乌帕替尼关键中间体的连续氢化合成  

The Continuous Hydrogenation Synthesis of Key Intermediate of Upadacitinib

作　　者：朱怡君 ZHU Yijun(Changzhou Pharmaceutical Factory Co.,Ltd.,Changzhou 213018,China)

机构地区：[1]常州制药厂有限公司,江苏常州213018

出　　处：《合成化学》2025年第3期160-165,共6页Chinese Journal of Synthetic Chemistry

基　　金：常州市科技计划项目(CF20240088)。

摘　　要：针对现有釜式氢化工艺安全性低、杂质多等问题,本文以(3S,4R)-3-乙基-4-(3H-咪唑并[1,2-a]吡咯并[2,3-e]苄基吡嗪-8-基)吡咯烷-1-羧酸酯(Ⅱ)为原料,通过固定床连续氢化进行苄氧羰基的脱除,合成乌帕替尼关键中间体8-((3R, 4S)-4-乙基吡咯烷-3-基)-3H-咪唑并[1,2-a]吡咯并[2,3-e]吡嗪(Ⅰ)。优化了反应溶剂、负载催化剂和反应温度、反应时间工艺参数,并经工业级中试放大,目标产物(Ⅰ)纯度为99.04%,收率为94%,进一步深化连续氢化在药物关键中间体中的应用。In view of the low safety and high impurity content of the existing batch hydrogenation process,through the continuous hydrogenation process using a fixed bed reactor,8-((3R,4S)-4-ethylpyrrolidin-3-yl)-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazine(Ⅰ)was synthesized by the removal of benzyloxycarbonyl group from(3S,4R)-benzyl 3-ethyl-4-(3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)pyrrolidine-1-carboxylate(Ⅱ)as hydrogenation substrate.The process parameters such as reaction solvent(methanol),5%(mass fraction,the same below)Pd/Al_(2)O_(3) supported catalyst and reaction temperature(70℃)were optimized,and the purity of the target product(Ⅰ)was 99.04%and the yield was 94%.This further deepens the application of continuous hydrogenation in the key intermediates of drugs.

关 键 词：乌帕替尼 关键中间体 连续氢化 釜式氢化 负载催化剂 

分 类 号：R914.5[医药卫生—药物化学]