An improved process for the preparation of belumosudil mesylate and its intermediates thereof

Abstract

The present invention relates to an improved process for the preparation of Belumosudil mesylate compound of formula-1a and its intermediates which is represented by the following structural formula: Formula-1a.

Description

[0001] AN IMPROVED PROCESS FOR THE PREPARATION OF BELUMOSUDIL MESYLATE AND ITS INTERMEDIATES THEREOF

[0002] Field of invention

[0003] The present invention relates to an improved process for the preparation of Belumosudil mesylate compound of formula-la and its intermediates which is represented by the following structural formula:

[0004] Formula- la

[0005] Background of invention

[0006] The drug substance 2-{3-[4-(l / / -indazol-5-ylamino)-2-quinazolinyl] phenoxy}-N-(propan-2-yl) acetamide methanesulfonate (1: 1) is commonly known as “Belumosudil mesylate”.

[0007] Belumosudil mesylate has been approved by U.S. Food and Drug Administration (FDA) in July, 2021 which is a kinase inhibitor indicated for the treatment of adult and pediatric patients 12 years and older with chronic graft- versus-host disease (chronic GVHD) after failure of at least two prior lines of systemic therapy.

[0008] US 8357693B2 disclosed the process for the preparation of Belumosudil and its intermediates.

[0009] CN106916145B also disclosed the process for the preparation of Belumosudil and its intermediates. Still there remains a need to develop a cost effective and commercially viable process for the preparation of Belumosudil mesylate which is useful in the preparation of pharmaceutical compositions.

[0010] Summary of invention:

[0011] The first aspect of the present invention is to provide an improved process for the preparation of Belumosudil mesylate compound of formula- la.

[0012] The second aspect of the present invention is to provide salts of Belumosudil intermediates and its process for the preparation.

[0013] The third aspect of the present invention is to provide a process for the preparation of crystalline form of Belumosudil mesylate compound of formula- la.

[0014] Detail description of invention:

[0015] The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" selected from aliphatic hydrocarbon solvents such as n- hexane, n-heptane, cyclohexane, petroleum ether and the like; and aromatic hydrocarbon solvents such as toluene, xylene and the like; "ether solvents" such as dimethyl ether, diisopropyl ether, diethyl ether, methyl tert-butyl ether, 1,2- dimethoxyethane, tetrahydrofuran, 1,4-dioxane, monoxime, dioxime and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as N, N-dimethylacetamide, N,N- dimethylformamide, dimethyl sulfoxide, N-methyl pyrrolidone (NMP) and the like; "chlorinated solvents" such as dichloromethane / methylene chloride, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert.amyl alcohol, t-butanol and the like; "polar solvents" such as water or mixtures thereof. As used herein the present invention, the term "anti-solvent" refers to a solvent which is used to precipitate the solid from a solution.

[0016] As used herein the present invention the term “suitable base” refers to “alkali metal carbonates” such as sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate and the like; “alkali metal bicarbonates” such as sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; “alkali metal alkoxides” such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-butoxide and the like; alkali metal hydrides such as sodium hydride, potassium hydride, lithium hydride and the like; alkali metal amides such as sodium amide, potassium amide, lithium amide and the like; “alkali metal phosphates” such as tribasic potassium phosphate or Tripotassium phosphate (K3PO4) and Trisodium phosphate (NasPCk) and the like; and organic bases like dimethylamine, diethylamine, diisopropylamine, diisopropylethylamine, diisobutylamine, triethylamine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) or mixtures thereof.

[0017] The first aspect of the present invention provides an improved process for the preparation of Belumosudil mesylate compound of formula- la, comprising of: a) Reacting anthranilamide of formula-2,

[0018] Formula-2 with 3-Hydroxy benzaldehyde of formula-3 Formula-3 in presence of Copper chloride dihydrate (CUCI2.2H2O) in a suitable solvent to provide 2-(3-hydroxyphenyl)-3H-quinazolin-4-one hydrochloride of formula-4, optionally purifying the obtained compound b) reacting the compound of formula-4 in-situ with acetic anhydride in presence of a suitable base to provide 2-[3-(Acetyloxy)phenyl]-4(3H)- quinazolinone of formula-5, optionally purifying the obtained compound with a suitable solvent, c) reacting the compound of formula-5 with phosphorus oxychloride (POCI3) in presence of a suitable base in a suitable solvent to provide 3-(4-Chloro- 2-quinazolinyl)phenol 1 -acetate of formula-6, d) reacting the compound of formula-6 in-situ with compound of formula-7, Formula-7 in a suitable solvent to provide 5-[[2-[3-(Acetyloxy)phenyl]-4- quinazolinyl] amino] - 1 H-indazole- 1 -carboxylic acid 1 , 1 -dimethylethyl ester hydrochloride of formula-8, e) reacting the compound of formula-8 with a suitable base to provide tertbutyl 5 - [ [2-(3 -hydroxyphenyl)quinazolin-4-yl] amino] indazole- 1 - carboxylate of formula-9, optionally purifying the obtained compound with a suitable solvent, f) reacting the compound of formula-9 with compound of formula- 10, Formula- 10 in presence of a suitable base in a suitable solvent to provide tert-butyl 5- [[2-[3-[2-(isopropylamino)-2-oxoethoxy]phenyl]quinazolin-4-yl]amino]-

[0019] 1 H-indazole- 1 -carboxylate of formula-11, optionally purifying the obtained compound with a suitable solvent,

[0020]

[0021] Formula- 11 g) treating the compound of formula- 11 with a suitable base in a suitable solvent to provide 2-{3-[4-(l / / -indazol-5-ylamino)-2-quinazolinyl] phenoxy}-N-(propan-2-yl)acetamide of formula-1, optionally purifying the obtained compound with a suitable solvent,

[0022] Formula- 1 h) reacting the compound of formula- 1 with methanesulfonic acid in a suitable solvent to provide 2-{3-[4-(l / / -indazol-5-ylamino)-2- quinazolinyl]phenoxy}-N-(propan-2-yl) acetamide mesylate of formula- la, optionally purifying the obtained compound with a suitable solvent to get pure compound of formula- la.

[0023] Wherein,

[0024] In step (b), (c), (e), (f) & (g) of the present invention, wherein the base used is selected from organic base or inorganic base. The organic base may be selected from triethylamine, diisopropylethylamine, tertiary butylamine, 1,8- diazabicyclo (5.4.0)undec-7-ene (DBU) or any other equivalent organic base. The inorganic base may be selected from alkali and alkaline metal acetates or carbonates such as sodium acetate, sodium bicarbonate, sodium carbonate, potassium acetate, potassium bicarbonate, potassium carbonate, cesium carbonate, alkali metal phosphates such as tribasic potassium phosphate or Tripotassium phosphate (K3PO4) or any other equivalent base.

[0025] In step-a to step-h) the suitable solvent is selected from alcoholic solvents, polar- aprotic solvents, hydrocarbon solvents, ester solvents, ether solvents, ketone solvents, chloro solvents, nitrile solvents and polar solvents such as water or mixtures thereof.

[0026] In a preferred embodiment of the present invention provides an improved process for the preparation of Belumosudil mesylate compound of formula- la, comprising of: a) Reacting anthranilamide of formula-2 with 3 -Hydroxy benzaldehyde of formula-3 in presence of Copper chloride dihydrate (CUCI2.2H2O) in isopropyl alcohol to provide 2-(3-hydroxyphenyl)-3H-quinazolin-4-one hydrochloride of formula-4, purifying the obtained compound with methyl tert-butyl ether to provide pure compound of formula-4, b) reacting the compound of formula-4 in-situ with acetic anhydride in presence of triethylamine to provide 2- [3 -(acetyloxy )phenyl]-4(3H)- quinazolinone of formula-5, purifying the obtained compound with DM water to provide pure compound of formula-5, c) reacting the compound of formula-5 with phosphorus oxychloride (POCI3) in presence of N,N-diethylaniline in toluene to provide 3-(4-Chloro-2- quinazolinyl)phenol 1 -acetate of formula-6, d) reacting the compound of formula-6 in-situ with compound of formula-7 in acetonitrile to provide 5-[[2-[3-(Acetyloxy)phenyl]-4-quinazolinyl] amino] -IH-indazole-l -carboxylic acid 1,1 -dimethylethyl ester hydrochloride of formula- 8, e) reacting the compound of formula-8 with aqueous ammonia to provide tert-butyl 5 - [ [2-(3 -hydroxyphenyl)quinazolin-4-yl] amino] indazole- 1 - carboxylate of formula-9, purifying the obtained compound with water to provide pure compound of formula-9, f) reacting the compound of formula-9 with compound of formula- 10 in presence of potassium phosphate tribasic and triethylamine in acetonitrile to provide tert-butyl 5-[[2-[3-[2-(isopropylamino)-2-oxo- ethoxy]phenyl] quinazolin-4-yl] amino] indazole- 1 -carboxylate of formula- 11, purifying the obtained compound with a 1:1 mixture of methylene chloride and methanol to provide pure compound of formula- 11, g) treating the compound of formula- 11 with potassium carbonate in methanol to provide 2-{3-[4-(l / / -indazol-5-ylamino)-2-quinazolinyl] phenoxy]-N-(propan-2-yl)acetamide of formula-1, purifying the obtained compound with acetonitrile and water to provide pure compound of formula- 1, h) reacting the compound of formula- 1 with methanesulfonic acid in tetrahydrofuran and methanol to provide 2-{3-[4-(l / / -indazol-5-ylamino)- 2-quinazolinyl]phenoxy]-N-(propan-2-yl)acetamide mesylate of formula- la, purifying the obtained compound with methanol to get pure compound of formula- la.

[0027] The second aspect of the present invention provides salts of Belumosudil intermediates and its process for the preparation.

[0028] Formula-4

[0029] In a preferred embodiment of the present invention provides a process for the preparation of 2-(3-hydroxyphenyl)-3H-quinazolin-4-one hydrochloride of formula-4, comprising of reacting anthranilamide of formula-2 with 3-Hydroxy benzaldehyde of formula-3 in presence of Copper chloride dihydrate (CUCI2.2H2O) in isopropyl alcohol to provide 2-(3-hydroxyphenyl)-3H-quinazolin-4-one hydrochloride of formula-4, purifying the obtained compound with methyl tertbutyl ether to provide pure compound of formula-4.

[0030] The third aspect of the present invention provides a process for the preparation of crystalline form of Belumosudil mesylate compound of formula- la, comprising of: a) Adding a solvent to Belumosudil of formula- 1, b) heating and stirring the reaction mixture, c) adding methanesulfonic acid to solution of step-(b), d) stirring and cooling the reaction mixture, e) filtering, washing and drying the compound to get the crystalline form of Belumosudil mesylate of formula-la.

[0031] Wherein in step-a) the suitable solvent is selected from ether solvents, chloro solvents, ester solvents, alcohol solvents, ketone solvents, polar aprotic solvents, hydrocarbon solvents, nitrile solvents and polar solvents or mixtures thereof.

[0032] In a preferred embodiment of the present invention provides a process for the preparation of crystalline form of Belumosudil mesylate compound of formula- la, comprising of: a) Adding a mixture of tetrahydrofuran and methanol to Belumosudil of formula- 1, b) heating and stirring the reaction mixture, c) adding methanesulfonic acid to solution of step-(b), d) stirring and cooling the reaction mixture, e) filtering, washing and drying the compound to get the crystalline form of Belumosudil mesylate of formula-la.

[0033] The anthranilamide of formula-2, 3-Hydroxy benzaldehyde of formula-3 and compound of formula-7 were are prepared from the processes known in the art. The process for the preparation of Belumosudil mesylate compound of formula-la is schematically represented as below:

[0034] 5 Scheme-I:

[0035] The inventors of the present invention have identified the following impurities and well controlled in the present process as per the ICH guidelines & regulatory requirements. The impurities have been illustrated as below:

[0036]

[0037] B EL / Impurity -III

[0038] The best mode of carrying out the present invention was illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation to the scope of the invention.

[0039] Examples:

[0040] Example- 1: Purification of 3-Hydroxy benzaldehyde (Formula-3)

[0041] Technical grade 3-Hydroxy benzaldehyde of formula-3 (250 g) and toluene (1250 ml) were charged into RB flask and stirred for 10 min at 25-30°C. Raised the temperature of reaction mass to 90-100°C and maintained for 10 min to get the clear solution. Cooled the reaction mass to 25-30°C and stirred for 60 min. Filtered the product and washed with toluene to get the wet product.

[0042] Toluene (1250 ml) was added to the above obtained wet product (-278) and stirred the slurry mass for 10 min at 25-30°C. Raised the temperature of reaction mass to 90-100°C and maintained for 10 min to get the clear solution. Cooled the slurry mass to 25-30°C and stirred for 60 min. Filtered the product and washed with toluene and dried to get the title product. Yield: 200 g; Purity: >98% by HPLC. Example-2: Process for the preparation of 2-(3-hydroxyphenyl)-3H- quinazolin-4-one, hydrochloride (Formula-4):

[0043] Anthranilamide of formula-2 (200 g; 1.0 m.eq.) and 3-Hydroxy benzaldehyde of formula-3 (188.34 g; 1.05 m.eq.) and isopropyl alcohol (1000 ml) were charged into a reaction flask and stirred for 10 minutes. CUCI2.2H2O (375.6 g; 1.5 m.eq.) and isopropyl alcohol (600 ml) were added into reaction mass and stirred for 10 minutes. The reaction mass temperature was raised to 80 to 85°C and maintained for about 4-5h. After completion of reaction, the reaction mass was cooled to 25-35°C and methyl tert-butyl ether (800 ml) was added and maintained for 45-60 min at 25-35°C. Reaction mass was filtered and washed with 1:1 premixture of isopropyl alcohol and methyl tert-butyl ether (600 ml) and suck dried. Wet weight: ~ 555g. Purity: >98% by HPLC.

[0044] Example-3: Process for the preparation of 2-[3-(Acetyloxy)phenyl]-4(3H)- quinazolinone (Formula-5).

[0045] Into the reaction flask, the above wet material (Formula-4), acetic anhydride (1000 ml) followed by triethylamine (267.4 g; 1.08 m.eq.) were added and heated to 100- 110°C for about 3-4h. After completion of reaction, cooled the reaction mass to 25-30°C, filtered the product and washed with Ethyl acetate (1000 ml) followed by DM water (600 ml).

[0046] The above wet material and DM water (1000 ml) were charged into a reaction flask and stirred at 25-30°C for 30-45 minutes. Filtered the product and washed with DM water (600 ml) and dried the wet product at 55-60°C under vacuum to get the title product. Yield: 312.4g;76%. Purity: >99% by HPLC.

[0047] Example-4: Process for the preparation of 3-(4-Chloro-2-quinazolinyl)phenol 1-acetate (Formula-6).

[0048] The compound of formula-5 (200 g; 1.0 m.eq.) and Toluene (3000 ml) were charged into a reaction flask and stirred for 5 minutes at 25-30°C. N, N-Diethyl aniline (159.7 g; 1.5 m.eq.) and POCI3 (90.81 g; 0.83 m.eq.) were added into the reaction mass and stirred for 5 min. The reaction mass was heated to 100-110°C and maintained for about 2-3h at the same temperature. After completion of reaction, the reaction mass was cooled to 25-30°C and then slowly added DM water (3000 ml) to the reaction mass at <35°C and stirred the biphasic solution for 15- 20min. Subsequently, organic and aqueous layers were separated, and the separated organic layer was transferred into reaction flask and washed with aq. HC1 (3000 ml, prepared by adding 300 ml of HC1 to 2700 ml of DM water) and followed by aq. NaOH (3000 ml, prepared by dissolving 240g of NaOH in 3000 ml of DM water). The organic layer was collected and concentrated under vacuum at below 65°C. Acetonitrile (400 ml) was added to the concentrated mass and distilled under vacuum at below 65°C to afford the title compound. Wet wt: ~312g. Purity: >98% by HPLC.

[0049] Example-5: Process for the preparation of 5-[[2-[3-(Acetyloxy)phenyl]-4- quinazolinyl]amino|- IH-indazole-l-carboxylic acid 1,1-dimethylethyl ester hydrochloride (1:1) (Formula-8).

[0050] The wet compound of formula-6 (312 g) and acetonitrile (4000 ml) and compound of formula-7 (166.45 g; 1.0 m.eq.) were charged into a reaction flask and stirred for 5 min at 25-30°C. The reaction mass was heated to 80-85°C and maintained for 2-3h at same temperature. After completion of the reaction, the reaction mass was cooled to at 25-30°C, the obtained product was filtered and washed with acetonitrile (1000 ml) and collected the wet material.

[0051] The above obtained wet material and acetonitrile (1600 ml) were charged into a reaction flask and heated the reaction mass to 80-85°C and maintained for 45 min at same temperature. Then the reaction mass was cooled to 25-30°C, filtered and washed with acetonitrile (1000 ml) and then dried the wet product at 60-65°C under vacuum to get the title compound. Yield: 359.75 g. 94%. Purity: >99% by HPLC.

[0052] Example-6: Process for the preparation of tert-butyl 5-[[2-(3-hydroxyphenyl) quinazolin-4-yl]amino]indazole-l-carboxylate (Formula-9).

[0053] The compound of formula-8 (300 g; 1.0 m.eq.) and aqueous ammonia (3000 ml) were charged into a reaction flask and stirred for 10 min at 25-30°C. Maintained the reaction mass for 30-35h at the same temperature. After completion of reaction, the obtained product was filtered and washed with water (3000 ml) and acetonitrile (600mL) and then dried the wet product under vacuum at 47.5±2.5°C to get the title compound. Yield: 252g; 98%. Purity: >95% by HPLC.

[0054] Example-7: Process for the preparation of tert-butyl 5-[[2-[3-[2-(isopropyl amino)-2-oxo-ethoxy]phenyl]quinazolin-4-yl]amino]indazole-l-carboxylate (Formula- 11).

[0055] The compound of formula-9 (200 g; 1.0 m.eq.) and acetonitrile (4000 ml) were charged into a reaction flask at 25-30°C under nitrogen atmosphere and stirred for 30-45minutes. Potassium phosphate tribasic (188.0 g; 2.0 m.eq.) followed by triethylamine (9.0 g; 0.2 m.eq.) and then compound of formula- 10 (99.4 g; 1.25 m.eq.) were charged into reaction mass at 25-30°C and maintained the reaction mass for 14- 15h at same temperature. After completion of reaction, acetic acid (40.0 g) was charged into the reaction mass and stirred at 25-30°C for 30- 40min.Thereafter, reaction mass was concentrated under vacuum at below 50°C. To the obtained residual mass, charged DM water (4000 ml) and stirred for about 45-60min at 25-30°C. Filtered the crude product and washed with DM water (2000 ml) followed by acetonitrile (400 ml) and dried the crude wet product under vacuum at 55-60°C.

[0056] Charged above obtained compound of formula- 11 crude (210 g) into a reaction flask containing solution of methylene chloride (525.0 ml) and methanol (525 ml) and stirred for 15-20min at 25-30°C. The slurry mass was heated to 40- 45°C and maintained for 60-90 min.Then reaction mass was cooled to 25-30°C and maintained for 60-90 min at 25-30°C. After completion of maintenance, filtered the product and washed with 1: 1 mixture of methylene chloride (105.0 ml) & methanol( 105.OmL) .

[0057] Methylene chloride (420.0 ml), methanol (420.0mL) and above obtained wet compound of formula- 11 were charged into a reaction flask and heated the slurry mass to 40-45°C and maintained for 60-90min. Then the reaction mass was cooled to 25-30°C and maintain for about 60-90 min at same temperature. After completion of maintenance, filtered the product washed with 1: 1 mixture of methylene chloride (105.0 ml) and methanol (105.0 ml). Collected the wet product and dried under vacuum at 55-60°C to get the title compound. Yield: 158.5g; 65%. Purity: >99% by HPLC.

[0058] Example-8: Process for the preparation of 2-{3-[4-(lH-indazol-5-ylamino)-2- quinazolinyl]phenoxy}-N-(propan-2-yl) acetamide (Formula-1):

[0059] The compound of formula-11 (150.0 g; 1.0 m.eq.) and methanol (1200 ml) were charged into a reaction flask and stirred for 15-20 min at 25-30°C. K2CO3 (47 g; 1.25 m.eq.) and methanol (300.0 ml) were charged into reaction mass at 25-30°C and stirred for 15-20 min. Heated the slurry mass to 50-60°C and maintained for 180-210 min. After completion of reaction, cooled the reaction mass to 40-45°C and concentrated the reaction mass under vacuum at below 45°C. Then the reaction mass was cooled to 25-30°C and DM water (3000 ml) was added into reaction mass and stirred for 60-90 min at same temperature. Precipitated-out compound was filtered and washed with DM water (1500 ml) followed by acetonitrile (300 ml) and dried under vacuum at 55-60°C.

[0060] The above crude product of formula- 1 (123g), acetonitrile and water mixture (1230 ml) (prepared by adding 1107 ml of acetonitrile to 123 ml of DM water) were charged into a reaction flask at 25-30°C. Thereafter, heated the slurry mass to 70-75°C and maintained for 60-90 min at same temperature. The reaction mass was cooled to 25-30°C and maintained for about 60-90 min. After completion of maintenance, the product was filtered and washed with acetonitrile (300 ml) and then dried under vacuum at 55-60°C to get the title compound. Yield: 108.5g; 88%. Purity: >99.7 by HPLC.

[0061] BEL / Impurity-I: 0.01%, BEL / Impurity-II: 0.02% & BEL / Impurity-III: <0.01 % by HPLC.

[0062] Example-9: Process for the preparation of 2-{3-[4-(lH-indazol-5-ylamino)-2- quinazolinyl]phenoxy}-N-(propan-2-yl)acetamide mesylate (F ormula-la) :

[0063] The compound of formula- 1 (15 g) and tetrahydrofuran (300 ml) and methanol (150 ml) were charged into a reaction flask at 25-30°C and stirred for 15- 20min. Passed the reaction mass from 0.45p -filter (to make the solution particle free). The filtrate was transferred into another reaction flask and charged tetrahydrofuran (30 ml) and methanol (15 ml) into solution. Heated the reaction mass to 50-55°C and methane sulfonic acid (3.75 g; 1.18 m.eq.) was added to reaction mass at 50-55°C for 10-15 min. Maintained the reaction mass for 2h at same temperature and then cooled to 25-30°C and maintained for 60-90 min. After completion of the maintenance, filter the obtained product and washed with methanol (30 ml).

[0064] Methanol (75 ml) was added to the wet product and stirred the slurry mass for 45-60 min. Filtered and washed the wet material with methanol (30 ml) and dried under vacuum to afford the title compound.

[0065] Yield: 17.3g; 95%. Purity: >99.7% by HPLC.

[0066] BEL / Impurity-I: 0.01%, BEL / Impurity-II: 0.02% & BEL / Impurity-III: <0.01 % by HPLC.

Claims

We Claim:

1. An improved process for the preparation of Belumosudil mesylate compound of formula- la having impurities < 0.05% by HPLC, comprising of: a) Reacting anthranilamide of formula-2,Formula-2 with 3-Hydroxy benzaldehyde of formula-3Formula-3 in presence of Copper chloride dihydrate (CUCI2.2H2O) in a suitable solvent to provide 2-(3-hydroxyphenyl)-3H-quinazolin-4-one hydrochloride of formula-4, optionally purifying the obtained compound with a suitable solvent,Formula-4 b) reacting the compound of formula-4 in-situ with acetic anhydride in presence of a suitable base to provide 2-[3-(Acetyloxy)phenyl]-4(3H)- quinazolinone of formula-5, optionally purifying the obtained compound with a suitable solvent,Formula-5c) reacting the compound of formula-5 with phosphorus oxychloride (POCI3) in presence of a suitable base in a suitable solvent to provide 3-(4-Chloro- 2-quinazolinyl)phenol 1 -acetate of formula-6,d) reacting the compound of formula-6 in-situ with compound of formula-7,Formula-7 in a suitable solvent to provide 5-[[2-[3-(Acetyloxy)phenyl]-4- quinazolinyl] amino] -IH-indazole-l -carboxylic acid 1,1 -dimethylethyl ester hydrochloride of formula-8,e) reacting the compound of formula- 8 with a suitable base to provide tert- butyl 5 - [ [2-(3 -hydroxyphenyl)quinazolin-4-yl] amino] indazole- 1 - carboxylate of formula-9, optionally purifying the obtained compound with a suitable solvent,f) reacting the compound of formula-9 with compound of formula- 10,Formula- 10 in presence of a suitable base in a suitable solvent to provide tert-butyl 5- [[2-[3-[2-(isopropylamino)-2-oxo-ethoxy]phenyl]quinazolin-4-yl]amino] indazole- 1 -carboxylate of formula- 11, optionally purifying the obtained compound with a suitable solvent,g) treating the compound of formula- 11 with a suitable base in a suitable solvent to provide 2- { 3 - [4- ( 1 H-indazol-5-ylamino)-2-quinazolinyl] phenoxy}-N-(propan-2-yl) acetamide of formula-1, optionally purifying the obtained compound with a suitable solvent,Formula- 1 h) reacting the compound of formula- 1 with methanesulfonic acid in a suitable solvent to provide 2-{3-[4-(l / / -indazol-5-ylamino)-2-quinazolinyl] phenoxy}-N-(propan-2-yl) acetamide mesylate of formula-la, optionally purifying the obtained compound with a suitable solvent to get pure compound of formula- la.

2. The process as claimed in claim- 1, wherein,In step (b), (c), (e), (f) & (g) the suitable base used is selected from organic base or inorganic base. The organic base may be selected from triethylamine, diisopropylethylamine, tertiary butylamine, 1,8 -diazabicyclo (5.4.0)undec- 7-ene (DBU) or any other equivalent organic base. The inorganic base may be selected from alkali and alkaline metal acetates or carbonates such as sodium acetate, sodium bicarbonate, sodium carbonate, potassium acetate, potassium bicarbonate, potassium carbonate, cesium carbonate, alkali metal phosphates such as tribasic potassium phosphate or Tripotassium phosphate (K3PO4) or any other equivalent base.In step-a to step-h) the suitable solvent is selected from alcoholic solvents, polar- aprotic solvents, hydrocarbon solvents, ester solvents, ether solvents, ketone solvents, chloro solvents, nitrile solvents and polar solvents such as water or mixtures thereof.

3. The process as claimed in claim-1, comprising of: a) Reacting anthranilamide of formula-2 with 3 -Hydroxy benzaldehyde of formula-3 in presence of Copper chloride dihydrate (CUCI2.2H2O) in isopropyl alcohol to provide 2-(3-hydroxyphenyl)-3H-quinazolin-4-onehydrochloride of formula-4, purifying the obtained compound with methyl tert-butyl ether to provide pure compound of formula-4, b) reacting the compound of formula-4 in-situ with acetic anhydride in presence of triethylamine to provide 2-[3-(acetyloxy)phenyl]-4(3H)- quinazolinone of formula-5, purifying the obtained compound with DM water to provide pure compound of formula-5, c) reacting the compound of formula-5 with phosphorus oxychloride (POCI3) in presence of N,N-diethylaniline in toluene to provide 3-(4-Chloro-2- quinazolinyl)phenol 1 -acetate of formula-6, d) reacting the compound of formula-6 in-situ with compound of formula-7 in acetonitrile to provide 5-[[2-[3-(Acetyloxy)phenyl]-4-quinazolinyl] amino] -IH-indazole-l -carboxylic acid 1,1 -dimethylethyl ester hydrochloride of formula- 8, e) reacting the compound of formula-8 with aqueous ammonia to provide tertbutyl 5 - [ [2-(3 -hydroxyphenyl)quinazolin-4-yl] amino] indazole- 1 - carboxylate of formula-9, purifying the obtained compound with water to provide pure compound of formula-9, f) reacting the compound of formula-9 with compound of formula- 10 in presence of potassium phosphate tribasic and triethylamine in acetonitrile to provide tert-butyl 5-[[2-[3-[2-(isopropylamino)-2-oxo-ethoxy]phenyl] quinazolin-4-yl]amino]indazole-l -carboxylate of formula-11, purifying the obtained compound with a 1 : 1 mixture of methylene chloride and methanol to provide pure compound of formula-11, g) treating the compound of formula- 11 with potassium carbonate in methanol to provide 2-{3-[4-(l / Z-indazol-5-ylamino)-2-quinazolinyl] phenoxy]-N- (propan-2-yl) acetamide of formula- 1, purifying the obtained compound with acetonitrile and water to provide pure compound of formula- 1, h) reacting the compound of formula- 1 with mathanesulfonic acid in tetrahydrofuran and methanol to provide 2-{3-[4-(l / Z-indazol-5-ylamino)- 2-quinazolinyl]phenoxy]-N-(propan-2-yl)acetamide mesylate of formula-la, purifying the obtained compound with methanol to get pure compound of formula- la.

4. The process as claimed in claim- 1 , wherein the process for the preparation of 2- (3-hydroxyphenyl)-3H-quinazolin-4-one hydrochloride of formula-4, comprising of reacting anthranilamide of formula-2 with 3 -Hydroxy benzaldehyde of formula-3 in presence of Copper chloride dihydrate (CUCI2.2H2O) in isopropyl alcohol to provide 2-(3-hydroxyphenyl)-3H- quinazolin-4-one hydrochloride of formula-4, purifying the obtained compound with methyl tert-butyl ether to provide pure compound of formula-4.

5. A process for the preparation of crystalline form of Belumosudil mesylate compound of formula- la, comprising of: a) Adding a solvent to Belumosudil of formula- 1, b) heating and stirring the reaction mixture, c) adding methanesulfonic acid to solution of step-(b), d) stirring and cooling the reaction mixture, e) filtering, washing and drying the compound to get the crystalline form of Belumosudil mesylate of formula-la.

6. The process as claimed in claim-5, wherein in step-a) the suitable solvent is selected from ether solvents, chloro solvents, ester solvents, alcohol solvents, ketone solvents, polar aprotic solvents, hydrocarbon solvents, nitrile solvents and polar solvents or mixtures thereof.

7. The process as claimed in claim-5, comprising of: a) Adding a mixture of tetrahydrofuran and methanol to Belumosudil of formula- 1, b) heating and stirring the reaction mixture, c) adding methanesulfonic acid to solution of step-(b), d) stirring and cooling the reaction mixture,e) filtering, washing and drying the compound to get the crystalline form of Belumosudil mesylate of formula-la.

8. The 2-(3-hydroxyphenyl)-3H-quinazolin-4-one hydrochloride of formula-4 having the structure of:Formula-49. The process as claimed in claim- 1, wherein the Belumosudil mesylate compound of formula- la having BEL / Impurity-I: <0.02% or BEL / Impurity-II: <0.03 % or BEL / Impurity-III: <0.01 % by HPLC.

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