CN112920005B - Preparation method of (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid - Google Patents
Preparation method of (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid Download PDFInfo
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- C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
- C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
- C07D261/04—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having one double bond between ring members or between a ring member and a non-ring member
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Abstract
The invention discloses a preparation method of (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid, belonging to the technical field of medical intermediates. 3-chloro-2-fluoro-o-chlorobenzaldehyde oxime is taken as a raw material, and is reacted with acrylic ester in the presence of organic base to obtain 3- (3-chloro-2-fluorophenyl) -4, 5-dihydro-isoxazole-5-carboxylic ester; then carrying out alkaline hydrolysis to obtain 3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid racemate; salt-forming resolution and dissociation are carried out by adopting (R) -alpha-phenylethylamine to obtain (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid. The method is simple and convenient to operate, high in reaction yield, high in purity of the obtained product more than 99.0%, more than or equal to 99.5% ee, less than 0.2% of single impurity, and has potential industrial amplification prospect.
Description
Technical Field
The invention relates to a preparation method of (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid, belonging to the technical field of medical intermediates.
Background
Isoxazole compounds as an important heterocyclic compound have unique chemical structures and important pharmacological activities, and have attracted extensive attention of researchers in chemistry and pharmaceutical chemistry in recent years. The compound has wide biological activities of relaxing the heart and blood vessels, regulating calcium ions, treating Alzheimer disease, resisting bacteria and the like, and shows excellent activity in the aspects of pesticides, herbicides and the like.
(R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid is an important isoxazole intermediate and is an important intermediate of a selective factor XIa inhibitor or a double inhibitor of FXIa and plasma kallikrein.
In the prior published patent or literature, the compound is less studied, so that it is necessary to intensively study the synthesis process of (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid and provide a relatively suitable preparation method to meet the increasing market demand.
Disclosure of Invention
In order to overcome the technical defects, the 3-chloro-2-fluoro-o-chlorobenzaldehyde oxime is taken as a raw material and is mixed with acrylic ester in the presence of organic base to obtain 3- (3-chloro-2-fluorophenyl) -4, 5-dihydro-isoxazole-5-carboxylic ester; then carrying out alkaline hydrolysis to obtain 3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid racemate; salt-forming resolution and dissociation are carried out by adopting (R) -alpha-phenylethylamine to obtain (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid.
The invention relates to a preparation method of (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid, which comprises the following steps:
wherein R is Me, Et or i-Pr;
the first step is as follows: performing a ring closure reaction on 3-chloro-2-fluoro-o-chlorobenzaldehyde oxime 1 and acrylate 2 in an organic solvent in the presence of organic base to obtain 3- (3-chloro-2-fluorophenyl) -4, 5-dihydro-isoxazole-5-carboxylic ester; adding inorganic base for hydrolysis to obtain 3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid 4;
the second step is that: salifying 3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid 4 and (R) -alpha-phenylethylamine in an organic solvent, filtering an acid-adding water solution to salify, extracting with the organic solvent, and processing to obtain (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid.
Further, in the above technical solution, in the first step, the organic base is selected from 1, 8-diazabicycloundecen-7-ene, and the organic solvent is selected from dichloromethane, diethoxymethane, cyclopentylmethyl ether or 2-methyltetrahydrofuran.
Further, in the technical scheme, in the first step, the molar ratio of the 3-chloro-2-fluoro-o-chlorobenzaldehyde oxime 1, the acrylate 2 and the organic base is 1:1.8-2.0: 1.0-1.2.
Further, in the above technical solution, in the first step, the inorganic base is selected from sodium hydroxide or potassium hydroxide.
Further, in the above technical solution, in the first step, after the hydrolysis is completed, hydrochloric acid is added to adjust the pH to 2-4, and the organic layer is evaporated to dryness to obtain 3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid 4.
Further, in the above technical solution, in the second step, the organic solvent is selected from the group consisting of isopropanol/ethyl acetate 1/4; the aqueous acid solution is selected from aqueous hydrochloric acid, hydrobromic acid or sulfuric acid.
Further, in the technical scheme, in the second step, the molar ratio of the 3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid 4 to the (R) -alpha-phenylethylamine is 1: 0.5-0.55.
Advantageous effects of the invention
1. The invention can complete the preparation of chiral products by two steps, wherein racemates are respectively subjected to ring closing in organic base, then (R) -alpha-phenylethylamine which is most easily obtained in the market is selected during hydrolysis and chiral resolution in inorganic base, and the resolution can be effectively carried out by adopting 0.5 equivalent in an isopropanol/ethyl acetate mixed solvent.
2. The method is simple and convenient to operate, high in reaction yield, high in purity and content of the obtained product more than 99%, more than or equal to 99.5% ee, less than 0.2% of single impurity, and has potential industrial amplification prospect.
DETAILED DESCRIPTION OF EMBODIMENT (S) OF INVENTION
The invention is further illustrated by the following specific examples.
These examples are to be construed as merely illustrative and not limitative of the remainder of the disclosure in any way whatsoever. After reading the description of the invention, one skilled in the art can make various changes and modifications to the invention, and such equivalent changes and modifications also fall into the scope of the invention defined by the claims.
Synthesis of (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid
Example 1
Under the protection of nitrogen, 104g (0.5mol) of 3-chloro-2-fluoro-o-chlorobenzaldehyde oxime and 500mL of dichloromethane are put into a reaction bottle. The materials were dissolved with stirring at room temperature, cooled to 10 ℃ and 77.5g (0.9mol) of methyl acrylate was added, DBU83.7g (0.55mol) was added dropwise, after the addition was complete, the temperature was slowly raised to room temperature for reaction for 8 hours, and HPLC assay of 0.9% starting material.
Adding saturated ammonium chloride aqueous solution for quenching, demixing, extracting the water phase once by using dichloromethane, combining organic phases, washing the organic phases by using 0.5N hydrochloric acid and saturated saline solution, concentrating the organic phases to obtain a non-flowing liquid, and adding 300mL of absolute ethyl alcohol. The materials are dissolved under stirring at room temperature, the temperature is reduced to 5 ℃, 134.6g (0.673mol) of 20 percent sodium hydroxide aqueous solution is slowly dripped, the temperature is slowly raised to room temperature after the dripping is finished, the reaction is carried out for 4 hours, and the HPLC detects 0.2 percent of the raw materials. Controlling the temperature at 10-25 ℃, dropwise adding a 2N hydrochloric acid aqueous solution to adjust the pH value to be 2-4, separating out solids at the moment, adding water, heating and concentrating to remove most of ethanol, filtering, leaching a filter cake with N-heptane, and drying to obtain 104.6g of 3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid with the yield of 85.9%, and performing HPLC: 99.7 percent.1HNMR(400MHz,CDCl3):10.8(s,1H),7.50-7.00(m,3H),5.32-5.28(m,1H),3.89-3.82(m,2H).
Example 2
Under the protection of nitrogen, 104g (0.5mol) of 3-chloro-2-fluoro-o-chlorobenzaldehyde oxime and 500mL of 2-methyltetrahydrofuran are put into a reaction bottle. The materials are dissolved under stirring at room temperature, the temperature is reduced to 10 ℃, 102.7g (0.9mol) of isopropyl acrylate is added, DBU83.7g (0.55mol) is added dropwise, after the dropwise addition, the temperature is slowly raised to room temperature for reaction for 8 hours, and the HPLC detection shows that the raw material is 0.1 percent.
Adding saturated ammonium chloride aqueous solution for quenching, layering, extracting the aqueous phase once by using 2-methyltetrahydrofuran, combining organic phases, washing the organic phases by using 0.5N hydrochloric acid and saturated salt water, cooling the organic phases to 5 ℃, slowly dropwise adding 134.6g (0.673mol) of 20% sodium hydroxide aqueous solution, slowly heating to room temperature after dropwise adding, reacting for 4 hours, and detecting 0.2% of raw materials by HPLC. Layering, keeping an aqueous phase, controlling the temperature at 10-25 ℃, dropwise adding a 2N hydrochloric acid aqueous solution to adjust the pH to be 2-4, separating a solid at the moment, adding water, heating and concentrating to remove a small amount of 2-methyltetrahydrofuran, filtering, leaching a filter cake with N-heptane, and drying to obtain 114.1g of 3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid with the yield of 93.7%, wherein the HPLC: 99.1 percent.
Example 3
Under the protection of nitrogen, 104g (0.5mol) of 3-chloro-2-fluoro-o-chlorobenzaldehyde oxime and 500mL of diethoxymethane are put into a reaction bottle. The materials are dissolved under stirring at room temperature, the temperature is reduced to 10 ℃, 90g (0.9mol) of ethyl acrylate is added, 83.7g (0.55mol) of DBUs are added dropwise, the temperature is slowly raised to room temperature after the dropwise addition is finished, the reaction is carried out for 8 hours, and the HPLC detection shows that the raw material is 0.2 percent.
Adding saturated ammonium chloride aqueous solution for quenching, demixing, extracting the water phase once by diethoxymethane, combining organic phases, washing the organic phases by 0.5N hydrochloric acid and saturated salt water, cooling the organic phases to 5 ℃, slowly dripping 188.8g (0.673mol) of 20% sodium hydroxide aqueous solution, slowly heating to room temperature after dripping is finished for reacting for 4 hours, and detecting 0.2% of raw materials by HPLC. Layering, keeping a water phase, controlling the temperature at 10-25 ℃, dropwise adding a 2N hydrochloric acid aqueous solution to adjust the pH to be 2-4, separating out solids at the moment, adding water, heating and concentrating to remove a small amount of diethoxymethane, filtering, leaching a filter cake with N-heptane, and drying to obtain 110.2g of 3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid with the yield of 90.5%, wherein the HPLC: 98.9 percent.
Example 4
Under the protection of nitrogen, 100g (0.41mol) of 3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid, 200mL of isopropanol and 800mL of ethyl acetate are added into a reaction bottle, the temperature is raised to reflux, 24.8g (0.205mol) of (R) -alpha-phenylethylamine is added dropwise, the reflux is carried out for 3-4 hours after the dropwise addition is finished until the materials are clear, the temperature is reduced to room temperature in a gradient manner (the temperature is reduced by 10 ℃ every 20 minutes, the temperature is finally reduced to 20 ℃), the stirring is carried out for 4-6 hours, and the filtration is carried out. Rinsing the filter cake with 2-methyltetrahydrofuran, adding into the kettle again (storing the filtrate), adding 500mL of dichloromethane, cooling to 0-5 deg.C, adding 2N hydrochloric acid dropwise to adjust pH to 1-2, layering, extracting the water phase with dichloromethane, mixing the organic phases, washing with saturated saline solution, and collecting the organic phaseConcentrating to obtain a non-flowing liquid, adding isopropyl ether, cooling to 10-15 ℃, pulping for 2-3 hours, separating out a large amount of solid, filtering, drying a filter cake to obtain 40.5g of (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid, wherein the yield is 40.5%, and HPLC: 99.4%, max monohetero 0.14%, 99.6% ee.1HNMR(400MHz,CDCl3):10.8(s,1H),7.82-7.77(m,1H),7.57-7.50(m,1H),7.20-7.16(m,1H),5.30-5.26(m,1H),3.87-3.80(m,2H).
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be able to cover the technical solutions and the inventive concepts of the present invention within the technical scope of the present invention.
Claims (7)
1. A preparation method of (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid is characterized by comprising the following steps:
the first step is as follows: performing a ring closure reaction on 3-chloro-2-fluoro-o-chlorobenzaldehyde oxime 1 and acrylate 2 in an organic solvent in the presence of organic base to obtain 3- (3-chloro-2-fluorophenyl) -4, 5-dihydro-isoxazole-5-carboxylic ester; adding inorganic base for hydrolysis to obtain 3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid 4; wherein R is Me, Et or i-Pr;
the second step is that: salifying 3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid 4 and (R) -alpha-phenylethylamine in an organic solvent, filtering an acid-adding water solution to salify, extracting with the organic solvent, and processing to obtain (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid.
2. The process for preparing (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid according to claim 1, characterized in that: in the first step, the organic base is selected from 1, 8-diazabicycloundec-7-ene and the organic solvent is selected from dichloromethane, diethoxymethane, cyclopentylmethyl ether or 2-methyltetrahydrofuran.
3. The process for preparing (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid according to claim 1, characterized in that: in the first step, the molar ratio of the 3-chloro-2-fluoro-o-chlorobenzaldehyde oxime 1, the acrylate 2 and the organic base is 1:1.8-2.0: 1.0-1.2.
4. The process for preparing (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid according to claim 1, characterized in that: in the first step, the inorganic base is selected from sodium hydroxide or potassium hydroxide.
5. The process for preparing (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid according to claim 1, characterized in that: in the first step, after hydrolysis was completed, hydrochloric acid was added to adjust pH 2 to 4, and the organic layer was evaporated to dryness to obtain 3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid 4.
6. The process for preparing (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid according to claim 1, characterized in that: in the second step, the organic solvent is selected from isopropanol/ethyl acetate 1/4; the aqueous acid solution is selected from aqueous hydrochloric acid, hydrobromic acid or sulfuric acid.
7. The process for preparing (R) -3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid according to claim 1, characterized in that: in the second step, the molar ratio of 3- (3-chloro-2-fluorobenzene) -4, 5-dihydroisoxazole-5-carboxylic acid 4 to (R) -alpha-phenylethylamine is 1: 0.5-0.55.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103857681A (en) * | 2011-08-05 | 2014-06-11 | 百时美施贵宝公司 | Novel macrocycles as factor XIA inhibitors |
| WO2019218899A1 (en) * | 2018-05-17 | 2019-11-21 | 四川科伦博泰生物医药股份有限公司 | Tetrahydroisoquinoline amide compound containing polyglycol ether and pharmaceutical use thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN103857681A (en) * | 2011-08-05 | 2014-06-11 | 百时美施贵宝公司 | Novel macrocycles as factor XIA inhibitors |
| WO2019218899A1 (en) * | 2018-05-17 | 2019-11-21 | 四川科伦博泰生物医药股份有限公司 | Tetrahydroisoquinoline amide compound containing polyglycol ether and pharmaceutical use thereof |
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