DESC:

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. The prior art processes require column purification and/or involves 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 under suitable reaction conditions to afford compound of Formula II,

formula III

Formula IV Formula II

Wherein R1 is selected from CO2-alkyl, -CN or –CONH2,

R2 is selected from CI, Br, I, OSO2Me, OSO2Ph, and OSO2Ph-p-Me X is any halogen selected from I, Br, Cl

b) converting compound of formula II to compound of formula I

c) optionally, purifying 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 under suitable reaction conditions to afford compound of Formula II,

Formula III
Formula IV Formula II

Wherein R1 is selected from CO2-alkyl, -CN or –CONH2,

R2 is selected from CI, Br, I, OSO2Me, OSO2Ph, and OSO2Ph-p-Me

X is any halogen selected from I, Br, Cl

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).
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, ethyl acetate is employed.

Compounds of Formula II where R1 is other than –CONH2 can be isolated as a crystalline solid to improve the purity.

b) converting compound of formula II to compound of formula I

The said step involves conversion of R1 to amide functionality. When R1 is an alkyl ester then compound of Formula II is treated with a suitable base and formamide in a suitable solvent to materialize the amidation. Prior to treatment with a base, optionally the reaction mixture can be treated with a dehydrating agent to improve the yields.

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 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, a mixture of DMF and methanol is employed as a solvent.

c) optionally, purifying compound of Formula I
Non-dissolved particles from a mixture of step a) can be removed suitably by filtration, centrifugation, decantation, or other techniques, such as passing the solution through paper, glass fiber, a particulate bed, or a membrane material.

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.

An aspect of the present application provides a compound of Formula IV;

An aspect of the present application provides a compound of Formula IV’;

Yet another aspect of the present application provides process for preparation of compound of Formula IV’ comprising;

a) reacting compound of Formula V with a suitable reducing agent to afford compound of Formula VI

Formula V Formula VI

b) converting compound of formula VI to compound of Formula IV’

The step a) involves reduction of nitro group of compound of Formula V in a suitable solvent. The suitable reducing agents employed in step a) includes but not limited to dithionate sources like sodium-, lithium-, potassium-, calcium-, magnesium, a tetra-alkylammonium- or a guanidinium-dithionate, sodium hydrosulfite, sodium sulfide, iron in acidic media, zinc/HCl or the like known in the art. In embodiments, Zn/HCl as a reducing agent and IPA as a solvent is employed.

The reactions of the synthetic methods claimed herein are carried out in suitable solvents which may be readily selected by one of skill in the art of organic synthesis, said suitable solvents generally being any solvent which is substantially non-reactive with the starting materials (reactants), the intermediates, or products at the temperature at which reactions are carried out, i.e., temperatures which may range from the solvents freezing temperature to the solvents boiling temperature. A given reaction may be carried out in one solvent or a mixture of more than one solvent. Depending on the particular reaction step, suitable solvents for a particular reaction step may be selected.

Suitable solvents will generally be inert to the reaction conditions and can be chosen from the list provided in aforementioned aspects. In a preferred embodiment, IPA is employed as a solvent.
The compound of Formula V can be prepared by using an adaptation of literature methods, such as described in US7396932 and CN101967145.

Step b) involves preparation of compound of Formula IV’ from Formula VI. The said conversion can be materialized in two ways i) by reaction of Formula VI with 5-bromovaleryl chloride followed by ring closure which is mediated by treatment with a suitable base or ii) by reaction of formula VI with ?-valerolactone to directly afford compound of Formula IV’.

Suitable base and solvent employed can be selected from the list mentioned above.

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, the 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 pure. 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).

Apixaban and drug-related impurities may be analyzed using high performance liquid chromatography (HPLC), for example by a method using a XBridge C 18, 150 x 4.6 mm, 3.5?m? column, with the following parameters:

Column XBridge C 18, 150 x 4.6 mm, 3.5?m?
Flow rate 0.8mL /min
Column oven temperature 27°C
Wave length 210nm
Injection Volume 10µl
Run time 55 minutes

Elution Gradient
Mobile Phase A Dissolve about 1.36 g of potassium dihydrogen phosphate in 1000 ml of MQ Water; adjust the pH to 3.5 with dilute ortho phosphoric acid (1ml in 10ml of water). Filter and degas.
Mobile Phase B Water and acetonitrile in the ratio of 30:70 (v/v)
Diluent Mix the volumes of water and acetonitrile in the ratio of 30:70 (v/v)
Sample Preparation Dissolve about 25 mg of test sample in 50mL of diluent
Gradient Programme Time (minutes) % Mobile phase-A % Mobile phase-B

0.01 60 40
10.00 60 40
12.00 45 55
25.00 45 55
30.00 20 80
50.00 20 80
50.01 60 40
55.00 60 40

Representative relative retention times for some impurities (Apixaban = 1) are as follows:
S. No Name of the Impurity RRT of Impurity
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 present in formulations of Apixaban by reducing the amount of the impurities during synthesis.

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 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 (Formula II)
A flask was charged with chloro[(4-methoxyphenyl)hydrazono]acetic acid ethyl ester (2.2 g), 3-chloro-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridin 2(1H)-one (2g), in ethyl acetate (50 mL). The reaction mixture was cooled to 5-10oC and the resulting reaction mixture was treated with triethylamine (1.98 g) at the same temperature. The reaction mixture was then warmed up to room temperature and stirred for 30 min. The mixture was then refluxed for an additional 8 h and completion of the reaction was monitored by TLC. The mixture was then cooled to room temperature followed by addition of water (200 mL). The layers were separated and aqueous layer was extracted with ethyl acetate (200 mL). The organic layers were combined and subjected to complete distillation under vacuum at below 55oC to afford the residue.

Then IPA (6 mL) was added to the residue and mixture was stirred for 30 minutes followed by isolation of solid by filtration. The solid was washed with IPA (2 mL) and dried under vacuum at below 55oC to afford the title compound having HPLC purity of about 97%.

EXAMPLE 2: PREPARATION OF 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 (Formula II)
A flask was charged with ethyl 2-chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate (100 g), 3-chloro-1-(4-(2-oxopiperidin-1-yl)phenyl)-5,6-dihydropyridin 2(1H)-one (86.6 g, 0.34 mol), in ethyl acetate (1000 mL). To the reaction mixture, triethylamine (85.25 g) was slowly added over a period of about 40 minutes at the same temperature. The reaction mixture was then heated up to reflux and stirred for about 8 h. The completion of the reaction was monitored by TLC. The mixture was then cooled to 5-10oC followed by slow addition of 4N hydrochloric acid (520 mL) over a period of 45 minutes. The reaction mixture was then stirred at room temperature overnight and then again cooled to 0-5oC at which water (2000 mL) was added under stirring. The solid obtained was isolated by filtration and washed with water (200 mL) followed by drying under vacuum at below 55oC to afford the title compound in about 79% yield having HPLC purity of about 96%.

EXAMPLE 3: PREPARATION OF APIXABAN
A flask is charged with 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 (100 g), DMF (755 mL) and formamide (226 g) at room temperature, and the resulting reaction mixture was stirred for 10 minutes followed by treatment with triethylorthoformate (14 g) and trifluoroacetic acid (4.7 g). The mixture was stirred at room temperature for 1 hour followed by cooling to 0-5oC. To the mixture a solution of sodium methoxide (22.11 g) in methanol (100 mL) was slowly added at the same temperature over a period of about 90 minutes followed by stirring for additional 90 minutes at which point completion of the reaction was monitored by TLC. In another flask containing pre-cooled water (2000 mL), above reaction mixture was added at 15-20oC over a period of 90 minutes followed by stirring for 1 hour at 20-45oC. The solid obtained was isolated by filtration and washed with water (500 mL) and MTBE (100 mL) followed by drying under vacuum at 50-55oC to afford the title compound in about 91% yield having HPLC purity of about 97%.

EXAMPLE 4: PURIFICATION OF APIXABAN
A flask was charged with Apixaban (75 g), N, N-dimethylformamide (525 mL) and methanol (750 mL) and the mixture was heated to 50-55oC for complete dissolution. The reaction mixture was cooled to room temperature and stirred for 1-1.5 hours. The solid obtained was isolated by filtration and washed with methanol (75 mL). The wet material was taken up in a mixture of DMF (350 mL) and methanol (500 mL) and the mixture was heated to 70-80oC for complete dissolution followed by cooling to room temperature and stirring at same temperature for about 1-1.5 hours. The solid obtained was isolated by filtration and washed with methanol (50 mL) followed by drying under vacuum below 55oC to afford Apixaban having HPLC purity of about 99.71%.

EXAMPLE 5: PREPARATION OF 1-(4-NITROPHENYL)PIPERIDIN-2-ONE
A flask was charged with 4-nitroaniline (50 g), chlorobenzene (130 mL), THF (107 mL) and 40% aqueous potassium carbonate (109 g, 84 mL). The mixture was allowed to cool to 10-15oC followed by addition of bromovaleryl chloride at the same temperature over a period of 45 minutes. The mixture was maintained for another 1-2 hours at the same temperature and reaction was monitored by TLC. Then, TBAB (2 g) was added followed by slow addition of 45% aqueous potassium hydroxide solution (98.5 mL) over a period of 1 hour at 10-15oC and mixture was maintained at the same temperature for 4-5 hours followed by addition of sodium chloride solution (150 mL). The layers were separated and organic layer was washed with water (100 mL). The organic layer was subjected to distillation under vacuum below 90oC followed by addition of n-hexane (150 mL) and stirring for 1 hour. The solid obtained is isolated by filtration and washed with n-hexane (50 mL). The solid is dried under vacuum below 50oC to afford the title compound (79.6 g).

EXAMPLE 6: PREPARATION OF 3,3-DICHLORO-1-(4-NITROPHENYL) PIPERIDIN-2-ONE
To a warm mixture of chlorobenzene (50 mL) and PCl5 (68.5 g) at 40-45oC, a solution of 1-(4-nitrophenyl)piperidin-2-one in chlorobenzene (100 mL) was added at 40-45oC. The mixture was heated to 50-55oC and maintained for 1-2 hours. Completion of the reaction is monitored by TLC and mixture was cooled to room temperature. The said mixture is slowly added to pre-cooled mixture of water (250 mL) and n-hexane (250 mL) at 0-5oC and stirred for about 1 hour at 0-5oC. The solid obtained was isolated by filtration and washed with n-hexane (50 mL) followed by drying under vacuum at 50-55oC to afford the title compound (26.4 g).

EXAMPLE 7: PREPARATION OF 3-CHLORO-1-(4-NITROPHENYL)-5,6-DIHYDROPYRIDIN-2(1H)-ONE
A dry flask was charged with 3,3-dichloro-1-(4-nitrophenyl) piperidin-2-one (45 g), DMF (450 mL) and stirred followed by addition of lithium chloride (3.15 g) and lithium carbonate (5.85 g). The reaction mixture was heated to 105-110oC and maintained at same for completion of reaction as monitored by TLC. The reaction mixture was cooled to 25-35oC followed by its slow addition to a flask containing cold water (900 mL). The mixture was stirred for 15-30 minutes followed by addition of hexane (900 mL). The mixture was stirred for 1-2 hours and solid obtained was isolated by filtration and washed with n-hexane (90 mL) and water (90 mL). The solid obtained was dried under vacuum at 50-60oC to afford the title compound (35.1 g).

EXAMPLE 8: PREPARATION OF 1-(4-AMINOPHENYL)-3-CHLORO-5,6-DIHYDROPYRIDIN-2(1H)-ONE
A flask was charged with 3-chloro-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one (25 g), isopropanol (250 mL) and hydrochloric acid (2N, 650 mL) and mixture was cooled to 10-15oC. To this mixture Zinc powder (64.3 g) was slowly added over a period of 1 hour. The temperature of the mixture was raised to room temperature and stirring was maintained for 3-4 hours followed by addition of dichloromethane (250 mL). The mixture was filtered and bed was washed with dichloromethane (100 mL). The layers were separated and DCM layer was subjected to complete distillation under vacuum followed by addition of isopropyl alcohol (75 mL) and stirring for 30 minutes. The solid obtained was washed with isopropyl alcohol (25 mL) and dried under vacuum to afford the title compound (21.2 g).

EXAMPLE 9: PREPARATION OF 3-CHLORO-1-(4-(2-OXOPIPERIDIN-1-YL)PHENYL)-5,6-DIHYDROPYRIDIN-2(1H)-ONE
A flask was charged with 1-(4-aminophenyl)-3-chloro-5,6-dihydropyridin-2(1H)-one (20 g), THF (100 mL) and potassium carbonate solution (40%, 32 mL). The mixture was cooled to 10-15oC followed by slow addition of bromovaleryl chloride (18 g) over a period of 40 minutes and subsequent stirring of the mixture for 1-1.5 hours at the same temperature. The completion of the reaction was monitored by TLC. Then water (100 mL) and DCM (150 mL) were added and layers were separated. The aqueous layer was washed with DCM (100 mL), then DCM layers were combined and subjected to complete distillation under vacuum. The residue obtained was taken up in THF (100 mL) and mixture was cooled to 0-5oC followed by addition of sodium hydride (60%, 14.3 g). The mixture was stirred for 1-1.5 hours at the same temperature followed by addition of DCM (150 mL) and water (100 mL). The layers were separated and aqueous layer was further extracted with DCM (100 mL). The DCM layers were combined and subjected to complete distillation under vacuum followed by addition of ethyl acetate (40 mL) and hexane (100 mL). The mixture was stirred and solid obtained was isolated by filtration followed by washing with hexane (20 mL) and subsequent drying under vacuum at below 55oC to afford the title compound.

EXAMPLE 10: PREPARATION OF 1-(4-NITROPHENYL)PIPERIDINE
A flask was charged with 4-fluoronitrobenzene (30 g) and DMF (90 mL), the mixture was cooled to 0-5oC. To the mixture sequentially, piperidine (36.2 g) and potassium tert-butoxide (29.82 g) were added and mixture was stirred at 15-25oC for 1 hour, completion of the reaction was monitored by TLC. After completion of the reaction water (300 mL) was added and mixture was stirred for 1 hour. The solid obtained was isolated by filtration and washed with water (60 mL) followed by drying under vacuum at below 55oC to afford the title compound in about 98% yield.

EXAMPLE 11: PREPARATION OF 1-(4-NITROPHENYL)PIPERIDIN-2-ONE
A flask was charged with 1-(4-nitrophenyl)piperidine (0.5 g), DCM (20 mL), benzyl triethylammonium chloride (1.68 g) and potassium permanganate (1.15 g). The mixture was heated to reflux and maintained for 2-3 hours, the completion of the reaction was monitored by TLC. After completion of reaction, mixture was cooled to 0-10oC followed by addition of aqueous sodium bisulfite solution (2 g in 25 mL of water). The mixture was filtered and bed was washed with DCM (25 mL) and water (25 mL). The layers were separated and DCM layer was subjected to complete distillation under vacuum followed by addition of hexane (5 mL). The mixture was stirred, solid obtained was isolated by filtration and washed with n-hexane (5 mL) followed by drying under vacuum at below 55oC to afford the title compound in about 94% yield.

EXAMPLE 12: PREPARATION OF 1-(4-AMINOPHENYL)-3-MORPHOLINO-5,6-DIHYDROPYRIDIN-2(1H)-ONE
A flask was charged with 3-morpholino-1-(4-nitrophenyl)-5,6-dihydropyridin-2(1H)-one (10 g) and methanol (100 mL). To this mixture, an aqueous solution of sodium sulfide (6.5 g in 30 mL) was added over a period of 20 minutes and mixture was heated to 50-55oC. The mixture was maintained at reflux for 2-3 hours and completion of the reaction was monitored by TLC. The reaction mixture was cooled to 10-15oC and maintained for 1 hour. The solid obtained was isolated by filtration and washed with water (10 mL) followed by drying under vacuum at below 55oC to afford the title compound in about 91% yield.

EXAMPLE 13: PREPARATION OF 3-MORPHOLINO-1-(4-(2-OXOPIPERIDIN-1-YL)PHENYL)-5,6-DIHYDROPYRIDIN-2(1H)-ONE
A flask was charged with 1-(4-aminophenyl)-3-morpholino-5,6-dihydropyridin-2(1H)-one (5 g), bromovaleryl chloride (3.83 g) and THF (50 mL) and mixture was cooled to 10-15oC followed by slow addition of triethylamine (3.7 g) over a period of 30 minutes. The reaction mixture was then stirred at room temperature for about 5 hours and completion of the reaction was monitored by TLC. Then mixture was cooled to 5-10oC followed by sequential addition of TBAB (0.2 g) and potassium hydroxide solution (11 g) at the same temperature. The mixture was stirred for about 3 hours at room temperature and completion of the reaction was monitored by TLC. To the mixture water (25 mL) was added and stirred for about 2 hours. The solid obtained was isolated by filtration and washed with water (10 mL) followed by drying under vacuum at below 55oC to afford the title compound in about 78% yield.

,CLAIMS:WE CLAIM:

1) A process for preparing Apixaban of Formula I, comprising,

Formula I
a) reacting a compound of Formula III with a compound of Formula IV under suitable reaction conditions to afford compound of Formula II,

Formula III Formula IV Formula II

wherein R1 is selected from CO2-alkyl, -CN or –CONH2,
R2 is selected from CI, Br, I, OSO2Me, OSO2Ph, and OSO2Ph-p-Me

X is any halogen selected from I, Br, Cl

b) converting compound of formula II to compound of formula I,

c) optionally, purifying compound of Formula I.

2) The process of claim 1, wherein suitable base is employed in step a).

3) The process of claim 2, where suitable base is selected from triethylamine, diisopropylethylamine, morpholine, N-methyl Morpholine, DABCO (1,4-diazabicyclo[2.2.2]octane).

4) The process of claim 1, wherein ethyl acetate is employed as solvent in step a).

5) The process of claim 1, wherein a mixture of DMF and methanol is employed as solvent in step b).

6) A compound of Formula IV’,

Formula IV’

7) A process for the preparation of compound of Formula IV’ comprising,

a) reacting compound of Formula V with a suitable reducing agent to afford compound of Formula VI,

Formula V Formula VI
b) converting compound of formula VI to compound of Formula IV’.

8) The process of claim 7, wherein Zn/HCl is employed as reducing agent and IPA as solvent in step a).

9) The process of claim 7, wherein step b) comprises reaction of Formula VI with 5-bromovaleryl chloride.

10) The process of claim 7, wherein step b) comprises reaction of Formula VI with ?-valerolactone.