DESC:FORM 2
THE PATENT ACT 1970
(39 OF 1970)
&
THE PATENT RULES, 2005

COMPLETE SPECIFICATION
[SEE SECTION 10 AND RULE 13]

A PROCESS FOR PREPARATION OF VILANTEROL AND INTERMEDIATE THEREOF;

GBR LABORATORIES PVT. LTD., AN INDIAN COMPANY, WHOSE ADDRESS IS, HNO 5-7-209/2, SRIPURAM COLONY, BN REDDY NAGAR, VANASTHALIPURAM,
HYDERABAD-500070, TELANGANA, INDIA
AND
RACHANA PHARMA TECH, AN INDIAN COMPANY, WHOSE ADDRESS IS FLAT NO 404, B-BLOCK, SURYA TOWERS, ROAD NO-2, SNEHAPURI COLONY, NACHARAM, HYDERABAD - 500076, TELANGANA, INDIA

THE FOLLOWING SPECIFICATION PARTICULARLY DESCRIBES THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

Field of the Invention
The present invention relates to a process for preparation of Vilanterol. The present invention also relates to a process for preparing chiral epoxide intermediate for the preparation of Vilanterol.

Background of the Invention
Vilanterol is a selective ultra-long-acting beta2 (ß2) adrenergic agonist (LABA) with inherent 24-hour activity for once daily treatment of Chronic obstructive pulmonary disease (COPD) and asthma. ß2 adrenoceptor agonist is the most widely used in clinical treatment of asthma and chronic obstructive pulmonary disease drugs. Its pharmacological effect is attributable to stimulation of intracellular adenylyl cyclase which catalyzes the conversion of adenosine triphosphate (ATP) to cyclic-3',5'-adenosine monophosphate (cAMP). Increases in cyclic AMP are associated with relaxation of bronchial smooth muscle and inhibition of release of hypersensitivity mediators from mast cells in the lungs. Over the last decade, the development of high potency, high selectivity, rapid onset, long duration of action, is administered once daily ß2-adrenoceptor agonists caused great concern in the pharmaceutical industry.

Vilanterol is approved for use in several combination products indicated for the long-term, once-daily maintenance treatment of airflow obstruction in patients with COPD, including chronic bronchitis and emphysema. It is also indicated for once-daily maintenance treatment of asthma in patients aged 18 or older with reversible obstructive airways disease.
Vilanterol is chemically described as 4-{(lR)-2-[6-{2-(2, 6-dichlorobenzyl)oxy] ethoxy}hexyl)amino]-l-hydroxyethyl}-2-(hydroxymethyl) phenol as represented by Formula (I).

Vilanterol is a dichlorobenzene derivative that is used in the form of its trifenatate salt for treatment of chronic obstructive pulmonary disease. It has a role as a beta-adrenergic agonist and a bronchodilator agent.

Vilanterol has been prepared by various methods such as one described in US20150239862A1. However, the disadvantage of the cited patent reference methods is low selectivity, stringent conditions, expensive reagents and low yields-and tedious work-up-procedures.

Thus, there is a need for an improved process for preparation of a Vilanterol with improved yield and purity, reduced cost, reducing the waste, and an industrially feasible processes that overcome the drawbacks of the aforesaid processes.

Summary of the Invention
In an aspect the present invention provides a process of preparing a compound of Formula I. The process comprises steps of:

a) adding a compound of Formula (VI) to a solvent in presence of a catalyst followed by treatment with a reagent to obtain a compound of Formula (X);

b) adding the compound of Formula (X) to a solvent in presence of a catalyst to obtain a compound of Formula (IX);

c) reacting the compound of Formula (IX) with a compound of Formula (XV) in presence of a base and a solvent to obtain a compound of Formula (XVI); and

d) reductive cleavage of the compound of Formula (XVI) in presence of a reducing agent and a solvent to obtain a compound of Formula (I).

Description of the Invention
The foregoing objects of the present invention are accomplished and the problems and shortcomings associated with the prior art, techniques and approaches are overcome by the present invention as described below in the preferred embodiments.

All materials used herein were commercially purchased as described herein or prepared from commercially purchased materials as described herein.

Although specific terms are used in the following description for sake of clarity, these terms are intended to refer only to particular structure of the invention selected for illustration in the drawings and are not intended to define or limit the scope of the invention.

In one aspect, the present invention relates to a process for preparation of a compound of Formula (I).

The process comprises steps of:
a) adding a compound of Formula (VI) to a catalyst solution prepared in a solvent followed by addition of a reagent at a temperature under an inert atmosphere of nitrogen to obtain a reaction mixture and heating the reaction mixture to a temperature for a time to obtain a compound of Formula (X);

b) adding the compound of Formula (X) to a solvent in presence of a catalyst followed by charging a gas at a pressure to obtain a compound of Formula (IX);

c) reacting the compound of Formula (IX) with a compound of Formula (XV) in presence of a base and a solvent at a temperature to obtain a compound of Formula (XVI); and

d) reductive cleavage of the compound of Formula (XVI) with a reducing agent in presence of a solvent at a temperature followed by addition of a halide compound in presence of the solvent and heating for a temperature for a time to obtain a compound of Formula (I).

The compound of Formula VI is a chiral epoxide compound.
In step (a) the catalyst is selected from MgI2 etherate (MgI2.OEt2), iodine (I2), lithium perchlorate (LiClO4), sodium iodide (NaI), lithium chloride (LiCl) or like. The solvent is selected from the group of tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, diethyl ether, or like. The reagent is selected from the group of benzyl isocyanate, p-methoxyphenyl isocyanate, sodium cyanate, or like. The temperature is in the range from 20°C to room temperature. Heating of the reaction mixture is done at temperature of 75°C to 80°C for a time of 2 hours to 4 hours.
In step (b) the solvent is selected from the group of methanol, ethanol, isopropyl alcohol, ethyl acetate, or like. The catalyst is selected from palladium supported on Carbon (Pd/C), Pd/BaSO4, Raney Nickel, or like. The gas is hydrogen gas and is charged at a pressure of 100 psi to 150 psi.
In step (c) the base is selected from the group of sodium hydride (NaH), potassium hydride, sodium methoxide, potassium tert-butoxide, sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), or like. The solvent is selected from a group of dimethyl formamide (DMF), N,N-dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP), tetrahydrofuran (THF) or like. The temperature is from 10°C to 20°C.
In step (d) the reducing agent is selected from a group of sodium boro hydride (NaBH4), sodium cyanoborohydride, sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al), lithium aluminum hydride (LAH), borane dimethyl sulfide complex (BH3.SMe2) or like. The solvent can be selected from a group of tetrahydrofuran (THF), methyl tert-butyl ether, diisopropyl ether, diethyl ether or like. The temperature is in the range from -5°C to 0°C. The halide compound is selected from a group of iodine compound, lithium chloride (LiCl), lithium bromide (LiBr), nickel chloride (NiCl2), zinc chloride ZnCl2), or like. The heating of the compound is done for a temperature of 0°C to 80°C for a time of 8 hours to 12 hours.
The compound of Formula (I) prepared by the process as disclosed above has a purity by HPLC of 99.8% to 99.9% and has yield of about 65% to 70%.

In an embodiment, a process for preparation of a compound of Formula (VI) is provided.

The process comprises steps of:
a) reacting a compound of Formula (IV) with a reducing agent solution prepared in a solvent at a temperature for a time in the presence of a catalyst solution prepared in a solvent to obtain a compound of Formula (V);

b) epoxide formation of the compound of Formula (V) in presence of a base and a solvent to obtain a compound of Formula (VI);

In step (a) the reducing agent is selected from the group of borane dimethyl sulfide complex (BH3-DMS), borane tetrahydrofuran (BH3-THF), BH3-pyridine, 9-borabicyclo(3.3.1)nonane (9-BBN), cateholborane, diisopinocampheylborane, alpine borane, or like prepared in a solution of a solvent selected from tetrahydrofuran (THF), dichloromethane (DCM), toluene, or like. The catalyst is selected from the group of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole ((R)-Me-CBS), 2-methyl-CBS-oxazaborolidine (S-Me-CBS), 1,1'-Bi-2-naphthol (BINOL), (2,2-bis(diphenylphosphino)-1,1-binaphthyl) (BINAP), or like. The solvent is selected from tetrahydrofuran, dichloromethane (DCM), toluene, or like. The temperature condition is 0°C to 5°C and the time is 1 hour to 1.5 hours.
In step (b) the solvent is a mixture of solvent is selected from tetrahydrofuran and methanol wherein the ratio of the mixture of the solvent is 1:1 v/v to 1:1.5 v/v. The base is selected from the group of potassium carbonate (K2CO3), sodium carbonate (Na2CO3), cesium carbonate (Cs2CO3), or like.
The compound of Formula (VI) prepared by the above disclosed process has a purity by HPLC of 99.7% to 99.9% and has yield of about 85 % to 93%.

In yet another embodiment, a process for preparation of a compound of Formula (VI) is provided.

The process comprises steps of:
reacting the compound of Formula (XXI) with a compound of Formula (XXIII) in presence of a strong base and a solvent and stirring at temperature for a time to obtain a compound of Formula (VI).

The process as described above wherein the strong base is selected from the group of potassium hydroxide (KOH), sodium hydroxide (NaOH), lithium hydroxide (LiOH), or like. The solvent is selected from the group of tert-butyl alcohol, isopropyl alcohol, methanol, or like. Stirring is done at temperature of 20°C to room temperature for a time of 42 hours to 48 hours.
The compound of Formula (VI) prepared by the above disclosed process has a purity by HPLC of 98% to 99.9% and has yield of about 80% to 85%.
The process of preparing the compound of Formula (VI) as disclosed above wherein the compound of Formula (XXI) is prepared by a process comprising steps of:
1) reacting a compound of Formula (XIX) with a catalyst in presence of a solvent followed by adding a dehydrating agent in presence of the solvent to obtain a compound of Formula (XX);

2) dissolving the compound of Formula (XX) in a solvent and cooling to a temperature and further adding a strong base and stirring the above reaction mixture at a temperature for a time to obtain a reaction mixture;
3) treating the above reaction mixture with a mixture of solvent at a ratio and stirring the reaction mixture at a temperature for a time to obtain a compound of Formula (XXI);

The compound of Formula (XIX) in step (1) is 5-bromo-2-hydroxybenzoic acid. In step (1) the catalyst is selected from the group of p-toluene sulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, or like. The solvent is selected from the group of dichloromethane, dichloroethane, chloroform, or like. The dehydrating agent is 2,2-dimethoxypropane.
In step (2) the solvent is tetrahydrofuran (THF), methyl tert-butylether, diisopropyl ether, diethyl ether, or like. The cooling is done to a temperature from 0°C to -78°C. The strong base is selected from the group of n-butyl lithium, s-butyl lithium, lithium diisopropylamide (LDA), potassium bis(trimethylsilyl)amide (KHMDS), or like. Further in step (2) stirring of the reaction mixture is done at a temperature from -70°C to -78°C and for a time of 2 hours to 3 hours.
In step (3) the mixture of solvent is N,N-dimethylformamide and tetrahydrofuran at a ratio of 1:1. Stirring of the reaction mixture is done at a temperature from -70°C to -78°C and for a time of 45 minutes to 1 hour.
In a further embodiment, the process for preparation of a compound of Formula (XXIII) used in the process of preparing the compound of Formula (VI) as described above is provided.

The process comprises steps of:
A) adding an elemental sulfur to a compound of Formula (A) along with a compound of Formula (B) or compound of Formula (C) and heating to a temperature under vigorous stirring for a time to obtain a compound of Formula (XXII);

B) preparing a solution of the compound of Formula (XXII) in a solvent and adding the solution to a methylating agent in presence of a catalyst to obtain a reaction mixture and stirring the reaction mixture at room temperature for a time to obtain a compound of Formula (XXIII).

The compound of Formula (A) is (R)-Limonene, the compound of Formula (B) is 1,4-cyclohexadiene and the compound of Formula (C) is ?-terpinene.
In step (A) the heating is done to a temperature under vigorous stirring from 105°C to 110°C for a time of 12 hours to 15 hours.
In step (B) the solvent is selected from the group of acetone, acetonitrile, dichloromethane, dichloroethane, or like. The methylating agent is selected from the group of methyl bromide, methyl iodide, or like. The catalyst is selected from the group of silver perchlorate, sodium perchlorate, or like. Stirring of the reaction mixture can be done for a time of 0.5 hours to 1 hour.
The compound of Formula (XXIII) prepared by the above disclosed process has a purity by HPLC of 99.2% to 99.8% and has yield of about 65 % to 70%.

In a further embodiment, the process of preparation of compound of Formula (XV) used in step (c) of the process of preparing the compound of Formula I as described above is provided.

The process comprises steps of:
(a) reacting a compound of Formula (XI) with an epoxide compound of Formula (XII) in presence of a catalyst and a solvent at a temperature to obtain a compound of Formula (XIII); and

(b) O-Alkylation of the compound of Formula (XIII) with a compound of Formula (XIIIA) in presence of phase transfer catalyst, a strong base and a solvent at a temperature to a time to obtain a compound of Formula (XV).

The compound of Formula (XI) in step (a) is 2,6-dichlorobenzyl alcohol.
In step (a) the catalyst is selected from the group of sodium hydride, potassium hydride, sodium methoxide, potassium tert-butoxide, triethylamine, N,N-diisopropylethylamine (DIPEA) or like. The solvent is selected from the group of tetrahydrofuran (THF), methyl tert-butyl ether, diisopropyl ether, diethyl ether, or like. The temperature is from 0°C to 5°C.
In step (b) the compound of Formula (XIIIA) is 1,6-dibromohexane. In step (b) the phase transfer catalyst is selected from the group of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium iodide, or like. The strong base is selected from the group of sodium hydroxide, potassium hydroxide, lithium hydroxide, or like. The solvent base is selected from the group of toluene, xylene, benzene, or like. The temperature is 55°C to 60°C and the time is 8 hours to 20 hours.
The compound of Formula (XV) prepared by the above disclosed process has a purity by HPLC of 99.5 % to 99.1 % and has yield of about 75% to 79%.

In an aspect, a process for preparation of a compound of Formula (I) is disclosed.

The process comprises steps of:
a) reacting compound of Formula (IV) with a amine source in presence of a solvent for a time at temperature to obtain a compound of Formula (VII);

b) reducing compound of Formula (VII) with a catalyst solution prepared in a solvent and with a reducing agent solution prepared in a solvent at a temperature for a time to obtain a compound of Formula (VIII); and

c) reductive amination of compound of Formula (VIII) with a reducing agent in presence of a solvent followed by addition of a compound of Formula (XVII) along with the addition of said reducing agent in presence of a halide compound and said solvent to obtain a compound of Formula (I).

In step (a) the amine source is selected from the group of sodium azide, sodamide, lithium amide, ammonia or like. The solvent is selected from the group of dimethyl formamide (DMF), tetrahydrofuran (THF), N-Methyl-2-pyrrolidone (NMP), dimethyl sulphoxide (DMSO), or like. The time is 20 minutes to 30 minutes and the temperature is 0°C to 25°C.

In step (b) the catalyst is selected from the group of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole ((R)-Me-CBS), ((R)-Ph-CBS), ((R)-ortho-toly-CBS), or like. The solvent is selected from the group of tetrahydrofuran (THF), DME-, t-Butylmethyl ether or like. The reducing agent is selected from the group of Borane dimethyl sulfide complex (BH3-DMS), BH3.THF, NaBH4-I2 or like. The temperature is 0°C to 5°C and the time is 1 hour to 1.5 hours.
In step (c) the reducing agent is selected from the group of sodium boro hydride (NaBH4), LiBH4, NiBH4, or like. The solvent is selected from the group of tetrahydrofuran (THF), or like. The halide compound is selected from the group of iodine compound, LiCl, LiBr, or like.
The compound of Formula (VII) prepared by the above disclosed process has a purity by HPLC of 98% to 99% and has yield of about 68% to 70%.
Further, the compound of Formula (I) prepared by the above disclosed process has a purity by HPLC of 98% to 99% and has yield of about 55% to 60%.

In yet another aspect, a process for preparation of a compound of Formula (IV) is provided.

The process comprises steps of:
a) reacting a compound of Formula (II) with a acylating agent in presence of a catalyst and a solvent and refluxing at a temperature for a time to obtain a compound of Formula (III);

b) acetonide protection of compound of Formula (III) using a catalyst and a solvent followed by adding a dehydrating agent in presence of the solvent to obtain a compound of Formula (IV);

In step (a) the acylating agent is selected from the group of chloroacetyl chloride, bromoacetyl bromide, bromoacetyl chloride, acetyl chloride or like. The catalyst is selected from the group of aluminum chloride, FeCl3, BF3.OEt2 or like. The solvent is selected from the group of dichloromethane, dichloroethane, chloroform, nitrobenzene or like. The refluxing is done at a temperature of 0°C to 25°C and for a time to of 24 hours to 48 hours.
In step (b), the catalyst is selected from the group of p-toluenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, or like. The dehydrating agent is selected from the group of 2,2-dimethoxypropane, acetone, cyclohexanone, or like. The solvent is selected from group of dichloromethane, dichloroethane, acetone, or like.
The compound of Formula (IV) prepared by the above disclosed process has a purity by HPLC of 98% to 99% and has yield of about 80% to 85%.

In yet another embodiment, a process of preparation of compound of Formula (XVII) used in step (c) of the process of preparing the compound of Formula (I) as described above is provided.

The process comprises steps of:
(I) reacting a compound of Formula (XI) with an epoxide compound of Formula (XII) in presence of a reducing agent and a solvent at a temperature to obtain a compound of Formula (XIV);

(II) reacting a compound of Formula (XIV) with a compound of Formula (XIVA) in presence of a phase transfer catalyst, a strong base and a solvent at a temperature to a time to obtain a compound of Formula (XVIII); and

(III) reacting the compound of Formula (VIII) with a oxidizing agent in presence of a solvent to obtain a compound of Formula (XVII).

The compound of Formula (XI) in step (I) is 2,6-dichlorobenzyl alcohol.
In step (I) the base is selected from the group of sodium hydride, potassium hydride, NaOMe, potassium t-butoxide (KtOBu) or like. The solvent is selected from the group of tetrahydrofuran (THF), DMF, dimethoxyethane (DME), or like. The temperature is from 0 °C to 25°C.
In step (II) the compound of Formula (XIVA) is selected from the group of 6-bromo-1-hexanol. The phase transfer catalyst is selected from the group of tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium iodide, benzyl triethylammonium chloride, or like. The strong base is selected from the group of sodium hydroxide, potassium hydroxide, lithium hydoxide, or like. The solvent base is selected from the group of toluene, hexane, THF, dimethoxyethane, or like. The temperature can be 55°C to 60°C and the time is 8 hours to 20 hours.
In step (III) the oxidizing agent is selected from the group of pyridinium chlorochromate, Cornforth reagent or pyridinium dichromate (PDC), 2-iodoxybenzoic acid (IBX), Dess–Martin periodinane (DMP), swern conditions, SO3.pyridine or like. The solvent is selected from the group of dichloromethane, dichloroethane, toluene, hexane or like.
The compound of Formula (XVII) prepared by the above disclosed process has a purity by HPLC of 98% to 99% and has yield of about 75% to 78%.

The reaction scheme for preparing a compound of Formula (I) using a compound of Formula (VI) is represented below:

The reaction scheme for preparing a chiral epoxide compound of Formula (VI) is represented below:

The reaction scheme for preparing a compound of Formula (VI) is represented below:




The reaction scheme for preparing a compound of Formula (I) using a compound of Formula (IV) is represented below:

The reaction scheme for preparing a compound of Formula (IV) is represented below:

EXAMPLES
The following examples illustrate the invention and are not limiting thereof.
Example 1 - Synthesis of Compound of Formula (I)
1. Preparation of cyclic carbamate (XIX)
To a stirred solution of freshly prepared MgI2.OEt2 (0.0064 mol) in THF (25 mL) was added (R)-2,2-dimethyl-6-(oxiran-2-yl)-4H-benzo[d][1,3]dioxin-4-one (VI) (3.5g, 0.016 mol) in dropwise manner followed by addition of the benzyl isocyanate (1.71g, 0.013 mol) at room temperature under nitrogen. After complete addition, the mixture was allowed to warm to 80 °C and stirred for 4 h. The resulting homogeneous mixture was quenched with saturated aqueous Na2SO3 solution and extracted with CH2Cl2 and purified by flash chromatography on silica gel using a gradient mixture of ethyl acetate-n-hexane (2:1) to give a compound of Formula (X) in the form of a yellow solid having yield of about 78%.

To the above compound of Formula (X) (2.0g, 0.0057 mol) in 30 ml of methanol was added 10% Pd/C (200 mg). The solution was placed in a stainless steel reactor, which was then charged with hydrogen gas (150 psi). After being stirred for 24 hours at room temperature, the mixture was filtered through Celite to remove the catalyst. The filtrate thus obtained was evaporated to give a compound of Formula (IX) having yield of about 95%.

2. Synthesis of Compound of Formula (XV)
i. (Epoxide opening):
To a mixture of a compound of Formula (XI) (7.0 g, 0.039 mol) and sodium hydride (60% oil dispersion; 2.38g, 0.099 mol) in THF at 0°C was added a compound of Formula (XII) (19.2 mL, 0.048 mol). The resulting mixture was continued until TLC showed the disappearance of benzyl alcohol. The reaction was quenched with brine solution at 0°C and diluted with water and extracted with ethyl acetate and extracted with ethyl acetate. The organic phase was washed with brine and dried over anhydrous MgSO4. The filtrate was evaporated to dryness to give the yellowish oily product. Further purification by flash column chromatography on silica gel gave a compound of Formula (III) having yield of about 85%.

ii. O-Alkylation:
A mixture of a compound of Formula (XIII) (5.0g, 0.022 mol.), a compound of Formula (XIIIA) (22.0 g, 0.090 mol) and tetrabutylammonium bromide (0.36 g, 0.001 mol.) and 50% aq. NaOH (3.6g, 0.090 mol) in toluene (40mL) were heated to 55 - 60 °C for 8 - 20 hours. Upon completion, the reaction mass was diluted with water and toluene under cooling conditions. The aqueous phase was separated and diluted with water then extracted with toluene. The combined toluene extracts were washed twice with water and then evaporated to dryness under vacuum to afford the crude compound. The excess dibromohexane was removed by vacuum distillation to get brown colour oil, which was purified by column chromatography (eluent: ethyl acetate - hexane) to afford the compound of Formula (XV) having yield of about 79% and purity by HPLC of 99.1%.

3. N-Alkylation of Compound of Formula (IX):
To a suspension of sodium hydride (60% oil dispersion; 0.54g, 0.023mol) in DMF (10 mL) at 0°C was added a solution of a compound of Formula (IX) (2.0g, 0.0076 mol). The mixture was stirred under nitrogen for 30 minutes and then a solution of (XV) (3.77g, 0.0098 mol) in DMF (5 mL) was added and stirred at 20°C for 1 hour. The mixture was quenched with phosphate buffer (pH 6.5) and then extracted with EtOAc (2 × 20 mL). The combined organic layers were washed with water (2 × 40 mL), dried and evaporated under reduced pressure. The residue was purified by chromatography on silica gel, eluting with EtOAc - cyclohexane (1:1) to give the compound of Formula (XVI) having yield of about 73%.

4. Reductive Cleavage of Compound of Formula (XVI) with NaBH4/I2 :
To a solution of a compound of Formula (XVI) (4.0g, 0.0071mol.) in dry THF (50 mL) were added NaBH4 at 0 °C followed by a solution of iodine (1.8g, 0.0071mol.) in dry THF (25 mL) drop wise. The mixture was heated to reflux overnight and then quenched with MeOH (˜200 mL) until a clear solution. The solvents were removed and the mixture was diluted with water and extracted with ethyl acetate. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3x200 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain the compound of Formula (I) as a white solid and having yield of about 70%.

Example 2 - Synthesis of Compound of Formula (VI):
1. Friedel - Crafts alkylation followed by acetonide protection:
Aluminium trichloride (48.3g, 0.36mol) was added batch wise to a compound of Formula (II) (10g, 0.072 mol) in dry dichloromethane at 0°C, and then chloroacetyl chloride (29.2 mL, 0.36 mol) was added drop wise. After refluxing for 48 hours at a temperature of 35°C to 45°C, the mixture was poured into ice water, and adjusted the pH to 6~7 using sat. NaHCO3 solution. The organic layer was separated and washed with water followed by sat. ammonium chloride solution, dried over anhydrous sodium sulphate, concentrated under reduced pressure to obtain a compound of Formula (III) in the form of a off-white solid and having yield of about 60%.

To a suspension of a compound of Formula (III) (5.0g, 0.023 mol) and p-toluenesulfonic acid (0.04g, 0.0002 mol) in 50 ml of dichloromethane, a solution of 2,2-dimethoxypropane (2.69 g, 0.025 mol) in dichloromethane (20 ml) was added in a drop wise manner. The suspension was stirred vigorously until it becomes homogeneous (light yellow). The reaction mixture was quenched with saturated NaHCO3 solution. The organic phase was separated and dried over MgSO4. The solvent was evaporated under reduced pressure to give a compound of Formula (IV) having yield of about 85%.

2. CBS - Reduction followed by Epoxide Formation
To a solution of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole (1M, 2.2 mL toluene) in THF (25 mL) at 0 °C, a solution of borane-THF complex (1M solution in THF, 35.8 ml) was added. The mixture was stirred under nitrogen for 15 minutes and then a solution of a compound of Formula (IV) (7.0g) in THF (40ml) was added drop wise over 1.5 h at 5°C. The resulting mixture was stirred for another 1 hour and then cautiously quenched with 2M HCl (100 ml) and extracted with ether and the organic layer was washed with 2N HCl followed by NaHCO3 solution and brine solution and dried over MgSO4. The solvent was removed by distillation and the residue was purified by column chromatography on silica gel, to give a compound of Formula (V) having yield of about 66%.

To a solution of the compound of Formula (V) (6.0g, 0.023mol) in a mixture of THF:MeOH (1:1), potassium carbonate (9.7g, 0.07mol) was added. The mixture was stirred vigorously at room temperature for 2 h and then filtered. The filtrate was concentrated under reduced pressure and then purified by flash column chromatography on neutral aluminum oxide (petroleum ether / ethyl acetate = 20/1) to give a compound of Formula (VI) as a yellowish oil having yield of about 93%.

Example 3 - Synthesis of a compound of Formula (VI)
i. Preparation of Compound of Formula (XXI):
To a suspension of a compound of Formula (XIX) (5.0g, 0.023 mol) and p-toluenesulfonic acid (0.04g, 0.0002 mol) in 50 ml of dichloromethane, a solution of 2,2-dimethoxypropane (2.64 g, 0.025 mol) in dichloromethane (20 ml) was added in drop wise manner. The suspension was stirred vigorously until it becomes homogeneous (light yellow). The mixture was quenched with sat. NaHCO3 solution. The organic phase was separated and dried over MgSO4. The solvent was evaporated under reduced pressure to give the compound of Formula (XX) having yield of about 82%.

The above bromo acetonide (XX) (4.0 g, 0.016mol.) was dissolved in dry THF, cooled to -78 °C and a 1.6 M solution of n-butyl lithium (19.53 mL, 1.6 M in hexane, 0.031 mol.) was added drop wise. The mixture was stirred at -78 °C for 2 h and then treated with dry N, N-dimethylformamide (17.1 mL, 0.23 mol) as a 1:1 solution in dry THF. The resulting mixture was stirred at -78 °C for 0.75 h and warmed slowly up to room temperature. Then the mixture was diluted with diethyl ether, washed with water followed by a brine solution and dried over MgSO4. The solvent was removed and the residue was purified by column chromatograph on silica gel to give a compound of Formula (XXI) having yield of about 68%.

ii. Preparation of Compound of Formula (XXIII)
a. Preparation of Compound of Formula XXII:
(R)-Limonene (A) (20 mL, 0.124 mol) was placed in a round bottom flask equipped with a reflux condenser. To this solution were added elemental sulfur (4.62 g, 0.14 mol) and ?-terpinene (C) (19.2 mL, 0.12 mol) or 1,4-cyclohexadiene (B) (11.6 mL, 0.12 mol). The resulting mixture was heated at 110 °C under vigorous stirring for overnight. After that, the mixture was allowed to cool to room temperature and then distilled using a distillation apparatus with a Vigreux column. After separation of various volatiles, the compound of Formula (XXIII) (36% yield, 99:1 e.r.) was obtained at 85–90 °C/5 mm Hg.

To a solution of sulphide (XXII) (1.0g, 0.0059 mol) in acetone (15 mL) were successively added methyl bromide (0.66g, 0.0071mol) and silver perchlorate (1.45g, 0.0071 mol). The resulting mixture was stirred at room temperature for 0.5 - 1 h and diluted with dichloromethane (40 mL) and then filtered to remove insoluble materials. The filtrate was evaporated and the residual crystals were washed with dry diethyl ether - hexane to give the sulfonium perchlorate, the compound of Formula (XXIII) as colourless fine crystals having yield of about 70 %.

iii. Chiral sulfide-mediated enantioselective epoxidation of aldehydes:
A mixture of a compound of Formula (XXI) (1.5g, 0.0073mol), a compound of Formula (XXIII) (2.5g, 0.0087mol) and powdered KOH (0.5g, 0.0087mol) in tert-butyl alcohol (20 mL) was stirred at room temperature for 48 h. Then the mixture was quenched with water and extracted with dichloromethane (20 mL x 3). The combined extracts were washed with sat. NaCl and dried over MgSO4. Evaporation of the solvent followed by purification on silica gel using a mixture of EtOAc - hexane (1: 9) as an eluent gave the epoxide, the compound of Formula (VI) having yield of about 85%.

Example 4 - Synthesis of Compound of Formula (I)
1. Synthesis of Compound of Formula (IV):
i. Friedel - Crafts alkylation followed by acetonide protection:
Aluminium trichloride (48.3g, 0.36mol) was added batch wise to a compound of Formula (II) (10g, 0.072 mol) in dry dichloromethane at 0°C, and then chloroacetyl chloride (29.2 mL, 0.36 mol) was added drop wise. After refluxing for 48 h, the mixture was poured into ice water, and adjusted the pH to 6~7 using sat. NaHCO3 solution. The organic layer was separated and washed with water followed by sat. ammonium chloride solution, dried over anhydrous sodium sulphate, concentrated under reduced pressure to obtain a compound of Formula (III) in the form of a off-white solid having yield of about 60%.

To a suspension of a compound of Formula (III)(5.0g, 0.023 mol) and p-toluenesulfonic acid (0.04g, 0.0002 mol) in 50 ml of dichloromethane was added a solution of 2,2-dimethoxypropane (2.69 g, 0.025 mol) in dichloromethane (20 ml) in a drop wise manner. The suspension was stirred vigorously until it becomes homogeneous (light yellow). The reaction mixture was quenched with saturated NaHCO3 solution. The organic phase was separated and dried over MgSO4. The solvent was evaporated under reduced pressure to give the compound of Formula (IV) having yield of about 85% yield.

2. Preparation of Compound of Formula (VIII):
To a solution of a compound of Formula (IV) (10 g, 0.039 mol) in DMF (50 mL) was treated with sodium azide (2.72 g, 0.043 mol) over 30 min at 0?C. The mixture was stirred for 2 h at 20 °C and then quenched with water and extracted with EtOAc (3x15 ml). The combined organic solutions were washed with sat. sodium bicarbonate, brine solution and dried over MgSO4. The solvent was removed under reduced pressure; the resulting orange solid was dissolved in dichloromethane and then filtered through silica by eluting with dichloromethane. Appropriate fractions were combined and evaporated under reduced pressure to give the compound of Formula (VII) in the form of a pale yellow solid having yield of about 97%.

To a solution of (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole (1M, 2.2 mL toluene) in THF (25 mL), a solution of Borane-THF complex (1M solution in THF, 35.8 ml) was added at 0°C. The mixture was stirred under nitrogen for 15 minutes and then a solution of a compound of Formula (VII) (8.0g) in THF (40 mL) was added drop wise over 1.5 hour at 5°C. The mixture was stirred for another 1 hour and then cautiously quenched with 2M HCl (30 mL) and then extracted with ether. The organic layer was washed with 2N HCl followed by a solution of NaHCO3 and brine and dried over MgSO4. The solvent was removed by distillation and the residue was purified by column chromatograph on silica gel, to give a compound of Formula (VIII) having yield of about 70 %.

3. Preparation of a Compound of Formula (XVII):
i. Epoxide opening:
To a mixture of a compound of Formula (XI) (7.0 g, 0.039 mol) and sodium hydride (60% oil dispersion; 2.38g, 0.099 mol) in THF, epoxide (XII) (19.2 mL, 0.048 mol) was added at 0°C. The resulting mixture was continued until TLC showed the disappearance of benzyl alcohol. The reaction was quenched with brine solution at 0°C and diluted with water and extracted with ethyl acetate and extracted with ethyl acetate. The organic phase was washed with brine and dried over anhydrous MgSO4. The filtrate was evaporated to dryness to give the yellowish oily product. Further purification by flash column chromatography on silica gel gave the desired product of a compound of Formula (XIV) having yield of about 85%.

ii. Preparation of a Compound of Formula (XVII):
A mixture of a compound of Formula (XIV) (5.0g, 0.022 mol.), a compound of Formula (XIVA) (4.5g, 0.025mol.) and tetrabutylammonium bromide (0.36 g, 0.001 mol.) and 50% aq. NaOH (3.6g, 0.090 mol) in toluene (40mL) were heated to 55 - 60 °C for 8 - 20 h. Upon completion, the reaction mass was diluted with water and toluene under cooling conditions. The aqueous phase was separated and diluted with water then extracted with toluene. The combined toluene extracts were washed twice with water and then evaporated to dryness under vacuum to afford the crude compound. The excess of the compound of Formula (XIVA) was removed by vacuum distillation to get brown colour oil, which was purified by column chromatography (eluent: ethyl acetate - hexane) to give a compound of Formula (XVIII) having yield of about 88%;

To a 0.5 ? solution of the respective isotopomer
of 3-(benzyloxy)-1-propanol (4a–c, 1.0 equiv.) in absolute dichloro-
methane was added pyridinium chlorochromate (1.5 equiv.). After
stirring at room temperature overnight, the reaction mixture was
filtered through silica gel and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (hexane/ethyl
acetate, 3:1) to give aldehydes 5a–c as colorless liquids. A
To a 0.5 ? solution of the respective isotopomer
of 3-(benzyloxy)-1-propanol (4a–c, 1.0 equiv.) in absolute dichloro-
methane was added pyridinium chlorochromate (1.5 equiv.). After
stirring at room temperature overnight, the reaction mixture was
filtered through silica gel and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (hexane/ethyl
acetate, 3:1) to give aldehydes 5a–c as colorless liquids. A
To a 0.5 ? solution of the respective isotopomer
of 3-(benzyloxy)-1-propanol (4a–c, 1.0 equiv.) in absolute dichloro-
methane was added pyridinium chlorochromate (1.5 equiv.). After
stirring at room temperature overnight, the reaction mixture was
filtered through silica gel and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (hexane/ethyl
acetate, 3:1) to give aldehydes 5a–c as colorless liquids. A
To a solution of a compound of Formula (XVIII) (5.0g, 0.0156mol.) in dichloromethane was added pyridinium chlorochromate (4.04g, 0.0187mol). After stirring at room temperature overnight, the mixture was filtered through silica gel and concentrated in vacuo. The residue was purified by column chromatography on silica gel (hexane/ethyl acetate) to give a compound of Formula (XVII) having yield of about 78%.

4. Reductive amination:

To a solution of a compound of Formula (VIII) (3.0g, 0.012 mol) in 5 ml of THF (30 mL) was added NaBH4 (2.3g, 0.027 mol). After being stirred for 24 h at room temperature, the mixture was quenched with water and ethyl acetate. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3x200 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated to afford the amine.
To a solution of amine in THF (30 mL), a compound of Formula was added (XVII) (3.8g, 0.012 mol) and the mixture was stirred until the formation of imine (checked by TLC).
To a solution of imine (4.0 g, 0.0083mol) in dry THF (50 mL) were added NaBH4 at 0 °C followed by a solution of iodine (2.1g, 0.0083mol) in dry THF (25 mL) drop wise. The mixture was heated to reflux overnight and then quenched with MeOH until a clear solution (˜200 mL). The solvents were removed and the mixture was diluted with water and extracted with ethyl acetate. The organic phase was separated and the aqueous phase was extracted with ethyl acetate (3x200 mL) and the combined organic layers were dried over Na2SO4, filtered, and concentrated to obtain a compound of Formula (I) in the form of a white solid having yield of about 60%.

The process of the present invention as described above results in high yield of the end product with maximum purity. It is an eco-friendly and a cost effective process and with minimum waste products. The process also provides intermediate with high yield and with maximum purity and high chirality. The process of preparing vilanterol as disclosed herein is very simple and can be applied for large scale synthesis and is also an industrially feasible process.

The foregoing description of specific embodiments of the present invention has been presented for purposes of illustration and description. They are not intended to be exhaustive or to limit the present invention to the precise forms disclosed, and obviously many modifications and variations are possible in light of the above teaching.

The embodiments were chosen and described in order to best explain the principles of the present invention and its practical application, to thereby enable others, skilled in the art to best utilize the present invention and various embodiments with various modifications as are suited to the particular use contemplated.

It is understood that various omission and substitutions of equivalents are contemplated as circumstance may suggest or render expedient, but such are intended to cover the application or implementation without departing from the spirit or scope of the present invention.
,CLAIMS:We Claim:
1. A process of preparing a compound of Formula I, the process comprising steps:
a) adding a compound of Formula (VI) to a solvent in presence of a catalyst followed by treatment with a reagent to obtain a compound of Formula (X);

b) adding the compound of Formula (X) to a solvent in presence of a catalyst to obtain a compound of Formula (IX);

c) reacting the compound of Formula (IX) with a compound of Formula (XV) in presence of a base and a solvent to obtain a compound of Formula (XVI); and

d) Reductive cleavage of the compound of Formula (XVI) in presence of a reducing agent and a solvent to obtain a compound of Formula (I).

2. The process as claimed in claim 1, wherein the reagent is selected from benzyl isocyanate, p-methoxyphenyl isocyanate, sodium cyanate, or like.

3. The process as claimed in claim 1, wherein the compound of Formula (VI) is prepared by a process comprising steps;
a) reacting a compound of Formula (IV) with a reducing agent in presence of a catalyst and a solvent to obtain a compound of Formula (V); and


b) epoxide formation of the compound of Formula (V) in presence of a base and a solvent to obtain the compound of Formula (VI);


4. The process as claimed in claim 1, wherein the compound of Formula (VI) is prepared by a process comprising step;
reacting a compound of Formula (XXI) with a compound of Formula (XXIII) in presence of a strong base and a solvent to obtain the compound of Formula (VI)


5. The process as claimed in claim 1, wherein the compound of Formula (XV) is prepared by a process comprising steps:
a) reacting a compound of Formula (XI) with a compound of Formula (XII) in presence of a catalyst and a solvent to obtain a compound of Formula (XIII); and

b) O-Alkylation of the compound of Formula (XIII) with a compound of Formula (XIIIA) in presence of a phase transfer catalyst, a base and a solvent to obtain the compound of Formula (XV).

6. The process as claimed in claim 5, wherein the base is selected from sodium hydroxide, potassium hydroxide, lithium hydroxide, or like.

7. The process as claimed in claim 1, wherein the compound of Formula (I) is prepared by a process comprising steps:
a) reacting a compound of Formula (IV) with an amine source in presence of a solvent to obtain a compound of Formula (VII);

b) reacting the compound of Formula (VII) with a reducing agent in presence of a solvent to obtain a compound of Formula (VIII); and

c) reacting the compound of Formula (VIII) with a compound of Formula (XVII) in presence of a reducing agent and a solvent to obtain the compound of Formula (I).

8. The process as claimed in claim 7, wherein the amine source is selected from a group consisting of sodium azide, sodamide, lithium amide, ammonia or like.

9. The process as claimed in claim 7, wherein the compound of Formula (IV) is prepared by a process comprising steps;
a) reacting a compound of Formula (II) with an acylating agent in presence of a catalyst and a solvent and refluxing it to obtain a compound of Formula (III);

b) acetonide protection of the compound of Formula (III) by reacting with a dehydrating agent in presence of a solvent to obtain the compound of Formula (IV);


10. The process as claimed in claim 9, wherein acylating agent is selected from the group consisting of chloroacetyl chloride, bromoacetyl bromide, bromoacetyl chloride, acetyl chloride or like.

11. The process as claimed in claim 9, wherein the dehydrating agent is selected from the group consisting of 2,2-dimethoxypropane, acetone, cyclohexanone, or like.

12. The process as claimed in any of the preceding claims, wherein the catalyst is selected from a group consisting of MgI2 etherate (MgI2.OEt2), Iodine (I2), lithium perchlorate (LiClO4), sodium iodide (NaI), lithium chloride (LiCl), palladium supported on Carbon (Pd/C), Pd/BaSO4, Raney Nickel, tetrabutylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium fluoride, tetrabutylammonium iodide, aluminium chloride, iron (III) chloride, zinc chloride, boron(III) fluoride etherate, p-toluene sulfonic acid, naphthalene-2-sulfonic acid, benzenesulfonic acid, methanesulfonic acid, camphorsulfonic acid, (R)-tetrahydro-1-methyl-3,3-diphenyl-1H,3H-pyrrolo[1,2-c][1,3,2]oxazaborole ((R)-Me-CBS), 2-Methyl-CBS-oxazaborolidine ((S)-Me-CBS), ((R)-Ph-CBS), ((R)-ortho-toly-CBS), 1,1'-Bi-2-naphthol (BINOL), (2,2-bis(diphenylphosphino)-1,1-binaphthyl) (BINAP) or like.

13. The process as claimed in any of the preceding claims, wherein the base is selected from the group consisting of from the group of sodium hydride (NaH), potassium hydride, sodium methoxide, potassium tert-butoxide, sodium bis(trimethylsilyl)amide (NaHMDS), potassium bis(trimethylsilyl)amide (KHMDS), and the reducing agent is selected from sodium borohydride (NaBH4), sodium cyanoborohydride, sodium bis(2-methoxyethoxy)aluminium hydride (Red-Al), lithium aluminum hydride (LAH), borane dimethyl sulfide complex (BH3.SMe2), borane dimethyl sulfide complex (BH3-DMS), borane tetrahydrofuran (BH3-THF), BH3-pyridine, 9-borabicyclo(3.3.1)nonane (9-BBN), cateholborane, diisopinocampheylborane, alpine borane, sodium borohydride (NaBH4), lithium borohydride (LiBH4), nickel borohydride (NiBH4) or like.

14. The process as claimed in any of the preceding claims, wherein the solvent is selected from a group consisting of tetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, diethyl ether, acetone, acetonitrile, dimethyl sulphoxide, methanol, ethanol, dichloromethane, dichloroethane, chloroform, toluene, isopropyl alcohol, ethyl acetate, dimethyl formamide (DMF), N,N-dimethylformamide, N,N-dimethylacetamide (DMAc), N-methyl-2-pyrrolidone (NMP) or like.

Dated this 4th day of February 2019

For GBR Laboratories Pvt. Ltd. and Rachana Pharma Tech
BY their Agent

GIRISH VIJAYANAND SHETH IN/PA 1022)
KRISHNA & SAURASTRI ASSOCIATES LLP