瑞德西韦核碱基单元的连续流合成  

Continuous-Flow Synthesis of the Nucleobase Unit of Remdesivir

作　　者：郭永兴 刘敏杰 姜梅芬 陶媛 程荡 陈芬儿 Yongxing Guo;Minjie Liu;Meifen Jiang;Yuan Tao;Dang Cheng;Fen-Er Chen(Pharmaceutical Research Institute,Key Laboratory of Green Chemical Engineering Process of Ministry of Education,School of Chemical Engineering and Pharmacy,Wuhan Institute of Technology,Wuhan 430205,China;Engineering Center of Catalysis and Synthesis for Chiral Molecules,Department of Chemistry,Fudan University,Shanghai 200433,China;Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs,Shanghai 200433,China)

机构地区：[1]Pharmaceutical Research Institute,Key Laboratory of Green Chemical Engineering Process of Ministry of Education,School of Chemical Engineering and Pharmacy,Wuhan Institute of Technology,Wuhan 430205,China [2]Engineering Center of Catalysis and Synthesis for Chiral Molecules,Department of Chemistry,Fudan University,Shanghai 200433,China [3]Shanghai Engineering Center of Industrial Asymmetric Catalysis for Chiral Drugs,Shanghai 200433,China

出　　处：《Engineering》2023年第2期92-100,M0005,共10页工程（英文）

基　　金：supported by the Chinese Academy of Engineering(2020-KYGG-01-01);the National Natural Science Foundation of China(21908029)。

摘　　要：本研究采用五步连续流法合成了抗病毒药物瑞德西韦的碱基单元7-溴吡咯[2,1-f][1,2,4]三嗪-4-胺。采用间歇式合成化学方法,以吡咯为原料,通过序流操作成功制备了7-溴吡咯[2,1-f][1,2,4]三嗪-4-胺。在最优流动条件下,7-溴吡咯[2,1-f][1,2,4]三嗪-4-胺的分离率为14.1%,总停留时间为79min,通量为2.96 g·h^(-1)。总停留时间明显短于批处理过程所消耗的总时间(>26.5 h)。在流动中,有利于高放热的Vilsmeier-Haack反应和N-胺化反应,这些反应涉及危险和不稳定的中间体、氧化液-液两相转化以及需要严格低温条件的溴化反应。这种合成的显著特点是,通过部署专用设备和分离单元,将后处理程序完全集成到反应序列中,从而形成一个流线型的连续流系统,最大限度地提高了整体工艺效率。该方法是一种更环保、更可持续的高效、安全制备这种碱基单元的方法。In this work,the nucleobase unit of the antiviral drug remdesivir,7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine,was synthesized through five-step continuous flow.By adapting batch synthetic chemistry,7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine was successfully produced through sequential flow operations from the widely available and inexpensive starting material pyrrole.Under optimal flow conditions,7-bromopyrrolo[2,1-f][1,2,4]triazin-4-amine was obtained in 14.1%isolated yield in a total residence time of 79 min with a throughput of 2.96 g·h^(-1).The total residence time was significantly shorter than the total time consumed in batch procedures(>26.5 h).In flow,the highly exothermic Vilsmeier-Haack and N-amination reactions involving hazardous and unstable intermediates,oxidative liquid-liquid biphasic transformation,and a bromination reaction requiring strict cryogenic conditions are favorably facilitated.The salient feature of this synthesis is that the workup procedures are fully integrated into the reaction sequences by deploying dedicated equipment and separation units,thus forming a streamlined continuous-flow system that maximizes the overall process efficiency.This method represents a greener and more sustainable process to prepare this nucleobase unit with high efficiency and safety.

关 键 词：合成化学 胺化反应 后处理程序 溴化反应 核碱基 专用设备 连续流 抗病毒药物 

分 类 号：R914.5[医药卫生—药物化学]