CN110590699B - Refining method of mirabegron - Google Patents
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- CN110590699B CN110590699B CN201910931258.6A CN201910931258A CN110590699B CN 110590699 B CN110590699 B CN 110590699B CN 201910931258 A CN201910931258 A CN 201910931258A CN 110590699 B CN110590699 B CN 110590699B
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
- C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
- C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D277/38—Nitrogen atoms
- C07D277/40—Unsubstituted amino or imino radicals
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
- C07B2200/00—Indexing scheme relating to specific properties of organic compounds
- C07B2200/13—Crystalline forms, e.g. polymorphs
Abstract
The invention discloses a refining method of mirabegron, which comprises the following steps: (A) Dissolving the crude mirabegron in an alcohol/water system according to the proportion of alcohol: water = 2-5, to obtain a solution with a concentration of 0.02-0.1 g/ml; (B) Adding mirabegron seed crystal with the mass ratio of 0.5-2.5 wt% to the mirabegron crude product at the temperature of 0-30 ℃, keeping the seed crystal with the particle size of 5 mu m or more and D90 or more and 35 mu m, standing for 1-2 h, stirring for 4-8 h at the stirring speed of 60-400 r/min; (C) Filtering, washing and drying to obtain the refined mirabegron. The method of the invention can obtain the mirabegron fine product which has uniform grain diameter and good fluidity and is suitable for the preparation.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a refining method of mirabegron.
Technical Field
Mirabegron (Mirabegron), CAS No. 223673-61-8, chemical name 2- (2-amino-1, 3-thiazol-4-yl) -N- [4 (2 { [ (2R) -2-hydroxy-2-phenylethyl ] amino } ethyl) phenyl ] acetamide, 2- (2-amino-1, 3-thiazole-4-yl) -N- [4 (2 { [ (2R) -2-hydroxy-2-phenylethyl ] amino } ethyl) phenyl ] acetamide, chemical structural formula as follows:
mirabegron is a selective β 3-adrenoreceptor agonist developed by pharmaceutical companies within the japan mountains (now incorporated into Astellas) that increases bladder filling and urine storage capacity by activating β 3-adrenoreceptors on the detrusor muscle of the bladder, and the united states Food and Drug Administration (FDA) approved overactive bladder (OAB) for the treatment of symptoms of urge incontinence, urgency, urinary frequency, etc., on day 6/28 of 2012.
At present, most of the reports on mirabegron refining simply use organic solvent/water to directly carry out refining crystallization, and specifically include:
domestic patent ZL201310225890.1 to 2014.11.12 discloses a synthesis method of mirabegron, and in the embodiment, the method discloses that methanol and water are used for refining a mirabegron crude product (without the proportion), so that the purity of the mirabegron refined product is 99.0%.
Domestic application CN201410177823.1 at 2014.07.02 discloses a synthesis method of mirabegron, in which the crude product in the examples is recrystallized with a methanol solution, wherein the volume ratio of methanol to water in the methanol solution is 10, and the purity is 99.96%.
Domestic patent ZL201410076461.7 at 2016.03.09 discloses a preparation method of mirabegron, and in the examples, the method discloses that 80% and 50% ethanol are used for refining a mirabegron crude product to obtain a mirabegron refined product with the purity of more than 99.0%.
Zhang Qiulong published "research on the synthesis process of mirabegron" in 2017, and the document reports a synthesis process of mirabegron, and the crude product is synthesized by using v (ethanol): and v (water) = 2.
Fangchini et al published "mirabegron synthesis process improvement" (fine chemical intermediate, 2016,46 (4)), which reported a synthesis process of mirabegron, examined the mirabegron recrystallization solvent, and screened out when v (ethyl acetate): v (water) =5, the maximum recrystallization yield of the mirabegron is 51.6 percent.
Mailogfei et al published "synthetic studies on mirabegron" and reported a synthetic process for mirabegron, where the crude product was synthesized with v (methanol): v (water) =3, and the purity of the mirabegron refined product is 99.51 percent.
In the prior art, most of the mirabegron is simply crystallized, and although the purity meets the requirement, the parameters such as yield, powder form and the like do not meet the requirement of a preparation process, so that a more accurate refining process is needed, and the problems of complicated granulation operation, tablet weight difference exceeding, content unevenness and the like in the preparation are solved by improving the quality of raw material medicines. According to the refining method, the crude mirabegron is dissolved by using an alcohol/water solution system with a specific ratio, and proper crystal seeds are added for crystallization, so that the mirabegron fine product which is uniform in particle size, good in fluidity and suitable for being used in a preparation is obtained.
Disclosure of Invention
The invention aims to overcome the defects of the prior art and provide a refining method of mirabegron, which can obtain a mirabegron fine product which has uniform particle size and good fluidity and is suitable for a preparation.
Specifically, the mirabegron refining method provided by the invention adopts specific alcohol/water as a solvent, and proper mirabegron crystals are precipitated by controlling the using amount of the solvent used for crystallization and the grain diameter, crystallization mode and crystallization time of the added seed crystal, and the obtained mirabegron refined product meets the requirements of subsequent preparation processes in the aspects of grain diameter, bulk density, fluidity and the like.
The beneficial effects of the invention are realized by the following technical scheme.
The refining method of mirabegron provided by the invention comprises the following steps:
(A) Dissolving the crude mirabegron in an alcohol/water system according to the proportion of alcohol: water = 2-5, to obtain a solution with a concentration of 0.02-0.1 g/ml;
(B) Adding mirabegron seed crystal with the mass ratio of 0.5-2.5 wt% to the mirabegron crude product at the temperature of 0-30 ℃, keeping the seed crystal with the particle size of 5 mu m or less and D90 or less and 35 mu m, standing for 1-2 h, stirring for 4-8 h at the stirring speed of 60-400 r/min;
(C) Filtering, washing and drying to obtain the refined mirabegron.
The proportion and concentration of the alcohol/water system used in the invention are one of the keys for realizing the technical effect, and when the alcohol/water system is ethanol/water, methanol/water and isopropanol/water, and the concentration of the solution is 0.04-0.8 g/ml, the dissolution of mirabegron and the subsequent precipitation of crystals are facilitated. Specifically, in the refining method of mirabegron, in the step (a), the alcohol/water system is methanol/water, ethanol/water or isopropanol/water, and the ratio of alcohol: water =3 to 4, and the solution concentration is 0.04 to 0.8g/ml.
More specifically, the method for refining mirabegron is characterized in that in the step (a), the alcohol/water system is ethanol/water, and the ratio of ethanol: water =3, solution concentration 0.05g/ml.
More specifically, the method for refining mirabegron is characterized in that in the step (A), the alcohol/water system is methanol/water, and the ratio of methanol: water =5, solution concentration 0.04g/ml.
More specifically, the method for purifying mirabegron of the present invention is characterized in that in the step (a), the alcohol/water system is isopropanol/water, and the ratio of isopropanol: water =4, solution concentration 0.08g/ml.
In the invention, the condition of adding the mirabegron seed crystal during crystallization is also one of key technologies, the seed crystal with proper grain size and a reasonable stirring mode are used, the nucleation and growth speed of the crystal are favorably improved, the refined mirabegron fine product has the characteristics of uniform grain size and good fluidity, the bulk density and the like of the mirabegron fine product meet the process requirements of subsequent preparations, and the yield is relatively high. When the seed crystal particle size is too large, the crystallization yield is easily reduced obviously, the shape of the final product is irregular, and the fluidity is deteriorated, and when the seed crystal particle size is too small, the particle size of the product is smaller. The inventor unexpectedly finds that the product with smaller particle size has lower bulk density, and the sticking phenomenon is easy to occur in the production process of tablets, so that the surface shape of the tablets has defects. Specifically, in the refining method of mirabegron, in the step (B), the temperature of adding seed crystals is 10-25 ℃, the mass ratio of the added seed crystals to the mirabegron crude product is 1-2 wt%, the particle size is 10 mu m or more and D90 or less and 30 mu m, the standing time is 1.5h, the post-stirring time is 5-7 h, and the stirring speed is 80-300 r/m.
The powder property of the obtained crystal can be influenced by the amount of the added seed crystal, when the amount of the added seed crystal is controlled to be 1wt% of the mass ratio of the seed crystal to the crude mirabegron, the uniform precipitation of the mirabegron is facilitated, and the phenomenon of sudden precipitation caused by excessive addition of the seed crystal or the production time greatly prolonged caused by the addition of too few seed crystals is avoided. More specifically, in the refining method of mirabegron, in the step (B), the temperature of adding the seed crystal is 15-20 ℃, the mass ratio of the added seed crystal to the crude mirabegron is 1wt%, the particle size is 15 mu m or more and D90 or less and 25 mu m or less, and the crystallization stirring speed is 100-200 r/min.
The invention is a preferred refining method of mirabegron, which is characterized in that the refining method of the mirabegron comprises the following steps:
(A) Dissolving the crude mirabegron in an ethanol/water system according to the proportion of ethanol: water =3, resulting in a solution with a concentration of 0.05 g/ml;
(B) Adding mirabegron seed crystal with the mass ratio of 1wt% to the mirabegron crude product at the temperature of 20 ℃, keeping the seed crystal with the particle size of 15 mu m to 25 mu m, standing for 1.5h, and stirring for 6h at the stirring speed of 150 r/min;
(C) Filtering, washing and drying to obtain the refined mirabegron.
Compared with the prior art, the invention has the following outstanding advantages and beneficial effects:
1. provides a specific refining method of mirabegron, and solves the problem that the mirabegron refined in the prior art can not meet the requirements of preparations.
2. The mirabegron fine product obtained by the refining method has the advantages of high uniformity, good fluidity, qualified color and proper particle size.
3. The process has reasonable integral design and simple and convenient operation, and the obtained mirabegron has high yield and purity and reaches the raw material drug standard required by the preparation.
Description of the drawings:
FIG. 1 is a graph showing the distribution of the particle size of mirabegron obtained in example 1.
Figure 2 is a graph of the mirabegron particle size distribution obtained in comparative example 4.
FIG. 3 is a graph showing the distribution of the particle size of mirabegron obtained in comparative example 6.
FIG. 4 is a graph showing the distribution of the particle size of mirabegron obtained in comparative example 7.
In the present invention, all amounts and percentages are mass units, and all raw materials and equipment are commercially available, unless otherwise specified.
The specific implementation mode is as follows:
the present invention will be described in further detail with reference to examples, but the embodiments of the invention are not limited thereto.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Example 1
The mirabegron is refined by the following steps:
(A) 1000g of crude mirabegron (purity greater than 95.0%) is dissolved in a 20L ethanol/water system in the ratio of ethanol: water =3, giving a solution with a concentration of 0.05 g/ml;
(B) Adding 10g of mirabegron seed crystal with the grain diameter of 15 mu m to 25 mu m at the temperature of 20 ℃, keeping the temperature, standing for 1.5h, and stirring for 6h at the stirring speed of 150 r/min;
(C) Suction filtration, filter cake washing with ethanol, 40 ℃ vacuum drying, get white solid 991g, yield 99.1%, HPLC detection its purity is 99.90%, bulk density is 0.49g/cm3, angle of repose is 29 °, the particle is fine loose, the particle size is 15-30 μm, the particle size distribution diagram is as shown in figure 1.
Example 2
The mirabegron is refined by the following steps:
(A) 1000g of crude mirabegron (purity greater than 95.0%) is dissolved in a 25L methanol/water system in the ratio methanol: water =5, resulting in a solution with a concentration of 0.04 g/ml;
(B) Adding 5g of mirabegron seed crystal with the grain diameter of D90 being more than or equal to 10 microns and less than or equal to 30 microns at the temperature of 10 ℃, keeping the temperature, standing for 1h, and stirring for 4h at the stirring speed of 100 revolutions per minute;
(C) Filtering, washing the filter cake with methanol, and vacuum drying at 40 ℃ to obtain 989g of white solid with the yield of 98.9 percent, the purity of the white solid is 99.20 percent by HPLC detection, the bulk density is 0.52g/cm < 3 >, the angle of repose is 29 degrees, the particles are fine and loose, and the particle size is 10-35 mu m.
Example 3
The mirabegron is refined by the following steps:
(A) 1000g of crude mirabegron (purity > 95.0%) is dissolved in a 12.5L isopropanol/water system in the ratio isopropanol: water =4, resulting in a solution with a concentration of 0.08 g/ml;
(B) Adding 20g of mirabegron seed crystal with the particle size of 5 mu m to 35 mu m, keeping the temperature, standing for 2h, and stirring for 8h at the stirring speed of 200 r/min;
(C) Filtering, washing the filter cake with isopropanol, and vacuum drying at 40 ℃ to obtain 985g of white solid with the yield of 98.5 percent, the purity of the white solid is 99.30 percent by HPLC detection, the bulk density is 0.51g/cm < 3 >, the angle of repose is 30 degrees, the particles are fine and loose, and the particle size is 10-40 mu m.
Example 4
The mirabegron is refined by the following steps:
(A) Dissolving 1000g of crude mirabegron (purity is more than 95.0%) in a 50L ethanol/water system, wherein the ratio of ethanol: water =4, giving a solution with a concentration of 0.02 g/ml;
(B) Adding 15g of mirabegron seed crystal with the grain diameter of 5 microns to 35 microns, keeping the temperature, standing for 2 hours, and stirring for 5 hours at the stirring speed of 60 revolutions per minute at 30 ℃;
(C) Filtering, washing the filter cake with ethanol, and vacuum drying at 40 ℃ to obtain 984g of white solid with the yield of 98.4%, the purity of the white solid is 99.00% by HPLC detection, the bulk density is 0.48g/cm < 3 >, the angle of repose is 35 degrees, the particles are fine and loose, and the particle size is 10-40 mu m.
Example 5
The mirabegron is refined by the following steps:
(A) 1000g of crude mirabegron (purity greater than 95.0%) is dissolved in a 10L methanol/water system in the ratio methanol: water =2, resulting in a solution with a concentration of 0.1 g/ml;
(B) Adding 20g of mirabegron seed crystal with the particle size of D90 being more than or equal to 10 microns and less than or equal to 30 microns at the temperature of 15 ℃, keeping the temperature, standing for 1 hour, and stirring for 4 hours at the stirring speed of 300 revolutions per minute;
(C) And (3) performing suction filtration, washing a filter cake by using methanol, and drying the filter cake in vacuum at 40 ℃ to obtain 86g of white solid with the yield of 98.6 percent, wherein the purity of the white solid is 98.90 percent by HPLC (high performance liquid chromatography) detection, the bulk density is 0.50g/cm & lt 3 & gt, the repose angle is 32 degrees, the particles are fine and loose, and the particle size is 10-35 mu m.
Example 6
The mirabegron is refined by the following steps:
(A) 1000g of crude mirabegron (purity > 95.0%) is dissolved in a 16.6L isopropanol/water system in the ratio isopropanol: water =3, resulting in a solution with a concentration of 0.06 g/ml;
(B) Adding 25g of mirabegron seed crystal with the grain diameter of 15 mu m to 25 mu m, keeping the temperature, standing for 2h, and stirring for 7h at the stirring speed of 400 r/min;
(C) Suction filtering, washing the filter cake with isopropanol, and vacuum drying at 40 ℃ to obtain 982g of white solid with yield of 98.2%, purity of 98.80% by HPLC detection, bulk density of 0.47g/cm3, angle of repose of 33 °, fine and loose particles with particle size of 15-30 μm.
Comparative example 1
The mirabegron is refined by the following steps:
(A) 1000g of crude mirabegron (purity greater than 95.0%) is dissolved in a 20L ethyl acetate/water system in the ratio ethyl acetate: water =3, resulting in a solution with a concentration of 0.05 g/ml;
(B) Adding 10g of mirabegron seed crystal with the grain diameter of 15 mu m to 25 mu m at the temperature of 20 ℃, keeping the temperature, standing for 1.5h, and stirring for 6h at the stirring speed of 150 r/min;
(C) Filtering, washing the filter cake with ethyl acetate, and vacuum drying at 40 deg.C to obtain 940g white solid with yield of 94.0%, purity of 96.50% by HPLC, bulk density of 0.55g/cm3, angle of repose of 42 °, larger particles with particle size greater than 100 μm.
Comparative example 2
The mirabegron is refined by the following steps:
(A) 1000g of crude mirabegron (purity greater than 95.0%) is dissolved in a 100L ethanol/water system in the ratio of ethanol: water =1, resulting in a solution with a concentration of 0.01 g/ml;
(B) Adding 1g of mirabegron seed crystal with the grain diameter of 35 mu m to D90 to 50 mu m at the temperature of minus 5 ℃, keeping the temperature, standing for 0.5h, stirring for 2h, and stirring at the speed of 30 r/min;
(C) Filtering, washing the filter cake with ethanol, and vacuum drying at 40 deg.C to obtain 950g of white solid with yield of 95.0%, purity of 97.50% by HPLC, bulk density of 0.55g/cm3, angle of repose of 38 °, large particle size of more than 100 μm.
Comparative example 3
The mirabegron is refined by the following steps:
(A) 1000g of crude mirabegron (purity greater than 95.0%) is dissolved in a 5L ethanol/water system in the ratio of ethanol: water =6, giving a solution with a concentration of 0.2 g/ml;
(B) Adding 50g of mirabegron seed crystal with the grain diameter of 35 mu m to 50 mu m at the temperature of 35 ℃, standing for 3 hours and stirring for 10 hours at the stirring speed of 500 revolutions per minute, wherein D90 is more than 35 mu m;
(C) Suction filtering, washing the filter cake with ethanol, and vacuum drying at 40 deg.C to obtain light white solid 952g with yield 95.2%, purity 96.40% by HPLC, bulk density 0.57g/cm3, angle of repose 42 °, larger particles with particle size > 100 μm.
Comparative example 4
The mirabegron is refined by the following steps:
(A) Dissolving 1000g of crude mirabegron (purity is more than 95.0%) in a 20L ethanol/water system, wherein the ratio of ethanol: water =3, giving a solution with a concentration of 0.05 g/ml;
(B) Adding 1g of mirabegron seed crystal with the grain diameter of more than 15 microns and less than D90 and less than 25 microns at the temperature of 20 ℃, keeping the temperature, standing for 1.5 hours, and stirring for 6 hours at the stirring speed of 150 revolutions per minute;
(C) Suction filtration, filter cake washing with ethanol, 40 ℃ vacuum drying, get white solid 941g, yield 94.1%, HPLC detection its purity is 98.20%, bulk density is 0.49g/cm3, angle of repose is 32 °, the particle is fine loose, the particle size is 15-35 μm, the particle size distribution diagram is as shown in figure 2.
Comparative example 5
The mirabegron is refined by the following steps:
(A) Dissolving 1000g of crude mirabegron (purity is more than 95.0%) in a 20L ethanol/water system, wherein the ratio of ethanol: water =3, giving a solution with a concentration of 0.05 g/ml;
(B) Adding 50g of mirabegron seed crystal with the grain diameter of more than 15 microns and less than D90 and less than 25 microns at the temperature of 20 ℃, keeping the temperature, standing for 1.5 hours, and stirring for 6 hours at the stirring speed of 150 revolutions per minute;
(C) Filtering, washing the filter cake with ethanol, and vacuum drying at 40 deg.C to obtain 961g of white solid with yield of 96.1%, purity of 97.20% by HPLC detection, and occurrence of precipitate and caking.
Comparative example 6
The mirabegron is refined by the following steps:
(A) Dissolving 1000g of crude mirabegron (purity is more than 95.0%) in a 20L ethanol/water system, wherein the ratio of ethanol: water =3, resulting in a solution with a concentration of 0.05 g/ml;
(B) Adding 10g of mirabegron seed crystal with the grain diameter of 1 mu m to D90 to 5 mu m at the temperature of 20 ℃, keeping the temperature, standing for 1.5h, and stirring for 6h at the stirring speed of 150 r/min;
(C) Suction filtering, washing the filter cake with ethanol, vacuum drying at 40 deg.C to obtain 945g white solid with yield of 94.5%, purity of 98.20% by HPLC, bulk density of 0.29g/cm3, angle of repose of 26 deg., fine and loose particles with particle size of 5-15 μm, and particle size distribution diagram as shown in FIG. 3.
Comparative example 7
The mirabegron is refined by the following steps:
(A) Dissolving 1000g of crude mirabegron (purity is more than 95.0%) in a 20L ethanol/water system, wherein the ratio of ethanol: water =3, resulting in a solution with a concentration of 0.05 g/ml;
(B) Adding 10g of mirabegron seed crystal with the grain diameter of 35 mu m to D90 to 50 mu m at the temperature of 20 ℃, keeping the temperature, standing for 1.5h, and stirring for 6h at the stirring speed of 150 r/min;
(C) Suction filtering, washing the filter cake with ethanol, vacuum drying at 40 deg.C to obtain 925g white solid with yield 92.5%, purity of 97.50% by HPLC, bulk density of 0.55g/cm3, angle of repose of 47 °, large and slightly sticky particles with particle diameter > 100 μm, and particle diameter distribution as shown in FIG. 4.
Comparative example 8
The mirabegron is purified by a method disclosed in patent ZL 201310225890.1.
(A) 1000g of crude mirabegron (purity greater than 95.0%) is dissolved in a 20L methanol/water system in the ratio methanol: water =5, yielding a 0.05g/ml solution, after standing for 3h at 20 ℃;
(B) Suction filtration, filter cake washing with methanol, 40 ℃ vacuum drying, get white solid 902g, yield 90.2%, HPLC detection its purity is 98.40%, bulk density is 0.57g/cm3, angle of repose is 46 °, the granule is bigger, the particle size is > 100 μm.
Comparative example 9
The mirabegron is refined by a method disclosed in patent ZL 201410076461.7.
(A) Dissolving 1000g of crude mirabegron (purity is more than 95.0%) in a 20L ethanol/water system, wherein the ratio of ethanol: water =4, resulting in a 0.05g/ml solution, standing at 20 ℃ for 3h;
(B) Suction filtration, washing of filter cake with ethanol, vacuum drying at 40 deg.C to obtain 854g of white solid with yield of 85.4%, purity of 98.20% by HPLC detection, bulk density of 0.58g/cm3, angle of repose of 49 °, large particles with particle size > 100 μm, partial agglomeration and slight stickiness.
Comparative example 10
The mirabegron is refined by a method disclosed in patent ZL 201410076461.7.
(A) Dissolving 1000g of crude mirabegron (purity is more than 95.0%) in a 20L ethanol/water system, wherein the ratio of ethanol: water =1, giving a solution with a concentration of 0.05g/ml, stirred at 20 ℃ for 6h, at a stirring speed of 150 rev/min;
(B) Suction filtration, washing of filter cake with ethanol, vacuum drying at 40 deg.C to obtain 837g white solid with yield 83.7%, purity of 97.90% by HPLC, bulk density of 0.59g/cm3, angle of repose of 50 °, large particles with particle size > 100 μm, partial agglomeration and slight stickiness.
Comparative example 11
The mirabegron is purified by referring to the method disclosed in patent ZL 201410177823.1.
(A) 1000g of crude mirabegron (purity greater than 95.0%) is dissolved in a 20L methanol/water system in the ratio methanol: water =10, giving a solution with a concentration of 0.05g/ml, stirred at 20 ℃ for 6h, at a stirring speed of 150 rev/min;
(B) Suction filtration, washing of filter cake with ethanol, vacuum drying at 40 deg.C to obtain 926g of white solid with yield 92.6%, purity 99.00% by HPLC detection, bulk density 0.55g/cm3, angle of repose 54 °, larger particles with particle size > 100 μm.
Comparative example 12
The mirabegron is refined according to a method reported in the synthesis process development research of the mirabegron.
(A) Dissolving 1000g of crude mirabegron (purity is more than 95.0%) in a 20L ethanol/water system, wherein the ratio of ethanol: water =2, giving a solution with a concentration of 0.05g/ml, stirred at 20 ℃ for 6h, at a stirring speed of 150 rev/min;
(B) Suction filtration, washing of filter cake with ethanol, vacuum drying at 40 deg.C to obtain 724g of white solid with yield of 72.4%, purity of 96.30% by HPLC detection, bulk density of 0.55g/cm3, angle of repose of 52 °, large particles with particle size of more than 100 μm.
Comparative example 13
The mirabegron is refined according to a method reported in the synthesis research of the mirabegron.
(A) 1000g of crude mirabegron (purity greater than 95.0%) is dissolved in a 20L ethanol/water system in the ratio methanol: water =3, giving a solution with a concentration of 0.05g/ml, stirred at 20 ℃ for 6h, at a stirring speed of 150 rev/min;
(B) Suction filtering, washing the filter cake with ethanol, and vacuum drying at 40 ℃ to obtain 936g of white solid with the yield of 93.6 percent, the purity of 99.00 percent, the bulk density of 0.52g/cm < 3 >, the angle of repose of 51 degrees, larger particles and the particle size of more than 100 mu m according to HPLC detection.
TABLE 1 yield, purity, angle of repose, bulk density comparison, and particle size comparison of Mirabegron refined by different methods
As can be seen from the data in table 1, the preparation method described in comparative example 1 involves ethyl acetate and water as the crystallization solvent, and the particle size obtained by crystallization is larger than that of the alcohol-water system, indicating that the alcohol-water system is superior to the ethyl acetate-water system for mirabegron crystallization. From the results of comparative examples 2 and 3 and comparative examples 6 and 7, it can be seen that the diameter of the crystallized seed crystal is large, and therefore the diameter of the mirabegron fine product obtained by induced crystallization is large, and the mirabegron fine product is easy to bind and low in fluidity. From the results of comparative examples 4 and 5, it can be seen that the amount of crystals during crystallization is small, crystallization is incomplete, the amount of crystals is large, sudden crystallization is easily caused, and the obtained mirabegron is bonded and agglomerated, i comparative examples 8 to 13 use a solvent alone for crystallization, and due to lack of induction of seed crystals, the yield and purity of the mirabegron obtained are low, and crystal nuclei are irregularly aggregated, so that the obtained particles have large particle size, large angle of repose, poor fluidity, and part of the crystals are bonded in blocks, which is not favorable for the requirements of subsequent preparations. And all parameters of the embodiments 1 to 6 fall within the scope of the invention, and a proper crystallization solvent is selected, so that the yield and the purity are ensured, and the obtained mirabegron fine product has the advantages of proper particle size and good fluidity by proper seed crystal and stirring conditions, and is more beneficial to the development and the use of subsequent preparations.
Claims (8)
1. A refining method of mirabegron is characterized by comprising the following steps:
(A) Dissolving the crude mirabegron in an alcohol/water system according to the proportion of alcohol: water = 2-5, to obtain a solution with a concentration of 0.02-0.1 g/ml;
(B) Adding mirabegron seed crystal with the mass ratio of 0.5-2.5 wt% to the mirabegron crude product at the temperature of 0-30 ℃, keeping the seed crystal with the particle size of 5 mu m or more and D90 or more and 35 mu m, standing for 1-2 h, stirring for 4-8 h at the stirring speed of 60-400 r/min;
(C) Filtering, washing and drying to obtain a refined mirabegron;
the alcohol/water system is methanol/water, ethanol/water, isopropanol/water.
2. The refining method of mirabegron as claimed in claim 1, wherein in step (A), the ratio of alcohol: water =3 to 4, and the solution concentration is 0.04 to 0.08g/ml.
3. The refining method of mirabegron as claimed in claim 1 or 2, wherein in step (a), the alcohol/water system is ethanol/water, and the ratio of ethanol: water =3, solution concentration 0.05g/ml.
4. The refining method of mirabegron as claimed in claim 1 or 2, wherein in step (a), the alcohol/water system is methanol/water, and the ratio of methanol: water =5, solution concentration 0.04g/ml.
5. The refining method of mirabegron as claimed in claim 1 or 2, wherein in step (a), the alcohol/water system is isopropanol/water, and the ratio of isopropanol: water =4, solution concentration 0.08g/ml.
6. The refining method of mirabegron as claimed in claim 1, characterized in that in the step (B), the temperature of the added seed crystal is 10-25 ℃, the mass ratio of the added seed crystal to the crude mirabegron is 1-2 wt%, the particle size is 10 μm or more and D90 or less and 30 μm, the standing time is 1.5h, the stirring time is 5-7 h, and the stirring speed is 80-300 r/min.
7. The refining method of mirabegron as claimed in claim 1 or 6, characterized in that in step (B), the temperature of adding seed crystal is 15-20 ℃, the mass ratio of the added seed crystal to the crude mirabegron is 1wt%, the particle size is 15 μm or more and D90 or more and 25 μm or less, and the crystallization stirring speed is 100-200 r/min.
8. A refining method of mirabegron is characterized by comprising the following steps:
(A) Dissolving the crude mirabegron in an ethanol/water system according to the proportion of ethanol: water =3, giving a solution with a concentration of 0.05 g/ml;
(B) Adding mirabegron seed crystal with the mass ratio of 1wt% to the mirabegron crude product at the temperature of 20 ℃, keeping the seed crystal with the particle size of 15 mu m to 25 mu m, standing for 1.5h, and stirring for 6h at the stirring speed of 150 r/min;
(C) Filtering, washing and drying to obtain the refined mirabegron.
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