Process of using resin-immobilized halohydrin dehalogenase to catalytically synthesize (R)-4-cyan-3-hydroxy ethyl butyrate

Abstract

The invention relates to a process of using resin-immobilized halohydrin dehalogenase to catalytically synthesize (R)-4-cyan-3-hydroxy ethyl butyrate. The process includes that (S)-4-chlorine-3-hydroxy ethyl butyrate (ATS-4) is used as a substrate to enzymatically synthesize ATS-5; aiming at the defect that an enzymatic method is low in reaction rate and conversion rate, resin is selected as a carrier, and adsorption method HDHH is adopted. By the process, enzyme can be repeatedly utilized, and substrate conversion rate and product yield are increased, so that production cost is lowered. Experiments show that fixation rate of HHDH is above 45%, ATS-5 product generation rate of the first time is above 75% and even reaches up to 94.13%, and second-time conversion rate of immobilized enzyme after being recycled is above 35% and reaches 50% at most. The process is mild in reaction condition, free of enzyme residue, supportive of enzyme recycling, high in reaction speed, low in cost, high in product yield, free of adverse reaction and suitable for industrialized large-scale production.

Description

technical field [0001] The invention relates to a preparation method of an atorvastatin intermediate, in particular to a process for catalyzing the synthesis of (R)-4-cyano-3-hydroxybutyric acid ethyl ester by immobilizing a resin halohydrin dehalogenase, and belongs to the field of medicine and chemical industry . Background technique [0002] Scientists have discovered 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. . The emergence of statins is an important milestone in the history of cardiovascular disease treatment, and it has become an assistant blood lipid regulating drug that is currently clinically used for all kinds of hyperlipidemia, prevention and treatment of atherosclerosis and coronary heart disease, and is also a well-known drug i...

AI Technical Summary

Problems solved by technology

Although ATS-5 is recovered by activated carbon adsorption and HHDH is removed at the same time, some enzymes still remain. After the post-stage distillation and rectification process, HHDH is decomposed into small molecular substances and remains in the product, which has a great impact on subsequent purification and reduces Yield and optical purity of ATS-5;

[0011] ②Because the enzyme and the substrate are added at one time, HHDH is removed after one reaction. On the one hand, there are many processes for removing HHDH, and at the same time, HHDH cannot be reused, which leads to an increase in the production cost of the entire process;

[0012] ③Because the HHDH used is an intracellular enzyme, the crude enzyme solution contains not only HHDH, but also other miscellaneous proteins, etc., when ATS-5 is recovered by activated carbon adsorption, some miscellaneous proteins will remain in ATS-5, which will undoubtedly increase the complexity of the entire process , resulting in low purity of the final product and increased production costs

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