2
Field of the Invention
The present invention relates to a process for the preparation of Mirabegron and
intermediates or salt thereof. The present invention also provides a solid form of Mirabegron
intermediates, ((R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol and (R)-N-(4-
aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof, having purity more than or
equal to 99 % by HPLC and process for the preparation thereof.
Background of the invention
Mirabegron (formerly YM- 178) is an orally active β-3 adrenoceptor agonist developed by
Astellas pharma for the potential treatment of urinary frequency, urinary incontinence, or
urgency associated with overactive bladder.
Mirabegron is chemically described as (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-
phenylethyl)amino]ethyl] acetanilide (henceforth "Mirabegron") and has the structural
formula I:
NH
O
S
N
NH2
NH
H OH
Formula-I
Mirabegron or a pharmaceutically acceptable salt thereof was first described in U.S. Patent
No. 6,346,532 with its process for the preparation. The other process of Mirabegron and its
intermediates is also elaborated in several patents and applications, e.g. U.S. Patent No.
7,342,117; WO2015/044965; CN103193730, CN 104016877, IN 3116/MUM/2013
CN 103232352, Vedantham et al., in J. Chem. Pharm. Res., 2015, 7(4): 1473-1478 and IN
1433/MUM/2014.
The prior art processes face one or the other problems such as use of highly flammable and
moisture sensitive reagents such as boran-tetrahydrofuran complex, borane-diethyl ether use
3
of palladium for the reduction. Hence, there is a need to be developed a process for
Mirabegron and its intermediates, which is inexpensive, industrial scalable and eco-friendly.
Summary of the Invention
One embodiment the present invention provides a process for the preparation of Mirabegron
or salt thereof, comprises:
i) reaction of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl-2-phenylacetamide or salt
thereof with reducing agent in presence of additive in an alcohol to provide (R)-N-(4-
aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof;
ii) reaction of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof
with reducing agent in presence of additive in a solvent to provide (R)-2-[[2-(4-
aminophenyl)ethyl]amino]-1-phenylethanol or salt thereof; and
iii) reaction of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylethanol or salt with 2-
aminothiazole-4-yl-acetic acid or salt thereof to provide Mirabegron.
Another embodiment, the present invention provides a process for the preparation of
Mirabegron or salt thereof, comprises:
i) reaction of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl-2-phenylacetamide or salt
thereof with sodium borohydride in presence of additive in an alcohol to provide (R)-
N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof;
ii) reaction of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof
with sodium borohydride in presence of additive in a solvent to provide (R)-2-[[2-(4-
aminophenyl)ethyl]amino]-1-phenylethanol or salt thereof; and
iii) reaction of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylethanol or salt with 2-
aminothiazole-4-yl-acetic acid or salt thereof to provide Mirabegron.
Another embodiment, the present invention provides a solid form of (R)-N-(4-
aminophenethyl)-2-hydroxy-2-phenylacetamideor salt thereof, compound of formula III
NH2
HN
OH
O
Formula III
has purity more than or equal to 99 % when measured by HPLC.
4
Another embodiment, the present application provides a process for the preparation of (R)-N-
(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof has purity more than or
equal to 99 % by HPLC, comprises:
i) reaction of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl-2-phenylacetamide or salt thereof
with reducing agent in presence of additive in alcohol to afford (R)-N-(4-aminophenethyl)-2-
hydroxy-2-phenylacetamide or salt thereof; and
ii) isolation of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereofby
means of acid treatment.
Another embodiment, the present invention provides a solid form of (R)-2-[[2-(4-
aminophenyl)ethyl]amino]-1-phenylethanol or salt thereof, compound of formula IV
NH2
HN
OH
Formula-IV
has purity more than 99 % when measured by HPLC.
Another embodiment of the present invention provides a process for the preparation of (R)-2-
[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol or salt thereof, compound of formula IV
NH2
HN
OH
Formula-IV
has purity more than 99 %, when measured by HPLC, the process includes the steps of
a) adding (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof in
ether solvent at suitable temperature,
b) contacting suitable reducing agent to the reaction mixture of step (a)
c) adding oxidizing agent or additive to the reaction mixture of step (b) at suitable
temperature,
d) refluxing the reaction mixture for suitable time period,
e) purification of obtained product in step (d) with suitable mixture of solvents to obtain
R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol or salt thereof, has purity
more than 99 %, when measured by HPLC.
5
Another embodiment, the present invention provides the use of solid forms of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide and (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol or salt thereof, as a reference standard in analytical technique such as HPLC method.
Description of the Invention
The “salt” of present invention is selected from hydrochloride, hydrobromide, sulphate, phosphate, hydrogen sulphate, and hydrogen phosphate.
One of the embodiment of the present invention provides a process for the preparation of Mirabegron or salt thereof, comprises:
i) reaction of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl-2-phenylacetamide or salt thereof with reducing agent in presence of additive in an alcohol to provide (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof;
ii) reaction of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof with reducing agent in presence of additive in a solvent to provide (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol or salt thereof; and
iii) reaction of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylethanol or salt with 2-aminothiazole-4-yl-acetic acid or salt thereof to provide Mirabegron.
The process involves addition of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide or salt thereof in alcoholic solvent at suitable temperature, followed by addition of suitable additive as a solution in miscible solvent. The reaction mixture may be stirred for a period of 0.5 hour to 3 hours. The invention involves lot wise addition of reducing agents at a temperature of about -10 to 25°C. The reaction mixture is allowed to cool to room temperature and stirred for one hour. The reaction mixture is subjected for reflux for the period of one hour.
The well known synthetic chemistry discloses that the reduction of nitro group to amine by using palladium/carbon, Raney Nickel, palladium hydroxide-carbon, platinum oxide, rhodium on carbon in presence of hydrogen gas or hydrogen generating source like ammonium formate, hydrazine hydrate and autoclave. However, the use of these reagents as
6
per the general chemistry are unfriendly and leads to low yield and purity. Hence, the present inventors found simple and cost effective reducing agent as sodium borohydride, borane-diethyl ether or lithium aluminium hydride. Further, the inventors of the present invention found that the use of oxidative agent or additive along with reducing agent enhances the reduction process.
The alcoholic solvent is selected from the group comprising one or more methanol, ethanol, propanol, isopropanol or n-butanol, iso-butanol, tert-butanol and the like.
The additive is selected from metal salt such as cupric sulphate (copper sulphate), zinc chloride, cobalt chloride, cerium chloride, calcium chloride, sulfur, zirconium chloride, diethyl selenium bromide, titanium tetrachloride, tin chloride, manganese chloride, aluminium oxide, trimethyl silyl chloride, ; halogen such as Iodine; acid such as sulfuric acid, acetic acid, trifluoroacetic acid; and Amberlyst-15(H+).
After completion of reaction, the reaction mixture is cooled to room temperature and filtered through celite bed. The filtrate is extracted with ethyl acetate solvent and washed the organic layer with water.
The obtained organic layer may be subjected for acid and base treatment followed by concentration to obtain residue, which can be used directly without isolation of solid for further step or subjected organic layer for solid isolation. The isolation of solid may involve the treatment of organic later with an acid.
The (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof of the present invention has purity more than or equal to 99% by HPLC.
The obtained R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof is reacted with reducing agent in presence of additive.
The process involves addition of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereofin a solvent such as ether solvent, at a suitable temperature, followed by cooling the reaction mixture to temperature of about 0°C to 5°C, wherein ether solvents is selected
7
from the group comprising one or more of tetrahydrofuran, 2-methyltetrahydrofuran, di-isopropyl ether or methyl-tert-butyl ether.
The reducing agent is selected from the group comprising one or more of lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxy borohydride or sodium borohydride.
The additive used for the step ii) includes but are not limited to metal salt such as cupric sulphate and in halogens such as iodine, BF3-etherate complex. The additive usually added to the reaction mixture as a solution in a miscible solvent. The suitable temperature is about -10 °C to +10 °C, preferably about -5 °C to +5 °C.
The reducing agent is added to the reaction mixture in lot wise at a temperature of about 0 °C to 5°C. The quantity of reducing agent may range from 2 to 6 molar equivalents per the mole of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or its salt.
The additive is added to the reaction mixture in a lot wise at temperature of about -10 °C to 20 °C. After completion of the addition, the reaction mixture may be heated toreflux and stirred for the period of 1 to 2 hours.
After completion of the reaction, the reaction mixture is cooled to room temperature and then water is added to the reaction mixture. The reaction mixture may be subjected further for acid and base treatment to get acidic and basic pH. Then, the reaction mixture may be subjected for separation of two layers. The obtained organic layer may be used directly for further reaction to get Mirabegron or salt thereof or it can be subjected for the isolation of solid. The solid can be isolated by the treatment of organic layer with an acid in alcohol. The acid used for acid treatment includes but are not limited to hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, acetic acid, formic acid, trifluoroacetic acid and the like. The alcohol is selected from methanol, ethanol and isopropanol, n-propanol, n-butanol and the like. The base used for the base treatment includes but are not limited to sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like.
The compound of (R)-2-[[2-(4-aminophenyl)ethyl] amino]-1-phenylethanol or its salt of the present invention has purity more than 99 % by HPLC.
8
The obtained (R)-2-[[2-(4-aminophenyl)ethyl] amino]-1-phenylethanol or its salt is reacted
with 2-aminothiazole-4-yl-acetic acid or its salt in presence of l-(3-dimethylaminopropyl)-3-
ethylcarbodiimide mono-hydrochloride (EDC.HCl) in water. The suitable temperature for the
reaction is about 20 to 40 °C. The reaction mixture is stirred for a period of 30 minutes to 2
hours or more to complete the reaction.
After completion of the reaction, the solid of Mirabegron is isolated by using base such as
sodium hydroxide.
Another embodiment, the present invention provides a process for the preparation of
Mirabegron or salt thereof, comprises:
i) reaction of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl-2-phenylacetamide or salt
thereof with sodium borohydride in presence of additive in an alcohol to provide (R)-
N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof;
ii) reaction of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof
with sodium borohydride in presence of additive in a solvent to provide (R)-2-[[2-(4-
aminophenyl)ethyl]amino]-1-phenylethanol or salt thereof; and
iii) reaction of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylethanol or salt with 2-
aminothiazole-4-yl-acetic acid or salt thereof to provide Mirabegron.
The preferred additive for the step i) is cupric sulphate and the preferred additive for the step
ii) is iodine in solvent such as ether solvent.
Another embodiment, the present invention relates to a solid form of (R)-N-(4-
aminophenethyl)-2-hydroxy-2-phenylacetamideor salt thereof, compound of formula III
NH2
HN
OH
O
Formula-III
has purity more than or equal to 99 % when measured by HPLC.
9
Another embodiment, the present application provides a process for the preparation of (R)-N-
(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof has purity more than or
equal to 99 % by HPLC, comprises:
i) reaction of(R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl-2-phenylacetamide or salt thereof with
reducing agent in presence of additive in alcohol to afford (R)-N-(4-aminophenethyl)-2-
hydroxy-2-phenylacetamide or salt thereof; and
ii) isolation of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereofby
means of acid treatment.
The present invention involves addition of reducing agent into the reaction mixture in lot
wise, preferably, two times, for a period of 10 minutes to 30 minutes or more. The reducing
agent of the present invention is sodium borohydride. The addition of reducing agent is
preferably at a temperature of about -10 to 20 ◦C.
The additive used for the reduction of nitro group is cupric sulphate. The addition of cupric
sulphate is also in lot-wise for a period of 10 minutes or more at a temperature of about -10 to
20 ◦C.
The alcohol used for the reduction step is methanol.
After completion of the reaction, the reaction mixture is subjected for isolation of solid. The
isolation process involves separation of layers, extraction of compound into ester solvent,
precipitation of solid by the addition of acid such as hydrochloric acid at a temperature of
about -10 to 10 ◦C.
Another embodiment of the present invention provides a solid form of (R)-2-[[2-(4-
aminophenyl)ethyl]amino]-1-phenylethanol or salt thereof, compound of formula IV
NH2
HN
OH
Formula-IV
has purity more than 99 % when measured by HPLC.
10
The solid form of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol or salt
thereof,whenstored at temperature 25°C for a period of 3 months did not show contamination
of other polymorphic forms.
Another embodiment of the present invention provides a process for the preparation of (R)-2-
[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol or salt thereof, compound of formula IV
NH2
HN
OH
Formula-IV
has purity more than 99 %, when measured by HPLC, the process includes the steps of
a) adding (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof in
ether solvent at suitable temperature,
b) contacting suitable reducing agent to the reaction mixture of step (a)
c) adding oxidizing agent or additive to the reaction mixture of step (b) at suitable
temperature,
d) refluxing the reaction mixture for suitable time period,
e) purification of obtained product in step (d) with suitable mixture of solvents to obtain
R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol or salt thereof, has purity
more than 99 %, when measured by HPLC.
The process involves the addition of (R)-N-(4-aminophenethyl)-2-hydroxy-2-
phenylacetamide or salt thereofin ether solvent, at suitable temperature, followed by cooling
the reaction mixture to temperature of about 0°C to 5°C, wherein ether solvents is selected
from the group comprising one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl
ether or methyl-tert-butyl ether.
The reaction mixture is charged with reducing agent, in lots at temperature of about 0 °C to
5°C, followed by drop by addition solution of suitable oxidizing agent at temperature of
about 0 °C to 5°C. The reaction mixture is allowed to cool at temperature in between range of
25 °C to 35°C. The reaction mixture is refluxed for the period of 1 hour to 2 hours.
11
After completion of reaction, the reaction mixture is cooled at temperature in between range of 25 °C to 35°C, followed by addition of water to reaction mixture. The reaction mixture is stirred for the period of 15 minutes.
The reducing agent is selected from the group comprising one or more of lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxy borohydride or sodium borohydride.
An oxidizing agent is chemical species, which is commonly used in chemical and pharmaceutical industry that removes an electron from another species. It is one component in an oxidation–reduction reaction. In the second sense, an oxidizing agent or an oxidizer is a chemical species that transfers electronegative atoms, usually oxygen, to a substrate. The oxidizing agents or additive are in metal salt such as cupric sulphate and in halogens such as iodine.
The suitable temperature is about -10 °C to +10 °C, preferably about -5 °C to +5 °C.
The purification process of (R)-2-[[2-(4-aminophenyl)ethyl] amino]-1-phenylethanol involve the addition of crude (R)-2-[[2-(4-aminophenyl)ethyl] amino]-1-phenylethanol in ester solvent. The reaction mixture is stirred for the period of about 10 minutes to 15 minutes and separated the both layers. The organic layer is concentrated under vacuum to get (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol, which again dissolved in non-polar solvent and concentrated hydrochloric acid to obtain (R)-2-[[2-(4-aminophenyl)ethyl] amino]-1-phenylethanol mono-hydrochloride has purity more than 99 %, when measured by HPLC, using non-polar solvent,
The solvent is selected from the group comprising one or more of ether, esters, hydrocarbon and water. The hydrocarbon solvent is used as non-polar solvent to remove non-polar impurities formed during the preparation of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol or salt thereof.
The scheme-1 depicts overall route of synthesis of Mirabegron or salt thereof
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NH2
HN
OH
O
NH2
HN
OH
Formula-IV
Formula-III
NH
O
S
N
NH2
HN
H OH
Mirabegron
Oxidizing
Agent
Reducing
Agent
Scheme-1
The embodiments of the specification are further illustrated by way of following examples,
which do not limit the scope of the claims. Certain modifications and equivalents will be
apparent to those skilled in the art and are intended to be included within the scope of the
claims.
Examples
Example-1: Preparation of (R)-2-hydroxy-N-[2-(4-nitrophenyl) ethyl]-2-phenylacetamide
To a mixture of 4-nitrophenylethylamine mono-hydrochloride (10 g), (R)-mandelic acid (7.5
g), trimethylamine (5 g), N,N-dimethylformamide (37ml), hydroxybenzotriazole (6.57 g) and
1-(3-dimethylaminopropyl)-3-ethylcarbodiimide mono-hydrochloride (EDC) (9.4 g) were
added and the reaction mixture was stirred at temperature of about 25°C to 35°C for the
13
period of 2 hours. EDC.HCl (0.5 g) was added to the reaction mixture and stirred at room temperature overnight. Water and ethyl acetate were added to the reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed successively with 1M hydrochloric acid aqueous solution (100 ml), 20% potassium carbonate aqueous solution (100 ml) and water (100 ml). The reaction mixture was concentrated under vacuum at 25°C to 35°C. The residue was dissolved in toluene (60 ml). The reaction mixturewas heated at temperature of about 85°C to 90°C. The reaction mixture was cooled at temperature of about 25 °C to 35°C to obtain (R)-2-hydroxy-N-[2-(4-nitrophenyl) ethyl]-2-phenyl acetamide, which was further investigated by 1H-NMR spectroscopy and Fourier Transform Infrared Spectroscopy (FTIR).
Yield:95 %
HPLC Purity: ≥ 99%
Example-2: Preparation of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide hydrochloride
To a stirred solution of (R)-2-hydroxy-N-[2-(4-nitrophenyl) ethyl]-2-phenylacetamide (5 g) in methanol (50 ml) at temperature of about 3°C, charged cupric sulphate solution (8.3 g in 25 ml water). The sodium borohydride (3.1 g) was added lot wise to reaction mixture at temperature of about 5 °C. The reaction was slowly allowed to come to temperature of about 25 °C to 35°C and stirred for one hour. sodium borohydride (1.6 g) was again added to the reaction mixture and then refluxed for a hour. After completion of reaction, the reaction mixture was cooled to room temperature and filtered through celite bed. The compound was extracted from the filtrate and then washed with ethyl acetate (100 ml), solution with water (100 ml). The organic layer was concentrated under vacuum to get oily mass. Ethyl acetate (10 ml) and conc. HCl (3 ml) were charged to it at 10-15°C. The reaction mixture was stirred for 1-2 hours and filtered (optional) the product as solid or used for further steps without filtering it, which was further investigated by 1H-NMR spectroscopy and Fourier Transform Infrared Spectroscopy (FTIR).
Yield:98 %
HPLC Purity: ≥ 99%
Example-3: Preparation of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol hydrochloride
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(R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamidehydrochloride (10 g) was dissolved in the mixture of water (50 ml) and ethyl acetate (50 ml). The pH of the reaction mixture was adjusted to 9-10 with 20% sodium hydroxide aq. solution. Two layers were separated and then the organic layer was concentrated. Tetrahydrofuran (40 ml; THF) was charged to the residue and chilled the solution to 0-5°C. Sodium borohydride (4.93 g) was charged to it followed by iodine solution (16.56 g iodine in 50 ml THF) or BF3-etherate solution (19 g) was charged to it slowly at 0-10°C. The reaction mixture was heated to reflux and stirred for 8-10 hours. After completion of the reaction, the reaction mixture was cooled to room temperature, followed by addition of water (50 ml) to reaction mixture. The pH of reaction mass was adjusted to 1-2 with conc HCl. Ethyl acetate (100 ml) was charged to the reaction mixture and then subjected for pH adjustment of reaction mass to 9-11 with 25% aq. sodium hydroxide solution. The organic layer was separated and concentrated under vacuum to get (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol. The obtained (R)-2-[[2-(4-aminophenyl) ethyl] amino]-1-phenylethanol residue was treated with concentrated hydrochloric acid (5 ml) in isopropyl alcohol (25 ml) to get (R)-2-[[2-(4-aminophenyl)ethyl] amino]-1-phenylethanol hydrochloride, which was further investigated by 1H-NMR spectroscopy and Fourier Transform Infrared Spectroscopy (FTIR).
Yield:97.6 %
HPLC Purity: ≥99%
Example-4: Preparation of crystalline Alpha-1 form of Mirabegron
To a mixed solution of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylethanol hydrochloride (10g), 2-aminothiazole-4-yl-acetic acid hydrochloride (6.6 g) and water (150 ml), l-(3-dimethylaminopropyl)-3-ethylcarbodiimide mono-hydrochloride (EDC.HCl) (7.2 g) was added at temperature of about 25 °C to 35°C and the reaction mixture was stirred for 1 hour at temperature of about 25 °C to 35°C. After completion of the reaction, 20% aqueous sodium hydroxide solution (20 ml) was charged drop wise to the reaction mixture. The obtained suspension was stirred for 1-2 hours at RT, followed by filtration to get the Mirabegron.
Dried the product at 40-50°C to get dried product (11.5 g).
The product (1 g) obtained above was dissolved in n-butanol (12 ml) or n-propanol at 70-80°C. Toluene (24 ml) was charged to the clear solution at 70-80°C. The reaction mixture was allowed to cool to RT slowly. The obtained suspension was stirred at RT for ~1 hour and
15
then filtered the suspension to get a titled compound as solid, which was further investigated by powder X-ray diffraction.
HPLC Purity: 99.92%
Moisture content:<3 % w/w (Karl Fischer titration method)
1H-NMR spectroscopy: 1H NMR was performed using Bruker-400 MHz instrument. DMSO-d6 was used as solvent for preparing sample for 1H NMR spectroscopy.
FTIR: Infra-red Spectroscopy was performed using Perkin- Elmer spectrophotometer using pellets with potassium bromide
Powder X-ray Diffraction (PXRD): The measurements were carried out with a Bruker powder X-ray diffractometer using Cu Ka radiation in the Bragg-Brentano reflection geometry. Generally, the 2Θ values are accurate within an error of ±0.1 -0.2°.
Figures
Figure 1 shows 1H-NMR Spectrum of (R)-2-hydroxy-N-[2-(4-nitrophenyl) ethyl]-2-phenyl acetamide
Figure 2 shows Infra-red spectogram of (R)-2-hydroxy-N-[2-(4-nitrophenyl) ethyl]-2-phenyl acetamide
Figure 3 shows 1H-NMR Spectrum of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide
Figure 4 shows IR Spectrum of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide
Figure 5 shows 1H-NMR Spectrum of (R)-2-[[2-(4-aminophenyl)ethyl] amino]-1-phenylethanol hydrochloride
Figure 6 shows IR Spectrum of (R)-2-[[2-(4-aminophenyl)ethyl] amino]-1-phenylethanol hydrochloride
Figure 7 shows XRPD of alpha-1 form of Mirabegron

We Claim:
1. A process for the preparation of Mirabegron or salt thereof, comprises:
i) reaction of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl-2-phenylacetamide or
salt thereof with reducing agent in presence of additive in an alcohol to
provide (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt
thereof;
ii) reaction of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt
thereof with reducing agent in presence of additive in a solvent to provide (R)-
2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol or salt thereof; and
iii) reaction of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylethanol or salt
with 2-aminothiazole-4-yl-acetic acid or salt thereof to provide Mirabegron.
2. The process of claim 1, wherein the additive is selected from cupric sulphate
(copper sulphate), zinc chloride, cobalt chloride, cerium chloride, calcium
chloride, sulfur, zirconium chloride, diethyl selenium bromide, titanium
tetrachloride, tin chloride, manganese chloride, aluminium oxide, trimethyl silyl
chloride; halogen such as Iodine; acid such as sulfuric acid, acetic acid,
trifluoroacetic acid; and Amberlyst-15(H+).
3. A solid form of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol or salt
thereof, compound of formula IV
NH2
HN OH
Formula-IV
has purity of more than or equal to 99 %, when measured by HPLC
.
4. A process for the preparation of (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-
phenylethanol or salt thereof, has purity more than 99 % by HPLC, the process
comprises the steps of
a) adding (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt
thereof in ether solvent at suitable temperature,
17
b) contacting reducing agent to the reaction mixture of step (a)
c) adding oxidizing agent or additive to the reaction mixture of step (b) at suitable temperature,
d) refluxing the reaction mixture for suitable time period,
e) purification of obtained product in step (d) with suitable mixture of solvents to obtain R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol or salt thereof, has purity more than 99 %, when measured by HPLC
5. The process according to claim 1, wherein ether solventsis selected from the group comprising one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether or methyl-tertbutyl ether.
6. The process according to claim 2, whereinreducing agent is selected from the group comprising one or more of lithium aluminium hydride, sodium cyanoborohydride, sodium triacetoxy borohydride, or sodium borohydride.
7. The process according to claim 1, whereinoxidizing agent or additive is selected from the group comprising one or more of cupric sulphate (copper sulphate), iodine,zinc chloride, cobalt chloride or acids.
8. The process according to claim 1, whereinstep (e) purification is carried out by means of treating the crude (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanolwith suitable mixture of solvents.
9. A process for the preparation of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof has purity more than or equal to 99 % by HPLC, comprises:
i) reaction of (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl-2-phenylacetamide or salt thereof with reducing agent in presence of additive in alcohol to afford (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereof; and
ii) isolation of (R)-N-(4-aminophenethyl)-2-hydroxy-2-phenylacetamide or salt thereofby means of acid treatment.