Practical asymmetric synthesis of a potent Cathepsin K inhibitor. Efficient palladium removal following Suzuki coupling.
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.
Chen
Cheng-Yi
CY
Department of Process Research, Merck Frosst Centre for Therapeutic Research, P.O. Box 1005, Pointe-Claire-Dorval, Québec, H9R 4P8, Canada.
Dagneau
Philippe
P
Grabowski
Edward J J
EJ
Oballa
Renata
R
O'Shea
Paul
P
Prasit
Peppi
P
Robichaud
Joël
J
Tillyer
Rich
R
Wang
Xin
X
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
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D010421:Pentanoic Acids; D010879:Piperazines; D010165:Palladium; D002403:Cathepsins; D056657:Cathepsin K