PROCESS FOR THE PREPARATION OF LINEZOLID

FIELD OF THE INVENTION

The present invention provides a process for the preparation of Linezolid, used for the treatment of infections caused by multi-resistant bacteria.

BACKGROUND OF THE INVENTION

Linezolid is a synthetic antibiotic, used for the treatment of serious infections caused by Gram-positive bacteria that are resistant to several other antibiotics. Linezolid is a synthetic antibiotic, the first of the oxazolidinone class, used for the treatment of infections caused by multi-resistant bacteria including streptococcus and methicillin-resistant Staphylococcus aureus (MRSA). Chemically linezolid I (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl] acetamide. The empirical formula is C16H20FN3O4. Its molecular weight is 337.35, and its chemical structure is represented below: Linezolid is marketed by Pfizer under the trade names Zyvox (in the United States, United Kingdom, Australia and several other countries), Zyvoxid (in Europe), and Zyvoxam (in Canada and Mexico). WO9507271 (Barbachyn et al, 1994), US5688792 and EP0717738 first claimed and disclosed Linezolid and its process of preparation. The process of the US5688792 patent describes the usage of R -glycidylbutyrate which results in the formation of (R)- N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methanol which in the subsequent stages has to be converted to various intermediary compounds to finally form linezolid. The said process also encompasses intermediary azide compound, which is difficult to handle at an industrial level.

WO2012114355 (Alia, Raghu Mitra et al, 2010), discloses a process for preparing Linezolid as described in the following scheme: The disadvantages of the invention covered under '355 are that it is a cumbersome process that may not be cost effective and being a lengthy process, the productivity will be affected. WO2012019632 (Bartos Petr, et al, 2010) appears to cover a process for preparing 3-(3-fluoro-4-(morpholin-4-yl)phenyl)-2-oxooxazolidin-5(S)-ylmethyl)amine and/or an acid addition salt, an intermediate used in the preparation of Linezolid, from compounds of formula (IXa) The drawbacks of '632 are the use of metal salt of diformylamide, which is not commercially available and therefore increasing the cost of API. Also, the disadvantages of using metal salt of diformylamide, is that it is sensitive to water and it may require special storage conditions like dehumidifier. US20070021417 (Serguei Fine et al, 2005) appears to cover a process for preparation of S-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl amine from R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) by catalytic hydrogenation comprising combining R-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl-methyl azide (III) with an organic solvent other than ethyl acetate. In the above described process, the drawbacks are the preparation of azide intermediate is not an industrially preferred reaction to handle, also catalytic hydrogenation requires special facility which increases the project cost and is environmentally hazardous. The use of catalyst can increase the analysis cost for heavy metal. The inventors of the present invention have developed cost-effective, simple and environmental friendly processes for preparation of Linezolid. The inventors have worked towards providing an operational friendly and cost effective process, wherein the formation of impurities is minimized and the yields are good.
The inventors have developed improved processes for preparing Linezolid using raw materials that are commercially available; don't require special storage conditions or any special equipments like autoclave.

OBJECT OF THE INVENTION

The main object of the present invention is to provide simple, operational and environmental friendly processes for preparing Linezolid. Another object of the present invention is to provide highly pure Linezolid that provides good yields of the product and wherein the formation of impurities is minimized. Yet another object of the present invention is to provide highly economical process for the preparation of Linezolid.

SUMMARY OF THE INVENTION

According to one aspect of the present invention, the process for preparing linezolid comprises

a) reacting 5-nitroisoindoline-l,3-dione (I) in presence of organic solvent, phase transfer catalyst and base such as sodium methoxide to obtain (S)-5-nitro-2-(oxiran-2-ylmethyl)isoindoline-l,3-dione, compound of formula (III);

b) condensation of compound of formula (III) with 3-fluoro-4-morpholinoaniline (IV) in presence of organic solvent to obtain (S)-2-(3-((3-fluoro-4-morpholinophenyl)amino)-2-hydroxypropyl)-5-nitroisoindoline-l,3-dione, compound of formula (V);

c) conversion of compound of formula (V) with carbonylating reagent, such as carbonyl diimidazole, phosgene, preferably carbonyl diimidazole in presence of polar solvent to obtain (S)-2-((3 -(3 -fluoro-4-morpholinophenyl)-2-oxooxazolidin-5 -yl)methyl)-5 -nitroisoindoline-1,3-dione, compound of formula (VI); Or in another variation condensation of methyl (3-fluoro-4 morpholinophenyl)carbamate in polar solvent with (S)-5-nitro-2-(oxiran-2-ylmethyl)isoindoline-l,3-dione, compound of formula (III) in presence of n-butyl lithium in hexane or lithium tertiary butoxide at a temperature range of 25 to 55 °C, preferably 25-30 °C to obtain (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)-5-nitroisoindoline-l,3-dione, compound of formula (VI);

d) reacting compound of formula (VI) in organic solvent with hydrazine hydrate or methylamine at a temperature range of 50-90 °C, preferably 70-85 °C to obtain non-isolated (5 S)-5-(aminomethyl)-3 - [3 -fluoro-4-(morpholin-4-yl)phenyl] -1,3-oxazolidin-2-one, compound of formula (VII) and e) the non-isolated compound of formula (VII) is further treated with acetic anhydride in presence of organic solvent to give N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-1,3 oxazolidin-5-yl}methyl)acetamide (Linezolid). According to another aspect of the present invention, process for preparing Linezolid comprising condensation of methyl (3-fluoro-4-morpholinophenyl)carbamate in polar solvent with (S)-5-nitro-2-(oxiran-2-ylmethyl)isoindoline-l,3-dione, compound of formula (III) in presence of n-butyl lithium in hexane or lithium tertiary butoxide at a temperature range of 25 to 55 °C, preferably 25-30 °C to obtain (S)-2-((3-(3-fluoro-4 morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)-5-nitroisoindoline-l,3-dione, compound of formula (VI); which is reacted with hydrazine hydrate or methylamine to obtain non-isolated (5S)-5-(aminomethyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-l,3-oxazolidin-2-one, compound of formula (VII) and treated with acetic anhydride to obtain N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (Linezolid). According to yet another aspect of the present invention, Linezolid is crystallized from non polar solvents such as cyclohexane, hexane, diethyl ether, preferably cyclohexane.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to a simple, operational and environmental friendly process for preparing pure crystalline form of Linezolid. The present invention relates to improved process for preparing Linezolid using raw materials that are commercially available. The present invention for preparation of Linezolid does not require special storage conditions or any special equipments like autoclave.
The present invention relates to an economical process for the preparation of Linezolid. The present invention relates to a process for preparing Linezolid which is depicted in Schemes A and B. Scheme A; According to one embodiment of the present invention, the process for the preparation of linezolid involves the reaction of 5-nitroisoindoline-l,3-ctione (I) with ((S)-2-(chloromethyl) oxirane) (II)
in presence of organic solvent, phase transfer catalyst and base such as sodium methoxide to obtain (S)-5-nitro-2-(oxiran-2-ylmethyl)isoindoline-l,3-dione, compound of formula (III). \—/ The organic solvent used in the reaction is selected from methanol, ethanol, isopropanol, preferably isopropanol and the phase transfer catalyst is selected from Tetra-n-butylammonium bromide, benzyl trimethylammonium chloride, benzyl trimethylammonium fluoride, preferably benzyl trimethylammnoium chloride. According to one embodiment of the present invention, (S)-5-nitro-2-(oxiran-2-ylmethyl)isoindoline-l,3-dione, compound of formula (III) is reacted with 3-fluoro-4-morpholinoaniline (IV) to give(S)-2-(3-((3-fluoro-4-morpholinophenyl)amino)-2-hydroxypropyl)-5-nitroisoindoline-1,3-dione, compound of formula (V) in presence of organic solvents such as methanol, isopropanol, ethanol, water and mixtures thereof, preferably methanol.

According to another embodiment of the present invention, (S)-2-(3-((3-fluoro-4-morpholinophenyl)amino)-2-hydroxypropyl)-5-nitroisoindoline-l,3-dione (V) is reacted with carbonyl diimidazole in presence of polar organic solvents such as DMF, N,N' -dimethyl acetamide, ethyl acetate ,Acetonitrile, preferably DMF and N,N'-dimethyl acetamide at a temperature range of 25-30 °C to give (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)-5-nitroisoindoline-1,3-dione (VI). According to an alternate embodiment of the present invention, (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)-5-nitroisoindoline-l ,3-dione (VI) is prepared by reacting methyl (3-fluoro-4 morpholinophenyl)carbamate and (S)-5-nitro-2-(oxiran-2-ylmethyl)isoindoline-l,3-dione, compound of formula (III) with n-butyl lithium in hexane or lithium tertiary butoxide in presence of polar solvents such as tetrahydrofuran, ethyl acetate, methylene dichloride, acetonitrile, preferably tetrahydrofuran at a temperature range of 25 to 55 °C, preferably 25-30 °C. In yet another embodiment of thepresent invention, (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)-5-nitroisoindoline-l,3-dione (VI) in organic solvent such as methanol, water and mixtures thereof is reacted with hydrazine hydrate or methylamine at 70-90 °C, preferably 70-85 °C to give non-isolated (5S)-5-(aminomethyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-l,3-oxazolidin-2-one (VII).

The residue of (5S)-5-(aminomethyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-l,3-oxazolidin-2-one (VII) is treated with acetic anhydride in presence of organic solvents such as dichloromethane, ethyl acetate, preferably dichloromethane to obtain N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (Linezolid), which is crystallized from non polar solvents such as cyclohexane, hexane, diethyl ether, preferably cyclohexane. While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.

EXAMPLES

Example 1: Preparation of (S)-5-nitro-2-(oxiran-2-ylmethyl)isoindoline-l,3-dione
To a suspension of 5-nitroisoindoline-l,3-dione (100 g, 0.52 moles) and benzyl trimethyl ammonium chloride (10 g) in Isopropanol (200 ml), S-Epichlorohydrin (100 g 1.08 moles) was added and the mixture was heated to 60°C and maintained for 5 h at the same temperature. 30% Sodium methoxide in methanol (160 g) was added portion wise at 10-15°C to the reaction mass, the temperature was raised to 25-30°C and the reaction mass was stirred for 2-3 h at the same temperature. After completion of the reaction, water (600 ml) was added, stirred for 10 min, filtered the solid obtained and washed with water to obtained titled compound. Weight: 100 g (77.5%)

Example-2: Preparation of (5S)2-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-5-nitro-isoindole-l,3-dione To a solution of methyl (3-fluoro-4-morpholinophenyl)carbamate (50 g,0.196 moles) in Tetrahydrofuran (250 ml), ~15%w/w n-butyl lithium in hexanes (164 ml,0.392moles) was added over a period of 30-40 min at 0 to -10°C and stirred for 30 min at 0 to -10°C. 5-nitro-2-[(2S)-oxiran-2-ylmethyl]-l#-isomdole-l,3(2//)-dione (55 g,0.221 moles) was added over 30-40 min at 0 to -10°C, stirred and the temperature was slowly raised to 50-55°C. The reaction was continued (~4 hrs) at 50-55°C till the conversion was about 75%. The solvent was removed by distillation under reduced pressure to obtain a thick residue. The residue was dissolved in Methylene chloride (500ml) and washed with water (300 ml x 2). The Methylene chloride layer was concentrated to get an oily residue. Isopropanol (100ml) was added to the residue and stirred for 15min at 50-55°C. The resulting product slurry was stirred for 30min, filtered, the wet cake was washed with pre cooled Isopropanol (25ml) and dried at 40-45°C to obtain crude (5S)2-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-5-nitro-isoindole-l,3-dione. A pure sample was obtained by re-crystallization from Isopropanol. Yield: 75 g (81%)

Example-3: Preparation of (5S)2-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazoIidin-5-ylmethyl]-5-nitro-isoindole-l,3-dione To a solution of methyl (3-fluoro-4-morpholinophenyl)carbamate (50 g,0.196 moles) in Tetrahydrofuran (250 ml), lithium tertiary butoxide (20 g, 0.25 moles) was added at 10 -15°Cand stirred for 30 min at 10 -15°C. 5-nitro-2-[(25)-oxiran-2-ylmethyl]-l/f-isoindole-l,3(2//)-dione (55 g, 0.221 moles) was added over 30-40 min at 10 -15°C, stirred and the temperature was slowly raised to 25-30°C. The reaction was continued for 24 hrs at 25-30°C. After completion of the reaction, THF was evaporated under reduced pressure below 45 °C to get a residue. The residue was dissolved in Methylene chloride (500ml) and washed with water (300ml x 2). The Methylene chloride layer was concentrated to get an oily residue. Isopropanol (100ml) was added to the residue and stirred for 15min at 50-55°C. The resulting product slurry was stirred for 30min, filtered and the wet cake was washed with pre cooled Isopropanol (25ml). The wet cake was dried at 40-45°C to obtain crude (5S)2-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-5-nitro-isoindole-l,3-dione. A pure sample was obtained by re-crystallization from Isopropanol. Yield: 75 g (81%)

Example-4: Preparation of Preparation of (S)-2-(3-((3-fluoro-4 morpholinophenyl)amino)-2-hydroxypropyl)-5-nitroisoindoline-l,3-dione
To a solution of 3-fluoro-4-morpholinoaniline (50 g , 0.255 moles) in methanol (500 ml), (S)-5-nitro-2-(oxiran-2-ylmethyl)isoindoline-l,3-dione (70 g, 0.282 moles) was added and refluxed for 24 h. After completion of reaction, the reaction mass was cooled to 10-15°C, the solid obtained was filtered and washed with chilled methanol (10 ml) to obtain the titled compound. Wt: 100 g (88%)

Example-5: Preparation of (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yI)methyl)-5-nitroisoindoline-l,3-dione To a solution of (S)-2-(3-((3-fluoro-4-morpholinophenyl)amino)-2-hydroxypropyl)-5-nitroisoindoline-l,3-dione (100 g, 0.225 moles) in DMF (300 ml), carbonyl di imidazole (60 g, 0.370 moles) was added and stirred at 25-30°C till completion of the reaction. After completion of the reaction, water (600 ml) was added to the reaction mass and the solid obtained was filtered to yield a titled compound as a light yellow compound. Wt: 100 g (85%)

ExampIe-6: Preparation of (S)-2-((3-(3-fluoro-4-morpholinophenyI)-2-oxooxazoIidin-5-yl)methyl)-5-nitroisoindoline-l,3-dione To a solution of (S)-2-(3-((3-fluoro-4-morpholinophenyl)amino)-2-hydroxypropyl)-5-nitroisoindoline-l,3-dione (50 g, 0.112 moles) in N,N-Dimethyl acetamide (100 ml) carbonyl di imidazole (30 g, 0.185 moles) was added and stirred at 25-30°C till completion of the reaction. After completion of the reaction, water (600 ml) was added to the reaction mass and the solid obtained was filtered to yield a titled compound as a white compound. Wt: 5 lg (86%).

Example 7: Preparation of (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)-5-nitroisoindoline-l,3-dione To a solution of (S)-2-(3-((3-fluoro-4-morpholinophenyl)amino)-2-hydroxypropyl)-5-nitroisoindoline-l,3-dione (10 g, 0.0225 moles) in N,N-Dimethyl acetamide (50 ml) carbonyl di imidazole (6 g, 0.037 moles) was added and stirred at 25-30°C till completion of the reaction. After completion of the reaction, water (10 ml) was added to the reaction mass and the solid obtained was filtered to yield a titled compound as a white compound. Wt:10g(85%)

Example 8: Preparation of N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (Linezolid) To a mixture of Methanol (100 ml), DM water (400 ml) and (5S)2-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-5-nitro-isoindole-l,3-dione (100 g 0.212 moles ) Methyl amine solution (47 g) was added to the reaction mixture at 25-30°C, stirred, the temperature was slowly raised to 80-85°C and stirred for 2-3 hours at 80-85°C. The reaction mixture was cooled to 25-30°C and dichloromethane (500 ml) was added to it. The reaction mixture was stirred for 15 min and the two layers were separated. MDC was distilled out by atmospheric pressure completely to get the residual product, (5S)-5-(amino methyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-l,3-oxazolidin-2-one. Dichloromethane (400 ml) was added to the residue and acetic anhydride (25 g) was slowly added at 25-30°C over a period of 60 min. The reaction mixture was stirred for 60 min at 25-30°C.The reaction was checked for its completion by HPLC/TLC. 5% aqueous sodium bicarbonate solution was slowly added to reaction mixture, stirred for 15 min and the two layers were separated. The dichloromethane layer was washed with D M Water (200 ml). The dichloromethane layer was filtered through hi-flo and dichloromethane was distilled out completely under vacuum below 40°C. Cyclohexane (500 ml) was added to the residue and heated to 45-50°C. The slurry obtained was cooled to 20-25 °C, stirred for 60 min, the solid obtained was filtered, washed with cyclohexane (200 ml) and dried at 45-55°C to furnish pure crystalline N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (Linezolid) (53 g 75%).

Example 9: Preparation of N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (Linezolid) To a mixture of Methanol (100 ml) ,DM water (400 ml) and (5S)2-[3-(3-Fluoro-4-morpholin-4-yl-phenyl)-2-oxo-oxazolidin-5-ylmethyl]-5-nitro-isoindole-l,3-dione (100 g 0.212 moles ), Hydrazine hydrate (50 g) was added to the reaction mixture at 25-30°C, stirred, the temperature was slowly raised to 70-75°C and stirred for 2-3 hours at 70-75°C. The reaction mixture was cooled to 25-30°C and dichloromethane (250 ml) was added to it. The reaction mixture was stirred for 15 min and the two layers were separated. MDC was distilled out by atmospheric pressure completely to get the residual product, (5S)-5-(aminomethyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-l,3-oxazolidin-2-one. Dichloromethane (200 ml) was added to the residue and acetic anhydride (13 g) was slowly added at 25-30°C over a period of 60 min. The reaction mixture was stirred for 60 min at 25-30°C. After completion of the reaction, 5% aqueous sodium bicarbonate solution was slowly added to reaction mixture, stirred for 15 min and the two layers were separated. The dichloromethane layer was washed with water (100 ml). The dichloromethane layer was filtered through hi-fio and dichloromethane was distilled out completely under vacuum below 40°C. Cyclohexane (250 ml) was added to the residue and heated to 45-50°C. The slurry obtained was cooled to 20-25 °C, stirred for 60 min, the solid obtained was filtered, washed with cyclohexane (100 ml) and dried at 45-55°C to furnish pure crystalline N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (Linezolid) (55 g 77 %).

We claim:

1. A process for preparing Linezolid comprising

a) reacting 5-nitroisoindoline-l,3-dione (I) with ((S)-2-(chloromethyl) oxirane) (II) in presence of organic solvent, phase transfer catalyst and base such as sodium methoxide to obtain (S)-5-nitro-2-(oxiran-2-ylmethyl)isoindoline-l,3-dione, compound of formula (III);

b) condensation of compound of formula (III) with 3-fluoro-4-morpholinoaniline (IV) in presence of organic solvent to obtain (S)-2-(3-((3-fluoro-4-moipholinophenyl)amino)-2-hydroxypropyl)-5-nitroisoindoline-l,3-dione, compound of formula (V);

c) conversion of compound of formula (V) with carbonylating reagent, such as carbonyl diimidazole, phosgene, preferably carbonyl diimidazole in presence of polar solvent to obtain (S)-2-((3 -(3 -fluoro-4-morpholinophenyl)-2-oxooxazolidin-5 -yl)methyl)-5 -nitroisoindoline-1,3-dione, compound of formula (VI); Or in another variation condensation of methyl (3-fluoro-4 morpholinophenyl)carbamate in polar solvent with (S)-5-nitro-2-(oxiran-2 ylmethyl)isoindoline-l,3-dione, compound of formula (III) in presence of n-butyl lithium in hexane or lithium tertiary butoxide at a temperature range of 25 to 55 "C, preferably 25-30 °C to obtain (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)-5-nitroisoindoline-l,3-dione, compound of formula (VI);

d) reacting compound of formula (VI) in organic solvent with hydrazine hydrate or methylamine at a temperature range of 70-90 °C, preferably 70-85 °C to obtain non-isolated (5S)-5-(aminomethyl)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-l,3-oxazolidin-2-one, compound of formula (VII) and e) the non-isolated compound of formula (VII) is further treated with acetic anhydride in presence of organic solvent to obtain N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (Linezolid).

2. A process according to claim 1, wherein Linezolid is crystallized from non polar solvents such as cyclohexane, hexane, diethyl ether, preferably cyclohexane.

3. A process according to claim 1 a), wherein the organic solvent is selected from methanol, ethanol, isopropanol, preferably isopropanol and the phase transfer catalyst is selected from Tetra-n-butylammonium bromide, benzyl trimethylammonium chloride, benzyl trimethylammonium fluoride, preferably benzyl trimethylammnoium chloride.

4. A process according to claim 1 b), wherein the organic solvent is selected from methanol, isopropanol, ethanol, water and mixtures thereof, preferably methanol.

5. A process according to claim 1 c), wherein the polar solvents are selected from DMF, N,N'-dimethylacetamide, THF, dichloromethane, ethyl acetate ,Acetonitrile , preferably DMF, N,N'-dimethylacetamide and THF.

6. A process according to claim 1 d), wherein the organic solvent is selected from methanol, ethanol, water and mixtures thereof, preferably methanol and water.

7. A process according to claim 1 e), wherein the organic solvents is selected from dichloromethane, ethyl acetate, preferably dichloromethane.

8. A process for preparing Linezolid comprising condensation of methyl (3-fluoro-4-morpholinophenyl)carbamate in polar solvent with (S)-5-nitro-2-(oxiran-2-ylmethyl)isoindoline-l,3-dione, compound of formula (III) in presence of n-butyl lithium in hexane or lithium tertiary butoxide at a temperature range of 25 to 55 °C, preferably 25-30 °C to obtain (S)-2-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)-5-nitroisoindoline-l,3-dione, compound of formula (VI); which is reacted with hydrazine hydrate or methylamine to obtain non-isolated (5S)-5-(aminomethyl)-3-[3-fluoro-4-(morpholin-4-yl) phenyl]-l,3-oxazolidin-2-one, compound of formula (VII), and treated with acetic anhydride to obtain N-({(5S)-3-[3-fluoro-4-(morpholin-4-yl)phenyl]-2-oxo-l ,3-oxazolidin-5-yl}methyl)acetamide (Linezolid).

9. A process according to claim 8, wherein the polar solvent is selected from THF, dichloromethane, ethyl acetate, acetonitrile, preferably THF.

10. An improved process according to any of the preceding claims substantially as herein described with reference to examples.