DESC:
FIELD OF THE INVENTION
The present application provides an improved industrial process for preparation of Pretomanid.

BACKGROUND OF THE INVENTION
Pretomanid, also known as PA-824, is a nitroimidazole-oxazine compound developed by Global Alliance for TB Drug Development. It is chemically known as (6S)-2-nitro-6-{[4-(trifluoromethoxy)benzyl]oxy}-6,7-dihydro-5H-imidazo[2,1-b][1,3]oxazine or (3S)-4-(trifluromethoxy)-benzyloxy-6-nitro-2H-3,4-dihydro-[2-1b]-imidazopyran and represented by following structure as shown in formula I.

Pretomanid in combination with bedaquiline and linezolid is used for treatment in extensively drug-resistant tuberculosis (XDR-TB) and intolerant or non-responsive multidrug-resistant tuberculosis (MDRTB). Pretomanid has many attractive characteristics for use to TB therapy, including a novel mechanism of action, activity in vitro against all tested drag-resistant clinical isolates, and activity as both a potent bactericidal and sterilizing agent.

Pretomanid and its pharmaceutically acceptable salts are disclosed in US 5,668,127 and US 6,087,358. US ‘358 discloses a process for the preparation of Pretomanid which includes dinitro imidazole as the starting material, series of protection-deprotection reactions and multiple chromatographic separations, making the process very tedious.

The Indian patent publication 201641030408 describes process for preparation of pretomanid wherein process involves use of alkali or alkaline metal hydrides which are hazardous reagents.

The process for preparation of pretomanid is also disclosed in the patent US 7,115,736; CN 104177372; Journal Medicinal Chemistry (2009), 52, 637 - 645; Bioorganic & Medicinal Chemistry Letters (2008), 18 (7), 2256 - 2262; and Journal Organic Chemistry (2010), 75 (2), 7479 – 82.

The prior art synthesis methods use dinitro imidazole which is explosive, sodium hydride reagent which is hazardous, expensive raw materials and chromatographic separations, making the process unsuitable for industrial scale.

Thus, there still exists a continued need to develop an improved process which is safe, efficient, industrially viable, involving less number of steps and avoiding use of dinitro imidazole and hazardous reagents.

SUMMARY OF THE INVENTION:

The present invention provides an improved process for preparing Pretomanid a compound of Formula I

which comprises:
a) reacting 4-nitroimidazole compound of formula IV

wherein X is chloro or bromo atom,
with a compound of formula V

wherein P is protecting group,
in the presence of base and a solvent to obtain a compound of formula III

wherein X is chloro or bromo atom and P is protecting group,
b) reacting compound of formula III with 4- trifluoro methoxybenzyl bromide in a solvent to obtain a compound of formula II

wherein X is chloro or bromo atom and P is protecting group,
wherein the reaction is carried out in presence of base excluding metal hydrides,
c) de-protecting compound of formula II to give compound of formula IIa

wherein X is chloro or bromo atom,
d) cyclizing compound of formula IIa using an alkali or alkaline metal hydroxide or alkoxide to obtain pretomanid of formula I.
e) optionally purifying pretomanid of formula I.

DETAILED DESCRIPTION OF THE INVENTION:

Thus, the present invention provides an improved process for preparing Pretomanid a compound of Formula I

comprising:
a) reacting 4-nitroimidazole compound of formula IV

wherein X is chloro or bromo atom
with a compound of formula V

wherein P is protecting group,
in the presence of base and a solvent to obtain a compound of formula III

wherein X is chloro or bromo atom and P is protecting group,
b) reacting compound of formula III with 4- trifluoro methoxybenzyl bromide in a solvent to obtain a compound of formula II

wherein X is chloro or bromo atom and P is protecting group
wherein the reaction is carried out in presence of base excluding metal hydrides,

c) de-protecting compound of formula II to give compound of formula IIa

wherein X is chloro or bromo atom
d) cyclizing compound of formula IIa using an alkali or alkaline metal hydroxide or alkoxide to obtain pretomanid of formula I.
e) optionally purifying pretomanid of formula I.

Protecting group/s used in the process of the present invention are hydroxy protecting group/s commonly used for the temporary protection of the hydroxy (—OH) functional group and may be selected from groups known to those skilled in the art, including protecting groups disclosed in Greene, Theodora W.; Wuts, Peter G. M., Protective Groups in Organic Synthesis. 3rd Ed. (1999). Examples of a hydroxy protecting group (P) may include but not limited to alkoxycarbonyl such as methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl; alkoxyalkyl such as methoxymethyl, ethoxymethyl; silyl such as trimethylsilyl (TMS), triethylsilyl (TES), t-butyldimethylsilyl (TBDMS), dimethylphenylsilyl (DMPS), Di-t-butyldimethylsilylene (DTBS) and analogous alkylated silyl radicals; aralkyl such as benzyl; acyl such as acetyl.

The base used in step a) of the above reaction may be inorganic or organic. Inorganic base may be selected from but not limited to sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, lithium carbonate, sodium bicarbonate, potassium bicarbonate, and the like. Organic base may be selected from but not limited to sodium methoxide, potassium methoxide, pyridine, dimethyl amine, triethyl amine (TEA), N,N-diisopropylethyl amine (DIPEA), 1,8-Diazabicyc10[5.4.0]undec-7-ene (DBU), 1,4-Diazabicyclo[2.2.2]octane (DABCO), N-methyl morpholine (NMM), N,N-dimethyl piperazine (DMP), N-methyl piperidine, and the like.

Solvent used throughout the process of the present invention may be any solvent which is inert to the reaction and selected from but not limited to alcohol selected from methanol, ethanol, propanol, isopropyl alcohol; halogenated hydrocarbon selected from dichloromethane, dichloroethane, chloroform; hydrocarbon selected from heptane, hexane, cyclohexane, toluene; ketone selected from acetone, methyl isobutyl ketone, methyl ethyl ketone; ester selected from ethyl acetate, isopropyl acetate; nitrile selected from acetonitrile, propionitrile; polar aprotic solvent selected from tetrahydrofuran (THF), dimethylformamide (DMF), dimethyl sulfoxide (DMSO); water or mixtures thereof.

Process of step b) of the present invention is carried out in presence of base excluding metal hydrides like sodium or lithium hydrides; step b) is carried out in presence of bases selected from sodium or potassium alkoxides such as sodium or potassium methoxide, sodium or potassium ethoxide, sodium or potassium tert-butoxide; sodium or potassium hydroxide, sodium or potassium carbonate. The reaction is optionally carried out in the presence of catalytic amount of sodium iodide or potassium iodide or tetrabutylammonium iodide.

De-protection in step c) can be carried out using the methods known to those skilled in the art for example by acid/base hydrolysis. The reaction can be carried out in an appropriate solvent.

Cyclization of compound of formula IIa) in step d) can be carried out in presence of base and solvent to give pretomanid compound of formula I. The base used is alkali or alkaline metal hydroxide or alkoxide selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium methoxide, sodium tert-butoxide, potassium tert-butoxide.

The Pretomanid of formula (I) obtained by the process of the present invention, can be optionally purified by conventional means, for example by recrystallization from a suitable solvent or mixture of solvents. Pretomanid (I) obtained by the process of the present invention has HPLC purity of greater than 98% and purified compound has HPLC purity of greater than 99.5%.

Pretomanid (I) obtained by the process of the present invention may be formulated in conventional manner using one or more pharmaceutically acceptable carriers, excipients, or diluents.

The following preparative and testing examples are set forth for the present invention, which are for the purpose of illustration only and are not to be construed as limiting the scope of the invention in any way.

Examples:
Example 1: Preparation of compound III (wherein X is bromo atom and P is tert-butyldimethylsilyl)

A mixture of 2-bromo-4-nitroimidazole (50 gm), isopropyl acetate (350 mL), tert-butyl-dimethyl-((S)-1-oxiranylmethoxy)-silane (63.7 gm) and N, N-diisopropylethylamine (16.83). was then heated to 60-80°C for 17-19 hours. The reaction mixture was cooled to 25-30°C, water was added, and the organic layer was separated. The organic layer was partially concentrated followed by addition of heptane (500 ml) and isopropyl acetate (70 mL). The mixture was heated to 60-80°C, cooled, filtered and dried under vacuum to give compound III (68.45 gm) (wherein halogen is bromine and protecting group is tert-butyldimethylsilyl).

Example 2: Preparation of pretomanid
A mixture of Compound III (wherein X is bromo atom and P is tert-butyldimethylsilyl) (50 gm), dimethylformamide (150 ml), 4- trifluoro methoxybenzyl bromide (40 gm) and potassium iodide (4.3 gm) was cooled to 0-10°C followed by addition of potassium hydroxide (23.5 gm), the reaction mixture as stirred at 0-10°C for 2 hours. Water (300 ml) and isopropyl acetate (250 ml) was added to reaction mixture, the layer was separated and concentrated. To the concentrate was added methanol (150 ml) and conc. HCl (37.5 ml) and stirred for 2 hours. Followed by addition of water (200 ml) and isopropyl acetate (350 ml). The organic layer was separated and concentrated. To the concentrate was then added methanol (250 ml) and potassium tert-butoxide (22 gm) and stirred for 2 hours at 20-30°C. Followed by addition of water (250 ml) and isopropyl acetate (350 ml). The organic layer was separated and concentrated and isopropyl alcohol (250 ml) was added. The above mixture was seeded with 250 mg pretomanid, filtered and dried under vacuum to give crude pretomanid (17.1 gm, HPLC purity: 99.10 %).

Example 3: Purification of pretomanid.
A mixture of crude pretomanid (20gm) and acetone (100 ml) was stirred to obtain a clear solution, water (200 ml) was added. The solid was filtered and dried under vacuum to give pure pretomanid, HPLC purity: 99.93%.
,CLAIMS:
1) A process for preparation of pretomanid, compound of formula I

comprising:
f) reacting 4-nitroimidazole compound of formula IV

wherein X represents chlorine or bromine atom,
with a compound of formula V

wherein P represents protecting group,
in the presence of base and a solvent to obtain a compound of formula III

wherein X represents chlorine or bromine atom and P represents protecting group,
g) reacting compound of formula III with 4- trifluoro methoxybenzyl bromide in a solvent to obtain a compound of formula II

wherein X represents chlorine or bromine atom and P represents protecting group
wherein the reaction is carried out in the absence of alkali or alkaline metal hydrides,
h) de-protecting compound of formula II to give compound of formula IIa

wherein X represents chlorine or bromine atom and P represents protecting group,
i) cyclizing compound of formula IIa using an alkali or alkaline metal hydroxide or alkoxide to obtain pretomanid of formula I, and
j) optionally purifying pretomanid of formula I.

2) The process as claimed in claim 1, wherein the base used in step a) is sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide, pyridine, dimethyl amine, triethyl amine, N,N-diisopropylethyl amine, 1,8-Diazabicyc10[5.4.0]undec-7-ene, 1,4-Diazabicyclo[2.2.2]octane, N-methyl morpholine, N,N-dimethyl piperazine or N-methyl piperidine.

3) The process as claimed in claim 1, wherein the protecting group is methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl, methoxymethyl, ethoxymethyl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, dimethylphenylsilyl, di-t-butyldimethylsilylene, benzyl or acetyl.

4) The process as claimed in claim 1, wherein the alkali or alkaline metal hydroxide or alkoxide in step (b) is sodium hydroxide, potassium hydroxide, lithium hydroxide, sodium methoxide, potassium methoxide, sodium tert-butoxide or potassium tert-butoxide.

5) The process as claimed in claim 1, wherein the solvent is alcohol, halogenated hydrocarbon, hydrocarbon, ketone, ester, nitrile or mixtures thereof.

6) The process as claimed in claim 1, wherein alcohol is methanol, ethanol, propanol or isopropanol.

7) The process as claimed in claim 5, wherein halogenated hydrocarbon is dichloromethane, dichloroethane or chloroform and hydrocarbon is heptane, hexane, cyclohexane or toluene.

8) The process as claimed in claim 5, wherein ketone is acetone or methyl isobutyl ketone.

9) The process as claimed in claim 5, wherein ester is ethyl acetate or isopropyl acetate.

10) The process as claimed in claim 1, wherein the solvent is acetonitrile, propionitrile, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide or water.