Industrial preparation method of benzbromarone

Abstract

The invention relates to the field of organic synthesis, in particular to an industrial preparation method of benzbromarone. According to the method, 2-ethylbenzofuran and 4-methoxybenzoyl chloride are used as starting raw materials, an activated carbon immobilized catalyst is adopted to integrate three-step reactions of acylation, demethylation and phenate formation into a one-pot method to prepare a benzarone alkali metal salt aqueous solution, and then a high-efficiency green catalytic oxidation bromination process is performed to prepare a benzbromarone refined product. The method disclosed by the invention is simple in process, low in cost, easy to operate and easy to realize industrial production, the use of corrosive materials can be reduced, the reaction temperature can be reduced, and high-purity and high-yield benzbromarone can be obtained.

Description

Technical Field

[0001] The invention relates to the field of organic synthesis, and in particular to an industrial preparation method of benzbromarone. Background Art

[0002] Benzbromarone, also known as Tongfenglixian, is a representative derivative of benzofuran. It was originally developed by the French company Labaz and was launched in China in 2000. Its structural formula is as follows:

[0003]

[0004] Benzbromarone, as a URAT1 inhibitor, has a strong deuricating effect and can also effectively inhibit the production of uric acid, playing a dual role in reducing the concentration of uric acid in the blood. After taking benzbromarone, gout patients can effectively block the reabsorption of uric acid by the renal tubules to enhance the excretion of uric acid in the intestine. It is mainly excreted from the body through urine and feces in the form of the original drug. It has a fast onset of action and few adverse reactions. It usually has no effect on liver and kidney function. It is suitable for the treatment of stable gout and has been widely used in China.

[0005] The industrial synthesis methods of benzbromarone reported in the literature all use 2-ethylbenzofuran as the starting material, and are divided into two methods according to the difference of the other reactant. Method one is to react 4-methoxybenzoyl chloride with 2-ethylbenzofuran as the reactant, and method two is to react 3,5-dibromo-4-hydroxybenzoyl chloride with or without a protecting group with 2-ethylbenzofuran.

[0006] In method one, as reported in patent CN102659727B, 2-ethylbenzofuran and 4-methoxybenzoyl chloride are subjected to Friedel-Crafts acylation under catalysis to obtain 2-ethyl-3-p-methoxybenzoyl-benzofuran, and then pyridine hydrochloride is used for high temperature demethylation to obtain 2-ethyl-3-p-hydroxybenzoyl-benzofuran, and then bromination reaction is performed to obtain benzbromarone. The above process synthesis route is relatively long, and the demethoxy protection requires a high temperature of about 200°C and acid-resistant conditions, which is not only not conducive to industrial production, but also has complicated steps and low production efficiency.

[0007] In method 2, such as CN111533718B, 3,5-dibromo-4-hydroxybenzoyl chloride with a protective group is reacted with 2-ethylbenzofuran, that is, compound 3,5-dibromo-4-hydroxybenzoic acid is used as a raw material, and a small amount of aluminum phosphate is added as a catalyst in an environment where dihydropyran is used as a solvent and a protective agent to obtain an oily compound II; then compound II is dissolved in dichloromethane, a small amount of dimethylformamide is added as a catalyst, and N,N-diisopropylethylamine is used as an acid-binding agent to control the internal The temperature does not exceed 25℃, thionyl chloride is added dropwise, after the addition is completed, the reaction is stirred at 30-35℃, filtered, dichloromethane and excess thionyl chloride are evaporated, and compound III is purified; then compound III is dissolved in dichloromethane, 2-ethylbenzofuran is added, aluminum chloride is added at -5-0℃, and compound IV is obtained by Friedel-Crafts acylation after post-treatment; then compound IV is added to ethanol, pyridine p-toluenesulfonate is added as a catalyst, and the reaction is stirred at 50℃ to reflux for 3h, and compound V is obtained by post-treatment. This method uses 3,5-dibromo-4-hydroxybenzoic acid as the starting material, and the starting material is protected and acylated by THP (2-tetrahydropyran), and then Friedel-Crafts acylation and deprotection are performed to obtain benzbromarone. This method is relatively cumbersome as a whole and requires protection and deprotection of phenolic hydroxyl groups. The production efficiency is not high, and the HPLC purity is too low, only about 98%. It has many impurities and is difficult to purify to a qualified level later.

[0008] In addition, in method 2, such as CN103333143B, 3,5-dibromo-4-hydroxybenzoyl chloride without a protecting group is reacted with 2-ethylbenzofuran, that is, 2-ethylbenzofuran is subjected to an acylation reaction with 3,5-dibromo-4-hydroxybenzoyl chloride in the presence of a catalyst and an inert protective solvent to obtain a crude benzbromarone product, which is then refined with a mixed solvent of ethanol and petroleum ether to obtain a fine benzbromarone product. The starting material 3,5-dibromo-4-hydroxybenzoyl chloride in the above method is extremely unstable, and it is very easy to decompose into by-products when it comes into contact with water and is difficult to store. Currently, there is a lack of commercial sources, and it requires high outsourcing costs. The biggest problem is that this method will also generate more specific isomer / dimer impurities, which are similar to the physical and chemical properties of the API and are difficult to remove. The use of solvents disclosed in the existing method, such as mixed solvent refining of ethanol and petroleum ether, cannot effectively remove isomer / dimer impurities, and thus cannot meet the registration declaration requirement that the relevant substances of the API shall not exceed 0.15%. The structural formulas of the isomer and dimer impurities are as follows:

[0009]

[0010] In summary, the above-mentioned technical routes all have various defects, and industrial implementation is difficult. The existing routes need to be improved in various aspects. Summary of the invention

[0011] In order to solve the above technical problems, the present invention uses 2-ethylbenzofuran and 4-methoxybenzoyl chloride as starting materials, optimizes the demethoxy step, greatly reduces the reaction temperature, has a simple process, a short route, and a low production cost. The intermediate products of the first two steps are not separated, and the obtained benzbromarone has a high yield, high purity (HPLC>99.90%), and few impurities (total impurities <0.1%).

[0012] The present invention adopts the following technical solution:

[0013] An industrial preparation method of benzbromarone is prepared by the following reaction route:

[0014] (1) Generate benzalkonium alkali metal salt:

[0015]

[0016] (2) Producing benzbromarone fine products:

[0017]

[0018] An industrial preparation method of benzbromarone comprises the following steps:

[0019] (1) Generate benzalkonium alkali metal salt:

[0020] At -10 to 0°C, add chlorinated hydrocarbon solvent, 4-methoxybenzoyl chloride, and activated carbon-supported ferric chloride catalyst into a reaction kettle, stir evenly, then drop 2-ethylbenzofuran into the reaction kettle for acylation reaction. After monitoring the reaction, drop a mixed solution of activated carbon-supported aluminum chloride catalyst and chlorinated hydrocarbon solvent into the reaction kettle at -5 to 5°C. After the addition is complete, heat the mixture to 55-65°C and keep it for 2-3h for demethylation reaction. After the reaction is complete, quench the mixture with ice water, filter, and extract the organic layer with alkaline water to obtain an aqueous solution of benzalkonium alkali metal salt.

[0021] (2) Producing benzbromarone fine products:

[0022] At 20-30° C., add lower alcohol, fatty acid and heteropolyacid oxidation bromination catalyst to the aqueous solution of benzalkonium alkali metal salt, then control the temperature to 80-90° C., and simultaneously drip hydrobromic acid and hydrogen peroxide in equal proportions. After the dripping is completed, keep warm, and detect the completion of the reaction by TLC, add activated carbon and reducing agent, dissolve, decolorize and filter at 85-95° C., crystallize, filter, wash with water until neutral, and dry to obtain benzbromarone fine product.

[0023] In some embodiments, the mass fraction of ferric chloride in the activated carbon-immobilized ferric chloride catalyst is 35-40%; the mass fraction of aluminum chloride in the activated carbon-immobilized aluminum chloride catalyst is 30% to 35%.

[0024] In some embodiments, the chlorinated hydrocarbon solvent is selected from one of chloroform, carbon tetrachloride, ethylene dichloride, or chlorobenzene.

[0025] In some embodiments, the mass ratio of the chlorinated hydrocarbon solvent, 4-methoxybenzoyl chloride, activated carbon-supported ferric chloride catalyst, and 2-ethylbenzofuran is (4-6):(1.15-1.25):(0.05-0.10):1.

[0026] In some embodiments, the mass ratio of the mixed liquid to 2-ethylbenzofuran is (10-15):1.

[0027] In some embodiments, the mass ratio of the activated carbon-supported aluminum chloride catalyst to the chlorinated hydrocarbon is 1:(2-3).

[0028] In some embodiments, the weight ratio of the mixed liquid to the quenching ice water is 1:1.

[0029] In some embodiments, the alkaline water is one of sodium hydroxide solution or potassium hydroxide solution, the weight ratio of alkaline water to chlorinated hydrocarbon solvent is 1.5:1, and the molar ratio of the solute sodium hydroxide or potassium hydroxide to 2-ethylbenzofuran in the alkaline water is (1.02-1.05):1. In some embodiments, the lower alcohol is selected from one of methanol, ethanol or isopropanol; the fatty acid is acetic acid or propionic acid; the heteropolyacid oxidative bromination catalyst is selected from one of phosphotungstic acid, phosphomolybdic acid, peroxyphosphotungstic acid, peroxyphosphomolybdic acid, sodium tungstate, sodium molybdate; the reducing agent is sodium thiosulfate or sodium dithionite.

[0030] In some embodiments, the concentration of hydrobromic acid is 48 wt % and the concentration of hydrogen peroxide is 35 wt %.

[0031] In some embodiments, the mass ratio of the aqueous solution of benzalkonium alkali metal salt, lower alcohol, fatty acid, heteropolyacid oxidative bromination catalyst, hydrobromic acid, hydrogen peroxide, activated carbon, and reducing agent is 1:(2-3):(1-2):(0.013-0.026):(0.35-0.42):(0.23-0.27):(0.03):(0.02-0.05).

[0032] Compared with the prior art, the beneficial effects of the present invention include at least:

[0033] 1. The present invention adopts 4-methoxybenzoyl chloride as a reactant to react with 2-ethylbenzofuran, optimizes the demethoxy step, reduces the reaction temperature from 200° C. to 55-65° C., and reduces the high temperature and acid resistance requirements.

[0034] 2. The reaction route of the present invention requires only two steps. The first step of preparing the alkali metal salt of benzalkonium does not require separation of intermediate products, and the obtained benzbromarone has a high yield, high purity (HPLC>99.90%), and few impurities (total impurities <0.1%). BRIEF DESCRIPTION OF THE DRAWINGS

[0035] Figure 1 : The HPLC detection spectrum of embodiment 1 product.

[0036] Figure 2 : The HPLC detection spectrum of embodiment 2 product.

[0037] Figure 3 : The HPLC detection spectrum of embodiment 3 product. DETAILED DESCRIPTION

[0038] In order to make the purpose, technical scheme and beneficial effects of the present invention clearer, the present invention is further described in detail below in conjunction with the accompanying drawings and specific embodiments. Examples of the embodiments are shown in the accompanying drawings. It should be understood that the specific embodiments described in the following embodiments of the present invention are only exemplary descriptions of the specific embodiments of the present invention, and are intended to be used to explain the present invention, but do not constitute a limitation of the present invention.

[0039] The endpoints of ranges and any values ​​disclosed herein are not limited to the exact range or value, and these ranges or values ​​should be understood to include approximations to these ranges.

[0040] Example 1

[0041] (1) Forming benzalkonium alkali metal salt: 400 kg of chloroform solvent, 115 kg of 4-methoxybenzoyl chloride and 5 kg of activated carbon-supported ferric chloride catalyst were added to a reaction kettle at -10°C. After stirring, 100 kg of 2-ethylbenzofuran was added dropwise at the same temperature to carry out acylation reaction. After monitoring the reaction, 1000 kg of a mixed liquid of activated carbon-supported aluminum chloride catalyst and chlorinated hydrocarbon solvent was added dropwise at -5°C. After the addition was completed, the temperature was raised to 55°C and kept warm for 2 hours to carry out demethylation reaction. After the reaction was completed, the mixed liquid was quenched with 1000 kg of ice water, filtered, and the organic layer was adjusted to pH = 7.5 with 600 kg of an aqueous solution containing 27.94 kg of sodium hydroxide to obtain about 805 kg of an aqueous solution of sodium salt of benzalkonium alkali metal salt.

[0042] (2) Production of benzbromarone fine product: 1610 kg of methanol, 805 kg of acetic acid, and 10.47 kg of phosphotungstic acid catalyst were added to the sodium salt aqueous solution of benzalkonium chloride, and the temperature was controlled at 80° C. At the same time, 281.75 kg of 48% hydrobromic acid and 185.15 kg of 35% hydrogen peroxide were added dropwise in equal proportions. After the addition was completed, the temperature was kept at 80° C. for 2 h. After the reaction was completed by TLC detection, 24.15 kg of activated carbon and 16.10 kg of sodium thiosulfate were added at 85° C. The solution was decolorized and filtered, and the filtrate was cooled to 20° C., crystallized, filtered, washed with water until neutral, and dried to obtain 233.46 kg of benzbromarone finished product, which was a white crystalline powder with a purity of 99.96% and a CP impurity I of less than 0.04% (see Figure 1 ), molar yield 80.39% (theoretical 290.41 kg).

[0043] Example 2

[0044] (1) Formation of Benzalkonium Alkali Metal Salt: Synthesis of Benzalkonium Alkali Metal Salt: At -10°C, 600 kg of ethylene dichloride solvent, 125 kg of 4-methoxybenzoyl chloride, and 10 kg of activated carbon-supported ferric chloride catalyst were added to a reaction kettle. After stirring, 100 kg of 2-ethylbenzofuran was added dropwise at the same temperature to carry out acylation reaction. After monitoring the reaction, 1500 kg of a mixed liquid of activated carbon-supported aluminum chloride catalyst and chlorinated hydrocarbon solvent was added dropwise at -5°C. After the addition was complete, the temperature was raised to 55°C and kept warm for 2-3 hours to carry out demethylation reaction. After the reaction was completed, the mixed liquid was quenched with 1500 kg of ice water and filtered. The organic layer was adjusted to pH = 7.5 with 900 kg of an aqueous solution containing 28.77 kg of sodium hydroxide, and about 1105 kg of an aqueous solution of sodium salt of Benzalkonium Alkali Metal Salt was obtained by extraction.

[0045] (2) Production of benzbromarone fine product: 3315 kg of ethanol, 2210 kg of propionic acid, and 28.73 kg of phosphomolybdic acid catalyst were added to the sodium salt aqueous solution of benzalkonium chloride, and the temperature was controlled at 80°C. At the same time, 464.1 kg of 48% hydrobromic acid and 298.9 kg of 35% hydrogen peroxide were added dropwise in equal proportions. After the addition was completed, the temperature was kept at 80°C for 2 h. After the reaction was completed by TLC detection, 33.15 kg of activated carbon and 55.25 kg of sodium thiosulfate were added at 85-90°C, the solution was decolorized and filtered, the filtrate was cooled to 20°C, crystallized, filtered, washed with water until neutral, and dried to obtain 223.35 kg of benzbromarone finished product, which was a white crystalline powder with a purity of 99.96% and a CP impurity I of less than 0.02% (see Figure 2 ), molar yield 76.98% (theoretical 290.41 kg).

[0046] Example 3

[0047] (1) Forming benzalkonium alkali metal salt: at -10°C, add 500 kg of chlorobenzene solvent, 115 kg of 4-methoxybenzoyl chloride, and 5 kg of activated carbon-supported ferric chloride catalyst to a reaction kettle, stir evenly, and then drop 100 kg of 2-ethylbenzofuran at the same temperature to carry out acylation reaction. After monitoring the reaction, drop 1200 kg of a mixed liquid of activated carbon-supported aluminum chloride catalyst and chlorinated hydrocarbon solvent at -5°C. After the dropwise addition is complete, heat the mixture to 55°C and keep the temperature for 2 hours to carry out demethylation reaction. After the reaction is completed, the mixed liquid is quenched with 1200 kg of ice water, filtered, and the organic layer is adjusted to pH = 7.5 with 750 kg of an aqueous solution containing 39.69 kg of potassium hydroxide, and about 955 kg of an aqueous solution of potassium salt of benzalkonium is extracted.

[0048] (2) Production of benzbromarone finished product: 2387.5 kg of isopropanol, 1432.5 kg of propionic acid, and 18.62 kg of peroxyphosphotungstic acid catalyst were added to the potassium salt aqueous solution containing the above benzalkonium salt, and the temperature was controlled at 80°C. At the same time, 367.68 kg of 48% hydrobromic acid and 238.75 kg of 35% hydrogen peroxide were added dropwise in equal proportions. After the addition was completed, the temperature was kept at 80°C for 2 hours. After the reaction was completed by TLC detection, 28.65 kg of activated carbon and 33.42 kg of sodium dithionite were added at 85°C, the solution was decolorized and filtered, the filtrate was cooled to 20°C, crystallized, filtered, washed with water until neutral, and dried to obtain 228.46 kg of benzbromarone finished product, which was a white crystalline powder with a purity of 99.94% and a CP impurity I of less than 0.04% (see Figure 3 ), molar yield 78.66% (theoretical 290.41 kg).

[0049] Example 4

[0050] (1) Forming benzalkonium alkali metal salt: at 0°C, add 400 kg of chloroform solvent, 115 kg of 4-methoxybenzoyl chloride, and 5 kg of activated carbon-supported ferric chloride catalyst to a reaction kettle. After stirring evenly, 100 kg of 2-ethylbenzofuran is added dropwise at the same temperature to carry out acylation reaction. After monitoring the reaction, 1000 kg of a mixed liquid of activated carbon-supported aluminum chloride catalyst and chlorinated hydrocarbon solvent is added dropwise at 5°C. After the addition is complete, the temperature is raised to 65°C and kept warm for 3 hours to carry out demethylation reaction. After the reaction is completed, the mixed liquid is quenched with 1000 kg of ice water, filtered, and the organic layer is adjusted to pH=8.5 with 600 kg of an aqueous solution containing 27.94 kg of sodium hydroxide to obtain about 805 kg of an aqueous solution of sodium salt of benzalkonium alkali metal salt.

[0051] (2) Production of benzbromarone finished product: 1610 kg of methanol, 805 kg of acetic acid, and 10.47 kg of phosphotungstic acid catalyst were added to the sodium salt aqueous solution of benzalkonium chloride, and the temperature was controlled at 90°C. At the same time, 281.75 kg of 48% hydrobromic acid and 185.15 kg of 35% hydrogen peroxide were added dropwise in equal proportions. After the addition was completed, the temperature was kept at 90°C for 3 h. After the reaction was completed by TLC detection, 24.15 kg of activated carbon and 16.10 kg of sodium thiosulfate were added at 90°C, the solution was decolorized and filtered, the filtrate was cooled to 30°C, crystallized, filtered, washed with water until neutral, and dried to obtain 227.18 kg of benzbromarone finished product, which was a white crystalline powder with a molar yield of 78.23% (theoretical 290.41 kg).

[0052] Example 5

[0053] (1) Formation of Benzalkonium Alkali Metal Salt: Synthesis of Benzalkonium Alkali Metal Salt: At 0°C, 600 kg of ethylene dichloride solvent, 125 kg of 4-methoxybenzoyl chloride, and 10 kg of activated carbon-supported ferric chloride catalyst were added to a reaction kettle. After stirring, 100 kg of 2-ethylbenzofuran was added dropwise at the same temperature to carry out acylation reaction. After monitoring the reaction, 1500 kg of a mixed liquid of activated carbon-supported aluminum chloride catalyst and chlorinated hydrocarbon solvent was added dropwise at 5°C. After the addition was complete, the temperature was raised to 65°C and kept warm for 2-3 hours to carry out demethylation reaction. After the reaction was completed, the mixed liquid was quenched with 1500 kg of ice water and filtered. The organic layer was adjusted to pH = 8.5 with 900 kg of an aqueous solution containing 28.77 kg of sodium hydroxide, and about 1105 kg of an aqueous solution of sodium salt of Benzalkonium Alkali Metal Salt was obtained by extraction.

[0054] (2) Production of benzbromarone finished product: 3315 kg of ethanol, 2210 kg of propionic acid, and 28.73 kg of phosphomolybdic acid catalyst were added to the sodium salt aqueous solution of benzalkonium chloride, and the temperature was controlled at 90°C. At the same time, 464.1 kg of 48% hydrobromic acid and 298.9 kg of 35% hydrogen peroxide were added dropwise in equal proportions. After the addition was completed, the temperature was kept at 90°C for 3 h. After the reaction was completed by TLC detection, 33.15 kg of activated carbon and 55.25 kg of sodium thiosulfate were added at 85-90°C, the solution was decolorized and filtered, the filtrate was cooled to 30°C, crystallized, filtered, washed with water until neutral, and dried to obtain 219.49 kg of benzbromarone finished product, which was a white crystalline powder with a molar yield of 75.58% (theoretical 290.41 kg).

[0055] Example 6

[0056] (1) Forming benzalkonium alkali metal salt: at 0°C, add 500 kg of chlorobenzene solvent, 115 kg of 4-methoxybenzoyl chloride, and 5 kg of activated carbon-supported ferric chloride catalyst to a reactor, stir evenly, and then drop 100 kg of 2-ethylbenzofuran at the same temperature to carry out acylation reaction. After monitoring the reaction, drop 1200 kg of a mixed liquid of activated carbon-supported aluminum chloride catalyst and chlorinated hydrocarbon solvent at 5°C. After the dropwise addition is complete, heat the mixture to 65°C and keep it for 3 hours to carry out demethylation reaction. After the reaction is completed, the mixed liquid is quenched with 1200 kg of ice water, filtered, and the organic layer is adjusted to pH=8.5 with 750 kg of an aqueous solution containing 39.69 kg of potassium hydroxide, and about 955 kg of an aqueous solution of potassium salt of benzalkonium alkali metal salt is obtained by extraction.

[0057] (2) Production of benzbromarone finished product: 2387.5 kg of isopropanol, 1432.5 kg of propionic acid, and 18.62 kg of peroxyphosphotungstic acid catalyst were added to the potassium salt aqueous solution containing the above benzalkonium salt, and the temperature was controlled at 90°C. At the same time, 367.68 kg of 48% hydrobromic acid and 238.75 kg of 35% hydrogen peroxide were added dropwise in equal proportions. After the addition was completed, the temperature was kept at 90°C for 3 h. After the reaction was completed by TLC detection, 28.65 kg of activated carbon and 33.42 kg of sodium dithionite were added at 90°C, the solution was decolorized and filtered, the filtrate was cooled to 30°C for crystallization, filtered, washed with water until neutral, and dried to obtain 222.39 kg of benzbromarone finished product, which was a white crystalline powder with a molar yield of 76.65% (theoretical 290.41 kg).

[0058] Finally, it should be noted that the above embodiments are only used to illustrate the technical solution of the present invention and do not constitute a limitation on the content of the present invention. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. An industrial preparation method of benzbromarone, characterized in that, Prepared by the following reaction route: (1) Generate benzalkonium alkali metal salt: (2) Producing benzbromarone fine products:

2. The industrial preparation method of benzbromarone according to claim 1, characterized in that: The steps include: (1) Generate benzalkonium alkali metal salt: At -10 to 0°C, add a chlorinated hydrocarbon solvent, 4-methoxybenzoyl chloride, and an activated carbon-supported ferric chloride catalyst to a reaction kettle, stir evenly, and then drop 2-ethylbenzofuran into the reaction kettle for acylation reaction. After monitoring the reaction, drop a mixed liquid of the activated carbon-supported aluminum chloride catalyst and the chlorinated hydrocarbon solvent into the reaction kettle at -5 to 5°C. After the dropwise addition is completed, heat the mixture to 55-65°C and keep the mixture for 2-3 hours for demethylation reaction. After the reaction is completed, quench the mixed liquid with ice water, filter, and extract the organic layer with alkaline water to obtain an aqueous solution of benzalkonium alkali metal salt. (2) Producing benzbromarone fine products: At 20-30° C., add lower alcohol, fatty acid and heteropolyacid oxidation bromination catalyst to the aqueous solution of benzalkonium alkali metal salt, then control the temperature to 80-90° C., and simultaneously drip hydrobromic acid and hydrogen peroxide in equal proportions. After the dripping is completed, keep warm, and detect the completion of the reaction by TLC, add activated carbon and reducing agent, dissolve, decolorize and filter at 85-95° C., crystallize, filter, wash with water until neutral, and dry to obtain benzbromarone fine product.

3. The industrial preparation method of benzbromarone according to claim 2, characterized in that: The mass fraction of ferric chloride in the activated carbon-immobilized ferric chloride catalyst is 35-40%; the mass fraction of aluminum chloride in the activated carbon-immobilized aluminum chloride catalyst is 30%-35%.

4. The industrial preparation method of benzbromarone according to claim 2, characterized in that: The chlorinated hydrocarbon solvent is selected from one of chloroform, carbon tetrachloride, ethylene dichloride, or chlorobenzene.

5. The industrial preparation method of benzbromarone according to claim 2, characterized in that: The mass ratio of the chlorinated hydrocarbon solvent, 4-methoxybenzoyl chloride, activated carbon-supported ferric chloride catalyst, and 2-ethylbenzofuran is (4-6):(1.15-1.25):(0.05-0.10):

1.

6. The industrial preparation method of benzbromarone according to claim 2, characterized in that: The mass ratio of the mixed liquid to 2-ethylbenzofuran is (10-15):1; the mass ratio of the activated carbon-supported aluminum chloride catalyst to chlorinated hydrocarbon is 1:(2-3); and the weight ratio of the mixed liquid to quenching ice water is 1:

1.

7. The industrial preparation method of benzbromarone according to claim 2, characterized in that: The alkaline water is one of sodium hydroxide solution or potassium hydroxide solution, the weight ratio of the alkaline water to the chlorinated hydrocarbon solvent is 1.5:1, and the molar ratio of the solute sodium hydroxide or potassium hydroxide to 2-ethylbenzofuran in the alkaline water is (1.02-1.05):

1.

8. The industrial preparation method of benzbromarone according to claim 2, characterized in that: The lower alcohol is selected from one of methanol, ethanol or isopropanol; the fatty acid is acetic acid or propionic acid; the heteropolyacid oxidative bromination catalyst is selected from one of phosphotungstic acid, phosphomolybdic acid, peroxyphosphotungstic acid, peroxyphosphomolybdic acid, sodium tungstate and sodium molybdate; the reducing agent is sodium thiosulfate or sodium dithionite.

9. The industrial preparation method of benzbromarone according to claim 2, characterized in that: The concentration of hydrobromic acid is 48 wt %, and the concentration of hydrogen peroxide is 35 wt %.

10. The industrial preparation method of benzbromarone according to claim 2, characterized in that: The mass ratio of the aqueous solution of benzalkonium alkali metal salt, lower alcohol, fatty acid, heteropolyacid oxidative bromination catalyst, hydrobromic acid, hydrogen peroxide, activated carbon, and reducing agent is 1:(2-3):(1-2):(0.013-0.026):(0.35-0.42):(0.23-0.27):(0.03):(0.02-0.05).

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