)，1.31(t，J＝7.5Hz，3H).MS(ES+)433.0(M+1，100).MS(ES-)431.0(M-1，100).HRMS(ES-)m/z calcd for(M-H；C19H12Cl2F3O4)：431.0059，found：431.0022.
the calculated value was 431.0059 and the measured value was 431.0022.
6-chloro-7- (substituted) phenoxy-2- (trifluoromethyl) using parallel synthesis Preparation of (E) -2H-chromene-3-carboxylic acid
The following examples in Table 7 were prepared as described above for 6-chloro-7- (2-chloro-4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid using a parallel synthesis setup.
Table 7: yield, purity and mass spectral data for 6-chloro-7- (substituted) phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared by parallel synthesis method 1.
7 th table
Examples LC MS(ES+) % purity % yield
473 3.375 403 100 64
474 3.553 417 98 28
475 3.420 421 95 56
476 4.173 441 95 8
477 3.783 413 100 49
1See general experimental section for description of recorded data. LC refers to chromatographic retention time in minutes. The% purity was determined by UV detection at 254 nm.
Example 474
6-chloro-7- (4-ethyl-2-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This product was prepared using the general parallel synthesis described in the 6-chloro-7- (2-chloro-4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid section. The sample was purified by reverse phase chromatography using Gilson (Gilson) to yield 18.7 mg (28%) of a pale yellow solid.
1H NMR(CDCl3，CD3OD/300MHz)1.16(t，3H，J＝7.5Hz)，2.57(q，2H，J＝7.5Hz)，5.46(m，1H)，6.24(s，1H)，6.93(m，2H)，7.22(d，1H，J＝1.5Hz)，7.30(s，1H)，7.56(s，1H)；MS(ES+)417(M+1，100)；
LC-MS purity 99% at 3.353 min (UV), 100% ELSD; HRMS (ES-) M/z (M-1; C)19H12O4ClF4) The calculated value was 415.0355 and the measured value was 415.0376.
Example 477
6-chloro-7- (4-ethyl-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This product was prepared using the general parallel synthesis described in the 6-chloro-7- (2-chloro-4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid section. Purification by reverse phase chromatography gave 67.5 mg (49%) of a pale yellow solid.
1H NMR(CDCl3，CD3OD/400MHz)1.26(t，3H，J＝7.6Hz，2.15(s，1H)，2.65(q，2H，J＝7.6Hz)，5.62(q，1H，J＝3.2Hz)，6.25(s，1H)，6.91(d，1H，J＝8.4Hz)，7.07(d，1H，J＝8Hz)，7.19(s，1H)，7.35(s，1H)，7.67(s，1H)；MS(ES+)413(M+1，100)；
LC-MS purity 100% in 3.779 min (UV vs ELSD); HRMS (ES-) M/z (M-1; C) 20H15ClF3O4) MeterThe calculated value was 411.0605, and the measured value was 411.0584.
6-chloro-7- (substituted) phenoxy-2- (tris) using Stille reaction Preparation of fluoromethyl) -2H-chromene-3-carboxylic acid
Example 478
6-chloro-7- (4-ethynyl-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-chloro-7- (4-ethynyl-2-methylphenoxy) -2- (trifluoromethyl) Preparation of (E) -2H-chromene-3-carboxylic acid esters
To a solution of 0.28 g (0.52 mmol) ethyl 6-chloro-7- (2-methyl-4-iodophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate and 12 mg (0.0104 mmol) tetrakis (triphenylphosphine) -palladium in 3.5 ml dry toluene was added 168 μ l (0.586 mmol) of tributyl (ethynyl) tin. The resulting solution was heated to 110 ℃ and shaken for 3 hours. LC-MS showed the reaction was complete. After cooling to room temperature, the reaction was quenched with the addition of 20% aqueous ammonium fluoride. The product was extracted with ethyl acetate. The organic layer was separated, washed with brine, and dried over anhydrous magnesium sulfate. After removal of the volatiles, the residue was purified on a silica gel column eluting with ethyl acetate/hexane (1: 9). The product was used for the next step.
Step 2: 6-chloro-7- (4-ethynyl-2-methylphenoxy) -2- (trifluoromethyl) -2H- Preparation of chromene-3-carboxylic acid
The product of step 1 (230 mg, 0.53 mmol) was dissolved in 3 ml of tetrahydrofuran. To the resulting solution was added a solution of lithium hydroxide (111 mg, 2.6 mmol) in 3 ml of water followed by 3 ml of ethanol. The resulting solution was heated at 80 ℃ for 1 hour. LC-MS showed the reaction was complete. The volatile material was removed. The residue was diluted with water and then acidified to pH 1.0 with dilute hydrochloric acid at 0 ℃. The product was extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After removal of the volatiles, the residue was purified by reverse phase HPLC. 70 mg (28.8%) of the product are obtained in the form of a pale yellow solid:
1H NMR(CDCl3/300MHz)7.82(s，1H)，7.48(s，1H)，7.42-7.40(m，2H)，6.93(d，J＝8.1Hz，1H)，6.36(s，1H)，5.66(q，J＝6.9Hz，1H)，3.11(s，1H)，2.23(s，3H).MS(ESI+)409.0(M+1，100).MS(ES-)407.0(M-H，100).HRMS(ES-)m/z calcd for(M-H；C20H11ClF3O4)：407.0292，found：407.0317
the calculated value was 407.0292 and the measured value was 407.0317.
Example 479
6-chloro-7- (4-ethynyl-2, 5-difluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using the general procedure described in the 6-chloro-7- (4-ethynyl-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid section, the product was prepared in 35.8% yield as a pale yellow solid.
1H NMR(CD3OD/300MHz)7.70(s，1H)，7.37-7.32(m，2H)，6.80(t，J＝8.4Hz，1H)，6.56(s，1H)，5.69(q，J＝6.3Hz，1H)，3.38(s，1H)；MS(ES+)430.9(M+1，100)；HRMS(ES-)m/z calcd for(M-1：C19H7ClF5O4)428.9948，found 428.9902.
The calculated value was 428.9948 and the measured value was 428.9902.
Example 480
6-chloro-7- (2-methyl-4-vinylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using the general procedure described in the 6-chloro-7- (4-ethynyl-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid section, 161.7 mg (31%) of the product was obtained as a light yellow solid.1H NMR(CD3OD/300MHz)2.21(s，3H)，5.27(d，1H，J＝11.1Hz)，5.77(m，2H)，6.28(s，1H)，6.77(dd，1H，J＝11.1Hz，17.7Hz)，6.94(d，1H，J＝8.4Hz)，7.38(dd，1H，J＝0.9Hz，8.1Hz)，7.45(s，1H)，7.56(s，1H)，7.80(s，1H)；MS(ES+)411(M+1，100)；
LC-MS purity 100% 3.605 min (UV vs ELSD); HRMS (ES-) M/z (M-1: C)20H13O4ClF3) The calculated value was 409.0449 and the measured value was 409.0447.
Example 481
6-chloro-7- (2-chloro-4-vinylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using the general procedure described for the 6-chloro-7- (4-ethynyl-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid moiety, 157.5 mg (27%) of the product was obtained as a light yellow solid.
1H NMR(CD3OD/300MHz)5.35(d，1H，J＝10.8Hz)，5.74(q，1H，J＝6.9Hz)，5.84(d，1H，J＝17.7Hz)，6.33(s，1H)，6.75(dd，1H，J＝11.1Hz，17.7Hz)，7.10(d，1H，J＝8.4Hz)，7.46(dd，1H，J＝2.1Hz，6.3Hz)，7.54(s，1H)，7.65(d，1H，J＝2.1Hz)，7.79(s，1H)；MS(ES+)432(M+1，100)；
LC-MS purity 100% 3.539 min (UV vs ELSD); HRMS (ES-) M/z (M-1: C)19H10O4Cl2F3) The calculated value was 428.9903 and the measured value was 428.9895.
Example 482
6-chloro-7- (2, 5-difluoro-4-vinylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Using the general procedure described for the 6-chloro-7- (4-ethynyl-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid moiety, 190.5 mg (37%) of the product was obtained as a light yellow solid.
1H NMR(CD3OD/300MHz)5.48(d，1H，，J＝11.1Hz)，5.81(m，1H)，5.94(d，1H，，J＝17.7Hz)，6.65(s，1H)，6.89(dd，1H，，J＝5.7Hz，9Hz)，7.13(dd，1H，，J＝7.2Hz，9Hz)，7.61(s，1H)，7.71(dd，1H，，J＝6.3Hz，9.9Hz)，7.83(s，1H)；MS(ES+)433(M+1，100)；
LC-MS purity 100% 3.493 min (UV vs ELSD); DRMS (ES-) M/z (M-1: C)19H9O4ClF5) The calculated value was 431.0104 and the measured value was 431.0099.
Example 483
6-chloro-7- (4-cyano-2-methylphenoxy) -2- (trifluoromethyl) -2H chromene-3-carboxylic acid
6-chloro-7- (4-cyano-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
In a solution of 0.34 g (0.63 mmol) ethyl 6-chloro-7- (2-methyl-4-iodophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate and 68 mg (0.76 mmol) copper (I) cyanide in 4 ml anhydrous dimethylformamide was stirred at 130 ℃ overnight. LC-MS showed the reaction was complete. After cooling to room temperature, the reaction was poured into 100 ml of ethyl acetate. The organic layer was then washed three times with 30% aqueous ethylenediamine to remove copper, then washed with brine, and dried over anhydrous magnesium sulfate. After removal of the volatiles, the residue was purified on a silica gel column eluting with 1: 9 ethyl acetate/hexane. The resulting compound (0.14 g, 0.32 mmol) was dissolved in 3 ml of tetrahydrofuran. To the resulting solution, 67.2 mg (1.6 mmol) of lithium hydroxide (LiOH 2H) was added2O) solution in 3 ml of water, followed by the addition of 3 ml of ethanol. The resulting solution was heated at 50 ℃ for 1 hour and then left at room temperature for 1 hour. The volatile material was removed. The residue was diluted with water, then acidified to pH 1 with dilute hydrochloric acid at 0 ℃ and the product extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. After removal of the volatiles, the residue was purified by reverse phase HPLC. The product was obtained in the form of a white solid with a purity of 100% and a yield of 27% at 70 mg.
1H NMR(CDCl3/CD3OD/300MHz)7.66(s，1H)，7.56(d，1H)，7.46(dd，J＝1.5，8.4Hz，1H)，7.34(s，1H)，6.80(d，J＝8.4Hz，1H)，6.51(s，1H)，5.66(q，J＝6.9Hz，1H)，2.31(s，3H)；MS(ES+)410(M+1，100)；HRMS(ES-)m/z calcd for(M-1；C19H10ClF3NO4)408.0245，found 408.0227.
The calculated value was 408.0245 and the measured value was 408.0227.
Preparation of 6-substituted-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
R is as described
(Synthesis of intermediate products with example 484-515)
Preparation of ethyl 6-iodo-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of 8 g (26.5 mmol) of ethyl 7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 60 ml of ethanol was added 2.8 g (11.2 mmol) of iodine followed by a solution of 9.0 g (39.5 mmol) of periodic acid in 25 ml of water. The resulting solution was heated to 70 ℃ for 5 hours. After cooling to room temperature, the volatile substances were removed, the residue was dissolved in ethyl acetate, and the organic layer was washed with saturated aqueous sodium sulfite solution and saturated brine. The resulting solution was dried over anhydrous magnesium sulfate, and volatile substances were removed. The residue was purified by chromatography on silica gel eluting with a hexane/ethyl acetate mixture to give 9.8 g (70%) of a light yellow solid:
1H NMR(CDCl3/300MHz)7.62(s，1H)，7.60(s，1H)，6.49(s，1H)，5.69(q，J＝6.9Hz，1H)，4.30(m，2H)，3.89(s，3H)，1.34(t，J＝7.2Hz，3H).MS(ESI+)428.9(M+1，100).HRMS(EI)m/z calcd for(C14H12F3IO4)427.9732，found 427.9741.
the calculated value was 427.9732 and the measured value was 427.9741.
7-methoxy-6-substituted-2- (trifluoromethyl) using Suzuki (Suzuki) coupling Preparation of yl) -2H-chromene-3-carboxylic acid
Example 484
7-methoxy-6-phenyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 7-methoxy-6-phenyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
A solution of 0.20 g (0.47 mmol) of ethyl 6-iodo-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 3 ml of anhydrous DMA was prepared and placed under nitrogen for 10 min. The solution was treated with 86 mg (0.70 mmol) of phenylboronic acid, 54 mg (0.1 eq, 0.0467 mmol) of tetrakis (triphenylphosphine) palladium (0) and 1.2 ml of degassed aqueous 2M sodium carbonate (4.8 eq, 2.24 mmol). The solution was flushed with nitrogen, capped and heated to 95 ℃ for 16 hours. After cooling to room temperature, brine was added, and the mixture was extracted 4 times with ethyl acetate. The organic layer was dried over sodium sulfate, filtered and concentrated under a stream of nitrogen. The product was pure enough to be used directly in the next step.
Step 2: preparation of 7-methoxy-6-phenyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester obtained in step 1 was hydrolyzed to the acid by dissolving the sample in 5 ml of ethanol and 1 ml of tetrahydrofuran. A solution of 165 mg of lithium hydroxide in 6 ml of water was prepared and added to the organic solution. The vessel was capped and heated to 80 ℃ for 1 hour. After cooling to room temperature, the solution was concentrated using a stream of nitrogen. The basic solution was acidified with 3N hydrochloric acid until pH 2 and extracted 4 times with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and the solvent removed. Mining The sample was purified by reverse phase chromatography to yield 107.8 mg (66%) of a light yellow solid:1H NMR(CDCl3，CD3OD/300MHz)3.77(s，3H)，5.61-5.68(m，1H)，6.56(s，1H)，7.09(s，1H)，7.24-7.39(m，5H)，7.68(s，1H)；MS(ES+)351(M+1，100)LC-MS purity 100％at 2.978min.(UVand ELSD)；HRMS(ES-)m/z calcd for(M-1；C18H12O4F3)349.0682，found 349.0663.
the calculated value was 349.0682 and the measured value was 349.0663.
7-methoxy-6-substituted-2- (trifluoromethyl) -2H-substituted carboxylic acids by parallel synthesis Preparation of chromene-3-carboxylic acid
The following examples in Table 8 were prepared as described above for the 7-methoxy-6-phenyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid moiety using a parallel synthesis setup.
Table 8: yield, purity and mass spectral data for 7-methoxy-6-substituted-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared by parallel synthesis method 1.
8 th table
Examples LC MS(ES+) % purity % yield
485 2.968 357 99 89
486 2.959 381 99 67
487 2.568 382 99 48
488 3.198 397 98 72
489 3.361 419 98 101
490 3.325 419 98 90
491 2.818 341 98 77
492 2.957 381 98 39
493 2.890 341 95 63
494 1.855 366 98 25
495 2.974 396 95 86
496 2.891 395 95 33
497 3.116 365 100 63
498 3.469 393 99 72
499 3.323 401 95 59
500 1.639 352 95 90
501 2.725 411 95 17
Examples LC MS(ES+) % purity % yield
502 2.393 413 100 49
503 2.428 381 99 43
504 1.930 402 100 20
484 2.978 351 100 66
505 3.262 385 96 59
506 3.025 385 95 48
507 3.027 369 100 73
1See general experimental section for description of recorded data. LC refers to chromatographic retention time in minutes. The% purity was determined by UV detection at 254 nm.
Example 508
6-iodo-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a solution of 3.0 g (7.0 mmol) ethyl 6-iodo-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 50 ml tetrahydrofuran was added a solution of 1.2 g (28 mmol) lithium hydroxide hydrate in 55 ml water. The resulting solution was heated to reflux for 4 hours. And removing the volatile substances. The residue was diluted with water. The resulting solution was acidified at 0 ℃ with dilute hydrochloric acid to a pH of 1.5. The product was extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated to obtain 2.5 g (81%) of a pale yellow solid:
1H NMR(CDCl3/400MHz)7.56(s，1H)，7.52(s，1H)，6.42(s，1H)，5.60(q，J＝6.8Hz，1H)，3.81(s，3H).MS(ESI+)400.9(M+1，100).MS(ES-)398.9(M-H，100).HRMS(ES-)m/z calcd for(C12H7F3IO4)M-H：398.9336，found 398.9359.
The calculated value was 398.9336 and the measured value was 398.9356.
Preparation of 6-substituted-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Example 509
6-Ethyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: wang (wang) resin 6-iodo-7-methoxy-2- (trifluoromethyl) -2H-color Preparation of alkene-3-carboxylic acid esters
To a mixture of 208 mg (0.64 mmol) cesium carbonate and 516 mg (1.28 mmol) 6-iodo-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was added 5 ml methanol. After stirring for 30 minutes, the mixture was stirredThe compound turned into a clear, light yellow solution, and bubbling was observed during this period. The solution was concentrated and the residue was dried in vacuo for 3 hours to give the cesium salt. bromo-Wang (Wang) resin (4- (bromomethyl) phenoxymethyl polystyrene, NovaBiochem model #01-64-0186, 1.20 meq/g) was washed sequentially with dichloromethane and anhydrous DMF, filtered and treated with a solution of cesium salt in 2 mL of DMF. The resulting resin syrup was heated to 60 ℃ and shaken for 2 hours. After cooling to room temperature, excess reagents were removed and the resin was washed 3 times with DMF/water (1: 1), DMF, DCM and dry DMF. By using1The resin adsorption was 0.40 mmol/g as determined by H NMR (HMDS as internal standard). The resin was used directly in the next step.
Step 2: preparation of 6-ethyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To the resin from step 1 was added 343 mg (2.48 mmol) of potassium carbonate, 78 mg (0.067 mmol) of tetrakis (triphenylphosphine) palladium (0), 2 ml of anhydrous DMF and 1.92 ml (1.0M solution in THF, 1.91 mmol) of triethylborane. The mixture was shaken at 110 ℃ for 15 hours. After cooling to room temperature, 3 ml of water were added. The reactor was shaken for 5 minutes and excess reagent and solvent were removed. The resin was washed 5 times with DMF/water (1: 1), 5 times with DMF and 3 times with DCM. The resin was treated with 95% TFA/DCM (2X 5 mL) for 45 min. The filtrate was collected and the resin was washed with DCM. The combined filtrates were concentrated and purified by silica chromatography (3: 7 ethyl acetate/hexanes) to yield 52 mg (81%) of a light yellow solid.
1H NMR(CDCl3/400MHz)7.83(s，1H)，7.00(s，1H)，6.50(s，1H)，5.66(q，J＝6.8Hz，1H)，3.86(s，3H)，2.55(q，J＝7.6Hz，2H，)，1.17(t，J＝7.6Hz，3H).MS(ESI+)303.1(M+1，100).MS(SE-)301.1(M-H，100).HRMS(ES-)m/z calcd for(C14H12F3O4)M-H：301.0682，found 301.0649.
The calculated value was 301.0682 and the measured value was 301.0649.
Example 510
6-methyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This compound was prepared using the same procedure used for the preparation of 6-ethyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. A pale yellow solid was obtained in 48 mg, yield 65% and purity 95%.
1H NMR(CDCl3/400MHz)7.80(s，1H)，7.00(s，1H)，6.49(s，1H)，5.65(q，J＝6.8Hz，1H)，3.86(s，3H)，2.13(s，3H).MS(ES+)289(M+1，100)；LC-MS(ES-)287(M-H，100)；HRMS(ES-)m/z calcd for(M-1；C13H11F3O4)287.0458，found 287.0450.
The calculated value was 287.0458 and the measured value was 287.0450.
7-methoxy-2- (trifluoromethyl) -6-quilt by Stille coupling Preparation of substituted-2H-chromene-3-carboxylic acids
Example 511
7-methoxy-2- (trifluoromethyl) -6-vinyl-2H-chromene-3-carboxylic acid
Step 1: ethyl 7-methoxy-2- (trifluoromethyl) -6-vinyl-2H-chromene-3-carboxylic acid Preparation of acid estersPrepare for
To a solution of 0.3 g (0.7 mmol) ethyl 6-iodo-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate and 16 mg (0.0139 mmol) tetrakis (triphenylphosphine) -palladium in 4.2 ml dry toluene under nitrogen was added 228 μ l (0.785 mmol) of tributyl (ethynyl) tin. The resulting solution was heated to 115 ℃ for 3 hours. To the cooled reaction mixture, 20 ml of 20% ammonium fluoride was added. After stirring for 15 minutes, the product was extracted 3 times with ethyl acetate. The combined organic extracts were washed 2 times with 20% ammonium fluoride, washed with brine, and dried over anhydrous magnesium sulfate. The crude product was purified by chromatography on silica eluting with ethyl acetate/hexane (1: 9) and used directly in the next step.
Step 2: preparation of 7-methoxy-2- (trifluoromethyl) -6-vinyl-2H-chromene-3-carboxylic acid Prepare for
The intermediate isolated in step 1 (150 mg, 0.46 mmol) was dissolved in 3 ml of tetrahydrofuran. To the resulting solution was added a solution of lithium hydroxide (2.3 mmol) in 3 ml of water. To the resulting mixture was added 3 ml of ethanol. The resulting solution was heated to 80 ℃ for 3 hours. The mixture was concentrated in vacuo and the residue was acidified with dilute hydrochloric acid to a pH of 1.0. The product was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. The solution was concentrated in vacuo to give 110 mg (52%) of the final product:
1H NMR(CDCl3/300MHz)7.80(s，1H)，7.48(s，1H)，6.98-6.88(dd，J＝17.7Hz，11.2Hz，1H)，6.66(s，1H)，5.80-5.69(m，2H)，5.20(d，J＝11.4Hz，1H)，3.90(s，3H).MS(ESI+)301.1(M+1，100).MS(ES-)299.1(M-H，100).HRMS(ES-)m/zcalcd for(C14H10F3O4)M-H：299.0526，found 299.0500.
the calculated value was 299.0526 and the measured value was 299.0500.
Example 512
6-ethynyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the general procedure for preparation of 7-methoxy-2- (trifluoromethyl) -6-vinyl-2H-chromene-3-carboxylic acid to give 93 mg (44.6%) of a light yellow solid.
1H NMR(CD3OD/300MHz)7.77(s，1H)，7.44(s，1H)，6.71(s，1H)，5.80(q，J＝6.9Hz，1H)，3.92(s，3H)，3.58(s，1H).MS(ESI+)299.1(M+1，100).
Example 513
6-acetyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the same procedure as that prepared for 7-methoxy-2- (trifluoromethyl) -6-vinyl-2H-chromene-3-carboxylic acid to give 40 mg (62.9%) of a yellow solid.
1H NMR(CDCl3/300MHz)7.62(s，1H)，7.61(s，1H)，6.49(s，1H)，5.61(q，J＝6.6Hz，1H)，3.84(s，3H)，2.46(s，3H).MS(ESI+)317.0(M+1，100).
Example 514
7-methoxy-6-prop-1-ynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the same procedure as that prepared for 7-methoxy-2- (trifluoromethyl) -6-vinyl-2H-chromene-3-carboxylic acid to give 50 mg (22.9%) of a yellow solid.
1H NMR(CDCl3/300MHz)7.69(s，1H)，7.26(s，1H)，6.53(s，1H)，5.68(q，J＝6.9Hz，1H)，3.92(s，3H)，2.11(s，3H).MS(ESI+)313.0(M+1，100).
Example 515
7-methoxy-6- (phenylethynyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the same procedure as that prepared for 7-methoxy-2- (trifluoromethyl) -6-vinyl-2H-chromene-3-carboxylic acid to give 56 mg (21.4%) of a yellow solid.
1H NMR(CDCl3/300MHz)7.73(s，1H)，7.57-7.54(m，2H)，7.39-7.29(m，4H)，6.58(s，1H)，5.73(q，J＝6.9Hz，1H)，3.96(s，3H).MS(ESI+)749.1(2M+1，100)，375.1(M+1，88).MS(ES-)373.1(M-H，100).HRMS(ES-)m/z calcd for(M-H；C20H12F3O4)：373.0682，found 373.0701.
The calculated value was 373.0682 and the measured value was 373.0701.
Preparation of 6-substituted-7-substituted oxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
R1、R2As described
(intermediates and Synthesis of example 516-526)
Example 516
7-hydroxy-6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the same procedure as for the preparation of 6-ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. Starting from ethyl 6-iodo-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate, 2.2 g (81%) of a yellow solid were obtained.
1H NMR(CD3OD/400MHz)7.69(s，1H)，7.63(s，1H)，6.45(s，1H)，5.69(q，J＝6.8Hz，1H).MS(ES-)386.9(M+H，100).
Preparation of 6-ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Example 517
6-Ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-ethyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
To a mixture of 13.2 g (30.9 mmol) ethyl 6-iodo-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate, 3.6 g (3.1 mmol) tetrakis (triphenylphosphine) palladium (0) and 12.8 g (93 mmol) potassium carbonate in 83 ml anhydrous DMF was added 43.3 ml (1.0M solution in THF, 43.3 mmol) triethylborane. The resulting mixture was heated to 110 ℃ (oil bath) and stirred for 7 hours. After cooling to room temperature, the reaction was added to 700 ml of ethyl acetate. The organic layer was then washed with brine and dried over anhydrous magnesium sulfate. After removal of the volatiles, the residue was purified by chromatography on silica eluting with ethyl acetate/hexane to yield 6.9 g (68%) of a light yellow solid:
1H NMR(CDCl3/400MHz)7.68(s，1H)，6.96(s，1H)，6.48(s，1H)，5.67(q，1H)，4.30(m，2H)，3.03(s，3H)，2.53(q，J＝7.6Hz，2H)，1.33(t，J＝6.8Hz，3H)，1.15(t，J＝7.6HZ，3H).MS(ESI+)331.1(M+1，100).HRMS(EI)m/z calcd for(C16H17F3O4)330.1079，found 330.1063.
the calculated value was 330.1079 and the measured value was 330.1063.
Step 2: ethyl-6-ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
To a solution of 6.8 g (20.6 mmol) ethyl 6-ethyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 30 ml anhydrous DMF at-78 ℃ in a dry ice/acetone bath, 206 ml (1.0M solution in DCM, 206 mmol) boron tribromide solution was added dropwise. After the addition was complete, the dry ice/acetone bath was removed. The reaction was stirred at room temperature overnight. The reaction was again cooled to-78 ℃ in a dry ice/acetone bath and treated dropwise with 250 ml of methanol. The reaction was allowed to warm to room temperature and then concentrated in vacuo. The residue was purified by chromatography on silica eluting with ethyl acetate/hexane (2: 8). The collected fractions were concentrated and used directly in step 3.
Step 3: preparation of 6-ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To the product of step 2, 80 ml of ethanol was added, followed by a solution of 3.5 g (83 mmol) of lithium hydroxide hydrate in 80 ml of water. The resulting solution was heated to reflux for 3 hours. The mixture was concentrated, the residue was treated with 50 ml of water and the resulting solution was acidified with dilute hydrochloric acid to a pH of 1.0. The product was extracted with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. After removal of volatiles, the residue was further purified by chromatography on silica eluted with 1% acetic acid in ethyl acetate/hexane (2: 8) to yield 5.6 g (94%) of a yellow-green solid:
1H NMR(CDCl3/400MHz)7.80(s，1H)，7.01(s，1H)，6.43(s，1H)，5.62(q，J＝6.8Hz，1H)，2.56(q，J＝7.6Hz，2H)，1.26(t，J＝7.6Hz，3H).MS(ESI+)289.1(M+1，100).MS(ES-)287.1(M-H，100).HRMS(ES-)m/z calcd for(M-H；C13H10F3O4)：287.0526，found 287.0504.
the calculated value was 287.0526 and the measured value was 287.0504.
Wang (Wang) resin 6-Ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
Commercially available 4- (bromomethyl) phenoxymethyl polystyrene (13 g, NovaBiovchem model #01-64-0186, 100 mesh, 1.20 meq/g) was swollen in anhydrous DMF for 1.5 hours. The resin was washed 2 times with anhydrous DMF followed by treatment with 180 ml of anhydrous DMF, 4 g (13.9 mmol) of 6-ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid and 7.6 g (23.1 mmol) cesium carbonate. The resin was stirred with a ceiling stirrer for 2 hours at room temperature. The thick slurry was filtered and the resin was treated with 4.0 grams of acid and 7.6 grams of cesium carbonate. After stirring at room temperature for 18 h, the resin was filtered off and washed 3 times with 50% DMF/water, DMF, methanol and DCM each. A small portion (about 100 mg) of the resin was cleaved by treatment with 50% TFA/DCM for 30 min. The resin was washed 2 times with DCM and collected The collected filtrate was concentrated in vacuo to obtain the liberated 6-ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid:1H NMR(CDCl3，TFA/400MHz)1.23(t，3H，J＝7.6)，2.58(q，2H，J＝7.6Hz)，5.61(q，1H，J＝6.8Hz)，6.49(s，1H)，7.07(s，1H)，7.92(s，1H)；
LC-MS purity 84% (UV), 95% (ELSD).
Preparation of 7-alkoxy-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Example 518
7-ethoxy-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
In a solid phase reaction polypropylene tube, a thick slurry of 100 mg (0.096 mmol) of Wang (Wang) resin 6-ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate in DCM was prepared and allowed to stand for 2 hours. The resin was filtered off, washed 2 times with dry THF, followed by 1 mL THF, 126 mg (0.483 mmol, 5 equivalents) of PPh328 microliters (0.483 mmol, 5 equivalents) of ethanol and 77 microliters (0.483 mmol, 5 equivalents) of DEAD treatment. The resin was then shaken overnight at room temperature under nitrogen. After 28 h, the resin was poured off and washed 4 times with each of THF, DMF, methanol and DCM. The resin (ca. 100 mg) was cleaved by treatment with 50% TFA/DCM for 30 min. The resin was washed 3 times with DCM, the collected filtrate was filtered through silica and the filtrate was concentrated in vacuo to yield 24.8 mg (26%) of a yellow solid:
1HNMR(d6-acetone/300MHz)1.20(t，3H，J＝7.5Hz)，1.46(t，3H，J＝6.9Hz)，2.60(q，2H，J＝7.8Hz)，4.16-4.20(m，2H)，5.78(q，1H，J＝7.2Hz)，6.64(s，1H)，7.24(s，1H)，7.84(s，1H)；MS(ES+)317(M+1，100)
LC-MS purity 72% (UV) at 3.163 min, 100% (ELSD). HRMS (ES-) M/z (M-1; C)15H14O4F3) The calculated value was 315.0839 and the measured value was 315.0832.
7-alkoxy-6-ethyl-2- (trifluoromethyl) -2H-chromenes by parallel synthesis Preparation of (E) -3-enoic acid
The following examples in Table 9 were prepared as described in the 7-ethoxy-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid section above using a parallel synthesis setup.
Table 9: yield, purity and mass spectral data for 7-alkoxy-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared by parallel synthesis method 1.
9 th table
Examples LC MS(ES+) % purity % yield
519 3.849 371 95 8.5
520 3.656 357 95 3.4
521 1.961 380 95 6.5
522 1.879 380 95 15
518 3.163 317 72 26
523 3.389 331 94 7.9
1See general experimental section for description of recorded data. LC refers to chromatographic retention time in minutes. The% purity was determined by UV detection at 254 nm.
Example 524
6-Ethyl-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This product was prepared according to the procedure described for the 7-ethoxy-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid moiety. The crude product was purified by chromatography on silica eluted with 1% TFA in ethyl acetate/hexane (2: 8) to give 60 mg (24.2%) of a light yellow solid:
1H NMR(CDCl3/400MHz)7.83(s，1H)，7.00(s，1H)，6.50(s，1H)，5.66(q，J＝6.8Hz，1H)，3.93-3.85(m，2H)，2.58-2.53(m，2H)，1.69(m，1H)，1.54-1.43(m，4H)，1.19-1.15(m，3H)，0.97-0.93(m，6H).MS(ES+)373.1(M+1，100).
Example 525
6-Ethyl-7- [ (4-methylbenzyl) oxy ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This product was prepared according to the procedure described for the 7-ethoxy-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid moiety. The filtrate was concentrated to give 13 mg of a pale yellow solid:
1H NMR(CDCl3/400MHz)7.83(s，1H)，7.25(s，1H)，7.14-7.09(m，4H)，6.95(s，1H)，5.70(q，J＝7.2Hz，1H)，4.00(m，2H)，2.51(q，J＝7.6Hz，2H)，2.30(s，3H)，1.19(t，J＝7.2Hz，3H).MS(ES+)393.1(M+1，100).
6-Ethyl-7- { [2- (methylthio) pyrimidin-4-yl]Oxygen } -2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acids
Example 526
6-Ethyl-7- { [2- (methylthio) pyrimidin-4-yl ] oxy } -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 6-ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
To a solution of 0.3 g (1.04 mmol) of 6-ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid in 5 ml of anhydrous dimethylformamide was added 255 mg (0.78 mmol) of cesium carbonate in one portion followed by 103. mu.l (1.7 mmol) of ethyl bromide. The reaction was stirred at room temperature overnight. The reaction was added to 100 ml of ethyl acetate. The organic layer was washed three times with brine and dried over anhydrous magnesium sulfate. After removal of the volatiles, the residue was purified by chromatography on silica eluting with ethyl acetate/hexane (3: 7) to yield 0.21 g (67%) of a light yellow solid:
1H NMR(CDCl3/400MHz)7.68(s，1H)，7.00(s，1H)，6.42(s，1H)，5.63(q，J＝7.2Hz，1H)，5.38(s，1H)，4.28(m，2H)，2.54(q，J＝7.2Hz，2H)，1.31(t，J＝7.2Hz，3H)，1.20(t，J＝7.6Hz，3H)，MS(ESI+)317(M+1，100).
Step 2: ethyl-6-ethyl-7- { [2- (methylthio) pyrimidin-4-yl]Oxygen } -2- (trifluoro benzene) Preparation of methyl) -2H-chromene-3-carboxylic acid esters
To a mixture of 172 mg (0.54 mmol) ethyl 6-ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate and 320 mg (1.95 mmol) potassium carbonate in 3 ml dry dimethylformamide was added 270 μ l (2.3 mmol) of 4-chloro-2-methylthiopyrimidine. The mixture was heated at 130 ℃ for half an hour. After cooling to room temperature, the reaction was poured into 50 ml of brine and the product was extracted with ethyl acetate. The combined organic layer was washed with brine and dried over anhydrous magnesium sulfate. After removal of the volatiles, the residue was purified by silica chromatography eluting with 1: 9 ethyl acetate/hexanes to give 102 mg (43%) of a yellow solid:
1H NMR(CDCl3/400MHz)8.35(d，5.2Hz，1H)，7.72(s，1H)，7.13(s，1H)，6.74(s，1H)，6.54(d，J＝5.6Hz，1H)，5.66(q，J＝6.8Hz，1H)，4.30(m，2H)，2.45(q，J＝7.6Hz，2H)，2.27(s，3H)，1.33(t，J＝7.2Hz，3H)，1.12(t，J＝7.6Hz，3H)；MS(ESI+)441(M+1，100).
step 3: 6-Ethyl-7- { [2- (methylthio) pyrimidin-4-yl]Oxygen } -2- (trifluoromethyl) Preparation of (E) -2H-chromene-3-carboxylic acid
To a solution of 100 mg (0.23 mmol) of the intermediate isolated in step 2 in 1.5 ml of tetrahydrofuran, a solution of 48 mg (1.2 mmol) of lithium hydroxide in 2.5 ml of water is added, followed by 2.5 ml of ethanol. The reaction was then heated to reflux for 1 hour. After cooling to room temperature, the volatiles were removed, the residue was diluted with water and then acidified to pH 1.0 with dilute hydrochloric acid at 0 ℃. The product was extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 50 mg (53%) of a yellow solid;
1H NMR(CDCl3/400MHz)8.40(d，J＝6Hz，1H)，7.85(s，1H)，7.17(s，1H)，6.78(s，1H，6.58(d，J＝5.6Hz，1H)，5.66(q，J＝7.2Hz，1H)，2.48(q，J＝7.2Hz，2H)，2.29(s，3H)，1.14(t，J＝7.6Hz，3H)；MS(ES+)413(M+1，100)，HRMS(EI)m/z calcd for(C18H16F3N2O4S)413.0777，found 413.0768.
The calculated value was 413.0777 and the measured value was 413.0768.
Preparation of 8-iodo-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Example 527
8-iodo-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 2-hydroxy-3-iodo-4-methoxybenzaldehyde
To a solution of 4.0 g (26.3 mmol) of 2-hydroxy-4-methoxybenzaldehyde in 30 ml of ethanol, 1.87 g (7.4 mmol) of iodine was added, followed by a solution of 6 g (26.3 mmol) of periodic acid in 10 ml of water. The resulting dark yellow solution was heated to 68 ℃ for 2 hours. After cooling to room temperature, the reaction was added to 300 ml of ethyl acetate. The resulting organic solution was washed with saturated aqueous sodium sulfite solution, washed with brine and dried over anhydrous magnesium sulfate. After removal of the volatiles, the crude product was purified by silica gel chromatography to yield 1.8 g (49%) of a light yellow solid:
1H NMR(CDCl3/400MHz，)12.18(s，1H)，9.63(s，1H)，7.53(d，J＝8.4Hz，1H)，6.56(d，J＝8.4Hz，1H)，3.99(s，3H).13C NMR(CDCl3/400MHz)194.2，165.3，163.0，136.3，116.1，103.6，57.2.MS(ESI+)278.9(M+1，100).
step 2: ethyl 8-iodo-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
To a mixture of 1.5 g (5.4 mmol) of 2-hydroxy-3-iodo-4-methoxybenzaldehyde, 3.1 ml (20.6 mmol) of ethyltrifluoromethylcrotonate and 4.2 g (12.9 mmol) of cesium carbonate was added 8 ml of anhydrous N, N-dimethylformamide. The mixture was heated to 90 ℃ overnight. After cooling to room temperature, 150 ml of ethyl acetate were added to the reaction. The organic solution was filtered, washed with brine, and dried over anhydrous magnesium sulfate. After removal of the volatiles, the residue was purified by chromatography on silica eluting with ethyl acetate/hexane (2: 8) to yield 0.3 g (14%) of a light yellow solid:
1H NMR(CDCl3/400MHz)7.65(s，1H)，7.17(d，J＝8.4Hz，1H)，6.50(d，J＝8.4Hz，1H)，5.80(q，J＝6.8Hz，1H)，4.30(m，2H)，3.92(s，3H)，1.33(t，J＝7.6Hz，3H).MS(ESI+)429.0(M+1，100).HRMS(EI+)m/z calcd for(C14H12F3IO4)427.9732，found 427.9715
The calculated value was 427.9732 and the measured value was 427.9715.
Step 3: preparation of 8-iodo-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a solution of 0.4 g (0.93 mmol) of ethyl 8-iodo-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 8 ml of tetrahydrofuran was added 155 mg (3.7 mmol) of lithium hydroxide hydrate (LiOH. H)2O) solution in 15 ml of water. The resulting solution was heated to reflux for 1 hour. After cooling to room temperature, the volatiles were removed and the residue was acidified to pH 1.5 with dilute hydrochloric acid at 0 ℃. The product was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to afford 0.30 g (81%) of a light yellow solid:
1H NMR(CDCl3/400MHz)7.67(s，1H)，7.18(d，J＝8.4Hz，1H)，6.51(d，J＝8.4Hz，1H)，5.78(q，J＝6.8Hz，1H)，3.92(s，3H).MS(ESI+)400.9(M+1，100).MS(ES-)398.9(M-H，100).HRMS(ES-)m/z calcd for(M-H；C12H7F3IO4)：398.9336，found 398.9368.
the calculated value was 398.9336 and the measured value was 398.9368.
6-ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-Chlorination and derivatization of carboxylic acids By using
Example 528-
Example 528
5-chloro-6-ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a mixture of 100 mg (0.35 mmol) of 6-ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid in 5 ml of anhydrous dichloromethane was added dropwise 0.42 ml (1.0M solution in dichloromethane, 0.42 mmol) of sulfuryl chloride. The resulting solution was stirred at room temperature for 1 hour. The sample was concentrated and the residue was purified on a silica gel column eluting with ethyl acetate/hexane/acetic acid to give 60 mg (52%) of a light yellow solid:
1H NMR(CDCl3/400MHz)7.71(s，1H)，6.71(s，1H)，5.99(s，1H)，5.65(q，J＝6.0Hz，1H)，2.38(m，1H)，2.06(m，1H)，0.84(t，J＝7.6Hz，3H)；MS(ESI+)323.0(M+1，100)；LCMS(ES-)321(M-H，100)；HRMS(ES-)m/z calcd for(M-1；C13H9ClF3O4)321.0136，found 321.0118.
The calculated value was 321.0136 and the measured value was 321.0118.
Example 529
5, 8-dichloro-6-ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a suspension of 1.5 g (5.2 mmol) of 6-ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid in 45 ml of anhydrous dichloromethane was added dropwise a 1.0M sulfuryl chloride solution (22.75 mmol, 4.4 eq). The resulting suspension was stirred at room temperature for 12 hours and the reaction turned into a clear yellow solution. The sample was concentrated, and the residue was dissolved in ethyl acetate, washed with brine and dried over anhydrous magnesium sulfate. Silica chromatography using ethyl acetate/hexane/ethanol as eluent gave 0.12 g (21.5%) of a white solid:
1HNMR(CDCl3/400MHz)7.72(s，1H)，6.68(s，1H)，5.79(q，J＝5.6Hz，1H)，2.42(m，1H)，2.11(m，1H)，0.85(t，J＝7.6Hz，3H).MS(ESI+)357.0(M+1，100).MS(ES-)355.0(M-H，100).HRMS(ES-)m/z calcd for(C13H8Cl2F3O4)M-H：354.9746，found：354.9724.
the calculated value was 354.9746 and the measured value was 354.9724.
Example 530
8-chloro-6-ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a mixture of 1.0 g (3.4 mmol) of 6-ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid in dry dichloromethane (30 ml) was added dropwise 4.2 ml (1.0M solution in DCM, 22 mmol) of sulfuryl chloride. The resulting mixture was stirred at room temperature for 24 hours, the sample was concentrated, and the residue was dissolved in 30 ml of acetic acid, followed by addition of 0.5 g of particulate zinc. The mixture was stirred at room temperature for 3 hours, filtered and the filtrate was evaporated. The residue was purified by chromatography to give 0.20 g (18%) of a white solid:
1H NMR(CDCl3/400MHz)7.79(s，1H)，7.26(s，1H)，5.77(q，J＝6.8Hz，1H)，2.63(q，J＝7.6Hz，2H)，1.21(t，J＝7.6Hz，3H).MS(ESI+)323.0(M+1，100).
Example 531
8-chloro-6-ethyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: methyl 8-chloro-6-ethyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3- Preparation of carboxylic acid esters
To a solution of 0.16 g (0.5 mmol) of 8-chloro-6-ethyl-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid and 49 μ l (2.4 mmol) of methanol in 3 ml of anhydrous tetrahydrofuran, 0.31 g (1.2 mmol) of triphenylphosphine and 474 μ l (1.5 mmol) of diethyl azadicarboxylate were added. The resulting yellow solution was stirred at room temperature for 1 hour. The volatiles were removed and the residue was purified on a silica gel column eluting with ethyl acetate/hexanes to give 162 mg (92.4%) of a white solid:
1HNMR(CDCl3/300MHz)7.66(s，1H)，6.96(s，1H)，5.76(q，J＝6.6Hz，1H)，3.86(s，3H)，3.84(s，3H)，2.60(q，J＝7.5Hz，2H)，1.19(t，J＝7.8Hz，3H).MS(ES+)351.0(M+1，100).
step 2: 8-chloro-6-ethyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of
To a solution of 0.14 g (0.4 mmol) of methyl 8-chloro-6-ethyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 5 ml of tetrahydrofuran was added a solution of 82 mg (1.95 mmol) of lithium hydroxide in 8 ml of water, followed by 3 ml of ethanol. The resulting solution was heated to reflux for 2 hours. The mixture was concentrated in vacuo. The residue was diluted with water and acidified with dilute hydrochloric acid to pH 1.0. The product was extracted with ethyl acetate, and the combined organic extracts were dried over anhydrous magnesium sulfate. Concentration in vacuo afforded 86 mg (64%) of the product as a white solid.
1H NMR(CDCl3/400MHz)7.80(s，1H)，7.01(s，1H)，5.77(q，J＝6.8Hz，1H)，3.89(s，3H)，2.62(q，J＝7.6Hz，2H)，1.21(t，J＝7.2Hz，3H).MS(ESI+)337.0(M+1，100).MS(ES-)335.0(M-H，100)，HRMS(ES-)m/z calcd for(C14H11ClF3O4)M-H：335.0292，found 335.0297.
The calculated value was 335.0292 and the measured value was 335.0297.
Preparation of 6, 8-dichloro-7-substituted oxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
R is as described
(intermediate products reacted with example 532-535)
Preparation of ethyl 5, 7-dichloro-6-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Step 1: preparation of ethyl 6-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
A mixture of 10 g (72.5 mmol) of 2, 4-hydroxybenzaldehyde, 15.3 ml (101.4 mmol) of ethyl 4-trifluoromethylcrotonate and 20 g (145 mmol) of potassium carbonate in 25 ml of anhydrous dimethylformamide is heated to 90 ℃ for 3 hours. After cooling to room temperature, the reaction was added to 500 ml of ethyl acetate. The organic layer was washed three times with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. Chromatography on silica eluting with ethyl acetate/hexane (3: 7) gave 19.0 g (98%) of a yellow solid:
1H NMR(CDCl3/400MHz)7.63(s，1H)，6.85(d，J＝8.8Hz，1H)，6.79(dd，J＝8.8Hz，2.8Hz，1H)，6.70(d，J＝2.8Hz，1H)，5.63(q，J＝6.8Hz，1H)，4.31(m，2H)，1.34(t，J＝7.2Hz，3H).MS(ESI+)289.1(M+1，100).
step 2: ethyl 5, 7-dichloro-6-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of esters
To a solution of 1.0 g (3.5 mmol) of ethyl 6-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 10 ml of anhydrous dichloromethane was added a solution of 1.5 ml (30 mmol) of iodine chloride in 5 ml of anhydrous dichloromethane. The resulting brown solution was stirred at room temperature for one hour. The reaction was added to 50 ml of ethyl acetate. The organic layer was washed three times with saturated sodium sulfite solution, three times with brine, and dried over anhydrous magnesium sulfate. Concentration in vacuo afforded 0.8 g (64%) of a yellow solid:
1H NMR(CDC3/300MHz)8.00(s，1H)，7.01(s，1H)，5.81(s，1H)，5.70(q，J＝6.6Hz，1H)，4.38(m，2H)，1.40(t，J＝7.2Hz，3H)；MS(ESI+)357.0(M+1，100).
Preparation of 5, 7-dichloro-6-alkoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Example 532
5, 7-dichloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: ethyl 5, 7-dichloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Preparation of acid esters
To a solution of 0.10 g (0.28 mmol) of ethyl 5, 7-dichloro-6-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 2 ml of anhydrous DMF was added 77 mg (0.56 mmol) of potassium carbonate and 23 μ l (0.31 mmol) of ethyl bromide.
The resulting solution was stirred at room temperature for 18 hours. The solution was poured into ethyl acetate and washed three times with brine. The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude ester was used directly in the next step without further purification.
Step 2: preparation of 5, 7-dichloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid Prepare for
The product of step 1 was dissolved in 5 ml of THF and 1 ml of ethanol. To this organic solution, a solution of 61 mg of lithium hydroxide monohydrate in 6 ml of water was added. The vessel was capped and heated to 80 ℃ for 1 hour. After cooling to room temperature, the sample was concentrated using a nitrogen stream. The basic solution was then acidified to pH 2 with 3N hydrochloric acid and extracted four times with ethyl acetate. The organic layers were combined, dried over sodium sulfate, filtered and the solvent removed. The sample was purified by reverse phase chromatography to give 72.6 mg (70%) of a brown solid:
1H NMR(CDCl3，CD3OD/300MHz)1.46(t，3H，J＝6.6Hz)，4.08(q，2H，J＝7.2Hz)，5.71(q，2H，J＝6.9Hz)，7.01(s，1H)，8.08(s，1H)；MS(ES+)357(M+1，100)，359(M+3，68)；
Purity 100% in 3.166 minutes (uv vs ELSD); HRMS (ES-) M/z (M-1; C)13H8O4Cl2F3) The calculated value was 354.9746 and the measured value was 354.9744.
Example 533
5, 7-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This compound was prepared using the method developed for 5, 7-dichloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. After removal of the volatiles, the residue was purified by reverse phase HPLC to obtain 60 mg (41%) of a white solid:
1HNMR(CDCl3/300MHz)8.19(s，1H)，7.06(s，1H)，5.71(q，J＝6.9Hz，1H)，3.92(s，3H).MS(ESI+)343.0.0(M+1，100).
example 534
6- (allyloxy) -5, 7-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This compound was prepared using the method developed for 5, 7-dichloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. After removal of the volatiles, the residue was purified by reverse phase HPLC to give 79.6 mg (73%) of a cream solid:
1H NMR(CDCl3，CD3OD/300MHz)4.46(d，2H，J＝6Hz)，5.24(dd，1H，J＝0.9Hz，10.2Hz)，5.37(dd，1H，J＝1.5Hz，17.1Hz)，5.63(q，1H，J＝6.6Hz)，6.02-6.07(m，1H)，6.94(s，1H)，7.97(s，1H)；MS(ES+)369(M+1，100)，371(M+3，64)；
LC-MS purity 95% over 3.212 min (purple)Outer line, 100% (ELSD); HRMS (ES-) M/z (M-1; C)14H8O4Cl2F3) The calculated value was 366.9746 and the measured value was 366.9753.
Example 535
5, 7-dichloro-6-isopropoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This compound was prepared using the method developed for 5, 7-dichloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. After removal of the volatiles, the residue was purified by reverse phase HPLC to give 67.2 mg (70%) of a cream solid:
1H NMR(CDCl3，CD3OD/300MHz)1.37(m，6H)，4.55(m，1H)，5.69(m，1H)，7.00(s，1H)，8.05(s，1H)；MS(ES+)371(M+1，100)，373(M+3，65)；
Purity 100% at 3.321 min (UV vs ELSD); HRMS (ES-) M/z (M-1; C)14H10O4Cl2F3) The calculated value was 368.9903 and the measured value was 368.9926.
Preparation of 6-chloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Example 536
6-chloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 1-chloro-2-fluoro (methoxymethoxy) benzene
A solution of 51.3 g (350 mmol) of 3-fluoro-4-chlorophenol in 700 ml of dichloromethane was prepared under nitrogen and cooled to 5 ℃. The stirred mixture was treated with 35.3 ml (37.5 g, 465 mmol) of chloromethyl methyl ether. The reactor was equipped with a thermocouple and an addition funnel. To the stirred mixture, 61 ml of DIEA (45.2 g, 350 mmol) were added dropwise, whereby the temperature did not exceed 10 ℃. After 30 minutes, an additional 30 ml of DIEA was added dropwise. After a total of 1 hour, an additional 30 ml DIEA was added. The mixture was allowed to stand overnight. The solution was washed with 900 ml of 1N hydrochloric acid and the aqueous layer was extracted three times with diethyl ether. The combined extracts were dried over magnesium sulfate, concentrated and distilled carefully at 78-81 ℃ under a vacuum of 9 torr to yield 62.5 g (93.7%) of a clear colorless liquid:
1H NMR(CDCl3/400MHz)3.46(s，3H)，5.13(s，2H)，6.77(ddd，J＝1H，8.9Hz，2.8Hz，1.3Hz)，6.87(dd，1H，J＝10.7Hz，2.8Hz)，7.26(t，1H，J＝8.7Hz)；19F NMR(CDCl3/400MHz)-113.5(t，1F，J＝9.7Hz)；13C NMR(CDCl3/100MHz)56.1，94.6，105.2(d，J＝24.2Hz)，112.8(d，J＝3.4Hz)，130.5(d，J＝1.1Hz)，156.9(d，J＝9.7Hz)，158.3(d，J＝248.1Hz)；MS(EI+)190(M+，12)，129(8)，117(8)，45(100)；HRMS(EI)m/z calcd for(C8H8O2ClF)190.0197，found190.0175.
The calculated value was 190.0197 and the measured value was 190.0175.
Step 2: preparation of 3-chloro-2-fluoro-6- (methoxymethoxy) benzaldehyde
A solution of 4.39 ml (3.38 g, 29.1 mmol) of TMEDA in 40 ml of THF is cooled to-78 ℃ before treatment with 22.4 ml (29.1 mmol) of 1.3M sec-butyllithium in cyclohexane. After stirring the mixture for 15 minutes, the solution was treated with 3.7 g (19.4 mmol) of 1-chloro-2-fluoro (methoxymethoxy) benzene and stirred for 30 minutes. The reaction mixture was then treated with 2.25 ml (29.1 mmol) of DMF, the ice bath was removed, and the reaction was stirred for 30 min. The reaction was treated sequentially with 4.0 ml of acetic acid and 100 ml of water. The mixture was extracted three times with diethyl ether, and the extracts after the mixture were washed with brine, dried and concentrated to give 4.26 g (100%) of a clear yellow oil which solidified upon standing: the melting point is 44-49 ℃;
1H NMR(CDCl3/400MHz)3.52(s，3H)，5.29(s，2H)，7.01(dd，1H，J＝9.0Hz，1.5Hz)，7.51(dd，J＝1H，9.0Hz，8.0Hz)，10.42(d，1H，J＝1.3Hz)；19F NMR(CDCl3/400MHz)-116.5(d，1F，J＝8.7Hz)；13C NMR(CDCl3/100MHz)56.7，95.2，111.5(d，J＝4.5Hz)，114.7(d，J＝17.7Hz)，115.8(d，J＝9.0Hz)，135.7(d，J＝2.3Hz)，157.9(d，J＝264.6Hz)，158.2(d，J＝4.4Hz)，186.3(d，J＝2.1Hz)；MS(ESI+)187(M-OCH3，100).
step 3: preparation of 3-chloro-2-fluoro-6-hydroxybenzaldehyde
To 3.25 g (14.9 mmol) of 3-chloro-2-fluoro-6- (methoxymethoxy) benzaldehyde were added 30 ml of THF, 39 ml of 2-propanol, 15 ml of water and 15 ml of concentrated hydrochloric acid. The mixture was stirred overnight and concentrated in vacuo to give a thick aqueous slurry. The thick slurry was extracted three times with diethyl ether, washed with brine, and concentrated to give 2.56 g of a yellow solid. The sample was dissolved in 40 ml of methanol, treated with 40 ml of water, and allowed to cool. Filtration and air drying gave 1.22 g (35.8%) of a yellow crystalline solid: the melting point is 78-79 ℃;
1H NMR(CDCl3/400MHz)6.76(d，1H，J＝9.1Hz)，7.51(t，1H，J＝8.7Hz)，10.27(s，1H)，11.39(s，1H)；19F NMR(CDCl3/400MHz)-123.5(d，1F，J＝6.8Hz)；13C NMR(CDCl3/100MHz)110.6(d，J＝17.0Hz)，111.1(d，J＝11.1Hz)，114.6(d，J＝4.4Hz)，138.4(d，J＝2.7Hz)，159.6(d，J＝260.2Hz)，161.3(d，J＝2.9Hz)，191.7(d，J＝9.0Hz)；MS(EI)174(M，100)，176(M+2，30).Anal.Calc’d for C7H4ClFO2：C，48.16；H，2.31.Found：C，48.34；H，2.45.
The calculation analysis shows that: carbon 48.16, hydrogen 2.31; and (3) measuring: carbon 48.34, hydrogen 2.45.
Step 4: preparation of ethyl 6-chloro-5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate Prepare for
To 1.1 g (6.7 mmol) of 3-chloro-2-fluoro-6-hydroxybenzaldehyde in 2 ml of DMF was added 1.0 g (7.2 mmol) of potassium carbonate and 3. ANG. molecular sieves. The stirred mixture was heated to 70 ℃ and treated with 1.5 ml (1.69 g, 10.0 mmol) of ethyl 4, 4, 4-trifluorocrotonate. After 1 hour, the mixture was treated with an additional 1.5 ml of ethyl 4, 4, 4-trifluorocrotonate and allowed to react overnight. To the cooled mixture was added 1N hydrochloric acid, the mixture was extracted three times with dichloromethane, and the mixed organic fractions were dried and concentrated. The resulting oil was dissolved in ether, washed three times with water, and concentrated to give an oil. Chromatography (silica, eluting with 5-10% ethyl acetate/hexanes) gave 0.76 g (35%) of a clear yellow oil:
1H NMR(CDCl3/400MHz)1.37(t，3H，J＝7.2Hz)，4.34(m，2H)，5.72(q，1H，J＝6.8Hz)，6.77(d，1H，J＝8.8Hz)，7.32(t，1H，J＝8.5Hz)，7.92(s，1H)；19F NMR(CDCl3/400MHz)-78.7(d，3F，J＝6.8Hz)，-119.6(d，1F，J＝7.7Hz)；13C NMR(CDCl3/100MHz)14.2，61.9，70.8(q，J＝33.4Hz)，110.0(d，J＝18.1Hz)，112.6(d，J＝4.0Hz)，114.4(d，J＝17.3Hz)，118.2(J＝2.3Hz)，123.2(q，J＝287.3Hz)，129.2(d，J＝4.6Hz)，133.2(d，J＝1.3Hz)，152.2(d，J＝4.4Hz)，154.9(d，J＝256.4Hz)，163.3；MS(ESI+)325(M+1，100)；MS(EI)324(M+，21)，255(100)，227(83)；HRMS(EI)m/z calcd for(C13H9O3ClF4)324.0176，found 324.0171.
the calculated value was 324.0176 and the measured value was 324.0171.
Step 5: ethyl 6-chloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate Preparation of
To 162.3 g (0.5 mmol) of ethyl 6-chloro-5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate, 75 mg (0.80 mmol) of phenol and 120 mg (0.87 mmol) of potassium carbonate in 1.5 ml of DMF were added. The mixture was heated to 110 ℃ and stirred overnight. After cooling, the mixture was diluted with water and extracted three times with diethyl ether. Washing the mixed organic liquid with water, drying and concentrating to obtain crude oil. Preparative reverse phase chromatography (C18, 4.0 cm × 10 cm column, gradient 50% -100% acetonitrile) was performed to give 50 mg (25.1%) of a clear colorless oil:
1H NMR(CDCl3/400MHz)1.28(t，3H，J＝7.1Hz)，4.26(m，2H)，5.70(q，1H，J＝6.7Hz)，6.82(d，2H，J＝7.9Hz)，6.87(d，1H，J＝8.7Hz)，7.06(t，1H，J＝7.4Hz)，7.31(t，2H，J＝8.1Hz)，7.38(d，1H，J＝8.9Hz)，7.79(s，1H)；19F NMR(CDCl3/400MHz)-78.7(d，3F，6.8Hz)；MS(ESI+)399(M+1，100)；MS(EI)398(M+，50)，329(100)，283(79)，231(32)；HRMS(EI)m/z calcd for(C19H14O4ClF3)398.0533，found 398.0538.
The calculated value was 398.0533 and the measured value was 398.0538.
Step 6: preparation of 6-chloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To the sample prepared in step 5, 3.5 ml of THF, 1 ml of methanol and 0.5 ml of a solution of 100 mg of lithium hydroxide monohydrate in water were added. The mixture was stirred and heated to 100 ℃ for 30 minutes. After stirring overnight at room temperature, the mixture was diluted with 1N hydrochloric acid and extracted three times with diethyl ether. The combined extracts were dried and concentrated in vacuo to yield 49.5 mg (quantitative) of a yellow solid:
1H NMR(d6-acetone/400MHz)5.89(q，1H，J＝7.0Hz)，6.88(d，2H，J＝7.8Hz)，7.06-7.12(m，2H)，7.37(t，2H，J＝8.1Hz)，7.61(d，1H，J＝9.0Hz)，7.77(s，1H)；19F NMR(d6-acetone/400MHz)-79.3(d，3F，J＝6.7Hz)；13C NMR(d6-acetone/100MHz)71.2(q，J＝33.0Hz)，115.1，115.8，116.6(q，J＝1.1Hz)，119.3(q，J＝0.8Hz)，122.0，123.8，124.5(q，J＝286.9Hz)，130.9，131.2，134.7，148.7，153.6，158.8，164.4；MS(ES+)283(M+1，100)；MS(ES-)369(M-H，100)；HRMS(ES-)m/z calcd for(C17H9O4ClF3)369.0136，found 369.0159.
the calculated value was 369.0136 and the measured value was 369.0159.
General procedure for sodium salt formation
Example 537
8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
A solution of 56.5 mg (0.187 mmol) of 8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid in 1.5 ml of ethanol was treated with 1.85 ml of 0.1008N sodium hydroxide. The resulting mixture was freeze-dried to obtain 59 mg (quantified) of an off-white solid:
1H NMR(CD3OD/400MHz)5.97(q，1H，J＝7.0Hz)，7.31(d，1H，J＝1.7Hz)，7.39(s，1H)，7.41(d，1H，J＝1.9Hz)，
exchange of acetylenic protons under basic conditions; MS (ES +)303(M +1, 100).
Example 538
8-but-1-ynyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
A solution of 75.8 mg (0.229 mmol) of 8-but-1-ynyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid in 2.0 ml of ethanol was treated with 2.274 ml of 0.1008N sodium hydroxide. The resulting mixture was freeze-dried to obtain a yellow solid in quantitative yield
1H NMR(CD3OD/400MHz)1.22(t，3H，J＝7.6Hz)，2.44(q，2H，J＝7.6Hz)，5.88(q，1H J＝7.2Hz)，7.17-7.19(m，2H)，7.32(s，1H).
Example 539
6-chloro-8- [ (2-fluorophenyl) ethynyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
A solution of 84.3 mg (0.213 mmol) of 6-chloro-8- [ (2-fluorophenyl) ethynyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid in 2.0 ml of ethanol was treated with 2.108 ml of 0.1008N sodium hydroxide. The resulting mixture was freeze-dried to obtain a yellow solid in quantitative yield:
1H NMR(CD3OD/400MHz)5.97(q，1H，J＝7.2Hz)，7.14-7.20(m，2H)，7.28-7.30(m，1H)，7.36-7.42(m，3H)，7.51-7.54(m，1H).
example 540
6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
A solution of 52.0 mg (0.135 mmol) of 6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid in 2.0 ml ethanol was treated with 1.334 ml of 0.1008N sodium hydroxide. The resulting mixture was freeze-dried to obtain a yellow solid in physicochemical yield.
1H NMR(CD3OD/400MHz)2.29(d，3H，J＝1.6Hz)，5.84(q，1H，J＝7.2Hz)，7.17-7.20(m，2H)，7.24-7.29(m，3H)，7.40(s，1H).
Example 541
6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
A solution of 51.9 mg (0.136 mmol) of 6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid in 2.0 ml of ethanol was treated with 1.345 ml of 0.1008N sodium hydroxide. The resulting mixture was freeze-dried to obtain a yellow solid in quantitative yield:
1H NMR(CD3OD/400MHz)1.25(t，3H，J＝7.6Hz)，2.67(q，2H，J＝7.6Hz)，5.82(q，1H，J＝7.2Hz)，7.21-7.25(m，4H)，7.38-7.40(m，3H).
Example 542
6-chloro-8- (4-chloro-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
A solution of 31.5 mg (0.078 mmol) of 6-chloro-8- (4-chloro-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid in 2.0 ml ethanol was treated with 0.775 ml of 0.1008N sodium hydroxide. The resulting mixture was freeze-dried to obtain a yellow solid in quantitative yield:
1H NMR(CD3OD/400MHz)2.39(s，3H)，5.77(q，1H，J＝6.8Hz)，7.25-7.28(m，1H)，7.34(d，1H，J＝2.4Hz)，7.37-7.40(m，3H)，7.79(s，1H).
example 543
6-chloro-8- (4-methoxy-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
A solution of 46.6 mg (0.117 mmol) of 6-chloro-8- (4-methoxy-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid in 2.0 ml of ethanol was treated with 1.160 ml of 0.1008N sodium hydroxide. The resulting mixture was freeze-dried to obtain a yellow solid in quantitative yield:
1H NMR(CD3OD/400MHz)2.20(s，3H)，3.85(s，3H)，5.77(q，1H，J＝6.8Hz)，6.93(d，1H，J＝8.0Hz)，7.26-7.32(m，4H)，7.78(s，1H).
example 544
6-chloro-7- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
A solution of 47.6 mg (0.119 mmol) of 6-chloro-7- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid in 1.5 ml of acetic acid was treated with 1.18 ml of 0.1008N sodium hydroxide. The resulting mixture was freeze-dried to obtain 51 mg (quantified) of an off-white solid:
1H NMR(CD3OD/400MHz)1.25(t，3H，J＝7.7Hz)，2.68(q，2H，J＝7.7Hz)，5.79(q，1H，J＝7.2Hz)，6.92(d，2H，J＝8.6Hz)，7.25(d，2H，J＝8.6Hz)，7.37(m，2H)；MS(ES+)399(M+1，100).
example 545
6-chloro-7- (5-fluoro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Following the general procedure for sodium salt formation, an off-white solid was prepared:
1H NMR(CD3OD/300MHz)2.22(s，3H)，5.85(q，1H，J＝7.2Hz)，6.38(s，1H)，6.64(dd，1H)，6.92(m，1H)，7.34(m，1H)，7.42(s，1H)，7.45(s，1H).
example 546
6-chloro-7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Following the general procedure used in example 545, an off-white solid was prepared:
1H NMR(CD3OD/300MHz)2.15(s，3H)，2.34(s，3H)，5.81(q，1H，J＝7.2Hz)，6.18(s，1H)，6.79(s，1H)，7.02(d，1H，J＝7.6Hz)，7.22(d，1H，J＝7.8Hz)，7.40(s，2H).
example 547
6-chloro-7- (4-ethoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Following the general procedure used in example 545, an off-white solid was prepared:
1H NMR(CD3OD/300MHz)1.43(t，3H，J＝6.9Hz)，4.08(q，2H，J＝7.0Hz)，5.81(q，1H，J＝7.1Hz)，6.32(q，1H)，7.00(s，4H)，7.39(s，1H)，7.40(s，1H).
example 548
6-chloro-7- (2-chloro-4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
According to the general procedure for sodium salt formation, an off-white solid was obtained.
LC-MS(ES-)431(M-H，100).HRMS(ES-)m/z calcd for(M-1；C19H12Cl2F3O4)431.0059，found 431.0025.
The calculated value was 431.0059 and the measured value was 431.0025.
Example 549
6-chloro-7- (2-fluoro-4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
According to the general procedure for sodium salt formation, a milky white solid was prepared:
1H NMR(CD3OD/300MHz)1.45(t，3H，J＝5.7Hz)，2.90(q，2H，J＝5.4Hz)，5.90(q，1H，J＝4.8Hz)，6.46(s，1H)，7.29(d，2H，J＝3.9Hz)，7.36(d，1H，J＝9Hz)，7.70(s，1H)，7.94(s，1H)；MS(ES+)417(M+1，100)；
LC-MS purity 99% in 3.515 min (UV, 100% (ELSD).
Example 550
Sodium 6-chloro-7- (4-ethynyl-2, 5-difluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
According to the general procedure for sodium salt formation, a pale yellow solid was prepared:
1H NMR(CD3OD/300MHz)7.49-7.44(m，3H)，6.85(dd，J＝6.6Hz，9.5Hz，1H)，6.68(s，1H)，5.89(q，J＝7.2Hz，1H)，
the acetylenic protons are exchanged under basic conditions.
Example 551
6-chloro-7- (4-cyano-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
According to the general procedure for sodium salt formation, a pale yellow solid was prepared:
1H NMR(CD3OD/300MHz)7.71(s，1H)，7.59-7.56(dd，J＝2.1Hz，8.4Hz，1H)，7.49(s，1H)，7.45(s，1H)，6.83(d，J＝8.4Hz，1H)，6.68(s，1H)，5.99(d，J＝7.2Hz，1H)，2.39(s，3H).
example 552
6-Ethyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
To a solution of 0.785 g (2.51 mmol) of 6-ethyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid in 20 ml of ethanol was added 24.9 ml of 0.1008N aqueous sodium hydroxide solution. The resulting solution was stirred at room temperature for half an hour. The volatile material was removed. The residue was dissolved in 20 ml of water. The resulting solution was frozen and freeze-dried to obtain a pale yellow solid:
LC-MS(ES-)301(M-H，100).HRMS(ES-)m/z calcd for(M-1；C14H12F3O4)301.0790，found 301.0810.
the calculated value was 301.0790 and the measured value was 301.0810.
Example 553
6-chloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
A solution of 110 mg (0.297 mmol) of sodium 6-chloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 3.0 ml ethanol was treated with 2.94 ml of 0.1008N sodium hydroxide. The resulting mixture was freeze-dried to yield 116 mg (quantified) of an off-white solid:
1H NMR(CD3OD/400MHz)5.90(q，1H，J＝7.2Hz)，6.81(d，2H，J＝8.3Hz)，6.93(d，1H，J＝8.9Hz)7.05(t，1H，J＝7.5Hz)，7.32(t，2H，J＝8.6Hz)，7.42(d，1H，J＝8.9H)，7.56(s，1H)；MS(ES+)371(M+1，100).
example 601a
(2R)6, 8-dichloro-7- (cyclohexylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The racemic mixture of the compound prepared in example 1f was resolved by chiral separation using a Chiralpak AD column eluting with iPA/heptane/TFA ═ 5/95/0.1 and detected at 254nm to give the R-enantiomer as peak 1 with a retention time of 3.29 min:
ESHRMS m/z423.0344(M-H，C18H16O4F3Cl2，Calc’d 423.0372).1H NMR(acetone-d6/400MHz)7.89(s，1H)，7.61(s，1H)，5.98(q，1H，J＝7.0Hz)，3.88(d，2H，J＝5.6Hz)，1.77(m，3H)，1.68(m，3H)，1.29(m，2H)，1.22(m，3H).19F NMR(d6-benzene；6eq of(R)-(+)-1-(1-naphthyl)ethylamine/400MHz)-78.14(d，3F，J＝7.8Hz，S-enantiomer)，-78.26(d，3F，J＝7.5Hz，R-enantiomer).
example 601b
(2S)6, 8-dichloro-7- (cyclohexylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The racemic mixture of the compound prepared in example 1f was resolved by chiral separation using a Chiralpak AD column eluting with iPA/heptane/TFA ═ 5/95/0.1 and detected at 254nm to give the S-enantiomer as peak 2 with a retention time of 6.56 min:
ESHRMS m/z 423.0392(M-H，C18H16O4F3Cl2，Calc’d 423.0372).1H NMR(acetone-d6/400MHz)7.89(s，1H)，7.61(s，1H)，5.98(q，1H，J＝7.0Hz)，3.88(d，2H，J＝5.6Hz)，1.77(m，3H)，1.68(m，3H)，1.29(m，2H)，1.22(m，3H).19F NMR(d6-benzene；6 eq of(R)-(+)-1-(1-naphthyl)ethylamine/400MHz)-78.14(d，3F，J＝7.8Hz，S-enantiomer)，-78.26(d，3F，J＝7.5Hz，R-enantiomer).
example 601c
(2R)6, 8-dichloro-7-isobutoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid the racemic mixture of the compound prepared in example 1e was resolved by chiral separation using a Chiralpak AD column eluting with iPA/heptane/TFA ═ 10/90/0.1 and detected at 254nm to give the R-enantiomer as peak 1 with a retention time of 3.99 min:
ESHRMS m/z 383.0016(M-H，C15H12O4F3Cl2，Calc’d 383.0059).1H NMR(acetone-d6/400MHz)7.87(s，1H)，7.60(s，1H)，5.97(q，1H，J＝7.2Hz)，3.86(d，1H，J＝6.4Hz)，2.15(m，1H)，1.07(d，6H，J＝6.4Hz).19F NMR(d6-benzene；6 eq of(R)-(+)-1-(1-naphthyl)ethylamine/400MHz)78.17(d，3F，J＝7.2Hz，S-enantiomer，)，-78.30(d，3F，J＝7.2Hz，R-enantiomer).
example 601d
(2S)6, 8-dichloro-7-isobutoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The racemic mixture of the compound prepared in example 1e was resolved by chiral separation using a Chiralpak AD column eluting with iPA/heptane/TFA ═ 10/90/0.1 and detected at 254nm to give the S-enantiomer as peak 2 with a retention time of 4.80 min:
ESHRMS m/z 383.0016(M-H，C15H12O4F3Cl2，Calc’d 383.0059)，1H NMR(acetone-d6/400MHz)7.87(s，1H)，7.60(s，1H)，5.97(q，1H，J＝7.2Hz)，3.86(d，1H，J＝6.4Hz)，2.15(m，1H)，1.07(d，6H，J＝6.4Hz).19F NMR(d6-benzene；6 eq of(R)-(+)-1-(1-naphthyl)ethylamine/400MHz)-78.17(d，3F，J＝7.2Hz，S-enantiomer，)，-78.30(d，3F，J＝7.2Hz，R-enantiomer).
Example 602a
6-chloro-7- { [ isopropyl (methyl) amino ] methyl } -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt
Step 1 preparation of Ethyl 6-chloro-7- { [ isopropyl (methyl) amino ] methyl } -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 7- (bromomethyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (01597/1PR) (1.0g, 2.5mmol) from step 3, example 16 was dissolved in DMF (5 mL). The solution was cooled under ice bath nitrogen and isopropyl (methyl) amine (0.26mL, 2.5mmol) was added to the solution followed by potassium carbonate (0.345g, 2.5 mmol). After stirring the mixture at room temperature for 3 hours, LCMS indicated product formation. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, over MgSO4Drying and filtering. The filtrate was concentrated to give the crude product. The ester was of suitable purity and was used without further purification.
Step 2.6 preparation of chloro-7- { [ isopropyl (methyl) amino ] methyl } -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from step 1 was dissolved in 10mL MeOH/THF-1/1 mixture, treated with sodium hydroxide (2.5N, 2.5mL) and stirred at room temperature overnight. Inverse directionThe mixture was acidified with 1.0N HCl to pH 1. The compound was extracted with EtOAc. The organic layer was washed with water and anhydrous MgSO 4And (5) drying. The filtrate was concentrated and purified by RPHPLC eluting with 40% -95% ACN in water containing 0.05% TFA to give 0.5g of an off-white solid (57% over 2 steps):
ESHRMS m/z 364.0922(M+H，C16H18O3F3NCl，Calc’d 364.0959).1H NMR(acetone-d6/400MHz)7.82(s，1H)，7.67(s，1H)，7.54(s，1H)，5.82(q，1H，J＝6.8Hz)，4.56(s，2H)，3.85(m，1H)，2.86(s，3H)，1.50(d，6H，J＝6.8Hz).
example 602b
6-chloro-7- [ (diisopropylamino) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt
6-chloro-7- [ (diisopropylamino) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate was prepared as a white foam by a procedure similar to that described in example 602a (37% over 2 steps):
ESHRMS m/z 392.1266(M+H，C18H22O3F3ClN，Calc’d 392.1235).1H NMR(acetone-d6/400MHz)7.89(s，1H)，7.72(s，1H)，7.51(s，1H)，5.88(q，1H，J＝7.0Hz)，4.71(s，2H)，4.10(m，2H)，1.57(d，12H，J＝6.4Hz).
example 602c
6-chloro-7- [ (2, 6-dimethylpiperidin-1-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt
By and with implementation ofExample 602a preparation of 6-chloro-7- [ (2, 6-dimethylpiperidin-1-yl) methyl]-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate as a yellow foam (38% over 2 steps): ESHRMS M/z404.1242(M + H, C)19H22O3F3ClN，Calc’d 404.1235).1H NMR(acetone-d6/400MHz)7.88(s，1H)，7.71(d，1H，J＝4.0Hz)，7.50(d，1H，J＝13Hz)，5.87(q，1H，J＝7.0Hz)，4.62(d，2H，J＝13Hz)，3.5(m，2H)，2.86(m，2H)，2.4(m，1H)，1.8(m，2H)，1.6(m，1H)，0.96(m，6H).
Example 602d
6-chloro-7- [ (2, 5-dimethylpyrrolidin-1-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt
6-chloro-7- [ (2, 5-dimethylpyrrolidin-1-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate was prepared as a yellow oil by a procedure similar to that described in example 602a (23.6% over 2 steps):
ESHRMS m/z390.1085(M+H，C18H20O3F3ClN，Calc’d 390.1078).1H NMR(acetone-d6/400MHz)7.89(m，1H)，7.71(m，2H)，5.88(q，1H，J＝7.0Hz)，4.72(s，2H)，3.91(m，2H)，2.40(m，2H)，1.9(m，2H)，1.40(m，6H).
Example 602e
6-chloro-7- { [ ethyl (methyl) amino ] methyl } -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt
6-chloro-7- { [ ethyl (methyl) amino ] methyl } -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt was prepared by a process similar to that described in example 602a as an off-white foam (18% over 2 steps):
ESHRMS m/z350.0792(M+H，C15H16O3F3ClN，Calc’d 350.0765).1H NMR(acetone-d6/400MHz)7.59(s，1H)，7.34(s，1H)，7.07(s，1H)，5.66(q，1H，J＝6.8Hz)，4.35(m，1H)，4.10(m，1H)，3.16(m，2H)，2.66(s，3H)，1.22(m，3H，J＝6.8Hz).
example 603a
(2R) 6-chloro-7- (isopentyloxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The racemic mixture of the compound prepared in example 3h was resolved by chiral separation using a Chiralpak AD-spring column eluting with iPA/heptane/TFA ═ 5/95/0.1 and detected at 254nm to give the R-enantiomer as peak 1 with a retention time of 4.74 min:
ESHRMS m/z 377.0777(M-H，C17H17O4F3Cl，Calc’d 377.0762).1H NMR(acetone-d6/300MHz)7.84(s，1H)，7.45(s，1H)，5.88(q，1H，J＝7.0Hz)，3.62(t，2H，J＝6.6Hz)，2.21(s，3H)，1.96(m，1H)，1.75(m，2H)，1.12(s，6H，J＝6.3Hz).19F NMR(d6-benzene；6eq of(R)-(+)-1-(1-naphthyl)ethylamine/300MHz)-78.20(d，3F，J＝7.8Hz，S-enantiomer，)，-78.35(d，3F，J＝7.5Hz，R-enantiomer).
example 603b
(2S) 6-chloro-7- (isopentyloxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The racemic mixture of the compound prepared in example 3h was resolved by chiral separation using a Chiralpak AD-spring column eluting with iPA/heptane/TFA ═ 5/95/0.1 and detected at 254nm to give the S-enantiomer as peak 2 with a retention time of 6.61 min:
ESHRMS m/z 377.0765(M-H，C17H17O4F3Cl，Calc’d 377.0762).H NMR(acetone-d6/300MHz)7.84(s，1H)，7.45(s，1H)，5.88(q，1H，J＝7.0Hz)，3.62(t，2H，J＝6.6Hz)，2.21(s，3H)，1.96(m，1H)，1.75(m，2H)，1.12(s，6H，J＝6.3Hz).19F NMR(d6-benzene；6eq of(R)-(+)-1-(1-naphthyl)ethylamine/300MHz)-78.20(d，3F，J＝7.8Hz，S-enantiomer，)，-78.35(d，3F，J＝7.5Hz，R-enantiomer).
example 604a
6-chloro-7- [ (5-methylpyridin-2-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt
Step 1. preparation of Ethyl 6-chloro-7- [ (5-methylpyridin-2-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Bromo (5-methylpyridin-2-yl) magnesium (10.4mL, 2.6mmol) was diluted with 5mL of THF under nitrogen and the solution cooled to-78 deg.C. Adding ZnCl into the solution2(340mg, 2.5mmol) and the mixture was stirred for 0.5 h. To the above mixture was added ethyl 7- (bromomethyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (01597/1PR) (1.0g, 2.5mmol) from step 3, example 16, followed by PdCl2(PPh3)2(18mg, 0.025 mmol). The mixture was warmed to room temperature and heated to 50 ℃ for 3 hours. LCMS indicated about 15% product formation. The solid was filtered off and the filtrate was concentrated to give a crude mixture, which was purified by RPHPLC with 10 to 95% ACN in water containing 0.05% TFAElution provided 150mg of the desired product as a brown oil (15% yield) of suitable purity which was used without further purification.
Step 2.6 preparation of chloro-7- [ (5-methylpyridin-2-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate
6-chloro-7- [ (5-methylpyridin-2-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate was prepared as a brown oil (29% yield) by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z384.0608(M+H，C18H14O3F3ClN，Calc’d 384.0609).1H NMR(acetone-d6/400MHz)8.73(m，1H)，8.27(dd，1H，J＝8.4，1.6Hz)，7.88(s，1H)，7.63(d，1H，J＝8.5Hz)，7.63(s，1H)，7.20(s，1H)，5.84(q，1H，J＝7.2Hz)，4.58(d，2H，J＝3.2Hz)，2.53(s，3H).
Example 604b
6-chloro-7- [ (4-methylpyridin-2-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt
Step 1. preparation of Ethyl 6-chloro-7- [ (4-methylpyridin-2-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Bromo (4-methylpyridin-2-yl) magnesium (10.4mL, 2.6mmol) was diluted with 5mL THF and the solution was cooled to-78 deg.C. Adding ZnCl into the solution2(340mg, 2.5mmol), the mixture was slowly warmed to room temperature and heated to 50 ℃ for 3 hours. The mixture was again cooled to-78 ℃ and to the above mixture was added ethyl 7- (bromomethyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.0g, 2.5mmol) from step 3, example 16, followed by PdCl2(PPh3)2(18mg, 0.025 mmol). The mixture was warmed to 50 ℃ for 3 hours. LCMS shows about 40% product formation. Quench the reaction with 1N HCl and extract with EtOAc. The organic layer was washed with brine, over MgSO4And (5) drying. The filtrate was concentrated to give the crude product, which was purified by RPHPLC eluting with 10 to 95% ACN in water containing 0.05% TFA to give 50mg of the desired product as a brown oil (5% yield) of suitable purity to be used without further purification.
Step 2.6 preparation of chloro-7- [ (4-methylpyridin-2-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate
Preparation of 6-chloro-7- [ (5-methylpyridin-2-yl) methyl ] by a procedure analogous to the procedure described in step 2, example 604a]-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate as a white solid (yield 45%): ESHRMS M/z384.0628(M + H, C)18H14O3F3ClN，Calc’d 384.0609).
Example 604c
6-chloro-7- [ (6-methylpyridin-2-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt
6-chloro-7- [ (6-methylpyridin-2-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate was prepared as a yellow solid by a procedure similar to that described in example 604b (4.2% over 2 steps):
ESHRMS m/z384.0628(M+H，C18H14O3F3ClN，Calc’d 384.0609).1H NMR(acetone-d6/300MHz)8.11(t，1H，J＝7.0Hz)，7.88(s，1H)，7.62(s，1H)，7.55(d，1H，J＝7.0Hz)，7.33(d，1H，J＝7.0Hz)，7.15(s，1H)，5.84(q，1H，J＝7.2Hz)，4.53(d，2H，J＝3.2Hz)，2.73(s，3H).
example 604d
6-chloro-7- [ (5-methoxypyridin-2-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt
Preparation of 6-chloro-7- [ (5-methoxypyridin-2-yl) methyl by a procedure similar to that described in example 604b]-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate as a yellow solid (5.3% in 2 steps): ESHRMS M/z400.0565(M + H, C)18H14O6F3ClN，Calc’d 400.0558).1H NMR(acetone-d6/400MHz)7.87(s，1H)，7.60(t，1H，J＝7.2Hz)，7.55(s，1H)，7.08(s，1H)，6.82(d，1H，J＝7.2Hz)，6.60(d，1H，J＝7.2Hz)，5.81(q，1H，J＝7.2Hz)，4.15(s，2H)，3.80(s，3H).
Example 604e
(2R) 6-chloro-7- (4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The racemic mixture of the compound prepared in example 9x was resolved by chiral separation using a Chiralpak AD column eluting with iPA/heptane/TFA ═ 20/80/0.1 and detected at 254nm to give the R-enantiomer as peak 1 with a retention time of 4.90 min:
ESHRMS m/z381.0536(M-H，C19H13O3F3Cl，Calc’d 381.0500).1H NMR(acetone-d6/400MHz)7.87(s，1H)，7.56(s，1H)，7.13(m 4H)，6.91(s，1H)，5.80(q，1H，J＝7.0Hz)，4.07(d，1H，J＝14.7Hz)，4.01(d，1H，J＝14.7Hz)，2.27(s，3H).19F NMR(d6-benzene；6eq of(R)-(+)-1-(1-naphthyl)ethylamine/300MHz)-78.20(d，3F，J＝7.5Hz，S-enantiomer)，-78.35(d，3F，J＝7.5Hz，R-enantiomer).
Example 604f
(2S) 6-chloro-7- (4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The racemic mixture of the compound prepared in example 9x was resolved by chiral separation using a Chiralpak AD column eluting with iPA/heptane/TFA ═ 20/80/0.1 and detected at 254nm to give the S-enantiomer as peak 2 with a retention time of 6.61 min:
ESHRMS m/z381.0540(M-H，C19H13O3F3Cl，Calc’d 381.0500).1H NMR(acetone-d6/400MHz)7.87(s，1H)，7.56(s，1H)，7.13(m 4H)，6.91(s，1H)，5.80(q，1H，J＝7.0Hz)，4.07(d，1H，J＝14.7Hz)，4.01(d，1H，J＝14.7Hz)，2.27(s，3H).19F NMR(d6-benzene；6eq of(R)-(+)-1-(1-naphthyl)ethylamine/300MHz)-78.20(d，3F，J＝7.5Hz，S-enantiomer)，-78.35(d，3F，J＝7.5Hz，R-enantiomer).
example 604g
6-chloro-7- (4-formylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-chloro-7- (4-formylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 7- (bromomethyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 3, example 16 (2.0g, 5.0mmol) with Pd (PPh)3)4(174mg, 0.15mmol) was mixed in DME (50mL) and the mixture was heated at 50 ℃ for 10 min. To the above mixture was added a solution of 4-formylphenylboronic acid (1.12g, 7.5mmol) in EtOH/DME (1: 1, 4mL), followed by 2M Na2CO3(5mL, 10 mmol). The mixture was then heated to 90 ℃ overnight. The reaction was quenched with water and extracted with EtOAc. The organic layer was washed with brine, over MgSO4Drying and filtering. The filtrate was concentrated to give the crude product, which was purified by Biotage chromatography eluting with 5 to 10% EtOAc in hexanes to give 1g of the desired product as a yellow solid (47%) of suitable purity to be used without further purification.
Step 2.6 preparation of chloro-7- (4-formylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-chloro-7- (4-formylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared as a white solid by a procedure similar to that described in step 2, example 2a (44% yield):
ESHRMS m/z 395.0327(M-H，C19H11O4F3Cl，Calc’d395.0292).1H NMR(acetone-d6/400MHz)10.00(s，1H)，7.88(s，1H)，7.87(d，2H，J＝7.6Hz)，7.59(s，1H)，7.48(d，2H，J＝7.6Hz)，7.04(s，1H)，5.82(q，1H，J＝7.2Hz)，4.23(d，2H，J＝4.4Hz).
example 604h
7- {4- [ (tert-Butoxycarbonyl) amino ] benzyl } -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
7- {4- [ (tert-Butoxycarbonyl) amino ] benzyl } -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared as a yellow solid by a procedure similar to the one described in example 604H (76% in step 1 and 54% in step 2):
1H NMR(acetone-d6/400MHz)8.34(bs，1H)，7.87(s，1H)，7.56(s，1H)，7.50(d，1H，J＝8.4Hz)，7.17(d，1H，J＝8.4Hz)，6.61(s，1H)，5.80(q，1H，J＝7.2Hz)，4.04(m，2H)，1.46(s，9H).
example 604i
7- (4-aminobenzyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt
Reacting 7- {4- [ (tert-butoxycarbonyl) amino group]Benzyl } -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (300mg, 0.62mmol) was stirred in 3mL dioxane and 0.62mL HCl (4M) for 6 hours.1H NMR indicated that the reaction mixture was 1: 1 starting material: and (3) obtaining the product. To the mixture was added another 0.3mL of 12N HCl in 2mL of water. After the mixture was stirred overnight, 0.3mL of 12N HCl was added. After stirring overnight, a solution of 3mL12N HCl in 3mL MeOH and 3mL water was added to the mixture and the mixture was stirred for 6 hours. The mixture was purified by RPHPLC eluting with 20 to 65% ACN in water containing 0.1% TFA to afford the desired product as a white solid with > 95% purity: ESHRMS M/z384.0594(M + H, C) 18H14O3F3ClN，Calc’d 384.0609).1H NMR(acetone-d6/400MHz)7.87(s，1H)，7.58(s，1H)，7.39(d，1H，J＝8.4Hz)，7.22(d，1H，J＝8.4Hz)，6.02(s，1H)，5.82(q，1H，J＝7.2Hz)，4.15(m，2H).
Example 604j
6-chloro-7- [4- (hydroxymethyl) benzyl]-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid 6-chloro-7- (4-formylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (example 604g) (210mg, 0.49mmol) was dissolved in MeOH: THF (1: 1) (3 mL). Add NaBH to the above solution in portions4(20mg, 0.49 mmol). After stirring for 15 minutes, the reaction was terminated. With saturated NH4The reaction was quenched with Cl and the organic layer was extracted with EtOAc over MgSO4Drying and filtering. The filtrate was concentrated to give the title compound asOil, solidified upon standing as a white solid 200mg (95% yield): ESHRMS M/z397.0457(M-H, C)19H13O4F3Cl，Calc’d 397.0449).1H NMR(acetone-d6/400MHz)7.87(s，1H)，7.57(s，1H)，7.31(d，2H，J＝8.2Hz)，7.22(d，2H，J＝8.2Hz)，6.92(s，1H)，5.80(q，1H，J＝7.2Hz)，4.59(s，2H)，4.09(d，2H，J＝4.3Hz).
Example 604k
7- (4-Acetylbenzyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
7- (4-Acetylbenzyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared as a white solid by a procedure similar to the one described in example 604H (40% over 2 steps):
ESHRMS m/z 409，0432(M-H，C20H13O4F3Cl，Calc’d409.0449).1H NMR(acetone-d6/400MHz)7.93(d，2H，J＝8.4Hz)，7.88(s，1H)，7.59(s，1H)，7.39(d，2H，J＝8.4Hz)，7.01(s，1H)，5.83(q，1H，J＝7.2Hz)，4.19(d，2H，J＝3.6Hz)，2.55(s，3H).
example 604l
6-chloro-7- (4-cyanobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-chloro-7- (4-cyanobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared as an off-white solid by a procedure similar to the method described in example 604H (49% in step 1, 99% in step 2):
ESHRMS m/z 392.0289(M-H，C19H10O3F3ClN，Calc’d 392.0296).1H NMR(acetone-d6/400MHz)7.88(s，1H)，7.72(d，2H，J＝8.0Hz)，7.59(s，1H)，7.47(d，2H，J＝8.0Hz)，7.06(s，1H)，5.83(q，1H，J＝7.2Hz)，4.22(d，2H，J＝3.6Hz).
example 604m
7- (4-carboxybenzyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
7- (4-carboxybenzyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared as a white solid by a procedure similar to the one described in example 604H (6% over 2 steps):
ESHRMS m/z 411.0207(M-H，C19H11O5F3Cl，Calc’d 411.0242).1H NMR(acetone-d6/400MHz)7.98(d，2H，J＝8.4Hz)，7.87(s，1H)，7.56(s，1H)，7.39(d，2H，J＝8.4Hz)，7.01(s，1H)，5.81(q，1H，J＝7.2Hz)，4.20(d，2H，J＝3.6Hz).
example 604n
6-chloro-7- [4- (dimethylamino) benzyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt
Preparation of 6-chloro-7- [4- (dimethylamino) benzyl by an analogous procedure to the one described in example 604h]-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate as a yellow oil (6.5% in 2 steps): ESHRMS M/z 412.0948(M + H, C)20H18O3F3ClN，Calc’d 412.0922).1H NMR(acetone-d6/400MHz)7.86(s，1H)，7.56(s，1H)，7.27(m，4H)，6.95(s，1H)，5.81(q，1H，J＝7.2Hz)，4.07(m，2H)，3.11(s，6H).
Example 604o
6-chloro-7- (pyrimidin-5-ylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid dihydrochloride
6-chloro-7- (pyrimidin-5-ylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid dihydrochloride was prepared as a yellow semisolid by a procedure similar to the one described in example 604H (13.1% in 2 steps): ESHRMS M/z371.0438(M + H, C)16H11O3F3ClN2，Calc’d 371.0405).H NMR(acetone-d6/400MHz)9.02(s，1H)，8.71(s，1H)，7.88(s，1H)，7.60(s，1H)，7.15(s，1H)，5.84(q，1H，J＝7.2Hz)，4.18(d，2H，J＝2.4Hz).
Example 604p
7- (4-aminobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt
Step 1. preparation of Ethyl 7- {4- [ (tert-butoxycarbonyl) amino ] benzyl } -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester from example 604h step 1 (100mg, 0.195mmol) was dissolved in THF. To the above solution was added 1% Pd/CaCO 3The mixture was hydrogenated at 25psi and 25 ℃ for 3 hours. LCMS indicated > 94% desired product and < 6% over-reduced product. The solid was filtered off and the filtrate was concentrated to give an off-white solid of suitable purity for use without further purification.
Step 2.7- (4-aminobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate preparation
The ester from step 1 is dissolved in 0.3mL of HCl in THF-H2O-1/1 solution. The mixture was stirred at room temperature for 2 days. An additional 2mL of TFA was added to the above solution and the solution was stirred for 2 days. LCMS indicated less than 10% product. The mixture was heated at 50 ℃ for 4 hours. After purification, the Boc-removed esters were combined and redissolved in THF/MeOH 2/1 and NaOH (2.5N, 2.5 eq). The mixture was stirred at room temperature overnight. The mixture was purified by RPHPLC to give the title compound as an amorphous solid:
ESHRMS m/z 350.0994(M+H，C18H15O3F3N，Calc’d 350.0999).1HNMR(acetone-d6/300MHz)7.38(m，3H)，7.11(d，1H，J＝8.4Hz)，7.00(d，1H，J＝8.1Hz)，6.93(s，1H)，6.71(d，1H，J＝8.1Hz)，5.78(q，1H，J＝7.2Hz)，4.04(s，2H).
example 604q
6-chloro-7- (thiophen-3-ylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-chloro-7- (thien-3-ylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 7- (bromomethyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (2.0g, 5.0mmol) from step 3, example 16 was dissolved in DME (10.8 mL). To the above solution was added thiophen-3-ylboronic acid (127.96mg, 5.0mmol), followed by addition of Pd (PPh) 3)4(40 mg). 2M Na was added2CO3After (5.0mL), the reaction was heated to 60-70 ℃. The color of the reaction changed from yellow to red and back to yellow. The solution was heated to reflux for 2 hours. To the above mixture was added another 107mg thiophen-3-ylboronic acid and Pd (PPh)3)4(8 mg). After 2h, the reaction was diluted with 5mL of water and extracted with EtOAc. The organic layer was washed with saturated NaHCO3Washing over MgSO4Drying and filtering. The filtrate was concentrated to give the title ester. The ester (dark oil) is chromatographically pureElution with 5 to 10% EtOAc in hexane afforded 620mg, of suitable purity, which was used without further purification.
Step 2.6 preparation of chloro-7- (thien-3-ylmethyl! -2- (trifluoromethyl! -2H-chromene-3-carboxylic acid
6-chloro-7- (thiophen-3-ylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 2 a:
1H NMR(acetone-d6/400MHz)7.88(s，1H)，7.42(s，1H)，7.39(m，1H)，7.09(m，1H)，6.98(m，1H)，6.85(s，1H)，5.78(q，1H，J＝7.2Hz)，4.0900(d，2H，J＝4.4Hz).
example 605a
8-formyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 8-formyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
2-hydroxy-5-methyl-1, 3-benzenedialdehyde (5.0g, 30.46mmol) and K2CO3A mixture of (8.41g, 60.92mmol) and ethyl 4, 4, 4-trifluorocrotonate (7.68g, 45.69mmol) in dry DMF (40.0mL) was dried N 2Heat to 80 ℃ for 18 hours under atmosphere. The mixture was then cooled, poured into 1.2N HCl (100mL), and extracted with EtOAc (2X 100 mL). The combined extracts were washed with brine (100mL) and MgSO4Drying, filtration and concentration in vacuo gave a dark red oil which was flash chromatographed (silica gel) on 50% CH2Cl2Hexanes elution gave a pale yellow solid (2.2g, 23%):
GCMS m/z314.0(M+).1H NMR(CDCl3/400MHz)10.42(s，1H)，7.70(s，1H)，7.65(s，1H)，7.26(s，1H)，5.80(q，1H，J＝7.0Hz)，4.33(m，2H)，2.32(s，3H)，1.35(m，3H).
step 2.8 preparation of formyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
8-formyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
LCMSm/z 287.3，309.2(M+H，M+23).1H NMR(acetone-d6/400MHz)10.42(s，1H)，7.91(s，1H)，7.62(s，1H)，5.98(q，1H，J＝7.0Hz)，2.35(s，3H).
example 605b
8- (hydroxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 8- (hydroxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8-formyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.32g, 1.02mmol) from step 1, example 605a was dissolved in a mixture of THF (1.5mL) and ethanol (1.5mL) and the solution was cooled to 0 ℃ (ice bath). To the above solution was added sodium borohydride (0.04g, 1.02mmol) in portions and the mixture was stirred for 1 hour. Quench the reaction with 0.5N HCl (5mL) and CH2Cl2Extraction (2X 10 mL). The combined extracts were washed with brine (20mL) and MgSO 4Dried, filtered and concentrated in vacuo to afford a yellow oil (0.3g, 93%):
GCMS m/z 316.0(M+).1H NMR(CDCl3/400MHz)7.78(s，1H)，7.11(s，1H)，6.96(s，1H)，5.71(q，1H，J＝7.0Hz)，4.67(m，2H)，4.30(m，2H)，2.27(s，3H)，1.33(m，3H).
step 2.8 preparation of (hydroxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
8- (hydroxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z 287.0520(M-H，C13H10O4F3，Calc’d 287.0526).1H NMR(DMSO-d6/400MHz)7.77(s，1H)，7.26(s，1H)，7.14(s，1H)，5.84(q，1H，J＝7.0Hz)，5.18(brs，1H)，4.46(s，2H)，2.23(s，3H).
example 605c
6-methyl-8- (phenoxymethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-methyl-8- (phenoxymethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Polymer-bound triphenylphosphine (1.2g, 3.6mmol) was suspended in anhydrous THF (10mL) and the mixture was stirred for 15 min. To the above mixture were added ethyl 8- (hydroxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.38g, 1.20mmol), phenol (0.17g, 1.80mmol) and DEAD (0.31g, 1.80mmol) prepared in step 1 of example 605b, and stirred for 18 hours. The resulting mixture was filtered through a plug of celite and concentrated in vacuo to give an off-white solid (0.47g, 98%). No further purification was performed. GCMS M/z392.0(M +).
Step 2.6 preparation of methyl-8- (phenoxymethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-methyl-8- (phenoxymethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMSm/z363.0831(M-H，C19H14O4F3，Calc’d 363.0839).1H NMR(acetone-d6/400MHz)7.88(s，1H)，7.30(s，1H)，7.26(m，4H)，6.97(m，3H)，5.86(q，1H，J＝7.0Hz)，5.12(s，2H)，2.30(s，3H).
Example 605d
6-methyl-8- [ (phenylthio) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-methyl- (phenylthio) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Polymer-bound triphenylphosphine (1.2g, 3.6mmol) was suspended in anhydrous THF (10mL) and the mixture was stirred for 15 min. To the above mixture were added ethyl 8- (hydroxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.38g, 1.20mmol), thiophenol (0.20g, 1.80mmol) and DEAD (0.31g, 1.80mmol) prepared in step 1, example 605b, and stirred for 18H. The resulting mixture was filtered through a celite plug and concentrated in vacuo to give a yellow oil (0.49g, 98%). No further purification was performed. GCMS M/z408.0(M +).
Step 2.6 preparation of methyl-8- (phenoxymethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-methyl-8- (phenoxymethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMSm/z379.0585(M-H，C19H14O3F3S，Calc’d 379.0610).1H NMR(CDCl3/400MHz)7.82(s，1H)，7.29(m，5H)，7.20(s，1H)，6.95(s，1H)，5.72(q，1H，J＝7.0Hz)，4.11(s，2H)，2.21(s，3H).
example 605e
8- (phenylaminomethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 8- (iodomethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Polymer-bound triphenylphosphine (0.29g, 0.88mmol) in anhydrous CH 2Cl2The suspension was cooled to 0 deg.C (ice bath) and stirred for 15 min (5 mL). To the above suspension were added ethyl 8- (hydroxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.20g, 0.63mmol), imidazole (0.06g, 0.88mmol) and iodine (0.19g, 0.76mmol) prepared in step 1, example 605b and stirred at 0 ℃ for 15 min. The mixture was warmed to room temperature and stirred for another 3 hours. The resulting mixture was filtered through a celite plug and concentrated in vacuo to give an oil. The oil was purified by flash chromatography (silica gel) eluting with 50% dichloromethane in hexane to give a pale yellow oil (0.14g, 79%): GCMS M/z426.00(M +).1H NMR(CDCl3/400MHz)7.64(s，1H)，7.11(s，1H)，6.94(s，1H)，5.79(q，1H，J＝7.0Hz)，4.44(m，2H)，4.31(m，2H)，2.24(s，3H)，1.33(m，3H).
Step 2. preparation of Ethyl 8- (phenylaminomethyl) -6-methyl-2- (' trifluoromethyl) -2H-chromene-3-carboxylate
A mixture of ethyl 8- (iodomethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.14g, 0.32mmol) and aniline (0.03mL, 0.32mmol) was dissolved in anhydrous DMF (2mL), the solution was warmed to 90 ℃ with K2CO3(0.05g, 0.39 mmol). The reaction was maintained at 90 ℃ for 24 hours, cooled to room temperature and filtered through celite. The filtrate was concentrated to give an oil. The oil was purified by flash chromatography (silica gel) eluting with 70% dichloromethane in hexane to give a pale yellow oil (0.11g, 88%):
GCMS m/z 391.00(M+).1H NMR(CDCl3/400MHz)7.70(s，1H)，7.19(m，3H)，6.94(s，1H)，6.74(m，1H)，6.65(m，2H)，5.77(q，1H，J＝7.0Hz)，4.33(m，4H)，4.18(brs，1H)，2.25(s，3H)，1.36(m，3H).
Step 3.8 preparation of (phenylaminomethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
8- (phenylaminomethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z362.0989(M-H，C19H15O3F3N，Calc’d 362.0999).1H NMR(acetone-d6/400MHz)7.74(s，1H)，7.28(s，1H)，7.15(s，1H)，7.07(m，2H)，6.62(m，2H)，6.58(m，1H)，5.87(q，1H，J＝7.0Hz)，4.35(m，2H)，2.21(s，3H).
example 605f
8- (methoxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 8- (methoxymethyl) -6-methyl-2- (trifluoromethyl-2H-chromene-3-carboxylate
Ethyl 8- (iodomethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.2g, 0.47mmol), prepared in step 2, example 605e, was dissolved in methanol (5mL) and the solution was cooled to 0 ℃ (ice bath). Sodium methoxide (0.32mL, 1.41mmol) was added dropwise to the solution, and the mixture was stirred at 0 ℃ for 2 hours. The solution was warmed to room temperature and stirred for an additional 2 hours. The reaction was concentrated in vacuo to give a yellow oil (0.15g, 98%). No further purification was performed: GCMSm/z 330.00(M +).
Step 2.8 preparation of (methoxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
8- (methoxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z301.0664(M-H，C14H12O4F3，Calc’d 301.0682).1H NMR(acetone-d6/400MHz)7.83(s，1H)，7.27(s，1H)，7.19(s，1H)，5.80(q，1H，J＝7.0Hz)，4.45(m，2H)，3.36(s，3H)，2.29(s，3H).
example 605g
8- (ethoxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 8- (ethoxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8- (iodomethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.2g, 0.47mmol), prepared in step 2, example 605e, was dissolved in methanol (5mL) and the solution was cooled to 0 ℃ (ice bath). Sodium ethoxide (0.10g, 1.41mmol) was added dropwise to the above solution, and stirred at 0 ℃ for 2 hours. The solution was warmed to room temperature and stirred for an additional 2 hours. The reaction was concentrated in vacuo to give a yellow oil (0.16g, 98%). No further purification was performed: GCMSm/z 344.00(M +).
Step 2.8 preparation of (ethoxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
8- (ethoxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z315.0852(M-H，C15H14O4F3，Calc’d 315.0839).1H NMR(acetone-d6/400MHz)7.82(s，1H)，7.29(s，1H)，7.18(s，1H)，5.79(q，1H，J＝7.0Hz)，4.49(m，2H)，3.53(m，2H)，2.24(s，3H)，1.18(s，3H).
example 605h
6-methyl-8- [ (methylthio) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-methyl-8- [ (methylthio) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8- (iodomethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.2g, 0.47mmol), prepared in step 2, example 605e, was dissolved in methanol (4mL) and cooled to 0 ℃ (ice bath). Sodium thiomethoxide (0.04g, 0.52mmol) was added dropwise, and the mixture was stirred at 0 ℃ for 2 hours. The solution was warmed to room temperature and stirred for an additional 2 hours. The reaction was concentrated in vacuo to give a yellow oil (0.16g, 98%). No further purification was performed: GCMS M/z 346.00(M +).
Step 2.8 preparation of (ethoxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
8- (ethoxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z317.0466(M-H，C14H12O3F3S，Calc’d 317.0454).1H NMR(acetone-d6/400MHz)7.82(s，1H)，7.22(s，1H)，7.17(s，1H)，5.82(q，1H，J＝7.0Hz)，3.68(s，3H)，2.27(s，3H).
example 605i
6-methyl-2- (trifluoromethyl) -2H-chromene-3, 8-dicarboxylic acid
Step 1 preparation of diethyl 6-methyl-2- (trifluoromethyl) -2H-chromene-3, 8-dicarboxylate
Ethyl 3-formyl-2-hydroxy-5-methylbenzoate (6.18g, 29.69mmol), K2CO3(8.19g, 59.38mmol), triethylamine (11.99g,118.75mmol) and ethyl 4, 4, 4-trifluorocrotonate (19.95g, 118.75mmol) in anhydrous DMSO (40.0mL) in dry N2Heated to 90 ℃ for 5 hours under an atmosphere. The mixture was then cooled and stirred at room temperature for 15 hours. The reaction was poured into 1.2N HCl (100mL) and extracted with EtOAc (2X 100 mL). The combined extracts were washed with brine (100mL) and MgSO4Drying, filtration and concentration in vacuo gave a dark red oil which was subjected to flash chromatography (silica gel) with 100% CH2Cl2Elution afforded a pale orange solid (4.5g, 42%):
1H NMR(acetone-d6/400MHz)7.84(s，1H)，7.61(s，1H)，7.46(s，1H)，5.86(q，1H，J＝7.0Hz)，4.30(m，4H)，2.31(s，3H)，1.33(m，6H).
step 2.6 preparation of methyl-2- (trifluoromethyl) -2H-chromene-3, 8-dicarboxylic acid
6-methyl-2- (trifluoromethyl) -2H-chromene-3, 8-dicarboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z301.0329(M-H，C13H8O5F3，Calc’d 301.0318).1H NMR(acetone-d6/300MHz)7.87(s，1H)，7.71(s，1H)，7.48(s，1H)，5.87(q，1H，J＝7.0Hz)，2.34(s，3H).
Example 605j
8- (hydroxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl [ hydroxy (phenyl) methyl ] -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8-formyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.45g, 1.43mmol), prepared in step 1, example 605a, was dissolved in anhydrous THF (5mL) and the solution was dissolvedCool to-78 ℃ (dry ice/acetone). Phenylmagnesium bromide (1.58mL, 1.58mmol) was added dropwise to the above solution, and the mixture was stirred for 4 hours. The reaction was quenched with saturated ammonium chloride (20mL) and extracted with EtOAc (2X 20 mL). The combined extracts were washed with brine (20mL) and MgSO4Dried, filtered and concentrated in vacuo to give an orange oil. The oil was purified by flash chromatography (silica gel) on 100% CH2Cl2Elution afforded a pale yellow oil (0.3g, 54%):
GCMS m/z 392.0(M+).1H NMR(CDCl3/400MHz)7.62(s，1H)，7.32(m，6H)，6.95(s，1H)，6.10(s，1H)，5.68(q，1H，J＝7.0Hz)，4.28(m，2H)，2.28(s，3H)，1.32(m，3H).
step 2. preparation of ethyl 8-benzyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Reacting ethyl 8- [ hydroxy (phenyl) methyl group]-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.28g, 0.70mmol) was dissolved in trifluoroacetic acid (5 mL). Triethylsilane (0.24g, 2.10mmol) was added dropwise to the above solution, and the mixture was stirred for 18 hours. The reaction was quenched with saturated sodium bicarbonate (15mL) and extracted with EtOAc (2X 20 mL). The combined extracts were washed with brine (20mL) and MgSO 4Drying, filtration and concentration in vacuo gave a yellow oil which was saponified after standing (0.3g, 98%): GCMS M/z 376.0(M +).1H NMR(CDCl3/400MHz)7.67(s，1H)，7.25(m，3H)，7.20(m，2H)，6.93(s，1H)，6.89(s，1H)，5.70(q，1H，J＝7.0Hz)，4.299(m，2H)，3.94(m，2H)，2.22(s，3H)，1.32(m，3H).
Step 3.8 preparation of (hydroxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
8- (hydroxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z 347.0859(M-H，C19H14O3F3，Calc’d 347.0890).1H NMR(CDCl3/300MHz)7.79(s，1H)，7.28(m，3H)，7.24(m，2H)，6.97(s，1H)，6.92(s，1H)，5.68(q，1H，J＝7.0Hz)，3.94(m，2H)，2.23(s，3H).
example 605k
6-methyl-8- (2, 2, 2-trifluoro-1-hydroxyethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of ethyl 6-methyl-2, 2, 2-trifluoro-1-hydroxyethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
A solution of the aldehyde from example 605a, step 1 (2.0g, 6.37mmol) in THF (20mL) was cooled to 0 deg.C and treated with 98% trimethyl (trifluoromethyl) silane (1.18g, 8.28mmol) and 15mg tetramethylammonium fluoride. The reaction was allowed to warm to room temperature and stirred overnight. HF (48%, 0.24mL) was added to the reaction and the reaction was stirred for 6 hours. LCMS indicated no starting material in the reaction, quenched with water, extracted with ethyl acetate, washed with water, brine, over MgSO4Dried and concentrated in vacuo to give a yellow semi-solid (2.84g) of suitable purity for use without further purification.
Step 2.6 preparation of methyl-8- (2, 2, 2-trifluoro-1-hydroxyethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-methyl-8- (2, 2, 2-trifluoro-1-hydroxyethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared as a yellow solid (78% yield) by a procedure similar to that described in step 2, example 2 a:
ESHRMS m/z355.0393(M-H，C14H9O4F6，Calc’d 355.0400).1H NMR(acetone-d6/400MHz)7.87(s，1H)，7.53(s，1H)，7.33(s，1H)，5.86(q，1H，J＝7.2Hz)，5.55(m，1H)，2.31(s，3H).
example 605l
8- (1-hydroxyethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 8- (1-hydroxyethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8-formyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.00g, 3.18mmol), prepared in step 1, example 605a, was dissolved in anhydrous THF (10mL) and the solution was cooled to-78 ℃ (dry ice/acetone). Methyl magnesium bromide (1.16mL, 3.50mmol) was added dropwise to the above solution, and the mixture was stirred for 2 hours. The reaction was quenched with saturated ammonium chloride (20mL) and extracted with EtOAc (2X 20 mL). The combined extracts were washed with brine (20mL) and MgSO4Dried, filtered and concentrated in vacuo to give a yellow oil. The oil was purified by flash chromatography (silica gel) with 10% MeOH/CH2Cl2Elution afforded a pale yellow oil (0.3g, 54%):
GCMS m/z 330.0(M+).1H NMR(CDCl3/400MHz)7.67(s，1H)，7.26(s，1H)，6.94(s，1H)，5.68(q，1H，J＝7.0Hz)，5.11(m，1H)，4.30(m，2H)，2.28(s，3H)，1.47(m，3H)，1.34(m，3H).
step 2.8 preparation of- (1-hydroxyethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
8- (1-hydroxyethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z 301.0681(M-H，C14H12O4F3，Calc’d 301.0682).1H NMR(acetone-d6/400MHz)7.82(s，1H)，7.45(s，1H)，7.12(s，1H)，5.80(q，1H，J＝7.0Hz)，5.12(m，1H)，3.94(m，2H)，2.29(s，3H)1.35(m，3H).
example 605m
6-methyl-8- (2, 2, 2-trifluoroethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-methyl-8- {2, 2, 2-trifluoro-1- [ (1H-imidazol-1-ylcarbo-hioyl) oxy ] ethyl } -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The alcohol from step 1, example 605k (2.20g, 5.73mmol) was dissolved in CH2Cl2(40 mL). To the above solution was added thiocarbonyldiimidazole (1.70g, 8.59mmol) followed by DMAP (89.6mg, 0.73 mmol). The mixture was stirred at room temperature overnight. To the above solution was added additional thiocarbonyldiimidazole (0.2g, 0.11mmol) and the reaction was stirred at room temperature for 4 hours. The mixture was passed through a plug of silica, washing the plug with 30% EtOAc in hexane to give a pale yellow oil (2.16g, 76%): LCMS M/z 495.05(M + H), of suitable purity, was used without further purification.
Step 2. preparation of ethyl 6-methyl-8- (2, 2, 2-trifluoroethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester from step 1 (2.1g, 4.25mmol) was dissolved in toluene (15 mL). Et was added to the above solution 3SiH (30mL, 0.18 mol). The mixture was heated to reflux. A solution of benzoyl peroxide (1.03g, 4.25mmol) in toluene (15mL) was added in 4 portions at 15 minute intervals. The mixture was heated to reflux for 2 hours and stirred at room temperature overnight. The mixture was passed through a silica plug, washing the plug with 5% -10% EtOAc in hexanes to give the crude product: LCMS M/z369.15(M + H). The ester was of suitable purity and was used without further purification.
Step 3.6 preparation of methyl-8- (2, 2, 2-trifluoro-1-hydroxyethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-methyl-8- (2, 2, 2-trifluoro-1-hydroxyethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared as an off-white solid by a procedure similar to the method described in step 2, example 2 a:
ESHRMS m/z 339.0467(M-H，C14H9O3F6，Calc’d339.0450).1H NMR(acetone-d6/400MHz)7.86(s，1H)，7.30(s，1H)，7.28(s，1H)，5.88(q，1H，J＝7.2Hz)，3.59(m，2H)，2.31(s，3H).
example 605n
8-Ethyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 8-ethyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8- (1-hydroxyethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.30g, 0.91mmol), prepared in step 1, example 6051, was dissolved in trifluoroacetic acid (5 mL). Triethylsilane (0.32g, 2.73mmol) was added dropwise to the above solution, and the mixture was stirred for 18 hours. Quench the reaction with saturated sodium bicarbonate (15mL) and Et 2O extraction (2X 20 mL). The combined extracts were washed with brine (20mL) and MgSO4Drying and filtering. The filtrate was concentrated in vacuo to give a yellow oil which solidified upon standing (0.28g, 98%):
GCMS m/z 314.0(M+).1H NMR(CDCl3/400MHz)7.66(s，1H)，6.98(s，1H)，6.85(s，1H)，5.70(q，1H，J＝7.0Hz)，4.30(m，2H)，2.61(m，2H)，2.25(s，3H)，1.32(m，3H)，1.15(m，3H).
step 2.8 preparation of ethyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
8-Ethyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z 285.0752(M-H，C14H12O3F3，Calc’d 285.0733).1H NMR(CDCl3/300MHz)7.82(s，1H)，7.02(s，1H)，6.89(s，1H)，5.68(q，1H，J＝7.0Hz)，2.64(m，2H)，2.26(s，3H)，1.18(m，3H).
example 605o
8-methoxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1.5 preparation of bromo-2-hydroxy-3-methoxybenzaldehyde
A solution of 2-hydroxy-3-methoxybenzaldehyde (10.0g, 65.79mmol) in acetic acid (50mL) was cooled to 0 deg.C (ice bath). Bromine (12.55g, 78.95mmol) was added dropwise to the above solution, and the mixture was stirred for 2 hours. The reaction was allowed to warm to room temperature and diluted with water (100 mL). A light brown precipitate formed. The solid was filtered and washed with water (50 mL). The filtrate was dried under high vacuum to give a light brown solid (12.2g, 80.0%): GCMS m/z231.0(m +).1HNMR(CDCl3/400MHz)10.97(s，1H)，9.82(s，1H)，7.29(s，1H)，7.15(s，1H)，3.89(m，3H).
Step 2. preparation of ethyl 6-bromo-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Adding 5-bromo-2-hydroxy-3-methoxybenzaldehyde (3.44g, 14.89mmol) and K2CO3A mixture of (4.10g, 29.78mmol), triethylamine (6.02g, 59.57mmol) and ethyl 4, 4, 4-trifluorocrotonate (10.00g, 59.57mmol) in anhydrous DMSO (5.0mL) in dry N 2Heat to 90 ℃ for 18 hours under atmosphere. The contents were poured into 2.4N HCl (50mL) and extracted with EtOAc (2X 100 mL). The combined extracts were washed with brine (100mL), MgSO4Drying, filtration and concentration in vacuo afforded a dark yellow oil which was subjected to flash chromatography (silica gel) eluting with 10% EtOAc in hexanes to afford a pale yellow oil which solidified upon standing (3.5g, 63%): GCMS M/z380.0(M +).1H NMR(CDCl3/400MHz)7.59(s，1H)，7.02(s，1H)，6.97(s，1H)，5.73(q，1H，J＝7.0Hz)，4.29(m，2H)，3.86(s，3H)，1.32(m，3H).
Step 3. preparation of Ethyl 8-methoxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 6-bromo-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.40g, 1.05mmol), trimethylboroxine (0.33g, 2.63mmol), Pd (PPh)3)4(0.13g, 0.11mmol) with K2CO3A mixture of (0.58g, 4.20mmol) in dry DMF (5.0mL) in dry N2Heat to 90 ℃ for 18 hours under atmosphere. The contents were poured into 2.4N HCl (20mL) and extracted with EtOAc (2X 20 mL). The combined extracts were washed with brine (20mL) and MgSO4Drying, filtration and concentration in vacuo afforded a yellow oil which was subjected to flash chromatography (silica gel) eluting with 10% EtOAc in hexanes to afford a pale yellow oil (0.23g, 70%):
GCMS m/z 316.0(M+).1H NMR(CDCl3/400MHz)7.64(s，1H)，6.74(s，1H)，6.63(s，1H)，5.70(q，1H，J＝7.0Hz)，4.28(m，2H)，3.85(s，3H)，2.26(s，3H)，1.32(m，3H).
step 4.8 preparation of methoxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
8-methoxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z287.0546(M-H，C13H10O4F3，Calc’d 287.0526).1H NMR(CDCl3/300MHz)7.82(s，1H)，7.02(s，1H)，6.89(s，1H)，5.68(q，1H，J＝7.0Hz)，2.64(m，2H)，2.26(s，3H)，1.18(m，3H).
example 606a
6-chloro-5-isopropyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1.3 preparation of chloro-6-hydroxy-2-isopropyl-5-methylbenzaldehyde
4-chloro-5-isopropyl-2-methylphenol (5.0g, 27.08mmol) and magnesium chloride (3.87g, 40.61mmol) were mixed in acetonitrile (150mL) and the mixture was cooled to 0 deg.C (ice bath). Triethylamine (10.28g, 101.55mmol) was added to the mixture, followed by paraformaldehyde (5.48g, 182.79mmol), and the mixture was stirred at 0 ℃ for 1 hour. The mixture was warmed to room temperature and then heated to 90 ℃ for 1 week. The contents were poured into water (100mL) and extracted with EtOAc (2X 100 mL). The combined extracts were washed with brine (50mL) and MgSO4Drying, filtration and concentration in vacuo afforded an off-white solid which was flash chromatographed (silica gel) on 100% CH2Cl2Elution afforded an off-white solid (1.83g, 32%): GCMS M/z 212.0(M +).
Step 2. preparation of ethyl 6-chloro-5-isopropyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
3-chloro-6-hydroxy-2-isopropyl-5-methylbenzaldehyde (1.83g, 8.6mmol), K 2CO3A mixture of (2.38g, 17.3mmol) and ethyl 4, 4, 4-trifluorocrotonate (2.17g, 12.9mmol) in anhydrous DMF (10.0mL) was dried N2Heat to 90 ℃ for 18 hours under atmosphere. The mixture was then cooled, poured into 0.5N HCl (50mL), and extracted with EtOAc (2X 50 mL). The combined extracts were washed with brine (50mL) and MgSO4Drying, filtration and concentration in vacuo gave a dark oil which was subjected to flash chromatography (silica gel) with 50% CH2Cl2Hexane elution gave a yellow oil (2.1g, 68%):
GCMS m/z 362.0(M+).1H NMR(CDCl3/400MHz)8.07(s，1H)，7.02(s，1H)，5.64(q，1H，J＝7.0Hz)，4.23(m，2H)，3.39(s，3H)，3.23(m，1H)，1.26(m，3H)，1.12(m，6H).
step 3.6 preparation of chloro-5-isopropyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-chloro-5-isopropyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z 333.0501(M-H，C15H13O3F3Cl，Calc’d 333.0500).1H NMR(acetone-d6/400MHz)8.20(s，1H)，7.31(s，2H)，5.84(q，1H，J＝7.0Hz)，3.73(s，1H)，2.20(s，3H)，1.41(m，6H).
example 606b
(2R) -6-chloro-8-isopropyl-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of the racemic mixture of the compound prepared in example 6 by chiral chromatography using a Kromasil 10CHI-DMB column, eluting with 20% MTBE in heptane with 0.2% acetic acid, detected at 280nm, gave the R-enantiomer, peak 1, with a retention time of 7.95 minutes:
1H NMR(acetone-d6/400MHz)7.54(s，1H)，7.12(s，1H)，5.64(q，1H，J＝7.0Hz)，3.08(m，1H)，2.22(s，3H)，1.01(m，6H).19F NMR(benzene-d6/400MHz；6eq.of(R)-(+)-(1-naphthyl)ethylamine)-77.95(d，3F，J＝10.4Hz，S-enantiomer)，-78.00(d，3F，J＝10.4Hz，R-enantiomer).
example 606c
(2S) -6-chloro-8-isopropyl-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of the racemic mixture of the compound prepared in example 6 by chiral chromatography using a Kromasil 10CHI-DMB column, eluting with 20% MTBE in heptane with 0.2% acetic acid, detected at 280nm, gave the S-enantiomer, peak 2, with a retention time of 10.26 minutes:
1H NMR(acetone-d6/400MHz)7.54(s，1H)，7.12(s，1H)，5.64(q，1H，J＝7.0Hz)，3.08(m，1H)，2.22(s，3H)，1.01(m，6H).19F NMR(benzene-d6/400MHz；6eq.of(R)-(+)-(1-naphthyl)ethylamine)-77.95(d，3F，J＝10.4Hz，S-enantiomer)，-78.00(d，3F，J＝10.4Hz，R-enantiomer).
example 607a
6-chloro-7- (isobutylsulfinyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-chloro-7- (isobutylsulfinyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (example 7d) (0.47g, 1.19mmol) was dissolved in a mixture of acetone (10mL) and water (10mL) and cooled to 0 deg.C (ice bath). The reaction was treated with oxone (0.73g, 1.19mmol) and stirred at 0 ℃ for 10 min followed by warming to room temperature for 4 h. The reaction mixture was diluted with water (20mL) and extracted with EtOAc (2X 50 mL). The combined extracts were washed with brine (50mL) and MgSO4Drying, filtration and concentration in vacuo afforded a yellow solid which was subjected to HPLC (reverse phase) eluting with 50-95% ACN/water containing 0.05% TFA afforded a yellow solid (0.4g, 82%):
LCMS m/z 411.0(M+H).1H NMR(CDCl3/400MHz)7.65(s，1H)，7.54(s，1H)，7.24(s，1H)，5.73(q，1H，J＝7.0Hz)，4.30(m，2H)，2.90(m，1H)，2.70(m，1H)，2.38(m，1H)，1.33(m，3H)，1.20(m，3H)，1.07(m，3H).
step 2.6 preparation of chloro-7- (isobutylsulfinyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-chloro-7- (isobutylsulfinyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z381.0142(M-H，C15H13O4F3ClS，Calc’d 381.0170).1H NMR(acetone-d6/400MHz)7.95(s，1H)，7.69(s，1H)，7.44(s，1H)，5.94(q，1H，J＝7.0Hz)，2.98(m，1H)，2.64(m，1H) 2.27(m，1H)，1.18(m，3H)，1.06(m，3H).
example 607b
6-chloro-7- (isobutylsulfonyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-chloro-7- (isobutylsulfonyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (example 7d, step 2) (0.44g, 1.12mmol) was dissolved in a mixture of acetone (5mL) and water (5mL) and cooled to 0 ℃ (ice bath). The reaction was treated with oxone (2.06g, 3.35mmol) and stirred at 0 ℃ for 10 min followed by warming to room temperature for 18 h. The reaction mixture was diluted with water (20mL) and extracted with EtOAc (2X 50 mL). The combined extracts were washed with brine (50mL) and MgSO4Drying, filtration and concentration in vacuo gave a yellow solid as a mixture of the oxidation products. The mixture was carried on to the next step without further purification: GCMS M/z 426.0(M +).
Step 2.6 preparation of chloro-7- (isobutylsulfonyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-chloro-7- (isobutylsulfonyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to the one described in step 2, example 602 a:
ESHRMS m/z397.0092(M-H，C15H13O5F3ClS，Calc’d 397.0119).1H NMR(acetone-d6/400MHz)7.97(s，1H)，7.85(s，1H)，7.65(s，1H)，5.98(q，1H，J＝7.0Hz)，3.41(m，2H)，2.21(m，1H)，1.06(m，6H).
Example 607c
(2R) -6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of the racemic mixture of the compound prepared in example 7d by Chiral chromatography using a Daicel Chiral Pak AD column, eluting with 30% ethanol in heptane, and detection at 244nm gave the R-enantiomer as peak 1 with a retention time of 6.86 min:
ESHRMS m/z 365.0270(M-H，C15H13F3O3ClS，Calc’d 365.0226).1H NMR(acetone-d6/400MHz)7.20(s，1H)，7.16(s，1H)，6.74(s，1H)，5.65(q，1H，J＝7.0Hz)，2.72(m，2H)，1.78(m，1H)，0.90(m，6H).19F NMR(benzene-d6/400MHz；6eq.of(R)-(+)-(1-naphthyl)ethylamine)-77.81(d，3F，J＝7.2Hz，S-enantiomer)，-78.01(d，3F，J＝8.4Hz，R-enantiomer).
example 607d
(2S) -6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of the racemic mixture of the compound prepared in example 7d by Chiral chromatography using a Daicel Chiral Pak AD column, eluting with 30% ethanol in heptane, and detection at 244nm gave the S-enantiomer, peak 2, with a retention time of 8.76 min:
ESHRMS m/z 365.0255(M-H，C15H13F3O3ClS，Calc’d 365.0226).1H NMR(acetone-d6/400MHz)7.20(s，1H)，7.16(s，1H)，6.74(s，1H)，5.65(q，1H，J＝7.0Hz)，2.72(m，2H)，1.78(m，1H)，0.90(m，6H).19F NMR(benzene-d6/400MHz；6eq.of(R)-(+)-(1-naphthyl)ethylamine)-77.81(d，3F，J＝7.2Hz，S-enantiomer)，-78.01(d，3F，J＝8.4Hz，R-enantiomer).
example 608a
6-chloro-7- (propylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-chloro-7- (propylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
A mixture of ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (example 7a, step 2) (0.5g, 1.54mmol) and propylamine (0.13mL, 1.54mmol) was dissolved in anhydrous DMF (5mL), warmed to 90 ℃ with K2CO3(0.25g, 1.84 mmol). The mixture was maintained at 90 ℃ for 24 hours, cooled to room temperature, filtered through celite, and concentrated to a viscous oil. The oil was purified by flash chromatography (silica gel) eluting with 40% dichloromethane in hexane to give a pale yellow oil (0.44g, 79%):
GCMS m/z363.00(M+).1H NMR(CDCl3/400MHz)7.57(s，1H)，7.08(s，1H)，6.23(s，1H)，5.63(q，1H，J＝7.0Hz)，4.73(brs，1H)，4.26(m，2H)，3.14(m，2H)，1.66(m，2H)，1.31(m，3H)，1.01(m，3H).
Step 2.6 preparation of chloro-7- (propylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-chloro-7- (propylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z334.0488(M-H，C14H12O3F3ClN，Calc’d 334.0452).1H NMR(acetone-d6/400MHz)7.74(s，1H)，7.35(s，1H)，6.37(s，1H)，5.71(q，1H，J＝7.0Hz)，3.27(m，2H)，1.68(m，2H)，0.98(m，3H).
example 608b
6-chloro-7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-chloro-7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
A mixture of ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (example 7a step 2) (0.5g, 1.54mmol) and isobutylamine (0.15mL, 1.54mmol) was dissolved in anhydrous DMF (5mL) and warmed to 90 deg.C with K2CO3(0.25g, 1.84 mmol). The mixture was maintained at 90 ℃ for 24 hours, cooled to room temperature, filtered through celite, and concentrated to a viscous oil. The oil was purified by flash chromatography (silica gel) eluting with 40% dichloromethane in hexane to give a pale yellow oil (0.44g, 76%):
GCMS m/z 377.00(M+).1H NMR(CDCl3/400MHz)7.57(s，1H)，7.09(s，1H)，6.30(s，1H)，5.63(q，1H，J＝7.0Hz)，4.27(m，2H)，3.00(m，2H)，1.95(m，1H)，1.31(m，3H)，1.00(m，6H).
step 2.6 preparation of chloro-7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-chloro-7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z348.0604(M-H，C15H14O3F3ClN，Calc’d 348.0609).1H NMR(acetone-d6/400MHz)7.74(s，1H)，7.35(s，1H)，6.37(s，1H)，5.71(q，1H，J＝7.0Hz)，3.31(m，2H)，2.00(m，1H)，0.98(m，6H).
example 608c
6-chloro-7- (butylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-chloro-7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
A mixture of ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (example 7a step 2) (0.5g, 1.54mmol) and butylamine (0.15mL, 1.54mmol) was dissolved in anhydrous DMF (5mL) and warmed to 90 ℃ with K2CO3(0.25g, 1.84 mmol). The mixture was maintained at 90 ℃ for 24 hours, cooled to room temperature, filtered through celite, and concentrated to a viscous oil. The oil was purified by flash chromatography (silica gel) eluting with 40% dichloromethane in hexane to give a pale yellow oil (0.46g, 79%):
GCMS m/z 377.00(M+).1H NMR(CDCl3/400MHz)7.58(s，1H)，7.08(s，1H)，6.23(s，1H)，5.63(q，1H，J＝7.0Hz)，4.70(brs，1H)，4.27(m，2H)，3.17(m，2H)，1.63(m，2H)，1.43(m，2H)，1.31(m，3H)，0.98(m，3H).
step 2.6 preparation of chloro-7- (butylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-chloro-7- (butylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z348.0599(M-H，C15H14O3F3ClN，Calc’d 348.0609).1H NMR(acetone-d6/400MHz)7.74(s，1H)，7.35(s，1H)，6.37(s，1H)，5.71(q，1H，J＝7.0Hz)，3.30(m，2H)，1.66(m，2H)，1.44(m，2H)，0.95(m，3H).
example 608d
6-chloro-7- (isopentylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of ethyl 6-chloro-7- (isopentylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
A mixture of ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (example 7a step 2) (0.5g, 1.54mmol) and isoamylamine (0.18mL, 1.54mmol) was dissolved in anhydrous DMF (5mL), warmed to 90 ℃ with K 2CO3(0.25g, 1.84 mmol). The mixture was maintained at 90 ℃ for 24 hours, cooled to room temperature, filtered through celite, and concentrated to a viscous oil. The oil was purified by flash chromatography (silica gel) eluting with 40% dichloromethane in hexane to give a pale yellow oil (0.49g, 82%):
GCMS m/z 393.00(M+).1H NMR(CDCl3/400MHz)7.58(s，1H)，7.09(s，1H)，6.31(s，1H)，5.64(q，1H，J＝7.0Hz)，4.27(m，2H)，3.19(m，2H)，1.71(m，1H)，1.57(m，2H)，1.31(m，3H)，0.96(m，6H).
step 2.6 preparation of chloro-7- (isopentylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-chloro-7- (isopentylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z 362.0732(M-H，C6H16O3F3ClN，Calc’d 362.0765).1H NMR(acetone-d6/400MHz)7.74(s，1H)，7.35(s，1H)，6.37(s，1H)，5.71(q，1H，J＝7.0Hz)，3.32(m，2H)，1.75(m，1H)，1.58(m，2H)，0.96(m，6H).
example 608e
6-chloro-7- [ (3, 3-dimethylbutyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-chloro-7- [ (3, 3-dimethylbutyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate
A mixture of ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (example 7a step 2) (0.5g, 1.54mmol) and 3, 3-dimethylbutylamine (0.21mL, 1.54mmol) was dissolved in anhydrous DMF (5mL), warmed to 90 ℃ with K2CO3(0.25g, 1.84 mmol). The mixture was maintained at 90 ℃ for 24 hours, cooled to room temperature, filtered through celite, and concentrated to a viscous oil. The oil was purified by flash chromatography (silica gel) eluting with 40% dichloromethane in hexane to give a pale yellow oil (0.54g, 87%):
GCMS m/z 405.00(M+).1H NMR(CDCl3/400MHz)7.58(s，1H)，7.08(s，1H)，6.22(s，1H)，5.64(q，1H，J＝7.0Hz)，4.26(m，2H)，3.16(m，2H)，1.57(m，2H)，1.33(m，3H)，0.98(s，9H).
Step 2.6 preparation of chloro-7- [ (3, 3-dimethylbutyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-chloro-7- [ (3, 3-dimethylbutyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z 376.0885(M-H，C17H18O3F3ClN，Calc’d 376.0922).1H NMR(acetone-d6/400MHz)7.74(s，1H)，7.35(s，1H)，6.37(s，1H)，5.71(q，1H，J＝7.0Hz)，3.32(m，2H)，1.61(m，2H)，0.99(s，9H).
example 608f
(2R) -6-chloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of the racemic mixture of compound 01598/IPR prepared in example 8c by chiral chromatography using a ChiralPak AD column, eluting with 10% isopropanol in heptane with 0.1% TFA, detected at 280nm gave the R-enantiomer as peak 1 with a retention time of 4.44 min: ESHRMS M/z 364.0944(M + H, C)16H18F3O4ClN，Calc’d 364.0922).1H NMR(acetone-d6/400MHz)7.21(s，1H)，7.12(s，1H)，6.62(s，1H)，5.61(q，1H，J＝7.0Hz)，2.67(m，2H)，2.52(s，3H)，1.71(m，1H)，0.68(m，6H).19F NMR(benzene-d6/400MHz；6eq.of(R)-(+)-(1-naphthyl)ethylamine)-77.86(d，3F，J＝8.4Hz，S-enantiomer)，-78.05(d，3F，J＝7.2Hz，R-enantiomer).
Example 608g
(2S) -6-chloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of the racemic mixture of compound 01598/IPR prepared in example 8c by chiral chromatography using a ChiralPak AD column, eluting with 10% isopropanol in heptane with 0.1% TFA, detected at 280nm gave the S-enantiomer as peak 2 with a retention time of 9.24 min: ESHRMS m/z364.0927(M+H，C16H18F3O4ClN，Calc’d364.0922).1H NMR(acetone-d6/400MHz)7.21(s，1H)，7.12(s，1H)6.62(s，1H)，5.61(q，1H，J＝7.0Hz)，2.67(m，2H)，2.52(s，3H)，1.71(m，1H)，0.68(m，6H).19F NMR(benzene-d6/400MHz；6eq.of(R)-(+)-(1-naphthyl)ethylamine)-77.86(d，3F，J＝8.4Hz，S-enantiomer)，-78.05(d，3F，J＝7.2Hz，R-enantiomer).
Example 608h
6-chloro-7- (neopentylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-chloro-7- (neopentylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
A mixture of ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (example 7a step 2) (0.5g, 1.54mmol) and pivaloylamine (0.13g, 1.54mmol) was dissolved in anhydrous DMF (5mL) and warmed to 90 deg.C with K2CO3(0.25g, 1.84 mmol). The mixture was maintained at 90 ℃ for 24 hours, cooled to room temperature, filtered through celite, and concentrated to a viscous oil (0.6g, 98%). No further purification was performed: GCMS M/z 391.00(M +).
Step 2.6 preparation of chloro-7- (neopentylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-chloro-7- (neopentylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z 362.0728(M-H，C16H16O3F3ClN，Calc’d 362.0765).1H NMR(CDCl3/400MHz)7.71(s，1H)，7.13(s，1H)，6.28(s，1H)，5.62(q，1H，J＝7.0Hz)，2.98(m，2H)，1.03(s，9H).
example 608i
6-chloro-7- (sec-butylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1 preparation of Ethyl 6-chloro-7- (sec-butylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
A mixture of ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (example 7a step 2) (0.5g, 1.54mmol) and sec-butylamine (0.11g, 1.54mmol) was dissolved in anhydrous DMF (5mL) and warmed to 90 ℃ with K2CO3(0.25g, 1.84 mmol). The mixture was maintained at 90 ℃ for 24 hours, cooled to room temperature, filtered through celite, and concentrated to a viscous oil (0.58g, 98%). No further purification was performed: GCMS M/z 377.00(M +).
Step 2.6 preparation of chloro-7- (sec-butylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-chloro-7- (sec-butylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z348.0624(M-H，C15H14O3F3ClN，Calc’d 348.0609).1H NMR(CDCl3/400MHz)7.73(s，1H)，7.12(s，1H)，6.25(s，1H)，5.62(q，1H，J＝7.0Hz)，3.48(m，1H)，1.62(m，2H)，1.26(m，3H)，1.00(m，3H).
example 609a
7-benzyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To the ester from step 1 of example 9k THF (7): EtOH (2): 1H2O (1), followed by LiOH (1.5eq), was heated to 40 ℃ for 4 hours. The reaction was cooled to room temperature and concentrated in vacuo. Acidification to pH1 with concentrated HCl and filtration of the solid subjected to preparative reverse phase chromatography gave the title compound (95%):
ESHRMS m/z 333.0751(m-H，C18H12O3F3 Calc’d 333.0733).1H NMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.76(s，1H)，7.33(d，1H，J＝7.5Hz)，7.13-7.26(m，5H)，6.84-6.88(m，2H)，5.81(q，1H，J＝7.1Hz)，3.27(s，2H).
example 609b
7- (2-chlorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from step 1, example 9n was hydrolyzed and purified using the same protocol as described in example 609d to give the carboxylic acid (99%): ESHRMSm/z 367.0323(M-H, C)18H11ClF3O3Calc’d 367.0343).1H NMR(DMSO-d6/400MHz)13.16(brs，1H)，7.78(s，1H)，7.23-7.43(m，5H)，6.83-6.85(m，1H)，6.80(s，1H)，5.83(q，1H，J＝7.1Hz)，4.04(s，2H).
Example 609c
7- (4-chlorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from step 1, example 9o, was hydrolyzed and purified using the same protocol as described in example 609d to give the carboxylic acid (99%): ESHRMSm/z 367.0368(M-H, C)18H11ClF3O3 Calc’d 367.0343).1H NMR(DMSO-d6/400MHz)13.15(brs，1H)，7.76(s，1H)，7.29-7.40(m，3H)，7.21-7.24(m，2H)，6.87(m，2H)，5.82(q，1H，J＝7.1Hz)，3.88(s，2H).
Example 609d
7- (2, 4-dimethylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To the ester from step 5 of example 9s was added THF (7): EtOH (2): H2O (1), followed by LiOH (1.5eq), was heated to 40 ℃ for 4 hours. The reaction was cooled to room temperature and concentrated in vacuo. Acidification to pH1 with concentrated HCl and filtration of the solid subjected to preparative reverse phase chromatography afforded the title compound (93%):
ESHRMS m/z361.1062(M-H，C20H16O3F3Calc’d 361.1046).1H NMR(DMSO-d6/400MHz)，13.19(s，1H)，7.77(s，1H)，7.33(d，1H，J＝7.6Hz)，7.00(m，3H)，6.77(d，1H，J＝7.7Hz)，6.70(s，1H)，5.82(q，1H，J＝7.1Hz)，3.87(s，2H)，2.2(s，3H)，2.10(s，3H).
example 609e
(2S) -7-butyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The racemic mixture of the compound prepared in step 5 of example 9a was resolved by chiral separation using a ChiralPak AD-spring column eluting with iPA/heptane containing TFA ═ 5/95/0.1 and detected at 254nm to give the S-enantiomer as peak 2 with a retention time of 7.83 min. ESHRMS M/z333.0519(M-H, C)15H13ClF3O3 Calc’d 333.0500).1H NMR(DMSO-d6/400MHz)，13.13(s，1H)，7.79(s，1H)，7.56(s，1H)，7.00(s，1H)，5.89(q，1H，J＝7.1Hz)，2.62(t，2H，J＝7.5Hz)，1.50(m，2H)，1.30(m，2H)，0.860(t，3H，J＝7.3Hz)：19F NMR(d6-benzene；6eq of(R)-(+)-1-(1-naphthyl)ethylamine)d-77.82(d，3F，J＝6.8Hz，R-enantiomer).
Example 609f
(2R) -7-butyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The racemic mixture of the compound prepared in step 5 of example 9a was chirally resolved using the same protocol as step 1 of example 609e and the R-enantiomer was identified as peak 1 with a retention time of 5.38 min. ESHRMS M/z 333.0489(M-H, C)15H13ClF3O3Calc’d 333.0500).1H NMR(DMSO-d6/400MHz)，13.13(s，1H)，7.79(s，1H)，7.56(s，1H)，7.00(s，1H)，5.89(q，1H，J＝7.1Hz)，2.62(t，2H，J＝7.5Hz)，1.50(m，2H)，1.30(m，2H)，0.860(t，3H，J＝7.3Hz).19FNMR(d6-benzene；6eq of(R)-(+)-1-(1-naphthyl)ethylamine)d-77.82(d，3F，J＝6.8Hz，R-enantiomer)，-77.78(d，3F，J＝6.8Hz，S-enantiomer).
Example 609g
(2R) -6-chloro-7- (3, 3-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The racemic mixture of the compound prepared in step 3 of example 9b was chirally resolved using the same protocol as step 1 of example 609e and the R-enantiomer was identified as peak 1 with a retention time of 4.26 min. ESHRMS M/z 361.0797(M-H, C) 17H17ClF3O3Calc’d 361.0813).1H NMR(DMSO-d6/400MHz)13.23(brs，1H)，7.80(s，1H)，7.55(s，1H)，7.01(s，1H)，5.89(q，1H，J＝7.1Hz)，3.30(m，2H)，2.56-2.60(m，2H)，1.31-1.37(m，2H)，0.91(s，9H).19F NMR(d6-benzene；6eq of(R)-(+)-1-(1-naphthyl)ethylamine)d-77.80(d，3F，J＝6.8Hz，R-enantiomer)，-77.77(d，3F，J＝6.8Hz，S-enantiomer).
Example 609h
(2S) -6-chloro-7- (3, 3-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The racemic mixture of the compound prepared in step 3 of example 9b was chirally resolved using the same protocol as step 1 of example 609e and the S-enantiomer was identified as peak 2 with a retention time of 10.35 min.
ESHRMS m/z 361.0848(M-H，C17H17ClF3O3Calc’d 361.0813).1H NMR(DMSO-d6/400MHz)13.23(brs，1H0，7.80(s，1H)，7.55(s，1H)，7.01(s，1H)，5.89(q，1H，J＝7.1Hz)，3.30(m，2H)，2.56-2.60(m，2H)，1.31-1.37(m，2H)，0.91(s，9H).19FNMR(d6-benzene；6eq of(R)-(+)-1-(1-naphthyl)ethylamine)d-77.80(d，3F，J＝6.8Hz，R-enantiomer)，-77.77(d，3F，J＝6.8Hz，S-enantiomer).
Example 609i
6-chloro-7- (cyclohexylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 7- (cyclohexylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of the ester from example 9a, step 2 (3.0g, 7.53mmol) in THF (25mL) was added Pd (dba)2(138mg, 2 mol%), tfp (69mg, 4 mol%), followed by syringe addition of cyclohexylmethylzinc chloride (30mL, 15 mmol). The reaction was heated to 65 ℃ for 6 hours. The reaction was cooled to room temperature, poured into saturated aqueous ammonium chloride (200mL), and extracted with ethyl acetate (2X 50 mL). The organic phases are combined and washed with NaHCO3Aqueous solution (2X 50mL), 1N HCl aqueous solution (2X 50mL) and brine (2X 50mL) were washed with Na2SO4Dried, filtered and concentrated in vacuo. The crude product was subjected to flash chromatography (silica, 5% ethyl acetate/hexane). The desired fractions were collected and the solvent was removed in vacuo to yield ethyl ester (2.10g, 75%). The ester was of suitable purity and was used without further purification: ESLRMS M/z369.2(M + H).
Step 2. preparation of Ethyl 6-chloro-7- (cyclohexylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester was chlorinated (step 1) (85%) via a method similar to that described in example 609m, step 1. The ester was of suitable purity and was used without further purification. ESLRMS M/z403.1(M + H).
Step 3.6 preparation of chloro-7- (cyclohexylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 2) (99%):
ESHRMS m/z 373.0832(M-H，C18H17ClF3O3Calc’d373.0813).1H NMR(DMSO-d6/400MHz)，13.28(brs，1H)，7.79(s，1H)，7.54(s，1H)，6.93(s，1H)，5.89(q，1H，J＝7.1Hz)，2.48-2.54(m，2H)，1.50-1.58(m，6H)，1.02-1.11(m，3H)，0.91-.097(m，2H).
example 609j
7- (cyclohexylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from example 609i (step 1) (99%) was hydrolyzed and purified using the same protocol as described in example 609 d:
ESHRMS m/z 339.1227(M-H，C18H18O3F3Calc’d 339.1203).1HNMR(DMSO-d6/400MHz)，13.13(s，1H)，7.79(s，1H)，7.33(d，1H，J＝7.7Hz)，6.78-6.83(m，2H)，5.83(q，1H，J＝7.1Hz)，2.49(m，2H)，1.32-1.61(m，5H)，1.05-1.20(m，4H)，0.84-0.91(m，2H).
example 609k
4, 6-dichloro-7- (cyclohexylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 4, 6-dichloro-7- (cyclohexylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester from example 609i (step 2) (34%) was further chlorinated following the same chlorination procedure as example 609m step 1. The ester was of suitable purity and was used without further purification. ESLRMS M/z 437.1(M + H).
Step 2.4, 6-dichloro-7- (cyclohexylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid preparation
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 1) (99%): ESHRMS M/z407.0396(M-H, C)18H16Cl2F3O3 Calc’d407.0923).1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.62(s，1H)，7.05(s，1H)，6.10(q，1H，J＝7.1Hz)，2.50-2.61(m，2H)，1.50-1.59(m，7H)，1.07-1.11(m，4H).
Example 609l
6-chloro-7- [ (6-chloropyridin-3-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl [ (6-chloropyridin-3-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 7- [ (6-chloropyridin-3-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate (85%) was prepared and purified via a similar procedure to that described in step 1, example 609i, with appropriate substitution of zinc 2-chloro-5-methylpyridine bromide. ESLRMS M/z 398.1(M + H).
Step 2. preparation of Ethyl 6-chloro-7- [ (6-chloropyridin-3-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester was chlorinated (step 1) (93%) using the same protocol as described in step 1, example 609 m. The ester was of suitable purity and was used without further purification. ESLRMS M/z432.0(M + H).
Step 3.6-chloro-7- [ (6-chloropyridin-3-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid preparation
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 2) (99%): ESHRMS M/z401.9936(M-H, C)17H9Cl2O3F3N Calc’d401.9906).1HNMR(DMSO-d6/400MHz)，13.13(s，1H)，8.29(d，1H，J＝2.1Hz)，7.81(s，1H)，7.62-7.65(m，2H)，7.43(d，1H，J＝8.1Hz)，7.12(s，1H)，5.89(q，1H，J＝7.1Hz)，4.04(s，2H).
Example 609m
6-chloro-7- (3-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-chloro-7- (3-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester from example 9w (step 1) (1.00g, 234mmol) was dissolved in acetic acid (25 mL). Chlorine gas was bubbled through the solution for 15 minutes. The solution was left at room temperature for 30 minutes. The reaction was cooled to room temperature and poured into H2O (150mL), extracted with ethyl acetate (2X 150 mL). The organic phases are combined and washed with NaHCO3Aqueous (2X 50mL), 3N aqueous HCl (2X 50mL), and brine (2X 50mL) were washed with Na2SO4Dried, filtered and concentrated in vacuo to give 7- (2-chloro-3-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (42%), 7- (4-chloro-3-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (35%) and the title compound (158mg, 17%) as an amber oil. The ester was of suitable purity and was used without further purification: ESLRMS M/z 427.0(M + H).
Step 2.6 preparation of chloro-7- (3-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 1) to give the carboxylic acid (99%): ESHRMS M/z 397.0460(M-H, C)19H13ClF3O4 Calc’d 397.0449).1HNMR(DMSO-d6/400MHz)13.16(brs，1H)，7.79(s，1H)，7.6(s，1H)，7.17-7.21(m，1H)，6.98(s，1H)，6.73-6.76(m，3H)，5.89(q，1H，J＝7.1Hz)，3.97(s，2H)，3.68(s，3H).
Example 609n
7- (3-hydroxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of methyl 7- (3-hydroxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a cooled (-20 ℃ C.) stirred solution of the ester of example 9w (step 1) (152mg, 0.500mmol) was added BBr31M CH2Cl2Solution (1.60mL, 1.67 mmol). The resulting solution was warmed to room temperature and stirred overnight. The reaction was cooled (-20 ℃ C.) and methanol was added via syringe. The solvent was removed in vacuo and the crude product was subjected to preparative reverse phase chromatography to give the title compound (146mg, 83%): ESLRMS M/z 365.0(M + H).
Step 2.7- (3-hydroxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid preparation
The ester was hydrolyzed and purified (step 1) (97%) using the same procedure as described in example 609 d: ESHRMS M/z 349.0683(M-H, C)18H12F3O4 Calc’d 349.0682).1HNMR(DMSO-d6/400MHz)13.16(brs，1H)，9.27(brs，1H)，7.78(s，1H)，7.35(d，1H，J＝7.6Hz)，7.04(t，1H，J＝7.6Hz)，6.84-6.88(m，2H)，6.55-6.63(m，3H)，5.83(q，1H，J＝7.1Hz)，3.80(s，2H).
Example 609o
6-chloro-7- (3-hydroxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of methyl 6-chloro-7- (3-hydroxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The acid from step 2 of example 609m was subjected to the same protocol as described in step 1 of 609n (77%): ESLRMS M/z 399.1(M + H).
Step 2.6 preparation of chloro-7- (3-hydroxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified (step 1) (99%) using the same procedure as described in example 609 d: ESHRMS M/z 383.0321(M-H, C) 18H11ClF3O4 Calc’d 383.0292).1HNMR(DMSO-d6/400MHz)13.16(brs，1H)，9.29(brs，1H)，7.80(s，1H)，7.60(s，1H)，7.05(t，1H，J＝7.7Hz)，6.96(s，1H)，6.54-6.61(m，3H)，5.89(q，1H，J＝7.1Hz)，3.91(s，2H).
Example 609p
7- [ (6-Chloropyridin-3-yl) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester in example 609l (step 1) (99%) was hydrolyzed and purified using the same protocol as described in example 609 d:
ESHRMS m/z 368.0302(M-H，C17H10ClF3NO3 Calc’d 368.0296).1HNMR(DMSO-d6/400MHz)，13.16(brs，1H)，8.83(d，1H，J＝2.2Hz)，7.79(s，1H)，7.69-7.79(m，1H)，7.37-7.42(m，2H)，6.91-6.93(m，2H)，5.89(q，1H，J＝7.1Hz)，3.94(m，2H).
example 609r
4, 6-dichloro-7-cyclohexyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 7-cyclohexyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 7-cyclohexyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (67%) was prepared and purified via a similar procedure as described in step 1, example 609i, with appropriate substitution with cyclohexylzinc bromide: ESLRMS M/z 355.1(M + H).
Step 2. preparation of ethyl 4, 6-dichloro-7-cyclohexyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester was chlorinated using the same protocol as described in step 1 of example 609m (step 1). The ester was of suitable purity and was used without further purification: ESLRMS M/z 423.0(M + H).
Step 3.4, 6-dichloro-7-cyclohexyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid preparation
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 2) (99%):
ESHRMS m/z393.0258(M-H，C17H14Cl2F3O3 Calc’d393.0267).1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.63(s，1H)，7.07(s，1H)，6.10(q，1H，J＝7.1Hz)，2.85(m，1H)，1.65-1.78(m，4H)，1.20-1.43(m，6H).
example 609s
7- (5-bromo-3-chloro-2-methoxybenzyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 7- (5-bromo-2-methoxybenzyl) -2- (trifluoromethyl-2H-chromene-3-carboxylate
Ethyl 7- (5-bromo-2-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (71%) was prepared and purified by a similar procedure as described in step 1, example 609i, with appropriate substitution with 2-methoxy-5-bromobenzylzinc bromide: ESLRMS M/z 471.0(M + H).
Step 2. preparation of Ethyl (5-bromo-3-chloro-2-methoxybenzyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester (step 1) was chlorinated using the same protocol as described in step 1, example 609m (83%). The ester was of suitable purity and was used without further purification: ESLRMS M/z538.9(M + H).
Step 3.7- (5-bromo-3-chloro-2-methoxybenzyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid preparation
The ester was hydrolyzed and purified (step 2) (93%) using the same protocol as described in example 609 d: ESHRMS M/z508.9182(M-H, C)19H11BrCl2F3O4 Calc’d508.9164).1HNMR(DMSO-d6/400MHz)，13.16(brs，1H)，7.84(s，1H)，7.64-7.65(m，2H)，7.13(m，2H)，6.88(m，1H)，5.89(q，1H，J＝7.1Hz)，4.04(m，2H)，3.66(s，3H).
Example 609t
7- (5-bromo-2-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The (91%) from step 1 of example 609s was hydrolyzed and purified using the same protocol as described in example 609 d: ESHRMS M/z440.9972(M-H, C)19H13BrF3O4 Calc’d 440.9944).1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.78(s，1H)，7.31-7.36(m，3H)，6.82-6.93(m，3H)，5.89(q，1H，J＝7.1Hz)，3.84(s，2H)，3.73(s，3H).
Example 609u
6-chloro-7- (3-chloro-2-methoxy-5-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-chloro-7- (3-chloro-2-methoxy-5-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester from step 2, example 609s was subjected to the same protocol as described in step 1, 611f (87%). The purity of the ester is suitable for the next step: ESLRMS M/z 475.0(M + H).
Step 2.6 preparation of chloro-7- (3-chloro-2-methoxy-5-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 1) (92%): ESHRMS M/z445.0246(M-H, C)20H14Cl2F3O4 Calc’d445.0216).1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.83(s，1H)，7.64(s，1H)，7.18(d，1H，J＝2Hz)，6.78(m，2H)，5.89(q，1H，J＝7.1Hz)，3.60(s，2H)，2.17(m，3H).
Example 609v
6-bromo-7- (2-bromobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 7- (2-bromobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
This compound was prepared and purified by a similar procedure as described in step 1 of example 609i, using appropriate substitution with 2-bromobenzylzinc bromide, to give the ester (87%): ESLRMS M/z441.0(M + H).
Step 2. preparation of ethyl 6-bromo-7- (2-bromobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester (step 1) was dissolved in (glacial) acetic acid (20mL), Br2 was added, and the solution was stirred at room temperature for 1 hour. The reaction was concentrated in vacuo. Water (50mL) was added to the residue, and the reaction was extracted with ethyl acetate (2X 50 mL). The combined organic layers were washed with brine (2X 50mL) and Na 2SO4Drying, filtration and concentration in vacuo gave the bromo ester (88%). The ester was of suitable purity and was used without further purification. ESLRMS M/z 518.9(M + H).
Step 3.6 preparation of bromo-7- (2-bromobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified (step 2) (93%) using the same protocol as described in example 609 d: ESHRMS M/z488.9010(M-H, C)18H10Br2F3O3 Calc’d488.8943).1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.81(s，1H)，7.63-7.65(m，1H)，7.05-7.33(m，4H)，6.60(s，1H)，5.89(q，1H，J＝7.1Hz)，4.08(s，2H).
Example 609w
6-chloro-7- (3-methylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 7- (3-methylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester from step 2 of example 9a (77%) was coupled using a similar protocol to that described in step 1 of example 611d, with appropriate substitution of 3-methylbut-1-ene: ESLRMS M/z 343.1(M + H).
Step 2. preparation of Ethyl 6-chloro-7- (3-methylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester was chlorinated (step 1) (91%) using the same protocol as described in step 1, example 609 m. The ester was of suitable purity and was used without further purification: ESLRMS M/z377.1(M + H).
Step 3.6 preparation of chloro-7- (3-methylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 2) (95%): ESHRMS M/z347.0685(M-H, C) 16H15ClF3O3 Calc’d347.0656).1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.81(s，1H)，7.56(s，1H)，7.00(s，1H)，5.89(q，1H，J＝7.1Hz)，2.47-2.64(m，2H)，1.52-1.54(m，2H)，1.37-1.41(m，3H)，0.87-0.89(m，6H).7.00(s，1H)，5.89(q，1H，J＝7.1Hz)，2.47-2.64(m，2H)，1.52-1.54(m，2H)，1.37-1.41(m，3H)，0.87-0.89(m，6H).
Example 609x
7- (5-bromo-2-methoxybenzyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of ethyl 6-chloro-7-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester from step 2, example 9a, was chlorinated (81%) using the same protocol as described in step 1, example 609 m. The ester was of suitable purity and was used without further purification: ESLRMS M/z 432.9(M + H).
Step 2. preparation of Ethyl 7- (5-bromo-2-methoxybenzyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester was coupled and purified via a similar procedure to that described in example 609i, step 1 (step 1) (89%) with 2-chloro-5-methylpyridinium zinc bromide with appropriate substitution: ESLRMS M/z504.9(M + H).
Step 3.7- (5-bromo-2-methoxybenzyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid preparation
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 2) (96%):
1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.83(s，1H)，7.40(m，1H)，7.08(d，1H，J＝2.4Hz)，6.96(d，1H，J＝8.7Hz)，6.76(s，1H)，5.89(q，1H，J＝7.1Hz)，3.93(m，2H)，3.73(s，3H).
example 610
6, 8-dichloro-7- (propylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6, 8-dichloro-7- (propylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Reacting ethyl 6-chloro-7- [ (cyclopropylmethyl) (propyl) amino]-2- (trifluoromethyl) -2H-chromene-3-carboxylate (example 8g) (0.45g, 1.07mmol) was dissolved in acetic acid (50 mL). Sodium acetate (0.7g, 8.56mmol) was added to dissolve. Chlorine gas was bubbled through the solution for 3 minutes until a white precipitate began to form. The solution was stirred for an additional 3 hours. Zinc dust (0.35g, 5.35mmol) was added and the solution was stirred for 30 min. The reaction was filtered through a celite plug and concentrated to a yellow suspension. The suspension was partitioned between ether and water. The organic phase was washed with brine, over MgSO 4Drying, filtration and concentration in vacuo gave a yellow oil (0.4g, 94%). No further purification was performed: GCMS M/z 398.00(M +).
Step 2.6, 8-dichloro-7- (propylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid preparation
6, 8-dichloro-7- (propylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a:
ESHRMS m/z368.0064(M-H，C14H11O3F3Cl2N，Calc’d 368.0063).1H NMR(acetone-d6/400MHz)7.80(s，1H)，7.43(s，1H)，5.90(q，1H，J＝7.0Hz)，3.57(m，2H)，1.61(m，2H)，0.93(m，3H).
example 611a
(2R) -7-benzyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The racemic mixture of the compound prepared in step 2 of example 42a was chirally resolved using the same protocol as step 1 of example 609e, identifying the R-enantiomer as peak 1 with a retention time of 5.45 min:
ESHRMS m/z 347.0875(M-H，C19H14F3O3Calc’d 347.0890).1HNMR(DMSO-d6/400MHz)13.19(brs，1H)，7.74(s，1H)，7.11-7.27(m，6H)，6.74(q，1H，J＝7.1Hz)，3.91(s，2H)，2.11(s，3H).R-isomer：19FNMR(d6-benzene；6eq of(R)-(+)-1-(1-naphthyl)ethylamine)d-77.76(d，3F，J＝6.8Hz，R-enantiomer)，-77.74(d，3F，J＝6.8Hz，S-enantiomer).
example 611b
(2S) -7-benzyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The racemic mixture of the compound prepared in step 2 of example 42a was chirally resolved using the same protocol as step 1 of example 609e, identifying the S-enantiomer as peak 2 with a retention time of 10.00 min: ESHRMS M/z347.0894(M-H, C)19H14F3O3Calc’d347.0890).1HNMR(DMSO-d6/400MHz)13.19(brs，1H)，7.74(s，1H)，7.11-7.27(m，7H)，6.74(q，1H，J＝7.1Hz)，3.91(s，2H)，2.11(s，3H).S-isomer：19F NMR(d6-benzene；6eq of(R)-(+)-1-(1-naphthyl)ethylamine)d-77.76(d，3F，J＝6.8Hz，R-enantiomer)，-77.74(d，3F，J＝6.8Hz，S-enantiomer).
Example 611c
6- (benzyloxy) -7-bromo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1.4- (benzyloxy) -3-bromophenol preparation
MeOH (50mL) in K at room temperature 2CO3(49.36g, 357mmol) of the mixture was added dropwise to a solution of commercially available 2-bromobenzene-1, 4-diol (15g, 79mmol) in MeOH (25mL) followed by syringe addition of benzyl bromide (14.93g, 10.38 mL). The resulting mixture was refluxed for 8 hours. The reaction was cooled to room temperature, poured into saturated aqueous ammonium chloride (500mL), and extracted with ethyl acetate (2X 150 mL). The organic phases are combined and washed with NaHCO3Aqueous (2X 150mL), 1N aqueous HCl (2X 150mL) and brine (2X 150mL) and washed with Na2SO4Dried, filtered and concentrated in vacuo. The crude product was subjected to flash chromatography (silica, 10% ethyl acetate/hexane). ESLRMSm/z 280.9(M + H).
Step 2.5- (benzyloxy) -4-bromo-2-hydroxybenzaldehyde preparation
To a cooled solution of phenol (step 1) (4.7g, 16.8mmol) in ACN was added MgCl in portions2(1.92g, 20mmol) while maintaining the temperature below 10 ℃ followed by paraformaldehyde (2.52g, 84mmol) and TEA (9.5mL, 67mmol) produced an exotherm of 15 ℃. The mixture was heated to 72 ℃ for 2 hours. The reaction was cooled to room temperature, poured into saturated aqueous ammonium chloride (500mL), and extracted with ethyl acetate (2X 150 mL). The organic phases are combined and washed with NaHCO3Aqueous (2X 150mL), 1N aqueous HCl (2X 150mL) and brine (2X 150mL) and washed with Na 2SO4Dried, filtered and concentrated in vacuo. The crude product was subjected to flash chromatography (silica, 5% ethyl acetate/hexane). ESLRMS M/z 306.9(M + H).
Step 3 preparation of Ethyl 6- (benzyloxy) -7-bromo-2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of the aldehyde (step 2) (1.80g, 5.86mmol) in DMF (50mL) was added potassium carbonate (1.21g, 8.79mmol) and ethyl 4, 4, 4-trifluorocrotonate (1.97g, 11.7 mmol). The mixture was heated to 65 ℃ for 4 hours. The reaction was cooled to room temperature and poured into H2In O (150mL)Extracted with ethyl acetate (2X 150 mL). The organic phases are combined and washed with NaHCO3Aqueous (2X 50mL), 3N aqueous HCl (2X 50mL), and brine (2X 50mL) were washed with Na2SO4Drying, filtration and concentration in vacuo gave ethyl ester (2.4g, 89%). ESLRMS M/z 457.0(M + H).
Step 4.6- (benzyloxy) -7-bromo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid preparation
The ester was hydrolyzed and purified (step 3) (99%) using the same procedure as described in example 609 d:
ESHRMS m/z 426.9835(M-H，C18H11BrF3O4Calc’d 426.9787).1HNMR(DMSO-d6/400MHz)，13.13(s，1H)，7.79(s，1H)，7.32-7.46(m，7H)，5.89(q，1H，J＝7.1Hz)，5.11(s，2H).
example 611d
7-benzyl-6- (benzyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 7-benzyl-6- (benzyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of β -benzyl 9-BBN (11.58mL, 5.78mmol) in THF (20mL) was added a solution of the ester from step 3 of example 611c (1.32mL, 2.89mmol) in THF (25mL), and the resulting solution was stirred at room temperature for 15 min. To this solution was added Pd (dppf) Cl 2Cl2(0.118g, 5 mol%) and K3PO4(aq) (3.18mL, 6.36 mmol). The reaction was heated to 60 ℃ for 4 hours. The reaction was cooled to room temperature and poured into H2O (150mL), extracted with ethyl acetate (2X 150 mL). The organic phases are combined and washed with NaHCO3Aqueous (2X 50mL), 3N aqueous HCl (2X 50mL), and brine (2X 50mL) were washed with Na2SO4Dried, filtered and concentrated in vacuo. The crude product is subjected to flash chromatography (dioxygen)Silica, 2% ethyl acetate/hexanes). The desired fractions were collected, combined and the solvent removed in vacuo to yield ethyl ester (1.22g, 90%). ESLRMS M/z 469.1(M + H).
Step 2.7 preparation of benzyl-6- (benzyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 1) (99%):
ESLRMS m/z439.1127(M-H，C25H18F3O4，Calc’d439.1152).1HNMR(DMSO-d6/400MHz)，13.13(s，1H)，7.76(s，1H)，7.14-7.35(m，11H)，6.82(s，1H)，5.80(q，1H，J＝7.1Hz)，5.03(s，2H)，3.8(m，2H).
example 611e
7-benzyl-6-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of methyl 7-benzyl-6-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester from example 611d (step 1) (98%) was deprotected using the same protocol as described in example 609 n. ESLRMS M/z 365.0M + H.
Step 2.7 preparation of benzyl-6-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 1) (99%):
ESHRMS m/z 349.0641(M-H，C18H12F3O4Calc’d349.0682).1HNMR(DMSO-d6/400MHz)13.16(brs，1H)，9.41(s，1H)，7.73(s，1H)，
Example 611f
6-methyl-7- (2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-methyl-7- (2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester from step 2, example 609v (1.0g, 1.92mmol) was added to a stirred DMF solution (15 mL). Trimethylboroxine (0.672mL, 4.80mmol) and Pd (PPh) were added3)4(0.222g, 10 mol%) followed by K2CO3. The solution was heated to 100 ℃ for 8 hours. The solution was poured into water (50mL), extracted with ethyl acetate (2X 50mL), and the organic layers were combined and washed with 1N HCl (2X 50mL), followed by brine (2X 50 mL). Subjecting the organic layer to Na2SO4Drying, filtration and concentration in vacuo gave the ester (90%). The ester was used directly in the next step. ESLRMS nez 391.1(M + H).
Step 2.6 preparation of methyl-7- (2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 1) (94%):
ESHRMS m/z361.1074(M-H，C20H16F3O3Calc’d361.1046).1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.74(s，1H)，7.24(s，1H)，7.06-7.17(m，3H)，6.85(d，1H，J＝7.7Hz)，6.37(s，1H)，5.74(q，1H，J＝7.1Hz)，3.85(s，2H)，2.45(s，3H)，2.12(s，3H).
example 611g
7-benzyl-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of methyl 7-benzyl-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Iodomethane (106mg, 0.684mmol) was added dropwise to a stirred solution of DMF (5mL) containing the acid from step 2, example 611e (80mg, 0.228mmol) and K 2CO3(0.0946mg, 0.68 mmol). The mixture was heated to reflux for 8 hours. The reaction was cooled to room temperature, poured into 3N HCl (50mL) and extracted with ethyl acetate. The combined organic phases were washed with brine (2X 150mL) and Na2SO4Dried, filtered and concentrated in vacuo. The crude product was subjected to flash chromatography (silica, 5% ethyl acetate/hexane). The compound was of suitable purity and was used without further purification. ESLRMS 379.1(M + H).
Step 2.7 preparation of benzyl-6-methoxy-2- (trifluoromethyl! -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 1) (99%):
ESHRMS m/z 363.0857(M-H，C19H14F3O4Calc’d363.0839).1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.78(s，1H)，7.11-7.26(m，6H)，6.75(s，1H)，5.89(q，1H，J＝7.1Hz)，3.90(s，2H)，3.70(s，3H).
example 611h
7-benzyl-6-butoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1 preparation of butyl 7-benzyl-6-butoxy-2- (trifluoromethyl! -2H-chromene-3-carboxylate
The acid from step 2, example 611e was subjected to a similar protocol to that described in step 1, example 611g, with appropriate substitution by 1-iodobutane. ESLRMS 463.2(M + H).
Step 2.7 preparation of benzyl-6- (butoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 1) (92%):
ESHRMS m/z 405.1329(M-H，C22H20F3O4Calc’d405.1308).1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.77(s，1H)，7.16-7.25(m，5H)，7.08(s，1H)，6.80(s，1H)，5.89(q，1H，J＝7.1Hz)，3.89(m，2H)，1.62-1.66(m，2H)，1.33-1.38(m，2H)，0.87(t，3H，J＝7.1Hz).
Example 611i
7-benzyl-6- (pentyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1 preparation of pentyl 7-benzyl-6- (pentyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The acid from step 2, example 611e was subjected to a similar protocol to that described in step 1, example 611g, with appropriate substitution with 1-iodopentane. ESLRMS 491.2(M + H).
Step 2.7 preparation of benzyl-6- (pentyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 1) (91%):
ESHRMS m/z419.1501(M-H，C23H22F3O4Calc’d419.1465).1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.77(s，1H)，7.15-7.23(m，5H)，7.07(s，1H)，6.80(s，1H)，5.89(q，1H，J＝7.1Hz)，3.88(m，2H)，3.85(m，2H)，1.66(brs，2H)，1.29-1.30.(m，4H)，0.84(t，3H，J＝4Hz).
example 611j
7-benzyl-6-hexyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 7-benzyl-6-hexyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester from step 1 of example 41 was coupled and purified using a similar protocol to that described in step 1 of example 611d, with appropriate substitution of 1-hexene to give the ester (71%). ESLRMSm/z 447.2(M + H).
Step 2.7 preparation of benzyl-6-hexyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 1) (94%):
ESHRMS m/z417.1638(M-H，C24H24F3O3Calc’d417.1672).1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.77(s，1H)，7.09-7.27(m，5H)，6.73(s，1H)，5.89(q，1H，J＝7.1Hz)，3.93(s，2H)，2.41(s，2H)，1.32-1.37(m，2H)，1.18-1.23(m，6H)，0.80(t，3H，J＝6Hz).
example 611k
7-benzyl-6-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 7-benzyl-6-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester from step 1 of example 41 (87%) was coupled and purified using a similar protocol to that described in step 1 of example 611d, with appropriate substitution of 1-pentene. ESLRMS M/z 432.1(M + H).
Step 2.7-benzyl-6-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid preparation
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 1) (94%):
ESHRMS m/z403.1512(M-H，C23H22F3O3Calc’d403.1516).1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.77(s，1H)，7.09-7.28(m，6H)，6.73(s，1H)，5.89(q，1H，J＝7.1Hz)，3.94(s，2H)，2.41(m，2H)，1.32-1.36(m，2H)，1.18-1.22(m，4H)，0.77-0.81(m，3H).
example 611l
7-benzyl-6- (4-cyanobutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 7-benzyl-6- (4-cyanobutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester from step 1, example 41 was coupled and purified (51%) using a similar protocol to that described in step 1, example 611d, with the appropriate substitution of pent-4-enenitrile. ESLRMS M/z443.1(M + H).
Step 2.7 preparation of benzyl-6- (4-cyanobutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 1) (96%):
ESHRMS m/z414.1311(M-H，C23H19F3NO3Calc’d414.1312).1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.78(s，1H)，7.25-7.28(m，3H)，7.17-7.19(d，1H，J＝7.3Hz)，7.12(d，2H，J＝7.1Hz)，5.89(q，1H，J＝7.1Hz)，3.94(s，2H)，2.42(m，2H)，1.51(brs，4H).
example 611m
7-benzyl-6- (4-oxobutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 7-benzyl-6- (4-oxobutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester from step 1 of example 41 (62%) was coupled and purified using a similar protocol to that described in step 1 of example 611d, with appropriate substitution of 4, 4-diethoxybut-1-ene. ESLRMS M/z 433.1(M + H).
Step 2.7 preparation of benzyl-6- (4-oxobutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 1) (91%):
ESHRMS m/z403.1190(M-H，C22H18F3O4Calc’d403.1152).1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，9.59(s，1H)，7.78(s，1H)，7.24-7.28(m，3H)，7.10-7.18(m，3H)，6.73(s，1H)，5.89(q，1H，J＝7.1Hz)，3.96(s，2H)，3.23-3.28(m，2H)，2.29-2.43(m，2H)，1.63-1.67(m，2H).
example 611n
6- (5-amino-5-oxopentyl) -7-benzyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The acid from step 2, example 6111 (500mg, 1.12mmol) was added to a solution of KOH (0.189g, 3.30mL) in t-BuOH (20 mL). The solution was refluxed for 24 hours. The reaction was cooled to room temperature, poured into 3N aqueous HCl (25mL), and usedExtraction with ethyl acetate (2X 25 mL). The combined organic phases were washed with brine (2X 50mL) and Na2SO4Dried, filtered and concentrated in vacuo. The crude product was subjected to preparative reverse phase chromatography to afford the title compound (99%).
ESHRMS m/z 432.1423(M-H，C23H21F3NO4Calc’d 432.1455).1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.75(s，1H)，7.22-7.27(m，3H)，7.08-7.16(m，3H)，6.69(s，1H)，6.62(brs，2H)，5.80(q，1H，J＝7.1Hz)，3.91(s，2H)，2.70(m，2H)，1.95-1.99(m，2H)，1.35-1.46(m，4H).
Example 611o
7-benzyl-6-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1 preparation of propyl 7-benzyl-6-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
The acid from step 2, example 611e was subjected to a similar protocol as described in step 1, example 611g (98%) with appropriate substitution of 1-iodopropane. ESLRMS 435.1(M + H).
Step 2.7 preparation of benzyl-6-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 1) (97%):
ESHRMS m/z 391.1135(M-H，C21H18F3O4Calc’d391.1152).1HNMR(DMSO-d6/400MHz)，13.13(s，1H)，7.76(s，1H)，7.12-7.26(m，5H)，7.07(s，1H)，6.80(s，1H)，5.76(q，1H，J＝7.1Hz)，3.83(m，4H)，1.67(m，2H).0.91(m，3H).
example 611p
7-benzyl-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 7-benzyl-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
The acid from step 2, example 611e was subjected to a similar protocol as described in step 1, example 611g (97%) with appropriate substitution of 1-iodoethane. ESLRMS 407.1(M + H).
Step 2.7 preparation of benzyl-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 1) (99%):
ESHRMS m/z 377.1033(M-H，C20H16F3O4Calc’d377.0995).1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.75(s，1H)，7.12-7.26(m，5H)，7.07(s，1H)，5.76(q，1H，J＝7.1Hz)，3.97(m，2H)，3.88(m，2H)，1.30(m，3H).
example 611q
7-bromo-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1 preparation of methyl 7-bromo-6-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ester from example 611c (step 3) (95%) was deprotected using the same protocol as described in example 609 n. ESLRMS M/z 352.9(M + H).
Step 2. preparation of methyl 7-bromo-6-methoxy-2- ((trifluoromethyl) -2H-chromene-3-carboxylate
The ester (step 1) was subjected to a similar protocol as described in example 611g, step 1 (92%) with appropriate substitution with 1-iodomethane. ESLRMS 366.9(M + H).
Step 3.7 preparation of bromo-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 2) (96%):
ESHRMS m/z 350.9449(M-H，C12H7BrF3O4Calc’d350.9474).1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.82(s，1H)，7.50(s，1H)，7.29(s，1H)，5.89(q，1H，J＝7.1Hz)，2.46(t，3H，J＝30Hz).
example 611r
7-benzyl-6- (hexyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1 preparation of hexyl 7-benzyl-6- (hexyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The acid from step 2, example 611e was subjected to a similar protocol (95%) as described in step 1, example 611g, with appropriate substitution of 1-iodohexane. ESLRMS 519.2(M + H).
Step 2.7 preparation of benzyl-6- (hexyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester was hydrolyzed and purified using the same protocol as described in example 609d (step 1) (92%):
ESHRMS m/z433.1630(M-H，C24H24F3O4Calc’d433.1621).1HNMR(DMSO-d6/400MHz)，13.13(brs，1H)，7.77(s，1H)，7.11-7.24(m，5H)，5.89(q，1H，J＝7.1Hz)，3.80(m，2H)，3.79(m，2H)，1.61-1.68(m，2H)，1.20-1.33(m，4H)，0.84(t，3H，J＝7Hz).
example 612a
7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1.2 preparation of hydroxy-4-fluorobenzaldehyde
To a mixture of 3-fluorophenol (10mL, 102mmol), anhydrous magnesium chloride (28.2g, 744.6mmol) in 500mL anhydrous acetonitrile was added anhydrous triethylamine (67mL, 382.5mmol) and paraformaldehyde (22.3g, 744.6 mmol). The mixture was then heated to reflux for 5 hours. After cooling to room temperature, 500mL of 5% aqueous hydrochloric acid was added. The product was extracted with ethyl acetate. The combined organic extracts were washed with 5% hydrochloric acid (× 3), brine and dried over anhydrous magnesium sulfate. After removal of volatiles, the residue was a light pink solid. 11g, yield 72%.
M.P：67.5-69.0℃.ESHRMS m/z139.0211(M-H，C7H4FO2calc’d 139.0201).1H NMR(CDCl3/300MHz)11.40(s，1H)，9.86(s，1H)，7.62-7.57(m，1H)，6.79-6.67(m，2H).13C(CDCl3/300MH)195.4，168.3(d，J＝258Hz)，164.4(d，J＝14.9Hz)，136.3(d，J＝12.6Hz)，118.2(d，J＝2.0Hz)，108.5(d，J＝23.3Hz)，104.9(d，J＝24.4Hz).19F(CDCl3/400MHz)-97.9(m).
Step 2. preparation of ethyl 7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate
A mixture of 2-hydroxy-4-fluorobenzaldehyde (10g, 71.4mmol), ethyl 4, 4, 4-trifluorocrotonate (15mL, 100mmol) and anhydrous potassium carbonate (14.8g, 107.1mmol) in 40mL anhydrous dimethylformamide was heated to 90 ℃ for 5 hours. LC-MS indicated the reaction was complete. After cooling to room temperature, 500mL of ethyl acetate was added to the reaction. The organic phase was washed with brine (× 3) and then dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified on a silica gel column, eluting with 1: 18 EtOAc: hexane. 12.5g (60%) of a pale yellow oil are obtained.
LCMS(ES+)291.0(M+1，100)，EIHRMS m/z 290.0586(M-H，C13H9F4O3calc’d 290.0566).1H NMR(CDCl3/300MHz)7.73(s，1H)，7.30-7.22(m，1H)，6.79-6.73(m，2H)，5.76(q，1H，J＝6.9Hz)，4.38(m，2H)，1.37(t，3H，J＝7.2Hz).13C(CDCl3/300MH)167.2，164.0，163.9，155.0(d，J＝13.0Hz)，136.3(d，J＝1.28Hz)，131.0(d，J＝10.4Hz)，123.5(q，J＝287.5Hz)，115.0(dd，J＝2.4，7.3Hz)，110(d，J＝22.5Hz)，104.4(d，J＝26.0Hz)，71.0(q，J＝33.2Hz)，61.7(d，J＝10.4Hz)，14.4.19F(CDCl3/300MHz)-79.0(d，J＝6.5Hz)，-104.8m).
Step 3. preparation of Ethyl 7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
A mixture of ethyl 7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.45g, 1.54mmol) and isobutylamine (0.11g, 1.54mmol) was dissolved in anhydrous DMF (5mL), warmed to 90 ℃ with K2CO3(0.25g, 1.84 mmol). The mixture was maintained at 90 ℃ for 24 hours, cooled to room temperature, filtered through celite, and concentrated to a viscous oil (0.53g, 98%). No further purification was performed. LCMS M/z 344.00(M + H).
Step 4.7 preparation of (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Ethyl 7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.53g, 1.54mmol) was dissolved in a mixture of THF (5.0mL) and ethanol (5.0 mL). 2.5N sodium hydroxide (1.54mL) was added and the reaction was heated to 55 deg.C (oil bath) for 3 hours. The reaction was cooled to room temperature and stirred for 18 hours. The reaction was concentrated in vacuo to give a yellow oil. The oil was redissolved in water (20mL), acidified to pH about 1 with 2.4N HCl, and extracted with EtOAc (2X 20 mL). The combined extracts were washed with brine (20mL) and MgSO4Drying and filteringConcentration in vacuo afforded a yellow oil, which was subjected to preparative HPLC (reverse phase) and eluted with 50-95% ACN/water containing 0.05% TFA to afford a yellow solid (0.1g, 21%).
ESHRMSm/z314.1023(M-H，C15H15O3F3N，Calc’d 314.0999).1HNMR(CDCl3/400MHz)7.78(s，1H)，7.01(s，1H)，6.24(s，2H)，5.60(q，1H，J＝7.0Hz)，2.97(m，2H)，1.91(m，1H)，0.98(m，6H).
Example 612b
Preparation of 7- (neopentylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 7- (neopentylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (example 612a, step 2) (0.45g, 1.54mmol) and 3, 3-dimethylbutylamine (0.13g, 1.54mmol) were dissolved in anhydrous DMF (5mL), warmed to 90 ℃ with K2CO3(0.25g, 1.84 mmol). The mixture was maintained at 90 ℃ for 24 hours, cooled to room temperature, filtered through celite, and concentrated to a viscous oil (0.55g, 98%). No further purification was performed. LCMSM/z358.00(M + H).
Step 2.7 preparation of (neopentylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
7- (neopentyl amino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 612 a.
ESHRMSm/z328.1121(M-H，C16H17O3F3N，Calc’d 328.1155).1HNMR(CDCl3/400MHz)7.71(s，1H)，6.99(s，1H)，6.28(s，1H)，5.60(q，1H，J＝7.0Hz)，2.93(m，2H)，0.98(s，9H).
Example 612c
7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (example 612a, step 2) (0.45g, 1.54mmol) and 3, 3-dimethylbutylamine (0.13g, 1.54mmol) were dissolved in anhydrous DMF (5mL), warmed to 90 ℃ with K2CO3(0.25g, 1.84 mmol). The mixture was maintained at 90 ℃ for 24 hours, cooled to room temperature, filtered through celite, and concentrated to a viscous oil (0.55g, 98%). No further purification was performed. LCMSM/z358.00(M + H).
Step 2.7 preparation of- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 612 a.
ESHRMSm/z328.1112(M-H，C16H17o3F3N，Calc’d 328.1155).1H NMR(CDCl3/400MHz)7.78(s，1H)，7.03(s，1H)，6.29(m，1H)，6.23(s，1H)，5.62(q，1H，J＝7.0Hz)，3.17(m，2H)，3.03(s，3H)，2.05(m，1H)，0.93(s，6H).
Example 613a
6-bromo-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1.5 preparation of bromo-2-hydroxy-3-methylbenzaldehyde
A solution of 2-hydroxy-3-methylbenzaldehyde (1.0g, 7.35mmol) in acetic acid (6mL) was cooled to 0 deg.C (ice bath). Bromine (1.36g, 8.52mmol) was added dropwise and stirred for 2 hours. The reaction was allowed to warm to room temperature and diluted with water (100mL) to give a pale orange precipitate. The solid was filtered and washed with water (10 mL). Drying under high vacuum gave a light brown solid (1.4g, 88.6%).
1HNMR(CDCl3/400MHz)11.16(s，1H)，9.79(s，1H)，7.48(s，1H)，7.46(s，1H)，2.23(s，3H).
Step 2. preparation of ethyl 6-bromo-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Adding 5-bromo-2-hydroxy-3-methoxybenzaldehyde (1.40g, 6.51mmol) and K2CO3A mixture of (1.80g, 13.02mmol), triethylamine (2.63g, 26.05mmol) and ethyl 4, 4, 4-trifluorocrotonate (4.38g, 26.05mmol) in anhydrous DMSO (5.0mL) in dry N2Heat to 90 ℃ for 18 hours under atmosphere. The contents were poured into 2.4N HCl (50mL) and extracted with EtOAc (2X 100 mL). The combined extracts were washed with brine (100mL) and MgSO4Drying, filtration, and concentration in vacuo afforded a dark yellow oil which was subjected to flash chromatography (silica gel) eluting with 10% EtOAc in hexane afforded a yellow solid (1.6g, 68%).
GCMSm/z364.0(M+).1H NMR(CDCl3/400MHz)7.59(s，1H)，7.27(s，1H)，7.16(s，1H)，5.70(q，1H，J＝7.0Hz)，4.29(m，2H)，2.19(s，3H)，1.32(m，3H).
Step 3.6 preparation of bromo-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-bromo-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a.
ESHRMSm/z334.9526(M-H，C12H7O3F3Br，Calc’d 334.9525).1H NMR(CDCl3/400MHz)7.75(s，1H)，7.32(s，1H)，7.22(s，1H)，5.70(q，1H，J＝7.0Hz)，2.27(s，3H).
Example 613b
6-methoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of ethyl 8-methyl-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Tricyclohexylphosphine (0.08g, 0.28mmol) was reacted with Pd (dba)2A suspension of (0.07g, 0.12mmol) anhydrous dioxane (20mL) was stirred for 15 minutes to give a red solution. Ethyl 6-bromo-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.43g, 3.92mmol), potassium acetate (0.58g, 5.88mmol) and bis (pinacolato) diboron (1.09g, 4.31mmol) prepared in step 2, example 613a were added and the resulting mixture was heated to 80 deg.C (oil bath) for 18 hours. The contents were poured into water (20mL) and extracted with EtOAc (2X 40 mL). The combined extracts were washed with brine (20mL) and MgSO4Dried, filtered and concentrated in vacuo to give a dark green oil (1.62g, 98%). No further purification was performed. GCMSm/z412.0(M +). LCMSM/z413.0(M + H).
Step 2. preparation of ethyl 6-hydroxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8-methyl-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) -2H-chromen-3-carboxylate (1.62g, 3.92mmol) was dissolved in THF (25mL) and cooled to 0 ℃ (ice bath). Hydrogen peroxide (0.67g, 5.88mmol) was added dropwise followed by 2.5N sodium hydroxide (1.57mL) and the resulting solution was stirred for 3 hours. The contents were poured into water (40mL), acidified to pH about 1 with 2.4N HCl, and extracted with EtOAc (2X 40 mL). The combined extracts were washed with brine (20mL) and MgSO 4The mixture is dried and then is dried,filtration and concentration in vacuo afforded a yellow oil which was subjected to flash chromatography (silica gel) eluting with 0-100% EtOAc in hexanes to afford a yellow solid (0.84g, 71%).
GCMSm/z302.0(M+).LCMS m/z303.0(M+H).1H NMR(CDCl3/400MHz)7.59(s，1H)，6.60(s，1H)，6.51(s，1H)，5.64(q，1H，J＝7.0Hz)，4.28(m，2H)，2.17(s，3H)，1.31(m，3H).
Step 3. preparation of Ethyl 6-methoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 6-hydroxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.2g, 0.66mmol) and K2CO3(0.48g, 3.44mmol) was suspended in acetone (7.5 mL). Methyl iodide (0.93g, 6.60mmol) was added and heated to 55 ℃ for 3 hours. The contents were filtered through a celite plug and washed with acetone. The solution was concentrated in vacuo to give a yellow solid (0.22g, 98%).
GCMSm/z316.0(M+).LCMSm/z317.0(M+H).1H NMR(CDCl3/400MHz)7.64(s，1H)，6.72(s，1H)，6.55(s，1H)，5.65(q，1H，J＝7.0Hz)，4.28(m，2H)，3.73(s，3H)，2.20(s，3H)，1.32(m，3H)。
Step 4.6 preparation of methoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-methoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a.
ESHRMSm/z287.0529(M-H，C13H10O4F3，Calc’d287.0526).1H NMR(CDCl3/300MHz)7.78(s，1H)，6.76(s，1H)，6.58(s，1H)，5.64(q，1H，J＝7.0Hz)，3.74(s，3H)，2.21(s，3H).
Example 613c
6-ethoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-ethoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 6-hydroxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.2g, 0.66mmol), prepared in step 2, example 613b, and K 2CO3(0.48g, 3.44mmol) was suspended in acetone (7.5 mL). Iodothane (1.03g, 6.60mmol) was added and heated to 55 ℃ for 3 hours. The contents were filtered through a celite plug and washed with acetone. The solution was concentrated in vacuo to give an orange solid (0.22g, 98%).
GCMSm/z330.0(M+).LCMSm/z331.0(M+H).1H NMR(CDCl3/400MHz)7.62(s，1H)，6.71(s，1H)，6.55(s，1H)，5.65(q，1H，J＝7.0Hz)，4.28(m，2H)，3.93(m，2H)，2.19(s，3H)，1.33(m，6H).
Step 2.6-ethoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid preparation
6-ethoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a.
ESHRMSm/z301.0706(M-H，C14H12O4F3，Calc’d301.0682).1H NMR(CDCl3/300MHz)7.78(s，1H)，6.76(s，1H)，6.56(s，1H)，5.63(q，1H，J＝7.0Hz)，3.94(m，2H)，2.21(s，3H)1.36(m，3H).
Example 614a
7- [ isobutyl (methyl) amino ] -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl [ isobutyl (methyl) amino ] -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 6-chloro-7- [ isobutyl (methyl) amino prepared in example 8c]-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.50g, 1.28mmol), trimethylboroxine (0.38g, 2.75mmol), [ (tBu)3P)PdBr]2(0.01g) with Cs2CO3(0.75g, 2.31mmol) in dry diglyme (10.0mL) in dry N2Heat to 115 ℃ for 18 hours under atmosphere. The contents were poured into water (40mL) and extracted with EtOAc (2X 40 mL). The combined extracts were washed with brine (20mL) and MgSO4Drying, filtration and concentration in vacuo afforded a yellow oil which was subjected to HPLC (reverse phase) and eluted with 50-85% ACN/water containing 0.05% TFA to afford a yellow solid (0.21g, 45%). No further purification was performed. GCMSm/z371.0(M +). LCMSM/z372.0(M + H).
Step 2.7 preparation of- [ isobutyl (methyl) amino ] -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
7- [ isobutyl (methyl) amino ] -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a.
ESHRMSm/z342.1333(M-H，C17H19O3F3N，Calc’d342.1312).1H NMR(CDCl3/300MHz)7.79(s，1H)，7.02(s，1H)，6.67(s，1H)，5.62(q，1H，J＝7.0Hz)，2.95(m，2H)，2.85(s，3H)，2.29(m，3H)1.85(m，1H)，0.89(m，6H).
Example 614b
7- (isobutylamino) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 7- (isobutylamino) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
The ethyl 6-chloro-7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylate prepared in step 1, example 608b (2.10g, 5.57mmol), trimethylboroxine (1.58mL, 12.66mmol), [ (tBu [ ] -methyl ] borane complex3P)PdBr]2(0.04g) with Cs2CO3A mixture of (3.17g, 9.74mmol) in dry diglyme (10.0mL) in dry N2Heat to 115 ℃ for 18 hours under atmosphere. The contents were poured into water (40mL) and extracted with EtOAc (2X 40 mL). The combined extracts were washed with brine (20mL) and MgSO4Drying, filtration and concentration in vacuo afforded a yellow oil which was subjected to HPLC (reverse phase) eluting with 0-15% EtOAc in hexanes to afford a yellow oil (0.5g, 25%). No further purification was performed. GCMSm/z357.0(M +). LCMSM/z358.0(M + H).
Step 2.7- (isobutylamino) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid preparation
7- (isobutylamino) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to the one described in step 2, example 602 a.
ESHRMSm/z330.1310(M+H，C16H19O3F3N，Calc’d330.1312).1HNMR(CDCl3/300MHz)7.72(s，1H)，6.87(s，1H) 6.23(s，1H)，5.58(q，1H，J＝7.0Hz)，2.99(m，2H)，2.06(m，3H)1.95(m，1H)，0.98(m，6H).
Example 615
7-tert-butyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 7-tert-butyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 7-tert-butyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (1g, 2.75mmol) from step 2, example 8 was dissolved in diglyme (20 mL). Adding Cs to the above solution2CO3(1.5g, 3.07mmol), trimethylboroxine (0.75mL, 5.36mmol) and [ (t-Bu)3P)PdBr]2(20 mg). The mixture was heated to 115 ℃ under nitrogen for 15 hours. LCMS indicated 50% conversion. The reaction was cooled down and water was added to quench the reaction. The product was extracted with EtOAc and washed with water. The crude product was purified by RPHPLC to give 360mg of the desired product as an oil (38% yield) of suitable purity for use without further purification.
Step 2.7 preparation of tert-butyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
7-tert-butyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared as a yellow solid (93%) by a procedure similar to the method described in step 2, example 2 a:
ESHRMSm/z313.1056(M-H，C16H16O3F3，Calc’d313.1046)。1H NMR(acetone-d6/400MHz)7.78(s，1H)，7.17(s，1H)，6.98(s，1H)，5.74(q，1H，J＝7.2Hz)，2.47(s，3H)，1.38(s，9H).
Example 616
6, 8-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of ethyl 8-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Tricyclohexylphosphine (0.01g, 0.04mmol) was reacted with Pd (dba)2(0.01g, 0.02mmol) of anhydrous dioxane (3mL) suspension was stirred 1For 5 minutes, a red solution was obtained. Ethyl 6-bromo-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.2g, 0.52mmol), potassium acetate (0.78g, 0.78mmol) and bis (pinacolato) diboron (0.19g, 0.57mmol) prepared in step 2, example 605o were added and the resulting mixture was heated to 80 deg.C (oil bath) for 18 hours. The contents were poured into water (10mL) and extracted with EtOAc (2X 20 mL). The combined extracts were washed with brine (20mL) and MgSO4Dried, filtered and concentrated in vacuo to give a dark green oil (0.21g, 95%). No further purification was performed. GCMSm/z428.0(M +). LCMSM/z429.0(M + H).
Step 2. preparation of ethyl 6-hydroxy-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8-methoxy-6- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -2- (trifluoromethyl) -2H-chromen-3-carboxylate (0.21g, 0.49mmol) was dissolved in THF (3mL) and cooled to 0 ℃ (ice bath). Hydrogen peroxide (0.25g,. 074mmol) was added dropwise, followed by 2.5N sodium hydroxide (0.20mL), and the resulting solution was stirred for 3 hours. The contents were poured into water (20mL), acidified to pH about 1 with 2.4N HCl, and extracted with EtOAc (2X 20 mL). The combined extracts were washed with brine (20mL) and MgSO 4Drying, filtration, and concentration in vacuo afforded a yellow oil which was subjected to flash chromatography (silica gel) eluting with 0-35% EtOAc in hexanes to afford a yellow solid (0.1g, 65%).
LCMSm/z319.0(M+H).1HNMR(CDCl3/400MHz)7.58(s，1H)，6.50(s，1H)，6.29(s，1H)，5.66(q，1H，J＝7.0Hz)，4.29(m，2H)，3.86(s，3H)，1.32(m，3H).
Step 3. preparation of Ethyl 6, 8-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 6-hydroxy-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.1g, 0.31mmol) and K2CO3(0.23g, 1.64mmol) was suspended in acetone (5.0 mL). Methyl iodide (0.44g, 3.1mmol) was added and heated to 55 deg.CFor 3 hours. The contents were filtered through a celite plug and washed with acetone. The solution was concentrated in vacuo to give a yellow solid (0.05g, 50%).
GCMSm/z332.0(M+).LCMSm/z333.0(M+H).1H NMR(CDCl3/400MHz)7.64(s，1H)，6.54(8，1H)，6.32(s，1H)，5.68(q，1H，J＝7.0Hz)，4.28(m，2H)，3.85(s，3H)，3.75(s，3H)，1.32(m，3H).
Step 4.6 preparation of 6, 8-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6, 8-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a.
ESHRMSm/z303.0448(M-H，C13H10O5F3，Calc’d303.0475).1H NMR(CDCl3/300MHz)7.77(s，1H)，6.57(s，1H)，6.34(s，1H)，5.68(q，1H，J＝7.0Hz)，3.86(s，3H)，3.76(s，3H)。
Example 617
6- (hydroxymethyl) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1.4-hydroxy-5-methyl-m-phthalaldehyde preparation
4-hydroxy-3-methylbenzaldehyde (7.0g, 51.41mmol) and magnesium chloride (7.3g, 77.12mmol) were mixed in acetonitrile (100mL) and cooled to 0 deg.C (ice bath). Triethylamine (19.51g, 192.79mmol) was added to the above mixture, followed by paraformaldehyde (10.41g, 347mmol), and stirred for 1 hour. The mixture was warmed to room temperature and then heated to 90 ℃ for 18 hours. The contents were poured into water (100mL) and extracted with EtOAc (2X 100 mL). The combined extracts were washed with brine (50mL) and MgSO 4Drying, filtering, and vacuum dryingConcentration to give an off-white solid which was flash chromatographed (silica gel) using 100% CH2Cl2Elution afforded an off-white solid (2.2g, 26%). GCMSm/z164.0(M +).
1H NMR(CDCl3/400MHz)11.82(s，1H)，9.96(s，1H)，9.89(s，1H)，7.96(s，1H)，7.92(s，1H)，2.32(s，3H).
Step 2. preparation of Ethyl 6-formyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
4-hydroxy-5-methyl-m-phthalaldehyde (2.2g, 13.41mmol) and K2CO3A mixture of (3.70g, 26.82mmol), triethylamine (5.42g, 53.66mmol) and ethyl 4, 4, 4-trifluorocrotonate (9.01g, 53.66mmol) in anhydrous DMSO (5.0mL) in dry N2Heat to 90 ℃ for 18 hours under atmosphere. The mixture was then cooled, poured into 1.2N HCl (50mL), and extracted with EtOAc (2X 50 mL). The combined extracts were washed with brine (50mL) and MgSO4Drying, filtration and concentration in vacuo gave a yellow oil which was subjected to flash chromatography (silica gel) with 80% CH2Cl2Hexane elution gave a yellow solid (1.9g, 45%).
GCMSm/z314.0(M+).1H NMR(CDCl3/400MHz)9.85(s，1H)，7.75(s，1H)，7.66(s，1H)，7.61(s，1H)，5.82(q，1H，J＝7.0Hz)，4.33(m，2H)，2.31(s，3H)，1.32(m，3H).
Step 3. preparation of Ethyl 6- (hydroxymethyl) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
A solution of ethyl 6-formyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.9g, 6.05mmol) in a mixture of THF (10ml) and ethanol (10ml) was cooled to 0 deg.C (ice bath). To the above solution was added sodium borohydride (0.11g, 3.00mmol) in portions over 30 minutes. The mixture was poured into 1.2N HCl (10ml) and extracted with EtOAc (2X 20 ml). The combined extracts were washed with brine (20ml), dried over MgSO4, filtered and concentrated in vacuo to give a yellow oil (1.9g, 98%). No further purification was performed. GCMSm/z316.0(M +).
Step 4.6- (hydroxymethyl) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid preparation
6- (hydroxymethyl) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a.
LCMSm/z289.0(M+H).Anal.Calcd.forC13H11O4F3：C，54.2；H，3.8；F，19.8.Found：C，54.0；H，4.1；F，19.7.1H NMR(acetone-d6/400MHz)7.86(s，1H)，7.26(s，2H)，5.83(q，1H，J＝7.0Hz)，4.55(s，2H)，2.24(s，3H).
Example 618
8-methyl-2- (trifluoromethyl) -2H-chromene-3, 6-dicarboxylic acid
Step 1.3 preparation of formyl-4-hydroxy-5-methylbenzoic acid
4-hydroxy-3-methylbenzoic acid (10.1g, 66.38mmol) was suspended in methanesulfonic acid (50mL) and cooled to 0 deg.C (ice bath). Hexamethylenetetramine (18.6g, 132.75mmol) was added portionwise over 1 hour. The reaction was allowed to warm to room temperature, followed by heating to 90 ℃ (oil bath) for 5 hours. The reaction was cooled to room temperature and stirred for 18 hours. The contents were poured into water (100mL) and extracted with EtOAc (2X 100 mL). The combined extracts were washed with brine (50mL) and MgSO4Drying, filtration and concentration in vacuo gave an off-white solid (9.0g, 75%).
1H NMR(DMSO/400MHz)12.84(brs，1H)，11.40(s，1H)，10.09(s，1H)，8.20(s，1H)，7.98(s，1H)，2.21(s，3H).
Step 2.3- (ethoxycarbonyl) -8-methyl-2- (trifluoromethyl) -2H-chromene-6-carboxylic acid preparation
3-formyl-4-hydroxy-5-methylbenzoic acid (8.8g, 48.89mmol), K2CO3A mixture of (13.49g, 97.78mmol), triethylamine (19.79g, 195.56mmol) and ethyl 4, 4, 4-trifluorocrotonate (32.85g, 195.56mmol) in anhydrous DMSO (20.0mL) in dry N 2Heat to 90 ℃ for 18 hours under atmosphere. The mixture was then cooled, poured into 2.0N HCl (100mL), and extracted with EtOAc (2X 100 mL). The combined extracts were washed with brine (100mL) and MgSO4Dried, filtered and concentrated in vacuo to give an oily solid. Redissolved in acetone to give a white precipitate, filtered and dried under high vacuum (7.2g, 51%).
GCMSm/z330.0(M+).1H NMR(DMSO/400MHz)12.99(s，1H)，8.11(s，1H)，8.06(s，1H)，7.94(s，1H)，6.19(q，1H，J＝7.0Hz)，4.35(m，2H)，2.31(s，3H)，1.36(m，3H).
Step 3.8 preparation of methyl-2- (trifluoromethyl) -2H-chromene-3, 6-dicarboxylic acid
8-methyl-2- (trifluoromethyl) -2H-chromene-3, 6-dicarboxylic acid was prepared by a procedure similar to that described in step 2, example 602 a.
ESHRMSm/z301.0328(M-H，C13H8O5F3，Calc’d301.0318).1H NMR(DMSO/400MHz)7.92(s，1H)，7.91(s，1H)，7.81(s，1H)，6.02(q，1H，J＝7.0HHz)，2.20(s，3H)。
Example 619a
6, 8-dichloro-5, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
5, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from example 34(WO00/23433) (150mg, 0.49mmol) in acetic acid (1.0mL) the solution was stirred at 10 ℃. Adding previously prepared Cl to the above solution2Acetic acid solution (gas) (1.1mL, 0.64 mmol). The mixture was stirred for 2 hours. Blow off Cl2After (gassing), Zn powder (5eq) was added to the mixture and the mixture was stirred for 30 minutes. The Zn salt was removed by filtration and the filtrate was evaporated to dryness. The residue was purified by RPHPLC eluting with 30 to 85% ACN in water containing 0.05% TFA. The 2 nd peak fractions were combined to give the desired compound 45mg (24.6%) as the dichloro compound:
LCMSm/z372.95(M+H)at 5.878min.ESHRMSm/z370.9743(M-H，C13H8O5F3Cl2，Calc’d 370.9695).1H NMR(CDCl3/400MHz)7.93(s，1H)，6.00(q，1H，J＝6.8Hz)，3.97(s，3H)，3.94(s，3H).
Example 619b
6-chloro-5, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
A solution of 5, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from example 34(WO00/23433) (150mg, 0.49mmol) in acetic acid (1.0mL) was stirred at 10 ℃. Adding previously prepared Cl to the above solution2Acetic acid solution (gas) (1.1mL, 0.64 mmol). The mixture was stirred for 2 hours. Blow off Cl2After (gassing), Zn powder (5eq) was added to the mixture and the mixture was stirred for 30 minutes. The Zn salt was removed by filtration and the filtrate was evaporated to dryness. The residue was purified by RPHPLC eluting with 30 to 85% ACN in water containing 0.05% TFA. The peak 1 fractions were combined to give 28.6mg (17.2%) of the desired compound as the monochloro compound:
LCMSm/z339.05(M+H)at 5.474min.ESHRMSm/z337.0112(M-H，C13H9O5F3Cl，Calc’d337.0085).1H NMR(CDCl3/400MHz)7.90(s，1H)，6.67(s，1H)，5.82(q，1H，J＝6.8Hz)，3.97(s，3H)，3.94(s，3H).
example 620
6-fluoro-7-methoxy-8- (methoxymethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 8- (bromomethyl) -6-chloro-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 6-chloro-7-methoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate from step 3, example 3a (3.3g, 9.4mmol) was dissolved in CCl4(30mL), the solution was heated to 60 ℃. To the warm solution was added NBS (1.84g, 10.3mmol) and Bzo 2O (100mg), the reaction was heated to reflux overnight. To the warm solution was added additional NBS (1.84g, 10.3mmol) and Bzo2O (100mg), the reaction was heated for 2 hours. LCMS indicated > 95% product formation. The reaction was cooled down and the solid was filtered off. The filtrate is treated with NaHCO3And a brine wash. The organic layer was dried over anhydrous MgSO4Drying and evaporating to dryness. The crude product is used as it is (1H NMR indicated 40/60 starting material/product ratio).
Step 2. preparation of methyl 6-chloro-7-methoxy-8- (methoxymethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The crude 8- (bromomethyl) chromene ester (4.1g, 9.5mmol) was dissolved in MeOH (40 mL). To the above solution was added NaOMe (25%) (6.15g, 28.5 mmol). The reaction was stirred at room temperature for 3 hours. LCMS indicated the formation of four new major peaks with no starting material present. The mixture was purified by Biotage chromatography to give 0.49g of the title compound as a yellow oil (14% over 2 steps). LCMSM/z389.05(M + Na).
Step 3.6-chloro-7-methoxy-8- (methoxymethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid preparation
6-chloro-7-methoxy-8- (methoxymethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared as a yellow solid (yield 64%) by a procedure similar to the one described in step 2, example 602 a:
ESHRMSm/z351.0254(M-H，C14H11O5F3Cl，Calc’d351.0242).1HNMR(acetone-d6/400MHz)7.87(s，1H)，7.61(s，1H)，5.89(q，1H，J＝7.2Hz)，4.49(d，2H，J＝2.8Hz)，3.91(s，3H)，3.34(s，3H).
Example 621a
8-benzyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of ethyl 8-benzyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
To beta-benzyl 9-BBN (4.12mL, 0.5M in THF, 2.06mmol) with Pd (dPPf) Cl-CH at room temperature2Cl2(58.8mg, 0.0721mmol) in dry THF (6mL) was added 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid ester (01597/1PR) (500mg, 1.03mmol), prepared in step 2, example 21a, followed by K3PO4Aqueous solution (1.16mL, 2.0M, 2.32 mmol). The resulting mixture turned black within 30 seconds and refluxed for 1.5 hours. The mixture was then poured into aqueous HCl (100mL, 1.0N) and extracted with EtOAc (200 mL). The layers were separated and the EtOAc layer was washed with brine (100mL) over MgSO4Dried, filtered and concentrated in vacuo to give a brown oil. Purification by chromatography on silica (9: 1 hexane: EtOAc) gave, in assumed quantitative yield, the impure product as a yellow crystalline solid: EIHRMSm/z446.0933(M +, C)21H16F6O4CalculatingValue 446.0953).
Step 2.8 preparation of benzyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To the ester prepared in step 1 (480mg, 1.08mmol) in 7: 2: 1 THF: EtOH: H 2Solution in O mixture (10mL) was added LiOH-H2O (67.7mg, 1.61 mmol). The mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was redissolved in H2O, acidified with 1N HCl and extracted with EtOAc (200 mL). The EtOAc extract was over MgSO4Dried, filtered and concentrated in vacuo to yield 440mg of crude product. Purification by reverse phase chromatography (acetonitrile: H containing 0.05% TFA)2O) to give 327mg (73% yield) of the product as a light yellow crystalline solid:
EIHRMSm/z418.0618(M+，C19H12F6O4，Calc’d418.0640).1H NMR(dmso-d6/300MHz)13.40(brs，1H)，7.86(s，1H)，7.46(s，1H)，7.27-7.13(m，6H)，5.98(q，J＝7.3Hz，1H)，3.93(s，2H).
example 621b
8-acetyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (2.41g, 5.00mmol), n-butynyl vinyl ether (3.22mL, 25.0mmol), Pd (OAc) prepared in step 2, example 21a2(33.4mg, 0.150mmol), DPPP (136mg, 0.330mmol) and K2CO3(0.830g, 6.00mmol) in DMF (12.5mL) with H2The mixture in O (1.5mL) was stirred at 100 ℃ for 17 hours. After the mixture was cooled to room temperature, 1N HCl (20mL) was added and the mixture was stirred for 30 min and then extracted with EtOAc (2X 200 mL). Combining the extracts with H2O (200mL), brine (100mL), over MgSO4Drying and filtering. The solvent was removed in vacuo to give the crude product as a dark brown oil. Purification by silica chromatography (20% EtOAc in hexanes with 1% HOAc) afforded 0.940g (47% yield) of the product as a tan crystalline solid:
EIHRMSm/z370.0258(M+，C14H8F6O5，Calc’d370.0276)1H NMR(dmso-d6/300MHz)13.59(brs，1H)，7.95(s，1H)，7.85(d，1H，J＝2.8Hz)，7.58(dd，1H，J＝4.0，2.2Hz)，6.19(q，1H，J＝7.0Hz)，2.58(s，3H).
Example 621c
8-phenyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 8-phenyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.500g, 1.04mmol), prepared in step 2, example 21a, phenylboronic acid (133mg, 1.09mmol), Pd (OAc)2(7.00mg, 0.031mmol), triphenylphosphine (24.4mg, 0.093mmol) and NaHCO3(132mg, 1.25mmol) in toluene (25mL) with H2The mixture in O (5mL) was stirred at room temperature for 21 hours, then refluxed for 1 hour. Adding Pd (PPh)3)4(120mg, 0.104mmol) and the mixture was refluxed for 1.5 hours. LCMS indicated a slight increase in product. To the above mixture was added additional Pd (PPh)3)4(120mg，0.104mmol)、NaHCO3(132mg, 1.25mmol) and phenylboronic acid (133mg, 1.09mmol), and EtOH (10mL), and the mixture was refluxed overnight. After cooling, the mixture was poured onto brine (100mL) and extracted with EtOAc (100 mL). The EtOAc layer was separated over MgSO4Drying and filtering. The crude product was purified by silica chromatography (0-10% EtOAc-hexanes),336mg (85% yield) of the product are obtained as an off-white solid: EIHRMSm/z432.0807(M +, C)20H14F6O4Calculated 432.0796).
Step 2.8 preparation of phenyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To the ester prepared in step 1 (327mg, 0.756mmol) in 7: 2: 1 THF: EtOH: H2Solution in O mixture (10mL) was added LiOH-H2O (47.6mg, 1.13 mmol). The mixture was stirred at room temperature for 17 hours. The solvent was removed in vacuo and the residue was redissolved in H2O, filtered and acidified with 1N HCl. Filtering the obtained crystalline solid, and adding H2O wash and dry in vacuo to afford 292mg (95% yield) of product as a white solid:
EIHRMSm/z404.0506(M+，C18H10F6O4，Calc’d404.0483).1H NMR(dmso-d6/300MHz)13.48(brs，1H)，7.94(s，1H)，7.64(d，1H，J＝2.2Hz)，7.50-7.38(m，6H)，5.98(q，1H，J＝7.3Hz)。
example 621d
(2R) -8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Racemic 8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared in step 2, example 21b (130mg) was resolved by Chiral separation using a Chiral Pak AD column eluting with IPA/heptane/TFA (5/95/0.1) and detected at 230nm as peak 1 with a retention time of 3.28 min to give 59mg (47% yield) of the product as the R-enantiomer:
EIHRMSm/z342.0356(M+，C13H8F6O4，Calc’d342.0327)；1H NMR(dmso-d6，400MHz)13.42(brs，1H)，7.85(s，1H)，7.42(m，1H)，7.31(m，1H)，5.99(q，1H，J＝7.3Hz)，2.20(s，3H).19F NMR(d6-benzene；6eq(of(R)-(+)-1-(1-naphthyl)ethylamine)-58.33(s，3F)，-78.23(d，3F，J＝7.2Hz，R-enantiomer)，-58.34(s，3F)，-78.21(d，3F，J＝7.2Hz，S-enantiomer).
example 621e
(2S) -8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Racemic 8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared in step 2, example 21b (130mg) was resolved by Chiral separation using a Chiral Pak AD column eluting with IPA/heptane/TFA (5/95/0.1) and detected at 230nm as peak 2 with a retention time of 3.97 min to give 57.1mg (45% yield) of the product as the S-enantiomer:
EIHRMSm/z342.0315(M+，C13H8F6O4，Calc’d342.0327)；1H NMR(dmso-d6，400MHz)13.41(brs，1H)，7.86(s，1H)，7.42(m，1H)，7.31(m，1H)，5.99(q，J＝7.3Hz，1H)，2.20(s，3H).19F NMR(d6-benzene；6eq of(R)-(+)-1-(1-naphthyl)ethylamine)-58.33(s，3F)，-78.23(d，3F，J＝7.2Hz，R-enantiomer)，-58.34(s，3F)，-78.21(d，3F，J＝7.2Hz，S-enantiomer)。
Example 621f
8- (aminomethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate
A mixture of 8-cyano-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (445mg, 1.26mmol) prepared in step 2, example 21p, and 10% Pd/C (100mg) in glacial acetic acid (20mL) was hydrogenated at 20psi for 1H, releasing the pressure. After standing overnight, the catalyst was filtered and the solvent removed in vacuo. Purification by reverse phase chromatography (acetonitrile: H containing 0.05% TFA)2O), 200mg (57% yield) of product is obtained:
ESHRMSm/z358.0510(M+H，C13H10F6O4，Calc’d 358.0509)；1H NMR(dmso-d6/300MHz)13.8(brs，1H)，8.29(brs，3H)，7.96(s，1H)，7.70(s，1H)，7.57(s，1H)，6.08(q，1H，J＝7.1Hz)，4.11(dd，2H，J＝17.7，5.84Hz).
example 621g
(2R) -8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Racemic 8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (1.56g) prepared in example 21i was resolved by Chiral separation using a Chiral Pak AD column eluting with IPA/heptane/TFA (2/98/0.1) and detected at 280nm as peak 1 with a retention time of 6.10 min to give 658mg (42% yield) of product as a pale yellow solid as the R-enantiomer:
ESHRMSm/z 369.0562(M-H，C15H11F6O4，Calc’d369.0567)；1H NMR(dmso-d6，300MHz)13.33(brs，1H)，7.87(s，1H)，7.44(d，1H，J＝2.2Hz)，7.26(d，1H，J＝2.4Hz)，5.99(q，1H，J＝7.3Hz)，2.65-2.47(m，2H)，1.60-1.48(m，2H)，0.86(t，3H，J＝7.3Hz).19F NMR(d6-benzene；6eq of(R)-(+)-1-(1-naphthyl)ethylamine)-58.33(s，3F)，-77.98(d，3F，J＝7.2Hz，R-enantiomer)，-58.35(s，3F)，-77.96(d，3F，J＝7.2Hz，S-enantiomer).
example 621h
(2S) -8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Racemic 8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (1.56g) prepared in example 21i was resolved by Chiral separation using a Chiral Pak AD column eluting with IPA/heptane/TFA (2/98/0.1) and detected at 280nm as peak 2 with a retention time of 7.15 min to give 735mg (47% yield) of product as a pale yellow solid as the S-enantiomer:
ESHRMSm/z369.0549(M-H，C15H12F6O4，Calc’d369.0567)；1H NMR(dmso-d6，300MHz)13.35(brs，1H)，7.87(s，1H)，7.44(d，1H，J＝2.2Hz)，7.26(d，1H，J＝2.4Hz)，5.99(q，1H，J＝7.3Hz)，2.65-2.47(m，2H)，1.60-1.48(m，2H)，0.86(t，3H，J＝7.3Hz).19F NMR(d6-benzene；6eq of(R)-(+)-1-(1-naphthyl)ethylamine)-58.33(s，3F)，-77.98(d，3F，J＝7.2Hz，R-enantiomer)，-58.35(s，3F)，-77.96(d，3F，J＝7.2Hz，S-enantiomer).
Example 621i
8- (1-hydroxyethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To 8-acetyl-6- (R) -prepared in example 621b at 0 deg.C under N2 atmosphereA solution of trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (0.980g, 2.65mmol) in a mixture of THF (25mL) and absolute EtOH (25mL) was added NaBH in portions4(0.100g, 2.65 mmol). After 15 minutes the ice bath was removed and the mixture was stirred at room temperature for 2.75 hours. The mixture was then poured into ice water (100mL), saturated with NaCl and extracted with EtOAc (2X 200 mL). The combined extracts were washed with brine and MgSO4Drying, filtration and concentration in vacuo gave the crude product as a pale yellow solid. Purification by silica chromatography (0% to 25% EtOAc: hexanes gradient) afforded the crude product, which was further purified by crystallization from acetonitrile to afford 516mg (52% yield) of the product as an off-white crystalline solid:
ESHRMSm/z371.0378(M-H，C14H9F6O5，Calc’d 371.0354)；1H NMR(dmso-d6，300MHz)13.42(brs，1H)，7.89(s，1H)，7.93(d，1H，J＝2.6Hz)，7.42(s，1H)，6.42(q，1H，J＝7.3Hz)，5.41(m，1H)，4.96(d，1H，J＝3.4Hz)，1.29(d，3H，J＝6.2Hz).
example 621j
8- (pyridin-2-ylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1 preparation of ethyl 8- (pyridin-2-ylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.00g, 2.07mmol), 2-pyridylacetylene (419. mu.L, 4.15mmol), CuI (39mg, 0.207mmol), PdCl prepared in step 2, example 21a 2(dppf)2-CH2Cl2A mixture of (169mg, 0.207mmol) and TEA (0.866mL, 6.21mmol) in dry toluene (10mL) at room temperatureN2Stirred under atmosphere for 5 days. The mixture was then diluted with hexane and purified by silica chromatography (0% to 75% EtOAc: hexane gradient) to give 0.73g (77% yield) of the title product as a light yellow crystalline solid: ESHRMSm/z458.0849(M + H, C)21H14F6NO4Calculated 458.0822).
Step 2.8 preparation of- (pyridin-2-ylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from step 1 was hydrolyzed via a similar procedure as described in step 2 of example 621c, using HOAc in the acidification step, to give the product as a light yellow solid:
ESHRMSm/z430.0507(M+H，C19H10F6NO4，Calc’d 430.0509)；1H NMR(drnso-d6，300MHz)13.55(brs，1H)，8.62(d，1H，J＝4.2Hz)，7.93(s，1H)，7.90-7.84(m，1H)，7.73-7.62(m，3H)，7.47-7.42(m，1H)，6.18(q，1H，J＝7.1Hz).
example 621k
8- (pyridin-3-ylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1 preparation of Ethyl 8- (pyridin-3-ylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.00g, 2.07mmol), 3-pyridylacetylene (419. mu.L, 4.15mmol), CuI (39mg, 0.207mmol), PdCl prepared in step 2, example 21a2(dppf)2-CH2Cl2A mixture of (169mg, 0.207mmol) and TEA (0.866mL, 6.21mmol) in dry toluene (10mL) at room temperature N 2Stirred under atmosphere for 5 days. The mixture is then diluted with hexane andpurification by silica chromatography (0% to 75% EtOAc: hexanes gradient) afforded 0.68g (72% yield) of the product as a light yellow crystalline solid: ESHRMSm/z458.0827(M + H, C)21H14F6NO4Calculated 458.0822).
Step 2.8 preparation of- (pyridin-3-ylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from step 1 was hydrolyzed via a similar procedure as described in step 2 of example 621c, using HOAc in the acidification step, to give the product as a light yellow solid:
ESHRMSm/z430.0527(M+H，C19H10F6NO4，Calc’d430.0509)；1H NMR(dmso-d6，300MHz)13.57(brs，1H)，8.73(d，1H，J＝1.2Hz)，8.62(dd，1H，J＝4.8，1.4Hz)，7.97-7.93(m，2H)，7.72(m，1H)，7.67(m，1H)，7.49(dd，1H，J＝7.9，5.0Hz)，6.17(q，1H，J＝7.0Hz).
example 621l
8- (pyridin-4-ylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1 Ethyl 8- (pyridin-4-ylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.00g, 2.07mmol), 4-pyridylacetylene (419. mu.L, 4.15mmol), CuI (39mg, 0.207mmol), PdCl prepared in step 2, example 21a2(dPPf)2-CH2Cl2A mixture of (169mg, 0.207mmol) and TEA (0.866mL, 6.21mmol) in dry toluene (10mL) at room temperature N2Stirred under atmosphere for 5 days. The mixture was then diluted with hexane and purified by silica chromatography (0% -75% EtOAc: hexane) Gradient) to yield 0.34g (36% yield) of the product as a light yellow crystalline solid: ESHRMSm/z458.0822(M + H, C)21H14F6NO4Calculated 458.0822).
Step 2.8 preparation of- (pyridin-4-ylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from step 1 was hydrolyzed via a similar procedure as described in step 2 of example 621c, using HOAc in the acidification step, to give the product as a light yellow solid:
ESHRMSm/z430.0531(M+H，C19H10F6NO4，Calc’d 430.0509)；1H NMR(dmso-d6，300MHz)14.5(brs，1H)，8.64(d，2H，J＝5.7Hz)，7.58-7.48(m，5H)，6.08(q，1H，J＝7.3Hz).
example 621m
8- (2-pyridin-2-ylethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
A mixture of 8- (pyridin-2-ylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (684mg, 1.59mmol), prepared in step 2, example 621j, and 10% Pd/C (100mg) in glacial acetic acid (20mL) was hydrogenated at 20psi for 2.5H. The catalyst was filtered, the solvent removed in vacuo, and the remaining HOAc removed azeotropically with hexane to give the crude product as a tan solid. Trituration of the solid with acetonitrile gave 362mg (53% yield) of the product as an off-white solid:
ESHRMSm/z434.0834(M+H，C19H14F6NO4，Calc’d 434.0822)；1H NMR(dmso-d6/300MHz)13.43(brs，1H)，8.50(d，1H，J＝4.8Hz)，7.90(s，1H)，7.67(t，1H，J＝7.7Hz)，7.46(s，1H)，7.26-7.17(m，3H)，6.06(q，1H，J＝7.3Hz)，3.32-3.01(m，4H).
example 621n
8- (3-pyridin-2-ylethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
A mixture of 8- (pyridin-3-ylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (455mg, 1.06mmol), prepared in step 2, example 621k, and 10% Pd/C (100mg) in glacial acetic acid (20mL) was hydrogenated at 20psi for 3.5H. An additional 10% Pd/C (200mg) was added and the mixture was hydrogenated at 20psi for 1 hour. The catalyst was then filtered, the solvent removed in vacuo, and the remaining HOAc removed azeotropically with hexane to give the crude product as a solid. The solid was suspended in MeOH and acetonitrile was added. The suspension was stirred, the solid was filtered, washed with acetonitrile and dried in vacuo to give 308mg (68% yield) of the product as an off-white solid:
ESHRMSm/z434.0835(M+H，C19H14F6NO4，Calc’d 434.0822)；1HNMR(dmso-d6/300MHz)13.40(brs，1H)，8.38-8.34(m，2H)，7.88(s，1H)，7.55(d，1H，J＝7.7Hz)，7.45(d，2H，J＝2.2Hz)，7.29-7.25(m，1H)，7.16(d，1H，J＝2.2Hz)，6.04(q，1H，J＝7.3Hz)，2.96-2.85(m，4H).
Example 621o
8- (4-pyridin-2-ylethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
8- (pyridin-4-ylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (241mg, 0.562mmol), prepared in step 2, example 6211, was reacted with 10% Pd/C(500mg) A mixture in glacial acetic acid (10mL) was hydrogenated at 20psi for 8.5 h. An additional 10% Pd/C (200mg) was added and the mixture was hydrogenated at 20psi for 1 hour. An additional 10% Pd/C (100mg) was added and the mixture was hydrogenated at 20psi for 23 hours. An additional 10% Pd/C (200mg) was added and the mixture was hydrogenated at 20psi for 1 hour. The catalyst was then filtered, the solvent removed in vacuo, and the remaining HOAc removed azeotropically with hexane to give the crude product as a yellow oil. Purification by reverse phase chromatography (acetonitrile: 0.05% TFA-H)2O), 82mg (34% yield) of product was obtained as a tan foam:
ESHRMSm/z434.0844(M+H，C19H14F6NO4，Calc’d 434.0822)；1H NMR(dmso-d6/300MHz)13.48(brs，1H)，8.71(s，2H)，7.92(s，1H)，7.66(d，J＝4.8Hz，2H)，7.50(s，1H)，7.28(s，1H)，6.06(q，1H，J＝7.3Hz)，3.18-2.99(m，4H).
example 621p
8- [ ({2- [ 3-carboxy-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromen-8-yl ] ethyl } amino) methyl ] -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromen-3-carboxylic acid trifluoroacetate
A mixture of 8-cyano-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (445mg, 1.26mmol) prepared in step 2, example 21p, and 10% Pd/C (100mg) in glacial acetic acid (20mL) was hydrogenated at 20psi for 1H, releasing the pressure. After standing overnight, the catalyst was filtered and the solvent removed in vacuo. Purification by reverse phase chromatography (acetonitrile: 0.5% TFA-H) 2O), 140mg (32% yield) of product is obtained:
ESHRMSm/z698.0694(M+H，C26H16F12NO8，Calc’d698.0679)；1H NMR(dmso-d6/300MHz)13.6(brs，1H)，13.1(brs，1H)，9.39(brs，2H)，9.39(brs，2H)，7.95-7.93(m，2H)，7.72-7.70(m，2H)，7.63-7.59(m，2H)，6.00-5.91(m，2H)，4.29-4.17(m，4H).
example 621q
8- (1, 2-dihydroxyethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 8- (1, 2-dihydroxyethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
To ethyl 6- (trifluoromethoxy) -2- (trifluoromethyl) -8-vinyl-2H-chromene-3-carboxylate prepared in step 1, example 21n (2.00g, 5.23mmol) in acetone (40mL) with H2Solution in O (6mL) mixture was added 4-methylmorpholine-N-oxide (1.23g, 10.5mmol) followed by OsO4(0.655mL, 2.5 wt% isobutanol solution, 0.0523mmol) and the resulting mixture stirred at room temperature for 5 hours. Then Na is added2SO3(3.55g, 20.4mmol) of H2O (10mL) solution and the mixture extracted with EtOAc (2X 200 mL). The combined extracts were washed with brine and MgSO4Dried, filtered and concentrated in vacuo. Crystallization from EtOAc-hexanes yielded 0.510g (27% yield) of product a as a crystalline solid: ESHRMSm/z415.0616(M-H, C)16H13F6O6Calculated 415.0592). The filtrate was concentrated in vacuo and the residue was purified by silica chromatography (0% to 75% EtOAc-hexanes gradient) to give 1.51g (69% yield) of product B as a colorless solid: ESHRMSm/z415.0616(M-H, C) 16H13F6O6Calculated 415.0592). The products A and B have different diastereomer ratios.
Step 2.8 preparation of- (1, 2-dihydroxyethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from product B from step 1 was hydrolyzed at 50 ℃ for 1 hour via a method similar to that described in step 2, example 621a to afford the product (7: 3 mixture of diastereomers) as an off-white solid:
ESHRMSm/z387.0259(M-H，C14H9F6O6，Calc’d387.0303)；1H NMR(dmso-d6，300MHz)13.40(brs，1H)，7.89(s，1H)，7.49(d，1H，J＝2.7Hz))，7.40(s，1H)，5.98(q，1H，J＝7.3Hz)，5.56(brs，0.7Hz)，5.48(brs，0.3H)，4.85(brs，1.4H)，4.79(brs，0.6H)，3.56-3.48(m，1H)，3.31-3.26(m，1H).
example 621r
8- (1, 2-dihydroxyethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from product a, step 1, example 621q was hydrolyzed at 50 ℃ for 1 hour via a method similar to that described in step 2, example 621a to afford the product (a 1: 9 mixture of diastereomers) as an off-white solid:
ESHRMSm/z387.0281(M-H，C14H9F6O6，Calc’d 387.0303)；1H NMR(dmso-d6，300MHz)13.41(brs，1H)，7.89(s，1H)，7.48(d，1H，J＝2.6Hz))，7.39(d，1H，J＝2.0Hz)，6.01(q，1H，J＝7.3H)，5.55(brs，0.1H)，5.48(brs，0.9H)，4.84(brs，2H)，3.57-3.53(m，1H)，3.31-3.25(m，1H).
example 621s
8- (carboxymethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1 preparation of tributyl (ethoxyethynyl) stannane
An n-butyllithium solution (18.7mL, 1.6M hexane solution, 30.0mmol) was added to anhydrous ether (20mL), and the resulting mixture was cooled to-30 to-40 ℃. A solution of ethoxyacetylene (5.00g, 40% in hexane, 28.5mmo1) in diethyl ether (10mL) was then added dropwise over 10 minutes. The resulting suspension was warmed to room temperature, tributyltin chloride (9.29g, 28.5mmol) was added dropwise over 10 minutes, and the mixture was stirred for 2 hours. The mixture was filtered through a pad of celite, washed with ether and concentrated in vacuo to give the crude product in assumed quantitative yield as a red oil:
1H NMR(dmso-d6/300MHz)4.04(q，2H，J＝7.05Hz)，1.54-1.44(m，6H)，1.34-1.21(m，12H)，0.96-0.78(m，15H)。
Step 2 preparation of ethyl 8- (ethoxyethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (01597/1PR) (10.6g, 21.9mmol), prepared in step 2 of example 21a, crude tributyl (ethoxyethynyl) stannane (10.4g, assumed 28.5mmol), triethylammonium chloride (3.63g, 21.9mmol) and Pd (PPh), prepared in step 1, were reacted with acetone to prepare a mixture3)2A mixture of (0.769g, 1.10mmol) in DMF (140mL) was stirred at room temperature overnight. Then the mixture is taken up with H2Diluted with O and extracted with ether (2X 200 mL). The combined extracts were washed with brine and MgSO4Dried, filtered and concentrated in vacuo. Purification by silica chromatography (5% -6.5% EtOAc: hexanes gradient) afforded 4.06g (44% yield) of the product as a yellow crystalline solid:
1H NMR(dmso-d6/300MHz)7.95(s，1H)，7.55(d，1H，J＝2.0Hz)，7.37(d，1H，J＝2.2Hz)，6.11(q，1H，J＝7.3Hz)，4.32-4.20(m，4H)，1.39(t，3H，J＝7.1Hz)，1.26(t，3H，J＝7.2Hz).
step 3 preparation of Ethyl 8- (2-ethoxy-2-oxoethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8- (ethoxyethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate prepared in step 2 (1.73g, 4.08mmo1) in acetone (32mL) with H2Solution in O (8mL) mixture with H2SO4(0.800g, 8.15mmol) and the resulting mixture stirred at room temperature for 2.5 h. Then saturated NaHCO was added 3(200mL) and then solid K was added2CO3The product was extracted with EtOAc (300 mL). The EtOAc solution was washed with brine, MgSO4Dried, filtered and concentrated in vacuo. The crude product was purified by silica chromatography (0% to 15% EtOAc-hexanes gradient) to give 1.47g (82% yield) of the product as a yellow crystalline solid: EIHRMS M/z 442.0880(M +, C)18H16F6O6Calculated 442.0851).
Step 4.8 preparation of (carboxymethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from step 1 was hydrolyzed via a similar procedure as described in step 2 of example 621a to give the product as a light yellow solid:
ESHRMSm/z385.0143(M-H，C14H7F6O6，Calc’d 385.0152)；1H NMR(dmso-d6，300MHz)13.3(brs，1H)，12.6(brs，1H)，7.90(s，1H)，7.53(d，1H，J＝24Hz)，7.38(d，1H，J＝2.2Hz)，5.98(q，1H，J＝7.2Hz)，3.67-3.55(m，2H)。
example 621t
8- (2-hydroxyethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1.8 preparation of (ethoxyethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from example 21s step 2 was hydrolyzed via a similar procedure as described in example 621a step 2, using HOAc in the acidification step, to give the product as a yellow solid: ESLRMSm/z397.0(M + H, C)16H10F6O5Calculated 396.0).
Step 2.8- (2-ethoxy-2-oxoethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid preparation
To the crude product from step 1 (2.13g) in acetone (80mL) with H 2Solution in O (10mL) mixture was added H2SO4(0.250g, 2.55mmo1), and the resulting mixture was stirred at room temperature for 2.5 hours. Brine (200mL) was added and the mixture was extracted with EtOAc (2X 100 mL). The combined extracts were washed with brine and MgSO4Drying, filtration and concentration in vacuo gave 2.10g of the crude product as a yellow oil: ESLRMSm/z414.0(M + H, C)16H12F6O6Calculated 415.0).
Step 3.8 preparation of- (2-hydroxyethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a solution of crude ethyl 8- (2-ethoxy-2-oxoethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (2.10g) prepared in step 2, example 621s in 1: 1 THF-ethanol (100mL) was added NaBH4(3.00g, 79.3mmol) and the mixture was stirred at room temperature for 1 hour. Then add additional NaBH4(3.00g, 79.3mmol) and the mixture was stirred for 4 hours. Then add additional NaBH4(3.00g，79.3mmol), the mixture is stirred for 3 hours. Addition of H2O (50mL), the mixture was stirred for 30 min. Brine (100mL) was added and the mixture was acidified with 1N HCl and extracted with EtOAc (2X 200 mL). The combined extracts were washed with brine (100mL) and MgSO4Dried, filtered and concentrated in vacuo. The crude product was purified by silica chromatography (25% EtOAc/1% HOAc in hexanes to 100% EtOAc/1% HOAc in hexanes) to afford an off-white crystalline solid. Recrystallization from EtOAc-hexanes yielded 427mg (23% yield) of the product as an off-white crystalline solid:
ESHRMSm/z371.0334(M-H，C14H9F6O5，Calc’d 371.0354)；1H NMR(dmso-d6/300MHz)13.40(brs，1H)，7.88(s，1H)，7.45(d，1H，J＝2.2Hz)，7.28(d，1H，J＝2.4Hz)，5.99(q，1H，J＝7.3Hz)，4.70(s，1H)，3.57(s，2H)，2.77-2.71(m，2H).
Example 621u
8- (1-hydroxy-1-methylethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1 preparation of Ethyl 8-acetyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (9.64g, 20.0 mmol 1), n-butynyl vinyl ether (12.9mL, 100mmol), Pd (OAc) prepared in step 2, example 21a2(135mg, 0.600mmol), DPPP (544mg, 1.32mmol) and K2CO3(3.32g, 24.0mmol) in DMF (50mL) with H2The mixture in O (6mL) mixture was stirred at 100 ℃ for 46 hours. After cooling the mixture to room temperature, 1N HCl (100mL) was added and the mixture was extracted with EtOAc (2)X200 mL). Combining the extracts with H2O (200mL), brine (100mL), over MgSO4Drying and filtering. The solvent was removed in vacuo and the crude product was purified by silica chromatography (20% EtOAc in hexanes with 1% HOAc) to afford 2.12g (29% yield) of 8-acetyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared in example 21b and 1.44g (18% yield) of the title compound as a yellow crystalline solid: ESHRMSm/z399.0654(M + H, C)16H13F6O5Calculated 399.0662).
Step 2 ethyl 8- (1-hydroxy-1-methylethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Drying N at-78 deg.C2Methyl magnesium bromide (1.30mL, 3.0M in ether, 3.90mmol) was added dropwise over 5 minutes to a solution of ethyl 8-acetyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.35g, 3.39mmol) prepared in step 1 in anhydrous THF (40mL) under an atmosphere. The mixture was stirred at-78 ℃ for 2 hours, then warmed to room temperature over 1 hour, and then saturated NH was added4Cl (20mL) was quenched. After stirring overnight, brine (100mL) was added and the mixture was extracted with EtOAc (2X 200 mL). The combined extracts were washed with brine (50mL) and MgSO4Dried, filtered and concentrated in vacuo to give a yellow oil. The crude product was purified by silica chromatography (0% to 20% EtOAc in hexanes) to give 700mg (50% yield) of the product as a yellow crystalline solid: EIHRMSm/z414.0895(M-H, C)17H16F6O5Calculated 414.0902).
Step 3.8 preparation of- (1-hydroxy-1-methylethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from step 2 was hydrolyzed via a similar method as described in step 2 of example 621c to give the product as an off-white solid:
ESHRMSm/z385.0498(M-H，C15H11F6O5，Calc’d 385.0511)；1H NMR(dmso-d6，300MHz)13.40(brs，1H)，7.87(s，1H)，7.58(d，1H)，J＝2.6Hz)，7.47(d，1H，J＝2.6Hz)，6.05(q，1H，J＝7.3Hz)，5.39(s，1H)，1.50(s，3H)，1.46(s，3H).
Example 621v
8-isopropyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To 8- (1-hydroxy-1-methylethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared in step 3, example 621u, anhydrous CH (200mg, 0.518mmol)2Cl2(10mL) solution triethylsilane (414. mu.L, 2.59mmol) was added and the mixture was stirred for 5 min. TFA (400. mu.L, 5.18mmol) was then added and the mixture was stirred at room temperature for 20 h. Additional triethylsilane (8.18mL, 51.8mmol) was then added and the mixture was stirred for 2 hours. Additional TFA (4.00mL, 51.8mmol) was added and the mixture was stirred at room temperature for 6 days. The mixture was concentrated in vacuo and the crude product was purified by reverse phase chromatography (acetonitrile: 0.05% TFA-H)2O), 150mg (78% yield) of the product is obtained as a white crystalline solid:
ESHRMSm/z369.0526(M-H，C15H11F6O4，Calc’d 369.0562；1H NMR(dmso-d6/300MHz)13.39(brs，1H)，7.87(s，1H)，7.44(d，1H，J＝1.8Hz)，7.27(d，1H，J＝2.6Hz)，6.01(q，1H，J＝7.3Hz)，3.24-3.17(m，1H)，1.18(d，3H，J＝7.0Hz)，1.16(d，3H，J＝6.9Hz).
example 621w
8-hydroxy-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1 preparation of ethyl 8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (2.01g, 4.16mmol), pinacolborane (1.81mL, 12.5mmol), Pd (dPPf) Cl-CH prepared in step 2, example 21a 2Cl2A solution of (170mg, 0.208mmol) and TEA (2.32mL, 16.6mmol) in anhydrous dioxane (10.0mL) was heated to 80 ℃ for 2 days. Additional pinacolborane (1.81mL, 12.5mmol) and Pd (dPPf) Cl-CH were added2Cl2(170mg, 0.208mmol) and the mixture was heated as above for 20 h. The mixture was poured into brine (100mL) and extracted with EtOAc (200 mL). The extract was passed over MgSO4Dried, filtered and concentrated in vacuo. The crude product was purified by silica chromatography (0% to 60% EtOAc in hexanes) to give 1.18g (59% yield) of the product as a yellow oil:
1H NMR(dmso-d6/300MHz)7.95(s，1H)，7.73(d，1H，J＝2.6Hz)，7.42(d，1H，J＝2.2Hz)，6.00(q，1H，J＝7.3Hz)，4.29-4.19(m，2H)，1.27-1.23(m，15H)。
step 2. preparation of ethyl 8-hydroxy-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of ethyl 8- (4, 4, 5, 5-tetramethyl-1, 3, 2-dioxaborolan-2-yl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (600mg, 1.24mmol) prepared in step 1 in THF (20mL) at 0 deg.C was added 30% H2O2(192. mu.L, 1.86mmol) and aqueous NaOH (500. mu.L, 2.5N, 1.25mmol), and the mixture was warmed to room temperature. After stirring for 3.5 h, the mixture was acidified with 1N HCl, brine (50mL) was added and the mixture was extracted with EtOAc (200 mL). The extract was passed over MgSO4Dried, filtered and concentrated in vacuo to afford a yellow crystalline solid. The crude product was purified by silica chromatography (0% to 25% EtOAc in hexanes) to give 422mg (91% yield) of the product as an off-white solid: EIHRMSm/z372.0421(M +, C) 14H10F6O5Calculated 372.0432).
Step 3.8 preparation of hydroxy-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from step 2 was hydrolyzed via a similar method as described in step 2 of example 621c to give the product as an off-white solid:
ESHRMSm/z343.0047(M-H，C12H5F6O5，Calc’d 343.0036)；1H NMR(dmso-d6，300MHz)13.39(brs，1H)，10.33(brs，1H)，7.80(s，1H)，7.02(d，1H，J＝1.8Hz)，6.84(d，1H，J＝2.0Hz)，5.90(q，1H，J＝7.3Hz).
example 621x
8-methoxy-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of ethyl 8-methoxy-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 8-hydroxy-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (165mg, 0.442mmol), prepared in step 2, example 621w, methyl iodide (82.8. mu.L, 1.33mmol), KI (7.34mg, 0.0442mmol), K2CO3A mixture of (184mg, 1.33mmol) in dry DMF (5.0mL) was stirred at room temperature for 17 h. The mixture was then poured into brine (100mL) and extracted with EtOAc (2X 100 mL). The combined extracts were washed with brine and MgSO4Drying and filtering the mixture inConcentration in vacuo gave a tan solid. The crude product was purified by silica chromatography (0% to 25% EtOAc in hexanes) to afford the product in assumed quantitative yield as an off-white crystalline solid: EIHRMSm/z386.0593(M +, C)15H12F6O5Calculated 386.0589).
Step 2.8 preparation of methoxy-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from step 1 was hydrolyzed via a similar method as described in step 2 of example 621c to give the product as an off-white solid:
ESHRMSm/z397.0217(M-H，C13H7F6O5，Calc’d 357.0192).1H NMR(dmso-d6，300MHz)13.53(brs，1H)，7.88(s，1H)，7.18(s，7H)，7.15(d，1H，J＝2.2Hz)，5.98(q，1H，J＝7.3Hz)，3.83(s，3H).
example 621y
8-ethoxy-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 8-ethoxy-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The title compound was prepared via a method similar to example 621x step 1 to give the product as an off-white solid: EI HRMSm/z400.0723(M +, C)16H14F6O5Calculated 400.0745).
Step 2.8 preparation of ethoxy-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The ester from step 1 was hydrolyzed via a similar method as described in step 2 of example 621c to give the product as an off-white solid:
ESHRMSm/z371.0306(M-H，C14H9F6O5，Calc’d 371.0349)；1H NMR(dmso-d6，300MHz)13.41(brs，1H)，7.85(s，1H)，7.17(s，1H).7.13(d，1H，J＝2.4Hz)，6.00(q，1H，J＝7.3Hz)，4.17-4.02(m，2H)，1.30(t，3H，J＝7.1Hz).
example 622
6-chloro-8-methoxy-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of ethyl 8-methoxy-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 5-bromo-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (2.3g, 6.037mmol), trimethylboroxine (0.84mL, 6.04mmol), PdCl from example 24a step 1 2(dPPf)2.CH2Cl2(0.487g, 0.604mmol) and Cs2CO3(5.9g, 18.11mmol) was mixed in dioxane (15mL) containing 10% water. The mixture was heated to 11 ℃ for 6 hours at room temperature overnight. The mixture was diluted with EtOAc and the organic layer was washed with water and MgSO4And (5) drying. The filtrate was concentrated and purified by Biotage chromatography eluting with 5% EtOAc in hexanes to give 1.41g of a yellow solid (74%): LCMSM/z317.15(M + H), 6.225min.
Step 2. preparation of ethyl 6-chloro-8-methoxy-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Ethyl 6-chloro-8-methoxy-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by a procedure similar to that described in step 1, example 619b as a yellow oil (100%) with appropriate purity and was used without further purification.
Step 3.6 preparation of chloro-8-methoxy-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
6-chloro-8-methoxy-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was prepared as a white solid by a procedure similar to the method described in step 2, example 602a (yield 20.5%):
ESHRMSm/z321.0163(M-H，C13H9O4F3Cl，Calc’d 321.0136).1H NMR(acetone-d6/400MHz)8.01(s，1H)，7.16(s，1H)，5.83(q，1H，J＝7.2Hz)，3.88(s，3H)，2.42(s，3H).
example 623a
6- (benzyloxy) -8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
To a solution of the carboxylic acid prepared in step 2, example 17d (332.8mg, 0.8650mmol) in EtOH (10mL) was added aqueous NaOH (1.728mL, 0.5006N, 0.8650 mmol). The solvent was removed in vacuo, the resulting solid was redissolved in water and filtered to remove turbidity. The solvent was removed in vacuo and the resulting solid dried in high vacuum to give 293mg (86% yield) of the product as a yellow crystalline solid:
1H NMR(dmso-d6/300MHz)7.44-7.29(m，5H)，7.20s，1H)，6.99(s，2H)，5.91(q，J＝7.5Hz，1H)，5.04(s，2H).
Example 623b
8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Using the carboxylic acid from example 21b, step 2, sodium 8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared via a method similar to that described in example 623a to give the product as an off-white solid:
1HNMR(dmso-d6/300MHz)7.23(s，1H)，7.17(m，1H)，7.09(m，1H)，5.93(q，J＝7.5Hz，1H)，2.16(s，3H).
example 623c
(2R) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
(2R) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from example 91 was dissolved in a small amount of EtOH. To the above solution was added dropwise NaOH (0.5016N, Aldrich) (1 eq of free acid) via a burette. The solvent was removed in vacuo and the resulting solid was redissolved in water. The solvent was removed in vacuo and dried in high vacuum to give the sodium salt.
1HNMR(DMSO-d6/400MHz)7.81(s，1H)，7.61(s，1H)，7.25-7.29(m，2H)，7.17-7.19(m，3H)，6.99(s，1H)，5.89(q，1H，J＝7.1Hz)，4.00(s，2H).
Example 623d
6-Ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Using the carboxylic acid from example 34a, sodium 6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by a similar procedure as described in example 623 a.
1H NMR(DMSO-d6/300MHz)7.21(s，1H)，7.08(d，1H，J＝1.6Hz)，7.00(dd，1H，J＝8.1，1.6Hz)，6.79(d，1H，J＝8.1Hz)，5.83(q，1H，J＝7.2Hz)，2.51(q，2H，J＝7.5Hz)，1.14(t，3H，J＝7.5Hz).
Example 623e
6-chloro-7- (2, 4-dimethylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
6-chloro-7- (2, 4-dimethylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from example 9s step 7 was dissolved in a small amount of EtOH. To the above solution was added dropwise NaOH (0.5016N, Aldrich) (1 eq of free acid) via a burette. The solvent was removed in vacuo and the resulting solid was redissolved in water. The solvent was removed in vacuo and dried in high vacuum to give the sodium salt.
1HNMR(DMSO-d6/400MHz)7.81(s，1H)，7.64(s，1H)，7.00(s，1H)，6.92(d，1H，J＝8.0Hz)，6.81(d，1H，J＝7.7Hz)，6.53(s，1H)，5.86(q，1H，J＝7.1Hz)，3.91(s，2H)，2.22(s，3H)，2.10(s，3H).
Example 623f
(2R) -8-Ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Using the carboxylic acid from example 211, sodium (2R) -8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by a method similar to that described in example 623a to give the product as an off-white solid:
1H NMR(dmso-d6/300MHz)7.25(s，1H)，7.18(m，1H)，7.07(m，1H)，5.94(q，J＝7.6Hz，1H)，2.68-2.51(m，2H)，1.11(t，J＝7.3Hz).
example 623g
6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Sodium 6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by a similar procedure as described in example 623a using the carboxylic acid from example 7d (01598/1 PR).
CASE01598/1PR.1H NMR(D2O/400MHz)7.12(s，1H)，7.00(s，1H)，6.62(s，1H)，5.61(q，1H，J＝7.0Hz)，3.08(m，2H)，2.63(m，1H)，0.97(m，6H).
Example 623h
6-chloro-7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Using the carboxylic acid from example 608b, sodium 6-chloro-7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by a similar procedure as described in example 623 a.
1H NMR(D2O/400MHz)7.20(s，1H)，7.09(s，1H)，6.25(s，1H)，5.60(q，1H，J＝7.0Hz)，2.86(m，2H)，1.78(m，1H)，0.80(m，6H)。
Example 623i
8-acetyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Using the carboxylic acid from example 621b, sodium 8-acetyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared via a similar procedure as described in example 623a to give the product as a tan solid:
1HNMR(dmso-d6/300MHz)7.65(d，1H，J＝2.8Hz)，7.41(d，1H，J＝2.2Hz)，7.37(s，1H)，6.10(q，1H，J＝7.5Hz)，2.57(s，3H).
Example 623j
(2S) -8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Using the carboxylic acid from example 621e, sodium (2S) -8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared via a similar procedure as described in example 623a to give the product as an off-white solid: ESLRMSm/z343.0(M + H, C)13H9F6O4Calculated 343.0).
Example 63k
(2R) -6-chloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Sodium (2R) -6-chloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by a similar procedure as described in example 623a using the carboxylic acid from example 608 f.
1H NMR(D2O/400MHz)7.21(s，1H)，7.12(s，1H)，6.62(s，1H)，5.61(q，1H，J＝7.0Hz)，2.67(m，2H)，2.52(s，3H)，1.71(m，1H)，0.68(m，6H)。
Example 623l
Sodium (2R) -6-chloro-7- (3, 3-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
(2R) -6-chloro-7- (3, 3-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid, from example 609g, was dissolved in a small amount of EtOH. To the above solution was added dropwise NaOH (0.5016N, Aldrich) (1 eq of free acid) via a burette. The solvent was removed in vacuo and the resulting solid was redissolved in water. The solvent was removed in vacuo and dried in high vacuum to give the sodium salt.
1HNMR(DMSO-d6/400MHz)7.80(s，1H)，7.55(s，1H)，7.01(s，1H)，5.89(q，1H，J＝7.1Hz)，3.30(m，2H)，2.56-2.60(m，2H)，1.31-1.37(m，2H)，0.91(s，9H).
Example 623m
(2S) -8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Using the carboxylic acid from example 621H, sodium (2S) -8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared via a similar procedure as described in example 623a to give the product as an off-white solid:
1H NMR(dmso-d6/300MHz)7.26(s，1H)，7.20(s，1H)，7.06(s，1H)，5.95(q，1H，J＝7.5Hz)，2.79-2.44(m，2H)，1.59-1.49(m，2H)，0.87(t，3H，J＝7.3Hz).
example 623n
(2S) -6-chloro-8-isopropyl-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Using the carboxylic acid from example 606c, sodium (2S) -6-chloro-8-isopropyl-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by a similar procedure as described in example 623 a.
1H NMR(D2O/400MHz)7.54(s，1H)，7.12(s，1H)，5.64(q，1H，J＝7.0Hz)，3.08(m，1H)，2.22(s，3H)，1.01(m，6H)。
Example 623o
6-chloro-7- (cyclohexylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
6-chloro-7- (cyclohexylmethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from example 609i was dissolved in a small amount of EtOH. To the above solution was added dropwise NaOH (0.5016N, Aldrich) (1 eq of free acid) via a burette. The solvent was removed in vacuo and the resulting solid was redissolved in water. The solvent was removed in vacuo and dried in high vacuum to give the sodium salt.
1HNMR(DMSO-d6/400MHz)7.79(s，1H)，7.54(s，1H)，6.93(s，1H)，5.89(q，1H，J＝7.1Hz)，2.48-2.54(m，2H)，1.50-1.58(m，6H)，1.02-1.11(m，3H)，0.91-.097(m，2H).
Example 623p
6-chloro-7- (4-formylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Sodium 6-chloro-7- (4-formylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by a procedure similar to that described in example 623a using the carboxylic acid from example 604 g.
1H NMR(acetone-d6/400MHz)10.00(s，1H)，7.84(d，2H，J＝8.1Hz)，7.58(s，1H)，7.42(d，2H，J＝8.1Hz)，7.18(s，1H)，6.76(s，1H)，6.00(q，1H，J＝7.2Hz)，4.08(m，2H，J＝5.7Hz).
Example 623q
(2R) -6-chloro-7- (4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Using the carboxylic acid from example 604e, sodium (2R) -6-chloro-7- (4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by a similar procedure to that described in example 623 a.
1H NMR(acetone-d6/400MHz)7.42(s，1H)，7.18(s，1H)，7.08(m，4H)，6.69(s，1H)，5.91(q，1H，J＝7.6Hz)，3.96(m，2H)，2.25(s，3H).
Example 623r
Sodium (2S) -6-chloro-8-methyl-7- (3-methylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
Sodium (2S) -6-chloro-8-methyl-7- (3-methylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by a similar procedure as described in example 623a using the carboxylic acid from example 603 b.
1H NMR(acetone-d6/400MHz)7.51(s，1H)，6.96(s，1H)，6.06(q，1H，J＝7.2Hz)，3.85(m，2H)，1.89(m，1H)，1.62(m，2H)，0.95(d，6H，J＝6.4Hz).
Example 623s
6-methyl-7- (2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
6-methyl-7- (2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from step 3, example 611f was dissolved in a small amount of EtOH. To the above solution was added dropwise NaOH (0.5016N, Aldrich) (leq as free acid) via a burette. The solvent was removed in vacuo and the resulting solid was redissolved in water. The solvent was removed in vacuo and dried in high vacuum to give the sodium salt.
1HNMR(DMSO-d6/400MHz)，7.74(s，1H)，7.24(s，1H)，7.06-7.17(m，3H)，6.85(d，1H，J＝7.7Hz)，6.37(s，1H)，5.74(q，1H，J＝7.1Hz)，3.85(s，2H)，2.45(s，3H)，2.12(s，3H).
Example 623t
(2R) -6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
Using the carboxylic acid from example 607c, sodium (2R) -6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate was prepared by a similar procedure as described in example 623 a.
1H NMR(D2O/400MHz)7.20(s，1H)，7.16(s，1H)，6.74(s，1H)，5.65(q，1H，J＝7.0Hz)，2.72(m，2H)，1.78(m，1H)，0.90(m，6H)。
Example 623u
(2S) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
(2S) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from example 9m was dissolved in a small amount of EtOH. To the above solution was added dropwise NaOH (0.5016N, Aldrich) (1 eq of free acid) via a burette. The solvent was removed in vacuo and the resulting solid was redissolved in water. The solvent was removed in vacuo and dried in high vacuum to give the sodium salt.1HNMR(DMSO-d6/400MHz)7.81(s，1H)，7.61(s，1H)，7.25-7.29(m，2H)，7.17-7.19(m，3H)，6.99(s，1H)，5.89(q，1H，J＝7.1Hz)4.00(s，2H).
Example 623v
6-chloro-7- (4-chlorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
6-chloro-7- (4-chlorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from step 3, example 9o was dissolved in a small amount of EtOH. To the above solution was added dropwise NaOH (0.5016N, Aldrich) (1 eq of free acid) via a burette. The solvent was removed in vacuo and the resulting solid was redissolved in water. The solvent was removed in vacuo and dried in high vacuum to give the sodium salt.
1HNMR(DMSO-d6/400MHz)7.82(s，1H)，7.61(s，1H)，7.33(d，2H，J＝8.3Hz)，7.20(d，2H，J＝8.3Hz)，7.03(s，1H)，5.91(q，1H，J＝7.1Hz)，4.00(s，2H).
Example 623w
5, 8-dichloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
5, 8-dichloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from step 2 of example 133 was dissolved in a small amount of EtOH. To the above solution was added dropwise NaOH (0.5016N, Aldrich) (1 eq of free acid) via a burette. The solvent was removed in vacuo and the resulting solid was redissolved in water. The solvent was removed in vacuo and dried in high vacuum to give the sodium salt.
1HNMR(Methanol-d4/400MHz)8.00(s，1H)，5.90(q，1H，J＝7.1Hz)，3.99(s，3H)，3.78(s，3H).
Example 623x
6-isopropyl-7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
(2S) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from example 156 was dissolved in a small amount of EtOH. To the above solution was added dropwise NaOH (0.5016N, Aldrich) (1 eq of free acid) via a burette. The solvent was removed in vacuo and the resulting solid was redissolved in water. The solvent was removed in vacuo and dried in high vacuum to give the sodium salt.
1HNMR(DMSO-d6/400MHz)7.58(s，1H)，7.24(s，1H)，6.76(s，1H)，5.81(q，1H，J＝7.5Hz)，2.95-3.06(m，1H)，2.26(s，1H)，1.16(s，3H)，1.14(s，3H).
Example 623z
(2R) -6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
(2R) -6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid from example 9e was dissolved in a small amount of EtOH. To the above solution was added dropwise NaOH (0.5016N, Aldrich) (1 eq of free acid) via a burette. The solvent was removed in vacuo and the resulting solid was redissolved in water. The solvent was removed in vacuo and dried in high vacuum to give the sodium salt.
1HNMR(DMSO-d6/400MHz)7.81(s，1H)，7.5(s，1H)，6.97(s，1H)，5.89(q，1H，J＝7.1Hz)，2.51(d，2H，J＝6.7Hz)，1.85-1.89(m，1H)0.843(m，6H).
Preparation of 6-chloro-7-aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
General method for preparing 6-chloro-7-aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid by parallel synthesis
Step 1. preparation of Ethyl 6-chloro-7- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of 325mg (1.0mmol) ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 2.5mL DMF were added 172mg (1.1mmol) 2-chloro-4, 5-dimethylphenol and 193.5mg (1.4mmol) potassium carbonate. The suspension was prepared in a sealed vial and placed in an aluminum heating zone equipped with a magnetic stirring device. The aluminum zone was heated to 110 ℃ for 16 hours. After allowing the vial to cool, the mixture was treated with 10mL of water and 2mL of diethyl ether. The organic layer was removed and the aqueous layer was extracted twice with diethyl ether. The organic extracts were combined, filtered through 5g of silica, and the silica was washed with 10mL of diethyl ether. In N 2The filtrate was concentrated under gas flow to give an off-white solid which was used for the next step without further purification:
1HNMR(CDCl3/300MHz)1.36(t，3H，J＝7.2Hz)，2.25，(s，3H)，2.27(s，3H)，4.32(m，2H)，5.66(q，1H，J＝6.8Hz)，6.27(s，1H)，6.93(2，1H)，7.25(s，1H)，7.33(s，1H)，7.66(s，1H)；19F NMR(CDCl3/300MHz)-78.9(d，3F，J＝6.2Hz).
step 2.6 preparation of chloro-7- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
In a suitable vial, 400mg of lithium hydroxide-hydrate, 1mL of water, 2mL of methanol and 7mL of THF were added to the product of step 1. The vial was sealed in an aluminum heating zone and heated to 100 ℃ for 30 minutes. After allowing the vial to cool to room temperature, the mixture was treated with 5mL of 1N HCl and 2mL of diethyl ether. The organic layer was removed and the aqueous layer was extracted twice with diethyl ether. The organic extracts are combined in N2Evaporation of the solvent under a stream of air, followed by drying in vacuo, yielded 150mg (34.6%) of a yellow solid:
1H NMR(CDCl3/300MHz)2.26(s，3H)，5.64(q，1H，J＝6.8hz)，6.27(s，1H)，6.94(s，1H)，7.26(s，1H)，7.3H(s，1H)，11.28(hs，1H)；MS(ES-)431(M-1，100)；HRMS(ES-)m/z calcd for(M-H；C19H12Cl2F3O4)431.0059，found 431.0048.
parallel preparation of 6-chloro-7-aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The examples in table 10 below were prepared by means of this general method, using a parallel synthesis apparatus, each reaction being carried out on a 0.5mmo1 scale. The product was purified by reverse phase chromatography as required (Cl8 column, 40mm i.d.. times.100 mm, gradient CH)3H of CN/0.1% TFA2O solution).
Table 10: yield, purity and mass spectral data of 6-chloro-7-aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared by parallel synthesis
Watch 10
Example # LC (minutes) MS(ES+) HRMS % purity % yield
700 3.248 429 427.0191 99 24
701 3.976 399 397.0449 99 24
702 3.499 401 399.0242 99 29
703 3.533 431 429.0347 99 27
704 3.491 413 411.0242 99 23
705 3.367 431 429.0347 99 22
706 3.545 4772 476.91693 99 6
707 4.15 413 411.0605 99 23
708 3.302 399 397.0085 99 22
709 3.432 443 441.0347 99 30
1See general experimental section for a description of the recorded data. LC indicates chromatographic retention time in minutes. HRMS indicates the molecular ion (M-H) observed in the electrospray negative mode by means of high resolution mass spectrometry techniques. % purity is determined by ELC.
2The ions listed are M +1(M +1, 77; M +3, 100) of the ClBr cluster.
3Electron spray negative mode (M +2-1) ions.
Preparation of 7-aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Preparation of ethyl 7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Step 1.2 preparation of hydroxy-4-fluorobenzaldehyde
To a mixture of 3-fluorophenol (10mL, 102mmol), anhydrous magnesium chloride (28.2g, 744.6mmol) in 500mL anhydrous acetonitrile was added anhydrous triethylamine (67mL, 382.5mmol) and paraformaldehyde (22.3g, 744.6 mmol). The mixture was then heated to reflux for 5 hours. After cooling to room temperature, 500mL of 5% aqueous hydrochloric acid was added. The product was extracted with ethyl acetate. The combined organic extracts were washed three times with 5% hydrochloric acid, brine and dried over anhydrous magnesium sulfate. After removal of volatiles, the product was obtained as a light pink solid, 11g, yield 72%. A small portion was further purified by silica gel column eluting with EtOAc/hexane mixtures for further analytical identification to give a white solid.
M.P.＝67.5-69.0C.1H NMR(CDCl3/300MHz)11.40(s，1H)，9.86(s，1H)，7.62-7.57(m，1H)，6.79-6.67(m，2H).13C(CDCl3/300MH)195.4，168.3(d，J＝258Hz)，164.4(d，J＝14.9Hz)，136.3(d，J＝12.6Hz)，118.2(d，J＝2.0Hz)，108.5(d，J＝23.3Hz)，104.9(d，J＝24.4Hz).19F(CDCl3/400MHz)-97.9(m).LC-MS couldn't observe the desiredpeak.HRMS(ES-)m/zcalcd for(C7H5FO2)139.0201(M-H)，found 139.0211(M-H)..
Step 2. preparation of ethyl 7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate
A mixture of 2-hydroxy-4-fluorobenzaldehyde (10g, 71.4mmol), ethyl 4, 4, 4-trifluorocrotonate (15mL, 100mmol) and anhydrous potassium carbonate (14.8g, 107.1mmol) in 40mL anhydrous dimethylformamide was heated to 90 ℃ for 5 hours. LC-MS indicated the reaction was complete. After cooling to room temperature, 500mL of ethyl acetate was added to the reaction. The organic phase was washed with brine (× 3) and then dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified on a silica gel column, eluting with 1: 18 EtOAc/hexane. 12.5g (60%) of the product are obtained as a pale yellow oil.
1H NMR(CDCl3/300MHz)7.73(s，1H)，7.30-7.22(m，1H)，6.79-6.73(m，2H)，5.76(q，J＝6.9Hz，1H)，4.38(m，2H)，1.37(t，J＝7.2Hz，3H).13C(CDCl3/300MH)167.2，164.0，163.9，155.0(d，J＝13.0Hz)，136.3(d，J＝1.28Hz)，131.0(d，J＝10.4Hz)，123.5(q，J＝287.5Hz)，115.9(dd，J＝2.4，7.3Hz)，110.2(d，J＝22.5Hz)，104.4(d，J＝26.0Hz)，71.0(q，J＝33.2Hz)，61.7(d，J＝10.4Hz)，14.4.19F(CDCl3/300MHz)-79.0(d，J＝6.5Hz)，-104.8(m).LC-MS(ES+)291.0(M+1，100)，HRMS(EI+)m/z calcd for(C13H10F4O3)290.0566(M+)，found 290.0586.
Example 713
7- (4-Propylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a mixture of ethyl 7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.29g, 1.0mmol) and potassium carbonate (0.21g, 1.4mmol) was added 4-propylphenol (0.153mL, 1.1mmol) and 3mL anhydrous DMF. The resulting mixture was heated at 110 ℃ for 15 hours. LC-MS indicated the reaction was complete. To the reaction was added 15mL EtOAc. The resulting organic phase was washed with brine and the volatiles were removed. To the residue were added 3mL of THF and 3mL of aqueous solution of lithium hydroxide hydrate (105mg, 2.5 mmol). Then 3mL of ethanol were added to the resulting mixture. The resulting solution was heated at 80 ℃ for 5 hours. LC-MS indicated the reaction was complete. The volatiles were removed and the residue was diluted with water, acidified to pH 1.0 with dilute HCl at 0 ℃, and the product extracted with ethyl acetate and dried over anhydrous magnesium sulfate. After removal of the volatiles, a pale yellow oil was obtained. The residue was purified by reverse phase HPLC. The product was obtained as a pale yellow solid, 80mg (21%).
M.P.＝143.5-146.5℃.1H(CDCl3/300Mhz)7.80(s，1H)，7.18-7.13(m，3H)，6.96(d，J＝8.4Hz，2H)，6.59-6.52(m，2H)，5.62(q，1H，J＝6.9Hz)，2.57(t，2H，J＝6.9Hz，)，1.67-1.57(m，2H)，0.93(t，J＝7.2Hz，3H).13C NMR(CDCl3/300MHz)169.5，163.6，155.5，153.0，139.7(d，J＝13.0Hz)，131.4，130.2(d，J＝5.3Hz)，123.7(q，J＝287.6Hz)，120.6，119.8，113.7，112.8，112.0，105.0，70.7(q，J＝33.5Hz)，73.6，24.9，14.1.
19F(CDCl3/300MHz)-78.96(d，J＝6.9Hz).LC-MS(EI+)379.1(M+1，100).HRMS(EI+)m/zcalcd for(C20H17F3O4)378.1079(M+)，found 378.1061.
General procedure for the parallel Synthesis of 7-aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acids
Example 714
7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
In a vessel, to a solution of 0.200g (0.689mmol) ethyl 7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 2.5mL DMF was added 0.118g (0.946mmol)2, 5-dimethylphenol followed by 0.131g (0.946mmol) potassium carbonate. The suspension was prepared in a sealed vial and placed in a J-KEM heating zone equipped with a shaker, condenser and nitrogen atmosphere. The heated zone was heated to 110 ℃ for 20 hours. For the treatment, 10mL of H was added to the mixture2O and 5mL ether. The organic layer was separated and the aqueous layer was then extracted 3 times with ether. The product was then passed through a prepackaged silica gel plug (20mL, 5g capacity) and the silica column washed with 4X 5mL ether. The solution was concentrated to give the product, which was used directly in the next step without further purification.
Step 2.7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid preparation
The product of step 1 was dissolved in 4mL EtOH and 2mL THF. A4 mL aqueous solution of 0.116g LiOH was prepared and added to the organic solution. The reaction was sealed and heated to 90 ℃ for 1 hour. After cooling to room temperature, 6mL of 1N HCl and 3mL of ether were added. The organic layer was separated and the aqueous layer was extracted twice with diethyl ether. The ether layer was concentrated under a stream of nitrogen and purified by reverse phase chromatography to give 116mg (46%) of a light yellow solid:
1H NMR(CD3OD/400MHz)2.08(s，3H)，2.29(s，3H)，5.69(q，1H，J＝6.8Hz)，6.35(d，1H，J＝2.0Hz)，6.47(dd，1H，J＝2Hz，8.0Hz)，6.80(s，1H)，6.98(d，1H，J＝7.6Hz)，7.16(d，1H，J＝8.0Hz)，7.24(d，1H，J＝8.4Hz)，7.74(s，1H)；MS(ES+)365(M+1，100)；LC-MS purity＞95％(UV and ELSD)at 3.432min.on UV spectra；HRMS(ES-)m/z calcd for(M-1；C19H14O4F3)364.0922，found 364.0904.
Parallel synthesis method for preparing 7-aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The examples in table 11 below were prepared by means of this general method, each reaction being carried out on a 0.5 mmol scale using a parallel synthesis apparatus. The product was purified by reverse phase chromatography as required (C18 column, 40mm i.d.. times.100 mm, gradient CH)3H of CN/0.1% TFA2O solution).
Table 11: yield, purity and mass spectral data of 7-aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared by means of a parallel synthesis method
TABLE 11
Example # LC (time) MS(ES+) HRMS % purity % yield
715 3.07 395 393.058 99 11
716 3.806 365 363.0839 99 18
717 3.317 367 365.0631 99 29
718 3.298 397. 395.0737 99 29
719 3.301 379 377.0631 99 16
720 3.175 397 395.0737 99 12
721 3.982 379 377.0995 99 23
722 3.117 365 363.0447 99 24
723 4.166 393 391.1152 99 23
724 3.301 409 407.0737 99 5
725 3.492 385 384.03892 94 27
726 3.379 365 364.09002 ＞95 11
727 3.603 379 378.10732 ＞95 10
728 3.245 383 382.04692 ＞95 23
729 2.898 372 37.101502 ＞95 4
730 3.638 365 364.09322 ＞95 16
732 3.601 429 427.98572 ＞95 25
733 3.656 365 364.09362 ＞95 24
734 3.195 355 354.05202 ＞95 37
735 3.245 373 372.04032 ＞95 30
736 3.407 369 368.06672 ＞95 16
737 3.145 372 371.01842 ＞95 4
738 3.005 362 361.05592 ＞95 4
740 3.447 351 350.07642 ＞95 30
741 3.354 401 400.02942 ＞95 26
742 3.401 381 380.08642 ＞95 28
743 3.257 373 372.04012 ＞95 38
744 3.542 399 397.0454 ＞95 48
745 3.272 369 367.0568 ＞95 44
746 3.269 433 430.9536 ＞95 33
747 3.343 4533 448.9442 ＞95 31
748 3.582 4953 490.8746 ＞95 20
749 3.542 4513 446.9279 ＞95 24
750 3.389 385 383.0273 ＞95 41
751 3.282 4333 430.9543 ＞95 22
752 3.241 389 387.0036 ＞95 53
753 3.209 456 454.0491 ＞95 5
754 3.663 477 474.9635 ＞95 29
755 3.316 389 387.0067 ＞95 52
756 3.374 433 430.9570 ＞95 43
757 1.732 352 350.0617 ＞95 26
758 3.151 381 379.0775 ＞95 37
759 3.254 351 349.0640 ＞95 46
760 3.610 379 377.0983 ＞95 34
761 3.414 365 363.0821 ＞95 40
762 3.282 351 349.0682 ＞95 37
763 3.337 371 369.0131 ＞95 10
764 3.831 371 369.0152 ＞95 47
1See general experimental section for a description of the recorded data. LC indicates chromatographic retention time in minutes. HRMS showsMolecular ions (M-H) observed in the negative mode of electrospray were obtained by means of high resolution mass spectrometry technique. % purity is determined by ELC.
2HRMS molecular ion Electron Impact (EI) mode.
3MS (M +3) ion.
Preparation of 7-arylthio-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
General method for preparing 7-arylthio-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid by parallel synthesis method
Step 1. preparation of Ethyl 7-arylthioxo-2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of 0.5mmol of ethyl 7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate or ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 1.2mL of DMF were added 0.55mmol of thiol (RSH) and 97mg (0.7mmol) of potassium carbonate. The suspension was prepared in a sealed vial and placed in an aluminum heating zone equipped with a magnetic stirrer. The aluminum zone was heated to 110 ℃ for 16 hours. After allowing the vial to cool, the mixture was treated with 5mL of water and 2mL of diethyl ether. The organic layer was removed and the aqueous layer was extracted twice with diethyl ether. The organic extracts were combined, filtered through 5g of silica, and the silica was washed with 10mL of diethyl ether. In N2The filtrate was concentrated under gas flow to give an off-white solid which was used in the next step without further purification.
Step 2.7 preparation of Arylthioxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
In a suitable vial, to the concentrated product of step 1 was added 200mg of lithium hydroxide monohydrate, 1mL of water, 2mL of methanol, and 7mL of THF. The vial was sealed, placed in an aluminum heating zone, and heated to 100 ℃ for 30 minutes. After allowing the vial to cool to room temperature, the mixture was treated with 5mL of 1N HCl and 2mL of diethyl ether. Removing organic layer and water layerExtracted twice with diethyl ether. The organic extracts are combined in N 2The solvent was evaporated under a stream of air, followed by concentration in vacuo. The product was purified by reverse phase chromatography as required (C18 column, 40mm i.d.. times.100 mm, gradient CH)3H of CN/0.1% TFA2O solution).
Parallel synthesis method for preparing 7-arylthio-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The examples in table 12 below were prepared by means of this general method, each reaction being carried out on the 0.5mmol scale using a parallel synthesis apparatus.
Table 12: yield, purity and mass spectral data of 7-arylthioxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared by means of a parallel synthesis method
TABLE 12
Examples # LC(minutes) MS(ES+) HRMS % purity % yield
765 3.896 387 385.2445 99 33
766 3.842 367 365.0493 99 26
767 3.619 383 381.0433 99 21
768 3.819 367 365.0479 99 28
769 3.886 387 385.2445 99 32
770 3.63 353 351.0325 99 42
771 4.044 401 399.0079 99 27
772 4.038 401 399.0047 99 43
773 4.069 421 418.9551 99 41
1See general experimental section for a description of the recorded data. LC indicates chromatographic retention time in minutes. HRMS indicates the molecular ion (M-H) observed in the electrospray negative mode by means of high resolution mass spectrometry techniques. % purity is determined by ELC.
Preparation of 5-aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Preparation of ethyl 5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Step 1.1 preparation of fluoro-3- (methoxymethoxy) benzene
In N2Preparation of 22.4g (200mmol) of 3-fluorophenol in 400mL of CH 2Cl2The solution was cooled to 5 ℃. The stirred mixture was treated with 23.1g (267mmol) of chloromethyl methyl ether. The reactor was equipped with a thermocouple and an addition funnel. 34.8mL DIEA (25.8g, 200mmol) was added dropwise to the stirred mixture so that the temperature did not exceed 10 ℃. After 30 minutes, an additional 18ml of IEA was added dropwise. After a total of 1 hour, another 18mL DIEA was added. The mixture was left overnight. The solution was washed with 500mL 1N HCl and the aqueous layer was CH2Cl2The extraction was performed twice. Combining the extracts with MgSO4Drying, careful concentration and distillation under vacuum at 61-68 ℃ @15 torr yield 28.7g (75.3%) of a clear colorless liquid
1HNMR(CDCl3/400MHz)3.46(s，3H)，5.14(s，2H)，6.70(tdd，1H，J＝8.3Hz，J＝2.4Hz，0.8Hz)，6.75-6.82(m，2H)，7.21(q，1H，J＝7.7Hz)；19F NMR(CDCl3/400MHz)-112.0(m，1F)；13C NMR(CDCl3/100MHz)56.1，94.5，104.1(d，J＝25.0Hz)，108.6(d，J＝21.3Hz)，111.9(d，J＝2.9Hz)，130.2(d，J＝9.9Hz)，158.6(d，J＝11.0Hz)，163.5(d，J＝245.3Hz).
Step 2.2 preparation of 2-fluoro-6-hydroxybenzaldehyde
A solution of 22.6mL (17.4g, 150mmol) of TMEDA in 200mL of THF was cooled to-78 deg.C and treated with 115.4mL of a 1.3M solution of sec-butyllithium in cyclohexane. After the mixture was stirred for 15 minutes, the solution was treated with 17.1g (110mmol) of 1-fluoro-3- (methoxymethoxy) benzene and stirred for 30 minutes. The reaction mixture was then treated with 12mL THF, the ice bath was removed, and the reaction was stirred for 1 hour. The mixture was added to 500mL of an aqueous solution of 20mL of acetic acid. After the solution reached room temperature, the mixture was extracted three times with diethyl ether, and the extracts were combined, washed with brine, dried, and concentrated to give 23.1g of a crude oil. The oil was dissolved in 150mL THF, treated with 150mL 2-propanol and 75mL water. 75mL of concentrated HCl was added dropwise to the stirred solution and the mixture was stirred overnight. The volatile solvent was distilled over a short column at atmospheric pressure to give an aqueous slurry of the product. The slurry was filtered and the solid collected and washed with water. The solid was air dried for 2 hours to give 8.89g (58%) of an off-white solid:
(lit.mp 37.5-38.0℃)；1HNMR(CDCl3/400MHz)6.61(ddd，1H，J＝0.8Hz，J＝8.3Hz，J＝9.0Hz)，6.74(d，1H，J＝8.5Hz)，7.44(dt，1H，J＝6.4Hz，J＝8.3Hz)，10.25(s，1H)，11.45(s，1H)；19F NMR(CDCl3/400MHz)-122.3(dd，1F，J＝6.8Hz，J＝10.6Hz)；13CNMR(CDCl3/100MHz)106.0(d，CH，J＝20.2Hz)，110.7(d，J＝11.4Hz)113.8(d，CH，J＝3.8Hz)，138.5(d，CH，J＝12.2Hz)，163.1(d，J＝3.6Hz)，164.9(d，J＝258.9Hz)，192.4(d，J＝9.5Hz).
[1170] Lit.Reference：Krause，G.H.，et.A1.，Z.Naturforsch B.Anorg.Chem.Org.Chem.Biochem.Biophy.Biol.27(1972)663-674.
Step 3. preparation of Ethyl 5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate
A mixture of 8.7g (62mmol) 2-fluoro-6-hydroxybenzaldehyde, 18.6mL (20.9g, 124mmol) ethyltrifluorocrotonate and 17.3mL (12.6g, 124mmol) triethylamine was heated to reflux. After 3 hours, another 18.6mL of ethyltrifluorocrotonate and 2g of potassium carbonate were added and the mixture was heated for 3 days. The mixture was cooled, concentrated in vacuo, diluted with 1N HCl and extracted three times with diethyl ether. The combined extracts were washed with 1N HCl, brine, dried, and concentrated to give a dark oil.Kuge lrohr distillation (0.2 torr, 50 ℃) afforded 11.2g (62%) of a white solid: mp 45.5-47.0 deg.C;1H NMR(CDCl3/400MHz)1.33(t，3H，J＝7.1Hz)，4.30(m，2H)，5.68(q，1H，J＝6.8Hz)，6.70(t，1H，J＝9.0Hz)，6.76(d，1H，J＝8.3Hz)，7.24(q，1H，J＝7.2Hz)，7.92(s，1H)；19F NMR(CDCl3/400MHz)-78.9(d，3F，J＝7.7Hz)，-118.9(m，1F)；13C NMR(CDCl3/100MHz)14.2，61.6，70.7(q，J＝33.2Hz)，108.7(d，J＝18.7Hz)，109.2(d，CH，J＝20.6Hz)，111.9(d，CH，J＝3.2Hz)，117.0，123.3(q，J＝287.5Hz)，129.9(d，CH，J＝5.0Hz)，133.2(d，CH，J＝10.3Hz)，153.9，158.5，162.3(d，J＝253.5Hz)；MS(ES+)291(M+1，100)；MS(EI)290(M+，13)，245(18)，221(100)，193(99)；HRMS(EI)m/z calcd for(C13H10O3F4)290.0566，found 290.0589.
example 774
5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a solution of 290mg (1.0mmol) ethyl 5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 7mL THF and 2mL methanol was added 85mg lithium hydroxide monohydrate in 1.0mL water. The mixture was heated to reflux for 30 minutes and cooled to room temperature. After stirring overnight, the mixture was treated with 75mL of 1N HCl and extracted three times with diethyl ether. The combined extracts were washed with brine, dried and concentrated in vacuo to give 210g (80%) of a white solid: 1HNMR(d6-acetone/400MHz)5.86(q，1H，J＝7.1Hz)，6.88(m，2H)，7.44(q，1H，J＝6.7Hz)，7.93(s，1H)；19F NMR(d6-acetone/400MHz)-120.9(t，1F，J＝7.7Hz)，-79.4(d，3F，J＝7.7Hz)；MS(ES+)263(M+1，100)；MS(ES-)261(M-1，100)；HRMS(ES-) m/z calcdfor(C11H6F4O3)261.0175，found 261.0193.
General procedure for the preparation of 5-aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acids by parallel synthesis
Step 1. preparation of Ethyl 5-aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of 0.5mmol ethyl 5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 1.2ml DMF were added 0.55mmol phenol (ROH) and 97mg (0.7mmol) potassium carbonate. The suspension was prepared in a sealed vial and placed in an aluminum heating zone equipped with a magnetic stirrer. The aluminum zone was heated to 110 ℃ for 16 hours. After allowing the vial to cool, the mixture was treated with 5mL of water and 2mL of diethyl ether. The organic layer was removed and the aqueous layer was extracted twice with diethyl ether. The organic extracts were combined, filtered through 5g of silica, and the silica was washed with 10mL of diethyl ether. In N2The filtrate was concentrated under gas flow to give an off-white solid which was used in the next step without further purification.
Step 2.5 preparation of aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
In a suitable vial, to the concentrated product of step 1 was added 200mg of lithium hydroxide monohydrate, 1mL of water, 2mL of methanol, and 7mL of THF. The vial was sealed, placed in an aluminum heating zone, and heated to 100 ℃ for 30 minutes. After allowing the vial to cool to room temperature, the mixture was treated with 5mL of 1N HCl and 2mL of diethyl ether. The organic layer was removed and the aqueous layer was extracted twice with diethyl ether. The organic extracts are combined in N 2The solvent was evaporated under a stream of air, followed by concentration in vacuo. The product was purified by reverse phase chromatography as required (C18 column, 40mm i.d.. times.100 mm, gradient CH)3H of CN/0.1% TFA2O solution).
Parallel preparation of 5-aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The examples in table 13 below were prepared by means of this general method, each reaction being carried out on the 1.0 or 0.5mmol scale using a parallel synthesis apparatus.
Table 13: yield, purity and mass spectral data of 5-aryloxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared by means of a parallel synthesis method
Watch 13
Example # LC (minutes) MS(ES+) HRMS % purity % yield
775 3.181 365 363.0839 99 14.99
776 3.446 337 335.0526 99 24.27
777 3.851 385 383.0292 82 27.81
778 3.619 351 349.0682 99 19.53
779 3.654 383 381.0403 99 24.11
780 3.664 351 349.0682 99 20.78
781 3.95 399 397.0449 99 21.62
782 3.661 371 369.0136 96 34.47
783 3.839 365 363.0839 99 15.21
784 3.82 365 363.0839 99 16.52
785 3.855 365 363.0839 99 21.08
786 3.659 351 349.0682 99 21.70
787 3.471 355 353.0447 93 17.56
788 3.672 371 369.0171 93 15.05
789 3.855 405 402.9764 98 23.50
790 3.789 387 386.07452 94 14.96
791 3.784 387 386.07872 85 11.60
792 3.391 381 379.0449 99 12.15
793 3.437 367 365.0612 99 10.48
794 3.996 379 377.0984 99 7.51
795 4.06 399 397.0441 99 20.81
796 3.606 3813 379.0795 86 10.25
797 3.407 355 353.0459 90 25.57
798 3.797 365 363.0856 84 8.45413
799 4.06 379 377.1007 99 13.85
800 3.305 3714 371.0318 99 13.70
801 3.563 401 399.0235 86 19.86
802 3.316 379 377.0619 93 7.40
803 3.38 3675 365.061 92 12.34
1See general experimental section for a description of the recorded data. LC indicates chromatographic retention time in minutes. HRMS indicates the molecular ion (M-H) observed in the electrospray negative mode by means of high resolution mass spectrometry techniques. % purity is determined by ELC.
2HRMS EI mode, M + ion.
3381(M+1，50)，363(100)。
4Electron spray negative mode M-1 ions; 371(M-1, 60), 307 (100).
5367(M+1，40)，349(100)。
Preparation of 5-arylthio-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
General procedure for the preparation of 5-arylthio-2- (trifluoromethyl) -2H-chromene-3-carboxylic acids by parallel synthesis
Step 1. preparation of Ethyl 5-arylthio-2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of 0.5mmol of ethyl 5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate or ethyl 5-n-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 1.2mL of DMF were added 0.55mmol of thiol (RSH) and 97mg (0.7mmol) of potassium carbonate. The suspension was prepared in a sealed vial and placed in an aluminum heating zone equipped with a magnetic stirrer. The aluminum zone was heated to 110 ℃ for 16 hours. After allowing the vial to cool, the mixture was treated with 5mL of water and 2mL of diethyl ether. The organic layer was removed and the aqueous layer was extracted twice with diethyl ether. The organic extracts were combined, filtered through 5g of silica, and the silica was washed with 10mL of diethyl ether. In N2The filtrate was concentrated under gas flow to give an off-white solid which was used in the next step without further purification.
Step 2.5 preparation of arylthio-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
In a suitable vial, to the concentrated product of step 1 was added 200mg of lithium hydroxide monohydrate, 1mL of water, 2mL of methanol, and 7mL of THF. The vial was sealed, placed in an aluminum heating zone, and heated to 100 ℃ for 30 minutes. After allowing the vial to cool to room temperature, the mixture was treated with 5mL of 1N HCl and 2mL of diethyl ether. The organic layer was removed and the aqueous layer was extracted twice with diethyl ether. The organic extracts are combined in N 2By evaporation of the solvent under a stream of gas, followed byTo concentrate in vacuo. The product was purified by reverse phase chromatography as required (C18 column, 40 mmi.d.. times.100 mm, gradient CH3H of CN/0.1% TFA2O solution).
Parallel preparation of 5-arylthio-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The examples in table 14 below were prepared by means of this general method, each reaction being carried out on the 1.0 or 0.5mmol scale using a parallel synthesis apparatus.
Table 14: yield, purity and mass spectral data of 5-arylthio-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared by means of a parallel synthesis method
TABLE 14
Examples # LC (minutes) MS(ES+) HRMS % purity % yield
804 3.93 421 418.9549 99 47
805 3.88 401 399.0099 99 30
806 3.72 417 415.0038 99 46
807 3.899 401 399.0049 99 28
808 3.912 421 418.953 99 27
809 3.723 387 385.2445 99 38
810 3.712 387 385.2445 99 24
811 3.75 367 365.0485 99 19
812 3.565 3832 381.0402 99 17
813 3.763 367 365.0468 99 22
814 3.771 387 385.2445 99 26
815 3.563 353 351.0302 99 30
1See general experimental section for a description of the recorded data. LC indicates chromatographic retention time in minutes. HRMS indicates the molecular ion (M-H) observed in the electrospray negative mode by means of high resolution mass spectrometry techniques. % purity is determined by ELC.
2383(M+1，40)，365(100)。
Preparation of 5-aryloxy-6, 8-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Preparation of ethyl 6, 8-dichloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Step 1.3 preparation of 3, 5-dichloro-2-fluoro-6-hydroxybenzaldehyde
To a solution of 20g (114.6mmol) of 3-chloro-2-fluoro-6-hydroxybenzaldehyde in 250mL of glacial acetic acid 27.8g Cl was added over 30 minutes 2And (4) qi. The mixture was stirred, heated to 60 ℃ for 2 hours, and stirred at room temperature overnight. The reaction mixture was diluted with 1L of water and extracted four times with diethyl ether. The combined extracts were washed with water and saturated brine, and concentrated in vacuo to give a syrup. 250mL of water was added to give a solid, which was collected by filtration and air-dried for 8 hours to give 20.42g (85%) of a yellow solid:
mp 58-62℃；1HNMR(CDCl3/400MHz)7.65(d，1H，J＝7.5Hz)，10.26(s，1H)，11.88(s，1H)；13C NMR(CDCl3/100MHz)111.2(d，J＝12.0Hz)，118.2(d，J＝4.6Hz)，127.8，137.6(C-H，d，J＝2.1Hz)，156.8(d，J＝3.0Hz)，158.3(d，J＝260.8Hz)，191.4(CHO，d，J＝8.8Hz)；19FNMR(CDCl3/400MHz)-124.7(d，1F，J＝7.7Hz)；MS(EI) 208(M+，100)；207(91)；HRMS(EI)m/z calcd for(C7H3O2Cl2F)207.9494，found 207.9470.
Anal.Calc'd for C7H3O2Cl2F+0.3H2O：C，39.21；H，1.69.Found：C，39.04；H，1.53.
step 2. preparation of ethyl 6, 8-dichloro-5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate
To 16.11g (77mmol) of 3, 5-dichloro-2-fluoro-6-hydroxybenzaldehyde was added 23mL (25.9g, 154mmol) of ethyltrifluorocrotonate followed by the slow addition of 21.5mL (15.6g, 154mmol) of triethylamine. The mixture was heated to reflux. After 1 hour, the mixture was treated with another 23mL of ethyltrifluorocrotonate and heating was continued for 24 hours. According to1H NMR measurements the reaction mixture contained 1: 2 product and starting material. The mixture was treated with another 23mL of ethyltrifluorocrotonate and heated for another 48 hours. The mixture was cooled, diluted with 1N HCl and extracted three times with dichloromethane. The combined extracts were filtered through a pad of silica and concentrated to give 19.0g of a crude dark brown oil. The oil was treated with hexane and filtered to remove solid impurities. The solid was washed with hexane, the filtrates combined and concentrated to give 15g of crude oil. Purification by reverse phase HPLC (C18, 4.2 cm. times.25 cm, 10 injections) gave 8.08g (29.2%) of a crystalline solid:
mp 72-73℃；1H NMR(CDCl3/400MHz)1.38(t，3H，J＝7.1Hz)，4.37(m，2H)，5.85(q，1H，J＝6.6Hz)，7.41(d，1H，J＝7.5Hz)，7.89(s，1H)；19FNMR(CDCl3/400MHz)-78.9(d，3F，J＝6.8Hz)，-120.8(d，1F，J＝6.8Hz)；13C NMR(CDCl3/100MHz)14.2，62.1，71.2(q，C2，J＝33.7Hz)，110.8(d，J＝19.8Hz)，114.7(d，J＝18.7Hz)，117.3(d，J＝4.0Hz)，119.1(d，J＝2.1Hz)，122.9(q，CF3，J＝287.1Hz)，128.6(d，C-H，J＝4.0Hz)，133.0(C-H)，147.8(d，J＝4.6Hz)，153.5(d，J＝256.6Hz)，162.8；MS(ES+)359(M+1，100，Cl2pattem)；MS(EI)358(M+，26，Cl2pattern)，289(100)，261(54)；HRM8(EI)m/z calcd for(C13H8O3Cl2F4)357.9787，found 357.9804.
Anal.Calc’d for C13H8O3Cl2F4：C，43.48；H，2.25.Found：C，43.47；H，2.28.
Example 816
Preparation of 6, 8-dichloro-5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To 359mg (1.0mmol) of ethyl 6, 8-dichloro-5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 7mL of THF and 2mL of methanol was added 90mg of lithium hydroxide monohydrate in 1.0mL of water. The mixture was heated to reflux for 60 minutes and cooled to room temperature. After stirring overnight, the mixture was treated with 75mL of 1N HCl and extracted three times with diethyl ether. The combined extracts were concentrated and purified by reverse phase chromatography to give 240mg of an impure white solid. Recrystallization from acetonitrile gave 51mg (15%) of a white crystalline solid:
1H NMR(d6-acetone/400MHz)6.08(q，1H，J＝7.0Hz)，7.74(d，1H，J＝7.7Hz)，7.94(s，1H)；19F NMR(d6-acetone/400MHz)-122.1(d，1F，J＝7.7Hz)，-79.4(d，3F，J＝6.8Hz)；MS(ES+)331(M+1，100)，333(M+3，57)；MS(ES-)329(M-1,100)，331(79)；HRMS(ES-)m/z calcd for(C11H4Cl2F4O3)328.9401，found328.9357.
general procedure for the preparation of 5-aryloxy-6, 8-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid by parallel synthesis
Step 1. preparation of Ethyl 5-aryloxy-6, 8-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of 0.5mmol ethyl 5-fluoro-6, 8-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 1.2mL DMF were added 0.55mmol phenol (ROH) and 97mg (0.7mmol) potassium carbonate. The suspension was prepared in a sealed vial and placed in an aluminum heating zone equipped with a magnetic stirrer. The aluminum zone was heated to 55 ℃ for 16 hours. After allowing the vial to cool, the mixture was treated with 5mL of water and 2mL of diethyl ether. The organic layer was removed and the aqueous layer was extracted twice with diethyl ether. The organic extracts were combined, filtered through 5g of silica, and the silica was washed with 10mL of diethyl ether. In N 2The filtrate was concentrated under gas flow to give an off-white solid which was used in the next step without further purification.
Step 2.5 preparation of aryloxy-6, 8-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
In a suitable vial, 400mg of lithium hydroxide monohydrate, 1mL of water, 2mL of methanol, and 7mL of THF were added to the concentrated product of step 1. The vial was sealed, placed in an aluminum heating zone, and heated to 100 ℃ for 30 minutes. After allowing the vial to cool to room temperature, the mixture was treated with 5mL of 1N HCl and 2mL of diethyl ether. The organic layer was removed and the aqueous layer was extracted twice with diethyl ether. The organic extracts are combined in N2The solvent was evaporated under a stream of air, followed by concentration in vacuo. The product was purified by reverse phase chromatography as required (C18 column, 40mm i.d.. times.100 mm, gradient CH)3H of CN/0.1% TFA2O solution).
Parallel preparation of 5-aryloxy-6, 8-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The examples in table 15 below were prepared by means of this general method, each reaction being carried out on the 1.0 or 0.5mmol scale using a parallel synthesis apparatus.
Table 15: yield, purity and mass spectral data of 5-aryloxy-6, 8-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared by means of a parallel synthesis method
Watch 15
Examples # LC (minutes) MS(ES+) HRMS % purity % yield
817 4.201 433 431.0068 99 34
818 4.016 419 416.9919 99 37
819 4.269 453 450.9524 99 39
820 3.334 4172 432.9852 99 35
821 4.141 453 450.9533 99 41
822 4.062 457 454.9273 99 46
823 4.073 437 434.9834 99 30
824 2.698 420 417.984 99 28
825 3.922 449 446.9977 99 34
826 4.056 439 436.9362 99 42
827 4.268 467 464.9675 99 33
828 3.741 440 437.9318 99 12
829 4.235 433 431.0038 99 25
830 3.971 437 434.9832 99 47
831 4.028 419 416.9911 99 44
832 4.049 4393 436.93783 99 49
833 4.196 433 431.0031 99 36
834 4.029 451 448.9621 99 44
835 4.022 449 446.9977 99 30
836 4.041 419 416.9893 99 31
837 3.663 430 427.9665 99 42
838 3.832 440 437.9298 99 18
839 4.199 433 431.0028 99 23
840 3.995 469 466.9426 99 44
1See general experimental section for a description of the recorded data. LC indicates chromatographic retention time in minutes. HRMS indicates the molecular ion (M-H) observed in the electrospray negative mode by means of high resolution mass spectrometry techniques. % purity is determined by ELC.
2The observed ion was M-18 (H)2O) fragments; 417(M +1-18,100)。
3Cl3observed ion of compound: 439(M +1, 80), 441(M +3, 100).
Preparation of 5-aryloxy-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
General procedure for the preparation of 5-aryloxy-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid by parallel synthesis
Step 1. preparation of Ethyl 5-aryloxy-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of 0.5mmol ethyl 5-fluoro-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 1.2mL DMF were added 0.55mmol phenol (ROH) and 97mg (0.7mmol) potassium carbonate. The suspension was prepared in a sealed vial and placed in an aluminum heating zone equipped with a magnetic stirrer. The aluminum zone was heated to 55 ℃ for 16 hours. After allowing the vial to cool, the mixture was treated with 5mL of water and 2mL of diethyl ether. The organic layer was removed and the aqueous layer was extracted twice with diethyl ether. The organic extracts were combined, filtered through 5g of silica, and the silica was washed with 10mL of diethyl ether. In N 2The filtrate was concentrated under gas flow to give an off-white solid which was used in the next step without further purification.
Step 2.5 preparation of aryloxy-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
In a suitable vial, 400mg of lithium hydroxide monohydrate, 1mL of water, 2mL of methanol, and 7mL of THF were added to the concentrated product of step 1. The vial was sealed, placed in an aluminum heating zone, and heated to 100 ℃ for 30 minutes. After allowing the vial to cool to room temperature, the mixture was treated with 5mL of 1N HCl and 2mL of diethyl ether. The organic layer was removed and the aqueous layer was extracted twice with diethyl ether. The organic extracts are combined in N2The solvent was evaporated under a stream of air, followed by concentration in vacuo. The product was purified by reverse phase chromatography as required (C18 column, 40mm i.d.. times.100 mm, gradient CH)3H of CN/0.1% TFA2O solution).
Parallel preparation of 5-aryloxy-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The examples in table 16 below were prepared by means of this general method, each reaction being carried out on the 0.5mmol scale using a parallel synthesis apparatus.
Table 16: yield, purity and mass spectral data of 5-aryloxy-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared by means of a parallel synthesis method
TABLE 16
Examples # LC (minutes) MS(ES+) HRMS % purity % yield
841 3.928 399 397.0441 99 27
842 3.746 385 383.0278 99 40
843 4.015 419 416.9879 99 40
844 3.08 3832 399.0244 99 24
845 3.888 419 416.9903 99 31
846 3.822 423 420.962 99 37
847 3.83 403 401.0176 99 36
848 2.445 386 384.0266 99 24
849 3.65 415 413.0393 99 35
850 3.811 405 402.9745 99 41
851 4.005 433 431.0035 99 33
852 3.967 399 397.0433 99 35
853 3.72 403 401.0204 99 42
854 3.767 385 383.0285 99 39
855 3.802 405 402.9772 99 41
856 3.929 399 397.0417 99 34
857 3.778 417 415.0017 99 35
858 3.76 415 413.0399 99 43
859 3.778 385 383.0305 99 35
860 3.423 396 394.0072 99 22
861 3.54 406 403.9716 99 9
862 3.939 399 397.0473 99 37
863 3.742 435 432.9858 99 37
1See general experimental section for a description of the recorded data. LC indicates chromatographic retention time in minutes. HRMS indicates the molecular ion (M-H) observed in the electrospray negative mode by means of high resolution mass spectrometry techniques. % purity is determined by ELC.
2The observed ion was M-18 (H)2O) fragments; 383(M +1-18, 100).
Preparation of 6-chloro-7- [ (5-ethylpyrimidin-2-yl) oxy ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Example 864
6-chloro-7- [ (5-ethylpyrimidin-2-yl) oxy ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-chloro-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a mixture of ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (6g, 18.5mmol) and 2- (methylsulfonyl) ethanol (3.45g, 27.7mmol) in 125mL anhydrous DMF at 0 deg.C was slowly added sodium hydride (60%, 2.22g, 55.5 mmol). After stirring at 0 ℃ for 45 minutes, LCMS indicated disappearance of most of the starting material. The reaction was allowed to warm to room temperature and stirred for an additional 20 minutes. The reaction was poured into a dilute hydrochloric acid/ice mixture with vigorous stirring. The product was then extracted with EtOAc. The resulting organic phase was washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified by silica gel column eluting with 1: 1 EtOAc/hexane containing 1% HOAc. The desired product was obtained as a green-yellow solid, 1.0g (16.7%).
M.P.＝118.0-125.0℃.1HNMR(CDCl3/400MHz)7.61(s，1H)，7.18(s，1H)，6.66(s，1H)，5.65(q，1H，J＝6.8Hz)，4.30(m，2H)，1.33(t，3H，J＝7.2Hz).13C NMR(CDCl3/400MHz)164.1，155.2，153.8，136.0，129.3，123.5(q，J＝287.7Hz)115.1，114.1，113.6，104.5，71.0(q，J＝33.2Hz)，61.7，14.4.19F NMR(CDCl3/400Hz)-78.9(d，J＝6.8Hz).LC-MS(ES+)323.7(M+H，80％)，295.2(M-27，100％).HRMS(EI+)m/z calcd for(C13H10ClF3O4)322.0220，found322.0231.
Step 2. preparation of Ethyl 6-chloro-7- [ (5-ethylpyrimidin-2-yl) oxy ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a mixture of ethyl 6-chloro-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.2g, 0.62mmol) and potassium carbonate (342mg, 2.48mmol) in 3mL anhydrous DMF was added 2-chloro-5-ethylpyrimidine reagent (450. mu.L, 3.72 mmol). The reaction was then heated at 130 ℃ for 51 hours. After cooling to room temperature, 150mL EtOAc were added to the reaction. The resulting organic phase was washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified over a short silica gel column, eluting with EtOAc/hexanes, to give 260mg of a brown oil, which was used in the next step without further purification.
Step 3.6 preparation of chloro-7- [ (5-ethylpyrimidin-2-yl) oxy ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To the product of step 2 (0.26g, 0.61mmol) in 3mL THF was added 3mL aqueous solution of lithium hydroxide hydrate (102mg, 2.44 mmol). To the resulting mixture was added 3mL of ethanol. The resulting clear solution was heated to 70 ℃ for 5 hours. LC-MS indicated the reaction was complete. The volatiles were then removed. The residue was diluted with water. The diluted aqueous solution was acidified with dilute hydrochloric acid at 0 ℃ to precipitate the product. The product was extracted with EtOAc. The organic extracts were combined and dried over anhydrous magnesium sulfate. Volatiles were removed on a rotary evaporator. After removal of the solvent, the residue was purified by reverse phase HPLC. 110mg (45%) of a pale yellow solid are obtained.
M.P.＝96.5-98.0℃.1H NMR(CDCl3/300MHz)8.50(s，2H)，7.72(s，1H)，7.40(s，1H)，6.99(s，1H)，5.72(q，J＝6.9Hz，1H)，2.69(q，J＝7.5Hz，2H)，1.33(t，J＝7.5Hz，3H).13C NMR(CDCl3/400MHz)167.3，162.7，159.3，153.1，152.5，136.9，132.6，130.8，123.4(q，J＝287.3Hz)，117.9，116.7，112.4，70.8(d，J＝33.5Hz)，22.9，15.2，2.2.19F(CDCl3/400MHz)-78.80(d，J＝5.6Hz).LC-MS(ES+)401.3(M+1，100).HRMS(ES+)m/z calcd for(C17H12ClF3N2O4)401.0510(M+H)，found 401.0530(M+H).
Preparation of 6-chloro-5-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Example 865
6-chloro-5-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1: preparation of 6-chloro-5-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a mixture of ethyl 6-chloro-5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (2g, 6.2mmol) and 2-methylsulfonylethanol (2.3g, 18.5mmol) in 40mL anhydrous DMF at 0 deg.C was slowly added sodium hydride (60% suspension in mineral oil, 1.48g, 37.2mmol) with stirring. Bubbling was observed during this process. The resulting black solution was then stirred at room temperature for 3 hours. LC-MS showed no more material observed. The reaction was poured into an ice/aqueous ammonium chloride mixture. The product was extracted with ethyl acetate and the resulting organic solution was washed with brine and dried over anhydrous magnesium sulfate. After removal of volatiles, the residue was purified over silica gel column using a 1: 1 EtOAc/hexanes + 1% HOAc. The product was obtained as a colourless oil, 0.8 g. A portion of the product was further purified by reverse phase HPLC to afford an off-white solid.
LC-MS(ES+)295.2(M+1，100).1H NMR(CD3OD/300MHz)8.11(s，1H)，7.30(d，J＝8.7Hz，1H)，6.53(d，J＝9.0Hz，1H)，5.75(q，J＝7.5Hz，1H)，.19F NMR(CDCl3/300MHz)-80.31(d，J＝7.1Hz).High resolution MS(ES-)：m/e calc.For C11H6ClFO4：292.9828(M-H)，found：292.9853.
Step 2: preparation of ethyl 6-chloro-5-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a mixture of 6-chloro-5-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (0.5g, 1.7mmol) and cesium carbonate (800mg, 0.94mmol) in 10mL DMF was added ethyl bromide (0.80mL, 6.2 mmol). The mixture was stirred at room temperature overnight. To the reaction was added 150mL of ethyl acetate, and the resulting organic solution was washed with brine and dried over anhydrous magnesium sulfate. After removal of volatiles, the residue was purified by silica gel column eluting with EtOAc/hexane mixture. 0.4g of a white solid was obtained. A portion of the product was further purified by reverse phase HPLC for analytical identification.
LC-MS(ES+)351.3(M+1，100)，19F NMR(CDCl3/400Hz)-78.782(d，J＝6.8Hz)；1H NMR(CDCl3/400Hz)7.94(s，1H)，7.27(d，J＝8.8Hz，1H)，6.70(d，J＝8.8Hz，1H)，5.66(q，J＝6.8Hz，1H)，4.32(m，2H)，4.10(m，2H)，1.42(t，J＝7.2Hz，3H)，1.34(t，J＝7.2Hz，3H)；13C NMR(CDCl3/400Hz)163.8，153.2，152.6，133.5，132.0，123.5(q，J＝287.6Hz)，121.2，117.2，115.6，112.6，71.4，70.5(q，J＝33.2Hz)，61.8，15.5，14.4.High resolution MS(ES+)m/e calc.for C15H15ClF3O4：351.0605(M+H)，351.0641(M+H，observed).
And step 3: preparation of 6-chloro-5-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a solution of ethyl 6-chloro-5-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (300mg, 0.93mmol) in 3mL THF was added 4mL of an aqueous solution of lithium hydroxide hydrate (156mg, 3.7mmol), followed by 3mL of ethanol. The resulting solution was heated to 80 ℃ for 4 hours. After removal of the solvent, the residue was acidified with ice-cold dilute hydrochloric acid at 0 ℃. The product was extracted with EtOAc. After removal of the solvent, the residue was purified by reverse phase HPLC. The product was obtained as a white solid (120 mg).
LC-MS(ES+)323.2(M+1，100).1H NMR(CDCl3/400MHz)8.11(s，1H)，7.32(d，J＝8.8Hz，1H)，6.73(d，J＝8.4Hz，1H)，5.65(q，J＝6.8Hz，1H)，4.12(m，2H)，1.44(t，J＝7.2Hz，3H).19F NMR(CDCl3/400MHz)-78.81(d，J＝6.8Hz).13CNMR(CDCl3/400MHz)169.5，153.5，152.8，134.9，134.3，123.4(q，J＝285.8Hz)，121.3，115.8，115.5，112.8，71.6，70.2(q，J＝33.4Hz)，15.5.HRMS(EI+)m/zcalc.For(C13H10ClF3O4)322.0220(M+)，found：322.0223.
Preparation of 5-aryl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Example 867
6-chloro-5- (2-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-chloro-5-azido-2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of ethyl 6-chloro-5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.0g, 3.1mmol) in 20mL of DMSO was added a solution of sodium azide (1.0g, 5mmol) in a small amount of water. The reaction was then heated to 85C for 15 hours. After cooling to room temperature, 200mL of ethyl acetate was added to the reaction. The resulting suspension was then washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified on a silica gel column, eluting with ethyl acetate/hexane, to give 0.8g of a yellow oil. A portion of the product was purified by reverse phase HPLC for further analytical identification. A pink solid was obtained.
LC-MS(ES+)348.3(M+1，70)，320.2(M-27，100).1H NMR(CDCl3/400MHz)7.99(s，1H)，7.24(d，J＝8.8Hz，1H)，6.75(d，J＝8.8Hz，1H)，5.67(q，J＝6.8Hz，1H)，4.32(m，2H)，1.35(t，J＝7.2Hz，3H).19F NMR(CDCl3/400Hz)-78.71(d，J＝6.8Hz).13C NMR(CDCl3/400Hz)163.7，152.7，134.4，133.9，131.9，123.3(q，J＝287.3Hz)，122.6，117.7，114.6，114.2，70.6(q，J＝33.3Hz)，61.9，14.4.HRSM(EI+)m/e calc.for(C13H9ClF3N3O3)347.0285(M+)，found：-347.0294(M+).
Step 2. preparation of ethyl 6-chloro-5-amino-2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a suspension of stannous chloride hydrate (5.5g, 24.1mmol) in 150mL methanol was added ethyl 6-chloro-5-azido-2- (trifluoromethyl) -2H-chromene-3-carboxylate (5.6g, 16.1mmol) in one portion at room temperature. The reaction mixture gradually turned yellow. After stirring at room temperature for about 45 minutes, the reaction became a clear yellow solution. The volatiles were then removed. The residue was dissolved in EtOAc and the resulting organic solution was washed with 5% sodium hydroxide solution (× 4), brine and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified on silica gel eluting with 3: 7Et0 Ac/hexane to give 3.2g of a yellow solid. A small portion of the product was further purified by reverse phase HPLC to give a yellow solid.
LC-MS(ES+)322.2(M+1，100).1H NMR(CDCl3/400MHz)7.80(s，1H)，7.16(d，J＝8.8Hz，1H)，6.35(d，J＝8.8Hz，1H)，5.65(q，J＝7.2Hz，1H)，4.31(m，2H)，1.34(t，J＝7.2Hz，3H).19F NMR(CDCl3/400M Hz)-78.55(d，J＝7.4Hz).13CNMR(CDCl3/300Mhz)164.1，152.8，141.3，133.1，131.7，123.7(q，J＝287.7Hz)，115.2，113.4，107.2，106.6，70.3(q，J＝33.2Hz)，61.7，14.5.MS(ES+)322.1(M+1，75％)，HRMS(EI+)m/z calc for(C13H11ClF3NO3)：321.0380(M+)，found，321.0359(M+).
Step 3. preparation of ethyl 6-chloro-5-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of 47% aqueous HI (11mL, 59mmol) in DMSO (11mL) was added dropwise a solution of ethyl 6-chloro-5-amino-2- (trifluoromethyl) -2H-chromene-3-carboxylate (3.8g, 11.8mmol) in a mixture of 11mL DMSO and potassium nitrite (1.63g, 23.6mmol) at 35 ℃ with stirring. The resulting mixture was stirred at 35 ℃ for 15 minutes and then transferred to 150mL of potassium carbonate (10g) in ice water. The product was extracted with ethyl acetate. The combined organic extracts were washed with saturated aqueous sodium carbonate, 5% aqueous sodium bisulfite and brine, and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified on a silica gel column eluting with 1: 9 EtOAc/hexane. The product is obtained as 2.5g of a pale yellow solid. A small amount of product was further purified by reverse phase HPLC. An off-white solid was obtained. LC-MS (ES) with m.p ═ 117.0-119.0 ℃ +)：433.2(M+1，100)；1HNMR(CDCl3/400MHz)7.93(s，1H)，7.36(d，J＝8.4Hz，1H)，6.91(d，J＝8.4Hz，1H)，5.65(q，J＝6.8Hz，1H)，4.33(m，2H)，1.36(t，J＝6.8Hz，3H).19F NMR(CDCl3/400Hz)-78.50(d，J＝6.8Hz)。13C NMR(CDCl3/400MHz)163.3，152.3，140.9，133.6，132.2，124.7，123.2(q，J＝287.7Hz)，119.4，117.6，104.5，70.3(q，J＝33.4Hz)，62.0，14.4.MS(EI+)432.0(M+，20)，363.0M-CF3，100).Highresolution MS(EI+) m/z calc.for Cl3H9ClF3IO3：431.9271(M+)，found：431.9238.
Rf.Baik，Woon Phil；Kim，Jung Min；Kim，Young Sam；Yoon，Cheol Hun；Kim，ShinJong；Lee，Seok Woo.WO 20002053545；Application No.WO 2001-KR1586
Step 4.6 preparation of chloro-5- (2-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a solution of ethyl 6-chloro-5-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate (300mg, 0.69mmol), tetrakis (triphenylphosphine) palladium (0) (80mg, 0.07mmol) and furan-2-boronic acid (112mg, 1mmol) in 9mL of anhydrous dimethylacetamide was added 1.7mL of 2.0M aqueous sodium carbonate. The resulting mixture was heated to 95 ℃ and shaken for 16 hours. After cooling to room temperature, 60mL of EtOAc was added to the reaction flask and the resulting mixture was washed with brine (x 3). After evaporation of the organic phase, THF (3mL), EtOH (3mL) and lithium hydroxide hydrate solution (116mg/3mL of water) were added to the residue. The resulting solution was heated to 80 ℃ for 3 hours. The volatiles were then removed. The residue was diluted with water and acidified with ice-cold dilute hydrochloric acid at 0 ℃. The product was extracted with EtOAc. After removal of the solvent, the residue was dissolved in acetonitrile and purified by reverse phase HPLC. A yellow solid was obtained. 191.0-193.0 ℃ (dark brown).
.LC-MS(ES+)345.2(M+1,100).1H NMR(CDCl3/400MHz)7.78(s，1H)，7.63(s，1H)，7.43(d，J＝8.8Hz，1H)，6.98(d，J＝8.8Hz，1H)，6.70(d，J＝3.2Hz，1H)，6.59(m，1H)，5.66(q，J＝6.8Hz，1H).19F NMR(CDCl3/400MHz)-78.59(d，J＝6.8Hz)13C NMR(CDCl3/400MHz)169.2，152.7，147.2，144.0，138.2，134.3，130.0，127.5，123.4(q，J＝287.5Hz)，119.9，117.5，116.0，114.3，111.5，69.9(q，J＝33.7Hz).
MS(ES-)：342.9(M-H，100)，High resolution MS(ES-)：m/z calc.for C15H7ClF3O4：342.9985(M-H)，found：343.0005.
Example 868
6-chloro-5-thiophen-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the same procedure described for the preparation of 6-chloro-5- (2-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. Light yellow solid, m.p. ═ 211.0-213.5 ℃ (dark brown).
.LC-MS(ES+)361.2(M+1，100)，19F NMR(CDCl3/400MHz)-78.64d，J＝7.4Hz).1H NMR(CDCl3/400MHz)7.58(s，1H)，7.45(m，1H)，7.42(d，J＝8.8Hz，1H)，7.27(s，broad，1H)7.10(s，broad，1H)，6.96(d，J＝8.8Hz，1H)，5.63(q，J＝6.8Hz，1H).13C NMR(CDCl3/400MHz)169.2，152.7，138.1，136.1，135.0，133.9，129.6，127.5，126.9，126.1，123.5(q，J＝287.7Hz)，120.0，116.7，115.9，69.9(q，J＝33.5Hz).MS(ES-) 358.9(M-H，100)；High resolution MS(ES-)：m/z calc.forC15H7ClF3O3S：358.9756(M-H)，found：358.9752
Example 869
6-chloro-5- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Preparation of 6-chloro-5- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the same procedure described for the preparation of 6-chloro-5- (2-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. Off-white solid
m.p.＝218.0-220.0℃.LC-MS(ES+)：369.2(M+1，100)，1H NMR(CDCl3/CD3OD/300MHz)7.45-7.43(m，2H)，7.33-7.26(m，3H)，7.06-7.00(m，2H)，5.68(q，J＝6.9Hz，1H)，2.47(s，3H).19F NMR(CDCl3/CD3OD/300MHz)-78.61(d，J＝6.9Hz).13CNMR(CDCl3/CD3OD/300MHz)167.0，152.6，140.9，138.7，136.9，133.4，132.4，130.9，129.9，129.5，129.2，127.2，123.7(q，J＝287.6Hz)，120.0，116.6，116.5，70.2(q，J＝33.3Hz)，21.6.MS(ES-)367.0(M-H，100)，High resolution MS(ES-)m/z calc.for C18H11ClF3O3：367.0349(M-H)，found 367.0325.
Example 870
6-chloro-5- (3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the same procedure described for the preparation of 6-chloro-5- (2-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. Off-white solid
m.p.＝222.5-224.0℃.LC-MS(ES+)：369.2(M+1，100).1H NMR(CD3OD/300MHz)7.51-6.90(m，7H)，5.79(q，J＝6.9Hz，1H)，2.44(s，3H).19F NMR(CDCl3/CD3OD/300MHz)-80.10(d，J＝7.0Hz).13C NMR(CD3OD/300MHz)：165.2，152.3，140.7，138.4(d，J＝31.5Hz)，135.6(d，J＝3.2Hz)，134.5(d，J＝5.7Hz)，132.8，130.5(d，J＝49.2Hz)，29.2(d)，128.3(d)，127.1，126.7，123.9(q，J＝287.1Hz)，119.9(d)，117.9(d)，116.3(d)，70.2(q，J＝32.7Hz)，20.3.MS(ES-)：367.0(M-H，100).High resolution MS(ES-)m/zcalc.for C18H11C1F3O3：367.0349(M-H)，found 367.0325
Example 871
6-chloro-5- (3-isopropylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the same procedure described for the preparation of 6-chloro-5- (2-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. Off-white solid
m.p.＝184.0-186.5℃.LC-MS(ES+)397.3(M+1，100).1H NMR(CDCl3/300MHz)9.53(s，broad，1H)，7.52-7.04(m，5H)，7.04-6.96(m，2H)，[1202] 5.68(q，J＝6.6Hz，1H)，3.02(q，J＝6.6Hz，1H)，1.34(m，6H).19FNMR(CDCl3/300MHz)-78.62.13C NMR(CDCl3/300MHz)169.5，152.8，149.3(d)，141.4，138.3(d)，135.1，133.9，129.4，128.5(d)，128.4(d)，127.5，127.2(d)，127.1(d)，123.6(q，J＝287.7Hz)，119.8，116.6，115.8，69.9(q，J＝33.7Hz)，34.3，24.1.MS(ES-)395.0(M-H，100)，High resoluton MS(ES-)m/z calc.for C20H15ClF3O3：395.0662M-H)，found：395.0642。
Example 872
6-chloro-5-phenyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the same procedure described for the preparation of 6-chloro-5- (2-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. Pale yellow solid
M.P.＝229.0-231.0℃.LC-MS(ES+)355.2(M+1，100)，1H NMR(CDCl3/CD3OD/300MHz)7.46-7.30(m，6H)，7.09(d，J＝7.5Hz，1H)，6.93(d，J＝9Hz，1H)，5.65(q，J＝6.6Hz，1H).19F NMR(CDCl3/CD3OD-/300MHz)-78.83.13C NMR(CDCl3/CD3OD/300MHz)169.8，156.4，144.5，139.5，139.4，137.0，134.8，133.9，132.7，132.6，132.3，130.9，127.6(q，J＝287.6Hz)，124.0，121.5，120.5，74.2(q，J＝33.2Hz).MS(ES-)353.0(M-H，100).High resoluton MS(ES-) m/z calc.for C17H9ClF3O3：353.0192(M-H)，found：353.0202.
Example 873
6-chloro-5-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a mixture of ethyl 6-chloro-5-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.3g, 0.7mmol), potassium carbonate (109mg, 2.87mmol), and tetrakis (triphenylphosphine) palladium (0) (81mg, 0.07mmol) in 3mL anhydrous DMF under nitrogen was added triethylboron (1.0M/THF, 1.05mL, 1.05 mmol). The resulting mixture was heated to 110 ℃ for 5 hours. The reaction was cooled to room temperature and diluted with 100mL of ethyl acetate. The organic phase was washed with brine. After removal of the solvent, the residue was dissolved in 3mL of THF, followed by addition of 3mL of an aqueous solution of lithium hydroxide hydrate. To the resulting mixture was further added 3mL of ethanol. The resulting solution was then heated to 80 ℃ for 3 hours. The volatiles were then removed. The residue was diluted with water and acidified with dilute hydrochloric acid in an ice/water bath. The product was extracted with ethyl acetate. The organic extract was washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified on short silica gel eluting with 3: 7Et0 Ac/hexane + 1% HOAc to remove polar impurities. After concentration of the collected fractions, the residue was further purified by reverse phase HPLC. 75mg of a yellowish solid are obtained.
M.P.＝171.5-172.5℃.1H NMR(CDCl3/400Mz)，8.07(s，1H)，7.32(d，J＝8.8Hz，1H)，6.82(d，J＝8.8Hz，1H)，5.65(q，J＝6.8Hz，1H)，2.91(m，2H)，1.18(t，J＝7.6Hz，3H).13CNMR(CDCl3/400MHz)169.5，152.8，141.5，136.5，134.1，127.7，123.4(q，J＝287.7Hz)，118.6，116.3，115.5，69.8(q，J＝33.4Hz)，23.1，14.7.19F NMR(CDCl3/400Mz)-78.72(d，J＝6.8Hz).MS(ES-)＝305.0(M-H，100).High resolution MS(ES-)，m/e calc.For C13H10ClF3O3：305.0198(M-H)，found：305.0157.
Example 874
6-chloro-5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a solution of ethyl 6-chloro-5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (1.1g, 3.4mmol) in 5mL THF was added 5mL aqueous solution of lithium hydroxide hydrate (0.72g, 17 mmol). To the resulting mixture was added 5mL of ethanol. The resulting solution was heated to reflux over 3 hours. The reaction turned red. After cooling to room temperature, the volatiles were removed and the residue was diluted with water. The resulting solution was acidified with ice cold dilute hydrochloric acid at 0 ℃. The product was then extracted with ethyl acetate. The organic extracts were combined and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified by reverse phase HPLC. A yellow solid (0.3g) was obtained. LC-MS (ES)+)297.2(M+1，100).1H NMR(CDCl3/CD3OD/400MHz)7.85(s，1H)，7.24(m，1H)，6.69(d，J＝8.8Hz，1H)，5.63(q，J＝6.4Hz，1H).19F(CDCl3/CCD3OD/400MHz)-78.94(d，J＝6.8Hz)，-111.92(d，J＝7.5Hz).13C NMR(CDCl3/CD3OD/400MHz)165.4，155.0(d，J＝64.4Hz)，152.3，133.2，129.4，123.3(q，J＝287.3Hz)118.5114.2(d，J＝4.3Hz)，112.6，110.1(d，J＝4.7Hz)，70.9(q，J＝33.2Hz).HRSM((EI+)m/z calc.for(C11H5ClF4O3)：295.9863(M+)，found 295.9875(M+).
Example 875
5-azido-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the same procedure described for the preparation of 6-chloro-5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. LC-MS (ES +)320.2(M +1, 45), 292.1(M-27, 100).1H NMR(CDC13/400MHz)8.15(s，1H)，7.28(d，J＝8.8Hz，1H)，6.77(d，J＝8.8Hz，1H)，5.65(q，J＝7.2Hz，1H).19FNMR(CDCl3/400MHz)-78.74(d，J＝6.8Hz).13C NMR(CDCl3/400Mhz)169.3，153.0，134.8，134.6，123.3(q，J＝287.6HZ)，122.7，116.4，114.4，114.2，106.5，70.3(q，J＝33.5Hz).HRMS(EI+)m/zcalc.for(C11H5ClF3N3O3)：318.9972(M+)，found：318.9973.
Example 876
5-amino-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared as a yellow solid using the same procedure described for the preparation of 6-chloro-5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid.
m.p.＝208.5-210.0℃.LC-MS(ES+)：294.2(M+1，100).19FNMR(CD3OD/300MHz)-81.64(d，J＝7.1Hz).1H NMR(CD3OD/300MHz)8.13(s，1H)，7.20(d，J＝8.7Hz，H)，6.27(d，J＝8.7Hz，1H)，5.69(q，J＝7.5Hz，1H)，4.91(s，broad peak).13CNMR(CD3OD/300MHz)166.0，152.8，143.2，132.7，132.6，124.1(q，J＝287.2Hz)，114.3，112.4，106.5，104.4，70.1(q，J＝32.8Hz).HRMS(ES-)m/zcalc.for(C11H6C1F3NO3)：291.9988(M-H)，found：291.9966.
Example 877
6-chloro-5-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the same procedure described for the preparation of 6-chloro-5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. Light yellow solid.
LC-MS(ES+)405.1(M+H，100).1H NMR(CDCl3/CD3OD/400Hz)8.04(s，1H)，7.39(d，J＝8.8Hz，1H)，6.94(d，J＝8.4Hz，1H)，5.65(q，J＝6.4Hz，1H).13C NMR(CDCl3/CD3OD/400Mhz)166.5，152.5，142.4，133.7，132.6，124.6，123.2(q，J＝287.1Hz)，118.7，117.7，104.7，70.5(q，J＝33.5Hz).19F(CDCl3/CD3OD/400Hz)：-78.55(d，J＝6.8Hz).Highresolution MS(ES-)：m/e calc.for C15H4ClF3O3I：402.8846(M-H)，observed：402.8857.
Preparation of 6-methyl-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Example 878
6-methyl-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of ethyl 6-bromo-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of ethyl 7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (5g, 34mmol) in 100mL of tetrachloromethane was added dropwise a solution of bromine (10.5mL, 204mmol) in 20mL of tetrachloromethane at room temperature. The resulting solution was stirred for 24 hours. To the reaction was added 500mL of ethyl acetate. The resulting organic phase was then washed with aqueous sodium thiosulfite to remove excess bromine, then washed with brine, and then dried over anhydrous magnesium sulfate. After removal of volatiles, the residue was purified by silica gel column eluting with 1: 9 EtOAc/hexanes. 5.6g of product are obtained. A small portion of the product was further purified by reverse phase HPLC for analytical identification. A white solid was obtained.
m.p.＝98.5-100.0℃.1HNMR(CDCl3/300MHz)7.67(s，1H)，7.46(d，J＝7.SHz，1H)，6.83(d，J＝9Hz，1H)，5.74(q，J＝6.6Hz，1H)，4.36(m，2H)，1.39(t，J＝7.2Hz，3H).19F NMR(CDCl3/300MHz)：-78.82(d，J＝6.5Hz)，-98.7(t，J＝7.9Hz).13C NMR(CDCl3/300MHz)：163.6，163.1，159.7，154.0(d，J＝11.5Hz)，135.1，133.4，123.4(q，J＝287.3Hz)，117.3，105.6(d，J＝26.7Hz)，102.2(d，J＝22.3Hz)，71.1(q，J＝33.3Hz)，61.9，14.4.LC-MS(ES+)：369.2(M+1，100).HRMS(EI+)：m/z calc.For C13H9BrF4O3：367.9671(M+)，found：367.9675.
Step 2.6 preparation of methyl-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a mixture of ethyl 6-bromo-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (2.2g, 6mmol), potassium carbonate (3.22g, 23.4 mmol 1), and tetrakis (triphenylphosphine) palladium (0) (700mg, 0.6mmol) in 18mL anhydrous DMF was added trimethylboroxine (2.5mL, 9 mmol 1). The resulting mixture was heated to 110 ℃ under nitrogen atmosphere for 15 hours. After cooling to room temperature, 200mL of ethyl acetate were added to the reaction, and the resulting organic phase was washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified over a short silica gel column, eluting with a hexane/EtOAc mixture. The collected fractions were then evaporated to dryness. 300mg of the purified intermediate was then dissolved in 9mL of 1: 1 THF/EtOH/water, followed by the addition of lithium hydroxide hydrate (102 mg). The resulting solution was heated to 80 ℃ for 1.5 hours. The volatiles were then removed and the residue was diluted with water and acidified with dilute hydrochloric acid at 0 ℃. A large amount of precipitate was formed. The product was then extracted with ethyl acetate. After removal of the solvent, the crude product was purified by reverse phase HPLC. Light yellow solid.
1HNMR(CDCl3/CD3OD/300MHz)7.76(s，1H)，7.07(d，J＝8.1Hz，1H)，6.68(d，J＝9.9Hz，1H)，5.65(q，J＝6.9Hz，1H)，2.20(s，3H).19F NMR(CDCl3/CD3OD/300MHz)-78.93(d，J＝6.9Hz)，-107.11(t，J＝7.9Hz).13C NMR(CDCl3/CD3OD/300MHz)168.0，165.8，162.3，153.2(d，J＝12.8Hz)，138.4，132.2，123.6(q，J＝287.5Hz)，119.8(d，J＝18.5Hz)，115.0(d，J＝43.2Hz)，104.1(d，J＝27.1hz)，70.7(q，J＝33.3Hz)，14.0(d，J＝3.2Hz).LC-MS(ES+)：277.2(M+1,100).Hight resolution mass(ES-)：m/z calc.For C12H8F4O3：275.0337M-H)，found：275.0341.
Preparation of 7- (4-chloro-2-methylphenoxy) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Example 879
7- (4-chloro-2-methylphenoxy) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 7- (4-chloro-2-methylphenoxy) -6-bromo-2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a mixture of ethyl 6-bromo-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.5g, 1.36mmol), potassium carbonate (560mg, 4.06mmol) and 5mL anhydrous DMF was added 4-C1-2-methylphenol (466mg, 3.23mmol) and 0.32mL diisopropylethylamine, and the resulting mixture was heated to 90 ℃ for 8 hours. After cooling to room temperature, 150mL of ethyl acetate was added to the reaction, and the resulting organic solution was washed with brine and dried over anhydrous magnesium sulfate. After removal of volatiles, the residue was purified over a short silica gel column, eluting with an EtOAc/hexane mixture. 400mg of a yellow solid are obtained. A small amount of product was further purified by reverse phase HPLC for analytical identification. A pale yellow solid was obtained.
1H NMR(CDCl3/300MHz)7.68(s，1H)，7.52(s，1H)，7.31(d，J＝2.7Hz，1H)，7.25(dd，J＝2.4，8.4Hz，1H)，6.95(d，J＝8.7Hz，1H)，6.29(s，1H)，5.65(q，J＝6.6Hz，1H)，4.35(m，2H)，2.21(s，3H)，1.38(t，6.9Hz，3H).19F NMR(CDCl3/300MHz)-78.84(d，J＝6.5Hz).13C NMR(CDCl3/300MHz)163.9，157.9，154.1，151.6，135.5，133.8，132.3，131.9，130.9，127.8，123.5(q，J＝287.5Hz)，121.9，115.9，115.5，105.3，104.6，71.2(q，J＝33.3Hz)，61.8，16.2，14.4.LC-MS(ES+)：491.3(M+1，70)，493.3(M+2，100).HighresolutionMass(EI+)：m/z calc.For C20H15BrClF3O4：489.9794(M+)，found：489.9765.
Step 2.7- (4-chloro-2-methylphenoxy) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid preparation
This example was prepared using the same procedure as described for the preparation of 6-methyl-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. Light yellow solid.
1H NMR(CDCl3/CD3OD/300MHz)7.76(s，1H)，7.29(m，1H)，7.20(dd，J＝2.4Hz，8.4Hz，1H)，7.11(s，1H)，6.87(d，J＝8.7Hz，1H)，6.20(s，1H)，5.62(q，J＝6.9Hz，1H)，2.28(s，3H)，2.19(s，3H).19F NMR(CDCl3/CD3OD/300MHz)-79.0(d，J＝6.5Hz).13CNMR(CDCl3/CD3OD/300MHz)167.3，159.9，153.3，152.2，138.1，132.1，132.0，131.7，130.1，127.7，123.7(q，J＝287.7Hz)，122.2，121.6，113.8，113.7，103.2，70.6(q，J＝33.1Hz)，16.2，15.6.LC-MS(ES+)：399.3(M+1，100).MS(ES-)：397.1(M-H，63)，333.1(M-65，100).Highresolution Mass(ES-)：m/z calc.For C19H13C1F3O4：397.0454(M-H)，found：397.0443.
Preparation of 6-methyl-7-substituted-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Example 880
6, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 7-hydroxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of ethyl 7-methoxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (5.2g, 16.4mmol) in 30mL of anhydrous dichloromethane was added dropwise a 1.0M solution of boron tribromide (164mL, 164mmol) at-78 ℃ in a dry ice/acetone bath. After the addition was complete, the dry ice/acetone bath was removed. The reaction was stirred at room temperature overnight. The reaction was then cooled to-78 ℃ in a dry ice/acetone bath. 200mL of ethanol are added dropwise. After the addition was complete, the cooling bath was removed. The reaction was allowed to warm to room temperature. LC-MS indicated the reaction was complete. Volatiles were removed on a rotary evaporator. The residue was then purified by column on silica eluting with 1: 9EtOAc in hexanes. The desired product was isolated as an off-white solid,
m.p.＝151.0-153.0C.1H NMR(CDCl3/CD3OD/300MHZ)：7.68(s，1H)，6.97(s，1H)，6.43(s，1H)，5.65(q，J＝7.2Hz，1H)，4.31(m，2H)，2.17(s，3H)，1.36(t，J＝6.9Hz，3H).19F NMR(CDCl3/CD3OD/300MHz)-79.03(d，J＝7.3Hz).13C(CDCl3/CD3OD/300Mhz)164.8，159.4，153.3，137.8，131.8，123.9(q，J＝287.9Hz)，119.4，112.5，111.8，102.6，70.9(q，J＝32.9Hz)，61.4，15.3，14.4.LC-MS(ES+)：303.1(M+1).MS(EI+)：302.0(M+，80)，233(M-69，100)；High resolution MS：m/zcalc.For C14H13F3O4：302.0766(M+，theoretical)，found：302.0763.
step 2. preparation of Ethyl 6-methyl-2- (trifluoromethyl) -7- { [ (trifluoromethyl) sulfonyl ] oxy } -2H-chromene-3-carboxylate
To a mixture of ethyl 7-hydroxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate (2.5g, 8.3mmoL) in anhydrous DCM was added DIEA (2.79mL, 16.6mmoL) in one portion. Then the obtained product is The yellow solution was cooled to 0 ℃ in an ice bath, stirred for 10 minutes and then added dropwise (TfO)2O (4.35mL, 25 mmol). Upon completion of the addition, the ice bath was removed and the reaction was stirred at room temperature for 2 hours. Then 20mL of 0.5N diluted HCl solution was added and the mixture was stirred for 10 minutes, then 50mL of DCM was added to the reaction and the aqueous phase was separated and extracted with DCM. The organic phases were combined and washed with saturated NaHCO3And brine, dried over anhydrous sodium sulfate, the volatiles were removed, and the residue was purified on a silica gel column, eluting with 1: 9EtOAc in hexanes. A white solid, 3.3g, was obtained.1HNMR(CDCl3/300MHz)：7.69(s，1H)，7.18(s，1H)，6.94(s，1H)，5.74(q，J＝6.6Hz，1H)，4.35(m，2H)，2.32(s，3H)，1.37(t，J＝7.2Hz，3H).19F NMR(CDCl3/300MHz)：-74.3，-78.92(d，J＝6.5Hz).13C NMR(CDCl3/300MHz)：163.6，152.3，150.3，135.4，132.2，123.4(q，J＝287.3Hz)，120.9，119.3，118.4，116.7，109.8，71.0(q，J＝33.3Hz)，61.9，15.7，14.2.LC-MS(ES+)：435.0(M+1，100).High resolution Mass(EI+)：m/z calc.For C12H12F6O6S：434.0259(M+)，found：434.0257.
Step 4.6, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid preparation
To a mixture of ethyl 6-methyl-2- (trifluoromethyl) -7- { [ (trifluoromethyl) sulfonyl ] oxy } -2H-chromene-3-carboxylate (0.3g, 0.7mmol), potassium carbonate (0.378g, 2.73mmol), tetrakis (triphenylphosphine) palladium (0) (81mg, 0.07mmol) and 3mL anhydrous DMF was added trimethylboroxine (292. mu.L, 2.1 mmol). The resulting mixture was heated to 110 ℃ and stirred at 110 ℃ for 2 hours. LC-MS indicated the reaction was complete. 100mL EtOAc was added to the reaction and the resulting organic solution was washed with brine and dried over anhydrous magnesium sulfate. After removal of volatiles, the residue was purified by silica gel column eluting with 1: 9 EtOAc/hexanes. A white solid, about 180mg, was obtained. The purified white solid was dissolved in 3mL of THF, and lithium hydroxide hydrate (118mg, 2.8mmol), 3mL of water and 3mL of ethanol were added to the resulting solution, and the resulting solution was heated to 80 ℃ and stirred for 45 minutes. After cooling to room temperature, the volatiles were removed on a rotary evaporator and the residue was diluted with water and acidified with ice-cold dilute hydrochloric acid in an ice bath. A large amount of white precipitate was formed. The solid was filtered, washed with water and dried in vacuo. The crude product was then purified by reverse phase HPLC. A white solid, 70mg, was obtained.
1H NMR(CDCl3/CD3OD/300MHz)7.73(s，1H)，6.97(s，1H)，6.79(s，1H)，5.65(q，J＝6.6Hz)，2.25(s，3H)，2.19(s，3H).13C NMR(CDCl3/CD3OD/300MHz)167.0，151.8，143.2，138.3，131.0，130.4，123.9(q，J＝287.9Hz)，117.1，116.9，115.2，70.7(q，J＝32.7Hz)，20.5，18.9.19F NMR(CDCl3/CD3OD/300MHz)-78.97(d，J＝6.5Hz).LC-MS(ES+)：273.2(M+1，100)。Highresolution Mass(ES-)：m/z calc.For C13H10F3O3：271.0582(M-H)，found：271.0563.
Example 881
7-ethyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the same procedure as described for the preparation of 6, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. Yellow solid.
LC-MS(ES+)：287.2(M+1，100).1H NMR(CD3OD/300MHz)7.73(s，1H)，7.06(s，lH)，6.79(s，1H)，5.69(q，J＝7.2Hz，1H)，2.62(q，J＝7.5Hz，2H)，1.21(t，J＝7.8Hz，3H).19FNMR(CD3OD/300MHz)-80.35(d，J＝7.1Hz).13C NMR(CD3OD/300MHz)166.0，151.9，148.5，137.1，130.6，130.1，124.1(q，J＝287.4Hz)，116.9，115.8，114.8，70.7(q，J＝32.5Hz)，26.2，17.1，13.2.High resolution Mass(ESS-)：m/z calc.For C14H12F3O3：285.0739(M-H)，found：285.0708.
Example 882
7-butyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the same procedure as described for the preparation of 6, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. Light yellow solid.
LC-MS(ES+)：315.1(M+1，100).1H NMR(CDCl3/300MHz)7.86(s，1H)，7.04(s，1H)，6.84(s，1H)，5.69(q，J＝6.9Hz，1H)，2.60(t，J＝7.2Hz，2H)，2.27(s，3H)，1.63-1.58(m，2H)，1.48-1.41(m，2H)，1.00(t，J＝7.5Hz，3H).13F NMR(CDCl3/300MHz)-78.90(d，J＝7.1Hz)13C NMR(CDCl3/300MHz)170.1，152.2，148.6，140.1，131.1，130.6，121.8(q，J＝287.9Hz)，116.6，116.3，114.2，70.5(q，J＝33.0Hz)，33.7，32.1，22.9，18.6，14.2.Highresolution MS(ES-)：m/z calc.For C16H16F3O3：313.1052(M-H)，found：313.1024.
Example 883
7- (2, 3-dimethylphenyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a mixture of ethyl 6-methyl-2- (trifluoromethyl) -7- { [ (trifluoromethyl) sulfonyl ] oxy } -2H-chromene-3-carboxylate (0.3g, 0.7mmol), tetrakis (triphenylphosphine) palladium (0) (4.5mg, 0.035mmol), crushed potassium phosphate (222mg, 1.05mmol) and 2, 3-dimethylphenylboronic acid (106mg, 0.84mmol) was added 5mL of anhydrous dioxane. The resulting mixture was heated to 85 ℃ and stirred for 6 hours. After cooling to room temperature, 100mL of ethyl acetate was added to the reaction. The organic phase was washed with brine and dried over anhydrous magnesium sulfate. After removal of the solvent, the residue was purified on a silica gel column, eluting with 1: 9EtOAc in hexanes. The collected fractions were evaporated to dryness, the residue was dissolved in 6mL of 1: 1 THF/ethanol, and lithium hydroxide hydrate (117mg, 2.8mmol) was added to the resulting solution, followed by the addition of 3mL of water. The resulting mixture was heated to 80 ℃ and stirred for 1.5 hours. After removal of volatiles, the residue was acidified with ice-cold dilute HC1 at 0 ℃. The product was then extracted with EtOAc. After removal of volatiles, the residue was purified by reverse phase HPLC. 39mg of pale yellow solid product are obtained.
1H NMR(CDCl3/CD3OD/300MHz)7.85(s，1H)，7.21-7.14(m，3H)，6.96(dd，J＝6.9Hz，15.6Hz，1H)，6.79(s，1H)，5.71(q，J＝7.2Hz，1H)，2.35(s，3H)，2.00(s，6H).19FNMR(CDCl3/300MHz)-78.81.13CNMR(CDCl3/CD3OD/300MHz)167.3，151.5，148.1，140.6(d，J＝4.8Hz)，138.5，137.3，134.1(d.J＝13.7Hz)，130.7，129.4，126.8，126.6，125.6，123.9(q，J＝287.9Hz)，118.0，117.2，115.9，70.8(q，J＝32，9Hz)，20.7，19.1，16.6.LC-MS(ES+)：363.2(M+1，100).High resolution MS(ES-)：m/z calc.For C20H16F3O3：361.1052(M-H)，found：361.1036.
Example 884
7-isobutyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the same procedure as described for the preparation of 7- (2, 3-dimethylphenyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. A white solid.
1H NMR(CDCl3/300MHz)7.86(s，1H) 7.05(s，1H)，6.80(s，1H)，5.69(q，J＝6.9Hz，1H)，2.49(m，2H)，2.27(s，3H)，1.92(m，1H)，0.97(dd，J＝0.9Hz，6.9Hz，6H).19F NMR(CDCl3/300MHz)-78.89(d，J＝7.3Hz).13C NMR(CDCl3/300MHz)170.0，151.9，147.5，140.1，131.2，130.9，123.8(q，J＝287.9Hz)，117.3，116.7，114.3，70.5(q，J＝33.2Hz)，43.1，29.2，22.9，18.9.LC-MS(ES+)：315.1(M+1，100)；High resolution MS(ES-)：m/z calc.For C16H16F3O3：313.1052(M-H)，found：313.1006.
Example 885
7- (4-ethylphenyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the same procedure as described for the preparation of 7- (2, 3-dimethylphenyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. Light yellow solid.
1H NMR(CDCl3/CD3OD/400MHz)7.82(s，1H)，7.23(s，4H)，7.10(s，1H)，6.88(s，1H)，5.68(q，J＝6.8Hz，1H)2.69(q，J＝7.6Hz，2H)，2.21(s，3H，)，1.27(t，J＝7.6Hz，3H).19F NMR(CDCl3/300MHz)-78.77(d，J＝6.8Hz).13CNMR(CDCl3/300MHz)151.7，147.6，143.9，138.8，138.1，131.4，130.0，129.0，128.0，125.8，123.8(q，J＝287.9Hz)，117.9，117.4，1156，70.8(q，J＝33.2Hz)，28.8，19.9，15.7..LC-MS(ES+)：363.2(M+1，100).High resolution MS(ES-)：m/z calc.for C20H16F3O3：361.1052(M-H)，Found：361.1046.
Example 886
7- (4-ethylphenoxy) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To ethyl 6-methyl-2- (trifluoromethyl) -7- { [ (trifluoromethyl) -sulfonyl]4mL of anhydrous toluene was added to a mixture of oxy } -2H-chromene-3-carboxylate (0.3g, 0.7mmol), ground potassium phosphate (297mg, 1.4mmol), palladium acetate (15.7mg, 0.07mmol), 2- (di-t-butylphosphino) biphenyl (31.3mg, 0.105mmol), and 4-ethylphenol (103mg, 0.84 mmol). The resulting mixture was heated to 110 ℃ and stirred at 110 ℃ for 4 hours. LC-MS indicated the reaction was complete. After cooling to room temperature, 100mL EtOAc can be added to the reaction. The organic phase was then extracted three times with brine and dried over anhydrous magnesium sulfate. After removal of volatiles, the residue was purified by silica gel column eluting with 1: 18 EtOAc/hexanes. The collected product was dissolved in THF (3mL), and ethanol (3mL) and water (3mL) were added to the resulting solution, followed by the addition of lithium hydroxide hydrate (90 mg). The resulting mixture was heated to 80 ℃ and stirred for 1.5 hours. LC-MS indicated the reaction was complete. The volatiles were removed and the residue was diluted with water and acidified with ice cold dilute hydrochloric acid at 0 ℃. The product was extracted with EtOAc. After removal of the solvent, the residue was purified by reverse phase HPLC. The product was isolated as a pale yellow solid, 100 mg. LC-MS (ES +): 379.2(M +1, 100). 1H NMR(CDCl3/CD3CD/300MHz)7.86(s，1H)，7.25(d，J＝8.4Hz，2H)，7.14(s，1H)，6.99(d，J＝8.4Hz，2H)，6.40(s，1H)，5.64(q，J＝6.6Hz，1H)，2.70(q，J＝7.5Hz，2H)，2.30(s，3H)，1.3o(t，J＝7.5Hz，3H).13C NMR(CDCl3/CD3OD/300MHz)170.0，161.2，153.5，153.4，140.9，139.8，132.2，129.6，123.7(q，J＝287.9Hz)，122.9，120.1，113.5，112.7，104.2，70.6(q，J＝33.3Hz)，28.5，15.9，15.7.High resolution MS(ES-)：m/z cacl.ForC20H16F3O4：377.1001(M-H)，found：377.0987.
Example 887
7- (2-chloro-4-methoxyphenoxy) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the same procedure described for the preparation of 7- (4-ethylphenoxy) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. Light yellow solid.
1H NMR(CDCl3/300MHz)：7.85(s，1H)，7.14(s，1H)，7.09(d，J＝8.7Hz，1H)，7.06(d，J＝2.7Hz，1H)，6.90(dd，J＝9Hz，3Hz，1H)，6.17(s，1H)，5.63(q，J＝6.9Hz，1H)，3.87(s，3H)，2.35(s，3H).13C NMR(CDCl3/300MHz)169.7，160.9，157.5，153.6，144.3，139.7，132.2，127.6，123.7(q，J＝287.7Hz)，123.6，122.0，116.2，114.3，113.3，122.6，102.3，70.7(q，J＝33.2Hz)，56.1，15.7.LC-MS(ES+)：415.1(M+1，100).High resolutionMS(ES-)：m/z cacl.For C19H13F3O5：413.0404(M-H)，found：413.0374.
Example 888
7- (4-fluoro-2-methylphenoxy) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the same procedure described for the preparation of 7- (4-ethylphenoxy) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid. Light yellow solid.
7.77(s，1H)，7.10(s，1H)，7.01(d，J＝8.4Hz，1H)，6.95-6.93(m，2H)，6.14(s，1H)，5.62(q，J＝6.9Hz，1H)，2.30(s，3H)，2.18(s，3H).19F NMR(CDCl3/300MHz)-79.02(d，J＝6.5Hz)，-118.52(m).13C NMR(CDCl3/CD3OD/300MHz)167.6, 160.6, 159.9(d, J ═ 243.5Hz), 153.4, 149.2, 138.4, 132.5(d, J ═ 8.1Hz), 132.0, 123.7(q, J ═ 286.8Hz), 122.3, 122.1, 121.8, 118.4(d, J ═ 23.0Hz), 114.2(d, J ═ 23.4Hz), 113.3(d, J ═ 7.3Hz), 102.4, 70.8(q, J ═ 33.0Hz), 16.4, 15.6.LC-MS (ES +): 383.1(M +1). high resolution: MS (ES)-) Calculated m/z: c19H13F4O4: 381.0750(M-H), found: 381.0754.
preparation of 8-methyl-7-substituted-2- (trifluoromethyl) -2H-chromene-3-carboxylic acids via aryl fluoride displacement
Preparation of ethyl 8-methyl-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate
Step 1.2 preparation of 2- (3-fluorophenoxy) tetrahydro-2H-pyran
To 75g (669mmol) of 3-fluorophenol was added 79g (928mmol) of 3, 4-dihydro-2H-pyran at-35 ℃. The ice bath was removed and 1.0mL of concentrated HCl was added. The temperature was allowed to warm to room temperature and the progress of the reaction was monitored by HPLC. To the reaction was added 500mL diethyl ether and 500mL 1M NaHCO3. NaHCO for organic layer3(2x) and brine wash. Subjecting the organic layer to Na2SO4Drying, filtration and concentration gave a yellow oil which was purified by silica gel chromatography eluting with EtOAc/hexane (1: 9). The desired fractions were concentrated to give 102.1g (78%) of a white solid:
1H NMR(CDCl3/400MHz)1.56-2.03(m，6H)，3.58-3.63(m，1H)，3.85-3.91(m，1H)，5.39(t，1H，J＝3.2Hz)，6.65-6.70(m，1H)6.78-6.84(m，2H)，7.21(dd，1H，J＝8.2，15.o Hz)；HRMS(EI+)m/z calcd for(C11H13FO2)196.0900，found 196.0890.
step 2.2 preparation of 2- (3-fluoro-2-methylphenoxy) tetrahydro-2H-pyran
To a cooled (-78 deg.C) solution of 9.33g (47.55mmol) of 2- (3-fluorophenoxy) tetrahydro-2H-pyran in 150mL of THF was added 38mL (95.1mmol) of n-BuLi (2.5M in hexane). The reaction mixture was stirred at-78 ℃ for 45 minutes and 11.9mL (190.2mmol) of methyl iodide was added slowly via syringe. The reaction was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated ammonium chloride and transferred to a round bottom flask. The volatiles were removed in vacuo and the mixture was partitioned between EtOAc and water. The layers were separated and the organic layer was washed with water (x2) and brine. Through Na2SO4Drying, filtration and concentration gave 9.01g (90%) of a yellow oil:
1H NMR(CDCl3/400MHz)1.46-2.09(m，6H)，2.21(d，3H，J＝2.0Hz)，3.60-3.65(m，1H)，3.86-3.92(m，1H)，5.44(t，1H，J＝3.2Hz)，6.70(t，1H，J＝8.8Hz)，6.90(d，1H，J＝8.4Hz)，7.08(dd，1H，J＝8.0，15.2Hz)；HRMS(EI+)m/z calcd for(C12H15FO2)210.1056，found 210.1070.
Step 3.3 preparation of 3-fluoro-2-methylphenol
5.0g (23.78mmol) of 2- (3-fluoro-2-methylphenoxy) tetrahydro-2H-pyran are dissolved in 120mL of methanol, followed by the addition of 3.21g (35.67mmol) of oxalic acid. The mixture was heated to 60 ℃ for 2 hours. The volatiles were removed in vacuo while maintaining a bath temperature < 29 ℃ to give an oil which was chromatographed on silica gel eluting with EtOAc/hexanes (9: 1). The desired fractions were concentrated to give 2.19g (73%) of a pale yellow oil which solidified on standing:
1HNMR(CDCl3/400MHz)2.16(d，3H，J＝2.0Hz)，5.17(s，1H)，6.57(d，1H，J＝8.4Hz)，6.64(t，1H，J＝8.8hz)，7.00(dd，1H，J＝8.4，14.8Hz)；HRMS(EI+)m/z calcd for(C7H7FO)126.0481，found 126.0470.
step 4.4 preparation of 4-fluoro-2-hydroxy-3-methylbenzaldehyde
To a solution of 2.19g (17.36mmol) of 3-fluoro-2-methylphenol in 87mL of anhydrous acetonitrile was added in portions 12.1g (126.73mmol) of MgCl2Followed by the addition of 9.0mL (64.93mmol) of TEA to give a pink reaction mixture. To this mixture was added 3.8g (126.73mmol) of paraformaldehyde and the resulting yellow mixture was heated to reflux for 4 hours. After cooling to room temperature, 5% HCl was slowly added to the mixture. The reaction was extracted with EtOAc (3 ×), washed with saturated NaCl (3 ×), and over MgSO4Drying, filtration and concentration gave an oil which was chromatographed on silica gel eluting with EtOAc/hexane (1: 9) to give 2.02g (75%) of a pale yellow-brown oil which solidified later:
1H NMR(CDCl3/400MHz)2.14(d，3H，J＝1.6Hz)，6.68(t，1H，J＝8.8Hz)，7.37(dd，1H，J＝6.4，8.4Hz)，9.78(s，1H)，11.59(d，1H，J＝2.0Hz)；HRMS(EI+)m/z calcd for(C8H7FO2)154.0430，found 154.0428.
step 5. preparation of Ethyl 7-fluoro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of 1.0g (6.49mmol) of 4-fluoro-2-hydroxy-3-methylbenzaldehyde in 1.6mL of anhydrous DMF was added 1.79g (12.98mmol) of K2CO3Followed by the addition of 1.64g (9.74mmol) ethyl-4, 4, 4-trifluorocrotonate. The reaction mixture was heated to 70 ℃ overnight. The next day, the reaction was monitored by LC/MS and LCMS indicated that starting material (-40%) remained. A further 1.79g (12.98mmol) of K are added2CO3And another 1.64g (9.74mmol) of ethyl-4, 4, 4-trifluorocrotonate, and the mixture was stirredHeated to 90 ℃ for 3 hours. After 3 hours, LCMS indicated < 10% starting material remaining. The crude product was purified by Gilson reverse phase chromatography (50-99% CH)3CN gradient) to yield 2.58g (65%) of a pale tan solid:
1H NMR(CDCl3/400MHz)1.33(t，3H，J＝7.2Hz)，2.15(d，3H，J＝2.0Hz)，4.26-4.34(m，2H)，5.73(q，1H，J＝6.8Hz)，6.68(t，1H，J＝8.8Hz)，7.03(dd，1H，J＝6.4，8.4Hz)，7.67(s，1H)；MS(ES+)305.2(M+H，100)；HRMS(EI+)m/z calcd for(C14H12F4O3)304.0723，found 304.0720.
example 889
7-fluoro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a solution of 0.150g (0.490mmol) ethyl 8-methyl-7-phenoxy-2- (trifluoromethyl) -2H chromene-3-carboxylate in 2.5mL THF: EtOH: H2To a solution in O (7: 2: 1) was added 0.031g (0.735mmol) of LiOH. The mixture was heated at 60 ℃ for 2 hours. Volatiles were removed in vacuo and HCl (10%), CH3Dilution with CN and DHF and purification by reverse phase chromatography gave 0.083g (61%) of an off-white solid: 1HNMR(CH3OD/400MHz)2.13(d，3H，J＝2.0Hz)，5.81(q，1H，J＝7.2Hz)，6.76(t，1H，J＝8.8Hz)，7.20(dd，1H，J＝6.4，8.4Hz)，7.75(s，1H)；MS(ES+)377(M+H，100)；HRMS(ES-)m/z calcd for(C12H8F4O3)275.0331，found 275.0283.
General procedure for the preparation of 8-methyl-7-substituted-2- (trifluoromethyl) -2H-chromene-3-carboxylic acids
Example 890
8-methyl-7-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of ethyl 8-methyl-7-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of 0.304g (1.00mmol) ethyl 7-fluoro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 5.0mL DMF was added 0.194g K2CO3(1.40mmol) and 0.105mL (1.20mmol) of phenol. The mixture was heated to 90 ℃ and LC/MS indicated that starting material remained. The mixture was then heated to 110 ℃ overnight and LC/MS still indicated that starting material remained. Add another 0.194g K2CO3(1.40mmol) and 0.105mL (1.20mmol) of phenol. Heating overnight and purification by Gilson reverse phase chromatography gave 0.107g (28%) of a light yellow solid:
1HNMR(CH3OD/400MHz)1.32(t，3H，J＝7.2Hz)，2.15(s，3H)，4.24-4.33(m，2H)，5.82(q，1H，J＝7.2Hz)，6.42(d，1H，J＝8.4Hz)，6.94-6.97(m，2H)，7.09-7.15(m，2H)，7.33-7.37(m，2H)，7.75(s，1H)；MS(ES+)379.3(M+H，100)；HRMS(EI+)m/z calcd for(C20H17F3O4)378.1079，found 378.1062.
step 2.8 preparation of methyl-7-phenoxy- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a solution of 0.090g (0.24mmol) ethyl 8-methyl-7-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 5mL THF: EtOH: H2To the solution in O (7: 2: 1) was added 0.015g (0.36mmol) of LiOH. Will be mixed withThe mixture was heated at 60 ℃ for 2 hours. Volatiles were removed in vacuo and HCl (10%), CH3Dilution with CN and DMF and purification by reverse phase chromatography gave 0.046g (55%) of a pale yellow solid: 1HNMR(CH3OD/400MHz)2.15(s，3H)，5.79(q，1H，J＝7.2Hz)，6.43(d，1H，J＝8.4Hz)，6.94-6.96(m，2H)，7.09-7.14(m，2H)，7.33-7.37(m，2H)，7.74(s，1H)；MS(ES+)351.2(M+H，100)；HRMS(ES-)m/z calcd for(C18H13F3O4)349.0688，found 349.0681.
Preparation of 8-methyl-7-substituted-2- (trifluoromethyl) -2H-chromene-3-carboxylic acids via aryl fluoro metathesis in parallel
The examples in table 17 below were prepared as previously described for 8-methyl-7-phenoxy- (trifluoromethyl) -2H-chromene-3-carboxylic acid using a parallel synthesis apparatus and purified by reverse phase chromatography.
Table 17: yield, purity and mass spectral data of 8-methyl-7-substituted-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid prepared by parallel synthesis
TABLE 17
Examples # LC (min) MS(ES+) HRMS % purity % yield
891 3.686 387 385.0470 100 14
892 3.656 387 385.0479 100 6
893 3.928 385 383.0298 100 7
894 3.934 385 383.0292 100 25
895 3.619 381 379.0780 100 11
896 4.015 399 397.0478 100 19
897 3.855 397 395.0584 100 22
898 3.870 365 363.0831 100 15
899 4.086 379 377.0989 100 16
900 3.889 365 363.0850 100 10
901 4.065 379 377.0958 100 10
902 4.222 393 391.1128 100 6
903 4.011 379 377.0959 100 9
904 4.233 393 391.1157 100 5
905 4.131 4192 416.9892 100 13
906 3.669 369 367.0559 100 31
907 3.602 369 367.0591 100 11
908 4.279 393 391.1126 100 13
909 3.729 395 393.0923 100 28
910 3.827 395 393.0948 100 15
911 2.219 366 364.0815 100 32
912 3.912 403 401.0213 100 3
913 3.969 4473 444.9734 100 4
914 4.154 413 411.0570 100 22
915 3.848 403 401.0198 100 7
916 3.813 383 381.0707 100 10
917 3.877 4494 444.9666 100 3
918 4.108 399 397.0452 100 14
919 4.020 401 399.0805 100 23
1Total isolated yield based on 2 steps reaction on 1mmol scale. Chromatographic retention time is in minutes. HRMS indicates the molecular ion (M-H) observed in the electrospray negative mode by means of high resolution mass spectrometry techniques. % purity is determined by ELC. HPLC retention time is determined by linear gradient from 5% at 0minAcetonitrile 0.1% TFA/water to 4.5min of 95% acetonitrile.
2MS shows Cl2Clustering: 419(M +1, 100), 421(M +3, 61).
3MS shows Br1Clustering: 447(M +1, 100), 449(M +3, 93).
4The ion enumerated is Br1Cluster M + 3: 447(M +1, 87), 449(M +3, 100).
Preparation of 8-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Example 920
8-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a cooled solution of 0.031g (0.054mmol) bis (dibenzylideneacetone) palladium (0) and 0.025g (0.107 mmol 1) tris-2-furanylphosphine in 5mL degassed THF was added 0.500g (0.535mmol) Wang resin-6-chloro-8-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylate, followed by 3.21mL (1.605mmol) of 0.5M benzylzinc bromide solution. The reaction mixture was heated to 60 ℃ overnight. The reaction mixture was transferred and washed as follows: THF (x5), NH4Aqueous Cl solution (x5), H20(x5), MeOH (x5) and CH2Cl2(x 5). The resin was washed with 2mL (TFA: CH)2Cl21: 1) for 30 minutes. Collecting filtrate, and repeatedly treating. Using resin CH2Cl2Wash (x2), combine all filtrates and concentrate. The oil obtained was purified by reverse phase chromatography to give 0.024g (12%) of a white crystalline solid:
1HNMR(CDCl3/400MHz)4.00(s，2H)，5.91(q，1H，J＝7.1Hz)，7.20(m，1H)，7.27(m，5H)，7.41(d，1H，J＝2.5Hz)，7.87(s，1H)；19F NMR(CDCl3/400MHz)-79.4(d，3F，J＝6.8Hz)；MS(ES+)369(M+1，100)；HRMS(ES-)m/z calcd for(M-H：C18H11O3ClF3)367.0343，found367.0333.
preparation of 3-substituted-6- (trifluoromethyl) -6H-furo [2, 3-g ] chromene-7-carboxylic acid and 1-substituted-7- (trifluoromethyl) -7H-furo [3, 2-f ] chromene-8-carboxylic acid
Preparation of ethyl 6- [2- (4-bromophenyl) -2-oxoethoxy ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate
A mixture of ethyl 6-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.0g, 3.47mmol), 2- (4-bromophenyl) -2-oxoethyl bromide (0.96g, 3.47mmol) and potassium carbonate (0.96g, 6.94mmol) in 4mL anhydrous DMF was heated to 70 deg.C, shaken for 2H, and then allowed to stand overnight at room temperature. The solid was filtered and washed with ethyl acetate. The organic phases were combined, washed with brine and then dried over anhydrous magnesium sulfate. After removal of volatiles, the residue was purified by silica gel column eluting with 1: 9 EtOAc/hexanes. 0.65g of a pale yellow solid (38.6%) are obtained.
M.P.＝130.5-131.5℃.1H NMR(CDCl3/400MHz)7.86(m，1H)，7.83(m，1H)7.65(m，1H)，7.63-7.62(m，2H)，6.89-6.88(m，2H)，6.77(m，1H)，5.64(q，J＝6.8Hz，1H，)，5.16(s，2H)，4.33-4.26(m，2H)，1.33(t，J＝7.2Hz，3H).13C NMR(CDCl3/300MHz)，193.8，163.9，153.3，148.2，136.8，133.3，132.5，129.9，129.5，123.6(q，J＝287.9Hz)，119.9，119.8，117.8，117.1，115.1，71.8，70.8(q，J＝32.8Hz)，61.7，14.4.19F(CDCl3/400MHz)-78.72(d，J＝6.8Hz).LC-MS：484.9(M+1，100)，486.9(M+3，100).Purity＝95％.HRMS(ES+)m/zcalcd for(C21H16BrFO5)502.0471(M+NH4)，504.0454(M+NH4+2)，found 502.0484，504.0492.
Preparation of ethyl 6- (3, 3-dimethyl-2-oxobutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
This example was prepared using the same procedure as for the preparation of ethyl 6- [2- (4-bromophenyl) -2-oxoethoxy ] -2- (trifluoromethyl) -2H-chromene-3-carboxylate. 3.5g (87.2%) of an off-white solid are obtained.
1HNMR(CDCl3/300MHz)7.68(s，1H)，6.91(s，1H)，6.90(d，J＝2.7Hz，1H)，6.77(d，J＝2.4Hz，1H)，5.68(q，J＝6.9Hz，1H)，4.86(s，2H)，4.34(m，2H)，1.38(t，J＝6.9Hz，3H)，1.27(s，9H).19F(CDCl3/400MHz)-78.73(d，J＝6.9Hz)..LC-MS(ES+)：387.4(M+1，100).HRMS(ES+)m/z calcd for(C19H21F3O5)404.1679(M+NH4)，found 404.1666.
Example 921
3- (4-bromophenyl) -6- (trifluoromethyl) -6H-furo [2, 3-g ] chromene-7-carboxylic acid
Step 1: preparation of ethyl 3- (4-bromophenyl) -6- (trifluoromethyl 1-6H-furo [2, 3-g ] chromene-7-carboxylate
A mixture of ethyl 6- (2- (4-bromophenyl) -2-oxoethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate (1.0g, 2.1mmol), TsOH (1.0g, 5.3mmol) and 10mL xylene was heated to reflux under nitrogen. The reaction was monitored by LC-MS until completion. For about 5 hours. After cooling to room temperature, the reaction was poured into 100mL of ethyl acetate. The organic phase was washed with aqueous sodium bicarbonate, brine and dried over anhydrous magnesium sulfate. After removal of the solvent, a brown oil was obtained. The crude product was further purified by reverse phase HPLC. The desired intermediate was obtained as a pale yellow solid, 100mg, 10%.
1HNMR(CDCl3/300MHz)ppm 7.87(s，1H)，7.85(s，1H)，7.65-7.62(m，2H)，7.50-7.47(m，2H)，7.42(s，1H)，7.37(s，1H)，5.75(q，J＝6.9Hz，1H)，4.40-4.36(m，2H)，1.41(t，J＝7.2Hz，3H).13CNMR(CDCl3/300MHz)164.1，151.5，149.8，144.6，137.6，132.5，130.3，130.2，129.1，123.8(q，J＝288.1Hz)，122.2，122.1，117.5，117.2，112.2，106.7，71.0(q，J＝32.7Hz)，61.7，14.5.LC-MS(ES+)466.7(M+1，100)，468.7(M+3，100).
Step 2: to a solution of the intermediate obtained in step 1 (100mg, 0.21mmol) in 3mL of THF was added 3mL of an aqueous solution of lithium hydroxide hydrate (90mg, 2.1mmol), followed by the addition of 3mL of ethanol. The resulting solution was heated to 80 ℃ for 2 hours. The volatiles were removed. The residue was diluted with water and acidified with dilute hydrochloric acid at 0 ℃. The product was extracted with EtOAc. The resulting organic solution was dried over anhydrous magnesium sulfate. After removal of the solvent, 60mg of the desired product are obtained as a yellow solid (65.2%).
M.P.＞250℃.1HNMR(CDCl3/drops ofCD3OD/300MHz)ppm 7.83(s，1H)，7.81(s，1H)，7.59-7.56(m，2H)7.46-7.42(m，2H)，7.38(s，1H)，7.31(s，1H)，5.67(q，J＝6.9Hz，1H).19F NMR(CDCl3/dropsofCD3OD/400MHz)78.51(d，J＝6.9Hz)。13C NMR(CDCl3/CD3OD/400MHz)166.0，151.5，149.8，144.6，138.0，132.4，130.3，130.2，129.1，123.8(q，J＝287.8Hz)，122.1，122.0，117.4，117.1，112.2，106.6，70.9(q，J＝32.7Hz).LC-MS(ES+)438.9(M+1，100)，440.7(M+3，100).HRMS(EI)(EI)m/zca1cd for(C19H10BrF3O4)437.9715，found 437.9730.
Example 922
1-p-bromophenyl-7- (trifluoromethyl) -7H-furo [3, 2-f ] chromene-8-carboxylic acid
This example was prepared using the same procedure as for the preparation of 3- (4-bromophenyl) -6- (trifluoromethyl) -6H-furo [2, 3-g ] chromene-7-carboxylic acid. Yellow solid.
M.P.＞250℃.1HNMR(CDCl3/drops of CD3OD/300MHz)ppm 7.86(s，1H)，7.67-7.63(m，3H)，7.50(d，J＝9.0Hz，1H)，7.41-7.37(m，2H)，7.02(d，J＝8.7Hz，1H)，5.73(q，J＝7.2Hz，1H).LC-MS(ES+)：438.7(M+1，100)，440.7(M+3，100).MS(ES-) 438.9(M-1，100)；HRMS(EI+)m/z calcd for(C19H10BrF3O4)437.9715(M+)，found 437.9738.
Example 923
1-tert-butyl-7- (trifluoromethyl) -7H-furo [3, 2-f ] chromene-8-carboxylic acid
This example was prepared using the same procedure as for the preparation of 3- (4-bromophenyl) -6- (trifluoromethyl) -6H-furo [2, 3-g ] chromene-7-carboxylic acid. Yellow solid, 60mg (16.3%). The compound decomposes at 220 ℃.
1HNMR(CDCl3/300MHz)ppm 8.57(s，1H)，7.47(s，1H)，7.41(d，J＝8.7Hz，1H)，6.95(d，J＝9Hz，1H)，5.68(q，J＝7.2Hz，1H)，1.47(s，9H).19F NMR(CDCl3/drops ofCD3OD/400MHz)78.65(d，J＝7.9Hz).LC-MS(ES+)341.1(M+1，100).MS(ES-)339.1(M-1，100)；HRMS(EI+)m/z calcd for(C17H15F3O4)：340.0992(M+)，found 340.0879..
Example 924
3-tert-butyl-6- (trifluoromethyl) -6H-furo [2, 3-g ] chromene-7-carboxylic acid
By reaction with 3- (4-bromophenyl) -6- (trifluoromethyl) -6H-furo [2, 3-g]Preparation of chromene-7-carboxylic acid this example was prepared by the same procedure. Yellow-grey solid. The compound decomposes at 250 ℃.1H NMR(CDCl3/300MHz)ppm7.86(s，1H)，7.40(s，1H)，7.32(s，1H)，7.30(s，1H)，5.70(q，J＝6.9Hz，1H)，1.41(s，9H).19FNMR(CDCl3/drops ofCD3OD/400MHz)78.55(d，J＝6.9Hz).LC-MS(ES+)341.1(M+1，100).MS(ES-) 339.1(M-1，100)；HRMS(EI+)m/z calcd for(C17H15F3O4)：340.0992，found340.0933.
Preparation of 2-substituted-7- (trifluoromethyl) -7H-furo [3, 2-g ] chromene-6-carboxylic acid and acrylic acid analogs
Preparation of ethyl 6-iodo-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
This example was prepared using the same procedure as for the preparation of ethyl 7-hydroxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate. Yellow solid.
LC-MS(ES+)：415.1(M+1，100).1H NMR(CDCl3/CD3OD/300MHz)：7.62(s，1H)，7.54(s，1H)，6.53(s，1H)，5.64(q，J＝6.6Hz，1H)，4.29(m，2H)，1.33(t，J＝7.2Hz，1H).19FNMR(CDCl3/CD3OD/300MHz)：-79.01(d，J＝7.2Hz).13C NMR(CDCl3/CD3OD/300MHz)：164.4，160.3，155.3，139.4，136.4，123.6(q，J＝287.5Hz)，114.2，113.7，102.9，76.1，71.0(q，J＝33.1Hz)，61.1，14.4.High resolution MS(ES-)：m/e calc.for(C13H10F3IO4)：412.9498(M-H)，found：412.9486.
Example 925
2- (2-methylphenyl) -7- (trifluoromethyl) -7H-furo [3, 2-g ] chromene-6-carboxylic acid
To a solution of ethyl 6-iodo-7-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate (0.3g, 0.72mmol), m-tolylacetylene (420mg, 3.6mmol) in 10mL of anhydrous acetonitrile was added Cu (I) I (33mg, 0.173mmol), [1, 1' -bis (diphenylphosphino) ferrocene]Palladium dichloride (I I) complex with dichloromethane (1: 1) (25mg, 0.043mmol) and triethylamine (2 mL). After addition of triethylamineThe reaction was heated to 55 ℃ under nitrogen for 72 hours. LC-MS indicated the reaction was complete, and the reaction was then diluted with 100mL EtOAc. The resulting organic solution was washed with an aqueous ammonium chloride solution and brine, and dried over anhydrous magnesium sulfate. After removal of volatiles, the residue was purified over a short silica gel column, eluting with a hexane/EtOAc mixture, and the collected fractions were evaporated to remove volatiles, then 3mL THF, 3mL ethanol, 100mg lithium hydroxide hydrate, and 3mL water were added to the residue. The resulting mixture was heated to 80 ℃ for 1 hour, then the organic solvent was removed, the residue was diluted with water and acidified with ice-cold dilute hydrochloric acid at 0 ℃. The isolated product was extracted with ethyl acetate. After removal of the solvent, the residue was purified by reverse phase HPLC. A yellow solid, 92mg, was obtained. 1H NMR(CDCl3/CD3OD/300MHz)：7.72(s，1H)，7.49-7.46(m，2H)，7.28(s，1H)，7.19(dd，J＝7.5Hz，1H)，7.040(d，J＝7.5Hz，1H)，7.00(s，1H)，6.80(s，1H)，5.58(q，J＝6.9Hz，1H)，2.29(s，3H).19F NMR(CDCl3/CD3OD/300MHz)-79.058(d，J＝6.5Hz).13C NMR(CDCl3/CD3OD/300MHz)170.3，161.5，161.1，155.5，142.7，142.1，133.9，133.7，132.9，129.4，128.9，127.8(q，J＝287.6Hz)，126.0，125.6，120.0，119.9，104.9，103.4，74.9(q，J＝32.7Hz)，25.4。LC-MS(ES+)：375.1(M+1，100).Highresolution MS(ES-)：m/e calc.for(C20H13F3O4)：373.0688(M-H)，found：373.0692.
Example 926
2- (2-phenylethyl) -7- (trifluoromethyl) -7H-furo [3, 2-g ] chromene-6-carboxylic acid
This example was prepared using the same procedure as for the preparation of 2- (2-methylphenyl) -7- (trifluoromethyl) -7H-furo [3, 2-g ] chromene-6-carboxylic acid. Light yellow solid.
1H NMR(CDCl3/CD3OD/300MHz)7.87(s，1H)，7.34-7.21(m，6H)，7.08(s，1H)，6.30(s，1H)，5.71(q，J＝7.2Hz，1H)，3.06(s，4H).19F NMR(CDCl3/CD3OD/300MHz)：-78.65(d，J＝7.2Hz).LC-MS(ES+)：389.1(M+1，100).High resolution MS(ES-)：m/e calc.for(C21H14F3O4)：387.0844(M-H)，found：387.0811.
Example 927
This example was prepared using the same procedure for the preparation of 2- (cyclopentylmethyl) -7- (trifluoromethyl) -7H-furo [3, 2-g ] chromene-6-carboxylic acid as 2- (2-methylphenyl) -7- (trifluoromethyl) -7H-furo [3, 2-g ] chromene-6-carboxylic acid. Yellow solid.
1H NMR(CDCl3/CD3OD/300MHz)：7.88(s，1H)，7.31(s，1H)，7.05(s，1H)，6.31(s，1H)，5.70(q，J＝6.9Hz，1H)，2.73(s，1H)，2.71(s，1H)，2.28(m，1H)，1.87-1.78(m，2H)，1.69-1.55(m，4H)，1.32-1.21(m，2H).19F NMR(CDCl3/CD3OD/300MHz)：-79.8(d，J＝5.8Hz).13CNMR(CDCl3/CD3OD/300MHz)：167.2，160.6，157.5，151.0，139.3，124.7，123.9(q，J＝287.9Hz)，121.2，115.4，115.0，102.1，99.4，70.8(q，J＝32.9Hz)，38.7，34.6，32.7，25.4，25.3.LC-MS(ES+)：367.1(M+1，100).High resolution MS(ES-)：m/e calc.for(C19H16F3O4)：365.1001(M-H)，found：365.1017.
Example 928
7-hydroxy-6- (3-methoxyprop-1-ynyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
This example was prepared using the same procedure as for the preparation of 2- (2-methylphenyl) -7- (trifluoromethyl) -7H-furo [3, 2-g ] chromene-6-carboxylic acid. Yellow solid.
1H NMR(CD3OD/300MHz)7.90(s，1H)，7.54(s，1H)，7.11(s，1H)，6.76(s，1H)，5.76(q，J＝6.9Hz，1H)，4.54(s，2H)，3.42(s，3H).19F NMR(CD3OD/300MHz)：-80.06(d，J＝6.5Hz).13C NMR(CD3OD/300MHz)：165.9，157.8，155.5，151.7，137.6，124.0(q，J＝287.2Hz)，123.8，122.1，116.2，116.1，105.7，88.9，70.8(q，J＝32.6Hz)，66.3，57.2.LC-MS(ES+)：329.0，(M+1，35)，297.0(M-31，100).High resolution MS(ES-)：m/e calc.for(C15H10F3O5)：327.0480(M-H)，found：327.0472.
Description of the Absolute configuration
The absolute configuration of the substituted 2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was determined by means of pi-pi transition analysis, which is observable in CD spectra. The chiral chromene ring system is known to exhibit the katteng effect due to the styrene chromophore in the 275-300nm region of the spectrum. A positive catamenial effect indicates that the twisted styrene chromophore forms a left-handed helix, corresponding to the (S) -enantiomer of 2-trifluoromethyl-chromene-3-carboxylic acid. This correlation was confirmed by measuring the series of compounds, which had been previously determined by X-ray crystallography.
The enantiomeric purity and absolute configuration of some substituted 2- (trifluoromethyl) -2H-chromene-3-carboxylic acids can be aided by19F NMR measurements, observing the inequivalence of the chemical shift induced in the presence of Chiral Solvating Agent (CSA). With 6-, 7-and 8-substituted chromenes observed19F NMR inequivalence, the meaning of which correlates with the previous description of the absolute configuration determined by means of X-ray and CD spectroscopy. However, 5-substituted chromenes show little or no inequality,19the F NMR method is not described for the absolute configuration of the 5-substituted examples.
General procedure for describing the absolute configuration of substituted 2- (trifluoromethyl) -2H-chromene-3-carboxylic acids
A mixture of 4mg of racemate and 4mg of enantiomer was carefully weighed out in a 1-inch vial to give a 1: 3 mixture of enantiomers. The mixture was taken up in 1.0mL d6-benzene and 25. mu.L (26.5mg, 155. mu. mo1) (R) - (+) -1- (1-naphthyl) ethylamine. Is obtained in the usual way19F and1HNMR, the degree and significance of inequivalence of each resonance are analyzed. Based on the inequivalence of the (R, R) diastereomer solvate observed for this series, the series19The up-shifted signal in F NMR is described as the R enantiomer.
Example 929
(2R) - (+) -8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 280mg of racemic 8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (97: 2.5: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 100.4mg (72%) of a yellow solid: 100% ee according to analytical HPLC; NMR anisovalent analysis using CSA, yielding a mixture of (R) and (S) enantiomers: 19F NMR (d)6-benzene; 3.6eq (R) - (+) -1- (1-naphthyl) ethylamine) -78.36(d, 3F, J ═ 6.8Hz, minor peak, S-enantiomer), -78.44(d, 3F, J ═ 6.8Hz, major peak, R-enantiomer); CD (MeOH)210([ theta ])]＝-7500)，250([θ]＝-8100)，294([θ]＝8500)；[a]22 D＝+46.8(EtOH，c＝5.0)；1H NMR(d6Acetone/400 MHz)3.74(s, 1H), 6.03(q, 1H, 6.8Hz), 7.61(m, 2H), 7.92(s, 1H); MS (ES +)303(M +1, 100).
Example 930
(2S) - (-) -8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 280mg of racemic 8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (97: 2.5: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 100.9mg (72%) of a yellow solid: 100% ee according to analytical HPLC;
HPLC；[a]22 D＝-46.0(EtOH，c＝5.0)；1H NMR(d6-acetone/400MHz)3.74(s，1H)，6.03(q，1H，6.8Hz)，7.61(m，2H)，7.92(s，1H)；MS(ES+)303(M+1，100).
6-chloro-7- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Step 1. preparation of Ethyl 6-chloro-7- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of 4.05g (12.5mmol) ethyl 6-chloro-7-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylate in 30mL DMF were added 1.86g (15.2mmol) 4-ethylphenol and 2.42g (17.5mmol) potassium carbonate. The stirred mixture was heated to 100 ℃ for 8 hours, cooled and treated with 100mL of water. The mixture was extracted three times with diethyl ether, the filtrates combined, filtered through 30g of silica, and the filtrate concentrated in vacuo to give the crude product. Recrystallization from methanol-water gave 4.43g (83%) of a yellow crystalline solid: mp109-110 ℃;1H NMR(d6-acetone/400MHz)1.22(t，3H，J＝7.5Hz)，1.30(t，3H，J＝7.1Hz)，2.66(q，2H，J＝7.6Hz)，4.28(m，2H)，5.81(q，1H，J＝7.0Hz)，6.44(s，1H)，7.04(d，2H，J＝8.8Hz)，7.31(d，2H，J＝8.6Hz)，7.67(s，1H)，7.86(s，1H)；19F NMR(d6-acetone/400MHz)-79.5(d，3F，J＝6.8Hz)；13C NMR(d6-acetone/100MHz)13.8，15.4，61.3，70.8(q，J＝32.8Hz)，105.5，115.2，115.9，117.5，119.9，123.8(q，J＝287.1Hz)，129.8，131.2，135.5，141.5，153.1，153.2，157.4，163.4；MS(ES+)427(M+1，100)；HRMS(ES+)m/z calcd for(C21H18O4ClF3)427.0918，found 427.0921.
Anal.Calc’d for C21H18O4ClF3：C，59.09；H，4.25.Found：C，59.21；H，4.24.
step 2.6 preparation of chloro-7- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
To a solution of 4.43g (10.4mmol) of the product of step 1 in 70mL of THF and 20mL of methanol was added 1.0g of lithium hydroxide monohydrate in 10mL of water. The mixture was heated to reflux for 30 minutes and cooled to room temperature. After stirring overnight, the mixture was treated with 75mL of 1N HCl and extracted three times with diethyl ether. The combined extracts were washed with brine, dried and concentrated in vacuo to give 4.02g (97%) of a yellow solid: mp 195.5-196.5 ℃; 1HNMR(d6-acetone/400MHz)1.22(t，3H，J＝7.5Hz)，2.66(q，2H，J＝7.6Hz)，5.78(q，1H，J＝7.1Hz)，6.45(s，1H)，7.04(d，2H，J＝8.4Hz)，7.31(d，2H，J＝8.3Hz)，7.66(s，1H)，7.87(s，1H)；19F NMR(d6-acetone/400MHz)-79.4(d，3F，J＝7.7Hz)；13C NMR(d6-acetone/100MHz)15.4，28.1，70.9(q，J＝32.7Hz)，105.6，115.3，116.0，117.5，119.9，123.9(q，J＝286.8Hz)，129.8，131.1，135.7，141.5，153.1，153.3，157.3，164.3；MS(ES-)397(M-1，100)；HRMS(ES-)m/z calcd for(C19H13ClF3O4)397.0449，found 397.0484.
Example 931
(2R) - (-) -6-chloro-7- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 3.3g of racemic 6-chloro-7- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralcel OJ) using heptane: ethanol: trifluoroacetic acid (60: 40: 0.1) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 1.48g (90%) of a yellow solid: according to analytical HPLC 100% ee. The sample was recrystallized in hexane-diethyl ether to give a white solid:
mp 130-131℃；[a]22 D＝-28.5(EtOH，c＝1.0)；1H NMR(d6-acetone/400MHz)1.22(t，3H，J＝7.5Hz)，2.66(q，2H，J＝7.6Hz)，5.78(q，1H，J＝7.1Hz)，6.45(s，1H)，7.04(d，2H，J＝8.4Hz)，7.31(d，2H，J＝8.3Hz)，7.66(s，1H)，7.87(s，1H)；MS(ES+)399(M+1，100)；NMR non-equivalence with CSA and a 3∶1mixture ofthe(R)and(S)enantiomers：19F NMR(d6-benzene；5eq of(R)-(+)-1-(1-naphthyl)ethylamine)-77.96(d，3F，J＝6.8Hz，minor peaks，S-enantiomer)，-78.20(d，3F，J＝6.8Hz，major peak，R-enantiomer)；CD(MeOH)214([theta]＝+14700)，296([theta]＝-10500).
example 939
(2S) - (+) -6-chloro-7- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 3.3g of racemic 6-chloro-7- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralcel OJ) using heptane: ethanol: trifluoroacetic acid (60: 40: 0.1) as mobile phase. The second eluted peaks from multiple chromatography were combined to give 1.16g (70%) of a yellow solid: according to analytical HPLC 100% ee.
mp 90-95℃；[a]22 D＝+30.5(EtOH，c＝1.0)；1H NMR(d6-acetone/400MHz)1.22(t，3H，J＝7.5Hz)，2.66(q，2H，J＝7.6Hz)，5.78(q，1H，J＝7.1Hz)，6.45(s，1H)，7.04(d，2H，J＝8.4Hz)，7.31(d，2H，J＝8.3Hz)，7.66(s，1H)，7.87(s，1H)；MS(ES+)399(M+1，100).
Example 940
(2R) - (-) -6-chloro-7- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 176.9mg of racemic 6-chloro-7- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chira1pak AD) using heptane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 62.3mg (70%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝-22.5(EtOH，c＝3.1)；1H NMR(d6-acetone/400MHz)2.21(s，3H)，5.79(q，1H，J＝7.1Hz)，6.43(s，1H)，7.03(d，1F，J＝8.6Hz)，7.3(dd，1H，J＝8.6Hz，J＝2.5Hz)，7.41(d，1H，J＝2.7Hz)，7.69(s，1H)，7.86(s，1H)；19F NMR(d6-acetone/400MHz)-79.5(d，3F，J＝6.8Hz)；MS(ES+)419(M+1，100)；NMR non-equivalence with CSA and a 1：3mixture of the(R)and(S)enantiomers：19F NMR(d6-benzene; 10 eq of (R) - (+) -1- (1-naphthyl) ethylamine) -77.99(d, 3F, J7.7 Hz, major peak, S-enatiomer), -78.19(d, 3F, J6.8 Hz, minor peak, R-enatiomer).
Example 941
(2S) - (+) -6-chloro-7- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 176.9mg of racemic 6-chloro-7- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 64.1mg (72%) of a yellow solid: according to analytical HPLC 95.3% ee.
[a]22 D＝+21.4(EtOH，c＝3.2)；1H NMR(d6-acetone/400MHz)2.21(s，3H)，5.79(q，1H，J＝7.1Hz)，6.43(s，1H)，7.03(d，1H，J＝8.6Hz)，7.3(dd，1H，J＝8.6Hz，J＝2.5Hz)，7.41(d，1H，J＝2.7Hz)，7.69(s，1H)，7.86(s，1H)；19F NMR(d6-acetone/400MHz)-79.5(d，3F，J＝6.8Hz)；MS(ES+)419(M+1，100).
Example 942
(2R) - (-) -6-chloro-7- (2, 4-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 128.3mg of racemic 6-chloro-7- (2, 4-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chira1pak AD) using heptane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 32.2mg (50%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝-40.1(EtOH，c＝1.6)；1H NMR(d6-acetone/400MHz)2.12(s，3H)，2.32(s，3H)，5.76(q，1H，J＝7.1Hz)，6.24(s，1H)，6.94(d，1H，J＝8.2Hz)，7.11(d，2H，J＝8.3Hz)，7.18(s，1H)，7.67(s，1H)，7.85(s，1H)；19FNMR(d6-acetone/400MHz)-79.5(d，3F，J＝6.8Hz)；MS(ES+)399(M+1，100)；NMR non-equivalence with CSA and a 1∶3mixture ofthe(R)and(S)enantiomers：19F NMR(d6-benzene；8eq of(R)-(+)-1-(1-naphthyl)ethylamine)-78.00(d，3F，J＝6.8Hz，major peaks，S-enantiomer)，-78.19(d，3F，J＝7.7Hz，minor peak，R-enantiomer).
Example 943
(2S) - (+) -6-chloro-7- (2, 4-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 128.3mg of racemic 6-chloro-7- (2, 4-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chira1pak AD) using heptane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 23.1mg (36%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝+34.7(EtOH，c＝1.2)；1H NMR(d6-acetone/400MHz)2.12(s，3H)，2.32(s，3H)，5.76(q，1H，J＝7.1Hz)，6.24(s，1H)，6.94(d，1H，J＝8.2Hz)，7.11(d，2H，J＝8.3Hz)，7.18(s，1H)，7.67(s，1H)，7.85(s，1H)；19F NMR(d6-acetone/400MHz)-79.5(d，3F，J＝6.8Hz)；MS(ES+)399(M+1，100).
Example 944
(2S) - (+) -6-chloro-7- (3, 5-dichloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 78.4mg of racemic 6-chloro-7- (3, 5-dichloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 26.1mg (67%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝+26.1(EtOH，c＝1.3)；1H NMR(d6-acetone/400MHz)2.41(s，3H)，5.78(q，1H，J＝7.1Hz)，6.18(s，1H)，7.45(s，2H)，7.71(s，1H)，7.86(s，1H)；19F NMR(d6-acetone/400MHz)-79.5(d，3F，J＝6.8Hz)；MS(ES+)453(M+1，90)，455(M+3，100)；NMRnon-equivalence withCSA and a 3∶1mixture ofthe(R)and(S)enantiomers：19F NMR(d6-benzene；9eq of(R)-(+)-1-(1-naphthyl)ethylamine)-78.11(d，3F，J＝7.7Hz，minor peaks，S-enantiomer)，-78.26(d，3F，J＝7.7Hz，major peak，R-enantiomer).
Example 945
(2R) - (-) -6-chloro-7- (3, 5-dichloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 78.4mg of racemic 6-chloro-7- (3, 5-dichloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chira1pak AD) using heptane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 24.5mg (63%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝-29.6(EtOH，c＝1.2)；1H NMR(d6-acetone/400MHz)2.41(s，3H)，5.78(q，1H，J＝7.1Hz)，6.18(s，1H)，7.45(s，2H)，7.71(s，1H)，7.86(s，1H)；19F NMR(d6-acetone/400MHz)-79.5(d，3F，J＝6.8Hz)；MS(ES+)453(M+1，90)，455(M+3，100).
Example 946
(2R) - (-) -6-chloro-7- (2-chloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 204.4mg of racemic 6-chloro-7- (2-chloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 76.9mg (75%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝-26.0(EtOH，c＝3.8)；1H NMR(d6-acetone/400MHz)2.38(s，3H)，5.78(q，1H，J＝7.0Hz)，6.31(s，1H)，7.16(d，1H，J＝8.3Hz)，7.26(dd，1H，J＝8.3Hz，J＝1.5Hz)，7.43(d，1H，J＝1.5Hz)，7.69(s，1H)，7.87(s，1H)；19F NMR(d6-acetone/400MHz)-79.5(d，3F，J＝7.7Hz)；MS(ES+)419(M+1，100)；NMR non-equivalence with CSA and a 1∶3mixture of the(R)and(S)enantiomers：19F NMR(d6-benzene; 9eq of (R) - (+) -1- (1-naphthyl) ethylamine) -78.02(d, 3F, J7.7 Hz, major peak, S-enatiomer), -78.21(d, 3F, J7.7 Hz, minor peak, R-enatiomer).
Example 947
(2S) - (+) -6-chloro-7- (2-chloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 204.4mg of racemic 6-chloro-7- (2-chloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 67.6mg (66%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝+26.4(EtOH，c＝3.4)；1H NMR(d6-acetone/400MHz)2.38(s，3H)，5.78(q，1H，J＝7.0Hz)，6.31(s，1H)，7.16(d，1H，J＝8.3Hz)，7.26dd，1H，J＝8.3Hz，J＝1.5Hz)，7.43(d，1H，J＝1.5Hz)，7.69(s，1H)，7.87(s，1H)；19F NMR(d6-acetone/400MHz)-79.5(d，3F，J＝7.7Hz)；MS(ES+)419(M+1，100).
Example 948
(2R) - (-) -2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylic acid
Resolution of 261.8mg of racemic 2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chira1pak AD) using heptane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 127.8mg (98%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝-69.6(EtOH，c＝6.4)；1H NMR(d6-acetone/400MHz)2.02(s，3H)，2.26(s，3H)，2.27(s，3H)，2.90(brs，1H)，5.76(q，1H，J＝7.2Hz)，6.42(d，1H，J＝2.1Hz)，6.53(dd，1H，J＝2.4Hz，J＝8.4Hz)，6.72(s，1H)，6.92(s，1H)，7.40(d，1H，J＝8.5Hz)，7.83(s，1H)；19F NMR(CDCl3/400MHz)-79.6(d，3F，J＝6.8Hz)；MS(ES+)379(M+1，100)；NMRnon-equivalence with CSA and a 1∶2mixture of the(R)and(S)enantiomers：19F NMR(d6-benzene；9eq of(R)-(+)-1-(1-naphthyl)ethylamine)-78.09(d，3F，J＝6.8Hz，major peaks，S-enantiomer)，-78.16(d，3F，J＝6.8Hz，minor peak，R-enantiomer).
Example 949
(2S) - (+) -2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylic acid
The resolution of 261.8mg of racemic 2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The second eluted peaks from multiple chromatography were combined to give 122.4mg (94%) of a yellow solid: according to analytical HPLC 99.8% ee.
[a]22 D＝+71.7(EtOH，c＝6.1)；1H NMR(d6-acetone/400MHz)2.02(s，3H)，2.26(s，3H)，2.27(s，3H)，2.90(brs，1H)，5.76(q，1H，J＝7.2Hz)，6.42(d，1H，J＝2.1Hz)，6.53(dd，1H，J＝2.4Hz，J＝8.4Hz)，6.72(s，1H)，6.92(s，1H)，7.40(d，1H，J＝8.5Hz)，7.83(s，1H)；19F NMR(CDCl3/400MHz)-79.6(d，3F，J＝6.8Hz)；MS(ES+)379(M+1，100)；CD(MeOH)214([theta]＝-16400)，250([theta]＝-8100)；294([theta]＝+8500).
Example 950
(2R) - (-) -7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 290.6mg of rac-7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (97: 2.5: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 136.1mg (94%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝-74.4(EtOH，c＝6.8)；1H NMR(d6-acetone/400MHz)2.10(s，3H)，2.30(s，3H)，2.85(brs，1H)，5.77(q，1H，J＝7.1Hz)，6.44(d，1H，J＝2.3Hz)，6.55(dd，1H，J＝2.4Hz，J＝8.5Hz)，6.87(s，1H)，7.01(d，1H，J＝8.3Hz)，7.21(d，1H，J＝7.8Hz)，7.42(d，1H，J＝8.5Hz)，7.84(s，1H)；19F NMR(CDCl3/400MHz)-79.6(d，3F，J＝6.8Hz)；MS(ES+)365(M+1，100)；NMR non-equivalence with CSA and a 1：2mixture of the(R)and(S)enantiomers：19F NMR(d6-benzene；6eq of(R)-(+)-1-(1-naphthyl)ethylamine)-78.10(d，3F，J＝6.8Hz，major peaks，S-enantiomer)，-78.17(d，3F，J＝6.8Hz，minor peak，R-enantiomer).
Example 951
(2S) - (+) -7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 290.6mg of rac-7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (97: 2.5: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 135.2mg (93%) of a yellow solid: according to analytical HPLC 99.8% ee.
[a]22 D＝+72.1(EtOH，c＝6.8)；1H NMR(d6-acetone/400MHz)2.10(s，3H)，2.30(s，3H)，2.85(brs，1H)，5.77(q，1H，J＝7.1Hz)，6.44(d，1H，J＝2.3Hz)，6.55(dd，1H，J＝2.4Hz，J＝8.5Hz)，6.87(s，1H)，7.01(d，1H，J＝8.3Hz)，7.21(d，1H，J＝7.8Hz)，7.42(d.1H，J＝8.5Hz)，7.84(s，1H)；19F NMR(CDCl3/400MHz)-79.6(d，3F，J＝6.8Hz)；MS(ES+)365(M+1，100)；CD(MeOH)212([theta]＝-18800)，250([theta]＝-7900)；294([theta]＝+9000).
Example 952
(2R) - (-) -7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 314mg of racemic 7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (97: 2.5: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 151.6mg (97%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝-73.4(EtOH，c＝7.6)；1H NMR(d6-acetone/400MHz)2.21(s，3H)，5.82(q，1H，J＝7.0Hz)，6.50(d，1H，J＝2.2Hz)，6.61(dd，1H，J＝8.5Hz，J＝2.4Hz)，7.10(d，1H，J＝8.0Hz)，7.24(t，1H，J＝6.8Hz)，7.31-7.41(m，2H)，7.47(d，1H，J＝8.5Hz)，7.90(s，1H)；19F NMR(CDCl3/400MHz)-79.5(d，3F，J＝7.2Hz)；MS(ES+)351(M+1，100)；NMR non-equivalence with CSA and a 2：1mixture of the(R)and(S)enantiomers：19F NMR(d6-benzene；6eq of(R)-(+)-1-(1-naphthyl)ethylamine)-78.02(d，3F，J＝7.2Hz，minor peaks，S-enantiomer)，-78.11(d，3F，J＝7.2Hz，majorpeak，R-enantiomer).
Example 953
(2S) - (+) -7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 314mg of racemic 7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (97: 2.5: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 151.5mg (97%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝+70.0(EtOH，c＝7.6)；1H NMR(d6-acetone/400MHz)2.21(s，3H)，5.82(q，1H，J＝7.0Hz)，6.50(d，1H，J＝2.2Hz)，6.61(dd，1H，J＝8.5Hz，J＝2.4Hz)，7.10(d，1H，J＝8.0Hz)，7.24(t，1H，J＝6.8Hz)，7.31-7.41(m，2H)，7.47(d，1H，J＝8.5Hz)，7.90(s，1H)；19F NMR(CDCl3/400MHz)-79.5(d，3F，J＝7.2Hz)；MS(ES+)351(M+1，100).
Example 954
(2R) - (-) -7- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 488.5mg of rac-7- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (97: 2.5: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 222.6mg (91%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝-55.9(EtOH，c＝11.1)；1H NMR(d6-acetone/400MHz)2.23(s，3H)，5.83(q，1H，J＝7.0Hz)，6.57(d，1H，J＝2.3Hz)，6.64(dd，1H，J＝8.2Hz，J＝2.4Hz)，7.12(d，1H，J＝8.4Hz)，7.35(dd，1H，J＝8.6Hz，J＝2.6Hz)，7.44(d，1H，J＝2.4Hz)，7.50(d，1H，J＝8.2Hz)，7.91(s，1H)；19F NMR(CDCl3/400MHz)-79.5(d，3F，J＝6.5Hz)；MS(ES+）385(M+1，100)；NMR non-equivalence with CSA and a 2∶1mixture ofthe(R)and(S)enantiomers：19F NMR(d6-benzene；6eq of(R)-(+)-1-(1-naphthyl)ethylamine)-78.02(d，3F，J＝7.2Hz，minor peaks，S-enantiomer)，-78.09(d，3F，J＝7.2Hz，major peak，R-enantiomer).
Example 955
(2S) - (+) -7- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 488.5mg of rac-7- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (97: 2.5: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 220.7mg (90%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝+56.0(EtOH，c＝11.0)；1H NMR(d6-acetone/400MHz)2.23(s，3H)，5.83(q，1H，J＝7.0Hz)，6.57(d，1H，J＝2.3Hz)，6.64(dd，1H，J＝8.2Hz，J＝2.4Hz)，7.12(d，1H，J＝8.4Hz)，7.35(dd，1H，J＝8.6Hz，.J＝2.6Hz)，7.44(d，1H，J＝2.4Hz)，7.50(d，1H，J＝8.2Hz).7.91(s，1H)；19F NMR(CDCl3/400MHz)-79.5(d，3F，J＝6.5Hz)；MS(ES+)385(M+1，100).
Example 956
(2R) - (-) -6-chloro-7- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 150.0mg of racemic 6-chloro-7- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 54.8mg (73%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝-29.2(EtOH，c＝2.7)；1H NMR(d6-acetone/400MHz)2.32(s，3H)，2.34(s，3H)，5.83(q，1H，J＝6.8Hz)，6.34(s，1H)，7.14(s，1H)，7.41(s，1H)，7.74(s，1H)，7.92(s，1H)；19F NMR(CDCl3/400MHz)-79.5(d，3F，J＝6.5Hz)；MS(ES+)433(M+1，100)，435(M+3，65)；NMR non-equivalence with CSA and a 2∶1mixture of the(R)and(S)enantiomers：19FNMR(d6-benzene；23eq of(R)-(+)-1-(1-naphthyl)ethylamine)-77.91(d，3F，J＝7.2Hz，minor peaks，S-enantiomer)，-78.08(d，3F，J＝7.2Hz，major peak，R-enantiomer).
Example 957
(2S) - (+) -6-fluoro-7- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 150.0mg of racemic 6-chloro-7- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 48.6mg (65%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝+29.2(EtOH，c＝2.4)；1H NMR(d6-acetone/400MHz)2.32(s，3H)，2.34(s，3H)，5.83(q，1H，J＝6.8Hz)，6.34(s，1h)，7.14(s，1H)，7.41(s，1H)，7.74(s，1H)，7.92(s，1H)；19F NMR(CDCl3/400MHz)-79.5(d，3F，J＝6.5Hz)；MS(ES+)433(M+1，100)，435(M+3，65).
Example 958a
(2R) - (-) -7- (1, 3-benzodioxol-5-yloxy) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The resolution of 179.2mg of racemic 7- (1, 3-benzodioxol-5-yloxy) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (85: 15: 0.5) as mobile phase. The first eluted peaks from multiple chromatographies were combined to give 61.5mg (69%) of a yellow solid: according to analytical HPLC 98.2% ee.
[a]22 D＝-22.3(EtOH，c＝3.1)；1H NMR(d6-acetone/400MHz)5.84(q，1H，J＝6.8Hz)，6.13(s，2H)，6.52(s，1H)，6.66(dd，1H，J＝8.5Hz，J＝2.0Hz)，6.80(d，1H，J＝2.5Hz)，6.96(d，1H，J＝8.3Hz)，7.69(s，1H)，7.90(s，1H)；19F NMR(CDCl3/400MHz)-79.4(d6，3F，J＝7.2Hz)；MS(ES+)415(M+1，100)；NMRnon-equivalence with CSA and a 2∶1 mixture ofthe(R)and(S)enantiomers：19F NMR(d6-benzene；18eq of(R)-(+)-1-(1-naphthyl)ethylamine)-77.84(d，3F，J＝7.2Hz，minor peaks，S-enantiomer)，-78.03(d，3F，J＝7.2Hz，majorpeak，R-enantiomer).
Example 958b
(2S) - (+) -7- (1, 3-benzodioxol-5-yloxy) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The resolution of 179.2mg of racemic 7- (1, 3-benzodioxol-5-yloxy) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (85: 15: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 63.5mg (71%) of a yellow solid: according to analytical HPLC 97.2% ee.
[a]22 D＝+20.5(EtOH，c＝3.2)；1H NMR(d6-acetone/400MHz)5.84(q，1H，J＝6.8Hz)，6.13(s，2H)，6.52(s，1H)，6.66(dd，1H，J＝8.5Hz，J＝2.0Hz)，6.80(d，1H，J＝2.5Hz)，6.96(d，1H，J＝8.3Hz)，7.69(s，1H)，7.90(s，1H)；19F NMR(CDCl3/400MHz)-79.4(d，3F，J＝7.2Hz)；MS(ES+)415(M+1，100).
Example 959
(2R) - (-) -6-chloro-7- [4- (methylthio) phenoxy ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 147.3mg of racemic 6-chloro-7- [4- (methylthio) phenoxy ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chira1pak OJ) using heptane: 2-propanol: acetic acid (70: 30: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 50.7mg (69%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝-21.3(EtOH，c＝2.5)；1H NMR(d6-acetone/400MHz)2.56(s，3H)，5.87(q，1H，J＝6.6Hz)，6.58(s，1H)，7.12(d，2H，J＝8.7Hz)，7.43(d，2H，J＝8.9Hz)，7.69(s，1H)，7.85(s，1H)；19FNMR(CDCl3/400MHz)-79.3(d，3F，J＝6.5Hz)；MS(ES+)417(M+1，100)，419(M+3，45)；NMR non-equivalence with CSA and a 4：1mixture of the(R)and(S)enantiomers：19FNMR(d6-benzene；26eq of(R)-(+)-1-(1-naphthyl)ethylamine)-77.80(d，3F，J＝6.5Hz，minor peaks，S-enantiomer)，-77.96(d，3F，J＝7.2Hz，major peak，R-enantiomer).
Example 960
(2S) - (+) -6-chloro-7- [4- (methylthio) phenoxy ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 147.3mg of racemic 6-chloro-7- [4- (methylthio) phenoxy ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak OJ) using heptane: 2-propanol: acetic acid (70: 30: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 23.9mg (32%) of a yellow solid: according to analytical HPLC 98.6% ee.
[a]22 D＝+20.9(EtOH，c＝1.2)；1H NMR(d6-acetone/400MHz)2.56(s，3H)，5.87(q，1H，J＝6.6Hz)，6.58(s，1H)，7.12(d，2H，J＝8.7Hz)，7.43(d，2H，J＝8.9Hz)，7.69(s，1H)，7.85(s，1H)；19FNMR(CDCl3/400MHz)-79.3(d，3F，J＝6.5Hz)；MS(ES+)417(M+1，100)，419(M+3，45).
Example 961
(2R) - (-) -6-chloro-7- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 217.7mg of racemic 6-chloro-7- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 80.4mg (74%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝-28.7(EtOH，c＝4.0)；1H NMR(d6-acetone/400MHz)2.40(s，3H)，5.84(q，1H，J＝7.0Hz)，6.49(s，1H)，7.07(d，2H，J＝8.5Hz)，7.34(d，2H，J＝8.3Hz)，7.72(s，1H)，7.92(s，1H)；19FNMR(CDCl3/400MHz)-79.4(d，3F，J＝7.2Hz)；MS(ES+)385(M+1，100)；NMRnon-equivalence with CSA and a 2：1mixture of the(R)and(S)enantiomers：19F NMR(d6-benzene；16eq of(R)-(+)-1-(1-naphthyl)ethylamine)-77.85(d，3F，J＝6.5Hz，minorpeaks，S-enantiomer)，-78.05(d，3F，J＝6.5Hz，major peak，R-enantiomer).
Example 962
(2S) - (+) -6-chloro-7- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 217.7mg of racemic 6-chloro-7- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 70.5mg (65%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝+29.0(EtOH，c＝3.5)；1H NMR(d6-acetone/400MHz)2.40(s，3H)，5.84(q，1H，J＝7.0Hz)，6.49(s，1H)，7.07(d，2H，J＝8.5Hz)，7.34(d，2H，J＝8.3Hz)，7.72(s，1H)，7.92(s，1H)；19FNMR(CDCl3/400MHz)-79.4(d，3F，J＝7.2Hz)；MS(ES+)385(M+1，100).
Example 963
(2R) - (-) -6-chloro-7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 180.7mg of racemic 6-chloro-7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AS) using heptane: 2-propanol: acetic acid (90: 10: 0.5) AS mobile phase. The first eluted peaks from multiple chromatography were combined to give 85.3mg (94%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝-37.0(EtOH，c＝4，3)；1H NMR(d6-acetone/400MHz)2.24(s，3H)，5.83(q，1H，J＝7.0Hz)，6.43(s，1H)，7.10(d，1H，J＝7.0Hz)，7.26(t，1H，J＝7.5Hz)，7.33-7.44(m，2H)，7.44(s，1H)，7.93(s，1H)；19F NMR(CDCl3/400MHz)-79.5(d，3F，J＝7.2Hz)；MS(ES+)385(M+1，100)；NMR non-equivalence with CSA and a 2：1mixture of the(R)and(S)enantiomers：19F NMR(d6-benzene；14eq of(R)-(+)-1-(1-naphthyl)ethylamine)-77.89(d，3F，J＝7.2Hz，minor peaks，S-enantiomer)，-78.09(d，3F，J＝7.2Hz，major peak，R-enantiomer).
Example 964
(2S) - (+) -6-chloro-7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 180.7mg of racemic 6-chloro-7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AS) using heptane: 2-propanol: acetic acid (90: 10: 0.5) AS mobile phase. The second eluted peaks from multiple chromatographies were combined to give 85.3mg (94%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝+36.5(EtOH，c＝4.3)；1H NMR(d6-acetone/400MHz)2.24(s，3H)，5.83(q，1H，J＝7.0Hz)，6.43(s，1H)，7.10(d，1H，J＝7.0Hz)，7.26(t，1H，J＝7.5Hz)，7.33-7.44(m，2H)，7.44(s，1H)，7.93(s，1H)；19F NMR(CDCl3/400MHz)-79.5(d，3F，J＝7.2Hz)；MS(ES+)385(M+1，100).
Example 965
(2R) - (-) -6-chloro-7- (2-chloro-4-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 223.3mg of racemic 6-chloro-7- (2-chloro-4-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 95.3mg (85%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝-24.4(EtOH，c＝4.8)；1H NMR(d6-acetone/400MHz)3.93(s，3H)，5.83(q，1H，J＝7.0Hz)，6.31(s，1H)，7.08(dd，1H，J＝8.9Hz，J＝2.9Hz)，7.22(d，1H，J＝2.8Hz)，7.32(d，1H，J＝8.9Hz)，7.73(s，1H)，7.92(s，1H)；19F NMR(CDCl3/400MHz)-79.5(d，3F，J＝7.2Hz)；MS(ES+)435(M+1，100)，437(M+3，65)；NMR non-equivalence with CSA and a 2∶1mixtureof the(R)and(S)enantiomers：19F NMR(d6-benzene；13eq of(R)-(+)-1-(1-naphthyl)ethylamine)-77.92(d，3F，J＝7.2Hz，minor peaks，S-enantiomer)，-78.10(d，3F，J＝7.2Hz，major peak，R-enantiomer).
Example 966
(2S) - (+) -6-chloro-7- (2-chloro-4-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 223.3mg of racemic 6-fluoro-7- (2-chloro-4-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 95.8mg (86%) of a yellow solid: according to analytical HPLC 95-8% ee.
[a]22 D＝+21.9(EtOH，c＝4.8)；1H NMR(d6-acetone/400MHz)3.93(s，3H)，5.83(q，1H，J＝7.0Hz)，6.31(s，1H)，7.08(dd，1H，J＝8.9Hz，J＝2.9Hz)，7.22(d，1H，J＝2.8Hz)，7.32(d，1H，J＝8.9Hz)，7.73(s，1H)，7.92(s，1H)；19FNMR(CDCl3/400MHz)-79.5(d，3F，J＝7.2Hz)；MS(ES+)435(M+1，100)，437(M+3，65).
Example 967
(2R) - (-) -6-chloro-7- (4-fluoro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 216mg of racemic 6-chloro-7- (4-fluoro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chira1pak OJ) using heptane: ethanol: acetic acid (75: 25: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 96.5mg (89%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝-35.6(EtOH，c＝4.8)；1H NMR(d6-acetone/400MHz)2.24(s，3H)，5.84(q，1H，J＝7.0Hz)，6.36(s，1H)，7.11-7.24(m，3H)，7.72(s，1H)，7.89(s，1H)；19F NMR(CDCl3/400MHz)-79.4(d，3F，J＝6.5Hz)，-117.9(m，1F)；MS(ES+)403(M+1，100)；NMR non-equivalence with CSA and a2∶1mixture ofthe(R)and(S)enantiomers：19F NMR(d6-benzene；14eq of(R)-(+)-1-(1-naphthyl)ethylamine)-77.87(d，3F，J＝6.5Hz，minor peaks，S-enantiomer)，-78.04(d，3F，J＝7.2Hz，major peak，R-enantiomer).
Example 968
(2S) - (+) -6-chloro-7- (4-fluoro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 216mg of racemic 6-chloro-7- (4-fluoro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak OJ) using heptane: ethanol: acetic acid (75: 25: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 91mg (84%) of a yellow solid: according to analytical HPLC 99.3% ee.
[a]22 D＝+34.3(EtOH，c＝4.6)；1H NMR(d6-acetone/400MHz)2.24(s，3H)，5.84(q，1H，J＝7.0Hz)，6.36(s，1H)，7.11-7.24(m，3H)，7.72(s，1H)，7.89(s，1H)；19FNMR(CDCl3/400MHz)-79.4(d，3F，J＝6.5Hz)，-117.9(m，1F)；MS(ES+)403(M+1，100).
Example 969
(2R) - (-) -6-chloro-7- (2-methoxy-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 267mg of racemic 6-chloro-7- (2-methoxy-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: ethanol: acetic acid (97: 2.5: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 109mg (82%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝-28.6(EtOH，c＝5.5)；1H NMR(d6-acetone/400MHz)2.42(s，3H)，3.82(s，3H)，5.80(q，1H，J＝7.0Hz)，6.24(s，1H)，6.91(d，1H，J＝8.0Hz)，7.09(m，2H)，7.67(s，1H)，7.90(s，1H)；19F NMR(CDCl3/400MHz)-79.5(d，3F，J＝6.5Hz)；MS(ES+)415(M+1，100)；NMR non-equivalence with CSA and a 2∶1mixture ofthe(R)and(S)enantiomers：19F NMR(d6-benzene；12eq of(R)-(+)-1-(1-naphthyl)ethylamine)-77.90(d，3F，J＝7.2Hz，minorpeaks，S-enantiomer)，-78.09(d，3F，J＝7.2Hz，major peak，R-enantiomer).
Example 970
(2S) - (+) -6-chloro-7- (2-methoxy-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 267mg of racemic 6-chloro-7- (2-methoxy-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: ethanol: acetic acid (97: 2.5: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 87.2mg (65%) of a yellow solid: according to analytical HPLC 97.7% ee.
[a]22 D＝+26.5(EtOH，c＝4.4)；1H NMR(d6-acetone/400MHz)2.42(s，3H)，3.82(s，3H)，5.80(q，1H，J＝7.0Hz)，6.24(s，1H)，6.91(d，1H，J＝8.0Hz)，7.09(m，2H)，7.67(s，1H)，7.90(s，1H)；19FNMR(CDCl3/400MHz)-79.5(d，3F，J＝6.5Hz)；MS(ES+)415(M+1，100).
Example 971
(2S) - (+) -5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 181.1mg of racemic 5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak ADH) using hexane: ethanol: acetic acid (97.5: 2: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 76.5mg (84%) of a yellow solid: according to analytical HPLC 98.8% ee.
[a]22 D＝+46.1(EtOH，c＝3.8)；1H NMR(d6-acetone/400MHz)5.85(q，1H，J＝7.2Hz)，6.50(d，1H，J＝8.3Hz)，6.80(d，1H，J＝8.3Hz)，7.10(d，2H，J＝7.6Hz)，7.21(t，1H，J＝7.4Hz)，7.36(t，1H，J＝8.3Hz)，7.44(m，2H)，8.06(s，1H)；19F NMR(d6-acetone/400MHz)-79.3(d，3F，J＝7.7Hz)；MS(ES+)337(M+1，100).
Example 972
(2R) - (-) -5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 181.1mg of racemic 5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak ADH) using hexane: ethanol: acetic acid (97.5: 2: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 76.7mg (84%) of a yellow solid: according to analytical HPLC 99.8% ee.
[a]22 D＝-43.7(EtOH，c＝3.8)；1H NMR(d6-acetone/400MHz)5.85(q，1H，J＝7.2Hz)，6.50(d，1H，J＝8.3Hz)，6.80(d，1H，J＝8.3Hz)，7.10(d.2H，J＝7.6Hz)，7.21(t，1H，J＝7.4Hz)，7.36(t，1H，J＝83Hz)，7.44(m，2H)，8.06(s，1H)；19F NMR(d6-acetone/400MHz)-79.3(d，3F，J＝7.7Hz)；MS(ES+)337(M+1，100)；CD(MeOH)214([theta]＝+26600)，276([theta]＝-15000).
Example 973
(2R) - (+) -6-chloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The resolution of 215mg of racemic 6-chloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak ADH) using hexane: 2-propanol: acetic acid (97.5: 2: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 98.8mg (92%) of a yellow solid: according to analytical HPLC 99.8% ee.
[a]22 D＝+12.6(EtOH，c＝4.9)；1H NMR(d6-acetone/400MHz)5.89(q，1H，J＝7.1Hz)，6.87(d，2H，J＝7.9Hz)，7.06(d，1H，J＝8.8Hz)，7.09(t，1H，J＝7.5Hz)，7.36(m，2H)，7.60(d，1H，J＝8.8Hz)，7.75(s，1H)；19F NMR(d6-acetone/400MHz)-79.3(d，3F，J＝7.7Hz)；MS(ES+)371(M+1，100)，373(M+3，34).
Example 974
(2S) - (-) -6-chloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The resolution of 215mg of racemic 6-chloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak ADH) using hexane: 2-propanol: acetic acid (97.5: 2: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 98.3mg (91%) of a yellow solid: according to analytical HPLC 99.0% ee.
[a]22 D＝-12.6(EtOH，c＝4.9)；1HNMR(d6-acetone/400MHz)5.89(q，1H，J＝7.1Hz)，6.87(d，2H，J＝7.9Hz)，7.06(d，1H，J＝8.8Hz)，7.09(t，1H，J＝7.5Hz)，7.36(m，2H)，7.60(d，1H，J＝8.8Hz)，7.75(s，1H)；19F NMR(d6-acetone/400MHz)-79.3(d，3F，J＝7.7Hz)；MS(ES+)371(M+1，100)，373(M+3，34)；CD(MeOH)218([theta]＝-20400)，276([theta]＝+21200).
Example 975
(2R) - (+) -6-chloro-5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 286mg of racemic 6-chloro-5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak ADH) using hexane: 2-propanol: acetic acid (97.5: 2: 0.5) as mobile phase. The first eluting peaks from multiple chromatographic treatments were combined to give 139.8mg (98%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝+20.4(EtOH，c＝7.0)；1H NMR(d6-acetone/400MHz)5.90(q，1H，J＝7.0Hz)，6.85(dd，1H，J＝8.3Hz，J＝2.4Hz)，6.94(t，1H，J＝2.2Hz)，7.09(d，1H，J＝8.9Hz)，7.14(dt，1H，J＝8.0Hz，J＝1.0Hz)，7.39(t，1H，J＝8.2Hz)，7.63(d，1H，J＝9.0Hz)，7.74(s，1H)；19F NMR(d6-acetone/400MHz)-79.3(d，3F，J＝7.0Hz)；MS(ES+)405(M+1，100)，407(M+3，80)；CD(MeOH)232([theta]＝+25200)，276([theta]＝-25000).
Example 976
(2S) - (-) -6-chloro-5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 286mg of racemic 6-chloro-5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chira1pak ADH) using hexane: 2-propanol: acetic acid (97.5: 2: 0.5) as mobile phase. The second eluting peaks from multiple chromatographic treatments were combined to give 139.6mg (98%) of a yellow solid: according to analytical HPLC 100% ee.
[a]22 D＝-20.1(EtOH，c＝7.0)；1H NMR(d6-acetone/400MHz)5.90(q，1H，J＝7.0Hz)，6.85(dd，1H，J＝8.3Hz，J＝2.4Hz)，6.94(t，1H，J＝2.2Hz)，7.09(d，1H，J＝8.9Hz)，7.14(dt，1H，J＝8.0Hz，J＝1.0Hz)，7.39(t，1H，J＝8.2Hz)，7.63(d，1H，J＝9.0Hz)，7.74(s，1H)；19F NMR(d6-acetone/400MHz)-79.3(d，3F，J＝7.0Hz)；MS(ES+)405(M+1，100)，407(M+3.80)；CD(MeOH)238([theta]＝-25200)，274([theta]＝+25000).
Example 977
(2S) - (+) -5, 7-diamino-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The resolution of 278mg of racemic 5, 7-dichloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (94.5: 5: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 105.4mg (75.8%) of an off-white solid: according to analytical HPLC 99.8% ee. NMR anisovalent analysis using CSA gave a 2: 1 mixture of the (S) and (R) enantiomers:
19F NMR(d6-benzene；9eq of(R)-(+)-1-(1-naphthyl)ethylamine)-78.06(d，3F，J＝6.5Hz，major peaks，S-enantiomer)，-77.89(d，3F，J＝6.5Hz，minor peak，R-enantiomer)；CD(MeOH)226([theta]＝negative)，292([theta]＝positive).[a]22 D＝+11.7(EtOH，c＝5.1).LC-MS(ES+)：357.0(M+1，100).1H NMR(CD3OD/300MHz)：8.02(S，1H)，7.13(s，1H)，5.85(q，J＝6.9Hz，1H)，4.09(q，J＝7.2Hz，2H)，1.46(t，J＝7.2Hz，3H).
example 978
(2R) - (-) -5, 7-dichloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The resolution of 278mg of racemic 5, 7-dichloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chi ra 1pak AD) using heptane: 2-propanol: acetic acid (94.5: 5: 0.5) as mobile phase. The first eluted peaks from multiple chromatographies were combined to give 128.8mg (92.7%) of an off-white solid: according to analytical HPLC 99.8% ee. NMR anisovalent analysis using CSA gave a 2: 1 mixture of the (S) and (R) enantiomers:
19F NMR(d6-benzene；9eq of(R)-(+)-1-(1-naphthyl)ethylamine)-78.06(d，3F，J＝6.5Hz，major peaks，S-enantiomer)，-77.89(d，3F，J＝6.5Hz，minor peak，R-enantiomer)；[a]22 D＝-11.9(EtOH，c＝6.38).LC-MS(ES+)：357.0(M+1，100).1H NMR(CD3OD/300MHz)：8.02(S，1H)，7.13(s，1H)，5.85(q，J＝6.9Hz，1H)，4.09(q，J＝7.2Hz，2H)，1.46(t，J＝7.2Hz，3H).
example 979
(2S) - (+) -6- (allyloxy) -5, 7-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The resolution of 270mg of racemic 6- (allyloxy) -5, 7-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (94.5: 5: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 129.5mg (96%) of an off-white solid: according to analytical HPLC 99.7% ee. NMR anisovalent analysis using CSA gave a 2: 1 mixture of the (S) and (R) enantiomers:
19F NMR(d6-benzene；3.6eq of(R)-(+)-1-(1-naphthyl)ethylamine)-78.11(d，3F，J＝6.5Hz，major peaks，S-enantiomer)，-77.93(d，3F，J＝6.5Hz，minor peak，R-enantiomer)；CD(MeOH)226([theta]＝negative)，290([theta]＝positive).[a]22 D＝+12.9(EtOH，c＝6.4)；LC-MS(ES+)：369.0(M+1，100).1HNMR(CD3OD/300MHz)：7.98(s，1H)，7.10(s，1H)，6.22-6.09(m，1H)，5.82(q，J＝7.2Hz，1H)，5.44(dd，J＝1.2Hz，17.1Hz，1H)，5.30(dd，J＝1.2Hz，10.5Hz，1H)，4.54(d，J＝6Hz，2H).
example 980
(2R) - (-) -6- (allyloxy) -5, 7-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
The resolution of 270mg of racemic 6- (allyloxy) -5, 7-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: 2-propanol: acetic acid (94.5: 5: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 122.4mg (91%) of an off-white solid: according to analytical HPLC 99.7% ee. NMR anisovalent analysis using CSA gave a 2: 1 mixture of the (S) and (R) enantiomers:
19F NMR(d6-benzene；3.6eq of(R)-(+)-1-(1-naphthyl)ethylamine)-78.11(d，3F，J＝6.5Hz，major peaks，S-enantiomer)，-77.93(d，3F，J＝6.5Hz，minor peak，R-enantiomer)；[a]22 D＝-12.3(EtOH，c＝6.1)；LC-MS(ES+)：369.0(M+1，100).1H NMR(CD3OD/300MHz)：7.98(s，1H)，7.10(s，1H)，6.22-6.09(m，1H)，5.82(q，J＝7.2Hz，1H)，5.44(dd，J＝1.2Hz，17.1Hz，1H)，5.30(dd，J＝1.2Hz，10.5Hz，1H)，4.54(d，J＝6Hz，2H).
example 981
(2S) - (+) -5, 7-dichloro-6-isopropoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 251mg of racemic 5, 7-dichloro-6-isopropoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: acetic acid (99.5: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 37.4mg (29.8%) of an off-white solid: according to analytical HPLC 92.8% ee. NMR anisovalent analysis using CSA gave a 2: 1 mixture of the (S) and (R) enantiomers:
19F NMR(d6-benzene；6.7eq of(R)-(+)-1-(1-naphthyl)ethylamine)—78.07(d，3F，J＝6.5Hz，major peaks，S-enantiomer)，-77.89(d，3F，J＝6.5Hz，minor peak，R-enantiomer)；CD(MeOH)226([theta]＝negative)，292([theta]＝positive)；[a]22 D＝+12.5(EtOH，c＝1.22)；LC-MS(ES+)：371.0(M+1，100).1HNMR(CD3OD/300MHz)：8.03(s，1H)，7.12(s，1H)，5.84(q，J＝7.2Hz，1H)，4.61(m，1H)，1.38(d，J＝6Hz，6H).
Example 982
(2R) - (-) -5, 7-dichloro-6-isopropoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 251mg of racemic 5, 7-dichloro-6-isopropoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: acetic acid (99.5: 0.5) as mobile phase. The first eluted peaks from multiple chromatographies were combined to give 41.5mg (33.1%) of an off-white solid: according to analytical HPLC 96.1% ee. NMR anisovalent analysis using CSA gave a 2: 1 mixture of the (S) and (R) enantiomers:
19F NMR(d6-benzene；6.7eq of(R)-(+)-1-(1-naphthyl)ethylamine)—78.07(d，3F，J＝6.5Hz，major peaks，S-enantiomer)，-77.89(d，3F，J＝6.5Hz，minor peak，R-enantiomer)；[a]22 D＝-7.4(EtOH，c＝1.89)；LC-MS(ES+)：371.0(M+1，100).1H NMR(CD3OD/300MHz)：8.03(s，1H)，7.12(s，1H)，5.84(q，J＝7.2Hz，1H)，4.61(m，1H)，1.38(d，J＝6Hz，6H).
example 984
(2S) - (-) -6-chloro-8- (methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 1.75g of racemic 6-chloro-8- (methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: ethanol: trifluoroacetic acid (85: 15: 0.1) as mobile phase. The first elution peaks from multiple chromatographic treatments were combined to give 0.920g (52%) of a yellow solid: according to analytical HPLC 100% ee. NMR anisovalent analysis using CSA gave a 2: 1 mixture of the (S) and (R) enantiomers:
19FNMR(d6-benzene；3.6eq of(R)-(+)-1-(1-naphthyl)ethylamine)-77.58(d，3F，J＝8.4Hz，majorpeaks，S-enantiomer)，-77.72(d，3F，J＝7.2Hz，minor peaks，R-enantiomer)；[a]22 D＝-6.51(EtOH，c＝0.049)；MS(ES+)369(M+1，100).
example 985
(2R) - (+) -6-chloro-8- (methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 1.75g of racemic 6-chloro-8- (methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using heptane: ethanol: trifluoroacetic acid (85: 15: 0.1) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 0.820g (47%) of a yellow solid: according to analytical HPLC% ee. NMR anisovalent analysis using CSA gave a 2: 1 mixture of the (R) and (S) enantiomers:
19F NMR(d6-benzene；3.6eq of(R)-(+)-1-(1-naphthyl)ethylamine)-77.59(d，3F，J＝7.2Hz，minor peaks，S-enantiomer)，-77.75(d，3F，J＝7.2Hz，major peaks，R-enantiomer)；[a]22 D＝+11.4(EtOH，c＝0.036)；1H NMR(CH3OD)/400MHz)2.35(s，3H)，5.72(q，1H，J＝6.8Hz)，7.20(d，2H，J＝8.0Hz)，7.29(dd，2H，J＝2.8，8.0Hz)，7.33(d，2H，J＝7.6Hz)，7.75(s，1H)；MS(ES+)369(M+1，100).
example 986
(2S) - (-) -8-but-1-ynyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 0.331g of racemic 8-but-1-ynyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using hexane: 2-propanol: acetic acid (98: 2: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 0.131g (79%) of a yellow solid: according to analytical HPLC 99.8% ee. NMR anisovalent analysis using CSA gave a 2: 1 mixture of the (S) and (R) enantiomers:
19F NMR(d6-benzene；3.6eq of(R)-(+)-1-(1-naphthyl)ethylamine)-78.13(d，3F，J＝8.4Hz，major peaks，S-enantiomer)，-78.31(d，3F，J＝7.2Hz，minor peaks，R-enantiomer)；[a]22 D＝-67.84(EtOH，c＝0.054)；MS(ES+)331(M+1，100).
example 987
(2R) - (+) -8-but-1-ynyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 0.331g of racemic 8-but-1-ynyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using hexane: 2-propanol: acetic acid (98: 2: 0.5) as mobile phase. The second eluted peaks from multiple chromatography were combined to give 0.132g (80%) of a yellow solid: according to analytical HPLC 98.4% ee.
CD(MeOH)244(+24200)，286(-17000)；[a]22 D＝+64.8(EtOH，c＝0.056)；1H NMR(CH3OD/400MHz)1.22(t，3H，J＝7.6Hz)，2.43(q，2H，J＝7.6Hz)，5.82(q，1H，J＝6.8Hz)，7.28-7.29(m，2H)，7.69(s，1H)；MS(ES+)331(M+1，100).
Example 988
(2S) - (-) -6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 0.246g of racemic 6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chira1pak AD) using hexane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 0.125g (102%) of a yellow solid: according to analytical HPLC 99.8% ee. NMR anisovalent analysis using CSA gave a 2: 1 mixture of the (S) and (R) enantiomers:
19FNMR(d6-benzene；3.6eq of(R)-(+)-1-(1-naphthyl)ethylamine)-77.65(d，3F，J＝7.2Hz，majorpeaks，S-enantiomer)，-77.77(d，3F，J＝6.8Hz，minor peaks，R-enantiomer)；[a]22 D＝-9.18(EtOH，c＝0.052)；1HNMR(CH3OD/400MHz)2.29(d，3H，J＝1.6Hz)，5.79(q，1H，J＝6.8Hz)，7.17-7.20(m，2H)，7.26-7.30(m，1H)，7.37(dd，2H，J＝2.4，12.8Hz)，7.79(s，1H)；MS(ES+)387(M+1，100).
example 989
(2R) - (+) -6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 0.246g of racemic 6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using hexane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The second elution peaks from multiple chromatographic treatments were combined to give 0.124g (101%) of a yellow solid: according to analytical HPLC 99.6% ee. [ a ] A]22 D＝+9.17(EtOH，c＝0.052)；MS(ES+)387(M+1，100).
Example 990
(2S) - (-) -6-chloro-8- [4- (ethylsulfanyl) phenyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 0.137g of racemic 6-chloro-8- [4- (ethylthio) phenyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using hexane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 0.059g (86%) of a yellow solid: according to analytical HPLC 100% ee. NMR anisovalent analysis using CSA gave a 2: 1 mixture of the (S) and (R) enantiomers:
19FNMR(d6-benzene；3.6eq of(R)-(+)-1-(1-naphthyl)ethylamine)-77.57(d，3F，J＝7.2Hz，majorpeaks，S-enantiomer)，-77.69(d，3F，J＝7.2Hz，minor peaks，R-enantiomer)；[a]22 D＝-35.37(EtOH，c＝0.020)；MS(ES+)415(M+1，100).
Example 991
(2R) - (+) -6-chloro-8- [4- (ethylthio) phenyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 0.137g of racemic 6-chloro-8- [4- (ethylthio) phenyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using hexane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The second elution peak from multiple chromatography treatments was combined to give 0.058g (84%) of a yellow solid: according to analytical HPLC 99.8% ee. NMR anisovalent analysis using CSA gave a 2: 1 mixture of the (S) and (R) enantiomers:
[a]22 D＝+36.43(EtOH，c＝0.020)；1HNMR(CH3OD/400MHz)1.31(t，3H，J＝7.6Hz)，2.99(q，2H，J＝7.6Hz)，5.78(q，1H，J＝6.8Hz)，7.35-7.37(m，4H)，7.42(d，2H，J＝8.4Hz)，7.79(s，1H)；MS(ES+)415(M+1，100).
example 992
(2S) - (-) -6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 0.134g of racemic 6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using hexane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The first eluted peaks from multiple chromatography were combined to give 0.056g (84%) of a yellow solid: according to analytical HPLC 100% ee. NMR anisovalent analysis using CSA gave a 2: 1 mixture of the (S) and (R) enantiomers:
19F NMR(d6-benzene；3.6eq of(R)-(+)-1-(1-naphthyl)ethylamine)-77.55(d，3F，J＝8.4Hz，major peaks，S-enantiomer)，-77.68(d，3F，J＝8.0Hz，minorpeaks，R-enantiomer)；[a]22 D＝-9.64(EtOH，c＝0.018)；1H NMR(CH3OD/400MHz)1.25(t，3H，J＝7.6Hz)，2.68(q，2H，J＝7.6Hz)，5.76(q，1H，J＝7.2Hz)，7.25(d，2H，J＝8.0Hz)，7.34(dd，2H，J＝2.4，11.2Hz)，7.39(d，2H，J＝8.0Hz)，7.79(s，1H)；MS(ES+)383(M+1，100).
example 993
(2R) - (+) -6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 0.134g of racemic 6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using hexane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The second eluted peaks from multiple chromatographies were combined to give 0.057g (85%) of a yellow solid: according to analytical HPLC 99.8% ee. [ a ] A]22 D＝+9.54(EtOH，c＝0.018)；MS (ES+)383(M+1，100).
Example 994
(2S) -6-chloro-8- (4-methoxy-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 0.159g of racemic 6-chloro-8- (4-methoxy-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using hexane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The first eluted peaks from multiple chromatographies were combined to give 0.084g (106%) of a yellow solid: according to analytical HPLC 100% ee. NMR anisovalent analysis using CSA gave a 2: 1 mixture of the (S) and (R) enantiomers:19F NMR(d6-benzene; 3.6eq (R) - (+) -1- (1-naphthyl) ethylamine) -77.49(d, 3F, J ═ 8.4Hz, major peak, S-enantiomer), -77.63(d, 3F, J ═ 8.4Hz, minor peak, R-enantiomer); MS (ES +)399(M +1, 100).
Example 995
(2R) -6-chloro-8- (4-methoxy-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid
Resolution of 0.159g of racemic 6-chloro-8- (4-methoxy-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was carried out by means of preparative chromatography (Chiralpak AD) using hexane: 2-propanol: acetic acid (95: 5: 0.5) as mobile phase. The first eluted peaks from multiple chromatographies were combined to give 0.084g (106%) of a yellow solid: according to analytical HPLC 99.6% ee.
CD(MeOH)230(＝-32300)，258(＝+11800)，286(＝-17000)；1HNMR(CH3OD/400MHz)2.19(s，3H)，3.83(s，3H)，5.73(q，1H，J＝6.8Hz)，6.90(d，1H，J＝8.4Hz)，7.24-7.27(m，4H)，7.74(s，1H)；MS(ES+)399(M+1，100)。
General procedure for the preparation of sodium 2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of 2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (0.1-0.3mmol) in 2.0mL EtOH was added an equimolar amount of 0.1008N NaOH. The resulting solution was stirred at room temperature for 15 minutes and the volatile solvent was removed under a stream of nitrogen at 55 ℃. The residue was dissolved in 2.0mL of H2And O, freeze drying and concentrating. The product is obtained as a dry white solid.
Example 996
Sodium 7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
To a solution of 116mg of 7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid (0.318mmol) in 4mL of ethanol and 2mL of THF was added 3.15mL (0.318mmol) of an aqueous solution of 0.1008N NaOH. The resulting solution was stirred at room temperature for 15 minutes. The volatiles were removed. 2mL of water was added to the solution, and the resulting suspension was cooled to-78 deg.C, solidified, and then lyophilized under high vacuum. The milky white solid was recorded as PHA-807535A:
1H NMR(CD3OD/400MHz)2.08(s，3H)，2.28(s，3H)，5.77(q，1H，J＝7.6Hz)，6.31(d，1H，J＝2.0Hz)，6.41(dd，1H，J＝2.4Hz，8.4Hz)，6.78(s，1H)，6.94(d，1H，J＝8.0Hz)，7.11-7.15(m，2H)，7.38(s，1H)；MS(ES+)365(M+1，100)；LC-MS purity 100％at 3.575min.(UV)，100％ELSD.
Example 997
Sodium 5- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The sodium salt was obtained as an off-white solid using the general procedure:
MS(ES+)385(M+1，100)；1H NMR(CD3OD/400MHz)2.22(s，3H)，5.84(q，1H，J＝7.3Hz)，6.25(d，1H，J＝8.2Hz)，6.67(d，1H，J＝8.2Hz)，6.80(d，1H，J＝8.7Hz)，7.14(m，2H)，7.29(d，1H，J＝2.5Hz)，7.80(s，1H)；19F NMR(CD3OD/400MHz)80.0(d，3F，J＝6.8Hz).
example 998a
Sodium (2S) - (+) -5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate
A solution of 36.4mg (0.108mmol) of (2S) - (+) -5- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid in 1.5mL of ethanol was treated with 1.07mL of 0.1008N NaOH. The resulting mixture was freeze dried to yield 40.8mg (quantitative) of an off-white solid:
MS(ES+)337(M+1，100)；1HNMR(CD3OD/400MHz)5.84(q，1H，J＝7.3Hz)，6.43(d，1H，J＝8.2Hz)，6.70(d，1H，J＝8.2Hz)，6.99(d.2H，J＝7.7Hz)，7.12(t，1H，J＝7.4Hz)，7.17(t，1H，J＝8.2Hz)，7.35(t，2H，J＝8.0Hz)，8.55(s，1H)；19F NMR(CD3OD/400MHz)80.0(d，3F，J＝7.7Hz)。
example 998b
Sodium (2S) - (-) -8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
A solution of 50.0mg (0.165mmol) of (2S) - (-) -8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid in 1.5mL of ethanol was treated with 1.64mL 0.1008N NaOH. The resulting mixture was freeze-dried to give 39.0mg (quantitative) of a yellow solid:
MS(ES+)303(M+1，100)；1H NMR(CD3OD/400MHz)5.95(q，1H，J＝7.1Hz)，7.29(d，1H，J＝1.8Hz)，7.37(s，1H)，7.39(d，1H，J＝1.8Hz)；19FNMR(CD3OD/400MHz)80.3(d，3F，J＝6.8Hz).
example 999
Sodium (2R) - (-) -7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
A solution of 53.8mg (0.148mmo 1) (2R) - (-) -7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid in 1.5mL of ethanol was treated with 1.47mL 0.1008N NaOH. The resulting mixture was freeze dried to give 55.6mg (97%) of an off-white solid:
MS(ES+)365(M+1，100)；1H NMR(CD3OD/400MHz)2.09(s，3H)，2.28(s，3H)，5.77(q，1H，J＝7.3Hz)，6.31(d，1H，J＝2.4Hz)，6.41(dd，1H，J＝8.3Hz，J＝2.3Hz)，6.78(s，1H)，6.94(d，1H，J＝7.7Hz)，7.14(m，2H)，7.38(s，1H)；19F NMR(CD3OD/400MHz)80.2(d，3F，J＝7.7Hz).
example 1000
Sodium (2R) - (-) -2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylate
A solution of 38.1mg (0.101mmol) of (2R) - (-) -2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylic acid in 1.5mL of ethanol was treated with 1.00mL 0.1008N NaOH. The resulting mixture was freeze dried to give 48.4mg (quantitative) of an off-white solid:
MS(ES+)379(M+1，100)；1H NMR(CD3OD/400MHz)2.01(s，3H)，2.24(s，3H)，2.26(s，3H)，5.76(q，1H，J＝7.4Hz)，6.28(d，1H，J＝2.4Hz)，6.38(dd，1H，J＝8.3Hz，J＝2.4Hz)，6.63(s，1H)，6.87(s，1H)，7.11(d，1H，J＝8.3Hz)，7.38(s，1H)；19F NMR(CD3OD/400MHz)80.2(d，3F，J＝7.7Hz).
example 1001
Sodium 7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The sodium salt was obtained as an off-white solid using the general procedure:
MS(ES+)351(M+1,100)；1H NMR(CD3OD/400MHz)2.17(s，3H)，5.79(q，1H，J＝7.3Hz)，6.34(d，1H，J＝2.1Hz)，6.44(dd，1H，J＝8.4Hz，J＝2.3Hz)，6.96(d，1H，J＝8.0Hz)，7.11-7.16(m，2H)，7.23(td，1H，J＝7.8Hz，J＝1.3Hz)，7.29(d，1H，J＝7.5Hz)，7.41(s，1H)；19F NMR(CD3OD/400MHz)80.2(d，3F，J＝7.7Hz).
example 1002
2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylic acid sodium salt
The sodium salt was obtained as an off-white solid using the general procedure:
MS(ES+)379(M+1，100)；1H NMR(CD3OD/400MHz)2.02(s，3H)，2.26(s，3H)，2.28(s，3H)，5.78(q，1H，J＝7.3Hz)，6.30(d，1H，J＝2.3Hz)，6.40(dd，1H，J＝8.3Hz，J＝2.4，Hz)，6.64(s，1H)，6.88(s，1H)，7.13(d，1H，J＝8.4Hz)，7.40(s，1H)；19F NMR(CD3OD/400MHz)80.2(d，3F，J＝7.7Hz).
example 1003
6-chloro-7- (2-propylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
The sodium salt was obtained as an off-white solid using the general procedure:
MS(ES+)413(M+1，100)；1H NMR(CD3OD/400MHz)0.90(t，3H，J＝7.4Hz)，1.61(septet，2H，J＝7.5Hz)，2.54(t，2H，J＝7.6Hz)，5.77(q，1H，J＝7.3Hz)，6.20(s，1H)，6.90(dd，1H，J＝8.0Hz，J＝1.1Hz)，7.18(td，1H，J＝7.4Hz，J＝1.2Hz)，7.25(td，1H，J＝7.8Hz，J＝1.7Hz)，7.32(dd；1H，J＝7.4Hz，J＝1.7Hz)，7.37(s，1H)，7.38(s，1H)；19F NMR(CD3OD/400MHz)80.1(d，3F，J＝7.7Hz).
example 1004
Sodium 6-chloro-5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate the sodium salt was obtained using the general procedure as an off-white solid:
MS(ES+)405(M+1，100)，407(M+3，66)；1H NMR(CD3OD/400MHz)5.88(q，1H，J＝7.2Hz)，6.72(dd，1H，J＝8.5Hz，J＝2.3Hz)，6.80(t，1H，J＝2.3Hz)，6.93(d，1H，J＝8.9Hz)，7.05(m，1H)，7.27(t，1H，J＝8.2Hz)，7.41(d，1H，J＝8.7Hz)，7.49(s，1H)；19F NMR(CD3OD/400MHz)80.0(d，3F，J＝7.7Hz).
example 1005
5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
The sodium salt was obtained as an off-white solid using the general procedure:
MS(ES+)337(M+1，100)；1H NMR(CD3OD/400MHz)5.84(q，1H，J＝7.3Hz)，6.43(d，1H，J＝8.3Hz)，6.70(d，1H，J＝8.2Hz)，6.99(d，2H，J＝7.7Hz)，7.12(t，1H，J＝7.4Hz)，7.17(t，1H，J＝8.2Hz)，7.35(t，2H，J＝8.0Hz)，8.55(s，1H)；19F NMR(CD3OD/400MHz)80.0(d，3F，J＝7.7Hz).
example 1006
Sodium 5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
The sodium salt was obtained as an off-white solid using the general procedure:
MS(ES+)371(M+1，100)；1H NMR(CD3OD/400MHz)5.85(q，1H，J＝7.4Hz)，6.54(d，1H，J＝8.3Hz)，6.79(d，1H，J＝8.2Hz)，6.90(m，1H)，6.98(t，1H，J＝2.1Hz)，7.11(m，1H)，7.25(t，1H，J＝8.3Hz)，7.32(t，1H，J＝8.1Hz)，7.70(s，1H)；19F NMR(CD3OD/400MHz)80.2(d，3F，J＝6.8Hz).
example 1007
(2S) - (-) -8-but-1-ynyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt
A2.0 mL solution of 98.9mg (0.299mmol) 8-but-1-ynyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was treated with 2.967mL 0.1008N NaOH. The resulting mixture was freeze-dried to give a quantitative yield of a yellow solid:
1H NMR(CD3OD/400MHz)1.22(t，3H，J＝7.6Hz)，2.44(q，2H，J＝7.6Hz)，5.88(q，1H，J＝7.2Hz)，7.17-7.19(m，2H)，7.32(s，1H).
example 1008
Sodium (2S) - (-) -6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
A2.0 mL solution of 95.1mg (0.246mmo1) (2S) - (-) -6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was treated with 2.439mL 0.1008N NaOH. The resulting mixture was freeze-dried to give a quantitative yield of a yellow solid:
1H NMR(CD3OD/400MHz)2.29(d，3H，J＝1.6Hz)，5.84(q，1H，J＝7.2Hz)，7.17-7.20(m，2H)，7.24-7.29(m，3H)，7.40(s，1H).
example 1009
Sodium (2S) - (-) -6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate
A2.0 mL solution of 31.8mg (0.083mmol) of (2S) - (-) -6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid is treated with 0.824mL 0.1008N NaOH. The resulting mixture was freeze-dried to give a quantitative yield of a yellow solid:
1H NMR(CD3OD/400MHz)1.25(t，3H，J＝7.6Hz)，2.67(q，2H，J＝7.6Hz)，5.81(q，1H，J＝7.2Hz)，7.21-7.25(m，4H)，7.38-7.40(m，3H).
example 1010
Sodium 7- (4-ethylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate
A2.0 mL solution of 40.3mg (0.107mmol) of 7- (4-ethylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid was treated with 1.057mL 0.1008N NaOH. The resulting mixture was freeze-dried to give a quantitative yield of a yellow solid:
1H NMR(CD3OD/400MHz)1.21(t，3H，J＝7.6Hz)，2.12(s，3H)，2.61(q，2H，J＝7.6Hz)，5.87(q，1H，J＝7.2Hz)，6.38(d，1H，J＝8.0Hz)，6.84(d，2H，J＝8.0Hz)，7.00(d，1H，J＝8.0Hz)，7.17(d，2H，J＝8.0Hz)，7.40(s，1H).
In view of the above examples, one skilled in the art can prepare the compounds in table 18 below:
watch 18
Biological assessment
Further description of the methods used for biological assessment can be found in U.S. patent No. 6077850, which is incorporated herein by reference. 6034256, also provides a description of the biological evaluation method. Additional description of these methods is provided in U.S. patent No.6,271,253, which is incorporated herein by reference.
Rat carrageenan paw edema test
Carrageenan paw edema assays can be performed using materials, reagents and procedures substantially as described in winter et al (proc.sco.exp.biol.med. p.111, page 544 (1962)). Male Sprague-Dawley (Sprague-Dawley) rats in each group were selected, whereby the mean body weights were as close as possible. Prior to the test, rats were fasted for more than 16 hours with free access to drinking water. Rats were administered orally (1 ml) either a compound suspended in a vehicle containing 0.5% methylcellulose and 0.025% surfactant, or the vehicle itself alone. After 1 hour, the volume of the injected foot was measured by injecting 0.1 ml of a 1% solution of carrageenan/sterile 0.9% saline plantar ly and using a displacement-type plethysmometer connected to a pressure transducer with a digital display. After 3 hours of carrageenan injection, the foot volume was measured again. Mean foot swelling in the drug-treated animal groups was compared to placebo-treated animal groups and the percent inhibition of edema was determined (Otternes vs. Bliven vs. "experimental mode for NSAID testing" in the book "nonsteroidal anti-inflammatory drugs" (edited by lombardino, 1985)).
In vitro evaluation of COX-1 and COX-2 activity
The compounds of the invention exhibit COX-2 inhibitory effects in vitro. The COX-2 inhibitory activity of the compounds of the invention shown in the examples was determined by the following method.
a. Preparation of recombinant COX baculovirus
Recombinant COX-1 and COX-2 were prepared as described by Gierse et al (J.Bi chem. 305, pp.479-84 (1995)). A2.0 kb fragment containing the coding region of human or murine COX-1 or human or murine COX-2 was cloned into the BamH1 site of baculovirus transfer vector pVL1393 (Invitrogen) in a manner similar to the method of D.R.O' Reilly et al ("baculovirus expression vector: A laboratory Manual (1992)) to produce a baculovirus transfer vector for COX-1 and COX-2. Transfection of 4. mu.g of baculovirus transfer vector DNA and 200 ng of linearized baculovirus plasmid DNA into SF9 using the calcium phosphate methodInsect cell (2X 10)8) And isolating the recombinant baculovirus. See "guide to methods for baculovirus vectors and insect cell culture procedures" by m.d. summers and g.e. smith on page 1555 (1987) of texas agricultural laboratory gazette. Purification of recombinant viruses by three rounds of plaque purification and production of high titer (10% 7-108Plaque forming units/ml). For large-scale production, SF9 insect cells (0.5X 10) were infected with a stock of recombinant baculovirus in a 10 liter fermentor6Per ml), whereby the multiplicity of infection is 0.1. After 72 hours, the cells were centrifuged and washed with 1% 3- [ (3-cholamidopropyl) dimethylaminobenzoic acid]Cell pellets were homogenized in Tris/sucrose (50 mM: 25%, pH 8.0) with-1-propanesulfonate (CHAPS). The homogenate was centrifuged at 10000XG for 30 minutes and the resulting supernatant was stored at-80 ℃ before analysis for COX activity.
Analysis of COX-1 and COX-2 Activity
Detecting the released prostaglandin by ELISA to form PGE2COX activity was assayed in the form of/. mu.g protein/time. CHAPS-lysed insect cell membranes containing the appropriate COX enzyme were cultured in potassium phosphate buffer (50mM and pH 8.0) containing epinephrine, phenol, and heme, with the addition of arachidonic acid (10. mu.M). The compound is incubated with the enzyme for 10-20 minutes prior to addition of arachidonic acid. After 10 minutes at 37 deg.C/room temperature, either reaction between arachidonic acid and the enzyme was stopped by transferring 40 microliters of the reaction mixture into 160 microliters of ELISA buffer and 25 μ M indomethacin (indomethacin). The PEG2 formed was measured using standard ELISA techniques (Cayman chemical company). The results are shown in table 2.
Improved assay for COX-1 and COX-2 activity
Detection of the released prostaglandin by ELISA and the resulting PGE2COX activity was assayed in the form of/. mu.g protein/time. Adding 20 microliter of 100. mu.M arachidonic acid (10. mu.M) in phosphoric acidInsect cell membranes lysed with CHAPS containing the appropriate COX enzyme were incubated in potassium buffer (0.05M potassium phosphate, pH 7.5, 2. mu.M phenol, 1. mu.M heme, and 300. mu.M epinephrine). The compound was incubated with the enzyme at 25 ℃ for 10 minutes prior to addition of arachidonic acid. After 2 minutes at 37 deg.C/room temperature, either reaction between arachidonic acid and the enzyme was stopped by transferring 40 microliters of the reaction mixture into 160 microliters of ELISA buffer and 25. mu.M indomethacin. The PGE formed was measured using standard ELISA techniques (Cayman chemical Co., Ltd.)2. The results are shown in Table 19.
No. 19 watch
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
1a ＞500 ＞500 113 ＞500
1b 5.73 ＜0.137 ＜0.137 ＜0.137
1b Repeat the test 5.56 0.0176 ＜0.137 0.021
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
1c 0.543 ＜0.00510 ＜0.137 ＜0.00510
1c Repeat the test 0.143 0.0122 ＜0.137 0.0076
1d 49.2 11.9 5.17 0.173
1e ＜0.137 ＜0.137 ＜0.137 ＜0.137
1e Repeat the test ＜0.137 ＜0.137 ＜0.137 ＜0.137
1e Repeat the test ＜0.137 0.0383 ＜0.137 0.0295
1e Repeat the test 0.0024 0.0308 0.0025 0.0276
1f 16.4 0.894 4.72 ＜0.137
1f Repeat the test 9.42 0.38 3.04 0.0336
1g 21 58.4 5.34 1.06
1h ＜0.137 0.224 ＜0.137 0.0283
1h Repeat the test ＜0.137 0.229 ＜0.137 ＜0.137
2a ＜0.137 0.64 ＜0.137 1.74
2a Repeat the test 0.347 1.71 0.122 0.398
2a Repeat the test 0.112 1.16 0.052 0.688
2b ＜0.686 0.205 ＜0.686 ＜0.137
2b Repeat the test ＜0.137 0.111 ＜0.137 0.0573
2b Repeat the test 0.0836 0.139 ＜0.0457 0.0482
2b Repeat the test ＞11.1 0.246 ＞11.1 0.0496
2c 51.6 0.535 9.71 0.164
2c Repeat the test 51.6 0.381 8.31 0.229
2d 44.3 0.121 0.448 0.131
2e 68.8 9.17 4.86 0.564
2f ＞100 ＞100 72.4 0.167
2g ＞500 0.886 203 0.0684
2g Repeat the test ＞100 1.09 ＞100 0.4
2h ＞100 ＞100 ＞100 5.91
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
2i ＞100 ＞3.70 ＞500 ＞100
3a ＞100 ＞100 ＞100 1.17
2i 187 ＞500 78.5 86.6
3b 15.8 ＜0.137 1.94 ＜0.137
3b Repeat the test 6.7 0.0262 1.33 0.0224
3c 2.3 0.0181 ＜0.0457 0.0157
3d ＜0.137 ＜0.137 ＜0.137 ＜0.137
3e ＜0.137 ＜0.137 ＜0.137 ＜0.137
3f 7.09 ＜0.137 0.533 ＜0.137
3f Repeat the test 9.55 0.0123 0.635 0.0077
3f Repeat the test 9.09 0.0176 0.897 0.0112
3g 74.4 0.167 5.69 0.185
3g Repeat the test 81.2 0.124 12.3 0.12
3h 17 0.2 3.08 ＜0.137
3h Repeat the test 18.5 0.0275 3.92 0.0134
3h Repeat the test 18.4 0.0492 5.58 0.0178
3i ＞97.6 5.45 ＞97.6 6.58
4a ＞500 237 ＞500 131
4a Repeat the test ＞500 241 ＞500 99.6
4a Repeat the test ＞100 ＞100 ＞100 33.7
4b ＞500 0.964 230 1.19
4b Repeat the test ＞500 3.24 44.4 1.43
5a ＞100 ＞100 90.1 11.2
5a Repeat the test 264 137 23.1 ＜0.137
5a Repeat the test 199 297 75.3 24.6
5b ＞500 3.45 ＞500 ＜0.137
5b Repeat the test ＞100 68 ＞100 0.484
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
5c ＞100 12.1 ＞100 4.75
5c Repeat the test 478 32.2 417 22.2
5d 31.9 25.2 15 6.07
5d Repeat the test 17.2 21.5 10.5 5.69
5e ＞100 ＞100 ＞100 ＞100
5f ＞100 ＞100 51 ＞100
5g ＞100 ＞100 ＞100 ＞100
6 ＞100 0.311 ＞100 0.327
6 Repeat the test 188 0.238 93.5 0.19
6 Repeat the test 194 0.185 60.7 0.095
7a ＞100 ＞100 ＞100 95.8
7b ＞100 59 50.8 0.27
7c ＞100 ＞100 31.1 ＜0.137
7d 19.5 ＜0.137 1.76 ＜0.137
7d Repeat the test 19.1 0.0193 5.42 0.0175
7e ＞100 ＞100 58.7 48.3
7f 70.8 17.9 23.3 ＜0.137
7g 7.2 ＜0.137 ＜0.137 ＜0.137
7g Repeat the test 6.35 0.0434 ＜0.137 0.0348
8a ＞100 0.782 37.1 0.923
8a Repeat the test 57.2 1.43 ＜0.686 0.164
8b 99 0.666 0.457 0.657
8b Repeat the test 189 1.19 35.2 0.121
8c ＞100 0.33 24.2 0.138
8c Repeat the test 78 0.208 15 0.0299
8c Repeat the test 46.8 0.194 6.75 0.0843
8d ＞100 2.88 33.3 1.71
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
8e ＞100 0.858 0.875 0.183
8e Repeat the test 130 0.185 1.68 0.139
8f ＞100 8.37 55.5 0.472
8g ＞100 0.696 47.2 0.514
8g Repeat the test 194 0.498 66.1 0.347
8h ＞100 80.4 ＞100 0.425
8i 14.1 21 1.02 2.75
8j ＞100 ＞100 ＞100 1.14
8k ＞100 ＞100 ＞100 1.67
8l 180 0.294 ＜0.686 0.149
8l Repeat the test ＞100 0.422 0.162 0.147
8l Repeat the test ＞33.3 0.429 0.42 0.181
8l Repeat the test ＞11.1 0.389 0.363 0.263
9a 9.97 ＜0.0152 0.143 ＜0.0152
9a Repeat the test 5.11 ＜0.137 ＜0.137 ＜0.137
9a Repeat the test 9.72 ＜0.686 ＜0.686 ＜0.686
9a Repeat the test 5.97 ＜0.137 ＜0.137 ＜0.137
9a Repeat the test 8.31 ＜0.0457 ＜0.0457 ＜0.0457
9a Repeat the test 9.5 ＜0.0152 ＜0.0152 ＜0.0152
9a Repeat the test ＞1.20 0.017 0.0305 0.0058
9b 19 ＜0.137 1.27 ＜0.137
9b Repeat the test 17.9 0.0941 0.56 0.122
9c 3.94 0.0328 ＜0.137 0.0357
9c Repeat the test 4.19 ＜0.137 ＜0.137 ＜0.137
9c Repeat the test 2 0.0075 ＜0.137 ＜0.137
9c Repeat the test 2.2 ＜0.137 ＜0.137
9d 4.82 0.0046 0.0552 0.0074
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
9c 5.76 ＜0.137 2.27 ＜0.137
9e ＞100 90 ＞100 0.913
9f 147 183 36.6 ＜0.686
9f Repeat the test ＞100 ＞100 66.6 0.301
9g 24.2 0.437 0.297 0.187
9g Repeat the test 25.1 1.03 1.63 0.164
9h 7.94 13 ＜0.137 ＜0.137
9i 12.7 0.289 6.77 ＜0.137
9i Repeat the test 12.5 0.858 6.25 0.168
9j 11.4 35.9 5.46 2.95
9j Repeat the test 14 34.4 4.43 1.18
9k 0.603 ＜0.137 ＜0.137 ＜0.137
9k Repeat the test 2.17 0.0113 ＜0.0457 0.0107
9l 3.05 ＜0.137 0.15 ＜0.137
9l Repeat the test 2.38 0.0076 ＜0.137 0.0052
9m 24.1 0.322 0.453 ＜0.137
9n 0.425 ＜0.137 ＜0.137 ＜0.137
9o 9.67 ＜0.137 4.67 ＜0.137
9o Repeat the test 12.1 0.0098 5.18 0.0077
9p 1.51 ＜0.137 0.519 ＞100
9q 99.9 ＞100 50.6 20
9r 80.8 74.3 33.7 5.4
9s 5.85 0.0137 0.912 ＜0.137
9s Repeat the test 5.72 ＜0.137
9t 5.5 3.03 1.54 0.388
9u 5.52 1.96 2.07 0.269
9w ＞100 ＞100 ＞100 ＞100
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
9x 5.59 0.0071 0.476 0.0057
9x Repeat the test 10.3 ＜0.137 3.34 ＜0.137
9y 4.69 11.3 0.477 ＜0.137
9z 27.4 30.5 8.73 ＜0.137
9aa ＞100 ＞100 51 46.9
9bb 37.4 35.9 13.1 ＜0.137
10 ＜0.137 ＜0.137 ＜0.137 ＜0.137
10 Repeat the test ＜0.137 0.0798 ＜0.137 0.0821
11 ＞100 ＞100 48.7 ＞100
12 ＞100 ＞100 ＞100 ＞100
13 4.18 ＜0.137 ＜0.137 ＜0.137
13 Repeat the test 2.79 0.132 ＜0.0457 0.0374
14a ＜0.137 ＜0.137 ＜0.137 ＜0.137
14b ＜0.137 ＜0.137 ＜0.137 ＜0.137
16 ＞100 ＞100 ＞100 3.13
17a 0.497 2.66 ＜0.137 0.996
17a Repeat the test 18.7 10.8 1.3 ＞11.1
17b ＞100 ＞100 43.6 0.973
17b Repeat the test 455 ＞500 127 28.8
17c 3.58 ＞100 ＜0.137 41.5
17c Repeat the test 0.623 176 0.271 98.5
17d 0.365 ＞100 ＜0.137 44
17d Repeat the test ＜0.137 127 ＜0.137 63.2
17e ＜0.137 5.44 ＜0.137 3.58
17e Repeat the test ＜0.137 3.88 ＜0.137 3.91
17f 11.1 ＞100 ＜0.137 67.6
17f Repeat the test 11.8 172 ＜0.137 84
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
17g 0.5 5.35 ＜0.137 2.93
17g Repeat the test 0.392 6.87 0.252 1.52
17h ＞100 ＞100 62.1 13.1
17i 81.1 0.154 0.455 0.171
17i Repeat the test 36.4 0.151 ＜0.686 0.0907
18a ＜0.137 1.13 ＜0.137 0.824
18a Repeat the test ＜0.137 0.562 ＜0.137 0.548
19 82.1 1.04 0.163 0.76
19 Repeat the test 34.7 0.442 ＜0.137 0.485
20a ＜0.137 0.373 ＜0.137 ＜0.137
20a Repeat the test ＜0.137 ＞1.20 ＜0.137 ＞1.20
21a 10.5 ＜0.137 ＜0.137 ＜0.137
21a Repeat the test 3.57 0.189 ＜0.137 ＜0.137
21b 2.46 0.157 ＜0.137 ＜0.137
21b Repeat the test 1.05 0.0278 ＜0.137 0.0162
21c 19.2 ＜0.137 ＜0.137 ＜0.137
21c Repeat the test 9.68 0.127 ＜0.137 0.246
21d 0.182 0.694 ＜0.137 0.5
21e 6.52 ＜0.137 ＜0.137 ＜0.137
21e Repeat the test 3.06 0.0846 0.363 0.131
21f ＜0.137 1.03 ＜0.137 0.433
21f Repeat the test 0.0312 0.435 0.0378 0.526
21g 24.4 0.15 0.257 ＜0.137
21g Repeat the test 21.6 0.16 1.6 0.132
21g Repeat the test 9.14 0.0527 1.13 0.0417
21g Repeat the test 10.7 ＜0.137 ＜0.137 ＜0.137
21h ＞100 0.738 70.5 0.253
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
21h Repeat the test 217 0.399 126 0.288
21i 20.5 ＜0.137 5.67 ＜0.137
21i Repeat the test 13.6 0.0723 8.64 0.0432
21j 40.4 67.5 17.1 0.206
21k 23.4 ＜0.137 0.6 ＜0.137
21k Repeat the test 27 0.0602 3.37 0.0669
21k Repeat the test 9.26 ＜0.137 0.528 ＜0.137
21k Repeat the test 11 ＜o.137 0.484 ＜0.137
21l ＞100 0.921 1.58 0.779
21l Repeat the test 115 0.756 6.8 0.656
21l Repeat the test 49.6 0.895 2.61 1.57
21n ＜0.137 ＜0.137 ＜0.137 ＜0.137
21o 54.8 0.357 18.8 0.367
21o Repeat the test 68.2 0.435 22.8
21p 39.2 6.05 1.67
21q 5.71 0.208 0.204 0.327
21r 83.8 4.99 30.1 0.42
21s ＞100 0.236 42.8 0.159
21s Repeat the test 119 0.176 58.3 0.152
21t 32.3 ＜0.137 ＜0.137 ＜0.137
21t Repeat the test 7.18 ＜0.137 ＜0.137 ＜0.137
21t Repeat the test 6.42 0.0548 0.194 0.0412
21t Repeat the test 8.06 ＜0.150 ＜0.150 ＜0.150
21t Repeat the test 18.4 ＜0.137 0.226 ＜0.137
21u ＞100 24.2 4.49 3.03
21u Repeat the test ＞100 1.1 0.735 0.854
21u Repeat the test ＞100 ＞100 3.44 ＞100
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
22 ＞1.00 ＞1.00 ＞1.00 0.477
22 Repeat the test 25.6 4 4.31 2.81
22 Repeat the test 12.4 3.06
23a ＞100 ＞100 ＞100 23.5
23a Heavy loadRepeat test ＞500 ＞500 ＞500 111
23b 159 430 33.7 ＜0.686
23b Repeat the test ＞100 ＞100 40.1 0.273
23c 48.4 ＞100 18 ＜0.137
23c Repeat the test 62.6 181 14.6 ＜0.686
23d ＞500 10.5 13.6 1.85
23d Repeat the test ＞100 42.5 63.4 1.23
23d Repeat the test ＞500 53.9 25.5 3.64
23e 0.471 0.526 0.123 0.336
23e Repeat the test ＜0.132 0.419 ＜0.132 0.457
23f ＞100 ＞100 ＞100 16.9
23f Repeat the test ＞500 ＞500 395 199
24a ＞500 ＞100 ＞500 2.95
24a Repeat the test ＞100 60.2 ＞100 2.45
24b ＞100 6.44 ＞100 0.39
24b Repeat the test ＞500 ＞33.3 ＞500 16.3
25a ＞500 ＞500 311 ＞500
25a Repeat the test ＞500 ＞100 292 ＞100
25a Repeat the test ＞100 ＞33.3 ＞100 ＞33.3
25b Repeat the test ＜0.686 3.36 ＜0.686 3.55
25b Repeat the test ＜0.137 3.47 ＜0.137 2.98
25b Repeat the test 0.14 8.41 0.117 1.83
25d ＞100 14.8 ＞100 10.7
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
25d Repeat the test ＞500 ＞33.3 435 6.8
25d Repeat the test ＞500 ＞33.3 417 6.39
25e ＞100 ＞100 ＞100 ＞100
25f ＞100 ＞100 ＞100 3.05
25g ＞100 ＞100 13.5 ＜0.137
25g Repeat the test 80.7 139 ＜0.686 ＜0.686
25h ＞100 2.01 4.15 0.483
25h Repeat the test 72.3 7.43 ＜0.686 0.263
26 ＞100 1.64 6.94 1.39
27 ＞100 ＜0.137 73.8 ＜0.137
27 Repeat the test 198 0.0864 58.9 0.0916
28a 43.6 99.8 49 ＜0.137
28a Repeat the test 41.3 188 36.7 ＜0.686
28b 41.7 ＞100 28.3 0.34
28c28d ＞100 19.7 42.4 ＜0.686
29 ＞100 0.143 60.2 0.119
29 Repeat the test 217 0.113 115 0.228
30 193 0.0726 62.2 0.0578
30 Repeat the test ＞100 ＜0.137 40.5 ＜0.137
31 ＞100 0.7 ＞100 1.55
31 Repeat the test ＞500 ＞33.3 ＞500 ＞33.3
32a ＞100 ＜0.137
32a Repeat the test 185 0.336
32a Repeat the test 204 0.397
32a Repeat the test 165 0.191
32a Repeat the test 128 0.221
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
32b ＞100 0.289 2.12 0.265
32c ＞100 ＞100 ＞100 ＞100
33 8.28 0.301 ＜0.137 0.424
33 Repeat the test 6.09 0.435 ＜0.137 0.513
33 Repeat the test 43.4 0.213 ＜0.686 ＜0.137
33 Repeat the test 18.5 0.131 ＜0.137 0.0993
34a 45.3 ＜0.137 0.144 0.737
34a Repeat the test 67.1 0.628 ＜0.137 ＜0.137
34a Repeat the test 4.1 0.168 0.0406 0.316
34a Repeat the test 76.7 0.27 0.265 0.326
34a Repeat the test 23.4 0.536 ＜0.137 0.407
34b 57.9 0.145 0.172 ＜0.137
34b Repeat the test 35.5 0.0929 ＜0.137 0.0913
34c ＞100 ＞100 ＞100 ＞100
34d 55.4 0.29 ＜0.137 1.4
34d Repeat the test ＞100 1.15 ＜0.137 ＜0.137
34d Repeat the test 4.42 0.78 0.125 0.453
34d Repeat the test 41.1 2.89 ＜0.137 2.05
34d Repeat the test 87.8 0.56 ＜0.137 0.736
34d Repeat the test ＜0.137 0.49
35 2.87 78 ＜0.137 ＜0.686
36 78.5 ＜0.137 ＜0.137 ＜0.137
36 Repeat the test 52.3 0.231 0.405 0.133
37a 69.4 71.3 38.6 37
37b ＞100 ＞100 66.3 53.1
38a ＜0.137 ＜0.137 ＜0.137 ＜0.137
38b ＞100 ＞100 15.2 0.591
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
38c ＜0.137 ＜0.137 ＜0.137 ＜0.137
39b 3.93 34 0.408 18.6
41 14.6 ＜0.137 4.46 ＜0.137
41 Repeat the test 12.9 0.0143 0.931 0.0121
42a 28.7 ＜0.137 6.58 ＜0.137
42a Repeat the test 25.2 0.0562 18.3 0.0183
42a Repeat the test 14.7 0.0398 6.76 0.031
42b ＞100 ＞100 47.4 0.634
42c ＞100 12.3 18.5 6.84
42d 58.3 1.92 8.64 1.86
44 0.185 0.314 0.0768 0.308
44 Repeat the test 0.12 0.11 0.0599 0.0704
44 Repeat the test ＜0.137 ＜0.137 ＜0.137 0.158
46 ＞100 2.42 14.7 1.25
47 ＞100 15.7 37.4 1.4
47 Repeat the test ＞500 1.54
48 42.7 ＞100 22.7 ＞100
100 30.2 ＜0.137 ＜0.137 ＜0.137
100 Repeat the test 29.4 0.135 ＜0.137 0.127
101 ＞100 1.17 10.7 1.21
101 Repeat the test 430 1.32 42.3 0.831
101 Repeat the test ＞100 2.29 24.4 2.26
101 Repeat the test ＞500 1.72 81 1.17
102 42.4 0.0608 4.67 0.0657
102 Repeat the test 32.7 ＜0.137 0.842 ＜0.137
102 Repeat the test 28 0.0897 0.389 0.0589
102 Repeat the test 24.6 ＜0.137 0.621 ＜0.137
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
102 Repeat the test 38.2 ＜0.137 4.37 ＜0.137
102 Repeat the test 31.4 ＜0.137 3.21 ＜0.137
103 33 0.172 ＜0.137 0.231
103 Repeat the test 39.9 0.0898 ＜0.137 0.129
104 6.75 0.156 ＜0.137 0.189
104 Repeat the test 12.1 0.125 ＜0.137 0.201
105 3.32 0.261 ＜0.137 ＜0.137
105 Repeat the test 2 0.177 ＜0.137 0.129
106 ＞100 39.6 4.65 ＜0.137
106 Repeat the test 93 ＞100 18 0.813
107 8.85 0.206 ＜0.137 0.162
107 Repeat the test ＜0.137 0.479 ＜0.137 0.142
108 ＞100 4.46 21.5 ＜0.137
108 Repeat the test 169 4.06 87 0.349
109 0.413 ＜0.137 ＜0.137 ＜0.137
109 Repeat the test ＜0.137 7.97 ＜0.137 1.07
110 16.1 0.238 0.554 ＜0.137
110 Repeat the test 13.1 ＜0.137 0.153
111 9.16 0.188 ＜0.137 ＜0.137
111 Repeat the test 9.17 ＜0.137 ＜0.137
112 ＞100 ＞100 ＞100 4.03
113 ＞100 ＞100 50.8 19.4
114 63.9 62.5 12.6 14
115 ＞100 ＞100 ＞100 ＞100
116 ＞100 18.9 90.9 3.13
117 77 26.5 1.45 12
117 Repeat the test 26.8 27.8 1.97 2.46
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
118 ＞100 5.48 5.4 4.05
119 ＞100 0.827 ＞100 0.792
119 Repeat the test ＞500 0.902 365 0.0886
120 ＞100 35 69.5 42.1
121 ＞100 ＞100 ＞100 ＞100
122 ＞100 ＞100 ＞100 ＞100
125 25.3 ＜0.137 3.87 ＜0.137
125 Repeat the test 19.3 0.0357 5.1 0.0201
127 ＞100 19.9 ＞100 8.41
127 Repeat the test ＞100 9.52 ＞500
127 Repeat the test ＞500 40.6
128 44.8 ＞100 11.5 11.4
129 ＞100 17.9 83.6 20
130 3.7 5.99 2.43 5.19
131 ＜0.137 ＜0.137 ＜0.137 ＜0.137
131 Repeat the test 0.99 0.0466 ＜0.137 0.0901
132 ＞100 74.3 89.6 53.1
132 Repeat the test ＞100 60.5 ＞100 27.2
133 ＜0.137 ＞100 ＜0.137 3.4
133 Repeat the test 0.0654 4.7 0.0697 3.77
134 4.36 3.35 0.804 3.11
135 ＞100 ＞100 ＞100 ＞100
136 44.4 0.176 8.04 ＜0.137
136 Repeat the test 39.8 0.272 6.88 0.121
137 ＞100 ＞100 ＞100 ＜0.137
137 Repeat the test ＞500 ＞500 ＞500 24.4
138 23.8 0.0872 0.531 0.0692
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
139 36.6 0.324 0.291 0.279
140 ＞500 ＞500 ＞500 343
140 Repeat the test ＞100 ＞100 ＞100 91.4
141 2.96 ＜0.137 ＜0.137 ＜0.137
141 Repeat the test 2.76 0.0957 ＜0.137 0.0881
142 18.6 5.64 0.226 0.39
143 1.23 1.51 ＜0.137 1.41
144 ＞100 0.679 63.7 0.584
144 Repeat the test 175 0.502 24.1 0.394
147 ＞100 ＞100 37.5 4.1
148 ＜0.137 ＜0.137 ＜0.137 ＜0.137
148 Repeat the test ＜0.137 0.13 ＜0.137 0.108
149 ＞100 0.331 ＞100 ＜0.137
149 Repeat the test ＞500 ＞3.70 ＞500 1.63
149 Repeat the test ＞100 3.75 ＞100 1.95
150 6.21 0.268 ＜0.137 0.236
150 Repeat the test 13.6 0.551 ＜0.137 0.321
151 18.6 ＜0.137 ＜0.137 ＜0.137
151 Repeat the test 12.7 0.0464 ＜0.686 0.0457
152 ＞100 ＞100 71.7 ＞100
153 66.8 85.3 0.429 ＞100
154 ＞100 0.262 ＞100 0.263
154 Repeat the test 287 0.347 144 0.377
155 9.22 18 0.178 3.02
156 ＜0.137 48.7 0.289 9.36
157 ＞100 3.07 ＞100 1.95
158 ＞100 10.5 ＞100 5.85
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
158 Repeat the test ＞500 5.71 ＞500 4.11
159 ＞100 ＞100 ＞100 15.5
160 ＞100 4.31 39.2 4.93
161 ＞100 ＞100 ＞100 3.07
162-a ＞100 6.58 ＞100 3.16
162-b ＞100 ＞100 ＞100 ＞100
163a ＞100 ＞100 ＞100 69.7
163b ＞100 83.1 ＞100 1.61
164 43.9 ＞100 23.6 11
165 ＞100 ＞100 55.6 0.262
166 27.9 5.89 2.45 3.85
167a 13.5 4.96 0.982 4.17
167b ＞100 ＞100 ＞100 ＞100
168a ＞100 3.97 ＞100 0.773
168b ＞100 ＞100 ＞100 6.68
169 ＞100 ＞100 ＞100 2.25
170 7.64 0.0145 0.184 0.0197
170 Repeat the test 8.8 ＜0.137 0.311 ＜0.137
170 Repeat the test 4.03 ＜0.137 ＜0.137 ＜0.137
170 Repeat the test 3.49 0.0069 ＜0.137 0.006
171 ＞100 21.6 ＞100 4.72
172 95.6 0.168 1.52 0.168
172 Repeat the test 78.4 0.165 3.58 0.161
173 5.93 1.42 0.171 0.616
173 Repeat the test 17.5 0.973 ＜0.137
174 29.2 3.58 2.72 0.702
175 ＞100 ＞100 ＞100 38.8
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
201 ＜0.137 ＜0.137 ＜0.137
201 Repeat the test 0.0398 ＜0.0152 0.0402
202 0.577 0.293 0.333
202 Repeat the test 0.627 0.297 0.54
203 2.31 13.1 1.74
203 Repeat the test 2.61 20.3 2.14
204 ＞100 3.84 22.3
204 Repeat the test ＞100 30.7 ＞100
205 ＞100 28.6 32.2
205 Repeat the test ＞100 36.3 60.4
206 16.9 0.821 3.7
206 Repeat the test 15.4 1.37 12.2
207 6.49 18.5 7.47
207 Repeat the test 14.3 16.2 7.47
208 3.89 0.242 3.48
208 Repeat the test 2.47 0.381 2.86
209 3.73 10.3 3.12
209 Repeat the test 2.14 5.55 2.03
203 92.8 2.31 13.1 1.74
203 Repeat the test ＞100 2.61 20.3 2.14
210 ＞100 14.4 9.93 2.8
211 ＞100 14.8 ＞100 19.2
212 4.36 0.377 0.292 0.382
213 ＞100 2.3 3.97 1.76
213 Repeat the test 453 2.09 1.39 1.49
214 17 3.59 ＜0.137 0.411
214 Repeat the test 18 2.14 ＜0.137 0.18
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
215 61.4 3.12 1.92 1.11
215 Repeat the test 41.1 0.982 0.925 0.205
216 ＞100 ＞100 9.59 ＞100
217 33.2 13 22.6 9.28
218 ＞100 5.47 4.38 4.9
218 Repeat the test 480 3.55 3.65 1.5
219 3.77 5.45 2.88 5.99
219 Repeat the test 3.03 ＞11.1 3.7 ＞11.1
220 2.18 3.87 0.823 2.6
220 Repeat the test 0.366 ＞11.1 2.11 4.49
221 51.8 29.7 ＜0.137 0.998
221 Repeat the test 17 ＞33.3 ＜0.137 2.42
222 32.7 0.64 ＜0.137 0.608
222 Repeat the test 2.67 0.322 ＜0.137 0.48
223 9.67 ＞100 3.01 52.9
224 9.28 3.24 1.39 2.28
225 2.43 2.15 0.266 2.44
226 23.7 23 4.68 16.3
227 10.9 ＞100 4.73 37.3
228 28.5 65.8 10.7 23.4
229 0.626 2.43 12.1
230 4.58 3.1 23.5
231 22.4 7.9 23.3
232 27 7.47 24.2
233 17.3 2.53 8.82
234 0.213 3.19 0.21 2.03
235 74.7 19.8 2.09 7.52
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
236 2.39 5.15 ＜0.137 2.15
237 7.16 2.68 0.649 1.23
238 52 ＞100 3.2 ＞100
239 17 4.7 6.5 3.11
240 4.18 ＞100 1.82 31.6
241 1.25 11.8 0.879 10.4
242 3.25 ＞100 2.51 21.7
243 9.97 0.764 0.288 0.675
244 1.06 3.19 0.15 3.69
245 72.3 38.4 19.8 31.8
246 7.19 ＞100 0.159 ＞100
247 ＞11.1 ＞3.70 ＞11.1 ＞3.70
247 Repeat the test ＜0.137 ＜0.137 ＜0.137 ＜0.137
247 Repeat the test 1.83 0.393 ＜0.137 0.893
248 27.4 73.6 7.18 3.86
248 Repeat the test 10.7 43.1 4.04 2.64
249 5.19 ＞11.1 1.68 1.24
249 Repeat the test 7.19 63 1.23
250 36.3 0.164 ＜0.137 0.158
250 Repeat the test 39.4 0.176 0.146 ＜0.137
251 16.4 0.577 0.683 0.497
251 Repeat the test 17.6 1.74 0.947 0.927
252 ＜0.137 1.15 ＜0.137 1.17
253 ＞100 31.5 10.8 25.9
254 ＞100 6.61 88.4 5.67
254 Repeat the test ＞500 ＞11.1 194 5.03
255 39.9 68.9 1.72 12.2
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
256 7.57 0.793 0.19 0.534
256 Repeat the test 3.03 1.27 0.206
257 ＞100 ＞100 ＞100 41.3
258 0.282 0.38 ＜0.137 0.476
259 0.289 32.8 0.187 5.97
260 ＞100 ＞100 ＞100 17.2
261 ＞100 ＞100 ＞100 63.2
262 26.2 38.2 1.52 0.178
263 5.02 3.7 1.39 4.59
264 173 2.32 2.48 1.84
265 169 27.5 164 13.5
266 18.2 30 58.5 23.2
267 28.2 36.2 ＜0.137 36.5
268 2.9 2.81 1.21 1.84
269 40.1 66.1 15.4 1.67
270 7.03 47.4 3.36 38.5
271 38.1 ＞100 31 ＞100
272 5.08 1.17 ＜0.137 0.813
273 ＞100 25.6 ＞100 33
274 ＞100 1.13 1.71 0.301
274 Repeat the test 209 1.82 4.49 1
275 ＞500 ＞100 ＞500 ＞100
275 Repeat the test ＞100 95.9 32.7 93.3
276 ＞100 0.548 ＞100 ＞100
276 Repeat the test ＞500 ＞3.70 366 0.242
277 51.6 0.178 13.1 34.9
277 Repeat the test 53.9 3.66 24.7 0.0623
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
278 34.8 4.48 6.86 31.4
279 12 0.723 9.95 0.586
280 ＞100 92.7 63.4 16.7
281 ＞100 ＞100 85 12.6
282 ＞100 ＞100 83.1 ＞100
283 30.3 6.95 5.25 4.04
284 42.6 4.22 8.27 3.41
285 52.2 ＜0.137 12.5 ＜0.137
285 Repeat the test 60.6 0.163 18.6 0.0438
286 28.6 17.5 13.7 0.293
287 26.3 28.3 12.2 5
288 ＞100 5.81 67.2 6.53
289 ＞100 0.858 19.9 0.964
289 Repeat the test ＞500 2.26 198 0.88
290 ＜0.137 0.209 ＜0.137 ＜0.137
290 Repeat the test 0.407 0.55 0.448 0.288
291 168 0.341 1.78 0.276
291 Repeat the test ＞100 0.422 1.02 0.342
292 36.8 ＜0.137 13.4 ＜0.137
292 Repeat the test 36.7 0.0902 19.4 0.0531
293 48.8 0.0586 1.32 0.0488
293 Repeat the test 53.7 ＜0.137 17.2 ＜0.137
294
295
296
297
298 0.737 ＞100 ＜0.137 ＞100
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
299 46.2 ＜0.137 50.4 ＜0.137
299 Repeat the test 42.7 0.392 36 0.148
300 23.5 0.223 21 ＜0.137
300 Repeat the test 39 ＞3.70 20.2 ＞3.70
301 30.9 ＞100 30.6 ＞100
302 79 ＞100 19.9 ＞100
303 ＞100 17.7 57.7 0.52
304 ＞100 29.1 36.8 2.76
305 ＞100 53 42.6 0.494
306 4.59 0.16 ＜0.137 ＜0.137
306 Repeat the test 4.11 0.0658 ＜0.0457 0.0616
307 60.3 ＞100 32.8 40.6
308 33.8 0.623 1.43 0.586
308 Repeat the test 0.271 0.289
309 32.1 0.497 0.513 0.504
309 Repeat the test 0.254 0.249
310 69.1 94.7 43.9 30.6
310 Repeat the test 72.6 85.4 35.8 36.7
311 ＞100 3.07 ＞100 2.33
312 411 1.75 59.6 0.991
312 Repeat the test ＞100 1.11 53.2 0.781
313 123 56 32.5 9.88
313 Repeat the test ＞100 57.8 23.6 8.64
314 11.3 40.6 6.15
315 15 1.29 0.22 0.484
316 40.4 45.6 15.5 27.9
316 Repeat the test 27 69.8 24.4 23.1
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
317 1.18 10.3 0.676 6.05
318 94.1 26 16.1 9.16
319 88.7 0.292 20.7 0.21
319 Repeat the test 63 0.192 39.7 0.161
320 ＞100 71.3 27.7 5.34
321 0.196 0.576 0.31 0.752
322 ＞100 4.73 53.9 3.47
323 110 0.333 47.6 0.87
323 Repeat the test 97.9 0.359 47.4 0.174
324 ＞100 ＞100 81 58.6
325 92.7 ＞100 64.4 65.9
326 84.5 83.8 38 48.5
327 39.8 0.943 29.5 0.307
327 Repeat the test 56.2 0.675 19.8 0.426
328 ＞100 ＞100 82.1 4.93
329 ＞100 1.25 65.9 0.232
330 22.7 39.4 14.6 8.77
331 25.2 10.3 16.6 1.15
332 ＞100 40.2 61
333 51.4 0.668 0.224 0.704
333 Repeat the test 37.3 1.28 0.653 1.2
334 17 ＜0.137 3.94 ＜0.137
334 Repeat the test 18.4 0.0784 3.07 0.0707
335 24.8 ＜0.137 6.02 ＜0.137
335 Repeat the test 24.7 0.0659 4.89 0.0525
336 11.4 1.08 8.62 1.1
337 ＞100 1.5 46.2 1.3
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
338 ＞100 10.6 56.4 ＜0.137
339 ＞100 19.4 36.7 21.7
340 2.44 6.38 0.557 6.32
341 26.6 ＞100 23.6 ＞100
342 2.91 3.48 0.755 3.07
343 ＞100 68.1 13.4 2.27
344 0.423 2.24 0.281 0.974
345 ＞100 31.8 ＞100 1.8
346 73.8 0.269 55.2 0.144
346 Repeat the test 69.2 0.0481 33.2 0.0661
347 ＞100 ＞100 91.9 ＞100
348 ＞100 ＞100 ＞100 ＞100
349 ＞100 96.6 ＞100 1.38
350 ＞100 ＞100 ＞100 28.2
351 ＞100 ＞100 ＞100 23
352 46 ＜0.137 2.6 0.142
352 Repeat the test 31.7 0.0833 2.78 0.129
353 ＞100 11 ＞100 11.3
354 ＞100 ＞100 ＞100 12
355 13.6 0.164 ＜0.137 0.19
355 Repeat the test 9.02 ＜0.137 ＜0.137 0.158
356 ＞100 0.526 ＞100 0.356
356 Repeat the test 221 0.152 60 0.216
357 26.5 13.4 21.5 0.606
358 ＞100 40.1 57 46.6
359 ＞100 ＞100 ＞100 ＞100
360 ＞100 14.9 20.3 17.7
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
361 23.6 24.9 22.4 11.3
362 ＞100 ＞100 ＞100 2.35
363 1.39 1.82 0.498 1.73
364 3.09 0.363 0.151 0.343
365 ＞100 1.09 ＞100 0.809
366 11.6 2.75 10.5 2.28
367 1.84 0.468 0.229 0.466
368 ＞100 25.3 64.8 0.476
369 15.9 6 5.86 8.89
370 9.01 0.151 1.75 ＜0.137
370 Repeat the test 23.4 3.64 12.2 0.221
371 35 68.8
372 2.49 ＜0.0457 ＜0.137 ＜0.0457
373 0.647 ＜0.0152 ＜0.137 ＜0.0152
374 4.17 0.454 1.21 0.0185
375 23.7 9.05 2.71 0.372
376 17.8 5.11 7.29 ＜0.0457
377 14.5 19.4 3.68 ＜0.137
378 ＜0.137 0.055 ＜0.137 0.0346
379 ＜0.0457 0.0664 ＜0.0457 0.0456
380 188 59.9 72 3.7
381 3.46 2.09
382 33.6 27.5 13 4.62
382 Repeat the test 20.2 22.5
383 18 16.8
384 14 0.475 2.27 0.199
385 30.6 10.2
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
386 11.2 6.85
387 32.7 19
388 ＜0.137 0.0119 ＜0.137 ＜0.00510
388 Repeat the test 0.351 0.03 ＜0.0152 0.0284
389 28.1 9.88
390 32.9 24.8 14 4.53
390 Repeat the test 33.4 32
391 2.58 ＜0.137 ＜0.137 ＜0.137
391 Repeat the test 1.31 0.0454 ＜0.0457 0.0331
392 1.22 ＜0.137 ＜0.137 ＜0.137
392 Repeat the test 0.382 0.0285 ＜0.0457 0.0122
393 92.8 28.4 18 0.727
394 11.5 0.17 ＜0.137 ＜0.137
394 Repeat the test 3.91 0.191 0.0551 0.108
394 Repeat the test 13.3 0.133 ＜0.137 0.118
394 Repeat the test 7.07 0.156 ＜0.137 ＜0.137
395 82.3 0.292 30.8 ＜0.137
395 Repeat the test 63.2 0.103 26.6 0.0132
395 Repeat the test ＞100 0.673 23.5 ＜0.137
396 ＞100 ＞100 55.8 2.47
397 2.84 1.69 ＜0.137 1.05
398 55.6 38.7 28 11.5
399 23.8 3.32 7.46 ＜0.137
400 0.527 ＜0.137 ＜0.137 ＜0.137
400 Repeat the test ＜0.0457 0.125 ＜0.0457 0.0636
401 ＜0.137 ＜0.137 ＜0.137 ＜0.137
401 Repeat the test ＜0.0457 0.061 ＜0.0457 0.0668
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
402 ＞100 ＞100 ＞100 6.58
403 ＞100 ＞100 ＞100 13.2
404 0.586 ＜0.137 ＜0.137 ＜0.137
404 Repeat the test 0.167 0.0453 ＜0.0457 0.0493
405 37.2 73.6 15.3 61.1
406 17.3 9.76 5.43 8.96
407 20 17.9 11 14.4
408 17.6 21.5 8.39 16.8
409 ＜0.137 ＜0.137 ＜0.137 ＜0.137
410 39.4 61.8 49.2 29
411 ＜0.137 ＜0.137 ＜0.137 ＜0.137
411 Repeat the test ＜0.0457 0.0546 ＜0.0457 0.0551
412 12.6 8.7 3.34 0.169
413 17.3 10 2.42 ＜0.137
414 8.3 9.25 3.34 0.632
415 0.586 ＜0.137 ＜0.137 ＜0.137
416 ＞100 29.5 ＜0.137 0.353
417 ＞100 52.6 7.68 14.5
418 59 13 4.99 ＜0.137
419 20.3 2.06 4.64 0.227
420 0.326 0.89 ＞100 ＜0.137
421 25 0.157 ＞100 ＜0.137
421 Repeat the test 24.5 0.268 12.1 0.0936
422 34 0.146 18.4 ＜0.137
423 6.97 0.362 ＜0.137 0.16
424 ＞100 33.6 ＞100 1.23
425 ＞100 94.4 71.2 4.2
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
426 35.7 19.6 17.8 1.17
427 26.9 17.2 13 2.34
428 26.3 4.88 6.8 0.545
428 Repeat the test 25.8 5.98 8.1 0.702
429 44.9 37.1 47.9 20.2
430 99.9 58.9 31.6 0.385
431 13.6 49.6 0.245 14.7
432 47.4 0.195 9.5 ＜0.137
432 Repeat the test 53.4 0.338 14.3 0.0919
433 ＜0.137 ＜0.137 ＜0.137 ＜0.137
434 46.4 39.8 15 7.87
435 38.4 33.6 17.2 5.57
436 36.8 23.3 19.9 4.08
437 ＜0.137 ＜0.137 ＜0.137 ＜0.137
438 13.3 ＜0.137 0.139 ＜0.137
439 Repeat the test 18.7 0.0321 1.09 0.0285
439 ＞100 88.3 39.6 15.2
440 55.1 16.4 9.98 ＜0.137
441 23 ＜0.137 3.61 ＜0.137
441 Repeat the test 18.6 0.04 4.41 0.0105
441 Repeat the test 16.2 0.0172 3.17 0.0081
441 Repeat the test 15.8 ＜0.137 5.22 ＜0.137
441 Repeat the test 18.6 0.0081 4.57 0.0054
441 Repeat the test 15.1 ＜0.137 4.21 ＜0.137
441 Repeat the test 21.1 0.0101 4.85 0.0091
442 20.4 5.04 3.33 ＜0.137
442 Repeat the test 15.3 10.8 6.16 0.105
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
443 0.727 ＜0.137 ＜0.137 ＜0.137
444 26.1 ＜0.137 7.64 ＜0.137
244 Repeat the test 20.6 0.0403 3.94 0.0629
445 7.32 ＜0.137 1.55 ＜0.137
446 19.1 44.9 11.3 15.6
447 21.8 4.49 12.3 0.22
448 ＞100 ＞100 55 ＞100
449 2.1 ＜0.137 ＜0.137 ＜0.137
450 1.21 ＜0.137 ＜0.137 ＜0.137
451 25.3 8.38 3.37 0.623
452 0.731 ＜0.137 ＜0.137 ＜0.137
453 0.152 ＜0.137 ＜0.137 ＜0.137
453 Repeat the test 0.645 ＜0.137 ＜0.137 ＜0.137
454 10.1 0.321 2.5 ＜0.137
454 Repeat the test 13.3 0.0985 2.95 0.148
455 19.4 8.9 11.5 3.16
456 ＞100 ＞100 12.6 1.64
457 15.1 19.3 10.9 8.4
458 72.3 3.24 28.7 0.23
459 31.2 25.2 12.2 1.55
460 46.7 0.588 1.96 0.576
461 ＞100 ＞100 ＞100 0.974
462 16.6 37.6 20.9 10.1
463 12.9 17.4 17.7 3.79
464 22.2 3.78 33.8 0.254
465 ＞100 18.7 ＞100 9.9
466 3.59 0.0049 0.0857 0.0077
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
466 Repeat the test 1.72 ＜0.137 ＜0.137 ＜0.137
467 ＞100 ＞100 ＞100 2.33
468 46.6 0.33 ＜0.686 0.261
468 Repeat the test 64.3 1.58 1.44 0.561
468 Repeat the test ＞500 1.42 1.67 0.431
469 5.81 1.02 0.602 0.915
470 8.55 17.8 1.33 1.11
471 295 21.8 117 4.16
471 Repeat the test ＞100 29.1 85.3 3.48
472 3.08 0.0124 0.306 0.0127
472 Repeat the test 5.85 ＜0.137 1.14 ＜0.137
473 ＜0.137 ＜0.137 ＜0.137 ＜0.137
474 1.24 ＜0.137 ＜0.137 ＜0.137
474 Repeat the test 1.51 0.005 0.0263 0.005
475 1.02 ＜0.137 ＜0.137 ＜0.137
475 Repeat the test 1.22 0.0085 ＜0.0152 0.007
475 Repeat the test 3.62 ＞1.24 ＜0.0152 0.0275
476 14.9 27.2 10.8 6.03
477 9.58 ＜0.137 1.9 ＜0.137
477 Repeat the test 7.93 0.0149 0.599 0.0166
478 6.71 ＜0.137 1.05 ＜0.137
478 Repeat the test 9.07 0.0089 2.39 0.009
479 25.6 0.106 8.22 ＜0.0931
479 Repeat the test 19.5 0.207 4.73 0.0268
479 Repeat the test ＞22.6 ＞2.52 7.79
480 0.652 ＜0.137 ＜0.137 ＜0.137
481 0.392 ＜0.137 ＜0.137 ＜0.137
Example numbering Repeat the test hCox-1IC5o(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modifiedIC50 type (uM)
482 10.3 ＜0.137 1.82 ＜0.137
482 Repeat the test 11.7 0.0955 2.69 0.0102
483 89.4 ＜0.137 19.5 ＜0.137
483 Heavy loadRepeat test 74.6 0.0854 33.3 0.0666
484 9.52 ＞100 6.14
485 ＞100 8.84 ＞100 10.1
486 ＞100 21 ＞100 23.5
487 ＞100 ＞100 ＞100 ＞100
488 ＞100 9 97.5 10.2
489 ＞100 9.4 ＞100 9.43
490 ＞100 8.79 87.2 7.99
491 ＞100 8.83 ＞100 8.3
492 ＞100 ＞100 ＞100 98.8
493 ＞100 8.22 ＞100 6
494 22.1 41.1 13 96.9
495 ＞100 23 ＞100 18
496 99 45.1 ＞100 32.1
497 ＞100 15.3 ＞100 12.5
498 ＞100 15.1 44 11.8
499 ＞100 9.62 36.8 7.35
500 ＞100 ＞100 ＞100 ＞100
501 ＞100 ＞100 79 ＞100
502 ＞100 ＞100 42.4 ＞100
503 ＞100 ＞100 ＞100 ＞100
504 ＞100 ＞100 ＞100 ＞100
505 4.08 55.1 2.47
506 12 58.2 9.3
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
507 ＞100 13.5 ＞100 8.2
508 ＞100 1.26 ＞100 0.835
508 Repeat the test ＞500 1.25 ＞500 1.03
509 ＞100 0.153 ＞100 0.603
509 Repeat the test ＞500 1.25 166 1.48
510 ＞100 1.87 ＞100 0.752
510 Repeat the test ＞500 ＞500
511 ＞100 19.5 ＞100 7.22
512 ＞100 ＞100 ＞100 11.7
513 ＞100 59 ＞100 26.6
514 ＞100 ＞100 ＞100 32.3
515 ＞100 11.2 6.82 4.46
516 ＞100 18.4 17.9 20.6
516 Repeat the test 132 11.3 13.6 18.8
517 ＞100 16.3 ＞100 12
518 ＞100 18.3 ＞100 2.57
519 ＞100 15.1 54.3 2.76
520 ＞100 45.5 ＞100 6.12
521 ＞100 92.3 ＞100 22.3
522 ＞100 ＞100 ＞100 35.2
523 ＞100 ＞100 94.3 0.691
524 ＞100 5.39 36.8 1.64
525 ＞100 ＞100 ＞100 ＞100
526 ＞100 ＞100 ＞100 12.5
527 ＞100 10.6 ＞100 5.56
527 Repeat the test ＞500 15.3 ＞500 11.2
528 ＞100 ＞100 ＞100 56
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
529 57.7 75.9 3.98 9.51
530 ＞100 ＞100 13.8 5.18
531 ＞100 ＞100 18.6 7.93
531 Repeat the test 76.5 24.2 18.9 3.23
532 0.245 ＜0.137 ＜0.137 ＜0.137
533 0.696 0.307 ＜0.137 0.376
534 3.29 ＜0.137 ＜0.137 ＜0.137
534 Repeat the test 1.59 0.492 ＜0.0457 0.0149
535 23.1 0.727 0.153 1.17
536 ＞100 0.626 22.1 0.656
536 Repeat the test 118 0.924 71.7 0.426
601a 31.6 7.96 14.7 0.137
601a Repeat the test 23.7 4.56 3.12 0.137
601b 17.9 0.335 5.8 0.176
601b Repeat the test 2.92 0.171 1.07 0.113
601c 0.137 0.137 0.137 0.137
601d 0.137 0.137 0.137 0.137
602a 100 100 49.1 91
602b 100 100 100 57.3
602c 100 62.2 100 15
602d 100 96 12.4 37.3
602e 100 21.3 51.6 12.3
603a 14.4 0.823 4.02 0.137
603b 71.7 0.354 13.3 0.0937
603b Repeat the test 45.9 0.137 15.1 0.206
604a 100 0.149 5.35 0.358
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
604a Repeat the test 283 0.203 25 0.136
604b 100 100 7.65 64.3
604c 100 83.1 4.89 1.39
604d 100 15.4 25.7 1.54
604e 10.8 0.137 1.86 0.0027
604e Repeat the test 6.21 0.0033 1.39 0.137
604f 41.4 12.7 15.4 0.832
604g 100 0.223 349 0.0601
604g Repeat the test 460 0.15
604h 100 2.85
604i 6.41 0.532 2.68 0.279
604j 100 9.83 84.3 0.276
604k 100 100 100 100
6041 100 6.53 100 0.137
604m 100 100 100 93.7
604n 8.21 16.6 6.98 4.06
604o 100 100 100 3.02
604p 16.1 9.36 14.1 0.549
604q 5.31 0.137 0.749 0.137
604q Repeat the test 6.18 0.0186 1.05 0.0151
605a 100 1.12 9.24 0.931
605b 100 30.5 100 16
605c 100 100 100 26.3
605d 84.4 100 49.5 40.4
605e 100 100 100 3.89
605f 100 7.03 100 3.43
605g 100 100 100 100
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
605h 100 100 100 69.8
605i 100 100 100 100
605j 100 100 72.1 97.4
605k 100 9.31 41.9 14.7
605l 100 100 100 100
605m 100 100 100 100
605n 100 0.72 75.2 0.137
605o 100 3.54 9.62 3.33
606a 100 100 80.4 0.284
606b 100 100 100 29.7
606b Repeat the test 100 100 100 43.1
606c 100 0.137 49.6 0.137
606c Repeat the test 121 0.0832 62.1 0.0702
607a 1.26 6.67 0.908 3.5
607b 0.516 0.526 0.287 0.448
607c 15.4 0.137 2.86 0.137
607c Repeat the test 15.2 0.0104 4.68 0.0076
607d 100 100 22.6 0.148
608a 100 100 100 0.333
608b 100 0.401 9.92 0.278
608b Repeat the test 99.7 0.27 24.1 0.349
608c 100 100 100 0.197
608d 100 1.12 100 0.387
608e 100 100 100 2.67
608f 54.3 0.356 14 0.137
608f Repeat the test 61.9 0.153 17.9 0.0848
608g 100 1.01 100 0.875
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
608h 100 1.35 100 100
608i 100 7.04 13.3 100
609a 55 0.137 100 100
609a Repeat the test 58.8 0.726 28.7 0.0207
609b 13.4 8.36 1.99 0.137
609c 37.2 6.67 17.6 0.137
609d 57.2 28.3 18.5 0.137
609e 100 10.7 1.95 0.137
609f 5.42 0.137 0.393 0.137
609f Repeat the test 3.75 0.008 0.494 0.0055
609g 20.4 0.137 4.6 0.137
609g Repeat the test 14.9 0.0683 2.56 0.0635
609g Repeat the test 6.86 0.137 0.371 0.137
609h 99.9 1.73 60.6 0.451
609h Repeat the test 66 0.743 28.5 0.525
609i 14.9 0.137 1.67 100
609i Repeat the test 25.9 0.0196 18.8 0.0341
609j 92.3 1.33 43.8 0.137
609k 1.33 1.07 0.195 100
609l 100 1.35 40.6 0.137
609m 100 83.2 20.2 2.88
609n 100 100 61 32.9
609o 40.8 79 3.39 0325
609p 100 100 100 100
609r 0.313 2.74 0.2 0.357
609s 7.38 4.5 0.757 0.61
609t 83.1 24.7 24.1 2.8
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified 1C50(uM)
609t Repeat the test 63.8 4.03 25.4 0.317
609u 3.24 0.575 0.452 0.241
609v 4.03 0.137 0.609 0.137
609v Repeat the test 5.84 0.0185 0.64 0.0134
609w 5.2 0.0122 0.435 0.0099
609w Repeat the test 5 0.137 0.692 0.137
609x 20.4 5.64 7.35 0.307
610 0.137 0.137 0.137 0.137
611a 15.8 0.147 5.23 0.137
611a Repeat the test 11.6 0.02 3.19 0.011
611b 100 100 63.6 0.475
611c 73.5 0.438 0.391 0.394
611c Repeat the test 52.4 0.419 7.79 0.273
611d 43.7 4.46 6.66 4.17
611e 5.42 3.3 0.397 0.157
611f 3.5 0.137 0.137 0.137
611f Repeat the test 6.11 0.0324 0.686 0.0051
611g 45.6 0.137 29.9 0.137
611g Repeat the test 194 1.37 58.4 0.0051
611h 76.9 41.5 29.4 24.7
611i 39.1 4.14 13.8 3.52
611j 13.1 2.19 2.74 2.09
611k 17.5 2.74 2.53 2.71
611l 100 100 89.8 100
611m 100 100 80.9 7.21
611n 100 100 100 100
611o 100 100 100 100
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50 (u)M)
611p 100 100 78.8 100
611q 100 1.36 100 0.694
611r 9.2 3.17 3.82 2.46
612a 100 100 100 9.86
612b 100 100 100 92.4
612c 31.3 100 18.4 58
613a 20.3 0.0507 2.22 0.0334
613a Repeat the test 16.2 0.137 0.137 0.137
613b 100 0.489 2.23 0.546
613c 79.3 0.655 1.23 0.851
614a 100 0.137 74.4 0.293
614b 100 100 100 5.67
615 100 5.5 100 0.54
616 100 6.84 24.4 5.89
617 100 9.13 3.03 6.81
618 72.4 100 41.1 80.2
619a 100 1.57 100 4.74
619a Repeat the test 472 3.09 310 0.0051
619b 100 100 100 28.3
620 100 100 100 23.9
621a 100 100 45.9 100
621b 100 0.285 11.9 0.45
621b Repeat the test 500 0.367 59.5 0.245
621c 0.351 0.149 0.137 0.161
621d 62.7 100 14.6 100
621d Repeat the test 100 100 21.1 100
621e 2.38 0.137 0.137 0.137
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
621e Repeat the test 2.99 0.0142 0.0457 0.0122
621e Repeat the test 0.492 0.137 0.137 0.137
621f 100 16.2 8.99 6.55
621g 100 1.7 22.2 1.34
621g Repeat the test 100 2.71 32.8 0.848
621g Repeat the test 56.4 0.137 15.7 0.137
621h 79.3 0.137 20.9 0.137
621h Repeat the test 64.1 0.0419 18 0.038
621h Repeat the test 100 9.08 26.4 8.75
621j 18.7 71.7 2.54 2.84
621k 1.58 10.3 0.811 4.57
621l 8.05 49.5 3.5 2.7
621m 100 6.03 100 100
621n 100 4 41.9 5.27
621o 100 10.5 5.75 12.8
621p 100 100 100 100
621q 100 100 100 72.8
621r 58.2 90.6 24.7 46.5
621s 100 100 100 100
621t 100 15.9 100 13.9
621u 100 14.3 100 6.97
621v 46.1 0.137 34.2 0.167
621w 100 1.06 4.17 0.952
621x 5.09 0.693 0.324 0.68
621y 100 0.743 12.9 0.723
622 3.5 0.871 0.478 0.775
623m 56.2 0.137 23.8 0.137
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
623n 100 0.21 80.1 0.137
700 100 2.05 100 0.627
700 Repeat the test 500 3.8 187 0.799
701 16.2 0.137 1.75 0.137
701 Repeat the test 12.3 0.137 1.22 0.137
702 85.9 0.615 1.72 0.167
702 Repeat the test 123 1.27 0.686 0.496
703 61.7 0.405 4.52 0.15
703 Repeat the test 93.3 2.09 0.686 0.495
704 52.5 0.137 12.3 0.137
704 Repeat the test 84.5 0.137 34.6 0.137
705 100 23 100 9.36
706 24.8 0.137 10.4 0.137
706 Repeat the test 45.6 0.0873 14.9 0.0518
707 12.3 0.137 4.96 0.137
707 Repeat the test 12.7 0.1 4.83 0.0771
708 81.3 0.137 31 0.137
708 Repeat the test 500 0.45 401 0.135
709 100 1.46 100 0.806
713 23.2 48.7 9.25 26.8
714 16.6 0.233 6.68 0.137
714 Repeat the test 27.8 0.124 21.7 0.0711
715 100 100 100 36.4
716 31.9 31.4 11.8 0.137
717 100 100 44.5 0.137
718 100 100 33.8 100
719 100 38 85.2 0.137
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
720 100 100 39.1 72.3
721 22.8 9.04 5.38 0.137
722 100 100 45.5 0.137
723 32.9 7.21 14.3 0.447
724 100 100 100 47.9
725 7.67 0.357 3.51 0.137
725 Repeat the test 8.87 0.0152 3.34 0.0152
725 Repeat the test 7.97 0.137 0.99 0.137
725 Repeat the test 11.1 0.0152 0.639 0.0152
725 Repeat the test 8.77 0.003 1.44 0.0023
726 52 100 7.45 3.74
727 48 90.7 18.8 31
728 18.4 29.6 8.09 1.81
729 100 100 100 100
730 12.9 2.2 2.64 0.137
732 8.51 8.69 1.67 0.412
733 38.5 31 14.8 10.7
734 4.22 0.43 0.137 0.137
735 26.8 89.1 9.25 41.2
736 64.7 59.8 30.3 52.8
737 100 100 21.3 5.22
739 100 100 100 29.4
740 5.21 7.87 0.427 0.137
741 9.11 9.92 1.79 0.137
742 100 84.7 90.7 19.2
743 2.62 0.164 0.137 0.137
744 40.5 23.6 20 22.2
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
745 8.72 2.3 1.18 0.137
746 21.7 100 11.3 62.4
747 27.2 100 18.2 60.3
748 6.59 0.849 2.25 0.192
749 3.52 0.141 1.12 0.137
751 9.01 13.6 1.56 4.82
752 4.04 3.09 0.291 0.345
753 100 100 100 100
754 8.06 0.137 2.66 0.137
754 Repeat the test 7.39 0.0051 3.59 0.0051
755 1.64 0.137 0.137 0.137
755 Repeat the test 1.45 0.0071 0.0586 0.0051
756 2.32 0.137 0.34 0.137
756 Repeat the test 2.09 0.0051 0.5 0.0051
757 7.43 0.137 0.137 0.137
757 Repeat the test 6.87 0.109 0.137 0.124
758 100 100 13.5 0.137
759 4.74 0.137 0.137 0.137
759 Repeat the test 2.98 0.0084 0.137 0.0074
760 30.3 0.15 6.8 0.137
760 Repeat the test 33.2 0.0972 5.72 3.7
761 2.54 2.51 0.137 0.137
762 59.3 100 18.6 2.82
763 3.93 0.22 0.585 0.137
764 61.4 100 27.8 27.1
765 24.7 12.4 7.17 4.12
766 100 100 72 100
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
767 100 100 64.3 56.1
768 55.8 40.1 16.7 13.3
769 64.7 79.9 28.8 41.2
770 11 31 4.52 16.6
771 15.5 33.6 8.28 12.8
772 16.2 10.8 6.82 0.859
773 44.4 50.4 18.8 8.52
774 100 100 100 0.878
775 63.9 3.24 49.3 3.91
775 Repeat the test 54 1.03 20.5 1.13
776 57.9 0.316 23.2 0.236
776 Repeat the test 380 0.405 207 0.203
777 23.2 0.331 11 0.456
777 Repeat the test 170 1.01 114 0.424
778 58 1.17 39.1 0.575
779 14.2 0.769 2.22 0.794
779 Repeat the test 21.2 0.898 2.27 0.667
780 62 0.162 25 0.3
780 Repeat the test 335 1.48 99.5 1.02
780 Repeat the test 265 1.89 56.2 1.04
781 28.1 0.473 12.5 1.94
782 26.1 0.137 14 0.137
782 Repeat the test 166 0.497 59 0.345
782 Repeat the test 112 0.524 22.3 0.212
783 26.4 0.265 14.6 0.405
783 Repeat the test 277 2.57 108 1.52
783 Repeat the test 158 4.24 77.2 2.6
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
784 48.5 0.814 30.2 2.79
785 6.76 0.317 3.41 0.287
786 41.6 0.419 3.63 0.427
786 Repeat the test 207 1.48 50.8 1.03
786 Repeat the test 121 1.77 14.5 1.2
787 344 1.08 62.9 0.753
787 Repeat the test 100 0.315 22 0.278
788 126 0.849 15.9 0.9
788 Repeat the test 41.6 0.261 5.17 0.26
789 10.4 0.163 0.799 0.17
790 14.3 0.851 1.51 3.05
790 Repeat the test 41.6 2.57 0.569 0.861
791 45 4.94 7.75 4.97
792 192 2.28 36.8 2.88
792 Repeat the test 82.8 0.672 13.5 0.972
793 63 1.05 3.89 1.32
794 41.7 19.8 8.48 7.87
795 11 1.79 1.51 1.99
796 100 3.96 49.8 4.1
797 500 1.24 203 1.06
797 Repeat the test 100 0.719 81.1 0.484
798 100 11.2 99 4.91
799 8.06 0.597 0.928 0.587
800 100 2.49 100 1.34
801 100 3.8 51.3 2.65
802 100 17.8 100 7.68
803 100 11.4 100 7.64
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
804 100 3.54 34.8 2.72
805 100 7.24 100 5.6
806 100 100 100 95.2
807 100 100 100 42.7
808 100 1.06 65.4 0.742
808 Repeat the test 72.7 0.206 28.6 0.156
809 100 0.786 66 0.731
809 Repeat the test 132 0.214 36.2 0.174
810 100 1.06 8.48 1.04
811 169 0.741 79.8 0.377
811 Repeat the test 100 0.631 36.5 0.202
812 10.5 0.644 0.206 0.635
813 40.7 0.473 2.39 0.426
813 Repeat the test 18.4 0.196 0.604 0.21
814 67.9 1.66 34.5 0.137
815 292 0.817 146 0.254
815 Repeat the test 100 0.693 69.7 0.154
816 0.137 0.137 0.137 0.137
817 56.2 100
818 100 25
819 100 100
820 100 100
821 100 100
822 43.2 100
823 100 100
824 100 100
825 100 100
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
826 1.48 13.4
827 100 100
828 1.13 27
829 100 100
830 100 100
831 18.9 100
832 100 18.1
833 100 100
834 21.7 100
835 9.35 100
836 100 49.2
837 14 100
838 8.09 100
839 7.6 100
840 46.5 87.7
841 100 69.7
842 100 8.59
843 100 37.8
844 100 100
845 100 18.9
846 100 25.9
847 100 29.4
848 100 100
849 100 100
850 24.7 0.824
851 62.1 5.07
852 100 9.99
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
853 100 100
854 100 5.32
855 84.5 0.595 224 0.879
855 Repeat the test 264 0.451
856 100 18.1
857 81.8 9.58
858 64.3 100
859 100 100
860 15.9 6.1
861 13.4 13.6
862 77.6 7.54
863 100 100
864 100 0.951 100 0.595
864 Repeat the test 500 0.873 46.6 0.634
865 100 100 100 100
867 100 46.3 100 0.427
868 100 100 80.3 3.82
869 27.5 1.9 0.375 1.98
870 100 20.2 100 9.49
871 56.8 81.1 45.3 7.81
872 100 100 68.4 4.64
873 100 100 66.7 28.8
874 10.1 0.529 0.628 0.175
875 100 64.6 100 1.01
876 100 100 100 1.48
877 100 100 100 0.213
878 100 100 100 0.273
Example No. Repeat Test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
879 4.53 0.137 0.475 0.137
879 Repeat the test 4.27 0.022 0.419 0.019
880 500 0.588 100 0.48
880 Repeat the test 100 0.633 500 0.344
881 100 100 100 57.2
882 22 0.137 4.17 0.137
883 0.137 0.137 0.137 0.137
884 100 2.93 75.9 0.137
885 61 42.6 29.7 9.88
886 22.2 5.21 7.18 0.137
887 8.72 0.137 1.55 0.137
888 4.59 0.137 0.137 0.137
889 100 100 100 100
890 0.137 0.137 0.137 0.137
891 0.137 0.137 0.137 0.137
893 0.189 0.137 0.137 0.137
894 8.73 13.9 3.34 0.137
895 0.668 0.137 0.137 0.137
896 0.137 0.137 0.137 0.137
897 0.387 0.137 0.137 0.137
898 0.137 0.137 0.137 0.137
899 1.33 0.0037 0.67 0.0028
899 Repeat the test 1.38 0.137 0.147 0.137
900 0.137 0.137 0.137 0.137
901 0.274 0.137 0.137 0.137
902 3.9 1.29 53.5 100
903 30.4 100 39.9 100
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
904 27.7 100 54.9 100
905 8.12 13.5 59.5 100
906 0.222 0.137 0.341 100
907 0.137 0.137 0.137 100
908 28.6 30.1 38.4 51.3
909 25.5 2.59 75.2 31.3
910 32.6 7.85 40.1 42.5
911 44.7 4.36 7.29 96.7
912 0.137 0.137 0.137 100
913 0.215 0.137 0.137 100
914 11.7 99.2 11.9 100
915 0.137 0.137 0.137 0.761
916 31.2 62.1
917 28.2 100
918 8.78 3.51
919 8.86 4.15
920 78.8 100 23.2 1.49
921 52.6 100 20.1 100
921 Repeat the test 48.7 100 10.9 100
922 4.96 1.45 0.195 1.25
923 100 100 100 1.71
924 100 4.45 100 3
925 40.3 100 18.4 99.9
925 Repeat the test 100 100 53.6 100
926 43.5 78.1 32.2 23.8
926 Repeat the test 100 100 100 22.5
927 87.3 53.6 56 17.4
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
927 Repeat the test 100 100 100 30.9
928 100 100 100 100
928 Repeat the test 100 100 100 100
929 100 100 100 100
930 21.5 0.137 0.137 0.137
930 Repeat the test 7.62 0.0359 0.686 0.0265
931 12.3 1.55 5.52 0.137
931 Repeat the test 13.2 0.41 6.71 0.137
931 Repeat the test 9.26 0.223 4.31 0.137
931 Repeat the test 11.9 0.0152 2.79 0.0152
931 Repeat the test 10.8 0.0124 2.14 0.0051
931 Repeat the test 6.72 0.137 2.77 0.137
931 Repeat the test 3.7 0.0062 1.91 0.0051
939 64.2 100 49 100
939 Repeat the test 73.5 100 44.3 83.4
939 Repeat the test 47.3 100 31.3 35.1
940 1.59 0.0082 0.0457 0.0086
940 Repeat the test 0.474 0.137 0.137 0.137
941 9.91 3.28 2.15 0.4
942 0.735 0.0136 0.0152 0.0128
942 Repeat the test 1.04 0.137 0.137 0.137
943 11.6 3.08 1.95 0.31
944 30.6 2.27 7.39 0.926
945 13.4 0.2 1.65 0.162
945 Repeat the test 9.75 0.207 0.955 0.192
946 0.123 0.0065 0.0051 0.0082
946 0.137 0.137 0.137 0.137
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
947 6.08 8.02 0.137 1.17
948 38.1 0.137 18.2 0.137
948 Repeat the test 37.3 0.0785 21.5 0.0638
949 36.9 0.401 7.23 0.137
949 Repeat the test 32.8 0.177 9.03 0.106
950 3.77 0.137 2.28 0.137
950 Repeat the test 8.65 0.0567 7.03 0.027
951 51.1 1.56 22.8 0.147
952 5.05 0.137 0.137 0.137
952 Repeat the test 4.07 0.186 0.137 0.0051
953 100 100 0.76.6 0.137
954 8.9 0.137 3.33 0.137
954 Repeat the test 8.67 0.15 3.83 0.0051
955 52.4 17.3 19.7 0.137
956 36.9 46.4 14.8 3.55
957 31.5 1.74 12.7 0.253
957 Repeat the test 11.1 2.26 11.1 0.211
958a 0.21 0.0358 0.0152 0.0293
958a Repeat the test 0.775 0.137 0.137 0.137
958b 41.7 100 0.587 21.6
959 9.44 0.137 1.47 0.137
959 Repeat the test 7.38 0.0469 1.89 0.0069
960 92.4 100 22.5 2.01
961 1.67 0.137 0.137 0.137
961 Repeat the test 0.907 0.0117 0.137 0.0091
962 16 53.4 0.204 0.706
963 0.137 0.137 0.137 0.137
Example numbering Repeat the test hCox-1IC50(uM) hCox-2IC50(uM) hCox-1 modified IC50(uM) hCox-2 modified IC50(uM)
964 29.3 62.8 0.137 0.218
965 0.773 0.137 0.137 0.137
966 9.4 0.266 0.137 0.137
967 0.479 0.137 0.137 0.137
968 22.1 10.3 0.137 0.26
969 38.9 0.256 0.61 0.229
969 Repeat the test 40.3 0.216 1.67 0.152
970 100 61.6 59.3 0.336
971 220 0.476 170 0.17
971 Repeat the test 100 0.364 64.3 0.137
972 100 72.1 100 16.5
973 100 100 100 18
974 90 0.466 67 0.204
974 Repeat the test 78.1 0.321 13.5 0.235
975 100 33.1 100 13.9
976 68.3 0.412 56.2 0.242
976 Repeat the test 72.9 0.513 24.4 0.374
977 0.137 0.137 0.137 0.137
977 Repeat the test 0.0301 0.0396 0.0098 0.0417
977 Repeat the test 0.686 0.0392 0.686 0.0339
978 71.6 100 34.8 100
979 1.19 0.137 0.137 0.137
979 Repeat the test 0.669 0.0315 0.0457 0.0334
980 77.4 100 39.4 0.137
981 7.55 0.137 0.168 100
981 Repeat the test 6.22 0.0808 0.137 0.0982
982 100 100 57.3 0.137

Claims (14)

1. A compound having the structural formula 1:
or a pharmaceutically acceptable salt thereof,
wherein:
x is selected from the group consisting of: hydrogen, alkyl and a pharmaceutically acceptable cation;
z is selected from the group consisting of: oxygen, sulfur and NH;
wherein R is1、R2、R3And R4Each independently selected from the group consisting of: hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonylalkyl, alkylthio, alkynyl, aminocarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkylamino, arylalkynyl, arylcarbonyl, aryloxy, cyano, dialkylamino, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkoxy, heteroarylcarbonyl, hydroxy and hydroxyalkyl; wherein each aryl group, at any position, is independently substituted with 1 to 5 substituents selected from the group consisting of: alkyl, alkoxy, alkylamino, cyano, halo, haloalkyl, hydroxy and nitro.
2. A compound having the structural formula 1 wherein Z is oxygen.
3. A compound of claim 2, wherein R1、R2、R3And R4Each independently selected from the group consisting of: hydrogen, (C) 2-C10) -alkenyl, (C)1-C10) -alkoxy, (C)1-C10) -alkoxy- (C)1-C10) Alkyl radicals, (C)1-C10) -alkoxycarbonyl- (C)1-C10) Alkyl radicals, (C)1-C10) Alkyl radicals, (C)1-C10) -alkylamino, (C)1-C10) -alkylcarbonyl, (C)1-C10) -alkylheteroaryl, (C)1-C10) -alkylsulfonyl- (C)1-C10) Alkyl radicals, (C)1-C10) Alkylthio group(s), (C)2-C10) -alkynyl, aminocarbonyl- (C)1-C10) Alkyl, aryl- (C)2-C10) -alkenyl, aryl- (C)1-C10) Alkoxy, aryl- (C)1-C10) Alkyl, aryl- (C)1-C10) -alkylamino, aryl- (C)2-C10) -alkynyl, arylcarbonyl, aryloxy, cyano, di- (C)1-C10) Alkylamino, halogeno- (C)1-C10) -alkoxy, halo- (C)1-C10) Alkyl, heteroaryl- (C)1-C10) Alkoxy, heteroarylcarbonyl, hydroxy and hydroxy- (C)1-C10) -an alkyl group; wherein each aryl group, at any position, is independently substituted with 1 to 5 substituents selected from the group consisting of: (C)1-C10) Alkyl radicals, (C)1-C10) -alkoxy, (C)1-C10) Alkylamino, cyano, halo- (C)1-C10) Alkyl, hydroxyl and nitro.
4. A compound of claim 3, wherein R1、R2、R3And R4Each independently selected from the group consisting of: hydrogen, (C)2-C10) -alkenyl, (C)1-C10) -alkoxy, (C)1-C10) Alkyl radicals, (C)1-C10) -alkylamino, (C)1-C10) -alkylcarbonyl, (C)1-C10) -alkylheteroaryl, (C)1-C10) -alkylsulfonyl- (C)1-C10) Alkyl radicals, (C) 1-C10) Alkylthio group(s), (C)2-C10) -alkynyl, aryl- (C)1-C10) Alkyl, aryl- (C)2-C10) -alkynyl, arylcarbonyl, aryloxy, di- (C)1-C10) Alkylamino, halogeno- (C)1-C10) Alkoxy, heteroaryl and heteroaryl- (C)1-C10) -an alkoxy group; wherein each aryl group, at any position, is independently substituted with 1 to 5 substituents selected from the group consisting of: (C)1-C10) Alkyl radicals, (C)1-C10) -alkoxy, (C)1-C10) Alkylamino, cyano, halo- (C)1-C10) Alkyl, hydroxyl and nitro.
5. A compound of claim 4, wherein R1、R2、R3And R4Each independently selected from the group consisting of: hydrogen, (C)2-C10) -alkenyl, (C)1-C10) -alkoxy, (C)1-C10) Alkyl radicals, (C)1-C10) -alkylamino, (C)1-C10) -alkylsulfonyl- (C)1-C10) Alkyl radicals, (C)1-C10) Alkylthio group(s), (C)2-C10) -alkynyl, aryl- (C)1-C10) Alkyl, aryl- (C)2-C10) -alkynyl, arylcarbonyl, di- (C)1-C10) Alkylamino, halogeno- (C)1-C10) -alkoxy and heteroaryl; wherein each aryl group, at any position, is independently substituted with 1 to 5 substituents selected from the group consisting of: (C)1-C10) Alkyl radicals, (C)1-C10) Alkoxy and halo.
6. A compound of claim 5, wherein R1、R2、R3And R4Each independently selected from the group consisting of: hydrogen, (C)1-C10) -alkoxy, (C)1-C10) Alkyl radicals, (C) 1-C10) Alkylthio group(s), (C)2-C10) -alkynyl, aryl- (C)1-C10) Alkyl, aryl- (C)1-C10) -alkynyl, arylcarbonyl, halo and halo- (C)1-C10) -an alkoxy group; wherein each aryl group, at any position, is independently substituted with 1 to 5 substituents selected from the group consisting of: (C)1-C10) -alkyl and halo.
7. A compound of claim 6, wherein R1、R2、R3And R4Each independently selected from the group consisting of: hydrogen, (C)1-C8) -alkoxy, (C)1-C8) Alkyl radicals, (C)1-C8) -alkylsulfonyl- (C)1-C8) Alkyl radicals, (C)1-C8) Alkylthio group(s), (C)2-C8) -alkynyl, aryl- (C)1-C8) Alkyl, aryl- (C)2-C8) -alkynyl, arylcarbonyl, halo and halo- (C)1-C8) -an alkoxy group; wherein each aryl group, at any position, is independently substituted with 1 to 5 substituents selected from the group consisting of: (C)1-C8) -alkyl and halo.
8. A compound of claim 7, wherein R1、R2、R3And R4Each independently selected from the group consisting of: hydrogen, (C)1-C5) -alkoxy, (C)1-C5) -alkyl, methyl alkylsulfonyl- (C)1-C8) Alkyl, (C)1-C5) Alkylthio group, (C)2-C5) -alkynyl, aryl- (C)1-C5) Alkyl, aryl- (C)2-C5) -alkynyl, arylcarbonyl, halo and halo- (C)1-C5) -an alkoxy group; wherein each aryl group, at any position, is independently substituted with 1 to 5 substituents selected from the group consisting of: (C) 1-C5) -alkyl and halo.
9. The compound of claim 7 selected from the group consisting of:
(2R) -6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-butoxy-6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-bromo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-butyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-methyl-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-ethylbutoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (isopentyloxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7-isobutoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (sec-butylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-chloro-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-bromo-6, 7-dichloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzoyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-pent-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-bromo-5, 7-dichloro-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (3, 3-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (methylthio) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 7-dichloro-8-methoxy-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-methyl-7- (neopentyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (phenylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-chloro-6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-5, 6-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid; and
(2S) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
Or isomers thereof and pharmaceutically acceptable salts thereof.
10. The compound of claim 7 selected from the group consisting of:
(2R) -6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-butoxy-6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-bromo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-butyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-methyl-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-ethylbutoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (isopentyloxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7-isobutoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (sec-butylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-chloro-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-bromo-6, 7-dichloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid; and
(2S) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
or isomers thereof and pharmaceutically acceptable salts thereof.
11. A compound according to claim 1 selected from the group consisting of:
7-benzoyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (pyridin-3-ylcarbonyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt;
7- (2-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-5, 6-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (2, 2, 2-trifluoroethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (benzyloxy) -8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (hexyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 8-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7, 8-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7- (3, 3-dimethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7-isobutoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (benzyloxy) -6, 8-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-tert-butoxy-6, 8-dichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5, 7, 8-trimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-tert-amyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-tert-amyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (1, 1-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (1, 1-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-tert-butyl-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-isopropenyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-methoxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-tert-butyl-5-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-tert-butyl-5, 8-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-hydroxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-1-benzopyran-3-carboxylic acid;
(2R) -6-chloro-7- (2-hydroxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (2-hydroxy-1, 1-dimethylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 8-dichloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-chloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (dipropylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-8-propyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-isopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-isopropyl-7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (ethoxymethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-tert-butyl-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-diethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- [3, 5-bis (trifluoromethyl) phenyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (4-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-thiophen-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (2-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (4-methylthiophen-2-yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (3-nitrophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (1, 3-benzodioxol-5-yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-pyridin-4-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (3-isopropylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (2-naphthyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-pyridin-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (1H-indol-6-yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-quinolin-8-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (3, 4-dimethoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
2- (trifluoromethyl) -6- [4- (trifluoromethyl) phenyl ] -2H-chromene-3-carboxylic acid;
2- (trifluoromethyl) -6- [3- (trifluoromethyl) phenyl ] -2H-chromene-3-carboxylic acid;
8-chloro-6-phenyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (4-chlorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (2-chlorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (4-fluorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-thiophen-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (2-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (3-nitrophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (1, 3-benzodioxol-5-yl) -8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (4-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (3-isopropylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (2-naphthyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-pyridin-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (1H-indol-5-yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-quinolin-8-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (3, 4-dimethoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-2- (trifluoromethyl) -6- [4- (trifluoromethyl) phenyl ] -2H-chromene-3-carboxylic acid;
8-chloro-2- (trifluoromethyl) -6- [3- (trifluoromethyl) phenyl ] -2H-chromene-3-carboxylic acid;
8-chloro-6- (3-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6- (3-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-butyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-butyl-8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-2- (trifluoromethyl) -6-vinyl-2H-chromene-3-carboxylic acid;
8-chloro-6- (phenylethynyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-cyano-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-acetyl-8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-allyl-8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-prop-1-ynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-methylbut-1-ynyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-prop-1-ynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-but-1-ynyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-fluorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-chloro-4-fluorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3, 5-dichlorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3, 4-dichlorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-fluorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-chlorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (2-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-2- (trifluoromethyl) -8- [3- (trifluoromethyl) phenyl ] -2H-chromene-3-carboxylic acid;
6-chloro-2- (trifluoromethyl) -8- [4- (trifluoromethyl) phenyl ] -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-ethoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-cyanophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-ethoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (2-ethoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- [3, 5-bis (trifluoromethyl) phenyl ] -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-pyridin-4-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-2- (trifluoromethyl) -8- [2- (trifluoromethyl) phenyl ] -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-cyanophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-pyridin-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3, 5-difluorophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3, 5-dimethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-isopropylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (4-tert-butylphenyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (2, 4-dimethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-methyl-3-nitrophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (4-butylphenyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (5-chloro-2-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (4-acetylphenyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3, 4-dimethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-hydroxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-chloro-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-fluoro-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-2- (trifluoromethyl) -8- (3, 4, 5-trimethoxyphenyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-fluoro-4-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-methoxy-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-isobutylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (4-methoxy-3, 5-dimethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-thiophen-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- (3-nitrophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8- [4- (dimethylamino) phenyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6-phenyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6-thiophen-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6- (4-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-2- (trifluoromethyl) -6- [4- (trifluoromethyl) phenyl ] -2H-chromene-3-carboxylic acid;
7-methoxy-2- (trifluoromethyl) -6- [3- (trifluoromethyl) phenyl ] -2H-chromene-3-carboxylic acid;
6- (3-furyl) -7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6- (3-methoxyphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (2-furyl) -7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6- (3-nitrophenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (1, 3-benzodioxol-5-yl) -7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (3-isopropylphenyl) -7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6- (2-naphthyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6-pyridin-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (3, 4-dimethoxyphenyl) -7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6-quinolin-8-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (4-chlorophenyl) -7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (2-chlorophenyl) -7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (4-fluorophenyl) -7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-iodo-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-2- (trifluoromethyl) -6-vinyl-2H-chromene-3-carboxylic acid;
6-ethynyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-acetyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-6-prop-1-ynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-ethoxy-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-7- (pyridin-3-ylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-7- (pyridin-4-ylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-iodo-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-chloro-6-ethyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 7-dichloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 7-dichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 7-dichloro-6-isopropoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
sodium 8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
8-but-1-ynyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
sodium 6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-chloro-8- (4-chloro-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-chloro-8- (4-methoxy-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-ethyl-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-chloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
5, 7, 8-trichloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-iodo-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (phenylethynyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-prop-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-pent-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-ethynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-isobutyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-pentyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (trifluoromethoxy) -2- (trifluoromethyl) -8-vinyl-2H-chromene-3-carboxylic acid;
8- (2-phenylethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-cyano-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-but-1-ynyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-butyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-allyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-chloro-8-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-chloro-8- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (benzyloxy) -5-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-chloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 6-dichloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 7-dichloro-8-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-bromo-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-bromo-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-butoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (benzyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (3-furylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-bromo-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-bromo-5, 7-dichloro-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 6, 7-trichloro-8-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-butoxy-5, 6, 7-trichloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 6, 7-trichloro-8-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 7-dichloro-8-methoxy-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (3, 3-dimethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (benzyloxy) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-tert-butoxy-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-bromo-6, 7-dichloro-8-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-ethoxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid compound with (1S) -1-phenylethylamine (1: 1);
(2R) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid compound with (1R) -1-phenylethylamine (1: 1);
5-chloro-6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (1, 1-difluoroethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-tert-butyl-8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (1-phenylvinyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (1-phenylethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7- (methylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-methoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-ethylbutoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-methyl-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-isobutoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-butoxy-6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-methyl-7- (neopentyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (isopentyloxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
sodium 6, 8-dichloro-7- (2-ethylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
8-ethoxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
sodium 6-chloro-7- (2-ethylbutoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium (2S) -6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2R) -6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
sodium 8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium (2S) -6, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 7- (sec-butylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
2- (trifluoromethyl) -8-propyl-6- (trifluoromethoxy) -2H-chromene-3-carboxylic acid sodium salt;
(S) -8-ethyl-2- (trifluoromethyl) -6- (trifluoromethoxy) -2H-chromene-3-carboxylic acid sodium salt;
(2S) -8-chloro-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
sodium 6-chloro-7- (3, 6-dihydropyridin-1 (2H) -yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
2- (trifluoromethyl) -8-phenethyl-6- (trifluoromethoxy) -2H-chromene-3-carboxylic acid sodium salt;
6-chloro-8-methyl-7-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
sodium 6-chloro-8-methyl-7- (neopentyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium (2S) -6-chloro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 8-allyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
7-benzyl-6-bromo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-propyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-butyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7, 8-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7, 8-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-tert-butoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-methoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-ethylbutoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-furylmethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-isopropyl-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (ethylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (isopentylthio) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (propylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro- (7-isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (butylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (sec-butylsulfanyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (3, 6-dihydropyridin-1 (2H) -yl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- [ ethyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- [ butyl (ethyl) amino ] -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- [ benzyl (methyl) amino ] -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (benzylamino) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (diethylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-butyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (3, 3-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-isopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
4, 6-dichloro-7-isopropyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-propyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid compound with (1R) -1-phenylethylamine (1: 1);
6, 8-dibromo-2- (trifluoro-methyl) -1, 2-dihydroquinoline-3-carboxylic acid;
8-bromo-6-methyl-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid;
6-chloro-8-methyl-2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid;
6- (4-fluorophenyl) -2- (trifluoromethyl) -1, 2-dihydroquinoline-3-carboxylic acid;
6-chloro-7- (2-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2, 3-dimethoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2, 6-dimethoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-propylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-propylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 3-dimethoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 6-dimethoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-propylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (5-isopropyl-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 6-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (-) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 4-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-chloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-fluoro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 5-difluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-fluoro-5-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-chloro-4-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-ethoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 4-difluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-fluoro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-bromo-5-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-bromo-4, 5-difluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 4-dibromophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-bromo-2-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-bromo-4-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-chloro-4-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-iodo-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-chloro-2-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-bromo-2-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-methoxy-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylic acid;
7- (2, 3-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (3-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2, 3-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (3-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2, 4-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (4-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (4-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (3, 4-dichlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2-naphthoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (1-naphthoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (4-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
2- (trifluoromethyl) -5- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylic acid;
5- (4-chloro-3, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2-methoxy-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2, 6-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (4-propylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2, 5-difluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2-chloro-4-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5- (2-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (2, 3-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (3-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (2-chloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (4-chloro-2-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (4-fluoro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (2-methoxy-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (4-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (2, 4-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (2-fluoro-5-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (4-ethoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5- (2-chloro-4-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2, 3-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (3-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2-chloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (4-chloro-2-fluorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (4-fluoro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2-methoxy-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (4-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2, 4-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2-fluoro-5-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (4-ethoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2-chloro-4-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (2-furyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5-thiophen-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (3-isopropylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5-phenyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5-fluoro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5-iodo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-fluoro-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-chloro-2-methylphenoxy) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 7-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-ethyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-butyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 3-dimethylphenyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-isobutyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-ethylphenyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-ethylphenoxy) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-chloro-4-methoxyphenoxy) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-fluoro-2-methylphenoxy) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-fluoro-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methyl-7-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 4-difluorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 5-difluorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-chlorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (3-chlorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-methoxyphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-chloro-4-methylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methyl-7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-ethylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methyl-7- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 4-dimethylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methyl-2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylic acid;
7- (2, 6-dimethylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (_ oxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (3, 4-dichlorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-fluorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-fluorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methyl-7- (4-propylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-methoxy-4-methylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-ethoxyphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-chloro-2-fluorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-bromo-2-fluorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-chloro-4, 5-dimethylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-chloro-4-fluorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-fluoro-5-methylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-bromo-5-fluorophenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-chloro-2-methylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methyl-7- (1-naphthyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (4-ethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (2, 4-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (2, 4-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (3, 5-dichloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (3, 5-dichloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (2-chloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (2-chloro-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylic acid;
(2S) -2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylic acid;
(2R) -7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -7- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -7- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (2-chloro-4, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (2-chloro-4-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (2-chloro-4-methoxyphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (4-fluoro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (4-fluoro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (2-methoxy-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-amino-7- (2-methoxy-4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 7-dichloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 7-dichloro-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 7-dichloro-6-isopropoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
5, 7-dichloro-6-isopropoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-8- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-8- (4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-8- (4-methoxy-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-8- (4-methoxy-3-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
sodium 7- (2, 5-dimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 5- (4-chloro-2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2S) -5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
(2S) -8-chloro-6-ethynyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
sodium (2R) -7- (2, 5-trimethylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium (2R) -2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylate;
sodium 7- (2-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 2- (trifluoromethyl) -7- (2, 3, 5-trimethylphenoxy) -2H-chromene-3-carboxylate;
sodium 6-chloro-7- (2-propylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-chloro-5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 5-phenoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 5- (3-chlorophenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2S) -8-but-1-ynyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
sodium (2S) -6-chloro-8- (3-fluoro-4-methylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
Sodium (2S) -6-chloro-8- (4-ethylphenyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 7- (4-ethylphenoxy) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2R) -6, 8-dichloro-7-isobutoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6, 8-dichloro-7-isobutoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- { [ isopropyl (methyl) amino ] methyl } -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt;
6-chloro-7- [ (diisopropylamino) methyl ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt;
6-chloro-7- { [ ethyl (methyl) amino ] methyl } -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid trifluoroacetate salt;
(2R) -6-chloro-8-methyl-7- (3-methylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-8-methyl-7- (3-methylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (4-cyanobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (hydroxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (methoxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (ethoxymethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-methyl-2- (trifluoromethyl) -2H-chromene-3, 8-dicarboxylic acid;
8-benzyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (1-hydroxyethyl) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-methyl-8- (2, 2, 2-trifluoroethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-ethyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methoxy-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5-isopropyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-8-isopropyl-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-8-isopropyl-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (propylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (butylamino) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (isopentylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- [ (3, 3-dimethylbutyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (neopentylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (sec-butylamino) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2-chlorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (4-chlorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (2, 4-dimethylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -7-butyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -7-butyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-chloro-7- (3, 3-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7- (3, 3-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (3-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (3-hydroxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (3-hydroxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (5-bromo-3-chloro-2-methoxybenzyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (5-bromo-2-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (3-chloro-2-methoxy-5-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-bromo-7- (2-bromobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (3-methylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (5-bromo-2-methoxybenzyl) -6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-7- (propylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -7-benzyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -7-benzyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (benzyloxy) -7-bromo-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6- (benzyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-hydroxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-methyl-7- (2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-butoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6- (pentyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-hexyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-pentyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-propoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6-ethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-bromo-6-methoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-benzyl-6- (hexyloxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (neopentyl amino) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-bromo-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-methoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-ethoxy-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- [ isobutyl (methyl) amino ] -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7- (isobutylamino) -6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
7-tert-butyl-6-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6- (hydroxymethyl) -8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-dichloro-5, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7-methoxy-8- (methoxymethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-benzyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-acetyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-phenyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (2-hydroxyethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8- (1-hydroxy-1-methylethyl) -6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-isopropyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-hydroxy-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-methoxy-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
8-ethoxy-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-8-methoxy-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
sodium 6- (benzyloxy) -8-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2R) -7-benzyl-6-chloro-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
sodium 6-ethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-chloro-7- (2, 4-dimethylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2R) -8-ethyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
sodium 6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-chloro-7- (isobutylamino) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
8-acetyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
(2S) -8-methyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
(2R) -6-chloro-7- [ isobutyl (methyl) amino ] -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
(2R) -6-chloro-7- (3, 3-dimethylbutyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
(2S) -8-propyl-6- (trifluoromethoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
(2S) -6-chloro-8-isopropyl-5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
(2R) -6-chloro-7- (4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
sodium (2S) -6-chloro-8-methyl-7- (3-methylbutoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-methyl-7- (2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2R) -6-chloro-7- (isobutylsulfanyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
sodium 5, 8-dichloro-6, 7-dimethoxy-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-chloro-7- (4-chlorobenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
sodium 6-isopropyl-7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2R) -6-chloro-7-isobutyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
6-ethyl-8-propyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6, 8-diethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
sodium 6, 8-diethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
(2R) -6-chloro-7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2S) -6-chloro-7, 8-dimethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid sodium salt;
5-chloro-6-ethyl-8-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (ethoxymethyl) -5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (hydroxymethyl) -7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (hydroxymethyl) -5-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (3-fluoro-4-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-ethylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-7- (2-ethylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
sodium 6-chloro-7- (2-methylbenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
6-ethyl-8-thiophen-3-yl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6, 8-diethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
(2R) -6-ethyl-8-propyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
sodium 6-chloro-7- (2-methoxybenzyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylate;
6- (4-methylphenoxy) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5- (ethoxymethyl) -7-methyl-2- (trifluoromethyl) -2H-chromene-3-carboxylic acid;
6-chloro-5, 7-bis (ethoxymethyl) -2- (trifluoromethyl) -2H-chromene-3-carboxylic acid; and
sodium (2R) -6, 8-diethyl-2- (trifluoromethyl) -2H-chromene-3-carboxylate;
or isomers thereof and pharmaceutically acceptable salts thereof.
12. The compound of claim 1 having the S-absolute configuration at the 2-carbon of formula I.
13. The compound of claim 1, wherein the pharmaceutically acceptable cation is selected from the group consisting of ammonium cations, alkylammonium cations, dialkylammonium cations, trialkylammonium cations, tetraalkylammonium cations, alkali metal cations, and alkaline earth metal cations.
14. A pharmaceutical composition comprising a compound having structural formula 1:
or a pharmaceutically acceptable salt thereof,
wherein:
x is selected from the group consisting of: hydrogen, alkyl and a pharmaceutically acceptable cation;
z is selected from the group consisting of: oxygen, sulfur and NH;
wherein R is1、R2、R3And R4Each independently selected from the group consisting of: hydrogen, alkenyl, alkoxy, alkoxyalkyl, alkoxycarbonylalkyl, alkyl, alkylamino, alkylcarbonyl, alkylheteroaryl, alkylsulfonylalkyl, alkylthio, alkynyl, aminocarbonylalkyl, aryl, arylalkenyl, arylalkoxy, arylalkyl, arylalkylamino, arylalkynyl, arylcarbonyl, aryloxy, cyano, dialkylamino, halo, haloalkoxy, haloalkyl, heteroaryl, heteroarylalkoxy, heteroarylcarbonyl, hydroxy and hydroxyalkyl; wherein each aryl group, at any position, is independently substituted with 1 to 5 substituents selected from the group consisting of: alkyl, alkoxy, alkylamino, cyano, halo, haloalkyl, hydroxy and nitro;
And a pharmaceutically acceptable excipient.
HK06106482.6A 2003-03-31 2004-03-26 Benzopyran compounds useful for treating inflammatory conditions HK1086559A (en)

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