CC BY 4.0 · Pharmaceutical Fronts 2021; 03(04): e194-e199
DOI: 10.1055/s-0041-1740944
Original Article

Enantioselective aza-Michael Cyclization Reaction Catalyzed by Quinine-Derived Monoquaternary Ammonium Salts: an Effective Route to Synthesize Letermovir

Liang Chen
1   State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Wei-Yuan Liu
1   State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Si-Ju Bi
1   State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Ting Zhou
1   State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Jing Pan
1   State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Xun-Lei Lv
1   State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Kuai-Le Lin
1   State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
,
Wei-Cheng Zhou
1   State Key Lab of New Drug & Pharmaceutical Process, Shanghai Key Lab of Anti-Infectives, Shanghai Institute of Pharmaceutical Industry, China State Institute of Pharmaceutical Industry, Shanghai, People's Republic of China
› Author Affiliations


Abstract

A series of mono- or bis-quaternary ammonium salts derived from cinchonidine or quinine was synthesized and screened as potent phase-transfer catalysts for the reaction of aza-Michael cyclization, the key step in the synthesis of letermovir. During the reaction of aza-Michael cyclization, the screened monoquaternary ammonium salt quinine derivative Q1 transferred 7 to 8 with 91.9% yield and 58% ee. The application of Q1 was preferred, due to its enantioselectivity, the possibility of reuse, and the lower cost in large-scale preparation. Furthermore, the racemization condition of letermovir enantiomer was also explored for the possibility to develop the resolution/racemization process. With the optimal catalyst Q1 in hand, the synthesis of letermovir may be more convenient and economical in the future.

Supplementary Information

Detailed information for the synthesis of the catalysts C1–C8, Q1–Q7, as well as the chiral HPLC diagrams of 8 is provided and available online only.




Publication History

Received: 20 October 2021

Accepted: 11 November 2021

Article published online:
30 December 2021

© 2021. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

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