PREPARATION OF MIRABEGRON AND ITS INTERMEDIATES
INTRODUCTION
Aspects of the present application relate to processes for the preparation of mirabegron and its intermediates.
Mirabegron is chemically described as (R)-2-(2-aminothiazol-4-yl)-4’-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide or 2-amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]-4-thiazoleacetamide. It has the structure of Formula I.
Mirabegron is an orally active beta-3 adrenoceptor agonist which is approved in USA, Europe, Canada and Japan for the treatment of urinary frequency, urinary incontinence, or urgency associated with overactive bladder by Astellas Pharma. U.S. Patent No. 6,346,532 B1 discloses mirabegron or a salt thereof and process for its preparation.
U.S. Patent No. 6,346,532B1 discloses the preparation of mirabegron wherein (R)-styrene oxide is reacted with 4-nitrophenylethylamine hydrochloride to provide (R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol which upon reaction with di-tert-butyl dicarbonate (Boc anhydride) to give boc-protected R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol. The boc-protected R)-2-[[2-(4-nitrophenyl)-ethyl] amino]-1-phenylethanol is reduced to provide boc-protected (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-1-phenylethanol which upon condensation with 2-aminothiazol-4-yl-acetic acid to provide boc-protected mirabegron followed by deprotection using a solution of 4N hydrogen chloride in ethyl acetate to give mirabegron dihydrochloride.
U.S. Patent No. 7,342,117 B2 discloses the preparation of mirabegron wherein (R)-mandelic acid is reacted with 4-nitrophenylethylamine hydrochloride or 4-nitrophenylethylamine hemisulfate to produce (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide which upon reduction of keto group followed by treating with concentrated hydrochloric acid provide (R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol hydrochloride. The R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol hydrochloride is reacted with a reducing agent to

provide (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-1-phenylethanol hydrochloride which upon condensation with 2-aminothiazol-4-yl-acetic acid gives (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]acetanilide (Mirabegron).
The prior art processes suffer from one or more drawbacks such as low purity, less yield, involving protection and deprotection of amino group and lengthy workup which does not result an industrially feasible process.
Hence, there is a need to provide simple, environment friendly, cost effective, industrially feasible processes for the preparation of mirabegron and its intermediates.
SUMMARY
In the first aspect, the application provides a process for the preparation of mirabegron of Formula I which comprises one or more of the following steps;
a) reacting (R)-styrene oxide with 4-nitrophenylethylamine or its salts to provide
a compound of Formula II or its salts;
b) reducing the compound of Formula II or its salts to provide a compound of Formula III or its salts;
Formula III
c) reacting the compound of Formula III or its salts with 2-aminothiazol-4-yl-acetic acid or its salts to provide mirabegron of Formula I; and
d) optionally purifying the product obtained from step (c) to provide pure mirabegron. In the second aspect, the application provides a process for the preparation of
mirabegron of Formula I which comprises one or more of the following steps;
a) converting the compound of Formula II or its salts in the presence of a suitable reagent to provide a compound of Formula IV or its salts;

b) reducing the compound of Formula IV or its salts to provide a compound of Formula V or its salts;
c) reacting the compound of Formula V or its salts with 2-aminothiazol-4-yl-acetic acid or its salts to provide a compound of Formula VI or its salts; and
d) hydrolyzing the compound of Formula VI or its salts to provide mirabagron of
Formula I or its pharmaceutically acceptable salts.
In the third aspect, the application provides a process for the preparation of mirabegron of Formula I which comprises one or more of the following steps;
a) reacting (R)-styrene oxide with benzylamine to provide a compound of
Formula VII;
b) debenzylating the compound of Formula VII with a suitable reagent to provide a compound of Formula VIII;

c) reacting the compound of Formula VIII with 4-nitrophenylethylhalide to provide a compound of Formula II or its salts; and
d) converting the compound of Formula II or its salts obtained from step c) to
Mirabegron of Formula I.
In the fourth aspect, the application provides a process for the preparation of mirabegron comprises the following step;
a) reacting p-nitro-toluene with N, N-dimethylformamidedimethylacetal (DMFA)
to provide a compound of Formula IX;
b) hydrolyzing the compound of Formula IX to provide 4-nitrophenylacetaldehyde;
c) reacting 4-nitrophenylacetaldehyde with (R)-2-amino-1-phenylethanol to provide the intermediate of Formula II; and
d) converting the compound of Formula II or its salt obtained from step c) to mirabegron.
In the fifth aspect, the application provides a compound of Formula IV or its salts and their use in the preparation of mirabegron.

In the sixth aspect, the application provides a compound of Formula V or its salts and their use in the preparation of mirabegron.
In the seventh aspect, the application provides a compound of Formula VI or its salts and their use in the preparation of mirabegron.
DETAILED DESCRIPTION In the first aspect, the application provides a process for the preparation of mirabegron of Formula I which comprises one or more of the following steps;
a) reacting (R)-styrene oxide with 4-nitrophenylethylamine or its salts to provide a compound of Formula II or its salts;

b) reducing the compound of Formula II or its salts to provide a compound of Formula III or its salts;
c) reacting the compound of Formula III or its salts with 2-aminothiazol-4-yl-acetic acid or its salts to provide mirabegron of Formula I; and
d) optionally purifying the product obtained from step (c) to provide pure mirabegron.
Step a) involves the reaction of (R)-styrene oxide with 4-nitrophenylethylamine or its salts to provide a compound of Formula II or its salts.
In embodiments of step a), 4-nitrophenylethylamine can be used as its free base or its any suitable salt. The suitable salt of 4-nitrophenylethylamine may be with inorganic acid or organic acid. The suitable salts of 4-nitrophenylethylamine which includes but are not limited to hydrochloride, hydrobromide, hydroiodide, hemisulfate, nitrate, phosphate, acetate, oxalate, methanesulfonate, p-toluenesulfonate, maleate, fumerate or the like.
In embodiments of step a), optionally when a salt of 4-nitrophenylethylamine is used in reaction can be converted to free base before reacting with (R)-styrene oxide. The salt of 4-nitrophenylethylamine is converted to its free base by using the procedures known in the art. Preferably the salt of 4-nitrophenylethylamine is converted to free base by adding an inorganic or organic base. The free base can be isolated by using techniques like extraction, evaporation of the solvent etc. Optionally the free base of 4-nitrophenylethylamine which is obtained from its salt can be reacted with (R)-styrene oxide without isolation i.e., in situ. The starting materials can be purified by any of the known methods to obtain desired purity.
In embodiment of step a) the base can be used for the conversion of salt of 4-nitrophenylethylamine to its free base included but are not limited to alkali metal hydroxide such as sodium hydroxide, potassium hydroxide or the like, alkaline earth metal hydroxides such as magnesium hydroxide, calcium hydroxide or the like, alkali metal carbonates such as sodium carbonate, potassium carbonate or the like, alkaline earth metal carbonates such as magnesium carbonate, calcium carbonate

or the like, alkali and alkaline earth metal bicarbonates such as sodium bicarbonate, potassium bicarbonate, magnesium bicarbonate, calcium bicarbonate or the like. Organic bases included but are not limited to methylamine, diethylamine, triethylamine, N, N-diisopropylethylamine, diisopropylamine, or the like;
In embodiments of step a), the reaction of (R)-styrene oxide with 4-nitrophenylethylamine or its salts can be carried out in the presence of a suitable inert solvent. Examples of such solvents include but are not limited to alcohols such as methanol, ethanol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, iso-butyl alcohol, t-butyl alcohol; ethers, such as diethyl ether, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, dioxane or dimethoxyethane; ketone solvents such as acetone, methyl ethyl ketone, methyl isobutyl ketone or diethyl ketone; ester solvents such as ethyl acetate, propyl acetate or butyl acetate; halogenated hydrocarbons such as dichloromethane, chloroform or chlorobenzene; polar aprotic solvents such as for examples, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, sulpholane, N-methylpyrrolidone or the like; nitrile solvents such as acetonitrile or propionitrile; or mixture of the said solvents.
In embodiments of step a), the reaction can be carried out at a temperature ranging from about 10°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 20°C to the reflux temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.
In embodiments of step a), the product of step (a) i.e., compound of Formula II may be isolated directly from the reaction mixture itself after the reaction is complete in step (a), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like. Isolation of compound of Formula II may also involve methods including removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like. Stirring or other alternate methods, such as for example, shaking, agitation, or the like, that mix the contents may also be employed for isolation. Optionally the reaction mass containing the compound of Formula II can be used for the next step without isolation.

In embodiments of step a), the compound of Formula II may be converted into its pharmaceutically acceptable salts. The suitable salts of compound of Formula II which includes but are not limited to hydrochloride, hydrobromide, hydroiodide, hemisulfate, nitrate, phosphate, acetate, oxalate, methanesulfonate, p-toluenesulfonate, maleate, fumerate or the like. Preferably the compound of Formula II can be isolated as hydrochloride salt or hemi sulfate salt.
In embodiments of step a), the salts of compound of Formula II can be prepared by following the procedures known in the art. In embodiments, the suitable salts of compound of Formula II can be prepared by making a solution of compound of Formula II in a suitable solvent and adding the source of a suitable acid to the solution or vice-versa. In embodiments, the salts of compound of Formula II can be prepared by dissolving compound of Formula II in a suitable solvent and adding the source of acid to the above solution.
In preferred embodiments, the compound of Formula II can be converted to its hydrochloride salt. The hydrochloride salt can be prepared by dissolving the compound of Formula II in a suitable solvent and adding the source of hydrochloric acid to the solution or vice-versa. The source of hydrochloric acid can be concentrated hydrochloric acid, hydrogen chloride gas, a solution of hydrochloric acid in a solvent or any source which gives hydrochloric acid etc.
In preferred embodiments, the salts of compound of Formula II can be isolated by using techniques includes removal of solvent, cooling, concentrating the reaction mass, adding an anti-solvent, extraction with a solvent, or the like.
The obtained compound in step (a) i.e. salts of compound of Formula II may be optionally further purified by recrystallization or by slurring in a suitable solvent or by column chromatography or any other suitable technique. Any of the solvents described in step a) as above can be used for the purification.
The isolated solid compound of Formula II or its salts may be optionally further dried at suitable temperatures, and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like. Optionally the salt of compound of Formula II can be used directly in the next step without drying.
Step b) involves the preparation of compound of Formula III or its salts by reducing the compound of Formula II or its salts by using a suitable reducing agent.

In embodiment of step b) the suitable reducing agent that may be used includes but are not limited to catalytic hydrogenation using palladium-on-carbon, platinum (IV) oxide, or Raney™ nickel, or the like; metal mediated reduction such as zinc and acetic acid, zinc and hydrochloric acid, tin and hydrochloric acid, sodium amalgam in ethanol, or iron and acetic acid; tin chloride (II), titanium (III) chloride, or the like; alkali metal hydrides, such as lithium aluminum hydride, sodium borohydride, sodium dihydro-bis-(2-methoxyethoxy) aluminate solution (VITRIDE®), diisobutyl aluminium hydride, sodium cyanoborohydride or the like; sodium dithionite in alkaline medium; iron oxide hydroxide; hydrazine hydrate; any combination thereof; or any other suitable reducing agent known in the art.
In embodiment of step b) the reaction may be carried out in a suitable inert
solvent. Suitable solvents that may be used include, but are not limited to: alcohols
such as for examples, methanol, ethanol, isopropyl alcohol, 1-propanol, 1-butanol, 2-
butanol, or the like; hydrocarbons such as for examples, toluene, xylene, hexanes,
heptanes, cyclohexane or the like; halogenated hydrocarbons such as for example
dichloromethane, ethylene dichloride, chloroform, or the like; ethers such as for
examples diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran,
dioxane or the like; polar aprotic solvents such as for examples, N,N-
dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, N-
methylpyrrolidone or the like; water; and mixtures thereof, and any other suitable
solvent.
In embodiments of step b), the reaction can be carried out at a temperature ranging from about 10°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 20°C to the reflux temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer. Optionally, the reaction mass containing the compound of Formula III or its salts can be used for the next step without isolation.
Optionally the product of step (b) i.e., compound of Formula III or its salts may be isolated as solid or used directly for the next step from the reaction mixture itself after the reaction is complete in step (b), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.

The obtained compound in step (b) i.e., salts of compound of Formula III may be optionally further purified by recrystallization or by slurring in a suitable solvent or by column chromatography or any other suitable technique.
The product of step (b) i.e., the compound of Formula III or its salts may be optionally further dried at suitable temperatures and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like. Optionally the salt of compound of Formula III can be used directly in the next step without drying.
Step c) involves the reaction of the compound of Formula III or its salts with 2-aminothiazol-4-yl-acetic acid or its salts to provide mirabegron of Formula I.
In embodiments of step c), 2-aminothiazol-4-yl-acetic acid can be used as its free base. Optionally 2-aminothiazol-4-yl-acetic acid can be used as its salt. The suitable salt of 2-aminothiazol-4-yl-acetic acid may be with inorganic acid or organic acid. The suitable salts of 2-aminothiazol-4-yl-acetic acid which includes but are not limited to hydrochloride, hydrobromide, hydroiodide, hemisulfate, nitrate, phosphate, acetate, oxalate, methanesulfonate, p-toluenesulfonate, maleate, fumerate or the like. The suitable salt of 2-aminothiazol-4-yl-acetic acid may be with base. The suitable salts of 2-aminothiazol-4-yl-acetic acid which includes but are not limited to sodium, potassium, lithium, calcium, magnesium, ammonium salt or the like.
In embodiment of step c), optionally the reaction can be carried out in the
presence of a suitable coupling agent. The suitable coupling agent includes but are
not limited to N,N'-Dicyclohexylcarbodiimide (DCC), N, N’-diisopropylcarbodiimide
(DIC), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide (EDC), O-(benzotriazol-1-yl)-
N,N,N',N'-tetramethyluronium-tetrafluoroborate (TBTU), O-(benzotriazol-1-yl)-
N,N,N',N'-tetramethyluronium-hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-
yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate (HATU), (benzothazol-1-
yloxy)-tris-(dimethylamino)-phosphonium-hexafluoro-phosphate (BOP),
(benzothazol-1-yloxy)-thpyrrolidinophosphonium-hexafluorophosphate (PyBOP),
cyanuric chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 4-(4,6-Dimethoxy-
1,3,5-triazin-2-yl)-4-methyl morpholinium chloride (DMTMM) or the like or any
mixture thereof.
In embodiment of step c), optionally the reaction can be carried out in the presence of a suitable catalyst or additives. The suitable catalysts or additives

include but are not limited to N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (6-Cl-HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HODhbt) and its aza derivative (HODhat) or the like.
In embodiment of step c), the reaction can be carried out in the presence of a suitable inert solvent. Examples of such solvents include but are not limited to water; alcohols, such as for example, methanol, ethanol, propanol, butanol, pentanol, ethylene glycol, glycerol, or the like; ketones, such as for example, acetone, butanone, pentanone, methyl isobutyl ketone, or the like; esters, such as for example, ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, or the like; ethers, such as for example, diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, dioxane, 1,2-dimethoxyethane, 2-methoxyethanol, 2-ethoxyethanol, anisole, or the like; aliphatic or alicyclic hydrocarbons, such as for example, pentane, hexane, heptane, cyclohexane, methylcyclohexane, or the like; halogenated hydrocarbons, such as for example, dichloromethane, chloroform or the like; aromatic hydrocarbons, such as for example, toluene, xylene, chlorobenzene, or the like; nitriles, such as for example, acetonitrile, propionitrile, or the like; polar aprotic solvents, such as for example, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, pyridine, dimethylsulphoxide, formamide, acetamide, or the like; or any mixtures thereof.
In embodiment of step c), the reaction can be carried out in the presence of a suitable base. The base may be inorganic or organic base. In embodiments, the reaction can be carried out in the presence of a base such as for example triethylamine, N, N-diisopropyl-N-ethyl-amine, diisopropylamine, morpholine, N-methylmorpholine and optionally in the presence of a catalyst such as 4-N,N-dimethylaminopyridine.
In embodiments of step c), the reaction can be carried out at a temperature ranging from about 10°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 20°C to about 50°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However,

provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.
The product of step (c) i.e., mirabegron or its salts can be isolated as solid from the reaction mixture itself after the reaction is complete in step (c), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.
In embodiments if the product obtained from step (c) is a salt of mirabegron then it can be converted to its free base by using conventional techniques known in the art. Optionally the wet mirabegron obtained from step (c) can be purified by the techniques known in the art without drying.
The product of step c), i.e., mirabegron may be optionally further dried at suitable temperatures and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like.
In embodiment of step d), optionally the mirabegron obtained from step (c) can be further purified to obtain highly pure mirabegron. In embodiments, the mirabegron can be purified by any method known in the art such as recrystallization involving single solvent, mixture of solvents, or solvent-anti solvent technique; reprecipitation; slurring in a solvent; or chromatography to enhance its chemical purity or chiral purity.
Any of the solvents listed in step c), can be used for the purification of mirabegron. Mirabegron can also be purified by converting mirabegron into acid-addition salt followed by neutralization with a base to produce the substantially pure mirabegron. Examples of such acids used for the purification of mirabegron include but are not limited to: inorganic acids such as hydrochloric acid, sulfuric acid, phosphoric acid, hydrobromic acid, or the like; and organic acids such as oxalic acid, maleic acid, fumaric acid, malic acid, tartaric acid, citric acid, benzoic acid, methanesulfonic acid, p-toluenesulfonic acid or the like. Any of the base listed in step a), can be used for the conversion of acid-addition salt of mirabegron into free base of mirabegron.
In embodiments of step d), mirabegron obtained in step c) can be purified by dissolving mirabegron in a suitable solvent and adding anti-solvent to obtain pure mirabegron. The methods known in the art or the methods described above can be used for the isolation and drying of the mirabegron after purification. If the

mirabegron obtained is an acid-addition salt after purification, then it can be converted to its free base by neutralization with a base by the procedures known in the art.
In the second aspect, the application provides a process for the preparation of mirabegron of Formula I which comprises one or more of the following steps;
a) converting the compound of Formula II or its salts in the presence of a
suitable reagent to provide a compound of Formula IV or its salts;
b) reducing the compound of Formula IV or its salts to provide a compound of Formula V or its salts;
c) reacting the compound of Formula V or its salts with 2-aminothiazol-4-yl-acetic acid or its salts to provide a compound of Formula VI or its salts; and
d) hydrolyzing the compound of Formula VI or its salts to provide mirabagron of Formula I or its pharmaceutically acceptable salts.
Step a) involves the conversion of compound of Formula II or its salts to compound of Formula IV or its salts.

In embodiments of step a) the reaction can be carried out in the presence of a suitable reagent. The examples of the suitable reagents include but are not limited to 1,1'-carbonyldiimidazole (CDI), diphenylcarbonate, phosgene, diphosgene, triphosgene, chloroformates or the like.
In embodiments of step a) the reaction may be carried out in the presence of a suitable base. The base may be an organic or inorganic base. The organic base may be an amine, for example, trialkyl amine, N-methylimidazole, quinuclidine, 1-methylpyrrolidine or morpholine. The inorganic base may be a hydroxide, for example, potassium, sodium, calcium, barium or magnesium hydroxide, or a carbonate, for example, sodium carbonate, potassium carbonate, magnesium carbonate, or bicarbonate, for example, sodium bicarbonate or potassium bicarbonate.
In embodiments of step a) the reaction can be carried out in a suitable solvent. The solvent may be selected from hydrocarbons, ethers, halogenated hydrocarbons, esters, nitriles, alcohols or mixtures thereof. The solvent may be, for example, hexane, heptane, toluene, methylene chloride, chloroform, methyl t-butyl ether, tetrahydrofuran or mixtures thereof.
In embodiments of step a), the reaction can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 10°C to about 60°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.
In embodiments of step a), the compound of Formula IV can be converted into pharmaceutically acceptable salts by using procedure known in the art or methods described in this application. The salt can be prepared by dissolving the compound of Formula IV in a solvent and combining with a source of a suitable acid.
The product of step (a) i.e., the compound of Formula IV or its salts can be isolated as solid from the reaction mixture itself after the reaction is complete in step (a), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like. Optionally the compound of Formula IV or its salts can be used in the next step without isolation i.e., in situ.

In embodiments of step a) the compound of Formula IV or its salts may be further purified by using the conventional procedures known in the art such as recrystallization, reprecipitation, slurring is a solvent etc.
The product of step (a) i.e., the compound of Formula IV or its salts may be optionally further dried at suitable temperatures and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like. Optionally the compound of Formula IV or its salts can be used in the next step without drying.
In embodiments of step a), the product of step-a), i.e., compound of Formula IV or its salts are new and useful intermediates in the synthesis of mirabegron.
Step b) involves the reduction of compound of Formula IV or its salts to provide a compound of Formula V or its salts.
In embodiment of step b) the suitable reducing agent that may be used includes but are not limited to catalytic hydrogenation using palladium-on-carbon, platinum (IV) oxide, or Raney™ nickel, or the like; metal mediated reduction such as zinc and acetic acid, zinc and hydrochloric acid, tin and hydrochloric acid, sodium amalgam in ethanol, or iron and acetic acid; tin chloride (II), titanium (III) chloride, or the like; alkali metal hydrides, such as lithium aluminum hydride, sodium borohydride, sodium dihydro-bis-(2-methoxyethoxy) aluminate solution (VITRIDE®), diisobutyl aluminium hydride, sodium cyanoborohydride or the like; sodium dithionite in alkaline medium; any combination thereof; or any other suitable reducing agent known in the art.
In embodiment of step b) the reaction may be carried out in a suitable solvent. Suitable solvents that may be used include, but are not limited to: alcohols such as for examples, methanol, ethanol, isopropyl alcohol, 1-propanol, 1-butanol, 2-butanol, or the like; hydrocarbons such as for examples, toluene, xylene, hexanes, heptanes, cyclohexane or the like; halogenated hydrocarbons such as for example dichloromethane, ethylene dichloride, chloroform, or the like; ethers such as for examples diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane or the like; polar aprotic solvents such as for examples, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulphoxide, sulpholane, N-methylpyrrolidone or the like; water; and mixtures thereof, and any other suitable solvent.

In embodiments of step b), the reaction can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 20°C to the reflux temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.
The compound of Formula V can be converted into pharmaceutically acceptable salts by using procedure known in the art or methods described in this application. The salt can be prepared by dissolving the compound of Formula V in a solvent and combining a source of a suitable acid.
Optionally the product of step (b) i.e., compound of Formula V or its salts may be isolated as solid or used directly for the next step from the reaction mixture itself after the reaction is complete in step (b), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.
In embodiments of step b) the compound of Formula V or its salts may be further purified by using the conventional procedures known in the art such as recrystallization, reprecipitation, slurring is a solvent etc.
The product of step (b) i.e., the compound of Formula V or its salts may be optionally further dried at suitable temperatures and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like. Optionally the compound of Formula V or its salts can be used in the next step without drying.
In embodiments of step b), the product of step-b), i.e., compound of Formula V or its salts are new and useful intermediates in the synthesis of mirabegron.
Step c) involves the reaction of the compound of Formula V or its salts with 2-aminothiazol-4-yl-acetic acid or its salts to provide a compound of Formula VI or its salts;
In embodiment of step c), the reaction can be carried out in the presence of a suitable coupling agent. The suitable coupling agent includes but are not limited to N,N'-Dicyclohexylcarbodiimide (DCC), N, N’-diisopropylcarbodiimide (DIC), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide (EDC), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-tetrafluoroborate (TBTU), O-(benzotriazol-1-yl)-N,N,N',N'-

tetramethyluronium-hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate (HATU), (benzothazol-1-yloxy)-tris-(dimethylamino)-phosphonium-hexafluoro-phosphate (BOP), (benzothazol-1-yloxy)-thpyrrolidinophosphonium-hexafluorophosphate (PyBOP), cyanuric chloride, 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT), 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methyl morpholinium chloride (DMTMM) or the like or any mixture thereof.
In embodiment of step c), optionally the reaction can be carried out in the presence of a suitable catalyst or additives. The suitable catalysts or additives include but are not limited to N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 1-hydroxybenzotriazole (HOBt), 6-chloro-1-hydroxybenzotriazole (6-Cl-HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HODhbt) and its aza derivative (HODhat) or the like.
In embodiment of step c), the reaction can be carried out in the presence of a suitable inert solvent. The suitable solvent which can be used but are not limited to dimethylformamide, dimethylacetamide, tetrahydrofuran, acetonitrile, N-methylpyrrolidone or dimethylsulphoxide, or the like.
In embodiment of step c), the reaction can be carried out in the presence of a suitable base. The base may be inorganic or organic base. In embodiments, the reaction can be carried out in the presence of a base such as for example triethylamine, N,N-diisopropyl-N-ethyl-amine, diisopropylamine and optionally in the presence of a catalyst such as 4-N,N-dimethylaminopyridine.
In embodiments of step c), the reaction can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 20°C to about 60°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.
Optionally the product of step (c) i.e., compound of Formula VI or its salts may be isolated as solid or used directly for the next step from the reaction mixture itself after the reaction is complete in step (c), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.

In embodiments of step c) the compound of Formula VI or its salts may be further purified by using the conventional procedures known in the art such as recrystallization, reprecipitation, slurring is a solvent etc.
The product of step c), may be optionally further dried at suitable temperatures and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like. Optionally the compound of Formula VI or its salts can be used in the next step without drying.
In embodiments of step c), the product of step-c), i.e., compound of Formula VI or its salts are new and useful intermediates in the synthesis of mirabegron.
Step (d) involves the hydrolysis of compound of Formula VI or its salts to provide mirabegron of Formula I or its pharmaceutically acceptable salts.
In embodiment of step (d) the hydrolysis of compound of Formula VI or its salts may be carried out in the presence of a suitable acid or suitable base. The suitable acid may be the inorganic acid or organic acid. Similarly the base can be the inorganic base or organic base. In embodiment of step d), the hydrolysis may be carried in presence of a base such as sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate in a suitable solvent. The solvents that can be used but not limited to; alcohols such as methanol, ethanol, 1-propanol, isopropanol, ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane or the like; or water or their mixtures.
In embodiment of step d), the reaction can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 10°C to about reflux temperature of the solvent used. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.
Optionally the product of step (d) i.e., mirabegron or its salts may be isolated as solid from the reaction mixture itself after the reaction is complete in step (d), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.
The product of step d), i.e., mirabegron may be optionally further dried at suitable temperatures and atmospheric or reduced pressures, for about 1-50 hours,

or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like.
If the product obtained from step (d) is a salt then it may be converted to its free base by using procedures described in this application or any of the procedure known in the art. In embodiments, mirabegron obtained according to the above process can be further purified by using procedures described in this application or any of the procedure known in the art to obtain more pure mirabegron.
In the third aspect, the application provides a process for the preparation of mirabegron of Formula I which comprises one or more of the following steps;
a) reacting (R)-styrene oxide with benzylamine to provide a compound of
Formula VII;
b) debenzylating the compound of Formula VII with a suitable reagent to provide a compound of Formula VIII;
c) reacting the compound of Formula VIII with 4-nitrophenylethylhalide to provide a compound of Formula II or its salts; and
d) converting the compound of Formula II or its salts obtained from step c) to Mirabegron of Formula I.
Step a) involves the reaction of (R)-styrene oxide with benzylamine to provide a compound of Formula VII.

In embodiments of step a) the reaction can be carried out in a suitable solvent. Any of the solvent listed in step (a) of the first aspect of the present application can be used for this step.
In embodiment of step a), the reaction can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 10°C to about reflux temperature of the solvent used. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.
Optionally the product of step (a) i.e., compound of Formula VII may be isolated or used directly for the next step, from the reaction mixture itself after the reaction is complete in step (a), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.
The product of step a), i.e., compound of Formula VII may be optionally further dried at suitable temperatures and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like. Optionally the wet compound of Formula VII may be used for the next step without drying.
Step b) involves the preparation of compound of Formula VIII by debenzylation of compound of Formula VII.
In an embodiment of step b), debenzylation of compound of Formula VII may be carried out in the presence of a suitable solvent and a debenzylating agent. In embodiment of step b), the debenzylation may be carried out in the presence of a noble metal catalyst and hydrogen gas, a phase transfer hydrogenation, or other deprotecting reagents. Other deprotecting agents include mineral acids, strong acids, Lewis acids, aqueous mineral bases. The deprotecting agents may be present in a suitable solvent. The debenzylation can be carried out in the presence of a noble metal catalyst and hydrogen gas. The catalyst may be selected from the group consisting of palladium, palladium hydroxide, palladium on activated carbon, palladium on alumina, platinum, platinum on activated carbon and Raney™ nickel in solvents such as methanol, ethanol, water, dioxane, tetrahydrofuran, acetic acid, ethyl acetate, dichloromethane, chloroform, dimethyl formamide, or mixtures thereof.

In an embodiment of the step b), the reaction can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 10°C to 50°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, for a period of for about 1 to about 24 hours or longer.
In embodiments of step b), the product of step (b) may be isolated directly from the reaction mixture itself after the reaction is complete, or after conventional work up with techniques such as quenching with a suitable reagent, extraction, or the like. In embodiments of step b) the product of step-b) i.e., compound of Formula VIII may be used in the next step without isolation.
Step c) involves the reaction of compound of Formula VIII with 4-nitrophenylethylhalide to provide a compound of Formula II or its salts.
In embodiment of step c), the 4-nitrophenylethylhalide can be 4-nitrophenylethylbromide, 4-nitrophenylethylchloride, 4-nitrophenylethylfluoride or 4-nitrophenylethyliodide.
In embodiment of step c), the reaction can be carried out in the presence of a base. Suitable bases that may be used in step (c) include, but are not limited to: organic bases, such as for example, triethylamine, tributylamine, N-methylmorpholine, N,N-diisopropylethylamine, N-methylpyrrolidine, pyridine, 4-(N,N-dimethylamino)pyridine, morpholine, or the like; inorganic bases, such as for example, alkali metal hydrides, such as for example, sodium hydride, potassium hydride, or the like; sodamide; alkali metal hydroxides, such as for example, sodium hydroxide, potassium hydroxide: alkaline metal hydroxides, such as for example, magnesium hydroxide, calcium hydroxide, or the like; alkali metal carbonates, such as for example, sodium carbonate, potassium carbonate or the like; alkaline earth metal carbonates, such as for example, magnesium carbonate, calcium carbonate, or the like; alkali metal bicarbonates, such as for example, sodium bicarbonate, potassium bicarbonate, or the like; or any other suitable bases.
In embodiment of step c), the reaction can be carried out in a suitable solvent. Any of the solvent listed in step (c) of the first aspect of the present application can be used for this step.

In embodiment of step c), the reaction can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 10°C to about 80°C. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.
Optionally the product of step (c) i.e., compound of Formula II may be isolated as solid from the reaction mixture itself after the reaction is complete in step (c), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like. Optionally the compound of Formula II can be used in the next step without isolation i.e., in-situ.
The product of step c), i.e., compound of Formula II may be optionally further dried at suitable temperatures and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the like. The wet compound of Formula II can be used in the next step without drying.
In embodiments, the compound of Formula II may be converted to a pharmaceutically acceptable salt. The salt can be prepared by following the procedure as described in step a) of the first aspect of present application.
Step (d) involves the preparation of mirabegron by converting the compound of Formula II or its salts. In embodiments of step (d), mirabegron can be prepared from compound of Formula II or its salts according to the procedure described in the step (c) of the first aspect of the present application or any method known in the art.
In embodiments, mirabegron obtained according to the above procedure can be optionally purified to get pure mirabegron. Mirabegron can be purified according to the procedure as described in step (d) of the first aspect of the present application or any suitable method known in art.
In the fourth aspect, the application provides a process for the preparation of Mirabegron comprises the following step;
a) reacting p-nitro toluene with N, N-dimethylformamidedimethylacetal (DMFA)
to provide a compound of Formula IX;

b) hydrolyzing the compound of Formula IX to provide 4-nitrophenylacetaldehyde;
c) reacting 4-nitrophenylacetaldehyde with (R)-2-amino-1-phenylethanol to provide the nitro intermediate compound of Formula II or its salt; and
d) converting the compound of Formula II or its salt obtained from step c) to mirabegron. Step (a) involves the reaction of p-nitro toluene with N, N-dimethylformamide
dimethylacetal (DMFA) to provide a compound of Formula IX.
In embodiments of step a), the reaction can be carried out in a suitable solvent. Any of the solvent listed in step (c) of the first aspect of the present application may be used for this step.
In embodiment of step a), the reaction can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 10°C to about the reflux temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.
Optionally the product of step (a) i.e., compound of Formula IX may be isolated from the reaction mixture itself after the reaction is complete in step (a), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like. Optionally the product of step a) may be used in the next step without isolation i.e., in situ.
The product of step a), i.e., compound of Formula IX may be optionally further dried at suitable temperatures and atmospheric or reduced pressures, for about 1-50 hours, or longer, using any types of drying equipment, such as a tray dryer, vacuum oven, air oven, fluidized bed dryer, spin flash dryer, flash dryer or the

like. Optionally the product of step a) i.e., wet compound of Formula IX may be used in the next step with drying.
Step (b) involves the hydrolysis of compound of Formula IX to provide 4-nitrophenylacetaldehyde.
In embodiment of step b), hydrolysis may be carried out in the presence of a suitable acid or suitable base. The suitable acid may be the inorganic acid or organic acid. Similarly the base can be the inorganic base or organic base.
In embodiment of step b), the hydrolysis may be carried in presence of an acid such as hydrochloric acid, sulphuric acid in a suitable solvent. The solvents that can be used but not limited to; alcohols such as methanol, ethanol, 1-propanol, isopropanol, ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, tetrahydrofuran, dioxane or the like; or water or their mixtures.
In embodiment of step b), the reaction can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 10°C to about reflux temperature. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.
Optionally the product of step (b) i.e., 4-nitrophenylacetaldehyde may be isolated from the reaction mixture itself after the reaction is complete in step (b), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like. Optionally, the product of step (b) may be used in the next step without isolation.
Step (c) involves the reaction of 4-nitrophenylacetaldehyde with (R)-2-amino-1-phenylethanol to provide a compound of Formula II or its salts.
In embodiments of step c) the reaction may be carried out in the presence of a reducing agent. The reducing agent that may be used includes but are not limited to sodium borohydride, sodium cyanoborohydride, sodium triacetoxyborohydride, or any other suitable reducing agent.
In embodiments of step c) the reaction may be carried out in a suitable solvent. Any of the solvent listed in step (b) of the first aspect of the present application may be used for this step.

In embodiment of step c), the reaction can be carried out at a temperature ranging from about 0°C to about boiling point of the solvent. In one embodiment, the reaction can be carried out from about 10°C to about the reflux temperature of the solvent. The time required for the reaction may also vary widely, depending on many factors, notably the reaction temperature and the nature of the reagents and solvent employed. However, provided that the reaction is effected under the conditions outlined above, a period of for about 1 to about 24 hours or longer.
Optionally the product of step (c) i.e., compound of Formula II may be isolated as solid from the reaction mixture itself after the reaction is complete in step (c), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like. Optionally, the product of step (c) may be used in the next step without isolation.
In embodiment of step c), optionally the compound of Formula II may be isolated as a suitable salt. The salt of compound of Formula II can be prepared by using the procedure described in the present application or any procedure known in the art.
Step (d) involves the conversion of a compound of Formula II or its salts to mirabegron. In embodiments, compound of Formula II or its salts can be converted into mirabegron according to the any of the process described in this application.
In embodiments, mirabegron obtained according to any of the methods described in this application may be optionally milled to get desired particle sizes. Milling or micronization may be performed before drying, or after the completion of drying of the product. Techniques that may be used for particle size reduction include, without limitation, ball, roller and hammer mills, and jet mills.
In an aspect of the application, mirabegron obtained according to certain processes of the present application has a particle size distribution wherein: mean particle size is less than about 200 µm or less than about 100 µm; d (0.5) is less than about 200 µm or less than about 25 µm; and d (0.9) is less than about 500 µm or less than about 50 µm.
In an aspect of the application, mirabegron prepared according to the processes of the present application can be substantially pure having a chemical purity greater than about 99%, or greater than about 99.5%, or greater than about 99.9%, by weight, as determined using high performance liquid chromatography (HPLC). Mirabegron produced by a method of present invention can be chemically

pure mirabegron having purity greater than about 99.5% and containing no single impurity in amounts greater than about 0.15%, by HPLC. Mirabegron produced by the methods of present invention can be chemically pure mirabegron having purity greater than about 99.8% and containing no single impurity in amounts greater than about 0.1%, by HPLC.
In an aspect of the application, mirabegron obtained by the methods of the present application can be further purified by using techniques known in the art to enhance its chemical purity and chiral purity. In embodiments, optionally a decolorizing agent may be used to removes colored impurities or any other impurities to enhance its chemical purity and chiral purity.
DEFINITIONS
The following abbreviations and acronyms are used herein and have the indicated definitions:
A “decolorizing agent” removes colored impurities by adsorption on the surface of the “decolorizing agent” particles. Examples of a “decolorizing agent” include, decolorizing carbon, activated alumina, activated clay, or silica gel.
Certain specific aspects and embodiments of the present application will be explained in greater detail with reference to the following examples, which are provided only for purposes of illustration and should not be construed as limiting the scope of the application in any manner. Variations of the described procedures, as will be apparent to those skilled in the art, are intended to be within the scope of the present application.
EXAMPLES
Example-1: Preparation of (R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-
phenylethanol: 4-nitrophenylethylamine hydrochloride (303.6g) and dichloromethane (1000 mL) were charged into a round bottom flask 25°C. 8N aqueous solution of sodium hydroxide (300 mL) was added to the obtained suspension and stirred for 20 minutes at 25°C. The layers were separated. The organic layer was dried over anhydrous sodium sulfate and solvent was evaporated. To the resulting residue 2-propanol (1500 mL) and (R)-styrene oxide (150.0 g) were added successively and the reaction mixture was heated to 81°C for 24 hours. After completion of the reaction, the solvent was evaporated in vacuum, and the residue was purified by silica gel column chromatography (eluent: dichloromethane followed

by hexane/ethyl acetate). The obtained product was further recrystallized in ether at -10°C and dried to give 90 g of the title compound.
Example-2 Preparation of ((R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-
phenylethanol monohydrochloride: (R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol (81 g) and methanol (600 mL) were charged into a round bottom flask at 25°C. The obtained suspension was stirred at 25°C to get clear solution and cooled to 0°C. The methanolic hydrochloric acid solution (300 mL) was added to the above clear solution and cooled to 0°C and stirred for 1 hour at the same temperature. The solvent was evaporated under vacuum at 45°C and the obtained solid product was washed with ether and dried to give 86 g of the title compound. HPLC purity: 99.42%
Example-3: (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-1-phenylethanol
monohydrochloride: (R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol
monohydrochloride (86 g), wet 10% palladium-carbon (45 g) and methanol (900 mL) were stirred under a hydrogen atmosphere for 1 hour at 25°C. After completion of the reaction, the reaction solution was filtered on hyflo, washed with methanol (250 mL) and filtrate was concentrated in vacuum at 50°C to give 84 g of the title compound.
Example-4: Preparation of Mirabegron: (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol monohydrochloride (84 g) and aqueous hydrochloric acid solution (28.4 g of hydrochloric acid dissolved in 1.26 L water) were charged into a round bottom flask at 25°C and stirred to get a clear solution. 2-aminothiazol-4-yl-acetic acid (45.5 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC.HCl) (59.8 g) were charged to the reaction mass and stirred for 1 hour 30 minutes at room temperature. After completion of the reaction, aqueous solution of sodium hydroxide (25 g dissolved in 420 mL water) was added slowly at 0°C. The gummy mass was obtained and the solvent was decanted. Water (1000 mL) was added to the gummy mass and stirred for 4 hours at room temperature. The solid was obtained by filtration. The solid compound (70 g) and diethyl ether (1500 mL) were charged into a flask and stirred for overnight at room temperature. The slurry was filtered to obtain the product. Yield: 64 g.

Example- 5: Preparation of (R)-3-(4-nitrophenethyl)-5-phenyloxazolidin-2-one:
(R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol (14 g), dichloromethane (140 mL) and 1,1’-carbonyldiimidazole (11.89 g) were charged into a round bottom flask at 27°C and stirred for 3 hours. After completion of the reaction, water (100 mL) was added to the reaction mass and stirred at 27°C for 15 minutes. The layers were separated and the organic layer dried over sodium sulfate and evaporated under vacuum at 45°C to give the title compound as orange-red colored solid. Yield: 13 g.
Example- 6: Preparation of (R)-3-(4-aminophenethyl)-5-phenyloxazolidin-2-one:
(R)-3-(4-nitrophenethyl)-5-phenyloxazolidin-2-one (13 g) and ethanol (130 mL) were charged into a round bottom flask at 27°C. SnCl2.H2O (42.2 g) was added to the reaction mass and the temperature of the reaction mass increased to 70°C and stirred for 2 hours at the same temperature. After completion of the reaction, the reaction solution was evaporated under vacuum at 55°C to obtain residue. Saturated sodium bicarbonate solution (200 mL) was added to the residue till the pH of the reaction mass become basic. The obtained turbid solution was filtered over celite and washed with ethyl acetate (4 x 200 mL) followed by 10% Methanol-dichloromethanol (2 x 200 mL). The combined organic layers were evaporated under vacuum at 50°C to get crude product. The obtained crude product was purified by using dichloromethane/hexane to get the title compound. Yield: 10 g.
Example- 7: Preparation of (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-(2-oxo-5-
phenyloxazolidin-3-yl)ethyl)phenyl)acetamide: (R)-3-(4-aminophenethyl)-5-
phenyloxazolidin-2-one (5 g), 2-aminothiazol-4-yl-acetic acid (3.08 g) and N,N-
dimethylformamide were charged into a round bottom flask at 27°C. O-(7-
Azabenzotriazol-1-yl)-N, N, N', N'-tetramethyluronium hexafluorophosphate (HATU)
(6.74 g) and diisopropylethylamine (4.6 mL) were charged into the reaction mass
and stirred for 3 hours at 27°C. After completion of the reaction, the reaction solution
was poured into ice-cooled water and extracted with ethyl acetate (4x 100 mL). The
combined organic layers were dried over sodium sulfate and concentrated under
vacuum at 50°C to obtain crude product. The crude product was purified by column
chromatography using silica gel (eluent: Dichloromethane/methanol) to get the title
compound as solid.

Example- 8: Preparation of Mirabegron: (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-(2-oxo-5-phenyloxazolidin-3-yl)ethyl)phenyl)acetamide and ethanol (420 mL) were charged into a round bottom flask at 27°C.1 N Potassium hydroxide solution (210 mL) was added to the reaction mass and heated to 78°C. The reaction mass was stirred for 4 hours 30 minutes at 78°C. After completion of the reaction, the reaction solution was evaporated and extracted with ethyl acetate. The combined ethyl acetate layers were dried over sodium sulfate and concentrated under vacuum at 50°C to obtain the crude solid. The crude solid was purified by column chromatography using silica gel (eluent: dichloromethane / methanol) get the title compound.
Example 9: Preparation of (R)-2-(benzylamino)-1-phenylethanol: (R)-styrene oxide (100 g) and isopropanol (800 mL) were charged into a round bottom flask at 27°C. Benzylamine (89 mL) was added to the reaction mass at 27°C and heated to 62°C. The reaction mass was stirred for 16 hours at 62°C. After completion of the reaction, the solvent was evaporated under vacuum at 50°C to result a residue. n-hexane (1000 mL) was added to the residue and cooled to 0°C. The slurry was stirred for 15 minutes at 0°C. The solid product was obtained by filtration and washed with n-hexane and dried under vacuum for 15 minutes to give 70 g of the title compound.
Example 10: Preparation of (R)-2-amino-1-phenylethanol: (R)-2-(benzylamino)-1-phenylethanol (130 g), 10% palladium-carbon (wet) (39g)) and methanol (1300 mL) were stirred under a hydrogen atmosphere for 16 hour at 27°C. After completion of the reaction, the reaction solution was filtered on celite and washed with methanol (4 X 150 mL) under nitrogen atmosphere. The filtrate was concentrated in vacuum to give 75 g of the title compound.
Example 11: Preparation of (R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol: (R)-2-amino-1-phenylethanol (30 g) and tetrahydrofuran (600 mL) and triethylamine (45.6 mL) were charged into a round bottom flask at 26°C and stirred for 15 minutes at the same temperature. 4-nitrophenylethylbromide (50.3 g) was added to the reaction mass at 26°C and heated to 52°C and stirred for 16 hours. After completion of the reaction, water (350 mL) and ethyl acetate (300 mL) were

added to the reaction mass at 27°C under stirring. The layers were separated and the aqueous layer was washed with ethyl acetate (2 X 200 mL). The ethyl acetate layer was dried over sodium sulfate and concentrated under reduced pressure at 45°C to give crude. The crude product was purified by column chromatography using silica gel (eluent: methanol / dichloromethane) to give 12.5 g of the title compound.
Example 12: Preparation of 4-nitrophenylethylbromide: Phenyl ethylbromide (50 g) and acetic anhydride (375 mL) were charged into a round bottom flask at 27°C. The obtained suspension was stirred and cooled to 0°C. The nitration mixture (prepared by adding nitric acid in acetic anhydride at 0°C) was added slowly to the reaction mass at 0°C in 30 minutes and stirred for 24 hours at room temperature. After completion of the reaction, water (3000 mL) was added to the reaction mass at 27°C under stirring and extracted with ethyl acetate (2 X 500 mL). The combined organic layer was washed with saturated sodium bicarbonate solution (2 x 500 mL) dried over sodium sulfate. The organic layer was concentrated under reduced pressure at 52°C to obtain crude. The crude material was dissolved in hexane (300 mL) and stirred for 30 minutes at 0°C. The precipitated product was filtered and washed with hexane (200 mL) and dried under suction for 2 hours to give 19 g of the title compound.
Example 13: Preparation of compound of Formula (IX): p-nitro toluene (20 g) and N, N-dimethylformamide (143 g) were charged into a round bottom flask at 25°C. N, N-dimethylformamidedimethylacetal (25.3 mL) was added to the reaction mass at 25°C and the reaction mass was heated to 125°C. The reaction mass was maintained for 9 hours at 125°C. N, N-dimethylformamidedimethylacetal (25.3 mL) was added to the reaction mass at 125°C and stirred for 10 hours at 125°C. The reaction mass was cooled to 25°C after completion of the reaction. The ice-cooled water (2.5 L) was added to the reaction mass and stirred for 3 hours 30 minutes. The precipitated solid was collected by filtration and washed with water (100 mL). The obtained product was dried under vacuum at 25°C for 30 minutes. The solid compound (65 g) and methanol (195 mL) were charged into a flask at 25°C. The obtained suspension was heated to 65°C and refluxed for 1 hour 30 minutes. The reaction mass was cooled to 25°C and filtered the solid and washed with methanol (100 mL) and dried to obtain 15.0 g of the title compound.

Example 14: Preparation of 4-nitrophenylacetaldehyde: Compound of Formula (IX) (5 g) (obtained from example 13) and chloroform (50 mL) were charged into a round bottom flask at 25°C. The aqueous solution of sulphuric acid (30%) was added to reaction mass at 25°C. The reaction mass was stirred for 16 hours at 25°C. After completion of the reaction dichloromethane (25 mL) was added and stirred for 5 minutes at 25°C. The organic and aqueous layers were separated. The aqueous layer was extracted with dichloromethane (25 mL). The combined organic layer was dried over anhydrous sodium sulphate and concentrated under vacuum to get the title compound.
Example 15: Preparation of (R)-2-amino-1-phenylethanol: Aqueous ammonia (250mL) was charged into a round bottom flask at 25°C and cooled to 5°C. The solution of (R)-styrene oxide (10 g) in methanol (100 mL) was added slowly under stirring in 7 hours at 5-10°C. The reaction mass was stirred for 1 hour at 25°C. After completion of the reaction, the reaction mass was concentrated under vacuum at 25°C to solid residue. Ethyl acetate (200 mL) was added to the solid residue and stirred at 25°C. Concentrated hydrochloric acid (7.6 mL) was added to the solution and stirred for 30 minutes at 25°C. The precipitated solid product was obtained by filtration and washed with ethyl acetate. The product was dried under vacuum at 25°C to obtain 10 g of the title compound.
Example 16: Preparation of of ((R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol monohydrochloride: 4-nitrophenylacetaldehyde (16.5 g) and dichloromethane (82.5 mL) were added into a round bottom flask at 30°C. (R)-2-amino-1-phenylethanol (20.8 g) was added to the reaction mass at 30°C. The reaction mass was stirred for 10 minutes at 30°C. Sodiumcyanoborohydride (12.4 g) was added to the reaction mass at 30°C and stirred for 30 minutes. Methanol (33 mL) was added to the reaction mass slowly in 15 minutes at 30°C and stirred for 3 hours at 30°C. After completion of the reaction, water (165 mL) and dichloromethane (82.5 mL) were added to the reaction mass and stirred for 5 minutes at 30°C.The organic and aqueous layers were separated and the aqueous layer was extracted with (41.5 mL). The combined organic layer was washed with brine solution and dried over anhydrous sodium sulphate. The organic layer was concentrated under

vacuum at 30°C to obtain the crude product. The crude product was dissolved in ethyl acetate (165 mL) and and water (165 mL). The pH of the solution was adjusted to 2 by adding dilute hydrochloric acid. The layers were separated and the pH of the aqueous layer was adjusted to 12 by adding aqueous solution of sodium hydroxide and dichloromethane (82.5 mL) was added at 30°C. The layers were separated. The organic layer was dried over anhydrous sodium sulphate and evaporated to obtain a residue. The obtained residue was dissolved in acetone (160 mL) at 30°C and cooled the solution to 0°C. Concentrated hydrochloric acid was added to the solution slowly at 0°C. The obtained slurry was stirred for 1 hour at 20°C. The precipitated solid material was filtered and washed with acetone and dried under vacuum at 30°C to obtain the title compound. HPLC purity: 98.7%
Example-17: (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-1-phenylethanol
monohydrochloride: (R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol
monohydrochloride (120 g), wet 20% RaneyTMNickel (24 g) and methanol (1200 mL) were charged into autoclave and stirred under a hydrogen pressure of 3.5 kg/cm3 for 6 hours at 28°C. After completion of the reaction, the reaction mass was filtered on hyflo, washed with methanol (120 mL) and filtrate was concentrated in vacuum at 60°C to obtain a residue. Ethyl acetate (330 mL) was added to the residue at 60°C and distilled ethyl acetate (220 mL) from the solution. The solution was cooled to 30°C and cyclohexane (770 mL) added and stirred for 1 hour 30 minutes at the same temperature. The obtained slurry was filtered and washed with cyclohexane (110 mL) and dried under vacuum at 60°C for 4 hours to give 96.5 g of the title compound. HPLC purity: 99.43%;
Example-18: (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-1-phenylethanol
monohydrochloride: (R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol
monohydrochloride (5 g), methanol (50 mL) and water (5 mL) were charged into a round bottom flask at 28°C and stirred for 10 minutes. Iron oxide hydroxide (0.25 g) was added to the reaction mass and stirred for 10 minutes at 28°C. Hydrazine hydrate (4.5 mL) was added to the reaction mass at 28°C and stirred for 10 minutes. The reaction mass was further heated to 66°C and stirred for 21 hours. The reaction mass was cooled to 30°C after completion and filtered through hyflo and washed

with methanol (5 mL). The filtrate was concentrated at 55°C to obtain 4.3 g of the title compound.
Example-19: Preparation of Mirabegron: 2-aminothiazol-4-yl-acetic acid (1.2 g) and water (24 mL) were added into a round bottom flask at 28°C and stirred for 5 minutes. (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol monohydrochloride (2.0 g) was added to the reaction mass at 28°C and stirred for 30 minutes at the same temperature. 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidemonohydro-chloride (EDC.HCl) (1.96 g) was added to the reaction mass at 28°C and stirred for 10 minutes. Aqueous hydrochloric acid solution (0.7 mL of concentrated hydrochloric acid in 6 mL water) was added to the reaction mass and stirred for 6 hours at 30°C. The reaction mass was cooled to 5°C after completion, and added 10% aqueous solution of sodium hydroxide to adjust the pH 7.5 to 8.0. The temperature of the reaction mass was raised to 25°C and stirred for 3 hours. The solid is collected by filtration and washed with water (10 mL) and dried under vacuum at 60°C for 4 hours to obtain 2.05 g of the title compound. Particle size data: D [4, 3]=18.291µ; D10= 2.253; D50= 9.422 µ; D90= 41.110 µ.
Example-20: Preparation of amorphous Mirabegron: Mirabegron (100 g) and methanol (1500 mL) were charged into a round bottom flask at 25°C and stirred to get a solution. The solution was filtered to obtain a clear solution and spray dried using a spray dryer to obtain amorphous mirabegron. HPLC purity: 99.64%; Analytical data: XRD: amorphous form

We Claim:
1. A process for preparing Mirabegron comprising;
a) reacting (R)-styrene oxide with 4-nitrophenylethylamine or its salts to provide a compound of Formula II or its salts;
b) reducing the compound of Formula II or its salts to provide a compound of Formula III or its salts;
c) reacting the compound of Formula III or its salts with 2-aminothiazol-4-yl-acetic acid or its salts to provide mirabegron of Formula I; and
d) optionally purifying the product obtained from step (c) to provide pure mirabegron.

2. The process as claimed in claim 1, wherein the reduction of compound Formula II or its salts as in step b) carried out with Raney Nickel or Palladium-carbon.
3. The process as claimed in claim 1, wherein the compound of Formula III is isolated as its hydrochloride salt.
4. The process as claimed in claim 1, wherein the coupling of compound of Formula III or its salts with 2-aminothiazol-4-yl-acetic acid or its salts in step c) is optionally carried out in the presence of a coupling agent.
5. The process as claimed in claim 4, wherein the coupling agent can be selected from N,N'-Dicyclohexylcarbodiimide (DCC), N, N’-diisopropylcarbodiimide (DIC), N-(3-dimethylaminopropyl)-N'-ethyl-carbodiimide (EDC), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-tetrafluoroborate (TBTU), O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium-hexafluorophosphate (HBTU), or the like or any mixture thereof.
6. A process for preparing Mirabegron comprising;

a) converting the compound of Formula II or its salts in the presence of a suitable reagent to provide a compound of Formula IV or its salts;
b) reducing the compound of Formula IV or its salts to provide a compound of Formula V or its salts;
c) reacting the compound of Formula V or its salts with 2-aminothiazol-4-yl-acetic acid or its salts to provide a compound of Formula VI or its salts; and
d) hydrolyzing the compound of Formula VI or its salts to provide mirabagron of
Formula I or its pharmaceutically acceptable salts. 7. A process for preparing Mirabegron comprising;
a) reacting (R)-styrene oxide with benzylamine to provide a compound of
Formula VII;

b) debenzylating the compound of Formula VII with a suitable reagent to provide a compound of Formula VIII;
c) reacting the compound of Formula VIII with 4-nitrophenylethylhalide to provide a compound of Formula II or its salts; and
d) converting the compound of Formula II or its salts obtained from step c) to Mirabegron of Formula I. 8. A compound selected from Formula IV or its salt and/or Formula V or its salt and/or Formula VI or its salt;
9. A process for preparing Mirabegron comprising;
a) reacting p-nitro-toluene with N, N-dimethylformamidedimethylacetal (DMFA) to provide a compound of Formula IX;

b) hydrolyzing the compound of Formula IX to provide 4-nitrophenylacetaldehyde; and
c) reacting 4-nitrophenylacetaldehyde obtained in step b), with (R)-2-amino-1-phenylethanol to provide the intermediate compound of Formula II; and
d) converting the compound of Formula II or its salt obtained from step c) to Mirabegron.
10. A Pharmaceutical composition comprising Mirabegron obtained from any of the processes as claimed in claim 1 to 9 and a pharmaceutically acceptable excipient.