【摘要】：尿嘧啶(2)經(jīng)1,3-二溴-5,5-二甲基乙內(nèi)酰脲(DBH)溴代得5-溴尿嘧啶(3),收率由文獻(xiàn)的86%提高至95%;3經(jīng)五氯化磷氯化得2,4-二氯-5-溴嘧啶(4),革除了劇毒且刺激性強(qiáng)的三氯氧磷,收率由文獻(xiàn)的88%提高至99%;4與環(huán)戊胺發(fā)生取代反應(yīng)得5-溴-2-氯-N-環(huán)戊基嘧啶-4-胺(5);以氯化鈀代替文獻(xiàn)的乙酸鈀作催化劑,5與巴豆酸經(jīng)Heck反應(yīng)后,再經(jīng)內(nèi)酰胺化成環(huán)得2-氯-8-環(huán)戊基-5-甲基吡啶并[2,3-d]嘧啶-7(8H)-酮(6),縮短了反應(yīng)時(shí)間(由36 h減少至6 h),收率也由80%提高至90%以上。6再經(jīng)溴化、取代、Heck偶聯(lián)、酸性水解以及脫保護(hù)反應(yīng)制得帕博昔布(1),總收率52.1%(以2計(jì))。
[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%).
【作者單位】： 中國(guó)醫(yī)藥工業(yè)研究總院上海醫(yī)藥工業(yè)研究院;
【分類(lèi)號(hào)】：R914.5
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本文編號(hào)：2525491