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, reducing the phtalimide 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.
2 . The method according to claim 1 wherein X is Br.
3 . The method according to claim 1 wherein P is CH 3 , tosyl, mesyl, carboxybenzyl, benzyl or amino.
4 . The method according to claim 1 wherein the step of deprotecting the piperazine ring 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 in an acid, base and under hydrogenation conditions.
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.
9 . The process according to claim 8 wherein the hydrogenation is carried out using hydrogen pressure and a catalyst.
10 . The process according to claim 9 wherein the catalyst comprises palladium and/or Raney nickel.
11 . A method of making ponatinib hydrochloride having the formula (I)
comprising reacting a 4-substituted-3-(trifluoromethyl) analogue having the formula (VIII)
wherein R is CN, R1 is COOR″, R2 is CH 2 N 3 and R″ is CH 3 , C 2 H 5 or a higher homologue, with 3-iodo-4-methylbenzoic acid of formula (IV)
to obtain an amide of the formula (IIa)
coupling the amide of formula IIa via reaction with 3-ethynylimidazo[1,2-b]pyridazine having the formula (V)
to obtain a compound of the formula (IIe)
subjecting the compound of formula (IIe) to reaction conditions to obtain a compound of formula (IIf), wherein the conditions comprise reduction when R is CN, esterification when R is COOH, and reduction, halogenation and azide formation and reduction of the azide when R is COOR
wherein R′ is CH 2 NH 2 or CH 2 OH,
forming a piperazine ring via reaction of the compound of formula (IIf) with
a) 2-chloro-N-(2-chloroethyl)-N-methylethanamine; or
b) 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.
12 . The method according to claim 11 wherein P is CH 3 , tosyl, mesyl, carboxybenzyl, benzyl or amino.
13 . The method according to claim 11 wherein the step of deprotecting the piperazine ring comprises N-methylation with methyl iodide.
14 . The method according to claim 11 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.
15 . The method according to claim 11 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.
16 . The method according to claim 1 wherein the esterification is carried out using sodium borohydride and lithium aluminium hydride.
17 . The method according to claim 11 , wherein the halogenation is carried out using thionyl chloride, phosphorous oxychloride, or phosphorous trichloride.
18 . The process according to claim 1 wherein the azide formation is carried out using a metal azide.
19 . The process according to claim 18 wherein the metal azide is sodium azide.
20 . The process according to claim 11 , wherein the said azide reduction is carried out using palladium and hydrogen.
21 . A method of making ponatinib hydrochloride having the formula (I)
comprising reacting 4-amino-2-(trifluoromethyl)benzaldehyde having the formula (IX)
with 3-ethynyl-4-methyl benzoic acid of formula (VII)
to obtain N-(4-formyl-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide having the formula (IIIa)
coupling the compound of formula (IIIa) with a compound having the formula (V)
to obtain a compound having the formula (IIIb)
subjecting the compound of formula (IIIb) to reductive amination with N-methyl piperazine to obtain compound having the formula (IIIc)
and subjecting the compound of formula (IIIc) to hydrogen chloride to obtain the ponatinib hydrochloride.
22 . The method according to claim 21 , wherein the reductive amination is carried out using a base and an organic solvent.
23 . The method according to claim 22 wherein the base is selected from sodium cyanoborohydride and sodium triacetoxyborohydride.
24 . The method according to the claim 22 , wherein the solvent is selected from acetic acid, isopropyl alcohol, methanol, ethanol and n-butanol.
25 . A method of making ponatinib hydrochloride having the formula (I)
comprising reacting a 4-substituted-3-(trifluoromethyl) analogue having the formula (VIII)
wherein R is CN, R1 is COOR″, R2 is CH 2 N 3 and R″ is CH 3 , C 2 H 5 or a higher homologue, with 3-ethynyl-4-methylbenzoic acid of formula (VII)
to obtain a compound having the formula (IVa)
subjecting the compound of formula (IVa) to treatment with a catalyst to obtain N-(4-(R′-substituted)-3-(trifluoromethyl)phenyl)-3-ethynyl-4-methylbenzamide of the formula (IVb)
wherein R′ is CH 2 NH 2 or CH 2 OH.
forming a piperazine ring by reacting the compound of formula (IVb) with either
a) 2-chloro-N-(2-chloroethyl)-N-methylethanamine; or
b) 2-chloro-N-(2-chloroethyl)-N-substituted derivative having the formula (VI)
wherein P is a protecting group and subsequently deprotecting the piperazine ring; and
forming the ponatinib hydrochloride using hydrogen chloride.
26 . The method according to claim 25 wherein P is CH 3 , mesyl, tosyl, carboxybenzyl, benzyl or nitrobenzyl.
27 . The method according to claim 25 , wherein the step of forming the piperazine ring comprises using substituted a 2-chloro-N-(2-chloroethyl)-N-substituted (VII) derivative in an organic solvent and a base.
28 . The method according to claim 25 , wherein deprotection of the piperazine ring is carried out in an acid, base and under hydrogenation conditions.
29 . The method according to claim 28 wherein the acid is selected from concentrated sulfuric acid, HBr in acetic acid and HBr in water.
30 . The method according to claim 29 wherein hydrogenation is carried out with hydrogen pressure and a catalyst.
31 . The method according to claim 30 wherein the catalyst is palladium and/or Raney Nickel.
32 . A method of making ponatinib hydrochloride having the formula (I)
comprising reacting 4-amino-2-(trifluoromethyl)benzaldehyde having the formula (IX)
with 3-ethynyl-4-methylbenzoic acid having the formula (VII)
to obtain 3-ethynyl-N-(4-formyl-3-(trifluoromethyl)phenyl)-4-methylbenzamide having the formula (Va)
subjecting the compound of formula (Va) to treatment with sodium triacetoxyborohydride and N-methylpiperazine to obtain 3-ethynyl-4-methyl-N-(4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)phenyl)benzamide having the formula (Vb)
subjecting the compound of formula (Vb) to reactive coupling with 3-ethynylimidazo[1,2-b]pyridazine having the formula (V)
to obtain a resulting product, subjecting the resulting product to reductive amination with N-methyl piperazine, and forming the ponatinib hydrochloride using hydrogen chloride.
33 . N-(4-((1,3-dioxoisoindolin-2-yl)methyl)-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide having the formula
34 . N-(4-(r-substituted)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide having the formula
wherein R′ is CH 2 NH 2 or CH 2 OH.
35 . N-(4-formyl-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide having the formula
36 . 3-ethynyl-N-(4-(substituted)- 3 -(trifluoromethyl)phenyl)-4-methylbenzamide having the formula
wherein R′ is CH 2 NH 2 or CH 2 OH.
37 . 3-ethynyl-N-(4-formyl-3-(trifluoromethyl)phenyl)-4-methylbenzamide having the formula