Field of the Invention:
The present invention provides an improved process for the preparation of (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-lmethylethyl]-amino]ethyl] formanilide compound of formula-1 and its fumarate dihydrate salt compound of formula-la represent by the following structural formula.
Background of the Invention:
Formoterol is first disclosed in US3994974. Later on it is also published in Chem. Pharma. Bull-1977, 25 (6), 1368-1377 by the same company.
Various processes for the preparation of formoterol, its enantiomers and related compounds, and their pharmaceutically acceptable salts are disclosed in 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 and WO 2008/035380 A2.
US3994974 patent first discloses the process for the preparation of (±)-2-hydroxy-5-
[(1RS)-1 -hydroxy-2- [ [(1 RS)-2-(4-methoxyphenyl)-1 -methylethyl] -amino] ethyl] formanilide
compound of formula-1, by the condensation of N-benzyl-l-(4-methoxyphenyl)propan-2-
amine compound of formula-7 with l-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanone
compound of formula-5 in the presence of 2-butanone provides 2-(benzyl(l-(4-
methoxyphenyl)propan-2-yl)amino)-1 -(4-(benzyloxy)-3 -nitrophenyl)ethanone compound of
formula-8, which undergoes reduction with sodium borohyride in ethanol provides 2-
(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl) ethanol
compound of formula-9, further successive reduction of compound of formula-9 in presence
of iron and hydrochloric acid provides l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl(l-(4-
methoxy phenyl)propan-2-yl)amino) ethanol compound of formula-10, subsequently
formylation of compound of formula-10 with a mixture of formic acid and acetic anhydride
provides N-(5-(2-(benzyl(l -(4-methoxyphenyl)propan-2-yl)amino)-1 -hydroxyethyl)-2-
(benzyloxy)phenyl)formamide compound of formula-11 having RR, RS, SS, SR isomers. Separation of RS, SR isomers from the compound of formula-11 is accomplished by the

conversion of compound of formula-11 into its fumaric acid salt compound of formula-11 a. The free base compound of formula-11 is liberated by neutralizing of its salt and is subjected to debenzylation using Pd/C to get formoterol free base as crystalline powder compound of formula-1. The base is then converted to its fumarate dihydrate salt of formula-la using fumaric acid in aqueous ethanol.
The said process suffers from several drawbacks including prolonged reaction time, low yields and purity of the intermediates as well as final product. Further, unwanted isomers of formoterol are separated at very late stage of the synthesis, due to which number of crystallization are required for the separation of the isomers.
In view of the above, there is a need in the art to develop an efficient, cost-effective, environment friendly and industrially advantageous process for the synthesis formoterol which overcomes the problems associated with the prior art.
Brief Description of the Invention:
The first aspect of the present invention is to provide an improved process for the preparation of (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-lmethyl ethyl]-amino] ethyl] formanilide compound of formula-1 and its fumarate dihydrate salt compound of formula-la.
The second aspect of the present invention is to provide a process for the preparation
of 2-(benzyl( 1 -(4-methoxyphenyl)propan-2-yl)amino)-1 -(4-(benzyloxy)-3 -nitrophenyl)
ethanone compound of formula-8.
The third aspect of the present invention is to provide a process for the purification of 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanone compound of formula-8.
The fourth aspect of the present invention is to provide a process for the preparation
of 2-(benzyl( 1 -(4-methoxyphenyl)propan-2-yl)amino)-1 -(4-(benzyloxy)-3 -nitrophenyl)
ethanol compound of formula-9.
The fifth aspect of the present invention is to provide l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl(l -(4-methoxyphenyl)propan-2-yl)amino)ethanol malic acid compound of formula-10a.
The sixth aspect of the present invention is to provide crystalline form-M of l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)ethanol

malic acid compound of formula-10a.
The seventh aspect of the present invention is to provide a process for the purification of(±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-l-methylethyl]-amino] ethyl] formanilide compound of formula-1.
Brief Description of Drawings:
Figure 1: Illustrates the PXRD pattern of crystalline form-M of l-(3-Amino-4-
(benzyloxy)phenyl)-2-(benzyl( 1 -(4-methoxyphenyl)propan-2-yl)amino)ethanol malic acid.
Figure 2: Illustrates the DSC thermogram of crystalline form-M of l-(3-Amino-4-
(benzyloxy)phenyl)-2-(benzyl( 1 -(4-methoxyphenyl)propan-2-yl)amino)ethanol malic acid.
Figure 3: Illustrates the PXRD pattern of crystalline form-S of (±)-2-hydroxy-5-[(lRS)-l-
hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-l-methylethyl]-amino]ethyl]formanilide.
Figure 4: Illustrates the DSC thermogram of crystalline form-S of (±)-2-hydroxy-5-[(lRS)-l-
hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-l-methylethyl]-amino]ethyl]formanilide.
Detailed description of the 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 tertachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; "nitrile solvents" such as acetonitrile, propionitrile, isobutyro nitrile 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, lithium bicarbonate, potassium 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 hexamethyl disilazide (KHMDS); n-butyl lithium or mixtures thereof.
The term suitable "reducing agents" used in the present invention refers to Ni, Raney Ni, Pd/C, Pt/C, PtC>2, Fe, Fe in acidic media like acetic acid, NH4CI; Sn-HCl, stannous chloride (SnCli), Zn in acidic media like acetic acid, NH4CI, 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/Fk, borane-tetrahydrofuran, NaBFbCN, sodium borohydride/BF3-etherate, vitride, sodium borohydride/aluminium chloride or borane/aluminium chloride and sodium borohydride/iodine.
As used herein, the suitable "acid" is selected from "organic acids" such as oxalic acid, succinic acid, malonic acid, malic acid, maleic acid, mandelic acid, tartaric acid, lactic acid, acetic acid, fumaric acid, benzoic acid, benzenesulfonic acid, citric acid, camphorsulfonic acid, ethane sulfonic acid, gluconic acid, glutamic acid, methanesulfonic acid, mucic acid, pamoic acid, pantothenic acid, paratoluene sulfonic acid and "inorganic acids" such as hydrochloric acid, hydrobromic acid, hydroiodic acid, nitric acid, sulfuric acid and phosphoric acid.
The first aspect of the present invention provides an improved process for the preparation of (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-l-methyl ethyl]-amino] ethyl] formanilide compound of formula-1 and its fumarate dihydrate salt compound of formula-la, comprising of the following steps:
a) Condensing the N-benzyl-l-(4-methoxyphenyl)propan-2-amine compound of formula-7 with l-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanone compound of formula-5

in presence of a suitable base in a suitable solvent provides 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanone compound of formula-8,
b) reducing the keto group of compound of formula-8 with a suitable reducing agent in a suitable solvent provides 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl) ethanol compound of formula-9,
c) reducing the nitro group of compound of formula-9 with a suitable reducing agent in combination with acetic acid in a suitable solvent provides l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl( 1 -(4-methoxy phenyl)propan-2-yl)amino) ethanol compound of formula-10,
d) treating the compound of formula-10 in-situ with malic acid in a suitable solvent provides 1 -(3 -amino-4-(benzyloxy)phenyl)-2-(benzyl( 1 -(4-methoxyphenyl)propan-2-yl)amino) ethanol malic acid salt compound of formula-10a,
e) neutralizing the compound of formula-10a with a suitable base in a suitable solvent provides compound of formula-10,
f) reacting the compound of formula-10 in-situ with formic acid in presence of a suitable solvent provides N-(5-(2-(benzyl( 1 -(4-methoxyphenyl)propan-2-yl)amino)-1 -hydroxy ethyl)-2-(benzyloxy) phenyl)formamide compound of formula-11,
g) optionally, converting the compound of formula-11 into its acid addition salts compound of general formula-12, followed by neutralizing the obtained salt with a suitable base provides compound of formula-11,
h) debenzylating the compound of formula-11 in-situ by treating it with a suitable debenzylating agent in a suitable solvent provides (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxy phenyl)-1-methylethyl]-amino]ethyl] formanilide compound of formula-1,
i) converting the compound of formula-1 into its fumarate dihydrate salt compound of formula-la by treating it with fumaric acid in a suitable solvent provides (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-l-methylethyl]-amino]ethyl] formanilide fumarate dihydrate compound of formula-la.
Wherein,
in step-a) the suitable base is selected from organic or inorganic bases; preferably
inorganic bases and the suitable solvent is selected from chloro solvents, ester solvents,
ketone solvents, alcohol solvents, polar solvents such as water or mixture thereof.
in step-b) the suitable reducing agent is selected form metal hydrides such as sodium

borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride; preferably sodium borohydride and suitable solvent is selected form alcohol solvents, hydrocarbon solvents, ester solvents, ether solvents, ketone solvents, polar solvents or mixture thereof.
in step-c) the suitable reducing agent is selected from iron, zinc, tin in combination with acetic acid and suitable solvent is selected from hydrocarbon solvents, alcohol solvents, ester solvents, ether solvents, polar solvents such as water or mixture thereof.
in step-d), f) & i) the suitable solvent is selected form alcohol solvents, hydrocarbon solvents, ester solvents, chloro solvents, ether solvents, ketone solvents, polar solvents such as water or mixture thereof.
in step-g) the suitable acid is selected from organic acid or inorganic acid; and the suitable base is selected from inorganic base and suitable solvent is selected from alcohol solvents, hydrocarbon solvents, ester solvents, ether solvents, ketone solvents, polar solvents such as water or mixture thereof.
in step-e) the suitable base is selected from inorganic base; preferably sodium carbonate and suitable solvent is selected form alcohol solvents, hydrocarbon solvents, ester solvents, ether solvents, ketone solvents, polar solvents such as water or mixture thereof.
in step-h) the suitable debenzylating agent is selected from Pd/C, palladium acetate, platinum oxide, platinum black, Raney Ni, Rh/C, Ni, Ir, Ru and the like in combination with hydrogen and the suitable solvent is selected from alcohol solvents, ester solvents.
In a preferred embodiment of the present invention provides an improved process for the preparation of (±)-2-Hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-l-methyl ethyl] -amino] ethyl] formanilide compound of formula-1 and its fumarate dihydrate salt compound of formula-la, comprising of the following steps:
a) Condensing the N-benzyl-l-(4-methoxyphenyl)propan-2-amine compound of formula-7 with l-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanone compound of formula-5 with potassium carbonate in acetone provides 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitro phenyl)ethanone compound of formula-8,
b) reducing the keto group of compound of formula-8 with sodium borohydride in a mixture of toluene and methanol provides 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitro phenyl)ethanol compound of formula-9,
c) reducing the nitro group of compound of formula-9 with Iron in combination with acetic acid in toluene provides l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl(l-(4-methoxy phenyl)propan-2-yl)amino)ethanol compound of formula-10,

d) treating the compound of formula-10 in-situ with malic acid in presence of a mixture of ethyl acetate and methanol provides l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl(l-(4-methoxyphenyl) propan-2-yl)amino)ethanol malic acid salt compound of formula-10a,
e) neutralizing the compound of formula-10a with sodium carbonate in a mixture of ethyl acetate and water provides compound of formula-10,
f) reacting the compound of formula-10 in-situ with formic acid in presence of tetrahydrofuran provides N-(5-(2-(benzyl(l -(4-methoxyphenyl)propan-2-yl)amino)-l -hydroxyethyl)-2-(benzyloxy) phenyl)formamide compound of formula-11,
g) optionally, converting the compound of formula-11 into its fumarate salt compound of formula-12a, followed by neutralizing the obtained salt with sodium carbonate in a mixture of ethyl acetate and water provides compound of formula-11,
h) debenzylating the compound of formula-11 in-situ with Pd/C in a mixture of methanol and ethyl acetate provides (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-l-methyl ethyl]-amino]ethyl]formanilide compound of formula-1,
i) converting the compound of formula-1 into its fumarate dihydrate salt compound of formula-la by treating it with fumaric acid in a mixture of water and methanol provides (±)-2-hydroxy-5-[(l RS)-1 -hydroxy-2-[[( 1 RS)-2-(4-methoxyphenyl)-1 -methylethyl]-amino] ethyl] formanilide fumarate dihydrate compound of formula-la.
The second aspect of the present invention provides a process for the preparation of 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanone compound of formula-8, comprising of condensing N-benzyl-1-(4-methoxyphenyl)propan-2-amine compound of formula-7 with l-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanone compound of formula-5 in presence of a suitable base in a suitable solvent provides 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanone compound of formula-8.
Wherein, the suitable base is selected from organic or inorganic base; preferably inorganic base and the suitable solvent is selected from chloro solvents, ester solvents, ketone solvents, alcohol solvents, polar solvents such as water or mixture thereof.
In a preferred embodiment of the present invention provides a process for the preparation of 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanone compound of formula-8, comprising of condensing N-benzyl-1-(4-methoxyphenyl)propan-2-amine compound of formula-7 with l-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanone compound of formula-5 in presence of potassium carbonate in

acetone provides 2-(benzyl(l -(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanone compound of formula-8.
US3994974 discloses the preparation of 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanone compound of formula-8 by the condensation of N-benzyl-l-(4-methoxyphenyl)propan-2-amine compound of formula-7 with l-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanone compound of formula-5 in the presence of methyl ethyl ketone at 75-80°C to produce compound of formula-8 as residue, which is isolated from ethanol. However, carrying out the reaction at high temperatures results in the formation of unwanted isomers and impurities and thereby decreases the yield as well as purity of the product.
Whereas, the present inventors carried out the same reaction in the presence of base like potassium carbonate in acetone at room temperature to produce compound of formula-8 as a solid. Further, the obtained compound of formula-8 is recrystallized from a mixture of isopropanol and ethyl acetate to get the pure compound of formula-8. Hence the present invention is advantageous over the prior art.
The third aspect of the present invention provides a process for the purification of 2-(benzyl( 1 -(4-methoxyphenyl)propan-2-yl)amino)-1 -(4-(benzyloxy)-3 -nitrophenyl)ethanone compound of formula-8, comprising of,
a) Suspending the compound of formula-8 in a suitable solvent,
b) stirring the reaction mixture at a suitable temperature,
c) filtering the solid and drying to get pure 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanone compound of formula-8.
Wherein, the suitable solvent is selected from alcohol solvents, ester solvents, ketone solvents, chloro solvents or mixture thereof; preferably a mixture of isopropanol and ethyl acetate and suitable temperature is ranging from ambient temperature to reflux temperature of the solvent.
In a preferred embodiment of the present invention provides a process for the purification of 2-(benzyl( 1 -(4-methoxyphenyl)propan-2-yl)amino)-1 -(4-(benzyloxy)-3 -nitrophenyl)ethanone compound of formula-8, comprising of,
a) Suspending the compound of formula-8 in a mixture of isopropanol and ethyl acetate,
b) stirring the reaction mixture at 25-30°C,
c) filtering the solid and drying to get pure 2-(benzyl(l -(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanone compound of formula-8.

The fourth aspect of the present invention provides a process for the preparation of 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanol compound of formula-9, comprises of reducing the 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanone compound of formula-8 with a suitable reducing agent in presence of a suitable solvent provides compound of formula-9.
Wherein, the suitable reducing agent is selected form metal hydrides such as sodium borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride; preferably sodium borohydride and the suitable solvent is selected form alcohol solvent, hydrocarbon solvent, ester solvents, ether solvents, ketone solvents or mixture thereof.
The preferred embodiment of the present invention provides a process for the preparation of 2-(benzyl( 1 -(4-methoxyphenyl)propan-2-yl)amino)-1 -(4-(benzyloxy)-3 -nitrophenyl)ethanol compound of formula-9, comprises of reducing the 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-1 -(4-(benzyloxy)-3-nitrophenyl)ethanone compound of formula-8 with sodium borohydride in the presence of a mixture of methanol and toluene provides compound of formula-9.
The ratio of methanol and toluene used in the present invention is in between 1.0: 9.0, preferably between 3.0: 7.0, most preferably between 1.0: 3.0 per one mole equivalent of compound of formula-8.
US3994974 discloses the reduction of compound of formula-8 using sodium borohydride in ethanol to provide compound of formula-9. Whereas, the usage of ethanol decreases the rate of the reaction and requires much longer time for the completion of the reaction, which leads to the formation of impurities and unwanted bi-products and thereby decreases the yield as well as purity of the product.
Moreover the said process also utilizes benzene for the extraction of the product, which is carcinogenic and not advisable in laboratory as well as commercially scale-up process.
WO2008/035380 A2 discloses the reduction of compound of formula-8 using sodium borohydride in methanol. Wherein, the said reduction requires excess amount of sodium borohydride when methanol is takes as a solvent and also decreases the rate of reaction and takes longer time for the completion of the reaction which decreases the yield and purity of the product.
Whereas the present invention involves the usage of sodium borohydride in a mixture

of methanol and toluene to provide compound of formula-9. It is observed that the rate of reaction is increased and also decreases the consumption of sodium borohydride to provide compound of formula-9 with high yield and purity when compared to the prior art. Hence the present process is cost effective and environment friendly when compared to the prior art.
The fifth aspect of the present invention provides l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)ethanol malic acid compound of formula-10a.
The compound of formula-10a obtained according to the present invention having HPLC purity of greater than 99.98 %, which is further useful in the preparation of highly pure compound of formula-1 and its fumarate dihydrate compound of formula-la.
The sixth aspect of the present invention provides crystalline form-M of l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl(l -(4-methoxyphenyl)propan-2-yl)amino)ethanol malic acid compound of formula-10a, characterized by:
a) Its powder X-ray diffractogram having peaks at 5.6, 6.8, 7.7, 9.5, 12.0, 12.6, 13.8, 15.5, 16.2, 17.2, 18.7, 19.0, 19.3, 19.7, 20.0, 20.6, 21.2, 21.7, 22.0, 22.8, 23.4, 23.5, 24.2, 25.2, 25.9, 26.4, 27.9, 28.4, 29.2, 31.3, 32.3, 34.2, 35.0, 36.9 and 40.1 ± 0.2 degrees of two-theta as illustrated in figure-1;
b) its DSC thermogram showing endotherm at 152.50°C as illustrated in figure-2.
The crystalline compound of formula-10a obtained by the above process is useful in the preparation of highly pure compound of formula-1 a.
The seventh aspect of the present invention provides a process for the purification of (±)-2-hydroxy-5-[(l RS)-1 -hydroxy-2-[[( 1 RS)-2-(4-methoxyphenyl)-1 -methylethyl]-amino] ethyl] formanilide compound of formula-1, comprising of;
a) Dissolving the compound of formula-1 in a suitable solvent,
b) heating the reaction mixture,
c) cooling the reaction mixture,
d) filtering the precipitated solid and dying provides compound of formula-1.
Wherein, the suitable solvent selected from alcohol solvents, chloro solvents, ester solvents, ketone solvents, hydrocarbon solvents or mixture thereof; preferably ketone solvents.

In a preferred embodiment of the present invention provides a process for the purification of (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-l-methylethyl]-amino] ethyl] formanilide compound of formula-1, comprising of:
a) Dissolving the compound of formula-1 in acetone,
b) heating the reaction mixture to 40-45°C,
c) cooling the reaction mixture,
d) filtering the precipitated solid and dying provides (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-l-methylethyl]-amino]ethyl]formanilide compound of formula-1.
The crystalline (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-l-methyl ethyl]-amino]ethyl] formanilide compound of formula-1 obtained according to the process disclosed in US3994974 is herein after designated as crystalline form-S. The powdered X-ray diffraction (PXRD) of crystalline form-S compound of formula-1 is shown in figure-3.
UPLC Method of Analysis:
2-(Benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyIoxy)-3-nitrophenyI) ethanone compound of formula-8:
Apparatus: A liquid chromatographic system equipped with variable wavelength UV-detector and integrator; Column: Acquity BEHC18, 50 x 2.1 mm, 1.7 um (or) equivalent; Flow rate: 0.48 ml/min; Wavelength: 210 nm; Column Temperature: 45°C; Injection volume: 1.2 uL; Run time: 13 min; Diluent: Acetonitrile : Water (90:10 v/v); Needle wash: Acetonitrile : Water (90:10 v/v); Elution: Gradient; Mobile phase-A: Buffer : Mobile phase-B: Acetonitrile : Water (90:10 v/v); Buffer: 1.36 grams of potassium dihydrogen orthophosphate in 1000 ml of water and filtered through 0.22 um Nylon membrane filter paper.
HPLC Method of Analysis:
The (±)-2-hydroxy-5-[(l RS)-1 -hydroxy-2-[[(l RS)-2-(4-methoxyphenyl)-1 -methyl ethyl]-amino] ethyl]formanilide compound of formula-1 and its intermediates obtained in the present invention were analyzed by HPLC under the following conditions:
l-(3-Amino-4-(benzyloxy)phenyl)-2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino) ethanol malic acid compound of Formula-lOa:

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 : Acetonitrile (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 Dipotassium hydrogen ortho phosphate in 1000 ml of water and filtered through 0.22 um Nylon membrane filter paper.
(±)-2-Hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-l-methylethylJ-amino] ethyl] formanilide compound of formula-1 and its fumarate dihydrate compound of formula-la:
Apparatus: A liquid chromatographic system equipped with variable wavelength UV-detector; Column: Zorbax SB C8, 150 x 4.6 mm, 5.0 urn (or) equivalent; Flow rate: 1.0 ml/min; Wavelength: 214 nm; Column Temperature: 25°C; Injection volume: 20 uL; Run time: 55 min; Diluent: Solution-A : Acetonitrile (84:16); Elution: Gradient; Mobile phase-A: Acetonitrile; Mobile phase-B: 3.73 grams of sodium dihydrogen phosphate monohydrate and 0.35 grams of phosphoric acid in 1000 ml of water and filtered through 0.22 um Nylon membrane filter paper; Solution-A: 6.10 grams of sodium dihydrogen phosphate monohydrate and 1.03 grams of disodium hydrogen phosphate dihydrate in 1000 ml of water and filtered through 0.22 um Nylon membrane filter paper.
P-XRD method of Analysis
PXRD analysis of compound of formula-10a and 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 Formoterol fumarate dihydrate:
The particle size distribution of formoterol fumarate dihydrate compound of formula-la is measured using Malvern Master sizer 2000 instrument.
The (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-l-
methylethyl] -amino] ethyl] formanilide fumarate dihydrate 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 provides an improved process for the preparation of formoterol fumarate dihydrate compound of formula-la which contains the unwanted isomers (RS and SR) below the pharmacopoeia limit (<0.3%) and which meets the specifications of the European Pharmacopoeia monograph. According to EP monograph nine impurities are identified and the limits for these impurities are fixed. List of the nine impurities with their limit and comparison with MSNL is given below.

The best mode of carrying out the present invention is illustrated by the below mentioned examples. These examples are provides as illustration only and hence should not be construed as limitation of the scope of the invention.

Examples:
Example-l: Preparation of 4-Hydroxy-3-nitroacetophenone [Formula-3]
4-Hydroxyacetophenone (500 gms) was slowly added to a pre-cooled cone, sulfuric acid (1800 ml) at 10-15 °C and stirred the reaction mixture for 20 minutes at the same temperature. Cone, 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 water at 5-10°C. Raised the temperature of the reaction mixture to 25-3 0°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid and washed with 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 at the same temperature. 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, washed with toluene and dried to get the title compound. Yield:430 g ; Melting point: 129-133°C.
ExampIe-2: Preparation of 4-Benzyloxy-3-nitroacetophenone (Formula-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. Benzyl chloride (384.3 gms) was slowly 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. Cooled the reaction mixture to 25-30°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 25-30°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-nitrophenyi)-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 25-30°C and stirred the reaction mixture for 2 hours at the same temperature. 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 N-benzyl-l-(4-methoxyphenyl)propan-2-amine
hydrochloride (Formula-7a)
Methanol (1250 ml) was added to 4-Methoxy phenyl acetone (250 gms) at 25-30°C. Cooled the reaction mixture to 0-5°C. Benzyl amine (179.5 gms) was slowly added to the above reaction mixture at 0-5°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 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 25-30°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. Ethyl acetate was added to the obtained residue at 25-3 0°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 gms.
Example-5: Preparation of 2-(Benzyl(l-(4-methoxyphenyl)propan-2-yI)amino)-l-(4-(benzyloxy)-3-nitro phenyl)ethanone: (Formula-8)
Methylene chloride (600 ml) was added to a solution of N-benzyl-l-(4-methoxyphenyl)propan-2-amine hydrochloride (233.3 gm) and water (1000 ml) at 25-30°C. pH of the reaction mixture was adjusted to 10 by using 20% aqueous sodium carbonate solution 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 completely from the organic layer and co-distilled with acetone. Acetone (1000 ml) was added to the obtained residue at 25-30°C. Potassium carbonate (78.9 gms) and l-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanone (200 gms) were added to the reaction mixture at 25-30°C and stirred for 5 hours at the same temperature. After completion of the reaction, water was added to the reaction mixture and stirred for 3 hours at 25-30°C. Filtered the precipitated solid and washed with water. To the obtained wet

solid, a mixture of ethyl acetate (600 ml) and isopropanol (600 ml) were at 25-30°C and stirred for 5 hours at the same temperature. Filtered the solid, washed with a mixture of ethyl acetate and isopropanol and dried to get the title compound. Yield: 190 gms; Melting point: 96-99°C; Purity by UPLC: 94.86%.
Example 6: Preparation of 2-(Benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzy!oxy)-3-nitro phenyl)ethanol: (Formula-9)
A mixture of methanol (625 ml) and toluene (1875 ml) were added to 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitro phenyl)ethanone (250 gms) at 25-30°C. Sodium borohydride (18.0 gms) was slowly added to the reaction mixture at 25-30°C and stirred for 2 hours at the same temperature. After completion of the reaction 95% aqueous acetic acid solution was added to the reaction mixture at 15-20°C and stirred for 15 minutes at 25-30°C. Both the organic and aqueous layers were separated and organic layer was washed with water and the resulting organic layer was taken into next step without isolation.
Example-7: Preparation of l-(3-Amino-4-(benzyloxy)phenyl)-2-(benzyl(l-(4-methoxy phenyl)propan-2-yl) amino)ethanol: (Formula-10)
Water (400 ml) was added to the compound of formula-9 obtained in example-6 at 25-30°C. Iron (159 gms) was added to the reaction mixture at 25-30°C. Heated the reaction mixture to 65-70°C and acetic acid (400 ml) was slowly added at 65-70°C for 3 hours. Stirred the reaction mixture for 3 hours at 65-70°C. Cooled the reaction mixture to 40-45°C and iron (26.5 gms) was added to the reaction mixture at the same temperature. Heated the reaction mixture to 65-70°C and stirred for 3 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C. Water was added the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Filtered the reaction mixture and washed with toluene. Both the organic and aqueous layers were separated and washed the organic layer with water. Distilled off the solvent completely from the organic layer and co-distilled with ethyl acetate. The resulting residue containing l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl(l-(4-methoxyphenyl) propan-2-yl)amino)ethanol compound of formula-10 was utilized in the next step without isolating from the reaction mixture. Example 8: Preparation of l-(3-Amino-4-(benzyloxy)phenyl)-2-(benzyl(l-(4-methoxy phenyl)propan-2-yl) amino)ethanol malic acid: (Formula-lOa)
Ethyl acetate (1000 ml) was added to the obtained compound in example-7 at 25-30°C. Malic acid solution {prepared by dissolving malic acid (63.7 gms) in methanol (250

ml)} was added to the reaction mixture at 25-30°C and stirred for 30 minutes at the same temperature. Heated the reaction mixture to 55-60°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 25-3 0°C and stirred for 4 hours at the same temperature. Filtered the precipitated solid, washed with ethyl acetate and dried to get the title compound. Yield: 125gms; Melting point: 130-135°C; Purity by HPLC: 99.90%. The PXRD of the obtained compound is shown in figure-1.
Example-9: Preparation of N-(5-(2-(Benzyl(l-(4-methoxvphenyl)propan-2-yl)amino)-l-hydroxyethyl)-2-(benzyloxy)phenyl)formamide (Formula-11)
Water (250 ml) and ethyl acetate (125 ml) were added to l-(3-amino-4-(benzyloxy) phenyl)-2-(benzyl(l-(4-methoxyphenyl)propan-2-yl) amino)ethanol malic acid (25.0 gms) at 25-30°C. Basefying the reaction mixture using 20% aqueous sodium carbonate solution at 25-30°C. Both organic and aqueous layers were separated and aqueous layer was extracted with ethyl acetate. Combined both the organic layers and washed with water. Distilled off the solvent completely from the organic layer and co-distilled with tetrahydrofuran. To the above obtained residue tetrahydrofuran (125 ml) was added at 25-30°C. Formic acid (58.4 ml) was slowly added to the reaction mixture at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 8 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-3 0°C and ethyl acetate was added at 25-3 0°C. Basefying the reaction mixture using 10% aqueous sodium carbonate solution at 25-30°C. Both the organic and aqueous layers were separated and aqueous layer was extracted with ethyl acetate. Combined the both organic layers and washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer to get the title compound. Yield: 20.2 gms.
Example-10: Preparation of N-(5-(2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-hydroxyethyl)-2-(benzyloxy)phenyl)formamide (Formula-11)
Water (500 ml) and ethyl acetate (500 ml) was added to l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl(l-(4-methoxyphenyl)propan-2-yl) amino)ethanol malic acid (100 gms) obtained in example-8 at 25-3 0°C. pH of the reaction mixture was adjusted using 20% Sodium carbonate solution {prepared by dissolving sodium carbonate (40 gms) in water (200 ml)} at 25-30°C. Both organic and aqueous layers were separated and aqueous layer was extracted with ethyl acetate. Combined both the organic layers and washed with water. Distilled off the solvent completely from the organic layer and co-distilled with tetrahydrofuran. Formic acid (58.4 ml) and tetrahydrofuran (500 ml) was added to the above obtained residue at 25-30°C for 1 hour. Heated the reaction mixture to 60-65°C and stirred

for 8 hours at the same temperature. After completion of the reaction, cooled the reaction mixture to 25-30°C and ethyl acetate was added at 25-30°C. pH of the reaction mixture was adjusted by using 10% sodium carbonate solution {prepared by dissolving sodium carbonate (30 gms) in water (300 ml)} at 25-30°C. Both the organic and aqueous layers were separated and aqueous layer is extracted from ethyl acetate. Combined both the organic layers and wash with sodium chloride solution. Distilled off the solvent completely from the organic layer. The resulting organic layer containing N-(5-(2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-hydroxyethyl)-2-(benzyloxy)phenyl)formamide compound of formula-11 was utilized in the next step without isolating from the reaction mixture.
Example-11: Preparation of N-(5-(2-(benzyI(l-(4-methoxyphenyl)propan-2-yl)amino)-l-hydroxyethyl)-2-(benzyloxy)phenyl)formamide fumaric acid (Formula-12a)
Methanol (100 ml) and ethyl acetate (900 ml) were added to the organic layer obtained in example-10 at 25-3 0°C and stirred for 15 minutes at the same temperature. Fumaric acid (22.1 gms) was added to the reaction mixture at 25-30°C and stirred for 4 hours at the same temperature. Filtered the precipitated solid, washed with a mixture of methanol and ethyl acetate and dried to get the tile compound. Yield: 71.5 gms; M.R: 130-135°C.
Example-12: Preparation of (±)-2-Hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxy phenyl)-l-methyl ethyl] -amino] ethyl] formanilide (Formula-1)
Water (700 ml) and ethyl acetate (700 ml) were added to the N-(5-(2-(benzyl(l-(4-
methoxy phenyl)propan-2-yl)amino)-1 -hydroxyethyl)-2-(benzyloxy)phenyl)formamide
fumaric acid (100 gms) at 25-30°C. pH of the reaction mixture was adjusted using 20% Sodium carbonate solution 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 from the organic layer. To the obtained residue, methnaol (400 ml) and ethyl acetate (400 ml) at 25-30°C and stirred the reaction mixture for 15 minutes at the same temperature. 5% Pd/C was added to the reaction mixture and hydrogenated for 8 hours under a hydrogen gas pressure of 4-5 kg/cm2 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 and co-distilled with acetone. To the obtained solid, acetone (40 ml) was added at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 10-15°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with acetone to get the title compound.

Yield: 65 gms; Purity by HPLC: 99.92%.
Example-13: Preparation of (±)-2-Hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxy phenyl)-l-methyl ethyl]-amino]ethyl]formanilide (Formula-1)
Methanol (75 ml) and ethyl acetate (75 ml) were added to the compound (20.0 gms) obtained in example-9 at 25-30°C and stirred the reaction mixture for 15 minutes at the same temperature. 5% Pd/C was added to the reaction mixture and hydrogenated for 8 hours under a hydrogen gas pressure of 4-5 kg/cm at 25-3 0°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 and co-distilled with acetone. To the obtained solid, acetone (40 ml) was added at 25-30°C. Heated the reaction mixture to 40-45°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 10-15°C and stirred for 2 hours at the same temperature. Filtered the precipitated solid, washed with acetone to get the title compound; Yield: 15 gms; Purity by HPLC: 99.90%; Impurity-A: 0.06%; Unknown Impurity: 0.04; Rest of the impurities B, C, D, F, G, H and I are not detected.
Example-14: Purification of (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxy phenyl)-l-methylethyl]-amino]ethyl]formanilide (Formula-1)
Methanol (100 ml) was added to (±)-2-Hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-l -methylethyl]-amino]ethyl]formanilide (40 gms) obtained by the process of example-13 at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 30 minutes at the same temperature. Active carbon (2.0 gms) was added to the reaction mixture at 60-65°C and stirred for 15 minutes at the same temperature. Filtered the reaction mixture through In¬flow bed and washed with methanol. Cooled the reaction mixture to 5-10°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, washed with chilled methanol and dried to get the title compound. Yield: 25 gms; Purity by HPLC: 99.94%; Impurity-A: 0.03%; Unknown Impurity: 0.02%; Impurity-G: 0.01%; Rest of the impurities B, C, D, F, H and I are not detected;The PXRD of the obtained compound is shown in figure-3.
Example-15: Purification of (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxy phenyl)-l-methylethyl] -amino]ethyl]formanilide fumarate dihydrate (Formula-la)
60% Aqueous methanol solution {prepared by adding methanol (60 ml) to water (90 ml)} was added to (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-l-methylethyl]-amino]ethyl]formanilide (30 gms) at 25-30°C. Heated the reaction mixture to 60-65°C and stirred for 45 minutes at the same temperature. Active carbon (3 gms) was added to the reaction mixture at 60-65°C and stirred for 10 minutes. Filtered the reaction

mixture through hi-flow bed and washed with 60% aqueous methanol. To the obtained filtrate 60% aqueous methanol was added at 25-30°C. Fumaric acid solution {prepared by dissolving fumaric acid (5.1 gms) in 20% aqueous isopropanol} was added to the reaction mixture at 25-30°C. Heated the reaction mixture 60-65°C and stirred for 30 minutes at the same temperature. Cooled the reaction mixture to 5-10°C and stirred for 3 hours at the same temperature. Filtered the precipitated solid, and washed with 60% aqueous methanol and dried to get the title compound. Yield: 26 gms; Purity by HPLC: 99.86%; Impurity-A: 0.06%; Unknown Impurity: 0.02%; Rest of the impurities B, C, D, F, H, G and I are not detected. Water content: 4.5%. Fumaric acid content: 14.2%. Particle size distribution: D(0.1) is 0.62 Urn; D(0.5) is 1.45 um; D(0.9) is 3.43 urn.
Example-16: Purification of (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxy phenyl)-l-methylethyl] -aminojethyl]formanilide fumarate dihydrate (Formula-la)
The above example can be repeated by taking 20% aqueous isopropanol instead of aqueous methanol to get the title compound.
Example-17: Preparation of N-(2-hydroxy-5-(l-hydroxy-2-(l-(4-methoxyphenyl) propan-2-yl-amino)ethyl) phenyl)formamide (Formula-1)
Water (300 ml) and ethyl acetate (350 ml) were added to the N-(5-(2-(benzyl(l-(4-
methoxy phenyl)propan-2-yl)amino)-1 -hydroxyethyl)-2-(benzyloxy)phenyl)formamide
fumaric acid (50 gms) obtained in example-11 at 25-30°C. pH of the reaction mixture was adjusted using 20% Sodium carbonate solution 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 from the organic layer. To the obtained residue, ethanol (770) at 25-30°C and stirred the reaction mixture for 15 minutes at the same temperature. Pd/C (23.6 gms) was added to the reaction mixture and hydrogenated for 8 hours under a hydrogen gas pressure of 4-5 kg/cm2 at 25-30°C. After completion of the reaction, filtered the reaction mixture through hi-flow bed and washed with ethanol. Distilled off the solvent completely. Ethanol (20 ml) was added to the obtained compound at 25-3 0°C and stirred for 1 hour at the same temperature. Filtered the solid, washed with ethanol and dried to get the title compound. Yield: 65 gms; Purity by HPLC: 99.92%; The PXRD of the obtained compound is shown in figure-3.

We Claim:
1. An improved process for the preparation of (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-l-methylethyl]-amino]ethyl] formanilide compound of formula-1 and its fumarate dihydrate compound of formula-la, comprising of the following steps:
a) Condensing the N-benzyl-l-(4-methoxyphenyl)propan-2-amine compound of formula-7,
with l-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanone compound of formula-5
in presence of a suitable base in a suitable solvent to provide 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanone compound of formula-8,
b) reducing the keto group of compound of formula-8 with a suitable reducing agent in a suitable solvent to provide 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanol compound of formula-9,
c) reducing the nitro group of compound of formula-9 with a suitable reducing agent in a suitable solvent to provide l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)ethanol compound of formula-10,

d) treating the compound of formula-10 in-situ with malic acid in presence of a suitable solvent to provide l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl(l-(4-methoxyphenyl) propan-2-yl)amino) ethanol malic acid salt compound of formula-10a,
e) neutralizing the compound of formula-10a with a suitable base in a suitable solvent to provide compound of formula-10,
f) reacting the compound of formula-10 in-situ with formic acid in presence of a suitable solvent to provide N-(5-(2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-hydroxyethyl)-2-(benzyloxy)phenyl)formamide compound of formula-11,
g) optionally, converting the compound of formula-11 into its acid addition salts compound of general formula-12 by treating it with a suitable acid in a suitable solvent,
followed by neutralizing the obtained salt with a suitable base provides compound of formula-11,
h) debenzylating the compound of formula-11 in-situ by treating it with a suitable debenzylating agent in a suitable solvent to provide (±)-2-Hydroxy-5-[(lRS)-l-hydroxy-2- [ [(1 RS)-2-(4-methoxyphenyl)-1 -methylethyl] -amino] ethyl] formanilide compound of formula-1,
i) converting the compound of formula-1 into its fumarate dihydrate salt compound of formula-la by treating with fumaric acid in a suitable solvent to provide (±)-2-Hydroxy-5-[(l RS)-1 -hydroxy-2-[[(l RS)-2-(4-methoxyphenyl)-1 -methylethyl] -amino] ethyl] formanilide fumarate dihydrate compound of formula-la.
2. The process according to claim-1, wherein,

in step-a) the suitable base used is selected from organic or inorganic bases; preferably
inorganic bases and the suitable solvent is selected from chloro solvents, ester solvents,
ketone solvents, alcohol solvents, polar solvents such as water or mixture thereof.
in step-b) the suitable reducing agent used is selected form metal hydrides such as sodium
borohydride, sodium cyanoborohydride and sodium triacetoxyborohydride; preferably
sodium borohydride and suitable solvent is selected form alcohol solvents, hydrocarbon
solvents, ester solvents, ether solvents, ketone solvents or mixture thereof.
in step-d), f) & i) the suitable solvent used is selected form alcohol solvents, hydrocarbon
solvents, ester solvents, chloro solvents, ether solvents, ketone solvents, polar solvents
such as water or mixture thereof.
3. An improved process for the preparation of (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxy phenyl)-l-methylethyl]-amino]ethyl] formanilide compound of formula-1 and its fumarate dihydrate salt compound of formula-la, comprising of the following steps;
a) Condensing the N-benzyl-l-(4-methoxyphenyl)propan-2-amine compound of formula-7 with l-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanone compound of formula-5 with potassium carbonate in acetone to provide 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-1 -(4-(benzyloxy)-3-nitrophenyl) ethanone compound of formula-8,
b) reducing the keto group of compound of formula-8 with sodium borohydride in a mixture of toluene and methanol to provide 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitro phenyl)ethanol compound of formula-9,
c) reducing the nitro group of compound of formula-9 with iron in a mixture of acetic acid and water to provide l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)ethanol compound of formula-10,
d) treating the compound of formula-10 in-situ with malic acid in presence of a mixture
of ethyl acetate and methanol to provide l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl(l-(4-methoxyphenyi) propan-2-yl)amino)ethanol malic acid salt compound of formula-10a,
e) neutralizing the compound of formula-10a with sodium carbonate in a mixture of ethyl acetate and water provides compound of formula-10,
f) reacting the compound of formula-10 in-situ with formic acid in presence of tetrahydrofuran to provide N-(5-(2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-

l-hydroxyethyl)-2-(benzyloxy) phenyl)formamide compound of formula-11, g) optionally, converting the compound of formula-11 into fumarate salt compound of formula-12a, followed by neutralizing the obtained salt with sodium carbonate in a mixture of ethyl acetate and water provides compound of formula-11, h) debenzylating the compound of formula-11 in-situ with Pd/C in a mixture of methanol and ethyl acetate to provide (±)-2-hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-l-methyl ethyl] -amino] ethyl] formanilide compound of formula-1, i) converting the compound of formula-1 into its fumarate dihydrate salt compound of formula-la by treating it with fumaric acid in a mixture of water and methanol to provide (±)-2-hydroxy-5-[(lRS)-1 -hydroxy-2-[[(lRS)-2-(4-methoxyphenyl)-1 -methyl ethyl]-amino] ethyl] formanilide fumarate dihydrate compound of formula-la.
4. A process for the preparation of 2-(benzyl( 1 -(4-methoxyphenyl)propan-2-yl)amino)-1 -(4-(benzyloxy)-3-nitrophenyl)ethanone compound of formula-8, comprising of condensing N-benzyl-l-(4-methoxyphenyl)propan-2-amine compound of formula-7 with l-(4-(benzyloxy)-3-nitrophenyl)-2-bromoethanone compound of formula-5 in presence of a suitable base selected from inorganic bases such as alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides and alkali metal alkoxides, preferably potassium carbonate in a suitable solvent selected from chloro solvents, ester solvents, ketone solvents, alcohol solvents, polar solvents such as water or mixture thereof preferably acetone to provide 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-(benzyloxy)-3-nitrophenyl)ethanone compound of formula-8.
5. A process for the preparation of 2-(benzyl( 1 -(4-methoxyphenyl)propan-2-yl)amino)-1 -(4-(benzyloxy)-3-nitrophenyl)ethanol compound of formula-9, comprises of reducing the 2-(benzyl( 1 -(4-methoxyphenyl)propan-2-yl)amino)-1 -(4-(benzyloxy)-3 -nitrophenyl) ethanone compound of formula-8 with sodium borohydride in a suitable solvent to provide compound of formula-9.
6. The process according to claim 5, wherein, the suitable solvent is selected from alcohol solvent, hydrocarbon solvent, ester solvents, ether solvents, ketone solvents or mixture thereof and the ratio of methanol and toluene used in the above aspect is in between 1.0:9.0, preferably between 3.0:7.0, more preferably between 1.0:3.0 per one mole equivalent of compound of formula-8.
7. 1 -(3-Amino-4-(benzyloxy)phenyl)-2-(benzyl(l -(4-methoxyphenyl)propan-2-yl)amino) ethanol malic acid, represented by the following structural formula.

8. Crystalline form-M of l-(3-amino-4-(benzyloxy)phenyl)-2-(benzyl(l-(4-methoxyphenyl)
propan-2-yl)amino)ethanol malic acid compound of formula-10a, characterized by:
a) Its powder X-ray diffractogram having peaks at 5.6, 6.8, 7.7, 9.5, 12.0, 12.6, 13.8, 15.5, 16.2, 17.2, 18.7, 19.0, 19.3, 19.7, 20.0, 20.6, 21.2, 21.7, 22.0, 22.8, 23.4, 23.5, 24.2, 25.2, 25.9, 26.4, 27.9, 28.4, 29.2, 31.3, 32.3, 34.2, 35.0, 36.9 and 40.1 ± 0.2 degrees of two-theta as illustrated in figure-1;
b) its DSC thermogram showing endotherm at 152.50°C as illustrated in figure-2.
9. A process for the purification of (±)-2-Hydroxy-5-[(lRS)-l-hydroxy-2-[[(lRS)-2-(4-
methoxy phenyl)-1-methyl ethyl]-amino]ethyl]formanilide compound of formula-1,
comprising of:
a) Dissolving the compound of formula-1 in acetone,
b) heating the reaction mixture,
c) cooling the reaction mixture,
d) filtering the precipitated solid provides (±)-2-Hydroxy-5-[(lRS)-l-hydroxy-2-[ [(1 RS)-2-(4-methoxyphenyl)-1 -methylethyl]-amino] ethyl] formanilide compound of formula-1.
10. A process for the purification of 2-(benzyl(l-(4-methoxyphenyl)propan-2-yl)amino)-l-(4-
(benzyloxy)-3-nitrophenyl)ethanone compound of formula-8,
a) Suspending the compound of formula-8 in a mixture of isopropanol and ethyl acetate,
b) stirring the reaction mixture at 25-30°C,
c) filtering the solid and drying provides the compound of formula-8.