title: A practical enantioselective synthesis of odanacatib, a potent Cathepsin K inhibitor, via triflate displacement of an alpha-trifluoromethylbenzyl triflate.
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.
authors.affiliation: Department of Process Research, Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe-Claire-Dorval, Québec, H9R 4P8, Canada. paul_oshea@merck.com
authors.forename: Paul D
authors.initials: PD
authors.lastname: O'Shea
authors.forename: Cheng-yi
authors.initials: CY
authors.lastname: Chen
authors.forename: Danny
authors.initials: D
authors.lastname: Gauvreau
authors.forename: Francis
authors.initials: F
authors.lastname: Gosselin
authors.forename: Greg
authors.initials: G
authors.lastname: Hughes
authors.forename: Christian
authors.initials: C
authors.lastname: Nadeau
authors.forename: Ralph P
authors.initials: RP
authors.lastname: Volante
mesh_terms: D000438:Alcohols / Q000737:chemistry; D001713:Biphenyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D004952:Esters / Q000737:chemistry; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry*; D006868:Hydrolysis; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013379:Substrate Specificity
chemical_list: D000438:Alcohols; D001713:Biphenyl Compounds; D004952:Esters; D006845:Hydrocarbons, Fluorinated; D011480:Protease Inhibitors; C501566:ortho-trifluoromethyl phenyl triflate; D002403:Cathepsins; D056657:Cathepsin K; C527128:odanacatib