Method for resolving 2-chloromandelic acid enantiomer by enzymatic interesterification kinetics

A technology of kinetic splitting and lipase-catalyzed ester, which is applied in fermentation and other directions, can solve the problems of low conversion rate, low thermal stability and stereoselectivity, long reaction time, etc., achieve high reuse rate and improve thermal stability performance, catalytic efficiency, and reduction of by-products

Inactive Publication Date: 2019-06-11
HUNAN INSTITUTE OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
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  • Application Information

AI Technical Summary

Problems solved by technology

And aiming at the problem of low thermal stability and stereoselectivity of lipase in aqueous medium, resulting in long reaction time and low conversion rate, by changing to an organic medium system, the thermal stability and catalytic activity of lipase are improved, thereby improving the conversion rate and optical activity

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] Add 1.25 mmol of racemic 2-chloromandelic acid enantiomers and 7.5 mmol of vinyl acetate into a 25 mL volumetric flask, and add methyl tert-butyl ether to constant volume to prepare a reaction solution. Add 50 mg of different commercial lipases and 0.10% phosphate buffer into a series of reaction tubes, then add 2 mL of reaction solution respectively, and heat the reaction at 500 rpm and 50 °C for 24 h; Chromatography was used to analyze the substrate conversion and the enantiomeric excess of the substrate. The analysis results showed that Pseudomonas fluorescens lipase preferentially recognized ( R )-2-chloromandelic acid, its ( R )-2-chloromandelic acid conversion rate was 99.26%, and the enantiomeric excess of the substrate was 98.48%.

Embodiment 2

[0019] In a 25 mL volumetric flask, add 1.25 mmol of racemic 2-chloromandelic acid enantiomer and 6.25 mmol of vinyl acetate, and then add methyl tert-butyl ether to make up to volume. In the reaction tube, add 50 mg of Pseudomonas fluorescens lipase and phosphate buffer with a water content of 0.10% (v / v) in sequence, then add 2 mL of reaction solution, and react at 500 rpm and 50 °C for 24 h . After the reaction, the substrate conversion rate and substrate enantiomeric excess were analyzed by high performance liquid chromatography. The results show that:( R The conversion rate of )-2-chloromandelic acid was 97.94%, and the enantiomeric excess of the substrate was 95.98%.

Embodiment 3

[0021] In a 25 mL volumetric flask, add 1.25 mmol of racemic 2-chloromandelic acid enantiomer and 7.50 mmol of vinyl acetate, and then add methyl tert-butyl ether to make up to volume. Add 50 mg of Pseudomonas fluorescens lipase and phosphate buffer with a water content of 0.10% (v / v) in turn to the reaction tube, then add 2 mL of reaction solution, and react at 45 °C and 500 rpm for 24 h. After the reaction, the substrate conversion rate and substrate enantiomeric excess were analyzed by high performance liquid chromatography. The results show that:( R )-2-chloromandelic acid conversion was 99.24 % and the enantiomeric excess of the substrate was 98.43 %.

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Abstract

This patent describes a method for resolving 2-chloromandelic acid enantiomer by biocatalyst catalytic interesterification kinetics. Racemic 2-chloromandelic acid is resolved in an organic solvent medium by catalytic interesterification kinetics by utilizing high-catalytic efficiency and high-stereoselectivity lipase so as to obtain (S)-2-chloromandelic acid and (R)-acetyl-2-chloromandelic acid. The reaction system adopts an organic solvent as a reaction medium, greatly improves the thermal stability and the catalytic efficiency of the lipase, and greatly improves the substrate conversion rateand the optical activity, and the optical activity of the substrate is 98.15% or above. Compared with other resolving technologies, the method has the advantages of mild reaction conditions, simple operation and little environmental pollution, and can obtain the (S)-2-chloromandelic acid and (R)-acetyl-2-chloromandelic acid with high optical purity, and the (R)-acetyl-2-chloromandelic acid is used as a precursor of a key intermediate for synthesizing a chiral resolving agent and clopidogrel with high application prospect. The patent provides a feasible obtaining method.

Description

technical field [0001] The invention belongs to the technical field of biocatalysis and uses a biocatalysis method to prepare chiral compounds. In particular, it relates to a method for using lipase AK (pseudomonas fluorescens lipase) stereoselectively to catalyze transesterification kinetics to split 2-chloromandelic acid enantiomers. Background technique [0002] 2-Chloromandelic acid belongs to hydroxy acid drug intermediates. optically pure ( R )-2-chloromandelic acid (( R )-2-ClMA) is an important intermediate in the synthesis of clopidogrel, a widely used anticoagulant that reduces the risk of cardiovascular failure in patients with acute coronary syndrome. Compared with aspirin, which has the same efficacy, aspirin can directly cause damage to the gastric mucosa, and can inhibit the synthesis of prostaglandins, thereby destroying the gastric mucosal barrier, resulting in hydrogen ion reperfusion, causing gastric mucosal damage. Clopidogrel is only slightly irritat...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P7/42C12P41/00
Inventor 唐课文袁欣张盼良许卫凤
Owner HUNAN INSTITUTE OF SCIENCE AND TECHNOLOGY
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