Field of invention
The present invention describes novel process for preparation of Apixaban and its intermediate by modified process for Ullmaan reaction without use of any ligands.
Background of invention
Anticoagulants (antithrombics, fibrinolytic and thrombolytics) medicines reduce the ability of the blood to clot. Apixaban (BMS-562247-01, tradename-ELIQUIS®) is one of the anticoagulant for the treatment of venous thromboembolic events. Apixaban is a highly selective, orally bioavailable, and reversible direct inhibitor of free and clot-bound factor Xa. A first synthetic and pharmaceutical formulation approach of Apixaban was reported in the .patent EP 1427415 Bl. The path of synthesis of patent EP 1427415 Bl describes in scheme-1.
A series of anticoagulant factor Xa inhibitors, l-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxyamide of formula-IV (Apixaban) make known in patent US 6,967,208 B2 and it is also published by the Bristol-Myers Squibb Company in J. Med. Chem. 2007, 50, 5339-5356 (scheme-2). In this, Ullmann reaction is carried out in dimethyl sulfoxide (DMSO) with K2CO3 and Cul at 130° C for 24 hrs. However, reaction yield is only 21%. For purification, column chromatography is needed which is not promising for industrial feasibility and bulk production.
Patent WO 03/049681 A2 also discloses synthesis of Apixaban of formula-IV as shown in scheme-3. For Ullmann reaction, 8-hydroxyquinoline was used as ligand in the presence of K2CO3 and Cul in Dimethyl sulfoxide (DMSO). This process needs ligand and at the same time saponification of the ester function occurs because, the acid of formula-V was synthesized in 68% yield as shown in the scheme-3. Acid group further converted in to mixed anhydride, which provided apixaban of formula-IV with 70% yield, after treating with ammonium hydroxide. Similarly, US 7,153,960 B2 also describes intermediate of formula-Ill in 77% yield as shown in scheme-4.
More recent patent application WO 2014/075648 Al, prepare Apixaban intermediate III, by using modified Ullmann reaction. In this reaction potassium phosphate (K3PO4) use as base, Cul as catalyst, N,N-Dimethylethylenediamine as ligand and cyclopentyl methyl ether

(CPME) as solvent, see scheme-5. Reaction was carried out in sealable pressure container. The crude product was obtained in the yield of 89%.
.Some other patent applications WO 2014/072884 Al (Scheme-6), WO 2012/168364 Al (Scheme-7), US 2006/0069258 Al (Scheme-8) and CN 101967145 B (Scheme-9), prepare Apixaban using a different sequence of synthetic steps and pass up Ullmann reaction for preparation of intermediate of formula IV.
As per above mention prior art, there is a need of development of method for preparation of Apixaban which provides a simple method which is suitable for industrial scale application and avoids use of ligands in reaction with generation of minimum impurity and easy isolation or purification process.


Object of Invention:
The object of the present invention is to provide new process for the preparation of Apixaban, intermediate and their use in the synthesis thereof.
Yet another object of present invention is process for preparation of Apixaban intermediate of formula-Ill.
Yet another object of present invention is to provide industrially feasible synthetic process of Apixaban using eco-friendly and low toxic solvent.
Detailed Description of the Invention
Accordingly, the present invention provides new process for the preparation of Apixaban and its intermediate of formula-Ill and their use in the synthesis thereof (Scheme-10),

which comprises
a) Reacting ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-l//-[3,4-c]pyridine-3-carboxylate of formula-I and piperidin-2-one of formula-II, in the presence of an inorganic base under catalysis in an aromatic aprotic solvent to form intermediate of formula - III;
b) Further intermediate of formula-Ill is converted to apixaban of formula (IV) in a suitable solvent.
The above process can be described schematically as below:

In one of the embodiment, inorganic bases are preferably, alkali metal carbonate salt. More preferably but not limiting to, alkali metal carbonate salt is potassium carbonate.
In one of the embodiment, catalyst is preferably, halogen salts of copper. More preferably but not limiting to, halogen salts of copper is CuBr or Cul.
Yet another embodiment, CuBr or Cul is added in amount in the range of 0.2 to 0.8 equivalents, more preferably, 0.8 mole equivalents.

In another embodiment, appropriate solvents for step (a) reaction are selected from group of aromatic aprotic solvents, e.g., solvents from the group of C\ to C9. Preferably; but not limiting to, toluene or xylene; more preferably, toluene.
In another embodiment, phase transfer catalyst (PTC) was used in reaction for efficient contact between reactant and inorganic base. Preferably but not limiting to TBAB (Tetra-«-butylammonium bromide) in 1 to 5 weight percentage.
In another embodiment, the above mentioned Ullmann reaction is carried out at reflux temperature of solvent.
In another embodiment, the solvent was continually dried by azeotropic distillation during the reaction.
In another embodiment, present invention provides industrially feasible synthetic process of Apixaban where step (b) of above mentioned reaction of formula-Ill is converted to Apixaban of formula-IV by using eco-friendly and low toxic solvent where eco-friendly and low toxic solvent is preferably but not limiting to NH3 in glycols more preferably NH3 in polyethylene glycol or ethylene glycol.
The intermediate III prepared as per modified process and hence Apixaban has higher purity.
The process is further described by following non-limiting examples within the scope of person of skilled in the art.

Experimental Part
Analytic method use for monitoring of conversion: High-Performance Liquid Chromatography (HPLC):

Instrumentation ShimadzuLC-2010HT
Column Agilent ZORBAX RX-C8 (250 x 4.6 mm,5u)
Detector UV/PDA
Wavelength 280nm
Flow rate 1.1 mL/min.
Injection Volume 20 uL
Column Temperature 30 °C
.RunTime 25 min
Sample cooler temperature 15 °C
Chemical / Solvent (1) Acetonitrile, (2) Potassium Dihydrogen phosphate and (3) Ortho phosphoric acid
Mobile Phase preparation:
Buffer preparation- Dissolve 1.36g Potassium Dihydrogen phosphate in lOOOmL water. Adjust the pH 3.8 with ortho phosphoric acid.
Mobile Phase A: Preparation a premixed and degassed mixture of buffer and acetionitrile in theratioof90:10(v/v)
Mobile Phase B: Acetonitrile Gradient table

Time (min.) Mobile Phase A (%) Mobile Phase B (%)
0 75 25
8 61 39
15 33 67
17 33 67
18 75 25
25 75 25

Example 1
Preparation of ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-
4,5,6,7-tetrahydro-l/7-pyrazolo-[3,4-c]pyridine-3-carboxylate
The preparation was carried out in a nitrogen atmosphere. In a typical reaction, K2CO3 (8.45 gm) and Cul (1.5 gm) was added in toluene (50 mL) in a 250 ml RBF, which is attach with dean stark. Initially, the reaction mass was degassed by using nitrogen gas. After that, toluene was dried by azeotropic distillation and added Ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate (5 gm) and reaction mass was maintained at azeotropic distillation mode for 1 to 2 hrs. Piperidin-2-one (1.9 gm) was diluted with toluene (50 mL) and adds dropwise within 3 to 4 hrs in the reaction mixture. • During reaction the mixture was heated up in an oil bath to 110°C for 24 hrs. In heating, the reaction mixture was diluted with a solvent; the solid salts were isolated by filtration and thoroughly washed on the filter. Filtrate washed with HC1 5% (20 mL) and H2O (2x10 mL). The organic phase is anhydrified with Na2SO4, filtered and concentrated under low pressure till five volumes. Add cyclohexane (50 mL) as an anti-solvent in the filtrate; the product was obtained in the isolated yield of 60% (2.8 gm) with the 82% HPLC purity.
Example 2
Preparation of ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-
4,5,6,7-tetrahydro-li/-pyrazolo-[3,4-c]pyridine-3-carboxylate
The preparation was carried out in a nitrogen atmosphere. In a typical reaction, K2CO3 (8.45 gm) and Cul (0.75 gm) was added in toluene (50 mL) in a 250 ml RBF which is attach with dean stark. Initially, the reaction mass was degassed by nitrogen gas. After that, toluene was dried by azeotropic distillation and add Ethyl 6-(4-iodopheriyi)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate (5 gm) and reaction mass was maintained at azeotropic distillation mode for 1 to 2 hrs. Piperidin-2-one (1.9 gm) was diluted with toluene (50 mL) and adds dropwise in reaction mixture within 3 to 4 hrs. After addition of piperidin-2-one, Cul was added (assortment of 0.375 gm) in every 6 hr up-to 0.8 equivalents. During reaction the mixture was heated up in an oil bath to 110°C for 24 hrs, with constant azeotropic distillation. In heating the reaction mixture was diluted with a solvent, the solid salts were isolated by filtration and thoroughly washed on the filter. Filtrate •washed with HC1 5% (20mL) and H2O (2x10 mL). The organic phase is anhydrified with Na2S04, filtered and concentrated under low pressure till five volumes. Add cyclohexane (50

mL) as an anti-solvent in the filtrate; the product was obtained in the isolated yield of 80% (3.8 gm) with the 90% HPLC purity.
Example 3
Preparation of ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-
4,5,6,7-tetrahydro-lH-pyrazolo-[3,4-c]pyridine-3-carboxylate
The preparation was carried out in a nitrogen atmosphere. In a typical reaction, K2CO3 (8.45 gm), Cul (0.75 gm) and TBAB (0.05 gm) was added in 50 mL toluene in a 250 ml RBF which, is attach with dean stark. Initially, the reaction mass was degassed by using nitrogen gas. After that, toluene was dried by azeotropic distillation and add Ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate (5 gm) and reaction mass was maintained at azeotropic distillation mode for another 1 to 2 hrs. Piperidin-2-one (1.9 gm) was diluted with toluene (50 mL) and add dropwise in the reaction mixture within 3 to 4 hrs. After addition of piperidin-2-one, Cul was added (assortment of 0.375 gm) in every 6 hrs up-to 0.8 equivalents. During reaction the mixture was heated up in an oil bath to 110°C for 24 hrs, with constant azeotropic distillation. In heating the reaction mixture was diluted with a solvent, the solid salts were isolated by filtration and thoroughly washed on the filter. Filtrate washed with HC1 5% (20 mL) and H2O (2x10 mL). The organic phase is anhydrified with Na2S04, filtered and concentrated under low pressure till five volumes. Add cyclohexane (50 mL) as an anti-solvent in the filtrate; the product was obtained in the isolated yield of 80% (3.8 gm) with the 94% HPLC purity.
Example 4
Preparation of ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxo-l- piperidin-l-yl)phenyl]-
4,5,6,7-tetrahydro-lH-pyrazolo-[3,4-c]pyridine-3-carboxylate
The preparation was carried out in a nitrogen atmosphere. In a typical reaction, CS2CO3 (9.38 gm), Cul (0.75 gm) and TBAB (0.05 gm) was added in toluene (50 mL) in a 250 ml RBF which is attach with dean stark. Initially, the reaction mass was degassed for 1 hr by using nitrogen gas. After that, toluene was dried by azeotropic distillation and add Ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate (5 gm) and reaction mass was maintained at azeotropic distillation mode for another 1 to 2 hrs. Piperidin-2-one (1.9 gm) was diluted with toluene (50 mL) and add dropwise in reaction mixture within 3 to 4 hrs. After addition of piperidin-2-one, Cul was added (assortment of 0.375 gm) in each 6 hrs up-to 0.8 equivalents. During reaction the

mixture was heated up in an oil bath to 110°C for 24 hrs, with constant azeotropic distillation. In heating the reaction mixture was diluted with a solvent, the solid salts were isolated by filtration and thoroughly washed on the filter. Filtrate washed with HC1 5% (20 mL) and H2O (2x10 mL). The organic phase is anhydrified with Na2SO4, filtered and concentrated under low pressure till five volumes. Add cyclohexane (50 mL) as an anti-solvent in the filtrate; the product was obtained in the isolated yield of 60% (2.8 gm) with the 87% HPLC purity.
Example 5
Preparation of ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo-[3,4-c]pyridine-3-carboxyIate
The preparation was carried out in a nitrogen atmosphere. In a typical reaction, K2CO3 (8.45 gm), CuBr (0.559 gm) and TBAB (0.15 gm) was added in toluene (50 ml) in a 250 ml RBF which is attach with dean stark. Initially, the reaction mass was degassed by using nitrogen gas. After that, toluene was dried by azeotropic distillation and add Ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxylate (5 gm) and reaction mass was maintained at azeotropic distillation mode for another 1 to 2 hrs. Piperidin-2-one (1.9 gm) was diluted with toluene (50 mL) and add dropwise in reaction mixture within 3 to 4 hrs. After addition of piperidin-2-one, CuBr was added (assortment of 0.139 gm) in each 6 hrs up-to 0.8 equivalents. During reaction the mixture was heated up in an oil bath to 110°C for 24 hrs, with constant azeotropic distillation. In heating the reaction mixture was diluted with a solvent, the solid salts were isolated by filtration and thoroughly washed on the filter. Filtrate washed with HC1 5% (20mL) and H2O (2x10 mL). The organic phase is anhydrified with Na2SO4, filtered and concentrated under low pressure till five volumes. Add cyclohexane (50 mL) as an anti-solvent in the filtrate; the product was •obtained in the isolated yield of 70% (3.4gm) with the 94% HPLC purity.

Example 6
Preparation of ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yI)phenyI]-4,5,6,7-tetrahydro-lH-pyrazoIo-[3,4-c]pyridine-3-carboxylate
The preparation was carried out in a nitrogen atmosphere. In a typical reaction, K2CO3 (26.6 gm) and Piperidin-2-one (9.3 gm) was added in toluene (250 mL) in a 500 mL RBF which is .attach with dean stark. Initially, the reaction mass was degassed by using nitrogen gas. After that, toluene was dried by azeotropic distillation and add Ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-xylate (25 gm), CuBr (5.5 gm) and TBAB (0.755 gm) in the reaction mass. Further, reaction was maintained at azeotropic distillation mode for another 1 to 2 hrs. Initially CuBr (2.75 gm) was added in the reaction mixture; remaining CuBr was added in the (assortment of 1.4 gm) in each 6 hrs up-to 0.8 equivalents. During reaction the mixture was heated up in an oil bath to 110°C for 24 hrs, with constant azeotropic distillation. In heating, the reaction mixture was diluted with a solvent; the solid salts were isolated by filtration and thoroughly washed on the filter. Filtrate washed with HC1 5% (20 mL) and H2O (2x10 mL). The organic phase is anhydrified with Na2SO4, filtered and concentrated under low pressure till five volumes. Add cyclohexane (50 mL) as an anti-solvent in the filtrate; the product was obtained in the isolated yield of 75% (17 gm) with the 99.51 % HPLC purity.
Example 7
Preparation of Apixaban
Ethyl l-(4-methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7-tetrahydro-lH-pyrazolo-[3,4-c]pyridine-3-carboxylate (100 g) was charged in autoclave pressure chamber with ethylene glycol (600 ml). After closing the system take ammonia gas pressure of 3 to 4 Kg at 100 °C temperature for 2 hrs. After cooling the reaction mixture was poured to of water (1500 ml). The crystalline product was separated in the yield of 87.65 % (82.4 gm) with 99 % HPLC purity.

We Claims
1. A modified process for preparing Apixaban of formula IV,

which comprising
(a) Reacting ethyl 6-(4-iodophenyl)-l-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-lH-[3,4-c]pyridine-3-carboxylate of formula-I with piperidin-2-one of formula-II,
in the presence of an alkali metal carbonate salt, catalyst and phase transfer catalyst in ' aromatic aprotic solvent to obtain intermediate of formula - III
(b) Reacting formula-Ill as prepared above step with ammonia in a suitable solvent to obtain Apixaban of formula-IV.
2. The process according to claim 1, wherein the salt of an alkali metal carbonate comprises of potassium carbonate.
3. The process according to claim 2, wherein the salt of an alkali metal carbonate is in the range of 2 to 6 equivalents.
4. The process according to claims 1, wherein the suitable catalyst comprises halogen salt of copper; preferably CuBr or Cul.

5. The process according to claims 4, wherein the suitable catalyst is in the range of 0.2 to 0.8 equivalents.
6. The process according to claim 1, wherein phase transfer catalyst comprises of quaternary ammonium salts; preferable quaternary ammonium salt is tetra-n-butylammonium bromide.
7. The process according to claims 1, wherein an aprotic solvent is selected from of Cyto
C9 alkyl benzene; preferably solvent is toluene.
8. The process according to claim 1-7, the reaction is carried out at reflux temperature of solvent.
9. The process according to claim 1-7, the solvent was continually dried by azeotropic distillation.
10. The process according to claim 1, wherein suitable solvent for the reaction of the
compound III with ammonia is glycols; preferably glycol is selected from polyethylene
glycol or ethylene glycol.