阅读说明：本技术 一种米拉贝隆α晶型原料的重结晶方法 (Recrystallization method of mirabegron alpha crystal form raw material ) 是由 王辉 张红芬 曹晓冉 孙晓伟 付香杰 何影 韩向云 杨雪 任军乐 赵飞船 于 2021-08-09 设计创作，主要内容包括：本发明提供一种米拉贝隆α晶型原料的重结晶方法,该方法采用单一溶剂重结晶,不需要加入晶种,仅采用简单的升降温程序,即可快速获得目标α晶型原料。另外,还可以通过进一步加入活性炭纯化,将杂质A的含量降至0.1％以下,大大提高了产品的质量。该方法容易回收利用溶剂、耗时较短,降低了生产成本,操作简单,产品纯度较高,更加利于工业化生产。(The invention provides a recrystallization method of a mirabegron alpha crystal form raw material, which adopts a single solvent for recrystallization, does not need to add seed crystals, and can quickly obtain a target alpha crystal form raw material only by adopting a simple temperature rise and fall program. In addition, the content of the impurity A can be reduced to be below 0.1 percent by further adding activated carbon for purification, and the quality of the product is greatly improved. The method has the advantages of easy solvent recycling, short time consumption, reduced production cost, simple operation, high product purity and contribution to industrial production.)

1. The recrystallization method of the mirabegron alpha crystal form raw material is characterized by comprising the following steps:

mixing the crude mirabegron with a single solvent, heating to reflux, cooling for crystallization after dissolution, and filtering to obtain a product;

the single solvent is acetonitrile, ethanol, methanol, n-butanol or 1, 4-dioxane.

2. The recrystallization method according to claim 1, wherein the single solvent is acetonitrile, ethanol, methanol, n-butanol.

3. The recrystallization method according to claims 1-2, wherein the volume-to-mass ratio of the single solvent to the crude mirabegron is (2-25) mL:1g, preferably (2-20) mL:1 g.

4. The recrystallization process according to claim 1, wherein the temperature reduction step is selected from natural temperature reduction, room temperature reduction or rapid cold water bath temperature reduction.

5. The recrystallization process according to claim 4, wherein the temperature reduction step is selected from rapid cooling in a cold water bath.

6. The recrystallization method according to any one of claims 1 to 5, comprising the steps of: mixing the crude mirabegron with a single solvent, heating to reflux, adding activated carbon after dissolution, filtering while hot, cooling for crystallization, and filtering to obtain the product.

7. The recrystallization process according to claim 6, wherein the weight ratio of the activated carbon to the crude mirabegron is not less than 0.006: 1.

8. The recrystallization method according to claim 7, wherein the weight ratio of the activated carbon to the crude mirabegron is (0.007-0.1): 1, preferably (0.010-0.013): 1, and more preferably 0.01: 1.

9. A composition of mirabegron alpha crystal form raw material obtained by the recrystallization method according to any one of claims 1 to 8, wherein the purity of the mirabegron alpha crystal form raw material in the composition is more than 99.9%, the content of impurity a is less than 0.08%, and the chemical structure of the impurity a is as follows:

10. the composition of mirabegron alpha crystal form feedstock of claim 9, wherein the purity of the mirabegron alpha crystal form feedstock in the composition is above 99.95% and the content of impurity a is below 0.05%.

Technical Field

The invention belongs to the technical field of pharmaceutical chemicals, and particularly relates to a recrystallization method of a mirabegron alpha crystal form raw material.

Background

Mirabegron (Mirabegron) is a drug developed by japan ansteli pharmaceutical company for urgency, frequency and incontinence caused by overactive bladder, is a selective β 3-adrenoceptor agonist, and is first marketed in japan in 2011 and approved by the U.S. FDA for the treatment of overactive bladder (OAB) in adults on 6/28 th 2012.

Mirabegron: c₂₁H₂₄N₄O₂S, CAS number: 223673-61-8, Chinese academy name: 2- (2-amino-1, 3-thiazol-4-yl) -N- [4- (2- { [ (2R) -2-hydroxy-2-phenylethyl)]Amino } ethyl) phenyl]Acetamide, of the formula:

prior art WO2003037881a1 (published 2003.5.8) discloses that mirabegron starting material exists in two crystal forms: alpha type and beta type, wherein the alpha type crystal is more stable, has good drug property and is a raw material drug crystal form used in products on the market of mirabegron.

The currently published recrystallization method of the mirabegron alpha crystal form mainly adopts mixed solvents to carry out recrystallization, and some of the mixed solvents need to be added with crystal seeds at the same time and carry out gradient cooling or repeated heating and cooling. However, these methods have the following disadvantages: (1) mixed crystals of alpha crystal form and beta crystal form are easy to generate; (2) the mixed solvent has high recycling difficulty in industrial production, and the material cost is increased; (3) seed crystals are added, so that the operation steps are increased, and the operation is more complicated; (4) the cooling crystallization consumes longer time, and the working hours and the power cost are increased.

For example, WO2003037881a1 discloses that the crude mirabegron needs to be refined twice with a mixed solvent of ethanol and water, wherein the second time is to add seed crystals during recrystallization and cooling, the temperature is reduced in steps of 10 ℃/h, and the time is at least 6 hours after calculation, so as to obtain the alpha crystal form raw material.

Patent application CN110590699A (published Japanese 2019.12.20) discloses dissolving a crude mirabegron in an alcohol/water system in a ratio of 2-5: 1 alcohol to water, adding seed crystals at 0-30 ℃, standing for 1-2 hours under heat preservation, stirring for 4-8 hours, filtering and drying to obtain an alpha crystal form raw material.

In patent application CN111072589A (published japanese 2020.4.28), a mixed solvent of alcohol and dichloromethane is adopted for recrystallization, and this method has the defect of difficult solvent recycling, and also has the problem of high toxicity of dichloromethane, which is not favorable for environmental protection.

In addition, recrystallization using a single solvent has been reported: in patent application CN111440126A (published japanese 2020.7.24), toluene was used for recrystallization, but toluene is easily left and can be carcinogenic and seriously harmful to humans and environment, and easily causes the risk of off-specification solvent residues in the finished product.

The inventors of the present application have also found during the development that an impurity (hereinafter referred to as "impurity a") in which two molecules of 2-aminothiazole-4-acetic acid are condensed is easily generated during the preparation of mirabegron, which has a chemical structure as shown in the following formula:

the impurity A has a chemical structure and physical and chemical properties similar to those of mirabegron, is difficult to remove, and easily causes that the product quality does not meet the specification. Therefore, the research on the recrystallization method of the mirabegron alpha crystal form raw material which can overcome the defects of the preparation process and has high purity has important significance for industrial production.

Disclosure of Invention

The invention aims to overcome the defects of the prior art and provides a recrystallization method of a mirabegron alpha crystal form raw material, which can quickly and stably obtain a target alpha crystal form raw material, is easy to recycle a solvent, has simple operation steps, short time consumption, easy removal of an impurity A and low production cost, and is more beneficial to industrial production.

Specifically, the recrystallization method of the mirabegron alpha crystal form raw material comprises the following steps:

mixing the crude mirabegron with a single solvent, heating to reflux, dissolving, cooling for crystallization, and filtering to obtain the product.

The single solvent includes, but is not limited to: acetonitrile, ethanol, methanol, n-butanol, and 1, 4-dioxane, and more preferably acetonitrile, ethanol, methanol, and n-butanol.

Further, the volume-to-mass ratio of the single solvent to the crude mirabegron is (2-25) mL:1g, and preferably (2-20) mL:1 g.

Further, the ratio of the acetonitrile dosage to the crude mirabegron is (19-21) mL:1g, and the ratio of the absolute ethyl alcohol, the absolute methyl alcohol, the n-butyl alcohol, the 1, 4-dioxane dosage to the crude mirabegron is (2-6) mL:1 g.

Further, according to the recrystallization method of the mirabegron alpha crystal form raw material, the temperature reduction step is selected from natural temperature reduction, room temperature reduction or cold water bath rapid temperature reduction, and preferably the cold water bath rapid temperature reduction.

In addition, the inventor finds that the mirabegron target alpha crystal form raw material can be quickly obtained by the recrystallization method, but the impurity A content in the final product is high. Tracing back the transfer process of the impurity A shows that other impurities except the impurity A in the crude product are all reduced to be below the limit (0.1%) through the recrystallization process of the ethanol-water mixed solvent, and aiming at the removal of the impurity A, the inventor tries various methods, such as recrystallization in different solvents, pulping, adsorption by different adsorption materials and other purification means, and unexpectedly finds that only activated carbon has a good impurity removal effect on the impurity A, the content of the impurity A can be controlled to be below 0.1%, the purification purpose is achieved, and other methods cannot effectively remove the impurity A.

Further, the recrystallization method of the mirabegron alpha crystal form raw material provided by the invention comprises the following steps: mixing the crude mirabegron with a single solvent, heating to reflux, adding activated carbon after dissolution, filtering while hot, cooling for crystallization, and filtering to obtain the product.

Further, the weight ratio of the activated carbon to the crude mirabegron is not less than 0.006:1, and more preferably (0.007-0.1): 1. From the comprehensive consideration of cost reduction and impurity removal effect, the weight ratio of the consumption of the activated carbon to the crude mirabegron is further preferably (0.010-0.013): 1, and most preferably 0.01: 1.

In addition, the invention also provides a composition of the mirabegron alpha crystal form raw material obtained by the recrystallization method, wherein the purity of the mirabegron alpha crystal form raw material in the composition is more than 99.9 percent, the content of the impurity A is less than 0.08 percent, and the chemical structure of the impurity A is as follows:

further, the mirabegron alpha crystal form raw material composition comprises the mirabegron alpha crystal form raw material with the purity of more than 99.95 percent and the content of impurity A of less than 0.05 percent.

Compared with the prior art, the invention has the beneficial effects that:

the recrystallization method of the mirabegron alpha crystal form raw material adopts a single solvent, does not need to add seed crystals, and can quickly obtain the target alpha crystal form raw material only by adopting a simple temperature rise and drop program. In addition, the content of the impurity A can be reduced to be below 0.1 percent by further adding activated carbon for purification, and the quality of the product is greatly improved. The method has the advantages of easy solvent recycling, short time consumption, reduced production cost, simple operation, high product purity and contribution to industrial production.

Description of the drawings:

FIG. 1: x-ray powder diffraction Pattern (alpha form) of Mirabegron raw Material powder obtained in comparative example 1

FIG. 2: x-ray powder diffraction pattern (mixed crystal of alpha crystal form and beta crystal form) of mirabegron raw material powder obtained in comparative example 2

FIG. 3: x-ray powder diffraction Pattern (alpha crystal form) of Mirabegron raw material powder obtained in example 1

FIG. 4: high performance liquid chromatogram of wet mirabegron in preparation example

FIG. 5: high performance liquid chromatogram of crude mirabegron in preparation example

FIG. 6: high performance liquid chromatogram of mirabegron obtained in example 11

Detailed Description

The invention discloses a recrystallization method of a mirabegron alpha crystal form raw material, and the method can be realized by appropriately improving process parameters by taking the contents of the invention as reference by the technical personnel in the field. It is expressly intended that all such similar substitutes and modifications apparent to those skilled in the art are deemed to be within the scope of the invention.

For a better understanding of the invention, and not as a limitation on the scope thereof, all numbers expressing quantities, percentages, and other numerical values used in this application are to be understood as being modified in all instances by the term "about". At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques.

The experimental methods used in the following examples are all conventional methods unless otherwise specified; reagents, materials and the like used in the following examples are commercially available unless otherwise specified.

The activated carbon information and raw material detection methods used in the examples and comparative examples of the present invention were as follows:

activated carbon: the source is as follows: wutian pharmaceutical company, lot number M30MS268, quality in accordance with pharmacopoeia regulations.

In the powder X-ray diffraction measurement, a BRUCKER D2 PHASER X-ray diffractometer is adopted to detect the following parameters: tube ball: cu, tube current: 10mA, tube voltage: 30kV, sample width: 0.020 °, scanning speed: 10 °/min, measurement diffraction angle range: 2 to 40 degrees.

The purity detection of the mirabegron is carried out by using a high performance liquid chromatography, and the detection conditions are as follows:

a chromatographic column: xelect chromatography column

Flow rate: 1.0ml/min

Wavelength: 214nm

Column temperature: 40 deg.C

Sample introduction amount: 10 μ l

Gradient elution conditions:

preparation example: preparation of crude mirabegron

In a 50L reaction tank, 15L of purified water was added, stirring was turned on, 1Kg of (R) -2- { [2- (4-aminophenyl) ethyl ] amino } -1-phenylethanol hydrochloride (mirabegron intermediate) was added, 0.67Kg of 2- (2-aminothiazole-4-yl) acetic acid hydrochloride and 0.9Kg of 1- (3-dimethylaminopropyl) -3-ethylcarbodiimide hydrochloride (EDCI), after the addition, reacting at room temperature for 5h, monitoring the complete reaction of the mirabegron intermediate by TLC, slowly adding 7L of 5% sodium hydroxide aqueous solution prepared in advance, separating out white solid in the adding process, after the addition, performing suction filtration to obtain a wet product (with the purity of 98.79%, the content of the impurity A of 0.19%, the retention time of the impurity A of 39.8min), and obtaining the purity detection result shown in figure 4.

Adding 8Kg of ethanol and 14Kg of water into a reaction tank, adding the wet product under stirring, heating to be completely dissolved, rapidly cooling to room temperature in a cold water bath, separating out a solid, filtering and drying to obtain a crude mirabegron (1.25Kg, yield 94.01, purity 99.62%, impurity A content 0.16%, crystal form beta crystal form), wherein the purity detection result is shown in figure 5.

Examples 1-2, comparative examples 1-3: influence of solvent, temperature reduction procedure and seed crystals on the test

Adding a solvent into a 1000mL three-necked bottle, adding 30g of crude product while stirring, heating and cooling, adding alpha crystal seed crystals (detailed in table 1), performing suction filtration, and drying in vacuum at 70 ℃ to obtain a mirabegron raw material product.

TABLE 1 Effect of temperature reduction procedure and seed crystals on the test

As can be seen from the above table, when the mixed solvent of water and ethanol is used for recrystallization, the temperature increase and decrease procedure needs to be strictly controlled, the time consumption is long, and the seed crystal needs to be added, otherwise, the pure target alpha crystal form raw material cannot be obtained, and when the ethanol single solvent is used for recrystallization, the temperature increase and decrease procedure is simple, the time consumption is greatly reduced, and the target alpha crystal form raw material can be obtained without adding the seed crystal.

Examples 2 to 11: investigation of different kinds of single solvent, activated carbon

Adding a single solvent into a three-neck bottle, adding 30g of crude mirabegron under stirring, heating to reflux, adding activated carbon (shown in table 2 in detail) after complete dissolution, filtering while hot, quickly cooling to room temperature in a cold water bath, cooling for about 0.5h, carrying out suction filtration, and vacuum-drying at 70 ℃ to obtain the mirabegron alpha crystal form raw material.

Example 2 the procedure is described in "examples 1-2, comparative examples 1-3: solvent, temperature reduction procedure and effect of seed crystals on the experiment ".

TABLE 2 investigation of different kinds of Single solvent, activated carbon

From the table above, it can be seen that the target alpha crystal form can be obtained in a short time by using ethanol, methanol, n-butanol, 1, 4-dioxane and acetonitrile, but the content of the impurity a is still high, after further adding activated carbon, the content of the impurity a is greatly reduced, the content of the impurity a is below 0.1%, even below 0.05%, the purity of mirabegron reaches above 99.9%, preferably above 99.92%, more preferably above 99.95%, and the yield influence is small.

Examples 10 to 11, 12 to 15: investigation of active carbon dosage

Adding 600mL of acetonitrile into a 1000mL three-neck flask, adding 30g of crude mirabegron under stirring, heating to reflux, adding activated carbon (see table 3 for details) after complete dissolution, filtering while hot, rapidly cooling to room temperature in a cold water bath, taking the cooling time for about 0.5h, carrying out suction filtration, and drying in vacuum at 70 ℃ to obtain the mirabegron alpha crystal form raw material.

TABLE 3 investigation of the amount of different active carbon additions

Numbering	Adding amount of activated carbon	Yield of	Purity of	Content of impurity A
					Example 10	0	94.32％	99.84％	0.15％
Example 12	0.03g	94.22％	99.83％	0.16％
					Example 13	0.2g	94.05％	99.90％	0.08％
Example 11	0.3g	93.78％	99.97％	0.02％
					Example 14	0.4g	93.33％	99.96％	0.03％
Example 15	3g	92.20％	99.97％	0.02％

As can be seen from the above table, when the weight ratio of the activated carbon to the crude mirabegron is less than 0.006:1, the content of the impurity a will be more than 0.08%, which may cause the quality to be out of compliance. The impurity removal effect is enhanced along with the increase of the adding amount of the activated carbon, but after the weight ratio of the activated carbon to the crude mirabegron is more than 0.1:1, the impurity removal effect is not changed any more, and the yield is gradually reduced.

Comparative examples 4 to 9: pulping purification investigation

Adding an organic solvent (see table 4 for details) into a three-neck bottle, adding 30g of crude mirabegron under stirring, pulping at room temperature for 2h, filtering, and drying in vacuum at 70 ℃ to obtain the mirabegron raw material.

TABLE 4 investigation of beating effect with different solvents

Numbering	Organic solvent	Amount of organic solvent	Yield of	Purity of	Content of impurity A
						Comparative example 4	Methanol	60mL	91.23％	99.72％	0.16％
Comparative example 5	Ethanol	90mL	92.56％	99.70％	0.16％
						Comparative example 6	Isopropanol (I-propanol)	150mL	91.12％	99.73％	0.15％
Comparative example 7	N-butanol	150mL	91.64％	99.74％	0.15％
						Comparative example 8	1, 4-dioxane	150mL	92.83％	99.72％	0.16％
Comparative example 9	Acetonitrile	150mL	93.20％	99.74％	0.16％

As can be seen from the table above, the pulping of various solvents has no impurity removal effect on the impurity A in the crude mirabegron.

Comparative examples 10 to 11: investigation of adsorbent materials

Adding 600mL of acetonitrile into a 1000mL three-neck flask, adding 30g of crude mirabegron under stirring, heating to reflux, adding an adsorbing material (see table 5 in detail) after complete dissolution, filtering while hot, rapidly cooling to room temperature in a cold water bath, performing suction filtration, and drying in vacuum at 70 ℃ to obtain the mirabegron alpha crystal form raw material.

TABLE 5 examination of adsorption Effect of different adsorbing materials

Numbering	Adsorbent material	Amount of adsorbent	Yield of	Purity of	Content of impurity A
						Comparative example 10	Macroporous resin	0.3g	94.13％	99.81％	0.16％
Comparative example 11	Silica gel	0.3g	93.24％	99.82％	0.15％

As can be seen from the above table, other adsorbing materials, macroporous resin and silica gel, cannot remove the impurity a in the crude mirabegron.