DESC:The present invention relates to an improved process for the preparation of Vilanterol trifenatate having the structural formula-I.

The present invention also relates to novel succinate salt of Vilanterol intermediate having the structural formula-V.

BACKGROUND OF THE INVENTION
Vilanterol is an ultra-long acting ß2 adrenoreceptor agonist which was approved in combination with fluticasone furoate for the treatment of chronic obstructive pulmonary disease in United states. Vilanterol is chemically known as 4-{(lR)-2-[6-{2-(2, 6-dichlorobenzyl) oxy] ethoxy} hexyl) amino]- l-hydroxyethyl}-2-(hydroxymethyl) phenol. Vilanterol and process for its preparation was first disclosed in WO 2003024439 A1. This patent discloses the various salts of Vilanterol like acetate, triphenyl acetate, phenyl cinnamate, 1-naphthoate and (R)-mandelate salts.
US 7361787 and Journal of Medicinal Chemistry, 2010, 53, 4522-4530 discloses the process for preparation of Vilanterol along with pharmaceutically acceptable salt. The process described in this patent, alcoholic solvent is used during the acetonide cleavage which enhances the formation of the corresponding ether impurities. This process requires repetitive purifications, which is not suitable for bulk scale up process. Moreover, the dibromo hexane used in the process contains the corresponding 1, 5-dibromo alkanes which tends to react in the same sequential manner to generate the corresponding analogues, which requires repetitive purifications to separate out from the final API. The '787 patent uses column chromatographic purification procedures which are not feasible on the commercial scale.
IN 201641015653 discloses the oxalate salt of Vilanterol intermediate which is used in the preparation of Vilanterol trifenatate. As on date, there is no other organic acid addition salts were reported in the prior art. There is a need to develop a novel organic acid addition salt which is very much efficient when compare to its corresponding oxalate salt and that results in the formation of final API with high purity and yield.
The reported procedures for the preparation of Vilanterol trifenatate is suffers from many disadvantages. The purity and the yield of vilanterol trifenatate are not satisfactory and also the said process involves chromatography techniques to isolate the intermediate compounds. The said techniques are tedious, high cost and time-consuming process which is not suitable for industrial scale. All these disadvantages effect the overall yield as well as the quality of the final product.
In view of all these disadvantages, there is a significant need in the art to develop an improved process for the preparation of highly pure Vilanterol trifenatate by avoiding column purifications and involving different types of reaction solvents, crystallization techniques or salt formations which are useful for the bulk scale up process with good yield and purity.
SUMMARY OF THE INVENTION
The present invention provides cost-effective, novel and an efficient process for the preparation of Vilanterol trifenatate with high yield and purity.
In one aspect, the present invention provides an improved process for the preparation of Vilanterol trifenatate of compound of formula-I

Which comprises;
a) condensation of compound of formula-II

with compound of formula-III

in presence of a base and solvent to obtain compound of formula-IV;

b) ring opening of compound of formula-IV in presence of a base and solvent to obtain compound of formula-IV(a) in in-situ manner

followed by salt formation with a succinic acid in a solvent to obtain compound of formula-V;

c) acetonide cleavage of compound of formula-V in presence of an acid and solvent to obtain Vilanterol free base;

d) salt formation of Vilanterol free base with triphenyl acetic acid in a solvent to obtain Vilanterol trifenatate of formula-I.
In another aspect, the present invention provides an improved process for the preparation of Vilanterol trifenatate of compound of formula-I

which comprises;
a) condensation of compound of formula-II

with compound of formula-III

in presence of potassium tert-butoxide and dimethyl formamide to obtain compound of formula-IV;

b) ring opening of compound of formula-IV in presence of sodium hydroxide and ethanol to obtain compound of formula-IV(a) in in-situ manner

followed by salt formation with a succinic acid in a solvent and anti-solvent system to obtain compound of formula-V;

c) acetonide cleavage of compound of formula-V in presence of hydrochloric acid and acetone to obtain Vilanterol free base;

d) salt formation of Vilanterol free base with triphenyl acetic acid in dichloromethane and methyl tert-butyl ether to obtain Vilanterol trifenatate of formula-I.
In another aspect, the present invention provides a novel succinate salt of Vilanterol intermediate of structural formula-V.

In another aspect, the present invention provides novel crystalline form of succinate salt of Vilanterol intermediate of structural formula-V characterized by its powder X-ray diffractogram having peaks at about 4.64, 9.29, 13.96, 14.36, 15.74, 17.13, 18.36, 19.26, 20.33, 20.80, 21.89, 22.73, 23.37, 24.42, 25.36, 26.84, 28.52, 31.31, 35.03 and 39.0 2? values. Further this polymorphic form is designated as form-N.

In yet another aspect, the present invention provides the process for the preparation of novel succinate salt of Vilanterol intermediate of structural formula-V.

Which comprises;
a) ring opening of compound of formula-IV

in presence of sodium hydroxide and ethanol to obtain in situ compound of formula-IV(a);

b) addition of succinic acid to compound of formula-IV(a) in a solvent;
c) isolation of succinate salt by addition of an anti-solvent.

BRIEF DESCRIPTION OF DRAWINGS
Figure-I: Illustrates PXRD of crystalline form-N of succinate salt of Vilanterol intermediate of formula-V.
Figure-II: Illustrates DSC of crystalline form-N of succinate salt of Vilanterol intermediate of formula-V.
DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides the novel process for the preparation of Vilanterol trifenatate of formula-I.

Scheme-I illustrates the process for the preparation of Vilanterol trifenatate of formula-I

Scheme-I
In step-1, the compound of formula-II is condensed with compound of formula-III in presence of a base and a solvent to get compound of formula-IV.
The base used in this reaction is selected from the group consisting of alkali metal hydroxides such as sodium hydroxide, potassium hydroxide; alkali metal carbonates such as sodium carbonate, potassium carbonate; alkali metal bicarbonates such as sodium bicarbonate, potassium bicarbonate; alkali metal hydroxides such as sodium methoxide, potassium methoxide and potassium tert-butoxide. Preferably using potassium tert-butoxide.
The solvent used in this reaction is selected from the group consisting of chloro solvents, alcohol solvents, hydrocarbon solvents, nitrile solvent, ether solvent, ester solvent or polar aprotic solvent like dimethyl formamide, dimethyl sulfoxide and its mixture thereof. Preferably using dimethyl formamide.
The reaction temperature may range from 5 to 35 °C and preferably at a temperature in the range from 25 to 30 °C. The duration of the reaction may range from 4-8 hours; preferably for a period of 5-6 hours.
In step-2, compound of formula-IV involved in the ring cleavage reaction in presence of a base to obtain compound of formula-IV(a) which is used in the process without isolation. Compound of formula-IV(a) involved in salt formation using dicarboxylic acid like succinic acid in a solvent.
The base used in this step is may be inorganic or organic base. Inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tert-butoxide and sodium methoxide. Organic base may be selected from the group consisting of triethyl amine, diisopropyl amine and diisopropyl ethyl amine; preferably using sodium hydroxide.
Solvent used in this reaction is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using ethanol.
Solvent used for the succinate salt formation is selected from alcoholic solvents, ether solvents, ester solvents, nitrile solvents, ketone solvents, chloro solvents and its mixture thereof. Preferably using alcoholic solvent and ether solvent mixture like isopropanol and methyl tert-butyl ether.
Isolation of succinate salt of Vilanterol intermediate of formula-V is carried out by various methods like crystallization or solvent-anti solvent techniques using single or multiple solvent system selected from alcoholic solvents, ether solvents, ester solvents, nitrile solvents, ketone solvents, chloro solvents and its mixture thereof. Preferably using mixture of isopropanol and methyl tert-butyl ether.
The reaction temperature may range from 50 to 80 °C and preferably at a temperature in the range from 55 to 75 °C. The duration of the reaction may range from 12-18 hours; preferably for a period of 14-16 hours.
In step-3, succinate salt of Vilanterol intermediate of formula-V is involved in neutralization process using a base followed by extraction using an organic solvent. The obtained compound is involved in acetonide ring cleavage in presence of an acid to obtain Vilanterol free base. Then it is converted to trifenatate salt by using triphenyl acetic acid in presence of a solvent.
Base used for neutralization may be inorganic or organic base. Inorganic base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tert-butoxide and sodium methoxide. Organic base may be selected from the group consisting of triethyl amine, diisopropyl amine and diisopropyl ethyl amine; preferably using sodium bicarbonate.
Solvent used in this reaction is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using dichloromethane.
Acid used for the acetonide cleavage reaction is selected from the group consisting of hydrochloric acid, hydrobromic acid, acetic acid, trifluoro acetic acid. Preferably using hydrochloric acid.
Solvent used for trifenatate salt formation is selected from the group consisting of alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof. Preferably using methyl tert-butyl ether.
The reaction temperature may range from 10 to 30°C and preferably at a temperature in the range from 25 to 30°C. The duration of the reaction may range from 2-5 hours; preferably for a period of 3-4 hours.
In another aspect, the present invention provides an improved process for the preparation of Vilanterol trifenatate of compound of formula-I

which comprises;
a) condensation of compound of formula-II

with compound of formula-III

in presence of potassium tert-butoxide and dimethyl formamide to obtain compound of formula-IV;

b) ring opening of compound of formula-IV in presence of sodium hydroxide and ethanol to obtain compound of formula-IV(a) in in situ manner

followed by salt formation with a succinic acid in a solvent and anti-solvent system to obtain compound of formula-V;

c) acetonide cleavage of compound of formula-V in presence of hydrochloric acid and acetone to obtain Vilanterol free base;

d) salt formation of Vilanterol free base with triphenyl acetic acid in dichloromethane and methyl tert-butyl ether to obtain Vilanterol trifenatate of formula-I.
solvent used in step-b) is selected from the group consisting of methanol, ethanol, propanol, isopropanol and its mixture.
Anti-solvent used in step-b) is selected from the group consisting of tetrahydrofuran, diethyl ether, dimethyl ether, methyl tert-butyl ether and its mixture.

The present invention provides novel succinate salt of Vilanterol intermediate of formula-V

The present invention provides novel crystalline form-N of Vilanterol trifenatate of formula-V which is characterized by its PXRD peaks at 4.64, 9.29, 13.96, 14.36, 15.74, 17.13, 18.36, 19.26, 20.33, 20.80, 21.89, 22.73, 23.37, 24.42, 25.36, 26.84, 28.52, 31.31, 35.03 and 39.0 2? values.
The PXRD pattern of crystalline form-N of Vilanterol intermediate of formula-V is depicted in figure-I. Further, it is characterized by its DSC thermogram. The DSC having endotherm at about 122°C. The DSC of crystalline form-N of Vilanterol intermediate of formula-V is depicted in figure-II.
The specific optical rotation of succinate salt of Vilanterol intermediate of formula-V is [a]D = -19.392 at C= 1.0004 %.

The present invention provides the process for the preparation of novel succinate salt of Vilanterol intermediate of formula-V

Which comprises;
d) ring opening of compound of formula-IV

in presence of sodium hydroxide and ethanol to obtain compound of formula-IV(a);

e) addition of succinic acid to compound of formula-IV(a) in a solvent;
f) isolation of succinate salt by addition of anti-solvent
wherein the solvent used in step-e) of the present invention is alcoholic solvents such as methanol, ethanol, propanol or isopropanol. Preferably using isopropanol.
The anti-solvent used in step-f) of the present invention is ether solvent such as tetrahydrofuran, diethyl ether, dimethyl ether or methyl tert-butyl ether. Preferably using methyl tert-butyl ether.
Isolation of succinate salt of Vilanterol intermediate of formula-V is carried out by using various methods like crystallization or solvent-anti solvent techniques.
Solvents used for the isolation of succinate salt of Vilanterol intermediate of formula-V is selected from alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ester solvent such as ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate, methyl acetate; nitrile solvent such as acetonitrile, propionitrile, butyronitrile, isobutyronitrile; ether solvent such as diethyl ether, tetrahydrofuran, methyl tert-butyl ether, ethyl-tert-butyl ether; ketone solvent such as acetone, ethyl methyl ketone, methyl isobutyl ketone, diethyl ketone; chloro solvents such as dichloromethane, chloroform, ethylene chloride, carbon tetrachloride and its mixture thereof
Process for the preparation of Vilanterol trifenatate using succinate salt of Vilanterol intermediate of formula-V overcomes the problems associated with the prior art procedures such as prolonged reaction time, stringent reaction conditions, low yields and tedious purifications.
Compounds of formulae-II and III used as starting materials in the present invention is prepared by well-known processes reported in the prior art literature.

EXPERIMENTAL PORTION:
The details of the invention are given in the examples provided below, which are given to illustrate the invention only and therefore should not be construed to limit the scope of the invention.
Example-1: Process for the preparation of (R)-3-(6-(2-((2,6-dichloro benzyl) oxy) ethoxy) hexyl)-5-(2,2-dimethyl-4H-benzo[d][1,3] dioxin-6-yl)oxazolidin-2-one:
Potassium tertiary butoxide (22.53 grams) was added to a mixture of (R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-1,3-oxazolidin-2-one (50 grams) and dimethyl formamide (350 mL) in a three neck round bottom flask at 0-5°C and stirred for 60minutes at the same temperature. 2-((2-((6-bromohexyl) oxy) ethoxy) methyl)-1,3-dichlorobenzene (84.76 grams) was suspended to the resulting reaction mixture at 0-5°C and stirred for 15 minutes at the same temperature. Raised the reaction temperature to 25-30°C and stirred for 5-6 hours at the same temperature. The reaction mixture was slowly added to a pre-cooled mixture of ethyl acetate and water at 5-10°C. Stirred the reaction mixture for 15 minutes at 25-30°C. both the aqueous and organic layers were separated and aqueous layer was extracted with ethyl acetate. Combine the organic layer and washed with aqueous sodium chloride solution. Volatiles were removed from the organic layer under reduced pressure to get the title compound.
Yield: 110 grams;
1H NMR (300 MHz, CDCl3) d values: 7.32-7.17(d, 2H), 7.15-7.10 (d, 2H),7.0(s, 1H), 6.85-6.82 (d, 1H), 6.74-6.71 (d, 1H), 5.342-5.36 (t, 2H), 4.84 (s, 2H), 4.83 (s, 2H), 372-3.67 (d, 2H), 3.62-3.59 (d, 2H), 3.48-3.23 (m, 5H), 2.91-2.71 (m, 4H), 1.60-1.58 (m, 4H), 1.54 (s, 6H), 1.37-1.35 (s, 4H).
Example-2: Process for the preparation of (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 succinate:
In a three neck round bottom flask, sodium hydroxide (43.84 grams) was added to a mixture of compound obtained in example-1 (110 grams) and ethanol (1100 mL) at 25-30 °C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 70-75 °C and stirred for 14-16 hours at the same temperature. After consumption of starting material, cooled the reaction mixture to 25-30 °C and volatiles were removed from the reaction mixture under reduced pressure. Toluene and water were added to the obtained reaction mass at 25-30 °C and stirred for 15 minutes at the same temperature. Both the aqueous and organic layers were separated and aqueous layer was extracted with toluene. combine the organic layer and washed with water followed by aqueous sodium chloride solution. Volatiles were removed from the organic layer under reduced pressure.
Isopropanol (220 mL) was added to the obtained crude compound at 25-30 °C and stirred for 15 minutes at the same temperature. Heated the reaction mixture to 50-60 °C. Succinic acid was added to the resulting reaction mixture at 50-55 °C and stirred for 30 minutes at the same temperature. Methyl tert-butyl ether (550 mL) was slowly added to the reaction mixture at 50-55 °C. Stirred the reaction mixture for 30 minutes at 50-55 °C. Cooled the reaction mixture to 25-30 °C and stirred for 2 hours at the same temperature. Filtered the precipitated solid and washed with methyl tert-butyl ether to get the title compound.
Yield: 86 grams; Purity by HPLC: 99.21%; DSC: 122°C
1HNMR (300MHz, CDCl3) d values: 7.31-7.26 (d, 2H), 7.19-7.10 (m, 2H), 6.98-6.90 (d, 3H), 6.76-6.73 (d, 1H), 4.91-4.90 (m, 1H), 4.88-4.87 (d, 2H), 4.81-4.78 (s, 2H),3.70-3.67 (m, 2H), 3.61-3.57(m, 2H), 3.45-3.41 (d, 2H), 2.97-2.79 (m, 4H), 2.54 (s,2H), 1.62-1.54 (s, 4H), 1.51(s, 6H)1.32-1.30 (s, 4H).
Example-3: Process for the preparation of 4-((1R)-2-((6-(2-((2,6-Dichlorophenyl) methoxy) ethoxy) hexyl) amino)- l-hydroxyethyl)-2-(hydroxymethyl)phenol triphenylacetate:
Succinate salt (60 grams) obtained in example-2 was dissolved in water (600 mL) at 25-30 °C. Dichloromethane (1080 mL) was added to the reaction mixture at 25-30 °C and stirred for 15 minutes at the same temperature. Aqueous sodium bicarbonate solution was added to the resulting reaction mixture at 25-30 °C and stirred for 30 minutes at the same temperature. Both the aqueous and organic layers were seperated and organic layer was washed with water. Volatiles were removed from the organic layer under reduced pressure. Codistilled the obtained crude compound with acetone.
Acetone (300 mL) was added to the obtained crude compound at 25-30 °C. Cooled the reaction mixture to 0-5 °C and 0.5 N hydrochloric acid solution was added to the resulting reaction mixture and stirred for 2-3 hours at 15-20 °C. Dichlroromethane was added to the reaction mixture at 15-20 °C and stirred for 15 minutes at the same temperature. Both the aqueous and organic layers were seperated and aqueous layer was extracted with dichloromethane. Combine the organic layer and washed with aqueous sodium bicarbonate solution. Both the aqueous and organic layers were seperated and volatiles were partially removed from the organic layer under reduced pressure.
Methyl tert-butyl ether (840 mL) was added to the resulting reaction mixture at 25-30 °C and stirred for 15 minutes at the same temperature. Triphenyl acetic acid (26.8 grams) was added to the reaction mixture at 25-30 °C and stirred for 2-3 hours at the same temperature. Filtered the precipitated solid and washed with methyl tert-butyl ether to get the title compound.
Yield: 60 grams; Purity by HPLC: 99.8%
1HNMR (300MHz, DMSO-d6) d values: 7.47 (d, 1H), 7.40 (s, 1H), 7.35 (d, 1H), 7.31 (s, 1H), 7.23-7.11 (m, 15H), 7.01-6.98 (d, 1H), 6.74-6.71 (d, 1H), 4.78-4.74 (d, 1H), 4.69 (s, 2H), 4.47 (s, 2H), 362-3.59(d, 2H), 3.51-3.48 (d, 2H), 3.37-3.33 (t, 2H), 2.91-2.71 (m, 4H), 1.50-1.42 (m, 4H), 1.24(s, 4H).
,CLAIMS:1. An improved process for the preparation of Vilanterol trifenatate of formula-I

which comprises;
a) condensation of compound of formula-II

with compound of formula-III

in presence of a base and solvent to obtain compound of formula-IV;

b) ring opening of compound of formula-IV in presence of a base and solvent to obtain compound of formula-IV(a) in in-situ manner

followed by salt formation with succinic acid in a solvent to obtain compound of formula-V;

c) acetonide cleavage of compound of formula-V in presence of an acid and solvent to obtain Vilanterol free base;

d) salt formation of Vilanterol free base with triphenyl acetic acid in a solvent to obtain Vilanterol trifenatate of formula-I.

2. The process as claimed in step-a) and step-b) of claim 1, where in the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium methoxide, potassium methoxide or potassium tert-butoxide.

3. The process as claimed in claim 1, where in the solvent is selected from the group consisting of chloro solvents, alcohol solvents, hydrocarbon solvents, nitrile solvents, ether solvents, ester solvents or polar aprotic solvent like dimethyl formamide and its mixture.

4. The process as claimed in step-c) of claim 1, wherein the acid is hydrochloric acid.

5. An improved process for the preparation of Vilanterol trifenatate of compound of formula-I

which comprises;
a) condensation of compound of formula-II

with compound of formula-III

in presence of potassium tert-butoxide and dimethyl formamide to obtain compound of formula-IV;

b) ring opening of compound of formula-IV in presence of sodium hydroxide and ethanol to obtain compound of formula-IV(a) in in situ manner.

followed by salt formation with a succinic acid in a solvent and anti-solvent system to obtain compound of formula-V;

c) acetonide cleavage of compound of formula-V in presence of hydrochloric acid and acetone to obtain Vilanterol free base;

d) salt formation of Vilanterol free base with triphenyl acetic acid in dichloromethane and methyl tert-butyl ether to obtain Vilanterol trifenatate of formula-I.

6. Novel succinate salt of Vilanterol intermediate of formula-V.

7. Novel crystalline form-N of succinate salt of Vilanterol intermediate of formula-V characterized by its powder X-ray diffractogram having peaks at about 4.64, 9.29, 13.96, 14.36, 15.74, 17.13, 18.36, 19.26, 20.33, 20.80, 21.89, 22.73, 23.37, 24.42, 25.36, 26.84, 28.52, 31.31, 35.03 and 39.0 2? values.

8. Process for the preparation of novel succinate salt of Vilanterol intermediate of formula-V.

which comprises;
a) ring opening of compound of formula-IV

in presence of sodium hydroxide and ethanol to obtain compound of formula-IV(a);

b) addition of succinic acid to compound of formula-IV(a) in a solvent;
c) isolation of succinate salt by addition of anti-solvent.

9. The process as claimed in claim 8, where in the solvent used in step-b) is selected from the group consisting of methanol, ethanol, propanol and isopropanol; the anti-solvent used in step-c) is selected from the group consisting of diethyl ether, tetrahydrofuran, dimethyl ether and methyl tert-butyl ether.

10. Use of novel succinate salt of Vilanterol intermediate of formula-V in the preparation of Vilanterol trifenatate of formula-I.