Synthesis of ABBV-168, a 2'-Bromouridine for the Treatment of Hepatitis C

J Org Chem. 2019 Apr 19;84(8):4723-4734. doi: 10.1021/acs.joc.8b02341. Epub 2018 Nov 19.

Abstract

ABBV-168 is a dihalogenated nucleotide under investigation for the treatment of hepatitis C virus. Three synthetic routes aimed at achieving the stereoselective installation of the C2' gem-Br,F substitution and subsequent Vorbruggen glycosylation were explored to prepare the penultimate nucleoside intermediate. Development culminated in a route to ABBV-168 featuring a de novo chromatography-free furanose synthesis, protecting group-directed Vorbruggen glycosylation, and highly selective phosphoramidation to furnish the API.

MeSH terms

  • Antiviral Agents / chemical synthesis
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • Hepacivirus / drug effects*
  • Hepatitis C / drug therapy*
  • Humans
  • Microbial Sensitivity Tests
  • Molecular Conformation
  • Nucleotides / chemical synthesis
  • Nucleotides / chemistry
  • Nucleotides / pharmacology*

Substances

  • Antiviral Agents
  • Nucleotides