title: 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.
authors.affiliation: Research Center, Kyorin Pharmaceutical Co., Ltd., Nogi-machi, Shimotsuga-gun, Tochigi, Japan. ichirou.araya@mb.kyorin-pharm.co.jp
authors.forename: Ichiro
authors.initials: I
authors.lastname: Araya
authors.forename: Shintaro
authors.initials: S
authors.lastname: Kanazawa
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Akita
mesh_terms: D002851:Chromatography, High Pressure Liquid; D003362:Cost-Benefit Analysis; D003500:Cyclization; D007202:Indicators and Reagents; D064729:Neurokinin-1 Receptor Antagonists; D010079:Oxazocines / Q000138:chemical synthesis* / Q000191:economics; D021241:Spectrometry, Mass, Electrospray Ionization; D016339:Spectrometry, Mass, Fast Atom Bombardment; D013056:Spectrophotometry, Ultraviolet
chemical_list: D007202:Indicators and Reagents; C527215:KRP-103; D064729:Neurokinin-1 Receptor Antagonists; D010079:Oxazocines