Refining method of mirabegron

Abstract

The invention provides a mirabegron refining method which comprises the following steps: adding sulfite or hydrosulfite into a mirabegron solution, and separating to obtain a mirabegron finished product. The method can effectively inhibit generation of color development impurities in mirabegron or remove the color development impurities, the refining method is high in yield, low in cost and suitable for industrial mass production, and after long-term storage, the color still meets the pharmacopeia standard.

Description

Technical field:

[0001] The invention relates to the field of pharmaceutical chemicals, and in particular to a method for refining mirabegron. Background technology:

[0002] Mirabegron is a β3 adrenergic receptor agonist and the first drug used to treat overactive bladder. However, during its production and storage, due to the instability of the material, various side reactions occur, resulting in the generation of one or more color-developing impurities. In general, these color-developing impurities account for a very low proportion of the material, and even chromatographic methods such as liquid chromatography and gas chromatography cannot detect them, but they can have a significant impact on human senses. The current pharmacopoeia stipulates that the appearance of mirabegron finished products is white, but the finished products obtained during the production or storage process are mostly yellow to brownish yellow, resulting in unqualified finished product properties. Therefore, it is necessary to find an effective method to solve the problem of the color of mirabegron finished products.

[0003] Patent US9981927B2 discloses a method for crystallizing mirabegron, which comprises dissolving mirabegron in a mixed organic solvent of alcohols, ketones, chlorinated hydrocarbons, esters or nitriles to obtain a mixture, then adding antioxidants such as butylated hydroxyanisole to the mixture, heating, cooling, and separating, with a yield of more than 74%. This method can effectively prevent mirabegron from changing color, but the loss of mirabegron is high during the refining process, so it is necessary to find an efficient and effective method for decolorizing mirabegron. Summary of the invention:

[0004] On one hand, the present invention provides a method for refining mirabegron, which comprises adding sulfite or bisulfite to a mirabegron solution, and separating to obtain a mirabegron finished product;

[0005] In some embodiments, the mirabegron solution is a solution formed by dissolving mirabegron in an alcohol solvent, wherein the alcohol solvent is selected from one or more of C1-C4 straight-chain or branched fatty alcohols;

[0006] In some embodiments, the alcohol solvent is methanol or ethanol; the mass volume ratio of mirabegron to the alcohol solvent is 1:5-20 g / ml;

[0007] In some embodiments, the sulfite is selected from sodium sulfite, potassium sulfite, and ammonium sulfite; the bisulfite is selected from sodium bisulfite, potassium bisulfite, and ammonium bisulfite;

[0008] In some embodiments, the bisulfite is sodium bisulfite or ammonium bisulfite; the sulfite is ammonium sulfite; wherein the sulfite or bisulfite is added in the form of an aqueous solution, wherein the mass volume ratio of the sulfite or bisulfite to water is 1:0.1 to 1:1 mg / ml;

[0009] In some embodiments, the mass ratio of mirabegron to sulfite or bisulfite is 1:0.01 to 1:0.2;

[0010] In some embodiments, the mass ratio of mirabegron to sulfite or bisulfite is 1:0.03 to 1:0.1;

[0011] In some embodiments, mirabegron is dissolved by heating at a temperature of 50 to 80° C. and a heating and heat preservation time of 1 to 3 hours;

[0012] In some embodiments, the mirabegron finished product is separated by cooling, the cooling temperature is 0 to 30° C., and the cooling stirring time is 5 to 8 hours.

[0013] Another aspect of the present invention provides a method for preparing mirabegron with a whiteness of ≥95%, the method comprising adding sulfite or bisulfite to a mirabegron solution, and separating to obtain a mirabegron finished product;

[0014] In some embodiments, the mirabegron solution is a solution formed by dissolving mirabegron in an alcohol solvent, wherein the alcohol solvent is selected from one or more of C1-C4 straight-chain or branched fatty alcohols;

[0015] In some embodiments, the alcohol solvent is methanol or ethanol; the mass volume ratio of mirabegron to the alcohol solvent is 1:5-20 g / ml;

[0016] In some embodiments, the sulfite is selected from sodium sulfite, potassium sulfite, and ammonium sulfite; the bisulfite is selected from sodium bisulfite, potassium bisulfite, and ammonium bisulfite;

[0017] In some embodiments, the bisulfite is sodium bisulfite or ammonium bisulfite; the sulfite is ammonium sulfite; wherein the sulfite or bisulfite is added in the form of an aqueous solution, wherein the mass volume ratio of the sulfite or bisulfite to water is 1:0.1 to 1:1 mg / ml;

[0018] In some embodiments, the mass ratio of mirabegron to sulfite or bisulfite is 1:0.01 to 1:0.2;

[0019] In some embodiments, the mass ratio of mirabegron to sulfite or bisulfite is 1:0.03 to 1:0.1;

[0020] In some embodiments, mirabegron is dissolved by heating at a temperature of 50 to 80° C. and a heating and heat preservation time of 1 to 3 hours;

[0021] In some embodiments, the mirabegron finished product is separated by cooling, the cooling temperature is 0 to 30° C., and the cooling stirring time is 5 to 8 hours.

[0022] Compared with the prior art, the present invention has the following positive technical effects:

[0023] 1. The present invention uses bisulfite or sulfite to purify mirabegron, which can effectively inhibit the generation of color-developing impurities or remove color-developing impurities. The refining method has high yield, low cost, good repeatability, and is suitable for large-scale industrial production.

[0024] 2. The color properties of the mirabegron finished product obtained according to the present invention meet the requirements of the pharmacopoeia, and can be stored for a long time with good stability. DETAILED DESCRIPTION

[0025] The following examples are used to further describe the specific embodiments of the present invention. The following examples are only used to illustrate the present invention, but are not used to limit the scope of the present invention.

[0026] All ranges recited in the present invention include those endpoints of the range between two values, and no matter whether it is indicated, all values ​​recited in the present invention include the expected experimental error, technical error and instrument error of the given technology used to measure the value. When the error degree is not recorded, all values ​​recited in the present invention include the range of ± 10% of the recorded value.

[0027] In the present invention, unless otherwise specified, % is a percentage of weight / weight (w / w).

[0028] Unless otherwise specified, the materials used in the present invention were obtained from commercial sources.

[0029] The method for determining the whiteness of a material of the present invention is as follows: the instrument used is a WSB-L whiteness meter produced by Shanghai Yidian Physical Optical Instrument Co., Ltd. After starting up, the 0 value and 100 value of the instrument are calibrated with the standard sample provided by the instrument, and then the sample to be tested is compacted in the detector provided by the instrument, and then the value thereof is tested, and the average value of the three tests is taken as the final result.

[0030] Example 1: Preparation of crude mirabegron

[0031] Add mirabegron amine hydrochloride (50g), 2-aminothiazole-4-acetic acid (28.4g) and water (750mL) to the reaction bottle, and slowly add concentrated hydrochloric acid under ice-water bath. After the dropwise addition, add EDCI (36.1g) and react at room temperature for 3-4h. Slowly add 30% NaOH solution, adjust pH to 9-10, add water to beat for 2-4h, filter, and dry the filter cake to obtain 54.8g of light yellow solid, yield 81%, purity: 98.9%.

[0032] Embodiment 2:

[0033] Add 10g of mirabegron crude product and 100mL of anhydrous ethanol to the reaction bottle, and heat to 65-70℃ to dissolve. Add 500mg of sodium bisulfite to 150mL of purified water to form a solution. Slowly drip the sodium bisulfite aqueous solution into the ethanol solution of mirabegron, and keep the temperature at 60-65℃. After the addition is complete, continue to keep warm for 1 hour. Reduce the temperature to 10-20℃, maintain 10-20℃ and stir for about 5 hours. Filter, rinse with 30mL of pre-cooled anhydrous ethanol, and dry to obtain 8.6g of mirabegron, with a yield of 86%, purity of 99.9%, and whiteness of 95.4.

[0034] Embodiment 3:

[0035] Put 10g of mirabegron crude product and 100mL of anhydrous ethanol into the reaction bottle, heat to 65-70℃ and dissolve. 500mg of ammonium bisulfite is added to 150mL of purified water to form a solution. The sodium bisulfite aqueous solution is slowly dripped into the ethanol solution of mirabegron, and the temperature is maintained at 60-65℃. After the addition is completed, continue to keep warm for 1 hour. Then cool to 45-50℃, add 0.05g of mirabegron seed to the reaction bottle, maintain 45-50℃, and keep warm and stir for 2 hours. Reduce the temperature to 10-20℃, maintain 10-20℃ and keep warm and stir for about 5 hours. Filter by suction, rinse with 30mL of pre-cooled anhydrous ethanol, and dry to obtain 8.3g of mirabegron with a yield of 83%, purity of 99.9%, and whiteness of 96.2.

[0036] Embodiment 4:

[0037] Add 10g of mirabegron crude product and 100mL of anhydrous ethanol to the reaction bottle, and heat to 65-70℃ to dissolve. Add 500mg of ammonium sulfite to 150mL of purified water to form a solution. Slowly drip the aqueous ammonium sulfite solution into the ethanol solution of mirabegron, and keep the temperature at 60-65℃. After the addition is complete, continue to keep warm for 1 hour. Lower the temperature to 10-20℃, maintain 10-20℃ and stir for about 5 hours. Filter, rinse with 30mL of pre-cooled anhydrous ethanol, and dry to obtain 8.9g of mirabegron, with a yield of 89%, a purity of 99.9%, and a whiteness of 97.8.

[0038] Example 5: Stability test study of mirabegron finished product

[0039] The mirabegron finished product obtained in Examples 2 to 4 was placed at a temperature of 40° C.±2° C. and a relative humidity of 75%±5% for 0 day, 3 months, and 6 months, and the whiteness thereof was tested. The test data are as follows:

[0040]

[0041] Comparative Example 1:

[0042] Add 10g of mirabegron crude product to the reaction bottle, then add 24mL of anhydrous methanol and 96mL of isopropanol, and then add 0.1g of BHA. Heat to 65-70°C and keep warm for 0.5 hours. Then cool to 45-50°C, add 0.05g of mirabegron seed to the reaction bottle, maintain 45-50°C, and stir for 2 hours. Lower the temperature to 10-20°C, maintain 10-20°C and stir for about 5 hours. Filter, rinse with 30mL of pre-cooled anhydrous ethanol, and dry to obtain 7.5g of mirabegron (yield: 75%). Purity: 99.8%, whiteness: 94.3.

[0043] Comparative Example 2:

[0044] Add 10g of mirabegron crude product and 100mL of anhydrous ethanol to the reaction bottle, heat to 65-70℃ to dissolve, then add 150mL of purified water. Cool to 45-50℃, add 0.05g of mirabegron seed to the reaction bottle, maintain 45-50℃, and stir for 2 hours. Lower the temperature to 10-20℃, maintain 10-20℃ and stir for about 5 hours. Filter, rinse with 30mL of pre-cooled anhydrous ethanol, and dry to obtain 9.1g of mirabegron (yield: 91%). Purity: 99.9%, whiteness: 85.7.

[0045] Comparative Example 3:

[0046] Add 10g of mirabegron crude product and 100mL of anhydrous ethanol to the reaction bottle, heat to 65-70℃ to dissolve. Add 30mg of BHA to 150mL of purified water to form a solution. The aqueous solution is slowly dripped into the ethanol solution of mirabegron, and the temperature is maintained at 60-65℃. After the addition is completed, continue to keep warm for 1 hour. Then cool to 45-50℃, add 0.05g of mirabegron seed to the reaction bottle, maintain 45-50℃, and keep warm and stir for 2 hours. Reduce the temperature to 10-20℃, maintain 10-20℃ and keep warm and stir for about 5 hours. Filter by suction, rinse with 30mL of pre-cooled anhydrous ethanol, and dry to obtain 7.5g of mirabegron (yield: 75%). Purity: 99.9%, whiteness: 93.8.

[0047] The specific embodiments described in the present invention are merely examples of the spirit of the present invention. Those skilled in the art of the present invention may make various modifications or additions to the specific embodiments described or replace them in similar ways, but they will not deviate from the spirit of the present invention or exceed the scope defined by the attached claims.

Claims

1. A method for refining mirabegron, characterized in that: The method comprises the steps of adding sulfite or bisulfite to a mirabegron solution and separating to obtain a mirabegron finished product.

2. The refining method according to claim 1, characterized in that The mirabegron solution is a solution formed by dissolving mirabegron in an alcohol solvent, wherein the alcohol solvent is selected from one or more of C1-C4 straight-chain or branched fatty alcohols; preferably methanol or ethanol; the mass volume ratio of mirabegron to the alcohol solvent is 1:5-20 g / ml;.

3. The purification method according to claim 1, characterized in that: The sulfite is selected from sodium sulfite, potassium sulfite and ammonium sulfite; the bisulfite is selected from sodium bisulfite, potassium bisulfite and ammonium bisulfite; preferably sodium bisulfite, ammonium bisulfite and ammonium sulfite.

4. The refining method according to claim 1, characterized in that: The mass ratio of mirabegron to sulfite or bisulfite is 1:0.01 to 1:0.2, preferably 1:0.03 to 1:0.

1.

5. The purification method according to claim 1, characterized in that: The sulfite or bisulfite is added in the form of an aqueous solution, wherein the mass volume ratio of the sulfite or bisulfite to water is 1:0.1 to 1:1 mg / ml.

6. The purification method according to claim 1, characterized in that: The mirabegron is dissolved by heating at a temperature of 50 to 80°C.

7. The purification method according to claim 1, characterized in that: The mirabegron finished product is separated by cooling, and the cooling temperature is 0 to 30°C.

8. The purification method according to claim 6, characterized in that: The heating time is 1 to 3 hours.

9. The refining method according to claim 7, characterized in that: The cooling and stirring time is 5 to 8 hours.

10. Mirabegron obtained by the purification method according to claims 1 to 9, characterized in that: Its whiteness is ≥95%.

Images