DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN 201941044812 filed on Nov 05, 2019.
FIELD OF THE INVENTION
The present disclosure relates to a process for the preparation of brigatinib. The present disclosure also relates to a process for the preparation of crystalline brigatinib Form A.
BACKGOUND OF THE INVENTION
Brigatinib (also known as AP26113) is an investigational small-molecule targeted cancer therapy being developed by ARIAD Pharmaceuticals. Brigatinib acts as both an anaplastic lymphoma kinase (ALK) and epidermal growth factor receptor (EGFR) inhibitor.

Brigatinib is chemically known as 5-chloro-N4-[2-(dimethylphosphinyl) phenyl]-N2-[2-methoxy-4-[4-(4-methyl-1-piperazinyl)-1-piperidinyl] phenyl]-2,4-pyrimidine diamine, having the structure below:

Formula-I

Brigatinib is marketed by ARIAD Pharmaceuticals, Inc under the brand name of ALUNBRIG for the treatment of patients with anaplastic lymphoma kinase (ALK)-positive metastatic non-small cell lung cancer (NSCLC) who have progressed on or are intolerant to crizotinib.

U.S. Patent No. 9,012,462 discloses brigatinib and process for its preparation, which is as shown below:

PCT Publication No. WO2016065028A1 discloses various crystalline forms of brigatinib including Form A, Form B, Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, crystal form L, amorphous form and also describe processes for the crystalline forms.

The prior-art process to prepare brigatinib involves the use of palladium on carbon for nitro reduction, which increases the manufacturing cost. Also, prior art process for crystalline Form A is tedious and involves mixture of solvents with number of purification steps, which is not feasible on commercial scale.

The inventors of the present invention have developed an industrially feasible process for the preparation of brigatinib, which avoids use of costly palladium on carbon and discloses a novel process for the preparation of crystalline brigatinib Form A.

SUMMARY OF THE DISCLOSURE
A first aspect of the present invention is to provide a process for the preparation of brigatinib, which comprises:
a) reduction of compound of formula IV using sodium sulphide to get the compound of formula III

; and
b) condensing the compound of formula III with 2,5-dichloro-N-[2-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (II) in presence of a protic acid to obtain brigatinib.


A second aspect of the present invention is to provide a process for the preparation of crystalline brigatinib Form A, which comprises crystallizing the brigatinib with an alcoholic solvent.

DETAILED DESCRIPTION OF THE DISCLOSURE
It is to be understood that the description of the present invention has been simplified to illustrate elements that are relevant for a clear understanding of the invention, while eliminating, for purposes of clarity, other elements that may be well known.

The present disclosure relates to an improved process for the preparation of brigatinib and a novel process for the preparation of crystalline brigatinib Form A.

In one embodiment, the present invention provides a process for the preparation of brigatinib, which comprises:
a) reduction of compound of formula IV using sodium sulphide to get the compound of formula III
; and
b) condensing the compound of formula III with 2,5-dichloro-N-[2-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (II) in presence of a protic acid to obtain brigatinib.

According to this embodiment of the present invention, a compound of formula IV is reduced with sodium sulphide to obtain a compound of formula III. The obtained compound of formula III is then reacted with a compound of formula II to yield brigatinib of formula I.
According to this embodiment of the present invention, the reduction step (a) may be carried out in the presence of a base and a solvent.
Within the context of the present invention, the base used in step (a) may be, for example, an alkali metal hydroxide. Examples of suitable alkali metal hydroxides include lithium hydroxide, sodium hydroxide, potassium hydroxide, cesium hydroxide, and mixtures thereof. In particularly useful embodiments of the present invention sodium hydroxide is used as base.
Within the context of the present invention, the solvent used in step (a) may be, for example, an alcohol such as methanol, ethanol or isopropyl alcohol, an ester such as ethyl acetate or isopropyl acetate or mixtures thereof. In particularly useful embodiments of the present invention methanol is used as solvent.
Within the context of the present invention, the protic acid used in step (b) may be, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, methane sulfonic acid, p-toluene sulfonic acid and mixtures thereof. In particularly useful embodiments of the present invention sulfuric acid is used.
According to this embodiment of the present invention, the step (b) may be carried out in the presence of a solvent.
Within the context of the present invention, the solvent used in step (b) may be, for example, an alcohol such as methanol, ethanol, isopropyl alcohol or n-butanol or mixtures thereof. In particularly useful embodiments of the present invention n-butanol is used as solvent.
Another embodiment of the present invention is to provide a process for the preparation of crystalline brigatinib Form A, which comprises crystallizing brigatinib with an alcoholic solvent.

According to this embodiment of the present invention, brigatinib is dissolved in an alcoholic solvent optionally at refluxed temperature. The solution was cooled to a temperature of 15-35 °C. The obtained solid was filtered and dried at 40-50 °C to get crystalline brigatinib Form A.

Within the context of this embodiment of the present invention, the alcoholic solvent employed may include ethanol, isopropyl alcohol or mixtures thereof.

According to the present invention, the input brigatinib used is any crystalline form or amorphous form for example as disclosed in WO2016065028A1 or mixture of any crystalline forms.

In view of the above description and the examples below, one of ordinary skill in the art will be able to practice the invention as claimed without undue experimentation. The foregoing will be better understood with reference to the following examples that detail certain procedures for the preparation of molecules, compositions and Formulations according to the present invention. All references made to these examples are for the purposes of illustration. The following examples should not be considered exhaustive, but merely illustrative of only a few of the many aspects and embodiments contemplated by the present disclosure.

EXAMPLES
Example 1: Preparation Dimethyl phosphine oxide
To a solution of methyl magnesium chloride (3M in THF) (725 mL, 2.17 moles, 3.0 eq.) was added diethyl phosphite (100.0 g, 0.724 moles, 1.0 eq.) at below 0 °C dropwise. After completion of the addition, the reaction mass was warmed to about 15 °C and stirred for additional 4 hours. After the completion of reaction as shown by TLC, the reaction mass was re-cooled to 0 °C and quenched by adding aqueous potassium carbonate solution (349 g in 500 mL water) by maintaining the reaction mass temperature at below 30 °C. Ethanol (1000 mL) was then added, stirred for about 60 minutes, filtered and concentrated the filtrate under vacuum at below 50 °C. The crude liquid product obtained was co-distillation with ethanol twice (2 X 200 mL) to get the semi solid natured crude product. To it, ethanol (500 mL) was added, stirred for about 30 minutes, filtered off the undissolved inorganic salts and concentrated the filtrate under vacuum at below 50 °C. The ethanol addition, filtration and concentrations were repeated twice (until no inorganic salts separates out) to obtain the required product as a colorless to yellow oil.
Yield: 40.0 g
Purity: ~90% by GC

Example 2: Preparation of 2-(dimethylphosphoryl) aniline
A suspension of 2-iodoaniline (100.0 g, 0.457 moles, 1.0 eq.), dimethyl phosphine oxide (71.4 g, 0.914 moles, 2.0 eq.), tripotassium phosphate (194.0 g, 0.914 moles, 2. eq) and xanthaphos (15.9 g, 0.027 moles, 0.06 eq.) in isopropyl alcohol (1000 mL) was degassed with nitrogen at room temperature for about 30 minutes. Palladium acetate (6.06 g, 0.027 moles, 0.06 eq.) was then added under nitrogen atmosphere and the reaction mass temperature was raised to 82 °C. The contents were stirred for 15 hours at the same temperature and when TLC showed the completion of reaction, the reaction mass was cooled to room temperature, filtered and concentrated the filtrate under vacuum to give the crude product. The crude product was dissolved in 2N hydrochloric acid (500 mL), filtered off the undissolved particles, washed with methyl tert-butyl ether (MTBE) (500 mL) and adjusted the pH to 12-13 with 30% sodium hydroxide solution. The aqueous layer was then extracted with a solution of DCM/ IPA (9/1) and concentrated the organic layer to obtain the crude product as a light brown liquid. To the crude liquid product, isopropyl ether (400 mL) was added, stirred for one hour, filtered under nitrogen and dried under vacuum at 35 °C to get the compound 2-(dimethylphosphoryl) aniline as light brown color solid.
Yield: 65.0 g
Purity: ~97% by HPLC

Example 3: Preparation of 2,5-dichloro-N-[2-(dimethylphosphoryl) phenyl] pyrimidin-4-amine (II)
A suspension of compound 2-(dimethylphosphoryl) aniline (100.0 g, 0.591 moles, 1.0 eq.), 2,4,5-trichloropyrimidine (111.8 g, 0.610 moles, 1.03 eq) and sodium bicarbonate (91.6 g, 1.09 moles, 2.0 eq) in dimethylformamide (300 mL, 3.0 vol.) was stirred at 65 °C for 12 hours. When the TLC showed the complete conversion, the reaction mass was cooled to room temperature, added water (500 ml), stirred for about 6 hours and filtered to afford the crude product. The crude product was further purified by recrystallizing in isopropyl alcohol (600 mL) to obtain the pure compound (3) as a off-white solid.
Yield: 130.0 g
Purity: ~99% by HPLC
Example 4: Preparation of 1-(1-(3-methoxy-4-nitrophenyl) piperidin-4-yl)-4 methyl piperazine (IV)
A solution of 5-Fluro-2-nitroanisole (100.0 g, 0.584 moles, 1.0 eq) in dimethylformamide (100 mL 1.0 vol.) was added dropwise at 80 °C to a suspension of 1-methyl-4-(piperidin-4-yl) piperazine (110.2 g, 0.601 moles, 1.03 eq) and potassium carbonate (161.7 g, 1.17 moles, 2.0 eq.) in dimethylformamide (200 mL, 2.0 vol.). After completion of the addition, the reaction was stirred at the same temperature for about 12 hours and cooled to 0 °C. Aqueous Sodium chloride solution (20% w/v) was then added, stirred for about 4 hours at 0-5 °C, filtered and dried at 50 °C to obtain the crude product as a yellow solid. The crude product was slurried in isopropyl alcohol (500 mL) at room temperature, filtered and dried to get the pure product as yellow colored solid.
Yield: 175.0 g
Purity: ~ 99% by HPLC

Example 5: Preparation of 2-methoxy-4-(4-(4-methylpiperazin-1-yl) piperidin-1-yl) aniline (III)
A solution of 1-(1-(3-methoxy-4-nitrophenyl) piperidin-4-yl)-4 methyl piperazine (100.0 g, 0.30
moles, 1.0 eq) in methanol (600 mL, 6.0 vol.) was added dropwise at 45 °C to a suspension of sodium sulphide (234.0 g, 3.0 moles, 10.0 eq.) and sodium hydroxide (24.0 g, 0.45 moles, 2.0 eq.) in methanol (400 mL, 4.0 vol.). After the completion of addition, the reaction mass was stirred at the same temperature for about 4 hours, concentrated under vacuum and was added with dichloromethane (500 mL) and water (500 mL). The organic layer was separated and concentrated under vacuum to afford the crude product as a light yellow to green solid. The crude product was recrystallized from cyclohexane (800 ml) to get pure product as a off-white solid.
Yield: 70.0 g
Purity: ~97% by HPLC

Example 6: Preparation of brigatinib
Sulfuric acid (62.0 g, 0.632 moles, 2.0 eq) was added to a solution of 2-methoxy-4-(4-(4-methylpiperazin-1-yl) piperidin-1-yl) aniline (100.0 g, 0.316 moles, 1.0 eq.) and 2,5-dichloro-N-[2-(dimethylphosphoryl) phenyl] pyrimidin-4-amine (96.2 g, 0.316 moles, 1.0 eq.) in n-butanol (800 mL) at room temperature. The resulting suspension was heated to 90 °C and stirred at the same temperature for 24 hours. After completion of the reaction as shown by TLC, the reaction mass was cooled to room temperature, added with water (1500 mL) and stirred for about 30 minutes. The two clear layers was separated, and the bottom aqueous layer was washed twice with dichloromethane (2 X 300 mL). The aqueous layer was then taken in a clean RBF and adjusted its pH to 10-13 with aqueous sodium hydroxide (10% w/v) at room temperature. The resulting reaction mass was stirred at room temperature for additional 6 hours for complete precipitation of the product. The obtained solid was filtered, washed with acetone (1000 mL) and dried to get the crude brigatinib as a solid.
Yield: 130.0 g
Purity: ~99.5% by HPLC

Example 7: Preparation of brigatinib
Hydrochloric acid (23.1 g, 0.632 moles, 2.0 eq) was added to a solution of 2-methoxy-4-(4-(4-methylpiperazin-1-yl) piperidin-1-yl) aniline (100.0 g, 0.316 moles, 1.0 eq.) and 2,5-dichloro-N-[2-(dimethylphosphoryl) phenyl] pyrimidin-4-amine (96.2 g, 0.316 moles, 1.0 eq.) in water (1000 mL) at room temperature. The resulting suspension was heated to 90 °C and stirred at the same temperature for 5 hours. After completion of the reaction as shown by TLC, the reaction mass was cooled to room temperature, filtered to remove the insoluble matter if any and adjusted its pH to 10-13 with aqueous sodium hydroxide (10% w/v) at room temperature. The resulting reaction mass was stirred at room temperature for additional 6 hours for complete precipitation of the product. The obtained solid was filtered, washed with acetone and dried to get the crude brigatinib as a solid.
Yield: 130.0 g
Purity: ~99.5% by HPLC

Example 8: Preparation of crystalline brigatinib Form A
A suspension of brigatinib crude (100.0 g, 0.171 moles, 1.0 eq.) in ethanol (1500 mL) was heated to reflux temperature and stirred for clear solution. The solution was filtered on 0.45 micron and stirred at room temperature for about 6 hours for the complete precipitation of product. The compound was then filtered and dried at 50 °C to get crystalline brigatinib Form A.
Yield: 85.0 g
Purity: ~99.7% by HPLC
,CLAIMS:1. A process for the preparation of brigatinib, which comprises:
a) reduction of compound of formula IV using sodium sulphide to get the compound of formula III

; and
b) condensing the compound of formula III with 2,5-dichloro-N-[2-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (II) in presence of a protic acid to obtain brigatinib.

2. The process as claimed in claim 1, wherein reduction step (a) may be carried out in the presence of a base.
3. The process as claimed in claim 2, wherein base is alkali metal hydroxide.
4. The process as claimed in claim 1, wherein the protic acid used in step (b) is selected from hydrochloric acid, hydrobromic acid, sulfuric acid, methane sulfonic acid, p-toluene sulfonic acid and mixtures thereof.
5. The process as claimed in claim 1, wherein step (b) may be carried out in the presence of a solvent.
6. The process as claimed in claim 5, wherein the solvent is selected from an alcohol such as methanol, ethanol, isopropyl alcohol or n-butanol and mixtures thereof.
7. A process for the preparation of crystalline brigatinib Form A, which comprises crystallizing brigatinib with an alcoholic solvent.
8. The process as claimed in claim 5, wherein alcoholic solvent employed is selected from ethanol, isopropyl alcohol or mixtures thereof.