Process Development and Large-Scale Synthesis of NK_1 Antagonist

概要

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A scaleable synthetic route is described to obtain 2-(4-acetylpiperadin-l-y1)-6-[3, 5-bis(trifluoromethyl)-phenylmethyl]-4-(2-methylpheny1)-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-dihydropy-rimidine-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.
公益社団法人日本薬学会の論文
2008-02-01