Processes for making ponatinib and intermediates thereof
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.
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 having the formula Ib
catalytically hydrogenating the phthalimide derivative of formula Ib to obtain a compound having the formula Ic
reacting the compound of formula Ic with 3-iodo-4-methylbenzoyl chloride having the formula
to obtain N-(4-((1,3-dioxoisoindolin-2-yl)methyl)-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide having the formula Id
reacting the compound of formula Id with 3-ethynylimidazo[1,2-b]pyridazine in a coupling reaction to obtain a compound of the formula Ie
subjecting the compound of formula Ie 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, wherein when the piperazine ring is formed using a) 2-chloro-N-(2-chloroethyl)-N-methylethanamine, subsequently forming the ponatinib hydrochloride using hydrogen chloride; and
wherein when the piperazine ring is formed using b) 2-chloro-N-(2-chloroethyl)-N-substituted derivative of the formula (VI), subsequently deprotecting the piperazine ring to obtain a compound having the formula Ih
methylating compound Ih and subsequently forming the ponatinib hydrochloride using hydrogen chloride.
2. The method according to claim 1 wherein X is Br.
3. The method according to claim 1 wherein P is tosyl, mesyl, carboxybenzyl, benzyl, nitro benzyl or amino.
4. The method according to claim 1 wherein the step of methylating the compound of formula Ih comprises N-methylation with methyl iodide.
5. The method according to claim 1 wherein the step of forming a piperazine ring comprises treatment of the N-(4-(aminomethyl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide with 2-chloro-N-(2-chloroethyl)-N-methylethanamine.
6. The method according to claim 1 wherein the step of forming a piperazine ring comprises 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-substituted derivative of the formula (VI) wherein P is a protecting group and subsequently deprotecting the piperazine ring.
7. The method according to claim 1 wherein the step of deprotection of the piperazine ring is carried out using an acid.
8. The method according to claim 7 wherein the acid is selected from the group consisting of concentrated sulfuric acid, HBr in acetic acid, HBr in water and trifluoroacetic acid.