Efficient synthesis of antiviral agent uprifosbuvir enabled by new synthetic methods

  • Chem Sci. 2021 May 19;12(26):9031-9036. doi: 10.1039/d1sc01978c.
Artis Klapars  1 ,  John Y L Chung  1 ,  John Limanto  1 ,  Ralph Calabria  1 ,  Louis-Charles Campeau  1 ,  Kevin R Campos  1 ,  Wenyong Chen  1 ,  Stephen M Dalby  1 ,  Tyler A Davis  1 ,  Daniel A DiRocco  1 ,  Alan M Hyde  1 ,  Amude M Kassim  1 ,  Mona Utne Larsen  1 ,  Guiquan Liu  2 ,  Peter E Maligres  1 ,  Aaron Moment  1 ,  Feng Peng  1 ,  Rebecca T Ruck  1 ,  Michael Shevlin  1 ,  Bryon L Simmons  1 ,  Zhiguo Jake Song  1 ,  Lushi Tan  1 ,  Timothy J Wright  1 ,  Susan L Zultanski  1
Affiliations
  • 1. Department of Process Research and Development, Merck & Co., Inc. Rahway New Jersey 07065 USA [email protected].
  • 2. WuXi STA 90 Delin Road, Waigaoqiao Free Trade Zone Shanghai 200131 China.
PMID: 34276931 DOI: 10.1039/d1sc01978c
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.

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