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

An efficient large-scale synthesis of acid 1, a penultimate precursor to the HCV NS5Ainhibitor BMS-986097, along with the final API step are described. Three routes were devised for the synthesis of 1 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 t-butyl 2-((diphenylmethylene)amino)acetate (24) to (E)-benzyl 4-(1-hydroxycyclopropyl)but-2-enoate (28) followed by cyclization and chiral separation to form 27c, the core skeleton of cap piece 1. The epimerization and chiral resolutionof 27c followed by further synthetic manipulations involving the carbamate formation, lactone reduction and cyclization, afforded cyclopropyl pyran1. A detailed study of diphenylmethanedeprotection via acid hydrolysis as well as a key lactone to tetrahydropyranconversion, in order to avoid a side reactionthat afforded an alternative cyclization product, are discussed. This synthesis was applied to t...