title: Practical asymmetric synthesis of a potent Cathepsin K inhibitor. Efficient palladium removal following Suzuki coupling.
abstract: A large-scale, chromatography-free synthesis of a potent and selective Cathepsin K inhibitor 1 is reported. The key asymmetric center was installed by addition of (R)-pantolactone to the in situ-generated ketene 4a. The final step of the convergent synthesis of 1 was completed via Suzuki coupling of aryl bromide 7a with unprotected aryl piperazine boronic acid 13. Residual palladium and iron generated in the Suzuki coupling were efficiently removed from crude 1 via a simple extractive workup using lactic acid.
authors.affiliation: Department of Process Research, Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe-Claire-Dorval, Québec, H9R 4P8, Canada.
authors.forename: Cheng-Yi
authors.initials: CY
authors.lastname: Chen
authors.forename: Philippe
authors.initials: P
authors.lastname: Dagneau
authors.forename: Edward J J
authors.initials: EJ
authors.lastname: Grabowski
authors.forename: Renata
authors.initials: R
authors.lastname: Oballa
authors.forename: Paul
authors.initials: P
authors.lastname: O'Shea
authors.forename: Peppi
authors.initials: P
authors.lastname: Prasit
authors.forename: Joël
authors.initials: J
authors.lastname: Robichaud
authors.forename: Rich
authors.initials: R
authors.lastname: Tillyer
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
mesh_terms: D002384:Catalysis; D056657:Cathepsin K; D002403:Cathepsins / Q000037:antagonists & inhibitors*; D020650:Combinatorial Chemistry Techniques; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010165:Palladium / Q000737:chemistry*; D010421:Pentanoic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology; D013237:Stereoisomerism
chemical_list: D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D010421:Pentanoic Acids; D010879:Piperazines; D010165:Palladium; D002403:Cathepsins; D056657:Cathepsin K