Field of the invention:

The present invention relates to an improved process for the preparation of anticoagulant drug i.e, 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl} methyl)-2-thiophene carboxamide represented by the following structural formula-1.

The present invention also relates to a novel intermediate which is useful in the preparation of anticoagulant drug compound of formula-1.

Background of the Invention

US7157456 (hereafter referred to as "456") first disclosed the product as well as the 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 which is commonly known as Rivaroxaban, an orally effective, direct inhibitor of the serine protease factor Xa which performs an essential function in regulating the coagulation of blood.

'456 disclosed a method for preparing 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide compound of formula-1, by reacting 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,3(2H)dione compound of formula-3 with 4-(4-aminophenyl)-3-morpholinone compound of formula-2 in the presence of ethanol/water to give 2-((2R)-2-hydroxy-3-{[4-(3-oxo-4-morpholinyl)-phenyl]amino}propyl)-lH-isoindole-l,3(2H)dinoe compound of formula-4. Subsequently, compound of formula-4 reacts with N,N-carbonyldiimidazole in the presence of 4-dimethylamino pyridine to give 2-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl} -methyl)-1 H-isoindole-l,3(2H)dione compound of formula-5. Further, elimination of the phthalimide protective group from compound of formula-5 in the presence of methyl amine affords crude 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholine-3-one compound of formula-6, which finally reacts with 5-chlorothiophene-2-carbonyl chloride in the presence of pyridine to give 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide compound of formula-1.

The major drawback of '456 process involves in condensation of crude compound of formula-6 with 5-chlorothiophene-2-carbonyl chloride in the presence of carcinogenic pyridine to provide 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl} methyl)-2-thiophenecarboxamide compound of formula-1 with high level of impurities and low yield. In order to reduce the level of impurities, there is a need for purification methods such as column chromatography which is a time consuming and tedious process and not suitable for commercial scale process. Moreover the said process uses pyridine as a base or solvent, which is carcinogenic and not advisable in laboratory and commercially scale process.

In view of the foregoing, there is an unmet need to develop an improved process for the preparation of Rivaroxaban substantially free of impurities with high yield and suitable for industrial scale process.

Brief description of the invention:

The first aspect 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]-l,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide compound of formula-1, comprising of reacting the compound of general formula-7 with (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-6 in the presence or absence of a suitable base in a suitable solvent to provide 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide compound of formula-1.

The second aspect 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]-l,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide compound of formula-1, comprising of:

a) Reacting the 5-chlorothiophene-2-carboxylic acid compound of formula-8 with a sulfonyl derivative compound of general formula-9 in the presence of a suitable base in a suitable solvent to provide the compound of general formula-7,

b) condensing the compound of general formula-7 with (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-6 in the presence or
absence of suitable base in a suitable solvent to provide 5-chloro-N-({(5S)-2-oxo-3-[4-(3-
oxo-4-morpholinyl)phenyl]-1,3 -oxazolidin-5-yl} methyl)-2-thiophene carboxamide
compound of formula-1.

The third aspect 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]-l,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide compound of formula-1, which comprising of the following steps:

a) Reacting the 4-(4-aminophenyl)morpholin-3-one compound of formula-2 with (S)-2-(oxiran-2-ylmethyl)isoindoline-l,3-dione compound of formula-3 in a suitable solvent to provide (S)-2-(2-hydroxy-3-(4-(3-oxomorpholino)phenylamino) propyl) isoindoline-1,3-dione compound of formula-4,

b) reacting the compound of formula-4 with N,N'-carbonyldiimidazole in the presence of a suitable catalyst in a suitable solvent to provide (S)-2-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)isoindoline-1,3-dione compound of formula-5,

c) optionally, purifying the compound of formula-5 obtained in step-(b) from a suitable solvent to provide pure compound of formula-5,

d) treating the compound of formula-5 with a suitable reagent in a suitable solvent to provide (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-6,

e) optionally, purifying the compound obtained in step-(d) from a suitable solvent to provide pure compound of formula-6,

f) reacting the 5-chlorothiophene-2-carboxylic acid compound of formula-8 with sulfonyl derivative compound of general formula-9 in presence of a suitable base in a suitable solvent to provide compound of general formula-7,

g) condensing the compound of general formula-7 in-situ with the compound of formula-6 obtained in step-(d) or step-(e) in a suitable solvent to provide 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl} methyl)-2-thiophene carboxamide compound of formula-1.

The fourth aspect of the present invention is to provide 5-chlorothiophene-2-carboxylic acid derivatives of general formula-7.

The fifth aspect of the present invention is to provide crystalline Form-M of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-6.
The sixth aspect of the present invention is to provide a process for the preparation of crystalline Form-M of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-6.

The seventh aspect of the present invention is to provide a process for the preparation of crystalline modification-1 of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide compound of formula-1.

The eighth aspect of the present invention is to provide crystalline Form-S of 5-chlorothiophene-2-carboxylic methanesulfonic anhydride compound of formula-7a.
The ninth aspect of the present invention is to provide a process for the preparation of compound of general formula-7, comprising of reacting 5-chlorothiophene-2-carboxylic acid compound of formula-8 with sulfonyl derivative compound of general formula-9 in the presence of a suitable base in a suitable solvent to provide compound of general formula-7.

Brief description of figures:

Figure 1: Illustrates the PXRD pattern of crystalline Form-M of (S)-4-(4-(5-(aminomethyl)- 2-oxooxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-6. Figure 2: Illustrates the DSC thermogram of crystalline Form-M of (S)-4-(4-(5-
(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-6. Figure 3: Illustrates the PXRD pattern of crystalline Form-S of 5-chlorothiophene-2-
carboxylic methanesulfonic anhydride compound of formula-7a. Figure 4: Illustrates the DSC thermogram of crystalline Form-S of 5-chlorothiophene-2-
carboxylic methanesulfonic anhydride compound of formula-7a.

Detailed Description of the Invention:

As used herein the term suitable solvent is selected from "alcoholic solvent" such as methanol, ethanol, isopropanol, n-propanol, butanol, ethylene glycol and the like; "ester solvents" such as ethyl acetate, methyl acetate, n-butyl acetate, isobutyl acetate, sec-butyl acetate, isopropyl acetate and the like, "ether solvents" such as tetrahydrofuran, diethylether, methyltert-butylether, dioxane and the like; "hydrocarbon solvents" such as toluene, xylene, cyclohexane, hexane, heptane, n-pentane and the like; "chloro solvents" such as methylene chloride, ethylene dichloride, carbon tetra chloride, chloroform and the like; "polar aprotic solvents" such as dimethylformamide, dimethylacetamide, dimethylsulfoxide and the like; "nitrile solvents" such as acetonitrile and the like; "ketone solvents" such as acetone, methyl isobutyl ketone.

As used herein the term "base" is selected from inorganic bases like alkali metal hydroxides such as lithium hydroxide, sodium hydroxide, potassium hydroxide; and the like; alkali metal alkoxides such as sodium tert-butoxide, potassium tert-butoxide; and the like; alkali metal carbonates like sodium carbonate, potassium carbonate; alkali metal bicarbonates like sodium bicarbonate and potassium bicarbonate and organic bases like triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropylethylamine, piperidine, pyridine, tributyl amine, 4-dimethylaminopyridine, N-methyl morpholine and the like.

As used herein the term "alkyl" refers to C1-C6 straight chain or branched chain alkyl group or the alkyl group is optionally substituted with halo group; the term aryl refers to phenyl or substituted phenyl; the term "substituted phenyl" means phenyl group optionally substituted with 1-5 substituents independently selected from C1-C5 alkyl, halogen, N02 wherein, halogen refers to chlorine, fluorine, bromine and iodine.

As used herein the term "sulfonyl derivatives" is selected from methanesulfonyl chloride, methane sulfonic acid, para-toluene sulfonyl chloride, para-toluene sulfonic acid, trifluoromethane sulfonyl chloride, parabromo benzene sulfonyl chloride, parabromo benzene sulfonic acid, para nitrobenzene sulfonyl chloride and paranitrobenzene sulfonic acid.

The first aspect 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 compound of formula-1, comprising of reacting the compound of general formula-7, with (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-6, in the presence or absence of a suitable base in a suitable solvent to provide 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide compound of formula-1.

Wherein, the suitable base used is selected from inorganic or organic bases and suitable solvent is selected from hydrocarbon solvents, chloro solvents and ester solvents or mixture thereof.

In a preferred embodiment of the present invention provides 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 compound of formula-1, comprising of condensing the compound of general formula-7 with (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3- one compound of formula-6 in the presence of diisopropylethylamine in dichloromethane to provide5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}
methyl)-2-thiophene carboxamide compound of formula-1.

The process disclosed in US 7,157,456 involves the condensation of crude (S)-4-(4-(5-(aminomethyl)-2-oxo-oxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-6 with 5-chlorothiophene-2-carbonyl chloride in the presence of pyridine and an inert solvent to provide 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide compound of formula-1.

The major drawback of the above said process relies on condensation of crude compound of formula-6 with 5-chlorothiophene-2-carbonyl chloride provides compound of formula-1 with high level of impurities and thereby decreases the yield of the final compound of formula-1. In order to reduce the impurities there is a need for purification methods such as column chromatography which is a time consuming and tedious workup process, especially for large samples, hence not suitable for large scale process.

Moreover, the above said process also involves the usage of pyridine which is carcinogenic, hence not advisable for laboratory process as well as commercial scale up process.

Whereas, the present invention involves the condensation of pure crystalline free base compound of formula-6 with 5-chlorothiophene-2-carboxylic methanesulfonic anhydride compound of formula-7a in the presence of diisopropylethyl amine in toluene or dichloromethane to provide compound of formula-1 with high yield and purity.

The present process avoids the tedious purification process as well as reduces the time cycle of the workup process. Hence the present process is more advantage and is commercially viable when compared over the prior art processes.

The second aspect 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]-l ,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide compound of formula-1, comprising of: a) Reacting the 5-chlorothiophene-2-carboxylic acid compound of formula-8,
with a sulfonyl derivative compound of general formula-9, (R = alkyl or aryl; X = halogen) in the presence of a suitable base in a suitable solvent to provide the compound of general formula-7,

b) condensing the compound of general formula-7 with (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-6 in the presence or absence of a suitable base in a suitable solvent to provide 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide compound of formula-1.

Wherein: in step-a) the suitable base is selected from inorganic or organic bases and suitable solvent is selected from hydrocarbon solvents, chloro solvents and ester solvents and mixtures thereof. in step-b) the suitable base is selected from inorganic or organic bases and suitable solvent is selected from hydrocarbon solvents, chloro solvents and mixture thereof.

In a preferred embodiment of the present invention provides 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 compound of formula-1, comprising of:

a) Reacting the 5-chlorothiophene-2-carboxylic acid compound of formula-8 with a sulfonyl derivative compound of general formula-9 in the presence of diisopropylethylamine in toluene or dichloromethane to provide compound of general formula-7,

b) condensing the compound of general formula-7 with (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-6 in the presence of diisopropylethylamine in dichloromethane to provide 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3 -oxazolidin-5 -yl} methyl)-2-thiophene carboxamide compound of formula-1.

The third aspect of the present invention 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-thiophene carboxamide compound of formula-1, which comprising of the following steps:

a) Reacting the 4-(4-aminophenyl)morpholin-3-one compound of formula-2,
with (S)-2-(oxiran-2-ylmethyl)isoindoline-l,3-dione compound of formula-3,
formula- j in a suitable solvent to provide (S)-2-(2-hydroxy-3-(4-(3-oxomorpholino) phenylamino) propyl)isoindoline-l,3-dione compound of formula-4,

b) reacting the compound of formula-4 with N,N'-carbonyldiimidazole in the presence a suitable catalyst in a suitable solvent to provide (S)-2-((2-oxo-3-(4-(3-oxo
morpholino)phenyl)oxazolidin-5-yl)methyl)isoindoline-l,3-dione compound of formula-
5,

c) optionally, purifying the compound of formula-5 obtained in step-(b) from a suitable solvent to provide pure compound of formula-5,

d) treating the compound of formula-5 with a suitable reagent in a suitable solvent to provide (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-6,


e) optionally, purifying the compound obtained in step-(d) from a suitable solvent to provide pure compound of formula-6,

f) reacting 5-chlorothiophene-2-carboxylic acid compound of formula-8, with sulfonyl derivative compound of general formula-9, in the presence of a suitable base in a suitable solvent to provide 5-chlorothiophene-2-carboxylic acid derivative compound of general formula-7,

g) condensing the compound of general formula-7 in-situ with compound of formula-6 obtained in step-(d) or step-(e) in a suitable solvent to provide 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide compound of formula-1.

Wherein: in step-a) the suitable solvent is aqueous alcoholic solvent selected from methanol, ethanol, isopropanol and butanol; in step-b) the suitable catalyst is dimethylamino pyridine and suitable solvent is selected from chloro solvents, ester solvents and keto solvents; in step-c) the suitable solvent is selected from alcoholic solvent, chloro solvent and keto solvent; in step-d) the suitable reagent is hydrazine hydrate or methyl amine and suitable solvent is selected from alcohol solvents, chloro solvents, hydrocarbon solvents and ester solvents. in step-e) the suitable solvent is selected from alcoholic solvents, chloro solvents and ester
solvents. in step-f) the suitable base is selected from inorganic or organic bases and suitable solvent is selected from hydrocarbon solvents, chloro solvents and ester solvents thereof. in step-g) the suitable solvent is selected from hydrocarbon solvents or chloro solvents and mixtures thereof.

In a preferred embodiment of the present invention provides 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 compound of formula-1, which comprising of the following steps:

a) Reacting the 4-(4-aminophenyl)morpholin-3-one compound of formula-2 with (S)-2-(oxiran-2-ylmethyl)isoindoline-l,3-dione compound of formula-3 in aqueous methanol to provide (S)-2-(2-hydroxy-3-(4-(3-oxomorpholino)phenylamino) propyl)isoindoline-1,3-dione compound of formula-4,

b) reacting the compound of formula-4 with N,N'-carbonyldiimidazole in a catalytic amount of dimethylaminopyridine in dichloromethane to provide (S)-2-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)isoindoline-1,3-dione compound of formula-5,
c) purifying the compound obtained in step-(b) in tetrahydrofuran to provide pure compound of formula-5,

d) treating the compound of formula-5 with hydrazine hydrate or methyl amine in dichloromethane to provide (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl) morpholin-3-one compound of formula-6,

e) purifying the compound obtained in step-(d) in isopropanol to provide pure compound of formula-6,

f) reacting the 5-chlorothiophene-2-carboxylic acid compound of formula-8 with methane sulfonyl chloride compound of formula-9a in the presence of diisopropylethylamine in dichloromethane to provide 5-chlorothiophene-2-carboxylic methanesulfonic anhydride compound of formula-7a,

g) condensing the 5-chlorothiophene-2-carboxylic methanesulfonic anhydride compound of formula-7a in-situ with compound of formula-6 obtained in step-(d) or step-(e) in dichloromethane to provide 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-1,3-oxazolidin-5-yl} methyl)-2-thiophenecarboxamide compound of formula-1.

US 7,351,823 describes the condensation of 2-[(2S)-2-oxiranylmethyl]-lH-isoindole-l,3(2H)dione compound of formula-2 with 4-(4-aminophenyl)-3-morpholinone compound of formula-3 in the presence of aqueous ethanol to provide compound of formula-4 and further the said step requires more time to complete the reaction. Moreover, the solid was isolated from the reaction mixture by the seeding of free sample of compound of formula-4 with low yield.

Whereas, the process of the present invention involves the usage of aqueous methanol in the above said condensation step, which is a low boiling solvent and cheaper when compare to the ethanol. Further, reaction completes faster when compare to the prior art process and product is directly isolated by cooling the reaction mixture with high yield & purity. Hence, the present process is more advantageous when compared to the prior art process.

US 7,157,456 discloses the cyclization of compound of formula-4 in the presence of CDI, dimethylamino pyridine and tetrahydrofuran solvent to provide compound of formula-5. Whereas, the said tetrahydrofuran has the high boiling point. And the said process takes more time for completion of the reaction, which leads to the formation of impurities thereby, decreases the yield of the compound of formula-5. Further the crude compound of formula-5 is isolated/purified by flash column chromatography. Whereas, the process of the present invention is carried out in dichloromethane as a solvent medium, which is low boiling solvent and is cheaper when compared to tetrahydrofuran.

The present invention requires less time for completion of the reaction when compared to prior art. The present invention also involves recrystallization of compound of formula-5 from tetrahydrofuran to obtain compound of formula-5 with chiral purity greater than 99.95% which was not disclosed in the prior reported processes. Hence the present process is more advantageous when compared to the prior art process.

The fourth aspect of the present invention is to provide 5-chlorothiophene-2-carboxylic derivatives of compound of general formula-7. ]

The term "alkyl" refers to C1-C6 straight chain or branched chain alkyl group or the alkyl group is optionally substituted with halo group; the term "aryl" refers to phenyl or substituted phenyl; the term "substituted phenyl" means phenyl group optionally substituted with 1-5 substituents independently selected from C1-C5 alkyl, halogen, NO2 wherein, halogen refers to chlorine, fluorine, bromine and iodine.

The fifth aspect of the present invention is to provide crystalline Form-M of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-6 characterized by:

a) its X-ray powder diffractogram having peaks at about 3.1, 6.2, 9.3, 12.5, 17.3, 17.7, 18.8, 19.5, 20.0, 20.94, 22.0, 22.8, 25.2, 25.7, 26.1, 26.8, 27.9, 28.6, 29.3, 30.6, 32.2, 33.0, 35.1, 38.1, 41.4 and 42.4 ± 0.2 degrees two-theta as illustrated in figure-1,

b) its DSC thermogram showing endotherm at 152.85°C as illustrated in figure-2.
The sixth aspect of the present invention is to provide process for the preparation of crystalline Form-M of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-6, which comprising of the following steps;

a) Dissolving the compound of formula-6 in isopropanol by heating to reflux temperature,

b) cooling the reaction mixture to 30°C,

c) stirring the reaction mixture for 1 hour at 30°C,

d) filtering the solid and dried to get the crystalline Form-M of compound of formula-6.

The seventh aspect of the present invention is to provide process for the preparation of crystalline modification-1 of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide compound of formula-1, which comprising of following steps;

a) Dissolving compound of formula-1 in ethylene glycol by heating to reflux temperature,

b) cooling the reaction mixture to 30°C,

c) stirring the reaction mixture for 1 hour at 30°C,

d) filtering the solid and dried to get the crystalline modification-1 of compound of formula-1.

The eighth aspect of the present invention is to provide crystalline Form-S of 5-chlorothiophene-2-carboxylic methanesulfonic anhydride compound of formula-7a characterized by:

a) its X-ray powder diffractogram having peaks at about 6.7, 7.0, 13.5, 14.0, 15.0, 15.4, 17.1, 18.1, 18.8, 21.1, 24.4, 26.6, 28.3, 31.7, 34.2, 34.8, 35.1 35.6, 42.1 and 43.0 ± 0.2 degrees two-theta as illustrated in figure-3,

b) its DSC thermogram showing endotherm at 88.71°C as illustrated in figure-4.

The ninth aspect of the present invention is to provide a process for the preparation of compound of general formula-7, comprising of reacting 5-chlorothiophene-2-carboxylic acid compound of formula-8 with sulfonyl derivative compound of general formula-9 in the presence of a suitable base in a suitable solvent to provide the compound of general formula-7.

Wherein, the suitable base is selected from inorganic or organic bases and suitable solvent is selected from hydrocarbon solvents or chloro solvents or mixtures thereof.
In a preferred embodiment of the present invention provides 5-chlorothiophene-2-carboxylic methanesulfonic anhydride compound of formula-7a, comprising of reacting 5-chlorothiophene-2-carboxylic acid compound of formula-8 with methane sulfonyl chloride compound of formula-9a in the presence of diisopropylethylamine in toluene or dichloromethane to provide 5-chlorothiophene-2-carboxylic methanesulfonic anhydride compound of formula-7a.

The process of the present invention is schematically represented as below:

The process described in the present invention was demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.

Examples:

Example-1: Preparation of (S)-2-(2-hydroxy-3-(4-(3-oxomorpholino)phenylamino) propyl)isoindol ine-l,3-dione (Formula-4)
(S)-2-(oxiran-2-ylmethyl)isoindoline-l,3-dione (148 g) was added to a solution of 4-(4-aminophenyl)morpholin-3-one (100 g) in methanol (1350 ml) and water (150 ml) at 30°C. Stirred the reaction mixture for 10 minutes at 30°C. Slowly raised the temperature to 65°C and stirred the reaction mixture for 16 hours at 65°C. After completion of the reaction, the reaction mixture was cooled to 25°C and stirred the reaction mixture for 1 hour at 25°C. Filtered the reaction mixture and washed with methanol and then dried to get the title compound. Yield: 92.3g; Melting point: 210-215°C. Purity by HPLC: 98%.

Example-2: Preparation of (S)-2-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)isoindoline-l,3-dione (Formula-5)
A solution of (S)-2-(2-hydroxy-3-(4-(3-oxomorpholino)phenylamino)propyl)isoindol ine-1,3-dione compound of formula-4 (50 g) and dichloromethane (150 ml) was added N,N-carbonyldiimidazole (30.8 g) and dimethylamino pyridine (1.5 g) at 37°C. Stirred the reaction mixture for 5 hours at 37°C. After completion of the reaction, distilled off the solvent completely below 40°C.

The obtained crude was co-distilled tetrahydrofuran. Further tetrahydrofuran was added to the reaction mixture and heated the reaction mixture to 70°C and stirred for 45 minutes. Cooled the reaction mixture to 28°C and stirred for 1 hour at the same temperature. Filtered and washed the solid with tetrahydrofuran and dried.

The obtained compound was dissolved in tetrahydrofuran at 70°C. Stirred the reaction mixture for 45 minutes. Cooled the reaction mixture to 28°C and stirred for 1 hour at the same temperature. Filtered and washed the solid with tetrahydrofuran and dried to get the title compound. Yield: 97.5g; Melting point: 212-222°C. Chiral 99.95Purity by HPLC: 99%.

Example-3: Preparation of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl) morpholin-3-one (Formula-6)
Hydrazine hydrate (40 g) was added to a mixture of (S)-2-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)isoindoline-l,3-dione compound of formula-5 (100 g) and dichloromethane (1000 ml) at 35°C. Heated the reaction mixture to 40°C and stirred the reaction mixture for 12 hours at 40°C.

After completion of the reaction, filtered the by¬product and then washed the by-product with dichloromethane. Distilled off the obtained filtrate completely under vacuum at 40°C and then co-distilled the crude with isopropanol. Further added isopropanol to the crude compound and stirred the reaction mixture for 20 minutes at 50°C. Cooled the reaction mixture to 30°C and then stirred for 1 hour. Filtered and washed the solid with isopropanol and dried to get the title compound. Yield: 99.75g; Melting point: 150-160°C. Purity by HPLC: 99%.

Example-4 Preparation of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl) morpholin-3-one (Formula-6) To a mixture of (S)-2-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)isoindoline-l,3-dione compound of formula-5 (12 g) and ethanol (200 ml) added 40% methylamine (27.4 ml) at 30°C. Heated the reaction mixture to 75°C. Stirred the reaction mixture to 2 hours at 75 °C. After completion of the reaction, distilled off the solvent from the reaction mixture below 60°C under vacuum to get the title compound. Yield: 96 g.

Example-5: Preparation of 5-chlorothiophene-2-carboxylic acid methanesulfonic anhydride (Formula-7a) Added 5-chlorothiophene-2-carboxylic acid (15.0 g) to dichloromethane (150 ml) under nitrogen. Stirred the solution for 10 minutes for 30°C. Cooled the solution to -20°C and added diisopropyl ethylamine (36.0 g). Slowly added methane sulfonyl chloride (16.0 g) to the above reaction mixture at -20°C for 45 minutes and stirred the reaction mixture for 2 hours.

After completion of the reaction, quenched the reaction mixture in chilled purified water. Raised the temperature of the reaction mixture to 30°C and stirred for 15 minutes. Both the organic and aqueous layers were separated. Extracted the compound with dichloromethane from the aqueous layer and distilled off the solvent completely under reduced pressure.

Diisopropyl ether was added to the obtained residue and stirred at 30°C for 45 minutes. Filtered the obtained solid and washed with diisopropyl ether. Yield: 47.29g; Melting point: 85-93°C.

Example-6: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide (Formula-1)
Dissolved 5-chlorothiophene-2-carboxylic acid (5.0 g) in dichloromethane (50 ml) under nitrogen at 30°C. Cooled the reaction mixture to -20°C and added diisopropyl ethylamine (12.0 g) to it. Slowly added methane sulfonyl chloride (5.3 g) to the above reaction mixture at -20°C. Stirred the reaction mixture for 2 hours at -20°C. (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one (7 g) was added to the reaction mixture at -20°C and stirred the reaction mixture for 1 hour at the same temperature.

After completion of the reaction, quenched the reaction mixture in purified water (100 ml) below 10°C. Raised the temperature of the reaction mixture to 30°C and stirred for 1 hour. Filtered the solid and washed with purified water and then dried to get the title compound. Yield: 97g; Melting point: 230°C. Purity by HPLC: 97.26%. Particle size distribution: D(0.1) is 6.85 urn; D(0.5) is 23.47 um; D(0.9) is 65.08 urn; The PXRD of the obtained compound matches with the prior-art crystalline modification-1 of Rivaraxoban.

Example-7: Purification of 5-chIoro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyI]-l,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide from Ethylene glycol (Formula-1)
5-chloro-N-( {(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide obtained from example-6 (5.0 g) was dissolved in ethylene glycol (100 ml) at 30°C. The reaction mixture was heated to 150°C and stirred for 15 minutes. Cooled the reaction mixture to 30°C and stirred for 1 hour. Filtered the obtained solid and washed with ethylene glycol and dried to get the title compound. Yield: 80g; Melting point 230°C. Purity by HPLC: 99.99%.

Particle size distribution: D(0.1) is 12.49 um; D(0.5) is 34.43 um; D(0.9) is 151.33 um; The PXRD of the obtained compound matches with the prior-art crystalline modification-1 of Rivaraxoban.

Example-8: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazoIidin-5-yl}methyl)-2-thiophenecarboxamide (Formula-1) 5-chlorothiophene-2-carboxylic methanesulfonic anhydride (2.0 g) was added to a solution of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one (2.0 g) and dichloromethane (20 ml) under nitrogen atmosphere.

The reaction mixture was stirred for 3 hours at 30°C. After completion of the reaction, distilled off the solvent from the reaction mixture. Added purified water to the obtained crude and then stirred for 30 minutes. Filtered the solid and washed with purified water to get the title compound. Yield: 2.5 g.

ExampIe-9: One pot 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 (Formula- )

A mixture of hydrazine hydrate (40 g) was added to the mixture of (S)-2-((2-oxo-3-(4-(3-oxomorpholmo)phenyl)oxazolidin-5-yl)methyl)isoindoline-l,3-dione compound of formula-5 obtained from the example-2 (100 g) and dichloromethane (500 ml) at 25-30°C. The reaction mixture heated to 35-40°C and stirred for 12 hours. After completion of the reaction, cooled the reaction mixture to 25-30°C, filtered the bi-product at 25-30°C and washed with dichloromethane.

The mixture of dichloromethane (10 ml) and 5-chlorothiophene-2-carboxylic acid (38 g) was taken into another round bottom flask at 25-30°C under nitrogen atmosphere and cooled to -10 to -20°C. Diisopropyl ethylamine (91 g) was added to the reaction mixture and slowly added methanesulfonyl chloride (40.3 g) to the reaction mixture at -10 to -20°C. Stirred the reaction mixture for 2 hours at -10 to -20°C. After completion of the reaction, added the above obtained dichloromethane filtrate to the reaction mixture at 0-5 °C for 45 minutes. Stirred the reaction mixture for 5 hours at 0-5°C. After completion of the reaction, quenched the reaction mixture in purified water. Stirred the reaction mixture for 25 minutes at 25-30°C. Filtered the precipitated solid, washed with purified water and dried to get the title compound. Yield: 82 g.

HPLC Method of Analysis for Rivaroxaban Intermediates:

Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Zorbax SB-C18 15 x 4.6 mm, 5 urn or equivalent. Flow rate: 1.0 ml/min; Wavelength: 240 run; Column Temperature: 50°C; Injection volume: 5 uL; Run time: 42 min; Diluent: Acetonitrile (100%) Mobile phase; Needle wash: Diluent; Elution: Gradient; Mobile phase: A mixture of 5 ml of orthophosphoric acid (85%), 2 g 1-Octane sulfonic acid sodium salt in 1000 ml of water.

HPLC Method of Analysis for Rivaroxaban: Apparatus: A liquid chromatographic system is to be equipped with variable wavelength UV-detector; Column: Hypersil BDS CI8, 100 x 4.6 mm, 3 urn or equivalent. Flow rate: 1.0 ml/min; Wavelength: 250 nm; Column Temperature: 45°C; Injection volume: 5 uL; Run time: 46 min; Diluent:

Acetonitrile: Water (60:40) v/v; Mobile phase; Needle wash: Diluent; Elution: Gradient; Mobile phase: A mixture of 5 ml of acetic acid in 1000 ml of water. Mobile phase: B Acetonitrile: Buffer (70:30) v/v
PSD Details for Rivaroxaban:

Rivaroxaban compound of formula-1 produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball mills, roller and hammer mills and jet mills. Milling or micronization may be performed before drying or after the completion of drying of the product.

The particle size distribution of rivaroxaban compound of formula-1 is measured using the following conditions:

Instrument: Malvern Master sizer 2000; Measuring range: 0.02 to 2000 um; Wet sample: Hydro 2000S; Dispersant: Water; Absorption Index: 0; Refractive Index of water: 1.33; Refractive Index of particle: 1.500; Stirrer speed: 2500 rpm; Obscuration range: 10-20%; Sensitivity: Normal; Measurement time: 12 seconds; Background time: 12 seconds; Internal sonication: 3 minutes; Measurement repeat: 3 times at zero second interval.

We Claim:

1. A compound of general formula-7 wherein, R = alkyl or aryl; the term "alkyl" refers to C1-C6 straight chain or branched chain alkyl group or the alkyl group is optionally substituted with halo group; the term "aryl" refers to phenyl or substituted phenyl; the term "substituted phenyl" means phenyl group optionally substituted with 1-5 substituents independently selected from C1-C5 alkyl, halogen, NO2 wherein, halogen refers to chlorine, fluorine, bromine and iodine.

2. 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 compound of formula-1, comprising of reacting the compound of general formula-7 (wherein, 'R' is defined as above) with (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3- l)phenyl)morpholin-3-one compound of formula-6 in the presence or absence of a suitable base in a suitable solvent to provide 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide compound of formula-1.

3. An improved 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 compound of formula-1, comprising of:

a) Reacting the 5-chlorothiophene-2-carboxylic acid compound of formula-8
with a sulfonyl derivative compound of general formula-9 Formula-9 (R = alkyl or aryl; X = halogen) in the presence of a suitable base in a suitable solvent to provide compound of general formula-7,

b) condensing the compound of general formula-7 with (S)-4-(4-(5-(aminomethyl)-2- oxooxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-6 in the presence or absence of a suitable base in a suitable solvent to provide 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide compound of formula-1.

4. The process according to claim-2 or 3, wherein the suitable base is selected from organic base such as triethylamine, isopropyl ethylamine, diisopropyl amine, diisopropylethylamine or inorganic base selected from alkali metal hydroxides, alkali metal alkoxides, alkali metal carbonates and alkali metal bicarbonates; and the suitable solvent is selected from alcoholic solvents, chloro solvents, hydrocarbon solvents and ester solvents.

5. 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-thiophene carboxamide compound of formula-1, which comprising of the following steps:

a) Reacting the 4-(4-aminophenyl)morpholin-3-one compound of formula-2 with (S)-2-(oxiran-2-ylmethyl)isoindoline-l,3-dione compound of formula-3 in aqueous methanol to provide (S)-2-(2-hydroxy-3-(4-(3-oxomorpholino) phenylamino) propyl)isoindoline-l,3-dione compound of formula-4,

b) reacting the compound of formula-4 with N,N'-carbonyldiimidazole in the presence of dimethylaminopyridine in dichloromethane to provide (S)-2-((2-oxo-3-(4-(3-oxomorpholino)phenyl)oxazolidin-5-yl)methyl)isoindoline-1,3-dione compound of formula-5,

c) optionally, purifying the compound of formula-5 obtained in step-(b) from tetrahydrofuran to provide pure compound of formula-5,

d) treating the compound of formula-5 with hydrazine hydrate in dichloromethane to
provide (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one
compound of formula-6,

e) optionally, purifying the compound obtained in step-(d) from isopropanol to provide pure compound of formula-6,

f) reacting the 5-chlorothiophene-2-carboxylic acid compound of formula-8 with methane sulfonyl chloride compound of formula-9a in presence of diisopropylethylamine in toluene or dichloromethane to provide 5-chlorothiophene-2-carboxylic methanesulfonic anhydride compound of formula-7a,

g) condensing the compound of formula-7a in-situ with the compound of formula-6
obtained in step-(d) or step-(e) in dichloromethane to provide 5-chloro-N-({(5S)-2-oxo-3-
[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxamide
compound of formula-1.

6. Crystalline Form-M of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl) morpholin- 3-one compound of formula-6 characterized by:

a) its X-ray powder diffractogram having peaks at about 3.1, 6.2, 9.3, 12.5, 17.3, 17.7, 18.8, 19.5, 20.0, 20.94, 22.0, 22.8, 25.2, 25.7, 26.1, 26.8, 27.9, 28.6, 29.3, 30.6, 32.2, 33.0, 35.1, 38.1, 41.4 and 42.4 ± 0.2 degrees two-theta as illustrated in figure-1,

b) its DSC thermogram showing endotherm at 152.85°C as illustrated in figure-2.

7. A process for the preparation of crystalline form-M of (S)-4-(4-(5-(aminomethyl)-2- oxooxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-6, comprising of the following steps;

a) Dissolving the compound of formula-6 in isopropanol by heating to reflux temperature,

b) cooling the reaction mixture,

c) stirring the reaction mixture for 1 hour,

d) filtering the precipitated solid and dried to get the crystalline Form-M of compound of formula-6.

8. Crystalline Form-S of 5-chlorothiophene-2-carboxylic methanesulfonic anhydride compound of formula-7a characterized by:

a) its X-ray powder diffractogram having peaks at about 6.7, 7.0, 13.5, 14.0, 15.0, 15.4, 17.1, 18.1, 18.8, 21.1, 24.4, 26.6, 28.3, 31.7, 34.2, 34.8, 35.1 35.6, 42.1 and 43.0 ± 0.2 degrees two-theta as illustrated in figure-3,

b) its DSC thermogram showing endotherm at 88.71 °C as illustrated in figure-4.

9. A process for the preparation of crystalline modification-1 of 5-chloro-N-({(5S)-2-oxo-3-[4- (3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophcarboxamide compound of formula-1, comprising of the following steps;

a) Dissolving the compound of formula-1 in ethylene glycol by heating to reflux temperature,

b) cooling the reaction mixture,

c) stirring the reaction mixture for 1 hour,

d) filtering the solid and dried to get the crystalline modification-1 compound of formula-1.

10. A process for the preparation of 5-chlorothiophene-2-carboxylic methanesulfonic anhydride compound of formula-7a, comprising of reacting the 5-chlorothiophene-2-carboxylic acid compound of formula-8 with methane sulfonyl chloride compound of formula-9a in the presence of a suitable base in a suitable solvent to provide 5-chlorothiophene-2-carboxylic methanesulfonic anhydride compound of formula-7a.