Field of the Invention

The present invention relates to the improved processes for the preparation of linezolid. In particular, the present invention is directed to a novel process for the preparation of linezolid, which avoids the use of sodium azide in the reaction. The present invention also includes preparation of linezolid going through a novel intermediate of Formula XIa. The present invention also includes the processes of preparation of linezolid, free of bis-linezolid impurity. Also, the present invention further relates to preparation of linezolid by preparing azide intermediate, and converting it into linezolid in one-pot. It also provides linezolid with high yield and high chemical purity without the use of tedious, complicated purification steps, such as chromatography.

Background of the Invention

Linezolid, (S)-N-[[3-(3-Fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidiny l]methyl] acetamide is an antimicrobial agent. Linezolid is an oxazolidinone, having the empirical formula C!6H ₂₀ FN3O ₄ and the following structure (I):

(I)

US Patent No. 5,688,792 claims linezolid and its use for the treatment of microbial infections. Various processes for preparation of linezolid are described in US 5,688,792; US 7,291,614; US2009093631 and Tetrahedron Lett 40(26), 4855, 1999. The synthesis of linezolid (Scheme-I) given in US 5,688,792, is also disclosed in Bricker, et al., J. Med. Chem., 39, 673-679 (1996) and is given as follows: Scheme-I

MeS0 ₂ CI

Et ₃ N

In the above described synthesis the intermediate azide, (R)-N-[[3-(3-fluoro-4- mo holinylphenyl)-2-oxo-5-oxazolidinyl]methyl]azide (X) is being prepared by (R)- N-[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]met hyl methanesulfonate (IX) using sodium azide as one of the critical reagents.

Moreover, it is disclosed in US 2006/0252932 that when the said azide intermediate

(X) is reduced to its corresponding amine, (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-

2-oxo-5-oxazolidinyl] methyl] amine (XI) in the solvent ethyl acetate by hydrogenation using hydrogen gas and a palladium/carbon catalyst, production of undesirable level of reaction by-products occur. The reaction is followed by acetylation of the intermediate amine (XI) to linezolid (I), and undesirably high levels of bis-linezolid (XII), as an impurity, are also obtained in linezolid.

(XII) Due to the formation of high levels of impurity, the purification becomes critical, resulting in poor yield of linezolid. Purification techniques such as chromatography is utilized to obtain pure linezolid resulting in low yields of linezolid.

Thus, it is desirable to have a simple, safe and efficient industrial process for producing pure intermediate amine (XI) used to prepare linezolid (I), which overcomes the drawbacks disclosed in the prior art.

Summary of the Invention

The present invention seeks to overcome the prior art limitations and provide a cost effective and industrially favorable process for the preparation of linezolid.

In one embodiment, the invention encompasses a process for preparation of linezolid comprising: (a) condensation of 3,4-difluoronitrobenzene (III) with morpholine (II) to obtain 3-fluoro-4-morpholinyl nitrobenzene (IV); (b) reduction of IV obtained in step 'a' to 3-fluoro-4-morpholinyl aniline (V); (c) protection of amino group of V obtained in step 'b' to generate a carbamate derivative like ethyl carbamate (Via) or benzyl carbamate (VIb); and the like (d) conversion of carbamate Via or VIb as obtained in step 'c' into oxazolidinone derivative, (R)-N-[3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methanol (VIII); (e) further, conversion of the hydroxy group of VIII as obtained in step 'd' into a leaving group e.g. mesylate, nosylate, tosylate, triflate, besylate or a halo compound. If the leaving group is tosylate the compound generated is (R)-N-[3-(3-fluoro-4-morpholinylphenyl)-2-oxo- 5 -oxazolidinyl] methyl /?-toluenesulfonate (IXa); (f) conversion of IXa as obtained in step 'e' to (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]amine./?-TSA salt (XIa), a novel intermediate compound, which helps in providing linezolid in high yield, it also helps in avoiding the use of sodium azide and hence the formation of X and (g) acetylation of XIa as obtained in step 'f to provide linezolid (I), free of bis-linezolid (XII).

In another embodiment, the present invention provides a process for preparing a linezolid comprising acetylating (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]amine.^-TSA salt (XIa) in presence of a base and solvent. In another embodiment, the present invention provides a novel intermediate (S)-N- [[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]meth yl]amine. 7-TSA salt of formula XIa.

In yet another embodiment, present invention provides a novel polymorph Form J of (S)-N-[[3 _^ (3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]me thyl]amine. ?-TSA salt (XIa), which is characterized by a powder X-Ray diffraction pattern with peaks at about 4.1, 15.6, 20.6, 22.7, 23.4 ±0.2° 2Θ, as depicted in Figure I.

In another embodiment, present invention provides a novel polymorph Form J of (S)- N-[[3-(3-fluoro-4-mo holinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine. )-TSA salt (XIa), which is characterized by Infrared spectrum having main bands at about 3440, 1746, 1518, 1421, 1224, 1153, 680 and 564 cm ^"1 , as depicted in Figure II.

In another embodiment, present invention provides a novel polymorph Form J of (S)- N- [ [3 -(3 -fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl] methyl] amine .p-TSA salt (XIa), which is characterized by DSC thermogram as depicted in Figure III and TGA as depicted in Figure IV.

In yet another embodiment of the present invention the reaction occurs in a similar fashion as in the first embodiment till the formation of (R)-N-[[3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]p-toluenesulf onate (IXa). Further, the reaction comprises (a) treatment of IXa with benzylamine leading to the formation of compound (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl] methyl] benzylamine (XIII) (b) hydrogenolysis of XIII as obtained in step 'a' to (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]amine (XI), i.e. an amine intermediate and (c) acetylation of XI as obtained in step 'b' to provide linezolid (I).

Use of sodium azide is avoided in the reaction and as the azide intermediate (X) is not being formed so I formed by following the said process is free of XII.

In another embodiment of the present invention, the reaction occurs in a similar fashion as in the earlier embodiment till the formation of (R)-N-[[3-(3-fluoro-4- morpholinylphenyi)-2-oxo-5-oxazolidinyl]methyl]p-toluenesulf onate (IXa). Further, the reaction comprises of: (a) conversion of IXa into corresponding (S)-N-[[3-(3- fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]azid e (X) and (b) the azide intermediate X obtained in step 'a' is reduced as well as acetylated simultaneously in one pot to form linezolid (I) avoiding the formation of bis linezolid (XII).

In another embodiment, present invention provides linezolid having a total purity of at least about 98%. Preferably, the total purity is at least about 99%, more preferably, total purity is at least about 99.8%.

Linezolid prepared by following the above processes is obtained in high chemical purity without the use of tedious, complicated purification steps, such as chromatography or repeated recrystallization. Description of the Drawings

Figure I: PXRD pattern of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]amine./7-TSA salt

Figure II: IR spectrum pattern of (8)-Ν-[[3-(3-ί^θΓθ-4^ο ^1ϊ^1ρ1ΐ6^1)-2-οχο-5- oxazolidinyl] methyl] amine .p-TS A salt

Figure III: DSC thermogram of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]amine./7-TSA salt Figure IV: TGA of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl] methyl] amine .p-TS A salt

Detailed Description of the Invention

In one embodiment of the present invention linezolid (I) is prepared comprising the steps of:

a) condensation of 3, 4-difluoronitrobenzene (III) with morpholine (II) in presence of a base and a solvent to ield 3-fluoro-4-morpholinyl nitrobenzene (IV).

The base may be selected from a group comprising of an organic or inorganic base. Organic base is selected from the group comprising of N,N-diisopropylethylamine, triethylamine, tributylamine, triisopropylamine, pyridine, diazabicyclo-[5.4.0]-undec- 7-ene (DBU), l,5-diazabicyclo[4.3.0]-non-5-ene (DBN), 1,4- diazabicyclo[2.2.2]octane (DABCO), 4-dimethylaminopyridine (4-DMAP) and mixtures thereof. The inorganic base is selected from group comprising of carbonates, bicarbonates, hydroxides of alkali and alkaline earth metals and the like. Preferably the inorganic base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate and the like. More preferably the base is sodium bicarbonate. The solvent as defined herein is selected from the group comprising of alcohols, nitriles, ketones, esters, chlorinated solvents, ethers, amides, dialkylsulfoxides, water or the mixtures thereof. Alcohols are selected . from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like. Nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like. Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like. Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like. Chlorinated solvents are selected from the group comprising of dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and the like. Ethers are selected from the group comprising of diethyl ether, Methyl tert-butyl ether (MTBE), diisopropyl ether, tetrahydrofuran (THF), dioxane and the like. Amides are selected from the group comprising of dimethylformamide, dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like. Dialkylsulfoxides are selected from the group comprising of dimethyl sulfoxide (DMSO), diethyl sulfoxide, dibutyl sulfoxide, sulfolane and the like. Preferred solvent is water; thus making the process more cost effective. b) reduction of the nitro derivative (IV) by hydrogenation or by metal hydrogen transfer like formic acid / alkali metal or ammonium salts in a suitable solvent to provide 3-fluoro-4-morpholinyl aniline (V).

The solvent as defined herein is selected from the group comprising of alcohols, esters^ chlorinated solvents, ethers or mixtures thereof. Alcohols are selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like. Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like. Chlorinated solvents are selected from the group comprising of dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and the like. Ethers are selected from the group comprising of diethyl ether, diisopropyl ether, MTBE, THF, dioxane and the like. The hydrogenation is carried out in presence of suitable catalyst, but not limited to Raney-Ni/H ₂ , Palladium-C/H ₂ and the like; c) carboxylation of an amino compound (V) with alkyl chloroformate or alkaryl chloroformate in an organic solvent in presence of base to yield carbamate derivative (VI). For example reaction of V with ethyl chloroformate or benzyl chloroformate in an organic solvent in presence of base to yield ethyl carbamate derivative nomenclatured as N-carboethoxy-3-fluoro-4-morpholinylaniline (Via) or benzyl carbamate nomenclatured as N-carbobenzoxy-3-fluoro-4-morpholinylaniline (VIb) respectively.

R is alkyl or alkaryl group

(Vlb)

Organic base is selected from the group comprising of N,N-diisopropylethylamine, triethylamine, tributylamine, triisopropylamine, pyridine, DBU, DBN, DABCO, 4-

DMAP and mixtures thereof. The inorganic base is selected from group comprising of carbonates, bicarbonates, hydroxides of alkali and alkaline earth metals and the like.

Preferably the inorganic base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate and the like. More preferably the base is sodium bicarbonate. The solvent as defined herein is selected from the group comprising of nitriles, ketones, esters, chlorinated solvents, ethers, amides, dialkylsulfoxides, water or the mixtures thereof. Nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like. Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like. Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like. Chlorinated solvents are selected from the group comprising of

DCM, chloroform, dichloroethane, chlorobenzene and the like. Ethers are selected from the group comprising of diethyl ether, diisopropyl ether, MTBE, THF, dioxane and the like. Amides are selected from the group comprising of dimethylformamide, dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like. Dialkylsulfoxides are selected from the group comprising of DMSO, diethyl sulfoxide, dibutyl sulfoxide, sulfolane and the like. Preferred solvent is DCM for ethyl carbamate and acetone for benzyl carbamate derivates. d) condensation of ethyl carbamate derivative (Via) or benzyl carbamate derivative (VIb) with (R)-glycidyl butyrate in a suitable solvent in presence of a base to yield (R)-N- [3 -(3 -fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl] methanol (VIII) .

(VIb)

The base may be selected from a strong base selected from the group comprising of organometallic or non-nucleophilic hindered base. Metal from organometallic base is selected from Li, Na, K and the like. It may be preferably selected from base containing Li ion e.g. n-butyl lithium, sec-butyl lithium, tert-butyl lithium, lithium diisopropyl amide, lithium bis(trimethylsilyl) amine, lithium t-butoxide or lithium amyloxide. The solvent may be selected from non protic inert polar solvents. The preferable non protic inert polar solvent is selected from a group comprising of tetrahydrofuran (THF), diethylether, dioxan, methyl tertiary butyl ether and the like; e) treatment of methanol derivative (VIII) with suitable reagent to convert the alcoholic group into a leaving group selected from the group comprising of: tosylate, mesylate, nosylate, triflate, besylate, halo and the like. The reaction except for halo derivative takes place in an organic solvent in presence of a base to yield (R)-N-[[3- (3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]d erivative (IXb) having LG as a leaving group. Methanol derivative on treatment with thionyl halide provides halo derivatives. Preferably the reaction is carried out with tosyl chloride to yield (R)- N- [ [3 - (3 -fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl] methyl]/?- toluenesulfonate (IXa).

For example:

The base may be selected from a group comprising of an organic or inorganic base.

Organic base is selected from the group comprising of N,N-diisopropylethylamine, triethylamine, tributylamine, triisopropylamine, pyridine, DBU, DABCO, DBN, 4-

DMAP and mixtures thereof. The inorganic base is selected from group comprising of carbonates, bicarbonates, hydroxides of alkali and alkaline earth metals and the like.

Preferably the inorganic base is selected from sodium bicarbonate, potassium bicarbonate, sodium carbonate and the like. The organic solvent as defined herein is selected from the group comprising of nitriles, ketones, esters, chlorinated solvents, ethers, amides, dialkylsulfoxides or mixtures thereof. Nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like.

Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like. Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like. Chlorinated solvents are selected from the group comprising of DCM, chloroform, dichloroethane, chlorobenzene and the like.

Ethers are selected from the group comprising of diethyl ether, diisopropyl ether,

MTBE, THF, dioxane and the like. Amides are selected from the group comprising of dimethylformamide, dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like. Dialkylsulfoxides are selected from the group comprising of dimethyl sulfoxide, diethyl sulfoxide, dibutyl sulfoxide, sulfolane and the like. Preferred solvent is selected from group comprising of DCM, chloroform, THF, dioxan or mixture thereof; f) reaction of (R)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]p-toluenesulfonate (IXa) with amine source which may be dissolved in solvent like water or alcohol. Preferred amine source is ammonium hydroxide. Reaction occurs in presence of a solvent to provide an amine intermediate (XIa). XIa is a novel intermediate compound, which helps in providing linezolid in high yield.

The solvent as defined herein is selected from the group comprising of alcohols, nitriles, ketones, esters, chlorinated solvents, ethers, amides, dialkylsulfoxides, water or the mixtures thereof. Alcohols are selected from the group comprising of methanol, ethanol, n-propanol, isopropanol (IPA), n-butanol and the like. Nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like. Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like. Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like. Chlorinated solvents are selected from the group comprising of DCM, chloroform, dichloroethane, chlorobenzene and the like. Ethers are selected from the group comprising of diethyl ether, diisopropyl ether, MTBE, THF, dioxane and the like. Amides are selected from the group comprising of dimethylformamide, dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like. Dialkylsulfoxides are selected from . the group comprising of dimethyl sulfoxide, diethyl sulfoxide, dibutyl sulfoxide, sulfolane and the like. Preferred solvent is selected from THF and IPA; g) acetylation of the intermediate amine (XIa) in the form of p-TSA salt, in presence of a base and a solvent provides linezolid (I) in high yields in comparison to the conversion into free amine and further free amine providing linezolid. Moreover, the preparation of intermediate XIa is economically and industrially more viable and is operationally safe.

The acetylating agent may be selected from acetic anhydride or acetyl chloride, preferably acetic anhydride. The base may be selected from a group comprising of an organic or inorganic base. Organic base is selected from the group comprising of Ν,Ν-diisopropylethylamine, triethylamine, tributylamine, triisopropylamine, pyridine, DBU, DABCO, DBN, 4-DMAP and mixtures thereof. The inorganic base is selected from group comprising of carbonates, bicarbonates, hydroxides of alkali and alkaline earth metals and the like. The solvent as defined herein is selected from the group comprising of water, nitriles, ketones, esters, hydrocarbons, chlorinated solvents, ethers, amides, dialkylsulfoxides or mixtures thereof. Nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like. Ketones are selected from the group comprising of acetone, methyl ethyl ketone, methyl isobutyl ketone and the like. Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like. Hydrocarbons are selected from toluene, xylene, cyclohexane and the like. Chlorinated solvents are selected from the group comprising of dichloromethane (DCM), chloroform, dichloroethane, chlorobenzene and the like. Ethers are selected from the group comprising of diethyl ether, diisopropyl ether, MTBE, THF, dioxane and the like. Amides are selected from the group comprising , of dimethylformamide, dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like. Dialkylsulfoxides are selected from the group comprising of dimethyl sulfoxide, diethyl sulfoxide, dibutyl sulfoxide, sulfolane and the like. The solvent may be preferably selected from hydrocarbons, halogenated hydrocarbons, C _2-4 acetates, water or mixtures thereof. More preferably the solvent is selected from DCM, ethyl acetate, chloroform, toluene or water and mixture thereof.

The present method involves the direct conversion of tosylate derivative (IXa) in to an amine salt (XIa), which is a novel intermediate used for the preparation of linezolid. The said process, avoids the usage of sodium azide, formation of azide intermediate (X), the use of hydrogen gas, high hydrogen pressure and moreover, reducing the number of the steps of the reaction and making the process cost effective as well as environment friendly. The crude linezolid formed can be obtained with high purity just by recrystallization avoiding cumbersome purification techniques.

In another embodiment, present invention provides linezolid having a total purity of at least about 98%. Preferably, the total purity is at least about 99%, more preferably, total purity is at least about 99.8%.

In another embodiment, the present invention provides a novel intermediate (S)-N- [ [3 -(3 -fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl]methyl] amine .p-TS A salt of formula XIa. In yet another embodiment, present invention provides a novel polymorph Form J of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidiny l]methyl]amine. 7-TSA salt (XIa), which is characterized by a powder X-Ray diffraction pattern with peaks at about 4.1, 15.6, 20.6, 22.7, 23.4 ±0.2° 2Θ, further characterized by 12.3, 18.8 and 24.1 ±0.2° 2Θ or as depicted in Figure I.

In another embodiment, present invention provides a novel polymorph Form J of (S)- N- [ [3 -(3 -fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl] methyl] amine .p-TS A salt (XIa), which is characterized by Infrared spectrum having bands at about 3440, 1746, 1518, 1421 , 1224, 1153, 680 and 564 cm ^"1 , further characterized by 2970, 1 195, 1175,1058, 801 cm ^"1 or as depicted in Figure II. In another embodiment, present invention provides a novel polymorph Form J of (S)- N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]me thyl]amine. >-TSA salt (XIa), which is characterized by DSC thermogram as depicted in Figure III and TGA as depicted in Figure IV. In yet another embodiment of the invention, the (R)-N-[[3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]p-toluenesulf onate (IXa) is treated with benzylamine to provide S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]benzylamine (XIII), which on hydrogenolysis leads to formation of S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl ]methyl]amine (XI), which is further converted to linezolid (I).

Starting from IXa the reaction comprises of the following steps: a) reaction of the compound having a leaving group e.g. tosylate derivative (IXa) with benzylamine to yield N-benzyl methyl amine derivative of oxazolidinone compound i.e. (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]benzylamine (XIII);

b) hydrogenolysis of N-benzyl methylamine derivative of oxazolidinone (XIII) in presence of catalysts and a reducing agent in an organic solvent to provide (S)-N-[[3- (3-fluoro-4-mo holinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine (XI)

The catalysts may be selected from the group comprising of zinc, nickel, platinum, palladium and the like. The metal catalyst may be provided on an inert support such as carbon, activated carbon or alumina. The reducing agent may be selected from formic acid and salts or acetic acid and salts thereof. The organic solvent is selected from the group comprising of alcohols, esters, chlorinated solvents, ethers, amides, dialkylsulfoxides, or the mixtures thereof. Alcohols are selected from the group comprising of methanol, ethanol, n-propanol, isopropanol, n-butanol and the like. Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like. Chlorinated solvents are selected from the group comprising of DCM, chloroform, dichloroethane, chlorobenzene and the like. Ethers are selected from the group comprising of diethyl ether, MTBE, diisopropyl ether, THF, dioxane and the like. Amides are selected from the group comprising of dimethylformamide, dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like. Dialkylsulfoxides are selected from the group comprising of DMSO, diethyl sulfoxide, dibutyl sulfoxide, sulfolane and the like.

Preferred solvent is selected from methanol, ethanol, toluene, DCM and the like; c) acetylation of the intermediate amine (XI) in presence of a base and a solvent to form linezolid (I).

The acetylating agent may be selected from acetic anhydride or acetyl chloride, preferably acetic anhydride. The base may be selected from a group comprising of an organic or inorganic base. Organic base is selected from the group comprising of Ν,Ν-diisopropylethylamine, triethylamine, tributylamine, triisopropylamine, pyridine, DBU, DABCO, DBN, 4-DMAP and mixtures thereof. The inorganic base is selected from group comprising of carbonates, bicarbonates, hydroxides of alkali and alkaline 5 earth metals and the like. The solvent as defined herein is selected from the group comprising of nitriles, ketones, esters, hydrocarbons, chlorinated solvents, ethers, amides, dialkylsulfoxides, or mixtures thereof. Nitriles are selected from the group comprising of acetonitrile, propionitrile, butyronitrile, valeronitrile and the like. Ketones are selected from the group comprising of acetone, methyl ethyl ketone,

10 methyl isobutyl ketone and the like. Esters are selected from the group comprising of ethyl acetate, propyl acetate and the like. Hydrocarbons are selected from toluene, Ht- xylene, cyclohexane and the like. Chlorinated solvents are selected from the group comprising of DCM, chloroform, dichloroethane, chlorobenzene and the like. Ethers are selected from the group comprising of diethyl ether, MTBE, diisopropyl ether,

15 THF, dioxane and the like. Amides are selected from the group comprising of DMF, dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like. Dialkylsulfoxides . are selected from the group comprising of DMSO, diethyl sulfoxide, dibutyl sulfoxide, sulfolane and the like. Preferred solvent is selected from DCM, ethyl acetate, chloroform or toluene.

20

The benefit of preparing the N-benzyl methyl amine derivative is that it avoids the usage of sodium azide. Accordingly, the formation of azide intermediate as well as bis-linezolid (XII) is avoided and linezolid (I) formed can be purified just by recrystallization. Thus, the process provides linezolid in purified form.

25

In yet another embodiment of the present invention, (R)-N-[[3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]p-toluenesulf onate (IXa) is converted into corresponding (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]azide (X). The azide intermediate X is reduced as well as 30 acetylated simultaneously in one pot to produce linezolid (I) avoiding the formation of bis-linezolid (XII).

Starting from IXa the reaction comprises of the following steps: a) reaction of (R)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl]methyl]p-toluenesulfonate (IXa) with sodium azide in presence of a solvent to yield an azide intermediate (X);

The solvent may be selected from the group of aprotic polar solvents comprising of nitriles, ketones, esters, chlorinated solvents, ethers, amides, dialkylsulfoxides or the mixtures thereof. Nitriles like acetonitrile etc., ketones like acetone, l-methyl-2- pyrrrolidinone etc., esters like ethyl acetate etc., chlorinated solvents like DCM etc., ethers like THF etc., amides like dimethylformamide (DMF) etc., dialkylsulfoxides like DMSO and the like. Preferred solvents are selected from DMF, l-methyl-2- pyrrrolidinone or DMSO. b) reaction of the azide intermediate (X) with a reducing agent in presence of acetylating agent in a solvent to form linezolid (I) in one pot avoiding the formation of an amine intermediate (XI).

The reducing agent may be selected from the group of catalysts comprising of zinc, nickel, platinum, palladium and the like combined with H ₂ source. The metal catalyst may be provided on an inert support such as carbon, activated carbon or alumina. The acetylating agent may be selected from acetic anhydride or acetyl chloride, preferably acetic anhydride. The solvent as defined herein is selected from the group comprising of esters, chlorinated solvents, hydrocarbons, ethers, amides, dialkylsulfoxides or mixtures thereof. Esters are selected from the group comprising of ethyl acetate, propyl - acetate and the like. Chlorinated solvents are selected from the group comprising of DCM, chloroform, dichloroethane, chlorobenzene and the like. Hydrocarbons are selected from benzene, toluene, cyclohexane and the like. Ethers are selected from the group comprising of diethyl ether, diisopropyl ether, MTBE, THF, dioxane and the like. Amides are selected from the group comprising of DMF, dimethylacetamide, N-methyl formamide, N-methyl pyrrolidone and the like. Dialkylsulfoxides . are selected from the group comprising of DMSO, diethyl sulfoxide, dibutyl sulfoxide, sulfolane and the like. Preferred solvents are selected from benzene, toluene, DCM, chloroform, ethyl acetate.

The present method involves the conversion of azide intermediate (X) directly to linezolid (I). The amine intermediate (XI) is formed in one pot and further produces converts into linezolid avoiding the formation of bis-linezolid. The crude linezolid formed can be obtained with high purity just by recrystallization avoiding cumbersome purification techniques.

The process disclosed above are further demonstrated in the 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 3-fluoro-4-morpholinylnitrobenzene (IV)

3, 4-Difluoronitrobenzene (100 g) was dissolved in water (100 ml), to it was added sodium bicarbonate (105.6 g). To the resulting suspension morpholine (60.2 g) was added under stirring at room temperature. The mixture was heated at 80-85°C for 18h. After the completion of reaction it was cooled to room temperature. The precipitated solid mass was filtered, washed with water and dried to obtain the titled compound (139 g) with 98% yield. Example-2: Preparation of 3-fluoro-4-morpholinylaniline (V)

3-Fluoro-4-morpholinylnitrobenzene (100 g) was dissolved in a mixture of methanol (900 ml) and ethanolamine (10 ml). To the resulting solution, Raney nickel (20 g) was added. Hydrogenation was carried out under 5 kg/cm ² hydrogen pressure at room temperature. After the completion of reaction, the reaction mass was filtered and washed with methanol. The filtrate was concentrated. To the resulting residue water (100 ml) was added and concentrated. The residue was cooled to room temperature and diluted with water (500 ml). The resulting suspension was stirred for lh. The solid mass was filtered, washed with water and dried to obtain the titled compound (78 g) with 90% yield.

Example-3: Preparation ofN-carboethoxy-3-fluoro-4-morpholinylaniline (Via)

3-Fluoro-4-morpholinylaniline (100 g) and sodium bicarbonate (107 g) was dissolved in DCM (575 ml). To the suspended mixture was added ethyl chloroformate (66.4 g) at 5-10°C over a period of 2h. The mixture was slowly warmed up to 25°C and stirred for 12h. After completion of the reaction, it was concentrated under atmospheric pressure at 35-40°C. To the resulting residue water (1500 ml) was added and was further concentrated. The mixture was warmed to 50°C and stirred for lh. The solid mass was filtered, washed with water and dried to obtain the titled compound (133 g) with 97% yield.

Example-4: Preparation of N-carbobenzoxy-3-fluoro-4-morpholinylaniline (VIb)

3-Fluoro-4-morpholinylaniline (100 g) was dissolved in a mixture of acetone (400 ml) and water (200 ml). To the resulting solution sodium bicarbonate (85.6 g) was added at 5-10°C followed by the addition of benzyl chloroformate (226g, 50%w/w solution in toluene). The mixture was warmed up to 25-30°C and stirred for lh. After completion of the reaction, water (1000 ml) was added and stirred for lh. The precipitated solid mass was filtered, washed with water and suck dried completely. The solid obtained was washed with cyclohexane and suck dried. The suck dried material was suspended in cyclohexane (1400 ml) and stirred at room temperature for lh. The solid material was filtered, washed with cyclohexane and dried to obtain the titled compound (157 g) with 94% yield. Example-S(a): Preparation of (R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2- oxo-5- oxazolidinyljmethanol (VIII) starting from N-carboethoxy-3-fluoro-4- morpholinylaniline

N-carboethoxy-3-fluoro-4-morpholinylaniline (100 g) was dissolved in THF (500 ml). To the resulting solution, n-butyllithium (245 ml in hexane) was added under nitrogen at -78°C over 1.5h and stirred for 2h, further a solution of R-(-)-glycidyl butyrate (53.75 g, in THF (100 ml)) was added. The resulting solution was stirred at -78°C for 2h, further it was warmed to room temperature and stirred for overnight. To the resulting thick slurry, saturated ammonium chloride (345 ml) was added followed by the addition of water (300 ml). It was stirred at room temperature for 30 min and was concentrated. Further, water (500 ml) was added and the suspension was again stirred at 50-55°C for lh and then at 25-30°C for next lh. The solid mass was filtered, washed with water and suck dried for lh. The filtrate was extracted with toluene. To the combined toluene layer, the suck dried material obtained above was added and heated to reflux and further concentrated. The concentrated solution was cooled to room temperature and stirred for lh. The solid mass was filtered, washed with toluene and dried to obtain the titled compound (110 g) with 80% yield.

ExampleS(b): Preparation of (R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2- oxo-5- oxazolidinyljmethanol (VIII) starting from N-carboethoxy-3-fluoro-4- morpholinylaniline

N-carboethoxy-3-fluoro-4-morpholinylaniline (50 g) was dissolved in THF (300 ml). To the resulting solution, n-butyllithium (122.5 ml in hexane) was added under nitrogen at -78°C over 30 min and stirred for 2h, further a solution of R-(-)-glycidyl butyrate (29.5 g, in THF (50 ml)) was added and stirred at -78°C for 2h. It was warmed to room temperature and stirred overnight. To the resulting thick slurry saturated ammonium chloride (173 ml) was added followed by the addition of water (50ml). The reaction mixture was stirred at room temperature for 30 min and further ethyl acetate (400 ml) was added to it, which was stirred for 15 min. Organic layer was separated and aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with water. The organic layer was concentrated under vacuum at 45-50°C, which resulted into an oily mass that was diluted with a mixture (1 : 1) of ethyl acetate and hexanes (750 ml). The suspended solution was warmed to 60°C and further stirred at 55-60°C for 30 min. The resulting clear solution was cooled to room temperature and stirred for 3h. The solid mass was filtered, washed with a mixture (1 : 1) of ethyl acetate and hexanes and suck dried. The suck dried material was suspended in ethyl acetate (380 ml) and heated to 80°C, which was further stirred at 75-80°C for 30 min. To the resulting clear solution, hexanes (380 ml) were added at 75-80°C and stirred at the same temperature for 15 min, further cooled to room temperature and stirred for lOh. The solid mass was filtered, washed with a mixture (1 :1) of ethyl acetate and hexanes and dried to obtain the titled compound (30.5 g) with 55% yield.

Example-6(a): Preparation of (R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidiny I] methanol (VIII) starting from N-carbobenzoxy-3-fluoro-4- morpholinylaniline

N-carbobenzoxy-3-fluoro-4-morpholinylaniline (50 g) was dissolved in THF (400 ml). To the resulting solution, n-butyllithium (99.5 ml in hexane) was added under nitrogen at -78°C over 40 min and stirred for 2h, further a solution of R-(-)-glycidyl butyrate (24 g in THF (50 ml)) was added and stirred for 2h. The reaction mixture was warmed to room temperature and stirred for overnight. To the resulting thick slurry saturated ammonium chloride (173 ml) was added and stirred for 30 min followed by the addition of water (50 ml). It was stirred at room temperature for next 30 min and concentrated. The resulting solution was cooled to room temperature and water (200 ml) was added. The obtained suspension was stirred at 50-55°C for 30 min and then at 25-30°C for next 30 min. The solid mass was filtered, washed with water and suck dried for 30 min. The filtrate was extracted with toluene. To the toluene layer, the suck dried material obtained above was added and heated to reflux. The resulting solution was concentrated and further cooled to room temperature and stirred for 15h. The solid mass was filtered, washed with toluene and dried to obtain the titled compound (24.6 g) with 55% yield. Example-6(b): Preparation of (R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyl] methanol (VIII) starting from N-carbobenzoxy-3-fluoro-4- morpholinylaniline

N-carbobenzoxy-3-fluoro-4-morpholinylaniline (100 g) was dissolved in THF (800 ml). To the resulting solution, n-butyllithium (208 ml in hexane) was added under nitrogen at -78°C over 1.5h and stirred for 2h, further a solution of R-(-)-glycidyl butyrate (52.3 g in THF (100 ml)) was added and stirred for 2h. The reaction mixture was warmed to room temperature and stirred for overnight. To the resulting thick slurry saturated ammonium chloride (345 ml) was added followed by the addition of water (50 ml). It was stirred at room temperature for 10 min and THF layer was separated from aqueous layer. Aqueous layer was extracted with ethyl acetate (2 x 250 ml). The combined ethyl acetate layer was washed with water and concentrated to get a residue in which THF layer was added and further concentrated completely. The solid mass obtained was cooled to room temperature and ethyl acetate (600 ml) was added. The reaction mixture was heated to 60-65°C and was stirred for 30 min, which was further cooled to 40-45 °C. The cooled reaction mixture was filtered and was washed with ethyl acetate (100 ml). To the filtrate cyclohexane (450 ml) was added at 25-35°C in 5 min. The resulting mixture was stirred for 12h. The precipitated solid was filtered, washed with a mixture (1 :1) of ethyl acetate and cyclohexane and dried to obtain the titled compound (62 g) with 70% yield.

Example-7: Preparation of (R)-[[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl] p-toluenesulfonate (IXa)

(R)-[N-3-(3-fluoro-4-morpholinylphenyl)-2- oxo-5-oxazolidinyl]methanol (100 g) and >-toluenesulfonyl chloride (97 g) were dissolved in DCM (600 ml). The resulting solution was cooled to 0-5°C and to the cold solution; triethylamine (58 g) was added. The obtained solution was warmed to room temperature and stirred for 18h. After the completion of reaction, water (300 ml) was added and stirred for 10 min. DCM layer was collected and concentrated. Further, methanol (500 ml) was added in the reaction mass and was stirred at room temperature for 30 min. The solid was filtered, washed with methanol and dried to obtain the titled compound (130 g) with 85% yield. Example-8: Preparation of (R)-[[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl] 4-methylmethanesulfonate (IX)

(R)-[N-3-(3-fluoro-4-mo holinylphenyl)-2- oxo-5-oxazolidinyl] methanol (6.5 g) and methanesulfonyl chloride (3.78 g) were dissolved in DCM (60 ml). The resulting solution was cooled to 0-5°C and to the cold solution; triethylamine (3.76 g) was added. The obtained solution was warmed to room temperature and stirred for lOh. After the completion of reaction, it was concentrated. In the resulting reaction mass, water (50 ml) was added and stirred at 50-55°C for lh and further at 25-30°C for next lh. The solid obtained was filtered, washed with water and suck dried. The suck dried material was suspended in methanol (65 ml) and heated to 60°C. The suspension was stirred at 55-60°C for 2h and further at room temperature for lh. The solid was filtered, washed with methanol at room temperature and dried to obtain the titled compound (6 g) with 73% yield. Example-9: Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl] amine p-TSA salt (XIa)

(R)- [ [N-3 -(3 -fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl] methyl] -p-toluene sulfonate (60 g) was dissolved in a mixture of (1 :1 :1) THF/IPA/aqueous ammonium hydroxide (900 ml) and heated in an autoclave to 85°C, further stirred at 80-85°C for 24 h. After completion of reaction, it was cooled to room temperature. The reaction mass was filtered. The filtrate was concentrated to dryness. Residual moisture was removed by using IP A (120 ml) followed by recovery. To the resulting residue IP A (180 ml) was added, heated to 50-55°C for 2h and cooled to room temperature. The solid mass was filtered and dried under vacuum at 50°C. To the above obtained solid, DCM was added and heated to reflux for 2h. Further, cooled to room temperature and stirred the obtained suspension for lh. The solid mass was filtered, washed with DCM and dried under vacuum at 50-55°C for overnight to obtain the titled compound (45 g) with 72% yield.

Example-10: Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2- oxazolidinyljmethyl] benzylamine (XIII) υ u 3

(R)- [ [Ν-3 -(3 -fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl] methyl] -p-toluene sulfonate (5 g) was added to benzylamine (17.8 g) and heated to 70°C and further, stirred for 5h. After completion of reaction it was cooled to room temperature and diluted with toluene (50 ml). The solution was successively washed with 10% sodium bicarbonate solution, 10% ammonium chloride solution and water. Toluene layer was concentrated to obtain the titled compound as oil.

Example-11: Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl] amine (XI)

(S -[[N-3-(3-fluoro-4-mo holinylphenyl)-2-oxo-5-oxazolidinyl]methyl]

benzylamine (5 g) was dissolved in methanol (55 ml). To the resulting solution ammonium formate (4.5 g) was added. Further, 10% Pd/C (0.55 g) was added to the resulting mixture. The mixture was heated to 65°C and stirred for 8 h. After completion of reaction it was cooled to room temperature. The solution was filtered and washed with methanol. The filtrate was concentrated under vacuum at 50-55°C to obtain the titled compound as oil.

Example-12: Preparation of (S)-N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl azide (X)

Dissolved (T )-[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]m ethyl-4- methylbenzene sulfonate (50 g) in DMF (150 ml), added sodium azide (14.44 g) to the solution, heated to 80-85°C and stirred at the same temperature for 4 h. After completion of reaction, it was cooled to room temperature and diluted with water (300 ml). Further, solution was stirred for lh. The solid mass was filtered, washed with water and dried to obtain the titled compound (32 g) with 90%) yield.

Example-13(a): Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl acetamide, Linezolid (I) starting from (S)-[[N-3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5-oxazolidinylJmethyl]amine p-TSA salt (S)-[P^-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidiny l]methyl]amine -TSA salt (5 g) obtained in example 9 and triethylamine (2.56 g) were dissolved in DCM (25 ml). The solution was cooled to 5°C and acetic anhydride (2.07 g) was added. The resulting reaction mixture was warmed to room temperature and stirred for 5h. After completion of reaction, water (50 ml) was added in reaction mixture and stirred for 30 min. Separation of DCM and aqueous layers was carried out. Aqueous layer was extracted with DCM. The combined DCM layers were washed with 10% sodium bicarbonate solution followed by washing with water. DCM layer was concentrated under vacuum at 35-40°C. Toluene (30 ml) was added into the residue and heated to 70°C. The suspended solution was stirred at 65-70°C for 30 min and further at room temperature for lh. The solid mass was filtered, washed with toluene and dried to obtain the titled compound (3 g) with 80% yield.

Example-13(b): Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl acetamide, Linezolid (I) starting from (S)-[[N-3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]aminep-TSA salt

(S)- [ [N-3 -(3 -fluoro-4-morpholinylphenyl)-2-oxo-5 -oxazolidinyl] methyl] amine p- TSA salt (50 g) obtained in example 9 was suspended in water (500 ml). To the resulting suspension, 6N hydrochloric acid (50 ml) was added at room temperature to adjust its pH to -0.5. Ethyl acetate (500 ml) was added in the above solution and further pH was readjusted to 4.5-4.7 using 10% sodium hydroxide solution. After separating ethyl acetate layer aqueous layer was washed with ethyl acetate. To the acidic aqueous layer, DCM (500 ml) and acetic anhydride (21.84 g) were added. The pH of the biphasic reaction mixture was adjusted to 4.5-4.7 using 10% sodium hydroxide solution (100 ml). The resulting reaction mixture was stirred at room temperature for 3h at the same pH. After completion of reaction pH of the reaction mixture was raised to -7-7.5 using 10% sodium hydroxide solution. Separation of DCM and aqueous layers was carried out. Aqueous layer was extracted with DCM (500 ml). The combined DCM layer was washed with water. DCM layer was concentrated and ethyl acetate (400 ml) was added in the concentrated DCM solution. The solvent was recovered completely to obtain a solid mass which was dissolved in ethyl acetate (1400 ml) at 60-65°C and then cooled to 35-40°C. To a cold (-15°C) mixture of cyclohexane (1575 ml) and ethyl acetate (175 ml) was added the above ethyl acetate solution at -15 to 0°C in 3-5 min. Further, the suspended solution was cooled down to -15°C and stirred for 2h. The solid mass was filtered, kept under suction for lh and dried to obtain the titled compound (23 g) with 63% yield.

Example-14: Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl acetamide, Linezolid (I) starting from (S)-[[N-3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine

(S)-[[N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidiny l]methyl]amine (3 g) obtained in example 11 and triethylamine (1.54 g) were dissolved in DCM (15 ml). The solution was cooled to 5°C and acetic anhydride (1.25 g) was added. The resulting reaction mixture was warmed to room temperature and stirred for 4h. After completion of reaction, water (50 ml) was added in reaction mixture and stirred for 30 min. Separation of DCM and aqueous layers was carried out. Aqueous layer was extracted with DCM. The combined DCM layers were washed with 10% sodium bicarbonate solution followed by washing with water. DCM layer was concentrated under vacuum at 35-40°C. Toluene (20 ml) was added into the residue and heated to 70°C. The suspended solution was stirred at 65-70°C for 30 min and further at room temperature for lh. The solid mass was filtered, washed with toluene and dried to obtain the titled compound (2.1 g) with 60% yield.

Example-15: Preparation of (S)-N-[[3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl acetamide, Linezolid (I) starting from (S)-N-3-(3-fluoro-4- morpholinylphenyl)-2-oxo-5- oxazolidinyljmethyl azide

(S^-N-3-(3-fluoro-4-morpholinylphenyl)-2-oxo-5-oxazolidin yl]methyl azide (10 g) obtained in example 12, and acetic anhydride (4.8 g) were dissolved in DCM (100 ml). To the resulting solution, 10% Pd/C (50% wet, 1.0 g) was added. The reaction mixture was hydrogenated under 1.5 kg/cm ² hydrogen pressure for 6h. After the completion of reaction, catalyst was removed by filtration. The filtrate was washed with water. The DCM layer was concentrated completely under vacuum at 35-40°C. To the resulting residue toluene (50 ml) was added and heated to 80°C. The suspended solution was stirred at 80-85°C for lh and further at room temperature for next lh. The solid mass was filtered, washed with toluene and dried to obtain the titled compound (8.0 g) with 80% yield. Example- 16(a): Purification of Linezolid

Linezolid (I) (2 g) was dissolved in ethyl acetate (50 ml) and heated to 65°C, further, was stirred at 60-65°C for 15 min. To the clear solution obtained hexanes (8 ml) were added at 50-55°C. The resulting solution was cooled to room temperature and stirred for lh. The solid mass was filtered, washed with a 1 : 1 mixture of ethyl acetate and hexanes (4 ml) and dried to obtain pure linezolid (1.6 g) with 70% yield.

Example-16(b): Purification of Linezolid

Linezolid (I) (10. Og) was dissolved in methanol (100 ml) and heated to 65°C, further, was stirred at 60-65°C for 30 min. The resulting solution was cooled to room temperature and stirred for 2h. The solid mass was filtered, washed with methanol (10 ml) and dried to obtain pure linezolid (8 g) with 80% yield.

Having described the invention with reference to particular preferred embodiments and illustrative examples, those in the art would appreciate modifications to the invention as that do not depart from the spirit and scope of the invention as disclosed in the specification. The examples are set forth to aid in understanding the invention but are not intended to, and should not be construed to limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinal skill in the art and are described in numerous publications. All references mentioned herein are incorporated in their entirety.