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Preparation of pregabalin chiral intermediate with bio-enzyme method

A chiral intermediate, pregabalin technology, applied in the field of pregabalin chiral intermediate preparation by biological enzymatic method, can solve the problems of low optical purity of pregabalin product, many reaction steps, difficult industrialization, etc., to achieve simple and more Synthesis, low cost, effect of reducing reaction steps

Active Publication Date: 2012-05-23
瑞博(杭州)医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0017] The object of the present invention overcomes the disadvantages such as the reaction reagent used in the above-mentioned prior art is poisonous, many reaction steps, resolution difficulty, conversion rate is low, the obtained product pregabalin optical purity is low, is difficult for industrialization, and a kind of new preparation (S )-3-(carbamoylmethyl)-5-methyl hexanoate synthetic method

Method used

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  • Preparation of pregabalin chiral intermediate with bio-enzyme method
  • Preparation of pregabalin chiral intermediate with bio-enzyme method
  • Preparation of pregabalin chiral intermediate with bio-enzyme method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Add 0.05g of diethyl isobutylglutarate, 0.02g of ammonium carbamate, 1mL of tert-butanol, and 0.02g of biological enzymes into a 2mL centrifuge tube in sequence, seal it and place it in a shaker at 28°C and 180rpm for 66h . After completion of the reaction, centrifuge at 12,000 rpm for 10 min to remove enzymes and solid particles, and perform chromatographic detection and analysis. The conversion rate of the substrate is 98.41%, and the ee value of the product is 99.12%.

Embodiment 2

[0041] Example 2; (S)-3-(carbamoylmethyl)-5-methylhexanoic acid ethyl ester

[0042] Add 0.05g of diethyl isobutylglutarate, 0.02g of ammonium carbamate, 1mL of n-hexane, and 0.02g of biological enzyme into a 2mL centrifuge tube, seal it and place it in a shaker at 28°C and 180rpm to react for 66h. After completion of the reaction, centrifuge at 12000 rpm for 10 min to remove enzymes and solid particles. According to chromatographic analysis, the conversion rate of the substrate is 75.19%, and the ee value of the product is 98.35%.

Embodiment 3

[0043] Example 3: (S)-3-(carbamoylmethyl)-5-methylhexanoic acid ethyl ester

[0044] Add 0.05g of diethyl isobutylglutarate, 0.02g of ammonium carbamate, 1mL of isopropyl ether, and 0.02g of biological enzyme into a 2mL centrifuge tube in turn, seal it and place it in a shaker at 28°C and 180rpm to react for 66h . After completion of the reaction, centrifuge at 12000 rpm for 10 min to remove enzymes and solid particles, and perform chromatographic detection and analysis. The conversion rate is 66.57%, and the ee value of the product is 97.83%.

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Abstract

The invention relates to the technical field of preparation of a pregabalin chiral intermediate with a bio-enzyme method, in particular to the preparation of the pregabalin chiral intermediate with the bio-enzyme method. According to a preparation method, a compound of isobutyl glutarate shown as a formula (I) is used as a raw material and used for generating a compound of (S)-3-(carbamoyl methyl)-5-methylcaproate shown as a formula (II) in an organic solvent under the action of bio-enzyme and ammonia, wherein R is preferentially direct-chain or side-chain alkyl of C1-C4.

Description

technical field [0001] The present invention relates to a biological enzymatic method for preparing a pregabalin chiral intermediate, in particular to a biological enzymatic method for preparing a pregabalin intermediate (S)-3-(carbamoylmethyl)-5-methylhexyl esters. Background technique [0002] Pregabalin is also known as CI-1008 and PD-14472, and its chemical name is (3S)-3-aminomethyl-5-methylhexanoic acid. [0003] [0004] It is an aminobutyric acid (GABA) receptor antagonist developed by Pfizer of the United States. It was approved by the European Union in July 2004 and was first listed in the UK immediately. It is clinically used to treat neuralgia caused by diabetes and postherpetic neuralgia. , as well as the adjuvant treatment of partial incomplete epileptic seizures in adult patients, is the first drug approved by the FDA for the treatment of more than two types of neuropathic pain, with fewer administration times and less adverse reactions, and has broad mark...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P13/02
Inventor 罗积杏壮晓健沈文和车大庆
Owner 瑞博(杭州)医药科技有限公司
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