Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods

Artis Klapars; John Y. L. Chung; John Limanto; Ralph Calabria; Louis-Charles Campeau; Kevin R. Campos; Wenyong Chen; Stephen M. Dalby; Tyler A. Davis; Daniel A. DiRocco; Alan M. Hyde; Amude M. Kassim; Mona Utne Larsen; Guiquan Liu; Peter E. Maligres; Aaron Moment; Feng Peng; Rebecca T. Ruck; Michael Shevlin; Bryon L. Simmons; Zhiguo Jake Song; Lushi Tan; Timothy J. Wright; Susan L. Zultanski

doi:10.1039/D1SC01978C

Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods†

Artis Klapars,

*^a John Y. L. Chung,

*^a John Limanto,^a Ralph Calabria,^a Louis-Charles Campeau,

^a Kevin R. Campos,^a Wenyong Chen,^a Stephen M. Dalby,^a Tyler A. Davis,^a Daniel A. DiRocco,^a Alan M. Hyde,^a Amude M. Kassim,^a Mona Utne Larsen,^a Guiquan Liu,^b Peter E. Maligres,^a Aaron Moment,^a Feng Peng,^a Rebecca T. Ruck,

^a Michael Shevlin,^a Bryon L. Simmons,^a Zhiguo Jake Song,^a Lushi Tan,^a Timothy J. Wright^a and Susan L. Zultanski

^a

Author affiliations

* Corresponding authors

^a Department of Process Research and Development, Merck & Co., Inc., Rahway, New Jersey 07065, USA
E-mail: artis_klapars@merck.com

^b WuXi STA, 90 Delin Road, Waigaoqiao Free Trade Zone, Shanghai 200131, China

Abstract

An efficient route to the HCV antiviral agent uprifosbuvir was developed in 5 steps from readily available uridine in 50% overall yield. This concise synthesis was achieved by development of several synthetic methods: (1) complexation-driven selective acyl migration/oxidation; (2) BSA-mediated cyclization to anhydrouridine; (3) hydrochlorination using FeCl₃/TMDSO; (4) dynamic stereoselective phosphoramidation using a chiral nucleophilic catalyst. The new route improves the yield of uprifosbuvir 50-fold over the previous manufacturing process and expands the tool set available for synthesis of antiviral nucleotides.

This article is part of the themed collections: 2021 ChemSci Pick of the Week Collection and 2021 Chemical Science HOT Article Collection

Chemical Science

Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods†

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