FIELD OF THE INVENTION
The present application provides an improved process for preparing Pretomanid using a compound of formula II.
BACKGROUND OF THE INVENTION
Pretomanid is chemically described as (6S)-2-Nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,l-b][l,3]oxazine (or) (3S)-4-(trifluromethoxy)-benzyloxy-6-nitro-2H-3,4-dihydro-[2-lb]-imidazopyran having the following structure as shown in formula I.
The nitroimidazooxazine Formula I (PA-824) is a new class of bioreductive drug for tuberculosis. The recent introduction of the nitroimidazooxazine Formula I (PA-824) to clinical trial by the Global Alliance for TB Drug Development is thus of potential significance, since this compound shows good in vitro and in vivo activity against Mycobacterium tuberculosis in both its active and persistent forms. Tuberculosis (TBa) remains a leading infectious cause of death worldwide, but very few new drugs have been approved for TB treatment in the past 35 years, the current drug therapy for TB is long and complex, involving multidrug combinations. The mechanism of action of Pretomanid is thought to involve reduction of the nitro group, in a process dependent on the bacterial . glucose^pphosphate dehydrogenase (FGDl^arjoVits cofactOE F4.2(^Morei recent studies on mutant strains showed that a 151-amino acid (17.37 kDa) protein of unknown function,

Rv3547, also, appears to be critical for this activation. Equivalent genes are present in M. boVis and MaVium.
Pretomanid product has been not yet approved by the country regulatory authorities and is under phase II clinical trials.
Pretomanid and its pharmaceutical ly acceptable salts were generically disclosed in US 5,668,127 A and specifically disclosed in US 6,087,358 A. US '358 patent discloses a process for the preparation of Pretomanid, which is as shown below in scheme I:
The overall yield of Pretonamid obtained according to the process provided in US '358 is around 70%.
CN 104177372 A discloses a process for the preparation of Pretomanid, which is as shown below in scheme II:

.The overall yield of Pretonamid obtained according to the process provided in this patent is around 80%.
Bioorganic & Medicinal Chemistry Letters 2008, Volume: 18, Issue: 7, Pages: 2256-2262 discloses a process for the preparation of Pretomanid, which is as shown below in scheme III:

The overall yield of Pretonamid obtained according to the process provided in this article is around 80%.'
US 7,115,736 B2 discloses a process for the preparation of 3S-Hydroxy-6-nitro-2H-3, 4-dihydro-[2-lb]-imidazopyran which is a key intermediate of Pretomanid, which is as shown below in scheme IV:
The above provided prior-art process for preparing Pretomanid key intermediate involves use of dinitroimidazole. Dinitroimidazole is industrially not useful due to its highly explosive nature and difficulty in handling.
Journal Medicinal Chemistry 2009, Volume: 52, Pages: 637 - 645 discloses a process for the preparation of Pretomanid, which is as shown below in scheme V:

Journal Organic Chemistry 2010; Volume: 75 (21), Pages: 7479-82 discloses a process for. the preparation of Pretomanid, which is as shown below in scheme VI:
The above provided prior-art process for preparing Pretomanid involves more number of steps, which makes the process not economical. Further the reported yields of this process were around 62%.
In view of the above the present inventors have noticed that there is a need for a process to prepare Pretnomid, which avoids the difficulties of the prior-arts and accordingly the present inventors have developed a process to prepare Pretnomid involving less number of steps and avoiding use of dinitroimidazole, yielding Pretnomid having high yields & purities.
The objective of the present invention is to provide an improved process for preparing Pretomanid, which is cost effective, economically viable and industrially applicable.
Another objective of the present invention is to provide an improved process for preparing Pretomanid having high yields and high purity.

The present invention relates to a. process for the preparation of Pretomanid a compound of Formula I;

e) optionally purifying the obtained compound of formula I.
Another aspect of the present invention is a process for the purification of Pretomanid, which comprises:
a) dissolving Pretomanid in a halogenated hydrocarbon solvent;
b) adding charcoal;
c) removing the charcoal and concentrating the solution to obtain a residue;
d) dissolving the residue in an alcohol solvent while heating at 75-80°C;
e) adding cyclohexane solvent;
f) cooling the reaction mass to room temperature and maintained overnight; and
g) isolating the Pretomanid having purity greater than 99%.
DETAILED DESCRIPTION OF THE INVENTION:
The present invention relates to a process for the preparation of Pretomanid, which comprises reacting 2-chloro-4-nitroimidazole compound of formula V with compound of formula IV in presence of an alkali or alkaline metal carbonates, wherein alkali or alkaline metal carbonates are selected from the group comprising of sodium carbonate, potassium carbonate, lithium carbonate, cesium carbonate in a solvent to obtained a compound of formula III. Compound of formula III is reacted with 4-trifluoromethoxybenzyi bromide in presence of an alkali or alkaline metal hydrides, wherein alkali or alkaline metal hydrides are selected from the group comprising of sodium hydride, potassium hydride and lithium hydride in a solvent and phase transfer catalyst, wherein selected from the group comprising of tetra-n-butylammonium iodide (TBAI), tetra-n-butylammonium bromide (TBAB), tetrabutylammonium tribromide, tetrabutylammonium fluoride (TBAF), tetrabutylammonium hydroxide (TBAOH or TBAH) to obtained compound of formula II.
The compound of formula II is deprotected using a de-protecting reagent, wherein de-protecting reagent is selected from the group comprising of tetrabutylammonium fluoride (TBAF), hydrochloride, Pyridine.HF, triethylamine trihydrofluoride (Et3N-3HF), tris(dimethylamino)sulfonium difluorotrimethylsilicate (TASF) and ammonium fluoride (H4N+F~) in a solvent. The obtained reaction mass, in situ cyclized to yield Pretnomid compound of formula I in presence of an alkali or alkaline metal hydroxide, wherein alkali or

alkaline metal hydroxide is selected from the group comprising of sodium hydroxide, potassium hydroxide and lithium hydroxide in a solvent.
In another embodiment the present invention relates to. a purification process of Pretomanid, which comprises dissolving Pretomanid in halogenated hydrocarbon solvent. To this solution charcoal has been added at room temperature and stirred for approximately 30 minutes and' thereafter removed the charcoal and concentrated the solution to obtain residue. The residue has been dissolved in an alcohol solvent while heating at 80°C. To this solution cyclohexane solvent has been added and the solution has been cooled to room temperature. The solution stirred for overnight at room temperature to obtained Pretomanid.
The obtained Pretomanid as per the present invention has a purity greater than 99% and after purification the purity of Pretomanid has been increased greater than 99.8%.
The overall yield of Pretomanid as per the present invention is around 90%.
The present invention to prepare Pretomanid has been shown schematically as below:

In another embodiment of the present invention, the obtained Pretomanid is commercially useful, doesn't involve explosive .compounds, have high yields & purities and residual solvents meet the regulatory ICH limit.
In another embodiment of the present invention the solvent used throughout the invention are selected from the group comprising of alcohols, halogenated hydrocarbon solvents, water, hydrocarbon solvents, ketone, esters, nitriles and / or mixtures thereof; wherein alcohol is selected from the group comprising of methanol, ethanol, propanol, isopropanol, cyclopropanol, butanol, isobutanol, tertiary butanol, benzyl alcohol; wherein halogenated hydrocarbon solvent is selected from the group comprising of dichloromethane, dichloroethane, chloroform, chlorobenzene; wherein hydrocarbon solvent is selected from the group comprising of heptane, hexane, toluene, Xylene, cycloheptane, cyclohexane, cyclooctane, cyclopentane; wherein ketone is selected from the group comprising of acetone, butanone, ethyl isopropyl ketone, methyl isobutyl ketone, methyl isopropyl ketone; wherein nitrile is selected from the group comprising of acetonitrile, proprionitrile, benzonitrile.
In another embodiment of the present invention, wherein the protecting group/s used throughout the invention are selected form the group comprising of Trimethylsilyl (TMS), Triethylsilyl (TES), Acetyl, Trityl chloride (TrCl), Benzyl, Tetrahydropyranyl, Dimethylisopropylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS), t-Butyldimethylsilyl (TBDMS), t-Butyldiphenylsilyl (TBDPS), Triisopropylsilyl (TIPS), Tetraisopropyldisilylene (TIPDS), Di-t-butyldimethylsilylene (DTBS).
The invention of the present application will be explained in more detail with reference to the following examples, which should not be construed as limiting the scope of the invention in any manner.
Examples:
Example 1: Preparation of (S)-l-(tcrt-Butyl-dimethyl-silanyloxy)-3-(2-chIoro-4-nitro-imidazol-l-yl)-propan-2-ol

butyi-dimethyl-((S)-l-oxiranylmethoxy)-silane (127.6 gm) to the above reaction mixture then stirred the reaction mixture for 18-:20 hours at 70°C, after completion of the. reaction, concentrated to obtained residue. Ethyl acetate and water was added to the residue and separate the layers, the organic layer washed first with 1.5 N HC1 and sodium bicarbonate solution, the obtained organic solution was dried with sodium sulfate then concentrated the -organic layer in a buchi flask at atmospheric pressure below 50°C, cyclohexane was added to the'obtained residue at room temperature and stirred for 1 hours and cooled the mass to -5oC to 0°C, stirred for 1 hour. The obtained solid was filtrated and washed with cyclohexane (100 ml chilled) to yield titled compound Yield: 150 gm Chromatographic purity: 98.57% (by HPLC).
Example 2: Preparation of (S)-l-(3-(tert-ButyldomethylsUyIoxy)-2-(4-trifluoromethoxy)-benzyIoxy)-propyl)-2-methyl-4-nitro-lH-imidazole
(S)-l-(tert-Butyl-dimethyl-silanyloxy)-3-(2-chloro-4-nitro-imidazol-l-yl)-propan-2-ol (150 gm) was dissolved in dimethylformamide (3000 ml) under nitrogen atmosphere at room temperature and stirred for 5 to 10 minutes, followed by addition of 4-trifluoromethoxybenzyl bromide (100.70 gm) at room temperature and stirred for 5 to 10 minutes under nitrogen atmosphere, followed by addition of tetrabutylammonium iodide (TBAI) (22.89 gm) and the reaction mixture is cooled to -55°C to -60°C. Then NaH (21.4* gm) was added portion wise to the above reaction mass over 5 to 10 minutes, after comple of NaH addition the reaction mixture was cooled to 0°C and stirred for 1 hour. Then H2O was added to the above reaction mass and extracted with EtOAc (3000 ml). Then combined organic layers were dried with sodium sulfate, and concentrated to give crude (S)-l-(3-(tert-Butyldomethylsilyloxy)-2-(4-(trifluoromethoxy)-benzyloxy)-propyl)-2-methyl-4-nitro-lH-imidazote. Yield: 122gm Chromatographic purity: 85.83% (by HPLC).
Example 3: Preparation of Pretomanid

temperature and stirred for 5 to 10 minutes then TBAF (95.6 ml) was added to the reaction mixture and stirred for 2 hours, at room temperature, after completion of the reaction removed solvent through vacuum to obtained residue, dissolved the residue in MDC (1800 ml) and water (1800 ml) stirred^ separated the layers and the organic layer washed with 10% sodium bicarbonate the obtained organic solution was concentrated under atmospheric pressure to obtained residue added MeOH (1730 ml) at room temperature and the reaction mixture was cooled to 0°C to 5°C, added KOH (24.5 gm) at the same temperature then cooled to room temperature and stirred for 24 hours. After completion of reaction DM Water added drop wise over 30 minutes at 10°C to 15° C and stirred for 1 hour to 1 hour 30 minutes at room'temperature, filtrated the compound and washed with DM water (133 ml) and dried under vacuum for 10 hours at 50° C. Yield: 53 gm Chromatographic purity: 97.69% (by HPLC)!
Example 4: Purification of Pretomanid
Pretomanid (53 gm) was dissolved in MDC (795 ml) at room temperature and stirred for 10 to 15 minutes, added charcoal (10 gm) and stirred for 30-35 minutes, remove the charcoal and concentrated to obtained residue: Dissolved the obtained residue in IPA (795 ml) and the reaction mixture was heated to 80°C maintained for 10-15 minutes, added cyclohexane (1600ml) for 30 minutes at 80° C, then cooled to room temperature and stirred the reaction mass for overnight, filtered the solid and washed with cyclohexane (265 ml), and dried under vacuum for 10 hours at 50° C. Yield: 48 gm (Percentage of Yield: 90%) Chromatographic purity: 99.97% by HPLC).

700161006
We Claim:
1. A process for the preparation of Pretomanid a compound of Formula I;
F F k^^O^^N-^y-NO, Formula I
which comprises:
a) reacting 2-chloro-4-nitroimidazole compound of formula V;
- 02N TV/CI
LNH Formula V
with a compound of formula IV;
O\>P
Formula IV wherein P represents protecting group
in the presence of an alkali or alkaline metal carbonates and a solvent to obtain a
compound of formula III;
02N N Cl
^—N ^—OP Formula III
OH
wherein P represents protecting group
b) condensation of the compound of formula III with 4-trifluoromethoxybenzyl bromide
in presence of an alkali or alkaline metal hydrides and a solvent to obtain a
compound of formula II;
02N. .N CI
N\_/""0P
O Formula II
OCF3
wherein P represents protecting group
c) de-protecting the compound of formula II and in situ cyclizing using an
alkali or alkaline metal hydroxide and a solvent to obtain a compound of formula I;

2. The process according to claim 1, wherein the protecting group is selected the group comprising of Trimethylsilyl (TMS), Triethylsilyl (TES), Acetyl, Trityl chloride (TrCl), Benzyl, Tetrahydropyranyl, Dimethylisopropylsilyl (IPDMS), Diethylisopropylsilyl (DEIPS), t-Butyldimethylsilyl (TBDMS), t-^Butyldiphenylsilyl (TBDPS), Triisopropylsilyl (TIPS), Tetraisopropyldisilylene (TIPDS), Di-t-butyldimethylsilylene (DTBS).
3. The process according to claim 1, wherein the solvent is selected from the group comprising of alcohols, halogenated hydrocarbon solvents, water, hydrocarbon solvents, ketone, esters, nitriles and / or mixtures thereof;
4. The process according to claim 3, wherein the alcohol is selected from the group comprising of methanol, ethanol, propanol, isopropanol, cyclopropanol, butanol, isobutanol, tertiary butanol, benzyl alcohol; wherein halogenated hydrocarbon solvent is selected from the group comprising of dichloromethane, dichloroethane, chloroform, chlorobenzene; wherein hydrocarbon solvent is selected from the group comprising of heptane, hexane, toluene, Xylene, cycloheptane, cyclohexane, cyclooctane, cyclopentane; wherein ketone is selected from the group comprising of acetone, butanone, ethyl isopropyl ketone, methyl isobutyl ketone, methyl isopropyl ketone; wherein nitrile is selected from the group comprising of acetonitrile, proprionitrile, benzonitrile.
5. The process according to claim 1, wherein the alkali or alkaline metal carbonates is selected from the group comprising of sodium carbonate, potassium carbonate, lithium carbonate and cesium carbonate.
6. The process according to claim 1, wherein the alkali or alkaline metal hydrides is selected from group the comprising of sodium hydride, potassium hydride and lithium hydride.
7. The process according to claim 1, wherein alkali or alkaline metal hydroxide is selected from the group comprising of sodium hydroxide, potassium hydroxide and lithium hydroxide.
8. A process for the purification of Pretomanid, which comprises:

c) removing the.charcoal and concentrating the solution to obtain a residue;
d) dissolving the residue in an alcohol solvent while heating at 75-80°C;
e) adding cyclohexane solvent; *
f) cooling the reaction mass to room temperature and maintained overnight; and
g) isolating the Pretomanid having purity greater than 99%.
9. The process according to claim 8, wherein halogenated hydrocarbon are selected from the
group comprising of dichloromethane, dichloroethane, chloroform and chlorobenzene
10. The process according to claim 8, wherein alcohols are selected from the group
comprising of methanol, ethanol, propanol, isopropanol, cyclopropanol, butanol, isobutanol,
tertiary butanol and benzyl alcohol.