CLIAMS:1. A process for the preparation of (R)-2-[2-(4-amino-phenyl)-ethylamino]-1-phenyl-ethanol, compound of formula-II,

Formula-II
has purity more than 99 % as measured by HPLC
the process comprises the steps of ;
a) reducing 2-[2-(4-nitro-phenyl)-ethylamino]-1-phenyl-ethanol of formula (III)

Formula-III
with suitable reducing agent in a alcoholic solvent, in presence of ammonium formate,
b) isolating compound of formula-II from reaction mixture thereof.

2. The process of claim 1, wherein suitable reducing agent is selected from the group comprising Pd/C, Pt/C, PtO2, Pd(OH)2, Nickel, Zinc-metal, Raney nickel, Rhodium and sodium amalgam.

3. The process of claim 2, wherein suitable reducing agent is Zn-metal.

4. The process of claim 2, wherein suitable reducing agent is Pd/C.

5. 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.

6. The process of claim 5, wherein the alcoholic solvent is methanol.

7. The process of claim 1, wherein the step (a) is carried out at temperature in between range of 40C to 60C.

8. The process of claim 1, wherein the step (b) isolation is carried out by adding tetrahydrofuran solvent.

9. The process according to claim 1, wherein (R)-2-[2-(4-amino-phenyl)-ethylamino]-1-phenyl-ethanol subsequently converted to Mirabegron or a pharmaceutically acceptable salt thereof.
,TagSPECI: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 (R)-2-[2-(4-amino-phenyl)-ethylamino]-1-phenyl-ethanol, which is one of key intermediate for the preparation of Mirabegron.

Background of the invention

Mirabegron is chemically described as 2-(2-aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy2-phenylethyl]amino}ethyl)phenyl]acetamide. Mirabegron is an orally active beta-3 adrenoceptor agonist and has the structure of Formula I

Formula I

Mirabegron is marketed under the trade name Myrbetriqtm by Astellas Pharma. Myrbetriqtm is approved for the treatment of urinary frequency, urinary incontinence or urgency associated with overactive bladder by the FDA.

US patent No. 6,346,532 (herein after referred as ' 532' patent) describes the Mirabegron or a pharmaceutically acceptable salt thereof with its process for the preparation. The process for the preparation also described in several patents, e.g. US patent No. 7,342,117 and PCT application WO 2014132270 A2.

The present invention provides improved process for the preparation of (R)-2-[2-(4-amino-phenyl)-ethyl amino]-1-phenyl-ethanol, which is simple, cost effective and industrially feasible.
Summary of the Invention

The present invention provides a process for the preparation of (R)-2-[2-(4-amino-phenyl)-ethylamino]-1-phenyl-ethanol, compound of formula-II,

Formula-II
has purity more than 99 % as measured by HPLC
the process includes the steps of
a) reducing 2-[2-(4-nitro-phenyl)-ethylamino]-1-phenyl-ethanol of formula (III) with suitable hydrogenating agents in alcoholic solvent, in presence of ammonium formate,
b) isolating compound of formula-II from reaction mixture thereof.

A further aspect of the present invention relates to conversion of (R)-2-[2-(4-amino-phenyl)-ethylamino]-1-phenyl-ethanol, compound of formula-II to Mirabegron or its pharmaceutical acceptable salts thereof.

Description of the Invention

In one embodiment, the present invention provides a process for the preparation of (R)-2-[2-(4-amino-phenyl)-ethylamino]-1-phenyl-ethanol, compound of formula-II,

Formula-II

has purity more than 99 % as measured by HPLC
the process includes the steps of
a) reducing 2-[2-(4-nitro-phenyl)-ethylamino]-1-phenyl-ethanol of formula (III)

Formula-III
with suitable reducing agents in alcoholic solvent, in presence of ammonium formate,
b) isolating compound of formula-II from reaction mixture thereof.

The step a) of the present invention involves the reacting (2-[2-(4-nitro-phenyl)-ethylamino]-1-phenyl-ethanol with suitable reducing agent in a alcoholic solvent at the temperature in between range of 40C to 60C, wherein reducing agent is selected from the group comprising Pd/C, Pt/C, PtO2, Pd(OH)2, Nickel, Zinc-metal, Raney nickel, Rhodium and sodium amalgam and ammonium formate.

The alcoholic solvent is selected from the group comprising one or more of 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.

The step b) the isolation of (R)-2-[2-(4-amino-phenyl)-ethylamino]-1-phenyl-ethanol, involves the filtration of the reaction mixture and subsequently removal of solvent, followed by addition of tetrahydrofuran solvent into the reaction mixture. The reaction mixture is washed with brine solution and the organic layer is collected and distilled under vacuum to obtain (R)-2-[2-(4-amino-phenyl)-ethylamino]-1-phenyl-ethanol as yellowish oily compound, wherein brine solution is statured solution of sodium chloride.

In another aspect, the present invention provides R)-2-[2-(4-amino-phenyl)-ethylamino]-1-phenyl-ethanol, compound of formula-II has purity more than 99 % as measured by HPLC

The process of the present invention is depicted in the following Scheme 1:

Scheme-1

The compounds R)-2-[2-(4-amino-phenyl)-ethylamino]-1-phenyl-ethanol can be converted into Mirabegron or its pharmaceutical acceptable salt thereof according to known methods in the art, e.g. US patent No. 6,346,532; 7,342,117 and PCT application WO 2014132270 A2.

The present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.

Examples

Example-1: Preparation of R)-2-[2-(4-amino-phenyl)-ethylamino]-1-phenyl-ethanol

Charged methanol (100 ml) and 2-[2-(4-nitro-phenyl)-ethylamino]-1-phenyl-ethanol (2.0 gm ; 0.0069 mol), followed by 5% Pd/C (200 mg) and ammonium formate (2.2 gm; 0.034 mol) were added to the reaction mixture. The reaction mixture was stirred for the period of 4-5 hours at temperature 45C to 50oC. After completion the reaction, reaction mixture was filtered over hyflobed. The solvent was distilled out, followed by tetrahydrofuran (25 mL) was added. The reaction mixture was washed with saturated brine solution and organic layer was collected. Organic layer is distilled out under vacuum to obtain title compound as yellowish oil.
Yield: 1.8 gm

Example-2: Preparation of R)-2-[2-(4-amino-phenyl)-ethylamino]-1-phenyl-ethanol

Charged methanol (50 ml) and 2-[2-(4-nitro-phenyl)-ethylamino]-1-phenyl-ethanol (500mg; 0.0017 mol), followed byZn-metal (370 mg; 0.0056 mol) and ammonium formate (274 mg; 0.0043 mol) were added to the reaction mixture. The reaction mixture was stirred for the period of 4-5 hours at temperature 45C to 50oC. After completion the reaction, reaction mixture was filtered over hyflobed
The solvent was distilled out, followed by tetrahydrofuran (10 mL) was added. The reaction mixture was washed with saturated brine solution and organic layer was collected. Organic layer was distilled out under vacuum to obtain title compound as yellowish oil.
Yield: 400 mg