Preparation method for catalytic synthesis of (R)-4-cyano-3-hydroxybutanoate by halohydrin dehalogenases

Abstract

The invention relates to a preparation method for catalytic synthesis of (R)-4-cyano-3-hydroxybutanoate by halohydrin dehalogenases. According to the invention, (S)-4-chloro-3-hydroxybutanoate (ATS-4) is taken as a substrate, and (R)-4-cyano-3-hydroxybutanoate (ATS-5) is enzymatically synthesized, by aiming at the defects of the enzymatic method of slow reaction rate and low conversion rate, resin is selected as a carrier, halohydrin dehalogenases are adsorbed, and a reaction system of which the conversion rate is 50% is introduced into a distillation device, so that the residence time of enzymes in the reaction system is shortened, the enzyme inactivation is reduced, the enzymes can be recycled, and the utilization rate of the enzymes is increased. The preparation method for the catalytic synthesis of (R)-4-cyano-3-hydroxybutanoate by halohydrin dehalogenases disclosed by the invention is mild in reaction conditions, quick in reaction speed, low in cost, good in operation stability, high in conversion rate which is up to 98.8%-99.4% and free of side effects, and the prepared products are high in optical purity and suitable for industrial production.

Description

technical field [0001] The invention relates to a method for preparing a pharmaceutical intermediate, in particular to a method for preparing (R)-4-cyano-3-hydroxybutyrate ethyl ester catalyzed by halohydrin dehalogenase. Background technique [0002] Atorvastatin (trade name Lipitor, Lipitor) is the world's first drug with annual sales of more than 10 billion US dollars. It lowers blood cholesterol levels by inhibiting hydroxymethylglutaryl-CoA reductase, the rate-limiting step in cholesterol synthesis in the liver. Recently, a large number of clinical research results have shown that: in addition to being the most effective cholesterol-lowering drug, statins also have significant curative effects on various diseases such as osteoporosis, Alzheimer's disease, heart disease and diabetes. If further development For new indications, statins will undoubtedly have a wider range of clinical applications. (R)-4-cyano-3-hydroxybutyric acid ethyl ester (ATS-5), which is a key chir...

AI Technical Summary

Problems solved by technology

[0007] However, the existing halohydrin dehalogenase catalytic method still has the following deficiencies: (1) the halohydrin dehalogenase cannot be reused, resulting in high production costs; (2) the enzyme stays in the reaction system during the stirring process The longer the time, the higher the dispersion of the immobilized halohydrin dehalogenase by the stirring paddle, which fundamentally affects the catalytic activity of the enzyme, resulting in a low utilization rate of the enzyme. (3) After the reaction is completed, it is necessary to use activated carbon When the halohydrin dehalogenase is adsorbed from the reaction system, on the one hand, a small amount of halohydrin dehalogenase remains in the reaction solution, and it is difficult to remove in the subsequent rectification process, thus affecting the quality of the product; On the other hand, activated carbon will also adsorb a part of (R)-4-cyano-3-hydroxybutyric acid ethyl ester (ATS-5) while adsorbing halohydrin dehalogenase, thereby affecting the yield of the product, especially increasing post-processing complexity

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