Format

Send to

Choose Destination
J Org Chem. 2017 Oct 6;82(19):10376-10387. doi: 10.1021/acs.joc.7b01852. Epub 2017 Sep 14.

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

Author information

1
Discovery Chemistry, Bristol-Myers Squibb, Pharmaceutical Research and Development , PO Box 4000, Princeton, New Jersey 08543, United States.
2
Department of Chemistry, The Scripps Research Institute , 10550 North Torrey Pines Road, La Jolla, California 92037, United States.
3
Discovery Chemistry, Bristol-Myers Squibb, Research and Development , 5 Research Parkway, Wallingford, Connecticut 06492, United States.

Abstract

An efficient large-scale synthesis of acid 1, a penultimate precursor to the HCV NS5A inhibitor 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 resolution of 27c followed by further synthetic manipulations involving the carbamate formation, lactone reduction and cyclization, afforded cyclopropyl pyran 1. 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 BMS-986097 for toxicology studies.

PMID:
28877441
DOI:
10.1021/acs.joc.7b01852
[Indexed for MEDLINE]

Supplemental Content

Full text links

Icon for American Chemical Society
Loading ...
Support Center