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Biological catalysis method for preparing statin medicinal intermediate

A technology of biocatalysis and intermediates, applied in biochemical equipment and methods, microorganism-based methods, microorganisms, etc., can solve the problems of difficult synthesis, difficult screening of biocatalysts, and no nitrilase strains.

Active Publication Date: 2010-08-18
ZHEJIANG UNIV OF TECH
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  • Abstract
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Problems solved by technology

However, since the substrate 4-cyano-3-hydroxybutyric acid ethyl ester or its hydroxy-substituted derivatives all contain an ester group, and generally hydrolytic enzyme-containing microbial cells contain esterase or lipase that hydrolyzes the ester group, so The screening of this biocatalyst is also a big problem, so far, there is no relevant report on this nitrilase strain
These factors make the synthesis of optically pure ethyl (R)-3-hydroxyglutarate or its hydroxy-substituted derivatives difficult to achieve

Method used

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  • Biological catalysis method for preparing statin medicinal intermediate
  • Biological catalysis method for preparing statin medicinal intermediate
  • Biological catalysis method for preparing statin medicinal intermediate

Examples

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Embodiment 1

[0038] Example 1: Using Co 2+ Screening of nitrilase strains capable of selectively catalyzing the hydrolysis of ethyl 4-cyano-3-hydroxybutyrate to ethyl (R)-3-hydroxyglutarate by ion chromatography

[0039] (1) Prepare 1% soil sample suspension and sewage suspension with sterile water, inoculate 5ml to 45ml enrichment medium respectively, and culture on a shaker at 30°C and 150rpm for 2 days. The composition of each liter of enrichment medium is: glucose 5g, K 2 HPO 4 0.5g, MgSO 4 ·7H 2 O 0.5g, NaCl 0.1g, FeSO 4 ·7H 2 O 0.02g, solvent is water, pH 6.5. After aliquoting, sterilize at 0.1 MPa for 20 minutes, and add sterile-filtered ethyl 4-cyano-3-hydroxybutyrate to 1% (v / v) before inoculation. After the cultivation, take the turbid culture solution and inoculate 1ml into 49ml enrichment medium respectively, culture on a shaker at 30°C and 150rpm for 2 days, and enrich in this way 4 times. Take the relatively well-growing culture solution to coat the separation plate,...

Embodiment 2

[0044] Example 2: Preparation of biocatalyst R. erythropolis CCTCC NO: M209244 cells

[0045] Pick a ring of bacteria from the inclined surface of the test tube of the new nitrilase-producing strain R.erythropolis CCTCCNO: M 209244 obtained by the present invention, inoculate it into 50ml sterile seed medium, and place it on a shaker at 30°C and 150rpm Cultivate for 24 hours to obtain seed solution. The composition of each liter of seed medium is: glucose 8g, peptone 5g, K 2 HPO 4 0.5g, MgSO 4 ·7H 2 O 0.2g, the solvent is water, the pH is natural, and sterilized at 0.1MPa for 20min.

[0046] The seed solution was transferred to 100.0ml sterile fermentation medium with 3% (v / v) inoculation amount, and cultured on a shaker at 30°C and 150rpm for 48h. The composition of each liter of fermentation medium is: glucose 20g, peptone 10g, caprolactam 1g, K 2 HPO 4 0.5g, MgSO 4 ·7H 2 O 0.2g, solvent is water, pH 7.0. Sterilize at 0.1MPa for 20min. After cultivating, obtain ...

Embodiment 3

[0047] Example 3: Preparation of biocatalyst R. erythropolis CCTCC NO: M 209149 cells The preparation method of the whole cell catalyst is the same as in Example 2.

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Abstract

The invention provides a method for preparing and synthesizing a statin medicinal intermediate, namely, an (R)-3-hydroxy-glutaric acid ethyl ester or a hydroxy substituted derivative of the (R)-3-hydroxy-glutaric acid ethyl ester with high optical activity by performing chiral separation on a racemic 4-cyano-group-3-hydroxy butyric acid ethyl ester or a hydroxy substituted derivative of the 4-cyano-group-3-hydroxy butyric acid ethyl ester and a strain. The method comprises the following steps: performing a conversion reaction in a reaction system in which a compound shown in a formula (11) is used as a substrate and an enzyme obtained by fermenting and culturing rhodococcus erythropolis CCTCC No:M 209244 or CCTCC No:M 209194 is used as a catalyst at the temperature of between 10 and 50 DEG C; and after the reaction, separating and purifying reaction liquid to obtain the compound shown in formula (I). The method realizes obtaining the (R)-3-hydroxy-glutaric acid ethyl ester or the hydroxy substituted derivative of the (R)-3-hydroxy-glutaric acid ethyl ester with high optical activity by catalyzing and hydrolyzing the racemic 4-cyano-group-3-hydroxy butyric acid ethyl ester or the hydroxy substituted derivative of the 4-cyano-group-3-hydroxy butyric acid ethyl ester in one step under the condition of not hydrolyzing an ester group in the substrate or producing any byproduct, and overcomes the defects of more byproducts, low target product yield, low optical purity and the like brought by a conventional synthetic method in a hydrolyzing process, such as a chemical method.

Description

(1) Technical field [0001] The invention relates to a method for producing a statin drug intermediate (R)-3-hydroxyglutaric acid ethyl ester or a hydroxy-substituted derivative thereof by a biocatalysis method, and a bacterial strain used in the production process. (2) Background technology [0002] Statins are currently the most effective drugs for the treatment of cardiovascular diseases such as hypertension and hyperlipidemia. Rosuvastatin, also known as super statin, has attracted increasing attention as a new type of statin with better efficacy. However, because the synthesis process of its chiral side chain is not perfect, its preparation cost is much higher than that of other statins, so the sales price has been high, which restricts its market development and development, and also hinders its development. Effective control and treatment of cardiovascular diseases. Because in the synthesis and preparation process of statins, the synthesis of chiral side chains with ...

Claims

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Application Information

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IPC IPC(8): C12P7/42C12P7/40C12N1/20C12R1/01
Inventor 郑裕国董华平沈寅初
Owner ZHEJIANG UNIV OF TECH
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