DESC:CROSS-REFERENCE TO RELATED APPLICATIONS
This application claims the benefit of earlier Indian provisional patent application IN 201841004428 filed on February 06, 2018, which are hereby incorporated by reference in their entireties.
FIELD OF THE INVENTION
The present invention relates to a novel process for the preparation of Delamanid.

BACKGROUND OF THE INVENTION
Delamanid is a medication used to treat tuberculosis. It is chemically described as (2R)-2-Methyl-6-nitro-2-[(4-{4-[4-(trifluoromethoxy) phenoxy]-1-piperidinyl} phenoxy) methyl]-2,3-dihydroimidazo[2,1-b] [1,3] oxazole and has the following structural formula-I.

Formula-I

Delamanid works by blocking the manufacture of mycolic acids thus destabilizing the bacteria's
cell wall. It is used along with other anti-tuberculosis medications, for active multidrug-resistant
tuberculosis.

United States Pat. No. US7262212 B2 claims Delamanid as a product and process for the preparation thereof.

US8598358B2 claims process for the preparation of compound of formula (I) by the following process.
a) Epoxidation of trifluoro methoxy mesylate to prepare trifluoro methoxy epoxy compound

b) reacting trifluoro methoxy epoxy compound with 2-Bromo 4-nitro imidazole to form Bromo Intermediate.

c) subjecting the Bromo Intermediate to a ring closure reaction to prepare the final compound.

The present invention relates to a cost effective and efficient process for the preparation of Delamanid.

SUMMARY OF THE INVENTION
Principle object of the present invention is to provide a process for the preparation of Delamanid.
One aspect of the present invention provides process for the preparation of Delamanid as shown in the schemes below:
Scheme-I

Scheme-II.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a novel process for the preparation of Delamanid.
One embodiment of the present invention relates to a process for preparation of Delamanid comprising the steps of:

a) converting compound of formula-A to compound of formula-D as shown below

b) Coupling of 4-[4-(trifluoromethoxy)phenoxy] piperidine with compound of formula-D in presence of suitable solvent to get crude Delamanid, which is optionally purified to obtain pure Delamanid compound.

According to the present invention the bromo diol compound of formula A is reacted with mesyl chloride in presence of suitable organic solvent such as toluene, ethyl acetate, cyclopentyl ether
Ethyl acetate, Isopropyl acetate, Dichloromethane, Toluene and a base such as Triethylamine
Pyridine, NMM, 2,6-lutidine, DIPEA, Dimethyl butyl amine and Tributylamine to form compound of formula B [bromodiol monomesylate]. Compound of formula B, with or without isolation may be treated with a base such as Potassium carbonate Sodium hydroxide, Potassium hydroxide, Lithium hydroxide, Sodium carbonate, Sodium methoxide and Sodium ethoxide in presence of a solvent such as Methanol, Ethanol, Isopropyl alcohol, Toluene Isopropyl acetate and Ethyl acetate to obtain compound of formula C [bromodiol epoxide]. Compound of formula C, with or without isolation may be treated with 2-halo-4-nitroimidazole [wherein halo can be chloro, bromo or iodo] in presence of a base such as Sodium acetate, Potassium acetate, Potassium hydrogen carbonate, Calcium acetate and Magnesium acetate in presence of a solvent such as tertiary butyl acetate and Toluene to obtain dihalo intermediate. To the dihalo intermediate, with or without isolation may be added with a suitable solvent such as methanol, ethanol and Isopropyl alcohol and treated with suitable base such as Sodium hydroxide, Potassium hydroxide, Lithium hydroxide, Potassium carbonate and Sodium carbonate to obtain compound of formula D [halo nitro imidazooxazole].
Compound of formula D may be coupled with 4-[4-(trifluoromethoxy) phenoxy] piperidine in presence tris(dibenzylideneacetone) dipalladium, 2-di-tert-butylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl and a base such as sodium-tert-butoxide, Potassium tertiary butoxide, Sodium hydroxide, Lithium hydroxide, Potassium hydroxide + tributylamine, Cesium carbonate, Potassium carbonate, Potassium phosphate tribasic, LiHMDS, KHMDS, Sodium hydride, Sodium methoxide and Sodium ethoxide in a suitable organic solvent such as Toluene, 1,2-dimethoxy ethane, Tetrahydrofuran, N,N-Dimethylformamide, Acetonitrile, 1,4-dioxane, Tertiary butanol and combination of above solvents in presence of catalyst such as Pd2(dba)3, Palladium acetate
[(allyl)PdCl]2, Tetrakis(triphenylphosphine)palladium(0), Peppsi – Ipr catalyst, Pd(dppf)2Cl2
(NHC)Pd(allyl)Cl, (Ethylene diamine) palladium (II) chloride, (1,2-Bis(dimethylamino)ethane) dichloro palladium, Phosphine RuAMPY catalyst, (CYPF-tBu)Pd, Pd(P(O-tol)3)2,(Pd(cinnamyl)Cl)2 and Ni(cod)2. The reaction mixture may be treated with ammonium chloride and extracted with a solvent. Removing the solvent obtains the crude product which may be recrystallized in a suitable solvent to obtain the pure Delamanid compound.

The examples are given solely for illustration and are not to be construed as limitations as many variations are possible without departing form scope of the invention.

Examples:

Example 1: Preparation of (2R)-3-(4-bromophenoxy)-2-methylpropane-1,2-diol (or) Bromo diol (or) formula A:

A mixture of beta-Methallyl alcohol (83.4 g), (-) Diisopropyl D-tartrate (16.3 g), Molecular Sieves powder (Grade 4Ao) (40.0 g) and toluene (400 ml) was stirred at -17 to -15°C. Titanium tetra isopropoxide (16.4 g) was added to the mixture and stirring was continued at -18 to -16°C for 30 minutes. Thereafter, 80% Cumene hydroperoxide (373.9 g) was added thereto at -18 to -16°C over a period of 2 hours and stirring was continued at -11 to -9°C for 5 hours. Dimethyl sulfoxide (90.3 g) was added at below 15°C over a period of 30 minutes. The resulting mixture was stirred at room temperature for 6 hours. After adding hyflo (15 g), stirring was continued for 30 minutes. The reaction mixture was filtered and obtained filtrate contains toluene solution consisting (S)-2-methylglycidyl alcohol.
4-Bromo phenol (100 g) and 25% w/w sodium hydroxide aqueous solution (101.7 g) were added sequentially to the toluene solution (as obtained above) and reaction mass was stirred at 40°C for 9 hours. After cooling the reaction mixture to room temperature, added activated carbon (2 g) and hyflo (40 g), stirring was continued for 30 minutes and subjected to filtration. Thus, obtained toluene filtrate was washed with water (500 ml) and concentrated under reduced pressure. Toluene was added to the residue followed by heating to 70°C to make homogeneous solution. The resulting solution was cooled to room temperature and stirred for 6 hours. Finally, precipitated product was collected by filtration, washed with toluene (100 ml) and dried under vacuum to yield 92 g of Bromo diol

Example 2: Preparation of 4-[4-(trifluoromethoxy)phenoxy] piperidine (or) Trifluoromethoxy piperidine:

To a solution of Hydroxy Piperidine ester (194 g), methane sulfonyl chloride (141 g) and toluene (300 ml) at 0 -10°C, Triethylamine (148 g) was added dropwise at below 20°C and stirring was continued at room temperature for 1 hour. Thereafter, charged water and separated layers.
To obtained organic layer, Trifluoromethoxy phenol (100 g), Toluene (200 ml), ~25% w/v Aq. sodium hydroxide solution (437 g), ~50% w/v Aq. Tetra butyl ammonium bromide solution (124 g) were added sequentially and refluxed for 2 hours. Thereafter, reaction mixture was cooled and aqueous layer was removed. Obtained organic layer was washed with water (200 ml).
Potassium hydroxide (283 g) and ethanol (200 ml) were added to the organic layer and reaction mixture was refluxed for 4 hours. After cooling, reaction mass was concentrated under vacuum. Charged toluene (1000 ml) to residue and the organic layer was washed with water (600 ml). Thereafter, organic layer was concentrated under vacuum added and isopropyl alcohol (100 ml), water (1000 ml) and ~ 25% w/v aq. sodium hydroxide solution (62.5 g) were added to the concentrated residue to make homogeneous solution and then cooled to 0-5°C and stirred for 6 hours. The precipitated product was collected by filtration, washed with water (200 ml) and dried under vacuum to provide 130 g of the Trifluoromethoxy piperidine

Example 3: Preparation of (2R)-2-[(4-bromophenoxy) methyl]-2-methyl-6-nitro-2,3-dihydroimidazo[2,1-b][1,3]oxazole (Or) Bromo nitro imidazooxazole (Or) formula D :
50 g of Bromo diol and 38.8 g of triethylamine were added sequentially to 500 ml of ethyl acetate and cooled to 0-5oC. 25.2 g of mesyl chloride was added by maintaining temperature below 10oC. After completion of the reaction, 50 ml of water and 100 ml of ethyl acetate were added to the reaction mass and separated the organic layer. Organic layer was concentrated under reduced pressure. 600 ml of methanol and 52.9 g of potassium carbonate were added to resulting product and the reaction mixture was stirred for 30 minutes at room temperature. The reaction mixture was concentrated under reduced pressure and added 350 ml of toluene and 250 ml water. The toluene layer was washed with water and concentrated under reduced pressure. To the resulting product charged 42 g of 2-Chloro-4-nitroimidazole, 3.1 g of sodium acetate were added sequentially to 50 ml of t-butyl acetate and stirred at 100oC for 4 hrs. Methanol (350 ml) was added to the reaction mixture and cool to 0oC. Thereafter, 25%w/v Aq. sodium hydroxide solution (400 g) was added slowly and resulting mixture was stirred at 0oC for 1hour and at room temperature for 90 minutes sequentially. Water (75 ml) and ethyl acetate (25 ml) were added thereto, and resulting mixture was further stirred at 50oC for 1 hour. The mixture was cooled to room temperature, filtered, washed with methanol (50 ml) and dried under reduced pressure to yield 30 g of Bromo nitro imidazooxazole.

Example 4: Preparation of (2R)-2-methyl-6-nitro-2-[(4-{4-[4-(trifluoromethoxy) phenoxy] piperidin-1-yl}phenoxy)methyl]-2,3-dihydroimidazo[2,1-b][1,3]oxazole (Or) Delamanid:

Under argon atmosphere Bromo nitro imidazooxazole (28g), Trifluoromethoxy piperidine (29g), tris(dibenzylideneacetone) dipalladium (0) (175 mg), 2-di-tert-butylphosphino-2’,4’,6’-triisopropyl-1,1’-biphenyl (195 mg), sodium-tert-butoxide (8.8 g) were added sequentially to toluene (140 ml) and stirred at 70oC for 4 hrs. After cooling, aqueous ammonium chloride was added to the reaction mixture and product was extracted with toluene. Thereafter, the organic layer was concentrated under reduced pressure to provide crude product. Methanol (280 ml) was added to the resulting product and contents were stirred under reflux for 30 minutes. The mixture was cooled to room temperature, filtered and washed with methanol (28 ml). Acetone (112 ml) and ethanol (112 ml) was added to the resulting product and contents were stirred under reflux for 30 minutes. The mixture was cooled, filtered, washed with ethanol (28 ml) and dried under reduced pressure, to yield Delamanid (22.4 g).
,CLAIMS:1. One pot synthesis of compound of formula D

2. The process as claimed in claim 1, wherein compound of formula A is converted to compound of formula B by treating with mesyl chloride in presence of an organic solvent and a base.

3. The process as claimed in claim 2, wherein the organic solvent is selected from toluene, ethyl acetate, cyclopentyl ether, ethyl acetate, Isopropyl acetate, dichloromethane and the base is selected from triethylamine, pyridine, NMM, 2,6-lutidine, DeIPEA, dimethyl butyl amine or tributylamine.

4. The process as claimed in claim 1, wherein the compound of formula B with or without isolation is converted to compound of formula C by treating with a base selected from potassium carbonate, sodium hydroxide, potassium hydroxide, Lithium hydroxide, sodium carbonate, sodium methoxide or sodium ethoxide in presence of a solvent selected from methanol, ethanol, Isopropyl alcohol, toluene Isopropyl acetate or ethyl acetate.

5. The process as claimed in claim 1, wherein the compound of formula C with or without isolation is converted to dihalo intermediate by treating with 2-halo-4-nitroimidazole in presence of a base selected from sodium acetate, potassium acetate, potassium hydrogen carbonate, calcium acetate or magnesium acetate and a solvent selected from tertiary butyl acetate or toluene.

6. The process as claimed in claim 5, wherein the halo represents chloro, bromo or iodo.

7. The process as claimed in claim 1, wherein the dihalo intermediate with or without isolation is converted to compound of formula D by treating with a base selected from sodium hydroxide, potassium hydroxide, Lithium hydroxide, potassium carbonate or sodium carbonate in presence of a solvent selected from methanol, ethanol or Isopropyl alcohol.

6. The process as claimed in claim 1, where the compound of formula D is coupled with 4-[4-(trifluoromethoxy)phenoxy] piperidine in presence of suitable solvent to get crude Delamanid, which is optionally purified to obtain pure Delamanid.