Araya Ichiro, Kanazawa Shintaro, Akita Hiroyuki
Research Center, Kyorin Pharmaceutical Co., Ltd., Nogi-machi, Shimotsuga-gun, Tochigi, Japan.
Chem Pharm Bull (Tokyo). 2008 Feb;56(2):176-80. doi: 10.1248/cpb.56.176.
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.
描述了一种可扩展的合成路线，以获得2-(4-乙酰基哌啶-1-基)-6-[3,5-双(三氟甲基)苯甲基]-4-(2-甲基苯基)-6,7,8,9-四氢-5H-嘧啶并[4,5-b][1,5]恶唑嗪-5-酮（1，KRP-103）作为神经激肽（NK）(1)拮抗剂。合成中的关键步骤是N-[3,5-双(三氟甲基)苯甲基]-N-(3-羟丙基)-4-氯-6-(2-甲基苯基)-2-甲基硫代嘧啶-5-甲酰胺（15）的分子内环化反应，该化合物是通过4-(2-甲基苯基)-2-甲基硫代-6-氧代-1,6-二氢嘧啶-5-羧酸（8）与3-[3,5-双(三氟甲基)苯甲基氨基]-1-丙醇（3）之间形成酰胺而得到的。用1,8-二氮杂双环[5,4,0]十一碳-7-烯处理15，得到6-[3,5-双(三氟甲基)苯甲基]-4-(2-甲基苯基)-2-甲基硫代-6,7,8,9-四氢-5H-嘧啶并[4,5-b][1,5]恶唑嗪-5-酮（6）。该中间体（6）通过两步反应转化为候选化合物（1）；氧化，以及所得砜（7）与1-乙酰基哌嗪的取代反应。这种合成方法无需色谱纯化，适合大规模合成。
