Field of the Invention:

The present invention provides a process for the preparation of crystalline form-XLI of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide compound of 5 formula-1, which is represented by the following structural formula:

Background of the Invention:

INLYTA (Axitinib) is a kinase inhibitor has the chemical name N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide has been shown to inhibit receptor tyrosine kinases including vascular endothelial growth factor receptors (VEGFR)-1, VEGFR-2, and VEGFR-3 at therapeutic plasma concentrations. These receptors are implicated in pathologic angiogenesis, tumor growth, and cancer progression. VEGF-mediated endothelial cell
proliferation and survival were inhibited by Axitinib in vitro and in mouse models. Axitinib was shown to inhibit tumor growth and phosphorylation of VEGFR-2 in tumor xenograft mouse models.

Axitinib, pharmaceutical^ acceptable salts and process for its preparation was first
disclosed in US Patent No. 6534524. 20 International (PCT) Publication No. WO2006/048751 A2 discloses various crystalline forms of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide, Form I, II, III, IV, VI, VII and VIII.
International (PCT) Publication No. WO2008/122858 A2 discloses various crystalline
forms of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide, Form XII, XV, XVI, XXV and XLI.

IPCOM000182442D publication discloses the crystalline form XLVI of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfariyl]-benzamide and process for its preparation.
Brief description of the Invention:

The first aspect of the present invention is to provide a process for the preparation of
crystalline form-XLI of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide compound of formula-1.

The second aspect of the present invention is to provide a process for the purification, of 10 (E)-3 -(2-(pyridin-2-yl)vinyl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazol-6-amine compound of formula-6.

The third aspect of the present rinventipn:4s te iproyide, a process for the purification of (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole compound of 15 formula-7.

The fourth aspect of the present invention is to provide a process for the purification of
(E)-N-methyl-2-(3 -(2-(pyridin-2-yl)vinyl)-1 -(tetrahydro-2H-pyran-2-yl)- 1 H-indazol-6-ylthio)
benzamide compound of formula-9. 20 The fifth aspect of the present invention is to provide an alternative process for the preparation of crystalline form-XLI of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6- ylsulfanyl]-benzamide compound of formula-1.

25 Brief description of the Figures:
Figure 1: Illustrates the PXRD pattern of crystalline form-XLI of N-methyl-2-[3-((E)-2-pyridin-
2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide compound of formula-1.

Figure 2: Illustrates the DSC thermogram of crystalline form-XLI of N-methyl-2-[3-((E)-2-
pyridin-2-yl-vinyl)-1 H-indazol-6-ylsulfanyl]-benzamide compound of formula-1. 30 Figure 3: Illustrates the PXRD pattern of crystalline of N-methyl-2-[3-((E)-2-pyridin-2-yl- vinyl)-lH-indazol-6-ylsulfanyl]-benzamide obtained according to example-9.

Figure 4: Illustrates the PXRD pattern of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-
6-ylsulfanyl]-benzamide obtained according to example-6.

Figure 5: Illustrates the PXRD pattern of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide obtained according to example-7 step-(a).

Detailed description of the Invention:

As used herein the term "suitable solvent" used in the present invention refers to
"hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, toluene, pentane,
cycloheptane, methyl cyclohexane, m-, o-, or p-xylene and the like; "ether solvents" such as
dimethoxymethane, tetrahydrofuran, 1,3-dioxane, 1,4-dioxane, furan, diethyl ether, ethylene
10 glycol dimethyl ether, ethylene glycol diethyl ether, diethylene glycol dimethyl ether, diethylene glycol diethyl ether, triethylene glycol dimethyl ether, anisole, t-butyl methyl ether, 1,2-dimethoxy ethane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide (DMA), dimethylformamide (DMF), dimethylsulfoxide (DMSO), N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutylketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, ethylene glycol, 2- methoxyethanol, 1,2-ethoxyethanol, diethylene glycol, 1, 2, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monoethyl ether, cyclohexanol, benzyl alcohol, phenol, or glycerol and the like; "polar solvents" such as water or mixtures thereof.

The first aspect of the present invention provides a process for the preparation of 25 crystalline form-XLI of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide compound of formula-1, comprising:

a) Adding a suitable solvent to N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-
ylsulfanylj-benzamide compound of formula-1,

30 b) heating the reaction mixture to a suitable temperature,
c) stirring the reaction mixture,

d) optionally, treating the reaction mixture with activated carbon,

e) filtering the reaction mixture through hy-flow bed,

f) distilling off the solvent completely from the reaction mixture,

g) adding a suitable solvent to the solid obtained in step-(f) at a suitable temperature, h) stirring the reaction mixture at a suitable temperature,

i) cooling the reaction mixture to a suitable temperature,
j) filtering the solid and drying under vacuum at 60-70°C,

k) adding a suitable solvent to the solid obtained in step-j),
1) heating the reaction mixture to a suitable temperature,

m) stirring the reaction mixture,

n) cooling the reaction mixture, filtering and drying to get the crystalline form-XLI of
N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide compound of formula-1.
Wherein,

in step-a), g) and k) the suitable solvent is selected from alcohol solvents, ketone
solvents, ether solvents, chloro solvents, ester solvents, polar aprotic solvents, nitrile solvents,
polar solvents such as water and acetic acid or mixture thereof;
in step-b) and 1) the suitable temperature is ranging from ambient temperature to the
reflux temperature of solvent used in the reaction;

in step-i) and n) the suitable temperature is ranging from 0°C to ambient temperature.
The preferred embodiment of the present invention provides a process for the preparation
of crystalline form-XLI of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-
benzamide compound of formula-1, comprising: 25

a) Adding a mixture of acetic acid and methanol to N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide compound of formula-1,

b) heating the reaction mixture to 60-65°C,

c) stirring the reaction mixture,

30 d) optionally, treating the reaction mixture "with activated carbon,

e) filtering the reaction mixture through hy-flow bed,

f) distilling off the solvent completely from the reaction mixture,

g) adding methanol to the solid obtained in step-(f) at 60-65°C,
h) stirring the reaction mixture at 60-65°C,

i) cooling the reaction mixture to 25-30°C,

j) filtering the solid and drying under vacuum at 60-70°C,

5 k) adding ethanol to the solid obtained in step-(j),

1) heating the reaction mixture to 70-75°C, m) stirring the reaction mixture,

n) cooling the reaction mixture, filtering and drying to get the crystalline form-XLI of
N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamid10 compound of formula-
In another preferred embodiment of the present invention provides a process for the
preparation of crystalline form-XLI of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-
ylsulfanyl]-benzamide compound of formula-1, comprising: 15

a) Adding a mixture of acetic acid and methanol to N-methyl-2-[3-((E)-2-pyridin-2-yl-
vinyl)-lH-indazol-6-ylsulfanyl]-benzamide compound of formula-1,

b) heating the reaction mixture to 60-65°C,

c) stirring the reaction mixture

d) optionally, treating the reaction mixture with activated carbon,
e) filtering the reaction mixture through hy-flow bed,

f) distilling off the solvent completely from the reaction mixture,

g) adding isopropanol to the solid obtained in step-(f) at 60-65 °C,

h) stirring the reaction mixture at 75-80°C,

25 i) cooling the reaction mixture to 25-30°C,

j) filtering the solid and drying under vacuum at 60-70°C,

k) adding ethanol to the solid obtained in step-(j),

1) heating the reaction mixture to 70-75°C,

m) stirring the reaction mixture,
30 n) cooling the reaction mixture, filtering and drying to get the crystalline form-XLI of
N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide compound of formula-1.

The crystalline form-XLI of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-yl sulfanyl]-benzamide compound of formula-1 obtained according to the present invention is prepared by using amorphous, hydrate, anhydrate and solvate forms of compound of formula-1.
5 The second aspect of the present invention proyides a process for the purification of (E)-
3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-6-amine compound of formula-6, comprising of,
a) Dissolving the (E)-3 -(2-(pyridin-2-yl)vinyI)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazol
-6-amine compound of formula-6 in a suitable solvent,
10 b) heating the reaction mixture to a suitable temperature,

c) cooling the reaction mixture to a suitable temperature,

d) stirring the reaction mixture,

e) filtering the precipitated solid and drying to get pure (E)-3-(2-(pyridin-2-yl)vinyl)-l-
(tetrahydro-2H-pyran-2-yl)-lH-indazol-6-amine compound of formula-6. 15
Wherein,

In step-a) the suitable solvent is selected from alcohol solvents such as methanol, ethanol,
propanol, isopropanol butanol, isobutanol or mixture thereof, preferably isopropanol;
in step-b) the suitable temperature is ranging from ambient temperature to the reflux
20 temperature of the solvent used in the reaction;

in step-c) the suitable temperature is ranging from -10 to 30°C.
The preferred embodiment of the present invention provides a process for the purification of (E)-3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-6-amine compound of 25 formula-6, comprising of,

a) Dissolving the (E)-3-(2-(pyridin-2-yl)vinyl)-1 -(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-amine compound of formula-6 in isopropanol,

b) heating the reaction mixture to 40-45°C,

c) cooling the reaction mixture to 0-5°C,

30 d) stirring the reaction mixture,

e) filtering the precipitated solid and drying to get pure (E)-3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-6-amine compound of formula-6.

The prior known process for the preparation of (E)-3-(2-(pyridin-2-yl)vinyl)-l-(tetra hydro-2H-pyran-2-yl)-lH-indazol-6-amine compound of formula-6 involves the usage of column chromatography as well as using solvents like nitrile, ether, ketone, ester and hydrocarbon solvents. When inventors of the present invention have repeated the purification using such 5 solvents, they have ended up with the compound of formula-6 as semi solid with low yield and purity. In order to obtain the pure compound of formula-6, requires more number of purification. This leads to the consumption of large amount of solvents and thereby decreases the yield and increases the cost of the process. Further, purification by column chromatography is tedious,

time consuming and not suitable on commercial scale. 10

The above problems were overcame, when the purification of (E)-3-(2-(pyridin-2- yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-6-amine compound of formula-6 was carried out using alcohol solvent such as isopropanol. Surprisingly, they have found that the compound of formula-6 was isolated as a solid with enhanced purity. Hence, when compared over the prior 15 art, the present invention is more advantageous, cost effective and avoids the usage of column chromatography as well as multiple number of purifications.

The third aspect of the present invention provides a process for the purification of (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole compound of formula-20 7, comprising of the following steps:

a) Adding a suitable solvent to (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole compound of formula-7,

b) heating the reaction mixture to a suitable temperature,

c) cooling the reaction mixture to a suitable temperature,
25 d) stirring the reaction mixture,

e) filtering the solid and drying to get (E)-6-iodo-3-(2-(pyridin-2-yl) vinyl)-l-(tetra hydro-2H-pyran-2-yl)-lH-indazole compound of formula-7.

Wherein,

30 In step-a) the suitable solvent is selected from alcohol solvents and ketone solvents or
mixture thereof, preferably a mixture of acetone and isopropanol;
T X

The mole ratio of ketone solvents and alcohol solvents was used in a ratio of 1: 15; preferably 1: 10; more preferably 1: 6.

in step-b) the suitable temperature is ranging from ambient temperature to the reflux 5 temperature of the solvent used in the reaction;

in step-c) the suitable temperature is ranging from 0°C to 25°C.

The preferred embodiment of the present invention provides a process for the purification 10 of (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole compound of formula-7, comprising of the following steps:
a) Adding a mixture of acetone and isopropanol to (E)-6-iodo-3-(2-(pyridin-2-yi)vmyl)-
1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazole compourid of formula-7,

b) heating the reaction mixture to 45-50°C,
15 c) cooling the reaction mixture to 10-15°C,
d) stirring the reaction mixture,

e) filtering the solid and drying to get (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro -2H-pyran-2-yl)-lH-indazole compound of formula-7.

20 WO2006/048745 Al discloses process for the preparation of (E)-6-iodo-3-(2-(pyridin-2- yl)vinyl)-l-(tetra hydro-2H-pyran-2-yl)-l H-indazole compound of formula-7. The said process involves the purification of compound of formula-7 by repeated number of column chromatography purifications. This leads to decrease in the yields, increase in the production cost and further the said column chromatography method is tedious, time consuming and not suitable on commercial scale.
Prior known process involves the purification of (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-1-(tetra hydro-2H-pyran-2-yl)-lH-indazole compound of formula-7 solvents like hydrocarbon solvents, ether solvents, ketone solvents, nitrile solvents and alcohol solvents to provide 30 compound of formula-7 with low purity.

In order to overcome the problems associated with the prior art, the present invention involves the usage of a mixture of ketone and alcohol solvents such as acetone and isopropanol for the purification of compound of formula-7. The compound of formula-7 was obtained with high purity when a mixture of solvents was used. Hence, when compared to the prior known process, the present invention is more advantageous and cost effective.

The fourth aspect of the present invention provides a process for the purification of (E)-5 N-methyl-2-(3-(2-(pyridin-2-yl)viny^ benzamide compound of formula-9, comprising of the following steps:

a) Adding a suitable solvent to (E)-N-methyl-2-(3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-
2H-pyran-2-yl)-lH-indazol-6-ylthio)benzamide compound of formula-9,

b) heating the reaction mixture to a suitable temperature,

10 c) cooling the reaction mixture to a suitable temperature,

d) stirring the reaction mixture,

e) filtering the solid and drying to get (E)-N-methyl-2-(3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1 H-indazol-6-ylthio)benzamide compound of formula-9.

15 Wherein,

In step-a) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, hydrocarbon solvents, polar solvents, ether solvents, polar solvents like water or mixture thereof;
in step-b) the suitable temperature is ranging from ambient temperature to the reflux

20 temperature of the solvent used in the reaction;

in step-c) the suitable temperature is ranging from 0°C to 25°C.
The preferred embodiment of the present invention provides a process for the purification of (E)-N-methyl-2-(3-(2-(pyridin-2-yl)vinyl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazol-6-ylthio) 25 benzamide compound of formula-9, comprising of the following steps:

a) Adding acetone to (E)-N-methyl-2-(3 -(2-(pyridin-2-yl)vinyl)-1 -(tetrahydro-2H-pyran-2-yl)-lH-indazol-6-ylthio)benzamide compound of formula-9,

b) heating the reaction mixture to 45-50°C,

c) cooling the reaction mixture to 10-15°C,

30 d) stirring the reaction mixture,

e) filtering the solid and drying to get (E)-N-methyl-2-(3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-1 H-indazol-6-ylthio)benzamide compound of formula-9.

The fifth aspect of the present invention provides an alternative process for the preparation of crystalline form-XLI of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-yl sulfanyl]-benzamide compound of formula-1, comprising of the following steps:

a) Adding a suitable solvent to crystalline form-IV of N-methyl-2-[3-((E)-2-pyridin-2-5 yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide and stirring the reaction mixture,

b) heating the reaction mixture to a suitable temperature,

c) stirring the reaction mixture,

d) cooling the reaction mixture to a suitable temperature,

e) filtering the solid and drying to get crystalline form-XLI of N-methyl-2-[3-((E)-2-

10 pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide compound of formula-1.Wherein,
In step-a) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents and polar solvent like water 15 or mixture thereof, preferably alcohol solvents;

in step-b) the suitable temperature is ranging from ambient temperature to reflex temperature of the solvent used in the reaction;

in step-d) the suitable temperature is ranging from 0°C to 30°C.
20 The preferred embodiment of the present invention provides an alternative process for the
preparation of crystalline form-XLI of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-l
H-indazol-6-ylsulfanylj-benzamide compound of formula-1, comprising of the following steps:
a) Adding ethanol to crystalline form-IV of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-
lH-indazol-6-ylsulfanyl]-benzamide and stirring the reaction mixture,
25 b) heating the reaction mixture to 65-70°C,

c) stirring the reaction mixture,

d) cooling the reaction mixture to 25-30°C,

e) filtering the solid and drying to get crystalline form-XLI of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-1 H-indazol-6-ylsulfanyl] -benzamide compound of formula-1.

The crystalline forms of N4neffiyl-^ 1 H-indazol-6-yl
sulfanylj-benzamide as depicted in figure-3, 4 and 5 are useful in the preparation of crystalline form-XLI of compound of formula-1.
The crystalline form-XLI of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-yl 5 sulfanyl]-benzamide compound of formula-1, having dimer impurity less than 0.1%; preferably less than 0.05%; more preferably less than 0.03% as measured by HPLC.
N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide compound
of formula-1 produced by the present invention can be further micronized or milled in a 10 conventional techniques 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. 15
The invention also encompasses pharmaceutical compositions comprising compound of
formularl or salts thereof of the present invention. As used herein, the term "pharmaceutical
compositions" or "pharmaceutical formulations" include tablets, pills, powders, liquids,
suspensions, emulsions, granules, capsules, suppositories, or injection preparations. 20
P-XRD Method of Analysis:

PXRD analysis of compounds produced by the present invention were carried out using
BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and
continuous scan speed of 0.0
3°/min. 25
DSC Method of Analysis:
Differential scanning calorimetric (DSC) analysis was performed with Q2000 V24.ll
Build 124 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at
a heating rate of 5°C per minute

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

5 Examples:

Example-1 Preparation of 3-Iodo-6-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (Formula-3)
Dichloromethane (1500 ml) was added to 3-iodo-6-nitro-lH-indazole (150 gms) compound of formula-2 at 25-30°C. 3,4-dihydro-2H-pyran (65.48 gms) followed by p-toluene
10 sulfonic acid (19.72 gms) was slowly added to the above reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Sodium carbonate (75.0 gms) was added to the reaction mixture at 25-30°C and stirred for 45 minutes at the same temperature. Hy-flow (75.0 gms) was added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hy-flow bed and washed with dichloromethane. Distilled
15 off the solvent completely from the filtrate under reduced pressure and co-distilled with acetonitrile. Acetonitrile (150 ml) was added to the obtained compound at 25-30°C. Cooled the reaction mixture to 0-5°C and stirred for 1 XA hour at the same temperature. Filtered the solid, washed with pre-cooled acetonitrile and dried to get the title compound. Yield: 149 gms.

20 Example-2 Preparation of (E)-6-nitro-3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yI)-lH-indazoIe (Formula-5)
Diisopropyl ethylamine (96.79 gms), 2-vinyl pyridine (39.44 gms), tri-o-toluyl phosphine (2.28 gms) and palladium acetate (3.37 gms) were added to a mixture of dimethyl formamide (980 ml) and 3-iodo-6-nitro-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (140 gms) at 25-30°C.

25 Heated the reaction mixture to 100-105°C and stirred for 18 hours at the same temperature. Cooled the reaction mixture to 25-30°C and filtered the reaction mixture through hy-flow bed and washed with dimethyl formamide. To the obtained filtrate, isopropanol (700 ml) was added at 25-30°C. Cooled the reaction mixture to 5-10°C and pre-cooled water (2800 ml) was slowly added to it. Stirred the reaction mixture for'4'5'-minutes atf'5-10°C. Filtered the precipitated solid,

30 washed with water. To the obtained wet compound, isopropanol (420 ml) was added at 25-30°C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 70-75°C and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 1

hour at the same temperature. Filtered the precipitated solid, washed with chilled isopropanol and dried to get the title compound. Yield: 98.2 gms.

Example-3 Preparation of (E)-3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-5 indazoI-6-amine (Formula-6) (E)-6-nitro-3 -(2-(pyridin-2-yl)vinyl> 1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazole (90 gms) was added to a solution of ammonium chloride (103.1 gms) and water (360 ml) at 25-30°C and stirred for 10 minutes at the same temperature. Methanol (900 ml) followed by iron powder (50.2 gms) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 60-65°C and 10 stirred for 5 hours at the same temperature. Cooled the reaction mixture to 25-30°C and filtered the reaction mixture through hy-flow bed and washed with dichloromethane. Water was added to the filtrate at 25-30°C and stirred for 30 minutes at the same temperature. Both the organic and aqueous layers were separated and aqueous layer was extracted with dichloromethane. Combined both organic layers and distilled off the solvent completely from the organic layer under reduced 15 pressure and co-distilled with isopropanol. Isopropanol (270 ml) was added to the obtained compound at 50-55°C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 0-5 °C and stirred for 40 minutes at the same temperature. Filtered the solid, washed with isopropanol and dried to get the title compound. Yield: 69.04 gms; M.R: 138-148°C

20 Example-4 Preparation of (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazole (Formula-7)

(E)-3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-6-amine (60 gms) was added to a pre-cooled solution of water (300 ml) and concentrated hydrochloric acid (60 ml) at 0-5°C. Sodium nitrite solution (sodium nitrite 12.92 gms in water 180 ml) was slowly added to 25 the reaction mixture at 0-5°C and stirred for 15 minutes at the same temperature. Dichloromethane (600 ml) and iodine solution (iodine 23.73 gms, potassium iodide 62.08 gms and water 120 ml) was added to the reaction mixture at 0-5°C and stirred for 1 54 hour at the same temperature. Quenched the reaction mixture using aqueous solution of sodium thio sulfate and sodium carbonate solution at 0-5°C and stirred for 15 minutes at the same temperature. Both 30 the organic and aqueous layers were separated and aqueous layer was extracted with dichloromethane. Combined the organic layers and washed with water. The organic layer was filtered through hy-flow bed and washed the bed with dichloromethane. Distilled off the solvent completely from the filtrate under reduced pressure and co-distilled with isopropanol. Acetone (30 ml) and isopropanol (180 ml) was added to the obtained compound at 45-50°C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture 10-15°C and stirred for 45 minutes at the same temperature. Filtered the solid, washed with isopropanol and dried to get the 5 title compound. Yield: 58.7 gms; M.R: 139-144°C.

Example-5 Preparation of (E)-N-methyl-2-(3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-6-ylthio)benzamide (Formula-9)

10 (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)4-(te^ (520

gms) was dissolved in dimethyl formamide (520 ml) at 25-30°C. 2-Mercapto-N-methyl benzamide (30.25 gms) compound of formula-8, cesium carbonate (64.82 gms) and [1,1-bis(diphenylphospino)ferrocene]dichloro palladium (2.6 gms) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 95-100°C and stirred for 5 hours at the same
15 temperature. Cooled the reaction mixture 25-30°C. Filtered the reaction mixture and washed with dimethyl formamide. Cooled the obtained filtrate to 10-15°C. Slowly added pre-cooled water (1300 ml) to the filtrate at 10-15°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid and washed with water. Dichloromethane (520 ml) and methanol (52 ml) was added to the obtained wet compound at 25-30°C and stirred for 15 minutes at the same

20 temperature. Water was added to the reaction mixture and stirred for 15 minutes. Both the organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed the organic layer with water. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with acetone. To the obtained compound, acetone (156 ml) was added at 40-45°C and

25 stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 10-15°C and stirred for 1 hour at the same temperature. Filtered the solid, washed with acetone and dried to get the title compound. Yield: 72.96 gms; M.R: 140-145°C.

Example-6 Preparation of A^methyW-P-^J^^-pyridin^-yl-vinyO-l/T-indazol^-30 ylsulfanyl]-benzamide (Formula-1)
(E)-6-iodo-3 -(2-(pyridin-2-yl)vinyl)-1 -(tetrahydro-2H-pyran-2-yl)-1 H-indazole (100
gms) was dissolved in dimethyl formamide (1000 ml) at 25-30°C. 2-Mercapto-N-methyl

benzamide (58.16 gms) compound of formula-8, caesium carbonate (188.87 gms) and [1,1-bis(diphenylphospino)ferrocene]dichloro palladium (2.0 gms) were added to the reaction mixture at 25-30°C. Heated the reaction mixture to 95-100°C and stirred for 5 hours at the same temperature. Cooled the reaction mixture 25-30°C. Filtered the reaction mixture and washed with 5 dimethyl formamide. Cooled the obtained filtrate to 10-15°C. Slowly added pre-cooled water (2500 ml) to the filtrate at 10-15°C and stirred for 1 hour at the same temperature. Filtered the precipitated solid and washed with waters Dichloromethane(1000 ml) and methanol (100 ml) was added to the obtained wet compound at 25-30°C and stirred for 15 minutes at the same temperature. Water was added to the reaction mixture and stirred for 15 minutes. Both the

10 organic and aqueous layers were separated and extracted the aqueous layer with dichloromethane. Combined the organic layers and washed the organic layer with water. Distilled off the solvent completely from the organic layer under reduced pressure and co-distilled with acetone. To the obtained compound, acetone (300 ml) was at 40-45°C and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 10-15°C and stirred for 1
15 hour at the same temperature. Filtered the solid and washed with acetone.

Methanol (100 ml) was added to the obtained wet compound at 25-30°C. Methane sulfonic acid (39 gms) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5°C

20 and stirred for 45 minutes at the same temperature. Filtered the precipitated solid, washed with methanol and suck dried the solid. Methanol (300 ml) was added to the obtained wet solid. Heated the reaction mixture to 60-65 °C and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid and washed with methanol and suck dried the solid. Methanol (300 ml) was

25 added to the obtained wet solid. Heated the reaction mixture to 60-65 °C and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 45 minutes at the same temperature. Filtered the solid and washed with methanol.

Water (600 ml) followed by ammonia (20 ml) was added to the obtained compound at
30 25-30°C and stirred for 45 minutes at the same temperature. Filtered the solid and washed with
water. Water was added to the obtained compound at 25-30°C and stirred for 45 minutes at the
same temperature. Filtered the solid and washed with water. Methanol (600 ml) and
dichloromethane (100 ml) was added to the obtained compound at 25-30°C and stirred for 45
minutes at the same temperature. Filtered the solid, washed with methanol and dried to get the
title compound. Yield: 61.96 gms; Melting range: 215-220°C.

The P-XRD pattern of the obtained compound is depicted in figure-4. 5
Example-7 Preparation of crystalline Form-XLI of Af-methyl-2-[3-((l^-2-pyridin-2-yl-
vinyl)-li/-indazol-6-ylsulfanyl]-benzaniide (Formula-1)
a) N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide (50
10 gms) was added to a mixture of acetic acid (500 ml) and methanol (150 ml) at 25-30°C under
nitrogen atmosphere. Heated the reaction mixture to 60-65 °C and stirred for 45 minutes at the same temperature. Activated carbon (10 gms) was added to the reaction mixture at 60-65°C and stirred for 1 hour at the same temperature. Filtered the reaction mixture through hy-flow bed and washed with a mixture of acetic acid and methanol. Distilled off the solvent completely from the 15 filtrate under reduced pressure. Methanol (500 ml) was added to the obtained compound at 60-65°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the solid, washed with methanol and dried the solid at 65-70°C for 10 hours.

The P-XRD pattern of the obtained compound is depicted in figure-5. 20

b) Ethanol (500 ml) was added to the above dried solid at 25-30°C. Heated the reaction
mixture to 65-70°C and stirred for 6 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the solid, washed with ethanol and dried to get the title compound. Yield: 34 gms; Melting point: 225.88 (by DSC); Purity by HPLC: 99.98 %. 25 The P-XRD pattern and DSC of the obtained compound is depicted in figure-1 and 2 respectively.

Example-8 Preparation of crystalline Form-XLI of JV-methyl-2-[3-((£])-2-pyridin-2-yl-vinyl)-l//-indazol-6-yIsulfanyI]-benzamide (Formula-1) 30 N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide (700 gms) was added to a mixture of acetic acid (7000 ml) and methanol (2100 ml) at 25-30°C under nitrogen atmosphere. Heated the reaction mixture to 60-65°C and stirred for 45 minutes at the same temperature. Activated carbon (140 gms) was added to the reaction mixture at 60-65°C andstirred for 1 hour at the same temperature. Filtered the reaction mixture through hy-flow bed and washed with a mixture of acetic acid and methanol. Distilled off the solvent completely from the filtrate under reduced pressure. Isopropanol (7000 ml) was added to the obtained compound at 70-75°C and stirred for 4 hours at the same temperature. Cooled the reaction mixture to 25-30°C. 5 Filtered the solid, washed with methanol and dried the solid at 65-70°C for 10 hours. Ethanol (7000 ml) was added to the above dried solid at 25-30°C. Heated the reaction mixture to 65-70°C and stirred for 6 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the solid, washed with ethanol and dried to get the title compound. Yield: 35 gms. The P-XRD pattern of the obtained compound is depicted in figure-1. 10 Example-9 Preparation of 7V-methyl-2-[3-((£^-2-pyridin-2-yI-vinyI)-l/f-indazoI-6-ylsulfanyl]-benzamide (Formula-1)

Methanol (350 ml) was added to (E)-N-methyl-2-(3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-6-ylthio)benzamide (98 gms) at 25-30°C. Methane 15 sulfonic acid (39 gms) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 3 hours at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 45 minutes at the same temperature. Filtered the precipitated solid and washed with methanol. To the obtained compound, methanol (300 ml) was added at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 1 hour at the same temperature. Cooled the reaction

20 mixture to 0-5°C and stirred for 45 minutes at the same temperature. Filtered the solid and washed with methanol. To the obtained compound, methanol (300 ml) was added at25-30°C. Heated the reaction mixture to 60-65°C and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 45 minutes at the same temperature. Filtered the solid, washed with methanol and dried the solid. Yield: 69 gms.

25 The P-XRD pattern of the obtained compound is depicted in figure-3.

Example-10 Preparation of crystalline Form-IV of iV-methyl-2-[3-((J^)-2-pyridin-2-yl-vinyl)-l//-indazol-6-yl sulfanyl]-benzamide (Formula-1)

30 N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide (35 gms)
was added to a mixture of methanol (105 ml) and acetic acid (350 ml) at 25-30°C under nitrogen atmosphere. Heated the reaction mixture to 60-65°C and stirred the reaction mixture for 45

I

minutes at the same temperature. Carbon (7.0 gms) was added to the reaction mixture at 6Q-65°C
and stirred for 1 hour at the same temperature. Filtered the reaction mixture through hy-flow bed
and wash the bed with a mixture of hot methanol and acetic acid. Distilled off the solvent
completely from the filtrate under reduced pressure and co-distilled with a mixture of m-xylene
5 (35 ml) and n-heptane (315 ml). To the obtained solid, n-Heptane (350 ml) was added at 85-
90°C under nitrogen atmosphere stirred for 30 minutes at the same temperature. Slowly cooled
the reaction mixture to 25-30°C and stirred for 30 minutes at the same. Filtered the precipitated
solid, washed with n-heptane and dried to get the title compound.

Yield: 31.9 gms; M.R: 215-220°C; Purity by HPLC: 99.89%. 10
Example-11 Preparation of crystalline Form-XLI of Af-methyl-2-[3-((£)-2-pyridin-2-yl-
vinyl)-l//-indazol-6-yl sulfanyl]-benzamide (Formula-1) Ethanol (50 ml) was added to N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-yl sulfanylj-benzamide (5 gms) at 25-30°c and stirred for 15 minutes at the same temperature. 15 Heated the reaction mixture to 65-70°C and stirred for hours at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the reaction mixture, washed with ethanol and dried to get the title compound. Yield: 7.3 gms; The P-XRD pattern of the obtained compound is depicted in figure-1.

20 Example-12 Preparation of crystalline Form-XLI of iV-methyl-2-[3-((^>2-pyridin-2-yI-vinyl)-l//-indazoI-6-ylsuIfanyI]-benzamide (Formula-1)

N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide (50 gms) was added to a mixture of acetic acid (500 ml) and methanol (150 ml) at 25-30°C under nitrogen atmosphere. Heated the reaction mixture to 60-65°C and stirred for 45 minutes at the same

25 temperature. Distilled off the solvent completely from the reaction mixture under reduced pressure. Methanol (500 ml) was added to the obtained compound at 60-65°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 25-30°C. Filtered the solid, washed with methanol. Ethanol (500 ml) was added to the above dried solid at 25-30°C. Heated the reaction mixture to 65-70°C and stirred for 6 hours at the same temperature. Cooled the

30 reaction mixture to 25-30°C. Filtered the solid, washed with ethanol and dried to get the title compound.

We Claim:
1. A process for the preparation of crystalline form-XLI of N-methyl^-P-^E^-pyridin^-
yl-viny^-lH-indazol^-ylsulfanyll-benzamide compound of formula-1, comprising:

5 a) Adding a suitable solvent to N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-
ylsulfanyl]-benzamide compound of formula-1,
b) heating the reaction mixture to a suitable temperature,
c) stirring the reaction mixture,
d) optionally, treating the reaction mixture with activated carbon, 10 e) filtering the reaction mixture through hy-flow bed,

f) distilling off the solvent completely from the reaction mixture,
g) adding a suitable solvent to the solid obtained in step-(f) at a suitable temperature, h) stirring the reaction mixture at a suitable temperature,
i) cooling the reaction mixture to a suitable temperature,
15 j) filtering the solid and drying under vacuum at 60-70°C,
k) adding a suitable solvent to the solid obtained in step-j),
1) heating the reaction mixture to a suitable temperature,
m) stirring the reaction mixture,
n) cooling the reaction mixture, filtering and drying to get the crystalline form-XLI of
20 N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide
compound of formula-1.
2. The process according to claim-1, wherein,
in step-a), g) and k) the suitable solvent is selected from alcohol solvents, ketone solvents, ether solvents, chloro solvents, ester solvents, polar aprotic solvents, nitrile solvents, 25 polar solvents such as water and acetic acid or mixture thereof;
in step-b) and 1) the suitable temperature is ranging from ambient temperature to the reflux temperature of solvent used in the reaction;
in step-i) and n) the suitable temperature is ranging from 0°C to ambient temperature.
30 3. A process for the preparation of crystalline form-XLI of N-methyl-2-[3-((E)-2-pyridin-2-
yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide compound of formula-1, comprising:

a) Adding a mixture of acetic acid and methanol.to N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide compound of formula-1,
b) heating the reaction mixture to 60-65°C,
c) stirring the reaction mixture,
5 d) optionally, treating the reaction mixture with activated carbon,
e) filtering the reaction mixture through hy-flow bed,
f) distilling off the solvent completely from the reaction mixture,
g) adding methanol to the solid obtained in step-(f) at 60-65 °C, h) stirring the reaction mixture at 60-65°C,
10 i) cooling the reaction mixture to 25-30°C,
j) filtering the solid and drying under vacuum at 60-70°C,
k) adding ethanol to the^ solid obtained;intstep-(j),
1) heating the reaction mixture to 70-75 °C,
m) stirring the reaction mixture,
15 n) cooling the reaction mixture, filtering and drying to get the crystalline form-XLI of
N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide compound of formula-1.
4. Use of crystalline forms of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6-yl
20 sulfanylj-benzamide as depicted in figure-3, 4 and 5 in the preparation of crystalline
form-XLI of compound of formula-1.
5. A process for the purification of (E)-3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-
yl)-lH-indazol-6-amine compound of formula-6, comprising of,
25 a) Dissolving the (E)-3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-lH-indazol
-6-amine compound of formula-6 in isopropanol,
b) heating the reaction mixture to 40-45°C,
c) cooling the reaction mixture to 0-5 °C,
d) stirring the reaction mixture,
30 e) filtering the precipitated solid and drying to get pure (E)-3-(2-(pyridin-2-yl)vinyl)-l-
(tetrahydro-2H-pyran-2-yl)-lH-indazol-6-amine compound of formula-6.

6. A process for the purification of (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-
pyran-2-yl)-lH-indazole compound of formula-7, comprising of the following steps:
a) Adding a mixture of acetone and isopropanol to (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-
l-(tetrahydro-2H-pyran-2-yl)-lH-indazole compound of formula-7,
5 b) heating the reaction mixture to 45-50°C,
c) cooling the reaction mixture to 10-15°C,
d) stirring the reaction mixture,
e) filtering the solid and drying to get (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-l-(tetra hydro-2H-pyran-2-yl)-lH-indazole compound of formula-7.
10 Wherein, in step-a) the mole ratio of acetone and isopropanol is in the ratio of 1: 15;
preferably 1: 10; more preferably 1: 6.
7. A process for the purification of (E)-N-methyl-2-(3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro
-2H-pyran-2-yl)-lH-indazol-6-ylthio)benzamide compound of formula-9, comprising of
15 the following steps:
a) Adding acetone to (E)-N-methyl-2-(3-(2-(pyridin-2-yl)vinyl)- l-(tetrahydro-2H-pyran-2-yl)-lH-indazol-6-ylthio)benzamide compound of formula-9,
b) heating the reaction mixture to 45-50°C,
c) cooling the reaction mixture to 10-15°C,
20 d) stirring the reaction mixture,
e) filtering the solid and drying to get (E)-N-methyl-2-(3-(2-(pyridin-2-yl)vinyl)-l-(tetrahydro-2H-pyran-2-yl)-1 H-indazol-6-ylthio)benzamide compound of formula-9.
8. An alternative process for the preparation of crystalline form-XLI of N-methyl-2-[3-((E)-
25 2-pyridin-2-yl-vinyl)-1 H-indazol-6-ylsulfanyl]-benzamide compound of formula-1,
comprising of the following steps:
a) Adding a suitable solvent to crystalline form-IV of N-methyl-2-[3-((E)-2-pyridin-2-
yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide and stirring the reaction mixture,
b) heating the reaction mixture to a suitable temperature,
30 c) stirring the reaction mixture,
d) cooling the reaction mixture to a suitable temperature,
e) filtering the solid and drying to get crystalline form-XLI of N-methyl-2-[3-((E)-2-

pyridin-2-yl-vinyl)-1 H-indazol-6-ylsulfanyl]-benzamide compound of formula-1.
9.
5
The process according to claim-8, wherein, in step-a) the suitable solvent is selected from alcohol solvents, ketone solvents, ester solvents, hydrocarbon solvents, ether solvents, polar aprotic solvents and polar solvent like water or mixture thereof, preferably alcohol solvents; in step-b) the suitable temperature is ranging from ambient temperature to reflex temperature of the solvent used in the reaction; in step-d) the suitable temperature is ranging from 0°C to 30°C.
10 10. The crystalline form-XLI of N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-mdazol-6-yl
sulfanylj-benzamide compound of formula-1 obtained according to the any of the preceding claims, the having dimer impurity less than 0.1%; preferably less than 0.05%; more preferably less than 0.03% as measured by HPLC.