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New method of biologically synthesizing (R)-3-hydroxylglutarate monoester

A technology for hydroxyglutaric acid monoester and hydroxybutyric acid monoester, which is applied in the fields of biocatalysis to prepare pharmaceutical intermediates and green chemistry

Inactive Publication Date: 2014-11-19
TIANJIN INST OF IND BIOTECH CHINESE ACADEMY OF SCI
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0022] We found that the current biocatalytic synthesis of ( R )-3-Hydroxyglutaric acid monoester technology, there is no use of biocatalysts by ( S )-4-chloro-3-hydroxybutyrate one-pot synthesis ( R )-3-hydroxyglutaric acid monoester method; moreover, there is no report on the tandem reaction of halohydrin dehalogenase and nitrilase for biocatalysis

Method used

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  • New method of biologically synthesizing (R)-3-hydroxylglutarate monoester
  • New method of biologically synthesizing (R)-3-hydroxylglutarate monoester
  • New method of biologically synthesizing (R)-3-hydroxylglutarate monoester

Examples

Experimental program
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Effect test

Embodiment 2

[0050] Example 2 Acquisition of genetically engineered bacteria that co-express halohydrin dehalogenase and nitrilase

[0051] According to standard methods, the above-mentioned halohydrin dehalogenase and nitrilase were constructed into the same pETDuet-1 vector. The structure of the double-enzyme co-expression plasmid for halohydrin dehalogenase and nitrilase is shown in Fig. figure 1 shown. The obtained co-expression vector is transferred into Escherichia coli BL21, Rosetta or Origami by conventional methods to construct co-expression genetically engineered bacteria, and screened out genetically engineered bacteria that have been established successfully. Preferably, the co-expressed genetically engineered bacteria are stored in the form of glycerol bacteria or milk freeze-dried bacteria.

Embodiment

[0052] Example 3 Cultivation of genetically engineered bacteria and preparation of resting cells

[0053] Pick a single colony on the plate and inoculate it into 5 ml of fermentation medium containing the corresponding antibiotics, cultivate it for about 15 hours as a seed solution, and inoculate it into 600 ml of fermentation medium according to the inoculum of 1%, at 37 ° C, 200 rpm on a shaker to OD 600 =0.6-0.8, add IPTG with a final concentration of 0.1 mM for induction at 25°C for more than 10 h, and centrifuge the culture medium at 8000 rpm to collect the bacteria.

[0054] Example 4 Co-expression recombinant bacteria resting cell synthesis ( R )-3-hydroxyglutaric acid monoester - a single input substrate

[0055] Take 3.0 g of resting cells (wet weight) of co-expressing genetically engineered bacteria and resuspend in 50 ml sodium phosphate buffer (50 mM, pH 8.0), add ( S )-4-chloro-3-hydroxybutyrate (2.5 g, 15 mmol), then utilize the pH on-line control system, ...

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Abstract

The invention relates to a new method of biologically synthesizing (R)-3-hydroxylglutarate monoester and more particularly provides a method of preparing the (R)-3-hydroxylglutarate monoester from (S)-4-chloro-3-hydroxybutyrate through halogenohydrin dehalogenase recombinant bacteria and nitrilase recombinant bacteria, or double-enzyme co-expression recombinant bacteria, in a one-pot manner. The (R)-3-hydroxylglutarate monoester is a key intermediate of statin medicines such as fluvastatin, rosuvastatin, pitavastatin and the like. The method is mild in reaction conditions, is free of pollution and is simple in process route.

Description

technical field [0001] The invention belongs to the field of biocatalytic preparation of pharmaceutical intermediates and green chemistry, and relates to a method consisting of ( S )-4-chloro-3-hydroxybutyrate prepared in one pot ( R )-3-hydroxyglutaric acid monoester method; mainly relates to a ( R )-3-Hydroxyglutaric acid monoester biological preparation method. Background technique [0002] Rosuvastatin (trade name: Crestor) is a statin blood lipid-lowering drug developed by AstraZeneca. The drug was first approved in the Netherlands in November 2002. It was first listed in Canada in February 2003, and then successively in New Zealand. , the UK and the US. Rosuvastatin has achieved satisfactory results in terms of efficacy and safety after being marketed, and it is called a "super statin". The side chain of rosuvastatin contains two chiral centers, ( R )-3-Hydroxyglutaric acid monoester is a key intermediate in the synthesis of rosuvastatin chiral side chain. Rosuva...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12P7/62
Inventor 姚培圆吴洽庆袁京王雷冯进辉朱敦明马延和
Owner TIANJIN INST OF IND BIOTECH CHINESE ACADEMY OF SCI
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