Field of the invention:

The present invention relates to an improved process for the preparation of 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino] -2-pyrimidinyl] amino] -2-methylbenzenesulfonamide or its pharmaceutically acceptable salts preferably hydrochloride salt represented by the compound of formula-I and its polymorphic forms.

5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methylbenzene sulfonamide hydrochloride is generally known as Pazopanib hydrochloride is a tyrosine kinase inhibitor which is indicated for the treatment of patients with advanced renal cell carcinoma and advanced soft-tissue sarcoma. Pazopanib hydrochloride is manufactured and marketed by GlaxoSmithKline (GSK) under the brand name VOTRIENT® in US and Europe.

Background of the Invention:

5 - [ [4- [(2,3 -dimethyl-2H-indazol-6-yl)methylamino] -2-pyrimidinyl] amino] -2-methylbenzene sulfonamide hydrochloride and its process for the preparation was first disclosed in US 7,105,530 (herein after referred as '530' patent). According to the process disclosed in '530' patent involves the methylation of 3-methyl-6-nitro-2H-indazole with trimethyloxoniurn tetrafluoroborate in acetone to give 2,3-dimethyl-6-nitro-2H-indazole, then followed by reduction with tin(II) chloride in presence of conc.HCl in 2-methoxyethyl ether to give HC1 salt of 2,3-dimethyl-2H-indazol-6-amine. Condensation of 2,3-dimethyl-2H-indazol-6-amine with 2,4-dichloropyrimidine in presence of sodium bicarbonate in mixture of THF and ethanol gives N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine which is then reacted with methyl iodide in presence of cesium carbonate in dimethyl formamide (DMF) to give N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine. Condensation of N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine with 5-amino-2-methylbenzenesulfonamide isopropanol and conc.HCl and then further dilution with diethyl ether to give Pazopanib hydrochloride as an off-white solid.

The process disclosed in the '530' patent involves the usage of costly and hazardous reagents and solvents such as trimethyloxoniumtetrafluoroborate, tin(II)chloride and 2-methoxyethylether and ethanol. The usage of above reagents and solvents for the preparation of Pazopanib HC1 on commercial level is unpractical and generates undesirable waste and by-products.

Later US2006/0252943 (herein after referred as '943' application) disclosed the different procedures for the methylation of 3-methyl-6-nitro-2H-indazole by using trimethyloxoniumtetra fluoroborate or trimethylorthoformate in presence of borontrifluoride-etherate or by using dimethyl sulfate and reduction of 2,3-dimethyl-6-nitro-2H-indazole by using tin (II) chloride in presence of conc.HCl or by hydrogenation in presence of Pd/C. '943' application also disclosed the several processes for the preparation of Pazopanib hydrochloride by condensing the N-(2-chloro pyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine with 5-amino-2-methylbenzenesulfonamide in presence of 1,4-dioxane.hydrochloric acid and in different solvents such as ethanol, methanol, tetrahydrofuran and acetonitrile. '943' application also disclosed the process for the preparation of Pazopanib hydrochloride monohydrate by reacting the Pazopanib HC1 with 0.05N hydrochloric acid in isopropanol solvent.

The process disclosed in the '943' application is also having significant drawbacks in manufacturing of Pazopanib HC1 on commercial scale such as usage of highly carcinogenic solvents such as 1,4-dioxane and costly reagents such as tin(II) chloride, cesium carbonate and trimethyloxoniumtetrafluoroborate and hazardous reagents such as Pd/C and borontrifluoride-etherate. Hence, there is a need in the art for replacing the environmentally hazardous and highly toxic solvents and reagents such as 1,4-dioxane and Pd/C and borontrifluoride-etherate with environmentally friendly solvents and reagents.

WO2011/058179, WO2012/073254 and WO2011/069053 disclosed the various processes for the preparation of Pazopanib HC1 and different crystalline forms of Pazopanib free base and its hydrochloride salts.

US2012/0197019 and WO2007/143483 disclosed the process for the preparation of anhydrous crystalline Form-I of Pazopanib hydrochloride from Pazopanib hydrochloride hydrate, and IPCOM000202288D journal also reported the VOTRIENT tablet analysis and characterized the crystalline form (Form-I) in the tablet by powder X-ray diffractogram.

The inventors of the present application had repeated the process disclosed the prior art and found that the usage of sodium bicarbonate, sodium carbonate and potassium carbonate in condensation of 2,3-dimethyl-2H-indazol-6-amine with 2,4-dichloropyrimidine resulted in incomplete reactions and the coupled product was obtained as impure. Also, the usage of tin(II)chloride or hydrogenation by using Pd/C catalyst or Raney-Ni catalyst in reduction of 2,3-dimethyl-6-nitro-2H-indazole resulted in the formation of emulsions and side-products and low yields were observed.

Despite of its toxicity, the present inventors have found that the usage of HC1 in 1,4-dioxane for the preparation of Pazopanib HC1 resulted in the formation of more impurities and the so formed impurities were not washed out easily and giving the product with low yield and quality.

Therefore, there is a need in the art for an improved process for the preparation of Pazopanib hydrochloride with high yield and purity. Brief Description of the Invention:

The first aspect of the present invention provides an improved process for reducing the 2,3-dimethyl-6-nitro-2H-indazole compound of formula-Ill by using a suitable reducing agent to provide 2,3-dimethyl-2H-indazol-6-amine having compound of formula-IV and optionally converting the compound of formula-IV into its hydrochloride salt.

The second aspect of the present invention provides an improved process for the preparation of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine compound of formula-V or its salts comprising reacting the 2,3-dimethyl-2H-indazol-6-amine compound of formula-IV or its hydrochloride salt with 2,4-dichloropyrimidine in the presence of an suitable organic base in a suitable solvent to provide the N-(2-chloropyrimidin -4-yl)-2,3-dimethyl-2H-indazol-6-amine compound of formula-V or its salts.

The third aspect of the present invention provides an improved process for the preparation of Pazopanib hydrochloride comprising condensing N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine compound of formula-VI with 5-amino-2-methylbenzenesulfonamide in presence of a suitable hydrochloric acid source and in a suitable solvent to provide the Pazopanib hydrochloride.

The fourth aspect of the present invention provides an improved process for the preparation of Pazopanib hydrochloride comprising of:

a) Reacting the 3-methyl-6-nitro-2H-indazole of formula-II with a suitable methylating agent in a suitable solvent to provide the 2,3-dimethyl-6-nitro-2H-indazole of formula-Ill,

b) reducing the compound of formula-Ill with a suitable reducing agent in a suitable solvent to produce the 2,3-dimethyl-2H-indazol-6-amine of formula-IV, and then optionally converting the compound of formula-IV into its hydrochloride salt,

c) condensing the compound of formula-IV or its hydrochloride salt with 2,4-dichloropyrimide in presence of suitable organic base in a suitable solvent to provide the N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine compound of formula-V,

d) methylating the compound of formula-V with a suitable methylating agent in a suitable solvent to provide the N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine compound of formula-VI,

e) condensing the compound of formula-VI with 5-amino-2-methylbenzenesulfonamide in presence of suitable hydrochloric acid source and in a suitable solvent to provide Pazopanib hydrochloride.

The fifth aspect of the present invention provides an improved process for the preparation of anhydrous crystalline form of Pazopanib hydrochloride (Form-I) comprising of,

a) Adding the Pazopanib hydrochloride monohydrate in alcohol or ketone solvents or mixture thereof,

b) heating the reaction mixture of step a) and,

c) cooling the reaction mixture of step b) and,

d) isolating the crystalline anhydrous Pazopanib hydrochloride (Form-I).

Brief description of the drawings:

Figure-1: Illustrates the X-Ray powder diffraction pattern of crystalline monohydrate of Pazopanib
hydrochloride.

Figure-2: Illustrates the X-Ray powder diffraction pattern of anhydrous crystalline form of
Pazopanib hydrochloride (Form-I).

Figure-3: Illustrates the X-Ray powder diffraction pattern of crystalline form of Pazopanib
hydrochloride obtained according to example-6.

Detailed description of the invention:

As used herein the present invention, the term "suitable solvent" refers to the solvent selected from "polar solvents" such as water; "polar aprotic solvents" such as dimethylsulfoxide, dimethylacetamide, dimethyl formamide and the like; "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile and isobutyronitrile and the like; "ether solvents" such as di-tert-butylether, diethylether, diisopropyl ether, 1,4-dioxane, methyltert-butylether, ethyl tert-butyl ether, tetrahydrofuran and dimethoxyethane; "alcohol solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol and t-butanol and the like; "chloro solvents" such as methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform, chloro benzene and the like; "hydrocarbon solvents" such as benzene, toluene, xylene, heptane, hexane and cyclohexane; "ketone solvents" such as acetone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like; "esters solvents" such as ethyl acetate, methyl acetate, n-butylacetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like; and their mixtures thereof.

As used herein the present invention, the term "base" refers to inorganic or organic base. According to the present invention, the examples of "inorganic base" include, but are not limited to, hydrides, hydroxides, carbonates, bicarbonates, oxides, carboxylates, and alkoxides of alkali or alkaline earth metals, such as lithium hydride, sodium hydride, potassium hydride, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, cesium carbonate, calcium oxide, and barium oxide or ammonium hydroxide. Alkali metal bicarbonates such as sodium bicarbonate and potassium bicarbonate; alkali metal alkoxides such as sodium methoxide, potassium methoxide, sodium tertiary butoxide, potassium tertiary butoxide or mixtures thereof.

According to the present invention, the examples of "organic base" include, but are not limited to, triethylamine, diisopropylamine, N,N-diisopropylethylamine (Hunig's base) , DABCO, triethanol amine, tributyl amine, pyridine, lutidine, 4-dimethylaminopyridine (DMAP), diethanolamine, 4-methylmorpholine, dimethylethanolamine, tetramethyl guanidine, tetramethyl ammonium hydroxide, tetraethyl ammonium hydroxide, N-methyl-l,5,9-triazabicyclo[4.4.0]decene, 1 ,8- diazabicyclo [5.4.0]undec-7-ene, dicyclohexyl amine, picoline and dicyclohexylamine.

According to the present invention, the examples of suitable "reducing agent" is selected from iron(III)chloride/Hydrazine , Fe/acetic acid, Fe/HCl, Fe/NH4C1, iron(II)chloride, iron(III)oxide/ hydrazine, iron(III)-MgO/hydrazine, Zn, Zn in acidic media like HC1 or NH4CI or acetic acid, NaBH4 with catalytic NiCl2.6H20 or CoCl2.6H20, Lithium borohydride, diborane, Sodium aluminium hydride, hydrazine hydrate, sodiumdithionate, sodium sulfide, ammonium sulfide, hydrogenation catalysts such as nickel, Raney nickel, rhodium, Pd-C combined with borohydrides , cyclohexene , acidic media like formic acid, H3P02 etc., Raney cobalt, Raney iron, lithium aluminum hydride, sodium amalgam, platinum oxide, borane- tetrahydrofuran complex and the like in combination with hydrogen and the like.
According to the present invention, the non-limiting example of suitable "methylating agent" is selected from dimethyl sulfate, methyl iodide, dimethyl carbonate, trimethylorthoformate, and the like.
According to the present invention, the suitable hydrochloric acid source is selected from aqueous hydrochloric acid, gaseous hydrochloric acid, dimethylformamide.HCl, methanolic HC1, ethylacetate.HCl, Isopropanolic HC1 and ether.HCl and the like.

The first aspect of the present invention provides an improved process for the preparation of 2,3-dimethyl-2H-indazol-6-amine compound of formula-IV or its hydrochloride salt comprising of:

a) reducing the 2,3-dimethyl-6-nitro-2H:-indazole compound of formula-Ill;

Formula-Ill by using a suitable reducing agent in a suitable solvent to provide 2,3-dimethyl-2H-indazol-6- amine having compound of formula-IV;

Formula-IV

b) optionally reacting the compound of formula-IV with a suitable hydrochloric acid source in
a suitable solvent to provide the 2,3-dimethyl-2H-indazol-6-amine.hydrochloride.

Wherein in step-a), the suitable reducing agent is selected form Hydrazine hydrate /iron(III)chloride , Fe/acetic acid, Fe/HCl, Fe/NRtCl, iron(II)chloride, iron(III)oxide/ hydrazine, Zn, Zn in acidic media like HC1 or NH4C1 or acetic acid, NaBH4 with catalytic NiCl2.6H20 or C0O2.6H2O, Lithium borohydride, diborane, Sodium aluminium hydride, hydrazine hydrate, sodiumdithionate, sodium sulfide, ammonium sulfide, hydrogenation catalysts such as nickel, Raney nickel, rhodium, Pd-C combined with borohydrides , cyclohexene , acidic media like formic acid, H3PO2 etc., Raney cobalt, Raney iron, lithium aluminum hydride, sodium amalgam, platinum oxide, borane-tetrahydrofuran complex and the like in combination with hydrogen; and the preferred reducing agent is hydrazine hydrate/ iron(III)chloride; and the suitable solvent is selected from water, alcohol solvents, chloro solvents, keto solvents or mixtures thereof. The preferred solvent is water or alcoholic solvents or mixture thereof.

Wherein in step-b) the suitable hydrochloric acid (HC1) source is selected from aqueous. Hydrochloric acid, gaseous hydrochloric acid, methanolic HC1, ethylacetate. HC1, Isopropanolic HC1 and the preferred hydrochloric acid (HC1) source is Isopropanolic HC1 ; and the suitable solvent is selected from water, alcoholic solvents, chloro solvents, ester solvents or keto solvents or mixture thereof. The more preferred solvents are alcohol solvents or chloro solvents or mixture thereof.

The preferred embodiment of the present invention provides an improved process for the preparation of hydrochloride salt of 2,3-dimethyl-2H-indazol-6-amine comprising of:

a) Reducing the 2,3-dimethyl-6-nitro-2H-indazole of formula-Ill with iron(III)chloride in presence of hydrazine hydrate in mixture of water and methanol to provide the 2,3-dimethyl-2H-indazol-6-amine compound of formula-IV,

b) reacting the compound of formula-IV with isopropanolic hydrochloric acid in a mixture of dichloromethane and isopropanol to provide the hydrochloride salt of 2,3-dimethyl-2H-indazol-6-amine.
The second aspect of the present invention provides an improved process for the preparation of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine compound of formula-V comprising of;

Formula-V condensing the 2,3-dimethyl-2H-indazol-6-amine compound of formula-IV or its hydrochloride salt with 2,4-dichloropyrimidine in the presence of suitable organic base in a suitable solvent to provide N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine compound of formula-V.

According to the above aspect, wherein the suitable organic base is selected from triethylamine, diisopropylamine, diisopropylethylamine, tert.butylamine, pyridine, 2,6-lutidine, Dimethylamino pyridine (DMAP), N-methylmorpholine and the suitable solvent is selected from water, alcoholic solvents, chloro solvents, ester solvents, keto solvents or mixture thereof, preferably alcohol solvents.

The preferred embodiment of the of the present invention provides an improved process for the preparation of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine of formula-V, comprising of condensing the hydrochloride salt of 2,3-dimethyl-2H-indazol-6-amine with 2,4-dichlorpyrimidine in the presence of triethylamine in methanol to provide the N-(2-chloro pyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine compound of formula-V.

The third aspect of the present invention provides an improved process for the preparation of Pazopanib hydrochloride comprising condensing the N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine compound of formula-VI;

Formula-VI with 5-amino-2-methylbenzenesulfonamide in presence of a suitable hydrochloric acid source and in a suitable solvent to provide the Pazopanib hydrochloride.

According to the above aspect, the suitable hydrochloric acid source is selected from HC1 in DMF.HC1, methanolic HC1, ethylacetate. HC1, Isopropanolic HC1 and the preferred hydrochloric acid (HC1) source is DMF.HC1; and the suitable solvent is selected from water, alcoholic solvents, keto solvents, chloro solvents, polar aprotic solvents, ester solvents or mixture thereof, preferably mixture of alcohol solvents and polar aprotic solvents and more preferably mixture of methanol and dimethyl formamide.

In a preferred embodiment of the above aspect, the present invention provides an improved process for the preparation of Pazopanib hydrochloride comprising; condensing the N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine compound of formula-VI with 5-amino-2-methylbenzenesulfonamide in presence of dimethylformamide-hydrochloric acid (DMF-HC1) in methanol to provide the Pazopanib hydrochloride.

J.Pharm.Biomed. Analysis 52 (2010) 493-507 and J.Pharm.Biomed. Analysis 50 (2009) 144-150 disclosed the presence of five genotoxic impurities in Pazopanib hydrochloride which are obtained from starting materials and reagents and intermediates used in the synthesis of Pazopanib hydrochloride. The presence of impurities in Pazopanib hydrochloride or in any other active pharmaceutical ingredient (API) is undesirable and in extreme cases these genotoxic impurities, might even be harmful to a patient treating with dosage form containing API.

In supporting to the above third aspect, the below table clearly distinguished the substantial improvement between the prior reported process for the preparation of Pazopanib hydrochloride (using 1,4-dioxane.HCl) over the present invention for the preparation of Pazopanib hydrochloride (using DMF.HC1).
The fourth aspect of the present invention provides an improved process for the preparation of Pazopanib hydrochloride compound of formula-I comprising of:

a) Reacting the 3-methyl-6-nitro-2H-indazole of formula-II;
Formula-II

with a suitable methylating agent in a suitable solvent to provide the 2,3-dimethyl-6-nitro-2H-indazole of formula-Ill,

Formula-Ill b) reducing the compound of formula-Ill with a suitable iron reducing agent in a suitable solvent to produce the 2,3-dimethyl-2H-indazol-6-amine of formula-IV, rui.iiiuia.-i v
optionally converting the compound of formula-IV into its hydrochloride salt, c) condensing the compound of formula-IV or hydrochloride salt with 2,4-dichloropyrimidine in presence of suitable organic base in a suitable solvent to provide the N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine compound of formula-V,

d) methylating the compound of formula-V with a suitable methylating agent in presence of suitable base and in a suitable solvent to provide the N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine compound of formula-VI,

Formula-VI e) condensing the compound of formula-VI with 5-amino-2-methylbenzenesulfonamide in presence of suitable hydrochloric acid source and in a suitable solvent to provide Pazopanib hydrochloride compound of formula-I.

Wherein, in step-d) the suitable methylating agent is selected from methyliodide, dimethyl sulfate, dimethylcarbonate; preferably methyl iodide; the suitable base is selected from inorganic base such as metal carbonates such as sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate or organic base such as triethylamine, diisopropylamine, diisopropyl ethylamine (DIPEA), pyridine and 2,6-lutidine, Dimethylaminopyridine (DMAP) or mixture thereof.

The preferred embodiment of the present invention provides an improved process for the preparation of Pazopanib hydrochloride comprising of;

a) Reacting the 3-methyl-6-nitro-2H-indazole of formula-II with dimethyl sulfate in a mixture of dimethylsulfoxide and dimethylformamide to provide the 2,3-dimethyl-6-nitro-2H-indazole of formula-Ill,

b) reducing the compound of formula-Ill with hydrazine hydrate in presence of iron (Ill)chloride in mixture of methanol and water to produce the 2,3-dimethyl-2H-indazol-6-amine of formula-IV,

c) reacting the compound of formula-IV with isopropanolic HC1 to provide the hydrochloric acid salt of 2,3-dimethyl-2H-indazol-6-amine,

d) condensing the hydrochloric acid salt of 2,3-dimethyl-2H-indazol-6-amine with 2,4-dichloropyrimidine in presence of triethylamine in methanol to provide the N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine compound of formula-V,

e) methylating the compound of formula-V with methyliodide in presence of potassium carbonate in dimethylsulfoxide to provide the N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine compound of formula-VI,

f) condensing the compound of formula-VI with 5-amino-2-methylbenzenesulfonamide in presence of hydrochloric acid in mixture of dimethylformamide and methanol to provide Pazopanib hydrochloride.
In yet another embodiment of the present invention provides a process for the preparation of Pazopanib hydrochloride monohydrate comprising of, reacting the Pazopanib hydrochloride with aqueous hydrochloric acid in isopropyl alcohol to provide the Pazopanib hydrochloride monohydrate.

The fifth aspect of the present invention provides an improved process for the preparation of anhydrous crystalline form of Pazopanib hydrochloride (Form-I) comprising of,

a) Adding the Pazopanib hydrochloride monohydrate to alcohol or ketone solvents or mixture thereof,

b) heating the mixture of step a) and,

c) cooling the mixture of step b) and,

d) isolating the crystalline anhydrous Pazopanib hydrochloride (Form-I).

wherein in step-s) the alcohol solvent is selected from methanol, ethanol, isopropanol or n-butanol or mixture thereof, and the ketone solvent is selected from acetone, methylisobutylketone (MIBK), methyl ethyl ketone (MEK) or mixtures thereof; in step-b) the suitable temperature for heating the reaction mixture is ranging from about 25°C to reflux temperature of the solvent used; in step-c) the suitable temperature for cooling the reaction mixture is between -10°C to 30°C, preferably 0°C to 30°C.

In a preferred embodiment of the above aspect, the present invention provides an improved process for the preparation of anhydrous crystalline form of Pazopanib hydrochloride (Form-I) comprising of,

a) Adding the Pazopanib hydrochloride monohydrate to methanol solvent,

b) heating the reaction mixture of step a) to a temperature of 60-65°C,

c) cooling the mixture of step b) to a temperature of 20-30°C,

d) isolating the crystalline anhydrous Pazopanib hydrochloride (Form-I).

PXRD analysis of anhydrous crystalline form of Pazopanib hydrochloride (Form-I) and crystalline monohydrate of Pazopanib hydrochloride were analyzed using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A0 and continuous scan speed of 0.037min.
Pazopanib hydrochloride as produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying or after the completion of drying of the product.

The particle size distribution of Pazopanib hydrochloride compound of formula-I is measured under the following conditions:

Instrument: Malvern Mastersizer 2000; Measuring range: 0.02 to 2000 urn; Wet sampler: Hydro 2000S (A); Dispersant: cyclohexane; Refractive Index of cyclohexane: 1.427; Refractive index of particle: 1.650; Obscuration range: 14.65%; Sensitivity: normal.

The present invention schematically represented as follows in Scheme-I:

The best mode of carrying out the present invention is 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.

Examples:
Example-1: Preparation of 2,3-dimethyl-6-nitro-2H-indazole compound of formula-Ill
To a solution of 3-Methyl-6-nitro-2H-indazole of formula-II (30g) in mixture of dichloromethane (150ml) and dimethylsulfoxide (30ml), dimethyl sulfate (30ml) was added at 30°C and heated the reaction mixture to 40-45°C and stirred for 12 hrs at same temperature. After completion of the reaction, cooled the reaction mixture 15-20°C and 150 ml of sodium carbonate (dissolve 10.5 g of Na2C03 in 150 ml of water) solution was slowly added to it and stirred for 10 . min. Organic and aqueous layers were separated and aqueous layer was extracted with dichloromethane. The total organic layers were combined and washed with water then dried the organic layer with sodium sulfate. Distilled of the solvent completely from organic layer under reduced pressure. Isopropyl alcohol was added to the obtained solid and then cooled the reaction mixture to 15-20°C and stirred the reaction mixture for 30 min at 15-20°C. Filtered the precipitated solid and washed with cyclohexane and dried the solid to get the title compound. Yield: 22.5 gm.

Example-2: Preparation of 2,3-dimethyl-2H-indazol-6-amine hydrochloride compound of formula-IV.
To a solution of 2,3-dimethyl-6-nitro-2H-indazole of formula-Ill (35g) in a mixture of methanol (175 ml) and water (105 ml), hydrazine hydrate (17.5 ml) and ferric chloride (0.89 g) was charged and heated the reaction mixture to 65-75°C. Stirred the reaction mixture for 8 hrs at the same temperature. After completion of the reaction, the reaction mixture was cooled to 40-45°C and filtered the reaction mixture through hiflow bed and distilled off the solvent completely from filtrate under reduced pressure. Water was added to the obtained compound and distilled the reaction mixture. Cooled the reaction mixture to 20-30°C. Dichloromethane (175 ml) was added to the reaction mixture and stirred for 10 min then both the organic and aqueous layers were separated.. 3.5 g of charcoal was added to the organic layer and stirred for 20 min at 25-30°C. Filtered the reaction mixture through hiflow bed and distilled off the solvent from filtrate completely under reduced pressure. 105 ml of isopropanol and 35 ml of dichloromethane was charged to the obtained compound and stirred for 15 min. To this solution, 42 ml of isopropanolic hydrochloride solution was added and cooled the reaction mixture to 0-5°C and stirred the reaction mixture for 2 hrs at same temperature. Filtered the precipitated solid and then washed with isopropanol and dried the obtained solid to get the title compound.

Yield: 30.33g

Example-3: Preparation of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine
compound of formula-V.

2,4-Dichloropyrimidine (30g) was added to a mixture of 2,3-dimethyl-2H-indazol-6-amine hydrochloride (30 g) and triethylamine (46g) in methanol (90 ml) at 20-25°C and stirred the reaction mixture for 10 min at same temperature. Heated the reaction mixture to 65-75°C and stirred the reaction mixture for 4 hrs at 65-75°C. After completion of the reaction, cooled the reaction mixture to 45-50°C and distilled off the solvent from reaction mixture under reduced pressure. 300 ml of water was added to the reaction mixture and stirred for 1.5 hrs at 15-20°C, then filtered the precipitated solid obtained and washed with water. Methanol was added to the obtained wet solid and stirred the reaction mixture for 45 min. filtered the reaction mixture and dried the compound to get the title compound. Yield: 33.6 g

Example-4: Preparation of N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine compound of formula-VI.

45.4 g of potassium carbonate was added to a solution of 30 g of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine in 90 ml of dimethyl formamide at 20-25°C. 34.2 g of methyliodide was added to the reaction mixture heated the reaction mixture to 30-3 5 °C and stirred the reaction mixture for 6 hrs at 20-25°C. After completion of the reaction, cooled the reaction mixture to 10-15°C and slowly charged 750 ml of water to the reaction mixture and stirred the reaction mixture for 1 hr at 10-15°C, then filtered the compound and washed with water. Dried the solid obtained to get the title compound. Yield: 19.6 g.
Example-5: Preparation of N-(2-chloropyrimidin-4-yl)-N,23-trimethyl-2H-indazol-6-amine compound of formula-VI.

48 g of potassium carbonate was added to a stirred solution of 24 g of N-(2-chloropyrimidin -4-yl)-2,3-dimethyl-2H-indazol-6-amine in 192 ml of dimethylsulfoxide at 25-30°C. 25 g of methyliodide was added to the reaction mixture and heated the reaction mixture to 30-35°C and stirred the reaction mixture for 4 hrs at same temperature. After completion of the reaction, cooled the reaction mixture to 10-15°C and slowly charged 600 ml of water to the reaction mixture and stirred the reaction mixture for 1 hr at 10-15°C, then filtered the compound and washed with water.

Dried the solid obtained to get the title compound.
Yield: 18.26 g.

Example-6: Preparation of Pazopanib hydrochloride compound of formula-I.
To a mixture of N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine (20g) and 2-methyl-5-amino-benzenesulfonamide (13.3g) in methanol (100ml), added 40 ml of HC1 in DMF (9.8 ml of conc.HCl dissolved in 30.2ml of dimethylformamide) at 20-30°C. Heated the reaction mixture to 65-75°C and stirred the reaction mixture for 5hrs at same temperature. After completion of the reaction, cooled the reaction mixture to 0-5°C and stirred for 1.5hr at same temperature then filtered the precipitated solid and washed with methanol and dried the solid obtained to get the title compound.

Yield: 29.7 g, Purity: 99.71 % by HPLC; PXRD: Figure-3. Example-7: Preparation of crystalline form of Pazopanib hydrochloride monohydrate.

To a solution of 45.0 g of Pazopanib hydrochloride in 630 ml of isopropanol was added 243 ml of 0.005N HC1 solution at 75-80°C and stirred the reaction mixture for 20 min at same temperature. 4.5 g of charcoal was added to the reaction mixture and stirred the reaction mixture for 20 min at 75-80°C and the reaction mixture was filtered. The obtained filtrate was heated to 70-80°C and cooled the filtrate to 60-65°C and seeded with Pazopanib hydrochloride monohydrate to at 60-65°C. Stirred the reaction mixture for 2 hrs at 60-65°C and cooled the reaction mixture to 0-5°C and stirred for 60 min at the same temperature. Filtered the reaction mixture and solid was washed with isopropanol and dried the obtained solid provides crystalline monohydrate of Pazopanib hydrochloride.

Yield : 38.5g, PXRD : Figure-1, water content: 4.5% Example-8: Preparation of anhydrous crystalline form of Pazopanib hydrochloride (Form-I)

270 ml of methanol was added to the obtained 38.5 g Pazopanib hydrochloride monohydrate obtained in example-7 and heated the reaction mixture to 60-65°C and stirred the reaction mixture for 5 hrs at same temperature .Cooled the reaction mixture to 25-30°C and stirred the reaction mixture for 30 min at 25-30°C and filtered the reaction mixture and the compound was washed with methanol and dried the obtained solid to get the title compound. Yield: 35.5 g, PXRD: Figure-2; Purity: 99.94% by HPLC.

Example-9: Preparation of anhydrous crystalline form of Pazopanib hydrochloride (Form-I)
To a solution of 45.0 g of Pazopanib hydrochloride in 630 ml of isopropanol was added 243 ml of 0.005N HC1 solution at 75-80°C and stirred the reaction mixture for 20 min at same temperature. 4.5 g of charcoal was added to the reaction mixture and stirred the reaction mixture for 20 min at 75-80°C and the reaction mixture was filtered. The obtained filtrate was heated to 70-80°C and cooled the filtrate to 60-65°C and seeded with Pazopanib hydrochloride monohydrate and stirred the reaction mixture for 2 hrs at 60-65 °C and slowly cooled the reaction mixture to 0-5 °C. Filtered the reaction mixture and compound was washed with isopropanol. 270 ml of methanol was added to the wet compound and heated the reaction mixture to 60-65°C and stirred the reaction mixture for 5 hrs at same temperature. Cooled the reaction mixture to 25-30°C and stirred the reaction mixture for 30 min at 25-30°C and filtered the reaction mixture and solid was washed with methanol and dried the obtained solid to get the title compound
Yield: 33.75g, PXRD: Figure-2, Purity: 99.94% by HPLC, Particle size distribution: Di0:2.919 urn, Ds0: 7.17um, D90: 17.524 urn, D (4,3):8.943 um.

We Claim:

1. A process for the preparation of N-(2-chloropyrirnidin-4-yl)-2,3-dirnethyl-2H-indazol-6-amine
compound of formula-V, comprising condensing the 2,3-dimethyl-2H-indazol-6-amine compound of formula-IV or its hydrochloride salt,

Formula-IV with 2,4-Dichlorpyrimidine in the presence of an organic base and in a suitable solvent to provide the N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine compound of formula-V,

Formula-V wherein the organic base is pyridine, 2,6-lutidine,triethylamine, diisopropylamine, diisopropyl ethylamine (DIPEA), dimethylaminopyridine (DMAP), 4-methylmorpholine.

2. The process according to claim 1, wherein the organic base is triethylamine and the suitable solvent is selected from alcohol solvents such as methanol, ethanol, isopropanol, n-butanol or mixture thereof.

3. A process for the preparation of 2,3-dimethyl-2H-indazol-6-amine compound of formula-IV or its hydrochloride salt comprising of;

a) Reducing the 2,3-dimethyl-6-nitro-2H-indazole compound of formula-Ill;

Formula-Ill with a suitable reducing agent in a suitable solvent to obtain the 2,3-dimethyl-2H-indazol-6-amine compound of formula-IV,

b) optionally reacting the compound of formula-IV with a suitable hydrochloric acid source to obtain the 2,3-dimethyl-2H-indazol-6-amine.hydrochloride.

4. The process according to claim 3, wherein step-a) the suitable iron catalyst is selected from iron(III)chloride/Hydrazine , Fe/acetic acid, Fe/HCl, Fe/NH4C1, iron(II)chloride, iron(III)oxide/ hydrazine; preferably hydrazine hydrate in presence of iron (Ill)chloride (iron(III)chloride/hydrazine hydrate) and the suitable solvent is selected from water or alcohol solvents or mixture thereof, wherein step-b) the suitable hydrochloric acid source is selected from dimethylformamide . hydrochloric acid (DMF.HC1), methanolic HC1, ethylacetate. HC1, isopropanolic HC1 and the preferred hydrochloric acid (HC1) source is dimethylformamide . hydrochloric acid (DMF.HC1)

5. A process for the preparing Pazopanib hydrochloride comprising, condensing the N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine compound of formula-VI;
Formula-VI with 5-amino-2-methylbenzenesulfonamide in presence of suitable hydrochloric acid source and in a suitable solvent to obtain the Pazopanib hydrochloride, wherein the suitable hydrochloric acid is selected from dimethyl formamide. hydrochloric acid (DMF.HC1), methanolic HC1, ethylacetate. HC1, isopropanolic HC1; wherein the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents or mixture thereof.

A process for the preparing Pazopanib hydrochloride comprising, condensing the N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine compound of formula-VI with 5-amino-2-methylbenzenesulfonamide in presence of Dimethylformamide-hydrochloric acid (DMF.HC1) in methanol to provide Pazopanib hydrochloride.

7. A process for preparing Pazopanib hydrochloride compound of formula-I comprising of;

Formula-I

a) Reacting the 3-methyl-6-nitro-2H-indazole of formula-II;

Formula-II with a suitable methylating agent in a suitable solvent to provide the 2,3-dimethyl-6-nitro-2H-indazole of formula-Ill,
Formula-Ill

b) reducing the compound of formula-Ill with a suitable reducing agent in a suitable solvent to
produce the 2,3-dimethyl-2H-indazol-6-amine of formula-IV, and then optionally converting the compound of formula-IV into its hydrochloride salt,

Formula-IV
c) condensing the compound of formula-IV or its hydrochloride salt with 2,4-
dichloropyrimidine in presence of suitable organic base in a suitable solvent to provide the
N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine compound of formula-V,

Formula-V
d) methylating the compound of formula-V with a suitable methylating agent in presence of suitable base and in a suitable solvent to provide the N-(2-chloropyrimidin-4-yl)-N,2,3- trimethyl-2H-indazol-6-amine compound of formula-VI,

Formula-VI
e) condensing the compound of formula-VI with 5-amino-2-methylbenzenesulfonamide in presence of suitable hydrochloric acid source and in a suitable solvent to provide Pazopanib hydrochloride compound of formula-I.

8. A process for preparing the preparation of Pazopanib hydrochloride comprising of:

a) Reacting the 3-methyl-6-nitro-2H-indazole of formula-II with dimethyl sulfate in mixture of dimethylsulfoxide and dimethylformamide to provide the 2,3-dimethyl-6-nitro-2H-indazole of formula-Ill,

b) reducing the compound of formula-Ill with iron(III)chloride in presence of hydrazine hydrate in mixture of methanol and water to produce the 2,3-dimethyl-2H-indazol-6-amine offormula-IV,

c) reacting the compound of formula-IV with isopropanolic HC1 to provide the hydrochloric acid salt of 2,3-dimethyl-2H-indazol-6-amine,

d) condensing the hydrochloric acid salt of 2,3-dimethyl-2H-indazol-6-amine with 2,4-dichloropyrimide in presence of triethylamine in methanol to provide the N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine compound of formula-V,

e) methylating the compound of formula-V with methyliodide in presence of potassium carbonate in dimethylsulfoxide to provide the N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine compound of formula-VI,

f) condensing the compound of formula-VI with 5-amino-2-methylbenzenesulfonamide in presence of dimethylformamide. hydrochloric acid (DMF.HC1) in methanol to provide Pazopanib hydrochloride.

9. A process for preparing anhydrous crystalline form of Pazopanib hydrochloride (Form-I) comprising of,

a) Adding the Pazopanib hydrochloride monohydrate to alcohol or ketone solvents or mixture thereof,

b) heating the reaction mixture of step a) to a temperature from about 30°C to about 75°C,

c) cooling the mixture of step b) to a temperature from about 0°C to about 30°C,

d) isolating the crystalline anhydrous Pazopanib hydrochloride (Form-I).

10. A process for preparing anhydrous crystalline form of Pazopanib hydrochloride (Form-I) comprising of,

e) Adding the Pazopanib hydrochloride monohydrate to methanol solvent,

f) heating the reaction mixture of step a) to a temperature of 60-65°C,

g) cooling the mixture of step b) to a temperature of 20-30°C,

h) isolating the crystalline anhydrous Pazopanib hydrochloride (Form-I).