WO2016108106A1

WO2016108106A1 - An improved process for preparation of axitinib

Info

Publication number: WO2016108106A1
Application number: PCT/IB2015/059346
Authority: WO
Inventors: Vimal Kumar Shrawat; Bhagat Raj PIPAL; Chaturvedi AKSHAY KANT
Original assignee: Shilpa Medicare Ltd
Current assignee: Shilpa Medicare Ltd
Priority date: 2014-12-29
Filing date: 2015-12-04
Publication date: 2016-07-07
Anticipated expiration: 2017-06-29

Abstract

The present invention relates to an improved process for the preparation Axitinib Formula (I). The present further relates to Axitinib containing the process related impurities A, B, C, D, E and F collectively below 0.3% and having a purity of greater than 99.5%.

Description

AN IMPROVED PROCESS FOR PREPARATION OF AXITINIB FIELD OF THE INVENTION

The present invention relates to an improved process for the preparation Axitinib Formula (I).

BACKGROUND OF THE INVENTION

N-methyl-2-[3-((E)2-pyridin-2-yl-vinyl)-lH-indazol-6-ylsulfanyl]-benzamide or Axitinib is tyrosine kinase inhibitor of vascular endothelial growth factor receptors (VEGFR)-l, VEGFR-2 and VEGFR-3. These receptors are implicated in pathologic angiogenesis, tumour growth, and metastatic progression of cancer. Axitinib has been shown to potently inhibit VEGF-mediated endothelial cell proliferation and survival. Axitinib inhibited the phosphorylation of VEGFR-2 in xenograft tumor vasculature that expressed the target in vivo and produced tumor growth delay, regression, and inhibition of metastases in many experimental models of cancer.

Axitinib is chemically known as N-methyl-2-[3-((E)-2-pyridin-2-yl-vinyl)-lH-indazol-6- ylsulfanyl]-benzamide (I). Axitinib is weak base, non-hygrospic, classified as Bio pharmaceutics Classification System (BCS) class II (low solubility, high permeability), and exhibits polymorphism.

Axitinib was approved by USFDA in 2012 and is marketed under the brand name Inlyta^®, and is indicated for the treatment of adult patients with advanced renal cell carcinoma (RCC) after failure of prior systemic treatment. Axitinib is marketed in a crystalline Form XLI.Axitinib is a white to light yellow powder with the empirical formula C22 Η18 N40S and a molecular weight of 386.47 Daltons. It acts as a highly soluble compound at below pH 5 and the solubility decreases with increase in pH. The solubility of Axitinib in aqueous media over the range pH 1.1 to pH 7.8 is in excess of 0.2 μ^πιΐ_^. The partition coefficient (n-octanol/water) is 3.5.

As per the scientific discussion "Five crystalline anhydrous forms have been identified (Form I, Form IV, Form VI, Form XXV and Form XLI). A number of crystalline solvates and hydrate forms have been observed and an amorphous form has been prepared. The polymorphic form intended for marketing is Form XLI. " Axitinib is generically and specifically disclosed in US 6,534,524. The process disclosed for

A iti ib

This patent not provided and insight about the impurity concern as well as disclosure of any purity of the final product.The process looks cumbersome and involves the formation of so many impurities as disclosed in Organic process Research and development 2014 18(1), 266-274. In view of this it is necessary to develop a process resulting in the product, which is complying with the ICH requirements of quality parameters.

US 7,232,910 and Organic process Research and development (OPRD) 2014 18(1), 266- 27

This patent further disclosed two more route of synthesis for the preparation of Axitinib. However, this patent not disclosed any generalized impurities formed during the process development. This patent not disclosed perfect purity obtained as per this process, this patent broadly mentioned the purity as > 99 % and does not disclosed the content of total impurities formed in the final active pharmaceutical ingredient (API).

Organic process Research and development 2014 18(1), 266-274 disclosed that condensation of 6-iodoindazole with 2-Mecapto N-methyl benzamide in presence of palladium catalyst leads to the formation of Xantphos impurities. The proposed mechanism for exchange of aryl groups on Xantphos and the observed side products are clearly disclosed in scheme 5 of this Journal. Further, this Journal clearly discloses that the formation of these impurities due to incompletion of reaction.

US 2006/0094763 discloseddifferent crystalline forms like crystalline Form I, Form II, Form III, Form IV, Form VI, Form VII and Form VIII of Axitinib. Further, this patent not disclosed any specific synthesis for the preparation of Axitinib.

US 2010/0179329 disclosed some more different crystalline forms like crystalline Form XLI, Form XXV, Form IX, Form XII, Form XV and amorphous form of Axitinib. Further, this patent not disclosed any specific synthesis for the preparation of Axitinib.

In view of the above it is pertinent to note that there is a need to develop new process for the preparation of Axitinib having further improved physical and/or chemical properties besides high purity levels. Hence it was thought worthwhile by the inventors of the present application to explore novel process for the preparation of Axitinib, which may further improve the characteristics of drug Axitiniband in developing the substantially pure Axitinib.

As polymorphism has been given importance in the recent literatures owing to its relevance to the drugs having oral dosage forms due to its apparent relation to dose preparation/suitability in composition steps/ bioavailability and other pharmaceutical profiles, stable polymorphic form of a drug has often remained the clear choice in compositions due to various reasons of handling, mixing and further processing including bioavailability and stability.

Exploring new process for developing a stable and pure form of Axitinib, which are amenable to scale up for pharmaceutically active useful compoundsin the preparation of Axitinib may thus provide an opportunity to improve the drug performance characteristics of products such as purity and solubility.Hence, inventors of the present application report a process for the preparation of a stable and substantially pure form of Axitinib, which may be industrially amenable and usable for preparing the corresponding pharmaceutical compositions.

The present invention provides an improved process for the preparation of substantially pure Axitinib, wherein substantially pure material having a purity of greater than 99.5% by HPLC and meeting the quality of ICH guidelines. Axitinibobtained by the process of the present invention is non-hygroscopic and chemically stable and has good dissolution properties.

In view of the above and to overcome the prior-art problems the present inventors had now developed an improved process for the preparation of substantially pure Axitinib, using industrially feasible and viable process, with the use of industrially friendly solvents, which does not include tedious work up and time lagging steps.

OBJECTIVE OF THE INVENTION

The main objective of the invention relates to a process for the preparation of Axitinib.

Yet another objective of the invention relates to a process for the preparation of substantially pure Axitinib, wherein Axitinib contains the process related impurities A, B, C, D, Eand F collectively below 0.3% and having a purity of greater than 99.5% (By HPLC).

Yet another objectiveof the invention relates a process for the preparation of Axitinib, which is free of process related impurities.

SUMMARY OF THE INVENTION

The present invention relates to a process for the preparation of Axitinib of Formula (I)

comprising the steps of - a) reacting 6-iodolH-indazole (II) with 2-mercapto-N-methylbenzamide(III) in presence of a metal halide to provide a 2- lH-indazol-6-yl)thio)-N-meth lbenzamide(IV);

b) halogenating compound of formula (IV) to provide 2-((3-iodo-lH-indazol-6-yl)thio)-N- methylbenzamide V); and

c) reacting compound of Formula (V) with an acylating agent followed by condensation with 2- Vinyl pyridine (VI) in the presence of organic base upto at least 3.5 Molar equivalent with respect to Formula (V) to provide Axitinib(I)

The present invention further relates to Axitinib that contains the process related impurities A, B, C, D, Eand F collectively below 0.3%.

Impurity-C Impurity-D

Impurity-E Impurity-F

The present invention further relates a process for the preparation of Axitinib of Formula (I),

wherein intermediate 2-((lH-indazol-6-yl)thio)-N-methylbenzamide(IV) is prepared comprising reacting 6-iodo lH-indazole (II) with 2-mercapto-N-methylbenzamide(III) in presence of a metal halide to provide a 2-((lH-indazol-6-yl)thio)-N-methylbenzamide(IV)

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a process for the preparation of Axitinib of Formula (I)comprising the steps of reacting 6-iodo lH-indazole (II) with 2-mercapto-N- methylbenzamide(III) in presence of a metal halide selected from Copper iodide, Sodium iodide, Potassium iodide; using a solvent selected from alcohol (CI -4) or Ketones (C3-6) or organic solvents (Cl-8 alkanes, dimethyl formamide, toluene, xylene) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran, Di-isopropyl ether ) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof; at a temperature ranging from 50°C to 90°C for a period of 20 hours to 30 hours to provide a 2-((lH-indazol- 6-yl)thio)-N-methylbenzamide(IV).

The use of metal halide in the condensation steps leads to the formation of substantially pure2-((lH-indazol-6-yl)thio)-N-methylbenzamide(IV), which further leads to the formation of highly pure Axitinib, which is free of process related impurities.

The prior art process clearly disclose that the condensation of 6-iodo lH-indazole (II) with 2-mercapto-N-methylbenzamide(III) is incomplete and around 10-12 % of 6-iodo indazole left blank, does not participate in the reactionand leads to the formation of process related impurities. The present inventors made so many changes to yield pure material using the prior art process. However, the present inventors failed in attaining the same. This is due to the use of Pd- catalyzed condensation reaction.

The present inventors surprisingly found that, the use of metal halide in present invention in the condensation step leads to completion of the reaction and minimizes the formation of process related impurities as well as side products as disclosed in the prior art, which finally leads to the formation of Axitinib, which is free of process related impurities A, B, C, D, E and F collectively below 0.3% and having a purity of greater than 99.5% (By HPLC).

Impurity-E Impurity-F The prior art publications discloses a use of Pd catalyzed reagents, which leads to the formation of process related impurities, and is carried out for further steps results in the formation of Axitinib having the corresponding excessively halogenated impurities. The Axitinib obtained as per the prior- art process does not meet the requirements of ICH guidelines. Extra purification is required to remove these process related impurities, which is cumbersome and the yield of the product is also comparatively low with respect to the present invention. However, the present inventors surprisingly found that the use of metal halide in the condensation step leads to the formation of pure condensed material, which leads to the formation of highly pure Axitinib free of process related impurities, which is novel and inventive and does not involve any extra purification for the as preparation of pure Axitinib.

The obtained pure 2-((lH-indazol-6-yl)thio)-N-methylbenzamide(IV) is halogenated using a halogen source selected from Iodine, Bromine, Chlorine, thionyl chloride, oxalyl chloride, Phosphorous tri-chloride, Phosphorous penta-chloride, Phosphorous oxy chloride; using a solvent selected from alcohol (CI -4) or Ketones (C3-6) or organic solvents (CI -8 alkanes, dimethyl formamide, toluene, xylene) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran, Di- isopropyl ether ) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof; at a temperature ranging from 25 °C to 60°C for a period of 2 hours to 6 hours to provide 2-((3-iodo-lH-indazol-6-yl)thio)-N- methylbenzamide( V) ;

The use of metal iodide in the previous step leads in the completion of reaction, which minimizes the formation of excess halogenated products, which further controls to carry forward to the next steps and leads to the excessive condensed impurities.

The obtained pure 2-((3-iodo-lH-indazol-6-yl)thio)-N-methylbenzamide(V) is directly taken forward for the next step and does not require further purifications to control the level of impurities as reportedin the prior art. Pure 2-((3-iodo-lH-indazol-6-yl)thio)-N- methylbenzamide(V) is reacted with anacylating agent selected fromAcetyl halides such as acetyl chloride, acetyl bromide or Acetic anhydride; to yield anacylated product, which was not isolated and continued to the next step by condensing with 2- Vinyl pyridine (VI) in presence of anorganic base selected from diisopropylethylamine, ethylamine, propyl amine, methyl amine and tertiary butyl amine upto at least 3.5 molar equivalent with respect to2-((3- iodo-lH-indazol-6-yl)thio)-N-methylbenzamide; and using a solvent selected from alcohol (Cl-4) or Ketones (C3-6) or organic solvents (Cl-8 alkanes, dimethyl formamide, toluene, xylene) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran, Di-isopropyl ether ) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof; at a temperature ranging from 25 °C to 60°C for a period of 2 hours to 6 hours to provide Axitinib(I). The Axitinibof the compound of the formula (I) obtained from the above stage may be purified by treating the compound of the formula (I) or a reaction mixture or a solvated form thereof is treated with an acid selected from methane sulphonic acid, sulphuric acid, trifluoro- methanesulphonic acid, difluoromethanesulphonic acid, dichloroacetic acid, glucornic acid, gluconic acid, Ferulate, glycols and glycol ethers; to form a salt of the compound of the formula (I) which precipitates from the solution containing the solvated compound of the formula (I), the salt of the compound of the formula (I) is then treated with an aqueous basic solution to precipitate the pure form of compound of the formula (I), preferably at a temperature of from 15° C. to 45° C, most preferably from 25° C. to 35° C. If required, repeat again the acidification followed by basification to obtained desired purity, which is greater than 99.5 %.

The Axitinib of the compound of the formula (I) is dissolved in a solvent selected from solvent selected from alcohol (Cl-3) or Ketones (C3-6) or organic solvents (Cl-8 alkanes, dimethyl formamide) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof. To the obtained solution acid was added at a temperature ranging from -10 to 30°C for 30 min to 2 hrs to yield wet product, which was dried under vacuum at 50-55°C for 2hrs to yieldAxitinib acid salt.

The obtained Axitinib acid saltis dissolved in a solvent selected from solvent selected from alcohol (Cl-4) or Ketones (C3-6) or organic solvents (Cl-8 alkanes, dimethyl formamide, toluene, xylene) or halogenated organic solvents (Methylene dichloride, Ethylene dichloride) or Ethers (Methyl tertiary butyl ether, tetrahydrofuran, Di-isopropyl ether ) or sulphoxides (dimethyl sulphoxide) or esters (Ethyl acetate, benzyl acetate, isoamyl acetate) or water or mixtures thereof at a temperature ranging from 25-30°C and stirred for 30min to get clear solution. The obtained solution was treated with an alkaline solution, wherein alkaline solution used is prepared using a base selected from organic base such as triethylamine, methylamine, pyridine, imidazole, benzimidazole; or inorganic base selected from carbonates such as sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate; hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide, ammonium hydroxide, barium hydroxide, magnesium hydroxide, lithium hydroxide, zinc hydroxide; bicarbonates such as sodium bicarbonate, potassium bicarbonate, ammonium bicarbonate, calcium bicarbonate, magnesium bicarbonate; in a solvent selected from organic solvent or water. The reaction mass was stirred for 30 min to 4 hrs depending on the acid used. After completion of the reaction, the reaction mass was cooled to a temperature ranging from 0- 10°C and maintained the reaction mass under stirring for 30min to 4 hrs. The precipitated product was filtered, washed with organic solvent or a mixture of organic solvent or mixture of organic solvent and water to get wet cake, which was dried under vacuum at 50-85°C for 3 hrs to 6hrs to yield pure Axitinib.

The obtained pure Axitinib was analyzed, if it is not matching with the desired purity; again repeat the process by treating the Axitinib with acid to prepare the corresponding salt, followed by treating with an alkali solution to obtain substantially pure Axitinib having a purity of greater than 99.5% and meeting the ICH guidelines.

In yet another embodiment of the invention related to a process for the preparation of substantially pure Axitinib, wherein substantially pure Axitinib contains the process related impurities A, B, C, D, E and F collectively below 0.3% and meeting the ICH guidelines.

Another embodiment of the present invention relates to a process for the preparation of Axitinib of Formula (I), wherein intermediate 2-((lH-indazol-6-yl)thio)-N- methylbenzamide(IV) is prepared comprising reacting 6-iodolH-indazole (II) with 2- mercapto-N-methylbenzamide(III) in presence of a metal halide to provide a 2-((lH-indazol- 6-yl)thio)-N-methylbenzamide(IV). Another embodiment of the present invention relates to substantially pure Axitinib having a purity of greater than 99.5 %, wherein substantially pure Axitinib is having an impurity profile meeting the ICH guidelines.

Another embodiment of the present invention relates to substantially pure Axitinib having a purity of greater than 99.5 %, wherein substantially pure Axitinib contains the process related impurities A, B, C, D, E and F collectively below 0.3% area percentage by HPLCand meeting the ICH guidelines.

The process related impurities that appear in the impurity profile of the Axitinib (I) may be substantially removed by the process of the present invention resulting in the formation of substantially Axitinib (I), which meets the ICH guidelines.

The merit of the process according to the present invention resides in that product isolated after drying is stable and having a purity of greater than 99.5% purity by HPLC, which was not disclosed in any of the prior-art. The product obtained as per the present invention is highly pure than the any of the prior-art products obtained. Still now no-publication discloses a purity of greater than 99.5%.

Solubility is one of the important parameters to achieve desired concentration of drug in systemic circulation for achieving required pharmacological response. Poorly water soluble drugs often require high doses in order to reach therapeutic plasma concentrations after oral administration. Low aqueous solubility is the major problem encountered with formulation development of new chemical entities as well as generic formulation development. Most of the drugs are either weakly acidic or weakly basic having poor aqueous solubility. The improvement of drug solubility thereby its oral bio-availability remains one of the most challenging aspects of drug development process especially for oral-drug delivery system. The poor solubility and low dissolution rate of poorly water soluble drugs in the aqueous gastrointestinal fluids often cause insufficient bioavailability. The enhancement in the purity of Axitinib, which is free of process related impurities inherently, increases the solubility of Axitinib, which plays a major role for enhancement of drug dissolution rate in solid oral dosage forms.

The present invention also relates to a process for the preparation of Axitinib, which is substantially pure having a purity of greater 99.5 % and meeting the ICH guidelines, by limiting the content of each impurity less than 0.3%. Further, the Axitinib obtained as per the present process is found devoid of any other process related impurities and is adequately stable to handle and store for longer time (at least up to more than 6 months) without any significant or measurable change in its morphology and physicochemical characteristics.

Drying may be also be performed by any conventional process not limited to spray drying or distillation to remove the solvent. Drying may be performed under reduced pressure conditions also. Reduced pressure conditions may be suitably utilized by person skilled in the art in order to obtain the dried material. The drying may be performed at a temperature ranging from 50-85°C for a time ranging from 5 to 10 hours depending upon the physical attributes of the end product obtained i.e. Pure Axitinib, which is obtained according to the present invention is having purity greater than 99.5%.

In another embodiment of the present invention the substantially pure Axitinib obtained by the processes of the present application may be taken as such in crystalline form for manufacture of solid dosage forms like tablets, capsules and/or for manufacture of oral liquids.

In another embodiment of the present invention the substantially pure Axitinib or its acid addition salt obtained by the processes of the present application may be manufactured as the amorphous form by processing with polymers like hydroxypropyl methylcellulose acetate succinate (HPMC-AS).

In another embodiment, the substantially pure Axitinib or its acid addition saltobtained 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.

In one embodiment of the present invention, it also includes premix comprising one or more pharmaceutically acceptable excipients in the range of 1 to 50% w/w with the substantially pure Axitinibor its acid addition salt, while retaining the crystalline nature of the premix

The compositions for parenteral administration can be suspensions, emulsions or 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 substantially pure Axitinib or its acid addition saltobtained as per the present application process- include, but are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, di-calcium phosphate, tri-calcium 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 substantially pure Axitinib or its acid addition saltof 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. 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 invention.

EXAMPLES

Example- 1

Preparation of 2-((lH-indazol-6-yl)thio)-N-methylbenzamide(IV)

Potassium carbonate (5.65 g, 0.0408 mol) and copper iodide (0.390 g, 0.0021 mol) are charged in to the reaction vessel containing isopropyl alcohol (50 ml) and ethylene glycol (2.54 g, 0.0409 mol) at 25-30 °C under nitrogen atmosphere. 6-Iodo-lH-indazole (5.0 g, 0.0204 mol) and 2-Mercapto-N-methylbenzamide (3.94 g, 0.0235 mol) were slowly added at 25-30 °C under stirring. The reaction mixture was heated to about 80°C and maintained for 20-24 hrs. The reaction mixture was cooled to 25-30°C under stirring. The reaction mixture filtered and filtrate concentrated to residue under vacuum. Water (50 ml) was added to the residue and stirred for 2-3 hrs. Filtered the solid, washed with water (10 ml) and dried under vacuum to obtain 2-((lH-indazol-6-yl)thio)-N-methylbenzamide (IV).

Yield: 4.20 g (72.41 % w/w),

Chromatographic Purity (By HPLC): 98.18% .

Example-2

Preparation of 2-((3-iodo-lH-indazol-6-yl)thio)-N-methylbenzamide(V)

N-methylpyrrolidone or NMP (11.9 ml) and 2-((lH-indazol-6-yl)thio)-N-methylbenzamide (3.4 g, 0.0119 mol) was charged into a RB flask at 25-30 °C in nitrogen atmosphere. Iodine(6.39 g, 0.0503 mol) solution prepared in NMP (3.91 ml) was slowly added at 25-30 °C under stirring. Added the solution of potassium hydroxide (3.10 g, 0.0552 mol) in water (3.4 ml) over at least 30 min at 25-30 °C under stirring. The reaction mixture was stirred at 25-30 °C for 5 hrs. The reaction mixture was quenched into a solution of ascorbic acid (2.21 g) and water (17 ml) for 30 min, heated to 45-50°C under stirring and stirred for 1 hour. Methanol (10. 2 ml) was added to slurry and stirred for 3 hrs at 45-50°C. The slurry is filtered warm. The obtained wet cake was washed with water (3.4 ml) and then followed by methanol (3.4 ml). Dried the solid under vacuum to obtain 2-((3-iodo-lH-indazol-6-yl)thio)-N- methylbenzamide as a pale yellow crystalline solid.

Yield: 3.8 g (77.38 % w/w)

Chromatographic Purity (ByHPLC): 99.17 % Example-3

Preparation of Axitinib (I)

N-methylpyrrolidone (7.0 ml), Palladium (II) acetate (0.081 g, 0.0004 mol) and Xantphos (0.210g, 0.0004 mol) was charged into a RB flask at 25-30 °C in nitrogen atmosphere. Charged diisopropylethylamine (2.85 g, 0.0220 mol) and 2-((3-iodo-lH-indazol-6-yl)thio)-N methylbenzamide (3.0 g, 0.0073 mol) under stirring. The reaction was heated to 50°C. Acetic anhydride (1.50 g, 0.0147 mol) was slowly added and stirred for 2-3 hrs at 50°C. 2- Vinylpyridine (4.63 g, 0.0440mol) was added slowly, raised the temperature of reaction mass to 90-95°C and maintained for 24 hrs. Cooled the reaction mixture to 50°C under stirring, diluted with THF (8 ml) and filtered. The reaction mass was further diluted with THF (2.6 g) and 1,2-diaminopropane (2.2 g). Stirred at 50°C for 30 min. Water (33 ml) wasadded slowly for 30 min followed by maintaining temperature 50°C under stirring for 12 hrs. Reaction mass cooled to 15°C and further maintained for 2 hrs, filtered the solid, washed with purified water (9 ml) and THF (8 ml). The obtained solid was dried under vacuum to afford highly pure Axitinib.

Yield: 1.8 g (66.38%)

Chromatographic Purity (By HPLC): 99.63% ;

M.P. (by Capillary Method): 215.2-216.2°C

Impurity levels-

While the foregoing pages provide a detailed description of the preferred embodiments of the invention, it is to be understood that the summary, description and examples are illustrative only of the core of the invention and non-limiting. Furthermore, as many changes can be made to the invention without departing from the scope of the invention, it is intended that all material contained herein be interpreted as illustrative of the invention and not in a limiting sense.

Claims

We Claim:

1) A process for the preparation of Axitinib of Formula (I)

comprising the steps of - a) reacting 6-iodolH-indazole (II) with 2-mercapto-N-methylbenzamide(III) in presence of a metal halide to rovide a 2- lH-indazol-6-yl)thio)-N-meth lbenzamide(IV);

b) halogenating compound of formula (IV) to provide 2-((3-iodo-lH-indazol-6-yl)thio)-N- meth lbenzamide(V); and

c) reacting compound of Formula (V) with an acylating agent followed by condensation with 2- Vinyl pyridine (VI) in the presence of organic base uptoat least3.5 Molar equivalent with res ect to Formula (V) to rovide Axitinib(I).

2) A process for the preparation of Axitinib according to claim 1, wherein Metal halide is selected from Copper iodide, Sodium iodide, Potassium iodide.

3) A process for the preparation of Axitinib according to claim 1, wherein halogenating process in step b) comprising halogen source selected from Iodine, Bromine, Thionyl chloride, oxalyl chloride, Phosphorous trichloride, Phosphorous pentachloride and Phosphorous oxy chloride.

4) A process for the preparation of Axitinib according to claim 1 , whereinacylating agent in step c) is selected from Acetyl halides such as acetyl chloride, acetyl bromide orAcetic anhydride.

5) A process for the preparation of Axitinib according to claim 1, wherein Axitinib obtained as per the process contains the process related impurities A, B, C, D, E and F collectively below 0.3% and having a purity of greater than 99.5% (By HPLC).

Impurity-A Impurity-B

Impurity-C Impurity-D

Impurity-E Impurity-F

6) Axitinib containing the process related impurities A, B, C, D, E and Fcollectively below 0.3%.

Impurity-E Impurity-F

7) Axitinib containing the process related impurities A, B, C, D, Eand F collectively below 0.3% according to claim 5, having a purity of greater than 99.5% w/w.

8) A process for the preparation of Axitinib of Formula (I),

wherein intermediate - 2-((lH-indazol-6-yl)thio)-N-methylbenzamide(IV) is prepared comprising reacting 6-iodolH-indazole (II) with 2-mercapto-N-methylbenzamide(III) in presence of a metal halide to provide a 2-((lH-indazol-6-yl)thio)-N-methylbenzamide(IV).

9) A process for the preparation of Axitinib according to claim 6, wherein Metal iodide is selected from Copper iodide, Sodium iodide, Potassium iodide.

10) A pharmaceutical composition comprising Axitinib that contains the process related impurities A, B, C, D, E and F collectively below 0.3% obtained according to the claim 5 and a pharmaceutically acceptable excipient.