Synthesis of an Anti-hepatitis B Agent, 2'-Fluoro-6'-methylene-carbocyclic Adenosine (FMCA) and Its Phosphoramidate (FMCAP)

J Org Chem. 2019 Jan 18;84(2):752-759. doi: 10.1021/acs.joc.8b02599. Epub 2019 Jan 9.

Abstract

2'-Fluoro-6'-methylene-carbocyclic adenosine (FMCA, 12) and its phosphoramidate prodrug (FMCAP, 14) have been proven as a potential anti-HBV agent against both adefovir-resistant as well as lamivudine-resistant double (rtL180M/rtM204V) mutants. Furthermore, in vitro, these agents have demonstrated significant activity against lamivudine/entecavir triple mutants (L180M + S202G + M204V). These preliminary results encourage us for further biological evaluation of FMCA and FMCAP to develop as a potential clinical candidate as an anti-HBV agent, which may overcome the problem of drug resistance in HBV therapy. To support the preclinical exploration, a scalable synthesis of this molecule was needed. In this communication, a practical and scalable synthesis of FMCA, and its prodrug, is reported via ketone 1. The selective opening of the isopropylidene group of 2 led to compound 3. Protection of the allylic hydroxyl group of 3, followed by fluorination and deprotection, afforded the key intermediate 10, which was condensed with a Boc-protected adenine, followed by deprotection, furnished the target nucleoside FMCA (12) in high yield. Further coupling of phosphorochloridate of L-alanine isopropyl ester (13) with FMCA gave its phosphoramidate prodrug FMCAP (14) in good yield.

MeSH terms

  • Adenosine / analogs & derivatives*
  • Adenosine / chemical synthesis
  • Adenosine / chemistry
  • Adenosine / pharmacology
  • Amides / chemical synthesis*
  • Amides / chemistry
  • Amides / pharmacology
  • Antiviral Agents / chemical synthesis*
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology
  • Hepatitis B virus / drug effects
  • Molecular Conformation
  • Phosphoric Acids / chemical synthesis*
  • Phosphoric Acids / chemistry
  • Phosphoric Acids / pharmacology

Substances

  • 2'-fluoro-6'-methylene-carbocyclic adenosine
  • Amides
  • Antiviral Agents
  • Phosphoric Acids
  • phosphoramidic acid
  • Adenosine