FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
[Section 10, and Rule 13]
Title
PROCESS FOR THE PREPARATION OF RIVAROXABAN AND INTERMEDIATES THEREOF
Applicant
Name: Torrent Pharmaceuticals Limited
Nationality: Indian
Address: Torrent House, Off Ashram Road, Near Dinesh
Hall, Ahmedabad 380 009, Gujarat, India
The following specification particularly describes the invention and the manner in which it is to performed:

PROCESS FOR THE PREPARATION OF RIVAROXABAN AND INTERMEDIATES THEREOF
FIELD OF THE INVENTION:
The present invention relates to a novel process for the preparation of Rivaroxaban of formula (I) and its pharmaceutically acceptable salts. The present invention also relates to novel intermediates, 5-(azidomethyl)-3-[4-(3-oxotetrahydro-2H-pyran-4-yl)phenyl]-1,3-oxazolidin-2-one of formula (VI) and its enantiomeric form, 5-chlorothiophene-2-carbothioic-S-acid of formula (VII), process for its preparation and use thereof for the preparation of Rivaroxaban of formula (I) and its pharmaceutically acceptable salts and pharmaceutical composition comprising the same.
BACKGROUND OF THE INVENTION:
5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl} methyl)-2-thiophenecarboxamide also known by the name Rivaroxaban, is represented by the structural formula (I) as below:

Rivaroxaban acts as inhibitor of clotting factor Xa (FXa) and is indicated for the treatment of various thromboembolic diseases, in particular of deep vein thrombosis, pulmonary embolism, myocardial infarction, angina pectoris, reocclusions and restenoses after angioplasty or aortocoronary bypass, cerebral stroke, transitory ischemic attacks, and peripheral arterial occlusive diseases.

Rivaroxaban is available as 10 mg film-coated tablet and marketed under the trade name Xarelto® in Europe.
Rivaroxaban and related compounds were first disclosed in International Patent Application No. WO 01/47919. WO 01/47919 discloses certain substituted oxazolidinone compounds including 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l ,3-oxazoIidin-5-yl} methyl)-2-thiophenecarboxamide (Rivaroxaban), method for its preparation, pharmaceutical composition using this compound and method of treatment of mammals especially human.
WO 01/47919 discloses process for preparing Rivaroxaban (I), comprising reacting 2-
[(2S)-2-oxiranylmethyl]-IH-isoindole-l,3 (2H)-dione with 4-(4-aminophenyl)-3-
morpholinone to give 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)-phenyl] amino}
propyl)-lH-isoindole-l,3-(2H)-dione. Subsequently, 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-
morpholinyl)-phenyl] amino} propyl)-lH-isoindole-l,3-(2H)-dione is converted into 2-
({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidin-5-yl }-methyl)-1H-
isoindoIe-l,3-(2H)dione with a N,N'-carbonyldiimidazole. Elimination of the phthalimide protective group affords 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl] phenyl}morpholine-3-one which is finally reacted with 5-chlorothiophene-2-carbonyl chloride to give 5-chloro-N-({5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide (I), This synthetic procedure is illustrated in Scheme-1.

Scheme-1

However, the process disclosed in WO 01/47919 has various disadvantages which have a particularly unfavorable effect when the compound of formula (I) is prepared on the industrial scale. The nitrogen atom in the oxazolidinone ring of the target molecule (I) is introduced in phthalimide protected form. However, the phthalic acid radical as protecting group has to be removed in the further course of the synthesis, which means an increase in number of stages and additional waste.
International Patent Application No. WO 2004060887 discloses reaction of 5-chloro thiophene-2-carbonyl chloride with (2S)-3-aminopropane-l,2-diol hydrochloride to give 5-chIorothiophene-2-carboxylic acid ((S)-2,3-dihydroxypropyl)-amide. Subsequently, 5-chIorothiophene-2-carboxylic acid ((S)-2,3-dihydroxypropyl)-amide is converted into 5-chlorothiophene-2-carboxyIic acid ((S)-3-bromo-2-hydroxypropyl) amide, which is then reacted with 4-(4-aminophenyl)-3-morpholinone to give 5-chlorothiophene-2-carboxylic acid {(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]-propyl}amide. Finally, 5-chlorothiophene-2-carboxylic acid {(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yI)phenyl

amino]-propy]}amide is reacted with phosgene or phosgene equivalent to give 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide (I). This synthetic procedure is illustrated in Scheme-2.
Scheme-2

This process uses toxic solvents and reagents which are generally undesirable for large-scale operations. In addition, these toxic substances must be removed from the final product (I) until below the maximum limit permissible in each case in the product for regulatory reasons, which signifies additional expense.
US 7598378 disclose process for preparing 4-(4-aminophenyl)-3-morpholinone by reacting 4-(4-nitrophenyl)-3-morpholinone with hydrogen in the presence of a hydrogenation catalyst, characterized in that the reaction is effected in an aliphatic alcohol. 4-(4-aminophenyl)-3-morpholinone is a central precursor in the synthesis of Rivaroxaban (I).
US 7351823 disclose a process for preparing 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide (I) starting

from 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,3-(2H)-dione, 4-(4-aminophenyl)-3-morpholinone and 5-chlrothiophene-2-carbonyl chloride.
International patent application No. WO 2010124385 discloses process for preparation of S-Rivaroxaban and/ or R-Rivaroxaban comprising reacting 5-chIorothiophene-2-carboxamide with morpholinone derivative.
There still exists a need for a process for the preparation of Rivaroxaban of formula (I), and its pharmaceutically acceptable salts, which may be scaled up for commercial production.
The present invention relates to a novel process for the preparation of Rivaroxaban of formula (I) and its pharmaceutically acceptable salts. The process has lesser number of steps, avoids use of toxic solvents and reagents, is simple, easy and convenient to carry out, gives better yield and purity, economical and commercially viable.
SUMMARY OF THE INVENTION:
In one aspect, the present invention provides a process for preparation of Rivaroxaban of formula (I) and its pharmaceutically acceptable salts,

comprising steps of;
(a) reacting compound of formula (VIa) with compound of formula (VII) optionally in the presence of suitable solvent to obtain the compound of formula (I); and


(b) optionally purifying the compound of formula (I).
In another aspect, the present invention provides a process for preparation of Rivaroxaban of formula (I) and its pharmaceutically acceptable salts,

comprising steps of;
(a) reacting compound of formula (VIa) with compound of formula (VII) optionally in the presence of triarylphosphine and suitable solvent to obtain the compound of formula (I); and

(b) optionally purifying the compound of formula (I).
In yet another aspect, the present invention provides a process for preparation of Rivaroxaban of formula (I) and its pharmaceutically acceptable salts,

comprising the steps of;
(a) condensing compound of formula (IV) with compound of formula (V) in presence of base, suitable solvent and optionally in presence of phase transfer catalyst,


to provide compound of formula (VIa);

(b) reacting the obtained compound of formula (VIa) of step (a) with compound of formula (VII) optionally in the presence of suitable solvent to obtain the compound of formula (I); and

(c) optionally purifying the compound of formula (I).
In yet another aspect, the present invention provides a compound of formula (VIa),
In yet another aspect, the present invention provides compound of formula (VI) and its enantiomeric form.



In another aspect, the present invention provides a process for preparation of compound of formula (VIa)

comprising the steps of;
(a) condensing compound of formula (IV) with compound of formula (V) in presence of base, suitable solvent and optionally in presence of phase transfer catalyst,

to provide compound of formula (VIa); and
(b) optionally purifying the compound of formula (VIa).
In yet another aspect, the present invention provides use of compound of formula (VI) and its enantiomeric form for the preparation of Rivaroxaban of formula (I) and its pharmaceutically acceptable salts.

In yet another aspect, the present invention provides use of compound of formula (VIa) for the preparation of Rivaroxaban of formula (I) and its pharmaceutically acceptable salts.
In yet another aspect, the present invention provides a process for preparation of Rivaroxaban of formula (I) and its pharmaceutically acceptable salts,

comprising the steps of;
(a) condensing compound of formula (IV) with compound of formula (V) in presence of base, suitable solvent and optionally in presence of phase transfer catalyst,

to provide compound of formula (VIa); and

(b) optionally purifying the compound of formula (VIa). In yet another aspect, the present invention provides a compound of formula (VII),

In yet another aspect, the present invention provides a process for the preparation of compound of formula (VII) comprising the step of;
(a) reacting 5-chlorothiophene-2-carboxylic acid (VIII) with thionyl chloride in presence of suitable solvent to obtain 5-chIorothiophene-2-carbonyl chloride (IX); and

(b) reacting the compound of formula (IX) with sodium hydrosulfide in the presence of suitable solvent to obtain the compound of formula (VII).
In yet another aspect, the present invention provides use of compound of formula (VII) for the preparation of Rivaroxaban of formula (I) and its pharmaceutically acceptable salts.
In yet another aspect, the present invention provides a process for the preparation of Rivaroxaban of formula (I) and its pharmaceutically acceptable salts,

comprising the steps of;

(a) reacting 5-chlorothiophene-2-carboxylic acid (VIII) with thionyl chloride in presence of suitable solvent to obtain 5-chlorothiophene-2-carbonyl chloride (IX); and

(b) reacting the compound of formula (IX) with sodium hydrosulfide in the presence of suitable solvent to obtain the compound of formula (VII),

In yet another aspect, the present invention provides the pharmaceutical composition of Rivaroxaban of formula (I) and its pharmaceutically acceptable salt prepared according to the present invention.
DETAILED DESCRIPTION:
The use of the terms "a" and "an" and "the" and similar referents in the context of describing the invention are to be construed to cover both the singular and the plural, unless otherwise indicated herein or clearly contradicted by context.
Throughout this specification and the appended claims it is to be understood that the words "comprise" and "include" and variations such as "comprises", "comprising", "includes", "including" are to be interpreted inclusively, unless the context requires otherwise. That is, the use of these words may imply the inclusion of an element or elements not specifically recited.

The present invention may, however, be embodied in many different forms and should not be construed as limited to the aspects set forth herein. In addition and as will be appreciated by one of skill in the art, the invention may be embodied as a method, system or process.
The present invention relates, in general, to a novel process for the preparation of Rivaroxaban of formula (I) and its pharmaceutically acceptable salts which is illustrated in scheme-3 as below:
Scbeme-3

In one aspect, the present invention provides a process for preparation of Rivaroxaban of formula (I) and its pharmaceutically acceptable salts,


comprising the steps of;
to provide compound of formula (VIa);
(a) condensing compound of formula (IV) with compound of formula (V) in presence of base, suitable solvent and optionally in presence of phase transfer catalyst


(b) reacting the obtained compound of formula (VIa) of step (a) with compound of formula (VII) optionally in the presence of suitable solvent to obtain the compound of formula (I); and

(c) optionally purifying the compound of formula (I).
In step (a), compound of formula (IV) is condensed with compound of formula (V) in presence of base and suitable solvent to provide compound of formula (VIa).
The base includes but are not limited to alkali metal alkoxides like sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, calcium methoxide, calcium ethoxide, magnesium methoxide, calcium ethoxide and the

like; alkali metal hydroxides like sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates like sodium carbonate, potassium carbonate and the like; organolithium reagents like n-Butyllithium, methyl lithium and the like; pyridine and the like.
The suitable solvents includes but are not limited to alcohols like methanol, ethanol, isopropanol, butanol and the like; ketones like acetone, methyl isopropyl ketone and the like; aliphatic ethers like diethyl ether, di tert butyl ether and the like; cyclic ethers like tetrahydrofuran, dioxane and the like; aliphatic esters like methyl acetate, ethyl acetate and the like; hydrocarbons like toluene, heptane, hexane and the like; chlorinated solvent like chloroform, dichloromethane and the like; nitriles like acetonitrile; polar aprotic solvent like dimethyl formamide; N-methyl pyrrolidone, pyridine and water or mixture thereof.
In step (a), compound of formula (IV) is condensed with compound of formula (V) in presence of base, suitable solvent and optionally in presence of phase transfer catalyst to provide compound of formula (VIa).
The phase transfer catalyst includes but is not limited to tetrabutylammonium bromide (TBAB), triethylbenzylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium hydroxide, tricaprylylmethylammonium chloride, dodecyl sulfate sodium salt, tetrabutylammonium hydrogensulfate, hexadecyl tributylphosphonium bromide, methyl trioctylammonium chloride or hexadecyl trimethylammonium bromide.
In step (a), reaction can be carried out at the temperature range of about room temperature to about reflux.
The compound as obtained in step (a) can be optionally purified by using solvent as used in step (a) or it can be directly taken for next step.

In step (b), the obtained compound of formula (VIa) of step (a) is reacted with compound of formula (VII) optionally in the presence of suitable solvent to obtain the compound of formula (I).
The suitable solvents includes but are not limited to alcohols like methanol, ethanol, isopropanol, butanol and the like; ketones like acetone, methyl isopropyl ketone and the like; aliphatic ethers like diethyl ether, di tert butyl ether and the like; cyclic ethers like tetrahydrofuran, dioxane and the like; aliphatic esters like methyl acetate, ethyl acetate and the like; hydrocarbons like toluene, heptane, hexane and the like; chlorinated solvent like chloroform, dichloromethane and the like; nitriles like acetonitrile; polar aprotic solvent like dimethyl formamide; N-methyl pyrrolidine, pyridine and water or mixture thereof.
In step (b), the obtained compound of formula (VIa) of step (a) is reacted with compound of formula (VII) optionally in the presence of triarylphosphine and suitable solvent to obtain the compound of formula (I).
The suitable solvents are same as described herein above and the triarylphosphine is preferably triphenylphosphine.
In step (b), when amide formation takes place in the presence of triphenylphosphine, it forms complex with compound of formula (VIa) at temperature of -10°C to 10°C. And the formed complex is subsequently reacted with compound of formula (VII) at temperature of 10°C-80°C for 2 to 50 hours to provide the compound of formula (I).
The Rivaroxaban of formula (I) can be isolated by using conventional techniques, like adding antisolvent, seeding of Rivaroxaban, stirring the solution till the precipitate comes out.
In step (c), the obtained Rivaroxaban of formula (I) can be optionally purified or re-crystallized by using one or more suitable solvent at ambient temperature. The obtained

Rivaroxaban is further dried under vacuum for 2-8 hours to obtain dry product at 35-65°C.
The suitable solvent used in formation of solution, isolation and crystallization of Rivaroxaban of formula (I) include but is not limited to alcohols (methanol, ethanol, isopropanol, butanol etc.), ketones ( acetone, methyl isopropyl ketone, etc.), aliphatic ethers (diethyl ether, di tert. butyl ether, etc.), cyclic ethers ( tetrahydrofuran, dioxane etc.), aliphatic esters (ethyl acetate etc.), hydrocarbons (toluene, heptane, hexane etc.), chlorinated solvent (chloroform, dichloromethane etc.), acetonitrile, polar aprotic solvents (DMF, DMAc etc.) or mixtures thereof.
In another aspect, the present invention provides a process for preparation of the compound of formula (IV),

comprising steps of;
(a) reacting compound of formula (II) with sodium azide and in suitable solvent to form compound of formula (III); and

(b) reacting the obtained compound of formula (III) of step (a) with phenoxy carbonyl chloride in presence of base and solvent to obtain compound of formula (IV).
In step (a), compound of formula (II) is reacted with sodium azide and suitable solvent at temperature of 0°C to 50°C to form compound of formula (III).

In step (b), compound of formula (III) of step (a) is reacted with phenoxy carbonyl chloride in presence of base and solvent at temperature of 0°C to 50°C to obtain compound of formula (IV).
The base includes but are not limited to alkali metal alkoxides like sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, potassium tert-butoxide, calcium methoxide, calcium ethoxide, magnesium methoxide, calcium ethoxide and the like; alkali metal hydroxides like sodium hydroxide, potassium hydroxide and the like; alkali metal carbonates like sodium carbonate, potassium carbonate and the like; organolithium reagents like n-Butyllithium, methyl lithium and the like; pyridine and the like.
In step (a) and (b), the suitable solvents includes but are not limited to alcohols like methanol, ethanol, isopropanol, butanol and the like; ketones like acetone, methyl isopropyl ketone and the like; aliphatic ethers like diethyl ether, di tert butyl ether and the like; cyclic ethers like tetrahydrofuran, dioxane and the like; aliphatic esters like methyl acetate, ethyl acetate and the like; hydrocarbons like toluene, heptane, hexane and the like; chlorinated solvent like chloroform, dichloromethane and the like; nitriles like acetonitrile; polar aprotic solvent like dimethyl formamide; N-methyl pyrrolidine, pyridine and water or mixture thereof.
In yet another aspect, the present invention provides compound of formula (VIa).

In yet another aspect, the present invention provides use of compound of formula (VIa) for the preparation of Rivaroxaban of formula (I) and its pharmaceutically acceptable salts.


In yet another aspect, the present invention provides a compound of formula (VII).
In yet another aspect, the present invention provides a process for the preparation of compound of formula (VII) comprising the step of;
(a) reacting 5-chlorothiophene-2-carboxylic acid (VIII) with thionyl chloride in presence of suitable solvent to obtain 5-chlorothiophene-2-carbonyl chloride (IX); and

(b) reacting the compound of formula (IX) with sodium hydrosulfide in the presence of suitable solvent to obtain the compound of formula (VII).
In step (a) and (b), the suitable solvents includes but are not limited to alcohols like methanol, ethanol, isopropanol, butanol and the like; ketones like acetone, methyl isopropyl ketone and the like; aliphatic ethers like diethyl ether, di tert butyl ether and the like; cyclic ethers like tetrahydrofuran, dioxane and the like; aliphatic esters like methyl acetate, ethyl acetate and the like; hydrocarbons like toluene, heptane, hexane and the like; chlorinated solvent like chloroform, dichloromethanc and the like; nitriles like acetonitrile; polar aprotic solvent like dimethyl formamide; N-methyl pyrrolidine, pyridine and water or mixture thereof.
In step (a), chlorination of compound of formula (VIII) is generally carried out by using chlorinating agent like thionyl chloride at temperature of 30°C-60°C for 2-6 hours.

In step (b), the compound of formula (IX) as obtained in step (a) can be directly reacted with sodium hydrosulfide without isolating the compound of formula (IX) at temperature of0°C to 25°C for 2-6 hours.
In yet another aspect, the present invention provides use of compound of formula (VII) for the preparation of Rivaroxaban of formula (I) and its pharmaceutically acceptable salts.
The starting compound 4-(4-aminophenyl)-3-morphoIinone (V) can be prepared by the process disclosed in WO 01/47919 or US 7598378.
In yet another aspect, the present invention provides the pharmaceutical composition of Rivaroxaban of formula (I) and its pharmaceutically acceptable salts.
The pharmaceutical compositions of the present invention comprise Rivaroxaban or its pharmaceutically acceptable salts, as an active ingredient and may also contain a pharmaceutically acceptable carrier, diluent, excipient, additive, filler, lubricant, solvent, binder, stabilizer and the like and optionally other ingredients used in pharmaceutical formulations. The compositions may also comprise one or more additional therapeutic agents. The compositions of this invention include compositions suitable for oral, rectal, topical, parenteral, ocular, pulmonary, or nasal administration, although the most suitable route in any given case will depend on the nature and severity of the conditions being treated and on the nature of the active ingredient. The compositions may be conveniently presented in unit dosage form and prepared by any of the methods well known in the art of the pharmacy.
Dosage forms include tablets, troches, dragees, powders, syrups, patches, liposomes, injections, dispersions, suspensions, solutions, capsules, creams, ointments and aerosols. Compositions which provide from 0.1 to 10.0 mg of the active ingredient are preferred.

In general, an effective amount means that amount of a compound of this invention that will elicit the biological or medical response that is being sought. Any suitable route of administration may be employed for providing a mammal, especially a human with an effective dosage of a compound of the present invention. For example, oral, rectal, topical, parenteral, ocular, pulmonary and nasal administration can be employed.
The processes described in the present invention were demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
EXAMPLES:
Example-1: Preparation of (2R)-l-azido-3-chloropropane-2-ol
80 ml of water, 16.86 gm of sodium azide and 13.87 gm of ammonium chloride were charged into the round bottom flask at 27±3°C. The reaction mass was cooled to 0±5°C. 20 gm of (R)-epichlorohydrin solution (20 gm in 2 ml ethanol) was slowly added to the reaction mass and stirred for 1 hour at 0±5°C. The temperature was raised to 27±3°C and the reaction mass was stirred for 12 hours. After completion of the reaction, 10 ml of water and 100 ml of ethyl acetate were charged to the reaction mass and aqueous and organic layers were separated. The organic layer was washed with 100 ml of water and dried over sodium sulphate. Ethyl acetate was distilled completely under vacuum at below 50°C and the residue was passed through column chromatography to obtain the title compound (Dry weight: 19 gm).
Example-2: Preparation of 3-chloro-2-((phenoxvcarbonvl)-oxv) propylazide
50 ml of methylene dichloride, 5 gm of (2R)-l-azido-3-chloropropane-2-ol and 5 ml of pyridine were charged into the round bottom flask. The reaction mass was cooled to 0±5°C. 6.35 gm of phenoxy carbonyl chloride (6.35 gm in 50 ml of methylene dichloride) was slowly added to the reaction mass at 0±5°C. The reaction mass was further stirred for 1 hour. After completion of the reaction, the reaction mass was

quenched with ice cold water and methylene dichloride layer was separated. The aqueous layer was extracted with methylene dichloride (100 ml) and the combined organic extract was washed with dil.HCl. The organic layer was further washed with water and dried over sodium sulphate. Methylene dichloride was distilled out under vacuum at 40±2°C and the residue was passed through column chromatography to obtain the title compound (Dry weight: 8.58 gm).
Example-3: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidin-5-yl} methyl)-2-thiophenecarboxamide
10 ml of DMF, 2.0 gm of 3-chloro-2-((phenoxycarbonyl)-oxy) propylazide, 0.0094 moles of 4-(4-aminophenyl)-3-morpholinone in DMF (10 ml), 2.7 gm of potassium carbonate and catalytic amount of triethylbenzylammonium chloride were charged into the round bottom flask. The reaction mass was heated at 80±5°C and stirred for 12 hours. After completion of the reaction, the reaction mass was quenched with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water and dried over sodium sulphate. The ethyl acetate layer was distilled out under vacuum at below 50°C to get (5R)-5-(azidomethyl)-3-[4-(3-oxotetrahydro-2H-pyran-4-yl)phenyl]-1,3-oxazolidin-2-one. 20 gm of 5-chlorothiophene-2-carbothioic-S-acid and 100 ml of N-methyl pyrrolidine were added and the reaction mass was stirred for 16-24 hours at ambient temperature. The reaction mass was concentrated and passed through column chromatography to get Rivaroxaban (Dry weight: 2.50 gm).
Example-4: Preparation of (2R)-l-azido-3-chloropropane-2-ol
160 ml of water, 33.72 gm of sodium azide and 27.74 gm of ammonium chloride were charged into the round bottom flask at 27±3°C. The reaction mass was cooled to 0±3°C. (R)-epichlorohydrin solution (40 gm in 40 ml ethanol) was slowly added to the reaction mass and stirred for 1 hour at 0±3°C. The temperature was raised to 27±3°C and the reaction mass was stirred for 12 hours. After completion of the reaction, 160 ml of water was added to the reaction mass and the obtained product was extracted thrice with 200 ml of ethyl acetate. The organic layer was washed twice with 200 ml of water and dried with

40 gm sodium sulfate. Ethyl acetate was distilled completely under vacuum at below 35°C to obtain the title compound (Weight: 42.0 gm).
Example-5: Preparation of 3-chloro-2-((phenoxvcarbonyl)-oxy) propylazide
400 ml of methylene dichloride, 40 gm of (2R)-l-azido-3-chIoropropane-2-ol and 40 ml of pyridine were charged into the round bottom flask. The reaction mass was cooled to 0±3°C. 50.8 gm of phenoxy carbonyl chloride was slowly added to the reaction mass at 0±3°C. The reaction mass was further stirred for 1 hour. 400 m] of water was added to the reaction mass and the temperature was raised to 27±3°C. The aqueous and organic layers were separated. The aqueous layer was extracted with methylene dichloride (200 ml) and the combined organic layer was washed with dil.HCl. The organic layer was further washed with water and dried over sodium sulphate. Methylene dichloride was distilled out under vacuum below 35°C to obtain the title compound (Weight: 66.0 gm).
Example-6: Preparation of 5-(azidomethyl)-3-[4-(3-oxotetrahvdro-2H-pvran-4-yl)phenyl]-1,3-oxazolidin-2-one
20 gm 3-chloro-2-((phenoxycarbonyl)-oxy) propylazide and 300 ml of toluene were added in round bottom flask. 15 gm of 4-(4-aminophenyl) morpholin-3-one, 32.4 gm of potassium carbonate and 0.5 gm of tetrabutylammonium bromide were further added to the round bottom flask. The reaction mass was heated at 110±2°C and maintained for 12 hours. Toluene was distilled out under vacuum at below 50°C. 200 ml of water and 400 ml of MDC were charged to the reaction mass and the two layers were separated. The organic layer was washed with 100 ml of dil. HCI and further with 100 ml of water. MDC was distilled out completely under vacuum and the obtained residue was taken for column purification to obtain the title compound.(Weight: 2.0 gm)
1 H NMR in accord with structure (400 MHz, DMSO-d6+D20) δ(ppm): 7.62-7.57 (2H, d), 7.42-7.40 (2H, d), 4.87-4.93 (1H, m), 4.25 (2H, s), 4.14-4.19 (2H, m), 3.77-3.81 (2H, m), 3.95-3.98 (2H, t), 3.70-3.72 (4H, m) & 3.75-3.76 (4H, m).

Example-7: Preparation of 5-chloro-N-(((5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-13-oxazolidm-5-vll methyl)-2-thiophenecarboxamide
0.5 gm of 5-(azidomethyl)-3-[4-(3-oxotetrahydro-2H-pyran-4-yl)phenyl]-I,3-oxazoIidin-2-one, 0.5 gm of triphenyl phosphine and 35 ml of acetonitrile were charged into round bottom flask. The reaction mass stirred for 1 hr at 0°C and further heated at 65±3°C. The reaction mass was stirred for 5 hours at 65±5°C and was cooled to 25±5°C. 0.19 gm of 5-chJorothiophene-2-carbothioic-S-acid was added to the reaction mass and stirred for 24 hours at 25±5°C. Acetonitrile was distilled out completely under vacuum at 40°C and residue was taken for chromatographic purification by column to obtain the title compound (Weight: 0.3 gm)
Example-8: Preparation of 5-chlorothiophene-2-carbothioic S-acid
10 gm of 5-chlorothiophene-2-carboxylic acid, 100 ml of MDC and 0.5 ml of DMF were charged into round bottom flask. The reaction mass was heated to 38±3°C. Thionyl chloride solution (11 gm of thionyl chloride in 25 ml of MDC) was added to the reaction mass and MDC was distilled out completely to obtain the reaction mass. 50 ml of MDC was further added to the reaction mass. The freshly prepared solution of sodium hydrosulfide in MDC (50 gm of sodium hydrosulfide in 50 ml MDC) cooled to 7±3°C. The MDC (containing compound of formula (IX)) layer was slowly added to sodium hydrosulfide solution and the reaction mass was stirred for 2 hours. 100 ml chilled ice water was charged to the reaction mass. The pH of the reaction mass was adjusted to 2.5±0.5 by 15% dil. HC1 solution. The two layers were separated. Aqueous layer was extracted with MDC. The organic layer was washed with water and was distilled out under vacuum below 35°C. The obtained residue was stripped out twice by 75 ml of hexane to obtain title compound (Weight: 8.5 gm).

I H NMR in accord with structure (400 MHz, DMSO-d6+D20) δ(ppm): 7.63-7.64 (1H, d)& 7.22-7.23 (lH,d).

We Claim:
1. A process for preparation of Rivaroxaban of formula (I) and its pharmaceutically acceptable salts,

comprising the steps of;
(a) condensing compound of formula (IV) with compound of formula (V) in presence of base, suitable solvent and optionally in presence of phase transfer catalyst,

to provide compound of formula (VIa); and


(b) optionally purifying the compound of formula (VIa). 2. A process for preparation of compound of formula (VIa)

comprising the steps of;
(a) condensing compound of formula (IV) with compound of formula (V) in presence of base, suitable solvent and optionally in presence of phase transfer catalyst,

to provide compound of formula (VIa); and (b) optionally purifying the compound of formula (VIa).
3. The process according to claim 1 or 2, wherein the phase transfer catalyst is selected from the group comprising of tetrabutylammonium bromide (TBAB), triethylbenzylammonium chloride, tetrabutylammonium chloride, tetrabutylammonium hydroxide, tricaprylylmethylammonium chloride, dodecyl sulfate sodium salt, tetrabutylammonium hydrogensulfate, hexadecyl tributylphosphonium bromide, methyl trioctylammonium chloride or hexadecyl trimethylammonium bromide.
4. The process according to any preceding claims, wherein the base is selected from the group comprising of alkali metal alkoxides, alkali metal hydroxides, alkali metal carbonates, organolithium reagents or pyridine.
5. A process for preparation of Rivaroxaban of formula (I) and its pharmaceutically acceptable salts,


comprising the steps of;
(a) reacting 5-chlorothiophene-2-carboxylic acid (VIII) with thionyl chloride in presence of suitable solvent to obtain 5-chlorothiophene-2-carbonyl chloride (IX); and

6. A process for the preparation of compound of formula (VII) comprising the step of;
(b) reacting the compound of formula (IX) with sodium hydrosulfide in the presence of suitable solvent to obtain the compound of formula (VII),


(a) reacting 5-chlorothiophene-2-carboxylic acid (VIII) with thionyl chloride in presence of suitable solvent to obtain 5-chlorothiophene-2-carbonyl chloride (IX); and


(b) reacting the compound of formula (IX) with sodium hydrosulfide in the presence of suitable solvent to obtain the compound of formula (VII).
9. A compound of formula (VII),
7. The process according to any preceding claims, wherein the solvent is selected from the group comprising of alcohols, ketones, cyclic ethers, aliphatic esters, hydrocarbons, chlorinated solvent, nitriles, polar aprotic solvent, N-methyl pyrrolidine, pyridine, water or mixture thereof.
8. A compound of formula (VI) or (VIa),


10. Use of the compound of formula (VI), (VIa) or (VII) for the preparation of Rivaroxaban of formula (I) or its pharmaceutically acceptable salts.