瑞舒伐他汀钙合成的新工艺  

A novel synthetic process of rosuvastatin calcium

作　　者：梅光耀 王飞 缪涵辉 郑蔚 汪海波 MEI Guang-yao;WANG Fei;MIAO Han-hui;ZHENG Wei;WANG Hai-bo(Zhejiang Hongyuan Pharmaceutical Co. , Ltd. , Linhai 317016, China)

机构地区：[1]浙江宏元药业股份有限公司,浙江临海317016

出　　处：《中国药物化学杂志》2018年第2期119-124,共6页Chinese Journal of Medicinal Chemistry

摘　　要：目的研究一种新的瑞舒伐他汀钙合成工艺。方法以3-O-叔丁基二甲基硅基戊二酸酐为原料,经酰胺化、活性酯制备、Wittig反应、脱保护、还原、水解及成盐等8步反应合成瑞舒伐他汀钙。结果与结论关键中间体及目标化合物的结构经~1H-NMR、^(13)C-NMR和MS谱确证,总收率22.5%(以3-O-叔丁基二甲基硅基戊二酸酐计),HPLC纯度99.9%。该合成路线操作简单、原料廉价易得、反应条件温和、收率高,适合工业化生产。Rosuvastatin calcium,a HMG-CoA reductase inhibitor,is an effective drug for the treatment of hypolipidemia. Herein,a novel synthetic process of rosuvastatin calcium was developed. Firstly,3-[（tertbutyldimethylsilyl） oxy]glutaric anhydride was reacted with S-（-）-α-methylbenzylamine in the presence of triethylamine to obtain（3S）-N-[（1 S）-1-phenylethylamino]-3-（tert-butyldimethylsilyl） oxy-1,5-glutaric monoamide,which was subsequently reacted with methyl chloroformate to give（3 S）-N-[（1 S）-1-phenylethylamino]-3-（tert-butyldimethylsilyl） oxy-5-O-methoxycarbonyl-1,5-glutaric acid-1-amide. Under strongly basic condition,the obtained intermediate was transformed into phosphorus ylide reagent,which was used in the Wittig reaction to provide（3 S,6 E）-7-[4-（4-fluorophenyl）-6-iso-propyl-2-（N-methyl-N-methylsulfonyl）aminnopyrimidine-5-yl]-3-（tert-butyldimethylsilyl） oxy-5-oxy-6-heptamide. The heptamide was deprotected with methanesulfonic acid to give a ketone. The ketone was reduced in the presence of KBH4 and converted to a diol,which was hydrolyzed in basic condition and salified with（CH3COO）2Ca to give the target compound,rosuvastatin calcium.

关 键 词：瑞舒伐他汀钙 工艺改进 降血脂药 HMG-COA还原酶抑制剂 

分 类 号：R914[医药卫生—药物化学]