FORM - 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION (See Section 10 and Rule 13)
NOVEL PROCESS FOR THE PREPARATION OF APIXABAN & N-1 POLYMORPH OF APIXABAN
M/S AMOLI ORGANICS PVT. LTD,
407 Dalamal House, J.B.Road,
Nariman Point, Mumbai-400021,
INDIA
The following specification particularly describes an invention and the manner in which it is to be performed.

NOVEL PROCESS FOR THE PREPARATION OF APIXABAN & N-1 POLYMORPH OF APIXABAN
FIELD OF THE INVENTION
The present invention relates to an improved process for the preparation of Apixaban and N-1 polymorph thereof.
BACKGROUND OF THE INVENTION
Apixaban is an anticoagulant drug disclosed in US 6,967,208. It is chemically known as 1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-l-yl)phenyl]-4,5,6,7- tetrahydro-IH-pyrazolo[3,4-c]pyridine-3-carboxyamide of formula (I). Said compound is used in the prevention and treatment of thromboembolic disorders.
US 6967208 disclose Apixaban having utility as Factor Xa inhibitor and also disclose the process for preparation of Apixaban as depicted in Scheme-1. Said methodology involves use of cost contributing starting material viz. 4-iodo aniline as well as reagents like 5-valerolactum, cesium carbonate. Further the reported methodology involves column chromatography purification techniques for the purification of intermediates as well as apixaban and thereby process was difficult to practice commercially.


International (PCT) publication No. WO 2007/001385 A2 and its corresponding U.S. Pat. No. 7,396,932 B2 discloses the process for the preparation of pyrazole-pyridine derivatives as depicted in Scheme-2.


IP.com Journal Vol. 12 (11A) Pg. 10, (2012) discloses the synthesis of
apixaban by reduction of nitro group of ethyl l-(4-methoxyphenyl)-6-(4-
nitrophenyl)-7-oxo- 4,5,6,7-tetrahydro-IH-pyrazolo[3,4-c]pyridine-3-
carboxylate by usage of 10% Pd/C catalyst in presence of formic acid and potassium formate and amidation with ethylene glycol saturated with ammonia to obtain 6-(4-aminophenyl)-l-(4- methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide followed by N-acylation with 5-bromovaleroyl chloride and intramolecular heterocyclization of the intermediate 6-(4-(5-bromopentanamido) phenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-IH-pyrazolo[3,4-c] pyridine-3-carboxamide.
CN 102675314 A discloses the process for the preparation of apixaban by cyclization of p-nitroaniline with 5-chloro-pentanoyl chloride or 5-bromo-pentanoyl chloride; the resulting l-(4-nitrophenyl)-2-piperidinone underwent dichlorination with phosphorus pentachloride followed elimination; the resulting 3-chloro-5,6-dihydro- 1 - (4-nitrophenyl)-2(IH)-pyridinone

underwent reaction with ethyl (2Z)-chloro[(4-
methoxyphenyl)hydrazono]acetate; the resulting ethyl 4,5,6,7-tetrahydro-l-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-IH-pyrazolo [3,4-c]pyridine-3-carboxylate underwent reduction followed by cyclization with 5-chlorovalaroyl chloride or 5- bromovalaroyl chloride; the resulting intermediate underwent amidation to give apixaban.
Reported processes for the preparation of Apixaban as aforementioned involves tedious steps and expensive solvents, has more scope for the formation of impurities and are difficult to practice on commercial scale. The present process is an improved, efficient, robust and production friendly process for the preparation of highly pure Apixaban and N-1 polymorph thereof.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of Apixaban and N-1 polymorphic form thereof, comprising the steps of;
(a) Reacting 3-Morpholino-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one, compound of Formula II with (Z)-Ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate, compound of Formula III in a solvent and in presence of a base to provide Ethyl 1-(4-methoxyphenyl)-7a-morpholino-6-(4-nitrophenyl)-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate of formula IV;

(b) Reacting Ethyl 1-(4-methoxyphenyl)-7a-morpholino-6-(4-nitrophenyl)-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine-3-

carboxylate, compound of formula IV with an acid in a solvent to provide Ethyl 1 -(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine-3-carboxylate, compound of Formula V;

(c) Reducing Ethyl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-
4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine-3-carboxylate, compound of
Formula V in a solvent in presence of a reducing agent to provide Ethyl 6-
(4-aminophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-
pyrazolo[3,4-c]-pyridine-3-carboxylate, compound of Formula VI;

(d) Reacting Ethyl 6-(4-aminophenyl)-1-(4-methoxyphenyl)-7-oxo-
4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]-pyridine-3-carboxylate, compound of
Formula VI with compound of Formula VII in a solvent and in presence of
base to provide compound of formula VIII;


(e) Cyclizing compound of formula VIII in a solvent in presence of a
base to provide Ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-
yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate,
compound of formula IX;

(f) Reacting Ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-
1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate,
compound of formula IX with ammonia gas in a solvent to provide crude
Apixaban of formula I;

(g) Purification of crude Apixaban
(h) Preparation of Apixaban N-1 Polymorphic form.
BRIEF DESCRIPTION OF THE DRAWINGS
FIG-1: X-ray powder diffraction (XRD) pattern of Form N-1 of Apixaban obtained as per the present invention

DETAILED DESCRIPTION OF THE INVENTION
In an aspect, the present invention relates to an improved process for the preparation of Apixaban and N-1 polymorphic form thereof, comprising the steps of;
(a) Reacting 3-Morpholino-1-(4-nitrophenyl)-5,6-dihydropyridin-
2(1H)-one, compound of Formula II with (Z)-Ethyl 2-chloro-2-(2-(4-
methoxyphenyl)hydrazono)acetate, compound of Formula III in a solvent
and in presence of a base to provide Ethyl 1-(4-methoxyphenyl)-7a-
morpholino-6-(4-nitrophenyl)-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-
pyrazolo[3,4-c]pyridine-3-carboxylate, compound of formula IV;

(b) Reacting Ethyl 1-(4-methoxyphenyl)-7a-morpholino-6-(4-
nitrophenyl)-7-oxo-3a,4,5,6,7,7a-hexahydro-1H-pyrazolo[3,4-c]pyridine-3-
carboxylate, compound of formula IV with an acid in a solvent to provide
Ethyl 1 -(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-
pyrazolo[3,4-c]pyridine-3-carboxylate, compound of Formula V;

(c) Reducing Ethyl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-
4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine-3-carboxylate, compound of

Formula V in a solvent in presence of a reducing agent to provide Ethyl 6-(4-aminophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]-pyridine-3-carboxylate, compound of Formula VI;

(d) Reacting Ethyl 6-(4-aminophenyl)-1-(4-methoxyphenyl)-7-oxo-
4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]-pyridine-3-carboxylate, compound of
Formula VI with compound of Formula VII in a solvent and in presence of
base to provide compound of formula VIII;

(e) Cyclizing compound of formula VIII in a solvent in presence of a
base to provide Ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-
yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate,
compound of formula IX;


(f) Reacting Ethyl 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-
1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate,
compound of formula IX with ammonia gas in a solvent to provide crude
Apixaban of formula I;

(g) Purification of crude Apixaban
(h) Preparation of N-1 Polymorphic form of Apixaban.
According to preferred embodiment, Compounds of formula IV, VIII and IX are not isolated.
The solvents employed in steps (a), (b), (c), (d), (e) and (f) comprise one or more of alcohols, nitriles, ketones, esters, ethers, amides, sulfoxide, water or mixtures thereof. In particular, alcohols comprises one or more of methanol, ethanol, n-propanol, isopropanol, and n-butanol; nitriles comprises one or more of acetonitrile, propionitrile, butyronitrile, and valeronitrile; ketones comprises one or more of acetone, methyl ethyl

ketone, and methyl isobutyl ketone; esters comprises one or more of ethyl acetate, propyl acetate, isopropyl acetate, and butyl acetate; chlorinated solvents comprises one or more of methylene dichloride, chloroform, ethylene dichloride, and chlorobenzene; ethers comprises one or more of diethyl ether, diisopropyl ether, methyl tert-butyl ether, tetrahydrofuran, and dioxane; amides comprises one or more of dimethylformamide, dimethylacetamide, and N-methylformamide; sulfoxide comprises of dimethylsulfoxide.
In general, the base comprises one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydride, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium tert-butoxide, ammonia, triethylamine, N,N-dimethyl aniline, N,N-diisopropyl ethyl amine, trimethylamine or pyridine.
In one of the embodiment, the reducing agent comprises one or more of Raney Nickel, Pd/C, Pt/C, Platinum oxide, Fe-HCI, Fe-acetic acid, Fe-NH4C1, Sn-HCI, and Na2Sx.
Preferably, the solvent and base used in step (a) is selected from ethyl acetate and triethylamine respectively.
In one of an embodiment, acid and solvent used in step (b) is selected from HCI and water respectively.
In an embodiment, the present invention provides novel and improved process for reduction of Ethyl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate, compound of Formula V to form Ethyl 6-(4-aminophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]-pyridine-3-carboxylate, compound of Formula VI in step (c) using acetic acid and iron powder as reducing agent and methylene dichloride as solvent.

In further embodiment, water was added drop wise to the reaction mass of step (c) comprising compound of Formula VI, methylene dichloride, iron powder and acetic acid at 35-40°C.
In additional embodiment, EDTA was also added to the reaction mass of step (c) to remove of iron.
In another preferred embodiment, solvent and base used in step (d) is selected from methylene dichloride and triethylamine respectively.
Further, in another embodiment of the present invention, X in a Compound of formula VII and VIII is preferably selected from CI.
In another aspect of the present invention, there is provided a novel process for preparation of compound of formula IX in step (e) involving the use of mixture of methylene dichloride and ethyl acetate as solvent, powdered KOH as base and KBr used as catalyst.
In further aspect of the present invention, solvent used in step (f) is selected from methanol.
In another embodiment of the invention, in step (g), purification of Apixaban obtained in step (f) is carried out by using Dimethyl formamide as solvent.
According to yet another embodiment, the present invention provides a novel process for preparation of N-1 form of Apixaban, the process comprising:
(a) Dissolving Apixaban obtained in step (g) in mixture of acetone and methanol by heating.
(b) Filtering and distilling out solvent from clear filtrate.
(c) Filtering the precipitate, washing and drying to obtain pure solid as crystalline form N-1 of Apixaban.
In one aspect, the advantages of the present invention are

i) In-situ intermediate compound of formula IV formed in step (a) was not isolated, resulting in reduction in time and energy resources for workup and isolation,and increase in yield and purity (above 99%).
ii) Use of methylene dichloride in step (c) resulted in reduction in unknown impurities compared to neat reaction.
iii) Slow addition of water at 35-40°C resulted in reduction of unknown impurities.
iv) Addition of EDTA resulted in removal of traces of iron.
v) Use of triethylamine in step (d) resulted in less side reactions compared to other bases like sodium hydroxide, potassium carbonate etc.
vi) Number of moles of base required for completion of reaction in step (e), was less in case of KOH as compared to other bases.
vii) Use of ethyl acetate as solvent in combination with methylene dichloride in step (e), resulted in maintaining acid impurity at control level.
viii) Use of KBr as catalyst in step (e) resulted in increase in speed of reaction.
ix) The compound of formula IX formed in step (e) was not isolated which prevented the yield loss and reduction in processing time.
x) Use of dimethyl formamide in step (g) resulted in removal of impurities and formation of pure compound.
xi) Use of Acetone and methanol in step (h) resulted in formation of desired polymorph (N-1) with high purity and yield.
EXAMPLES
The present invention is described in the examples given below; further these are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention. EXAMPLE 1: Preparation of Ethyl 1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate

400 ml Ethyl acetate, 100 gm of 3-Morpholino-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one and 93.2 gm of (Z)-Ethyl 2-chloro-2-(2-(4-methoxyphenyl) hydrazono)acetate were added to a round bottom flask and reaction mass was heated to 50°C. 315 ml of triethylamine solution in ethyl acetate was added at 50-60X. Reaction mass was heated to 70-80°C and maintained for 5 hours. Reaction mass was cooled up to 20-30°C and 280 ml water and 660 ml 4N HCI solution were charged. Reaction mass was stirred for 8 hrs at 20-30°C. Product was filtered, washed with water and dried in oven.
EXAMPLE 2: Preparation of Ethyl 6-(4-aminophenyl)-1-(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate
100 gm of Ethyl-1-(4-methoxyphenyl)-6-(4-nitrophenyl)-7-oxo-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxylate and 500 ml methylene dichloride were charged into a round bottom flask at 25-30°C. 25.7 gm Iron powder and 120 ml acetic acid were charged at 25-30°C and reaction mass was heated at 35-40°C. 100 ml water was added at 35-40°C and reaction mass was maintained for 1 hr at 35-40°C. 1500 ml of methylene dichloride was charged at 35-40°C and reaction mass was filtered at 35-40°C. The precipitate was washed with 500 ml methylene dichloride at 30-35°C and filtrate was charged in a round bottom flask at 30-35°C. Organic layer was washed with water followed by EDTA solution at about 35°C. Methylene dichloride layer was then charged into a round bottom flask at 30-35°C. 650 ml Methanol was charged and methanol was distiled out up to 150 ml at 60-65°C. Distillation was stopped and reaction mass was stirred for 1 hr at 60-65°C. Reaction mass was then cooled to 20-30X and 1000 ml water was charged at 20-30°C. Reaction mass was maintained for 1 hr at 20-30°C followed by filtration, washing with water and drying at 75-80°C in vacuum dryer for 10 hrs.

EXAMPLE 3: Preparation of Apixaban
1000 ml methylene dichloride and 100 gm of Ethyl 6-(4-aminophenyl)-1 -(4-methoxyphenyl)-7-oxo-4,5,6,7-tetrahydro-1 H-pyrazolo[3,4-c]pyridine-3-carboxylate were charged into a round bottom flask at 20-30°C. 49.78 gm Triethylamine was charged at 20-30°C and reaction mass was cooled up to 0-10°C. Mixture of 5-chlorovaleroyl chloride in methylene dichloride was added at 0-10°C. Reaction mass was maintained at 0-10°C for 2 hrs. methylene dichloride layer was washed with water. Methylene dichloride was distille out upto approx. 200 ml. Reaction mass was cooled at 25-30°C, 200 ml methylene dichloride, 100 ml ethyl acetate, 31.05 gm powdered potassium hydroxide and 100 mg potassium bromide were added at 25-30°C and maintained for 4-5 hours. After completion of reaction, methylene dichloride layer was washed with water. Methylene dichloride was distilled out completely.
1500 ml methanol and degassed mass were charged in an autoclave at 25-35°C. Reaction mass was heated to 40-45°C. Ammonia pressure of 5-6 kg was applied and maintained for 30 hrs at 50-55°C. Reaction mass was cooled to 45-50°C and transferred to a round bottom flask. Methanol was distilled out completely. Reaction mass was cooled to 25-35°C and 500 ml dimethylformamide was added to the reaction mass at 25-35°C. Reaction mass was heated to 80-85X and maintained for 1 hour. Reaction mass was cooled to 20-25°C and.Wet solid slurry two time in dimethylformamide at 80-85°C. EXAMPLE 4: Preparation of N-1 polymorphic form of Apixaban
3500 ml Acetone, 3000 ml Methanol and 100 gm Apixaban were charged into a round bottom flask and reaction mass was heated to 55-60°C.charcolisation of reaction mass at 55-60°C. Reaction mass was filtered through hyflo bed, clear solution was charged into another round bottom flask and solvent was distilled out up to 25-30% under vacuum. Reaction mass was cooled and solid was filtered. Wet solid was dried under vacuum to obtain N-1 polymorphic form of Apixaban.

We Claim
A process for the preparation of Apixaban comprising the steps of
(a) reacting compound of Formula II with compound of Formula III in
presence a solvent and a base to provide compound of formula IV;

(b) reacting compound of formula IV with an acid in a solvent to provide
compound of Formula V;

(c) reducing, compound of Formula V in a solvent in presence of a
reducing agent and a solvent to provide compound of Formula VI;

(d) reacting compound of Formula VI with compound of Formula VII in
presence of a solvent and a base to provide compound of formula VIII;


(e) Cyclizing compound of formula VIII in a solvent in presence of a base and a catalyst to provide, compound of formula IX;

(f) reacting, compound of formula IX with ammonia source in a solvent to
provide Apixaban of formula I;

(g) Optionally purifying the compound obtained in step (f)
2. The process as claimed in claim 1, wherein the compounds of formula IV, VIM and IX are optionally isolated.
3. A process for the reduction of compound of Formula V to a compound of Formula VI using a reducing agent and a halo hydrocarbon solvent.
4. The process as claimed in claim 3, wherein the reducing agent is Iron powder.
5. The process as claimed in claim 3, wherein the halo hydrocarbon is Dichloromethane.
6. A process for the conversion of compound of Formula VI obtained
according to claim 3 to Apixaban.

7. A process for preparation of compound of formula IX comprising use of mixture of methylene dichloride and ethyl acetate as solvent, KOH as base and KBr as a catalyst.
8. A process for the conversion of compound of Formula IX obtained according to claim 8 to Apixaban.
9. A process for preparation of N-1 form of Apixaban, the process
comprising:
(a) dissolving Apixaban in mixture of acetone and methanol,
(b) making the solution particle free,
(c) concentrating of the filtrate,
(d) isolating crystalline form N-1 of Apixaban from the resulting
concentrated mass.