DESC:FORM 2
THE PATENT ACT 1970
(39 of 1970)
&
The Patents Rules, 2003

COMPLETE SPECIFICATION
(See section 10 and rule 13)
“PROCESS FOR PREPARATION OF AMORPHOUS MIRABEGRON”

Glenmark Pharmaceuticals Limited;
an Indian Company, registered under the Indian company’s Act 1957 and having its registered office at
Glenmark House,
HDO- Corporate Bldg, Wing-A,
B. D. Sawant Marg, Chakala,
Andheri (East), Mumbai- 400 099

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 process for the preparation of amorphous mirabegron.
Background of The Invention
Mirabegron which is chemically known as 2-(2-Amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide, is represented by compound of Formula I.

I
MYRBETRIQ™ Astellas Pharma’s (R)-mirabegron (25mg and 50mg extended-release tablets) is a beta-3 adrenergic agonist indicated for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.
Summary of the Invention
In one embodiment, the present invention provides a process for the preparation of amorphous mirabegron, a compound of formula I, comprising:

I
a) suspending mirabegron mandelate or mirabegron phosphate in water to obtain a reaction mixture;
b) basifying the reaction mixture of step ‘a’ followed by extracting the reaction mixture with a first organic solvent;
c) removing the first organic solvent to obtain a residue;
d) adding a second organic solvent or a mixture of organic solvents to step ‘c’ to obtain a solution; and
e) lyophilizing the solution of step ‘d’ to obtain amorphous mirabegron.
In one embodiment, the present invention provides a process for the preparation of mirabegron phosphate or mirabegron mandelate comprising the steps of:
a) condensing a compound of formula II with a compound of formula III in the presence of a coupling agent to obtain a reaction mixture;

II III
b) basifying the reaction mixture of step ‘a’ and extracting the reaction mixture with a solvent; and
c) adding mandelic acid or orthophosphoric acid to the above step ‘b’ to obtain mirabegron mandelate or mirabegron phosphate thereof.
In one embodiment, the present invention provides a salt of mirabegron selected from the group consisting of mirabegron phosphate and mirabegron mandelate.
In one embodiment, the present invention provides mirabegron phosphate characterized by 1HNMR (DMSO-d6 300MHz) having peaks at 1.14, 2.0-2.1, 2.94, 3.09, 3.45, 4.97 6.30, 6.9, 7.16-7.19, 7.28-7.39, 7.53-7.56, 10.09 and mirabegron mandelate characterized by 1HNMR (DMSO-d6 300MHz) having peaks at 2.68-2.97, 3.10-3.13 , 3.44 , 4.78, 4.87-4.90, 6.30, 7.13-7.13, 7.21-7.39, 7.51-7.54 10.01.
In one embodiment, the present invention provides amorphous mirabegron wherein the content of 1-(2-amino-1,3-thiazol-4-yl)-N-[4-(2- {[(2S)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide is less than 0.15%, as determined high performance liquid chromatography.

IV
Brief Description of the Drawings
Fig. 1: NMR of Mirabegron mandelate according to example 1.
Fig. 2: NMR of Mirabegron phosphate according to example 2.
Detailed Description of the Invention
In one embodiment, the present invention provides a process for the preparation of amorphous mirabegron, a compound of formula I, comprising:

I
a) suspending mirabegron mandelate or mirabegron phosphate in water to obtain a reaction mixture;
b) basifying the reaction mixture of step ‘a’ followed by extracting the reaction mixture with a first organic solvent;
c) removing the first organic solvent to obtain a residue;
d) adding a second organic solvent or a mixture of organic solvents to step ‘c’ to obtain a solution; and
e) lyophilizing the solution of step ‘d’ to obtain amorphous mirabegron.
In one embodiment, step ‘a’ of the above process mirabegron mandelate salt is suspended in water to obtain a reaction mixture.
The reaction mixture is cooled to a temperature of about 0°C to about 30°C. Preferably, the suspension of mirabegron mandelate in water is cooled to a temperature of about 10°C to 20°C.
In one embodiment, step ‘b’ of the above process involves basifying the reaction mixture of step ‘a’ followed by extracting the reaction mixture with a first organic solvent.
In one embodiment the suspension of mirabegron mandelate in water is basified using a suitable base. The base may selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and strontium hydroxide; carbonates such as sodium carbonate, potassium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate, aqueous ammonia, ammonia gas and the like.
The basified reaction mixture is extracted with a first organic solvent. The first organic solvent may be selected from the group consisting of C1-C5 alcohol such as methanol, ethanol, isopropanol, n-propanol, n-butanol; ketones such as methyl ethyl ketone, methyl isobutyl ketone and the like; halogenated hydrocarbons such as methylene chloride, chloroform, ethylene dichloride and the like; esters such as ethyl acetate, ethers such as tetrahydrofuran, diethyl isopropyl ether and the like and mixtures thereof. Preferably the first organic solvent is n-butanol.
In one embodiment, the basified reaction mixture is extracted with n-butanol to obtain n-butanol solution comprising mirabegron.
In one embodiment, step ‘c’ of the above process involves removing the first organic solvent to obtain a residue. The removal of solvent may be accomplished by complete evaporation of the solvent or concentrating the solution, cooling the solution if required and filtering the obtained solid. The solution may also be completely evaporated, for example, a rotavapor, a vacuum paddle dryer or in a conventional reactor under vacuum above about 720mm Hg, or evaporated by lyophilisation, freeze-drying technique, spray drying, fluid bed drying, flash drying, spin flash drying, thin-film drying.
In one embodiment, the n-butanol solution comprising mirabegron is distilled at a temperature of about 40°C to about 60°C. Preferably, the solution is distilled at a temperature of about 50°C to about 55°C to obtain an oily residue.
In one embodiment, step ‘d’ of the process involves adding a second organic solvent or a mixture of organic solvents to step ‘c’ to obtain a solution.
In one embodiment, in step ‘d’ the second organic solvent is selected from a group consisting of C1-C5 alcohol such as methanol, ethanol, tertiary butanol and the like, esters such as ethyl acetate, isopropyl acetate; amides such as dimethyl acetamide, dimethyl formamide and the like; water; nitriles such as acetonitrile and mixtures thereof.
In one embodiment, in step ‘d’ the second organic solvent is a mixture of tertiary butanol and water.
In one embodiment, in step ‘d’ of the process, the amount of second organic solvent or mixture of organic solvents is not less than five times by volume per gram of mirabegron mandelate or mirabegron phosphate.
In one embodiment, the second solvent is a mixture of water and tertiary butanol.
In one embodiment, the mixture of water and tertiary butanol is added to the residue obtained in step ‘c’ to obtain a solution.
In one embodiment, the amount of the mixture of water and tertiary butanol is not less than five times by volume per gram of mirabegron mirabegron mandelate or mirabegron phosphate.
In one embodiment, the amount of the mixture of water and tertiary butanol is ten times by volume per gram of mirabegron mandelate or mirabegron phosphate.
In one embodiment, step ‘e’ of the process involves lyophilizing the solution of step ‘d’ to obtain amorphous mirabegron.
In one embodiment, in step ‘e’ the lyophilisation is carried out at a pressure of about less than 100 millitorr.
In one embodiment, the lyophilisation is carried out under following condition:
Lyophilizer Instrument: BenchTop Pro with Omnitronics TM SP Scientific
Lyophilisation condition: Condenser temperature: -75°C to -85°C, Vacuum: less than 100 millitorr, Run time: 24 hrs to 48 hrs
In one embodiment, step ‘e’ the amorphous mirabegron is further subjected to drying to obtain amorphous mirabegron having a moisture content of less than about 2 percent.
In one embodiment, the present invention provides a process for the preparation of amorphous mirabegron, a compound of formula I, comprising:

I
a) suspending mirabegron mandelate or mirabegron phosphate in water to obtain a reaction mixture;
b) basifying the reaction mixture of step’a’; and
c) isolating amorphous mirabegron.
In one embodiment, the step ‘a’ may be performed as discussed above.
In one embodiment, the step ‘b’ involving basification may be performed as discussed above.
In one embodiment, in step ‘c’, isolation of amorphous mirabegron from the basified reaction mixture of step ‘b’ may be achieved by methods selected from the group consisting of extracting the reaction mixture with a solvent or a mixture of solvents and isolation by removal of solvent. The removal of solvent may be partial removal followed by filtering the precipitated solid or complete removal of solvent to obtain amorphous mirabegron. The isolation of amorphous mirabegron may be achieved by subjecting the mixture of solvents to lyophilisation.
The solvent may be selected from the group consisting of C1-C5 alcohol such as ethanol, methanol, isopropanol, n-propanol, butanol; esters such as ethyl ester, isopropyl ester; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone and the like; amides such as dimethyl formamide; ethers such as diethyl ether, tetrahydrofuran, water and mixtures thereof.
In one embodiment, the basified reaction mixture is extracted with a mixture of tertiary butanol and water and subjected to lyophilisation.
In one embodiment, the present invention provides a process for the preparation of mirabegron phosphate salt or mirabegron mandelate comprising the steps of:
a) condensing a compound of formula II with a compound of formula III in the presence of a coupling agent to obtain a reaction mixture;

II III
b) basifying the reaction mixture of step ‘a’ and extracting the reaction mixture with a solvent; and
c) adding mandelic acid or orthophosphoric acid to the above step ‘b’ to obtain mirabegron mandelate or mirabegron phosphate thereof.
In one embodiment, step ‘a’ of the above process involves condensing a compound of formula II with a compound of formula III in the presence of a coupling agent to obtain a reaction mixture.
In one embodiment, the coupling agent is selected from the group consisting of EDC hydrochloride [1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride], cabonyldiimidazoleDicylcohexycarbodiimide (DCC), 1-[Bis(dimethylamino) methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxide hexafluorophosphate (HATU), 3-[Bis(dimethylamino)methyliumyl]-3H-benzotriazol-1-oxide hexa?uorophosphate (HBTU), O-(6-Chlorobenzotriazol-1-yl)-N,N,N’,N’-tetramethyluroniumhexafluoro phosphate (HCTU). Preferably, the coupling agent is EDC hydrochloride.
In one embodiment, the solvent may be selected from the group consisting of water, C1-C5 alcohols such as methanol, ethanol, n-butanol, tertiary butanol and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone.
In one embodiment, the condensation of the compound of formula II with a compound of formula III in the presence of a coupling agent is carried out at a temperature of about -5°C to about 30°C. Preferably, the reaction is carried out at a temperature of about 10°C to about 20°C.
In one embodiment, optionally the reaction mixture of step ‘a’ may be subjected to charcoal treatment.
In one embodiment, step ‘b’ of the process involves basifying the reaction mixture of step ‘a’ and extracting the reaction mixture with a solvent.
The solvent may be selected from the group consisting of water, C1-C5 alcohols such as methanol, ethanol, n-butanol, tertiary butanol and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone.
In one embodiment, the base may selected from the group consisting of hydroxides such as sodium hydroxide, potassium hydroxide, calcium hydroxide and strontium hydroxide; carbonates such as sodium carbonate, potassium carbonate; bicarbonates such as sodium bicarbonate, potassium bicarbonate, aqueous ammonia, ammonia gas and the like. Preferably, the base is sodium hydroxide.
The reaction mixture after basification is extracted with a solvent.
The solvent may be selected from the group consisting of water, C1-C5 alcohols such as methanol, ethanol, n-butanol, tertiary butanol and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone. Preferably, the reaction mixture after basification is extracted with n-butanol.
In one embodiment, step ‘c’ of the process involves adding mandelic acid or orthophosphoric acid to the above step ‘b’ to obtain mirabegron mandelate or mirabegron phosphate thereof.
In one embodiment, step ‘c’ of the process involves adding mandelic acid to the above step ‘b’ to obtain mirabegron mandelate.
In one embodiment, step ‘c’ of the process involves adding orthophosphoric acid to the above step ‘b’ to obtain mirabegron phosphate.
In one embodiment, the reaction mixture comprising mirabegron mandelate is subjected to distillation to obtain mirabegron mandelate.
In one embodiment, the reaction mixture comprising mirabegron phosphate is subjected to distillation to obtain mirabegron phosphate.
In one embodiment, the present invention further provides a process comprising recrystallizing the mirabegron mandelate or mirabegron phosphate with acetone.
In one embodiment, the present invention provides a process for the recrystallisation of mirabegron mandelate salt comprising;
a) adding a suitable solvent to mirabegron mandelate to obtain a reaction mixture;
b) heating the reaction mixture of step ‘a’ to obtain a suspension;
c) cooling the solution to obtain mirabegron mandelate; and
d) isolating mirabegron mandelate.
In one embodiment, in step ‘a’ the solvent is selected from the group consisting of water, C1-C5 alcohols such as methanol, ethanol, n-butanol, tertiary butanol and the like; esters such as ethyl acetate, methyl acetate, isopropyl acetate; ketones such as acetone, methyl ethyl ketone, methyl isobutyl ketone. Preferably, the solvent is acetone.
In one embodiment, in step ‘b’ the reaction mixture is heated to the reflux temperature of the solvent to obtain a solution. The reaction mixture is then cooled.
In one embodiment, in step ‘c’ mirabegron mandelate is isolated by methods such as filtration, centrifugation and the like.
In one embodiment, the present invention provides salt of mirabegron selected from the group consisting of mirabegron mandelate or mirabegron phosphate thereof.
In one embodiment, the present invention provides mirabegron phosphate characterized by 1H NMR (DMSO-d6 300MHz) having peaks at d 1.14, 2.0-2.1 ,2.94, 3.09, 3.45, 4.97, 6.30, 6.9, 7.16-7.19, 7.28-7.39, 7.53-7.56, 10.09 and mirabegron mandelate characterized by 1H NMR (DMSO-d6 300MHz) having peaks at 2.68-2.97, 3.10-3.13 , 3.44, 4.78, 4.87-4.90, 6.30, 7.13-7.13, 7.21-7.39, 7.51-7.54, 10.01.
In one embodiment, the present invention provides amorphous mirabegron wherein the content of 2-(2-amino-1,3-thiazol-4-yl)-N-[3-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino} ethyl) phenyl]acetamide, the compound formula V, 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl) phenyl] acetamide, the compound of formula VI , (1R)-2-{[2-(4-aminophenyl)ethyl]amino}-1-phenylethanol, the compound of formula VII, 2-(2-amino-1,3-thiazol-4-yl)-N-[4-{[(2-Phenylethyl] amino} Ethyl) phenyl] acetamide, the compound of formula VIII, 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2S)-2-hydroxy-2-phenylethyl]amino}ethyl) phenyl]acetamide, the compound formula IV is less than 0.15, as determined by high performance liquid chromatography(HPLC).

V VI

VII VIII

IV
In one embodiment, the present invention provides amorphous mirabegron amorphous mirabegron wherein the content of 1-(2-amino-1,3-thiazol-4-yl)-N-[4-(2- {[(2S)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide) is less than 0.15, as determined by high performance liquid chromatography (HPLC).

IV
In one embodiment, the present invention provides amorphous mirabegron, wherein substantially free of 1-(2-amino-1,3-thiazol-4-yl)-N-[4-(2- {[(2S)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide, the compound of formula IV, as determined by high performance liquid chromatography (HPLC).
In one embodiment, the term, ‘substantially free’ means that 1-(2-amino-1,3-thiazol-4-yl)-N-[4-(2- {[(2S)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide, the compound of formula IV is less than 0.1% w/w with respect to amorphous mirabegron, as determined high performance liquid chromatography.
In one embodiment, the present invention provides amorphous mirabegron with a chemical purity of at least 99% w/w.
In one embodiment, the present invention provides amorphous mirabegron having less than about 50% crystalline mirabegron, more preferably less than about 20%, and most preferably less than about 10%, and most preferably less than 5%, and most preferably less than 1% crystalline material as measured by area percentage XRD.
In one embodiment, the present invention provides process for preparation of amorphous mirabegron which does not involve formation of crystalline mirabegron as an intermediate.
In one embodiment, the present invention provides process for preparation of amorphous mirabegron without the formation of a form of mirabegron as an intermediate.
In one embodiment, the present invention provides process for preparation of amorphous mirabegron without the formation of ß form of mirabegron as an intermediate.
In one embodiment, the present invention provides a process for recrystallizing a form of mirabegron with acetone.
The examples that follow are provided to enable one skilled in the art to practice the invention and are merely illustrative of the invention. The examples should not be read as limiting the scope of the invention as defined in the features and advantages.

Examples:
Example 1: Process for the preparation of 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide Mandelate .
Stage A: The reaction mixture of water (1650mL) and (1R)-2-{[2-(4-aminophenyl) ethyl]amino}-1-phenylethanol (110g) was cooled to 10-20°C and to this was charged conc hydrochloric acid solution (89.5g) to obtain a clear solution. To this solution was charged (2-amino-1,3-thiazol-4-yl)acetic acid (74.66g) at 10-20°C followed by EDC hydrochloride (98.73g). The reaction mixture was maintained for 3h and treated with activated carbon. The reaction mass was filtered through hyflo bed and washed the bed with water. To the obtained filtrate n-butanol (1100mL) was charged and cooled to 0-5°C. This was basified to a pH 9.0-10.0 using (5%) aqueous solution of sodium hydroxide and further stirred the reaction mass for 1h at about 20-30°C. The n-butanol and water layer were separated and mandelic acid (105.9g) was added to the n-butanol layer to obtain a reaction mixture. This reaction mixture was stirred for an hour followed by distillation. The reaction mass was concentrated under reduced pressure at about 50-55°C and degassed at about 65-70°C to get crude mirabegron mandelate salt.
To the crude mirabegron mandelate salt was charged acetone (2200mL) and heated to reflux at about 50-55°C for about 1h. The reaction mass was cooled to 25-30°C and further maintained at same temperature for next 3h. The slurry was filtered and wet cake was dried in vacuum tray drier at 50-55°C for 12h. Yield: 80-100g HPLC purity : > 99.0 %. mirabegron mandelate 1HNMR 2.68-2.97, 3.10-3.13, 3.44, 4.78, 4.87-4.90, 6.30, 7.13-7.13, 7.21-7.39, 7.51-7.54, 10.01.
Stage B: The reaction mixture of mirabegron mandelate (50g) and water(750mL) was cooled to 10-20°C. To this reaction mixture aqueous sodium hydroxide solution was added to adjust pH to 9.0 to 10.0. To this n-butanol (500mL) was added and stirred for 1h. The layers were separated and the n-butanol layer was distilled at 50-55°C to get oily mass. This was further stripped using water. To this residue, tert-butanol (500mL) and water (500mL) was added and stirred at 40-50°C for about 30min. The reaction mixture was filtered by micron filtration and washed with water. The reaction mass was cooled to 25-30°C and freezed and then subjected to lyophilization by cooling to about -84°C to about -65°C under vacuum (Not less than 100millitorr) for about 30-50h using lyophilizer. Yield: 90%; HPLC purity: >99.0%
Example 2: Process for preparation of amorphous form of mirabegron from mirabegron phosphate:
Stage A: The reaction mixture of water (1650mL) and (1R)-2-{[2-(4-aminophenyl) ethyl]amino}-1-phenylethanol (110g) was cooled to about 10-20°C and to this was charged conc hydrochloric acid solution (89.5g) to obtain a clear solution. To this solution was charged (2-amino-1,3-thiazol-4-yl)acetic acid (74.66g) at 10-20°C followed by EDC hydrochloride (98.73g). The reaction mixture was maintained for 3h and treated with activated carbon. The reaction mass was filtered through hyflo bed and the bed was washed with water. To the obtained filtrate, n-butanol (1100mL) was charged and cooled to about 0-5°C. This was basified to a pH 9.0-10.0 using (5%) aqueous solution of sodium hydroxide and the reaction mass was further stirred for 1h at 20-30°C. The n-butanol and water layers were separated and ortho phosphoric acid (84.10g) was added to the n-butanol layer to obtain a reaction mixture. The reaction mixture was stirred for an hour followed by distillation. The reaction mass was concentrated under reduced pressure at 50-55°C and degassed at 65-70°C to get crude mirabegron phosphate salt.
The reaction mixture of mirabegron phosphate and acetone (2200mL) was maintained for 3h. The slurry was filtered and washed with di-isopropyl ether and the wet was dried cake in vacuum tray drier at 40-55°C for 12h. Yield: 80-100g, HPLC purity: > 99%. 1HNMR (DMSO-d6 300MHz): 1.14, 2.0-2.1, 2.94, 3.09, 3.45, 4.97, 6.30, 6.9, 7.16-7.19, 7.28-7.39, 7.53-7.56, 10.09.
Stage B: Process for preparation of mirabegron amorphous form from 2-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2R)-2-hydroxy-2-phenylethyl]amino}ethyl) phenyl] acetamide phosphate
The reaction mixture of mirabegron phosphate (50g) and water (750mL) was cooled to 10-20°C. To this reaction mixture, aqueous sodium hydroxide solution was added to adjust pH to 9.0 to 10.0. To this n-butanol (500mL) was added and stirred for about 1h. The layers were separated and the n-butanol layer was distilled at 50-55°C to get oily mass. This was further stripped using water. To this residue, tert-butanol (500mL) and water (500mL) was added and stirred at 40-50°C for about 30min. The reaction mixture was filtered by micron filtration and washed with water. The reaction mass was cooled to 25-30°C and freezed and then subjected to lyophilization by cooling to about -84°C to about -65°C under vacuum (Not less than 100millitorr) for about 30-50h using lyophilizer. Yield: 90%; HPLC purity: >99.0%
Example 3: Process for the preparation of (1R)-2-[[2-4-aminophenyl)ethyl]amino}-1-phenyl ethanol:
In an autoclave was charged a mixture of methanol (800mL) and (1R)-2-[[2-4-nitrophenyl)ethyl]amino}-1-phenyl ethanol (80g). The mixture was flushed with nitrogen and to this 4g of 10% Pd/C was charged. The reaction mixture was maintained with 1-2 kg/cm2 of H2 gas pressure under stirring. The reaction mass was filtered and filtrate was distilled to obtain oily residue. To this residue, toluene (80mL) was added and heated to 55-65°C. This was cooled to 25-30°C and further cooled to 0-5°C, the precipitate was filtered and dried to obtain 68g of title product.
Example 4: Process for the preparation of alpha form of mirabegron:
A reaction mixture of water (900mL) and (1R)-2-{[2-(4-aminophenyl)ethyl]amino}-1-phenyethanol (60g) was cooled to 15-20°C and acidified using conc hydrochloric acid. To this reaction mixture was charged (2-amino-1,3-thiazol-4-yl)acetic acid under stirring. To this 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide monohydrochloride (53.85g) was added and stirred. The reaction mixture was subjected to charcoal treatment and basified using sodium hydroxide to adjust the pH to about 8 -8.5. The slurry was filtered, washed with water and dried under vacuum to not less than 650 mm/Hg to obtain 75g of crude mirabegron.
A mixture of crude mirabegron (75g) and acetone (2625mL) was heated to about 50°C to 60°C to obtain a solution. The solution was filtered and the filtrate was distilled till solvent remains to around 9.5 -11.5 volumes of the total reaction mass. The slurry was filtered and dried in vacuum tray drier to obtain 63g of alpha form of mirabegron.
,CLAIMS:We claim:
1] A process for the preparation of amorphous mirabegron, a compound of formula I, comprising:
I
a) suspending mirabegron mandelate salt or mirabegron phosphate salt in water to obtain a reaction mixture;
b) basifying the reaction mixture of step ‘a’ followed by extracting the reaction mixture with a first organic solvent;
c) removing the first organic solvent to obtain a residue;
d) adding a second solvent or a mixture of solvents to step ‘c’ to obtain a solution; and
e) lyophilizing the solution of step ‘d’ to obtain amorphous mirabegron.
2] The process as claimed in claim 1, wherein in step ‘d’, the amount of second solvent or mixture of solvents is not less than five times by volume per gram of mirabegron.
3] The process as claimed in claim 1, wherein in step ‘d’, the second solvent is selected from a group consisting of C1-C5 alcohol, esters, amides, water and mixtures thereof.
4] The process as claimed in claim 3, wherein second solvent is a mixture of tertiary butanol and water.
5] The process as claimed in claim 1, wherein in step ‘e’, the lyophilisation is carried out at a pressure of about less than 100 millitorr and the amorphous mirabegron is subjected to drying to obtain amorphous mirabegron having a moisture content of less than about 2 percent.
6] A process for the preparation of mirabegron phosphate salt or mirabegron mandelate as claimed in claim 1, comprising the steps of:
a) condensing a compound of formula II with a compound of formula III in the presence of a coupling agent to obtain a reaction mixture;

II III
b) basifying the reaction mixture of step ‘a’ and extracting the reaction mixture with a solvent;
c) adding mandelic acid or orthophosphoric acid to the above step ‘b’ to obtain mirabegron mandelate salt or mirabegron phosphate salt thereof.
7] The process as claimed in claim 6, further comprising recrystallizing the mirabegron mandelate salt or mirabegron phosphate salt with acetone.
8] A salt of mirabegron selected from the group consisting of mirabegron phosphate salt and mirabegron mandelate salt wherein the mirabegron phosphate is characterized by 1HNMR having peaks at 1.14, 2.0-2.1, 2.94, 3.09, 3.45, 4.97, 6.30, 6.9, 7.16-7.19, 7.28-7.39, 7.53-7.56, 10.09 and mirabegron mandelate characterized by 1HNMR having peaks at 2.68-2.97, 3.10-3.13, 3.44, 4.78, 4.87-4.90, 6.30, 7.13-7.13, 7.21-7.39, 7.51-7.54, 10.01.
9] Amorphous mirabegron wherein the content of 1-(2-amino-1,3-thiazol-4-yl)-N-[4-(2- {[(2S)-2-hydroxy-2-phenylethyl]amino}ethyl)phenyl]acetamide, a compound of formula IV, is less than 0.15% as determined high performance liquid chromatography.
10] Amorphous mirabegron as claimed in claim 9, which is substantially free of the 1-(2-amino-1,3-thiazol-4-yl)-N-[4-(2-{[(2S)-2-hydroxy-2-phenylethyl]amino}ethyl) phenyl]acetamide as determined high performance liquid chromatography.
Dated this 21st day of November, 2017
(Signed)_____ _
Dr. Madhavi Karnik
General Manager-IPM
Glenmark Pharmaceuticals Limited