PROCESS FOR PREPARING LINEZOLID
FIELD There are provided novel intermediates of linezolid, process for their preparation and their use in the preparation of linezolid or its pharmaceutical acceptable salts, hydrates and solvates.
BACKGROUND Linezolid is the adopted name for a compound having the chemical name (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-acetamide and is represented by the structural Formula I

Linezolid is a synthetic anti bacterial agent useful for the treatment of bacterial infections in humans and is commercially available under the brand name Zyvox as I.V.injection, oral suspension and tablets.
Barbachyn et al., in U.S.Patent No.5,688,792 disclose linezolid and related compounds, processes for their preparation and their therapeutic uses. A process for preparation of linezolid as disclosed in US 792 is summarized in the scheme-1.


Scheme-1: Process disclosed in US 5,688,792 for the preparation of Linezolid.
Lohray et al., in Tetrahedron Letters, 40 (1999) 4855-4856; discloses process for tlie preparation of linezolid. The process is summerized in scheme-2:


Scheme-2: Process for the preparation of linezolid as disclosed in Tetrahedron Letters 40 (1999) 4855-4856.
Pearlman et al., in U.S.Patent No.5,837,870 disclose a process for the preparation of linezolid. The process for the preparation of linezolid as disclosed in US '870 is summerized in scheme-3:

Imbordino et al., in WO 2007/116284 disclose a process for the preparation of linezolid. The process for the preparation of linezolid as disclosed in WO '284 is summerized in scheme-6.
HO N>. X / \ /=\ 11 .R J \,, /=\ /\n
< is chlorohenyl, bromophenyl,
or 2,4-dichloropheyl; ^ '^ benzyl or C1 -8 alkyl ^^^^^^ ^.^
Acylation
^ >=\ k
Linezolid Q
Scheme-6: Process for the preparation of linezolid as disclosed in WO 2007/116284
The various processes disclosed in the prior art suffer from one or the other drawbacks like poor yield, lower purity at various stages of the synthesis.
Thus there is still a need for an alternative and industrially viable process for the preparation of linezolid and its pharmaceutically acceptable salts, hydrates and solvate.
SUMMARY The present invention provides process for the preparation of linezolid of Formula I and/or its pharmaceutically acceptable salts, hydrates or solvates.
In an embodiment there is provided a process for the preparation of linezolid, comprising in the steps of:
a) cyclizing the compound of Formula III


Q N

in the presence of suitable base to afford the compound of Formula II;
L 1 '

V-Na
b) reacting the compound 5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one of Formula II with 2 to 10 equivalents of thioacetic acid to afford the compound linezolid of Formula I.
In another embodiment there is provided a process for the preparation of intermediate compound of Formula III, which process comprises the following steps:
a) condensing the compound of Formula VI
F, RO

VI with the compound (R)-epichlorohydrin of Formula V
o
^^'
V

to afford the compound of Formula IV, wherein R is d-s alkyl or C1.8 alkyl substituted by aryl group

IV b) reacting the compound of Formula IV with sodium azide to afford the compound of Formula III;
F. OH

III
In another embodiment, there is provided novel intermediates of Formula and/or Formula IV, which are useful in the preparation of linezolid of Formula I.

IV
In yet another embodiment, there is provided a pharmaceutical compositions that includes linezolid or its pharmaceutically acceptable salt, prepared by the process of the present invention and atleast one pharmaceutically acceptable carrier useful for treatment of bacterial infections in humans and other warm blooded animals.
DETAILED DESCRIPTION

The present invention provides process for the preparation of linezolid of Formula I and/or its pharmaceutically acceptable salts, hydrates or solvates.
In an embodiment there is provided a process for the preparation of linezolid, comprising in the steps of:
a) cyclizing the compound of Formula III
F> OH

in the presence of suitable base to afford the compound of Formula II;


O- ^ F
■ N

O

V-Na
b) reacting the compound 5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one of Formula II with 2 to about 10 equivalents of thioacetic acid to afford the compound linezolid of Formula I.
Step a) involves cyclizing the compound of Formula III in the presence of suitable base to afford the compound of Formula II;
The cyclization reaction can be carried out in the presence of a suitable base and solvent.
Suitable bases which can be used include but are not limited to: inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, and potassium bicarbonate; organic

bases such as methylamine, dimethylamine, triethylamlne, ethyl-di-isopropylamine, and butylamine; preferably potassium carbonate.
The quantity of the base that can be used in the step (c) may range from about 1 to about 3 mole equivalents, per equivalent of compound of Formula III.
Suitable solvents which can be used include but are not limited to: ketonic solvents such as acetone, ethylmethyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, and t-butyl acetate; nitrile solvents such as acetonitrile, and propionitrlle; aprotic polar solvents such as N,N-dimethylformamide (DMF), Dimethylsulfoxide (DMSO), and N,N-dimethylacetamide (DMA); or mixtures thereof or their combination with water in various proportions without limitation.
Suitable temperatures for conducting the reaction can range from about 20 °C to about 100 °C, preferably at 60 °C.
Step b) reacting the compound 5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one of Formula II with thioaceticacid to afford linezolid of Formula I.
Optionally, Step b) is carried out in the presence or absence of solvent. Solvents include but are not limited to: ketonic solvents such as acetone, ethyl
The quantity of thioaceticacid in step b) range from about 2 to about 10 molar equivalents per equivalent of Formula II.


methyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, and t-butyl acetate; nitrile solvents such as acetonitrile, and propionitrile; aprotic polar solvents such as DMF, DMSO, and DMA; or mixtures thereof or their combination with water in various proportions in various proportions.
Suitable temperatures for conducting the reaction range from about 20 °C to about 85 °C. The suitable time for the completion of the reaction can range form about 30 minutes to about 10 hours.
The obtained linezolid may be optionally purified by column chromatography, recrystallization or slurring in suitable solvents.
Linezolid obtained by the process of the present invention may be converted to a pharmaceutically acceptable salt.
Pharmaceutically acceptable salts include acid addition salts formed with inorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, nitric acid, and phosphoric acid; or with organic acids such as acetic acid, propionic acid, hexanoic acid, heptanoic acid, malonic acid, succinic acid, malic acid, tartaric acid, citric acid, and oxalic acid, preferably hydrochlohc acid.
In another embodiment, there is provided a process for the preparation of intermediate of Formula III, which process includes: a) condensing the compound of Formula VI
F, RO
r~\ y-\ )^o
VI with the compound (R)-epichlorohydrin of Formula V

o
XI
V to afford the compound of Formula IV, wherein R is C1.8 alkyl or C1.8 alkyl substituted by aryl group;

RO IV b) reacting the compound of Formula IV with sodium azide to afford the compound of Formula III;
h OH

Step a) involves condensing the compound of Formula VI with the compound (R)-epichlorohydrin of Formula V to afford the compound of Formula IV, wherein R is C1.8 alkyl or Ci-a alkyl substituted by aryl group.
The compound of Formula VI of the present invention can be prepared by the reaction of 3-fluoro-4-morpholinyl-aniline with alkyl or benzyl chloroformate in the presence of base and solvent.
The condensation reaction can be carried out in the presence of a suitable base and solvent.
Suitable bases that can be used include but are not limited to: inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate.

potassium carbonate, sodium bicarbonate, and potassium bicarbonate; organic bases such as methylamine, dimethylamine, triethylamine, di-isopropylethylamine, and tertiary butyl amine;
The quantity of the base that can be used in the step (a) may range from about 1 to about 3 mole equivalents, per equivalent of compound of Formula VI.
Suitable solvents, which can be used include but are not limited to: ketonic solvents such as acetone, ethylmethyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, and t-butyl acetate; nitrile solvents such as acetonitrile, and propionltrile; aprotic polar solvents such as DMF, DMSO, and DMA; or mixtures thereof or their combination with water in various proportions.
Suitable temperatures for conducting the reaction can range from about 10 °C to about 50 °C. The suitable time for the completion of the reaction can range from about 30 minutes to about 10 hours.
The obtained compound of Formula IV may be used directly in the next processing step or solid can be isolated using suitable techniques.
Suitable techniques used for isolation of solid include techniques of crystallization, slurrying, or trituration in a suitable solvent.
Step b) reacting the compound of Formula IV with sodium azide to afford the compound of Formula III;
The reaction of formula V with sodium azide to form Formula III can be carried out in the presence of phase transfer catalyst like t-butyl ammonium chloride.

Suitable organic solvents that can be used include but are not limited to: alcohols such as methanol, ethanol, isopropylalcohol, and n-butanol; ketonic solvents such as acetone, ethyl methyl ketone, and methyl isobutyl ketone; esters such as ethyl acetate, n-propyl acetate, n-butyl acetate, and t-butyl acetate; nitrile solvents such as acetonitrile, and propionitrile; halogenated solvents such as dichloromethane, ethylene dichloride, and chloroform; aprotic solvents such as DMF, DMSO, and DMA; or mixtures thereof or their combination with water in various proportions.
The reaction is carried out at room temperature, however, if required the reaction may be carried out at elevated temperatures. The obtained product can be purified by conventional methods such as column chromatography, preparative HPLC purification and/or crystallization using a solvent or a mixture of solvents.
Suitably, one or more of the steps may be carried out without isolation of the intermediate compounds.
The present invention may include the removal of the solvent (s) in each stage by techniques which include but are not limited to: distillation, evaporation, oven drying, tray drying, rotational drying (such as the buchi rotavapor), spray drying, freeze drying, fluid bed drying, flash drying, spin flash drying and utral film agitated thin film dryer (ATFD).
The solvent(s) may be removed by distillation under vacuum. The solvent may be distilled under reduced pressure for example at about 1 to about 100 mbar. The distillation can be conducted at a temperature, for example from about 30 °C to about 125 °C to dryness.
The solids obtained from the solution in the present application may include optionally drying. Drying can be suitably carried out in a tray dryer.

vacuum oven, air oven, fluidized bed drier, spin flash dryer, and flash dryer. The drying can be carried out at temperatures from about 35° C to about 75° C for the time period that achieves the desired result.
The overall process for the preparation of linezolid is summarized in the sheme-7.
.0^ ^O^ ^O.

r
o Scheme-?: process for the preparation of linezolid.
In another embodiment, there are provided novel intermediates of Formula and/or Formula IV


•^^ V F OH
RO RO'

IV III
where R is Ci-salkyl or Ci.8alkyl substituted by aryl group; which are useful in the preparation of linezolid.
The compound of Formula III and the compound of Formula IV are characterized by spectral analysis like C^^ NMR, IR, ^H NMR.
The drug substance can be formulated as solid compositions for oral administration; tablets, pills, powders or granules may be used. In these compositions, the active product according to the invention is mixed with one or more inert diluents such as sucrose, lactose or starch. These compositions can also comprise substances other than diluents, e.g. a lubricant such as magnesium stearate.
The drug substance can be formulated as liquid compositions for oral administration, solutions, suspensions, syrups, elixirs and pharmaceutically acceptable emulsions, containing inert diluents such as water or liquid paraffin, may be used. These compositions can also comprise substances other than diluents, e.g. wetting, sweetening or flavouring products.
The compositions for parenteral administration can be suspensions, emulsions or aqueous or non-aqueous, sterile solutions. As a solvent or vehicle, propylene glycol, polyethylene glycol, vegetable oils, especially olive oil, and injectable organic esters, e.g. ethyl oleate, may be employed. These compositions can contain adjuvants, especially wetting, emulsifying and dispersing agents. The sterilization may be carried out in several ways, e.g. using a bacteriological filter, by incorporating sterilizing agents in the composition, by

irradiation or by heating. They may be prepared in the form of sterile compositions, which can be dissolved at the time of use in sterile water or any other sterile injectable medium.
Pharmaceutically acceptable carriers that are of use in the present invention are but not limited to diluents such as starch, pregelatinized starch, lactose, powdered cellulose, microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, mannitol, sorbitol, sugar and the like; binders such as acacia, guar gum, tragacanth, gelatin, polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxypropyl methyl cellulose, pregelatinized starch and the like; disintegrants such as starch, sodium starch glycolate, pregelatinized starch, crospovidone, croscarmellose sodium, colloidal silicon dioxide and the like; lubricants such as stearic acid, magnesium stearate, zinc stearate and the like; glidants such as colloidal silicon dioxide and the like; solubility or wetting enhancers such as anionic or cationic or neutral surfactants, complex forming agents such as various grades of cyclodextrins, resins; release rate controlling agents such as hydroxypropyl cellulose, hydroxymethyl cellulose, hydroxypropyl methyl cellulose, ethyl cellulose, methyl cellulose, various grades of methyl methacrylates, waxes and the like. Other pharmaceutically acceptable excipients that are of use include but not limited to film formers, plasticizers, colorants, flavoring agents, sweeteners, viscosity enhancers, preservatives, and antioxidants.
The process of the present invention is efficient, cost effective, ecofriendly, reproducible, scalable, robust and commercially feasible.
Certain specific aspects and embodiments of the present invention will be explained in more detail with reference to the following examples, which are provided by way of illustration only and should not be construed as limiting the scope of the invention in any manner.

EXAMPLES Example-1: Prepration of N-carboethyloxy-3-fluoro-4-morphollnyl aniline
3-Fluoro-4-morpholinyl-aniline (1 g), potassium carbonate (1.05 g) and acetone (10 ml) were charged into a clean round bottom flask followed by stirring at a temperature of about 25 °C to about 35 °C for about 10 minutes. Ethyl chloroformate (0.6 g) was added slowly for a period of 10 minutes at a temperature of about 25 °C to about 30 °C followed by stirring for about 30 minutes. The resultant reaction suspension was filtered and the solid was washed with acetone (5 ml) and dichloromethane (10 ml). The filtrate was washed with water followed by the separation of the organic and aqueous phases. The organic phase was dried over anhydrous sodium sulphate. The organic layer was distilled completely at about 50 °C under vaccum. The solid obtained was dried at a temperature of about 45 °C to afford 1.0 g of the title compound. MS m/z 269.0 [M*+H]
^H NMR (CDCI3 200 MHz): 5 7.27 (m, 1H), 6.93 (m, 2H), 6.59 (s, 1H) 4.21 (q, J = 14.2 Hz, J'=7 Hz, 2H), 3.86 (t, J = 4.2 Hz, 4H), 3.03 (t, J = 4.8 Hz, 4H), 1.30 (t, J = 7.2 Hz, 3H). IR: (KBr, cm"^); 3248 (NH), 1717 (C=0) 1600, 1510 (Aromatic C=C).
Example-2: Preparation of [3-fluoro-4- (4-morpholinyl) phenyl] oxranyl methylcarbamic acid ethyl ester
N-carboethyloxy-3-fluoro-4-morpholinyl aniline (10 g), acetone (150 ml) were charged into a clean and dry round bottom flask followed by stirring for about 5 minutes. Potassium carbonate (32 g), R (-) epichlorohydrin (27 g) and tertiary butyl ammonium bromide (0.2 g) were charged to the reaction mixture. The resultant reaction mixture was heated to about 60 °C followed by stirring for about 25 hours. After completion of the reaction, the reaction mass was cooled to about 30 °C. The separated solid was filtered and the solid was washed with acetone (30 ml). The resultant filtrate was distilled completely at a temperature of about 45 °C under vacuum. The obtained crude was extracted with 4 x 150ml

of n-hexane followed by distillation of solvent completely at a temperature of about 55 °C under vacuum to afford 10.1 g of the title compound. MS (D/z 347.0 [M%Na]
^H NMR (DMSO-de 400 MHz): 6 7.07 (m, 3H), 4.05 (q, J = 14 Hz, J' = 6.8 Hz, 2H), 3.87 (dd, J= 15.2 Hz, J'= 4 Hz, 1H), 3.74 (m, 4H), 3.48 (dd, J= 15.2 Hz, S = 6 Hz, 1H)3.12(m, 1H)3.0 (t, 4H) 2.49 (m, 2H), 1.16 (t, J = 7.2, 3H) IR: (KBr, cm-^); 3546 (NH), 1698 (C=0).
Example-3: Preparation of (3-azido-2-hydroxy-propyl)-(3-fluoro-4-morpholin-4-yl-phenyl)-carbamic acid ethyl ester
Sodium azide (0.36 g), ammonium chloride (0.27 g) were charged into a clean and dry round bottom flask followed by stirring for about 15 minutes. [3-fluoro-4- (4-morpholinyl) phenyl] oxranyl methyl carbamic acid ethyl ester (1.5 g) dissolved in methanol (6 ml) was added slowly over about 30 minutes. The resultant reaction mixture was stirred at a temperature of about 25 °C to about 30 °C for about 15 hours followed by quenching the reaction mixture by the addition of water (3 ml). The reaction suspension was extracted with ethyl acetate (10 ml) followed by separation of organic and aqueous phases. The organic phase was dried over anhydrous sodium sulphate followed by distillation of solvent completely at a temperature of about 30 °C under vaccum. The residue was subjected to column chromatography and collected fractions of the title product using n-hexane and ethyl acetate in the ratio of 7.5: 2.5 followed by distillation of the fractions collected at about 28 X under vacuum to afford 0.5 g of title compound.
MS m/z 368 (M+1), 390 (M+Na) IR: 3118 (NH), 2101 (N3), 1695 (C=0)
Example-4: Preparation of 5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one
(3-Azido-2-hydroxy-propyl)-(3-fluoro-4-morpholin-4-yl-phenyl)-carbamic acid ethyl ester (4 g), dimethyl formamide (DMF) (10 ml), and potassium

carbonate (3 g) were charged into a clean and dry round bottom flask followed by stirring for about 10 minutes. The resultant reaction mixture was heated to about 80 °C followed by stirring for about 10 hours. After completion of the reaction, the reaction mixture was cooled to about 30 °C followed by charging of water (20 ml). The reaction suspension was extracted with ethyl acetate (2 x 20 ml) followed by separation of organic and aqueous layers. The separated organic layer was washed with water (20 ml) followed by drying the organic layer over anhydrous sodium sulphate. The organic layer was distilled off completely at a temperature of about 35 °C under vacuum to afford 3.1 g of the title compound.
Example-5: Preparation of Linezolid (Formula I)
5-Azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (0.5 g) and thioacetic acid (0.9 g) were charged into a clean and dry round bottom flask followed by stirring at a temperature of about 30 °C for about 5 hours. After the completion of the reaction, the resultant reaction mass was quenched by addition of 10% sodium bicarbonate solution (20 ml). The reaction suspension was extracted with ethyl acetate (20 ml) followed by separation of organic and aqueous phases. The organic layer was dried over sodium sulphate. The obtained clear organic layer was distilled off completely at a temperature of about 35 °C under vacuum. The residue was subjected to column chromatography and collected fractions of the title product using n-hexane and ethyl acetate in the ratio of 7: 3 as eluant followed by distillation of the fractions collected at about 35 °C under vacuum to afford 0.1 g of pure title compound. Purity: 99.92 % by HPLC
Example-6: Preparation of linezolid (Formula I)
5-Azidomethyl-3-(3-fluoro-4-morpholin-4-yl-phenyl)-oxazolidin-2-one (15 g) was dissolved in ethylacetate (150 ml) and then charged into autoclave. Raney nickel (1.5 g) was charged into reaction solution and applied hydrogen gas pressure (3 kg/cm^) followed by stirring for 12 hours at a temperature of about 35 °C. The reaction mixture was filtered and washed the solid with ethyl

acetate (50 ml). The obtained filtrate was distilled upto 50 % under vacuum and cooled to 5 °C to about 10 °C followed by passing of hydrochloric acid gas. Then the solid was filtered and washed the solid with ethyl acetate (20 ml). Ethyl acetate (75 ml) was charged to the obtained solid and cooled to 10 to about 15 °C. Triehtylamine (11.5 ml) was charged to the reaction mixture followed by the addition of acetic anhydride (6 g) over a period of 15 minutes and then stirred the reaction mixture for 2 hours at a temperature of about 8 °C. The solid was filtered. Ethyl acetate (100 ml) and acetonitrile (20 ml) were charged to the obtained solid and heated to 80 to about 85 °C. The reaction suspension was stirred for 15 minutes and filtered. The obtained solid was taken and repeated eaching process two times using ethyl acetate (2x100 ml) and acetonitrile (2x20). Total filtrate combined and distilled completely at a temperature of about 50 °C. Ethyl acetate (100 ml) and acetonitrile (20 ml) were charged to the obtained reaction crude and heated to 80 °C. The reaction mixture was stirred for 20 minutes and filtered. The obtained filtrate was distilled completely at a temperature of about 55 to about 60 °C and then dried the solid at a temperature of about 60 °C under vacuum for about 2 hours to afford 4.8 g of title compound.

We claim:
1. A process for preparing linezolid of Formula I

which comprises
a) cyclizing the compound of Formula III

wherein R is Ci-a alkyl or Ci-s alkyl substituted by aryl group; to afford the compound of Formula II;

b) reacting the compound 5-azidomethyl-3-(3-fluoro-4-morpholin-4-yl-
phenyl)-oxazolidin-2-one of Formula II with thioaceticacid to afford the compound
linezolid of Formula I.
2. The process according to claim 1, wherein the reaction in step a) is carried
out in the presence of suitable base and a solvent.

3. The process according to claim 1, wherein the quantity of thioaceticacid is about 2 to about 10 molar equivalents per equivalent of Formula II.

b) reacting the compound of Formula IV with sodium azide to afford the compound of Formula III.
5. The process according claim 4, wherein the reaction in the step a) carried out in the presence of base and solvent.

6. The process according claim 4, wlierein tlie reaction in tlie step b) carried out in tine presence of salt like ammonium chloride.

to afford the compound of Formula IV, wherein R is same as above;

10. A process for preparing compound of Formula II