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《工程(英文)》 >> 2023年 第21卷 第2期 doi: 10.1016/j.eng.2021.07.029

瑞德西韦核碱基单元的连续流合成

a Key Laboratory of Green Chemical Engineering Process of the Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430205, China
b Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China
c Shanghai Engineering and Technology Research Center for Industrial Asymmetric Catalysis of Chiral Drugs, Shanghai 200433, China

收稿日期: 2021-02-19 修回日期: 2021-06-20 录用日期: 2021-07-06 发布日期: 2022-03-26

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摘要

本研究通过五步连续流合成了抗病毒药物瑞德西韦的核碱基单元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,利用广泛可用且廉价的起始原料吡咯,通过顺序流动操作成功生产了7-溴吡咯[2,1-f][1‒2,4]三嗪-4-胺。在最佳流动条件下,7-溴吡咯[2,1-f][1‒2,4]三嗪-4-胺的分离收率为14.1%,总停留时间为79 min,通量为2.96 g∙h−1,总停留时间明显短于批处理程序中消耗的总时间(大于26.5 h)。在流动中,有利地促进了涉及危险和不稳定的中间体的高度放热的Vilsmeier-Haack 和N-胺化反应、氧化液-液双相转化及需要严格低温条件的溴化反应。这种合成方法的显著特点是,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,从而形成一个精简的连续流系统,最大限度地提高整个过程的效率。该方法是一种更环保、更可持续的高效、安全地制备核碱基单元的方法。

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