posted on 2024-01-30, 11:04authored byGary M. Chinigo, Emma L. McInturff, Scott W. Bagley, Richard
W. Barnhart, David C. Blakemore, Lu Han, Taegyo Lee, Javier Magano, J. Christopher McWilliams, Sebastien Monfette, James J. Mousseau, Senliang Pan, Dylan Pedro, Hahdi
H. Perfect, Jeffrey W. Raggon, Peter R. Rose, John Sagal, John
I. Trujillo, Jared Van Haitsma, Michael G. Vetelino, Xiaojing Helen Yang
The original synthesis of a CCR6
antagonist and subsequent enablement
for kilogram manufacture is presented. Highlighted improvements made
in the preparation for the scale-up campaign include (1) a refined
route to access a key iodopyrazole which previously suffered from
low yield due to poor regioselectivity, (2) optimization of a sulfinimine
addition reaction to form a sterically congested amine with high stereocontrol,
(3) implementation of a route to an aminopyridine fragment, and (4)
efficient construction of the target molecule by sequential substitution
of diethyl squarate with two elaborated amines. These enablement efforts
have resulted in the successful preparation of >7 kg of crystalline
API to perform early toxicological studies and initiate Phase 1 clinical
trials.