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

Paul D O'Shea, Cheng-yi Chen, Danny Gauvreau, Francis Gosselin, Greg Hughes, Christian Nadeau, Ralph P Volante

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

The Journal of organic chemistry 2009 Feb 20

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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.

Citation

Paul D O'Shea, Cheng-yi Chen, Danny Gauvreau, Francis Gosselin, Greg Hughes, Christian Nadeau, Ralph P Volante. A practical enantioselective synthesis of odanacatib, a potent Cathepsin K inhibitor, via triflate displacement of an alpha-trifluoromethylbenzyl triflate. The Journal of organic chemistry. 2009 Feb 20;74(4):1605-10