DESC:FORM 2

THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(Section 10 and Rule 13)

AN IMPROVED PROCESS FOR THE PREPARATION OF PONATINIB OR SALT THEREOF

AUROBINDO PHARMA LTD HAVING CORPORATE OFFICE AT
THE WATERMARK BUILDING,
PLOT NO.11, SURVEY NO.9,
HITECH CITY, KONDAPUR,
HYDERABAD - 500 084,
TELANGANA, INDIA
AN INDIAN ORGANIZATION

The following specification particularly describes and ascertains the nature of this invention and the manner in which the same is to be performed.
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Ponatinib or its pharmaceutically acceptable salt. Further, the present invention relates to an improved process for the preparation of intermediates of Ponatinib.

BACKGROUND OF THE INVENTION
3-(Imidazo[1,2-b]pyridazin-3-yl ethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluomethyl) phenyl}benzamide hydrochloride (I) is generically known as Ponatinib hydrochloride, which is marketed under the brand name ICLUSIG®:

Formula I
Ponatinib hydrochloride is a kinase inhibitor and is used for the treatment of adult patients with T315I-positive chronic myeloid leukemia (CML) (chronic phase, accelerated phase, or blast phase) or T315I-positive Philadelphia chromosome positive acute lymphoblastic leukemia (Ph+ ALL).

US 8,114,874 describes Ponatinib hydrochloride and process thereof. The process of US ‘874 involves reaction of ethynyl toluic acid of Formula II with oxalyl chloride ((COCl)2) and then with amino methyl piperazine of Formula III to obtain Ponatinib free base, which is treated with hydrochloric acid to obtain Ponatinib HCl. The process is represented in the following scheme-1:
Scheme-1

Further, WO 2014/093583A2 discloses a process for the preparation of Ponatinib, which involves reaction of an ester derivative of Formula A with amino methyl piperazine of Formula III to provide Ponatinib free base. The process is represented in the scheme-2:

Scheme-2
The processes provided in the prior art faces one or the other problem like yield and purity of Ponatinib and its intermediates. Therefore, there is a need to develop an improved process for the preparation of Ponatinib or its pharmaceutically acceptable salt, which is simple, cost-effective and industrially feasible.

OBJECTIVE OF INVENTION
The main objective of the present invention is to provide an improved process for preparing Ponatinib or its pharmaceutically acceptable salt, which comprises activation of ethynyl toluic acid of Formula II with an amide coupling agent and its conversion to Ponatinib or its pharmaceutically acceptable salt.
SUMMARY OF THE INVENTION
In an aspect, the present invention provides a process for the preparation of Ponatinib or its pharmaceutically acceptable salt, comprising the steps of:
a) activation of ethynyl toluic acid of Formula II:

with an amide coupling agent to provide an active amide derivative;
b) optionally, reaction of the activated derivative of step (a) with C1-4 alcohol to provide an ester derivative of Formula II’; and

c) condensation of activated derivative of step (a) or the ester derivative of step b) with amino methyl piperazine of Formula III:

to provide Ponatinib or its pharmaceutically acceptable salt.

In another aspect, the present invention provides a process for the purification of nitro methyl piperazine of Formula IIIA:

which comprises:
i) treating nitro methyl piperazine of Formula IIIA with an organic acid to provide an acid addition salt of Formula IIIA;
ii) optionally, isolating the acid addition salt of step (a); and
iii) treating the acid addition salt with a base to provide pure nitro methyl piperazine.

In another aspect, the present invention provides an improved process for the preparation of ethynyl toluic acid of Formula II, which comprises condensation of 3-ethynylimidazo[1,2-b]pyrazines (Formula B):

with 3-iodo-4-methylbenzoic acid (Formula C):

in presence of dimethylacetamide.

DETAILED DESCRIPTION OF THE INVENTION
The present invention refers to a “solid state”, unless specified otherwise, that the compounds or salts thereof are isolated as solid. The solid state can be in the crystalline, partially crystalline, amorphous, or polymorphous form, preferably in the crystalline form.

Further, the present invention refers to a “pure”, unless specified otherwise, that the compounds or salts thereof are having purity of about 99.5% by HPLC. Further, the “pure” refers to the material of present invention is substantially free from impurities i.e. the impurities are less than about 1% or less than about 0.6% or less than about 0.3% or less than about 0.1% by HPLC analysis.

Furthermore, the present invention refers to a “pharmaceutically acceptable salt” or “salt” that may be obtained from inorganic acid or organic acid. The inorganic acid is selected from hydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acid; the organic acid may be selected from oxalic acid, acetic acid, maleic acid, succinic acid and methane sulfonic acid.

In an aspect, the present invention provides a process for the preparation of Ponatinib or its pharmaceutically acceptable salt, comprising the steps of:
a) activation of ethynyl toluic acid of Formula II:

with an amide coupling agent to provide an active amide derivative;
b) optionally, reaction of the activated derivative of step (a) with C1-4 alcohol to provide an ester derivative of Formula II’; and

c) condensation of activated derivative of step (a) or the ester derivative of step b) with amino methyl piperazine of Formula III:

to provide Ponatinib or its pharmaceutically acceptable salt

The amide coupling agent comprises carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), N, N'-diisopropylcarbodiimide (DIC) or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC). The activation of the compound of Formula II or its salt is carried out using an amide coupling agent, with or without an additional additive, in the presence of a suitable base and in a suitable solvent.

The additional additive comprises N-hydroxysuccinimide, N-hydroxy succinimide, 2-hydroxypyridine or N-hydroxyphthalimide. The base used for activation reaction comprises an organic and/or inorganic base. The inorganic base comprises sodium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate and potassium carbonate; the organic base is selected from triethylamine (TEA), diethyl amine, N-ethyldiisopropylamine, 2,6-lutidine, pyridine, magnesium di-tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, sodium tert-amyl alkoxide, potassium tert-butoxide, sodium methoxide or mixture thereof.

The solvent used for activation comprises chlorinated solvent selected from dichloromethane, 1,2-dichloroethane and chloroform, ether solvent comprises dimethylether, diethylether, methyltertiarybutylether, ethylmethylether, diisopropylether, tetrahydrofuran or methyl tetrahydrofuran; ester solvent comprises ethyl acetate, n-propyl acetate, isopropylacetate and n-butyl acetate, or mixture thereof.

The resultant active amide derivative is optionally reacted with an alcohol. The alcohol comprises methanol, ethanol, isopropyl alcohol, n-propanol, n-butanol, iso-butyl alcohol or tert-butyl alcohol. The reaction is carried out in presence of a solvent comprises chlorinated solvent, ether solvent, ester solvent, water or mixture thereof.

The active amide derivative of step a) or the ester derivative is reacted with amino methyl piperazine of Formula III to provide Ponatinib or its pharmaceutically acceptable salt. The reaction may be carried out in presence of a base in a solvent at a temperature of about 20 °C to about 100 °C. The solvent used for condensation comprises an alcohol, chlorinated solvent, an ether, an ester, hydrocarbon comprises toluene, xylene, cyclohexane, n-hexane and n-heptane and an amide solvent comprises N,N-dimethylformide (DMF) and N,N-dimethylacetamide (DMA) or combination thereof. The base comprises an organic and inorganic base. In an embodiment, the base used in condensation is potassium t-butoxide or sodium hydride.

In a preferred embodiment, the present invention provides a process for the preparation of Ponatinib or its pharmaceutically acceptable salt, comprising the steps of:
a) activation of ethynyl toluic acid of Formula II with a carbonyldiimidazole to provide an active amide derivative; and
b) condensationof the active amide derivative of step a) with amino methyl piperazine of Formula III to provide Ponatinib or its pharmaceutically acceptable salt.

In another aspect, the present invention provides a process for the purification of nitro methyl piperazine of Formula IIIA:

whichcomprises:
i) treating nitro methyl piperazine of Formula IIIA with an organic acid to provide an acid addition salt of Formula IIIA;
ii) optionally, isolating the acid addition salt of step (a); and
iii) treating the acid addition salt with a base to provide pure nitro methyl piperazine.

The compound, nitro methyl piperazine of Formula IIIA may be obtained by the process disclosed in the prior art, for example, WO 2014/093583 A1, or may be obtained by the process steps of: nitration of 1-(bromomethyl)-2-(trifluoromethyl)benzene to produce 1-bromomethyl-2-(trifluoromethyl)-4-nitrobenzene followed by reaction with 1-methylpiperazine to provide nitro methyl piperazine (i.e.1-(2-(trifluoromethyl)-4-nitrobenzyl)-4-methylpiperazine) of Formula IIIA.
The purification of nitro methyl piperazine of Formula IIIA comprises providing a solution of compound of Formula IIIA, which may be provided either by dissolving it in a suitable solvent or it may be provided directly from a reaction mixture containing it that is obtained during the course of its manufacture, and treating the solution with an organic acid comprises oxalic acid, tartaric acid and succinic acid to obtain corresponding salt of Formula III. The obtained salt is isolated by filtration by using known techniques.
In an embodiment, the present invention provides Oxalate salt of amino methyl piperazine of Formula IIIB in a solid form.

Formula IIIB
The solid of oxalate salt of nitro methyl piperazine is non-hygroscopic and having the purity greater than 92.0% by HPLC.
The salt of Formula IIIA is treated with a base in presence of a solvent to produce nitro methyl piperazine of Formula IIIA. The solvent used for the purification comprises an ester, an alcohol, chlorinated solvent, water or combination thereof. The base comprises an inorganic or an organic base.
The purified salt of Formula IIIA of the present invention improves the quality of further intermediate i.e. amino methyl piperazine of Formula III which is obtained by reduction of Formula IIIA with Pd/carbon. The purity of amino methyl piperazine intermediate obtained from the oxalate salt of nitro methyl piperazine is greater than 99.5% by HPLC with other regioisomer/Ortho Isomer <0.2%.
In another aspect, the present invention provides a process for the preparation of ethynyl toluic acid of Formula II, which comprises condensation of 3-ethynylimidazo[1,2-b]pyrazines (Formula B) with 3-iodo-4-methylbenzoic acid (Formula C) in presence of dimethylacetamide.
The present inventors observed that the process of prior art, US 8,114,874, wherein the reaction is performed in dimethyl formamide, gives purity of compound less than 90% by HPLC. Therefore, the inventors of the present invention developed an improved process by using selective solvent i.e. dimethyl acetamide to achieve purity of ethynyl toluic acid of Formula II greater than 99%.
The condensation reaction is carried out in presence of metal halide and palladium catalyst (i.e. tetrakis(triphenylphosphine)palladium), in presence of a base, which is selected from an organic and inorganic base.
The resultant ethynyl toluic acid of Formula II has purity greater than or equal to 99.8% by HPLC.
The compound of Formula II and Formula IIIA obtained by the process of present invention are converted to Ponatinib or its pharmaceutically acceptable salt.
Having described the invention with reference to certain aspects embodiments, embodiments will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing the preparation of Ponatinib hydrochloride. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
EXAMPLES:
EXAMPLE 1: Preparation of Amino methyl piperazine of Formula III:

The bromo compound (100 g) was suspended in H2SO4 (380 ml) at 0-10°C and then cooled to 0 to -5°C. Nitric acid (70 % w/w, 39.5 g) was added to the suspension of bromo Compound and stirred for 2 hours. Then, the reaction mass was allowed to reach the temperature 20-25°C and stirred for 1 hour. After completion of the reaction, the reaction mass was quenched into the mixture of water and methylene chloride at 0-5°C. The temperature of the reaction mass was raised to 20-30°C, stirred for about 20-30 minutes and separated the layers. Thereafter, aqueous layer was extracted with methylene chloride (100 ml). The combined organic layer was treated with 5% w/v aqueous NaHCO3 solution (250 ml) and separated the layers. Then, the organic layer was washed with (200 ml) water. The separated organic layer having the product Nitro bromo Compound (~118.8 g) was taken as such for next step.

The obtained organic layer (Nitro bromo Compound) was added to the mixture of N-methylpiperazine (41.84 g) and triethylamine (50.8 g) in methylene chloride (100 mL) at 20-30°C and stirred for 2 hours. After completion of the reaction, water (400 mL) was charged to the reaction mass and separated the layers. The separated organic layer was concentrated at 30-40°C under reduced pressure up to 100 mL of the reaction mass. Further, ethyl acetate (100 mL) was charged and concentrated at 30-40°C under reduced pressure up to 100 mL of the mass. Further, ethyl acetate (1000 mL) was charged at 30-35°C to obtain clear solution and then oxalic acid (44 g) was added and stirred for 2 hours. The product was filtered and washed with Ethyl acetate (200 mL), and the wet material was taken as such for next step.
Yield: 140 g (85%); Chromatographic Purity (by HPLC): 92.81%

The previously obtained Nitro methyl piperazine oxalate (140 g) of Formula IIIB was added to the mixture of ethyl acetate (700 mL) and water (1000 mL) and treated with 10% w/v aqueous NaOH solution (280 mL) at 25-35°C to obtain the pH 8-9. The obtained layers were separated and the aqueous layer again extracted with ethyl acetate (300 mL). The combined organic layer was washed with water (300 mL). 10% palladium on carbon (50% w/w wet, 3.0 g) was added to the organic layer at 40-45°C and hydrogenated in autoclave for 4-6 hours under hydrogen gas pressure. After completion of the reaction, the reaction mass was filtered on hyflow bed and washed the bed with ethyl acetate. The obtained filtrate was concentrated at <55°C up to 200 mL of the reaction mass. Then, n-heptane (1500 mL) was added and heated to reflux, 95-100°C to obtain the clear solution. Thereafter, n-heptane (~900 mL) was recovered atmospherically at 95-100°C, then the reaction mass was cooled to 20-25°C and stirred for 4 hours. The resultant compound was filtered, washed with n-heptane and dried at 60-65°C till “Loss on Drying” is not more than 1.0 % w/w.
Yield: 65 g; Chromatographic Purity (by HPLC): 99.71%

EXAMPLE-2: Preparation of Ethynyl toluic acid of Formula II
Ethynyl Pyridazine (100 g) and iodo toluic acid (201.3 g) were taken in N, N-dimethylacetamide (1000 mL) at 25-35°C. Then, triethylamine (176.7 g) was added at 25-35°C to obtain the clear solution. Nitrogen gas was purged in to the reaction mass at 25-35°C for around 30-45 minutes. Then, copper (I) Iodide (2.6 g) was added followed by tetrakis(triphenylphosphine)palladium (0) (8.1 g) in to the above reaction mixture under the nitrogen atmosphere. The contents were heated to 35-40°C and stirred for about 4-6 hours under the Nitrogen atmosphere. The progress of reaction was monitored by in-process HPLC. After completion of the reaction, the reaction mass was cooled to 25-35°C and pH adjusted to 3-4 with aq.HCl (37% w/w; ~85 mL). Further, the reaction mass was heated to 130-135°C and stirred for about 1 hour. Then, the reaction mass was cooled to 25-35°C and again pH adjusted to 3-4 with aq.HCl (37% w/w; ~2 mL). The suspension was stirred for about 2-3 hours at 25-35°C. The product was filtered and washed the wet material with DMAc (400.0 mL). The above wet material (~180 g) was taken in to water (1000.0 mL) and heated to 50-60°C. The suspension was heated for 30-45 minutes at 50-60°C, filtered the product, washed the wet material with hot (50-60°C) water (200 ml) and dried under vacuum at 70-75°C till the water content is not more than 1.0 % w/w.
Yield: 150 g (77%); Chromatographic Purity (by HPLC): 99.84%

EXAMPLE-3: Preparation of Ponatinib Free base:
Method A:
Carbonyldiimidazole (84.85g) was added to the suspension of ethynyl toluic acid (111.6 g) in methylene chloride (1670 mL), and heated to reflux and stirred for 2 hours to get the clear solution. After completion of the reaction, methanol (558 mL) was added at 35-40°C, stirred for 1 hour and cooled to 20-30°C and then water (1110 mL) was added to the reaction mass and then separated the layers. Further, the organic layer was washed with water, concentrated at <35°C up to ~200 mL of the reaction mass and then continued distillation with toluene (500 mL) till the reaction mass temperature reached to 80-85°C. Amino methyl piperazine (100 g) at 80-85°C was added to the reaction mass and heated to 100-110°C to remove water azeotropically to <0.10% w/w and then concentrated up to the reaction mass volume ~300 mL. The reaction mass was cooled to 65-70°C, 2-methyltetrahydrofuran (400 mL) was added and then cooled to 10-15°C. 25% w/w Potassium tert-butoxide in THF solution (295.4 g) was added under nitrogen atmosphere, raised the temperature to 20-30°C and stirred for 1 hour. After completion of the reaction, water (1000 mL) was added and separated the layers. The aqueous layer was extracted with 2-methyltetrahydrofuran (400 mL) and water (500 mL) was added to the combined organic layer followed by pH was adjusted to 6.8-7.5 by using 1N aq. HCl (~8 mL) solution and separated the layers. Thereafter, organic layer was treated with carbon enoanticromos (10 g), filtered on hyflow bed & washed the bed with 2-methyltetrahydrofuran. The filtrate was concentrated at <55°C up to 250 mL of the reaction mass, acetonitrile (200 mL) was added and concentrated at <55°C under reduced pressure up to 250 mL of the reaction mass. Then, acetonitrile (600 mL) was added at <55°C, heated to reflux (80-85°C) and stirred for 30-45 minutes. The reaction mass was cooled to 20-30°C and stirred for 2-3 hours. The suspension was filtered and washed with acetonitrile (200 mL), which was dissolved in methanol (500 mL) and acetonitrile (100 mL) at 60-65°C. Water (200 mL) was added, stirred for 30-45 minutes and cooled to 20-30°C, which was stirred for 2-3 hours. The product was filtered, washed with mixture of MeOH (62 mL), ACN (13 mL) and water (25 mL), and then with water (2X100 mL). Unloaded the wet material and dried in vacuum at 70-75°C till the water content is not more than 4.0 % w/w.
Yield: 165 g (82.5%); Chromatographic Purity (by HPLC): 99.91%
Method B:
Triethylamine (7.3 g) followed by 1, 1’-carbonyldiimidazole (8.8g) were added to the stirred suspension of ethynyl toluic acid (10 g) in THF (150 mL) at 25-35°C under nitrogen atmosphere. The contents were heated to reflux (55-60°C) and stirred for about 4-5 hours at reflux. The progress of reaction was monitored by in-process HPLC. After completion of the reaction, reaction mass was cooled to 25-30°C and then amino methyl piperazine (10.8 g) was added under nitrogen atmosphere. The contents were stirred for about 5-10 minutes and then sodium hydride (2.9 g; 60 % w/w dispersion in mineral oil) was added under nitrogen atmosphere at 25-30°C. The contents were heated to 65-70°C and stirred for about 4-6 hours. After completion of the reaction, the reaction mass was added slowly in to methanol (50 mL) and stirred for 10-15 minutes. The reaction solution was distilled completely to get the residual mass and then water (100 mL) followed by 10% methanol/MDC solution (110 mL) were added. The contents were stirred for about 10-15 minutes and separated the organic layer. Further, the aqueous layer was extracted with 10% methanol/MDC solution (55 mL). The combined organic layer was distilled at 55-60°C, under vacuum to get the residual mass. Further, acetonitrile (50 mL) was added and distilled at 55-60°C under vacuum to get the residual mass. Then isopropyl alcohol (20 mL) and acetonitrile (60 mL) were added at 55-60°C. The contents were heated to 80-85°C and stirred for about 30-45 minutes. The reaction mass was cooled to 25-35°C and stirred for about 2 hours. The product was filtered at 25-35°C and washed the wet material with mixture of isopropyl alcohol (5 mL), acetonitrile (15 mL) and dried in vacuum at 60-65°C till “Loss on Drying” is not more than 4.0 % w/w.
Yield: 16 g (80%)
Chromatographic Purity (by HPLC): 99.58%

EXAMPLE-4: Preparation of Ponatinib Hydrochloride-Amorphous
Aqueous hydrochloride solution [prepared by diluting HCl, (49.6g, 35.2% w/w) in water (250 mL)] was added to the suspension of Ponatinib base (255 g) in absolute EtOH (2550 mL), at 25-35°C to get the clear solution. Water (260 mL) was added to the solution and stirred for 30 minutes. Thereafter, the reaction mass was treated with carbon enoanticromos (10 g) and filtered on Hyflow bed & washed the bed with mixture of ethanol (408 mL) & water (102 mL). The reaction mixture was filtered and concentrated at 60-65°C under reduced pressure (650-400 mm Hg) up to ~ 380 mL of the reaction mass. Thereafter, continued the concentration under reduced pressure (200 mm Hg) for about 1-2 hours to get the foamy solid. Further, continued the concentration under reduced pressure (50 mm Hg) for about 3 hours and cooled the reaction mass to 20-30°C. Then, n-heptane (2550 mL) was added to the foamy solid at 20-30°C and stirred for 4-6 hours. The product was filtered at 20-30°C and washed the wet material with n-heptane (510 mL) and dried at 80-85°C till the “Loss on Drying” is not more than = 3.0% w/w.

Yield: 259 g (95.8%)
Chromatographic Purity (by HPLC): 99.92% ,CLAIMS:WE CLAIM:

1. A process for the preparation of Ponatinib or its pharmaceutically acceptable salt, comprising the steps of:
a) activation of ethynyl toluic acid of Formula II:

with an amide coupling agent to provide an active amide derivative;
b) optionally, reaction of the activated derivative of step (a) with C1-4 alcohol to provide an ester derivative of Formula II’; and

c) condensation of activated derivative of step (a) or the ester derivative of step b) with amino methyl piperazine of Formula III:

to provide Ponatinib or its pharmaceutically acceptable salt.

2. The process as claimed in claim 1, wherein the amide coupling agent used in step a) comprises carbonyldiimidazole (CDI), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC) or 1-ethyl-3-(3-dimethylaminopropyl) carbodiimide (EDC).

3. The process as claimed in claim 1, wherein the activation and condensation steps are carried out in presence of a base comprises organic base or inorganic base.

4. The process as claimed in claim 3, wherein the base used for activation comprises triethylamine.

5. The process as claimed in claim 3, wherein the base used for condensation step is selected from potassium tert-butoxide or sodium hydride.

6. The process as claimed in claim 1, wherein the C1-4 alcohol comprises methanol, ethanol, n-propanol, isopropyl alcohol, n-butanol, iso-butyl alcohol or tert-butyl alcohol.

7. A process for the purification of nitro methyl piperazine of Formula IIIA comprising of:

i) treating nitro methyl piperazine of Formula IIIA with an organic acid to provide an acid addition salt of Formula IIIA;
ii) optionally, isolating the acid addition salt of step (a); and
iii) treating the acid addition salt with a base to provide pure nitro methyl piperazine.

8. The process as claimed in claim 7, wherein the organic acid comprises oxalic acid, tartaric acid or succinic acid.

9. The process as claimed in claim 7, wherein the base comprises sodium hydride, potassium hydride, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate or mixture thereof.

10. An improved process for the preparation of ethynyl toluic acid of Formula II, which comprises condensation of 3-ethynylimidazo[1,2-b]pyrazines of Formula B with 3-iodo-4-methylbenzoic acid of Formula C in presence of dimethylacetamide:
.