Preparation method of ethyl (R)-4-cyano-3-hydroxybutyrate

A technology of ethyl hydroxybutyrate and hydroxybutyrate, which is applied in the field of preparation of pharmaceutical intermediates, can solve the problems of low yield, complicated post-processing, high production cost, etc., achieve simple post-processing, high operational stability, and benefit The effect of production costs

Inactive Publication Date: 2015-12-09
JIANGSU UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0014] The purpose of the present invention is to solve the problems of the existing halohydrin dehalogenase method with high production cost, complicated post-treatment and low yield, and provide a ( R) The preparation method of -4-cyano-3-hydroxybutyrate

Method used

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Examples

Experimental program
Comparison scheme
Effect test

example 1）

[0030] This example is the preparation method of immobilized halohydrin dehalogenase:

[0031] S1: Dilute the commercially purchased HheC halohydrin dehalogenase solution (initial enzyme activity of 8 million U / g protein) to a protein content of 10 mg / mL to obtain a halohydrin dehalogenase solution.

[0032] S2: Take 200 mL of the halohydrin dehalogenase solution obtained in step S1 (enzyme protein is 2 g), add 30 g of D151 / D152 type adsorption resin, and stir and adsorb at a temperature of 25 ° C for 8 h.

[0033] S3: Add 2 mL of glutaraldehyde solution (25%, v / v), and cross-link for 0.5 h.

[0034] S4: Finally, filter and wash with buffer solution for 3 times to obtain immobilized halohydrin dehalogenase.

[0035] The immobilized halohydrin dehalogenase was stored at 4°C until use.

[0036] The enzyme activity of the immobilized halohydrin dehalogenase prepared in this example is 189,100 U / g.

[0037] Enzyme activity definition: under constant temperature conditions of 30...

example 2～ example 10）

[0039] The preparation method of the immobilized halohydrin dehalogenase of each example is basically the same as Example 1, and the differences are shown in Table 1.

[0040] Table 1

[0041]

[0042] It can be seen from Table 1 that, under other conditions being the same, the immobilized halohydrin dehalogenase prepared in Example 1 and Example 6 had the highest enzyme activity.

Embodiment 1）

[0044] The preparation method of (R)-4-cyano-3-hydroxybutyric acid ethyl ester of this embodiment has the following steps:

[0045] ①Add 400g of water and 900g of 30wt% sodium cyanide solution to a 2L reaction kettle, slowly adjust the pH value to 8.0 with 30wt% dilute sulfuric acid, and then add 910g of (S)-4- Ethyl chloro-3-hydroxybutyrate (e.e. value 99%), and then adjust the pH value to 7.0±0.2 with a 30 wt% sodium cyanide solution.

[0046]②Slowly heat up to 50°C, then add 15g of the immobilized halohydrin dehalogenase prepared in Example 1, add dropwise a 30wt% sodium cyanide solution to adjust the pH to 7.0±0.2, and track the reaction by gas phase detection process, when the content of ethyl (R)-4-cyano-3-hydroxybutyrate reaches more than 50%, add 15g of the immobilized halohydrin dehalogenase prepared in Example 1, and keep the temperature at 50°C and The pH value was 7.0±0.2, and the reaction was terminated when the content of ethyl (S)-4-chloro-3-hydroxybutyrate was...

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Abstract

The invention discloses a preparation method of ethyl (R)-4-cyano-3-hydroxybutyrate. According to the preparation method, ethyl (S)-4-chloro-3-hydroxybutyrate is taken as a substrate, immobilized halohydrin dehalogenase is taken as a catalyst, the substrate and the catalyst react with cyanide salt under the condition of pH value in a range from 6.5 to 8.0, and ethyl (R)-4-chloro-3-hydroxybutyrate is obtained; a preparation method of immobilized halohydrin dehalogenase comprises steps as follows: adsorbent resin is added to a halohydrin dehalogenase solution, the halohydrin dehalogenase is adsorbed on the adsorbent resin and crosslinked by a difunctional crosslinking agent, finally, the adsorbent resin is separated from the halohydrin dehalogenase solution and washed, and the immobilized halohydrin dehalogenase is obtained. The enzyme recovery rate of the immobilized halohydrin dehalogenase is high, the operation stability is high, reduction of production cost is facilitated, when the immobilized halohydrin dehalogenase is used for preparing ethyl (R)-4-cyano-3-hydroxybutyrate, the process is simple, the resolution effect is excellent, e.e. value can be up to 99%, particularly, the postprocessing is simpler, and the yield can be higher than 91%.

Description

technical field [0001] The invention relates to a preparation method of a pharmaceutical intermediate, in particular to a preparation method of ethyl (R)-4-cyano-3-hydroxybutyrate. Background technique [0002] (R)-4-cyano-3-hydroxybutyrate ethyl ester is an important intermediate for the synthesis of atorvastatin calcium, and its preparation methods mainly include chemical and enzymatic methods. [0003] Among them, chemical methods mainly include the following: [0004] (1) Using S-epichlorohydrin as the starting material, (R)-4-cyano-3-hydroxybutyric acid ethyl ester was prepared through hydrolysis reaction, esterification reaction, chiral center protection reaction and deprotection reaction (See the literature LettOrgChem, 2012, No. 9, pp. 520-521); the disadvantage of this method is: the yield is low, and the optical purity of the product is also low, thereby limiting its application in industry. [0005] (2) Using L-malic acid as the starting material, (R)-4-cyano-3-...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P13/00
Inventor 汪斌梁国斌刘维桥顾梦涛翟良创张春勇周全法
Owner JIANGSU UNIV OF TECH
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