Process for the preparation of Mirabegron alpha-form crystals

Abstract

The present invention provides a process for the preparation of -Form crystals of Mirabegron using a solvent selected from water.

Claims

1. A process for the preparation of -Form crystals of Mirabegron comprising the steps of: (a) suspending Mirabegron in water; (b) heating the suspension of step (a); (c) precipitating -Form crystals of Mirabegron by cooling the suspension obtained in step (b); (d) isolating pure -Form crystals of Mirabegron.

2. The process as claimed in claim 1, the resulting suspension in step-(b) is optionally seeded with -Form crystals of Mirabegron to obtain pure form of -Form crystals of Mirabegron.

3. The process as claimed in claim 1, the -Form crystals of Mirabegron have water content0.5% w/w.

4. The process as claimed in claim 1, suspending Mirabegron in water at a temperature about 10 C. to 35 C.

5. The process as claimed in claim 1, heating the suspension at a temperature of about 50 C. to 90 C.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

(1) FIG. 1 Illustrates the X-ray powder diffraction pattern of -Form crystals of Mirabegron produced by the present invention.

(2) FIG. 2 Illustrates the differential scanning calorimetry of -Form crystals of Mirabegron produced by the present invention.

DETAILED DESCRIPTION OF THE INVENTION

(3) In one aspect, the present invention provides a process for the preparation of -Form crystals of Mirabegron comprising the steps of: a) suspending Mirabegron in a solvent selected from water; b) heating the suspension of step (a); c) precipitating -Form crystals of Mirabegron by cooling the suspension obtained in step (b); d) isolating pure -Form crystals of Mirabegron.

(4) In another aspect, the Mirabegron is suspended in a solvent selected from water at a temperature about 10 C. to 35 C. The resulting suspension is heated at a temperature of about 50 C. to 90 C., continue stirring and monitor the complete conversion to -Form crystals of Mirabegron by DSC. Thereafter, the suspension is cooled to 20-35 C. and slurry is stirred at same temperature for 1 to 5 hours.

(5) In another aspect, the resulting slurry is optionally seeded with -Form crystals of Mirabegron to obtained pure form of -Form crystals of Mirabegron. The obtained -Form crystals of Mirabegron are filtered and washed with water and finally dried at temperature about 45-75 C. under reducing pressure till the water content is 0.5% w/w.

(6) In another aspect, Mirabegron used in present invention is prepared by condensing 4-nitrophenyl ethylamine hydrochloride (IV) with (R)-styrene oxide in the presence of a base in a solvent to produce (R)-1-phenyl-2-[[2-(4-nitrophenyl)ethyl]amino]ethanol (V), which is further protected with a protecting agent selected from tert-butoxy carbony group (Boc) in a solvent to produce tert-butyl-(R)-N-(2-hydroxy-2-phenylethyl)-N-[2-(4-nitro-phenyl)ethyl]carbamate (VI), which undergoes reduction in the presence of palladium-carbon and hydrogen in a solvent to produce tert-butyl-(R)-N-[2-(4-aminophenyl)-N-(2-hydroxy-2-phenylethyl)ethyl]-carbamate (VII). This compound (VII) is condensed with 2-amino-4-thiazoleacetic acid (III) in the presence of a base in a solvent to produce Boc-protected Mirabegron (VIII) and then treating with hydrochloride to produce Mirabegron dihydrochloride.

(7) The process is as shown in Scheme-II below:

(8) ##STR00003##

(9) In another aspect, Mirabegron used in present invention is prepared by condensing compound of formula (IIa) with a compound of formula (IIIa) in a solvent followed by removal of protecting group to produce Mirabegron (I).

(10) The process is as shown in Scheme-III below:

(11) ##STR00004##

(12) The following examples are provided to illustrate the invention and are merely for illustrative purpose only and should not be construed to limit the scope of the invention.

EXAMPLES

(13) Preparation of -Form Crystals of Mirabegron:

Example-1

(14) Mirabegron (100 g) was suspended in DM water (1.50 Lt) at 25-30 C. The above suspension was cooled to 2-5 C. and concentrated hydrochloric acid (57.86 g, 35% w/w Assay) was added at 2-5 C. slowly over a period of 30 min. The suspension was stirred at 2-5 C. for 30 min to obtain a clear solution and carbon enoanticromos (10 g) was added at 2-5 C. The stirring was continued at 2-5 C. for 3010 min. Thereafter, carbon was removed by filtration through hyflo at 2-5 C. and the residue was washed with DM water (250 ml) at 2-5 C. In the meantime, sodium hydroxide (Reagent grade, 23.23 g) dissolved in DM water (500 ml), was added to the above filtrate at 2-5 C. slowly over a period of 45 min during which Mirabegron precipitated out. The above contents were stirred at 2-5 C. for 1 h10 min for complete precipitation of Mirabegron. Thereafter, the temperature of the above contents was raised to 20-25 C. The product was filtered and it washed with DM water (300 ml) at 20-25 C. The wet filtered mass was suspended in DM water (1.50 Lt) at 20-25 C. The suspension was heated to 70-75 C. The heating was continued at 70-75 C. and the complete conversion of Mirabegron -Form crystals was monitored by DSC. Thereafter, the above suspension was cooled to 25-30 C. The slurry was stirred at 25-30 C. for 2 h10 min. The product was filtered and washed it with DM water (100 ml2) at 25-30 C. Finally, the product was dried at 50-60 C. under reduced pressure (20 mm Hg) till the water content is 0.3% w/w. Yield: Mirabegron -Form crystals: 90 g.

Example-2

(15) Mirabegron (30 g) was suspended in DM water (450 ml) at 25-30 C. The above suspension was cooled to 2-5 C. and concentrated hydrochloric acid (17.38 g, 35% w/w assay) was added at 2-5 C. slowly over a period of 30 min. The suspension was stirred at 2-5 C. for 30 min to obtain a clear solution and carbon enoanticromos (3 g) was added at 2-5 C. The stirring was continued at 2-5 C. for 3010 min. Thereafter, carbon was removed by filtration through hyflo at 2-5 C. and the residue was washed with DM water (30 ml) at 2-5 C. In the meantime, sodium hydroxide (Reagent grade, 6.97 g) dissolved in DM water (150 ml), was added to the above filtrate at 2-5 C. slowly over a period of 45 min during which Mirabegron precipitated out. The above contents were stirred at 2-5 C. for 1 h10 min for complete precipitation of Mirabegron. Thereafter, the temperature of the above contents was raised to 20-25 C. The product was filtered and it washed with DM water (330 ml) at 20-25 C. The wet filtered mass was suspended in DM water (450 ml) at 20-25 C. The suspension was heated to 70-75 C. The heating was continued at 70-75 C. and the complete conversion of Mirabegron -Form crystals was monitored by DSC. Thereafter, the above suspension was cooled to 25-30 C. The slurry was stirred at 25-30 C. for 2 h10 min. The product was filtered and washed it with DM water (30 ml2) at 25-30 C. Finally, the product was dried at 50-60 C. under reduced pressure (20 mm Hg) till the water content is 0.3% w/w. Yield: Mirabegron -Form crystals: 21.86 g.