FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)

1. TITLE OF THE INVENTION -
AN IMPROVED PROCESS FOR PREPARATION OF
MIRABEGRON OR ITS PHARMACEUTICALLY
ACCEPTABLE SALTS
2. APPLICANT(S)
(a) NAME: MEHTA API PVT. LTD.
(b) NATIONALITY: An Indian Company
(c) ADDRESS: 203, Centre Point, J B Nagar, Andheri (East),
Mumbai 400059
3. PREAMBLE TO THE DESCRITION
The following specification particularly describes the invention and the manner in which it is to be performed:

FIELD OF THE INVENTION:
The present invention relates to an improved process for the preparation of Mirabegron of formula (1) or its pharmaceutically acceptable salts thereof. More particularly the present invention is directed to an improved process for preparation of Mirabegron of formula (1) or its pharmaceutically acceptable salts, thereof employing the use of environment friendly solvent and fewer unit operations.
BACKGROUND OF THE INVENTION:
Mirabegron,(R)-2-(2-aminothiazol-4-yl)-4'-[2-[(2-hydroxyl-2-phenylethyl)amino] ethyl]acetanilide of formula (1) is an orally active beta-3-adrenoreceptor agonist approved by USFDA and marketed under the brand name Myrbetriq for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.

US6346532B1 discloses Mirabegron or a salt thereof and process for its preparation. Specifically it discloses Mirabegron Dihydrochloride which is highly hygroscopic and unstable.
US7342117B1 discloses a and β forms of Mirabegron and process for preparation as represented below,


As represented above, the process involves use of dimethylformamide (DMF) as
solvent for preparing compound of formula-(4) along with N-ethyl-N'-[3-
(dimethylamino)propyl]- carbodiimide hydrochloride (EDC) in presence of 1 -
hydroxybenzotriazole (HOBT) as coupling additives.
WO 1995027727 discloses generically that typically all EDC-mediated amide
formation reactions were carried out in a polar solvent such as acetonitrile or
dimethylformamide. WO2014132270 also discloses use of DMF as solvent for
preparing compound of formula-(4). WO2015044965 discloses acetonitrile as
solvent for preparing compound of formula-(4).
WO 1995027727 further discloses that work-up involving these solvents is
difficult and time consuming, requiring repetitive back extractions.

WO2014132270 and WO2015044965 discloses tedious work-up involving diluting the reaction mass with water followed by multiple back extractions and further subjected to aqueous acidic as well as basic washings followed by concentration to give a concentrate mass. The product is finally isolated from the said concentrate mass using solvent.
All the disclosed prior-art processes for preparing compound of formula - (4) employ use of solvents which demand extensive effluent treatment processes resulting in an increased load on effluent treatment systems thereby rendering the processes not environment friendly. Furthermore the processes disclosed in the prior art for preparing compound of formula - (4) employ tedious work-up involving multiple unit operations like dilution, extractions, washings and concentration, thereby making process unsuitable for industrial production.
In view of the problems occurred in above methods, there remains a need for an environment friendly and industrially suitable process, which overcomes the drawbacks as disclosed in the prior art for the preparation of mirabegron.
The present inventors have investigated an efficient process for synthesis of mirabegron, wherein the reaction for preparing compound of formula-(4) is carried out using water as solvent. Furthermore the compound of formula-(4) is isolated directly from reaction mass thereby rendering the process environment friendly and industrially suitable.
OBJECTS OF THE INVENTION:
It is an object of the present invention to provide an improved process for the
preparation of Mirabegron of formula (1) or its pharmaceutically acceptable salts
thereof.
It is another object of the present invention to provide an improved process for the
preparation of Mirabegron of formula (1) or its pharmaceutically acceptable salts

thereof, employing use of water as solvent for preparing compound of formula-
(4).
It is yet another object of the invention to provide an improved process for the
preparation of Mirabegron of formula (1) or its pharmaceutical^ acceptable salts
thereof avoiding tedious work-up and employing direct isolation of compound of
formula-(4).
SUMMARY OF THE INVENTION:
According to an aspect of the present invention there is provided an improved
process for the preparation of Mirabegron of formula (1) or its pharmaceutically
acceptable salts thereof comprising the steps of:
a) condensing a compound of formula-(5)

with a compound of formula-(6) or its acid addition salt of formula (6a) thereof.

characterized in using water as solvent in the presence of suitable base and suitable coupling reagent optionally along with suitable coupling additives to obtain compound of formula-(4);


b) reducing the compound of formula-(4) with suitable reagent in suitable solvent to give the compound of formula-(3) or its acid addition salt of formula-(3a) thereof;

c) hydrogenating the compound of formula-(3) or its acid addition salt of formula-(3a) thereof in suitable solvent using hydrogenation catalyst to give compound of formula-(2) or its acid addition salt of formula (2a) thereof.

d) condensing the compound of formula-(2) or its acid addition salt of formula (2a) thereof with compound of formula-(7) or its acid addition salt thereof in suitable solvent in presence of suitable coupling agent to afford Mirabegron of formula-(l).


According to yet another aspect of this invention there is provided an improved process for preparation of mirabegron wherein direct isolation of compound of formula - (4) is employed thereby avoiding tedious work-up.
DETAILED DESCRIPTION OF THE INVENTION:
The term "suitable solvent" used in the present invention refers to "hydrocarbon
solvents" such as n-pentane, n-hexane, n-heptane, cyclohexane, methyl
cyclohexane, cycloheptane, pet ether, chlorobenzene, toluene, xylene and the like;
"ether solvents" such as dimethyl ether, diethyl ether, diisopropyl ether, methyl
tert-butyl ether, ethyl tert-butyl ether, di- tert-butyl ether, dimethoxy methane, 1,2-
dimethoxy ethane (monoglyme), diglyme, 1,4- dioxane, tetrahydrofuran, 2-methyl
tetrahydrofuran, morpholine and the like; "ester solvents" such as methyl acetate,
ethyl acetate, n-propyl acetate, isopropyl acetate, n-butyl acetate, iso- butyl
acetate, tert-butyl acetate, diethyl carbonate and the like; "polar-aprotic solvents"
such as dimethylacetamide (DMAc), N,N-dimethylformamide (DMF),
dimethylsulfoxide (DMSO), N- methyl-2-pyrrolidone (NMP),
hexamethylphosphoramide (HMPA) and the like; "nitrile solvents" such as acetonitnle, propionitrile, butyronitrile, isobutyronitrile and like; "chloro solvents" such as dichloromethane, dichloroethane, chloroform, carbon tetrachloride and the like; "ketone solvents" such as acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, methyl isobutyl ketone and the like; "alcoholic solvents" such as methanol, ethanol, n-propanol, isopropanol, n-butanol, iso-butanol, tert-butanol, 2-pentanol, ethylene glycol, diethylene glycol, propylene glycol, 2-ethyl hexanol, benzyl alcohol and the like; "polar solvents", such as water and/or mixtures thereof.

As used herein the present invention the term "suitable base" refers to "inorganic bases" which comprises of "alkali metal carbonates" such as sodium carbonate, potassium carbonate, lithium carbonate and the like; "alkali metal bicarbonates" such as sodium bicarbonate, potassium bicarbonate and the like; "alkali metal hydroxides" such as sodium hydroxide, potassium hydroxide, lithium hydroxide and the like; "alkali metal alkoxides" such as sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide and the like; "alkali metal hydrides" such as sodium hydride, potassium hydride and the like; "alkali metal amides" such as sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA) and the like; "alkali metal phosphates" such as disodium hydrogen phosphate, dipotassiumhydrogen phosphate; and "organic bases" like triethylamine, diisopropyl amine, diisopropylethyl amine, diisobutylamine, tert.butyl amine or methyl amine, pyridine, 4- dimethylaminopyridine (DMAP), N-methyl morpholine (NMM), l,8-diazabicyclo[5.4.0]undec- 7-ene (DBU), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), 1,4-diazabicyclo [2.2.2]octane (DABCO), imidazole or mixtures thereof.
As used herein the present invention the term "addition salts" refer to salts of organic or inorganic acid comprising of hydrochloric acid, hydrobromic acid, sulfuric acid, formic acid, acetic acid, oxalic acid, isopropyl alcohol hydrochloride solution, ethyl acetate hydrochloride solution and the like. Preferable acid addition salt is salt of Hydrochloric acid.
The present invention relates to an improved process for synthesis of mirabegron avoiding use of solvents requiring extensive effluent treatment processes. According to this aspect of the present invention there is provided a process for preparation of Mirabegron of formula (1) or its pharmaceutically acceptable salts comprising the steps of:
a) condensing a compound of formula-(5)


with a compound of formula-(6) or its acid addition salt of formula (6a)thereof

characterized in using water as solvent in presence of suitable base and suitable coupling reagents optionally along with suitable coupling additives to obtain compound of formula-(4);

Suitable base in step a) comprises of .organic base selected from a group of triethylamine, diisopropyl amine, diisopropylethyl amine, diisobutylamine, tert.butyl amine, methyl amine or inorganic bases. Suitable base in step a) is preferably is triethylamine..
Suitable coupling reagents in step a) is selected from a group of reagents comprising of N-ethyl-N'-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (EDC), dicyclohexylcarbodiimide (DCC) and diisopropylcarbodiimide, N,N-

carbonyldiimidazole (CDI), N,N-diisopropylcarbodiimide (DIC), ditolyl carbodiimide.
Suitable coupling additives in step a) is selected from a group of additives comprising 1 - hydroxybenzotriazole (HOBT) and 1 -hydroxy-7-azabenzotriazole (HOAT), N- hydroxysuccinimide (HOSU), 2- hydroxypyridine-N-oxide (HOPO) and endo-N-hydroxy-5-norbornene-2,3-dicarboximide (HONB).
The reaction in step a) may be preferably carried out at temperatures ranging from about but not limiting to 20°C to 50°C, preferably 30°C to 40°C.
In an embodiment according to this aspect of the invention, after the reaction complies the compound of formula-(4) is directly filtered from the reaction mass.
Thus present invention provides an efficient process for synthesis of mirabegron employing use of environment friendly solvent and direct isolation of product thereby avoiding increased load on effluent treatment systems and fewer unit operations.
b) reducing the compound of formula-(4) with a suitable reagent in suitable solvent to give compound of formula-(3) or its acid addition salt of formula (3a) thereof;

Suitable reagent used for reduction in step b) is selected from a group of reducing agents comprising of sodium borohydride, calcium borohydride, potassium borohydride, sodium triacetoxyborohydride, sodium cyanoborohydride, diborane,

borane-dimethyl sulfide, borane-THF complex, LiBH4, trialkyl boranes and the
like.
The suitable reagent preferably used for reduction in step b) is sodium
Borohydride.
In an embodiment according to this aspect of present invention the reduction reaction is carried out in presence of boron trifluoride etherate complex.
The suitable solvent used in reduction reaction in step b) is selected from a group
of solvents comprising of ether solvents; hydrocarbon solvents; alcoholic solvents.
and/or mixtures thereof.
The suitable solvent used in reduction reaction in step b) preferably is
Tetrahydrofuran.
The reaction in step b) may be preferably carried out at temperatures ranging from about but not limiting to 55°C to 85°C, preferably 65°C to 75°C.
According to one aspect of this invention, after the reaction complies the reaction mass is quenched with water followed by basifying the reaction mass and extracting with a suitable solvent.
Suitable solvent selected for extraction in step b) is selected from a group of solvents comprising alcoholic solvent, ether solvents, ester solvents, hydrocarbon solvents, polar solvents, polar aprotic solvents or mixtures thereof.
c) hydrogenating the compound of formula-(3) or its acid addition salt of formula (3a) thereof in suitable solvent in presence of hydrogenation catalyst to give compound of formula-(2) or its acid addition salt of formula (2a) thereof.


Suitable hydrogenation catalyst selected in step c) may include but not limited to Pd on carbon, raney nickel, or Pd(OH)2 under a hydrogen atmosphere or in presence of 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 and the likes.
Suitable solvent selected for reduction reaction in step c) is selected from a group of solvents comprising of hydrocarbon solvents, ether solvents, ester solvents, chloro solvents, polar-aprotic solvents, nitrile solvents, ketone solvents, alcoholic solvents, polar solvents.
The reaction in step c) may be preferably carried out at temperatures ranging from about but not limiting to 37°C to 60°C, preferably 45°C to 50°C.
In an embodiment according to this aspect of present invention, after the reaction _ complies the reaction mass is filtered to remove the hydrogenation catalyst and the filtrate is concentrated followed by isolation of compound of formula-(2) or its acid addition salt of formula (2a) thereof from suitable solvent. The suitable solvent used for isolation is preferably methylene chloride.
d) condensing the compound of formula-(2) or its acid addition salt of formula (2a) with compound of formula-(7) or its acid addition salt in suitable solvent in presence of base and coupling reagents to obtain Mirabegron of formula-(l).


Suitable solvents in step d) according to this aspect of the present invention are selected from the group of solvents comprising of polar solvents, hydrocarbon solvents, ether solvents, ester solvents, chloro solvents, polar-aprotic solvents, nitrile solvents, ketone solvents, alcoholic solvents. The suitable solvent is preferably water.
Suitable coupling reagents in step d) is selected from a group of reagents comprising of N-ethyl-N'-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (EDC), dicyclohexylcarbodiimide (DCC) and diisopropylcarbodiimide, N,N-carbonyldiimidazole (CDI), N,N-diisopropylcarbodiimide (DIC), ditolyl carbodiimide.
The reaction in step d) may be preferably carried out at temperatures ranging from about but not limiting to 20°C to 40°C, preferably 25°C to 35°C.
In an embodiment according to this aspect of present invention, after the reaction complies the reaction mass is basified and the compound of formula (1) is directly isolated.
According to another embodiment of this invention the compound of formula (1) obtained after basifying the reaction, is further purified using ethanol and water mixture.
According to another aspect of this invention the condensation reaction in step a) is carried out in a suitable solvent in presence of suitable base and suitable

coupling reagents optionally in presence of suitable coupling additives to obtain compound of formula-(4), wherein after the reaction complies the compound of formula-(4) is directly isolated from the reaction mass by precipitating with water.
Suitable solvents in step a) according to this aspect of the present invention are selected from the group of solvents comprising of "hydrocarbon solvents, ether solvents, ester solvents, polar-aprotic solvents, nitrile solvents, ketone solvents", alcoholic solvents, polar solvents except water.
In an embodiment according to this aspect of the present invention, if the solvent is water miscible, the reaction mass is diluted with water to precipitate the compound of formula-(4), which is further isolated by filtration.
In yet another embodiment according to this aspect of the present invention, if the solvent is water immiscible, the reaction mass is concentrated and then the concentrated reaction mass is diluted with water to precipitate the compound of formula-(4), which is further isolated by filtration.
EXAMPLES: Example 1
To a round bottom flask, Charged 4-Nitrophenylethylamine hydrochloride (1.00 kg) in N,N-dimethylformamide (3.50 lit.), Triethylamine (0.008 lit.) and R-Mandelic Acid (0.77 kg), 1 - hydroxybenzotriazole (HOBT) (0.65 kg), N-ethyl-N'-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (EDC) (0.95 Kg) and stirred the reaction mass at 0-5.°C till the reaction complies. Charged Water (20 lit.) to the reaction mass. Filtered the reaction mass. Dried the wet cake at 50-55 °C to obtain 1.35 Kg of the title compound. (Yield: 91.0% on theoretical basis)
Example 2
To a round bottom flask, charged Tetrahydrofuran (5.00 lit.), Sodiumborohydride (0.19 kg). Cooled the reaction mass to 0-5°C and charged Stage-I (1.00 kg).

Charged Boron trifluoride etherate (1.37 kg) gradually to the reaction mass and raised the temperature to 65-70°C. Maintained the reaction mass at same temperature till TLC complies. Cooled the reaction mass to 0-5°C. Charged Water (0.50 lit.) followed by 1:1 HC1 (0.50 lit.). Raised the temperature to 65-70°C and maintained till reaction complies. Cooled the reaction mass to 5-10°C Basified the reaction mass using aq. Sodium Carbonate. Extracted the reaction mass with ethyl acetate and charged 10% Ethyl Acetate HC1 to the organic layer till pH below 4. Stirred the reaction mass for 3 hrs. Filtered the reaction mass. Dried the wet-cake to obtain 1.04 kg title compound. (Yield: 96.8% on theoretical basis)
Example 3
To a clean and dry autoclave, charged Methanol (7 lit.), Stage-11 (1 kg.) and Raney Nickel (0.10 kg) under Nitrogen atmosphere. Flushed out nitrogen gas and applied hydrogen gas upto a pressure of 2.5 to 4.5 Kg. Heated the reaction to 45-50°C and maintained at same temperature till the reaction complies. Cooled the reaction mass and filtered the catalyst. Concentrated the filtrate and charged methylene chloride to the reaction mass. Stirred for 30 mins and filtered the reaction mass. Dried the wet-cake to obtain 0.85 kg of the title compound. (Yield: 93.7% on theoretical basis)
Example 4
To a round bottom flask, charged water (1.2 lit), cone HC1 (0.4 kg), Stage-Ill (1.00 kg), 2-(2-Aminothiazol-4-yl)-acetic acid (0.55 kg), EDC.HC1 (0.72 kg) and stirred till the reaction complies at 25-30°C. Basified the reaction mass with sodium hydroxide at 0-5°C and filtered the reaction mass and washed with water. Dried the wet-cake to obtain the title compound which is further re-crystallized from Isopropanol and toluene mixture to give 1.12 kg pure title compound. (Yield: 82.7% on theoretical basis)

CLAIMS:
We claim:
1. An improved process for the preparation of Mirabegron of formula (1) or its pharmaceutically acceptable salts

comprising the steps of:
with a compound of formula-(6) or its acid addition salt thereof.
a) condensing a compound of formula-(5)


characterized in using water as solvent in presence of suitable base and suitable coupling reagent optionally along with suitable coupling additives to obtain compound of formula-(4);


b) reducing the compound of formula-(4) with suitable reducing reagent in suitable solvent to give compound of formula-(3) or its acid addition salt thereof;

c) hydrogenating the compound of formula-(3) or its acid addition salt thereof in suitable solvent in presence of hydrogenation catalyst to give compound of formula-(2) or its acid addition salt thereof.

d) condensing the compound of formula-(2) or its acid addition salt with compound of formula-(7) or its acid addition salt thereof in suitable solvent in presence of suitable coupling reagents to obtain Mirabegron of formula-(l).
2. A process according to claim 1, wherein the suitable base in step a) is triethylamine.
3. A process according to claim 1, wherein the suitable coupling reagent in step a) and step d) is N-ethyl-N'-[3-(dimethylamino)propyl]-carbodiimide hydrochloride (EDC).
4. A process according, to claim 1, wherein the suitable reagent in step b) is sodium borohydride
5. A process according to claim 1, wherein the suitable solvent in step b) is tetrahydrofuran.

6. A process according to claim 1, wherein the hydrogenating catalyst in step c) is palladium on carbon or Raney Nickel and suitable solvent is Methanol.
7. A process according to claim 1, wherein the suitable solvent in step d) is water.
8. A process for the preparation of Mirabegron of formula (I) or its pharmaceutically acceptable salts wherein after the reaction complies in step a), the compound of formula (4) is isolated by filtration directly from the reaction mass by addition of anti-solvent.
9. A process according to claim 8 wherein the anti-solvent is water.