辛伐他汀的合成工艺改进

A modified synthetic route of simvastatin

目的改进新型降血脂药辛伐他汀(simvastatin)的合成工艺。方法以洛伐他汀(lovastatin)为起始原料,经酰胺化、选择性酯化、碳负离子形成、甲基化、水解、中和与环合等反应制得辛伐他汀。结果与结论目标化合物的结构经元素分析、IR、UV、1H-NMR1、3C-NMR及MS谱确证,辛伐他汀的质量符合国内外药典标准,总收率为84.3%。新工艺路线用氯甲酸甲酯替代有机氯硅烷保护羟基,不仅解决了传统工艺中有机氯硅烷脱保护后生成的产物有机硅醇和溶剂甲醇不能循环利用的问题,而且省去了脱有机硅保护基的酸水解和产品精制过程,原料成本显著降低。

Aim To improve the synthetic process of simvastatin,a new cholesterol-lowering drug.Methods Simvastatin was synthesized via acetylization,selective esterification,carbanion formation,methylation,hydrolyzation,neutralization and cyclization starting from lovastatin.Results and conclusion The target compound structure was identified by elementary analysis,infra-red spectrum,ultra-violet spectrum,^1H-NMR spectrum,^13C-NMR spectrum and MS spectrum.The raw materials′ cost is significantly reduced in this novel synthetic process and the product of simvastatin with a overall yield of 84.3%,which conforms to internal and external pharmacopedia specifications.Methyl chloroformate in stead of organochlorosilane was used to protect hydroxyl.It not only solved the problem for conventional process in which the solvent containing organosilicon alcohol originated from organochlorosilane can not be recycled,but also abolished acid hydrolysis for deprotection and purification of crude product as well.