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

• 生物与医药化工 • 上一篇    下一篇

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. 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 CHENG1,2(),Fen’er CHEN1,2()   

  1. 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:

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

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