FORM 2
THE PATENTS ACT 1970
(Act 39 of 1970)
and
THE PATENTS RULES, 2003
COMPLETE SPECIFICATION (See section 10 and rule 13)
"PROCESS FOR THE PREPARATION OF RIVAROXABAN"
Glenmark Pharmaceuticals Limited; Glenmark Generics Limited
an Indian Company, registered under the Indian company's Act 1957 and having its registered
office at
Glenmark House,
HDO - Corporate Bldg, Wing -A,
B.D. Sawant Marg, Chakala, Andheri (East), Mumbai - 400 099
The following specification particularly describes the invention and the manner in which it is to be performed.

PRIORITY
This application claims the benefit to Indian Provisional Application No. 3264/MUM/2012, filed on November 09, 2012 and United States Provisional Application No. 61749017, filed on January 04,2013, the contents of which are incorporated by reference herein.
FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of rivaroxaban.
BACKGROUND OF THE INVENTION
Rivaroxaban, chemically known as 5-chloro-N({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyI)phenyl]-l,3oxazolidin-5-yl}methyl)-2-fhiophenecarboxamide, and has the following structural Formula I:

Rivaroxaban acts as an inhibitor of clotting factor Xa, and marketed in the United States under the trade name XARELTO® as tablets in the dosage strength of 1 Omg, 15mg and 20mg.
Rivaroxaban can be used for the prevention and treatment of various thromboembolic disease, in particular of deep vein thrombosis (DVT), pulmonary embolism (PE), myocardial infract, angina pectoris, reocclusions and restenoses after angioplasty or aortocoronary bypass, cerebral stroke, transitory ischemic attacks, and peripheral arterial occlusive diseases.
United States Patent No.7,157,456 discloses process for the preparation of rivaroxaban by reacting a compound of Formula II


with 5-chlorothiophene-2-carbonyI chloride.
United States Patent Nos. 7,351,823, 7,598,378, 7,816,355 and 8,106,192 also discloses process
for rivaroxaban.
United States Patent No. 7,943,656 discloses rivaroxaban in the modification II or in the amorphous form,
United States Patent Publication US2011/288294 and PCT Patent Publication WO2011/012321, WO2011/080341, WO 2011/098501, and WO2012/051692 also disclose process for rivaroxaban.
There is a need for an improved process for the preparation of rivaroxaban, which avoids the formation of isomeric and other process-related impurities, while affording the desired rivaroxaban product with high yield and purity.
We have now developed a novel process for the preparation of rivaroxaban which is simple, reproducible, robust and well suited on commercial scale.
Summary Of The Invention
The present invention relates generally to an improved process for the preparation of rivaroxaban of Formula I.
The present invention provides a process for the preparation of (S)-rivaroxaban, a compound of Formula I,

comprising: reacting a compound of Formula II,

wherein R is selected from
or - OS02R1, wherein Rl is selected from the group
consisting of C1-C6 alkyl, alkylaryl, aryl and substituted aryl wherein the substituent on the aryl is present at one or more positions on the aryl ring, selected from the group consisting of halogen, nitro, C1-C6 alkyl, and C1-C6 alkoxy.


The present invention provides a compound of formula IIIb.
The present invention provides use of compound of formula IIIb, for the preparation of (S)-rivaroxaban, a compound of Formula I.
Detailed Description of the Invention
As mentioned above, the present invention is directed to an improved process for the preparation of rivaroxaban.
Present health care reforms and legislation lead to evolving and increasingly rigorous requirements demanded of drug manufacturers. Subsequent therefrom and coupled with prevailing disadvantages, which may be present with the prior art processes, paves opportunities for improved processes for the preparation of rivaroxaban and its intermediates, which would circumvent the formation of process related impurities, while ensuring a target rivaroxaban product with optimum yield and purity.

comprising: reacting a compound of Formula II,
In one embodiment the present invention relates to process for the preparation of (S)-rivaroxaban, a compound of Formula I,

with a compound of formula III,

wherein R is selected from
or - OS02R , wherein R1 is selected from the group
consisting of C1-C6 alkyl, alkylaryl, aryl and substituted aryl wherein the substituent on the aryl is present at one or more positions on the aryl ring, selected from the group consisting of halogen, nitro, C1-C6 alkyl, and C1-C6 alkoxy.
The term "alkyl" as used herein includes a straight or branched chain hydrocarbon containing from J to 6 carbon atoms. Representative examples of alkyl include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, n-pentyl, isopentyl, neopentyl, n-hexyl.
The term "aryl" as used herein, refers to aromatic ring systems, which may include fused rings. Representative examples of aryl include, but are not limited to, phenyl, and naphthyl, anthracenyl, phenant
The term "alkylaryl" as used herein, refers to an aryl group, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein. Representative examples of alkylaryl include, but are not limited to, benzyl, 2-phenylethyl, 3-phenylpropyl, and 2-naphth-2-yl ethyl.

The term "alkoxy" as used refers to an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom. Representative examples of alkyloxy include, but are not limited to, methoxy, ethoxy, propoxy, butoxy.
The term "substituted aryl" as used refers to substituent on the aryl is present at one or more positions on the aryl ring, selected from the group consisting of halogen such as chloro, bromo, iodo; nitro; C1-C6 alkyl wherein alkyl refers to methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert- butyl, n-pentyl, isopentyl, neopentyl, n-hexyl and C1-C6 alkoxy wherein alkoxy refers to methoxy, ethoxy, propoxy/butoxy.
In one embodiment, the present invention provides a process for preparing a compound of


formula I wherein R is a compound of formula
or p-toluene sulfonyl, methane

sulphonyl, trifluoromethane sulphonyl, benzene sulphonyl and the like.

comprising: reacting a compound of Formula II,
In one embodiment, the present invention relates to process for the preparation of (S)-rivaroxaban, a compound of Formula I,



with a compound of formula IIIa,
wherein R1 is C1-C6 alkyl group such as methyl, ethyl, n-propyl, isopropyl, butyl, pentyl or hexyl.
In one embodiment, in the above process a compound of formula II, is reacted with a compound of formula III or formula IIIa in the presence of a suitable solvent.
A suitable solvent may be selected from, but is not limited to esters such as ethyl acetate, propyl acetate, butyl acetate; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-propanone; hydrocarbon such as toluene, benzene, xylene, cyclohexane; halogenated hydrocarbons such as methylene dichloride, ethylene dichloride, chloroform, carbon tetrachloride, alcohols such as methanol, ethanol, n-propanol, 2-propanol, tert-butanol, n-butanol; ethers such as diethyl ether, di-isopropy! ether, tetrahydrofuran, dioxane, water or mixtures thereof. Preferably, the solvent is methylene dichloride and tetrahydrofuran.
The reaction may be optionally carried out in presence of coupling reagent selected from the group consisting of 1-hydroxybenzotriazole (HOBT), 1, 8-Diazabicyclo [5.4.0] undec-7-ene (DBU), carbonyldiimidazole (CDI), diisopropylylcarbodiimide (DIC), dicyclohexylcarbodiimide (DCC) and the like or mixtures thereof.

The reaction may be carried out in presence or absence of base. A suitable base may be selected from organic or inorganic base. The inorganic base may be selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide; alkoxides such as sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide; carbonates such as sodium carbonate, potassium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like. The organic base may be selected from triethyl amine, trimethyl amine, diisopropyl ethylamine, dimethyl amino pyridine, picoline, dimethyl amino pyridine and pyridine. Preferably, the base is triethyl amine,
In one embodiment, the present invention provides a process for preparing a compound of formula I wherein R is a compound of formula,

the reaction is carried out in absence of a base.
In one embodiment, present invention provides a process for the preparation of compound of


formula III (wherein R is

comprising reacting 5-chloro-2-thiophenecarboxylic acid

with 1,1-carbonyl diimidazole.
In one embodiment, present invention provides a process for the preparation of compound of formula III (wherein R is p-toluene sulfonyl) comprising reacting 5-chloro-2-thiophenecarboxylic acid with p-toluene sulfonyl chloride.
In one embodiment, present invention provides a process for the preparation of compound of formula IIIa (wherein R is OCOOCH31 OCOOC2H5) comprising reacting 5-chloro-2-thiophenecarboxylic acid with methyl chloroformate or ethyl chloroformate.
In one embodiment of present invention, the compound of formula III or formula IIIa prepared is not isolated from the reaction mixture and compound of formula II is added to the compound of formula III or formula IIIa.

In one embodiment of present invention, the compound of formula III or formula IIIa prepared can be isolated, optionally purified, for example, by crystallization using suitable organic solvents and/or subjected to column chromatography etc; and then treated with compound of formula II to synthesize the compound of Formula I.
In one embodiment, the present invention provides a compound of formula IIIb.

In one embodiment of present invention, the compound of formula IIIb used in the synthesis of rivaroxaban.

comprising: reacting a compound of Formula IV,
In one embodiment, the present invention provides a process for the preparation of compound of formula II,


with a suitable solvent and a base.
A suitable solvent may be selected from, but is not limited to alcohols such as methanol, ethanol, n-propanol, 2-propanol, tert-butanol, n-butanol; hydrocarbon such as toluene, benzene, xylene, cyclohexane; halogenated hydrocarbons such as methylene dichloride, ethylene dichloride; esters such as ethyl acetate, propyl acetate, butyl acetate; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-propanone; ethers such as diethyl, ether, di-isopropyl ether, tetrahydrofuran; water or mixtures thereof. Preferably, the solvent is methanol, water.
A suitable base may be selected from organic or inorganic base. The inorganic base may be selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide; aqueous ammonia; alkoxides such as sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide; carbonates such as sodium carbonate, potassium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate and the like. The organic base may be selected from methyl amine, triethyl amine, trimethyl amine, diisopropyl ethylamine, dimethyl amino pyridine, picoline, dimethyl amino pyridine and pyridine or aqueous mixtures thereof. Preferably the reaction is carried out in the presence of aqueous methyl amine.
In one embodiment, compound of formula II may be crystallized/purified by solvent selected from alcohols, esters, ethers, ketones, nitriles, hydrocarbons or mixtures thereof.
In one embodiment, the present invention provides a process for the preparation of compound of formula IV,


comprising: reacting a compound of Formula V,

with l,l'-carbonyl diimidazole in presence of suitable solvent.
A suitable solvent may be selected from, ethers such as diethyl ether, di-isopropyl ether, tetrahydrofuran; hydrocarbon such as toluene, benzene, xylene, cyclohexane; halogenated hydrocarbons such as methylene dichloride, ethylene dichloride; esters such as ethyl acetate, isopropyl acetate, butyl acetate; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-propanone; acetonitrile or mixtures thereof.
In one embodiment, the present invention provides a process for the preparation of compound of formula V, comprising reacting a compound of Formula VI,


with a compound of formula VII, in presence of suitable solvent.

A suitable solvent may be selected from alcohols such as methanol, ethanol, n-propanol, 2-propanol, tert-butanol, n-butanol; halogenated hydrocarbons such as methylene dichloride, ethylene dichloride; esters such as ethyl acetate, propyl acetate, butyl acetate; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone, 2-propanone; ethers such as diethyl ether, di-isopropyl ether, tetrahydrofuran; acetonitrile, water or mixtures thereof.
In one embodiment, the present invention provides a process for the preparation of compound of formula V, comprising reacting a compound of Formula VI,



with a compound of formula VII, in presence of water.
After completion of the reaction, the desired compounds can be obtained from the reaction mixture by conventional means known in the art. For example, the working-up of reaction mixtures, especially in order to isolate desired compounds, follows customary procedures, known to the organic chemists skilled in the norms of the art and steps, e.g. selected from the group comprising but not limited to extraction, neutralization, crystallization, chromatography, evaporation, drying, filtration, centrifugation and the like. Preferably, crystallization.

In one embodiment, the present invention provides a process for purifying (S)-rivaroxaban comprising:
a) Providing a solution of rivaroxaban in a solvent or a mixture of solvents or their aqueous mixtures;
b) precipitating the solid from the solution; and
c) recovering the pure rivaroxaban.
The solvent or mixture of solvents is selected from a C2-C5 nitrile, a C2-C6 ester, C3-C5 ketone, C1-C5 alcohol, cyclic ether, hydrocarbon solvents and their halogenated derivatives, The C2-C5 nitrile include acetonitrile, propionitrile and the like; C2-C6 ester include ethyl acetate, isopropyl acetate, isobutyl acetate, t-butyl acetate and the like; C3- C5 ketone include acetone, methyl ethyl ketone, ethyl methyl ketone and the like; C1-C5 alcohol include methanol, ethanol, isopropanol, isobutanol, 2-butanol; cyclic ether include tetrahydrofuran (THF), dioxane and the like; hydrocarbon solvents and halogenated derivatives thereof may include pentane, n-hexane, heptane, cyclohexane, petroleum ether, m-,o-,or p-xylene, dichloromethane (MDC), chloroform, carbon tetrachloride, 1, 2-dichloroethane; polar solvent such as dimethylformamide, dimethylsulfoxide, dimethyl acetamide, water or mixtures thereof
In one embodiment, the present invention provides (S)-rivaroxaban having des-chloro rivaroxaban impurity lower than about 0.15%, preferably lower than about 0.08%, more preferably below detection limit (BDL).
In one embodiment, the present invention provides (S) - rivaroxaban, having purity greater than about 99.0%, more preferably greater than about 99.5%.
The processes, herein described, for the preparation of rivaroxaban are simple, eco-friendly, inexpensive, reproducible, robust and well suited on industrial scale.
The present invention provides a pharmaceutical composition comprising rivaroxaban obtained by the processes of present invention and at least a pharmaceutically acceptable carrier.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention,

EXAMPLES
Example 1: Preparation of (2-[(2S)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl) phenyl] amino} propyl]-lH-isoindole-l,3(2H)-dione (Formula V)
In a clean round bottom flask, lOOgm of 4-(4-aminophenyl) morpholin-3-one, 126.9gm of 2-[(25)-oxiran-2-ylmethyl]-lH-isoindole-,3(2H)-drone and 21iter water were charged. The reaction mixture was heated to a temperature of about 55-60°C and maintained for about 15 hours. The reaction mass was cooled to room temperature and stirred for about one hour, filtered, washed with water and dried in air oven at about 50°C-55°C to yield 200gm of titled compound.
Example 2: Preparation of (2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)"dione (Formula IV)
In a clean round bottom flask, 200gm of 2-[(25)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl) phenyl] amino} propyl]-lH-isoindole-l, 3(2H)-dione, lOgm of 4-dimethyl amino pyridine, 164gm of 1, l'-carbonyl diimidazole (CDI) and 3 liter of tetrahydrofuran (THF) were charged. The reaction mixture was heated to a temperature of about 55-60°C and stirred for about 12 hours. A second lot of 164gm of 1, 1-carbonyl diimidazole (CDI) was charged and the reaction mass was maintained for about 12 hours. The reaction mass was then cooled to about 0°C to 5°C and stirred for about 2 hours, filtered, washed with chilled THF and dried in air oven at about 50°C-55°C to yield 162gm of titled compound.
Example 3: Preparation of (2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-1,3-oxazoIidin-5-yl}methyl)~lH-isoindole-l,3(2H)-dione (Formula IV)
In a clean round bottom flask, lOOgm of 2-[(2S)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl) phenyl] amino} propyl]-lH-isoindole-l, 3(2H)-dione, 5gm of 4-dimethyl amino pyridine, 82gm of 1, l'-carbonyl diimidazole (CDI) and 2.5Iiter of toluene were charged. The reaction mixture was heated to a temperature of about 55-60°C and stirred for about 12 hours. A second lot of 82gm of 1, 1-carbonyl diimidazole (CDI) was charged and the reaction mass was maintained for about 12 hours. The reaction mass was then cooled to about 0°C to 5°C and stirred for about 2 hours, filtered, washed with chilled toluene and dried in air oven at about 50°C-55°C to yield 90gm of titled compound.

Example 4: Preparation of compound of Formula IIIb.
In a clean round bottom flask, 30gm of 5-chlorothiophene-2-carboxylic acid, 300ml of methylene dichloride (MDC) were charged and stirred at room temperature then 38.71 gm of p-toluene sulfonyl chloride was added. The reaction mass was cooled to about 0°C-5°C and triethylamine (TEA) was added drop wise and stirred for about 2-3 hours at same temperature. 300ml of 5% sodium bicarbonate solution was added to the reaction mass and stirred. Separated organic layer washed with 5% sodium bicarbonate solution followed by water. MDC layer was distilled off under vacuum and degassed for about one hour to get thick solid mass. 60ml of n-hexane was added to obtained mass and stirred for about one hour, filtered and dried to yield 32gm of titled compound,
Example 5: Preparation of compound of Formula IIIb.
In a clean round bottom flask, 30gm of 5-chlorothiophene-2"Carboxylic acid, 300ml of toluene were charged and stirred at room temperature then 38.71gm of p-toluene sulfonyl chloride was added. The reaction mass was cooled to about 0°C-5°C and potassium carbonate was added. The reaction mass was stirred for about 10-12 hours at room temperature, filtered and toluene layer was washed with 5% sodium bicarbonate solution followed by water. Toluene layer was distilled off under vacuum and degassed for about one hour to get thick solid mass. 60ml of cyclohexane was added to obtained mass and stirred for about one hour, filtered and dried to yield 32gm of titled compound.
Example 6: Preparation of (4-{4-[(5S)-5-(amino methyI)-2'Oxo-l, 3-oxazolidin-3-yl] phenyl} morpholin-3-one (Formula II)
In a clean round bottom flask, lOOgm of (2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-l, 3-oxazolidin-5-yI} methyl)-lH-isoindole-l, 3(2H)-dione), 1 liter of methanol and 223.6gm of 40% aq. methyl amine solution were charged at room temperature. The reaction mixture was heated to a temperature of about 60°C-65°C for about 2 hours. The reaction mixture was then cooled about 40°C and distilled off completely under vacuum. The residue was dissolved in methylene dichloride (MDC) and washed with sodium chloride solution. The methylene dichloride layer was dried over sodium sulphate and distilled of MDC under vacuum. The solid thus obtained was stirred in ethyl acetate, filtered, washed with ethyl acetate and dried in air oven at about 50°C -55°C to yield 65gm of titled compound.

Example 7: Preparation of 4-{4-[(5S)-5-(araino methyl)-2-oxo-l, 3-oxazolidin-3-yl] phenyl} morpholin-3-one (Formula II)
In a clean round bottom flask, l0gm of (2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-l, 3-oxazolidin-5-yl} methyI)-lH-isoindole-l, 3(2H)-dione, 30ml of water and 22.42gm of 40% aq. methyl amine solution were charged. The reaction mixture was heated to about 60°C-65°C, maintained for about 3 hours and distilled off under vacuum below about 50°C, the residue stripped with 50ml of toluene. To obtained residue 200ml MDC added and stirred. MDC layer dried over sodium sulphate and distilled off under vacuum below 45°C to yield titled compound.
Example 8: Preparation of 4-{4-[(5S)-5-(amino methyl)-2-oxo-l, 3-oxazoIidin-3-yl] phenyl} morpholin-3-one (Formula II)
In a clean round bottom flask, lOgm of (2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-l, 3-oxazolidin-5-yl} methyl)-lH-isoindole-1, 3(2H)-dione, 30ml of water and 22.42gm of 40% aq. methyl amine solution were charged. The reaction mixture was heated to about 60°C-65°C, maintained for about 3 hours. The reaction mixture was cooled to room temperature and saturated with sodium chloride and extracted with acetonitrile. Organic layer washed with saturated sodium chloride solution. Distilled off organic layer completely under vacuum. Solid obtained stirred with 20ml of ethyl acetate at room temperature, filtered, washed with ethyl acetate and dried in air oven at about 50°C-55°C to yield titled compound.
Example 9: Preparation of 5-chloro-jV-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenylj-1, 3-oxazoIidin-5-yl} methyl) thiophene-2-carboxamide (Formula I)
In a clean round bottom flask, 15gm of 5-Chloro thiophene-2-carboxylic acid, 150ml of tetrahydrofuran (THF) and 18gm of I, 1-Carbonyl diimidazole were charged and stirred for about one hour. To this reaction mixture 12.5gm of 1-Hydroxybenzotriazole (HOBT), 40.3 gm of 4-{4-[(5S)-5-(amino methyl)-2-oxo-l,3-oxazolidin-3-yl] phenyl} morpholin-3-one were charged. The reaction mixture was stirred overnight, filtered and washed with THF. The wet cake obtained was washed with 5% sodium bicarbonate solution and water and dried in air oven at about 50°C-55°C to yield 32gm to yield titled compound. Purity: 96.42% by HPLC.

Example 10: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorphoIin-4-yl) phenyl]-l, 3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide (Formula I)
In a clean round bottom flask, 0.557gm of 5-chloro thieophene-2-carboxylic acid, 5m! of THF and 0,557gm of 1,1-Carbonyldiimidazole (CDI) were charged at room temperature and stirred for about one hour, 1.5gm of 4-{4-[(5S)-5-(amino methyl)-2-oxo-l, 3-oxazolidin-3-yl] phenyl} morpholin-3-one was added to reaction mixture and stirred overnight at room temperature, filtered, washed with THF and dried in air oven at about 50°C-55°C to yield titled compound.
Example 11: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-l, 3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide (Formula I)
In a clean round bottom flask, 0.5gm of 5-Chloro thieophene-2-carboxyIic acid and 10ml of tetrahydrofuran (THF) were charged under nitrogen atmosphere and then 0.6lgm of 1, 1-Carbonyl diimidazole (CDI) was added and stirred for about 2 hours. To this reaction mixture 0.47gm of 1, 8-Diazabicyclo [5.4.0] undec-7-ene (DBU), 0.90gm of 4-{4-[(5S)-5-(amino methyl)-2-oxo-1, 3-oxazo!idin-3-yl] phenyl} morpholin-3-one were charged and stirred overnight at room temperature. The reaction mixture was quenched with water and extracted with ethyl acetate. The ethyl acetate layer was washed with 5% HCl solution and 5% sodium bicarbonate solution, followed by saturated sodium chloride solution. The ethyle acetate layer was dried over sodium sulphate and distilled off to yield titled compound.
Example 12: Preparation of 5-chIoro-iV-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-l, 3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide (Formula I)
In a clean round bottom flask, 2gm of 5-Chloro thieophene-2-carboxylic acid and 20ml of tetrahydrofuran (THF) were charged and cooled to about 0°C -10°C. To this reaction mass 1.9gm of triethyl amine (TEA), 2.60gm of p-toluene sulphonyl chloride (PTSC) were added and stirred for about 20- 60 minutes and then 5.4gms of 4-{4-[(5S)-5-(amino methyl)-2-oxo-l, 3-oxazolidin-3-yl] phenyl} morpholin-3-one was added and stirred for about 5 hours at about 0°C -10°C. To this reaction mass water was added and the temperature was raised to room temperature and further stirred for about 10-30 minutes, filtered, washed with water and dried in air oven at about 50°C-55°C to yield 3.3gm of titled compound. Purity: 97.15% by HPLC

Example 13: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-l, 3-oxazolidin-5-yI} methyl) thiophene-2-carboxamide (Formula I)
In a clean round bottom flask, 5gm of 4-{4-[(5S)-5-(amino methyI)-2-oxo-l,3-oxazolidin-3-yi] phenyl} morpholin-3-one, 50ml of tetrahydrofuran (THF) and 5.4gm of compound of formula IIIb were charged at room temperature. The reaction mass was stirred for about 12- 15 hours at room temperature and 100ml of water was added and further stirred for about one hour. The reaction mass was filtered, washed with water and dried in air oven at about 50°C-55°C to yield 4.8gm of titled compound.
Example 14: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-l, 3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide (Formula I)
In a clean round bottom flask, 5gm of 4-{4-[(5S)-5-(amino methyl)-2-oxo-l,3-oxazolidin-3-yl] phenyl} morpholin-3-one, 50ml of dimethylformamide (DMF) and 5.4gm of compound of formula IIIb were charged at room temperature. The reaction mass was stirred for about 5- 6 hours at room temperature and 100ml of water was added and further stirred for about one hour. The reaction mass was filtered, washed with water and dried in air oven at about 50°C-55°C to yield 4.8gm of titled compound.
Example IS: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-l, 3-oxazoIidin-5-yI} methyl) thiophene-2-carboxamide (Formula I)
In a clean round bottom flask 2gm of 5-chloro thiophene-2-carboxylic acid and 20ml of methylene dichloride (MDC) were charged and reaction mixture was cooled to about -5°C to -10°C and then 1.5gm of diethyl amine (TEA) was added and stirred for about 5-20 minutes. To this reaction mass 1.5gm of ethyl chloroform ate or methyl chloroformate was added and stirred for about one hour and then 3.6gm of 4-{4-[(5S)-5-(amino methyl)-2-oxo-l,3-oxazolidin-3-yl] phenyl} morpholin-3-one was added and further stirred for about one hour at about -5°C to -10°C. The temperature of reaction mass was raised to room temperature and quenched with ice-cold water.
The organic layer was washed with 5% HC1 solution and 5% sodium bicarbonate solution, followed by saturated sodium chloride solution, dried over sodium sulphate, distilled off and degassed to titled compound. Purity: 95.27% by HPLC.

Example 16: Preparation of 5-chIoro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-l, 3-oxazolidin-5-yI} methyl) thiophene-2-carboxamide (Formula I)
In a clean round bottom flask, lgm of 5-Chloro thieophene-2-carboxylic acid and 20ml of methylene dichloride (MDC) were charged and reaction mixture was cooled to about-5°C to -10°C and then 1.4gm of triethyl amine (TEA) was added and stirred for about 5-20 minutes. To this reaction mass 0.74gm of ethylchloroformate was added stirred for about 30 minutes and then 2gm of 4-{4-[(5S)-5-(amino methyl)-2-oxo-l, 3-oxazolidin-3-yl] phenyl} morpholin-3-one hydrochloride was added and stirred overnight at about -5°C to -10°C. The reaction mass was then quenched with water and the organic layer was washed with 5% HC1 solution and 5% sodium bicarbonate solution, followed by saturated sodium chloride solution. The organic layer was dried over sodium sulphate, distilled and degassed to yield titled compound.
Example 17: Purification of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxornorphoIin-4-yl) phenyl]-!, 3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide
In a clean round bottom flask, 3lgm of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-l, 3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide, 2635ml of acetonitrile were charged. The reaction mass was refluxed and to this 30ml of dimethyl formamide (DMF) was added and stirred for about 30 minutes and cooled to room temperature. The reaction mixture further cooled to about 0°C -5°C, stirred for about 2 hours, filtered, washed with cold acetonitrile and dried in air oven at about 50°C-55°C to yield 25gm of titled compound.
Example 18: Purification of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-l, 3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide
In a clean round bottom flask, 5gm of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorphoIin-4-yl) phenyl]-l,3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide and mixture of methanol and chloroform (1:1) were charged and refluxed for about one hour. Obtained clear solution was cooled to room temperature (RT) and stirred overnight at room temperature, filtered, washed with mixture of methanol and chloroform, dried in air oven at about 50°C-55°C to yield titled compound.

We claim:
1] A process for the preparation of (S)-rivaroxaban, a compound of Formula I,

wherein R is selected from
or - OS02R1, wherein Rl is selected from the group
consisting of C1-C6 alkyl, alkylaryl, aryl and substituted aryl wherein the substituent on the aryl is present at one or more positions on the aryl ring, selected from the group consisting of halogen, nitro, C1-C6 alkyl, and C1-C6 alkoxy.


2] The process as claimed in claim 1, wherein R in compound of formula 111 is


3] The process as claimed in claim 1, wherein when R is carried out in presence of a base.

the reaction is optionally

4] The process as claimed in claim 1, wherein when R is absence of abase.

the reaction is carried out in

5] The process as claimed in claim 2. wherein the reaction is carried out in the presence of a coupling agent selected from the group consisting of carbodiimides, 1-hydroxybenzotriazole, 1,8-diazabicyclo [5.4.0] undec-7-ene.
6] The process as claimed in claim 1, wherein R in compound of formula III is OS02R1, wherein Rl is substituted aryl.
7] The process as claimed in claim 6, wherein Rl is phenyl substituted with C1-C6 alkyl.

9] Use of compound of formula Mb in the preparation of rivaroxaban, a compound of Formula I.
8] A compound of formula 1Kb.