DESC:Technical Field of the Invention:

The present invention relates to a novel process for the preparation of nitroimidazole compounds and to novel intermediates which are produced during the course of carrying out the said novel process.

Background of the Invention:

Tuberculosis (TB) is a devastating bacterial infection that kills more than 1.8 million people each year worldwide. Over 98% of TB fatalities result from one specific bacterial strain, Mycobacterium tuberculosis (Mtb), where the presence of a single bacterium can propagate a fatal infection. Although Mtb was identified nearly 130 years ago and antibiotics have been available to treat TB since the 1940s, this pathogen remains a persistent problem because of the emergence of multidrug resistant (MDR-TB) and extremely drug resistant (XDR-TB) strains, as well as the lack of resources available to provide drugs to endemic areas.

Currently, there are at least ten anti-TB drug candidates with varying biological mechanisms of action being evaluated in clinical trials. These therapies fit into two general classes: (1) those already used in first- and second-line treatment of active TB, and (2) those with novel mechanisms of action against both replicating and non-replicating TB.

Among the second group, bicyclic nitroimidazoles have emerged as a promising structural class. While metronidazole is widely used as a general antibacterial treatment, PA-824 stands out as an exciting experimental anti-TB drug candidate.

PA-824 was found to inhibit TB with minimum inhibitory concentration (MIC) values of 0.015-0.25 µg/mL

PA-824 chemically termed as (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine of formula (I) or a pharmaceutically acceptable salt and represented by following structure;

Formula (I)

(6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3] oxazine was first disclosed in the US patent 6087358.

Imidazopyrane derivative of formula (II)

Formula (II)

is an important intermediate of (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3] oxazine. The synthetic method employed is depicted in following reaction Scheme 1.

Scheme-1

According to this process, glycidol (VIII) is reacted with t-butyldimethylsilyl chloride The compound (VIIA) is reacted with 2,4-dinitroimidazole (VIA) to obtain compound (VA), and after protecting the hydroxy group of the resulting siloxy alcohol (VA) with 3,4-dihydro-2H-pyran; the tetrahydropyranyl (THP) ether compound (IVA) is subjected to desilylation and cyclization to form protected imidazopyran (III). After removal of THP group, the imidazopyran derivative (II) obtained, which is further reacted with 1-(bromomethyl)-4-(trifluoromethoxy) benzene to obtain PA-824.

However, according to this known method, after glycidol t-butyldimethylsilyl ether (VIIA) is once prepared from glycidol (VIII) and is isolated, the compound has to be reacted with dinitroimidazole (VIA) and the procedure is troublesome. The yield of compound (VA) from compound (VIII) is less than 50%, and the yield of compound (II) from compound (VA) is 46%.

Further, dinitroimidazole is explosive, and both (VI) and the starting epoxide i. e. glycidol t-butyldimethylsilyl ether (VII) are expensive for use on large scale. Furthermore, the synthesis requires four chromatographic separations and an inefficient protection-deprotection sequence in order to selectively construct the oxazine core that are not suitable for use on industrial scale.

An alternate process was disclosed in EP1650211 B1 is depicted below in scheme-2.

Scheme-2

wherein R1 means C6-C10 aryl group such as phenyl group and C2-C4 alkenyl group substituted by C6-C10 aryl group such as 2-phenylethenyl group.

However this process has also some disadvantage wherein intermediate (VA), (IVB) and (IIIB)- purified with silica gel column chromatography.

Although (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine and its pharmaceutically acceptable salts have been made by various processes as disclosed in the prior art, due to an expensive route of synthesis, and a complicated tablet formulation (due to its low solubility), there is a need for further improvement in efficacy.

Thus, there still exists a continued need to develop a safe, efficient, and industrially suitable process to synthesize cost effective anti TB drug.

Object of the Invention:

The object of the present invention is to provide processes for the preparation of (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine of formula (I) or pharmaceutically acceptable salts thereof.

Another object of the present invention is to provide processes for the preparation of imidazopyrane derivative of formula (II).

Yet another object of the present invention is to provide novel intermediates that are useful in the synthesis of (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine or pharmaceutically acceptable salts thereof.

Yet another object of the present invention is to provide a process which is simple, economical and suitable for industrial scale-up.

Summary of the Invention:

The present invention relates to the process for preparing (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3] oxazine of formula (I) or a pharmaceutically acceptable salt thereof.
According to a first aspect of the present invention, there is provided a process for preparing an imidazopyran derivative of formula (II)

which may be useful intermediate for preparing antitubercular agents, which comprises steps of

d) reacting compound (IV)

with a base in a suitable solvent to obtain compound (III)

and ;
e) hydrolyzing compound (III) to obtain compound (II)

In an embodiment compound (IV) is in the form of stereoisomers and optical isomers.
According to yet another aspect of the present invention, there is provided a process for preparing compound of formula (IV), comprising;

c) reacting compound (V)

with THP to provide compound (IV).

In an embodiment compound (V) is in the form of stereoisomers and optical isomers.

According to yet another aspect of the present invention, there is provided a process for preparing compound of formula (V), comprising;

a) reacting phenyl acetic acid with (oxiran-2-yl)methanol (VIII)

in the presence of coupling agent to obtain compound (VII)

;
and
b) reacting compound (VII) with 2-chloro-4-nitro-1H-imidazole (VI)

to obtain compound (V).

In an embodiment, compounds (II), (III), (IV), (V), and (VII) are in the form of stereoisomers and optical isomers. The stereochemistry of the method of the present invention is determined by the enantiomer selected for use for the non-sterically hindered substituted epoxide (VIII). Accordingly, the enantiomer afforded by the method of the present invention can be either the (S)- or the (R)-enantiomer, depending on the choice of the enantiomer used in the epoxide starting material.

Thus, the optically active isomers of intermediates (II), (III), (IV), (V) and (VII) can be prepared without racemization by using optically active 2,3-epoxy-1-propanol (VIII) as a starting material.

The selective formation of regioisomers is another aspect of this invention.

In one embodiment compound (II) is in the form of an optically active (S)-isomer and the process of the present invention may further comprises the step of;

f) contacting a compound of formula (II)

with 1-(bromoethyl)-4(trifluoromethoxy) benzene (IX)

in the presence of a base to provide compound (6S)-2-nitro-6-{[4-(trifluoromethoxy) benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3] oxazine of formula (I).

In another embodiment compound (II) is in the racemic form (IIA)

and the process of the present invention may further comprise the step of;

g) lipase-catalyzed kinetic resolution via acylation of racemic compound (IIA)

to obtain a mixture of compound (IIB) and compound (IIC);

h) followed by an insitu chemical stereoinversion of the unreacted alcohol (IIC) by a Mitsunobu reaction to optically active compound (II);
and
i) contacting a compound of formula (II) with 1-(bromoethyl)-4(trifluoromethoxy) benzene (IX) in the presence of a base to provide compound (6S)-2-nitro-6-{[4-(trifluoromethoxy) benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3] oxazine of formula (I).

The compound of formula (I) obtained by the process of the present invention may be optionally converted to a pharmaceutically acceptable salt thereof by reaction with a suitable base.

An advantage of the process provided by this invention lies in that a well-defined stereochemistry of the starting material can be used, as this configuration is not affected during the synthetic process.

Another additional object of this invention consists of synthesis intermediates produced during the process provided by this invention.

In another aspect, the present invention provides a use of (6S)-2-nitro-6-{[4-(trifluoromethoxy) benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3] oxazine of formula (I) or a pharmaceutically acceptable salt thereof, obtainable by the process of the present invention for the manufacture of therapeutic agent, preferably an anti-tuberculosis agent for the treatment of both replicating and hypoxic, non-replicating Mycobacterium tuberculosis

In another aspect the present invention provides a use of (6S)-2-nitro-6-{[4-(trifluoromethoxy) benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3] oxazine of formula (I) or a pharmaceutically acceptable salt thereof, obtainable by the process of the present invention, for treating both replicating and hypoxic, non-replicating Mycobacterium tuberculosis.

In another aspect the present invention provides a method of treating both replicating and hypoxic, non-replicating Mycobacterium tuberculosis, comprising administering the (6S)-2-nitro-6-{[4-(trifluoromethoxy) benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3] oxazine of formula (I) or a pharmaceutically acceptable salt thereof, obtainable by a process of the present invention.

In another aspect, the present invention provides a process substantially as herein described with reference to the examples.

Further features of the present invention are defined in the dependent claims.

DETAILED DESCRIPTION OF THE INVENTION:

In an embodiment of the present invention, there is provided a process for preparing (6S)-2-nitro-6-{[4-(trifluoromethoxy) benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3] oxazine of formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof.

In one embodiment, compound (I) is prepared by using optically active 2,3-epoxy-1-propanol (VIII) as a starting material as depicted below in the reaction Scheme 3.

Scheme 3

In an alternative embodiment, compound (I) is prepared by using racemic 2,3-epoxy-1-propanol (VIII) as a starting material as exemplified in Scheme 4.

Scheme 4

Compounds of formula (II), (III), (IV), (V), (VII) and (VIII) may be in the form of the R or S isomer or a mixture thereof.

The compounds of formula (IV) and (V) are hitherto unreported intermediates useful in the process for the preparation of (6S)-2-nitro-6-{[4-(trifluoromethoxy) benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3] oxazine of formula (I) as described herein.

In step a, 2,3-epoxy-1-propanol (VIII) is coupled with phenyl acetic acid using a coupling reagent in the presence of an inert organic solvent or mixture of solvents thereof to provide compound (VII).

A suitable coupling reagent for use in the process according to the present invention can be selected from the group comprising of phenylsilane, 1,1’-carbonyldiimidazole (CDI), benzotriazol-1-yloxytris (dimethylamino) phophonium hexafluorophosphate (BOP), 1-hydroxy benzotriazole hydrate (HOBt), PyBOP (Analog of the BOP), 1,3-dicyclohexyl carbodiimide (DCC), N-Ethyl-N’-(3-dimethylaminopropyl)carbodidimide hydrochloride (EDC HCl), HATU, chloroformates such as Ethyl chloroformate or isobutyl chloroformate. A particularly suitable coupling reagent for use in the above process according to the present invention is EDC HCl

By “inert organic solvent” is meant an organic solvent, which under the reaction conditions of a process according to the present invention, does not react with either the reactants or the products. A suitable inert organic solvent for use in a process according to the present invention can be selected from the group consisting of ethyl acetate, dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), dimethyl carbonate N-methyl pyrrolidone (NMP), sulfolane, diglyme, 1,4-dioxane, tetrahydrofuran(THF), acetonitrile, acetone, dichlromethane (MDC), toluene, xylene and other inert organic solvents known in the art. A particularly suitable inert organic solvents for use in the above process according to the present invention are toluene and ethyl acetate.

The coupling reaction is carried out at a temperature ranging from about -5°C to the boiling point of the reaction mass until no starting material is detectable.

In step b, compound (V) is prepared by reacting substituted epoxide compound (VII) with a haloimidazole compound i.e.2-chloro-4-nitro-1H-imidazole (VI).

In yet another embodiment, the molar ratio of substituted epoxide compound (VII) to the haloimidazole compound (VI) is less than or equal to 1:1.

In a preferred embodiment, the substituted epoxide compound (VII) is reacted with a haloimidazole compound (VI), to form the adduct with an alcohol functional group.

Optionally the reaction may be carried out in the presence of a fluoride salt. The fluoride salt includes an alkali metal fluoride and an alkaline earth metal fluoride, especially preferably cesium fluoride.

The reaction may be conducted in the presence or absence of a solvent and in the presence or absence of the base.

The reaction is preferably conducted in the absence of a solvent. The neat reaction avoids formation of unwanted isomeric impurities which are likely to form when one uses solvents like methanol and ethyl acetate. This forms another aspect of the present invention.

A base used is selected from organic bases and inorganic bases such as trimethylamine (TEA), diisopropyl ethylamine ( DIPEA) and the like.

The reaction temperature is preferably -10 to 90°C, especially preferably 10 to 85°C, more preferably 40 to 70°C.

In step c, the hydroxy group of the resulting compound (V) is protected as its tetrahydropyranyl ether (DHP) derivative (IV). The reaction is performed in an aprotic solvent such as MDC, EDC, ethyl acetate, toluene and the like, optionally in presence of an acidic catalyst.

An acidic catalyst is selected from for example, a mineral acid, such as hydrochloric acid, sulfuric acid or the like; an organic acid, such as pyridinium p-toluenesulfonic acid (PPTS) or the like. Preferably, reaction is conducted using organic acid.

The said reaction is generally carried out about at 0 to 100°C, preferably at 0 to 70° C, most preferably 20 to 30°C and is finished in about 1 to 30 hours.

Removal of phenyl acetyl group of compound (IV) followed by cyclization in step d, results in bicyclic nitro imidazole THP ether compound (III). The reaction is performed with a base in a suitable solvent at a temperature in the range of from about 20°C to 50°C, more preferably at 30 to 40°C.

A suitable base for use in a process according to the present invention can be selected from
organic base and inorganic base such as sodium hydride, metal hydroxides such as sodium hydroxide, potassium hydroxide, potassium t-butoxide,, Sodium t-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, a fluoride compound like cesium fluoride, tetrabutylammonium fluoride (TBAF), hydrogen fluoride pyridine complex and the like in an inert and dry organic solvent.

An inert and dry organic solvent used in this reaction includes preferably a alcohol solvent such as methanol, ethanol, isopropanol or t-butanol and the like;. a hydrocarbon-solvent such as hexane, benzene, or toluene and the like; a chlorinated solvent such as chloroform, 1 ,2-dichloroethane, or dichloromethane, a nitrile-solvent such as acetonitrile, an ether-solvent such as diethyl ether, diisopropyl ether, t-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane ( DME) or tetrahydrofuran, and an aprotic polar solvent such as N,N-dimethylformamide, or dimethyl sulfoxide. In a preferred embodiment solvent used are alcoholic solvents.
Preferably, the reaction is performed in KOH/ MeOH or tetrabutylammonium fluoride/ THF under inert atmosphere.

In step d, the THP group of compound (III) was deprotected using acetic acid in aqueous THF or PTSA/ MeOH at room temperature to reflux temperature to afford alcohol compound (II).

An advantage of the process provided by this invention lies in that a well-defined stereochemistry of the starting material can be used, as this configuration is not affected during the synthetic process.

Thus in one embodiment, the intermediate compounds (II), (III), (IV), (V), (VII), and compound (I) related to the present invention exist in the form of optically active isomers. The optically active isomers of compound (II), bicyclic nitro imidazole THP ether compound (III), tetrahydropyranyl ether (DHP) derivative (IV), compound (V), oxiran compound (VII) can be prepared without racemization by using optically active 2,3-epoxy-1-propanol (VIII) as a starting material. Preferably, compounds (I), (II), (III), (IV), and (V) are in the form of their (S) -isomers and compounds (VIII) and (VII) are in the form of their (R) -isomers.

In another embodiment when 2,3-epoxy-1-propanol (VIII) used is in the racemic form, the intermediate compound (II) exist as compound (IIa) in the racemic form. The present invention also includes the process for converting racemic compound (IIa) into optically active isomer of compound (II).

In an embodiment, efficient enzyme-catalyzed resolution of the racemic alcohol through lipase-catalyzed acylation, followed by Mitsunobu chemical stereoinversion results into desired optically active isomer of compound (II).

Preferably, in step g, acetate is synthesized by acetylation of the corresponding alcohol of racemic compound (IIa) in the presence of lipase.

In an embodiment lipase used may be Candida antarctica lipase A (CAL A) or Candida antarctica lipase B (CAL B).

Acetylation is performed using enol acetate such as isopropyl acetate , vinyl acetate and the like to give the desired S- isomer of acetylated alcohol (IIB) and undesired R- isomer of unreacted alcohol (IIC). The corresponding (S)-acetate (IIB) was obtained in good yields and enantiomeric excesses.

Acetylation is performed in the presence of a suitable solvent selected from ether such as diethyl ether, di-isopropyl ether , dimethyl ether or cyclopentylmethyl ether and the like; esters such as vinyl acetate or isopropyl acetate and the like. The reaction is carried out at a temperature ranging from 25-30°C.

At 50% conversion, the reaction mixture was filtered on Celite. The ee’s of the ester produced and the unreacted alcohol measured on chiral chromatography.

The corresponding (S)-acetates (IIB) and the produced (R)-alcohol (IIC) were obtained in good yields and showed an excellent enantiomeric excess.

At the appropriate; conversion and after removal of the enzyme by filtration, the crude mixture of (S)-acetate and the formed (R)-alcohol underwent Mitsunobu reaction in step h.

In one embodiment, to the filtrate was added azodicarboxylate such as diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD) at 0°C. The reaction mass was stirred for about 24 to 30 hours at 25 to 30°C to convert the unreacted (R)-alcohol (IIC) into the (S)- alcohol (II).

In an alternative embodiment, triphenylphosphine and acetic acid were added to the mixture followed by the addition of diisopropylazodicarboxylate (DIAD) at 0°C to convert the formed (R)-alcohol (IIC) into the corresponding (S)-acetate (IIB).

The reaction mixture containing mixture of (S)- acetate (IIB) and/or (S)- alcohol(II) is hydrolyzed in step i, in the presence of a suitable base to yield optically pure compound (II). A suitable base is selected from inorganic and organic base

The advantage of the process is hydrolysis reactions proceeded with an excellent enantioselectivity. The isolated (S)- alcohol (II) showed ee >99%.

The imidazopyran derivative of formula (II) may be converted by further chemical transformation to another API.

In an embodiment , the optically pure compound (II) is then contacted with 1-(bromoethyl)-4(trifluoromethoxy) benzene (IX) in the presence of a suitable base to provide compound (6S)-2-nitro-6-{[4-(trifluoromethoxy) benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3] oxazine of formula (I).

The suitable base is selected from organic and inorganic base.

The reaction is performed in the present of an inert solvent like polar protic and aprotic solvent.

The processes of the present invention allow the synthesis of imidazopyran derivative of formula (II) and (6S)-2-nitro-6-{[4-(trifluoromethoxy) benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3] oxazine of formula (I) with a high degree of chromatographic and optical purity.
Preparation method of the present invention is a simple in operation and without requires complicated purification process. Therefore, making the overall process even more cost-effective, efficient and amenable to large scale synthesis·

The compound (I) produced by the process of the present invention may be used as an API and formulated into finished pharmaceutical products.

The following non-limiting examples illustrate the processes and uses of the present invention

Examples :

Example 1: Preparation of ((R)-oxiran-2-yl)methyl 2-phenylacetate[compound VII]
To a mixture of (R)-glycidol (50 g, 675 mmoles) & toluene (1.0 lit), added N,N- dimethylaminopyridine (DMAP)(16.5 g,135 mmoles) & N-ethyl-N’-(3-dimethylaminopropyl) carbodidimide hydrochloride (EDC HCl)(155 g,810 mmoles). The reaction mass was cooled to 0-5°C. Prepared a solution of phenyl acetic acid (110 g, 810 mmoles) in toluene & added to the reaction mass at 0-5°C. Stirred the reaction mass for 2 hrs. Added water (500 ml) and stirred for 10 min. The organic layer was separated toluene layer, washed with 10% HCl solution, followed by 10% sodium bicarbonate solution. Distilled of toluene completely under vacuum to get 116 g of ((R)-oxiran-2-yl)methyl 2-phenylacetate.
Yield : 90%
HPLC Purity: 95%

Example 2: Preparation of ((R)-oxiran-2-yl)methyl 2-phenylacetate [compound VII]
To a mixture of (R)-glycidol (50 g,675 mmoles) & ethyl acetate(0.5 lit),added N,N-dimethylaminopyridine (DMAP)(16.5 g,135 mmoles) & N-ethyl-N’-(3-dimethylaminopropyl) carbodidimide hydrochloride (EDC HCl)(155 g,810 mmoles). The reaction mass was cooled to 0-5°C. Prepared a solution of phenyl acetic acid(110 g,810 mmoles) in 0.5 lit ethyl acetate & added to reaction mass at 0-5°C.Stirred the reaction mass for 2 hrs. Added water (500 ml) and stirred for 10 min. The organic layer was separated, washed with 10% HCl solution, followed by 10% sodium bicarbonate solution. Distilled of ethyl acetate under vacuum to get 116 g of ((R)-oxiran-2-yl)methyl 2-phenylacetate.
Yield : 90%
HPLC purity: 95%

Example 3: Preparation of ((R)-oxiran-2-yl)methyl 2-phenylacetate [compound VII]
To a mixture of (R)-glycidol (50 g,675 mmoles) & dichloromethane(DMC)(0.5 lit) ,added N,N-dimethylaminopyridine (DMAP)(16.5 g,135 mmoles) & N-ethyl-N’-(3-dimethylaminopropyl) carbodidimide hydrochloride (EDC HCl)(155 g,810 mmoles). The reaction mass was cooled to 0-5°C. Prepared a solution of phenyl acetic acid (110 g, 810 mmoles) in 0.5 lit of dichloromethane(DMC) & added to the reaction mass at 0-5°C. Stirred the reaction mass for 2 hrs. Added water (500 ml) and further stirred for 10 min. The separated organic layer was washed with 10% HCl solution, followed by 10% sodium bicarbonate solution. Distilled of dichloromethane completely under vacuum to give 125 g of ((R)-oxiran-2-yl)methyl 2-phenylacetate.
Yield : 95%
HPLC purity: 95%

Example 4: Preparation of (S)-3-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-hydroxypropyl 2-phenylacetate [compound V]
To ((R)-oxiran-2-yl)methyl 2-phenylacetate [Compound VII] (115 g,599 mmoles) from example 2, added 2-chloro-4-nitroimidazole [compound VI] (80 g,544 mmoles) & trimethylamine (5.5 g,54.4 mmoles). The reaction mass was heated to 60°C for about 10 hrs. After completion of reaction, added ethyl acetate (1.0 lit) & stirred for 20 mins. The ethyl acetate layer was washed with 10% HCl solution, followed by 10% bicarbonate solution. The ethyl aceate was distilled of completely under vacuum and toluene ( 200 ml) was add & stirred. The solid was isolated by filtration and purified in ethyl acetate & toluene mixture to give 92 g of (S)-3-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-hydroxypropyl 2-phenylacetate.
Yield: 65%
HPLC purity: 90%
Example 5: Preparation of (S)-3-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-(tetrahydro-2H-pyran-2-yloxy)propyl 2-phenylacetate [Compound IV]
To a mixture of (S)-3-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-hydroxypropyl 2-phenylacetate [Compound V] (90 g, 265.4 mmoles) & ethyl acetate (900 ml) was added pyridinium-p-toluenesulphonate(PPTS) (13 g, 52.1 mmoles) & 3,4-dihydropyran (66.8 g, 794 mmoles) at room temperature. The reaction mass was stirred for 2 hrs. After completion of reaction the organic layer was washed with 10% bicarbonate solution. Distilled off ethyl acetate completely under vacuum to give 112 g of (S)-3-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-(tetrahydro-2H-pyran-2-yloxy)propyl 2-phenylacetate,112 g.
Yield: 98%

Example 6: Preparation of (S)-6,7-dihydro-2-nitro-6-(tetrahydro-2H-pyran-2-yloxy)-5H-imidazo[2,1-b][1,3]oxazine [Compound III]
(S)-3-(2-chloro-4-nitro-1H-imidazol-1-yl)-2-(tetrahydro-2H-pyran-2-yloxy)propyl-2-phenylacetate (110 g,260 mmoles) [Compound IV] was stirred with 110 ml of methanol at room temperature for 10 mins. Added a solution of potassium hydroxide,(44 g,780 mmoles) solution in 220 ml methanol slowly at 0-5°C. The reaction mass was further stirred for 1 hr. After completion of the reaction, water (200 ml) was added. The reaction mass was extracted with ethyl acetate (3 x 300 ml). The combined organic layer was washed with water. Distilled off ethyl acetate under vacuum and the solid was isolated by filtration. The solid was purified in a mixture of methanol - water to give 60 g of (S)-6,7-dihydro-2-nitro-6-(tetrahydro-2H-pyran-2-yloxy)-5H-imidazo[2,1-b][1,3]oxazine.
Yield: 85%
HPLC purity: 95%

Example 7: Preparation of (S)-6,7-dihydro-2-nitro-5H-imidazo[2,1-b][1,3]oxazin-6-ol [Compound II]
To a mixture of (S)-6,7-dihydro-2-nitro-6-(tetrahydro-2H-pyran-2-yloxy)-5H-imidazo[2,1-b][1,3]oxazine, (60 g,223 mmoles) [Compound II] ( 60 g, mmoles) & 180 ml methanol, was added p-toluenesulphonic acid(11.5 g,66.6 mmoles). The reaction mass was stirred for 1 hr at room temperature. After completion of the reaction the reaction mass was filtered, washed with methanol & dried to get 30 g of (S)-6,7-dihydro-2-nitro-5H-imidazo[2,1-b][1,3]oxazin-6-ol.
Yield: 70%
HPLC Purity: 98-99%

Example 8: Preparation of Pretomanid((S)-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-2-nitro-5H-imidazo[2,1-b][1,3]oxazine) [Compound I]
To a mixture of (S)-6,7-dihydro-2-nitro-5H-imidazo[2,1-b][1,3]oxazin-6-ol (25 g,135 mmoles) [Compound II] and 250 ml of N,N-dimethylformaamide was added sodium t-butoxide (19.5 g,202 mmoles) at 0-5°C. Added 4-(trifluoromethoxy)benzyl bromide (41 g,162 mmoles) in lots at 0-5°C. The reaction mass was further stirred for 3 hrs at 0-5°C. After completion of reaction, the reaction mass was quenched in water and stirred. The solid was isolated by filtration, washed with water and purified in isopropyl alcohol to give 34 g of (S)-6-(4-(trifluoromethoxy)benzyloxy)-6,7-dihydro-2-nitro-5H-imidazo[2,1-b][1,3]oxazine.
Yield: 70%
HPLC purity: 99.7%
Chiral purity: > 99.8%
,CLAIMS:
1. A process for preparing an imidazopyran derivative of formula (II)

which comprises the steps of;
a) reacting compound (IV)

with a base in a suitable solvent to obtain compound (III)

and;
b) hydrolyzing compound (III) to obtain compound (II).

2. The process of claim 1, wherein the base is selected from organic base and inorganic base such as sodium hydride, metal hydroxides such as sodium hydroxide, potassium hydroxide, potassium t-butoxide, sodium t-butoxide, sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, cesium fluoride, tetrabutylammonium fluoride (TBAF) and hydrogen fluoride pyridine complex.

3. The process of claim 1, wherein the solvent is selected from a alcohol solvent such as methanol, ethanol, isopropanol or t-butanol and the like; a hydrocarbon-solvent such as hexane, benzene, or toluene and the like; a chlorinated solvent such as chloroform, 1 ,2-dichloroethane, or dichloromethane, a nitrile-solvent such as acetonitrile, an ether-solvent such as diethyl ether, diisopropyl ether, t-butyl methyl ether, cyclopentyl methyl ether, dimethoxyethane ( DME) or tetrahydrofuran, and an aprotic polar solvent such as N,N-dimethylformamide, or dimethyl sulfoxide.

4. The process of claim 1, wherein the hydrolysis of compound (III) is carried out in the presence of acetic acid in aqueous THF or PTSA/ MeOH.

5. A process for preparing a compound (II) according to claims 1 to 4, which further comprises the steps of;

c) reacting compound (V)

with 3,4-dihydro-2H-pyran to provide compound (IV).

6. The process of claim 5, wherein the reaction is carried out in the presence of a solvent selected from aprotic solvent and optionally in presence of an acidic catalyst selected from a mineral acid and an organic acid.

7. The process of claim 6, wherein the solvent is selected from MDC, EDC, ethyl acetate, toluene and the like.

8. The process of claim 6, wherein a mineral acid is selected from hydrochloric acid, sulfuric acid and the like and an organic acid is selected from pyridinium p-toluenesulfonic acid (PPTS) and the like.

9. A process for preparing a compound (II) according to any preceding claim, which further comprises the steps of;
c) reacting phenyl acetic acid with (oxiran-2-yl)methanol (VIII)

in the presence of coupling agent to obtain compound (VII)

and;
d) reacting compound (VII) with 2-chloro-4-nitro-1H-imidazole (VI)

to obtain compound (V).

10. The process of claim 9, wherein the coupling agent is selected from a phenylsilane, 1,1’-carbonyldiimidazole (CDI), benzotriazol-1-yloxytris (dimethylamino) phophonium hexafluorophosphate (BOP), 1-hydroxy benzotriazole hydrate (HOBt), PyBOP (Analog of the BOP), 1,3-dicyclohexyl carbodiimide (DCC), N-Ethyl-N’-(3-dimethylaminopropyl)carbodidimide hydrochloride (EDC HCl), HATU, chloroformates such as Ethyl chloroformate and isobutyl chloroformate.

11. The process of claim 9 or 10, wherein the coupling is carried out in the presence of an inert organic solvent selected from ethyl acetate, dimethylformamide (DMF), dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), dimethyl carbonate N-methyl pyrrolidone (NMP), sulfolane, diglyme, 1,4-dioxane, tetrahydrofuran(THF), acetonitrile, acetone, dichlromethane (MDC), toluene, xylene and the like.

12. The process of claim 9, wherein compound (VII) is reacted with compound (VI) in absence of a solvent and in the presence of a base.

13. The process of claim 12, wherein the base is selected from organic base and inorganic base, preferably trimethylamine (TEA), diisopropyl ethylamine ( DIPEA) and the like.

14. The process of claim 13, wherein the reaction is carried out at a temperature ranging from -10 to 90°C, preferably 10 to 85°C, more preferably 40 to 70°C.

15. The process according to any preceding claims, wherein compounds (II), (III), (IV), and (V) are in the form of their (S) -isomers and compounds (VIII) and (VII) are in the form of their (R) -isomers.

16. A process for preparing a compound (I)

Formula (I)
comprises preparing compound (II) according to any preceding claims, and converting compound (II) to compound (I).

17. A process according to claim 16, wherein the conversion comprise reacting compound (II) with 1-(bromoethyl)-4(trifluoromethoxy) benzene compound (IX)

in the presence of a base to provide compound (I).

18. The process of claim 17, wherein base is selected from organic and inorganic base.

19. The process according to any one of claims 16 to 18, wherein the reaction is carried out in the presence of solvent selected from polar protic and aprotic solvents.

20. The process according to any preceding claims, wherein the compound (I) is prepared as an optically active (S)- isomer starting from an optically active (R )-isomer of 2,3-epoxy-1-propanol (VIII).

21. A compound of the formula (IV)

,
or its optically active isomers thereof.

22. A compound of the formula (V)

,
or its optically active isomers thereof.