帕博昔布的合成

Synthesis of Palbociclib

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)。

5-Bromouracil （3） was prepared via bromination of uracil （2） in the presence of 1,3-dibromo-5,5- dimethylhydantoin with a yield of 95 %. Then 2,4-dichloro-5-bromopyrimidine （4） was synthesized via chlorination of 3. In this step, phosphorus pentachloride was used instead of phosphoryl chloride so that the yield was increasd from 88 % to 99 % . 4 reacted with cyclopentylamine to give 5-bromo-2-chloro-N-cyclopentylpyrimidin-4-amine （5）. Then 5 was subjected to Heck reaction with crotonic acid followed by lactamization to afford 2-chloro-8-cyclopentyl-5- methylpyrido [2,3-d]pyrimidin-7 （8H）-one （6）. In this step, palladium chloride was used instead of palladium acetate to shorten the reaction time from 〉36 h to 6 h and increase the yield from 80% to 〉90% . Palbociclib （1） was obtained after bromination of 6, substitution, Heck coupling reaction, acidic hydrolysis and deprotection with an overall yield of 52.1% （based on 2）.