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Rhodococcus qingshengii and application thereof in preparation of ethyl (S)-4-chloro-3-hydroxy butyrate

A technology of Rhodococcus and Qingsheng, applied to Rhodococcus Qingsheng and its application field in the preparation of (S)-4-chloro-3-hydroxybutyric acid ethyl ester, can solve the problem that the catalyst is expensive and the reactor requirements are relatively high. High, high production costs

Active Publication Date: 2014-02-19
ZHEJIANG UNIV OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Chemical catalysis is the use of chiral ruthenium compounds (such as RuX 2 [(S)-BINAP]) is used as a catalyst for asymmetric hydrogenation reduction, and the e.e. value of the product can reach more than 97%. higher cost

Method used

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  • Rhodococcus qingshengii and application thereof in preparation of ethyl (S)-4-chloro-3-hydroxy butyrate
  • Rhodococcus qingshengii and application thereof in preparation of ethyl (S)-4-chloro-3-hydroxy butyrate
  • Rhodococcus qingshengii and application thereof in preparation of ethyl (S)-4-chloro-3-hydroxy butyrate

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Experimental program
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Effect test

Embodiment 1

[0038] Embodiment 1: the screening of bacterial strain

[0039] Isolation of carbonyl reductase-producing bacteria: add 1g of soil sample to 9mL of 0.85% normal saline, mix thoroughly on a vortex shaker to form a uniform soil suspension; draw 1.0mL of soil suspension and inoculate in Put 39mL enrichment medium in a 250mL Erlenmeyer flask, place it at 28°C, and incubate on a shaker at 150rmp for 72h. After the enrichment solution becomes turbid, transfer 1.0mL to a fresh enrichment medium and continue to incubate for 72h. ; Carry out three rounds of enrichment in this way, dilute the enriched culture solution in multiple gradients and spread it on the separation plate to obtain a single colony;

[0040] The composition of the enrichment medium is as follows (final concentration): glucose 8g / L, peptone 5g / L, yeast extract 5g / L, beef extract 4g / L, NaCl 4g / L, prepared with distilled water, adjusted with 1.0mol hydrochloric acid or NaOH solution pH to 7.0; the isolation plate medi...

Embodiment 2

[0042] Embodiment 2: the fermentation culture of Rhodococcus qingshengii ZJB-12028

[0043] (1) Slant culture: Rhodococcus qingshengii ZJB-12028 was inoculated on the slant medium and cultured at 28° C. for 24 hours to obtain slant cells. Slant medium formula: glucose 8g / L, peptone 5g / L, yeast extract 5g / L, beef extract 4g / L, NaCl 4g / L, agar 20g / L, prepared with distilled water, natural pH.

[0044] (2) Seed culture: pick a ring of bacteria from the slant with an inoculation loop and inoculate it in the seed medium, and cultivate it at 28° C. and 150 r / min for 24 hours to obtain a seed liquid. The formula of the seed medium is: glucose 8g / L, yeast extract 5g / L, peptone 5g / L, beef extract 4g / L, NaCl 4g / L, distilled water, and the initial pH is 6.0.

[0045] (3) Fermentation culture: Inoculate the cultured seed solution into the fermentation medium at a volume ratio of 2%, and cultivate it for 24 hours at 28°C and a shaker rotation speed of 150r / min to obtain a fermentation liq...

Embodiment 3

[0046] Embodiment 3: the fermentation culture of Rhodococcus qingshengii ZJB-12028

[0047] Fermentation culture: Inoculate the seed solution cultivated according to the steps (1) to (2) of the example into the fermentation medium at a volume ratio of 2%, and cultivate it for 24 hours at 30°C and 150r / min on the shaking table. Obtain the fermented liquid containing bacteria cells. The obtained fermentation broth containing bacteria cells was centrifuged, the supernatant was discarded, washed twice with normal saline, and then collected by centrifugation to obtain wet bacteria. The yield of bacteria was 11.3g / L (dry weight basis). The formula of the fermentation medium is: glucose 40g / L, yeast extract 20g / L, peptone 10g / L, beef extract 5g / L, MgSO 4 ·7H 2 O0.5g / L, NaCl4g / L, K 2 HPO 4 0.5g / L, the solvent is water, and the initial pH is 7.0.

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Abstract

The invention provides a new strain-Rhodococcus qingshengii ZJB-12028 and an application of the strain in preparation of an atorvastatin key chiral intermediate ethyl (S)-4-chloro-3-hydroxy butyrate ((S)-CHBE) through microbial asymmetric reduction of ethyl-4-chloroacetoacetate. The strain is preserved in China Center for Type Culture Collection, wherein the address is Wuhan University, Wuhan, China 430072, the preservation date is September 4, 2013, and the preservation number is CCTCC NO: M2013390. The strain has good stability, strict stereoselectivity and high optical purity of product and has the advantages of mild reaction conditions, environmental friendliness and the like when being used for preparing (S)-CHBE, so that the strain has a high industrial application potential.

Description

(1) Technical field [0001] The present invention relates to a new bacterial strain - Rhodococcus qingshengii ZJB-12028, and the key chiral intermediate (S) of atorvastatin prepared by the bacterial strain by asymmetric reduction of ethyl 4-chloroacetoacetate - Application of ethyl 4-chloro-3-hydroxybutyrate. (2) Background technology [0002] (S)-4-chloro-3-hydroxybutanoate (Ethyl(S)-4-chloro-3-hydroxybutanoate, (S)-CHBE) is an important chiral drug intermediate, which can be used in the synthesis of statins Drug-like competitive inhibitor of hydroxymethylglutaryl CoA (HMG-CoA) reductase, which can inhibit the synthesis of cholesterol in the liver, thereby reducing the content of cholesterol in the blood and reducing the incidence of cardiovascular and cerebrovascular diseases. The trade name of the drug is Lipitor (atorvastatin calcium), which is the first drug with an annual sales volume of more than 10 billion US dollars in the United States, and is currently the drug wi...

Claims

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Application Information

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IPC IPC(8): C12N1/20C12P7/62C12R1/01
Inventor 郑裕国孙丽慧朱斌斌沈寅初
Owner ZHEJIANG UNIV OF TECH
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