HIV-1抑制剂依曲韦林的合成

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.

Synthesis of HIV-1 inhibitor etravirine

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.