posted on 2021-08-06, 14:36authored byThomas E. La Cruz, Francisco González-Bobes, Martin D. Eastgate, Chris Sfouggatakis, Bin Zheng, Nathaniel Kopp, Yi Xiao, Yu Fan, Kay A. Galindo, Charles Pathirana, Michael A. Galella, Joerg Deerberg
BMS-813160 is a pharmaceutical entity
currently in development
at Bristol Myers Squibb. Its defining structural feature is a unique
chiral all cis triamino cyclohexane core. Medicinal
and process chemistry groups at BMS have previously published synthesis
strategies for chemotypes similar to the target molecule, but a streamlined
approach amenable for longer-term supply was necessary. A new synthetic
route was conceptualized, experimentally investigated, and determined
to meet the criteria for efficiency that addressed key limitations
of previous approaches. Adopting/optimizing the Trost asymmetric allylic
amination desymmetrization methodology was a key tool used to produce
a synthesis intermediate with high optical purity. In addition, developing
a tandem Mannich–aza-Michael reaction to obviate the need for
a Curtis/acylation sequence and a novel reductive amination/thermal
lactamization to circumvent Freidinger-type pyrrolidone preparation
are some of the synthesis improvements that enabled access to the
target molecule to fulfill long-term supply requirements.