Diastereoselective arylithium addition to an alpha-trifluoromethyl imine. Practical synthesis of a potent cathepsin K inhibitor.
A practical, chromatography-free synthesis of potent cathepsin K inhibitor 1 is described. The addition of 4-bromophenyllithium to an alpha-trifluoromethylimine derived from commercially available (S)-leucinol was accomplished in a highly diastereoselective manner (97.6% de, 91% yield). Subsequent Suzuki cross-coupling afforded biaryl 7. Oxidation of the alcohol and sulfide functionalities led to the formation of carboxylic acid 8. Crystallization of 7 and acid 8 as its dicyclohexylamine salt gave excellent impurity rejection. The final amide coupling with commercially available aminoacetonitrile hydrochloride afforded 1 in excellent purity (99.6A% by HPLC, 100% de, <3 ppm Pd, W, Cr).
Roy
Amélie
A
Department of Process Research, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Québec H9H 3L1, Canada. amelie_roy@merck.com
Gosselin
Francis
F
O'Shea
Paul D
PD
Chen
Cheng-y
CY
D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D007097:Imines / Q000737:chemistry*; D008094:Lithium / Q000737:chemistry*; D015394:Molecular Structure
D007097:Imines; D008094:Lithium; D002403:Cathepsins; D056657:Cathepsin K