【作者】 禹艳坤；

【导师】 冀亚飞；

【作者基本信息】 华东理工大学 ， 制药工程与技术， 2011， 硕士

【摘要】 尼洛替尼是一种具有高度选择性的酪氨酸激酶抑制剂,临床用于治疗对伊马替尼耐药或不能耐受的成人慢性期和加速期的慢性粒细胞白血病。在本论文中,以三氟甲苯为原料,经硝化-溴化“一锅煮”、还原、与4-甲基-1-咪唑亲核取代反应得到重要中间体5-(4-甲基-1H-1-咪唑基)-3-三氟甲基苯胺。对甲基苯甲酸经溴化、酯化制得中间体3-溴-4-甲基苯甲酸乙酯,3-乙酰基吡啶与N,N-二甲基甲酰胺二甲缩醛缩合、与硝酸胍环合得到中间体4-(3-吡啶基)-2-氨基嘧啶,然后,3-溴-4-甲基苯甲酸乙酯与4-(3-吡啶基)-2-氨基嘧啶发生亲核取代、水解得到重要中间体4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯甲酸。最后,5-(4-甲基-1H-1-咪唑基)-3-三氟甲基苯胺与4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯甲酸发生酰胺化反应得到目标产物尼洛替尼,总收率46.4%。其中,采用三氟甲苯为原料,经硝化-溴化“一锅煮”制备1-溴-3-硝基-5-三氟甲苯,操作简便,后处理简单。采用3-溴-4-甲基苯甲酸乙酯与4-(3-吡啶基)-2-氨基嘧啶发生亲核取代制备4-甲基-3-[[4-(3-吡啶基)-2-嘧啶基]氨基]苯甲酸乙酯,步骤简便,条件温和,收率较高。中间体及目标产物的化学结构经MS、1H NMR确证,并讨论了影响各步反应的主要因素,从中得到合成尼洛替尼较佳的反应条件。更多还原

【Abstract】 Nilotinib is a highly selective tyrosine kinases inhibitor for the clinical treatment of chronic myelogenous leukemia patients possessing imatinib resistance. In this dissertation of the part for the synthesis of nilotinib, trifluoromethylbenzene was nitrated and brominated with "one-pot" process, followed a reduction, and a nucleophilic substitution with 4-methyl-1H-imidazole to achieve a key intermediate 5-(4-methyl-lH-imidazol-l-yl)-3-trifluoromethylaniline. Another key intermediate,4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl) amino)benzoic acid was prepared from 3-bromo-4-methylbenzoic acid via a serial of reactions of esterification, nucleophilic substitution with 4-(pyridin-3-yl)-2-aminopyrimidine, which was synthesized by condensation reaction between 3-acetyl-pyridine and N,N-dimethylformamide dimethyl acetal and cyclization reaction with guanidine nitate and hydrolysis. In the last step,4-methyl-3-((4-(pyridin-3-yl)pyrimidin-2-yl)amino)benzoic acid was amidated with 5-(4-methyl-1H-imidazol-1-yl)-3-trifluoromethylaniline to give the target niltinib with an overall yield of 46.4%. In the preparation of 1-bromo-3-nitro-5-(trifluoromethyl)benzene, the "one-pot" process was carried out since its convenient operation and easy workup. A unique nucleophilic substitution between ethyl 3-bromo-4-methylbenzoate and 4-(pyridin-3-yl)-2-aminopyrimidine was employed to decrease the reaction steps and make the reaction more modrerate and efficient. The structures of the intermediates and products were confirmed by 1H-NMR and MS. Better technical parameters of synthesizing nilotinib were obtained from the discussion of factors of affecting the reactions above.更多还原