FIELD OF INVENTION

The present invention relates to an improved process for the preparation of (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl)amino)-ethyl)-phenyl) acetamide of formula I by using sulfur containing reducing agent and subsequent condensation in presence or absence of water or in an organic solvent or mixtures thereof.

BACKGROUND OF THE INVENTION

Mirabegron is chemically described as (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl)amino)-ethyl)phenyl)acetamide or 2-amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]-4-thiazoleacetamide. The molecular structure of Mirabegron is represented by Formula I.
Mirabegron, a selective beta 3-adrenoceptor agonist, was authorized for the treatment of overactive bladder (OAB) with symptoms of urgency, urgency incontinence, and urinary frequency. It was developed and marketed by Astellas Pharma under the brand ñame MYRBETRIQ ™ Mirabegron represents a new class of treatment for overactive bladder (OAB). This drug works in a different mechanistic path way when compared to the other overactive bladder medications with proven effícacy and good tolerability.

Mirabegron and its pharmaceutically acceptable acid addition salts are fírst disclosed in US 6,346,532 Bl (herein after US'532). The patent US'532 discloses a process for the preparation of Mirabegron as a dihydrochloride salt in an Example- 41 which comprise of deprotection of tert-butyl (R)- N-[2-[4-[2-(2-aminothiazol-4-yl)acetamido]phenyl]ethyl-N-[(2-hydroxy-2-phenyl)ethyl]carbamate (Boc protected Mirabegron) with hydrochloric acid in a mixture of methanol and ethyl acétate followed by purifícation with reverse phase column chromatography using water/methanol (2:1) as an eluent.
The process for preparation of Mirabegron dihydrochloride is depicted in the following scheme-1.

Scheme-1
The patent US'532 involves the usage of reverse phase column chromatography which is not suggestible for commercial scale. Further dihydrochloride of Mirabegron suffers with strong hygroscopicity and is unstable for use in medication.

Mirabegron free base is disclosed in US 7,342,117 B2 (herein after US'l 17). Process for preparation of Mirabegron free base is depicted in the following scheme-2. Scheme-2 In Chínese patent CN103304511, discloses a process for the preparation of Mirabegron free base as depicted in the following scheme-3.

Scheme-3

In Chínese patent publication CN103232352, discloses a process for the preparation of Mirabegron free base as depicted in the following scheme-4

Scheme-4
In Chínese patent publication CN103387500, discloses a process for the preparation of Mirabegron as depicted here in the following scheme-5

Scheme-5
An article in Chem. Pharm. Bull. 58(4), 2010, 533-545 discloses an analogue of Mirabegron in which an intermedíate's process was disclosed as depicted in the following scheme-6.

Scheme-6
In Chínese patent publication CN103864713, discloses a process for the preparation of Mirabegron as depicted in the following scheme-7

Scheme-7
All above mentioned prior art processes for the preparation of Mirabegron compound of formula I suffers from one or more disadvantages like decrease in yield of final Mirabegron, isolation of intermediates as well as Mirabegron by column chromatography, which are not economic on commercial scale. Most of the above mentioned processes involves the conversión of nitro to amine group using catalytic hydrogenation which is a hazardous reaction, thereby safe and cheaper altematives were investigated which leads to develop an improved process for the preparation of Mirabegron that can be practiced on large scale production in cost effective manner.

OBJECTIVE OF THE INVENTION
The main objective of the present invention is to provide an improved process for the preparation of Mirabegron compound of Formula I or its pharmaceutically acceptable salts thereof. Another objective of the present invention is to provide a safe and commercially viable, improved process for the preparation of Mirabegron compound of Formula I or its pharmaceutically acceptable salts thereof.
Yet another objective of the present invention is use of sulfur containing reducing agénts and subsequent condensation for the preparation of Mirabegron compound of Formula I or its pharmaceutically acceptable salts thereof.

SUMMARY OF THE INVENTION
The present invention relates to a process for the preparation of (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl)amino)ethyl)phenyl)-acetamide of formula-I.
comprising:

a) condensation of (R)-2-hydroxy-2-phenylacetic acid compound of formula-2 or its acid derivatives of formula-2a with 2-(4-nitrophenyl)ethanamine compound of formula-3 or its salts of compound of formula-3a in presence of suitable coupling agent, base in a suitable solvent to provide (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide compound of formula-4

b) reducing the compound of formula-4 with a suitable reducing agent in presence of solvent to provide (R)-2-(4-nitrophenethylamino)-l-phenylethanol compound of formula-5 optionally isolating, conversión of compound of formula-5 into its'salt compound of formula-5a.

c) reducing the compound of formula-5 or formula-5a with a sulfur containing reducing agent in a suitable solvent to provide (R)-2-(4-aminophenethylamino)-1-phenylethanol compound of formula-6 or its acid addition salí compound of formula-6a,

d) condensing the compound of formula-6 or fomula-6a with 2-(2-aminothiazol-4-yl) acetic acid compound of formula-7 or its acid derivatives of formula-7a in presence of a suitable coupling agent, solvent optionally in presence of base under hydrous or anhydrous médium to provide (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl)-amino)-ethyl)phenyl)-acetamide of formula I.wherein, in step-a, the suitable condensing or coupling agent is selected form N,N-carbonyldiimidazole (CDI), alkyl and aryl carbodiimides such as N,N-diisopropylcarbodiimide (DIC), N,N-dicyclohexyl carbodiimide (DCC), l-ethyl-3-(3-

dimethylaminopropyl)carbodiimide hydróchloride (EDC.HC1), ditolyl carbodiimide optionally in combination with hydroxybenzotriazole or N-hydroxysuccinimide (NHS) or N-hydroxysulfosuccinimide (Sulfo-NHS), l,r-carbonyl-di-(l,2,4-triazole), alkyl and aryl haloformates such ás ethyl chloroformate, phenyl chloroformate, benzyl chloroformate, dialkyl, diaryl and alkyl aryl carbonates of the formula Rl-O-CO-0-R2, wherein "Rl" and "R2" are independently selected from branched or unbranched C1-C4 alkyl or substituted or unsubstituted phenyl group;
In step-a, suitable base is selected from organic or inorganic bases; Organic base is selected from group but not limited to triethylamine, N,N-diethylisopropylamine, N,N-diisopropylethylamine (DIPEA), diethylamine, tripropylamine trioctylamine, pyridine, lutidine, dimethylaminopyridine (DMAP), and dicyclohexylamine. Inorganic bases selected from alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates such as sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate and calcium bicarbonate.
In step-a, the suitable solvent is selected from water, alcoholic solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutanol, tert-butanol etc, polar aprotic solvents such as DMF, DMSO, DMA, NMP, N-methylmorpholine, pyridine; ketone solvents such as acetone, methylethyl ketone, methylisobutyl ketone; ester solvents such as ethyl acétate, methyl acétate, ¡sopropyl acétate, tert-butyl acétate; chlorinated solvents such as dichloromethane, chloroform; ether solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, THF, dioxane, 2-methyl THF; hydrocarbon solvents such as toluene, xylene, nitrile solvents such as ACN, propionitrile; Sulfolane or mixtures thereof;

In step-b, the suitable reducing agent is selected from diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, NaBH», NaBH4-BF3.etherate, LÍBH4 and the like; and the suitable solvent is selected from alcoholic solvent, ether solvents, ester solvents, hydrocarbon solvents, sulfolane, polar solvents or mixtures thereof;
In step-c, the suitable sulfur containing reducing agent is selected from sodium sulfite, sodium sulfide, sodium dithionite, sodium metabisulphite, sodium hydrosulfíde etc.
In step-c, the suitable solvent is selected from alcoholic solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutanol, tert-butanol etc, polar aprotic solvents such as DMF, DMSO, DMA, NMP, N-methylmorpholine, pyridiñé; ketone solvents such as acetone, methylethyl ketone, methylisobutyl ketone; ester solvents such as ethyl acétate, methyl acétate, isopropyl acétate, tert-butyl acétate; chlorinated solvents such as dichloromethane, chloroform; ether solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, THF, dioxane, 2-methyl THF; hydrocarbon solvents such as toluene, xylene, nitrile solvents such as ACN, propionitrile; sulfolane, optionally in presence of water or mixtures thereof;
In step-d, the suitable condensing or coupling agent is selected form N,N-carbonyldiimidazole (CDI), alkyl and aryl carbodiimides such as N,N-diisopropylcarbodiimide (DIC), N,N-dicyclohexyl carbodiimide (DCC), l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC.HC1), ditolyl carbodiimide optionally in combination with hydroxybenzotriazole or N-hydroxysuccinimide (NHS) or N-hydroxysulfosuccinimide (Sulfo-NHS), l,l'-carbonyl-di-(l,2,4-triazole), alkyl and aryl haloformates such as ethyl chloroformate, phenyl chloroformate, benzyl chloroformate, dialkyl, diaryl and alkyl aryl carbonates of the formula Rl-O-

C0-0-R2, wherein "Rl" and "R2" are independently selected from branched or unbranched C1-C4 alkyl or substituted or unsubstituted phenyl group;
In step-d, base is selected from organic or inorganic bases; Organic base is selected from group but not limited to triethylamine, N,N-diethylisopropylamine, N,N-diisopropylethylamine (DIPEA), diethylamine, tripropylamine trioctylamine, pyridine, lutidine, dimethylaminopyridine (DMAP), and dicyclohexylamine. Inorganic bases selected from alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates such as sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate.
In step-d, the suitable solvent is selected from alcoholic solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutanol, tert-butanol etc, polar aprotic solvents such as DMF, DMSO, DMA, NMP, N-methylmorpholine, pyridine; ketone solvents such as acetone, methylethyl ketone, methylisobutyl ketone; ester solvents such as ethyl acétate, methyl acétate, isopropyl acétate, tert-butyl acétate; chlorinated solvents such as dichloromethane, chloroform; ether solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, THF, dioxane, 2-methyl THF; hydrocarbon solvents such as toluene, xylene, nitrile solvents such as ACN, propionitrile; sulfolane, optionally in presence of water or mixtures thereof
The term "acid addition salts" of the present invention includes but not limited to organic or inorganic acids. Organic acids such as sulfonic acids, oxalic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, succinic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, mandelic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid etc; Inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid.

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to the process for the preparation of Mirabegron compound of Formula-1, which involves the reduction of (R)-2-(4-nitrophenethylamino)-l-phenylethanol compound of formula-5 or formula-5a using sulfur containing reducing agent in presence or absence of water or in an organic solvent or mixture thereof ata particular temperature to give compound of formula-6 or formula-6a; Subsequently coupled with 2-(2-aminothiazol-4-yl)acetic acid of formula-7 or its acid derivatives of formula-7a, using suitable coupling agent and solvent optionally in presence of base under hydrous or anhydrous conditions to provide Mirabegron compound of formula-I.
The present invention is schematically represented as depicted in the following scheme-8

a) reduction of compound of formula-5 or formula-5a with sulfur containing reducing agents in presence or absence of water or organic solvent or mixture of thereof at a preferable temperature 20-150 °C, most preferably 60-100 °C to provide compound of formula -6,

b) adjusting the pH of reaction mass from step-a to 8-10 with an inorganic base and extraction to an organic solvent and evaporation of volátiles to give compound of formula -6

c) optionally converting compound of formula -6 form step-b, to its acid addition salts in aqueous media to provide compound of formula-6a

d) treating compound of formula-6 from step-b, with 2-(2-aminothiazol-4-yl)acetic acid of formula-7 or its acid derivatives using coupling agent, solvent optionally in presence of base under anhydrous conditions to get compound of formula-l.(or)

e) treating compound of formula-6a from step-c, with 2-(2-aminothiazol-4- yl)acetic acid of formula-7 in presence of suitable coupling agent, optionally in presence of water and solvent to get the compound of formula-1.
The term "sulfur containing reducing agents" is selected from sodium sulfide, sodium hydrosulfíde, sodium dithionite, sodium sulfíte, sodium metabisulphite etc.
The term "organic solvent" of the invention is selected from alcoholic solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, isobutanol, tert-butanol etc, polar aprotic solvents such as DMF, DMSO, DMA, NMP, N-methylmorpholine, pyridine; ketone solvents such as acetone, methylethyl ketone, methylisobutyl ketone; ester solvents such as ethyl acétate, methyl acétate, isopropyl acétate, tert-butyl acétate; chlorinated solvents such as dichloromethane, chloroform; ether solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, THF, dioxane, 2-

methyl THF; hydrocarbon solvents such as toluene, xylene, nitrile solvents such as ACN, propionitrile; and sulfolane.
The term "inorganic base" of the invention is selected from alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates such as sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate.
The term "acid derivatives" of the present invention includes but not limited to acid halides, anhydrides, esters, imidazolyl, sulfonyl derivatives.
The term "acid addition salts" of the present invention includes but not limited to organic or inorganic acids. Organic acids such as sulfonic acids, oxalic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, maleic acid, succinic acid, fumaric acid, malic acid, citric acid, tartaric acid, lactic acid, benzoic acid, or methanesulphonic acid, mandelic acid, benzenesulphonic acid, toluenesulphonic acid or naphthalenedisulphonic acid etc; Inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid.
The following examples ülustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.
Example-l Preparation of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-

phenylacetamide:
To the suspensión of (R)-2-hydroxy-2-phenylacetic acid (20.0 g, 0.13 mol), 4-nitrophenyl-ethylamine hydrochloride (27.2 g, 0.13 mol), triethyl amine (185 mL, 1.33 mol) in DMF (70 mL) at room temperature, hydroxybenzotriazole (17.76 g, 0.13 mol) and EDC.HC1 (25.2 g, 0.13 mol) were added and stirred overnight. Then reaction was diluted with water (120 mL) and extracted with EtOAc (3x150 mL). The organic layer was washed sequentially with IN HC1 (120 mL), 20% K2C03 (120 mL), water (120 mL), brine and concentrated under reduced pressure to give a residue. The residue was taken in toluene (120 mL), heated to 80-85 °C until clear. solution obtained and slowly allowed to come to room temperature. Stirring was continued for further 10 h at RT to give crystals which were filtered, washed with toluene (30 mL) and dried in vacuo to give (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (33.5 g, 85%).
Example-2 Preparation of (R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochlóride:
To the mixture of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (30.0 g, 0.1 mol) in THF (350 mL) at 10 °C was added sodium borohydride (5.7 g, 0.15 mol) and stirred for 20 min. The reaction mass was cooled to -10 to -5 °C and BF3OEt2 (37 mL, 0.3 mol) was added. The reaction temperature was slowly increased to 65-70 °C and refluxed for 6 h. After that water (30 mL) and conc. HC1 (30 mL) were added at -5 to 0 °C and refluxed at 70 °C for 5 h. Then reaction pH was adjusted to 8-9 with K2CO3 and extracted into EtOAc (3x150 mL). The ethyl acétate layer was washed successively with water (200 mL), brine followed by drying over anhy. Na2SC>4 and concentration in vacuo gave a residue which was taken in 2-propanol (200 mL) and conc.HCl (10.3 mL) was added drop wise and stirred over night. The solid precipitated was filtered, washed with 2-propanol (50 mL), dried in vacuo to give (R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochlóride (29.0 g).

Example-3 Preparation of (R)-2-(4-aminophenethylamino)-l-phenylethanoI:

MeOH (30 mL) and H20 (60 mL) were charged into an RBF containing to (R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochioride (3.0 g, 9.28 mmol) stirred for 10 min and heated to 80 °C. Then sodium dithionite (8.08 g, 46.4 mmol) dissolved in water (16 mL) was added to the reaction at 80 °C temperature and heating continued for 8 h. Then cooled to room temperature and reaction mass pH was adjusted to 8-9 using aq. K2CO3. The reaction mass was extracted with chloroform (3x50 mi), combined organic layers were washed with brine, dried over anhy.Na2SC>4 and concentrated under reduced pressure to obtain (R)-2-((4-aminophenethyl)amino)-l-phenylethanol (0.85 g, 36%).

Example-4 Preparation of (R)-2-(4-aminophenethylamino)-l-phenylethanol:
A suspensión of (R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochioride (0.3 g, 0.93 mmol) in Ethanol and H20 at 80 °C, Na2S204 (0.8 g, 4.64 mmol) dissolved in water (2 mL) was added to the reaction mass at and continued the reaction at same temperature for 5 h. Then the reaction was cooled to R.T, diluted with water and reaction mass pH was adjusted to 8-9 with K2CO3. The reaction mass was extracted with chloroform (3x20 mL). The combined organic layers were washed with brine solution, dried over anhy.Na2S04 and concentrated in vacuo to give (R)-2-((4-aminophenethyl)amino)-l-phenylethanol (0.15 g, 63%).

Example-5 Preparation of (R)-2-(4-aminophenethylamino)-l-phenylethanol:
To a solution of (R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochioride (0.3 g, 0.93 mmol) in 3.6 mL DMF/H20 (1:1) at 80 °C was added a solution of sodium dithionite (0.8 g, 4.64 mmol) in water (2 mL) and stirred for lh. Then the reaction was cooled to RT and pH was adjusted to 7.5-8 with K2CO3. The reaction mass was extracted with CHCI3 (3x20 mL) and the combined organic layers were washed with sat. NaCf solution. The organic phase was dried over anhy.Na2S04 and concentrated in vacuo to furnish (R)-2-((4-aminophenethyl)amino)-l-phenylethanol (0.12 g, 55%).

Example-6 Preparation of (R)-2-(4-aminophenethylamino)-l-phenylethanol:
To a solution of (R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochloride (0.3 g, 0.93 mmol) in 3.6 mL DMSO/H20 (1:1) at 80 °C was added a solution of sodium dithionite (0.8 g, 4.64 mmol) in water (2 mL) and stirred for lh. Then the reaction was cooled to RT and pH was adjusted to 7.5-8 with K2CO3. The reaction mass was extracted with CHCI3 (3x20 mL) and the combined organic layers were washed with sat. NaCl solution. The organic phase was dried over anhy.Na2SC«4 and concentrated in vacuo to furnish (R)-2-((4-aminophenethyl)amino)-l-phenylethanol (0.1 g, 45%).

Example-7 Preparation of (R)-2-(4-aminophenethylamino)-l-phenylethanol:
To a suspensión of (R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochloride (0.3 g, 0.93 mmol) in water (12 mL) at 80 °C was added a solution of sodium dithionite (0.8 g, 4.64 mmol) in water (mL) and continued the reaction till starting material consumed completely by TLC (5 h). Then the reaction was cooled and pH was adjusted to 8-9 with K2CO3 solution and extracted with Chloroform (3x20 mi). The combined organic layers were given brine wash and concentrated under reduced pressure to provide (R)-2-((4-aminophenethyl)amino)-l-phenylethanol (0.12 g, 50%).

Example-8 Preparation of (R)-2-(4-aminophenethylamino)-l-phenylethanol:
To the 1:1 WatenIPA (3.6mL) solution, (R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochloride (0.3 g, 0.93 mmol) was added and heated to 80 °C. Sodium dithionite (0.8 g, 4.64 mmol) pre-dissolved in water (0.6 mL) was added to the reaction mass at 80 °C and stirred for 5 h. Then cooled to room temperature and pH was adjusted to 8-9 with K2CO3. Then the reaction mass was extracted with chloroform (3x20 mL), washed with brine, dried over anhy. Na2SÜ4 and concentrated in vacuo to furnish (R)-2-((4-aminophenethyl)amino)-l-phenylethanol (0.1 g, 42%).

Example-9 Preparation of (R)-2-(4-aminophenethyIamino)-l-phenylethanol:
To a solution of (R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochloride (0.3 g, 0.93 mmol) in 3.6 mL n-Propanol/FbO (1:1) at 80 °C was added a solution of sodium dithionite (0.8 g, 4.64 mmol) in water (2 mL) and stirred for lh. Then the reaction was cooled to RT and pH was adjusted to 7.5-8 with K2CO3. The reaction mass was extracted with CHCI3 (3x20 mL) and the combined organic layers were washed with sat. NaCl solution. The organic phase was dried over anhy. Na2SC«4 and concentrated in vacuo to furnish (R)-2-((4-aminophenethyl)amino)-l-phenylethanol (0.1 g, 42%). *

Example-10 Preparation of (R)-2-(4-aminophenethylamino)-l-phenylethanol:
To a solution of (R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochloride (0.3 g, 0.93 mmol) in 1:1 Aceton¡tr¡le:H20 (3.6 mL) at 80 °C, Na2S204 (0.8 g, 4.64 mmol) dissolvéd in water (2 mL) was added to the reaction mass at and continued the reaction at same temperature for 5 h. Then the reaction was cooled to R.T, diluted with water and reaction mass pH was adjusted to 8-9 with K2CO3. The reaction mass was extracted with chloroform (3x20 mL). The combined organic layers were washed with brine solution, dried over anhy. Na2S04 and concentrated in vacuo to give (R)-2-((4-aminophenethyl)amino)-l-phenylethanol (0.15g, 63%).

Example-11 Preparation of (R)-2-(4-aminophenethylamino)-l-phenylethanol:
(R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochloride (0.3 g, 0.93 mmol) was added to the 1:1 THF:H20 mixture (3.6 mL) and heated to 80 °C after which Sodium dithionite (0.8 g, 4.64 mmol) dissolved in water (0.6 mL) was added to the reaction at 80 °C. The heating was continued with stirring for 7 h. Then reaction was brought to room temperature and adjusted its pH to 8-9 with K2CO3 which on extraction with chloroform (3x20 mL), washing the combined organic layers with brine, drying over anhy. Na2S04 and removing the volátiles in vacuo left (R)-2-((4-aminophenethyl)amino)-l-phenylethanol (0.14 g, 58%).

Example-12 Preparation of (R)-2-(4-aminophenethylamino)-l-phenyIethanol:
(R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochloride (0.5 g, mmol) was charged into the 1:1 mixture of Acetone :H2Ü (3.6 mL) and heated to 80 oC. Sodium dithionite (0.8 g, 4.64 mmol) pre-dissolved in water (0.6 mL) was added to the reaction mass at 80 °C and stirred for 5 h. Then cooled to room temperature and volátiles were removed under reduced pressure. Then pH of the obtained residue was adjusted to 8-9 with.K^COs followed by extraction with chloroform (3x20 mL), washing with brine, drying over anhy. Na2SÜ4 and concentration in vacuo furnished (R)-2-((4-aminophenethyl)amino)-l-phenylethanol (50 mg, 13%).

Example-13 Preparation of (R)-2-(4-aminophenethyIamino)-l-phenylethanol:
Charged (R)-2-((4-nitrophenethyl)arnino)-l-phenylethanol hydrochloride (0.3 g, 0.93 mmol) into MeOH (5 mL) at RT and heated to 65-70 °C. 30% aq. NaSH solution (2.3 mL, 4.64 mmol) was added to the mixture at 65 °C and continued stirring for 2 h. Then removal of MeOH under reduced pressure, extraction of the remaining residue with chloroform (3x20 mL), washing combined organic layers with brine, drying over anhy. Ña2SC>4 followed by concentration in vacuo afforded (R)-2-((4-aminophenethyl)amino)-l-phenylethanol (0.2 g, 83%).

Example-14 Preparation of (R)-2-(4-aminophenethylamino)-l-phenylethanol:
To a solution of (R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochloride (1.0 g, 3.1 mmol) in 12 mL EtOH at 80 °C was added 30% aq. sodium hydrosulfide solution (2.3 mL, 4.64 mmol) and refluxed for 6-8 h. Then the reaction mass was concentrated in vacuo to remove the volátiles. The residue was extracted with CHCI3 (3x50 mL) and the combined organic layers were washed with sat. NaCl solution. The organic phase was dried over anhy. Na2S04 and concentrated in vacuo to furnish (R)-2-((4-aminophenethyl) amino)-l-phenylethanol (0.75 g, 94%).

Example-15 Preparation of (R)-2-(4-aminophenethylamino)-l-phenylethanol:
(R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochloride (0.3 g, 0.93 mmol) and «-propanol (3 mL) were charged into an RBF and heated to 80 °C. 30% aq. NaSH solution (2.3 mL, 4.64 mmol) was added at the same temperature and stirring continued for 5 h. After which time, the reaction mass was cooled and n-propanol was removed in vacuo. Then the residue was extracted with chloroform (3x20 mL) and combined organic layers were washed with brine, dried over anhy. Na2SC>4, concentrated under reduced pressure to give (R)-2-((4-aminophenethyl) amino)-l-phenylethanol (0.13 g, 54%).

Example-16 Preparation of (R)-2-(4-aminophenethylamino)-l-phenylethanol:
To the (R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochloride (0.3 g, 0.93 mmol) and IPA (3 mL) suspensión at 70 °C was added 30% aq. NaSH solution (2.3 mL, 4.64 mmol) and continued stirring at same temperature for 5 h. Then cooled to RT and IPA was removed in vacuo. The residue left behind was extracted with chloroform (3x20 mL). All the chloroform layers were given brine wash, dried over anhy. Na2SÜ4 and concentrated under reduced pressure to give (R)-2-((4-aminophenethyl) amino)-l-phenylethanol (0.2 g, 83%).

Example-17 Preparation of (R)-2-(4-aminophenethyIamino)-l-phenylethanol:
Charged 30% aq. NaSH solution (4.6 mL, 9.3 mmol) into the suspensión of (R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochloride (0.3 g, 0.93 mmol) in acetonitrile (5 mL) at 70 °C and continued the reaction for completion of starting material. Work up of the reaction mixture as per example 16 gave (R)-2-((4-aminophenethyl) amino)-l-phenylethanol (90 mg, 38%)
Example-18 Preparation of (R)-2-(4-aminophenethylamino)-l-phenylethanol:

To the 70 °C suspensión of (R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochloride (0.4 g, 1.24 mmol) in DMSO (5 mL), 30% aq. NaSH solution (3.3 mL, 6.18 mmol) was added and continued reaction at same temperature. After complete consumption of starting material by TLC, reaction was cooled to room temperature and extracted with chloroform (3x30 mL). The combined organic layers were washed with brine, dried over anhy.Na2S04, concentrated in vacuo to provide (R)-2-((4-aminophenethyl) amino)-l-phenylethanol (0.21 g, 66%).

Example-19 Preparation of (R)-2-(4-aminophenethylamino)-l-phenylethanol:
The reaction was carried out as per the procedure described in example using (R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochloride (0.7 g, 2.17 mmol) in DMF (7 mL) and 30% aq NaSH solution (5.75 mL, 11.6 mmol) to furnish (R)-2-((4-aminophenethyl) amino)-l-phenylethanol (0.21 g, 58%)

Example-20 Preparation of (R)-2-(4-aminophenethyIamino)-l-phenylethanol:
30% aq. NaSH solution (1.16 mL, 7.7 mmol) was charged to the suspensión of (R)-2-((4-nitrophenethyl)amino)-l-phenylethanol hydrochloride (0.5 g, 1.55 mmol) in water (10 mL) at 70 °C and stirring continued for 8 h. Then reaction mass was cooled to RT and extracted with chloroform (3x30 mL). Washing of total organic layers with brine, drying over anhy.Na2S04 and evaporation in vacuo resulted (R)-2-((4-aminophenethyl) amino)-l-phenylethanol (0.3 g, 76%)

Example-21 Preparation of (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl)amino)-ethyl)phenyl)acetam¡de:
To the suspensión of (R)-2-(4-aminophenethylamino)-l-phenylethanol (0.7 g, 2.73 mmol) from example 3 in water (5 mL) at 20 °C was added conc.HCl (0.33 mL) and Stirred for 4 h. Then water (5 mL), 2-(2-aminothiazol-4-yl) acetic acid (0.43 g, 2.73 mmol) followed by conc.HCl (0.35 mL) were added sequentially and stirred for 20 min. After which time EDCHC1 (0.63 g, 3.28 mmol) was added to the reaction mass. After completion of reaction, NaOH (0.21 g) in water (4 mL) was added to the reaction mass and stirred for 4 h. Then the reaction mass was filtered and the solid collected was dried in vacuo to give the title compound (0.7 g, 66%).

Example-22 Preparation of (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl)-amino)-ethyl)phenyl)acetamide:
To a mixture of (R)-2-(4-aminophenethylamino)-l-phenylethanol (0.75 g, 2.83 mmol) from example 14 and water (15 mL), conc.HCl (0.35 mL) and stirred for 2 h. To this mixture 2-(2-aminothiazol-4-yl) acetic acid (0.46 g, 2.93 mmol), conc.HCl (0.35 mL) were added and stirred for 30 min. Then EDCHC1 (0.62 g, 3.22 mmol) was added to the reaction mass. After completion of reaction, NaOH (0.245 g) in water (4 mL) charged into the mass and stirred for 4 h. During which time formed solid was filtered and dried to give the title compound (0.31 g, 27%).

Example-23 Preparation of (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl)-amino)-ethyl)phenyl)acetamide:
To the solution of (R)-2-(4-aminophenethylamino)-l-phenylethanol (0.3 g,. 1.17 mmol) in DMF (2 mL) at room temperature, 2-(2-aminothiazol-4-yl) acetic acid (0.18 g, 1.17 mmol), EDCHC1 (0.24 g, 1.28 mmol) and HOBt (0.17 g, 1.28 mmol) were added sequentially and reaction continued for 5 h. After completion of reaction, the reaction mixture pH was adjusted to 8-10 with solid K2CO3 and stirring continued for 2 h. Then the precipitated solid was filtered and dried in vacuo to give title compound (0.21 g, 45%).

Claims:

1. A process for preparation of (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl)am¡no)-ethyl)phenyl)acetamide or its pharmaceutically acceptable salts comprising the steps of:

a) condensation of (R)-2-hydroxy-2-phenylacetic acid compound of formula-2 or its acid derivatives of formula-2a with 2-(4-nitrophenyl)ethanamine compound of formula-3 or formula-3a to give (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide compound of formula-4

b) reducing the compound of formula-4 to give (R)-2-(4-nitrophenethylamino)-l-phenylethanol compound of formula-5 optionally converting the compound of formula-5 into compound of formula-5a

c) reducing the compound of formula-5 or formula-5a with a suitable sulfur containing reducing agent ín organic solventa optionally in presence of water at suitable temperature to give (R)-2-(4-aminophenethylamino)-l-phenylethanol compound of formula-6 or its acid addition salt compound of formula-6a
d) condensing the compound of formula-6 or fomula-6a with 2-(2-aminothiazol-4-yl)acetic acid compound of formula-7 or its acid derivatives of formula-7a optionally in presence of base, using organic solvents or water or mixture thereof togive(R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl)amino)-ethyl)phenyl)acetamide of formula I.

2. The process according to claim-1 (a) & (d), wherein condensation agent is selected from the group N,N-carbonyldiimidazole (CDI), alkyl and aryl carbodiimides such as N,N-diisopropylcarbodiimide (DIC), N,N-dicyclohexyl carbodiimide, l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC.HCl), ditolyl carbodiimide optionally in combination with hydroxybenzotriazole or N-hydroxysuccinimide (NHS) or N-hydroxysulfosuccinimide (Sulfo-NHS), l,r-carbonyl-di-(l,2,4-triazole), alkyl and aryl haloformates such as ethyl chloroformate, phenyl chloroformate, benzyl chloroformate; suitable solvent is selected from water, alcoholic solvents such as methanol, ethanol, 1-propanol, 2-propanol, 1-butanol, ¡sobutanol, tert-butanol etc, polar aprotic solvents such as DMF, DMSO, DMA, NMP, N-methylmorpholine, pyridine; ketone solvents such as acetone, methylethyl ketone, methylisobutyl ketone; ester solvents such as ethyl acétate, methyl acétate, isopropyl acétate, tert-butyl acétate; chlorinated solvents such as dichloromethane, chloroform; ether solvents such as diethyl ether, diisopropyl «ther, methyl tert-butyl ether, THF, dioxane, 2-methyl THF; hydrocarbon solvents such as toluene, xylene, nitrile solvents such as ACN, propionitrile; Sulfolane or mixtures thereof; Suitable base is selected from organic or inorganic bases; Organic base is selected from group but not limited to triethylamine, N,N-diethylisopropylamine, DIPEA, diethylamine, tripropylamine trioctylamine, pyridine, lutidine, DMAP, and dicyclohexylamine. Inorganic bases selected from alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates such as sodium hydroxide, potassium hydroxide, cesium hydroxide, barium hydroxide, magnesium hydroxide, calcium hydroxide, strontium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, calcium bicarbonate.

3. The process according to claim-1 (b), suitable reducing agent is selected from diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, NaBFLt, NaBFLrBFs.etherate, LÍBH4 and the like; and the suitable solvent is selected from alcoholic solvent, ether solvents, ester solvents, hydrocarbon solvents, sulfolane, polar solvents or mixtures thereof.

4. The process according to claim-1 (c), sulphur containing reducing agent is selected from sulphur like sodium sulfíte, sodium sulphide, sodium dithionite, sodium metabusulfíte, sodium hydrosulfide etc; suitable solvent is selected from water or an organic solvent selected from alcohol such as methanol, ethanol, n-propanol, IPA, butanol or ether solvents such as dioxane or THF or ester solvents such as Ethyl acétate, isopropryl acétate or dipolar aprotic solvent such as DMF, DMA, and DMSO, NMP, Sulfolane, or mixture thereof; suitable temperature is selected between temperature ranging from 20-150 °C.

5. The process for the preparation of (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2- hydroxy-2-phenylethyl)amino)-ethyl)phenyl)acetamide or its pharmaceutically acceptable salts comprising the steps of:

a) reducing the compound of formula-5 or hydrochloride salts compound of formula-5a with a suitable sulfur containing reducing agent, solvent optionally in presence of water or mixture thereof at suitable temperature to give (R)-2-(4-aminophenethylamino)-l-phenylethanol compound of formula-6 or its acid addition salt compound offormula-6a

b) condensing the compound of formula-6 or formula-6a with 2-(2^aminothiazol-4-yl)acetic acid compound of formula-7 or its acid derivatives of formula-7a using coupling agent, solvent optionally in presence of base in hydrous or anhydrous conditions togive(R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenylethyl)amino)-ethyl)phenyl)acetamide of formula I.

6. The process according to claim-5 (a), sulfur containing reducing agent is selected from sulphur like sodium sulfíte, sodium sulphide, sodium hydrosulfide, sodium dithionite, sodium metabusulfíte etc; solvent is selected from water or an organic solvent selected from alcohol such as methanol, ethanol, n-propanol, IPA, butanol or ether solvents such as dioxane or THF or ester solvents such as Ethyl acétate, or dipolar aprotic solvent such as DMF, DMA, and DMSO, NMP, Sulfolane or mixture thereof; suitable temperature is selected between temperature ranging from 20-150°C.

7. The process according to claim-5 (b), suitable coupling agent is selected from the group N,N-carbonyldiimidazole (CDI), l-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC.HC1), more preferably EDC.HC1, N,N-diisopropylcarbodiimide (DIC), N,N-dicyclohexyl carbodiimide (DCC), ditolyl carbodiimide optionally in combination with hydroxybenzotriazole or N-hydroxysuccinimide (NHS) or N-hydroxysulfosuccinimide (Sulfo-NHS), ; suitable solvent is selected from water or an organic solvent selected from alcohol such as methanol, ethanol, n-propanol, IPA or ether solvents such as water dioxane, THF, 2- Me THF, Ethyl acétate, isopropryl acétate or dipolar aprotic solvent such as DMF, DMA, DMSO, NMP, Sulfolane, or mixture thereof. Suitable base is selected from organic or inorganic bases; Organic base is selected from group but not limited to triethylamine, N,N-diethylisopropylamine, DIPEA, diethylamine, tripropylamine trioctylamine, pyridine, lutidine, DMAP and dicyclohexylamine. Inorganic bases selected from alkali metal or alkaline earth metal hydroxides, carbonates, bicarbonates^
8. The process according to claim-6, suitable sulfur containing reducing agent is selected from sodium hydrosulfíde, sodium sulfite, sodium sulphide, sodium dithionite, sodium metabusulfite, more preferably sodium dithionite, sodium hydrosulfíde ; suitable solvent is selected from water, alcohols, acetone, DMF, DMSO; more preferably mixture of water/alcohols; suitable temperature is selected between60-100°C.

9. The process according to claim-7, suitable coupling agent is selected from the group N,N-carbonyldiimidazole (CDI), l-ethyl-3-(3-dimethylaminopropyl)- carbodiimide hydrochloride (EDC.HC1), more preferably EDC.HC1; suitable base is selected from TEA, DIPEA, and solvent is selected from DMF, DMSO, THF, or water or mixture thereof.

10. The process according to claim-l(a), l(d) & 5(b), acid derivatives are selected from acid halides, anhydrides, esters, imidazolyl or sulfonyl derivatives; more preferably acid chlorides.