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Method for splitting S-(+)-o-chlorobenzene glycine methyl ester

A technology of phenylglycine methyl ester and process, which is applied in the field of splitting 2-substituted phenylglycine methyl ester, can solve the problems of large solvent usage, potential danger, and unfavorable industrialization, and achieve high raw material utilization rate and short operation cycle The effect of shortening and saving the use of solvent and resolving agent

Inactive Publication Date: 2009-08-05
SHANGHAI ECUST BIOMEDICINE CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0013] 2. The yield of the process is only 40-45%, the loss of raw materials is large, and the process is complicated
[0014] 3. Because the yield of the process is only 40-45%, this requires the use of a large amount of solvent, which is potentially dangerous
[0015] 4. Use a lot of solvents and resolution reagents, which is not conducive to industrialization
[0016] 5. Long response time
This method takes a long time to react and consumes a lot of solvent

Method used

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  • Method for splitting S-(+)-o-chlorobenzene glycine methyl ester
  • Method for splitting S-(+)-o-chlorobenzene glycine methyl ester
  • Method for splitting S-(+)-o-chlorobenzene glycine methyl ester

Examples

Experimental program
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Effect test

example 1

[0037] Add L-(+)-tartaric acid (6.6 g, 0.044 mol) and anhydrous methanol (64 ml) into a 100 ml three-necked flask, and stir at room temperature until they are completely dissolved. A mixed solution of 2-chlorophenylglycine methyl ester (8.0 g, 0.04 mol) and acetone (16 ml) was added dropwise into the reactor, and solids were precipitated during the dropwise addition, which took about one hour. After the dropwise addition, react at 28-32°C for 15-20 hours. After the reaction was cooled, stirring was continued for one hour. Suction filtration and filter cake drying to obtain dry solid (S)-(+)-2-chlorophenylglycine methyl ester tartrate, yield 86%, melting point 164-166°C (document: 163-167°C) optical rotation [α] D +86 0 (C=1, CH 3 OH) (Document: [α] D +88 0 (C=1, CH 3 OH)).

example 2

[0039] Add L-(+)-tartaric acid (6.6 g, 0.044 mol) and anhydrous methanol (64 ml) into a 100 ml three-necked flask, and stir at room temperature until they are completely dissolved. After adding a catalytic amount of acetophenone, a mixed solution of 2-chlorophenylglycine methyl ester (8.0g, 0.04mol) and acetone (16ml) was added dropwise to the reactor. During the dropwise addition, solids were precipitated, which took about One hour. After the dropwise addition, react at 28-32°C for 5-6 hours. After the reaction was cooled, stirring was continued for one hour. Suction filtration and drying of the filter cake gave dry solid (S)-(+)-2-chlorophenylglycine methyl ester tartrate. Yield 92%, melting point 164-166°C (document: 163-167°C) optical rotation [α] D +88 0 (C=1, CH 3 OH) (Document: [α] D +88 0 (C=1, CH 3 OH)).

example 3

[0041]Add L-(+)-tartaric acid (6.6 g, 0.044 mol) and anhydrous methanol (64 ml) into a 100 ml three-necked flask, and stir at room temperature until they are completely dissolved. After adding a catalytic amount of formaldehyde, a mixed solution of 2-chlorophenylglycine methyl ester (8.0g, 0.04mol) and acetone (16ml) was added dropwise into the reactor, and solids were precipitated during the dropwise addition, which took about one hour . After the dropwise addition, react at 28-32° C. for 10-20 hours. After the reaction was cooled, stirring was continued for one hour. Suction filtration and drying of the filter cake gave dry solid (S)-(+)-2-chlorophenylglycine methyl ester tartrate. Yield 85%, melting point 164-166°C (document: 163-167°C) optical rotation [α] D +88 0 (C=1, CH 3 OH) (Document: [α] D +88 0 (C=1, CH 3 OH)).

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Abstract

The invention relates to division of a clopidogrel intermediate 2-substituted phenylglycine methyl ester (or acid), which is a medicine for resisting platelet aggregation. The 2-substituted phenylglycine methyl ester (or acid) has the structure shown in a structural formula I. By utilizing the method, the raw materials and the reagents are low-priced and easily obtained, the reaction conditions are mild and the yield is satisfactory, reaching 98 percent. Therefore, the method for dividing the 2-substituted phenylglycine methyl ester (or acid) is easily industrialized. In the structural formula I, R is equal to H, alkyl (C1-C4, benzene)X is equal to a halogen, and for OR1 and SR1, R1 is equal to H or alkane(C1-C3) is equal to a benzene or the benzene for free substitution.

Description

technical field [0001] The present invention relates to a high-yield resolution process for 2-substituted phenylglycine methyl esters (or acids), wherein S-(+)-o-chlorophenylglycine methyl esters are used to prepare clopidogrel, a drug with high activity against platelet aggregation important intermediates. [0002] The 2-substituted phenylglycine methyl ester and acid in the structural formula I prepared by the present invention are important non-natural amino acids with physiological activity, and are also important intermediates of the highly active anti-platelet aggregation drug clopidogrel. [0003] [0004] Structural Formula I [0005] Here, R=H, alkyl (C 1 -C 4 ,benzene) [0006] X = halogen, OR 1 、SR 1 [0007] here R 1 = H or alkane (C 1 -C 3 ) [0008] = Benzene and optionally substituted benzene Background technique [0009] Clopidogrel is a new generation of platelet aggregation inhibitors, mainly used in the treatment of atherosclerosis, acute co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C229/36C07C227/34C07B57/00
CPCY02P20/582
Inventor 吴范宏赵敏杨雪艳顾秀娟丁桂俐
Owner SHANGHAI ECUST BIOMEDICINE CO LTD
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