DESC:RELATED APPLICATION:
This application claims the benefit of the earlier filing date of Indian Provisional Patent Application No. 202021001198 filed on Jan.10, 2020
FIELD
The present application describes an improved process of preparation of benzimidazole compounds such as Binimetinib.
BACKGROUND
Binimetinib, is chemically known as 5-[(4-Bromo-2-fluorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-l-methyl-lH-benzimidazole-6-carboxamide. Binimetinib is represented by the following chemical structure according to Formula I.

Binimetinib is indicated, in combination with encorafenib, for the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.
Selumetinib of Formula II, is chemically known as 5-[(4-Bromo-2-chlorophenyl)amino]-4-fluoro-N-(2-hydroxyethoxy)-l-methyl-lH-benzimidazole-6-carboxamide.

Selumetinib is under clinical trials for various types of cancer such as Biliary cancer, Colorectal cancer, Gastric cancer, Gastrointestinal stromal tumours, Glioma, Histiocytosis, Neurofibromatoses, Non-Hodgkin's lymphoma, Non-small cell lung cancer, Solid tumours, Thyroid cancer, Uveal melanoma, Astrocytoma, Kaposi's sarcoma, Precursor cell lymphoblastic leukaemia-lymphoma.
Patents US 7,425,637 and US 9,156,795 provide processes for the preparation of Selumetinib; and Patents US 7,777,050, US 8,039,637, and US 9,238,627 provide processes for the preparation of Binimetinib. The process in US ‘050 is as shown in below scheme:

Scheme I
US9562016 directed to process for the preparation of crystallized Form of Binimetinib which comprises crystallizing Binimetinib from aqueous ether solution by adding water.
WO2016131406A1 patent application discloses polymorph forms designated as Form A and Form B.
Considering the importance of Binimetinib there exists a need in the art for the development of an easy, cost-effective, and industrially advantageous process for the preparation of Binimetinib.
BRIEF DESCRIPTION OF THE DRAWINGS
Fig 1. - Depicts a powder X-ray diffraction (PXRD) pattern of Form-Al-1 of Binimetinib obtained in Example 6.
Fig 2. - Depicts a powder X-ray diffraction (PXRD) pattern of Form-A of Binimetinib obtained in Example 5.
Fig 3. - Depicts a DSC thermogram of Form-A of Binimetinib obtained in Example 5.
SUMMARY
An aspect of the invention relates to process for the preparation of Binimetinib comprising treating Binimetinib solvate with water.
Another aspect of the invention is related to preparation of Binimetinib containing R-COOH either in stoichiometric or non-stoichiometric level.
DETAILED DESCRIPTION
A process of preparation of Binimetinib comprising
a. treating Binimetinib with an organic acid (R-COOH);
b. adding an organic solvent to step (a) reaction mass followed by stirring;
c. filtering the obtained solid ; and
d. isolating the Binimetinib containing R-COOH either in stoichiometric or non-stoichiometric level.
Accordingly the organic acid (R-COOH) used in step (a) is selected from formic acid, acetic acid, propionic acid and the like; preferably acetic acid.
The amount of organic acid (R-COOH) in the Binimetinib isolated may be either in stoichiometric level like 0.5, 1, 1.5 or 2 mole equivalent OR in non-stoichiometric level.
The compound isolated in step (d) is taken to next stages with or without drying; preferably dried. The solvent used in step (b) includes, but not limited to, toluene, anisole, MTBE, diisopropyl ether, methyl THF and the like.
The step (b) solution is stirred at a temperature in the range of 20-50 deg for about 1-15 hours. Preferably stirred at ambient temperatures.
In another aspect there is provided a process of preparation of Binimetinib comprising treating Binimetinib containing organic acid (R-COOH) in stoichiometric or non-stoichiometric level with water. Binimetinib containing organic acid (R-COOH) is selected from Binimetinib acetate, Binimetinib formate, Binimetinib propionate and the like.
In yet another aspect there is provided a process of preparation of Binimetinib comprising treating Binimetinib containing acetic acid in stoichiometric or non-stoichiometric level with water.
Accordingly the said treatment with water is carried out at a temperature in the range of 20 to 80oC. The reaction mass containing Binimetinib acetic acid solvate in water is stirred for about 30 min to 3 hour. The pure Binimetinib obtained is optionally again slurry washed to get pharmaceutically acceptable level of acid molecule. The isolation is carried out by conventional method, preferably by filtration.
The Binimetinib thus isolated is in crystalline Form; preferably having PXRD that corresponds to Form A.
In another aspect there is provided a process for the preparation of crystalline form of Binimetinib which comprising treating solvated form of Binimetinib with water.
The solvate form of Binimetinib may be prepared from conventional methods and the solvate includes but not limited to propylene glycol, ethylene glycol, ethanol, benzyl alcohol, IPA, glycerol and the like.
Alternatively the Binimetinib may be obtained by treating Binimetinib containing R-COOH in stoichiometric or non-stoichiometric level with polar solvent or aqueous polar solvent. The polar solvent includes, but not limited to, methanol, ethanol and the like.
The staring material i.e Binimetinib used herein is prepared by any conventional methods or by following the processes given as shown by following scheme or by following the examples described herein.

Scheme II

Scheme III

Scheme IV
In certain embodiments, Binimetinib used herein is prepared by any conventional methods or by following the processes given as shown by following scheme or by following the examples described herein.

Scheme V
In certain embodiments, Binimetinib used herein is prepared by any conventional methods or by following the processes given as described herein has below impurities as per ICH guideline.


Binimetinib obtained according to the process described herein is designated as Form-A and is characterized by an X-ray powder diffraction pattern having peaks expressed as 2-theta angle positions at about 6.75, 7.64, 9.46, 11.14, 11.79, 12.76, 13.50, 15.30, 16.01, 16.30, 17.09, 18.41, 18.97, 19.39, 20.33, 20.50, 21.33, 21.68, 22.24, 22.70, 23.72, 24.28, 24.47, 25.05, 25.21, 25.56, 25.97, 26.35, 27.12, 27.40, 28.34, 28.82, 29.14, 29.62, 29.99, 30.41,30.89, 31.23, 31.49, 31.88, 32.33, 32.67, 32.92, 33.84, 34.21, 34.61, 35.32, 36.64, 36.94, 37.34 and 39.34± 0.2 degrees substantially in accordance with FIG. 2 ;
Form A can further be characterized by an DSC endothermic peak at about 224° C.±2° C. Alternatively, Form A can be characterized by a DSC thermogram as shown in FIG. 3.
The D10, D50, and D90 values are useful ways for indicating a particle size distribution. D90 refers to the value for the particle size for which at least 90 volume percent of the particles have a size smaller than the value. Likewise D50 and D10 refer to the values for the particle size for which 50 volume percent, and 10 volume percent, of the particles have a size smaller than the value. Methods for determining D10, D50 and D90 include laser diffraction, such as using Malvern Instruments Ltd. (of Malvern) equipment.
Binimetinib obtained according to the process described herein or after performing size reduction operations such as milling or micronization, has a particle size distribution pattern of D10 less than or equal to about 150 µm, D50 less than or equal to about 300 µm, and D90 less than or equal to about 500 µm. There is no specific lower limit for any of the D values.
Wherever applicable in the example of the present invention, the reaction solution may optionally be treated with carbon, flux-calcined diatomaceous earth (Hyflow) or any other suitable material to remove color, insoluble materials, improve clarity of the solution, and/or remove impurities adsorbable on such material. Optionally, the solution obtained above may be filtered to remove any insoluble particles. The insoluble particles may be removed suitably by filtration, centrifugation, decantation, or any other suitable techniques under pressure or under reduced pressure. The solution may be filtered by passing through paper, glass fiber, cloth or other membrane material, or a bed of a clarifying agent such as Celite® or Hyflow. Depending upon the equipment used and the concentration and temperature of the solution, the filtration apparatus may need to be preheated to avoid premature crystallization.
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 melting points are measured using Differential Scanning Calorimetry (DSC). The equipment is a TA-Instruments DSC-Q1000 calibrated at 10°/min to give the melting point as onset value. About 2 mg of sample is heated 10°/min in a loosely closed pan under nitrogen flow.
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 4-amino-2-[(4-bromo-2-fluorophenyl)amino]-3-fluoro-5-nitrobenzoic acid.
4-amino-2, 3-difluoro-5-nitrobenzoic acid (100 g) was added to the N,N-diisopropyl ethylamine (178 g) and 4-bromo-2-fluoroaniline (262 g) at room temperature, and the temperature of the reaction mixture was raised to 107±5 °C and stirred till the completion of the reaction. The reaction mixture temperature was cooled to 25±5°C, process water was added, and then the reaction mixture pH was adjusted 4.0 to 4.5 using acetic acid, stirred, filtered and dried. The obtained dried material was added to acetonitrile at 35±5°C, stirred, filtered and dried under vacuum to obtain title compound. (Yield 89 %).
Purification of 4-amino-2,3-difluoro-5-nitrobenzoic acid :
4-amino-2.3-difluoro-5-nitrobenzoic acid (100gm) was added to N-methyl pyrrolidone (1000ml) and heated to 57±3°C for one hour. The reaction was cooled to room temperature and water (1000ml) was added slowly. The reaction mass was stirred for 4 hours and filtered the solid. The obtained wet cake was again stirred with water (1000ml), stirred and filtered the solid. Dried it. (Yield~85%).
Purification of 4-bromo-2-fluoroaniline:
4-bromo-2-fluoroaniline (100gm) was stirred with methanol (200ml), followed by adding water (600ml) for 4 hours at room temperature. Filtered the solid and dried under vaccum. (yield~85%)
Purification of 4-bromo-2-fluoroaniline: 4-bromo-2-fluoroaniline (100gm) was stirred with n-Heptane (400ml) at 45±3°C followed by filtration at 2±3°C and dried under vacuum. (yield~85%)
Example 2: Preparation of 4,5-diamino-2-[(4-bromo-2-fluorophenyl)amino]-3-fluoro-benzoic acid
To a solution of methanol and tetrahydrofuran in hydrogenator, 4-amino-2-[(4-bromo-2-fluorophenyl)amino]-3-fluoro-5-nitrobenzoic acid (100 g) was added at room temperature. quinoline (33.26 g), and 5% Pt/C (50% wet) in methanol was added to the reaction mixture in hydrogenator. 1-1.5 Kg/cm2 hydrogen gas pressure was applied and stirred till the completion of reaction. The reaction mixture was filtered and concentrated. Methanol was added to the obtained residue and stirred at 45±5°C, cooled, filtered and dried to obtain title compound. (Yield ~93%).
Example 3: Preparation of 6-(4-bromo-2-fluoro-phenylamino)-7-fluoro-3H-benzoimidazole-5-carboxylic acid
To acetonitrile, 4,5-diamino-2-[(4-bromo-2-fluorophenyl)amino]-3-fluoro-benzoic acid (100g), para toluenesulphonic acid (69.04 g) and water were added and stirred at room temperature. To this reaction mixture diethoxymethane (63.98 g) was added, temperature was raised to 60±3 °C and stirred till the completion of reaction. The reaction mixture was cooled to RT, stirred and filtered. Water was added to the obtained wet material; pH was adjusted to 7.5-8.5 using aq. ammonia solution, stirred at room temperature, filtered and dried. Obtained dried material was added to Formic acid and heated to 65±3°C, acetone was added to the reaction material, stirred at 47±3°C, cooled to room temperature, stirred, filtered and dried to obtain title compound. (Yield: ~60 %).
Example 4: Preparation of 6-(4-bromo-2-fluoro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole -5-carboxylic acid (2-vinyloxy-ethoxy)-amide
6-(4-bromo-2-fluoro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carboxylic acid (100 g), O-(2-vinyloxy-ethyl)-hydroxylamine (40.47 g), HOBt (45.99 g), triethylamine (12.18 g) and EDC.HCl (65.04 g) were dissolved in dimethylformamide (700 mL) and stirred at room temperature till completion of reaction. 2-methyl tetrahydrofuran and water was added into the reaction mixture, pH was adjusted between pH 7.5-8.5 using 10%sodium hydroxide solution, Layers were separated. The organic layer was concentrated. Ethanol (denatured with 0.5% cyclohexane) was added to the obtained residue and the temperature was raised to 65±3°C. Carbon treatment was performed to the obtained clear solution and n-heptane was added to the filtrate obtained after carbon treatment at 57±5°C, Reaction mixture was cooled to room temperature, stirred, filtered. Obtained wet cake was stirred with water, filtered and dried under vacuum. (Yield: 77%).
Example 5: Preparation of Binimetinib
6-(4-bromo-2-fluoro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole -5-carboxylic acid (2-vinyloxy-ethoxy)-amide (100 g) was charged to in ethanol (2100 mL) at room temperature, cooled to 0±3 °C. Conc. HCl (30% aq. solution) was added to the reaction mixture at 0±3 °C and the temperature was raised to 17±3 °C and stirred for completion of reaction. pH was adjusted to 7.5-8.5 using 10% sodium hydroxide solution. Ethyl acetate was added to the reaction mass, stirred at room temperature, layers were separated, organic layer was concentrated. Ethyl acetate was added to the obtained solid and stirred at 72±3°C for 1 hour. The solid was filtered and sucked dried. The obtained wet cake was stirred with acetic acid (500ml), followed by addition of toluene (1250ml). The reaction mass was stirred for 6 hours and then filtered the solid, washed with toluene and suck dried. The obtained wet cake was stirred with water (900ml) for 2 hours at room temperature and filtered the solid and dried under vacuum, (yield~70%)
Example 6: Preparation of Binimetinib acetate.
Binimetinib (100 g) was stirred in acetic acid (400 mL) at room temperature. Toluene (1250 mL) was added to the reaction mass and stirred for 12 hours at room temperature. Filtered the solid and washed with toluene. The material was dried in VTD for 8 hours at 50oC. (Acetic acid content: 7 %).
Example 7: Preparation of Binimetinib.
Binimetinib obtained in above step was added to water at room temperature; temperature was raised to 65±3°C and stirred for 2 hours. The solid was filtered at 65°C and washed with hot water. The material was dried in VTD for 8 hours at 50oC to obtain pure Binimetinib. (Yield: ~80 %).
Example 8: Preparation of Binimetinib.
Binimetinib diacetate (Form B) solvate was added to water at room temperature; temperature was raised to 65±3°C and stirred for about 1-3 hours. The solid was filtered at ambient temperature and washed with water at ambient temperature. The material was dried in VTD for 8 hours at 50oC to obtain pure Binimetinib. (Yield: ~80 %).

,CLAIMS:We Claim:
1. A process of preparation of Binimetinib comprising treating Binimetinib solvate with water.
2. The process as claimed in claim 1, wherein the Binimetinib solvate is selected from organic acid solvate of Binimetinib, propylene glycol solvate of Binimetinib, IPA solvate of Binimetinib, or benzyl alcohol solvate of Binimetinib.
3. The process as claimed in claim 2, wherein the organic acid in Binimetinib organic acid solvate is selected from formic acid, acetic acid and propionic acid.
4. The process as claimed in claim 1 wherein the said treatment of Binimetinib organic acid solvate with water is carried out at a temperature in the range of 20 to 80°C.
5. The process as claimed in claim 1, further comprising isolating Binimetinib substantially free of solvate.
6. The process as claimed in claim 2, wherein Binimetinib containing organic acid is prepared by steps of:
a. treating Binimetinib with an organic acid;
b. adding an organic solvent to step (a) reaction mass followed by stirring; and
c. isolating the obtained solid .
7. The process as claimed in claim 6, wherein the organic acid in Binimetinib organic acid solvate is either stoichiometric level or non-stoichiometric level.
8. The process as claimed in claim 6, wherein the organic solvent used in step (b) is selected from toluene, anisole, MTBE, di-isopropyl ether, methyl THF and the like.
9. The process according to claim 6, wherein the process further comprises step of isolating Binimetinib containing organic acid in stoichiometric or non-stoichiometric level and wherein the amount of organic acid in the isolated Binimetinib is in stoichiometric level 0.5, 1, 1.5, 2 mole equivalent or in non-stoichiometric level by filtration.

10. The process as claimed in claim 1, wherein the process of preparation of Binimetinib comprises treating Binimetinib acetic acid solvate with water.