PROCESSES FOR MAKING PONATINIB AND INTERMEDIATES THEREOF

摘要

Novel synthetic approaches to make 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-[4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl)phenyl]benzamide, intermediates and pharmaceutically acceptable salts thereof are provided.

主权项

1. A method for the production of ponatinib hydrochloride of the formula (I) comprising reacting a compound of formula (II) 1-(halo methyl)-4-nitro-2-(trifluoromethyl)benzene wherein X is a halogen, with potassium phthalimide to obtain a phthalimide derivative, reducing the phthalimide derivative, reacting the reduced phthalimide derivative with 3-iodo-4-methylbenzoyl chloride having the formula (IV) to form an amide, reacting the amide with 3-ethynylimidazo[1,2-b]pyridazine of the formula (V) in a coupling reaction, subjecting a product of the coupling reaction to hydrolysis to obtain N-(4-(aminomethyl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide, subsequently forming a piperazine ring by treatment of the N-(4-(aminomethyl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide with a) 2-chloro-N-(2-chloroethyl)-N-methylethanamine; or b) a 2-chloro-N-(2-chloroethyl)-N-substituted derivative of the formula (VI) wherein P is a protecting group and subsequently deprotecting the piperazine ring; and forming the ponatinib hydrochloride using hydrogen chloride.