title: Diastereoselective arylithium addition to an alpha-trifluoromethyl imine. Practical synthesis of a potent cathepsin K inhibitor.
abstract: 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).
authors.affiliation: Department of Process Research, Merck Frosst Centre for Therapeutic Research, 16711 Trans Canada Highway, Kirkland, Québec H9H 3L1, Canada. amelie_roy@merck.com
authors.forename: Amélie
authors.initials: A
authors.lastname: Roy
authors.forename: Francis
authors.initials: F
authors.lastname: Gosselin
authors.forename: Paul D
authors.initials: PD
authors.lastname: O'Shea
authors.forename: Cheng-y
authors.initials: CY
authors.lastname: Chen
mesh_terms: D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D007097:Imines / Q000737:chemistry*; D008094:Lithium / Q000737:chemistry*; D015394:Molecular Structure
chemical_list: D007097:Imines; D008094:Lithium; D002403:Cathepsins; D056657:Cathepsin K