Claims:1. A process for the preparation of (R)-2-[2-(4-amino-phenyl)-ethylamino]-1-
phenyl-ethanol, compound of formula-II or its salts, comprises
a) reducing 2-[2-(4-nitro-phenyl)-ethylamino]-1-phenyl-ethanol of formula (III) or salts

Formula-III
with hydrazine, iron compound and an activated carbon in presence of suitable alcoholic solvent at preferable temperature to get compound of formula-II or salts

Formula-II
b) optionally purifying the compound of formula-II or salts from step-a, is treated with 2-(2-aminothiazol-4-yl) acetic acid or its salts to get Mirabegron compound of formula-I or its salts thereof.
2. The process of claim 1, wherein the alcoholic solvent is selected from the group comprising one or more of as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert-butanol, 2-pentanol, ethylene glycol, diethylene glycol, propylene glycol, 2-ethyl hexanol, benzyl alcohol, water and mixture thereof.
3. The process of claim-2, wherein the alcoholic solvent is methanol, ethanol and isopropanol.
4. The process of claim 1, wherein the step (a) is carried out at temperature in between range of 60oC to 85oC.

5. The process of claim 1, wherein suitable iron compounds are selected from Ferric compounds selected from but not limited to iron (III) oxide, a ferric halide, a ferric sulfate, and a ferric nitrate.
6. The process of claim 5, wherein suitable iron compound is ferric halide; more preferably Fe (III)Cl3.
7. The process for the preparation of (R)-2-[2-(4-amino-phenyl)-ethylamino]-1-
phenyl-ethanol, compound of formula-II or its salts, comprises
a) reducing 2-[2-(4-nitro-phenyl)-ethylamino]-1-phenyl-ethanol of formula (III) or salts

Formula-III
in presence of suitable alcoholic solvent at preferable temperature with hydrazine hydrate, ferric halide and an activated carbon, to get compound of formula-II or salts

Formula-II.
8. The compound of formula-II or salts as per claim-7, is used to prepare the Mirabegron compound of formula-I or its salts thereof.
, Description:FIELD OF INVENTION
The present invention relates to a process of preparation of Mirabegron intermediate. In the particular aspect of present invention relates to an improved process for the preparation of compound of formula-II i.e. (R)-2-[2-(4-amino-phenyl)-ethylamino]-1-phenyl-ethanol or its salt, is one of key intermediate for the preparation of Mirabegron.

Formula-II

BACKGROUND OF THE INVENTION
Mirabegron is chemically described as (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl)amino)-ethyl)phenyl)acetamide or 2-amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]-4-thiazoleacetamide. The molecular structure of Mirabegron is represented by Formula I.

Formula I
Mirabegron, a selective beta 3-adrenoceptor agonist, was authorized for the treatment of overactive bladder (OAB) with symptoms of urgency, urgency incontinence, and urinary frequency. It was developed and marketed by Astellas Pharma under the brand name MYRBETRIQ TM
Mirabegron represents a new class of treatment for overactive bladder (OAB). This drug works in a different mechanistic path way when compared to the other overactive bladder medications with proven efficacy and good tolerability.
Mirabegron and its pharmaceutically acceptable acid addition salts are first disclosed in US 6,346,532 B1 (herein after US’532). The patent US’532 discloses a process for the preparation of Mirabegron as a dihydrochloride salt in an Example- 41 which comprise of deprotection of tert-butyl (R)- N-[2-[4-[2-(2-aminothiazol-4-yl)acetamido]phenyl]ethyl-N-[(2-hydroxy-2-phenyl)ethyl]carbamate (Boc protected Mirabegron) with hydrochloric acid in a mixture of methanol and ethyl acetate followed by purification with reverse phase column chromatography using water/methanol (2:1) as an eluent.

The process for preparation of Mirabegron dihydrochloride as per US’532 is depicted in the following scheme-1.

Scheme-1
The patent US’532 involves the usage of reverse phase column chromatography which is not suggestible for commercial scale. Further dihydrochloride of Mirabegron suffers with strong hygroscopicity and is unstable for use in medication.

Mirabegron free base is disclosed in US 7,342,117 B2 (herein after US’117). Process for preparation of Mirabegron free base is depicted in the following scheme-2.

Scheme-2

Apart from above, some of other reported process of Mirabegron and its intermediates is elaborated in several patent publications, e.g. CN 104230840, CN 104016943, CN 104016877, CN 103896872, CN 103864713, CN 103387500, CN 103232352, CN103304511, CN104876889, CN 104876890, CN 104496841, CN 105198830, CN 105111165, CN 105481705, IN 2012CH02221, IN 2015CH05453, IN 201621009117, IN 201811011300. IN 201811011301, WO 2014132270, WO 2015162536, WO 2015155664, WO 2016024284, WO 2016020440, WO 2016181283 and WO 2019081972.
In all above-mentioned prior art processes for the preparation of Mirabegron intermediate i.e. (R)-2-[2-(4-amino-phenyl)-ethylamino]-1-phenyl-ethanol or its salt suffers from one or the other problems such as use of highly expansive, flammable and moisture sensitive reagents, thereby safe and cheaper alternatives were investigated which leads to develop an improved process for the preparation of Mirabegron and its intermediates, can be practiced on large scale production in cost effective manner.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of Mirabegron intermediate compound of Formula II or its pharmaceutically acceptable salts thereof.

Formula-II

Another objective of the present invention is to provide a safe, commercially viable, and cost-effective process for the preparation of Mirabegron intermediate (R)-2-[2-(4-aminophenyl)-ethylamino]-1-phenyl-ethanol, compound of Formula II or its salts.

Yet another objective of the present invention relates to conversion of (R)-2-[2-(4-aminophenyl)-ethylamino]-1-phenyl-ethanol, compound of formula-II or its salts, to prepare Mirabegron or its pharmaceutical acceptable salts thereof.

SUMMARY OF THE INVENTION
The present invention is to provide a process for the preparation of (R)-2-[2-(4-aminophenyl)-ethylamino]-1-phenyl-ethanol, compound of Formula II or its pharmaceutically acceptable salts thereof, comprising

a) reducing 2-[2-(4-nitro-phenyl)-ethylamino]-1-phenyl-ethanol of formula (III) or its salts,

Formula-III

in suitable alcoholic solvent at suitable temperature with hydrazine compound in the presence of an iron compound and an activated carbon

b) isolating compound of formula-II or salts from reaction mixture thereof.

Formula-II

c) covertion of compound of formula-II or its salts to Mirabegron or its salts thereof.
wherein, in step-a, the suitable alcoholic solvents selected from but not limited to one or more of as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert-butanol, 2-pentanol, ethylene glycol, diethylene glycol, propylene glycol, 2-ethyl hexanol, benzyl alcohol, water and mixture thereof., More preferably methanol, ethanol.

In step-a, iron compound is a ferric compound. Ferric compounds selected from but not limited to iron (III) oxide, a ferric halide, a ferric sulfate, and a ferric nitrate. More preferably ferric halide.

In step-a, suitable temperature is temperature 20-150 oC, most preferably 60-85 oC

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the process for the preparation of Mirabegron compound of Formula-1, which involves the reduction of (R)-2-(4-nitrophenethylamino)-1-phenylethanol compound of formula-III or salt using hydrazine compound, ferric compound and an activated carbon in presence of suitable alcohol solvent at suitable temperature to give compound of formula-II or salts; Subsequently coupled with 2-(2-aminothiazol-4-yl) acetic acid or its salts, to provide Mirabegron compound of formula-I.

The present invention is schematically represented as depicted in the following scheme-3

Scheme-3
a) reduction of compound of formula-III or salts in presence of suitable alcoholic solvent at a preferable temperature, with hydrazine hydrate, iron compounds and an activated carbon to provide compound of formula -II or salts,

b) optionally purifying the compound of formula-II or salts from step-a, is treating with 2-(2-aminothiazol-4-yl) acetic acid or its salt to get compound of formula-1.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

Example-1: Preparation of R-(2)-((4-aminophenethyl)amino)-1-phenyl ethanol
To a solution of R-(2) -((4-nitrophenethyl)amin0)-1-phenyl ethanol (50 g ,0.1746 moles) in methanol (500 ml), anhydrous ferric chloride (5.66 g, 0.0349 moles) and activated carbon (20 g) was added. Raised the temperature to reflux at 65-68 deg. and maintained for 30 minutes. To the above reaction mixture 80% hydrazine hydrate (25 g) was added over a period of 30 minutes. Maintained the reaction mass under reflux at 65-68 deg for 10-12 hours. After completion of the reaction, filtered the mass at 65 deg and washed the carbon bed with hot methanol (50 ml). Distilled out the filtrate below 50 deg under reduced pressure. Charged water (250 ml) to the residue and adjusted the pH to 9-10 with sodium hydroxide solution. Cooled the mass to 5-10 deg. and maintained for 1 hour. Filtered the product and washed with chilled water (50 ml). Dried the product at 50-55 deg under vacuum to get R-(2)-((4-aminophenethyl)amino)-1-phenyl ethanol (38 g) as a cream colored solid,
MR: 101.2-102.4 deg.

Example-2 Preparation of R-(2)-((4-aminophenethyl)amino)-1-phenyl ethanol:
To a solution of R-(2)-((4-Nitrophenethyl)amin0)-1-phenyl ethanol (25 g, 0.1746 moles) in methanol (250 ml), anhydrous ferric chloride (2.83 g, 0.0349 moles) and activated carbon (10 g) was added. Raised the temperature to reflux at 65-68 deg and maintained for 30 minutes. To the above reaction mixture 80% hydrazine hydrate (12.5 g) was added over a period of 30 minutes. Maintained the reaction mass under reflux at 65 deg for 12 hours. After completion of the reaction, filtered the mass at 60-65 deg and washed the carbon bed with hot methanol (25 ml). Distilled out the solvent completely under vacuum below 50 deg from the filtrate. Charged methanol (100 ml) and adjusted pH to 1.5-2.5 with conc. HCl. Reaction mixture was cooled to 0 to -5 deg and maintained for 1 hour. Wash the filtrate with chilled methanol (20 ml) and dried under vacuum to get R-(2)-((4-aminophenethyl)amino)-1-phenyl ethanol hydrochloride (16.5 g) as white crystalline solid.

Example-3 Preparation of R-(2)-((4-aminophenethyl)amino)-1-phenyl ethanol: To a solution of R-(2)-((4-Nitrophenethyl)amino)-1-phenyl ethanol (100 g) in methanol (1000 ml), anhydrous ferric chloride (11.32 g) and activated carbon (40 g) was added. Raised the temperature to reflux at 65 deg and maintained for 30 minutes. To the above reaction mixture 80% hydrazine hydrate (50 g) was added over a period of 30-40 minutes and maintain the reaction mass for 12 h. After completion of the reaction, filter the reaction mass and washed with hot methanol (150 ml). Adjusted the pH of the filtrate to 1.5-2.5 with conc. HCl and distilled out the solvent completely under vacuum. To the residue, water (500 ml) was added and stirred for 10-15 minutes till clear solution. Cooled the solution to 20-25 deg and adjusted the pH to 9-10 with sodium hydroxide solution and maintained the reaction mass for 2 hours. Filtered the product and washed with water (100 ml) and dried the product under vacuum to obtained R-(2)-((4-aminophenethyl)amino)-1-phenyl ethanol (40 g).

Example-4: Preparation of R-(2)-((4-aminophenethyl)amino)-1-phenyl ethanol:
To a solution of R-(2)-((4-Nitrophenethyl)amin0)-1-phenyl ethanol (50 g), in isopropyl alcohol (500 ml), anhydrous ferric chloride (5.66 g) and activated carbon (20 g) was added. Raised the temperature at 75 deg and maintained for 30 minutes. To the above reaction mixture 80% hydrazine hydrate (25 g) was added over a period of 30 minutes. Maintained the reaction mass at 75 deg for 12 hours. After completion of the reaction, filter the reaction mass at 70-75 deg and washed with hot isopropyl alcohol (100 ml). Adjusted the pH of the filtrate to 1.5-2.0 with conc. HCl and cooled to 0-5 deg and filtered the product and dried to get R-(2)-((4-Aminophenethyl) amino)-1-phenyl ethanol hydrochloride (18 g) as white solid.

Example-5 Preparation of R-(2)-((4-aminophenethyl)amino)-1-phenyl ethanol:
To a solution of R-(2)-((4-nitrophenethyl)amino)-1-phenyl ethanol hydrochloride (48.5 g) in methanol (450 mL), anhydrous ferric chloride (5.6 g) and activated carbon (20 g) was added. Raised the temperature to reflux and maintained for 30 minutes. To the above reaction mixture hydrazine hydrate (31.5 g) was added over a period of 30 min. Maintained the reaction mass under reflux for 8 hours. After completion of the reaction, filter the reaction mass at 60-65 deg and washed with hot methanol. Distilled out the filtrate completely, to the obtained residue water (75 ml) and isopropyl alcohol (150 ml) was added and adjusted the pH to 9-10 with sodium hydroxide solution. Cooled the mass to 0-5 deg. and maintained for 3 h. Wash the filtrate with chilled isopropyl alcohol (50 ml) and dried under vacuum to afford R-(2)-((4-aminophenethyl)amino)-1-phenyl ethanol (25 g) as a white solid.

Example-6 Preparation of (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl)-amino)-ethyl)phenyl)acetamide:
To the solution of (R)-2-(4-aminophenethylamino)-l-phenylethanol (0.3 g, 1.17 mmol) in DMF (2 mL) at room temperature, 2-(2-aminothiazol-4-yl) acetic acid (0.18 g, 1.17 mmol), EDC·HCl (0.24 g, 1.28 mmol) and HOBt (0.17 g, 1.28 mmol) were added sequentially and reaction continued for 5 h. After completion of reaction, the reaction mixture pH was adjusted to 8-10 with solid K2CO3 and stirring continued for 2 h. Then the precipitated solid was filtered and dried in vacuo to give title compound (0.21 g, 45%).