Preparation method of simvastatin

Abstract

The invention discloses a method for preparing simvastatin. The method is as follows: a. lovastatin and alkylamine are prepared into lovastatin amide; b. hydroxyl groups in lovastatin amide molecules are protected, and lovastatin amide di-(trimethyl) silyl ether is generated; c. the lovastatin amide dimethyl (trimethyl) silyl ether is subjected to methylation, so as to obtain simvastatin amide di-silyl ether; d. the simvastatin amide di-silyl ether is protected, and simvastatin amide is generated; e. the simvastatin amide is subjected to hydrolysis and is added with ammonia gas, and simvastatin ammonium salt is obtained; and f. the simvastatin ammonium salt is subjected to ring closure to generate the simvastatin. The method takes a composite solvent of tetrahydrofuran and cyclonexane as a solvent for the protective reaction; the lovastatin amide di-(trimethyl) silyl ether can directly perform methylation reaction without alkaline washing and water scrubbing; after water scrubbing of methylate, protective groups are automatically fallen off, thereby the reaction for removing the protective groups is saved and the products can directly perform ammonium salt reaction. The method simplifies the synthesis technique of the simvastatin.

Description

technical field [0001] The invention relates to a preparation method of simvastatin. Background technique [0002] Simvastatin, as an inhibitor of hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase, is one of the most popular blood lipid-lowering drugs on the market. Cerebrovascular disease. The method for preparing simvastatin at present has: [0003] (1), Lovastatin amide, using tert-butyldimethylsilyl chloride as a hydroxyl protection reagent, imidazole as a catalyst, methyl iodide as a methylation reagent, and methylating the side chain of 2-methylbutyrate Method (US Patent USP4820850); [0004] (2), the method of directly methylating lovastatin amide without hydroxyl protection (US Patents USP6506929, USP4444784, USP6573385, USP6573392, USP6603022, British Patent EP0864596); [0005] (3), hydrolyze lovastatin with potassium hydroxide, eliminate 2-methyl butyrate side chain, then carry out lactonization reaction to obtain glycol ester, protect with acetal, acylate,...

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Problems solved by technology

[0008] Among the above-mentioned methods, the reaction specificity of method (1) is better, but the reaction conditions are harsh, the technical difficulty is high, the used hydroxyl protection reagent tert-butyldimethylchlorosilane is expensive, and the deprotection reaction needs to be carried out under strongly acidic conditions. The process route is longer; the method (2) process route is short, but the temperature requirement of methylation is very harsh, and methylation may occur in other parts of the molecule, thereby introducing by-products, resulting in the yield and purity of the final product Neither is ideal; method (3) 2-methyl butyl ester has a large steric hindrance, and ester hydrolysis requires high temperature, strong alkali and long-term reaction (about 50h~60h), and under this condition, the six-membered lactone ring is easily Ring-opening, acyl group is difficult to remove completely, causes product yield not high (about 40%), and affects product quality; Method (4) utilizes the high specificity, high reactivity, low cost, low pollution characteristics of enzyme method, makes This semi-synthetic method using microorganisms and enzymes will become the trend of future drug production, but it is currently limited by the low level of fermentation and is difficult to achieve large-scale industrial production; method (5) purifies the dimer content of simvastatin products Most of the methods are more complicated and require more times of recrystallization

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