FORM 2
THE PATENTS ACT, 1970 (39 of 1970)
&
THE PATENTS RULES, 2003
Complete Specification
[See. Sections 10 and rule 13]
Title: A Method For The Preparation Of Rivaroxaban
Applicant: (a) INTAS Pharmaceuticals Limited
(b) Company Registered under Indian Company ACT
(c) 2nd Floor, Chinubhai Centre, Ashram Road, Ahmedabad 380009 Gujarat. India
The following specification particularly describes the invention and the manner in which it is to be performed:.

FIELD OF THE INVENTION
The invention also relates to novel intermediates of following structural formula
Present invention relates to preparation of Rivaroxaban of following structure


wherein R can be selected from substituted or unsubstituted aromatic or heterocyclic compounds.
The invention further relates to a process for preparation of novel intermediates of formula (II) and their use in preparation of rivaroxaban (I)
BACKGROUND OF THE INVENTION
Rivaroxaban (Ia), (5-chloro-N-{[5S)-2-oxo-3-[4-(3-oxo-morpholin-4-yl) phenyl] oxazolidin-5-yl]methyl}thiophene-2-carboxamide)


is an oral anti-coagulant. It is marketed as XARELTO, It is the first available orally active direct factor Xa inhibitor. Rivaroxaban can be used for different type of thrombo embolic diseases,
with 5-chlorothiophene-2-carboxylic acid of following formula (IV)
Rivaroxaban and process for its preparation are disclosed in US 7,576,111. The process disclosed in US 7.576,III comprises reacting oxazolidinone (IIIa)


or else with a corresponding carbonyl halide, or with a corresponding symmetric or mixed carboxylic anhydride. The reaction is carried out in an inert solvent, if appropriate in the presence of an activating or coupling agent and/or a base.
US 2007/0149522 reports a process for preparation of rivaroxaban which comprises reacting 5-chlorothiophene-2-carbonylchloride, 2(S)-3-amino-propane-l,2-diol and 4-(4-aminophenyl)-3-morpholinone.
US 7,598.378 disclosed a process for preparation of 4-(4-aminophenyl)-3-morpholinone by reacting 4-{4-nitropheny))-3-morpholinone with hydrogen in presence of a hydrogenation catalyst.

The process disclosed in US 7,351,823 involves reaction of 4-[4-[(5S)-5-(aminomethyl)-2-oxo-1,3-oxazolidin-3-yl]phenyl]rnorpholin-3-one hydrochloride with 5-chlorothiophene-2-carbonyl chloride in presence of inorganic base. WO 2007/039132 discloses amorphous, crystalline form II and solvates of rivaroxaban.
with oxazolidinone intermediate of formula (VI)
Reaction of 5-chlorothiophene-2-carboxamide of formula (V)


to obtain rivaroxaban either in (S) or (R) enantiomeric form is disclosed in US 7,816,355.
Since rivaroxaban constitutes an important therapeutic agent, additional and improved ways of preparing rivaroxaban either (R) or (S) enantiomer are of value to pharmaceutical science. Thus the present invention provides a process for preparation of rivaroxaban which is simple and commercially viable.
OBJECTS OF THE INVENTION
The main objective of the present invention is to provide a process For preparation of Rivaroxaban.

Another object of the invention is to provide novel intermediates of Rivaroxaban and their preparation.
SUMMARY OF THE INVENTION
The present invention provides a process for preparation of rivaroxaban of formula (I), which comprises reacting compound of formula (III)

wherein X represents an acid capable of forming salts, with a compound of general formula (III)

wherein R can be selected from substituted or unsubstituted aromatic or heterocyclic compound and the invention also provides novel intermediates of formula (II) and their preparation.
DETAILED DESCRIPTION
The process of the present invention comprises reacting oxazolidine derivative (HI) or its salts either in S or R enantiomeric form with a compound of general formula (II).

The compounds of formula (II) are active ester derivatives of 5-chloro-thiophene-2-carboxylic acid. These active ester derivatives can be selected from compounds prepared by reacting 5-chlorothiophene-2-carboxylic acid with hydroxyl group containing compounds. Preferably the active esters used in process of present invention are selected from pentafluorophenyl-5-chlorothiophene-2-carboxylate (VII), 4-chloro-2,3,5,6-tetrafluorophenyl-5-chlorothiophene-2-carboxyiate (VIII); 2,4,5-trich1oropheny1-5-ch1orothiophene-2-carboxylate (IX), 1 -hydroxypyrrolidine-2,5-dione-5-chlorothiophene-2-carboxylate (X); 4-nitrophenyl-5-chlorothiophene-2-carboxylate (XI); 3-hydroxy-1,2,3-benzotriazin-4-(3H)-one-5-chlorothiophene-2-carboxylate (XII) as depicted by following structural formula

Thus, in an embodiment the present invention provides a process to prepare above mentioned active ester derivatives of general formula (II).
The reaction for preparing the active ester of the present invention can be carried out in presence of solvent, coupling agent and optionally a base.

The solvent is selected from the group comprising of chlorinated hydrocarbon, aromatic hydrocarbon, ether, ketone, ester and mixture thereof. Specifically, the solvent is selected from the group comprising of dichloromethane, chloroform, dichloroethane, isobutanol acetate, ethyl acetate.
The coupling agent can be selected from carbodiimide for example N'N'
dicyclohexylcarbodiimide (DCC); 1,3-Diisopropylcarbodiimide; triazole for
example 1-hydroxybenzotriazole, or any coupling agent suitable for the process
such as (2-(endo-5-norbornene-2,3-dicarboxyiimide)-l ,1,3,3-tetramethyluronium
tetrafluoroborate (TNTU), 0-((Ethoxycarbonyi)cyanomethyleneamino)~N,N,N',N'-
tetramethyluronium BF4 (TOTU), 2-Succinimido-1,1,3,3-tetramethyluronium
tetrafluoroborate (TSTU), (2-(6-Chloro-1H-benzotriazole-l-yl)-l,l ,3,3-
tetramethylaminiumhexafluorophosphate (HCTU), Benzotriazole-1-yl-
oxytripyrrolidinophosphonium hexafluorophosphate (PyBOP)
Preferably carbodiimides are used for present process, more preferably dicyclohexylcarbodiimide.
The base can be selected from any organic or inorganic class of compound. Preferably pyridine, diethylaminepyridine, 4-methoxypyridine, potassium carbonate, sodium carbonate; more preferably dimethyl amino pyridine is used.
In an embodiment the process involves mixing the reactants in a solvent and adding coupling agent. The coupling agent can be added at any suitable temperature for example at ambient temperature or under cooling for example 0-15 °C.
The reaction may be carried out at suitable temperature, either under cooling or at ambient temperature. Although the reaction can be carried out under heating preferably it is carried out at 20-30 °C.

On completion of reaction the product of formula (II) can be recovered from the reaction mixture by conventional methods. The compounds (11) thus prepared can be directly used or can be purified before subsequent use. The purification can be carried out in any solvent used conventionally for recrystallization or purification of organic compounds or a mixture of solvent can also be used.
In a principal embodiment compound of general formula (II) is reacted with oxazolidone intermediate of formula (III) to obtain rivaroxaban.
This reaction is carried out in presence of solvent and a base. The base used in the process can be selected from organic or inorganic class of compound. Exemplary organic base include but not limited to triethyl amine, diethyl amine, tributylamine, tert-butyl amine, diisopropylethylamine and mixture thereof. Preferably triethyl amine is used. The inorganic base used in the present process can be selected from potassium carbonate, sodium carbonate, sodium hydroxide, sodium bicarbonate, potassium bicarbonate and mixture thereof.
Exemplary solvent used in the above process include but not limited to water, alcohol, ketone, nitrile, hydrocarbon, ester, ether, amide, chlorinated hydrocarbon, polar aprotic solvent and mixture thereof. Water, isopropyl alcohol, methanol, ethanol, butanol, chloroform, dichloromethane. acetonitrile, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, methyl acetate, toluene, diisopropyl ether, petroleum ether, tetrahydrofuran, cyclohexane, hexane or a mixture can be used.
The reaction can be carried out at a temperature of about ambient temperature to the reflux temperature of the solvent used, preferably the reaction is carried out at about 30-65 °C.

The product (1) is isolated by allowing it to crystallize spontaneously or is isolated forcibly. In one embodiment the crystallisation is carried out by stirring the reaction mixture at a temperature of about 20-25 °C for at least 3 hrs, specifically for about 2 hrs.
The recovery of rivaroxaban can be affected by conventional techniques such as filtration, centrifugation, or decantation. If desired rivaroxaban thus prepared can be further purified / recrystallized by any conventionally known process of purification / recrystallization.
The compound of formula III or IIIa used to prepare rivaroxaban can be prepared by processes known in. the art or according to the process of following scheme:


In the process of present disclosure 4-(4-aminophenyl)-morpholin-3-one (XIII) is reacted with 2-[(2S)-oxiran-2-ylmethyl]-1H-isoindole-1,3(2H)-dione (XIV) in presence of isopropanol and water. In the next step 2-[(2R-)-2-hydroxy-3-{[4-(3-oxomorpholin-4-yl)phenyl]amino;propyl]-1H-isoindole-1,3(2H)-dione (XV) is reacted in presence of coupling agent like carbonyldiimidazole and solvent like chlorobenzene or isopropanol to obtain 2-({(5S)-2-oxo-3-[4-(3-oxomorphotin-4-yl)phenyl]-l,3-oxazolidin-5-yl}methyl)-1H-isoindole-l,3(2H)-dione of formula (XVI), In the next step compound of formula (XVI) is reacted with monomethyl amine in presence of isopropanol and aqueous hydrochloride to obtain compound of formula (III),
The following examples are illustrative of the invention but not limitative of the scope thereof:
Examples:
Example I- Preparation of pentafluorophenyl-5-chlorothiophene-2-carboxylate (VII)
To a stirred solution of 5-chlorothiophene-2-carboxylic acid (5.0g) in ethyl acetate (50 ml), pentafluorophenol (6.6g) and dimethyl amino pyridine (0.75g) were added while maintaining the temperature at 25-30 °C. The reaction mixture was cooled to 0-5 °C and a solution of N,N'-dicyclohexylcarbodiimide (1.6%) in 25 ml of ethyl acetate was added to it. The resulting mixture was stirred at 25-30 °C for 2 hours. After completion of reaction the reaction mixture was filtered and the filtrate was distilled under vacuum to afford 10.2g of title compound.
Example 2- Preparation of Rivaroxaban (I)

A mixture of 4-{4-(5S)-5-(aminomehlyl)-2-oxo-1,3-oxazolidine-3-yl]phenyl} morpholin-3-one hydrochloride (3.0g), triethyl amine (1.1g), dimethylformamide (30ml) was heated to 55-60 °C for 30 minutes. Later, pentafluorophenyl-5-chlorothiophene-2-carboxylate (6.0g) was added to the reaction mixture and further stirred for 4-5 hours at the same temperature. After completion of reaction 70 ml water was added to the reaction mixture; the reaction mixture was cooled to 25-30 °C; filtered and the solid thus obtained was dried under vacuum to obtain 3.2g of title compound.
Example 3- Preparation of 4-nitrophenyl-5-chlorothophene-2-carboxylafe
5-chlorothiophene-2-carboxylic acid (700.0g), 4-nitrophenol (628.8gm) and dichloromethane (3.5lit) were mixed and the resultant reaction mixture was cooled to 10-20 oC, to this a solution of dicyclohexylcarbodimide (1066g) in dichluromethane (1050) was added and the temperature was raised to 30-35 °C. The reaction mixture is stirred at the same for 2-3 hours after completion of reaction the title product was isolated by distilling off the solvent; the product thus obtained was treated with hexane and dried to obtain 1224 g of title compound.
1H NMR (400 MHz, CDCI3) 6 8.20 (d,.J= 9.2 Hz, 2H, Ar). 7.76 (d, .J = 4.0 Hz, 1H. AR), 7.38 (d, J= 9.2 Hz, 2H, Ar), 7.00 (d, J= 4.0 Hz, 1H, Ar).
Mass 306.31 (M+23)
Example 4- Preparation of Rivaroxaban (I)
4-{4-[(5S)-5-(aminomethyl)-2-oxo-1.3-oxazolidine-3-yl]phenyl}morpholin-3-one hydrochloride (850g), triethyl amine (288.6g) and dimethylformamide (4.2501) were mixed and the temperature of the resultant reaction mixture was raised to 65-70°C . To this 4-nitrophenyl-5-chlorothiophene-2-carboxylate (1109.40g) was added and the reaction mixture was stirred for 3-4 hours, followed by addition of isopropyl

alcohol (12.751). Reaction mixture was cooled to 5-10 °C; the product thus precipitated was separated by filtration and dried to obtain 1127g of title compound.

We claim:
1. A process for preparation of rivaroxaban of formula (I) comprising:

reacting a compound of formula (III),

wherein X represents an acid capable of forming salts; with a compound of formula (II)

wherein R can be selected from substituted or unsubstituted aromatic or heterocyclic compounds.
2. A process as claimed in claim 1, wherein the reaction is carried out in presence of base and solvent.

3. A process as claimed in claim 2. wherein the solvent can be selected form alkanol, ketone, hydrocarbon, ester, ether, amide, chlorinated hydrocarbon, polar aprotic solvent, water, or mixture thereof.
4. A process as claimed in claim 2, wherein the base is selected from organic or inorganic base.
5. A compound of formula II

wherein R can be selected from substituted or unsubstituted aromatic or heterocyclic compounds,
6. Use of compound of II in process of preparing rivaroxaban of formula (I).
7. A process to prepare compound of formula II comprising reacting 5-chlorothiophene-2-carboxylic acid with compound containing hydroxy group.

8. A process as claimed in claim 7 wherein hydroxy group containing compound is selected from pentafluorophenol, 4-chloro-2,3,5,6-tetrafluorophenol, 2,4,5-trichloro phenol. 4-nitrophenol, 1-hydroxypyrrolidme-2,5-dione, 3-hydroxy-1,2,3-benzotriazine-4 (3H)-one.