Preparation method of mirabegron and intermediate thereof

Abstract

The invention provides a preparation method of a mirabegron intermediate, which is characterized in that the preparation method comprises the following steps: carrying out condensation reaction on a compound as shown in a formula III and a compound as shown in a formula V in an organic solvent to obtain the mirabegron intermediate VI: # imgabs0 #. D-mandelic acid is ingeniously converted into an acetonylidene analogue through reagents such as 2, 2-dimethoxypropane (DMP) and the like; according to the preparation method, carboxyl on D-mandelic acid is activated and then directly reacts with amino in a compound shown in a formula V, expensive condensing agents such as EDCI and HOBT are not used, toxic reagents such as triphosgene are not needed, materials are economical, easy to obtain and environmentally friendly, the obtained product is high in yield and purity, and the content of isomers can be effectively controlled.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, in particular to a method for preparing a mirabegron intermediate. Background Art

[0002] Overactive bladder (OAB) is one of the common clinical manifestations of urinary dysfunction, characterized by urinary urgency with or without urge incontinence, often accompanied by frequent urination and nocturia. Currently, the incidence of OAB is high. According to statistics, about 1 / 6 of the European population over 40 years old suffers from OAB, and the incidence of OAB in the United States has reached 17%. Epidemiological surveys conducted in some parts of my country show that the incidence of urinary incontinence ranges from 18% to 53%, and the incidence in elderly women is as high as 70%. Many OAB patients feel shy and embarrassed because of repeated frequent urination, urgency and incontinence, which seriously affects the patients' normal daily life and social activities. Therefore, the current research on the treatment of OAB has become one of the hot topics at home and abroad.

[0003] Mirabegron is a novel selective β3 adrenergic receptor agonist developed by Astellas Pharmaceuticals Co., Ltd. of Japan. It was first launched in Japan in 2011 and was approved by the U.S. Food and Drug Administration (FDA) the following year for the treatment of overactive bladder in adults. The structural formula of Mirabegron is shown below:

[0004]

[0005] Compound patent CN1136193C discloses a method for synthesizing a mirabegron intermediate. The route mainly uses 4-nitrophenylethylamine hydrochloride as a raw material, reacts with (R)-styrene oxide to obtain R)-[[[2-(4-nitrophenyl)ethyl]amino]methyl]benzyl alcohol. The synthetic route is shown in the following formula:

[0006]

[0007] Chinese patent CN1243740 discloses a method for synthesizing a mirabegron intermediate, which comprises adding HOBT and EDC to a mixture of D-mandelic acid and 4-nitrophenylethylamine hydrochloride in N,N-dimethylformamide to react to obtain (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide. The synthesis route is shown in the following formula:

[0008]

[0009] Chinese patent CN108727212B discloses a method for synthesizing a mirabegron intermediate, which comprises subjecting R-mandelic acid and triphosgene to an esterification reaction in the presence of a base to generate an intralactide intermediate I; then, the intermediate I is subjected to an acylation reaction with 4-nitrophenylethylamine in a solvent to obtain (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide. The synthesis route is shown in the following formula:

[0010]

[0011] PCT patent WO2016024284 discloses a method for synthesizing a mirabegron intermediate, which comprises first treating R-mandelic acid with p-toluenesulfonyl chloride, and then reacting with 4-nitrophenylethylamine to obtain (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide. The synthesis route is shown in the following formula:

[0012]

[0013] Chinese patent CN104016943 discloses a method for synthesizing a mirabegron intermediate, which comprises subjecting R-mandelic acid ester to an amine transesterification reaction with 4-nitrophenylethylamine salt to obtain (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide, wherein the R-mandelic acid ester comprises methyl ester, ethyl ester, isopropyl ester, tert-butyl ester and benzyl ester, and the synthesis route is shown in the following formula:

[0014]

[0015] Chinese patent CN105801438 discloses a method for synthesizing a mirabegron intermediate, which comprises firstly reacting R-mandelic acid with pivaloyl chloride in a solvent to generate a mixed anhydride intermediate I, then subjecting the mixed anhydride intermediate I to an acylation reaction with 4-nitrophenylethylamine to obtain an intermediate II, and then subjecting the intermediate II to a hydrolysis reaction to obtain (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide. The synthesis route is shown in the following formula:

[0016]

[0017] Chinese patent CN104744292A discloses a method for synthesizing a mirabegron intermediate. The method uses D-mandelic acid as a starting material, reacts with an acylating agent to form an ester, and then reacts the ester with p-nitrophenylethylamine or its hydrochloride through a condensing agent to obtain (R)-2-((4-nitrophenylethyl)amino)-2-oxo-1-phenylethyl acetate or a derivative thereof. The ester can also be dissolved in a solvent and added with thionyl chloride for reaction, and then reacted with p-nitrophenylethylamine or its hydrochloride to obtain (R)-2-((4-nitrophenylethyl)amino)-2-oxo-1-phenylethyl acetate or a derivative thereof, and then (R)-2-((4-nitrophenylethyl)amino)-2-oxo-1-phenylethyl acetate or a derivative thereof is hydrolyzed to form (R)-2-hydroxy-N-[2-(4-nitrophenyl)ethyl]-2-phenylacetamide. The synthesis route is shown in the following formula:

[0018]

[0019] In view of the fact that the reagents used in the prior art methods for preparing mirabegron intermediates are expensive, resulting in high costs, complicated post-processing steps and high reagent toxicity, it is very necessary to develop a method for preparing mirabegron intermediates that is simple to operate, economical and environmentally friendly for industrial large-scale production. Summary of the invention

[0020] In view of the shortcomings and deficiencies in the prior art, the present invention provides a synthesis of a mirabegron intermediate. The method has readily available raw materials, is economical and environmentally friendly, has a high reaction efficiency, can effectively control the isomer and impurity content, and has convenient and easy post-treatment, and is suitable for large-scale industrial production.

[0021] In one aspect, the present invention provides a method for preparing a mirabegron intermediate, which comprises condensing a compound of formula III with a compound of formula V in an organic solvent to obtain a mirabegron intermediate VI:

[0022]

[0023] Where R 1 and R 2 are independently H, C1-C12 straight or branched alkyl, substituted or unsubstituted aryl; R 1 and R 2 It can also be a five-membered ring or a six-membered ring containing C1-C12 connected by a ring; R 5 is nitro or amino;

[0024] In some embodiments, R 1 and R 2 are independently H, methyl, ethyl, phenyl, or R 1 and R 2C1-C6 five-membered ring or six-membered ring linked by a ring; R 5 is nitro or amino;

[0025] In some embodiments, R 1 is methyl, R 2 is methyl; R 5 is nitro or amino;

[0026] In some embodiments, the organic solvent is one or more of an alcohol solvent, an aromatic hydrocarbon solvent, an alkane solvent, a halogenated hydrocarbon solvent, an ether solvent, a nitrile solvent, a ketone solvent, an ester solvent, an amide solvent, and a sulfoxide solvent;

[0027] In some embodiments, the alcohol solvent is methanol or ethanol; the aromatic hydrocarbon solvent is toluene, xylene, dichlorotoluene, or chlorobenzene; the alkane solvent is cyclohexane, n-hexane, or n-heptane; the halogenated hydrocarbon solvent is dichloromethane, dichloroethane, or chloroform; the ether solvent is methyl tert-butyl ether, tetrahydrofuran, or methyltetrahydrofuran; the nitrile solvent is acetonitrile; the ketone solvent is acetone; the ester solvent is ethyl acetate or isopropyl acetate; the amide solvent is N,N-dimethylformamide or N,N-dimethylacetamide; the sulfoxide solvent is dimethyl sulfoxide;

[0028] In some embodiments, the organic solvent is toluene, xylene, or chlorobenzene;

[0029] In some embodiments, the condensation reaction temperature is 20°C to 150°C, and the condensation reaction time is 1-48 hours;

[0030] In some embodiments, the condensation reaction temperature is 80° C. to 120° C., and the condensation reaction time is 2-8 hours.

[0031] In some embodiments, the molar ratio of the compound of formula V to the compound of formula III is 1:0.9-2.0, and the molar ratio of the compound of formula V to the organic solvent is 0.05-10 g / ml;

[0032] In some embodiments, the ratio of the compound of formula V to the organic solvent is 0.1 to 5 g / ml;

[0033] In some embodiments, the condensation reaction is carried out with or without the addition of water;

[0034] In some embodiments, when the condensation reaction is carried out with the addition of water, the amount of water added is 0 to 100% by mass of the compound of formula V;

[0035] In some embodiments, when the condensation reaction is carried out with the addition of water, the amount of water added is 1-10% of the amount of the compound of formula V used.

[0036] In some embodiments, the compound of formula III is obtained by reacting D-mandelic acid with a compound of formula II or a compound of formula IV in the presence or absence of a reaction solvent:

[0037]

[0038] Where R 1 and R 2 are independently H, C1-C12 straight or branched alkyl, substituted or unsubstituted aryl; R 1 and R 2 It can also be a five-membered ring or a six-membered ring containing C1-C12 connected by a ring; R 3 and R 4 Each independently represents H, a C1-C6 straight or branched alkyl group;

[0039] In some embodiments, R 1 and R 2 are independently H, methyl, ethyl, phenyl, or R 1 and R 2 A C1-C6 five-membered ring or six-membered ring linked by a ring;

[0040] In some embodiments, R 1 is methyl, R 2 is methyl, R 3 is methyl, R 4 is methyl;

[0041] In some embodiments, the reaction solvent is one or more of an alcohol solvent, an aromatic hydrocarbon solvent, an alkane solvent, a halogenated hydrocarbon solvent, an ether solvent, a nitrile solvent, a ketone solvent, an ester solvent, an amide solvent, and a sulfoxide solvent;

[0042] In some embodiments, the alcohol solvent is selected from methanol and ethanol; the aromatic hydrocarbon solvent is selected from toluene, xylene, dichlorotoluene, and chlorobenzene; the alkane solvent is selected from cyclohexane, n-hexane, and n-heptane; the halogenated hydrocarbon solvent is selected from dichloromethane, dichloroethane, and chloroform; the ether solvent is selected from methyl tert-butyl ether, tetrahydrofuran, and methyltetrahydrofuran; the nitrile solvent is selected from acetonitrile; the ketone solvent is selected from acetone; the ester solvent is selected from ethyl acetate and isopropyl acetate; the amide solvent is selected from N,N-dimethylformamide and N,N-dimethylacetamide; the sulfoxide solvent is selected from dimethyl sulfoxide;

[0043] In some embodiments, the reaction solvent is toluene, xylene, or chlorobenzene;

[0044] In some embodiments, the reaction temperature for preparing the compound of formula III is 50°C to 150°C, and the reaction time is 1-10 hours;

[0045] In some embodiments, the reaction temperature for preparing the compound of formula III is 80°C to 120°C, and the reaction time is 3-7 hours;

[0046] In some embodiments, the molar ratio of D-mandelic acid to the compound of formula II or formula IV is 1:0.9-2.0, and the molar ratio of D-mandelic acid to the reaction solvent is 0.1-5 g / ml;

[0047] Another aspect of the present invention provides a method for preparing mirabegron, wherein the mirabegron intermediate prepared by the above steps is further converted into mirabegron.

[0048] In some embodiments, the mirabegron intermediate 6 is obtained by reacting the compound of formula 3 with 4-nitrophenylethylamine.

[0049] In some embodiments, the compound of Formula 3 is obtained by reacting D-mandelic acid with 2,2-dimethoxypropane.

[0050]

[0051] In some embodiments, a mixed solvent and D-mandelic acid are heated, 2,2-dimethoxypropane is added, and the mixture is kept warm for reaction to obtain a D-mandelic acid acetone formate solution; water is optionally added, and then 4-nitrophenylethylamine is added, and after the addition is completed, the mixture is kept warm for reaction; after the reaction is completed, the mixture is cooled and crystallized to obtain compound 6.

[0052] In some embodiments, compound 6 is further converted to mirabegron.

[0053] Compared with the prior art, the present invention has the following positive technical effects:

[0054] 1. The present invention ingeniously converts D-mandelic acid into an acetone foride analogue by using reagents such as 2,2-dimethoxypropane (DMP), activates the carboxyl group on the D-mandelic acid, and then directly reacts with the amino group in the compound of formula V, thereby avoiding the use of expensive condensation agents such as EDCI and HOBT, and does not need to use toxic reagents such as triphosgene. The materials are economical, easy to obtain, green and environmentally friendly, and the obtained product has high yield and high purity, and can effectively control the isomer content.

[0055] 2. The present invention can effectively control the isomer content by adding a small amount of water into the reaction solution.

[0056] 3. The preparation method provided by the present invention has simple steps, no complicated protection-deprotection steps are required, the post-treatment is simple, the impurities are few, the conversion rate is high, the product purity is high, and it is suitable for large-scale industrial production. DETAILED DESCRIPTION

[0057] 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.

[0058] 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.

[0059] In the present invention, unless otherwise specified, % is a percentage of weight / weight (w / w).

[0060] The HPLC analysis method used for determining isomers of the present invention is:

[0061] Chromatographic column: CHIRALPAK AD-H 250×4.6mm, 5μm

[0062] Mobile phase: n-hexane: isopropanol = 75:25 (V / V)

[0063] Detection wavelength: 270nm

[0064] Flow rate: 0.7mL / min

[0065] Column temperature: 30°C

[0066] Running time: 30 minutes

[0067] The HPLC analytical method used for measuring purity of the present invention is:

[0068] Column: Waters XTerra phenyl, 250×4.6 mm, 5 μm

[0069] Mobile phase A: 1 mL phosphoric acid to 1000 mL water

[0070] Mobile phase B: acetonitrile

[0071] Detection wavelength: 218nm

[0072] Flow rate: 1.0mL / min

[0073] Column temperature: 40°C

[0074] Run time: 35 minutes

[0075] The nuclear magnetic analysis method used in the present invention to determine the structure of a substance:

[0076] Agilent 400MHz

[0077] The sources of D-mandelic acid and 2,2-dimethoxypropane (DMP) used in the present invention are:

[0078] The supplier of D-mandelic acid is Jiangxi Keyuan Biopharmaceutical Co., Ltd.

[0079] The supplier of 2,2-dimethoxypropane (DMP) is Zhejiang Hu Tu Silicon Co., Ltd.

[0080] Embodiment 1:

[0081]

[0082] Preparation of acetone fork:

[0083] Add 80.0 mL of toluene and 11.9 g of D-mandelic acid to a stirred glass flask, raise the internal temperature to 105°C, quickly add 11.5 mL of 2,2-dimethoxypropane (DMP) dropwise, and reflux for 5 hours to obtain an acetone-containing toluene solution.

[0084] White solid, 1 H NMR (400MHz, DMSO-d6) δ7.46-7.43(m,2H),7.46-7.42(m,2H),7.42-7.38(m,1H),5.75-5.72(s,1H),1.71-1.69(s,3H),1.67-1.64(s,3H). 13 C NMR (400MHz, DMSO-d6) δ171.52,134.87,128.85,128.62,126.99,110.54,75.35,26.63,25.43.

[0085] Preparation of the target product: At 105°C, add 0.4 mL of water to the above acetone-toluene solution, and then drop 10.0 g of 4-nitrophenylethylamine. After the dropwise addition, continue to heat and reflux for 6 hours. After the reaction is completed, slowly cool to 20°C, keep warm and stir for crystallization for 2 hours, filter, purify, and dry to obtain 13.56 g of brown-yellow solid, with a yield of 75%, an ee value of 99.85%, and a purity of 99.62%.

[0086] Brown yellow solid, 1H NMR(400MHz, DMSO-d6)δ8.08-8.05(d,J=9.00Hz,2H),7.42-7.37(d,J=9.00Hz,2H),7.34-7.30(m,2H),7.30-7 .27(m,1H),7.28-7.24(m,2H),4.87-4.84(s,1H),3.46-3.40,3.39-3.32(m,2H),2.90-2.85(t,J=7.04Hz,2H). 13 C NMR (400MHz, DMSO-d6) δ172.09,147.85,145.95,141.26,130.02,127.79,127.28,126.51,123.21,73.49,38.94,34.71.

[0087] Example 2

[0088] Preparation of acetone fork:

[0089] Under nitrogen protection, add 80.0 mL of toluene and 11.9 g of D-mandelic acid into a stirred glass flask. After the internal temperature is raised to 105°C, 11.5 mL of 2,2-dimethoxypropane (DMP) is quickly added dropwise. After the reaction is refluxed for 5 hours, an acetone-containing toluene solution is obtained.

[0090] Preparation of target product:

[0091] Under nitrogen protection, 0.7 mL of water was added dropwise to the above acetone-toluene solution at 105°C, and then 10.0 g of 4-nitrophenylethylamine was added dropwise. After the addition, the mixture was kept warm and refluxed for 4 h. After the reaction, the temperature was slowly lowered to 20°C, and the mixture was kept warm and stirred for crystallization for 2 h. The mixture was filtered, purified, and dried to obtain 13.92 g of a brown-yellow solid with a yield of 77%, an ee value of 99.99%, and a purity of 99.75%.

[0092] Example 3

[0093] Preparation of acetone fork:

[0094] Under nitrogen protection, add 79.1mL toluene, 10.7mL 2,2-dimethoxypropane (DMP) and 11.9g D-mandelic acid to a stirred glass flask, stir evenly, slowly raise the internal temperature to 80℃, and add a water separator to separate the liquid. After 3h of heat preservation reaction, add 0.9mL 2,2-dimethoxypropane (DMP) and continue to heat preservation reaction for 2h. After the heat preservation reaction is completed, spin dry the reaction system to obtain crude acetone fork.

[0095] Preparation of target product:

[0096] Under nitrogen protection, 79.1 mL of dichloromethane was added to the obtained crude acetone fork, and after the internal temperature was raised to 35°C, 0.33 mL of water was added dropwise, and then 10.0 g of 4-nitrophenylethylamine was added dropwise. After the addition, the reaction was continued for 48 hours. After the reaction was completed, the reaction system was directly spin-dried, and 9.27 g of brown-yellow solid was obtained after purification and drying, with a yield of 51%, an ee value of 99.62%, and a purity of 99.54%.

[0097] Example 4

[0098] Preparation of acetone fork:

[0099] Under nitrogen protection, add 11.0g D-mandelic acid and 16.5mL 2,2-dimethoxypropane (DMP) to a stirred glass flask, stir evenly, slowly raise the internal temperature to 80°C, and keep reflux for 5h. After the insulation reaction is completed, spin dry the reaction system to obtain crude acetone fork. Preparation of target product:

[0100] Under nitrogen protection, add 79.1 mL of toluene to the obtained crude acetone fork, raise the internal temperature to 95°C, drop 0.33 mL of water, and then drop 10.0 g of 4-nitrophenylethylamine. After the dropwise addition, continue to keep warm for 2 hours. After the reaction is completed, slowly cool to 20°C, keep warm and stir for crystallization for 2 hours, filter, purify, and dry to obtain 14.49 g of brown-yellow solid, with a yield of 80%, an ee value of 99.86%, and a purity of 99.87%.

[0101] Example 5

[0102] Preparation of acetone fork:

[0103] Add 80.0 mL of toluene and 11.9 g of D-mandelic acid to a stirred glass flask, raise the internal temperature to 105°C, quickly add 11.5 mL of 2,2-dimethoxypropane (DMP) dropwise, and reflux for 5 hours to obtain an acetone-containing toluene solution.

[0104] Preparation of the target product: 10.0 g of 4-nitrophenylethylamine was added dropwise to the above acetone-toluene solution at 105°C. After the addition, the mixture was kept warm and refluxed for 6 h. After the reaction, the mixture was slowly cooled to 20°C, stirred and crystallized for 2 h, filtered, purified, and dried to obtain 13.38 g of a brown-yellow solid with a yield of 74%, an ee value of 92.34%, and a purity of 99.65%.

[0105] Embodiment 6:

[0106] Preparation of acetone fork:

[0107] Under nitrogen protection, add 23.8g D-mandelic acid and 35.7mL 2,2-dimethoxypropane (DMP) to a stirred glass flask, stir evenly, slowly raise the internal temperature to 80°C, and keep reflux for 5h. After the insulation reaction is completed, spin dry the reaction system to obtain crude acetone fork. Preparation of target product:

[0108] Under nitrogen protection, add 158.0 mL of chlorobenzene to the obtained crude acetone fork, raise the internal temperature to 95°C, and then drop 20.0 g of 4-nitrophenylethylamine. After the dropwise addition, continue to keep warm for 4 hours. After the reaction is completed, slowly cool to 15°C, keep warm and stir for crystallization for 2 hours, filter, purify, and dry to obtain 29.3 g of brown-yellow solid, with a yield of 81%, an ee value of 99.88%, and a purity of 99.89%.

[0109] Embodiment 7:

[0110]

[0111] Preparation of acetone fork:

[0112] Add 4.7 g of D-mandelic acid and 15.0 mL of toluene to a stirred glass flask, raise the internal temperature to 85°C, add 4.6 mL of 2,2-dimethoxypropane (DMP), and react for 5 hours to obtain an acetone-containing toluene solution.

[0113] Preparation of target product:

[0114] At 85°C, add 0.2 mL of water to the above acetone-toluene solution, and then add a toluene solution containing 3.2 g of 4-aminophenylethylamine, and continue to add for 16 hours. After the addition, continue to keep warm for 6 hours. After the reaction is completed, slowly cool to 20°C, keep warm and stir for 2 hours to crystallize, filter, purify, and dry to obtain 4.35 g of light yellow solid, with a yield of 68%:

[0115] Comparative Example: Compound 10 (i.e., the target product, mirabegron intermediate) was prepared by repeating the method of Org.Process Res.Dev.2016, 20, 1993-1996

[0116] At 0-5°C, pivaloyl chloride (7.9 g) was slowly added dropwise to a dichloromethane solution (400 ml) of D-mandelic acid (5 g) and triethylamine (6.8 g). The reaction mixture was stirred for 0.5 h, heated to 20-30°C, and H2O (4 ml) was added. After that, the reaction mixture was heated to reflux for 1.5-2.0 h, and then the resulting reaction mixture was cooled to room temperature, dichloromethane was separated from the aqueous phase, 4-nitrophenylethylamine (5.18) was added dropwise to the dichloromethane layer solution at room temperature, stirred for 2-3 h, washed with hydrochloric acid (1M, 8 mL), the dichloromethane layer was concentrated in vacuo, and ethanol (400 mL) was added. NaOH solution (1.44 g) was added to the mixture, and stirred at 5°C for 2 h until the intermediate product was completely consumed, and the solvent was concentrated to saturation in vacuo. Then 800 ml of water was added dropwise, stirred for 1 hour, filtered, washed with water, and dried to obtain the target product, mirabegron intermediate, with an ee value of 74.89% and a purity of 90.18%.

[0117] 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 preparing a mirabegron intermediate, characterized in that: The preparation method comprises condensing a compound of formula III with a compound of formula V in an organic solvent to obtain a mirabegron intermediate VI: Where R 1 and R 2 are independently H, C1-C12 straight or branched alkyl, substituted or unsubstituted aryl; R 1 and R 2 It can also be a five-membered ring or a six-membered ring containing C1-C12 connected by a ring; Preferred R 1 and R 2 are independently H, methyl, ethyl, phenyl, or R 1 and R 2 A C1-C6 five-membered ring or six-membered ring linked by a ring; More preferably R 1 is methyl, R 2 is methyl; R 3 It is nitro or amino.

2. The preparation method according to claim 1, characterized in that: The organic solvent is selected from one or more of alcohol solvents, aromatic hydrocarbon solvents, alkane solvents, halogenated hydrocarbon solvents, ether solvents, nitrile solvents, ketone solvents, ester solvents, amide solvents, and sulfoxide solvents; preferably, the alcohol solvent is selected from methanol and ethanol, the aromatic hydrocarbon solvent is selected from toluene, xylene, dichlorotoluene, and chlorobenzene; the alkane solvent is selected from cyclohexane, n-hexane, and n-heptane, the halogenated hydrocarbon solvent is selected from dichloromethane, dichloroethane, and chloroform, the ether solvent is selected from methyl tert-butyl ether, tetrahydrofuran, and methyltetrahydrofuran, the nitrile solvent is selected from acetonitrile, the ketone solvent is selected from acetone, the ester solvent is selected from ethyl acetate and isopropyl acetate, the amide solvent is selected from N,N-dimethylformamide and N,N-dimethylacetamide, and the sulfoxide solvent is selected from dimethyl sulfoxide; more preferably, toluene, xylene, and chlorobenzene.

3. The preparation method according to claim 1, characterized in that: The condensation reaction temperature is 20°C to 150°C, preferably 80°C to 120°C; the condensation reaction time is 1-48 hours, preferably 2-8 hours.

4. The preparation method according to claim 1, characterized in that: The molar ratio of the compound of formula V to the compound of formula III is 1:0.9-2.0, and the ratio of the compound of formula V to the organic solvent is 0.05-10 g / ml; preferably, the ratio of the compound of formula V to the organic solvent is 0.1-5 g / ml.

5. The preparation method according to claim 1, characterized in that: The preparation method is carried out with or without adding water.

6. The preparation method according to claim 5, characterized in that: When water is added in the preparation method, the amount of water added is 0 to 100% by mass of the compound of formula V, preferably 1 to 10%.

7. The preparation method according to claim 1, characterized in that: The preparation method of the compound of formula III comprises reacting D-mandelic acid with a compound of formula II or a compound of formula IV in the presence or absence of a reaction solvent to obtain a compound of formula III Where R 1 and R 2 As claimed in claim 1, R 3 and R 4 are independently H, C1-C6 straight or branched alkyl; preferably R 1 is methyl, R 2 is methyl, R 3 is methyl, R 4 It is methyl.

8. The preparation method according to claim 7, characterized in that: The reaction solvent is selected from one or more of alcohol solvents, aromatic hydrocarbon solvents, alkane solvents, halogenated hydrocarbon solvents, ether solvents, nitrile solvents, ketone solvents, ester solvents, amide solvents, and sulfoxide solvents; preferably, the alcohol solvent is selected from methanol and ethanol, the aromatic hydrocarbon solvent is selected from toluene, xylene, dichlorotoluene, and chlorobenzene, the alkane solvent is selected from cyclohexane, n-hexane, and n-heptane, the halogenated hydrocarbon solvent is selected from dichloromethane, dichloroethane, and chloroform, the ether solvent is selected from methyl tert-butyl ether, tetrahydrofuran, and methyltetrahydrofuran, the nitrile solvent is selected from acetonitrile, the ketone solvent is selected from acetone, the ester solvent is selected from ethyl acetate and isopropyl acetate, the amide solvent is selected from N,N-dimethylformamide and N,N-dimethylacetamide, and the sulfoxide solvent is selected from dimethyl sulfoxide; the reaction solvent is preferably toluene, xylene, and chlorobenzene.

9. The preparation method according to claim 7, characterized in that: The reaction temperature is 50°C to 150°C, preferably 80°C to 120°C, and the reaction time is 1-10 hours, preferably 3-7 hours.

10. The preparation method according to claim 7, characterized in that: The molar ratio of the D-mandelic acid to the compound of formula II or the compound of formula IV is 1:0.9-2.0, and the molar ratio of the D-mandelic acid to the reaction solvent is 0.5-5 g / ml.

11. A method for preparing mirabegron, wherein the method comprises the steps according to any one of claims 1 to 12, and further comprises converting the mirabegron intermediate into mirabegron.

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