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Biocatalytic hydrogenation composition and method for synthesis of Rosuvastatin chiral intermediate

A biocatalysis and composition technology, applied in biochemical equipment and methods, microorganism-based methods, microorganisms, etc., can solve the problems of poor product stereoselectivity, unsuitable for large-scale production, unfavorable large-scale production, etc., and achieve product stereoselectivity. The effect of poor selectivity, high product stereoselectivity and low cost

Inactive Publication Date: 2016-06-29
ANGELYEAST CO LTD
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  • Description
  • Claims
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Problems solved by technology

The report involves a total of eight steps of reaction, the operation is cumbersome, the yield is low, and it is not conducive to large-scale production
[0007] The methods reported in the above literatures generally require 6-8 steps of chemical reactions, the operation process is cumbersome, the overall yield is low, and it is not suitable for large-scale production
Moreover, they are all chemical synthesis methods, with low safety, serious pollution, harsh reaction conditions, low yield, and poor product stereoselectivity

Method used

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  • Biocatalytic hydrogenation composition and method for synthesis of Rosuvastatin chiral intermediate
  • Biocatalytic hydrogenation composition and method for synthesis of Rosuvastatin chiral intermediate
  • Biocatalytic hydrogenation composition and method for synthesis of Rosuvastatin chiral intermediate

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preparation example Construction

[0051] The present invention also provides a kind of preparation method of rosuvastatin intermediate, comprises the steps:

[0052] (1) In the tetrahydrofuran solution, according to the ratio of the amount of substances (S)-3-hydroxybutyrolactone: tert-butyl acetate = 1:2 feeding, under the protection of argon, under low temperature conditions, through diisopropylamino Lithium-catalyzed Claisen condensation reaction to generate (S)-5,6-dihydroxy-3-oxohexanoic acid tert-butyl ester;

[0053] (2) Mix (S)-5,6-dihydroxy-3-oxohexanoic acid tert-butyl ester with glucose dehydrogenase, ketoreductase and coenzyme to prepare (3R,5S)-3,5 , tert-butyl 6-trihydroxyhexanoate;

[0054] (3) tert-butyl (3R,5S)-3,5,6-trihydroxyhexanoate obtained in step (2) is reacted with 2,2-methoxypropane under the catalysis of methanesulfonic acid to obtain acetonylidene Protected tert-butyl (3R,5S)-3,5,6-trihydroxyhexanoate. In the preparation method, in step (2), (S)-5,6-dihydroxy-3-oxohexanoic acid t...

Embodiment 1

[0108] Preparation and activity detection of embodiment 1 ketoreductase and glucose dehydrogenase

[0109] 1. Preparation and Activity Detection of Ketoreductase

[0110] 1.1 Preparation of Ketoreductase

[0111] (1) Shake flask fermentation culture of ketoreductase

[0112] Inoculate the recombinant Escherichia coli from the slant medium into 30mL liquid LB medium containing 20uL ampicillin, and then complete the primary culture process for 18 hours at 25°C and 240rpm. Then, the primary culture seeds were inoculated into 1 L of liquid LB medium containing 5-10 mL of arabinose inducer, and cultured at the same temperature and rotation frequency for 20 hours to complete the secondary culture process. After the culture solution was centrifuged at 4000rpm for 12 minutes, the bacteria were collected, and the wet weight of the bacteria was weighed, and then the mass volume ratio was m bacteria: v buffer = 1:10 concentration ultrasonic / high pressure disruption. After complete cru...

Embodiment 2

[0142] Preparation and activity detection of embodiment 2 ketoreductase and glucose dehydrogenase

[0143] 1. Preparation and Activity Detection of Ketoreductase

[0144] 1.1 Preparation of Ketoreductase

[0145] (1) Shake flask fermentation culture of ketoreductase

[0146] Inoculate the recombinant Escherichia coli from the slant medium into 30mL liquid LB medium containing 25uL ampicillin, and then complete the primary culture process for 19 hours at 30°C and 240rpm. Then, the primary culture seeds were inoculated into 1 L of liquid LB medium containing 8 mL of arabinose inducer, and cultured at the same temperature and rotation frequency for 22 hours to complete the secondary culture process. After the culture solution was centrifuged at 4000rpm for 12 minutes, the bacteria were collected, and the wet weight of the bacteria was weighed, and then the mass volume ratio was m bacteria: v buffer = 1:8 concentration ultrasonic / high pressure disruption. After complete crushin...

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Abstract

A selective biocatalytic hydrogenation composition comprises glucose dehydrogenase, ketoreductase and coenzyme. The present invention also provides a preparation method of tert-butyl (3R, 5S) 3,5,6-trihydroxy hexanoate, and the tert-butyl (3R, 5S) 3,5,6-trihydroxy hexanoate is prepared by mixing tert-butyl (S)-5,6-dihydroxy-3-oxo-hexanoate with the glucose dehydrogenase, the ketoreductase and the coenzyme for reaction. The present invention also provides a method for synthesis of a Rosuvastatin intermediate, and the Rosuvastatin intermediate is mainly prepared from the selective biocatalytic hydrogenation composition. Compared with the prior art, the method has the advantages of being mild in reaction conditions, safe, environmentally-friendly, low in cost, high in product stereoselectivity, and the like.

Description

technical field [0001] The invention relates to a selective biocatalytic hydrogenation composition and a method for synthesizing (3R,5S)-3,5,6-trihydroxyhexanoic acid tert-butyl ester. Specifically, the present invention belongs to the technical field of preparation of pharmaceutical intermediates. Specifically, the present invention relates to the biocatalytic synthesis of rosuvastatin chiral intermediate (3R,5S)-3,5,6-trihydroxyacetic acid tertiary butyl ester. Background technique [0002] Hyperlipidemia, characterized by high levels of cholesterol and triglycerides or accompanied by low levels of serum high-density lipoprotein cholesterol, is the main cause of atherosclerosis and subsequently coronary heart disease, hypertension and cerebrovascular disease. Hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitors lipid-lowering drugs are currently the first choice for lowering cholesterol. Statins limit the metabolic pathway of cholesterol in the body by inhibit...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12N9/04C12P7/62C12R1/19
Inventor 戴秋红俞学锋李知洪姚鹃邹林汉余华顺李明付坤林平磊
Owner ANGELYEAST CO LTD
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