DESC:FIELD OF THE INVENTION
The present invention relates to novel polymorphic form of Brigatinib and process of preparing thereof. Further, present invention involves novel acid addition salts of Brigatinib and process of preparing thereof. Present invention also provides process for purification of Brigatinib.
BACKGROUND OF THE INVENTION
Brigatinib, has a chemical name 5-chloro-N4-[2-(dimethylphosphoryl) phenyl]-N2-{2-methoxy-4[4-(4-methylpiperazin-1-yl) piperidin-1-yl]phenyl} pyrimidine-2,4-diamine. Brigatinib is represented by the following chemical structure according to Formula (I).

Brigatinib is a tyrosine kinase inhibitor with in vitro activity at clinically achievable concentrations against multiple kinases including ALK, ROS1, insulin-like growth factor-1 receptor (IGF-1R), and FLT-3 as well as EGFR deletion and point mutations. Brigatinib inhibited autophosphorylation of ALK and ALK-mediated phosphorylation of the downstream signaling proteins STAT3, AKT, ERK1/2, and S6 in in vitro and in vivo assays. Brigatinib also inhibited the in vitro proliferation of cell lines expressing EML4-ALK and NPM-ALK fusion proteins and demonstrated dose-dependent inhibition of EML4-ALK-positive NSCLC xenograft growth in mice.
Patent no. US 9,012,462 (IN2010KN03939) disclose Brigatinib and a process for the preparation thereof. US’462 patent discloses condensation of (2-{{2,5-dichloro pyrimidin-4-yl)amino}phenyl)-dimethylphosphine oxide and 2-methoxy-4-(4-(4-methyl piperazin-1-yl)piperidin-1-yl)aniline in presence of ethanolic hydrochloric acid to obtain Brigatinib. Further, US 9,012,462 teaches that, said condensation is performed in closed system such as sealed tube at 120 °C and stirred for 5.5 hrs to obtain crude Brigatinib which is purified by chromatography followed by re-crystallization.
Patent no. WO2016065028 discloses various polymorphs of Brigatinib. WO’028 patent discloses form A, B, C, D, E, F, G, H, I, J, K, L and amorphous form of Brigatinib.
SUMMARY OF THE INVENTION
The present invention relates novel crystalline form of Brigatinib benzyl alcohol solvate Form Al-1 and process of preparation thereof.
Another aspect of present invention is to provide novel acid addition salts of Brigatinib and process of preparation thereof.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1 shows the X-ray powder diffractogram ("PXRD") pattern of benzyl alcohol solvate Form Al-I of Brigatinib.
DETAILED DESCRIPTION OF THE INVENTION
An embodiment of the present invention relates to benzyl alcohol solvate of Brigatinib form Al-1.
In one embodiment invention relates to benzyl alcohol solvate of Brigatinib polymorph Form Al-1 characterized with an XRPD pattern showing at least one characteristic peak (2theta±0.2) at 18.21, 19.82, 20.45 and 24.83; and further characterized by having XRPD peaks (2theta±0.2) at 4.92, 8.44, 9.82, 10.08, 10.53, 11.06, 11.27, 11.91, 12.36, 12.85, 13.97, 14.75, 15.84, 16.08, 18.21, 18.51, 18.89, 19.12, 19.44, 19.82, 20.45, 20.89, 21.37, 21.77, 22.25, 23.20, 24.83, 25.48, and 25.81. Benzyl alcohol solvate of Brigatinib Form Al-1 can alternatively characterized by an XPRD pattern having 2 theta values as shown in Figure-1.
In one embodiment the invention provides a process for preparation of benzyl alcohol solvate of Brigatinib Form Al-1 comprises;
a) providing a solution of Brigatinib in benzyl alcohol optionally in presence of suitable solvent; and
b) isolating the benzyl alcohol solvate of Brigatinib from the solution.
Providing a solution of Brigatinib in benzyl alcohol solvent means the solution of Brigatinib may be obtained by dissolving Brigatinib in benzyl alcohol solvent, or such a solution may be obtained directly from a chemical synthesis mixture in which Brigatinib is formed. Providing a solution of Brigatinib in benzyl alcohol optionally involves use of other suitable solvents capable of dissolving Brigatinib. Then optionally, filtering the solvent solution to remove any extraneous matter; and finally isolating by removing the solvent from the solution to afford Brigatinib benzyl alcohol solvate. Removal of solvent is accomplished by, for example, filtering the solid, substantially complete evaporation of the solvent, concentrating the solution and filtering the solid.
Another embodiment of the present invention is to provide pharmaceutically acceptable novel acid addition salt of Brigatinib.
In an embodiment, the suitable pharmaceutically acceptable acid addition salts which may be used are selected from such as salt of adipic acid, lactic acid, succinic acid, oxalic acid, tartaric acid, malic acid, fumaric acid, methane sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, sulfuric acid, citric acid, gluconic acid, hydrochloric acid, hydrobromic acid, ortho phosphoric acid, nitric acid.
Another embodiment of the present invention relates to process of preparation of acid addition salt of Brigatinib, comprising;
a) treating a solution of Brigatinib in a suitable solvent or mixture of solvent with an acid ; and
b) isolating the acid addition salt of Brigatinib from the solution.
Isolation of Brigatinib acid addition salt is done by removal of solvent. Removal of solvent is accomplished by, for example, filtering the solid, substantially complete evaporation of the solvent, concentrating the solution and filtering the solid.
In another aspect of the present invention relates to process of purification of Brigatinib of Formula-(I), comprising;

a) treating of the Brigatinib with a suitable acid;
b) isolating the acid addition salt of Brigatinib; and
c) treating acid addition salt of Brigatinib with a suitable base to provide highly pure Brigatinib.
Wherein, suitable acid in step (a) is selected from the group of carboxylic acid such as acetic acid, formic acid, propionic acid, propanedioic acid, butyric acid, pentanoic acid, hexanoic acid, oxalic acid, 2-oxopropanoic acid, citric acid, tartaric acid, gluconic acid, lactic acid; mineral acid such as sulfuric acid, nitric acid, boric acid, hydrochloric acid, hydrobromic acid, hydrofluoric acid, hydro iodic acid; phosphoric acid such as orthophosphoric acid, Pyrophosphoric acid, polyphosphoric acid; sulfonic acid such as methansulfonic acid, ethansulfonic acid, benzene sulfonic acid, trifluromethansulfonic acid, polystyrenesulfonic acid, p-toluene sulfonic acid; wherein the reaction is performed in presence of or absence of solvent or mixture of solvent.
Wherein, the solvent is selected from the group of anisole, toluene, xylene, chlorobenzene, cyclohexane, hexane, heptane, 1,2-dichlroethane,dichloromethane, chloroform, diethyleneglycol, glycerine, ethylene glycol, 1,4 dioxane, N-methyl-2-pyrrolidinone (NMP), DMF, DMSO, n-butanol, tert-butanol, 2-butanol, isopropanol, 1-propanol, ethanol, methanol, amyl alcohol , isoamyl alcohol , hexanol, cyclohexanol, 2-methoxy ethanol, 2-ethoxyethanol, acetic acid, trifluroaceticacid, formic acid, water, methyl isobutyl ketone, acetonitrile, acetone, butanone, ethyl acetate, methyl acetate, methyl t-butyl ether (MTBE), tetrahydrofuran, sulfolane, petroleum ether, 2-methyl tetrahydrofuran and mixture thereof .
Wherein, suitable base in step (c) is selected from the group of metal carbonates or hydroxides such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide or sodium hydroxide, more preferably sodium hydroxide.
In another aspect the compound of Formula (II) can be prepared by condensing 2-(dimethylphosphoryl)aniline, a compound of formula (IV) and 2,4,5-trichloropyrimidine, acompound of formula (V) in presence of suitable reagents in suitable solvent.

Wherein, suitable reagents may buffer which is selected from the group of Potassium phosphate tribasic, dipotassium phosphate, monopotassium phosphate, sodium dihydrogen phosphate, sodium hydrogen phosphate, dihydrogen phosphate, ammonium dihydrogen phosphate , diammonium phosphate , sodium acetate, ammonium acetate, potassium acetate, sodium maleate, sodium Adipate, potassium Adipate, ammonium Adipate, ammonium maleate, potassium maleate, Sodium malonate dibasic , potassium malonate dibasic, ammonium malonate, sodium glutarate, sodium citrate.
Wherein, suitable reagents may organic or inorganic base which is selected from the group consisting of potassium hydroxide, sodium hydroxide, lithium hydroxide, Sodium carbonate, Cesium carbonate, sodium bicarbonate, Potassium bicarbonate, calcium carbonate, Ammonium hydroxide, cesium hydroxide.
Wherein, the solvent is selected from the group of anisole, toluene, xylene, chlorobenzene, cyclohexane, hexane, heptane, 1,2-dichlroethane,dichloromethane, chloroform, diethyleneglycol, glycerine, ethylene glycol, 1,4 dioxane, N-methyl-2-pyrrolidinone (NMP), DMF, DMSO, n-butanol, tert-butanol, 2-butanol, isopropanol, 1-propanol, ethanol, methanol, amyl alcohol , isoamyl alcohol , hexanol, cyclohexanol, 2-methoxy ethanol, 2-ethoxyethanol, acetic acid, trifluroaceticacid, formic acid, water, methyl isobutyl ketone, acetonitrile, acetone, butanone, ethyl acetate, methyl acetate, methyl t-butyl ether (MTBE), tetrahydrofuran, sulfolane, petroleum ether, 2-methyl tetrahydrofuran and mixture thereof .
Further, Brigatinib can be prepared by methods known to those in the art.
In an embodiment the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of the Formula (I) obtained according to present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, or excipient thereof.
In an embodiment, the Brigatinib disclosed herein for use in the pharmaceutical compositions of the present invention, wherein 90 volume-percent of the particles (D90) have a size of less than or equal to about 500 microns, specifically less than or equal to about 300 microns, more specifically less than or equal to about 200 microns, still more specifically less than or equal to about 100 microns, and most specifically less than or equal to about 15 microns.
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope of the invention.
Examples
Example-1: Preparation of Brigatinib benzyl alcohol Al-1
To a solution of Brigatinib (2.0 g) in DCM (15 ml), benzyl alcohol (2.0 ml) was added and. reaction mass was concentrated to obtain residue. Residue was stirred in cyclohexane for 4-5 hours at room temperature. The reaction mass was filtered to obtain solid and dried. (1.5 g, 64% yield).
Example-2: Preparation of (2-{{2,5-dichloro-pyrimidin-4-yl)amino}phenyl)-dimethyl phosphine oxide
To a solution of 2-(dimethylphosphoryl)aniline (100 g) and 2,4,5-trichloro pyrimidine (120 g) in DMF (600 ml), potassium phosphate tribasic (131 g) and tetrabutyl ammonium hydrogen sulfate (20 g) were added and heated at 60-65°C. After completion of reaction, reaction mass was cooled to room temperature and treated with water and filtered. Obtained wet solid was dissolved in mixture of water and toluene at 70-75°C. The organic phase was separated, cooled to 10-15°C and filtered to obtain (2-{{2,5-dichloro-pyrimidin-4-yl)amino}phenyl)-dimethyl phosphine oxide (135 g).
Example-3: Preparation of 1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine
A solution of 5-fluoro-2-nitroanisole (100 g), 1-methyl-4-(piperidin-4-yl)-piperazine dihydrochloride (117 g) and potassium carbonate (290 g) in acetonitrile (700 ml) was heated to 80°C and stirred. After completion of reaction, the reaction mass was cooled and filtered to obtain 1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine(170 g).
Example-4: Preparation of Brigatinib di-sulphate
A solution of 1-[1-(3-methoxy-4-nitrophenyl)piperidin-4-yl]-4-methylpiperazine (100 g), Pd/C (5 g) in 2-methoxyethanol (1000 ml) was heated to 35-40°C and stirred under hydrogen pressure (3-4 kg). The reaction mass was filtered and to the obtain filtrate, 2,5-dichloro-N-[2-(dimethyl phosphoryl)phenyl]pyrimidin-4-amine (96.4) and solution of H2SO4 in water (65 g in 200 ml water) were added and heated to 95-100°C and stirred. After completion of reaction, reaction mass was cool and filtrated. The solid was purified in methanol (10 Volume) and water (4.0 volumes) to obtain Brigatinib di-sulphate (160 g).
Example-5: Preparation of Brigatinib
A the solution of Brigatinib di-sulphate (100 g), methanol (50 ml) and ethyl acetate (1000 ml) was heated to 60-65°C and solution of NaOH (30 g in 500 ml water) was added to reaction mass and stirred. After completion of reaction, the organic layer was separated and cooled. Water (500ml) was added in to the reaction mass and was filtered and dried under vacuum to obtain Brigatinib (50g).
,CLAIMS:We claim;
1. A Crystalline Brigatinib benzyl alcohol solvate form Al-1.
2. A crystalline form Al-1 of Brigatinib benzyl alcohol solvate having an X-ray powder diffractogram comprising at least one peak at diffraction 2-theta angle selected from 18.21, 19.82, 20.45, 20.89 and 24.83 ± 0.2°.
3. An acid addition salt of Brigatinib, wherein the acid is selected from adipic acid, lactic acid, succinic acid, oxalic acid, tartaric acid, malic acid, fumaric acid, methane sulfonic acid, benzene sulfonic acid, p-toluene sulfonic acid, sulfuric acid, citric acid, gluconic acid, hydrochloric acid, hydrobromic acid, ortho phosphoric acid, nitric acid, formic acid, acetic acid.
4. A Brigatinib di-sulphate.
5. A process of purification of Brigatinib comprising:
a) treating Brigatinib with sulphuric acid;
b) isolating Brigatinib sulphate salt; and
c) treating Brigatinib sulphate salt with sodium hydroxide to provide highly pure Brigatinib.
6. The process of purification of Brigatinib comprising treating Brigatinib acid addition salt as claimed in claim 3, with base.
7. The process of purification of Brigatinib as claimed in claim 6, wherein base are selected from the group of metal carbonates or hydroxides such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, potassium hydroxide or sodium hydroxide, more preferably sodium hydroxide.