利匹韦林关键中间体的合成研究  

Synthesis of Key Intermediates of Rilpivirine

作　　者：邓梁丹 钱碧莎 丁利红 肖艳华 DENG Liangdan;QIAN Bisha;DING Lihong;XIAO Yanhua(Key Laboratory for Green Chemical Process of Ministry of Education,Hubei Key Laboratory of Novel Reactor and Green Chemical Technology,School of Chemical Engineering and Pharmacy,Wuhan Institute of Technology,Wuhan 430205,China)

机构地区：[1]武汉工程大学化工与制药学院绿色化工过程教育部重点实验室湖北省新型反应器与绿色化学工艺重点实验室,湖北武汉430205

出　　处：《化学与生物工程》2025年第2期32-35,共4页Chemistry & Bioengineering

基　　金：国家自然科学基金项目(22004095)。

摘　　要：对利匹韦林关键中间体4-((4-氯-2-嘧啶基)氨基)苯甲腈(1)与(E)-3-(4-氨基-3,5-二甲基苯基)丙烯腈(2)的合成工艺进行了优化。结果表明,以尿嘧啶为起始原料,通过氯代反应和偶联反应合成关键中间体1,合成原料廉价,较已报道的路线更简单环保。以4-溴-2,6-二甲基苯胺(5)为起始原料、DMA为反应溶剂,在n(5)∶n(丙烯酰胺)∶n(醋酸钯)∶n(三(邻甲基苯基)膦)为1∶2∶0.1∶0.3、反应温度为120℃、反应时间为24 h时,经Heck反应合成(E)-3-(4-氨基-3,5-二甲基苯基)丙烯酰胺,收率达到85.94%;然后改变后处理方式,将反应液缓慢滴加至冰水中,并在-5℃下搅拌2 h,得到关键中间体2,合成路线更经济环保,更有利于工业生产。We optimized the synthesis process of the key intermediates of Rilpivirine,4-((4-chloro-2-pyrimidinyl)amino)benzonitrile(1)and(E)-3-(4-amino-3,5-dimethylphenyl)acrylonitrile(2).The results show that,when uracil is taken as a starting material,the key intermediate 1 is synthesized through chlorination and coupling reactions,and the synthetic raw materials are inexpensive and more environmentally friendly than the reported routes.When 4-bromo-2,6-dimethylaniline(5)is taken as a starting material and using DMA as the reaction solvent,(E)-3-(4-amino-3,5-dimethylphenyl)acrylamide is synthesized with the yield of 85.94%via Heck reaction under the optimal conditions as follows:the n(5)∶n(acrylamide)∶n(palladium acetate)∶n(tris(2-methylphenyl)phosphine)of 1∶2∶0.1∶0.3,the reaction temperature of 120℃,and the reaction time of 24 h.Then,by changing the post-treatment method which the reaction solution is slowly added dropwise to ice water and stirring at-5℃for 2 h,the key intermediate 2 is obtained.The synthetic route is more economical,environmentally friendly,and conducive to industrial production.

关 键 词：利匹韦林 关键中间体 4-((4-氯-2-嘧啶基)氨基)苯甲腈 (E)-3-(4-氨基-3 5-二甲基苯基)丙烯腈 

分 类 号：TQ463[化学工程—制药化工] R978.7[医药卫生—药品]