Claims:1) A process for the preparation of formoterol fumarate dehydrate comprising;
a) reacting 1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo ethanone compound of formula-III with N-benzyl-1-(4-methoxy phenyl)propan-2-amine hydrochloride compound of formula-IV in water and suitable polar aprotic solvent and in the presence of a base, K2CO3 to obtain (2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanone) compound of formula-V,

Formula-III Formula-IV Formula-V
b) reducing the (2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanone) compound of formula-V with Sodium borohydride in the presence of suitable alcoholic solvent and halogenated hydrocarbon solvent to obtain 2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanol compound of formula VI,

Formula-VI
c) reducing the 2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanol compound of formula VI with anhydrous Ferric Chloride in the presence of hydrazine hydrate and hydrocarbon solvent to yield 1-(3-Amino-4-benzyloxy-phenyl)-2-{benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-ethanol of compound of formula-VII followed by reaction with fumaric acid in methanol to obtain the fumarate salt of compound of formula-VII having purity greater than 98%;

Formula-VII

d) formylating the (3-Amino-4-benzyloxy-phenyl)-2-{benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-ethanol compound of formula VII with Formamide and formic acid to obtain crystals of N-[5-(2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-formamide compound of formula VIII;

Formula-VIII
e) debenzylating the N-[5-(2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-formamide compound of formula VIII with 10% Pd-C in the presence of alcoholic solvent and an ester solvents to obtain N-(2-Hydroxy-5-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1-methyl-ethylamino]-ethyl}-phenyl)-formamide (Formoterol); and

Formula-I
f) reacting Formoterol with fumaric acid in the presence of an alcoholic solvent and water to obtain Formoterol fumarate dehydrate of formula-II.
Formula II

2) The process according to claim 1, wherein, the suitable polar aprotic solvents used in step a) are selected from the group consisting of dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide and mixture thereof.
3) The process according to claim 1, wherein the alcoholic solvents used in the step b) are selected from the group consisting of methanol, ethanol, isopropanol and mixture thereof and the halogenated hydrocarbon solvents used in step b) are selected from the group consisting of Dichloromethane, dichloroethane, chloroform and mixture thereof.
4) The process according to claim 1, wherein, the solvent used in step c) is selected from the group consisting of toluene, hexane, heptanes and cyclohexane.
5) The process according to claim 1, wherein the crystals of compound of formula VIII obtained in step d) are washed with Isopropyl alcohol to achieve the enantiomeric purity greater than 99.0%.
6) The process according to claim1, wherein, the alcoholic solvents used in the step e) is selected from the group consisting of methanol, ethanol, isopropanol and mixture thereof and the ester solvents used in step e) are selected from the group consisting of ethyl acetate, isopropyl acetate, n-butyl acetate and mixture thereof.
7) An improved process for the preparation of formoterol fumarate dihydrate of formula-II comprising formylating (3-Amino-4-benzyloxy-phenyl)-2-{benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-ethanol compound of formula VII with formylation mixture consisting of Formamide and formic acid to obtain N-[5-(2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-formamide compound of formula VIII.
8) An improved process for the preparation of formoterolfumaratedihydrate of formula-II comprising reducing 2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanol compound of formula VI with anhydrous Ferric Chloride in the presence of hydrazine hydrate and hydrocarbon solvent to yield 1-(3-Amino-4-benzyloxy-phenyl)-2-{benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-ethanol of compound of formula-VII..
9) A process for the preparation of enantiomerically pure N-[5-(2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-formamide compound of formula VIII having enantiomeric purity > 99.0%,

Formula VIII

which comprises;
a) reacting 1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo ethanone compound of formula-III with N-benzyl-1-(4-methoxy phenyl)propan-2-amine hydrochloride compound of formula-IV in water and suitable polar aprotic solvent and in the presence of a base, K2CO3 to obtain (2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanone) compound of formula-V

Formula-III Formula-IV Formula-V
b) reducing the (2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanone) compound of formula-V with Sodium borohydride in the presence of suitable alcoholic solvent and halogenated hydrocarbon solvent to obtain 2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanol compound of formula VI,

Formula-VI
c) reducing the 2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanol compound of formula VI with anhydrous Ferric Chloride in the presence of hydrazine hydrate and hydrocarbon solvent to yield1-(3-Amino-4-benzyloxy-phenyl)-2-{benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-ethanolcompound of formula-VII followed by reaction with fumaric acid in methanol to obtain the fumarate salt of compound of formula-VII;

Formula-VII
d) formylating the (3-Amino-4-benzyloxy-phenyl)-2-{benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-ethanol compound of formula VII with Formamide and formic acid to obtain crystals of N-[5-(2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-formamide compound of formula VIII and
e) washing the crystals of the compound of formula VIII with Isopropyl alcohol to achieve the compound of formula VIII with enantiomeric purity greater than 99.0%. , Description:FIELD OF INVENTION:
The present invention relates to an industrially applicable process for the preparation of Formoterol Fumarate dihydrate.

BACKGROUND OF THE INVENTION:
Formoterol is a long-acting ß2 agonist used in the management of asthma and chronic obstructive pulmonary disease (COPD). It is marketed in four forms: a dry-powder inhaler, a metered-dose inhaler, an oral tablet, and an inhalation solution, under various trade names including Foradil/Foradile (Schering-Plough in the U.S., Novartis rest of world), Forpack Discair (Neutec inhaler), and Oxeze/Oxis. It is also marketed in the combination formulation, budesonide/formoterol. Formoterol Fumarate dihydrate having following structural formula;

Formoterol is commercially available as racemic mixture of (R, R) AND (S, S) in a (1:1) ratio, and the generic name formoterol refers to this racemic mixture.
Formoterol is developed by Yamanouchi Pharmaceutical Company as a long-acting beta-2 adrenoceptor agonist. Formoterol fumarate dihydrate is available in the market as Foradil Aerolizer, a capsule dosage form containing a dry powder formulation of formoterol fumarate dihydrate for oral inhalation with the aerolize inhaler. It is indicated in the maintenance treatment of asthma and in the prevention of bronchospasm, including exercise-induced bronchospasm, in both adult and pediatric patients. Formoterol given by inhalation has much longer duration of action than any other bronchodilators in the market. Therefore it avoids the nocturnal asthma, which often causes considerable anxiety and debility to the patients. The product is also indicated in the treatment of patients with chronic obstructive pulmonary disease (COPD).
Formoterol is first disclosed in a Japanese patent application (Application No.13121 (1972) by Yamanouchi. The corresponding German Patent is DE 2305092 and US patent is US 3,994,974 by Yamanouchi. It describes a process for the preparation of Formoterol starting from 4-benzyloxy 3-nitro-a-bromo acetophenone. It reacts with a secondary amine of formula-III to

obtain a ketone derivative of formula-IV. The keto group is reduced to the corresponding alcohol of formula V by using sodium borohydride. Successive reduction of nitro group by iron-HCl and the formylation of resulting aniline derivative with acetic anhydride and formic acid gave the dibenzyl formoterol of formula VII which is having four isomers RR, RS, SS, SR. The separation of RR and SS is accomplished by converting the above dibenzyl formoterol into its fumarate salt and selective crystallization from isopropyl alcohol. The purified dibenzyl formoterol base of formula VII is liberated from its salt and is subjected to hydrogenation using Pd/C to get formoterol base of formula I (A). The base is then converted to its pharmaceutically acceptable fumarate salt of formula I (B).
The process disclosed in US 3,994,974 for the preparation of formoterol fumarate has the following disadvantages.
(a) Chemical purity as well as enantiomeric purity of the intermediates and the final product is not disclosed.
(b) It is observed that separation of unwanted isomers is not easy. It will require a number of crystallizations to remove these isomers from the required dibenzyl formoterol of formula-VII. This would lead to poor recovery of wanted formoterol.
(c) Process for the preparation of the stable dihydrate form of formoterol fumarate or its analysis is not mentioned in this patent.
A modified process for formoterol is disclosed in WO92/05147(1992) and in the corresponding US Pat. No. 5434304 (1995).In this route nitro epoxide is reacted with benzyl protected amine derivative to get the nitro alcohol derivative in the form of four stereoisomers namely RR, SS, RS and SR. The dibenzyl formoterol is obtained either by reduction of nitro compound over platinum oxide and successive formylation of the resultant aniline derivative with formic acid or in a single step using Raney nickel and formic acid. The crude dibenzyl formoterol thus obtained was then converted into its fumarate salt to remove unwanted isomers (RS and SR) by selective crystallization of the crude fumarate salt. The pure set of crystalline isomers (RR and SS) is isolated by filtration, neutralized with a base to get dibenzyl formoterol and hydrogenated over Pd/C to get the formoterol which was then converted to its pharmaceutically acceptable fumarate salt.

The drawbacks of this process are:
1) Longer reaction time (69 hr) and higher temperature (90°C) are required to couple the nitro epoxide with benzyl protected secondary amine derivative.
2) Unwanted isomers (RS and SR) formed in the first step of the process are nearly 40% which were carried forward up to dibenzyl formoterol stage and separated at this stage via fumarate salt formation followed by selective and repeated crystallizations. Such a process would require more reagents thereby making the process expensive and polluting.
US 6,040,344 disclosed the method for the preparation of optically pure isomers of formoterol by the reaction of an optically pure 4-benzyloxy-3-formamidostyrene oxide with an optically pure 4-methoxy-a-methyl-N-(phenyl methyl) benzene ethanamine followed by debenzylation. Useful intermediates in the process are also disclosed, as are the novel L-tartrate salt of R, R-formoterol and pharmaceutical composition thereof.
WO2008035380 discloses an improved process for the preparation of high purity Formoterol and its pharmaceutically acceptable salts (Scheme-2).
The crude oily compound of formula-V is prepared as per the process disclosed in US3, 994,974. Accordingly, 1-[4-(benzyloxy)-3-nitrophenyl]-2-bromoethanoneof formula-II is reacted with excess of N-benzyl-1-(4-methoxyphenyl)propan-2-amineof formula-III in Methyl Ethyl Ketone solvent medium at reflux temperature to get the tertiary amine derivative of formula-IV. Reduction of the keto group present in the compound of formula-IV with sodium borohydride in alcoholic solvent medium gave the crude nitro alcohol derivative of formula-V which is then triturated with a non polar solvent such as diisopropyl ether to get a yellow solid after filtration of the solvent. Reduction of the nitro group present in the compound of formula-V with Raney-nickel in polar solvent such as methanol under hydrogenation conditions gave the crystalline amino compound as a dark yellow solid. The crystalline amino compound of formula-VI is converted to the N-formyl derivative of formula-VII using formic acid or acetic formic anhydride. Debenzylation of the compound of formula VII using Pd/C in methanol-ethyl acetate solvent medium gave formoterol base of formula-IA. The formoterol base obtained from the hydrogenation step can be recrystallized from isopropyl alcohol. The pure formoterol base is then converted into fumarate salt.

Disadvantages of the process disclosed in WO2008035380A2 are below:
1) WO2008035380 describe the use of methyl ethyl ketone for the step-I i.e. reaction of 1-[4-(benzyloxy)-3-nitrophenyl]-2-bromoethanone with excess of N-benzyl-1-(4-methoxyphenyl) propan-2-amine that escalates the overall cost of the production asMethyl ethyl ketone is a costly solvent.
2) In WO2008035380 at stage III (compound of formula VI) reduction product obtained is gummy solid, which requires purification techniques such as trituration and recrystallization.
3) WO2008035380 describe the use of acetic anhydride and formic acid for formylation. However, acetic anhydride is carcinogenic, difficult to handle and not easily available.

In the light of the foregoing drawbacks, there remains a need in the art to provide an alternate process for synthesis of Formoterol fumarate that is cost-effective and industrially scalable.
Accordingly, it is an objective of the present invention to provide an efficient and cost-effective process for synthesis of Formoterol fumarate which is simple and easier to carry on industrial scale.

SUMMARY OF THEINVENTION
Formoterol fumarate has become a well-known bronchodilator that has now been on the market is a valuable anti-asthmatic drug with few side effects. Considering the difficulties in commercialization of the above mentioned prior art processes for the preparation of Formoterol fumarate, the present inventors have developed a simple and industrially applicable process for the production of Formoterol fumarate dihydrate.
In one aspect, the present invention describes the process for the preparation of N-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl) propan-2-ylamino]ethyl] phenyl]formamide (Formoterol) which comprises:
a) reacting 1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo ethanone compound of formula-III with N-benzyl-1-(4-methoxy phenyl)propan-2-amine hydrochloride compound of formula-IV in water and suitable polar aprotic solvent and in the presence of a base,K2CO3 to obtain (2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanone)compound of formula-V;
b) reducing the (2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanone) compound of formula-V, with sodium borohydride in the presence of suitable alcoholic solvent and halogenated hydrocarbon solvent to obtain 2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanolcompound of formula VI;
c) reducing the2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanol compound of formula VI with anhydrous Ferric Chloride in the presence of hydrazine hydrate and hydrocarbon solvent yields 1-(3-Amino-4-benzyloxy-phenyl)-2-{benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-ethanolcompound of formula-VII followed by conversion into its fumarate salt;
d) formylating the (3-Amino-4-benzyloxy-phenyl)-2-{benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-ethanol compound of formula VII with Formamide and formic acid to obtain N-[5-(2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-formamide compound of formula VIII;
e) debenzylating the N-[5-(2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-formamidecompound of formula VIII with 10% Pd-C in the presence of alcoholic solvent and an ester solvent to obtain N-(2-Hydroxy-5-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1-methyl-ethylamino]-ethyl}-phenyl)-formamide (Formoterol);and
f) reacting the Formoterol with fumaric acid in the presence of isopropyl alcohol and water to obtain Formoterol fumarate dihydrate.
The crystals of compound of formula VIII are washed several times with isopropyl alcohol to achieve enantiomeric purity greater than 99.0%, prior to subjecting to debenzylation, which becomes another feature of the present invention.
Accordingly, in another aspect, the present invention, provides a process for preparation of enantiomerically pure N-[5-(2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-formamide compound of formula VIII having enantiomeric purity 99.0%, which comprises;
a) reacting 1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo ethanone compound of formula-III with N-benzyl-1-(4-methoxy phenyl)propan-2-amine hydrochloride compound of formula-IV in water and suitable polar aprotic solvent and in the presence of a base,K2CO3 to obtain (2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanone) compound of formula-V;
b) reducing the(2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanone) compound of formula-V with sodium borohydride in the presence of suitable alcoholic solvent and halogenated hydrocarbon solvent to obtain 2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanol compound of formula VI;
c) reducing the2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanol compound of formula VI with anhydrous Ferric Chloride in the presence of hydrazine hydrate and hydrocarbon solvent yields 1-(3-Amino-4-benzyloxy-phenyl)-2-{benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-ethanol compound of formula-VII followed by conversion into its fumarate salt;
d) Formylating the (3-Amino-4-benzyloxy-phenyl)-2-{benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-ethanol compound of formula VII with Formamide and formic acid to obtain N-[5-(2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-formamide compound of formula VIII; and
e) Washing the crystals of the compound of formula VIII several times with Isopropyl alcohol to achieve the enantiomeric purity greater than 99.0%.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a cost effective, industrially applicable process for preparation of Formoterol fumarate dihydrate. The process for the preparation of Formoterol fumarate dihydrate in accordance with the present invention is given below in Scheme-3.
Scheme-3

In one aspect, the present invention provides a process for the preparation of (R, R)-N-[2-hydroxy-5-[1-hydroxy-2-[1-(4-methoxyphenyl) propan-2-ylamino] ethyl] phenyl]Formamide (Formoterol) which comprises:
a) reacting 1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo ethanone compound of formula-III with N-benzyl-1-(4-methoxy phenyl)propan-2-amine hydrochloride compound of formula-IV in water and suitable polar aprotic solvent and in the presence of a base, K2CO3 to obtain (2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanone) compound of formula-V;

Formula-III Formula-IV Formula-V
b) Reducing the (2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanone) compound of formula-V with sodium borohydride in the presence of suitable alcoholic solvent and halogenated hydrocarbon solvent to obtain (2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanol) compound of formula VI,

Formula-VI
c) Reducing the2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanol compound of formula VI with anhydrous Ferric Chloride in the presence of hydrazine hydrate and hydrocarbon solvent yields 1-(3-Amino-4-benzyloxy-phenyl)-2-{benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-ethanol compound of formula-VII, followed by reaction with fumaric acid in methanol to obtain the fumarate salt of compound of formula-VII;

Formula-VII
d) Formylating the1-(3-Amino-4-benzyloxy-phenyl)-2-{benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-ethanol compound of formula VII with Formamide and formic acid to obtain N-[5-(2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-formamide compound of formula VIII.

Formula-VIII
e) Debenzylating theN-[5-(2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-formamide compound of formula VIII with 10% Pd-C in the presence of alcoholic solvent and an ester solvent to obtain N-(2-Hydroxy-5-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1-methyl-ethylamino]-ethyl}-phenyl)-formamide (Formoterol); and

Formula-I
f) reacting Formoterol with fumaric acid in the presence of an alcoholic solvent and water to obtain Formoterol fumarate dehydrate of formula-II

Formula II.

The polar aprotic solvent used in step a) includes dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide preferably Dimethyl formamide.
The alcoholic solvent used in the step b) includes methanol, ethanol, isopropanol preferably methanol. The halogenated hydrocarbon solvent used in step b) includes Dichloromethane, dichloroethane preferably dichloromethane.
The hydrocarbon solvent used in the step c) includes toluene, xylene preferably toluene.
The ester solvent used in step d) includes ethyl acetate, isopropyl acetate, n-butyl acetate preferably ethyl acetate.
The alcoholic solvent used in the step e) includes methanol, ethanol, isopropanol preferably methanol.The ester solvent used in step e) includes ethyl acetate, isopropyl acetate, n-butyl acetate preferably ethyl acetate.
The alcoholic solvent used in the step f) includes methanol, ethanol, isopropyl alcohol preferably isopropyl alcohol.
In another aspect, the present invention describes the process for preparation of enantiomerically pure N-[5-(2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-formamide compound of formula VIII

Formula VIII
which comprises;
a) reacting 1-[4-(benzyloxy)-3-nitrophenyl]-2-bromo ethanone compound of formula-III with N-benzyl-1-(4-methoxy phenyl)propan-2-amine hydrochloride compound of formula-IV in water and suitable polar aprotic solvent and in the presence of a base,K2CO3to obtain (2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanone) compound of formula-V

Formula-III Formula-IV Formula-V
b) reducing the (2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanone) compound of formula-V with NaBH4 in the presence of suitable alcoholic solvent and halogenated hydrocarbon solvent to obtain 2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanol compound of formula VI,

Formula-VI
c) reducing the 2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanol compound of formula VI with anhydrous Ferric Chloride in the presence of hydrazine hydrate and hydrocarbon solvent yields 1-(3-Amino-4-benzyloxy-phenyl)-2-{benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-ethanol compound of formula-VII, followed by reaction with fumaric acid in methanol to obtain the fumarate salt of compound of formula-VII;

Formula-VII
d) formylating the (3-Amino-4-benzyloxy-phenyl)-2-{benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-ethanol compound of formula VII with Formamide and formic acid to obtain N-[5-(2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-formamide compound of formula VIII; and
e) washing the crystals of the compound of formula VIII several times with Isopropyl alcohol to achieve the compound with enantiomeric purity greater than 99.0%.

Formula VIII
The polar aprotic solvent used in step a) includes dimethyl formamide, dimethyl acetamide and dimethyl sulfoxide preferably Dimethyl formamide.
The alcoholic solvent used in the step b) includes methanol, ethanol, isopropanol preferably methanol. The halogenated hydrocarbon solvent used in step b) includes Dichloromethane, dichloroethane preferably dichloromethane.
The hydrocarbon solvent used in the step c) includes toluene, xylene preferably toluene.
The key economic advantages associated with the present invention over the prior arts are listed below other than obtaining the formoterol fumarate dihydrate with good yield and purity:
The reaction of 1-[4-(benzyloxy)-3-nitrophenyl]-2-bromoethanone with excess of N-benzyl-1-(4-methoxyphenyl) propan-2-amine is conducted in water and DMF instead of costly solvent, Methyl ethyl ketone. Further, the additional advantage associated with this process modification is that the compound of formula VI, 2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanol, obtained is a clear solid when compared to gummy solid of WO2008035380, which requires purification methods such as trituration and crystallizations.
A further advantage of the present invention involved in avoiding the carcinogenic acetic anhydride, which is also difficult to handle and store, instead, the present invention uses cheaper formamide and formic acid combination for formylation of (3-Amino-4-benzyloxy-phenyl)-2-{benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-ethanol compound of formula VII. Also, the industrial handling of formamide is simpler and easier when compared to acetic anhydride.
The invention further provides the compound of formula-VII, 1-(3-Amino-4-benzyloxy-phenyl)-2-{benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-ethanol as fumarate salt so as to increase chemical and enatiomeric purity of formula VII. Fumarate salt of Formula VII is re-converted into free base of formula VII with high eenatiomeric purity, and used in further preparation of Formoterol fumarate.
The invention is further illustrated by following examples. These examples are provided for illustrative purpose only and are not intended to limit the scope of the invention in any way.

Examples:

Example- 1: Preparation of (2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanone)
1-[4-(benzyloxy)-3-nitrophenyl]-2-bromoethanone 50g, N-benzyl-1-(4-methoxy phenyl)propan-2-amine hydrochloride 36g ,N,N-dimethylformamide (100 ml)and Water 400ml were charged into a 1 Lit round bottom flask equipped with a mechanical stirrer. Potassium carbonate 40g was added at 30°C. The reaction mixture was heated to 85 °C and maintained the temperature for 4 hours. The reaction mixture was cooled to 30°C and pre cooled water (300 ml) was added. The solid formed was collected by filtration and washed with pre cooled water (150 ml); the solid was dried in oven under vacuum at 50°C to get 65 gm of the title compound. The dry material was charged into 500 ml round bottom flask and methanol (220 ml) was added and the mixture was heated to reflux temperature and maintained for 1 hour. The mixture was cooled to 10°C and maintained for 2 hours. The solid was collected by filtration and washed with methanol (50 ml). The solid was dried in oven under vacuum at 80°C to get 60 gm of pure title compound. Purity 98%.

Example- 2: Preparation of 2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanol
To a 1lit round bottom flask, charged (2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanone)50g in a mixture of methanol 50ml and dichloromethane 200ml. The reaction mixture was added with 4.3 g of sodium borohydride in portions, under strong stirring, at room temperature. The temperature is kept at 15-20°C during the addition, after that the mixture is left under stirring for about 2 hours at room temperature. The mixture was then added with 50 ml of glacial acetic acid and water 100mlstirred for 30min at roomtemperature. The aqueous layer was separated and charged into another flask and 200 ml of dichloromethane was added stirred for 20min then the organic layer was separated.Combined the organic layers and evaporated under vacuum at below 45°C. Toluene (100 ml) was added to the residue and taken for further step without purification. Purity 97%

Example-3: Preparation of 1-(3-Amino-4-benzyloxy-phenyl)-2-{benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-ethanol
In a 1lit reaction flask anhydrousferric chloride was added 18g, activated carbon 18g,Toluene 200ml and 50g of 2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-(4-benzyloxy-3-nitro-phenyl)-ethanol, stirred and heated to 80°C, slowly added 85% hydrazine hydrate 145ml, after addition refluxed for 6hours. Filtered and the filtrate was concentrated to dryness. 7.0 gm fumaric acid dissolved in methanol (200 ml) was added to the residue and stirred the reaction mass for 2 to 5 hours at ambient temperature. Filteredthe crystals of fumarate salt of the title compound.Purity 98-99%.

Example -4:Preparation of N-[5-(2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-formamide
150ml of formamide,40g formic acid and 50g of 1-(3-Amino-4-benzyloxy-phenyl)-2-{benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-ethanol were introduced, under a nitrogen atmosphere, into a round bottom flask equipped with a stirrer system. The reaction mixture was heated to a temperature of between 96° C. and 101° C. and is maintained at this temperature for 10 hours. 150 ml of deionised water and 250ml ethylacetate are then added at approximately 20° C. Separated the layers and taken organic layer, washed with 50ml of water and 5% sodium chloride solution. Distilled completely and added IPA then stirred at 0-5°C. The crystals of N-[5-(2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-formamidewereseparated out.Filtered the product and washed several times with Isopropyl alcohol and thendried in an oven.Purity 98%

Example-5: N-(2-Hydroxy-5-{1-hydroxy-2-[2-(4-methoxy-phenyl)-1-methyl-ethylamino]- ethyl}-phenyl)-formamide.
N-[5-(2-{Benzyl-[2-(4-methoxy-phenyl)-1-methyl-ethyl]-amino}-1-hydroxy-ethyl)-2-benzyloxy-phenyl]-formamide (50 gm) was dissolved in methanol (250 ml), followed by addition of ethyl acetate (250 ml) to the reaction mixture. Then 10% Pd/C was added to the reaction mixture and applied hydrogen pressure 3-4 Kg/cm3. The content was stirred for 4.0 hours at 25-30°C, filtered and the filtrate was distilled. The residue was dissolved in ethyl acetate (50 ml), stirred the contents for 10 min and distilled.IPA (50 ml) was added to the residue and maintained at 10-15°C for 2-4 hours to obtain the title compound in crystalline form. Yield: 80%, purity 98%

Example-6: Preparation of formoterol fumarate dihydrate:
Fumaric acid (3.2 g,) was dissolved in Isopropyl alcohol (200 ml) and added to a solution of formoterol free base (20g) in Water (60 ml). The reaction mixture was brought to reflux for 15 minutes then cooled to 0-5°C for 2hours. Dry ether (250 ml) was then added and a few seed crystals introduced and maintained for 2-4 hours at an ambient temperature. Filtered the solid and dried under vacuum oven at 45°C for4 hours to obtain formoterolfumaratedihydrate.Yield: 22.1g, purity : 99.8%.