Weinreb Amide Approach to the Practical Synthesis of a Key Remdesivir Intermediate

J Org Chem. 2021 Apr 2;86(7):5065-5072. doi: 10.1021/acs.joc.0c02986. Epub 2021 Mar 18.

Abstract

Currently, remdesivir is the first and only FDA-approved antiviral drug for COVID-19 treatment. Adequate supplies of remdesivir are highly warranted to cope with this global public health crisis. Herein, we report a Weinreb amide approach for preparing the key intermediate of remdesivir in the glycosylation step where overaddition side reactions are eliminated. Starting from 2,3,5-tri-O-benzyl-d-ribonolactone, the preferred route consisting of three sequential steps (Weinreb amidation, O-TMS protection, and Grignard addition) enables a high-yield (65%) synthesis of this intermediate at a kilogram scale. In particular, the undesirable PhMgCl used in previous methods was successfully replaced by MeMgBr. This approach proved to be suitable for the scalable production of the key remdesivir intermediate.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Monophosphate / analogs & derivatives*
  • Adenosine Monophosphate / chemical synthesis
  • Alanine / analogs & derivatives*
  • Alanine / chemical synthesis
  • Amides / chemistry*
  • Antiviral Agents / chemical synthesis*

Substances

  • Amides
  • Antiviral Agents
  • remdesivir
  • Adenosine Monophosphate
  • Alanine