Preparation method for continuous cyclic synthesis of ethyl(R)-4-cyano-3-hydroxybutyrate

Abstract

The invention relates to a preparation method for continuous cyclic synthesis of ethyl(R)-4-cyano-3-hydroxybutyrate. The preparation method comprises the following step: ethyl(S)-4-chloro-3-hydroxybutyrate(ATS-4) is used as a substrate; ethyl(R)-4-cyano-3-hydroxybutyrate (ATS-5) is synthesized by adopting an enzymatic method; aiming at the defects that in the enzymatic method reaction process, immobilized enzymes are likely to smash by a stirring paddle to cause the service cycles of the immobilized enzymes to be reduced; a primary circulating pump is utilized to input a reaction liquid from the bottom of a device filled with immobilized halohydrin dehalogenase microspheres capable of regulating and controlling pH and to output the reaction liquid from the upper part of the device, so that a circulation catalytic reaction is realized; the reaction process is detected in real time by utilization of gas chromatography. The immobilized enzyme microspheres cannot be smashed, the service cycle of the immobilized enzyme can be greatly prolonged, the enzyme utilization ratio is high, and the catalytic effect is good; the preparation method is mild in reaction condition, high in reaction speed, low in cost, simple to operate, good in stability, and suitable for industrial continuous production.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and relates to a method for preparing an atorvastatin intermediate, in particular to a method for continuously synthesizing ethyl (R)-4-cyano-3-hydroxybutyrate. Background technique [0002] Scientists have found that statins not only have a powerful lipid-lowering effect, but also have multiple effects. They can improve intravascular cardiomyocyte remodeling and inhibit cardiac electrophysiological remodeling, prevent cardiomyocyte apoptosis and regulate cardiac autonomic function, etc. Wait. The emergence of statins is an important milestone in the history of cardiovascular disease treatment, and has become an assistant blood lipid regulating drug for the treatment of various types of hyperlipidemia, prevention and treatment of arteriosclerosis and coronary heart disease, and is also a well-known drug in the global pharmaceutical market. "Blockbuster" drugs. Atorvastatin (trade n...

AI Technical Summary

Problems solved by technology

[0005] However, the existing halohydrin dehalogenase catalytic method still has the following disadvantages: (1) the halohydrin dehalogenase cannot be reused, resulting in high production costs; (2) the enzyme stays in the reaction system for a long time, which affects the enzyme Catalytic activity, resulting in low enzyme utilization

Chinese patent CN 101760468 discloses a method for catalyzing the production of (R)-4-cyano-3-hydroxybutyric acid ethyl ester by using the mutated halohydrin dehalogenase, but the enzyme activity is low, the catalytic efficiency is low, and the cost is high. Conducive to large-scale industrial production

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