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"
Glenmaik Pharmaceuticals Limited; Glerunark 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. 1113/MUM/2013, filed on March 25,2013, 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-oxo4-morpholinyl)phenyl]-lJ3oxazolidin-5-yl}methyl)-2-thiophenecarboxamideJ has the following structural Formula I:

Rivaroxaban, an inhibitor of clotting factor Xa, is marketed in the United States under the trade
name XARELTO® as tablets in the dosage strength of l0mg, 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 a process for the preparation of rivaroxaban by
reacting a compound of Formula II

with 5-chIorothiophene-2-carbonyl chloride.

United States Patent Nos. 7,351,823, 7,598,378, 7,816,355 and 8,106,192 also disclose process
for rivaroxaban.
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

comprising the steps of a) contacting a compound of Formula II or salt thereof

with an oxidizing agent to form a first reaction mixture;
b) then contacting the first reaction mixture with a compound of formula VIII,
The present invention relates to process for the preparation of rivaroxaban, a compound of Formula I,


to form a second reaction mixture; and
c) isolating a compound of formula I from the second reaction mixture
The present invention relates to process for purifying rivaroxaban, a compound of Formula I,
comprising:
a) providing a solution of rivaroxaban in a mixture of alcohol solvent and halogenated
hydrocarbon solvent or their aqueous mixtures;
b) precipitating the solid from the solution; and
c) isolating the pure rivaroxaban, a compound of Formula I.
Detailed Description of the Invention
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. There is need 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.
In one embodiment, the present invention relates to process for the preparation of rivaroxaban, a compound of Formula I.

comprising the step of a) contacting a compound of Formula II or salt thereof,



with an oxidizing agent to form a first reaction mixture;
b) then contacting the first reaction mixture with a compound of formula VIII,
to form a second reaction mixture; and
c) isolating a compound of formula I from the second reaction mixture. In step a), the oxidizing agent is selected from the group consisting of tert-butyl hydroperoxide, benzoyl peroxide, cumene hydro peroxide, and the like. Preferably, tert-butyl hydroperoxide. In step a), the amount of oxidizing agent is from about 1 mole to about 3 moles per mole of the compound of formula II or salt. Preferably, from about 1 mole to about 2 moles per mole of the compound of formula II or salt.
In one embodiment, the compound of formula II or salt thereof is contacted with an oxidizing agent in presence of a base to form a first reaction mixture.
A suitable base may be selected from an inorganic base or organic base. The inorganic base may • be selected from alkali metal or alkaline earth metal hydroxide, such as sodium hydroxide, potassium hydroxide, calcium hydroxide, lithium hydroxide, alkali metal alkoxide such as sodium methoxide, potassium methoxide, alkali metal or alkaline earth metal carbonates or bicarbonates such as sodium carbonate, potassium carbonate, calcium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate, cesium carbonate and the like. Preferably, calcium carbonate.
The organic base may be selected from the group consisting of organic amines such as triethylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, 4-dimethylaminopyridine, l,5-diazabicyclo[4.3.0]non-5-ene, l,8-diazabicyclo[5.4.0]undec-7-ene, tri-n-butylamine, N-methylmorpholine and the like.

In one embodiment, the compound of formula II or salt thereof is contacted with an oxidizing
agent in presence of a catalyst to form a first reaction mixture.
A suitable catalyst may be selected from copper iodide (Cul), copper bromide (CuBr), sodium
iodide (Nal), sodium bromide (NaBr), lithium bromide (LiBr), silver iodate (AgIO3), sodium
iodate (AgIO3) and the like or mixtures thereof. Preferably copper iodide (Cul) and silver iodate
(AgI03).
The catalyst can be used from about 0.01 mole to about 0.05 moles per mole of the compound of
formula II or salt thereof, preferably about 0.01 mole to about 0.005 moles per mole of the
compound of formula II or salt thereof.
>
In one embodiment, the compound of formula II or salt thereof is contacted with an oxidizing agent in presence of a base and a catalyst to form a first reaction mixture. The base and catalyst are same as described above.
In one embodiment, the compound of formula II or salt thereof is contacted with an oxidizing agent in presence of a solvent to form a first reaction mixture.
The solvent may be selected from nitriles such as acetonitrile. propionitrile, butyronitrile, isobutyronitrile, benzonitrile and the like; esters such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, and like; alcohols such as methanol, ethanol, n-propanol, 2-propanol, tert-butanol, n-butanol and the like; ethers such as diethyl ether, di-isopropyl ether, tetrahydrofuran, dioxane and the like, water or mixture thereof. Preferably, acetonitrile and ethyl acetate. In one embodiment, the compound of formula II or salt thereof is contacted with an oxidizing agent in presence of copper iodide, silver iodate and calcium carbonate in nitrile solvent to generate a first reaction mixture,
In one embodiment, the first reaction mixture may be stirred for a period of about 10 minutes to 60 minutes.
In step b), the first reaction mixture generated is contacted with compound of formula VIII. The compound of formula VIII is added to first reaction mixture at a temperature in the range of about 25° C to 50° C and the reaction mass was stirred for a period of about 2 to 6 hours to generate a second reaction mixture.
The stirring may be carried out at a temperature range of about 30-50 C. The compound of formula I is isolated from the second reaction mixture by workup. In one embodiment, the compound I is isolated by filtration from second reaction mixture.

In one embodiment, prior to filtration the second reaction mixture is treated with an acidic medium and then subjected to filtration to isolate compound of formula In one embodiment, the compound of formula I thus obtained is treated with formic acid followed by addition of water to precipitate the compound of formula I and followed by isolating the compound I by filtration.
In one embodiment, the above reaction is carried out at about 5° C to about 80°. Surprisingly, it has been found that the process of the present invention involving preparation of rivaroxaban, a compound of formula I, by contacting compound of formula II or salt thereof with an oxidizing agent and then adding compound of formula VIII, has a significant advantage of obtaining rivaroxaban with high purity (HPLC Purity: 90%) for pharmaceutical use. In contrast if the oxidizing agent is added after the reaction of compound of formula II or salt thereof with a compound of formula VIII, then the rivaroxaban obtained has a purity to the extent of about 70% only and is contaminated with impurities.
Without wishing to be bound by theory it is believed that the process of the present invention involving contacting a compound of formula II or salt thereof with an oxidizing agent followed by addition of compound of formula VIII proceeds through oxidative amidation to form rivaroxaban and not via compound of formula XI, as demonstrated by HPLC.

In one embodiment, the present invention provides rivaroxaban a compound of Formula I, obtained by the process described above, which is free of compound of formula XI.


In one embodiment, the present invention provides a process for the preparation of rivaroxaban,
a compound of Formula I, comprising simultaneous addition of a compound of formula II, an
oxidizing agent and a compound of formula VIII.
In one embodiment, compound I is treated with DMF and the solution obtained is passed
through neutral alumina column, followed by addition of water to eluted DMF solution to
precipitate the compound I and followed by isolating the pure compound I by filtration to obtain
compound I with HPLC purity of 99.5%.
In one embodiment, the present invention provides process for purifying rivaroxaban, a
compound of Formula I, comprising:
a) providing a solution of rivaroxaban in a mixture of alcohol solvent and halogenated hydrocarbon solvent or their aqueous mixtures;
b) precipitating the solid from the solution; and
c) isolating the pure rivaroxaban, a compound of Formula I.
In step a), the solvent may be selected from alcohol such as methanol, ethanol, n-propanol, 2-propanol, tert-butanol, n-butanol and the like; halogenated hydrocarbon solvent such as methylene chlorie (MDC), ethylene chloride (EDC), chloroform and the like, water or mixture thereof. prefrably mixture of methanol and methylene chloride (MDC). In one embodiment, in step a), the reaction mixture is heated and stirred at about 35 °C to about 55 °C.
In step b), precipitation of the solid from the solution is achieved by distillation of solvent at about 40 °C to about 70 °C and by cooling the solution to room temperature. In step c), isolated rivaroxaban is dried at about 45 °C to about 75 °C, preferably at about 50 °C to about 60 °C.
In one embodiment, the present invention provides rivaroxaban wherein the level of compound of formula IX less than 0.15%, w/w preferably below detection limit (BDL) w/w relative to the amount of rivaroxaban as determined by HPLC.
In one embodiment, the present invention provides rivaroxaban wherein the level of compound of formula X is less than 0.15% w/w, preferably less than 0.05% w/w relative to the amount of rivaroxaban as determined by HPLC.
In one embodiment, the present invention provides rivaroxaban a compound I, obtained by the processes herein described, which is subatantially free of compound of formula XI.


The term substantially free means that rivaroxaban prepared in accordance with present invention contains less than about 0.15% w/w, preferably less than about 0.05% w/w. and more preferably below detection limit of compound XI as measured by HPLC.

In one embodiment, the present invention provides rivaroxaban a compound of Formula I, free of compound of formula XI.

Reaction mixture is analysed by HPLC using GL-Science, Inertsil ODS 3V column at 243 nm. Buffer used is 0.01 M ammonium acetate in water. Mobile phase is Methanol: Acetonitrile (60: 40) with flow rate 1.0 ml/min. compound of formula XI is eluted at 33.0 min. (RRT 1.10). In one embodiment, the present invention provides rivaroxaban wherein the level of compound of formula IX is less than 0.15%, w/w relative to the amount of rivaroxaban as determined by HPLC.


In one embodiment, the present invention provides rivaroxaban wherein the level of compound X is less than 0.15%, w/w relative to the amount of rivaroxaban as determined by HPLC.

In one embodiment, the present invention provides rivaroxaban wherein the level of compound XII is less than 0.15%, w/w relative to the amount of rivaroxaban as determined by HPLC.

In one embodiment, the present invention provides rivaroxaban wherein the level of compound of formula XII is less than 0.15%, w/w relative to the amount of rivaroxaban as determined by HPLC.


In one embodiment, the present invention provides rivaroxaban wherein the level of compound of formula XII is less than 0.15% w/w, preferably below detection limit relative to the amount of rivaroxaban as determined by HPLC.

In one embodiment, the present invention provides rivaroxaban a compound of Formula I, wherein the level of (R)-rivaroxaban impurity is present less than 0.15% w/w relative to the amount of rivaroxaban as determined by chiral HPLC.
In one embodiment, the present invention provides rivaroxaban a compound of Formula I, obtained by the processes herein described, having purity more than about 99.6% as measured by High Performance Liquid Chromatography (HPLC).
In one embodiment, the present invention provides rivaroxaban, wherein level of one or more compounds of formula II, IV, V, VIII, IX, X , XII, XIII and XIV is level of less than 0.15% w/w relative to the amount of rivaroxaban as determined by HPLC and (R)-rivaroxaban less than 0.15% w/w relative to the amount of rivaroxaban as determined by chiral-HPLC. In one embodiment the present invention provides rivaroxaban, compound of formula I, having bulk density of 0.312 g/cc.
In one embodiment the present invention provides rivaroxaban, compound of formula I, having taped density of 0.47 g/cc.
In one embodiment the present invention provides rivaroxaban, compound of formula I having specific surface area of about 0.31 m2/g.

In one embodiment the present invention provides rivaroxaban, compound of formula I having
hausner ratio is 1.51.
In one embodiment the present invention provides rivaroxaban, compound of formula I having
aspect ratio is 3.62.
In one embodiment, the present invention provides modification I of rivaroxaban,
In one embodiment, the present invention provides rivaroxaban a compound of Formula I,
obtained by the processes herein described, is rivaroxaban modification I, characterized by X-
ray powder diffraction (XRPD) and near infra-red (MR) spectra.
In one embodiment the present invention provides a process for preparing rivaroxaban
compound of formula I in the modification I characterized by X-ray powder diffraction having
peaks expressed as 20 values at about 8.9,14.3,16.5,17.4, 18.0,19.5,19.9,21.7,22.5,23.3,
24.7,25.6,26.4, 26.6, 30.0, and 31.8 ±0.2.
In one embodiment, the present invention provides rivaroxaban a compound of Formula I,
obtained by the processes herein described, having a D90 particle size of about 103 microns, D50
particle size of about 55 microns and D10 particle size of about 15 microns.
In one embodiment, the present invention provides micronized rivaroxaban a compound of
Formula I, obtained by the processes herein described, having a D% particle size of about 65
microns, D50 particle size of about 35 microns and D10 particle size of about 12 microns.
In one embodiment, the present invention relates to process for the preparation of compound of
Formula VIII,
comprising: reacting 2-chlorothiophene with phosphorous oxychloride.
In one embodiment, 2-chlorothiophene reacted with phosphorous oxychloride in presence of a
solvent.
The solvent may be selected from dimethyl formamide (DMF), acetonitrile, toluene, and the like.
Preferably, dimethyl formamide (DMF),
In one embodiment, reaction of 2-chlorothiophene with phosphorous oxychloride is carried out
at about 40°C-65°C1 preferably at about 50°C-55°C.
In one embodiment, the present invention provides a process for the preparation of compound of
formula II or salt thereof,

comprising reacting a compound of Formula IV

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, isopropanol, 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, THF; 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, the above reaction may be carried out in the presence of an acid. The acid that can be used in the reaction may be selected from the group consisting of hydrochloric acid, acetic acid, phosphoric acid, trifluoracetic acid, trifluoromethane sulfonic acid, methane sulfonic acid, nitric acid, sulfuric acid or the mixtures thereof

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'-carbony] 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 purifying compound of formula
IV from solvent may be selected from alcohol such as methanol, ethanol, propanol and like;
hydrocarbon solvent such as cyclohexane, MDC, EDC, chloroform and the like; ketone such as
acetone, methyl isobutyl ketone (MIBK), propanone and the like; nitrile such as acetonitrile,
propionitrile and the like; ether such as tetrahydrofuran (THF), diethyl ether, dimethyl
formamide, dimethyl acetamide, nitrobenzene, water or mixture thereof. Preferably methanol and
nitrobenzene.
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.
The processes, herein described, for the preparation of rivaroxaban are simple, eco-friendly,
inexpensive, reproducible, robust and well suited on industrial scale.
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-[(2R)-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-[(2S)-oxiran-2-ylmethyl]-lH-isoindole-l,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 about 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-oxomorphoIin-4-yl) phenyl]-l,3-oxazoIidin-5-yl}methyl)-lH-isoindole-l,3(2H)-dione (Formula IV). In a clean round bottom flask, 200gm of 2-[(2S)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl) phenyl] amino} propyl]-lH-isoindole-l, 3(2H)-dione, 10gm of 4-dimethyl amino pyridine, 164gm of 1, 1 '-carbonyl diimidazole (CDI) and 3 liter of tetrahydrofuran (THF) were charged. The reaction mixture was heated to about 55-60°C and stirred for about 12 hours. A second Jot 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]-l,3-oxazolidm-5-yl}methyI)-lH-isoindoIe-l,3(2H)-dione (Formula IV). In a clean round bottom flask, l00gm of 2-[(2S)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl) phenyl] amino} propyl]- lH-isoindoIe-l, 3(2H)-dione, 5gm of 4-dimethyl amino pyridine, 82gm of 1, F-carbonyl diimidazole (CDI) and 2.51iter of toluene were charged. The reaction mixture was heated to about 55-60°C and stirred for about 12 hours. A second lot of 82gm of 1. I-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 (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-yi) phenyl]-l, 3-oxazolidin-5-yl} methyl)-lH-isoindole-l, 3(2H)-dione), 1 liter of methanol and 223.6gm of 40% aq. methyl amine solution were charged at about room temperature. The reaction mixture was heated to about 60°C-65°C for about 2 hours. The reaction mixture was then cooled to 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 (MDC) layer was dried over sodium sulphate and MDC was distilled off 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 5: Preparation of 4-{4-[(5S)-5-(amino methyl)-2-oxo-l, 3-oxazolidin-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-65oC, 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 6: Preparation of 4-{4-[(5S)-5-(amino methyl)-2-oxo-l, 3-oxazolidin-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]-1, 3-oxazolidir!-5-yl} methyl)-lH-isoindo]e-], 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. The organic layer was then washed with saturated sodium chloride solution. The organic layer was distilled off completely under vacuum. The solid obtained was stirred with 20ml of ethyl acetate at about room temperature, filtered, washed with ethyl acetate and dried in air oven at about 50°C-55°C to yield titled compound.

Example 7: Purification of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorphoIin-4-yl) phenyl]-l, 3-oxazoIidin-5-yl} methyl) thiophene-2-carboxamide.
In a clean round bottom flask, 31gm of 5-chloro-N({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)
phenyl]-l, 3-oxazoIidin-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 8: Purification of 5-chIoro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yI) 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-oxomorpholin-4-yl)
phenyi]-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.
Example 9: Preparation of (2-[(2R)-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, 105.7gm of 2-
[(25}-oxiran-2-ylmethyl]-lH-isoindole-l,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. 300ml of methanol was added to reaction mass and maintained for about 3 hours at about
55-60oC, filtered, washed with water and dried in air oven at about 50°C-60°C to yield 175gm of
titled compound. HPLC purity: 94%
Example 10: Preparation of (2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenylJ-1,3-
oxazolidin-5-yl}methyl)-H-isoindole-l,3(2H)-dione (Formula IV).
In a clean round bottom flask, l00gm of 2-[(2S)-2-hydroxy-3-{[4-(3-oxomorpho3in-4-yl) phenyl]
amino} propyl]-1H-isoindole-l, 3(2H)-dione, 5gm of 4-dimethyl amino pyridine, 82gm of 1, 1!-
carbonyl diimidazole (CDI) and 1 liter of toluene were charged. The reaction mixture was heated
to a temperature of about 50-60°C and stirred for about 12 hours. The reaction mass was cooled
to about 25°C -30°C, filtered and washed with toluene. 1 liter of purified water was added to

obtained cake and stirred for about 1 hour, filtered, washed with water and dried in air oven at about 50°C-60°C to yield 86gm of titled compound.
Example 11: Purification of (2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yI) phenyl]-l,3-oxazolidin-5-yl}methyl)-lH-isoindoIe-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 and 800ml of nitrobenzene were charged. Reaction mass was heated to about 80°C-95°C, stirred for about 30 minutes and cool to about 60°C-65°C, 1000ml of methanol was added slowly to reaction mass and cooled to about 25°C-30°C and further cooled to about 0°C-5°C. The reaction mass was stirred for about 2 hours at same temperature, filtered, washed with chilled methanol and dried in air oven at about 50°C-60°C to yield 86gm of titled compound.
Example 12: Preparation of (4-{4-[(5S)-5-(amino methyl)-2-oxo-l, 3-oxazolidin-3-yL] phenyl} morpholin-3-one hydrochloride (Formula Ha).
In a clean round bottom flask, lOOgm of (2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-l, 3-oxazolidin-5-yl} methyl)-lH-isoindole-l, 3(2H)-dione), 1500ml of methylene dichloride (MDC) and 239.5gm of 40% aq. methyl amine solution were charged at room temperature. The reaction mixture was heated to a temperature of about 35°C-45°C for about 15 hours and cooled to about 25°C-30°C. Layer was separated and MDC layer distilled off under vacuum. 500ml of methanol was added to reaction mass and heated to about 40°C-45°C for dissolution and then 20ml of 35% HCL solution was added till pH 1-3. The slurry was stirred for about 30 minutes, cooled, filtered, washed with methanol and dried in air oven at about 50°C-55°C to yield 58gm of titled compound.
Example 13: Preparation of 2-[(2,5)-oxiran-2-ylmethyl]-lH-isoindo]e-l,3(2H)-dione (Formula VII).
In a clean round bottom flask, 5gm of phthalimide, 7.85gm of S- epichlorohydrin, 6.9 gm sodium acetate and 50ml of isopropyl alcohol were charged. The reaction mass was heated to about 65°C-70°C and maintained for about 24 hours to about 30 hours. The reaction mass was cooled to about 25°C and concentrated under reduced pressure at below 40°C then 50 ml of toluene was added and stirred for about 30mintus and filtered. To obtained filtrate 17.76gm of potassium carbonate was added and reaction mass was heated to about 100°C-110°C and maintained for about 3 hours to about 5 hours at same temperature. The reaction mass was

cooled to about 25°C, filtered and concentrated and degassed. 50ml of cyclohexane was added
to reaction mass and stirred for about 30 minutes, filtered and dried under reduced pressure at
about 50-55°C to yield titled compound as oil (5gm)
Example 14; Preparation of 5-chloro thieophene-2-carboxaldehyde (Formula VIII).
In a clean round bottom flask, 19.38gm of phosphorous oxychloride, 5gm of 2-Chloro thiophene
were charged and reaction mass was heated to about 50°C-55°C. 9.244gm of dimethyl
formamide (DMF) was added to reaction mass at same temperature and cooled to about 0°C-
5°C. 10% sodium hydroxide solution was added to reaction mass & extracted with methylene
dichloride then obtained organic layer washed with water followed by sodium chloride solution.
The organic layer distilled off & degassed under vacuum below 45°C to yield titled compound as
oily mass. HPLC purity: 98%.
Example 15: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-l,
3-oxazoIidin-5-yl} methyl) thiophene-2-carboxamide (Formula I).
In a clean round bottom flask, 3gm of 4-{4-[(5S)-5-(amino methyl)-2-oxo-l, 3-oxazolidin-3-yl]
phenyl} morpholin-3-one hydrochloride, 6ml of acetonitrile, 0.026 gm of silver iodate, 0.017 gm
copper iodide, 0.82 gm of calcium carbonate and 1.3gm of 70% tertiary butyl hydro peroxide
were charged and stirred for about 10 minutes then reaction mixture was heated to about 40°C-
45°C. 2gm of 5-chloro thiophene-2-carboxaldehyde was added at about 40°C-45°C and
maintained the reaction for about 6 to about 7 hours. After completed the reaction (checked by
TLC) 20ml of dimethyl formamide (DMF) was added and reaction mass was heated to about 70 -
75°C, filtered and washed with DMF. To he obtained filtrate water was added drop wise at about
0°C -10°C, stirred for about 3-4 hours and filtered to yield 3gm of titled compound.
Example 16: 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, 3gm of 4-{4-[(5S)-5-(amino methyl)-2-oxo-i, 3-oxazolidin-3-yI]
phenyl} morpholin-3-one hydrochloride, 6ml of acetonitrile, 0.026 gm of silver iodate, 0.017 gm
copper iodide, 0.82 gm of calcium carbonate were charged and stirred for about 10 minutes
then reaction mixture was heated to about 40°C-45°C. 2gm of 5-chloro thiophene-2-
carboxaldehyde was added to reaction mixture at about 40°C-45°C then 1.3gm of 70% tertiary
butyl hydro peroxide was charged to reaction mixture and maintained the reaction for about 6 to
about 7 hours. After completed the reaction (checked by TLC) 20ml of dimethyl formamide

(DMF) was added and reaction mass was heated to about 70 -75°C, filtered and washed with
DMF. To the obtained filtrate, water was added drop wise at about 0°C -10°C, stirred for about
3-4 hours and filtered to yield 3gm of titled compound.
Example 17: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpho]in-4-yJ) pheny)]-l,
3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide (Formula I).
In a clean round bottom flask, 3gm of 4-{4-[(5S)-5-(amino methyl)-2-oxo-l, 3-oxazolidin-3-yI]
phenyl} morpholin-3-one hydrochloride, 6ml of acetonitrile, 0.026 gm of silver iodate, 0.017 gm
copper iodide, 1 gm of sodium bicarbonate and 1.3gm of 70% tertiary butyl hydro peroxide
were charged and stirred for about 10 minutes then reaction mixture was heated to about 40°C-
45°C. 2gm of 5-chloro thiophene-2-carboxaldehyde was added at about 40°C-45°C and
maintained the reaction for about 6 to about 7 hours. After completed the reaction (checked by
TLC) 20ml of dimethyl formamide (DMF) was added and reaction mass was heated to about 70 -
75°C, filtered and washed with DMF. To he obtained filtrate water was added drop wise at about
0°C -10°C, stirred for about 3-4 hours and filtered to yield lgm of titled compound.
Example 18: 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 1).
In a clean round bottom flask, 3gm of 4-{4-[(5S)-5-(amino methyl)-2-oxo-l, 3-oxazolidin-3-yI]
phenyl} morpholin-3-one hydrochloride, 6ml of acetonitrile, 0.026 gm of silver iodate, 0.017 gm
copper iodide. 1.2gm of potassium carbonate and 1.3gm of 70% tertiary butyl hydro peroxide
were charged and stirred for about 10 minutes then reaction mixture was heated to about 40°C-
45°C. 2gm of 5-chloro thiophene-2-carboxaldehyde was added at about 40°C-45°C and
maintained the reaction for about 6 to about 7 hours. After completed the reaction (checked by
TLC) 20ml of dimethyl formamide (DMF) was added and reaction mass was heated to about 70 -
75°C, filtered and washed with DMF. To he obtained filtrate water was added drop wise at about
0°C -10°C, stirred for about 3-4 hours and filtered to yield lgm of titled compound.
Example 19: Preparation of 5-chloro-jV-({(5S)-2-oxo-3-[4-(3-oxoniorpholin-4-yI) phenyl]-l,
3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide (Formula I).
In a clean round bottom flask, 3gm of 4-{4-[(5S)-5-(amino methyl)-2-oxo-l, 3-oxazolidin-3-yl]
phenyl} morpholin-3-one hydrochloride, 6ml of ethyl acetate, 0.026 gm of silver iodide, 0.017
gm copper iodide, lgm of sodium bicarbonate and 1.3gm of 70% tertiary butyl hydro peroxide
were charged and stirred for about 10 minutes then reaction mixture was heated to about 40°C-

45°C. 2gm of 5-chloro thiophene-2-carboxaldehyde was added at about 40°C-45°C and
maintained the reaction for about 6 to about 7 hours. After completed the reaction (checked by
TLC) 20ml of dimethyl formamide (DMF) was added and reaction mass was heated to about 70 -
75°C, filtered and washed with DMF. To he obtained filtrate water was added drop wise at about
0°C -10°C, stirred for about 3-4 hours and filtered to yield 1.5gm of titled compound.
Example 20: Purification of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorphoIin-4-yI) phenyl]-l,
3-oxazoIidin-5-yl} methyl) thiophene-2-carboxamide.
In a clean round bottom flask, 2gm of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)
phenyl]-l, 3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide was dissolved in 20ml acetic
acid at reflux. 20ml of water was added to reaction mass, cooled to about room temperature and
maintained for about 3 to about 5 hours, filtered and washed with water to yield pure titled
compound.
Example 21: Purification of 5-chloro-iV-({(5S)-2-oxo-3-[4-(3-oxomorpho]in-4-yl) phenyl]-l,
3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide.
In a clean round bottom flask, 2gm of 5-chloro-N-{(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yLl)
phenyl]-l,3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide was dissolved in a mixture of
methanol (40ml) and MDC (60ml) at reflux. Charcoal was added to reaction mass and filtered
on hyflo. The obtained filtrate was cooled to 25-30 °C and maintained for about 3-5hours,
filtered, washed with methanol to yield pure titled compound.
Example 22: Purification of 5-chloro-N-({(5S)-2-ox<)-3-[4-(3-oxomorpholin-4-yl) phenyl]-l,
3-oxazoIidin-5-yl} methyl) thiophene-2-carboxamide.
In a clean round bottom flask, 2gm of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)
phenyI]-l,3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide was dissolved in a mixture of
methanol (40ml) and MDC (60ml) at reflux. After dissolution solvent was distilled out the
solvent under vacuum till 50 ml, cooled to about 25-30°C and maintained for about 3 hours to
about 5 hours, filtered and washed with methanol to yield pure titled compound.
Example 23: Purification of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorphoIin-4-yl) phenyl]-l,
3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide.
In a clean round bottom flask, 2gm of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)
phenyl]-l,3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide was dissolved in a mixture of
methanol (40ml) and MDC (60ml) at reflux. After dissolution solvent was distilled out the

solvent under vacuum till 50 ml, cooled to about 0-5°C and maintained for about 5 hours to
about 7 hours, filtered and washed with methanol to yield pure titled compound.
Example 24: Preparation of (2-[(2R)-2-hydroxy-3-{[4-(3-oxomorphoIin-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-l,3(2H)-drone, 1.51iter water and 100 ml methanol 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 about room temperature and stirred for about
one hour, filtered, washed with water and dried in air oven at about 50°C-60°C to yield 174gm of
titled compound.
Example 25: Preparation of (2-({(5S)-2-oxo-3-[4-(3-oxomorphoIin-4-yl) phenyl]-l,3-
oxazolidin-5-yl}methyl)-lH-soindole-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]-1H-isoindole-1, 3(2H)-dione, 5gm of 4-dimethyl amino pyridine, 82gm of 1, 1'-
carbonyl diimidazole (CDI) and 1.5Iiter of toluene were charged. The reaction mixture was
heated to about 50-55°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-5°C and stirred for about 2 hours, filtered, washed
with chilled toluene and dried in air oven at about 50°C-60°C to yield 90gm of titled compound.
Example 26: Purification of (2-({(5S)-2-oxo-3-[4-(3-oxomorphoIin-4-yl) phenyl]-1,3-
oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)-dione (Formula IV).
In a clean round bottom flask, lOOgm of 2-[(25)-2-hydroxy-3-{[4-(3-oxomorphoIin-4-yl) phenyl]
amino} propyl]-lH-isoindole-l, 3(2H)-dione and 700 ml of nitrobenzene and 1000 ml methanol
were charged. Reaction mass was heated to about 85-90°C, cooled to about 25-30°C, stirred for
about 120 minutes and filtered, washed with methanol and dried in vacuum oven at about 50°C-
60°C to yield 86gm of titled compound.
Example 27: Purification 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, 2gm of 2-[(2S)-2-hydroxy-3-{[4-(3-oxomorpho!in-4-yl) phenyl]
amino} propyl]-lH-isoindole-l, 3(2H)-dione and 16ml of acetonitrile and 4 ml acetone were
charged. Reaction mass was heated to about 50-55°C, cooled to about 25-30°C, stirred for about

120 minutes and filtered, washed with acetonitrile and dried in vacuum oven at about 50°C-60°C
to yield 1.7gm of titled compound.
Example 28: Purification 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, 2gm of 2-[(2S)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl) phenyl]
amino} propyl]-lH-isoindole-l, 3(2H)-dione and 20ml of water and 4ml DMF were charged.
Reaction mass was heated to about 70-75°C, stirred for about 120 minutes and filtered, washed
with water and dried in vacuum oven at about 50°C-60°C to yield 1.6gm of titled compound.
Example 29: Purification of (2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-l,3-
oxazoIidin-5-yl}methylH-isoindole-l,3(2H)-dione (Formula IV).
In a clean round bottom flask, 2gm of 2-[(2S)-2-hydroxy-3-{[4-(3-oxomorphoIin-4-yl) phenyl]
amino} propyl]-lH-isoindole-l, 3(2H)-dione and 10ml of THF. Reaction mass was heated to
about 65-70°C, stirred for about 120 minutes, cool to RT and filtered, washed with THF and
dried in vacuum oven at about 50°C-60°C to yield 1.6gm of titled compound.
Example 30: Purification of (2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-l,3-
oxazolidin-5-yl}methyI)-lH-isoindole-l,3(2H)-dione (Formula IV).
In a clean round bottom flask, 2gm of 2-[(2,S)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl) phenyl]
amino} propyl]-lH-isoindole-1, 3(2H)-dione and 10ml of acetonitrile. Reaction mass was heated
to about 65-70°C, stirred for about 120 minutes, cool to RT and filtered, washed with acetonitrile
and dried in vacuum oven at about 50°C-60°C to yield 1.5gm of titled compound.
Example 31: Purification of (2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yI) phenyl]-l,3-
oxazolidin-5-yl}methyl)-lH-isoindole-l,3(2H)-dione (Formula IV).
In a clean round bottom flask, 2gm of 2-[(2S)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yI) phenyl]
amino} propyl]-lH-isoindole-l, 3(2H)-dione, 16ml of acetonitrile and 4 ml cyclohexane.
Reaction mass was heated to about 65-70°C, stirred for about 120 minutes, cool to room
temperature (RT) and filtered, washed with acetonitrile and dried in vacuum oven at about 50°C-
60°C to yield 1.7gm of titled compound.
Example 32: Preparation of (4-{4-[(5S)-5-(amino methyl)-2-oxo-l, 3-oxazolidin-3-yl]
phenyl} morpholin-3-one hydrochloride (Formula Ha).
In a clean round bottom flask, lOOgm of (2-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-1,
3-oxazolidin-5-yl} methyl)-1H-isoindole-1, 3(2H)-dione), 1500ml of methanol and 239.5gm of

40% aq. methyl amine solution were charged at room temperature. The reaction mixture was heated to a temperature of about 36-45°C for about 15 hours and cooled to about 25°C-30°C. IPA-HC1 solution was added till pH 1-3. The slurry was stirred for about 30 minutes, cooled, filtered, washed with methanol and dried in air oven at about 50°C-55°C to yield 55gm of titled compound. HPLC purity; 99.30%.
Comparative Example 33: 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, 4.4gm of 4-{4-[(5S)-5-(amino methyl)-2-oxo-l, 3-oxazolidin-3-yl] phenyl} morpholin-3-one hydrochloride, 5.2ml of acetonitrile, 0.025gm of silver iodate, 0.017gm copper iodide and 0.8gm of calcium carbonate and stirred for about 10 minutes. 2gm of 5-chloro thiophene-2-carboxaldehyde was added at about 25-30°C. Then, 1.3gm of 70% tertiary butyl hydro peroxide was added. The reaction mixture was heated to about 40-50°C and maintained for 6 hours at same temperature. After completed the reaction ethyl acetate and HC1 was added, filtered and washed with ethyl acetate and dried in air oven at about 50-60°C to yield 2.1gm of titled compound. HPLC purity: 70.46%.
Example 34: Preparation of 5-chIoro-N-{(5S)-2-oxo-3-[4-(3-oxomorphoIin-4-yI) phenyl]-l, 3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide (Formula I).
In a clean round bottom flask, 3gm of 4-{4-[(5S)-5-(amino methyl)-2-oxo-l, 3-oxazolidin-3-yl] phenyl} morpholin-3-one hydrochloride (Formula IIa) , 6ml of acetonitrile, 0.026gm of silver iodate, 0.0087gm copper iodide, 0.82gm of calcium carbonate and l,3gm of 70% tertiary butyl hydro peroxide were charged and stirred for about 10 minutes then 2gm of 5-chloro thiophene-2-carboxaldehyde (Formula VIII) was added at about 25-30°C. The reaction mixture was heated to about 40-50°C and maintained for about 6 to about 8 hours at same temperature. After completed the reaction ethyl acetate and HC1 was added, filtered and washed with ethyl acetate and dried. To obtained compound, formic acid was added and heated to about 40-50°C and then washed with toluene. To the formic acid layer, water was added, filtered, washed with water and dried. To the dried compound, dimethyl formamide (DMF) was added and heated to about 70-80°C and filtered. DMF solution is then passed through neutral alumina column and to eluted DMF solution, water was added, filtered, washed with water and died in air oven at about 50-60°C to yield 2.2gm of titled compound. HPLC purity: 99.5%.

The reaction was periodically monitored by HPLC, starting from zero hour and then every 15 minute upto one hour and thereafter every hour till 12 hour time period. The HPLC data generated demonstrates that reaction pathway proceeds through oxidative amidation to directly give rivaroxaban and does not proceed via intermediate compound of formula XI, as is seen by the insignificant level of compound XI in the below table. The data shows that initially at 15 minute more than 60% of rivaroxaban is formed and compound of formula XI does not exceed more than 0.27% at any time throughout the 12 hours monitoring of the reaction mixture.

Reaction monitoring for % compound of formula XI
Time % Compound IIa % Rivaroxaban % Compound XI
Ohr 6.08 60.31 0.27
15 min 2.43 62.59 0.06
30min 1.64 62.59 0.06
45 min 2.22 65.75 0.05
1 hour 1.56 71.65 0.16
2 hour 1.1 75.87 0.13
3 hour 0.62 77.19 0.04
4 hour 0.62 74.05 0.07
5 hour 0.7 75.21 0.09
6 hour 0.64 75.19 0.08
7 hour 0.64 75.82 0.1
8 hour 0.51 71.37 0.15
9 hour 0.49 73.2 0.14
10 hour 0.98 72.91 0.12
11 hour 0.9 74.16 0.13
12 hour 0.79 73.88 0.13
Isolated solid (Rivaroxaban) 0.05 93.51 0.05
Example 35: Purification of 5-ch]oro-N-[{(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yI) phenyl]-1, 3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide.
In a clean round bottom flask, 2gm of 5-chloro-A'-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-l,3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide was dissolved in a mixture of methanol (40ml) and MDC (60ml) at reflux. After dissolution solvent was distilled out atmospherically till 30ml, cooled to about 25-30°C and maintained for about 1 hour to about 2 hours, filtered and washed with methanol to yield pure titled compound. HPLC purity: 99.7%; Chiral HPLC purity: 99.99%; Bulk density: 0.31 gm/cm3; Tap density: 0.47 gm/cm3; surface

area: 0.32 m2/gm ; Particle size distribution: d10 about 14 microns, d50 about 37 microns and d90
about 75 microns; Particle size distribution after micronization: d10 about 6 microns, d50 about 28
microns and d90 about 70 microns.
Example 36: Purification of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yl) phenyl]-l,
3-oxazoIidin-5-yl} methyl) thiophene-2-carboxamide.
In a clean round bottom flask, 2gm of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxomorpholin-4-yI)
phenyl]-l,3-oxazolidin-5-yl} methyl) thiophene-2-carboxamide was dissolved in a mixture of
methanol (40ml) and MDC (60ml) at reflux. After dissolution solvent was distilled out
atmospherically till 30ml, cooled to about 25-30°C and maintained for about 1 hour to about 2
hours, filtered and washed with methanol-MDC (1:1) mixture to yield pure titled compound.
HPLC purity: 99.7% and Chiral HPLC purity: 99.99%

We Claims:

comprising the steps of a) contacting a compound of Formula II or salt thereof

1. A process for the preparation of rivaroxaban, a compound of Formula I,
with an oxidizing agent to form a first reaction mixture;
b) then contacting the first reaction mixture with a compound of formula VIII,

to form a second reaction mixture; and
c) isolating a compound of formula I from the second reaction mixture.
2. The process as claimed in claim 1 a), wherein the oxidizing agent selected from the group consisting of tert-butyl hydroperoxide, benzoyl peroxide and cumene hydro peroxide.
3. The process as claimed in claim 2, wherein the oxidizing agent is tert-butyl hydroperoxide.
4. The process as claimed in claim 1 a), wherein the amount of oxidizing agent is from about 1 mole to about 3 moles per mole of the compound of formula II or salt.
5. The process as claimed in claim 1 c), wherein contacting of compound of formula VIII is carried out at about 25° C to about 50° C.
6. The process as claimed in claim 1, wherein the reaction is carried out at about 5° C to about 80° C.

7. The process as claimed in claim 1, wherein rivaroxaban a compound of Fonnula I is free of compound of formula XI.

8. A process for purifying rivaroxaban, a compound of Formula I, comprising:
a) providing a solution of rivaroxaban in a mixture of alcohol solvent and halogenated hydrocarbon solvent or their aqueous mixtures;
b) precipitating the solid from the solution; and
c) isolating the pure rivaroxaban, a compound of Fonnula I.
9. The process as claimed in claim 8, wherein alcoholic solvent is methanol.
10. The process as claimed in claim 8, wherein halogenated hydrocarbon solvent is
dichloromethane (MDC),