A PROCESS FOR THE PREPARATION OF (5S)-(N)-f[3-[3-FLUORO-4-{4-MORPHOLINYL) PHENYL]-2-OXO-5-OXAZOLIDINYL] METHYL] ACETAMIDE

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a novel, industrially viable and cost effective process for manufacturing (5S)-N-[[3"[3-Fluoro-4-(4-morpholinyl)phenylI-2-oxo-5-oxazolidinyl] methyl] acetamide.

BACKGROUND OF THE INVENTION

(5S)-(,N)-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide commonly known as Linezolid a compound of Formula I is an oxazolidinonc derivative useful as an antibacterial agent, active against a number of pathogenic microorganisms.

US5688792 (EP0717738) first time disclosed the product Linezolid and its process comprising converting (5R)-N-[[3-(3-fluoro-4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methanol of formula II to its sulphonatc salt of formula III and further to azide of Formula IV in presence of sodium azide, solvent such as dimethylformamide or l-methyl-2-pyrrolidinone, in presence of phase transfer catalyst such as !8-crown-6. The azide of formula IV is reduced in presence of 10% Pd/C, methanol to an amine of formula V, which is further acylated in presence of acetic anhydride and solvent such as pyridine to give Linezolid of Formula I. The crude compound is purified by column chromatography. This reaction can be illustrated by scheme I below:

WO2007116284 describes a process for the preparation of Linezolid as shown in Scheme II below which comprises coupling of substituted imine moiety of formula VI with a carbamate of formula VII in presence of base and an aprotic solvent to give compound of formula VIII,

which is hydrolyzed in presence of water and strong acid to give hydrochloride salt of formula IX and acylated with acetic anhydride in presence of mixture of water and water immiscible solvent such as methylene dichloride to give Linezolid of Formula I.
WO2006008754 describes a process, which comprises the reaction of 3-fluon>4-morpholinyl aniline with epichlorohydrin to give compound of formula X which is treated with potassium phthalamide to give a compound of formula XII. Alternatively 3-fluoro-4-morphoIinyl aniline can react with phthalimido oxiranyl compound of formula XI to give N-[3-pthalimido-2-(R)-hydroxypropyI]-3-fluoro-4-morphoIinylaniline of formula XII

The compound of formula XII is further carbonylated to give (S)-N-[[3-fluoro-4-(4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methylphthalimide of formula XIII which is deprotected with hydrazine hydrate or aqueous methylamine to give (S)-N-[[3-[3-fluoro-4-[4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyI]methyl]amine of formula V. The amine of formula V is acylated in presence of acetyl chloride or acetic anhydride in presence of solvent such as toluene or acetone to give Linezolid of Formula I.

US2007032472 describes a process shown in Scheme IV. This process comprises the reaction of 3-fluoro-4-morpholinyl aniline with (R)-epichlorohydrin to give N-[3-chloro-2-(R)-hydroxypropyI]-3-fluoro-4-morpholinylaniline of formula X which undergoes carbonylation in presence of carbonylating reagents to give (5R)-5-(chloromethy])-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone of formula XiV. The compound XIV undergoes azidation and simultaneous reduction to give (5S)-(M)-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl]methylamine of formula V. Alternatively, (5R)-5-(chloromethyl)-3-[3-fluoro-4-(4"morpholinyl)phenyl]-2-oxaxolidinone of formula XIV reacts with potassium phthalamide to give (5S)-(N)-[[3-[3-fluoro-4-[4-morpholinyl]phenyl]-2-oxo-5" oxazolidinyl] methyl]phthalamide of formula XIII which is converted to (5S)-(N)-[[3-[3-fluoro-4-(4-morpholiny])phenyl-2-oxo-5-oxazo]idinyl] methylamine of formula V. The amine of formula V undergoes acylation with acetyl chloride or acetic anhydride in presence of solvent such as ethyl acetate or methylene dichloride to give Linezolid of Formula I.

US2007021417 describes a process for the preparation of Linezolid intermediate as shown in Scheme V. This process comprises the reduction of (5R)-[[N-(4-morpholinyl -3-fluorophenyl)-2-oxo-5-oxazolidinyl]methyl]azide of formula IV in presence of suitable reducing agents, solvent, base and phase transfer catalyst to give (5S)-(N)-(4-morpholinyl-3-fluorophenyI)-2-oxo-5-oxazolidinyl]methyI]amine of formula V.

US5837S70 discloses a process for the preparation of Linezolid as shown in scheme VI. In this process compound of formula VII is reacted with (S)-(+)-3-ehloro-l, 2-propane- diol to give (5R)-N-[3-(3-t1uoro-4-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methanot of formula II which is further reacted with 4-nitrobenzene sulphonyl chloride, followed by quenching with hydrochloric acid to give (5R)-(N)-[[3-3-fluoro-4-morpholinylphenyl]-2-oxo-5-oxazolidinyl]methanol-4-nilrobenzenesulfonate ester of formula XV. The ester of formula XV is converted to (5S)-[N-3-[3-fluoro-4-morpholinylphenyI]-2-oxo-5-oxazolidinylJ methylamine salicylaldehyde imine of formula XVI. The compound XVI is treated with 37% hydrochloric acid, toluene, acetic anhydride and solvent such as, methylene dichloride, ethyl acetate to give Linezolid of Formula I.

US6362334 describes the process for its preparation of Linezolid as shown in scheme VII which comprises the conversion of (S)-]-amino-3-chloro-2-propanol hydrochloride of formula XVII with acetic anhydride to give (S)-N-(2-hydroxy-3-chloro)acetamide of formula XVIII and further converted to (S)-glycidyl acetamide. (S)-glycidyl acetamide is reacted with (N)-carbomethoxy-3-fluoro-4-morphlinyI aniline of formula VII in presence of lithium t-butoxide to give Linezolid of Formula I.

WO2002085849 reports a process for the preparation of Linezolid as shown in scheme VIII below. This process comprises reaction of (N)-carbobenzoxy-3-fluoro-4-morpholinylaniline of formula XIX with (S)-(N)-[2-(acetyIoxy)-3-chloropropyl]acetamide of formula VII in presence of N,N-dimethylformamide (or tetrahydrofuran), methanol, lithium t-butoxide, aq. ammonium chloride, water, sodium chloride (or acetic acid , water) and methylene dichloride to give Linezolid of Formula I.

EP1255754 disc/oses Linezo/id Form /( and its process for its preparation. This patent provides a process for preparation of Form II of Linezolid by starting with Linezolid of enantiomeric purity more than 98%. The Linezolid of greater than 98% enantiomeric purity is mixed with ethyl acetate and stirred at a temperature below 80 °C until crystals of Form II is obtained.

Drawbacks of the Prior art:

a) Most of the reported prior art processes proceed via azide intermediate, which is not easy to handle at large scale.

b) Most of the process disclosed in the prior art require column chromatographic purification of the final compound, which is lime consuming and not preferred at commercial scale, moreover it reduces the yield.

c) Salicylaldehyde is used in some of prior arts, which is combustible and incompatible with strong bases and strong acids used at commercial scale.

d) Potassium t-butoxide used in the prior art is highly corrosive and incompatible for commercial scale reaction

e) Most of the process after getting Linezolid further go for a purification to obtain a pure Linezolid form II, which makes reaction lengthy and decreases the yield substantially

Therefore there is still a continuing need of developing new processes for manufacturing Linezolid which is cost effective and industrially viable,

SUMMARY OF THE INVENTION

The principal aspect of present invention is to provide a novel process for the synthesis of Linezolid comprising:

a) conversion of (5R)-(N)-[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methanol of formula II to give compound of formula XX;

b) optional halogenation of compound of formula XX to give (5R)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]halide of formula XXI (where X is Cl, Br, I);

c) amination of compound of formula XX or (5R)-(N)-[[3-f1uoro-(4-morpholinyIphenyl)-2-oxo-5-oxazolidinyl]methyl]halide of formula XXI with substituted or unsubstituted benzylamine to obtain a compound of formula XXII or its acid addition salt;

d) deprotection of compound XXII or its acid addition salt to give (5S)-{N)-[[3-fluoro-<4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine of formula V or its acid addition salt; and

e) acylation of compound of formula V or its acid addition salt in presence of a base in solvent and acetic anhydride to give (5S)-(N)-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide of formula I.

In another aspect, the present invention provides novel intermediates of the formula XXIII

where, X is Br or I, Z is O, S, SO or SO2
In another aspect, the present invention provides novel intermediates of the intermediates of the formula XXIV and its acid addition salt

where, R is substituted or unsubstituted benzyl and Z is O, S, SO or S02
In another aspect, the present invention provides novel crystalline form of hydrochloride salt of compound of formula V

V Where the novel crystalline Form of (5S)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl]amine hydrochloride is characterised by characterised by a powder X-Ray diffraction pattern with peaks at 2.8573, 3.8195, 5.6764, 6,0519, 11.3477, 13.5399, 14,2743,15.7351, 17.79.8. 18.4282, 19.1175, 19.4426, 20.8834, 22.6963, 23.2676, 24.4569, 25.1108, 25.2-348, 25.7859, 26.6613, 27,2147, 28.4793, 29.1220, 30.4464, 32,2931, 33,4371, 34.3074, 35.3599, 37,2139, 38.4590, 40.2361, 43.2659, 44.0735, 45.4430, 46.3811 ± 0.2 degree 26 or substantially as indicated in figure 1.
In another aspect, the present invention provides a novel hydrobromide salt of compound of formula V

In another aspect, the present invention provides a novel crystalline Form of (5S)-(N)-[[3-fluoro-(4-morpholinylphenyl)-'2-oxo-5-oxazolidinyr] methylamine hydrobromide, which is characterised by a powder X-Ray diffraction pattern with peaks at 5.6150, 6.0556, 8.2863, 11.2256, 12.2041, 12.7626, 14.2995, 15.2086, 16.8592. 17.7950, 17.9146, 18.5177, 18,8185, 19.1798, 20.5387, 20,8364, 21.3311, 21.7952, 22.5113. 23.0950, 23,3384, 24.2757, 24.5123, 24.9863. 25,1603, 26.0177, 26.7433, 27.5435, 27.7923, 28.2463, 28.4927, 28.8051. 29.1759, 30.6270. 31.3431, 31.6763, 32.3296, 32,8381, 33.1555, 34.0031, 34.5944, 35.2688, 36,0216, 36.6446, 37.5140, 38.0724, 39.0874, 39.5629 ± 0.2 degree 29 or substantially as indicated in figure 3.

In yet another aspect, the present invention provides a novel process for the acetylation of compound of formula V or its acid addition salt in absence of any organic solvent and organic base to obtain Linezolid Form II

BRIEF DESCRIPTION OF THE ACCOMPANYING DRAWINGS
Fig 1: XRD of (5S)-(N)-[[3-fluoro-(4-morpho/inyJphenyl)-2-oxo-5-oxazoIidinylJ methyljamine hydrochloride of the present invention.

Fig 2: DSC thermogram of (5S)-(N)-[[3~fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyll methyljamine hydrochloride of the present invention.

Fig 3: XRD of (5S)-(N)-[[3-fiuoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methyljamine hydrobromide of the present invention.

Fig 4: DSC thermogram of (5S)-(N)-[[3-fluoro-(4—morpholinylphenyl)-2-oxo-5-oxazolidiny]] methyl]amine hydrobromide of the present invention.

Fig 5: XRD of (5S)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo~5-oxazolidinyl] benzylamine

Fig 6: DSC thermogram of (5S)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] benzyl amine

Fig 7: XRD of (5S)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxO"5-oxazolidinyl] benzylamine hydrochloride

Figure 8: DSC thermogram of (5S)-(N)-[[3-fluoro-(4-morpholinylphenyI)-2-oxo-5-oxazolidinyl] benzylamine hydrochloride

Figure 9: X-ray powder diffractogram of (5S)-(N)-[[3-fIuoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinylj benzylamine hydrobromide

Figure 10: DSC thermogram of (5S)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] benzylamine hydrobromide

DETAILS OF THE DESCRIPTION

Accordingly in an embodiment, the present invention provides a novel process for the manufacturing of Linezolid

The present invention discloses the conversion of (5R)-(N)-[[3-fluoro-(4-morpholinyl phenyl)]-2-oxo-5-oxazolidinyl]methanol of formula II to a compound of formula XX (where L is a leaving group) carried out in the presence of reagents selected from methanesulfonyl chloride, p-totuenesulfonyl chloride, o-toluenesulfonyl chloride, 4-nitrobcnzenesulfonyl chloride, 4-bromobenzene sulfonyl chloride and trifluromethanesulfonyl chloride preferably methanesulfonyl chloride in an organic solvent selected from methylene dichloride, ethylene dichloride, toluene, ethylacetate and acetonitrile preferably methylene dichloride and base such as pyridine, trimethylamine, diisopropyl ethyl amine, DMAP, triethylamine, sodium bicarbonate, potassium carbonate and sodium carbonate preferably triethylamine.

The compound of formula XX is treated with alkali metal halide such as potassium bromide, sodium iodide, lithium bromide and others: haloacetamide such as bromoacetamide, iodoacetamide, chloroacetamide preferably alkali metal halide as lithium bromide in presence of an organic solvent selected from tetrahydrofuran, acetonitrile, dimethylformamide and 1,4-dioxan preferably tetrahydrofuran to give (5R)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]halide of formula XXI.

(5R)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methylJhalide undergoes animation in presence of reagents selected from benzylamine, 4-(trifluoromethyl)benzyIamine, 4-(trifluoromethoxy)benzylamine, 3-methoxybenzylamine and 4-methoxybenzylamine more preferably benzylamine (without or) with solvent like dimethylformamide, dimethylsulpoxide at reflux temperature to obtain compound of formula XXII (where R is a substituted benzyl).

(5R)-(N)-[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]bromide undergoes animation in presence of reagents selected from benzylamine, 4-(triflouromethy!)-benzylarnine, (trifluoromethyObenzylaminettrifluoromethoxyJbenzylamineJ-methoxy- benzylamine and 4-methoxybenzylamine more preferably benzylamine at 150°C temperature. The mixture is cool to 40°C to 45"C and add organic solvents like acetone, Ethylacetate, Toluene, Cyclohexane, MDC, EDC more preferably acetone to form clear solution then add water to obtain solid compound of formula XXII (Where R is a substituted benzyl)
(5RHN)-|3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]sulphonate
undergoes animation in presence of reagents selected from benzylamine, 4-(triflouromethyl)-benzylamine, 4-(trifluoromethyl)benzylamine,4-(trifluoromethoxy)benzy]amine,3-methoxy-bcnzylamine and 4-methoxybenzylamine more preferably benzylamine at 150°C temperature. The mixture is cool to 40"C to 45°C and add organic solvents like acetone, Ethylacetate. Toluene, Cyclohexane, MDC, EDC more preferably acetone to form clear solution then add water and organic acid like HC1, HBr, CH3COQH, H2S04 more preferably HCl at 25"C to 30°C to obtain solid compound of formula XXII acid salt (Where R is a substituted benzyl)

The compound of formula XXII is deprotected by hydrogenation in presence of catalyst such as palladium/carbon or platinum / carbon preferably palladium on carbon in acidic medium such as acetic acid, formic acid, trifluoroacetic acid, acid salt of pyridine, N,N-dimethylamine, N,N-diethylamine and diphenylamine more preferably acetic acid and solvent such as methanol, ethanol, isopropyl alcohol, ethylacetate, toluene, acetic acid and butanol, more preferably methanol at 5 to 6 Kg /cm2 pressure to give (5SHN)-[[3-[3-fluoro-4-(4-morphoIinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl] amine of formula V.

The compound of formula XXII acid salt is deprotected by hydrogenation in presence of catalyst such as Palladium/Carbon or platinum / carbon preferably palladium on carbon in acidic medium such as acetic acid, formic acid, triflouro acetic acid more preferably acetic acid and solvent such as methanol, ethanol, isopropyl alcohol, ethylacetate, toluene, acetic acid and butanol more preferably methanol at 5 to 6 kg /cm2 Pressure to give (5S)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine acid salt of formula V.

The compound (5SHN)-[[3-fluoro-(4-morphoIinylphenyl)-2-oxo-5-oxazolidinyl]methyl| amine or its acid salts is acylated with acetyl anhydride or acetic anhydride in presence of inorganic or organic base in organic solvent or water or mixture of water and an organic solvent. Base selected from ammonia in liqiud or gaseous form, trialkylamine, pyridine, DMAP, metal hydroxide such as sodium hydroxide, potassium hydroxide, metal carbonate such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate preferably aqueous ammonia to give (5S)-(N)-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl acetamide of formula I.

In another embodiment of the present invention provides a process for the acetylation of compound of formula V or its acid addition salt in presence of water and absence of any organic solvent and organic base to obtain Linezolid Form II
In another embodiment, the present invention provides novel intermediates of the formula XXIII

where, X is Br or I,
Z is O, S, SO or S02

In another embodiment, the present invention provides novel intermediates of the formuli XXIV and its acid addition salt where, R is substituted or unsubstilutcd benzyl and Z is O, S, SO or SO? These compounds of formula XXIII and XXIV are ale key intermediates of for the preparation of oxazolidinone antibacterials. The compounds of formula XXIII and XXIV and their acid addition salts are especially preferred when Z is oxygen, which are the preferred intermediates for the preparation of Linezolid.

The examples are provided to illustrate particular aspect of the disclosure and do not limit the scope of the present invention as defined by the claims.

EXAMPLES

Exampk-1; Preparation of(5R)-(N)-[[3-jluoro-(4-morpholinylphenyt)-2-oxo-5-oxazolidinylJ methylfsulphonate.

(5R)-(N)-[3-fluoK>(4-morpholinyIphenyl)-2-oxo-5"OxazoIidinyl]methanol (1 mole eq, 100 g) was taken in 600 ml methylene dichloride and cooled to 0-5°C, to it was added triethylamine 1.92 mol eq, 90.2 ml). The reaction mixture was stirred to 10-J5mins followed by the addition of methanesulfonyl chloride (1.44 mole eq, 37,5ml) at the same temperature. The temperature of the reaction mixture was raised to room temperature and further to 40°C with continuous stirring for 7 - 8 hours. The reaction mixture was quenched with water and stirred for lhr at room temperature, filtered, washed with methylene dichloride and dried to obtain the titled compound (Yield : 90%).

Example-2: Preparation of (SR)-(N)-ff3-fluoro-(4-morpholinytphenyl)-2-oxo-5-oxazoUdinylj methyl J bromide (5R)-(N)-[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazoIidinyl]methyl]sulphonate (1 mole eq, 100 g) and lithium bromide(2,0 mole eq, 46.36 g) were taken in tetrahydrofuran (1.0 L) under nitrogen at 27 - 30DC and heated to reflux for 8-9 hours. The reaction mixture was cooled to room temperature and distilled out completely. To the residue was added water (350 ml), stirred for lhr at room temperature, filtered, washed with water and dried to obtain the titled compound (Yield : 90%).

Exampte-3: Preparation of(5S)-(N)-[[3-fluoro-(4-morpholinylphenyt)-2-oxo-5-oxazolidinylf benzylamine.hydrochloride
(5R)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazoIidinyl]methyl]sulphonate (1.0 mole eq, 50 g) was reacted with benzylamine (3.0 mole eq, 35.78 g) and heated to 150°C for 1 hour. The reaction mixture was cooled to 40°C- 45°C to it was added acetone {150 ml) and water (50 ml) and adjust PH 4.5 to 5 with Con HCI. Which is stirred it 30 min and cool to 0 to 5°C with in 1 hr and filtered and washed with acetone (50 ml) and dried to obtain the filtered compound. (Yield: 80%), M,P240°C-243°C.

Example-4: Preparation of(5S)-(N)-[[3-fluoro-(4-morphotinylphenyl)-2-oxo-5-oxazolidinyll benzylamine (5R)-(N)-[[3-iluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]bromide (lmole eq.100 g) was reacted with benzylamine (1.5 mole eq, 43.91 g) and heated to 150°C for 1-2 hours. The reaction mixture was cooled to 60°C, to it was added ethylacetate (500 ml) and stirred at 50-60°C for 1-2 hours, cooled to room temperature, filtered, washed with ethylacetate and dried to obtain the crude compound (Yield: 80%). The crude compound was taken in methylene dichloride and water mixture, stirred for an hour at room temperature, filtered and dried to get pure titled compound. (Yield; 45%), M.P220°C

Example-5: Preparation of(5S)-(N)-[[3-fluoro-(4-morpholinylphenyl)~2-oxo-5-oxazolidinyl] methylamine. Hydrochloride.

(5S)-(N)-[[3-tluoro-(4-morpholinylphenyl)-2-oxo-5 oxazolidinyl]benzylamine.hydrochloride (1.0 mole eq. 75 gms) Pd/C (5%) (15 gms)acetic acid (1.0 L) were taken together in methanol (1.0 L) and heated to 45°C to 5G°C under hydrogen pressure (5 to 6 kg) for 8 to 10 hours. The reaction mixture was filtered and the filtrate was distilled of completely to the residue was added ethylacetate (225 ml) and stirred for 1 hr, filtered & dried to get the title compound (yield:90%), M,P287°C-288°C.

Exampte-6; Preparation of[(5S)-(N)-[[3-ftuoro-(4-morpholinylphenyt)~2-oxo-5-oxazolidinyl] methylamine- (5S)-(N)-p-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]benzylamine (1.0 mole eq, 50 gms), Pd/C (5%) (25 gms), acetic acid (25 ml) were taken together in methanol (1.5 L) and heated to 40°C under hydrogen pressure (10-12 kg) for 8-10 hours. The reaction mixture was filtered and the filtrate was distilled off completely. To the residue was added ethyl acetate (750 ml) and stirred for lhr, filtered and dried to get the titled compound (Yield: 95%), M.P: 270°C.

Example-7; Preparation of(5S)~(N)-[[3-ftuoro-(4-rnorpholinyiphenyl)-2-oxo-5-oxazolidittylj methyl acetamide (Form II) (5S)-(N)-[[3-fluoro-(4-morpholinylphenyl)"2-oxo-5-oxazo)idinyl]methylamine (20 gms) was added in water (200 ml) and ethyl acetate (80 ml) and the mixture was stirred at 25°C-30°C followed by the addition of acetic anhydride (19.2 ml, 3 eq.) at the same time. The reaction mixture was neutralized to 6-8 pH with aqueous ammonia and stirred for 2 hours. The reaction mixture was then filtered, to give (5S)-(N)-[3-fluoro-(4-morpho]inylpheny])-2-oxo-5-ox*izolidinyJ (methyl acetamide (Yield: 68%)

Example-8: Preparation of (5S)-(N)-([3-fluoro-(4-morpholmylphenyl)-2-oxo-*5-oxazolidinyl] methyl acetamide (Form II) (5S)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine (20 g) was added in water (180 ml). The content was stirred at 25°C-30°C followed by the addition of acetic anhydride (19.2 ml7 3 eq.) at the same time. The reaction mixture was neutralized to 6-8 pH with aqueous ammonia and stirred for 2 hours. The reaction mixture was then filtered, to give (5S)-(N)-[3-i1uoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl acetamide (Yield: 68%).

We claim:

1. A process for the manufacturing of Linezolid of formula I comprising:

a) conversion of (5R)-(N)-[3-fluoro-(4'morpholinylphenyl)-2-oxo-5-oxazolidinyl] methanol of
formula II to give compound of formula XX

where L is a leaving group selected from methanesulphonate, p-toluenesulphonate, o-toluenesulphonate, 4-nitrobenzene sulphonate. 4-bromobenzene sulphonate, and trifluromethylsulphonate;

b) optional halogenation of compound of formula XX to give (5R)-(N)-[[3-fluoro-(4-morpholinylphenyI)-2-oxo-5-oxazolidinyl]methyl]halide of formula XXI where X is Cl, Br, I;

c) amination of compound of formula XX or (5R)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]halide of formula XXI with substituted or unsubstituted benzylamine to obtain a compound of formula XXII or its acid addition salt where R is a substituted or unsubstituted benzyl; d) deprotection of compound XXII or its acid addition salt to give (5S)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl]methyl]amine of formula V or its acid addition salt; and

e) acylation of compound of formula V or its acid addition salt in presence of a base in solvent and acetic anhydride "to give (5S)-(N)-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide of formula I, 2. A process according to claim 1, wherein the conversion of (5R)-(N)-[[3-fluoro-(4-morpholinyl phenyl)]-2-oxo-5-oxazolidinyl]methanol of formula II to a compound of formula XX in step (a) is carried out in the presence of reagents selected from methanesulfonyl chloride, p-toluenesulfonyl chloride, o-toluenesulfonyl chloride, 4-nitrobenzenesulfonyl chloride, 4-bromobenzene sulfonyl chloride and trifluromethanesulfonyl chloride; in an organic solvent selected from the group consisting of methylene dichloride, ethylene dichloride. toluene, ethylacetate and acetonitrile; and base selected from the groupe consisting of pyridine, trimethylamine, diisopropyl ethyl amine, DMAP, triethylamine, sodium bicarbonate, potassium carbonate and sodium carbonate.

3. A process according to claim 2, wherein the reagent for the conversion is methanesulfonyl chloride, the organic solvent is methylene dichloride and the base is triethylamine.

4. A process according to claim 1, wherein the halogenation in step (b) is carried out by treating compound of formula XX with alkali metal halide selected from the group consisting of potassium bromide, sodium iodide, lithium bromide or with haloacetamide selected from the group consisting of bromoacetamide, iodoacetamide, chloroacetamide in presence of an organic solvent selected from tetrahydrofuran, acetonitrile, dirnethylformamide and 1,4-dioxan.

5. A process according to claim 4, wherein the halogenation in step (b) is carried out by treating compound of formula XX with lithium bromide in presence of tetrahydrofuran.

6. A process according to claim 1. wherein the amination of compound of formula XX in step (c) is carried out in presence of a reagent selected from the group consisting of benzylamine, 4-(trifluoromethyl)benzylamine, 4-(trifluoromethoxy)benzylamine, 3-methoxybenzylamine and 4-methoxybenzylamine in presence of solvent selected from dimethylformamide, dimethylsulpoxide or in the absence of any solvent.

7. A process according to claim 6, wherein the deprotection of compound XXII or its acid addition salt is carried out in presence of a catalyst selected from the group palladium/carbon or platinum / carbon in acidic medium such as acetic acid, formic acid, trifluoroacetic acid, acid salt of pyridine, N,N-dimethylamine, N,N-diethylamine and diphenylamine and solvent selected from the group methanol, ethanol, isopropyl alcohol, ethylacetate, toluene, acetic acid and butanol.

8. A process according to claim 7, wherein the deprotection of compound XXII or its acid addition salt is carried out in presence of a catalyst palladium on carbon in acetic acid and methanol at 5 to 6 Kg/cm(to the power of 2) hydrogen pressure.

9. A process according to claim I, wherein the acylation of compound of formula V or its acid addition salt in step (e) is carried out with acetyl anhydride or acetic anhydride in presence a base in an organic solvent or water or mixture thereof,

10. A process according to claim 9, wherein the base for acylation is selected from ammonia, trialkylamine, pyridine, DMAP, sodium hydroxide, potassium hydroxide, such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate.

11. A process according to claim 9, wherein the base for acylation is aqueous ammonia.

12. A process for the acetylation of compound of formula V or its acid addition salt in absence of any organic solvent and organic base to obtain Linezolid Form II,

13. A process according to the claim 12, where acylation is carried out in presence of water, acetic anhydride and aqueous ammonia.

14. A compound of the formula XXUI where, X is Br or I, Z is O, S, SO or SO,

15. A compound of the formula XXIV and its acid addition salt where, R is substituted or unsubstituted benzyl and Z is O, S, SO or SO2

16. A crystalline form of (5S)-(NH[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl]amine hydrochloride characterised by characterised by a powder X-Ray diffraction pattern with peaks at 2.8573, 3.8195, 5.6764, 6.0519, 11.3477, 13,5399, 14.2743,15.7351, 17.79.8, 18,4282, 19.1175, 19.4426, 20.8834, 22,6963, 23.2676, 24.4569, 25.1108. 25.2348, 25.7859, 26.6613, 27.2147, 28.4793, 29.1220, 30.4464, 32.2931, 33.4371, 34.3074, 35.3599, 37.2139, 38,4590, 40.2361, 43.2659, 44.0735, 45,4430, 46.3811 ± 0.2 degree 2G or substantially as indicated in figure I.

17. A crystalline form of (5S)-(N)-[[3-fluoro-(4-morpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl]amine hydrobromide characterised by a powder X-Ray diffraction pattern with peaks at 5.6150, 6.0556, 8.2863, 11.2256, 12.2041, 12.7626, 14.2995, 15.2086, 16.8592, 17.7950, 17.9146. 18.5177, 18.8185, 19.1798, 20.5387, 20.8364, 21.3311, 21.7952, 22.5113, 23.0950, 23.3384, 24.2757, 24,5123, 24.9863, 25.1603, 26.0177, 26.7433, 27.5435, 27.7923. 28.2463, 28,4927, 28.8051, 29.1759, 30.6270, 31.3431, 31.6763, 32.3296, 32.8381, 33,1555, 34.0031, 34.5944, 35.2688, 36,0216, 36.6446, 37.5140, 38.0724, 39.0874, 39.5629 ± 0.2 degree 2G or substantially as indicated in figure 3