曲伏前列素的合成  

Synthesis of Travoprost

作　　者：陈祥伟 苏专专 黄文战 甘春丽 CHEN Xiangwei;SU Zhuanzhuan;HUANG Wenzhan;GAN Chuni(Dept.of Pharmaceutical Chemistry and Natural Pharmaceutical Chemistry,College of Pharmacy,Harbin Medical University,Harbin 150081)

机构地区：[1]哈尔滨医科大学药学院,药物化学与天然药物化学教研室,黑龙江哈尔滨宾150081

出　　处：《中国医药工业杂志》2024年第1期42-47,95,共7页Chinese Journal of Pharmaceuticals

基　　金：黑龙江省高等教育本科教育教学改革研究重点委托项目(SJGZ20220079);黑龙江省博士后科研启动金(21042220041);哈尔滨医科大学药学院优秀青年人才基金(2019-YQ-04)。

摘　　要：以苯甲酰Corey内酯(1)为起始物料,经过2,2,6,6-四甲基哌啶氧化物(TEMPO)/次氯酸钠选择性氧化、Wittig-Hornor反应、手性还原、脱苯甲酰基、三乙基氯硅烷保护羟基、内酯还原、Wittig反应、成酯、羟基保护与脱保护共10步反应,得到最终产物曲伏前列素(13),总收率15.3%。终产物经^(1)H NMR、^(13)C NMR和MS进行结构确证。该合成路线中使用乙醇/正己烷打浆法、甲基叔丁基醚重结晶和硅胶柱色谱等方法对各个中间体的分离纯化操作进行简化,原料易得、条件温和且可控,为国内曲伏前列素类仿制药的工业生产提供了参考。Travoprost(13)was obtained with benzoyl Corey lactone(1)as the starting material in a ten-step synthetic route,which consisted of selective oxidation in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy(TEMPO)/sodium hypochlorite,Wittig-Hornor reaction,chiral reduction,debenzoylation,triethylchlorosilane protection of hydroxyl,lactone reduction,Wittig reaction,ester formation,hydroxyl protection and deprotection,with the total yield of 15.3%.The structure of the final product was confirmed by ^(1)H NMR,^(13)C NMR and MS.In this paper,the separation and purification processes of various intermediates were simplified by pulping with ethanol/n-hexane,recrystallization by methyl tert-butyl ether and separation by silica gel column chromatography.By the way,the synthetic route had the advantages of availability of raw materials,and mild and controllable reaction conditions,which could provide some references for the industrial production of travoprost generic drugs.

关 键 词：曲伏前列素 苯甲酰Corey内酯 中间体 合成 WITTIG反应 

分 类 号：R988.1[医药卫生—药品] TQ460.6[医药卫生—药学]