FORM 2
THE PATENT ACT 1970
(39 of 1970)
The Patents Rules, 2003 COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
Process for Green Synthesis of (l.R)-2-{ [2- (4-aminophenyl) ethyl] amino}-1-phenylethanol and its Dihydrochloride, an intermediate for Mirabegron
2. APPLICANT (S)
(a) NAME: Wanbury Ltd.
(b) NATIONALITY: An Indian Company incorporated under the Indian Companies ACT 1956.
(c) ADDRESS:
Wanbury Ltd., BSEL Tech park, B-wing, 10th floor, sec -30A, opp. Vashi Railway station, Vashi, Navi- Mumbai-400703, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed.

Process for Green Synthesis of (1R) -2-{ [2- (4-aminophenyl) ethyl] amino}-l-phenylethanol and its Dihydrochloride, an intermediate for Mirabegron
Field of the invention:
The present invention relates to a process for a green synthesis of (2R)-2-Phenyloxirane Formula 2. (2R) -2-Phenyloxirane Formula 2 is then condensed with an intermediate resulting from reaction of 4-Nitrophenylethylamine Hydrochloride with Benzyl halide. The intermediate resulting from the condensation reaction is reduced to produce (li?) -2-{ [2- (4-aminophenyl) ethyl] amino}-l-phenylethanol and its Dihydrochloride Formula 5 and Formula 5a.
Brief description of the invention:
, The first aspect of the present invention is to provide a process for the preparation of {1R)-2-{ [2- (4-aminophenyl) ethyl] amino}-1-phenylethanol compound of Formula-5 and its Dihydrochloride compound of Formula-5a.
The second aspect of the present invention is to provide a process for the preparation of (R)-2-chloro-1-phenylethanol of Formula-1.
The third aspect of the present invention is to provide an in-situ process for the preparation of (2R)-2-Phenyloxirane of Formula-2 from (R)-2-chloro-l-phenylethanol of Formula-1.

The fourth aspect of the present invention is to provide a process for the preparation of N-benzyl-2- (4-nitrophenyl) ethanamine of Formula-3, comprising of N-alkylation of 2- (4-nitro phenyl) ethanamine hydrochloride compound of Formula-lb with benzyl halide.
The fifth aspect of the present invention is to provide a process for the preparation of (R)-2-(benzyl (4-nitrophenethyl) amino)-1-phenylethanol of Formula-4, . comprising of reaction with N-benzyl-2-(4-nitrophenyl) ethanamine of Formula-3 and (2R)-2-Phenyloxirane of Formula-2.
Detailed description of the invention:
The term wsuitable solvent7' used in the present invention refers to w hydrocarbon solvents'' such as n-heptane, n-pentane, cyclohexane, methyl cyclohexane, c yclo heptanes, pet ether, chloro benzene, toluene, xylene and the like; A' ether solvents' ' such as di methyl . ether, Diisopropyl ether, methyl tert-butyl ether, di- tert-butyl ether, dimethoxy methane, 1,2-dimethoxy ethane (monoglyme), diglyme, 1,4-dioxane, tetrahydrofuran,2-methyl tetrphydro furan, Morpholine and the like; w ester solvents'' such as methyl acetate, ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, Iso-butyl acetate, tert-butyl acetate, diethyl carbonate and the like;'' polar solvents'' such as Dimethyl acetamide (DMAc) , N,N-dimethyl formamide(DMF) , dimethyl sulphoxide (DMSO), N-methyl-2-pyrrolidone (NMP), hexamethyl phosphoramide

(HMPA) , Acetic acid and like w chloro solvents' ' such as Dichloro methane, Dichloro ethane, chloroform, carbon tetrachloride and the like , w ketone solvents such as acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone, and the like; A' alcoholic solvents'' such as methanol, ethanol, n-propanol, iso propanol, n-butanol, iso-butanol, tert-butanol, 2-pentanol, ethylene glycol, diethylene glycol, propylene glycol, 2-ethyl hexanol, benzyl alcohol and the like; wpolar solvents'' such as water and/or mixtures thereof.
As used here in the present invention the term w suitable base A' refers to *' alkali metal carbonates'' such as sodium carbonate, potassium carbonate, lithium carbonate and the like ; x' alkali metal; bicarbonates'' such as sodium bicarbonate, potassium bicarbonate and the like w alkali metal hydroxides'' such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like *'organic bases'' such as methyl amine, Diisopropyl amine, diisopropylethyl amine, triethylamine, pyridine, and the like *'hydrogenation reagents'' such as Nickel ,raney Nickel, Pd/C, Pt/C, Pt02, Pd(0H)2.
The first aspect of the present invention is to provide a process for the preparation of (1R)-2-{ [2- (4-aminophenyl) ethyl] amino}-1-phenylethanol compound of Formula-5 and its Dihydrochloride compound of Formula-5a, comprising of;
a) Condensing the (2R) -2-Phenyloxirane compound of Formula-2

With N-benzyl-2-(4-nitrophenyl) ethanamine compound of formula-3
In presence of a suitable alcohol solvent and or as neat reaction of Formula-3 and Formula-2 to provide (R)-2-(benzyl (4-nitrophenethyl) amino)-1-phenylethanol compound of Formula-4
b) reducing the compound of formula-4 with a suitable
reducing agent in a suitable solvent to provide
(1R)-2-{[2-(4-aminophenyl) ethyl] amino}-l-
phenylethanol of Formula-5 or its Dihydrochloride of
Formula-5a

c) optionally converting the compound of Formula-5 into its Dihydrochloride salt compound of Formula-5a
Where in, in step-a)
i) the said reaction conducted in suitable solvent
is selected from alcohol solvent
ii) the said reaction conducted as neat reaction of
Formula-3 and Formula-2 to provide (R)-2-(benzyl (4-
nitrophenethyl)amino)-1-phenylethanol compound of
Formula-4
Where in, in step-b)
the suitable hydrogenation reagent is selected from
Nickel ,raney Nickel, Pd/C, Pt/C, Pt02, Pd(0H)2 and the
like; and the suitable solvent is selected from
alcoholic solvent, ester solvent, polar solvents and
mixtures thereof;
in step-c) the conversion of * compound -5 into its HC1
salt compound of Formula-5a is carried out by using a
suitable HC1 source selected from HC1 gas, Aq HC1,
Ethyl acetate-HCl , Methanol-HCl and IPA-HC1 in a
suitable solvent.

A preferred embodiment of the present invention provides a process for the preparation of (lJ?)-2-{[2-(4-aminophenyl) ethyl] amino}-1-phenylethanol compound of Formula-5 and its Dihydrochloride compound of Formula-5a, comprising of;
a) Condensing the (2R)-2-Phenyloxirane compound of Formula-2 with AJ-benzyl-2- (4-nitrophenyl) ethanamine compound of formula-3 to provide (R)-2-(benzyl(4-nitrophenethyl)amino)-1-phenylethanol compound of Formula-4
b) Reducing the (R)-2-(benzyl (4-nitrophenethyl) amino)-1-phenylethanol compound of Formula-4 with Pd-C under hydrogen atmosphere in mixture of Methanol and ethyl acetate to provide (li?) -2-{ [2- (4-aminophenyl) ethyl] amino}-1-phenylethanol compound of Formula-5
Purifying the compound obtained in step-b by recrystalisation with hydrocarbon solvent for to control the impurity (<0.1%) which is Formula-6
rormuia-o
Purifying the compound obtained in step-b by recrystalisation twice with hydro carbon solvent for to complete removal of Formula-6.
The prior reported process involves the reduction of Formula-4 to Formula-5 using Pd-C in methanol. When we carried out the same experiment in our laboratory for above 50g scale, we have found that reaction not completing totally and needs more heat and more

maintenance time to complete. Due to this increasing of temperature unwanted chiral impurity gets increasing and as well as yields are decreasing. We found that this mainly due to solubility issue in Methanol. Whereas, in the present invention of the same reaction carried out in the solvent mixture contain Methanol and Ethyl Acetate instead of only methanol, the solubility of the Formula-4 is good and thereby enhanced the purity and yields of step-b.
c) Converting the Compound of Formula-5 into its hydrochloride salt by treating it with Methanol-HCl in Methanol to provide (lR)-2-{[2-(4-aminophenyl) ethyl] amino}-1-phenylethanol Dihydrochloride compound of Formula-5a
W02014/13227 0 patent discloses the condensation of (2R)-2-Phenyloxirane (2.Omoles) compound of Formula-2 with AT-benzyl-2- (4-nitrophenyl) ethanamine (1.0 moles) compound of formula-3 in isopropanol at reflux temperature for 24hrs. However yields are coming in this process is 52% only. Hence not suggestible.
The present inventors carried out the said reaction step without using of solvent media, that is neat reaction between (2R)-2-Phenyloxirane (1.Omoles) compound of Formula-2 and N-benzyl-2-(4-nitrophenyl) ethanamine (1.Omoles) compound of formula-3 at 40 to 45°C for 6-8 hrs to give 80% yields. In this process the main advantage is decreased 1.0 molar ratio of (2R)-2-Phenyloxirane by completely removed the solvent media and decreased the reaction maintenance time and finally increased yields upto 25-30% and hence the

process of the present invention is advantageous over prior-art process.
The second aspect of the present invention provides a process for the preparation of . (R)-2-chloro-l-phenylethanol of Formula-1, comprising of; Converting 2-Chloro-l-phenylethanone compound of Formula-la to Formula-1
with ketoreductase enzyme, buffer with a co solvent at appropriate pH and temperature;
Where in, the suitable enantio selective reduction enzyme KRED 2-1-1 selected from Ketoreductase group of enzymes; the suitable co-factor selected as NAD or NADP and the like; the suitable co-solvent selected from alcoholic solvents -
A preferred embodiment of the present invention provides a process for the preparation of (R)-2-chloro-1-phenylethanol of Formula-1, comprising of; Enzymatic reduction of 2-Chioro-1-phenylethanone compound of Formula-la in potassium phosphate buffer solution by using KRED 2-1-1 enzyme and using NAD or NADP as co-factor and isopropanol or 2-butanol using as co-factor regeneration to provide (R)-2-chloro-l-phenylethanol of Formula-!

The third aspect of the present invention provides in-situ process for the preparation of (2R)-2-Phenyloxirane of Formula-2, comprising of, Converting of (R)-2-chloro-l-phenylethanol of Formula-1 to Formula-2 in the presence of basic media
Where in, In-situ conversion reaction mass contain Formula-1 by treating with basic aqueous media provides formula-2 and the basic reagent is selected from inorganic base such as NaOH, KOH, LiOH, K2C03, Na2C03, NaHC03.
A preferred embodiment of the present invention provides a process for the preparation of (2R)-2-Phenyloxirane of Formula-2, comprising of, In-situ reaction conversion of (R)-2-chloro-l-phenylethanol of Formula-1 by using Aq NaOH solution to provide (2R)-2-Phenyloxirane of Formula-2.
The fourth aspect of the present invention provides a process for the preparation of AT-benzyl-2- (4-nitrophenyl) ethanamine of Formula-3, comprising of

N-Benzylation of 2- (4-nitro phenyl) ethanamine hydrochloride compound of Formula-lb with benzyl halide in basic conditions.
Where in, the benzyl halide is selected from Benzyl chloride, Benzyl Bromide, Benzyl iodide and the like; suitable base is selected from * organic or inorganic bases; and the suitable solvent is selected from polar solvents, ketone solvents, chloro solvents.
The 2-(4-nitro phenyl) ethanamine hydrochloride compound of Formula-lb utilized in the fourth aspect of the present invention can be synthesized by any of the prior reported processes, for example it can be synthesized by the processes disclosed in j.Org. Chem., 1978, 43(1), 31-33 and Tetrahedron Letters, Volume 10, issue 52, 1969, 4555-4558.
A preferred embodiment of the present invention provides a process for the preparation of AT-benzyl-2-
(4-nitrophenyl) ethanamine of Formula-3, comprising of Reaction of 2-(4-nitro phenyl) ethanamine hydrochloride compound of Formula-lb with Benzyl chloride in presence of triethylamine in Chloroform to provide N-benzyl-2-
(4-nitrophenyl) ethanamine of Formula-3,

Purifying the obtained compound of Formula-3 in fourth aspect by recrystalisation with Hexane to provide compound of Formula-3
The fifth aspect of the present invention is to provide a process for the preparation of (R)-2-(benzyl (4-nitrophenethyl) amino) -1-phenylethanol of Formula-4', comprising of
Reaction with AT-benzyl-2-(4-nitrophenyl) ethanamine of Formula-3 and (2R)-2-Phenyloxirane of Formula-2.
Where in, the said reaction between Formula-3 and Formula-2 in suitable solvent selected from alcohol solvents such as methanol, ethanol, Iso propanol, n-butanol.
Where in, the said reaction between Formula-3 and Formula-2 as neat reaction.
A preferred embodiment of the present invention provides a process for the preparation of (R)-2-(benzyl (4-nitrophenethyl) amino)-1-phenylethanol of Formula-4, comprising of;
Neat reaction between Af-benzyl-2- (4-nitrophenyl) ethanamine compound of Formula-3 and (2R)-2-Phenyloxirane compound of Formula-2 to provide (R)-2-

(benzyl (4-nitrophenethyl) amino)-1-phenylethanol compound of Formula-4,
Purifying the obtained compound of Formula-4 in fifth aspect by recrystalisation with Methanol to provide compound of Formula-4.
The present invention is schematically represented as follows. Scheme-I:

The impurities that are formed during the synthesis of (1R)~2~{[2-(4-aminophenyl) ethyl] amino}-l-phenylethanol compound of Formula-5 and its Dihydrochloride compound of Formula-5a are as follows

(1R)-2-{[2-(4-aminophenyl) ethyl] amino}-!-phenylethanol obtained by the present invention is having purity about 99.0% by HPLC. All the impurities that are formed during the synthesis of Compound of Formula-5 and its Dihydrochloride salt of Formula-5a are controlled (Limits: Formula-6 NMTO.1%, Formula-4 NMT 0.15% and S-isomer NMT 0.15%) to not detected level.
a) In this scheme-1, Des Hydroxy Impurity of Formula-6(NMT-0.1%) was controlled by recrystalisation with Xylene
b) In this scheme-1, Des Hydroxy Impurity of Formula-6(Should be absent) was controlled by recrystalisation Twice with Xylene
(1R)-2-{[2-(4-aminophenyl) ethyl] amino}-l-phenylethanol and its related substances are measured by using HPLC with the following chromatographic conditions:
Apparatus: A liquid chromatography is equipped with variable wane length UV-detector; Column: Cosmosil C18(

250 x 4.6) nun, 5pm or equivalent; Flow rate: 1.0 ml/min; Elution: Gradient; Wave length: 236 nm; Column
temperature: 25° C; Injection volume: 10 jiL; Run time: 45 min; Diluent : Buffer : Methanol (50:50 v/v); Mobile phase A: Buffer; Mobile phase B: Methanol; Buffer preparation: Transfer 0.68 g of potassium Dihydrogen ortho phosphate in 1000 mL water, adjust pH 3.6 with dilute orthophosphoric acid, filter through 0.45p. membrane filter.
The Retention time of mirabegron is about 6 minutes. The relative retention times are given below

S.No. Name RRT
1 Formula-5 1.0
2 Formula-6 1.2 2
3 Formula-4 3.8
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 constructed as limitation to the scope of the invention.
Examples:
Example-1: Preparation of (R)-2-chloro-l-phenylethanol (Formula-1)
"4
Isopropyl alcohol (7 5ml) containing 2-Chloro-l-phenylethanone compound of Formula-la (lOOg) were added to the mixture containing KRED 2-1-1 (0.5g), NAD (O.OOlg), and Phosphate Buffer of ,pH 6.0±0.5 (200ml) at 46°C and stirred at same temperature for 24hrs. Added Acetone (100ml) and stirred for 15min for enzyme precipitation. Filtered the enzyme precipitated solids

and obtained mother liquor were goes to next stage without isolation of the Formula-1.
Example-2: Preparation of (2R)-2-Phenyloxirane (Formula-2)
To the above reaction mass obtained in Example-1 added Aqueous NaOH solution (28.lg, l.lmoles in 50ml of water) at 25-30°C and stirred at same temperature for 2hrs. Ethyl Acetate (1000ml) was added to the reaction mixture at 25-30°C and stirred for 15 min. Separated the both aqueous and organic layers and the organic layer was washed with 5% NaCl solution (1000ml) and finally with water(100ml). Distil off the solvents completely from the organic layer under reduced pressure to get the title compound. Yield: 73.7g (95%). 1H-NMR (CDC13, 4 00 MHz) : 2.7 9 (dd, 1H) , 3.14 (t, 1H) , 3.85 (t, 1H), 7.31 (m, 5H); Mwt: M+l:120.7
Example-3: Preparation of N-benzyl-2-(4-nitrophenyl) ethanamine (Formula-3)
Chloroform (100ml) solution containing Benzyl chloride
(62.6g, l.Omole) were added to the Chloroform
containing 2-(4-nitro phenyl) ethanamine hydrochloride
(lOOg, lmole) compound of Formula-lb, Triethyl amine
(125g, 2.5moles) at 0-5°C for 15min.The reaction
mixture was slowly heated to 4 5°C and maintained at
same temperature for 24hrs. Water was added to the
reaction mass and the layers were separated. Distill
off the solvent completely from the organic layer under
reduced pressure. Hexane was added to the obtained
crude material, heated the reaction mass to 50-55°C and
stirred for 30min at the same temperature. Filtered the

title compound and dried at 30-35°C to get the title
compound. Yield: 69.5 6g (55%)
^-NMR (DMSO, 400 MHz):2.11 (br, 1H) , 2.84 (dd, 4H) ,
3.7 (s, 2H), 7.2(m, 5H), 7.47 (d, 2H), 8.11(d, 2H) Mwt:
M+l:256.29
Example-4:
Example-4.1:
Preparation of (R) -2-(benzyl (4-nitrophenethyl) amino)-
1-phenylethanol (Formula-4)
Isopropyl alcohol (20ml) solution contain N-benzyl-2-(4-nitrophenyl) ethanamine compound of formula-3 (2g, l.Omole) and (2R)-2-Phenyloxirane compound of Formula-2 (1.87g, 2.Omoles) at 25-30°C. Slowly heated the reaction mass to 55-60°C and maintained at same temperature for 24hrs. Distilled off the solvents completely to get crude material. Hexane (10ml) was added to this crude and stirred for 15min. Decaned the solvents and was added methanol (10ml) to the obtained crude material and was heated to 40-45°C and maintained for 15min. Cooled the reaction mass to 0-5°C. Filtered and dried at 50-55°C to get the title compound. Yield: 0.87g (30%); XH-NMR (DMSO, 4 00 MHz):2.64 (t, 2H), 2.71 (t, 2H), 3.69 (q, 2H) , 4.67 (br, 1H) , 4.98 (s, 1H) 7.2 (m, 5H) , 7.22 (m, 4H) , 7.32 (d, 2H) , 8- 05 (d, 2H) , Mwt: M+l:377.1
Example-4.2:
Preparation of (R)-2-(benzyl (4-nitrophenethyl) amino)-
1-phenylethanol (Formula-4)
DMF (20ml) solution contain N-benzyl-2-(4-nitrophenyl) ethanamine compound of formula-3 (2g, 1.Omole) and (2R)-2-Phenyloxirane compound of Formula-2 (1.87g,

2.Omoles) at 25-30°C. Slowly heated the reaction mass to 55-60°C and maintained at same temperature for 24hrs. Distilled off the solvents completely to get crude material. Water (20ml) was added to this crude and stirred for 15min. Compound was extracted with ethyl acetate (20ml) . Separated the both aqueous and organic layers and the organic layer was washed with 5% NaCl solution (10ml) and finally with water (10ml). Distil off the solvents completely from the organic layer under reduced pressure to get the crude compound. Methanol (10ml) was added to the obtained crude material and was heated to 4 0-45°C and maintained for 15min. cooled the reaction mass to 0-5°C. Filtered and dried at 50-55°C to get the title compound. Yield: 0.638g (23%)
Example-4.3:
Preparation of (R) -2- (benzyl (4-nitrophenethyl) amino)-
1-phenylethanol (Formula-4)
Tert-butanol (20ml) solution contain N-benzyl-2-(4-nitrophenyl) ethanamine compound of formula-3 (2g, l.Omole) and (2R)-2-Phenyloxirane compound of Formula-2 (1.87g, 2.Omoles) at 25-30°C. Slowly heated the reaction mass to 55-60°C and maintained at same temperature for 24hrs. Distilled off the solvents completely to get crude material. Hexane (10ml) was added to this crude and stirred for 15min. Decaned the solvents and was added methanol (10ml) to the obtained crude material and was heated to 40-45°C and maintained for 15min. Cooled the reaction mass to 0-5°C. Filtered and dried at 50-55°C to get the title compound. Yield: 0.92g (32%)

Example-4.4:
Preparation of (R)-2-(benzyl (4-nitrophenethyl) amino)-
1-phenylethanol (Formula-4)
Methanol (20ml) solution contain N-benzyl-2-(4-nitrophenyl) ethanamine compound of formula-3 (2g, 1.Omole) and (2R)-2-Phenyloxirane compound of Formula-2 (1.87g, 2.0moles) at 25-30°C. Slowly heated the reaction mass to 55-60°C and maintained at same temperature for 24hrs. Distilled off the solvents upto 60% volume. Slowly cooled the reaction mass to 0-5°C and stirred for 15min at the same temperature. Filtered and dried at 50-55°C to get the title compound. Yield: 1.16g (40%)
Example-4.5:
Preparation of (R)-2-(benzyl (4-nitrophenethyl) amino) -
1-phenylethanol (Formula-4)
Methanol (7 04ml) solution contain N-benzyl-2-(4-nitrophenyl) ethanamine compound of formula-3 (88g, 1.Omole) and (2R)-2-Phenyloxirane compound of Formula-2 (70g, 1.7moles) at 25-30°C. Slowly heated the reaction mass to reflux temperature and maintained at same temperature for 18hrs. Distilled off the solvents upto 60% volume. Slowly cooled the reaction mass to 0-5°C and stirred for Ihr at the same temperature. Filtered and dried at 50-55°C to get the title compound. Yield: 71g (54.8%)
Example-4.6:
Preparation of (R)-2-(benzyl (4-nitrophenethyl) amino) -
1-phenylethanol (Formula-4)
Added N-benzyl-2- (4-nitrophenyl) ethanamine compound of formula-3 (lOOg, 1.Omole) and (2R)-2-Phenyloxirane

compound of Formula-2 (46.82g, l.Omoles) at 25-30°C. Slowly heated the reaction mass to 40-45°C and maintained at same temperature for 8hrs. Slowly cooled the reaction mass to 25-30°C and was charged Methanol (500ml) and maintained for 30min at same temperature. Cooled the reaction mass to 0-5°C and stirred for lhr at the same temperature. Filtered the compound and dried at 50-55°C to get the title compound- Yield: 117.5g (80%)
Example-5: Example-5.1:
Preparation of (1.R) -2-{ [2- (4-aminophenyl) ethyl] amino}-l-phenylethanol (Formula-5) and its Dihydrochloride salt (Formula-5a)
5% Pd-C (2.4g) was added to methanol (300ml) solution containing (R)-2-(benzyl (4-nitrophenethyl) amino)-1-phenylethanol compound of Formula-4 (30g) at 25-30°C. 6-8kg/Cm of hydrogen gas pressure was applied to the reaction mass at 25-30°C and stirred for 6hrs at the same temperature and pressure. Filtered the reaction mixture through hyflo bed, distilled off the solvent completely from the filtrate. Methanol (180ml) was added to the obtained crude at 25-30°C. Heated the reaction mixture to 40-45°C and was added Methanol-HCl (34ml) at the same temperature for 15min. cooled the reaction mixture to 0-5°C and stirred for 30min at the same temperature. Filtered the title compound of Formula-5a and dried at 40-45°C. HPLC .showing 99.38% purity with 0.04 % of Des Hydroxy Impurity of Formula-6 and Chiral Purity is 99.83%. Yield: 22.3g (85%); 1H-NMR (DMSO, 4 00 MHz) :2.96 (m, 3H) , 3.0 (m, 3H) , 4.99 (d, 1H), 6.21 (br, 1H), 7.05 (d, 2H), 7.19 (d, 2H), 7.31(m,

1H) , 7.38 (m, 4H) , 8.93(br, 3H) , 9.38 (br, 3H) , ;Mwt: M+l: 330.1
Example-5.2:
Preparation of (1R) -2-{[2-(4-aminophenyl) ethyl]
amino}-1-phenylethanol (Formula-5) and its
Dihydrochloride salt (Formula-5a)
5% Pd-C (2.4g) was added to mixture of methanol (150ml) and ethyl acetate (150ml)solution containing (R) -2-(benzyl (4-nitrophenethyl) amino)-1-phenylethanol compound of Formula-4 (30g) at 25-30°C. 6-8 kg/Cm2 of hydrogen gas pressure was applied to the reaction mass at 25-30°C and stirred for 6hrs at the same temperature and pressure. Filtered the reaction mixture through hyf lo bed, distilled off the solvent completely from the filtrate. Methanol (180ml) was added to the obtained crude at 25-30°C. Heated the reaction mixture to 40-45°C and was added Methanol-HCl (34ml) at the same temperature for 15min. cooled the reaction mixture to 0-5°C and stirred for 30min at the same temperature. Filtered the title compound and dried at 40-45°C. HPLC showing 99.54% purity with 0.25 % of Des Hydroxy Impurity of Formula-6 and Chiral Purity is 99.96%. Yield: 22g (84%) .
Example-5.3:
Preparation of (1R) -2-{[2-(4-aminophenyl) ethyl] amino}-1-phenylethanol (Formula-5) and its Dihydrochloride salt (Formula-5a)
5% Pd-C (2.4g) was added to mixture of methanol (150ml)
and ethyl acetate (150ml)solution containing (R)-2-
(benzyl (4-nitrophenethyl) amino)-1-phenylethanol
compound of Formula-4 (30g) at 25-30°C. 6-8kg/Cm2 of

hydrogen gas pressure was applied to the reaction mass at 25-30°C and stirred for 6hrs at the same temperature and pressure. Filtered the reaction mixture through hyflo bed, distilled off the solvent completely from the filtrate and the obtained compound was co-distilled with Xylene (30ml) . 120ml of Xylene was added to the obtained crude and was heated to 55-60°C and maintained for lhr at same temperature. Cooled the reaction mass to 25-30°C. Filtered the title compound of Formula-5. Added Methanol (180ml) to the compound of Formula-5 at 25-30°C. Heated the reaction mixture to 40-45°C and was added Methanol-HCl (34ml) at the same temperature for 15min. cooled the reaction mixture to 0-5°C and,stirred for 30min at the same temperature. Filtered the title compound and dried at 4 0-4 5°C. HPLC showing 99.31% purity with 0.04 % of Des Hydroxy Impurity of Formula-6 and Chiral Purity is 99.92%. Yield: 21.7g 82.8%.
Example-5.4:
Preparation of (IB) -2-{ [2- (4-aminophenyl) ethyl] amino}-1-phenylethanol (Formula-5) and its Dihydrochloride salt (Formula-5a)
5% Pd-C (2.4g) was added to mixture of methanol (150ml) and ethyl acetate (150ml)solution containing (R)-2-(benzyl (4-nitrophenethyl) amino)-1-phenylethanol compound of Formula-4 (30g) at 25-30°C. 6-8kg/Cm2 of hydrogen gas pressure was applied to the reaction mass at 25-30°C and stirred for 6-8hrs at the same temperature and pressure. Filtered the reaction mixture through hyflo bed, distilled off the solvent completely from the filtrate and the obtained compound was co-distilled with Xylene (30ml). 120ml of Xylene was added to the obtained crude and was heated to 55-60°C and

maintained for lhr at same temperature. Cooled the reaction mass to 25-30°C. Filtered the title compound of Formula-5. Again added 120ml of Xylene to the Formula-5 and was heated to 55-60°C and maintained for lhr at same temperature. Cooled the reaction mass to 25-30°C. Filtered the title compound of Formula-5. Added methanol (180ml) to the compound of Formula-5 at 25-30°C. Heated the reaction mixture to 40-45°C and was added methanol-HCl (34ml) at the same temperature for 15min. cooled the reaction mixture to 0-5°C and stirred for 30min at the same temperature. Filtered the title compound and dried at 40-45°C. HPLC showing 99.77% purity with absent of Des Hydroxy Impurity of Formula-6 and Chiral Purity is 99.98%. Yield: 20.9g (80%).
Example-6:
Preparation of (1R) -2-{[2-(4-nitrophenyl) ethyl]
amino}-l-phenylethanol (Formula-4a)
Sodium hydroxide (9.8g, 1.0 mole) was added to a mixture of 4-Nitrophenyl ethylamine Hydrochloride of Formula-lb (50g, lmole), water (300ml) and ethyl acetate (500ml) at 25-30°C and stirred for 30min at the same temperature. Separated the both aqueous and organic layers. Distilled off the solvent completely from the organic layer under reduced pressure and the obtained compound was co-distilled with methanol. Methanol (500ml) was added to the obtained crude compound and was added (2R)-2-Phenyloxirane (59g, 2.0 moles) at 25-30°C. The reaction mixture was heated to the reflux temperature and maintained for 24hrs at same temperature. Distilled off the solvents and the crude obtained was purified with column chromatography using

10% Methanol + Chloroform as eluent to get the title compound. Yield: 8.8g (12.5%).
Example-7:
Preparation of (1R)-2-{[2-(4-aminophenyl) ethyl] amino}-l-phenylethanol (Formula-5) and its Dihydrochloride salt (Formula-5a)
5% Pd-C (0.65g) was added to methanol solution containing (lR)-2-{[2-(4-nitrophenyl) ethyl] amino}-l-phenylethanol (6.5g) at 25-30°C into an autoclave.4-5kg/cm2 hydrogen gas pressure was applied to the reaction mixture at 40-45°C and stirred for 4-6hrs at the same temperature and pressure. Cooled the reaction mixture to 25-30°C and filtered through hyflo bed. Distilled off the solvent completely from the filtrate under reduced pressure. Added IPA (25ml) to the obtained compound and heated to 40-45°C and was added IPA-HC1 (12ml) at the same temperature for 15min. cooled the reaction mixture to 0-5°C and stirred for 30min at the same temperature. Filtered the title compound and dried at 40-45°C.Yield: 6g (80%).

We Claim: Claim-1:
An improved Process for the preparation of (lR)-2-{[2-(4-aminophenyl) ethyl] amino}-1-phenylethanol of Formula-5 and its Dihydrochloride of Formula-5a, comprising of;
Condensing the (2R)-2-Phenyloxirane compound of Formula-2
With N-benzyl-2-(4-nitrophenyl) fethanamine compound of formula-3

in the presence of alcoholic solvents or neat reaction to provide (R)-2- (benzyl(4-nitrophenethyl)amino)-1-phenylethanol compound of Formula-4
reducing the Formula-4 with a suitable reducing agent in a suitable solvent to provide (1R)-2-{[2-(4-aminophenyl)ethyl]amino}-1-phenylethanol compound of Formula-5 or its Dihydrochloride salt compound of Formula-5a.
Claim-2:
An improved Process for the preparation of (2R)-2-
Phenyloxirane compound of Formula-2 comprising of;
a) Converting 2-Chloro-l-phenylethanone compound of
Formula-la to Formula-1 with ketoreductase KRED 2-
1-1 in presence of buffer, co solvent and co-factor
at appropriate pH and temperature;

b) In Basic conditions Formula-1 converting to Formula-2 of (2R)-2-Phenyloxirane.
Claim-3:
The process according to Claim-2, where in, the Process for the preparation of (R)-2-chloro-l-phenylethanol compound of Formula-1 from Formula-la by enantio selective reduction by using Ketoreductase class of enzymes in presence of buffer media at appropriate pH and temperature with co-solvent and co-factor. Where in,
a) The enantio selective Ketoreductase is selected from Ketoreductase group of enzymes and more preferably by KRED 2-1-1
b) co-solvent is selected from alcoholic solvents more preferably Isopropyl aolcohol,2-butanol
c) Co-factor used in this reaction selected as NAD, NADP
d) The used buffer solution for this reaction is citrate buffer, phosphate buffer, acetate buffer with the molarity range of 0.01-0.5M preferably used 0.05-0.2 M
e) The pH of the buffer maintained in the range of pH-5.0 to pH-12 and more preferably at pH 7.5±2.0
f) The said reaction preferably carried out at temperature 30-60°C and more preferably at 35-45°C

Claim-4:
The process according to Claim-2, where in, the Process for the preparation of (R)-2-chloro-l-phenylethanol compound of Formula-1 from Formula-la, where in, the said reaction there is no intermediate isolation of Formula-1 when its go for Formula-2.
Claim-5:
The process according to Claim-2, where in, the Process for the preparation of (2R)-2-Phenyloxirane compound of Formula-2 from (R)-2-chloro-l-phenylethanol compound of Formula-1,where in , in-situ conversion of Formula-1 to Formula-2 in basic reagent such as inorganic bases such as NaHC03, Na2C03,K2C03,NaH, Na Metal, Cs2C03, KOH, NaOH, LiOH and Organic bases such as methyl amine, Diisopropyl amine, diisbpropylethyl amine, triethylamine, pyridine preferably used NaOH and carried out the reaction at temperature -5to 60 °C and more preferable at 25-30°C .After completion of the reaction the suitable extraction solvent selected from acetate solvent, Hydro carbon solvent, Chloride solvent and preferably used acetate solvent.
Claim-6:
The process according to Claim-1, where in, the Process for the preparation of N-benzyl-2-(4-nitrophenyl)ethanamine of Formula-3, comprising of N-alkylation of 4-Nitrophenyl ethylamine or its Hydrochloride of Formula-lb with Benzyl halide in presence of suitable base in a suitable solvent. Where in,

a) the suitable base is selected from NaHC03, Na2C03,triethylamine,Diisopropyl ethylamine, Pyridine, KOH, NaOH and selected preferably organic bases like triethylamine, Diisopropyl ethylamine, Pyridine -
b) the suitable solvent is selected from alcohol solvent, DMF, DMSO, Chlorinated solvents, ketone solvents and selected preferably Chlorinated solvents.
c) suitable solvent for the recrystalisation of N-benzyl-2-(4-nitrophenyl)ethanamine compound of Formula-3 is selected from alcohol solvent, acetate solvents, hydro carbon solvents, ether solvents and selected preferably hydro carbon solvents.
Claim-7:
The process according to Claim-1, where in, the Process for the preparation of Formula-4 of (R)-2-(benzyl(4-nitrophenethyl)amino)-1-phenylethanol, where in, reacting of Formula-2 with Formula-3 in a suitable solvent or without solvent. The suitable solvent is selected from alcohol solvent, Chlorinated solvent, ether solvent, ketone solvents, DMF, DMSO, and selected preferably Alcoholic solvents.
Claim-8:
The process according to Claim-1, where in, the Process for the preparation of (R)-2-(benzyl(4-nitrophenethyl)amino)-1-phenylethanol compound of

Formula-4, where in, reacting of Formula-2 with Formula-3 as a neat reaction at appropriate temperature and finally obtained compound of Formula-4 was purified with suitable solvent. Where in,
a) the said reaction is neat reaction between compound of Formula-3 and compound of Formula-2.
b) the said reaction preferably carried out at temperature 30-145°C and more preferably at 40-45°C.
c) the said reaction maintained for 4-24hrs and preferably for 6-12hrs.
d) After completion of the reaction, suitable solvent for the recrystalisation is selected . from alcohol solvent, acetate solvents, hydro carbon solvents, ether solvents and selected preferably alcohol solvents.
Claim-9:
The process according to CIaim-1, where in, the Process for the preparation of Formula-5 (1R)-2-{ [2- (4-aminophenyl)ethyl]amino}-1-phenylethanol compound of Formula-5 or its Dihydrochloride of Formula-5a, comprising of reducing the (R)-2-(benzyl(4-nitrophenethyl)amino)-1-phenylethanol compound of Formula-4 with a suitable reducing agent in a suitable solvent to provide (1R)-2-{[2-(4-aminophenyl) ethyl]amino}-1-phenylethanol compound of Formula-5 or its Dihydrochloride of Formula-5a
a) the suitable hydrogenation catalyst selected from Pd/C, Pt/C, Pt02, Pd(0H)2, Nickel, raney nickel and preferably Pd/C.
b) the suitable solvent is selected from alcoholic solvent, ester solvent, polar solvents and preferably selected alcoholic solvent and most

preferably selected mixture of alcoholic solvent and ester solvent.
c) the temperature of the reaction between 20-65°C preferably at 25-30°C
d) the maintenance of the reaction is 4-48hrs and preferably at 6-8hrs
Claim-10:
The Process for the preparation of (1R)-2-{[2-(4-aminophenyl)ethyl]amino}-1-phenylethanol compound of Formula-5 and its Dihydrochloride of Formula-5a with containing <0.1% impurity such as 4-{2-[(2-phenylethyl)amino]ethyl}aniline compound of Formula-6
a) Where in, the said process at purification of (1R)-2-{[2-(4-aminophenyl)ethyl]amino}-1-phenylethanol compound of -5 with suitable solvents such as alcoholic solvents, ester solvents, chlorinated solvents, ether solvents and hydro carbon solvents preferably hydrocarbon solvent to control Formula-6 upto <0.1%.
b) Where in, the temperature with hydrocarbon solvent purification between at 25-120°C and more preferable at 75-80°C.
c) Where in, the filtration of the compound of formulat-5 at temperature between 0-40°C, more preferable at 25-30°C.

Claim-11:
The Process for the preparation of (1R)-2-{[2-(4-aminophenyl)ethyl]amino}-1-phenylethanol compound of Formula-5 and its Dihydrochloride of Formula-5a with absence of impurity of 4-{2-[(2-phenylethyl)amino] ethyl}aniline compound of Formula-6
a) Where in, the said process at purification of (1R)-2-{[2-(4-aminophenyl)ethyl]amino}-1-phenylethanol compound of -5 with suitable solvents such as alcoholic solvents, ester solvents, chlorinated solvents, ether solvents and hydro carbon solvents preferably hydrocarbon solvent to complete remove of Formula-6
b) Where in, twice the purification of (1R)-2-{[2-(4-aminophenyl)ethyl]amino}-1-phenylethanol compound of Formula-5 with hydrocarbon solvent.
c) Where in, the temperature of the purification with hydrocarbon solvent at 25-120°C and more preferably at 55-60°C
d) Where in, the filtration of the compound of Formula-5 at temperature between 0-40°C, more preferably at 25-30°C

Claim-12:
(2R)-2-Phenyloxirane is having purity greater than 99.5% by Chiral HPLC, preferably greater than 99.9%, more preferably greater than 99.98%**
Claim-13:
(1R)-2-{[2-(4-aminophenyl) ethyl] amino}-l-phenylethanol is having purity of
a) greater than 98.5% by Achiral HPLC, preferably greater than 99%, more preferably greater than 99.3%'
b) greater*- than 99.5% by Chiral HPLC, preferably greater than 99.8%, more preferably greater than 99.95%.