Processes for making ponatinib and intermediates thereof

Abstract

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.

What is claimed is: 
     
         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