FIELD OF INVENTION

The present invention relates to a facile and cost-effective 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.

BACKGROUND OF THE INVENTION

Mirabegron is chemically described as (R)-2-(2-aminothiazol-4-yl)-N-(4-(2-((2-hydroxy-2-phenyIethyl)amino)-ethyl)phenyl)acetamide or 2-amino-N-[4-[2-[[(2R)-2-hydroxy-2-phenylethyl]amino]ethyl]phenyl]-4-thiazoIeacetamide. 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 arid marketed by Astellas Pharma under the brand name 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 efficacy and good tolerability.

Mirabegron and its pharmaceutically acceptable acid addition salts are first disclosed in US 6,346,532 Bl (herein after US'532). The patent US5532 discloses a process for the preparation of Mirabegron as a dihydrochloride salt in an Example- 41 which comprise of deprotection of tert-butyl (R)- 7V-[2-[4-[2-(2-aminothiazol-4-yl)acetamido]phenyl]ethyl-7^-[(2-hydroxy-2-phenyl)ethyl]carbamate (Boc protected Mirabegron) with hydrochloric acid in a mixture of methanol and ethyl acetate followed by purification 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.

The patent US5532 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' 117). Process for preparation of Mirabegron free base is depicted in the following scheme-2.

In Chinese patent CN103304511, discloses a process for the preparation of Mirabegron free base as depicted in the following scheme-3.

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

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

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

In Chinese patent publication CN103864713, discloses a process for the preparation of Mirabegron as depicted in the following 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 product, carryover impurities, isolation of intermediates as well as Mirabegron by column chromatography, which are not economic on commercial scale.

Hence, there is a need to provide an improved as well as novel process for the preparation of Mirabegron; which is economic, efficient, eco-friendly and to eliminate excess usage of solvents.

OBJECTIVE OF THE INVENTION

The main objective of the present invention is to provide an improved novel, safe and commercially viable process for the preparation of Mirabegron compound of Formula I or its pharmaceutical^ acceptable salts thereof.

Another objective of the present invention is to provide a simple process for the preparation of Mirabegron compound of Formula I or its pharmaceutical^ acceptable salts thereof with less consumption of solvents.

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-!. 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 keto reducing agent in presence of solvent to provide (R)-2-(4-nitrophenethylamino)-l-phenylethanol compound of formula-5 insolvents.

c) without isolating compound of formula-5 is treated with suitable nitro reducing agent in same solvent medium to provide (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 in presence of a suitable coupling agent, solvent optionally in presence of base under hydrous or anhydrous medium 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 from N,N-carbonyldiimidazole (CDI), alkyl and aryl carbodiimides such as N,N-diisopropylcarbodiimide (DIC),N,N-dicyclohexyl carbodiimide (DCC), l-ethyl-3-(3-dimethylaminoprppyl)carbodiimide hydrochloride (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 as ethyl chloroformate, phenyl chloroformate, benzyl chloroformate, dialkyl, diaryl and alkyl aryl carbonates of the formula Rl-O-CO-0-R2, wherein "Rl" and MR2" 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-diethylisopropyIamine, 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 acetate, methyl acetate, isopropyl acetate, tert-butyl acetate; chlorinated solvents such as dichloromethane, chloroform; ether solvents such as diethyl ether, di isopropyl 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 keto reducing agent is selected from diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, NaBFLi, NaBH4-BF3.etherate, LiBH4+, diethyl methoxy borane+NaBH4, Trialkyl boranes 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 nitro reducing agent is selected from palladium-carbon, palladium hydroxide-carbon, platinum oxide, rhodium on carbon, Raney nickel and the like and in presence of hydrogen gas or hydrogen generating source such as but not limited to ammonium formate, hydrazine hydrate etc., or sulfur containing reducing agents is selected from sodium sulfide, sodium hydrosulfide, sodium dithionite, sodium sulfite, sodium metabisulphite etc.

In step-b & c, the suitable solvent is selected from ether solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, THF, dioxane, 2-methyl THF etc; ester solvents such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate etc; 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; chlorinated solvents such as dichloromethane, chloroform;; 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,r-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-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-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 dicyclphexylamine. 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, l-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 acetate, methyl acetate, isopropyl acetate, tert-butyl acetate; 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 derivatives" of formula- 7a 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.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to one pot process for the preparation of Mirabegron compound of Formula-1, which involves the reduction of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide of formula-4 to obtained (R)-2-(4-nitrophenethylamino)-l-phenylethanol of formula-5 is subsequently converted to (R)-2-(4-aminophenethyIamino)-l-phenyIethanol of formula-6 or its salts formula-6a. The obtained product is 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

i) reducing the compound of formula-4 with suitable ketp reducing agents in presence of suitable solvent or mixture thereof at a preferable temperature to obtain compound of formula-5

ii) without isolating compound of formula-5 is treated with suitable nitro reducing agents in presence same solvent medium to obtain compound of formula -6 or 6a.

iii) treating compound of formula-6 or 6a from step-ii, with formula-7 or 7a in presence of suitable coupling agent, optionally in presence of water and solvent to get the compound of formula-1.

The term "suitable keto reducing agent" in step-(i) is selected from diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, NaBH4, NaBH4-BF3.etherate, LiBH4, diethyl methoxy borane+NaBH4, Trialkyl boranes+NaBI-L* and the like;

The term "suitable nitro reducing agent" in step-(ii) is selected from palladium-carbon, palladium hydroxide-carbon, platinum oxide, rhodium on carbon, Raney nickel and the like and in presence of hydrogen gas or hydrogen generating source such as but not limited to ammonium formate, hydrazine hydrate etc., or sulfur containing reducing agents is selected from sodium sulfide, sodium hydrosulfide, sodium dithionite, sodium sulfite, sodium metabisulphite etc.

The term "suitable solvent" in step-(i) & (ii) is is selected from ether solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, THF, dioxane, 2-methylTHF etc- ester solvents such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate etc; 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; chlorinated solvents such as dichloromethane, chloroform;; 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 methanesulfonic acid, mandelic acid, benzenesulfonic acid, toluenesulfonic acid or naphthalenedisulfonic acid etc; Inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid and sulfuric acid.

The following examples illustrate the nature of the invention and are provided for illustrative purposes only and should not be construed to limit the scope of the invention.

Reference Example for the preparation of compound of formula-4

To the suspension of (R)-2-hydroxy-2-phenylacetic acid (150.0 g, 0.98 mol), 4-nitrophenyl-ethylamine hydrochloride (200 g, 0.98 mol), triethyl amine (137 mL, 0.98 mol) in DMF (450 mL) at room temperature, hydroxybenzotriazole (133.2 g, 0.98 mol) and EDC.HC1 (188.2 g, 0.98 mol) were added and stirred overnight. Then reaction was diluted with water (4.5 Lit.) and extracted with EtOAc (3x500 mL). The organic layer was washed sequentially with IN HC1 (1500 mL), 20% K2C03 (1500 mL), water (900 mL), brine and concentrated under reduced pressure to give a residue. The residue was taken in toluene (900 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 (150 mL) and dried in vacuo to give (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (251.6 g, 85%).

Example-1

Preparation of (7?)-2-((4-aminophenethyl)amino)-l-phenylethanol using THF: To the THF (1500 mL) solution of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (150.0 g, 0.5 mol) at 0 °C was added NaBH4 (26.6 g, 0.7 mol) and stirred for 10 min. Then BF3*OEt2 (46.26 mL, 1.4 mol) was slowly added at -10 to -5 °C and after the completion of addition the reaction mass was heated to 60-65 °C until starting material was consumed by TLC. The reaction was quenched with water at -5 to 0 °C and conc.HCl followed by heating the resultant mixture at 60-65 °C for 3-4 hrs. The reaction mass brought to RT, adjusted pH to 8-9 and extracted with ethyl acetate (3x250 mL). The organic layer was dried over anhy.Na2S04 and the organic layer was taken to the next step without isolation.

The above organic layer was taken in auto clave and hydrogenation was carried out with Pd/C (7.5 g, 5%) under H2 atmosphere. After completion, the reaction mass was filtered over celite bed, concentrated under reduced pressure to leave a residue which was heated in toluene at 80-90 °C for 1-2 h before stirring at RT for 5-6 h to give (R)-2-((4-aminophenethyl)amino)-l-phenylethanol (96.0 g, 75%) solid after filtration and drying.

Purity by HPLC: 99.5%; Assay by Potentiometry: 98%.

Example-2

Preparation of (7?)-2-((4-aminophenethyl)amino)-l-phenylethanol using diglyrne:

To the diglyrne (75 mL) solution of (R)-2-hydroxy-N-(4-hitrophenethyI)-2-phenylacetamide (15.0 g, 0.05 mol) at 0 °C was added NaBH4 (2.66 g, 0.07 mol) and stirred for 10 min. Then BF3»OEt2 (4.6 mL, 0.14 mol) was slowly added at -10 to -5°C and after the completion of addition the reaction mass was heated to 60-65 °C until starting material was consumed by TLC. The reaction was quenched with water at -5 to 0 °C and conc.HCl followed by heating the resultant mixture at 60-65 °G for 3-4 hrs. The reaction mass brought to RT, adjusted pH to 8-9 and extracted with ethyl acetate (3x25 mL). The organic layer was dried over anhy.Na2S04 and the organic layer was taken to the next step without isolation.

The above organic layer was taken in auto clave and hydrogenation was carried out with Pd/C (0.75 g, 5%) under H2 atmosphere. After completion, the reaction mass was filtered over celite bed, concentrated under reduced pressure to leave a residue which was heated in toluene at 80-90 °C for 1-2 h before stirring at RT for 5-6 h to give (R)-2-((4-aminophenethyl)amino)-l-phenylethanol (8.96 g, 75%) solid after filtration and drying. Purity by HPLC: 99.4%; Assay by Potentiometry: 98%

Example-3

Preparation of (7?)-2-((4-aminophenethyl)amino)-l-phenylethanol using THF:MTBE(1:1): To the THF: MTBE (1:1, 50 mL) mixture of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (5.0 g, 16.7 mmol) at 0 °C was added NaBH4 (0.88 g, 23.3 mmol) and stirred for 10 min. Then BF3»OEt2 (5.76 mL, 23.3 mmol) was slowly added at -10 to -5 °C and after the completion of addition the reaction mass was heated to 60-65 °C until starting material was consumed by TLC. The reaction was quenched with water at -5 to 0 °C and conc.HCl followed by heating the resultant mixture at 60-65 °C for 3-4 hrs. The reaction mass brought to RT, adjusted pH to 8-9 and extracted with ethyl acetate (3x15 mL). The organic layer was dried over anhy.Na2S04 and the organic layer was taken to the next step without isolation.

The above organic layer was taken in auto clave and hydrogenation was carried out with Pd/C (0.25 g, 5% w/w) under H2 atmosphere. After completion, the reaction mass was, filtered over .celite bed, concentrated under reduced pressure to leave a residue which was heated in toluene at 80-90 °C for 1-2 h before stirring at RT for 5-6 h to give (R)-2-((4-aminophenethyl)amino)-l-phenylethanol (3.4 g, 80%) solid after filtration and drying. Purity by HPLC: 99.5%; Assay: 98%.

Example- 4

Preparation of (if)-2-((4-aminophenethyI)amino)-l-phenylethanol using 2-Me THF:

To the 2-MeTHF (50 mL) mixture of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (5.0 g, 16.7 mmol) at 0 °C was added NaBH4 (0.88 g, 23.3 mmol) and stirred for 10 min. Then BF3«OEt2 (5.76 mL, 23.3 mmol) was slowly added at -10 to -5 °G and after the completion of addition the reaction mass was heated to 60-65 °C until starting material was consumed by TLC. The reaction was quenched with water at -5 to 0 °C and conc.HCl followed by heating the resultant mixture at 60-65 °C for 3-4 hrs. The reaction mass brought to RT, adjusted pH to 8-9 and extracted with ethyl acetate (3x15 mL); The organic layer was dried over anhy.Na2S04 and the organic layer was taken to the next step without isolation.

The above organic layer was taken in auto clave and hydrogenation was carried out with Pd/C (0.25 g, 5% w/w) under H2 atmosphere. After completion, the reaction mass was filtered over celite bed, concentrated under reduced pressure to leave a residue which was heated in toluene at 80-90 °C for 1-2 h before stirring at RT for 5-6 h to give (R)-2-((4-aminophenethyl)amino)-l-phenylethanol (3.4 g, 80%) solid after filtration and drying. Purity by HPLC: 99.5%; Assay: 99%

Example-5

Preparation of (7?)-2-((4-aminophenethyl)amino)-l-phenylethanol using MTBE:

To the MTBE (100 mL) mixture of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (5.0 g, 16.7 mmol) at 0 °C was added NaBH4 (0.88 g, 23.3 mmol) and stirred for 10 min. Then BF3#0£t2 (5.76 mL, 23.3 mmol) was slowly added at -10 to -5 °G and after the completion of addition the reaction mass was heated to 60-65 °C until starting material was consumed by TLC. The reaction was quenched with water at -5 to 0 °C and conc.HCI followed by heating the resultant mixture at 60-65 °C for 3-4 hrs. The reaction mass brought to RT, adjusted pH to 8-9 and extracted with ethyl acetate (3x15 mL)^ The organic layer was dried over anhy.Na2SC>4 and the organic layer was taken to the next step without isolation.

The above organic layer was taken in auto clave and hydrogenation was carried out with Pd/C (0.25 g, 5% w/w) under H2 atmosphere. After completion, the reaction mass was filtered over celite bed, concentrated under reduced pressure to leave a residue which was heated in toluene at 80-90 °C for 1-2 h before stirring at RT for 5-6 h to give (R)-2-((4-aminophenethyl)amino)-l-phenylethanol (3.0 g, 70%) solid after filtration and drying. Purity by HPLG: 99.5%; Assay: 98%

Example -6

Preparation of (/?)-2-((4-aminophenethyl)amino)-l-phenylethanol using THF andNaSH:

To the THF (380 mL) solution of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (37.5 g, 0.125 mol) at 0 °C was added NaBH4 (6.65 g, 0.175 mol) and stirred for 10 min. Then BF3»OEt2 (11.56 mL, 0.35 mol) was slowly added at -10 to -5 °C and after the completion of addition the reaction mass was heated to 60-65 °C until starting material was consumed by TLC. The reaction was quenched with water at -5 to 0 °C and conc.HCl followed by heating the resultant mixture at 60-65 °C for 3-4 hrs. The reaction mass brought to RT, adjusted pH to 8-9 and extracted with ethyl acetate (3x65 mL). The organic layer was dried over anhy.Na2S04 and the organic layer was taken to the next step without isolation.

To above organic layer at 80 °C was added 30% aq. sodium hydrosulfide solution (112.0 mL, 0.75 mol) and refluxed for 6-8 h. Then the reaction mass was concentrated in vacuo to remove the volatiles. The residue was extracted with CH2CI2 (3x100 mL) and the combined organic layers were washed with sat. NaCl solution. The organic phase was concentrated under reduced pressure to leave a residue which was heated in toluene at 80-90 °C for 1-2 h before stirring at RT for 5-6 h to give (R)-2-((4-aminophenethyl)amino)-l-phenylethanol (22.4 g, 70%) solid after filtration and drying.

Purity by HPLC: 99.8%; Assay by Potentiometry: 94%

Example-7

Preparation of (if)-2-(2-aminothiazoI-4-yl)-N-(4-(2-((2-hydroxy-2-phenyIethyl)- amino)-ethyI)phenyl)-acetamide:

To the water (900 mL) suspension of solid (90.0 g, 0.35 mol) obtained in example-1, cone. HC1 (47.6 mL, 0.38 mol) was added at 0 °C and stirred for 2-3 hrs at RT. Then charged 2-amino-Thiazolyl-4-Acetic acid (55.4 g, 0.35 mol) followed by conc.HCl (47.0 mL, 0.38 mol) and stirred for 30 min. before EDCHC1 (154.6 g, 0.8 mol) was added. After completion of starting material by TLC, the pH of reaction mass adjusted to 8.5-9.5 using liq.ammonia. The solid obtained was filtered and dried to give the title compound (133.0g, 95%). Purity by HPLC: 99.5%;

Assay: 98%.

ExampIe-8

Preparation of (^)-2-(2-aminothiazol-4-yl)-A^(4-(2-((2-hydroxy-2-phenylethyl)- amino)-ethyl)phenyI)-acetamide; To the water (200 mL) suspension of solid (20.0 g, 0.08 mol) obtained in experiment no:6, concHCl (8.9 mL, 0.09 mol) was added at 0 °C and stirred for 2-3 hrs at RT. Then charged 2-amino-Thiazolyl-4-Acetic acid (13.6 g, 0.09 mol) followed by conc.HCl (8.9 mL, 0,09 mol) and stirred for 30 min. before EDCHC1 (33.0 g, 0.17 mol) was added. After completion of starting material by TLC, the pH of reaction mass adjusted to 8.5-9.5 using liq.ammonia. The solid obtained was filtered and dried to give the title compound (28.0g, 90%). Purity by HPLC: 99.5; Assay: 97%.

Claims:

1. A process for 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) 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 with suitable solvent to give (R)-2-(4- nitrophenethylamino)-l-phenylethanol compound of formula-5

c) without isolating the compound of formula-5 is treated with suitable nitro reducing agent in a same solvent medium as in step-(b) 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 fofmula-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.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 as ethyl chloroformate, phenyl chloroformate, benzyl chloroformate; suitable solvent is selected from water, alcoholic solvents such as methanol, ethanol, 1-propanol, 2-propanoI, 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 acetate, methyl acetate, isopropyl acetate, tert-butyl acetate; 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; 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 keto reducing agent is selected from, diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, NaBFU, NaBH4-BF3.etherate, LiBH4, diethyl methoxy borane+NaBFLj, Trialkyl boranes+NaBH4 and the like;

4. The process according to claim-1 (c), suitable nitro reducing agent is selected from palladium-carbon, palladium hydroxide-carbon, platinum oxide, rhodium on carbon, raney nickel and the like and in presence of hydrogen gas or hydrogen generating source such as but not limited to ammonium formate, hydrazine hydrate etc., or sulfur containing reducing agents is selected from sodium sulfide, sodium hydrosulfide, sodium dithionite, sodium sulfite, sodium metabisulphite etc.

5. The process according to claim-1 (b) & (c) suitable solvent is selected from ether solvents such as diethyl ether, diisopropyl ether, methyl tert-butyl ether, THF, dioxane, 2-methyl THF etc; ester solvents such as ethyl acetate, methyl acetate, isopropyl acetate, tert-butyl acetate etc; 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; chlorinated solvents such as dichloromethane, chloroform;; hydrocarbon solvents such as toluene, xylene, nitrile solvents such as ACN, propionitrile; sulfolane, optionally in presence of water or mixtures thereof;

6. 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 pharmaceutical^ acceptable salts comprising the steps of:

a) treating the compound of formula-4 with suitable keto reducing agent in presence of solvent to obtain compound of formula-5

b) without isolating the compound of formula-5 is treated with nitro compound reducing agent in presence of same solvent medium to obtain compound of formula-6 or 6a

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

7. The process according to claim-6 (a), suitable keto reducing agent is selected from diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, NaBH4, NaBH4-BF3.etherate, LiBH4, diethyl methoxy borane+NaBH4, Trialkyl boranes+NaBH4 and the like; more preferably NaBH4-BF3.etherate, borane-THF complex

8. The process according to claim-6(b), suitable nitro reducing agent is selected from palladium-carbon, palladium hydroxide-carbon, platinum oxide, rhodium on carbon, raney nickel and the like and in presence of hydrogen gas or hydrogen generating source such as but not limited to ammonium formate, hydrazine hydrate etc. and sulfur containing reducing agents is selected from sodium sulfide, sodium . hydrosulfide, sodium dithionite, sodium sulfite, sodium metabisulphite and the like; more preferably palladium-carbon.

9. The one-pot process for the preparation of (R)-2-((4-aminophenethyl)amino)-l-phenylethanol or its pharmaceutical^ acceptable salts comprising the steps of:

a) treating the compound of formula-4 with suitable keto reducing agent in presence of solvent to obtain compound of formula-5

b) without isolating the compound of formula-5, the solvent mixture containing formula-5 is treated with nitro reducing agent in presence of same solvent medium to obtain compound of formula-6 or 6a

10. The process according to claim-9, suitable keto reducing agent is selected from NaBH4-BF3.etherate, borane-THF complex, diethyl methoxy borane+NaBH4, Trialkyl boranes+NaBI-Lj; more preferably NaBH4-BF3.etherate5; suitable nitro reducing agent is selected from palladium-carbon, palladium hydroxide-carbon; more preferably palladium- carbon, suitable solvent is selected from ether, ester, alcohols, chloro solvents; more preferably ether and ester solvents or mixture thereof.