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

• DOI: 10.1021/op100186c
• Publication Date: 2010-08-10T15:07:49Z
• Authors: Richard Bellingham; A. Mark Buswell; Bernie M. Choudary; Andrew H. Gordon; Steve O. Moore; Matthew Peterson; Mike Sasse; Amin Shamji; Michael W. J. Urq...
• Keywords: Friedel–Crafts reaction; Benzamide

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