Practical Asymmetric Synthesis of a Potent Cathepsin K Inhibitor. Efficient Palladium Removal Following Suzuki Coupling

• Published in: Journal of organic chemistry 2003-04, Vol.68 (7), p.2633-2638
• Main Authors: Chen, Cheng-yi, Dagneau, Philippe, Grabowski, Edward J. J, Oballa, Renata, O'Shea, Paul, Prasit, Peppi, Robichaud, Joël, Tillyer, Rich, Wang, Xin
• Format: Article
• Language: English
• Subjects: Catalysis; Cathepsin K; Cathepsins - antagonists & inhibitors; Chemistry; Combinatorial Chemistry Techniques; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Exact sciences and technology; Heterocyclic compounds; Heterocyclic compounds with several n hetero atoms in the same ring, in separated rings or in fused rings; Indicators and Reagents; Magnetic Resonance Spectroscopy; Molecular Structure; Organic chemistry; Palladium - chemistry; Pentanoic Acids - chemical synthesis; Pentanoic Acids - pharmacology; Piperazines - chemical synthesis; Piperazines - pharmacology; Preparations and properties; Stereoisomerism
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo0205614

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.