DESC:NOVEL INTERMEDIATES AND PROCESS FOR THE PREPARATION OF AXITINIB

FIELD OF THE INVENTION:
The present invention relates to cost effective industrial process for the preparation of Axitinib (formula I) and pharmaceutically acceptable salt thereof. The present invention also relates to process having high yield and low process impurities with novel intermediates.

BACKGROUND OF THE INVENTION:
Axitinib (previously known as AG013736) is a kinase inhibitor indicated for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy.
Axitinib (CAS ID: 319460-85-0) exists as white to light-yellow powder with a pKa of 4.8

AXITINIB
Axitinib is presently marketed salt in the formulation having brand name “INLYTA®” which was first approved by the United States Food and Drug Administration (USFDA) during January, 27, 2012. Primarily, it was approved by the USFDA for the treatment of for the treatment of advanced renal cell carcinoma after failure of one prior systemic therapy
Axitinib was first described in WO2001/002369 and its corresponding Indian product patent no. 232353 which is assigned to Agouron pharmaceuticals Inc. The process described as in WO2001/002369 for the synthesis of Axitinib has its own limitations like the number of steps for the preparation of Axitinib is more and this process has less industrial applicability.

Scheme-1: Process reported in WO2001002369

WO2006/048744 discloses the process as follows:

Scheme-2: Process reported in WO2006048744

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 2: 99 % and does not disclosed the content of total impurities formed in the final active pharmaceutical ingredient

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
The first generation of synthesis of Axitinib is described as follows:

Scheme-3: First generation synthesis of Axitinib
One disadvantage of this route is that the potentially genotoxic intermediates 7 and 8 may require stringent control in the drug substance. In addition, the Sandmeyer reaction is relatively low yielding and not an operation that is desirable to conduct toward the end of a manufacturing route due to the energetic nature and potential toxicity of the intermediates involved.
The main disadvantage of carrying out the Heck reaction early in the process is that the olefin moiety is potentially prone to degradation and impacts yield and quality of the final product.
The second generation of synthesis of Axitinib is described as follows:

Scheme-4: Second generation synthesis of Axitinib
The main disadvantage of the second-generation synthesis is less yield which is obtained at the end of the reaction around 45-65%.
The major problem which was recognized was the Heck reaction as a step that required substantial development due to the need to control various process impurities resulting from the relatively high reaction temperatures used.

Indian patent application 6686/CHE/2014discloses the process as follows:



Scheme-5
Inventors of the present invention have found out novel intermediates and process for synthesis for Axitinib (formula I), which decrease the impurities and increases quality and yield.
Here in the present invention, intermediates like acetyl and tetrahydropyran are not used, which during the heck reaction were deprotected and that impacted the final purity, quality and yield of Axitinib. In addition, all the processes disclosed in prior art publications are time consuming and difficult to carry out as they involve many steps and also not suitable for synthesis of API because the final product is not obtained in desired purity as well as in desired quantity.
Costly palladium catalyst such as xantphos and tris (benzylideneacetone) dipalladium which are difficult to recover, are also avoided which results in a cost-effective process.
Thus, the present invention fulfills the above need by providing a process for the preparation of Axitinib (formula I) wherein use of expensive reagents such as palladium catalyst or another reagent is avoided. The inventors of the present invention have developed an alternative improved process but yet simple, efficient and industrially advantageous process for the preparation of Axitinib with high yield, high purity with novel intermediates. The present invention also entails an economical large-scale industrial process for the preparation of Axitinib (formula I)

OBJECTIVE OF THE INVENTION:
The principal objective of present invention is to provide an industrially advantageous and cost-effective process for the synthesis of Axitinib (formula I) and pharmaceutically acceptable salts thereof.
Another object of the present invention is to provide an industrially advantageous process for the preparation of Axitinib (formula I) which circumvents the use of expensive reagent such as Xantphos and tris (benzylideneacetone) dipalladium.
Another object of the present invention is to provide an industrially advantageous process for the preparation of Axitinib (formula I) which uses novel intermediates.
Yet another object of present invention is to provide an efficient process for the preparation of Axitinib (formula I) and salt thereof which yields final product with high purity and high yield.
Another object of the present invention is to provide large-scale advantageous process for the preparation of Axitinib (formula I) with lesser step in shorter span to produce low-cost final product.

SUMMARY OF THE INVENTION:
One aspect of the present invention relates to preparation of Axitinib (formula I) comprising the reaction steps as below.
a) Coupling of 6-iodo-indazole with N-methyl-2-sulfanylbenzamide in the presence of 1,2 dimethoxybenzene, copper iodide and ethylene glycol with potassium carbonate to form 2[(1H-indzaol-6-yl) sulfanyl] N-methyl benzamide (compound 1)
b) 2[(1H-indzaol-6-yl) sulfanyl] N-methyl benzamide (compound 1) is reacted in the presence of NMP, iodine and potassium hydroxide to form 2[3-iodo-1H-indazol-6-yl sulfanyl] N-methyl benzamide (compound 2)
c) Addition of Trityl chloride with 2[3-iodo-1H-indazol-6-yl sulfanyl] N-methyl benzamide (compound 2) in the presence of potassium tertbutoxide and THF to form 2-((3-iodo-1-trityl-1H-indazol-6-yl) thio)-N-methylbenzamide.
(compound 3)
d) Reaction of 2-((3-iodo-1-trityl-1H-indazol-6-yl) thio)-N-methylbenzamide (compound 3) in the presence of NMP, DIPEA or sodium bicarbonate, with palladium acetate, tri-(o-tolyl) phosphine and vinyl pyridine to provide (E)-N-methyl-2-((3-(2-(pyridin-2-yl) vinyl)-1-trityl-1H-indazol-6-yl) thio) benzamide (compound 4)
e) Reaction of (E)-N-methyl-2-((3-(2-(pyridin-2-yl) vinyl)-1-trityl-1H-indazol-6-yl) thio) benzamide (compound 4) in the presence of methanol and concentrated HCL to yield (E)-N-methyl-2-((3-(2-(pyridin-2-yl)vinyl)-1-trityl-1H-indazol-6-yl)thio)benzamide hydrochloride (compound 5)
f) Addition of water and sodium bicarbonate in (E)-N-methyl-2-((3-(2-(pyridin-2-yl)vinyl)-1-trityl-1H-indazol-6-yl)thio)benzamide hydrochloride (compound 5) to yield (E)-N-methyl-2-((3-(2-(pyridin-2-yl)vinyl)-1H-indazol-6 yl)thio)benzamide
(Axitinib as formula I)

In another aspect of the present invention, the process of the present invention may be depicted as a whole in below scheme-6.

Scheme-6: Process of the present invention

In another aspect, the present invention provides polymorphic form of Axitinib characterized by X-ray powder diffraction (XRD) pattern having major peaks at about 11.58, 11.98, 17.53, 19.00 and 25.26 ± 0.20 degrees 2-theta.

BRIEF DESCRIPTION OF THE DRAWINGS:
Figure 1 shows an X-ray powder diffractogram of polymorphic form of Axitinib prepared as per the present invention.

DETAILED DESCRIPTION OF THE INVENTION:
Accordingly, the present invention relates to an improved, economic and process having novel intermediates for the preparation of Axitinib (formula I) and pharmaceutically acceptable salt thereof.
One embodiment of the present invention provides a process for the preparation of Axitinib (formula I).
Another embodiment of the present invention provides a process for the preparation of intermediate of compound 1 by the coupling of 6-iodo-indazole with N-methyl-2-sulfanylbenzamide in the presence of 1,2 dimethoxybenzene, copper iodide and ethylene glycol with potassium carbonate.

One embodiment of the present invention involve process for the preparation of intermediate of compound 2 by reaction of 2[(1H-indzaol-6-yl) sulfanyl] N-methyl benzamide (compound 1) in the presence of NMP, iodine and potassium hydroxide

Another embodiment of the present invention involve process for the preparation of intermediate of compound 3 by addition of Trityl chloride with 2[3-iodo-1H-indazol-6-yl sulfanyl] N-methyl benzamide (compound 2) in the presence of potassium tertbutoxide and THF.

In another embodiment of the present invention involve process for the preparation of intermediate of compound 4 by reaction of 2-((3-iodo-1-trityl-1H-indazol-6-yl) thio)-N-methylbenzamide (compound 3) in the presence of NMP, DIPEA or sodium bicarbonate, with palladium acetate, tri-(o-tolyl) phosphine and vinyl pyridine.

In another embodiment of the present invention involve process for the preparation of intermediate of compound 5 by reaction of (E)-N-methyl-2-((3-(2-(pyridin-2-yl) vinyl)-1-trityl-1H-indazol-6-yl) thio) benzamide (compound 4) in the presence of methanol and concentrated HCL.

One embodiments of the present invention include preparation of Axitinib (formula I) by addition of water and sodium bicarbonate in (E)-N-methyl-2-((3-(2-(pyridin-2-yl) vinyl)-1-trityl-1H-indazol-6-yl) thio) benzamide hydrochloride (compound 5).

As per one embodiments of the present invention Axitinib (formula I) can be optionally purified to enhance purity and/or to remove impurity in the product. Any suitable purification method can be employed such as slurry wash, crystallization, base acid treatment and the like.

In one embodiment of the present invention, polymorphic form of Axitinib is characterized by X-ray powder diffraction (XRD) pattern having major peaks at about 11.58, 11.98, 17.53, 19.00 and 25.26 ± 0.20 degrees 2-theta. This crystalline form has better physicochemical parameters than prior-art polymorphs which includes lower hygroscopic and good flow property.

In another embodiment of the present invention wherein crude Axitinib is converted to pure Axitinib using acetone and water.

Examples:
Having described the invention with reference to certain preferred embodiments, other aspects will become apparent to one skilled in the art from consideration of the specification. The invention is further defined by reference to the following examples describing in detail by the preparation of the compounds of the invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
The following examples are provided for illustrative purpose only and these examples are in no way limitative on the present invention.

Example 1: (2[(1H-indzaol-6-yl) sulfanyl] N-methyl benzamide (Compound 1)

6-Iodo-1H-indazole (50g, 0.204moles) and 1, 2-dimethoxyethane (500ml) charged in to assembly equipped with heating bath and water condensor at 25-30°C under stirring. Charged N-methyl-2-sulfanylbenzamide (37.68g, 0.225moles) and charged copper iodide (2.5g, 0.013moles). Charged anhydrous potassium carbonate (56.54g, 0.409moles) and charged ethylene glycol (25ml). Reaction mass heated to 80-90°C and stirred for 12-13 hrs. Reaction monitored on TLC basis. Cool the reaction mass to RT and charged dichloromethane (250ml) and stir for 30 min at 25-30°C, filter the reaction mass and wash with dichloromethane (100ml). Distilled out filter ml under vacuum at 50-55°C to get oily residue. Water was charged in oily residue and stir for 1 hours at 25-30°C and solid was filter under vacuum to get solid wet cake, wet cake was dry in to air tray drier at 50-55°C to get 45-48g compound-1.
Benefit of compound-1 process: Compound-1 was prepare using this process is cost effective due to avoid of costly palladium catalyst like Xantphos and Tris (dibenzylideneacetone) dipalladium (0) and also reduce the cost for recovery of palladium catalyst.

Example 2: (2[3-iodo-1H-indazol-6-yl sulfanyl] N-methyl benzamide (Compound 2)

N-methyl pyrrolidone (100ml), compound-1 (45g, 0.159moles) were charged in assembly under stirring at 25-30°C. Addition of iodine solution (156g, 0.614moles) in N-methyl pyrrolidone (100ml) to reaction, at 25-30°C, Addition of potassium hydroxide solution (34.6g, 0.614moles) in water (50ml) at 25-30°C. Stirred the reaction for 2 hrs. at 25-30°C. Reaction was monitored by TLC, Addition of reaction mass in to ascorbic acid solution (37.56g, 0.212moles) in water (250ml) at 45-50°C and stirred for 30 min. charged methanol (50ml) and reaction mass stirred for 2.5-3.0 hours at 45-50°C. Reaction mass cool to 15-20°C and stirred for 2 hrs. filtered the reaction mass and wet cake was washed with water (150ml), wet cake was dry in vaccum tray drier at 50°C for 12-15 hours to get 50-60g as a compound-2.

Example 3: 2-((3-iodo-1-trityl-1H-indazol-6-yl) thio)-N-methylbenzamide (compound 3)

Tetrahydrofuran (500 ml), compound-2 (50g, 0.122moles), potassium tert-butoxide (20g, 0.178 moles) were charged in assembly, trityl chloride (44.2g, 0.158moles) is added lot wise at 25-30°C, maintain the reaction mass for 2 to 3 hours, reaction was monitored by TLC, water (500ml) was added slowly in to the reaction mass at 25-30°C and stir the reaction mass for 1 hour, solid was filtered and wet cake was washed with water (100 ml), wet cake was dry in to air tray drier at 50-55°C for 10-12 hours to get 70-80g compound-3.

Benefit of compound-3 process: This process provides a novel and stable intermediate as a compound-3, in existing reported process, intermediate like acetyl and tetrahydro pyran are deprotected during heck reaction, so impurity formation observed during heck reaction was impacted on quality and yield.

Example 4: (E)-N-methyl-2-((3-(2-(pyridin-2-yl) vinyl)-1-trityl-1H-indazol-6-yl) thio) benzamide (compound 4)

N-methyl pyrrolidone (250ml), 2-vinyl pyridine (21 ml), tri-(o-tolyl) phosphine (3.0g, 0.0097 moles) N, N-Diisopropyl ethylamine (40ml), compound-3 (50g, 0.076 moles) were charged in assembly equipped with heating bath, cooling condensor and nitrogen purging at 25-30°C. Purge nitrogen in to reaction mass for 30 min. at 25-30°C, palladium acetate (1.7g, 0.007 moles) was charged under nitrogen and heated the reaction mass for 90-100°C with nitrogen purging for 8-10 hours. Reaction was monitored by TLC, cool the reaction up to 40-45°c and filter through celite bed. Celite bed was wash with N-methyl pyrrolidone (50ml), water (300 ml) was added in to filter ml at 15-20°C, stir and maintain for 2 hours at 15-20°C, filter solid under vacuum and wet cake was washed with water (100 ml), wet cake was dry in air tray drier at 60-65°C for 10-12 hours to get 40-42g compound-4.

Benefit of compound-4 process: Yield was improved using novel stable intermediate compound-3 during heck reaction.

Example 5: (E)-N-methyl-2-((3-(2-(pyridin-2-yl) vinyl)-1-trityl-1H-indazol-6-yl) thio) benzamide hydrochloride (compound 5).

Methanol (200 ml), compound-4 (40 gm, 0.063 moles) were charged in to assembly at 25-30°C, cool the reaction up to 10-15°C, con. Hydrochloric acid was added to get pH 1.5 to 2.5 at 10-15°C, stir and maintain the reaction mass for 2 hours at 25-30°C, reaction was monitored by TLC, water (500 ml) was added slowly in to reaction mass at 25-30°C, stir the reaction mass for 2 hours at 25-30°C, reaction mass was filtered under vacuum and wet cake was washed with water (100ml), wet cake was dry in to air tray drier at 60-65°C to get 20-22g compound-5.

Benefit of compound-5 process: Better quality was achieved via isolation as hydrochloride salt.

Example 6: Axitinib (formula I)

Water (100 ml) and compound-5 (20g, 0.047 moles) were charged in to assembly at 25-30°C, cooled the reaction mass up to 10-15°C, 10% sodium carbonate solution was added slowly to get pH 8.5-9.5, stir the reaction for 2 hours at 25-30°C, reaction mass was filtered and wet cake was washed with water, dried the wet cake in vacuum tray drier at 55-60°C for 12 hours to get 15-17g Axitinib (formula I)

Example 7: Purification of Axitinib (formula I)

Crude Axitinib was charged to the reaction at 25 to 30°C and water was added to the reaction mass and stirred for 15min. The reaction mass was then heated to 50-55°C under 30 minutes continuous stirring and the cooling the said reaction mass at 20-25°C. The reaction mass was then filtered and washed with Acetone: purified water mixture (0.5v:0.5V) followed by drying to obtain pure Axitinib.

The invention described herein comprises in various objects and their description as mentioned above, with respect to characteristics and processes adopted. While these aspects are emphasised in the invention, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as described.

,CLAIMS:We Claim:

1. An improved process for the preparation of Axitinib comprising of following steps:
a) reacting 6-Iodo-1H-indazole with N-methyl-2-sulfanylbenzamide in the presence of 1,2-dimethoxyethane and copper iodide to yield 2[(1H-indzaol-6-yl)sulfanyl]-N-methyl-benzamide;

b) adding iodine and N-methyl pyrrolidone to 2[(1H-indzaol-6-yl)sulfanyl]-N-methyl-benzamide obtained in step-a in the presence of inorganic base to obtain 2[3-iodo-1H-indazol-6-yl sulfanyl] N-methyl benzamide;

c) reacting 2[3-iodo-1H-indazol-6-yl sulfanyl]-N-methyl benzamide obtained in step-b with trityl chloride in the presence of tetrahydrofuran and metal alkoxide to obtain novel intermediate 2-((3-iodo-1-trityl-1H-indazol-6-yl)thio)-N-methylbenzamide;

d) adding N-methyl-pyrrolidone to 2-((3-iodo-1-trityl-1H-indazol-6-yl)thio)-N-methylbenzamide obtained in step-c in the presence of a base to obtain (E)-N-methyl-2-((3-(2-(pyridin-2-yl) vinyl)-1-trityl-1H-indazol-6-yl)thio) benzamide;

e) adding methanol and conc. HCl in (E)-N-methyl-2-((3-(2-(pyridin-2-yl) vinyl)-1-trityl-1H-indazol-6-yl)thio)benzamide as prepared in step-d to obtain (E)-N-methyl-2-((3-(2-(pyridin-2-yl)vinyl)-1-trityl-1H-indazol-6-yl)thio)benzamide hydrochloride;

f) adding a base to (E)-N-methyl-2-((3-(2-(pyridin-2-yl)vinyl)-1-trityl-1H-indazol-6-yl)thio)benzamide hydrochloride obtained in step-e with water to yield Axitinib.

2. The improved process for the preparation of Axitinib as claimed in claim 1, wherein base is selected from N,N-Diisopropylethylamine, triethyl amine, sodium carbonate and inorganic base is selected as potassium hydroxide.

3. The improved process for the preparation of Axitinib as claimed in claim 1, wherein metal alkoxide is selected from potassium tert-butoxide.

4. The improved process for the preparation of Axitinib as claimed in claim 1, wherein stage-d further comprising Palladium (II) acetate as catalyst and other reagents selected from tri(O-tolyl)phosphine and 2-vinyl pyridine.

5. A novel process for preparation of 2-((3-iodo-1-trityl-1H-indazol-6-yl)thio)-N-methylbenzamide wherein 2-[3-iodo-1H-indazol-6-yl sulfanyl]-N-methyl benzamide is reacted with trityl chloride in the presence of tetrahydrofuran and potassium tert-butoxide to obtain novel intermediate 2-((3-iodo-1-trityl-1H-indazol-6-yl)thio)-N-methylbenzamide.

6. A novel process for preparation of (E)-N-methyl-2-((3-(2-(pyridin-2-yl) vinyl)-1-trityl-1H-indazol-6-yl)thio) benzamide wherein N-methyl-pyrrolidone is added to 2-((3-iodo-1-trityl-1H-indazol-6-yl)thio)-N-methylbenzamide followed by addition of base selected from N-Diisopropylethylamine or triethyl amine or sodium carbonate in the presence of Palladium (II) acetate, tri(O-tolyl)phosphine and 2-vinyl pyridine to obtain (E)-N-methyl-2-((3-(2-(pyridin-2-yl) vinyl)-1-trityl-1H-indazol-6-yl)thio) benzamide.

7. A novel intermediate of following formula:

8. A novel intermediate of following formula:

9. An improved process for the preparation of Axitinib comprising of following steps:
a) reacting 2[3-iodo-1H-indazol-6-yl sulfanyl]-N-methyl benzamide with trityl chloride in the presence of tetrahydrofuran and potassium tert-butoxide to obtain novel intermediate 2-((3-iodo-1-trityl-1H-indazol-6-yl)thio)-N-methylbenzamide;

b) adding N-methyl-pyrrolidone to 2-((3-iodo-1-trityl-1H-indazol-6-yl)thio)-N-methylbenzamide obtained in step-a in the presence of a base to obtain (E)-N-methyl-2-((3-(2-(pyridin-2-yl) vinyl)-1-trityl-1H-indazol-6-yl)thio) benzamide,

wherein base is selected from N,N-Diisopropylethylamine or triethyl amine or sodium carbonate;

c) adding methanol and conc. HCl in (E)-N-methyl-2-((3-(2-(pyridin-2-yl) vinyl)-1-trityl-1H-indazol-6-yl)thio)benzamide as prepared in step-b to obtain (E)-N-methyl-2-((3-(2-(pyridin-2-yl)vinyl)-1-trityl-1H-indazol-6-yl)thio)benzamide hydrochloride;

d) adding sodium carbonate to (E)-N-methyl-2-((3-(2-(pyridin-2-yl)vinyl)-1-trityl-1H-indazol-6-yl)thio)benzamide hydrochloride obtained in step-c with water to yield Axitinib.

10. An improved process for preparation of purified polymorphic form of Axitinib, having major peaks at about 11.58, 11.98, 17.53, 19.00 and 25.26 ± 0.20 degrees 2-theta, comprising dissolving crude Axitinib into water and followed by treatment with acetone to obtain pure Axitinib.