A practical synthesis of renin inhibitor MK-1597 (ACT-178882) via catalytic enantioselective hydrogenation and epimerization of piperidine intermediate

J Org Chem. 2011 Feb 18;76(4):1062-71. doi: 10.1021/jo102070e. Epub 2011 Jan 20.

Abstract

A practical enantioselective synthesis of renin inhibitor MK-1597 (ACT-178882), a potential new treatment for hypertension, is described. The synthetic route provided MK-1597 in nine steps and 29% overall yield from commercially available p-cresol (7). The key features of this sequence include a catalytic asymmetric hydrogenation of a tetrasubstituted ene-ester, a highly efficient epimerization/saponification sequence of 4 which sets both stereocenters of the molecule, and a short synthesis of amine fragment 2.

MeSH terms

  • Catalysis
  • Cresols / chemistry*
  • Cyclopropanes / antagonists & inhibitors*
  • Cyclopropanes / chemical synthesis*
  • Cyclopropanes / chemistry
  • Cyclopropanes / pharmacology*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / chemistry
  • Enzyme Inhibitors / pharmacology*
  • Hydrogenation
  • Hypertension / drug therapy
  • Molecular Structure
  • Piperidines / chemistry*
  • Pyridines / antagonists & inhibitors*
  • Pyridines / chemical synthesis*
  • Pyridines / chemistry
  • Pyridines / pharmacology*
  • Renin / antagonists & inhibitors*
  • Renin / chemistry
  • Stereoisomerism

Substances

  • Cresols
  • Cyclopropanes
  • Enzyme Inhibitors
  • Piperidines
  • Pyridines
  • 4-cresol
  • piperidine
  • Renin
  • MK-1597