DESC:FIELD OF THE INVENTION
The present invention relates to an eco-friendly and efficient process for preparing mirabegron and its key intermediate.
In particular aspect of present invention relates to an improved process for the preparation of compound of Formula 2 i.e. (2R)-2-hydroxy-N-[2-nitrophenyl) ethyl]-2-phenylacetamide or its salt.

Formula 2

The compound of Formula 2 is a key intermediate for the preparation of mirabegron.
BACKGROUND OF THE INVENTION
Mirabegron chemically known as 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide and represented by compound of Formula 1.

Formula 1

Mirabegron is used in the treatment of overactive bladder. Mirabegron, a selective beta 3-adrenoceptor agonist, was authorized for the treatment of overactive bladder (OAB). It was developed and marketed by Astellas Pharma under the brand name MYRBETRIQTM.
US patent no. 6,346,532 discloses mirabegron or a salt thereof and process for its preparation. Specifically it discloses mirabegron dihydrochloride which is highly hygroscopic and unstable.
US patent no. 7,342,117 discloses synthesis of mirabegron and process for preparation as represented by the below scheme:

The compound of Formula 2 is an important indermediate of mirabegron and as shown above dimethylformamide (DMF) is used as solvent for preparing compound of Formula 2 along with N-ethyl-N'-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (EDC) in presence of 1-hydroxybenzotriazole (HOBt) as coupling additives.
The said process for preparing Formula 2 is suffering from drawback such as use of coupling additives or coupling/condensing agent and use of high volume of solvent for reaction and workup.
Indian application publication no. 201621009117 disclosed methodology for preparing compound of Formula 2 as shown schematically by the below Scheme.

condensing a compound of Formula 5 with a compound of Formula 6 or its acid addition salt in presence of water as solvent, suitable base and suitable coupling reagent optionally along with suitable coupling additives to obtain compound of Formula 2. Wherein after the reaction completion, the compound of Formula 2 is directly isolated from the reaction mass by precipitating with water. However, the said Indian application does not exemplify the said process.
The above drawback viz. use of coupling additives or coupling/condensing agent overcome by the following references. Even though, the said below references are also suffering from another drawback such as use of high volume solvent during reaction and workup.
Chinese patent no. 109456277 disclosed a process for the preparation of mirabegron as shown schematically by the below scheme.

In the said process xylene is used as a solvent and high temperature (140 ?) is required for completing the reaction. After the completion of reaction, dichloromethane is added and clear solution washed with 5% diluted hydrochloric acid (500mL x 2) and then 5% sodium hydroxide (500mL x 2) respectively, drying an organic phase by anhydrous sodium sulfate, removing dichloromethane under reduced pressure to obtain Formula 2. Further, the compound of Formula 2 is converted to mirabegron as per the above scheme.
Indian patent no. 330350 disclosed a process for the preparation of mirabegron as shown schematically by the below scheme.

In the said process acetonitrile is used as a solvent. After the completion of reaction, the reaction mixture is diluted with ethylacetate and aqueous hydrochloric acid. The separated organic layer is washed with aqueous hydrochloric acid followed by washing with 5% aqueous sodium hydroxide solution and brine. The organic layer is concentrated and residue is crystallized with toluene to obtain compound of Formula 2. Further, the compound of Formula 2 is converted to mirabegron as per the above scheme.

Therefore, in view of the above prior art references, there is an urgent need to develop an eco-friendly and industrially efficient process which overcome the drawbacks as disclosed in the prior art related to preparation of mirabegron.
The present inventors have developed an efficient process for synthesis of mirabegron, wherein the reaction for preparing compound of Formula 2 is carried out in absence of solvent.

Furthermore the compound of Formula 2 is isolated directly from reaction mixture without extraction by using solvent, thereby making the process eco- friendly and industrially efficient.

OBJECTIVE OF THE INVENTION
The principal object of the present invention is to provide an eco-friendly and efficient process for preparing mirabegron and its key intermediate.
Another object of the present invention is to provide an improved process for the preparation of mirabegron, wherein compound of Formula 2 or salt thereof is prepared without using solvent during the reaction or workup.

SUMMARY OF THE INVENTION
The present invention provides an eco-friendly and efficient process for preparing mirabegron of Formula 1 or its pharmaceutically acceptable salt,

Formula 1

comprises:
i) coupling a compound of Formula 5,

Formula 5

with a compound of Formula 6 or salt,

Formula 6
in presence of boron reagent and suitable base to give compound of Formula 2;

Formula 2

ii) reducing the compound of Formula 2 with suitable reducing reagent in suitable solvent to give the compound of Formula 3 or acid addition salt thereof;

Formula 3

iii) hydrogenating the compound of Formula 3 or acid addition salt thereof in suitable solvent using hydrogenation catalyst in presence of hydrogen to give compound of Formula 3a or acid addition salt thereof and

Formula 3a

iv) coupling the compound of Formula 3a or acid addition salt thereof with compound of Formula 4 or its acid addition salt thereof,

Formula 4

in suitable solvent in presence of suitable coupling agent to afford mirabegron of Formula l or its pharmaceutically acceptable salt.

One aspect of the present invention provides an eco-friendly and efficient process for preparing mirabegron or its pharmaceutically acceptable salt,

Formula 1

comprises:
i) coupling a compound of Formula 5,

Formula 5

with a compound of Formula 6 or salt,

Formula 6
in presence of boron reagent and suitable base to give compound of Formula 2,

Formula 2
ii) converting the resulting compound of Formula 2 to Mirabegron of Formula l.

In another aspect, the present invention is to provide an eco-friendly and efficient process for preparing compound of Formula 2,

Formula 2
comprises:
coupling a compound of Formula 5,

Formula 5

with a compound of Formula 6 or salt,

Formula 6
in presence of boron reagent and suitable base to give compound of Formula 2;
wherein the coupling reaction is carried out in absence of solvent.
In another aspect, the present invention is to provide an eco-friendly and efficient process for preparing mirabegron of Formula 1 or its pharmaceutically acceptable salt comprises
i) precipitating compound of Formula 2 from reaction mixture by addition of aqueous hydrochloric acid or aqueous base and followed by addition of water or vice-versa;
wherein the reaction mixture is obtained after completion of coupling reaction of compound of Formula 5 and Formula 6;
ii) converting the precipitated compound of Formula 2 to mirabegron of Formula 1 or its pharmaceutically acceptable salt.

DETAILED DESCRIPTION OF THE INVENTION
The term "efficient process" used herein means a chemical transformation with a chemical yield of more than 90% plus an isolated yield of more than 85% without further purification and having chemical or chromatographic (area % HPLC) purity of at least 99.0 %, preferably at least 99.6% and/or single highest unknown impurity is not more than 0.05% and total impurities are not more than 0.06% by high-performance liquid chromatography (HPLC).
The instant invention relates to an eco-friendly and efficient process for preparing mirabegron, its key intermediate compound of Formula 2.
According to an embodiment, there is provided an eco-friendly and efficient process for preparing mirabegron of Formula 1 or its pharmaceutically acceptable salts thereof. The said process involves coupling of compound of Formula 5 with a compound of Formula 6 or salt using boron reagent and suitable base to obtain Formula 2.
The inventors of the present invention conducted the said reaction in the absence of solvent.
The term “absence of solvent” means the reaction can be performed solvent free viz. neat or with solvent as diluent. The quantity of the solvent used as diluent is very small viz. in the range of 0.5 volume to 4 volume w.r.t. compound of formula 6. Further, no more solvents are used for downstream processing for extraction and crystallization of the product of Formula 2.
The solvent used as diluent may be selected from but not limited to acetonitrile, tetrahydrofuran, methanol, dimethyl sulfoxide, dioxane, acetone and alike or mixture thereof.
The boron reagent used for the said reaction may be selected from but not limited to boric acid and its ester such as phenyl boronic acid, trimethyl borate, triethyl borate and alike or mixture thereof.
The base used for the said reaction may be selected from organic or inorganic base. The organic and inorganic base may be selected from but not limited to ammonia, methylamine, ethylamine, diisopropylamine, N,N-diisopropyl ethylamine (DIPEA), triethylamine, dimethylamine, trimethyl amine, dicyclohexylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and n-methyl morpholine and alike or mixture thereof.
In the said process, the mixture of (R)-mandelic acid i.e. compound of Formula 5 and boron reagent is heated to 50°C to 70°C. Then, suitable base and compound of Formula 6 or its salt are added at temperature of 40°C to 60°C and followed by refluxing the reaction mixture to a temperature in the range of 75°C to 85°C. The said reaction is completed in 1 to 24 hours or preferably 4 to 16 hours.
After completion of the reaction, the resulting reaction mixture is cooled to a temperature of 10°C to 40°C or preferably 20°C to 30°C and then acid or base followed by water are added to get a solid precipitate. The solid precipitate is washed with base followed by water till neutral pH . The wet solid was dried to obtain compound of Formula 2.
The acid and base used during the workup may be in aqueous form. The acid may be selected from sulfuric acid, hydrochloric acid and nitric acid acetic acid, hydrobromic acid and alike or mixture thereof.
The base used herein are same as defined above.
The compound of Formula 2 prepared by the present invention has chromatographic (area % HPLC) purity of at least 99.0 % and preferably at least 99.6%.
In one embodiment, the resulting compound of Formula 2 is reduced with suitable reducing reagent in suitable solvent to give the compound of Formula 3 or acid addition salt thereof.
In one embodiment, the resulting compound of Formula 2 is reduced optionally in presence of acid selected from methane sulphonic acid, ethane sulphonic acid, propane sulphonic acid, p-toluene sulfonic sulphonic acid and alike or mixture thereof.
The suitable reducing reagent is selected from diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, NaBH4, NaBH4/BF3-etherate, LiBH4, LiAlH4 and the like.
The suitable reducing reagent is preferably selected from diborane, borane-dimethyl sulfide, borane-THF complex, NaBH4, NaBH4/BF3-etherate.
The suitable solvent is selected from alcoholic solvent such as methanol, ethanol, propanol, isopropanol; ether solvent such as tetrahydrofuran, tetrahydropyran, di-tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, 1,4-dioxane; ester solvents such as methyl acetate, ethyl acetate; hydrocarbon solvents such as toluene, hexane, xylene; polar solvents such as acetone, acetonitrile, dimethylformamide (DMF), dimelthylsulfoxide (DMSO), polar aprotic solvents or mixtures thereof and preferably selected from alcoholic solvent and ether solvents.
After completion of the reduction reaction, the compound of Formula 3 or acid addition salt thereof may be isolated by any technique known in the prior art such as extraction, filtration, distillation and alike or combination thereof.
Preferably, the compound of Formula 3 or acid addition salt thereof may be isolated by using extraction method comprises acid-base treatment followed by washing of organic layer with brine solution and distillation under vacuum to obtain of Formula 3.
Optionally, the resulting compound is treated with acid in presence of alcoholic solvent to obtain acid addition salt of Formula 3.
In one embodiment, the resulting compound of Formula 3 or acid addition salt thereof is hydrogenated in suitable solvent using hydrogenation catalyst in presence of hydrogen to give compound of Formula 3a or acid addition salt thereof.
The hydrogenation catalyst used in the reaction may be selected from Nickel, Raney nickel, Rhodium, sodium amalgam, Pt/C, PtO2 and Pd/C, Pd(OH)2 and alike. The suitable solvent is selected from alcoholic solvents such as methanol, ethanol, propanol, isopropanol; ether solvent such as tetrahydrofuran, tetrahydropyran, di-tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, 1,4-dioxane; ester solvents such as methyl acetate, ethyl acetate; polar solvents such as acetone, acetonitrile, dimethylformamide (DMF), dimelthylsulfoxide (DMSO); hydrocarbon solvents such as toluene, hexane, xylene or mixtures thereof. The suitable solvent is preferably selected from alcoholic solvents such as methanol, ethanol, isopropanol and alike or mixture thereof. After completion of the reaction, the catalyst is filtered out and compound of Formula 3a or acid addition salt thereof is isolated by solvent distillation or any known technique of prior art.
In a specific embodiment, the compound of Formula 3 is hydrogenated using Raney nickel catalyst in presence of hydrogen . After completion of the reaction, the catalyst is filtered out and optionally, ethylenediaminetetraacetic acid (EDTA) disodium dihydrate is added to the filtrate. Then, solvent of the reaction mixture was distilled out and pH of the resulting reaction mass is adjusted in the range of 8-11 by using aqueous base solution such as sodium hydroxide. The resulting solid is filtered, washed with water and cooled to 0°C to 20 °C. Finally, compound of Formula 3a is isolated by filtration and wherein Nickel content is present in the acceptable limit (< 20ppm).
Heavy metals like Nickel, Lead, Palladium, Molybdenum, Vanadium, Cobalt and Arsenic are toxic in nature and can be removed effectively by using EDTA if present in trace levels in any drug substance. Ethylenediaminetetraacetic acid disodium dihydrate (EDTA) is an excellent chelating agent. Its two amino groups and four carboxyl groups can be used as the binding sites of metal ions. Therefore, it is advantageous to use EDTA disodium dihydrate during hydrogenation step to control metal content in the acceptable limit.
In one embodiment, the resulting compound of Formula 3a or acid addition salt is coupled with 2-(2-aminothiazol-4-yl)acetic acid viz. compound of Formula 4 or its acid addition salt thereof in suitable solvent in presence of suitable coupling agent to afford mirabegron of Formula l.
The suitable coupling agent is selected form N,N-carbonyldiimidazole (CDI); alkyl and aryl carbodiimides optionally in combination with hydroxybenzotriazole or N-hydroxysuccinimide (NHS) or N-hydroxy sulfosuccinimide (Sulfo-NHS), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC, EDAC or EDCI), carbonyl- di-l,2,4-triazole; alkyl and aryl haloformates such as ethyl chloroformate, phenyl chloroformate and benzyl chloroformate.
The suitable solvent is selected from water, ketone solvents, ester solvents, chloro solvents, ether solvent, hydrocarbon solvents, nitrile solvents or mixtures thereof.
After completion of the reaction, mirabegron of Formula 1 or its pharmaceutically acceptable salts may be isolated by using any technique known in the prior art such as extraction, filtration, precipitation, crystallization, distillation and/or combination of the said techniques.
In one embodiment, mirabegron of Formula 1 prepared by the present invention may be converted to any polymorph as reported in prior art such as mirabegron form-a or form-ß.

In one embodiment, the mirabegron of Formula 1 or its pharmaceutically acceptable salts and/or its intermediate prepared by the present invention may be purified by any technique known in the art such as crystallization, precipitation, filtration, slurry wash and alike or combination of these techniques.

One aspect of the present invention provides an eco-friendly and efficient process for preparing mirabegron or its pharmaceutically acceptable salt which involves coupling of a compound of Formula 5 with a compound of Formula 6 or salt using boron reagent and suitable base to obtain Formula 2; wherein the said coupling is carried out in absence of solvent.
The reaction parameters used in the coupling reaction such as reagent, solvent, temperature and isolation technique(s) are same as defined herein before.
The compound of Formula 2, prepared by the present invention, is converted to Mirabegron of Formula l or its pharmaceutically acceptable salt by the methods known in the prior art or by the process of present invention as discussed herein before.

In another aspect, the present invention is to provide an eco-friendly and efficient process for preparing compound of Formula 2 by coupling compound of Formula 5 with a compound of Formula 6 or salt using boron reagent and suitable base to obtain compound of Formula 2; wherein the said coupling is carried out in absence of solvent.
The reaction parameters used in the coupling reaction such as reagent, solvent, temperature and isolation technique(s) are same as defined herein before.
The salt of Formula 6 and acid addition salt of formulas 3, 3a and 4 are selected from hydrochloride, hydrobromide, hydroiodide, hydrogen sulfate, benzoate, tosylate and alike.
In another aspect, the present invention is to provide an eco-friendly and efficient process for preparing compound of Formula 2, comprises precipitation of compound of Formula 2 from reaction mixture by addition of aqueous hydrochloric acid or aqueous base and followed by addition of water or vice-versa; wherein the reaction mixture is obtained after completion of coupling reaction of compound of Formula 5 with Formula 6.
In another aspect, the present invention is to provide an eco-friendly and efficient process for preparing mirabegron of Formula I and its salt by precipitating Formula 2 from the reaction mixture obtained after completion of coupling reaction of compound of Formula 5 and Formula 6 via the process as discussed herein above.

The purity of final product/intermediates, reaction completion and monitoring of the reaction of the present invention is checked by any analytical techniques known in the prior art such as high-performance liquid chromatography (HPLC), thin-layer chromatography (TLC), gas chromatography (GC) and alike.

In one embodiment, mirabegron of Formula 1 or its pharmaceutically acceptable salts, prepared by the present invention, may be characterized by analytical techniques known in the prior art are selected from but not limited to X-ray diffraction crystallography (XRD), differential scanning calorimetry (DSC), infrared spectroscopy (IR) and melting point.

EXAMPLES
Example 1. Preparation of (2R)-2-Hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenyl acetamide (Formula 2)
Method A:
(R)-Mandelic acid (11.3 g, 0.074 moles) and trimethyl borate (7.68 g, 0.074 moles) were heated to 60 oC to 65oC for 1 hour and the resulting mixture was cooled to 50 oC to 55oC . To the said reaction mixture were added DIPEA (9.48 g, 0.074 moles) and 2-(4-nitrophenyl)ethanamine hydrochloride (10 g, 0.049 moles). The resulting reaction mixture was heated to reflux for 15 hours. After completion of reaction, the reaction mixture was cooled to 25-30oC and aqueous HCl (10 mL, 6N) followed by water (80 mL) was added to obtain solid precipitate. The solid precipitate was filtered and sequentially washed with 3% aq. NaOH solution (40 mL) and with water (40 mL). The wet solid was dried at 55 oC to 60 oC to give 13.5g (91%) of the title compound with 99.2% purity by HPLC.
Method B:
(R)-Mandelic acid (11.3 g, 0.074 moles) and trimethyl borate (7.68 g, 0.074 moles) were heated to 60 oC to 65oC for 1 hour and resulting reaction mass was cooled to 50 oC to 55oC. To the said reaction mixture were added TEA (7.4 g, 0.074 moles) and 2-(4-nitrophenyl)ethanamine hydrochloride (10 g, 0.049 moles). The resulting reaction mixture was heated to reflux for 15 hours. After completion of reaction, the reaction mixture was cooled to 25-30 oC and aqueous HCl (10 mL, 6N) followed by water (80 mL) was added to obtain solid precipitate. The solid precipitated was filtered, washed with 3% aq. NaOH solution and with water (40 mL). The wet solid was dried at 55 oC to 60 oC to give 13.5g (90.6%) of the titled product with 99.5% purity by HPLC.
Method C:
(R)-Mandelic acid (56.3 g, 0.37 moles) and trimethyl borate (38.4 g, 0.37 moles) were heated to 60 oC to 65 oC for 1 hour and the resulting reaction mixture was cooled to 35 oC to 40 oC. To the said reaction mixture were added DIPEA (47.6 g, 0.37 moles) and 2-(4-nitrophenyl)ethanamine hydrochloride (50 g, 0.246 moles). The resulting reaction mixture was heated to reflux for 15 hours. After completion of reaction, the reaction mixture was cooled to 25 oC to 30 oC and aqueous HCl (50 mL, 6N) followed by water (450 mL) was added. Then, the reaction mixture was stirred for 3 hours to obtain a solid. The solid was filtered and washed with 20% aq. Na2CO3 solution (200 mL) followed by washing with water till neutral pH. The wet solid was dried at 55 oC to 60 oC under vacuum to give 68.5g (92.5%) of the titled product with 99.5% purity by HPLC.
Method D:
(R)-Mandelic acid (11.3 g, 0.074 moles), acetonitrile (20 mL) and trimethyl borate (7.68 g, 0.074 moles) were heated to 60 oC to 65 oC for 1 hour and the resulting reaction mixture was cooled to 50 oC to 55oC. To the said reaction mixture were added DIPEA (9.48 g, 0.074 moles) and 2-(4-nitrophenyl)ethanamine hydrochloride (10 g, 0.049 moles). The resulting reaction mixture was heated to reflux for 15 hours. After completion of reaction, acetonitrile was distilled under vacuum at 60 oC. The concentrated reaction mixture was cooled to 25 oC to 30 oC and aqueous HCl (10 mL, 6N) followed by water (80 mL) was added to obtain solid precipitate. The solid precipitated was filtered, sequentially washed with 5% aq. NaOH solution (60 mL) and with water (40 mL). The wet solid was dried at 55oC to 60oC to give 13.6g (91%) of the titled product with 99.6% purity by HPLC.

Example 2: Process for preparing compound of Formula 3 (Amide reduction)
To a cooled solution (-20oC to -25oC) of Formula 2 (200 g, 0.66 moles) in THF (1.7 L), were added sequentially sodium borohydride (35.2 g, 0.93 moles), methane sulphonic acid (19.2 g, 0.199 moles) and then boron trifluoride etherate (134.2g, 0.94 moles) dropwise. The reaction mixture was heated to 60-65 oC and stirred for 4-5 hours. After completion of the reaction, the reaction mixture was cooled to 0-10oC and quenched with aqueous HCl (600 mL, 1N) and pH of the reaction mixture was adjusted to 9-10 with 20% aqueous sodium hydroxide solution. The reaction mixture was stirred at 25oC to 30oC for 30 minutes and layers were separated after salt filtration. The aqueous layer was extracted with THF and layers were separated. The combined THF layer was washed with brine solution. Water (2.0 L) was added to the upper layer containing product and THF was distilled out under vacuum at 60 oC to 65 oC. The reaction mixture was cooled to 25 oC to 30oC and methanol (1.0 L) was added to it. pH was adjusted to 1-2 with concentrated HCl and the reaction mixture was heated to 65oC to 70oC to get clear solution. The solution was cooled to 0oC to 10oC under stirring for 2 hours. Solid formed was filtered, washed with mixture of methanol and water (30% methanol + 70% water) and dried under vacuum at 40 oC to 45oC to give 194.5g (91%) of compound of Formula 3 with 99.92 % purity by HPLC.
[Deoxy impurity = 0.07%]

Example 3: Process for preparing compound of Formula 3a (nitro reduction)
To a reaction mixture of compound of Formula 3 (135 g, 0.42 moles) and methanol (810 mL), Raney Nickel (13.5 g, 10 %) was added. The reaction mixture was hydrogenated at 45-50oC at 5 kg/cm2 hydrogen pressure for 4 hours. After completion of reaction, the reaction mixture was filtered through hyflo bed to remove the catalyst. Solvent was distilled out to get the crude product with 99.87% purity by HPLC.
To the crude product, MDC (340 mL) was added, the reaction mixture was cooled to 5oC to 10oC and stirred for 1 hour. Solid was filtered and dried under vacuum at 40oC to 45oC to give 122g (99 %) of pure product as an off-white powder with 99.79 % purity by HPLC.

Example 3a: Process for preparing compound of Formula 3a (nitro reduction)
To a reaction mixture of compound of Formula 3 (20 g, 0.062 moles) and methanol (120 mL), Raney Nickel (2 g, 10%) was added. The reaction mixture was hydrogenated at 45-50 °C at 5 kg/cm2 hydrogen pressure for 6 hours. After completion of the reaction, the reaction mixture was filtered through hyflo bed to remove the catalyst and washed with methanol. To the filtrate EDTA disodium dihydrate (500 mg) was charged and solvent was distilled out completely under vacuum. The pH of the resulting crude reaction mass was adjusted to 8.5-10.5 using 10% aqueous sodium hydroxide solution. The solid was filtered, washed with water and the reaction mixture was cooled to 5-10 °C. The mixture was filtered and the wet solid was dried at 55 °C under vacuum to give 90% of Formula 3a with 99.79% purity and having 8.02 ppm Nickel content.

Example 4: Process for preparing Mirabegron of Formula 1
To a reaction mixture of compound of Formula 3a (10 g, 0.034 moles) and water (50 mL), aqueous HCl (1N) was added to adjust pH to 2.5-3.0. The compound of Formula 4 (5.3 g, 0.033 moles) followed by EDC.HCl (7.2 g, 0.037 moles) were added to the reaction mixture and the mixture was stirred for 2 hours at 25-30oC. After completion of the reaction, pH of reaction mixture was adjusted to 9-10 with 5% aqueous NaOH solution and stirred for 30 minutes. Th reaction mixture was heated to 50-55°C and stirred for 1 hour. Reaction mixture was cooled to 25-30°C and stirred for 1.5 hours. Solid formed was filtered and washed with water. to give crude Mirabegron with 99.72% purity by HPLC.
[Deoxy impurity = 0.04%]
Purification: Crude product with ethanol (50 mL) and water (34 mL) mixture was heated to 60-65°C to get clear solution and filtered hot to remove any extraneous matter. Alpha form seed was added to the filtered mass at 50-55°C, reaction mixture was stirred for 1 hour at 45-50 °C, then reaction mixture was cooled to 20-25°C and stirred for 1.5 hours to result a solid compound. The solid formed was filtered, washed, and dried under vacuum at 55-60°C to give pure 12.2 g (90.3%) of mirabegron (Alpha form) with 99.77 % purity by HPLC.
[Deoxy impurity = 0.05%]

Example 4a: Process for preparing mirabegron of Formula 1
To a reaction mixture of compound of Formula 3a (10g, 0.039 moles) and water (60 mL), aqueous HCl (1N) was added to adjust pH to 2.5-3.0. The reaction mixture was cooled to 5-15 °C. The compound of Formula 4 (6.05 g, 0.038 moles) followed by EDC.HCl (8.98 g, 0.046 moles) were added to the reaction mixture and stirred for 1 hour at 5-15 oC. After completion of the reaction, the temperature of reaction mixture was raised to 20-25 °C. Activated carbon was charged to the reaction mixture, stirred and filtered via hyflo bed. The pH of filtrate reaction mixture was adjusted to 9-10 with aqueous NaOH solution and stirred for 30 minutes. The resulting reaction mixture was heated to 50-55 °C for 1 hour and then cooled to 25-30 °C. The reaction mixture was filtered to obtain a white solid.
Purification: The wet solid was washed with water and heated to 55-65 °C in a mixture of MeOH-water (1:1, 11 vol) to get clear solution. To the solution mirabegron (Alpha form) was seeded and allowed to cool to 25-35 °C. The resulting solid was filtered and washed with aqueous methanol. The wet solid was dried under vacuum at 55 °C to give 13.5 g (90%) of mirabegron as white to off white crystalline powder and having 99.97 % of HPLC Purity and 3.87 ppm Nickel content.

Example 5: Preparation of mirabegron as a white crystalline powder
Method A: Mirabegron (20g) was suspended in water and pH was adjusted to 2-3 using aqueous HCl to get a clear solution. Methanol (100 mL) and Norit carbon (CASPF, 2g) were added to the solution and stirred for 1 hour at room temperature. Carbon was removed by filtering the mass and washed with water. The pH of the filtered solution was adjusted to 8.0-8.5 by using 10% aqueous NaOH and stirred for 2 hours at 20-30 °C. White solid precipitated was filtered, washed with water and dried under vacuum to give mirabegron as a white crystalline powder.
Method B: Mirabegron (8g) was stirred in a mixture of methanol (44 mL, 5.5 v) and water (44 mL, 5.5 v) at room temperature for 5 hours. White suspension was filtered, washed with aqueous methanol and dried under vacuum at 55 °C to give mirabegron as a white crystalline powder.
Method C: Mirabegron (10g) was stirred in ethyl acetate (50 mL, 5 v) at 55-65 °C for 1 hour, cooled to 20-30 °C. White solid was filtered and dried under vacuum at 50-55 °C to give mirabegron as a white crystalline powder.
Method D: Mirabegron (20g) was stirred in acetone (100 mL, 5 v) for 1 hour at 20-30 °C. White solid was filtered, washed with acetone and dried under vacuum at 50-55 °C to give mirabegron.
Method E: Mirabegron (20g) was suspended in water and pH was adjusted to 2-3 using aqueous HCl to get a clear solution. Methanol (100 mL) was added followed by the addition of 2% aqueous solution of sodium metabisulfite (20 mL, 1 vol). Norit carbon (2g) was added and stirred for 1 hour at room temperature. Carbon was removed by filtration and pH of the filtered solution was adjusted to 8.0-8.5 by using 10% aqueous NaOH. White suspension was stirred for 2 hours at 20-30 °C and solid was filtered, washed with water followed by suck drying. Wet solid was suspended in a mixture of methanol and water (1:1) under stirring for 5-6 hours. Then, filtered and washed the resulting solid with aqueous methanol and the solid was dried under vacuum at specific time intervals from room temperature to 55 °C to give mirabegron as a white crystalline powder.

It will be apparent to those skilled in the art that various modifications and variations can be made in the present invention and specific examples provided herein without departing from the spirit and scope of the invention. Thus, it is intended that the present invention covers the modifications and variations of this invention that come within the scope of any claims and their equivalents.
,CLAIMS:WE CLAIM
Claim 1. An eco-friendly and efficient process for preparing mirabegron of Formula 1 or its pharmaceutically acceptable salt,

Formula 1

comprises:
i) coupling a compound of Formula 5,

Formula 5

with a compound of Formula 6 or salt,

Formula 6
in presence of boron reagent and suitable base to give compound of Formula 2;

Formula 2

ii) reducing the compound of Formula 2 with suitable reducing reagent in suitable solvent to give the compound of Formula 3 or acid addition salt thereof;

Formula 3

iii) hydrogenating the compound of Formula 3 or acid addition salt thereof in suitable solvent using hydrogenation catalyst in presence of hydrogen to give compound of Formula 3a or acid addition salt thereof, and

Formula 3a

iv) coupling the compound of Formula 3a or acid addition salt thereof with compound of Formula 4 or its acid addition salt thereof,

Formula 4

in suitable solvent in presence of suitable coupling agent to afford mirabegron of Formula l or its pharmaceutically acceptable salt.

Claim 2. An eco-friendly and efficient process for preparing mirabegron or its pharmaceutically acceptable salt,

Formula 1

comprises:
i) coupling a compound of Formula 5,

Formula 5

with a compound of Formula 6 or salt,

Formula 6
in presence of boron reagent and suitable base to give compound of Formula 2, and

Formula 2
ii) converting the resulting compound of Formula 2 to mirabegron of Formula l.

Claim 3. An eco-friendly and efficient process for preparing mirabegron of Formula 1 or its pharmaceutically acceptable salt comprises:
i) precipitating compound of Formula 2 from reaction mixture by addition of aqueous hydrochloric acid or aqueous base and followed by addition of water or vice-versa;
wherein the reaction mixture is obtained after completion of coupling reaction of compound of Formula 5 with Formula 6, and
ii) converting the precipitated compound of Formula 2 to mirabegron of Formula 1 or its pharmaceutically acceptable salt.

Claim 4. An eco-friendly and efficient process for preparing compound of Formula 2,

Formula 2
comprises:
coupling a compound of Formula 5,

Formula 5

with a compound of Formula 6 or salt,

Formula 6
in presence of boron reagent and suitable base to give compound of Formula 2;
wherein the coupling reaction is carried out in absence of solvent.

Claim 5. The process as claimed in claims 1, 2 and 4; wherein the coupling reaction is carried out in absence of solvent and the compound of Formula 2 is precipitated from reaction mixture by addition of acid or base followed by addition of water or vice-versa to the reaction mixture at a temperature selecetd from 10°C to 40°C.
Claim 6. The process as claimed in claims 1, 2 and 4; wherein the boron reagent is selcted from boric acid and its ester such as phenyl boronic acid, trimethyl borate and triethyl borate.
Claim 7. The process as claimed in claims 1 to 4, wherein the suitable base is selcted from ammonia, methylamine, ethylamine, diisopropylamine, N,N-diisopropyl ethylamine (DIPEA), triethylamine, dimethylamine, trimethyl amine, dicyclohexylamine, sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and n-methyl morpholine.
Claim 8. The process as claimed in claims 1, wherein the suitable reducing reagent is selected from diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, NaBH4, NaBH4/BF3-etherate, LiBH4, LiAlH4 and the hydrogenation catalyst is selected from nickel, Raney nickel, rhodium, sodium amalgam, Pt/C, PtO2 and Pd/C, Pd(OH)2 and alike.
Claim 9. The process as claimed in claims 1, wherein in step ii) and step iii) the suitable solvent is alcohol solvent selected from methanol, ethanol, propanol, isopropanol and ether solvent selected from tetrahydrofuran, tetrahydropyran, di-tert-butyl ether, methyl tert-butyl ether, diisopropyl ether, 1,4-dioxane or mixtures thereof.
Claim 10. The process as claimed in claims 1, wherein in step iv) the suitable coupling agent is selected form N,N-carbonyldiimidazole (CDI); alkyl and aryl carbodiimides optionally in combination with hydroxybenzotriazole or N-hydroxysuccinimide (NHS) or N-hydroxy sulfosuccinimide (Sulfo-NHS), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), carbonyl-di-l,2,4-triazole; alkyl and aryl haloformates such as ethyl chloroformate, phenyl chloroformate and benzyl chloroformate.

Dated this 20th day of December 2022.

Kapil
Manager-II, IPR
Ind-Swift Laboratories Limited