FIELD OF THE INVENTION:
The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of Sutezolid and its intermediates.
BACKGROUND OF THE INVENTION:
Sutezolid (PNU-100480) is a synthetic antibiotic, the first of the oxazolidinone class, used for the treatment of extensively drug-resistant tuberculosis (TB) and other infectious diseases. However, sutezolid has better antimycobacterial activity than linezolid both in vitro and in a mouse model of TB. Sutezolid has an improved safety profile compared to linezolid and shows better time dependent killing in an ex vivo whole blood culture test. In addition, it has activity against both drug susceptible and drug resistant TB.
Sutezolid is chemically known as (S)-N-[[3-(3-fluoro-4-thiomorpholinylphenyl)-2-oxo-5-oxazolidinyl] methyl] acetamide having the formula (I).
Sutezolid is first disclosed in U.S. Pat. No. 5,880,118 and its process comprises the use of R-glycidylbutyrate which results in the formation of (R)-N-[[3-[3-fluoro-4-thiomorpholinyl] phenyl]-2-oxo-5-oxazolidinyl] methanol which in the subsequent stages has to be converted to various intermediary compounds to finally form Sutezolid, which is depicted in the scheme-I given below.

The above said prior art process, also encompasses an intermediary azide compound, which is difficult to handle at industrial level:
WO 2010/122456 A2 discloses a process for the preparation of Sutezolid, which is comprises compound of formula (XIV) reacted with the compound of formula (XIII) to get the (S)-l-chloro-3-[(4-chloro-E-benzylidene)-amino]-propan-2-ol of formula (XII), further it reacts with (3-fluoro-4-moipholin-4-yl-phenyl)-carbamic acid benzyl ester and followed by deprotection to obtained (S)-5-(aminomethyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazolidin-2-one dihydrochloride compound of formula (XVIIIa) and subsequently reacted with acetic anhydride to afford Sutezolid, which is depicted in the scheme-II given below:

In view of the above aforesaid methods available for Sutezolid, there is a need for simple and cost effective processes for the preparation of Sutezolid that provides improved efficiency per reaction volume in terms of yield and purity, including both chemically and chirally.
There is consequently a need for an alternative method for the preparation of Sutezolid and its intermediates, which does not involve the problems described above. Therefore, there is a need in the art for a simple and facile process for the synthesis of Sutezolid, and our inventors have developed a cost-effective and industrially viable process.
SUMMARY OF THE INVENTION
The present invention relates to an improved process for the preparation of sutezolid and its intermediates in terms of yield and purity, including both chemically and chirally.
In one aspect of the present invention provides an improved process for the preparation of (S)-5-(aminomethyl)-3-(3-fluoro-4-thiomorpholinophenyl) oxazolidin-2-one of formula (XVIII) comprising, treating ^-(3-(3-fluoro-4-thiomorpholino

phenyl)-2-oxooxazolidin-5-yl) methyl methanesulfonate compound of formula (XXI) with ammonia gas in presence of organic solvent.
In another aspect of the present invention provides an improved process for the preparation of Sutezolid of formula (I) comprising the steps of;
a) reacting the compound of formula (XVI) with (R)-oxiran-2-yl-methyl butyrate of formula (VI) in the presence of base and organic solvent to give a compound of formula (V),
b) reacting the compound of formula (V) with sulfonating agent in presence of base and organic solvent to give compound of formula (XXI),
c) the compound of formula (XXI) is treated with ammonia gas in presence of organic solvent,
d) acylating the product of step c) and
e) isolating the compound of formula (I).
The above synthetic process is illustrated by the following Scheme:

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to an improved, commercially viable and industrially advantageous process for the preparation of Sutezolid and its intermediates.
In one embodiment of the present invention provides an improved process for the preparation of (S)-5-(aminomethyl)-3-(3-fluoro-4-thiomorpholinophenyl)oxazolidin-2-one of formula (XVIII), which comprises treating a (2^-(3-(3-fluoro-4-thiomorpho linophenyl)-2-oxooxazolidin-5-yl)methyl methanesulfonate compound of formula (XXI) with ammonia gas in presence of organic solvent.
According to an embodiment of the present invention, the compound of (R)-3-(3-fluoro-4-thiomorpholin-4-yl-phenyl)-2-oxo-oxazolidin-5yl)-methylmethanesulfonate (XXI) treated with ammonia gas at room temperature and isolate the solid with a suitable organic solvent to get a compound of (5S)-5-(amino methyl)-3-[3-fluoro-4-(Thiomorpholin-4-yl) phenyl]-l,3 oxazolidin-2-one (XVIII).

In another embodiment of the present invention, an improved process for the preparation of Sutezolid the compound of formula (I) comprising the steps of;
a) reacting the compound of formula (XVI) with (R)-oxiran-2-yl-methyl butyrate of formula (VI) in the presence of base and organic solvent to give a compound of formula (V),
b) reacting the compound of formula (V) with sulfonating agent in presence of base and organic solvent to get compound of formula (XXI),
c) the compound of formula (XXI) treated with ammonia gas in presence of organic solvent,
d) acylating the product of step c) and
e) isolating the compound of formula (I).
According to an embodiment of the present invention, the reaction between the compound of formula (XVI) with ^-oxiran-2-yl-methyl butyrate of formula (VI) is carried out in the presence of a suitable base and organic solvent at a suitable temperature and allow to stir at 20-40° C for 15 mins, preferably 25-30° C for 10 mins to obtain a compound of formula (V); this compound reacted with sulfonating agent in presence of base and organic solvent at ambient temperature and allow to stir for 10 mins and then cool to 0-5° C to give a compound of formula (XXI) and followed by treated with ammonia gas at room temperature and isolate the solid with a suitable organic solvent to get a compound of formula (XVIII), which is subsequently acylated with acetic anhydride or acetyl chloride in presence of dichloromethane (MDC) at 20-25C and allow to stir for 60 min to give (S)-N-[[3-(3-fluoro-4-thiomorpholin ylphenyl)-2-oxo-5-oxazolidinyl]methyl] acetamide (Sutezolid) of formula I.
According to one embodiment of the present invention, the acylation is carried out in the presence of acetic anhydride or acetyl chloride.
According to one embodiment of the present invention, the sulfonating agent is selected from methanesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenz enesulfonyl chloride, 4-nitrobenzenesulfonyl chloride and trifluoromethane sulfonyl chloride. Preferably methanesulfonyl chloride.

According to embodiments of the present invention, the suitable base is selected from the alkali metal tert butoxides, which are potassium tert-butoxide, lithium tert-butoxide, magnesium tert-butoxide and sodium tert-butoxide; amines are methyl amine , dimethyl amine, trimethyl amine, triethyl amine and diisopropyl ethyl amine.
According to an embodiments of the present invention, suitable solvent is selected from alcohols such as methanol, ethanol, isopropyl alcohol and the like or mixture thereof; ketones such as methyl isobutyl ketone, methyl ethyl ketone, n-butanone and the like; halogenated solvents such as dichloromethane, ethylene dichloride, chloroform and the like; esters such as ethyl acetate, n-propyl acetate, isopropyl acetate and the like; hydrocarbon solvents such as toluene, xylene, cyclohexane and the like; ethers such as 1,4-dioxane, tetrahydrofuran and the like; and amides such as N,N-dimethylformamide, N,N-dimethylacetamide and the like or dimethylsulfoxide or mixture of solvents thereof.
Advantages of the present invention:
1. The present invention is a simple, operation friendly and industrially
applicable process.
2. The process is commercially viable and provides the compounds in high yield,
which makes the process cost effective.
3. The reaction sequence of the present invention is carried out in a shorter time
span with high purity and less impurity profile.
The process details of the invention are provided in the examples given below, which are provided by way of illustration only and therefore should not be construed to limit the scope of the invention.
Experimental procedure:
Example-1:
Preparation of (R)-3-(3-fluoro-4-thiomorpholin-4-vl-phenyl)-5-(hvdroxv methyfl-
oxazolidin-2-one

Methyl (3-fluoro-4-thiomorpholinophenyl) carbamate (50 g, 0.160 moles) were added in tetrahydrofuran (200 ml) and then added one lot of R(-) glycidylbutyrate (50 g, 0.347 moles) and potassium tertiary butoxide (20 g,0.178 moles) at 25 to 30°C.The resulting reaction mass was stirred about 24 hrs at 25 to 30°C, till completion of the reaction, checked by thin layer chromatography (TLC). The reaction mixture solvent was distilled out under reduced pressure at below 50°C and further cooled to 25-30 °C, added ethyl acetate (500 ml) and purified water (200 ml) stir for 15 min, to separate the layers. The resultant ethyl acetate layer was washed with purified water and then the obtained organic layer (ethyl acetate) was distilled out under reduced pressure at below 60° C to get solid material and then added methanol (100ml), stir at below 60° C and further cooled to 25-30° C. The resultant solid was filtered to get the product pure (S^-3-(3-Fluoro-4-thiomorpholin-4-yl-phenyl)-2-oxooxazolidin-5-yl) methylmethane sulfonate. Yield: 55g,(88%)
Example-2:
Preparation of (R) -3-(3-fluoro-4-thiomorpholin-4-yl-phenyl)-5- (hydroxyl methyl) -
oxazolidin-2-one
Methyl (3-fluoro-4-thiomorpholinophenyl) carbamate (50 g, 0.160 moles) were added in N,N-dimethylformamide (200 ml) and stirred for 10 min at 25 to 30°C. Followed by one lot addition of R(-)glycidylbutyrate (50g, 0.347 moles) and sodium hydride (4.0g,0.166 moles) at same temperature, till completion of the reaction checked by TLC. The reaction mixture solvent was distilled out under reduced pressure at below 50°C and further cooled to 25-30 °C, added ethyl acetate (500 ml) and purified water (200 ml), stir for 15 min, separate the layers. The resultant ethyl acetate layer was washed with purified water and then the obtained organic layer solvent (ethyl acetate) was distilled out under reduced pressure at below 60° C to get solid material and then added methanol (100ml), stir at below 60° C and further cooled to 25-30°C. The resultant solid was filtered to get the product pure (S^)-3-(3-Fluoro-4-thiomorpholin-4-yl-phenyl)-2-oxooxazolidin-5-yl) methylmethanesulfonate. Yield: 50g, (80%)

Example-3:
Preparation of (R) -3-(3-Fluoro-4-thiomorpholin-4-yl-phenyl)-2- oxo- oxazolidin-
5yl)-methylmethanesulfonate
A mixture of (S)-3-(3-Fluoro-4-thiomorpholin-4-yl-phenyl)-5-(hydroxyl methyl)-oxazolidin-2-one (50 g, 0.160 moles) , dichloromethane (200 ml) and triethylamine (32.0 g ,0.316 moles) was stirred for 10 min at 25 to 30°C. The reaction mixture was cooled to 0-5°C and slowly added methanesulfonylchloride (22.Og, 0.192moles) over a period of 1-2 hrs at below 10°C and then allow to stir for 2-4 hrs at 25-30°C to complies the reaction, checked by TLC. Further, the reaction mixture was cooled to below 30° C, added water (200 ml) and stir for 10 min at 25-30° C to separate the layers. The resultant dichloromethane layer was washed with purified water (50 ml) and then the obtained organic layer solvent (MDC) was distilled out under reduced pressure at below 40 °C to get solid material and then added isopropanol (100ml),stir at below 60° C and further cooled to 25-30°C. The resultant solid was filtered to obtained pure (R)-3-(3-Fluoro-4-thiomorpholin-4-yl-phenyl)-2-oxo-oxazolidin-5yl) methyl methane sulfonate. Yield: 50g, (80%)
Example-4:
Preparation of (R) -3-(3-Fluoro-4-thiomorpholin-4-vl-phenyl)-2- oxo- oxazolidin-
5yl)-methylmethanesulfonate
A mixture of (R)-3-(3-Fluoro-4-thiomorpholin-4-yl-phenyl)-5-(hydroxymethyl)-oxazolidin-2-one (50g,0.160moles), toluene (200 ml) and triethylamine (32.0g,0.316 moles) was stirred for 10 min at 25 to 30°C. The reaction mixture was cooled to 0-5°C and slowly added methanesulfonylchloride (22.5g, 0.196moles) over a period of 1-2 hrs at below 10°C and then allow to stir for 2-4 hrs at 25-30°C to complies the reaction, checked by TLC. Further, the reaction mixture was cooled to below 30° C, added water (200 ml) and stir for 10 min at 25-30° C to separate the layers. The resultant toluene layer was washed with purified water (50 ml) and then the obtained organic layer solvent (toluene) was distilled out under reduced pressure at below 60 °C to get solid material and then added methanol (100ml), stir at below 60° C and further

cooled to 25-30°C. The resultant solid was filtered to obtained pure (R)-3-(3-Fluoro-4-thiomorpholin-4-yl-phenyl)-2-oxo-oxazolidin-5yl) methyl methane sulfonate. Yield : 45g,(72%)
Example-5:
(5S)-5-(amino methyl)-3-]3-fluoro-4-(Thiomorpholin-4-yl) phenyl]-l,3oxazolidin-2-
one
(R)-3-(3-Fluoro-4-thiomorpholin-4-yl-phenyl)-2-oxooxazolidin-5-yl)methyl methane sulfonate (50g, 0.128moles) was added in methanol (500ml) and stirred for 10-20 min at 25-30°C. The reaction mixture was taken into an autoclave and pass ammonia gas up to 3.0-4.0 kg pressure at below 30°C, till completion of the reaction, checked by TLC. The resultant reaction mass was taken into R.B flask and then solvent was distilled out under reduced pressure at below 50°C to get solid material and then added Ethyl acetate (100ml) and cool the mixture at 25-30°C. The resultant solid was filtered, washed with ethyl acetate and dried at 60-65°C to afford a (5S)-5-(amino methyl)-3-[3-fluoro-4-(Thiomorpholin-4-yl) phenyl]-l,3oxazolidin-2-one. Yield: -30g, (75%).
Example-6:
(5S)-5-(amino methyl)-3-]3-fluoro-4-(Thiomorpholin-4-yl) phenyl]-!,3 oxazolidin-
2-one
(R)-3-(3-Fluoro-4-Thiomorpholin-4-yl-phenyl)-2-oxooxazolidin-5-yl)methyl methane sulfonate (50g,0.128moles) were added in methanol (500ml) and stirred for 10-20 min at 25-30°C.The reaction mixture was taken into an autoclave and pass ammonium carbonate (200g, 2.08 moles) at below 30°C and heated to reflux temperature, till completion of the reaction (-2-4 hrs) and then cooled to 25-30°C and filtered the solid to get a cleared solution. The resultant clear solution was taken into R.B flask and distilled out solvent completely under reduced pressure at below 50°C to get solid material and then added toluene (50ml) and cool the reaction mixture at 25-30°C. The resultant solid was filtered, washed with toluene and dried at 60-65°C to afford a (5S)-5-(amino methyl)-3-[3-fluoro-4-(Thiomorpholin-4-yl) phenyl]-l,3oxazolidin-2-one.

Yield : 35g, (88%).
Example - 7
Preparation of N-({(5S)-3-]3-fluoro-4-(thiomorpholin-4-yl) phenyl]-2-oxo-l,3-
oxazolidin-5-yl} methyl) acetamide (Sutezolid)
A solution of (5S)-5-(aminomethyl)-3-[3-fluoro-4-(thiomorpholin-4-yl)phenyl]-l,3-oxazolidin-2-one (50 g, 0.160 moles) in dichloromethane (250 ml) was stirred at 25-30°C, slowly added acetic anhydride (32.Og, 0.313 moles) at below 30°C. The reaction mixture was stirred for 2-3 hrs till complies the reaction, checked by TLC. The afford mixture was cooled to 0-5°C and maintained for 60 min at same temperature. The resultant solid was filtered, washed with methanol (25ml) and dried at 55-60°C to obtained pure product N-({(5S)-3-[3-fluoro-4-(Thiomorpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (Sutezolid). Yield: 35g,(62%).
Example - 8:
Preparation of N-({(5S)-3-]3-fluoro-4-(Thiomorpholin-4-yl) phenyl]-2-oxo-l, 3-
oxazolidin-5-yl} methyl) acetamide (Sutezolid)
A solution of (5S)-5-(aminomethyl)-3-[3-fluoro-4-(Thiomorpholin-4-yl) phenyl]-l, 3 oxazolidin-2-one (50 g , 0.160 moles) in ethyl acetate (250 ml) was stirred at 25-30°C, slowly added acetic anhydride (32.0 g , 0.313 moles) at below 30°C. The reaction mixture was stirred for 4-5hrs till complies the reaction, checked by TLC. The afford mixture was cooled to 0-5°C and maintained for 60 min at same temperature. The resultant solid was filtered, washed with ethyl acetate (25ml) and dried at 55-60°C to obtained pure product N-({(5S)-3-[3-fluoro-4-(Thiomorpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (Sutezolid). Yield: 40 g (70%).
Example -9:
Preparation of N-({(5S)-3-]3-fluoro-4-(Thiomorpholin-4-yl) phenyl]-2-oxo-l, 3-
oxazolidin-5-yl} methyl) acetamide (Sutezolid)

A solution of (5S)-5-(aminomethyl)-3-[3-fluoro-4-(Thiomorpholin-4-yl) phenyl]-l, 3 oxazolidin-2-one (50 g , 0.160 moles) in toluene (250 ml) was stirred at 25-30°C, slowly added acetic anhydride (32.Og, 0.313moles) at below 30°C. The reaction mixture was stirred for 4-5 hrs till complies the reaction, checked by TLC. The afford mixture was cooled to 0-5°C and maintained for 60 min at same temperature. The resultant solid was filtered, washed with toluene (25ml) and dried at 55-60°C to obtained pure product N-({(5S)-3-[3-fluoro-4-(Thiomorpholin-4-yl)phenyl]-2-oxo-l,3-oxazolidin-5-yl}methyl)acetamide (Sutezolid). Yield : 40 g (70%).

We Claims:
1. An improved process for the preparation of (S)-5-(aminomethyl)-3-(3-fluoro-4-thioraorpholinophenyl)oxazoiidin-2-one of formula (XVIII), which comprises reacting a ^-(3-(3-fluoro-4-tliiomorpholinophenyl)-2~oxo oxazolidin-5-yl)methyl methanesulfonate compound of formula (XXI) with ammonia gas in presence of organic solvent.
2. A process for the preparation of Sutezolid of formula (I) comprising the steps;
a) reacting the compound of formula (XVI) with (R)-oxiran-2-yl-methyl butyrate of formula (VI) in the presence of base and organic solvent to give a compound of formula (V),
b) reacting the compound of formula (V) with sulfonating agent in presence of base and organic solvent to get compound of formula (XXI),
c) the compound of formula (XXI) treated with ammonia gas in presence of organic solvent,
d) acylating the product of step c) and
e) isolating the compound of formula (I).

3. The process as claimed in claim 2, wherein the base is selected from the group consisting of alkali metal tert butoxides, which are potassium tert-butoxide, lithium tert-butoxide, magnesium tert-butoxide and sodium tert-butoxide and amines are methyl amine, dimethyl amine, trimethyl amine, isopropyl ethylamine, triethyl amine and tri-n-butyl amine.
4. The process as claimed in claim 2, wherein the acylating reagent is selected from the group consisting of acetic anhydride or acetyl chloride.

5. The process as claimed in preceding claims, wherein the solvent is selected from the group consisting of ethyl acetate, dimethyl formamide, methanol, ethanol, isopropyl alcohol, dichloromethane and dimethyl sulfoxide or mixtures thereof.
6. The process as claimed in preceding claims, wherein the sulfonating agent is selected from the group consisting of methanesulfonyl chloride, p-toluenesulfonyl chloride, p-bromobenzene sulfonyl chloride, 4-nitrobenzenesulfonyl chloride and trifluoromethane sulfonyl chloride.