Processes for making ponatinib and intermediates thereof
Methods are disclosed for making 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.
1. A method of making ponatinib or a pharmaceutically acceptable salt thereof, comprising the steps of:
reacting 3-iodo-4-methylbenzoyl chloride with a solution of 4-amino-2-(trifluoromethyl)benzaldehyde to obtain N-(4-formyl-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide;
adding a base, an iodide reagent and a catalyst to a solution of N-(4-formyl-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide to obtain a reaction mixture, and adding 3-ethynylimidazo[1,2-b]pyridazine to the reaction mixture to obtain N-(4-formyl-3-(trifluoromethyl)-phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide;
reacting a solution of N-(4-formyl-3-(trifluoromethyl)-phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide with sodium borohydride to obtain N-(4-(hydroxymethyl)-3-(trifluoromethyl)-phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide;
reacting a solution of N-(4-(hydroxymethyl)-3-(trifluoromethyl)-phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide with a chloride compound to obtain N-(4-(chloromethyl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide; and
reacting a solution of N-(4-(chloromethyl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide with N-methylpiperazine to obtain 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide.
2. The method of claim 1 comprising the further step of saturating a solution of the 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide with HCl gas to form ponatinib hydrochloride.
3. The method of claim 1 wherein the base is selected from the group consisting of N,N-diisopropylethylamine (DIPEA), triethyl amine (TEA) and diethylamine (DEA).
4. The method of claim 1 wherein the iodide reagent is CuI.
5. The method of claim 1 wherein the catalyst is selected from the group consisting of PdCl 2 (PPh 3 ) 2 , Pd(PPh 3 ) 4 , Pd(dppe)Cl, Pd(dppp)Cl 2 , and Pd(dppf)Cl 2 .
6. The method of claim 1 wherein the chloride is selected from the group consisting of phosphoryl chloride, thionyl chloride, oxalyl chloride, cyanuric chloride and phosphorous pentachloride.
7. The method of claim 1 wherein the 4-amino-2-(trifluoromethyl) benzaldehyde is obtained by reacting a solution of 4-nitro-2-(trifluoromethyl)benzaldehyde in AcOH with iron.