DESC:The following specification particularly describes the invention and the manner in which it is to be performed.

INTRODUCTION
Aspects of the present application relate to processes for the preparation of Mirabegron, crystalline and amorphous forms thereof.
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.

I
Mirabegron is an orally active beta-3 adrenoceptor agonist and is under pre-registration in USA and Europe for the potential treatment of urinary frequency, urinary incontinence, or urgency associated with overactive bladder by Astellas Pharma. Mirabegron is approved in Japan. U.S. Patent No. 6,346,532 B1 discloses Mirabegron or a salt thereof and process for its preparation. In addition, it also discloses the pharmaceutical composition and method of treating diabetes mellitus and obesity in a human or animal patient.
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 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).
U.S. Patent No. 7,342,117 B2 also discloses crystalline alpha and beta forms of Mirabegron and their preparative processes.
PCT application No. WO 2012156998 A2 discloses the amorphous form of Mirabegron, its solid dispersion and preparative processes thereof.
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, efficient, industrially feasible processes for the preparation of Mirabegron and its intermediates. Further, there exists a need to provide robust and optimum process conditions to consistently produce the suitable polymorphic forms of Mirabegron.

SUMMARY
Aspects of the application provide the processes for the preparation of Mirabegron, crystalline and amorphous forms thereof.

In an aspect, the application provides a process for the preparation of Mirabegron of Formula I which comprises the steps of:
a) reducing nitro compound of Formula II or its salts to obtain amine compound of formula III or its salts;

Formula II Formula III
b) reacting the compound of Formula III or its salts with 2-aminothiazol-4-yl-acetic acid or its acid addition salts to provide Mirabegron of Formula I;
c) optionally purifying Mirabegron obtained in step (b) to provide pure Mirabegron.

In another aspect, the application provides a process for the preparation of crystalline alpha form of Mirabegron which comprises the steps of:
a) providing a solution of Mirabegron in a suitable solvent or a mixture thereof;
b) optionally seeding the reaction mass of step a) with crystalline alpha form;
c) optionally adding an anti-solvent to the reaction mass of step b) or a);
d) recovering crystalline alpha form of Mirabegron.

In another aspect, the application provides a process for the preparation of amorphous form of Mirabegron which comprises the steps of:
a) providing the solution of Mirabegron in a suitable solvent or a mixture thereof;
b) evaporating the solvent of step a) by spray drying;
c) recovering amorphous form of Mirabegron.

DETAILED DESCRIPTION
Aspects of the application provide the processes for the preparation of Mirabegron, crystalline and amorphous forms thereof.

In an aspect, the application provides a process for the preparation of Mirabegron of Formula I which comprises;
a) reducing nitro compound of Formula II or its salts to obtain amine compound of formula III or its salts;

Formula II Formula III
b) reacting the compound of Formula III or its salts with 2-aminothiazol-4-yl-acetic acid or its acid addition salts to provide Mirabegron of Formula I; and
c) optionally purifying Mirabegron obtained in step (b) to provide pure Mirabegron.
The starting material, compound of Formula II can be produced according to the methods known in art or by following the procedures described in the instant application. Starting materials can be purified according to any of the methods known in the art such as recrystallization, slurrying, chromatographic separation or the like before using.
Step a) 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 a) 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 a) 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 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. 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 (a) 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 (a), or after conventional work up with techniques such as filtration, quenching with a suitable reagent, extraction or the like.
The obtained compound in step (a) 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 b) involves the reaction of the compound of Formula III or its salts with 2-aminothiazol-4-yl-acetic acid or its acid addition salts to provide Mirabegron of Formula I.
In embodiments of step b), 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 acid addition 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.
In embodiment of step b), 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) or a salt thereof, 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 b), 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 b), 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, n-propanol, 2-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, cyclohexane, 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 b), optionally 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 b), the reaction can be carried out at a temperature ranging from about 0°C to about boiling point 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 product of step (b) i.e., Mirabegron or its salts can be isolated as solid 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 if the product obtained from step (b) is a salt of Mirabegron then it can be converted to its free base by using conventional techniques known in the art.
The product of step b), 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.
Mirabegron obtained at step b), can be in any of the known or unknown crystalline forms or mixtures thereof or amorphous form or mixture of crystalline and amorphous form.
Step c) involves the optional purification of Mirabegron obtained from step (b). In embodiments, Mirabegron obtained from step (b) can be further purified to obtain highly pure Mirabegron by the techniques known in the art. 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-antisolvent technique; reprecipitation; slurring in a solvent; or chromatography to enhance its chemical purity or chiral purity.
Any of the solvents listed in step b), 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 c), Mirabegron obtained in step b) can be purified by recrystallizing Mirabegron in a suitable solvent or solvent mixture to obtain pure Mirabegron. Mirabegron can be purified by employing any of the procedures described in the instant application or methods known in the art. The methods known in the art or the methods described in the instant application can be used for the isolation and drying of the Mirabegron after purification.
Mirabegron obtained by the process of this aspect can be in any of the known or unknown crystalline forms or their mixtures or amorphous form or mixture of crystalline and amorphous form. Depending upon the requirement, suitable solvents and conditions can be employed to produce the desired polymorphic form of Mirabegron. For example, recrystallization of Mirabegron in an alcohol solvent with optional seeding can be employed to produce crystalline form alpha.

In another aspect, the application provides a process for the preparation of crystalline alpha form of Mirabegron which comprises the steps of:
a) providing a solution of Mirabegron in a suitable solvent or a mixture thereof
b) optionally seeding the reaction mass of step a) with crystalline alpha form.
c) optionally adding an anti-solvent to the reaction mass of step b) or a).
d) recovering crystalline alpha form of Mirabegron.
Step a) involves providing the solution of Mirabegron in a suitable solvent or a mixture thereof. Mirabegron used in step a) can be obtained by any methods known in the art or by following the procedures described in the present application. Mirabegron used in step a) of this aspect can be in any of the crystalline or amorphous forms known in the literature or mixtures thereof.
Suitable solvent may include, but not limited to alcohols, such as methanol, ethanol, n-propanol, 2-propanol , butanol, pentanol, or the like; ketones, such as acetone, butanone, pentanone, methyl isobutyl ketone, or the like; esters, such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, 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. Preferably alcohols such as 2-propanol, ethanol, methanol or the like.
In embodiments, the solution of Mirabegron can be obtained directly from the synthetic reaction mass containing Mirabegron and a solvent or by combining Mirabegron with the solvent.
In embodiments, a solution of Mirabegron can be obtained by heating a mixture of Mirabegron and the suitable solvent to about 30°C to boiling point of the solvent or solvent mixture.
In embodiments, a solution of Mirabegron can be filtered to make it clear, free of unwanted particles. In embodiments, a solution of Mirabegron can be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution can be optionally treated with an adsorbent material, such as carbon and/or hydrose and/or alumina, to remove colored components, etc., before filtration.
Step b) of this aspect involves optionally seeding the reaction mass of step a) with crystalline alpha form. In embodiments, the solution obtained in step a) can be cooled before addition of seed to suitable temperature.
In embodiments, seed can be added at a suitable temperature and in sufficient quantity which does not dissolve completely in the reaction mass of step a). In embodiments, seed can be added in single lot or multiple lots. The reaction mass may be stirred for sufficient time after adding seed such that the seed crystals can grow.
In embodiments, the reaction mass obtained in step b) can be cooled to suitable temperature and at a cooling suitable rate, after addition of seed. Cooling can be carried out slowly or gradually in a single step or step wise in multiple steps.
Step c) involves the optionally adding an anti-solvent to the reaction mass of step-b) or a). In embodiments, anti-solvent may be added to the reaction mass at suitable temperature and in sufficient quantity to isolate the Mirabegron in maximum yield.
Anti-solvent is the solvent in which Mirabegron has minimum solubility. Suitable anti-solvent that can be used in step c) of this aspect may include, but not limited to water; ethers, such as diethyl ether, diisopropyl ether, t-butyl methyl ether, dibutyl ether, tetrahydrofuran, dioxane, or the like; aliphatic or alicyclic hydrocarbons, such as 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, cyclohexane, or the like; or mixtures thereof. Preferably, the anti-solvent can be water.
In embodiments, addition of anti-solvent can be carried out slowly or rapidly either in a single lot or multiple lots. The reaction mass may be stirred for sufficient time after adding anti-solvent.
Step d) involves the recovering crystalline alpha form of Mirabegron.
In embodiments, crystalline alpha form of Mirabegron can be recovered by the techniques known in the art such as filtration. In embodiments, crystalline alpha form of Mirabegron can be optionally dried at the suitable temperature and pressure for a suitable time to get desired the quality of crystalline alpha form of Mirabegron.

In another aspect, the application provides a process for the preparation of amorphous Mirabegron which comprises the steps of:
a) providing the solution of Mirabegron in a suitable solvent or a mixture thereof.
b) evaporating the solvent of step a) by spray drying.
c) recovering amorphous Mirabegron.
Step a) involves providing the solution of Mirabegron in a suitable solvent.
Mirabegron used in step a) can be obtained by any methods known in the art or by following the procedures described in the present application. Mirabegron used in step a) of this aspect may be in any of the crystalline forms known in the literature or mixtures thereof.
In embodiments, providing the solution of Mirabegron can be carried out by dissolving Mirabegron in a suitable solvent at about 0°C to boiling point of the solvent used.
Suitable solvent may include, but not limited to alcohols, such as methanol, ethanol, n-propanol, 2-propanol, butanol, pentanol, or the like; ketones, such as acetone, butanone, pentanone, methyl isobutyl ketone, or the like; esters, such as ethyl formate, methyl acetate, ethyl acetate, propyl acetate, butyl acetate, methyl propionate, ethyl propionate, 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. Preferably alcohol such as methanol.
In embodiments, the solution of Mirabegron can be obtained directly from the synthetic reaction mass containing Mirabegron and a solvent or by combining Mirabegron with the solvent.
In embodiments, a solution of Mirabegron can be obtained optionally by heating a mixture of Mirabegron and solvent.
In embodiments, a solution of Mirabegron can be filtered to make it clear, free of unwanted particles. In embodiments, the obtained solution can be optionally treated with an adsorbent material, such as carbon and/or hydrose and/or alumina, to remove colored components, etc., before filtration.
Step b) of this aspect can be carried out by evaporating the solvent from the solution of step a) by spray drying.
Evaporation of the solvent can be carried out using a suitable spray drying apparatus according to methods known in art or by following the procedures described in the instant application.
In embodiments, spray drying can be carried out under controlled spray conditions such as inlet temperature, solution pumping rate, nitrogen pressure, etc.
In embodiments, spray drying can be carried out under controlled spray conditions wherein the out let temperature of the spray drying system is stabilized below the glass transition temperature of resulting amorphous form of Mirabegron.
In embodiments, spray drying can be carried out at suitable inlet temperature at about 40°C to boiling point of methanol.
In embodiments, spray drying can be carried out by feeding the solution of step a) at suitable pump rate to evaporate methanol completely. In embodiments, feeding of the solution of step a) at may be carried out at a pumping rate of about 2 mL to 20 mL per minute.
In embodiments, spray drying can be carried out by feeding the solution of step a) under nitrogen pressure of about 3 to 6 kg/cm2.
In embodiments, amorphous form of Mirabegron can be recovered by the techniques known in the art. In embodiments, amorphous form of Mirabegron can be optionally dried at the suitable temperature and pressure for a suitable time to get desired the quality of amorphous form of Mirabegron.
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 10 µm or less than about 25 µm; and d (0.9) is less than about 20 µm or less than about 30 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.

EXAMPLES

Example-1: Preparation of (R)-2-hydroxy-N-(4-nitrophenylethyl)-2-phenylacetamide
A mixture of 2-(4-nitrophenyl) ethyan-1-amine hydrochloride (50 g), (R)-2-hydroxy-2-pheny acetic acid (37.5 g) and dimethyl formamide (150 mL) was taken in a flask and 1-hydroxy benzotriazole (16.5 g) was added at 38°C. Triethylamine (25 g) was added to the above mixture and stirred for 10 minutes at the 34°C. A solution of N, N – dicyclohexylcarbodiimide (61 g) in dimethyl formamide (50 mL) was added slowly to the reaction mass at 35°C in 1 hour. The reaction mass was stirred at 33°C for 4 hours. After completion of the reaction, ethyl acetate (150 mL) was added and stirred for 10 minutes at 38°C. Reaction mass was filtered and washed the filter with ethyl acetate (100 mL). The filtrate was evaporated under vacuum at 58°C to remove the solvent and the residue obtained was charged slowly in 40 minutes to a solution of potassium carbonate (62.5 g) and water (1250 mL) at 38°C. After stirring at 32°C for 15 minutes, the reaction mass was filtered and the product was washed with water (250 mL). The wet compound was combined with toluene (200 mL) and heated to 65°C and stirred at the same temperature for 1 hour. The reaction mass was cooled to 30°C and stirred for 1.5 hours at the same temperature. Product was filtered and washed with toluene (50 mL). The solid was dried at 55°C for 5 hours under vacuum to obtain 66.0 g of title compound.
HPLC Purity: 98.88%

Example-2: Preparation of (R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol monohydrochloride.
Tetrahydrofuron (180 mL) was cooled in a flask to 5°C and sodium borohydride (29.4 g) was added. BF3. etherate (180 mL) was added slowly in 45 minutes to the above mixture at 5°C. A solution of (R)-2-hydroxy-N-(4-nitrophenylethyl)-2-phenylacetamide (60 g) and tetrahydrofuran (120 mL) was dried with molecular sieves and added to the above reaction mixture slowly for 30 minutes at 7°C and stirred at the same temperature for 25 minutes. The reaction mixture was heated to 39°C and stirred for 7.5 hours at the same temperature. After the completion of the reaction, mixture was cooled to 5°C and added slowly in 45 minutes to the solution of hydrochloric acid (90 mL) and water (300 mL) at 5°C. The reaction mixture was heated to 43°C and stirred for 1.5 hours at same temperature. The reaction mixture was cooled to 28°C. Half of the reaction mixture was taken further and evaporated the solvent partially. Reaction mixture was cooled to 5°C and water (150 mL). The pH of the reaction mass was adjusted to 9 with aqueous ammonia (150 mL) and toluene (300 mL) was added. Heated the reaction mixture to 43°C and stirred for 15 minutes at the same temperature. Organic layer was separated and the aqueous layer was extracted to toluene (150 mL). The combined organic layer was washed with water (150 mL) and a part of the organic layer (110 g) was taken further. Solvent was evaporated completely under vacuum at 50°C and dried the compound at same temperature for 30 minutes under vacuum. The crude compound was dissolved in toluene (100 mL) at 50°C and cyclohexane (140 mL) was added slowly in 15 minutes at 45°C. Cooled the reaction mass to 28°C and stirred for 1 hour at the same temperature. Filtered the solid and washed with cyclohexane (40 mL). A part of this wet compound (10 g) was dried at 58°C for 6 hours under vacuum and combined with ethyl acetate (100 mL). Ethyl acetate - HCl (20 ml) was added slowly in 20 minutes to the above mixture at 28°C and stirred at the same temperature for 1.5 hours. The solid was filtered and washed with ethyl acetate (20 mL). The solid was dried at 50°C for 6 hour under vacuum to obtain 9.0 g of title compound.
HPLC purity: 99.84%

Example-3: Preparation of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-1-phenylethanol monohydrochloride.
(R)-2-[[2-(4-nitrophenyl)-ethyl]amino]-1-phenylethanol monohydrochloride (50 g), RaneyTM Nickel (10 g) and methanol (500 mL) were charged into autoclave and stirred under a hydrogen pressure of 4 kg/cm3 for 4.5 hours at 40°C. After the completion of the reaction, hydrogen pressure was released and the reaction mass was cooled to 28°C. The reaction mass was filtered on hyflow, washed with methanol (100 mL). Activated carbon (5 g) was added to the filtrate and stirred for 50 minutes and filtered through hyflow bed. The filtrate was concentrated under vacuum at 40°C to obtain a residue. Ethyl acetate (500 mL) was added to the residue at 40°C and partially distilled ethyl acetate (250 mL) from the solution. The solution was cooled to 28°C and stirred for 1 hour at the same temperature. The obtained slurry was filtered and washed with ethyl acetate (100 mL) and dried under vacuum at 50°C for 5 hours to obtain 41.3 g of title compound.
HPLC purity: 99.6%.

Example-4: Preparation of Mirabegron
Concentrated hydrochloric acid (61.78 g), water (2250 mL) and 2-aminothiazol-4-yl-acetic acid (85.2 g) were added into a round bottom flask at 29°C and stirred for 30minutes. (R)-2-[[2-(4-aminophenyl)ethyl]amino]-1-phenylethanol monohydrochloride (150 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidemonohydro- chloride (EDC.HCl) (132.7 g) were added to the reaction mass at 29°C and stirred for 3 hours at the same temperature. After the completion of the reaction activated carbon (7.5 g) was added and stirred for 30 min at 29°C and filtered through hyflow bed was added to the reaction mass at 28°C and stirred for 30 minutes at the same temperature. Heated the reaction mass to 43°C and added aqueous ammonia solution (7 ml of ammonia diluted in 150 ml of water) slowly in 45 min at same temperature. Stirred the reaction mass at 43°C for 1.5 hours and filtered the solid. The solid was washed with water (30 mL) and filtered. Water (150 mL) was added to the above wet solid and stirred for 45 minutes at 28°C. Filtered the solid and washed with water (50 mL) and cyclohexane (30 mL). The solid was dried under vacuum at 55°C for 6 hours to obtain 11.6 g of title compound.
HPLC purity: 99.78%; XRD: Matching with mixture of alpha and beta forms.

Example-5: Preparation of crystalline form alpha of Mirabegron
Mirabegron (10 g) and Isopropyl alcohol (60 mL) were taken in a round bottom flask and stirred for 15 minutes at 28°C. Neutral alumina (2 g) and water (20 mL) were added to the reaction mass and heated to 57°C and stirred for 30 min at same temperature. Filtered the reaction mass on hyflow bed at 57°C and washed with mixture of Isopropyl alcohol and water (20 mL). The filtrate was cooled to 47°C in a round bottom flask and crystalline form alpha seed material (0.2 g) was added at 41°C. The reaction mass was stirred for 1 hour at 40°C and cooled further. The reaction mass was cooled to 36°C and stirred for 1.5 hours at same temperature. The reaction mass was cooled to 29°C and water (200 mL) was added slowly in 1 hour and stirred for 45 minutes at the same temperature. Solid was filtered and washed with water (20 mL) and cyclohexane (30 mL). The solid was dried under vacuum at 55°C for 7.5 hours to obtain 8.9 g of title compound.

Example-6: Preparation of crystalline form alpha of Mirabegron: Mirabegron (3 g), methanol (12 mL) and water (12 mL) were charged into a round bottom flask at 26°C. The obtained suspension was stirred and heated to 62°C to get a clear solution. The clear solution was cooled to 27°C and stirred for 3 hours at the same temperature. The precipitated solid was collected by filtration and washed with water (5 mL) and dried under vacuum at 70°C for 4 hours to obtain 2.0 g of title compound.

Example-7: Preparation of crystalline form alpha of Mirabegron: Mirabegron (2.0 g) and ethanol (20 mL) were charged into a round bottom flask at 27°C. The obtained suspension was stirred and heated to 75°C to get a clear solution. The solution was cooled to 27°C under stirring in 1 hour and stirred for 2 hours at 27°C. The precipitated solid compound was filtered and dried under vacuum at 50°C for 2.5 hours to obtain 1.2 g of the title compound.

Example-8: Preparation of amorphous Mirabegron: Mirabegron (1.5 kg) and methanol (38 L) were charged into a reactor at 13 °C and stirred to get a solution. The solution was filtered through micro filter to obtain a clear solution and transferred the solution to feed tank of spray drier. The heater of the spray drier system was set with nitrogen pressure of 5.5 Kg/ cm 2 and inlet temperature at 60°C and The spray drier system was stabilized for 15-30 minutes at outlet temperature 38°C, maintaining chamber pressure at 240 mm WC. The reaction mass from the feed tank is feeded into the spray drier through feed pump at outlet temperature of 38°C and chamber pressure of240 mm WC. After the end of total reaction mass, methanol (3 L) was added to the feed tank of spray dryer from and feeded into the spray drier. The solid was unloaded from the spray drier after 30 minutes of completion of feeding of reaction mass and dried the wet solid in vacuum tray drier at 32°C for 9 hours to obtain 1.15 kg of title compound.
HPLC purity: 99.9%; XRD: Amorphous form.
,CLAIMS:We Claim:
1. A process for the preparation of Mirabegron of Formula I which comprises the step of reducing nitro compound of Formula II or its salts to obtain amine compound of formula III or its salts in the presence of a reducing agent;

Formula II Formula III

wherein the reducing agent is selected from the group comprising of palladium-on-carbon; platinum (IV) oxide; Raney™ nickel; 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; alkali metal hydrides such as lithium aluminum hydride; sodium borohydride; sodium dihydro-bis-(2-methoxyethoxy) aluminate solution (VITRIDE®); diisobutyl aluminium hydride; sodium cyanoborohydride; sodium dithionite in alkaline medium; iron oxide hydroxide; hydrazine hydrate; or any combination thereof.
2. A process for the preparation of crystalline alpha form of Mirabegron which comprises the steps of:
a) providing a solution of Mirabegron in a suitable solvent or a mixture thereof;
b) optionally seeding the reaction mass of step a) with crystalline alpha form;
c) optionally adding an anti-solvent to the reaction mass of step b) or a);
d) recovering crystalline alpha form of Mirabegron.
3. A process of claim 2, wherein suitable solvent that may be used at step a) is an alcohol solvent selected from the group comprising of methanol, ethanol, 2-propanol or a mixture thereof.
4. A process of claim 2, wherein anti-solvent that may be used at step c) is water.
5. A process for the preparation of amorphous form of Mirabegron which comprises the steps of:
a) providing the solution of Mirabegron in a suitable solvent or a mixture thereof;
b) evaporating the solvent of step a) by spray drying;
c) recovering amorphous form of Mirabegron.
6. A process of claim 5, wherein suitable solvent that may be used at step a) is methanol.