Synthesis method and insecticide of broflanilide

Abstract

This invention relates to the field of insecticide technology in the agrochemical industry, specifically to a method for synthesizing brofenoxam and an insecticide thereof. The method for synthesizing brofenoxam includes: mixing ethyl 2-fluoro-3-nitrobenzoate, paraformaldehyde, a Pd / C catalyst, an acidic compound, and an ionic liquid under pressure for a reductive hydrogenation methylation reaction. Then, intermediate II undergoes acylation and hydrolysis, and finally, it is mixed with 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline and continuously condensed under ultrasonic irradiation to obtain brofenoxam. This synthesis method uses a one-pot process for reductive methylation and continuously produces the brofenoxam technical material under ultrasonic irradiation, thus achieving energy saving, environmental friendliness, and stable product quality. This synthesis method has mild reaction conditions, short synthesis steps, and can improve the yield of brofenoxam.

Description

Technical Field

[0001] This invention relates to the field of pesticide technology in the agrochemical industry, and more specifically, to a method for synthesizing bromufenoxam and an pesticide. Background Technology

[0002] Brofentanil dimethyl ...

[0003] Specifically, there are currently several routes for the synthesis of bromufenoxam:

[0004] (1) Japanese Mitsui Chemicals patent CN102119144B ​​uses 2-chloro-3-nitrobenzoic acid as the starting material, and through esterification, chlorofluorination, reduction, acylation, methylation and hydrolysis to 2-fluoro-3-(N-methylbenzoyl)-aminobenzoic acid, and then synthesizes bromfenac bisamide with 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline under the action of thionyl chloride; another route in this patent also uses 2-chloro-3-nitrobenzoic acid as the starting material, and through esterification, chlorofluorination, reduction, methylation and acylation, it can be hydrolyzed to 2-fluoro-3-(N-methylbenzoyl)-aminobenzoic acid, and finally synthesizes bromfenac bisamide with 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline under the action of thionyl chloride.

[0005] (2) Mitsui Chemicals patent CN104245665A uses 2-chloro-3-nitrobenzoic acid as the starting material, and esterifies, chlorofluorinates, reduces, acylates, methylates and hydrolyzes it to 2-fluoro-3-(N-methylbenzoyl)-aminobenzoic acid. Then, it undergoes acylation, condensation with 2-trifluoromethylaniline, and finally perfluoroisopropylation and bromination to obtain bromoxynil diamide.

[0006] (3) Patent CN109206335 uses ethyl 2-fluoro-3-nitrobenzoate as the starting material, which is reduced, methylated, acylated and hydrolyzed to 2-fluoro-3-(N-methylbenzoyl)-aminobenzoic acid, which is then acylated, and then synthesized with 2-bromo-4-perfluoroisopropylaniline and trifluoromethylated to form bromonitrile benzoic acid bisamide.

[0007] (4) Patent US2011201687 uses 2-chloro-3-nitrobenzoic acid as the starting material, and synthesizes bromoxynil diamide by acid acyl chlorination, condensation with 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline, followed by chlorofluorination, reduction, methylation and acylation.

[0008] (5) Wang Jie et al. published a paper on modern pesticides that used 2-fluoro-3-nitrobenzoic acid as the starting material and synthesized bromoxynil diamide through acid acyl chlorination, condensation with 2-trifluoromethylaniline, reduction, methylation, acylation, perfluoroisopropylation and bromination.

[0009] The processes described in the aforementioned patents and documents suffer from drawbacks such as long processing routes, low overall yields, and cumbersome operations, which would present various limitations for industrial-scale production. Therefore, it is urgent for those skilled in the art to find more suitable industrial-scale production methods.

[0010] In view of this, the present invention is proposed. Summary of the Invention

[0011] The purpose of this invention is to provide a method for synthesizing brofenoxam and an insecticide. The synthesis method provided in this invention aims to overcome the shortcomings of existing technologies, such as long routes, low yields, complex operations, and long reaction times. The synthesis method provided in this invention features mild reaction conditions, a short route, simple operation, short reaction time, and can effectively improve the yield of brofenoxam.

[0012] This invention is implemented as follows:

[0013] In a first aspect, embodiments of the present invention provide a method for synthesizing bromonitrile benzoyl diamide, comprising: mixing ethyl 2-fluoro-3-nitrobenzoate, paraformaldehyde, a Pd / C catalyst, an acidic compound, and an ionic liquid to carry out a pressurized hydrogenation-reduction methylation reaction.

[0014] In a preferred embodiment of the present invention, the conditions for the pressurized hydrogenation-reduction methylation reaction include: pressure of 0.1-10 MPa, temperature of 30-160°C, and time of 1-24 h.

[0015] Preferably, the conditions for the pressurized hydrogenation-reduction methylation reaction include: pressure of 0.2-5 MPa, temperature of 40-110°C, and time of 1-15 h.

[0016] In a preferred embodiment of the present invention, the acidic compound includes a weak acid, preferably any one or at least two combinations of tartaric acid, acetic acid, acetic anhydride, oxalic acid, maleic acid and benzoic acid; preferably acetic acid and acetic anhydride.

[0017] Preferably, the acetic acid content is 95-99%, more preferably 99%;

[0018] Preferably, the content of acetic anhydride is greater than 98%; preferably, the content of the Pd / C catalyst is 1-10%, and more preferably 5%.

[0019] In a preferred embodiment of the present invention, the molar ratio of ethyl 2-fluoro-3-nitrobenzoate to paraformaldehyde is 1:1.3-1.8; preferably 1:1.4-1.6.

[0020] Preferably, the molar ratio of ethyl 2-fluoro-3-nitrobenzoate to the Pd / C catalyst is 1:0.01-0.3; more preferably, it is 1:0.05-0.1.

[0021] Preferably, the molar ratio of ethyl 2-fluoro-3-nitrobenzoate to acetic acid is 1:0.01-0.15; more preferably, it is 1:0.05-0.1.

[0022] Preferably, the molar ratio of ethyl 2-fluoro-3-nitrobenzoate to acetic anhydride is 1:0.8-1.2.

[0023] In a preferred embodiment of the present invention, intermediate II, formed by pressurized hydrogenation-reduction methylation reaction, is synthesized into intermediate IV via the following synthetic pathway:

[0024] .

[0025] In a preferred embodiment of the present invention, the method includes: mixing intermediate IV, 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline, sulfonyl chloride compound, condensation catalyst, organic base and solvent, and carrying out a continuous catalytic condensation reaction under ultrasonic treatment.

[0026] In a preferred embodiment of the present invention, the conditions for the continuous catalytic condensation reaction include: a temperature of 10-180°C and an ultrasonic time of 5-1200 s.

[0027] Preferably, the conditions for the continuous catalytic condensation reaction include: a temperature of 30-160℃ and an ultrasonic time of 10-800 s;

[0028] Preferably, the ultrasonic frequency is 20-40 kHz.

[0029] In a preferred embodiment of the present invention, the sulfonyl chloride compound includes at least one of methylsulfonyl chloride, p-methylbenzenesulfonyl chloride, and p-nitrobenzenesulfonyl chloride; preferably p-nitrobenzenesulfonyl chloride;

[0030] Preferably, the condensation catalyst comprises at least one of DMAP, 4-PPY, and HOBT; preferably, it is DMAP.

[0031] Preferably, the organic base includes at least one selected from triethylamine, pyridine, 3-methylpyridine, sodium methoxide, and potassium tert-butoxide, with triethylamine being the most preferred.

[0032] Preferably, the solvent is selected from at least one or a mixture of at least two of aromatic solvents, ester solvents, nitrile solvents, alcohol solvents, ether solvents, amide solvents and alkane solvents;

[0033] Preferably, the solvent is selected from any one or a mixture of at least two of acetonitrile, toluene, chlorobenzene, ethyl acetate, sec-butyl acetate, dichloroethane, and dichloromethane; more preferably, it is DMF.

[0034] In a preferred embodiment of the present invention, the molar ratio of intermediate IV to 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline is 1:1.0-1.5; preferably 1:1.1-1.3.

[0035] Preferably, the molar ratio of intermediate IV to the sulfonyl chloride compound is 1:1-6; more preferably, it is 1:1.5.

[0036] Preferably, the molar ratio of intermediate IV to the condensation catalyst is 1:0.05-0.15; more preferably, it is 1:0.06-0.1.

[0037] Preferably, the molar ratio of intermediate IV to the organic base is 1:1-10; more preferably, it is 1:1.5-2.

[0038] Secondly, embodiments of the present invention provide an insecticide comprising brofenoxam prepared by the above-described method for synthesizing brofenoxam.

[0039] The present invention has the following beneficial effects: the synthesis method provided in the embodiments of the present invention has mild reaction conditions, a short route, simple operation, short reaction time, and can effectively improve the yield of brofentanil. It can effectively overcome the shortcomings of existing brofentanil synthesis methods, such as long routes, low yields, complicated operations, and long reaction times. Detailed Implementation

[0040] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention will be clearly and completely described below. Where specific conditions are not specified in the embodiments, conventional conditions or conditions recommended by the manufacturer shall apply. Reagents or instruments whose manufacturers are not specified are all conventional products that can be purchased commercially.

[0041] This invention provides a method for synthesizing bromofenacin, which is carried out according to the following synthetic route:

[0042] The specific process is as follows:

[0043] (1) Formation of intermediate II;

[0044] The existing technology generally involves a two-step process of reducing the nitro group in ethyl 2-fluoro-3-nitrobenzoate and then N-methylating it. However, the embodiments of the present invention optimize this process into a one-pot, one-step reaction using specific raw materials and methods. This reduces the number of reaction steps and the overall reaction time, lowers production costs, and ensures the yield and purity of intermediate II.

[0045] Specifically, ethyl 2-fluoro-3-nitrobenzoate, paraformaldehyde, Pd / C catalyst, acidic compound and ionic liquid are mixed and subjected to a pressurized hydrogenation-reduction methylation reaction.

[0046] The acidic compound includes a weak acid, preferably at least one of tartaric acid, acetic acid, acetic anhydride, oxalic acid, maleic acid and benzoic acid; preferably acetic acid and acetic anhydride; the content of acetic acid is 95-99%, preferably 99%; the content of acetic anhydride is greater than 98%.

[0047] The content of the Pd / C catalyst is 1-10%, preferably 5%.

[0048] It should be noted that the acetic acid content and the Pd / C catalyst content mentioned above refer to the purity of the substances.

[0049] Furthermore, the conditions for the pressurized hydrogenation-reduction methylation reaction include: pressure of 0.1-10 MPa, temperature of 30-160℃, and time of 1-24 h.

[0050] The ionic liquid used in this invention is a commercially available functional ionic liquid, such as an imidazole ionic liquid, specifically 1-ethyl-3-methylimidazolium nitrate, 1-butyl-3-methylimidazolium tetrafluoroborate, 1-ethyl-3-methylimidazolium toluenesulfonyl ester, or 1,2-dimethyl-3-propylimidazolium bis(trifluoromethanesulfonyl)imide (purchased from Beijing Bailingwei Technology Co., Ltd.). Preferably, it is 1,2-dimethyl-3-propylimidazolium bis(trifluoromethanesulfonyl)imide. In this invention embodiment, 2-6 grams of ionic liquid are added for every gram of ethyl 2-fluoro-3-nitrobenzoate.

[0051] For example, the pressure can be any value between 0.1 and 10 MPa, or a range between any two values, such as 0.1 MPa, 1 MPa, 2 MPa, 3 MPa, 4 MPa, 5 MPa, 6 MPa, 7 MPa, 8 MPa, 9 MPa, and 10 MPa, preferably 0.2-5 MPa.

[0052] The temperature is any value between 30 and 160 degrees Celsius, or any range between any two values, such as 30°C, 50°C, 80°C, 100°C, 120°C, 150°C, and 160°C, preferably 40-110°C.

[0053] The time is any value between 1 and 24 hours, or any range between any two values, such as 1 hour, 5 hours, 10 hours, 15 hours, 20 hours, and 24 hours, preferably 1 to 15 hours.

[0054] The molar ratio of ethyl 2-fluoro-3-nitrobenzene to paraformaldehyde is 1:1.3-1.8; for example, it is any value between 1:1.3-1.8 or any range between any two values, such as 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7 and 1:1.8, preferably 1:1.4-1.6.

[0055] The molar ratio of ethyl 2-fluoro-3-nitrobenzoate to the Pd / C catalyst is 1:0.01-0.3; for example, it is any value between 1:0.01 and 0.3, or any range between any two values, such as 1:0.01, 1:0.05, 1:0.1, 1:0.15, 1:0.2, 1:0.25, and 1:0.3, preferably 1:0.05-0.1.

[0056] The molar ratio of ethyl 2-fluoro-3-nitrobenzoate to the acidic compound is 1:0.01-1.5. For example, the molar ratio of ethyl 2-fluoro-3-nitrobenzoate to acetic acid is 1:0.01-0.15; for example, any value between 1:0.01 and 0.15, or any range between any two values, such as 1:0.01, 1:0.05, 1:0.10, and 1:0.15, is preferred to be 1:0.05-0.1.

[0057] The molar ratio of ethyl 2-fluoro-3-nitrobenzoate to acetic anhydride is 1:0.8-1.2. For example, it can be any value between 1:0.8 and 1:1.2, or any range between any two values, such as 1:0.8, 1:0.9, 1:1, 1:1.1, and 1:1.2.

[0058] (2) Formation of intermediate IV;

[0059] Intermediate II is acylated and hydrolyzed to form intermediate IV (hereinafter also referred to as 2-fluoro-3-(N-methyl-benzamide)benzoic acid (Ⅳ)). The process of intermediate II forming intermediate IV is a conventional method, which will not be described in detail in the embodiments of the present invention. For example, it can be synthesized with reference to CN102119144B.

[0060] (3) Formation of bromoxynil diamide VI;

[0061] Specifically, intermediate IV, 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline, sulfonyl chloride compounds, condensation catalyst, organic base and solvent are continuously condensed in a static mixer under ultrasonic action to obtain bromonitrile diphenyl bisamide VI.

[0062] This enables continuous production of this step of the reaction, thereby greatly shortening the reaction time, increasing production capacity, significantly reducing production costs, simplifying operation, and effectively improving the yield of bromfenac.

[0063] The sulfonyl chloride compounds include at least one of methylsulfonyl chloride, p-methylbenzenesulfonyl chloride, and p-nitrobenzenesulfonyl chloride; preferably p-nitrobenzenesulfonyl chloride.

[0064] The condensation catalyst includes at least one of DMAP, 4-PPY and HOBT; preferably DMAP.

[0065] The organic base includes at least one of triethylamine, pyridine, 3-methylpyridine, sodium methoxide and potassium tert-butoxide, preferably triethylamine.

[0066] The solvent is selected from at least one or a mixture of at least two of aromatic solvents, ester solvents, nitrile solvents, alcohol solvents, ether solvents, amide solvents and alkane solvents; preferably, the solvent is selected from any one or a mixture of at least two of acetonitrile, toluene, chlorobenzene, ethyl acetate, sec-butyl acetate, dichloroethane and dichloromethane; more preferably, it is DMF.

[0067] Furthermore, the molar ratio of intermediate IV to 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline is 1:1.0-1.5; for example, it is any value between 1:1.0-1.5 or any range between any two values, such as 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4 and 1:1.5, preferably 1:1.1-1.3.

[0068] The molar ratio of intermediate IV to the sulfonyl chloride compound is 1:1-6; for example, it is any value between 1:1-6 or any range between any two values, such as 1:1, 1:2, 1:3, 1:4, 1:5 and 1:6, preferably 1:1.5.

[0069] The molar ratio of intermediate IV to the condensation catalyst is 1:0.05-0.15; for example, it is any value between 1:0.05-0.15 or any range between any two values, such as 1:0.05, 1:0.07, 1:0.09, 1:0.1, 1:0.12, and 1:0.15, preferably 1:0.06-0.1.

[0070] The molar ratio of intermediate IV to the organic base is 1:1-10; for example, it is any value between 1:1-10 or any range between any two values, such as 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 and 1:10, preferably 1:1.5-2.

[0071] The synthesis method provided in this invention aims to overcome the shortcomings of existing patent and literature methods for synthesizing brofenoxam, such as long process routes, low overall yield, and cumbersome operations. It achieves continuous production of brofenoxam technical by using a one-pot method for the reductive methylation step and continuous production under ultrasonic treatment for the condensation step, thereby achieving energy saving, environmental friendliness, and stable product quality. The synthesis method provided in this invention features mild reaction conditions, short synthesis steps, and improved yield of brofenoxam.

[0072] Secondly, embodiments of the present invention provide an insecticide comprising brofenoxam prepared by the above-described method for synthesizing brofenoxam.

[0073] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0074] Example 1

[0075] This embodiment provides a method for synthesizing bromofenopram:

[0076] Add 400g of ionic liquid (1,2-dimethyl-3-propylimidazolium bis(trifluoromethanesulfonyl)imide) (CAS No.: 169051-76-7) (purchased from Beijing Bailingwei Technology Co., Ltd.), 16.6g (0.525mol) of paraformaldehyde (purchased from Sinopharm Chemical Reagent Co., Ltd.), 108.5g (0.5mol) of ethyl 2-fluoro-3-nitrobenzoate (I) (purchased from Zhengzhou Huiju Chemical Co., Ltd.), 3.0g (0.05mol) of acetic acid, 10.8g of 5% Pd / C (containing 50% water) (purchased from Shaanxi Ruike New Material Co., Ltd.), and 52.0g (0.5mol) of acetic anhydride to the high-pressure reactor. Purge the reactor with nitrogen to 2MPa, then release the pressure to atmospheric pressure. Repeat this cycle three times to replace the air in the reactor. Then, replace the nitrogen in the reactor with hydrogen three times using the same method. Start the stirrer, purge the reactor with hydrogen to 2 MPa, turn on the heater, and begin heating. When the temperature reaches 40°C, add hydrogen to bring the pressure up to 5 MPa to proceed with the reaction. After the reaction is complete, filter to recover the catalyst. Add acetic acid dropwise to the filtrate at room temperature until the pH is approximately 2, stir for 1 hour, filter, and the residue is the acetate of intermediate II, which can be directly used in the next reaction (yield 83%).

[0077] Intermediate II forms intermediate IV (see CN102119144B).

[0078] A DMF solution containing 2-fluoro-3-(N-methyl-benzamide)benzoic acid (Ⅳ) (278.5 g, 1 mol), 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline (Ⅴ) (493.9 g, 1.15 mol), p-nitrobenzenesulfonyl chloride (339.1 g, 1.5 mol), DMAP (12.4 g, 0.1 mol), and triethylamine (204 g, 2 mol) was heated to 150 °C using a plunger pump and then continuously pumped into a static mixer under 40 kHz ultrasonic waves. After the material remained in the mixer for 800 seconds, it entered a receiving tank. 5% dilute hydrochloric acid was added to the tank to adjust the pH to neutral, and 10% of the total volume of water was added dropwise. The mixture was cooled to allow crystallization, filtered, and the filter cake was washed with 5% dilute hydrochloric acid and dried to obtain bromoxynilbisamide (Ⅵ) with a purity of 99% and a single-step yield of 98%.

[0079] Example 2

[0080] This embodiment provides a method for synthesizing bromofenopram:

[0081] Add 400g of ionic liquid (1,2-dimethyl-3-propylimidazolium bis(trifluoromethanesulfonyl)imide), 18.2g (0.575mol) of paraformaldehyde, 108.5g (0.5mol) of ethyl 2-fluoro-3-nitrobenzoate (I), 3.0g (0.05mol) of acetic acid, 10.8g of 5% Pd / C (containing 50% water), and 52.0g (0.5mol) of acetic anhydride to a high-pressure reactor. Purge the reactor with nitrogen to 2MPa, then release the pressure to atmospheric pressure. Repeat this cycle three times to replace the air in the reactor. Then, replace the nitrogen in the reactor with hydrogen three times using the same method. Start stirring, purge the reactor with hydrogen to 2MPa, turn on the heater, and begin heating. When the temperature reaches 40℃, add hydrogen to bring the pressure to 5MPa and proceed with the reaction. After the reaction is complete, filter to recover the catalyst. Acetic acid was added dropwise to the filtrate at room temperature until the pH was about 2. The mixture was stirred for 1 hour and then filtered. The residue was the acetate of intermediate II, which was used directly in the next reaction (yield 85%).

[0082] A DMF solution containing 2-fluoro-3-(N-methyl-benzamide)benzoic acid (Ⅳ) (278.5 g, 1 mol), 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline (Ⅴ) (493.9 g, 1.15 mol), p-nitrobenzenesulfonyl chloride (339.1 g, 1.5 mol), DMAP (12.4 g, 0.1 mol), and triethylamine (204 g, 2 mol) was heated to 110 °C using a plunger pump and then continuously pumped into a static mixer under 40 kHz ultrasonic waves. After the material remained in the mixer for 800 seconds, it entered a receiving tank. 5% dilute hydrochloric acid was added to the tank to adjust the pH to neutral, and 10% of the total volume of water was added dropwise. The mixture was cooled to allow crystallization, filtered, and the filter cake was washed with 5% dilute hydrochloric acid and dried to obtain bromfenac-based dibenzonitramide (Ⅵ) with a purity of 97% and a single-step yield of 95%.

[0083] Example 3

[0084] This embodiment provides a method for synthesizing bromofenopram:

[0085] Add 400g of ionic liquid (1,2-dimethyl-3-propylimidazolium bis(trifluoromethanesulfonyl)imide), 19.7g (0.625mol) of paraformaldehyde, 108.5g (0.5mol) of ethyl 2-fluoro-3-nitrobenzoate (I), 3.0g (0.05mol) of acetic acid, 10.8g of 5% Pd / C (containing 50% water), and 52.0g (0.5mol) of acetic anhydride to a high-pressure reactor. Purge the reactor with nitrogen to 2MPa, then release the pressure to atmospheric pressure. Repeat this cycle three times to replace the air in the reactor. Then, replace the nitrogen in the reactor with hydrogen three times using the same method. Start stirring, purge the reactor with hydrogen to 2MPa, turn on the heater, and begin heating. When the temperature reaches 40℃, add hydrogen to bring the pressure to 5MPa and proceed with the reaction. After the reaction is complete, filter to recover the catalyst. Acetic acid was added dropwise to the filtrate at room temperature until the pH was about 2. The mixture was stirred for 1 hour and then filtered. The residue was the acetate of intermediate II, which was used directly in the next reaction (yield 87%).

[0086] A DMF solution containing 2-fluoro-3-(N-methyl-benzamide)benzoic acid (Ⅳ) (278.5 g, 1 mol), 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline (Ⅴ) (493.9 g, 1.15 mol), p-nitrobenzenesulfonyl chloride (339.1 g, 1.5 mol), DMAP (12.4 g, 0.1 mol), and triethylamine (204 g, 2 mol) was heated to 80°C via a plunger pump and then continuously pumped into a static mixer under 40 kHz ultrasonic waves. After the material remained in the mixer for 800 seconds, it entered a receiving tank. 5% dilute hydrochloric acid was added to the tank to adjust the pH to neutral, and 10% of the total volume of water was added dropwise. The mixture was cooled to allow crystallization, filtered, and the filter cake was washed with 5% dilute hydrochloric acid and dried to obtain bromfenac-methylbisamide (Ⅵ) with a purity of 95% and a single-step yield of 94%.

[0087] Example 4

[0088] This embodiment provides a method for synthesizing bromofenopram:

[0089] Add 400g of ionic liquid (1,2-dimethyl-3-propylimidazolium bis(trifluoromethanesulfonyl)imide), 21.3g (0.675mol) of paraformaldehyde, 108.5g (0.5mol) of ethyl 2-fluoro-3-nitrobenzoate (I), 3.0g (0.05mol) of acetic acid, 10.8g of 5% Pd / C (containing 50% water), and 52.0g (0.5mol) of acetic anhydride to a high-pressure reactor. Purge the reactor with nitrogen to 2MPa, then release the pressure to atmospheric pressure. Repeat this cycle three times to replace the air in the reactor. Then, replace the nitrogen in the reactor with hydrogen three times using the same method. Start stirring, purge the reactor with hydrogen to 2MPa, turn on the heater, and begin heating. When the temperature reaches 40℃, add hydrogen to bring the pressure to 5MPa and proceed with the reaction. After the reaction is complete, filter to recover the catalyst. Add acetic acid dropwise to the filtrate at room temperature until the pH is about 2, stir for 1 hour, filter, and the residue is the acetate of intermediate II, which can be used directly in the next reaction (yield 90%).

[0090] A DMF solution containing 2-fluoro-3-(N-methyl-benzamide)benzoic acid (Ⅳ) (278.5 g, 1 mol), 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline (Ⅴ) (493.9 g, 1.15 mol), p-nitrobenzenesulfonyl chloride (339.1 g, 1.5 mol), DMAP (12.4 g, 0.1 mol), and triethylamine (204 g, 2 mol) was heated to 80°C via a plunger pump and then continuously pumped into a static mixer under 40 kHz ultrasonic waves. After the material remained in the mixer for 600 seconds, it entered a receiving tank. 5% dilute hydrochloric acid was added to the tank to adjust the pH to neutral, and 10% of the total solution volume of water was added dropwise. The mixture was cooled to allow crystallization, filtered, and the filter cake was washed with 5% dilute hydrochloric acid and dried to obtain bromoxynil dibenzoic acid (Ⅵ) with a purity of 96.5% and a single-step yield of 96%.

[0091] Example 5

[0092] This embodiment provides a method for synthesizing bromofenopram:

[0093] Add 400g of ionic liquid (1,2-dimethyl-3-propylimidazolium bis(trifluoromethanesulfonyl)imide), 24.5g (0.775mol) of paraformaldehyde, 108.5g (0.5mol) of ethyl 2-fluoro-3-nitrobenzoate (I), 3.0g (0.05mol) of acetic acid, 10.8g of 5% Pd / C (containing 50% water), and 52.0g (0.5mol) of acetic anhydride to a high-pressure reactor. Purge the reactor with nitrogen to 2MPa, then release the pressure to atmospheric pressure. Repeat this cycle three times to replace the air in the reactor. Then, replace the nitrogen in the reactor with hydrogen three times using the same method. Start stirring, purge the reactor with hydrogen to 2MPa, turn on the heater, and begin heating. When the temperature reaches 40℃, add hydrogen to bring the pressure to 5MPa and proceed with the reaction. After the reaction is complete, filter to recover the catalyst. Acetic acid was added dropwise to the filtrate at room temperature until the pH was about 2. The mixture was stirred for 1 hour and then filtered. The residue was the acetate of intermediate II, which was used directly in the next reaction (yield 90.5%).

[0094] A DMF solution containing 2-fluoro-3-(N-methyl-benzamide)benzoic acid (Ⅳ) (278.5 g, 1 mol), 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline (Ⅴ) (493.9 g, 1.15 mol), p-nitrobenzenesulfonyl chloride (339.1 g, 1.5 mol), DMAP (12.4 g, 0.1 mol), and triethylamine (204 g, 2 mol) was heated to 80°C using a plunger pump and then continuously pumped into a static mixer under 40 kHz ultrasonic waves. After the material remained in the mixer for 200 seconds, it entered a receiving tank. 5% dilute hydrochloric acid was added to the tank to adjust the pH to neutral, and 10% of the total volume of water was added dropwise. The mixture was cooled to allow crystallization, filtered, and the filter cake was washed with 5% dilute hydrochloric acid and dried to obtain bromfenac-methylbisamide (Ⅵ) with a purity of 94.6% and a single-step yield of 92%.

[0095] Example 6

[0096] This embodiment provides a method for synthesizing bromofenopram:

[0097] Add 400g of ionic liquid (1,2-dimethyl-3-propylimidazolium bis(trifluoromethanesulfonyl)imide), 21.3g (0.675mol) of paraformaldehyde, 108.5g (0.5mol) of ethyl 2-fluoro-3-nitrobenzoate (I), 2.3g (0.038mol) of acetic acid, 10.8g of 5% Pd / C (50% water content), and 52.0g (0.5mol) of acetic anhydride to a high-pressure reactor. Purge the reactor with nitrogen to 2MPa, then release the pressure to atmospheric pressure. Repeat this cycle three times to replace the air in the reactor. Then, replace the nitrogen in the reactor with hydrogen three times using the same method. Start stirring, purge the reactor with hydrogen to 2MPa, turn on the heater, and begin heating. When the temperature reaches 40℃, add hydrogen to bring the pressure to 5MPa and proceed with the reaction. After the reaction is complete, filter to recover the catalyst. Acetic acid was added dropwise to the filtrate at room temperature until the pH was about 2. The mixture was stirred for 1 hour and then filtered. The residue was the acetate of intermediate II, which was used directly in the next reaction (yield 89%).

[0098] A DMF solution containing 2-fluoro-3-(N-methyl-benzamide)benzoic acid (Ⅳ) (278.5 g, 1 mol), 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline (Ⅴ) (493.9 g, 1.15 mol), p-nitrobenzenesulfonyl chloride (339.1 g, 1.5 mol), DMAP (12.4 g, 0.1 mol), and triethylamine (204 g, 2 mol) was heated to 80°C via a preheater and continuously pumped into a static mixer under 30 kHz ultrasonic waves. After the material remained in the mixer for 200 seconds, it entered a receiving tank. 5% dilute hydrochloric acid was added to the tank to adjust the pH to neutral, and 10% of the total solution volume of water was added dropwise. The mixture was cooled to allow crystallization, filtered, and the filter cake was washed with 5% dilute hydrochloric acid and dried to obtain bromfenac-based dibenzonitramide (Ⅵ) with a purity of 98% and a single-step yield of 95%.

[0099] Example 7

[0100] This embodiment provides a method for synthesizing bromofenopram:

[0101] Add 400g of ionic liquid (1,2-dimethyl-3-propylimidazolium bis(trifluoromethanesulfonyl)imide), 21.3g (0.675mol) of paraformaldehyde, 108.5g (0.5mol) of ethyl 2-fluoro-3-nitrobenzoate (I), 1.5g (0.025mol) of acetic acid, 10.8g of 5% Pd / C (50% water content), and 52.0g (0.5mol) of acetic anhydride to a high-pressure reactor. Purge the reactor with nitrogen to 2MPa, then release the pressure to atmospheric pressure. Repeat this cycle three times to replace the air in the reactor. Then, replace the nitrogen in the reactor with hydrogen three times using the same method. Start stirring, purge the reactor with hydrogen to 2MPa, turn on the heater, and begin heating. When the temperature reaches 40℃, add hydrogen to bring the pressure to 5MPa and proceed with the reaction. After the reaction is complete, filter to recover the catalyst. Acetic acid was added dropwise to the filtrate at room temperature until the pH was about 2. The mixture was stirred for 1 hour and then filtered. The residue was the acetate of intermediate II, which was used directly in the next reaction (yield 83%).

[0102] A DMF solution containing 2-fluoro-3-(N-methyl-benzamide)benzoic acid (Ⅳ) (278.5 g, 1 mol), 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline (Ⅴ) (493.9 g, 1.15 mol), p-nitrobenzenesulfonyl chloride (339.1 g, 1.5 mol), DMAP (12.4 g, 0.1 mol), and triethylamine (204 g, 2 mol) was heated to 80°C via a preheater and continuously pumped into a static mixer under 20 kHz ultrasonic waves. After the material remained in the mixer for 200 seconds, it entered a receiving tank. 5% dilute hydrochloric acid was added to the tank to adjust the pH to neutral, and 10% of the total volume of water was added dropwise. The mixture was cooled to allow crystallization, filtered, and the filter cake was washed with 5% dilute hydrochloric acid and dried to obtain bromoxynil dibenzoic acid (Ⅵ) with a purity of 91% and a single-step yield of 85%.

[0103] Example 8

[0104] This embodiment provides a method for synthesizing bromofenopram:

[0105] Add 400g of ionic liquid (1,2-dimethyl-3-propylimidazolium bis(trifluoromethanesulfonyl)imide), 21.3g (0.675mol) of paraformaldehyde, 108.5g (0.5mol) of ethyl 2-fluoro-3-nitrobenzoate (I), 3.0g (0.05mol) of acetic acid, 7.6g of 5% Pd / C (50% water content), and 52.0g (0.5mol) of acetic anhydride to a high-pressure reactor. Purge the reactor with nitrogen to 2MPa, then release the pressure to atmospheric pressure. Repeat this cycle three times to replace the air in the reactor. Then, replace the nitrogen in the reactor with hydrogen three times using the same method. Start stirring, purge the reactor with hydrogen to 2MPa, turn on the heater, and begin heating. When the temperature reaches 40℃, add hydrogen to bring the pressure to 5MPa and proceed with the reaction. After the reaction is complete, filter to recover the catalyst. Acetic acid was added dropwise to the filtrate at room temperature until the pH was about 2. The mixture was stirred for 1 hour and then filtered. The residue was the acetate of intermediate II, which was used directly in the next reaction (yield 86%).

[0106] A DMF solution containing 2-fluoro-3-(N-methyl-benzamide)benzoic acid (Ⅳ) (278.5 g, 1 mol), 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline (Ⅴ) (472.4 g, 1.1 mol), p-nitrobenzenesulfonyl chloride (339.1 g, 1.5 mol), DMAP (12.4 g, 0.1 mol), and triethylamine (204 g, 2 mol) was heated to 80°C using a plunger pump and then continuously pumped into a static mixer under 20 kHz ultrasonic waves. After the material remained in the mixer for 200 seconds, it entered a receiving tank. 5% dilute hydrochloric acid was added to the tank to adjust the pH to neutral, and 10% of the total volume of water was added dropwise. The mixture was cooled to allow crystallization, filtered, and the filter cake was washed with 5% dilute hydrochloric acid and dried to obtain bromoxynil dibenzoic acid (Ⅵ) with a purity of 95% and a single-step yield of 94%.

[0107] Example 9

[0108] This embodiment provides a method for synthesizing bromofenopram:

[0109] Add 400g of ionic liquid (1,2-dimethyl-3-propylimidazolium bis(trifluoromethanesulfonyl)imide), 21.3g (0.675mol) of paraformaldehyde, 108.5g (0.5mol) of ethyl 2-fluoro-3-nitrobenzoate (I), 3.0g (0.05mol) of acetic acid, 5.4g of 5% Pd / C (containing 50% water), and 52.0g (0.5mol) of acetic anhydride to a high-pressure reactor. Purge the reactor with nitrogen to 2MPa, then release the pressure to atmospheric pressure. Repeat this cycle three times to replace the air in the reactor. Then, replace the nitrogen in the reactor with hydrogen three times using the same method. Start stirring, purge the reactor with hydrogen to 2MPa, turn on the heater, and begin heating. When the temperature reaches 40℃, add hydrogen to bring the pressure to 5MPa and proceed with the reaction. After the reaction is complete, filter to recover the catalyst. Acetic acid was added dropwise to the filtrate at room temperature until the pH was about 2. The mixture was stirred for 1 hour and then filtered. The residue was the acetate of intermediate II, which was used directly in the next reaction (yield 82%).

[0110] A DMF solution containing 2-fluoro-3-(N-methyl-benzamide)benzoic acid (Ⅳ) (278.5 g, 1 mol), 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline (Ⅴ) (450.9 g, 1.05 mol), p-nitrobenzenesulfonyl chloride (339.1 g, 1.5 mol), DMAP (12.4 g, 0.1 mol), and triethylamine (204 g, 2 mol) was heated to 80°C via a plunger pump and then continuously pumped into a static mixer under 20 kHz ultrasonic waves. After the material remained in the mixer for 200 seconds, it entered a receiving tank. 5% dilute hydrochloric acid was added to the tank to adjust the pH to neutral, and 10% of the total solution volume of water was added dropwise. The mixture was cooled to allow crystallization, filtered, and the filter cake was washed with 5% dilute hydrochloric acid and dried to obtain bromoxynilbisamide (Ⅵ) with a purity of 92% and a single-step yield of 88%.

[0111] Example 10

[0112] This embodiment provides a method for synthesizing bromofenopram:

[0113] Add 400g of ionic liquid (1,2-dimethyl-3-propylimidazolium bis(trifluoromethanesulfonyl)imide), 21.3g (0.675mol) of paraformaldehyde, 108.5g (0.5mol) of ethyl 2-fluoro-3-nitrobenzoate (I), 3.0g (0.05mol) of acetic acid, 10.8g of 5% Pd / C (containing 50% water), and 52.0g (0.5mol) of acetic anhydride to a high-pressure reactor. Purge the reactor with nitrogen to 2MPa, then release the pressure to atmospheric pressure. Repeat this cycle three times to replace the air in the reactor. Then, replace the nitrogen in the reactor with hydrogen three times using the same method. Start stirring, purge the reactor with hydrogen to 2MPa, turn on the heater, and begin heating. When the temperature reaches 40℃, add hydrogen to bring the pressure to 3MPa and proceed with the reaction. After the reaction is complete, filter to recover the catalyst. Acetic acid was added dropwise to the filtrate at room temperature until the pH was about 2. The mixture was stirred for 1 hour and then filtered. The residue was the acetate of intermediate II, which was used directly in the next reaction (yield 87%).

[0114] A DMF solution containing 2-fluoro-3-(N-methyl-benzamide)benzoic acid (Ⅳ) (278.5 g, 1 mol), 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline (Ⅴ) (450.9 g, 1.05 mol), p-nitrobenzenesulfonyl chloride (339.1 g, 1.5 mol), DMAP (9.9 g, 0.08 mol), and triethylamine (204 g, 2 mol) was heated to 80°C using a plunger pump and then continuously pumped into a static mixer under 20 kHz ultrasonic waves. After the material remained in the mixer for 200 seconds, it entered a receiving tank. 5% dilute hydrochloric acid was added to the tank to adjust the pH to neutral, and 10% of the total volume of water was added dropwise. The mixture was cooled to allow crystallization, filtered, and the filter cake was washed with 5% dilute hydrochloric acid and dried to obtain bromoxynil dibenzoic acid (Ⅵ) with a purity of 96.5% and a single-step yield of 96%.

[0115] Example 11

[0116] This embodiment provides a method for synthesizing bromofenopram:

[0117] Add 400g of ionic liquid (1,2-dimethyl-3-propylimidazolium bis(trifluoromethanesulfonyl)imide), 21.3g (0.675mol) of paraformaldehyde, 108.5g (0.5mol) of ethyl 2-fluoro-3-nitrobenzoate (I), 3.0g (0.05mol) of acetic acid, 10.8g of 5% Pd / C (50% water content), and 52.0g (0.5mol) of acetic anhydride to a high-pressure reactor. Purge the reactor with nitrogen to 2MPa, then release the pressure to atmospheric pressure. Repeat this cycle three times to replace the air in the reactor. Then, replace the nitrogen in the reactor with hydrogen three times using the same method. Start stirring, purge the reactor with hydrogen to 0.1MPa, turn on the heater, and begin heating. When the temperature reaches 40℃, add hydrogen to 0.2MPa to proceed with the reaction. After the reaction is complete, filter to recover the catalyst. Acetic acid was added dropwise to the filtrate at room temperature until the pH was about 2. The mixture was stirred for 1 hour and then filtered. The residue was the acetate of intermediate II, which was used directly in the next reaction (yield 77%).

[0118] A DMF solution containing 2-fluoro-3-(N-methyl-benzamide)benzoic acid (Ⅳ) (278.5 g, 1 mol), 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline (Ⅴ) (450.9 g, 1.05 mol), p-nitrobenzenesulfonyl chloride (339.1 g, 1.5 mol), DMAP (7.4 g, 0.06 mol), and triethylamine (204 g, 2 mol) was heated to 80°C using a plunger pump and then continuously pumped into a static mixer under 20 kHz ultrasonic waves. After the material remained in the mixer for 200 seconds, it entered a receiving tank. 5% dilute hydrochloric acid was added to the tank to adjust the pH to neutral, and 10% of the total solution volume of water was added dropwise. The mixture was cooled to allow crystallization, filtered, and the filter cake was washed with 5% dilute hydrochloric acid and dried to obtain bromoxynil dibenzoic acid (Ⅵ) with a purity of 94% and a single-step yield of 93%.

[0119] Example 12

[0120] This embodiment provides a method for synthesizing bromofenopram:

[0121] Add 400g of ionic liquid (1,2-dimethyl-3-propylimidazolium bis(trifluoromethanesulfonyl)imide), 21.3g (0.675mol) of paraformaldehyde, 108.5g (0.5mol) of ethyl 2-fluoro-3-nitrobenzoate (I), 3.0g (0.05mol) of acetic acid, 10.8g of 5% Pd / C (containing 50% water), and 52.0g (0.5mol) of acetic anhydride to a high-pressure reactor. Purge the reactor with nitrogen to 2MPa, then release the pressure to atmospheric pressure. Repeat this cycle three times to replace the air in the reactor. Then, replace the nitrogen in the reactor with hydrogen three times using the same method. Start stirring, purge the reactor with hydrogen to 2MPa, turn on the heater, and begin heating. When the temperature reaches 80℃, add hydrogen to bring the pressure to 5MPa and proceed with the reaction. After the reaction is complete, filter to recover the catalyst. Add acetic acid dropwise to the filtrate at room temperature until the pH is about 2, stir for 1 hour, filter, and the residue is the acetate of intermediate II, which can be used directly in the next reaction (yield 90%).

[0122] A DMF solution containing 2-fluoro-3-(N-methyl-benzamide)benzoic acid (Ⅳ) (278.5 g, 1 mol), 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline (Ⅴ) (450.9 g, 1.05 mol), p-nitrobenzenesulfonyl chloride (339.1 g, 1.5 mol), DMAP (7.4 g, 0.06 mol), and triethylamine (183.6 g, 1.8 mol) was heated to 80°C using a plunger pump and then continuously pumped into a static mixer under 20 kHz ultrasonic waves. After the material remained in the mixer for 200 seconds, it entered a receiving tank. 5% dilute hydrochloric acid was added to the tank to adjust the pH to neutral, and 10% of the total volume of water was added dropwise. The mixture was cooled to allow crystallization, filtered, and the filter cake was washed with 5% dilute hydrochloric acid and dried to obtain bromoxynil dibenzoic acid (Ⅵ) with a purity of 97% and a single-step yield of 96%.

[0123] Example 13

[0124] This embodiment provides a method for synthesizing bromofenopram:

[0125] Add 400g of ionic liquid (1,2-dimethyl-3-propylimidazolium bis(trifluoromethanesulfonyl)imide), 21.3g (0.675mol) of paraformaldehyde, 108.5g (0.5mol) of ethyl 2-fluoro-3-nitrobenzoate (I), 3.0g (0.05mol) of acetic acid, 10.8g of 5% Pd / C (50% water content), and 52.0g (0.5mol) of acetic anhydride to a high-pressure reactor. Purge the reactor with nitrogen to 2MPa, then release the pressure to atmospheric pressure. Repeat this cycle three times to replace the air in the reactor. Then, replace the nitrogen in the reactor with hydrogen three times using the same method. Start stirring, purge the reactor with hydrogen to 2MPa, turn on the heater, and begin heating. When the temperature reaches 110℃, add hydrogen to bring the pressure to 5MPa and proceed with the reaction. After the reaction is complete, filter to recover the catalyst. Add acetic acid dropwise to the filtrate at room temperature until the pH is about 2, stir for 1 hour, filter, and the residue is the acetate of intermediate II, which can be used directly in the next reaction (yield 95%).

[0126] A DMF solution containing 2-fluoro-3-(N-methyl-benzamide)benzoic acid (Ⅳ) (278.5 g, 1 mol), 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline (Ⅴ) (450.9 g, 1.05 mol), p-nitrobenzenesulfonyl chloride (339.1 g, 1.5 mol), DMAP (7.4 g, 0.06 mol), and triethylamine (153 g, 1.5 mol) was heated to 80°C using a plunger pump and then continuously pumped into a static mixer under 20 kHz ultrasonic waves. After the material remained in the mixer for 200 seconds, it entered a receiving tank. 5% dilute hydrochloric acid was added to the tank to adjust the pH to neutral, and 10% of the total volume of water was added dropwise. The mixture was cooled to allow crystallization, filtered, and the filter cake was washed with 5% dilute hydrochloric acid and dried to obtain bromfenac-based dibenzoic acid (Ⅵ) with a purity of 95.5% and a single-step yield of 86%.

[0127] The NMR data for product (VI) are as follows:

[0128] HNMR(400MHz,DMSO-d6) δ10.69(s,1H), 8.41(s,1H),7.96(s,1H), 7.63 7.57(m, 2H), 7.42 7.20 (m, 6H), 3.37 (s, 3H).

[0129] Comparative Example 1

[0130] Brombutamide was prepared according to the synthesis method provided in Example 1, except that a pressurized hydrogenation-reduction methylation reaction was carried out, and the ionic liquid was replaced with methanol.

[0131] Add 400g methanol, 16.6g paraformaldehyde (0.525mol), ethyl 2-fluoro-3-nitrobenzene (Ⅰ) (108.5g, 0.5mol), acetic acid (3.0g, 0.05mol), 10.8g 5% Pd / C (50% water content), and acetic anhydride (52.0g, 0.5mol) to a high-pressure reactor. Purge the reactor with nitrogen to 2MPa, then release the pressure to atmospheric pressure. Repeat this cycle three times to replace the air in the reactor. Then, replace the nitrogen in the reactor with hydrogen three times using the same method. Start stirring, purge the reactor with hydrogen to 2MPa, turn on the heater, and begin heating. When the temperature reaches 40℃, add hydrogen to bring the pressure to 5MPa and proceed with the reaction. After the reaction is complete, filter to recover the catalyst. Add acetic acid dropwise to the filtrate at room temperature until the pH is approximately 2, stir for 1 hour, filter, and the residue is the acetate of intermediate II, which can be directly used in the next reaction (yield 33%).

[0132] Analysis shows that if the ionic liquid is changed to a conventional solvent, the yield of intermediate II will be significantly reduced, and it may even affect the yield and purity of the final product, bromoxynil dimethyl ether.

[0133] Comparative Example 2

[0134] Bromnipotentiamide was prepared according to the synthesis method provided in Example 1, except that an ultrasonic static mixer was replaced with a stirred reactor when carrying out the product condensation reaction.

[0135] Add 2-fluoro-3-(N-methyl-benzamide)benzoic acid (Ⅳ) (278.5 g, 1 mol), 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline (Ⅴ) (493.9 g, 1.15 mol), p-nitrobenzenesulfonyl chloride (339.1 g, 1.5 mol), DMAP (12.4 g, 0.1 mol), and DMF to a reaction vessel. Start stirring and rapidly add a DMF solution of triethylamine (204 g, 2 mol) dropwise over 30 min at 130℃±5℃. After the addition is complete, continue the reaction for 3 h. After the reaction is completed, transfer the reaction solution to a receiving vessel. Add 5% dilute hydrochloric acid to the vessel to adjust the pH to neutral. Add water at 10% of the total volume of the solution. Cool down to allow crystallization. Filter, wash the filter cake with 5% dilute hydrochloric acid, and dry to obtain bromoxynil dibenzoic acid (Ⅵ) with a purity of 97% and a single-step yield of 89%.

[0136] In this comparative example, after the addition of triethylamine, the reaction solution was analyzed by high-performance liquid chromatography (HPLC) after 800 seconds. The analysis revealed a large amount of reactant present, indicating that the reaction was almost incomplete. Approximately 80% of the reactant remained unreacted.

[0137] Analysis shows that without microwaves (ultrasound), the reaction hardly proceeds within the same time frame, with only about 20% of the reaction occurring. This demonstrates that using microwaves (ultrasound) can significantly accelerate the reaction.

[0138] Comparative Example 3

[0139] Brombutamide was prepared according to the synthesis method provided in Example 1, except that no condensing agent was used when performing the product condensation reaction.

[0140] A DMF solution containing 2-fluoro-3-(N-methyl-benzamide)benzoic acid (Ⅳ) (278.5 g, 1 mol), 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline (Ⅴ) (493.9 g, 1.15 mol), p-nitrobenzenesulfonyl chloride (339.1 g, 1.5 mol), and triethylamine (204 g, 2 mol) was heated to 150 °C using a plunger pump and then continuously pumped into a static mixer under 40 kHz ultrasonic waves. After the material remained in the mixer for 800 seconds, it entered a receiving tank. 5% dilute hydrochloric acid was added to the tank to adjust the pH to neutral, and 10% of the total volume of water was added dropwise. The mixture was cooled to allow crystallization, filtered, and the filter cake was washed with 5% dilute hydrochloric acid and dried to obtain bromoxynil dibenzoic acid (Ⅵ) with a purity of 93% and a single-step yield of 91%.

[0141] Analysis shows that the absence of a condensing agent will reduce the yield and purity of the product, thus affecting the performance of the final product.

[0142] Comparative Example 4

[0143] Bromnipotentiamide was prepared according to the synthesis method provided in Example 1, except that paraformaldehyde was replaced with a 37% aqueous formaldehyde solution during the pressurized hydrogenation-reduction methylation reaction.

[0144] Add ionic liquid (400g), 37% formaldehyde (42.5g, 0.525mol), ethyl 2-fluoro-3-nitrobenzoate (I) (108.5g, 0.5mol), acetic acid (3.0g, 0.05mol), 5% Pd / C (50% water content) 10.8g, and acetic anhydride (52.0g, 0.5mol) to a high-pressure reactor. Purge the reactor with nitrogen to 2MPa, then release the pressure to atmospheric pressure. Repeat this cycle three times to replace the air in the reactor. Then, replace the nitrogen in the reactor with hydrogen three times in the same way. Start stirring, purge the reactor with hydrogen to 2MPa, turn on the heater, and start heating. When the temperature reaches 40℃, add hydrogen to 5MPa and proceed with the reaction. After the reaction is complete, filter to recover the catalyst. Add acetic acid dropwise to the filtrate at room temperature until the pH is about 2, stir for 1 hour, filter, and the filter residue is the acetate of intermediate II, which can be directly used in the next reaction (yield 70.5%).

[0145] Analysis shows that if paraformaldehyde is replaced with a 37% aqueous formaldehyde solution, the yield of intermediate II will be significantly reduced.

[0146] Comparative Example 5

[0147] Bromnipotentiamide was prepared according to the synthesis method provided in Example 1, except that the Pd / C catalyst was changed to radium-niobium nickel during the pressurized hydrogenation-reduction methylation reaction.

[0148] Add ionic liquid (400g), paraformaldehyde (16.6g, 0.525mol), ethyl 2-fluoro-3-nitrobenzene (I) (108.5g, 0.5mol), acetic acid (3.0g, 0.05mol), radium-niobium-nickel catalyst (10.8g), and acetic anhydride (52.0g, 0.5mol) to a high-pressure reactor. Purge the reactor with nitrogen to 2MPa, then release the pressure to atmospheric pressure. Repeat this cycle three times to replace the air in the reactor. Then, replace the nitrogen in the reactor with hydrogen three times in the same manner. Start stirring, purge the reactor with hydrogen to 2MPa, turn on the heater, and begin heating. When the temperature reaches 40℃, add hydrogen to bring the pressure to 5MPa and proceed with the reaction. After the reaction is complete, filter to recover the catalyst. Add acetic acid dropwise to the filtrate at room temperature until the pH is approximately 2, stir for 1 hour, and filter. The residue is the acetate of intermediate II, which can be directly used in the next reaction (yield 75%).

[0149] Analysis shows that if the Pd / C catalyst is changed to a radium-niobium-nickel catalyst, the yield of intermediate II will decrease.

[0150] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method of synthesizing broflanilide, characterized by, include: Ethyl 2-fluoro-3-nitrobenzoate, paraformaldehyde, Pd / C catalyst, acidic compound and ionic liquid were mixed and subjected to a pressurized hydrogenation-reduction methylation reaction; The conditions for the pressurized hydrogenation-reduction methylation reaction include: pressure of 0.1-10 MPa, temperature of 30-160℃, and time of 1-24 h. The acidic compounds are acetic acid and acetic anhydride; the ionic liquid is 1,2-dimethyl-3-propylimidazolium bis(trifluoromethanesulfonyl)imide; The molar ratio of ethyl 2-fluoro-3-nitrobenzoate to paraformaldehyde is 1:1.3-1.8; The molar ratio of ethyl 2-fluoro-3-nitrobenzoate to the Pd / C catalyst is 1:0.01-0.3; The molar ratio of ethyl 2-fluoro-3-nitrobenzoate to acetic acid is 1:0.01-0.15; The molar ratio of ethyl 2-fluoro-3-nitrobenzoate to acetic anhydride is 1:0.8-1.2; The intermediate II formed by the pressure hydrogenation reduction methylation reaction is then converted to intermediate IV according to the following synthetic pathway: Next, intermediate IV, 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline, sulfonyl chloride compounds, condensation catalyst, organic base and solvent are mixed and subjected to a continuous catalytic condensation reaction under ultrasonic treatment; the sulfonyl chloride compounds include at least one of methylsulfonyl chloride, p-methylbenzenesulfonyl chloride and p-nitrobenzenesulfonyl chloride; The conditions for the continuous catalytic condensation reaction include: temperature of 10-180℃, ultrasonic time of 5-1200s, and ultrasonic frequency of 20-40KHz. The molar ratio of intermediate IV to 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline is 1:1.0-1.5; The molar ratio of intermediate IV to the sulfonyl chloride compound is 1:1-6; The molar ratio of intermediate IV to the condensation catalyst is 1:0.05-0.15; The molar ratio of intermediate IV to the organic base is 1:1-10.

2. The method for synthesizing brofentanil according to claim 1, characterized in that, The conditions for pressurized hydrogenation-reductive methylation reaction include: pressure of 0.2-5 MPa, temperature of 40-110℃, and time of 1-15 h.

3. The method for synthesizing brofentanil according to claim 1, characterized in that, The acetic acid content is 95-99%; The content of the acetic anhydride is greater than 98%; The content of the Pd / C catalyst is 1-10%.

4. The method of synthesizing broflanapyr according to claim 1, wherein, The acetic acid content is 99%; the Pd / C catalyst content is 5%.

5. The method of synthesizing broflanapyr according to claim 1, wherein, The molar ratio of ethyl 2-fluoro-3-nitrobenzoate to paraformaldehyde is 1:1.4-1.6; The molar ratio of ethyl 2-fluoro-3-nitrobenzoate to the Pd / C catalyst is 1:0.05-0.1; The molar ratio of ethyl 2-fluoro-3-nitrobenzoate to acetic acid is 1:0.05-0.

1.

6. The method for synthesizing brofentanil according to claim 1, characterized in that, The conditions for continuous catalytic condensation reaction include: temperature of 30-160℃ and ultrasonic time of 10-800s.

7. The method for synthesizing brofentanil according to claim 1, characterized in that, The condensation catalyst includes at least one of DMAP, 4-PPY and HOBT; The organic base includes at least one of triethylamine, pyridine, 3-methylpyridine, sodium methoxide, and potassium tert-butoxide; The solvent is selected from at least one or a mixture of at least two of the following: aromatic solvents, ester solvents, nitrile solvents, alcohol solvents, ether solvents, amide solvents, and alkane solvents.

8. The method of synthesizing broflanapyr according to claim 1, wherein, The sulfonyl chloride compound is p-nitrobenzenesulfonyl chloride; The condensation catalyst is DMAP; The organic base is triethylamine; The solvent is selected from any one or a mixture of at least two of acetonitrile, toluene, chlorobenzene, ethyl acetate, sec-butyl acetate, dichloroethane, and dichloromethane.

9. The method of synthesizing broflanapyr according to claim 6, wherein, The molar ratio of intermediate IV to 2-trifluoromethyl-4-perfluoroisopropyl-6-bromoaniline is 1:1.1-1.3; The molar ratio of intermediate IV to the sulfonyl chloride compound is 1:1.5; The molar ratio of intermediate IV to the condensation catalyst is 1:0.06-0.1; The molar ratio of intermediate IV to the organic base is 1:1.5-2.

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