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Process Development of a CRF1 Receptor Antagonist Based on the Selective Chlorination of a Benzimidazolone via Chlorine Migration

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journal contribution
posted on 12.01.2017 by Yasuhiro Sawai, Osamu Yabe, Keiichiro Nakaoka, Tomomi Ikemoto
A practical synthesis of 4-chloro-2-(2,4-dichloro-6-methylphenoxy)-1-methyl-7-(pentan-3-yl)-1H-benzo­[d]­imidazole 1, a novel corticotropin-releasing factor 1 (CRF1) receptor antagonist, has been developed. The key chemical transformations were (1) a novel regioselective chlorination at the 4-position of a benzimidazolone intermediate with 1,3,5-trichloro-1,3,5-triazinane-2,4,6-trione in the presence of sodium tertiary butoxide via a chlorine migration mechanism (N-3 to C-4) and (2) a one-pot, three-step dehydroxylation sequence (dehydration, isomerization, and hydrogenation) of a benzylic tertiary alcohol in the presence of p-toluenesulfonic acid and a Pd catalyst. The endgame was also optimized for quality and yield improvement. The chromatography-free six-step process starting from a commercially available material afforded 1 in 35% overall yield and greater than 99% purity.