PREPARATION OF PAZOPANIB AND ITS INTERMEDIATES

INTRODUCTION

Aspects of the present application provide processes for the preparation of pazopanib or its pharmaceutically acceptable salts and intermediates therein.

The drug compound known as "pazopanib hydrochloride" has a chemical name 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]-2-pyrimidinyl]amino]-2-methyl benzenesulfonamide monohydrochloride . It has the structure of formula (I).

Pazopanib hydrochloride is an oral angiogenesis inhibitor targeting the tyrosine kinase activity associated with vascular endothelial growth factor receptor (VEGFR)-1, -2 and -3, platelet-derived growth factor receptor (PDGFR)-a, and PDGFR-p, and stem cell factor receptor (c-KIT) and is the active ingredient in a product sold by GlaxoSmithKline as VORTRIENT in the form of tablets for oral use, for the treatment of patients with patients with advanced renal cell carcinoma.

U.S. Patent No. 7,105,530, describes a process for the preparation of pazopanib hydrochloride which involves methylating 3-methyl-6-nitro-1 H-indazole using trimethyloxonium tetrafluoroborate in the presence of acetone to give 2,3-dimethyl-6-nitro-2H-indazole, reducing the obtained product in the presence of 10% Pd-C and ammonium formate to give 2,3-dimethyl-6-amino-2H-indazole, followed by condensation with 2,4-dichloro pyrimidine and methylation using methyl iodide in the presence of cesium carbonate to give N-(2-chloropyrimidin-4-yl)-N,2,3-trimethyl-2H-indazol-6-amine, and subsequent condensation with 5-amino-2-methyl benzenesulfonamide to give pazopanib.

U.S. Patent application publication No. 2006/0252943 A1 describes a process for the preparation of pazopanib hydrochloride and intermediates. It also discloses processes for the preparation of 2,3-dimethyl-6-nitro-2H-indazole by methylating 3-methyl-6-nitro-1 H-indazole using trimethyloxonium tetrafluoroborate, trimethyl orthoformate and boron trifluoride etherate, or dimethyl sulfate and concentrated sulfuric acid as the methylating agents. Further, it also discloses reduction of 2,3-dimethyl-6-nitro-2H-indazole using tin(ll)chloride and concentrated hydrochloride acid or 10% Pd-C and ammonium formate as the reducing agents.

Despite the existence of various processes for the preparation of pazopanib or its salts and its intermediates, there remains a need for improved processes for the preparation of pazopanib and its salts, producing high yields and purity, and being well-suited for use on an industrial scale.

SUMMARY

In an aspect, the present application provides a process for the preparation of pazopanib or its salts, comprising:

a) reacting a compound of formula (II):

with a methylating agent, which is methyl 2,2,2-trichloroacetimidate to give a compound of formula (III); and

b) converting the compound of formula (III) to pazopanib or its salts. In an aspect, the present application provides a process for the preparation of pazopanib or its salts, comprising:

a) reacting a compound of formula (II):

with a methylating agent in the presence of a phase transfer catalyst to give a compound of formula (III); and

b) converting the compound of formula (III) to pazopanib or its salts. In an aspect, the present application provides a process for the preparation of pazopanib or its salts, comprising:

a) reducing the compound of formula (III):

in the presence of iron-powder and a hydrogen source to obtain a compound of the formula (IV); and

b) converting the compound of formula (IV) to pazopanib or its salts. In an aspect, the present application provides a process for the preparation of pazopanib or its salts, comprising:

a) reacting the compound of formula (IV)

with 2,4-dichloro pyrimidine in the presence of a base and a phase transfer catalyst to obtain a compound of formula (V);

b) converting the compound of formula (V) to pazopanib or its salts.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of Pazopanib hydrochloride prepared according to Example 11.

DETAILED DESCRIPTION

In an aspect, the present application provides a process for the preparation of pazopanib or its salts, comprising:

a) reacting a compound of formula (II):

with a methylating agent, which is methyl 2,2,2-trichloroacetimidate to give a compound of formula (III); and

b) converting the compound of formula (III) to pazopanib or its salts.

Step a) involves reacting a compound of formula (II) with a methylating agent which is methyl 2,2,2-trichloroacetimidate to give a compound of formula (III).

The above reaction using methyl 2,2,2-trichloroacetimidate may be carried out in the presence of an acid selected from hydrochloric acid, sulphuric acid, phosphoric acid, trifluoromethanesulfonic acid, or the like. The amount of methylating agent used may range from about 1 molar equivalent to about 4 molar equivalents, per molar equivalent of the compound of formula (II).

The amount of the acid used may range from about 0.1 molar equivalents to about 2 molar equivalents, per molar equivalent of the compound of formula (II).

The reaction may be carried out in the presence of a solvent. Useful solvents include, without limitation thereto, nitrile solvents such as acetonitrile, propionitrile or the like; halogenated hydrocarbon such as dichloromethane, chloroform or the like; or mixtures thereof.

It has been found that known process for the methylation of the compound of formula (II) uses the reagents such as trimethyloxonium tetrafluoroborate or boron trifluoride etherate which are costly or difficult to handle or uses the reagent dimethyl sulfate and concentrated sulfuric acid which required long reaction times (about 72 hours) and resulted in incomplete reaction with up to 9% starting materials left over. These finding are disclosed by Procedure 3 and Procedure 4 on page 15 of US2006/0252943A1.

The reaction of step a) may be carried out at temperatures ranging from about 25°C to about 100°C, or about 60°C to about 80°C. After the completion of the reaction, the compound of formula (III) may be isolated and optionally purified. In an embodiment, the compound of the formula (1111) may be isolated by a process as described in the present application.

It has been surprisingly found that the rate of reaction completion is accelerated by using 2,2,2-trichloroacetimidate and the product is obtained with high yields and purity, e.g., with the content of the isomeric impurity (A) less than about 1 %, or less than about 0.5%.

In an embodiment, the present application provides process for the preparation of 2,3-dimethyl-6-nitro-2H-indazole of formula (III), which comprises reacting 3-methyl-6-nitro-1H-indazole of formula (II) with trichloroacetimidate in the presence of trifluoromethanesulfonic acid and dichloromethane.

Step b) involves converting the compound of formula (III) to pazopanib or its salts.

The compound of the formula (III) may be converted to pazopanib or its salts by the processes described in the literature. For example, the compound of formula (III) may be converted to pazopanib or its salts by a process described in U.S. Patent application publication No. 2006/0252943 A1 or by a process described in the present application. In an embodiment the compound of the formula (III) may be converted to pazopanib hydrochloride.

In an aspect, the present application provides a process for the preparation of pazopanib or its salts, comprising:

a) reacting a compound of formula (II):

with a methylating agent in the presence of a phase transfer catalyst to give a compound of formula (III); and

b) converting the compound of formula (III) to pazopanib or its salts.

Step a) involves reacting a compound of formula (II) with a methylating agent in the presence of catalyst, to give a compound of formula (III).

Methylating agents that may be used in the process of step a) may be selected from but not limited to iodomethane, bromomethane, chloromethane, dimethyl sulfate, methyl nitrate, methyl mesylate, methyl besylate, methyl tosylate, 2,2,2-trichloroacetimidate, or methyl triflate. In an embodiment, dimethyl sulfate is used as the methylating agent in step a).

Phase transfer catalyst that may be used in this process includes but not limited to the quaternary ammonium salts tetramethyl ammonium chloride, tetrabutyl ammonium bromide, tetraethyl ammonium bromide, or the like. Typical amounts of methyl 2,2,2-trichloroacetimidate or dimethyl sulfate used may range from about 1 to about 4 molar equivalents, per molar equivalent of the compound of formula (II).

Typical amounts of the catalyst used may range from about 0.1 to about 2 molar equivalents, per molar equivalent of the compound of formula (II).

The reaction may be carried out in the presence of a solvent. Useful solvents include, without limitation thereto, nitrile solvents such as acetonitrile, propionitrile or the like; halogenated hydrocarbon such as dichloromethane, chloroform or the like; or mixtures thereof.

The above reaction may be carried out in the presence of an acid selected from hydrochloric acid, sulphuric acid, phosphoric acid, trifluoromethanesulfonic acid, or the like. The amount of the acid used may range from about 0.1 molar equivalents to about 2 molar equivalents, per molar equivalent of the compound of formula (II).

It has been found that known process for the methylation of the compound of formula (II) uses the reagents such as trimethyloxonium tetrafluoroborate or boron trifluoride etherate which are costly or difficult to handle or uses the reagent dimethyl sulfate and concentrated sulfuric acid which required long reaction times (about 72 hours) and resulted in incomplete reaction with up to 9% starting materials left over. These finding are disclosed by Procedure 3 and Procedure 4 on page 15 of US2006/0252943A1.

The reaction of step a) may be carried out at temperatures ranging from about 25°C to about 100°C, or about 60°C to about 80°C. After the completion of the reaction, the compound of formula (III) may be isolated and optionally purified. In an embodiment, the compound of the formula (Mil) may be isolated by a process as described in the present application.

It has been surprisingly found that the rate of reaction completion is accelerated by a methylating agent in the presence of a phase transfer catalyst and the product is obtained with high yields and purity, e.g., with the content of the isomeric impurity (A) less than about 1%, or less than about 0.5%.

In an embodiment, the present application provides process for the preparation of 2,3-dimethyl-6-nitro-2H-indazole of formula (III), which comprises reacting 3-methyl-6-nitro-1H-indazole of formula (II) with dimethyl sulfate in the presence of tetrabutyl ammonium bromide and sulphuric acid.

Step b) involves converting the compound of formula (III) to pazopanib or its salts.

The compound of the formula (III) may be converted to pazopanib or its salts by the processes described in the literature. For example, the compound of formula (III) may be converted to pazopanib or its salts by a process described in U.S. Patent application publication No. 2006/0252943 A1 or by a process described in the present application.

In an embodiment, the compound of the formula (III) may be converted to pazopanib or its salt by processes comprising:

(i) reacting the compound of formula (III) with a reducing agent to obtain a compound of formula (IV);

(ii) reacting the compound of formula (IV) with 2,4-dichloro pyrimidine in the presence of a base to obtain a compound of formula (V);

(V) (iii) reacting the compound of formula (V) with a methylating agent to obtain a compound of formula (VI); and

(iv) condensing the compound of formula (VI) with 5-amino-2-methyl benzene sulfonamide to obtain pazopanib or its salts.

In an embodiment the compound of the formula (III) may be converted to pazopanib hydrochloride by carrying the steps (i) to (iv) as descried in the present application.

In an aspect, the present application provides a process for the preparation of pazopanib or its salts, comprising:

a) reducing the compound of formula (III):

in the presence of iron-powder and a hydrogen source to obtain a compound of the formula (IV); and

b) converting the compound of formula (IV) to pazopanib or its salts.

Step a) involves reducing the compound of formula (III) in the presence of an iron-powder and a hydrogen source to obtain a compound of formula (IV). The reaction may be carried out in the presence of a solvent. Useful solvents include, without limitation thereto, water; an alcohol solvent such as methanol, ethanol, 2-propanol or the like; or mixtures thereof. In an embodiment a mixture of water and isopropyl alcohol is used as the solvent. Hydrogen source that maybe used in this process may be selected from ammonium chloride, ammonium formate or the like. In an embodiment, ammonium chloride is used as the hydrogen source. Typical amounts of iron-powder used may range from about 1 molar equivalent to about 5 molar equivalents, per molar equivalent of the compound of formula (III). In an embodiment, the Iron powder and the hydrogen source selected may be added in lots to increase the reaction rate and for obtaining better yield and purity of the product.

The reaction of step a) may be carried out at temperatures ranging from about 25°C to about 100°C or about 60°C to about 85°C.

After the completion of the reaction, the compound of formula (IV) may optionally be isolated and purified. In an embodiment, the compound of the formula (IV) may be isolated by cooling the reaction mass 25-35°C, adding dichloromethane and extracting the compound into dichloromethane, and distilling off the solvent to obtain the product. In another embodiment, the compound of formula (IV) may be isolated by a process as described in the present application.

This process of the present application involving the use of iron-powder is advantageous over the known process for the reduction of the compound of formula (III) using tin (II) chloride or palladium on charcoal, which are pyrophoric under certain conditions and requires utmost care while handling.

Step b) involves converting the compound of formula (III) to pazopanib or its salts. The compound of the formula (III) may be converted to pazopanib or its salts by a process as described in the present application or by the processes described in the literature. For example, the compound of formula (IV) may be converted to pazopanib or its salts as per the process described in U.S. Patent application publication No. 2006/0252943 A1, the disclosure of which in its entirety is hereby incorporated by reference.

In an embodiment, the present application provides process for the preparation of 2,3-dimethyl-2H-indazol-6-amine (IV) which comprises reacting 2,3-dimethyl-6-nitro-2H-indazole of formula (III), with iron-powder in the presence of ammonium chloride.

In an aspect, the present application provides a process for the preparation of pazopanib or its salts, comprising:

a) reacting the compound of formula (IV)

with 2,4-dichloro pyrimidine in the presence of a base and a phase transfer catalyst to obtain a compound of formula (V);

b) converting the compound of formula (V) to pazopanib or its salts.

Step a) involves reacting a compound of formula (IV) with 2,4-dichloro pyrimidine in the presence of a base and a phase transfer catalyst to obtain a compound of formula (V).

Base that may be used in the process of step a) may be selected from carbonates such as sodium carbonate, potassium carbonate or cesium carbonate and bicarbonates such as sodium bicarbonate, potassium bicarbonate, Phase transfer catalyst that may be used in this process includes but not limited to the quaternary ammonium salts tetramethyl ammonium chloride, tetrabutyl ammonium bromide, tetraethyl ammonium bromide, or the like. Typical amounts of base used may range from about 1 to about 4 molar equivalents, per molar equivalent of the compound of formula (IV). Typical amounts of the catalyst used may range from about 0.1 to about 2 molar equivalents, per molar equivalent of the compound of formula (II).

The reaction may be carried out in the presence of a solvent. Useful solvents include, without limitation thereto, alcohol such as methanol, ethanol, isopropanol or the like.

The reaction of step a) may be carried out at temperatures ranging from about 25°C to about 100°C, or about 60°C to about 70°C, based on the solvent employed. After the completion of the reaction, the compound of formula (V) may be isolated and optionally purified. In an embodiment, the compound of the formula (V) may be isolated by a process as described in the present application. In an embodiment, the compound of formula (V) may be isolated by adding water to the reaction mixture in alcohol to precipitate the compound. The compound of formula (V) may be further purified by combining with ethylacetate and n-heptane, maintaining at 25-35°C for about 30 minutes, followed by maintaining at 0-5°C for 2-3 hours and isolating the purified product.

It has been surprisingly found that the rate of reaction completion is accelerated by using the phase transfer catalyst and the product is obtained with high yields and purity

In an embodiment, the present application provides process for the preparation of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine of formula (V), which comprises reacting 2,3-dimethyl-2H-indazol-6-amine of formula (IV) with 2,4-dichloro pyrimidine in the presence of a sodium bicarbonate and tetrabutyl ammonium bromide.

Step b) involves converting the compound of formula (V) to pazopanib or its salts

The compound of the formula (V) may be converted to pazopanib or its salts by the processes described in the literature. For example, the compound of formula (V) may be converted to pazopanib or its salts by a process described in U.S. Patent application publication No. 2006/0252943 A1 or by a process described in the present application.

In an embodiment, the present application provides a process for the preparation of pazopanib or its salts, comprising:

with a methylating agent in the presence of a phase transfer catalyst to give a compound of formula (III); and

a) reacting a compound of formula (II):

b) reducing the compound of formula (III) in the presence of iron-powder and a hydrogen source to obtain a compound of the formula (IV); and

c) converting the compound of formula (IV) to pazopanib or its salts. In an embodiment, the compound of formula (IV) may be converted to Pazopanib or its salts, by processes comprising: i) reacting the compound of formula (IV),

with 2,4-dichloro pyrimidine in the presence of a base and optionally in the presence of a phase transfer catalyst to obtain a compound of formula (V);

(V) ii) reacting the compound of formula (V) with a methylating agent to obtain a compound of formula (VI); and

iii) condensing the compound of formula (VI) with 5-amino-2-methyl benzene sulfonamide to obtain pazopanib or its salts.

The above steps may be carried out by process as described in the present application.

DEFINITIONS

The following definitions are used in connection with the present invention unless the context indicates otherwise. The term "reacting" is intended to represent bringing the chemical reactants together under conditions such to cause the chemical reaction indicated to take place.

An "alcohol solvent" is an organic solvent containing a carbon bound to a hydroxyl group. "Alcohol solvents" include but are not limited to methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, i-butyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, glycerol, Calcohols, or the like.

A "halogenated hydrocarbon solvent" is an organic solvent containing a carbon bound to a halogen. "Halogenated hydrocarbon solvents" include but are not limited to dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride, or the like.

A "methylating agent" is a reagent comprising a methyl group susceptible to nucleophilic attack and a leaving group. Examples of such agents include iodomethane, bromomethane, chloromethane, dimethyl sulfate, methyl nitrate, methyl mesylate, methyl besylate, methyl tosylate, 2,2,2-trichloroacetimidate, or methyl triflate.

A "nitrile solvent" is an organic solvent containing a cyano -(CEN) bonded to another carbon atom. "Nitrile solvents" include but are not limited to acetonitrile, propionitrile, C2-6nitriles, and the like.

A "phase transfer catalyst" is a catalyst that facilitates the migration of a reactant from one phase into another phase where reaction occurs. This catalyst is used when the reaction takes place in a heterogeneous reaction medium. Phase transfer catalysts include, but are not limited to tetraalkylammonium or phosphonium halide such as tetrabutylammonium bromide, tetrabutylammonium fluoride, or tetrabutylammonium hydrogen sulfate; crown ethers like 15-crown-5 or 18-crown-6; and the like.

Certain specific aspects and embodiments of the present application will be explained in detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner.

EXAMPLES EXAMPLE 1:

Preparation of 2,3-dimethyl-6-nitro-2H-indazole (III).

3-Methyl-6-nitro-1 H-indazole (5.0 g) and dichloromethane (125 mL) are charged into a round bottom flask at 25-30°C, stirred for 15 minutes, and trifluoromethane sulfonic acid (0.62 mL) is slowly added. Methyl 2,2,2-tricholoracetimidate (12.4 g) is added to the reaction mixture and stirred at a temperature of 25-30°C for 19 hours. Saturated sodium bicarbonate solution (50 mL) is added under stirring and maintained for 20 minutes. The organic layer is separated, washed with saturated sodium bicarbonate solution (50 mL), and evaporated under reduced pressure at 50°C to obtain the crude product. Diisopropyl ether (40 mL) and the crude product are charged into a round bottom flask, stirred for 80 minutes, the solid is collected by filtration, washed with diisopropyl ether (5 mL), and dried under vacuum at 47°C to give the title compound. Yield: 5.1 g (94.9%)

EXAMPLE 2:

Preparation of 2,3-dimethyl-6-nitro-2H-indazole (III).

3-Methyl-6-nitro-1 H-indazole (5.0 g), acetonitrile (30 mL) and tetra-n-butyl ammonium bromide (0.45 g) are charged into a round bottom flask at 25-30°C, stirred for 10 minutes, and concentrated sulphuric acid (1.8 mL) is slowly added. Dimethyl sulfate (8.0 mL) is added, the reaction mixture is heated to 74°C, and maintained at the same temperature for about 22 hours. The reaction mixture is cooled to 27°C, water (50 mL) added, and the reaction mixture is stirred for about 40 minutes. The obtained solid is collected by filtration, washed with water (10 mL), and dried under reduced pressure at 28°C to give crude product. Diisopropyl ether (25 mL) and the crude product were charged in a round bottom flask, stirred at 27°C for about 1 hours, the solid collected by filtration, washed with diisopropyl ether (5 mL), and dried under vacuum at 45°C to give the title compound. Yield: 4.9 g (90.9%)

EXAMPLE 3:

Preparation of 2,3-dimethyl-2H-indazol-6-amine (IV).

2,3-Dimethyl-6-nitro-2H-indazole (3.0 g) and 2-propanol:water (63 mL, 2-propanol (42 mL) and water(21 mL)) are charged into a round bottom flask at 25-30°C and stirred. Ammonium chloride (4.19 g) and iron-powder (2.62 g) are added in portions and the reaction mixture is heated to 79°C. The reaction is maintained at the same temperature for about 75 minutes, cooled to 28°C, ethyl acetate (30 mL) added, and stirred for about 1 hour. The reaction mass is filtered through a Celite® bed and washed with ethyl acetate (15 mL). The filtrate was concentrated under reduced pressure at 45°C to give the title compound as a white solid. Yield: 2.4 g (96 %)•

EXAMPLE 4:

Preparation of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (V).
2,3-Dimethyl-2H-indazol-6-amine (40.0 g) and methanol (480 mL) are charged into a round bottom flask at 25-30°C and stirred. Sodium bicarbonate (25.0 g), 2,4-dichloro pyrimidine (44.4 g) and tetrabutyl ammonium bromide.(7.9 g) are added and the reaction mixture is heated to reflux temperature (about 64°c). The reaction is maintained at the same temperature for about 15 hours. The reaction mixture is cooled to room temperature, charged with sodium bicarbonate (4.17 g) and the reaction mixture is stirred at a temperature of about 30°C for 1 hour, and concentrated under reduced pressure at temperatures below 30 °C. Methanol (120 mL) is added to the reaction mass and stirred for 30 minutes. Water (480 mL) is added to the reaction mass, which is stirred at a temperature of about 30°C for 2-3 hours, filtered, the collected product washed with water (80 mL), and dried under reduced pressure at 30°C to give 72.1 g of the title compound.

A 20 g portion of the obtained compound and ethyl acetate (60 mL) are charged into a round bottom flask at 27°C and stirred for about 30 minutes. Heptane (10 mL) is charged to the reaction mixture and stirred for about 30 minutes. The reaction mixture is cooled to a temperature of less than 5°C, maintained for 3 hours, the solid collected by filtration, washed with ethyl acetate (20 mL), and the obtained solid dried at a temperature of 50°C under vacuum for about 6 hours to obtain 15.9 g of the title compound.

EXAMPLE 5:

Preparation of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (V).
2,3-Dimethyl-2H-indazol-6-amine (2.0 g) and a tetrahydrofuran:ethanol mixture (27 ml_, 1:4) are charged into a round bottom flask at 25-30°C and stirred. 2,4-Dichloropyrimidine (2.7 g) and sodium bicarbonate (3.10 g), are added and the reaction mixture is heated to reflux temperature (about 75°C). The reaction is maintained at the same temperature for about 11 hours. The reaction mixture is allowed to a temperature of about 27°C, cooled to a temperature of about 10°C, and maintained at the same temperature for about 1 hour. The solid obtained is collected by filtration under vacuum, washed with ethyl acetate (6 ml_), followed by water (30 mL), and dried under reduced pressure at 45°C for 7 hours to obtain 2.5 g of the title compound (Yield: 73.9%)

EXAMPLE 6:

Preparation of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (V).
2,3-Dimethyl-2H-indazol-6-amine (2.0 g) and methanol (24 mL) are charged into a round bottom flask at 25-30°C and stirred. Sodium bicarbonate (1.25 g) and 2,4-dichloro pyrimidine (2.2 g) are added and the reaction mixture is heated to reflux temperature (about 65°C). The reaction is maintained at the same temperature for about 11 hours. The reaction mixture is cooled to 29°C and concentrated under reduced pressure at a temperature of about 45°C to obtain 4.8 g of crude. Methanol (6 mL) is charged to the obtained compound and stirred for about 90 minutes. Water (24 mL) is added and the reaction mixture maintained for 1 hour. The solid obtained is collected by filtration under reduced pressure, washed with water (4 mL), and dried with suction. Ethyl acetate (6 mL) and the obtained compound are charged into a round bottom flask at 27°C, stirred for about 2 hours, the solid collected by filtration, washed with ethyl acetate (2 mL), and the obtained solid dried at a temperature of 45°C under vacuum to obtain 2.4 g of the title compound.

Example 7:

Preparation of 2,3-dimethyl-6-nitro-2H-indazole (III).
3-Methyl-6-nitro-1 H-indazole (20 g), dimethyl sulfoxide (60 mL) are charged into a round bottom flask at 25-35°C, stirred, and cooled the reaction mixture to a temperature of 10-15°C. Concentrated sulphuric acid (12.02 mL) is slowly added at a temperature below 20°C. Cooled the reaction mixture to 15-20°C and dimethyl sulfate (64.22 mL) is slowly added. The reaction mixture is maintained at a temperature of 25-35°C for about 23 hours, dichloromethane (60 mL) is added and stirred. 8% bicarbonate solution (200 mL) is charged into a second round bottom flask, cooled to temperature of 10-20°C, and slowly added the reaction mass from the first round bottom flask. Dichloromethane (140 mL) is added to the reaction mixture, stirred and separated the organic layer. Dichloromethane (2X100 mL) are added to the reaction mixture, stirred and separated the organic layer. The organic layers are combined, washed with demineralized water (4X100 mL) and concentrated under reduced pressure to obtain 17.4 g of the crude compound. Diisopropyl ether (160 mL) and the crude product were charged in a round bottom flask, stirred at 28°C for about 1 hours, collected the solid by filtration, washed with diisopropyl ether (40 mL), and dried under vacuum at about 43°C to give the title compound. Yield: 14.9 g Purity by HPLC: 98.8%

EXAMPLE 8:

Preparation of 2,3-dimethyl-2H-indazol-6-amine (IV).
2,3-Dimethyl-6-nitro-2H-indazole (50 g), a mixture of 2-propanol:water (1050 mL, 2-propanol (700 mL) and water(350 mL)) are charged into a round bottom flask at 25-30°C and stirred. Ammonium chloride (55.95 g), iron-powder (43.81 g) are added and the reaction mixture is heated to 80°C. The reaction mixture is maintained at the same temperature for about 60 minutes and ammonium chloride (13.98 g) and iron-powder (14.60 g) are added. The reaction mixture is maintained at the same temperature for about 2 hours, cooled to 25-30°C, dichloromethane (500 mL) is added and stirred. The reaction mass is filtered through a Celite® bed and washed with dichloromethane (100 mL). The filtrate is taken into a round bottom flask, stirred and separated the organic layer. The aqueous layer is charged into a round bottom flask, dichloromethane (150 mL) is added, stirred and separated the organic layer. The organic layers are combined and concentrated under reduced pressure to remove the solvent. Ethyl acetate (100 mL) is added is the reaction mass and distilled off reduced pressure to remove the solvent. Ethyl acetate (100 mL) is added is the reaction mass and distilled off the solvent completely reduced pressure to give 41. 3 g of the compound.
Purity by HPLC: 96.56%

Example 9:

Preparation of N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (V).
2,3-Dimethyl-2H-indazol-6-amine (30 g) and methanol (360 mL) are charged into a round bottom flask at 25-30°C and stirred. Sodium bicarbonate (18.7 g), 2,4-dichloro pyrimidine (33.2 g) and tetra-butyl ammonium bromide (5.9) are added to the reaction mixture and heated to reflux temperature (about 65°C). The reaction mixture is maintained at the same temperature for about 11 hours. The reaction mixture is cooled to 29°C. Sodium bicarbonate (3.1) is added and stirred the reaction mixture for about 30 minutes. The reaction mixture Is concentrated under reduced pressure at a temperature of about 45°C. Methanol (90 mL) is charged to the obtained compound and stirred for about 40 minutes. Water (360 mL) is added and the reaction mixture maintained for 2 hour. The solid obtained is collected by filtration under reduced pressure, washed with water (60 mL), and dried with suction. Ethyl acetate (150 mL) and the obtained compound are charged into a round bottom flask at 27°C, stirred for about 30 minutes. N-heptane (25 mL) is added, stirred for about 30 minutes, cooled the reaction mixture to 0-5°C and maintained at the same temperature for about 1 hours. The solid is collected by filtration, washed with ethyl acetate: heptane, and the obtained solid dried at a temperature of 45-50°C under vacuum to obtain 42.9 g of the title compound. Purity by HPLC: 97.5%

EXAMPLE 10:

Preparation of N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine (VI)
N-(2-chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (5.0 g) and dimethylformamide (30 mL) are charged into a round bottom flask at 27°C and stirred. Potassium carbonate (8.3 g) and methyl iodide (3.2 g) are charged and the reaction mixture is stirred at a temperature of 25-35°C for about 16 hours. The reaction mixture is cooled to a temperature of about 15°C, 8% aqueous sodium chloride solution (100 mL) is added and stirred to about 15 minutes. Dichloromethane (10 mL) is added to the reaction mixture, stirred for 20-30 minutes and separated the organic layer. Dichloromethane (10 mL) is added to the reaction mixture, stirred for 20-30 minutes and separated the organic layer. The organic layers are combined, washed with 8% aqueous sodium chloride solution (2 x 50 mL) and subsequently with demineralized water (2x50 mL). Charged the organic layer into a round bottom flask and heated to a temperature of 40°C. Activated carbon (SC 40) (50% loading) is added, stirred the contents for 20-30 minutes and filtered the reaction mass through a hyflow bed. Charged the filtrate into a round bottom flask, heated to a temperature of 40°C, added activated carbon (SC 40) (50% loading) , stirred the contents for 20-30 minutes and filtered the reaction mass through on a hyflow bed. The filtrate obtained is concentrated under reduced pressure to obtain 3.2 g of the crude compound. Isopropyl alcohol (20 mL) and the obtained compound are charged into a round bottom flask at 30°C, distilled off the solvent completely under vacuum at below 60°C. The solid obtained is cooled to 30°C, isopropyl alcohol (10 mL) is added and stirred the reaction mixture for 10-15 minutes. Diisopropyl ether (40 mL) is added, cooled the reaction mixture to 0-5°C, maintained at the same temperature for about 3 hours, filtered, washed with diisopropyl ether (20 mL), and the solid obtained is dried at a temperature of 55°C under vacuum to obtain 3.0 g of the title compound.

EXAMPLE 11:

Preparation of pazopanib hydrochloride.

N-(2-chloropyrimidin-4-yl)-N-2,3-trimethyl-2H-indazol-6-amine (2.87 g) is charged into a round bottom flask at 27°C, added a solution of 5-amino-2-methyl benzene sulfonamide (1.95 g) dissolved in dimethylformamide (4.5 mL) and stirred at the same temperature for about 20 minutes. Isopropyl alcohol (29 mL) and concentrated hydrochloric acid (0.02 ml) are charged and the reaction mixture is heated to a temperature of about 75-80°C. The reaction is maintained at the same temperature for about 17 hours The reaction mixture is cooled to 0-5°C, maintained at the same temperature for about 1 hours, filtered, washed with isopropyl alcohol (21 mL) and the solid obtained is dried at a temperature of 55-60°C under vacuum to obtain 4.1 g of the title compound.

Purity by HPLC: 98.5%

XRPD: Figure 1.

Claims:

1. A process for the preparation of pazopanib or its salts, comprising:

a) reacting a compound of formula (II):

with a methylating agent in the presence of a phase transfer catalyst to give a compound of formula (III); and

b) reducing the compound of formula (III) in the presence of iron-powder and a hydrogen source to obtain a compound of the formula (IV); and

c) converting the compound of formula (IV) to pazopanib or its salts.

2. The process of claim 1, wherein the methylating agent is selected from iodomethane, bromomethane, chloromethane, dimethyl sulfate, methyl nitrate, methyl mesylate, methyl besylate, methyl tosylate, 2,2,2-trichloroacetimidate, or methyl triflate and phase transfer catalyst is selected from quaternary ammonium salts such as tetramethyl ammonium chloride, tetrabutyl ammonium bromide, tetraethyl ammonium bromide.

3. The process of claim 1, wherein the solvent used in step a) is selected from nitrile solvents such as acetonitrile, propionitrile; halogenated hydrocarbon such as dichloromethane, chloroform and the solvent used in step b) is selected from water; an alcohol solvent such as methanol, ethanol, 2-propanol or mixtures thereof.

4. The process according to claim 1, further comprises the steps of:

i) reacting the compound of formula (IV)

with 2,4-dichloro pyrimidine in the presence of a base and optionally in the presence of a phase transfer catalyst to obtain a compound of formula (V);

ii) reacting the compound of formula (V) with a methylating agent to obtain a compound of formula (VI); and

iii) condensing the compound of formula (VI) with 5-amino-2-methyl benzene sulfonamide to obtain pazopanib or its salts.

5. A process for the preparation of pazopanib or its salts, comprising:

a) reacting a compound of formula (II):

with a methylating agent in the presence of a phase transfer catalyst to give a compound of formula (III); and

b) converting the compound of formula (III) to pazopanib or its salts.

6. A process for the preparation of pazopanib or its salts, comprising: a) reducing the compound of formula (III):

in the presence of iron-powder and a hydrogen source to obtain a compound of the formula (IV); and

b) converting the compound of formula (IV) to pazopanib or its salts.

7. A process for the preparation of pazopanib or its salts, comprising:

a) reacting a compound of formula (II):

with a methylating agent, which is methyl 2,2,2-trichloroacetinnidate to give a compound of formula (III); and

b) converting the compound of formula (III) to pazopanib or its salts.

8. A process for the preparation of pazopanib or its salts, comprising:

a) reacting the compound of formula (IV)

with 2,4-dichloro pyrimidine in the presence of a base and a phase transfer catalyst to obtain a compound of formula (V);

b) converting the compound of formula (V) to pazopanib or its salts.

9. The process of claim 8, wherein the base is selected from carbonates such as sodium carbonate, potassium carbonate or cesium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate and the phase transfer catalyst is selected from quaternary ammonium salts such as tetramethyl ammonium chloride, tetrabutyl ammonium bromide, tetraethyl ammonium bromide.