FORM - 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patent Rules, 2003
COMPLETE SPECIFICATION
(See Section 10 and Rule 13)
PROCESS FOR THE PREPARATION OF INTERMEDIATE OF MIRABEGRON AND MIRABEGRON THEREOF
M/S AMOLI ORGANICS PVT. LTD,
407 Dalamal House, J.B.Road,
Nariman Point, Mumbai-400021,
INDIA
The following specification particularly describes the invention and the manner
in which it is to be performed

PROCESS FOR THE PREPARATION OF INTERMEDIATE OF
MIRABEGRON AND MIRABEGRON THEREOF
FIELD OF THE INVENTION
The present invention relates to a process for the preparation of a key intermediate "(R)-2-[(2-(4-aminophenyl)ethyl)amino]-1-phenylethanol" or its hydrochloride of Mirabegron and also process for the synthesis of Mirabegron from that intermediate.
BACKGROUND OF THE INVENTION
Mirabegron is sold with brand name MYRBETRIQ®, is a beta-3 adrenergic agonist. The chemical name is 2-(2-aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide having an empirical formula of C21H24N4O2S and a molecular weight of 396.51. The structural formula of mirabegron is

Mirabegron was approved in USA, Europe, Canada, Japan and India for the treatment of urinary frequency, urinary incontinence or urgency associated with overactive bladder.
(R)-2-[(2-(4-aminophenyl)ethyl)amino]-1-phenylethanol of chemical formula-(II) or its hydrochloride salt is identified as one of the key intermediates in the synthesis of Mirabegron.

Several methods have been reported for the preparation of the key intermediate (R)-2-[(2-(4-aminophenyl) ethyl) amino]-1-phenylethanol of chemical formula-(ll) or its hydrochloride salt. It is generally prepared by

reduction of (R)-2-[(2-(4-nitrophenyl)ethyl)amino]-1-phenylethanol of chemical formula-(lll) or its hydrochloride salt which in turn is prepared by reduction of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide, which is mostly prepared by condensation of (R)-2-hydroxy-2-phenylacetic acid and 2-(4-nitrophenyl)ethan-1-amine or its derivatives.

The process for preparation of (R)-2-[(2-(4-aminophenyl) ethyl)amino]-1-phenylethanol or its hydrochloride salt has been described in many patents including US 7342117B2, US RE44872E1, JP 2011105685, IN 2221/CHE/2012, WO 2014/0132270A2, IN 2517/CHE/2013, WO 2015/044965, WO 2015/0155664A1, IN 1203/MUM/2015, IN 1056/MUM/2015, IN 1203/MUM/2015, IN 2337/CHE/2015, IN 5453/CHE/2015.IN 201621009117, IN 201621016064.
Even though, the above mentioned prior art discloses processes for the preparation of (R)-2-[(2-(4-aminophenyl)ethyl)amino]-1-phenylethanol of chemical formula-(ll) or its hydrochloride salt, they are often not viable on a commercial scale and suffer from many drawbacks such as use of costly catalysts and flammable solvents; involving complex workup and resulting in low yield and purity.
Most of the processes for the reduction of (R)-2-[(2-(4-nitrophenyl)ethyl) amino]-1-phenylethanol or its hydrochloride salt reported in prior art involves use of methanol as solvent. Methanol is released to the environment during its industrial use and it is also associated with the fire hazard. Acute exposure (short-term) or chronic (long-term) exposure of humans to methanol by inhalation or ingestion may result in blurred vision, headache, dizziness, and nausea. Hence, there remains a need to provide simple, scalable, high yielding, industrially suitable, green and eco-friendly processes for producing

high quality intermediates of Mirabegron.
In view of above, the present invention provides a simple, cost-effective and commercially viable process for the preparation of (R)-2-[(2-(4-aminophenyl)ethyl)amino]-1-phenylethanol of chemical formula-(ll) or its hydrochloride salt and process for the preparation of Mirabegron from that intermediate.
SUMMARY OF THE INVENTION
One embodiment of the present invention provides an improved process for the preparation of key intermediate of Mirabegron, specifically (R)-2-[(2-(4-aminophenyl)ethyl)amino]-1-phenylethanol of chemical formula-(ll) or its hydrochloride salt.

Another embodiment of the present invention provides an improved process for the preparation of Mirabegron of chemical formula-(l) from (R)-2-[(2-(4-aminophenyl)ethyl)amino]-1-phenylethanol of chemical formula-(ll) or its hydrochloride salt.

DETAILED DESCRIPTION OF THE INVENTION
One embodiment of the present invention relates to an improved process for the preparation of key intermediate of Mirabegron, specifically (R)-2-[(2-(4-aminophenyl)ethyl)amino]-1-phenylethanol of chemical formula-(ll) or its hydrochloride salt,


the process comprises,
a) reducing (R)-2-(4-nitrophenethylamino)-1-phenylethanol hydrochloride of chemical formula-(lll) with a suitable reducing agent using water as solvent to provide (R)-2-(4-aminophenethylamino)-1-phenylethanol chemical formula-(II), or its hydrochloride salt.
In preferred embodiment of the present invention, reducing agent used in step a) is Raney Ni.
The temperature at which the reaction is carried at is 5°C-100°C, preferably 5°C-50°C, more preferably 5°C-35°C
Another embodiment of the present invention provides an improved process for the preparation of Mirabegron of chemical formula-(l) from (R)-2-[(2-(4-aminophenyl)ethyl)amino]-1-phenylethanol of chemical formula-(ll) or its hydrochloride salt.

the process comprises the steps of,
a) reducing the (R)-2-(4-nitrophenethylamino)-1-phenylethanol
monohydrochloride of chemical formula-(lll) or its hydrochloride salt with a suitable reducing agent using water as solvent to provide (R)-2-(4-aminophenethylamino)-1-phenylethanol of chemical formula-(ll), or its hydrochloride salt,


b) condensing the compound (R)-2-(4-aminophenethylamino)-1-phenylethanol of chemical formula-(ll), or its hydrochloride salt, with 2-(2-aminothiazol-4-yl)acetic acid compound of chemical formula-(IV) or its hydrochloride salt

in the presence of a suitable coupling agent and an acid in a suitable solvent to obtain Mirabegron of chemical formula-(l)
In preferred embodiment of the present invention, reducing agent used in step
a) is Raney Ni.
The temperature at which the reaction is carried at is 5°C-100°C, preferably 5°C-50°C, more preferably 5°C-35°C
In another embodiment of the present invention, the suitable coupling agent used in step-b) is selected form N,N-carbonyldiimidazole (CDI); alkyl and aryl carbodiimides such as N,N-diisopropylcarbodiimide (DIC), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC.HCI), N,N-dicyclohexylcarbodiimide (DCC), ditolyl carbodiimide optionally in combination with hydroxybenzotriazole or N-hydroxysuccinimide (NHS) or N-hydroxysulfosuccinimide (Sulfo- NHS); carbonyl-di-l,2,4-triazole; alkyl and aryl halo formates such as ethyl chloroformate, phenyl chloroformate, benzyl chloroformate; carbonates having the formula R1-O-CO-O-R2, wherein "R1" and "R2" are independently selected from branched or unbranched C1-C4 alkyl or substituted or unsubstituted phenyl group.
In preferred embodiment of the present invention, coupling agent used in step
b) is selected from EDC.HCI and solvent used in step b) is preferably water.

In a further embodiment of the present invention, Mirabegron of chemical formula-(l) is optionally purified to obtain pure Mirabegron of chemical formula-l.
The procedural improvement employed in the present invention involves use of water as solvent for the reduction of (R)-2-[(2-(4-nitrophenyl)ethyl) amino]-1-phenylethanol of chemical formula-(lll) or its hydrochloride salt to produce (R)-2-[(2-(4-aminophenyl)ethyl)amino]-1-phenylethanol of chemical formula-(II) or its hydrochloride salt which makes reduction process green and eco-friendly compared to prior art. In addition, use of water as solvent is associated with many advantages as it is easily available, cheap, non-toxic and non-flammable.
Thus, the present invention provides an improved, commercially viable, safe and eco-friendly process for the manufacture of key intermediate "(R)-2-((4-aminophenethyl)amino)-1-phenylethanol" of Mirabegron.
EXAMPLES
The present invention is described in the examples given below; further these are provided only to illustrate the invention and therefore should not be construed to limit the scope of the invention.
EXAMPLE 1 Preparation of (R)-2-((4-aminophenethyl)amino)-1-phenylethanol from (R)-2-((4-nitrophenethyl)amino)-1-phenylethanol Hydrochloride
1400 ml purified water, slurry of 100 gm (R)-2-((4-nitrophenethyl)amino)-1-phenylethanol Hydrochloride in 500 ml purified water were charged in an autoclave at 25-30°C. Slurry of 10 gm Raney Nickel in 25 ml of purified water was charged into the reaction mixture of autoclave at 25-35°C. Reaction mass was cooled to 10-15°C and hydrogen pressure was applied at 10-15°C and maintained at 10-15°C under at 4-5 kg/cm2 hydrogen pressure for 16 hr. The reaction mass was filtered through hyflo bed to remove catalyst. pH was adjusted to 9-10 by adding freshly prepared 10% Sodium Hydroxide solution

at 25-35°C. The reaction mass was stirred for 30 min at 25-35X. The reaction mass was filtered at 25-35X, washed with purified water and suck dried well. EXAMPLE 2: Preparation of Mirabegron from (R)-2-((4-aminophenethyl)amino)-1-phenylethanol hydrochloride and 2-amino 4-thiazole acetic acid
1400 ml purified water was charged in a round bottom flask at 25-35°C. 100 gm of (R)-2-((4-aminophenethyl)amino)-1-phenylethanol was charged in a round bottom flask at 25-35 °C. The reaction mass was cooled to 10-20°C. pH was adjusted to 2-3 by addition of cone. HCI at 10-20°C. 68 gm of 2-Amino thiazol-4-yl acetic acid was added to the reaction mixture at 10-20°C. 96 gm EDC.HCI was added at 10-20°C. The reaction mass was stirred at 15-20°C for 2-3 hours. Ammonia solution was added in reaction mass at temperature below 35°C till pH of reaction mass is adjusted between 9-10. The reaction mass was stirred for 30 minutes at 25-35°C. The reaction mass was filtered, washed with water at 25-35°C and suck dried well. 1500 ml water and wet cake were charged into a round bottom flask at 25-35°C. Reaction mass was stirred for 30 minutes, filtered and washed with water at 25-35°C and suck dried well to obtain Mirabegron.

We Claim
1. A process for the preparation of compound of Formula-(ll) or its HCI salt
comprising

the step of a) reducing (R)-2-(4-nitrophenethylamino)-1-phenylethanol hydrochloride of chemical formula-(lll)

with a suitable reducing agent using water as a solvent.
2. A process as claimed in claim 1, wherein the reducing agents used is Raney Ni.
3. A process for the preparation of Mirabegron of chemical formula-(l)

comprising the steps of
a) reducing the (R)-2-(4-nitrophenethylamino)-1-phenylethanol of chemical formula-(lll) or its hydrochloride salt with a suitable reducing agent using water as a solvent to provide (R)-2-(4-aminophenethylamino)-1-phenylethanol of chemical formula-(ll), or its hydrochloride salt,


b) condensing the compound (R)-2-(4-aminophenethylamino)-1-phenylethanol of chemical formula-(ll), or its hydrochloride salt, with 2-(2-aminothiazol-4-yl)acetic acid compound of chemical formula-(IV) or its hydrochloride salt

in the presence of a suitable coupling agent in a suitable solvent to obtain Mirabegron of chemical formula-(l).
4. A process as claimed in claim 3, wherein the reducing agents used is Raney Ni.