Synthesis and crystal characteristics of nirmatrelvir

Several synthetic routes of nirmatrelvir (the ingredient of a new drug to treat COVID-19 made by Pfizer) have been reported. We focused on a second route to improve the synthetic method of nirmatrelvir with a methodology that included different steps. The first step was an analysis of reaction bypro...

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Bibliographic Details
Published in:Reaction chemistry & engineering 2023-06, Vol.8 (7), p.1747-1759
Main Authors: Jiang, Bibo, Li, Gang, Yu, Jun, Xu, Xiaoyan, Pan, Hongjuan, Zhao, Chuanmeng, Zhong, Jialiang, Zhang, Fuli
Format: Article
Language:English
Subjects:
Acetonitrile
Condensates
Dehydration
High performance liquid chromatography
Purity
Single crystals
Solvents
Temperature dependence
Tetrahydrofuran
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Summary:Several synthetic routes of nirmatrelvir (the ingredient of a new drug to treat COVID-19 made by Pfizer) have been reported. We focused on a second route to improve the synthetic method of nirmatrelvir with a methodology that included different steps. The first step was an analysis of reaction byproducts using acetonitrile as a solvent of the condensation reaction to improve the inversion rate. Then, we used isobutyl acetate as a crystalline solvent to obtain the key intermediate as a solvate, which was a stable crystal product with high purity. Complementarily, we also used trifluoroacetic anhydride as the primary-amide dehydrating agent, and 2-methyl tetrahydrofuran as the solvent to prepare nirmatrelvir, which led to an overall yield of 48% via four steps and a purity of 99.5% according to high-performance liquid chromatography. We also investigated the crystal form of nirmatrelvir: the single-crystal features and transformation from a crystal form to nirmatrelvir were dependent upon temperature. Our data have great value for study of the synthetic method and crystal stability of nirmatrelvir. Several synthetic routes of nirmatrelvir (the ingredient of a new drug to treat COVID-19 made by Pfizer) have been reported.
ISSN:2058-9883
2058-9883
DOI:10.1039/d3re00019b