A Design of Experiments Approach to a Robust Final Deprotection and Reactive Crystallization of IPI-926, A Novel Hedgehog Pathway Inhibitor

Abstract

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.

Data-Rich Experimentation Enables Palladium-Catalyzed Couplings of Piperidines and Five-Membered (Hetero)aromatic Electrophiles

“…Because of the condensed timeframes in which drug discovery/optimization programs operate, we aimed to identify existing catalysts that would overcome the present challenges to enable rapid evaluation of structure–activity relationships (SAR) and accelerate access to the desired chemical matter. Herein we report a series of studies involving high-throughput experimentation (HTE) efforts and application of Design of Experiments (DoE) methodology that resulted in the identification of a ligand-supported precatalyst and a set of conditions capable of enabling the desired transformation. The scope of both coupling partners was broadly evaluated, and reaction progress kinetic analysis (RPKA) was used to shed light on the kinetics of this system.…”

Development of a Multi Kilogram-Scale, Tandem Cyclopropanation Ring-Expansion Reaction en Route to Hedgehog Antagonist IPI-926

“…While 3a was a substrate of choice during the early optimization phase of the cyclopropanation reaction, bis-Cbz substrate 3b proved to be the preferred intermediate due to streamlined downstream processing to D-homocyclopamine 5. Oppenauer oxidation of 5 into 6 sets the stage for stereoselective reduction of the enone, 6 methanesulfonamide installation, 7 and finally salting of the piperidine ring 8 to produce the active pharmaceutical ingredient 2. This paper focuses primarily on the D-ring homologation chemistry, whereas the optimization of the large-scale production of 2 from 6 will be the topics of other publications.…”

Magnetic separation of immobilized biocatalyst enables continuous manufacturing with a solids-forming reaction

“…One can imagine, for example, immobilizing metal/organometallic catalysts in a similar manner for continuous solid-solid separation. [48][49][50] As both continuous pharmaceutical processes and reactive crystallizations are gaining traction, the design of new unit operations, including separators, is needed to accelerate the adoption of continuous, heterogeneously catalyzed reactive crystallizations and more generally expand the chemistries and processes amenable to continuous manufacturing.…”