连续流微反应技术在药物合成中的应用研究进展

doi:10.16085/j.issn.1000-6613.2018-1174

化工进展 ›› 2019, Vol. 38 ›› Issue (01): 556-575.DOI: 10.16085/j.issn.1000-6613.2018-1174

连续流微反应技术在药物合成中的应用研究进展

程荡^1,²(),陈芬儿^1,²()

1. 复旦大学手性分子催化与合成工程中心，复旦大学化学系，上海 200433
2. 上海市手性药物工业不对称催化;工程技术研究中心，上海 200433

收稿日期:2018-06-05 修回日期:2018-10-09 出版日期:2019-01-05 发布日期:2019-01-05
通讯作者: 陈芬儿
作者简介:程荡（1985—），男，博士，青年研究员，研究方向为连续流化学制药。E-mail：<email>dcheng@fudan.edu.cn</email>。|陈芬儿，中国工程院院士，教授，研究方向为药物分子设计与化学合成。E-mail：<email>rfchen@fudan.edu.cnmail.</email>
基金资助:
上海市“浦江人才计划”项目(18PJ1401100);复旦大学引进人才科研启动项目(JIH1615108);上海市“浦江人才计划”项目（18PJ1401100）；复旦大学引进人才科研启动项目（JIH1615108）。

Progress in applied research of the continuous-flow micro-reaction technology in drug synthesis

Dang CHENG^1,²(),Fen’er CHEN^1,²()

1. Engineering Center of Catalysis and Synthesis for Chiral Molecules, Department of Chemistry, Fudan University, Shanghai 200433, China
2. Shanghai Engineering & Technology Research Center of Industrial Asymmetric Catalysis for Chiral Drugs, Shanghai 200433, China

Received:2018-06-05 Revised:2018-10-09 Online:2019-01-05 Published:2019-01-05
Contact: Fen’er CHEN

摘要/Abstract

摘要：

基于微反应器的连续流微反应技术在化学制药行业还是相对较新的概念，相比于传统釜式合成方式，该反应技术具有传质传热效率高、本质安全、过程重复性好、产品质量稳定、连续自动化操作和时空效率高等诸多优势，其用于化学药物合成中的研究越来越多。本文综述了近年来连续流微反应技术在实现从起始原料到终端原料药或制剂的“端-到-端”连续合成制备方面的研究进展，以典型案例分析的方式具体阐明了它的技术优势和重要意义，分析总结了其应用于化学药物合成目前所存在的问题。总体来说，化学药物合成的工艺路线较长，各步反应间常存在体系兼容性、溶剂置换、分离纯化和加料顺序等方面的问题，造成各单步合成转化之间的工艺衔接和耦合后处理步骤是“端-到-端”多步连续流微反应技术的难点和挑战，亟待进一步发展。同时指出发展能与微反应器有效耦合的工艺衔接及后处理技术与装备将逐步成为该领域的研究热点。

关键词: 微反应器, 药物, 合成, 在线分离纯化, 系统集成

Abstract:

The continuous-flow micro-reaction technology based on micro-reactors is an emerging technology in drug synthesis. It offers many advantages, as compared to the conventional batch-wise synthesis, including excellent heat- and mass-transfer characteristics, inherent safety, high process reproducibility, consistent product quality, facile automation, and exceptional space-time efficiency. Its advantages are increasingly appreciated by the drug synthesis community. In this review, the recent research progress of end-to-end continuous-flow synthesis and preparation of active pharmaceutical ingredients (APIs) and final dosages from starting materials were highlighted. The technologic advantages and significance of continuous-flow micro-reaction technology were further illustrated by means of analyzing typical research examples. The limitations of this technology applied to drug synthesis were summarized. In general, drug synthesis comprises multiple steps, and is constantly faced with issues such as system inconsistency, solvent replacement, separation and purification and the sequence of raw-material addition, etc. The connection between consecutive reaction steps and coupling of post-processing steps presented difficulties and challenges for end-to-end continuous-flow synthesis and preparation of active pharmaceutical ingredients (APIs) and final dosages from starting materials, which needs to be addressed. Therefore, the development of new technology and equipment to connect multiple reaction steps and for post-processing which can be effectively coupled with micro-reactors is gradually becoming a hot research topic in this field.

Key words: microreactors, pharmaceuticals, synthesis, in-line separation and purification, system integration

中图分类号:

TQ460

程荡, 陈芬儿. 连续流微反应技术在药物合成中的应用研究进展[J]. 化工进展, 2019, 38(01): 556-575.

Dang CHENG, Fen’er CHEN. Progress in applied research of the continuous-flow micro-reaction technology in drug synthesis[J]. Chemical Industry and Engineering Progress, 2019, 38(01): 556-575.

图/表 32

图1 荷兰帝斯曼公司微反应器工业装置[40]

图2 布洛芬（1）

图3 布洛芬三步连续流合成工艺[47]

图4 改进的布洛芬钠盐三步连续流合成工艺[49]

图5 伊马替尼（8）

图6 伊马替尼多步连续流合成工艺[58]

图7 反应中间体13

图8 氟西汀（15）

图9 氟西汀连续流合成工艺[64]

图10 Vapourtec R系列流动反应器[64]

图11 青蒿素分子（24）

图12 青蒿素多步连续流反应工艺[70]

图13 青蒿素衍生物连续流合成工艺[72]

图14 法奈替唑（34）

图15 “管中管”（tube-in-tube）反应器结构示意图[75]

图16 法奈替唑连续流合成工艺[75]

图17 合成法奈替唑的连续流反应系统[75]

图18 盐酸苯海拉明（38）

图19 盐酸苯海拉明连续流合成工艺[46]

图20 卢非酰胺（41）

图21 卢非酰胺连续流合成工艺[86]

图22 改进的卢非酰胺连续流合成工艺[85]

图23 奥氮平（51）

图24 奥氮平连续流合成工艺[89]

图25 阿米替林（57）

图26 阿米替林分子的母核（58）

图27 阿米替林连续流合成工艺[92]

图28 阿利吉仑（63）

图29 阿利吉仑连续流生产系统[6]

图30 阿利吉仑“端-到-端”多步连续流工艺路线[6]

图31 “端-到-端”连续流工艺制出的阿利吉仑片剂[6]

图32 麻省理工学院“冰箱式”迷你制药工厂[45]

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连续流微反应技术在药物合成中的应用研究进展

Progress in applied research of the continuous-flow micro-reaction technology in drug synthesis

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