Farina, V.; Shu, C.; Zeng, X.; Wei, X., Han, Z.; Yee, N. K.; Senanayake, C. H. Second-generation process for the HCV protease inhibitor BILN 2061: a greener approach to Ru-catalyzed ring-closing metathesis. Org. Process Res. Dev. 2009, 13, 250-254.
Any conversation about olefin metathesis in the pharmaceutical world has to include the work out of Boehringer Ingelheim on their HCV protease inhibitor. The 15-membered ring with a trans cyclopropane and cis olefin looks tough to make on a large scale for a number of reasons, yet BI generated hundreds of kilograms of RCM product to prepare for clinical trials. But BI had faith in their process chemists and rightfully so.
The most recent in a series of papers on the synthesis of BILN 2061 was published earlier this year in OPR&D. This paper and the references therein go into all the gory details of how they optimized the key ring closing metathesis (RCM) reaction. And it wasn’t easy. I won’t get into the nitty-gritty here, but when the dust settled, the BI chemists had developed a process that used only 0.1 mol% catalyst and was run fairly concentrated (0.2 M).