FIELD OF INVENTION
The present invention generally relates to chemical process. In particular it pertains to a novel, simplified and improved process for preparation of formoterol and its salts, hydrates and enantiomers.

BACKGROUND OF THE INVENTION
Formoterol, (I) is a highly potent and selective ß-2 adrenergic receptor agonist. It is chemically known as (±) N-[2-hydroxy 5-[1-hydroxy-2[[2-(p-methoxyphenyl)-2-propyl] amino] ethyl] phenyl]formamide. It is indicated in the maintenance treatment of asthma and in the prevention of bronchospasm. Formoterol is administered by inhalation has much longer duration of action than any currently available bronchodilators. Formoterol is also indicated in the treatment of patients with chronic obstructive pulmonary disease (COPD), including chronic bronchitis and emphysema.

Formula (I)

Formoterol is available commercially as a racemic diastereomers, (R, R) and (S, S) in a 1:1 ratio, and the generic name Formoterol refers to this enantiomeric mixture. The racemic mixture available commercially for administration is a dihydrate of the fumarate salt or its pure enantiomer mixture Arformetrol tartatare.

Formoterol was first disclosed in a Japanese patent application by Yamanouchi Pharmaceutical, (Application no 13121 (1972), 39416 (1972), 51013 (1972) and 52925 (1972)). The corresponding German Patent is DE 2 305 092 and the US Patent is 3 994 974.
The aforesaid patent discloses reaction of phenacylbromo derivative with benzyl protected secondary amine to form a coupled keto derivative. The keto group is then reduced to the corresponding nitro alcohol using sodium borohydride. Further, the reduction of nitro group is performed using Iron and HCl to form amine derivative. The formylation of resulting amine derivative is carried out with acetic formic anhydride to give the dibenzylformoterol having all four isomers RR, RS, SS, and SR. The separation of RR and SS enantiomers is performed by converting the dibenzyl formoterol into its fumarate salt and selective crystallization from isopropyl alcohol. The purified dibenzyl formoterol base is liberated from its salt and is subjected to hydrogenation using palladium and charcoal to get Formoterol base. The base is then converted to its pharmaceutically acceptable fumarate salt. However, this process does not disclose stable dihydrate form, chemical and enantiomeric purity.

The synthesis of formoterol and similar compounds has also been disclosed in Chem. Pharm. Bull, 25(6), 13684377 (1977), in which 3-nitro-4-benzyloxy-a-(N-substituted amino methyl)benzyl alcohols are used as the key intermediate. Raney-nickel is used for the reduction of the nitro group has been rejected due to difficulties in obtaining pure products without a chromatographic step. However, the general procedure disclosed for the preparation of 3-amino-4-benzyloxy-a-(N-substituted aminomethyl) benzyl alcohols reported in said research paper involves a tedious and cumbersome column chromatographic step on silica gel using benzene and ethyl acetate as the eluent.

ES 2 005 492 disclose another process for preparation of formoterol. This process discloses coupling reaction between 3-formamido-4-benzyloxyphenyloxirane and the unprotected 2-(4-methoxyphenyl)-1-methylethylamine to obtain the intermediate compound. The O-debenzylation of the synthesized intermediate compound is carried out by treating it with hydrofluoric acid to get Formoterol. Further, process of this patent utilizes expensive chemical (crown ethers), hazardous reagents (hydrofluoric acid), and carcinogenic solvents (benzene). This process is not suitable for large scale operation as it leads to environmental and health problems.

US 5434304 disclose another improved process for preparation of Formoterol. In this process nitro epoxide is reacted with benzyl protected amine derivative to get nitro alcohol derivative containing all four stereoisomers, namely RR, SS, RS, and SR. The dibenzylformoterol is obtained either by reduction over platinum oxide of the nitro compound and successive formylation of the resultant aniline derivative with formic acid or in a single step process utilizing Raney nickel and formic acid. The crude dibenzyl formoterol thus obtained was then converted to its fumarate salt to remove unwanted isomers. Process disclosed in US ‘304 requires longer reaction time(69 hours) and high temperature in coupling of nitro epoxide and secondary amine which is not suitable for industrial scale up and leads to low yield and low purity of product. Further, % impurity disclosed in the final compound does not meet the pharmacopeial requirements (0.3%). So, this process is not viable for industrial scale up.
Hence, there is a strong need of synthesizing Formoterol, its salts, hydrates and enantiomers using green chemistry with increased yield and purity.

OBJECT OF THE INVENTION
An object of the present invention is to provide an improved process for the preparation of Formoterol and its salts hydrates, and enantiomers.

SUMMARY OF THE INVENTION
Accordingly, the present invention provides a novel process for the preparation of compound of formula (I) and its salt, hydrates and stereoisomer;

comprising the steps of:
i. reacting benzyloxy-nitro phenacyl bromide of formula (II) with secondary amine compound of formula (III) to obtain tertiary amine intermediate compound of formula (IV) in presence of base and metal halide

ii. one pot reduction of keto group of compound of formula (IV) with a reducing agent (1) and polar solvent and reduction of nitro group of compound of formula (IV) on solid support with ferric chloride in presence of polar solvent and reducing agent (2) and then formylation of amino group of compound of formula (IV) to obtain compound of formula (V) with formylating agent and organic solvent.

iii. debenzylation of compound of formula (V) by hydrogenation with metal catalyst/charcoal in organic solvent and purification and isolation by salt formation of compound of formula (V) in presence of fumaric acid and organic solvent and selective crystallization in presence of organic solvent to obtain compound of formula (I).

wherein the compound of formula (I) is 1:1 racemic isomer (R,R : S,S)
and salt, hydrate ratio is 2:1:2.

iv. treating compound of formula (III) with chiral acid in presence of polar solvent followed by treatment with ammonia to obtain R-isomer of compound of formula (IIIA)

v. reacting benzyloxy-nitro phenacyl bromide of formula (II) with R-isomer of secondary amine compound of formula (IIIA) to obtain enantiomer of tertiary amine intermediate compound of formula (IVA) in presence of base and metal halide,

vi. one pot reduction of keto of compound of formula (IVA) with reducing agent (1) and polar solvent and reduction of nitro group of compound of formula (IVA) on solid support with ferric chloride in presence of polar solvent and reducing agent (2) and then formylation of amino group of compound of formula (IVA) with formylating agent and organic solvent to obtain compound of formula (VA)

vii. debenzylation of compound of formula (VA) by hydrogenation with metal catalyst/charcoal in organic solvent and purification and isolation by salt formation of compound of formula (VA) in presence of tartaric acid and organic solvent and selective crystallization in presence of organic solvent to obtain compound of formula (I).

wherein the compound of formula (I) is pure enantiomer (R, R) and salt ratio is 1:1.

DETAILED DESCRIPTION OF THE INVENTION
Accordingly, the present invention provides an improved process for the preparation of compound of formula (I), which comprises the steps:
a novel process for the preparation of compound of formula (I) and its salt, hydrates and stereoisomer;

comprising the steps of:
i. reacting benzyloxy-nitro phenacyl bromide of formula (II) with secondary amine compound of formula (III) to obtain tertiary amine intermediate compound of formula (IV) in presence of base and metal halide

ii. one pot reduction of keto group of compound of formula (IV) with a reducing agent (1) and polar solvent and reduction of nitro group of compound of formula (IV) on solid support with ferric chloride in presence of polar solvent and reducing agent (2) and then formylation of amino group of compound of formula (IV) to obtain compound of formula (V) with formylating agent and organic solvent.

iii. debenzylation of compound of formula (V) by hydrogenation with metal catalyst/charcoal in organic solvent and purification and isolation by salt formation of compound of formula (V) in presence of fumaric acid and organic solvent and selective crystallization in presence of organic solvent to obtain compound of formula (I).
wherein the compound of formula (I) is 1:1 racemic isomer (R,R : S,S)
and salt, hydrate ratio is 2:1:2.

iv. treating compound of formula (III) with chiral acid in presence of polar solvent followed by treatment with ammonia to obtain R-isomer of compound of formula (IIIA)


v. reacting benzyloxy-nitro phenacyl bromide of formula (II) with R-isomer of secondary amine compound of formula (IIIA) to obtain enantiomer of tertiary amine intermediate compound of formula (IVA) in presence of base and metal halide,

vi. one pot reduction of keto of compound of formula (IVA) with reducing agent (1) and polar solvent and reduction of nitro group of compound of formula (IVA) on solid support with ferric chloride in presence of polar solvent and reducing agent (2) and then formylation of amino group of compound of formula (IVA) with formylating agent and organic solvent to obtain compound of formula (VA)

vii. debenzylation of compound of formula (VA) by hydrogenation with metal catalyst/charcoal in organic solvent and purification and isolation by salt formation of compound of formula (VA) in presence of tartaric acid and organic solvent and selective crystallization in presence of organic solvent to obtain compound of formula (I).

wherein the compound of formula (I) is pure enantiomer (R, R) and salt ratio is 1:1.

In the present invention, the compound of the formula (I) may be as illustrated in the following scheme 1 and scheme 2:

Scheme 1: The process for preparation of Formoterol fumarate
Stage 1:

Stage 2:

Stage 3:

Scheme 2: The process for preparation of Arformoterol tartrate

Stage-I

Stage-I I

Acetone/Potassium carbonate/ potassium iodide

Stage-III

Methanol/ sodium borohydride

Hydrazine hydrate/ Ferric chloride
Acetic anhydride/ formic acid
Fumaric acid / liq. Ammonia

Stage-IV

Methanol
Palladium charcoal
Hydrogen gas

Stage-V

Ethanol
Isopropyl alcohol
L-(+)-Tartaric acid

The process of the present invention is described herein below in detail. The description is an embodiment of the present invention and may not be construed to limit the invention in any manner.

The various steps of the process of the present invention may be set out as below:
1. reaction of benzyloxy-nitro phenacyl bromide of formula (II) with secondary amine compound of formula (III) to obtain tertiary amine intermediate compound of formula (IV).
(±)-N-Benzyl-N-(1-methyl-2-(4-methoxy phenyl)-ethyl) amine may be dissolved in base and acetone and reacted with 4-benzyloxy-3-nitroacetophenone in presence of metal halide to obtain tertiary amine intermediate of compound of formula (IV). The base may be selected from group comprising sodium carbonate, potassium carbonate, lithium carbonate, preferably potassium carbonate. The metal halide may be selected from group comprising sodium iodide, potassium iodide, preferably potassium iodide. The reaction may be conducted at a temperature range of 20-40 deg. C, preferably in the range of 30-35 deg. C for 24 hours.

2. one pot reduction of keto and nitro group and further formylation of compound of formula (IV) to obtain compound of formula (V)
The keto group present in tertiary amine compound of formula (IV) may be reduced in presence of polar solvent. The reduction may be may be conducted with a suitable reducing agent selected from the group comprising sodium borohydride, lithium triethylborohydride, L-Selectride, preferably, sodium borohydride. The polar solvent may be selected from group comprising tetrahydrofuran, methanol, ethanol, isopropanol, preferably methanol. The reaction may be conducted at a temperature range of 40-70 deg. C, preferably in the range of 50-55 deg. C.
The nitro group present in tertiary amine compound of formula (IV) may be reduced on solid support and ferric chloride in polar solvent. The reduction may be may be conducted with a suitable reducing agent selected from the group comprising hydrazine hydrate, catalytic hydrogenation using palladium-on-carbon, platinum(IV) oxide, Raney nickel preferably, hydrazine hydrate. The solid support may be may be selected from the group comprising carbon, silica, neutral alumina preferably, neutral alumina. The polar solvent may be selected from group comprising methanol, ethanol, isopropanol, preferably methanol. The reaction may be completed in 20-30 hours.
The formylation of amino compound in organic solvent to converted N-formyl derivative of compound of formula (V) by using formylating agent. The organic solvent may be selected from group comprising ethanol, methanol, dichloromethane or combination thereof, preferably mixture of ethanol and dichloromethane. The formylating agent may be selected from group comprising acetic anhydride and formic acid mixture or formic acid and iodine, preferably acetic anhydride and formic acid mixture. The formylation may be conducted at a temperature range of 15-30 deg. C, preferably in the range of 20-25 deg. C. The reaction may be completed in 7-18 hours.

3. debenzylation and conversion to fumarate salt of compound of formula (V) to obtain compound of formula (I).
The debenzylation of compound of formula (V) may be conducted by hydrogenation using metal catalyst/charcoal in solvent. The metal catalyst may be selected from group comprising palladium on activated carbon, palladium acetate on activated carbon, preferably palladium on carbon. The solvent employed in debenzylation may be selected from group comprising tetrahydrofuran, acetic acid, methanol, ethyl acetate or there mixture thereof, preferably methanol. The hydrogenation may be carried out at 4-8 kg of hydrogen pressure preferably 4 kg. The hydrogen pressure may be maintained for 2-6 hours preferably 3 hours.
The purification and isolation of pure diastereomers RR and SS may be carried out by salt formation and selective crystallization.
The salt formation may be carried out using fumaric acid in solvent. The solvent may be selected from group comprising ethanol, methanol, tetrahydrofuran, preferably tetrahydrofuran. The salt formation may be conducted at a temperature range of 40-65 deg. C for 5 hours, preferably in the range of 50-55 deg. C for 3 hours.
The selective crystallization may be conducted in solvent selected from group comprising ethanol, methanol, tetrahydrofuran, preferably methanol. The crystallization may be conducted at a temperature range 60-70 deg. C, preferably in range of 60-65 deg. C.

4. treating compound of formula (III) with chiral acid in presence of polar solvent followed by treatment with ammonia to obtain R-isomer of compound of formula (IIIA)
(±)-N-Benzyl-N-(1-methyl-2-(4-methoxy phenyl)-ethyl) amine (III) (0.392mol) may be stirred with L-Mandelic acid and Charged with Methylene dichloride. Then pH basic is adjusted by by liq. Ammonia to get (R)-N-Benzyl-N-(1-methyl-2-(4-methoxy phenyl)-ethyl) amine (IIIA).

5. reacting benzyloxy-nitro phenacyl bromide of formula (II) with R-isomer of secondary amine compound of formula (IIIA) to obtain enantiomer of tertiary amine intermediate compound of formula (IVA) in presence of base and metal halide,

(R)-N-Benzyl-N-(1-methyl-2-(4-methoxy phenyl)-ethyl) amine(IIIA) may be dissolved in base and acetone and reacted with 4-benzyloxy-3-nitroacetophenone in presence of metal halide to obtain tertiary amine intermediate of compound of formula (IVA). The base may be selected from group comprising sodium carbonate, potassium carbonate, lithium carbonate, preferably potassium carbonate. The metal halide may be selected from group comprising sodium iodide, potassium iodide, preferably potassium iodide. The reaction may be conducted at a temperature range of 20-40 deg. C, preferably in the range of 30-35 deg. C for 24 hours.

6. one pot reduction of keto of compound of formula (IVA) with reducing agent (1) and polar solvent and reduction of nitro group of compound of formula (IVA) on solid support with ferric chloride in presence of polar solvent and reducing agent (2) and then formylation of amino group of compound of formula (IVA) with formylating agent and organic solvent to obtain compound of formula (VA)
The keto group present in tertiary amine compound of formula (IVA) may be reduced in presence of polar solvent. The reduction may be may be conducted with a suitable reducing agent selected from the group comprising sodium borohydride, lithium triethylborohydride, L-Selectride, preferably, sodium borohydride. The polar solvent may be selected from group comprising tetrahydrofuran, methanol, ethanol, isopropanol, preferably methanol. The reaction may be conducted at a temperature range of 40-70 deg. C, preferably in the range of 50-55 deg. C.
The nitro group present in tertiary amine compound of formula (IVA) may be reduced on solid support and ferric chloride in polar solvent. The reduction may be may be conducted with a suitable reducing agent selected from the group comprising hydrazine hydrate, catalytic hydrogenation using palladium-on-carbon, platinum(IV) oxide, Raney nickel preferably, hydrazine hydrate. The solid support may be may be selected from the group comprising carbon, silica, neutral alumina preferably, neutral alumina. The polar solvent may be selected from group comprising methanol, ethanol, isopropanol, preferably methanol. The reaction may be completed in 20-30 hours.
The formylation of amino compound in organic solvent to converted N-formyl derivative of compound of formula (VA) by using formylating agent. The organic solvent may be selected from group comprising ethanol, methanol, dichloromethane or combination thereof, preferably mixture of ethanol and dichloromethane. The formylating agent may be selected from group comprising acetic anhydride and formic acid mixture or formic acid and iodine, preferably acetic anhydride and formic acid mixture. The formylation may be conducted at a temperature range of 15-30 deg. C, preferably in the range of 20-25 deg. C. The reaction may be completed in 7-18 hours.

7. debenzylation of compound of formula (VA) by hydrogenation with metal catalyst/charcoal in organic solvent and purification and isolation by salt formation of compound of formula (VA) in presence of tartaric acid and organic solvent and selective crystallization in presence of organic solvent to obtain compound of formula (I).
The debenzylation of compound of formula (VA) may be conducted by hydrogenation using metal catalyst/charcoal in solvent. The metal catalyst may be selected from group comprising palladium on activated carbon, palladium acetate on activated carbon, preferably palladium on carbon. The solvent employed in debenzylation may be selected from group comprising tetrahydrofuran, acetic acid, methanol, ethyl acetate or there mixture thereof, preferably methanol. The hydrogenation may be carried out at 4-8 kg of hydrogen pressure preferably 4 kg. The hydrogen pressure may be maintained for 2-6 hours preferably 3 hours.
The purification and isolation of pure enantiomer (R, R) may be carried out by salt formation and selective crystallization.
The salt formation may be carried out using fumaric acid in solvent. The solvent may be selected from group comprising ethanol, methanol, tetrahydrofuran, preferably tetrahydrofuran. The salt formation may be conducted at a temperature range of 40-65 deg. C for 5 hours, preferably in the range of 50-55 deg. C for 3 hours.
The selective crystallization may be conducted in solvent selected from group comprising ethanol, methanol, tetrahydrofuran, preferably methanol. The crystallization may be conducted at a temperature range 60-70 deg. C, preferably in range of 60-65 deg. C.

In one embodiment, the compound of Formula-I is Formoterol fumarate dihydrate, Arformoterol tartrate.

The dihydrate form of Formoterol fumarate is characterized by one or more of following properties:
a) X-ray diffraction pattern having characteristic peaks at about 5.5, 9.2, 11.2, 12.4, 26.4 degrees.
b) Water content in an amount ranging from 4.77 to 4.89 wt %.
c) Weight loss in range of 2.9 - 3.8% at around 100 oC.
d) The M.P in range of 121-127 oC as measured by DSC characteristic to dihydrate form of Formoterol fumarate.

Without being limited by the theory, the process of the present invention provides a novel and efficient process for the preparation of formoterol of formula 1. The process of present invention provides preparation of highly pure formoterol fumarate dihydrate possessing 99.79 % (HPLC) and arformetrol possessing 99.79 % (HPLC) with impurities below the specified limits in various pharmacopoeias . The process of present invention avoids large no. of steps, purification in the intermediate steps, which are tedious, help in cost reduction and low yielding. The process of present invention eliminates the use of toxic and hazardous chemicals like benzene and crown ethers and utilizes better solvents like methanol which are economically and commercially viable and environment friendly. The process of present invention also provides one pot reaction (reduction of keto and nitro group and formylation of amine) which avoids lengthy separation and purification of the intermediate chemical compounds which ultimately would save time and resources while increasing chemical yield.
The invention is now described in detail with reference to the following examples; however, the following examples should not be construed as limiting the scope of the present invention in any way.

Example 1: Preparation of Formoterol Fumarate Dihydrate (I)
Stage-I
Preparation of 2-(benzyl (4-methoxyphenethyl) amino)-1-(4-(benzyloxy)-3-nitrophenyl) ethanone:

Charge 40.0L of acetone (8.9 volumes) , 4.5kg of potassium carbonate (32.56 mol) and 4.50 kg of (±)-N-Benzyl-N-(1-methyl-2-(4-methoxy phenyl)ethyl) amine (17.62 mol) (III) in a glass flask under stirring and maintain at 25°C±5°C, stir for 15 minutes and added 4.50 kg of 4-Benzyloxy-3-nitro acetophenone(12.85 mol)(II) , 0.27kg of potassium iodide (1.63 mol) and maintained at 30°C±2°C for 24 hours±30min., in-process check by TLC for absence of 4-Benzyloxy-3-nitro acetophenone, adding 135L of purified water at 30°C±2°C and stir at same temperature for 02 hours . Filter the material through centrifuge and wash with 135L of purified water and spin dry for 30 minutes. Wet cakes unload in a poly bag.
Charge 90L of methanol (20 volumes) in a glass flask and added above wet cake and maintain at 40°C±2°C for 02 hours. Cool to 0°C and stir at 0°C±5°C for one hour. Filter the material through Centrifuge and wash with 5.0 L of methanol, spin dry for 30 minutes. Dry the wet material at 35°C±5°C till moisture content less than 2.0%. Yield =5.78 kg (85.76%), HPLC Purity=97.5%

Stage-II
Preparation of N-(5-(2-(benzyl (1-(4-methoxyphenyl) propan-2-yl) amino)-1-hydroxy ethyl)-2-(benzyloxy) phenyl)formamide

Charge 120.0 L of methanol (20.76 volumes), 5.78kg of stage-I (11.02 mol), cool to 15°C, added 1.20 kg of sodium borohydride (31.72 mol) solution with 1.2 L of sodium hydroxide (1N) at 20°C±5°C,maintained at 50°C±5°C for one hour, in- process check by TLC for absence of stage-I.

Reaction mass cool to 30°C±2°C, added 7.5L of hydrazine hydrate (152.8 2mol), 1.2 kgof activate charcoal, 0.6 kg of neutral alumina, heated to 45°C and added 0.245kg of ferric chloride (1.51mol) solution in 3.0L of methanol. Raised the temperature up to reflux, reflux for 24 hours. In- process check by TLC for absence of previous material. Cool to 30°C±5°C, Filter the reaction mass through hyflow bed and wash with 3.0L of methanol, combine the filtrate and washing, distilled under vacuum at 50°C till thick mass, cool to 25°C±5°C.
Added 50.0L of MDC (8.7 volumes) and stir till clear solution, wash with 20L of purified water (3.46 volumes). Separate MDC layer, charge MDC layer in a glass flask, added 10L of ethanol (1.73volumes), cool to 0°C, added premix 6.0L of acetic anhydride (63.53 mol) and 3.0L of formic acid (79.57 mol) at 0°C±5°C, maintained at same temperature for one hour. Raised the temperature up to 18°C, maintained at 20°C±2°C for 12±4hours, in-process check by TLC-less than 5.0% of previous material. Cool to 0°C and adjust pH neutral by liq. ammonia and wash with 10L of purified water (1.73 volumes), collect MDC layer in a glass flask, distilled till thick mass under reduced pressure, degases with 2.0L of acetone (0.35 volumes), charge 30L of acetone (5.2 volumes). Raised the temperature up to 55°C±5°C, added 0.65kg of fumaric acid (5.60 mol) at 55°C±5°C, maintain for 03 hours at 55°C±5°C. Cool to 25°C±5°C, maintain at same temperature for 12 hours. Filter through centrifuge and wash with 6.0L of acetone (1.04 volumes), wet material unload in polythene bag. Charge 25L of purified water (4.33 volumes) in a glass assembly, added above wet cake in purified water, stir for 30 minutes. Adjust pH neutral by liq. Ammonia, stir for 30 minutes. Filter through centrifuge and wash with purified water till neutral pH Wet material dry at 50°C±5°C till moisture content less than 1.0%, Yield = 3.22 kg (55.71%)

Charge 30L of acetone (9.32 volumes),3.22 kg of crude (6.14mol) (Having HPLC Purity=91.7%, isomer=3.9%)and heat to 55°C±5°C than added 0.65 kg of fumaric acid (5.6mol) than maintained for 03 hours at same temperature. Cool to 25°C±5°C, stir for 12 hours at same temperature. Filter through centrifuge and wash with 3.0L of acetone (0.93volumes), spin dry for 15 minutes

Charge 25L of purified water, added above wet cake in a glass assembly. Adjust pH neutral liq. Ammonia at ambient temperature, stir for 30 minutes. Filter through centrifuge and wash with purified water till neutral pH, spin dry for 15 minutes. Wet material is dry at 50°c±5°c till moisture contents less than 1.0%
(This process repeated 4 times)
Yield =1.05kg (18.17%)
HPLC purity= 97.85% (RR &SS

Stage-III

Charge 11.0L of methanol (10.54 volumes), 1.044kg of stage-II (1.99 mol) in a hydrogenator, added 0.44kgof palladium charcoal (0.42w/w) containing 2.5L of methanol (2.4volumes). Raised the temperature up to 30°C±5°C, apply hydrogen gas and attained 4.0 kg of hydrogen pressure, maintained for 3 hours. In- process check by TLC for absence of stage-II. Filter through hyflow bed and wash with 2.5L of methanol (2.4 volumes).Collect the filtrate in a glass flask, recovery of methanol under vacuum at 55°C±5°C. Cool to 25°C±5°C, added 6.0L of tetra hydro furan (5.75volumes), 0.11L of purified water (0.1volumes). Raised the temperature up to 50°C, added 0.13kg of fumaric acid (1.12mol) at 55°C±5°C. Maintained for 03 hours at 55°C±5°C. Cool to 30°C±2°C, maintained for 02 hours at same temperature. Filter through centrifuge and washed with 1.0L of tetrahydrofuran (0.96volumes). Dry the wet material in tray dryer at 40°C±5°c till moisture content less than 10%. Crude Yield=0.52kg (62.13%), HPLC purity= 97.43%

Charge 3.0L of methanol (5.77volumes), 0.52kg of stage-III (0.62mol) in a glass flask. Raised the temperature up to 60°C, stir till clear solution at 65°C±5°C, added 0.06 kg of charcoal activated at 65°C±5°C, stir for 30 minutes at same temperature. Filter through hyflow bed and wash with 0.7L of methanol (1.35volumes). Collect the filtrate and washing in a glass flask, cool to 25°C±5°C. Maintain at same temperature for 12 hours, cool to 0°C, maintain for 02 hours at 0°C±5°C. Filter through centrifuge and wash with 0.4L of methanol (0.77volumes) and spin dry for 30 minutes. Dry the wet material in tray drier at 50°C±5°C until the moisture content between 4.0% to 5.0%.

Charge 2.5L of methanol (4.8volumes) and above dried material in a glass flask. Heated to 65°C±5°C, stir till clear solution at same temperature, added 0.06 kg of charcoal activated at 65°C±5°C, stir for 30 minutes. Filter the reaction mass through hyflow bed and washed with 0.7L of methanol (1.35volumes). Collect the filtrate and washing in a glass flask. Cool to 25°C±5°C, stir for 12 hours at same temperature, Cool to 0°C, stir for 02 hours at same temperature. Filter through centrifuge and wash with 0.4L of methanol (0.77volumes), spin dry for 30 minutes. Wet material dry in vacuum tray drier at 50°C±5°C until the moisture content between 4.0% to 5.0%
Yield=0.342kg (40.86%)
HPLC purity= 99.79% ( RR & SS), 0.2%(RS &SR)

Example 2: Preparation of Arformoterol tartrate pure enantiomer (R, R)

Stage-I: Charge 1.0 L of Methanol (10.0 volumes) , 100gm of (±)-N-Benzyl-N-(1-methyl-2-(4-methoxy phenyl)-ethyl) amine (0.392mol), 70.0 gm of L-Mandelic acid (0.460mol) in a glass flask under stirring, heated to reflux and maintain reflux for 02hours. Cool to 20°c to 25°c and maintain for 18hours at 25°c±5°c, Filter the material and wash with 100 ml of Methanol and spin dry for 30 minutes. Wet cake unload in a poly bag, wet material is dry at 50°c±5°c for one hour. Charge 325 ml of Methylene dichloride (3.25 volume) in a glass flask and added above wet cake and adjust pH basic by liq. Ammonia, add 100 ml of purified water, separate methylene dichloride layer and dry over sodium sulphate, distil methylene dichloride layer under vacuum to get (R)-N-Benzyl-N-(1-methyl-2-(4-methoxy phenyl)-ethyl) amine.
Yield =47gm (94.0%)
Specific Optical Rotation=-35.36° (standard SOR=-35°)

Stage-II:

Acetone/Potassium carbonate/ potassium iodide

Charge 135 ml of acetone (9.0volumes), 15 gm of potassium carbonate (0.11mol). Cool to 0°c to 5°c, add 13.5 gm of (R)-N-Benzyl-N-(1-methyl-2-(4-methoxy phenyl)-ethyl) amine (0.053mol), 15 gm of 4-Benzyloxy-3-Nitro acetophenone (0.043mol), 0.90gm of potassium iodide (0.005mol) and maintained at 0°c to 5°cfor 24 hours±30min., in-process check by TLC-absence of 4-benzyloxy-3-Nitro acetophenone, adding 450 ml of purified water at 0°c to 10°c and stir at same temperature for 01 hour. Filter the material and wash with 450 ml of purified water and spin dry for 30 minutes. Wet cake unload in a poly bag.Charge 150 ml of methanol (10 volume) in a glass flask and added above wet cake and maintain at40°c±2°c for 02 hours. Cool to 0°c and stir at 0°c±5°c for one hour. Filter the material and wash with 15 ml of methanol, spin dry for 30 minutes. Dry the wet material at 35°c±5°c till moisture content less than 2.0%.
Yield =16gm (71.2%)
HPLC Purity=99.33%
Stage-III:

Methanol/ sodium borohydride

Hydrazine hydrate/ Ferric chloride
Acetic anhydride/ formic acid
Fumaric acid / liq. Ammonia

Charge 240 ml of methanol (10.0volume), 24.0 gm of stage-II (0.046mol), cool to 20°c±(5°c), added 4.8 gm of sodium borohydride (0.13mol) solution with 24 ml of sodium hydroxide (1N) at 20°c±(5°c),maintained at 40°c to 45°c for one hour, in- process check by TLC-absence of stage-I. Reaction mass cool to 30°c±(2°c),added 56.8 mlof hydrazine hydrate (0.93mol), 2.4 gmof activate charcoal, 4.8 gmof neutral alumina, heated to 50°c and added2.0 gm of ferric chloride (0.012mol) solution in 24 ml of methanol. Raised the temperature up to reflux, reflux for 56hours. In- process check by TLC-absence of previous material. Cool to 40°c to 45°c, Filter the reaction mass through hyflow bed and wash with 30 ml of methanol, Combine the filtrate and washing, distilled under vacuum at 50°c till thick mass, cool to 35°c. Added 240 ml of MDC (10.0volume) and stir till clear solution, wash with 120 ml of purified water (5.0volume). Separate MDC layer, charge MDC layer in a glass flask, added 48 ml of ethanol (2.0volume), cool to 0°c, added premix 25.6 gm of acetic anhydride (0.25mol) and 12.0 ml of formic acid (0.32mol) at 0°c±5°c,maintained at same temperature for one hour. Raised the temperature up to 18°c, maintained at 20°c±2°c for 24±4hours, in-process check By TLC-less than 5.0% of previous material. Cool to 0°c and adjust pH neutral byliq. Ammonia and wash with 48 ml of purified water (2.0volume), collect MDC layer in a glass flask, distilled till thick mass under reduced pressure, degases with 24 ml of acetone (1.0volume), charge 97.0 ml of acetone (4.0volume), purified water 3.0 ml (0.13volume), raised the temperature up to 55°c±5°c, added 2.64 gm of fumaric acid (0.023mol) at 55°c±5°c, maintain for 03 hours at 55°c±5°c. Cool to 25°c±5°c, maintain at same temperature for 12 hours. Filter through centrifuge and wash with 24.0 ml of acetone (1.0volume), wet material unload in polythene bag. Charge 48 ml of purified water (2.0volume) in a glass assembly, added above wet cake in purified water, stir for 30 minutes. Adjust pH neutral by liq. Ammonia, stir for 30 minutes. Filter through centrifuge and wash with purified water till neutral pH Wet material dry at 50°c±5°c till moisture content less than 1.0%.
Yield = 5.0gm (20.83%)
HPLC purity= 98.2%

Stage-IV:

Methanol
Palladium charcoal
Hydrogen gas

Charge 30 ml of methanol (10.0volume), 3.0 gm of stage-III (0.0057mol) ina par hydrogenator, added 1.5 gm of palladium charcoal (0.5volume) containing 9.0 ml of methanol (3.0volume). Raised the temperature up to 30°c±5°c, apply hydrogen gas and attained 4.0 kg of hydrogen pressure, maintained for 4.0 hours. In- process check by TLC –absence of stage-III. Filter through hyflow bed and wash with 9.0 ml of methanol (3.0 volume).Collect the filtrate in a glass flask, recovery of methanol under vacuum at 55°c±5°ctill thick mass.
Yield=1.8gm (free base Arformoterol oil)
HPLC Purity=92.28%
Specific Optical Rotation=-39.15° (standard SOR=-40°)

Stage-V:

Ethanol
Isopropyl alcohol
L-(+)-Tartaric acid

Charge 15 ml of ethanol (10.0volume), 1.5 gm of stage-IV (0.0044mol), 8.0 ml of isopropyl alcohol (5.3 volume), 2.3 ml of Purified water (1.5 volume), 1.5 gm of L-(+)-Tartaric acid in a round bottom glass flask, heat to 70°c to 80°c and continue stir till clear solution. Cool to 25°c to 30°c, stir for 02hours. Cool to 0°c to 5°c, stir for 6hours, filter and suck dry. Wet material is dry at 40°c±5°c till constant weight.
Yield=0.8gm
HPLC Purity=98%
Specific Optical Rotation=-30.04° (standard SOR=-30°)

CLAIMS:
1. A novel process for the preparation of compound of formula (I) and its salt, hydrates and stereoisomer;

comprising the steps of:
viii. reacting benzyloxy-nitro phenacyl bromide of formula (II) with secondary amine compound of formula (III) to obtain tertiary amine intermediate compound of formula (IV) in presence of base and metal halide

ix. one pot reduction of keto group of compound of formula (IV) with a reducing agent (1) and polar solvent and reduction of nitro group of compound of formula (IV) on solid support with ferric chloride in presence of polar solvent and reducing agent (2) and then formylation of amino group of compound of formula (IV) to obtain compound of formula (V) with formylating agent and organic solvent.

x. debenzylation of compound of formula (V) by hydrogenation with metal catalyst/charcoal in organic solvent and purification and isolation by salt formation of compound of formula (V) in presence of fumaric acid and organic solvent and selective crystallization in presence of organic solvent to obtain compound of formula (I).
wherein the compound of formula (I) is 1:1 racemic isomer (R,R : S,S)
and salt, hydrate ratio is 2:1:2.

xi. treating compound of formula (III) with chiral acid in presence of polar solvent followed by treatment with ammonia to obtain R-isomer of compound of formula (IIIA)


xii. reacting benzyloxy-nitro phenacyl bromide of formula (II) with R-isomer of secondary amine compound of formula (IIIA) to obtain enantiomer of tertiary amine intermediate compound of formula (IVA) in presence of base and metal halide,

xiii. one pot reduction of keto of compound of formula (IVA) with reducing agent (1) and polar solvent and reduction of nitro group of compound of formula (IVA) on solid support with ferric chloride in presence of polar solvent and reducing agent (2) and then formylation of amino group of compound of formula (IVA) with formylating agent and organic solvent to obtain compound of formula (VA)

xiv. debenzylation of compound of formula (VA) by hydrogenation with metal catalyst/charcoal in organic solvent and purification and isolation by salt formation of compound of formula (VA) in presence of tartaric acid and organic solvent and selective crystallization in presence of organic solvent to obtain compound of formula (I).

wherein the compound of formula (I) is pure enantiomer (R, R) and salt ratio is 1:1.

2. The process as claimed in claim 1, wherein the compound of the formula (I) is Formoterol fumarate dihydrate, Arformoterol tartrate.

3. The process as claimed in claim 1, wherein the compound of the formula (I) is Formoterol fumarate, Arformoterol tartrate and hydrates, stereoisomers thereof.

4. The process as claimed in claim 1(i) and claim1 (v), wherein the base is selected from group comprising sodium carbonate, potassium carbonate, lithium carbonate, preferably potassium carbonate and the metal halide is selected from group comprising sodium iodide, potassium iodide, preferably potassium iodide and

5. The process as claimed in claim 1, wherein the reaction in step (i) is conducted at a temperature in the range of 20-40 deg. C, preferably in the range of 28-32 deg. C for 24 hours and the reaction in step (v) is conducted at temperature in the range of 0-5 deg.C for 24 hours.

6. The process as claimed in claim 1(ii) and claim(1)(vi), wherein the reducing agent(1) is selected from the group comprising sodium borohydride, lithium triethylborohydride, L-Selectride, preferably, sodium borohydride and the reducing agent(2) is selected from the group comprising hydrazine hydrate, catalytic hydrogenation using palladium-on-carbon, platinum(IV) oxide, Raney nickel preferably, hydrazine hydrate and the solid support is selected from the group comprising carbon, silica, neutral alumina preferably, neutral alumina and the organic solvent is selected from the group comprising ethanol, methanol, dichloromethane or combination thereof, preferably mixture of ethanol and dichloromethane.

7. The process as claimed in claim 1(ii) and claim (1)(vi), the formylating agent is selected from group comprising acetic anhydride and formic acid mixture or formic acid and iodine, preferably acetic anhydride and formic acid mixture and the reaction is conducted at a temperature range of 15-30 deg. C, preferably in the range of 18-22 deg. C. and the reaction is completed in 7-18 hours.

8. The process as claimed in claim 1(iii) and claim1(vii), wherein the metal is selected from group comprising palladium on activated carbon, palladium acetate on activated carbon, preferably palladium on carbon and the organic solvent is selected from group comprising tetrahydrofuran, acetic acid, methanol, ethyl acetate or there mixture thereof, preferably methanol, tetrahydrofuran.

9. The process as claimed in claim 1(iii) and claim1(vii), wherein the salt formation reaction is conducted at a temperature range of 40-65 deg. C for 5 hours, preferably in the range of 50-60 deg. C for 3 hours and the crystallization is conducted at a temperature range 20-70 deg. C, preferably in range of 30-60 deg. C.

10. The process as claimed in claim 1, wherein the polar solvent is selected from group comprising tetrahydrofuran, methanol, ethanol, isopropanol, preferably methanol.