A method for synthesizing 3,5-dibromo-4-hydroxycinnamic acid

Abstract

The application relates to the technical field of chemical synthesis, and discloses a synthesis method of 3,5-dibromo-4-hydroxybenzonitrile; the synthesis method of 3,5-dibromo-4-hydroxybenzonitrile comprises the following steps: mixing p-hydroxybenzoic acid and a brominating agent in solvent I to obtain a mixture, adding an acidic reagent, carrying out reaction I, and obtaining 3,5-dibromo-4-hydroxybenzoic acid; mixing 3,5-dibromo-4-hydroxybenzoic acid and a chloride in solvent II, carrying out reaction II, and obtaining a reaction liquid containing 3,5-dibromo-4-hydroxybenzoyl chloride; adding an alkaline reagent to the reaction liquid containing 3,5-dibromo-4-hydroxybenzoyl chloride, carrying out reaction III, and obtaining 3,5-dibromo-4-hydroxybenzamide; contacting 3,5-dibromo-4-hydroxybenzamide with a dehydrating agent in solvent III, carrying out reaction IV, and obtaining 3,5-dibromo-4-hydroxybenzonitrile; the raw material p-hydroxybenzoic acid used in the application is cheap and easy to obtain, the raw material cost is low, the safety is high, the environmental protection pressure is small, and the technology is self-controllable.

Description

Technical Field

[0001] This invention relates to the field of chemical synthesis technology, and more specifically to a method for synthesizing 3,5-dibromo-4-hydroxybenzonitrile. Background Technology

[0002] 3,5-Dibromo-4-hydroxybenzonitrile (Bromoxynil), also known as bromobenzonitrile, has the chemical formula C7H3Br2NO and CAS number 1689-84-5. It appears as a grayish-white crystalline powder with a melting point of 189-191℃, a boiling point of 265.6±40.0℃, and a density of 2.2±0.1 g / cm³. 3 It has a flash point of 114.4±27.3℃. This substance is flammable and decomposes upon heating to produce toxic fumes such as nitrogen oxides and bromides. It is mainly used as a post-emergence herbicide for cereals, flax, and other crops to control broadleaf weeds. The oral LD50 for mice is 110 mg / kg, and the oral LD50 for rats is 190 mg / kg. It is irritating to the eyes, skin, and mucous membranes. It should be stored in a cool, dry place in a sealed container, away from oxidizers and strong acids. Currently, the synthesis of bromobenzonitrile uses p-cyanophenol (CN102333758 A, Chemistry–A European Journal 23.5 (2017): 1044-1047.) and 3,5-dibromo-4-hydroxybenzaldehyde as starting materials. These two raw materials are fine chemicals, and their preparation is subject to patent restrictions and technological barriers, while their purchase is expensive.

[0003] Chinese patent CN103787918A discloses a method for synthesizing bromobenzonitrile, comprising the following steps: (I) Synthesis of p-hydroxybenzonitrile; a. Select a 250mL three-necked flask, the three-necked flask being equipped with a stirrer, a thermometer, and a reflux condenser. b. Weigh 13-14g of p-hydroxybenzoic acid, 8-10g of urea, 19-20g of aminosulfonic acid, and 40-60mL of p-cresol and add them sequentially to the three-necked flask in step a, and start stirring. c. Heat the mixture in the flask in step b, slowly raising the temperature to 140-160℃ and holding the temperature for 35-45min. d. After the holding temperature reaction in step c is completed, raise the temperature again to 180-200℃, add another 2-4g of urea, and continue holding the temperature for 55-65min. e. Filter the mixture after the reaction in step d, wash the filter residue with a hot melt solvent, combine the filtrates, and distill under reduced pressure to obtain p-hydroxybenzonitrile. (II) Bromination reaction of p-hydroxybenzonitrile; a. Select a 250mL four-necked flask, which is equipped with a stirrer, thermometer, reflux condenser, and dropping funnel. b. Weigh 11-12g of p-hydroxybenzonitrile, 35-45mL of 95% ethanol, 10-20mL of water, and 0.05-0.15g of concentrated hydrochloric acid and add them sequentially to the flask in step a. Start stirring until the p-hydroxybenzonitrile is fully dissolved. c. Heat the mixture in the flask in step b, slowly raise the temperature to 30-40℃, and then add 16-17g of bromine dropwise over 55-65 minutes, continuing the reaction. d. After the reaction solution in step c has decolorized, add 3.5-4.5g of sodium chlorate and 5-7mL of water to the flask, and continue the reaction for 180 minutes. e. Filter the mixture from step d, wash with water until the solution is neutral, and then dry to obtain the bromobenzonitrile finished product, which is then packaged and stored. However, this method uses expensive raw materials, and liquid bromine is a hazardous reagent, resulting in insufficient safety and environmental friendliness. Summary of the Invention

[0004] The purpose of this invention is to address the problems of existing methods for synthesizing 3,5-dibromo-4-hydroxybenzonitrile, which require hazardous reagents such as bromine and involve intense exothermic reactions during bromination, posing significant production challenges. This invention provides a method for synthesizing 3,5-dibromo-4-hydroxybenzonitrile that avoids the use of expensive raw materials such as p-hydroxybenzonitrile and dibromoaldehyde. The raw material used in this invention, p-hydroxybenzoic acid, is inexpensive and readily available. Furthermore, bromination, acylation, amination, and dehydration are all classic reactions with mild and mature operating conditions, ensuring safe operation, few side reactions, and ease of control and scale-up. Simultaneously, it avoids the use of hazardous reagent liquid bromine, resulting in lower raw material costs, higher safety, less environmental pressure, and a more competitive overall production cost. Moreover, the technology is independently controllable.

[0005] To achieve the above objectives, the present invention specifically adopts the following technical solution: This invention provides a method for synthesizing 3,5-dibromo-4-hydroxybenzonitrile, comprising the following steps: In solvent I, p-hydroxybenzoic acid and a brominating agent are mixed to obtain a mixture. An acidic reagent is added, and reaction I is carried out to obtain 3,5-dibromo-4-hydroxybenzoic acid. In solvent II, 3,5-dibromo-4-hydroxybenzoic acid and chloride are mixed and reaction II is carried out to obtain a reaction solution containing 3,5-dibromo-4-hydroxybenzoyl chloride; In a reaction solution containing 3,5-dibromo-4-hydroxybenzoyl chloride, an alkaline reagent is added to carry out reaction III to obtain 3,5-dibromo-4-hydroxybenzoamide; In solvent III, 3,5-dibromo-4-hydroxybenzamide and a dehydrating agent are contacted and then reaction IV is carried out to obtain 3,5-dibromo-4-hydroxybenzonitrile.

[0006] In this invention, the reaction pathway of the synthesis method is as follows: .

[0007] Furthermore, solvent I is selected from at least one of water, dichloromethane, ethanol, and 1,2-dichloroethane.

[0008] Further, the brominating agent is selected from a combination of sodium bromide and sodium bromate or a combination of sodium bromide and sodium chlorate; preferably, the mass ratio of sodium bromide to sodium bromate in the combination of sodium bromide and sodium bromate is 1:(0.8-2.0); and / or, the mass ratio of sodium bromide to sodium chlorate in the combination of sodium bromide and sodium chlorate is 1:(0.8-2.0).

[0009] Further, the mass ratio of p-hydroxybenzoic acid, brominating agent, hydrochloric acid and solvent I is (30-50):(85-105):(75-85):(220-260).

[0010] Further, the acidic reagent is selected from at least one of hydrochloric acid solution, sulfuric acid solution, phosphoric acid solution, trichloroacetic acid solution, and acetic acid; preferably, the mass concentration of the hydrochloric acid solution is 30% to 40%; and / or, the mass concentration of the sulfuric acid solution is 20% to 30%; and / or, the mass concentration of the phosphoric acid solution is 25% to 45%; and / or, the mass concentration of the trichloroacetic acid solution is 40% to 50%.

[0011] Furthermore, the method also includes cooling the mixture to 10°C–15°C before adding the acidic reagent.

[0012] Furthermore, the conditions for reaction I include: a temperature of 20℃~30℃, a time of 3h~5h, and a stirring rate of 100rpm~300rpm.

[0013] In this invention, after reaction I is completed, the process further includes adding an extractant such as dichloromethane to the reaction solution, stirring to separate the layers, and concentrating the organic layer under reduced pressure to obtain 3,5-dibromo-4-hydroxybenzoic acid.

[0014] Furthermore, solvent II is selected from at least one of toluene, dichloromethane, 1,2-dichloroethane, chlorobenzene, and tetrahydrofuran.

[0015] Furthermore, the chloride is selected from at least one of thionyl chloride, oxalyl chloride, and cyanuryl chloride.

[0016] Further, the mass ratio of the 3,5-dibromo-4-hydroxybenzoic acid, chloride, and solvent II is (30-50):(10-25):200.

[0017] Furthermore, the conditions for reaction II include: a temperature of 60℃ to 80℃, a time of 0.2h to 1h, and a stirring rate of 100rpm to 300rpm.

[0018] In this invention, after reaction II is completed, a step of removing the solvent under reduced pressure is also included.

[0019] Further, the alkaline reagent is selected from at least one of ammonia water, ammonia gas, ammonium acetate, ammonium carbonate, ammonium carbamate, and methylamine aqueous solution; preferably, the mass concentration of the ammonia water is 30% to 40%; and / or, the mass concentration of the methylamine aqueous solution is 20% to 40%.

[0020] Furthermore, the mass ratio of the reaction solution containing 3,5-dibromo-4-hydroxybenzoic acid to the alkaline reagent is 120:(2-10).

[0021] Furthermore, in the reaction solution containing 3,5-dibromo-4-hydroxybenzoic acid, the mass percentage of 3,5-dibromo-4-hydroxybenzoic acid is 30% to 40%, preferably 33.35%, and the content of 3,5-dibromo-4-hydroxybenzoic acid is 95.5%.

[0022] Furthermore, the conditions for reaction III include: a temperature of 0°C to 5°C and a time of 3 to 5 hours.

[0023] In this invention, after reaction III is completed, the reaction further includes washing with water in the reaction solution, taking the upper organic layer, and recrystallizing it, i.e., heating to 80℃~90℃, holding at that temperature for 0.5h~1h, and then slowly cooling to 20℃~30℃ to precipitate crystals, which are 3,5-dibromo-4-hydroxybenzamide.

[0024] Furthermore, solvent III is selected from at least one of dichloromethane, acetonitrile, tetrahydrofuran, toluene, and 1,2-dichloroethane.

[0025] Further, the dehydrating agent is selected from at least one of the following: trifluorosulfonic anhydride / triethylamine system, phosphorus oxychloride / pyridine system, p-toluenesulfonyl chloride / diisopropylethylamine system, and Burgess reagent; preferably, in the trifluorosulfonic anhydride / triethylamine system, the mass ratio of trifluorosulfonic anhydride to triethylamine is 1:(0.5-1.0); and / or, in the phosphorus oxychloride / pyridine system, the mass ratio of phosphorus oxychloride to pyridine is 1:(0.5-1.0); and / or, in the p-toluenesulfonyl chloride / diisopropylethylamine system, the mass ratio of p-toluenesulfonyl chloride to diisopropylethylamine is 1:(0.5-1.0).

[0026] Further, the mass ratio of the 3,5-dibromo-4-hydroxybenzamide, the dehydrating agent, and solvent III is (20-40):(40-60):150.

[0027] Furthermore, the contact conditions include a temperature of 0°C to 5°C.

[0028] Furthermore, the conditions for reaction IV include: a temperature of 20°C to 30°C and a time of 3 to 5 hours.

[0029] In this invention, after reaction IV is completed, an extractant such as water is added to the reaction solution, and after extraction and separation, the organic layer is desolventized and evaporated to obtain 3,5-dibromo-4-hydroxybenzonitrile.

[0030] The beneficial effects of this invention are as follows: This invention uses p-hydroxybenzoic acid as a starting material, which is inexpensive and readily available. The process involves 3,5-dibromo-4-hydroxybenzoic acid and a corresponding amide intermediate, followed by hydrolysis to obtain the final product, forming a novel method for synthesizing bromobenzonitrile. The reaction conditions are mature, and bromination can be carried out in a safer aqueous phase. The synthesis method described in this invention features low raw material costs, high safety, and minimal environmental impact, resulting in a more competitive overall production cost. Furthermore, the technology is independently controllable. Detailed Implementation

[0031] 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. Obviously, the described embodiments are some embodiments of the present invention, but not all embodiments.

[0032] Based on the embodiments of this invention, all other embodiments obtained by those skilled in the art without inventive effort are within the scope of protection of this invention.

[0033] Example 1 A method for synthesizing 3,5-dibromo-4-hydroxybenzonitrile Preparation of 3,5-dibromo-4-hydroxybenzoic acid: In a 1000 mL four-necked flask, 40 g of p-hydroxybenzoic acid, 46.3 g of sodium bromide, 49.0 g of sodium bromate, 204.4 g of dichloromethane, and 43.3 g of water were added sequentially, and stirring was started (200 rpm) for 5 min. The mixture was cooled to 12 °C in an ice bath, and 79.0 g of a 30% hydrochloric acid aqueous solution was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature (25 °C) for 4 h. A sample was taken for analysis, and the p-hydroxybenzoic acid concentration was 0.5% (normalized area of ​​HPLC), indicating the reaction was complete. 100 g of dichloromethane was added, and the mixture was stirred to separate the layers. The organic layer was concentrated under reduced pressure to obtain 83.04 g of crude product (normalized area of ​​HPLC), with a yield of 90% and a purity of 93%.

[0034] Preparation of 3,5-dibromo-4-hydroxybenzoyl chloride: 40 g of 3,5-dibromo-4-hydroxybenzoic acid and 200 g of toluene were added sequentially to a 500 mL four-necked flask. Stirring was started (200 rpm) for 5 min, and the temperature was raised to 70 °C. 19.4 g of thionyl chloride was slowly added dropwise, and the mixture was kept at this temperature for 0.5 h after the addition was complete. A sample was taken for analysis; the 3,5-dibromo-4-hydroxybenzoic acid concentration was 0.72% (normalized area of ​​liquid chromatography), indicating the reaction was complete. Excess thionyl chloride was removed by desolvation under reduced pressure to obtain 120 g of toluene solution containing 3,5-dibromo-4-hydroxybenzoyl chloride (containing 40.02 g of 3,5-dibromo-4-hydroxybenzoyl chloride, yield 96.5%, purity 95.5%).

[0035] Preparation of 3,5-dibromo-4-hydroxybenzoamide: 120 g of toluene solution containing 3,5-dibromo-4-hydroxybenzoyl chloride (containing 40.02 g of 3,5-dibromo-4-hydroxybenzoyl chloride, purity 95.5%) was added to a 500 mL four-necked flask, and the temperature was lowered to 0 °C. 4.35 g of ammonia water (mass concentration 30%) was slowly added dropwise, and the mixture was kept at this temperature for 4 h after the addition was complete. A sample was taken for analysis; the concentration of 3,5-dibromo-4-hydroxybenzoyl chloride was 0.62% (normalized area of ​​liquid chromatography), indicating the reaction was complete. 100 g of water was added, and the mixture was washed. The upper organic solution was heated to 80 °C and kept at this temperature for 0.5 h, then slowly cooled to 25 °C to induce crystallization, yielding 32.05 g of pure 3,5-dibromo-4-hydroxybenzoamide, with a yield of 90% and a purity of 99% (normalized area of ​​liquid chromatography).

[0036] Preparation of 3,5-dibromo-4-hydroxybenzonitrile: 30 g of 3,5-dibromo-4-hydroxybenzoamide and 150 g of dichloromethane were added sequentially to a 500 mL four-necked flask. The mixture was stirred until dissolved and cooled to 3 °C. 31.25 g of trifluoromethanesulfonic anhydride was slowly added dropwise while maintaining the temperature at 3 °C. After the addition was complete, 20.44 g of triethylamine was slowly added dropwise while maintaining the temperature at 3 °C. After the addition was complete, the mixture was brought to room temperature (25 °C) and kept at this temperature for 4 hours. A sample was taken for analysis; the 3,5-dibromo-4-hydroxybenzoamide concentration was 0.83% (normalized area of ​​liquid chromatography), indicating the reaction was complete. 100 g of water was added, and the mixture was extracted and separated. The organic layer was desolventized and evaporated to dryness, yielding 25.11 g of 3,5-dibromo-4-hydroxybenzonitrile with a purity of 98% and a yield of 88%.

[0037] The yield is calculated as follows: 25.11g (3,5-dibromo-4-hydroxybenzonitrile) * 98% (content) / 30g (3,5-dibromo-4-hydroxybenzonitrile) * 99% (content) / 294.87 (relative molecular mass of 3,5-dibromo-4-hydroxybenzonitrile) * 276.92 (relative molecular mass of 3,5-dibromo-4-hydroxybenzonitrile).

[0038] Example 2 A method for synthesizing 3,5-dibromo-4-hydroxybenzonitrile The synthesis method is the same as in Example 1, except that... Preparation of 3,5-dibromo-4-hydroxybenzoic acid: 40 g of p-hydroxybenzoic acid, 53 g of sodium bromide, 49.0 g of sodium bromate, 204.4 g of dichloromethane, and 43.3 g of water were added sequentially to a 1000 mL four-necked flask. Stirring was started (200 rpm) for 5 min. The mixture was cooled to 12 °C in an ice bath, and 79.0 g of a 30% hydrochloric acid aqueous solution was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature (25 °C) for 4 h. A sample was taken for analysis; the p-hydroxybenzoic acid concentration was 1.3%, indicating the reaction was complete. 100 g of dichloromethane was added, and the mixture was stirred to separate the layers. The organic layer was concentrated under reduced pressure to obtain 78.42 g of crude product, with a yield of 85% and a purity of 93%.

[0039] Following the method in Example 1, 24.88 g of 3,5-dibromo-4-hydroxybenzonitrile was finally prepared, with a purity of 98% and a yield of 87.2%.

[0040] Example 3 A method for synthesizing 3,5-dibromo-4-hydroxybenzonitrile The synthesis method is the same as in Example 1, except that... Preparation of 3,5-dibromo-4-hydroxybenzoyl chloride: 40 g of 3,5-dibromo-4-hydroxybenzoic acid and 200 g of toluene were added sequentially to a 500 mL four-necked flask. Stirring was started (200 rpm) for 5 min, and the temperature was raised to 70 °C. 12.3 g of thionyl chloride was slowly added dropwise, and the mixture was kept at this temperature for 0.5 h after the addition was complete. A sample was taken for analysis; the content of 3,5-dibromo-4-hydroxybenzoic acid was 1.6%, indicating the reaction was complete. Excess thionyl chloride was removed by desolvation under reduced pressure to obtain 108 g of toluene solution containing 3,5-dibromo-4-hydroxybenzoyl chloride (containing 35.25 g of 3,5-dibromo-4-hydroxybenzoyl chloride, yield 80.4%, purity 90.3%).

[0041] Following the method in Example 1, 24.46 g of 3,5-dibromo-4-hydroxybenzonitrile was finally prepared, with a purity of 95% and a yield of 83.1%.

[0042] Example 4 A method for synthesizing 3,5-dibromo-4-hydroxybenzonitrile The synthesis method is the same as in Example 1, except that... Preparation of 3,5-dibromo-4-hydroxybenzoamide: 120 g of toluene solution containing 3,5-dibromo-4-hydroxybenzoyl chloride (containing 40.02 g of 3,5-dibromo-4-hydroxybenzoyl chloride, purity 95.5%) was added to a 500 mL four-necked flask, and the temperature was lowered to 0 °C. 8.6 g of methylamine aqueous solution (mass concentration 30%) was slowly added dropwise, and the mixture was kept at this temperature for 4 h after the addition was complete. A sample was taken for analysis; the concentration of 3,5-dibromo-4-hydroxybenzoyl chloride was 2.3%, indicating the reaction was complete. 100 g of water was added, and the mixture was washed. The upper organic solution was heated to 80 °C and kept at this temperature for 0.5 h, then slowly cooled to 25 °C to induce crystallization, yielding 30.38 g of pure 3,5-dibromo-4-hydroxybenzoamide, with a yield of 83% and a purity of 98.3%.

[0043] Example 5 A method for synthesizing 3,5-dibromo-4-hydroxybenzonitrile The synthesis method is the same as in Example 1, except that... Preparation of 3,5-dibromo-4-hydroxybenzonitrile: 30 g of 3,5-dibromo-4-hydroxybenzoamide and 150 g of dichloromethane were added sequentially to a 500 mL four-necked flask. The mixture was stirred until dissolved and cooled to 3 °C. 26.5 g of trifluoromethanesulfonic anhydride was slowly added dropwise while maintaining the temperature at 3 °C. After the addition was complete, 17.5 g of triethylamine was slowly added dropwise while maintaining the temperature at 3 °C. After the addition was complete, the mixture was brought to room temperature (25 °C) and kept at this temperature for 4 hours. A sample was taken for analysis; the content of 3,5-dibromo-4-hydroxybenzoamide was 1.86%, indicating the reaction was complete. 100 g of water was added, and the mixture was extracted and separated into layers. The organic layer was desolventized and evaporated to dryness, yielding 21.75 g of 3,5-dibromo-4-hydroxybenzonitrile, with a purity of 90% and a yield of 70.2%.

[0044] Comparative Example 1 A method for synthesizing 3,5-dibromo-4-hydroxybenzonitrile The synthesis method is the same as in Example 1, except that... Preparation of 3,5-dibromo-4-hydroxybenzoic acid: 40 g of p-hydroxybenzoic acid, 204.4 g of dichloromethane, and 43.3 g of water were added sequentially to a 1000 mL four-necked flask, and stirring was started (200 rpm) for 5 min. The mixture was cooled to 12 °C in an ice bath, and 92.8 g of bromine was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature (25 °C) for 4 h. A sample was taken for analysis, and the p-hydroxybenzoic acid content was 2.5%, indicating the reaction was complete. 100 g of dichloromethane was added, and the mixture was stirred to separate the layers. The organic layer was concentrated under reduced pressure to obtain 79.9 g of crude product, with a yield of 82% and a purity of 88%.

[0045] Comparative Example 2 A method for synthesizing 3,5-dibromo-4-hydroxybenzonitrile The synthesis method is the same as in Example 1, except that... Preparation of 3,5-dibromo-4-hydroxybenzoyl chloride: 40 g of 3,5-dibromo-4-hydroxybenzoic acid and 200 g of toluene were added sequentially to a 500 mL four-necked flask. Stirring was started (200 rpm) for 5 min, and the temperature was raised to 70 °C. 11.2 g of phosphorus trichloride was slowly added dropwise, and the mixture was kept at this temperature for 0.5 h after the addition was complete. A sample was taken for analysis; the content of 3,5-dibromo-4-hydroxybenzoic acid was 1.63%, indicating the reaction was complete. Excess phosphorus trichloride was removed by desolvation under reduced pressure to obtain 115 g of toluene solution containing 3,5-dibromo-4-hydroxybenzoyl chloride (containing 36.44 g of 3,5-dibromo-4-hydroxybenzoyl chloride, yield 76%, purity 82.6%).

[0046] Comparative Example 3 A method for synthesizing 3,5-dibromo-4-hydroxybenzonitrile The synthesis method is the same as in Example 1, except that... Preparation of 3,5-dibromo-4-hydroxybenzoic acid: 40 g of p-hydroxybenzoic acid, 46.3 g of sodium bromide, 204.4 g of dichloromethane, and 43.3 g of water were added sequentially to a 1000 mL four-necked flask. Stirring was started (200 rpm) for 5 min. The mixture was then cooled to 12 °C in an ice bath, and 79.0 g of a 30% hydrochloric acid aqueous solution was slowly added dropwise. After the addition was complete, the mixture was stirred at room temperature (25 °C) for 4 h. A sample was then taken for testing; no reaction was observed.

[0047] Comparative Example 4 A method for synthesizing 3,5-dibromo-4-hydroxybenzonitrile The synthesis method is the same as in Example 1, except that... Preparation of 3,5-dibromo-4-hydroxybenzoamide: 120 g of toluene solution containing 3,5-dibromo-4-hydroxybenzoyl chloride (containing 40.02 g of 3,5-dibromo-4-hydroxybenzoyl chloride, purity 95.5%) was added to a 500 mL four-necked flask, and the temperature was lowered to 0 °C. 14.8 g of 70% ethylamine aqueous solution was slowly added dropwise, and the mixture was kept at this temperature for 4 h after the addition was complete. A sample was taken for analysis; the concentration of 3,5-dibromo-4-hydroxybenzoyl chloride was 0.95%, indicating the reaction was complete. 100 g of water was added, and the mixture was washed. The upper organic solution was heated to 80 °C and kept at this temperature for 0.5 h, then slowly cooled to 25 °C to induce crystallization, yielding 32.20 g of pure 3,5-dibromo-4-hydroxybenzoamide, with a yield of 87% and a purity of 97.2%.

[0048] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the description of the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention should be considered equivalent substitutions and are included within the protection scope of the present invention.

[0049] The above are merely preferred embodiments of the present invention and are not intended to limit the present 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 for synthesizing 3,5-dibromo-4-hydroxybenzonitrile, characterized in that, Includes the following steps: In solvent I, p-hydroxybenzoic acid and a brominating agent are mixed to obtain a mixture. An acidic reagent is added, and reaction I is carried out to obtain 3,5-dibromo-4-hydroxybenzoic acid. In solvent II, 3,5-dibromo-4-hydroxybenzoic acid and chloride are mixed and reaction II is carried out to obtain a reaction solution containing 3,5-dibromo-4-hydroxybenzoyl chloride; In a reaction solution containing 3,5-dibromo-4-hydroxybenzoyl chloride, an alkaline reagent is added to carry out reaction III to obtain 3,5-dibromo-4-hydroxybenzoamide; In solvent III, 3,5-dibromo-4-hydroxybenzamide and a dehydrating agent are contacted and then reaction IV is carried out to obtain 3,5-dibromo-4-hydroxybenzonitrile.

2. The synthesis method according to claim 1, characterized in that, Solvent I is selected from at least one of water, dichloromethane, ethanol, and 1,2-dichloroethane; And / or, the brominating agent is selected from a combination of sodium bromide and sodium bromate or a combination of sodium bromide and sodium chlorate; preferably, the mass ratio of sodium bromide to sodium bromate in the combination of sodium bromide and sodium bromate is 1:(0.8-2.0); and / or, the mass ratio of sodium bromide to sodium chlorate in the combination of sodium bromide and sodium chlorate is 1:(0.8-2.0). And / or, the mass ratio of p-hydroxybenzoic acid, brominating agent, hydrochloric acid and solvent I is (30-50):(85-105):(75-85):(220-260); And / or, the acidic reagent is selected from at least one of hydrochloric acid solution, sulfuric acid solution, phosphoric acid solution, trichloroacetic acid solution, and acetic acid; preferably, the mass concentration of the hydrochloric acid solution is 30%–40%; and / or, the mass concentration of the sulfuric acid solution is 20%–30%; and / or, the mass concentration of the phosphoric acid solution is 25%–45%; and / or, the mass concentration of the trichloroacetic acid solution is 40%–50%. And / or, the method further includes cooling the mixture to 10°C to 15°C before adding the acidic reagent; And / or, the conditions for reaction I include: a temperature of 20°C to 30°C, a time of 3 hours to 5 hours, and a stirring rate of 100 rpm to 300 rpm.

3. The synthesis method according to claim 1, characterized in that, Solvent II is selected from at least one of toluene, dichloromethane, 1,2-dichloroethane, chlorobenzene, and tetrahydrofuran; And / or, the chloride is selected from at least one of thionyl chloride, oxalyl chloride, and cyanuryl chloride; And / or, the mass ratio of the 3,5-dibromo-4-hydroxybenzoic acid, chloride and solvent II is (30-50):(10-25):

200.

4. The synthesis method according to claim 1, characterized in that, The conditions for reaction II include: a temperature of 60℃ to 80℃, a time of 0.2h to 1h, and a stirring rate of 100rpm to 300rpm.

5. The synthesis method according to claim 1, characterized in that, The alkaline reagent is selected from at least one of ammonia water, ammonia gas, ammonium acetate, ammonium carbonate, ammonium carbamate, and methylamine aqueous solution; preferably, the mass concentration of the ammonia water is 30% to 40%; and / or, the mass concentration of the methylamine aqueous solution is 20% to 40%. The mass ratio of the reaction solution containing 3,5-dibromo-4-hydroxybenzoic acid to the alkaline reagent is 120:(2-10). And / or, in the reaction solution containing 3,5-dibromo-4-hydroxybenzoic acid, the mass percentage of 3,5-dibromo-4-hydroxybenzoic acid is 30% to 40%, preferably 33.35%, and the content of 3,5-dibromo-4-hydroxybenzoic acid is 95.5%; And / or, the conditions for reaction III include: a temperature of 0°C to 5°C and a time of 3h to 5h.

6. The synthesis method according to claim 1, characterized in that, Solvent III is selected from at least one of dichloromethane, acetonitrile, tetrahydrofuran, toluene, and 1,2-dichloroethane.

7. The synthesis method according to claim 1, characterized in that, The dehydrating agent is selected from at least one of the following: trifluorosulfonic anhydride / triethylamine system, phosphorus oxychloride / pyridine system, p-toluenesulfonyl chloride / diisopropylethylamine system, and Burgess reagent; preferably, in the trifluorosulfonic anhydride / triethylamine system, the mass ratio of trifluorosulfonic anhydride to triethylamine is 1:(0.5-1.0); and / or, in the phosphorus oxychloride / pyridine system, the mass ratio of phosphorus oxychloride to pyridine is 1:(0.5-1.0); and / or, in the p-toluenesulfonyl chloride / diisopropylethylamine system, the mass ratio of p-toluenesulfonyl chloride to diisopropylethylamine is 1:(0.5-1.0). And / or, the mass ratio of the 3,5-dibromo-4-hydroxybenzamide, the dehydrating agent, and solvent III is (20-40):(40-60):

150.

8. The synthesis method according to claim 1, characterized in that, The contact conditions include a temperature of 0°C to 5°C.

9. The synthesis method according to claim 1, characterized in that, The conditions for reaction IV include: a temperature of 20°C to 30°C and a time of 3 to 5 hours.