FIELD OF THE INVENTION
The present invention relates to improved, commercially viable and industrially advantageous processes for the preparation of Linezolid and its intermediate, (S)-N-[[3-[3-Fluoro-4-(4-moipholinyI)phenyI]-2-oxo-5-oxazolidinyl]methyl]amine, in high yield and purity.
BACKGROUND OF THE INVENTION
U.S. Patent No. 5,688,792 (hereinafter referred to as the US'792 patent), assigned to Pharmacia & Upjohn Company, discloses a variety of oxazine and thiazine oxazolidinone derivatives and their stereochemically isomeric forms, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof. These compounds are useful antimicrobial agents, effective against a number of human and veterinary pathogens, particularly gram-positive aerobic bacteria such as multiply-resistant staphylococci, streptococci and enterococci as well as anaerobic organisms and acid-fast organisms. Among them, Linezolid, a member of the oxazolidinone class of drugs and chemically named as N-[[(5S)-3-[3-fluoro-4-(4-morphoIinyl)phenyl3-2-oxo-5-oxazolidinyl]methyl]acetamide, is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin-resistant Staphylococcus aureus (MRSA). Linezolid is represented by the following structural formula I:
The main indications of linezolid are infections of the skin and soft tissues and pneumonia (particularly hospital-acquired pneumonia). Linezolid is marketed by Pfizer under the trade names Zyvox (in the United States, United Kingdom, Australia, and several »5 other countries), Zyvoxid (in Europe), and Zyvoxam (in Canada and Mexico).

Various processes for the preparation of Linezolid, its polymorphic forms, and its penultimate intermediate, (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyI]-2-oxo-5-oxazolidinyl]methyl]amine, were described in U.S. Patent Nos. US 5,688,792, US 6,559,305, US 7,429,661, US 7,307,163 and US 7,714,128; PCT Publication Nos. WO 2012/114355, WO 2013/190559, WO 2014/045292, WO2014/174522 and WO 2015/162622; Chinese Patent Application Publication Nos. CN 103103229, CN 103382200, CN 102229577, CN 102850228 and CN 102898394; and Journal Articles: J. Med. Chem. 39(3), 673-679,1996.
The synthesis of Linezolid was first described in the US'792 patent. According to the US'792 patent, the Linezolid is prepared by a process as depicted in scheme 1:

The synthesis of Linezolid as described in the US'792 patent involves the following main reaction steps: a) 3-Fluoro-4-morpholinyl aniline is reacted with benzyl chloroformate in the presence of sodium bicarbonate to produce N-carbobenzyloxy-3-fluoro-4-morphoIinyl aniline; b) the N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline is reacted with a solution of (R)-glycidyl butyrate in tetrahydrofuran in the presence of n-butyl lithium/hexane at a temperature of -78°C under nitrogen atmosphere, followed by tedious work-up and isolation methods to produce the (5R)-5-(hydroxymethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone; c) the (5R)-5-(Hydroxymethyl)-3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxazolidinone is reacted with methanesulfonyl chloride in the presence of triethylamine in methylene chloride solvent under nitrogen atmosphere to produce (5R)-[[3-[3-fluoro-4~(4-morpholinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl methane sulfonate; d) (i) the (5R)-[[3-[3-fluoro-4-(4-morpholinyI)]phenyl]-2-oxo-5-oxazoIidinyl]methyl methane sulfonate is reacted with sodium azide to produce (5R)-[[3-[3-fluoro-4-(4-morpholinyl)]phenyl]-2-oxo-5-oxazoIidinyl]methyI azide, or alternatively (ii) the (5R)-[[3-[3-fIuoro-4-(4-morpholinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl methane sulfonate intermediate is reacted with potassium phthalimide to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide; e) (i) the (5R)-[[3-[3-fluoro-4-(4-morpholinyl)]phenyl]-2-oxo-5-oxazolidinyl]methyl azide intermediate is hydrogenated in the presence of 10% palladium/carbon to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyI]methyl]amine, or (ii) the (S)-N-[[3-[3-FIuoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyI]methyl]phthalimide intermediate is reacted with aqueous methyl amine to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl] amine; and f) the amino-methyl-oxazolidinone intermediate is then subjected to acetylation with acetic anhydride to produce Linezolid.
However, the processes described in the US'792 patent suffer from the following disadvantages and limitations: i) the processes involve the use of highly flammable and dangerous reagent like n-butyl lithium in hexanes, which is an explosive and pyrophoric reagent; ii) handling of n-butyl lithium is very difficult at lab scale and in commercial scale operations since n-butyl lithium is stored and available as solutions in highly flammable liquids like alkanes (hexanes) and exposure to air or water causes flash fire or explosion;

iii) the reaction between N-carbobenzyloxy-3-fluoro-4-morpholinyl aniline (Benzyl ester intermediate) and (R)-glycidyl butyrate in tetrahydrofuran in the presence of n-butyl lithium/hexane or lithium tert-butoxide should be performed at extremely low temperatures (-78°C to -16°C) under very strict control of reaction conditions; processes involving extremely low temperatures are undesirable for large-scale operations since they require special equipment and an additional reactor, adding to the cost, thereby making the processes commercially unfeasible; iv) the processes involve the use of additional process steps (SIX), longer reaction times, nitrogen atmosphere, thereby leading to low overall yields of the product; v) the processes require the use of highly toxic and/or expensive reagents like benzyl chloroformate, sodium azide and (R)-glycidyl butyrate, Palladium on Carbon; vi) the processes involve the use of tedious and cumbersome procedures like prolonged reaction time periods, multiple process steps, multiple isolation /re-crystallizations; vii) the processes involve the use of multiple and excess amounts of hazardous solvents like n-hexane, heptanes and dioxane; viii) the processes involve the use of highly hazardous reagents like phosgene, methanesulfonyl chloride and pyridinium p-toluenesulfonate; ix) the processes require the use of slow, expensive and time-consuming column chromatographic purifications - methods involving column chromatographic purifications are generally undesirable for large-scale operations, thereby making the process commercially unfeasible; x) the overall processes generate a large quantity of chemical waste which is difficult to treat.
The aforesaid problems have been solved by the commercially viable, industrially advantageous and environmentally friendly processes for the preparation of Linezolid using novel intermediates as disclosed in the U.S. Patent Nos. 7,307,163 and 7,429,661 and which involve the use of reduced number of reaction steps (only FIVE process steps) to produce Linezolid (starting from the key starting material "3-Fluoro-4-morphoIinyl aniline").
U.S. Patent No. 7,307,163 B2 (hereinafter referred to as the US'163 patent) discloses a novel, commercially viable and industrially advantageous process for the preparation of Linezolid and its intermediates. The process described in the US'163 patent is depicted in the below scheme 2:

As per the process described in US'163 patent, Linezolid is prepared by the following main reaction steps: i) 3-Fluoro-4-morpholinyl aniline is reacted with (R)-epichlorohydrin to produce N-[3-chloro-2(R)-hydroxypropyl3-3-fluoro-4-morpholinyl aniline; ii) carbonylating the N-[3-chloro-2(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline with a carbonylating agent (preferably N,N-carbonyldiimidazole) in an aprotic solvent to produce (5R)-5-(chloromethyI)-3-[3-fluoro-4-morpholinyI)phenyl]-2-oxazolidinone; iii) reacting the resulting chloromethyl compound with potassium phthalimide to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]phthaIimide, iv) reacting the resulting phthalimido-methyl-oxazolidinone compound with hydrazine hydrate in an alcoholic solvent (preferably methanol, ethanol or isopropyl alcohol) to produce (S)-N-[[3-[3-Fluoro-4-(4-

morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine, which is finally reacted with acetic anhydride to produce Linezolid.
U.S. Patent No. 7,429,661 B2 (hereinafter referred to as the US!661 patent) discloses another novel, commercially viable and industrially advantageous process for the preparation of Linezolid and its intermediates. The process described in the US'661 patent is depicted in the below scheme 3:

As per the process described in US'661 patent, Linezolid is prepared by the following main reaction steps: i)(a) N-[3-chloro-2(R)-hydroxypropyl]-3-fluoro-4-morpholinyl aniline is reacted with potassium phthalimide to produce N-[3-phthaIimido-2(R)-hydroxypropyl]-3-fluoro-4-(4-morpholinyl)aniline, or alternatively (b) 3-fluoro-4-5 morpholinyl aniline is reacted with (S)-N-2,3-epoxypropyI phthalimide to produce N-[3-phmalimido-2(R)-hydroxypropyl]-3-fluoro-4-(4-morpholinyI)aniline; ii) the resulting N-[3-phthalimido-2(R)-hydroxypropyl]-3-fluoro-4-(4-morpholinyI)aniline is subjected to carbonylation with a carbonylating agent, preferably N,N-carbonyldiimidazole, in an aprotic solvent to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-
10 oxazolidinyl]methyl]phthalimide; iii) reacting the resulting phthalimido-methyl-oxazolidinone compound with hydrazine hydrate in an alcoholic solvent (preferably methanol, ethanol or isopropyl alcohol) to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine, which is finally reacted with acetic anhydride to produce Linezolid.
15 U.S. Patent No. 6,559,305 (hereinafter referred to as the US'305 patent) discloses
two crystal forms (Form I & Form II) of Linezolid. According to the '305 patent, the crystalline Form II of Linezolid is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions 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
20 27.77 degrees; and an IR spectrum having bands at 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.
The US'305 patent further states that when Linezolid was originally produced, for example, as per the processes exemplified in the US'792 patent (example 5) and J. Med.
25 Chem. 39 (3), 673-679, 1996, the crystal form was Form I, which is characterized by having melting point of 181.5-182.5°C, and an IR spectrum having bands at 3284, 3092, 1753, 1728, 1649, 1565, 1519, 1447, 1435 cm'1. Crystal Form II differs from Form I in its IR spectrum, X-ray powder diffraction spectrum (XRPD) and melting point.
U.S. Patent No. 7,714,128 B2 (hereinafter referred to as the US'128 patent)
30 discloses a novel, stable and enantiomerically pure crystalline form (Form III) of Linezolid and processes for preparation thereof. According to the US'128 patent, the crystalline

Form III of Linezolid is characterized by a powder X-ray diffraction spectrum having peaks expressed as 2-theta angle positions at about 7.6, 9.6, 13.6, 14.9, 18.2, 18.9, 21.2, 22.3, 25.6, 26.9, 27.9 and 29.9 ± 0.2 degrees; and an IR spectrum having main bands at about 3338, 1741, 1662, 1544, 1517, 1471, 1452, 1425, 1400, 1381, 1334, 1273, 1255,
5 1228, 1213, 1197, 1176, 1116, 1082, 1051, 937, 923, 904, 869, 825 and 756 cm-1. Various processes for the preparation of Linezolid crystalline Form III were described and exemplified in the US' 128 patent.
PCT Publication No. WO 2013/190559 describes various alternative processes for the preparation of Linezolid crystalline Form III.
) In the processes for the preparation of Linezolid described in the prior art, the
aminomethyl-oxazolidinone compound, namely (S)-N-[[3-[3-FIuoro-4-(4-
morpholinyI)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine, of formula II:
is a key penultimate intermediate.
As per the processes described in the prior art, the aminomethyl-oxazolidinone I compound of formula II is prepared by reacting phthalimido-methyl-oxazolidinone compound, chemically named (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl3-2-oxo-5-oxazolidinyl]methyl]phthalimide, with hydrazine hydrate in presence of an organic solvent, specifically in presence of an alcoholic solvent, and more specifically in the presence of methanol, ethanol or isopropyl alcohol. Moreover, the reaction of phthalimido-methyl-oxazolidinone compound with hydrazine hydrate described in the prior art requires the use of excessive amounts of alcoholic solvent, i.e., about 6 times of the alcoholic solvent with respect to the quantity of phthaiimido-methyl-oxazolidinone compound.
However, a need still remains for an improved, commercially viable, cost effective and environmentally friendly process of preparing Linezolid and its key penultimate aminomethyl-oxazolidinone compound of formula II with high yields and purity, to

resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation.
SUMMARY OF THE INVENTION
The present inventor has surprisingly and unexpectedly found that Linezolid penultimate intermediate, (S)-N~[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine, can be prepared, with high yield and purity, by reacting (S)-N-[[3 - [3 -fiuoro-4-(4-morpholinyl)pheny 1] -2-oxo-5 -oxazol idiny l]methyl]phthalimide with hydrazine hydrate in presence of water as a solvent to produce the aminomethyl-oxazolidinone intermediate of formula II, which is then reacted with acetic anhydride in a suitable solvent to produce Linezolid or a polymorphic form thereof.
In one aspect, provided herein is an improved, commercially viable and industrially advantageous process for the preparation of Linezolid penultimate intermediate, (S)-N-[[3-[3-FIuoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine, of formula II by reacting the phthalimido-methyl-oxazolidinone compound with hydrazine hydrate in presence of water as a solvent.
In another aspect, provided herein is an improved, commercially viable and industrially advantageous process for the preparation of Linezolid by reacting the phthalimido-methyl-oxazolidinone compound with hydrazine hydrate in presence of water as a solvent to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyljmethyl] amine, followed by acetylation with a suitable acetylating agent to produce Linezolid with high yield and purity.
The processes disclosed herein avoids the use of organic solvents, let alone excessive amounts of organic solvents, in the reaction of phthalimido-methyl-oxazolidinone compound with hydrazine hydrate to produce the primary amine compound of formula II, thereby reducing the organic chemical waste and making the process more commercially viable and environmentally friendly, which are more convenient to operate at lab scale and in commercial scale operations.

BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 is a characteristic powder X-ray diffraction (XRPD) pattern of Linezolid Crystalline Form II obtained according to Example 3.
Figure 2 is a characteristic infra-red (FT-IR) spectrum of Linezolid Crystalline Form II obtained according to Example 3.
Figure 3 is a characteristic powder X-ray diffraction (XRPD) pattern of Linezolid Crystalline Form III obtained according to Example 4.
Figure 4 is a characteristic infra-red (FT-IR) spectrum of Linezolid Crystalline Form III obtained according to Example 4.
DETAILED DESCRIPTION OF THE INVENTION According to one aspect, there is provided an improved, commercially viable and industrially advantageous process for the preparation of Linezolid of formula I:
which comprises:
a) reacting (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl3-phthalimide of formula III:
o with hydrazine hydrate in presence of water as a solvent to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyI]methyl]amine of formula II:

or a sail inercui, b) acetylation of the amino-methyl-oxazolidinone compound of formula II obtained in
step-(a) with an acetylating agent, optionally in the presence of a base, in a suitable
solvent to produce highly pure Linezolid or a polymorphic form or a mixture of
polymorphic forms thereof.
The structural formulae of the compounds I, II and III designated herein contain one chiral centre and thus exist as two optical isomers, i.e. enantiomers (R & S-isomers). Unless otherwise specified, the process disclosed herein encompasses the preparation of both enantiomers and mixtures thereof in all proportions.
Unless otherwise specified, the (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl3methyl]phthalimide employed as starting material in the present invention can be prepared by the processes known in the art, for example, as per the processes described in the U.S. Patent Nos. US 5,688,792, US 7,429,661 and US 7,307,163.
Specifically, the starting material (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyI]-2-oxo-5-oxazolidinyl]methyl]phthalimide employed in the present invention is prepared as per the commercially viable and industrially advantageous processes described in the U.S. Patent Nos. US 7,429,661 and US 7,307,163.
Exemplary salts of the amino-methyl-oxazolidinone compound of formula II include, but are not limited to, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like.
In one embodiment, the reaction in step-(a) is carried out at a temperature of about 80°C to about 100°C, specifically at a temperature of about 85°C to about 99°C, and more specifically at a temperature of about 95°C to about 98°C. The reaction time may vary from about 1 hour to about 6 hours, and more specifically from about 2 hours to about 4 hours.

Advantageously, the reaction in step-(a) does not require excess amounts of water solvent. Usually, 2 volumes to about 3 volumes of water, specifically about 2.5 volumes of water with respect to the quantity of phthalimido-methyl-oxazolidinone compound of formula III is sufficient.
The reaction mass containing the amino-methyl-oxazolidinone compound of formula II or a salt thereof obtained in step-(a) may be subjected to usual work up methods such as a washing, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof. The reaction mass may be used directly in the next step to produce the Linezolid of formula I, or the amino-methyl-oxazolidinone compound of formula II or a salt thereof may be isolated and/or recrystallized and then used in the next step.
The carbon treatment is carried out by methods known in the art, for example, by stirring the solution with finely powdered carbon at a temperature of about 40°C to the reflux temperature for at least 5 minutes, specifically at the reflux temperature; and filtering the resulting mixture through charcoal bed to obtain a filtrate containing amino-methyl-oxazolidinone compound of formula II by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
In one embodiment, the amino-methyl-oxazolidinone compound of formula II or a salt thereof may be isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution^ evaporation, vacuum distillation, or a combination thereof.
In one embodiment, the solvent used for work up, isolation and/or recrystallization of the amino-methyl-oxazolidinone compound of formula II obtained by the process described herein is selected from the group consisting of water, an alcohol, a ketone, an ether, an ester, a hydrocarbon, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.

A most preferable solvent used for extraction and/or isolation of amino-methyl-oxazolidinone compound of formula II is dichloromethane.
In one embodiment, the acetylation in step-(b) is carried out by the methods known in the art, for example, as per the processes described in the U.S. Patent Nos. US 5,688,792, US 7,429,661 and US 7,307,163; and WO 2013/190559.
Exemplary acetylating agents used in step-(b) include, but are not limited to, acetic anhydride, acetyl chloride and the like. A most specific acetylating agent is acetic anhydride.
Exemplary solvent used for acetylation in step-(b) include, but are not limited to, water, an alcohol, a ketone, an ether, an ester, a nitrite, a hydrocarbon, a halogenated hydrocarbon, a polar aprotic solvent, and mixtures thereof.
Specifically, the solvent used for acetylation in step-(b) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-proply acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof.
Most specifically, the solvent used for acetylation in step-(b) is selected from the group consisting of dichloromethane, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, and mixtures thereof.
In another embodiment, the base used in step-(b) is selected from the group consisting of trimethylamine, triethylamine, tributylamine, diisopropylethylamine and N-methylmorpholine. A most specific base is triethylamine.
In one embodiment, the acetylation in step-(b) is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 10°C to about 50°C, and more specifically at a temperature of about 20°C to about 40°C. The reaction time may vary from about 20 minutes to about 5 hours.
The reaction mass containing the Linezoiid of formula I obtained in step-(b) may be subjected to usual work up such as a washing, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment or a combination thereof, followed by isolation and/or recrystallization from a suitable solvent by

conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
In one embodiment, the solvent used for work up, isolation and/or recrystallization of Linezolid obtained by the process described herein is selected from the group consisting of water, an alcohol, a ketone, an ether, an ester, a hydrocarbon, a halogenated hydrocarbon, and mixtures thereof. Specifically, the solvent is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.
The solid separated is collected by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.
In one embodiment, the Linezolid solid obtained by the processes described in the present invention is Linezolid crystalline Form II characterized by having an X-ray powder diffraction pattern substantially in accordance with Figure 1, and further characterized by an infra red (FT-IR) spectrum substantially in accordance with Figure 2.
In another embodiment, the Linezolid solid obtained by the processes described in the present invention is Linezolid crystalline Form III characterized by having an X-ray powder diffraction pattern substantially in accordance with Figure 3, and further characterized by an infra red (FT-IR) spectrum substantially in accordance with Figure 4.
The highly pure Linezolid or a polymorphic form thereof obtained by the above processes may be further dried in, for example, a Vacuum Tray Dryer, a Rotocon Vacuum Dryer, a Vacuum Paddle Dryer or a pilot plant Rota vapor, to further lower residual solvents. Drying can be carried out under reduced pressure until the residual solvent content reduces to the desired amount such as an amount that is within the limits given by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use ("ICH") guidelines.
In one embodiment, the drying is carried out at atmospheric pressure or reduced pressures, such as below about 200 mm Hg, or below about 50 mm Hg, at temperatures

such as about 35°C to about 90°C, and specifically at about 75°C to about 85°C. The drying can be carried out for any desired time period that achieves the desired result, such as times about 1 to 20 hours. Drying may also be carried out for shorter or longer periods of time depending on the product specifications. Temperatures and pressures will be chosen based on the volatility of the solvent being used and the foregoing should be considered as only a general guidance. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, or using a fluidized bed drier, spin flash dryer, flash dryer, and the like.
The highly pure Linezolid or a polymorphic form or a mixture of polymorphic forms thereof obtained by the process disclosed herein has a total purity (including both chemical and enantiomeric purities) of greater than about 99.5%, specifically greater than about 99.8%, more specifically greater than about 99.9%, and most specifically greater than about 99.95% as measured by HPLC. For example, the chemical purity of the highly pure Linezolid or a polymorphic form or a mixture of polymorphic forms thereof obtained by the processes disclosed herein is about 99.5% to about 99.99% as measured by HPLC, and the enantiomeric purity is greater than about 99.95% and most specifically about 99.95 to about 100% as measured by HPLC.
As used herein, the term "reflux temperature" means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
As used herein, the term "ambient temperature" refers to a temperature of about 15°C to about 45°C. For example, the term "ambient temperature" can refer to a temperature of about 20°C to about 40°C.
The term "Linezolid Crystalline Form III", as used herein is intended to mean the Linezolid Form III as disclosed in the U.S. Patent No. US 7,714,128.
The term "Linezolid Crystalline Form II", as used herein is intended to mean the Linezolid Form II as disclosed in the U.S. Patent No. US 6,559,305.
According to another aspect, there is provided an improved, commercially viable and industrially advantageous process for the preparation of (S)-N-[[3-[3-FIuoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine of formula II:

or a salt thereof, comprising reacting (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]-phthalimide of formula III:
// 0
with hydrazine hydrate in presence of water as a solvent to produce pure amino-methyl-
oxazolidinone compound of formula II, optionally converting the compound of formula II
into its salts thereof.
The preparation of (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-
oxazolidinyl]methyI]amine of formula II by reacting (S)-N-[[3-[3-fluoro-4-(4-
morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide of formula III with
hydrazine hydrate in water solvent is carried out by the methods, conditions and
parameters as described hereinabove.
INSTRUMENTAL DETAILS: X-Ray Powder Diffraction (P-XRD):
The X-ray powder diffraction spectrum was measured on a BRUKER AXS D8 FOCUS X-ray powder diffractometer equipped with a Cu-anode (copper-Ka radiation). Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees 2-theta, at 0.03 degrees to theta per step and a step time of 38 seconds. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 KV and current 35 mA.

Infra-Red Spectroscopy (FT-IR):
FT-IR spectroscopy was carried out with a Bruker vertex 70 spectrometer. For the
production of the KBr compacts approximately 5 mg of sample was powdered with 200
mg of KBr. The spectra were recorded in transmission mode ranging from 3800 cm"1 to
650 cm"1.
HPLC Method for measuring Chemical Purity:
The chemical purity was measured by HPLC using Shimadzu LC-2010 CHT system with
LC solutions software or its equivalent under the following conditions: Column =
Kromasil 100 CI8, 250 mm x 4.6 mm, 5um or Equivalent; Detector wavelength = 254 nm;
Flow Rate = 0.5 ml/minute; Injection volume = 20uL; Oven temperature = 40°C; Run time
= 30 minutes; Diluent - Acetonitrile; Elution = Isocratic; Mobile Phase = Water (400 ml):
acetonitrile (600 ml): triethyl amine (1.8 ml): acetic acid (1.3 ml).
HPLC Method for measuring Chiral Purity:
The chiral purity was measured by HPLC using Shimadzu LC-2010 CHT system with LC
solutions software or its equivalent under the following conditions: Column = Chiralpak
AD-H, 250 mm x 4.6 mm, 5um or Equivalent; Detector wavelength = 254 nm; Flow Rate
= 1.5 mL/minute; Injection volume = lOuL; Oven temperature = 25°C; Run time = 30
minutes; Diluent = Mobile phase; Elution = Isocratic; Mobile Phase = n-hexane (700 ml) :
ethanol (300 ml): diethyl amine (1 ml).
The following examples are given for the purpose of illustrating the present invention and should not be considered as limitation on the scope or spirit of the invention.
EXAMPLES Example 1 Preparation of (S)-N-[[3-[3-FIuoro-4-(4-morpholinyl)phenyI]-2-oxo-5-oxazolidinyl] methyl] amine
(S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyI]-2-oxo-5-oxazolidinyl]methyl3phthalimide (40 g), hydrazine hydrate (15 ml) and water (100 ml) were taken into a reaction flask at 25-30°C. The resulting mixture was heated to reflux temperature (95-98°C) and then stirred the mass for 2-3 hours at the same temperature. The reaction mass was cooled to 25-30°C and then extracted with dichloromethane (100 ml x 3). The resulting organic layers were

separated, washed the combined organic layer with water (100 ml x 3) and then distilled off the solvent under vacuum at 35-40°C to produce 25 g of pure (S)-N~[[3-[3-FIuoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine as a off-white solid [Purity by HPLC: 98%; and Yield: 90%].
Example 2 Preparation of Linezolid
(S)-N-[ [3 - [3 -fluoro-4-(4-morpholiny l)phenyl] -2-oxq-5 -oxazol idinyl]methy 1] phthalimide (40 g), hydrazine hydrate (15 ml) and water (100 ml) were taken into a reaction flask at 25-30°C. The resulting mass was heated to reflux temperature (95-98°C) and then maintained for 2-3 hours at the same temperature. After completion of reaction the reaction mass was cooled to 25-30°C and then extracted thrice with dichloromethane (100 ml x 3) to obtain the organic layer containing (S)-N-[[3-[3-Fluoro-4-(4-morpholinyI)phenyl]-2-oxo-5-oxazoIidinyl]methyl]amine. The resulting organic layers were combined and then washed with water (100 ml x 2), followed by the addition of triethylamine (12 g) at 25-30°C. The resulting mass was cooled to 15-25°C and then acetic anhydride (11 g) was added drop-wise at the same temperature. The resulting mixture was stirred for 1 hour at 25-30°C. Carbon powder (4 g) was added to the reaction mass, stirred for 10 minutes and then filtered through carbon bed. The resulting filtrate was distilled under vacuum at 35-40°C to obtain a solid. To the resulting solid, water (65 ml) was added and the resulting suspension was heated to 60-65°C, followed by stirring for 30 minutes at the same temperature. The resulting mass was cooled to 25-30°C. The separated solid was filtered, washed with water (40 ml) and then dried the material at 60-65°C for 5-6 hours to produce 26 g of Linezolid [Purity by HPLC: 99.8%; Enantiomeric Purity by HPLC: 99.99%].
Example 3 Preparation of Linezolid Crystalline Form II
Methanol (90 ml) was added to the Linezolid (20 g, obtained in Example 2) at 25-30°C and then stirred for 5 minutes. The resulting suspension was heated to reflux temperature, and then stirred for 10 minutes at reflux to obtain a clear solution. Activated carbon powder (2 g) was added to the refluxing solution and then stirred for 5-10 minutes. The resulting

mixture was filtered and washed the bed with hot methanol (10 ml). The resulting filtrate was cooled to 25-30°C and then stirred for 10 minutes at the same temperature. The resulting mass was further cooled to 0-5°C and then stirred for 30 minutes at the same temperature. The solid obtained was filtered, washed with chilled methanol (20 ml) and then dried the material at 60-65°C for 5-6 hours to produce 18.2 g of highly pure Linezolid crystalline Form II [Purity by HPLC: 99.95%; Enantiomeric Purity by HPLC: 99.99%].
Example 4 Preparation of Linezolid Crystalline Form III
Ethyl acetate (500 ml) was added to (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine (20 g, obtained in example 1) at 25-30°C, the resulting mixture was heated to reflux and then stirred for 10-15 minutes at reflux to form a clear solution. Activated carbon powder (2 g) was added to the refluxing solution and then stirred for 5-10 minutes. The resulting mixture was filtered and washed the bed with ethyl acetate (20 ml). Acetic anhydride (20 ml) was slowly added to the resulting filtrate over a period of 5-10 minutes at ambient temperature, followed by stirring the mass for 1 hour at ambient temperature. The separated solid was filtered, washed with ethyl acetate (20 ml) and then dried the material under vacuum at 50-55°C for 4-5 hours to produce 18.4 g of highly pure Linezolid crystalline Form III [Purity by HPLC: 99.98%; Enantiomeric Purity by HPLC: 99.99%].
All ranges disclosed herein are inclusive and combinable. While the invention has been described with reference to a preferred embodiment, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted for elements thereof without departing from the scope of the invention. In addition, many modifications may be made to adapt a particular situation or material to the teachings of the invention without departing from essential scope thereof. Therefore, it is intended that the invention not be limited to the particular embodiment disclosed as the best mode contemplated for carrying out this invention, but that the invention will include all embodiments falling within the scope of the appended claims.

A process for the preparation of Linezolid of formula I:
6 which comprises:
a) reacting (S)-N-[[3-[3-fJuoro-4-(4-morphoIinyl)phenyl]-2-oxo-5-oxazolidinyl]-
methyljphthalimide of formula III:
u with hydrazine hydrate in presence of water as a solvent to produce (S)-N-[[3-[3-Fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]amine of formula II:
or a salt thereof; and b) acetylation of the amino-methyl-oxazolidinone compound of formula II obtained in step-(a) with an acetylating agent, optionally in the presence of a base, in a suitable

solvent to produce highly pure Linezolid or a polymorphic form or a mixture of polymorphic forms thereof.
2. The process of claim 1, wherein the reaction in step-(a) is carried out at a temperature of about 85 °C to about 99°C; and wherein the water used as solvent in step-(a) is about 2 volumes to about 3 volumes with respect to the quantity of phthalimido-methyl-oxazolidinone compound of formula III.
3. The process of claim 1, wherein the reaction in step-(a) is carried out at a temperature of about 95 °C to about 98°C; and wherein the water used as solvent in step-(a) is about 2.5 volumes with respect to the quantity of phthaHmido-methyl-oxazolidinone compound of formula III.
4. The process of claim 1, wherein the reaction mass containing the amino-methyl-oxazolidinone compound of formula II or a salt thereof obtained in step-(a) is subjected to a washing, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof; and wherein the amino-methyl-oxazolidinone compound of formula II or a salt thereof obtained in step-(a) is isolated and/or recrystallized from a suitable solvent by cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
5. The process of claim 1, wherein the acetylating agent used in step-(b) is acetic anhydride; wherein the solvent used for acetylation in step-(b) is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-proply acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, N,N-dimethylformamide, N,N-dimethyIacetamide, and mixtures thereof; and wherein the base used in step-(b) is selected from the group consisting of trimethylamine, triethylamine, tributylamine, diisopropylethylamine and N-methylmorpholine.
6. The process of claim 1, wherein the Linezolid or a polymorphic form or a mixture of polymorphic forms thereof obtained in step-(b) has chemical purity of about 99.5% to about 99.99% as measured by HPLC, and enantiomeric purity of about 99.95% to

about 100% as measured by HPLC; and wherein the polymorphic form of Linezolid obtained in step-(b) is crystalline Form II or crystalline Form III. 7. A process for the preparation of (S)-N-[[3-[3-Fluoro-4-(4-morphoiinyl)phenyI]-2-oxo-5-oxazolidinyl]methyl]amine of formula II:
or a salt thereof, comprising reacting (S)-N-[[3-[3-fluoro-4-(4-morpholinyl)phenyl]-2-oxo-5-oxazolidinyl]methyl]phthalimide of formula III:
with hydrazine hydrate in presence of water as a solvent to produce pure amino-methyl-oxazolidinone compound of formula II, optionally converting the compound of formula II into its salts thereof.
8. The process of claim 7, wherein the reaction is carried out at a temperature of about 85°C to about 99°C; and wherein the water used as solvent is about 2 volumes to about 3 volumes with respect to the quantity of phthalimido-methyl-oxazolidinone compound of formula III.
9. The process of claim 7, wherein the reaction is carried out at a temperature of about 95°C to about 98°C; and wherein the water used as solvent is about 2.5 volumes with respect to the quantity of phthalimido-methyl-oxazolidinone compound of formula III.
10. The process of claim 7, wherein the reaction mass containing the amino-methyl-oxazolidinone compound of formula II or a salt thereof obtained is subjected to a

washing, an extraction, a pH adjustment, an evaporation, a layer separation, decoiorization, a carbon treatment, or a combination thereof; and wherein the amino-methyl-oxazolidinone compound of formula II or a salt thereof obtained is isolated and/or recrystallized from a suitable solvent by cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.