Field of the Invention:
The present invention relates to an improved process for the preparation of N-[2-hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-2(4-methoxyphenyl)-l-methylethyl]amino]ethyl] phenyl]-formamide tartrate compound of formula-1.

Formula-1
Background of the Invention:
US3994974 discloses a variety of a-aminomethylbenzyl alcohol derivatives, processes for their preparation, pharmaceutical compositions comprising the derivatives, and method of use thereof. These compounds have the utility as p-adrenergic stimulants and thus have great activity on respiratory smooth muscle and are suitable as bronchodilating agents. Among them, Formoterol, (±)-N-[2-hydroxy-5-[l-hydroxy-2-[[2-(4-methoxyphenyl)-l-methylethyl] amino] ethyl]phenyl] formamide, is a highly potent and P2-selective adrenoceptor agonist having a long lasting bronchodilating effect when inhaled.
Various processes for the preparation of formoterol, its enantiomers and related compounds, and their pharmaceutically acceptable salts are disclosed in US3994974; US5434304; US6268533 and US6472563; Chem. Pharma. Bull.-1978, 26, 1123-1129; Chirality-1991, 3, 443-450; Drugs of the Future-2006, 31,(11), 944-952.
Murase et al. [Chem.Pharma.Bull.-1978, 26, (4), 1123-1129 synthesized all four isomers of formoterol and examined for p2-stimulant activity. In the process, racemic formoterol was subjected to optical resolution with tartaric acid.
The syntheses of all four isomers of formoterol have been reported in the journals, Chem. Pharma. Bull.-1978, 26, 1123-1129 (hereinafter referred to as the 'CPB Journal') and Chirality-1991, 3, 443-450 (hereinafter referred to as the 'Chirality journal'. In the CPB Journal, the (R,R) and (S,S)-isomers are obtained by diastereomeric crystallization of racemic formoterol with tartaric acid. In the Chirality journal, racemic 4-benzyloxy-3-nitrostyrene oxide is coupled with an optically pure (R,R) or (S,S)-N-(l-phenylethyl)-N-(l-(p-methoxy phenyl)-2-propyl)amine to give a diastereomeric mixture of formoterol precursors, which are

then separated by semi-preparative HPLC and transformed to the pure formoterol isomers. Both syntheses suffer long synthetic procedure and low overall yield and are impractical for large scale production of optically pure (R,R) or (S,S)-formoterol.
Hence, there is an obvious need in the art to develop an alternate process for the preparation of Formoterol and its enantiomers.
Brief Description of the Invention:
The first aspect of the present invention is to provide a process for the preparation of N-[2-hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-2(4-methoxyphenyl)-l-methylethyl]amino] ethyl]phenyl]-formamide tartrate compound of formula-1, comprising of the following steps:
a) Reacting (R)-N-benzyl-l-(4-methoxyphenyl)propan-2-amine L-(+)-mandelate compound of formula-10a with sodium carbonate in a suitable solvent to provide (R)-N-benzyl-l-(4-methoxy phenyl)propan-2-amine compound of formula-10,
b) reacting the compound of formula-10 with 2-(4-(benzyloxy)-3-nitrophenyl)oxirane compound of formula-7 at a suitable temperature to provide 2-(benzyl((R)-l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanol compound of formula-11,
c) reducing the compound of formula-11 with a suitable reducing agent in presence of acetic acid in a suitable solvent to provide l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl((R)-l-(4-methoxyphenyl)propan-2-yl)amino)ethanol compound of formula-12,
d) reacting the compound of formula-12 with formic acid in a suitable solvent to provide (R)-N-(5-(2-(benzyl-( 1 -(4-methoxyphenyl)propan-2-yl)amino)-1 -hydroxyethyl)-2-(benzyloxy)phenyl) formamide compound of formula-13,
e) debenzylating the compound of formula-13 by treating it with a suitable debenzylating agent in a suitable solvent to provide N-(2-hydroxy-5-(l-hydroxy-2-((R)-l-(4-methoxy phenyl)propan-2-yl-amino)ethyl)phenyl)formamide compound of formula-14,
f) treating the compound of formula-14 with L(+)-tartaric acid in a suitable solvent to provide N-[2-hydroxy-5-[(l R)-1 -hydroxy-2-[[(l R)-2(4-methoxyphenyl)-l -methyl ethyl]amino]ethyl]phenyl]-formamide tartrate compound of formula-1.

The second aspect of the present invention is to provide a process for the preparation of 1 -(3 -amino-4-(benzyloxy)phenyl)-2-(benzyl((R)-1 -(4-methoxyphenyl)propan-2-yl)amino) ethanol compound of formula-12, comprising of reducing 2-(benzyl((R)-l-(4-methoxy phenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanol compound of formula-11 with a suitable reducing agent in presence of acetic acid in a suitable solvent to provide compound of formula-12.
The third aspect of the present invention is to provide a process for the preparation of (R)-N-(5-(2-(benzyl-(l-(4-methoxyphenyl)propan-2-yl)amino)-l-hydroxyethyl)-2-(benzyl oxy)phenyl) formamide compound of formula-13, comprising of reacting l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl((R)-l-(4-methoxyphenyl)propan-2-yl)amino)ethanol compound of formula-12 with formic acid to provide compound of formula-13.
The fourth aspect of the present invention is to provide a process for the preparation
of N-[2-hydroxy-5-[( 1R)-1 -hydroxy-2-[[( 1 R)-2(4-methoxyphenyl)-1 -methylethyl] amino]
ethyl] phenyl]-formamide tartrate compound of formula-1, comprising of treating the
compound of formula-14 with L-(+)-tartaric acid in a suitable solvent to provide N-[2-
hydroxy-5-[(lR)-l -hydroxy-2-[[(lR).-2(4-methoxyphenyl)-l -methylethyl] amino]ethyl]
phenyl]-formamide tartrate compound of formula-1.
The fifth aspect of the present invention is to provide a process for the preparation of l-(4-(Benzyloxy)-3-nitrophenyl)-2-bromoethanone compound of formula-5 comprising of reacting 4-benzyloxy-3-nitroacetophenone compound of formula-4 with a suitable brominating agent in presence of a suitable catalyst in a suitable solvent to provide compound of formula-5.
Brief Description of the Drawings:
Figure 1: Illustrates the PXRD pattern of crystalline form-M of N-[2-hydroxy-5-[(lR)-l-
hydroxy-2-[[(lR)-2(4-methoxy phenyl)-l-methylethyl]amino]ethyl]phenyl]-formamide
tartrate.
Figure 2: Illustrates the DSC thermogram of crystalline form-M of N-[2-hydroxy-5-[(lR)-l-
hydroxy-2-[[(lR)-2(4-methoxy phenyl)-l-methylethyl]amino]ethyl]phenyI]-formamide
tartrate.

Detailed Description of Invention:
The term "suitable solvent" used in the present invention refers to "hydrocarbon solvents" such as n-hexane, n-heptane, cyclohexane, pet ether, benzene, toluene, xylene and the like; "ether solvents" such as dimethyl ether, diethyl ether, methyl tert-butyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, 1,4-dioxane and the like; "ester solvents" such as methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate and the like; "polar-aprotic solvents such as dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone (NMP) and the like; "chloro solvents" such as methylene chloride, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyronitrile and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, t-butanol and the like; "polar solvents" such as water; acetic acid or mixtures thereof.
The term "suitable base" used in the present invention refers to inorganic bases selected from "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate, lithium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide, lithium tert.butoxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride, lithium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide and the like; ammonia; and organic bases like methylamine, dimethylamine, diethylamine, diisopropyl amine, diisopropylethylamine, diisobutylamine, triethylamine, tributylamine, tert.butyl amine, pyridine, 4-dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), 2,6-lutidine, lithium diisopropylamide (LDA), l,8-diazabicyclo[5.4.0]undec-7-ene (DBU), l,5-diazabicyclo[4.3.0]non-5-ene (DBN), l,4-diazabicyclo[2.2.2]octane (DABCO) and the like; organosilicon bases such as lithium hexamethyldisilazide (LiHMDS), sodium hexamethyldisilazide (NaHMDS), potassium hexamethyldisilazide (KHMDS); n-butyl lithium or mixtures thereof.
The term suitable "reducing agent" used in the present invention refers to Ni, Raney Ni, Pd/C, Pt/C, Pt02, Fe, Fe in acidic media like acetic acid; NH4C1; Sn-acetic acid, stannous chloride (SnCl2), Zn in acidic media like acetic acid; NH4C1; Zinc dust, DIBAL-H, lithium

aluminiumhydride, sodium borohydride, potassium borohydride, lithium borohydride, sodium aluminium hydride, diborane, hydrazine hydrate, sodium dithionate, sodium sulfide, ammonium sulfide, Na-Hg/H2, borane-tetrahydrofuran, NaBH3CN, sodium borohydride/BF3-etherate, vitride, sodium borohydride/aluminium chloride or borane/aluminium chloride, sodium borohydride/iodine and borane-DMS.
The first aspect of the present invention provides a process for the preparation of N-[2-hydroxy-5 -[(1R)-1 -hydroxy-2- [ [(1 R)-2(4-methoxyphenyl)-1 -methylethyl] amino] ethyl]phenyl]-formamide tartrate compound of formula-1, comprising of the following steps:
a) Reacting (R)-N-benzyl-l-(4-methoxyphenyl)propan-2-amine L-(+)-mandelate
compound of formula-10*
with sodium carbonate in a suitable solvent provides (R)-N-benzyl-l-(4-methoxyphenyl)propan-2-amine compound of formula-10,

b) reacting the compound of formula-10 with 2-(4-(benzyloxy)-3-nitrophenyl)oxirane
compound of formula-7,
at a suitable temperature in absence of solvent provides 2-(benzyl((R)-l-(4-
methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanol compound of formula-11,

Formula-11

c) reducing the compound of formula-11 with a suitable reducing agent in presence of
acetic acid in a suitable solvent provides l-(3-amino-4-(benzyloxy)phenyl)-2-
(benzyl((R)-l-(4-methoxyphenyl)propan-2-yl)amino) ethanol compound of formula-

Formula-12
d) reacting the compound of formula-12 with formic acid in absence of a solvent
provides (R)-N-(5-(2-(benzyl-( 1 -(4-methoxyphenyl)propan-2-yl)amino)-1 -hydroxy
ethyl)-2-(benzyloxy)phenyl)-formamide compound of formula-13,

Formula-13
e) debenzylating the compound of formula-13 by treating it with a suitable
debenzylating agent in a suitable solvent provides N-(2-hydroxy-5-(l-hydroxy-2-((R)-
l-(4-methoxyphenyl) propan-2-yl-amino)ethyl)phenyl)formamide compound of
formula-14,
Formula-14
f) treating the compound of formula-14 with L(+)-tartaric acid in a suitable solvent
provides N-[2-hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-2(4-methoxy phenyl)-1-methyl
ethyl]amino]ethyl]phenyl]-formamide tartrate compound of formula-1.
Wherein;
in step-a) the suitable solvent is selected from chloro solvents, ester solvents, ketone solvents,

hydrocarbon solvents, polar aprotic solvents, polar solvents such as water or
mixture thereof, in step-b) the suitable temperature is ranging from ambient temperature to 150°C; preferably
at 70-130°C; more preferably at 110-115°C; in step-c) the suitable reducing agent is selected from iron, zinc, tin in combination with
acetic acid and suitable solvent is selected from chloro solvents, alcohol solvents,
ester solvents, polar solvents such as water and acetic acid or mixture thereof; in step-e) the suitable debenzylating agent is selected from Pd/C, palladium acetate, platinum
oxide, platinum black, Rh/C, Ni, Ir, Ru and the like in combination with hydrogen;
and the suitable solvent is selected from alcohol solvents; in step-f) the suitable solvent is selected from ester solvents, alcohol solvents, chloro
solvents, ether solvents, polar solvents such as water or mixture thereof.
In a preferred embodiment of the present invention provides a process for the preparation of N-[2-hydroxy-5-[( 1R)-1 -hydroxy-2-[[( 1 R)-2(4-methoxyphenyl)-1 -methyl ethyl] amino] ethyl]phenyl]-formamide tartrate compound of formula-1, comprising of the following steps:
a) Reacting (R)-N-benzyl-l-(4-methoxyphenyl)propan-2-amine L-(+)-mandelate compound of formula-10a with sodium carbonate in a mixture of methylene chloride and water provides (R)-N-benzyl-l-(4-methoxy phenyl)propan-2-amine compound of formula-10,
b) reacting the compound of formula-10 with 2-(4-(benzyloxy)-3-nitrophenyl)oxirane compound of formula-7 at 110-115°C provides 2-(benzyl((R)-l-(4-methoxyphenyl) propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanol compound of formula-11,
c) reducing the compound of formula-11 with iron in presence of acetic acid in toluene provides 1 -(3 -amino-4-(benzyloxy)phenyl)-2-(benzyl((R)-1 -(4-methoxy phenyl) propan-2-yl)amino) ethanol compound of formula-12,
d) reacting the compound of formula-12 with formic acid provides (R)-N-(5-(2-(benzyl-(1 -(4-methoxyphenyl)propan-2-yl)amino)-1 -hydroxyethyl)-2-(benzyloxy)phenyl) formamide compound of formula-13,
e) debenzylating the compound of formula-13 with Pd/C in a mixture of methanol and isopropanol provides N-(2-hydroxy-5-(l-hydroxy-2-((R)-l-(4-methoxyphenyl) propan-2-yl-amino) ethyl)phenyl)formamide compound of formula-14,

f) treating the compound of formula-14 with L(+)-tartaric acid in presence of a mixture
of ethyl acetate and methanol provides N-[2-hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-
2(4-methoxyphenyl)-l-methylethyl]amino]ethyl]phenyl]-formamide tartrate
compound of formula-1.
The second aspect of the present invention provides a process for the preparation of 1-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl((R)-l-(4-methoxyphenyl)propan-2-yl)amino) ethanol compound of formula-12, comprising of reducing 2-(benzyl((R)-l-(4-methoxy phenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl) ethanol compound of formula-11 with a suitable reducing agent in presence of acetic acid in a suitable solvent provides compound of formula-12.
Wherein the suitable solvent used is same as defined in step-a) of first aspect of the present invention.
In a preferred embodiment of the present invention provides a process for the preparation of 1 -(3 -amino-4-(benzyloxy)phenyl)-2-(benzyl((R)-1 -(4-methoxyphenyl)propan-2-yl)amino)ethanol compound of formula-12, comprising of reducing 2-(benzyl((R)-l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl) ethanol compound of formula-11 with iron in presence of acetic acid in toluene provides compound of formula-12.
IE2000138 discloses the reduction of compound of formula-11 with iron in strong acidic media like hydrochloride to provide compound of formula-12. The usage of hydrochloric acid results in the formation of high level of unwanted bi-products and impurities which leads to decrease in the yield as well as purity of the product.
Whereas, the present invention involves the usage of Iron with weak acidic medium like acetic acid for the reduction of nitro group of compound of formula-11 to provide the compound of formula-12. It is observed that, replacement of hydrochloric acid with acetic acid controlled the level of impurities and unwanted bi-products and increased the yield and purity of the product. Hence the present invention is advantageous over the prior art.
The third aspect of the present invention provides a process for the preparation of (R)-N-(5-(2-(benzyl-( 1 -(4-methoxyphenyl)propan-2-yl)amino)-1 -hydroxyethyl)-2-(benzyl oxy)phenyl)formamide compound of formula-13, comprising of reacting l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl((R)-l-(4-methoxyphenyl)propan-2-yl)amino)ethanol

compound of formula-12 with formic acid in absence of a solvent provides compound of formula-13.
Prior reported processes for the preparation of compound of formula-13 involve the usage of acetic anhydride and formic acid in a mixture of ether solvents, hydrocarbon solvents. The said reaction involves the usage of solvents and also takes longer time to complete the reaction. Whereas, the present invention involves the usage of only formic acid to complete the reaction without usage of solvents. Hence the present invention is having advantage over the prior reported process.
The fourth aspect of the present invention provides a process for the preparation of N-
[2-hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-2(4-methoxyphenyl)-l-methylethyl]amino] ethyl]
phenyl] -formamide tartrate compound of formula-1, comprising of treating the compound of
formula-14 with L-(+)-tartaric acid in a suitable solvent provides N-[2-hydroxy-5-[(lR)-l-
hydroxy-2-[[(lR)-2(4-methoxyphenyl)-l-methylethyl]amino]ethyl] phenyl]-formamide
tartrate compound of formula-1.
In a preferred embodiment of the present invention provides a process for the preparation of N-[2-hydroxy-5-[( 1R)-1 -hydroxy-2-[[(l R)-2(4-methoxyphenyl)-1 -methyl ethyl]amino]ethyl]phenyl]-formamide tartrate compound of formula-1, comprising of treating the compound of formula-14 with L(+)-tartaric acid in a mixture of ethyl acetate and methanol provides N-[2-hydroxy-5-[( 1R)-1 -hydroxy-2-[[( 1 R)-2(4-methoxyphenyl)-1 -methyl ethyl]amino]ethyl]phenyl]-formamide tartrate compound of formula-1.
The fifth aspect of the present invention provides a process for the preparation of 1-(4-(Benzyloxy)-3-nitrophenyl)-2-bromoethanone compound of formula-5,
Formula-5 comprising of reacting 4-benzyloxy-3-nitroacetophenone compound of formula-4,

with a suitable brominating agent in presence of a suitable catalyst in a suitable solvent provides compound of formula-5.
Wherein, the suitable brominating agent is selected from bromine, tetraalkyl ammonium tribromide, dioxane dibromide, N-bromo succinamide, carbon tetrabromide, phosphorous tribromide, 5-bromo hydantoin, 2,4,4,6-tetrabromo-2,5-cyclohexadien-l-one, Br2-alumina, HBr-DMSO, P205-Bu4NBr, NaBr03-H2S04, HBr, NaBr03-NaHS03, bromine chloride and aluminum tribromide.
In a preferred embodiment of the present invention provides a process for the preparation of l-(4-(Benzyloxy)-3-nitrophenyl)-2-bromoethanone compound of formula-5, comprising of reacting 4-benzyloxy-3-nitroacetophenone compound of formula-4 with N-bromo succinamide in presence of paratoluene sulfonic acid in methylene chloride provides compound of formula-5.
The N-[2-hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-2(4-methoxyphenyl)-l-methylethyl] amino]ethyl]phenyl]-formamide tartrate compound of formula-1 is first reported in Chem. Pharma. BulL-1978, 26, (4), 1123-1129 as a crystalline solid having melting point 185°C. Further, the article does not disclose the solid characteristic data.
The present inventors have repeated the process disclosed in Chem. Pharma. BulL-1978, 26, (4), 1123-1129. The melting point of the obtained compound of formula-1 showing 185°C (by capillary method) which is well matched with the reported melting point. Further, the present inventors characterized the obtained compound using PXRD and DSC and designated as crystalline form-M.
The crystalline form-M is characterized by its powder X-ray diffractogram having peaks at 4.7, 9.4, 12.0, 12.5, 14.2, 15.1, 15.6, 16.8, 17.1, 18.9, 19.7, 20.1, 20.8, 23.0, 23.6, 24.0, 24.9, 25.7, 26.7, 30.9 and 36.0 ± 0.2 degrees of two-theta as illustrated in figure-1. Further, the DSC thermogram showing endotherm at 194.65°C as illustrated in figure-2.
The PXRD pattern of compound of formula-1 obtained in the present invention is similar to the pattern of disclosed crystalline form-M.
HPLC Method of Analysis:
2-(Benzyl((R)-l-(4-methoxvphenyl)propan-2-yl)amiiio)-l-(4-(benzyloxy)-3-nitrophenyl) ethanol compound of formula-11:

Apparatus: A liquid chromatographic system equipped with variable wavelength UV-detector; Column: Cosmicsil Aura ODS, 150 x 4.6 mm, 5 um (or) equivalent; Flow rate: 1.0 ml/min; Wavelength: 220 nm; Column Temperature: 25°C; Injection volume: 10 uL; Run time: 48 min; Diluent: Acetonitrile : Water (90:10 v/v); Elution: Gradient; Mobile phase-A: Buffer (100%); Mobile phase-B: Acetonitrile : Water (90:10 v/v); Buffer: 1.36 grams of potassium dihydrogen orthophosphate and 2.0 grams of 1-octane sulphonic acid in 1000 ml of water. Adjust pH to 3.70 (±0.05) orthophosphoric acid and filtered through 0.22um Nylon membrane filter paper and sonicate to degas it.
l-(3-Ammo-4-(benzyloxy)phenyl)-2-(benzyl((R)-l-(4-methoxyphenyI)propan-2-yl)amino) ethanol compound of formula-12:
Apparatus: A liquid chromatographic system equipped with variable wavelength UV-detector; Column: Kinetix CI8, 100 x 4.6 mm, 2.6 um (or) equivalent; Flow rate: 1.5 ml/min; Wavelength: 220 nm; Column Temperature: 30°C; Injection volume: 10 uL; Run time: 52 min; Diluent: Acetonitrile : Water (90:10 v/v); Needle wash: Acetonitrile : Water (90:10 v/v); Elution: Gradient; Mobile phase-A: Buffer (100%) Acetonitrile : Water (90:10 v/v); Mobile phase-B: Acetonitrile : Methanol : Water (65:10:25 v/v); Buffer: 1.36 grams of potassium dihydrogen orthophosphate and 1.74 grams of Di-potassium hydrogen orthophosphate in 1000 ml of water. Filtered through 0.22um Nylon membrane filter paper and sonicate to degas it.
(R)-N-(5-(2-(Benzyl-(l-(4-methoxyphenyl)propan-2-yl)amino)-l-hydroxyethyl)-2-(benzyl oxy)phenyl)formamide compound of formula-13:
Apparatus: A liquid chromatographic system equipped with variable wavelength UV-detector; Column: Kinetix CI8,100 x 4.6 mm, 2.6 um (or) equivalent; Flow rate: 1.0 ml/min; Wavelength: 220 nm; Column Temperature: 25°C; Injection volume: 10 uL; Run time: 34 min; Diluent: Acetonitrile : Water (90:10 v/v); Elution: Gradient; Mobile phase-A: Buffer: Acetonitrile : Water (90:10 v/v); Mobile phase-B: Acetonitrile : Buffer (75:25 v/v); Buffer: 1.36 grams of potassium dihydrogen orthophosphate and 1.74 grams of di-potassium hydrogen orthophosphate in 1000 ml of water. Filtered through 0.22 um Nylon membrane filter paper and sonicate to degas it.
HPLC Method of Analysis for compound of formula-14 and Arformoterol tartrate compound of formula-1:
Apparatus: A liquid chromatographic system equipped with variable wavelength UV-detector; Column: Zorbax SBC8, 150 x 4.6 mm, 5 um (or) equivalent; Flow rate: 1.0 ml/min;

Wavelength: 214 ran; Column Temperature: 25°C; Injection volume: 20 uL; Run time: 55 min; Diluent: Solution-A : Acetonitrile (84:16 v/v); Elution: Gradient; Needle wash: Acetonitrile; Mobile phase-A: Dissolve 3.73 grams of sodium dihydrogen phosphate monohydrate and 0.35 grams of phosphoric acid in 1000 ml of water. Adjust pH to 3.0 (±0.1). Filtered through 0.22pm Nylon membrane filter paper and sonicate to degas it. Solution-A: Dissolve 6.10 grams of sodium dihydrogen phosphate monohydrate and 1.03 grams of Disodium hydrogen phosphate dihydrate in 1000 ml of water. Adjust pH to 6.0 (±0.1). Filtered through 0.22urn Nylon membrane filter paper and sonicate to degas it.
The N-[2-Hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-2(4-methoxyphenyl)-l-methylethyl] amino]ethyl]phenyl]formamide tartrate produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.
P-XRD method of Analysis
PXRD analysis of compound of formula-1 produced by the present invention was carried out using BRUKER/AXS X-Ray diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.037min.
Differential scanning calorimetric (DSC) analysis was performed with Q10 V9.6 Build 290 calorimeter. Samples of about 2 to 3 milligrams held in a closed pan were analyzed at a heating rate of 10°C per minute. PSD Details for Arformoterol tartrate:
The particle size distribution of formoterol fumarate dihydrate compound of formula-la is measured using Malvern Master sizer 2000 instrument.
The N-[2-Hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-2(4-methoxyphenyl)-l-methylethyl] amino] ethyl] phenyl] formamide tartrate produced by the present invention can be further micronized or milled to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements. Techniques that may be used for particle size reduction include, but not limited to ball, roller and hammer mills, and jet mills. Milling or micronization may be performed before drying, or after the completion of drying of the product.

The present invention is schematically represented as follows.

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provided as illustration only and hence should not be construed as limitation of the scope of the invention.
Examples
Example-1: Preparation of 4-Hydroxy-3-nitroacetophenone [Formula-3]
4-Hydroxyacetophenone (500 gms) was slowly added to a pre-cooled concen. sulfuric acid (1800 ml) at 10-15°C and stirred the reaction mixture for 20 minutes at the same temperature. Concen. nitric acid (239.5 ml) was added to the above reaction mixture at 5-10°C and stirred for 3 hours at the same temperature. After completion of the reaction, the reaction mixture was slowly added to a pre-cooled purified water at 5-10°C. Raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid and washed with purified water. Water (250 ml) and toluene (3500 ml) were added to the obtained wet solid at 25-3 0°C. Heated the reaction mixture to 75-80°C and stirred for 30 minutes for dissolution. Both the organic layer and aqueous layer were separated at 50°C. Organic layer was cooled to 5-10°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid at 5-10°C and washed with toluene and dried to get the title compound. Yield: 430 gms; Melting point: 129-133°C.
ExampIe-2: Preparation of 4-Benzyloxy-3-nitroacetophenone (FormuIa-4)
Potassium carbonate (457.7 gms) was slowly added to a mixture of 4-hydroxy-3-nitroacetophenone (500 gms) and dimethylformamide (1500 ml) at 25-30°C. Potassium iodide (18.3 gms) was added to the reaction mixture at 25-30°C and stirred for 20 minutes at

the same temperature. Slowly benzyl chloride (384.3 gms) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 75-80°C and stirred for 2 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-3 0°C. Water was added to the reaction mixture at 25-3 0°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid and washed with water. To the obtained wet solid, water (2500 ml) was added at 25-3 0°C and stirred for 1 hour at the same temperature. Filtered the solid, washed with water and dried to get the title compound. Yield: 690 gms; Melting point: 130-133°C.
Example-3: Preparation of l-(4-(Benzyloxy)-3-nitrophenyl)-2-bromoethanone (Formula-5)
Bromine (282.7 gms) was slowly added to a mixture of 4-benzyloxy-3-nitro acetophenone (400 gms) and 1,4-dioxane (1200 ml) at 25-3 0°C and stirred the reaction mixture for 2 hours at the same temperature. After completion of the reaction, water was added to the reaction mixture at 25-30°C. Ethyl acetate was added to the reaction mixture. Heated the reaction mixture to 75-80°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with water and dried to get the title compound. Yield: 340 gms; Melting point: 133-135°C.
Example-4: Preparation of 2-(4-(Benzyloxy)-3-nitrophenyl)oxirane (Formula-7)
Sodium borohydride (7.56 gms) was added to a pre-cooled solution of l-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanone (100 gms) and methanol (500 ml) at 0-10°C. Stirred the reaction mixture at 0-5°C for 2 hours. Potassium carbonate (49.3 gms) was added to the reaction mixture at 0-5°C. Slowly raised the temperature of the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to below 25°C. Water was added to the reaction mixture below 25°C and stirred for 1 hour at 25-3 0°C. Filtered the precipitated solid. Methanol (600 ml) was added to the obtained wet solid at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 20 minutes at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with chilled methanol and dried to get the title compound. Yield: 65 gms.
Example-5: Preparation of (RS)-N-benzyl-l-(4-methoxyphenyl)propan-2-amine hydrochloride (Formula-9a)

Methanol (1250 ml) was added to 4-Methoxy phenyl acetone (250 gms) at 25-30°C. Cooled the reaction mixture to 0-5°C. Slowly benzyl amine (179.5 gms) was added to the above reaction mixture at 0-5°C and stirred the reaction mixture for 5 hours at the same temperature. Slowly sodium borohydride (34.6 gms) was added to the reaction mixture at 0-5°C and stirred the reaction mixture for 3 hours at the same temperature. After completion of the reaction, distilled off the solvent completely from the reaction mixture. Cooled the reaction mixture to 25-30°C. Water was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. Methylene chloride was added to the reaction mixture at 25-3 0°C. Both the organic and aqueous layers were separated and extracted the aqueous layer with methylene chloride. Combined both organic layers and washed with water and distilled off the solvent from the organic layer and followed by co-distilled with ethyl acetate. Cooled the obtained residue to 25-3 0°C. Ethyl acetate was added to the residue at 25-30°C and stirred the reaction mixture for 15 minutes at the same temperature. Slowly added hydrochloric acid solution (2000 ml) to the reaction mixture at 10-15°C and stirred the reaction mixture for 3 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 710.0 gms.
Example-6: Preparation of (R)-N-Benzyl-l-(4-methoxyphenyl)propan-2-amine L(+)-Mandelate (Formula-lOa)
Methylene chloride (2500 ml) was added to a mixture of (RS)-N-Benzyl-N-(l-methyl-2-p-methoxyphenyl)amine hydrochloride (1000 gms) and water (3000 ml) at 25-30°C. Adjusted the pH of the reaction mixture to 9.0-11.0 using 30% sodium carbonate solution [prepared by dissolving sodium carbonate (750 gms) in water (2500 ml)] at 25-30°C and stirred the reaction mixture for 15 minutes at the same temperature. Both the aqueous and organic layers were separated and extracted the aqueous layer with methylene chloride. Combined both the organic layers and washed with purified water. Distilled off the solvent completely from the organic layer and followed by co-distilled with methanol. To the obtained residue, methanol (2500 ml) was added at 25-30°C and stirred the reaction mixture for 15 minutes at the same temperature. L(+)-mandelic acid solution [prepared by dissolving L(+)-mandelic acid (504.4 gms) in methanol (1000 ml)] was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 45 minutes at the same temperature. Cooled the reaction mixture to 25-3 0°C and stirred for 20 hours at the same temperature. Filtered the precipitated solid and washed with methanol. To the obtained wet solid, methanol (2500 ml) was added at 25-30°C. Heated the reaction mixture to 60-65°C and

stirred for 45 minutes at the same temperature. Cooled the reaction mixture to 25-3 0°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, and washed with methanol to the compound. To the obtained wet solid, methanol (2500 ml) was added at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 45 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with methanol and dried to get the title compound. Yield: 280.0 gms. SOR: (+) 20.0° to (+) 25.0°.
Example-7: Preparation of 2-(Benzyl((R)-l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitro phenyl)ethanol (Formula-11)
Methylene chloride (2000 ml) was added to a mixture of (R)-N-benzyl-l-(4-methoxyphenyl)propan-2-amine L-(+)-mandelate (250 gms) compound of formula-10a and water (2500 ml) at 25-30°C. Adjusted the pH of the reaction mixture to 9.0-11.0 using 30% sodium carbonate solution [prepared by dissolving sodium carbonate (75 gms) in water (250 ml)] at 25-30°C. Both the organic and aqueous layers were separated and aqueous layer was extracted with methylene chloride. Combined both the organic layers and washed with water. Distilled off the solvent from the organic layer completely. Cooled the reaction mixture to 25-30°C and 2-(4-(benzyloxy)-3-nitrophenyl)oxirane (166.4 gms) compound of formula-7 of example-4 was added at the same temperature. Heated the reaction mixture to 110-115°C and stirred for 4 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to 45°C. Toluene (750 ml) and water (1000 ml) were added to the reaction mixture at 45°C and stirred the reaction mixture for 15 minutes. Both organic and aqueous layers were separated and aqueous layer was extracted with toluene. Combined both the organic layers and washed with water. The resulting organic layer containing 2-(Benzyl((R)-l-(4-methoxy phenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanol was used in the next step without isolation.
Example-8: Preparation of l-(3-Amino-4-(benzyloxy)phenyl)-2-(benzyl((R)-l-(4-methoxyphenyl)propan-2-yl)amino)ethanol(Formula-12)
Iron (31.1 gms) and water (469.9 ml) were added to organic layer obtained in example-7 at 25-30°C. Heated the reaction mixture to 70-75°C and acetic acid (469.6 ml) was added at the same temperature. Stirred the reaction mixture for 4 hours at 70-75°C. Cooled the reaction mixture to 40-45 °C and iron (31.1 gms) was added at the same temperature. Heated the reaction mixture to 70-75°C and stirred for 2 hours at the same

temperature. After completion of the reaction, cooled the reaction mixture to 25-3 0°C. Water was added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture through hi-flow bed and washed with toluene. Both the organic and aqueous layers were separated from the obtained filtrate and washed the organic layer with twice with water. Distilled off the solvent completely to get the title compound. Yield: 250.0 gms; Purity by HPLC: (RR) 49.39% (SR) 45.45%; Specific optical rotation: [a]D20(-) 27.53° (C = 1, chloroform).
ExampIe-9: Preparation of (R)-N-(5-(2-(Benzyl-(l-(4-methoxyphenyl)propan-2-yI) ammo)-l-hydroxyethyl)-2-(benzyloxy)phenyl)formamide (Formula-13)
Formic acid (71.7 ml) was added to l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl-((R)-l-(4-methoxyphenyl)propan-2-yl)amino)ethanol (118 gms) at 40-45 °C. Heated the reaction mixture to 65-70°C and stirred the reaction mixture for 3 hours the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C. Water (590 ml) and ethyl acetate (590 ml) were added to the reaction mixture at 25-3 0°C. Adjusted the pH of the reaction mixture to 9.0-11.0 using 20% sodium carbonate solution {prepared by dissolving sodium carbonate (240 gms) in (water 1180 ml)} at 25-30°C. Both the organic and aqueous layers were separated and extracted the aqueous layer with ethyl acetate. Combined both the organic layers and washed with water. Distilled off the solvent completely to the title compound. Yield: 120.0 gms; Purity by HPLC: (RR) 47.49% (SR) 46.61%; Specific optical rotation: [a]D20(-) 26.44° (C = 1, chloroform).
Example-10: Preparation of N-(2-hydroxy-5-(l-hydroxy-2-((R)-l-(4-methoxyphenyl) propan-2-yl-amino)ethyl) phenyl)formamide [Formula-14]
Methanol (375 ml) and isopropanol (375 ml) were added to (R)-N-(5-(2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-1 -hydroxyethyl)-2-(benzyloxy)phenyl)formamide (100 gms) at 25-30°C. Pd/C (40 gms) was added to the reaction mixture at 25-30°C. The reaction mixture was hydrogenated for 8 hours under a hydrogen gas pressure of 5.0-6.0 kg/cm at 25-30°C. After completion of the reaction, filtered the reaction mixture through hi-flow bed and washed with methanol. Distilled off the solvent completely from the filtrate to get the title compound. Yield: 64.0 gms.
Example-11: Preparation of N-[2-Hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-2(4-methoxy phenyl)-l-methylethyl] amino] ethyl]phenyl]formamide tartrate [Formula-1]

Ethyl acetate (350 ml) and methanol (250 ml) were added to N-(2-hydroxy-5-(l-hydroxy-2-((R)-l-(4-methoxyphenyl)propan-2-yl-amino)ethyl)phenyl)formamide (64 gms) at 25-30°C and stirred the reaction mixture for 15 minutes at the sane temperature. L-(+)-Tartaric acid solution {prepared by dissolving L-(+)-Tartaric acid (28.6 gms) in methanol (100 ml)} was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 15 minutes at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C and stirred for 12 hours at the same temperature. Filtered the precipitated solid, washed with methanol and then followed by ethyl acetate. To the obtained wet solid, methanol (350 ml) and ethyl acetate (350 ml) were added at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 20 minutes at the same temperature. Cooled the reaction mixture to 25-30°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with a solution of methanol and ethyl acetate mixture. 50% Aqueous isopropanol solution {prepared by mixing isopropanol (375 ml) with water (75 ml)} was added to the obtained wet compound at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Carbon (1.2 gms) was added to the reaction mixture at 55-60°C and stirred for 10 minutes at the same temperature. Filtered the reaction mixture through hi-flow bed and washed with 50% aqueous isopropanol solution. Cooled the obtained filtrate to 25-30°C and stirred for 10 hours at the same temperature. Filtered the precipitated solid, washed with 50% aqueous isopropanol solution and dried to get the title compound. Yield: 16.0 gms; Purity by Chiral HPLC: 95.85%; Diastereomeric content: (S,S: 0.19%; S,R: 2.95%; R,S: 1.01%); Tartaric acid content: 30.37% w/w. Particle size distribution: D10: 2.2 um; D50: 7.5 um; D90: 21.3 urn.
Example-12: Purification of N-[2-Hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-2(4-methoxy phenyl)-l-methylethyl] amino]ethyl]phenyl]-formamide tartrate [Formula-1]
Isopropanol (75 ml) and water (75 ml) were added to N-[2-Hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-2(4-methoxyphenyl)-l-methylethyl]amino]ethyl]phenyl]formamide tartrate (25.0 gms) at 25-30°C. Heated the reaction mixture to 55-60°C and stirred for 1 hour at the same temperature. Carbon (2.5 gms) was added to the reaction mixture at 55-60°C and stirred for 10 minutes at the same temperature. Filtered the reaction mixture through hi-flow bed and washed with 50% aqueous isopropanol solution. Cooled the obtained filtrate to 25-30°C and stirred for 10 hours at the same temperature. Filtered the precipitated solid, washed with 50% aqueous isopropanol solution and dried to get the title compound. Yield: 12.0 gms; M.R: 182-185°C; Purity by Chiral HPLC: 99.87%; Diastereomeric content: (S,S: Not detected; S,R:

0.04%; R,S: 0.09%); Specific optical rotation SOR: [a]D20: (-) 29.18°; Tartaric acid content: 30.35% w/w.
Example-13: Preparation of (RS)-N-benzyl-l-(4-methoxyphenyl)propan-2-amine hydrochloride (Formula-9a)
Methanol (1250 ml) was added to 4-methoxy phenyl acetone (250 gms) at 25-30°C. Cooled the reaction mixture to 5-10°C. Benzyl amine was slowly was added to the reaction mixture at 5-10°C and stirred the reaction mixture for 5 hours at the same temperature. Sodium borohydride (34.6 gms) was slowly added to the reaction mixture at 5-10°C and stirred the reaction mixture for 3 hours at the same temperature. After completion of the reaction, distilled off the solvent completely from the reaction mixture. Cooled the reaction mixture to 25-30°C. Water was added to the reaction mixture and stirred for 15 minutes at 25-30°C. Ethyl acetate was added to the reaction mixture. Both the organic and aqueous layers were separated and aqueous layer was extracted with ethyl acetate. Combined the both organic layers and washed with sodium chloride solution. Distilled off the solvent from the organic layer. Cooled the obtained residue to 25-3 0°C. Ethyl acetate was added to the obtained residue at 25-30°c and stirred for 15 minutes at the same temperature. Cooled the reaction mixture to 10-15°C. Hydrochloric acid solution (1000 ml) was slowly added to the reaction mixture and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 375 gms.
Example-14: Preparation of (R)-N-Benzyl-l-(4-methoxvphenyl)propan-2-amine L(+)-Mandelate (Formula-10a)
Water (100 ml) was added to sodium hydroxide (16.45 gms) at 25-3 0°C and stirred for 15 minutes. A mixture of (RS)-N-benzyl-l-(4-methoxyphenyl)propan-2-amine hydrochloride (100 gms) and methylene chloride (300 ml) was added to the above mixture at 25-30°C and stirred for 20 minutes at the same temperature. Both organic and aqueous layers were separated and aqueous layer was extracted with methylene chloride. Combined the both organic layers and distilled off the solvent from the organic layer. Cooled the reaction mixture to 25-30°C. Methanol (100 ml) was added to the reaction mixture at 25-30°C and stirred for 15 minutes at the same temperature. L-(+)-Mandelic acid solution {prepared by dissolving L-(+)-mandelic acid (26.07 gms) in methanol (50 ml)} was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 1 hour at the same temperature. Cooled the reaction mixture to 0-5°C and stirred for 2 hours at the same

temperature. Filtered the precipitated solid, washed with methanol. The obtained wet compound was recrystallized thrice from methanol to get the title compound. Yield: 28 gms.
Example-15: Preparation of l-(4-(Benzyloxy)-3-nitrophenyl)-2-bromoethanone (Formula-5)
Methylene chloride (375 ml) was added to l-(4-(benzyloxy)-3-nitrophenyl)ethanone (50 gms) at 25-30°C. Para toluene sulfonic acid (5.25 gms) followed by N-bromo succinamide (41 gms) was added to the reaction mixture at 25-3 0°C. Heated the reaction mixture to 40-45°C and stirred for 24 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C. Water was added to the reaction mixture and stirred for 15 minutes. Both the organic and aqueous layers were separated and aqueous layer is extracted with methylene chloride. Combined the organic layers and washed with 10% sodium thiosulfate solution followed by sodium chloride solution. Distilled off the solvent completely from the organic layer and co-distilled with ethyl acetate. Cooled the obtained compound to 25-30°C. Ethyl acetate (50 ml) was added to the obtained compound at 25-30°C and stirred the reaction mixture for 2 hours at the same temperature. Filtered the solid, washed with ethyl acetate and dried to get the title compound. Yield: 78 gms.

We Claim:
1. An improved process for the preparation of N-[2-hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-2(4-methoxyphenyl)-l-methylethyl]amino]ethyl]phenyl]-formamide tartrate compound of formula-1, comprising of the following steps:
a) Reacting (R)-N-benzyl-l-(4-methoxyphenyl)propan-2-amine L-(+)-mandelate
compound of formula-10a,

Formula-10a with sodium carbonate in a suitable solvent provides (R)-N-benzyl-l-(4-methoxyphenyl)propan-2-amine compound of formula-10,

Formula-10
b) reacting the compound of formula-10 with 2-(4-(benzyloxy)-3-nitrophenyl)oxirane
compound of formula-7,

Formula-7 at a suitable temperature in absence of a solvent provides 2-(benzyl((R)-l-(4-methoxy phenyl)propan-2-yl)amino)-1 -(4-(benzyloxy)-3-nitrophenyl)ethanol compound of formula-11,
Formula1
c) reducing the compound of formula-11 with a suitable reducing agent in presence of
acetic acid in a suitable solvent provides l-(3-amino-4-(benzyloxy)phenyl)-2-

(benzyl((R)-l-(4-methoxyphenyl)propan-2-yl)amino) ethanol compound of formula-12,
d) reacting the compound of formula-12 with formic acid provides (R)-N-(5-(2-(benzyl-(1 -(4-methoxyphenyl)propan-2-yl)amino)-1 -hydroxyethyl)-2-(benzyloxy)phenyl) formamide compound of formula-13,
e) debenzylating the compound of formula-13 by treating it with a suitable debenzylating agent in a suitable solvent provides N-(2-hydroxy-5-(l-hydroxy-2-((R)-l-(4-methoxyphenyl) propan-2-yl-amino)ethyl)phenyl)formamide compound of
formula-14,

Formula-14
f) treating the compound of formula-14 with L(+)-tartaric acid in a suitable solvent
provides N-[2-hydroxy-5-[( 1R)-1 -hydroxy-2-[[( 1 R)-2(4-methoxyphenyl)-1 -methyl
ethyl] amino] ethyl]phenyl]-formamide tartrate compound of formula-1.
2. The process according to claim-1, wherein;
in step-a) the suitable solvent is selected from chloro solvents, ester solvents, ketone solvents, hydrocarbon solvents, polar aprotic solvents, polar solvents such as water or mixture thereof;

in step-b) the suitable temperature is ranging from ambient temperature to 150°C; preferably at 70-130°C; more preferably at 110-115°C;
in step-c) the suitable reducing agent is selected from iron, zinc, tin in combination with acetic acid and suitable solvent is selected from chloro solvents, alcohol solvents, ester solvents, polar solvents such as water and acetic acid or mixture thereof;
in step-e) the suitable debenzylating agent is selected from Pd/C, palladium acetate,
platinum oxide, platinum black, Rh/C, Ni, Ir, Ru and the like in combination with hydrogen; and the suitable solvent is selected from alcohol solvents;
in step-f) the suitable is selected from ester solvents, alcohol solvents, chloro solvents, ether solvents, polar solvents such as water or mixture thereof.
3. A process for the preparation of N-[2-hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-2(4-methoxyphenyl)-l-methyl ethyl]amino]ethyl]phenyl]-formamide tartrate compound of formula-1, comprising of the following steps:
a) Reacting (R)-N-benzyl-l-(4-methoxyphenyl)propan-2-amine L-(+)-mandelate compound of formula-10a with sodium carbonate in a mixture of methylene chloride and water provides (R)-N-benzyl-l-(4-methoxy phenyl)propan-2-amine compound of formula-10,
b) reacting the compound of formula-10 with 2-(4-(benzyloxy)-3-nitrophenyl)oxirane compound of formula-7 at 110-115°C provides 2-(benzyl((R)-l-(4-methoxyphenyl) propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanol compound of formula-
11,
c) reducing the compound of formula-11 with iron in presence of acetic acid in toluene provides 1 -(3 -amino-4-(benzyloxy)phenyl)-2-(benzyl((R)-1 -(4-methoxy phenyl) propan-2-yl)amino) ethanol compound of formula-12,
d) reacting the compound of formula-12 with formic acid provides (R)-N-(5-(2-(benzyl-(1 -(4-methoxyphenyl)propan-2-yl)amino)-1 -hydroxyethyl)-2-(benzyloxy)phenyl) formamide compound of formula-13,
e) debenzylating the compound of formula-13 with Pd/C in a mixture of methanol and isopropanol provides N-(2-hydroxy-5-( 1 -hydroxy-2-((R)-1 -(4-methoxyphenyl) propan-2-yl-amino) ethyl)phenyl)formamide compound of formula-14,
f) treating the compound of formula-14 with L(+)-tartaric acid in a mixture of ethyl acetate and methanol provides N-[2-hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-2(4-

methoxyphenyl)-l-methylethyl]amino]ethyl]phenyl]-formamide tartrate compound of formula-1.
4. A process for the preparation of 2-(benzyl((R)-l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl) ethanol compound of formula-11, comprising of condensing the 2-(4-(benzyloxy)-3-nitrophenyl)oxirane compound of formula-7 with (R)-N-benzyl-l-(4-methoxyphenyl)propan-2-amine compound of formula-10 at a suitable temperature in absence of a solvent provides 2-(benzyl((R)-l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl) ethanol compound of formula-11.
5. A process for the preparation of l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl((R)-l-(4-methoxyphenyl)propan-2-yl)amino)ethanol compound of formula-12, comprising of reducing 2-(benzyl((R)-1 -(4-methoxyphenyl)propan-2-yl)amino)-1 -(4-(benzyloxy)-3-nitrophenyl)ethanol compound of formula-11 with iron in presence of acetic acid in toluene provides compound of formula-12.
6. A process for the preparation of (R)-N-(5-(2-(benzyl-(l-(4-methoxyphenyl)propan-2-yl)amino)-1 -hydroxyethyl)-2-(benzyloxy)phenyl)formamide compound of formula-13, comprising of reacting l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl((R)-l-(4-methoxy phenyl)propan-2-yl)amino)ethanol compound of formula-12 with formic acid provides compound of formula-13.
7. A process for the preparation of N-[2-hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-2(4-methoxyphenyl)-l-methylethyl] amino] ethyl]phenyl]-formamide tartrate compound of formula-1, comprising of treating the compound of formula-14 with L(+)-tartaric acid in a mixture of ethyl acetate and methanol provides N-[2-hydroxy-5-[(lR)-l-hydroxy-2-[[(lR)-2(4-methoxyphenyl)-l-methylethyl]amino]ethyl]phenyl]-formamide tartrate compound of formula-1.
8. A process for the preparation of l-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanone compound of formula-5,

comprising of reacting 4-benzyloxy-3-nitroacetophenone compound of formula-4,
Formula-4 with a suitable brominating agent in presence of a suitable catalyst in a suitable solvent.
9. A process for the preparation of l-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanone compound of formula-5, comprising of reacting 4-benzyloxy-3-nitroacetophenone compound of formula-4 with N-bromo succinamide in presence of paratoluene sulfonic acid in methylene chloride.
10. The compounds of following structural formulae: