CN113582843A - Preparation method of 5-chloro-2-fluoro-3-hydroxybenzoic acid ethyl ester - Google Patents
Preparation method of 5-chloro-2-fluoro-3-hydroxybenzoic acid ethyl ester Download PDFInfo
- Publication number
- CN113582843A CN113582843A CN202111054787.6A CN202111054787A CN113582843A CN 113582843 A CN113582843 A CN 113582843A CN 202111054787 A CN202111054787 A CN 202111054787A CN 113582843 A CN113582843 A CN 113582843A
- Authority
- CN
- China
- Prior art keywords
- compound
- preparation
- chloro
- fluoro
- reaction
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- XPALSYQRHAWUNH-UHFFFAOYSA-N ethyl 5-chloro-2-fluoro-3-hydroxybenzoate Chemical compound CCOC(=O)c1cc(Cl)cc(O)c1F XPALSYQRHAWUNH-UHFFFAOYSA-N 0.000 title claims abstract description 17
- 238000002360 preparation method Methods 0.000 title claims abstract description 17
- 238000006243 chemical reaction Methods 0.000 claims abstract description 26
- 229940126214 compound 3 Drugs 0.000 claims abstract description 19
- 229940125782 compound 2 Drugs 0.000 claims abstract description 16
- 238000000034 method Methods 0.000 claims abstract description 11
- 229940125904 compound 1 Drugs 0.000 claims abstract description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims abstract description 6
- 239000001257 hydrogen Substances 0.000 claims abstract description 6
- 230000009471 action Effects 0.000 claims abstract description 5
- -1 boric acid ester Chemical class 0.000 claims abstract description 5
- 238000006555 catalytic reaction Methods 0.000 claims abstract description 5
- 238000005886 esterification reaction Methods 0.000 claims abstract description 5
- 239000004327 boric acid Substances 0.000 claims abstract description 4
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 4
- 229910052741 iridium Inorganic materials 0.000 claims abstract description 3
- GKOZUEZYRPOHIO-UHFFFAOYSA-N iridium atom Chemical compound [Ir] GKOZUEZYRPOHIO-UHFFFAOYSA-N 0.000 claims abstract description 3
- 239000002904 solvent Substances 0.000 claims description 15
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 14
- 238000003756 stirring Methods 0.000 claims description 14
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 11
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- QAOWNCQODCNURD-UHFFFAOYSA-N sulfuric acid Substances OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 8
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N Potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 claims description 7
- 229910052700 potassium Inorganic materials 0.000 claims description 7
- 239000011591 potassium Substances 0.000 claims description 7
- 230000008569 process Effects 0.000 claims description 7
- TXNLQUKVUJITMX-UHFFFAOYSA-N 4-tert-butyl-2-(4-tert-butylpyridin-2-yl)pyridine Chemical compound CC(C)(C)C1=CC=NC(C=2N=CC=C(C=2)C(C)(C)C)=C1 TXNLQUKVUJITMX-UHFFFAOYSA-N 0.000 claims description 5
- 238000010992 reflux Methods 0.000 claims description 5
- IPWKHHSGDUIRAH-UHFFFAOYSA-N bis(pinacolato)diboron Chemical compound O1C(C)(C)C(C)(C)OB1B1OC(C)(C)C(C)(C)O1 IPWKHHSGDUIRAH-UHFFFAOYSA-N 0.000 claims description 4
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 4
- 239000003054 catalyst Substances 0.000 claims description 2
- 230000008901 benefit Effects 0.000 abstract description 5
- 239000002994 raw material Substances 0.000 abstract description 2
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 36
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 12
- 239000012074 organic phase Substances 0.000 description 10
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 9
- 229910052731 fluorine Inorganic materials 0.000 description 9
- 229940079593 drug Drugs 0.000 description 8
- 239000003814 drug Substances 0.000 description 8
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 7
- 238000001035 drying Methods 0.000 description 7
- 238000005406 washing Methods 0.000 description 7
- DQIQQERKWZQXCN-UHFFFAOYSA-N ethyl 5-chloro-2-fluorobenzoate Chemical compound CCOC(=O)C1=CC(Cl)=CC=C1F DQIQQERKWZQXCN-UHFFFAOYSA-N 0.000 description 6
- 239000011737 fluorine Substances 0.000 description 6
- 239000003208 petroleum Substances 0.000 description 6
- 239000012265 solid product Substances 0.000 description 6
- YCKRFDGAMUMZLT-UHFFFAOYSA-N Fluorine atom Chemical compound [F] YCKRFDGAMUMZLT-UHFFFAOYSA-N 0.000 description 5
- 239000000243 solution Substances 0.000 description 5
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 4
- 239000012295 chemical reaction liquid Substances 0.000 description 4
- 238000002156 mixing Methods 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- MIZKCMSSYVUZKD-UHFFFAOYSA-N 2-chloro-5-fluorobenzoic acid Chemical compound OC(=O)C1=CC(F)=CC=C1Cl MIZKCMSSYVUZKD-UHFFFAOYSA-N 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 238000006193 diazotization reaction Methods 0.000 description 3
- 239000003480 eluent Substances 0.000 description 3
- 125000004494 ethyl ester group Chemical group 0.000 description 3
- 229960001617 ethyl hydroxybenzoate Drugs 0.000 description 3
- 238000001914 filtration Methods 0.000 description 3
- 238000010438 heat treatment Methods 0.000 description 3
- 238000006396 nitration reaction Methods 0.000 description 3
- 238000002390 rotary evaporation Methods 0.000 description 3
- 229910052938 sodium sulfate Inorganic materials 0.000 description 3
- 235000011152 sodium sulphate Nutrition 0.000 description 3
- 239000007787 solid Substances 0.000 description 3
- DHCDFWKWKRSZHF-UHFFFAOYSA-N sulfurothioic S-acid Chemical compound OS(O)(=O)=S DHCDFWKWKRSZHF-UHFFFAOYSA-N 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- KTYAQHYBYRVCGD-UHFFFAOYSA-N [Ir].COC1=CC=CCCCC1 Chemical class [Ir].COC1=CC=CCCCC1 KTYAQHYBYRVCGD-UHFFFAOYSA-N 0.000 description 2
- 230000015572 biosynthetic process Effects 0.000 description 2
- UNXISIRQWPTTSN-UHFFFAOYSA-N boron;2,3-dimethylbutane-2,3-diol Chemical compound [B].[B].CC(C)(O)C(C)(C)O UNXISIRQWPTTSN-UHFFFAOYSA-N 0.000 description 2
- 125000001153 fluoro group Chemical group F* 0.000 description 2
- IVDFJHOHABJVEH-UHFFFAOYSA-N pinacol Chemical compound CC(C)(O)C(C)(C)O IVDFJHOHABJVEH-UHFFFAOYSA-N 0.000 description 2
- 239000000047 product Substances 0.000 description 2
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical class O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 description 2
- 238000001228 spectrum Methods 0.000 description 2
- 238000003786 synthesis reaction Methods 0.000 description 2
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- KRHYYFGTRYWZRS-UHFFFAOYSA-M Fluoride anion Chemical compound [F-] KRHYYFGTRYWZRS-UHFFFAOYSA-M 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 230000003321 amplification Effects 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 1
- 230000008859 change Effects 0.000 description 1
- 238000004440 column chromatography Methods 0.000 description 1
- 230000007547 defect Effects 0.000 description 1
- 239000012954 diazonium Substances 0.000 description 1
- 150000001989 diazonium salts Chemical class 0.000 description 1
- 238000007877 drug screening Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 230000006872 improvement Effects 0.000 description 1
- 230000003993 interaction Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 239000002207 metabolite Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- SYSQUGFVNFXIIT-UHFFFAOYSA-N n-[4-(1,3-benzoxazol-2-yl)phenyl]-4-nitrobenzenesulfonamide Chemical class C1=CC([N+](=O)[O-])=CC=C1S(=O)(=O)NC1=CC=C(C=2OC3=CC=CC=C3N=2)C=C1 SYSQUGFVNFXIIT-UHFFFAOYSA-N 0.000 description 1
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 1
- 238000003199 nucleic acid amplification method Methods 0.000 description 1
- 230000003647 oxidation Effects 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000009467 reduction Effects 0.000 description 1
- 238000006722 reduction reaction Methods 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 239000003053 toxin Substances 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
- C07C67/31—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of functional groups containing oxygen only in singly bound form
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic Table
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention discloses a preparation method of 5-chloro-2-fluoro-3-hydroxybenzoic acid ethyl ester, which comprises the following steps: (1) carrying out esterification reaction on the compound 1 to obtain a compound 2; (2) carrying out a carbon-hydrogen boronization reaction on the compound 2 under the action of iridium catalysis to obtain a compound 3; (3) and carrying out boric acid ester oxidation reaction on the compound 3 to obtain the 5-chloro-2-fluoro-3-hydroxybenzoic acid ethyl ester. The method has the advantages of easily obtained raw materials, simple operation and higher yield, and obtains the product with a single target configuration.
Description
Technical Field
The invention relates to the technical field of synthesis of medical intermediates, in particular to a preparation method of 5-chloro-2-fluoro-3-ethyl hydroxybenzoate.
Background
Introduction of fluorine atoms or fluorine-containing groups into drug molecules can change the permeability and metabolic stability of the drug molecules, adjust the pKa and lipid solubility of the drug molecules, and influence the absorption and distribution of the drug molecules and the interaction with biological targets, thereby gradually becoming a common means for drug screening. However, with the development and popularization of fluorine-containing drugs, the chemical stability of fluorine-containing drugs in human bodies and the influence of metabolites generated by enzymes on human bodies need to be considered, and the safety problem during the administration treatment needs to be paid attention to. Recently, doctor Yue Pan of the national Nowa biomedical research institute (NIBR) summarizes possible metabolic pathways of fluorine-containing drugs with different structures in human bodies in ACS journal of Medicinal Chemistry, ACS Medicinal Chemistry Letters, and proposes feasible suggestions on improvement of certain structures, wherein part of drug molecules are decomposed to generate fluoride and fluorine-containing toxic metabolites.
The preparation method for synthesizing 5-chloro-2-fluoro-3-ethyl hydroxybenzoate at present is similar to the report, and the synthesis is carried out through reactions such as nitration, reduction and diazotization. The method has the defects of long reaction steps, harsh conditions, incapability of realizing further amplification, complex post-treatment and the like, and has uncertainty of isomers in the nitration reaction. The diazonium salt generated during the diazotization reaction has instability, so that the treatment after the reaction requires the operation below zero degree, and the operation has uncertainty.
The development of a synthetic route with the advantages of short route, simple operation, single configuration and the like is the main research direction of technicians at present.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a preparation method of 5-chloro-2-fluoro-3-ethyl hydroxybenzoate. The method has the advantages of easily obtained raw materials, simple operation and higher yield, and obtains the product with a single target configuration.
The technical scheme of the invention is as follows:
a preparation method of ethyl 5-chloro-2-fluoro-3-hydroxybenzoate is carried out according to the following steps:
(1) carrying out esterification reaction on the compound 1 to obtain a compound 2;
(2) carrying out a carbon-hydrogen boronization reaction on the compound 2 under the action of iridium catalysis to obtain a compound 3;
(3) and carrying out boric acid ester oxidation reaction on the compound 3 to obtain the 5-chloro-2-fluoro-3-hydroxybenzoic acid ethyl ester.
The specific process of the step (1) is as follows: and (3) refluxing the compound 1 for 18 hours by using ethanol as a solvent under the catalysis of concentrated sulfuric acid, and performing esterification reaction to obtain a compound 2.
The mass concentration of the concentrated sulfuric acid is 98 percent; the proportion of the compound 1 and concentrated sulfuric acid is 1g/1 mL-1 g/5 mL.
The specific process of the step (2) is as follows: compound 2 was reacted with B2Pin2 in MTBE solvent at 80 ℃ for 18 hours using [ (COD)2Ir (M-OMe) ]2 and dtbpy (4,4' -di-tert-butylbipyridine) as catalysts to obtain compound 3.
The molar ratio of the compound 2 to the B2Pin2 is 1: 1.1-2.0; the molar ratio of the compound 2 to [ (COD)2Ir (M-OMe) ]2 is 1: 0.015-0.1; the molar ratio of the compound 2 to dtbpy is 1: 0.03-0.2.
The specific process of the step (3) is as follows: and (3) using acetone and water as solvents, and reacting the compound 3 under the action of potassium peroxymonosulfonate for 18 hours at room temperature under stirring to obtain the 5-chloro-2-fluoro-3-hydroxybenzoic acid ethyl ester.
The molar ratio of the compound 3 to the potassium peroxymonosulfonate is 1: 1.2-10.0.
The volume ratio of acetone to water is 1:1.
The beneficial technical effects of the invention are as follows:
the invention is based on the uncertainty of the position of the nitro group in the original nitration reaction process. In addition to being prepared by diazotization, OH can also be prepared by oxidation and conversion by using boric acid ester. And in the position advantage, the difference of the atomic radii of Cl and F and the advantage that the ortho position of fluorine is occupied by ethyl ester are just utilized, the position with smaller resistance is positioned and selected for carrying out the carbon-hydrogen boronization reaction, the formed product is clearer, the operation is simple, and the yield is 80%. In addition, F, Cl and ethyl ester groups are on the benzene ring of the invention, the difference of the atomic radius of F and Cl groups is small, and the second step reaction mainly occurs in the meta position of ethyl ester.
Drawings
FIG. 1 is a hydrogen spectrum of Compound 3 obtained in example 1 of the present invention;
FIG. 2 is a hydrogen spectrum of ethyl 5-chloro-2-fluoro-3-hydroxybenzoate obtained in example 1 of the present invention.
Detailed Description
The present invention will be described in detail with reference to the accompanying drawings and examples.
Example 1
A preparation method of ethyl 5-chloro-2-fluoro-3-hydroxybenzoate, comprising the following steps:
(1) dissolving 2-chloro-5-fluorobenzoic acid (65g, 0.37mol) in solvent ethanol (650mL), slowly dropwise adding concentrated sulfuric acid (65mL) at room temperature, heating to reflux and stirring for reaction for 18h, pouring the reaction liquid into crushed ice after the reaction is finished, continuously stirring, adjusting the pH value to be more than 7 by using 15% NaOH aqueous solution, extracting by using ethyl acetate, washing an organic phase by using saturated saline solution, drying by using anhydrous sodium sulfate, and concentrating to obtain 47 g of 5-chloro-2-fluorobenzoic acid ethyl ester as a yellow oily substance, wherein the yield is 63%, and the content is 96%.
(2) Adding 5-chloro-2-fluorobenzoic acid ethyl ester (20g, 99mmol), 4,4 '-di-tert-butyl-2, 2' -bipyridine (0.8g, 3mmol), methoxy (cyclooctadiene) iridium dimer (0.98g, 1.5mmol) and pinacol diboron diboride (28g, 108mmol) into a solvent of methyl tert-butyl ether (50mL), mixing, stirring and reacting at 85 ℃ for 18h under a sealed tank condition, pouring the reaction liquid into water after the reaction is finished, continuously stirring, extracting with ethyl acetate, washing an organic phase with saturated common salt water, drying and concentrating the organic phase with sodium sulfate, using petroleum ether/ethyl acetate (20/1) as an eluent, purifying by a column, and carrying out rotary evaporation and concentration to obtain 26 g of a white solid product, namely the compound 3(ethyl 5-chloro-2-fluoro-3- (4,4,5, 5-tetramethy-1, 3,2-dioxaborolan-2-yl) benzoate), yield 80%, content 95%.
1H NMR(400MHz,DMSO-d6+D2O)：δ7.96(dd,J＝5.9,2.9Hz,0.75H),7.85(dd,J＝6.1,3.1Hz,0.25H),7.77(dd,J＝4.2,2.9Hz,0.75H),7.75–7.69(m,0.25H),4.33(q,J＝7.1Hz,2H),1.32(d,J＝3.0Hz,12H),1.08(s,3H)。
(3) Adding compound 3(10g, 30mmol) into a solvent acetone/water (50mL/50mL), mixing, slowly adding potassium peroxymonosulfonate (23g, 36mmol) at room temperature, continuing to react for 18h, adding thiosulfuric acid into the reaction solution after the reaction is finished, continuously stirring, extracting with ethyl acetate, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, adding petroleum ether to precipitate a solid, and filtering to obtain 3.5 g of a pink solid product, namely ethyl 5-chloro-2-fluoro-3-hydroxybenzoate, wherein the yield is 52% and the content is 97%.
1HNMR(400MHz,DMSO-d6)：δ10.81(s,1H),7.24–7.16(m,2H),4.30(q,J＝7.1Hz,2H),1.29(t,J＝7.1Hz,3H)。
Example 2
A preparation method of ethyl 5-chloro-2-fluoro-3-hydroxybenzoate, comprising the following steps:
(1) dissolving 2-chloro-5-fluorobenzoic acid (65g, 0.37mol) in solvent ethanol (650mL), slowly dropwise adding concentrated sulfuric acid (325mL) at room temperature, heating to reflux and stirring for reaction for 18h, pouring the reaction liquid into crushed ice after the reaction is finished, continuously stirring, adjusting the pH value to be more than 7 by using 15% NaOH aqueous solution, extracting by using ethyl acetate, washing an organic phase by using saturated saline solution, drying by using anhydrous sodium sulfate, and concentrating to obtain 50 g of 5-chloro-2-fluorobenzoic acid ethyl ester as a yellow oily substance, wherein the yield is 67%, and the content is 96%.
(2) Ethyl 5-chloro-2-fluorobenzoate (20g, 99mmol), 4,4 '-di-tert-butyl-2, 2' -bipyridine (5.3g, 20mmol), methoxy (cyclooctadiene) iridium dimer (6.5g, 9.9mmol) and pinacol diboron diboride (50.9g, 196mmol) were added to a solvent of methyl tert-butyl ether (50mL) and mixed, the mixture was stirred at 85 ℃ for 18 hours in a closed tank, after completion of the reaction, the reaction solution was poured into water and stirred continuously, after which it was extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate and concentrated, using petroleum ether/ethyl acetate (20/1) as an eluent, column-purified, and concentrated by rotary evaporation to give 27 g of a white solid product, compound 3, yield 83%, content 96%.
(3) Adding compound 3(10g, 30mmol) into solvent acetone/water (200mL/200mL), mixing, slowly adding potassium peroxymonosulfonate (192g, 300mmol) at room temperature, continuing to react for 18h, adding thiosulfuric acid into the reaction solution after the reaction is finished, continuously stirring, extracting with ethyl acetate, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, adding petroleum ether to precipitate a solid, and filtering to obtain 4.0 g of a pink solid product, namely ethyl 5-chloro-2-fluoro-3-hydroxybenzoate, wherein the yield is 59% and the content is 97%.
Example 3
A preparation method of ethyl 5-chloro-2-fluoro-3-hydroxybenzoate, comprising the following steps:
(1) dissolving 2-chloro-5-fluorobenzoic acid (65g, 0.37mol) in solvent ethanol (650mL), slowly dropwise adding concentrated sulfuric acid (162mL) at room temperature, heating to reflux and stirring for reaction for 18h, pouring the reaction liquid into crushed ice after the reaction is finished, continuously stirring, adjusting the pH value to be more than 7 by using 15% NaOH aqueous solution, extracting by using ethyl acetate, washing an organic phase by using saturated saline solution, drying by using anhydrous sodium sulfate, and concentrating to obtain 47 g of 5-chloro-2-fluorobenzoic acid ethyl ester as a yellow oily substance, wherein the yield is 63%, and the content is 96%.
(2) Ethyl 5-chloro-2-fluorobenzoate (20g, 99mmol), 4,4 '-di-tert-butyl-2, 2' -bipyridine (2.7g, 10mmol), iridium bis methoxy (cyclooctadiene) (3.3g, 5mmol) and pinacol diborate (25.5g, 98mmol) were mixed with methyl tert-butyl ether (50mL) as a solvent, stirred at 85 ℃ under a closed tank condition for 18 hours, the reaction solution was poured into water with continuous stirring after completion of the reaction, and then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over sodium sulfate and concentrated, and purified by column chromatography using petroleum ether/ethyl acetate (20/1) as an eluent, and concentrated by rotary evaporation to obtain 25 g of a white solid product, i.e., Compound 3, yield 77%, content 96%.
(3) Adding compound 3(10g, 30mmol) into a solvent acetone/water (100mL/100mL), mixing, slowly adding potassium peroxymonosulfonate (96g, 150mmol) at room temperature, continuing to react for 18h, adding thiosulfuric acid into the reaction solution after the reaction is finished, continuously stirring, extracting with ethyl acetate, washing an organic phase with saturated saline solution, drying with anhydrous sodium sulfate, concentrating, adding petroleum ether to precipitate a solid, and filtering to obtain 3.8 g of a pink solid product, namely ethyl 5-chloro-2-fluoro-3-hydroxybenzoate, wherein the yield is 56% and the content is 97%.
Claims (8)
1. The preparation method of the 5-chloro-2-fluoro-3-hydroxybenzoic acid ethyl ester is characterized by comprising the following steps:
(1) carrying out esterification reaction on the compound 1 to obtain a compound 2;
(2) carrying out a carbon-hydrogen boronization reaction on the compound 2 under the action of iridium catalysis to obtain a compound 3;
(3) and carrying out boric acid ester oxidation reaction on the compound 3 to obtain the 5-chloro-2-fluoro-3-hydroxybenzoic acid ethyl ester.
2. The preparation method according to claim 1, wherein the specific process of step (1) is as follows: and (3) refluxing the compound 1 for 18 hours by using ethanol as a solvent under the catalysis of concentrated sulfuric acid, and performing esterification reaction to obtain a compound 2.
3. The preparation method according to claim 2, wherein the mass concentration of the concentrated sulfuric acid is 98%; the proportion of the compound 1 and concentrated sulfuric acid is 1g/1 mL-1 g/5 mL.
4. The preparation method according to claim 1, wherein the specific process of step (2) is as follows: compound 2 was reacted with B2Pin2 in MTBE solvent at 80 ℃ for 18 hours using [ (COD)2Ir (M-OMe) ]2 and dtbpy (4,4' -di-tert-butylbipyridine) as catalysts to obtain compound 3.
5. The preparation method according to claim 4, wherein the molar ratio of the compound 2 to the B2Pin2 is 1: 1.1-2.0; the molar ratio of the compound 2 to [ (COD)2Ir (M-OMe) ]2 is 1: 0.015-0.1; the molar ratio of the compound 2 to dtbpy is 1: 0.03-0.2.
6. The preparation method according to claim 1, wherein the specific process of step (3) is as follows: and (3) using acetone and water as solvents, and reacting the compound 3 under the action of potassium peroxymonosulfonate for 18 hours at room temperature under stirring to obtain the 5-chloro-2-fluoro-3-hydroxybenzoic acid ethyl ester.
7. The preparation method according to claim 6, wherein the molar ratio of the compound 3 to the potassium peroxymonosulfonate is 1: 1.2-10.0.
8. The method according to claim 6, wherein the volume ratio of acetone to water is 1:1.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111054787.6A CN113582843A (en) | 2021-09-09 | 2021-09-09 | Preparation method of 5-chloro-2-fluoro-3-hydroxybenzoic acid ethyl ester |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202111054787.6A CN113582843A (en) | 2021-09-09 | 2021-09-09 | Preparation method of 5-chloro-2-fluoro-3-hydroxybenzoic acid ethyl ester |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN113582843A true CN113582843A (en) | 2021-11-02 |
Family
ID=78241578
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202111054787.6A Pending CN113582843A (en) | 2021-09-09 | 2021-09-09 | Preparation method of 5-chloro-2-fluoro-3-hydroxybenzoic acid ethyl ester |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN113582843A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114163361A (en) * | 2021-12-14 | 2022-03-11 | 无锡捷化医药科技有限公司 | Preparation method of 3-bromo-5-hydroxybenzenesulfonamide |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009094847A1 (en) * | 2007-12-28 | 2009-08-06 | Topharman Shanghai Co., Ltd. | A capecitabine hydroxyl-derivative, its preparation processes and uses for preparing capecitabine |
| CN101671309A (en) * | 2009-09-30 | 2010-03-17 | 长兴中昊化工有限公司 | Synthesis method of 6-ethyl-4-hydroxyl-5-fluorine-2-cloro pyridine ammonium salt |
| WO2011007856A1 (en) * | 2009-07-17 | 2011-01-20 | 日本たばこ産業株式会社 | Triazolopyridine compound, and action thereof as prolyl hydroxylase inhibitor and erythropoietin production inducer |
| CN102558149A (en) * | 2010-12-29 | 2012-07-11 | 中国医学科学院药物研究所 | Pyrimidine derivative, preparation method thereof, medicinal composition and application thereof |
| CN115279359A (en) * | 2019-11-29 | 2022-11-01 | 速通医疗公司 | new thyromimetic drugs |
-
2021
- 2021-09-09 CN CN202111054787.6A patent/CN113582843A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2009094847A1 (en) * | 2007-12-28 | 2009-08-06 | Topharman Shanghai Co., Ltd. | A capecitabine hydroxyl-derivative, its preparation processes and uses for preparing capecitabine |
| WO2011007856A1 (en) * | 2009-07-17 | 2011-01-20 | 日本たばこ産業株式会社 | Triazolopyridine compound, and action thereof as prolyl hydroxylase inhibitor and erythropoietin production inducer |
| CN101671309A (en) * | 2009-09-30 | 2010-03-17 | 长兴中昊化工有限公司 | Synthesis method of 6-ethyl-4-hydroxyl-5-fluorine-2-cloro pyridine ammonium salt |
| CN102558149A (en) * | 2010-12-29 | 2012-07-11 | 中国医学科学院药物研究所 | Pyrimidine derivative, preparation method thereof, medicinal composition and application thereof |
| CN115279359A (en) * | 2019-11-29 | 2022-11-01 | 速通医疗公司 | new thyromimetic drugs |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114163361A (en) * | 2021-12-14 | 2022-03-11 | 无锡捷化医药科技有限公司 | Preparation method of 3-bromo-5-hydroxybenzenesulfonamide |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN109879733B (en) | Synthetic method of monofluoro bromoacetone derivative | |
| JP2020158516A (en) | Process of making cenicriviroc and related analogs | |
| CN110437172A (en) | A kind of 3,7- bis- replaces phenoxazine analog derivative and preparation method thereof | |
| Li et al. | Rapid incorporation of a difluoroacetate radical into para-quinone methides via radical 1, 6-conjugate addition | |
| CN113582843A (en) | Preparation method of 5-chloro-2-fluoro-3-hydroxybenzoic acid ethyl ester | |
| Qian et al. | Asymmetric Michael addition of malonates to unsaturated ketones catalyzed by rare earth metal complexes bearing phenoxy functionalized chiral diphenylprolinolate ligands | |
| CN112266355A (en) | Method for synthesizing C-5 trifluoromethylated 8-aminoquinoline by using microchannel reaction device under visible light | |
| CN111848480A (en) | A kind of method for synthesizing aryl difluoromethylselenyl ether from aryl boronic acid and its application | |
| CN116239508A (en) | A kind of preparation method of aryl sulfimine compound | |
| Jensen et al. | Synthesis and structure determination of Os3 [1, 2-. mu.-H; 1, 2-. mu.-O: C (Me)][1-C (OMe) Me][CO) 9: the first cluster complex containing a Fischer-type carbene group | |
| CN114634482A (en) | Diazo difluoromethylation reagent and synthesis method and application thereof | |
| US20210388007A1 (en) | Compound and preparation method and application thereof | |
| CN103145515B (en) | A kind of preparation method of 3-halo-2-alkynyl-1-ketone group naphthalene series compound | |
| Jia et al. | Synthesis of six 8-quinolinate-based ruthenium complexes with high catalytic activity for nitroarene reduction | |
| CN116143681B (en) | N-aryl phthalimide derivative and application thereof in organic photochemistry | |
| CN105399644A (en) | Molecular tweezer compounds with (1S,2S)-1,2-cyclohexanediamine as spacer group and isosteviol as chiral arm, and preparation method and application thereof | |
| CN114349656B (en) | Preparation method of hydrazide compound | |
| CN102898342A (en) | Chiral compound | |
| CN117069586A (en) | Polysubstituted cyclopenta-hydrogenated phenanthrene derivative, and preparation method and application thereof | |
| US7368593B1 (en) | Method of selective esterification | |
| CN109776409B (en) | Method for synthesizing C-2-bit polyfluoro functional group substituted quinoline by using microchannel reaction device | |
| CN110272332A (en) | A kind of carbon nano ring and its synthetic method of methoxyl group modification | |
| CN108383754B (en) | Preparation method and application of aryl oxime ester compound | |
| CN116082131A (en) | One-pot method for synthesizing 1-indanone compound method | |
| CN114149356A (en) | Preparation method of methyl indolcarbate compound |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20211102 |