A practical enantioselective synthesis of odanacatib, a potent Cathepsin K inhibitor, via triflate displacement of an alpha-trifluoromethylbenzyl triflate.
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.
O'Shea
Paul D
PD
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
Chen
Cheng-yi
CY
Gauvreau
Danny
D
Gosselin
Francis
F
Hughes
Greg
G
Nadeau
Christian
C
Volante
Ralph P
RP
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
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