DESC:Field of the invention: The invention relates to a process for preparation of oxazolidinone derivatives. More particularly, the invention relates to a novel process for preparation of epererezolid and sutelozid by making use of the novel intermediates.

Background of the invention: Oxazolidinones are a class of compounds containing 2-oxazolidone in the structure. The general structure of oxazolidinone is given below:-

It has been reported that oxazolidinone derivatives show a number of biological activities such as antibacterial, anticoagulant, anti-tubercular, antidepressant, anti-thyroid, agriculture fungicide etc. Some of the oxazolidinone derivatives include Linezolid, Torezolid, Radezolid, Eperezolid, Sutezolid and Rivaroxaban. Among these, eperezolid and sutezolid are oxazolidinone antibiotics.

Eperezolid is chemically known as N-({(5S)-3-[3-Fluoro-4-(4-glycoloyl-1-piperazinyl)phenyl]-2-oxo-1,3-oxazolidin-5-yl}methyl)acetamide (I) and is a synthetic antibacterial agent of oxazolidinone class. Sutezolid is chemically known as N-({(5S)-3-[3-fluoro-4-(thiomorpholin-4-yl) phenyl]-2-oxo-oxazolidin-5-yl}methyl) acetamide (II) also acts as an antibacterial agent of oxazolidinone class.

(I) (II)

The process for preparation of oxazolidinones is described in U.S Patent No. 5,688,792. The PCT publication also WO 2011/114210 describes a process for preparation of oxazolidinones. The prior art processes synthesize oxazolidinones do not use selective alpha hydroxylation. The prior art processes use stereo selective raw materials which leads to the formation of the unwanted isomers which further needs to be purified, This ultimately leads to the loss of yields The present invention makes use of selective alpha hydroxylation for the preparation of sutezolid and eperezolid to avoid formation of the unwanted isomer, to increase the yield and the overall cost of the synthesis.

Summary of the Invention:
The present invention is related to a novel process for the preparation of oxazolidinones. The present invention is related to a novel process for the preparation of eperezolid using novel intermediates tert-butyl (R)-4-(4-((3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypropyl)amino)-2-fluorophenyl)piperazine-1-carboxylate (EPE-II) and tert-butyl (S)-4-(4-(5((1,3-dioxoisoindolin-2-yl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE-III). The present invention is also related to the preparation of sutezolid using novel intermediates (R)-2-(3-((3-fluoro-4-thiomorpholinophenyl)amino)-2-hydroxypropyl)isoindoline-1,3-dione (SUT-II) and (S)-2-((3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-yl)methyl)isoindoline-1,3-dione (SUT-III).

Detailed description of the invention:
The invention provides a novel process for preparation of oxazolidinones. The synthetic scheme for the preparation of the oxazolidinones is depicted in Scheme (I). Acryalaldehyde is treated with phthalimide to give INT-I. INT-I is treated with the corresponding amine to give INT-II is further cyclized to INT-III which is further converted to INT-IV. INT-IV is treated with acetic anhydride to give oxazolidinone compounds.

Scheme (I)

Scheme (II) discloses the process for the preparation of Eperezolid.

Scheme (II)

Scheme (II) involves the syntheses of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate, in step 1 by the reaction of 1,2 difluoro-4-nitrobenzene and N-Boc piperazine in the presence of organic base and a solvent.

The base used in step 1 of scheme-II is selected an organic base that can be used in step 1 includes pyridine, N-methyl morpholine, N-methyl pyrrolidine, tertiary alkyl amine such as triethyl amine, tertiary butyl amine etc, the most preferred base is triethyl amine.

The process of step 1 of scheme-II of the present invention can be carried out in organic solvent that include aromatic hydrocarbons like benzene, toluene and xylene; esters like ethyl acetate and isopropyl acetate; ethers such as ethyl ether, methyl t-butyl ether, di-isopropyl ether and tetrahydrofuran; amides such as formamide, dimethylforamide and N-methyl-pyrrolidone; nitriles such as acetonitrile and propionitrile; chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone and mixtures thereof. The most preferred solvent for step 1 is methanol.

The reaction of step 1 of scheme-II is carried at a temperature ranging from 20 to 100° C, more preferably, at 40 to 90 ° C.

The scheme (II) involves step 2 which involves the reduction of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate to tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate using a reducing agent and a solvent.

The reduction of step 2 of scheme-II can be done in the presence of reducing agents such as palladium on carbon, iron/ammonium chloride, iron/acetic acid, raney nickel etc. The solvent used in step 2 is selected from chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform, alcohols such as methanol, ethanol and isopropanol, esters such as ethyl acetate and mixtures thereof.

The scheme (II) involves step 3 which involves the coupling of tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate and 3-(1,3-dioxoisoindolin-2-yl) propanal (EPE-I) in the presence of L-proline and nitrosobenzene in the presence of chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform to give tert-butyl (R)-4-(4-((3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypropyl)amino)-2-fluorophenyl)piperazine-1-carboxylate (EPE-II).

The reaction of step 3 of scheme-II is carried at a temperature ranging from –10 to 20° C, more preferably, at 0 to 5 ° C.

The novel intermediate tert-butyl (R)-4-(4-((3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypropyl) amino)-2-fluorophenyl) piperazine-1-carboxylate (EPE-II) has the following NMR and Mass

1H NMR (CDCl3): ? 7.86 (dd, 2H J=7.0 and 3.5 Hz) ; ? 7.50 (dd, 2H J=7.0 and 3.5 Hz); ? 6,82 (m 1H); ? 6.44-6.38 (m, 2H); ? 4.14 (m, 1H) ; ? 3.90 (m, 2H); ? 3.57 (m, 4H); ? 3.23 (dd, J=13.0 and 5.0 Hz 1H); ? 3.13 (dd, 1H, J=13.0 and 5.0 Hz) ; ? 2.90 (m, 4H); ? 1.49 (s, 9H)

Mass (M/Z): 499.3 (M+1)

The scheme (II) involves step 4 which involves the cyclization of tert-butyl (R)-4-(4-((3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypropyl) amino)-2-fluorophenyl) piperazine-1-carboxylate (EPE-II) to give tert-butyl (S)-4-(4-(5((1,3-dioxoisoindolin-2-yl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE-III) in the presence of cyclizing agent such as 1,1’ -carbonyl diimidazole or diethyl carbonate or dimethyl carbonate in the presence of catalytic amount of dimethyl aminopyridine. The solvents used for the reaction are aromatic hydrocarbons like benzene, toluene and xylene; esters like ethyl acetate and isopropyl acetate; ethers such as ethyl ether, methyl t-butyl ether, di-isopropyl ether and tetrahydrofuran; amides such as formamide, dimethylforamide and N-methyl-pyrrolidone; nitriles such as acetonitrile and propionitrile; chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone and mixtures thereof. The most preferred solvent being dichloromethane.

The reaction of step 4 of scheme-II is carried at a temperature ranging from 10 to 50° C, more preferably, at 30 to 35 ° C.

The novel intermediate (S)-4-(4-(5((1,3-dioxoisoindolin-2-yl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE-III) has the following NMR and Mass

1H NMR (CDCl3): ? 7.90 (dd, 2H J=7.0 and 3.5 Hz) ; ? 7.78 (dd, 2H J=7.0 and 3.5 Hz); ? 7.40 (dd, 1H J=14.0 and 2.5 Hz); ? 7.12 (d, 1H J=9.0 and 2.0 Hz); ? 6.93 (m, 1H); ? 4.98 (m 1H); ? 4.17-4.08 (m, 2H); ? 3.99 (dd, 1H J = 8.5 and 6.0 Hz) ; ? 3.88 (dd, 1H J= 9.0 and 6.0 Hz); ? 3.60 (m, 4H); ? 3.0 (m, 4H) and ? 1.50 (s, 9H)

Mass (M/Z): 525.2 (M+1)

The scheme (II) involves step 5 which involves formation of tert-butyl (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE IV) from (S)-4-(4-(5((1,3-dioxoisoindolin-2-yl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE-III) using reagent and a solvent. The reagent may be selected from methyl amine, hydrazine hydrate.

The solvent used in step 5 of scheme-II is selected from chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform, alcohols such as methanol, ethanol and isopropanol. The most preferred solvent is isopropanol.

The reaction of step 5 of scheme-II is carried at a temperature ranging from 50 to 100° C, more preferably, at 60 to 80 ° C.

The scheme (II) involves step 6 which involves formation of tert-butyl (S)-4-(4-(5-(acetamidomethyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE V) from tert-butyl (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE-IV) using reagent and a solvent. The reagent may be selected from acetic anhydride or acetyl chloride. The most preferred being acetic anhydride. The solvent used in step 6 of scheme-II are aromatic hydrocarbons like benzene, toluene and xylene. The most preferred being toluene.

The reaction of step 6 of scheme-II is carried at a temperature ranging from 5 to 50° C, more preferably, at 15 to 40 ° C.

The scheme (II) involves step 7 which involves formation of (S)-N-((3-(3-fluoro-4-(piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide (EPE-VI) from tert-butyl (S)-4-(4-(5-(acetamidomethyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE V) by using a deprotecting agent such as trifluoroacetic acid or hydrochloric acid in methanol. The solvent used in step 7 of scheme-II are chlorinated hydrocarbons like dichloromethane, chloroform, carbon tetrachloride. The most preferred being dichloromethane.

The reaction of step 7 of scheme-II is carried at a temperature ranging from 10 to 50° C, more preferably, at 15 to 40 ° C.

The scheme (II) involves step 8 which involves formation of eperezolid (I) from (S)-N-((3-(3-fluoro-4-(piperazin-1-yl) phenyl)-2- oxooxazolidin-5-yl) methyl) acetamide (EPE-VI). The reagents used in step 7 are selected from N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, N,N’-dicyclohexylcarbodiimide/HATU/HOBT. The solvents used in step 8 are amides such as formamide, dimethylforamide and N-methyl-pyrrolidone. The preferred solvent being dimethyl formamide.

Scheme (III) discloses the process for the preparation of Sutezolid.

Scheme (III)

Scheme (III) involves the syntheses of 4-(2-fluoro-4-nitrophenyl)thiomorpholine, in step 1 by the reaction of 1,2 difluoro-4-nitrobenzene and thiomorpholine in the presence of organic base and a solvent.

The base used in step 1 of scheme-III is selected an organic base that can be used in step 1 includes pyridine, N-methyl morpholine, N-methyl pyrrolidine, N,N-diisopropylethyl amine, tertiary alkyl amine such as triethyl amine, tertiary butyl amine etc, the most preferred base is N,N-diisopropylethyl amine.

The process of step 1 of scheme-III of the present invention can be carried out in organic solvent that include aromatic hydrocarbons like benzene, toluene and xylene; esters like ethyl acetate and isopropyl acetate; ethers such as ethyl ether, methyl t-butyl ether, di-isopropyl ether and tetrahydrofuran; amides such as formamide, dimethylforamide and N-methyl-pyrrolidone; nitriles such as acetonitrile and propionitrile; chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone and mixtures thereof. The most preferred solvent for step 1 is acetonitrile.

The reaction of step 1 of scheme-III is carried at a temperature ranging from 10 to 100° C, more preferably, at 20 to 90 ° C.

The scheme (III) involves step 2 which involves the reduction of 4-(2-fluoro-4-nitrophenyl) thiomorpholine to 3-fluoro-4-thiomorpholinoaniline using a reducing agent and a solvent.

The reduction of step 2 of scheme-III can be done in the presence of reducing agents such as palladium on carbon, iron/ammonium chloride, iron/acetic acid, raney nickel etc. The solvent used in step 2 is selected from chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform, alcohols such as methanol, ethanol and isopropanol, esters such as ethyl acetate and mixtures thereof.

The scheme (III) involves step 3 which involves the coupling of 3-fluoro-4-thiomorpholinoaniline and 3-(1,3-dioxoisoindolin-2-yl) propanal (EPE-I) in the presence of L-proline and nitrosobenzene in the presence of chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform to give (R)-2-(3-((3-fluoro-4-thiomorpholinophenyl)amino)-2-hydroxypropyl)isoindoline-1,3-dione (SUT-II).

The reaction of step 3 of scheme-III is carried at a temperature ranging from –10 to 20° C, more preferably, at 0 to 10 ° C.

The novel intermediate (R)-2-(3-((3-fluoro-4-thiomorpholinophenyl)amino)-2-hydroxypropyl)isoindoline-1,3-dione (SUT-II) has the following NMR and Mass
1H NMR [MeOD] : d 7.87 (dd, 2H J=10 & 5 Hz) ; d 7.82 (dd, 2H J=10.0 & 5 Hz) ; d 6.90 (t, 1H J=10 & 15 Hz) ; d 6.40-6.43 (m 2H) ; d 4.13 (m, 1H) ; d 3.80 (m, 2H) ; d 3.09-3.21 (m,6H) ; d 2.77(m,4H)

Mass (M/Z): 416.0 (M+1)

The scheme (III) involves step 4 which involves the cyclization of (R)-2-(3-((3-fluoro-4-thiomorpholinophenyl)amino)-2-hydroxypropyl)isoindoline-1,3-dione (SUT-II) to give (S)-2-((3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-yl)methyl)isoindoline-1,3-dione (SUT-III) in the presence of cyclizing agent such as 1,1’ -carbonyl diimidazole or diethyl carbonate or dimethyl carbonate in the presence of catalytic amount of dimethyl aminopyridine. The solvents used for the reaction are aromatic hydrocarbons like benzene, toluene and xylene; esters like ethyl acetate and isopropyl acetate; ethers such as ethyl ether, methyl t-butyl ether, di-isopropyl ether and tetrahydrofuran; amides such as formamide, dimethylforamide and N-methyl-pyrrolidone; nitriles such as acetonitrile and propionitrile; chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone and mixtures thereof. The most preferred solvent being dichloromethane.

The reaction of step 4 of scheme-III is carried at a temperature ranging from 10 to 50° C, more preferably, at 20 to 40 ° C.

The novel intermediate (S)-2-((3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-yl)methyl)isoindoline-1,3-dione (SUT-III) has the following NMR and Mass

1H NMR [CDCl3] : d 7.87 (dd, 2H J=10 & 5 Hz) ; d 7.91 (dd, 2H J=10.0 & 5 Hz) ; d 7.43 (dd, 1H J=10 & 5 Hz) ; d 7.12 (m 2H) ; d 4.98 (m, 1H) ; d 4.93 (m, 1H) ; d 4.17 (m,1H) ; d 3.95 (dd, 1H J=10.0 & 5.0 Hz) ; d 3.87 (m,2H) ; d 3.20 (m,4H) d 2.50 (m, 4H).

Mass (M/Z): 883.1s (M+1)

The scheme (III) involves step 5 which involves formation of (SUT IV) from (S)-2-((3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-yl)methyl)isoindoline-1,3-dione (SUT-III) using reagent and a solvent. The reagent may be selected from methyl amine, hydrazine hydrate.

The solvent used in step 5 of scheme-III is selected from chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform, alcohols such as methanol, ethanol and isopropanol. The most preferred solvent is isopropanol.

The reaction of step 5 of scheme-III is carried at a temperature ranging from 50 to 100° C, more preferably, at 60 to 80 ° C.

The scheme (III) involves step 6 which involves formation of sutezolid from (SUT-IV) using reagent and a solvent. The reagent may be selected from acetic anhydride or acetyl chloride. The most preferred being acetic anhydride. The solvent used in step 6 of scheme-III are chlorinated hydrocarbons like dichloromethane, chloroform or carbon tetrachloride. The most preferred being dichloromethane.

The reaction of step 6 of scheme-II is carried at a temperature ranging from 5 to 50° C, more preferably, at 15 to 40 ° C.

The aforementioned process for the preparation of oxazolidinones has the following advantages:
i) Higher yields,
ii) simple and quick process,
iii) easy to scale up,
iv) economical process,
v) avoids multiple purifications and
vi) avoids formation of the unwanted isomers.

The principles, preferred embodiments, and modes of operation of the present invention have been described in the foregoing examples. The following examples are provided to illustrate the process of the present invention and are not intended to be construed as limitations of the present invention.

Examples :
Example 1: Tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate
1,2 difluoro-4-nitrobenzene (5 gm) was added to methanol (100 ml). The reaction mixture was stirred followed by addition of triethylamine (1.2 equivalent) and Boc-pipererazine (1.1 equivalent). The reaction was stirred at 50 to 60 °C for 17 hours. The reaction mixture was cooled followed by addition of water and stirring. The solid was filtered and dried under reduced pressure to get the title compound.
Yield : 91%

Example 2: Tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate
Tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate ( 5 gm) was added to dichloromethane (100 ml) followed by addition of 10 % Pd-C (0.5 w/w) and stirred. After co0mpletion of the reaction, it was filtered and washed followed by drying under reduced pressure to give the title compound.
Yield: 95%

Example 3: Tert-butyl (R)-4-(4-((3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypropyl)amino)-2-fluorophenyl)piperazine-1-carboxylate (EPE-II)
L-proline was charged to chloroform and cooled to 4 °C. Nitrosobenzene was added followed by addition of 3-(1,3-dioxoisoindolin-2-yl) propanal (EPE-I). The reaction mass was stirred at 0-5°C. The reaction mixture was concentrated and diluted with dichloromethane. The resulting solution was added to Tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate and sodium triacetoxyborohydride at 0°C. The organic layer was concentrated and dried under reduced pressure to give the title compound.
Yield: 75%

1H NMR (CDCl3): ? 7.86 (dd, 2H J=7.0 and 3.5 Hz) ; ? 7.50 (dd, 2H J=7.0 and 3.5 Hz); ? 6,82 (m 1H); ? 6.44-6.38 (m, 2H); ? 4.14 (m, 1H) ; ? 3.90 (m, 2H); ? 3.57 (m, 4H); ? 3.23 (dd, J=13.0 and 5.0 Hz 1H); ? 3.13 (dd, 1H, J=13.0 and 5.0 Hz) ; ? 2.90 (m, 4H); ? 1.49 (s, 9H)
Mass (M/Z): 499.3 (M+1)

Example 4: Tert-butyl (S)-4-(4-(5((1,3-dioxoisoindolin-2-yl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE-III)
Tert-butyl (R)-4-(4-((3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypropyl)amino)-2-fluorophenyl)piperazine-1-carboxylate (EPE-II) was charged in dichloromethane. 1,1’-carbonyldiimidazole was added followed by the addition of catalytic dimethyl amino pyridine. The reaction mass was stirred at 30-35°C.The reaction was quenched by water. The organic layer was separated and concentrated to give the title compound.
Yield: 92%

1H NMR (CDCl3): ? 7.90 (dd, 2H J=7.0 and 3.5 Hz) ; ? 7.78 (dd, 2H J=7.0 and 3.5 Hz); ? 7.40 (dd, 1H J=14.0 and 2.5 Hz); ? 7.12 (d, 1H J=9.0 and 2.0 Hz); ? 6.93 (m, 1H); ? 4.98 (m 1H); ? 4.17-4.08 (m, 2H); ? 3.99 (dd, 1H J = 8.5 and 6.0 Hz) ; ? 3.88 (dd, 1H J= 9.0 and 6.0 Hz); ? 3.60 (m, 4H); ? 3.0 (m, 4H) and ? 1.50 (s, 9H)
Mass (M/Z): 525.2 (M+1)

Example 5: Tert-butyl (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE IV)
Tert-butyl (S)-4-(4-(5((1,3-dioxoisoindolin-2-yl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE-III) was added to isopropyl alcohol. Aqueous methyl amine was added and the reaction mixture was stirred at 70-75°C. The reaction mixture was cooled and concentrated under reduced pressure to give the title compound.
Yield: 92%

Example 6: Tert-butyl (S)-4-(4-(5-(acetamidomethyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE V)
Tert-butyl (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE IV) was added to dichloromethane. Acetic anhydride was added and the reaction mass was stirred at 20-30°C. After completion of the reaction the mass was quenched with sodium bicarbonate and the organic layer was separated. The organic layer was concentrated and purified.
Yield: 95%

Example 7: (S)-N-((3-(3-fluoro-4-(piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide (EPE-VI)
(S)-4-(4-(5-(acetamidomethyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl) piperazine-1-carboxylate (EPE V) was added to dichloromethane. To the reaction mixture, trifluoroacetic acid was added and the reaction mass was stirred. The reaction mass was concentrated and purified using column chromatography to give title compound.
Yield: 90%

Example 8: Eperezolid
Glycolic acid was added to dimethyl formamide. N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride was added to the reaction mixture and stirred at 20-30°C. (S)-N-((3-(3-fluoro-4-(piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide (EPE-VI) was added to the reaction mixture. The mixture was quenched with water and extracted with ethyl acetate and concentrated to give eperezolid.
Yield: 83%

Example 9: 4-(2-fluoro-4-nitrophenyl)thiomorpholine
1,2 difluoro-4-nitrobenzene and N,N-diisopropylethyl amine was added to acetonitrile followed by the addition of thiomorpholine. The reaction mixture was refluxed. The reaction mass was cooled and concentrated under reduced pressure to give title compound.
Yield: 99%

Example 10: 3-fluoro-4-thiomorpholinoaniline
4-(2-fluoro-4-nitrophenyl) thiomorpholine was charged in ethyl acetate followed by the addition of ammonium chloride (3 v/w) and iron powder. The reaction mixture was heated to 60-70°C for 5 hours. Ethyl acetate was added after cooling. The solid was filtered and dried under reduced pressure to give the title compound.
Yield: 90%

Example 11: (R)-2-(3-((3-fluoro-4-thiomorpholinophenyl)amino)-2-hydroxypropyl)isoindoline-1,3-dione (SUT-II)
L-proline was charged to chloroform and cooled to 4 °C. Nitrosobenzene was added followed by addition of 3-(1,3-dioxoisoindolin-2-yl) propanal (EPE-I). The reaction mass was stirred at 0-5°C. The reaction mixture was concentrated and diluted with dichloromethane. The resulting solution was added to Tert-butyl 3-fluoro-4-thiomorpholinoaniline and sodium triacetoxyborohydride at 0°C. The organic layer was concentrated and dried under reduced pressure to give the title compound.
Yield: 65%

1H NMR [MeOD] : d 7.87 (dd, 2H J=10 & 5 Hz) ; d 7.82 (dd, 2H J=10.0 & 5 Hz) ; d 6.90 (t, 1H J=10 & 15 Hz) ; d 6.40-6.43 (m 2H) ; d 4.13 (m, 1H) ; d 3.80 (m, 2H) ; d 3.09-3.21 (m,6H) ; d 2.77(m,4H)
Mass (M/Z): 416.0 (M+1)

Example 12: (S)-2-((3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-yl)methyl)isoindoline-1,3-dione (SUT-III)
(R)-2-(3-((3-fluoro-4-thiomorpholinophenyl)amino)-2-hydroxypropyl)isoindoline-1,3-dione (SUT-II) was charged in dichloromethane. 1,1’-carbonyldiimidazole was added followed by the addition of catalytic dimethyl amino pyridine. The reaction mass was stirred at 30-35°C.The reaction was quenched by water. The organic layer was separated and concentrated to give the title compound.
Yield: 90%

1H NMR [CDCl3] : d 7.87 (dd, 2H J=10 & 5 Hz) ; d 7.91 (dd, 2H J=10.0 & 5 Hz) ; d 7.43 (dd, 1H J=10 & 5 Hz) ; d 7.12 (m 2H) ; d 4.98 (m, 1H) ; d 4.93 (m, 1H) ; d 4.17 (m,1H) ; d 3.95 (dd, 1H J=10.0 & 5.0 Hz) ; d 3.87 (m,2H) ; d 3.20 (m,4H) d 2.50 (m, 4H).
Mass (M/Z): 883.1s (M+1)

Example 13: SUT-IV
(S)-2-((3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-yl)methyl)isoindoline-1,3-dione (SUT-III) was added to isopropyl alcohol. Aqueous methyl amine was added and the reaction mixture was stirred at 70-75°C. The reaction mixture was cooled and concentrated under reduced pressure to give the title compound.
Yield: 93%

Example 14: Sutezolid
(SUT IV) was added to dichloromethane. Acetic anhydride (1.2 eq) was added and the reaction mass was stirred at 20-30°C. After completion of the reaction the mass was qauenched with sodium bicarbonate and the organic layer was separated. The organic layer was concentrated and purified.
Yield: 93%
,CLAIMS:
1) A compound of formula EPE-II

2) A compound of formula EPE-III

3) The process for the preparation for Eperezolid which comprises the steps of
a) syntheses of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate by reaction of 1,2 difluoro-4-nitrobenzene and N-Boc piperazine in the presence of organic base and a solvent;
b) reduction of tert-butyl 4-(2-fluoro-4-nitrophenyl)piperazine-1-carboxylate to tert-butyl 4-(4-amino-2-fluorophenyl)piperazine-1-carboxylate using a reducing agent and a solvent;
c) coupling of tert-butyl 4-(4-amino-2-fluorophenyl) piperazine-1-carboxylate and 3-(1,3-dioxoisoindolin-2-yl) propanal (EPE-I) to give tert-butyl (R)-4-(4-((3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypropyl)amino)-2-fluorophenyl)piperazine-1-carboxylate (EPE-II) in the presence of L-proline and nitrosobenzene and in presence of chlorinated hydrocarbons;
d) cyclization of tert-butyl (R)-4-(4-((3-(1,3-dioxoisoindolin-2-yl)-2-hydroxypropyl)amino)-2-fluorophenyl)piperazine-1-carboxylate (EPE-II) to give tert-butyl (S)-4-(4-(5((1,3-dioxoisoindolin-2-yl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE-III) ;
e) formation of tert-butyl (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE IV) from (S)-4-(4-(5((1,3-dioxoisoindolin-2-yl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE-III) using reagent and a solvent;
f) tert-butyl (S)-4-(4-(5-(acetamidomethyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE V) from tert-butyl (S)-4-(4-(5-(aminomethyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE-IV) using reagent and a solvent;
g) formation of (S)-N-((3-(3-fluoro-4-(piperazin-1-yl)phenyl)-2- oxooxazolidin-5-yl)methyl)acetamide (EPE-VI) from tert-butyl (S)-4-(4-(5-(acetamidomethyl)-2-oxooxazolidin-3-yl)-2-fluorophenyl)piperazine-1-carboxylate (EPE V) and
h) formation of eperezolid (I) from (S)-N-((3-(3-fluoro-4-(piperazin-1-yl) phenyl)-2- oxooxazolidin-5-yl) methyl) acetamide (EPE-VI).

4) The process of claim 3 (a) wherein solvent used is selected from a group of aromatic hydrocarbons like benzene, toluene and xylene; esters like ethyl acetate and isopropyl acetate; ethers such as ethyl ether, methyl t-butyl ether, di-isopropyl ether and tetrahydrofuran; amides such as formamide, dimethylforamide and N-methyl-pyrrolidone; nitriles such as acetonitrile and propionitrile; chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone and mixtures thereof.

5) The process of claim 3 (a) wherein the base is selected from a group of pyridine, N-methyl morpholine, N-methyl pyrrolidine, tertiary alkyl amine such as triethyl amine, tertiary butyl amine etc, the most preferred base is triethyl amine.

6) The process of claim 3 (b) wherein the reducing agent is selected from reducing agents such as palladium on carbon, iron/ammonium chloride, iron/acetic acid, raney nickel.

7) The process of claim 3 (b) wherein solvent used is selected from a group of chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform, alcohols such as methanol, ethanol and isopropanol, esters such as ethyl acetate and mixtures thereof.

8) The process of claim 3 (c) wherein the solvent is selected from a group of chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform.

9) The process of claim 3 (d) wherein the cyclizing agent is selected from group of 1,1’ -carbonyl diimidazole or diethyl carbonate or dimethyl carbonate.

10) The process of claim 3 (d) wherein the catalyst used is dimethyl amino pyridine.

11) The process of claim 3 (d) wherein solvent is selected from a group of aromatic hydrocarbons like benzene, toluene and xylene; esters like ethyl acetate and isopropyl acetate; ethers such as ethyl ether, methyl t-butyl ether, di-isopropyl ether and tetrahydrofuran; amides such as formamide, dimethylforamide and N-methyl-pyrrolidone; nitriles such as acetonitrile and propionitrile; chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone and mixtures thereof.

12) The process of claim 3 (e) wherein the reagent is selected from a group of methyl amine, hydrazine hydrate.

13) The process of claim 3 (e) wherein the solvent is selected from group of chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform, alcohols such as methanol, ethanol and isopropanol.

14) The process of claim 3 (f) wherein reagent is selected from acetic anhydride or acetyl chloride.

15) The process of claim 3 (f) wherein the solvent is selected from aromatic hydrocarbons like benzene, toluene and xylene.

16) The process of claim 3 (g) wherein the deprotecting agent is selected from trifluoroacetic acid or hydrochloric acid.

17) The process of claim 3 (g) wherein the solvent is selected from chlorinated hydrocarbons like dichloromethane, chloroform, carbon tetrachloride. The most preferred being dichloromethane.

18) The process of claim 3 (h) wherein the eperezolid is synthesized from (S)-N-((3-(3-fluoro-4-(piperazin-1-yl) phenyl)-2- oxooxazolidin-5-yl) methyl) acetamide.

19) The process of claim 3 (h) wherein N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride, N, N’-dicyclohexylcarbodiimide/HATU/HOBT.

20) The process of claim 3 (h) wherein amides such as formamide, dimethylforamide and N-methyl-pyrrolidone.

21) Process for the preparation of Sutezolid which comprises the steps of
a) synthesis of 4-(2-fluoro-4-nitrophenyl) thiomorpholine by the reaction of 1,2 difluoro-4-nitrobenzene and thiomorpholine in the presence of organic base and a solvent;
b) reduction of 4-(2-fluoro-4-nitrophenyl) thiomorpholine to 3-fluoro-4-thiomorpholinoaniline using a reducing agent and a solvent;
c) coupling of 3-fluoro-4-thiomorpholinoaniline and 3-(1,3-dioxoisoindolin-2-yl) propanal (EPE-I) in the presence of L-proline and nitrosobenzene in the presence of solvent;
d) cyclization of (R)-2-(3-((3-fluoro-4-thiomorpholinophenyl) amino)-2-hydroxypropyl) isoindoline-1,3-dione (SUT-II) to give (S)-2-((3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-yl)methyl)isoindoline-1,3-dione (SUT-III) in the presence of cyclizing agent;
e) formation of (SUT IV) from (S)-2-((3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-yl) methyl)isoindoline-1,3-dione (SUT-III) using reagent and a solvent;
f) formation of sutezolid from (SUT-IV) using reagent and a solvent.

22) The novel intermediate (R)-2-(3-((3-fluoro-4-thiomorpholinophenyl)amino)-2-hydroxypropyl)isoindoline-1,3-dione (SUT-II)

23) The process of claim 21 (a) wherein base used is organic base selected from pyridine, N-methyl morpholine, N-methyl pyrrolidine, N,N-diisopropylethyl amine, tertiary alkyl amine such as triethyl amine, tertiary butyl amine.

24) The process of claim 21 (a) wherein organic solvent is selected from a group of aromatic hydrocarbons like benzene, toluene and xylene; esters like ethyl acetate and isopropyl acetate; ethers such as ethyl ether, methyl t-butyl ether, di-isopropyl ether and tetrahydrofuran; amides such as formamide, dimethylforamide and N-methyl-pyrrolidone; nitriles such as acetonitrile and propionitrile; chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone.

25) The process of claim 21 (b) wherein reducing agent is selected from a group of palladium on carbon, iron/ammonium chloride, iron/acetic acid, raney nickel.

26) The process of claim 21 (b) wherein solvent is selected from chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform, alcohols such as methanol, ethanol and isopropanol, esters such as ethyl acetate and mixtures thereof.

27) The process of claim 21 (c) wherein coupling reaction is done in the presence of L-proline and nitrosobenzene and in the presence of chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform.

28) The process of claim 21 (d) wherein cyclizing agent is selected from 1,1’ -carbonyl diimidazole or diethyl carbonate or dimethyl carbonate in the presence of catalytic amount of dimethyl aminopyridine.

29) The process of claim 21 (d) wherein solvent is selected from aromatic hydrocarbons like benzene, toluene and xylene; esters like ethyl acetate and isopropyl acetate; ethers such as ethyl ether, methyl t-butyl ether, di-isopropyl ether and tetrahydrofuran; amides such as formamide, dimethylforamide and N-methyl-pyrrolidone; nitriles such as acetonitrile and propionitrile; chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform, alcohols such as methanol, ethanol, isopropanol, ketones such as acetone, methyl ethyl ketone and mixtures thereof.

30) The process of claim 21 (e) wherein reagent used is methyl amine, hydrazine hydrate.

31) The process of claim 21 (e) wherein solvent used is chlorinated hydrocarbons such as dichloromethane, ethylene dichloride and chloroform, alcohols such as methanol, ethanol and isopropanol.

32) The process of claim 21(f) wherein reagent may be selected from acetic anhydride or acetyl chloride.

33) The process of claim 21(f) wherein solvent used is chlorinated hydrocarbons like dichloromethane, chloroform or carbon tetrachloride.

34) The novel intermediate (S)-2-((3-(3-fluoro-4-thiomorpholinophenyl)-2-oxooxazolidin-5-yl) methyl) isoindoline-1,3-dione (SUT-III)