DESC:
CROSS REFERENCE TO RELATED APPLICATION
This patent application claims the benefit of priority to Indian Provisional Patent Application No. 201941018232, filed on May 7, 2019, which is incorporated herein by reference in their entirety.
FIELD OF THE INVENTION
The present invention relates to novel, commercially viable and industrially advantageous processes for the preparation of Vilanterol intermediates, in high yield and purity.

BACKGROUND OF THE INVENTION
U.S. Patent No. US RE 44,874 E (hereinafter referred to as the US‘874 patent) discloses phenethanolamine derivatives, salts, solvates, and physiologically functional derivatives thereof, processes for their preparation, pharmaceutical compositions comprising the derivatives, and methods of use thereof. These compounds are useful in the prophylaxis and treatment of clinical conditions for which a selective ß2-adrenoreceptor agonist is indicated. Among them, Vilanterol trifenatate, chemically named as 4-[(R)-2-[[6-[2-(2,6-dicholorobenzyloxy)-ethoxy]-hexyl]-amino]-1-hydroxyethyl]-2-hydroxymethyl-phenol triphenylacetate salt, is a selective ß2-adrenoreceptor agonist used for the treatment of chronic obstructive pulmonary disease (COPD). Vilanterol trifenatate is represented by the following structural formula I:

Vilanterol trifenatate, was approved in combination with Fluticasone Furoate and Umeclidinium bromide for the treatment of patients with chronic obstructive pulmonary disease (COPD). Vilanterol trifenatate was developed by GlaxoSmithKline and approved in the United States and European Union and marketed for inhalation under the trade names Anoro Ellipta (Umeclidinium bromide, Vilanterol trifenatate), Breo Ellipta (Fluticasone Furoate, Vilanterol trifenatate) and Trelegy Ellipta (Umeclidinium bromide, Fluticasone Furoate, Vilanterol trifenatate) in the United States and Anoro Ellipta (Umeclidinium bromide, Vilanterol trifenatate), Relvar Ellipta (Fluticasone Furoate, Vilanterol trifenatate) and Elebrato Ellipta (Umeclidinium bromide, Fluticasone Furoate, Vilanterol trifenatate) in the European Union.
Various processes for the preparation of Vilanterol trifenatate, its intermediates, and related compounds are described in U.S. Patent No. US RE 44874; PCT Publication Nos. WO 2014/041565, WO 2017/001907; Chinese Patent Nos. CN 103923058B, CN 104744271B, CN 105646285B; and Journal of Medicinal Chemistry, 53, 4522-4530, 2010.
The synthesis of Vilanterol trifenatate was first described in the US’874 patent. According to the US’874 patent, Vilanterol trifenatate is prepared by a process as depicted in scheme-1:

As per the process described in steps-(iii) to (v) of Example-77 of the US’874 patent, Vilanterol is prepared by the following reaction steps: (i) a solution of 2-[2-(6-bromo-hexyloxy)-ethoxymethyl]-1,3-dichloro-benzene is added to a mixture of potassium tert-butoxide and a solution of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one in dimethylformamide under nitrogen atmosphere at ambient temperature, and the resulting mass was maintained for 20 hours at ambient temperature to produce (R)-3-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]hexyl}-5-(2,2-dimethyl-4H-benzo[1,3-]dioxin-6-yl)oxazolidin-2-one; (ii) the solution of the resulting compound in tetrahydrofuran is reacted with potassium trimethylsilanolate under nitrogen atmosphere at 80°C to produce (R)-2-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]hexylamino}-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)-ethanol; (iii) the resulting compound is reacted with 1N hydrochloric acid in ethanol to yield a residue, which is chromatographed using silica gel column chromatography to produce 4-((R)-2-{6-[2-(2,6-dichlorobenzyloxy)-ethoxy]-hexylamino}-1-hydroxyethyl)-2-hydroxymethylphenol (Vilanterol). Further, as per the process described in step-(i) of Example 78 of the US’874 patent, Vilanterol trifenatate is prepared by adding triphenylacetic acid to a solution of Vilanterol in ethanol and the resulting mixture was heated to 80°C to obtain a solution, which is cooled to ambient temperature, and the resulting product is filtered, washed with ethanol and dried at 50°C to produce Vilanterol trifenatate as a white crystalline solid.
In the synthesis of Vilanterol trifenatate, the following compound, (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one, of formula II is used as a key intermediate (Intermediate-1):

In the synthesis of Vilanterol trifenatate, the following compound, 2-[2-(6-bromo-hexyloxy)-ethoxymethyl]-1,3-dichloro-benzene of formula II is used as another key intermediate (Intermediate-2):

In the synthesis of (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one of formula II (Intermediate-1), the following compound, 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone, of formula XI is a key starting material:

According to the US’874 patent, (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (Intermediate-1 of Vilanterol trifenatate) is prepared by a process as depicted in scheme-2:

As per the process described in steps (i)-(iv) of Example-1 of the US’874 patent, (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (Intermediate-1) is prepared by the following main reaction steps: (i) Cesium carbonate is added to a stirred suspension of 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (key starting material) and di-tert-butyliminodicarboxylate in acetonitrile under nitrogen atmosphere, and the resulting mass is maintained for 24 hours at 21°C, followed by usual work up procedure to produce the di-(tert-butyl)-2-(2,2-dimethyl-4H-1,3-benzo-dioxin-6-yl)-2-oxoethylimidodicarbonate in three crops, in which the third crop is obtained by using silica gel column chromatography; (ii) to the resulting compound, trifluoroacetic acid is added and the obtained crude product is recrystallized from diethyl ether, and further product is obtained from the mother liquors by evaporation and chromatography to produce tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate; (iii) the resulting compound is added to a mixture of 2M solution of borane-dimethyl sulphide (BH3.DMS) in tetrahydrofuran and 1M solution of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H-3H-pyrrolo[1,2-c][1,3,2]oxazaborole [(R)-MeCBS] in toluene at 0°C under nitrogen atmosphere, and the resulting mixture is subjected to usual work-up and the product is purified by silica gel column chromatography to produce tert-butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate; (iv) a solution of the resulting compound in dimethyl formamide is added drop-wise to a stirred suspension of sodium hydride (60% oil dispersion) in dimethylformamide with cooling. The resulting mixture is stirred for 2 hours at 21°C, followed by usual work-up to produce (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one.
According to the US’874 patent, 2-[2-(6-bromo-hexyloxy)-ethoxymethyl]-1,3-dichloro-benzene (Intermediate-2 of Vilanterol trifenatate), is prepared by a process as depicted in scheme-3:

As per the process described in steps (i)-(iv) of Example 77 of the US’874 patent, 2-[2-(6-bromo-hexyloxy)-ethoxymethyl]-1,3-dichloro-benzene (Intermediate-2) is prepared by the following main reaction steps: (i) Sodium methoxide is added portion-wise to ethylene glycol under nitrogen atmosphere at the temperature below 35°C, after 1-2 hours, 2,6-dichlorobenzylbromide is added and maintained for 1 hour at 55-60°C, and the resulting mass is cooled to 20°C, followed by usual work-up to afford a colourless oil and purifying with silica gel column chromatography to produce 2-(2,6-dichlorobenzyloxy)ethanol; (ii) to the resulting compound, 50% aqueous sodium hydroxide, 1,6-dibromohexane and tetrabutylammonium bromide in toluene were added and the resulting mixture is heated to 55-60°C and maintained for 8-20 hours, the resulting mass is cooled and further subjected to usual work-up procedure to produce a crude product which is further purified with silica gel column chromatography to afford 2-[2-(6-bromo-hexyloxy)-ethoxymethyl]-1,3-dichloro-benzene (Intermediate-2).
PCT Publication No. WO2014/041565 (hereinafter referred to as WO’565 publication) discloses a process for the preparation of key starting material of Vilanterol, 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone. According to the WO’565 publication, 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone is prepared by a process as depicted in scheme-4:

As per the process disclosed in the WO’565 publication, 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone is prepared by the following main reaction steps: (i) Aluminum chloride is added to a mixture of 5-bromo-2-hydroxy benzyl alcohol and tetrahydrofuran at 0-5°C, the temperature of the reaction mass is raised to 25-30°C and maintained for 1 hour, after completion of reaction, and the resulting mass is subjected to usual work-up to produce 6-bromo-2,2-dimethyl-4H-1,3-benzodioxine; (ii) the resulting compound is dissolved in tetrahydrofuran at 25-30°C and further cooled to -70 to -75°C, n-Butyl lithium is added slowly to the above reaction mass and stirred for 60 minutes, followed by the addition of N-methoxy-N-methyl-acetamide at the same temperature, after completion of reaction, the resulting mass is subjected to usual work-up to produce 1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone; and (iii) the resulting compound is dissolved in tetrahydrofuran at room temperature and the temperature of the reaction mass is lowered to -70 to -75°C, sodium bis(trimethylsilyl)amide (1M in THF) is added slowly to the above reaction mass and allowed to stir over a period of 1 hour, TMSCl is added to the above reaction mass slowly, a solution of bromine is added to the above reaction mass and maintained at -70 to -75°C, after completion of reaction, the temperature is raised to -25°C and MTBE is added, followed by usual work-up to produce 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone.
According to Chinese Patent No. CN 105646285 B (hereinafter referred to as the CN’285 patent), a key intermediate of Vilanterol, (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one is prepared by a process as depicted in Scheme-5:

According to Chinese Patent No. CN 104744271 B (hereinafter referred to as the CN’271 patent), Vilanterol is prepared by a process as depicted in Scheme-6:

The processes for the preparation of Vilanterol trifenatate and its intermediates as described in the aforementioned prior art suffer from the following major disadvantages and shortcomings:
a) the process exemplified in step-(v) of Example 7 of the US’787 patent involves the use of alcohol solvent during the acetonide cleavage to produce Vilanterol, which tends to result in the formation of the corresponding ether impurities;
b) the processes involve the use of dangerous, pyrophoric and explosive alkali metal hydrides such as sodium hydride (in the preparation of key intermediate-1) - the use of alkali metal hydrides is not advisable for commercial scale operations from safety point of view;
c) the processes involve the use of highly dangerous and pyrophoric reagents like n-butyl lithium which are operated at very low temperatures (-70°C to -75°C) handling of these reagents is very difficult at large scale operations; and
d) the processes involve the use of tedious and cumbersome procedures like chromatographic purifications - which are not suitable for industrial scale operations.
A need remains for novel, commercially viable and environmentally friendly processes for the preparation of Vilanterol trifenatate and its intermediates with high yields and purity, to resolve the problems associated with the processes described in the prior art, and that will be suitable for large-scale preparation.

SUMMARY OF THE INVENTION
The object of the present invention is to provide novel, commercially viable and industrially advantageous processes for the preparation of Vilanterol intermediates, in high yields and purity.
In one aspect, provided herein is a novel process for the preparation of Vilanterol intermediate, (5R)-5-(5,5-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (Intermediate-1), which comprises the following reaction steps: (a) reacting 4-hydroxy-acetophenone with paraformaldehyde in the presence of concentrated hydrochloric acid to produce 1-[3-(chloromethyl)-4-hydroxy-phenyl]ethanone; (b) the compound obtained in step-(a) is reacted with acetic anhydride in the presence of sodium acetate and acetic acid to produce 1-[4-acetyloxy-3-(acetyloxymethyl)-phenyl]ethanone; (c) the compound obtained in step-(b) undergoes bromination with a suitable reagent to produce 2-bromo-1-[4-acetyloxy-3-(acetyloxymethyl)-phenyl]ethanone; (d) the compound obtained in step-(c) is then hydrolyzed with a suitable reagent to produce 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)-phenyl]ethanone; (e) the compound obtained in step-(d) is further reacted with 2,2-dimethoxypropane to produce 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone; (f) the compound obtained in step-(e) is reacted with di-tert-butyl-iminodicarboxylate to produce di-(tert-butyl) 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate; (g) the compound obtained in step-(f) is further reacted with trifluoroacetic acid to produce tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate; (h) the compound obtained in step-(g) is then reacted with a suitable reducing agent to produce tert-butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl-carbamate; and (i) the compound obtained in step-(h) finally undergoes oxazolidinone ring formation in the presence of a suitable reagent such as potassium tert-butoxide to produce (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one. The process for the preparation of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one of formula II as disclosed herein may be represented by the following schematic diagram as depicted in scheme-7:

In another aspect, provided herein is a novel process for the preparation of 2-[2-(6-bromohexyloxy)ethoxymethyl]-1,3-dichlorobenzene (Intermediate-2), which comprises: reacting 2,6-dichlorobenzyl chloride with ethylene glycol in the presence of a base to produce 2-(2,6-dichlorobenzyloxy)ethanol, which is then reacted with 1,6-dibromo-hexane in the presence of a base, optionally in the presence of a phase transfer catalyst, to produce 2-[2-(6-bromohexyloxy)ethoxymethyl]-1,3-dichlorobenzene. The process for the preparation of 2-[2-(6-bromohexyloxy)ethoxymethyl]-1,3-dichlorobenzene of formula III as disclosed herein may be represented by a schematic diagram as depicted in scheme-8:

The processes disclosed herein are more convenient to operate at laboratory scale and on a commercial scale, which avoid the tedious and cumbersome prior art processes, thereby resolving the problems associated with the processes described in the prior art.
The process for the preparation of Vilanterol intermediates described herein have the following advantages over the processes described in the prior art:
i) the processes avoid the use of the pyrophoric, explosive and difficult to handle reagents such as Sodium hydride and n-butyl lithium;
ii) the processes avoid the use of extreme low temperatures (-70°C to -75°C);
iii) the processes avoid the use of tedious and cumbersome procedures such as prolonged reaction time periods, multiple process steps, column chromatographic purifications, multiple isolations, additional and excess amounts of solvents; and
iv) the processes involve the use of the less expensive raw materials like 2,6-dichlorobenzyl chloride and less expensive reagents such as (-)-ß-chlorodiisopinocampheylborane ((-)-DIP chloride).

DETAILED DESCRIPTION OF THE INVENTION
According to one aspect, there is provided a novel and industrially advantageous process for the preparation of (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one of formula II:

or a salt thereof, which comprises:
a) reacting 4-Hydroxyacetophenone of formula VI:

with paraformaldehyde and concentrated hydrochloric acid to produce 1-[3-(Chloromethyl)-4-hydroxy-phenyl]ethanone of formula VII:

b) reacting the compound of formula VII with a suitable acetylating agent in the presence of a suitable reagent in a suitable solvent to produce the 1-[4-acetyloxy-3-(acetyloxymethyl)-phenyl]ethanone of formula VIII:

c) bromination of the compound of formula VIII with bromine solution in a suitable solvent to produce 2-Bromo-1-[4-acetyloxy-3-(acetyloxymethyl)-phenyl]ethanone of formula IX:

d) deacetylation of the compound of formula IX using a suitable deprotecting agent in presence of a suitable solvent to produce 2-Bromo-1-[4-hydroxy-3-(hydroxymethyl)-phenyl]-ethanone of formula X:

e) reacting the compound of formula X with 2,2-dimethoxypropane in presence of a suitable catalyst in a suitable solvent to produce 2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone of formula XI:

f) reacting the compound of formula XI with di-tert-butyl-iminodicarboxylate in presence of a suitable base in a suitable solvent to produce di-(tert-butyl) 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate of formula XII:

g) deprotecting the compound of formula XII in the presence of a suitable acid in a suitable solvent to produce tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate of formula XIII:

or a salt thereof;
h) reducing the compound of formula XIII with a suitable reducing agent, optionally in the presence of a suitable chiral auxiliary, to obtain enantiomerically pure tert-butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl-carbamate of formula XIV:

or a salt thereof; and
i) reacting the compound of formula XIV with a suitable reagent in a suitable solvent to produce (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one of formula II or a salt thereof.
Unless otherwise specified, the solvent used for isolating, purifying and/or recrystallizing the compounds obtained by the processes described in the present invention is selected from the group consisting of water, an alcohol, a ketone, an ether, an ester, a hydrocarbon, a halogenated hydrocarbon, an amide solvent, a nitrile solvent, and mixtures thereof. Specifically, the solvent is selected from the group consisting of water, methanol, ethanol, 1-propanol, isopropyl alcohol, n-butanol, acetone, N,N-dimethymformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, cyclohexane, toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof.
Unless otherwise specified, the carbon treatment is carried out by methods known in the art, for example, by stirring the reaction mass/solution with finely powdered carbon at a temperature of about 40°C to the reflux temperature for at least 5 minutes, specifically at the reflux temperature; and filtering the resulting mixture through charcoal bed to obtain a filtrate containing compound by removing charcoal. Specifically, finely powdered carbon is a special carbon or an active carbon.
Unless otherwise specified, the term ‘base’ as used herein includes, but is not limited to, organic bases and inorganic bases such as carbonates, bicarbonates, hydroxides, alkoxides, acetates and amides of alkali or alkali earth metals.
Specifically, the inorganic base is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, potassium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, and mixtures thereof.
Specifically, the organic base is selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di-n-butylamine, diisobutylamine, triethylamine, tributylamine and tert-butyl amine.
Unless otherwise specified, the term ‘phase transfer catalyst’ as used herein includes, but is not limited to, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltrimethyl ammonium chloride, benzyltriethyl ammonium chloride, methyltributyl ammonium chloride, crown ethers and the like.
Unless otherwise specified, the term ‘salt’ as used herein may include acid addition salts and base addition salts.
Acid addition salts may be derived from organic and inorganic acids. For example, the acid addition salts are derived from a therapeutically acceptable acid such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid, propionic acid, phosphoric acid, succinic acid, maleic acid, fumaric acid, citric acid, glutaric acid, tartaric acid, benzenesulfonic acid, toluenesulfonic acid, malic acid, ascorbic acid, and the like.
Exemplary acid addition salts include, but are not limited to, hydrochloride, hydrobromide, sulphate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, tartrate, and the like. A most specific acid addition salt is hydrochloride salt.
Base addition salts may be derived from an organic or an inorganic base. For example, the base addition salts are derived from alkali or alkaline earth metals such as sodium, calcium, potassium and magnesium, ammonium salt and the like.
As used herein, the term “reflux temperature” means the temperature at which the solvent or solvent system refluxes or boils at atmospheric pressure.
As used herein, the term “room temperature” refers to a temperature of about 20°C to about 35°C. For example, “room temperature” can refer to a temperature of about 25°C to about 30°C.
In another embodiment, the reaction in step-(a) is carried out at a temperature of about 25°C to about 70°C, specifically at a temperature of about 35°C to about 60°C, and more specifically at a temperature of about 45°C to about 50°C. The reaction time may usually vary from about 3 hours to about 10 hours, and more specifically from about 5 hours to about 7 hours.
The reaction mass containing the 1-[3-(Chloromethyl)-4-hydroxy-phenyl]ethanone of formula VII obtained in step-(a) may be subjected to conventional work up methods such as a washing, a quenching, an extraction, a pH adjustment, an evaporation, a layer separation, decolorization, a carbon treatment, or a combination thereof. The reaction mass may be used directly in the next step to produce the compound of formula VIII, or the compound of formula VII may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula VII may be isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for work up, isolation and/or recrystallization of the compound of formula VII obtained by the process described herein is selected from the group as described hereinabove.
Exemplary solvents used in step-(b) include, but are not limited to, acetic acid, a halogenated hydrocarbon, a ketone, an ester, a hydrocarbon, and mixtures thereof.
Specifically, the solvent used in step-(b) is selected from the group consisting of acetic acid, dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, toluene, xylene, and mixtures thereof. A most specific solvent is acetic acid.
In one embodiment, the acetylating agent used in step-(b) is selected from the group consisting of acetic anhydride and acetyl chloride.
Exemplary reagents used for acetylation reaction in step-(b) include, but are not limited to, sodium acetate and potassium acetate. A most specific reagent used for acetylation reaction in step-(b) is sodium acetate.
In another embodiment, the reaction in step-(b) is carried out at a temperature of about 25°C to the reflux temperature of the solvent used, specifically at a temperature of about 35°C to the reflux temperature of the solvent used, and more specifically at reflux temperature of the solvent used. The reaction time may vary from about 30 minutes to about 5 hours, more specifically from about 1 hour to about 3 hours.
The reaction mass containing the 1-[4-Acetyloxy-3-(acetyloxymethyl)-phenyl]ethanone of formula VIII obtained in step-(b) may be subjected to conventional work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula IX, or the compound of formula VIII may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula VIII may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for work up, isolation and/or recrystallization of the compound of formula VIII obtained by the process described herein is selected from the group as described hereinabove.
Exemplary solvents used in step-(c) include, but are not limited to, a halogenated hydrocarbon, a ketone, an ether, an ester, a hydrocarbon, and mixtures thereof.
Specifically, the solvent used in step-(c) is selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof. A most specific solvent is chloroform or dichloromethane.
In one embodiment, the reaction in step-(c) is carried out at a temperature of about 0°C to about 40°C, specifically at a temperature of about 25°C to about 35°C. The reaction time may vary from about 30 minutes to about 4 hours, specifically from about 1 hour to about 3 hours.
The reaction mass containing the 2-Bromo-1-[4-acetyloxy-3-(acetyloxymethyl)-phenyl]ethanone of formula IX obtained in step-(c) may be subjected to conventional work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula X, or the compound of formula IX may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula IX may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for work up, isolation and/or recrystallization of the compound of formula IX obtained by the process described herein is selected from the group as described hereinabove.
In one embodiment, the deprotecting agent used in step-(d) is an acid or a base. The acid used in step (d) is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid and propionic acid; the base used in step-(d) is selected from the group consisting of triethylamine, aqueous ammonia, sodium hydroxide, calcium hydroxide, magnesium hydroxide, potassium hydroxide, lithium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, lithium carbonate, sodium tert-butoxide, sodium isopropoxide and potassium tert-butoxide. A most specific deprotecting agent is hydrobromic acid.
In another embodiment, the solvent used in step-(d) is dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof. A most specific solvent is selected from the group consisting of acetone, N,N-dimethylformamide, N,N-dimethylacetamide and tetrahydrofuran.
In another embodiment, the reaction in step-(d) is carried out at a temperature of about 25°C to the reflux temperature of the solvent used, specifically at a temperature of about 35°C to the reflux temperature of the solvent used, and more specifically at reflux temperature of the solvent used. The reaction time may vary from about 30 minutes to about 5 hours, more specifically from about 45 minutes to about 3 hours.
The reaction mass containing the 2-Bromo-1-[4-hydroxy-3-(hydroxymethyl)-phenyl]-ethanone of formula X obtained in step-(d) may be subjected to conventional work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula XI, or the compound of formula X may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula X may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for work up, isolation and/or recrystallization of the compound of formula X obtained by the process described herein is selected from the group as described hereinabove.
In one embodiment, the solvent used in step-(e) is dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof. A most specific solvent is dichloromethane.
In another embodiment, the reaction in step-(e) is carried out at a temperature of about 20°C to about 40°C, specifically at a temperature of about 25°C to about 35°C. The reaction time may vary from about 30 minutes to about 20 hours, specifically from about 10 hour to about 18 hours.
In another embodiment, the catalyst used in step-(e) is selected from the group consisting of p-toluenesulfonic acid and camphorsulfonic acid. A most specific catalyst used is p-toluenesulfonic acid.
The reaction mass containing the produce 2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone of formula XI obtained in step-(e) may be subjected to conventional work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula XII, or the compound of formula XI may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula XI may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for work up, isolation and/or recrystallization of the compound of formula XI obtained by the process described herein is selected from the group as described hereinabove.
In one embodiment, the base used in step-(f) is an organic base or inorganic base selected from the group as described hereinabove. Specifically, the base used in step-(f) is an inorganic base. A most specific base used in step-(f) is cesium carbonate.
In another embodiment, the solvent used in step-(f) is selected from the group consisting of acetonitrile, dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof. A most specific solvent is acetonitrile.
The reaction mass containing the compound, di-(tert-butyl) 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate, of formula XII obtained in step-(f) may be subjected to conventional work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula XIII, or the compound of formula XII may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula XII may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for work up, isolation and/or recrystallization of the compound of formula XII obtained by the process described herein is selected from the group as described hereinabove.
In one embodiment, the suitable acid used for deprotection in step-(g) is selected from the group consisting of hydrochloric acid, hydrobromic acid and trifluoroacetic acid. A most specific deprotecting agent is trifluoroacetic acid.
In one embodiment, the solvent used in step-(g) is selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof. A most specific solvent is dichloromethane.
The reaction mass containing the compound, tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate, of formula XIII obtained in step-(g) may be subjected to conventional work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula XIV, or the compound of formula XIII may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula XIII may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for work up, isolation and/or recrystallization of the compound of formula XIII obtained by the process described herein is selected from the group as described hereinabove.
In one embodiment, the reducing agent used in step-(h) is selected from borane reagent complexes such as (-)-ß-chlorodiisopinocampheylborane, BH3-THF, BH3-DMS, BH3-pyridine, BH3-diethylaniline, BH3-1,4-thioxane, 9-BBN, catechol borane, thexyl borane, disamyl borane, alpine borane, and the like. Specific reducing agents are (-)-ß-chlorodiisopinocampheylborane and BH3-DMS, and most specifically (-)-ß-chlorodiisopinocampheylborane.
In another embodiment, the chiral auxiliary used in step-(h) is selected from the group consisting of pseudoephedrine, chiral ligands such as BINOL, BINAP, DuPhos; chiral oxazolidinones such as CBS catalysts including (R)-MeCBS, (S)-MeCBS and the like. A most specific chiral auxiliary is (R)-MeCBS.
The reaction mass containing the compound, tert-butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl-carbamate, of formula XIV obtained in step-(h) may be subjected to conventional work up as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula II, or the compound of formula XIV may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula XIV may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for work up, isolation and/or recrystallization of the compound of formula XIV obtained by the process described herein is selected from the group as described hereinabove.
In one embodiment, the base used in step-(i) is an organic base or inorganic base selected from the group as described hereinabove. A most specific base used in step-(i) is potassium tert-butoxide.
In another embodiment, the solvent used in step-(i) is selected from the group consisting of is selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, dimethylformamide, dimethylacetamide, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof. A most specific solvent is dimethylformamide.
The reaction mass containing the compound, (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one, of formula II obtained in step-(i) may be subjected to conventional work up methods as described hereinabove.
In one embodiment, the compound of formula II may be isolated and/or re-crystallized from a suitable solvent by conventional methods as described hereinabove.
The solvent used for work up, isolation and/or recrystallization of the compound of formula II obtained by the process described herein is selected from the group as described hereinabove.
According to another aspect, there is provided a novel and industrially advantageous process for the preparation of 2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone of formula XI:

which comprises:
a) reacting of 4-Hydroxyacetophenone compound of formula VI:

with paraformaldehyde and concentrated hydrochloric acid to produce 1-[3-(Chloromethyl)-4-hydroxy-phenyl]ethanone of formula VII:

b) reacting the compound of formula VII with a suitable acetylating agent in the presence of a suitable reagent in a suitable solvent to produce the 1-[4-Acetyloxy-3-(acetyloxymethyl)-phenyl]ethanone of formula VIII:

c) bromination of the compound of formula VIII with bromine solution in a suitable solvent to produce 2-Bromo-1-[4-acetyloxy-3-(acetyloxymethyl)-phenyl]ethanone of formula IX:

d) deacetylation of the compound of formula IX using a suitable deprotecting agent in presence of a suitable solvent to produce 2-Bromo-1-(4-hydroxy-3-hydroxymethyl-phenyl)-ethanone of formula X:

e) reacting the compound of formula X with 2,2-dimethoxypropane in the presence of a suitable catalyst in a suitable solvent to produce 2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone of formula XI.
The preparation of 2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone of formula XI as described in the above process steps-(a), (b), (c), (d) and (e) can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
According to another aspect, there is provided a novel and industrially advantageous process for the preparation of (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one of formula II:

or a salt thereof, which comprises:
a) reacting 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone of formula XI:

with di-tert-butyl-iminodicarboxylate in presence of a suitable base in a suitable solvent to produce di-(tert-butyl) 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethyl-imidodicarbonate of formula XII:

b) deprotecting the compound of formula XII in the presence of a suitable acid in a suitable solvent to produce tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate of formula XIII:

or a salt thereof;
c) reducing the compound of formula XIII with a suitable reducing agent, optionally in the presence of a suitable chiral auxiliary, to obtain enantiomerically pure tert-butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate of formula XIV:

or a salt thereof; and
d) reacting the compound of formula XIV with a suitable reagent in a suitable solvent to produce (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one of formula II or a salt thereof.
The preparation of (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one of formula II or a salt thereof as described in the above process steps-(a), (b), (c) and (d) can be carried out by using the suitable solvents, reagents, methods, parameters and conditions as described hereinabove.
According to another aspect, there is provided a novel and industrially advantageous process for the preparation of 2-[2-(6-bromohexyloxy)ethoxymethyl]-1,3-dichlorobenzene of formula III:

which comprises:
a) reacting 2,6-dichlorobenzyl chloride of formula XV:

with ethylene glycol in the presence of a suitable base to produce 2-(2,6-dichlorobenzyloxy)ethanol compound of formula XVI:

or a salt thereof; and
b) reacting the compound of formula XVI obtained in step-(a) with 1,6-dibromohexane in the presence of a base, optionally in the presence of a suitable phase transfer catalyst, in a suitable solvent to produce the compound of formula III.
In one embodiment, the base used in step-(a) is an organic base or an inorganic base selected from the group as described hereinabove. Specifically, the base used in step-(a) is an inorganic base selected from the group as described hereinabove. A most specific base used in step-(a) is sodium hydroxide or potassium hydroxide.
In another embodiment, the reaction in step-(a) is carried out at a temperature of about 30°C to about 100°C, and specifically at a temperature of about 60°C to about 90°C. The reaction time may vary from about 30 minutes to about 5 hours, and specifically from about 1 hour to about 3 hours.
The reaction mass containing the 2-(2,6-dichlorobenzyloxy)ethanol compound of formula XVI obtained in step-(a) may be subjected to conventional work up methods as described hereinabove. The reaction mass may be used directly in the next step to produce the compound of formula III, or the compound of formula XVI may be isolated and/or recrystallized and then used in the next step.
In one embodiment, the compound of formula XVI may be isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for work up, isolation and/or recrystallization of the compound of formula XVI obtained by the process described herein is selected from the group as described hereinabove.
In one embodiment, the base used in step-(b) is an organic base or an inorganic base selected from the group as described hereinabove. Specifically, the base used in step-(b) is an inorganic base selected from the group as described hereinabove. A most specific base used in step-(b) is sodium hydroxide or potassium hydroxide.
In another embodiment, the solvent used in step-(b) is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof; and a most specific solvent is toluene.
In another embodiment, the reaction in step-(b) is carried out at a temperature of about 15°C to about 70°C, and specifically at a temperature of about 30°C to about 60°C. The reaction time may vary from about 30 minutes to about 5 hours, and specifically from about 1 hour to about 3 hours.
In another embodiment, the phase transfer catalyst used in step-(b) is selected from the group as described hereinabove. A specific phase transfer catalyst used in step-(b) is tetrabutyl ammonium bromide.
The reaction mass containing the 2-[2-(6-bromohexyloxy)ethoxymethyl]-1,3-dichlorobenzene of formula III obtained in step-(a) may be subjected to conventional work up methods as described hereinabove.
In one embodiment, the compound of formula III may be isolated and/or re-crystallized from a suitable solvent by conventional methods such as cooling, seeding, partial removal of the solvent from the solution, by adding an anti-solvent to the solution, evaporation, vacuum distillation, or a combination thereof.
The solvent used for work up, isolation and/or recrystallization of the compound of formula III obtained by the process described herein is selected from the group as described hereinabove.
The compounds obtained in any of the above process steps may be collected by filtration, filtration under vacuum, decantation, centrifugation, filtration employing a filtration media of a silica gel or celite, or a combination thereof.
According to another aspect, there is provided a process for the preparation of Vilanterol of formula I:

or a pharmaceutically acceptable salt thereof, which comprises:
a) reacting (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one compound formula II:

or a salt thereof obtained by the processes described in the present invention, with 2-[2-(6-bromohexyloxy)ethoxymethyl]-1,3-dichlorobenzene compound of formula III:

obtained by the processes described in the present invention, in the presence of a suitable base using a suitable solvent to produce (R)-3-[6-[2-(2,6-dichlorobenzyloxy)ethoxy]hexyl]-5-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)
oxazolidin-2-one compound of formula IV:

b) converting the compound of formula IV obtained in step-(a) into Vilanterol of formula I or a pharmaceutically acceptable salt thereof, and optionally purifying the Vilanterol or a pharmaceutically acceptable salt thereof using a suitable solvent to produce highly pure Vilanterol or a pharmaceutically acceptable salt thereof.
Exemplary pharmaceutically acceptable salts of the Vilanterol of formula I include, but are not limited to, trifenatate, hydrochloride, hydrobromide, sulfate, nitrate, phosphate, acetate, propionate, oxalate, succinate, maleate, fumarate, benzenesulfonate, toluenesulfonate, citrate, and tartrate. A most specific pharmaceutically acceptable salt of the Vilanterol of formula I is trifenatate salt.
In one embodiment, Vilanterol of formula I or a pharmaceutically acceptable salt thereof (preferably Vilanterol trifenatate) can be prepared by reacting the key intermediates of formula II and III obtained by the processes disclosed herein as per the methods known in the art, for example, as per the processes described in US Reissue Patent No. US RE 44874E, PCT Publication Nos. WO 2014/041565; WO 2017/001907; Chinese Patent Nos. CN 103923058 B, CN 104744271 B, CN 105646285 B; and Journal Article: Journal of Medicinal Chemistry, 53, 4522-4530, 2010.
The following examples are given only to illustrate the present invention. However, they should not be considered as limitation on the scope or spirit of the invention.

EXAMPLES
Example 1
Preparation of 1-[3-(Chloromethyl)-4-hydroxy-phenyl]ethanone
Paraformaldehyde (62 g) was added to a suspension of 4-hydroxyacetophenone (200 g) in conc. hydrochloric acid (870 ml) at room temperature (25-30ºC). The resulting mixture was stirred for 6 hours at 50ºC. After completion of the reaction, the resulting mass was filtered, and washed with hot water (2 x 500 ml) and further with dichloromethane (2 x 500 ml) to produce 217 g of 1-[3-(chloromethyl)-4-hydroxy-phenyl]ethanone as a reddish colour solid. (Purity by HPLC: 88.12%).

Example 2
Preparation of 1-[4-Acetyloxy-3-(acetyloxymethyl)-phenyl]ethanone
Sodium acetate (107 g) and acetic anhydride (260 ml) were added to a solution of 1-[3-(chloromethyl)-4-hydroxy-phenyl]ethanone (221 g) in acetic acid (550 ml) at room temperature (25-30ºC). The resulting mixture was refluxed for 2 hours. After completion of the reaction, the solvent was distilled off under vacuum. The residue obtained was diluted with water (1657 ml) and dichloromethane (221 ml). The organic phase was separated and extracted with dichloromethane (2 x 109 ml). The combined organic phases were concentrated under reduced pressure to produce 321 g of 1-[4-acetyloxy-3-(acetyloxymethyl)-phenyl]ethanone as a brown colour liquid.

Example 3
Preparation of 2-Bromo-1-[4-acetyloxy-3-(acetyloxymethyl)-phenyl]ethanone
Bromine solution (266 g of bromine in 996 ml of chloroform) was added to a solution of 1-[4-acetyloxy-3-(acetyloxymethyl)-phenyl]ethanone (332 g) in chloroform (3 liters) at room temperature for 1 hour 30 minutes. The reaction mixture was stirred for 3 hours at room temperature and the resulting mass was poured into ice cold water (3 liters) and stirred for 30 minutes at the same temperature. The pH of the resulting mass was adjusted to 6-7 using sodium bicarbonate (200 g). The phases were separated and the organic phase was extracted with dichloromethane (2 x 700 ml), washed with brine solution (700 ml) concentrated under reduced pressure to produce 487 g of 2-bromo-1-[4-acetyloxy-3-(acetyloxymethyl)-phenyl]ethanone as a dark brown viscous liquid.

Example 4
Preparation of 2-Bromo-1-[4-hydroxy-3-(hydroxymethyl)-phenyl]ethanone
To a solution of 2-bromo-1-[4-acetyloxy-3-(acetyloxymethyl)-phenyl]ethanone (100 g) in tetrahydrofuran (750 ml), 1.3M HBr solution (750 ml) was added at room temperature. The resulting mass was heated to reflux temperature and maintained for 2 hours at the same temperature. After completion of reaction, the solvent was distilled under vacuum and the resulting residue was cooled to room temperature. The pH of the resulting mass was adjusted to 5 to 6 using sodium bicarbonate (142 g). Ethyl acetate (300 ml) was added to the resulting mass and stirred for 10 minutes. The phases were separated and the aqueous phase was extracted with ethyl acetate (2 x 200 ml). The combined organic phases were washed with brine solution (200 ml), and concentrated under reduced pressure to get 91 g of crude 2-bromo-1-(4-hydroxy-3-hydroxymethyl-phenyl)-ethanone as a brown viscous liquid. Dichloromethane (182 ml) was added to the crude compound. The resulting mass was heated to reflux temperature and maintained for 1 hour at the same temperature. The resulting mass was cooled to room temperature and maintained for 1 hour at the same temperature. The solid obtained was filtered and washed with dichloromethane (2 x 20 ml) to produce 24.5 g of 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)-phenyl]ethanone as a pale pink amorphous solid. (Purity by HPLC: 86.8%).

Example 5
Preparation of 2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone
A solution of 2,2-dimethoxypropane (113 ml in 323 ml of dichloromethane) was added slowly (drop-wise) to a suspension of 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)-phenyl]ethanone (113 g) in dichloromethane (2.5 lit) for 20 minutes at room temperature. To the resulting mass, catalytic amount of p-toluenesulfonic acid (400 mg) was added. The resulting mixture was stirred for 16 hours at room temperature followed by the addition of water (565 ml) and NaHCO3 (11.3 g). The organic phase was separated and extracted twice with dichloromethane (2 x 339 ml). The combined organic layers were concentrated under reduced pressure to produce 128 g of crude 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone as a brown viscous liquid. N-Hexane (1280 ml) was added to the crude compound and the resulting mass was heated to reflux temperature and maintained for 1 hour at the same temperature. The resulting mass was cooled to room temperature and maintained for 1 hour at the same temperature. The resulting mass was concentrated under reduced pressure to produce 96 g of 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone as an off-white semi solid. (Purity by HPLC: 80.18%).

Example 6
Preparation of Di-(tert-butyl) 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethyl
imidodicarbonate
Cesium carbonate (68.5 g) was added to a solution of 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone (60 g) and di-tert-butyl-iminodicarboxylate (45.7 g) in acetonitrile (600 ml) at room temperature under N2 atmosphere. The reaction mixture was stirred for 16 hours at the same temperature. The resulting mass was diluted with water (1 L) and diisopropylether (1 L). The organic phase was separated and extracted with diisopropylether (3 x 180 ml). The combined organic phases were washed with brine solution (300 ml) concentrated under reduced pressure to produce 103 g of crude di-(tert-butyl) 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate as a brown colour gummy mass. Diisopropyl ether (159 ml) was added to the above crude compound and stirred for 1 hour at the room temperature. The resulting mass was cooled to 0-5ºC and maintained for 1 hour at the same temperature. The solid obtained was filtered, washed with pre-cooled diisopropyl ether (2 x 20 ml) to produce 43 g of di-(tert-butyl) 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate as an off-white solid. (Purity by HPLC: 99.69%).
Example 7
Preparation of tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethyl-carbamate
Trifluoroacetic acid (24 ml in 220 ml of dichloromethane) solution was added to a solution of di-(tert-butyl) 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate (110 g) in dichloromethane (880 ml) at room temperature and the resulting mass was stirred for 4 hours at the same temperature. To the resulting solution, aqueous sodium hydroxide solution (0.5M, 750 ml) was added. The organic phase was separated and extracted twice with dichloromethane (2 x 350 ml) and washed with water (550 ml). The combined organic phases were concentrated under reduced pressure to get 82 g of crude tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate as a pale brown colour semi solid. Diisopropyl ether (164 ml) was added to the crude compound and stirred for 1 hour at room temperature. The resulting mass was cooled to 0-5°C and maintained for 1 hour at the same temperature. The solid obtained was filtered, washed with pre-cooled diisopropyl ether (2 x 20 ml) to produce 58 g of tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate as an off-white solid. (Purity by HPLC: 99.23%).

Example 8
Preparation of tert-butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate
A solution of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole [(R)-MeCBS] in toluene (1M, 15.57 ml, 0.1 eq) was added to a solution of borane dimethyl sulphide (BH3-DMS) in tetrahydrofuran (1 M, 155.7 ml, 1.0 eq) and tetrahydrofuran (500 ml) at room temperature under N2 atmosphere. After 30 minutes, a solution of tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate (50 g) in tetrahydrofuran (500 ml) was added for 90 minutes. The resulting mixture was cooled to 5-10ºC and quenched with drop-wise addition of hydrochloric acid (2M, 75 ml). To the resulting mass, ethyl acetate (1.5 L) and water (1.5 L) were added and stirred for 10-20 minutes. The organic phase was separated and extracted with ethyl acetate (3 x 250 ml). The combined organic extracts were washed with brine (500 ml) and concentrated under reduced pressure to produce 54 g of crude tert-butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate as an ash colour semi-solid. Diisopropyl ether (108 ml) was added to the crude compound. The resulting mass was stirred for 2 hours at the room temperature. The solid obtained was filtered, washed twice with diisopropyl ether (2 x 20 ml) to produce 35 g of tert-butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate as an off white solid. (Purity by HPLC: 92.9%; and Chiral Purity by HPLC: 95.88%).

Example 9
Preparation of (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one
Potassium tertiary butoxide (23.76 g) was added portion-wise to a solution of tert-butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate (57 g) in dimethylformamide (456 ml) at 10-15ºC under N2 atmosphere. The reaction mixture was stirred at room temperature for 1 hour. The resulting mixture was poured into ice-cold water (4.5 L) and stirred for 1 hour at room temperature. The solid obtained was filtered, washed with water (2 x 50 ml) to produce 30 g of (5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one as an off-white solid. (Purity by HPLC: 99.60%; Chiral Purity by HPLC: 99.63%).

Example 10
Preparation of di-tert-butyl-iminodicarboxylate
Formamide (44 g) was added to a solution of dimethylaminopyridine (12 g) in dry acetonitrile (132 ml) under N2 atmosphere at room temperature and stirred for 10 minutes at the same temperature. To the resulting mass, di-tert-butyl dicarbonate solution (469 g, in 440 ml of acetonitrile) was added for 1 hour. The resulting mixture was gently heated to 35-40ºC and stirred for 1 hour at the same temperature. The resulting mass was stirred for 5 hours at room temperature. N,N-diethylethylenediamine (136.2 g) was added to resulting mass at 10-15ºC, followed by stirring the mass at room temperature for 16 hours. The solvents were removed under reduced pressure at 40ºC to afford a brown yellow syrup, to which diisopropylether (2.0 L) and potassium bisulphate solution (1M, 2.0 L) were added. The layers were separated and the organic layer was washed with potassium bisulphate (1M, 3 x 600 ml) sodium bicarbonate (1M, 3 x 600 ml) and brine solution (600 ml). The combined organic phases were treated with charcoal. The resulting mass was filtered and concentrated under reduced pressure to produce 185 g of di-tert-butyl-iminodicarboxylate as an off-white crystalline solid.

Example 11
Preparation of 2-(2,6-Dichlorobenzyloxy)ethanol
2,6-Dichlorobenzyl chloride (30 g) was added to a solution of sodium hydroxide (7.35 g) in ethylene glycol (137 ml) at room temperature. The resulting mass was heated to 80ºC and stirred for 2 hours at the same temperature. After completion of reaction, the reaction mixture was cooled to room temperature, followed by addition of water (300 ml) and ethyl acetate (300 ml). The organic phase was separated and extracted with ethyl acetate (2 x 150 ml). The combined extracts were concentrated under reduced pressure to produce 43 g of 2-[2,6-Dichlorobenzyloxy]ethanol as a colourless viscous liquid. (Purity by HPLC: 93.8%).

Example 12
Preparation of 2-[2-(6-Bromohexyloxy)ethoxymethyl]-1,3-dichlorobenzene
Sodium hydroxide solution (50%, 76 ml) was added to a mixture of 2-[2,6-Dichlorobenzyloxy]ethanol (19 g) and 1,6-dibromohexane (105 g) in toluene (76 ml) at room temperature. To the resulting mass, tetrabutylammonium bromide (1.38 g) was added at room temperature and stirred at 55-60ºC for 2 hours. After completion of reaction, the resulting mixture was cooled to room temperature, followed by addition of water (95 ml) and toluene (95 ml). The organic phase was separated and extracted with toluene (2 x 50 ml). The combined extracts were concentrated under reduced pressure to get yellow liquid, which was purified by column chromatography using Ethyl acetate/hexane to produce 19 g of 2-[2-(6-Bromohexyloxy)ethoxymethyl]-1,3-dichlorobenzene as a pale yellow liquid. (Purity by HPLC: 93.2%).
,CLAIMS:
1. A process for the preparation of (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one of formula II:

or a salt thereof, which comprises:
a) reacting 4-hydroxyacetophenone of formula VI:

with paraformaldehyde and concentrated hydrochloric acid to produce 1-[3-(Chloromethyl)-4-hydroxy-phenyl]ethanone of formula VII:

b) reacting the compound of formula VII with a suitable acetylating agent in the presence of a suitable reagent in a suitable solvent to produce the 1-[4-acetyloxy-3-(acetyloxymethyl)-phenyl]ethanone of formula VIII:

c) bromination of the compound of formula VIII with bromine solution in a suitable solvent to produce 2-bromo-1-[4-acetyloxy-3-(acetyloxymethyl)-phenyl]ethanone of formula IX:

d) deacetylation of the compound of formula IX using a suitable deprotecting agent in presence of a suitable solvent to produce 2-bromo-1-[4-hydroxy-3-(hydroxymethyl)-phenyl]-ethanone of formula X:

e) reacting the compound of formula X with 2,2-dimethoxypropane in the presence of a suitable catalyst in a suitable solvent to produce 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone of formula XI:

f) reacting the compound of formula XI with di-tert-butyl-iminodicarboxylate in presence of a suitable base in a suitable solvent to produce di-(tert-butyl) 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate of formula XII:

g) deprotecting the compound of formula XII in the presence of a suitable acid in a suitable solvent to produce tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate of formula XIII:

or a salt thereof;
h) reducing the compound of formula XIII with a suitable reducing agent, optionally in the presence of a suitable chiral auxiliary, to obtain enantiomerically pure tert-butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethyl-carbamate of formula XIV:

or a salt thereof; and
i) reacting the compound of formula XIV with a suitable reagent in a suitable solvent to produce (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one of formula II or a salt thereof.
2. The process as claimed in claim 1, wherein the solvent used in step-(b) is selected from the group consisting of acetic acid, dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, toluene, xylene, and mixtures thereof; wherein the acetylating agent used in step-(b) is selected from the group consisting of acetic anhydride and acetyl chloride; wherein the reagent used in step-(b) is selected from the group consisting of sodium acetate and potassium acetate; wherein the solvent used in step-(c) is selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof; wherein the deprotecting agent used in step-(d) is an acid or a base, wherein the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid and propionic acid; wherein the solvent used in step-(d) is dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof; wherein the solvent used in step-(e) is dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof; wherein the catalyst used in step-(e) is selected from the group consisting of p-toluenesulfonic acid and camphorsulfonic acid; wherein the inorganic base used in step-(f) is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, potassium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, and mixtures thereof; wherein the solvent used in step-(f) is selected from the group consisting of acetonitrile, dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof; wherein the acid used for deprotection in step-(g) is selected from the group consisting of hydrochloric acid, hydrobromic acid and trifluoroacetic acid; wherein the solvent used in step-(g) is selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof; wherein the reducing agent used in step-(h) is selected from borane reagent complexes such as (-)-ß-chlorodiisopinocampheylborane, BH3-THF, BH3-DMS, BH3-pyridine, BH3-diethylaniline, BH3-1,4-thioxane, 9-BBN, catechol borane, thexyl borane, disamyl borane and alpine borane; wherein the chiral auxiliary used in step-(h) is selected from the group consisting of pseudoephedrine, chiral ligands such as BINOL, BINAP, DuPhos; chiral oxazolidinones such as CBS catalysts including (R)-MeCBS and (S)-MeCBS; wherein the base used in step-(i) is an inorganic base used in step-(i) is selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, potassium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, and mixtures thereof or an organic base selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di n-butylamine, diisobutylamine, triethylamine, tributylamine and tert-butyl amine; and wherein the solvent used in step-(i) is selected from the group consisting of is selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, dimethylformamide, dimethylacetamide, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof.

3. The process as claimed in claim 2, wherein the solvent used in step-(b) is acetic acid; wherein the acetylating agent used in step-(b) is acetic anhydride; wherein the reagent used in step-(b) is sodium acetate; wherein the solvent used in step-(c) is chloroform or dichloromethane; wherein the deprotecting agent used in step-(d) is hydrobromic acid; wherein the solvent used in step-(d) is selected from the group acetone, methyl ethyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran; wherein the solvent used in step-(e) is dichloromethane; wherein the catalyst used in step-(e) is p-toluenesulfonic acid; the inorganic base used in step-(f) is cesium carbonate; wherein the solvent used in step-(f) is acetonitrile; wherein the acid used for deprotection in step-(g) is trifluoroacetic acid; wherein the solvent used in step-(g) is dichloromethane; wherein the reducing agent used in step-(h) is (-)-ß-chlorodiisopinocampheylborane and BH3-DMS; wherein the chiral auxiliary used in step-(h) is (R)-MeCBS; wherein the inorganic base used in step-(i) is potassium tert-butoxide; and wherein the solvent used in step-(i) is dimethylformamide.

4. A process for the preparation of 2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone of formula XI:

which comprises:
a) reacting of 4-Hydroxyacetophenone compound of formula VI:

with paraformaldehyde and concentrated hydrochloric acid to produce 1-[3-(Chloromethyl)-4-hydroxy-phenyl]ethanone of formula VII:

b) reacting the compound of formula VII with a suitable acetylating agent in the presence of a suitable reagent in a suitable solvent to produce the 1-[4-Acetyloxy-3-(acetyloxymethyl)-phenyl]ethanone of formula VIII:

c) bromination of the compound of formula VIII with bromine solution in a suitable solvent to produce 2-Bromo-1-[4-acetyloxy-3-(acetyloxymethyl)-phenyl]ethanone of formula IX:

d) deacetylation of the compound of formula IX using a suitable deprotecting agent in presence of a suitable solvent to produce 2-Bromo-1-(4-hydroxy-3-hydroxymethyl-phenyl)-ethanone of formula X:

e) reacting the compound of formula X with 2,2-dimethoxypropane in the presence of a suitable catalyst in a suitable solvent to produce 2-Bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone of formula XI.

5. The process as claimed in claim 4, wherein the solvent used in step-(b) is selected from the group consisting of acetic acid, dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, toluene, xylene, and mixtures thereof; wherein the acetylating agent used in step-(b) is selected from the group consisting of acetic anhydride and acetyl chloride; wherein the reagent used in step-(b) is selected from the group consisting of sodium acetate and potassium acetate; wherein the solvent used in step-(c) is selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof; wherein the deprotecting agent used in step-(d) is an acid or a base, wherein the acid is selected from the group consisting of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, oxalic acid, acetic acid and propionic acid; wherein the solvent used in step-(d) is dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, N,N-dimethylformamide, N,N-dimethylacetamide, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof; wherein the solvent used in step-(e) is dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof; and wherein the catalyst used in step-(e) is selected from the group consisting of p-toluenesulfonic acid and camphorsulfonic acid.

6. A process for the preparation of (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one of formula II:

or a salt thereof, which comprises:
a) reacting 2-bromo-1-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)ethanone of formula XI:

with di-tert-butyl-iminodicarboxylate in presence of a suitable base in a suitable solvent to produce di-(tert-butyl) 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylimidodicarbonate of formula XII:

b) deprotecting the compound of formula XII in the presence of a suitable acid in a suitable solvent to produce tert-butyl 2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxoethylcarbamate of formula XIII:

or a salt thereof;
c) reducing the compound of formula XIII with a suitable reducing agent, optionally in the presence of a suitable chiral auxiliary, to obtain enantiomerically pure tert-butyl (2R)-2-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-hydroxyethylcarbamate of formula XIV:

or a salt thereof; and
d) reacting the compound of formula XIV with a suitable reagent in a suitable solvent to produce (5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one of formula II or a salt thereof.

7. The process as claimed in claim 6, wherein the inorganic base used in step-(a) is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, potassium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, and mixtures thereof; wherein the solvent used in step-(a) is selected from the group consisting of acetonitrile, dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof; wherein the acid used for deprotection in step-(b) is selected from the group consisting of hydrochloric acid, hydrobromic acid and trifluoroacetic acid; wherein the solvent used in step-(b) is selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof; wherein the reducing agent used in step-(c) is selected from borane reagent complexes such as (-)-ß-chlorodiisopinocampheylborane, BH3-THF, BH3-DMS, BH3-pyridine, BH3-diethylaniline, BH3-1,4-thioxane, 9-BBN, catechol borane, thexyl borane, disamyl borane and alpine borane; wherein the chiral auxiliary used in step-(c) is selected from the group consisting of pseudoephedrine, chiral ligands such as BINOL, BINAP, DuPhos; chiral oxazolidinones such as CBS catalysts including (R)-MeCBS and (S)-MeCBS; wherein the base used in step-(d) is an inorganic base selected from the group consisting of sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, potassium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, and mixtures thereof or an organic base selected from the group consisting of dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, di n-butylamine, diisobutylamine, triethylamine, tributylamine and tert-butyl amine; and wherein the solvent used in step-(d) is selected from the group consisting of dichloromethane, dichloroethane, chloroform, acetone, methyl ethyl ketone, dimethylformamide, dimethylacetamide, tetrahydrofuran, 2-methyl-tetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, cyclohexane, toluene, xylene, and mixtures thereof.

8. A process for the preparation of 2-[2-(6-bromohexyloxy)ethoxymethyl]-1,3-dichlorobenzene of formula III:

which comprises:
a) reacting 2,6-dichlorobenzyl chloride of formula XV:

with ethylene glycol in the presence of a suitable base to produce 2-(2,6-dichlorobenzyloxy)ethanol compound of formula XVI:

or a salt thereof; and
b) reacting the compound of formula XVI obtained in step-(a) with 1,6-dibromohexane in the presence of a base, optionally in the presence of a suitable phase transfer catalyst, in a suitable solvent to produce the compound of formula III.

9. The process as claimed in claim 8, wherein the inorganic base used in step-(a) is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, potassium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, and mixtures thereof; wherein inorganic base used in step-(b) is selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert-butoxide, potassium tert-butoxide, sodium amide, potassium amide, ammonia, sodium acetate, potassium acetate, magnesium acetate, calcium acetate, and mixtures thereof; wherein the solvent used in step-(b) is selected from the group consisting of toluene, xylene, dichloromethane, dichloroethane, chloroform, and mixtures thereof; and wherein the phase transfer catalyst used in step-(b) is selected from the group consisting of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyltrimethyl ammonium chloride, benzyltriethyl ammonium chloride, methyltributyl ammonium chloride and crown ethers.

10. The process as claimed in claims 1 and 6, wherein the compound of formula II:

or a salt thereof, obtained is further reacted with 2-[2-(6-bromohexyloxy) ethoxymethyl]-1,3-dichlorobenzene compound of formula III:

in the presence of a suitable base using a suitable solvent to produce (R)-3-[6-[2-(2,6-dichlorobenzyloxy)ethoxy]hexyl]-5-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl) oxazolidin-2-one compound of formula IV:

which is further converted into Vilanterol of formula I:

or a pharmaceutically acceptable salt thereof, and optionally purifying the Vilanterol or a pharmaceutically acceptable salt thereof using a suitable solvent to produce highly pure Vilanterol or a pharmaceutically acceptable salt thereof.