DESC:FIELD OF INVENTION:
The present invention relates to a method for the preparation of substantially pure mirabegron or its pharmaceutically acceptable salts.

BACKGROUND OF THE INVENTION:
2-(2-Aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl] acetamide of Formula I,

commonly known as mirabegron. Mirabegron is in a class of medications called beta-3 adrenergic agonists.
Mirabegron is used to treat overactive bladder (a condition in which the bladder muscles contract uncontrollably and cause frequent urination, urgent need to urinate, and inability to control urination). It works by relaxing the bladder muscles to prevent urgent, frequent, or uncontrolled urination.
Mirabegron was developed by Astellas Pharma and was approved in the United States on 28th June 2012.
US6346532B1 (herein after referred as '532' patent) first discloses the process for the preparation of 2-(2-aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino} ethyl) phenyl] acetamide and its pharmaceutically acceptable acid addition salts.
The '532' patent discloses two synthetic processes for the preparation of mirabegron.
According to the first process, p-nitro phenethylamine HCl is condensed with (R)-styrene oxide in the presence of NaOH to afford (R)-2-(4-nitrophenethylamino) -1-phenyl ethanol, which is protected as t-Butyl(R)-N-( 2-hydroxy-2-phenyl ethyl)-N-[2-(4-nitrophenyl)ethyl ]carbamate by treatment with Boc2O in THF. The nitro group is reduced by catalytic hydrogenation over Pd/C to afford t-butyl (R)-N-[2-(p-amino phenyl)-N-2-hydroxy-2-phenylethyl]ethyl] carbamate which is finally coupled with 2-(2-amino thiazol-4-yl)acetic acid in the presence of EDC in aqueous solution to obtain tert-butyl (R)- N-[2-[4-[2-(2-amino-thiazol-4-yl)acetamido] phenyl] ethyl]-N-[(2-hydroxy-2-phenyl) ethyl] carbamate, which is further deprotected with hydrochloric acid in a mixture of methanol and ethyl acetate to obtain mirabegron dihydrochloride salt.
Mirabegron dihydrochloride prepared according to this process is further purified by reverse phase column chromatography using water/methanol (2: 1) as eluent to obtain pure mirabegron dihydrochloride salt.
The process disclosed in the said '532' patent involves the usage of reverse phase column chromatography technique for the purification of dihydrochloride salt of mirabegron, which is not economical and feasible on commercial scale.
Another synthetic route has also been proposed in US’532, however, not exemplified.
According to the process disclosed in US7342117, p-nitrophenethylamine hydrochloride is condensed with (R)-mandelic acid utilizing EDC and HOBt to produce (R)-N-(4-nitrophenethyl)-2-hydroxy-2-phenylacetamide, which is reduced to (R)-2-(4-nitrophenethylamino)-1-phenylethanol by means of borane-tetrahydrofuran complex in 1,3-dimethyl-2-imidazolinone/THF. The nitro group of (R)-2-(4-nitrophenethylamino)-1-phenylethanol is reduced by catalytic hydrogenation over Pd/C to produce (R)-2-(4-aminophenethylamino)-1-phenylethanol, which is finally coupled with 2-(2-aminothiazol-4-yl) acetic acid in the presence of EDC and Con. HCl in aqueous solution to obtain mirabegron.
CN103193730A discloses the process for the preparation of mirabegron, which comprises of protection the amino group of 2-amino-4-thiazoleacetic acid, followed by condensation reaction with 4-amino benzene ethanol, oxidation, and reductive amination with (R)-2-amino-2-benzene ethanol in the presence of reducing agent and removing the protecting group to give mirabegron.

CN103387500A discloses the process for the preparation of mirabegron, by ring opening of (R)-phenyloxirane with N-benzyl-N-[2-(4-nitrophenyl)ethyl]amine in isopropanol to afford (R)-2-[[[2-(4-nitrophenyl)ethyl] (phenylmethyl) amino]methyl] benzenemethanol, which undergoes hydrogenation with Pd/C and acylation with 2-amino-4-thiazolyl acetic acid.

International Patent Application Publication No. WO 2014132270A2 discloses process for the preparation of 2-(2-aminothiazol-4-yl)- N-[4-(2- {[(2R)-2-hydroxy-2-phenylethyl]amino} ethyl)phenyl]acetamide monohydrochloride by amidation reaction of (R)-2-hydroxy-2-phenylacetic acid with 2-(4-nitrophenyl)ethylamine hydrochloride to afford (R)-a-hydroxy-N-[2-(4-nitrophenyl)ethyl]benzeneacetamide, which underwent reduction, acylation with 2-(2-aminothiazol-4-yl)acetic acid to obtain mirabegron.
However mirabegron prepared according to this process is found to be contaminated with dehydroxy impurities A, B and C.
The dehydroxy impurities formed during reaction are as follows.

Regulatory authorities worldwide require that drug manufacturers isolate, identify and characterize the impurities in their products. Moreover, it is required to control the levels of these impurities in the final drug compound obtained by the manufacturing process and to ensure that the impurity is present in the lowest possible levels, even if structure determination is not possible.

Providing substantially pure mirabegron free from these and other impurities and processes for preparing such pure mirabegron would be a significant contribution to the art.

Therefore, there is a need to develop industrially feasible process for preparing mirabegron wherein the dehydroxy impurities A, B and C are controlled and removed from the final product.

OBJECTIVE OF THE INVENTION:
The primary object of the present invention is to provide an improved and commercially viable process for the preparation of mirabegron of formula I or its pharmaceutically acceptable salts thereof, wherein the dehydroxy impurities A, B and C are efficiently controlled and removed from the final product.
Another object of the present invention is to provide a process for preparation of mirabegron of formula (I) or its pharmaceutically acceptable salts, which is substantially free from dehydroxy impurities, and thereby eliminating the required purification steps and further making the process cost effective and efficient.
Yet another object of the present invention is to minimize the formation of dehydroxy impurity which forms during the preparation of intermediates of mirabegron or its pharmaceutically acceptable salts.

SUMMARY OF THE INVENTION:
According to one aspect, provided herein is an improved process for the preparation of mirabegron of formula I or its pharmaceutically acceptable salt thereof having dehydroxy impurity C, less than 0.1%;

which comprises steps of:
a) coupling D(-)-mandelic Acid-(VII);

with 2-(4-nitro phenyl) ethyl amine - (VI);

using a suitable coupling agent and additive in a suitable solvent, optionally in presence of a suitable base to obtain (R)-N-(4-nitrophenethyl)-2-hydroxy-2-phenylacetamide - (V);

b) reducing (R)-N-(4-nitrophenethyl)-2-hydroxy-2-phenylacetamide - (V) characterized in that the reaction is carried out in presence of a reducing agent and acid catalyst in a suitable solvent to obtain (R)-2-(4-nitrophenethylamino)-1-phenylethanol. HCl - (IV);

c) reducing (R)-2-(4-nitrophenethylamino)-1-phenylethanol. HCl - (IV) in presence of a reducing agent in a suitable solvent to obtain (R)-2-(4-aminophenethylamino)-1-phenylethanol - (III);

d) condensing (R)-2-(4-aminophenethylamino)-1-phenylethanol - (III) with
2-amino thiazol-4-ylacetic acid-(II);

using a suitable coupling agent in presence of acid catalyst with or without solvent to obtain mirabegron (I); and

e) optionally purifying mirabegron (I).

Another aspect of the present invention relates to a process for the preparation of mirabegron of formula (I), which is free from dehydroxy impurities (IMP-A, IMP-B, IMP-C) and thereby eliminating the required purification steps and further making the process cost effective and efficient.

In another aspect of the present invention mirabegron obtained by the process of the present invention may be further converted to the pharmaceutically acceptable salts thereof.

In yet another aspect of the present invention there is provided a pharmaceutical formulation comprising a therapeutically effective amount of mirabegron of formula I or its pharmaceutically acceptable salts thereof, and at least one pharmaceutically acceptable excipient.

Further aspect of the present invention provides use of mirabegron of formula I or its pharmaceutically acceptable salts thereof, obtainable by the process of the present invention for the manufacture of therapeutic agent.

In yet another aspect of the present invention there is provided use of mirabegron of formula I or its pharmaceutically acceptable salts thereof, obtainable by the process of the present invention, for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency and urinary frequency.

In yet another aspect of the present invention there is provided a method for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency and urinary frequency, comprising administering the mirabegron of formula I or its pharmaceutically acceptable salts thereof, obtainable by a process of the present invention.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention provides an efficient synthetic route for producing mirabegron or its pharmaceutically acceptable salts in high yield and high purity.

In particular, the process of the present invention efficiently converts the substrate to the desired product and reducees or eliminates side reactions that give rise to impurities in the final product. Reduction in the levels of dehydroxy impurities A, B and C ultimately increases the overall yield and purity of mirabegron or its pharmaceutically acceptable salt thereby complying with pharmacopeial requirements.

In an embodiment of the present invention, there is provided an improved synthesis of mirabegron, as depicted below in scheme I.

The term "high purity” used in the present invention is in the context of mirabegron or its pharmaceutically acceptable salts having purity more than 99 %, preferably more than 99.5 %. The impurity contents described herein relate only to the total of mirabegron and related compound impurities, as determined by high performance liquid chromatography ("HPLC"), and any residual solvent impurities.

The term " substantially pure” used in the present invention is mirabegron or its pharmaceutically acceptable salts having an HPLC purity greater than 99.5% and having dehydroxy impurity C, less than 0.1%.

Mirabegron or its pharmaceutically acceptable salts obtained by the process disclosed herein preferably contains dehydroxy impurity in an amount of less than about 0.25%, more preferably less than 0.15%.

According to an embodiment of the invention, mirabegron having about 0.002% to about 0.2%, or to about 0.15 %, by weight of the dehydroxy impurity A,
no greater than about 0.1% by weight of the dehydroxy impurity B and no greater than about 0.1% by weight of the dehydroxy impurity C, as determined by HPLC, is provided. Mirabegron is considered to be "substantially free" of a particular impurity if that impurity is present at concentrations no greater than about 0.1 % by weight, as determined by HPLC.

In one embodiment as depicted in step-I of scheme-I, D (-)-mandelic Acid-(VII) is coupled with 2-(4-nitro phenyl) ethyl amine or its hydrochloride salt (VI) using a suitable coupling agent and additive in a suitable solvent, optionally in presence of a suitable base to obtain (R)-N-(4-nitrophenethyl)-2-hydroxy-2-phenylacetamide - (V).

Suitable coupling agent employed in step-I can be selected from but not limited to dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), N-tert-butyl-N'-methylcarbodiimide (TBMC), and N-tert-butyl-N'-ethylcarbodiimide (TBEC), 1, 1’-Carbonyldiimidazole (CDI), triphosgene, phosgene, diphosgene, carbonildiimidazole, chlorothionyl imidazole, thionyl diimidazole. Preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCI) is used.

The additive used in step-I is selected from the group of N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 1 -hydroxybenzotriazole (HOBT), 6-chloro-1 -hydroxybenzotriazole (6-CI-HOBT), 1 -hydroxy-7- azabenzotriazole (HOAt) and 3-hydroxy-4-oxo-3,4-dihydro-1 ,2,3-benzotriazine (HODhbt) or hydrates thereof.

The base used in step-I for the coupling reaction is selected from N-Methylmorpholine (NMM), di-isopropylethylamine (DIPEA) or Hunig base, triethylamine (TEA) and the like.
The suitable temperature for step-I is room temperature, for example, is about 20°C to about 50°C.
The solvent employed in step-I include but are not limited to ester such as ethyl acetate, isopropyl acetate, 2-methoxyethyl acetate and the like; nitrile such as acetonitrile, propionitrile, and the like, chlorinated solvent such as dichloromethane, chlorobenzene and the like; formamides such as dimethyl formamide, dimethyl acetamide and the like; ethers such as diethyl ether, diisopropyl ether, ethyl tert- butyl ether, 1 ,4-dioxane, THF, and the like; alcohols such as methanol, ethanol, propanol, butanol, glycerol, propylene glycol; polyglycols such as polyethylene glycol 200, polyethylene glycol 300 and polyethylene glycol 400; pyrrolidones such as N-methyl pyrrolidone and 2-pyrrolidone glycol ethers such as propylene glycol monomethyl ether, dipropylene glycol monomethyl ether and diethylene glycol ethyl ether, ?,?,-dimethyl acetamide, PEG 300, propylene glycol; dimethyl sulfoxide, N-methyl pyrrolidine; or mixtures thereof.
Yet another embodiment of the present invention as depicted in step II of scheme-I wherein the process comprises of reducing (R)-N-(4-nitrophenethyl)-2-hydroxy-2-phenylacetamide - (V) in presence of a reducing agent and acid catalyst in a suitable solvent to obtain (R)-2-(4-nitrophenethylamino)-1-phenylethanol. HCl - (IV).

Suitable reducing agent for step –II is selected from but not limited to noble metal catalyst such as ruthenium, rhodium, palladium, silver, osmium, iridium, platinum and gold which are supported on various materials such as activated carbon, calcium carbonate, silicon dioxide, triphenyl phosphine; nickel based catalyst such as Raney nickel, Urushibara nickel; zinc dust, palladium acetate, Iron, alumina, silica, calcium carbonate, barium sulphate, zeolites, Fe in acidic media like NH4C1 or HCl or acetic acid, Sn in acidic media like HCl, Zn dust, Zn in acidic media like HCl or NH4CI or acetic acid, stannous chloride (SnCl2), LiAlH4, LiBH4, diborane, borane-THF complex, hydrazine hydrate, sodium dithionate, sodium amalgam and the like.

Suitable acid catalyst for step –II is selected from but not limited to hydrochloric acid, hydrobromic acid, methanesulfonic acid, ethane sulphonic acid , propane sulphonic acid, p-toluene sulfonic acid, Lewis acid such as boron trifluoride (BF3), aluminum chloride (AICI3), or titanium chloride (TiCI) and the like.
The inventors of the present invention surprisingly found that the use of acid catalyst during the reduction of (R)-N-(4-nitrophenethyl)-2-hydroxy-2-phenylacetamide of formula (V) effectively and substantially reduces the dehydroxy impurity A thereby reducing the further dehydroxy impurities B and C in subsequent process steps. The reduction of these impurities substantially enhances the purity and yield of the final product, mirabegron or its pharmaceutically acceptable salts. The mirabegron or its pharmaceutically acceptable salts obtained in accordance with the present invention meets the pharmacopeial requirements without involving extensive purifications unlike in prior art processes.
One preferable acid catalyst in accordance with the invention is methanesulfonic acid.
Suitable solvent for step –II is selected from alcoholic solvents, ether solvents, ester solvents, polar solvents, hydrocarbon solvents or mixtures thereof.

The reaction is carried out at a temperature in the range of 25°C to reflux temperature of the solvents used.

(R)-2-(4-nitrophenethylamino)-1-phenylethanol.HCl obtained by the process is having dehydroxy impurity A 0.2% as compared to the prior art process wherein the dehydroxy impurity is in the range of 0.8 % to 1.5%.

Yet another embodiment of the present invention as depicted in step III of scheme-I wherein the process comprises of reducing (R)-2-(4-nitrophenethylamino)-1-phenylethanol.HCl - (IV) in presence of a reducing agent in a suitable solvent to obtain (R)-2-(4-aminophenethylamino)-1-phenylethanol - (III).

Suitable reducing agent in step –III is selected from but not limited to noble metal catalyst such as ruthenium, rhodium, palladium, silver, osmium, iridium, platinum and gold which are supported on various materials such as activated carbon, calcium carbonate, silicon dioxide, triphenyl phosphine; nickel based catalyst such as Raney nickel, Urushibara nickel; zinc dust, palladium acetate, Iron, alumina, silica, calcium carbonate, barium sulphate, zeolites, Fe in acidic media like NH4C1 or HCl or acetic acid, Sn in acidic media like HCl, Zn dust, Zn in acidic media like HCl or NH4CI or acetic acid, stannous chloride (SnCl2), LiAlH4, LiBH4, diborane, borane-THF complex, hydrazine hydrate, sodium dithionate, sodium amalgam and the like.

Suitable solvent or solvent mixture employed for step III is selected from the group comprising C1-C5 alcohols, ketones such as acetone, water and like. Preferable solvent is water.

The step III reaction is carried out at a temperature in the range of 25°C to 50°C.

(R)-2-(4-aminophenethylamino)-1-phenylethanol - (III) obtained by the process of the present invention is having dehydroxy impurity B, less than 0.2% as compared to the prior art process wherein the dehydroxy impurity B is in the range of 0.8 % to 0.9%.

Yet another embodiment of the present invention as depicted in step IV of scheme-I wherein the process comprises of condensing (R)-2-(4-aminophenethylamino)-1-phenylethanol - (III) with 2-amino thiazol-4-ylacetic acid-(II) using coupling agent in presence of acid catalyst with or without solvent to obtain mirabegron (I).

Suitable coupling agent employed for step IV is selected from but not limited to dicyclohexylcarbodiimide (DCC), N, N'-diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), N-tert-butyl-N'-methylcarbodiimide (TBMC), and N-tert-butyl-N'-ethylcarbodiimide (TBEC), 1, 1’-Carbonyldiimidazole (CDI), triphosgene, phosgene, diphosgene, carbonildiimidazole, chlorothionyl imidazole, thionyl diimidazole. Preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCI) is used.

Suitable acid catalyst for step –IV is selected from but not limited to hydrochloric acid, hydrobromic acid, acetic acid, formic acid, nitric acid, phosphoric acid propionic acid, oxalic acid, malonic acid, succinic acid, methanesulfonic acid, p-toluene sulfonic acid, Lewis acid such as boron trifluoride (BF3), aluminum chloride (AICI3), or titanium chloride (TiCI4) and the like.
Suitable solvent for step –IV is selected from alcoholic solvents, ether solvents, ester solvents, polar solvents, hydrocarbon solvents or mixtures thereof.

The step IV reaction is carried out at a temperature in the range of 25°C to 50°C.

The processes of the present invention further provides substantially pure mirabegron of formula I having an HPLC purity greater than 99.5% and having dehydroxy impurity C, less than 0.1%.
Mirabegron obtained by the process of the present invention may be further converted to the pharmaceutically acceptable salts by treating mirabegron with a corresponding acid in a suitable solvent.

Suitable pharmaceutically acceptable salts of mirabegron include salts of mirabegron with acetic acid, formic acid, benzoic acid, fumaric acid, benzoic acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid propionic acid, oxalic acid, malonic acid, succinic acid, lactic acid, malic acid, carbonic acid, picric acid, glutamic acid, and the like.

The present invention also relates to a pharmaceutical composition comprising mirabegron of formula I prepared by the process of the present invention and a pharmaceutically acceptable carrier or diluent.

The phrase “pharmaceutically acceptable” means the carrier, diluent or excipient must be compatible with the active and other ingredients of the formulation and not deleterious to the recipient thereof.

The present invention also relates to the use of mirabegron of formula I or pharmaceutically acceptable salts thereof, obtainable by the process of the present invention for the manufacture of therapeutic agent.
The present invention also provides methods of using pharmaceutical formulations for treating overactive bladder (OAB) with symptoms of urinary incontinence, urgency and urinary frequency.

The detailed experimental parameters suitable for this process of making mirabegron are provided by the following examples, which are intended to be illustrative and not limiting of all possible aspects of the invention.

Examples:
Example 1: Preparation (R)-N-(4-nitrophenethyl)-2-hydroxy-2-phenylacetamide
To a reaction mixture of 10 gm of 2-(4-nitrophenyl) ethyl amine hydrochloride in 90ml polyethylene glycol at 25 to 30oC, charged 7.6ml triethylamine, 0.75gm 1-hydroxy benzotrizole and 11.4 gm EDC.HCl. Stirred at 25 to 30oC. 8.3 gm (D)-mandelic acid was charged to the reaction mixture. Stirred for 16 hours at 25-300C. 200 ml purified water was charged to the reaction mixture and stirred for 15 hours at 25-30oC. The obtained solid was filtered and washed with 50 ml water. The obtained solid was treated with 10% HCl solution, followed by treatment with 10% potassium carbonate solution, and washed with water. The obtained solid was dried.
Yield = 12gm
Efficiency = 80.8 %

Example 2: Preparation (R)-N-(4-nitrophenethyl)-2-hydroxy-2-phenylacetamide
To a reaction mixture of 10 gm 2-(4-nitrophenyl) ethyl amine Hydrochloride in 90ml THF at 25 to 30oC, charged 7.6 ml triethylamine, 0.75 gm 1-hydroxy benzotrizole, and 11.4 gm EDC.HCl. Stirred at 25 to 30oC. 8.3 gm (D)-mandelic acid was charged to the reaction mixture. Stirred for 4 hours at 25-30oC. 200 ml purified water was charged to the reaction mixture at 25-30oC. THF was distilled at 75oC completely at atmospheric temperature. The reaction mixture was cooled to 25-30°C and stirred for 1 to 3 hours. Cooled and stirred at 10oC. The obtained solid was filtered and washed with 50ml water.
Yield = 14gms
Efficiency = 94.4%

Example 3: Preparation (R)-N-(4-nitrophenethyl)-2-hydroxy-2-phenylacetamide
To a reaction mixture of 10 gm 2-(4-Nitrophenyl) ethyl amine Hydrochloride in 90ml dichloromethane at 25 to 30oC, charged 7.6ml triethylamine and 0.75gm 1-Hydroxy benzotrizole, 11.4 gm EDC.HCl. Stirred at 25 to 30oC. 8.3 gm (D)-Mandelic acid was charged to the reaction mixture. Stirred for 4 hrs at 25-300C. Reaction was monitored by TLC. 100ml purified water was charged to the reaction mixture and layers were separated. The obtained organic layer was washed with 10% HCl solution, followed by treatment with 10% potassium carbonate solution, and washed with water. The obtained organic layer was distilled to get solids.
Yield = 13gm
Efficiency = 88.0%
Purity by HPLC = 90.2 %, Dehydroxy impurity A = 0.29%

Example 4: Preparation of (R)-2-(4-nitrophenethylamino)-1-phenylethanol HCl
To a reaction mixture of 180g (R)-N-(4-nitrophenethyl)-2-hydroxy-2-phenylacetamide in 1500 ml of THF at 0 to 5oC, charged 31.5 gm sodium borohydride and 11ml methane sulphonic acid followed by drop wise addition of 105.3 ml of boron trifluoro diethyl etherate (BF3 Etherate) below 10oC. The reaction mixture was heated to 65-70oC and stirred for 3 hours. Reaction mixture was cooled to 5 to 10oC and quenched with drop wise addition of 540 ml 10% HCl solution and stirred for 30 minutes. The pH of the reaction mixture was adjusted to 8-9 using 20% sodium hydroxide solution. The reaction mixture was stirred for 1 hour at 25-30oC and separated layers. Charged 1800 ml of water and distilled out THF at 65-70oC. The reaction mixture was cooled to 25-30oC and charged 900 ml methanol to reaction mixture. The pH was adjusted to 1-2 by using conc. HCl at 25-300C. The reaction mixture was refluxed for 15 minutes. The reaction mixture was cooled and the solid was filtered. The filtered solid was washed with water and dried under vacuum.
Yield= 162 gms
Efficiency = 84.1%
Purity by HPLC = 94.6 %, Dehydroxy impurityA = 0.12%

Example 5: Preparation of (R)-2-(4-aminophenethylamino)-1-phenylethanol
To a reaction mixture of 160 gm (R)-2-(4-nitrophenethylamino)-1-phenylethanol HCl in 1600 ml of water, charged 8.0 gm of 10% wet Pd/C. The reaction mixture was hydrogenated at 5 to 100C under 3 Kg pressure of H2 atmosphere for 2 hours. . The reaction mixture was filtered through Hyflo bed to remove the catalyst. The pH of the filtrate was adjusted using 10% sodium hydroxide solution at 25-300C. 800 ml of methanol was charged to the reaction mixture. The reaction mixture was refluxed for 30 minutes. The reaction mixture was cooled and filtered. Washed with water. Material obtained was purified using Methanol: water. Dried under vacuum.

Yield: 120 gm
Efficiency = 94.5 %
Purity by HPLC = 99.6%, Dehydroxy impurity B= 0.016%

Example 6: Preparation of Mirabegron
To a reaction mixture of 100g (R)-2-(4-aminophenethylamino)-1-phenylethanol, charged Conc. HCl to adjust pH to 2-3 at 25 to 30oC. To the reaction mixture charged 86.4 gm of 2-aminothiazol-4-yl acetic acid and 96.0 gm of EDC.HCl at 25 to 30°C. The reaction mixture was stirred for 2 hours at 25-30oC. The pH of the reaction mixture was adjusted to 10-11by adding Liq. ammonia. The solid was filtered and charged along with methanol. Heated the reaction mixture to 50 to 55oC. To the clear solution charged 10 gm activated charcoal & Scavenger carbon and filtered hot. Methanol was distilled under vacuum. To the solid added 400 ml methanol and 400.0ml distilled water. Heated the reaction mixture to 80-85°C for 30 minutes & cooled. The solid obtained was filtered and washed with water and dried at 40 to 45°C under vacuum.
Yield = 135.0 gm
Efficiency = 87.6 %
Purity by HPLC = 99.7%, Dehydroxy impurity C= 0.012%
Comparative data of the present invention vis-à-vis WO 2014132270A2 as shown below in table 1 clearly indicates that the use of the acid catalyst in the reduction of compound of formula V as described in the present invention provides highly pure Mirabegron with low content of Dehydroxy impurities A, B and C over the teachings of WO’270.
Dehydroxy impurity Purity by HPLC
Mira Nitroamine
Base
(V) Present invention (example 3) 0.295 90.161
WO 2014132270A2 (example 1) 0.832 76.429
Mira Nitroamine HCl
(IV) Present invention(example 4)
0.124 94.677
WO 2014132270A2 (example 2) 0.379 94.372
Mira Amine base
(III) Present invention(example 5)
0.016% 99.6%
WO 2014132270A2(example 4)
0.922 80.04
Mira amine base pure
(I) Present invention (example 6)
0.016 99.649
WO 2014132270A2 (example 14) 0.804 93.661

,CLAIMS:
1. An improved process for the preparation of mirabegron or its pharmaceutically acceptable salts having dehydroxy impurity C, less than 0.1%

comprising the steps of ;

a) reducing (R)-N-(4-nitrophenethyl)-2-hydroxy-2-phenylacetamide (V) characterized in that the reaction is carried out in presence of a reducing agent and an acid catalyst in a suitable solvent to obtain (R)-2-(4-nitrophenethylamino)-1-phenylethanol. HCl - (IV);

b) reducing (R)-2-(4-nitrophenethylamino)-1-phenylethanol. HCl - (IV) in presence of a reducing agent in a suitable solvent at a temperature in the range of 25°C to 50°C to obtain (R)-2-(4-aminophenethylamino)-1-phenylethanol - (III);

c) condensing (R)-2-(4-aminophenethylamino)-1-phenylethanol - (III) with
2-amino thiazol-4-ylacetic acid-(II);

using a suitable coupling agent in presence of acid catalyst with or without solvent at a temperature in the range of 25°C to 50°C to obtain mirabegron (I); and
d) optionally purifying mirabegron (I) and further converting into pharmaceutical salt.

2. The process according to claim 1, wherein, the suitable coupling agent employed in step-I and step-IV can be selected from the group consisting of dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDAC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (EDC), N-tert-butyl-N'-methylcarbodiimide (TBMC), and N-tert-butyl-N'-ethylcarbodiimide (TBEC), 1, 1’-Carbonyldiimidazole (CDI), triphosgene, phosgene, diphosgene, carbonildiimidazole, chlorothionyl imidazole, thionyl diimidazole, preferably 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC-HCI).

3. The process according to claim 1, wherein, the additive used in step-I is selected from the group consisting of N-hydroxysuccinimide (HOSu), N-hydroxy-5-norbornene-2,3-dicarboximide (HONB), 1 -hydroxybenzotriazole (HOBT), 6-chloro-1 -hydroxybenzotriazole (6-CI-HOBT), 1 -hydroxy-7- azabenzotriazole (HOAt) and 3-hydroxy-4-oxo-3,4-dihydro-1 ,2,3-benzotriazine (HODhbt) or hydrates thereof.

4. The process according to claim 1, wherein, the base used in step-I for the coupling reaction is selected from N-Methylmorpholine (NMM), di-isopropylethylamine (DIPEA) or Hunig base and triethylamine (TEA).

5. The process according to claim 1, wherein, the solvent employed in step-I include ester such as ethyl acetate, isopropyl acetate, 2-methoxyethyl acetate and the like; nitrile such as acetonitrile, propionitrile, and the like, chlorinated solvent such as dichloromethane, chlorobenzene and the like; formamides such as dimethyl formamide, dimethyl acetamide and the like; ethers such as diethyl ether, diisopropyl ether, ethyl tert- butyl ether, 1 ,4-dioxane, THF, and the like; alcohols such as methanol, ethanol, propanol, butanol, glycerol, propylene glycol; polyglycols such as polyethylene glycol 200, polyethylene glycol 300 and polyethylene glycol 400; pyrrolihdones such as N-methyl pyrrolidone and 2-pyrrolidone glycol ethers such as propylene glycol monomethyl ether, dipropylene glycol monomethyl ether and diethylene glycol ethyl ether, ?,?,-dimethyl acetamide, PEG 300, propylene glycol; dimethyl sulfoxide, N-methyl pyrrolidine; or mixtures thereof.

6. The process according to claim 1, wherein, the suitable acid catalyst for step –II is selected from the group consisting of hydrochloric acid, hydrobromic acid, methanesulfonic acid, ethane sulphonic acid , propane sulphonic acid, p-toluene sulfonic acid, Lewis acid such as boron trifluoride (BF3), aluminum chloride (AICI3), or titanium chloride (TiCI4).

7. The process according to claim 1, wherein, the reaction of step-II is carried out at a temperature in the range of 25°C to reflux temperature of the solvents used.
8. The process according to claim 1, wherein, the suitable solvent or solvent mixture employed for step III is selected from the group comprising C1-C5 alcohols, ketones such as acetone, water and like.

9. The process according to claim 1, wherein, the suitable reducing agent used for step –II and step-III are selected from the group consisting of noble metal catalyst such as ruthenium, rhodium, palladium, silver, osmium, iridium, platinum and gold which are supported on various materials such as activated carbon, calcium carbonate, silicon dioxide, triphenyl phosphine; nickel based catalyst such as Raney nickel, Urushibara nickel; zinc dust, palladium acetate, Iron, alumina, silica, calcium carbonate, barium sulphate, zeolites, Fe in acidic media like NH4C1 or HCl or acetic acid, Sn in acidic media like HCl, Zn dust, Zn in acidic media like HCl or NH4CI or acetic acid, stannous chloride (SnCl2), LiAlH4, LiBH4, diborane, borane-THF complex, hydrazine hydrate, sodium dithionate or sodium amalgam.

10. The process according to claim 1, wherein, the suitable acid catalyst for step –IV is selected from the group consisting of hydrochloric acid, hydrobromic acid, acetic acid, formic acid, nitric acid, phosphoric acid propionic acid, oxalic acid, malonic acid, succinic acid, methanesulfonic acid, p-toluene sulfonic acid, Lewis acid such as boron trifluoride (BF3), aluminum chloride (AICI3), or titanium chloride (TiCI).

11. The process according to claim 1, wherein, the suitable solvent for step II and step–IV is selected from the group consisting of alcoholic solvents, ether solvents, ester solvents, polar solvents, hydrocarbon solvents or mixtures thereof.

12. The process according to claim 1, wherein, the purification of Mirabegron comprises dissolving Mirabegron with C1 to C5 alcohols under heating at 50 to 60C to obtain clear solution; filtering the solution over charcoal followed by distilling the alcohol and crystallizing the Mirabegron from mixture of alcohol and water.

13. The process according to claim 1, wherein, the step of conversion of mirabegron into pharmaceutical salt comprise treating the mirabegron with suitable acid selected from the group consisting of acetic acid, formic acid, benzoic acid, fumaric acid, benzoic acid, maleic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluene sulfonic acid, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid propionic acid, oxalic acid, malonic acid, succinic acid, lactic acid, malic acid, carbonic acid, picric acid or glutamic acid, to obtain respective pharmaceutical salt.

14. A pharmaceutical composition comprising mirabegron or its pharmaceutically acceptable salts having dehydroxy impurity C, less than 0.1% in association with at least one pharmaceutical excipient.

15. The process according to claim 1, wherein, the (R)-N-(4-nitrophenethyl)-2-hydroxy-2-phenylacetamide (V) is prepared by coupling D(-)-mandelic Acid-(VII);

with 2-(4-nitro phenyl) ethyl amine - (VI);

using a suitable coupling agent and additive in a suitable solvent, optionally in presence of a suitable base at a temperature of about 20°C to about 50°C.

16. An improved process for the preparation of mirabegron or its pharmaceutically acceptable salts having dehydroxy impurity C, less than 0.1% comprising;

reducing (R)-N-(4-nitrophenethyl)-2-hydroxy-2-phenylacetamide (V) characterized in that the reaction is carried out in presence of a reducing agent and an acid catalyst in a suitable solvent to obtain (R)-2-(4-nitrophenethylamino)-1-phenylethanol. HCl - (IV).