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.