甲磺酸伊马替尼有关物质的合成  

Synthesis of imatinib mesylate related substances

作　　者：徐玲芬 高瑞阳 姜宇飞 王伊文 李响 程青芳 XU Ling-fen;GAO Rui-yang;JIANG Yu-fei;WANG Yi-wen;LI Xiang;CHENG Qing-fang(School of Pharmacy,Jiangsu Ocean University,Lianyungang 222005,China;Lianyungang Guike Pharmaceutical Co.,Ltd.,Lianyungang 222000,China)

机构地区：[1]江苏海洋大学药学院,江苏连云港222005 [2]连云港贵科药业有限公司,江苏连云港222000

出　　处：《化学研究与应用》2024年第6期1427-1432,共6页Chemical Research and Application

基　　金：连云港市科技成果转化“揭榜挂帅”专项资金项目(CA202101)资助;研究生科研与实践创新计划项目(KYCX2023-52)资助。

摘　　要：为了控制甲磺酸伊马替尼在生产过程中的质量,分别制备了甲磺酸伊马替尼的5个有关物质:以对氯甲基苯甲酸为起始原料,改进合成方法合成4-(氯甲基)-N-[4-甲基-3-[[4-(3-吡啶基)嘧啶-2-基]氨基]苯基]苯甲酰胺(有关物质A),收率为91.4%。以有关物质A为起始原料,设计了新的合成路线得到4-[[[4-[(4-甲基哌嗪-1-基)甲基]-苯甲酰基]-基-哌嗪-1-基]-甲基]-N-[4-甲基-3-[[4-(3-吡啶基)嘧啶-2-基]氨基]苯基]苯甲酰胺(有关物质B),收率为77.5%。4-[(4-甲基-1-氧化哌嗪-1-基)甲基]-N-[4-甲基-3-[[4-(3-吡啶基)嘧啶-2-基]氨基]苯基]苯甲酰胺(有关物质C)、4-[(4-甲基-4-氧化哌嗪-1-基)甲基]-N-[4-甲基-3-[[4-(3-吡啶基)嘧啶-2-基]氨基]苯基]苯甲酰胺(有关物质D)和4-[(4-甲基-1,4-二氧化哌嗪-1-基)甲基]-N-[4-甲基-3-[[4-(3-吡啶基)嘧啶-2-基]氨基]苯基]苯甲酰胺(有关物质E)结构相似,本研究设计了新的合成方法,其收率分别为85.5%、78.2%和82.5%,并通过MS和NMR对上述五个有关物质结构进行了表征。In order to control the quality of imatinib mesylate in the production process,5 related substances of imatinib mesylate were prepared.Using p-chloromethylbenzoic acid as the starting material,the synthetic method was improved to synthesize 4-(chlo-romethyl)-N-[4-methyl-3-[[4-(3-pyridyl)pyrimidin-2-yl]amino]phenyl]benza-mide(related substance A)to obtain a yield of 91.4%.And the relevant substance A was used as the starting material,a new synthetic route was designed to obtain 4-[[[4-[(4-methylpiperazine-1-yl)methyl]-benzoyl]-yl-piperazine-1-yl]-methyl]-N-[4-methyl-3-[[4-(3-pyridyl)pyrimidin-2-yl]amino]phe-nyl ] benzamide(related substa-nce B)in 77.5%yield.4-[(4-Methyl-1-oxidepiperazine-1-yl)methyl]-N-[4-methyl-3-[[4-(3-pyri-dyl)pyrimidin-2-yl]amino ] Phenyl]benzamide(related substance C),4-[(4-methyl-4-oxidazine-1-yl)methyl]-N-[4-methyl-3-[[4-(3-pyridyl)pyrimidin-2-yl]amino]phenyl]benzamide(related substance D)and 4-[(4-methyl-1,4-dioxidepiperazine-1-yl)methyl]-N-[4-methyl-3-[[4-(3-pyridyl)pyrimidin-2-yl]amino]phenyl]benzamide(related substance E)were prepared through new synthetic methods,and the yields were 85.5%,78.2%and 82.5%,respectively.The structures of the above five related sub-stances were confirmed by MS and NMR.

关 键 词：甲磺酸伊马替尼 小分子抗癌药 有关物质 合成 

分 类 号：O621.3[理学—有机化学]