全连续流反应技术在药物合成中的新进展(2019~2022)

doi:10.6023/cjoc202307005

有机化学 ›› 2024, Vol. 44 ›› Issue (2): 378-397.DOI: 10.6023/cjoc202307005 上一篇下一篇

综述与进展

全连续流反应技术在药物合成中的新进展(2019~2022)

冯康博^a^,^b, 陈炯^a^,^b, 古双喜^a^,^b^,^c^,^*(), 王海峰^a^,^b^,^c^,^*(), 陈芬儿^a^,^b^,^d^,^*()

a 武汉工程大学化工与制药学院绿色化工过程教育部重点实验室武汉 430205
b 武汉工程大学药物研究院武汉 430205
c 武汉工程大学新型反应器与绿色化学工艺湖北省重点实验室武汉 430205
d 复旦大学化学系手性分子催化与合成工程中心上海 200433

收稿日期:2023-07-09 修回日期:2023-09-16 发布日期:2023-09-28
基金资助:
国家自然科学基金(22377097); 国家自然科学基金(21877087); 湖北省自然科学基金(2021CFB556); 湖北省自然科学基金(2022CFB156); 绿色化工过程教育部重点实验室开放基金(GCP20200201); 新型反应器与绿色化学工艺湖北省重点实验室(武汉工程大学)开放基金(40201002)

New Progress of Fully Continuous Flow Reaction Technologies in Pharmaceutical Synthesis (2019~2022)

Kangbo Feng^a^,^b, Jiong Chen^a^,^b, Shuangxi Gu^a^,^b^,^c(), Haifeng Wang^a^,^b^,^c(), Fen'er Chen^a^,^b^,^d()

a Key Laboratory for Green Chemical Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan 430205
b Pharmaceutical Research Institute, Wuhan Institute of Technology, Wuhan 430205
c Hubei Key Laboratory of Novel Reactor and Green Chemical Technology, Wuhan Institute of Technology, Wuhan 430205
d Department of Chemistry, Fudan University, Shanghai 200433

Received:2023-07-09 Revised:2023-09-16 Published:2023-09-28
Contact: * E-mail: shuangxigu@163.com; skytacle@139.com; rfchen@fudan.edu.cn
Supported by:
National Natural Science Foundation of China(22377097); National Natural Science Foundation of China(21877087); Natural Science Foundation of Hubei Province(2021CFB556); Natural Science Foundation of Hubei Province(2022CFB156); Key Laboratory for Green Chemical Process of Ministry of Education Open Fund(GCP20200201); Hubei Key Laboratory of Novel Reactor and Green Chemical Technology (Wuhan Institute of Technology) Open Fund(40201002)

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摘要/Abstract

连续流动化学作为化学制药行业的一项新兴技术, 相较于传统的间歇釜式反应, 连续流反应具有快速传质传热的优势, 改进反应过程的可控性和安全性, 也可以将在线分析和纯化步骤集成到柔性的操作序列中. 主要介绍了2019~2022年连续流反应技术在实现从起始原料到最终活性药物成分(API)的全连续流合成工艺方面的新进展, 从连续流反应的流程图着手, 阐述了其制备工艺及技术优势, 同时指出全连续流反应技术在各单步合成转化的工艺衔接和耦合处理仍存在一定挑战, 有待进一步提升发展.

关键词: 流动化学, 药物, 全连续流, 合成工艺

Continuous flow chemistry is an emerging technology in the chemical pharmaceutical industry. Compared with the traditional batch kettle reaction, continuous flow reaction has the advantages of rapid mass and heat transfer, improves the controllability and safety of the reaction process, and can also integrate the online analysis and purification steps into the flexible operation sequence. The new progress of continuous flow reaction technology in the continuous synthesis process from starting raw material to final active pharmaceutical ingredient (API) from 2019 to 2022 is introduced. Starting from the flow chart of continuous flow reaction, the preparation process and technical advantages of continuous flow reaction are described. At the same time, it is pointed out that the fully continuous flow reaction technology still has some challenges in the process connection and coupling treatment of each single step synthesis transformation, which needs to be further improved.

Key words: flow chemistry, pharmaceuticals, fully continuous flow, synthetic process

引用此文

冯康博, 陈炯, 古双喜, 王海峰, 陈芬儿. 全连续流反应技术在药物合成中的新进展(2019~2022)[J]. 有机化学, 2024, 44(2): 378-397.

Kangbo Feng, Jiong Chen, Shuangxi Gu, Haifeng Wang, Fen'er Chen. New Progress of Fully Continuous Flow Reaction Technologies in Pharmaceutical Synthesis (2019~2022)[J]. Chinese Journal of Organic Chemistry, 2024, 44(2): 378-397.

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图/表 35

图1. 酰胺醇类抗生素的结构

Figure 1. Structures of amphenicol antibiotics

图式1. 酰胺醇类抗生素的多步连续流合成工艺[16]

Scheme 1. Multistep continuous flow synthesis of amphenicol antibiotics[16]

图2. 利奈唑胺的结构

Figure 2. Structure of linezolid

图式2. 多步连续流合成利奈唑胺[19]

Scheme 2. Multistep continuous flow synthesis of linezolid[19]

图3. 磷酸奥司他韦结构

Figure 3. Structure of oseltamivir phosphate

图式3. 多步连续流合成磷酸奥司他韦[23]

Scheme 3. Multistep continuous flow synthesis of oseltamivir phosphate [23]

图4. 司他夫定结构

Figure 4. Structure of stavudine

图式4. 多步连续流合成司他夫定[39]

Scheme 4. Multistep continuous flow synthesis stavudine[39]

图5. 洛莫司汀结构

Figure 5. Structure of lomustine

图式5. 洛莫司汀的连续流合成[44]

Scheme 5. Continuous flow synthesis of lomustine[44]

图6. 伊马替尼结构

Figure 6. Structure of imatinib

图式6. 连续流合成伊马替尼[50]

Scheme 6. Continuous-flow synthesis of imatinib[50]

图7. HSN608的结构

Figure 7. Structure of HSN608

图式7. HSN608的连续流合成[55]

Scheme 7. Continuous-flow synthesis of HSN608[55]

图8. 卡培他滨结构

Figure 8. Structure of capecitabine

图式8. 连续流合成卡培他滨Jamison (上)/Miranda(下)[61]

Scheme 8. Continuous flow synthesis of capecitabine reported by Jamison (top)/Miranda (bottom) [61]

图9. 泊马度胺的结构

Figure 9. Structure of pomalidomide

图式9. 多步连续流合成泊马度胺[63]

Scheme 9. Multistep continuous flow synthesis of pomalidomide[63]

图10. 雷西那德结构

Figure 10. Structure of lesinurad

图式10. 五步连续流合成雷西那德[72]

Scheme 10. Five-step continuous flow synthesis of lesinurad[72]

图11. 双氯芬酸钠的结构

Figure 11. Structure of diclofenac sodium

图式11. 六步连续流合成双氯芬酸钠[76]

Scheme 11. Six-step continuous flow synthesis of diclofenac sodium[76]

图12. 塞来昔布的结构

Figure 12. Structure of celecoxib

图式12. 塞来昔布的连续流合成[79]

Scheme 12. Continuous flow synthesis of celecoxib[79]

图13. 丙泊酚的结构

Figure 13. Structure of propofol

图式13. Martins的连续流合成工艺[89]

Scheme 13. Martins?s continuous flow synthesis process[89]

图式14. Charette的连续流合成工艺[90]

Scheme 14. Charette?s continuous flow synthesis process[90]

图14. 苯佐卡因的结构

Figure 14. Structure of benzocaine

图式15. 连续流加氢级联还原/酯化反应合成苯佐卡因[93]

Scheme 15. Synthesis of benzocaine by continuous-flow hydro- genation cascade reduction/esterification[93]

图15. 四氢原小檗碱生物碱的结构

Figure 15. Structures of tetrahydroproberberine alkaloids

图式16. 小檗碱多步连续流合成工艺[96]

Scheme 16. Multistep continuous flow synthesis of berberine[96]

图16. 氯硝西泮的结构

Figure 16. Structure of clonazepam

图式17. 氯硝西泮的连续流合成工艺[99]

Scheme 17. Continuous flow synthesis of clonazepam[99]

图17. 依达拉奉的结构

Figure 17. Structure of edaravone

图式18. 依达拉奉的连续流合成工艺[107]

Scheme 18. Continuous flow synthesis of edaravone[107]

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全连续流反应技术在药物合成中的新进展(2019~2022)

New Progress of Fully Continuous Flow Reaction Technologies in Pharmaceutical Synthesis (2019~2022)

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