FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents [Amendment] Rules, 2006
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE PNVENTION
Process For Producing(S)-N-[[3-[3-Fluoro-4-(4-Morpholinyl)Phenyl]-2-Oxo-5-Oxazolidinyl]Methyl]Acetamide And Its Polymorphic Form 2
2. APPLICANT
NAME : Frichem Private Limited
NATIONALITY : IN
ADDRESS : 12, Concord, Bullock Road, Band Stand, Bandra West, Mumbai-400 050,
India
3. PREAMBLE TO THE DESCRIPTION
COMPLETE
The following specification particularly describes the invention and the manner in which it is to be performed.

Field of the Invention
In general, this invention relates to a process for producing pure (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)pheny!]-2-oxo-5-oxazolidinyI]methy]]acetamide(Linezo!id) and its polymorphic Form I. More particularly, the present invention provides an improved and cost effective process for the preparation of pure crystalline form I which is free from other polymorphic and process impurities on commercial scale.
Background of the Invention
Linezolid, also known as (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methy]]acetamide, can be represented by the structure of general Formula I.

Linezolid is a synthetic antibacterial agent of the oxazolidinone class. Linezolid has clinical utility in the treatment of infections caused by aerobic Gram-positive bacteria. The in vitro spectrum of activity of Linezolid also includes certain Gram-negative bacteria and anaerobic bacteria. Linezolid inhibits bacterial protein synthesis through a mechanism of action different from that of other antibacterial agents, therefore, cross-resistance between linezolid and other classes of antibiotics is unlikely, Linezolid binds to a site on the bacterial 23S ribosomal RNA of the 50S subunit and prevents the formation of a functional 70S initiation complex, which is an essential component of the bacterial translation process. The results of time-kill studies have shown linezolid to be bacteriostatic against enterococci and staphylococci. For streptococci, linezolid was found to be bactericidal for the majority of strains. Linezolid is commercially sold under the trade name Zyvox®. See, e.g.. The Merck Index, Thirteenth Edition, 2001, p. 986-87,

monograph 5526; and Physician's Desk Reference, "Zyvox," 58th Edition, pp. 2808-2815
(2004).
U.S. Patent No. 5,688,792 discloses Linezolid and a process for its preparation. US'792
claim Linezolid and its use for the treatment of microbial infections. This patent also
discloses, but doesn't claim, the following method of preparation:

This method of preparation also disclosed in Bricker et. al, J. Med. Chem., 39, 673-679 (1996), where it was stated that the above route avoids the use of phosgene to make the carbamate precursor of the oxazolidinone ring. The authors also disclose that the use of

NaN3 can be avoided by using potassium phthalimide, followed by de-blocking of the phthalimide with aqueous methyl amine.
In the above-described synthesis, the intermediate amine, (S)-N-(4-morphoIinyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl amine, having the following structure (II)..

is reacted without isolation with acetic anhydride as an oily product or in solution to produce the acetamide, linezolid (I). This is followed by procedures for isolating the linezolid such as those described in the US792 patent (col. 15, 11. 22-28) wherein a method of chromatography and separation of the desired fraction is described, followed by evaporation and trituration of the product to obtain pure linezolid. Due to the necessary treatment required for recovery, linezolid is derived in low yields.
In the above-described syntheses, the intermediate azide, (R)-N-(4-morpholinyl-3-f[uorophenyl)-2-oxo-5-oxazoIidinylmethyf azide (III)

III
is reduced to its corresponding amine, (S)-N-(4-morpho|inyl-3-fluorophenyl)-2-oxo-5-oxazolidinyfmethyl amine (II) through catalytic hydrogenation in the presence of a palladium/carbon catalyst in the solvent ethyl acetate. These reaction conditions lead to

the production of an undesirable level of reaction by-products, and thereby, following the acetylation of the intermediate amine (II) to linezolid (I), to undesirably high levels of bis-linezofid (TV). Further, the polymorph obtained by the process disclosed in US792 patent is the crystalline Form 1, which is contaminated with form II.

J. T
On the other hand U.S. Patent Nos. 6,444,813 and 6,559,305 ("the US'305 patent") disclose crystal Form II of Linezolid. The US'305 patent further discloses that crystal Form II of Linezolid has a powder X-ray diffraction spectrum of characteristic peaks (expressed in degrees 29 + 0.2 degree 9) at 7.10, 9.54, 13.88, 14.23, 16.18, 16.79, 17.69, 19.41, 19.69, 19.93, 21.61, 22.39, 22.84, 23.52, 24.16, 25.28, 26.66, 27.01 and 27.77 and an infrared (IR) spectrum as a mineral oil mull: 3364, 1748, 1675, 1537, 1517, 1445, 1410, 1401, 1358, 1329, 1287, 1274, 1253, 1237, 1221, 1145, 1130, 1123, 1116, 1078, 1066, 1049,907, 852 and 758 cm"1.
U.S. Patent application no. 20060142283 claims a crystalline Form IV, also claimed by PCT application No. 2005035530 but as crystalline Form III, which is stated to be more compact and less electrostatic than the Form II. U.S. Patent application no. 20060111350 discloses various polymorphic forms and claims linezolid in the hydrate form. Finally, PCT application No. 2007026369 discloses the amorphous form of linezolid.
It is well known that the physical properties of a drug are fundamental for the preparation of pharmaceutical forms in pharmaceutical technique. In particular, solid drugs characterized by not very dense, highly electrostatic crystals are difficult to mill. A further important characteristic is the flowability of the powders resulting from the milling of the solid: in fact, when the powdered compound particles do not flow, they

stick to one another. A further important aspect, which is affected by the crystalline structure of the product, is its dissolution rate in aqueous fluids, hence its bioavailability.
Therefore, It would be desirable to have a simple, efficient, industrial process for producing pure prepare Linezolid (I) from azide intermediate (III) without the need of applying complicated and time consuming purification treatments, such as column chromatography, before the last trituration or recrystallization and which produces a stable, consistently reproducible pure crystalline form I of Linezolid.
Objects and Summary of the Invention
It is an object of the present invention to provide a process for preparing the pure (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide with high purity and yield at large scale industrial production.
It is another object of the present invention to provide a process for preparing pure (S)-N-[[3-[3-fluoro-4-(4-morpholinyI)phenyl]-2-oxo-5-oxazoIidinyl]methyl]acetamide, wherein the process doesn't involve the use of sophisticated, time consuming and costly techniques such as column chromatography etc.
It is another object of the present invention to provide a process for preparing pure (S)-N-[[3-[3-fluoro-4-(4-morphoIinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, wherein the process avoids use of high reaction pressure.
It is another object of the present invention to provide a novel process for the synthesis of (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide Form I in pure form, which is more convenient and efficient than the previously known method.
The above and other objects of the present invention are attained according to following preferred embodiments of the present invention. However the scope of the invention is not restricted to the particular embodiments discussed herein after.

In accordance with one embodiment of the present invention, there is provided A process
for producing (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-
oxazolidinyl]methyl]acetamide (I) comprises of treating (R)-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl azide (III) with reducing agent in presence of solvent, wherein said reducing agent used herein is palladium on carbon with ammonium formate, palladium on aluminum with ammonium formate, sodium borohydride and cobalt chloride, iron with ammonium chloride or zinc with ammonium chloride, isolating the resultant (S)-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl amine (II) optionally, treating the resultant with acetylating agent and isolating the pure (S)-N-[[3-[3-fIuoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide.
In accordance with one embodiment of the present invention there is provided a process for producing polymorphic Form I of (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyI]methyi]acetamide (I) comprises of providing a solution of (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (I) in an organic solvent selected from diethyl ketone, isobutanol, ethyl benzene and methyl cyclohexane, heating the resultant solution at about 70-90°C and recovering the pure form I (S)-N-[[3-f3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl] acetamide (I).
In accordance with one embodiment of the present invention, there is provided a process for producing polymorphic Form J of (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (I) comprises of treating (R)-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl azide (III) with reducing agent in presence of solvent, wherein said reducing agent used herein is palladium on carbon with ammonium formate, palladium on aluminum with ammonium formate, sodium borohydride and cobalt chloride, iron with ammonium chloride or zinc with ammonium chloride, treating the resultant with acetylating agent; and isolating the pure (S)-N-[[3-[3-fluoro-4-(4-morpho[inyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide, solubilising the resultant in an organic solvent selected from diethyl ketone, isobutanol, ethyl benzene and methyl

cyclohexane, heating the resultant solution at about 70-90°C and recovering the pure
form I (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyI]-2-oxo-5-
oxazolidinyl]methyl]acetamide (I).
Brief Description of the Drawings
Further objects of the present invention together with additional features contributing
thereto and advantages accruing there from will be apparent from the following
description of preferred embodiments of the invention which are shown in the
accompanying drawing figures, wherein:
FIG. I is a characteristic powder x-ray diffraction pattern of Linezolid of the present
invention.
FIG. 2 is a characteristic infrared spectrum of Linezolid of the present invention.
Detailed Description of the Invention
While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.
The disclosed embodiment of the present invention deals with a process for preparing S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (linezolid) with high purity. The process of the present invention is advantageous over the prior art due to the use of specific reaction condition in reduction of azide compound to amino compound and its further conversion into linezolid, thereby reducing the costly reducing agent and controlling the formation of process impurities. This makes the process economical, commercially viable and feasible for large-scale manufacture of pure crystalline form I of linezolid.
Accordingly, the present invention provides a process for preparing linezolid with high purity comprising the reduction of azide compound (R)-N-(4-morphoIinyI-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl azide of formula (III) in presence of reducing

agent and a solvent to afford the amine compound (S)-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl amine of formula (II), followed by treatment with acetylating agent to yield linezolid with high purity.
The process further comprising optionally isolating the amine compound (S)-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl amine of formula (II).
The reducing agent used herein is selected from the group consisting of but not limited to palladium on carbon with ammonium formate, palladium on aluminum with ammonium formate, sodium borohydride and cobalt chloride, iron with ammonium chloride and zinc with ammonium chloride, preferably zinc with ammonium chloride. The obtained linezolid is further treated with a solvent to get the pure form 1 which is free from other polymorphs.
According to the process of the invention, the reducing agent used is in the ratio of 1:1 to 2:1 with respect to the azide compound of formula III.
In accordance with an embodiment of the present invention, the reducing agent used is zinc with ammonium chloride in the ratio of 1:1 to 2;1 with respect to azide compound of formula III.
The palladium used herein is in amount of about 2-20% compared to azide while zinc is in an amount of about 1 to 2 equivalents, relative to the azide. The acetylating agent used herein is selected from the group consisting of acetic anhydride and acetyl chloride. Further, the solvent used for the reduction reaction is selected from the group consisting of but not limited to ester, alcohol and water or mixture thereof. Once obtaining the amine compound of formula obtained from reduction step, recovery may be performed by any method known in the art. Preferably, the recovery is performed by filtering, more preferably through a celite filter and removal of the solvent.
In another aspect of the present invention, there are provided method of preparing linezolid comprising one of the methods described above to reduce the azide of formula

Ill to the amine of formula IF and further treating the amine of formula to linezolid by methods known in the art. The linezolid obtained is of high chemical purity, with respect to the inactive R-enantiomer and bis-linezolid, and is in high yield, without the need for tedious, complicated purification steps, such as chromatography.
In another aspect of the present invention, a one-pot process is also provided wherein amine of formula is not isolated from the reduction reaction mixture but rather is converted directly in the solution to linezolid by acetylation. Even without precipitation and/or further purification of the amine of formula, linezolid free from undesirable levels of impurities so as not to require purification by such means as chromatography, can be produced.
By the process of the present invention, linezolid can be produced having a purity of more than 99%, preferably more than 99.5% with a content of bis-linezolid impurity less than 0.5%, preferably less than 0.1% and more preferably less than 0.05%.
The present invention further provides a process for preparing pure crystalline polymorphic form J of linezolid comprising:
(a) solubilising linezolid in an organic solvent or mixture thereof;
(b) heating the content to about 70-90°C; and
(c) recovering the linezolid pure form 1 by filtration or centrifugation.
The solvent herein is selected from the group consisting of but limited to isobutanol, methyl cyctohexane, diethyl ketone, ethyl benzene and ethyl acetate preferably methyl cyclohexane. Linezolid obtained by a known method may be used in the process. The solution obtained as above is cooled to below 15°C, preferably 0-10°C and more preferably 0-5°C.
Further details of the invention will be apparent from examples. However, these are not intended in any way to limit the scope of the present invention.

Example I Preparation of Linezolid pure form I
To a solution of azide of formula III (5gm) and ethanol (40 ml), a solution of NH4CI (2.8gm) in water (10ml) was added. The reaction mass was refluxed in presence of Zn powder (2gm) and amine compound of formula II formed was extracted in aqueous medium followed by treatment with acetic anhydride (3.4gm) in presence of NaOH at pH 6-7. The reaction mass was extracted in methylene chloride, charcoalized and filtered. The filtrate was distilled out to get the residue mass followed by the addition of isobutanol (15ml) and the solution obtained was refluxed for 4-10 hours. The resultant obtained solid was filtered and dried in oven at 45-50aC. Dried weight: 4.2gm. The solid resembles the XRPD pattern of Form I.
Example 2 Preparation of Linezolid pure form I
Linezolid Form II (2gm) crystalline solid (99.72 % pure), was suspended in ethylbenzene (14ml) stirred and heated in oil-bath to 100-105°C. The reaction mass was stirred for 3 hours, followed by cooling to room temperature. The obtained solid was filtered and washed with ethylbenzene. Product is dried in oven at 45-50°C at atmospheric pressure. Solid thus obtained is crystalline form I: 1.9gm.
Example 3 Preparation of Linezolid pure form I
Azide of formula III (5gm) and ethanol (40 ml) were mixed at ambient temperature to which a solution of NH4CI (2.8gm) in water (10m!) was added. The reaction mass was refluxed in presence of Zn powder (2gm) for 2-8 hours. Amine of formula II formed during reduction reaction was extracted in aqueous medium and then reacted with acetic anhydride (3.4gm) in presence of NaOH at pH 6-7. The reaction mass was extracted in methylene chloride, charcoalized and filtered over celite bed. The filtrate was distilled out to get the residual mass and to the residual mass, methyl cyclohexane (15ml) was added and refluxed for 4-10 hours. The resultant obtained solid was filtered and dried in oven at 45-50°C. Dried weight: 4.2gm. The solid resembles the XRPD pattern of Form I.

Example 4 Preparation of Linezolid form I
Linezolid Form II (2gm) crystalline solid (99.72 % pure), was suspended in diethyl ketone (14ml) stirred and heated in oii-bath to 100-105°C. The reaction mass was stirred for 3 hours, followed by cooling at room temperature. The obtained solid was filtered over suction, washed with diethyl ketone. Product was dried in oven at 45-50°C at atmospheric pressure. Solid thus obtained is crystalline form I: 1.9gm.
While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention.

We claim:
1. A process for producing (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (I) comprising:
a. treating(R)-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl azide (III) with reducing agent in presence of solvent, wherein
said reducing agent used herein is palladium on carbon with ammonium formate,
palladium on aluminum with ammonium formate, sodium borohydride and cobalt
chloride, iron with ammonium chloride, or zinc with ammonium chloride;
b. isolating the resultant (S)-N-(4-rnorpho]Jnyl-3-fluoropheny])-2-
oxo-5-oxazolidinylmethyl amine (II) optionally;
c. treating the resultant with acetylating agent; and
d. isolating the pure (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-
oxo-5-oxazolidinyl]methyl]acetarnide.
2. The process as claimed in claim 1, wherein the reducing agent used in the
ratio of 1:1 to 2:1 with respect to azide compound of formula III.
3. The process as claimed in claim 1, wherein the reducing agent used is zinc with ammonium chloride.
4. The process as claimed in claim 3, wherein zinc as reducing agent used in the ratio of 1:1 to 2:1 with respect to azide compound of formula III.
5. The process as claimed in claim 1, wherein the solvent used is ester, alcohol or water or mixture thereof.
6. The process as claimed in claim 1, wherein acetylating agent used is acetic anhydride and acetyl chloride.

7. The process according to claim 1, wherein the of (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (I) produced is having a purity of more than 99.5%.
8. The process according to. claim 1, wherein the of (S)-N-[[3-[3-fluoro-4-(4-morpholiny])phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (I) produced is having bis-linezolid impurity less than 0.5%.
9. A process for the preparing polymorphic Form I of (S)-N-[[3-[3-fluoro-4-(4-morpho]iny])pheny]]-2-oxo-5-oxazoJidinyl]methy]]acetamide (J) comprising;
providing a solution of (S)-N-[[3-[3-fluoro-4-(4-morpho!inyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (I) in an organic solvent selected from diethyl ketone, isobutanol, ethyl benzene and methyl cyclohexane;
heating the resultant solution at about 70-90°C; and
recovering the pure form I (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazoIidinyl]methy]]acetamide (I).
10. The process as claimed in claim 9, wherein the recovery is performed
employing filtration or centrifugation.
11. A process for the preparing polymorphic Form 1 of (S)-N-[[3-[3-fluoro-4-
(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]acetamide (I) comprising:
treating (R)-N-(4-morpholinyl-3-fluorophenyl)-2-oxo-5-oxazolidinylmethyl azide (III) with reducing agent in presence of solvent, wherein said reducing agent used herein is palladium on carbon with ammonium formate, palladium on aluminum with ammonium formate, sodium borohydride and cobalt chloride, iron with ammonium chloride or zinc with ammonium chloride;
treating the resultant with acetylating agent; and isolating the pure (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyI]acetamide;
solubilising the resultant in an organic solvent selected from diethyl ketone, isobutanol, ethyl benzene and methyl cyclohexane;

heating the resultant solution at about 70-90°C; and recovering the pure form I (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5- oxazolidinyI]methyl]acetamide(I).