HK1022299A - Process for preparing hydroxamic acids - Google Patents
Process for preparing hydroxamic acids Download PDFInfo
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- HK1022299A HK1022299A HK00101285.2A HK00101285A HK1022299A HK 1022299 A HK1022299 A HK 1022299A HK 00101285 A HK00101285 A HK 00101285A HK 1022299 A HK1022299 A HK 1022299A
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Description
The present invention relates to a process for preparing hydroxamic acids from carboxylic acid intermediates which do not have reactive substituents such as hydroxyl or amino groups.
It is well known that inhibitors of Matrix Metalloproteinases (MMP) are useful in the treatment of conditions including arthritis (e.g., osteoarthritis and rheumatoid arthritis), inflammatory bowel disease, Crohn's disease, emphysema, acute respiratory distress syndrome, asthma, chronic obstructive pulmonary disease, Alzheimer's disease, organ transplant toxicity, cachexia, anaphylaxis, allergic contact hypersensitivity, cancer, tissue ulceration, restenosis, periodontal disease, epidermolysis bullosa, osteoporosis, prosthetic joint implant relaxation, atherosclerosis (including atherosclerotic plaque rupture), aortic aneurysm (including abdominal aortic aneurysm and intracranial aortic aneurysm), congestive heart failure, myocardial infarction, stroke, cerebral ischemia, brain trauma, spinal cord injury, neurodegenerative disease (acute and chronic), autoimmune disease, inflammatory bowel disease, inflammatory, Huntington's chorea, parkinson's disease, migraine, depression, peripheral neuropathy, pain, cerebral amyloid angiopathy, psychogenic or cognitive enhancement, amyotrophic lateral sclerosis, multiple sclerosis, ocular angiogenesis, corneal injury, macular degeneration, abnormal wound healing, burns, diabetes, tumor invasion, tumor growth, tumor metastasis, corneal scarring, scleritis, aids, sepsis, septic shock, and other diseases characterized by inhibition of metalloproteinase or ADAM expression, including TNF-alpha. In addition, the products prepared by the compounds and methods of the present invention may be used in combination therapy with conventional non-steroidal anti-inflammatory drugs (hereinafter, referred to as NSAIDs), COX-2 inhibitors, and analgesics for the treatment of arthritis, and in the treatment of cancer, with cytotoxic drugs such as doxorubicin, daunorubicin, cisplatin, etoxelate, paclitaxel, taxotere, and alkaloids such as vincristine.
Matrix metalloproteinase inhibitors have long been known in the literature. In particular, PCT application publication WO 96/33172, 1996, 10/24 relates to cyclic arylsulfonylamino hydroxamic acids useful as MMP inhibitors. U.S. patent 5,672,615, PCT application publication WO 97/20824, PCT application publication WO 98/08825, PCT application publication WO 98/27069, and PCT application publication WO 98/34918 entitled "arylsulfonyl hydroxamic acid derivatives" published at 8/13 of 1998 all relate to cyclic hydroxamic acids useful as MMP inhibitors. PCT application publications WO 96/27583 and WO 98/07697, published at 3/7/1996 and 2/26/1998, respectively, relate to arylsulfonyl hydroxamic acids. PCT application publication WO 98/03516, published on 29/1 of 1998, relates to phosphate esters having MMP activity. PCT application publication WO 98/34915, entitled "N-hydroxy- β -sulfonylpropionamide derivatives", published at 13.8.1998, relates to propionyl hydroxamic acids useful as MMP inhibitors. PCT application publication WO 98/33768, entitled "arylsulfonylamino hydroxamic acid derivatives", published at 6.8.1998, relates to N-unsubstituted arylsulfonylamino hydroxamic acids. PCT application publication WO 98/30566, entitled "cyclic sulfone derivatives", published at 16.6.1998, relates to cyclic sulfone hydroxamates useful as MMP inhibitors. U.S. provisional patent application 60/55208 filed 8/1997 relates to diaryl hydroxamic acids useful as MMP inhibitors. U.S. provisional patent application 60/55207 entitled "aryloxyarylsulfonylamino hydroxamic acid derivatives", filed 8/1997, relates to aryloxyarylsulfonylhydroxamic acids useful as MMP inhibitors. The entire disclosures of each of the related publications and applications identified above are hereby incorporated by reference.
The present invention relates to a method for preparing a hydroxamic acid group-containing molecule, which comprises reacting hydroxylamine or a salt thereof with ((C) in the presence of a base1-C6) Alkyl radical)3Silyl halides, preferably ((C)1-C6) Alkyl radical)3A silyl chloride, followed by reaction with an acyl halide-containing molecule, followed by reaction with an acid, provided that the acyl halide-containing molecule does not contain a hydroxyl, primary amine, secondary amine, or thiol group.
The invention relates to a preparation method of a compound shown in the formula
Z is > CH2Or > NR1；
Q is (C)1-C6) Alkyl, (C)6-C10) Aryl group, (C)2-C9) Heteroaryl, (C)6-C10) Aryloxy radical (C)1-C6) Alkyl, (C)6-C10) Aryloxy radical (C)6-C10) Aryl group, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)6-C10) Aryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryloxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryloxy (C)6-C10) Aryl group, (C)2-C9) Heteroaryloxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)6-C10) Aryl or (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)2-C9) A heteroaryl group;
wherein said (C)6-C10) Aryl group, (C)2-C9) Heteroaryl, (C)6-C10) Aryloxy radical (C)1-C6) Alkyl, (C)6-C10) Aryloxy radical (C)6-C10) Aryl group, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)6-C10) Aryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryloxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryloxy (C)6-C10) Aryl group, (C)2-C9) Heteroaryloxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)6-C10) Aryl or (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)2-C9) Each of the heteroaryl groups (C)6-C10) Aryl or (C)2-C9) Heteroaryl groups may optionally be optionally substituted on said ring carbon atoms which may be further bonded, at each ring, with one or more substituents independently selected from fluorine, chlorine, bromine, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, perfluoro (C)1-C3) Alkyl, perfluoro (C)1-C3) Alkoxy and (C)6-C10) An aryloxy group;
R1is hydrogen, (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)1-C6) Alkyl or a group of the formula
Wherein R is2And R3Independently of each other, hydrogen, (C)1-C6) Alkyl or R2And R3Together form a 3-7 membered cycloalkyl ring, a pyran-4-yl ring or a bicyclic ring of formula
Wherein the asterisks indicate R2And R3A common carbon atom of (a);
and R is4Is (C)1-C6) An alkyl group;
n is an integer from 1 to 6;
the method comprises the following steps:
a) in the presence of a first base, preferably pyridine, 2, 6-lutidine or diisopropylethylamine, in a solvent, preferably pyridineAmine or salt thereof and ((C)1-C6) Alkyl radical)3The silyl halide, preferably trimethylsilyl chloride, is reacted to form in situ ((C)1-C6) Alkyl radical)3(ii) a silylated hydroxylamine, which is,
b) (C) forming said in situ1-C6) Alkyl radical)3The silylated hydroxylamine is reacted with a compound of the formula
Wherein R is2、R3Z and Q are as defined above, with a second base, preferably pyridine, 2, 6-lutidine or diisopropylethylamine, to form a compound of the formula
Wherein R is7Is ((C)1-C6) Alkyl radical)3-Si-and R8Is hydrogen or ((C)1-C6) Alkyl radical)3-Si-, and
c) hydrolyzing the compound of formula VI with an acid.
The term "alkyl", as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals containing straight, branched, or cyclic chains or combinations thereof.
The term "alkoxy" as used herein includes 0-alkyl groups wherein "alkyl" is as defined above.
The term "aryl" as used herein, unless otherwise indicated, includes organic groups derived from aromatic hydrocarbons by removal of one hydrogen, such as phenyl or naphthyl.
The term "heteroaryl" as used herein, unless otherwise indicated, includes organic groups derived from aromatic heterocyclic compounds by removal of one hydrogen, such as pyridyl, furyl, pyrrolyl, thienyl, isothiazolyl, imidazolyl, benzimidazolyl, tetrazolyl, pyrazinyl, pyrimidinyl, quinolinyl, isoquinolinyl, benzofuryl, isobenzofuryl, benzothienyl, pyrazolyl, indolyl, isoindolyl, purinyl, carbazolyl, isoxazolyl, thiazolyl, oxazolyl, benzothiazolyl or benzoxazolyl. Preferred heteroaryl groups include pyridyl, furyl, thienyl, isothiazolyl, pyrazinyl, pyrimidinyl, pyrazolyl, isoxazolyl, thiazolyl, or oxazolyl. Most preferred heteroaryl groups include pyridyl, furyl or thienyl.
The term "acyl", as used herein, unless otherwise indicated, includes groups of the general formula R- (C = O) -wherein R is alkyl, alkoxy, aryl, aralkyl or aralkoxy and the term "alkyl" or "aryl" is as defined above.
The term "acyloxy", as used herein, includes an O-acyl group, wherein "acyl" is as defined above.
The compounds of the formulae I to VI may contain chiral centers and may therefore exist in different diastereomeric or enantiomeric forms. The present invention relates to optical isomers and stereoisomers of all compounds of formulae I-VI and mixtures thereof. Preferably, the compounds of formula I' are present in the form of the exo isomers of the formula
The following reaction schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated, n, R in the schemes and discussion section below1、R2、R3、R4、R5Q and Z are as defined above.
Reaction scheme 1
Reaction scheme 2
Scheme 1 relates to the preparation of matrix metalloproteinase compounds of formula I.
Such as reactionAs shown in scheme 1, the compounds of formula I may be prepared from hydroxylamines of formula VIII (wherein R9Is hydrogen chloride, hydrogen sulfide or R9Absent). In particular, a compound of formula VIII is reacted with ((C) in the presence of a base1-C4) Alkyl radical)3The silyl halide reacts to form a compound of formula VII in situ, wherein R7Is ((C)1-C6) Alkyl radical)3-Si-and R8Is hydrogen or ((C)1-C6) Alkyl radical)3-Si-. Suitably ((C)1-C6) Alkyl radical)3The silyl halide includes trimethylsilyl chloride, triethylsilyl chloride, trimethylsilyl iodide, triethylsilyl iodide, trimethylsilyl bromide, t-butyldimethylsilyl chloride or triethylsilyl bromide, preferably trimethylsilyl chloride. Suitable bases include pyridine, 2, 6-lutidine or diisopropylethylamine, with pyridine being preferred. The reaction is carried out at a temperature of about 0 ℃ to about 22 ℃ (e.g., room temperature) for about 1 hour to about 12 hours, preferably about 1 hour.
The compound of formula VII formed in situ is then reacted with the compound of formula II or the acid chloride of the compound of formula V obtained in scheme 2 in the presence of a base to form the compound of formula VI in situ, wherein R2、R3、R7、R8And Q is as defined above and Z is > NR1. Suitable bases include pyridine, 2, 6-lutidine or diisopropylethylamine, with pyridine being preferred. The reaction is carried out at a temperature of about 0 ℃ to about 22 ℃ (e.g., room temperature) for about 1 hour to about 12 hours, preferably about 1 hour.
Converting a compound of formula VI, wherein Z is > NR, to a compound of formula I by acid hydrolysis1. Suitable acids include hydrochloric acid or sulfuric acid, preferably hydrochloric acid. The reaction is carried out at a temperature of about 0 ℃ to about 22 ℃ (e.g., room temperature) for about 1 hour to about 12 hours, preferably about 1 hour.
In addition, where Z is- (CH)2) The compounds of the formula I can be prepared by reacting a compound of the formula
Wherein R is2And R3And Q is as defined above. Compounds of formula IX may be prepared by methods well known to those of ordinary skill in the art.
Scheme 2 relates to the preparation of compounds of formula II which are useful as intermediates in the preparation of compounds of formula I in the processes described in scheme 1.
As shown in scheme 2, a process for the preparation of N-dimethylformamide comprising reacting R with oxalyl chloride or thionyl chloride, preferably oxalyl chloride, and a catalyst, preferably about 2% N, N-dimethylformamide, in an inert solvent such as dichloromethane or toluene10A compound of formula III which is hydrogen affords a compound of formula II. The above reaction is carried out at a temperature of from about 0 c (e.g., room temperature) to about 70 c, preferably from about 20 c to about 50 c, and most preferably about 20 c. The above reaction is carried out for about 1 to 7 hours, preferably about 2 hours.
Wherein R is10Compounds of formula III which are hydrogen can be prepared by reduction in polar solvents from compounds in which R is6Is an optionally substituted benzyl group. Suitable reducing agents include palladium-catalyzed reduction reactions such as hydrogen/palladium, hydrogen/palladium/carbon or palladium hydroxide/carbon, preferably hydrogen/palladium/carbon. Suitable solvents include tetrahydrofuran, methanol, ethanol and isopropanol and mixtures thereof, preferably ethanol. The above reaction is carried out at a temperature of about 22 c (i.e., room temperature) for 1 to 7 days, preferably about 2 days.
A compound of formula III (wherein R10Other than hydrogen, for example protonated amines (e.g. protonated primary, secondary or tertiary amines), alkali metals or alkaline earth metals) may be isolated from compounds of formula III (wherein R is a dicyclohexylamine salt) by treatment with an aqueous or basic solution containing an acceptable cation (e.g. sodium, potassium, dicyclohexylamine, calcium and magnesium, preferably dicyclohexylamine), followed by evaporation of the resulting solution to dryness, preferably under reduced pressure or filtration of the precipitate, preferably a dicyclohexylamine salt10Is hydrogen).
The compounds of formula IV can be prepared by the Michael addition reaction of propiolates in polar solvents in the presence of a baseShould be represented by formula V (wherein R is6Is an optionally substituted benzyl group). Suitable propynyl esters are those of the formula H-C.ident.C-CO2R4(wherein R is4Is (C)1-C6) Alkyl) compounds. Suitable bases include tetrabutylammonium fluoride, potassium carbonate, tertiary amines and cesium carbonate, with tetrabutylammonium fluoride being preferred. Suitable solvents include tetrahydrofuran, acetonitrile, t-butanol, t-amyl alcohol and N, N-dimethylformamide, preferably tetrahydrofuran. The above reaction is carried out at a temperature in the range of about-10 c to about 60 c, preferably 0 c to about 22 c (i.e., room temperature). The compounds of formula IV are obtainable as mixtures of geometric isomers of olefinic double bonds; it is not necessary to separate the isomers.
A compound of formula V (wherein R2And R3Is tetrahydropyran-4-yl or a bicyclic ring of formula
Wherein the asterisks indicate R2And R3The common carbon atom of (1) can be prepared in a similar manner to that described in examples 3 and 4.
A compound of formula V (wherein R6Is an optionally substituted benzyl) can be prepared according to methods well known in the art. Examples of such preparation methods are included in the following publications and application documents. Matrix metalloproteinase inhibitors have long been known in the literature. In particular, PCT application publication WO 96/33172, 1996, 10/24 relates to cyclic arylsulfonylamino hydroxamic acids useful as MMP inhibitors. U.S. patent 5,672,615, PCT application publication WO 97/20824, PCT application publication WO 98/08825, PCT application publication WO 98/27069, and PCT application publication WO 98/34918, entitled "arylsulfonyl hydroxamic acid derivatives," which are published at 13.8.1998, are all directed to cyclic hydroxamic acid compounds useful as MMP inhibitors. PCT application publications WO 96/27583 and WO 98/07697, published at 3/7/1996 and 2/26/1998, respectively, relate to arylsulfonyl hydroxamic acids. PCT application publication WO 98/03516, published on 29/1 of 1998, relates to phosphate esters having MMP activity. Is disclosed in 1998 at 8/13 under the name "N-hydroxy-beta-sulfonylpropionamideDerivative PCT application publication WO 98/34915 relates to propionyl hydroxamic acids useful as MMP inhibitors. PCT application publication WO 98/33768, entitled "arylsulfonylamino hydroxamic acid derivatives", published at 6.8.1998, relates to N-unsubstituted arylsulfonylamino hydroxamic acids. PCT application publication WO 98/30566, published at 16.7.1998 under the name "cyclic sulfone derivatives", relates to cyclic sulfone hydroxamates useful as MMP inhibitors. U.S. provisional patent application 60/55208 filed 8/1997 relates to diaryl hydroxamic acids useful as MMP inhibitors. U.S. provisional patent application 60/55207 entitled "aryloxyarylsulfonylamino hydroxamic acid derivatives", filed 8/1997, relates to aryloxyarylsulfonylhydroxamic acids useful as MMP inhibitors. Each of the related publications and applications identified above is incorporated herein by reference in its entirety.
The compounds of formula I which are basic in nature can form various types of salts with various inorganic or organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is generally desirable that the compound of formula i initially isolated from the reaction mixture be a non-pharmaceutically acceptable salt which is then readily converted to the free base compound by treatment with an alkaline reagent and subsequently converted to the pharmaceutically acceptable acid addition salt. Acid addition salts of the basic compounds of the present invention are readily prepared by treating the basic compound with substantially equal amounts of the selected mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. After careful evaporation of the solvent, the desired solid salt was obtained.
Acids which can be used for the preparation of pharmaceutically acceptable acid addition salts of the basic compounds of the invention are those which form non-toxic acid addition salts, i.e. salts containing physiologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulphate or bisulphate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulphonate and pamoate (i.e. 1, 1' -methylene-bis- (2-hydroxy-3-naphthoate) ].
The compounds of formula I, which may also be acidic in nature, are capable of forming base salts with various physiologically acceptable cations. Examples of such salts include alkali metal or alkaline earth metal salts and in particular sodium and potassium salts. Such salts can be prepared by conventional methods. The chemical base reagents useful in preparing the pharmaceutically acceptable base salts of the present invention are those which form non-toxic base salts with the acidic compounds of formula I described herein. These non-toxic base salts include those derived from pharmacologically acceptable cations such as sodium, potassium, calcium, and magnesium. These salts can be readily prepared by treating the corresponding acidic compound with an aqueous solution containing the desired pharmacologically acceptable cation and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they can be prepared by mixing a lower alkanol solution of the acidic compound with the desired alkali metal salt of alkanol and then evaporating the resulting solution to dryness in the same manner as described above. In each case, it is preferred to use stoichiometric amounts of reagents in order to ensure complete reaction and maximum production of product.
The compounds of formula I or their pharmaceutically acceptable salts (hereinafter referred to as active compounds) inhibit the production of matrix metalloproteases or Tumor Necrosis Factor (TNF) and are therefore indicated to be effective in treating a variety of diseases characterized by the production of matrix metalloproteases or tumor necrosis factor as determined by one of ordinary skill in the art using well known in vitro assays.
The following examples illustrate the preparation of the compounds of the present invention. The melting point is uncorrected. NMR data are in parts per million (δ) and correspond to the deuterium peak lock signal of the sample solvent (deuterated chloroform unless otherwise indicated). Commercial reagents were used without purification. THF means tetrahydrofuran. DMF refers to N, N-dimethylformamide. Chromatography refers to column chromatography performed on 32-63mm silica gel under nitrogen pressure (flash chromatography). The room temperature or ambient temperature means 20-25 ℃. For convenience and to obtain maximum yield, all anhydrous reactions were carried out under nitrogen atmosphere. Concentration under reduced pressure is carried out using a rotary evaporator. Example 1
3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (1-hydroxycarbamoylcyclopentyl) -amino ] -propionic acid
A) Benzyl 1- [4- (4-fluorophenoxy) benzenesulfonylamino ] cyclopentanecarboxylate
To a mixture of 12.41g (0.032mol) benzyl 1-aminocyclopentanecarboxylate, toluene-4-sulfonate (which can be prepared as described in U.S. Pat. No. 4,745,124) and 10.0g (0.035mol,1.1 equivalents) 4- (4-fluorophenoxy) benzenesulfonyl chloride in 113ml toluene was added 11.0ml (0.079mol,2.5 equivalents) triethylamine. The reaction mixture was stirred at ambient temperature overnight, washed with 2N hydrochloric acid (2X 100ml) and brine (100ml), dried over sodium sulphate and concentrated to 30 ml. 149ml of hexane were added dropwise over 3 hours to give a solid precipitate, which was granulated at 0 ℃ for 1 hour and filtered to give 12.59g (85%) of benzyl 1- [4- (4-fluorophenoxy) benzenesulfonylamino ] cyclopentanecarboxylate.
1H NMR(CDCl3)δ7.78-7.82(m,2H),7.30-7.39(m,5H),7.06-7.12(m,2H),6.99-7.04(m,2H),6.93-6.97(m,2H),5.15(s,1H),5.02(s,2H),2.04-2.13(m,2H),1.92-1.98(m,2H),1.62-1.69(m,4H).
The 4.0g sample was granulated overnight in a mixture of 4ml ethyl acetate and 40ml hexane to give 3.72g (93% recovery) benzyl 1- [4- (4-fluorophenoxy) benzenesulfonylamino ] cyclopentanecarboxylate as a light brown solid, mp 97.0-97.5 ℃.
B)1- { (2-Ethoxycarbonylvinyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } -cyclopentane-carboxylic acid benzyl ester
25.0g (53.2mmol) of 1- [4- (4-fluorophenoxy) benzenesulfonylamino]Benzyl cyclopentanecarboxylate and 10.8ml (106mmol,2 equiv.) of ethyl propiolate in 200ml dry tetrahydrofuran are treated with 53.2ml (53.2mmol,1 equiv.) of tetrabutylammonium fluoride in tetrahydrofuran (1M) at 1 ℃ for 45 minutes. The resulting solution was allowed to warm slowly to ambient temperature and stirred throughAnd (4) at night. Toluene was used instead of tetrahydrofuran under reduced pressure and the toluene solution was washed with water and brine, diluted to 600ml with toluene, stirred with 90g silica gel for 3 hours, filtered and concentrated to give 25.14g (83%) 1- { (2-ethoxycarbonylvinyl) - [4- (4-fluorophenoxy) benzenesulfonyl as an orange oil]Amino } -cyclopentanecarboxylic acid benzyl ester.1H NMR(CDCl3) Indicating a trans/cis ratio of 1.5: 1.
Trans δ 7.74-7.78(m,2H),7.72(d, J =14Hz,1H),7.26-7.36(m,5H),6.96-7.12(m,4H),6.78-6.84(m,2H),5.44(d, J =14Hz,1H),5.11(s,2H),4.12(q, J =7.1Hz, 2H),2.08-2.43(m,4H),1.63-1.80(m,4H),1.24(t, J =7.1Hz,3H), cis δ 7.68-7.72(m,2H),7.26-7.36(m,5H),6.96-7.12(m,4H),6.86-6.91(m,2H), 647 (d, J =8.1, 90H), 1.8 = 1H (m,5H), 1.93 (m,4H), 3.93-1H), 1.17 (t, J =7.2Hz,3H).
C)1- { (2-Ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } -cyclopentane-carboxylic acid
A solution of 2.50g (4.4mmol) of benzyl 1- { (2-ethoxycarbonylvinyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylate in 25ml of ethanol was treated with 2.5g of 10% palladium on carbon catalyst wetted with 50% water and shaken under 53psi of hydrogen pressure for 21 hours. The catalyst was filtered off and washed with ethanol (4X 25 ml). The filtrate and washings were combined and concentrated in vacuo to give 1.74g (82%) of 1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid as a crude product as a viscous oil.
1H NMR(CDCl3)δ7.78-7.82(m,2H),6.94-7.09(m,6H),4.09(q,J=7.2Hz,2H).3.56-3.60(m,2H),2.75-2.79(m,2H),2.33-2.39(m,2H),1.93-2.03(m,2H),1.69-1.76(m,2H),1.56-1.63(m,2H),1.22(t,J=7.2Hz,3H).
D)1- { (2-Ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } -cyclopentane-carboxylic acid, dicyclohexylammonium salt
A solution of 3.10g (6.5mmol) of crude 1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid in 30ml of ethanol is treated with 1.28ml (6.5mmol,1 eq) of dicyclohexylamine at ambient temperature, and a solid forms within 5 minutes. The mixture was stirred at ambient temperature overnight and at 0 ℃ for 5 hours. A white solid was isolated by filtration, washed with 10ml of cold ethanol and air-dried to give 2.89g (67%) of 1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid, dicyclohexylammonium salt.
1H NMR(CDCl3)δ7.86-7.91(m,2H),6.99-7.09(m,4H),6.90-6.94(m,2H),5.3(brs,2H),4.07(q,J=7.1Hz,2H),3.54-3.59(m,2H),2.88-2.95(m,4H),2.31-2.38(m,2H),1.95-2.22(m,6H),1.68-1.77(m,6H),1.53-1.60(m,4H),1.40-1.50(m,4H),1.21(t,J=7.1Hz,3H),1.14-1.22(m,6H).Mp164.5-165.9℃.
E)1- { (2-Ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } -cyclopentane-carboxylic acid
A solution of 3.0g (4.5mmol) of 1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid, dicyclohexylammonium salt in 30ml of dichloromethane at ambient temperature is treated with 30ml of 2N hydrochloric acid, yielding a solid precipitate immediately. The mixture was stirred at ambient temperature for 3 hours. The solid was filtered, the aqueous phase extracted with dichloromethane, and the combined organic phases were washed with water, dried over sodium sulfate, and concentrated in vacuo to give 2.2g (100%) of 1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid as a clear oil.
1H NMR(DMSO-d6)δ12.68(bs,1H),7.76-7.80(m,2H),7.25-7.31(m,2H),7.16-7.21(m,2H),7.03-7.08(m,2H),4.01(q,J=7.1Hz,2H),3.48-3.54(m,2H),2.64-2.70(m,2H),2.13-2.21(m,2H),1.90-1.98(m,2H),1.52-1.59(m,4H),1.14(t,J=7.1Hz,3H).
F)3- { (1-Chlorocarbonylcyclopentyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } propanoic acid Ethyl ester
A solution of 7.26g (15.1mmol) of 1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid in 73ml of dichloromethane was treated with 1.4ml (17mmol,1.1 equiv.) of oxalyl chloride and 0.02ml (0.3mmol,0.02 equiv.) of dimethylformamide at ambient temperature, generating some bubbles, and stirred overnight. The resulting ethyl 3- { (1-chlorocarbonyl cyclopentyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } propanoate was used, without isolation, for the preparation of ethyl 3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (1-hydroxycarbamoylcyclopentyl) amino ] propanoate.
A solution of ethyl 3- { (1-chlorocarbonyl cyclopentyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } propanoate prepared in a similar manner was concentrated in vacuo to give an oil.
1H NMR(CDCl3)δ7.84-7.87(m,2H),6.97-7.12(m,6H),4.10(q,J=7.2Hz,2H),3.55-3.59(m,2H),2.68-2.72(m,2H),2.47-2.53(m,2H),1.95-2.02(m,2H),1.71-1.76(m,4H),1.24(t,J=7.2Hz,3H).
G)3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (1-hydroxycarbamoylcyclopentyl) amino ] propanoic acid ethyl ester
A solution of 1.37g (19.7mmol,1.3 equivalents) hydroxylamine hydrochloride in 9.2ml (114mmol,7.5 equivalents) anhydrous pyridine at 0 deg.C was treated with 5.8ml (45mmol,3.0 equivalents) trimethylsilyl chloride to precipitate a white solid which was allowed to warm to ambient temperature overnight. The mixture was cooled to 0 ℃ and treated with 7.54g (15.1mmol) of ethyl 3- { (1-chlorocarbonyl cyclopentyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } propanoate prepared without isolation as described above in 73ml of dichloromethane, causing an exotherm to 8 ℃. The mixture was stirred at 0 ℃ for 30 minutes and at ambient temperature for 1 hour, after which it was treated with 50ml of 2N aqueous hydrochloric acid and stirred at ambient temperature for 1 hour. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with 2N aqueous hydrochloric acid (2X 50ml) and water (50 ml). This solution of ethyl 3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (1-hydroxycarbamoylcyclopentyl) amino ] propanoate in dichloromethane was used without isolation for the preparation of 3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (1-hydroxycarbamoylcyclopentyl) amino ] propanoic acid. An aliquot was concentrated to give a foam.
1H NMR(DMSO-d6)δ10.37(s,1H),8.76(s,1H),7.74-7.79(m,2H),7.24-7.30(m,2H),7.14-7.20(m,2H),7.01-7.05(m,2H),3.99(q,J=7.1Hz,2H),3.42-3.47(m,2H),2.62-2.67(m,2H),2.16-2.23(m,2H),1.77-1.85(m,2H),1.43-1.52(m,4H),1.13(t,J=7.1Hz,3H).
The solution prepared in a similar manner was concentrated in vacuo to give 6.71g (89%) of ethyl 3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (1-hydroxycarbamoylcyclopentyl) amino ] propionate as a dry, hard foam.
H)3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (1-hydroxycarbamoylcyclopentyl) amino ] propanoic acid
A solution of 7.48g (15.1mmol) of ethyl 3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (1-hydroxycarbamoylcyclopentyl) amino ] propanoate in dichloromethane was concentrated by rotary evaporation after addition of 75ml of toluene. The solution is treated with 75ml of water, cooled to 0 ℃ and treated with 6.05g (151mmol,10 equivalents) of sodium hydroxide particles for 10 minutes under vigorous stirring. The mixture was stirred at 0 ℃ for 15 minutes and warmed to ambient temperature over 1 hour. The aqueous phase is separated, diluted with 7.5ml of tetrahydrofuran, cooled to 0 ℃ and treated with 33ml of 6N aqueous hydrochloric acid for 20 minutes. The mixture is stirred with 75ml of ethyl acetate at from 0 ℃ to ambient temperature, the ethyl acetate phase is separated off and washed with water. The ethyl acetate solution was slowly treated with 150ml of hexane at ambient temperature, a solid precipitated and stirred overnight. Filtration gave 5.0g of 3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (1-hydroxycarbamoylcyclopentyl) amino ] propanoic acid as a white solid (71% yield starting from 1- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } cyclopentanecarboxylic acid).
1H NMR(DMSO-d6) δ 12.32(s,1H).10.43(s,1H),8.80(s,1H),7.82(d, J =8.6Hz,2H),7.28-7.35(m,2H),7.20-7.26(m,2H),7.08(d, J =8.9Hz,2H),3.44-3.49(m,2H),2.61-2.66(m,2H),2.24-2.29(m,2H),1.86-1.90(m,2H),1.54-1.55(m,4H). mp162.9-163.5 ℃ (dec). example 2
3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -amino ] propanoic acid
A)4- [ N- (diphenylmethylene) amino ] tetrahydropyran-4-carboxylic acid benzyl ester
To a suspension of sodium hydride (6.56g,0.164mol) in ethylene glycol dimethyl ether (150ml) was added dropwise a solution of N- (diphenylmethylene) glycine benzyl ester (0.07398mol) in ethylene glycol dimethyl ether (50ml) at 0 ℃ via a dropping funnel. A solution of 2-bromoethyl ether (23.21g,0.090mol) in ethylene glycol dimethyl ether (50ml) was then added to the ethylene glycol dimethyl ether solution in one portion per 10ml over about 5 minutes. The ice bath was removed and the reaction stirred at room temperature for 16 hours. The mixture was diluted with ether and washed with water, and the aqueous layer was extracted with ether. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give the crude product. Chromatographic purification on silica gel eluting first with 4L of 5% ethyl acetate/hexane and then with 4L of 10% ethyl acetate/hexane afforded benzyl 4- [ N- (diphenylmethylene) amino ] tetrahydropyran-4-carboxylate as a clear yellow oil.
B) 4-Aminotetrahydropyran-4-carboxylic acid benzyl ester
To a solution of benzyl 4- [ N- (diphenylmethylene) amino ] tetrahydropyran-4-carboxylate (16.0g,0.047mol) in diethyl ether (120ml) was added 1M aqueous hydrochloric acid (100 ml). The mixture was stirred vigorously at room temperature for 16 hours, the layers were separated and the aqueous layer was washed with ether. The aqueous layer was adjusted to pH10 with dilute aqueous ammonium hydroxide and extracted with dichloromethane. The organic extracts were dried over sodium sulfate and concentrated to give benzyl 4-aminotetrahydropyran-4-carboxylate.
C)4- [4- (4-fluorophenoxy) benzenesulfonylamino ] tetrahydropyran-4-carboxylic acid benzyl ester
To a solution of benzyl 4-aminotetrahydropyran-4-carboxylate (0.0404mol) in N, N-dimethylformamide (40ml) was added triethylamine (5.94ml,0.043 mol). To the above solution was added 4- (4-fluorophenoxy) benzenesulfonyl chloride solid (12.165g,0.0424mol) in portions, and the resulting mixture was stirred at room temperature for 16 hours and most of the solvent was evaporated under vacuum. The residue was partitioned between saturated sodium bicarbonate solution and dichloromethane, the aqueous layer was separated and extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was distilled off in vacuo to give the crude benzyl 4- [4- (4-fluorophenoxy) benzenesulfonylamino ] tetrahydropyran-4-carboxylate. Purification by flash chromatography on silica gel eluting with 25% ethyl acetate/hexane followed by 50% ethyl acetate/hexane afforded benzyl 4- [4- (4-fluorophenoxy) benzenesulfonylamino ] tetrahydropyran-4-carboxylate.
D) Benzyl 4- { (2-ethoxycarbonylvinyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } -tetrahydropyran-4-carboxylate
A solution of the product described in the previous step (53.2mmol) and 10.8ml (106mmol,2 equiv.) of ethyl propiolate in 200ml dry tetrahydrofuran was treated with 53.2ml (53.2mmol,1 equiv.) of tetrabutylammonium fluoride in tetrahydrofuran (1M) at 1 ℃ for 45 minutes. The resulting solution was allowed to warm slowly to ambient temperature and stirred overnight. The tetrahydrofuran was replaced by toluene under reduced pressure and the toluene solution was washed with water and brine, diluted to 600ml with toluene, stirred with 90g of silica gel for 3 hours, filtered and concentrated to give the title compound.
E)4- { (2-Ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } -tetrahydropyran-4-carboxylic acid
A25 mL ethanol solution of the product described in step D (4.4mmol) was treated with 2.5g of a 10% palladium on carbon catalyst wetted with 50% water and shaken under 53psi of hydrogen for 21 hours. The catalyst was filtered off and washed with ethanol (4X 25 ml). The filtrate and washings were combined and concentrated in vacuo to give the crude product.
F)3- { (4-Chlorocarbonyltetrahydropyran-4-yl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } propanoic acid ethyl ester
A solution of the product described in step E (15.1mmol) in 73ml of dichloromethane was treated with 1.4ml (17mmol,1.1 equiv.) of oxalyl chloride and 0.02ml (0.3mmol,0.02 equiv.) of dimethylformamide at ambient temperature, generating some bubbles, and stirred overnight. The title compound solution obtained was used without isolation for the next step.
G)3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -amino ] propanoic acid ethyl ester
A solution of hydroxylamine hydrochloride (19.7mmol,1.3 equiv.) in 9.2ml (114mmol,7.5 equiv.) of anhydrous pyridine at 0 deg.C was treated with 5.8ml (45mmol,3.0 equiv.) of trimethylsilyl chloride, a white solid precipitated, and the mixture was allowed to warm to ambient temperature overnight. This mixture was then cooled to 0 ℃ and treated with a solution of the product described in step F (15.1mmol) in 73ml of dichloromethane, causing an exotherm to 8 ℃. The mixture was stirred at 0 ℃ for 30 minutes and at ambient temperature for about 1 hour, then treated with 50ml of 2N aqueous hydrochloric acid and stirred at ambient temperature for 1 hour. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with 2N aqueous hydrochloric acid (2X 50ml) and water (50 ml). This dichloromethane solution of the title compound was used for the next step.
H)3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (4-hydroxycarbamoyl-tetrahydro-pyran-4-yl) -amino ] propanoic acid
A solution of the product described in step G (15.1mmol) in dichloromethane was concentrated by rotary evaporation after addition of 75ml of toluene. The solution is treated with 75ml of water, cooled to 0 ℃ and treated with 6.05g (151mmol,10 equivalents) of sodium hydroxide particles for 10 minutes under vigorous stirring. The mixture was stirred at 0 ℃ for 15 minutes and warmed to ambient temperature over 1 hour. The aqueous phase is separated, diluted with 7.5ml of tetrahydrofuran, cooled to 0 ℃ and treated with 33ml of 6N aqueous hydrochloric acid for 20 minutes. The mixture is stirred with 75ml of ethyl acetate at from 0 ℃ to ambient temperature, the ethyl acetate phase is separated off and washed with water. The ethyl acetate solution was concentrated to give the title compound. Example 3
3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (3-hydroxycarbamoyl-8-oxa-bicyclo [3.2.1] oct-3-yl) amino ] propanoic acid
A) Benzyl 3- (diphenylmethyleneamino) -8-oxabicyclo [3.2.1] octane-3-carboxylate
To a suspension of sodium hydride (0.41g,17.1mmol) in N, N-dimethylformamide (50ml) was added dropwise a solution of benzyl N- (diphenylmethylene) glycine (7.8mmol) in N, N-dimethylformamide (50ml) at 0 ℃. After stirring for 30 minutes at room temperature, a solution of cis-2, 5-bis (hydroxymethyl) tetrahydrofuran xylene sulfonate (4.1g,9.3mmol) (prepared as described in the literature, e.g., JOC,47,2429-2435 (1982)) in N, N-dimethylformamide (50ml) was added dropwise. The reaction mixture was gradually heated to 100 ℃ in an oil bath and stirred at this temperature overnight. The solvent was evaporated in vacuo and the residue was dissolved in water and extracted twice with ether. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give the crude product.
B) 3-amino-8-oxabicyclo [3.2.1] octane-3-carboxylic acid benzyl ester hydrochloride
A two-phase mixture of benzyl 3- (diphenylmethyleneamino) -8-oxabicyclo [3.2.1] octane-3-carboxylate (3.9mmol) in 1N aqueous hydrochloric acid (100ml) and diethyl ether (100ml) was stirred at room temperature overnight. The aqueous layer was concentrated to give the title compound.
C) 3-exo- [4- (4-fluorophenoxy) benzenesulfonylamino ] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid benzyl ester
A solution of benzyl 3-amino-8-oxabicyclo [3.2.1] octane-3-carboxylate hydrochloride (2.9mmol), 4- (4-fluorophenoxy) benzenesulfonyl chloride (923mg,3.2mmol) and triethylamine (0.9ml,6.5mmol) in N, N-dimethylformamide (45ml) was stirred at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in saturated aqueous sodium bicarbonate. After two extractions with dichloromethane, the combined organic layers were washed with brine, dried over magnesium sulfate and concentrated to give a brown oil. Chromatography on silica gel using 1% methanol in dichloromethane as eluent gave the title compound.
D) Benzyl 3- { (2-ethoxycarbonylvinyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } -8-oxabicyclo [3.2.1] octane-3-carboxylate
A solution of the product described in the previous step (53.2mmol) and 10.8ml (106mmol,2 equiv.) of ethyl propiolate in 200ml dry tetrahydrofuran are treated with 53.2ml (53.2mmol,1 equiv.) of tetrabutylammonium fluoride in tetrahydrofuran (1M) at 1 ℃ for 45 minutes. The resulting solution was allowed to warm slowly to ambient temperature and stirred overnight. The tetrahydrofuran was replaced by toluene under reduced pressure and the toluene solution was washed with water and brine, diluted to 600ml with toluene, stirred with 90g of silica gel for 3 hours, filtered and concentrated to give the title compound.
E)3- { (2-ethoxycarbonylethyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } -8-oxabicyclo [3.2.1] octane-3-carboxylic acid
A25 mL ethanol solution of the product described in step D (4.4mmol) was treated with 2.5g of a 10% palladium on carbon catalyst wetted with 50% water and shaken under 53psi of hydrogen for 48 hours. The catalyst was filtered off and washed with ethanol (4X 25 ml). The filtrate and washings were combined and concentrated in vacuo to give the crude product.
F)3- { (3-Chlorocarbonyl-8-oxabicyclo [3.2.1] oct-3-yl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } propanoic acid ethyl ester
A solution of the product described in step E (15.1mmol) in 73ml of dichloromethane was treated with 1.4ml (17mmol,1.1 equiv.) of oxalyl chloride and 0.02ml (0.3mmol,0.02 equiv.) of dimethylformamide at ambient temperature, generating some bubbles, and stirred overnight. The title compound solution obtained was used without isolation for the next step.
G)3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (3-hydroxycarbamoyl-8-oxabicyclo [3.2.1] oct-3-yl) amino ] propanoic acid ethyl ester
A solution of hydroxylamine hydrochloride (19.7mmol,1.3 equivalents) in 9.2ml (114mmol,7.5 equivalents) of anhydrous pyridine at 0 deg.C was treated with 5.8ml (45mmol,3.0 equivalents) of trimethylsilyl chloride and a white solid precipitated. The mixture was allowed to warm to ambient temperature overnight, then the mixture was cooled to 0 ℃ and treated with a solution of the product described in step F (15.1mmol) in 73ml dichloromethane causing an exotherm to 8 ℃. The mixture was stirred at 0 ℃ for 30 minutes and at ambient temperature for about 1 hour, then treated with 50ml of 2N aqueous hydrochloric acid and stirred at ambient temperature for 1 hour. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with 2N aqueous hydrochloric acid (2X 50ml) and water (50 ml). This dichloromethane solution of the title compound was used for the next step.
H)3- [ [4- (4-fluorophenoxy) benzenesulfonyl ] - (3-hydroxycarbamoyl-8-oxabicyclo [3.2.1] oct-3-yl) amino ] propanoic acid
A solution of the product described in step G (15.1mmol) in dichloromethane was concentrated by rotary evaporation after addition of 75ml of toluene. This solution was treated with 75ml of water, cooled to 0 ℃ and treated with 6.05g (15lmmol,10 eq) of sodium hydroxide particles for 10 minutes under vigorous stirring. The mixture was stirred at 0 ℃ for 15 minutes and warmed to ambient temperature over 1 hour. The aqueous phase is separated, diluted with 7.5ml of tetrahydrofuran, cooled to 0 ℃ and treated with 33ml of 6N aqueous hydrochloric acid for 20 minutes. The mixture is stirred with 75ml of ethyl acetate at from 0 ℃ to ambient temperature, the ethyl acetate phase is separated off and washed with water. The ethyl acetate solution was concentrated to give the title compound.
Example 4
3-exo- [4- (4-fluorophenoxy) benzenesulfonylmethyl ] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide
A) 8-oxabicyclo [3.2.1] octane-3, 3-dicarboxylic acid diethyl ester
Sodium hydride (2.28g,95mmol) was added portionwise to a stirred solution of diethyl malonate (15ml,99mmol) in N, N-dimethylformamide (400 ml). The mixture was stirred for 45 minutes at which time hydrogen evolution was complete. A solution of cis-2, 5-bis (hydroxymethyl) tetrahydrofuran dibenzenesulfonate (19.0g,43mmol) in N, N-dimethylformamide (400ml) was then added dropwise and the mixture was heated overnight at 140 ℃ in an oil bath. After cooling to room temperature, the mixture was quenched by addition of saturated aqueous ammonium chloride solution and concentrated in vacuo. The residual oil was dissolved in water and extracted with ether. The organic extracts were washed with water and brine, dried over magnesium sulfate and concentrated to give an oil.
B) 3-exo-hydroxymethyl-8-oxabicyclo [3.2.1] octane-3-carboxylic acid ethyl ester
A1.2M solution of diisobutylaluminum hydride in toluene (75mmol) was added dropwise at-40 deg.CTo 8-oxabicyclo [3.2.1]]Octane-3, 3-dicarboxylic acid diethyl ester (30mmol) in toluene (80 ml). The mixture was warmed to 0 ℃ over 3 hours with stirring, then allowed to cool to-15 ℃ and ethanol (8ml) was added slowly while maintaining this temperature. After stirring at-15 ℃ for 1h, sodium borohydride (1.1g,30mmol) was added, the mixture was stirred at room temperature overnight and quenched by the dropwise addition of saturated aqueous sodium sulfate solution. Ethyl acetate was added, stirred for 20 minutes and then passed through Celite (Celite)TM) Insoluble matter was removed by filtration. The filtrate was washed with brine, dried over magnesium sulfate and concentrated to give the title compound as a clear oil.
C) 3-exo-hydroxymethyl-8-oxabicyclo [3.2.1] octane-3-carboxylic acid
Lithium hydroxide hydrate (59.5mmol) was added to 3-exo-hydroxymethyl-8-oxabicyclo [ 3.2.1%]Ethyl octane-3-carboxylate (23.8mmol) in a mixture of methanol (25ml), tetrahydrofuran (25ml) and water (2.5 ml). The mixture was heated at reflux overnight, cooled and purified by addition of Amberlite IR-120TMThe ion exchange resin quenches it. After stirring for 20 minutes, the resin was filtered off and washed with tetrahydrofuran. The solvent was evaporated and the residue was triturated with ether to give the title compound.
D)3 ', 8-dioxaspiro [ bicyclo [3.2.1] octane-3, 1 ' -cyclobutane ] -2 ' -one
Benzenesulfonyl chloride (13.5mmol) was added dropwise to a solution of 3-exo-hydroxymethyl-8-oxabicyclo [3.2.1] octane-3-carboxylic acid (12.3mmol), triethylamine (24.7mmol) and 4-dimethylaminopyridine (2.5mmol) in dichloromethane (50ml) at 0 ℃. The mixture was stirred at 0 ℃ for 1 hour, diluted with dichloromethane and washed with 1N aqueous hydrochloric acid, saturated aqueous sodium bicarbonate and brine. After drying over magnesium sulfate, the solvent was distilled off to obtain the title compound.
E) 3-exo- [4- (4-fluorophenoxy) phenylthiomethyl ] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid
A solution of 4- (4-fluorophenoxy) thiophenol (10mmol) in tetrahydrofuran (10ml) was added dropwise to a slurry of sodium hydride (11.3mmol) in tetrahydrofuran (20ml) at-10 ℃. The mixture was allowed to warm to room temperature while stirring for 30 minutes. After cooling again to-10 ℃ a solution of 3 ', 8 dioxaspiro [ bicyclo [3.2.1] octane-3, 1 ' -cyclobutane ] -2 ' -one (10mmol) in tetrahydrofuran (20ml) was added dropwise. The cooling bath was removed and stirring was continued at room temperature for 2 hours, after which the mixture was quenched with 1N aqueous hydrochloric acid and extracted twice with dichloromethane. The combined organic extracts were washed with water and brine, dried over magnesium sulfate and concentrated to give a solid.
F)3- [4- (4-fluorophenoxy) phenylthiomethyl ] -8-oxabicyclo [3.2.1] octane-3-carbonyl chloride
A solution of the product described in step E (15.1mmol) in 73ml of dichloromethane was treated with 1.4ml (17mmol,1.1 equiv.) of oxalyl chloride and 0.02ml (0.3mmol,0.02 equiv.) of dimethylformamide at ambient temperature, generating some bubbles, and stirred overnight. The title compound solution obtained was used without isolation for the next step.
G)3- [4- (4-fluorophenoxy) phenylthiomethyl ] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide
A solution of hydroxylamine hydrochloride (19.7mmol,1.3 equivalents) in 9.2ml (114mmol,7.5 equivalents) of anhydrous pyridine at 0 deg.C was treated with 5.8ml (45mmol,3.0 equivalents) of trimethylsilyl chloride and a white solid precipitated. The mixture was allowed to warm to ambient temperature overnight, then the mixture was cooled to 0 ℃ and treated with a solution of the product described in step F (15.1mmol) in 73ml dichloromethane causing an exotherm to 8 ℃. The mixture was stirred at 0 ℃ for 30 minutes and at ambient temperature for about 1 hour, then the reaction was treated with 50ml of 2N aqueous hydrochloric acid and stirred at ambient temperature for 1 hour. The aqueous phase was extracted with dichloromethane and the combined organic phases were washed with 2N aqueous hydrochloric acid (2X 50ml) and water (50 ml). The organic phase was concentrated to give the title compound
H)3- [4- (4-fluorophenoxy) benzenesulfonylmethyl ] -8-oxabicyclo [3.2.1] octane-3-carboxylic acid hydroxyamide
Mixing potassium hydrogen persulfate preparation (Oxone)TM) (8.63mmol) was added to the product described in the previous step(3.63mmol) in a mixture of water (30ml), methanol (40ml) and tetrahydrofuran (12 ml). The resulting mixture was stirred at room temperature overnight, diluted with water and extracted twice with ethyl acetate. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give the title compound.
Example 5
4- [4- (4-fluorophenoxy) benzenesulfonylamino ] -tetrahydropyran-4-carboxylic acid hydroxyamide
A)4- [ N- (diphenylmethylene) amino ] tetrahydropyran-4-carboxylic acid benzyl ester
To a suspension of sodium hydride (6.56g,0.164mol) in ethylene glycol dimethyl ether (150ml) was added dropwise a solution of N- (diphenylmethylene) glycine benzyl ester (0.07398mol) in ethylene glycol dimethyl ether (50ml) at 0 ℃ via a dropping funnel. A solution of 2-bromoethyl ether (23.21g,0.090mol) in ethylene glycol dimethyl ether (50ml) was then added to the ethylene glycol dimethyl ether solution in one portion per 10ml over about 5 minutes. The ice bath was removed and the reaction stirred at room temperature for 16 hours. The mixture was diluted with ether and washed with water, and the aqueous layer was extracted with ether. The combined organic extracts were washed with brine, dried over magnesium sulfate and concentrated to give the crude product. Chromatographic purification on silica gel eluting first with 4L of 5% ethyl acetate/hexane and then with 4L of 10% ethyl acetate/hexane afforded benzyl 4- [ N- (diphenylmethylene) amino ] tetrahydropyran-4-carboxylate as a clear yellow oil.
B) 4-Aminotetrahydropyran-4-carboxylic acid benzyl ester
To a solution of benzyl 4- [ N- (diphenylmethylene) amino ] tetrahydropyran-4-carboxylate (16.0g,0.047mol) in diethyl ether (120ml) was added 1M aqueous hydrochloric acid (100 ml). The mixture was stirred vigorously at room temperature for 16 hours, the layers were separated and the aqueous layer was washed with ether. The aqueous layer was adjusted to pH10 with dilute aqueous ammonium hydroxide and extracted with dichloromethane. The organic extracts were dried over sodium sulfate and concentrated to give benzyl 4-aminotetrahydropyran-4-carboxylate.
C)4- [4- (4-fluorophenoxy) benzenesulfonylamino ] tetrahydropyran-4-carboxylic acid benzyl ester
To a solution of benzyl 4-aminotetrahydropyran-4-carboxylate (0.0404mol) in N, N-dimethylformamide (40ml) was added triethylamine (5.94ml,0.043 mol). To the above solution was added 4- (4-fluorophenoxy) benzenesulfonyl chloride solid (12.165g,0.0424mol) in portions, and the resulting mixture was stirred at room temperature for 16 hours and most of the solvent was evaporated under vacuum. The residue was partitioned between saturated sodium bicarbonate solution and dichloromethane, the aqueous layer was separated and extracted with dichloromethane. The combined organic layers were washed with brine and dried over sodium sulfate. The solvent was distilled off in vacuo to give the crude benzyl 4- [4- (4-fluorophenoxy) benzenesulfonylamino ] tetrahydropyran-4-carboxylate. Purification by flash chromatography on silica gel eluting with 25% ethyl acetate/hexane followed by 50% ethyl acetate/hexane afforded benzyl 4- [4- (4-fluorophenoxy) benzenesulfonylamino ] tetrahydropyran-4-carboxylate.
D) Benzyl 4- { (2-ethoxycarbonylvinyl) - [4- (4-fluorophenoxy) benzenesulfonyl ] amino } -tetrahydropyran-4-carboxylate
A solution of the product described in the previous step (53.2mmol) and 10.8ml (106mmol,2 equiv.) of ethyl propiolate in 200ml dry tetrahydrofuran was treated with 53.2ml (53.2mmol,1 equiv.) of tetrabutylammonium fluoride in tetrahydrofuran (1M) at 1 ℃ for 45 minutes. The resulting solution was allowed to warm slowly to ambient temperature and stirred overnight. The tetrahydrofuran was replaced by toluene under reduced pressure and the toluene solution was washed with water and brine, diluted to 600ml with toluene, stirred with 90g of silica gel for 3 hours, filtered and concentrated to give the title compound.
E)4- [4- (4-fluorophenoxy) benzenesulfonylamino ] -tetrahydropyran-4-carboxylic acid chloride
A solution of 4.40kg (11.13mol)4- [4- (4-fluorophenoxy) benzenesulfonylamino ] -tetrahydropyran-4-carboxylic acid in 40L of dichloromethane was treated with 19ml of dimethylformamide and 1.075L (12.32mol,1.1 eq) of oxalyl chloride at ambient temperature and stirred for 16 h. The resulting solution of the title compound was used without isolation in the following step F.
F)4- [4- (4-fluorophenoxy) benzenesulfonylamino ] tetrahydropyran-4-carboxylic acid hydroxyamide
A solution of 1.160kg (16.69mol,1.5 equivalents) hydroxylamine hydrochloride in 6.8L (84.08mol,7.5 equivalents) pyridine was treated with 2.8L (22.06mol,20 equivalents) trimethylsilyl chloride at 0-10 deg.C to precipitate a white solid. The mixture was stirred at 0-2 ℃ for 4 hours before treatment with the product of step E in dichloromethane, causing an exotherm. The mixture was stirred at 0-2 ℃ for 1 hour, then at 20 ℃ for 1.5 hours. The reaction mixture was treated with 132L of 2N aqueous hydrochloric acid and stirred at ambient temperature for 1 hour. The aqueous phase was extracted with ethyl acetate (3X 100L) and the combined organic phases were washed with water (2X 130L) and concentrated to 17L. The resulting suspension was stirred at 0 ℃ for 3 hours and filtered to give 4.068kg (89%) of the title compound as an off-white solid.
Claims (8)
1. A method of preparing a hydroxamic acid group containing molecule comprising reacting hydroxylamine or a salt thereof with a silyl halide in the presence of a base, followed by reaction with an acid halide containing molecule, and then with an acid, with the proviso that the acid chloride containing molecule does not contain a hydroxyl, primary amine, secondary amine, or thiol group.
2. A process for the preparation of a compound of the formula
Z is >CH2Or > NR1；
Q is (C)1-C6) Alkyl, (C)6-C10) Aryl group, (C)2-C9) Heteroaryl, (C)6-C10) Aryloxy radical (C)1-C6) Alkyl, (C)6-C10) Aryloxy radical (C)6-C10) Aryl group, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)6-C10) Aryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryloxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryloxy (C)6-C10) Aryl group, (C)2-C9) Heteroaryloxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)6-C10) Aryl or (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)2-C9) A heteroaryl group;
wherein said (C)6-C10) Aryl group, (C)2-C9) Heteroaryl, (C)6-C10) Aryloxy radical (C)1-C6) Alkyl, (C)6-C10) Aryloxy radical (C)5-C10) Aryl group, (C)6-C10) Aryloxy radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)6-C10) Aryl radical (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)6-C10) Aryl group, (C)2-C9) Heteroaryl (C)2-C9) Heteroaryl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)6-C10) Aryl group, (C)6-C10) Aryl radical (C)1-C6) Alkoxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryloxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryloxy (C)6-C10) Aryl group, (C)2-C9) Heteroaryloxy (C)2-C9) Heteroaryl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)6-C10) Aryl or (C)2-C9) Heteroaryl (C)1-C6) Alkoxy (C)2-C9) Each of the heteroaryl groups (C)6-C10) Aryl or (C)2-C9) Heteroaryl groups may optionally be optionally substituted on said ring carbon atoms which may be further bonded, at each ring, with one or more substituents independently selected from fluorine, chlorine, bromine, (C)1-C6) Alkyl, (C)1-C6) Alkoxy, perfluoro (C)1-C3) Alkyl, perfluoro (C)1-C3) Alkoxy and (C)6-C10) An aryloxy group;
R1is hydrogen, (C)1-C6) Alkyl, (C)6-C10) Aryl radical (C)1-C6) Alkyl, (C)2-C9) Heteroaryl (C)1-C6) Alkyl or a group of the formula
Wherein R is2And R3Independently of each other, hydrogen, (C)1-C6) Alkyl or R2And R3Together form a 3-7 membered cycloalkyl ring, a pyran-4-yl ring or a bicyclic ring of formula
Wherein the asterisks indicate R2And R3A common carbon atom of (a);
and R is4Is (C)1-C6) An alkyl group;
n is an integer from 1 to 6;
the method comprises the following steps:
a) reacting hydroxylamine or a salt thereof with ((C) in the presence of a first base1-C6) Alkyl radical)3The silyl halide reacts to form in situ ((C)1-C6) Alkyl radical)3(ii) a silylated hydroxylamine, which is,
b) (C) forming said in situ1-C6) Alkyl radical)3The silylated hydroxylamine is reacted with a compound of the formula
Wherein R is2、R3Z and Q are as defined above, with a second base to form a compound of the formula
Wherein R is7Is ((C)1-C6) Alkyl radical)3-Si-and R8Is hydrogen or ((C)1-C6) Alkyl radical)3-Si-; and
c) hydrolyzing the compound of formula VI with an acid.
3. The process of claim 2, wherein the first base is pyridine, 2, 6-lutidine, or diisopropylethylamine.
4. The process of claim 2, wherein the first base is pyridine.
5. The method of claim 2, wherein the reaction product ((C)1-C6) Alkyl radical)3The silyl halide is trimethylsilyl chloride.
6. The process of claim 2, wherein the second base is pyridine, 2, 6-lutidine, or diisopropylethylamine.
7. The process of claim 2, wherein the second base is pyridine.
8. The method of claim 2, wherein the solvent is pyridine.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US081,365 | 1998-04-10 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| HK1022299A true HK1022299A (en) | 2000-08-04 |
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