5 research outputs found
An Efficient, Direct Bis-ortho-chlorination of 4-(Difluoromethoxy)aniline and Its Application to the Synthesis of BMS-665053, a Potent and Selective Pyrazinone-Containing Corticotropin-Releasing Factor-1 Receptor Antagonist
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)Âamino)Âacetate (<b>24</b>) to (<i>E</i>)-benzyl 4-(1-hydroxycyclopropyl)Âbut-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