阅读说明：本技术 一种α晶型米拉贝隆的制备方法 (Preparation method of alpha crystal form mirabegron ) 是由 王先登 毛逸飞 田森群 于 2021-01-19 设计创作，主要内容包括：本发明提供了一种α晶型米拉贝隆的制备方法。该制备方法具有质量稳定,收率搞,成本低的优点,可用于工业化生产。(The invention provides a preparation method of alpha crystal mirabegron. The preparation method has the advantages of stable quality, high yield and low cost, and can be used for industrial production.)

1. The invention provides a preparation method of alpha crystal Mirabegron, which comprises the following steps:

1) dissolving the mirabegron raw material medicine in ethanol, heating and refluxing, and filtering;

2) adding water into the filtrate to obtain 30-35% ethanol water solution;

3) adding about 0.8% to 1.2% of mirabegron in alpha crystal form to the solution;

4) slowly cooling to 0-5 ℃ at a speed of 5-15 ℃/h, stirring and crystallizing;

5) filtering and drying to obtain the alpha crystal form mirabegron.

2. The process of claim 1, wherein in step 1), the mass-to-volume ratio of mirabegron to ethanol is 1: 7-10, preferably 1: 8.

3. The method as claimed in claim 1, wherein in the step 2), the ethanol water solution is 30-35% ethanol water solution, and the mass volume ratio of the ethanol water solution to the mirabegron raw material drug is 23-33%.

4. The method according to claim 1, wherein the amount of the added seed in step 3) is 0.8% to 1.2%.

5. The method of claim 1, wherein in the step 4), the temperature is reduced at a rate of 5-15 ℃/h and in a range of 0-5 ℃, preferably at a rate of 10 ℃/h and in a range of 0-5 ℃.

1. Field of the invention

The invention relates to a preparation method of alpha crystal Mirabegron.

2. Background of the invention

Mirabegron was developed by Astelai (Astelas) pharmaceutical in Japan for the treatment of overactive bladder with symptoms of urgency, incontinence and frequency. This product was subjected to clinical trials in japan in 2005 and approved in japan at 7/1/2011. China is admitted to import in 2017 in 9 months. The product is chemically 2- (2-aminothiazol-4-yl) -N- [4- (2- { [ (2R) -2-hydroxy-2-phenylethyl ] amino } ethyl) phenyl ] acetamide and has the following structure:

chinese patent ZL98121375.8 discloses the structural formula of the product and the application in diabetes.

Chinese patent ZL02821370.X discloses a preparation method of two crystal forms of mirabegron, namely an alpha crystal form and a beta crystal form, wherein the alpha crystal form is a medicinal crystal form with better stability.

The preparation method of the alpha crystal form comprises the following steps: adding a solvent (37-50% of ethanol aqueous solution) into the beta crystal form, heating and dissolving at about 70-80 ℃, cooling at the speed of about 10 ℃ for 1 hour to obtain the alpha crystal form, and during industrial production, the alpha crystal form is easy to crystallize in large-scale production and can be preferentially precipitated through inoculation. Examples 3 and 4 describe in detail the process for preparing the form alpha from the form beta.

The preparation method of the beta crystal form comprises the following steps of adding a mixed solution of water and ethanol into a wet product, heating and dissolving at 80 ℃, setting the external temperature to be 20 ℃, rapidly cooling, filtering generated crystals, and drying to obtain the beta crystal form. Example 2 describes the preparation of the beta crystalline form.

According to the embodiment, the two different crystallization methods are different in cooling speed, the alpha crystal form is cooled slowly, the crystallization speed is slow, and the alpha crystal form is obtained through control by adding about 0.1% of seed crystal.

In the research, the mirabegron bulk drug is not dissolved in water and is slightly soluble in ethanol. The ethanol-water mixed solution is directly used for recrystallization, and the phenomenon of rapid crystallization exists only by controlling the cooling speed, so that mixed crystals are caused, and a small amount of beta crystal forms are doped in the alpha crystal forms. The beta crystal form is a metastable crystal form, and the existence of the crystal form causes the change of the properties of the mirabegron raw material drug, thereby influencing the product quality, so the prior technical scheme is not suitable for industrialized production. In addition, the existing technical scheme has the defects of low product yield, difficulty in controlling the cost of the raw material medicine and lack of market competitive advantage.

3. Summary of the invention

The invention provides a preparation method of a mirabegron alpha crystal form, which has the advantages of stable production process and lower cost and is suitable for industrial production.

The invention provides a preparation method of a mirabegron alpha crystal form, which comprises the following steps:

1) dissolving the mirabegron raw material medicine in ethanol, heating and refluxing, and filtering;

2) adding water into the filtrate to obtain a 30-35% ethanol aqueous solution;

3) adding about 0.8-1.2% of alpha crystal form mirabegron bulk drug into the solution;

4) slowly cooling to 0-5 ℃ at the speed of about 5-15 ℃/h, and stirring for crystallization;

5) filtering and drying to obtain the alpha crystal form mirabegron.

More specifically, in the step 1), the mass-to-volume ratio of the mirabegron to the ethanol is 1: 7-10, preferably 1: 8, and the mixture is heated and refluxed until the mixture is clear;

researches show that under the mass-volume ratio, the mirabegron has good solubility in ethanol under the reflux state, and the phenomenon of crystallization is not easy to occur in the process of membrane filtration, so that the phenomenon of mixed crystals caused by violent crystallization is avoided. According to the prior technical scheme, a mixed system of ethanol and water is directly adopted for recrystallization, so that the phenomenon of crystallization caused by cold-heat exchange in a filtering link is easily caused.

Research results show that ethanol is used as a solvent, no precipitation phenomenon occurs during hot filtration when the mass volume ratio is within the range of 7-10%, on the contrary, the precipitation phenomenon can be avoided only when the mass volume ratio is increased to nearly 30% during filtration after 50% ethanol water solution is adopted for hot dissolution, and the yield is obviously reduced when a higher mass volume is used.

In the step 2), after filtering, adding water into the filtrate to obtain an ethanol water solution with the volume ratio of about 30-35%, wherein a patent ZL02821370.X discloses that the ethanol water solution is 37-50%, and the using amount of ethanol is large. According to the existing technical scheme, ethanol with a lower proportion is adopted, under the condition that sudden precipitation is avoided, the proportion of water is properly increased, the yield of the mirabegron alpha crystal form can be remarkably improved, and researches show that the yield is up to more than 90% by precipitation in 30-35% ethanol water solution and is remarkably higher than that of the embodiment scheme in the patent ZL02821370.X, so that the manufacturing cost of the product is favorably reduced.

In the step 3), about 0.8-1.2% of alpha crystal Mirabegron bulk drug is added into the filtrate for induced crystallization. The proportion of added seeds in patent zl02821370.x is about 0.1%. Researches show that 0.1% of seed crystal is adopted for inoculation, the crystallization period is long, the crystallization is incomplete, and the researches show that the yield is still less than 80% after the crystal is stirred and added and is crystallized for 5 hours, the yield is low, and a small amount of mixed crystals exist. This study increased the seed dosage significantly to about 10-fold, corresponding to 1% of the mirabegron charge. Research shows that the crystallization speed can be obviously improved under the proportion, and the prepared alpha crystal form has no mixed crystal phenomenon.

In the step 4), slowly cooling to 0-5 ℃ at a speed of about 5-15 ℃/h, and stirring for crystallization. Compared with patent ZL02821370.X, the cooling speed is equivalent, and the cooling end point is lower and is 0-5 ℃. The yield is further improved by further controlling the temperature to be lower.

Test code	The dosage of solvent	Seed crystal	Temperature of crystallization	Yield of
					7	Mirabegron 30% ethanol water solution (m/v) ═ 1: 27	1.2％	0～5℃	92.3％
8	Mirabegron 30% ethanol water solution (m/v) ═ 1: 33	0.8％	0～5℃	91.0％
					9	Mirabegron 35% ethanol water solution (m/v) ═ 1: 28	1％	0～5℃	93.2％
10	Mirabegron 35% ethanol water solution (m/v) ═ 1: 23	1％	0～5℃	93.3％
					11	Mirabegron 35% ethanol water solution (m/v) ═ 1: 28	1％	10℃	85.0％
12	Mirabegron 45% ethanol water solution (m/v) ═ 1: 25	0.1％	10℃	81.2％
					13	Mirabegron 45% ethanol water solution (m/v)＝1∶30	0.15％	10℃	76.7％

And 5) filtering the filtrate after crystallization is finished, and drying to obtain the alpha crystal form mirabegron.

The present invention will be further described with reference to the drawings and the embodiments thereof, it should be understood that the following embodiments are merely illustrative of the present invention and the scope of the present invention should not be construed as being limited to the following embodiments.

4. Description of the drawings

FIG. 1, DSC pattern of alpha crystal Mirabegron

FIG. 2 shows XRD pattern of mirabegron in alpha crystal form

FIG. 3, HPLC chromatogram of alpha crystal Mirabegron

5. Detailed description of the preferred embodiments

The present invention is further described with reference to the drawings and the following embodiments, it should be understood that the following embodiments are merely illustrative of the present invention and the scope of the present invention should not be construed as being limited to the following embodiments.

Example 1: preparation of alpha crystal form mirabegron

10Kg of mirabegron is dissolved in 80L of ethanol, heated to reflux and filtered while hot. And slowly adding 190L of water into the filtrate, slowly cooling to 55 ℃, adding 120g of alpha crystal form mirabegron, stirring, slowly cooling to 0-5 ℃, continuously stirring for about 1 hour, filtering, washing the obtained filter cake with a precooled 30% ethanol water solution, and drying to obtain 9.23Kg of alpha crystal form mirabegron, wherein the mass yield is 92.3%, and the HPLC purity is more than 99.5%.

Example 2: preparation of alpha crystal form mirabegron

10Kg of mirabegron is dissolved in 80L of ethanol, heated to reflux and filtered while hot. And slowly adding 250L of water into the filtrate, slowly cooling to 55 ℃, adding 80g of alpha crystal form mirabegron, stirring, slowly cooling to 0-5 ℃, continuously stirring for about 1 hour, filtering, washing the obtained filter cake by using a precooled 30% ethanol water solution, and drying to obtain 9.1Kg of alpha crystal form mirabegron, wherein the mass yield is 91%, and the HPLC purity is more than 99.5%.

Example 3: preparation of alpha crystal form mirabegron

10Kg of mirabegron is dissolved in 100L of ethanol, heated to reflux and filtered while hot. And slowly adding 230L of water into the filtrate, slowly cooling to 55 ℃, adding 100g of alpha crystal form mirabegron, stirring, slowly cooling to 0-5 ℃, continuously stirring for about 1 hour, filtering, washing the obtained filter cake with a precooled 35% ethanol water solution, and drying to obtain 9.32Kg of alpha crystal form mirabegron, wherein the mass yield is 92.3%, and the HPLC purity is more than 99.5%.

Example 4: preparation of alpha crystal form mirabegron

10Kg of mirabegron is dissolved in 100L of ethanol, heated to reflux and filtered while hot. And slowly adding 180L of water into the filtrate, slowly cooling to 55 ℃, adding 100g of alpha crystal form mirabegron, stirring, slowly cooling to 0-5 ℃, continuously stirring for about 1 hour, filtering, washing the obtained filter cake with a precooled 35% ethanol water solution, and drying to obtain 9.23Kg of alpha crystal form mirabegron, wherein the mass yield is 93.3%, and the HPLC purity is more than 99.5%.

Example 5: preparation of alpha crystal form mirabegron

Dissolving 10Kg of mirabegron in 250L of 45 percent ethanol water solution, heating to reflux, filtering while hot, slowly cooling to 55 ℃, adding 10g of alpha crystal mirabegron, stirring and slowly cooling to 10 ℃, continuously stirring for about 5 hours, filtering, washing an obtained filter cake by using precooled 45 percent ethanol water solution, and drying to obtain 8.12Kg of alpha crystal mirabegron, wherein the mass yield is 81.25 percent, and the HPLC purity is more than 99.5 percent.

Example 6: preparation of alpha crystal form mirabegron

Dissolving 10Kg of mirabegron in 300L of 45 percent ethanol water solution, heating to reflux, and filtering while the solution is hot. Slowly cooling to 55 ℃, adding 15g of alpha crystal form mirabegron, stirring, slowly cooling to 10 ℃, continuously stirring for about 5 hours, filtering, washing an obtained filter cake by using precooled 45% ethanol water solution, and drying to obtain 7.67Kg of alpha crystal form mirabegron, wherein the mass yield is 76.7%, and the HPLC purity is more than 99.5%.