DESC:FIELD OF THE INVENTION:
The present invention relates to the process for the preparation of highly pure crystalline Pazopanib Hydrochloride of formula (I).

Another object of the present invention is to provide a novel crystalline form of Pazopanib hydrochloride formula (I) designated as Crystalline Form S1.
BACKGROUND OF THE INVENTION:
VOTRIENT is a tyrosine kinase inhibitor, is the Hydrochloride salt of Pazopanib. Pazopanib Hydrochloride is chemically name as 5- [[4¬ [(2, 3-dimethyl-2H-indazol-6-yl) methylamino]-2-pyrimidinyl] amino]-2-methylbenzenesulfonamide monohydrochloride. The molecular formula for Pazopanib Hydrochloride is C21H23N7O2S.HCl and its structural formula is:

Pazopanib Hydrochloride is manufactured and marketed by GlaxoSmithKline (GSK) under the brand name VOTRIENT® in US and Europe in the form of tablet. Pazopanib is a cancer medicine that is used to treat patients with kidney cancer (advanced renal cell carcinoma) and advanced soft-tissue sarcoma.
Boloor et al in US7105530B2, US7262203B2 and US8114885B2 disclosed Pyrimidineamines and their derivatives such as Pazopanib, Processes for their preparation, pharmaceutically composition comprising the derivatives and method of use thereof. According to US patent no. US7105530B2 Pazopanib Hydrochloride can be prepared by reacting the N-(2-chloropyrimidin-4-yl)-N, 2,3-trimethyl-2H-indazol-6-amine and 5-amino-2-methylbenzenesulfonamide in the presence of hydrochloric acid in isopropyl alcohol and ether, which follows the synthetic pathway as given in the Scheme-1:

Scheme -1: Process as per US7105530B2
Kumar et al in US9802923B2 described Process for the preparation of Pazopanib or salts thereof. The synthetic pathway of Pazopanib Hydrochloride as given in the Scheme-2:

Scheme -2: Process as per US9802923B2
Reddy et al in US9150547B2 disclosed a Process for the preparation of Pazopanib Hydrochloride, which involves condensation of 2,4 dichloropyrimidine of Formula II with 5-amino-2-methylbenzenesulfonamide of Formula III in presence of a base like NaHCO3 and a solvent like ethanol to give 5-((4-chloropyrimidin-2-yl)amino)-2-methylbenzenesulfonamide of Formula IV. Resulting compound was condensed with N, 2,3-trimethyl-2H-indazol-6-amine compound of Formula V in alcoholic solvent like methanol or ethanol. This patent also disclosed purification of Pazopanib Hydrochloride from alcoholic solvent and water, which follows the reaction pathway as given in the Scheme-3:

Scheme -3: Process as per US9150547B2
Rendell et al in WO2011069053A1 disclosed process for the preparation of Pazopanib Hydrochloride can be prepared by reacting the N-(2- chloropyrimidin-4-yl)-2,3-dimethyl-2H-indazol-6-amine (CPMI) and 5-amino-2- methylbenzenesulfonamide (AMBS) with acetic acid or a mixture of water and acetic acid. This Publication also disclosed crystalline Forms of Pazopanib HCl (Form-II, Form-III, Form-IV, Form-V, Form-VI, Form-VII, Form-VIII, Form-IX, Form-X, Form-G, Form-A Form-XI, Form-XII, Form-XIII, & crystalline Pazopanib di-HCl Form-I, di-HCl Form-XIV, di-HCl Form-XV).
Further, in view of the existence of various literature known for processes related to preparation of Pazopanib Hydrochloride, there exist a need of processes, which are not only industrially and economically feasible process but also responsible to scale up and provide improved yields & quality.
SUMMARY OF THE INVENTION
The main aspect of the present invention relates to a process for the preparation of crystalline Pazopanib Hydrochloride of Formula (I).

Different aspects of the present application are summarized herein below individually.
In one aspect of the present application, the present invention relates to a process for preparation of compound of formula (I),

Comprising the steps of:
a). condensing 2,3-dimethyl-2H-indazol-6-amine Hydrochloride of formula (II) with 2,4-dichloropyrimidine of formula (III), in the presence of a base and 5-15% of ether solvent in alcohol solvent (C1-C4) at a temperature ranging between 35-60°C;

b). reacting N-(2-chloro-4-pyrimidinyl)-2, 3- dimethyl-2H-indazol-6-amine of formula (IV) in the presence of an organic solvent and alkali metal hydride with a methylating agent at a temperature ranging between -5 to 15°C to isolate the compound N-(2-chloropyrimidin-4-yl)-N-methyl-2,3-dimethyl-2H-indazol-6-amine of formula (V);

c). condensing of N-(2-chloropyrimidin-4-yl)-N-methyl-2,3-dimethyl-2H-indazol-6-amine of formula (V) with 5-amino-2-methylbenzenesulfonamide of formula (VI) in the presence of alcohol (C1-C4) solvent and catalytic amount of hydrochloric acid at a temperature ranging between 55-70°C to obtain Pazopanib Hydrochloride crude of formula (VII);

d). purifying the formula (VII) to get the crystalline Pazopanib Hydrochloride of formula (I) having purity greater than 99.9% (Area % by HPLC).
Another aspect of the present invention relates to a crystalline form of Pazopanib Hydrochloride of formula (I) designated as Form S1 is characterised by
i). XRPD diffraction angle peaks at 5.8, 10.7, 13.9, 15.7, 16.5, 17.0, 19.9, 23.7, 24.2, 24.5, 25.5 and 26.2 ± 0.2°2?;
ii). DSC thermogram having an endothermic peak ranging between 292±5°C.
Further specific aspects of the invention are detailed in the description part of the specification, wherever appropriate.

BRIEF DESCRIPTION OF THE DRAWINGS:
FIG 1: is an illustration of X-Ray powder Diffraction (XRPD) pattern of the crystalline Pazopanib Hydrochloride of formula (I).
FIG 2: is an illustration of a Differential Scanning Calorimetric (DSC) Curve of the crystalline Pazopanib Hydrochloride of formula (I).
FIG 3: is an illustration of a High Performance Liquid Chromatography Curve of the crystalline Pazopanib Hydrochloride of formula (I).
FIG 4: is an illustration of X-Ray powder Diffraction (XRPD) pattern of the crystalline Pazopanib Hydrochloride of formula (I) obtained after 9 months stability.
FIG 5: is an illustration of a Differential Scanning Calorimetric (DSC) Curve of the crystalline Pazopanib Hydrochloride of formula (I) obtained after 9 months stability.

DETAILED DESCRIPTION:
As set forth herein, embodiments of the present invention relates to a process for preparation of crystalline Pazopanib Hydrochloride (I). The present invention deals with a simple and industrially amenable process for making the compound of formula (I), which exhibits various advantages over other processes known in the state of arts. The advantages are discussed on the relevant places of further description. Individual embodiments of the present invention are detailed herein below separately.
In one embodiment according to the present application, it provides a process for preparation of compound of formula (I) or a salt thereof,

In one aspect of the present application, the present invention relates to a process for preparation of compound of formula (I),

Comprising the steps of:
a). condensing 2,3-dimethyl-2H-indazol-6-amine Hydrochloride of formula (II) with 2,4-dichloropyrimidine of formula (III), in the presence of a base and 5-15% of ether solvent in alcohol solvent (C1-C4) at a temperature ranging between 35-60°C;

b). reacting N-(2-chloro-4-pyrimidinyl)-2, 3- dimethyl-2H-indazol-6-amine of formula (IV) in the presence of an organic solvent and alkali metal hydride with a methylating agent at a temperature ranging between -5 to 15°C to isolate the compound N-(2-chloropyrimidin-4-yl)-N-methyl-2,3-dimethyl-2H-indazol-6-amine of formula (V);

c). condensing of N-(2-chloropyrimidin-4-yl)-N-methyl-2,3-dimethyl-2H-indazol-6-amine of formula (V) with 5-amino-2-methylbenzenesulfonamide of formula (VI) in the presence of alcohol (C1-C4) solvent and catalytic amount of hydrochloric acid at a temperature ranging between 55-70°C to obtain Pazopanib Hydrochloride crude of formula (VII);

d). purifying the formula (VII) to get the crystalline Pazopanib Hydrochloride of formula (I) having purity greater than 99.9% (Area % by HPLC).
Individual steps of the process according to the present invention are detailed herein below.
In step a) the reaction of 2,3-dimethyl-2H-indazol-6-amine Hydrochloride (II) with 2,4-dichloropyrimidine (III) is carried out at temperature ranging between 35-60°C in the presence of base and 5-15% of ether solvent in alcohol solvent (C1-C4). The suitable base in step a) may be selected from sodium bicarbonate, potassium bicarbonate or caesium bicarbonate, more preferably sodium bicarbonate was used in the present invention.
The ether solvent used in step a) is selected form dioxane, tetrahydropyran, more preferably dioxane was used in the present invention.
The role of base in the condensation reaction was found to be significantly important.
Inventors of the present invention found that the base used in presence of 5-15% of ether solvent and alcohol solvent (C1-C4) for the preparation of N-(2-chloro-4-pyrimidinyl)-2, 3- dimethyl-2H-indazol-6-amine of formula (IV) is the most viable and cost effective process for industrial scale-up.
The use of Toluene as an solvent for the isolation of N-(2-chloro-4-pyrimidinyl)-2, 3- dimethyl-2H-indazol-6-amine of formula (IV) with good yield and quality.
In step b) reaction is carried out of N-(2-chloro-4-pyrimidinyl)-2, 3- dimethyl-2H-indazol-6-amine (IV) at a temperature ranging between -5 to 15°C in the presence of an organic solvent and alkali metal hydride with a methylating agent to isolate the compound N-(2-chloropyrimidin-4-yl)-N-methyl-2,3-dimethyl-2H-indazol-6-amine (V). The organic solvent in step b) is selected from dimethyl ketone, ethyl methyl ketone, isopropyl ketone, methyl isobutyl ketone, diethyl ketone or tetrahydrofuran, more preferably dimethyl ketone was used in the present invention.
The alkali metal hydride used in step b) is selected form lithium hydride, sodium hydride or potassium hydride, more preferably sodium hydride was used in the present invention.
In another embodiment of the present invention the methylating agent used in step b) is dimethyl sulphate or methyl iodide, more preferably dimethyl sulphate was used in the present invention.
The inventors of the present invention observed that the use of organic solvent and alkali metal hydride with a methylating agent is a unique combination for the methylation reaction for preparation of compound N-(2-chloropyrimidin-4-yl)-N-methyl-2,3-dimethyl-2H-indazol-6-amine (V) without formation of other impurities.
The use of alkali metal hydride for quick completion of reaction which gives desired product.
In step c) condensing of N-(2-chloropyrimidin-4-yl)-N-methyl-2,3-dimethyl-2H-indazol-6-amine (V) with 5-amino-2-methylbenzenesulfonamide (VI) at a temperature ranging between 55-70°C in the presence of alcohol (C1-C4) solvent and catalytic amount of hydrochloric acid to obtain 5- [[4¬ [(2, 3-dimethyl-2H-indazol-6-yl) methylamino]-2-pyrimidinyl] amino]-2-methylbenzenesulfonamide monohydrochloride or Pazopanib Hydrochloride crude of formula (VII);
In one embodiment of the present invention the alcohol (C1-C4) solvent used in step a, b, c and d) may be selected from methanol, ethanol, propanols (isopropanol and n-propanol) or butanols (n-butanol, isobutanol and tert-butanol), more preferably methanol was used in the present invention.
The inventors of the present invention found that the solvent need to be alcoholic and catalytic amount of hydrochloric acid for the reaction to occur in the manner to give Pazopanib Hydrochloride crude of formula (VII) for industrial scale. The inventors have investigated methanol, ethanol, propanols (isopropanol and n-propanol) and butanols (n-butanol, isobutanol and tert-butanol) for step c) of the present invention.
In another embodiment, step d) proceeds with the isolation of the pure crystalline Pazopanib Hydrochloride of formula (I) in an alcohol (C1-C4) solvent.
Crystalline Form S1 of Pazopanib Hydrochloride (I), of the present invention is further characterized by X-ray powder diffraction pattern according to FIG. 1 and 4, DSC isothermal pattern according to FIG. 2 and 5 and High performance liquid chromatographic purity according to FIG. 3.
Another aspect of the present invention relates to a crystalline form of Pazopanib Hydrochloride of formula (I) designated as Form S1 is characterised by XRPD diffraction angle peaks at 5.8, 10.7, 13.9, 15.7, 16.5, 17.0, 19.9, 23.7, 24.2, 24.5, 25.5 and 26.2 ± 0.2°2? and DSC thermogram having an endothermic peak ranging between 292±5°C.
In still another embodiment crystalline Form S1 of Pazopanib Hydrochloride of formula (I) having purity greater than 99.9% (Area % by HPLC).
The inventors of the present invention observed that an alcohol (C1-C4) solvent is suitable for the preparation of crystalline Form S1 of Pazopanib Hydrochloride.
The process related impurities, including unreacted intermediates, side products, degradation products and other medium dependent impurities, that appears in the impurity profile of the Pazopanib Hydrochloride can be removed by the process of the present invention resulting in the formation of Pazopanib Hydrochloride, which parallel leads to the formation of stable crystalline Form S1 of Pazopanib Hydrochloride.
The Process of the present invention avoids the formation of by-products and process related impurities in the formation of crystalline Form S1 of Pazopanib Hydrochloride.
Inventors of the present application performed 9 months stability for the crystalline Form S1 according to the following temperature and relative humidity conditions:
S. No. Temperature Relative Humidity
A. 25°C ± 2°C 60% ± 5%
B. 30°C ± 2°C 65% ± 5%

The below mentioned table shows the thermodynamic stability nature of the polymorphic Form S1 and the HPLC purity indicates to retain substantially pure form nature with purity exceeding 99.9% (% w/w by HPLC).
Moisture Content (by KF method)
Not more than 0.5% w/w Initial 1M 2M 3M 6M 9M
A 0.30 0.33 0.35 0.30 0.31 0.33
B 0.30 0.31 0.33 0.33 0.33 0.35
Assay (by HPLC; on anhydrous basis) Between 98.0 to 102.0% w/w Initial 1M 2M 3M 6M 9M
A 99.79 99.84 99.92 99.90 99.55 99.56
B 99.79 99.78 99.88 99.92 99.80 98.71

XRPD Initial peaks:
After nine months at 30°C± 2/65± 5% RH condition
5.8, 10.7, 13.9, 15.7, 16.5, 17.0, 19.9, 23.7, 24.2, 24.5, 25.5 and 26.2 ± 0.2°2?; 5.7, 10.6, 13.9, 15.6, 16.5, 16.9, 19.8, 23.7, 24.2, 24.5, 25.5, and 26.1 ± 0.2°2?;

Wherein, A = 25°C± 2/60± 5% RH; B = 30°C± 2/65± 5% RH
Fig. 4 illustrates the comparative X-ray powder diffraction (XRPD) pattern of Pazopanib Hydrochloride of formula (I) of initial stage and after 9 month’s stability (30°C± 2/65± 5% RH conditions), which reveals that the crystalline form remains unchanged and indicative of thermodynamic stable nature.
In yet further another embodiment, it provides that the crystalline Form S1 of Pazopanib Hydrochloride obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules useful in the treatment lung cancer and pancreatic cancer.
Crystalline Form S1 of Pazopanib Hydrochloride of the present invention may have one or more advantageous and desirable properties compared to the known Pazopanib Hydrochloride, which are not limited to better stability, solubility and quality parameter leading to improved storage and distribution.
In another embodiment, the pure crystalline Form S1 of Pazopanib Hydrochloride obtained by the processes of the present application may be formulated as solid compositions for oral administration in the form of capsules, tablets, pills, powders or granules. In these compositions, the active product is mixed with one or more pharmaceutically acceptable excipients. The drug substance can be formulated as liquid compositions for oral administration including solutions, suspensions, syrups, elixirs and emulsions, containing solvents or vehicles such as water, sorbitol, glycerin, propylene glycol or liquid paraffin.
The compositions for parenteral administration can be suspensions, emulsions or an aqueous or non-aqueous sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
Pharmaceutically acceptable excipients used in the compositions comprising Pazopanib Hydrochloride of the present application include, but are not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, pre-gelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, antioxidants and the like.
Pharmaceutically acceptable excipients used in the compositions derived from Pazopanib Hydrochloride of the present application may also comprise to include the pharmaceutically acceptable carrier used for the preparation of solid dispersion, wherever utilized in the desired dosage form preparation.
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
Certain specific aspects and embodiments of the present application will be explained in more detail with reference to the below examples, which are provided by way for illustration purpose only and should not be construed as limiting the scope of the invention in any manner.
The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the present invention.
Example:
STAGE – 1: Synthesis of N-(2-Chloro-4-pyrimidinyl)-2, 3-dimethyl-2H-indazol-6-amine

Charged 900 ml methanol and 100 ml 1, 4 dioxane in 2 L 4 neck round bottom flask at 25-30°C. Charged 100gm 2, 3-dimethyl-2H-indazol-6-amine hydrochloride into above RBF under stirring at 25-30°C. Charged 106.24 gm NaHCO3 under stirring at 25-30°C and stirred the reaction mixture for 10 minutes at 25-30°C. Charged 98.0 gm 2, 4-dichloropyrimidine into the above RBF under stirring at 25-30°C. Stirred the reaction mixture for 10 minutes at 25-30°C. Raised the temperature of reaction mass to 45-50°C under stirring. Maintained the reaction mass for 15 hrs at 45-50°C under stirring. Distilled out reaction mass completely under vacuum at 45-50°C. Charged 1000 ml water into the degas mass and cooled the reaction mass 25 to 30°C. Stirred the reaction mass for 60 minutes at 25 to 30°C. Filtered the solid and wash the wet cake with 200 ml purified water. Suck dried the material for 10 to 15 minute. Charged wet cake again into RBF at 25 to 30°C. Charged 800 ml toluene into above at 25 to 30°C. Raised the temperature of reaction mass to 65-70°C under stirring. Stirred the slurry mass for 40 to 45 minutes at 65-70°C. Cooled the slurry mass to 40 to 45°C under stirring. Stirred the slurry mass for 40 to 45 minutes at 40 to 45°C. Filtered the solid obtained and washed the wet cake with 200 ml toluene. Suck dried the material under vacuum for 15 to 20 minutes. Dried the material under vacuum for 12 hrs at 50-55°C. Unloaded the material.
Output: 115gm
Yield (w/w): 1.15
STAGE-2: Synthesis of N-(2-Chloropyrimidin-4-yl)-N-methyl-2, 3-dimethyl-2H-indazol-6-amine

2a). Charged 750 ml acetone into 2 L 4 neck round bottom flask under stirring at 25-30°C. Charged 100 gm N-(2-Chloro-4-pyrimidinyl)-2, 3- dimethyl- 2H-indazol-6-amine of formula (IV) into above round bottom flask the flask under stirring at 25-35°C. Cool the reaction mass 0 to 10°C under stirring. Added 18.9 gm sodium hydride slowly into the reaction mass under stirring at 0 to 10°C. Stirred reaction mass 10 to 15 minutes at 0 to 10°C. Added 52.3 ml dimethyl sulfate through dropping funnel into reaction mass under stirring at 0 to 10°C. Raised temperature of reaction mass 25-30°C. Maintained the reaction mass for 2 hrs under stirring at 25-30°C. Charged 50 gm ammonium chloride into reaction mass under stirring at 25-30°C. Stirred reaction mass 10 to 15 minutes at 25-30 °C. Charged 2500 ml water slowly into the reaction mass at 25-35°C. Stirred the reaction mixture for 1hrs at 25-35°C. Filtered the solid and washed the cake with 500 ml water. Again washed the wet cake with 100 ml toluene. Suck dried the wet cake for 15 to 30 minutes. Unloaded wet cake and dried the material at 55 to 60°C under vacuum for about 12 hrs. Unloaded the material.
Output: 85gm
Yield (w/w): 0.85

2b). Charged 1000 ml THF into 2 L 4 neck round bottom flask under stirring at 25-30°C. Charged 100 gm N-(2-Chloro-4-pyrimidinyl)-2, 3- dimethyl- 2H-indazol-6-amine of formula (IV) into above round bottom flask under stirring at 25-35°C. Cooled the reaction mass 0 to 10°C under stirring. Added 18.9 gm sodium hydride slowly into the reaction mass under stirring at 0 to 10°C. Stirred reaction mass 10 to 15 minutes at 0 to 10°C. Added 52.3 ml dimethyl sulfate through dropping funnel into reaction mass under stirring at 0 to 10°C. Raised the temperature of reaction mass 25-30°C. Maintained the reaction mass for 2 hrs under stirring at 25-30°C. Charged 50 gm ammonium chloride into the reaction mass under stirring at 25-30°C. Stirred reaction mass 10 to 15 minutes at 25-30°C. Charged 2500 ml water slowly into the reaction mass at 25-30°C. Stirred the reaction mixture for 1hr at 25-30°C. Filtered the solid and washed the cake with 500 ml water. Unloaded wet cake and dry the material at 55 to 60°C under vacuum for about 12 hrs. Unloaded the material.
Output: 87gm
Yield (w/w): 0.87

2c). Charged 750 ml acetone into 2 L 4 neck round bottom flask under stirring at 25-30°C. Charged 100 gm N-(2-Chloro-4-pyrimidinyl)-2, 3- dimethyl- 2H-indazol-6-amine of formula (IV) into above round bottom flask under stirring at 25-35°C. Cooled the reaction mass 0 to 10°C under stirring. Added 23.5 gm sodium hydride slowly into the reaction mass under stirring at 0 to 10°C. Stirred reaction mass 10 to 15 minutes at 0 to 10°C. Added 117.5 gm methyl iodide through dropping funnel into reaction mass under stirring at 0 to 10°C. Raised temperature of reaction mass 25-30°C. Maintained the reaction mass for 2 hrs under stirring at 25-30°C. Charged 50 gm ammonium chloride into reaction mass under stirring at 25-30°C. Stirred reaction mass 10 to 15 minutes at 25-30°C. Charged 2500 ml water slowly into the reaction mass at 25-30°C. Stirred the reaction mixture for 1 hr at 25-30°C. Filter the solid and washed the cake with 500 ml water. Unloaded wet cake and dried the material at 55 to 60°C under vacuum for about 12 hrs. Unloaded the material.
Output: 85gm
Yield (w/w): 0.85
STAGE-3: Synthesis f Pazopanib Hydrochloride crude

Charged 3000 ml methanol and 100 gm N-(2-Chloropyrimidin-4-yl)-N-methyl-2,3- dimethyl-2H-indazol-6-amine of compound of formula (V) to a clean 5 L 4 neck round bottom flask the flask at 25-30°C under stirring. Charged 84.2 gm 5-amino-2-methyl benzenesulfonamide into above reaction under stirring at 25-30°C. Raised temperature of reaction mass 60 to 65°C under stirring. Added 0.5 gm conc. hydrochloric acid into the above reaction under stirring at 60 to 65°C. Maintained the reaction mass for 5 hrs under stirring at 60 to 65°C. Added 0.5 gm conc. Hydrochloric acid into the above reaction under stirring at 60 to 65°C. Maintained the reaction mass for 5 hrs under stirring at 60 to 65°C. Added 0.5 gm conc. Hydrochloric acid into the above reaction under stirring at 60 to 65°C. Maintained the reaction mass for 5 hrs under stirring at 60 to 65°C. Added 0.5 gm conc. Hydrochloric acid into the above reaction under stirring at 60 to 65°C. Maintained the reaction mass for 5 hrs under stirring at 60 to 65°C. Distilled out methanol from reaction mass under vacuum at 60 to 65°C upto 10 to 11 volume (approx.) remain inside reaction mass. Cooled the reaction mass up to 25-30°C. Stirred reaction mass for 1hr at 25-30°C. Filter the solid and washed the cake with 200 ml methanol. Suck dried the wet cake for 10 to 15 minutes. Unloaded cake and dry the material at 60 to 65°C under vacuum for about 12 hrs. Unload the material.
Output: 130gm
Yield (w/w): 1.3
Purity: 99.83 (Area % by HPLC)

STAGE-4: Purification of Pazopanib crude

Charged 6000 ml methanol and 100 gm crude Pazopanib Hydrochloride to a clean 10 L 4 neck round bottom flask the flask at 25-30°C under stirring. Raised the temperature of reaction mass 60 to 70°C. Stirred the reaction mass at 60 to 70°C to clear solution. Added 10 gm activated charcoal into the above reaction mass and maintain for 1 hr at 60 to 70°C. Prepared Hyflo bed using 25 gm hyflo and 200 ml methanol. Filtered the reaction mass through hyflo bed and washed the bed with 100 ml methanol. Collected the filtrate in another round bottom flask. Distilled solvent to reduce reaction volume upto 1000 to 1200 ml in round bottom flask under vacuum at 40 to 50°C. Cool the remaining mass 25 to 30°C under stirring. Filtered the solid and washed the cake with 200 ml methanol. Suck dried the wet cake for 10 to 15 minutes. Unloaded cake and dried the material at 65 to 70°C under vacuum for about 24 hrs. Unloaded the material. The unloaded material is crystalline Pazopanib Hydrochloride of formula (I) is characterised by XRPD diffraction angle peaks at 5.8, 10.7, 13.9, 15.7, 16.5, 17.0, 19.9, 23.7, 24.2, 24.5, 25.5 and 26.2 ± 0.2°2? and DSC thermogram having an endothermic peak ranging between 292±5°C.
Output: 75gm
Yield (w/w): 0.75
Purity: 99.96 (Area % by HPLC)
The above mentioned examples, which are provided by way of illustration, should not be construed as limiting the scope of the invention with respect toparameter/s, ingredient/s and quantities use etc.
,CLAIMS:We Claim:
1. A process for preparing of crystalline Pazopanib Hydrochloride of formula (I),

comprising:
a). condensing 2,3-dimethyl-2H-indazol-6-amine hydrochloride of formula (II) with 2,4-dichloropyrimidine of formula (III), in the presence of a base and 5-15% of ether solvent in alcohol solvent (C1-C4) at a temperature ranging between 35-60°C;

b). reacting N-(2-chloro-4-pyrimidinyl)-2, 3- dimethyl-2H-indazol-6-amine of formula (IV) in the presence of an organic solvent and alkali metal hydride with a methylating agent at a temperature ranging between -5 to 15°C to isolate the compound N-(2-chloropyrimidin-4-yl)-N-methyl-2,3-dimethyl-2H-indazol-6-amine of formula (V);

c). condensing of N-(2-chloropyrimidin-4-yl)-N-methyl-2,3-dimethyl-2H-indazol-6-amine of formula (V) with 5-amino-2-methylbenzenesulfonamide of formula (VI) in the presence of alcohol (C1-C4) solvent and catalytic amount of hydrochloric acid at a temperature ranging between 55-70°C to obtain Pazopanib Hydrochloride crude of formula (VII);

d). purifying the formula (VII) to get the crystalline Pazopanib Hydrochloride of formula (I) having purity greater than 99.9% (Area % by HPLC).
2. The process for the preparation of formula (I) as claimed in claim 1, wherein base used in step a) is selected from sodium bicarbonate, potassium bicarbonate or caesium bicarbonate.
3. The process for the preparation of formula (I) as claimed in claim 1, wherein the ether solvent used in step a) is selected from dioxane, tetrahydropyran.
4. The process for the preparation of formula (I) as claimed in claim 1, wherein the alkali metal hydride used in step b) is selected from lithium hydride, sodium hydride or potassium hydride.
5. The process for the preparation of formula (I) as claimed in claim 1, wherein the methylating agent used in step b) is selected from dimethyl sulphate or methyl iodide and the organic solvent used in step b) is selected from dimethyl ketone, ethyl methyl ketone, isopropyl ketone, methyl isobutyl ketone, diethyl ketone or tetrahydrofuran.
6. The process for the preparation of formula (I) as claimed in claim 1, wherein the alcohol (C1-C4) solvent used in step a) and step c) is selected from methanol, ethanol, isopropanol, n-propanol, n-butanol, isobutanol or tert-butanol.
7. The process for the preparation of formula (I) as claimed in claim 1, wherein catalytic amount of hydrochloric acid used in step c) is 1:50 (%w/w) with respect to N-(2-chloropyrimidin-4-yl)-N-methyl-2,3-dimethyl-2H-indazol-6-amine of formula (V).
8. The process for preparing N-(2-chloropyrimidin-4-yl)-N-methyl-2,3-dimethyl-2H-indazol-6-amine of formula (V) according to step b) of claim 1, comprising the steps of-
a). charging compound of formula (IV) into an organic solvent at room temperature;
b). cool the reaction mass upto 0-10°C under stirring;
c). adding alkali metal hydride and stir for 15 minutes at 0-20°C;
d). adding methylating agent at 0-10°C;
e). raising the reaction mass temperature upto 25-30°C;
f). isolating the compound of formula (V);
g). purifying the compound of formula (V).
9. A crystalline form of Pazopanib Hydrochloride of formula (I) designated as Form S1 is characterised by
i). XRPD diffraction angle peaks at 5.8, 10.7, 13.9, 15.7, 16.5, 17.0, 19.9, 23.7, 24.2, 24.5, 25.5 and 26.2 ± 0.2°2?;
ii). DSC thermogram having an endothermic peak ranging between 292±5°C.
10. The process for preparation of crystalline Form S1 of Pazopanib Hydrochloride of formula (I) as claimed in claim 9, comprising the steps of;
a). providing a mixture of Pazopanib Hydrochloride crude of formula (VII) in methanol;
b). raising the temperature of the reaction mass upto 60-70°C;
c). stirring the reaction mass till dissolution;
d). adding activated carbon;
e). filtering and distilling the reaction mass;
f). cooling the reaction mass to 20°C;
g). isolating the compound of formula (I).