FORM 2
THE INDIAN PATENT ACT 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION (See Section 10 and Rule 13)
"An industrial process for the preparation of (S)-N-({3-[3-fluoro-4-(morpholin-4-yl) phenyl]-2-oxo-l, 3-oxazolidin-5-yl} methyl) acetamide (Form I)"
M/S AMOLIORGANICS 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 describes and ascertains the nature of this invention

Field Of Invention
This invention relates to (S)-N-({3-[3-fluoro-4-(morpholin-4-yl) phenyl]-2-oxo-l, 3-oxazolidin-5-yl} methyl) acetamide (Formula I), a process for preparing and isolating Form I of the compound.
Background of the Invention
Linezolid is a synthetic antibiotic used for the treatment of serious infections caused by Gram-positive bacteria that are resistant to several other antibiotics. Linezolid is chemically, (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide and is represented by Formula I. Linezolid is known from US Patent No 5,688,792 and is used as an antibacterial agent.

Several processes for the preparation of Linezolid are known in literature such as those described in U.S. Patent Nos. 5,688,792, 6,887,995, 7,291,614, 7,307,163 and 7,429,661, PCX Publication No. WO 2007/116284 and Tetrahedron Letters 40 (1999) 4855-4856, which are herein incorporated by reference.
U.S. Patent No. 5,688,792 describes a process for the preparation of Linezolid comprising reducing (R)-N-[[3-[3-fluoro-4-morpholinyl]phenyl]-2-oxo-5-oxazolidinyl] methyl] azide with hydrogen in the presence of 10% palladium/carbon in ethyl acetate to produce iS'-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinyl methyl amine followed by reacting with acetic anhydride to produce linezolid, which is being isolated

by the tedious and cumbersome producers of chromatography and solid obtained was triturated with ethyl acetate and dried to give off white solid with 181.5-182.5°C m.p.
Tetrahedron Letters 40 (1999) 4855-4856 describes a process for the preparation of Linezolid by treating (R)-N-[[3-[3-fluoro-4-morpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methyl] azide with thioacetic acid without mentioning the isolation process. The said process leads to the formation of an undesirable level of reaction by-products such as compounds of Formula II and Formula III.

In light of the above drawbacks in the prior art processes, there is a need for the development of a process for the isolation of Linezolid which is convenient to operate on an industrial scale and gives substantially pure product in good yield.
Linezolid is known to exhibit polymorphism and several crystalline forms are so far known in literature such as those described in U.S.Patent No. 6,559,305, U.S.Publication Nos. 2006/0128703, 2006/111350, 2006/0142283 and 2007/0020329 which are incorporated herein as reference.
Linezolid is known to exhibit polymorphism and two crystalline forms are so far known. U.S. Pat.No.6559305 and 6444813 addressed that the product obtained by the process described by J. Med. Chem. 39(3), 673-679, 1996 is form I and is characterized by melting point of 181.5-182.5°C and by IR spectrum having bands at 3284, 3092,1753, 1728,1649,1565,1519,1447 cm -1.

The prior art process described in U.S.Patent No. 5,688,792 results in to crystalline Linezolid compound which is contaminated with other polymorphs and particularly Form II of Linezolid.
WO 2011/077310 also describes a process for the preparation of linezolid form I by acylating in the presence of a ketonic solvent and crystallization is carried out in propanol. The X-ray powder diffraction graph of form I was used as reference.
Hence there is a need to develop the crystallization process which results into pure crystalline form which is not contaminated with Form II or Form III of Linezolid. Also there is a need to develop the process of acetylation by using thioacetic acid. The further object of the present invention is to provide a process which results the product in high chemical and polymorphic purity without compromising the yield of the product.
Object of the Invention
It is the object of the present invention to provide a process with specified conditions for the preparation of form I of Linezolid of formula I.

Summary of the Invention
In one aspect, the invention encompasses a new industrially viable process for the manufacture of (S)-N-[[3-[3-FIuoro-4-(4-morpholinyI) phenyl]-2-oxo-5-oxazolidinyI] methyl] acetamide, denoted by Formula I, having the following structure:


In this process the reagents used are thioacetic acid with pyridine and the purification is carried out in ethyl acetate and activated carbon.
In the second aspect, the invention describes a method to isolate pure Linezolid Form I by dissolving linezolid wet cake in a solvent, heating it and distilling it azeotropically under specified conditions.
Brief Description of the Figures
FIG 1 is a representative of the graph of X-ray powder diffraction FIG 2 is a representative of the DSC graph
Detailed Description of the Invention
The present invention gives an industrial process for the manufacture of (S) - N -[[3- [3-Fluoro-4-(4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl] acetamide, denoted by Formula I, having the following structure:

The compound of formula I is characterized by an X-ray powder diffraction spectrum as shown in figure 1. The crystalline linezolid form I is further characterized by its melting range determined by DSC as depicted in figure 2.

The process comprises: (a) reacting (R)-(3-(3-fiuoro-4-morpholinophenyl)-2-oxo-oxazolidin-5-yl) methyl methanesulfonate (II) with dimethyl formamide and sodium azide to give (R)-5-(azidomethyl-3-(3-fluoro-4-morpholinophenyl)-2-oxo-oxazolidin-5-yl methyl (Azido Compound) (III), (b) This Azido compound (III) is then reacted with pyridine, thio acetic acid, ethyl acetate and activated carbon to give (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl) phenyl]2-oxo-5-oxazolidinyl] methyl] acetamide (I) i.e. Linezolid.(c) The wet cake linezolid is then refluxed with toluene and azeotropically distilled to form a slurry. The slurry is then cooled and filtered and washed with toluene to give pure linezolid of form I.

In step (a), nitration of (R)-(3-(3-fluoro-4-morphoIinophenyI)-2-oxo-oxazolidin-5-yl) methyl methanesulfonate (II) may be carried out in the presence of solvating reagent such as dimethylformamide and nitrating agent such as sodium azide. The extraction may be carried out by quenching with water and by filtering and drying it to give (R)-5-(azidomethyl)-3-(3-fluoro-4-morpholinophenyl) oxazolidin-2-one (III).

In step (b), (R)-5-(azidomethyl)-3-(3-fluoro-4-morpholinophenyl) oxazolidin-2-one (III) may be reacted with pyridine and thioacetic acid. The mixture of pyridine and

thioacetic acid may then be distilled out. The residue (1) may be stripped with ethyl acetate and washed repeatedly with the same. The residue (2) obtained may then be reacted with ethyl acetate and activated carbon and slurried and filtered. The residue thus obtained may repeatedly be washed with ethyl acetate to give (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl) phenyl]-2-oxo-5-oxazolidinyl] methyl] acetamide, i.e. Linezolid.
The wet cake thus formed may be refluxed with an adequate solvent such as toluene. The mixture of linezolid wet cake and toluene may be heated and the solvent may be azotropically distilled under slight vacuum. After some time the vacuum may be increased while gradually reducing the temperature to form a slurry and the precipitates of linezolid thus formed may be washed and dried in a suitable solvent such as toluene and suck dried to give pure linezolid form I.
Examples
Example 1
(R)-5-(azidomethyl-3-(3-fluoro-4-morpholinophenyl)-2-oxo-oxazolidin-5-yl methyl (Azido Compound) (III)
450mL of Dimethyl Formamide was charged into a 3 necked flask fitted with a stirrer and a thermometer pocket at 30-35°C. Then sodium azide along with methane sulfonic acid-3-(3-fluro-4-morpholine-4-yl-phenyl)-2-oxo-oxazolidine-5-yl methyl ester was charged into the flask keeping the temperature constant. The reaction mass temperature was then raised to 80-85°C and maintained for 4 hrs. After 4 hrs, a sample was taken for HPLC. After HPLC had complied, the reaction mass was cooled to 30-35°C.
Into another 3 necked flask with stirrer and thermometer, 2250mL water was charged and the above reaction mass was quenched for 30 mins and the slurry maintained at 30-35°C for 1 hr. The slurry was then filtered and suck dried and washed with 150mL water at 30-35°C. It was then again filtered and suck dried and the wet cake was dried at 50-55°C till the moisture content was not more than 1.0%.

Example 2
(S)-N-[[3-[3-Fluoro-4-(4-morpholinyl) phenyl] -2-oxo-5-oxazolidinyl] methyl]
acetamide (I).
240 mL of pyridine at 30-35°C was taken in a 3 necked flask with a stirrer and a thermometer pocket. 120gms of (R)-5-(azidomethyl-3-(3-fluoro-4-morpholinophenyl)-2-oxo-oxazoJidin-5-yl methyl (Azido Compound) was charged into the flask at 30-35°C. The reaction mass was cooled to 20-25°C for 45-60 mins and 135 gms of thio acetic acid was added to it. The temperature was raised to 25-30°C and maintained for 12 hrs and a HPLC sample was taken. After HPLC complied, the mixture of pyridine and thioacetic acid was distilled off under vacuum below 50°C and degassed for 30 mins. Then it was stripped with 120 ml ethyl acetate below 50°C. The vacuum was then removed and 600 mL of ethyl acetate was added and the reaction mass was heated to 60°C for 30 mins. The mixture was cooled to 30°C and maintained for 1 hr, filtered and washed with 120 mL ethyl acetate at 30-35°C and the wet cake was isolated.
In a 1 lit. 3 neck flask with a stirrer and thermometer, 2400ml of ethyl acetate was charged at 30-35°C and the wet cake was added to it. The reaction mass was refluxed at 65°C and 6gm activated carbon was added to it. The slurry was maintained at 65CC for 30 mins and clarified by passing through Hyflow. The carbon bed was washed with 60ml ethyl acetate and the filtrate was cooled to 30-35°C where it was maintained for 1 hr. The reaction mass was filtered and washed twice with 60 ml ethyl acetate at 30-35°C and suck dried.
To the wet cake was charged 2900ml of toluene at 30-35°C into a 5L 3 necked RBF fitted with a stirrer and condenser. The temperature was raised to 105°C in the span of 1 hour and maintained for 2 hrs and the solvent was distilled azeotropically under slight vacuum. After 2 hrs, the vacuum was slowly increased and the temperature gradually reduced to 65°C till the toluene volume was reduced to 1200 ml to form slurry. The slurry was cooled to 10-15°C in the time duration of 1 to 4 hours and was maintained for 45 mins to an hour. It was then filtered and washed with 120 ml of toluene at 30-35°C and suck dried. The pure linezolid Form I was thus obtained after drying. Purity of Linezolid Form I: > 99.5% Chiral Isomer: < 0.15%


We Claim:
I) A process for the preparation of Form I of compound of formula I comprising
a) the wet compound of formula I being dissolved in adequate solvent and being heated till complete dissolution takes place;
b) solution is heated under vacuum, the solvent azeotropically distilled to give a slurry;
c) Slurry is cooled, filtered and washed with solvent to give pure Form I of compound of formula I i.e. Linezolid.

2) A process according to claim 1, wherein wet cake of compound of formula I is dissolved in toluene and heated for 1 to 6 hrs at a temperature between 80-105 °C.
3) A process according to claim 2, wherein the solution is heated for 2hrs between 100°Candl05°C.
4) A process according to claim 2, wherein the solution is heated for 2 hrs at 105°C under slight vacuum, undergoing azeotropic distillation.
5) A process according to claim 1, wherein the compound of formula I is dissolved in toluene and the temperature is raised to 105°C in the time duration of 1 hour and maintained for 2 hours with azeotropic distillation being carried out under slight vacuum.
6) A process according to claim 6, wherein after 2 hours, the vacuum is slowly increased and the temperature gradually reduced to 65 °C till the volume of toluene is reduced to less than half.
7) A process according to claim 7, wherein the compound of formula I-toluene slurry is cooled to 10-15°C in the time duration of 1 to 4 hours and maintained for 45 mins to 1 hour and filtered and washed with toluene.
8) A process according to claim 8, wherein the washed linezolid is suck dried to give pure Linezolid Form I having purity >99.5% and chiral isomer <0.15%.

9) Linezolid Form I obtained is characterized by an X-ray powder diffraction spectrum as shown in figure 1, wherein the crystalline linezolid form I is further characterized by its melting range determined by DSC as depicted in figure 2.