Field of the Invention:

The present invention relates to novel 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 represented by the following structural formula-1.
o Formula-1 The present invention also relates to novel intermediates, which are useful in the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophenecarboxarnide compound of formula-1.

Background of the invention:

US7157456 (hereafter referred to as "456") first disclosed 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-1,3-oxazolidin-5-yl}methyl)-2-thiophene carboxamide, 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.

The present 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 is simple, eco-friendly, cost effective, reproducible, robust, and is well amenable on industrial scale.

Brief Description of the Invention:

The first aspect of the present invention is to provide a novel 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 compound of
formula-1.

The second aspect of the present invention is to provide a process for the preparation of (R)-5-cWoro-N-

(2-hyclroxy-3-(4-nitrophenylaniino)propyl)thiophene-2-carboxarnide compound of formula-5 through compound of formula-11.

The third aspect of the present invention is to provide a process for the preparation of (R)-5-cUoro-N-(2-hydroxy-3-(4-nitrophenylamino)propyl)thiophene-2-carboxarnide compound of formula-5 through compound of formula-15.

The fourth aspect of the present invention is to provide another process for the preparation of (R)-5-chloro-N-(2-hydroxy-3 -(4-nitrophenylamino)propyl)thiophene-2-carboxamide compound of formula-5 through compound of formula-15.

The fifth aspect of the present invention is to provide another process for the preparation of (R)-5-chloro-N-(2-hydroxy-3-(4-nitrophenylamino)propyl)thiophene-2-carboxamide compound of formula-5 through compound of formula-15.

The sixth aspect of the present invention is to provide another process for the preparation of (R)-5-cUoro-N-(2-hydroxy-3-(4-nitrophenylamino)propyl)thiophene-2-carboxamide compound of formula-5 through compound of formula-15.

The seventh aspect of the present invention relates to novel intermediate compounds for the synthesis of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene compound of formula-1.

The eighth aspect of the present invention is to provide 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 compound of formula-1 through compound of formula-19.

The ninth aspect of the present invention is to provide another 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 compound of formula-1 through compound of formula-19.

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, diethyl ether, methyl tert-butyl ether, 1,4-dioxane, diisopropyl ether, di-tert-butyl ether, ethyl tert-butyl ether, dimethoxy ethane and the like; "hydrocarbon solvents" such as benzene, toluene, xylene, cyclohexane, hexane, heptane, 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; "polar solvent" such as water and the like; "nitrile solvents" such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile and the like; "ketone solvents" such as acetone, methyl isobutyl ketone, ethyl methyl ketone, diethyl ketone, methyl tert-butyl ketone, isopropyl ketone and the like; and/or their mixtures thereof.
As used herein the present invention the term "suitable base" refers to "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium tert.butoxide and the like; "alkali metal phosphates" such as sodium phosphate, potassium phosphate, disodium hydrogen phosphate, dipotassium hydrogen phosphate and "organic bases" like ammonia, diisopropyl amine (DIPA), diisopropylethylamine (DIPEA), diisobutylamine, triethylamine, pyridine, N,N-diethylaniline, 4-pyrrolidinopyridine, 4-dimethylamino pyridine (DMAP), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), 1,5-diaza bicyclo[4.3.0] non-5-ene (DBN), dimethylamine, diethylamine, 2,6-lutidine, lithium diisopropylamide (LDA); "organosilicon bases" such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS) and the like; alkyl lithiums, alkyl magnesium halides, and lithium amides and the like. "Organolithium compounds" such as n-butyl lithium, isobutyl lithium and the like.

As used herein, the term "coupling agent" is selected from dicyclohexylcarbodiimide (DCC), diisopropylcarbodiimide (DIC), ethyl-(N',N'-dimethyl amino)propylcarbodiimide hydrochloride (EDC), carbonyldiimidazole (CDI), DABAL-Me3.

As used herein the term "cyclizing agent" is selected from N,Ncarbonyl d4imidazole/NMP,N,N-Carbonyldiimidazole/DMAP.

As used herein the term "reducing agent" is selected from Fe, Fe in acidic media like NH4C1 or HC1 or acetic acid, Sn in acidic media like HC1, Zn, Zn in acidic media like HC1 or NH4C1 or acetic acid, NaBH4 with catalytic NiC12.6H20 or CoC12.6H20, Lithium borohydride, diborane, Sodium aluminium hydride, hydrazine hydrate, sodiumdithionate, sodium sulfide, ammonium sulfide, hydrogenation catalysts such as nickel, Raney nickel, rhodium, Pd-C combined with borohydrides , cyclohexene , acidic media like formic acid, H3PO2 etc., Raney cobalt, Raney iron, lithium aluminum hydride, sodium amalgam, platinum oxide, borane- tetrahydrofuran complex and the like in combination with hydrogen, DIBAL-H, lithium aluminiumhydride, sodiumborohydride, lithiumborohydride, NaBH3CN, sodiumborohydride/BF3-etherate, vitride, sodium borohydride/aluminium chloride or borane/aluminium chloride, sodiumborohydride /iodine and 9-BBN; and "sulfur derivatives" like sodium sulfite, sodium sulfide, sodium dithionate, sodium metabisulfite and the like.

As used herein the term "chiral reducing agent" refers to (R)-Methyl CBS, DIP-chloride, borane-THF, borane-DMS and the like.

As used herein the present invention the term "resoluting agent" refers to chiral acid selected from mandelic acid, tartaric acid, di-p-tolyl tartaric acid, dibenzoyl tartaric acid, camphor sulfonic acid and the like.

As used herein the term "sulfonyloxy" refers to toluenesulfonyloxy, methanesulfonyloxy and trifluoro methanesulfonyloxy and the like.

As used herein the term "chlorination agent" is selected from thionyl chloride, oxalyl chloride, pivaloyl chloride, POCI3, PC13 and PC15.

As used herein, the term "alkyl" refers to straight chain or branched hydrocarbon groups, generally having specified number of carbon atoms. A "Q.12 alkyl" refers to alkyl group having 1 to 12 carbons. Examples of Ci to C12 alkyl groups include, but are not limited to groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pent-1-yl, pent-2-yl, pent-3-yl, 3-methylbut-l-yl, 3-methylbut-2-yl, 2-methylbut-2-yl, 2,2,2-trimethyleth-l-yl, n-hexyl and the like.
As used herein the term "arylalkyl" refers to include those radicals in which an aryl group is attached to a "Q-C12 alkyl straight chain or branched groups.

As used herein, the term "alkoxy" refers to a C1-C12 alkoxy straight or branched groups.

The first aspect of the present invention provides novel 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 compound of formula-1, comprising the following steps of:

a) Reacting the 4-nitroaniline compound of formula-9, with l,3-dichloropropan-2-ol compound of formula-8 in the presence of a suitable base in a suitable solvent to provide l-chloro-3-(4-

nitrophenylamino)propan-2-ol compound of formula-22, and the obtained compound of formula-22 can be further resolution with a suitable resolving agent in a suitable solvent provides (R)-l-chloro-3-(4-
nitrophenylamino)propan-2-ol compound of formula-7,

b) condensing the compound of formula-7 with 5-chlorothiophene-2-carboxamide compound of
formula-6 in the presence of a suitable base in a suitable solvent to provide (R)-5-chloro-N-
(2-hydroxy-3-(4-nitrophenylamino)propyl)thiophene-2-carboxamide compound of formula-
5,

c) reacting the compound of formula-5 with a suitable cyclizing agent in presence of a suitable base in a suitable solvent to provide (S)-5-chloro-N-((3-(4-nitrophenyl)-2-oxo-l,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide compound of formula-4,

d) reducing the compound of formula-4 in the presence of a suitable reducing agent in a suitable solvent to provide (S)-N-((3-(4-aminophenyl)-2-oxo-l,3-oxazolidin-5-yl)methyl)-5-chloro thiophene-2-carboxamide compound of formula-3,

e) reacting the compound of formula-3 with 2-chloroethanol in the presence of a suitable base in a suitable solvent to provide (S)-5-chloro-N-((3-(4-(2-hydroxyethylamino) phenyl)-2-oxo-l,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide compound of formula-2,

f) reacting the compound of formula-2 with chloroacetyl chloride in the presence 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 compound of formula-1.

Wherein, in step-a), b), e) & f) the suitable base is selected from organic or inorganic bases and suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, ketone solvents, ether solvents, alcohol solvents and mixture thereof.

in step-a) the suitable resolving agent is selected from L(+)-mandelic acid, acetyl mandelic acid, tartaric acid, di-p-tolyl tartaric acid, dibenzoyl tartaric acid, camphor sulfonic acid and the like.
in step-c) the suitable cyclizing agent is N,N-carbonyldiimidazole and suitable base is selected from organic and inorganic base and suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, ketone solvents, ether solvents, alcohol solvents and mixture thereof.

in step-d) the suitable reducing reducing agent is selected from DIBAL-H, lithium aluminiumhydride, Pd-C, Fe in acidic media like HC1 or acetic acid, Raney-Ni, sodiumborohydride, lithiumborohydride, NaBHsCN, sodiumborohydride/BF3-etherate, vitride, sodium borohydride/aluminium chloride or borane/aluminium chloride, sodiumborohydride/iodine and 9-BBN; and "sulfur derivatives" like sodium sulfite, sodium sulfide, sodium dithionate, sodium metabisulfite and the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, ketone solvents, ether solvents, alcohol solvents and mixture thereof.

The second aspect of the present invention provides a process for the preparation of (R)-5-chloro-N-(2-hydroxy-3 -(4-rutrophenylamino)propyl)thiophene-2-carboxarnide compound of formula-5, comprises of:
a) Reacting the 4-nitroaniline compound of formula-9 with (R)-l-amino-3-chloropropan-2-ol compound of formula-10 in the presence or absence of a suitable base in a suitable solvent to provide (R)-l-amino-3-(4-mtrophenylamino)propan-2-ol compound of formula-11,

b) condensing the compound of formula-11 with thiophene derivative compound of general formula-12 in the presence of a suitable base in a suitable solvent to provide (R)-5-chloro-N-(2-hydroxy-3-(4-mtrophenylarnino)propyl)thiophene-2-carboxamide compound of formula-5.

Wherein, in step-a) & b) the suitable base and solvents are same as defined in first aspect.

The third aspect of the present invention provides a process for the preparation of (R)-5-chloro-N-(2-hydroxy-3 -(4-nitrophenylamino)propyl)thiophene-2-carboxamide compound of formula-5, comprises of:

a) Reacting the 4-nitroaniline compound of formula-9 with l-amino-3-chloropropan-2-one compound of formula-13 in the presence or absence of a suitable base in a suitable solvent to provide l-arnino-3-(4-nitrophenylamino)propan-2-one compound of formula-15,

b) reducing the compound of formula-15 in the presence of a suitable chiral reducing agent in a suitable solvent to provide (R)-l-amino-3-(4-nitrophenylamino)propan-2-ol compound of formula-11,

c) condensing the compound of formula-11 with thiophene derivative compound of general formula-12 in the presence of a suitable base in a suitable solvent to provide (R)-5-chloro-N-(2-hydroxy-3-(4-nitrophenylamino)propyl)thiophene-2-carboxamide compound of formula-5.

The fourth aspect of the present invention provides a process for the preparation of (R)-5-chloro-N-(2-hydroxy-3-(4-nitrophenylamino)propyl)thiophene-2-carboxamide compound of formula-5, comprises of:

a) Reacting the 4-nitroaniline compound of formula-9 with l-amino-3-hydroxypropan-2-one compound of formula-14 in the presence or absence of a suitable base in a suitable solvent to provide l-amino-3-(4-nitrophenylamino)propan-2-one compound of formula-15,

b) reducing the compound of formula-15 in the presence of a suitable chiral reducing agent in a suitable solvent to provide (R)-l-amino-3-(4-nitrophenylamino)propan-2-ol compound of formula-11,

c) condensing the compound of formula-11 with thiophene derivative compound of general formula-12 in the presence of a suitable base in a suitable solvent to provide (R)-5-chloro-N-(2-hydroxy-3-(4-nitrophenylamino)propyl)thiophene-2-carboxamide compound of formula-5.

The fifth aspect of the present invention provides a process for the preparation of (R)-5-chloro-N-(2-hydroxy-3 -(4-nitrophenylamino)propyl)thiophene-2-carboxamide compound of formula-5, comprises of:

a) Reacting the 4-nitroaniline compound of formula-9 with l-amino-3-chloropropan-2-one compound of formula-13 in the presence or absence of a suitable base in a suitable solvent to provide l-amino-3-(4-nitrophenylamino)propan-2-one compound of formula-15, condensing the compound of formula-15 with thiophene derivative compound of general formula-12 in the presence of a suitable base in a suitable solvent to provide 5-chloro-N-(3-(4-nitrophenylamino)-2-oxopropyl)thiophene-2-carboxamide compound of formula-16,

c) reducing the compound of formula-16 in the presence of a suitable chiral reducing agent in a suitable solvent to provide (R)-5-chloro-N-(2-hydroxy-3-(4-nitrophenyl amino)propyl) thiophene-2-carboxamide compound of formula-5.

Wherein, in step-a) & b) the suitable base is selected from organic or inorganic base and suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, ketone solvents, ether solvents, alcohol solvents and mixture thereof.

In step-c) the suitable chiral reducing agent is selected from (R)-Methyl CBS and DIP-chloride.

Further (R)-5-chloro-N-(2-hydroxy-3-(4-nitrophenylamino)propyl)thiophene-2-carboxamide compound of formula-5 is also prepared by reducing the compound of formula-16 with a suitable reducing agent and the obtained racemic compound is further converted into compound of formula-5 by resolving the racemic compound with a suitable resolving agent.

The sixth aspect of the present invention provides a process for the preparation of (R)-5-chloro-N-(2-hydroxy-3 -(4-nitrophenylamino)propyl)thiophene-2-carboxamide compound of formula-5, comprises of:

a) Reacting the 4-nitroaniline compound of formula-9 with l-amino-3-hydroxypropan-2-one compound of formula-14 in the presence or absence of a suitable base in a suitable solvent to provide l-amino-3-(4-nitrophenylamino)propan-2-one compound of formula-15,

b) condensing the compound of formula-15 with thiophene derivative compound of general formula-12 in the presence of a suitable base in a suitable solvent to provide 5-chloro-N-(3-(4-nitrophenylamino)-2-oxopropyl)thiophene-2-carboxamide compound of formula-16,

c) reducing the compound of formula-16 in the presence of a suitable chiral reducing agent in a suitable solvent to provide (R)-5-chloro-N-(2-hydroxy-3-(4-nitrophenyl amino)propyl) thiophene-2-carboxamide compound of formula-5.

Wherein, in step-a) & b) the suitable base is selected from organic or inorganic base and suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, ketone solvents, ether solvents, alcohol solvents and mixture thereof.

In step-c) the suitable chiral reducing agent and suitable solvents are same as defined in step c) of fifth aspect.

The seventh aspect of the present invention provides novel intermediate (R)-5-chloro-N-(2-hydVoxy-3-(4-nitrophenylamino)propyl)thiophene-2-carboxamide compound of formula-5 & 5-cUoro-N-(3-(4-nitrophenylamino)-2-oxopropyl)thiophene-2-carboxamide compound of formula-16 which are used in the preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene compound of formula-1, which are represented by the below mentioned structural formulae:

Formula-5 Formula-16
The eighth aspect 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-
thiophene compound of formula-1, comprising the following steps of:

a) Reacting the compound of general formula-17 with (R)-glycidyl butyrate compound of formula-18 in the presence of a suitable base in a suitable solvent to provide (R)-4-(4-(5-(hydroxymethyl)-2-oxo-l,3-oxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-19,

b) chlorination of compound of formula-19 with a suitable chlorinating agent in the presence of a suitable base in a suitable solvent to provide (S)-4-(4-(5-(chloromethyl)-2-oxo-l,3-oxazolidin-3-yl)phenyl) morpholin-3-one compound of formula-20,

c) reacting the compound of formula-20 with ammonia in the presence of a suitable solvent to provide (S)-4-(4-(5-(aminomethyl)-2-oxo-1,3 -oxazolidin-3 -yl)phenyl)morpholin-3 -one compound of formula-21,

d) condensing the compound of formula-21 with thiophene derivative compound of general formula-12 in the presence 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 compound of formula-1.

Wherein, in step-a) the suitable base is selected from organic or inorganic base and suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, ketone solvents, ether solvents, alcohol solvents and mixture thereof.

in step-b) the suitable base is selected from organic or inorganic base and the suitable chlorinating agent is selected from thionyl chloride, oxalyl chloride, sulfuryl chloride, pivaloyl chloride, POCI3, PCI3 and PCI5 and suitable solvent is selected from hydrocarbon solvents, ester solvents, ketone solvents, ether solvents, alcohol solvents and mixture thereof.

in step-d) the suitable base is selected from organic or inorganic base and suitable solvent used in step-c) & d) are selected from chloro solvents, hydrocarbon solvents, ester solvents, ketone solvents, ether solvents, alcohol solvents and mixture thereof.

The ninth aspect 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-thiophene compound of formula-1, comprising the following steps of:

a) Reacting the compound of general formula-17 with (R)-glycidyl butyrate compound of formula-18 in the presence of a suitable base in a suitable solvent to provide (R)-4-(4-(5-(hydroxymethyl)-2-oxo-l,3-oxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-19,

b) chlorination of compound of formula-19 with a suitable chlorinating agent in the presence of a suitable base in a suitable solvent to provide (S)-4-(4-(5-(chloromethyl)-2-oxo-l,3-oxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-20,

c) reacting the compound of formula-20 with 5-chlorothiophene-2-carboxamide compound of formula-6 in the presence 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 compound of formula-1.
Wherein, in step-a), b) & c) the suitable base, suitable chlorinating agent and suitable solvents are same as defined in step-a), b) & c) of the eighth aspect of the present invention.

The present invention is schematically represented by following schemes:

Scheme-I:

X = Halogen, alkoxy, OH, sulfonyloxy

Base RT


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 l-amino-3-(4-nitrophenylamino)propan-2-ol (Formula-22)
Sodium carbonate (1.3 gm) was added to a mixture of 4-nitroaniline compound of formula-9 (3 gm) and dichloromethane (30 ml) at 25-30°C. l,3-dichloropropan-2-ol compound of formula-8 (8.13 gm) was added to the reaction mixture at 25-30°C, heated to reflux temperature and stirred for 5 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Water was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced preessure to get the title compound.Yield: 3.0 g.

Example-2: Preparation of (R)-l-chloro-3-(4-nitrophenylamino)propan-2-ol (Formula-7)
L-(+)-mandelic acid (3.3 gms) was added to the mixture of (R)-l-chloro-3-(4-nitrophenylamino)propan-2-ol compound of formula-22 (5 gms) and isopropyl alcohol (20 ml) at 25-30°C. Heated the reaction mixture to reflux temperature and stirred for 30 min at the same temperature. Cooled the reaction mixture to 25°-30°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with isopropyl alcohol. Dichloromethane and water were added to the obtained wet compound. Basify the reaction mixture with sodium carbonate solution at 25-30°C. Separated both the organic and aqueous layers. Aqueous layer was extracted with dichloromethane and combined the organic layers. Distilled off the solvent from the organic layer under reduced pressure and get the title compound. Yield: 2.2 g.
Example-3: Preparation of (R)-5-chloro-N-(2-hydroxy-3-(4-nitrophenylamino)propyl) thiophene-2-carboxamide (Formula-5)

(R)-l-chloro-3-(4-nitrophenylamino)propan-2-ol compound of formula-7 (5.4 gm) was added to a pre-cooled mixture of 5-chlorothiophene-2-carboxamide compound of formula-6 (5 gm) and dichloromethane (50 ml) at 0-5°C. Triethylamine (5 ml) was slowly added to the reaction mixture at 0-5°C and stirred for 30 min at the same temperature. Quenched the reaction mixture with purified water and then raised the temperature of the reaction mixture to 20-25°C and stirred for 30 min at the same temperature. Both the both organic and aqueous layers. Distilled off the solvent from the organic layer under reduced pressure and the obtained residue was purified by column chromatography using cyclohexane and ethyl acetate as eluents. Yield:6 g.

Example-4: Preparation of (R)-l-amino-3-(4-nitrophenylamino)propan-2-ol (Formula-11)
Sodium carbonate (2.3 gm) was added to a mixture of 4-nitroaniline compound of formula-9 (5 gm) and tetrahydrofuran (25 ml) at 25-30°C. (R)-l-amino-3-chloropropan-2-ol compound of formula-10 (11.8 gm) was added to the reaction mixture at 25-30°C, heated to reflux temperature and stirred for 5 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Water (30 ml) followed by dichloromethane (30 ml) was added to the reaction mixture at 25-3 0°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced preessure to get the title compound.Yield: 5.3 g.

Example-5: Preparation of (R)-5-chloro-N-(2-hydroxy-3-(4-nitrophenylamino)propyl) thiophene-2-carboxamide (Formula-5)

Thionyl chloride (5.5 gm) was added to a mixture of 5-chlorothiophene-2-carboxylic acid compound of formula-12a (5 gm), dichloromethane (50 ml) and N,N-dimethylformamide (0.5 ml) at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 2 hrs at the same temperature. After completion of the reaction, distilled off the solvent completely from the reaction mixture under reduced pressure. Cooled the obtained compound to 0-5°C. A mixture of (R)-l-amino-3-(4-nitrophenylamino)propan-2-ol compound of formula-11 (5.4 gm) and dichloromethane (25 ml) was added to the obtained compound at 0-5°C and stirred the reaction mixture for 40 min at the same temperature. After completion of the reaction, triethylamine (5 ml) was slowly added to the reaction mixture at 0-5°C and stirred for 30 min at the same temperature. Quenched the reaction mixture with purified water and then raised the temperature of the reaction mixture to 20-25°C and stirred for 30 min at the same temperature. Both the both organic and aqueous layers. Distilled off the solvent from the organic layer under reduced pressure and the obtained residue was purified by column chromatography using cyclohexane and ethyl acetate as eluents. Yield: 6 g;

Example-6: Preparation of (S)-5-chloro-N-((3-(4-nitrophenyl)-2-oxooxazolidin-5-yl)methyl) thiophene-2-carboxamide (FormuIa-4)

(R)-5-cMoro-N-(2-hyoVoxy-3-(4-nitrophenylamino)propyl)thiophene-2-carboxamide compound of formula-5 (5 gm) was added to a mixture of dichloromethane (25 ml), N,N-carbonyldiimidazole ( 6.8 gm) and dimethyl amino pyridine ( 0.34 gm) at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 2 hrs at the same temperature. After completion of the reaction, reaction mixture was cooled to 25-30°C. Water was added to the reaction mixture and pH of the reaction mixture was adjusted to 2 using dilute hydrochloric acid. Separated both the organic layer and aqueous layer. The organic layer was washed with water followed by 10% sodium carbonate solution. Distilled off the solvent completely from the organic layer under reduced pressure. The obtained compound was purified by column chromatography by using cyclohexane and ethyl acetate to get the title compound. Yield: 4.0 g.

Example-7: Preparation of (S)-N-((3-(4-aminophehyl)-2-oxooxazoIidin-5-yl)methyl)-5-chlorothiophene-2-carboxamide (Formula-3)
A mixture of (S)-5-chloro-N-((3-(4-nitrophenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide compound of formula-4 (2 gm), iron turnings (0.6 gm), ethanol (10 ml) and water (5 ml) was stirred at 25-30°C for 10 min. The reaction mixture was cooled to 15-20°C and 10 ml of concentrated hydrochloride was added to it. Slowly heated the reaction mixture to 60-65°C and stirred for 3 hrs at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C. Poured the reaction mixture into ice and stirred for 30 min.Filtered the reaction mixture and washed with water.

Dichloromethane was added to the filtrate at 25-30°C and stirred the reaction mixture for 15 min at the same temperature. Both the organic and aqueous layers were separated and the pH of the organic layer was adjusted to 8.5 by using 10% sodium hydroxide solution. Both the organic and aqueous layers were seperated and adjusted the pH of the aqueous layer to 1.2 with concentrated hydrochloric acid. Extracted the reaction mixture with dichloromethane and dried the dichloromethane layer over sodium sulfate. Distilled off the solvent completely from the organic layer under reduced pressure to get the title compound. Yield: 1.10 g.

ExampIe-8: Preparation of (S)-N-((3-(4-aminophenyl)-2-oxooxazolidin-5-yl)methyl)-5-chlorothiophene-2-carboxamide (Formula-3) [Alternative process]
(S)-5-chloro-N-((3-(4-nitrophenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide compound of formula-4 (3 gm) and methanol (30 ml) were charged into a par hydrogenator at 25-30°C. 5% Pd/C (0.5 gm) was added to the reaction mixture under nitrogen atmosphere at 25-30°C. 3-4 Kg/Cm2 hydrogen gas pressure was applied to the reaction mixture at 25-30°C and heated the reaction mixture to 40-45°C. Stirred the reaction mixture for 6 hrs at the same temperature. After completion of the reaction, the reaction mixture was cooled to 25-30°C and filtered the Pd/C through hyflow bed and washed with methanol. Distilled off the solvent completely from the filtrate under reduced pressure to get the title compound. Yield: 1.35 g.

Example-9: Preparation of (S)-5-chloro-N-((3-(4-(2-hydroxyethylamino)phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide (Formula-2)

Sodium carbonate (0.54 gm) was added to a mixture of (S)-N-((3-(4-aminophenyl)-2-oxooxazolidin-5-yl)methyl)-5-chloro thiophene-2-carboxamide compound of formula-3 (3 gm) and tetrahydrofiiran (15 ml) at 25-30°C. 2-chloroethanol (2.05 gm) was added to the reaction mixture at 25-3 0°C, heated to reflux temperature and stirred for 5 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Water (30 ml) followed by dichloromethane (30 ml) was added to the reaction mixture at 25-30°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced pressure to get the title compound.Yield: 2.19 g.

Example-10: Preparation of Rivaroxaban (Formula-1)
A mixture of isopropyl alcohol (3 ml) and (S)-5-chloro-N-((3-(4-(2-hydroxyethylamino) phenyl)-2-oxooxazolidin-5-yl)methyl)thiophene-2-carboxamide compound of formula-2 (3 gm) was stirred for 10 min at 25-30°C and water (3 ml) was added to it. Heated the reaction mixture to 35-40°C and sodium hydroxide solution (1.35 gm of NaOH in 3 ml of water) was added at the same temperature. Chloroacetyl chloride (1.86 gm) was added to the reaction mixture at 35-40°C. The NaOH solution and chloroacetyl chloride were added simultaneously at such a rate that pH maintained between 12.5-13.0. The reaction mixture was stirred for 60 min at the same temperature. After completion of the reaction, the reaction mixture was cooled to 30-35°C and stirred for 30 minutes. Filtered the precipitated solid and washed with water. The obtained compound was recrystallized in ethylene glycol. Yield: 3.3 g

Example-11: Preparation of (R)-4-(4-(5-(hydroxymethyl)-2-oxooxazolidin-3-yl)phenyl) morpholin-3-one
[Formula-19]
Potassium tertiary butoxide (2.25 gm) was added to the mixture of tetrahydrofuran (30 ml) and tert-butyl 4-(3-oxomorpholino)phenyl carbamate (3 gms) at 25-3 0°C and stirred for 15 minutes. (R)-glycidyl butyrate compound of formula-18 (1.56 ml) was added to the reaction mixture at 25-30° and stirred for 24 hours at die same temperature. After completion of the reaction, quenched the reaction mixture with water. Extracted the reaction mixture with methylene chloride. The organic layer was dried over sodium sulphate and distilled off the solvent completely from the organic layer under reduced pressure. The obtained compound was recrystallized from ethyl acetate to get the tile compound. Yield: 2.1 g.

Example-12: Preparation of (R)-4-(4-(5-(chloromethyl)-2-oxooxazolidin-3-yl)phenyI) morpholin-3-one [Formula-20]

Methylene chloride (20 ml) and triethyl amine (1.5 gms) were added to (R)-4-(4-(5-(hydroxymethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one (4 gms) at 25-30°C and stirred for 10 minutes at the same temperature. Thionyl chloride (3 gms) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 1 hour at the same temperature. After completion of the reaction, reaction mixture was cooled to25-30°C and quenched it with water. Both the organic and aqueous layers were separated and aqueous layer was extracted with methylene chloride. Combined the organic layers and distilled off the solvent completely from the organic layer to get the title compound. The obtained compound was purified by column chromatography using ethyl acetate/cyclohexane to get the title compound. Yield: 3 g.

Example-13: Preparation of (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)phenyl) morpholin-3-one [Formula-21]
Toluene (30 ml) was added to (R)-4-(4-(5-(chloromethyl)-2-oxooxazolidin-3-yl)phenyl) morpholin-3-one (5 gms) and cooled the reaction mixture to 0-5°C. Liq. Ammonia (7 ml) was slowly added to the reaction mixture at 0-5°C and stirred for 1 hour at the same temperature. After completion of the reaction, water was added to the reaction mixture and separated both the organic and aqueous layers. Distilled off the solvent from organic layer to get the title compound. The obtained compound was purified by column chromatography using ethyl acetate/cyclohexane to get the title compound. Yield: 3.5 g.
Example-14: Preparation of 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene

[Formula-1]
5-chlorothiophene-2-carboxylic methanesulfonic anhydride (2.4 gm) was added to a mixture of 4-{4-[(5S)-5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl]phenyl}morpholin-3-one (3.0 gm) and methylene dichloride (30 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.

Example-15: Preparation of 5-chIoro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morphoIinyl)phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene [Formula-1]
Cooled the mixture of 5-chlorothiophene-2-carboxamide (2.6 gm) compound of formula-6 and dichloromethane (35 ml) under nitrogen to 0-5°C. Diisopropyl ethylamine (6.2 gm) was added to it. Stirred the reaction mixture for 15 minutes at the same temperature. (R)-4-(4-(5-(chloromethyl)-2-oxooxazolidin-3-yl)phenyl)morpholin-3-one (5 g) compound of formula-20 was added to the reaction mixture at 0-5°C and stirred the reaction mixture for 1 hour at the same temperature. After completion of the reaction, quenched the reaction mixture with purified water at 0-5°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 1 hour. Filtered the precipitated solid and purified by column chromatography using ethyl acetate/cyclohexane to get the title compound. Yield: 5.25 g.

Example-16: Preparation of l-amino-3-(4-nitrophenyIamino)propan-2-one [FormuIa-15]
Sodium carbonate (1.3 gm) was added to a mixture of 4-nitroaniline compound of formula-9 (3 gm) and tetrahydrofuran (15 ml) at 25-30°C. (R)-l-amino-3-chloropropan-2-ol compound of formula-13 (7 gm) was added to the reaction mixture at 25-30°C, heated to reflux temperature and stirred for 5 hrs at the same temperature. Cooled the reaction mixture to 25-30°C. Water (30 ml) followed by dichloromethane (30 ml) were added to the reaction mixture at 25-3 0°C and stirred for 15 min at the same temperature. Both the organic and aqueous layers were separated and distilled off the solvent completely from the organic layer under reduced preessure to get the title compound. Yield: 3.18 g.

Example-17: Preparation of 5-chloro-N-(3-(4-nitrophenylamino)-2-oxopropyl)thiophene-2-carboxamide [Formula-16]

Dissolved 5-chlorothiophene-2-carboxylic acid (5 gms) in dichloromethane (50 ml) under nitrogen at 30°C. Cooled the reaction mixture to -20°C and added diisopropyl ethylamine (12.0 gms) to it. Slowly added methane sulfonyl chloride (5.3 gms) to the above reaction mixture at -20°C. Stirred the reaction mixture for 2 hours at -20°C. l-amino-3-(4-nitrophenylamino)propan-2-one compound of formula-15 (7 gms) 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: 9 g.
Example-18: Preparation of (R)-5-chloro-N-(2-hydroxy-3-(4-nitrophenylamino) propyl) thiophene-2-carboxamide

[Formula-5]
Methylene chloride (30 ml) was added to a mixture of borane DMS (4.3 ml) and R-methyl CBS (2 ml) at 25-30°C and stirred for 30 minutes at the same temperature. A solution of 5-chloro-N-(3-(4-nitrophenylamino)-2-oxopropyl)thiophene-2-carboxamide (3 gms) in methylene chloride was slowly added to the above reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. Cooled the reaction mixture to 0-10°C. Methanol was added to the reaction mixture at 0-10°C. Hydrogen peroxide solution followed by sulfuric acid solution was added to the reaction mixture at 10-15°C. Raised the temperature of the reaction mixture to 25-30°C. Both the organic and aqueous layers were separated and extracted the aqueous layer with methylene chloride. Combined the organic layers and washed with sodium sulphite solution followed by sodium chloride solution. Distilled off the solvent completely from the organic layer to get the title compound. The obtained compound was purified by column chromatography using ethyl acetate/cyclohexane to get the title compound. Yield: 2 gms.

We Claim:

1. A novel 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 compound of formula-1, comprising the following steps of:

a) Reacting the 4-nitroaniline compound of formula-9 with (R)-l-amino-3-chloropropan-2-ol
compound of formula-10

Formula-10 in the presence or absence of a suitable base in a suitable solvent to provide (R)-l-amino-3-(4-nitrophenylamino)propan-2-ol compound of formula-11,

b) condensing the compound of formula-11 with thiophene derivative compound of general
formula-12

Formula-12 (Wherein X = Halogen or Ci-Cn alkoxy or OH; alkyl/aryl sulfonyloxy) in the presence of a suitable base in a suitable solvent to provide (R)-5-chloro-N-(2-hydroxy-3-(4-mtrophenylamino)propyl)thiophene-2-carboxamide compound of formula-5,

Formula-5
c) reacting the compound of formula-5 with a suitable cyclizing agent in presence of a suitable
base in a suitable solvent to provide (S)-5-chloro-N-((3-(4-nitrophenyl)-2-oxo-l,3-
oxazolidin-5-yl)methyl)thiophene-2-carboxamide compound of formula-4,

o Formula-4
d) reducing the compound of formula-4 with a suitable reducing agent in a suitable solvent to
provide (S)-N-((3-(4-aminophenyl)-2-oxo-1,3-oxazolidin-5-yl)methyl)-5-chloro thiophene-2-
carboxamide compound of formula-3,
o Formula-3

e) reacting the compound of formula-3 with 2-chloroethanol in the presence or absence of a
suitable base in a suitable solvent to provide (S)-5-chloro-N-((3-(4-(2-hydroxyethyl amino)
phenyl)-2-oxo-l,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide compound of formula-
2, o Formula-2

f) reacting the compound of formula-2 with chloroacetyl chloride in the presence 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 compound of formula-1.

2. The process according to claim-1, wherein,

in step-a), b), e) & f) the suitable base is selected from organic or inorganic bases and
suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, ketone solvents, ether solvents, alcohol solvents and mixture thereof.

in step-c) the suitable cyclizing agent is N,N-carbonyldiimidazole and suitable base is selected from organic and inorganic base and suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, ketone solvents, ether solvents, alcohol solvents and mixture thereof, in step-d) the suitable reducing reducing agent is selected from DIBAL-H, Pd-C, Fe in acidic media like HC1 or acetic acid, lithium aluminiumhydride, sodiumborohydride, lithiumborohydride, NaBHsCN, sodiumborohydride/BF3-etherate, vitride, sodium borohydride/aluminium chloride or borane/aluminium chloride, sodiumborohydride/iodine and 9-BBN; and "sulfur derivatives" like sodium sulfite, sodium sulfide, sodium dithionate, sodium metabisulfite and the suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, ketone solvents, ether solvents, alcohol solvents and mixture thereof.

3. A novel 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 compound of formula-1, comprising the following steps of:
a) Reacting the 4-nitroaniline compound of formula-9 with (R)-l-amino-3-chloropropan-2-ol compound of formula-10 in the presence of sodium carbonate in tetrahydrofuran to provide (R)-l-amino-3-(4-nitrophenylamino)propan-2-ol compound of formula-11,

b) condensing the compound of formula-11 with 5-chlorothiophene-2-carboxylic acid compound of formula-12a in the presence of triethylamine in dichloromethane to provide (R)-5-chloro-N-(2-hydroxy-3-(4-nitrophenylamino)propyl)thiophene-2-carboxamide compound of formula-5.

c) reacting the compound of formula-5 with N,N-carbonyldiimidazole in presence of dimethyl amino pyridine in dichloromethane to provide (S)-5-chloro-N-((3-(4-nitrophenyl)-2-oxo-l,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide compound of formula-4,

d) reducing the compound of formula-4 in the presence of Pd/C in methanol or Fe in acidic media like HC1 or acetic acid to provide (S)-N-((3-(4-aminophenyl)-2-oxo-l,3-oxazolidin-5-yl)methyl)-5-chlorothiophene-2-carboxamide compound of formula-3,

e) reacting the compound of formula-3 with 2-chloroethanol in the presence of sodium carbonate in tetrahydrofuran to provide (S)-5-chloro-N-((3-(4-(2-hydroxyethylamino) phenyl)-2-oxo-l,3-oxazolidin-5-yl)methyl)thiophene-2-carboxamide compound of formula-2,

f) reacting the compound of formula-2 with chloroacetyl chloride in the presence of aqueous NaOH in isopropanol to provide 5-chloro-N-({(5S)-2-oxo-3-[4-(3-oxo-4-morpholinyl) phenyl]-l,3-oxazolidin-5-yl}methyl)-2-thiophene compound of formula-1.

4. 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 compound of formula-1, comprising the following steps of:

a) Reacting the compound of general formula-17
Formula-17 (Wherein R = alkyl, substituted alkyl, aryl, aryl alkyl, substituted aryl) with (R)-glycidyl butyrate compound of formula-18

Formula-18 in the presence of a suitable base in a suitable solvent to provide (R)-4-(4-(5-(hydroxyl methyl)-2-oxo-1,3-oxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-19,
Formula-19

b) chlorination of compound of formula-19 with a suitable chlorinating agent in the presence of
a suitable base in a suitable solvent to provide (S)-4-(4-(5-(chloromethyi)-2-oxo-l,3-
oxazolidin-3-yl)phenyl) morpholin-3-one compound of formula-20,
Formula-20

c) reacting the compound of formula-20 with ammonia in the presence of a suitable solvent to
provide (S)-4-(4-(5-(aminomethyl)-2-oxo-l,3-oxazolidin-3-yl)phenyl)morpholin-3-one
compound of formula-21,

Formula-21

d) condensing the compound of formula-21 with thiophene derivative compound of general
formula-12

Formula-12 (Wherein X = Halogen or Ci-Cg alkoxy or OH; alkyl/aryl sulfonyloxy) in the presence of a suitable base selected from organic or inorganic 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 compound of formula-1.
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 compound of formula-1, comprising the following steps of:

a) Reacting the compound of general formula-17
Formula-17 (Wherein R = alkyl, substituted alkyl, aryl, aryl alkyl, substituted aryl) with (R)-glycidyl butyrate compound of formula-18 in the presence of a suitable base in a suitable solvent to provide (R)-4-(4-(5-(hydroxymethyl)-2-oxo-l,3-oxazolidin-3-yl)phenyl)morpholin-3-one compound of formula-19,

b) chlorination of compound of formula-19 with a suitable chlorinating agent in the presence of
a suitable base in a suitable solvent to provide (S)-4-(4-(5-(chloromethyl)-2-oxo-l,3-oxa
zolidin-3-yl)phenyl) morpholin-3-one compound of formula-20,

c) reacting the compound of formula-20 with 5-chlorothiophene-2-carboxamide compound of formula-6 in the presence of a suitable base selected from organic or inorganic 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 compound of formula-1.

6. The process according to claim 4 or 5, wherein,
in step-a) step-c) & step-d) the suitable base is selected from organic or inorganic base and suitable solvent is selected from chloro solvents, hydrocarbon solvents, ester solvents, ketone solvents, ether solvents, alcohol solvents and mixture thereof.

in step-b) the suitable chlorinating agent is selected from thionyl chloride, sulfuryl chloride, oxalyl chloride, pivaloyl chloride, POCI3, PCI3 and PCI5 and suitable solvent is selected from hydrocarbon solvents, ester solvents, ketone solvents, ether solvents, alcohol solvents and mixture thereof.

7. A novel process for the preparation of (R)-5-chloro-N-(2-hydroxy-3-(4-nitro phenylamino)
propyl)thiophene-2-carboxamide compound of formula-5, comprising the following steps of:

a) Reacting the 4-nitroaniline compound of formula-9,
02N—I j— NH2 Formula-9 with l,3-dichloropropan-2-ol compound of formula-8
OH

Formula-8 in the presence of a suitable base in a suitable solvent to provide l-chloro-3-(4-nitrophenyl amino)propan-2-ol compound of formula-22,

Formula-22 and followed by resolution of the compound of formula-22 with suitable resolving agent to provide the (R)-l-chloro-3-(4-nitrophenylamino)propan-2-ol compound of formula-7,

Formula-7 b) condensing the compound of formula-7 with 5-chlorothiophene-2-carboxamide compound of
formula-6

Formula-6 in the presence of a suitable base in a suitable solvent to provide (R)-5-chloro-N-(2-hydroxy-3-(4-nitrophenylamino)propyl)thiophene-2-carboxamide compound of formula-5.

8. A process for the preparation of 5-chloro-N-(3-(4-nitrophenylamino)-2-oxopropyl)
thiophene-2-carboxamide compound of formula-16,

Formula-16 comprises of:

a) Reacting the 4-nitroaniline compound of formula-9 with l-amino-3-chloropropan-2-one compound of formula-13 in the presence or absence of a suitable base in a suitable solvent to provide l-amino-3-(4-nitrophenylamino)propan-2-one compound of formula-15,
b) condensing the compound of formula-15 with thiophene derivative compound of general formula-12 in the presence of a suitable base in a suitable solvent to provide 5-chloro-N-(3-(4-ru^ophenylamino)-2-oxopropyl)thiophene-2-carboxamide compound of formula-16.

9. A process for the preparation of 5-cUoro-N-(3-(4-nitrophenylamino)-2-oxopropyl)
thiophene-2-carboxamide compound of formula-16, comprises of:

a) Reacting the 4-nitroaniline compound of formula-9 with l-amino-3-hydroxypropan-2-one compound of formula-14 in the presence or absence of a suitable base in a suitable solvent to provide l-amino-3-(4-nitrophenylamino)propan-2-one compound of formula-15,

b) condensing the compound of formula-15 with thiophene derivative compound of general formula-12 in the presence of a suitable base in a suitable solvent to provide 5-chloro-N-(3-(4-nitrophenylamino)-2-oxopropyl)thiophene-2-carboxamide compound of formula-16.

10. The compounds having the following structural formulae: