CLIAMS:We Claim:

1. A process for preparation of crystalline Linezolid Form III comprising the steps of:
(a) suspending crystalline Linezolid in a solvent at 25-30° C to obtain a solution;
(b) heating the solution obtained in step (a) to 75-80° C and stirring;
(c) slowly cooling the whole reaction mass obtained in step (b) to 25-30° C and stirring to cause the crystallization;
(d) recovering the crystalline Linezolid Form-III from the reaction mass of step (c) and washing with fresh solvent to obtain highly pure crystalline Form-III of Linezolid.

2. The process as claimed in claim 1, wherein the solvent used in step (a) and step (d) is an organic solvent selected from a cyclic ether, e.g. 1,4-dioxane; an aliphatic ether e.g. diethyl ether, methyl tert-butyl ether; an aliphatic ester, e.g. ethyl acetate; an aliphatic alcohol, e.g. methanol, ethanol, 1-propanol, isopropanol or 1-butanol; toluene, xylene, chloroform, methylene dichloride, acetonitrile, acetone and methyl ethyl ketone.

3. The process as claimed in claims 2, wherein the organic solvent used in step (a) and step (d) is 1,4-dioxane.

4. A process for preparation of crystalline Linezolid Form III comprising the steps of:
(a) providing a solution of (R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one in an organic solvent and adding water to the solution at 25-30°C;
(b) cooling the reaction mass obtained in step (a) to 10-15°C and slowly adding a reducing agent at the same temperature;
(c) heating the whole content obtained in step (b) to 85-90°C for 2-3 hrs;
(d) cooling the content of step (c) to 25-30°C and adjusting the pH to 1.0 with dil HCl;
(e) separating aqueous layer and organic layer, adding fresh MDC to the aqueous layer and adjusting pH to 13-14 with 10% NaOH solution.
(f) separating organic layer and treating the organic layer with acetic anhydride;
(g) heating the reaction mass of step (f) to reflux temperature for 30-40 min;
(h) recovering the pure crystalline Linezolid Form III from the reaction mass of step (g) with 1,4-dioxane or ethyl acetate.

5. The process as claimed in claim 4, wherein the solvent in step (a) is selected from cyclic ether e.g. 1,4-dioxane, toluene, tetrahydrofuran, alcoholic solvents such as methanol, ethanol, isopropyl alcohol, and mixtures thereof.

6. The process as claimed in claim 5, wherein the solvent is 1,4-dioxane or toluene.

7. The process as claimed in claim 4, wherein the reducing agent used in step (b) is selected from Pd-C/H2, trialkyl and triaryl phosphine.

8. The process as claimed in claim 7, wherein the reducing agent is triphenyl phosphine (TPP).

9. A process for preparation of crystalline Linezolid Form III comprising the steps of:
(a) providing a solution of (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one in a solvent;
(b) adding acetic anhydride to the solution obtained in step (a) at 25-30°C;
(c) slowly raising the temperature to 35-40°C and stirring for 1-2 hrs;
(d) distilling the reaction mass of step (c) and recovering pure crystalline Linezolid Form III in 1,4-dioxane or ethyl acetate.

10. The process as claimed in claim 9, wherein the solvent in step (a) is an organic solvent selected from methylene dichloride, 1-4-dioxane and ethyl acetate.

11. The process as claimed in claim 10, wherein the solvent is methylene dichloride.

12. A process for preparation of Crystalline Linezolid Form III comprising the steps of:
(a) providing a solution of (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one in a solvent;
(b) adding acetic anhydride to the solution obtained in step (a) at 25-30°C;
(c) slowly raising the temperature to 65-70°C and stirring for 1-2 hrs followed by cooling to 25-30°C and stirring for 25-30 min;
(d) filtering the solid to recover pure crystalline Linezolid Form III.

13. The process as claimed in claim 12, wherein the solvent in step (a) is an organic solvent selected from ethyl acetate and 1-4-dioxane.

14. The process as claimed in claim 13, wherein the solvent in step (a) is 1,4-dioxane.

15. A process for preparation of crystalline Linezolid Form III comprising the steps of:
(a) suspending crystalline Linezolid in 1,4-dioxane at 25-30° C to obtain a solution;
(b) heating the solution obtained in step (a) to 75-80° C and stirring for 50-60 minutes at the same temperature;
(c) slowly cooling the whole reaction mass obtained in step (b) to 25-30° C and stirring for 50-60 minutes at the same temperature to cause the crystallization;
(d) recovering the crystalline Linezolid Form-III from the reaction mass of step (c) and washing with 1,4-dioxane to obtain highly pure crystalline Form-III of Linezolid.

16. A process for preparation of crystalline Linezolid Form III comprising the steps of:
(a) providing a solution of (R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one either in 1,4-dioxane or toluene and adding water to the solution at temperature 25-30°C;
(b) cooling the reaction mass obtained in step (a) to 10-15°C and slowly adding triphenyl phosphine at the same temperature;
(c) heating the whole content obtained in step (b) to 85-90°C for 2-3 hrs;
(d) cooling the content of step (c) to 25-30°C and adjusting the pH to 1.0 with dilute HCl and stirring for 10-15 min;
(e) separating aqueous layer and organic layer and adding fresh MDC to the aqueous layer and adjusting pH to 13-14 with 10% NaOH solution;
(f) separating organic layer and treating the organic layer with acetic anhydride;
(g) heating the reaction mass of step (f) to reflux temp for 30-40 min;
(h) recovering the pure crystalline Linezolid Form III from the reaction mass of step (g) with 1,4-dioxane or ethyl acetate.

17. A process for preparation of crystalline Linezolid Form III comprising the steps of:
(a) providing a solution of (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one in methylene dichloride;
(b) adding acetic anhydride to the solution obtained in step (a) at 25-30°C;
(c) slowly raising the temperature to 35-40°C and stirring for 1-2 hrs;
(d) distilling the reaction mass of step (c) and recovering pure crystalline Linezolid Form III in 1,4-dioxane or ethyl acetate.

18. A process for preparation of Crystalline Linezolid Form III comprising the steps of:
(a) providing a solution of (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one in 1,4-dioxane or ethyl acetate;
(b) adding acetic anhydride to the solution obtained in step (a) at 25-30°C;
(c) slowly raising the temperature to 65-70°C and stirring for 1-2 hrs followed by cooling to 25-30°C and stirring for 25-30 min;
(d) filtering the solid to recover pure crystalline Linezolid Form III.
,TagSPECI:FIELD OF INVENTION

The invention relates to novel process for preparing crystalline Linezolid Form III.

BACKGROUND OF THE INVENTION:

Linezolid is an oxazolidinone compound chemically known as (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide. Linezolid is used for the treatment of serious infections caused by Gram positive bacteria that are resistant to other antibiotics and also gram-negative microorganism such as Pasteurella multocida. It is mostly active against streptococci, methicillin-resistant Staphylococcus aureus (MRSA) and vancomycin-resistant enterococci (VRE).

Linezolid is represented by the following structure:

US Patent No. 5,688,792 first disclosed Linezolid and related compounds, processes for their preparation and their therapeutic uses.

Linezolid is known to exhibit different polymorphic forms. Linezolid described in J. of Med. Chem. 39(3), 673-679 is reported as Form I which is characterized by having melting point of 181.5-182.5°C and by IR spectrum having bands at 3284, 3092, 1753, 1728, 1649, 1565, 1519, 1447, 1435 cm-1.

US Patent No. 6,559,305 discloses crystalline Linezolid Form II characterized by powder X-ray diffraction spectrum having 2? values at 7.10, 9.54, 13.88, 14.23, 16.18, 16.79, 17.69, 19.41, 19.69, 19.93, 21.61, 22.39, 22.84, 23.52, 24.16, 25.28, 26.66, 27.01 and 27.77 degrees and IR spectrum having bands at 3364, 1748, 1675, 1537, 1517, 1445, 1410, 1401, 1358, 1329, 1287, 1274, 1253, 1237, 1221, 1145, 1130, 1123, 1116, 1078, 1066, 1049, 907, 852 and 758 cm-1.

WO2005/035530 (US 7,714,128) discloses crystalline Linezolid Form III characterized by peaks in the powder x-ray diffraction spectrum having 2? angle positions at about 7.6, 9.6, 13.6, 14.9, 18.2, 18.9, 21.2, 22.3, 25.6, 26.9, 27.9 and 29.9 degrees; and characterized by IR spectrum having main bands at about 3338, 1741, 1662, 1544, 1517, 1471, 1452, 1425, 1400, 1381, 1334, 1273, 1255, 1228, 1213, 1197, 1176, 1116, 1082, 1051, 937, 923, 904, 869, 825 and 756 cm-1.

Many other polymorphic forms have been disclosed so far. Among all, Linezolid Form III possesses good thermal stability favouring its utility for preparation of solid dosage forms.

In WO2005/035530 crystalline Linezolid Form III is prepared by directly heating Linezolid at 90°C -200°C. This document also describes a process of preparing Linezolid Form-III by mixing the Linezolid with a solvent at the boiling point of the solvent. Solvents are selected from toluene, xylene, chloroform, methylene dichloride, acetonitrile, water, methanol, ethanol, propanol, isopropyl alcohol, ter-butyl alcohol, acetone, mehyl ethyl ketone, ethyl acetate, diethyl ether and methyl tert. Butyl ether. This document preferably uses toluene, xylene and isopropyl alcohol.

In WO 2013190559 water has been used as solvent at about 80°C to about 95°C for crystallization process to obtain crystalline Linezolid Form-III. This document also discloses a process wherein the suspension of the Linezolid in water is seeded with crystals of Linezolid Form-III.

US Pat. No. 7,989,618 claims a process for the preparation of Linezolid in crystalline Form III, which comprises treating an first aqueous solution of a Linezolid addition salt with an alkali metal carbonate, in the presence of a low-boiling organic solvent, having a boiling point below 85° C, separating phases of the first solution after treatment with the alkali metal carbonate, to provide an organic second solution, treating the organic second solution with toluene to obtain Linezolid crystalline Form III. The addition salt is selected from Linezolid dihydrochloride, Linezolid sulfate and Linezolid camphorsulfonate.

WO 2011051384 [(family WO2011050826 and WO2011050865 (all from Synthon B.V)] discloses process for preparation of Crystalline Linezolid designated as Form A (Corresponds to Linezolid Form I or Form III) comprising a step of dissolving linezolid in an organic solvent at an enhanced temperature (at reflux) to obtain a solution followed by a step of adding the obtained solution into an antisolvent kept at a pre-selected temperature and, optionally, seeded with crystals of the desired crystalline form of linezolid.

Therefore, though various methods of preparation of crystalline Linezolid Form-III are disclosed in the prior arts but due to commercial importance of the product, there is still need and scope for a new process which is advantageous over the prior art processes for industrial scale manufacture of Linezolid Form-III.

OBJECT OF THE INVENTION

The primary object of the present invention is to provide novel process for preparation of crystalline Linezolid Form III.

SUMMARY OF THE INVENTION

Accordingly the present invention provides novel process for the preparation of Linezolid Crystalline Form III.

In one embodiment the invention provides a process for preparation of Crystalline Linezolid Form III comprising the steps of:

(a) suspending crystalline Linezolid in a solvent at 25-30° C to obtain a solution;
(b) heating the solution obtained in step (a) to 75-80° C and stirring;
(c) slowly cooling the whole reaction mass obtained in step (b) to 25-30° C and stirring to cause the crystallization;
(d) recovering the crystalline Linezolid Form-III from the reaction mass of step (c) and washing with fresh solvent to obtain highly pure crystalline Form-III of Linezolid.

The solvent used in step (a) and in step (d) is an organic solvent selected from a cyclic ether, e.g. 1,4-dioxane; an aliphatic ether e.g. diethyl ether, methyl tert-butyl ether; an aliphatic ester, e.g. ethyl acetate; an aliphatic alcohol, e.g. methanol, ethanol, 1-propanol, isopropanol or 1-butanol; toluene, xylene, chloroform, methylene dichloride, acetonitrile, acetone, methyl ethyl ketone etc. In one preferred embodiment the organic solvent used in step (a) and step (d) is 1,4-dioxane.

The stirring in step (b) is done for about 50-60 minutes at 75-80° C. Stirring in step (c) is done for about 50-60 minutes at 25-30° C.

In another embodiment, the invention provides a process for preparation of Crystalline Linezolid Form III comprising the steps of:

(a) providing a solution of (R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one in an organic solvent and adding water to the solution at 25-30°C;
(b) cooling the reaction mass obtained in step (a) to 10-15°C and slowly adding a reducing agent at the same temperature;
(c) heating the whole content obtained in step (b) to 85-90°C for 2-3 hrs;
(d) cooling the content of step (c) to 25-30°C and adjusting the pH to 1.0 with dil HCl;
(e) separating the aqueous layer and organic layer;
(f) washing the aqueous layer with methylene dichloride;
(g) adding fresh methylene dichloride to aqueous layer and adjusting the pH to 13-14;
(h) separating the organic layer and treating with acetic anhydride;
(i) heating the reaction mass of step (h) to reflux temp. for 30-40 min;
(j) recovering the pure crystalline Linezolid Form III from the reaction mass of step (i) with 1,4-dioxane or ethyl acetate.

The organic solvent in step (a) used to obtain the solution of (R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one may be selected from cyclic ether, e.g. 1,4-dioxane, toluene, tetrahydrofuran, alcoholic solvents such as methanol, ethanol, isopropyl alcohol, and mixtures thereof. In one preferred embodiment the organic solvent is either 1,4-dioxane or toluene.

The reducing agent used in step (b) is selected from Pd-C/H2, trialkyl and triaryl phosphine. In one preferred embodiment the reducing agent is triphenyl phosphine (TPP).

In a further embodiment, the invention provides a process for preparation of Crystalline Linezolid Form III comprising the steps of:

(a) providing a solution of (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one in a solvent;
(b) adding acetic anhydride to the solution obtained in step (a) at 25-30°C;
(c) slowly raising the temperature to 35-40°C and stirring for 1-2 hrs;
(d) distilling the reaction mass of step (c) and recovering pure crystalline Linezolid Form III either in 1,4-dioxane or ethyl acetate.

The solvent used in above step (a) is an organic solvent selected from methylene dichloride, 1,4-dioxane and ethyl acetate. In one preferred embodiment the organic solvent selected in step (a) is methylene dichloride.

In a further embodiment, the invention provides a process for preparation of crystalline Linezolid Form III comprising the steps of:

(a) providing a solution of (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one in a solvent;
(b) adding acetic anhydride to the solution obtained in step (a) at 25-30°C;
(c) slowly raising the temperature to 65-70°C and stirring for 1-2 hrs followed by cooling to 25-30°C and stirring for 25-30 min;
(d) filtering the solid and recovering pure crystalline Linezolid Form III in 1,4-dioxane or ethyl acetate.

The solvent used in above step (a) is an organic solvent selected from methylene dichloride , 1,4-dioxane and ethyl acetate. In one preferred embodiment the organic solvent selected in step (a) is 1,4-dioxane.

DETAILED DESCRIPTION OF THE INVENTION

The invention relates to novel process for the preparation of Crystalline Linezolid Form III.

Linezolid is chemically N-[[(5S)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide and is represented by following structure

The Crystalline Linezolid Form III prepared in the present invention corresponds to Linezolid Form III disclosed in International Publication No. WO2005/035530.

WO2005/035530 discloses Linezolid Form III characterized by peaks in the powder x-ray diffraction spectrum having 2? angle positions at about 7.6, 9.6, 13.6, 14.9, 18.2, 18.9, 21.2, 22.3, 25.6, 26.9, 27.9 and 29.9 degrees; and characterized by IR spectrum having main bands at about 3338, 1741, 1662, 1544, 1517, 1471, 1452, 1425, 1400, 1381, 1334, 1273, 1255, 1228, 1213, 1197, 1176, 1116, 1082, 1051, 937, 923, 904, 869, 825 and 756 cm-1.

According to one embodiment of the invention, Crystalline Linezolid Form III is prepared by a process comprising the steps of:

(a) suspending crystalline Linezolid in a solvent at 25-30° C to obtain a solution;
(b) heating the solution obtained in step (a) to 75-80° C and stirring;
(c) slowly cooling the whole reaction mass obtained in step (b) to 25-30° C and stirring to cause the crystallization;
(d) recovering the crystalline Linezolid Form-III from the reaction mass of step (c) and washing with fresh solvent to obtain highly pure crystalline Form-III of Linezolid.

The crystalline Linezolid used in step (a) may be obtained by any viable process known in the prior art. The solvent used in steps (a) and (d) is an organic solvent selected from cyclic ether, e.g. 1,4-dioxane; an aliphatic ether e.g. diethyl ether, methyl tert-butyl ether; an aliphatic ester, e.g. ethyl acetate; an aliphatic alcohol, e.g. methanol, ethanol, 1-propanol, isopropyl alcohol or 1-butanol; toluene, xylene, chloroform, methylene dichloride, acetonitrile, acetone, methyl ethyl ketone etc. Preferably the solvent selected is a cyclic ether such as 1,4-dioxane. The solvent used in step (d) is the same organic solvent as used in step (a). In one preferred embodiment the solvent used in step (a) and step (d) is 1,4-dioxane.

In step (b) the contents obtained after step (a) is then heated to temperature 75-80° C and stirred for 50-60 minutes at same temperature i.e. 75-80° C.

The stirring in step (b) is done for about 50-60 minutes at 75-80° C. Stirring in step (c) is done for about 50-60 minutes at25-30° C.

The Crystalline Linezolid Form III obtained in step (d) is further dried at temperature 70-75° C.

Accordingly, in one preferred embodiment, the process for preparation of Crystalline Linezolid Form III comprises:

(a) suspending crystalline Linezolid in 1,4-dioxane at 25-30° C to obtain a solution;
(b) heating the solution obtained in step (a) to 75-80° C and stirring for 50-60 minutes at the same temperature;
(c) slowly cooling the whole reaction mass obtained in step (b) to 25-30° C and stirring for 50-60 minutes at the same temperature to cause the crystallization;
(d) recovering the crystalline Linezolid Form-III from the reaction mass of step (c) and washing with 1,4-dioxane to obtain highly pure crystalline Form-III of Linezolid.

In another embodiment, Crystalline Linezolid Form III is prepared by a process comprising the steps of:

(a) providing a solution of (R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one in an organic solvent and adding water to the solution at temperature 25-30°C;
(b) cooling the reaction mass obtained in step (a) to 10-15°C and slowly adding a reducing agent at the same temperature;
(c) heating the whole content obtained in step (b) to 85-90°C for 2-3 hrs;
(d) cooling the content of step (c) to 25-30°C and adjusting the pH to 1.0 with dil HCl;
(e) separating the aqueous layer and organic layer;
(f) washing the aqueous layer with methylene dichloride;
(g) adding fresh methylene dichloride to aqueous layer and pH adjusted to 13-14;
(h) separating the organic layer and treating with acetic anhydride;
(i) heating the reaction mass of step (h) to reflux temp for 30-40 min;
(j) recovering the pure crystalline Linezolid Form III from the reaction mass of step (i) with 1,4-dioxane or ethyl acetate.

Thus Crystalline Linezolid Form III is prepared starting from intermediate (R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one.

The organic solvent in step (a) used to obtain the solution of (R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one may be selected from cyclic ether e.g. 1,4-dioxane, toluene, tetrahydrofuran, alcoholic solvents such as methanol, ethanol, isopropyl alcohol, and mixtures thereof. In one preferred embodiment the organic solvent is either 1,4-dioxane or toluene.

The reducing agent used in step (b) is selected from Pd-C/H2, trialkyl and triaryl phosphine. In one preferred embodiment the reducing agent is triphenyl phosphine (TPP).

In step (b) the mass obtained in step (a) is cooled to 10-15°C and reducing agent is added portions wise at the same temperature. The reducing agent in step (b) may be selected from Pd-C/H2, trialkyl and triaryl phosphine. In one preferred embodiment the reducing agent is triphenyl phosphine (TPP).

Then in step (c) the whole reaction contents of step (b) is heated to 85-90°C for 2-3 hours and after that cooled to 25-30°C.

In step (d) the pH is adjusted to 1.0 with dilute HCl (Hydrochloric acid) and stirred for 10-15 min.

The step (e) comprises separation of aqueous layer and organic layer. In step (f) the aqueous layer obtained in step (e) is washed with methylene dichloride.

The step (g) comprises addition of fresh methylene dichloride to aqueous layer and the pH is adjusted to 13-14 with 10% sodium hydroxide solution.

The step (h) comprises separation of the organic layer and the aqueous layer and treating the organic layer with acetic anhydride.

In step (i) the reaction mass of step (h) is heated to reflux temperature for 30-40 min.

In step (j) the organic layer is distilled and isolated Crystalline Linezolid Form III either in 1,4-dioxane or ethyl acetate.

Accordingly, in one preferred embodiment, the process for preparation of Crystalline Linezolid Form III comprises:

(a) providing a solution of (R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one either in 1,4-dioxane or toluene and adding water to the solution at temperature 25-30°C;
(b) cooling the reaction mass obtained in step (a) to 10-15°C and slowly adding triphenyl phosphine at the same temperature;
(c) heating the whole content obtained in step (b) to 85-90°C for 2-3 hrs;
(d) cooling the content of step (c) to 25-30°C and adjusting the pH to 1.0 with dilute HCl and stirring for 10-15 min;
(e) separating the aqueous layer and organic layer;
(f) washing the aqueous layer with methylene dichloride;
(g) adding fresh methylene dichloride to aqueous layer and adjusting the pH to 13-14;
(h) separating the methylene dichloride layer and treating with acetic anhydride;
(i) heating the reaction mass of step (h) to reflux temp for 30-40 min;
(j) recovering the pure crystalline Linezolid Form III from the reaction mass of step (i) with 1,4-dioxane or ethyl acetate.

In a further embodiment, the invention provides a process for preparation of Crystalline Linezolid Form III starting with (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one.

The process comprises:
(a) providing a solution of (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one in a solvent;
(b) adding acetic anhydride to the solution obtained in step (a) at 25-30°C;
(c) slowly raising the temperature to 35-40°C and stirring for 1-2 hrs;
(d) distilling the reaction mass of step (c) and recovering pure crystalline Linezolid Form III in 1,4-dioxane or ethyl acetate.

The solvent used in above step (a) is an organic solvent selected from methylene dichloride, ethyl acetate and 1, 4-dioxane. In one preferred embodiment the organic solvent selected in step (a) is methylene dichloride.

The step (b) comprises addition of acetic anhydride to the intermediate solution obtained in step (a). The addition of acetic anhydride takes place at temperature 25-30°C. Then the temperature is raised slowly to 35-40°C followed by stirring for 1-2 hrs.

The recovery of pure crystalline Linezolid Form III in step (d) is done either in 1,4-dioxane or ethyl acetate.

Thus in a proffered embodiment the above process comprises the steps of:

(a) providing a solution of (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one in methylene dichloride;
(b) adding acetic anhydride to the solution obtained in step (a) at 25-30°C;
(c) slowly raising the temperature to 35-40°C and stirring for 1-2 hrs;
(d) distilling the reaction mass of step (c) and recovering pure crystalline Linezolid Form III in 1,4-dioxane or ethyl acetate.

In a further embodiment, the invention provides a process for preparation of Crystalline Linezolid Form III comprising the steps of:

(a) providing a solution of (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one in a solvent;
(b) adding acetic anhydride to the solution obtained in step (a) at 25-30°C;
(c) slowly raising the temperature to 65-70°C and stirring for 1-2 hrs followed by cooling to 25-30°C and stirring for 25-30 min;
(d) filtering the solid to recover pure crystalline Linezolid Form III and drying at 65-70°C.

The solvent used in above step (a) is an organic solvent selected from ethyl acetate and 1,4-dioxane. In one preferred embodiment the solvent used in step (a) is 1,4-dioxane.

The step (b) comprises addition of acetic anhydride to the intermediate solution obtained in step (a). The addition of acetic anhydride takes place at temperature 25-30°C. Then the temperature is raised slowly to 65-70°C followed by stirring for 1-2 hrs. Then further cooled to 25-30°C followed by stirring for 25-30 min.

The recovery of pure crystalline Linezolid Form III in step (d) is done either in 1,4-dioxane or ethyl acetate.

Thus in a proffered embodiment the above process comprises the steps of:

(a) providing a solution of (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one in a 1,4-dioxane;
(b) adding acetic anhydride to the solution obtained in step (a) at 25-30°C;
(c) slowly raising the temperature to 65-70°C and stirring for 1-2 hrs followed by cooling to 25-30°C and stirring for 25-30 min;
(d) filtering the solid to recover pure crystalline Linezolid Form III and drying at 65-70°C.

Various aspects of the invention are further explained in following examples.

EXAMPLES
Example-1:
1,4-Dioxane (500.0 mL) was added to crystalline Linezolid (100.0 gr) at 25-30°C. The total contents were heated to 75-80°C and stirred for 50-60 min at same temperature. Then the whole reaction mass was cooled to 25-30°C and stirred for 50-60 min at same temperature. The precipitated solid was filtered and washed with fresh 1,4-dioxane (100.0 mL). The filtered solid was dried at 70-75°C to get Crystalline Linezolid Form III.

Example-2:
To a solution of (R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (50.0 gr) in toluene (250.0 mL) was added water (10.0 mL) at 25-30°C. The reaction mass was cooled to 10-15°C and triphenyl phosphine (41.0 gr) was added portions wise at same temperature. The total contents were heated to 85-90°C for 2-3 hrs. The progress of the reaction was monitored by TLC. After completion of reaction, total contents were cooled to 25-30°C. The reaction mass PH was adjusted to 1.0 with dilute HCl and stirred for 10-15 min. Then separate the toluene layer and aqueous layer wash with methylene dichloride (MDC). Take aqueous layer and add fresh MDC, then reaction mass PH adjusted to 13-14 with 10.0% sodium hydroxide solution. Separate the organic layer and again extract the compound with MDC. Combined organic layers and dried with anhydrous Na2SO4 and add acetic anhydride (22.5 mL), followed heated to reflux temp for 30-40 min. Then distilled the solvent and add ethyl acetate and stirred for 30 min to get Crystalline Linezolid Form III.

Example-3:
To a solution of (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (25.0 gr) in methylene dichloride (125.0 mL), acetic anhydride (9.6 mL) was added at 25-30°C. Slowly temperature was raised to 35-40°C and stirred for 1-2 hrs. The reaction mass was distilled and followed by isolate in ethyl acetate to get crystallized Linezolid form III.

Example-4:
To a solution of (R)-5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (25.0 gr) in 1,4-dioxane (125.0 mL) was added water (5.0 mL) at 25-30°C. The reaction mass was cooled to 10-15°C and triphenyl phosphine (20.5 gr) was added portions wise at same temperature. The total contents were heated to 85-90°C for 2-3 hrs. The progress of the reaction was monitored by TLC. After completion of reaction, total contents were cooled to 25-30°C. The reaction mass PH was adjusted to 1.0 with dilute HCl and stirred for 10-15 min. Then separate the 1,4-dioxane layer and aqueous layer wash with methylene dichloride (MDC). Take aqueous layer and add fresh MDC, then reaction mass PH adjusted to 13-14 with 10.0% sodium hydroxide solution. Separate the organic layer and again extract the compound with MDC. Combined organic layers and dried with anhydrous Na2SO4 and add acetic anhydride (22.5 mL), followed heated to reflux temp for 30-40 min. Then distilled the solvent and add 1,4-dioxane and stirred for 30 min to get Crystalline Linezolid Form III.

Example-5:
To a solution of (S)-5-aminomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (50.0 gr) in 1,4-Dioxane (250.0 mL), acetic anhydride (19.2 mL) was added at 25-30°C. Slowly temperature was raised to 65-70°C and stirred for 1-2 hrs. The reaction mass was cooled to 25-30°C and stirred for 25-30 minutes and thrown out solid was filtered to get crystallized Linezolid form III.