FIELD OF THE INVENTION:

The present invention relates to an improved process for the preparation of Mirabegron. The present invention further relates to (R)-acetoxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide , a novel intermediate in the preparation of Mirabegron.

BACKGROUND OF THE INVENTION:

Mirabegron is used for the treatment of overactive bladder. Mirabegron activates the p3 adrenergic receptor in the detrusor muscle in the bladder which leads to muscle relaxation and an increase in bladder capacity. Mirabegron is chemically known as 2-(2-aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide and has the following structural formula: Mirabegron is an agonist of the human beta-3 adrenergic receptor (AR) as demonstrated by in vitro laboratory experiments using the cloned human beta-3 AR. Mirabegron relaxes the detrusor smooth muscle during the storage phase of the urinary bladder fill-void cycle by activation of beta-3 AR which increases bladder capacity. Mirabegron and its pharmaceutically acceptable salts were first disclosed in US6346532B1. This patent disclosed the preparation of Mirabegron by two manufacturing methods. The first manufacturing method involves reacting 4-nitrophenyl ethylamine Hydrochloride with R-styrene oxide in the presence of ethyl acetate and IN aqueous solution of NaOH to give (R)-l-phenyl-2-[[2-(4-nitrophenyl) ethyl]amino]ethanol. The obtained compound reacts with di-tert-butyl dicarbonate in THF to get tert-butyl (R)-N-(2-hydroxy-2-phenylethyl)-N-[2-(4-nitro phenyl)ethyl]carbamate which is reduced by 10% Palladium in the presence of ethanol to obtain tert-butyl (R)-N-[2-(4-aminophenyl)-N-(2-hydroxy-2-phenylethyl)ethyl]-carbamate. The resultant compound reacts with 2-Aminothiazole-4-yl-acetic acid in the presence of a condensation agent to give tert-butyl (R)-N-[2-[4-[2-(2-aminothiazol-4-yl)acetamino]phenyl]ethyl]-N-[(2-hydroxy-2-phenyl)ethyl]carbamate.

The resultant compound is treated with methanol and a solution of 4N hydrogen chloride in ethyl acetate to give of Mirabegron. In another manufacturing method 4'-(2-aminomethyl)-2-(2-aminothiazol-4-yI) acetanilide reacted with styrene oxide to give Mirabegron. US7342117 disclosed a process for the preparation of a-form crystal & [3-form crystal of Mirabegron. The process involves reacting 4-nitrophenylethylamine monohydrochloride, with (R)-mandelic acid in the presence of triethylamine, N,N-Dimethylformamide, hydroxybenzotriazoie and l-(3-dimethyIaminopropyI)-3-ethyIcarbodiimide monohydrochloride (EDC) to give (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide which is reduced using boran-tetrahydrofuran solution in presence of l,3-dimethyl-2-imidazolidinone to give R)-2-[[2-(4-nitrophenyl)ethyl] amino] -1 -phenylethanol monohydrochloride. This resultant compound is treated with palladium-carbon to give (R)-2- [[2-(4-aminophenyI)ethyl] amino] -1-phenylethanol monohydrochloride which is further reacted with 2-aminothiazol-4-yl acetic acid in the presence of a condensing agent l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDC) to give Mirabegron.

JP2011105685 disclosed type II crystal of (IR) - 2- [(4 - amino phenyl)-ethyl amino] - 1 -phenyl ethanol HCI [an intermediate of Mirabegron] and a process for the preparation of Mirabegron by reacting 4-nitrophenylethylamine monohydrochloride with (R)-mandelic acid in the presence of triethylamine, N,N-Dimethylformamide, hydroxybenzotriazoie and l-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDCI) to give (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide which is then reduced using 1M boran-tetrahydrofuran solution in presence of l,3-dimethyl-2-imidazolidinone and THF to give (R)-2-[[2-(4-nitrophenyl)ethyl] amino] -1 -phenylethanol monohydrochloride which is followed by treatment with palladium-carbon in methanol to give (R)-2- [[2-(4-aminophenyl)ethyl] amino] -1-phenylethanol monohydrochloride. The resultant compound is condensed with 2-aminothiazol-4-yl acetic acid in the presence of a condensing agent such as l-(3-Dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (EDCI) in presence of concentrated HC1 to obtain Mirabegron which is then recrystallized. The inventors of the present invention has developed an improved process for the preparation of Mirabegron using cheaper condensing agents such as N,N'-Dicyclohexylcarbodiimide (DCC) and reducing agents which enhances the rate of the reaction as well reduce the costs. Further the inventors of the present invention developed a novel intermediate which is useful in the preparation of Mirabegron.

SUMMARY OF THE INVENTION:

The main aspect of the present invention relates to an improved process for the preparation of Mirabegron. Another aspect of the present invention relates to the process for the preparation of Mirabegron comprising the steps of:

a) reacting 4-nitrophenylethylamine monohydrochloride with (R)- Mandelic acid in presence of a suitable condensing agent, base and solvent to obtain (R)-2-hydroxy -N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide,

b) reducing the compound of step a in the presence of a polar aprotic solvent to obtain (R)- 2-[[2'-(4-nitrophenyl)-ethyl] amino]-1-phenylethanol, which is optionally converted to its pharmaceutically acceptable salt;

c) reducing the nitro compound of step b in the presence of a suitable solvent to obtain (R)-2 [[2-(4- aminophenyl)ethyl]-amino]-1 -phenylethanol monohydrochloride.

d) treating the compound of step c with 2-aminothiazol-4-yl- acetic acid in the presence of a condensing agent and an acid followed by treatment .with a base to obtain Mirabegron, and

e) optionally crystallizing crude Mirabegron using a suitable solvent to get pure Mirabegron. In yet another aspect, the present invention relates to (R)-acetoxy-N-[2-(4-nitrophenyl)ethyl]-2 phenylacetamide, a novel intermediate for use in the preparation of Mirabegron.

Yet another aspect of the present invention relates to a process for the preparation of Mirabegron using (R)-acetoxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide, a novel intermediate comprising the steps of:

a) treating R-Mandelic acid with R-Acetoxy Mandelic acid in the presence of suitable solvent,

b) converting R-Acetoxy Mandelic acid to (R)-acetoxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide by reacting with 4-nitro phenyl ethylamine hydrochloride in the presence of suitable solvent,

c) reducing (R)-acetoxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide to give (R)-2-[[2'-(4-nitrophenyl)-ethyl] amino]-!-phenylethanol using suitable reducing agent and organic solvent,

d) reducing (R)- 2-[[2'-(4-nitrophenyl)-ethyl] amino]-1-phenylethanol in the presence of solvent to afford (R)-2-[[2-(4- aminophenyl)ethyl]-amino]-l-phenylethanol monohydrochloride,

e) reacting (R)-2-[[2-(4- aminophenyl)ethyl]-amino]-1 –phenylethanol monohydrochloride with' 2-aminothiazole-4-yl-acetic acid in presence of a suitable condensing agent, an acid followed by treatment with a base to obtain Mirabegron of compound of the formula I, and

f) optionally crystallizing crude Mirabegron of formula I to get pure Mirabegron.

DETAILED DESCRIPTION OF THE INVENTION:

The present invention provides an improved process for the preparation of Mirabegron. In one embodiment, the present invention provides an improved process for the preparation of Mirabegron comprising the steps of:

(a) reacting 4-nitrophenylethylamine monohydrochloride of formula II with (R)-Mandelic acid of formula VII, in the presence of a suitable condensing agent, base and a solvent to obtain ;(R)-2-hydroxy -N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide of Formula III,

(b) reducing the compound of formula III using a suitable reducing agent in presence of a organic solvent to get (R)- 2-[[2'-(4-nitrophenyl)-ethyl] amino]- 1-phenylethanol formula IV,

(c) reducing the compound of formula IV in the presence of a catalyst and solvent to V obtain (R)-2-[[2-(4- aminophenyl)ethyl]-amino]-l-phenylethanol monohydrochloride,

(d) reacting the compound of the formula V with 2-aminothiazol-4-yl- acetic acid of formula VI in presence of a condensing agent and an acid followed by treatment with a base to obtain compound of the formula I, and

(e) optionally crystallizing crude Mirabegron of formula I to get pure Mirabegron. According to the present invention, 4-nitrophenylethylamine monohydrochloride of formula II may be reacted with (R)- Mandelic acid in the presence of suitable condensing agents such as N'-dicyclohexylcarbodiimide(DCC), 1,1 '-carbonyldiimidazole(CDI), diphenylphosphorylazide(DPPA), diethylphosphoryl cyanide (DEPC) preferably N,N'- dicyclohexylcarbodiimide (DCC), suitable racemization suppressing agents such as 1- hydroxy-beztriazole (HOBt), l-hydroxy-7- azabenzotriazole (HOAt), N- hydroxysuccinimide (HOSU) preferably 1-hydroxy-beztriazole (HOBt), suitable base such as triethylamine, methylamine, ammonia and phenylamine preferably triethylamine and suitable solvent such as N,N-Dimethylformamide, dimethylacetamide or dimethylsulfoxide, dichloromethane preferably N,N-dimethylformamide to obtain (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide of Formula III;

The compound of formuja III may be reduced using suitable reducing agent such as Borane-tetrahydrofuran (BTHF) and borane-dimethyl sulfide (BMS, DMSB) preferably Borane-tetrahydrofuran complex (BTHF) in a polar aprotic solvent such as 1,3-dimethyl-2-imidazollidinone, tetrahydrofuran, Ethyl acetate, dimehtylformamide, dimethyl sulfoxide and acetonitrile and mixtures thereof to obtain (R)- 2-[[2'-(4-nitrophenyl)-ethyl] amino]-l-phenylethanol, of formula IV; or The compound of formula III is reduced using a suitable reducing agent such as sodium borohydride, Lithium borohydride, Aluminium borohydride preferably sodium borohydride in presence of a strong acid such as sulfuric acid, nitric acid, hydrochloric acid preferably sulfuric acid and a polar aprotic solvents such as l,3-dimethyl-2-imidazollidinone, tetrahydrofuran, Ethyl acetate, dimehtylformamide, dimethyl sulfoxide preferably tetrahydrofuran to obtain (R)- 2-[[2'-(4-nitrophenyl)-ethyl] amino]-1-phenylethanol, compound of formula IV; The compound of formula IV may be reduced in the presence of suitable catalysts such as palladium carbon, lindlar catalyst (or lindlar's Palladium) preferably palladium carbon in presence of a suitable solvent such as methanol, ethanol, isopropanol, n-butanol, preferably, methanol to get (R)-2-[[2-(4- aminophenyl)ethyl]-amino]-l-phenylethanol monohydrochloride, of formula V;

The compound of formula V may be condensed with 2-aminothiazole-4-yl acetic acid using a suitable condensing agent such as N'-dicyclohexylcarbodiimide (DCC), 1,1'-carbonyldiimidazole (CDI), diphenylphosphorylazide (DPPA), diethylphosphoryl cyanide (DEPC) preferably .N.N'-dicyclohexylcarbodiimide (DCC) in the presence of a an acid such as hydrochloric acid and water and the resultant mass may be treated with a base such as sodium hydroxide to obtain Mirabegron. The crude Mirabegron is optionally recrystallized from a suitable solvent to obtain pure Mirabegron. In another embodiment, the crude (R)-2-[[2-(4- aminophenyl)ethyl]-amino]-l- phenylethanol monohydrochloride, the compound of formula V may be crystallized from suitable solvents such as ethers like diethyl ether, dimethyl ether or diisopropyl ether to obtain pure (R)-2-[[2-(4- aminophenyl)ethyl]-amino]-l-phenylethanol monohydrochloride in crystalline form. In yet another embodiment, the present invention provides a novel intermediate of the compound of formula IX, an intermediate in the preparation of Mirabegron. In yet another embodiment, the present invention provides a process for the preparation of Mirabegron using novel intermediate of the compound of formula IX comprising the psof:

a) reacting the compound of the formula VII with anacylation reagent in the presence of an oraanic solvent to eet comnound of formula VIII.

(b) treating the compound of the formula VIII with a compound of the formula II in the presence of suitable base and solvent to obtain compound of the formula IX

(c) reducing the compound of the formula IX using a reducing agent in presence of a suitable solvent to afford a compound of the formula IV.

(d) reducing the compound of the formula IV in the presence of solvent to afford the compound of the formula V.

(e) reacting the compound of the formula V with the compound of the formula VI in presence of a condensing agent and acid followed by treatment with a base to get compound of the formula I, and

f) optionally crystallizing the crude Mirabegron of formula I to get pure Mirabegron.

According to the present invention, (R)-mandelic acid of formula VII may be treated with acylation reagents such as acetyl chloride, acetic anhydride, acetic acid preferably acetyl chloride in the. presence of suitable organic solvents such as toluene, xylene n-hexane, n-heptane, cyclohexane preferably toluene to get compound of (R)-acetoxy mandelic acid of formula VIII. (R)-acetoxy mandelic acid of formula VIII may be reacted with 4-nitrophenylethylamine of formula II in the presence of an base such as triethylamine and suitable organic solvent such as dichloromethane to .obtain (R)-acetoxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide of formula IX. (R)-acetoxy-N-{2-(4-nitrophenyl)eth_ylJ-2-phen_ylacetamide of formula IX may be reduced using suitable reducing agents such as Borane-tetrahydrofuran (BTHF) and borane-dimethyl sulfide (BMS, DMSB), preferably Borane-tetrahydrofuran (BTHF) in presence of a polar aprotic solvents such as l,3-dimethyl-2-imidazollidinone, tetrahydrofuran, Ethyl acetate, dimehtylformamide, dimethyl sulfoxide and acetonitrile or mixtures thereof to get (R> 2-[[2'-(4-nitrophenyl)-ethyl] amino]-l-phenylethanol formula IV; or

The compound of the formula IX is converted to compound of the formula IV in presence of a reducing agent such as sodium borohydride, Lithium borohydride, Aluminium is reduced borohydride preferably sodium borohydride in presence of a strong acid such as sulfuric acid, nitric acid, hydrochloric acid preferably sulfuric acid and polar aprotic solvents such as l^-dimethyl^-imidazollidinone, tetrahydrofuran, Ethyl acetate, dimehtylformamide, dimethyl sulfoxide preferably tetrahydrofuran. Further conversion of compound of formula IV to Mirabegron of compound of formula I is carried as described above. In yet another embodiment, the present invention provided an improved process for the preparation of Mirabegron as shown in the scheme below: The following non-limiting examples illustrate specific embodiments of the present invention. The examples are not intended to be limiting the scope of present invention in any way.

Experimental procedure:

Example - 1: Process for the Preparation of (R)-2-hydroxy -N- [2-(4-n it ro phenyl) ethyl]-2-phenylacetamide. A mixture of (100 g) of 4- Nitrophenylethylamine monohydrochloride, (75.0 g) of (R)-Mandelic acid, (49.8 g) of Triethylamine were taken in a vessel. This mixture was added with (380 ml) of DMF, (66.6g) of hydroxybeztriazole and (101.8 g) of N,N'-Dicyclohexylcarbodiimide (DCC) and the reaction mixture was stirred for 2hours at room temperature. TLC revealed the absence of staring material. The reaction solution was diluted with (1900 ml) of water and extracted with ethyl acetate (1000 ml and 500 ml). The organic layer was washed with (1000 ml) of a IM hydrochloric acid aqueous solution, (1000 ml) of a 20% Potassium carbonate aqueous solution and water (1000 ml and 1000 ml), and then concentrated under vacuum at 15-20°C. The residue was dissolved in 600 ml of toluene by heating at 85-87°C. The mixture was cooled and then stirred at 20°C for 3-4 hours. The obtained crystals were filtered and washed with 150 ml of toluene, and dried under vacuum at 40-45°C to obtain 100-130 g of desired product -(R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide.

Example - 2: Process for the Preparation of (R)-2-hydroxy -N-[2-(4-nitrophenyl)-ethyl|-2-phenylacetamide. A mixture of (100 g) of 4- Nitrophenylethylamine monohydrochloride, (75.0 g) of (R) -Mandelic acid, (49.8 g) of Triethylamine was taken in a vessel. To the mixture was added dichloromethane, (66.6g) of hydroxybeztriazole, (101.8g) of N, N'-Dicyclohexylcarbodiimide (DCC) and stirred at room temperature for 2hours. TLC revealed the absence of staring material. The reaction solution was diluted with (1900 ml) of water and extracted with ethylacetate (1000 ml and 500 ml). The organic layer was washed with (1000 ml) of a IM hydrochloric acid aqueous solution, (1000 ml) of a 20% Potassium carbonate aqueous solution and water (1000 ml and 1000 ml), and then concentrated under vacuum at 15-20°C. The residue was dissolved in 600 ml of toluene by heating at 85-87°C. Cooled the reaction mass and stirred at 20°C for 3-4 hours. The crystals formed were collected by filtration and washed with (150 ml) toluene, dried under vacuum at 40-45°C to obtain 85-100 g "of (R)-2-hydroxy -N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide.

Example-3: Preparation of (R) - 2-[[2'-(4-nitrophenyl)-ethyI] amino]-l-phenylethanol monohydrochloride. A mixture of (100 g) of (R)-2-hydroxy -N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide, (306 ml) of l^-dirhethyl^-imidazollidinone and (306 ml) Tetrahydrofuran were taken in the vessel and the mixture was cooled to -18°C. This mixture was added with (657 g) of 1M borane tetrahydrofuran solution at below -8°C. Thereafter the reaction temperature was increased to 70°C and stirred for 3 hours. The reaction mixture was cooled to -12°C. To this mixture (38.6 g) of methanol and (78.5 g) of concentrated hydrochloric acid were added at below 5°C. The reaction mixture was stirred at 68°C for 1 hour and concentrated under vacuum till the inner volume became (500 ml). To this mixture (800 g) of 30% Potassium carbonate aqueous solution and (80 ml) of water was added and the mixture was extracted with (1000 ml) of ethyl acetate. The organic layer was washed with (1000 ml) water and concentrated under vacuum. To the residue was added (1000 ml) Isopropanol at 40°C and the solution was crystallized from (32.7 g) of Cone. Hydrochloric acid and stirred at 23°C for 3-4 hours. The crystals were collected by filtration and washed with 200 ml Isopropanol and dried under vacuum at 40-45°C to obtain (90-100 g) of (R)- 2-[[2'-(4-nitrophenyl)-ethyl] amino]-1-phenylethanol monohydrochloride.

Example-4: Preparation of (R) - 2-[[2'-(4-nitrophenyl)-ethyl] amino]-l-phenylethanol monohydrochloride. Mixture of (100 g) of (R)-2-hydroxy -N-[2-(4-nitrophenyl) ethylJ-2-phenyIacetamide, (850 ml) of tetrahydrofuran were taken in the vessel and added with (50.4 g) of sodium borohydride at 25-35°C. The reaction mixture was cooled to 0-5°C and slowly added a mixture of (78.4 g) of sulfuric acid and (650 ml) THF at below 0-5°C. Thereafter, the reaction temperature was increased to 60-70°C and the reaction mixture was stirred for 2-3 hours till TLC shows absence of starting material. The reaction mixture was cooled to 0-5°C and added (38.6 g) of methanol and (78.5 g) concentrated hydrochloric acid at below 5°C. The mixture was stirred at 68°C for 1 hour and concentrated under vacuum till the inner volume became (500 ml). (800 g) of 30% Potassium carbonate aqueous solution and (80 ml) of water were added and the mixture was extracted with (1000 ml) of ethylacetate. The organic layer was washed with (1000 ml) water and concentrated in vacuum. To the residue was added (1000 ml) of Isopropanol at 40°C and the solution was crystallized from (32.7 g) of Cone. Hydrochloric acid followed by stirring at 23°C for 3-4 hours. The crystals formed were collected by filtration and washed with (200 ml) Isopropanol and dried under vacuum at 40-45°C to obtain (90-100 g) of (R)- 2-[[2'-(4-nitrophenyl)-ethyl] amino]-1-phenylethanol monohydrochloride

Example-5: (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylethanol Monohydrochloride formula V. Mixture of (100 g) of (R)-2-[[2-(4-aminophenyI) ethyl]-amino]-1 -phenylethanol monohydrochloride, (1000 ml) of methanol and (1 lg) of wet 10% palladium-carbon were taken in a vessel and stirred under hydrogen atmosphere until absorption of hydrogen stopped. The reaction solution was filtered and the filtrate was concentrated under vacuum. To the obtained residue was dissolved (360 ml) in methanol at 40°C and the solution was crystallized from (2000 ml) of diisopropylether and stirred at 20°C for 3 hours. The crystals formed were collected by filtration and washed with (270 ml) of diisopropyl ether, dried under vacuum to afford (75-80g) of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylethanol monohydrochloride.

Example-6: Preparation of Mirabegron formula I lOOg of (R)-2-[[2-(4-aminophenyl)ethyl]-amino]-I-phenylethanol monohydrochloride, (54 g) of 2-aminothiazol-4-yl-acetic acid and (33 g) of cone. HCl were taken in a reaction vessel. To the reaction solution was added (1500 ml) of water and (88 g) of N, N'-Dicyclohexylcarbodiimide (DCC) at room temperature. The reaction mixture was stirred for 1 hour. A mixed solution of (30 g) of sodium hydroxide and (500 ml) of water were added to reaction solution and crystallized. The crystals formed were filtered and washed with water (300 ml) and dried under vacuum to obtain 100-125g Mirabegron.

Example-7: Preparation of (R)- Acetoxy Mandelic Acid. 100 g of (R)-Mandelic acid and (150 g) of acetyl chloride were taken in the vessel and stirred at 45-50°C for 3-4 hours. TLC revealed the absence of staring material. The excess acetyl chloride was distilled out completely under vacuum at 50-55°C. The residue was recrystallized from (300 ml) of toluene and the formed crystals were collected by filtration, washed with (50 ml) toluene and dried under vacuum at 40-45°C to afford (70-90 g) of (R)- Acetoxy Mandelic Acid.

ExampIe-8: Preparation (R)-Acetoxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide formula IX A solution of (100 g) of (R)- Acetoxy Mandelic Acid in (500 ml) Dichloromethane was taken in a reaction vessel and cooled to -15 to -10°C. To this mixture was added (57.25 g) of triethylamine and (61.5 g) of Ethylchloroformate maintaining the temperature at -15 to -10°C. The reaction mixture was stirred for 30 min at -15 to -10°C. In another RBF, a suspension of (104.25g) of 4-Nitrophenylethyl amine hydrochloride in (500 ml) of dichloromethane was taken and cooled to 0-5°C. To this suspension was added (50g) of triethylamine and stirred for 10-15 min at 0-5°C. This reaction mass was added to the main reaction mass at -15 to -10°C. The reaction mass was stirred for 1 hour at -15 to -10°C. TLC revealed the absence of starting material. The reaction mixture temperature was increased to 20-25°C and added (500 ml) of water and separated the layers. The aqueous layer was extracted with Dichloromethane (500 ml). The combined organic layers were washed with (500 ml) of 5% Sodium bicarbonate solution and (500 ml) of water and concentrated under vacuum. To the residue was added (300 ml) cylcohexane and stirred for 1 hour at 25-30°C. The obtained crystals were collected by filtration and washed with (250 ml) cyclohexane, dried under vacuum at 40-45°C to obtain (100-110 g)of(R)-Acetoxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide.

Example-9: Preparation (R)- 2-[[2'-(4-nitrophenyl)-ethyl] amino]-l-phenylethanol monohydrochloride formula IV. A mixture of (100 g) of (R)-Acetoxy-N-[2-(4-nitrophenyl) ethyl]-2-phenylacetamide formula IX, (306 ml) of 1, 3-dimethyl-2-imidazollidinone and (306 ml) Tetrahydrofuran were taken in the vessel and cooled to -18°C. To this mixture was added (730ml) of 1M borane tetrahydrofuran solution at below -8°C. Thereafter, the temperature was increased to 70°C and the mixture was stirred for 3 hours. The reaction mixture was cooled to -12°C. To this mixture, (38.6 g) of methanol and (78.5 g) of concentrated hydrochloric acid at below 5°C were added. The mixture was stirred at 68°C for 1 hour and concentrated under vacuum till the inner volume became (500 ml). To the resultant mass, (800 g) of 30% Potassium carbonate aqueous solution and (80 ml) of water was added. The reaction mixture was extracted with (1000 ml) of ethylacetate. The organic layer was washed with (1000 ml) water and concentrated under vacuum. The residue was added 1000 ml of Isopropanol at 40°C and the solution was crystallized from (32.7 g) of Cone. Hydrochloric acid followed by stirring at 23°C for 3-4 hours. The obtained crystals were collected by filtration and washed with (200 ml) Isopropanol, followed by drying under vacuum at 40-45°C to obtain (80-95)' of (R)- 2-[[2'-(4-nitrophenyl)-ethyl] amino]-1-phenylethanol monohydrochloride.

Example-10: Preparation of (R) - 2-[[2'-(4-nitrophenyl)-ethyl] amino]-l-phenylethanol monohydrochloride. A mixture of (100 g) of (R)-Acetoxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide, (850 ml) tetrahydrofuran were taken in a vessel and added Sodium borohydride (50.4 g) at 25-35°C. The reaction mixture was cooled to 0-5°C and slowly added mixture of (78.4 g) of sulfuric acid and (650 ml) of tetrahydrofuran at below 0-5°C. Thereafter the temperature was increased to 60-70°C and the mixture was stirred for 2-3 hours till TLC shows absence of starting material. The reaction mixture was cooled to 0-5°C and added (38.6 g) of methanol and (78.5 g) of concentrated hydrochloric acid at below 5°C. The mixture was stirred at 68°C for 1 hour and concentrated under vacuum till the inner volume became 500 ml. (800 g) of 30% Potassium carbonate aqueous solution and (80 ml) of water was added and the mixture was extracted with 1000 ml of ethylacetate. The organic layer was washed with (1000 ml) of water and concentrated under vacuum. The residue was added (1000 ml) of Isopropanol at 40°C and the solution was crystallized from (32.7 g) of Conc.Hydrochloric acid followed by stirring at 23°C for 3-4 hours. The crystals were collected by filtration and washed with (200 ml) of Isopropanol followed by drying under vacuum at 40-45°C to obtain (80-90 g) of (R)- 2-[[2'-(4-nitrophenyl)-ethyl] amino]-l-phenylethanol monohydrochloride.

We claim:

1. A process for the preparation of Mirabegron comprising trie steps of:

(a) reacting the compound of the formula VII with an acylation reagent in the presence of an organic solvent to get compound of formula VIII.

(b) treating the compound of the formula VIII with a compound of the formula II in the presence of suitable base and solvent to obtain compound of the formula IX

(c) reducing the compound of the formula IX using a reducing agent in presence of a suitable solvent to afford a compound of the formula IV.

(d) reducing the compound of the formula IV in the presence of solvent to afford the compound of the formula V.

(e) reacting the compound of the formula V with the compound of the formula VI in presence of a condensing agent and acid followed by treatment with a base to get compound of the formula I, and

f) optionally crystallizing the crude Mirabegron of formula I to get pure Mirabegron.

2. The process according to claim 1, wherein the acylating agent in step (a) is selected from acetyl chloride, acetic anhydride or acetic acid and the organic solvent is selected from toluene, xylene n-hexane, n-heptane or cyclohexahe,

3. The process according to claim 1, wherein the base in step (b) is selected from triethylamine, methylamine, ammonia or phenylamine and the solvent is selected from chlorinated solvents such as dichloromethane.

4. The process according to claim 1, wherein the reducing agent in step (c) is selected from Borane-tetrahydrofuran (BTHF) or borane-dimethyl sulfide (BMS, DMSB) in the presence of an aprotic solvent such as l,3-dimethyl-2-imidazollidinone, tetrahydrofuran, ethyl acetate, dimehtylformamide,. dimethyl sulfoxide or acetonitrile or their mixtures thereof; or the reducing agent in step (c) is selected from sodium borohydride, lithium borohydride or aluminium borohydride in presence of a strong acid such as sulfuric acid, nitric acid or hydrochloric acid and the solvent is selected from polar aprotic solvents such as 1,3-dimethyl-2-imidazollidinone, tetrahydrofuran, ethyl acetate, dimehtylformamide or dimethyl sulfoxide.

5. The process according to claim 1 wherein the reduction in step (d) is carried out in presence of a suitable catalyst such as palladium carbon, lindlar catalyst (or lindlar's Palladium) in presence of a suitable solvent such as methanol, ethanol, isopropanol or n- butanol.

6. The process according to claim 1 wherein the condensation in step (e) is carried using a suitable condensing agent such as N'-dicyclohexylcarbodiimide (DCC), 1,1'- carbonyldiimidazole (CDI), diphenylphosphorylazide (DPPA) or diethylphosphoryl cyanide (DEPC) in presence of an acid such as hydrochloric acid, sulfuric acid or phosphoric acid.

7. A compound of formula

8. A process for the preparation of Mirabegron comprising the steps of:

(a) reacting 4-nitrophenylethylamine monohydrochlorjde of formula II with (R)-Mandelic acid of formula VII, in the presence of a suitable condensing agent, racemization suppressing agent, base and solvent to obtain (R)-2-hydroxy -N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide of Formula III.

(b) reducing the compound of formula III using a reducing agent in presence of a organic solvent to get (R)- 2-[[2'-(4-nitrophenyl)-ethyl] amino]- 1-phenylethanol formula IV,

(c) reducing the compound of formula IV in the presence of a catalyst and solvent to obtain (R)-2-[[2-(4- aminophenyl)ethyl]-amino]-l-phenylethanol monohydrochloride.

(d) reacting the compound of the formula V with 2-aminothiazol-4-yl- acetic acid of -formula VI in presence of a condensing agent and acid followed by treatment with a base to get compound of the formula I, and

(e) optionally crystallizing crude Miraoegron or iormuia I to get pure ivnraoegron.

9. The process according to claim 8, wherein:

i) the condensing agent in step (a) is selected N'-dicyclohexylcarbodiimideCDCCXU'-carbonyldiimidazole(CDI), diphenylphosphorylazide(DPPA) or diethylphosphoryl . cyanide (DEPC);

ii) the base is selected from triethylamine, methylamine, ammonia and phenylamine, preferably triethylamine in presence of suitable solvent such as N,N-Dimethylformamide, dimethylacetamide or dimethylsulfoxide, dichloromethane;

iii) the reduction in step (b) is carried using boron-THF complex and an organic solvent selected from l,3-dimethyl-2-imidazollidinone, tetrahydrofuran, ethyl acetate, dimehtylformamide, dimethyl sulfoxide or acetonitrile or mixtures thereof; or reduction in step (b) is carried out using reducing agents such as sodium borohydride, Lithium borohydride, Aluminium borohydride preferably sodium borohydride in presence of a strong acid such as sulfuric acid, nitric acid or hydrochloric acid;

iv) reduction in step (c) is carried in the presence of suitable catalyst such as palladium carbon or lindlar catalyst (or lindlar's Palladium) and suitable solvent such as methanol, ethanol, isopropanol or n-butanol; and

v) condensation in step (d) is carried out using suitable condensing agent such as N'- dicyclohexylcarbodiimide (DCC), 1,1 '-carbonyldiimidazole (CDI), diphenylphosphorylazide (DPPA) or diethylphosphoryl cyanide (DEPC).