Preparation method of enzymatic synthesis of simvastatin

Abstract

The invention discloses a preparation method for simvastatin by adopting enzymatic synthesis. The method comprises the following steps: carrying out basic hydrolysis on lovastatin so as to obtain a alkaline hydrolysis product; carrying out enzyme hydrolysis on the prepared alkaline hydrolysis product under the existence of immobilized hydrolase so as to obtain enzymic hydrolysate and 2,2-dimethyl acyl-S-methyl propionate, wherein the immobilized hydrolase is a composite which is formed by immobilizing lovastatin hydrolase on porous resin; carrying out acylation reaction on the prepared enzymic hydrolysate and 2,2-dimethyl acyl-S-methyl propionate under the existence of immobilized acylase so as to obtain acylate, wherein the immobilized acylase is a composite which is formed by immobilizing lovastatin acylation enzyme on the porous resin; and carrying out cyclization on the prepared acylate so as to obtain the simvastatin. By adopting the the method disclosed by the invention, the total molar yield of the simvastatin achieves 80%, the content of total impurities in the simvastatin is smaller than or equal to 0.5%; the content of a single impurity in the simvastatin is smaller than or equal to 0.2%; the content of the lovastatin in the simvastatin is smaller than or equal to 0.2%. The technology is significantly better than an existing production technology of the simvastatin.

Description

technical field [0001] The invention relates to a method for synthesizing simvastatin, a blood lipid-lowering drug, in particular, it provides a method for preparing simvastatin by enzymatic synthesis. Belongs to the field of medicine. Background technique [0002] Simvastatin is a hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, which is mainly used clinically to treat hypercholesterolemia and hypertriglyceridemia. The drug was first launched in Sweden in 1988, and has been widely used in more than 70 countries in 1995. In recent years, it has been found that in addition to blood lipid regulation, it also has other effects, such as anti-oxidation, anti-inflammation, inhibition of cell proliferation, promotion of bone anabolism, and treatment of heart failure. The existing simvastatin production process, such as CN1290261A, CN1612872A, CN1493570A, etc., is mainly a chemical synthesis method, not only has many and complicated reaction steps, but also has high...

AI Technical Summary

Problems solved by technology

The existing simvastatin production process, such as CN1290261A, CN1612872A, CN1493570A, etc., is mainly a chemical synthesis method, not only has many and complicated reaction steps, but also has high impurities in the product, and the process has serious environmental pollution

CN102703539A discloses a method for preparing simvastatin from lovastatin through a process comprising enzymatic hydrolysis and enzymatic acylation and the enzymes used in the method, however, there are many by-products in the product obtained by this method , the number and content of impurities in the prepared simvastatin product are difficult to meet the quality requirements of pharmaceutical grade simvastatin raw materials, and the enzymes and some reagents or raw materials used in the method are not easy to obtain in China, the process cost is relatively high, and it is difficult to industrialize