FORM-2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See Section 10 and Rule 13)
PROCESS FOR PREPARATION OF LINEZOLID
M/S AMOLI ORGANICS PVT. LTD, 407 DALAMAL HOUSE, J.B.ROAD, NARIMAN POINT, MUMBAI-400021, INDIA, an Indian company incorporated under
the companies Act, 1956
The following specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

Field of the invention
The present invention relates to "A PROCESS FOR PREPARATION OF LINEZOLID"
Background of the invention
Linezolid is a synthetic antibiotic, the first of the oxazolidinone class, used for the treatment of infections caused by multi-resistant bacteria including streptococcus and methicillin-resistant Staphylococcus aureus (MRSA). The drug works by inhibiting the initiation of bacterial protein synthesis.
Linezolid is developed by PHARMACIA & UPJOHN Co., and commercially marketed by Pfizer as ZYVOX . It is chemically designated as (S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide. Its empirical formula is C16H20FN3O4, its molecular weight is 337.34g/mol, and its structural formula is;

The process for preparation of Linezolid has been described in various patents and to cite a few references, US Patent No. 5,688,792 describes the preparation of Linezolid, in which key intermediate (II) is obtained by reacting N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline of formula (IVa) with (R)-glycidyl butyrate of formula (III). Compound of formula (II) is converted to (IIb) by tosylation and reaction with sodium azide. Reduction of Linezolid azide of formula (IIb) in the presence of palladium/carbon in ethyl acetate solvent to obtain Linezolid amine (Ia), which is further treated with acetic anhydride in presence of pyridine to obtain Linezolid of formula (I). The purification process involves chromatography and separating the desired fraction, followed by evaporation and triturating the product to' obtain pure Linezolid as describe in the following Scheme A;


Scheme: A As describe above the prior art method for the preparation of Linezolid suffers from many disadvantages which includes tedious purification methods drastic environmental condition and use of health hazardous reagents like pyridine which makes the process unattractive for the large scale manufacturing at commercial level.
J. Org. Che. 53, 1580-1582 (1988) and J. Am. Che. Soc. 125, 7754-7755 (2003) describes the reaction of thio acids with Azides as shown in generalized scheme B, said research paper also describes the use of Pyridine as a base to get the adequate yield of the product. As it is a well known fact that pyridine is always associated with health hazards, and even more difficult to handle in large scale production at industrial scale, thus there is an emerging need to use the safe and economical base to replace pyridine and to overcome the problems associated with the use of pyridine in the large scale production of Linezolid.

Tetrahedron Letters 49, (2008) 3060-3062 disclose a stereoselective synthesis of novel (R)- and (S)-5-azidomethyl-2-oxazolidinones in which author has shown the reaction scheme as shown in scheme C. Said method uses thioacetic acid for conversion of Azide compound (7) to Linezolid but, this method is also suffers from the low yield.

Scheme: C Heteroatom chemistry, Vol. 19, Number 3 (2008) describes a method for the synthesis of oxazolidinone antibacterial Linezolid from (S)-glyceraldehyde acetonide as describe in scheme D.

As per the available prior art process for the preparation of Linezolid has the scope of improvement in terms of yield and purity of the product, Herein the present invention, we surprisingly found that by using a mineral anionic clay like Hydrotalcite in reaction may improve the yield as well as successfully eliminate the problem of epimerization. Impurities as obtained in prior art is illustrated as Formula (3)

Pyridine is always associated with health and environmental hazards so there is always a need to develop the process for preparation of Linezolid which successfully eliminate the use of such health hazardous chemicals.
Object and Summary of the Invention
The principal object of the present invention is to overcome the use of drastic reaction condition and health hazardous solvent like Pyridine.
Yet another object of the present invention is to provide an industrially feasible process for preparation of Linezolid.
Further object of the present invention is to provide the process for preparation of Linezolid in its substantially pure form with high yield.
The present invention provides a process for preparation of (S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide, compound of formula (1). Preferred embodiment of the process comprises;
(a) reacting compound of formula (2) (prepared as per the prior art), with thioacetic
acid in presence of hydrotalcite to prepare the compound of formula (1);


(b) Further purity the resulting compound using suitable purification method.
Detailed description of the invention
We have now developed industrially feasible process for the preparation of (S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide, compound of formula (1), starting from compound of formula (2) as prepared from the known art. Process for the preparation of Linezolid of the present invention can be schematically illustrated as following scheme I;

One embodiment of the invention comprises reacting compound of the formula (2) with thioacetic acid in presence of suitable anionic clay as a base to get the compound of formula (1) and subsequent purification would lead to formation of substantially pure title compound. The present invention describes the preparation of Linezolid comprises;
Reacting (R)-(3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl methanesulfonate with sodium azide in polar aprotic solvent which include but not

limited to the solvents like Dichloromethane, tetrahydrofurane, Ethyl acetate, Dimethyl formamide and Dimethyl sulfoxide but most preferably polar aprotic solvent is Dimethyl formamide or mixture thereof, while the present invention uses the Dimethyl formamide with subsequent addition of water. The course of reaction may be monitored by common analytical techniques, eg. by TLC or HPLC.
Further embodiment of the present invention comprises the said azido compound as obtained above is a compound of formula (2)
According to one more embodiment of the present invention compound of formula (2) is reacted with thioacetic acid in suitable anionic clay which replaces the pyridine in the reaction.
The compound of formula (2) is reacted with thioacetic acid in presence of suitable anionic clay, and said clay is Hydrotalcite.
Title compound as obtain from the above mentioned process can be further purified by the known processes of the prior art. Present invention describes one such purification method in which solvent employed for the recrystallization includes but not limited to Ethyl acetate, methyl acetate and isopropyl acetate preferably the solvent used is Ethyl acetate.
Already described the invention with reference to certain preferred embodiments, other embodiment will be come apparent to person skilled in the art from consideration of the specification. The invention is further described by reference to the following examples disclosing in detail the preparation of Linezolid. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.
The details of the invention are further illustrated in the following examples. Example 1: Preparation of (R)-5-(azidomethyl)-3-(3-fluoro-4-morpholinophenvl) oxazolidin-2-one
In a 3 liter 3-necked flask, equipped with stirrer, thermometer and reflux
condenser, (R)-N-(3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl
methanesulfonate (100g, 0.267mole) was charged in Dimethyl formamide (200 ml) subsequently Sodium azide (72g, l.lmole) was added in to the solution and the mixture

was heated to 80°-85°C. after completion of the reaction cool the reaction mass to 25°-30°C. Reaction mass was quenched in water and stirred for 2-3 hours. Resulted slurry obtained was filtered and dried at 50°-60°C and product was weighed 80g. (HPLC purity-99% and Yield 93.8%).
Example 2: Preparation of (S)-N-((3-(3-fluoro-4-morpholinophenvlV2-oxooxazolidin-5-yl)methyl)acetamide
In a 3 liter 3-necked flask, equipped with stirrer, thermometer and reflux condenser, Thioacetic acid (78g, 1.02mole) was charged and (R)-N-5-(azidomethyl)-3-(3-fluoro-4-morpholinophenyl) oxazolidin-2-one (70g, 0.217mole), Hydrotalcite (HYDROTALCITE) (14g, 0.023mole) w as added in to it, the reaction mixture was cooled to 25°-30°C. Reaction mixture was stirred for 12-15 hrs. After completion of the reaction, solvent is distilled out under vacuum at 50°-55°C. To the resulting mass Ethyl acetate (75ml) was added solvent was distilled out and refluxed in Ethyl acetate (350 ml) for 20-30 min, cooled to 25°-30°C and product was filtered and dried at 50°-60°C and product was weighed 70g. (HPLC purity-99% and Yield 96%).
Example 3: Purification of (S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide
In a 3 liter 3-necked flask, equipped with stirrer, thermometer and reflux condenser,(S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl) acetamide as obtain in Example 2 was added in methanol (350ml), heated at 65°-70°C to dissolve the material and 2.5g Activated charcoal was added. The mixture was maintained at same temperature for 20-30 min. the resulting mixture was filtered through hyflow bed and washed with methanol (70 ml). The solution is distilled out at 50°C stripped out with 70ml Ethyl acetate and refluxed with Ethyl acetate (700 ml), maintained for 30min. Resulting solution was cooled to 25°-30°C. Product was filtered and dried at 50°-60°C and weighed 64g. (HPLC purity-99.8% and Yield 80%).

We claim:
1. A process for preparation of (S)-N-((3-(3-fluoro-4-morpholinophenyl)-2-oxooxazolidin-5-yl)methyl)acetamide, compound of formula (1),

Said process comprises;
a) reacting compound of formula (2) with thioacetic acid in presence of suitable anionic clay as a base;

b) further purify the resulting compound using suitable purification method.
2. The process as claimed in claim 1 (a) wherein said anionic clay is hydrotalcite.
3. The process as claimed in claim 1 (a) wherein, molar ratio of compound of formula (2) to Hydrotalcite is about 1:0.05 to 1:0.2.
4. The process as claimed in claim 1 (a) wherein, reaction is carried out within a temperature range of from 20°C to about 90oC.
5. The process as claimed in claim 1(b) wherein further purification of the product is done by recrystallisation using Ethyl acetate as solvent.