Method for preparing (S)-2-chlorophenylglycine methyl ester single enantiomer by virtue of biological enzyme catalysis

A chlorophenylglycine methyl ester, a catalytic preparation technology, applied in the field of medicine, can solve the problems of expensive chiral resolving agent, complicated operation process, low production efficiency, etc., and achieve simple and easy control of the operation process, low cost and low emission Effect

Inactive Publication Date: 2015-01-21
NINGXIA UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The preparation of (S)-2-chlorophenylglycine methyl ester by chemical method is usually resolved with chiral reagents such as D-camphorsulfonic acid and L-tartaric acid (US6812363B2, 2002-10-15), but the required chiral The resolving agent is expensive, the product purity is low, the operation process is complicated, and the production efficiency is low

Method used

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  • Method for preparing (S)-2-chlorophenylglycine methyl ester single enantiomer by virtue of biological enzyme catalysis
  • Method for preparing (S)-2-chlorophenylglycine methyl ester single enantiomer by virtue of biological enzyme catalysis

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Embodiment 1

[0026] In reactor, add 5.0g racemic 2-chlorophenylglycine methyl ester and 50mL pH 7.0, 0.2mol / L sodium phosphate buffer solution, now the concentration of racemic 2-chlorophenylglycine methyl ester is 100g / L, Then add 0.1 g of immobilized penicillin G acylase IPA750. At this time, the mass ratio of immobilized penicillin G acylase to 2-chlorophenylglycine methyl ester is 1:50. The temperature of the water bath is controlled at 30°C and the speed is controlled at 300r. / min, reacted for 30 hours, and finally separated the immobilized enzyme.

[0027] The reactor can adopt the batch reactor commonly used in industry.

Embodiment 2

[0029] In reactor, add 5.0g racemic 2-chlorophenylglycine methyl ester and 50mL pH 7.0, 0.2mol / L sodium phosphate buffer solution, now the concentration of racemic 2-chlorophenylglycine methyl ester is 100g / L, Then add 0.2 g of immobilized penicillin G acylase IPA750, at this time the mass ratio of immobilized penicillin G acylase to 2-chlorophenylglycine methyl ester is 2:50, the temperature of the water bath is controlled at 30°C, and the control speed is 300r / min, reacted for 20 hours, and finally separated the immobilized enzyme.

Embodiment 3

[0031] Add 5.0g racemic 2-chlorophenylglycine methyl ester and 50mL pH 7.0, 0.01mol / L sodium phosphate buffer solution in reactor, the concentration of racemic 2-chlorophenylglycine methyl ester is 100g / L now, Then add 0.1 g of immobilized penicillin G acylase IPA750. At this time, the mass ratio of immobilized penicillin G acylase to 2-chlorophenylglycine methyl ester is 1:50. The temperature of the water bath is controlled at 30°C and the speed is controlled at 300r. / min, reacted for 30 hours, and finally separated the immobilized enzyme.

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Abstract

The invention discloses a method for preparing an (S)-2-chlorophenylglycine methyl ester single enantiomer by virtue of biological enzyme catalysis. The method comprises the following steps: adding racemized 2-chlorophenylglycine methyl ester and a sodium phosphate buffer solution into a reactor with the water bath constant temperature of 30 DEG C, stirring, then adding penicillin G acylase, controlling the stirring rotating speed to be 100-500r / min, controlling the reaction time to be 20-60 hours, continuously stirring until reaction ends, and finally recycling penicillin G acylase. The method disclosed by the invention has the beneficial effects that PGA is adopted as a catalyst, and reaction under normal temperature and normal pressure by using the activity, high selectivity and specificity to substrates of PGA to prepare (S)-2-chlorophenylglycine methyl ester through one-step, so that protection and deprotection processes of reactive groups in chlorophenylglycine can be saved, the (S)-2-chlorophenylglycine methyl ester single enantiomer with higher optical purity also can be obtained, and the enantiomer excess can reach more than 95%; and the method is simple and easily-controllable in operation process, is low in energy consumption in a preparation process, is low in emission, and is of an environment-friendly preparation method.

Description

technical field [0001] The invention relates to a method for preparing a single enantiomer of (S)-2-chlorophenylglycine methyl ester, in particular to a method for preparing a single enantiomer of (S)-2-chlorophenylglycine methyl ester catalyzed by biological enzymes, which belongs to medical technology field. Background technique [0002] 2-Chlorophenylglycine is a biologically active unnatural amino acid, and (S)-2-chlorophenylglycine methyl ester is the key chiral structural unit of the new drug clopidogrel for the treatment of thrombotic diseases. Clopidogrel is a safe and effective platelet aggregation inhibitor with remarkable efficacy, safety and strong tolerance, and has been widely used in clinical treatment. [0003] [0004] Clopidogrel is a chiral drug, and its S-configuration molecule has strong platelet aggregation inhibitory activity, and its tolerance is 40 times that of the R-configuration, and the R-configuration will produce convulsions after administr...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P41/00C12P13/00
Inventor 薛屏帅慧慧马原张立根李鹏
Owner NINGXIA UNIVERSITY
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