FIELD OF 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-thiophenecarboxamide of formula I by sequential nitration and reduction of 4-phenyl-3-morpholinone with reducing agent in water or in an organic solvent or in mixtures thereof and its further conversion to Rivaroxaban.

BACKGROUND OF THE INVENTION

Thromboembolic disorders are the most frequent cause of morbidity and mortality in most industrialized countries. The first well known anticoagulant is heparin which is administered parenterally and subcutaneously. By virtue of more favourable pharmacokinetic properties, low molecular weight, heparin is used widely. Heparin is orally ineffective and has very short half life. Since heparin inhibits several factors of the blood coagulation cascade simultaneously, its action is unselective. There is very high risk of bleeding, where in particular cerebral bleeding or bleeding in the gastrointestinal tract may clinically complicate the recovery of patients.

Recently, a new therapeutic approach for treatment of Thromboembolic disorders has been described. The aim of novel therapeutic approach is the inhibition of factor Xa. In accordance with the central role which factor Xa plays in the blood coagulation cascade, factor Xa is the most important target for anticoagulant therapeutic option.

The present invention relates to the synthesis of Rivaroxaban of Formula I, an inhibitor of Factor Xa of blood coagulation cascade.

The proprietary name of this compound I is Rivaroxaban and is used as an inhibitor of factor Xa and used as agent for prophylaxis and / or treatment of thromboembolic disorders, especially myocardial infraction, angina petoris, reocclussions and restenores of the angioplasty. It is used for pulmonary thrombolisys and deep venous thromboses.

It surprisingly found that combination of Oxazolidinones with acetyl alicyclic acid and ADP receptor antagonists have interesting properties and more suitable for treatment of Thromboembolic disorders than active individual active agents.

The first synthesis of Rivaroxaban was disclosed in WO AO1/047919 as depicted in
Scheme I.

Scheme l:

However, this process exhibits various disadvantages mainly in the synthesis of V which is very expensive because of usage of p-fluoronitrobenzene as depicted in Scheme la.

US 2005/0182055 Al describes preparation of Rivaroxaban of compound I, by reacting 4-[4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl-morpholin-3-one HCl with 5-chlorothiophene-2-carbonyl chloride, in presence of organic solvent, water and inorganic base.

All the above synthetic processes makes use of morpholinone of the formula V shown in Scheme II. Prior art processes for the preparation of the same are given below for reference. In all these synthetic methods following sequence shown in Scheme III is adopted.

Scheme III.

WO2009/023233 describes catalytic hydrogenation using very high catalyst quantity (20% Pd/C based on nitro compound).

Heterocycles, Vol. 74, p. 437-445 (2007) and WO2005/26135 describes catalytic hydrogenation processes using very high hydrogen pressures.

EP1479675 describes reduction process using SnCl2 dihydrate in a mixture of ethanol and ethyl acetate.

WO2006/63293 or US 2006/160790 describes a different strategy for the synthesis of formula V using 4-amino-iodobenzene as shown in scheme IV. Scheme IV.

Main disadvantage in the above processes is the yield of the final product is very low, and purification is difficult.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide an improved process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide (I) which is simple, yielding high purity products and industrially applicable.

Yet another main objective is to generate a process for the preparation of 4-(4-aminophenyl)-3-morpholinone (V) using reducing agent which is ecofriendly, commercially viable and easily adoptable in plant scale.

SUMMARY OF THE INVENTION

A process for the preparation of 5-chIoro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-
morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide of Formula I,
which comprises:

a) nitration of 4-phenyl-3-morpholinone of formula III,

with nitrating agent to give 4-(4-nitrophenyl)-3-morpholinone of formula IV;

b) reduction of compound of formula IV with sulphur containing reducing agent in water or in an organic solvent or a mixture thereof at a temperature ranging 20-150°C, preferably in the range of 90-100°C to give 4-(4-aminophenyl)-3-morpholinone of formula V;

c) reacting [(2S)-2-oxiranylmethyl]-1 H-isoindole-1,3(2H)-dione of formula VI,

with compound of formula V obtained as per step 1 (b), to give 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-lH-isoindole-l,3-(2H)-dione of formula VII;
d) reacting compound of formula VII with carbonylating reagent optionally in presence of acid trapping agent to give 2-({5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl- lH-isoindole-1,3-(2H)dione of formula VIII;

e) removal of phthalimido protecting group of formula VIII to give 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one of formula IX;

f) reacting compound of formula IX with 5-chlorothiophene-2-carboxylic acid of formula X, in presence of amide forming reagent (OR) reacting compound of formula IX with activated 5-chlorothiophene-2-carboxylic acid derivatives of formula XI, where in X= halo, imidazolyl, mixed anhydride in an organic solvent, optionally in presence of acid trapping agent to afford Rivaroxaban of Formula I.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to the process for the preparation of Rivaroxaban of formula I, which involves the reduction of 4-(4-nitrophenyI)-3-morpholinone compound of formula IV to 4-(4-aminophenyl)-3-morpholinone compound of formula V using reducing agent selected from derivatives of sulphur in water or in an organic solvent or mixtures thereof at a particular temperature.

The reducing agent is selected from derivatives of sulphur like sodium sulfite, sodium sulphide, sodium dithionite, sodium metabisulfite etc., preferably sodium dithionite, a cheap alternate to the costly catalysts used in the catalytic reduction process of nitro compound. The reduction is carried out in water or an organic solvent or a mixture of water and an organic solvent, wherein an organic solvent selected from alcohol such as methanol, IPA, ethanol, butanol or ether such as dioxane, THF or dipolar aprotic solvent such as DMF, DMA, DMSO, NMP, sulfolane.

In the reduction step, the 4-(4-nitrophenyl)-3-morpholinone compound of formula IV is suspended in water or in a mixture of organic solvent and water at 20-150°C, more preferably 20-50°C and solution is maintained at 50-150°C, preferably 90-100°C after the addition of reducing agent. After completion of the reaction, which takes 4-48 hours, preferably 24 hours and the reaction mass is cooled to 20-3 5°C, more preferably to about 25°C and basified with an inorganic base and the product is isolated by extracting the reaction mass with an organic solvent or by direct filtration.

The inorganic bases for basification of reaction can be selected from alkali earth metal or alkaline earth metal hydroxides, carbonates, bicarbonates such as sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate etc and the like preferably NaOH and the product extracted with an organic solvent like IPE, MTBE, MDC, ECDC, Toluene, Xylene, Ethyl acetate preferably Ethyl acetate. The product is obtained after removal of organic solvent.

In the present embodiment the first step of the process involves the preparation of N-phenylethanolamine compound of formula II by the alkylation of aniline with chloroethanol which further undergo acylation followed by cyclization with a-halo acetyl halide in presence of a base such as sodium hydroxide, potassium hydroxide, magnesium hydroxide, calcium hydroxide and so on, preferably sodium hydroxide to form 4-phenyl-3-morpholinone compound of formula III as depicted in Scheme A. Scheme A.

Nitration of 4-phenyl-3-morphoUnone compound (III) with nitrating agents to form 4-(4-nitrophenyl)-3-morpholinone compound of formula IV in presence of acid at a low temperature. Nitration can be carried out with Cone. HNO3, Fuming nitric acid, preferably. Cone. HNO3 in presence of acetic acid or Cone. H2SO4 or mixtures thereof 4-(4-Nitrophenyl)-3-morpholinone compound (IV) is reduced in presence of sulphur containing reducing agent to give 4-(4-aminophenyl)-3-morpholinone compound of formula (V) as described in the description earlier.

The resulting 4-(4-aminophenyl)-3-morpholinone compound of formula V is reacted with 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,3-(2H)dione (VI) in presence of base to give 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-lH-isoindole-l,3-(2H)-dione (VII). Oxazolidinone ring is formed between 5-NH2 and 3- OH of formula VII with carbonylating reagent like CDI, phosgene, diphosgene, triphosgene etc., optionally in presence of acid trapping agent and solvent.

Deprotection of phthalimido group of resulting compound 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl }methyl-1 H-isoindole-1,3-(2H)dione (VIII) was carried out with hydrazine hydrates, N-alkylamines such as N-methylamine, N-ethylamine, preferably N-methylamine to form 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one (IX). The amino group of compound of formula IX is acylated with 5-chlorothiophene-2-carbonylchloride (X) in dichloromethane optionally in presence of acid trapping agent selected from triethylamine, pyridine, NaaCOs, NaHCOs, preferably triethylamine to afford Rivaroxaban.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

EXPERIMENTS:

Experiment I: Preparation of N-phenylethanolamine (II) Example 1.

Aniline 20 ml (0.215 mol) and chloroethanol 5.2 ml (0.3 equivalents) were mixed and the mixture was refluxed at the temperature of 110°C for 1-2 hours and cool the reaction mixture at 50°C. Unreacted. aniline was distilled out from the reaction mixture by keeping external temperature below 50''C under vacuum (5 mm) to afford N-phenylethanolamine (15 ml).

Example 2.

In a 1 It flask 100 g (1.075 mol) of Aniline and 26 g (0.3 equivalents) of chloroethanol mixed at room temperature and refluxed at 100-110°C for 1 h 30 minutes then cooled to 50°C and unreacted Aniline was distilled out as mentioned in Example 1 to afford N-phenylethanolamine (80 g).

Experiment II: Preparation of 4-phenyl-3-morpholinone (III)

Example 1.

N-phenylethanolamine (16.5 g, 0.12 mol) was dissolved at room temperature in 150 ml of ethanol and subsequently admixed with 5 ml of water with stirring. The solution is heated to 38°C. Chloroacetyl chloride (4 g, 3.0 equivalents) and NaOH solution (45%, 6.5 g) are then added simultaneously at an internal temperature of 38-43°C within 1 hr 30 minutes. The basic mixture is stirred at this pH for 15 minutes then cooled to 2°C and stirred at the same temperature for 30 minutes. The precipitated product is filtered and washed with water. The moist product is dried to constant mass at 50°C under reduced pressure to give 4-phenyl-3-morpholinone (17g)

Example 2.

N-phenylethanolamine (10 ml, 80 mmol) was charged into 250 ml flask containing ethanol followed by addition of aqueous sodium hydroxide solution (50 ml, ION NaOH). The solution was heated to 40-45°C and treated with chloroacetylchloride (19.08 ml, 240 mmol). Additional lot of sodium hydroxide solution was simultaneously added to the stirring solution so that pH was maintained between 12 and 12.5. After addition was completed, the solution was cooled to 0°C and stirred for 1 h. The solids were collected and washed with water (2x70ml cold water). The solids were dried at 50°C at 0.2mm Hg for 36h to afford 4-phenyl morpholin-3-one (8.83 g). 'HNMR (400 MHz, CDCb-d) 3.75-3.80 (m, 2H) 4.02-4.06 (m, 2H) 4.35 (s, 2H) 7.27-7.36 ((m, 3H) 7.39-7.46 (m, 2H).

Experiment III: Preparation of 4-(4-nitrophenyl)-3-morpholinone (IV)

4-phenyl-3-morpholinone (17.7 g) was introduced portionwise into a flask containing Cone. H2SO4 (72.8 g). The resulting mixture is heated to 25°C and stirred at the same temperature for 30 minutes. The mixture is cooled to -5°C ±2°C and Cone. HNO3 (11 g, 65%, 1.05 equivalents) below 10°C was added slowly while maintaining internal temperature below 0-5°C. The reaction was stirred for 1 hr at the same temperature and poured into cold water (100 ml). The product was extracted with ethylacetate (200 ml). Removal of solvent gave 4-(4-nitrophenyl)-morpholin-3-one (15 g).

Experiment IV: Preparation of 4-(4-aminophenyl)-3-morphoIinone (V)

Example 1.

4-(4-nitrophenyl)-3-morpholinone (5 g, 0.023 mol) was dissolved in 20 ml of ethanol at room temperature and subsequently admixed with 20 ml of water and the resulting mixture is heated to 80°C and then sodium dithionite Na2S204 (12 g, 3 mol, 6 equivalent portions) was added in about 4 hours and the resulting mixture was refluxed at 90-100°C for 24 hours then cooled to room temperature. Ethanol was distilled out then resulting mass is basified with aqueous sodium bicarbonate and extracted with ethylacetate (2x60 ml). Removal of solvent resulted 4-(4-aminophenyl)-3-morpholinone (2 g, Yield: 47%) as white solid. ^H-NMR (300 MHz, CDCI3): 3.67 (m, 2H, CH2CH2), 3.99 (m, 2H, CH2CH2), 4.27 (s, 2H, CH2CO), 6.68 (d, 2H, ^J=8.71 Hz, CHCH), 7.03 (d, 2H, ^J=8.71 Hz, CHCH)

Example 2.

4-(4-nitrophenyl)-3-morpholinone (10 g, 0.045 mol) was charged into flask containing Isopropyl alcohol (40 ml) and water (60 ml) and then heated to 80°C. Sodium dithionite (24 g, 3.0 equivalents) was added in about 6 hr at the same temperature, then the reaction mixture was refluxed at 100°C for 24 hours. After completion of the reaction, Isopropyl alcohol was distilled out and the reaction mass was basified with sodium bicarbonate and extracted with ethylacetate and the solvent was removed by evaporation to afford 4-(4-aminophenyl)-morpholin-3-one (4.0 g. Yield: 45%).

Example 3.

5 g of dried 4-(4-nitrophenyl)-morpholin-3-one was placed in a glass reactor containing water (50 ml) at room temperature and the temperature was raised to 80°C. Sodium dithionite (12 g, 4.0 equivalents) were added to the above mass and heated to 100°C for 12 hours and the reaction was monitored by TLC. After the reaction complies, reaction mass was basified with sodium bicarbonate solution and then extracted with ethylacetate and the solvent was evaporated under reduced pressure yields 4-(4-aminophenyl)-3-morpholinone (2.0 g. Yield: 48%).

Example 4.
4-(4-nitrophenyl)-3-morpholinone (3 g, 0.014 mol) is taken in a round bottomed flask containing DMF (15 ml) and water (15 ml) at room temperature then heated to 80°C. At the same temperature Sodium dithionite Na2S204 (7 g, 3.0 equivalents) was added in about 3 hours then the reaction mixture was refluxed at 120°C for 4 hours and the reaction was monitored by TLC. After the completion of the reaction, the reaction mass was allowed to room temperature, then the mass was basified with NaHCOs and extracted with ethylacetate (2x30 ml) and the solvent was distilled off in vacuo yields 4-(4-aminophenyl)-3-morpholinone (1.3 g. Yield: 50%).

Example 5.

4-(4-nitrophenyl)-3-morpholinone (3 g, 0.014 mol) was charged into a flask containing DMSO (15 ml) and water (15 ml) at room temperature then heated to 80°C. At the same temperature Sodium dithionite Na2S204 (7 g, 3.0 equivalents) was added in about 3 hours then the reaction mixture was refluxed at 120°C for 4 hours, then the reaction was monitored by TLC. After the reaction complies, the reaction mass was basified with NaHCOs and extracted with ethylacetate (2x30 ml) and the solvent was removed by the evaporation to afford 4-(4-aminophenyl)-3-morpholinone (1.7 g. Yield: 65%).

Example 6.

5 g of dried 4-(4-nitrophenyl)-morpholin-3-one was placed in a flask containing methanol (20 ml) and water (20 ml) at room temperature and the temperature was raised to 80°C. Sodium dithionite (12 g, 3.0 equivalents) were added to the above mass and refluxed at 100°C for 10 hours and the progress of the reaction was monitored by TLC. After completion of the reaction, the reaction mass was cooled to room temperature. Methanol was distilled out and the resulting mass was basified with sodium bicarbonate solution and then extracted with ethylacetate (2x60 ml), removal of solvent yields 4-(4-aminophenyl)-3-morpholinone (2.3 g. Yield: 55%).

Example 7.

4-(4-nitrophenyl)-3-morpholinone (5 g, 0.023 mol) dissolved at room temperature in 20 ml of ethylene glycol and subsequently admixed with 20 ml of water and the resulting mixture is heated to 80°C and then sodium dithionite Na2S204 (12 g, 3 mol, 6 equivalent portions) were added in about 4 hours and the resulting mixture was refluxed at 90-100°C for 12 hours, then cooled to room temperature. Ethylene glycol was distilled out from the reaction mass, then the resulting mass was basified with sodium bicarbonate solution and extracted with ethylacetate (2x60 ml) and the solvent was removed by evaporation to afford 4-(4-aminophenyl)-3-morpholinone (1.12 g, Yield: 45%).

Example 8.

4-(4-nitrophenyl)-3-morpholinone (3 g, 0.0135 mol) dissolved at room temperature in 20 ml of ethylene glycol. The resulting mixture is heated to 80°C and then sodium dithionite Na2S204 (7 g, 3 mol, 5 equivalent portions) were added in about 2 hours and the resulting mixture was refluxed at 90-100°C for 12 hours, then cooled to room temperature. The resulting mass was basified with sodium bicarbonate solution and extracted with ethylacetate (2x50 ml) and the solvent was removed by evaporation to afford 4-(4-aminophenyl)-3-morpholinone (0.98 g. Yield: 35%).

Example 9.

4-(4-nitrophenyl)-3-morpholinone (3 g, 0.0135 mol) dissolved at room temperature in 20 ml of DMSO. The resulting mixture is heated to 80°C and then sodium dithionite Na2S204 (7 g, 3 mol, 5 equivalent portions) were added in about 2 hours and the resulting mixture was refluxed at 90-100°C for 20 hours, then cooled to room temperature. The resulting mass was basified with sodium bicarbonate solution and extracted with ethylacetate (2x50 ml) and the solvent was removed by evaporation to afford 4-(4-aminophenyl)-3-morpholinone (0.62 g, Yield: 25%).

Example 10.

4-(4-nitrophenyl)-3-morpholinone (3 g, 0.0135 mol) dissolved at room temperature in 20 ml of DMSO. The resulting mixture is heated to 80°C and then sodium sulphite Na2S03 (5 g, 3 mol, 4 equivalent portions) were added in about 2 hours and the resulting mixture was refluxed at 100-120°C for 20 hours, then cooled to room temperature. The resulting mass was basified with sodium bicarbonate solution and extracted with ethylacetate (2x50 ml), the solvent was removed and purified by column chromatography to afford 4-(4-aminophenyl)-3-morpholinone (0.38 g. Yield: 15%).

Example 11.

4-(4-nitrophenyl)-3-morpholinone (3 g, 0.0135 mol) dissolved at room temperature in 20 ml of ethylene glycol. The resulting mixture is heated to 80°C and then sodium sulphite Na2S03 (5 g, 3 mol, 4 equivalent portions) were added in about 2 hours and the resulting mixture was refluxed at 100-120°C for 20 hours, then cooled to room temperature. The resulting mass was basified with sodium bicarbonate solution and extracted with ethylacetate (2x50 ml), the solvent was removed and purified by column chromatography to afford 4-(4-aminophenyl)-3-morpholinone (0.5 g. Yield: 20%).

Experiment V: Preparation of 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morphoIinyl)phenyl]amino}propyl)-lH-isoindole-l,3-(2H)dione(VII)

2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,3-(2H)dione (VI) (5 g, 0.025 mol) and 4-(4-aminophenyl)-3-morpholinone (V) (5.2 g, 0.025 mol) are mixed at 20°C with water (28 ml) and ethanol (60 ml), and the suspension is heated to 60°C and the resulting solution is stirred for 24 hours. The progress of the reaction monitored by TLC. After completion of the reaction, the reaction mixture was cooled to room temperature. The precipitated reaction product was filtered and washed with ethanol

and then dried to give 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-
morpholinyl)phenyl]amino}propyl)-lH-isoindole-l,3-(2H)dione(6.48g).

Experiment VI: Preparation of 2-({(5S)-2-oxo-3-[4-(3-oxo-4-
niorpholinyl)phenyl]-l,3-oxazolidin-5-yI}methyl-lH-isoindole-l,3(2H)dione (VIII)

2-((2R)-2-hydroxy-3-{ [4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-1 H-isoindole-l,3-(2H)-dione (VII) (6 g, 0.015 mol) was suspended in 50 ml of dichloromethane at room temperature. Triethylamine (6.5 ml, 0.045 mol, 3 equivalents) was added and the mixture was stirred for 30 min and then triphosgene (3.6 g, 0.012 mol, 0.3 equivalents) was added, the reaction mixture was stirred for 24h at 20-30°C. After completion of the reaction, triphosgene was quenched with sodium bicarbonate solution and was extracted with dichloromethane (200 ml) and the solvent was distilled off in vacuo yields 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl-IH-isoindole-l,3(2H)dione (3.5 g).

'HNMR (DMS0-d6, 200 MHz): 7.98-7.80 (m, 4H), 7.53 (d, J=9.1 Hz, 2H), 7.40 (d, J-9.1 Hz, 2H), 5.04-4.87 (m, IH), 4.22 (t, J=9.1 Hz, IH), 4.19 (s, 2H), 4.04-3.84 (m, 5H), 3.71 (dd, J-5.4 Hz, 4.6 Hz, 2H)

Experiment VII: Preparation of 4-{4-[(5S)-5-(aminomethyI)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one(IX).

2-( {(5S)-2-oxo-3 -[4-(3-oxo-4-morpholiny l)phenyl] -1,3-oxazolidin-5 -yl} methyl-1H-isoindole-l,3(2H)dione (VIII) (5 g, 0.012 mol) was suspended in 30 ml of ethanol at 22°C and methylamine solution (15 ml, 40% strength in water) was added to the reaction mixture and was heated to 60-65°C. The resulting solution was stirred at the same temperature for 2h. After cooling to 55°C a total of 8.6 g of Hydrochloric acid solution (20% strength in water) was added until the pH is 2.7 after which product started to crystallize. After cooling the reaction mass to 20°C, the precipitated product is filtered off with suction, washed with methanol and dried to give 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one (3.21 g) as hydrochloride salt.

'HNMR (DMS0-d6, 300 MHz): 7.59 (d, J=9.1 Hz, 2H), 7.40 (d, J=9.1 Hz, 2H), 4.67-4.57 (m, IH), 4.19 (s, 2H), 4.08 (t, J=8.9 Hz, IH), 3.97 (dd, J=5.3 Hz, 3.7 Hz. 2H), 3.87 (dd, J=8.9 Hz, 6.4 Hz, IH), 3.71 (dd, J=5.3 Hz, 3.7 Hz, 2H), 2.90-2.76 (m, 2H).

Experiment VIII: Preparation of 5-cliioro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-niorpholinyl)phenyl]-l,3-oxazoIidin-5-yl}methyl)-2-thiophenecarboxamide (I) (Rivaroxaban)

Example 1.

4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one (IX) (3 g, 0.018 mol) was dissolved in 20 ml of dichloromethane, then triethylamine (4.5 ml, 0.03 mol) was added, the mixture was stirred for 15 min. To this solution 5-chlorothiophene-2-carbonyl chloride (X) (2.24 g, 0.012 mol) was added at 0°C and the resulting mixture was allowed to warm to room temperature for 16 hours. The progress of the reaction was monitored by TLC. After completion of the reaction, reaction mixture was poured into saturated aqueous sodium bicarbonate (100 ml) and extracted with ethyl acetate (2x200 ml). The combined organic layers were washed with brine (200 ml), then dried over sodium sulphate. The solvent was concentrated in vacuo yields 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide (1.8 g).

'HNMR (DMS0-d6, 200 MHz): 8.98 (t, J=5.8 Hz, IH), 7.70 (d, J=4.1 Hz, IH), 7.56 (d, J=9.0 Hz, 2H), 7.41 (d, J=9.0 Hz, 2H), 7.20 (d, J=4.1 Hz, IH), 4.93-4.75 (m, IH), 4.19 (s, 2H), 4.02-3.91 (m, 2H), 3.84 (dd, J=9.2 Hz, 6.1 Hz, IH), 3.76-3.66 (m, 2H), 3.66-3.54 (m, 2H).

Example 2.

5-chlorothiophene-2-carboxylic acid (2 g, 0.010 mol) was dissolved in 15 ml of DCM, triethylamine (3.2 g, 0.013 mol) was added and the reaction mixture was stirred for 15 min. Ethylchloroformate (1.4 g, 0.013 mol) was added at room temperature and the reaction mixture was stirred for 30 min. 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one (IX) (3.2 g, 0.011 mol) was added and the resulting mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC, after completion of the reaction, the reaction mixture was decomposed with water and extracted with ethylacetate (2x100 ml) and washed with brine solution and solvent was concentrated in vacuo to yield 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide (2.2 g).

Example 3.

5-chlorothiophene-2-carboxylic acid (2 g, 0.010 mol) was dissolved in 15 ml of DCM, DCC (2.7 g, 0.013 mol) and catalytic amount of DMAP were added and the reaction mixture was stirred for 30 min. 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one (IX) (3.2 g, 0.011 mol) was added and the resulting mixture was stirred at room temperature for 12 hours. The progress of the reaction was monitored by TLC, after completion of the reaction, the product was extracted with ethylacetate (2x100 ml) after quenching the reaction mass with water. The solvent was concentrated in vacuum and purified by column chromatography to yield 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide (2.3 g).

We Claim:
1. A process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide of Formula I,
which comprises:

a) nitration of 4-phenyl-3-morpholinone of formula III,

with nitrating agent to give 4-(4-nitrophenyl)-3-morpholinone of formula IV;

b) reduction of compound of formula IV with sulphur containing reducing agent in water or in an organic solvent or mixtures thereof at a temperature ranging 20-150°C, preferably in the range of 90-100°C to give 4-(4-aminophenyl)-3-morpholinone of formula V;

c) reacting [(2S)-2-oxiranylmethyl]-1 H-isoindole-1,3(2H)-dione of formula VI,
with compound of formula V obtained as per step 1 (b), to give 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino}propyl)-lH-isoindole-l,3-(2H)-dione of formula (VII);

d) reacting compound of formula VII with carbonylating reagent optionally in presence of acid trapping agent to give 2-({5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl-lH-isoindole-l,3-(2H)dione of formula VIII;

e) removal of phthalimido protecting group of formula VIII to give 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one of formula IX;

g) reacting compound of formula IX with 5-chlorothiophene-2-carboxylic acid of formula X,

in presence of amide forming reagent (OR) reacting compound of formula IX with activated 5-chlorothiophene-2-carboxylic acid derivatives of formula XI,

where in X= halo, imidazolyl, mixed anhydride

in an organic solvent, optionally in presence of acid trapping agent to afford Rivaroxaban of Formula I.

2. According to the process claimed in claim 1 (b), sulphur containing reducing agent is selected from derivatives of sulphur, like sodium sulfite, sodium sulphide, sodium dithionite, sodium metabisulfite etc., preferably sodium dithionite.

3. According to the process claimed in claim 1 (b), organic solvent is selected from alcohol such as methanol, IPA, ethanol, butanol or ether such as dioxane or THF or dipolar aprotic solvent such as DMF, DMA, DMSO, NMP, sulfolane, preferably DMSO.

4. According to the process claimed in claim 1 (b), reduction is carried out at a temperature ranging from 20-150 °C, preferably 90-100 °C.
5. According to the process claimed in claim 1 (b), wherein the reaction time takes between 4-48 hours, preferably 24 hours.

6. According to the process in claim 1(d), carbonylating agent is selected from CDI, phosgene, diphosgene, triphosgene etc., preferably triphosgene.

7. According to the process in claim 1 (f), organic solvent is selected from THF, DCM, toluene etc., preferably DCM.

8. According to the process in claim 1 (f), amide forming reagent is selected from Dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-(N',N'-dimethylamino)propyl carbodiimide (EDC) etc., preferably DCC.

9. According to the process in claim 1 (f), acid trapping agent is selected from triethylamine, pyridine, Na2C03, NaHCOs, preferably triethylamine.