PROCESSES FOR MAKING PONATINIB AND INTERMEDIATES THEREOF

1 . A method of making ponatinib or a pharmaceutically acceptable salt thereof, comprising the steps of:

reacting 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

adding N-methylpiperazine to a solution of N-(4-(chloromethyl)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide 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 chloride compound is selected from the group consisting of phosphoryl chloride, thionyl chloride, oxalyl chloride, cyanuric chloride and phosphorous pentachloride.

4 . The method of claim 1 wherein the step of reacting 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 comprises adding thionyl chloride to a solution of N-(4-(hydroxymethyl)-3-(trifluoromethyl)-phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide.

5 . The method of claim 1 wherein the step of reacting 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 comprises adding N-(4-(hydroxymethyl)-3-(trifluoromethyl) phenyl)-3-(imidazo [1,2-b] pyridazin-3-ylethynyl)-4-methylbenzamide to a solution of dimethylformamide and POCl 3 .

6 . The method of claim 1 wherein the N-(4-(hydroxymethyl)-3-(trifluoromethyl)-phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide is obtained by a process comprising dissolving 4-(3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamido)-2-(trifluoromethyl) benzyl acetate in a solvent and then adding a base.

7 . The method of claim 6 wherein the solvent is selected from the group consisting of tetrahydrofuran (THF) and 2-methyl tetrahydrofuran (2-Me THF).

8 . The method of claim 6 wherein the base is selected from the group consisting of NaOH, KOH and LiOH.

9 . The method of claim 1 wherein the N-(4-(hydroxymethyl)-3-(trifluoromethyl)-phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide is obtained by a process comprising dissolving N-(4-formyl-3-(trifluoromethyl)-phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide in a solvent and then adding sodium borohydride.

10 . The method of claim 1 wherein the N-(4-(hydroxymethyl)-3-(trifluoromethyl) phenyl)-3-(imidazo [1,2-b] pyridazin-3-ylethynyl)-4-methylbenzamide is obtained by a process comprising dissolving N-(4-(hydroxymethyl)-3-(trifluoromethyl) phenyl)-3-iodo-4-methylbenzamide in a solvent to form a solution, adding a base, an iodide reagent and a catalyst to the solution, and subsequently adding 3-ethynylimidazo[1,2-b] pyridazine to the solution.

11 . The method of claim 10 wherein the base is selected from the group consisting of N,N-diisopropylethylamine (DIPEA), triethyl amine (TEA), and diethylamine (DEA).

12 . The method of claim 10 wherein the iodide reagent is CuI.

13 . The method of claim 10 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 .

14 . The method of claim 10 wherein the N-(4-(hydroxymethyl)-3-(trifluoromethyl) phenyl)-3-iodo-4-methylbenzamide is obtained by a process comprising combining (4-amino-2-(trifluoromethyl) phenyl) methanol in dichloromethane and adding pyridine, and subsequently adding 3-iodo-4-methylbenzoyl chloride solution in dichloromethane.