DESC:FIELD OF THE INVENTION
The present application provides an improved process for preparation of Ponatinib hydrochloride.
BACKGROUND OF THE INVENTION
Ponatinib hydrochloride, has a chemical name 3-(imidazo [1,2-b]pyridazin-3ylethynyl)-4-methyl-N-{4-[(4-methylpiperazin-1-yl)methyl]-3-(trifluoromethyl) phenyl}benzamide hydrochloride. Ponatinib hydrochloride is represented by the following chemical structure according to Formula (I).

Formula I
Ponatinib hydrochloride is a kinase inhibitor which is indicated for the treatment of chronic myeloid leukaemia (CML) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy or Philadelphia chromosome positive acute lymphoblastic leukaemia (Ph+ALL) that is resistant or intolerant to prior tyrosine kinase inhibitor therapy.
US 8,114,874 describe Ponatinib and its hydrochloride salt and a process for the preparation thereof. US 9,493,470 describe crystalline Ponatinib hydrochloride Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form I, Form J, Form K and a process of preparation of thereof. Further US ’470 discloses though Form A is an anhydrate form, it consist residual ethanol at a level of approximately 1% by weight.
Considering the importance of Ponatinib hydrochloride in the pharmaceutical field, there is need to develop an improved process for the preparation of Ponatinib HCl preferably in polymorph form A which meets the limits as specified by ICH guideline.
SUMMARY OF THE INVENTION
An aspect of the present invention provides an improved process for preparation of Ponatinib hydrochloride comprising;
a. mixing Ponatinib base in a suitable solvent;
b. adding HCl at less than 1 molar equivalent with respect to the Ponatinib base in a solvent at a temperature about 50° C to reflux temperature;
c. adding additional HCl to the mixed solution under heating, wherein the additional HCl is added in such an amount that the total molar equivalent thereof with the HCl of step (b) is 1 molar equivalent or more with respect to the Ponatinib base; and
d. cooling the reaction mass; and
e. isolating Ponatinib hydrochloride.
An aspect of the present invention provides an improved process for preparation of Ponatinib hydrochloride comprising;
a. mixing Ponatinib base in a suitable solvent;
b. adding HCl at less than 1 molar equivalent with respect to the Ponatinib base in lot-wise at a temperature about 50° C;
c. cooling the reaction mass at a temperature about 0-30oC; and
d. isolating Ponatinib hydrochloride.
In another aspect, the present application provides Ponatinib hydrochloride the meets the specification as specified by ICH guideline.

BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 shows the X-ray powder diffractogram ("PXRD") pattern Ponatinib hydrochloride Form A obtained from example 1.
DETAILED DESCRIPTION OF THE INVENTION
In an embodiment of the present invention provides an improved process for preparation of Ponatinib hydrochloride comprising;
a. mixing Ponatinib base in a suitable solvent;
b. adding 0.9 to 1.1 molar equivalent HCl with respect to the Ponatinib base in lot-wise at a temperature about 50° C to reflux temperature;
c. cooling the reaction mass at a temperature about 0-30oC; and
d. isolating Ponatinib hydrochloride.
The term “comprising” is used herein in their open-ended and non-limiting sense unless otherwise noted.
As used herein, the term “suitable solvent” is selected from but not limited to group comprising of alcohols, esters, nitrile, chlorinated hydrocarbons, hydrocarbons, ethers or mixtures thereof, examples of which include but are not limited to methanol, ethanol, isopropanol, ethyl acetate, methyl acetate, butyl acetate, isopropyl acetate, chloroform, methylene dichloride, ethylene dichloride, acetonitrile, methyl-tert-butylether (MTBE), tert-amylmethylether, tetrahydrofuran (THF), dioxane, diethyl ether, 2-methyltetrahydrofuran, dimethyl sulfoxide, Hexafluorobenzene, n-heptane, n-hexane, cyclohexane, toluene, xylene, anisole, and the like or mixtures thereof.
In an embodiment of the invention, step (a) involves mixing Ponatinib base with suitable solvent. In one preferred embodiment, the suitable solvent is ethanol. The amount of solvent used is generally 5V to 50V with respect to Ponatinib base, preferably 10V. In a preferred embodiment the step (a) involves suspending Ponatinib base with about 10V of ethanol. The mixture is then heated with stirring, suitably to about room temperature to about refluxing temperature, for example to about 50oC.
As used herein, the term “HCl” is selected HCl gas or HCl gas absorbed in a solvent such as ethyl acetate-HCl, methanol-HCl, ethanol-HCl, isopropyl alcohol-HCl, HCl/dioxane, diethyl ether-HCl, and the like, wherein HCl gas absorbed in solvent is 10-20%, more preferably 15%.
It has been found that addition of HCl in a single lot may causes solvent gets trapped in crystal lattice, while addition of alcoholic HCl in a controlled manner such as lot wise addition is considerably favourable to minimize the solvent trapped during crystallisation.
As used herein, the term “lot-wise” denotes addition of distinct portions of a reagent to a reaction mass. Preferably, the HCl is added in two or more lots. The time variation between each lot of HCl may be from 1 hour to 10 hours or more. Suitably, the addition of HCl is carried out slowly range from about 10 minutes to 1 hour, or more to maintain the reaction temperature below about 500C. The addition of HCl lot-wise provides Ponatinib HCl that meets the specification as per ICH guideline.
Ponatinib free base as well as hydrochloride salt thereof is sparingly soluble in suitable solvent at room temperature. Accordingly, a preferred manner of operation according to the present invention is to make a suspension of the free base in the solvent and add to that an appropriate quantity of hydrochloric acid, preferably as a solution in a lower alkanol such as 0.4 to 0.5 molar with respect to Ponatinib base in first lot, so as to form the Ponatinib hydrochloride salt partially which allows to form a clear solution for a time being and after that started precipitate out. Suitable amounts of acid are from about 0.9 to about 1.1 equivalents, and most preferably from 0.95 to 1.0 equivalent, per equivalent of free base.
To improve yields, the methods may include heating or cooling to temperatures above or below room temperature. Frequently, the reaction mass may be heated to temperatures ranging from about 30° C to about 150° C or reflux temperature, and more frequently from about 50° C to about 60° C. During crystallization, it may be desirable to cool the reaction mass to a temperature that is at or below room temperature, for example between about 0° C and about 30° C., preferably to about 25° C.
The isolated compound according to the present invention may be recovered by methods including decantation, centrifugation, evaporation, gravity filtration, suction filtration, or any other technique for the recovery of solids under pressure or under reduced pressure. The recovered solid may optionally be dried. Drying may be carried out in a tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, or the like. The drying may be carried out at temperatures less than about 100° C., less than about 80° C., less than about 60° C., less than about 50° C., less than about 30° C., or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the compound is not degraded in quality. The drying may be carried out for any desired times until the required product quality is achieved. The dried product may optionally be subjected to a size reduction procedure to produce desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer milling, and jet milling.
In another embodiment of the present invention provides an improved process for preparation of Ponatinib hydrochloride comprising;
a. mixing Ponatinib base in a suitable solvent;
b. adding HCl at less than 1 molar equivalent with respect to the Ponatinib base in a solvent at a temperature about 50° C to reflux temperature;
c. adding additional HCl to the mixed solution under heating, wherein the additional HCl is added in such an amount that the total molar equivalent thereof with the HCl of step (b) is 1 molar equivalent or more with respect to the Ponatinib base; and
d. cooling the reaction mass at a temperature about 0-30oC; and
e. isolating Ponatinib hydrochloride.
In another embodiment of the present invention provides an improved process for preparation of Ponatinib hydrochloride comprising;
a. mixing Ponatinib base in ethanol and heating at about 50oC;
b. dropwise adding about 0.5M of ethanolic solution of HCl ;
c. stirring for 0.5-15 hours;
d. dropwise adding about 0.5M of ethanolic solution of HCl;
e. stirring for 0.5-10 hours;
f. cooling reaction mass at a temperature about 0-30oC; and
g. isolating Ponatinib hydrochloride.
In another embodiment of the present invention provides an improved process for preparation of Ponatinib hydrochloride comprising;
a. suspending Ponatinib base in 10V ethanol and heating at about 50oC;
b. dropwise adding about 0.5M of ethanolic solution of HCl (15%) in slurry obtained from step a) at temperature about 50oC;
c. stirring for 0.5-15 hours at temperature about 50oC;
d. dropwise adding about 0.5M of ethanolic solution of HCl (15%) in slurry obtained from step c) at temperature about 50oC;
e. stirring for 0.5-10 hours at temperature about 50oC;
f. cooling reaction mass at a temperature about 0-30oC; and
g. isolating Ponatinib hydrochloride.
The X-ray powder diffraction (XRPD) spectrum according to the present invention was measured on a PANalytical X'Pert PRO X- Ray Diffractometer. The parameters of the X-ray powder diffraction method of the present invention were as follows:
X-ray Reflection: Cu, Ka
Ka1 (Å): 1.54060; Ka2 (Å): 1.54443
Ka2 / Ka1 intensity ratio: 0.50
Voltage: 45 (kV), Current: 40 (mA)
Scan range: from 2.5084 degree to 40.0 degree.
The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
Examples
Example 1: Preparation of Ponatinib hydrochloride:
Mixture of Ponatinib base (100 g) and ethanol (1000 ml) was stirred at room temperature, followed by heating at 50°C for 15 minutes. An ethanolic solution of HCl (3.596g, 15%) was dropwise added at 50°C. After addition, reaction mass was stirred for 10 hours at 50°C. Another lot of an ethanolic solution of HCl (3.596g, 15%) was dropwise added at 50°C. The reaction mass was gradually cooled and stirred up to 25°C under Nitrogen atmosphere. The wet cake was washed with ethanol and was suck dried. The obtained product is dried for 12 hour at 65±5°C. (Ethanol content: < 5000 ppm)
Example 2: Preparation of 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzoic acid
To stirred reaction mass of 3-iodo-4-methyl benzoic acid (100 g), 3-ethynylimidazo [1,2-b]pyridazine (54.6 g) and DMSO (400 ml); triethylamine (96.5 g), CuI (copper iodide) (1.44 g) and PdCl2 (PPh3)2 (5.33 g) were charged at about 25oC. After completion of reaction, liq. ammonia was added to the reaction mass followed by addition of water, aqueous sodium hydroxide and DCM. The aqueous layer was separated from reaction mass and cooled to about 0-10oC along with stirring and filtered to obtain solid. To this solid was added water followed by addition of conc. HCl along with stirring and filtered to obtain titled compound.
Example 3: Preparation of 1-methyl-4-(4-nitro-2-trifluoromethylbenzyl) piperazine
To stirred reaction mass of 2-methyl-5-nitrobenzotrifluoride (100 g) in 1, 2 dichloroethane (1000 ml); N-bromo succinimide (NBS) (95.4 g) and 2,2'-azobis(2-methylpropionitrile (AIBN) (8 g) were charged in lot-wise manner at about 25oC. The reaction mass was further heated to about 70-80oC. After completion of reaction, the reaction mass was cooled to about 25oC and filtered. To the filtrate was added aqueous sodium bicarbonate solution and water. The organic layer was separated and washed with sodium chloride solution and distilled under vacuum to obtain residue.
To the residue obtained in previous step, 1-methylpiperazine (53.7 g), triethylamine (72 g) and DCM (100 ml) were charged at about 25oC along with stirring. After completion of reaction, water was added to reaction mass followed by addition of conc. HCl and DCM. The aqueous layer was separated and aqueous sodium hydroxide solution was added followed by addition of DCM. The organic layer was separated and distilled under vacuum to obtain titled compound.
Example 4: Preparation of 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline
To stirred reaction mass of water (250 ml), ethanol (125 ml), iron powder (91.24 g) and ammonium chloride (52.9 g), solution of 1-methyl-4-(4-nitro-2-trifluoromethylbenzyl)piperazine (100 g) in ethanol (125 ml) was charged at about 85-95oC along with stirring. After the reaction was completed, the reaction mass was filtered and evaporated to obtain residue. To the residue, charge water, DCM and aqueous sodium hydroxide solution along with stirring. The organic layer was separated and distilled under vacuum to obtain titled compound.

Example 5: Preparation of Ponatinib base

Thionyl chloride (800 ml) was added to 3-(imidazo[1,2-b]pyridazin-3-ylethynyl)-4-methylbenzoic acid (111.6 g) and reaction mass was heated to about 35-45oC along with stirring. After completion of reaction, thionyl chloride was distilled out and DCM (1000 ml) was added to the reaction mass followed by addition of solution of 4-((4-methylpiperazin-1-yl)methyl)-3-(trifluoromethyl)aniline (100 g) in DCM (200 ml ) along with stirring at about 25oC. After completion of reaction, water was added to reaction mass. The aqueous layer was separated and filtered. To the filtrate, aqueous sodium hydroxide solution and DCM were added. The organic layer was separated and distilled out under vacuum. To obtained residue was added acetonitrile and heated to about 65-75oC along with stirring. The reaction mass was cooled, filtered and dried under vacuum to obtain titled product.

Dated this: 01th of August 2023 Dr. S. Ganesan
Alembic Pharmaceuticals Limited
,CLAIMS:WE CLAIM:
1. A process for preparation of Ponatinib hydrochloride comprising of following steps:
(a) mixing Ponatinib base in a solvent;
(b) adding 0.9 to 1.1 molar equivalent HCl with respect to the Ponatinib base in lot-wise manner at a temperature of about 50° C to reflux temperature;
(c) cooling the reaction mass at a temperature about 0-30oC; and
(d) isolating Ponatinib hydrochloride.
2. A process for preparation of Ponatinib hydrochloride comprising of following steps:
(a) mixing Ponatinib base in a solvent;
(b) adding HCl at less than 1 molar equivalent with respect to the Ponatinib base in a solvent at a temperature about 50° C to reflux temperature;
(c) adding additional HCl to the mixed solution under heating, wherein the additional HCl is added in such an amount that the total molar equivalent thereof with the HCl of step (b) is 1 molar equivalent or more with respect to the Ponatinib base; and
(d) cooling the reaction mass at a temperature about 0-30oC; and
(e) isolating Ponatinib hydrochloride.
3. The process as claimed in step (a) of claim 1 or claim 2, wherein solvent is alcohol selected from methanol, ethanol and isopropanol.

4. The process as claimed in step (b) of claim 1 or claim 2, wherein HCl is selected from HCl gas or HCl gas absorbed in a solvent such as ethyl acetate-HCl, methanol-HCl, ethanol-HCl, isopropyl alcohol-HCl, HCl/dioxane and diethyl ether-HCl.

5. A process for preparation of Ponatinib hydrochloride comprising of following steps:
(a) mixing Ponatinib base in ethanol and heating at about 50oC;
(b) dropwise adding about 0.5M of ethanolic solution of HCl at a temperature about 50° C;
(c) stirring for 0.5-15 hours;
(d) dropwise adding about 0.5M of ethanolic solution of HCl;
(e) stirring for 0.5-10 hours;
(f) cooling reaction mass at a temperature about 0-30oC; and
(g) isolating Ponatinib hydrochloride.

Dated this: 01st of August 2023 Dr. S. Ganesan
Alembic Pharmaceuticals Limited