Field of Invention :

The present invention relates to an improved process for the preparation of Rivaroxaban, which is chemically 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazoldin-5-yl} methyl) -2-thiophenecarboxamide,

Background of the Invention :

Rivaroxaban is chemically 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazoIdin-5-yl}methyl)-2-thiophenecarboxamide, having the structure shown in Formula I:
Rivaroxaban inhibits the clotting factor Xa and is useful in treating thromboembolic disorders. It is marketed by Bayer under the brand name Xarelto.
US patent 7,157,456, assigned to Bayer, describes a process for the preparation of Rivaroxaban, where4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazoIidin-3-yl]phenyl}-morphoIin-3-one(II) was reacted with 5-chlorothiophene-2-carbonyl chloride (III) in the presence of pyridine at 0° C under argon blanket (Scheme 1).

In another patent, US 7,351,823, Bayer modified the Scheme 1, where instead of the free base, hydrochloride salt of (II) was reacted with (III) in the presence of an inorganic base, preferably sodium carbonate.

The main drawback of the processes described in the prior art is the use of the base for the condensation of (II) with (III). The reactant (III) is highly reactive and undergoes degradation in the presence of a strong base. For example, (III) can react with a base such as sodium carbonate, especially in the presence of moisture, to give the corresponding acid or its salt.On the other hand the "823" patent process uses hydrochloride salt, requiring even more quantity of base, which adds to the problem. The process also requires pyridine as medium for the reaction. Use of pyridine on large scale is not desirable because of its unpleasant odor and difficulty in removing it subsequently. Thus there is a need for an improved process.

Summary of the Invention :
The present invention describes a novel process for the preparation of rivaroxaban by reacting 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}-morpholin-3-one (II) or its hydrochloride with 5-chlorothiophene-2-carbonyl chloride (III) in the presence of a non-basic acid scavenger. Epoxide derivatives such as epoxybutane, epichlorohydrin and propylene oxide are found to be excellent non-basic acid scavengers in eliminating the hydrogen chloride liberated during the reaction. Since the reaction is carried in the absence of a base, the stability of the acid chloride (III) is increased and its degradation is prevented. Furthermore, the epoxides react with the liberated hydrogen chloride to give a chloro compound, which is soluble in organic solvents, unlike insoluble salts formed when inorganic base is used. This makes the process simple avoiding additional filtration step.

Detailed Description of the Invention :

The present invention describes a novel process for the preparation of rivaroxaban comprising reacting 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazoIidin-3-yl]phenyl}-morpholin-3-one (II), or its hydrochloride salt with 5-chlorothiophene-2-carbonyl chloride (III) using epoxide derivatives as non-basic acid scavengers.
The main oxazolidinone intermediate (II) as its hydrochloride salt is prepared according to Scheme 2.
The 4-(4-nitrophenyl)morpholin-3-one of formula (IV) is first reduced to 4-(4-aminophenyl) morpholin-3-one of formula (V). The compound (V) on reaction with (S)-glycidylphthalimide of formula (VI), is converted to the hydroxyl intermediate of formula (VII). Subsequently, the compound (VII) is reacted with phosgene equivalent reagent such as diimidazole carbonyl, to give oxazolidinone of formula (VIII). Removal of the phthalyl protecting group gives the required amino oxazolidinone of the formula (II).
The reduction of 4-(4-nitrophenyl)morpholin-3-one (IV) to 4-(4-aminophenyl)morpholin-3-one (V) is described in the literature. Patent application WO 2014/175563 describes reduction of 4-(4-nitro phenyl)morpholin-3-one using various reagents such as sodium hydrosulfite, iron powder, hydrazine hydrate, etc. The US patent 7,365,088 describes a reduction process using tin chloride. The Chinese patent CN103980221A describes a process using iron powder in glacial acetic acid. But these methods are not friendly to the environment and result in huge effluent problems.

Bayer reported (US 7,157,456) reduction of (IV) by catalytic hydrogenation using 5% Pd/carbon in THF as solvent at a temperature of 70°C and 50 bar pressure for about 8 hours. By this process only 38% product was obtained. Bayer further modified the process (US 7,598,378) by hydrogenating using Pd/C in ethanol as solvent at 80°C and 2 to 10 bar pressure for about 1 hour. This resulted in about 93% product. Although (IV) is insoluble in ethanol at room temperature, it dissolves at 80°C during the reaction. However, the product (V) formed is insoluble in ethanol and precipitates out thereby mixing with the insoluble Pd/C catalyst, leading to cumbersome situation.
The catalytic hydrogenation process was explored by us in detail. This resulted in identifying water as a better solvent compared to THF or ethanol reported in the prior art. When hydrogenation is conducted with Pd/C in water at about 80°C and 30 to 35 bar pressure for 4 to 6 hours, product (V) is obtained in 95% yield (99.6% HPLC purity).

The reaction also proceeds at lower pressure such as 15 bar, but takes longer time for completion. The starting compound (IV) is not soluble in water. However, the product is soluble and the solution can be easily filtered to remove the catalyst. Furthermore, if the reaction is incomplete, the insoluble starting compound present along with the catalyst can be recovered by filtration and extraction with a solvent.

The amino compound (V) is reacted with (S)-glycidylphthalimide of formula (VI) by stirring the mixture of (V) and (VI) in water at about 60 to 65°C for about 24 hours. The clear solution on cooling and filtering gives the solid hydroxyl compound (VII) in good yields and purity.

The hydroxyl compound (VII) is reacted with a phosgene equivalent reagent such as diimidazole carbonyl by refluxing in toluene for about 2 hours. Cooling and normal workup gives the oxazolidinone of formula (VIII).

The phthalyl group is removed from (VIII) by reacting the ethanoloic solution of (VIII) with 40% solution of monomethylamine by stirring at 60 to 65°C for about 2 hours, followed by acidification using hydrochloric acid. The required amino oxazolidinone (II) is obtained as hydrochloride salt in a pure form (> 99.5% HPLC)

The (S)-glycidylphthalimide intermediate of the formula (VI) is prepared according to the scheme The US patent 7,135,576 describes a process for the preparation of (XI) from phthalimide (IX) and (S)-epichlorohydrin (X) in an organic solvent in the presence of alkali metal carbonate or bicarbonate using quaternary ammonium salt as phase transfer catalyst. An improved process was reported in US 6,875,875 by the same group, where alkali metal phthalimide, instead of free phthalimide, was reacted with (S)-epichlorohydrin (X) to obtain (XI) in the presence of phase transfer catalyst. The "875" patent further describes the cyclization of (XI) to the required (S)-glycidylphthalimide (VI) using alkali metal alkoxide such as potassium ter/-butoxide.

A simplified process is developed using 4-dimethylaminopyridine (DMAP) as base in catalytic amount eliminating the need for quaternary ammonium compound and alkali metal carbonate or hydrogencarbonate. Phthalimide (IX) was reacted with (S)-epichlorohydrin (X) in isopropanol using catalytic amount of DMAP. Stirring the reaction mixture at 55 to 60°C for about two hours resulted in (XI). The crude (XI) is taken in toluene and powdered potassium carbonate is added. The reaction mixture is refluxed for about 10 hours for the cyclization to give the required (S)-glycidylphthalimide (VI). In this process, apart from eliminating the requirement of phase transfer catalyst, a milder base such as solid potassium carbonate is used for scavenging the hydrogen chloride liberated in the reaction avoiding stronger base such as alkali metal alkoxide used in the prior art.

Studies also showed that the DMAP can be replaced with N,N-dimethyl aniline or N,N-diethyl aniline, although dimethyl aniline gives better results. A temperature range of 50 to 60°C is optimum, where the reaction is completed in about two hours in the case of DMAP. At higher temperature such as 80°C, about 5% racemization was observed, while at room temperature reaction takes more than 24 hours for the completion.

The condensation of (II) with 5-chlorothiophene-2-carbonyl chloride (III) is carried out using epoxides as non-basic reagents for scavenging the hydrogen chloride liberated during the reaction. The amine (II) can be in the form of either a hydrochloride salt or a free base.

As given in the scheme 2, the amine (II) is isolated as hydrochloride salt with high purity (>99.5% HPLC). Hence, the amine (II) as hydrochloride salt can be directly condensed with (III) in the presence of epoxides. Here, the epoxides act at dual levels, one at neutralizing the HC1 salt of (II) to free base and another at scavenging the hydrogen chloride liberated during the reaction.

The hydrochloride salt of (II) and 5-chlorothiophene-2-carbonyI chloride (III) are suspended in 1,2-epoxybutane and the suspension is heated to about 60 to 65°C and stirred. The reaction completes in about 15 h, as monitored by TLC. After cooling to room temperature, the reaction mixture is filtered and the product is washed with little amount of suitable solvent to remove excess epoxy butane. The suitable solvent can be selected from the group consisting of alcohols, ethers, ketones, esters and hydrocarbons in which epoxy butane is soluble. After drying the material under vacuum at room temperature for an hour, (I) is obtained in about 96% yield with 96% purity by HPLC. The material is further suspended in acetic acid and refluxed to obtain a clear solution. After cooling, the precipitated product is filtered and washed with small amount of acetic acid followed by water. On drying under vacuum at room temperature, (I) is obtained in 89% yield with 99.9% purity by HPLC.

When epichlorohydrin is used as the acid scavenger, product of 99.8% purity is obtained in 93% yield before crystallization. After crystallization with acetic acid, the yield is 90.7% with 99.91% purity.

Good results are also obtained when the reaction is conducted in a solvent. The intermediate (II) hydrochloride salt and epichlorohydrin in terf-butanol are reacted with (III) at 60 to 65°C for about 15 hours. After the work up, (I) is obtained in 95% yield with >99% purity. After recrystallization (I) is obtained in 92% yield with 99.9% purity.

Similarly, when the reaction is conducted in other solvents such as ethyl acetate, acetone or acetonitrile, (I) is obtained in good yields and high purity.

When the reaction is conducted in a solvent, about 8 equivalents of epoxide are required for optimum results.

Use of propylene oxide as acid scavenger results in lower yields (45%) with 99.4% purity. The lower yields may be due to the lower boiling point of propylene oxide (35°C), because of which the reaction has to be conducted below 30°C.

Instead of hydrochloride salt, (II) as a free base also reacts with (III) in the presence of epoxides and gives (I).

The embodiments of the present invention are illustrated in the following examples, which are not intended in any way to limit the scope of the invention. One skilled in the art can modify the details to suit the inputs and desired outcomes without affecting the present invention.

EXAMPLES:

Example-1: Preparation of 4-(4-Aminophenyl)morpholin-3-one(V) :

A suspension of 4-(4-nitrophenyl)morpholin-3-one (IV) (22.5 gm, 0.101 mol) and 5% palladium-on-charcoal (1.15 gm) in water (220.0 mL) was hydrogenated at 30 to 35 bar pressure at 80 °C until the starting material disappeared (4 to 6 hours). After completion of the reaction, the reaction mixture was cooled to 40 to 45°C and the catalyst was removed by filtration. The filtrate was concentrated under reduced pressure at 60°C to yield 18.9 gm (97.1 %) of 4-(4-aminophenyl) morpholin-3-one (V), M.R: 170 -173°C, 99.89% purity by HPLC.

Example-2: Preparation of 4-(4-Aminophenyl)morpholin-3-one (V) :
Hydrogenation was carried out as in Example 1 at 15 to 20 bar pressure at 80°C. The reaction was completed in 10 to 12 hours. After the workup 4-(4-aminophenyl)morphoIin-3-one was obtained in 95% yield.

ExampIe-3: Preparation of (S)-glycidylphthalimide (VI) :
Phthalimide (IX, 20.0 gm, 0.136 mol), (S)-epichlorohydrin (X, 22.65 gm, 0.244 mol) and N, N-dimethylaniline (3.3 gm, 0.027 mol) were suspended in 50.0 mL isopropanol and stirred for 8 hours at 55 to 60°C. The reaction mixture was concentrated under reduced pressure at 40°C and the resulting residue was dissolved in 200.0 mL toluene and treated with 20.0 mL dil.HCl. After stirring at 50°C fori5 min, the toluene layer was separated and washed with 20.0 ml water, 20.0 mL brine and dried using anhydrous Na2SC>4.
Potassium carbonate (45.1 gm, 0.326 mol) was added to the toluene solution and the reaction mixture was stirred for 8 to 10 hours at 110°C. After cooling to room temperature, salts were filtered. Toluene layer was washed with 20.0 mL water, 20.0 mL brine and subsequently dried over Na2S04. Concentration of the toluene solution under reduced pressure at 50°C resulted in (VI) as white solid (17.3 gm, 63% yield, 99.12% ee by HPLC, M.R: 97-100°C).

Example-4: Preparation of (S)-glycidylphthalimide (VI):
The above example-3 was repeated by replacing N, N-dimethylaniline with N, N-diethyl aniline (0.027 mol) as the base. The reaction was completed in 8 hours at 55 to 60°C. The product (VI) was obtained in 60% yield, 99.09% ee by HPLC.

Example-5: Preparation of (S)-glycidylphthalimide (VI):
The above example-3 was repeated by replacing N, N-dimethylaniline with 4-Dimethylamino-pyridine (0.034 mol) as the base. The reaction was completed in 2 hours at 55 to 60°C. The compound (VI) was obtained in 63% yield, 99.22% ee by HPLC.

Example-6: Preparation of 2-((R)-2-Hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino} propyl)-lH-isoindoline-l, 3 (2H)-dione (VII) :
4-(4-aminophinyl) morpholin-3-one (V) (10.0 gm, 0.052 mol) and (S)-glycidylphthalimide (VI) (12.7 gm, 0.0625 mol) were suspended in water (150.0 mL) and stirred at 60 to 65°C for 20 to 22 hours till the reaction was completed. The reaction mixture was cooled to 25 to 30°C and the precipitated solid was filtered, washed with water (100.0 mL) to afford a wet solid, which was stirred in ethanol (190.0 mL) at 75 to 80°C for 1 hour, followed by stirring at 20 to 25°C for 1 hour. The solid was filtered, washed with ethanol (50.0 mL) and dried to yield 17.7 gm (86%) of 2-((R)-2-Hydroxy-3-{[4-(3-oxo-4-morpholinyl) phenyl] amino} propyI)-lH-isoindoline-l, 3 (2H)-dione. M.R: 210-214°C; 96.82% Purity by HPLC; 98.16% ee by HPLC.

ExampIe-7: Preparation of 2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morphoIinyI)phenyI]-l,3-oxazolidin-5-yI} methyI)-lH-isoindole-l, 3-(2H)-dione (VIII) :
To a suspension of 2-((R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl) phenyl] amino} propyl)-lH-isoindoline-1, 3 (2H)-dione (VII) (17.2 gm, 0.043 mol) in toluene (150.0 mL) was added N, N-carbonyl diimidazole (9.17 gm, 0.056 mol). The reaction mixture was refluxed for two hours, cooled to 55 to 60°C, added ethanol (30.0 mL) and stirred for about 15 min. The. reaction mixture was further cooled to 10 to 15°C and stirred for about 15 min. The precipitated product was filtered, washed with ethanol (30.0 mL) and dried to yield 16.8 gm (91.7%) of 2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morpholinyI) phenyl]-l, 3-oxazolidin-5-yl} methyl)-lH-isoindoIe-1, 3-(2H)-dione (VIII), 99.97% HPLC; 99.91% ee by HPLC.

Example-8: Preparation of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyI}-morphoIin-3-one (II) hydrochloride :
Methylamine (40% strength in water, 33.8 gm, 37.7 mL) is added to a suspension of 2-({(5S)-2-Oxo-3-[4-(3-oxo-4-morphol inyl)phenyl]-l,3-oxazolidin-5-yl} methyl)- lH-isoindole-1, 3-(2H)-dione (VIII) (42.0 gm, 0.099 mol) in ethanol (315.0 mL) at 15 to 20°C for 15 min while stirring. The reaction mixture is heated to 60 to 65°C and stirred for 2 hours, cooled to about 55 to 60°C, pH adjusted to 2.5 to 2.7 with aq. HC1 (20% strength in water) and stirred for about 10 to 15 min. The reaction mixture was cooled to 20 to 25°C, further cooled to 5 to 10°C and stirred for about 30 min. The precipitated product was filtered, washed with ethanol (30.0 mL) and dried to yield 28.8 gm (88.2%) of 4-{4- [(5S)-5-(aminomethyl) -2-oxo-l,3-oxazolidin-3-yl] phenyl}-morpholin-3-one hydrochloride (II), 99.72% HPLC; 99.87% ee by HPLC.
Example-9: Preparation of 5-chlorothiophene-2-carbonyl chloride (III) :
A suspension of 5-chlorothiophene-2-carboxylic acid (23.0 gm, 0.141 mol), N, N-Dimethyl formamide (0.2 mL) in toluene (120.0 mL) was heated to 75 to 80°C to get a clear solution. Thionyl chloride (20.2 gm, 0.170 mol) was added drop wise and further heated to 105 to 110°C, stirred for 2 hours. The reaction mixture was cooled to 25 to 30°C and concentrated under reduced pressure at 50 to 55°C to obtain a yellow liquid. It was further purified by fractional distillation (B.P. 45 to 50°C/ 0.5 mmHg) to yield 24.0 gm (93.7%) of 5-chloro thiophene-2-carbonyl chloride (III) as pale yellow liquid.

Example-10: Preparation of 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morphoIinyl)-phenyl]-l, 3-oxazoIidin-5-yI} methyl)-2- thiophenecarboxamide (Rivaroxaban, I) :
To a suspension of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}-morpholin-3-one (II) hydrochloride (5.0 gm, 0.0152 mol) in 1,2-epoxy butane (25.0 mL) was added 5-chloro thiophene-2-carbonyl chloride (III) (3.3 gm, 0.0182 mol). The reaction mixture was heated to 60 to 65°C and stirred at this temperature for 15 hours. After completion of the reaction (indicated by TLC), the suspension was cooled to 25 to 30°C and the product was filtered and washed with toluene (10.0 mL). The obtained solid was dried under vacuum at 25 to 30°C for 1 hour to yield 6.4 gm (96.2%) of (I), 96.24% Purity by HPLC; 99.93% ee by HPLC.
Recrystallization: The above crude product (6.4 gm) was suspended in acetic acid (32.0 mL) and refluxed to obtain a clear solution. When required, the solution was filtered hot to remove any particles. The solution was cooled to 20 to 25°C, stirred for 30 min. The precipitated product was filtered, washed with acetic acid (5.0 mL) and water (25.0 mL), dried under vacuum to yield 5.7gm (89.1%) of 5-Chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl} methyl)-2- thiophenecarboxamide (Rivaroxaban, I). M.R: 230-232°C; 99.87% Purity by HPLC; 99.93% ee by HPLC. FT-IR (KBr, cm"1): v max 3352, 2976, 2934, 2897, 2867, 1735, 1669, 1643, 1605, 1546,1517, 1485,1468,1428,1408, 1373,1340, 1323, 1307,1278,1210,1163, 1145,1119, 1076, 1055, 1010, 990, 919, 846, 826, 756, 745, 707, 685, 564; 'H NMR (300 MHz, CDCb): 5H 3.58-3.62 (m, 2H), 3.69-3.72 (m, 2H), 3.82-3.87 (dd, J= 9.0, 6.3 Hz, IH), 3.95-3.98 (m,2H), 4.16-4.22 (m, IH), 4.19 (s, 2H), 4.80-4.88 (m, IH), 7.19-7.20 (d, J=4.2 Hz, 2H), 7.38-7.41 (d, J= 9.0 Hz, 2H), 7.54-7.57 (d, J= 9.0 Hz, 2H), 7.68-7.69 (d, J= 4.2 Hz, 2H), 8.97-9.01 (t, J= 5.7 Hz, 3H); 13CNMR(75MHz, CDCb): <5c42.68, 47.91, 49.48, 63.94, 68.19, 71.80, 118.82, 126.40, 128.59, 128.91, 133.76, 136.96, 137.53, 138.90, 154.57, 161.29, 166.46; MS: m/z 453 [M+H20]+; DSC Peak at: 230.69 °C; PXRD: 8.95, 11.96, 14.27, 16.47, 17.39, 18.01, 19.48, 19.88, 21.64, 22.46, 23.30, 24.07, 24.46, 24.69, 25.57, 26.38, 26.60, 30.01, 30.94, 31.75.

Example-ll: Preparation of Rivaroxaban (I):
The above example-10 was repeated by replacing 1,2-epoxybutane with epichlorohydrin. After recrystallization from acetic acid, (I) was obtained in 90.7% yield having 99.91% purity by HPLC and 99.96%) ee by HPLC.

Example-12: Preparation of Rivaroxaban (I) :
To a suspension of (II) hydrochloride (1.0 gm, 0.003 mol) in propylene oxide (10.0 mL) was added (III) (0.81 gm, 0.0045 mol). The reaction mixture was stirred for 24 hours. The product was filtered, washed with toluene (5.0 mL) and dried under vacuum at 25 to 30°C for 1 hour to yield 1.20 gm (90.22%) of (I) 69.98% Purity by HPLC. After recrystallization in acetic acid yielded 0.6 gm (45%), 99.4% Purity by HPLC; 100% ee by HPLC.

Example-13: Preparation of Rivaroxaban (I):
To a suspension of (II) hydrochloride (3.0 gm, 0.0091 mol), epichlorohydrin (6.77 gm, 0.0732 mol) in tert-butano\ (9.0 mL) was added (III) (2.0 gm, 0.011 mol) at 25 to 30 °C. The reaction mixture was heated to 60 to 65°C and stirred for 15 hours. After completion of the reaction (indicated by TLC), the suspension was cooled to 25 to 30 °C, further cooled to 0 to 5 °C and stirred for 30 min. The product was filtered, washed with terf-butanol (5.0 mL) and dried under vacuum at 25-30°C for 2 hours to yield 3.80 gm (95,24%) of (I), 99.64% Purity by HPLC; 99.94% ee. The above crude product (3.80 gm) was recrystallized from acetic acid as given in Example 10, to give 3.50 gm (92.1%) of (I), 99.89% Purity by HPLC; 99.95% ee by HPLC.

Example-14: Preparation of Rivaroxaban (I):
The example-13 was repeated by replacing ter/-butanol with acetone as solvent. After recrystallization from acetic acid, (I) was obtained in 93.5 % yield having 99.90% purity by HPLC and 99.96% ee by HPLC.

Example-15: Preparation of Rivaroxaban (I):
The example-13 was repeated by replacing tert-butano\ with ethyl acetate as solvent. The (I) was obtained in 97 % yield having 99.13% purity by HPLC and 99.86% ee by HPLC, without further recrystallization.

Example-16: Preparation of Rivaroxaban (I) :
The example-13 was repeated by replacing /err-butanol with acetonitrile as solvent. The (I) was obtained in 94 % yield having 99.88% purity by HPLC and 99.91% ee by HPLC, without further recrystallization.

Example-17: Preparation of Rivaroxaban (I) :
To a suspension of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazoIidin-3-yI]phenyl} morpholin-3-one (II) free base (1.0 gm, 0.0034 mbl) in epichlorohydrin (10.0 mL) was added 5-chlorothiophene-2-carbonyl chloride (III) (0.81 gm, 0.0045 mol) at 25 to 30°C. The reaction mixture is then heated to 60 to 65°C and stirred at this temperature for 2 to 3 hours. After completion of the reaction, the suspension was cooled to 25 to 30°C and further cooled to 5 to 10°C. The product was filtered, washed with toluene (3.0 mL) and dried under vacuum at 25 to 30°Cfor 1 hour to yield LlOgm (73.5%) of (I), 97.38% Purity by HPLC; 99.83% ee by HPLC.

in the presence of a tertiary amine, wherein the tertiary amine is selected from the group consisting of N,N-dimethylaniline, N,N-diethylaniline, and N,N-dimethyl-4-aminopyridine.

We Claim

1. A process for the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l,3-oxazoldin-5-yl}methyl)-2-thiophenecarboxamide (rivaroxaban) having the formula (I),
comprising:

(a) reacting 4-(4-Aminophenyl)morpholin-3-one (V)
with (S)-glycidylphthalimide (VI)
to obtain 2-((R)-2-Hydroxy-3-{[4-(3-oxo-4-morpholinyl)phenyl]amino} propyl)-lH-isoindoline-1, 3 (2H)-dione (VII), and subsequently converting (VII) to 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yI]phenyl}-morpholin-3- one having the formula (II),

(b) reacting 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}-morpholin-3- one of formula (II), or its hydrochloride salt, with 5-chlorothiophene-2-carbonyl chloride having the formula (III) in the presence of an epoxide.
2. Process according to claim 1 wherein epoxide is selected preferably from the group consisting of 1,2-epoxybutane, epichlorohydrin and propylene oxide.

3. Process according to claim 1, wherein the reaction is carried out, optionally in the presence of a solvent, wherein the solvent is selected from the group consisting of ethyl acetate, acetone, tert-butano\ and acetonitrile.

4. Process according to claim 1 wherein the 4-(4-aminophenyl)morpholin-3-one of the formula (V) is prepared by reacting 4-(4-nitrophenyl)morpholin-3-one of the formula (IV) with hydrogen using hydrogenation catalyst in water. 5. Process according to claim 1 wherein the (S) - glycidylphthalimide of the formula (VI), is prepared by reacting phthalimide of the formula (IX): with (S)-epichlorohydrin of the formula (X)