Form 2THE PATENTS ACT, 1970(39 of 1970)&THE PATENTS RULES 2003PROVISIONAL SPECIFICATION[See section 10 and rule 13]1. TITLE OF THE INVENTION"Process for preparation of (S) (N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2- oxo-5-oxazolidinyl] methyl]acetamide"2. APPLICANT1. NAME: US VOMITED2. NATIONALITY: Indian Company incorporated under theCompanies Act 19563. ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088, Maharashtra, India3. PREAMBLE TO THE DESCRIPTIONThe following specification describes the invention.

Technical field:
The present invention relates to process for preparation of (S) (N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]acetamide, also known as Linezolid of formula (I) in high yield and purity.

Background of invention:
Linezolid is a synthetic antibacterial agent of the oxazolidinone class. Linezolid is useful in the treatment of infections caused by aerobic gram positive bacteria. Linezolid is marketed in United States of America by Pfizer Inc as an injection, tablets & oral suspension under the name Zyvox.
US5688792 discloses reduction of (R)-N-[[3-[3-Fluoro-4-morpholinylphenyl]-2-oxo-5-oxazolidinyl]methylazide (II) to provide the intermediate amine (R)-N-[[3-[3-Fluoro-4-morpholinylphenyl]-2-oxo-5-oxazolidinyl] methyl amine (III) which on acetylation gives a gummy mass which is further purified by column chromatography followed by evaporation & trituration of the product to obtain pure (S)-Linezolid. The reaction scheme is represented below as (Scheme I).

Disadvantage of this process is use of column chromatography to get the pure compound which requires high quantity of solvent thus expensive, inconsistent and time consuming, use of pyridine in the acetylation stage which is difficult to remove the traces of pyridine from the product and leads to numerous aqueous washing steps and thereafter increasing work up volumes and provides low yield and purity of Linezolid.
There are other processes disclosed in the prior art for the preparation of Linezolid and its polymorphs viz. US6107519, US5837870, US6288239, US6559305, US6444813, WO01/57035 US20060128703, US2006252932, US20060142283 & US20070015753.
Objects of the invention:
An object of the present invention is to provide process for the preparation of Linezolid (S)(N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide of formula (I) from the intermediate of formula (II) by one pot process.
Another object of the present invention is to provide a cost effective, simple, scalable and

robust process for obtaining Linezolid with good yield and high purity.
Another object of the present invention is to provide process for preparing Linezolid avoiding column chromatography technique.
Summary of the invention:
The present invention discloses an improved process for the preparation of highly pure
Linezolid (S) (N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]
methyl]acetamide in high yield. (Scheme II).
According to the invention (R)-N-[[3-[3-Fluoro-4-morpholinylphenyl]-2-oxo-5-oxazolidinyl]methylazide (II) is reduced using reduction catalyst in presence of an organic solvent, organic acid, acetylating reagent to provide (S)-N-[[3-[3-Fluoro-4-morpholinylphenyl]-2-oxo-5-oxazolidinyl]methylamine(III) which is further purified to obtain pure Linezolid with high purity of 99.9%.


Detailed description of the invention:
The process for the preparation of Linezolid formula (I) according to the present invention, comprises the steps of:
a) suspending (R)-N-[[3-[3-Fluoro-4-morpholinylphenyl]-2-oxo-5-oxazolidinyl] methylazide (II) in an organic solvent, organic acid and acetylating reagent;

b) hydrogenating the obtained reaction mixture in presence of reduction catalyst for several hours;
c) adding base to the obtained reaction mixture;
d) isolating the compound of formula (I) and
e) purifying the compound of formula (I) with suitable organic solvent to get pure Linezolid.

The organic solvent is selected from C|.4 alkyl ester such as methyl acetate, ethyl acetate, butyl acetate, isobutyl acetate, preferably ethyl acetate.
The organic acid is selected from acetic acid or formic acid, preferably acetic acid.
The acetylating reagent is selected from acetic anhydride or acetyl chloride.
The reduction catalyst is selected from Pd/C, platinum oxide and Raney nickel.
The base is selected from the group comprising sodium hydroxide, potassium hydroxide,

sodium carbonate, sodium bicarbonate, potassium carbonate, preferably sodium bicarbonate.
Optionally liquid ammonia may be added to the reaction mixture of step (c).
The suitable organic solvent used for purification of Linezolid is selected from the group consisting of a polar aprotic solvents such as tetrahydrofuran, 1,4-dioxane, 1,2-diethoxy ethane, 1,2-methyoxy ethane, diethyl ether, diisopropyl ether, methyl tertiarybutylether (MTBE) or mixture thereof, preferably 1,4-dioxane and diisopropyl ether.
According to a preferred embodiment of the invention, (R)-N-[[3-[3-Fluoro-4-morpholinylphenyl]-2-oxo-5-oxazolidinyl]methylazide of formula (II) is reduced with Pd/C catalyst by suspending in organic solvent, organic acid and acetylating reagent mixture. The mixture is then hydrogenated in hydrogen gas at about 30 psi and at a temperature range of about 25 to 35° C for 5 hrs. After the completion of the reaction, 5% sodium bicarbonate solution is added to the reaction mixture and stirred to get a residue which is further stirred with suitable solvent to yield Linezolid in high yield and high purity of greater than 99.5%.
According to another embodiment of the present invention, Linezolid obtained above is further purified by suspending in suitable organic solvent at 45 to 55°C followed by cooling at temperature range of about 10 to 15°C and further adding suitable organic solvent under stirring and isolating the solid by filtration and further dried to get pure Linezolid of purity greater than 99.9% .
While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are included within the scope of the present invention. The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention.

Examples
Preparation of (S) (N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl] methyl]acetamide (Linezolid) (I)
Example 1
(R)-N-[[3-[3-Fluoro-4-morpholinylphenyl]-2-oxo-5-oxazolidinyl]methylazide 10.0 g and 0.75 g 10% Pd/C (50% moist) was suspended in 200 ml ethyl acetate, 3.0 ml acetic acid and 7 ml acetic anhydride mixture. The mixture was then hydrogenated in hydrogen gas at 30 psi at temperature of 25 to 35° C for 5 hrs. After the completion of the reaction, 100 ml of 5% sodium bicarbonate solution was added to the mixture and stirred for 10 min. The catalyst was then filtered off. Separated aqueous layer was washed with 100 ml ethyl acetate and the combined ethyl acetate layer was evaporated under reduced pressure at temperature of 50 to 55° C to get the residue. Further the residue was stirred in 25 ml ethyl acetate, filtered and washed with 20 ml ethyl acetate and dried at 60 to 70° C to get Linezolid. Yield: 8.0 g; 76% Purity: > 99.5%
Purification of Linezolid Example 2:
8 g of Linezolid obtained from Example 1, was suspended in 160 ml 1,4-dioxane. The reaction mass was warmed at 45 to 55°C and filtered at 45 to 55°C. The filtrate was cooled to 10 to 15°C and diisopropyl ether (320 ml, previously cooled) was added to this at temperature 10 to 15°C under stirring for 1 hour. The solid obtained was filtered, washed with 25 ml diisopropyl ether and dried at 100°C for 2 hrs and then at 140°C for 3 to 4 hr to get pure Linezolid. Yield: 7.44 g.; Percentage: 93% Purity: > 99.9%
Example 3: 5g Linezolid was dissolved in 200 ml ethyl acetate at 70-75°C. The clear solution was filtered to remove any suspended solid. The clear hot solution was subjected

to rapid cooling at -5 to 5°C. The solid starts separating out at 15-20°C. The solution was stirred at same temperature for 2-4 hrs. The separated solid was filtered and dried at 60-70°C.