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作 者:徐乐 李志威 汤雅东 马幸幸 刘亚婧[1] 侯云雷[1] XU Le;LI Zhi-wei;TANG Ya-dong;MA Xing-xing;LIU Ya-jing;HOU Yun-lei(Key Laboratory of Structure-Based Drug Design and Discovery(Shenyang Pharmaceutical University),Ministry of Education,Shenyang 110016,China)
机构地区:[1]沈阳药科大学基于靶点的药物设计与研究教育部重点实验室,辽宁沈阳110016
出 处:《中国药物化学杂志》2021年第2期95-99,共5页Chinese Journal of Medicinal Chemistry
基 金:中国博士后科学基金项目(2019TQ0215);辽宁省博士科研启动基金指导计划项目(2020-BS-130)。
摘 要:目的研究PLK1抑制剂BI-2536的合成工艺。方法以D-2-氨基丁酸为起始原料,依次经酯化、还原胺化、亲核取代、还原环合、甲基化反应,得到关键中间体(7R)-2-氯-8-环戊基-7-乙基-7,8-二氢-5-甲基-6(5H)-蝶啶酮;以3-甲氧基-4-硝基苯甲酸为起始原料,经氯代、酰胺化、硝基还原,得到关键中间体4-氨基-3-甲氧基-N-(1-甲基-4-哌啶基)苯甲酰胺;上述两个中间体经盐酸催化的C-N偶联反应制得目标化合物BI-2536。结果与结论目标化合物的结构经1H-NMR和MS谱确证。总收率达51.0%(以D-2-氨基丁酸计),产品纯度为99.6%。A synthetic process to prepare PLKI inhibitor BI-2536 has been developed based on the synthetic methods reported in literatures.With(D)-2-aminobutanoic acid as the starting material,the key intermediate(R)-2-chloro-8-cyclopentyl-7-ethyl-5-methyl-7,8-dihydropteridin-6(5H)-one(6) was synthesized by sequential esterification,reductive amination,nucleophilic substitution,reductive cyclization and methylation reactions.Another key intermediate 4-amino-3-methoxy-N-(1-methylpiperidin-4-yl)benzamide(7) was prepared by sequential chlorination,amidation and nitro reduction.Finally,BI-2536 was prepared via coupling reaction of intermediate 6 and 7.The total yield was 51.0% calculated from(D)-2-aminobutanoic acid,with HPLC purity of 99.6%.The structures of the target compound and intermediates were confirmed by 1H-NMR and ESI-MS.
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