Synthesis of a NO-releasing prodrug of rofecoxib

J Org Chem. 2006 Jan 20;71(2):480-91. doi: 10.1021/jo051712g.

Abstract

[reaction: see text] A newly developed synthesis of a NO-releasing prodrug of rofecoxib is described. The highly productive process consists of five chemical steps and produces prodrug 1 in an overall 64% yield from commercially available 3-phenyl-2-propyn-1-ol (4). The synthesis is highlighted by the carbometalation reaction of propargyl alcohol 4 to generate the tetrasubstituted olefin core, sulfone acid 2. Additionally, two alternate end-game strategies to prepare NO-COXIB 1 from this intermediate were explored and developed: (1) a convergent synthesis where a bromonitrate side chain is introduced in one step and (2) a two-step sequence that first installs the requisite six-carbon ester side chain followed by chemoselective nitration.

MeSH terms

  • Carbon Dioxide
  • Cyclooxygenase Inhibitors / chemical synthesis*
  • Cyclooxygenase Inhibitors / chemistry
  • Indicators and Reagents
  • Lactones / chemical synthesis*
  • Lactones / chemistry
  • Models, Molecular
  • Molecular Conformation
  • Nitric Oxide / analysis*
  • Prodrugs / chemical synthesis
  • Prodrugs / chemistry
  • Sulfones / chemical synthesis*
  • Sulfones / chemistry

Substances

  • Cyclooxygenase Inhibitors
  • Indicators and Reagents
  • Lactones
  • Prodrugs
  • Sulfones
  • rofecoxib
  • Carbon Dioxide
  • Nitric Oxide