Preparation of mirabegron disubstituted compound as well as obtained product and detection of mirabegron disubstituted compound

Abstract

The invention discloses a preparation method of a mirabegron disubstituted compound and a product obtained by the preparation method. According to the preparation method, the obtained mirabegron disubstituted compound product is high in yield (75% or above), high in purity (HPLC purity is larger than or equal to 99.0%), low in energy consumption, low in cost and more suitable for industrial production. Besides, the invention also provides a high performance liquid chromatography detection method for the mirabegron disubstituted compound in the test sample, the detected chromatographic peaks have no obvious interference, the separation degree is high, the detection result is accurate and reliable, the relevant regulations and / or requirements of accuracy and precision are met, and qualitative and / or quantitative detection can be realized.

Description

Technical Field

[0001] The present invention belongs to the field of medicinal chemistry, and particularly relates to the preparation of a mirabegron disubstituted compound and the resulting product and detection thereof. Background Art

[0002] The Pharmacopoeia of the People's Republic of China (2020 edition) explicitly states that impurities are key quality attributes of pharmaceuticals and can affect the safety and effectiveness of products; it is necessary to strengthen qualitative and quantitative research on impurities in chemical drugs and control known and unknown impurities separately. Impurities in pharmaceutical quality standards refer to impurities introduced by the production process or raw materials of pharmaceuticals produced in accordance with processes and raw materials approved by the national drug supervision and administration authorities in accordance with the law, or impurities generated during storage.

[0003] For APIs, it is necessary to control both the purity (active ingredients) of the API products and the limit of impurities in the API products, so as to meet the requirements of product safety and efficacy (see: "Pharmacopoeia of the People's Republic of China" (2020 edition) Part IV: pages 483-485, 9102 Guidelines for Drug Impurity Analysis).

[0004] Mirabegron, CAS number: 223673-61-8, is a selective β3-adrenergic receptor agonist, mainly used to treat urinary urgency, urinary frequency, urinary incontinence and other symptoms caused by overactive bladder.

[0005] Among the numerous impurities, the following disubstituted mirabegron impurities are known to be important impurities and are often inevitably present in the API and / or formulation of mirabegron, requiring detection and control limits. Furthermore, the disubstituted impurities have a chemical polarity very similar to that of mirabegron, making them generally difficult to completely separate and accurately measure (see: CN 111072589A).

[0006]

[0007] In view of this, the present invention is proposed in order to obtain a high-yield and / or high-purity mirabegron disubstituted compound reference substance and further to achieve accurate determination of the disubstituted compound in the mirabegron product. Summary of the Invention

[0008] In response to the problems and / or deficiencies of the prior art, the present invention aims to provide a method for preparing a disubstituted mirabegron compound and the resulting product. This preparation method provides a high yield (over 75%), high purity (HPLC purity ≥99.0%), low energy consumption, and low cost, making it more suitable for industrial production. Furthermore, a high-performance liquid chromatography (HPLC) method for detecting disubstituted mirabegron compounds in a test sample is provided. The detected chromatographic peaks exhibit no significant interference, high resolution, and accurate and reliable test results, meeting relevant regulations and / or requirements for accuracy and precision, enabling qualitative and / or quantitative detection.

[0009] The present invention provides a method for preparing a mirabegron disubstituted compound, comprising the following steps:

[0010]

[0011] In the presence of a dehydrating agent and a catalyst, mirabegron and 2-aminothiazole-4-acetic acid undergo a condensation reaction in a nitrogen-containing solvent to generate a mirabegron disubstituted compound; wherein the dehydrating agent comprises 1-hydroxybenzotriazole and / or N,N-dicyclohexylcarbodiimide.

[0012] Further,

[0013] In any of the above technical solutions (method for preparing mirabegron disubstituted compounds), the catalyst is an organic amine catalyst; and / or the nitrogen-containing solvent is a nitrogen-containing solvent containing an amide structure;

[0014] Preferably, the catalyst is triethylamine; and / or the nitrogen-containing solvent is N,N-dimethylformamide or N,N-dimethylacetamide.

[0015] Further,

[0016] In any of the above technical solutions (methods for preparing mirabegron disubstituted compounds), the molar ratio of mirabegron to 2-aminothiazole-4-acetic acid is 1:1 to 1.5 (for example, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, etc.); and / or the amount of catalyst used per mole of mirabegron is 1 mol to 1.5 mol (for example For example, 1.05 mol, 1.1 mol, 1.15 mol, 1.2 mol, 1.25 mol, 1.3 mol, 1.35 mol, 1.4 mol, 1.45 mol, etc.); and / or, the amount of nitrogen-containing solvent per gram of mirabegron is 5 ml to 50 ml (for example, 8 ml, 10 ml, 12 ml, 15 ml, 20 ml, 25 ml, 30 ml, 35 ml, 40 ml, 45 ml, etc.);

[0017] Preferably, the molar ratio of mirabegron to 2-aminothiazole-4-acetic acid is 1:1.05-1.15; and / or the amount of catalyst used per mole of mirabegron is 1.15 mol-1.25 mol; and / or the amount of nitrogen-containing solvent used per gram of mirabegron is 10 ml-15 ml.

[0018] Further,

[0019] In any of the above technical solutions (method for preparing mirabegron disubstituted compounds), the dehydrating agent comprises 1-hydroxybenzotriazole and N,N-dicyclohexylcarbodiimide;

[0020] Preferably, the amount of 1-hydroxybenzotriazole used per mole of mirabegron is 1 mol to 1.5 mol (e.g., 1.05 mol, 1.1 mol, 1.15 mol, 1.2 mol, 1.25 mol, 1.3 mol, 1.35 mol, 1.4 mol, 1.45 mol, etc.); and / or the amount of N,N-dicyclohexylcarbodiimide used per mole of mirabegron is 1 mol to 1.5 mol (e.g., 1.05 mol, 1.15 mol, 1.25 mol, 1.35 mol, 1.45 mol, etc.). 1 mol, 1.15 mol, 1.2 mol, 1.25 mol, 1.3 mol, 1.35 mol, 1.4 mol, 1.45 mol, etc.); and / or, the molar ratio of 1-hydroxybenzotriazole to N,N-dicyclohexylcarbodiimide is 1:1.01 to 1.1 (for example, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1.09, etc.);

[0021] More preferably, the amount of 1-hydroxybenzotriazole per mole of mirabegron is 1.05 mol to 1.15 mol; and / or the amount of N,N-dicyclohexylcarbodiimide per mole of mirabegron is 1.05 mol to 1.15 mol; and / or the molar ratio of 1-hydroxybenzotriazole to N,N-dicyclohexylcarbodiimide is 1:1.01 to 1.05.

[0022] Further,

[0023] In any of the above technical solutions (methods for preparing mirabegron disubstituted compounds), the reaction temperature of the condensation reaction is 5°C to 50°C (for example, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, etc.); and / or the reaction time of the condensation reaction is 2 hours to 12 hours (for example, 2 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, etc.);

[0024] Preferably, the reaction temperature of the condensation reaction is 10° C. to 35° C.; and / or the reaction time of the condensation reaction is 3 hours to 5 hours.

[0025] Further,

[0026] In any of the above technical solutions (methods for preparing mirabegron disubstituted compounds), the preparation method further comprises a post-treatment step: after the condensation reaction is completed, water is added to obtain a reaction solution, a solid is precipitated, and the solvent is removed, and then a purification step is optionally included to obtain the mirabegron disubstituted compound;

[0027] Preferably, the amount of water used per gram of mirabegron is 8 ml to 12 ml (for example, 9 ml, 10 ml, 11 ml, 12 ml, etc.); and / or, the solvent in the purification step comprises an alcohol solvent and an ether solvent; wherein the alcohol solvent is methanol and / or ethanol, and the ether solvent is methyl tert-butyl ether;

[0028] More preferably, the amount of alcohol solvent per gram of mirabegron is 1.5 ml to 5 ml (for example, 1.8 ml, 2 ml, 2.2 ml, 2.5 ml, 3 ml, 3.5 ml, 4 ml, 4.5 ml, etc.); and / or, the amount of ether solvent per gram of mirabegron is 8 ml to 12 ml (for example, 9 ml, 10 ml, 11 ml, 12 ml, etc.); and / or, the volume ratio of the alcohol solvent to the ether solvent is 1:2 to 10 (for example, 1:3, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:7, 1:8, 1:9, etc.) or 1:5;

[0029] Further preferably, the purification step is: after removing the solvent, adding an alcohol solvent and heating to 60°C±5°C, then adding an ether solvent, cooling to room temperature, precipitating a solid, filtering, and drying.

[0030] The present invention also provides a mirabegron disubstituted compound product, wherein the HPLC purity of the mirabegron disubstituted compound is ≥99.0% or ≥99.5%; preferably, the mirabegron disubstituted compound is prepared by any of the above preparation methods.

[0031] The present invention also provides a high performance liquid chromatography method for detecting a mirabegron disubstituted compound in a test sample, wherein the mirabegron disubstituted compound described above (the mirabegron disubstituted compound has an HPLC purity of ≥99.0% or ≥99.5%; preferably, the mirabegron disubstituted compound is prepared by any of the preparation methods described above) is used as a reference sample for detection, and the test sample is a mirabegron bulk drug or preparation;

[0032] Preferably, the chromatographic conditions of the high performance liquid chromatography detection method include:

[0033] Chromatographic column: C18 column or its equivalent;

[0034] Mobile phase A: 0.01 mol / L potassium dihydrogen phosphate aqueous solution containing 0.01 mol / L sodium octane sulfonate;

[0035] Mobile phase B: acetonitrile;

[0036] Perform gradient elution according to the following program:

[0037] Time / min Mobile phase A / %, volume percentage Mobile phase B / %, volume percentage 0 77 23 3 77 23 30 67 33 45 55 45

[0038] Detection wavelength: 180-280 nm (e.g., 185 nm, 190 nm, 195 nm, 200 nm, 205 nm, 210 nm, 215 nm, 220 nm, 225 nm, 230 nm, 235 nm, 238 nm, 240 nm, 242 nm, 245 nm, 250 nm, 255 nm, 260 nm, 265 nm, 270 nm, 275 nm, etc.);

[0039] More preferably,

[0040] The chromatographic column is a Kromasil 100-5-C18 chromatographic column;

[0041] And / or, the specifications of the chromatographic column are: 4.6 mm × 250 mm, 5 μm;

[0042] and / or, the mobile phase A is adjusted to a pH value of 2.50±0.05 with phosphoric acid;

[0043] And / or, the detection wavelength is 250 nm.

[0044] Further,

[0045] In any of the above technical solutions (high performance liquid chromatography detection method),

[0046] Column temperature: 15°C to 45°C (e.g., 20°C, 25°C, 28°C, 30°C, 32°C, 35°C, 40°C, 42°C, 45°C, etc.); preferably, the column temperature is 30°C;

[0047] and / or, injection volume: 0.5 μl to 25 μl (for example, the injection volume is 1 μl, 2 μl, 3 μl, 4 μl, 5 μl, 6 μl, 7 μl, 8 μl, 9 μl, 10 μl, 15 μl, 20 μl, 25 μl, etc.); preferably, the injection volume is 10 μl;

[0048] And / or, mobile phase flow rate: 0.1ml / min~2ml / min (for example, the mobile phase flow rate is 0.5ml / min, 0.6ml / min, 0.7ml / min, 0.8ml / min, 0.9ml / min, 1.0ml / min, 1.2ml / min, 1.5ml / min, etc.); preferably, the mobile phase flow rate is 1.0ml / min~1.5ml / min.

[0049] Further,

[0050] In any of the above technical solutions (high performance liquid chromatography detection method), the high performance liquid chromatography detection method is a qualitative detection or a quantitative detection; preferably, the high performance liquid chromatography detection method performs quantitative detection according to the internal standard method or the external standard method.

[0051] Beneficial effects

[0052] The preparation method of the mirabegron disubstituted compound provided by the present invention has mild reaction conditions, good safety, and is easy to operate and / or control. The obtained mirabegron disubstituted compound product has a high yield (results of multiple batch tests of small and pilot tests show that the yield is above 75%), high purity (HPLC purity ≥99.0%), low energy consumption, low cost, and is more suitable for industrial production.

[0053] also,

[0054] The present invention provides a high-performance liquid chromatography method for detecting mirabegron disubstituted compounds in a test sample. The method has no obvious interference between the chromatographic peaks detected, has high separation, and provides accurate and reliable detection results. The method can meet relevant regulations and / or requirements for accuracy and precision, thereby achieving qualitative and / or quantitative detection. This method provides an effective method for detecting products such as mirabegron raw materials, thereby enabling more effective monitoring and assurance of their product quality, thereby better protecting the quality and / or safety of their downstream preparations, and has good economic and social value.

[0055] Obviously, based on the above contents of the present invention, according to common technical knowledge and customary means in this field, without departing from the above basic technical ideas of the present invention, other various forms of modifications, replacements or changes can be made. BRIEF DESCRIPTION OF THE DRAWINGS

[0056] Figure 1 The compound P06 obtained in Example 1 of the present invention 1 H-NMR spectrum.

[0057] Figure 2 The compound P06 obtained in Example 1 of the present invention 13 C-NMR spectrum.

[0058] Figure 3 This is an HPLC chart of the impurity compound P06 detected in the mirabegron raw material drug according to Example 4 of the present invention. DETAILED DESCRIPTION

[0059] The present invention will be clearly and completely described below with reference to specific embodiments. Those skilled in the art will understand that the embodiments described below are only some embodiments of the present invention, rather than all embodiments, and are only used to illustrate the present invention and should not be regarded as limiting the scope of protection of the present invention.

[0060] In the present invention, if the specific conditions are not specified, the conventional conditions or the conditions recommended by the manufacturer shall be followed. If the manufacturer of the reagents or instruments is not specified, they are all conventional products that can be purchased commercially.

[0061] Regarding the definitions of terms used in the present invention, unless otherwise stated, the initial definitions provided for the terms in this document apply to the terms throughout the text; for terms not specifically defined herein, the meanings that can be given to them by those skilled in the art should be given based on the disclosure content and / or context.

[0062] For example, chromatographic conditions such as 0.01 mol / L potassium dihydrogen phosphate aqueous solution containing 0.01 mol / L sodium octane sulfonate and gradient elution are defined and interpreted in accordance with the 2015 edition of the "Chinese Pharmacopoeia".

[0063] Example 1

[0064]

[0065] To the reaction flask, 10 g (about 25.2 mmol) of mirabegron (HPLC purity ≥99%) and 110 ml of N,N-dimethylformamide (DMF), as well as 3.75 g (about 27.8 mmol) of 1-hydroxybenzotriazole (HOBT), 5.8 g (about 28.1 mmol) of N,N-dicyclohexylcarbodiimide (DCC) and 4.4 g (about 27.8 mmol) of 2-aminothiazole-4-acetic acid were added and stirred. 3 g (about 29.6 mmol) of triethylamine was added and the reaction was stirred at room temperature for 4 h. After the reaction was completed, 100 ml of purified water was added to precipitate a solid. The solvent was removed, 20 ml of methanol was added to the obtained solid and the temperature was raised to 60° C. 100 ml of methyl tert-butyl ether was added, the mixture was cooled to room temperature, stirred, a solid was precipitated, filtered, and dried to give compound P06 with a yield of 78.5% and an HPLC purity of 99.58% (peak area normalization method).

[0066]

[0067] Compound P06 1 H-NMR and 13 C-NMR, see Figure 1 and Figure 2 ; Infrared (IR) spectrum data are shown in Table 1, mass spectrum (MS) data M+H + =537.20.

[0068] Table 1. IR spectrum data of compound P06

[0069] <![CDATA[Absorption wave number (cm -1 )]]> Attribution 3309 NH stretching vibration 2925，2854 Saturated CH stretching vibration 1608，1516 Benzene ring C=C stretching vibration 1339 CN stretching vibration 826，757，701 Benzene ring CH bending vibration

[0070] Example 2

[0071] Chinese patent applications CN202011327875.4 (invention name: Preparation method of mirabegron and its intermediates; application date: 2020 / 11 / 24) and CN 202211032793.6 (invention name: A pharmaceutical composition containing mirabegron and its preparation and application, application date: 2022 / 8 / 26) are incorporated herein by reference in their entirety.

[0072] Preparation of mirabegron

[0073]

[0074] (1) Under the protection of inert gas (e.g., nitrogen), 100 g (about 0.34 mol) of compound 5, 62 g (about 0.39 mol) of 2-aminothiazole-4-acetic acid, 35 g of concentrated hydrochloric acid (mass fraction 36 wt% to 38 wt%, containing about 0.35 mol of HCl), 75.3 g (about 0.39 mol) of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC), and 1314 g of purified water were added to a three-necked flask, stirred evenly, and reacted at 20-30°C for 1-3 h. After TLC or HPLC showed that the reaction was complete, a reaction solution was obtained;

[0075] (2) Sodium hydroxide (32.8 g) and purified water (1512 g) were added to the reaction solution, stirred for 1 h, filtered, and slurried twice with purified water (about 3 kg of purified water each time), and then filtered to obtain wet product B (identified as mirabegron β-form by X-ray powder diffraction (XRD) analysis);

[0076] (3) The wet product B obtained above (containing approximately 150 g of water) was added to a mixed solvent of isopropyl acetate (2248.5 g) and purified water (75 g), and the mixture was heated to 68-78°C while stirring. After complete dissolution, the mixture was cooled to 15-25°C (cooling rate of 5°C / 10 min), stirred for 40 min, and filtered to obtain wet product A (identified as mirabegron α crystal form by X-ray powder diffraction (XRD) analysis);

[0077] (4) The wet product A obtained above (about 290 g) was added to 422 g of ethanol, heated to 50-60°C, stirred to dissolve, and filtered. 108 g of ethanol and 840 g of purified water were added to the filtrate, heated to 65-75°C, and then slowly cooled to 5-10°C (cooling rate of 5°C / 10 min). The mixture was stirred at this temperature for 1 h, filtered, and dried to obtain an off-white mirabegron raw material (identified as mirabegron α crystal form) with an HPLC purity of ≥99.8%.

[0078] Example 3

[0079] Under nitrogen protection, 16.5 kg (1 equivalent) of compound 5, 9.37 kg (1.05 equivalents) of 2-aminothiazole-4-acetic acid, 5.78 kg of concentrated hydrochloric acid (1.05 equivalents of HCl), 12.5 kg of 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDC; 1.15 equivalents), and 217 kg of purified water were added to a glass-lined reaction tank, stirred evenly, and reacted at 25° C. for 3 h. 5.41 kg of sodium hydroxide and 250 kg of purified water were added, stirred for 1 h, centrifuged, slurried with purified water 1 to 2 times, and centrifuged again to obtain wet product B (mirabegron β crystal form);

[0080] The obtained wet product B was added to a mixed solvent of isopropyl acetate and purified water (crystallization solvent), heated to 72°C while stirring, and after complete dissolution, cooled to 20°C (cooling rate of 5°C / 10min), stirred for 1 hour, centrifuged, and dried to obtain the mirabegron α crystal form; the mirabegron α crystal form can then be optionally recrystallized using ethanol / water.

[0081] Example 4

[0082] The mirabegron raw material obtained above was tested using high performance liquid chromatography (HPLC) under the chromatographic conditions shown in Table 2, as follows:

[0083] Table 2. Chromatographic conditions of high performance liquid chromatography (HPLC)

[0084]

[0085]

[0086] Test solution: Weigh approximately 25 mg of the test sample (mirabegron API to be tested) accurately into a 25 mL volumetric flask. Dissolve in 6 mL of methanol, then dilute to the mark with purified water and shake well. Prepare two aliquots in the same manner.

[0087] The above-mentioned HPLC conditions were used for sample injection detection (in compliance with the provisions and requirements for methodological validation of the 2020 edition of the Chinese Pharmacopoeia), and the peak area normalization method was used for calculation (or, using the impurity compound P06 obtained in Example 1 as a reference substance, calculated by the internal standard method or the external standard method): the HPLC purity of the mirabegron raw material (retention time was 29.737 min) was 99.42%, and the content of the impurity compound P06 (retention time was 34.077 min) was 0.12% (detection limit was 0.01%, and the quantification limit was 0.04%). Figure 3 As shown; it complies with the provisions and requirements of the ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use) guidelines that the amount of known impurities allowed in active pharmaceutical ingredients should not exceed 0.15%.

[0088] Of course, the present invention may have many other embodiments. Without violating the spirit and essence of the present invention, those skilled in the art may make various corresponding changes and / or deformations based on the present invention. These corresponding changes and / or deformations should all fall within the scope of protection of the claims attached to the present invention.

Claims

1. A method for preparing a mirabegron disubstituted compound, characterized in that: The following steps are involved: In the presence of a dehydrating agent and a catalyst, mirabegron and 2-aminothiazole-4-acetic acid undergo a condensation reaction in a nitrogen-containing solvent to generate a mirabegron disubstituted compound; wherein the dehydrating agent comprises 1-hydroxybenzotriazole and / or N,N-dicyclohexylcarbodiimide.

2. The preparation method according to claim 1, characterized in that The catalyst is an organic amine catalyst; and / or the nitrogen-containing solvent is a nitrogen-containing solvent containing an amide structure; Preferably, the catalyst is triethylamine; and / or the nitrogen-containing solvent is N,N-dimethylformamide or N,N-dimethylacetamide.

3. The preparation method according to claim 1 or 2, characterized in that The molar ratio of mirabegron to 2-aminothiazole-4-acetic acid is 1:1 to 1.5; and / or the amount of catalyst used per mole of mirabegron is 1 mol to 1.5 mol; and / or the amount of nitrogen-containing solvent used per gram of mirabegron is 5 ml to 50 ml; Preferably, the molar ratio of mirabegron to 2-aminothiazole-4-acetic acid is 1:1.05-1.15; and / or the amount of catalyst used per mole of mirabegron is 1.15 mol-1.25 mol; and / or the amount of nitrogen-containing solvent used per gram of mirabegron is 10 ml-15 ml.

4. The preparation method according to claim 1 or 2, characterized in that The dehydrating agent comprises 1-hydroxybenzotriazole and N,N-dicyclohexylcarbodiimide; Preferably, the amount of 1-hydroxybenzotriazole used per mole of mirabegron is 1 mol to 1.5 mol; and / or the amount of N,N-dicyclohexylcarbodiimide used per mole of mirabegron is 1 mol to 1.5 mol; and / or the molar ratio of 1-hydroxybenzotriazole to N,N-dicyclohexylcarbodiimide is 1:1.01 to 1.1; More preferably, the amount of 1-hydroxybenzotriazole per mole of mirabegron is 1.05 mol to 1.15 mol; and / or the amount of N,N-dicyclohexylcarbodiimide per mole of mirabegron is 1.05 mol to 1.15 mol; and / or the molar ratio of 1-hydroxybenzotriazole to N,N-dicyclohexylcarbodiimide is 1:1.01 to 1.

05.

5. The preparation method according to claim 1 or 2, characterized in that The reaction temperature of the condensation reaction is 5°C to 50°C; and / or the reaction time of the condensation reaction is 2 hours to 12 hours; Preferably, the reaction temperature of the condensation reaction is 10° C. to 35° C.; and / or the reaction time of the condensation reaction is 3 hours to 5 hours.

6. The preparation method according to claim 1 or 2, characterized in that The preparation method further includes a post-processing step: after the condensation reaction is completed, water is added to obtain a reaction solution, a solid is precipitated, and the solvent is removed, and then a purification step is optionally included to obtain a mirabegron disubstituted compound; Preferably, the amount of water used per gram of mirabegron is 8 ml to 12 ml; and / or, the solvent in the purification step comprises an alcohol solvent and an ether solvent; wherein the alcohol solvent is methanol and / or ethanol, and the ether solvent is methyl tert-butyl ether; More preferably, the amount of alcohol solvent used per gram of mirabegron is 1.5 ml to 5 ml; and / or the amount of ether solvent used per gram of mirabegron is 8 ml to 12 ml; and / or the volume ratio of the alcohol solvent to the ether solvent is 1:2 to 10 or 1:5; Further preferably, the purification step is: after removing the solvent, adding an alcohol solvent and heating to 60°C±5°C, then adding an ether solvent, cooling to room temperature, precipitating a solid, filtering, and drying.

7. A mirabegron disubstituted compound product, characterized in that: The HPLC purity of the mirabegron disubstituted compound is ≥99.0% or ≥99.5%. Preferably, the mirabegron disubstituted compound is prepared by the preparation method according to any one of claims 1 to 6.

8. A high performance liquid chromatography method for detecting mirabegron disubstituted compounds in a test sample, characterized in that: The mirabegron disubstituted compound according to claim 7 is used as a reference substance for detection, and the test substance is the mirabegron raw material or preparation; Preferably, the chromatographic conditions of the high performance liquid chromatography detection method include: Chromatographic column: C18 column or its equivalent; Mobile phase A: 0.01 mol / L potassium dihydrogen phosphate aqueous solution containing 0.01 mol / L sodium octane sulfonate; Mobile phase B: acetonitrile; Perform gradient elution according to the following program: Detection wavelength: 180~280nm; More preferably, The chromatographic column is a Kromasil 100-5-C18 chromatographic column; And / or, the specifications of the chromatographic column are: 4.6 mm × 250 mm, 5 μm; and / or, the mobile phase A is adjusted to a pH value of 2.50±0.05 with phosphoric acid; And / or, the detection wavelength is 250 nm.

9. The high performance liquid chromatography detection method according to claim 8, characterized in that Column temperature: 15°C to 45°C; preferably, the column temperature is 30°C; and / or, injection volume: 0.5 μl to 25 μl; preferably, the injection volume is 10 μl; And / or, mobile phase flow rate: 0.1 ml / min to 2 ml / min; preferably, the mobile phase flow rate is 1.0 ml / min to 1.5 ml / min.

10. The high performance liquid chromatography detection method according to claim 8, characterized in that: The high performance liquid chromatography detection method is a qualitative detection or a quantitative detection; preferably, the high performance liquid chromatography detection method performs quantitative detection according to the internal standard method or the external standard method.

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