Process development and large-scale synthesis of NK1 antagonist

Abstract

A scaleable synthetic route is described to obtain 2-(4-acetylpiperadin-1- yl)-6-[3,5-bis(trifluoromethyl)-phenylmethyl]-4-(2-methylphenyl)-6,7,8, 9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (1, KRP-103) as a neurokinin (NK)1 antagonist. The key step in the synthesis is the intramolecular cyclization of N-[3,5-bis(trifluoromethyl) phenylmethyl]-N-(3-hydroxypropyl)-4- chloro-6-(2-methylphenyl)-2-methylthiopyrimidine-5-carboxamide (15) which was obtained by amide formation between 4-(2-methylphenyl)-2-methylthio-6-oxo-1,6- dihydropyrimidine-5-carboxylic acid (8) and 3-[3,5-bis(trifluoromethyl) phenylmethylamino]-1-propanol (3). Treatment of 15 with 1,8-diazabicyclo[5,4,0] undec-7-ene provided 6-[3,5-bis(trifluoromethyl)phenylmethyl]-4-(2-methylphenyl) -2-methylthio-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,5]oxazocin-5-one (6). This intermediate (6) is transformed into the candidate compound (1) by two steps; oxidation, and substitution reaction of the resultant sulfone (7) with 1-acetylpiperazine. This synthetic method is free of chromatographic purification and is amenable to large scale synthesis. © 2008 Pharmaceutical Society of Japan.