阅读说明：本技术 一种米拉贝隆的精制方法 (Refining method of mirabegron ) 是由 谭珍友 邓军 罗日康 张振锋 祁健斌 于 2019-09-29 设计创作，主要内容包括：本发明公开了一种米拉贝隆的精制方法,包括以下步骤：(A)将米拉贝隆粗品溶解于醇/水体系,比例为醇：水＝2～5:1,得到浓度为0.02～0.1g/ml溶液；(B)在0～30℃下,加入与米拉贝隆粗品质量比为0.5～2.5wt％的米拉贝隆晶种,晶种粒径为5μm≤D90≤35μm,保持前述温度下,静置1～2h后,搅拌4～8h,搅拌速度为60～400转/分；(C)过滤、洗涤及干燥,得到米拉贝隆精品。用本发明的方法能够获得粒径均匀,流动性好,适合制剂使用的米拉贝隆精品。(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: obtaining a solution with the concentration of 0.02-0.1 g/ml by using water as a ratio of 2-5: 1; (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 at the temperature of 5 mu m or more and D90 or more and 35 mu m or less, standing for 1-2 hours, and stirring for 4-8 hours at the stirring speed of 60-400 rpm; (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.)

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: obtaining a solution with the concentration of 0.02-0.1 g/ml by using water as a ratio of 2-5: 1;

(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 at the temperature of 5 mu m or more and D90 or more and 35 mu m or less, standing for 1-2 hours, and stirring for 4-8 hours at the stirring speed of 60-400 rpm;

(C) filtering, washing and drying to obtain the refined mirabegron.

2. The refining method of mirabegron as claimed in claim 1, wherein in step (A), the alcohol/water system is methanol/water, ethanol/water, isopropanol/water, and the ratio of alcohol: the ratio of water to water is 3-4: 1, and the concentration of the solution is 0.04-0.8 g/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 3:1, solution concentration 0.05 g/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 5:1, solution concentration 0.04 g/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: 1, solution concentration 0.08 g/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 more and 30 μm or less, the standing time is 1.5h, the post-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 the added seed crystal is 15-20 ℃, the mass ratio of the added seed crystal to the crude mirabegron is 1 wt%, 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 3:1 to give a 0.05g/ml solution;

(B) adding mirabegron seed crystal with the mass ratio of 1 wt% to the mirabegron crude product at the temperature of 20 ℃, keeping the seed crystal with the particle size of 15 mu m or more and D90 or more and 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.

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 beta 3-adrenoceptor agonist developed by pharmaceutical corporation in japan mountains (now incorporated into astella) that increases bladder filling and urine storage capacity by activating the beta 3-adrenoceptor on the detrusor of the bladder, and the united states Food and Drug Administration (FDA) approved overactive bladder (OAB) for the treatment of symptoms such as 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 and 2014.11.12 discloses a synthesis method of mirabegron, and examples disclose that methanol and water are used for refining a mirabegron crude product (without related proportion), so that the purity of the mirabegron refined product is 99.0%.

Domestic application CN201410177823.1 to 2014.07.02 discloses a synthesis method of mirabegron, in the examples, the crude product is recrystallized by methanol solution, wherein the volume ratio of methanol to water in the methanol solution is 10:4, and the purity is 99.96%.

Domestic patent ZL201410076461.7 and 2016.03.09 disclose a preparation method of mirabegron, and in the embodiment, 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 development of mirabegron' in 2017, and the document reports a synthesis process of mirabegron, and a crude product is synthesized by using v (ethanol): and (5) recrystallizing 2:3 to obtain the refined mirabegron.

Fangchini et al published "mirabegron synthesis process improvement" (fine chemical intermediates, 2016,46(4)), which reported a synthesis process of mirabegron, examined the mirabegron recrystallization solvent, and screened out when v (ethyl acetate): when v (water) is 5:1, the maximum recrystallization yield of the mirabegron can reach 51.6%.

Mailogfei et al published "synthetic studies on mirabegron" and reported a synthetic process for mirabegron, where the crude product was synthesized with v (methanol): and (5) recrystallizing with water at a ratio of 3:1 to obtain the mirabegron refined product with the purity of 99.51%.

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 of the invention comprises the following steps:

(A) dissolving the crude mirabegron in an alcohol/water system according to the proportion of alcohol: obtaining a solution with the concentration of 0.02-0.1 g/ml by using water as a ratio of 2-5: 1;

(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 at the temperature of 5 mu m or more and D90 or more and 35 mu m or less, standing for 1-2 hours, and stirring for 4-8 hours at the stirring speed of 60-400 rpm;

(C) filtering, washing and drying to obtain the refined mirabegron.

The proportion and the concentration of an alcohol/water system used in the method are one of the keys for realizing the technical effect, and when the alcohol/water system is ethanol/water, methanol/water or 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: the ratio of water to water is 3-4: 1, and the concentration of the solution is 0.04-0.8 g/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 3:1, solution concentration 0.05 g/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 5:1, solution concentration 0.04 g/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: 1, solution concentration 0.08 g/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 poor, and when the seed crystal particle size is too small, the product particle size 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 is defective. Specifically, in the refining method of mirabegron, in the step (B), the temperature of adding the 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 microns or more and D90 or less and 30 microns or less, the standing time is 1.5 hours, the post-stirring time is 5-7 hours, and the stirring speed is 80-300 r/min.

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 1 wt% 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 seed crystal addition or the production time greatly prolonged caused by too little seed crystal addition 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 1 wt%, the particle size is 15 microns or more and D90 or more and 25 microns or less, and the crystallization stirring speed is 100-200 r/min.

A preferred method for purifying mirabegron of the present invention is characterized by comprising the steps of:

(A) dissolving the crude mirabegron in an ethanol/water system according to the proportion of ethanol: water 3:1 to give a 0.05g/ml solution;

(B) adding mirabegron seed crystal with the mass ratio of 1 wt% to the mirabegron crude product at the temperature of 20 ℃, keeping the seed crystal with the particle size of 15 mu m or more and D90 or more and 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 fine mirabegron prepared 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.

Figure 3 is a graph of the mirabegron particle size distribution 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.