DESC:
Field of the invention
The present invention relates to an improved, industrially scalable process for preparation of key intermediates of Mirabegron, chemically described as (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide of formula (II) and (R)-2-[(2-(4-Nitrophenyl) ethyl) amino]-1-phenylethanol of formula (III).

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 (R) -2-(2-aminothiazol-4-yl)-4’-[2-[(2-hydroxy-2-phenylethyl) amino] ethyl]-acetanilide. It has the chemical formula (I) and is represented by the CAS registration no. 223673-61-8.

Mirabegron is an orally active beta-3-adrenoreceptor agonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.

US6346532 discloses Mirabegron or a salt thereof and process for its preparation.
Mostly two methodologies are described in the literature for the preparation of Mirabegron. First method utilizes (R)-2-((4-aminophenethyl) amino)-1-phenylethan-1-ol as the key starting material to which aminothiazole moiety is coupled to yield Mirabegron. In this approach the amine groups are either protected or free, based on the reactants, the sequence of reaction and reagents selected. Mostly the amino group of (R)-2-((4-aminophenethyl) amino)-1-phenylethan-1-ol is in the form of nitro group until its reduction to amino group before coupling with 2-amino-4-thiazole acetic acid.

Second method involves reaction of a suitable derivative of the key structural moiety N-(p-ethylphenyl)-aminothiazolylacetamide with the (ß)-hydroxyethylamine moiety to afford Mirabegron.

(R)-2-[(2-(4-nitrophenyl) ethyl) amino]-1-phenylethanol of formula (III) is identified as a key intermediate for the synthesis of Mirabegron.

Several methods have been reported for the preparation of the key intermediate, (R)-2-[(2-(4-nitrophenyl) ethyl) amino]-1-phenylethanol of formula (III). It is generally prepared by reduction of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide of formula (II), which in turn is mostly prepared by condensation of (R)-2-hydroxy-2-phenylacetic acid and 2-(4-nitrophenyl)ethan-1-amine or its derivatives.

The process for preparation of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide and (R)-2-[(2-(4-nitrophenyl) ethyl) amino]-1-phenylethanol has been described in WO 99/020607, JP2011105685, US7342117, WO 2014/132270, IN2013CH02517, IN2015CH02679, IN2015MU01203, WO2015/044965, IN201621009117, WO2018/028679, which are incorporated herein by way of references in its entirety.

Even though, the above mentioned prior art discloses processes for the preparation of Mirabegron intermediates viz. (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide and (R)-2-[(2-(4-nitrophenyl) ethyl) amino]-1-phenylethanol, they are often not amenable on commercial scale because of procedural complications involving complex unit operations of workup, low yield and purity.

The processes described in the art involve time consuming, tedious work up including multiple phase separation/ repetitive back extraction unit operations together with aqueous acidic as well as basic washing of the phase containing the product. The said process increases unit operations at large scale leading to increase in batch time cycle.

Hence, there remains a need to provide simple, scalable, high yielding and industrially suitable processes for producing high quality intermediates of Mirabegron.

The procedural improvement employed in the present invention provides efficient isolation of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide and (R)-2-[(2-(4-Nitrophenyl) ethyl) amino]-1-phenylethanol of high chemical purity and yield and also provides commercial advantages over the processes known in the art.

Objects of the invention
It is an object of the present invention to provide an improved process for preparation of key synthetic intermediates of Mirabegron, specifically (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide of formula (II) and (R)-2-[(2-(4-Nitrophenyl) ethyl) amino]-1-phenylethanol of formula (III).

It is another object of the present invention to provide an economical and industrially feasible process avoiding complex unit operational steps like phase separation for preparation of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide of formula (II) and (R)-2-[(2-(4-Nitrophenyl) ethyl) amino]-1-phenylethanol of formula (III).

It is yet another object of the present invention to use the above mentioned intermediates in the preparation of Mirabegron.

Description of the invention
The present invention relates to processes for the preparation of key intermediates of Mirabegron and Mirabegron thereof.

The terms 'reacting', 'treating', ‘adding’ and ‘contacting’, as used herein refers to bringing at least two distinct chemical species to close vicinity so that a reaction between the two or more chemical molecules can occur or the process of bringing a solid or a solution of a chemical compound in a solvent, which may be a filtrate, in close proximity to another solvent so that washing or precipitation can occur. The terms 'reacting', 'treating', ‘adding’ and ‘contacting’ may comprise mixing and continuously stirring the solvents.

The term 'slurring' as used herein means a process wherein a solid is treated with a solvent, which includes mixing, agitating, leaching, triturating and stirring.

The present invention relates to an improved processes for preparation of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide of formula (II) and (R)-2-[(2-(4-Nitrophenyl) ethyl) amino]-1-phenylethanol of formula (III).

In one aspect of the present invention, said process for the preparation of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide of formula (II) comprises of the following steps:

(a) reacting (R)-2-hydroxy-2-phenylacetic acid and 2-(4-nitrophenyl)ethan-1-amine or a salt thereof in a suitable solvent in the presence of a base and an amide coupling agent; and
(b) isolating (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide of formula (II), wherein the isolation comprises of the following steps:
i. treating the reaction mixture of step (a) with an inorganic base;
ii. slurring the residue of step(i) in a first solvent; and
iii. contacting the filtrate of step (ii) with a second solvent to obtain (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide of formula (II)
wherein the isolation step does not involve any phase separation/solvent extraction/separating the reaction mixture into organic and aqueous layers.

The suitable solvent of step (a) is selected from alcohols such as methanol, ethanol, isopropanol, n- butanol and the like; aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbon such as dichloromethane, dichloroethane and the like; formamide such as ?,?-dimethylformamide, N,N- dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic amides such as N-methylpyrrolidinone and the like; nitriles such as acetonitrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, diisopropyl ether, methyl tert-butyl ether and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; or a mixture thereof.

The base of step (a) is an organic base, selected from organic bases selected from but not limited to l,8-diazabicyclo[5.4.0]undec-7-ene; l ,5-diazabicyclo[4.3.0]non-5-ene; primary amines such as but not limited to methylamine, propyl amine, 2-propyl amine, butyl amine and the like; secondary amines such as but not limited to ?,?-diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, morpholine and the like; tertiary amines such as but not limited to triethylamine, ?,?-dimethyl aniline, ?,?-diisopropyl ethyl amine, trimethyl amine and the like.
The amide coupling reagent of step (a) is selected from carbodiimide reagents such as ?,?'- dicyclohexylcarbodiimide (DCC) and 1-ethyl-3-(3-dimethylaminoprpyl)carbodiimide (EDC) or its salt; or imidazole reagents such as carbonyldiimidazole (CDI) and the like.

In a preferred embodiment the amide coupling agent is high yielding DCC and the fact that it is relatively inexpensive making the overall process cost-effective.

The inorganic base of isolation step (i) is selected from alkali metal carbonates such as but not limited to potassium carbonate, sodium carbonate, cesium carbonate and the like; alkali metal bicarbonates such as but not limited to sodium bicarbonate, potassium bicarbonate and the like; alkali metal hydroxides such as but not limited to sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide and the like; metal alkoxides such as but not limited to sodium methoxide, sodium ethoxide, potassium tert butoxide and the like; and ammonium hydroxide.

The first solvent of isolation step (ii) is selected from the group comprising of halogenated hydrocarbons such as dichloromethane, dichloroethane and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; ethers such as diethyl ether, diisopropyl ether, di-methyl ether, methyl tertiary butyl ether and the like; or mixtures thereof.

The second solvent of isolation step (iii) is selected from the group comprising of aliphatic hydrocarbons such as hexane, heptane and the like; aromatic hydrocarbons such as toluene, xylene and the like; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; nitriles such as acetonitrile and the like; ethers such as diisopropyl ether, methyl tertiary butyl ether and the like; cyclic ethers such as tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane and the like; alcohols such as methanol, ethanol, isopropyl alcohol and the like; amides such as N,N- dimethylformamide, ?,?-dimethylacetamide and the like; or mixtures thereof.

In another aspect of the present invention, said process for the preparation of (R)-2-[(2-(4-Nitrophenyl) ethyl) amino]-1-phenylethanol of formula (III) comprises of the following steps:

(a) reacting compound of formula (II) with a reducing agent in a solvent;
(b) isolating (R)-2-[(2-(4-Nitrophenyl) ethyl) amino]-1-phenylethanol of formula (III), wherein the isolation comprises of the following steps:
(i) treating the reaction mixture of step (a) with an alcoholic solvent and an aqueous acid solution;
(ii) partially concentrating the reaction mixture of step(i);
(iii) adding an alcoholic solvent and filtering;
(iv) treating the wet solid with water; and
(v) adjusting pH of reaction mixture of step (iv) to 9 to 12 to obtain (R)-2-[(2-(4-Nitrophenyl) ethyl) amino]-1-phenylethanol of formula (III)
wherein the isolation step does not involve any phase separation/solvent extraction/separating the reaction mixture into organic and aqueous layers.

The solvent of step (a) is selected from alcohols such as methanol, ethanol, isopropanol, n- butanol and the like; aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbon such as dichloromethane, dichloroethane and the like; formamide such as ?,?-dimethylformamide, N,N- dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic amides such as N-Methylpyrrolidinone and the like; nitriles such as acetonitrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, 2- methyltetrahydrofuran, diisopropyl ether, methyl tert-butyl ether and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; or a mixture thereof.

The reducing agent of step (a) is selected from but not limited to borane reagents such as diborane, borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, NaBH4-BF3.etherate, Lithium borohydride (LiBH4), diethyl methoxy borane/NaBH4, trialkyl boranes and the like; and the solvent is selected from alcoholic solvents, ether solvents, ester solvents, hydrocarbon solvents, sulfolane polar solvents or mixtures thereof;

The alcoholic solvent of isolation step (i) is selected from C1to C4 straight or branched chain alcohol and the acid of isolation step (i) is an inorganic acid selected from the group comprising of hydrochloric acid, sulfuric acid, nitric acid, hydrofluoric acid, phosphoric acid and hydrobromic acid.

The alcoholic solvent of isolation step (iii) is selected from C1to C4 straight or branched chain alcohol.

The pH of isolation step (v) is adjusted using aqueous solution of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like and ammonium hydroxide to obtain (R)-2-[(2-(4-Nitrophenyl) ethyl) amino]-1-phenylethanol of formula (III).

In yet another aspect of the present invention, said process for the preparation of (R)-2-[(2-(4-Nitrophenyl) ethyl) amino]-1-phenylethanol of formula (III) comprises of the following steps:

(a) providing compound of formula (II) with borane-dimethyl sulfide in a solvent;
(b) isolating (R)-2-[(2-(4-Nitrophenyl) ethyl) amino]-1-phenylethanol of formula (III), wherein the isolation comprises of the following steps:
(i) treating the reaction mixture of step (a) with an alcoholic solvent and an aqueous acid solution;
(ii) partially concentrating the reaction mixture of step(i);
(iii) adding an alcoholic solvent and filtering;
(iv) treating the wet solid with water; and
(vi) adjusting pH of reaction mixture of step (iv) to 9 to 12 to obtain (R)-2-[(2-(4-Nitrophenyl) ethyl) amino]-1-phenylethanol of formula (III)
wherein the isolation step does not involve any phase separation/solvent extraction/separating the reaction mixture into organic and aqueous layers.

The solvent of step (a) is selected from alcohols such as methanol, ethanol, isopropanol, n- butanol and the like; aromatic hydrocarbons such as toluene, xylene, and the like; aliphatic hydrocarbons such as hexane, heptane and the like; halogenated hydrocarbon such as dichloromethane, dichloroethane and the like; formamide such as ?,?-dimethylformamide, N,N- dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; cyclic amides such as N-Methylpyrrolidinone and the like; nitriles such as acetonitrile and the like; ketones such as acetone, methyl isobutyl ketone and the like; ethers such as tetrahydrofuran, 2- methyltetrahydrofuran, diisopropyl ether, methyl tert-butyl ether and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate and the like; or a mixture thereof.

The alcoholic solvent of isolation step (i) is selected from C1to C4 straight or branched chain alcohol and the acid of isolation step (i) is an inorganic acid selected from the group comprising of hydrochloric acid, sulfuric acid, nitric acid, hydrofluoric acid, phosphoric acid and hydrobromic acid.

The alcoholic solvent of isolation step (iii) is selected from C1to C4 straight or branched chain alcohol.

The pH of isolation step (v) is adjusted using aqueous solution of alkali metal hydroxide such as sodium hydroxide, potassium hydroxide and the like and ammonium hydroxide to obtain (R)-2-[(2-(4-Nitrophenyl) ethyl) amino]-1-phenylethanol of formula (III).

The intermediates of the present invention are used for preparation of Mirabegron API for pharmaceutical preparation.

The process according to this invention is described in detail. The reaction conditions such as solvents and temperature given are meant to provide preferred ranges and examples for the respective transformation that can be principally applied but are not supposed to restrict them to the selection given.

Starting materials that may be used as the input for the process of the present invention may be obtained commercially or by any process including the processes described in the art.

Following Examples are set forth to aid in the understanding of the invention, and are not intended and should not be interpreted as a limitation thereon. Modifications to reaction conditions, for example, temperature, duration of the reaction or combinations thereof, are envisioned as part of the present invention.

Table-1: Comparative data with and without phase separation unit operation:
Intermediate Without phase separation/extraction unit operation With phase separation/extraction
Yield (%) Quality (by HPLC) Yield (%) Quality (by HPLC)

89 % - 95 % 99.98 % 84 % 98.44%

82 % - 85 % ~99.90% 45 % - 73 % ~99.85%

Table-2: Comparative data vis-à-vis performance of reducing agent used in the preparation of (R)-2-((4-nitrophenethyl) amino)-1-phenylethan-1-ol of formula (III):
Sr. No. Reducing agent Yield % Purity by HPLC
1 NaBH4/BF3.Et2O 77% 99.59%
2 NaBH4/I2 29.5% NA
3 NaBH4/CH3COOH NA NA
4 BH3-DMS 84% 99.98%
5 BH3-THF 53.68% 98.07%

EXAMPLES
Example-1: Preparation of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide
To a mixture of (R)-2-hydroxy-2-phenylacetic acid (0.826 Kg) and 2-(4-nitrophenyl)ethan-1-amine hydrochloride (1.0 kg) in N,N-dimethylformamide (4 L) was added triethylamine , 1-hydroxybenzotriazole and N,N-dicyclohexyl carbodiimide and the reaction mixture was stirred for 3 to 4 hrs at 25-35oC. Thereafter the reaction mixture was diluted with ethylacetate 15 l and water 20 l and stirred for 1 to 2 hrs and filtered. The filtrate was allowed to settle and layers were separated. Organic layer was preserved. The aqueous layer was extracted with ethylacetate 5L and combined with the preserved organic layer. The combined organic layer was washed with 10 L 10% aq. HCl followed by 10L 15% aqueous potassium carbonate and 10l 20% brine solution. Thereafter the solvent was distilled off to about 3V at bath temp. of about 90oC, cooled to 50-60oC and added cyclohexane 5L and stirred the reaction mixture for 1 hr, further cooled the reaction mixture to 25-35 oC and stirred for 1 to 3 hrs further cooled to 10-15 oC and stirred for 3 to 5 hrs. The precipitated solid was filtered and dried under vacuum to afford 1.3 kg of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide.

Example-2: Preparation of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide
To a mixture of (R)-2-hydroxy-2-phenylacetic acid (0.826 Kg) and 2-(4-nitrophenyl)ethan-1-amine hydrochloride (1.0 kg) in N,N-dimethylformamide (4 L) was added triethylamine , 1-hydroxybenzotriazole and a solution of N,N-dicyclohexyl carbodiimide in DMF and the reaction mixture was stirred for 3 to 4hrs at 25-35oC. Thereafter added 0.5N aq. sodium hydroxide solution to the reaction mixture and stirred for 2 to 10 hrs at 25-35oC, filter the reaction mixture, wash with water 10l and suck dry. The wet cake was treated with ethylacetate 25l and stirred for 1-2 hrs and filtered. The filtrate was distilled off to 3V and 3V at bath temp. of about 90oC, cooled to 50-60oC and added cyclohexane 5L and stirred the reaction mixture for 1 hr, further cooled the reaction mixture to 25-35 oC and stirred for 1 to 3 hrs further cooled to 10-15 oC and stirred for 3 to 5 hrs. The precipitated solid was filtered and dried under vacuum to afford 1.4 kg of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide.

Example-3: Preparation of (R)-2-((4-nitrophenethyl) amino)-1-phenylethan-1-ol
To a cooled mixture of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide in tetrahydrofuran was added borane dimethyl sulphide at -5 to 5 oC and stirred for 15 to 30 min. Thereafter the temperature of the reaction mass was raised to 20-30 oC and stirred for 15 to 30 min. The reaction mixture was heated to reflux and stirred for 2 to 6 hrs. Then the reaction mass was gradually cooled under nitrogen to -5 to 5 oC followed by addition of methanol and aq. 50%HCl.Then reaction mixture was heated to 60-70 oC and stirred for 1-2 hr. Thereafter the reaction mixture was cooled to 40-50 oC, the solvent volume was reduced to about 3V, and isopropanol was added at 25-35 oC and filtered. The wet cake was added to water and the pH was adjusted to 9-10.5 using aq. ammonia (1L). The slurry mass was stirred at 25-35 oC for 1 to 3 hrs filtered, and dried under vacuum to afford 750 gm of (R)-2-((4-nitrophenethyl) amino)-1-phenylethan-1-ol.

Example-4: Preparation of (R)-2-((4-nitrophenethyl) amino)-1-phenylethan-1-ol
To a cooled mixture of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide (1.0 Kg) in tetrahydrofuran (10L) was added borane dimethyl sulphide (0.65L) at -5 to 5 oC and stirred for 15 to 30 min. Thereafter the temperature of the reaction mass was raised to 20-30 oC and stirred for 15 to 30 min. Then the reaction mass was heated to reflux and stirred for 2 to 6 hrs at reflux. Then the reaction mass was gradually cooled under nitrogen to -5 to 5 oC followed by addition of methanol and aq. 50%HCl.Then reaction mixture was heated to 60-70 oC and stirred for 1-2 hr. Thereafter the reaction mixture was cooled to 40-50 oC, the solvent volume was reduced to about 3V, and isopropanol was added at 25-35 oC and filtered. The wet cake was added to water and pH was adjusted to 10-11.5 using 0.5N aq. sodium hydroxide solution (0.8L). The slurry mass was stirred at 25-35 oC for 1 to 3 hrs filtered, dried under vacuum to afford 800gm of (R)-2-((4-nitrophenethyl) amino)-1-phenylethan-1-ol.

Example-5: Preparation of Mirabegron
Step-1: A mixture of (R)-2-((4-nitrophenethyl) amino)-1-phenylethan-1-ol (1 Kg) in methanol (9.5 L) was added to an autoclave and 10% Pd/C (50% wet; 0.025 Kg) was added and hydrogenated under hydrogen pressure of about 2.0 Kg and stirred for 2 to 4 hrs at 20-35 oC. After completion of reaction, the reaction mass was filtered and the solvent was distilled off up to 1.5 V. Then ethylacetate was added and the solvent was distilled off up to 1.5V. Again ethylacetate was added and the solvent was distilled off up to 1.5V. Slowly HCl in ethylacetate was added to the reaction mass under nitrogen atmosphere, the reaction mass was stirred for 1-2 hrs at 25-30 oC, filtered and dried under vacuum to afford 85 gm of (R)-2-[2-(4-aminophenyl)-ethylamino]-1-phenyl ethanol hydrochloride.

Step-2: To (R)-2-[2-(4-aminophenyl)-ethylamino]-1-phenyl ethanol hydrochloride (1 kg) 4000ml water was added and the reaction mixture was stirred for 10-20 min at 25-30oC. Thereafter (2-amino-thiazol-4-yl)-acetic acid (480 gm) was added, followed by Conc. HCl (240ml) and the reaction mixture was stirred for 10-20 min. at 25-30 oC. A solution of EDC.HCl (687gm) in water (1L) was prepared and added to the reaction mixture gradually at 25-30 oC and the reaction mixture was stirred for 60-120 min. After completion of reaction, 6.0% aqueous NaOH was gradually added to the reaction mixture till pH 9-9.5 is attained and stirred for 30-60 min at 25-30 oC. Thereafter the reaction mass was filtered and washed with water (2x 2L) and suck dried. The wet cake was slurry washed with 15L of water filtered, washed with water and vacuum dried at 45-50 deg till water content is less than 5%w/w to afford Mirabegron.

Example-6: Preparation of a-form crystal of Mirabegron
(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide (1 Kg) was added to mixture of methanol (2.4 L) in isopropyl alcohol (9.6 L) followed by addition of butylated hydroxy anisole (BHA) (0.010 Kg).The reaction mixture was heated to 65-70 °C and stirred for 30-40 min. The reaction mixture was micron filtered and filtrate was transferred to clean flask. The contents were cooled and stirred for 2-3 hr at 25-30 °C and then further cooled to 0-5 °C and stirred for 2-3 hr. The precipitated solid was filtered and dried to yield 760 gm (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl) amino] ethyl]-acetanilide.HPLC Purity = >99%

Example-7: Preparation of a-form crystal of Mirabegron
(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)amino]ethyl]-acetanilide (1 Kg) was added to mixture of methanol (2.4 L) in isopropyl alcohol (9.6 L) followed by addition of butylated hydroxy anisole (BHA) (0.010 Kg).The reaction mixture was heated to 65-75 °C and stirred for 30-40 min. The reaction mixture was filtered through celite bed followed by micron filteration. The celite bed and micron filter was washed with hot methanol: isopropanol mixture (2:8; 1.0 L). The filtrate was transferred to a clean flask. The contents were cooled and stirred for 2-3 hr at 25-30 °C and then further cooled to 0-5 °C and stirred for 2-3 hr. The precipitated solid was filtered and dried at 45-50 oC. The dried product was multi milled followed by cad milling using #60 mesh QS equivalent 61 followed by sifting using #40 mesh to yield 760 gm of (R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl) amino] ethyl]-acetanilide.HPLC Purity = >99%
,CLAIMS:1. A process for preparation of (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide of formula (II),

comprising:
(a) reacting (R)-2-hydroxy-2-phenylacetic acid and 2-(4-nitrophenyl)ethan-1-amine or a salt thereof in solvent in the presence of a base and an amide coupling agent; and
(b) isolating (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide of formula (II), wherein the isolation comprises of the following steps:
i. treating the reaction mixture of step (a) with an inorganic base;
ii. slurring the residue of step(i) in a first solvent; and
iii. contacting the filtrate of step (ii) with a second solvent to obtain (R)-2-hydroxy-N-(4-nitrophenethyl)-2-phenylacetamide of formula (II)
wherein, the isolation step does not involve any phase separation or solvent extraction or separating the reaction mixture into organic and aqueous layers.

2. The process according to claim 1, wherein the amide coupling agent is selected from ?,?'- dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminoprpyl)carbodiimide (EDC) and carbonyldiimidazole (CDI).

3. The process according to claim 1, wherein the base of step (a) is selected from to l,8-diazabicyclo[5.4.0]undec-7-ene; l ,5-diazabicyclo[4.3.0]non-5-ene, methylamine, propyl amine, 2-propyl amine, butyl amine, ?,?-diisopropyl amine, dimethylamine, diethyl amine, N-methyl propyl amine, morpholine, triethylamine, ?,?-dimethyl aniline, ?,?-diisopropyl ethyl amine, trimethyl amine .

4. The process according to claim 1, wherein the inorganic base of isolation step (i) is selected from potassium carbonate, sodium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide, potassium hydroxide, barium hydroxide, lithium hydroxide sodium methoxide, sodium ethoxide, potassium tert butoxide and ammonium hydroxide.

5. The process according to claim 1, wherein the first solvent of isolation step (ii) is selected from dichloromethane, dichloroethane, ethyl acetate, methyl acetate, isopropyl acetate, diethyl ether, diisopropyl ether, di-methyl ether, methyl tertiary butyl ether or mixtures thereof.

6. The process according to claim 1, wherein the second solvent of isolation step (iii) is selected from hexane, heptane, toluene, xylene, acetone, methyl ethyl ketone, methyl isobutyl ketone, ethyl acetate, methyl acetate, isopropyl acetate, acetonitrile, diisopropyl ether, methyl tertiary butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, 1 ,4-dioxane, methanol, ethanol, isopropyl alcohol, N,N- dimethylformamide, ?,?-dimethylacetamide or mixtures thereof.

7. A process for the preparation of (R)-2-[(2-(4-Nitrophenyl) ethyl) amino]-1-phenylethanol of formula (III)

comprising:
(a) reacting compound of formula (II) with a reducing agent in a solvent;
(b) isolating (R)-2-[(2-(4-Nitrophenyl) ethyl) amino]-1-phenylethanol of formula (III), wherein the isolation comprises of the following steps:
(i) treating the reaction mixture of step (a) with an alcoholic solvent and an aqueous acid solution;
(ii) partially concentrating the reaction mixture of step(i);
(iii) adding an alcoholic solvent and filtering;
(iv) treating the wet solid with water; and
(v) adjusting pH of reaction mixture of step (iv) to 9 to 12 to obtain (R)-2-[(2-(4-Nitrophenyl) ethyl) amino]-1-phenylethanol of formula (III).
wherein, the isolation step does not involve any phase separation/solvent extraction/separating the reaction mixture into organic and aqueous layers.

8. The process according to claim 7, wherein the reducing agent of step (a) is selected from borane-dimethyl sulfide, borane-THF complex, sodium triacetoxyborohydride, sodium cyanoborohydride, NaBH4-BF3.etherate, Lithium borohydride and trialkyl boranes.

9. The process according to claim 7, wherein the pH of isolation step (v) is adjusted using aqueous solution of sodium hydroxide or potassium hydroxide or ammonium hydroxide.

10. The process according to claim 1 and claim 7, wherein the solvent of step (a) is selected from methanol, ethanol, isopropanol, n- butanol, toluene, xylene, hexane, heptane, dichloromethane, dichloroethane, ?,?-dimethylformamide, N,N- dimethylacetamide, dimethylsulfoxide, N-Methylpyrrolidinone, acetonitrile, acetone, methyl isobutyl ketone, tetrahydrofuran, 2- methyltetrahydrofuran, diisopropyl ether, methyl tert-butyl ether, ethyl acetate, methyl acetate, isopropyl acetate.