A practical enantioselective synthesis of odanacatib, a potent Cathepsin K inhibitor, via triflate displacement of an alpha-trifluoromethylbenzyl triflate

J Org Chem. 2009 Feb 20;74(4):1605-10. doi: 10.1021/jo8020314.

Abstract

An enantioselective synthesis of the Cathepsin K inhibitor odanacatib (MK-0822) 1 is described. The key step involves the novel stereospecific S(N)2 triflate displacement of a chiral alpha-trifluoromethylbenzyl triflate 9a with (S)-gamma-fluoroleucine ethyl ester 3 to generate the required alpha-trifluoromethylbenzyl amino stereocenter. The triflate displacement is achieved in high yield (95%) and minimal loss of stereochemistry. The overall synthesis of 1 is completed in 6 steps in 61% overall yield.

MeSH terms

  • Alcohols / chemistry
  • Biphenyl Compounds / chemical synthesis*
  • Biphenyl Compounds / chemistry
  • Cathepsin K
  • Cathepsins / antagonists & inhibitors*
  • Esters / chemistry
  • Hydrocarbons, Fluorinated / chemistry*
  • Hydrolysis
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Stereoisomerism
  • Substrate Specificity

Substances

  • Alcohols
  • Biphenyl Compounds
  • Esters
  • Hydrocarbons, Fluorinated
  • Protease Inhibitors
  • ortho-trifluoromethyl phenyl triflate
  • Cathepsins
  • Cathepsin K
  • odanacatib