CROSS REFERENCE TO RELATED APPLICATION This patent application claims the benefit of priority to Indian Provisional Patent Application No. 5809/CHE/2014, filed on November 19, 2014, which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION The present invention relates to improved, commercially viable and industrially advantageous processes for the preparation of 5-Hydroxymethyl-oxazolidin-2-one derivatives or pharmaceutically acceptable salts thereof using novel intermediates, in high yield and purity.
BACKGROUND OF THE INVENTION
U.S. Patent No. 8,124,623 (hereinafter referred to as the c623 patent) discloses a variety of 5-hydroxymethyI-oxazolidin-2-one derivatives that are obtained from oxazolidinone derivatives linked to a quinolone or naphthyridinone via a spacer, and their stereochemically isomeric forms, pharmaceutically acceptable salts, processes for their preparation, pharmaceutical compositions comprising the derivatives, and use of these compounds in the manufacture of medicaments for the treatment of bacterial infections. These chimeric compounds are useful antibacterial agents effective against a variety of human and veterinary pathogens including among others Gram-positive aerobic bacteria, Gram-negative bacteria, anaerobic organisms and acid-fast organisms. Among them, Cadazolid is a strong inhibitor of Clostridium difficile protein synthesis leading to strong suppression of toxin and spore formation.
Cadazolid is developed by Actelion Pharmaceuticals Limited and it is currently under Phase III clinical trials. Cadazolid is chemically named as l-cyclopropyl-6-fluoro^7-[4-[[2-fluoro-4-[(5i?)-5-(hydroxymethyl)-2-oxo-l,3-oxazolidin-3-yl]phenoxy]methyl]-4-hydroxypiperidin-l-yl]-4-oxo-l,4-dihydro- quinolin-3-carboxyIic acid and is represented by the following structural formula 1:

Various processes for the preparation of Cadazolid and related compounds are described in the US'623 patent. Processes for the preparation of the key intermediates of Cadazolid are described in the U.S. Patent Nos. 4,244,961; 8,158,797 and 4,940,794.
The synthesis of Cadazolid as exemplified in the US'623 patent involves the following main reaction steps: a) 4-benzyloxy-3-fluoro-aniline is reacted with benzyl chloroformate in the presence of sodium bicarbonate to produce (4-benzyIoxy-3-fluoro-phenyl)-carbamic acid benzyl ester; b) the carbamate compound is reacted with (R)-glycidyl butyrate in the presence of n-butyl lithium solution in n-hexane at -78°C to produce (5R)-3-(4-benzyloxy-3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one; c) the benzyloxy compound is then deprotected by hydrogenation over palladium on charcoal catalyst to produce (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-hydroxymethyl-oxazolidin-2-one; d) the resulting hydroxy-phenyl compound is condensed with l-oxa-6-aza-spiro[2.5] octane-6-carboxylic acid benzyl ester to give 4-[2-fluoro-4-((R)-5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxymethyl]-4-hydroxy-piperidine-l-carboxylic acid benzyl ester; e) the benzyl ester compound is then deprotected by hydrogenation over palladium on charcoal catalyst to produce (R)-3-[Fluoro-4-(4-hydroxy-piperidine-4-yl-methoxy)-phenyl]-5-hydroxymethyl-oxazolidine-2-one; f) the resulting piperidine compound is reacted with 7-chloro-1 -cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid boron diacetate complex in the presence of N,N-diisopropylethylamine in N-methylpyrrolidinone, followed by treatment with hydrochloric acid in methanol to produce Cadazolid.

The schematic representation of the synthesis of Cadazolid as described in the US'623 patent is depicted in scheme 1:
As per the processes for the preparation of Cadazolid described in the prior art, (R)-3-(3-fIuoro-4-hydroxy-phenyl)-5-hydroxymethyl-oxazolidin-2-one of formula 2:

is a key intermediate.
The processes for the preparation of Cadazolid and its key intermediate 3-(3-fluoro-4-hydroxy-phenyl)-5-hydroxymethyl-oxazolidin-2-one described in the aforementioned prior art suffer from several disadvantages such as low overall yields, use of corrosive and explosive reagents like n-butyl lithium; use of expensive and highly flammable solvents like n-hexane and N-methylpyrrolidinone; use of tedious and cumbersome procedures like prolonged reaction time periods, very low temperature conditions (-78°C) and multiple process steps.
The USC623 patent also describes various general synthetic routes for the preparation of Cadazolid and its key intermediates as depicted in scheme 2:

Based on the aforementioned drawbacks, the prior art processes have been found to be unsuitable for the preparation of Cadazolid and its intermediates in commercial scale operations.
A need remains for novel, commercially viable and environmentally friendly processes of preparing Cadazolid and its intermediates with high yield 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 object of the present application is to provide improved and industrially advantageous processes for the preparation of Cadazolid and its intermediates with high yield and purity.
In one aspect, provided herein are novel, industrially advantageous and environmentally friendly processes for the preparation of Cadazolid in high yield and with high purity, using novel intermediate compounds.
In another aspect, provided herein are industrially advantageous and environmentally friendly processes for the preparation of (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-hydroxymethyl-oxazolidin-2-one of formula 2 and its derivatives, in high yield and with high purity, and without using expensive and explosive reagents like n-butyl lithium and highly flammable solvents like n-hexane.
The processes disclosed herein avoid the tedious and cumbersome procedures of the prior processes like prolonged reaction time periods, extreme low temperature conditions (-78°C) and multiple process steps, thereby resolving the problems associated with the processes described in the prior art, which are more convenient to operate at lab scale and in commercial scale operations.
DETAILED DESCRIPTION OF THE INVENTION . According to one aspect, there is provided a process for the preparation of Cadazolid of formula 1:

or an enantiomeric form or a mixture of enantiomeric forms thereof, or a pharmaceutically acceptable salt thereof, which comprises reacting (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one of formula 2:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, with l-oxa-6-aza-spiro compound of formula 20:
or a salt thereof, wherein the group 6P' represents hydrogen atom or an alkyl group Pi;
in the presence of a base to produce Cadazolid of formula 1, and optionally converting the
compound of formula 1 obtained into its pharmaceutically acceptable salts thereof.
In one embodiment, the group P in the compounds of formula 20 is hydrogen.
In another embodiment, the group P in the compounds of formula 20 is an alkyl group 'Pi' selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl. Most specifically, P] is methyl.
Unless otherwise specified, the term "alkyl", as used herein, denotes an aliphatic hydrocarbon group which may be straight or branched having 1 to 12 carbon atoms in the

chain. Preferred alkyl groups have 1 to 6 carbon atoms in the chain. The alkyl may be substituted with one or more "cycloalkyl groups". Exemplary alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n- butyl, iso-butyl, t-butyl, and n-pentyl.
The term "cycloalkyl", as used herein, denotes a non-aromatic mono- or multicyclic ring system of 3 to 10 carbon atoms, preferably of about 5 to 10 carbon atoms. Exemplary monocyclic cycloalkyl groups include cyclopentyl, cyclohexyl, cycloheptyl and the like.
The term "aralkyl", as used herein, denotes an aryl-alkyl group wherein the aryl and alkyl are as herein described. Preferred aralkyls contain a lower alkyl moiety. Exemplary aralkyl groups include benzyl, 2-phenethyl and naphthalenemethyl.
The term "aryl", as used herein, denotes an aromatic monocyclic or multicyclic ring system of 6 to 10 carbon atoms. The aryl is optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Exemplary aryl groups include phenyl, tolyl, nitrophenyl or naphthyl.
Unless otherwise specified, the solvent used for isolating and/or recrystallizing the compounds obtained by the processes described in the present application is generally 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, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.
Unless otherwise specified, the term 'salt' as used herein may include acid addition salts and base addition salts.
Acid addition salts may be derived from organic and inorganic acids. For example, the acid addition salts are derived from a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumade acid, citric acid, glutaric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, malic acid, ascorbic acid, and the like.
Exemplary acid addition salts include, but are not limited to, hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, propionate, oxalate, succinate,

maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like. A most specific acid addition salt is hydrochloride salt.
Base addition salts may be derived from an organic or an inorganic base. For example, the base addition salts are derived from alkali or alkaline earth metals such as sodium, calcium, potassium and magnesium; ammonium salt, organic amines such as methylamine, ethylamine, tert-butylamine, diethylamine, diisopropylamine, and the like.
In one embodiment the reaction between the compound of formula 2 and 20 is carried out in the presence of a solvent or a mixture of solvents.
Exemplary solvents used in the above reaction include, but are not limited to, water, an alcohol, a hydrocarbon solvent, a nitrile solvent, an ether, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.
Specifically, the solvent is selected from the group consisting of water, acetonitrile,
methanol, ethanol, isopropyl alcohol, n-butyl alcohol, toluene, xylene, tetrahydrofuran, 2-
methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether,
monoglyme, diglyme, N,N-dimethylformamide, N,N-dimethylacetamide,
dichloromethane, dichloroethane, and mixtures thereof. Most specific solvents are water, acetonitrile and mixtures thereof.
In one embodiment, the base used in the above reaction is an organic or an inorganic base, and most specifically an inorganic base.
Exemplary bases include, but are not limited to, methylamine, trimethylamine, tributylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, and 1-alkylimidazole; and hydroxides, alkoxides, bicarbonates and carbonates of alkali or alkaline earth metals. Specific bases are sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium ^carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; and most specifically, the base is potassium carbonate.
The reaction temperature and time period will ordinarily depend on the starting compounds and the solvent employed in the reaction.
In one embodiment, the reaction between the compound of formula 2 and 20 is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 30°C to the reflux temperature of the solvent used,

and more specifically at the reflux temperature of the solvent used. The reaction time may vary between about 3 hours to about 20 hours, specifically about 4 hours to about 15 hours, and more specifically about 6 hours to about 12 hours.
The reaction mass containing the Cadazolid of formula 1 obtained may be subjected to usual work up methods such as a washing, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, or a combination thereof.
In one embodiment, the Cadazolid of formula 1 is 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.
According to another aspect, there is provided a l-oxa-6-aza-spiro compound of formula 20:
or a salt thereof, wherein the group 'P' represents hydrogen atom or an alkyl group Pj.
In one embodiment, the group P in the compounds of formula 20 is hydrogen. In another embodiment, the group P in the compounds of formula 20 is an alkyl group cPi' selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl. Most specifically, Pi is methyl.
In one embodiment, a specific l-oxa-6-aza-spiro compound of formula 20 prepared by the process described herein is l-Cyclopropyl-6-fluoro-7-(l-oxa-6-aza-spiro[2.5]oct-6-yl)-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid of formula 20(a) (formula 20, wherein P is hydrogen):
or a salt thereof.

In another embodiment, a specific l-oxa-6-aza-spiro compound of formula 20 prepared by the process described herein is methyl l-cyclopropyl-6-fluoro-7-(l-oxa-6-aza-spiro[2.5]oct-6-yl)-4-oxo-l34-dihydro-quinoline-3-carboxylate of formula 20(b) (formula ♦ 20, wherein P is methyl):
or a salt thereof.
According to another aspect, there is provided a process for the preparation of (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one of formula 2:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, which comprises:
a) reacting (R)-5-(Chloromethyl)-3-(3-fluoro-4-benzyloxy-phenyl)-oxazolidin-2-one of formula 22:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, with a suitable reagent to produce (R)-5-(acetyloxymethyl)-3-(3-fluoro-4-benzyloxy-phenyl)-oxazolidin-2-one of formula 23:

or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof; b) hydrolysing the compound of formula 23 to produce (R)-5-(hydroxymethyl)-3-(3-fluoro-4-benzyloxyphenyl)-oxazolidin-2-one of formula 24:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof; and c) deprotecting the compound of formula 24 to produce the (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one of formula 2 or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, and optionally converting the compound of formula 2 into Cadazolid or a pharmaceutical^ acceptable salt thereof. In one embodiment, the reagent used in step-(a) is sodium acetate or potassium acetate.
In another embodiment, the reaction in step-(a) is carried out in the presence of a solvent or a mixture of solvents. Exemplary solvents used in step-(a) include, but are not limited to, a hydrocarbon solvent, an ether, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof. A most specific solvent used in step-(a) is toluene.
The reaction temperature and time period will ordinarily depend on the starting compounds and the solvent employed in the reaction.
Specifically, the reaction in step-(a) is carried out at a temperature of about 20°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature

of the solvent used. The reaction time may vary between about 5 hours to about 25 hours, and specifically about 10 hours to about 20 hours.
The reaction mass containing the (R)-5-(acetyloxymethyl)-3-(3-fluoro-4-benzyloxy-phenyl)-oxazolidin-2-one of formula 23 obtained in step-(a) may be subjected to usual work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula 24, or the compound of formula 23 may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula 23 may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The hydrolysis in step-(b) is carried out by treating the compound of formula 23 with an acid or a base, in a reaction inert solvent.
Specifically, the hydrolysis in step-(b) is carried out by treating the compound of formula 23 with a base.
The base used for hydrolysis is an organic or an inorganic base selected from the group as described hereinabove. Exemplary bases, include, but are not limited to, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide. Most specifically, the base used in step-(b) is sodium carbonate or potassium carbonate.
The acid used for hydrolysis in step-(b) is an organic or an inorganic acid. Exemplary acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, formic acid, and the like, or a combination thereof. A most specific acid is hydrochloric acid.
o
The hydrolysis in step-(b) is carried out in the presence of a solvent or a mixture of
solvents. Exemplary solvents used in step-(b) include, but are not limited to, water, an
alcohol, a hydrocarbon solvent, an ether, a polar aprotic solvent, a halogenated
hydrocarbon solvent, and mixtures thereof. *>
Specifically, the solvent used in step-(b) is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, and mixtures thereof. Most specific solvents are methanol, ethanol, isopropyl alcohol, and mixtures thereof.

Specifically, the hydrolysis in step-(b) is carried out at a temperature of about 20°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used. The reaction time may vary between about 5 hours to about 20 hours, and specifically about 8 hours to about 15 hours.
The reaction mass containing the (R)-5-(hydroxymethyl)-3-(3-fluoro-4-benzyloxyphenyl)-oxazolidin-2-one of formula 24 obtained in step-(b) may be subjected to usual work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula 2, or the compound of formula 24 may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula 24 may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The deprotection in step-(c) is carried out by subjecting the oxazolidinone compound of formula 24 to hydrogenolysis under hydrogen pressure in the presence of a metal catalyst such as zinc, nickel, palladium, palladium on carbon, and the like.
In one embodiment, the deprotection in step-(c) is carried out in the presence of a solvent or a mixture of solvents. Exemplary solvents used for deprotection in step-(c) include, but are not limited to, water, an alcohol, a ketone, a halogenated solvent, an ester, a hydrocarbon solvent, an ether, a nitrile, a polar aprotic solvent, and mixtures thereof. Specifically, the solvent used in step-(c) is an ester solvent and most specifically ethyl acetate.
In one embodiment, the deprotection in step-(c) is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 20°C to about 50°C, and more specifically at a temperature of about 20°C to about 45 °C. The reaction time may vary from about 1 hour to about 15 hours, specifically from about 2 hours to about 8 hours, and more specifically from about 4 hours to about 7 hours.
The reaction mass containing the (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one of formula 2 obtained in step-(c) may be subjected to usual work up, and followed by isolating and/or recrystallizing from a suitable solvent by the methods as described hereinabove.
The conversion of the intermediate compound of formula 2 into Cadazolid or a pharmaceutical^ acceptable salt thereof in step-(c) can be carried out as per the processes described herein or by known methods.

According to another aspect, there is provided a process for the preparation of 1-cyclopropyl-6-fluoro-7-(l-oxa-6-aza-spiro[2.5]oct-6-yl)-4-oxo-l54-dihydro-quinoline-3-carboxylic acid of formula 20(a):
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof,
which comprises:
a) reacting l,4-dioxa-8-aza-spiro[4.5]decane hydrochloride of formula 28:
or an acid addition salt thereof, with 7-Chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-3-quinoIinecarboxylic acid boron diacetate complex of formula 19(a):
to produce l-Cyclopropyl-7-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-6-fluoro-4-oxo-l54-dihydro-quinoline-3-carboxylic acid of formula 26:
or a salt thereof;

b) reacting the compound of formula 26 with an acid to produce l-Cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-piperidin-l-yI)-l?4-dihydro-quinoline-3-carboxylic acid of formula 25(a):
or a salt thereof; and c) reacting the compound of formula 25(a) with trimethylsulfoxonium iodide to produce l-cyclopropyl-6-fluoro-7-(l-oxa-6-aza-spiro[2.5]oct-6-yI)-4-oxo-l?4-dihydro-quinoline-3-carboxylic acid of formula 20(a) or a salt thereof.
Specifically, the acid addition salt of formula 28 used in step-(a) is a hydrochloride salt.
In one embodiment, the reaction in step-(a) is carried out in the presence of a suitable base or a combination of suitable bases.
In another embodiment, the base used in step-(a) is an organic or an inorganic base, or a combination thereof.
Exemplary bases include, but are not limited to, methylamine, trimethylamine, tributylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, and 1-alkylimidazole; and hydroxides, alkoxides, bicarbonates and carbonates of alkali or alkaline earth metals. Specific bases are diisopropylethylamine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; and most specifically potassium carbonate and diisopropylethylamine.
In another embodiment, the reaction in step-(a) is carried out in the presence of a solvent or a mixture of solvents. Exemplary solvents used in step-(a) include, but are not limited to, a hydrocarbon solvent, an ether, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof. A most specific solvent used in step-(a) is N-methyl-2-pyrrolidone.

The reaction in step-(a) is optionally carried out in the presence of a phase transfer catalysts such as tetra-n-butylammonium bromide.
The reaction temperature and time period will ordinarily depend on the starting compounds and the solvent employed in the reaction.
Specifically, the reaction in step-(a) is carried out at a temperature of about 20°C to the reflux temperature of the solvent used, and more specifically at a temperature of about 50°C to the reflux temperature of the solvent used. The reaction time may vary between about 5 hours to about 15 hours, and specifically about 6 hours to about 12 hours.
The reaction mass containing the l-Cyclopropyl-7-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-6-fluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid of formula 26 obtained in step-(a) may be subjected to usual work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula 25(a), or the compound of formula 26 may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula 26 may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The acid used in step-(b) is an organic or an inorganic acid. Exemplary acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, formic acid, and the like, or a combination thereof. A most specific acid is hydrochloric acid.
The reaction in step-(b) is carried out in the presence of a solvent or a mixture of solvents. Exemplary solvents used in step-(b) include, but are not limited to, water, an alcohol, a hydrocarbon solvent, an ether, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof. A most specific solvent used in step-(b) is a mixture of water and acetonitrile.
Specifically, the reaction in step-(b) is carried out at a temperature of about 20°C to the reflux temperature of the solvent used, and more specifically at a temperature of about 50°C to the reflux temperature of the solvent used. The reaction time may vary between about 4 hours to about 12 hours, and specifically about 6 hours to about 10 hours.
The reaction mass containing the 1 -Cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-piperidin-l-yl)-l,4-dihydro-quinoline-3-carboxylic acid of formula 25(a) obtained in step-(b) may be subjected to usual work up methods as described hereinabove. The reaction

mass may be used directly in the next step to produce the compound of formula 20(a), or the compound of formula 25(a) may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula 25(a) may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
In another embodiment, the reaction in step-(c) is carried out in the presence of a solvent or a mixture of solvents. Exemplary solvents used in step-(c) include, but are not limited to, water, an alcohol, a ketone, a halogenated solvent, an ester, a hydrocarbon solvent, an ether, a nitrile, a polar aprotic solvent, and mixtures thereof. Specifically, the solvent used in step-(c) is dimethyl sulfoxide.
In one embodiment, the reaction in step-(c) is carried out in the presence of a suitable base. The base is an organic or an inorganic base selected from the group as described hereinabove.
Specific bases are diisopropylethylamine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; and most specifically potassium tert-butoxide.
In one embodiment, the reaction in step-(c) is carried out at a temperature of about 0°C to about 45°C, specifically at a temperature of about 20°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 1 hour to about 10 hours, and specifically from about 2 hours to about 6 hours.
The reaction mass containing the l-cyclopropyl-6-fluoro-7-(l-oxa-6-aza-spiro[2.5]oct-6-yl)-4-oxo-l?4-dihydro-quinoline-3-carboxylic acid of formula 20(a) obtained in step-(c) may be subjected to usual work up, and followed by isolating and/or recrystallizing from a suitable solvent by the methods as described hereinabove.
According to another aspect, there is provided a process for the preparation of
methyl l-cyclopropyl-6-fluoro-7-(l-oxa-6-aza-spiro[2.5]oct-6-yl)-4-oxo-l,4-dihydro-
quinoline-3-carboxylate of formula 20(b):

or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof,
which comprises:
a) reacting l,4-dioxa-8-aza-spiro[4.5]decane hydrochloride of formula 28:
or an acid addition salt thereof, with 7-Chloro-l-cyclopropyl-6-fluoro-l,4-dihydro^4-oxo-3-quinolinecarboxylic acid boron diacetate complex of formula 19(a):
to produce l-Cyclopropyl-7-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-6-fluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid of formula 26:
or a salt thereof; b) reacting the compound of formula 26 with an acid to produce l-Cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-piperidin-l-yl)-l,4-dihydro-quinoline-3-carboxylic acid of formula 25(a):

or a salt thereof; c) reacting the compound of formula 25(a) with dimethylsulfate in the presence of a base to produce methyl l-cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-piperidin-l-yl)-l54-dihydro-quinoline-3-carboxylate of formula 25(b):
or a salt thereof; and d) reacting the compound of formula 25(b) with trimethylsulfoxonium iodide to produce methyl l-cyclopropyl-6-fluoro-7-(l-oxa-6-aza-spiro[2.5]oct-6-yl)-4-oxo-l,4-dihydro-quinoline-3-carboxylate of formula 20(b) or a salt thereof.
Specifically, the acid addition salt of formula 28 used in step-(a) is a hydrochloride salt.
In one embodiment, the reaction in step-(a) is carried out in the presence of a suitable base or a combination of suitable bases.
In another embodiment, the base used in step-(a) is an organic or an inorganic base, or a combination thereof.
Exemplary bases include, but are not limited to, methylamine, trimethylamine, tributylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, and 1-alkylimidazole; and hydroxides, alkoxides, bicarbonates and carbonates of alkali or alkaline earth metals. Specific bases are diisopropylethylamine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate,

lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; and most specifically potassium carbonate and diisopropylethylamine.
In another embodiment, the reaction in step-(a) is carried out in the presence of a solvent or a mixture of solvents. Exemplary solvents used in step-(a) include, but are not limited to, a hydrocarbon solvent, an ether, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof. A most specific solvent used in step-(a) is N-methyl-2-pyrrolidone.
The reaction in step-(a) is optionally carried out in the presence of a phase transfer catalysts such as tetra-n-butylammonium bromide.
The reaction temperature and time period will ordinarily depend on the starting compounds and the solvent employed in the reaction.
Specifically, the reaction in step-(a) is carried out at a temperature of about 20°C to the reflux temperature of the solvent used, and more specifically at a temperature of about 50°C to the reflux temperature of the solvent used. The reaction time may vary between about 5 hours to about 15 hours, and specifically about 6 hours to about 12 hours.
The reaction mass containing the l-Cyclopropyl-7-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-6-fluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid of formula 26 obtained in step-(a) may be subjected to usual work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula 25(a), or the compound of formula 26 may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula 26 may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The acid used in step-(b) is an organic or an inorganic acid. Exemplary acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, formic acid, and the like, or a combination thereof. A most specific acid is hydrochloric acid.
The reaction in step-(b) is carried out in the presence of a solvent or a mixture of solvents. Exemplary solvents used in step-(b) include, but are not limited to, water, an alcohol, a hydrocarbon solvent, an ether, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof. A most specific solvent used in step-(b) is a mixture of water and acetonitrile.

Specifically, the reaction in step-(b) is carried out at a temperature of about 20°C to the reflux temperature of the solvent used, and more specifically at a temperature of about 50°C to the reflux temperature of the solvent used. The reaction time may vary between about 4 hours to about 12 hours, and specifically about 6 hours to about 10 hours.
The reaction mass containing the l-Cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-piperidin-l-yl)-l,4-dihydro-quinoline-3-carboxylic acid of formula 25(a) obtained in step-(b) may be subjected to usual work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula 25(b), or the compound of formula 25(a) may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula 25(a) may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
In one embodiment, the reaction in step-(c) is carried out in the presence of a solvent or a mixture of solvents. Exemplary solvents used in step-(c) include, but are not limited to, water, an alcohol, a ketone, a halogenated solvent, an ester, a hydrocarbon solvent, an ether, a nitrile, a polar aprotic solvent, and mixtures thereof. Specifically, the solvent used in step-(c) is acetone.
In one embodiment, the reaction in step-(c) is carried out in the presence of a suitable base. The base is an organic or an inorganic base selected from the group as described hereinabove.
Specific bases are sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; and a most specific base is potassium carbonate.
Specifically, the reaction in step-(c) is carried out at a temperature of about 20°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used. The reaction time may vary between about 1 hour to about 6 hours, and specifically about 2 hours to about 4 hours.
The reaction mass containing the methyl l-cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-piperidin-l-yl)-l,4-dihydro-quinoline-3-carboxylate of formula 25(b) obtained in step-(c) may be subjected to usual work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula 20(b), or the

compound of formula 25(b) may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula 25(b) may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
In one embodiment, the reaction in step-(d) is carried out in the presence of a solvent or a mixture of solvents. Exemplary solvents used in step-(d) include, but are not limited to, water, an alcohol, a ketone, a halogenated solvent, an ester, a hydrocarbon solvent, an ether, a nitrile, a polar aprotic solvent, and mixtures thereof. Specifically, the solvent used in step-(d) is dimethyl sulfoxide.
In one embodiment, the reaction in step-(d) is carried out in the presence of a suitable base. The base is an organic or an inorganic base selected from the group as described hereinabove.
Specific bases are diisopropylethylamine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; and most specifically potassium tert-butoxide.
In one embodiment, the reaction in step-(d) is carried out at a temperature of about 0°C to about 45°C, specifically at a temperature of about 20°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 1 hour to about 10 hours, and specifically from about 2 hours to about 6 hours.
The reaction mass containing the methyl l-cyclopropyl-6-fluoro-7-(l-oxa-6-aza-spiro[2.5]oct-6-yl)-4-oxo-l,4-dihydro-quinoline-3-carboxylate of formula 20(b) obtained in step-(d) may be subjected to usual work up, and followed by isolating and/or recrystallizing from a suitable solvent by the methods as described hereinabove.
According to another aspect, there is provided methyl l-cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-piperidin-l-yl)-l,4-dihydro-quinoline-3-carboxylate of formula 25(b):

or a salt thereof.
According to one aspect, there is provided a process for the preparation of (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one of formula 2:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof,
which comprises:
a) reacting a substituted-aniline compound of formula 7:
or a salt thereof, wherein 'A' represents a protecting group; with a compound of formula 6:
or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is hydrogen or a hydroxy protecting group Ri, L represents a leaving group and Y represents a hydroxy group; or L and Y together with the atoms to which they are bonded form an oxirane ring having the structural formula 6a:
or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is as defined above; to produce a 3-amino-2-hydroxy-propyl derivative of formula 5:

or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the group A is as defined in formula 7, and wherein the group R is as defined in formula 6; b) subjecting the compound of formula 5 to carbonylation by reacting with a suitable carbonylating agent to produce the compound of formula 3:
or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein the
groups A and R are as defined above; and c) deprotecting the compound of formula 3 to produce the compound of formula 2 or an
enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, and
optionally converting the compound of formula 2 into Cadazolid or a pharmaceutical^
acceptable salt thereof.
Unless otherwise specified, the Cadazolid intermediate compounds of formulae 2, 3 and 5, each independently, contains one chiral centre and thus exists as two optical isomers, i.e. enantiomers (R & S-isomers). The process disclosed herein encompasses the preparation of both enantiomers and mixtures thereof in all proportions.
The protecting group 'A? in the compounds of formulae 3, 5 and 7 is a hydroxyl protecting group.
In one embodiment, the leaving group 'L5 in the compound of formula 6 is a halogen, or an alkyl or aryl sulfonyloxy group. Specifically, the leaving group L is selected from the group consisting of CI, Br, I, methanesulfonyloxy, toluenesulfonyloxy and

trifluoromethanesulfonyloxy group; and a most specific leaving group is CI or toluenesulfonyloxy.
In one embodiment, the group R in the compounds of formulae 3, 5, 6 and 6a is hydrogen atom. In another embodiment, the group R in the compounds of formulae 3, 5, 6 and 6a is a hydroxyl protecting group R\.
Unless otherwise indicated, the "protecting group for a hydroxyl group" is not particularly limited provided that it can stably protect the hydroxyl group in the reaction, and specifically refers to a protecting group capable of being cleaved by a chemical step such as hydrogenolysis, hydrolysis, electrolysis and photolysis.
Exemplary hydroxyl protecting groups 'A' and 'Ri', each independently, includes, but are not limited to, a substituted or unsubstituted aralkyl, a substituted or unsubstituted trityl, an aliphatic acyl group including an alkanoyl group, an aromatic acyl group including an arylcarbonyl group, a tri(Ci_6 alkyl)silyl (where the alkyl groups may be the same or different), a tri(C6-io aryl)silyl, an alkylcarbonyl group substituted with a carboxy group, an alkylcarbonyl group substituted with a halogen atom, a saturated cyclic hydrocarbon-carbonyl group, an alkylcarbonyl group substituted with a lower alkoxy group, an unsaturated alkylcarbonyl group, a halogenoarylcarbonyl group, an arylcarbonyl group substituted with a lower alkyl group, a lower alkoxylated arylcarbonyl group, an arylcarbonyl group substituted with a carboxy group, a nitrated arylcarbonyl group, an arylcarbonyl group substituted with a lower alkoxycarbonyl group, an arylcarbonyl group substituted with an aryl, and the like.
In one embodiment, the hydroxyl protecting groups 'A' and cRi\ each independently, are selected from the group consisting of formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, succinoyl, glutamyl, adipoyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, cyclopropylcarbonyl, cyclobutylcarbonyl, methoxyacetyl, benzoyl, a-naphthoyl, b-naphthoyl, pyridoyl, furoyl, 2-bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, p-toluoyl, p-anisoyl, 2-carboxybenzoyl, p-nitrobenzoyl, trityl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, o-nitrobenzyl, benzyl, p-methoxybenzyl, trimethylsilyl, triisopropylsilyl and t-butyldiphenylsilyl.

Specifically, the hydroxy! protecting groups 'A' and cRi', each independently, are selected from the group consisting of acetyl, propionyl, butyryf, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, trichloroacetyl, trifluoroacetyl, benzoyl, p-toluoyl, p-anisoyl, trityl, o-nitrobenzyl, benzyl and p-methoxybenzyl; and most specifically acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl and benzyl.
In one embodiment, the reaction in step-(a) is carried out in the presence of a solvent or a mixture of solvents.
Exemplary solvents used in step-(a) include, but are not limited to, water, an alcohol, a hydrocarbon solvent, an ether, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof
Specifically, the solvent used in step-(a) is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, dichloroethane, chloroform, and mixtures thereof Most specific solvents are methanol, ethanol, isopropyl alcohol, and mixtures thereof
In another embodiment, the reaction in step-(a) is optionally carried out in the presence of a base. Specifically, the base is an organic or inorganic base, and most specifically an inorganic base.
Exemplary bases include, but are not limited to, methylamine, trimethylamine, tributylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, and 1-alkylimidazole; and hydroxides, alkoxides, bicarbonates and carbonates of alkali or alkaline earth metals. Specific bases are collidine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide.
The reaction temperature and time period will ordinarily depend on the starting compounds and the solvent employed in the reaction.
In one embodiment, the reaction in step-(a) is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 30°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used. The reaction time may vary between about 5 hours to

about 35 hours, specifically about 8 hours to about 30 hours, and more specifically about 12 hours to about 28 hours.
The reaction mass containing the 3-amino-2-hydroxy-propyl intermediate compound of formula 5 obtained in step-(a) may be subjected to usual work up such as washing, extraction, pH adjustment, evaporation, layer separation, decolorization, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula 3, or the compound of formula 5 may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the 3-amino-2-hydroxypropyl compound of formula 5 is 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.
Unless otherwise specified, the solvent used for isolating and/or recrystallizing the compounds obtained by the processes described in the present application is generally 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, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.
In one embodiment, a specific 3-amino-2-hydroxypropyl derivative of formula 5 prepared by the process described herein is (2R)-3-(4-benzyloxy-3-fluoro-phenylamino)-propane-l,2-diol of formula 5a (formula 5, wherein R is hydrogen and A is benzyl):
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof.
In another embodiment, a specific 3-amino-2-hydroxypropyl derivative of formula 5 prepared by the process described herein is (2R)-3-(4-benzyloxy-3-fluoro-phenylamino)-

2-hydroxy-propyl butanoate of formula 5b (formula 5, wherein R is butyryl and A is benzyl):
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof.
In another embodiment, a specific 3-amino-2-hydroxypropyl derivative of formula 5 prepared by the process described herein is (2R)-l-benzyloxy-3-(4-benzyloxy-3-fluoro^-phenylamino)-2-propanol of formula 5c (formula 5, wherein R is benzyl and A is benzyl):
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof.
In one embodiment, a specific 3-amino-2-hydroxypropyl derivative of formula 5 prepared by the process described herein is (2R)-3-(4-acetyloxy-3-fluoro-phenylamino)-propane-l,2-diol of formula 5d (formula 5, wherein R is hydrogen and A is acetyl):
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof.
In another embodiment, a specific 3-amino-2-hydroxypropyl derivative of formula 5 prepared by the process described herein is (2R)-3-(4-acetyloxy-3-fluoro-phenylamino)-2-hydroxy-propyl butanoate of formula 5e (formula 5, wherein R is butyryl and A is acetyl):

or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof.
In another embodiment, a specific 3-amino-2-hydroxypropyl derivative of formula 5 prepared by the process described herein is (2R)-l-benzyloxy-3-(4-acetyloxy-3-fluoro-phenylamino)-2-propanol of formula 5f (formula 5, wherein R is benzyl and A is acetyl):
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof.
In another embodiment, a specific 3-amino-2-hydroxypropyl derivative of formula 5 prepared by the process described herein is (2R)-3-(4-acetyloxy-3-fluoro-phenylamino)-2-hydroxy-propyl acetate of formula 5g (formula 5, wherein R is acetyl and A is acetyl):
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof.
The 3-amino-2-hydroxypropyl derivative of formula 5 or an enantiomeric form of a mixture of enantiomeric forms thereof, or a salt thereof, is novel and forms another aspect of the present invention.
The use of the 3-amino-2-hydroxypropyl derivative of formula 5 or a salt thereof in the process for manufacture of Cadazolid is novel and forms further aspect of the present invention.

In one embodiment, the reaction in step-(b) is carried out in the presence of a solvent or a mixture of solvents.
Exemplary solvents used in step-(b) include, but are not limited to, water, an alcohol, a hydrocarbon solvent, an ether, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.
Specifically, the solvent used in step-(b) is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof. Most specific solvents are dichloromethane, methanol, ethanol, isopropyl alcohol, and mixtures thereof.
The carbonylation reaction in step-(b) is performed by reacting with a suitable carbonylating agent commonly known for such purpose.
Exemplary carbonylating agents used in step-(b) include, but are not limited to, N,N'-carbonyldiimidazole, phosgene, diphosgene, triphosgene, dialkyl carbonates, substituted or unsiibstituted alkyl chloroformates, substituted or unsubstituted aryl chloroformates, substituted or unsubstituted aralkyl chloroformates, or a combination thereof.
Specific carbonylating agents used in step-(b) are N,N'-carbonyldiimidazole, diethyl carbonate, di-tert-butyl dicarbonate (BOC anhydride), phenyl chloroformate and benzyl chloroformate; and most specifically N,N'-carbonyldiimidazole, diethyl carbonate and di-tert-butyl dicarbonate (BOC anhydride).
In one embodiment, the carbonylating agent in step-(b) is used in a ratio of about 1 to 5 equivalents, specifically about 1 to 1.5 equivalents, with respect to the 3-amino-2-hydroxypropyl compound of formula 5 in order to ensure a proper course of the reaction.
In another embodiment, the reaction in step-(b) is optionally carried out in the presence of a base. Specifically, the base is an organic or inorganic base, and most specifically an organic base, selected from the group as described hereinabove.
In one embodiment, the reaction 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 15°C to the reflux temperature of the solvent used, and most specifically at a temperature

of about 30°C to the reflux temperature of the solvent used. The reaction time may vary between about 1 hour to about 30 hours, specifically about 2 hours to about 20 hours, and more specifically about 3 hours to about 6 hours.
In another embodiment, the resulting compound obtained after completion of the carbonylation reaction step-(b) is, optionally, required to be reacted with a suitable base or an acid in a suitable solvent to obtain the oxazolidinone compound of formula 3. Specifically, the base used for such purpose is an inorganic base selected from the group as described herein above and the solvent is an alcohol solvent. Most specifically, the inorganic base is sodium carbonate or potassium carbonate, and the solvent is methanol.
The reaction mass containing the oxazolidinone compound of formula 3 obtained in step-(b) may be subjected to usual work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula 2, or the compound of formula 3 may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the oxazolidinone compound of formula 3 is isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The removal of protecting groups in step-(c) can be achieved by conventional methods used in organic chemistry and are described e.g. in the relevant chapters of standard reference works such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973; in T.W. Greene and P.G.M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999.
For example, the deprotection in step-(c) is performed by subjecting the N-protected compound of formula 3 to hydrolysis, hydrogenolysis, or a combination thereof.
In one embodiment, the deprotection in step-(c) is carried out by treating the oxazolidinone compound of formula 3 with a suitable deprotecting agent such as an acid or a base, in a reaction inert solvent.
Specifically, the deprotection in step-(c) is carried out by treating the oxazolidinone compound of formula 3 with a base.
In another embodiment, the deprotection in step-(c) is carried out by subjecting the oxazolidinone compound of formula 3 to hydrogenolysis under hydrogen pressure in the presence of a metal catalyst such as zinc, nickel, palladium, palladium on carbon, and the . like.

The base used for deprotection is an organic or an inorganic base selected from the group as described hereinabove. Specific bases are collidine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide.
The acid used for deprotection in step-(c) is an organic or an inorganic acid. Exemplary acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, formic acid, and the like, or a combination thereof. A most specific acid is hydrochloric acid.
For example, the acid used may be in the form of aqueous solutions or in the form of a solution in an organic solvent. The organic solvent used for dissolving the acid is selected from the group consisting of ethanol, methanol, isopropyl alcohol, ethyl acetate, diethyl ether, dimethyl ether and acetone.
In one embodiment, the deprotection in step-(c) is carried out in the presence of a solvent or a mixture of solvents. Exemplary solvents used for deprotection in step-(c) include, but are not limited to, water, an alcohol, a ketone, a halogenated solvent, an ester, a hydrocarbon solvent, an ether, a nitrile, a polar aprotic solvent, and mixtures thereof.
Specifically, the solvent used in step-(c) is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, acetone, methyl isobutyl ketone, dichloromethane, dichloroethane, chloroform, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and mixtures thereof. Most specific solvents are water, dichloromethane, methanol, ethanol, isopropyl alcohol, and mixtures thereof.
In one embodiment, the deprotection in step-(c) is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 20°C to about 50°C, and more specifically at a temperature of about 20°C to about 45°C. The reaction time may vary from about 15 minutes to about 12 hours, specifically from about 20 minutes to about 4 hours, and more specifically from about 30 minutes to about 3 hours.

The reaction mass containing the (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one of formula 2 obtained in step-(c) may be subjected to usual work up, and followed by isolating and/or recrystallizing from a suitable solvent by the methods as described hereinabove.
In one embodiment, the isolation of (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one of formula 2 is carried out by cooling the reaction mass while stirring at a temperature below about 30°C and more specifically at about 0°C to about 25°C.
The conversion of the intermediate compound of formula 2 into Cadazolid or a pharmaceutically acceptable salt thereof in step-(c) can be carried out either as per the methods known in the prior art, for example, as per the processes described in the U.S. Patent No. 8,124,623, or as per the processes described herein.
According to another aspect, there is provided a process for the preparation of (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one of formula 2 or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, which comprises: a) reacting the 3-amino-2-hydroxypropyl derivative of formula 5:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein R is hydrogen or a hydroxyl protecting group Ri, and 'A5 represents a protecting group;
with a suitable activating agent, wherein the activating agent is an anhydride compound of formula 8a, or a chloroformate compound of formula 8b:

wherein R' is OR2 or CX3, wherein the radical R2 is C1.12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; and X is a halogen atom selected from F, CI, Br and I; to produce an N-protected compound of formula 4:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the groups R, R' and A are as defined above; and b) converting the N-protected compound of formula 4 obtained in step-(a) into the compound of formula 2 or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, by reacting with a suitable reagent or a combination of suitable reagents.
Advantageously, the above process steps-(a) and (b) can be carried out in a single pot.
In one embodiment, the group R in the compounds of formulae 4 and 5 is hydrogen. In another embodiment, the group R in the compounds of formulae 4 and 5 is a hydroxyl protecting group Ri selected from the group as described hereinabove.
In another embodiment, the protecting group 'A' in the compounds of formulae 4 and 5 is a hydroxyl protecting group selected from the group as described hereinabove.
Specific hydroxyl protecting groups are acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, trichloroacetyl, trifluoroacetyl, benzoyl, p-toluoyl,

p-anisoyl, trityl, o-nitrobenzyl, benzyl and p-methoxybenzyl; and most specifically acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl and benzyl.
In one embodiment, the group R' is OR2, wherein the radical R2 in the compounds of formulae 8a, 8b and 4 is methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, chloromethyl, phenyl, tolyl, benzyl, p-nitrobenzyl, dibromophenyl or p-methoxybenzyl; and most specifically R2 is ethyl or tert-butyl.
In one embodiment, the reaction in step-(a) is carried out in the presence of a solvent or a mixture of solvents. Exemplary solvents used in step-(a) include, but are not limited to, water, an alcohol, a hydrocarbon solvent, an ester, a ketone, an ether, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.
Specifically, the solvent used in step-(a) is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, acetone, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, dichloroethane, chloroform, and mixtures thereof. Most specific solvents are dichloromethane, methanol, ethanol, isopropyl alcohol, and mixtures thereof.
In another embodiment, the reaction in step-(a) is optionally carried out in the presence of a base. Specifically, the base is an organic or inorganic base, specifically an organic base, selected from the group as described hereinabove.
In one embodiment, the activating agent in step-(a) is used in a ratio of about 1 to 3 equivalents, specifically about 1.1 to 1.5 equivalents, with respect to the 3-amino-2-hydroxypropyl compound of formula 5 in order to ensure a proper course of the reaction.
In one embodiment, the reaction in step-(a) is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 15°C to the reflux temperature of the solvent used, and most specifically at a temperature of about 20°C to about 40°C. The reaction time may vary between about 20 minutes to about 30 hours, specifically about 2 hours to about 20 hours, and more specifically about 3 hours to about 6 hours.
The reaction mass containing the N-protected compound of formula 4 obtained in step-(a) may be subjected to usual work up methods as described above. The reaction mass

may be used directly in the next step to produce the compound of formula 2, or the compound of formula 4 may be isolated and/or recrystallized from a suitable solvent by conventional methods, as described hereinabove, and then used in the next step.
In one embodiment, the reaction mass or residue containing the N-protected compound of formula 4 is used directly in the next step to produce the compound of formula 2.
The solvent used for isolating and/or recrystallizing the N-protected compound of formula 4 is selected from the group as described hereinabove for such purpose.
In one embodiment, a specific N-protected compound of formula 4 prepared by the process described herein is (2R)-3-[N-(ethoxycarbonyl)-N-(4-benzyloxy-3-fluoro-phenyl)]-amino-2-hydroxy-propyl butanoate of formula 4a (formula 4, wherein R is butyryl, R' is ethoxy and A is benzyl):
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof.
In another embodiment, a specific N-protected compound of formula 4 prepared by the process described herein is tert-butyl (R)-N-[(2,3-dihydroxy-propyl)-N-(4-benzyloxy-3-fluoro-phenyl)]-carbamate of formula 4b (formula 4, wherein R is hydrogen, R' is tert-butoxy and A is benzyl):
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof.
In another embodiment, a specific N-protected compound of formula 4 prepared by the process described herein is (2R)-3-[N-(ethoxycarbonyl)-N-(4-acetyloxy-3-fluoro-

phenyl)]-amino-2-hydroxy-propyl butanoate of formula 4c (formula 4, wherein R is butyryl, R' is ethoxy and A is acetyl):
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof.
In another embodiment, a specific N-protected compound of formula 4 prepared by the process described herein is (2R)-3-[N-(ethoxycarbonyl)-N-(4-acetyIoxy-3-fluoro-phenyl)]-amino-2-hydroxy-propyl acetate of formula 4d (formula 4, wherein R is acetyl, R' is ethoxy and A is acetyl):
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof.
The conversion in step-(b) is carried out by subjecting the N-protected compound of formula 4 to hydrolysis, hydrogenolysis, or a combination thereof.
In one embodiment, the conversion in step-(b) is carried out by treating the N-protected compound of formula 4 with a suitable reagent such as an acid, a base, or a combination thereof, in an inert solvent.
Specifically, the conversion in step-(b) is carried out by treating the N-protected compound of formula 4 with a suitable base. The base used for cyclization in step-(b) is an organic or an inorganic base selected from the group as described above.
Specific bases are collidine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide. Most specific bases are sodium carbonate or potassium carbonate.

In another embodiment, the cyclized compound obtained in step-(b) may be, optionally, required to be deprotected by hydrogenolysis under hydrogen pressure using a a suitable metal catalyst selected from the group as described hereinabove.
In one embodiment, the conversion in step-(b) is carried out in the presence of a solvent or a mixture of solvents. Exemplary solvents used for conversion in step-(b) include, but are not limited to, water, an alcohol, a halogenated solvent, as ester, a hydrocarbon solvent, an ether, a nitrile, a polar aprotic solvent, and mixtures thereof. Most specific solvents are water, dichloromethane, methanol, ethanol, isopropyl alcohol, and mixtures thereof.
The reaction mass containing the (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one of formula 2 obtained in step-(b) may be subjected to usual work up, and followed by isolating and/or recrystallizing from a suitable solvent by the methods as described hereinabove.
The solids obtained in any of the above process steps may be collected by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof. For example, the compound of formula 2 obtained by the processes disclosed herein 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. 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 80°C.
The intermediate compound, (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-
(hydroxymethyl)-oxazolidin-2-one, of formula 2 obtained by the processes disclosed herein has a total purity, both chemical and enantiomeric purity, of greater than about 95%, specifically greater than about 98%, more specifically greater than about 99%, and most specifically greater than about 99.5% as measured by HPLC.
Aptly the processes of the invention are adapted to the production of 5-(hydroxymethyl)-oxazolidin-2-one derivatives, preferably Cadazolid, in high yield and high enantiomeric and chemical purity.
Cadazolid or a pharmaceutical^ acceptable salt thereof can be prepared in high purity by using the substantially pure (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-

(hydroxymethyl)-oxazolidin-2-one of formula 2 or a salt thereof obtained by the methods disclosed herein, by known methods.
According to another aspect, there is provided a 3-amino-2-hydroxypropyl derivative of formula 5:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein R is hydrogen or a hydroxyl protecting group Rj; and A' represents a protecting group.
In one embodiment, the group R in the compound of formula 5 is hydrogen. In another embodiment, the group R in the compound of formula 5 is a hydroxyl protecting group Ri, wherein the radical R\ is selected from the group as described above. In another embodiment, the protecting group CA' in the compounds of formulae 5 is a hydroxyl protecting group.
In one embodiment, the hydroxyl protecting groups CA' and 'Ri5, each independently, are selected from the group consisting of formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, succinoyl, glutaroyl, adipoyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, cyclopropylcarbonyl, cyclobutylcarbonyl, methoxyacetyl, benzoyl, a-naphthoyl, b-naphthoyl, pyridoyl, furoyl, 2-bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, p-toluoyl, p-anisoyl, 2-carboxybenzoyl, p-nitrobenzoyl, trityl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofiiranyl, o-nitrobenzyl, benzyl, p-methoxybenzyl, trimethylsilyl, triisopropylsilyl and t-butyldiphenylsilyl.
Specifically, the hydroxyl protecting groups 'A' and 'Ri', each independently, are selected from the group consisting of acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, trichloroacetyl, trifluoroacetyl, benzoyl, p-toluoyl, p-anisoyl, trityl, o-nitrobenzyl, benzyl and p-methoxybenzyl; and most specifically acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl and benzyl.

According to another aspect, there is provided an N-protected compound of formula 4:
or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is hydrogen or a hydroxyl protecting group Ri, and 'A5 represents a protecting group; and wherein R' is OR2 or CX3, wherein the radical R2 is C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; and X is a halogen atom selected from F, CI, Br and I.
In one embodiment, the group R in the compounds of formula 4 is hydrogen. In another embodiment, the group R in the compounds of formula 4 is a hydroxyl protecting group Ri, wherein Ri is selected from the group as described above.
Specific hydroxyl protecting groups are acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, trichloroacetyl, trifluoroacetyl, benzoyl, p-toluoyl, p-anisoyl, trityl, o-nitrobenzyl, benzyl and p-methoxybenzyl; and most specifically acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl and benzyl.
In one embodiment, the group R' is OR2, wherein the radical R2 is methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, chloromethyl, phenyl, tolyl, benzyl, p-nitrobenzyl, dibromophenyl or p-methoxybenzyl; and most specifically R2 is. ethyl or tert-butyl.
According to another aspect, there is provided a process for the preparation of (R)-5-chloromethyl-3-(3-fluoro-4-hydroxy-phenyl)-oxazolidin-2-one of formula 9:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, .
which comprises:
a) reacting a substituted-aniline compound of formula 7:

or a salt thereof, wherein the group ' A' represents a protecting group; with (R)-epichlorohydrin of formula 12:
or an enantiomeric form or a mixture of enantiomeric forms thereof, to produce a 3-chIoro-2-hydroxy-propyl derivative of formula 11:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the group 'A' is as defined in formula 7; b) subjecting the compound of formula 11 to carbonylation by reacting with a suitable carbonylating agent to produce a chloromethyl-oxazolidinone compound of formula 10:
or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein the group A is as defined above; and c) deprotecting the compound of formula 10 to produce the compound of formula 9 or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, and

optionally converting the compound of formula 9 into Cadazolid or a pharmaceutically acceptable salt thereof.
Unless otherwise specified, the Cadazolid intermediate compounds of formulae 9, 10 and 11, each independently, contains one chiral centre and thus exists as two optical isomers, i.e. enantiomers (R & S-isomers). The process disclosed herein encompasses the preparation of both enantiomers and mixtures thereof in all proportions.
The protecting group 'A' in the compounds of formulae 7, 10 and 11 is a hydroxyl protecting group selected from group as described hereinabove.
In one embodiment, the hydroxyl protecting group CA' is selected from the group consisting of formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, succinoyl, glutaroyl, adipoyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, cyclopropylcarbonyl, cyclobutylcarbonyl, methoxyacetyl, benzoyl, a-naphthoyl, b-naphthoyl, pyridoyl, furoyl, 2-bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, p-toluoyl, p-anisoyl, 2-carboxybenzoyl, p-nitrobenzoyl, trityl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, o-nitrobenzyl, benzyl, p-methoxybenzyl, trimethylsilyl, triisopropylsilyl and t-butyldiphenylsilyl.
Specifically, the hydroxyl protecting group 'A5 is selected from the group consisting of acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, trichloroacetyl, trifluoroacetyl, benzoyl, p-toluoyl, p-anisoyl, trityl, o-nitrobenzyl, benzyl and p-methoxybenzyl; and most specifically acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl and benzyl."
In one embodiment, the reaction in step-(a) is carried out in the presence of a solvent or a mixture of solvents.
Exemplary solvents used in step-(a) include, but are not limited to, an alcohol, water, an ether, a polar aprotic solvent, and mixtures thereof. Specifically, the solvent used in step-(a) is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, N,N-dimethylformamide, N,N-dimethylacetamide, and mixtures thereof. Most specific solvents are methanol, ethanol, isopropyl alcohol, and mixtures thereof.

In another embodiment, the reaction in step-(a) is optionally carried out in the presence of a base. Specifically, the base is an organic or inorganic base selected from the group as described hereinabove. Specific bases are sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide.
The reaction temperature and time period will ordinarily depend on the starting compounds and the solvent employed in the reaction.
In one embodiment, the reaction in step-(a) is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 30°C to the reflux temperature of the solvent used, and more specifically at the reflux temperature of the solvent used. The reaction time may vary between about 2 hours to about 30 hours, specifically about 5 hours to about 25 hours, and more specifically about 12 hours to about 20 hours.
The reaction mass containing the 3-chloro-2-hydroxy-propyl compound of formula 11 obtained instep-(a) may be subjected to usual work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula 10, or the compound of formula 11 may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the 3-chloro-2-hydroxy-propyl compound of formula 11 is 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, a specific 3-chloro-2-hydroxy-propyl derivative of formula 11 prepared by the process described herein is N-[3-chloro-2(R)-hydroxy-propyl]-4-acetyloxy-3-fluoro-aniline of formula 1 la (formula 11, wherein A is acetyl):
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof.

In another embodiment, a specific 3-chloro-2-hydroxy-propyl derivative of formula 1.1 prepared by the process described herein is N-[3-chloro-2(R)-hydroxy-propyl]-4-benzyloxy-3-fluoro-aniline of formula 1 lb (formula 11, wherein A is benzyl):
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof
In one embodiment, the reaction in step-(b) is carried out in the presence of a solvent or a mixture of solvents.
Exemplary solvents used in step-(b) include, but are not limited to, an alcohol, a hydrocarbon solvent, an ether, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof
Specifically, the solvent used in step-(b) is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, dichloromethane, dichloroethane, chloroform, and mixtures thereof Most specific solvents are dichloromethane, methanol, ethanol, isopropyl alcohol, and mixtures thereof
The carbonylation reaction in step-(b) is performed by reacting with a suitable carbonylating agent commonly known for such purpose.
Exemplary carbonylating agents used in step-(b) include, but are not limited to, N,N'-carbonyldiimidazole, phosgene, diphosgene, triphosgene, dialkyl carbonates, substituted or unsubstituted alkyl chloroformates, substituted or unsubstituted aryl chloroformates, substituted or unsubstituted aralkyl chloroformates, and the like.
Specific carbonylating agents used in step-(b) are N,N'-carbonyldiimidazole, diethyl carbonate, di-tert-butyl dicarbonate (BOC anhydride), phenyl chloroformate and benzyl chloroformate; and most specifically N,N'-carbonyldiimidazole, diethyl carbonate and di-tert-butyl dicarbonate (BOC anhydride).

In one embodiment, the carbonylating agent in step-(b) is used in a ratio of about 1 to 5 equivalents, specifically about 1 to 1.5 equivalents, with respect to the 3-amino-2-hydroxypropyl compound of formula 11 in order to ensure a proper course of the reaction.
In another embodiment, the reaction in step-(b) is optionally carried out in the presence of a base. Specifically, the base is an organic or inorganic base, and most specifically an organic base, selected from the group as described hereinabove.
In one embodiment, the reaction 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 15°C to the reflux temperature of the solvent used, and most specifically at a temperature of about 25°C to the reflux temperature of the solvent used. The reaction time may vary between about 1 hour to about 25 hours, specifically about 2 hours to about 22 hours, and more specifically about 6 hours to about 12 hours.
In another embodiment, the resulting compound obtained after completion of the carbonylation reaction step-(b) may be, optionally, required to be treated with a suitable base or an acid, in a suitable solvent, in order to obtain the oxazolidinone compound of formula 10. Specifically, the base used for such purpose is an inorganic base selected from the group as described herein above and wherein the solvent used is an alcohol solvent. Most specifically, the inorganic base is sodium carbonate or potassium carbonate, and the solvent is methanol.
The reaction mass containing the chloromethyl-oxazolidinone compound of formula 10 obtained in step-(b) may be subjected to usual work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula 9, or the compound of formula 10 may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the chloromethyl-oxazolidinone compound of formula 10 is isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The removal of protecting groups in step-(c) can be achieved by conventional methods as described hereinabove.
For example, the deprotection in step-(c) is performed by subjecting the N-protected compound of formula 10 to hydrolysis, hydrogenolysis, or a combination thereof.

In one embodiment, the deprotection in step-(c) is carried out by treating the oxazolidinone compound of formula 10 with a suitable deprotecting agent such as an acid or a base, in a reaction inert solvent.
Specifically, the deprotection in step-(c) is carried out by treating the oxazolidinone compound of formula 10 with a base.
In another embodiment, the deprotection in step-(c) is carried out by subjecting the oxazolidinone compound of formula 10 to hydrogenolysis under hydrogen pressure in the presence of a metal catalyst such as zinc, nickel, palladium, palladium on carbon, and the like.
The base used for deprotection is an organic or an inorganic bas selected from the group as described hereinabove. Specific bases are collidine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide.
The acid used for deprotection in step-(c) is an organic or an inorganic acid. Exemplary acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, formic acid, and the like, or a combination thereof. A most specific acid is hydrochloric acid.
In one embodiment, the deprotection in step-(c) is carried out in the presence of a solvent or a mixture of solvents. Exemplary solvents used for deprotection in step-(c) include, but are not limited to, water, an alcohol, a ketone, a halogenated solvent, an ester, a hydrocarbon solvent, an ether, a nitrile, a polar aprotic solvent, and mixtures thereof.
Specifically, the solvent used in step-(c) is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, acetone, methyl isobutyl ketone, dichloromethane, dichloroethane, chloroform, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, acetonitrile, propionitrile, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, and mixtures thereof. Most specific solvents are water, dichloromethane, methanol, ethanol, isopropyl alcohol, and mixtures thereof.
In one embodiment, the deprotection in step-(c) is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of

about 20°C to about 50°C, and more specifically at a temperature of about 20°C to about 45°C. The reaction time may vary from about 1 hour to about 15 hours, specifically from about 2 hours to about 8 hours, and more specifically from about 4 hours to about 7 hours.
The reaction mass containing the (R)-5-chloromethyl-3-(3-fluoro-4-hydroxy-phenyl)-oxazolidiri-2-one of formula 9 obtained in step-(c) may be subjected to usual work up, and followed by isolating and/or recrystallizing from a suitable solvent by the methods as described hereinabove.
In one embodiment, the isolation of (R)-5-chloromethyl-3-(3-fluoro-4-hydroxy-phenyl)-oxazolidin-2-one of formula 9 is carried out by cooling the reaction mass while stirring at a temperature below about 30°C and more specifically at about 0°C to about 25°C.
The conversion of the intermediate compound of formula 9 into Cadazolid or a pharmaceutically acceptable salt thereof in step-(c) can be carried out as per the processes described hereinafter.
According to another aspect, there is provided a process for the preparation of (R)-5-chloromethyl-3-(3-fluoro-4-hydroxy-phenyl)-oxazolidin-2-one of formula 9 of an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, which comprises: a) reacting the 3-chloro-2-hydroxy-propyl derivative of formula 11:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the group 'A' represents a protecting group;
with a suitable activating agent, wherein the activating agent is an anhydride compound . of formula 8a, or a chloroformate compound of formula 8b:

wherein R" is 0R2 or CX3, wherein the radical R2 is C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; and X is a halogen atom selected from F, CI, Br and I; to produce an N-protected compound of formula 18:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the groups A and R' are as defined above; and b) converting the N-protected compound of formula 18 obtained in step-(a) into the compound of formula 9 or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, by reacting with a suitable reagent or a combination of suitable reagents.
Advantageously, the above process steps-(a) and (b) can be carried out in a single pot.
In another embodiment, the protecting group 'A' in the compounds of formulae 11 and 18 is a hydroxyl protecting group selected from the group as described hereinabove.
Specific hydroxyl protecting groups are acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, trichloroacetyl, trifluoroacetyl, benzoyl, p-toluoyl, p-anisoyl, trityl, o-nitrobenzyl, benzyl and p-methoxybenzyl; and most specifically acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl and benzyl.
In one embodiment, the group R' is OR2, wherein the radical R2 in the compounds of formulae 8a, 8b and 18 is methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl,

chloromethyl, phenyl, tolyl, benzyl, p-nitrobenzyl, dibromophenyl or p-methoxybenzyl; and most specifically R2 is ethyl or tert-butyl.
In one embodiment, the reaction in step-(a) is carried out in the presence of a solvent or a mixture of solvents. Exemplary solvents used in step-(a) include, but are not limited to, water, an alcohol, a hydrocarbon solvent, an ester, a ketone, an ether, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.
Specifically, the solvent used in step-(a) is selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl methyl acetate, ethyl formate, acetone, cyclohexane, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, N,N-dimethylformamide, N,N^ dimethylacetamide, dichloromethane, dichloroethane, and mixtures thereof. Most specific solvents are dichloromethane, methanol, ethanol, isopropyl alcohol, and mixtures thereof.
In another embodiment, the reaction in step-(a) is optionally carried out in the presence of a base. Specifically, the base is an organic or inorganic base, specifically an organic base, selected from the group as described hereinabove.
In one embodiments the activating agent in step-(a) is used in a ratio of about 1 to 3 equivalents, specifically about 1.1 to 1.5 equivalents, with respect to the 3-chloro-2-hydroxy-propyl derivative of formula 11 in order to ensure a proper course of the reaction.
In one embodiment, the reaction in step-(a) is carried out at a temperature of about 0°C to the reflux temperature of the solvent used, specifically at a temperature of about 15°C to the reflux temperature of the solvent used, and most specifically at a temperature of about 20°C to about 40°C. The reaction time may vary between about 20 minutes to about 30 hours, specifically about 2 hours to about 20 hours, and more specifically about 3 hours to about 6 hours.
The reaction mass containing the N-protected compound of formula 18 obtained in step-(a) may be subjected to usual work up methods as described above. The reaction mass may be used directly in the next step to produce the compound of formula 9, or the compound of formula 18 may be isolated and/or recrystallized from a suitable solvent by conventional methods, as described hereinabove, and then used in the next step.

In one embodiment, the reaction mass or residue containing the N-protected compound of formula 18 is used directly in the next step to produce the compound of formula 9.
The solvent used for isolating and/or recrystallizing the N-protected compound of formula 9 is selected from the group as described hereinabove for such purpose.
In one embodiment, a specific 3-chloro-2-hydroxy-propyl derivative of formula 18 prepared by the process described herein is N-[3-chIoro-2(R)-hydroxy-propyl]-N-(ethoxycarbonyl)-4-acetyloxy-3-fluoro-aniline of formula 18a (formula 18, wherein R' is ethoxy and A is acetyl):
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof.
In another embodiment, a specific 3-chloro-2-hydroxy-propyl derivative of formula 18 prepared by the process described herein is N-[3-chloro-2(R)-hydroxy-propyI]-N-(tert-butyloxycarbonyl)-4-acetyloxy-3-fluoro-aniline of formula 18b (formula 18, wherein R' is tert-butyloxy and A is acetyl):
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof.
The conversion in step-(b) is carried out by subjecting the N-protected compound of formula 18 to hydrolysis, hydrogenolysis, or a combination thereof.
In one embodiment, the conversion in step-(b) is carried out by treating the N-protected compound of formula 18 with a suitable reagent such as an acid, a base, or a combination thereof, in a reaction inert solvent.

Specifically, the conversion in step-(b) is carried out by treating the N-protected compound of formula 18 with a suitable base. The base used for cyclization in step-(b) is an organic or an inorganic base selected from the group as described above. Most specific bases are sodium carbonate or potassium carbonate.
In another embodiment, the cyclized compound obtained in step-(b) may be, optionally, required to be deprotected by hydrogenolysis under hydrogen pressure using a suitable metal catalyst selected from the group as described hereinabove.
In one embodiment, the conversion in step-(b) is carried out in the presence of a solvent or a mixture of solvents. Exemplary solvents used for conversion in step-(b) include, but are not limited to, water, an alcohol, a halogenated solvent, as ester, a hydrocarbon solvent, an ether, a nitrile, a polar aprotic solvent, and mixtures thereof. Most specific solvents are water, dichloromethane, methanol, ethanol, isopropyl alcohol, and mixtures thereof.
The reaction mass containing the compound of formula 9 obtained in step-(b) may be subjected to usual work up, and followed by isolating and/or recrystallizing from a suitable solvent by the methods as described hereinabove.
The solids obtained in any of the above process steps may be collected by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof. For example, the compound of formula 9 obtained by the processes disclosed herein above 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.
The intermediate compound, (R)-5-chloromethyl-3-(3-fluoro-4-hydroxy-phenyl)-oxazolidin-2-one of formula 9 obtained by the processes disclosed herein has a total purity, both chemical and enantiomeric purity, of greater than about 95%, specifically greater than about 98%, more specifically greater than about 99%, and most specifically greater than about 99.5% as measured by HPLC.
Aptly the processes of the invention are adapted to the production of 5-(hydroxymethyl)-oxazolidin-2-one derivatives, preferably Cadazolid, in high yield and high enantiomeric and chemical purity.
According to another aspect, there is provided a process for the preparation of Cadazolid of formula 1:

or an enantiomeric form or a mixture of enantiomeric forms thereof, or a pharmaceutically acceptable salt thereof, which comprises:
a) reacting (R)-5-chloromethyl-3-(3-fluoro-4-hydroxy-phenyl)-oxazolidin-2-one of formula 9:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, with a l-oxa-6-aza-spiro[2.5]octane compound of formula 13:
wherein the group G represents a nitrogen-protecting group; to produce the compound of formula 15:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the group G is as defined in formula 13; b) deprotecting the compound of formula 15 obtained in step-(a) by reacting with a suitable reagent to produce the compound of formula 14:

or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof; c) condensing the compound of formula 14 with a 3-quinolinecarboxylic acid derivative of formula 19:
or a salt or a complex thereof, wherein the group P represents hydrogen atom or an alkyl group Pi; to produce the compound of formula 16:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the group P represents hydrogen atom or an alkyl group Pi; d) reacting the compound of formula 16 obtained in step-(c) with a suitable reagent to produce the compound of formula 17:

or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the group P represents hydrogen atom or an alkyl group Pi; and P2 represents an alkyl group; and e) reacting the compound of formula 17 with a suitable reagent to produce Cadazolid of formula 1, and optionally converting the compound of formula 1 obtained into its pharmaceutical^ acceptable salts thereof.
Exemplary nitrogen protecting group 'G' in the compounds of formulae 13 and 15 includes, but are not limited to, a substituted or unsubstituted aralkyl, a substituted or unsubstituted trityl, an aliphatic acyl group including an alkanoyl group, an aromatic acyl group including an arylcarbonyl group, an alkoxycarbonyl group, and the like.
In one embodiment, the nitrogen-protecting groups CG' is selected from the group
consisting of methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl,
isopropyloxycarbonyl, tert-butyloxycarbonyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, cyclopropylcarbonyl, cyclobutylcarbonyl, benzoyl, 4-chlorobenzoyl, p-nitrobenzoyl, trityl, ~ benzyl and the like.
Specifically, the nitrogen-protecting groups 'G' is selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl and benzyl.
In one embodiment, the group P in the compounds of formulae 16, 17, and 19 is hydrogen.
Specifically, the compound of formula 19 is employed in the form of a complex, and most specifically in the form of boron diacetate complex.

In another embodiment, the group P in the compounds of formulae 16, 17, and 19 is an alkyl group Pi selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl. Most specifically, Pi is ethyl or methyl.
In another embodiment, the group P2 in the compound of formula 17 is an alkyl group selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl. A most specific alkyl group P2 is methyl.
The reaction in the above process steps (a), (b), (c), (d) and (e) may be, each independently, carried out in the presence or absence of a solvent, wherein the solvent used may be same or different.
In one embodiment, the solvent used in the above process steps (a), (b), (c), (d) and (e) may, each independently, include, but are not limited to, waterman alcohol, a ketone, a hydrocarbon solvent, an ester, a nitrile solvent, an ether, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof.
Specifically, the solvent used in the above process steps (a), (b), (c), (d) and (e) may be, each independently, selected from the group consisting of water, methanol, ethanol, isopropyl alcohol, n-butyl alcohol, acetone, ethyl acetate, toluene, xylene, tetrahydrofuran, 2-methyl tetrahydrofuran, dioxane, diethyl ether, diisopropyl ether, methyl tert-butyl ether, monoglyme, diglyme, N,N-dimethylformamide, N,N-dimethylacetamide, dichloromethane, dichloroethane, chloroform, and mixtures thereof. Most specific solvents are methanol, ethanol, isopropyl alcohol, and mixtures thereof.
In one embodiment, the deprotection in step-(b) is carried out by treating the chloromethyl-oxazolidinone compound of formula 15 with a suitable deprotecting agent such as an acid or a base, in a reaction inert solvent.
Specifically, the deprotection in step-(b) is carried out by treating the oxazolidinone compound of formula 15 with an acid.
• In another embodiment, the deprotection in step-(b) may be carried out by subjecting the oxazolidinone compound of formula 15 to hydrogenolysis under hydrogen pressure in the presence of a suitable metal catalyst as described hereinabove.
The base used for deprotection is an organic or an inorganic base selected from the group as described hereinabove. Specific bases are collidine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium

carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide.
The acid used for deprotection in step-(b) is an organic or an inorganic acid. Exemplary acids include, but are not limited to, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, formic acid, and the like, or a combination thereof. A most specific acid is hydrochloric acid.
For example, the acid used may be in the form of aqueous solutions or in the form of a solution in an organic solvent. The organic solvent used for dissolving the acid is selected from the group consisting of ethanol, methanol, isopropyl alcohol, ethyl acetate, diethyl ether, dimethyl ether and acetone.
Exemplary reagents used in step-(d) include, but are not limited, sodium acetate, potassium acetate, sodium propionate, potassium propionate, and the like. A most specific reagent used in step-(d) is sodium acetate.
In one embodiment, the reagents used in step-(e) include, but are not limited to, organic or inorganic bases. Specific bases are collidine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide.
The reaction in the above process steps (a), (b), (c), (d) and (e) may optionally be carried out in the presence or absence of a base, wherein the base used may be same or different selected from the group as described hereinabove.
The reaction temperature and time periods in the above process steps (a), (b), (c), (d) and (e) will ordinarily depend on the starting compounds and the solvent employed in the. reaction. In one embodiment, the reactions in the above process steps (a), (b), (c), (d) and (e) may be, each independently, carried out at a temperature of about 0°C to the reflux temperature of the solvent used and specifically at a temperature of about 30°C to the reflux temperature of the solvent used.
The reaction mass containing the compounds of formulae 14, 15, 16 and 17 obtained in the above process steps may be subjected to usual work up such as washing, extraction, pH adjustment, evaporation, layer separation, decolorization, or a combination thereof. The reaction mass may be used directly in the next step, or the compounds may be isolated and/or recrystallized and then used in the next step.

In one embodiment, the compounds of formulae 1, 14, 15, 16 and 17 are 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.
According to another aspect, there is provided a process for the preparation of Cadazolid of formula 1 or an enantiomeric form or a mixture of enantiomeric forms thereof, or a pharmaceutically acceptable salt thereof, which comprises: a) reacting (R)-5-chloromethyl-3-(3-fluoro-4-hydroxy-phenyl)-oxazolidin-2-one of formula 9:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, with a compound of formula 20:
wherein the group P represents hydrogen atom or an alkyl group Pi; to produce the compound of formula 16:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the group P represents hydrogen atom or an alkyl group Pi:

b) reacting the compound of formula 16 obtained in step-(a) with a suitable reagent to produce the compound of formula 17:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the group P represents hydrogen atom or an alkyl group Pi; and P2 represents an alkyl group; and c) reacting the compound of formula 17 with a suitable reagent to produce Cadazolid of formula 1, and optionally converting the compound of formula 1 obtained into its pharmaceutical^ acceptable salts thereof.
In one embodiment, the group P in the compounds of formulae 16, 17 and 20 is hydrogen.
In another embodiment, the group P in the compounds of formulae 16, 17 and 20 is an alkyl group Pi selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl. A most specific alkyl group Pi is ethyl or methyl.
In another embodiment, the group P2 in the compound of formula 17 is an alkyl group selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl. A most specific alkyl group P2 is methyl.
The reaction in the above process steps (a), (b) and (c), may be, each independently, carried out in the presence or absence of a solvent, wherein the solvent used may be same or different.
In one embodiment, the solvent used in the above process steps (a), (b) and (c) may, each independently, include, but are not limited to, water, an alcohol, a ketone, a hydrocarbon solvent, an ester, a nitrile solvent, an ether, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof. Most specific solvents are water, methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, toluene and mixtures thereof.

Exemplary reagents used in step-(b) include, but are not limited, sodium acetate, potassium acetate, sodium propionate, potassium propionate, and the like. A most specific reagent used in step-(b) is sodium acetate.
In one embodiment, the reagents used in step-(c) include, but are not limited to, organic or inorganic bases. Specific bases are collidine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide.
The reaction in the above process steps (a) and (b) may optionally be carried out in the presence or absence of a base, wherein the base used may be same or different selected from the group as described hereinabove.
The reaction temperature and time periods in the above process steps (a), (b) and (c) will ordinarily depend on the starting compounds and the solvent employed in the reaction. In one embodiment, the reactions in the above process steps (a), (b) and (c) may be, each independently, carried out at a temperature of about 0°C to the reflux temperature of the solvent used and specifically at a temperature of about 10°C to the reflux temperature of the solvent used.
The reaction mass containing the compounds of formulae 1, 16 and 17 obtained in the above process steps may be subjected to usual work up as described hereinabove. The reaction mass may be used directly in the next step, or the compounds may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compounds of formulae 1, 16 and 17 are isolated and/or re-crystallized from a suitable solvent by as described hereinabove.
According to one aspect, there is provided a process for the preparation of (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one of formula 2:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof,
»
which comprises:

a) reacting (R)-5-chloromethyl-3-(3-fluoro-4-hydroxy-phenyl)-oxazolidin-2-one of formula 9 or an ester derivative of formula 10a:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein P2 represents an alkyl group, with a suitable reagent to produce the compound of formula 21:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof,
wherein P2 represents an alkyl group; and b) reacting the compound of formula 21 with a suitable reagent to produce the compound
of formula 2, and optionally converting the compound of formula 2 obtained into
Cadazolid or a pharmaceutically acceptable salts thereof.
In another embodiment, the group P2 in the compounds of formulae 10a and 21 is an alkyl group, each independently, selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl. A most specific alkyl group P2 is methyl.
The reaction in the above process steps (a) and (b) may be, each independently, carried out in the presence or absence of a solvent, wherein the solvent used may be same or different.
In one embodiment, the solvent used in the above process steps (a) and (b) may, each independently, include, but are not limited to, water, an alcohol, a ketone, a hydrocarbon solvent, an ester, a nitrile solvent, an ether, a polar aprotic solvent, a halogenated hydrocarbon solvent, and mixtures thereof. Most specific solvents are water,

methanol, ethanol, isopropyl alcohol, dichloromethane, acetone, toluene and mixtures thereof.
Exemplary reagents used in step-(a) include, but are not limited, sodium acetate, potassium acetate, sodium propionate, potassium propionate, and the like. A most specific reagent used in step-(a) is sodium acetate.
In one embodiment, the reagents used in step-(b) include, but are not limited to, organic or inorganic bases. Specific bases are collidine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide.
The reaction temperature and time periods in the above process steps (a) and (b) will ordinarily depend on the starting compounds and the solvent employed in the reaction. In one embodiment, the reactions in the above process steps (a) and (b) may be, each independently, carried out at a temperature of about 0°C to the reflux temperature of the solvent used and specifically at a temperature of about 10°C to the reflux temperature of the solvent used.
The reaction mass containing the compounds of formulae 2 and 21 obtained in the above process steps may be subjected to usual work up as described hereinabove. The reaction mass may be used directly in the next step, or the compounds may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compounds of formulae 2 and 21 are isolated and/or re-crystallized from a suitable solvent by as described hereinabove.
The compounds of formulae 9, 10, 10a, 11, 14, 15, 16, 17 and 18, or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, disclosed herein are novel and forms another aspect of the present invention.
The use of the compounds of formulae 9, 10, 10a, 11, 14, 15, 16, 17 and 18, or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, in the process for manufacture of Cadazolid described herein is also novel and forms further aspect of the present invention.
The use of inexpensive, non-explosive, non-hazardous, readily available and easy to handle reagents and solvents allows the processes disclosed herein to be suitable for preparation of the Cadazolid of formula 1 at lab scale and in commercial scale operations.

The compounds of formulae 3, 4, 5, 6 and 6a, 9, 10, 10a, 11, 12, 14, 15, 16, 17 and 18 have the right stereochemical configuration to produce the Cadazolid of formula 1. The stereochemical configurations of the formulae 3, 4, 5, 6 and 6a, 9, 10, 10a, 11, 12, 14, 15, 16, 17 and 18 are retained throughout the sequence of reactions of the invention. However, it is readily apparent to one skilled in the art that one could easily perform the identical process steps with the opposite enantiomeric form, or a racemic form thereof, to produce the corresponding stereo isomers.
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 "room temperature" or "RT" refer to a temperature of about 20°C to about 35°C, preferably to a temperature of about 25°C to about 30°C.
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 (2R)-3-(4-benzyloxy-3-fluoro-phenylamino)-2-hydroxy-propyl butanoate
4-Benzyloxy-3-fluoro-aniline (55 g), isopropyl alcohol (550 ml) and (R)-glycidyl butyrate (36.6 g) were taken into a reaction flask at room temperature (25-30°C), and the resulting mass was heated to reflux and then stirred for 28 hours at the same temperature. After completion of the reaction, the solvent was distilled under vacuum to obtain a residue. Diisopropyl ether (560 ml) was added to the residue at the room temperature and the resulting solution was heated to reflux, followed by stirring for 15 minutes at the same temperature. The reaction mass was cooled to 25-30°C and then stirred for 30 minutes at the same temperature. The separated solid was filtered and then washed with diisopropyl ether (100 ml) to produce 62 g of (2R)-3-(4-benzyloxy-3-fluoro-phenylamino)-2-hydroxy-propyl butanoate (Purity by HPLC: 98.6%).

Example 2 Preparation of (2R)-3-[N-(ethoxycarbonyl)-N-(4-benzyloxy-3-fluoro-phenyl)]-amino-2-hydroxy-propyl butanoate
Dichloromethane (55 ml), (2R)-3-(4-benzyloxy-3-fluoro-phenylamino)-2-hydroxy-propyl butanoate (5.5 g) and ethyldiisopropyl amine (3.0 g) were taken into a reaction flask at room temperature and the contents were stirred for 5 minutes at the same temperature. Ethyl chloroformate (2 g) was added drop-wise to the reaction mass at room temperature, followed by stirring mixture for 4 hours at the same temperature. Water (50 ml) was added to the reaction mass at room temperature and then stirred for 10 minutes at the same temperature. The resulting layers were separated and the organic layer was distilled under vacuum to produce 6.5 g of (2R)-3-[N-(ethoxycarbonyl)-N-(4-benzyloxy-3-fluoro-phenyl)]-amino-2-hydroxy-propyl butanoate as a residue.
Example 3 Preparation of (R)-3-(4-Benzyloxy-3-fluoro-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one
Methanol (32.5 ml), (2R)-3-[N-(ethoxycarbonyl)-N-(4-benzyloxy-3-fluoro-phenyl)]-amino-2-hydroxy-propyl butanoate (6.5 g) and potassium carbonate (1.0 g) were taken into a reaction flask at room temperature and the resulting solution was heated to reflux and then maintained for 2 hours at the same temperature. After completion of the reaction, the solvent was distilled under vacuum to produce 4 g of (R)-3-(4-Benzyloxy-3-fluoro-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one as a solid.
Example 4 Preparation of (R)-3-(3-Fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one
Ethyl acetate (150 ml), (R)-3-(4-benzyloxy-3-fluoro-phenyl)-5-hydroxymethyl-oxazolidin-2-one (5 g) and Pd/C (0.5 g) were taken into an autoclave. To the resulting mixture, Hydrogen pressure (4 kg/m ) was applied. The reaction mixture was heated to 38-42°C and then maintained for 1 hour at the same temperature. After completion of the reaction, Pd/C catalyst was filtered and the filtrate was washed with ethyl acetate (30 ml), followed by

distillation under vacuum to produce 2.5 g of (R)-3-(3-Fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one as a solid.
Example 5 Preparation of N-[3-Chloro-2(R)-hydroxy-propyl]-4-benzyloxy-3-fluoro-aniline
Methanol (570 ml), 4-benzyloxy-3-fluon>aniline (57 g) and (R)-epichlorohydrin (24.3 g) were taken into a reaction flask at room temperature. The reaction mass was heated to reflux and then stirred for 16 to 18 hours at the same temperature. After completion of the reaction, the solvent was distilled under vacuum to produce 73 g of N-[3-chloro-2(R)-hydroxy-propyl]-4-benzyloxy-3-fluoro-aniline as a residue.
Example 6 Preparation of (R)-5-(Chloromethyl)-3-(4-benzyloxy-3-fluoro-phenyl)«oxazolidin-2-one
Dichloromethane (800 ml) and N-[3-chloro-2(R)-hydroxy-propyl]-4-benzyloxy-3-fluoro-aniline (80 g) were taken into a reaction flask at room temperature. To the resulting mixture, a solution of carbonyldiimidazole (48.0 g) in dichloromethane (500 ml) was slowly added for 1 hour. The resulting solution was stirred for 9 to 10 hours at room temperature. After completion of the reaction, water (500 ml) was added to the reaction mass and then stirred for 10 minutes at the same temperature. The organic layer was washed with water (500 ml x 2). The organic layer was distilled under vacuum to obtain a residue. Ethanol (735 ml) was added to the residue and the resulting solution was heated for complete dissolution and then filtered the reaction mass. The resulting filtrate was cooled to 0-5 °C and then maintained for 30 minutes at the same temperature. The separated solid was filtered and then washed with chilled methanol (100 ml) to produce 51 g of (R)-5-(Chloromethyl)-3-(4-benzyloxy-3-fluoro-phenyl)-oxazolidin-2-oiie (Purity by HPLC: 99.4%).
Example 7 Preparation of (R)«5-(Chloromethyl)-3-(3-fluoro-4-hydroxy-phenyl)-oxazolidin-2-one
Ethyl acetate (600 ml), (R)-3-(4-benzyloxy-3-fluoro-phenyl)-5-(chloromethyl)-oxazolidin-2-one (20 g) and Pd/C (2 g) were taken into an autoclave at room temperature. To the resulting mass, hydrogen pressure (4 kg/m ) was applied at the room temperature. The

resulting mixture was heated to 38-42°C and then stirred for 4 to 6 hours at the same temperature. After completion of the reaction, Pd/C catalyst was filtered and the filtrate was washed with 50 ml of ethyl acetate, followed by distillation under vacuum to produce 16 g of (R)-5-(chloromethyl)-3-(3-fluoro-4-hydroxy-phenyl)-oxazolidin-2-one as a solid.
Example 8
Preparation of (R)-4-[2-Fluoro-4-(5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-
phenoxymethyl]-4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester
Dimethylformamide (200 ml), (R)-3-(3-Fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one (20 g), potassium carbonate (20 g) and l-oxa-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (24 g) were taken into a reaction flask. The resulting mixture was heated at 80-82°C and then stirred for 2 hours to 2 hours 30 minutes at the same temperature. After completion of the reaction, the reaction mass was cooled to room temperature, water (500 ml) was added to the mass and then stirred for 10 minutes at the same temperature. The aqueous layer was extracted twice with ethyl acetate (2 x 500 ml) and the resulting organic layer was washed with water (2 x 500 ml). The resulting organic layer was distilled under vacuum to produce crude product as solid (32 g). The resulting solid was taken in ethanol (213 ml) at room temperature and the mixture was heated to 75-80°C, followed by stirring for 10-15 minutes at the same temperature to form a clear solution. The reaction mass was filtered and then washed with ethanol (20 ml). The resulting filtrate was cooled to 0-5°C and then stirred for 30 minutes at the same temperature. The separated solid was filtered and then washed with chilled ethanol (30 ml) to produce (R)-4-[2-Fluoro-4-(5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxymethyl]-4-hydroxy-piperidine-l-carboxylic acid tert-butyl ester.
Example 9 Preparation of (R)-3-[3-Fluoro-4-(4-hydroxy-piperidin-4-yl-methoxy)-phenyl]-5-(hydroxymethyi)-oxazoIidin-2-one hydrochloride salt
(R)-4-[2-Fluoro-4-(5-hydroxymethyl-2-oxo-oxazolidin-3-yl)-phenoxymethyl]-4-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (10 g) was added to methanolic-HCl solution (100 ml) at 0-5°C and the mixture was stirred for 15-20 minutes at the same temperature. The temperature of the reaction mass was brought to 25-30°C and then stirred for 2 hours

30 minutes at the same temperature. The reaction mass was cooled to 0-5°C and then stirred for 30 minutes at the same temperature. The separated solid was filtered, washed with chilled methanol (10 ml) and then dried to produce 6 g of (R)-3-[3-Fluoro-4-(4-hydroxy-piperidin-4-yl-methoxy)-phenyl]-5«(hydroxymethyl)-oxazolidin-2-one hydrochloride salt (Purity by HPLC: 99.7%). The remaining filtrate ML's were evaporated under vacuum to produce 2g of the titled compound.
Example 10 Preparation of (R)-5-(AcetyIoxymethyl)"3-(3-fluoro-4-benzyloxy-phenyl)-oxazolidin-2-one
(R)-5-(Chloromethyl)-3-(3-fluoro-4-benzyloxy-phenyl)-oxazolidin-2-one (42 g), sodium acetate (26 g), toluene (840 ml) and tetra-n-butylammonium bromide (8.4 g) were taken into a reaction flask at room temperature (25-30°C), followed by heating the resulting mixture to reflux temperature and then stirring the mass for 16 hours at the same temperature. After completion of the reaction the reaction mass was cooled to room temperature and then filtered. The filtrate was distilled off under vacuum at 80-85°C to obtain a residue. Ethanol (382.5 ml) was added to the residue and the resulting mass was heated to reflux to form a clear solution. The resulting solution was stirred for 5 minutes at the same temperature and then cooled to room temperature. The resulting mass was again cooled to 0-5°C and then stirred for 30 minutes at the same temperature. The separated solid was filtered, washed with ethanol (50 ml) and then dried the material to produce 35 g of (R)-5-(acetyloxymethyl)-3-(3-fluoro-4-benzyloxy«phenyl)«oxazolidin-2-one.
Example 11 Preparation of (R)-5-(hydroxymethyl)-3-(3-fluoro-4-benzyloxyphenyl)-oxazolidin-2-one
(R)-5-(Acetyloxymethyl)-3-(3-fluoro-4-benzyloxy-phenyl)-oxazolidin-2-one (35 g), potassium carbonate (4 g) and methanol (144 ml) were taken into a reaction flask at room temperature (25-30°C), and the resulting mixture was heated to reflux temperature and then stirred for 10 hours at reflux. After completion of reaction, the resulting mass was distilled off under vacuum at 60-65°C to obtain a solid. Water (65 ml) and ethyl acetate (65 ml) were added to the resulting solid and stirred for 15 minutes at room temperature. The

separated solid was filtered, washed with ethyl acetate and then dried the material to produce 20 g of (R)-5-(hydroxymethyl)-3-(3-fluoro-4-benzyloxyphenyl)-oxazolidin-2-one.
Example 12 Preparation of (R)«5-(hydroxymethyl)-3-(3-fluoro-4-hydroxyphenyl)-oxazolidin-2-one
(R)-5-(Hydroxymethyl)-3-(3-fluoro-4-benzyloxyphenyl)-oxazolidin-2-one (20 g), wet Pd/C (2.5 g) and ethyl acetate (600 ml) were taken into an autoclave at room temperature (25-30°C). The reaction mixture was heated to 40°C under hydrogen pressure, followed by maintaining the reaction mass for 4 hours at the same temperature. After completion of reaction, the reaction mass was transferred into a beaker, followed by the addition of acetone (500 ml) and then stirring the mass for 5 minutes at room temperature. The reaction mass was filtered and the filtrate was distilled off under vacuum at 75-75°C to produce 13.5 g of (R)-5-(hydroxymethyl)-3-(3-fluoro-4-hydroxyphenyl)-oxazolidin-2-one.
Example 13 Preparation of l-Cyclopropyl-7-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-6«fluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
N-Methyl -2-pyrrolidone (150 ml), l,4-dioxa-8-aza-spiro[4.5]decane hydrochloride (30 g), N-ethyldiisopropylamine (60 ml) and potassium carbonate (45 g) were taken into a reaction flask at room temperature (25-30°C) and the resulting mixture was stirred for 5 minutes at the same temperature. 7-Chloro-l-cyclopropyl-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid boron diacetate complex (30 g), tetra-n-butylammonium bromide (4.5 g) and N-Methyl-2-pyrrolidone (100 ml) were added to the reaction mass and the resulting mass was heated to 95°C, followed by stirring the reaction mass for 8 hours at the same temperature. After completion of the reaction, the resulting mass was cooled to room temperature and then filtered and washed with N-methyl-2-pyrrolidone (60 ml). The mother liquors were taken into a separate reaction flask, followed by the addition of hydrochloric acid (60 ml) and water (315 ml) and then stirring the reaction mass for 10 minutes at room temperature (25-30°C). Solid separation was observed. Methanol (315 ml) was added to the mass and stirred for 1 hour at room temperature (25-30°C). The separated solid was filtered, washed with methanol (60 ml) and then dried to produce 23 g of 1-

CyclopropyI-7-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-6-fluoro-4-oxo-lJ4-dihydro-quinoline-3-carboxylic acid.
Example 14 Preparation of l-CyclopropyI-6-fluoro-4-oxo-7-(4-oxo-piperidin-l-yl)-l,4-dihydro-quinoline-3-carboxyIic acid
l-Cyclopropyl-7-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-6-fluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (31 g), acetonitrile (250 ml), hydrochloric acid (50 ml) and water (100 ml) were taken into a reaction flask at room temperature (25-30°C), and the resulting mixture was heated to 70°C, followed by stirring for 8 hours at the same temperature. After completion of the reaction, the resulting mass was cooled to room temperature. The separated solid was filtered and washed with water (50 ml x 2) to produce 24 g of 1 -Cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-piperidin-1 -yl)-1,4-dihydro-quinoline-3-carboxylic acid.
Example 15 Preparation of methyl l-Cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-piperidin-l-yl)-l,4-dihydro-quinoline-3-carboxylate
l-Cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-piperidin-l-yl)-l,4-dihydro-quinoline-3-carboxylic acid (2 g), potassium carbonate (3 g) and acetone (50 ml) were taken into a reaction flask at room temperature (25-30°C), and the resulting mixture was heated to reflux, followed by stirring for 30 minutes at the same temperature. Dimethyl sulfate (3 ml) was added to the reaction mass at reflux and then stirred for 2 hours at the same temperature. After completion of the reaction, the reaction mass was cooled to room temperature. Water (40 ml) was added to the reaction mass and stirred for 15 minutes at room temperature. The separated solid was filtered and then washed with water (20 ml x 2) to produce 1.5 g of methyl l-Cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-piperidin-l-yl)-l,4-dihydro-quinoline-3-carboxylate.

Example 16 Preparation of methyl l-cycIopropyl-6-fluoro-7-(l-oxa-6-aza-spiro[2.5]oct-6-yl)^4-oxo-l,4-dihydro-quinoline-3-carboxylate
Dimethyl sulfoxide (90 ml) and potassium tert-butoxide (2 g) were taken into a reaction flask under nitrogen atmosphere at room temperature (25-30°C) and the resulting mixture was stirred for 10 minutes at the same temperature. Trimethylsulfoxonium iodide (4 g) was added to the resulting mass at room temperature, followed by stirring the mass for 1 hour 30 minutes at the same temperature. To the reaction mass, methyl l-Cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-piperidin-l-yl)-l54-dihydro-quinoline-3-carboxylate (5 g) and dimethyl sulfoxide (60 ml) were added slowly under nitrogen atmosphere at room temperature (25-30°C), followed by stirring the mass for 2 hours at the same temperature. After completion of the reaction the reaction mass was filtered and washed with dimethyl sulfoxide (20 ml). The mother liquors were taken into a reaction flask and then ethyl acetate (150 ml) was added at room temperature. The reaction mass was cooled to 0°C, followed by the addition of water (150 ml) at the same temperature. The resulting mass was stirred for 15 minutes at the room temperature. The layers were separated and the aqueous layer was extracted with ethyl acetate (200 ml). The organic layers were combined and then distilled off under vacuum up to 65°C to produce 1 g of methyl l-cyc!opropyl-6-fluoro-7-(l-oxa-6-aza-spiro[2.5]oct-6-yl)-4-oxo-l,4-dihydro-quinoline-3-carboxylate.
Example 17 Preparation of Cadazolid
(R)-3-(3-fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one (1 g), potassium carbonate (3 g) and acetonitrile (50 ml) were taken into a reaction flask at room temperature (25-30°C) and the resulting mixture was heated to reflux, followed by stirring for 10 minutes at the same temperature. Methyl l-cyclopropyl-6-fluoro-7-(l-oxa-6-aza-spiro[2.5]oct-6-yl)«4-oxo-l,4-dihydro-quinoline-3-carboxylate (2 g) was added to the resulting mass reflux, followed by stirring the reaction mass for 6 hours at reflux. After completion of the reaction, the reaction mass was cooled to room temperature and then water (30 ml) was added. The resulting mass was cooled to 0°C, followed by stirring for 15 minutes at 0°C. Methanol (20 ml) was added to the resulting mass and then stirred for

15 minutes at 0°C. The separated solid was filtered, washed with methanol (10 ml) and then dried the material to produce 1.5 g of Cadazolid.
Example 18 Preparation of l-cyclopropyl-6-fluoro-7-(l-oxa-6-aza-spiro[2.5]oct-6-yl)-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid
Dimethyl sulfoxide (50 ml) and potassium tert-butoxide (3.5 g) were taken into a reaction
flask under nitrogen atmosphere at room temperature (25-30°C), and the resulting solution
was cooled to 20°C. Trimethylsulfoxonium iodide (2.5 g) was added slowly to the
resulting mass under nitrogen atmosphere. The temperature of the reaction mass was raised
to room temperature, followed by stirring the mass for 1 hour 30 minutes at the same
temperature under nitrogen atmosphere. The reaction mass was cooled to 20°C. A mixture
of 1 -cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-piperidin-1 -yl)-1,4-dihydro-quinoIine-3-
carboxylic acid (3 g) and dimethyl sulfoxide (25 ml) was slowly added to the resulting mass, followed by raising the temperature to room temperature and then stirring the mass for 2 hours under nitrogen atmosphere at the same temperature. The resulting mass was cooled to 20°C, water (50 ml) was added at the same temperature, followed by slow addition of methanol (50 ml). The resulting mixture was stirred for 5 minutes at the same temperature, followed the addition of a mixture of sodium bisulphate (2.5 g) and water (30 ml) and then stirring the mass for 15 minutes at 20°C. The separated solid was filtered, washed with methanol (10 ml) and then dried the material to produce 4.5 g of 1-cyclopropyl-6-fluoro-7-(l-oxa-6-aza-spiro[2.5]oct-6-yl)-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid.
Example 19 Preparation of Cadazolid
(R)-(3-(3-Fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one (1 g), potassium carbonate (3 g) and acetonitrile (50 ml) were taken into a reaction flask at room temperature (25-30°C), and the resulting mixture was heated to reflux, followed and stirring the mass for 10 minutes at the same temperature. l-Cyclopropyl-6-fluoro-7-(l-oxa-6-aza-spiro[2.5]oct-6-yl)-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid (2 g) was added to the resulting mass at reflux and then stirred the reaction mass for 6 hours at the same

temperature. After completion of the reaction, the reaction mass was cooled to room temperature and then water (30 ml) was added, followed by cooling the reaction mass to 0°C. The reaction mass was stirred for 10 minutes at 0°C, methanol (20 ml) was added, followed by stirring for 10 minutes at the same temperature. The separated solid was filtered, washed with methanol (10 ml) and then dried to produce 1.0 g of Cadazolid.

We claim:
1. A process for the preparation of Cadazolid of formula 1:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a pharmaceutically acceptable salt thereof, which comprises reacting (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one of formula 2:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, with l-oxa-6-aza-spiro compound of formula 20:
or a salt thereof, wherein the group 'P' represents hydrogen atom or an alkyl group Pi; in the presence of a base to produce Cadazolid of formula 1, and optionally converting the compound of formula 1 obtained into its pharmaceutically acceptable salts thereof. 2. The process of claim 1, wherein the group P in the compounds of formula 20 is an alkyl group 'Pi' selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl; and wherein the base used in the reaction is an organic or an inorganic base selected from the group consisting of methylamine, trimethylamine, tributylamine, triethylamine, diisopropylethylamine, N-methylmorpholine, and 1-

alkylimidazole; and hydroxides, alkoxides, bicarbonates and carbonates of alkali or alkaline earth metals. 3. A l-oxa-6-aza-spiro compound of formula 20:
or a salt thereof, wherein the group T' represents hydrogen atom or an alkyl group Pi.
4. The compound of claim 3, wherein the alkyl group 'Pi' is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl.
5. A process for the preparation of (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one of formula 2:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, which comprises:
a) reacting (R)-5-(Chloromethyl)-3-(3-fluoro-4-benzyloxy-phenyl)-oxazolidin-2-one of formula 22:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, with a suitable reagent to produce (R)-5-(acetyloxymethyl)-3-(3-fluoro-4-benzyloxy-phenyl)-oxazolidin-2-one of formula 23:

or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof; b) hydrolysing the compound of formula 23 to produce (R)-5-(hydroxymethyl)-3-(3-fluoro-4-benzyloxyphenyl)-oxazolidin-2-one of formula 24:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof; and c) deprotecting the compound of formula 24 to produce the (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one of formula 2 or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, and optionally converting the compound of formula 2 into Cadazolid or a pharmaceutically acceptable salt thereof.
6. The process of claim 5, wherein the reagent used in step-(a) is sodium acetate or potassium acetate; wherein the hydrolysis in step-(b) is carried out by treating the compound of formula 23 with an acid or a base, in a reaction inert solvent; and wherein the deprotection in step-(c) is carried out by subjecting the oxazolidinone compound of formula 24 to hydrogenolysis under hydrogen pressure in the presence of a metal catalyst.
7. The process of claim 6, wherein the base used for hydrolysis in step-(b) is an organic or an inorganic base selected from the group consisting of sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium

carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; and wherein the metal catalyst used in step-(c) is selected from the group consisting of zinc, nickel, palladium, palladium on carbon. 8. A process for the preparation of l-cyclopropyl-6-fluoro-7-(l-oxa-6-aza-spiro[2.5]oct-6-yl)-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid of formula 20(a):
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof,
which comprises:
a) reacting l,4-dioxa-8-aza-spiro[4.5]decane hydrochloride of formula 28:
or an acid addition salt thereof, with 7-Chloro-l-cyclopropyl-6^fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid boron diacetate complex of formula 19(a):
to produce l-Cyclopropyl-7-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)«6-fluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid of formula 26:

or a salt thereof; b) reacting the compound of formula 26 with an acid to produce l-Cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-piperidin-l-yl)-l,4-dihydro-quinoline-3-carboxylic acid of formula 25(a):
or a salt thereof; and
c) reacting the compound of formula 25(a) with trimethylsulfoxonium iodide to
produce l-cyclopropyl-6-fluoro-7-(l-oxa-6-aza-spiro[2.5]oct-6-yl)-4-oxo-l,4-
dihydro-quinoline-3-carboxylic acid of formula 20(a) or a salt thereof.
9. The process of claim 8, wherein the acid addition salt of formula 28 used in step-(a) is a hydrochloride salt; wherein the reaction in step-(a) is carried out in the presence of a base or a combination of suitable bases; wherein the acid used in step-(b) is an organic or an inorganic acid; and wherein the reaction in step-(c) is carried out in the presence of abase.
10. The process of claim 9, wherein the base used in step-(a) is an organic or an inorganic base selected from the group consisting of diisopropylethylamine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; wherein the acid used in step-(b) is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, formic acid, and the like, or a combination thereof; and wherein the base used in step-(c) is selected from the group consisting of diisopropylethylamine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide.

11. A process for the preparation of methyl l-cyclopropyl-6-fluoro-7-(l-oxa-6-aza-spiro[2.5]oct-6-yl)-4-oxo-l,4-dihydro-quinoline-3-carboxylate of formula 20(b):
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof,
which comprises:
a) reacting l,4-dioxa-8-aza-spiro[4.5]decane hydrochloride of formula 28:
or an acid addition salt thereof, with 7-Chloro-d-cyclopropyI-6-fluoro-l,4-dihydro-4-oxo-3-quinolinecarboxylic acid boron diacetate complex of formula 19(a):
6
to produce l-Cyclopropyl-7-(l,4-dioxa-8-aza-spiro[4.5]dec-8-yl)-6-fluoro-4-oxo-l,4-dihydro-quinoline-3-carboxylic acid of formula 26:
or a salt thereof;

b) reacting the compound of formula 26 with an acid to produce 1-Cyclopropyl-6-fluoro^-oxo-T^-oxo-piperidin-l-yO-l^-dihydro-quinoline-S-carboxylic acid of formula 25(a):
or a salt thereof; c) reacting the compound of formula 25(a) with dimethylsulfate in the presence of a base to produce methyl l-cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-piperidin-l-yl)-l,4-dihydro-quinoline-3-carboxylate of formula 25(b):
or a salt thereof; and d) reacting the compound of formula 25(b) with trimethylsulfoxonium iodide to produce methyl l-cyclopropyl-6-fluoro-7-(l-oxa-6-aza-spiro[2.5]oct-6-yl)-4-oxo-l,4-dihydro-quinoline-3-cafboxylate of formula 20(b) or a salt thereof.
12. The process of claim 11, wherein the acid addition salt of formula 28 used in step-(a) is a hydrochloride salt; wherein the reaction in step-(a) is carried out in the presence of a a base or a combination of suitable bases; wherein the acid used in step-(b) is an organic or an inorganic acid; wherein the reaction in step-(c) is carried out in the presence of a base; and wherein the reaction in step-(d) is carried out in the presence of a suitable base.
13. The process of claim 12, wherein the base used in step-(a) is selected from the group consisting of diisopropylethylamine, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate,

sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide; wherein the acid used in step-(b) is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, acetic acid, formic acid, and a combination thereof; wherein the base used in steps (c) and (d) is, each independently, selected from the group consisting of sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide. 14. Methyl 1 -cyclopropyl-6-fluoro-4-oxo-7-(4-oxo-piperidin-1 -yl)-1,4-dihydro-quinoline-3-carboxylate of formula 25(b):
or a salt thereof. 15. A process for the preparation of (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one of formula 2:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof,
which comprises:
a) reacting a substituted-aniline compound of formula 7:
or a salt thereof, wherein 'A5 represents a protecting group;

with a compound of formula 6:
or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is hydrogen or a hydroxy protecting group Ri, L represents a leaving group and Y represents a hydroxy group; or L and Y together with the atoms to which they are bonded form an oxirane ring having the structural formula 6a:
or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is as defined above; to produce a 3-amino-2-hydroxy-propyl derivative of formula 5:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the group A is as defined in formula 7, and wherein the group R is as defined in formula 6; b) subjecting the compound of formula 5 to carbonylation by reacting with a suitable carbonylating agent to produce the compound of formula 3:
or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein the groups A and R are as defined above; and

c) deprotecting the compound of formula 3 to produce the compound of formula 2 or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, and optionally converting the compound of formula 2 into Cadazolid or a pharmaceutical^ acceptable salt thereof.
16. The process of claim 15, wherein the protecting group 'A' in the compounds of formulae 3, 5 and 7 is a hydroxyl protecting group; wherein the leaving group 'L' in the compound of formula 6 is a halogen, or an alkyl or aryl sulfonyloxy group; wherein the group R in the compounds of formulae 3, 5, 6 and 6a is hydrogen atom or an hydroxyl protecting group Rj.
17. The process of claim 16, wherein the hydroxyl protecting groups ;A' and 'Ri', each independently, are selected from the group consisting of formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, succinoyl, glutaroyl, adipoyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, cyclopropylcarbonyl, cyclobutylcarbonyl, methoxyacetyl, benzoyl, a-naphthoyl, b-naphthoyl, pyridoyl, fiiroyl, 2-bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, p-toluoyl, p-anisoyl, 2-carboxybenzoyl, p-nitrobenzoyl, trityl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl, o-nitrobenzyl, benzyl, p-methoxybenzyl, trimethylsilyl, triisopropylsilyl and t-butyldiphenylsilyl.
18. The process of claim 15, wherein the reaction in step-(a) is optionally carried out in the presence of a base; wherein the carbonylation reaction in step-(b) is performed by reacting with a suitable carbonylating agent selected from the group consisting of N,N'-carbonyldiimidazole, phosgene, diphosgene, triphosgene, dialkyl carbonates, substituted or unsubstituted alkyl chloroformates, substituted or unsubstituted aryl chloroformates, substituted or unsubstituted aralkyl chloroformates, or a combination thereof; wherein the reaction in step-(b) is optionally carried out in the presence of a base; wherein the compound obtained after completion of the carbonylation reaction step-(b) is, optionally, required to be reacted with a suitable base or an acid in a suitable solvent to obtain the oxazolidinone compound of formula 3; and wherein the deprotection in step-(c) is performed by subjecting the N-protected compound of formula 3 to hydrolysis, hydrogenolysis, or a combination thereof.

19. A process for the preparation of (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one of formula 2 or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, which comprises: a) reacting the 3-amino-2-hydroxypropyl derivative of formula 5:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein R is hydrogen or a hydroxyl protecting group Ri, and 'A' represents a protecting group;
with a suitable activating agent, wherein the activating agent is an anhydride compound of formula 8a, or a chloroformate compound of formula 8b:
wherein R' is OR2 or CX3, wherein the radical R2 is CM2 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; and X is a halogen atom selected from F, CI, Br and I; to produce an N-protected compound of formula 4:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the groups R, R' and A are as defined above; and

b) converting the N-protected compound of formula 4 obtained in step-(a) into the compound of formula 2 or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, by reacting with a suitable reagent or a combination of suitable reagents.
20. The process of claim 19, wherein the group R in the compounds of formulae 4 and 5 is hydrogen or a hydroxyl protecting group Ri; the protecting group 'A' in the compounds of formulae 4 and 5 is a hydroxyl protecting group; wherein the group R' is OR2, wherein the radical R2 in the compounds of formulae 8a, 8b and 4 is methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, chloromethyl, phenyl, tolyl, benzyl, p-nitrobenzyl, dibromophenyl or p-methoxybenzyl.
21. The process of claim 20, wherein.the hydroxyl protecting group is selected from the group consisting of acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, trichloroacetyl, trifluoroacetyl, benzoyl, p-toluoyl, p-anisoyl, trityl, 0-nitrobenzyl, benzyl and p-methoxybenzyl.
22. The process of claim 19, wherein the reaction in step-(a) is optionally carried out in the
*
presence of a base; and wherein the conversion in step-(b) is carried out by subjecting the N-protected compound of formula 4 to hydrolysis, hydrogenolysis, or a combination thereof.
23. A 3-amino-2-hydroxypropyl derivative of formula 5:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof,
wherein R is hydrogen or a hydroxyl protecting group Rj; and A' represents a
protecting group.
24. The compound of claim 23, wherein the hydroxyl protecting groups CA' and 'Ri', each
independently, are selected from the group consisting of formyl, acetyl, propionyl,
butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl,
decanoyl, 3-methylnonanoyl, succinoyl, glutamyl, adipoyl, chloroacetyl,
dichloroacetyl, trichloroacetyl, trifluoroacetyl, cyclopropylcarbonyl,

cyclobutylcarbonyl, methoxyacetyl, benzoyl, a-naphthoyl, b-naphthoyl, pyridoyl, furoyl, 2-bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, p-toluoyl, p-anisoyl, 2-carboxybenzoyl, p-nitrobenzoyl, trityl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofiiranyl, o-nitrobenzyl, benzyl, p-methoxybenzyl, trimethylsilyl, triisopropylsilyl and t-butyldiphenylsilyl. 25. An N-protected compound of formula 4:
or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein R is hydrogen or a hydroxyl protecting group Ri, and 'A' represents a protecting group; and wherein R' is OR2 or CX3, wherein the radical R2 is C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; and X is a halogen atom selected from F, CI, Br and I. 26. A process for the preparation of (R)-5-chloromethyl-3-(3-fluoro-4-hydroxy-phenyl)-oxazolidin-2-one of formula 9:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof,
which comprises:
a) reacting a substituted-aniline compound of formula 7:
or a salt thereof, wherein the group 'A5 represents a protecting group; with (R)-epichlorohydrin of formula 12:

or an enantiomeric form or a mixture of enantiomeric forms thereof, to produce a 3-chloro-2-hydroxy-propyl derivative of formula 11:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the group ' A' is as defined in formula 7; b) subjecting the compound of formula 11 to carbonylation by reacting with a suitable carbonylating agent to produce a chloromethyl-oxazolidinone compound of formula 10:
or an enantiomeric form or a mixture of enantiomeric forms thereof, wherein the
group A is as defined above; and c) deprotecting the compound of formula 10 to produce the compound of formula 9 or
an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof,
and optionally converting the compound of formula 9 into Cadazolid or a
pharmaceutical^ acceptable salt thereof. 27. The process of claim 26, wherein the protecting group 'A' in the compounds of formulae 7, 10 and 11 is a hydroxyl protecting group selected from group consisting of formyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, octanoyl, nonanoyl, decanoyl, 3-methylnonanoyl, succinoyl, glutaroyl, adipoyl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, cyclopropylcarbonyl, cyclobutylcarbonyl, methoxyacetyl, benzoyl, a-naphthoyl, b-naphthoyl, pyridoyl,

furoyl, 2-bromobenzoyl, 4-chlorobenzoyl, 2,4,6-trimethylbenzoyl, p-toluoyl, p-anisoyl, 2-carboxybenzoyl, p-nitrobenzoyl, trityl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydroforanyl, tetrahydrothiofiiranyl, o-nitrobenzyl, benzyl, p-methoxybenzyl, trimethylsilyl, triisopropylsilyl and t-butyldiphenylsilyl.
28. The process of claim 26, wherein the reaction in step-(a) is optionally carried out in the presence of a base; wherein the carbonylation reaction in step-(b) is performed by reacting with a suitable carbonylating agent selected from the group consisting of N,N'-carbonyldiimidazole, phosgene, diphosgene, triphosgene, dialkyl carbonates, substituted or unsubstituted alkyl chloroformates, substituted or unsubstituted aryl chloroformates, substituted or unsubstituted aralkyl chloroformates; wherein the reaction in step-(b) is optionally carried out in the presence of a base; wherein the compound obtained after completion of the carbonylation reaction step-(b) is, optionally, required to be treated with a suitable base or an acid, in a suitable solvent, in order to obtain the oxazolidinone compound of formula 10; and wherein the deprotection in step-(c) is performed by subjecting the N-protected compound of formula 10 to hydrolysis, hydrogenolysis, or a combination thereof.
29. A process for the preparation of (R)-5-chloromethyl-3-(3-fluoro-4-hydroxy-phenyl)-oxazolidin-2-one of formula 9 or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, which comprises:
a) reacting the 3-chloro-2-hydroxy-propyl derivative of formula 11:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the group 'A' represents a protecting group; with a suitable activating agent, wherein the activating agent is an anhydride compound of formula 8a, or a chloroformate compound of formula 8b:

wherein R' is OR2 or CX3, wherein the radical R2 is C1-12 straight or branched chain alkyl, cycloalkyl, haloalkyl, substituted or unsubstituted aryl, or substituted or unsubstituted aralkyl; and X is a halogen atom selected from F, CI, Br and I; to produce an N-protected compound of formula 18:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the groups A and R' are as defined above; and b) converting the N-protected compound of formula 18 obtained in step-(a) into the compound of formula 9 or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, by reacting with a suitable reagent or a combination of suitable reagents. 30. The process of claim 29, wherein the protecting group 'A' in the compounds of formulae 11 and 18 is a hydroxyl protecting group selected from the group consisting of acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, isovaleryl, trichloroacetyl, trifluoroacetyl, benzoyl, p-toluoyl, p-anisoyl, trityl, o-nitrobenzyl, benzyl and p-methoxybenzyl; wherein the group R' is OR2, wherein the radical R2 in the compounds of formulae 8a, 8b and 18 is methyl, ethyl, propyl, isopropyl, isobutyl, tert-butyl, chloromethyl, phenyl, tolyl, benzyl, p-nitrobenzyl, dibromophenyl or p-' methoxybenzyl.

31. The process of claim 29, wherein the reaction in step-(a) is optionally carried out in the presence of a base; and wherein the conversion in step-(b) is carried out by subjecting the N-protected compound of formula 18 to hydrolysis, hydrogenolysis, or a combination thereof.
32. A process for the preparation of Cadazolid of formula 1:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a pharmaceutically acceptable salt thereof, which comprises:
a) reacting (R)-5-chloromethyl-3-(3-fluoro-4-hydroxy-phenyl)-oxazolidin-2-one of formula 9:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, with a l-oxa-6-aza-spiro[2.5]octane compound of formula 13:
wherein the group G represents a nitrogen-protecting group; to produce the compound of formula 15:

or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the group G is as defined in formula 13; b) deprotecting the compound of formula 15 obtained in step-(a) by reacting with a suitable reagent to produce the compound of formula 14:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof; c) condensing the compound of formula 14 with a 3-quinolinecarboxylic acid derivative of formula 19:
or a salt or a complex thereof, wherein the group P represents hydrogen atom or an alkyl group Pi; to produce the compound of formula 16:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the group P represents hydrogen atom or an alkyl group Pi; d) reacting the compound of formula 16 obtained in step-(c) with a suitable reagent to produce the compound of formula 17:

or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the group P represents hydrogen atom or an alkyl group Pi; and P2 represents an alkyl group; and e) reacting the compound of formula 17 with a suitable reagent to produce Cadazolid of formula 1, and optionally converting the compound of formula 1 obtained into its pharmaceutical^ acceptable salts thereof.
33. The process of claim 32, wherein the nitrogen protecting group 'G' in the compounds of formulae 13 and 15 is a substituted or unsubstituted aralkyl, a substituted or unsubstituted trityl, an aliphatic acyl group including an alkanoyl group, an aromatic acyl group including an arylcarbonyl group, an alkoxycarbonyl group; and wherein the group P in the compounds of formulae 16, 17, and 19 is an alkyl group Pi selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl; and wherein the group P2 in the compound of formula 17 is an alkyl group selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl
34. The process of claim 33, wherein the nitrogen protecting group CG' is selected from the group consisting of methoxycarbonyl, ethoxycarbonyl, propyloxycarbonyl, isopropyloxycarbonyl, tert-butyloxycarbonyl, acetyl, propionyl, butyryl, isobutyryl, pentanoyl, pivaloyl, valeryl, chloroacetyl, dichloroacetyl, trichloroacetyl, trifluoroacetyl, cyclopropylcarbonyl, cyclobutylcarbonyl, benzoyl, 4-chlorobenzoyl, p-nitrobenzoyl, trityl, benzyl; and wherein the alkyl group Pi is ethyl or methyl; and wherein the group P2 is methyl.
35. The process of claim 32, wherein the deprotection in step-(b) is carried out by treating the chloromethyl-oxazolidinone compound of formula 15 with an acid or a base; wherein the deprotection in step-(b) is carried out by subjecting the oxazolidinone compound of formula 15 to hydrogenolysis under hydrogen pressure in the presence of

a suitable metal catalyst; wherein the reagent used in step-(d) is selected from the group consisting of sodium acetate, potassium acetate, sodium propionate and potassium propionate; and wherein the reagent used in step-(e) an organic or inorganic base. 36. A process for the preparation of Cadazolid of formula 1 or an enantiomeric form or a mixture of enantiomeric forms thereof, or a pharmaceutically acceptable salt thereof, which comprises:
a) reacting (R)-5-chloromethyl«3-(3-fluoro-4-hydroxy-phenyl)-oxazolidin-2-one of formula 9:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, with a compound of formula 20:
wherein the group P represents hydrogen atom or an alkyl group Pi; to produce the compound of formula 16:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the group P represents hydrogen atom or an alkyl group Pi: b) reacting the compound of formula 16 obtained in step-(a) with a suitable reagent to produce the compound of formula 17: .

or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the group P represents hydrogen atom or an alkyl group Pi; and P2 represents an alkyl group; and c) reacting the compound of formula 17 with a suitable reagent to produce Cadazolid of formula 1, and optionally converting the compound of formula 1 obtained into its pharmaceutical^ acceptable salts thereof.
37. The process of claim 36, wherein the group P in the compounds of formulae 16, 17 and 20 is an alkyl group Pi selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl; and wherein the group P2 in the compound of formula 17 is an alkyl group selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl andtert-butyl.
38. The process of claim 36, wherein the reagent used in step-(b) is selected from the group consisting of sodium acetate, potassium acetate, sodium propionate, potassium propionate; and wherein the reagent used in step-(c) is an organic or an inorganic base.
39. A process for the preparation of (R)-3-(3-fluoro-4-hydroxy-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one of formula 2:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, which comprises:
a) reacting (R)-5-chloromethyl-3-(3-fluoro-4-hydroxy-phenyl)-oxazolidin-2-one of formula 9 or an ester derivative of formula 10a:
c

or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein P2 represents an alkyl group, with a suitable reagent to produce the
compound of formula 21:
0
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein P2 represents an alkyl group; and b) reacting the compound of formula 21 with a suitable reagent to produce the compound of formula 2, and optionally converting the compound of formula 2 obtained into Cadazolid or a pharmaceutical^ acceptable salts thereof.
40. The process of claim 39, wherein the group P2 in the compounds of formulae 10a and 21 is an alkyl group, each independently, selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl and tert-butyl; wherein the reagent used in step-(a) is selected from the group consisting of sodium acetate, potassium acetate, sodium propionate and potassium propionate; and wherein the reagent used in step-(b) is an organic or an inorganic base.
41. Compounds of formulae 9, 10, 11, 14, 15, 16, 17 and 18:
or an enantiomeric form or a mixture of enantiomeric forms thereof, or a salt thereof, wherein the protecting group 'A' in the compounds of formulae 10, 11 and 18 is a hydroxyl protecting group; wherein the group P in the compounds of formulae 16 and 17 is hydrogen or an alkyl group Pi; and wherein the group 'G' in the compound of formula 15 is a nitrogen protecting group.