Wang, H.; Matsuhashi, H.; Doan, B. S.; Goodman, S. N.; Ouyang, X.; Clark, W. M., Jr. Large-scale synthesis of SB-462795, a cathepsin K inhibitor: the RCM-based approaches. Tetrahedron 2009, 65, 6291 (and references therein).
The GlaxoSmithKline process group has a number of reports on their body of work in which they developed an efficient process for the synthesis of relacatib (SB-462795), a clinical candidate for treatment of osteoporosis and osteoarthritis. While certainly not the only challenge, the key synthetic step is a ring closing metathesis (RCM) reaction to provide the azepine ring structure, and this series of papers is an excellent example of effective process optimization of an RCM reaction. The team prepared a number of potential substrates, controlled for catalyst-killing impurities, and developed reproducible methods for trace ruthenium removal.
Ultimately, the GSK team developed a process that proceeds through the route below. A yield of 96% with 0.5 mol% catalyst loading made for a process efficient enough to prepare over 200 kg of API.
The authors say in a footnote in the 2009 Tetrahedron paper that a detailed account of their investigation into alternate catalysts will appear shortly. I’ll certainly be keeping my eye out…