N
‐acetyl‐
N
‐phenylhydroxylamine via catalytic transfer hydrogenation of nitrobenzene using hydrazine and rhodium on carbon
solvent: 100 mL of petroleum ether
product: N‐acetyl‐N‐phenylhydroxylamine
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.
The development of the synthetic process to the PPAR-α receptor antagonist 5-((4-(tert-butoxy)-3-methylphenoxy)methyl)-3-(4-(tert-butyl)phenyl)-1,2,4-oxadiazole (GW641597X) 1 is described. The discussion ranges from the initial supply route, used to deliver early batches for preliminary safety studies to enable dosing in man, to an efficient manufacturing route, which delivered 35 kg of drug substance following on from a pilot plant campaign. The process includes a key oxidative Baeyer−Villiger reaction, where process development identified sodium perborate in acetic acid as a safer alternative to m-chloroperoxybenzoic acid that was used in the initial supply route. Described within is a discussion of impurities, how they are formed, and the process modifications incorporated to either reduce or remove them. There is also a discussion of potential mutagenic impurities within the synthetic process and a retrospective evaluation using ICH M7 control options. Finally, an alternative route to GW641597X is described, which offers the advantage that all intermediates are crystalline facilitating material handling, offering purification opportunities through recrystallization if required, and potentially providing greater controls for the process. This new route was also retrospectively assessed using ICH M7 option controls and highlighted that ICH M7 option 4 controls can be implemented even with excess mutagenic reagents being introduced near to the drug substance as long as the science for its purging is well understood.
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