DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. IN201841038321 filed on Oct 09, 2018.
FIELD OF THE INVENTION
The present disclosure relates to novel salts of brigatinib and processes for their preparation thereof.

BACKGROUND 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 a 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.

PCT Publication No. WO2016065028A1 discloses various crystalline forms of brigatinib and also amorphous form.

The inventors of the present disclosure have developed novel salts of brigatinib.

SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide novel salts of brigatinib.

A second aspect of the present invention is to provide a brigatinib orotate salt of formula-II and a process for the preparation thereof.

Formula-II
Wherein X is 1 or 2.

A third aspect of the present invention is to provide crystalline Form M1 of brigatinib mono-orotate salt and a process for the preparation thereof.

Another aspect of the present invention is to provide crystalline Form M1 of brigatinib mono-orotate salt, which is characterized by powdered X-ray diffraction pattern as shown in Fig 1.

A fourth aspect of the present invention is to provide crystalline Form M2 of brigatinib mono-orotate salt and a process for the preparation thereof.

In another aspect the present invention provides crystalline Form M2 of brigatinib mono-orotate salt, which is characterized by powdered X-ray diffraction pattern as shown in Fig 2.

A fifth aspect of the present invention is to provide crystalline Form M1 of brigatinib di orotate salt and a process for the preparation thereof.

Another aspect of the present invention is to provide crystalline Form M1 of brigatinib di orotate salt, which is characterized by powdered X-ray diffraction pattern as shown in Fig 3.

BRIEF DESCRIPTION OF THE FIGURES
Further aspects of the present disclosure together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of embodiments of the disclosure which are shown in the accompanying drawing figures wherein:

Figure. 1 is an X-ray powder diffractogram of crystalline Form M1 of brigatinib mono-orotate salt.
Figure. 2 is an X-ray powder diffractogram of crystalline Form M2 of brigatinib mono-orotate salt.
Figure. 3 is an X-ray powder diffractogram of crystalline Form M1 of brigatinib di orotate salt.

DETAILED DESCRIPTION OF THE INVENTION
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 polymorph of the present disclosure is characterized by its X-ray powder diffraction pattern. Thus, the X-ray diffraction patterns of the polymorphs of the disclosure were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of ?/2? configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 2? range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

The present disclosure relates to novel salts of brigatinib and processes for the preparation thereof.

In one embodiment, the present invention provides brigatinib orotate salt of formula-II and a process for the preparation thereof.

Formula-II
Wherein X is 1 or 2.

Another embodiment of the present invention is to provide crystalline Form M1 of brigatinib mono-orotate salt and a process for the preparation thereof.

Within the context of the present invention, crystalline Form M1 of brigatinib mono-orotate salt may be characterized by a PXRD pattern having peaks at 2? angle positions of 8.64, 14.16, 22.95 and 27.12 ± 0.2 °.
Within the context of the present invention, the crystalline Form M1 of brigatinib mono-orotate salt may be further characterized by a PXRD pattern as shown in Figure 1.
Yet another embodiment of the present invention is to provide a process for the preparation of crystalline Form M1 of brigatinib mono-orotate salt, which comprises:
a) suspending brigatinib in a solvent or mixture of solvents;
b) adding orotic acid to the suspension obtained in step (a)
c) heating the reaction mixture to obtain a clear solution;
d) cooling the solution to ambient temperature obtained in step (c)
e) adding an organic solvent; and
f) isolating crystalline Form M1 of brigatinib mono-orotate salt.

According to the present invention, brigatinib is suspended in a solvent or mixture of solvents and orotic acid is added to the suspension. The reaction mixture is heated to a temperature of 75-85 °C to obtain a clear solution. The clear solution is cooled to a temperature of 20-30 °C and an organic solvent is added. The reaction mixture is stirred for 10-12 hours, then filtered and suck dried to obtain crystalline Form M1 of brigatinib mono-orotate salt.

Within the context of the present disclosure, the molar ratio of brigatinib to orotic acid is in the range of about 1:1 to 1:1.2.
Within the context of the present invention, the solvent used in step (a) is selected from water and water miscible solvents such as dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran. In a preferred embodiment a mixture of water and dimethyl sulfoxide used a solvent mixture.
Within the context of the present invention, the organic solvent used in step (e) is selected from acetone.
In another embodiment of the present invention is to provide crystalline Form M2 of brigatinib mono-orotate salt and a process for the preparation thereof.

Within the context of the present invention, crystalline Form M2 of brigatinib mono-orotate salt may be characterized by a PXRD pattern having peaks at 2? angle positions of 8.36, 14.38, 15.58, 16.12 and 18.71 ± 0.2°.
Within the context of the present invention, the crystalline Form M2 of brigatinib mono-orotate salt may be further characterized by a PXRD pattern as shown in Figure 2.
Yet another embodiment of the present invention is to provide a process for the preparation of crystalline Form M2 of brigatinib mono-orotate salt, which comprises:
a) suspending brigatinib and orotic acid in a solvent or mixture of solvents;
b) heating the reaction mixture and stirring to obtain a solution;
c) cooling the solution to ambient temperature obtained in step (b); and
d) isolating crystalline Form M2 of brigatinib mono-orotate salt.

According to the present invention, brigatinib and orotic acid is suspended in a solvent or mixture of solvents. The reaction mixture is heated to a temperature of 75-85 °C to obtain a clear solution. The clear solution is slowly cooled to a temperature of 20-30 °C and stirred for 10-12 hours. The obtained solid is filtered and suck dried to obtain crystalline Form M2 of brigatinib mono-orotate salt.

Within the context of the present invention, the solvent used in step (a) is selected from water and water miscible solvents such as dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran. In a preferred embodiment dimethyl sulfoxide is used as solvent.
Another embodiment of the present invention is to provide crystalline Form M1 of brigatinib di orotate salt and a process for the preparation thereof.

Within the context of the present invention, crystalline Form M1 of brigatinib di-orotate salt may be characterized by a PXRD pattern having peaks at 2? angle positions of 7.57, 8.04, 10.06, 15.28 and 20.07 ± 0.2°.
Within the context of the present invention, the crystalline Form M1 of brigatinib di-orotate salt may be further characterized by a PXRD pattern as shown in Figure 3.
Yet another embodiment of the present invention is to provide a process for the preparation of crystalline Form M1 of brigatinib di-orotate salt, which comprises:
a) suspending brigatinib in a solvent or mixture of solvents;
b) adding orotic acid to the suspension obtained in step (a)
c) heating the reaction mixture to obtain a clear solution;
d) cooling the solution to ambient temperature obtained in step (c)
e) adding an organic solvent; and
f) isolating crystalline Form M1 of brigatinib di-orotate salt.

According to the present invention, brigatinib is suspended in a solvent or mixture of solvents and orotic acid is added to the suspension. The reaction mixture is heated to a temperature of 75-85 °C to obtain a clear solution. The clear solution is cooled to a temperature of 20-30 °C and an organic solvent is added. The reaction mixture is stirred for 10-12 hours, then filtered and suck dried to obtain crystalline Form M1 of brigatinib di-orotate salt.

Within the context of the present disclosure, the molar ratio of brigatinib to orotic acid is in the range of about 1:2 to 1:2.2.
Within the context of the present invention, the solvent used in step (a) is selected from water and water miscible solvents such as dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran. In a preferred embodiment a mixture of water and dimethyl sulfoxide used as a solvent mixture.
Within the context of the present invention, the organic solvent used in step (e) is selected from acetone.
According to the present invention, the input brigatinib is prepared by any prior-art process example of U.S. Patent No. 9,012,462.

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 of crystalline Form M1 of Brigatinib mono-orotate salt
Suspended brigatinib (0.5 g) in a mixture of dimethyl sulfoxide (2.5 mL) and water (3 mL) at 25±5°C. Added orotic acid (0.133 g) at 25±5°C, then heated to 80±5°C and stirred for 30min at this temperature. The resulting clear solution was slowly cooled to 25±5°C, added acetone (10 mL) and stirred for 12h at 25±5°C. Filtered the reaction mass and suck-dried for 30 min. The solid obtained was identified as crystalline Form M1 of brigatinib mono-orotate salt.

Example 2: Preparation of crystalline Form M2 of Brigatinib mono-orotate salt Suspended Brigatinib (0.5 g) and orotic acid (0.15 g) in dimethyl sulfoxide (5 mL) at 25±5°C and heated to 80±5°C and maintained under stirring for 30min for complete dissolution. The clear solution was slowly cooled to 25±5°C and stirred for 12h. The product obtained was filtered and suck-dried for 30min. The solid obtained was identified as crystalline Form M2 of brigatinib mono-orotate salt.

Example 3: Preparation of crystalline Form M1 of Brigatinib di-orotate salt
Suspended Brigatinib (0.5 g) in a mixture of dimethyl sulfoxide (2.5 mL) and water (3 mL) at 25±5°C. Added orotic acid (0.28 g) to the reaction mass, heated to 80±5°C and maintained under stirring for 30 min for complete dissolution. The clear solution was slowly cooled to 25±5°C, added acetone (10 mL) and stirred for 12h at 25±5°C. The product obtained was filtered and suck-dried for 30min. The solid obtained was identified as crystalline Form M1 of brigatinib di-orotate salt.

Example 4: Preparation of crystalline Form M1 of Brigatinib di-orotate salt
Suspended Brigatinib (1 g) in dimethyl sulfoxide (2 mL) and water (2 mL) mixture at 25±5°C. Added orotic acid (0.6 g) at 25±5°C to the reaction mass, heated to 80±5°C and maintained under stirring for 30 min for complete dissolution. The clear solution was slowly cooled to 25±5°C and stirred for 1h. Added acetone (10 mL) and stirred for 12h at 25±5°C. The product obtained was filtered and suck-dried for 30min. The solid obtained was identified as crystalline Form M1 of Brigatinib di-orotate salt.

,CLAIMS:1. A crystalline brigatinib mono-orotate salt Form M1, which has a powder X-ray diffraction pattern having significant peaks at 2? angles positions at about 8.64, 14.16, 22.95 and 27.12 ± 0.2° and characterized by a PXRD pattern as shown in Figure 1.
2. A process for the preparation of crystalline brigatinib mono-orotate salt Form M1, comprising the steps of:
a) suspending brigatinib in a solvent or mixture of solvents;
b) adding orotic acid to the suspension obtained in step (a);
c) heating the reaction mixture to obtain a clear solution;
d) cooling the solution to ambient temperature obtained in step (c);
e) adding an organic solvent; and
f) isolating crystalline brigatinib mono-orotate salt Form M1.

3. The process as claimed in claim 2, wherein the solvent used in step (a) is selected from water and water miscible solvents such as dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran; and the organic solvent used in step (e) is acetone.
4. A crystalline brigatinib mono-orotate salt Form M2, which has a powder X-ray diffraction pattern having significant peaks at 2? angles positions at about 8.36, 14.38, 15.58, 16.12 and 18.71 ± 0.2° and characterized by a PXRD pattern as shown in Figure 2.
5. A process for the preparation of crystalline brigatinib mono-orotate salt Form M2, comprising the steps of:
a) suspending brigatinib and orotic acid in a solvent or mixture of solvents;
b) heating the reaction mixture and stirring to obtain a solution;
c) cooling the solution to ambient temperature obtained in step (b); and
d) isolating crystalline brigatinib mono-orotate salt Form M2.

6. The process as claimed in 5, wherein the organic solvent used in step (a) is selected from the group consisting of water and water miscible solvents such as dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran.
7. A crystalline brigatinib di-orotate salt Form M1, which has a powder X-ray diffraction pattern having significant peaks at 2? angles positions at about 7.57, 8.04, 10.06, 15.28 and 20.07 ± 0.2° and characterized by a PXRD pattern as shown in Figure 2.
8. A process for the preparation of crystalline brigatinib di-orotate salt Form M1, which comprising the steps of:
a) suspending brigatinib in a solvent or mixture of solvents;
b) adding orotic acid to the suspension obtained in step (a)
c) heating the reaction mixture to obtain a clear solution;
d) cooling the solution to ambient temperature obtained in step (c);
e) adding an organic solvent; and
f) isolating crystalline Form M1 of brigatinib di-orotate salt.
9. The process as claimed in claim 8, wherein the solvent used in step (a) is selected from the group consisting of water and water miscible organic solvents such as dimethyl sulfoxide, 1,4-dioxane, tetrahydrofuran; and the organic solvent used in step (e) is selected from acetone.