Synthesis Of Nilotinib

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.