FORM 2
THE PATENTS ACT 1970
(39 OF 1970)
COMPLETE SPECIFICATION
(SECTION 10)
AN IMPROVED PROCESS FOR THE PREPARATION OE APIXABAN AND INTERMEDIATES THEREOF
UNICHEM LABORATORIES LIMITED, A COMPANY REGISTERED
UNDER THE COMPANIES ACT, 1956, HAVING ITS REGISTERED
OFFICE LOCATED AT UNICHEM BHAVAN, PRABHAT ESTATE, OFF
S. V. ROAD, JOGESHWARI (WEST), MUMBAI - 400 102.
MAHARASTRA, INDIA
The following specification particularly describes the invention and the manner in which it is to be performed.

AN IMPROVED PROCESS FOR THE PREPARATION OF APIXABAN AND INTERMEDIATES THEREOF
FIELD OF INVENTION
The present invention is related to an improved process for the preparation of Apixaban and to a process to prepare intermediates to be used therein.
BACKGROUND OF THE INVENTION
Apixaban, a factor Xa inhibitor, marketed as ELIQUIS® reduces the risk of stroke and systemic embolism in patients with nonvalvular atrial fibrillation and for the prophylaxis of deep vein thrombosis (DVT), is chemically described as 1-(4-methoxyphenyi)-7-oxo-6-[4-(2-oxopiperidin-l-yi)phenyI]-4:5,6,7-tetrahydro-lH-pyrazolo[3,4-c]pyridine-3-carboxamide i.e. compound of formula (1).
US 6,413,980 by Bristol-Mayer first disclosed Apixaban, but is silent on process to prepare Apixaban. It is disclosed in US 6,967,208.It teaches use of multiple bases, TEA as acid scavenger and potassium tert-butoxide as strong condensing agentto produce iodo-lactam compound of formula (4) in 81% yield which isdichlorinated with phosphorus pentachloride (PCI5) in presence of chloroform to obtain morpholine compound of formula (5) in 63% yield and finally to obtain iodo compound of formula (7) in 18 % yield. Compound of formula (7) undergoes Ullmann reaction with piperidine-2-one catalyzed by copper or bivalent copper ions in presence of base at 130°C for 24hrs to obtain ester of compound of formula (8) followed by aminolysis in presence of ethylene glycol at 125°C to obtain Apixaban compound of formula (1) in 68% yield as depicted in Scheme 1.

PCT application 2012/168364 described process to prepare Apixaban by reacting Para-Iodo ketolactam compound of formula (19) with trimethylsilyl chloride to obtain diene compound of formula (20).On cycloaddition with hydrazono compound of formula (6),it produces iodo compound of formula (7) in 63% yield. It on Ullmann reaction with Pipyridin-2-one in presence of Copper produces ester compound of formula (8) in 67% yield followed by aminolysis with aq. Ammonia to obtain Apixaban compound of formula (1) as shown in scheme 2.
US'980 and WO' 364 teach use of costly Iodo-compounds.Ullmann reaction/condensation involves use of copper besides drawbacks of harsh reaction conditions, need of high reaction temperature, long reaction time, high metal loading and the reaction has a reputation for erratic yields.

PCT application no. 2007/001385 discloses process to prepare of Apixaban by reacting 4-nitroaniline compound of formula (9) with compound of formula (3) in presence of K2CO3/KOH in the mixture of THF and chlorobenzene to obtain nitrolactam compound of formula (10). It on dichlorination with PCl5produces dichloro compound of formula (11). On dehydrohalogenation in presence of lithium carbonate,it produced mono chloro intermediate compound of formula (12). It on reaction with hydrazono compound of formula (6) produced compound of formula (13). It is reduced to compound of formula (I4)in presence of Pd/C in THF. Its reaction with, compound of formula (3) produces compound of formula (15). On cyclization and aminolysis with ammonia in presence of propylene glycolit produces Apixaban compound of formula (1) as depicted in Scheme 3. WO'385 discloses use of expensive compound of formula (3). uses mixture of chlorobenzene and THF during chlorination of compound of formula (10) with PC15. Work up procedure for isolation of compound of formula (11) is tedious and required expensive and hygroscopic strong base such as potassium ethoxide for the cyclization of compound of formula (15).
Synthetic communication, 2013, 43, 72-79 disclosed preparation of Apixaban using key intermediate compound of formula (18). The starting material 4-nitroaniline compound of formula (9) is reacted with compound of formula (3) in presence of triethyl amine/THF and cyclization is carried out in presence of potassium fert-butoxideto obtain compound of formula (10) which on chlorination with PCI5, followed by the condensation-elimination process with excessive morpholine produced nitro-morpholine compound of formula (16) in 78% yield followed by reduction of nitro group in presence of sodium sulfide to obtain aniline-morpholine compound of formula (17). Similarly second acylation/cyclization of compound of formula (17) with compound of formula (3") in two steps, produced key intermediate having lactam compound of formula (18), wherein acylation is carried out in presence of triethyl amine/THF and cyclization is carried out in presence of potassium tert-butoxide. The compound of formula (18) is reacted with hydrazono compound of formula (6) to obtain ester compound

of formula (8) which by aminolysis in methanolic ammonia solution produced Apixaban compound of formula (1) as depicted in Scheme 4.
Above non-patent literature discloses the use of TEA as an acid scavenger in the acylatibn reaction and then potassium tert-butoxide as a strong condensing agent in the subsequent cyclization during the preparation of compound of formula (10) and (18). It uses large volume of THF for preparation of (10) and (18) and Potassium tert-butoxide is hygroscopic, corrosive in nature. The chlorination of compound of formula (10) requires overall 25 volumes of chloroform with PCI5. which, is undesirable. It uses Na2S. a potential environmentally hazardous compound for the reduction of nitro group. The reaction uses TEA and Potassium tert-butoxide in one pot acylation/cyclization sequence to prepare compound of formula (10) and (18). The overall process is costly.

CN 103626689 patent application discloses the reaction of aniline with compound of formula (3") in presence of organic base in organic solvent to obtain compound of formula (24). which is then reacted with inorganic base to obtain compound of formula (21). Nitrating compound of formula (21) by cone, sulfuric acid and nitric . acid produces compound of formula (10). The process to prepare (21) needs with two bases, organic base for acylation and inorganic base for cyclization.This multiplied material requirement has disadvantages associated with it. Reported yields in some stages are poor and it is silent on purity aspects. Various processes are disclosed in CN101967145, CN102675314 and WO2013119328 for the preparation of Apixaban which are quite complicated. In view of prior art methods available for the preparation Apixaban and its intermediates, there is a need for simple and cost effective processes as well as industrial and environmental friendly improved process for preparing Apixaban. Industry needs a simpler process that uses relatively inexpensive starting materials to provide significant economic advantages yet produces Apixaban in high yield.
OBJECT OF THE INVENTION:
The main object of the invention is to provide a simple and improved process toprepareApixaban starting from Aniline and the intermediates required in the process.

Another object of the invention is to provide the process to prepare intermediate
compound of the formula (10), intermediate amino- morpholine compound of the
formula (17) andintermediate lactam compound of the formula (18).
The present invention is to provide a process for the preparation of Apixaban
which ameliorate the problems of the prior art.
Yet another object of the present invention is to provide a process to prepare
Apixaban with high yields of Apixaban compound of formula (1) and which can
be carried out under milder conditions.
Another object of the invention is to provide industrially scalable, robust process
for the preparation of Apixaban and intermediates thereof.
Yet another object of the invention is to provide cost effective, environment
friendly process to prepare Apixaban and its intermediates.
SUMMARY OF THE INVENTION:
The invention provides a simple and improved process to prepare Apixaban from starting from Anilineand the intermediates required in the process. According to another aspect of the invention, there is provided an improved process to prepare compound of the formula (10) comprising steps of:
. a. reacting aniline with halovalerylhalide in presence of inorganicbase, and optionally in presence of a phase transfer catalyst to obtain compound of formula (24), wherein X is halogen;
b. optionally isolating the compound of formula (24);
c. cyclizing compound of formula (24) in presence of inorganicbase to obtain
compound of formula (21);
d. nitrating compound of formula (21) to obtain compound of formula (10).

According to one aspect of the invention is provided the process to prepare amino-morpholine compound of the formula (17) comprising steps of:
a. reacting a compound of formula (10) with chlorinating agent in presence of
non- halogenated solvent to obtain chlorinated compound of formula (11);
b. reacting compound of formula (11) with morpholine to obtain nitro-
morpholine compound of formula (16):
c. optionally isolating and purifying the nitro-morphoiine compound of
formula (16) obtained in step b.;
d. reducing nitro-morpholine compound of formula (16) in presence of a metal
catalyst/reagent to obtain compound of formula (17).
According to one aspect of the invention is provided the single step process to prepare compound of the formula (18). The process comprises steps of:
a. reacting amino-morpholine compound of formula (17) with hafovalerylhalide in presence of inorganic base to obtain an amide-compound of formula (23); wherein X is halogen;
b. optionally isolating the amide-compound of formula (23);
c. cyclizing amide- compound of formula (23) in presence of
inorganicbase to obtain a lactam compound of formula (18).
According to one aspect of the invention is provided a process for the preparation of Apixaban as described in the scheme 5.

DETAILED DESCRIPTION OF THE INVENTION:
The invention mainly provides the improved process to prepare Apixaban starting from Aniline and the intermediates required in the process. According to another aspect of the invention, there is provided an improved process to prepare compound of the formula (10) comprising steps of;
a. reacting aniline with halovalerylhalide in presence of inorganic base to
obtain compound of formula (24), wherein X is halogen selected form
group consisting of CL Br, F and I;
b. optionally isolating the compound of formula (24);

c. cyclizing compound of formula (24) in presence of inorganicbase to obtain
compound of formula (21);
d. nitrating compound of formula (21) to obtain compound of formula (10).
The halovalerylhalide used is selected from bromovalerylchloride (BVC) or chlorovalerychloride (CVC); more preferably chlorovaieryl chloride. The inorganic base used in step a) and step c) is selected from sodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide. potassium hydroxide, ammonium hydroxide.lithium hydrate, potassium hydrate, sodium hydrate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and mixture(s) thereof. Preferred base used is potassium hydroxide.
The reaction in step a) and step c) can be conveniently carried out in presence of a
solvent. The example of solvent in step a) and step c) may include but not limited
to dichloromethane. ethyl acetate, methyl acetate, chloroform, toluene,
chlorobenzene, dimethylformamide, dimethylacetamide, N-methylpyrrolidone,
acetonitrile, dimethyl sulfoxide, terrahydrofuran, dioxane and mixture(s) thereof,
preferably used are dimethylformamide or dichloromethane.
The reaction in step a) and step c) can be conveniently and optionally carried out
in presence of a phase transfer catalyst. The examples of phase transfer catalyst is
selected from quaternary ammonium and phosphonium salts such as
methyltridecyl ammonium chloride, trimethyl ammonium chloride, tetrabutyl
ammonium bromide, dimethylethylhexadecyl ammonium bromide, ethyltripentyl
ammonium iodide, hexadecyltributylphosphonium bromide
benzyltrirnethylammonium chloride, and the like.
The reaction is successfully carried out with or without the isolation of compound of the formula (24).Isolation of compound of formula (24) can be carried out by any known method present in the art such as cooling, filtration, centrifugation, washing, drying and combination thereof.

The molar equivalent of halovalerylhalide used in step a) from 1.0, 1.05, 1.1, 1.25, 1.35. to 1.5 equivalents, preferably between 1.1 to 1.5 equivalents and more preferably between 1.1 to 1.2 equivalents. The molar equivalent of base used in step a) from 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1,
1.2, 1.3, 1.4 to 1.5 and in step c) from 2.0, 2.5, 3.0, 3.5 to 4.0, more preferably 3.0
equivalents.
The reaction of step a) and c) is performed preferably in a temperature range between 0°C to ambient temperature.
Inventive step of the present invention resides in use of single inorganic base as against two bases used in CN 103626689 and in Synthetic Communication 2013, Vol 43, Page 72-79. CN 103626689 and other prior art could synthesize compound from Aniline and Halovaleryhalide in presence of inorganic base. Inherent limitations of the reaction forced use of organic base in early part of reaction, as is evident from the claim 1 of CN 103626689. Prior art discloses acylation/cyclization reaction in presence of multiple bases such as TEA and potassium fcr/-butoxide which is hygroscopic and corrosive in nature; however according to the present invention acylation/cyclization reaction for the preparation of compound of formula (21) is performed in the presence of single inorganic base such as KOH instead of use of multiple bases such as prior art disclosed organic and inorganic base. Further, invention disclosed in the present ' application provides flexibility to use more than one inorganic base to carry out the same reaction. Invenitve step also resides in improved purity and better yields. Present invention provides a cleaner method free of tedious and cumbersome procedures for isolation of product. Surprisingly the yields of acylation and cyclization are far better than the yields disclosed by CN 103626689. The nitration of compound of formula (21) in step d) is carried out with a nitrating agent, such as nitric acid in presence of sulfuric acid or acetic acid. The molar equivalent of nitrating agent used is from 0.9. 1.0. 1.05 0.9, 1.0 1.05, 1.1 to 1.2, more preferably 1.05 equivalents. The amount of sulfuric acidused from 1.0, 1.2,
1.3, 1.5, 1.8 to 2.0 Vol wrt the compound of formula (21), preferred being 1.6 Vol.

The nitration of compound of formula (21) can be performed in a temperature between -10°C to ambient temperature, more preferably at temperature in between -5°C to 10°C.
Another aspect of the present invention is to provide a process for the preparation of amino- morphotine compound of formula (17) comprising steps of:
a. reacting a compound of formula (10) with chlorinating agent in presence
of non- halogenated solvent, to obtain compound of formula (11);
b. reacting compound of formula (11) with morpholine to obtain nitro-
morpholine compound of formula (16);
c. optionally isolating and purifying the obtained nitro-morpholine
compound of formula (16);
d. reducing nitro-morpholine compound of formula (16) in presence of a
metal catalyst/reagent to obtain compound of formula (17)
In a preferred embodiment of the invention, the chlorination of compound of formula (10) in step a) can be carried out using non-halogenated solvents and mixture(s) thereof, preferably used is toluene.
Chlorinating agents selected from group consisting of thionyl chloride (SOCb), phosphorous trichloride (PCl3), phosphorus pentachloride (PCI5). The molar equivalent of chlorinating agent used from 2.5, 2.7, 2.9, 3.0, 3.2, 3.4, to 3.5 more preferably 3.0 equivalents. The said chlorination can be performed in a temperature between 45°C to 90°C more preferably at temperature 65°C-75°C. Non limiting examples of non- halogenated solventsare toluene, xylene, benzene, acetic acid, ethyl acetate, tetrahydrofuran, methyl t-butyl ether, dioxane and mixture(s) thereof.
The nitro-morpholine compound of formula (16) of step b) is obtained by simultaneous condensation- elimination reaction with excess of morpholine with

compound of formula (11). The excess of morpholine used from 2.0, 3.0, 4.0 to 5.0 volumes, more preferably 2.0 to 3.0 volumes wrt the compound of formula (11). The reaction can be performed at a temperature 90°C to 130°C. The obtained product can be optionally recrystallized in presence of suitable solvent selected from a group of alcohols, ketones, esters, ethers, nitrilesand mixture(s) thereof. The amino-morpholine compound of formula (17) of step d) is obtained by reducing nitro-morpholine compound of formula (16).
Prior art disclose the reduction of nitro group in presence of Na2S a potential environmentally hazardous compound. It is also reported in the presence of expensive metals like palladium, platinum, ruthenium etc. and is underlined with precautions, because of their flammable nature in the air and it also required compressed hydrogen gas. which is highly diffusible and flammable. The reaction is carried out at reflux temperature for longer hours under reduced condition under hydrogen atmosphere and involves complicated experimental procedure. Reduction of nitro group of nitro-morpholine compound of formula (16) can be carried out by reacting hydrazine hydrate in presence of catalytic amount of Raney Nickel in the presence of a solvent at temperature in between 50°C to 75°C. Solvent is selected from water, isopropyl alcohol, ethanol methanol, n-propanol or aq. solution thereof and mixture(s) thereof or aqueous solutions thereof. The molar equivalent of hydrogenating agent is used from 2.0, 3.0, 4.0, 5.0, to 6.0 equivalents more preferably 4.0 mole equivalent. The mole ration of catalyst includes 2%, 3%, 4% to 5% more preferably around 4%.
Another aspect of the present invention is to provide a single step process for the preparation of intermediate lactam compound of formula (18) comprising steps of:

a. reacting amino-morpbolwe compound of formula (37) with
halovalerylhalide in presence of base, to obtain amide-compound of
formula (23), wherein X is halogen;
b. optionally isolating the amide- compound of formula (23);
c. cyclizing amide- compound of formula (23) in presence of base to
obtain lactam compound of formula (38).
Inventive step resides in using single base to complete the reaction. The reactionis successfully carried out with or without the isolation of compound of the formula (23). This is strikingly different from the prior art where in multiple solvents are used in addition to use of base. For example Synthetic communication, 2013, 43, 72-79 disclosed a reaction in which TEA, THF and Potassium tert-butoxideis used. Inherent limitations of the disclosures of Synthetic communication, 2013, 43, 72-79 necessitate use of multiple bases. Inventive step of the present invention over Synthetic communication, 2013, 43, 72-79, resides in the fact that use of single base achieves acylation and cyclization and thereby eliminates disadvantages of material procurement, inventories besides technical drawbacks. Further, invention disclosed in the present invention provides flexibility to use more than 1 inorganic bases to carry out the same reaction. The examples of inorganic base used in step a) and step c) may include but not limited tosodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, lithium hydrate, potassium hydrate, sodium hydrate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and mixture(s) thereof. Preferred base used is potassium hydroxide.
The reaction in step a) and step c) is conveniently carried out in presence of a solvent. The example of solvent in step a) and step c) may include but not limited to dichloromethane, toluene, ethyl acetate, methyl acetate, chloroform, chlorobenzene. dimethylformamide, diemthylacetamide, N-methylpyroolidone, acetonitrile, dimethyl sulfoxide, tetrahydrofuran, dioxane and mixture(s) thereof, preferably used dimethylformamide or dichloromethane.

The reaction in step a) and step c) can be conveniently and optionally carried out in presence of a phase transfer catalyst. The examples of phase transfer catalyst mat include quaternary ammonium and phosphonium salts such as methyltridecyl ammonium chloride, methyltridecyl ammonium chloride, trimethyl ammonium chloride, tetrabutyl ammonium bromide, dimethylethylhexadecyl ammonium bromide, ethyltripentyl ammonium iodide, benzyltrimethylamrnoniumchloride .hexadecyltributylphosphonium bromide and the like.
The molar equivalent of halovalerylhalide used in step a) from 1.0, 1.05, 1.1, 1.25, 1.35, to 1.5 equivalents, preferably between 1.1 to 1.5 equivalents and more preferably between 1.1 to 1.2 equivalents.
The molar equivalent of base used in step a) from 0.5, 0.6, 0.7, 0.8, 0.9, 1.0, 1.1, 1.2, 1.3, 1.4 to 1.5 and in step c) from 2.0, 2.5, 3.0, 3.5 to 4.0, more preferably 3.0 equivalents.
The reaction of step a) and b) is can be performed preferably in a temperature between 0°C to ambient temperature.
According to the present invention acylation/cyclization reaction for the preparation of compound of formula (18) can be performed in the presence of single inorganic base such as KOH.
During formation of the lactam compound of formula (18); amide-compound of formula (23) can be optionally isolated and purified by common purification processes such as recrystallization, leaching or slurry washing, or by co-precipitation with a suitable solvent(s) and anti-solvent(s).The solvent essentially refers to a media in which is compound is readily soluble and the anti-solvent essentially refers to a media in which is compound is insoluble or poorly soluble. The amide compound of formula (23) can be converted in-situ to the lactam compound of formula (18). This simultaneous amide and lactam formation is achieved with base in a suitable solvent. The examples of base are potassium hydroxide, sodium hydroxide, and lithium hydroxide, more preferably potassium hydroxide. The examples of solvent is tetrahydrofuran, toluene,dichloromethane, dimethyl formamide, dimethyl acetamide. chloroform, chlorobenzene and mixture(s) thereof, preferably dichloromethane or dimethyl formamide.

The amount of solvent used is from about 5 vol to about 15 vol with respect to compound of formula (17) and said reaction canbe performed in a temperature between 5°C to 35°C, more preferably at temperature between 10°C 15°C. Preparation of hydrazono compound of formula (6):
The process for the preparation of hydrazono compound of formula (6) comprising reacting p-anisidine with sodium nitrite and hydrochloric acid, followed by reaction with ethyl-2-chloroacetoacetate it is well known in the art.
Preparation of ester compound of formula (8):
The 1,3-cycloaddition involves reaction of hydrazono compound of formula (6)
with lactam compound of formula (18) in presence of a solvent and base at
ambient temperature to reflux temperature to obtain ester compound of formula
(8).
The example of solvents may include but not limited to ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile and mixture(s) thereof. The examples of base may include triethyl amine, diisopropyiethylamine and the like at temperature between 0°C to ambient more preferably at room temperature.
Preparation of Apixaban:
The final conversion involves the reaction of ester compound of formula (S) with ammonia at temperature between 40°C to 65°C. The reaction can optionally be carried out in a closed autoclave condition.

The product can be isolated by conventional means involving either direct
filtration of the solid product or addition of antisolvent followed by filtration of
the product, or evaporation of the solvent either completely or partially and
recovering the product.
The obtained product can optionally be purified by conventional means, such as
recrystallization from a suitable solvent or mixture(s) of solvents, recrystallization
using solvent-anti-solvent mixture(s), reslurrying in solvent or mixture(s) of
solvent, treatment with a base or an acid.
In following examples, some synthesis products are listed as having been isolated
as a residue. It will be understood by one of ordinary skill in the art that the term
"residue" does not limit the physical state in which the product was isolated and
may include, for example, a solid, oil, foam, a gum, syrup, and the like.
The following examples are set forth to aid the understanding of the invention,
and are not intended and should not be construed to limit in any way the invention
set forth in the claims which follow thereafter.
The present invention provides process for preparation of Apixaban which is
devoid of Ullmann reaction.
EXAMPLES:
Example -la: Preparation of 5-Chloro-pentanoic acid phenylamide (24)
A solution of 5-chlorovaleroyl chloride (CVC, 520gm, 3.35mol) in methylene dichloride (400ml) was added to the suspension of aniline (250gm, 2.68mol), potassium hydroxide (165gm, 3.06mol). TBAB (2.5gm) in methylene dichloride ( 2.1L) and water (412ml) at 0-10°C over 2hrs.The reaction mixture was then

stirred at room temperature for lhr, Organic layer separated, washed with water (1L), dried over anhydrous sodium sulfate and distilled at 50°C to get a residue. The residue is purified in Hexane to give white crystals.Yield: 539.87 g, 95.15%
Example -I: Preparation of l-(phenyl)piperidin-2-one (21)
A solution of 5-chlorovaleroyl chloride (CVC, 520gm. 3.35mol) in methylene dichloride (400ml) was added to the suspension of aniline (250gm, 2.68mol), potassium hydroxide (450gm, 8.35mol). TBAB (2.5gm) in methylene dichloride ( 2.1L) and DMF (500ml) at 0-10°C over 2hrs.The mixture was slowly brought to 25 to 30°C and stirred overnight under N2 atmosphere. The reaction mass was then quenched with chilled water (1.5L) below 10°C. Organic layer separated, washed with water (1L), dried over anhydrous sodium sulfate and distilled atmospherically at 50°C to get a residue. To the residue was added Toluene (400ml) and stirred at same temperature for 30min. The resulting suspension was gradually cooled to 0-5°C and filtered. Solid dried at about 50°C to afford the desired product as white crystals.Yield: 400 g, 85.15%
Example -II Preparation of l-(4-Nitrophenyl)piperidin-2-one (10)
Cold nitric acid (70%, 54g. 0.6mol) was added drop wise to the precooled solution of example-I (lOOgm, 0.57mol) in 160ml of Sulphuric acid at 0-5°C over 1- 2 hrs. After complete addition, reaction mass was quenched over ice-water and stirred for lhr. Filtered off solid, washed with cold water (65ml x 3times ),

unloaded and dried at 50-60°C in hot air oven for about 5-6hrs. Pale yellow solid was obtained. Yield: 100.5 gm, 80%. The product can be optionally purified from Isopropyl alcohol to give off white solid.
Example-Ill: Preparation of 3-Morpholino-l-(4-Nitrophenyl)-5,6-dihydro pyridin-2(lH)-one (16)
PCI5 (212.5 g, 1.02 mol) was slowly added to a solution of the product of example-II (75 g, 0.340mol) in Toluene (225 mL) at 25-30°C. Resulting mixture was gradually heated to 75-80 C for Ih.Poured into ice water (1L). keeping temperature below 10 C. Quenched mass was stirred at 0-5°C for Ih.Filtered under suction.Pale yellow colored product dried in air oven at 55-60°C for 6-8hrs. Dried product was dissolved in morpholine (170 mL).Refluxed for lh.Reaction mixture was cooled to 90 C.Water was added to the reaction mass at the same temperature. The resulting slurry was filtered under suction, washed with water to give a yellow solid. Recrystallization of the solid from methanol afforded the desired product as an off-white solid. Yield: 82 g, 79.38%
Example -IV:-1-(4-Aminophenyl)-3-morpholino-5,6-dihvdropyridin-2(1H)-one (17)
Hydrazine hydrate 80% (60gm, 1.19mol) was added drop wise at around 60-65°C to the solution containing product of example-Ill (50gm, 0.16mol), Raney nickel (lgm, 2%) in ethanol (750ml) and water (150ml). After completion of

addition, stirred for 30min at same temperature and brought to room temperature. The reaction mass was filtered through celite bed, concentrated under vacuum, added ethyl acetate (100ml) and filter under suction. Dried the wet cake in air oven to afford the desired product as a cream colored solid. Yield: 43 gm; 95.55%
Example-Va: 5-Chloro-pentanoic acid [4-(5-morpholin-4-yl-6-oxo-3,6-
dihydro-2H-pyridin-l-yl)-phenyl]-amide (23)
A solution of 5-chlorovaleroyl chloride (14.1 g, 0.09 mol) in MDC (lOmL) was added to a solution containing product of example-IV (20 g, 0.073mol), KOH (6.14gm, 0.109mol) and TBAB (0.2gm) in MDC (200ml) and DMF (40m!) below 10 C. The mixture was stirred under N2 for lHr and Quenched with water, stirred and separated organic layer was concentrated in vacuum and dried to afford desired product as a cream colored solid. Yield: 25.80 g, 90%
Example-V: 3-Morpholino-l-(4-(2-oxopiperidin-l-yl)phenyl)-5,6-dihydro
pyridin-2(lH)-one (18)
A solution of 5-chlorovaleroyl chloride (14.1 g. 0.09 mol) in MDC (lOmL) was added to a solution containing product of example-IV (20 g, 0.073mol), KOH (12.29gm, 0.219mol) and TBAB (0.2gm) in MDC (200ml) and DMF (40ml) below 10°C. The mixture was slowly raised to 25°C and stirred under N2 for 3-5 hrs. The reaction mass was cooled to 10°C-15°C temperature and quenched with

water, Stirred and separated organic layer was concentrated in vacuum and dried to afford desired product as a cream colored solid. Yield: 22.10 g, 85%
Example-VI:(Z)-Ethyl 2-Chloro-2-(2-(4-methoxyphenyl)hydrazono)acetate(6)
Hydrochloric acid (35-36%, 60 ml, 0.6 mol) was added to a solution of 4-methoxyaniline (24.6 g, 0.2 mol) in water (120 mi) at -5 to 0°C. A solution of sodium nitrite (16.6 g, 0.24 mol) in water (80 mL) was added to the mixture dropwise below 0°C. Then, the reaction solution was stirred for 30 min at 0°C, followed by the addition of sodium acetate (32.8 g, 0.40 mol) until pH 5-6. To this, a solution of ethyl 2- chloroacetoacetate (28 mL, 32.8 g? 0.2 mol) in methanol (300 mL) was added dropwise maintaining temperature between 0 - 5 C. The resulting solution was stirred at 25-30°C for 4-6 h; concentrated in vacuum at low pressure, and the residue so obtained was dissolved in water (100 mL) and ethyl acetate (200 ml). Organic layer was separated. Aqueous phase was extracted with ethyl acetate (2 X 100 ml). The combined organic phase was washed with water (2 X 100 ml) and brine (2 X 100 ml), dried over anhydrous sodium sulfate, filtrated, and concentrated till residual stage. Recrystaliization of the product from ethyl acetate afforded the pure product as a pale yellow solid. Yield: 39.4 g. 77%
Example-VII: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 (8)

Product of example-V(14.2 g, 0.04mol), triethylamine (17mL, 0.12 mol), and potassium iodide (0.64 g,0.004mol) were added to a solution of the product of example-VI (11.3 g, 0.044 mol) in ethyl acetate(200mL) at room temperature. The mixture was stirred for 6 h under reflux and then cooled to 0°C, To the resulting mixture was added 4.ON hydrochloric acid (50mL; 0.02mol) drop wise and stirred at room temperature for 2 h. Thereafter water (100 mL) was added to the mixture to separate the organic layer. The aqueous layer was extracted with ethyl acetate (3x100 mL), and then the combined organic extracts were washed with brine (2x100 mL), dried over anhydrous sodium sulfate, and concentrated to dryness. Recrystallization of the residue from ethyl acetate and drying in vacuum afforded as cream colored solid. Yield: 14.6 g, 75% Alternately the same reaction can also be performed in Dichloromethane.
Example-
The product of example-VD (17.5 g, 35.82mmol) was suspended in 100 ml 33% ammonia and 200ml methanol and mixture was heated to 45°C,methanol 250ml added till completely dissolved and solution kept under stirring for 2h. Addition of another lot of 33% ammonia (50ml) was performed and solution was left under stirring for 18hrs at 45°C. The solvent was evaporated under low pressure and solid residue obtained was suspended in 200ml water and left under stirring for 2 hr; solid filtered through Buchner funnel and washed with 50ml water, dried in vacuum at 50°C to afford the desired product.Yield: 12.60 g, 76%;

WE CLAIM:
1. A process for preparation of compound of formula (10) comprising steps of; a. reacting aniline with halovalerylhalide in presence of inorganic base to obtain compound of formula (24) wherein X is halogen;
b. optionally isolating the compound of formula (24); c. cyclizing compound of formula (24) in presence of inorganic base to obtain compound of formula (21);
d. nitrating compound of formula (21) to obtain compound of formula (10).
* 2. A process for preparation of amino- morpholine compound of the formula (17) comprising steps of:
a. reacting a compound of formula (10) with chlorinating agent in presence of non- halogenated solventto obtain compound of formula (11);

b. reacting compound of formula (11) with morpholine to obtain nitro-morpholine compound of formula (16);
c. optionally isolating and purifying the nitro-morpholine compound of
formula (16)obtained in step b.;
d. reducing nitro-morpholine compound of formula (16) in presence of a
metal catalyst/reagent to obtain compound of formula (17).
3. A process for preparation of compound of formula (18) comprising steps of; a., reacting amino-morpholine compound of formula (17) with halovalerylhalide in presence of inorganic base to obtain amide-compound of formula (23) wherein X is halogen;
b. optionally isolating the amide-compound of formula (23);
c. cyclizing amide-compound of formula (23) in presence of inorganic base
to obtain a lactam compound of formula (18).

4. A process for the preparation of Apixaban compound of formula (1) comprising steps of;
a. reacting aniline with halovalerylhalide in presence of inorganic base, to obtain compound of formula (24) wherein X is halogen;
b. optionally isolating the compound of formula (24);
c. cyclizing compound of formula (24) in presence of inorganic base to
obtain compound of formula (21);
d. nitrating compound of formula (21) to obtain compound of formula (10);
e. .reacting a compound of formula (10) with chlorinating agent in presence of non- halogenated solvent to obtain compound of formula (11);

f. reacting compound of formula (11) with morpholine to obtain nitro-morpholine compound of formula (16);
g. optionally isolating and purifying the obtained nitro-morpholine
compound of formula (16); h. reducing nitro-morpholine compound of formula (16) in presence of a
metal catalyst/ reagent to obtain compound of formula (17);
i. reacting amino-morpholine compound of formula (17) with halovalerylhalide in presence of inorganic base to obtain an amide-compound of formula (23) wherein X is halogen;
j. optionally isolating the amide- compound of formula (23);

k. cyclizing amide-compound of formula (23) in presence of inorganic base to obtain a lactam compound of formula (18);
I. 1,3-cycloaddition reaction of hydrazono compound of formula (6) with lactam compound of formula (18) in presence of a solvent and base to obtain ester compound of formula (8):
m. convertingester compound of formula (8) into the Apixaban compound of formula (1) in presence of ammonia.
5. The process according to claim 1, 3, 4(a), 4 (c) 4 (i) and 4 (k), wherein inorganic base is selected form the group consisting ofsodium carbonate, potassium carbonate, lithium carbonate, lithium hydroxide, sodium hydroxide, potassium hydroxide, ammonium hydroxide, lithium hydrate, potassium hydrate, sodium hydrate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate and mixture(s) thereof.

6. The process according to claim 1,3, 4 (a) ,4 (c), 4 (i) and 4 (k), wherein the reaction is carried out in presence of a solvent selected from group consisting of dichloromethane, toluene, ethyl acetate, methyl acetate, chloroform, chiorobenzene, dimethyfformamide, diem thy lacetamide. N-methylpyroolidone, acetonitrile, dimethyl sulfoxide, tetrahydrofuran, dioxane and mixture(s) thereof.
7. The process according to claim 1 , 3 and 4, wherein the reaction is optionally carried out in presence of a phase transfer catalyst selected from group consisting of methyltridecyl ammonium chloride, trimethyl ammonium chloride , tetrabutyl ammonium bromide, dimethylethylhexadecyl ammonium bromide, ethyltripentyl ammonium iodide, benzyltrimethylammonium chloride ,hexadecyItributylphosphonium bromide.
8. The process according to claim 1 (d) and 4 (d), wherein nitration of compound of formula (21) is performed in presence of nitric acid in sulfuric acid or acetic
acid.
9. The process according to claim 2 and 4(e), wherein non-halogenated solvent is selected from the group consisting of toluene, xylene, benzene, tetrahydrofuran, methyl t-butyl ether, dioxane and mixture(s) thereof.
10. The process according to claim 2 and 4 (e), wherein chlorinating agent selected form group consisting of thionyl chloride (SOCl2), phosphorous trichloride (PCl3), phosphorus pentachloride (PCI5).
11. The process according to claim 2 (d) and 4 (h), wherein reduction is carried
out in presence of hydrazine hydrate with catalytic amount of Raney Nickel.

12. The process according to claim 2 (d) and 4 (h), wherein the reaction is carried out in presence of a solvent selected from group water, isopropyl alcohol, ethanol methanol, n-propanol or aq. solution thereof and mixture(s) thereof or aqueous solutions thereof at temperature range of 50°C to 75°C.
13. The process according to claim 4 (1), wherein solvent is selected form the group consisting of ethyl acetate, dichloromethane, tetrahydrofuran, acetonitrile and mixture(s) thereof.
14. The process according to claim 4 (!), wherein base is selected form the group consisting of triethyl amine, diisopropylethylamine,
15. Apixaban obtained by a process according to any of the claims and examples mentioned above.