DESC:The following specification particularly describes the invention and the manner in which it is to be performed.

INTRODUCTION
Aspects of the present application relates to processes for preparation of Apixaban and intermediates thereof.
The drug compound having the adopted name “apixaban” has a chemical name 1-(4-Methoxyphenyl)-7-oxo-6-[4-(2-oxopiperidin-1-yl)phenyl]-4,5,6,7-tetrahydro -1H-pyrazolo[3,4-c]pyridine-3-carboxamide, and the structure of Formula I. Apixaban is being developed by Bristol-Myers Squibb (BMS) and Pfizer for the prevention of venous thromboembolic events (VTE) in adults who have undergone elective hip or knee replacement surgery. Apixaban is having the structure:

Formula I

Apixaban is disclosed in U.S. Patent No. 6,967,208 which is herein incorporated by reference in its entirety, has utility as a Factor Xa inhibitor, and is being developed for oral administration in a variety of indications that require the use of an anti-thrombotic agent.
US patents viz., US6919451B2 and US7396932B2 reported processes for preparation of Apixaban. Also, patent applications viz., WO2012168364A1, WO2014075648A1 and WO2014072884A1, reported processes for preparation of Apixaban. The reported processes require either column purification and/or involve multi-step synthesis.
Thus there remains a need for commercially viable process for preparation of Apixaban while overcoming the drawbacks presented by the processes described in the art.
SUMMARY
In an aspect, the present application provides processes for preparing Apixaban, comprising;

a) reacting a compound of Formula III with a compound of Formula IV to afford compound of Formula II,

Formula III

Formula IV Formula II
Wherein
R1 is selected from -COOH, -CN or –CONH2 or a group convertible to –CONH2,
R2 is selected from CI, Br, I, OSO2Me, OSO2Ph, and OSO2Ph-p-Me,
R3 and R4 are selected from C1-4 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, benzyl; alternatively, NR3R4 is a 3-8 membered ring consisting of carbon atoms, N, and 0-1 O atoms,
b) contacting the compound of Formula II with an acid to form either a compound of Formula Ia where R1 is selected from –CN, -COOH or directly compound of Formula I.

Formula Ia Formula I

c) optionally converting compound of formula Ia to a compound of formula I.
d) isolating and recovering the compound of Formula I.

In yet another aspect, the present application provides processes for preparing Apixaban, comprising;
a) reacting a compound of Formula IIIa with a compound of Formula IVa to afford compound of Formula IIa,

Formula IIIa

Formula IVa Formula IIa

wherein R5 is selected from H, C1-4 alkyl.
b) converting compound of formula IIa to compound of formula IIb under suitable reaction conditions.

Formula IIb

c) contacting the compound of Formula IIb with a suitable acid to afford compound of Formula I.

Formula I

d) isolating and recovering the compound of Formula I.
Yet another aspect of the present application provides use of compound of Formula IIb for preparation of Apixaban.
Yet another aspect of the present application comprises a process for preparation of Apixaban wherein one or more intermediate compounds may not be isolated and used in reaction mixture itself for next step. For example, compound of Formula IIa can be reacted with a reagent to give compound of Formula IIb which optionally without isolation is reacted with a suitable acid to afford compound of Formula I.

DETAILED DESCRIPTION
In an aspect, the present application provides processes for preparing apixaban, comprising;
a) reacting a compound of Formula III with a compound of Formula IV to afford compound of Formula II,

Formula III Formula IV Formula II

Wherein
R1 is selected from -COOH, -CN or –CONH2,
R2 is selected from CI, Br, I, OSO2Me, OSO2Ph, and OSO2Ph-p-Me,
R3 and R4 are selected from C1-4 alkyl, cyclopropyl, cyclobutyl, cyclopentyl, phenyl, benzyl; alternatively, NR3R4 is a 3-8 membered ring consisting of carbon atoms, N, and 0-1 O atoms,
The step a) is materialized in presence of a suitable base in a solvent.
Suitable bases that can be employed include, but are not limited to: organic bases such as triethylamine, diisopropylethylamine, morpholine, N-methyl Morpholine, DABCO (1,4-diazabicyclo[2.2.2]octane). In a preferred embodiment, triethyl amine is employed.
Suitable solvents that can be employed include, but are not limited to: alcohols, such as methanol, ethanol, 2-propanol, n-butanol, isoamylalcohol and ethylene glycol; ethers, such as diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), methyl THF, and diglyme; esters, such as ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; nitriles, such as acetonitrile; polar aprotic solvents, such as N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, and the like; water; and any mixtures of two or more thereof. In a preferred embodiment, toluene is employed.
Compounds of Formula II can optionally be isolated to improve the purity.
b) contacting the compound of Formula II with an acid to form either a compound of Formula Ia where R1 is selected from –CN, -COOH or compound of Formula I.

Formula Ia Formula I

The acid in step b) can be selected from: trifluoroacetic acid, sulfuric acid nitric
acid, hydrochloric acid and like. In a preferred embodiment, HCl is employed.
Suitable solvent employed in step b) is inert to the reaction medium and can be selected from aforementioned list of solvents.
c) optionally converting compound of formula Ia to a compound of formula I.
The said step involves conversion of R1 to amide functionality when R1 is an acid or cyano group. When R1 is an acid then compound of Formula Ia is treated with a suitable amidating agent in a suitable solvent to materialize the amidation. If R1 is acid then prior to treatment with a base, optionally the reaction mixture can be treated with a dehydrating agent to remove the moisture followed by an activating agent to improve the yields. Suitable amidating agent can be ammonium hydroxide.
In case R1 is –CN then the desired conversion can be done either by addition of H2O to –CN or by first hydrolyzing the –CN to –COOH followed by amidation with suitable amidating agents such as ammonia, formamide etc.
Suitable dehydrating reagents include strong acids and orthoformates. Examples of strong acids include (a) TFA, (b) sulfuric acid, and (c) sulfonic acids. Examples of orthoformates include (a) trimethyl orthoformate, triethyl orthoformate, diethyl phenyl orthoformate, tributyl orthoformate, triisopropyl orthoformate, tripentyl orthoformate, and tripropyl orthoformate and (b) triethyl orthoformate. The amount of orthoformate added depends upon the level of moisture present prior to dehydration and the amount of water desired after dehydration.
Suitable solvents will generally be inert to the reaction conditions and can be chosen from the list provided above for formation of the compound of Formula II. In embodiments, toluene is employed as a solvent.
Optionally, purifying compound of Formula I by conventional methods. The compound of Formula I may be purified by using conventional crystallization techniques or by a basification-acidification process. The suitable crystallization techniques include, but are not limited to precipitation or slurrying in a solvent, concentrating, cooling, stirring or shaking a solution containing the compound, combining a solution containing a compound with an anti-solvent, seeding and partial removal of the solvent or combinations thereof, evaporation, flash evaporation and the like. An anti-solvents as used herein refers to a liquid in which a compound of Formula I is poorly soluble. Compound of Formula I can be subjected to any of the purification techniques more than one time until the desired purity for a compound of Formula I is attained.
The compound of Formula I can also be purified by re-crystallization from an appropriate re-crystallization solvent or mixture of solvents by methods customary to one of skill in the art. In a preferred embodiment, DMF is used as solvent for recrystallization.
d) isolating and recovering the compound of Formula I.
The isolation of Apixaban may be induced by using conventional techniques known in the art. For example, useful techniques include but are not limited to, concentrating, cooling, stirring, shaking, combining with an anti-solvent, adding seed crystals, evaporation, flash evaporation, simple evaporation, rotational drying, spray drying, thin-film drying, freeze-drying, or the like. The solid that is obtained may carry a small proportion of occluded mother liquor containing a higher percentage of impurities and, if desired, the solid may be washed with a solvent to wash out the mother liquor. Evaporation as used herein refers to distilling of solvent almost completely at atmospheric pressure or under reduced pressure. Flash evaporation as used herein refers to distilling of solvent by using a technique includes but is not limited to tray drying, spray drying, fluidized bed drying, thin film drying under reduced pressure, or thin film drying at atmospheric pressure. The recovery of Apixaban can be done by decantation, centrifugation, gravity filtration, suction filtration and like.
The recovered solid may optionally be dried. Drying may be carried out in any of a tray dryer, air tray dryer, vacuum oven, air oven, cone vacuum dryer, rotary vacuum dryer, fluidized bed dryer, spin flash dryer, flash dryer, and the like. The drying may be carried out at temperatures less than about 100°C, less than about 80°C, less than about 60°C, less than about 55°C, or any other suitable temperatures, at atmospheric pressure or under a reduced pressure, as long as the apixaban quality is not affected. The drying may be carried out for any desired times until the required product quality is achieved.
The dried product may optionally be subjected to a particle size reduction procedure to produce desired particle sizes and distributions. Milling or micronization may be performed before drying, or after the completion of drying of the product. Equipment that may be used for particle size reduction include, without limitation thereto, ball, roller, and hammer mills, and jet mills.
In a preferred embodiment, Apixaban is subjected to micronization to afford particle having D90 less than 20 microns, preferably D90 less than 15 microns and more preferably D90 less than 10 microns.
In yet another aspect, the present application provides processes for preparing apixaban, comprising
a) reacting a compound of Formula IIIa with a compound of Formula IVa to afford compound of Formula IIa,

Formula IIIa Formula IVa

Formula IIa

wherein R5 is selected from H, C1-4 alkyl.
The conditions are as described in aforementioned aspect of the application. In a preferred embodiment, triethyl amine is used as a base and toluene is employed as a solvent.
In yet another preferred embodiment, the mixture from step a) is used for the next step without isolation of compound of Formula IIa.

b) converting compound of formula IIa to compound of formula IIb under suitable reaction conditions.

Formula IIb
The conditions are as described in aforementioned aspect of the application. In a preferred embodiment, sodium methoxide, formaldehyde are employed as reagents.
Optionally the reaction mixture can be treated with a dehydrating agent to remove the moisture followed by amidation to improve the yields and quality.
In yet another preferred embodiment, the mixture from step b) is used for the next step without isolation of compound of Formula IIb.
c) contacting the compound of Formula IIb with a suitable acid to afford compound of Formula I.

Formula I

The conditions are as described in aforementioned aspect of the application. In a preferred embodiment, aqueous HCl is employed.
d) isolating and recovering the compound of Formula I.
The compound is isolated by conventional methods as described above.
Yet another aspect of the present application provides processes for preparing apixaban, comprising contacting compound of Formula IIb with an acid to afford compound of Formula I.

Formula IIb

Yet another aspect of the present application provides use of compound of Formula IIb for preparation of Apixaban.
Yet another aspect, the present application comprises a process for preparation of Apixaban wherein one or more intermediate compounds may not be isolated and used in reaction mixture itself for next step. For example, compound of Formula IVa can be reacted with Formula IIIa to afford compound of Formula IIa which without isolation can be reacted with a reagent to give compound of Formula IIb which optionally without isolation is reacted with a suitable acid to afford compound of Formula I.
An aspect of the present application provides a novel compound of Formula IIb;

Formula IIb

The chemical transformations described throughout the specification may be carried out using substantially stoichiometric amounts of reactants, though certain reactions may benefit from using an excess of one or more of the reactants. Additionally, many of the reactions disclosed throughout the specification, may be carried out at ambient temperatures, but particular reactions may require the use of higher or lower temperatures, depending on reaction kinetics, yields, and the like. Furthermore, many of the chemical transformations may employ one or more compatible solvents, which may influence the reaction rates and yields. Depending on the nature of the reactants, one or more solvents may be polar protic solvents, polar aprotic solvents, non-polar solvents, or any of their combinations.
The compounds obtained by the chemical transformations of the present application can be used for subsequent steps without further purification, or can be effectively separated and purified by employing a conventional method well known to those skilled in the art, such as recrystallization, column chromatography, by transforming them into a salt, or by washing with an organic solvent or with an aqueous solution, and eventually adjusting pH. Compounds at various stages of the process may be purified by precipitation or slurrying in suitable solvents, or by commonly known recrystallization techniques. The suitable recrystallization techniques include, but are not limited to, steps of concentrating, cooling, stirring, or shaking a solution containing the compound, combination of a solution containing a compound with an anti-solvent, seeding, partial removal of the solvent, or combinations thereof, evaporation, flash evaporation, or the like. An anti-solvent as used herein refers to a liquid in which a compound is poorly soluble. Compounds can be subjected to any of the purification techniques more than one time, until the desired purity is attained.
Compounds may also be purified by slurrying in suitable solvents, for example, by providing a compound in a suitable solvent, if required heating the resulting mixture to higher temperatures, subsequent cooling, and recovery of a compound having a high purity. Optionally, precipitation or crystallization at any of the above steps can be initiated by seeding of the reaction mixture with a small quantity of the desired product. Suitable solvents that can be employed for recrystallization or slurrying include, but are not limited to: alcohols, such as, for example, methanol, ethanol, and 2-propanol; ethers, such as, for example, diisopropyl ether, methyl tert-butyl ether, diethyl ether, 1,4-dioxane, tetrahydrofuran (THF), and methyl THF; esters, such as, for example, ethyl acetate, isopropyl acetate, and t-butyl acetate; ketones, such as acetone and methyl isobutyl ketone; halogenated hydrocarbons, such as dichloromethane, dichloroethane, chloroform, and the like; hydrocarbons, such as toluene, xylene, and cyclohexane; nitriles, such as acetonitrile and the like; water; and any mixtures of two or more thereof. In embodiments, slurrying with water is employed.
Apixaban manufactured by the present invention is substantially free from impurities. Typically Apixaban is of high purity such as atleast about 98%, 99% or 99.5%, by weight. Correspondingly, the level of impurities may be less than about 2%, 1% or 0.5%, by weight, as determined by using high performance liquid chromatography (HPLC).
The presence of impurities in Apixaban may pose a problem for pharmaceutical product formulation, in that impurities often affect the safety and shelf life of a formulation. The present invention provides a method for ameliorating the effect of impurities by reducing the amount of the impurities during synthesis of Apixaban.
DEFINITIONS
The following definitions are used in connection with the present application unless the context indicates otherwise.
The term “anti-solvent” refers to a liquid that, when combined with a solution of apixaban, reduces solubility of the apixaban in the solution, causing crystallization or precipitation in some instances spontaneously, and in other instances with additional steps, such as seeding, cooling, scratching, and/or concentrating.
Celite® is flux-calcined diatomaceous earth. Celite® is a registered trademark of World Minerals Inc.
Hyflow is flux-calcined diatomaceous earth treated with sodium carbonate. Hyflo Super Cel™ is a registered trademark of the Manville Corp.
An “aliphatic or alicyclic hydrocarbon solvent” refers to a liquid, non-aromatic, hydrocarbon, which may be linear, branched, or cyclic. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of a hydrocarbon solvent include, but are not limited to, n-pentane, isopentane, neopentane, n-hexane, isohexane, 3-methylpentane, 2,3-dimethylbutane, neohexane, n-heptane, isoheptane, 3-methylhexane, neoheptane, 2,3-dimethylpentane, 2,4-dimethylpentane, 3,3-dimethylpentane, 3-ethylpentane, 2,2,3-trimethylbutane, n-octane, isooctane, 3-methylheptane, neooctane, cyclohexane, methylcyclohexane, cycloheptane, C5-C8 aliphatic hydrocarbons, ligroin, petroleum ethers, and mixtures thereof.
“Aromatic hydrocarbon solvent” refers to a liquid, unsaturated, cyclic, hydrocarbon containing one or more rings having at least one 6-carbon ring containing three double bonds. It is capable of dissolving a solute to form a uniformly dispersed solution. Examples of an aromatic hydrocarbon solvent include, but are not limited to, benzene, toluene, ethylbenzene, m-xylene, o-xylene, p-xylene, indane, naphthalene, tetralin, trimethylbenzene, chlorobenzene, fluorobenzene, trifluorotoluene, anisole, C6-C10 aromatic hydrocarbons, and mixtures thereof.
An “alcohol” is an organic compound containing a carbon bound to a hydroxyl group. “C1-C6 alcohols” include, but are not limited to, methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, isobutyl alcohol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol, and the like
An “ester” is an organic compound containing a carboxyl group -(C=O)-O- bonded to two other carbon atoms. “C3-C6 esters” include, but are not limited to, ethyl acetate, n-propyl acetate, n-butyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, and the like.
An “ether” is an organic compound containing an oxygen atom –O- bonded to two carbon atoms. Ethers include, but are not limited to, diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole, C3-6 ethers, and the like.
A “ketone” is an organic compound containing a carbonyl group -(C=O)- bonded to two other carbon atoms. “C3-C6 ketones” include, but are not limited to, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ketones, and the like.
As used herein, "comprising" means the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms "having" and "including" are also to be construed as open ended unless the context suggests otherwise. 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. Such terms will be defined by the circumstances and the terms that they modify, as those terms are understood by those of skill in the art. This includes, at very least, the degree of expected experimental error, technique error, or instrument error for a given technique used to measure a value.
All percentages and ratios used herein are by weight of the total composition and all measurements made are at about 25°C and about atmospheric pressure, unless otherwise designated. All temperatures are in degrees Celsius unless specified otherwise. As used herein, the terms “comprising” and “comprises” mean the elements recited, or their equivalents in structure or function, plus any other element or elements which are not recited. The terms “having” and “including” are also to be construed as open ended. All ranges recited herein include the endpoints, including those that recite a range between two values. Whether so indicated or not, all values recited herein are approximate as defined by the circumstances, including the degree of expected experimental error, technique error, and instrument error for a given technique used to measure a value.
The term “optional” or “optionally” is taken to mean that the event or circumstance described in the specification may or may not occur, and that the description includes instances where the event occurs and instances where it does not.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the disclosure in any manner.

EXAMPLES
EXAMPLE 1: PREPARATION OF APIXABAN
A flask was charged with 3-morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridin-2(1H)-one (25 g), ethyl (Z)-2-chloro-2-(2-(4-methoxyphenyl) hydrazono)acetate (60.5 g) and toluene (250 mL). The reaction mixture is stirred for 15 minutes at room temperature followed by addition of triethylamine (39.7 g) over a period of about 35 minutes at the same temperature. The reaction mixture is heated to about 77oC and maintained at the same temperature for about 6 hours at which point completion of the reaction is monitored by TLC. The reaction mixture is cooled to about 10-15oC followed by addition of formamide solution (76 g) and slow addition of 25% sodium methoxide solution (53 g) over a period of 15 minutes. The reaction mixture is allowed to attain the room temperature and progress of the reaction is monitored by TLC. After completion of the reaction, the mixture is cooled to 0-5oC and then 35% hydrochloric acid solution (81.7 mL and 61 mL) is added in two lots over a period of about 40 minutes. During addition of aqueous HCl solution, temperature of the mixture reached to about 20-25oC and solid precipitation started. Then the mixture is allowed to stir at room temperature for about 3 hours and solid obtained is isolated by filtration. The wet cake is washed with toluene (50 mL), water (100 mL) and dried under vacuum at 65oC for about 11 hours to afford the title compound (28.1 g) in about 87% yield.

EXAMPLE 2: PREPARATION OF 1-(4-AMINOPHENYL)-3-MORPHOLINO -5,6-DIHYDROPYRIDIN-2(1H)-ONE
A reactor is charged with methanol (285 L), 3-morpholino-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one (19 Kg), Sodium sulphide nanohydrate (23.40 Kg), and water (95 L). The temperature of the reaction mixture is raised to 60-65oC and maintained for 4 hours. Completion of the reaction is checked by TLC. After completion of reaction, reaction mixture is filtered at 60-65oC and solid is washed with preheated methanol (19L). The solvent from the filtrate is subjected to partial distillation under vacuum at 60oC and then remaining solvent is sequentially cooled to 25-35oC, then to 0-5oC followed by addition of water (38 L) at 0-5oC to afford the solid. The obtained solid is washed with chilled water and subjected to drying under vacuum at 60-65oC for 14 hours to afford the title compound.

EXAMPLE 3: PREPARATION OF 3-MORPHOLINO-1-(4-(2-OXOPIPERIDIN-1-YL)PHENYL)-5,6-DIHYDROPYRIDIN-2(1H)-ONE
A reactor is charged with toluene (182 L), 1-(4-aminophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one (13 Kg), triethylamine (12 Kg) at room temperature. The reaction mixture is cooled to 0-5oC. To this, a mixture of 5-Chlorovaleroyl chloride (11.8 kg) in toluene (19.5 L) is slowly added at 0-5oC and reaction mass is stirred for 15-20 minutes at 0-5oC, then temperature is raised to 35-40oC and maintained for 2 hours. After completion of reaction, sodium chloride solution (7.8 Kg sodium chloride in 78 L of water) is added to the mixture and solid obtained is isolated by centrifugation. Then this solid is taken up in toluene (182 L) at 25-35oC, followed by addition of tetrabutylammonium bromide (1.30 Kg). Then potassium hydroxide solution (21.32 Kg KOH in about 19.5 L of water) is added and temperature of reaction mass is increased to 55-60oC at which point it is maintained for 4 hours. After completion of reaction, the mixture is cooled to 25-35oC and water (39L) is added followed by cooling of the mixture to 0-5oC. The mixture is maintained at this temperature for 30-60 minutes. The solid obtained is isolated and washed with precooled water (19.5L). Separately, a reactor is charged with potassium hydroxide solution (0.54 Kg KOH in 130 L of methanol) and the above solid obtained is charged into this reactor at 25-30oC. The temperature is raised to 50-55oC and mixture is maintained for about 2 hours followed by partial distillation of solvent under vacuum at below 50oC. Then mixture is sequentially cooled to 25-30oC, -5-0oC at which point it is maintained for 1 hour. The solid obtained is isolated and washed with chilled methanol (19.5 L) followed by drying of solid under vacuum at 55-65oC for about 5 hours to afford the title compound.

EXAMPLE 4: PREPARATION OF APIXABAN
A flask is charged with 3-morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridin-2(1H)-one (100g), toluene (1000mL), ethyl (Z)-2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (87 g) and triethylamine (85 g) at room temperature. The mixture is heated to about 60oC and stirred at the same temperature for about 4 hours. The mixture is cooled to room temperature and filtered, the bed is washed with toluene (100 mL). The filtrate is subjected to complete distillation under vacuum at about 55oC to afford the crude compound. Then DMF (400 mL) is added at about 50oC and mixture is cooled to room temperature followed by addition of Formamide (279 g), trimethyl orthoformate (14.93 g). The mixture is stirred for about 10-15 minutes followed by sequential addition of trifluroacetic acetic acid (1.6 g) and 30% sodium methoxide solution (28.9 g) at 24oC. The mixture is maintained at room temperature for about 3 hours followed by cooling to 1oC at which point trifluoroacetic acid (96 mL) is slowly added. The mixture is stirred at about 10oC for 10 minutes and then at about 25oC for about 2 hours. The solid obtained is filtered and washed with water (400mL, 500 mL and 100 mL) and then subjected to drying under vacuum at 70oC for about 20 hours to afford title compound in about 73% yield.

EXAMPLE 5: PREPARATION OF APIXABAN
A flask is charged with 3-morpholino-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridin-2(1H)-one (100g), toluene (1000mL), ethyl (Z)-2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (87 g) and triethylamine (85 g) at room temperature. The mixture is heated to about 70oC and stirred at the same temperature for about 8 hours. The mixture is cooled to room temperature and filtered, the bed is washed with toluene (200 mL). The filtrate is subjected to complete distillation under vacuum at about 60oC to afford the crude compound. Then DMF (400 mL) is added at room temperature followed by addition of Formamide (279 g), trimethyl orthoformate (32.8 g). The mixture is stirred for about 10-15 minutes followed by sequential addition of trifluroacetic acetic acid (1.6 g). Again, trimethyl orthoformate (13.7 g) and trifluroacetic acetic acid (1.6 g) is added to the mixture and mixture is maintained for 40 minutes at room temperature followed by slow addition of 30% sodium methoxide solution (28.9 g) over a oeriod of 40 minutes at 24oC. The mixture is maintained at room temperature for about 3 hours followed by cooling to 0oC at which point trifluoroacetic acid (112 mL) is slowly added. The mixture is stirred at about room temperature for 2 hours followed by cooling of the mixture to about 5-10oC and maintenance for about 2 hours. The solid obtained is filtered and washed with DMF:water (200:200 mL). The solid is slurried in water (500 mL) for about 1 hour and then again filtered and washed with water (250mL) and then subjected to drying under vacuum at 70oC for about 12 hours to afford title compound in about 71% yield.

EXAMPLE 6: PREPARATION OF APIXABAN
A flask is charged with Apixaban (500 g) in DMF (30 mL), mixture is subjected to heating at 75oC till clear solution is obtained. The mixture is filtered and bed is washed with DMF (50 mL) and it is cooled to a temperature of about 20oC. The mixture is maintained at this temperature for about 4 hours. The solid obtained is isolated by filtration under vacuum and washed with precooled DMF (50 mL). The obtained solid is subjected to drying under vacuum at about 65oC for about 24 hours to afford Apixaban having 99.83% HPLC purity.

EXAMPLE 7: PREPARATION OF APIXABAN
A flask is charged with Apixaban (13.8 g) obtained from above experiment, water (160 mL) and DMF (3 g). The mixture is subjected to heating to 70-75oC and seeding with N-1 form is done at the same temperature. The mixture is maintained at about 70oC for about 1 hour and then cooled to about 30oC. The solid is isolated by filtration and washed with water (60 mL), then subjected to drying under vacuum at about 80-85oC to afford N-1 form of Apixaban having HPLC purity of 99.84% and D90 as 28.67 microns.

,CLAIMS:WE CLAIM:
Claim 1: A process for preparation of Apixaban, comprising;
a) reacting a compound of Formula IIIa with a compound of Formula IVa to afford compound of Formula IIa,

Formula IIIa Formula IVa

Formula IIa

wherein R5 is selected from H, C1-4 alkyl.
b) converting compound of formula IIa to compound of formula IIb under suitable reaction conditions.

Formula IIb

c) contacting the compound of Formula IIb with a suitable acid to afford compound of Formula I.

Formula I
d) isolating and recovering the compound of Formula I.

Claim 2: The process of claim 1, wherein step a) is performed in toluene and triethyl amine is used as a base.

Claim 3: The process of claim 1, wherein solvent employed in step b) comprises DMF.

Claim 4: The process of claim 1, wherein step b) is done in presence of dehydrating agent and a strong base.

Claim 5: The process of claim 4, wherein dehydrating agent is selected from trimethylorthoformate and trifluroacetic acid.

Claim 6: The process of claim 1, wherein step c) is done at a temperature less than 15oC.

Claim 7: The process of claim 1, wherein step c) is done at a temperature less than 5oC.

Claim 8: The process of claim 1, wherein steps a) to c) are done in one-pot without isolation of intermediates.

Claim 9: The process of claim 1, wherein step d) involves an additional step of purification.

Claim 10: The process of claim 9, wherein recrystallization is done with DMF.