帕博昔布的合成
发布时间：2019-08-11 20:10
【摘要】：尿嘧啶(2)经1,3-二溴-5,5-二甲基乙内酰脲(DBH)溴代得5-溴尿嘧啶(3),收率由文献的86%提高至95%;3经五氯化磷氯化得2,4-二氯-5-溴嘧啶(4),革除了剧毒且刺激性强的三氯氧磷,收率由文献的88%提高至99%;4与环戊胺发生取代反应得5-溴-2-氯-N-环戊基嘧啶-4-胺(5);以氯化钯代替文献的乙酸钯作催化剂,5与巴豆酸经Heck反应后,再经内酰胺化成环得2-氯-8-环戊基-5-甲基吡啶并[2,3-d]嘧啶-7(8H)-酮(6),缩短了反应时间(由36 h减少至6 h),收率也由80%提高至90%以上。6再经溴化、取代、Heck偶联、酸性水解以及脱保护反应制得帕博昔布(1),总收率52.1%(以2计)。
[Abstract]:Uracil (2) was brominated to 5-bromouracil (3) by 1, 3-dibromo-5, 5-Dimethylllidyl urea (DBH) brominated. The yield of 5-bromouracil (3) was increased from 86% to 95% by phosphorus pentachloride chlorination to 2, 4-dichloro-5-bromopyrimidine (4). The highly toxic and irritating phosphorus oxychloride was removed, and the yield was increased from 88% to 99% in the literature. (4) 5-bromo-2-chloro-N-cyclopentylpyrimidine-4-amine (5) was obtained by substitution reaction with cyclopentylamine. Palladium chloride was used as catalyst to synthesize 2-chloro-8-cyclopentyl-5-methylpyridine 2-chloro-8-cyclopentyl-5-methylpyridine (2, 3 脳 d) pyrimidine-7 (8H)-ketone (6), and the reaction time (from 36 h to 6 h),) was also increased from 80% to more than 90%. 6 was then brominated, substituted and coupled by Heck. Paboxib (1) was prepared by acid hydrolysis and deprotection with an overall yield of 52.1% (in 2%).
【作者单位】： 中国医药工业研究总院上海医药工业研究院;
【分类号】：R914.5
，
本文编号：2525491
[Abstract]:Uracil (2) was brominated to 5-bromouracil (3) by 1, 3-dibromo-5, 5-Dimethylllidyl urea (DBH) brominated. The yield of 5-bromouracil (3) was increased from 86% to 95% by phosphorus pentachloride chlorination to 2, 4-dichloro-5-bromopyrimidine (4). The highly toxic and irritating phosphorus oxychloride was removed, and the yield was increased from 88% to 99% in the literature. (4) 5-bromo-2-chloro-N-cyclopentylpyrimidine-4-amine (5) was obtained by substitution reaction with cyclopentylamine. Palladium chloride was used as catalyst to synthesize 2-chloro-8-cyclopentyl-5-methylpyridine 2-chloro-8-cyclopentyl-5-methylpyridine (2, 3 脳 d) pyrimidine-7 (8H)-ketone (6), and the reaction time (from 36 h to 6 h),) was also increased from 80% to more than 90%. 6 was then brominated, substituted and coupled by Heck. Paboxib (1) was prepared by acid hydrolysis and deprotection with an overall yield of 52.1% (in 2%).
【作者单位】： 中国医药工业研究总院上海医药工业研究院;
【分类号】：R914.5
，
本文编号：2525491
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