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

doi:10.6023/cjoc202307005

Chinese Journal of Organic Chemistry ›› 2024, Vol. 44 ›› Issue (2): 378-397.DOI: 10.6023/cjoc202307005 Previous Articles Next Articles

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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)

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

Cite this article

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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Fig. & Tab. 35

Figure 1. Structures of amphenicol antibiotics

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

Figure 2. Structure of linezolid

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

Figure 3. Structure of oseltamivir phosphate

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

Figure 4. Structure of stavudine

Scheme 4. Multistep continuous flow synthesis stavudine[39]

Figure 5. Structure of lomustine

Scheme 5. Continuous flow synthesis of lomustine[44]

Figure 6. Structure of imatinib

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

Figure 7. Structure of HSN608

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

Figure 8. Structure of capecitabine

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

Figure 9. Structure of pomalidomide

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

Figure 10. Structure of lesinurad

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

Figure 11. Structure of diclofenac sodium

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

Figure 12. Structure of celecoxib

Scheme 12. Continuous flow synthesis of celecoxib[79]

Figure 13. Structure of propofol

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

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

Figure 14. Structure of benzocaine

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

Figure 15. Structures of tetrahydroproberberine alkaloids

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

Figure 16. Structure of clonazepam

Scheme 17. Continuous flow synthesis of clonazepam[99]

Figure 17. Structure of edaravone

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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