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US 2016/0108053 A1Published application
Processes for making ponatinib and intermediates thereof
AssigneeApicore US LLC
InventorsRavishanker Kovi, Jayaraman Kannapan, Sanjay F. Thakor, Rajesh A. Patel
Life of this patent
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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.
Claims33
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 phthalimide 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.
9 more elements
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 CH2N3 and R″ is CH3, C2H5 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 CH2NH2 or CH2OH,
- 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.
11 more elements
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.
4 more elements
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 CH2N3 and R″ is CH3, C2H5 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 CH2NH2 or CH2OH.
- 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.
9 more elements
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[12-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.
3 more elements
A compound selected from:
- N-(4-((1,3-dioxoisoindolin-2-yl)methyl)-3-(trifluoromethyl)phenyl)-3-iodo-4-methylbenzamide having the formula
- N-(4-(r-substituted)-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide having the formula
- wherein R′ is CH2NH2 or CH2OH;
- N-(4-formyl-3-(trifluoromethyl)phenyl)-3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzamide having the formula
- 3-ethynyl-N-(4-(substituted)-3-(trifluoromethyl)phenyl)-4-methylbenzamide having the formula
- wherein R′ is CH2NH2 or CH2OH;
- 3-ethynyl-N-(4-formyl-3-(trifluoromethyl)phenyl)-4-methylbenzamide having the formula
- or a pharmaceutically acceptable salt of one or more of the foregoing compounds.
5 more elements
Dependencies are inferred from the claim text.