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DOI: 10.1055/a-2735-5050
An Improved Synthesis Route of Molnupiravir and its Key Impurities
Authors
Funding This work was supported in part by Shanghai Oriental Elite Program (Grant No. 2024023) from Shanghai Science and Technology Commission, the National Key Laboratory of Lead Druggability Research Program (Grant No. NKLYT2023012), Platform-oriented Exploratory Program (Grant No. 2023TS006), Champion-Bid R&D Program (Grant No. ZH24009) from China State Institute of Pharmaceutical Industry Co., Ltd., which are gratefully acknowledged.
Abstract
This paper aims to improve the synthetic process of molnupiravir based on previously reported synthetic routes. The route begins with uracil (ML-2), which is protected with an isopropyl group to yield ML-3 (Step 1), followed by an esterification and a triazolation reaction (Steps 2 and 3) to produce ML-5, which, via a hydroxylation reaction and deprotection (Steps 4 and 5), gives the target product ML-1. Nuclear magnetic resonance (1H NMR) and mass spectra were used for chemical structure identification. There are mainly the following improvements, including: (1) replacing the separate addition of acetone and concentrated H2SO4 with 2,2-dimethoxypropane and catalytic p-toluenesulfonic acid monohydrate in Step 1, simplifying the workup operation and reducing the dosage of reaction solvent. (2) Optimize the synthesis conditions of ML-5, reduce the formation of impurities, and improve the purity of the crude product from 43.12 to 85.21%. (3) Three impurities were isolated, two of which are new compounds. This article lays a foundation to obtain molnupiravir with controllable quality and a stable process for the treatment of coronavirus disease 2019.
Supporting Information
1H NMR and MS spectra of compounds mentioned in the article, as well as X-ray of ML-5 and ML-5-Z3 ([Supplementary Figs. S1]–[S16], available in online version), can be found in the “Supporting Information” section of this article's webpage.
Publication History
Received: 11 September 2025
Accepted: 30 October 2025
Article published online:
11 December 2025
© 2025. 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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