Development of the Large-Scale Synthesis of Tetrahydropyran Glycine, a Precursor to the HCV NS5A Inhibitor <b>BMS-986097</b>

An efficient large-scale synthesis of acid <b>1</b>, a penultimate precursor to the HCV NS5A inhibitor <b>BMS-986097</b>, along with the final API step are described. Three routes were devised for the synthesis of <b>1</b> at the various stages of the program. The third generation route, the one that proved scalable and is the main subject of this paper, features a one-step Michael addition of <i>t</i>-butyl 2-((diphenylmethylene)­amino)­acetate (<b>24</b>) to (<i>E</i>)-benzyl 4-(1-hydroxycyclopropyl)­but-2-enoate (<b>28</b>) followed by cyclization and chiral separation to form <b>27c</b>, the core skeleton of cap piece <b>1</b>. The epimerization and chiral resolution of <b>27c</b> followed by further synthetic manipulations involving the carbamate formation, lactone reduction and cyclization, afforded cyclopropyl pyran <b>1</b>. A detailed study of diphenylmethane deprotection via acid hydrolysis as well as a key lactone to tetrahydropyran conversion, in order to avoid a side reaction that afforded an alternative cyclization product, are discussed. This synthesis was applied to the preparation of more than 100 g of the final API <b>BMS-986097</b> for toxicology studies