2 research outputs found
A Design of Experiments Approach to a Robust Final Deprotection and Reactive Crystallization of IPI-926, A Novel Hedgehog Pathway Inhibitor
A design of experiments (DoE) approach
was taken to optimize purity
and reaction yield of the final debenzylation and hydrochloride salt
formation of IPI-926. The study involved a careful dissection of the
different process steps to enable an independent investigation of
these steps while ensuring that process streams were representative.
The results enabled a streamlined process from the final chemical
transformation to the salting and isolation and led to the elimination
of variability in the process as well as a robust control of impurities.
The optimized process was applied to production and demonstrated on
the kilogram scale
Development of a Multi Kilogram-Scale, Tandem Cyclopropanation Ring-Expansion Reaction en Route to Hedgehog Antagonist IPI-926
The
formation of the d-homocyclopamine ring system in
IPI-926 is the key step in its semisynthesis and proceeds via a chemoselective
cyclopropanation followed by a stereoselective acid-catalyzed carbocation
rearrangement. In order to perform large-scale cyclopropanation reactions,
we developed new iodomethylzinc bis(aryl)phosphate reagents that were
found to be both effective and safe. These soluble reagents can be
prepared under mild conditions and are stable during the course of
the reaction. Importantly, they have favorable energetics relative
to other cyclopropanating agents such as EtZnCH<sub>2</sub>I. Herein,
we describe the process optimization studies that led to successful
large-scale production of the d-homocyclopamine core necessary
for IPI-926