HIV-1抑制剂依曲韦林的合成  

Synthesis of HIV-1 inhibitor etravirine

作　　者：古双喜[1,2] 乔恒[1,2] 段婷[1,2] 朱园园[3] 陈金芳[1,2] 巨修练[1,2] 

机构地区：[1]武汉工程大学化工与制药学院,湖北武汉430074 [2]绿色化工过程教育部重点实验室(武汉工程大学),湖北武汉430074 [3]武汉工程大学化学与环境工程学院,湖北武汉430074

出　　处：《武汉工程大学学报》2014年第6期10-13,共4页Journal of Wuhan Institute of Technology

基　　金：湖北省教育厅科学技术研究计划青年人才项目(Q20141505)

摘　　要：为了解决依曲韦林(Ⅰ)目前合成工艺中普遍存在的成本高问题,采用Joshi-Maikap合成策略以更佳的工艺条件合成得到Ⅰ:原料2,4,6-三氯嘧啶(Ⅱ)和3,5-二甲基-4-羟基苯腈(Ⅲ)在N,N-二异丙基乙胺作用下于1,4-二氧六环中发生嘧啶环C-4亲核取代反应得到中间体Ⅳ,收率为82.3%;Ⅳ与对氨基苯腈于N-甲基吡咯烷酮中发生嘧啶环C-2亲核取代反应得到中间体Ⅴ,收率为61.7%;Ⅴ与氨水于1,4-二氧六环中发生嘧啶环C-6亲核取代反应得到中间体Ⅵ,收率为84.5%;Ⅵ与液溴于二氯甲烷中发生溴代反应得到Ⅰ,收率为81.3%.四步反应的总收率由文献报道的30.4%提高到34.9%.中间体和产品的熔点、质谱和核磁数据均与文献报道数据吻合.To overcome the high-cost problem in the present synthetic process of etravirine（Ⅰ）,JoshiMaikap synthetic strategy was adopted to prepareⅠaccording to optimized process as follows：raw materials 2,4,6-Trichloropyrimidine（Ⅱ）and 3,5,-dimethyl-4-hydroxybenzonitrile（Ⅲ）were subject to nucleophilic substitution at C-4position on pyrimidine ring to get intermediateⅣin the presence of N,N-diisopropylethylamine and 1,4-dioxane in a yield of 82.3%.ThenⅣand 4-aminobenzonitrile reacted at C-2position on pyrimidine ring to afford intermediateⅤin a yield of 61.7%,followed by aminolysis ofⅤin the presence of ammonia and 1,4-dioxane to get C-6nucleophilic substituted intermediateⅥin ayield of 84.5%.Finally,Ⅵ was brominated in dichloromethane to getⅠin a yield of 81.3%.And the four-step total yield was raised to 34.9%from the reported 30.4%.The data of melting point,mass spectrometry and 1H NMR are in accordance with that in literature.

关 键 词：依曲韦林 HIV-1抑制剂 艾滋病 二芳基嘧啶类化合物 

分 类 号：O626.41[理学—有机化学]