DESC:Technical filed:
The present invention relates to an improved process for the preparation of vilanterol and its salts via novel intermediates. The invention also relates to said intermediates, per se.

Background of the invention:
Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease that is characterized by progressive airway obstruction that, unlike asthma, is relatively insensitive to bronchodilators and to the classic anti-inflammatory therapy, corticosteroids. It is a leading cause of morbidity and mortality worldwide with an overall prevalence in adults aged >40 years estimated currently at 9–10%. The World Health Organization (WHO) estimates that, by 2020, COPD will be the third leading cause of mortality and the fifth leading cause of morbidity in the world. The primary cause of COPD is smoking, with 30–40% of smokers estimated to develop the disease.

The aim of therapy for COPD is to prevent and control symptoms and reduce mortality by reducing the frequency and severity of exacerbations, improving health status and exercise tolerance, and, ultimately, preventing the accelerated decline in lung function.

With chronic diseases such as COPD and asthma, patient adherence to medication plans is a major obstacle to successful management (Bender, 2002). One factor contributing to poor adherence is a complicated or multiple treatment regimens, and simplified dosing regimens are known to improve
compliance (Claxton et al., 2001; Bender, 2002). Therefore, a main step in simplifying COPD and asthma management is to reduce the dose frequency to the minimum necessary to maintain disease control (Tamura and Ohta, 2007). In particular, the incorporation of once-daily dosing seems to be an important strategy to improve compliance, and is a regimen preferred by most patients (Campbell, 1999).
A variety of ß2-adrenoceptor agonists with longer half-lives are currently under development with the hopes of achieving once-daily dosing. These once-daily bronchodilators, called ultra-LABAs, such as carmoterol, indacaterol and vilanterol.

Vilanterol (GW642444M) is a novel, long-acting ß2 agonist with inherent 24-h activity under development as a once-daily combination therapy with an inhaled corticosteroid for COPD and asthma. It is chemically termed as 4-{(1R)-2-[{6-{2-(2,6-Dichlorobenzyl)oxy]-ethoxy}-hexyl) amino]-1-hydroxyethyl}-2-(hydroxymethyl) phenol represented by the formula I

The U.S. patent 7361787 disclosed phenethanolamine derivatives including vilanterol. The process described in US7361787 for the preparation of vilanterol is as follows:-

Scheme 1

However, this process of making vilanterol as mentioned in the prior art has certain limitations like, most of the intermediates are purified on column chromatography, making the process cumbersome on industrial scale.

There is thus a need in the art for an improved process for preparing vilanterol and its salts suitable for industrial scale up.

The process of the present invention provides large scale synthesis of vilanterol and its salts having high degree of chromatographic and optical purity and low residual solvent content.

Objects of the Invention
The object of the present invention is to provide a novel process for preparing vilanterol and its salts.

Yet another object of the present invention is to provide a novel process which proceeds via novel salt for the synthesis of vilanterol and its salts.

Yet another object of the present invention is to provide vilanterol and its salts which are substantially free from dimeric impurities.

A further object of the present invention is to a process for the synthesis of vilanterol and its salts which reduces or substantially eliminates the formation of dimeric impurities.

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

Summary of the invention:
According to the present invention, there is provided an improved process for the preparation of vilanterol and its salts via novel intermediates.

According to a first aspect of the present invention there is provided a process for the preparation of vilanterol of formula (I) or a pharmaceutically acceptable salts thereof:

comprising the steps of:

a) converting (R)-2-[6-[2-(2,6-Dichlorobenzyloxy)-ethoxy]-hexylamino]-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol 2,2,2-triphenylacetate of formula (III)

to (R)-2-[6-[2-(2,6-Dichlorobenzyloxy)-ethoxy]-hexylamino]-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol of formula (II)

b) deprotecting compound (II) with ortho phosphoric acid to obtain vilanterol of formula (I); and

c) optionally converting the vilanterol of formula (I) into its pharmaceutically acceptable salts.

In an embodiment, compounds (I), (II) and (III) are optically pure.

Throughout this specification “optically pure” is to mean having an enantiomeric excess greater than 97%. Preferably, greater than 98%, most preferably greater than 99%.

Compounds (I), (II) and (III) are depicted above in the form of their R enantiomers.

Compound (III) is hitherto unreported intermediates useful in the process for the preparation of vilanterol as described herein.

In an embodiment the R-enantiomer of compound (III) may be obtained by reacting
(R)-2-[6-[2-(2,6-Dichlorobenzyloxy)-ethoxy]-hexylamino]-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol of formula (IV)

with 2,2,2-triphenyl acetic acid.

In an embodiment, compound (IV) is optically pure.

Compound (IV) is depicted above in the form of the (R)-isomer.

In an embodiment compound (IV) may be obtained by reacting compound (R)-3-(6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)-5-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)oxazolidin-2-one of formula (V)

with potassium trimethylsilanolate.

In an embodiment, compound (V) is optically pure.

Compound (V) is depicted above in the form of the (R)-isomer.

In an embodiment compound (IV) may be obtained by coupling compound (R)-5-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)oxazolidin-2-one of formula (VI)

with compound 2-((2-((6-bromohexyl)oxy)ethoxy)methyl)-1,3-dichlorobenzene of formula (VII)

In an embodiment, compound (VI) is optically pure.

Compound (VI) is depicted above in the form of the (R)-isomer.

According to yet another aspect of the present invention there is provided novel compound (III). The compound may be prepared according to the process described above.

Further, the present invention provides vilanterol of formula (I) or its pharmaceutically acceptable salt thereof, prepared according to the process described above, having a purity of more than about 99% and a chiral purity of more than about 99% by HPLC.

There is also provided by the present invention vilanterol of formula (I) or its pharmaceutically acceptable salt thereof prepared by a process as described above.

According to another aspect of the present invention, there is provided a pharmaceutical composition comprising vilanterol of formula (I) or its pharmaceutically acceptable salt thereof, prepared by a process as described above, together with one or more pharmaceutically acceptable excipients. Such excipients and compositions are well known to those skilled in the art.

According to another aspect of the present invention, there is provided the use of vilanterol of formula (I) or its pharmaceutically acceptable salt thereof, prepared by a process as described above in medicine.

According to another aspect of the present invention, there is provided the use of vilanterol of formula (I) or its pharmaceutically acceptable salt thereof, prepared by a process as described above, in the manufacture of a medicament for treating COPD.

According to another aspect of the present invention, there is provided the use of vilanterol of formula (I) or its pharmaceutically acceptable salt thereof, prepared by a process as described above in the treatment of COPD.

According to still another aspect of the present invention, there is provided a method of treating COPD in a patient in need of such treatment, which method comprises administering to the patient a therapeutically effective amount of vilanterol of formula (I) or its pharmaceutically acceptable salt thereof, prepared by a process as described above.

Brief Description of Accompanying Drawings
Figure 1 is the X-ray powder diffractogram (XRD) of crystalline form of (R)-2-[6-[2-(2,6-Dichlorobenzyloxy)-ethoxy]-hexylamino]-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol 2,2,2-triphenylacetate (III) of the present invention.

Figure 2 is a Differential Scanning Calorimetry (DSC) thermogram of crystalline form of the (R)-2-[6-[2-(2,6-Dichlorobenzyloxy)-ethoxy]-hexylamino]-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol 2,2,2-triphenylacetate (III) of the present invention.

Detailed description of the invention
The present invention provides an improved process for the synthesis of vilanterol of formula (I) and its pharmaceutically acceptable salts involving novel intermediates.

Accordingly, an embodiment of the process for the preparation of vilanterol of formula (I) and its pharmaceutically acceptable salts is as shown in scheme 2.

Scheme 2

In an embodiment, compounds (I), (II), (III), (IV), (V) and (VI) are optically pure.

Compounds (I), (II), (III), (IV), (V) and (VI) are depicted above in the form of the (R)-enantiomer.

Compound (III) is hitherto unreported intermediate salt useful in the process for the preparation of vilanterol as described herein.

Accordingly, in a preferred embodiment, the present invention provides a process for the preparation of vilanterol of formula I or an acid addition salt thereof, comprising the following steps:

Coupling compound (VI) with compound (VII) to obtain compound (V).

Preferably, the coupling is carried out in the presence of a suitable base and a suitable solvent.

A suitable base used for the reaction may be an inorganic or organic base. The inorganic base may be selected from the group comprising of alkali or alkaline earth metal carbonates, such as cesium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate or barium carbonate; alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, sodium t-butoxide, or potassium t-butoxide; metal hydride such as sodium hydride, potassium hydride. Organic bases may be aliphatic or aromatic and may be selected from, but not limited to triethyl amine, diisopropylamine, pyridine, picoline, diethyl amine, piperidine, N,N-diisopropylethyl amine.

The solvent used for condensation reaction may be selected from the group comprising of aromatic hydrocarbons, aprotic polar solvents, protic polar solvents, aliphatic ethers, mixtures of water and one or more organic solvents. Preferably suitable solvents can be selected from one or more solvents comprising dimethylformamide, dimethylsulfoxide, dimethylacetamide, sulfolane, N-methylpyrrolidone, tetrahydrofuran, 2-methyl tetrahydrofuran, C1-C6 alcohols, C3-C6 ketones or C3-C6 esters.

Preferably, the reaction is carried out at a temperature ranging from about 15°C to the reflux temperature of the solvent used, preferably about 20°C to about 50°C, more preferably about 20°C to about 30°C.

Advantage of the is that no column chromatography is required as reported in the prior art. The compound (V) is isolated from the reaction by simple work-up procedure like quenching with water & extracting in a suitable solvent such as ethyl acetate or toluene. Distillation of solvent gives pale yellow coloured oily residue which is directly subjected to next step without column purification.

In an embodiment, compound (V) is then cleaved with a suitable base to obtain compound (IV).

A suitable base used for the cleavage reaction may be an inorganic or organic base. The inorganic base may be selected from the group comprising of alkali or alkaline earth metal carbonates, such as cesium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate or barium carbonate; alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, sodium t-butoxide, or potassium t-butoxide; lithium trimethylsilanolate, sodium trimethylsilanolate, and potassium trimethylsilanolate. Organic bases may be aliphatic or aromatic and may be selected from, but not limited to triethyl amine, diisopropylamine, pyridine, picoline, diethyl amine, piperidine, N,N-diisopropylethyl amine. A base selected may be an aqueous base or non aqueous base.

Cleavage is carried put in the presence of a suitable solvents.

The solvent used for cleavage reaction may be selected from the group comprising of aromatic hydrocarbons, aprotic polar solvents, aliphatic ethers or mixtures of one or more organic solvents.

Preferably suitable solvents can be selected from one or more solvents comprising of tetrahydrofuran, chloroform, methylene dichloride, toluene, xylene, methyl t-Butyl ether (MTBE) and cyclopentyl methyl ether(CPME).

Preferably, compound (V) is treated with two equivalents of potassium trimethysilanolate in refluxing tetrahydrofuran to give compound (IV).

Alternatively, cleavage conditions involve the use of an excess hydroxide in an aqueous organic solvent and at elevated temperatures.

In yet an alternative embodiment, compound (V) are hydrolysed by the use of polymer supported hydroxide (Dowex 1 × 8–100) and the second involving the use of polymer-supported ethylenediamine [N-(2-aminoethyl)aminomethyl polystyrene].

In yet an alternative embodiment compound (V) are hydrolysed under strongly acidic conditions (6 M hydrochloric acid for 3 h at reflux).

Advantage of the process is that it avoids column chromatography is as reported in the prior art.

In an embodiment, compound (IV) is reacted with triphenyl acetic acid and isolated as trifenetate salt (III).

Preferably, compound (IV) is treated with triphenyl acetic acid in the presence of a suitable solvent such as polar solvent like alcohols such as methanol, ethanol, isopropanol and non polar solvents like toluene, ethyl acetate and the like, preferably methanol.

Advantage of the process is that it removes unreacted starting materials as well as undesired impurities formed in both stages. The process of the invention is advantages as the isolated salt has purity of more than 99%. Further, trifenatate salt of compound (III), a hitherto unreported salt, is easy to purify , handle and store on large scale. Hence, suitable for industrial synthesis.

The trifenatate salt according to the invention is characterised by good crystallinity and low amorphization during grinding and compression. In addition, it is not hygroscopic and is readily soluble in physiologically acceptable solvents.

In an embodiment, crystalline form of the trifenatate salt (III) is characterized by having a XRD pattern as shown in Figure 1.

The crystalline form of the trifenatate salt (III), according to the invention is further characterised by a melting point (determined by DSC, = Differential Scanning Calorimetry; evaluated by the peak maximum; heating rate: 10° C./min).

Differential scanning calorimetry (DSC) analysis of this crystal shows a melting point between about 137°C and about 141°C, in certain embodiments between about 139°C and about 142°C, and in certain embodiments at about 141°C and about 143°C.

In an embodiment, crystalline form of the trifenatate salt (III) is characterized by having a DSC spectrum as shown in Figure 2.

In an embodiment, isolated salt is further treated with suitable base to obtain compound (II).

The reaction is carried out in a suitable solvent such as water, or in a mixture of water with water immiscible solvents like toluene, xylene, ethyl acetate, THF and the like. Preferably the solvent used is toluene.

A suitable base used for the reaction may be an inorganic or organic base. The inorganic base may be selected from the group comprising of alkali or alkaline earth metal carbonates, such as cesium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate or barium carbonate; alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, sodium t-butoxide, or potassium t-butoxide; metal hydride such as sodium hydride, potassium hydride. Organic bases may be aliphatic or aromatic and may be selected from, but not limited to triethyl amine, diisopropylamine, pyridine, picoline, diethyl amine, piperidine and N,N-diisopropylethyl amine. Preferably the base used is sodium hydroxide or potassium hydroxide.

In an embodiment, the compound (II) may be further deprotected by hydrolysis under aqueous acidic condition to obtain vilanterol base (I) which may then be converted to its pharmaceutically acceptable salt. Preferably the acid used is aqueous orthophosphoric acid.

In an embodiment deprotection is carried out in the presence of a suitable solvent selected from polar and non polar solvent or mixture thereof. Preferably, the solvent may be selected from the group comprising of C1-C5 alcohols, C3-C6 ethers, tetrahydrofuran, 2- methyl tetrahydrofuran, hexane, toluene, diglyme or mixture thereof. Preferably the solvent used is toluene.

Prior art teaches acetonide deprotection using aqueous acid, for example acetic acid or hydrochloric acid in a suitable solvent. The process of the present invention is advantages as the acetonide group is deprotected completely using aq. orthophosphoric acid. Hence, intermediate (II) is found to be absent in the final salt. This forms one aspect of the present invention. Further, deprotection with acetic acid or hydrochloric acid results in the racemization of vilanterol base upto 4-6%, whereas in the process of the present invention, racemization of vilanterol base is observed upto 0.1 to 0.5 %. The better control on racemization and unwanted isomer, over the prior art process is another aspect of the present invention.

The deprotection is highly enantioselective (a single isomer is typically formed with an enantiomeric excess greater than 98%, even when using a lower amount of orthophosphoric acid).

Advantage of deprotection of acetonide by using o-phosphoric acid is control on formation of dimer impurity as below:--

In an embodiment, vilanterol (I) base contains less than about 0. 2% of dimeric impurity, preferably not more than about 0.15%, more preferably not more than about 0.1%. This forms one aspect of the present invention.

Further, vilanterol (I) base contains HPLC purity of more than 99% and less than about 0.2% of undesired isomer. This forms another aspect of the present invention.

Further prior art teaches purification of vilanterol base by column chromatography. The isolated base is oil and hence difficult to store on large scale. In the process of the present invention, no column chromatography is required as vilanterol base obtained by the process of the present invention without isolation further converted to suitable salts. Preferably, vilanterol is converted to its trifenatate salt. Process of the present invention avoids chromatographic purification of both vilanterol base as well as salt. This forms yet another aspect of the present invention.

The vilanterol trifenatate obtained by the process of the present invention contains less than about 0.2% of dimeric impurity, preferably not more than about 0.15%, more preferably not more than about 0.1%. This forms yet another aspect of the present invention.

Further, vilanterol trifenatate contains HPLC purity of more than 99% and less than about 0.2% of undesired isomer. This forms yet another aspect of the present invention.

According to a further aspect of the present invention, there is provided vilanterol of formula (I) or salt thereof obtained by a process according to any process of the present invention as described in the present disclosure.

While emphasis has been placed herein on the specific steps of the preferred process, it will be appreciated that many steps can be made and that many changes can be made in the preferred steps without departing from the principles of the invention. These and other changes in the preferred steps of the invention will be apparent to those skilled in the art from the disclosure herein, whereby it is to be distinctly understood that the foregoing descriptive matter is to be interpreted merely as illustrative of the invention and not as a limitation.

The following non-limiting examples further illustrate the manner of carrying out the invention described herein.

EXAMPLES

Example 1 : Preparation of Compound (V)
100.0g (R)-5-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)oxazolidin-2-one (compound VII) was stirred with 800 ml DMF & cooled the reaction mass to 20-25°C. Charged 45 g of potassium tert-butoxide under nitrogen atmosphere & stirred for 1 hr. A solution of 153.9 g of 2-((2-((6-bromohexyl)oxy)ethoxy) methyl)-1,3-dichlorobenzene (compound VI) in 200 ml DMF was added to the reaction mass slowly. The reaction mass was stirred for 5 hrs at 20-25°C. After completion of reaction, the reaction mass was quenched with chilled water & extracted with toluene. The toluene layer was washed with 10% brine, followed by water. Distilled out toluene atmospherically at 110°C to yield compound V residue.

HPLC purity :-, 85-90 %
Enantiomeric excess (% ee) :- 99.9 %

Example 2 : Preparation of Compound (IV)
220.0 g of compound (V) was stirred in 1000 ml THF for 10min to get clear solution. Charged 160g of potassium trimethylsilanolate & the reaction mass was heated to 65-70°C and maintained for 10 hrs under reflux. After completion of reaction, THF was distilled off atmospherically. Reaction mass was cooled to 30-40°C and charged 1000 ml water &1000 ml toluene. The layers were separated and the toluene layer was washed with brine followed by water. Distilled out toluene under vacuum below 50°C yield compound (IV).
Yield :- 209g
Purity: - 85-90 %
Enantiomeric excess (% ee) :- 99.9 %

Example 3: Preparation of Compound (III)
209 g of compound (IV) was stirred in 3600 ml methanol for 10min at 25-30°C to get clear solution. Charged 100 g Triphenyl acetic acid and the reaction mass stirred for 10min. The reaction mass was heated to 75-80°C and further stirred for 30min. The clear solution was gradually cooled to 25-30°C and stirred further for 1hr at 25-30°C. The reaction mass was chilled to 10-15°C and stirred further for 1hr at 10-15°C. The solids were isolated by filtration, washed with Methanol and dried under vacuum at 45-50°C to yield compound (III).

Yield :- 268 g
HPLC purity :- 98-99 %
Enantiomeric excess (% ee) :- 99.9 %

Example 4: Preparation of Compound (II)
268 g compound (III) was stirred in 2000ml toluene at RT for 10min. Charged 1500ml water to reaction mass and stirred for 10min. The reaction mass was treated with10% sodium hydroxide solution. The toluene layer was washed with water . Distilled out toluene layer under vacuum below 50°C to get compound (II) as an oil.

Yield :- 170 g
HPLC purity :- 98-99 %
Enantiomeric excess (% ee) :- 99.9 %

Example 5 : Preparation of vilanterol (Compound I)
Stirred 160.0gm of compound (II) in 320 ml toluene at RT to get clear solution. Charged 3200 ml of 0.5M ortho phosphoric acid (Prepared by adding 85 ml ortho phosphoric acid in 3115 ml water). The reaction mass was stirred for 16.0 hrs at 25 to 30°C. After completion of reaction, the layers were separated. The aqueous layer was stirred with 1600 ml MDC, stirred and cooled the reaction mass to 0-5°C. The pH of the reaction mass was adjusted to 7.5-8 using 10% sodium bicarbonate maintaining temperature below 5°C. The layers were separated , the MDC layer was washed with 100ml 10% brine followed by water and dried over Sodium Sulphate.

HPLC purity :- 98-99.2%
Enantiomeric excess (% ee) :- 99.5 %

Different reactions were carried out using varying equivalence of o-phosphoric acid & molarity of solution in water. The chromatographic purity & enantiomeric purity data is tabulated as below:

Orthophosphoric acid equivalence Normality of solution Vilanterol base
Purity by HPLC Vilanterol base Enantiomeric Purity
Undesired isomer VLT Dimer impurity
4.5 0.5 98.9 0.05 0.037
2.0 0.7 98.4 0.098 0.070
7.0 0.7 99.06 0.087 0.015
2.0 0.3 99.17 0.08 0.050
7.0 0.3 99.426 0.096 0.083

Example 6: Preparation of vilanterol trifenatate
To a solution of vilanterol base in MDC was charged 66.0 gm of triphenyl acetic acid and stirred for 20min at 20-30°C. The MDC was distilled off below 25°C under vacuum. The residue was stirred in 900 ml acetone for 30 min and the reaction mass was further chilled to 5-10°C. The solids were filtered, washed with 100 ml of chilled acetone and dried under vacuum for 4hrs below 50°C. The dried material was shifted & milled to achieve desired particle size.

Yield :-140 g
HPLC purity :- 99.6%
Enantiomeric excess (% ee) :- 99.9%

Different reactions were carried out using varying equivalence of o-phosphoric acid & molarity of solution in water. The chromatographic purity & enantiomeric purity data is tabulated as below:

Orthophosphoric acid equivalence Normality of solution Vilanterol Trifenatate Purity by HPLC Vilanterol Trifenatate Enantiomeric Purity
Undesired isomer VLT Dimer impurity
4.5 0.5 99.43 0.057 0.028
2.0 0.7 98.30 0.096 0.089
7.0 0.7 99.58 0.099 0.042
2.0 0.3 99.43 0.078 0.040
7.0 0.3 99.45 0.081 0.026
,CLAIMS:1. A process for the preparation of vilanterol of formula (I) or a pharmaceutically acceptable salts thereof:

comprising the steps of:

d) converting (R)-2-[6-[2-(2,6-Dichlorobenzyloxy)-ethoxy]-hexylamino]-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol 2,2,2-triphenylacetate of formula (III)

to (R)-2-[6-[2-(2,6-Dichlorobenzyloxy)-ethoxy]-hexylamino]-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol of formula (II)

e) deprotecting compound (II) with ortho phosphoric acid to obtain vilanterol of formula (I); and
f) optionally converting the vilanterol of formula (I) into its pharmaceutically acceptable salts.

2. A process according to claim 1, wherein compounds (I), (II) and (III) are optically pure, having an enantiomeric excess greater than 97%, preferably, greater than 98%, most preferably greater than 99%.

3. A process according to claim 1, wherein conversion comprises treating compound (III) with a suitable base in the presence of a suitable solvent.

4. A process according to claim 3, wherein the base is selected from but not limited to inorganic base such as alkali or alkaline earth metal carbonates, such as cesium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate or barium carbonate; alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, sodium t-butoxide, or potassium t-butoxide; metal hydride such as sodium hydride, potassium hydride and organic bases such as triethyl amine, diisopropylamine, pyridine, picoline, diethyl amine, piperidine and N,N-diisopropylethyl amine.

5. A process according to claim 4, wherein the base used is sodium hydroxide or potassium hydroxide.

6. A process according to any of claims 2 to 5, wherein solvent is selected from water, or a mixture of water with water immiscible solvents like toluene, xylene, ethyl acetate, THF.

7. A process according to claim 6, wherein water immiscible solvent is toluene.

8. A process according to claim 1, wherein deprotection is carried out in the presence of a suitable solvent selected from polar and non polar solvent or mixture thereof.

9. A process according to claim 8, wherein solvent is selected from the group comprising of C1-C5 alcohols, C3-C6 ethers, tetrahydrofuran, 2-methyl tetrahydrofuran, hexane, toluene, diglyme or mixture thereof.

10. A process according to claim 9, wherein solvent is toluene.

11. A process according to any of claims 1 to 10, wherein the resulting phosphate salt of vilanterol (I) is extracted and basified to provide solution of vilanterol (I).

12. A process according to any of claims 11, wherein vilanterol (I) base contains less than about 0.1% of dimeric impurity

.

13. A process according to any one of claims 11 or 12, wherein the vilanterol (I) contains HPLC purity of more than 99%.
14. A process according to any one of claims 11 to 13, wherein the vilanterol (I) contains less than about 0.2% of undesired isomer.

15. A process according to claim 11, wherein the vilanterol (I) is not isolated and converted to the trifenatate salt.

16. A process according to claim 15, wherein vilanterol trifenatate contains less than about 0.1% of dimeric impurity.
17. A process according to any one of claims 15 or 16, wherein the vilanterol trifenatate contains HPLC purity of more than 99%.

18. A process according to any one of claims 15 to 17, wherein the vilanterol trifenatate
contains less than about 0.2% of undesired isomer.

19. An intermediate compound (R)-2-[6-[2-(2,6-Dichlorobenzyloxy)-ethoxy]-hexylamino]-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol 2,2,2-triphenylacetate of formula (III)

20. A process for the preparation of compound (R)-2-[6-[2-(2,6-Dichlorobenzyloxy)-ethoxy]-hexylamino]-1-(2,2-dimethyl-4H-benzo[1,3]dioxin-6-yl)ethanol 2,2,2-triphenylacetate of formula (III), comprising the steps of:

a) coupling compound (R)-5-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)oxazolidin-2-one of formula (VI)

with compound 2-((2-((6-bromohexyl)oxy)ethoxy)methyl)-1,3-dichlorobenzene of formula (VII)

to obtain compound (R)-3-(6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)-5-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)oxazolidin-2-one of formula (V)

;

b) cleaving, compound (R)-3-(6-(2-((2,6-dichlorobenzyl)oxy) ethoxy) hexyl)-5-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)oxazolidin-2-one (V) with a suitable base to obtain compound (R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)ethan-1-ol of formula (IV)

;

and ;

c) reacting (R)-2-((6-(2-((2,6-dichlorobenzyl)oxy)ethoxy)hexyl)amino)-1-(2,2-dimethyl-4H-benzo[d][1,3]dioxin-6-yl)ethan-1-ol of formula (IV) with triphenyl acetic acid to obtain trifenatate salt (III).

21. A process according to claim 19, wherein compounds (IV), (V) and (VI) are optically pure, having an enantiomeric excess greater than 97%, preferably, greater than 98%, most preferably greater than 99%.

22. A process according to claim 20, wherein the coupling is carried out in the presence of a suitable base and a suitable solvent.

23. A process according to claim 22, wherein the base is selected from an inorganic and organic base.

24. A process according to claim 23, wherein the inorganic base is selected from but not limited to the group comprising of alkali or alkaline earth metal carbonates, such as cesium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate or barium carbonate; alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, sodium t-butoxide, or potassium t-butoxide; metal hydride such as sodium hydride, potassium hydride and the organic base such as triethyl amine, diisopropylamine, pyridine, picoline, diethyl amine, piperidine, N,N-diisopropylethyl amine.

25. A process according to claim 22, wherein the solvent is selected from the group comprising of aromatic hydrocarbons, aprotic polar solvents, protic polar solvents, aliphatic ethers, mixtures of water and one or more organic solvents.

26. A process according to claim 25, wherein the solvent is selected from one or more solvents comprising dimethylformamide, dimethylsulfoxide, dimethylacetamide, sulfolane, N-methylpyrrolidone, tetrahydrofuran, 2-methyl tetrahydrofuran, C1-C6 alcohols, C3-C6 ketones or C3-C6 esters.

27. A process according to any one of claims 22 to 26, wherein said coupling is carried out under an inert atmosphere at a temperature in the range of 20 to 30°C.
28. A process according to claim 27, wherein further to said coupling, said reaction mass is quenched in water, extracted in a suitable solvent such as ethyl acetate or toluene and distilled to obtain compound (V).

29. A process according to claim 20, wherein the base for cleavage is selected from an inorganic or organic base.

30. A process according to claim 29, wherein the inorganic base is selected from but not limited to the group comprising of alkali or alkaline earth metal carbonates, such as cesium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate, calcium carbonate or barium carbonate; alkali or alkaline earth metal hydroxides such as sodium hydroxide, potassium hydroxide, lithium hydroxide, magnesium hydroxide, calcium hydroxide, barium hydroxide, sodium t-butoxide, or potassium t-butoxide; lithium trimethylsilanolate, sodium trimethylsilanolate, and potassium trimethylsilanolate and the organic base is selected from, but not limited to triethyl amine, diisopropylamine, pyridine, picoline, diethyl amine, piperidine, N,N-diisopropylethyl amine.

31. A process according to claim 20 , wherein the solvent for cleavage is selected from the group comprising of aromatic hydrocarbons, aprotic polar solvents, protic polar solvents, aliphatic ethers or mixtures of one or more organic solvents.

32. A process according to claim 31, wherein the solvent is selected from one or more solvents comprising tetrahydrofuran, chloroform, methylene dichloride, toluene, xylene, methyl t-Butyl ether (MTBE), cyclopentyl methyl ether(CPME).

33. A process according to claims 29 to 32, wherein the said base is potassium trimethysilanolate and the said solvent is THF.

34. A process according to the claim 20, wherein trifenatate salt (III) contains HPLC purity of more than 99%.

35. A process according to the claim 20, wherein trifenatate salt (III) contains enantiomeric purity of more than 99%.

36. A process according to clam 20, wherein trifenatate salt (III) is in the crystalline form.

37. A crystalline trifenatate salt (III) according to claim 36, is characterized by having a XRD pattern as shown in Figure 1.

38. A crystalline trifenatate salt (III) according to claim 36, is characterized by a DSC spectrum as shown in Figure 2.
39. A pharmaceutical composition comprising vilanterol of formula (I) or its pharmaceutically acceptable salt thereof, prepared by a process according to any of claims 1 to 18, together with one or more pharmaceutically acceptable excipients

A method for the prevention or treatment of COPD which method comprises administering therapeutically effective amounts to a patient in need thereof vilanterol of formula (I) or its pharmaceutically acceptable salt thereof, according to any of claims 1 to 18.