AN IMPROVED PROCESS FOR THE PREPARATION OF SALMETEROL AND ITS SALTS
INTRODUCTION
The present application relates to an improved process for the preparation of salmeterol and its pharmaceuticaliy acceptable salts and intermediates thereof.
BACKGROUND
Salmeterol xinafoate is chemically known as 4-hydroxy-a1-[[[6-(4-phenylbutoxy) hexyl] amino] methyl]-1,3-benzenedimethanol,1-hydroxy-2-naphthalenecarboxylate and has the following structural Formula I.

Formula I
Salmeterol is a long-acting highly selective Pa-adrenergic agonist and is used in the treatment of asthma and chronic bronchitis. Pharmaceutical products containing salmeterol xinafoate as the active ingredient are commercially available in the market under the brand name SEREVENT™ as a powder and an aerosol for inhalation.
U.S. Patent No. 4,992,474 discloses salmeterol, its physiologically acceptable salts and solvates, pharmaceutical compositions comprising salmeterol or its physiologically acceptable salts and solvates and their use in the treatment of asthma or chronic bronchitis.
It also discloses a process for the synthesis of salmeterol xinafoate in which the process comprises reacting [4-((6-Bromohexyl)oxy)-butyl]-benzene compound of Formula II with a^-(aminomethyl)-4-hydroxy-1,3-benzenedimethanol compound of Formula III using potassium iodide and triethylamine in dimethylformamide (DMF) to give salmeterol free base, which is then reacted with 1-hydroxy-2-naphthoic acid in the

presence of isopropanol to give salmeterol xinafoate. The process is depicted by scheme 1.

The aforesaid patent also discloses a process for the preparation of [4-((6-Bronnohexyl) oxy)-butyl]-benzene compound of Formula 1! by the condensation of 4-phenyl-1-butanol compound of Formula VI with 1,6-dibromohexane compound of Formula VII in the presence of sodium hydride, which is further purified by column chromatography and high vacuum distillation.
The foregoing processes suffer from serious disadvantages such as low yields of salmeterol freebase use of hazardous or expensive reagents and solvents, usage of column chromatography for purification, rendering the processes unsuitable for industrial scale manufacturing.

Consequently, it would be a significant contribution to the art to provide an improved process for the preparation of salmeterol xinafoate and intermediates thereof, which would be cost effective, and environment friendly
SUMMARY
In an embodiment, there is provided a process for the preparation of salmeterol and its salts preferably, salmeterol xinafoate, which is substantially free of process related impurities.
In another embodiment, there is provided a improved process for the preparation of salmeterol xinafoate of Formula I, which includes the steps of:
a) condensing [4-((6-Bromohexyl)oxy)-butyl]-benzene of Formula II with a^-(aminomethyl)-4-hydroxy-1,3-benzenedimethanol of Formula III in the presence of dimethyl sulfoxide to give salmeterol free base of Formula IV;

Formula II

Formula III

Formula IV b) reacting salmeterol freebase of Formula IV with 1-hydroxy-2-naphthoic acid of Formula V in the presence of a suitable solvent to give crude salmeterol xinafoate
OH
.COOH
Formula V

c) purifying the crude salmeterol xinafoate comprising recrystallizing from a suitable solvent to give pure salmeterol xinafoate of Formula I.
Xr^"
COOH
OH

Formula I
In another embodiment, there is provided a process for the preparation of [4-((6-Bromohexyl) oxy)-butyl]-benzene of Formula VI, a key intermediate in the preparation of salmeterol xinafoate, which includes the steps of:
a) condensing 4-phenyl-1-butanol of Formula VI with 1,6-dibromohexane of
Formula VII in the presence of sodium hydride as base and toluene to give [4-
((6-Bromohexyl) oxy)-butyl]-benzene of Formula II;

Formula VI Formula II
b) purifying [4-((6-Bromohexyl) oxy)-butyl]-benzene of Formula II by distillation under vacuum.
In another embodiment, there is provided a process for the preparation of a^-(aminomethyl)-4-hydroxy-1, 3-benzenedimethanol of Formula III, a key intermediate in the preparation of salmeterol xinafoate, which Includes the steps of:
a) acetylating 2-hydroxy-benzoic acid methyl ester of Formula VIII with acetyl
chloride in the presence of aluminum chloride and dichloromethane to give 5-
acetyl-2-hydroxy-benzoic acid methyl ester of Formula IX;



HaC

■ H

.CH,

Formula VII Formula IX
b) brominating 5-acetyl-2-hydroxy-benzoic acid methyl ester of Formula IX with
bromine in presence of 1,4-dioxane to give 5-(2-bromoacetyl)-2-hydroxy benzoic
acid methyl ester of Formula X;

Br
o 0
H2G
Formula X c) reacting the 5-(2-bromoacetyl)-2-hydroxy benzoic acid methyl ester of Formula X with di-benzyl amine in a presence of acetone to give 5-dibenzylaminoacetyl-2-hydroxy benzoic acid methyl ester of Formula XI;

0CH3

Formula XI d) reducing the 5-dibenzylaminoacetyl-2-hydroxy benzoic acid methyl ester of Formula XI with NaBH4 in the presence of suitable solvent to give (4-(2-dibenzylamino)-1-hydroxyethyl)-2-hydroxymethyl phenol of Formula XII;


Formula XII e) debenzylating the (4-(2-dibenzylamino)-1-hydroxyethyl)-2-hydroxymethyl phenol of Formula XII with palladium on carbon in the presence methanol to give a^-(aminomethyl)-4-hydroxy-1,3-benzene dimethanol of Formula III.
OH H2N.

Formula III
Brief description of the Drawings
Fig. 1 is an XRPD pattern of the product obtained in example 9 measured using copper Ka radiation (1.541 A wave length).
DETAILED DESCRIPTION
In an embodiment, there is provided a process for the preparation salmeterol and its salts preferably, salmeterol xinafoate, which is substantially free of process related impurities.
In another embodiment, there is provided an improved process for the preparation of salmeterol xinafoate of formula I, which includes the steps of:
a) condensing [4-((6-Bromohexyl)oxy)-butyl]-benzene of Formula II with a^-(amino methyl)-4-hydroxy-1,3-benzenedimethanol of Formula III in the presence of dimethyl sulfoxide to give salmeterol free base of Formula IV


^^^

Formula II

.OH OH
Formula IV The amount of solvent that was used to dissolve the a^-(amino methyl)-4-hydroxy-1,3-benzenedimethanol reaction can range from about 1 times to 10 times preferable 4 times to the weight of the a^-(amino methyl)-4-hydroxy-1,3-benzenedimethanol. Suitable temperatures for conducting the reaction can range from about 20 to 150° C, or about 50 to 100° C, or about 60 to 90° C.
Salmeterol thus obtained in the reaction may or may not be isolated. The same can be converted in-situ to its pharmaceutically acceptable salt by reaction with a suitable acid in suitable solvent.
Step b) comprises reacting salmeterol freebase of Formula IV with 1-hydroxy-2-naphthoic acid of Formula V in the presence of a suitable solvent to give crude salmeterol xinafoate


COOH

Formula V
Suitable solvents that can be used in the reaction include, but are not limited to, C1-C5 alcohols such as methanol, ethanol, isopropanol and the like; nitrite solvents uch as acetonitrile, propionitrile and the like;
Alternatively other physiologically acceptable salts of salmeterol may be prepared by choosing suitable acid reagents. Suitable acids that can be used in the reaction include, but are not limited to: hydrochloric, hydrobromic and the like.
Step c) includes purification of crude salmeterol xinafoate by recrystallizing in a suitable solvent to give pure salmeterol xinafoate of Formula I.


COOH

Formula I
Purification of salmeterol xinafoate may include dissolving any form of salmeterol xinafoate in a suitable solvent, or obtaining an existing solution from a previous processing step, such as a final step in the synthesis of the compound.
Solvents that can be used for the dissolving salmeterol xinafoate include but are not limited to any solvent or mixture of solvents in which required components are soluble. Examples include hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile and the like; ketones such as acetone, methyl ethyl ketone, 2-pentanone and the like; C1-C5 alcohols such as methanol, ethanol.isopropanol and the like
The amount of solvent that was used to dissolve the crude salmeterol xinafoate can range from about 1 times to 15 times to the weight of crude salmeterol xinafoate. The temperature for dissolution can range from about 25 °C to about 100 °C or reflux temperature of the solvents used.
The method by which the solid material is recovered from the final mixture, with or without cooling below the operating temperature, can be any of techniques such as filtration by gravity, or by suction, centrifugation, and the like. The crystals so isolated will carry a small proportion of occluded mother liquor containing a higher percentage of impurities. If desired the crystals can be washed on the filter with a solvent to wash out the mother liquor.
The isolated wet solid is optionally dried by using techniques, such as for example fluid bed drying (FBD), aerial drying, oven drying or other techniques known in the art. The drying can be conducted at temperatures of about 20-100° C or about 60-70° C with or without application of a vacuum. Drying can be carried out under inert conditions.

The purification procedure stated above can be repeated for as many numbers of times as required to increase the product purity.
The compound of Formula I purified according to the present process is substantially free from the process related impurities. The pure salmeterol xinafoate Formula I obtained by the above process has purity equal or more than 99% by High Performance Liquid Chromatography (HPLC).
In another embodiment, there is provided a process for the preparation of [4-((6-Bromohexyl) oxy)-butyl]-benzene of Formula VI, a key Intermediate in the preparation of salmeterol xinafoate, which includes the steps of:
a) condensing 4-phenyl-1-butanol of Formula VI with 1,6-dibromohexane of
Formula VII in the presence of sodium hydride as base and toluene to give [4-
((6-Bromohexyl) oxy)-butyl]-benzene of Formula II;

Formula VI Formula II
Suitably addition of 4-phenyl-1-butanol and 1,6-dibromohexane is carried out slowly to control the exothermicity of the reaction and maintain the temperature of the reaction medium below about 10 to below about 30°C. Increases in the temperature will cause decreases in the purity of the product.
Suitable temperatures for conducting the reaction range from about SOX to about 90°C. The suitable time for the completion of the reaction can range from about 30 minutes to about 20 hours, or longer, depending on the chosen conditions.
b) purifying of the [4-((6-Bromohexyl) oxy)-butyl]-benzene of Formula II by
distillation under vacuum.
The product is purified by distillation at about 50 to 200° C, or about 90 to 180° C, and under reduced pressure, such as about 0.1-10 mmHg.
The purification procedure stated above can be repeated for as many numbers of times as required to increase the product purity.

The compound of Formula II purified according to the present process is substantially free from the process related impurities. The pure [4-((6-Bromohexyl) oxy)-butyl]-benzene Formula II obtained by the above process has purity equal or more than 99% by High Performance Liquid Chromatography (HPLC).
In another embodiment, there is provided a process for the preparation of a^-(aminomethyl)-4-hydroxy-1,3-benzenedimethanol compound of Formula III, a key intermediate in the preparation of salmeterol xinafoate, which includes the steps of:
a) acetylating 2-hydroxy-benzoic acid methyl ester of Formula VIII with acetyl
chloride in the presence of aluminum chloride and dicloromethane to give 5-
acetyl-2-hydroxy-benzoic acid methyl ester of Formula IX;
O GO
Formula VII Formula IX
Suitable temperature for addition of 2-hydroxy-benzoic acid methyl ester into the reaction mixture containing acetyl chloride and aluminum chloride is carried out slowly to control the exothermicity. Suitable temperature for addition 2-hydroxy-benzoic acid benzyl can range from about 0°C to about 15°C. Increase in temperature will decrease in the purity of the product.
The obtained acetylated product can be recovered from the reaction medium by usual workup procedures already know in the art.
b) brominating 5-acetyl-2-hydroxy-benzoic acid methyl ester of Formula IX with
bromine in presence of 1,4-dioxane to give 5-(2-bromoacetyl)-2-hydroxy benzoic
acid methyl ester of Formula X;
S%C/V.^^..^^.^C^3
o o
"OH
Formula X

Suitably addition of liquid bromine is carried out slowly to control the exothermicity of the reaction and maintain the temperature of the reaction medium below about -20 to below about 10X. Increases in the temperature will cause decreases in the purity of the product Suitable temperatures for conducting the reaction range from about -10X to about 20X, or for about 5X to about 10X.
Optionally the obtained brominated product can be purified by recrystallization in suitable solvent. Suitable solvent that can be used for recrystallization limited to alcoholic solvent such as methanol, ethanol, isopropanol and the like or mixtures thereof.
c) reacting 5-(2-bromoacetyl)-2-hydroxy benzoic acid methyl ester of Formula X
with a di-benzyl amine in presence of acetone to give 5-dibenzylaminoacetyl-2-
hydroxy benzoic acid methyl ester of Formula XI;

Formula XI
Suitable temperature for addition of dibenzylamine in step (c) may range from about 10X to about SOX or from about 25X to about SOX. If reaction is conducted at higher temperatures and/or has longer duration, formation of side products and process related impurities might increase.
The compound of Formula XI can be optionally purified either be in the form of a free base or an acid addition salt. The term "acid addition salt" as used herein means salt between the compound of the formula XI and an acid, which may be a non-toxic acid including inorganic acids such as hydrochloric acid, and hydrobromic acid and the like; and organic acids such as acetic acid, tartaric acid and the like.
The acid addition salt may be also recrystallized by using an organic solvent. Suitable organic solvents include but are not limited to C2-C5 ketones, for example acetone, ethyl methyl ketone, butanone and the like; C1-C5 alcohols for example

methanol, ethanoi, n-propanol, isopropanol, butanol and the like; ethers for example tetrahydrofuran, 1,4-dioxane and the like; esters for example ethyl acetate, n-propyl acetate, butyl acetate and the like; and mixtures thereof in various proportions without limitation. In a preferred embodiment, the suitable solvent for the crystallization of compound of Formula XI or its salts such as hydrochloride is acetone.
d) reducing the 5-dibenzylaminoacetyi-2-hydroxy benzoic acid methyl ester of Formula XI with NaBH4 in the presence suitable of a suitable solvent to give (4-(2-dlbenzylamino)-1-hydroxyethyl)-2-hydroxymethyl phenol of Formula XI.

Formula XII
Solvents that can be used for the process of step d) include but are not limited to alcohols such as methanol, ethanoi, propanol, tertiary butanol and the like or mixtures thereof.
Suitable temperatures for conducting the reaction range from about ICC to about 90°C.The suitable time for the completion of the reaction can range from about 30 minutes to about 20 hours, or longer, depending on the chosen conditions.
The obtained product may be optionally isolated as solid or the same may be converted into an acid addition salt to achieve higher purity. In one embodiment the product is reacted with hydrochloric acid to form a hydrochloride salt.
e) debenzylating the (4-(2-dibenzylamino)-1-hydroxyethyl)-2-hydroxymethyl phenol
of Formula XII with palladium on carbon in the presence methanol to give a^-
(aminomethyl)-4-hydroxy-1,3-benzene dimethanol of Formula III.
OH H2N.
Formula

Suitable temperatures for conducting the debenzylation reaction range from about 10°C to about SOX and the suitable pressure can range from about 1 to about 5 kg/cm^. The suitable time for the completion of the reaction can range from about 30 minutes to about 20 hours, or longer, depending on the chosen conditions.
The obtained product may be optionally isolated as solid or the same may be converted into an acid addition salt to achieve higher purity.
The process of the present invention is simple, improved, eco-friendly, cost-effective, commercially viable, robust and reproducible on an industrial scale.
Having thus described the invention with reference to particular preferred embodiments and illustrative example, those in the art may appreciate modification to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification. The examples are set to aid in understanding the invention but are not intended to, and should not be construed to; limit its scope in any way. The examples do not include detailed descriptions of conventional methods. Such methods are well known to those of ordinary skill in the art and are described in numerous publications. All references mentioned herein are incorporated in their entirety
EXAMPLE S EXAMPLE 1: Preparation of 5-acetyl-2-hydroxy-benzoic acid methyl ester (Formula IX)
2.18 g of anhydrous aluminum chloride was charged into a round-bottomed flask containing 9 ml of chloroform and stirred for about 10 minutes under nitrogen atmosphere. The reaction mass was cooled to about 0° C and 1.23 g of acetyl chloride was added slowly to the reaction mass for about 1 hour at about 3° C. 1.0 g of 2-hydroxy-benzoic acid methyl ester was charged to the reaction mass slowly for about 30 minutes. Reaction mass was allowed to attain 25°C and stirred for about 15 minutes. Reaction completion was confirmed by thin layer chromatography and reaction mass was cooled to about 0° C. Reaction mass was quenched by adding a mixture of 36% aqueous hydrochloric acid (3.5 ml) and water (350 ml) at about 2-3° C and then the temperature was raised to about 23° C. The Aqueous layer was separated and extracted with chloroform (50 ml). Organic layers were combined and washed with 5%

aqueous sodium bicarbonate solution (10 ml) and then with water (2X5 ml). The solvent was distilled off completely under vacuum at about 45° C and the residue obtained was cooled to about 28° C. Petroleum ether (50 ml) was charged to the residue and stirred for about 1 hour. The solid was filtered and washed with 5 ml of petroleum ether. The solid was dried at about 48-50° C for about 4 hours 30 minutes to afford 1.18 g of the title compound as a solid.
EXAMPLE 2: Preparation of 5-(2-bromoacetyl)-2-hydroxy benzoic acid methyl ester (Formula X)
59 g of 5-acetyl-2-hydroxy-benzoic acid methyl ester was charged into a round-
bottomed flask containing 118 ml of 1,4-dioxane and stirred for about 10 minutes. The
reaction mass was cooled to about 10° C and 15.6 ml of liquid bromine was added
slowly to the reaction mass for about 1 hour at about 10° C. Reaction mass was stirred
for about 11 hours and reaction completion was confirmed by thin layer
chromatography. The resultant reaction solution was distilled off completely under
vacuum about 60°C. The residue was dissolved in per ether (600 ml) and stirred for
about 40 minutes. The solid was filtered and washed with petroleum ether (100 ml) and
dried at 60°C under vacuum to afford 74 g of title compound.
The obtained compound (60 g) was charged into a round bottom flask-containing methanol (600 ml) and heated to reflux and stirred for about 45 minutes. The resultant reaction mass was cooled to about 0°C and stirred for about 60 minutes. The separated solid was filtered and washed with methanol 120 ml and suck dried for about 30 minutes to afford the 52 g of the title compound.
EXAMPLE 3: Preparation of 5-dibenzylaminoacetyl-2-hydroxy benzoic acid methyl ester (Formula XI)
60 g of 5-(2-bromoacetyl)-2-hydroxy benzoic acid methyl ester was charged into
a round-bottomed flask containing 420 ml of acetone and stirred for about 10 minutes.
86.5 g of dibenzylamine was added slowly to the reaction mass for about 1 hour at
about 26° C. Reaction mass was stirred for about 11 hours and reaction completion was
confirmed by thin layer chromatography. The solid was filtered and washed with 60 ml

of acetone. Filtrate mis was charged into another flask and pH was adjusted to about 5.2 with 11.2 ml of 36% aqueous hydrochloric acid. The reaction mass was stirred for about 15 minutes, filtered the solid and washed with acetone (60 ml). Filtrate mis was charged into another flask and pH was adjusted to about 1.2 with 6 ml of 36% aqueous hydrochloric acid. The reaction mass was stirred for about 10 minutes, the solid was filtered and washed with acetone (60 ml). The solid was dried at about 50° C for about 4 hours 30 minutes to afford 78.2 g of hydrochloride salt of the title compound as a solid.
150 g of 5-dibenzylaminoacetyl-2-hydroxy benzoic acid methyl ester hydrochloride obtained above was charged into a round-bottomed flask containing 1500ml of water and stirred for about 5 minutes. 300 ml of ethyl acetate was charged into the reaction mass and pH was adjusted to about 9.6 with 20% aqueous sodium carbonate solution (200 ml). The aqueous layer was separated and extracted with ethyl acetate (150 ml). Organic layers were combined and washed with water (2 X 150 ml). The solvent was distilled off completely under vacuum to afford 145 g of the title compound as a residue.
EXAMPLE 4: Preparation of (4-(2-dibenzylamino)-1-hydroxyethyl)-2-hydroxymethyl phenol (Formula XII)
6.5 g of sodium borohydride was charged into a round-bottomed flask containing 85 ml of tertiary butanol and stirred for about 40 minutes at about 30° C. A mixture of 5-dibenzylaminoacetyl-2-hydroxy benzoic acid methyl ester (18.5 g) and tertiary butanol (55 ml) was added to the reaction mass for about 1 hour 30 minutes at about 30° C. The reaction mass was heated to about 80° C and 50 ml of methanol was added slowly to the reaction mass for about 75 minutes at 80°C. Reaction mass was maintained at reflux for about 12 hours and, reaction completion was confirmed by thin layer chromatography. 15 ml of methanol was added slowly to the reaction mass for about 30 minutes at 75°C and stirred for about 10 minutes. Reaction mass was quenched by adding 40 ml of water at 80°C and stirred for about 10 minutes. The solvent was distilled off completely under vacuum at about 75° C and then cooled to 30° C. A mixture of water (250 ml) and ethyl acetate (100 ml) was charged to the residue and stirred for about 10 minutes. Reaction mass pH was adjusted to 2.5 with 50 ml of IPA HCI and

stirred for 10 minutes. Aqueous layer was separated and extracted with ethyl acetate (2X100 ml). Organic layers were combined and 100 ml of water was charged to the organic layer. The reaction mass pH was adjusted to about 9.4 using 10 % aqueous sodium carbonate solution (100 ml). The aqueous layer was separated and extracted with ethyl acetate (200 ml). All the organic layers were combined and washed with 10% aqueous sodium carbonate solution (3X100 ml). Solvent was distilled off completely under vacuum at about 50-55° C and then cooled to about 25° C. A mixture of petroleum ether (30 ml) and acetone (5 ml) was charged to the residue and stirred for about 30 minutes. The reaction mass was cooled to about 0° C and stirred for about 1 hour 15 minutes. Solid was filtered and washed with 40 ml of petroleum ether. The solid was dried at 50° C for about 8 hours to afford 11.2 g of the title compound as crystalline solid.
EXAMPLE 5: Preparation of a^-(aminomethyl)-4-hydroxy-1,3-benzene dimethanol (Formula III)
4.6 g of 5% palladium charcoal was charged into an autoclave vessel containing 16 ml of water at about 25° C. A mixture of (4-(2-dibenzylamino)-1-hydroxyethyl)-2-hydroxymethyl phenol (10 g), methanol (130 ml) and 0.8 ml of isopropanol hydrogen chloride was charged to the reaction mass. 2-kg/cm^ hydrogen gas pressure was built up in the vessel and maintained for about 8 hours. Reaction completion was confirmed by thin layer chromatography and the catalyst was removed by filtration through a Hyflow bed and the bed was washed with methanol (50 ml). Solvent was removed from the filtrate and distilled off completely under vaccum at about 50° C. 10 ml of methanol was added to the solid and stirred for about 20 minutes. The reaction mass was cooled to about 5° C and stirred for about 30 minutes. The solid was filtered and washed with methanol (2 ml). The solid was dried at 60° C for about 3 hours to afford 3.5 g of the title compound.

EXAMPLE 6: PREPARATION OF [4-((6-BROMOHEXYL)OXY)-BUTYL]-BENZENE (FORMULA II)
15 g of sodium hydride (60% dispersion in oil) was added lot wise into a round-bottomed flask containing 200 ml of toluene under nitrogen atmosphere. 65 g of 1,6 dibromohexane was added to the reaction mass for about 80 minutes. 20 g of 4-phenyl-1-butanol was added to the reaction mass for about 1 hour and heated the contents to 85° C. The reaction mass was maintained for about 18 hours at about 85° C. The contents were then cooled to about 0°C and 40 ml of methanol was added to the reaction mass slowly. 40 ml of water was added to the reaction mass and stirred for about 10 minutes. The aqueous layer was separated and extracted with toluene (2X200 ml). Total organic layers were combined and washed with water (2X50 ml). The solvent was distilled off completely under vacuum (about 500 mmHg) at about 80° C to get 70.2 g of the residue containing the title compound.
The residue was charged into a round-bottomed flask and heated to 160° C under vacuum of about 0.1-0.2 mmHg. First fraction containing unreacted starting materials and impurities was removed for about 3 hours at a vapor temperature of about 100-190° 0. After words the product was obtained at a vapor temperature of about 190-197° C as a colorless liquid to afford 32 g of the title compound. This compound was further purified by distilling under high vacuum of about 0.1-0.2 mmHg at a vapor temperature of about 160-192° 0 to get 17.2 g of pure [4-((6-bromohexyl)oxy)-butyl]-benzene.
EXAMPLE 7: PREPARATION OF SALMETEROL (FORMULA IV)
3 g of a^-(aminomethyl)-4-hydroxy-1, 3-benzenedimethanol was charged into a round bottom flask containing 12 ml of dimethylsulfoxide under stirring. The contents were heated to about 75° C to get clear solution and stirred for about 25 minutes at 75° C. 5.2 g of [4-((6-Bromohexyl)oxy)-butyl]-benzene was added slowly to the reaction mass for about 55 minutes. The reaction mass was stirred for about 3 hours 20 minutes and reaction completion was confirmed by thin layer chromatography. Reaction mass was then cooled to about 30° C and 36 ml of water was added slowly for about 10

minutes. 36 ml of ethyl acetate was charged to the reaction mass and pH was adjusted to 8.47 with 1 ml of triethyl amine. Aqueous layer was separated and extracted with ethyl acetate (2X60 ml). Combined organic layer was washed with water (2X18 ml) dried over sodium sulfate. Final organic layer was concentrated at about 72° C to get 4.8 g of the title compound as a residue.
EXAMPLE 8: PREPARATION OF SALMETEROL XINAFOATE
20 g of salmeterol freebase was charged into a round bottom flask containing 80 ml of acetonitrile. The contents were heated to about 74° C and 11 g of 1-hydroxy-2-naphthoic acid was charged in to the reaction mass at 74° C. The reaction mass was stirred for about 15 minutes at about 74° C to get clear solution. It was then cooled slowly to about 28° C and stirred for about 1 hour. The separated solid was filtered and washed with 10 ml of acetonitrile. The solid was suck dried for about 30 minutes to afford 14.5 g of the title compound as solid. The wet solid was taken up for purification.
EXAMPLE 9; PURIFICATION OF SALMETEROL XINAFOATE
14.5 g of salmetrol xinafoate was charged into a round bottom flask containing a mixture of toluene (7.2 ml) and acetonitrile (29 ml) and stirred for 15 minutes. Reaction mass was heated to about 78° C to get clear solution. About 50 % of the solvent was distilled off at 60-75° C and then cooled to about 2° C. The separated solid was filtered and washed with 7.2 ml of acetonitrile. The wet solid thus obtained was charged into a round bottom flask containing a mixture of isopropanol (8.2 ml) and acetone (16.5 ml) and stirred for 15 minutes. Reaction mass was heated to about 70° C and stirred for 40 minutes to get a clear solution. 50% of the solvent was distilled off at 70° C and then cooled to about 0° C. The reaction mass was stirred for about 50 minutes. The solid separated was filtered and washed with 5.5 ml of acetone to get 6.5 g of a wet solid.
4.4 g of the wet solid obtained above was charged into a round bottom flask containing a mixture of isopropanol (4.4 ml) and acetone (8.8 ml) and stirred for 15 minutes. Reaction mass was heated to about 70° C and stirred for 40 minutes to get a clear solution. 0.15 g of activated charcoal was charged into the reaction mass and

stirred for about 20 minutes. Reaction mass was filtered hot through a Hyflow bed and the bed was washed with acetone (5 ml). About 60% of the solvent was distilled off at 70-72° C and then cooled to about 3° C. The reaction mass was stirred for about 30 minutes. The solid separated was filtered and washed with 2.5 ml of acetone. The solid was dried at about 50° C for about 6 hours to afford 3.0 g of the title compound as crystalline solid.
Fig. 1 is an XRPD pattern of the product, obtained using copper Ka radiation (1.541 A wave length).

We Claim:
1. A process of preparing salmeterol xinafoate, comprising of the steps of:
(a) reacting [4-((6-Bromohexyl)oxy)-butyl]-benzene with a (aminomethyl)-4 hydroxy-1,3-benzenedimethanol in the presence of dimethyl sulfoxide to give
salmeterol free base;
(b) reacting salmeterol freebase with 1-hydroxy-2-naphthoic acid in the presence of
a suitable solvent to give crude salmeterol xinafoate.
2. The process of claim 1, where in the reaction of step (a) is carried out at about 60 °C to about 90 "C.
3. The process of claim 1, where in salmeterol freebase is not isolated before being reacted with 1-hydroxy-2-naphthoic acid and the solvent used in step (b) comprises acetonitrile
4. A process for purification of crude salmeterol xinafoate comprising recrystallizing from a suitable solvent to give pure salmeterol xinafoate.
5. The process of claim 4, where in the solvent comprises alcohols selected from C1 to C5 alcohols, C2 to C5 Ketones, nitrile solvents and aromatic hydrocarbons or mixtures there of.
6. The process of claim 5, where in the alcohols is isopropanol, Ketone is acetone, nitrile is acetonitrile and aromatic hydrocarbons is toluene or mixtures there of.
7. A Process of preparing [4-((6-bromohexyl)oxy)-butyl]-benzene, comprises of;

(a) condensing 4-phenyl-1-butanol with 1,6-dibromohexane in presence of sodium hydride as base and toluene to give 4-((6-bromohexyl)oxy)-butyl]-benzene;
(b) purifying crude 4-((6-bromohexyl)oxy)-butyl]-benzene by high vaccum distillation.

8. The process of claim 7, where in the 4-((6-bromohexyl)oxy)-butyl]-benzene is
distilled at vapor temperature of about 90 °C to about 180 °C.
9. A Process for preparing a^-(aminomethyl)-4-hydroxy-1, 3-benzenedimethanol
comprises of:
(a) acetylating 2-hydroxy-benzoic acid methyl ester with acetyl chloride in the
presence aluminum chloride and dichloromethane to give 5-acetyl-2-hydroxy-
benzoic acid methyl ester,
(b) brominating 5-acetyl-2-hydroxy-benzoic acid methyl ester with liquid bromine in
the presence of 1,4-dioxane to give 5-(2-bromoacetyl)-2-hydroxy benzoic acid
methyl ester,
(c) reacting the 5-(2-bromoacetyl)-2-hydroxy benzoic acid methyl ester with dibenzyl
amine in the presence of acetone to give 5-dibenzylaminoacetyl-2-hydroxy
benzoic acid methyl ester,
(d) reducing the 5-dibenzylaminoacetyl-2-hydroxy benzoic acid methyl ester with
NaBH4 in the presence of suitable solvent to give (4-(2-dibenzylamino)-1-
hydroxyethyl)-2-hydroxymethyl phenol;
(e) debenzylating the (4-(2-dibenzylamino)-1-hydroxyethyl)-2-hydroxymethyl phenol
with palladium on carbon, in methanol to give a^-(amJnomethyl)-4-hydroxy-1,3-
benzene-di-methanol.
10. The process of claim 9, where in the solvent used in step (d) includes t-butanol.