FIELD OF THE INVENTION:
An advantageous process for preparing s-isomer of Mirabegron. BACKGROUND OF THE INVENTION:
Mirabegron is chemically known as 2-(2-aminothiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy2-phenylethyl]amino}ethyl)phenyl]acetamide (Formula-1). Mirabegron, a beta-3-adrenergic agonist,used for treatment of overactive bladder and is marketed under the trade name MYRBETRIQ.
US 6346532 (herein after reffered as' US'532) discloses novel amide derivatives or salts thereof. The said patent desribes the synthesis of mirabegron as dihydrochloride salt given in below scheme and related compounds by using different methods.

The above said process for the preparation of mirabegron dihydrochloride includes reaction of (R)-styrene oxide of the formula with 4-nitrophenyl ethylamine hydrochloride of the formula in EPA at reflux temperature for 12 hrs. After purification by silica gel column chromatography, reacted with Boc anhydride, followed by silica gel column chromatography purification. Further hydrogenated with Pd/C followed by reaction with 2- aminothiazol-4-yl-aceticacid of formula. Acidified with MeOH/HCl gives Mirabegron dihydrochloride. The above said process involves (R)- styrene oxide which is expensive and results in lower yield makes process uneconomical. The protection and deprotection steps with tedious work up make the process lengthy and poorer at atom economy. Moreover US'532 involve reverse phase column chromatography technique for purification is not adaptable at commercial scale.
CN103193730 discloses a novel process for preparation of Mirabegron wherein the amino group of 2-aminothiazole-5-acetic acid is protected with a protecting group and is condensed with 4-amino phenyl ethanol to obtain an intermediate (A); which on further oxidation yields intermediate (B). The intermediate B is subjected to reductive amination with (R)-2-amino-l phenyl ethanol and deprotection, simultaneously to yield Mirabegron. The schematic representation is as Scheme-2.

CN103387500 discloses the process for the preparation of mirabegron. by ring opening of (R)-phenyloxirane with N-benzyl-N-[2-(4-nitrophenyl)ethyl]amine in isopropanol to afford (R)-2-[[[2-(4-nitrophenyl)ethyl] (phenylmethyl) amino] methyl] benzenemethanol, which undergoes hydrogenation with Pd/C and acylation with 2-amino-4-thiazolyl acetic acid.
The single enantiomeric form of a chiral drug is now considered as an improved chemical entity that may offer a better pharmacological profile and an increased therapeutic index, with a more favourable adverse reaction profile. For the manufacturers of a single enantiomeric drug (eutomer), the undesirable stereoisomers in drug control are considered in the same manner as other organic impurities. There are many drugs in which only single enantiomer is active. In such cases the inactive enantiomer is considered as an impurity.
FDA has approved Mirabegron R-isomer as a drug. Thus S-isomer is recognized as an enatiomeric impurity for Mirabegron. Most of the prior art reported for preparation of R-isomer rather than S-isomer of Mirabegron.
Thus, there is need to develop improved, effective process for preparing S-isomer of Mirabegron.
The present invention provides a robust, commercially viable process for preparing S-isomer of Mirabegron.
SUMMARY OF THE INVENTION:
The present invention relates to effective, robust and safe process for preparing S- isomer of Mirabegron of Formula-1 a
One aspect of the present invention provides a process for preparing (S)-2-hydroxy-N-[2-(4nitrophenyl)ethyl]-2-phenylacetamide comprising the steps of;

(a) Condensing (s)-mandelic acid with 4-Nitrophenylethylamine Hydrochloride in presence of base, solvent, catalyst, condensing agent
(b) Isolating (S)-2-hydroxy-N-[2-(4nitrophenyi)ethyl]-2-phenylacetamide
One aspect of the present invention provides a process for preparing (S)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-pheny[ehtanol comprising the steps of;
(a) Reducing (S)-2-hydroxy-N-[2-(4nitrophenyl)ethyl]-2-phenylacetamide in presence of solvent, reducing agent
(b) Isolating (S)-2-[[2-(4-aminophenyl)ethyl]-amino]-1 -phenylehtanol
One aspect of the present invention provides a process for preparing s-isomer of Mirabegron comprising the steps of;
(a) Condensing (S)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylehtanol with 2-
aminothiazol-4-yl-acetic acid dihydrochloride in presence/absence of solvent,
condensing agent
(b) Isolating S-isomer of Mirabegron
DETAIL DESCRIPTION OF THE INVENTION:
The present invention relates to improved, economical and industrially applicable process for the preparation of S- isomer of Mirabegron of Formula-1 a
One aspect of the present invention provides a process for preparing (S)-2-hydroxy-N-[2-(4nitrophenyl)ethylj-2-phenylacetamide comprising the steps of;
(a) Condensing (s)-mandelic acid with 4-Nitrophenylethylamine Hydrochloride in presence of base, solvent, catalyst, condensing agent
(b) Isolating (S)-2-hydroxy-N-[2-(4nitrophenyl)ethyl]-2-phenylacetamide
The process for preparation of (S)-2-hydroxy-N-[2-(4nitrophenyl)ethyl]-2-phenylacetamide of formula-4 depicted in the following reaction scheme-3

The organic or inorganic base for step (a) is selected from the group consisting of primary
amines like methylamine, propyl amine, 2-propyl amine, butyl amine and the like; secondary
amines like N,N-diisopropyl amine, dimethyl amine, diethyl amine, N-methyl propyl amine,
morpholine, tertiary amines like triethylamine, N,N-dimethyl aniline, N,N-diisopropyl ethyl
amine, trimethyl amine.
The solvent for step (a) is selected from the group consisting of dimethylformamide,
isopropylacetate, dichloromethane, dimethylsulfoxide. acetone or mixtures of.
The condensing agent in step (a)-is selected from the group consisting of carbodiimide
reagents like N,N'- dicyclohexylcarbodiimide (DCC) and l-ethyl-3-(3-
dimethylaminoprpyl)carbodiimide (EDC) or its salt; l,r-Carbonyldiimidazole (CD1).
triphosgene, phosgene, diphosgene, carbonildiimidazole, chlorothionyl imidazole, thionyl
diimidazole: borane reagents like boric acid, phenyl boronic acid, trimethyl borate.
The catalyst for step (a) is selected from the group consisting of 1-hydroxybenzotriazole
(HOBT). N-hydroxy-5-norbornene-2.3-dicarboximide (HONB), N-hydroxysuccinimide.
(HOSu), 3-hydroxy-4-oxo-3,4-dihydro-1,2,3-benzotriazine (HODhbt), 6-chloro-1
hydroxybenzotriazole (6-CI-HOBT) and 1 -hydroxy-7- azabenzotriazole (HOAt).
One aspect of the present invention provides a process for preparing (S)-2-[[2-(4-
aminophenyl)ethy!]-amino]-l-phenylehtanol comprising the steps of;
(a) Reducing (S)-2-hydroxy-N-[2-(4nitrophenyl)ethyl]-2-pheny!acetamide in presence of solvent, reducing agent
(b) Isolating (S)-2-[[2-(4-aminophenyl)ethyl]-amino]-l -phenylehtanol
The process for preparation of (S)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylehtanol of formula-6 depicted in the following reaction scheme-4

The solvent for step (a) is selected from the group consisting of ethers like tetrahydrofuran, 2-methyltetrahydrofuran; esters like ethyl acetate, methyl acetate, isopropyl acetate; alcohols like methanol, ethanol, isopropanol or a mixture thereof;.
The reduction agent for step (a) is selected from the group consisting of sodium borohydride and BF3etherate; lithium aluminium hydride, sodium borohydride in presence of Iodine, acids like sulfuric acid, acetic acid, trifluoroacetic acid, zinc chloride, cobalt chloride; sodium borohydride and RzSeX?, where R is alkyl and X is halide group; diborane solutions like BH3:THF, BH;j:SMe2. BFhiNRj; palladium-carbon, palladium hydroxide-carbon, platinum oxide, rhodium on carbon, raney nickel; in presence of hydrogen gas or hydrogen generating source like ammonium formate, hydrazine hydrate.
One aspect of the present invention provides a process for preparing s-isomer of Mirabegron . comprising the steps of;
(a) Condensing (S)-2-[[2-(4-aminophenyi)ethyl]-amino]-l-phenylehtanol with 2-aminothiazol-4-yl-acetic acid dihydrochloride in presence/absence of solvent, condensing agent fc -
(b) Isolating S-isomer of Mirabegron
The process for preparation of S-isomer of Mirabegron of formula-la given in the below reaction scheme-5

The condensing agent for step (a) is selected from the group consisting of l-(3-
dimethylaminopropyl)-3-ethylcarbodiimide (EDC); dicyclohexylcarbodiimide (DCC), l-(3-
dimethylaminopropyI)-3-ethylcarbodiimide hydrochloride (EDAC), N, N-
diisopropylcarbodiimide (DIC). N-tert-butyl-N-methylcarbodiimide (TBMC),
carbonildiimidazole. 1,1-Carbonyldiimidazole (CDr). chlorothionyl imidazole, thionyl diimidazole, N-tert-butyl-N-ethylcarbodiimide (TBEC) and so on.
The following examples explain various other embodiments without limiting the scope of the present invention.
Example-1: Preparation of (S)-2-hydroxy-N-|2-(4nitrophenyl)ethyl|-2-phenylacetamide
To the mixture of (S)-Mandelic acid added 4-Nitrophenylethylamine Hydrochloride, Triethylamine, DMF. 1 -Hydroxybenzotriazole, N-(3-dimethylanimopropyl)-N-ethyl carboiimide hydrochloride (EDC HG1). The reaction mixture was stirred at room temperature for 16 h. The reaction was poured with water and extracted with Isopropyl acetate. The organic layer was washed with IN Hydrochloride solution and followed by 10 % Potassium carbonate solution. The organic layer distilled off under vacuum to obtain residue. The residue was dissolved in toluene at 60 - 70° C and cooled to room temperature. The suspension was filtered and washed with toluene. The wet cake was dried under vacuum oven to obtained 90% of said product as off white powder.
Example-2: Preparation of (S)-2-[[2-(4-aminophenyl)ethyl|-amino|-l-phenylehtanol To the stirred solution of (S)-2-hydroxy-N-[2-(4nitrophenyl)ethyl]-2-phenylacetamide and THF slowly added Sodium borohydrate and Boron trifluoride etharate solution at 0 - 5 ° C.

without isolating of (S)-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide. The mixture of said
organic layer and 5 % Pd/C was stirred under hydrogen pressure at 50 - 55 °C for 5 to 6 h.
Palladium was recovered by filtration with sintered funnel and filtrate mL was distilled off
under vacuum. The crude residue was isolated with cyclohexane (120 mL) and dried under
vacuum to get 71% (S)-2-[[2-(4-aminophenyl)ethyl]-amino]-t-phenylehtanol as off white
solid.
Example-3: Preparation of S-isomer of Mirabegron
To the mixture of (S)-2-[[2-(4-aminophenyl)ethyl]-amino]-l-phenylehtanol and 2-
aminothiazol-4-yl-acetic acid dihydrochloride slowly added Nr(3-dimethylanimopropyl)-N-
ethyl carboiimide hydrochloride (EDC HO), water, Hydrochloride acid at room temperature.
The reaction mixture was stirred for 1 h at room temperature. Solution of sodium hydroxide
was added into reaction and stirred for 1 h. The solid material was filtered, washed and dried
under vacuum to get 68% (S)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxy-2-phenylethyl)
amino]ethyl]acetanilide as white solid.
HPLC Purity: 99.94 %A
Chiral HPLC Purity: 100.0 % A
SOR: +19.21°(l% in MeOH)