Discovery and Development of an Efficient, Scalable, and Robust Route to the Novel CENP-E Inhibitor GSK923295A

Abstract

The discovery and development of an efficient manufacturing route to the CENP-E inhibitor 3-chloro-N-{(1S)-2-[(N,Ndimethylglycyl)amino]-1-[(4-{8-[(1S)-1-hydroxyethyl]imidazo[1,2-a]pyridin-2-yl}phenyl)methyl]ethyl}-4-[(1-methylethyl)oxy]benzamide (GSK923295A) is described. The existing route to GSK923295A was expensive, nonrobust, used nonideal reagents, and consistently struggled to deliver the API needed for clinical studies. The new synthesis commences from the readily available L-phenylalaninol, which is smoothly converted through to GSK923295A using key Friedel-Crafts acylation as well as selective acylation chemistries. Downstream chemistry to GSK923295A is both high yielding and robust, and the resulting process has been demonstrated first on the kilo scale and subsequently in the pilot plant where 55 kg was successfully prepared. The resulting process is simple, uses cheaper raw materials, is greener in that it avoids using aluminum, tin, and bromination chemistries, and obviates the need for chromatographic purification. Also discussed are the route derived impurities, how they were unambiguously prepared to confirm structure and processing amendments to control their formation, and enhancements to the new process to facilitate future processing.

Cenp-E inhibitor GSK923295: Novel synthetic route and use as a tool to generate aneuploidy

“…To experimentally induce whole chromosome aneuploidies, we set out to synthesise the Cenp-E inhibitor, GSK923295 by following previously published routes [ 40 , 42 ]. A key step involves resolution of racemic 1-(2-amino-3-pyridinyl)ethanol (Fig.…”

Rapid, metal-free and aqueous synthesis of imidazo[1,2-a]pyridine under ambient conditions

“…The imidazo[1,2-a]pyridine scaffold, found at the core of many pharmaceutical drugs such as zolimidine ( peptic ulcer), 1 zolpidem (insomnia and brain disorders) 2 and rifaximin (hepatic encephalopathy), 3,4 is one of the most privileged nitrogencontaining heterocycles in drug design. [5][6][7][8] Industrial routes to imidazo [1,2-a]pyridines have often been via condensations between 2-aminopyridines and α-bromoketones/α-chloroketones (Scheme 1), 9,10 with an aryl or a carboxylate group at the β position for subsequent reduction to an OH group and derivatisation. [11][12][13] Recent synthetic methods have focused on functionalisation of the core scaffold through metal catalysed coupling reactions (e.g.…”

Development of a Scalable Process for the PPAR-α Agonist GW641597X Incorporating Baeyer–Villiger Chemistry and Retrospective ICH M7 Assessment

“…An authentic sample of this material was readily accessible by reaction of 8 with sodium hydride in tetrahydrofuran and dimethylformamide to give a very good yield of 14 , further highlighting the risk of having excess potassium tert -butoxide within this process. The authors have observed this type of reactivity in a previous process; it is also reported for the base-mediated self-condensation of phenacyl halides, which is suggested to proceed via the intermediacy of an unsaturated dicarbonyl …”