DESC:
FIELD OF THE INVENTION
The field of invention relates to an improved process for preparation of axitinib and novel intermediate thereof. In particular, the invention relates to an improved process for preparation of substantially pure axitinib using novel intermediate.

BACKGROUND OF THE INVENTION
The following discussion of the prior art is intended to present the invention in an appropriate technical context and allow its significance to be properly appreciated. Unless clearly indicated to the contrary, however, reference to any prior art in this specification should be construed as an admission that such art is widely known or forms part of common general knowledge in the field.
Axitinib (previously identified as AG013736, CAS No. [319460-85-0]) is a tyrosine kinase inhibitor. It inhibit multiple targets including Vascular Endothelial Growth Factor (VEGFR-1), VEGFR-2, VEGFR-3, platelet derived growth factor and cKIT. It has been shown to significantly inhibit growth of breast cancer in xenograft models and has been successful in trials with renal cell carcinoma (RCC) and several other tumor types.
Axitinib is chemically describe as N-Methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl]sulfanyl]benzamide, having molecular weight 386.469 g/mol and empirical formula is C22H18N4OS. Axitinib can be structurally represented as Formula (I).

(I)
U.S. Patent No. 6,534,524 B1 (the US ‘524 Patent) discloses indazole compounds including axitinib and process for preparation thereof.
U.S. Patent No. 6,531,491 B1 (the US ‘491 Patent) discloses several protein kinases including indazole class of compounds and process for preparation thereof.
U.S. Patent No. 7,232,910 B2 (the US ‘910 Patent) discloses methods for preparing indazole compounds which includes axitinib, and an intermediate for the preparation thereof.
International (PCT) publication WO 2006/048744 A1 discloses a process for preparation of axitinib and intermediates thereof.
International (PCT) publication WO 2006/048745 A1 discloses a process for preparation of axitinib and intermediates thereof.
Org. Process Res. Dev., Vol.12, No.4, pp. 637–645 (2008) also discloses the similar process for preparation of axitinib.
Recently published article in Org. Process Res. Dev. published online on 24th May, 2013 entitled ‘Development of an efficient Pd-Catalyzed coupling process for axitinib’ also discloses the process for preparation of axitinib and intermediates thereof.
In view of the above, it is therefore, desirable to provide an efficient process for the preparation of axitinib. Synthetic process as available in the existing art is suffering from the one or more disadvantage like long steps synthesis and tedious process and problem related to palladium removal. The present invention discloses a novel intermediate and its utilization for preparation of axitinib. A process of present invention is efficient to provide high yield which makes this process suitable for large scale production having economic significance. The present invention thereby provides useful alternative for the preparation of axitinib with substantial purity.

SUMMARY OF THE INVENTION
In one general aspect, there is provided a compound of Formula (II) useful for the preparation of axitinib,

(II)
wherein, X represents any halogen selected from Cl, Br, I or F.
In another general aspect, there is provided a process for the preparation of axitinib of Formula (I) or its pharmaceutically acceptable salts;

(I)
the process comprising:
a) reducing 6-nitro-3-((E)-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole compound of Formula (V),

(V)
with a reducing agent in one or more organic solvents to obtain a compound of Formula (IV),

(IV)
(b) reacting the compound of Formula (IV) with sodium nitrite in the presence of an acid in one or more organic solvents and followed by halogenation with a halogenating agent to obtain a compound of Formula (III),

(III)
wherein, X represents any halogen selected from Cl, Br, I or F;
(c) deprotecting a compound of Formula (III) with a deprotecting agent in one or more organic solvents obtain compound of Formula (II),

(II)
wherein, X represents any halogen selected from Cl, Br, I or F;
(d) condensing the compound of Formula (II) with 2-mercapto-N-methylbenzamide in the presence of a metal catalyst and a base to obtain compound of Formula (I), and
(e) optionally converting the compound of Formula (I) to its pharmaceutically acceptable salts thereof.
In another general aspect, there is provided substantially pure axitinib having a purity of at least about 99% or more, particularly of at least about 99.5% or more, more particularly at least about 99.8% or more and most particularly at least about 99.9% or more, when measured by area percentage of HPLC.
In another general aspect, there is provided substantially pure axitinib having particle size distributions wherein the (D10) is of about 50 µm or less, (D50) is of about 200 µm or less, or the (D90) is of about 400 µm or less, or any combination thereof.
In further aspect, the substantially pure axitinib may be micronized to achieve the better particle size distribution in order to make a suitable Formulation.
In another general aspect, there is provided a pharmaceutical composition comprising pure axitinib together with one or more pharmaceutically acceptable carrier, diluents and excipients.

DETAILED DESCRIPTION OF THE INVENTION
The above and other objects of the present invention are achieved by the process of the present invention, which leads to an improved process for the preparation of axitinib and novel intermediates thereof.
Optionally, the solution, prior to any solids formation, can be filtered to remove any un-dissolved solids, solid impurities and the like prior to removal of the solvent. Any filtration system and filtration techniques known in the art can be used.
All ranges recited herein include the endpoints, including those that recite a range “between” two values. Terms such as “about”, “generally”, “substantially,” and the like are to be construed as modifying a term or value such that it is not an absolute. This includes, at very least, the degree of expected experimental error, technique error and instrument error for a given technique used to measure a value.
As used herein, the terms “substantially pure axitinib” refers to axitinib which has a purity of at least about 99%, particularly of at least about 99.5%, more particularly of at least about 99.8% and most particularly of at least about 99.9%, by area percentage of HPLC.
As used herein, the term “crystallizing” refers to a process comprises: heating a mixture of a starting material and a solvent to a temperature of between about 10ºC below and above the reflux temperature of the solvent to obtain a solution, and cooling the solution to a temperature of about 0ºC to about 30ºC.
In one general aspect, there is provided a compound of Formula (II) useful for the preparation of axitinib,

(II)
wherein, X represents any halogen selected from Cl, Br, I or F.
In general, the compound of Formula (II) comprises compound (E)-6-chloro-3-(2-(pyridin-2-yl)vinyl)-1H-indazole (IIa), (E)-6-bromo-3-(2-(pyridin-2-yl) vinyl)-1H-indazole (IIb), and (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-1H-indazole (IIc).

(IIa) (IIb) (IIc)

In another general aspect, there is provided a process for the preparation of axitinib of Formula (I) or its pharmaceutically acceptable salts,

(I)
the process comprising:
a) reducing 6-nitro-3-((E)-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole compound of Formula (V),

(V)
with a reducing agent in one or more organic solvents to obtain a compound of Formula (IV),

(IV)
(b) reacting the compound of Formula (IV) with sodium nitrite in the presence of an acid in one or more organic solvents followed by halogenation with a halogenating agent to obtain a compound of Formula (III),

(III)
wherein, X represents any halogen selected from Cl, Br, I or F;
(c) deprotecting the compound of Formula (III) with a deprotecting agent in one or more organic solvents to obtain a compound of Formula (II),

(II)
wherein, X represents any halogen selected from Cl, Br, I or F;
(d) condensing the compound of Formula (II) with 2-mercapto-N-methyl benzamide in the presence of a metal catalyst and a base to obtain a compound of Formula (I), and
(e) optionally converting the compound of Formula (I) to its pharmaceutically acceptable salts thereof.

In general, the reducing agent comprises of Fe/HCl, Sn/HCl, Na2Sx, Pd/C, Pt/C, Raney Nickel, ammonium chloride-Iron powder or zinc powder to obtain compound of Formula (IV).
In general aspect, the organic solvent comprises one or more of alcohols selected from methanol, ethanol, n-propanol, isopropanol and n-butanol; nitriles selected from acetonitrile, propionitrile, butyronitrile and valeronitrile; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; chlorinated solvents selected from methylene dichloride, chloroform, ethylene dichloride and chlorobenzene; ethers selected from diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran and dioxane; amides selected from dimethylformamide, dimethylacetamide and N-methylformamide; and dimethylsulfoxide.
In general, an acid comprises of carboxylic acid selected from acetic acid, triflouroacetic acid, citric acid, formic acid, gluconic acid, lactic acid, oxalic acid, tartaric acid and ascorbic acid; sulfonic acids selected from methansulfonic acid, ethanesulfonic acid, benzenesulfionic acid, p-toluenesulfonic acid and trifluoromethanesulfonic acid; mineral acids selected from HCl, H2SO4, H3PO4 and HBr.
In general, the halogenating agent comprises one or more of potassium iodide, sodium iodide, bromine, xenone difluoride, cobalt(III) fluoride, hydrogen chloride, vinyl chloride and iodonium donating systems selected from NIS–CF3SO3H, iodine–Ag2SO4, iodine–HgO, NIS, iodine–tetrabutylammonium peroxydisulfate, n-BuLi–CF3CH2I and ICl.
In general, the deprotecting agent comprises p-toluene sulphonic acid monohydrate, aqueous phosphoric acid, aqueous hydrochloric acid and sulfuric acid.
The embodiments of the process further includes condensation of the compound of Formula (II) with 2-mercapto-N-methylbenzamide using metal catalyst comprises of Pd2(dba)3, Xanthfos, Palladium diacetate, P(O-tol)3 and Pd(dppf) Cl2.DCM.
In general, the base comprises of one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium tert-butoxide, triethylamine, diisopropylethylamine, diethylamine, pyridine, piperidine and 1,8-diazabicyclo[5.4.0]undec-7-ene.
In general, the pharmaceutically acceptable salts comprises one or more of hydrochloride, hydrobromide, sulfate, phosphate, nitrate, fumarate, malate, maleate, succinate, acetate, oxalate, tartarate, salicylate, tannate, citrate, mesylate, ethane sulfonic acid, edisylate, besylate, tosylate, 1-napsylate, 2-napsylate, 1,5-dinapsylate, lysinate, and arginate.
In another general aspect, there is provided axitinib of having particle size distributions wherein the (D10) is of about 50 µm or less, (D50) is of about 200 µm or less, or the (D90) is of about 400 µm or less, or any combination thereof.
In further aspect, the axitinib may be micronized to achieve the better particle size distribution in order to make a suitable Formulation. Such micronized active ingredient may be produced by using a high energy media mill or an agitator bead mill, for example, the Netzsch high energy media mill, or the DYNO-mill (Willy A. Bachofen AG, Switzerland).
In another general aspect, there is provided pure axitinib which is substantially free from one or more of impurities.
In another general aspect, there is provided a pharmaceutical composition comprising pure axitinib together with one or more pharmaceutically acceptable carrier, diluents and excipients.
In another general aspect, there is provided an improved process for the preparation of axitinib of Formula (I) as shown in reaction scheme-I.
Scheme-1
The invention also encompasses pharmaceutical compositions comprising axitinib of the invention. As used herein, the term "pharmaceutical compositions" includes pharmaceutical formulations like tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
In another general aspect, there is provided a pharmaceutical composition comprising pure axitinib substantially free from impurities together with one or more pharmaceutically acceptable carrier, diluents and excipients.
Having described the invention with reference to certain preferred embodiments, other embodiments, reaction conditions, temperature control and solvent system may become apparent to one skilled in the art from consideration of the examples provided herein after.

Examples
Example-1:
Preparation of 6-amino-3-((E)-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole
In a 50 mL four necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, ethanol (10 mL) and water (8 mL) with 6-nitro-3-((E)-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole (2 g) was added and stirred. Ammonium chloride (2.32 g) was added into the reaction mixture followed by iron powder (1.28 g). The resultant reaction mixture was heated to 50-55°C. Tetrahydrofuran (30 mL) was added and stirred for 30 min. The product thus obtained was filtered and dried under vacuum at 50ºC for 4 hour, and weighed 1.62 g (Yield = 88.58%).

Example-2:
Preparation of 6-iodo-3-((E)-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole
In a 50 mL four necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, sodium nitrite (0.175 g) and water (1.5 mL) was added and cooled to 0 to 5°C. The suspension of 6-amino-3-((E)-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole (0.5 g) in acetic acid (3.25 mL) was added in to the chilled sodium nitrite solution. Conc. HCl (0.28 mL) in 0.5 ml water was added into the reaction mixture and stirred for 30 min. Dichloromethane (2 mL) and a solution of potassium iodide (0.531 g) and iodine (0.198 g) in water (1.5 mL) was added and reaction mixture was stirred till reaction completion. 20% Sodium thiosulphate solution (5 mL) was added to the reaction mixture. Layers were separated and aqueous layer was extracted with dichloromethane (2 mL), combined the organic layers, were cooled and pH was adjusted to 9 to 14 using sodium hydroxide solution. Ammonia solution (1.5 mL) was added into the reaction mixture and stirred. The organic layer was separated, concentrated and precipitated with water. The product thus obtained was filtered and dried under vacuum at 50ºC for 4 hour, and weighed 0.42 g (Yield = 62%).

Example-3:
Preparation of (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-1H-indazole
In a 100 mL four necked round bottom flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, methanol (14 mL), water (2 mL) and (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazole (2 g) was added. p-Toluene sulfonic acid monohydrate (4.4 g) was added into the reaction mixture and heated to reflux, water (30 mL) was added into the reaction mixture and pH was adjusted to 9.5 to 10.5 using sodium carbonate solution. The product thus obtained was filtered, washed and dried under vacuum at 50ºC for 4 hour, and weighed 1.5 g (Yield = 93.17%).

Example-4:
Preparation of N-Methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl] sulfanyl]benzamide (Axitinib)
In a 50 mL four necked round bottomed flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, Dimethylformamide (1.5 mL) and (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-1H-indazole (0.25 g) was added. 1, 1'-Bis-(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (Pd (dppf) Cl2.DCM) (30 mg) was added into the reaction mixture followed by cesium carbonate (0.352 g) and 2-mercapto-N-methylbenzamide (0.157 g). The reaction mixture was heated 80-85°C. Ethyl acetate (5 mL) and water (5 mL) was added and stirred for 1 hour. The product thus obtained was filtered, washed and dried under vacuum at 50ºC for 4 hour, and weighed 0.18 g (Yield = 65%).

Example-5:
Preparation of N-Methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl] sulfanyl] benzamide (Axitinib)
In a 50 mL four necked round bottomed flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, N-methyl-2-pyrrolidone (1.5 mL) and (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-1H-indazole (0.2 g) was added and reaction mixture was stirred. Palladium diacetate (6.47 mg) and P(O-tol)3 (22.8 mg) followed by proton sponge (123.47 mg), lithium bromide (310.2 mg) and 2-mercapto-N-methyl benzamide (135 mg) was added into the reaction mixture and heated to 110°C till reaction completion. The product thus obtained was filtered, washed and dried under vacuum at 50ºC for 4 hour, and weighed 162 mg (Yield = 73%).

Example-6:
Preparation of N-Methyl-2-[[3-[(E)-2-pyridin-2-ylethenyl]-1H-indazol-6-yl] sulfanyl] benzamide (Axitinib)
In a 100 mL four necked round bottomed flask equipped with nitrogen atmosphere facility, mechanical stirrer, thermometer and an addition funnel, N-methyl pyrrolidine (2 ml), 2-mercapto-N-methyl benzamide (135 mg) and (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-1H-indazole (0.2 g) was added and reaction mixture was stirred. Tris (dibenzylideneacetone) dipalladium (Pd2(dba)3) (16 mg), Xantphos (3.5 mg) and 50% cesium hydroxide solution (0.2 mL) was added and reaction mixture was heated to 80°C. The product thus obtained was filtered, washed and dried under vacuum at 50ºC for 4 hour, and weighed 178 mg (Yield = 80%).
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
,CLAIMS:We Claim:

1. A compound of Formula (II), useful for the preparation of axitinib.

(II)
wherein, X represents any halogen selected from Cl, Br, I or F.

2. The compound of Formula (II) as claimed in claim 1 is compound (E)-6-chloro-3-(2-(pyridin-2-yl)vinyl)-1H-indazole (IIa), (E)-6-bromo-3-(2-(pyridin-2-yl) vinyl)-1H-indazole (IIb) and (E)-6-iodo-3-(2-(pyridin-2-yl)vinyl)-1H-indazole (IIc).

(IIa) (IIb) (IIc)

3. A process for the preparation of axitinib of Formula (I) or its pharmaceutically acceptable salts;

(I)
the process comprising:
(a) reducing 6-nitro-3-((E)-pyridin-2-yl-vinyl)-1-(tetrahydropyran-2-yl)-1H-indazole a compound of Formula (V),

(V)
with a reducing agent in one or more organic solvents to obtain a compound of Formula (IV),

(IV)
(b) reacting the compound of Formula (IV) with sodium nitrite in the presence of an acid in one or more organic solvents followed by halogenation with a halogenating agent to obtain a compound of Formula (III),

(III)
wherein, X represents any halogen selected from Cl, Br, I or F;
(c) deprotecting the compound of Formula (III) with a deprotecting agent in one or more organic solvents obtain compound of Formula (II),

(II)
wherein, X represents any halogen selected from Cl, Br, I or F;
(d) condensing the compound of Formula (II) with 2-mercapto-N-methylbenzamide in the presence of a metal catalyst and a base to obtain a compound of Formula (I), and
(e) optionally converting the compound of Formula (I) to its pharmaceutically acceptable salts thereof.

4. The process as claimed in claim 3, wherein the reducing agent comprises one or more of Fe/HCl, Sn/HCl, Na2Sx, Pd/C, Pt/C, Raney Nickel, ammonium chloride-Iron powder and zinc powder.

5. The process as claimed in claim 3, wherein one or more of alcohols selected from methanol, ethanol, n-propanol, isopropanol and n-butanol; nitriles selected from acetonitrile, propionitrile, butyronitrile and valeronitrile; ketones selected from acetone, methyl ethyl ketone and methyl isobutyl ketone; esters selected from ethyl acetate, propyl acetate, isopropyl acetate and butyl acetate; chlorinated solvents selected from methylene dichloride, chloroform, ethylene dichloride and chlorobenzene; ethers selected from diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran and dioxane; amides selected from dimethylformamide, dimethylacetamide and N-methylformamide; and dimethylsulfoxide.

6. The process as claimed in claim 3, wherein the acid comprises of carboxylic acid selected from acetic acid, triflouroacetic acid, citric acid, formic acid, gluconic acid, lactic acid, oxalic acid, tartaric acid and ascorbic acid; sulfonic acids selected from methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid and trifluoromethanesulfonic acid; mineral acids selected from HCl, H2SO4, H3PO4 and HBr.

7. The process as claimed in claim 3, wherein the halogenating agent comprises one or more of potassium iodide, sodium iodide, bromine, xenone difluoride, cobalt(III) fluoride, hydrogen chloride, vinyl chloride and iodonium donating systems selected from NIS–CF3SO3H, iodine–Ag2SO4, iodine–HgO, NIS, iodine–tetrabutylammonium peroxydisulfate, n-BuLi–CF3CH2I and ICl.
8. The process as claimed in claim 3, wherein the deprotecting agent comprises one or more of p-toluene sulphonic acid monohydrate, aqueous phosphoric acid, aqueous hydrochloric acid and sulfuric acid.

9. The process as claimed in claim 3, wherein the metal catalyst comprises of Pd2(dba)3, Xanthfos, Palladium diacetate, P(O-tol)3 and Pd(dppf) Cl2.DCM.

10. The process as claimed in claim 3, wherein the base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium tert-butoxide, triethylamine, diisopropylethylamine, diethylamine, pyridine, piperidine and 1,8-diazabicyclo[5.4.0]undec-7-ene.

11. The process as claimed in claim 3, wherein axitinib has a purity of at least about 99% when measured by area percentage of HPLC.

12. A pharmaceutical composition comprising pure axitinib as claimed in claim 3, together with one or more of pharmaceutically acceptable carriers, excipients or diluents.
Dated this the 22nd day of July 2014.

(H. SUBRAMANIAM)
SUBRAMANIAM & ASSOCIATES
ATTORNEYS FOR THE APPLICANTS