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Method for catalytic esterification resolution of 2-(4-methylphenyl) propionic acid enantiomer via stereoselective enzyme

A technology of stereoselectivity and methyl phenyl, which is applied in the field of biocatalytic preparation of chiral compounds, can solve the problems of low thermal stability, low stereoselectivity, and low conversion rate, and achieve improved thermal stability and catalytic efficiency, High reusability, improved purity and yield

Active Publication Date: 2018-10-12
HUNAN INSTITUTE OF SCIENCE AND TECHNOLOGY
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  • Summary
  • Abstract
  • Description
  • Claims
  • 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 low conversion rate, by changing to an organic medium system, the thermal stability and catalytic activity of lipase are improved, thereby improving conversion rate and optical activity

Method used

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  • Method for catalytic esterification resolution of 2-(4-methylphenyl) propionic acid enantiomer via stereoselective enzyme

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Add 2.5 mmol of racemic 2-(4-methylphenyl)propionic acid enantiomer and 2.5 mmol of n-hexanol into a 25 mL volumetric flask, and add n-hexane to make up to volume. In a 25 mL reaction tube, pipette 2 mL of the reaction solution, add 60 mg of different commercial lipases, and heat the reaction at 600 rpm and 50 °C for 5 h; after the reaction, use high performance liquid chromatography The conversion rate of the substrate and the optical purity of the product were analyzed by an instrument. The analysis results showed that when the immobilized Candida antarctica lipase B was used as the catalyst, (R)-2-(4-methylphenyl)propionic acid was preferentially recognized, and the substrate conversion rate was 47.79%. The purity is 27.24%.

Embodiment 2

[0023] In a 25 mL reaction tube, add 0.1 mmol 2-(4-methylphenyl)propionic acid enantiomer and 0.1 mmol n-hexanol as the reaction substrate, 1 mL of different organic solvents as the reaction medium, add 50 mg immobilized Candida antarctica lipase B was reacted at 600 rpm and 50 °C for 1 h. After the reaction, the conversion rate of the substrate and the optical purity of the product were analyzed by high performance liquid chromatography. The analysis results showed that when n-hexane was used as the reaction medium, the conversion rate of the substrate was 53.79 %, and the optical purity of the substrate was 30.91 %.

Embodiment 3

[0025] In a 25 mL reaction tube, add 0.1 mmol 2-(4-methylphenyl)propionic acid enantiomer and 0.1 mmol different kinds of alcohols as reaction substrates, 1 mL n-hexane as reaction medium, add 50 mg immobilized Candida antarctica lipase B was reacted at 600 rpm and 50 °C for 10 min. After the reaction, the conversion rate of the substrate and the optical purity of the product were analyzed by high performance liquid chromatography. The analysis results showed that when n-hexanol was used as the acyl donor, the conversion rate of the substrate was 5.93%, and the optical purity of the substrate was 3.38%.

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Abstract

The invention discloses a method for catalytic esterification resolution of a 2-(4-methylphenyl) propionic acid enantiomer via stereoselective enzyme. On the basis of high catalysis efficiency and high stereoselectivity of lipase, catalytic esterification resolution of racemic 2-(4-methylphenyl) propionic acid is conducted in an organic solvent medium, so that the (S)-2-(4-methylphenyl) propionicacid is prepared. The reaction system, with the application of an organic solvent system, can improve thermal stability and catalysis efficiency of the lipase to a great extent, so that a substrate conversion rate and optical activity are greatly improved, and the optical activity of the substrate is greater than or identical to 97.84%. In comparison with other resolution technologies, the methodis gentle in reaction conditions, simple to operate and low in environmental pollution, and the obtained (S)-2-(4-methylphenyl) propionic acid is relatively high in optical purity; and with the (S)-2-(4-methylphenyl) propionic acid serving as a key intermediate product, a feasible method is provided for the preparation of loxoprofen sodium.

Description

technical field [0001] The invention belongs to the preparation of chiral compounds by biocatalysis, and in particular relates to a method for splitting 2-(4-methylphenyl)propionic acid enantiomers by using immobilized Antarctic yeast lipase B to catalyze stereoselective esterification. Background technique [0002] 2-(4-methylphenyl)propionic acid (MPPA) is a key intermediate in the synthesis of loxoprofen sodium, which has anti-inflammatory and analgesic effects. Loxoprofen sodium, as a kind of arylpropionic acid non-steroidal anti-inflammatory drug (NSAID), compared with clinically similar drugs, its characteristics are mainly reflected in: stronger (good clinical effect), faster (oral 30 Plasma concentration reaches the peak value in minutes), safer (less side effects); and wide indications, it can be widely used clinically for anti-inflammatory analgesia, rheumatoid arthritis, low back pain, frozen shoulder, neck, shoulder and wrist syndrome, etc. Analgesic and anti-in...

Claims

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Application Information

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IPC IPC(8): C12P41/00C12P7/40
CPCC12P7/40C12P41/00
Inventor 唐课文张盼良王璐骏袁欣许卫凤
Owner HUNAN INSTITUTE OF SCIENCE AND TECHNOLOGY
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