Concise Synthesis of Molnupiravir

  • Author: ChemistryViews
  • Published: 05 November 2021
  • Copyright: Wiley-VCH GmbH
  • Associated Societies: American Chemical Society (ACS), USA
thumbnail image: Concise Synthesis of Molnupiravir

Molnupiravir (pictured) is an oral antiviral drug for the treatment of COVID-19. It is a nucleoside analog originally developed to treat influenza. Molnupiravir works against viral infections by interfering with viral RNA replication.

John A. McIntosh, Patrick S. Fier, Merck & Co., Inc., Rahway, NJ, USA, and colleagues have developed a short, high-yielding, and sustainable three-step synthesis of molnupiravir. The team started from ribose and used a biocatalytic cascade to synthesize the target compound.

Ribose was first 5-acylated using isobutyric anhydride and an immobilized lipase enzyme. Then, the resulting 5-isobutyryl ribose was converted to ribosyl-1-phosphate and reacted with uracil using several optimized enzymes, including an engineered ribosyl-1-kinase and uridine phosphorylase. In a final step, an oxime group was introduced at the uracil unit, using hexamethyldisilazane (HMDS), NH4HSO4, and imidazole to promote the transformation.

The new synthetic route is much shorter and has a seven-fold higher overall yield than the originally used route. Since it uses only simple raw materials and enzymes, it could provide a rapid supply of molnupiravir on a large scale.

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