FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"A NOVEL PROCESS FOR PREPARING RIVAROXABAN."
Enaltec Labs Pvt Ltd. an Indian Company, having its Registered Office at 17thFloor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

A NOVEL PROCESS FOR PREPARING RIVAROXABAN FIELD OF THE INVENTION:
The present invention relates to a novel process for preparing rivaroxaban. The process comprises condensing a compound of structural formula II with compound of structural formula III to get rivaroxaban compound of structural formula I.

Formula II Formula III Formula I
BACKGROUND OF THE INVENTION:
Formula I
Rivaroxaban is chemically 5-Chloro- N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l, 3-oxazolidin-5-yl} methyl)-2-thiophenecarboxamide and is known from U.S Patent No. 7,157,456 and is represented by a compound of structural formula I.


Rivaroxaban is sold in USA under the proprietary name of "XARELTO" and is indicated for the prophylaxis of deep vein thrombosis (DVT), which may lead to pulmonary embolism (PE) in patient undergoing knee or hip replacement surgery.
Scheme I
U.S Patent No. 7,157,456 describes two processes of preparing rivaroxaban compound of structural formula I as shown below in scheme no. I and scheme no. II,



Scheme II
US Patent No. 7,816,355 describes general processes of preparing rivaroxaban compound of structural formula I by condensing compound of structural formula XII with compound of structural formula XIII to get rivaroxaban compound of structural formula I as shown below scheme no. III.

Scheme III
wherein,
R4 is selected from the group consisting of:


wherein G is OR1, NR2R3, or CX3; R1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl, or substituted aryl alkyl; R2 and R3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded; R2 and R3, when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl, R2 and R3, when together form a single ring group with the N to which they are bonded, are a heteroaryl ring; X is halogen; and L2 is a halogen or sulfonyloxy group.
U.S. Patent Publication No. 2010/0081807 describes a process of preparing rivaroxaban compound of structural formula 1 as shown below in scheme no. IV.


U.S. Patent Publication No. 2011/0034465 describes a process of preparing rivaroxaban compound of structural formula I as shown below in scheme no. V.

Scbeme V
wherein L1 is a leaving group selected from the group consisting of: halogen, imidazole, ester, C1 -C4 alkoxy, trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol, N-hydroxyphthalimide, and N-hydroxybenzotriazole; X and Y are either i) separate groups or ii) together form a single ring group with the two carbons to which they are bonded; and when: i) X and Y are separate groups, X is a halogen and Y is —OH; or ii) X and Y together form a single ring group with the two carbons to which they are bonded, they are an oxygen atom; and X is a leaving group selected from the group consisting of halogen, sulfonyloxy, imidazole, ester, C1-C4 alkoxy, substituted C1 -C4 alkoxy, trihalomethoxy, N-hydroxysuccinimide, p-nitrophenol, N-hydroxyphthalimide, and N-hydroxybenzotriazole.
G1 is OR1, NR2R3 or CQ3; R1 is alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl or substituted arylalkyl; R2 and R3 are either (a) two independent groups or (b) together form a single ring group with the N to which they are bonded; R and R , when independent groups, are independently selected from the group consisting of: H, alkyl, substituted alkyl, aryl, substituted aryl, arylalkyl and substituted arylalkyl; R2 and R3, when together form a single ring group with

the N to which they are bonded, are a heteroaryl ring; and Q is halogen; and G2 is a primary amine precursor.
The compound of structural formula XXI may also be prepared by reacting compound of structural formula IV with compound of structural formula XX to get compound of structural formula XXIII and then reacting compound of structural formula XXIII with compound of structural formula XVIII to get compound of structural formula XXI as shown below.

Scheme VI
PCT publication no. 2011/080341 describes a process of preparing rivaroxaban compound of structural formula I as shown in scheme no. VI.


wherein, X represents any halogen atom, preferably chloride; R3 is a radical selected from the group consisting of (C1-C4)-alkyl, phenyl, and phenyl mono- or disubstituted by a (C1-C4 )-alkyl radical to an amination reaction; R1 is a (C4-C10)-alkyl radical which is attached to the N atom by a tertiary C atom; R2 is a radical selected from the group consisting of a halogen and a radical of formula (C1-C8)COO.
PCT publication no. 2011/098501 describes processes of preparing rivaroxaban compound of structural formula I as shown in scheme no. VII, scheme no.VII, scheme no. IX, scheme X and scheme XI.

Scheme XI
wherein R1 is selected from the group consisting of C1-4 alkyl groups and a phenyl group optionally substituted with a alkyl group; and Hal is a halogen atom or a pseudohalogen; R2 is a C1-6 alkyl group or a benzyl group; X is a suitable leaving group such as a halogen atom (such as F, CI, Br or I) or a pseudohalogen (such as CN). In the case of R1S02 X, X can also be a carboxylate such as an anhydride. Preferably X is a halogen such as CI.
Chinese patent publication no. 102250077 discloses process of preparing rivaroxaban compound of structural formula I as shown in scheme XII.


There is a need for the commercially viable synthetic process for the preparation of rivaroxaban compound of structural formula I. Accordingly the present invention provides a commercially viable novel synthetic process for the preparation of rivaroxaban compound of structural formula I.
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a novel process for preparing rivaroxaban compound of structural formula I comprises condensing a compound of structural formula II with compound of structural formula III to get rivaroxaban compound of structural formula I.

A second aspect of the present invention is to provide a novel compound of structural formula III.

Formula I1I
A third aspect of the present invention is to provide a process of preparing compound of structural formula III.


A fourth aspect of the present invention is to provide a process of preparing compound of structural formula III comprises reacting compound of structural formula IX with an alkali metal sulphide or alkali metal hydrogen sulphide to get compound of structural formula III.
Another aspect of the present invention is to provide a use of compound of structural formula III for the preparation of rivaroxaban compound of structural formula I.
DETAIL DESCRIPTION OF THE INVENTION:
The compound of structural formula II used in the present invention may be prepared by method known in art such as those described in Chinese patent publication no. 102250077 which are incorporated herein by reference only.
The compound of structural formula IX used in the present invention may be prepared by method known in art such as those described in U.S Patent No. 7,157,456 and U.S. Patent Publication No. 2010/0081807 which are incorporated herein by reference only.
A compound of structural formula III may be prepared by reacting compound of structural formula IX with an alkali metal sulphide or alkali metal hydrogen sulphide in an organic solvent at a temperature in the range of-20°C to 100°C for period of 30 minutes to 16 hours.
The examples of an alkali metal sulphide may include but not limited to sodium sulphide, potassium sulphide, lithium sulphide, cesium sulphide or mixture thereof.

The examples of alkali metal hydrogen sulphide may include but not limited to sodium hydrogen sulphide, potassium hydrogen sulphide, lithium hydrogen sulphide, cesium hydrogen sulphide or mixture thereof.
Examples of organic solvents may include ketones, alcohols, esters, nitriles, halogenated aliphatic hydrocarbon solvents, ethers or mixtures thereof.
The ketone solvents may include but not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof.
The alcohol solvents may include but not limited to methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof.
The ester solvents may include but not limited to ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof.
The nitrile solvents may include but not limited to acetonitrile, propionitrile or mixture(s) thereof.
The halogenated aliphatic hydrocarbon solvents may include but not limited to dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof.
The ether solvents may include but not limited to tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether or mixture(s) thereof.
A compound of structural formula III may be isolated by concentrating reaction mixture under reduced pressure to get residue. The resulting residue was dissolved in water, acidified with dilute hydrochloric acid and extracted with an above mentioned organic solvent. The resulting

organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to get compound of structural formula III.
The reaction of compound of structural formula II with compound of structural formula III may be carried out in the presence of base in an above mentioned organic solvent at a temperature in the range of -10°C to 40°C for a period of 2 hours to 24 hours to get rivaroxaban compound of structural formula I.
The example of base may include inorganic base or organic base.
The examples of an inorganic base may include but not limited to sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium hydroxide or lithium carbonate.
The examples of organic base may include but not limited to triethyl amine, diisopropyl amine, 1, 8-diazabiicyclo [5.4.0] undec-7-ene, N-methyl morpholine
The rivaroxaban compound of structural formula I may be isolated by quenching the reaction
mixture with water followed by separation of organic layer.
The organic layer containing the rivaroxaban compound of structural formula I may be washed with 1N HC1 solution and an aqueous solution of sodium bicarbonate (10%).
The organic layer containing the rivaroxaban compound of structural formula I may be concentrate under reduced pressure to get a rivaroxaban compound of structural formula I.
The resulting rivaroxaban compound of structural formula I may be further purified by crystallization in an above mentioned organic solvent.

The purified rivaroxaban compound of structural formula I may be isolated by the steps of filtration, centrifugation, washing, drying or the combination thereof.
The isolated purified rivaroxaban compound of structural formula I may be dried under reduced pressured at a temperature in the range of 50°C to 60°C.
The purified rivaroxaban compound of structural formula I may be crystalline or amorphous in nature.
The resulting purified rivaroxaban compound of structural formula I may have more than 99% w/w purity as determined by HPLC technique.
EXAMPLES
In the following examples, the preferred embodiments of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.
Example 1: Preparation of 5-chlorothiopheue-2-carbothioic S-acid compound of structural formula III.
The 5-chlorothiophene-2-carbonyl chloride compound of structural formula II (15gm) was added drop by drop and over a period of several minutes, to the sodium hydrogen sulphide solution (5gm dissolved in 150ml of ethanol) at 25°C. The resulting reaction mixture was vigorously stirred and heated at 65-70°C and then the reaction mixture was refluxed on water bath for 1 hour. The resulting reaction mixture was concentrated under reduced pressure to get residue. The resulting residue was dissolved in water (90ml), acidified with dilute hydrochloric acid and extracted with diethyl ether (75ml). The resulting ether layer was washed with water (15ml), dried over anhydrous sodium sulfate (5gm) and concentrated under reduced pressure to get title compound. Yield: 14.5gm

Purity: 99.8% (By HPLC)
Example 2: Preparation of rivaroxaban compound of structural formula I.
To a solution of (S)-4-(4-(5-(azidomethyl)-2-oxooxazolidin-3-yl) phenyl) morpholin-3-one compound of structural formula II (10gm) in dichloromethane (150ml) was added 5-chlorothiophene-2-carbothioic S-acid compound of structural formula III (5.7gm), potassium bicarbonate (3.2gm) at 30°C and stirred for 5 hours. The resulting reaction mixture was quenched with water (100ml) and organic layer was separated. The resulting organic layer was washed with hydrochloric acid solution (IN, 50ml); aqueous sodium bicarbonate solution (10%, 50ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure to get solid. The resulting solids were suspended in ethanol (50ml) at 25°C and stirred for 1 hour. The resulting solids were filtered, washed with ethanol (10ml) and dried at 50°C under reduced pressure to get title compound. Yield: 13.5gm Purity: 99.9% (By HPLC)

WE CLAIM:
1. A novel process for preparing rivaroxaban compound of structural formula I comprises condensing a compound of structural formula II with compound of structural formula III to get rivaroxaban compound of structural formula I.

Formula II Formula III Formula I
Formula III
2. The process according to claim no. 1, wherein the reaction of compound of structural formula II with compound of structural formula III is carried out in the presence of base in an organic solvent at a temperature in the range of -10°C to 40°C for a period of 2 hours to 24 hours.
3. The process according to claim no. 2, wherein base is selected from the group comprising of inorganic base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium hydroxide, lithium carbonate or organic base such as triethyl amine, diisopropyl amine, 1, 8-diazabiicyclo [5.4.0] undec-7-ene, N-methyl morpholine.
4. A novel compound of structural formula III.


5. A process of preparing compound of structural formula III comprises reacting compound of structural formula IX with an alkali metal sulphide or alkali metal hydrogen sulphide to get compound of structural formula III.

6. The process according to claim no. 5, wherein reaction of compound of structural formula IX with an alkali metal sulphide or alkali metal hydrogen sulphide is carried out in an organic solvent at a temperature in the range of -20°C to 100°C for period of 30 minutes to 16 hours.
7. The process according to claim nos. 5 and 6, wherein the examples of alkali metal sulphide is selected from the group comprising of sodium sulphide, potassium sulphide, lithium sulphide, cesium sulphide or mixture thereof; Examples of alkali metal hydrogen sulphide is selected from the group comprising of sodium hydrogen sulphide, potassium hydrogen sulphide, lithium hydrogen sulphide, cesium hydrogen sulphide or mixture thereof.
8. The process according to claim nos. 2 and 6, wherein the examples of organic solvent is selected from the group comprising of ketones solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone, dibutyl ketone, diethyl ketone, dipropyl ketone, diisopropyl ketone, methyl butyl ketone, methyl propyl ketone, methyl isopropyl ketone, ethyl isopropyl ketone or mixture(s) thereof; alcohol solvents such as methanol, ethanol, propanol, isopropanol, butanol, isobutanol, t-butanol, pentanol or mixture(s) thereof; ester solvents such as ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, tertiary butyl acetate, pentyl acetate or mixture(s) thereof; nitrile solvents such as acetonitrile, propionitrile or mixture(s) thereof; halogenated aliphatic hydrocarbon solvents such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride or mixture(s) thereof; ether solvents such as tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, dibutyl

ether, methyl tertiary butyl ether, methyl ethyl ether, methyl isobutyl ether or mixture(s) thereof.
Formula III
9. The process according to claim no. 5, wherein the compound of structural formula III was isolated by concentrating reaction mixture under reduced pressure to get residue. The resulting residue was dissolved in water, acidified with dilute hydrochloric acid and extracted with an organic solvent. The resulting organic layer was dried over anhydrous sodium sulfate and concentrated under reduced pressure to get compound of structural formula III.
10. Use of compound of structural formula III for the preparation of rivaroxaban compound of structural formula I.