DESC:Related application
This application claims the benefit of priority of our Indian patent application numbers 3286/MUM/2014 filed on Oct. 14. 2010 and 4215/MUM/2014 filed on Dec. 30, 2014 which are incorporated herein by reference.
Field of invention:
The present invention provides an improved process for the preparation of Axitinib of formula-I and its substantially pure Form-IV. The polymorphic form of Axitinib obtained by the process of the present invention is characterized by high polymorphic purity and high chemical and physical stability.

Background of the invention:
Axitinib is a kinase inhibitor. The product is marketed under trade name of INLYTA. INLYTA is indicated for the treatment of advanced renal cell carcinoma (RCC) after failure of one prior systemic therapy.
Axitinib was firstly disclosed in US 6534524. The ‘524 patent also discloses a process for the preparation of Axitinib. However, the process has its own limitations like the number of steps for the preparation of Axitinib is more and this process has less industrial applicability and has lesser overall yield of final product. It was purified by silica gel chromatography (9:1 dichloromethane/ethyl acetate)
The patents, WO2006048744 and WO2006048745 describe another process for the preparation of Axitinib.
Although, many process for the preparation of Axitinib were disclosed in patents as well as literatures, there is need to develop a process in which less step is involved for the preparation of Axitinib and have a good overall yield and purity of final product.
Further, subsequent patent and application discloses various crystalline form of Axitinib.
WO2006123223A1 disclosed amorphous form of Axitinib.
WO2006048751A1 claims crystalline form I, II, III, IV, VI, VII and VIII. Form-I, IV, VI are anhydrous form, crystalline form II is hydrate form, crystalline form-III is ethyl acetate solvate form, form VII is isopropanol solvate form and form VIII is dioxane solvate form.
WO2008122858A2 disclosed crystalline form VII, XVI, XXV, XLI, IX, XII and XV. This application tells that form XLI is most stable form. Crystalline form XVI is isopropanol solvate form, XXV and XLI are anhydrous form, IX is hydrate form, XII and XV are ethanol solvate crystalline form.
Moreover, Journal of Pharmaceutical sciences, vol. 99, No. 9, September 2010 discloses 72 crystalline forms of Axitinib.
There are many methods for preparing Axitinib Form-IV for example according to WO2006048744, Form-IV is prepared by refluxing with THF, DMF and MeOH and followed by addition of HOAc and Xylenes.
WO2006048745 discloses preparation of Form-IV from Form-III using acetic acid, methanol and xylenes.
WO2006048751 discloses different methods of preparation of Form-IV such as (i) direct desolvation of polymorphic Form III in vacuum 10-135°C; (ii) via solid- state conversion of polymorphic Form III by slurrying polymorphic Form III in toluene or xylene at 110-140°C; (iii) via recrystallization of Axitinib from dichloromethane/methanol solution followed by slurrying the precipitate in toluene at 140°C; (iv) via solid-state conversion of polymorphic Form VI by refluxing polymorphic Form VI as a toluene slurry at 140°C; and (v) via precipitation of Axitinib in PEG-400 solution with water.
Org. Process Res. Dev. 2014, 18, 266-274, discloses preparation of Form-IV via Axitinib isopropanol solvate.
Journal of Pharmaceutical sciences, vol. 99, No. 9, September 2010 discloses different crystalline forms and their preparation.
Each of the above mentioned methods have their own disadvantages such as use of high boiling solvents such as toluene, DMF, acetonitrile. Removal of the solvents is difficult and the left over solvent may lead to formation of solvate Forms, as mentioned in Journal of Pharmaceutical sciences, vol. 99, No. 9, September 2010, the Axitinib has a high tendency to form solvates.
It is well known that polymorphs of the same substance can have dramatic differences in pertinent pharmaceutical properties, such as solubility and stability that can often have a significant impact on bioavailability and overall drug product performance.
Therefore, polymorphic purity of active pharmaceutical ingredient is very important property in pharmaceutical industry. Contaminations of other polymorphic forms have an impact on stability of active pharmaceutical product and cause polymorphic conversion during stability.
Thus, there is a need to provide a process for preparation of Crystalline Forms with substantial purity.
SUMMARY OF THE INVENTION:
The present invention provides an improved process for the preparation of Axitinib of formula-I

comprising,
a. reacting compound of formula-VII’ with N-methyl-2-sulfanylbenzamide in presence of Cu catalyst, suitable base and suitable solvent provides compound of formula-VIII’

wherein, RP is nitrogen protecting group; and X is selected form –F, -Cl, -Br, -I or OTf.
b. deprotection of nitrogen protecting group to get Axitinib.
The present invention also provides acid base purification process for the preparation of substantially pure Axitinib comprising,
a. deprotection of compound of formula-VIII’ using conc. HCl in suitable solvent
b. filtering the reaction mixture of step-a to get Axitinib hydrochloride
c. providing solution of Axitinib hydrochloride in suitable organic solvent
d. further, neutralising the resulting solution of step-c by base such as NaHCO3 solution
e. filtering the reaction mixture of step-d to get substantially pure free base of Axitinib
The present invention also provides novel process for the preparation of substantially pure crystalline form-IV of Axitinib in suitable organic solvent and water.
The present invention also relates to a novel process for the preparation of crystalline form-IV of Axitinib comprising,
a. dissolving Axitinib crude in a suitable solvent
b. stirred the reaction mixture until clear solution was observed or filtered the resulting solution of step-a to remove any extraneous material
c. add purified water into resulting solution of step-b
d. maintaining pH of resulting solution of step-c below 7
e. filtering the resulting solution of step-d and dried it to get pure crystalline form-IV of Axitinib.
The present invention also relates to a novel process for the preparation of crystalline form-IV of Axitinib comprising,
a. dissolving Axitinib crude in a suitable solvent
b. stirring the reaction mixture until clear solution was observed or filtered the resulting solution of step-a to remove any extraneous material
c. adding suitable anti solvent to precipitate Axitinib
d. filtering the solid
e. first drying at50-55°C
f. further drying at 143± 3°C to convert solvated form in to the pure form IV.

Further, the present invention also relates to a process of purification of Axitinib and thus to afford a substantially pure crystalline form-IV.
Additionally, the present invention also relates to novel compounds as impurities in the preparation of Axitinib
BRIEF DESCRIPTION OF THE DRAWINGS:

Fig 1 is an illustration of a powder X-ray diffraction (PXRD) pattern of the Axitinib, prepared according to Example 8(B)(b)

DETAILED OF THE INVENTION:
In one aspect the present invention provides an improved process for the preparation of Axitinib of formula-I

comprising,
a. reacting compound of formula-VII’ with N-methyl-2-sulfanylbenzamide in presence of Cu catalyst, suitable base and suitable solvent provides compound of formula-VIII’.

wherein, RP is nitrogen protecting group; and X is selected form –F, -Cl, -Br, -I or OTf.
b. deprotection of nitrogen protecting group to get Axitinib.
In one aspect of the invention, the coupling reaction between compound of formula-VII’ and N-methyl-2-sulfanylbenzamide to provide compound of formula-VIII’ is accomplished in the presence of a catalyst, a base and optionally, one or more solvents.
In certain embodiments, the catalyst may be either a palladium or a copper catalyst. For example, palladium catalysts which are useful in the above coupling reaction include but are not limited to Pd(dppf)CI2-CH2CI2, [Pd(P'-Bu3)(µ-Br)]2, Pd(PCy3)2CI2, Pd(P(o-tolyl)3)2CI2, [Pd(P(OPh-2,4-t- BuJ)2CI]2, FibreCat® 1007 (PCy2-fibre/Pd(OAc)2), FibreCat® 1026 (PCy2-fibre/PdCI2/CH3CN), FibreCat® 1001 (PPh2-fibre/Pd(OAc)2), Pd(dppf)CI2, Pd(dppb)CI2, Pd(dppe)CI2, Pd(PPh3)4, Pd(PPh3)CI2, and the like. Other useful catalysts for the above transformation include those where one or more ligands, especially phosphine ligands, additionally complexes to the palladium catalyst, for example: Pd2(dba)3 complexed to a phospine ligand such as 2-(tert-butyl2- phosphino)biphenyl; Pd(dba)2 complexed to P(t-Bu)3; Pd(OAc)2 complexed to (o-biphenyl)P(t- Bu)2; and Pd2(dba)3 complexed to (o-biphenyl)P(t-Cy)2. Copper catalysts which are useful in the above coupling reaction include those catalysts in which the copper is complexed with one or more ligands, including but not limited to Cul/ethylene glycol complex; CuBr/DBU complex, Cu(PPh3)Br; and Cu(PPh3)Br additionally complexed to 1 ,10-phenanthroline or neocuproine (e.g., Cu(phen) (PPh3)Br and Cu(neocup)(PPh3)Br, respectively), and the like.
In certain embodiments, the bases which are useful in the above coupling reaction include but are not limited to potassium carbonate, sodium carbonate, cesium carbonate, sodium tert-butoxide, potassium tert- butoxide, potassium phenoxide, triethylamine, and the like, or mixtures thereof. Solvents may be used in such coupling reactions including but not limited to toluene, DMSO, DMF, xylenes, diglyme, tetrahydrofuran, dimethylethyleneglycol, and the like, or mixtures thereof.
In a preferred embodiment, the catalyst is selected from copper catalyst includes but not limited to CuI, CuOTf, CuBr, Cu(PPh3)Br and Cu(PPh3)Br, and the like. In most preferred embodiment, the catalyst is CuI.
In a preferred embodiment, the base is potassium carbonate and the solvent is DMSO.
In certain embodiments, the suitable nitrogen protecting groups useful as Rp include, but are not limited to, silyl protecting groups (e.g., SEM: trimethylsilylethoxymethyl, TBDMS: tert-butyldimethylsilyl); alkyl ether protecting groups such as cycloalkyl ethers (e.g., THP: tetrahydropyran); carbamate protecting groups such as alkyloxycarbonyl (e.g., Boc: t-butyloxycarbonyl), aryloxycarbonyl (e.g., Cbz: benzyloxycarbonyl, and FMOC: fluorene-9-methyloxycarbonyl), alkyloxycarbonyl (e.g., methyloxycarbonyl), alkylcarbonyl or arylcarbonyl, substituted alkyl, especially arylalkyl (e.g., trityl (triphenylmethyl), benzyl and substituted benzyl), and the like.
In a preferred embodiment of the invention, the nitrogen protecting group is tetrahydropyran.
In one aspect of the invention, such Nitrogen protecting groups may be deprotected by treating the subject compound with organic or inorganic acids or Lewis acids. The choice of a particular reagent will depend upon the type of nitrogen protecting group present as well as the other reaction conditions.
Examples of suitable reagents include, but are not limited to, hydrochloric acid, sulfuric acid, nitric acid, para-toluenesulfonic acid, methanesulfonic acid, or Lewis acids such as boron trifluoride etherate.
In a preferred embodiment of the invention, the suitable reagent is Conc. HCl.
In one aspect the present invention provides an acid base purification process for the preparation of substantially pure Axitinib comprising,
a. deprotection of compound of formula-VIII’ using conc. HCl in suitable solvent.
b. filtering the reaction mixture of step-a to get Axitinib hydrochloride
c. further, neutralising the resulting solution of step-b
d. filtering the reaction mixture of step-c to get substantially pure free base of Axitinib
In certain embodiments of the invention, wherein in step a) the suitable solvent is alcohol and preferably, methanol.
In an embodiment the neutralization is provided by addition of base solution such as NaHCO3, ammonia solution. Preferably, aqueous ammonia solution.
In another aspect the present invention also provides novel process for the preparation of substantially pure crystalline form-IV of Axitinib in suitable organic solvent and water.
In an embodiment the invention provides a novel process for the preparation of crystalline form-IV of Axitinib comprising,
a. dissolving Axitinib crude in a suitable solvent
b. stirring the reaction mixture until clear solution was observed or filtered the resulting solution of step-a to remove any extraneous material
c. adding purified water into resulting solution of step-b
d. maintaining pH of resulting solution of step-c below 7
e. filtering resulting solution of step-d and dried it to get pure crystalline form-IV of Axitinib.
Wherein, the said substantially pure Axitinib Form-IV has a purity of greater than about 98%, preferably greater than about 99% and more preferably greater than about 99.5%.
Axitinib obtained according to present invention has specific surface area of 0.5-1 m2/g, preferably, 0.961 m2/g.
Axitinib obtained according to present invention has particle size distribution of d(0.1)= 2-5 µm, d(0.5)=10-20 µm, d(0.9)=100-150 µm and d(0.1)=350-400 µm; preferably d(0.1)=3.3, d(0.5)=15.4, d(0.9)=127.3, d(0.1)=373 µm.
In an aspect of the invention the suitable solvent can be selected from NMP, DMF, DMAC, water, DMSO and the like, or mixtures thereof.
In a preferred embodiment, the suitable solvent is preferably is DMSO and Water.
In an aspect of the invention, the substantially pure crystalline Form-IV is provided by maintaining the pH of the resulting solution of step-d below 7 by adding buffering agent.
In another aspect of the invention, pH of the resulting solution of step-d is adjusted below 7 by adding acids.
In certain embodiments, the said buffering agent is selected from the group consisting of acetate salt, phosphate salt, phthalate, citrate salt, succinate salt, gluconate salt, lactate, citric acid-disodium hydrogen phosphate buffer, , acetic acid-sodium acetate buffer, acetic acid-ammonium acetate buffer, ethanol-acetic acid buffer, Tris(hydroxymethyl) aminomethane (TRIS, THAM), ethylenediamine tetraacetic acid, tris(hydroxymethyl)aminomethane (Tris), (N-(2-hydroxyethyl)piperazine-N'-(2-ethanesulfonic acid) (HEPES), MOPS buffer (3-(N-morpholino)propanesulfonic acid),ACES (2-[(2-amino-2-oxoethyl)amino]ethanoesulfonic acid) buffer, ADA (N-(2-acetamido)2-iminodiacetic acid) buffer, AMPSO (3-[(1,1-dimethyl-2-hydroxyethyl)amino]-2-propanesulfonic acid) buffer, BES (N,N-bis(2-hydroxyethyl)-2
aminoethanesulfonic acid buffer, Bicine (N,N-bis(2-hydroxyethylglycine) buffer, Bis-Tris (bis-(2-hydroxyethyl)imino-tris(hydroxymethyl)methane buffer, CAPS (3-(cyclohexylamino)-1-propanesulfonic acid) buffer, CAPSO (3-(cyclohexylamino)-2-hydroxy-1 -propanesulfonic acid) buffer, CHES (2-(N-cyclohexylamino)ethanesulfonic acid) buffer, DIPSO (3-[N,N-bis(2-hydroxyethyl)amino]-2-hydroxy-propanesulfonic acid) buffer, HEPPS (N-(2-hydroxyethylpiperazine)-N'-(3-propanesulfonic acid) buffer, HEPPSO (N-(2-
hydroxyethyl)piperazine-N'-(2-hydroxypropanesulfonic acid) buffer, MES (2-(N-
morpholino)ethanesulfonic acid) buffer, triethanolamine buffer, imidazole
buffer, glycine buffer, ethanolamine buffer, phosphate buffer, MOPSO (3-(N-morpholino)-2-
hydroxypropanesulfonic acid) buffer, PIPES (piperazine-N,N'-bis(2-ethanesulfonicacid) buffer, POPSO (piperazine-N,N'-bis(2-hydroxypropaneulfonic acid) buffer; TAPS (N-tris[hydroxymethyl)methyl-3-aminopropanesulfonic acid) buffer, TAPSO (3-[N-tris(hydroxymethyl)methylamino]-2-hydroxy-propanesulfonic acid) buffer, TES (N-tris(hydroxymethyl)methyl-2-aminoethanesulfonic acid) buffer, tricine (N-tris(hydroxymethyl)methylglycine buffer), 2-amino-2-methyl-1,3-propanediol buffer, 2-amino-2-methyl-1-propanol buffer, and combinations thereof.
In an embodiment, the said salts are formed from a group consisting of alkali metal and ammonium and the mixture thereof. Preferably alkali metal salts and more preferably sodium and potassium.
In certain embodiments, the said acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, hypochlorous acid, chlorous acid, chloric acid, perchloric acid, sulfuric acid, fluorosulfuric acid, nitric acid, phosphoric acid, fluoroantimonic acid, fluoroboric acid, hexafluorophosphoric acid, chromic acid, boric acid, acetic acid, citric acid, formic acid, gluconic acid, lactic acid, oxalic acid, tartaric acid or mixtures thereof.
In preferred embodiment the pH is maintained below 7, by addition of the buffer. The buffer preferably selected from acetate salts, most preferable being sodium acetate.
In an embodiment the invention provides a novel process for the preparation of crystalline form-IV of Axitinib comprising,
a. dissolving Axitinib crude in a suitable solvent
b. stirring the reaction mixture until clear solution was observed or filtered the resulting solution of step-a to remove any extraneous material
c. adding suitable anti solvent to precipitate Axitinib
d. filtering the solid
e. first drying at50-55°C
f. further drying at 143± 3°C to convert solvated form in to the pure form IV.

Wherein suitable solvent is DMSO and suitable anti solvent is ethyl acetate.
Surprisingly, the present inventors have found that by the process of preparation of the Axitinib according to present invention, novel compounds as impurities were being formed not known earlier along with the known impurities.
The present invention thus, provides new impurities of formula, shown as Impurity IV and V below:
N-Methyl-2-[3-[2-(2-pyridin-2-yl)ethyl]-1H-indazole-6-ylsulfanyl]benzamide represented as Di-Hydro analogue-IV (Di-Hydro analogue)

(Di-Hydro analogue -IV)
N-Methyl-2-[3-[2-(2-pyridyl)vinyl]-1H-indazole-6-ylsulfanyl]benzamide N-Oxide represented as N-Oxide Axitinib-V (N-Oxide Axitinib)

(N-Oxide Axitinib-V)
In one embodiment, the preparation of 6-Nitro indazole used as starting material for preparation of Axitinib is as shown below (as disclosed in US3843678)

In another embodiment, 6-Nitro indazole is prepared according to any method known in the art.
In one embodiment, the preparation of 2-vinyl pyridine used in preparation of Axitinib is as shown below

Yet in another embodiment, 2-vinyl pyridine is prepared according to any method known in the art.
In one embodiment, the preparation of 2-mercapto-N-methylbenzamide used in the preparation of Axitinib is as shown below

Yet in another embodiment, 2-mercapto-N-methylbenzamide is prepared according to any method known in the art.
In one embodiment, the preparation of 3,4-dihydro pyran used in the preparation of Axitinib is as shown below

In another embodiment, 3, 4-dihydro pyran is prepared according to any method known in the art.
In one embodiment, (E)-6-Iodo-3-[2-(pyridine-2yl)ethenyl]-1-(tetrahydro-2H- pyran-yl)-1H-indazole used in preparation of Axitinib is prepared as shown below

In an embodiment of the invention, Heck reaction between 3-iodo-6-nitro-1-(tetrahydropyran-2-yl)-1H-indazole and 2-vinyl pyridine is accomplished by heating the reactants in the presence of a catalyst such as palladium(ll) acetate (Pd(OAc)2), a ligand such as tri-o-tolylphosphine, a suitable base such as N,N-diisopropylethyl-amine, triethylamine and a solvent such as DMF, DMSO to provide 6-nitro-3-((E)-2-pyridin-2-yl- vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole. Preferably, the base is triethylamine and the solvent is DMSO.
In one embodiment of the invention, 6-nitro-3-(E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole is reduced to the 6-amino compound by treatment with iron metal in the presence of an aqueous solution of ammonium formate to provide 6-amino-3-(E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1 H-indazole (as shown in step-4 of scheme).
In another embodiment, the above mentioned reduction is carried out by treatment with metals, such as Zn (zinc), Sn (tin) and In (indium) in presence of aqueous solutions selected from ammonia, ammonium chloride and ammonium formate and like and the mixtures thereof.
In one embodiment, the diazotization reaction according to step-5 as shown in above scheme can be carried out using diazotizing reagents. The Diazotizing reagents useful for converting an amino group to a diazonium salt include but are not limited to sodium nitrite and tert-butyl nitrite and like. These diazotizing reactions are carried in the presence of a strong acid such as hydrochloric acid or acetic acid and the like or the mixtures thereof to convert the amino group into the diazonium salt. Alkali metal halides, such as lithium, sodium and potassium halides are a convenient source of nucleophilic halide anions.
In one embodiment, the diazotizing reagent is sodium nitrile and the metal halide is potassium iodide (Kl ) and iodine (I2) is used to facilitate the iodination process. The said reaction is carried out in the presence of acetic acid.
In another embodiment, the step-5 further involves crystallization of the obtained Iodo compound, (E)-6-Iodo-3-[2-(pyridine-2yl)ethenyl]-1-(tetrahydro-2H- pyran-yl)-1H-indazole in presence of a solvent such as MDC or methanol and the mixtures thereof. Preferably, crystallization can carried out in presence of MDC and methanol mixture.
In one embodiment, the process for the preparation of Axitinib Form-IV is describes in below scheme.

In another embodiment, the process for the preparation of Axitinib Form-IV is describes in below scheme.

In another embodiment, the process for the preparation of Axitinib Form-IV is describes in below scheme

The invention is further exemplified by the following non-limiting examples, which are illustrative representing the preferred modes of carrying out the invention. The invention's scope is not limited to these specific embodiments only but should be read in conjunction with what is disclosed anywhere else in the specification together with those information and knowledge which are within the general understanding of the person skilled in the art.
Example 1: Preparation of 3-Iodo-6-nitro-indazole
6-Nitro-1H-indazole (100 g) was dissolved in DMF (350 ml) at 27 ± 3°C, the reaction mixture was stirred for 10 mins followed by potassium carbonate. Iodine solution (Iodine 77.77 g dissolve in 100 mL DMF) was added to it at 27 ± 3°C, stirred for 3 hrs and if needed add more iodine solution. The mixture was then added to a solution sodium bisulphite in water, followed by washing the solids with water and methanol to obtain 3-iodo-6-nitro-indazole.
Example 2: Preparation of 3-iodo-6-nitro-1-(tetrahvdropyran-2-yl)-1 H-indazole
3-iodo-6-nitroindazole (100 g) was dissolved in ethyl acetate (500 ml), and methanesulfonic acid (7.96 g) is carefully added and reaction mixture was stirred for 5-10 mins at RT. To this DHP (54.12 g) was added and stirred for 2-3 hrs. The mixture is then carefully added to an ammonia solution at 27 ± 3°C and stirred to adjust the pH 8-9. The reaction mixture was heated to 65 ± 3°C and stirred for 30 min, then cooled to RT and then gradually to 10 ± 3°C. Filtered solid at 10 ± 3°C, washed the wet cake with ethyl acetate and dried to obtain 3-iodo-6-nitro-1-(tetrahvdropyran-2-yl)-1 H-indazole.
Example 3: Preparation of 6-nitro-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1 H-indazole
3-iodo-6-nitro-1-(tetrahydropyran-2-yl)-1 H-indazole (100 g, 25 g X 4) is added to a solution of 2-vinyl pyridine (33.81, 8.45g X 4), triethylamine (54.24 g), Disodium hydrogen phosphate anhydrous (38.03g) and tri-o-tolylphosphine (5.71 g) in DMSO (200 ml). Pd(OAc)2 (2 g) is added and the mixture is agitated for 12 to 18 hours at 900C (until the reaction is complete by HPLC). The mixture is then cooled to 550C and methanol is added. The mixture is stirred for 4 hrs at RT and cooled to 0 ± 3°C, filter the product and washed with methanol. Add water at 25± 3°C, heat the mixture to 70± 3°C and stirred for 30 mins, followed by washing with water and methanol at 25± 3°C to afford 6-nitro-3-(E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole
Example 4: Preparation of 3-[(E)-2-(pyridin-2-yl) ethenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-6-amine
6-nitro-3-(E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole (100 g) was dissolved in an aqueous solution of ammonium formate (34.33 g of ammonium formate in 50 ml water); and methanol (400 ml) was added. Electrolytic Iron powder (78 g) added under stirring and the mixture is agitated for 2 to 8 hours at 72 0C, add required amount of aq. solution of ammonium formate and maintaining temperature at 72± 3°C and stirring (until the reaction is complete by HPLC). The mixture is then cooled to 27± 3°C and Dichloromethane (1000 ml) is added followed by sodium sulphate (150g). The cake was rinsed with Dichloromethane (300 ml), combine filtrate and wash, separate organic an Aq layer. Followed by rinsing with dichloromethane and add ethyl acetate, heat to 50 ± 3°C and stir for 15-20 min and gradually cool to 3± 3°C, filter the product and wash with ethyl acetate to provide (3-[(E)-2-(pyridin-2-yl) ethenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H- indazol-6-amine).
Example 5: Preparation of (E)-6-Iodo-3-[2-(pyridine-2yl)ethenyl]-1-(tetrahydro-2H- pyran-2-yl)-1H-indazole
6-amino-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1 H-indazole (100 g) dissolved in acetic acid (6.5 L) is added over 1.5 hours to a solution of sodium nitrite (35 g) dissolved in water (3.0 L) at O0C (-3 ± 3°C). The mixture is stirred for 1 hour at O0C, and a solution of hydrochloric acid (560 mL diluted in 1 L of water) at O0C is added over 15 minutes. The mixture is stirred for 1 hour at O0C. The formation of the diazonium salt is monitored by HPLC. Dicholoromethane (400 ml) at O0C is added over 10 minutes to the diazonium salt solution at O0C, and a solution of potassium iodide (207. 25 g) dissolved in water (300 ml) at O0C is added over 1.5 hours. The reaction mixture is agitated for 3 hours at O0C (until complete by HPLC). The mixture is then poured into a solution of sodium bisulfite in process water [Sodium bisulfite (200g) dissolve in process water (500mL) at 27± 3°C] and Dicholoromethane (400 ml) below 270C, agitated, and the layers separated. The aqueous layer is extracted with Dichloromethane (100 ml) at 270C and combined. A solution of aqueous ammonia (100 ml) at 27± 3°C is added over 40 minutes to the combined organic layers until the aqueous phase is basic (pH = 9 to 12). Distill out dichloromethane and add methanol and heat to 50 ± 3°C and stir it at this temperature for 15 min and then stir for 30 min at RT, followed by washing with methanol. Add dichloromethane and heat to 45± 3°C and add activated carbon at this temperature. Followed by addition of methanol and dichloromethane (if required) and stir the reaction mixture at 27± 3°C for 30 min and cool it to 0±3°C and stir 1 hr and wash with methanol to provide (E)-6-Iodo-3-[2-(pyridine-2yl)ethenyl]-1-(tetrahydro-2H- pyran-2-yl)-1H-indazole.
Example 6(a): Preparation of 6-(2-mercapto-N-methylbenzamide)-3-(E)-2-pyridin-2-yl-vinyl)-1-(tetrahvdropyroan-2-yl)-1H-indazole [(E)-N-methyl-2-(3-(2-(pyridine-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-6-ylthio) benzamide]
6-iodo-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyroan-2-yl)-1 H-indazoIe (100 g) dissolved in DMSO (400 ml) is added to [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium (II), complex with dichloromethane (Pd(dppf)Cl2-CH2CI2) (8g), and potassium carbonate (48.05 g). 2-mercapto-N-methylbenzamide (42.62 g) is added and the mixture is agitated for 4 to 16 hours at 83±3°C (until the reaction is complete by HPLC). The mixture is then cooled to 27±30C and ethyl acetate (1000 ml) is added and the mixture is agitated for 30 min at 27±30C. Water (1000 ml) is added and the mixture is agitated at 27±30C for 30 min. Cool the reaction mixture to 7 ± 3°C and stir at this temperature for 1 hr. The mixture is f?Itered and the solids are washed with ethyl acetate (100 ml) and dried to provide 20.2 Kg of 6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yl-vinyl)-1 -(tetrahydropyran-2-yl)-1 H-indazole.
Example 6(b): Preparation of 6-(2-mercapto-N-methylbenzamide)-3-(fE)-2-pyridin-2-yl-vinyl)-1-(tetrahvdropyroan-2-yl)-1H-indazole (formula-VIII)
Condensation of (E)-6-Iodo-3-[2-(pyridine-2yl)ethenyl]-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (formula- VII) with N-methyl-2-sulfanyl benzamide (1.5 eq) in presence of DMSO( 6V), Sodium methoxide (3 eq) and Copper iodide (0.2 T) at 50 °C.
Example 7(A): Preparation of 6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yl-vinvp-1-H-indazole (Axitinib crude)
6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yl-vinyl)-1-(tetrahydropyroan-2-yl)-1H-indazole (100 g), Conc HCl (95.46 71.60, 23.88 g), methanol (400 ml) and activated carbon are combined and agitated for 1 to 5 hours at 60± 3°C. The mixtures is then cooled to 57± 3°C and add methanol then heat to 67± 3°C, distil out solvents and add methanol and conc HCl and repeat this process until reaction is completed. Add methanol, ethyl acetate and water below 70°C and then cool the mixture to 12 ± 3°C followed by neutralization by addition of aqueous ammonia solution (180 g) (aqueous phase pH = 7) and then heated to 42 ± 3°C. The reaction mixture is then cooled to RT and stirred for 30 min and gradually to 7± 3°C and stirred for 1 hr. The mixture is filtered and the solids are washed with methanol, ethyl acetate and water to obtain 6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yl-vinvp-1-H-indazole (Axitinib crude).
Example 7(B): Preparation of Axitinib Form-IV
Deprotection of 6-(2-mercapto-N-methylbenzamide)-3-(fE)-2-pyridin-2-yl-vinyl)-1-(tetrahvdropyroan-2-yl)-1H-indazole (formula-VIII) in Methanol (10V) and conc. hydrochloric acid (7eq) 70 °C then neutralized with sodium bicarbonate (7.2 eq) in ethylacetate (5V) to give Axitinib crude. Purification of Axitinib crude in DMSO (5V) and Acetone (15V) at 70 °C to give Axitinib pure then Axitinib dissolved in DMSO (7V) at 70 °C and precipitated into D M Water (70V) at 25 °C to give Axitinib Form-IV.
Example 8(A): Preparation of Axitinib Form-IV.
Axitinib (100 gm) solution was prepared by adding DMSO (800 ml) into it. Solution was filtered at and washed with DMSO (100 ml). This solution was charged into purified water (6300 ml) containing RBF at 27 ± 3°C. Reaction mixture was stirred for 2 hrs at 27 ± 3°C. Reaction mixture was cooled to 10 ± 3°C. Filtered the solid at 67 ± 3°C. Purified water (1000 ml) was added into wet cake at 27 ± 3°C and reaction mixture was heated up to 90 ± 3°C and stirred it for 2hrs. Reaction mass was cooled to 50 ± 3°C and filtered it to get wet cake. Wet cake was dried under VTD at 52 ± 3°C for 10-12 hrs to get pure Form IV of Axitinib.
Example 8(A)(a) Axitinib dissolved in NMP (7V) at 70 °C and precipitated into D M Water (70V) at 25 °C to give Axitinib Form-IV.
Example 8(A)(b)
Axitinib dissolved in DMF (7V) at 70 °C and precipitated into D M Water (70V) at 25 °C to give Axitinib Form-IV.
Example 8(A)(c)
Axitinib dissolved in DMAC (7V) at 70 °C and precipitated into D M Water (70V) at 25 °C to give Axitinib Form-IV.
Example 8(A)(d)
Prepare slurry of Axitinib in D M Water (5V) at 90 °C and stir for 2 hrs and filter to give Axitinib Form-IV.
Example 8(B): Preparation of 6-(2-mercapto-N-methylbenzamide)-3-((E)-2-pyridin-2-yl-vinvp-1-H-indazole (Axitinib Form IV)
Example 8(B)(a): Axitinib (100 g) obtained according to above examples is dissolved in DMSO (500 ml) and heated to 70 ± 3°C and left under agitation until clear solution is formed. To the obtained solution acetone (1500 ml) was added below 73°C, the reaction mixture was cooled to RT and then gradually to 7 ± 3°C and kept under stirring condition for 1 hr. The solid is filtered at 7 ± 3°C and washed with acetone.
Example 8(B)(b): The wet cake of obtained according to example 8(a) is dissolved in DMSO (500 ml) at RT and the reaction mixture is heated to 70 ± 3°C and left under agitation until clear solution is formed. Activated carbon is added and the mixture is stirred below 73°C and the add ethyl acetate, then the mixture is cooled to RT and gradually to 7 ± 3°C and washed with ethyl acetate.
Example 8(B)(c): Preparation of substantially pure crystalline form-IV of Axitinib:
Axitinib obtained as per example 8 (b) was dissolved in DMSO (600 ml) in reaction vessel at 27 ± 3°C. Reaction mixture was stirred for 5 min at 27 ± 3°C and then heated to 70 ± 3°C. The reaction mixture was stirred until clear solution was observed at 70 ± 3°C. The resulting mixture was filtered through cartridge filter at 70 ± 3°C. filtrate was collected and into it sodium acetate solution (solution was prepared by adding 7000 ml purified water into 42.45 g of sodium acetate solid in reaction vessel at 27 ± 3°C) was added and stirred it for 1 hr at 30°C. The resulting mixture was filtered and wet cake was washed with purified water (300 ml). Wet cake was dried in VTD at 57 ± 3°C for 10-12hrs to get pure crystalline form-IV of Axitinib.
Example 8(B)(d): Preparation of substantially pure crystalline form-IV of Axitinib:
Axitinib obtained as per example 8 (b) was dissolved in DMSO (500 ml) at RT and the reaction mixture is heated to 70 ± 3°C and left under agitation until clear solution is formed, added ethyl acetate 1500 ml, then the mixture is cooled to RT and gradually to 7 ± 3°C and solid formed was filtered. The obtained wet cake was dried in VTD at 57 ± 3°C for 2 hrs. Then it was passed through 20 mesh size and finally dried in VTD at 143 ± 3°C to obtain Axitinib Form-IV.
,CLAIMS:1. A process for the preparation of substantially pure crystalline Form-IV of Axitinib comprising:
a) dissolving Axitinib in a suitable solvent;
b) maintaining pH of resulting solution of step-b below 7;
c) obtaining substantially pure crystalline form-IV of Axitinib.
2. The process as claimed in claim 1, wherein said suitable solvent is DMSO, NMP, DMF, ethyl acetate, DMAC, water, or mixtures thereof.
3. The process as claimed in claim 1, the pH is maintained below 7 by addition of a buffering agent or an acid.
4. The process according to claim 3, the buffering agent is selected from the group consisting of alkali metal or ammonium salt of acetate, phosphate, phthalate, citrate, succinate, gluconate, lactate; citric acid-disodium hydrogen phosphate buffer, acetic acid-sodium acetate buffer, acetic acid-ammonium acetate buffer, ethanol-acetic acid buffer, Tris(hydroxymethyl) aminomethane (TRIS, THAM), Ethylenediamine, tetraacetic acid, tris(hydroxymethyl) aminomethane or mixture thereof; the acid is selected from a group of hydrochloric acid, hydrobromic acid, hydroiodic acid, hypochlorous acid, chlorous acid, chloric acid, perchloric acid, sulfuric acid, fluorosulfuric acid, nitric acid, phosphoric acid, fluoroantimonic acid, fluoroboric acid, hexafluorophosphoric acid, chromic acid, boric acid, acetic acid, citric acid, formic acid, gluconic acid, lactic acid, oxalic acid, tartaric acid or mixtures thereof.
5. The process according to claim 1, the suitable solvent is DMSO and water and the buffering agent is sodium acetate.
6. A process for the preparation of crystalline form-IV of Axitinib comprising:
a. dissolving Axitinib crude in a suitable solvent;
b. stirring the reaction mixture until clear solution was observed or filtered the resulting solution of step-a to remove any extraneous material;
c. adding suitable anti solvent to precipitate Axitinib;
d. filtering the solid;
e. first drying at 50-55°C;
f. further, drying at 143± 3°C to convert solvated form in to the pure form IV.
7. The process according to claim 1, the suitable solvent is DMSO and suitable anti solvent is water.
8. A compound of formula –IV.

IV
9. N-Oxide Axitinib of formula-V.

V