磷酸奥司米韦的合成研究

Synthesis of oseltamivir phosphate

目的研究磷酸奥司米韦的合成方法。方法以莽草酸为起始原料,通过酯化、缩酮保护、甲磺酰化、缩酮交换、还原,闭环反应得关键中间体(3R,4S,5S)-4,5-环氧基-3-(1-乙基丙氧基)-1-环己烯甲酸乙酯(2);化合物2在氯化镁催化下和叔丁胺反应,经甲磺酰化、闭环得氮丙啶中间体,再经开环、乙酰化、脱叔丁基、脱烯丙基、成磷酸盐共13步反应得抗病毒药磷酸奥司米韦。结果与结论合成的磷酸奥司米韦经1H-NMR和M S谱确证结构,总收率为29.5%。

Aim To investigate an improved synthetic process of oseltamivir phosphate, an antiviral drug. Methods Starting from （ - ） -shikimic acid, the key intermediate ethyl （ 3R, 4S, 5S） -4,5-epoxy-3- （ 1 -ethyl- propoxy） -1 -cyclohexene-1 -carboxylate （2） was synthesized via esterification, ketalization, mesylation, tran- sketalization, reduction and intramolecular SN2 reaction. 2 was treated with tert-butylamine for epoxide-opening in the presence of MgC12, and then brought into mesylation and intramolecular SN2 reaction to form the aziridine ethyl （ 3 R, 4S, 5 R） -4,5- （ 1,1 -dimethylethyl ） imino-3- （ 1 -ethylpropoxy） -1 -cyclohexene-1 -carboxyl- ate. After MsOH-promoted opening of the aziridine with diallylamine, followed by acetylation and successive removal of ten-butyl and allyl group, oseltamivir was eventually obtained. Results and conclusion Oseltamivir phosphate was synthesized via a 13-step sequence in a total yield of 29.5% and its structure was identi- fied by ^1H-NMR and MS.