FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. Title of the invention -: AN IMPROVED PROCESS FOR THE PREPARATION
OF RIVAROXABAN
2. Applicant(s)
(a) NAME: ALEMBIC PHARMACEUTICALS LIMITED
(b) NATIONALITY: An Indian Company.
(c) ADDRESS: Alembic Campus, Alembic Road,
Vadodara-390, 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention and the manner in which is to be performed

Field of the invention
The present invention relates to a process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l ,3-oxazolidin-5-yl}methyl)-2-thiophen-carboxamide (I) by reacting 5-chlorothiphene-2-carbonyl chloride and 4-[4-((S)-4-aminomethyl-2-oxoimidazolidin-l-yl)phenyl]morpholine-3-one hydrochloride in the presence of buffer reagent.

Background of the invention
The compound of the formula (I) acts as inhibitor of clotting factor Xa and can be employed as agent for the prophylaxis and/or treatment of thromboembolic disorders, in particular myocardial infarction, angina pectoris (including unstable angina), reocclusions and restenoses after angioplasty or aortocoronary bypass, stroke, transient ischaemic attacks, peripheral arterial occlusive diseases, pulmonary embolisms or deep venous thromboses. The compound of formula (I) also known as rivaroxaban and marketed in a number of countries under the trade designation Xarelto.
WO-A 01/47919 disclosed the compound of formula (I). WO-A 01/47919 also describes a method for preparing the compound of the formula (I) in the gram range starting from the same starting compounds 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,3(2H)-dione (II), 4-(4-aminophenyl)-3-morpholinone (III) and 5-chlorothiophene-2-carbonyl chloride (IV):


It provides process wherein, 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,3(2H)dione (H) is
reacted with 4-(4-aminophenyl)-3-morpholinone (1E) to give 2-((2R)-2-hydroxy-3-{[4-(3-
oxo-4-morpholinyl)-phenyl]amino}propyl)-1H-isoindole-1,3(2H)dione (V). Subsequently,
(V) is converted with a phosgene equivalent into 2-({(5S)-2-oxo-3-[4-(3-oxo-4-
morpholinyl)phenyl]-1,3-oxazolidin-5-yl}-methyl)-lH-isoindole-l,3(2H)dione (VI).
Elimination of the phthalimide protective group affords 4-{4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl}morpholine-3-one (VII) which is finally reacted with 5-chlorothiophene-2-carbonyl chloride (IV) to give 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl] -1,3 -ox azolidi n-5 -yl} methyl) -2-thiophenecarboxamide(I). However, this process disclosed in WO-A 01/47919 exhibits number of challenges in the reaction management which may adversely affect the preparation of the compound of the formula (I) on the industrial scale.
DE 10300111.5 discloses an alternative process for synthesizing the compound of the formula (I) starting from 5-chlorothiophene-2-carbonyl chloride (IV), (2S)-3-aminopropane-1,2-diol hydro-chloride (VIII) and 4-(4-aminophenyl)-3-morpholinone (III):


It provides process wherein, 5-chlorothiophene-2-carbonyl chloride (IV) is reacted with (28)-3-aminopropane-l,2-diol hydrochloride (VII) to give 5-chlorothiophene-2-carboxylic acid ((S)-2,3-dihydroxypropyl)-amide (IX). Subsequently, (IX) is converted into 5-chlorothiophene-2-carboxylic acid ((S)-3-bromo-2-hydroxypropyl)amide (X), which is then reacted with 4-(4-aminophenyl)-3-morpholinone (III) to give 5-chlorothiophene-2-carboxylic acid {(R)-2-hydroxy-3-[4-(3-oxomorpholin-4-yl)phenylamino]-propyl}amide (XI). Finally, (XI) is reacted with phosgene or a phosgene equivalent to give 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl} methyl)-2-thiophenecarboxamide(I).
US7351823B2 discloses an alternative process for synthesizing the compound of the formula (I) by reacting by reacting 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl} morpholin-3-one (VII) hydrochloride with 5-chlorothiophene-2-carbonyl chloride (IV), characterized in that the reaction is carried out in a solvent selected from the group of ether, alcohol, ketone and water or in a mixture thereof with use of an inorganic base.
The' 823 patent, however, does not disclose the chemical purity of the rivaroxaban obtained by the modified process. The experimental example (d, 3rd step) describes a melting point of 230 °C for rivaroxaban after recrystallization from acetic acid, filtration, washing with acetic acid and water and drying. The reported melting point is lower than the melting point of rivaroxaban with 100% chemical purity described in the WO-A 01/47919, i.e. 232-233 °C, and which corresponds to crystalline form I.
The authors of the present invention have found that the rivaroxaban obtained by the modified process disclosed in the ' 823 patent contains high amounts of specific impurities, and

therefore the process is not suitable for the preparation of compound (I) on an industrial scale. One significant undesired by-product found in the rivaroxaban obtained by the modified process disclosed in the example (d. 2nd step) of the '823 patent is the N,N'-bis[{(5,S)-2-oxo-3-[4-(3-oxomorpholin-4-yl)phenyl]-l,3-oxazolidin-5- yl}methyl]urea, which has not been previously described in the literature.
The object of the present invention derives therefrom, of providing a simplified process for preparing the compound (I) on the industrial scale, avoiding toxic solvents or reagents, especially in the last steps of the process.
Surprisingly, it has now been found that the synthetic linking of the amide bond form 5-chlorothiphene-2-carbonyl chloride (IV) and the primary amino function in the 4-[4-((S)-5-aminomethyl-2-oxo-l,3-oxazolidine-3-yl]-phenyl-morpholin-3-one hydrochloride (VII) can be carried out particularly well in a solvent selected from the group of aromatic hydrocaran, ketone, polar aprotic solvents, water or in a mixture thereof with use of buffer reagent.

The present invention also provides process for the purification of Rivaroxaban.
Object of the invention:
It is an object of the present invention is to provide a process for the preparation of Rivaroxaban (I) comprising a step of reacting 4-[4-((S)-5-aminomethyI-2-0xo-l,3-oxazolidine-3-yl]-phenyl-morpholin-3-onehydrochloride(VII) with 5-chlorothiphene-2-carbonylchloride (IV), in the presence of buffer reagent and a solvent selected form the group of ketone, aromatic hydrocarbon, polar aprotic solvent, water or mixture thereof or mixture of two or more solvents.

For the present invention preferred polar aprotic solvents are sulfolane, N-methyl pyrollidine, 1 ,3-Dimethy] -3,4,5,6-tetrahydro-2( 1 H)-pyrimidinone(DMPU), Hexamethylphosphoramide (HMPA). Dimethylformamide, water or mixture thereof or mixture of two or more solvents. Preferably, mixture of sulfolane and water.
For the present invention preferred solvents are: ketone such as methyl ethyl ketone, methyl isobutyl ketone or acetone or mixture thereof; aromatic hydrocarbon such as toluene, xylene or water or mixture of two or more solvents. Preferably, mixture of toluene, acetone and water
More Preferred buffer reagents are sodium acetate, sodium citrate, sodium phosphate, calcium acetate, calcium citrate, calcium phosphate, specifically sodium acetate.
Further object of the present invention is to provide process for the purification of Rivaroxaban comprising the steps of
I) dissolving rivaroxaban in a sulfolane
II) optionally adding antisolvent to the said solution
III) cooling the said solution
IV) Crystallization of rivaroxaban
The crystallization according to IV) is achieved by decreasing the temperature of Rivaroxaban crystallization mixture.
For the present invention preferred antisolvents are hexane, heptane, cyclohexane or water. More preferred antisolvent is water.
Detailed description of the invention:
Accordingly, present invention provides a process for the preparation of Rivaroxaban (I) comprising a step of reacting 4-[4-((S)-5-aminomethyl-2-Oxo-l,3-oxazolidine-3-yl]-phenyl-morpholin-3-onehydrochloride(VII) with 5-chlorothiphene-2-carbonylchloride (IV) in the

presence of buffer reagent and a solvent selected form the group of ketone, aromatic hydrocarbon, polar aprotic solvent, water or mixture thereof or mixture of two or more
solvents.
Examples of particularly preferred dipolar aprotic solvents are: sulfolane, N-methyl pyrollidine (NMP), l,3-Dimethyl-3,4,5,6-terahydro-2(1H)-pyrimidinone (DMPU), Hexamethylphosphoramide (HMPA), Dimethylformamide, water or mixture thereof or mixture of two or more solvents. Preferably, mixture of sulfolane and water.
For the present invention preferred solvents are: ketone such as methyl ethyl ketone, methyl isobutyl ketone or acetone or mixture thereof; aromatic hydrocarbon such as toluene, xylene; water or mixture of two or more solvents. Preferably, mixture of toluene, acetone and water
Examples of preferred buffer reagent used herein above includes but not limited to: citrate buffer, acetate buffer, phosphate buffer or mixture thereof.
More preferred buffer reagents are sodium acetate, sodium citrate, sodium phosphate, calcium acetate, calcium citrate or calcium phosphate, especially sodium acetate.
The present invention also provides process for the purification of Rivaroxaban comprising the steps of
I) dissolving Rivaroxaban in sulfolane
II) optionally adding antisolvent to the said solution
III) cooling the said solution
IV) crystallization of Rivaroxaban
For the present invention preferred antisolvents are hexane, heptanes, cyclohexane or water. More preferred antisolvent is water.

According to purification process of present invention, Rivaroxaban is heated up to 100-130 qC in sulfolane to obtained clear solution. Optionally water is added to the said solution at 100-130 °C. Reaction mixture is cooled to obtain crystals of Rivaroxaban.
Rivaroxaban obtained by the present invention having purity at least 99.0 area % determined by HPLC.
The following example illustrates the invention further. It should be understood however, that the invention is not confined to the specific limitations set forth in the individual example but rather to the scope of the appended claims.
Examples:
Process for the preparation of Rivaroxaban
3.10 g of 5-chlorothiophene-2-carboxylic acid is suspended in 25 ml Tetrahydrofuran at 25-30°C. At this temperature, 3.77 g Oxalyl chloride is added drop wise, followed by stirring at 25-30°C for 2 hours. After the reaction mixture is distilled under reduced pressure at 25-30°C, 12.5 ml toluene is added (approximate 30% strength solution of the acid chloride in Toluene).
5.0 g of 4-{4-[(55)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one hydrochloride is successively added to a solution of 25 ml Water, 20 ml Sulfolane and 3.75 g sodium acetate at 25-30°C, and 5-chlorothiophene-2-carbonyl chloride solution in Toluene is added at 10-20°C.The reaction mixture is then heated to 50-55°C for 8-10 hours. After cooling to 25-30°C, the precipitated reaction product is filtered off and washed with water and acetone.
Process for the purification of Rivaroxaban
The above solid from Example 1 is suspended in 20 ml Sulfolane, heated the reaction mixture at 120°C, and added drop wise 30 ml water at 105-110 ° C. After cooling to 25-30°C, the precipitated reaction product is filtered off and washed with water. Dried the solid. Yield 5 g., Melting point 232-233 °C.

Process for the purification of Rivaroxaban
The above solid from Example 1 is suspended in 20 ml Sulfolane, heated the reaction mixture at 120°C. After cooling to 25-30°C, the precipitated reaction product is filtered off. Dried the solid. Melting point 232-233 °C.

CLAIMS

with 5-chlorothiphene-2-carbonylchloride (IV),

1. A process for the preparation of Rivaroxaban (I) comprising a step of reacting 4-[4-((S)-5-aminomemyl-2-0xo-l,3-oxazoIidine-3-yl]-phenyl-morpholin-3-onehydrochloride(VII)
in the presence of buffer reagent and solvent selected form the group of ketone, polar aprotic solvent and water or mixture thereof.
2. The process according to claim 1, wherein the solvent is dipolar aprotic solvent or
mixture of dipolar aprotic solvent and water.
3. The process according to claim 1 where in the dipoar aprotic solvent is sulfolane, N-
methyl pyrollidine, l,3-Dimethyl-3,4,5,6-tetrahydro-2(lH)-pyrimidinone, (DMPU), Hexamethylphosphoramide (HMPA), Dimethylformamide (DMF), or mixture thereof
4. Process according to claim 1 where in the solvent is sulfolane or mixture of sulfolane
and water.
5. Process according to claim 1 where in the buffer reagent is citrate buffer, acetate buffer,
phosphate buffer or mixture thereof.

6. Process according to claim 3 where in the buffer reagent is sodium acetate, sodium
citrate, sodium phosphate, calcium acetate, calcium citrate or calcium phosphate.
7. Process according to claim 1 where in solvent is sulfolane/water mixture and the buffer
reagent is sodium acetate.
8. Process for the purification of rivaroxaban comprising the steps of
I) dissolving Rivaroxaban in sulfolane
II) optionally adding antisolvent to the said solution
IV) cooling the said solution
III) crystallization of Rivaroxaban.
9. Process according to claim 8 wherein antisolvent is hexane. hepatnae, cyclohexane or
water.
10. The process according to claim 8 wherein preferred antisolvent is water.