PREPARATION OF SALMETEROL AND SALTS THEREOF

INTRODUCTION

The present application relates to processes for the preparation of salmeterol, its pharmaceutically acceptable salts, and intermediates thereof.

Salmeterol xinafoate has a chemical name 4-hydroxy-a1-[[[6-(4-phenylbutoxy) hexyllaminolmethyll-I.S-benzenedimethanol-hydroxy-Z-naphthalenecarboxylate and has structural Formula I.

Formula I

Salmeterol is a long-acting highly selective p2-adrenergic agonist and is used in the treatment of asthma and chronic bronchitis. It is marketed, like many other chiral drugs, as a racemate. Pharmaceutical products containing salmeterol xinafoate as the active ingredient are commercially available, including those sold under the brand name SEREVENT™ as a powder and an aerosol for inhalation. Unlike other bronchodilator drugs, Salmeterol is much more lipophilic and displays many unusual pharmacological properties.

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.

The patent also discloses several processes for the synthesis of salmeterol
xinafoate, one process comprising the reaction of 2-bromo-1-[4-hydroxy-3-
(hydroxymethyl)phenyl]ethanone with N-[6-phenylbutoxy)hexyl]
benzenemethanamine in the presence of diisopropylethylamine in THF, followed by usual work-up and purification. The viscous oil so obtained was subjected to hydrogenation in absolute ethanol over 10% palladium on carbon and 10% platinum on carbon catalysts to afford salmeterol free base, which was then reacted with 1- hydroxy-2-naphthoic acid in the presence of isopropanol to give salmeterol xinafoate. The process is depicted by Scheme 1.

Scheme 1

International Application Publication No. WO 2007/045857A1 relates to a process for preparation of substantially pure salmeterol and its intermediates.

Additionally, processes for preparation of intermediates that are useful in the synthesis of salmeterol are disclosed in Tetrahedron Letters (1994), 35 (50), 9375-9378, Anon. UK Research Disclosure (2006), 506(June), P717 and several other journals.

However, these processes require cumbersome column purifications or high vacuum distillations for achieving a pure compound. A need remains for improved processes.

SUMMARY

In an aspect, there are provided processes for the preparation of purified salmeterol and its pharmaceutical^ acceptable salts, substantially free of process related impurities.

In an embodiment, there is provided a process for the preparation of salmeterol and its pharmaceutical^ acceptable salts, comprising:

a) condensing a compound of Formula II with a compound of Formula VIII in an organic solvent, in the presence of a suitable base, under suitable reaction conditions to afford the compound of Formula IX,

wherein Bn is a benzyl group and Ph is a phenyl group;

b) reducing the compound of Formula IX obtained in step a) in the presence of a suitable reducing agent in a suitable solvent to afford a compound of Formula X; and

c) debenzylating the compound of Formula X to afford crude salmeterol free
base of Formula V.

d) optionally reacting the compound of Formula V with a pharmaceutical^ acceptable acid in presence of suitable solvent at suitable reaction condition to afford a pharmaceutically acceptable acid addition salt of the compound of Formula V.

In another embodiment of the present invention, there is provided salmetrol free base of Formula V compound substantially free from the following potential process related impurity 4-{2-[6-(4-Cyclohexyl-butoxy)hexylamino]-1-hydroxy-ethyl}-2-hydroxymethyl-phenol of Formula (XI) at relative retention time of about 2.0 RRT by HPLC.

In an embodiment, there is provided a process for the purification of salmeterol free base of Formula V, which includes recrystallization of the free base using suitable organic solvents.

In another embodiment, there is provided a process for the preparation of N-benzylhexyl-4-phenylbutyl ether of Formula II, an intermediate in the preparation of salmeterol, comprising:

a) condensing 4-bromobutyl benzene of Formula Ha with 1,6-hexanediol of Formula lib in an organic solvent in the presence of a suitable base, to afford 6-(4-phenylbutoxy)hexan-1-ol of Formula lie;

b) reacting a compound of Formula lie with a compound providing a leaving group, in the presence of a suitable base and solvent, to afford a compound of Formula lid;

c) reacting a compound of Formula lid with benzylamine in an aromatic hydrocarbon in the presence of a base to yield the compound of Formula II as an oil. In a further embodiment, there is provided a chemical purification method for the compound of Formula II, comprising:

a) Reacting a solution of a crude compound of Formula II in a polar organic solvent with an aqueous solution of an organic acid to form a compound of Formula lie,

where Org is an anion of the organic acid;

b) isolating the organic acid addition salt of Formula lie; and

c) suspending the acid addition salt in a non-polar solvent and adding an aqueous inorganic base to a suspension of organic acid addition salt in a non-polar solvent, then isolating a purified amine intermediate of Formula II.

In another embodiment, there is provided a process for the preparation of 2-benzyloxy-5-(2-bromo-acetyl)-benzoic acid methyl ester of Formula VIM, an intermediate in the preparation of salmeterol, comprising:

a) acetylating 2-hydroxybenzoic acid methyl ester of Formula Villa with acetyl chloride in the presence of aluminum chloride and dichloroethane, to give 5~acetyl-2-hydroxybenzoic acid methyl ester of Formula VIIIb;

b) benzylating the 5-acetyl-2-hydroxybenzoic acid methyl ester of Formula VII lb with benzyl chloride in acetone in the presence of potassium carbonate and potassium iodide, to give methyl 5-acetyl-2-(phenylmethoxy)benzoate of Formula VIIIc; and

c) brominating the methyl 5-acetyl-2-(phenylmethoxy)benzoate of Formula VIIIc with bromine in methanol, to give 2-benzyloxy-5-(2-bromo-acetyl)benzoic acid methyl ester of Formula VIII.

In another embodiment, the present invention provides a method for preparing salmeterol xinafoate substantially free of an impurity having RRT of ~ 1.69 minutes, generated from 1-Hydroxy-2-naphthoicacid (HNA) and sulphated ash. The said method includes starting with a sample of HNA, comprising a sufficiently low level of the impurity with RRT -1.69 and sulphated ash. Preferably, the amount of the impurity is less than about 0.5% as an area percentage by HPLC.

This method comprises:

a) obtaining one or more samples of one or more batches of HNA;

b) measuring the level of impurity having RRT of - 1.69 minutes and
sulphated ash in each of the samples of step (a);

c) selecting the HNA batch that comprises a level of said impurity less than about 0.5% as an area percentage by HPLC based on the measurement conducted in step (b); and

d) using the batch selected in step (c) for further purification.
In another embodiment, there is provided a purification process for HNA on a commercial scale using a laboratory grade HNA, and use of substantially pure HNA for the preparation of salmeterol xinafoate. The process comprises:

a) heating a solution of commercially available HNA in a mixture of water and a water miscible organic solvent, which was optionally pretreated with activated carbon and filtered, to reflux temperature for clear dissolution.

b) cooling the mass to a temperature sufficient to crystallize the HNA
compound, followed by filtration of the solid formed and subsequent washing
of the solid with a mixture of water and a water miscible organic solvent, then
drying.

In another aspect, the present invention provides processes for preparing salmeterol xinafoate comprising synthesizing salmeterol xinafoate from a sample of HNA purified by the aforementioned process, wherein the process analyzes the level of an impurity having a RRT of -1.69 minutes present in an initial sample of HNA and purifying during the synthetic process to control amount of the impurity in salmeterol xinafoate.

In another aspect, the present invention provides processes for preparing salmeterol xinafoate, an embodiment comprising:

a) analyzing HNA for the presence of an impurity with RT -1.69 minutes;

b) selecting a HNA that has no greater than about 0.5% (as an area
percentage by HPLC) of the impurity in HNA;

c) purifying the HNA selected in b); and

d) reacting purified HNA from c) with crystalline salmeterol free base in an organic solvent under suitable conditions to obtain salmeterol xinafoate.
In another embodiment, there is provided a compound of Formula IX useful as an intermediate for the preparation of salmeterol,

wherein Bn is a benzyl group and Ph is a phenyl group.

In another aspect of the present invention provides an organic acid addition salt of Formula He,

wherein Org is an anion from an organic acid.

In a further embodiment, there is provided a compound of Formula 11f.

In another embodiment, there is provided crystalline salmeterol free base having a purity (chemical and polymorphic) of at least about 98%.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 is a powder X-ray diffraction pattern of the crystalline salmeterol free base product obtained in Example 5, determined using copper Ka radiation (1.541 A wavelength).

DETAILED DESCRIPTION

According to a first aspect of the invention there is provided an improved process for the preparation of salmeterol and its salts, including salmeterol xinafoate, substantially free of process related impurities.

In another embodiment, there is provided a process for the preparation of salmetrol and its pharmaceutical^ acceptable salts, which includes the steps of:

a) condensing a compound of Formula II with a compound of Formula VIII in an organic solvent, in the presence of a suitable base, under suitable reaction conditions to afford a compound of Formula IX,

wherein Bn is a benzyl group and Ph is a phenyl group;

b) reducing the compound of formula IX in presence of a suitable reducing
agent in a suitable solvent to afford a compound of Formula X; and

c) debenzylating a compound of Formula X under suitable reaction conditions in suitable solvents to afford crude salmeterol free base of Formula V.

d) optionally reacting the compound of Formula V with an pharmaceutical acceptable salts in presence of suitable solvent at suitable reaction condition to afford the compound of Formula I.

Suitable organic solvents that may be used in step a) include: alcohols such as methanol, ethanol, isopropyl alcohol, and n-butanol; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone, and n-butanone; halogenated solvents such as dichloromethane (DCM), ethylene dichloride (EDC), and chloroform; esters such as ethyl acetate, n-propyl acetate,and isopropyl acetate; hydrocarbon solvents such as toluene, xylene, n-hexane, n-heptane, and cyclohexane; ethers such as 1,4-dioxane, tetrahydrofuran; and mixtures thereof in various proportions. In embodiments, the reaction of step a) is carried out in halogenated non-polar solvents such as DCM, EDC, or chloroform, or in a polar aprotic solvent such as acetonitrile, etc.

Suitable bases useful in step a) include triethylamine, K2CO3, Na2C03t N,N-diisopropylethylamine, pyridine, etc.

Suitable temperatures for conducting the reaction range from about 10°C to about the reflux temperature of the solvent used.

The reaction may be carried out for any desired time periods to achieve the desired product yield and purity. The reaction times vary from about 30 minutes to about 10 hours, or longer.

Suitable solvents that may be used in step b) of the process include, but are not limited to, ethers such as 1,4-dioxane, and tetrahydrofuran, and aromatic hydrocarbons such as benzene, toluene, and xylene.

The suitable reducing agents employed in step b) include Lithium aluminium hydride, NaBH4, Vitride (a solution of £65% by wt. of sodium bis(2-methoxyethoxy)aluminum hydride in toluene).

Vitride may provide a more complete reduction of keto and ester moieties than NaBH4, and is safer to use than LAH.

After completion of the reduction, the reaction mass is quenched with a reagent such as sodium potassium tartrate, rather than a more conventionally used HCI solution to avoid the cleavage of an ether linkage.

The debenzylation reaction of step c) may be carried out using hydrogen and a catalyst such as platinum oxide, platinum on activated carbon, palladium on barium sulfate, or palladium on activated carbon. The amount of catalyst employed may be 1-100% by weight, or 5-50%, or 5-25%, of the weight of a compound of Formula X.

The reaction may be suitably carried out in a solvent inert to the reaction conditions such as; an alcohol such as methanol, ethanol, and isopropanol; an ether such as 1, 4-dioxane and THF; an ester like ethyl acetate, isopropyl acetate, and t-butyl acetate; halogenated hydrocarbons such as dichloromethane, dichloroethane, chloroform and the like; hydrocarbons such as toluene, xylene, cyclohexane and the like; acetic acid; and mixtures thereof in various proportions.

The hydrogen gas pressure for conducting the reaction may vary from about 1-100 Kg/cm2, or 1-25 Kg/cm2, or 1-10 Kg/cm2. The reaction times vary depending on the activity of the catalyst and the amounts thereof used. In an embodiment, the reaction is conducted at about 2-5 Kg/cm2 for a period of about 2-5 hours, so as to control the formation of Impurities F and G.

The crude salmeterol free base is isolated using a mixture of low boiling solvents to control the unidentified impurity with RRT -0.7. Typical solvents useful for isolation include, but are not limited to: alcohols such as methanol, ethanol, and isopropanol; ketones such as acetone and methyl isobutyl ketone; halogenated solvents such as dichloromethane, ethylene dichloride, and chloroform; and mixtures thereof in various proportions.

Suitable organic solvent that may be used in the step d) include: alcohols such as methanol, ethanol, isopropyl alcohol, and n-butanol; ketones such as acetone, methyl isobutyl ketone, methyl ethyl ketone, and n-butanone; and mixtures thereof in various proportion.

Suitably 1-hydroxy-2-napthoic acid can be added into the reaction solution by dissolving the 1-hydroxy-2-napthoic acid salt in a same solvent used to dissolve sal metro I free base. Suitable time taken to add 1-hydroxy-2-napthoic acid solution may range from about 15 minutes to about 5 hours.

The purity of 1-hydroxy-2-napthoic acid salt used for this reaction may be greater than 98%. Optionally napthoic salt can be purified by using conventional purification techniques in order to achieve higher purity.

Suitable temperatures for conducting the reaction range from about 0°C to about 45°C as increase in the temperature and time of the reaction may welt lead to the formation of side products and process related impurities.

The reaction may be carried about for any desired time periods to achieve the desired product yield and purity. The reaction times vary from about 30 minutes to about 10 hours or longer

Recovery of solid can be carried out by conventional techniques such as filtration, decantation, centrifugation and the like in the presence or absence of inert atmosphere such as for example nitrogen and the like.

The product may optionally be further dried. Drying can be suitably carried out in a tray dryer, vacuum oven, air oven, fluidized bed drier, spin flash dryer, flash dryer and the like. The drying can be carried out at temperatures of about 35° C to about 90° C with or without vacuum. The drying can be carried out for any desired time until the required product purity is achieved, time periods from about 1 to 20 hours frequently being sufficient.

In an embodiment, there is provided a process for the purification of the salmetrol free base Formula V, which includes recrystallization from a suitable organic solvent.

In an embodiment, a first crystallization is carried out in a polar organic solvent. Typical polar organic solvents include acetonitrile, N, N-dimethylformamide, methanol, ethanol, ethyl acetate, and isopropyl acetate. The first crystallization assists in controlling the amounts of process related impurities F and G in the final product.

A second crystallization can be carried out using a solvent-anti-solvent process, wherein useful solvents include but are not limited to methanol, ethanol, isopropanol, acetone, methyl ethyl ketone, and methyl isobutyl ketone, and useful anti-solvents include, without limitation, acetonitrile and water. In an embodiment, a solvent is methanol and an anti-solvent is acetonitrile.

In yet another embodiment of the present invention, there is provided salmetrol free base of Formula (if) compound substantially free from the following potential process related impurity 4-{2-[6-(4-Cyclohexyl-butoxy)-hexylamino]-1-hydroxy-ethyl}-2-hydroxymethyl-phenol of Formula (XI) at relative retention time of about 2.0 RRT by HPLC.

The above-mentioned impurity is analyzed by the high performance liquid chromatography (HPLC) method using a symmetry C8, 250 x 4.6 mm x 5 ja columns with the following parameters

Salmeterol can be further converted into a salt, for example the xinafoate. Useful solvents employed for the conversion comprise ethyl acetate, acetone, isopropanol, etc.

Salmeterol can be used as an active pharmaceutical ingredient In its free base form or it can be converted to acid addition salt form. Acid addition salts are typically pharmaceutically acceptable, non-toxic addition salts with suitable acids, including but not limited to inorganic acids such as hydrohalogenic acids (for example, hydrofluoric, hydrochloric, hydrobromic and hydroiodic acids) or other inorganic acids (for example, nitric, perchloric, sulphuric and phosphoric acids); or organic acids such as organic carboxylic acids (for example, xinafoic, oxalic, propionic, butyric, glycolic, lactic, mandelic, citric, acetic, benzoic, 2- or 4-methoxy-benzoic, 2- or 4-hydroxy-benzoic, 2- or 4-chlorobenzoic, salicylic, succinic, malic, hydroxysuccinic, tartaric, fumaric, maleic, hydroxymaleic, oleic, glutaric, mucic, galactaric, gluconic, pantothenic and pamoic acids), organic sulphonic acids (for example, methanesulphonic, trifluoromethanesulphonic, ethanesulphonic, 2-hydroxyethanesulphonic, benzenesulphonic, toluene-p-sulphonic, naphthalene-2-sulphonic and camphorsulphonic acids) and amino acids (for example, ornithinic, glutamic and aspartic acids).

In addition to pharmaceutical^ acceptable acid addition salts, other acid addition salts are included in the present invention, since they have potential to serve as intermediates in the purification of the free base or preparation of other, for example, pharmaceutical^ acceptable, acid addition salts, or are useful for identification and characterization.

The method by which a 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 can carry a small proportion of occluded mother liquor. If desired the crystals can be washed with a solvent to wash out the mother liquor.

The isolated wet solid is optionally dried using techniques such as, for example, fluid bed drying (FBD), aerial drying, oven drying, or any other techniques known in the art. The drying can be conducted at temperatures about 20-100°C, or about 60-70X, with or without application of a vacuum. Drying also can be carried out under inert atmosphere conditions.

The compound of Formula I obtained according to the present process is subtantially free from process related impurities. A pure salmeteroi xinafoate of Formula I obtained by the described process has a purity at least 98% by HPLC.

In an embodiment, there is provided an improved process for the preparation of N-benzyl-hexyl-4-phenylbutyl ether Formula II, an intermediate in the preparation of salmeterol, comprising:

a) Brominating 4-Phenylbutanol with hydrobromic acid in the presence of sulphuric acid to give 4-bromobutylbenzene of Formula Ma.

b) Condensing 4-bomobutylbenzene of Formula 11a with 1,6-hexanediol of Formula lib in the presence of a suitable base and organic solvent to afford 6-(4-phenylbutoxy)hexan-1-ol of Formula lie.

c) Activating the compound of Formula lie by addition of methanesulfonyl chloride in presence of an organic base such as triethylamine to give a methanesulfonate salt of 6-(4-phenylbutoxy)hexan-1-ol of Formula lid.

d) Reacting the Methanesulfonic acid 6-(4-phenyl-butoxy) hexyl ester with benzylamine in an aromatic hydrocarbon in the presence of an inorganic base to yield a compound of Formula II as oil.

Suitable solvents for step b) of the reaction include: ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone; halogenated hydrocarbons such as

dichloromethane, methylene chloride, and ethylene dichloride; nitriles such as acetonitrile; and aromatic hydrocarbons such as benzene, toluene, and xylene.

The bases employed in step b) include but are not limited to: organic bases such as methylamine, dimethylamine, triethylamine, ethyl di-isopropylamine, butylamine and the like; and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like. In embodiments, an inorganic base such as NaOH is employed.

Suitable solvents for step c) of the reaction include aromatic hydrocarbons such as benzene, toluene, and xylene.

The bases employed in step c) include but are not limited to: organic bases such as methylamine, dimethylamine, triethylamine, ethyl di-isopropylamine, butylamine and the like; and inorganic bases such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like. In embodiments, an inorganic base such as NaOH is employed.

Suitable solvents for step d) include aromatic hydrocarbons such as benzene, toluene, xylene, and the like. Suitable inorganic bases include KOH, NaOH, Na2CO3 etc.
The invention also provides a chemical purification process for an amine intermediate, not involving a cumbersome purification technique like high vacuum fractional distillation or chromatographic purification, comprising:

a) reacting a crude amine intermediate of Formula El in an organic solvent,
such as a polar organic solvent, with an aqueous solution of an organic acid,
to give a compound of Formula lie;

where Org is an anion of an organic acid; and

b) reacting a suspension of a compound of Formula lie in a non-polar
halogenated solvent with an aqueous inorganic base to form a purified amine
intermediate of Formula II.

In step a), useful polar organic solvents include methanol, acetone, acetonitrile, etc.

Org- is the anion of an organic acid. Typical organic acids include formic acid, succinic acid, oxalic acid, etc. Organic acid addition salts generally give less reactivity associated with the ether moiety of the amine intermediate of Formula II than do mineral acids, which may result in lessened formation of impurities that affect the overall purity of salmeterol and its salts such as the xinafoate.

Non-polar halogenated solvents useful for forming a purified amine intermediate of Formula II include dichloromethane, dichloroethane, chloroform and mixtures thereof.

An aspect of the present invention provides an organic acid addition salt of Formula lie, prepared according to aforesaid process of the present invention, where Org is an anion of an organic acid.

In a further aspect of the present invention there is provided an organic acid addition salt of Formula 11f

In an embodiment, there is provided a process for the preparation of 2-benzyloxy-5-(2-bromo-acetyl)-benzoic acid methyl ester of Formula VIII, an intermediate useful in the preparation of salbutamol, salmeterol, comprising:

a) acetylating 2-hydroxybenzoic acid methyl ester of Formula Villa with acetyl chloride in the presence of aluminum chloride and dichloroethane, to give 5-acetyl-2-hydroxybenzoic acid methyl ester of Formula VIIIb;

b) benzylating 5-acetyl-2-hydroxybenzoic acid methyl ester of Formula VIIIb with benzyl chloride in a polar organic solvent in the presence of an inorganic base and an alkali metal iodide, to give methyl 5-acetyl-2-(phenylmethoxy)benzoate of Formula Vc; and
c) brominating methyl 5-acetyl-2-(phenylmethoxy)benzoate of Formula VIIIc with bromine in methanol to give 2-benzyloxy-5-(2-bromoacetyl)benzoic acid methyl ester of Formula VIII.
Step b) of the process is carried out in a polar organic solvent, such as acetone. The step is carried out in the presence of an inorganic base such as sodium carbonate or potassium carbonate and an alkali metal iodide such as sodium iodide.

Solvents that can be used for the process of step c) include but are not limited to alcohols such as methanol, ethanol, propanol, t-butanol and the like, and mixtures thereof.

The presence of impurities in salmeterol and its salts, such as the xinafoate, may pose a problem for formulation in that impurities often affect the safety and shelf life of a formulated product. The present invention provides methods for ameliorating the effect of an impurity present in formulations of salmeterol and its salts by reducing the amount of the impurity during synthesis. The impurity having RT ~3.4 minutes has not been identified and thus its structure is not presently known.

In order to demonstrate the correlation of the impurity having RRT ~ 1.69 minutes present in HNA with that of salmeterol xinafoate (RRT ~ 0.20 ± 0.04) prepared using the HNA. Salmeterol xinafoate was prepared by the described procedure (following Examples 7 and 8) of the present invention from purified and unpuhfied LR grade HNA (Laboratory grade (LR) NHA is defined as HNA having a 1.69 RRT impurity and sulphate ash content greater than 0.1%).

The LR grade HNA from Aldrich Chemical Company Inc. contained 0.36% and 1.09% as area percentages by HPLC of the impurity (RT~3.5 minutes) and sulphated ash, respectively. The levels were reduced to 0.06% (RT -3.4 minutes) and 0.07% of sulphated ash after performing the purification process described above. The salmeterol xinafoate prepared using unpurified HNA contained 0.17% as an area percentage by HPLC of the impurity and 1% of sulphated ash, whereas salmeterol xinafoate prepared employing purified HNA contained 0.07% as an area percentage by HPLC of the impurity and 0.05% of sulphated ash. These results correlate well with HPLC analyses of the starting HNA materials, suggesting that the impurity present in the starting material would also be present in the final product in the same or a comparable ratio.

Accordingly, the present invention provides a process for preparing salmeterol xinafoate having a low level of the impurity by checking for the impurity in the starting material and choosing a starting material which has a low level of the impurity, followed by its purification.

Thus there is provided a purification process for 1-hydroxy-2-naphthoic acid on a commercial scale using lower quality 1-hydroxy-2-naphthoic acid and use of substantially pure 1-hydroxy-2-naphthoic acid for the preparation of salmeterol. The process comprises:

a) Heating a solution of laboratory grade HNA, provided in a mixture of water and a water miscible organic solvent in a ratio from 1:1 to 1:4 by volume, to reflux temperature for dissolution.

b) Cooling the mass to about 10-20°C for about 1-2 hours, followed by separation of the precipitated compound and subsequent washing of the compound with a mixture of water and a polar solvent, then drying.

Useful water miscible organic solvents include at least one of C3-5 ketones, nitriles, and CM alcohols. In embodiments, a water miscible organic solvent is at least one of acetone, methanol, ethanol, n-propanol, isopropanol, acetonitrile, methyl ethyl ketone, or tetrahydrofuran.

The mixture should be cooled to a temperature at which HNA crystallizes. The appropriate temperature may easily be determined by the skilled artisan as the temperature at which crystals become visible. Typically, the reaction mixture of HNA is cooled to a temperature from about 0°C to about 30°C, or about 10°C to about 20°C,

The HNA crystals are separated using any method commonly known to one of ordinary skill in the art. Such methods include but are not limited to centrifuging, and filtration using a funnel, belt, or press. Subsequently, the HNA crystals are washed with a solution of water and a water miscible organic solvent, such as in a 1:1 volume ratio. Thereafter, the collected HNA crystals are dried using techniques commonly known to one of ordinary skill in the art. The pure HNA is then used to synthesize a high purity salmeterol.

The related substances in salmeterol or its salts, such as the xinafoate of Formula I, may be analyzed using high performance liquid chromatography (HPLC), for example by a method using an Inertsil ODS-2 Size: L = 0.15 m, 0 = 4.6 mm and 5 M-m column. The other parameters are given in Table 1.

Table 1

The processes of the present invention are simple, improved, eco-friendly, cost-effective, commercially viable, robust and reproducible on an industrial scale.
The invention is described with reference to particular embodiments and the following illustrative examples, and those skilled in the art will appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention. The examples are provided to aid in understanding specific aspects and embodiments of 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.

EXAMPLES

EXAMPLE 1: Preparation of 2-Bromo-4-benzyloxy-3-methoxycarbonylacetophenone or 2-benzyloxy-5-(2-bromoacetyl)-benzoic acid methyl ester (Formula VIII).

(a) Preparation of 5-acetylmethyl salicylate (Formula VIIIb).
54 Kg of anhydrous aluminum chloride was charged into a reactor containing 168 L of ethylene dichloride at 20-30°C and the reaction mass was cooled to about 0-10°C, followed by slow addition of 27 Kg of acetyl chloride and subsequent stirring for about 25-35 minutes. Then 30 Kg of methyl salicylate was charged to the reaction mass maintained at 0-10°C over a period of about 5 hours. The reaction mass was allowed to attain 15-25°C and was stirred for about 5 hours. Reaction completion was confirmed by thin layer chromatography and the reaction mass was quenched by adding a mixture of ice and 24 L of cone, hydrochloric acid at about 0-25°C and allowed to decompose for about 1 hour. The organic layer was separated and washed with dil. HCl solution, water and sodium carbonate solution and finally by water. The solvent was distilled completely under vacuum below 9D°C. The solid was air dried to afford the title compound as a solid. HPLC assay Purity: 99.1%.

(b) Preparation of Methyl-5-acetyl-2-(benzyloxy)berizoate (Formula VIIIc).
A mixture of 39 Kg of methyl 5-acetylsajjcylate, 28.86 Kg of potassium carbonate and 1.44 Kg of potassium iodide in 172 L of acetone was stirred at about 25-35°C for 30 minutes. Then 28.86 Kg of benzyl chloride was added to the reaction mass at 25-35 °C and heated to reflux at 55-65°C for 36 hours. Reaction completion was confirmed by thin layer chromatography and solvent was evaporated under vacuum at 50-60°C, The reaction mass was cooled to 25-35°C followed by addition of distilled water and stirring for 2 hours. The mass obtained was filtered and washed with water (4x94 L). The filtered solid was dissolved in methanol (78 L) and stirred at about 45-55°C for 2 hours, followed by addition of aqueous HCI to adjust pH of the mass to 6.5-7. The mass was cooled to ambient temperature and stirred for 2 hours, followed by filtration. The solid material obtained was dried under vacuum to afford the title compound as brown crystals. HPLC assay Purity: 98.95%.

(c) Preparation of 2-benzyloxy-5-(2-bromoacetyl)-benzoic acid methyl ester (Formula VIII).

A solution of methyl-O-benzyl-5-acetylsalicyiate (50 Kg) in methanol (800 L) was heated to 35-45°C for dissolution, followed by dropwise addition of aqueous

bromine solution (1166 L) at 35-40°C over about 4 hours. The reaction mixture was stirred at same temperature for about 1 hour and reaction completion was confirmed by TLC. The reaction mixture was cooled to ambient temperature and centrifuged, then the solid was washed with chilled methanol. The solid was charged to a solution of sodium bicarbonate and stirred for about 30 minutes below 35°C followed by centrifugation. The solid was washed with water and spin dried. The solid was added to methanol (60 L) and the mixture was heated to reflux for about 3 hours, followed by cooling to ambient temperature. The mass was centrifuged and the solid was washed with methanol followed by drying at 50-60°C to yield 2-benzyloxy-5-(2-bromoacetyi)benzoic acid methyl ester,

EXAMPLE 2: Preparation of N-benzylhexyl 4-phenylbutyl ether (Formula II).

(a) Preparation of benzoylpropanoic acid.

100 Kg of succinic anhydride was charged into a reactor containing 460 L of benzene and the mass was cooled to 0-5°C, followed by slow lot-wise addition of aluminium chloride (228 Kg) at the same temperature. The reaction mass was stirred for 1 hour at 0-5°C followed by stirring at 35-40°C for 6 hours. The reaction mixture was poured into a mixture of ice and hydrochloric acid (36 N) (600 L) and stirred for 1 hour followed by centrifugation. The material so obtained was washed with benzene and spin dried to afford 155 kg of the title compound.

(b) Preparation of phenylbutanoic acid.

A mixture of 155 Kg of benzoylpropanoic acid, acetic acid (930 L) and butanol was subjected to hydrogenation using 10% Pd on carbon (7.75 Kg) and hydrogen gas 3-5 Kg for about 9-12 hours, and reaction completion was checked by TLC. The reaction mass was filtered and the filtrate was distilled completely. The residue was cooled to ambient temperature, mixed with chilled water (27 L) and centrifuged. The solid was filtered and dried to give a crude material. The crude material was mixed with water and heated to 50°C; pH was adjusted with caustic soda (54 L) to 12 and checked for dissolution. To the solution, activated carbon (21 Kg) was added and stirred for 30 minutes, followed by filtration and subsequent washing of the carbon bed with water. The filtrate was cooled to 15-20°C and pH was adjusted with hydrochloric acid (35 L) to 1-2, and the mixture was stirred for 2 hours. The mixture was centrifuged and the solid material was washed with water until the washings had a neutral pH. The solid was dried to give 105 kg of the title compound.

(c) Preparation of methyl-4-phenyl butanoate.

A mixture of phenylbutanoic acid (105 Kg), toluene (420 L), methanol (262.5 L) and cone, sulphuric acid (5.25 Kg) was azetropically refluxed for 8 hours. Completion of the reaction was checked using TLC and the reaction mixture was cooled to ambient temperature. The reaction mixture was washed with water (2*500 L) and the organic layer was separated and distilled completely under vacuum below 110°C. The residue was cooled to ambient temperature to give the 105 kg title compound as oil.

(d) Preparation of 4-phenyl-1-butanol.

A mixture of methyl-4-phenyl butanoate (100 Kg) and tetrahydrofuran (300 L) was brought to 0-10°C, Lithium aluminium hydride (18 Kg) was added slowly under nitrogen atmosphere at 10-20°C and stirred for 6 hours at ambient temperature. Completion of the reaction was checked by TLC, followed by addition of sodium sulphate (36 Kg) and water. Then reaction mixture was stirred for 1 hour at 10°C, followed by filtration and washing of the solid with tetrahydrofuran. Then the solvent was distilled under vacuum followed by subsequent high vacuum distillation to give 100 kg of the title compound.

(e) Preparation of 4-bromobutylbenzene.

115.2 L of hydrobromic acid (48%) was charged into a round-bottomed flask and 50.75 L of sulphuric acid was added below 35°C over about 45 minutes, followed by addition of 40 Kg of 4-phenyl-1-butanol. Another 30.8 L of sulphuric acid was added dropwise below 35°C over about 5-6 hours. The reaction mixture was heated to 45-55°C and stirred for about 10 hours at this temperature. The temperature was raised to 70-80°C for about 6 hours. Reaction completion was confirmed by gas chromatography and the mass was cooled to ambient temperature, followed by addition of 24 L of dichloromethane below 35°C. The organic layer was separated and washed sequentially with of 5% NaHC03 (300 L) and water (2*200 L). The solvent from the organic layer was distilled completely under vacuum at 60-70°C to give the 35 kg of the title product as an oil.

(f) Preparation of N-benzylhexyl 4-phenylbutyl ether (Formula II).

A mixture of 1,6-hexanediol (120 Kg) and NaOH flakes (21 Kg) in toluene (300 L) was heated at 40-50°C. Then 30 Kg of 4-Bromobutylbenzene was added dropwise at 40-5Q°C over 3-4 hours. The reaction mixture (additional toluene was added, if the reaction mass was thick) was heated to reflux at 100-110°C for about 5 hours. Reaction completion was confirmed by thin layer chromatography and the reaction mixture was cooled to 30-40°C. The organic layer was washed with water (1x300 L and 1^240 L) until there was no remaining 1,6-hexanediol. The organic layer was distilled under atmospheric pressure at 100-110°C until the water content was below 0.5% and then cooled below 35°C. The organic layer was brought to 5-15°C followed by addition of triethylamine (43.5 L) at the same temperature. The mixture was cooled to 0-10°C, and then methanesulphonyl chloride (25.5 L) was added dropwise at the same temperature over about 4 hours. The reaction mixture was stirred for another 4 hours at 0-10°C and reaction completion was confirmed by thin layer chromatography, then the reaction mixture was cooled to 0-10°C, The reaction mass was filtered and the solid was washed with toluene (100 L). To the filtrate, caustic soda solution (50%, 21 L) was slowly added below 35°C, followed by addition of benzylamine (67.5 L) at the same temperature. The reaction mixture was refluxed and stirred for 10 hours at 100-110°C and reaction completion was confirmed by thin layer chromatography. The organic layer was washed with water (1x300 L) at 35-45°C, followed by distillation under vacuum at 100-110 °C and removal of traces of benzylamine to result in the title compound as a 29 kg of title compound as an brownish residue.

EXAMPLE 3: Purification of N-benzylhexyl 4-phenylbutyl ether (Formula II).

29 Kg of the compound obtained in Example 2 was mixed with 232 L of acetone and stirred for 30 minutes at ambient temperature. To the mixture, aqueous oxalic acid solution (4.65%, ~232 L) was slowly added and stirred for 2 hours. The reaction mass was filtered followed by washing the solid with acetone (87 L) and subsequent drying of the solid under vacuum, at which point the HPLC purity was determined. The oxalate salt was mixed with dichloromethane (240 L) and stirred for 30 min at ambient temperature, followed by subsequent treatment of the organic layer with 10% sodium carbonate solution (-290 L). The organic layer was separated and washed with water (290 L). The organic layer was distilled at 40 °C under hot water circulation to give 15 g of N-benzylhexyl 4-phenyl butyl ether as oil.

EXAMPLE 4: Purification of N-benzyl-hexyl 4-phenyl butyl ether (Formula II):

a) High Vacuum Distillation.

400 g of crude compound of Formula II having a HPLC purity of 80.06% was placed in a round bottom flask and heated to 250-260°C with simultaneous application of vacuum. The fraction corresponding to a vapor temperature of 220°C was collected and the flask was maintained at the same temperature for another 15- 30 minutes, after which the heating was stopped. The desired compound having a HPLC purity of 89.02% remained in the flask,

b) Saltifying-Desaltifying.
100 g of the compound obtained in step a) was mixed with 1000 ml of acetone and stirred for 30 minutes at ambient temperature. Aqueous oxalic acid solution (4.65%, ~800 ml) was slowly added and stirred for 2 hours. The reaction mass was filtered followed by washing of the solid with acetone (200 ml) and subsequent drying of the solid. The oxalate salt obtained was mixed with dichloromethane and stirred for 30 minutes at ambient temperature, followed by treatment of the organic layer with sodium carbonate solution (10%, 1 L). The organic layer was further washed with water (1 L) and then separated. The organic layer was distilled at 40°C under hot water circulation to give N-benzylhexyl 4-phenyl butyl ether in 81.5 % yield. HPLC purity: 97.17%.

EXAMPLE 5: Preparation of crystalline salmeterol free base.

A mixture of N-Benzylhexyl 4-phenylbutyl ether (50 g, 0.147 mol), methyl-2-benzyloxy-5-bromoacety! benzoate (53.5 g, 0.147 mol) and diisopropyiethylamine (51.4 ml, 0.294 mol) in dichloromethane (500 ml) was stirred at 25-35°C for 2.5-3.5 hours. Reaction completion was confirmed by thin layer chromatography and the organic layer was washed with water (2x250 ml). The organic layer was distilled under vacuum below 35°C to form a residue. Toluene (400 ml) was charged to the residue at 25-35°C followed by stirring and cooling of the mixture to 0-5°C. Separately, a dilute solution of vitride (70% solution, 183 ml) was prepared in toluene (100 ml) was slowly charged to the above reaction mixture, maintained at 0-5°C. The reaction mixture was allowed to stir at the same temperature for 1.5-2 hours, at which point reaction completion was checked using TLC. The reaction was quenched by adding the reaction mass slowly to an aqueous solution of sodium potassium tartrate (183 g dissolved in 425 ml of water) followed by stirring at 25-35°C for 30-35 minutes. The resulting mixture was filtered followed by separation of organic and aqueous layers of the filtrate. The desired compound was extracted from aqueous layer by charging toluene (100 ml). The combined organic layers were subjected to sequential washings with aq. Vacuum salt solution sodium chloride solution (100 g in 500 ml), aq. acetic acid solution (5 ml in 500 ml of water), sodium bicarbonate solution (5 g in 500 ml) and water (500 ml). Then the organic layer was distilled completely under vacuum below 50°C to result in a residue. 700 ml of methanol was charged to the residue and the mass was stirred for 10-15 minutes at 25-35°C, followed by addition of activated carbon (8 g) and stirring at same temperature for 30-45 minutes. The mass was filtered and the carbon bed was washed with methanol (100 ml). The filtrate was charged to a dry hydrogenation autoclave vessel and cooled to 20-25°C, followed by addition of a 10% Pd on carbon slurry (25 g in 50 ml water) and stirring under 2-4 kg/cm2 H2 pressure at 20-30°C for 2.5-3 hours. Reaction completion was confirmed by thin layer chromatography, the mixture was filtered, and the solid was washed with methanol (50 ml). To the filtrate, vacuum salt solution (10 ml in 850 ml of water) and dichloromethane (850 ml) were charged followed by separation of the organic layer. The organic layer was washed with aqueous methanol (4*850 mi, 425 ml methanol + 425 ml water). The organic layer was completely distilled under vacuum below 40°C to give a residue which was mixed with ethyl acetate (50 ml) followed by distillation under vacuum below 40°C until solid separated. Ethyl acetate (250 ml) was mixed with the solid and heated to 45-50°C for dissolution. The solution was brought to 25-30°C and stirred for 1.5-2 hours at the same temperature. The solid that formed was filtered, washed with ethyl acetate (50 ml), and suction dried. The wet material was taken up in methanol (111 ml) and stirred, acetonitrile (111 ml) and activated carbon (2 g) were added, and the mixture was stirred for 20-30 minutes at 25-30°C. The mixture was filtered and the solid was washed with acetonitrile (111 ml) and suction dried. To the filtrate, acetonitrile (166.5 ml) was added followed by stirring for 10-15 minutes and the mass was brought to 0-5°C, followed by stirring at the same temperature for 2.5-3 hours. The solid that formed was filtered and washed with 74 ml of acetonitrile at 0-5°C. The wet compound was dried under vacuum at 40-45°C to afford the title compound as a crystalline solid in 45.8% yield. The XRD pattern is depicted in Fig. 1.HPLC Purity: 99.55%.

EXAMPLE 6: Purification of 1-Hydroxy-2-napthoic acid.

A round bottom flask was charged with 30 g of 1-Hydroxy-2-napthoic acid (LR grade) and 150 ml of acetone and stirred for dissolution under reflux. To the homogeneous solution so obtained 75 ml of water was added, and stirred under reflux for 10-15 minutes followed by cooling to 10-20°C. The solid that formed was filtered and washed with a 1:1 mixture of acetone and water (30 ml+30 ml), followed by drying at 50-55°C to give purified 1-Hydroxy-2-napthoic acid in a 48.3% yield. HPLC purity: 99.8%.

Sulphated Ash: 0.07%.

Impurity with RT 3,46 min and RRT 1.69 = 0.06%.

EXAMPLE 7: Preparation of salmeterol xinafoate employing commercial quality
HNA.

A round bottom flask was charged with 31.0 g of salmeterol free base and 186 ml of acetone, stirred for dissolution at 40°C, and filtered to remove undissolved material. Separately, a solution of 1-Hydroxy-2-napthoic acid (14 g, LR grade)*was prepared in acetone (186 ml), and was then added to the above-prepared solution of salmeterol free base in acetone. The mixture was stirred for -2 hours at 25-35°C. The solid that formed was filtered and washed with acetone (31 ml) followed by drying at 50°C to afford the title compound in 85.5% yield. HPLC Purity: 99.49%.
Impurity (RT= 3.7 minutes, RRT = 0.24) = 0.17% ROI = 1,0%.

EXAMPLE 8: Preparation of salmeterol xinafoate employing purified HNA.

1 g of crystalline salmeterol free base was mixed with 8.5 ml of acetone and heated to 35-40°C with stirring for dissolution. A solution of 1-hydroxy-2-napthoic acid (0.45 g, purity of 99.8% with ROI: 0.07%) in acetone (8.5 ml) was prepared and filtered to remove undissolved material. The filtered solution of 1-hydroxys-naphthoic acid was added to the above-prepared solution of salmeterol free base and stirred at 25-35°C for 3-4 hours. The solid that formed was filtered and washed with acetone (2 ml) followed by drying at 45-50°C to give the title compound in 89.5 % yield.

HPLC Purity: 98.4%, saturated salmeterol: 0.0138%

Impurity (RT= 3.45 minutes,; RRT = 0.208) = 0.07%.

ROI: 0.05%.

EXAMPLE 9: Purification of 1-Hydroxy-2-napthoic acid.

A mixture of 10 Kg of 1-Hydroxy-2-napthoic acid, acetone (50 L) and water (25 L) was stirred to obtain a clear solution. 500 g of carbon was charged to the solution and stirred for 15-20 minutes, followed by filtration. To the filtrate, 25 L of water was added and checked for formation of solid. The mass was heated to 65-70°C for dissolution and stirred at reflux for another 30 minutes. The mass was brought to 10-20°C and stirred at the same temperature for 1 hour, followed by filtration. The solid was washed with a solvent mixture of acetone and water (1:1 v/v, 10L + 10L) at 10-20°C and spin dried followed by drying under vacuum (625-675 mm Hg) at 60-65°C for 6-8 hours to give purified 1-Hydroxy-2-naphthoic acid in 51.5% yield.

EXAMPLE 10: Preparation of salmeterol xinafoate employing purified HNA.

2.5 Kg of crystalline salmeterol free base and acetone (22.5 L) were heated to 35-40°C and stirred for 10-15 minutes for dissolution, followed by filtration through a micro filter, washing with acetone (5 L) and subsequent cooling of the filtrate to 25-30°C. Separately, 1.15 Kg of 1-Hydroxynapthoic acid and acetone (12.5) were stirred at 25-35°C for 10-20 minutes for dissolution, followed by filtration through a micro filter to remove undissolved particles, washing the filter with acetone (5 L). The filtered solution was added to the solution of salmeterol free base in acetone at 20-30°C. The mixture was stirred for about 4-5 hours at 20-30°C, followed by filtration through pressure nutch filter and washing of the bed with chilled acetone (5 L). The wet solid was dried under a nitrogen atmosphere for about 2-3 hours followed by drying at 45-50°C under vacuum for 10 hours to give 2.95 Kg of title compound. The dried material was milled in a Multimill using a 0.5 mm screen, and then the material was sifted through a 20 mesh sieve. The material was slowly introduced into a micronizer, which had an injection pressure of 4-4.5 Kg/cm2 and mill pressure of 3.5-4.0 Kg/cm2 to give salmeterol xinafoate. HPLC purity: 99.9%.

Claims:

1. A process for preparation of Salmeterol and its pharmaceutically acceptable salts which comprises,

a) reacting intermediate II and VIII in an organic solvent, preferably halogenated non-polar solvent in presence of base preferably organic base, most preferably diisopropylethylamine to afford compound of Formula IX.

b) reducing intermediate IX in presence of in presence of a suitable reducing agent in a suitable solvent to afford a compound of Formula X.

c) debenzylating a compound of Formula X under suitable reaction conditions in suitable solvents to afford crude salmeterol free base of Formula V
AM

d) optionally reacting the compound of Formula V with a pharmaceutically acceptable acid in presence of suitable solvent at suitable reaction condition to afford the corresponding salt.

2. A one pot process for the preparation of Crystalline Salmeterol free base, which includes the steps,

a) reacting intermediate II and VIII in an organic solvent, preferably halogenated non-polar solvent in presence of base preferably organic base, most preferably diisopropylethylamine to afford compound of Formula IX.

b) reducing intermediate IX in presence of in presence of a suitable reducing agent in a suitable solvent to afford a compound of Formula X.

c) debenzylating a compound of Formula X under suitable reaction conditions in suitable solvents to afford crude salmeterol free base of Formula V

d) crystallizing crude Salmeterol free base from a polar organic solvent or a mixture of polar protic and polar aprotic solvents

3. A process of claim 2, where polar organic solvent is preferably, ethyl acetate, polar protic solvent is methanol and polar aprotic solvent is acetonitrile.

4. An improved process for the preparation of N-benzyl-hexyl-4-phenylbutyl ether Formula II, an intermediate in the preparation of salmeterol, comprising:

a) brominating 4-Pnenylbutanol with hydrobromic acid m the presence of sulphuric acid to give 4-bromobutylbenzene of Formula IIa.

b) condensing 4-bomobutylbenzene of Formula Ma with 1,6-hexanediol of Formula lib in the presence of a suitable base and organic solvent to afford 6-{4-phenylbutoxy)hexan-1-ol of Formula IIc.

c) activating the compound of Formula He by addition of methanesulfonyl chloride in presence of an organic base such as triethylamine to give a methanesulfonyl ester of
6-(4-phenylbutoxy)hexan-1-ol of Formula lid.

d) reacting the Methanesulfonic acid 6-(4-phenyl-butoxy) hexyl ester with
benzylamine in an aromatic hydrocarbon in the presence of an inorganic base to
yield a compound of Formula II.

5. A chemical purification process for an amine intermediate comprising: a) reacting a crude amine intermediate of Formula II in an organic solvent, such as a polar organic solvent, with an aqueous solution of an organic acid, to give a compound of Formula IIe;

where Org is an anion of an organic acid; and

b) reacting a suspension of a compound of Formula lie in a non-polar halogenated solvent with an aqueous inorganic base to form a purified amine intermediate of Formula II.

6, An organic acid addition salt of Formula IIe, prepared according to process of claim 5,
where org can be any organic acid, preferably oxalic, mane, succinic acid; most preferably oxalic acid.

7. A novel compound of Formula IIf (Oxalate salt) employed in the purification of compound of Formula II.

8. Crystalline Salmeterol free base or its pharmaceutical^ acceptable salt of at least 99.4% chemical purity.