DESC:Field of the invention
The present invention provides a process for preparation of a-form crystal of Mirabegron.
Background and the prior art
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 (1)

Mirabegron is an orally active beta-3-adrenoreceptor agonist approved by USFDA for the treatment of overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency.
U.S Patent No. 6,346,532 B1 discloses Mirabegron or a salt thereof and process for its preparation. The crystalline a-form and ß-form of Mirabegron has been covered in the U.S Patent No. 7,342,117.The said patent discloses the process for preparation of a-form crystal and ß-form crystal of Mirabegron.
The method for the preparation of a-form crystal and ß-form crystal of Mirabegron as disclosed in US’117 involves the use of mixture of water and ethanol as the only solvent system. The process disclosed requires temperatures as high as 70-80 oC for dissolution, gradual or rapid cooling and use of seed material. The cooling rate of about 10 oC per hour appears to be an industrially cumbersome process
PCT application WO2012156998A2 discloses processes for preparation of a-form crystal and ß-form crystal of Mirabegron.
2588/MUM/2012 discloses processes for preparation of crystalline form of Mirabegron
The method for the preparation of crystalline a-form of Mirabegron described in the literature suffer from one or more drawbacks such as elevated temperature, gradual cooling rate, use of seed material and less yield which do not lead to an industrially reasonable process.
In view of the above there exists a need to provide an alternative process for preparation of a-form crystal of mirabegron which is consistent, cost effective and industrially feasible.
Objects of the invention
It is an object of the present invention to provide an economical and industrially feasible process for preparation of a-form crystal of Mirabegron.
It is another object of the present invention to provide a process for preparation of a-form crystal of mirabegron comprising preparing slurry of Mirabegron or Mirabegron crude in a suitable solvent and obtaining a-form crystal of mirabegron by removal of solvent.
It is yet another object of the present invention to provide a process for preparation of a-form crystal of mirabegron comprising preparing a solution of Mirabegron or Mirabegron crude in isopropanol and obtaining a-form crystal of mirabegron by adding an anti-solvent.
It is another object of the present invention to provide a process for preparation of a-form crystal of mirabegron comprising preparing a solution of Mirabegron or Mirabegron crude in a suitable solvent and adding the said solution to water under stirring and obtaining a-form crystal of mirabegron by removal of solvent medium.
Brief Description of the drawing
Figure 1 is an illustration of a PXRD pattern of a-form crystal of Mirabegron obtained as per Ex.-2
Figure 2 is an illustration of a DSC endotherm peak of a- form crystal of Mirabegron obtained as per Ex.-2
Figure 3 is an illustration of an Infra-Red spectrum of a-form crystal of Mirabegron obtained as per to Ex.-2

Detailed Description of the invention
The present invention provides a process for the preparation of a-form crystal of Mirabegron.
The present invention further provides an improved, economical and industrially feasible process for preparation of a-form crystal of Mirabegron.
The term "slurry”, unless otherwise mentioned, defines a heterogeneous mixture where complete dissolution do not occur at ambient or elevated temperature.
The term “Mirabegron crude”, unless otherwise mentioned defines the input Mirabegron obtained upon condensation of (R)-2-[2-(4-aminophenyl)-ethylamino]-1-phenyl ethanol hydrochloride and (2-amino-thiazol-4-yl)-acetic acid in the presence of N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl), that is used for preparation of a-form crystal of Mirabegron .
The term “Mirabegron”, unless otherwise specified defines the input Mirabegron other than Mirabegron crude which is used for preparation of a-form crystal of Mirabegron.
The term “elevated temperature”, unless otherwise specified defines heating either a heterogeneous or homogenous mixture at a temperature from about 30 oC to boiling point of solvent.
The term “ambient temperature” unless otherwise specified defines the temperature of heterogeneous or homogenous mixture at a temperature of 25 ± 2 oC.
Unless mentioned otherwise the term “alkanol” refers to alcohols selected from C1 to C4 straight or branched chain alcohol. The C1 to C4 straight or branched chain alcohols include methanol, ethanol, propanol, isopropanol and butanol.
In an aspect of the present invention the process for the preparation of a-form crystal of Mirabegron comprises of;
(i) preparing a slurry of Mirabegron or Mirabegron crude in a suitable solvent at ambient temperature
(ii) heating the slurry obtained in step (i) and maintaining the slurry at elevated temperature
(iii) gradually cooling the reaction mixture
(iv) isolating the a-form crystal of Mirabegron.
(v) drying the product under reduced pressure
In a preferred aspect of the present invention the moisture content of input Mirabegron should not be more than 10 % W/W, preferably not more than 7%, more preferably not more than 5%, most preferably not more than 3% .
In another aspect of the present invention the reaction mixture should be in the form of slurry.
The present inventors have observed that the moisture content of input mirabegron is critical to practice the process of the present invention. If the water content is more than 5%w/w the input Mirabegron or Mirabegron crude goes into solution and poses difficulty in re-precipitation and requires cooling at subzero temperature for recrystallization.
In yet another aspect of the present invention, the suitable solvent medium for the present invention is selected from the group of alkanol. The term “alkanol” refers to alcohols selected from C1 to C4 straight or branched chain alcohol. The C1 to C4 straight or branched chain alcohols include methanol, ethanol, propanol, isopropanol and butanol wherein the volume of solvent used is 5-10 times, preferably 5-7 times of the input Mirabegron.
The preferred alcohol of the invention is isopropanol.
In an aspect of the present invention the heating of the reaction mixture is done gradually, preferably in 45-60 min.; or more preferably in 35-40 min.
In yet another aspect, the temperature of the slurry of input Mirabegron in isopropanol is to be kept below 60 o C; preferably below 50 o C; or more preferably below 40 o C for a time period of 30 to 60 minutes.
Temperature control of reaction mixture with respect to rate of heating and maintenance is an important aspect of the present invention, so as to avoid formation of colored impurities which impart color to the final API.
In another aspect of the invention the reaction mass is gradually cooled to -10 to -5 o C; or more preferably to 0 to 5 o C in 20-30 min. and maintained for 45-60 min.
In an aspect of the present invention the process for the preparation of a-form crystal of Mirabegron, comprises of;
(i) preparing a solution of Mirabegron or Mirabegron crude in isopropanol;
(ii) adding an anti-solvent to the solution of step (i), selected from n-heptane, p-xylene, o-xylene, ethyl acetate, acetone and acetonitrile;
(iii) Cooling the reaction mixture of step (ii); and
(iv) isolating a-form crystal of Mirabegron.
The solution of step (i) is prepared in 5 to 20 volumes of isopropanol, more preferably in 10 to 15 volumes of isopropanol.
The solution of step (i) is prepared at reflux temperature of isopropanol.
In an aspect of the present invention the process for the preparation of a-form crystal of mirabegron comprises of;
(i) preparing a solution of Mirabegron or Mirabegron crude in a suitable solvent;
(ii) adding the solution obtained from step (i) to water; and
(iii) isolating a-form crystal of Mirabegron
The suitable solvent medium for the present invention is selected from the group of alkanol. The term “alkanol” refers to alcohols selected from C1 to C4 straight or branched chain alcohol. The C1 to C4 straight or branched chain alcohols include methanol, ethanol, propanol, isopropanol and butanol wherein the volume of solvent used is 2-10 times of the input Mirabegron.
The solution of step (i) is prepared at reflux temperature of the solvent.
The solution of step (i) is added lot wise to water of step (ii) maintained at 5-25 oC, more preferably at 10-20 oC.
In an aspect of the present invention the process for the preparation of a-form crystal of mirabegron comprises of;
(i) preparing a solution of Mirabegron or Mirabegron crude in dimethylformamide at ambient temperature;
(ii) adding the solution obtained from step (i) to water; and
(iii) isolating a-form crystal of Mirabegron
In another aspect the a-form crystal of Mirabegron can be isolated using known techniques in the art such as decantation, filtration by gravity or suction or centrifugation for removal of solvent.
In an aspect of the invention, Mirabegron prepared according to the processes of the present invention is pure having a chemical purity greater than about 99%, or greater than about 99.5%, or greater than about 99.9%, by weight, as determined using high performance liquid chromatography (HPLC). Mirabegron produced by a method of present invention is chemically pure mirabegron having purity greater than about 99.5% and containing no single impurity in amounts greater than about 0.15%, by HPLC. Mirabegron produced by the methods of present invention is chemically pure mirabegron having purity greater than about 99.8% and containing no single impurity in amounts greater than about 0.1%, by HPLC.
Mirabegron which is used as a starting material in the present invention can be in any physical form such as crystalline, amorphous, mixture of crystalline and amorphous, solvates and/or hydrates etc. Mirabegron used as input material for the processes of the present invention may be obtained by any process including the processes described in the art and optionally can be purified using any method known in the art to enhance its chemical purity or chiral purity.
For example input Mirabegron may be prepared by the processes described in the US 6, 346,532 or US 7, 342,117.
The a-form crystal of mirabegron of the present invention can be used in the preparation of pharmaceutical composition for overactive bladder (OAB) with symptoms of urge urinary incontinence, urgency, and urinary frequency. Such pharmaceutical composition can be prepared using one or more pharmaceutically acceptable carriers, excipients or diluents by methods known in the literature.

Present invention is further illustrated with the following non-limiting examples.
Example-1:
Preparation of Mirabegron crude
To a mixed solution of water (750ml), Conc. HCl (16.5 gm) and (R)-2-[2-(4-aminophenyl)-ethylamino]-1-phenyl ethanol hydrochloride (R-APPE HCl) 50gm, (2-amino-thiazol-4-yl)-acetic acid (30.8gm) was added in a single lot followed by addition of N-(3-Dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (EDC.HCl) 41.1gm.Then the pH of the reaction mass was adjusted to 3-4 and the reaction mass was maintained for 60-120 min. at 28-32o C (till R-APPE HCl <2.0%) . After the completion of reaction charcoal was added to the reaction mass and maintained for 30 min. The reaction mass was filtered through celite, washed with acidic D.M water (pH adjusted to 2-3 using Conc. HCl).The filtrate was basified with Liq. Ammonia solution (pH: 8-9) and stirred for 30 min. The precipitated solid was filtered suck dried and washed with water. The wet solid was further slurry washed with water at 45-50 o C for 30-45min. The wet cake was dried at 45-50 o C under reduced pressure to afford Mirabegron crude.
Yield = 66 to 81%
HPLC purity = >98.5%
Example-2:
Preparation of a-form crystal of Mirabegron
To isopropanol (700ml) mirabegron crude (100gm) was added and the reaction mixture was heated to 35-40 o C in 35-40 min. and maintained for 30-60 min. The reaction mass was cooled gradually to 0-5 o C in 20-30 min. and maintained for 45-60 min. The reaction mass was filtered at 0-5 o C , followed by drying under reduced pressure at 45-50 o C to yield a-form crystal of Mirabegron.
Yield = 80 to 95%
HPLC purity = > 99%
Example-3:
Preparation of a-form crystal of Mirabegron
5gm of Mirabegron crude was dissolved in 75 ml of isopropanol at reflux temperature (75-85 oC). Thereafter n-heptane (75ml) was added at 75-80 oC. The reaction mixture was cooled gradually. Crystals were observed at 65 oC. The reaction mixture was cooled further to 0-5oC and maintained at 0-5oC for 30 min followed by filtration to afford 3.8 gm of a-form crystal of Mirabegron.
DSC endotherm peak: 142.07 oC
Example-4:
Preparation of a-form crystal of Mirabegron
5gm of Mirabegron crude was dissolved in 75 ml of isopropanol at reflux temperature (75-85 oC). Thereafter p-xylene (75ml) was added at 75-80 oC. The reaction mixture was cooled gradually. Crystals were observed at 28 oC. The reaction mixture was cooled further to 0-5oC and maintained at 0-5oC for 30 min followed by filtration to afford 3.7 gm of a-form crystal of Mirabegron.
DSC (Differential scanning calorimetry) endotherm peak: 141.74 oC
Example-5:
Preparation of a-form crystal of Mirabegron
5gm of Mirabegron crude was dissolved in 75 ml of isopropanol at reflux temperature (75-85 oC). Thereafter o-xylene (85ml) was added at 75-80 oC. The reaction mixture was cooled gradually. Crystals were observed at 11 oC. The reaction mixture was cooled further to 0-5oC and maintained at 0-5oC for 30 min followed by filtration to afford 2.2 gm of a-form crystal of Mirabegron.
DSC endotherm peak: 141.8 oC
Example-6:
Preparation of a-form crystal of Mirabegron
5gm of Mirabegron crude was dissolved in 75 ml of isopropanol at reflux temperature (75-85 oC). Thereafter ethylacetate (25ml) was added at 75-80 oC. The reaction mixture was cooled gradually. Crystals were observed at 41 oC. The reaction mixture was cooled further to 0-5oC and maintained at 0-5oC for 30 min followed by filtration to afford 3.7 gm of a-form crystal of Mirabegron.
DSC endotherm peak: 141.66 oC
Example-7:
Preparation of a-form crystal of Mirabegron
5gm of Mirabegron crude was dissolved in 75 ml of isopropanol at reflux temperature (75-85 oC). Thereafter acetone (25ml) was added at 75-80 oC. The reaction mixture was cooled gradually. Crystals were observed at 10 oC. The reaction mixture was cooled further to 0-5oC and maintained at 0-5oC for 30 min followed by filtration to afford 4.0 gm of a-form crystal of Mirabegron.
DSC endotherm peak: 140.77 oC
Example-8:
Preparation of a-form crystal of Mirabegron
5gm of Mirabegron crude was dissolved in 75 ml of isopropanol at reflux temperature (75-85 oC). Thereafter acetonitrile (25ml) was added at 75-80 oC. The reaction mixture was cooled gradually. Crystals were observed at 22 oC. The reaction mixture was cooled further to 0-5oC and maintained at 0-5oC for 30 min followed by filtration to afford 1.5 gm of a-form crystal of Mirabegron.
DSC endotherm peak: 141.48
Example-9:
Preparation of a-form crystal of Mirabegron
10gm of Mirabegron crude was dissolved in 110 ml of isopropanol at reflux temperature (75-85 oC). Thereafter the solution was added lot wise to water (240ml) at 10-24 oC agitating at 198-200 RPM. The precipitated crystals were isolated at 15oC by filtration to afford 9.1 gm of a-form crystal of Mirabegron.
Example-10:
Preparation of a-form crystal of Mirabegron
10gm of Mirabegron crude was dissolved in 40 ml of methanol at 28 oC. Thereafter the solution was added lot wise to water (240ml) at 10-20 oC agitating at 180-200 RPM. The precipitated crystals were isolated at 17oC by filtration to afford 9.0 gm of a-form crystal of Mirabegron.
Example-11:
Preparation of a-form crystal of Mirabegron
10gm of Mirabegron crude was dissolved in 70 ml of ethanol at reflux temperature (68 oC). Thereafter the solution was added lot wise to water (200ml) at 10-20 oC. The precipitated crystals were isolated at 15oC by filtration to afford 8.9 gm of a-form crystal of Mirabegron.
Example-12:
Preparation of a-form crystal of Mirabegron
10gm of Mirabegron crude was dissolved in 10 ml of dimethylformamide at 29 oC. Thereafter the solution was added lot wise to water (240ml) at 10-13 oC. The precipitated crystals were isolated at 15oC by filtration to afford 6.0 gm of a-form crystal of Mirabegron.
,CLAIMS:1. A process for the preparing a-form crystal of Mirabegron comprising of;
(i) preparing slurry of Mirabegron or Mirabegron crude in a suitable solvent at ambient temperature
(ii) heating the slurry obtained in step (i) and maintaining the slurry at elevated temperature
(iii) gradually cooling the reaction mixture of step (iii)
(iv) isolating the a-form crystal of Mirabegron.
(v) drying the product under reduced pressure
2. The process according to claim-1 wherein the moisture content of Mirabegron or Mirabegron crude is not more than 5%.
3. The process according to claim 1 wherein the suitable solvent is selected from the group of alkanol wherein, the term “alkanol” refers to alcohols selected from C1 to C4 straight or branched chain alcohol.
4. The process according to claim-3, wherein the alcohol is isopropanol.
5. The process according to claim-1 wherein the temperature of the slurry is not more than 40 oC.
6. The process according to claim-1 wherein the reaction mixture is cooled to 0 to 5 oC.