Method for synthesizing N-(4-amino-2,5-diethoxyphenyl)benzamide

Abstract

The present invention relates to the technical field of organic synthesis, and specifically to a method for synthesizing Fast Blue BB Salt. The method includes: (1) obtaining 1,4-dibromo-2,5-diethoxybenzene by bromination reaction of 1,4-diethoxybenzene; (2) reacting 1,4-dibromo-2,5-diethoxybenzene with benzamide to obtain N-(4-bromo-2,5-diethoxyphenyl)benzamide; (3) reacting N-(4-bromo-2,5-diethoxyphenyl)benzamide with trifluoroacetamide to obtain N-(2,5-diethoxy-4-(2,2,2-trifluoroacetylamino)phenyl)benzamide; and (4) obtaining Fast Blue BB Salt by hydrolysis of N-(2,5-diethoxy-4-(2,2,2-trifluoroacetylamino)phenyl)benzamide. The method has a short reaction route, mild reaction conditions, and meets the requirements of green and safe development.

Description

[Technical Field]

[0001] (Cross-reference of related applications) This application claims priority to the prior application filed in China on 31 October 2023, application number 202311439148.0, which is incorporated herein by reference in whole.

[0002] (Technical field) The present invention relates to the technical field of organic synthesis, and more specifically to a method for synthesizing N-(4-amino-2,5-diethoxyphenyl)benzamide. [Background technology]

[0003] N-(4-amino-2,5-diethoxyphenyl)benzamide, also known as Fast Blue BB salt, is a dye with the color index number 37175 and is a color developer that can be used for dyeing and printing cotton, viscose, and silk fabrics. Currently, the synthesis of this product is mainly carried out by a five-step reaction of nitration, reduction, acylation, renitration, and rereduction of 1,4-diethoxybenzene. The nitration step requires the use of concentrated nitric acid, which requires advanced equipment and not only is it prone to corrosion, but it also poses a significant safety risk. Furthermore, the synthesis route is long, resulting in low overall efficiency, high energy consumption and costs in synthesis, and thus increasing production costs.

[0004] Therefore, developing new, more efficient, greener, and safer synthesis methods has become a practical need in the production and use of Fastblue BB Salt. [Overview of the project] [Problems that the invention aims to solve]

[0005] In relation to the above-mentioned issues, the technical problem that the present invention aims to solve is to provide a novel method for synthesizing Fastblue BB salt that has fewer reaction steps, a higher yield, is greener, and is safer. [Means for solving the problem]

[0006] Specifically, the present invention provides the following technical solutions. The present invention includes the following steps: N-(4- amino This invention provides a method for synthesizing (-2,5-diethoxyphenyl)benzamide. (1) 1,4-dibromo-2,5-diethoxybenzene is obtained by the bromination reaction of 1,4-diethoxybenzene. (2) In the presence of an alkaline reagent, a copper salt catalyst, its ligand, and an additive, the 1,4-dibromo-2,5-diethoxybenzene prepared in step (1) is reacted with benzamide in a first organic solvent to obtain N-(4-bromo-2,5-diethoxyphenyl)benzamide. (3) In the presence of an alkaline reagent, a copper salt catalyst, its ligand, and an additive, the N-(4-bromo-2,5-diethoxyphenyl)benzamide prepared in step (2) is reacted with trifluoroacetamide in a second organic solvent to obtain N-(2,5-diethoxy-4-(2,2,2-trifluoroacetylamino)phenyl)benzamide. (4) N-(2,5-diethoxy-4-(2,2,2-trifluoroacetylamino)phenyl)benzamide prepared in step (3) is hydrolyzed to obtain N-(4-amino-2,5-diethoxyphenyl)benzamide.

[0007] In some embodiments of the present application, the bromination reaction described in step (1) is carried out by adding the brominating reagent to a mixed solution of 1,4-diethoxybenzene and a third organic solvent under the protection of an inert gas, preferably at a reaction temperature of -10 to 10°C, and more preferably for a reaction time of 2 to 10 hours.

[0008] In some embodiments of the present application, the bromination reagent is selected from one or more of bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium bromide perbromide, carbon tetrabromide, 1,3-dibromo-1,3,5-triazine-2,4,6-trione, N-bromophthalimide and N-bromosaccharin, and preferably, it is bromine. Preferably, the molar ratio of bromine element in the bromination reagent to 1,4-diethoxybenzene is 2-6:1. Preferably, the third organic solvent is selected from one or more of acetic acid, dichloromethane, chloroform or carbon tetrachloride, preferably, it is dichloromethane or chloroform, and more preferably, the weight of the third organic solvent is 1-20 times the weight of 1,4-diethoxybenzene.

[0009] In some embodiments of the present application, the copper salt catalysts described in step (2) and step (3) are each independently selected from one or more of cuprous iodide, cuprous chloride, cuprous oxide, cuprous acetate, copper sulfate, copper trifluoromethanesulfonate, cupric chloride, cupric bromide and cupric oxide, and preferably, they are cuprous iodide and / or cupric chloride. Preferably, based on the molar percentage, the usage amount of the copper salt catalyst described in step (2) is 0.2-10% of 1,4-dibromo-2,5-diethoxybenzene, preferably, it is 0.5-5%, and more preferably, it is 1-5%. And / or, based on the molar percentage, the usage amount of the copper salt catalyst described in step (3) is 1-10% of N-(4-bromo-2,5-diethoxyphenyl)benzamide, preferably, it is 1-5%.

[0010] In some embodiments of the present application, the ligands of the catalysts described in step (2) and step (3) are each independently selected from one or more of proline, tetramethylethylenediamine, N,N'-dimethylethylenediamine, bipyridine, 1,10-phenanthroline, triphenylphosphine and tricyclohexylphosphine, and preferably, they are N,N'-dimethylethylenediamine and / or proline. Preferably, based on mole percentage, the amount of the ligand of the catalyst described in step (2) is 1 to 20% of 1,4-dibromo-2,5-diethoxybenzene, preferably 1 to 10%, and more preferably 5 to 10%. And / or, based on mole percentage, the amount of the ligand described in step (3) is 1 to 20% of N-(4-bromo-2,5-diethoxyphenyl)benzamide, preferably 5 to 10%.

[0011] In some embodiments of the present application, the alkaline reagents described in step (2) and step (3) are each independently selected from one or more of sodium carbonate, potassium carbonate, sodium acetate, sodium bicarbonate, potassium phosphate, triethylamine and pyridine, and preferably potassium carbonate and / or potassium phosphate. Preferably, the molar ratio of the alkaline reagent described in step (2) to 1,4-dibromo-2,5-diethoxybenzene is 1 to 3:1. And / or, the molar ratio of the alkaline reagent described in step (3) to N-(4-bromo-2,5-diethoxyphenyl)benzamide is 1 to 3:1.

[0012] In some embodiments of the present application, the additives described in step (2) and step (3) are each independently selected from one or more of sodium iodide, lithium iodide, potassium iodide and tetrabutylammonium iodide, and preferably sodium iodide. Preferably, based on mole percentage, the amount of the additive described in step (2) is 1 to 20% of 1,4-dibromo-2,5-diethoxybenzene, preferably 1 to 10%, and more preferably 5 to 10%. And / or, based on mole percentage, the amount of the additive described in step (3) is 1 to 300% of N-(4-bromo-2,5-diethoxyphenyl)benzamide, preferably 50 to 200%.

[0013] In some embodiments of the present application, the first organic solvent and the second organic solvent are each independently selected from toluene, tetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate, dimethyl sulfoxide, and N,N-dimethylformamide, and are preferably toluene and / or 1,4-dioxane. Preferably, the mass ratio of the first organic solvent described in step (2) to 1,4-dibromo-2,5-diethoxybenzene is 1 to 10:1, and more preferably, the first organic solvent is toluene. And / or, The mass ratio of the second organic solvent described in step (3) to N-(4-bromo-2,5-diethoxyphenyl)benzamide is 1 to 10:1, and more preferably the second organic solvent is 1,4-dioxane.

[0014] In some embodiments of the present application, the molar ratio of 1,4-dibromo-2,5-diethoxybenzene to benzamide described in step (2) is 1:1 to 2, preferably 1:1 to 1.5.

[0015] In some embodiments of the present application, the molar ratio of N-(4-bromo-2,5-diethoxyphenyl)benzamide to trifluoroacetamide described in step (3) is 1:1 to 3, preferably 1:1.5 to 2.

[0016] In some embodiments of the present application, the reaction temperature for the reactions described in step (2) and step (3) is 60 to 140°C, and preferably the reaction time is 20 to 40 hours.

[0017] In some embodiments of the present application, the hydrolysis reaction described in step (4) is carried out in water or an aqueous solution of alcohol, preferably an aqueous solution of alcohol, more preferably the aqueous solution of alcohol is one of an aqueous solution of methanol, an aqueous solution of ethanol, or an aqueous solution of propanol, and preferably the volume ratio of alcohol to water in the aqueous solution of alcohol is 1:1 to 4. And / or, the temperature of the hydrolysis reaction described in step (4) is 50 to 80°C, and preferably the duration of the hydrolysis reaction is 4 to 10 hours. [Effects of the Invention]

[0018] The beneficial effects of this invention are as follows: This invention provides a novel synthetic route for N-(4-amino-2,5-diethoxyphenyl)benzamide, which consists of only four steps: bromination, two amidations, and hydrolysis. This route fundamentally avoids highly hazardous and polluting reactions such as nitration, and has advantages such as a short reaction route, mild reaction conditions, high process safety, and environmental friendliness, thus meeting the demands for greening and safe development. [Modes for carrying out the invention]

[0019] In this invention, unless otherwise specified in the specific context, the numerical ranges shown herein include upper and lower limits, and “greater than or equal to” and “less than or equal to” include the endpoint values ​​and all integers and fractions within the range, and are not limited to the specific values ​​shown when describing the range. “And / or” as used herein is an inclusive term; for example, “A and / or B” refers to the case where only A is present, or only B is present, or both A and B are present.

[0020] The entire synthesis route of the method for synthesizing N-(4-amino-2,5-diethoxyphenyl)benzamide according to the present invention can be represented by the following reaction equation. [ka]

[0021] The design principle of the synthesis reaction of the present invention is as follows. The present invention uses 1,4-diethoxybenzene as a starting material, obtains 1,4-dibromo-2,5-diethoxybenzene by electrophilic bromination with a brominating reagent, then obtains N-(4-bromo-2,5-diethoxyphenyl)benzamide by amidation with benzamide under a copper catalyst, and finally obtains the product N-(4-amino-2,5-diethoxyphenyl)benzamide by hydrolysis after amidation with trifluoroacetamide using a copper catalyst.

[0022] In a first aspect of the present application, a specific embodiment includes the following steps: N-(4- amino This invention provides a method for synthesizing (-2,5-diethoxyphenyl)benzamide. (1) 1,4-dibromo-2,5-diethoxybenzene is obtained by the bromination reaction of 1,4-diethoxybenzene. (2) In the presence of an alkaline reagent, a copper salt catalyst, its ligand, and an additive, the 1,4-dibromo-2,5-diethoxybenzene prepared in step (1) is reacted with benzamide in a first organic solvent to obtain N-(4-bromo-2,5-diethoxyphenyl)benzamide. (3) In the presence of an alkaline reagent, a copper salt catalyst, its ligand, and an additive, the N-(4-bromo-2,5-diethoxyphenyl)benzamide prepared in step (2) is reacted with trifluoroacetamide in a second organic solvent to obtain N-(2,5-diethoxy-4-(2,2,2-trifluoroacetylamino)phenyl)benzamide. (4) N-(2,5-diethoxy-4-(2,2,2-trifluoroacetylamino)phenyl)benzamide prepared in step (3) is hydrolyzed to obtain N-(4-amino-2,5-diethoxyphenyl)benzamide.

[0023] The bromination reaction described in step (1) involves adding a brominating reagent to a mixed solution of 1,4-diethoxybenzene and a third organic solvent under the protection of an inert gas, with a reaction temperature of -10 to 10°C, preferably 0 to 10°C, more preferably a reaction time of 2 to 10 hours, and even more preferably a reaction time of 2 to 4 hours.

[0024] In some embodiments of the present application, the brominating reagent used in the bromination reaction of step (1) is selected from one or more of bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium bromide perbromide, carbon tetrabromide, 1,3-dibromo-1,3,5-triazine-2,4,6-trione, N-bromophthalimide, and N-bromosaccharin, and is preferably bromine. Considering various factors such as cost, efficiency, yield, and product purity, the molar ratio of bromine element to 1,4-diethoxybenzene in the brominating reagent is preferably 2 to 6:1. In some embodiments of the present application, the molar ratio of bromine element to 1,4-diethoxybenzene in the brominating reagent may be 2:1, 3:1, 4:1, 5:1, or 6:1, or within a numerical range defined by two of the above specific numerical values ​​as endpoints. It should be understood that in specific embodiments, any of the above ranges may be combined with any other range, as long as the N-(4-amino-2,5-diethoxyphenyl)benzamide of the present application is obtained.

[0025] The reaction solvent has a significant impact on whether the bromination reaction proceeds smoothly. A suitable reaction solvent can improve the selectivity of the bromination reaction, suppress the occurrence of dibromination side reactions, reduce the amount of brominating reagent used, and improve the purity of the product. The third organic solvent described in this application is selected from one or more of acetic acid, dichloromethane, chloroform, and carbon tetrachloride, and is preferably chloroform or dichloromethane. If the amount of solvent used is too much or too little, it will adversely affect the reaction. Preferably, the amount of the third organic solvent used is 1 to 20 times the amount of 1,4-diethoxybenzene of the reaction raw material, more preferably 5 to 15 times, even more preferably 6 to 11 times, and even more preferably 5 to 7 times.

[0026] The gas produced in step (1) is treated by passing it through an aqueous solution of Na2SO3 and / or NaHCO3, and after the reaction is complete, the reaction is quenched with a saturated aqueous solution of Na2SO3.

[0027] This invention further includes the step of separating and purifying the reaction product of step (1) in order to obtain high-purity 1,4-dibromo-2,5-diethoxybenzene.

[0028] In some embodiments of the present application, the copper salt catalyst described in steps (2) and (3) is independently selected from one or more of the following: cuprous iodide, cuprous chloride, cuprous oxide, cuprous acetate, copper sulfate, copper trifluoromethanesulfonate, cupric chloride, cupric bromide, and cupric oxide, preferably cuprous iodide and / or cupric chloride, and more preferably cuprous iodide. On a molar basis, the amount of copper salt catalyst used in step (2) is 0.2 to 10% of the raw material 1,4-dibromo-2,5-diethoxybenzene, preferably 0.5 to 5%, and more preferably 1 to 5%. On a molar basis, the amount of copper salt catalyst used in step (3) is 1 to 10% of the raw material N-(4-bromo-2,5-diethoxyphenyl)benzamide, preferably 1 to 5%.

[0029] In some embodiments of the present application, the amount of copper salt catalyst used in step (2) above may be 0.2-10%, 0.2-9%, 0.2-8%, 0.2-7%, 0.2-6%, 0.2-5%, 0.2-4%, 0.2-3%, 0.2-2%, 0.2-1%, 0.5-10%, 1-10%, 2-10%, 3-10%, 4-10%, 5-10%, 6-10%, 7-10%, 8-10%, or 9-10% of the raw material 1,4-dibromo-2,5-diethoxybenzene. In some embodiments, the amount of copper salt catalyst used in step (2) above may be 0.2%, 0.5%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the raw material 1,4-dibromo-2,5-diethoxybenzene, or a value within a numerical range configured with two of the above specific numerical values ​​as endpoints. It should be understood that in specific embodiments, any of the above ranges may be combined with any other range, as long as the Fast Blue BB Salt of the present invention is obtained.

[0030] In some embodiments of the present application, the amount of copper salt catalyst used in step (3) above may be 1-10%, 1-9%, 1-8%, 1-7%, 1-6%, 1-5%, 1-4%, 1-3%, 1-2%, 2-10%, 3-10%, 4-10%, 5-10%, 6-10%, 7-10%, 8-10%, or 9-10% of the raw material N-(4-bromo-2,5-diethoxyphenyl)benzamide. In some embodiments, the amount of copper salt catalyst used in step (2) above may be 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, or 10% of the raw material N-(4-bromo-2,5-diethoxyphenyl)benzamide, or a value within a numerical range configured with two of the above specific numerical values ​​as endpoints. It should be understood that in specific embodiments, any of the above ranges may be combined with any other range, as long as the Fast Blue BB Salt of the present invention is obtained.

[0031] In some embodiments of the present application, the ligands of the catalyst described in step (2) and step (3) are independently selected from one or more of proline, tetramethylethylenediamine, N,N'-dimethylethylenediamine, bipyridine, 1,10-phenanthroline, triphenylphosphine, and tricyclohexylphosphine, and are preferably N,N'-dimethylethylenediamine and / or proline. Preferably, the amount of ligand used in step (2) is 1 to 20% of the 1,4-dibromo-2,5-diethoxybenzene raw material, preferably 1 to 10%, and more preferably 5 to 10%, on a molar basis. And / or, the amount of ligand used in step (3) is 1 to 20% of the raw material N-(4-bromo-2,5-diethoxyphenyl)benzamide, preferably 5 to 10%, on a molar basis.

[0032] In some embodiments of the present application, the amount of ligand used in step (2) above may be 1-20%, 1-19%, 1-18%, 1-17%, 1-16%, 1-15%, 1-14%, 1-13%, 1-12%, 1-11%, 1-10%, 2-20%, 3-20%, 4-20%, 5-20%, 6-20%, 7-20%, 8-20%, 9-20%, or 10-20% of the raw material 1,4-dibromo-2,5-diethoxybenzene. In some embodiments, the amount of copper salt catalyst used in step (2) above may be 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of the raw material 1,4-dibromo-2,5-diethoxybenzene, or a value within a numerical range configured with two of the above specific numerical values ​​as endpoints. It should be understood that in specific embodiments, any of the above ranges may be combined with any other range, as long as the Fast Blue BB Salt of the present invention is obtained.

[0033] In some embodiments of the present application, the amount of ligand used in step (3) above may be 1-20%, 1-19%, 1-18%, 1-17%, 1-16%, 1-15%, 1-14%, 1-13%, 1-12%, 1-11%, 1-10%, 2-20%, 3-20%, 4-20%, 5-20%, 6-20%, 7-20%, 8-20%, 9-20%, or 10-20% of the raw material N-(4-bromo-2,5-diethoxyphenyl)benzamide. In some embodiments, the amount of copper salt catalyst used in step (2) above may be 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of the raw material 1,4-dibromo-2,5-diethoxybenzene, or a value within a numerical range configured with two of the above specific numerical values ​​as endpoints. It should be understood that in specific embodiments, any of the above ranges may be combined with any other range, as long as the Fast Blue BB Salt of the present invention is obtained.

[0034] In some embodiments of the present application, the alkaline reagent described in step (2) and step (3) is independently selected from one or more of sodium carbonate, potassium carbonate, sodium acetate, sodium bicarbonate, potassium phosphate, triethylamine, and pyridine, and is preferably potassium carbonate and / or potassium phosphate. Preferably, the molar ratio of the alkaline reagent described in step (2) to 1,4-dibromo-2,5-diethoxybenzene is 1 to 3:1. And / or, the molar ratio of the alkaline reagent described in step (3) to the starting material N-(4-bromo-2,5-diethoxyphenyl)benzamide is 1 to 3:1.

[0035] In some embodiments of the present application, the additives described in step (2) and step (3) are each independently selected from sodium iodide, lithium iodide, potassium iodide, and tetrabutylammonium iodide, preferably sodium iodide, which promotes the conversion of the starting material brominate by generating a more active aromatic iodine compound in situ through halogen ion exchange.

[0036] Preferably, the amount of the additive described in step (2) used is 1 to 20% of 1,4-dibromo-2,5-diethoxybenzene on a molar basis, preferably 1 to 10%, and more preferably 5 to 10%. And / or, the amount of the additive described in step (3) used, on a molar basis, is 1 to 300% of N-(4-bromo-2,5-diethoxyphenyl)benzamide, preferably 50 to 200%.

[0037] In some embodiments of the present application, the amount of additive used in step (2) above may be 1-20%, 1-19%, 1-18%, 1-17%, 1-16%, 1-15%, 1-14%, 1-13%, 1-12%, 1-11%, 1-10%, 2-20%, 3-20%, 4-20%, 5-20%, 6-20%, 7-20%, 8-20%, 9-20%, or 10-20% of the raw material 1,4-dibromo-2,5-diethoxybenzene. In some embodiments, the amount of additive used in step (2) above may be 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 11%, 12%, 13%, 14%, 15%, 16%, 17%, 18%, 19%, or 20% of the raw material 1,4-dibromo-2,5-diethoxybenzene, or a value within a numerical range configured with two of the above specific numerical values ​​as endpoints. It should be understood that in specific embodiments, any of the above ranges may be combined with any other range, as long as the Fast Blue BB Salt of the present invention is obtained.

[0038] In some embodiments of the present application, the amount of additive used in step (3) above is 1-10%, 1-20%, 1-30%, 1-40%, 1-50%, 1-60%, 1-70%, 1-80%, 1-90%, 1-100%, 1-200%, 1-250%, 1-300%, 10-300%, 20-300%, 30-300%, 40-300%, 50-300%, 60-300%, 70-300%, The amount may be 80-300%, 90-300%, 100-300%, or 200-300%, and in some embodiments, the amount of additive used in step (3) above may be 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, 200%, or 300% of N-(4-bromo-2,5-diethoxyphenyl)benzamide, or a value within a numerical range configured with two of the above specific numerical values ​​as endpoints. It should be understood that in specific embodiments, any of the above ranges may be combined with any other range, as long as the Fast Blue BB Salt of the present invention is obtained.

[0039] To mitigate the occurrence of side reactions, the reaction must be carried out in a suitable solvent. The first and second organic solvents are each independently selected from toluene, tetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate, dimethyl sulfoxide, and N,N-dimethylformamide, and are preferably toluene and / or 1,4-dioxane. The solvent is added mainly to dissolve and disperse the reaction materials, ensuring good dispersion and facilitating the reaction. Too much or too little solvent can adversely affect the reaction. Preferably, the amount of the first organic solvent is 1 to 10 times the amount of 1,4-dibromo-2,5-diethoxybenzene, more preferably the first organic solvent is toluene. Even more preferably, the amount of the second organic solvent is 1 to 10 times the amount of N-(4-bromo-2,5-diethoxyphenyl)benzamide, more preferably the second organic solvent is 1,4-dioxane.

[0040] The choice of reaction temperature depends on the solvent used. To accelerate the reaction rate, the reaction temperature may be appropriately raised to reach the boiling point of the solvent used. That is, the reaction system reacts under reflux, and raising the reaction temperature can accelerate the reaction rate. However, if the reaction temperature is too high, side reactions become active, which is detrimental to improving product purity, and if the reaction temperature is too low, the reaction rate becomes very slow, and production efficiency decreases. Therefore, preferably, the reaction temperatures in both step (2) and step (3) are 60 to 140°C, and preferably, the reaction times are 20 to 40 hours. More preferably, the reaction temperature in step (2) is 100 to 120°C, and even more preferably, the reaction temperature in step (2) is 100 to 140°C, and preferably 100 to 120°C.

[0041] In one embodiment of the present invention, the molar ratio of 1,4-dibromo-2,5-diethoxybenzene to benzamide described in step (2) is 1:1 to 2, preferably 1:1 to 1.5. If the amount of benzamide is too small, it is difficult to satisfy the reaction conditions, and if the amount of benzamide is too large, diamination side reactions are likely to occur, which is unfavorable for the reaction.

[0042] In one embodiment of the present invention, the molar ratio of N-(4-bromo-2,5-diethoxyphenyl)benzamide to trifluoroacetamide described in step (3) is 1:1 to 3, preferably 1:1.5 to 2.0. Although the reaction activity of N-(4-bromo-2,5-diethoxyphenyl)benzamide is low, increasing the amount of trifluoroacetamide used as appropriate is advantageous for the progress of the reaction.

[0043] The hydrolysis reaction described in step (4) is carried out in water or an aqueous solution of alcohol, preferably an aqueous solution of alcohol, which helps to homogeneously mix the organic matter and water, prevents stratification, and promotes contact between the reactants and water. More preferably, the aqueous solution of alcohol is one of an aqueous solution of methanol, an aqueous solution of ethanol, or an aqueous solution of propanol, and preferably, the volume ratio of alcohol to water in the aqueous solution of alcohol is 1:1 to 4. The temperature of the hydrolysis reaction described in step (4) is 50 to 80°C, and preferably the duration of the hydrolysis reaction is 4 to 10 hours.

[0044] The synthesis method of N-(4-amino-2,5-diethoxyphenyl)benzamide and its beneficial effects will be described in detail below using examples and comparative examples.

[0045] The synthesis route for producing Fastblue BB Salt according to the following examples is as follows: [ka]

[0046] The raw materials or reagents used in this invention are purchased from major manufacturers in the market, and unless the manufacturer or concentration is specified, they are analytically pure raw materials or reagents available through normal procurement channels, and are not particularly limited as long as they can produce the desired effect. The apparatus and equipment used in this embodiment are all purchased from major manufacturers in the market and are not particularly limited as long as they can produce the desired effect. Where the technique or conditions are not specifically specified in this embodiment, the technique or conditions or product descriptions described in the literature in the art shall be followed.

[0047] Table 1 shows the reagents and apparatus used in the following examples. Table 1: Information on raw materials used in the examples [Table 1]

[0048] Example 1: Preparation of 1,4-dibromo-2,5-diethoxybenzene 1,4-diethoxybenzene (13.0 g, 78.2 mmol) was weighed and placed in a two-necked round-bottom flask equipped with a stirring bar, and CHCl3 (90 mL) was added as the solvent. The reaction apparatus was placed in an ice bath at 0°C, and under the protection of an inert gas, bromine (195 mmol) was added dropwise until the addition was completed in 25 minutes. The gas produced by the reaction was treated with aqueous solutions of Na2SO3 and NaHCO3. After the addition was complete, the timer was started and the reaction was allowed to proceed for 3 hours. The reaction was then quenched with saturated aqueous solution of Na2SO3 and stirred until the solution became colorless. The organic and aqueous phases were obtained by liquid-liquid separation using a separatory funnel. The aqueous phase was extracted twice with dichloromethane (100 mL of dichloromethane was used per extraction). The extracted dichloromethane phase and the organic phase were combined, and the organic phase was washed once with water and then with saturated brine, respectively. After drying the organic phase with anhydrous magnesium sulfate, the solvent was removed using a rotary evaporator to obtain a white solid. Finally, the solid was recrystallized with a mixed solvent of methanol and dichloromethane (volume ratio of methanol to dichloromethane: 1:4) to obtain 22.8 g of a white product, which was identified as 1,4-dibromo-2,5-diethoxybenzene by nuclear magnetic resonance. The purity of 1,4-dibromo-2,5-diethoxybenzene, as measured by high-performance liquid chromatography, was 99%, and the yield was 90%.

[0049] The nuclear magnetic resonance (NMS) identification results for 1,4-dibromo-2,5-diethoxybenzene were as follows: 1 H NMR(600MHz,CDCl3)δ 7.09(s,2H),4.03(q,J=7.0Hz,4H),1.44(t,J=7.0Hz,6H). 13 C NMR(151MHz,CDCl3)δ 149.99,118.61,111.17,65.93,14.77.

[0050] Example 2: Preparation of 1,4-dibromo-2,5-diethoxybenzene 1,4-diethoxybenzene (13.0 g, 78.2 mmol) was weighed and placed in a two-necked round-bottom flask equipped with a stirring bar, and dichloromethane (100 mL) was added as the solvent. Under the protection of an inert gas, bromine (195 mmol) was added, and the addition was completed dropwise in 25 minutes. The gas produced by the reaction was treated with aqueous solutions of Na2SO3 and NaHCO3. The reaction was carried out at 10°C, and after the addition was completed, the timer was started and the reaction was allowed to proceed for 2 hours. The reaction was then quenched with saturated aqueous solution of Na2SO3 and stirred until colorless. The organic phase and aqueous phase were obtained by separation using a separatory funnel. The aqueous phase was extracted twice with dichloromethane (using 100 mL of dichloromethane per extraction), and the extracted dichloromethane phase and organic phase were combined. The organic phase was then washed once with water and once with saturated brine, respectively. After drying the organic phase over magnesium sulfate, the solvent was removed using a rotary evaporator to obtain a white solid. Finally, the product was recrystallized in a mixed solvent of methanol and dichloromethane (volume ratio of methanol to dichloromethane: 1:4) to obtain a white product, which was identified as 1,4-dibromo-2,5-diethoxybenzene by nuclear magnetic resonance. The purity of 1,4-dibromo-2,5-diethoxybenzene measured by high-performance liquid chromatography was 98%, and the yield was 92%. Analysis of 1,4-dibromo-2,5-diethoxybenzene using nuclear magnetic resonance yielded the following results. 1 H NMR(600MHz,CDCl3)δ 7.09(s,2H),4.03(q,J=7.0Hz,4H),1.44(t,J=7.0Hz,6H). 13 C NMR(151MHz,CDCl3)δ 149.99,118.61,111.17,65.93,14.77.

[0051] Example 3: Preparation of 1,4-dibromo-2,5-diethoxybenzene 1,4-diethoxybenzene (13.0 g, 78.2 mmol) was weighed and placed in a two-necked round-bottom flask equipped with a stirring bar, and CHCl3 (100 mL) was added as the solvent. Under the protection of an inert gas, 1,3-dibromo-5,5-dimethylhydantoin (33.5 g, 117.3 mmol) was added. After reacting at 5°C for 10 hours, the reaction was quenched with saturated Na2SO3 aqueous solution. The organic phase and aqueous phase were obtained by liquid-liquid extraction using a separatory funnel, and the aqueous phase was extracted twice with dichloromethane (using 100 mL of dichloromethane per extraction). The extracted dichloromethane phase and organic phase were combined, and the organic phase was washed once with water and then once with saturated brine, respectively. After drying the organic phase over anhydrous magnesium sulfate, the solvent was removed using a rotary evaporator to obtain a solid. Finally, the product was subjected to chromatography to obtain a white product, which was identified as 1,4-dibromo-2,5-diethoxybenzene by nuclear magnetic resonance. The purity of 1,4-dibromo-2,5-diethoxybenzene measured by high-performance liquid chromatography was 98%, and the yield was 78%. Analysis of 1,4-dibromo-2,5-diethoxybenzene using nuclear magnetic resonance yielded the following results. 1 H NMR(600MHz,CDCl3)δ 7.09(s,2H),4.03(q,J=7.0Hz,4H),1.44(t,J=7.0Hz,6H). 13 C NMR(151MHz,CDCl3)δ 149.99,118.61,111.17,65.93,14.77.

[0052] Example 4: Preparation of N-(4-bromo-2,5-diethoxyphenyl)benzamide The 1,4-dibromo-2,5-diethoxybenzene (324 mg, 1 mmol), benzamide (133 mg, 1.1 mmol), cuprous iodide (1.9 mg, 0.01 mmol), N,N'-dimethylethylenediamine (0.05 mmol), sodium iodide (7.5 mg, 0.05 mmol), and potassium carbonate (276 mg, 2 mmol) prepared in Example 1 were weighed and placed in a tube reactor equipped with a stirring bar. Toluene (2 mL) was added to the tube reactor, the tube reactor was sealed, and the mixture was heated to 110°C and reacted for 24 hours with stirring. After the reaction was complete, saturated saline solution was added to quench the reaction, ethyl acetate was added to dilute and dissolve the mixture, and then the organic phase was separated using a separatory funnel. The organic phase was dried with anhydrous magnesium sulfate, the solvent was removed from the organic phase using a rotary evaporator, and the product was further purified by chromatography (stationary phase: silica gel, eluent: DCM (dichloromethane):PE (petroleum ether) volume ratio = 1:2) to obtain a white solid product. This product was analyzed by nuclear magnetic resonance and identified as N-(4-bromo-2,5-diethoxyphenyl)benzamide. The purity of N-(4-bromo-2,5-diethoxyphenyl)benzamide measured by high-performance liquid chromatography was 99%, the yield was 75%, and the nuclear magnetic resonance results were as follows. 1 H NMR(600MHz,CDCl3)δ 8.60(s,1H),8.40(s,1H),7.91-7.85(m,2H),7.57(t,J=7.4Hz,1H),7.52(t,J=7.5H z,2H),7.09(s,1H),4.16(q,J=7.0Hz,2H),4.10(q,J=7.0Hz,2H),1.50-1.44(m,6H). 13 C NMR(151MHz,CDCl3)δ 165.07,149.64,141.74,134.91,131.99,128.93,127.96,126.93,116.04,106.08,105.04,65.67,65.22,14.94,14.83.

[0053] Example 5: Preparation of N-(4-bromo-2,5-diethoxyphenyl)benzamide 1,4-Dibromo-2,5-diethoxybenzene (324 mg, 1 mmol) prepared in Example 1, benzamide (133 mg, 1.1 mmol), cuprous iodide (1.9 mg, 0.01 mmol), N,N'-dimethylethylenediamine (0.05 mmol), sodium iodide (7.5 mg, 0.05 mmol), and potassium carbonate (276 mg, 2 mmol) were weighed and placed in a tube reactor equipped with a stir bar. Solvent 1,4-dioxane (2 mL) was added to the tube reactor. After sealing the tube reactor, it was heated to 100 °C and reacted with stirring for 24 hours. After completion of the reaction, saturated brine was added for quenching, and ethyl acetate was added for dilution and dissolution. Next, it was separated with a separatory funnel to obtain an organic phase, and the organic phase was dried over anhydrous magnesium sulfate. The solvent was removed from the organic phase by rotary evaporation, and the product was further purified by chromatography (the stationary phase was silica gel, and the eluent was DCM (dichloromethane):PE (petroleum ether) volume ratio = 1:2). A white solid product was obtained. The product was analyzed by nuclear magnetic resonance and identified as N-(4-bromo-2,5-diethoxyphenyl)benzamide. The purity of N-(4-bromo-2,5-diethoxyphenyl)benzamide measured by high performance liquid chromatography was 99%, the yield was 65%, and the nuclear magnetic resonance results were as follows. 1 H NMR(600MHz,CDCl3)δ 8.60(s,1H),8.40(s,1H),7.91-7.85(m,2H),7.57(t,J=7.4Hz,1H),7.52(t,J=7.5Hz,2H),7.09(s,1H),4.16(q,J=7.0Hz,2H),4.10(q,J=7.0Hz,2H),1.50-1.44(m,6H). 13 C NMR(151MHz,CDCl3)δ 165.07,149.64,141.74,134.91,131.99,128.93,127.96,126.93,116.04,106.08,105.04,65.67,65.22,14.94,14.83.

[0054] Example 6: Preparation of N-(4-bromo-2,5-diethoxyphenyl)benzamide The 1,4-dibromo-2,5-diethoxybenzene (324 mg, 1 mmol), benzamide (133 mg, 1.1 mmol), cuprous iodide (9.5 mg, 0.05 mmol), N,N'-dimethylethylenediamine (0.10 mmol), sodium iodide (7.5 mg, 0.05 mmol), and potassium carbonate (276 mg, 2 mmol) prepared in Example 1 were weighed and placed in a tube reactor equipped with a stirring bar. Toluene (2 mL) was added to the tube reactor, and after sealing the tube reactor, it was heated to 110°C and reacted with stirring for 24 hours. After the reaction was complete, saturated saline solution was added to quench the reaction, and ethyl acetate was added to dilute and dissolve the mixture. Next, the organic phase was separated using a separatory funnel and dried over anhydrous magnesium sulfate. The solvent was removed from the organic phase by rotational evaporation, and the product was further purified by chromatography (stationary phase: silica gel, eluent: DCM (dichloromethane):PE (petroleum ether) volume ratio = 1:2). A white solid product was obtained, which was identified as N-(4-bromo-2,5-diethoxyphenyl)benzamide by nuclear magnetic resonance analysis. The purity of N-(4-bromo-2,5-diethoxyphenyl)benzamide measured by high-performance liquid chromatography was 99%, the yield was 85%, and the nuclear magnetic resonance results were as follows. 1 H NMR(600MHz,CDCl3)δ 8.60(s,1H),8.40(s,1H),7.91-7.85(m,2H),7.57(t,J=7.4Hz,1H),7.52(t,J=7.5H z,2H),7.09(s,1H),4.16(q,J=7.0Hz,2H),4.10(q,J=7.0Hz,2H),1.50-1.44(m,6H). 13 C NMR(151MHz,CDCl3)δ 165.07,149.64,141.74,134.91,131.99,128.93,127.96,126.93,116.04,106.08,105.04,65.67,65.22,14.94,14.83.

[0055] Example 7: Preparation of N-(4-bromo-2,5-diethoxyphenyl)benzamide The 1,4-dibromo-2,5-diethoxybenzene (324 mg, 1 mmol), benzamide (133 mg, 1.1 mmol), cuprous iodide (1.9 mg, 0.01 mmol), N,N'-dimethylethylenediamine (0.05 mmol), sodium iodide (7.5 mg, 0.05 mmol), and potassium phosphate (424 mg, 2 mmol) prepared in Example 1 were weighed and placed in a tube reactor equipped with a stirring bar. Toluene (2 mL) was added to the tube reactor, and after sealing the tube reactor, it was heated to 110°C and reacted with stirring for 24 hours. After the reaction was complete, saturated saline solution was added to quench the reaction, and ethyl acetate was added to dilute and dissolve the mixture. Next, the organic phase was separated using a separatory funnel and dried over anhydrous magnesium sulfate. The solvent was removed from the organic phase by rotational evaporation, and the product was further purified by chromatography (stationary phase: silica gel, eluent: DCM (dichloromethane):PE (petroleum ether) volume ratio = 1:2). A white solid product was obtained, which was identified as N-(4-bromo-2,5-diethoxyphenyl)benzamide by nuclear magnetic resonance analysis. The purity of N-(4-bromo-2,5-diethoxyphenyl)benzamide measured by high-performance liquid chromatography was 99%, the yield was 72%, and the nuclear magnetic resonance results were as follows. 1 H NMR(600MHz,CDCl3)δ 8.60(s,1H),8.40(s,1H),7.91-7.85(m,2H),7.57(t,J=7.4Hz,1H),7.52(t,J=7.5H z,2H),7.09(s,1H),4.16(q,J=7.0Hz,2H),4.10(q,J=7.0Hz,2H),1.50-1.44(m,6H). 13 C NMR(151MHz,CDCl3)δ 165.07,149.64,141.74,134.91,131.99,128.93,127.96,126.93,116.04,106.08,105.04,65.67,65.22,14.94,14.83.

[0056] Example 8: Preparation of N-(4-bromo-2,5-diethoxyphenyl)benzamide 1,4-dibromo-2,5-diethoxybenzene (324 mg, 1 mmol), benzamide (242 mg, 2 mmol), cuprous iodide (1.43 mg, 0.01 mmol), proline (0.03 mmol), tetrabutylammonium iodide (0.01 mmol), and sodium carbonate (1 mmol), prepared in Example 2, were weighed and placed in a tube reactor equipped with a stirring bar. 3 mL of 1,4-dioxane solvent was added to the tube reactor, and after sealing the reactor, it was heated to 100°C and reacted with stirring for 30 hours. After the reaction was complete, saturated brine was added to quench the reaction, and ethyl acetate was added to dilute and dissolve the mixture. The mixture was then separated using a separatory funnel to obtain the organic phase, which was dried over anhydrous magnesium sulfate. The solvent was removed from the organic phase by rotary evaporation, and the product was further purified by chromatography (stationary phase: silica gel, eluent: DCM (dichloromethane):PE (petroleum ether) volume ratio = 1:2). A white solid product was obtained and analyzed by nuclear magnetic resonance (NMRI) to identify it as N-(4-bromo-2,5-diethoxyphenyl)benzamide. The purity of N-(4-bromo-2,5-diethoxyphenyl)benzamide measured by high-performance liquid chromatography was 99%, the yield was 54%, and the nuclear magnetic resonance results were as follows. 1 H NMR(600MHz,CDCl3)δ 8.60(s,1H),8.40(s,1H),7.91-7.85(m,2H),7.57(t,J=7.4Hz,1H),7.52(t,J=7.5H z,2H),7.09(s,1H),4.16(q,J=7.0Hz,2H),4.10(q,J=7.0Hz,2H),1.50-1.44(m,6H). 13 C NMR(151MHz,CDCl3)δ 165.07,149.64,141.74,134.91,131.99,128.93,127.96,126.93,116.04,106.08,105.04,65.67,65.22,14.94,14.83.

[0057] Example 9: Preparation of N-(4-bromo-2,5-diethoxyphenyl)benzamide 1,4-dibromo-2,5-diethoxybenzene (324 mg, 1 mmol), benzamide (1.2 mmol), cupric chloride (0.05 mmol), N,N'-diethylethylenediamine (0.1 mmol), tetrabutylammonium iodide (0.1 mmol), and sodium carbonate (2 mmol), prepared in Example 3, were weighed and placed in a tube reactor equipped with a stirring bar. Dimethyl sulfoxide (1 mL) was added to the tube reactor, and after sealing the tube reactor, it was heated to 120°C and reacted with stirring for 20 hours. After the reaction was complete, saturated saline solution was added to quench the reaction, and ethyl acetate was added to dilute and dissolve the mixture. The mixture was then separated using a separatory funnel to obtain the organic phase, which was dried over anhydrous magnesium sulfate. The solvent was removed from the organic phase by rotary evaporation, and the product was further purified by chromatography (stationary phase: silica gel, eluent: DCM (dichloromethane):PE (petroleum ether) volume ratio = 1:2). A white solid product was obtained, and the purity of N-(4-bromo-2,5-diethoxyphenyl)benzamide, measured by high-performance liquid chromatography, was 99%, with a yield of 60%. The product was identified as N-(4-bromo-2,5-diethoxyphenyl)benzamide by nuclear magnetic resonance (NMS) analysis, and the NMS results were as follows. 1 H NMR(600MHz,CDCl3)δ 8.60(s,1H),8.40(s,1H),7.91-7.85(m,2H),7.57(t,J=7.4Hz,1H),7.52(t,J=7.5H z,2H),7.09(s,1H),4.16(q,J=7.0Hz,2H),4.10(q,J=7.0Hz,2H),1.50-1.44(m,6H). 13 C NMR(151MHz,CDCl3)δ 165.07,149.64,141.74,134.91,131.99,128.93,127.96,126.93,116.04,106.08,105.04,65.67,65.22,14.94,14.83.

[0058] Example 10: Production of Fast Blue BB Salt The N-(4-bromo-2,5-diethoxyphenyl)benzamide (364 mg, 1 mmol), trifluoroacetamide (169 mg, 1.5 mmol), cuprous iodide (9.5 mg, 0.05 mmol), N,N'-dimethylethylenediamine (0.1 mmol), sodium iodide (75 mg, 0.5 mmol), and potassium carbonate (276 mg, 2 mmol) prepared in Example 4 were weighed and placed in a tube reactor equipped with a stirring bar. 1 mL of 1,4-dioxane solvent was added, the tube reactor was sealed, and the mixture was heated to 100°C and stirred for 24 hours. After the reaction was complete, a methanol / H2O (4 mL:4 mL) mixture was added, and the mixture was stirred at 60°C for 6 hours. After the reaction was complete, water and ethyl acetate (volume ratio of water to ethyl acetate: 1:3) were added for extraction. The organic phase was obtained by separation using a separatory funnel, and the organic phase was dried over anhydrous magnesium sulfate. The solvent was removed from the organic phase by rotational evaporation, and the product was further purified by chromatography (stationary phase: silica gel, eluent: EA (ethyl acetate):PE (petroleum ether) volume ratio = 1:2) to obtain a pale gray solid product, which was identified as N-(4-amino-2,5-diethoxyphenyl)benzamide (Fast Blue BB salt) by nuclear magnetic resonance. The purity of N-(4-amino-2,5-diethoxyphenyl)benzamide measured by high-performance liquid chromatography was 99%, the yield was 74%, and the total yield was 50%. The nuclear magnetic resonance results were as follows. 1 H NMR(600MHz,CDCl3)δ 8.44(s,1H),8.18(s,1H),7.87(d,J=7.2Hz,2H),7.56-7.46(m,3H),6.39(s,1H),4.18-3.97(m,4H),3.67(br,2H),1.49-1.37(m,6H). 13 C NMR(151MHz,CDCl3)δ 164.44,142.11,140.14,135.51,132.39,131.44,128.77,126.83,119.27,105.75,100.47,64.99,64.70,15.10,15.07.

[0059] Example 11: Production of Fast Blue BB Salt The solid reagents prepared in Example 5, N-(4-bromo-2,5-diethoxyphenyl)benzamide (364 mg, 1 mmol), trifluoroacetamide (169 mg, 1.5 mmol), cuprous iodide (9.5 mg, 0.05 mmol), N,N'-dimethylethylenediamine (0.1 mmol), sodium iodide (75 mg, 0.5 mmol), and potassium carbonate (276 mg, 2 mmol), were weighed and placed in a tube reactor equipped with a stirring bar. Toluene (1 mL) was added, the tube reactor was sealed, and the mixture was heated to 110°C and stirred for 24 hours. After the reaction was complete, a methanol / H2O (4 mL:4 mL) mixture was added, and the mixture was reacted at 60°C with stirring for 6 hours. After the reaction was complete, water and ethyl acetate were added for extraction. The organic phase was obtained by separation using a separatory funnel, and the organic phase was dried over anhydrous magnesium sulfate. The solvent was removed from the organic phase by rotational evaporation, and the product was further purified by chromatography (eluent:EA (ethyl acetate):PE (petroleum ether) volume ratio = 1:2) to obtain a pale gray solid product, which was identified as N-(4-amino-2,5-diethoxyphenyl)benzamide (Fast Blue BB salt) by nuclear magnetic resonance. The purity of N-(4-amino-2,5-diethoxyphenyl)benzamide measured by high-performance liquid chromatography was 99%, the yield was 65%, and the total yield was 38%. The nuclear magnetic resonance results were as follows. 1 H NMR(600MHz,CDCl3)δ 8.44(s,1H),8.18(s,1H),7.87(d,J=7.2Hz,2H),7.56-7.46(m,3H),6.39(s,1H),4.18-3.97(m,4H),3.67(br,2H),1.49-1.37(m,6H). 13 C NMR(151MHz,CDCl3)δ 164.44,142.11,140.14,135.51,132.39,131.44,128.77,126.83,119.27,105.75,100.47,64.99,64.70,15.10,15.07.

[0060] Example 12: Production of Fast Blue BB Salt The solid reagents prepared in Example 6, N-(4-bromo-2,5-diethoxyphenyl)benzamide (364 mg, 1 mmol), trifluoroacetamide (169 mg, 1.5 mmol), cuprous iodide (9.5 mg, 0.05 mmol), N,N'-dimethylethylenediamine (0.1 mmol), sodium iodide (300 mg, 2.0 mmol), and potassium carbonate (276 mg, 2 mmol), were weighed and placed in a tube reactor equipped with a stirring bar. 1 mL of 1,4-dioxane solvent was added, the tube reactor was sealed, and the mixture was heated to 100°C and reacted with stirring for 36 hours. After the reaction was complete, a methanol / H2O (4 mL:4 mL) mixture was added and the mixture was stirred at 60°C for 6 hours. After that, water and ethyl acetate (volume ratio of water to ethyl acetate: 1:3) were added for extraction. The organic phase was obtained by separating the mixture using a separatory funnel and drying the organic phase over anhydrous magnesium sulfate. The solvent was removed from the organic phase by rotational evaporation, and the product was further purified by chromatography (stationary phase: silica gel, eluent: EA (ethyl acetate):PE (petroleum ether) volume ratio = 1:2) to obtain a pale gray solid product, which was identified as N-(4-amino-2,5-diethoxyphenyl)benzamide (Fast Blue BB salt) by nuclear magnetic resonance. The purity of N-(4-amino-2,5-diethoxyphenyl)benzamide measured by high-performance liquid chromatography was 99%, the yield was 80%, and the total yield was 61.2%. The nuclear magnetic resonance results were as follows. 1 H NMR(600MHz,CDCl3)δ 8.44(s,1H),8.18(s,1H),7.87(d,J=7.2Hz,2H),7.56-7.46(m,3H),6.39(s,1H),4.18-3.97(m,4H),3.67(br,2H),1.49-1.37(m,6H). 13 C NMR(151MHz,CDCl3)δ 164.44,142.11,140.14,135.51,132.39,131.44,128.77,126.83,119.27,105.75,100.47,64.99,64.70,15.10,15.07.

[0061] Example 13: Production of Fast Blue BB Salt The N-(4-bromo-2,5-diethoxyphenyl)benzamide (364 mg, 1 mmol), trifluoroacetamide (169 mg, 1.5 mmol), cuprous iodide (9.5 mg, 0.05 mmol), N,N'-dimethylethylenediamine (0.1 mmol), sodium iodide (75 mg, 0.5 mmol), and potassium carbonate (276 mg, 2 mmol) prepared in Example 7 were weighed and placed in a tube reactor equipped with a stirring bar. Xylene (1 mL) was added, the tube reactor was sealed, and the mixture was heated to 140°C and reacted with stirring for 24 hours. After the reaction was complete, a methanol / H2O (4 mL:4 mL) mixture was added and the mixture was reacted with stirring at 60°C for 6 hours. After the reaction was complete, water and ethyl acetate (volume ratio of water to ethyl acetate: 1:3) were added and the mixture was extracted. The organic phase was obtained by separation using a separatory funnel and dried over anhydrous magnesium sulfate. The solvent was removed from the organic phase by rotational evaporation, and the product was further purified by chromatography (stationary phase: silica gel, eluent: EA (ethyl acetate):PE (petroleum ether) volume ratio = 1:2) to obtain a pale gray solid product, which was identified as N-(4-amino-2,5-diethoxyphenyl)benzamide (Fast Blue BB salt) by nuclear magnetic resonance. The purity of N-(4-amino-2,5-diethoxyphenyl)benzamide measured by high-performance liquid chromatography was 99%, the yield was 68%, and the total yield was 44%. The nuclear magnetic resonance results were as follows. 1 H NMR(600MHz,CDCl3)δ 8.44(s,1H),8.18(s,1H),7.87(d,J=7.2Hz,2H),7.56-7.46(m,3H),6.39(s,1H),4.18-3.97(m,4H),3.67(br,2H),1.49-1.37(m,6H). 13C NMR(151MHz,CDCl3)δ 164.44,142.11,140.14,135.51,132.39,131.44,128.77,126.83,119.27,105.75,100.47,64.99,64.70,15.10,15.07.

[0062] Example 14: Production of Fast Blue BB Salt The N-(4-bromo-2,5-diethoxyphenyl)benzamide (364 mg, 1 mmol), trifluoroacetamide (124 mg, 1.1 mmol), cuprous oxide (0.01 mmol), proline (0.03 mmol), tetrabutylammonium iodide (0.01 mmol), and sodium carbonate (2 mmol) prepared in Example 8 were weighed and placed in a tube reactor equipped with a stirring bar. Tetrahydrofuran (4 mL) was added, the tube reactor was sealed, and the mixture was heated to 60°C and reacted with stirring for 30 hours. After the reaction was complete, an ethanol / H2O (2 mL:4 mL) mixture was added and the mixture was reacted with stirring at 50°C for 10 hours. After the reaction was complete, water and ethyl acetate (volume ratio of water to ethyl acetate: 1:3) were added and the mixture was extracted. The organic phase was obtained by separating it with a separatory funnel and drying the organic phase over anhydrous magnesium sulfate. The solvent was removed from the organic phase by rotational evaporation, and the product was further purified by chromatography (stationary phase: silica gel, eluent: EA (ethyl acetate):PE (petroleum ether) volume ratio = 1:2) to obtain a pale gray solid product, which was identified as N-(4-amino-2,5-diethoxyphenyl)benzamide (Fast Blue BB salt) by nuclear magnetic resonance. The purity of N-(4-amino-2,5-diethoxyphenyl)benzamide measured by high-performance liquid chromatography was 99%, the yield was 45%, and the total yield was 22.3%. The nuclear magnetic resonance results were as follows. 1 H NMR(600MHz,CDCl3)δ 8.44(s,1H),8.18(s,1H),7.87(d,J=7.2Hz,2H),7.56-7.46(m,3H),6.39(s,1H),4.18-3.97(m,4H),3.67(br,2H),1.49-1.37(m,6H). 13C NMR(151MHz,CDCl3)δ 164.44,142.11,140.14,135.51,132.39,131.44,128.77,126.83,119.27,105.75,100.47,64.99,64.70,15.10,15.07.

[0063] Example 15: Production of Fast Blue BB Salt The N-(4-bromo-2,5-diethoxyphenyl)benzamide (364 mg, 1 mmol), trifluoroacetamide (2 mmol), cupric chloride (0.1 mmol), N,N'-diethylethylenediamine (0.2 mmol), tetrabutylammonium iodide (0.1 mmol), and potassium carbonate (276 mg, 2 mmol) prepared in Example 9 were weighed and placed in a tube reactor equipped with a stirring bar. Dimethyl sulfoxide (2 mL) was added, the tube reactor was sealed, and the mixture was heated to 120°C and reacted with stirring for 20 hours. After the reaction was complete, a mixture of propanol / H2O (1 mL:4 mL) was added and the mixture was reacted with stirring at 60°C for 6 hours. After the reaction was complete, water and ethyl acetate (volume ratio of water to ethyl acetate: 1:3) were added and the mixture was extracted. The organic phase was obtained by separation using a separatory funnel and dried over anhydrous magnesium sulfate. The solvent was removed from the organic phase by rotational evaporation, and the product was further purified by chromatography (stationary phase: silica gel, eluent: EA (ethyl acetate):PE (petroleum ether) volume ratio = 1:2) to obtain a pale gray solid product, which was identified as N-(4-amino-2,5-diethoxyphenyl)benzamide (Fast Blue BB salt) by nuclear magnetic resonance. The purity of N-(4-amino-2,5-diethoxyphenyl)benzamide measured by high-performance liquid chromatography was 99%, the yield was 51%, and the total yield was 23.8%. The nuclear magnetic resonance results were as follows. 1 H NMR(600MHz,CDCl3)δ 8.44(s,1H),8.18(s,1H),7.87(d,J=7.2Hz,2H),7.56-7.46(m,3H),6.39(s,1H),4.18-3.97(m,4H),3.67(br,2H),1.49-1.37(m,6H). 13 C NMR(151MHz,CDCl3)δ 164.44,142.11,140.14,135.51,132.39,131.44,128.77,126.83,119.27,105.75,100.47,64.99,64.70,15.10,15.07.

[0064] (Comparative Example 1) The synthesis route for Comparative Example 1 was as follows. [ka] The specific synthesis steps based on the aforementioned synthesis route were as follows: (1) Add 1,4-diethoxybenzene (6.64 g, 40 mmol) to a 250 mL reaction flask, add dichloromethane (100 mL) and acetic acid (50 mL), cool in an ice bath at 0°C, add fuming nitric acid (98%, 25 mL) dropwise, stir for 2 hours, and after the reaction is complete, pour the reaction solution into ice water (200 mL). Separate using a separatory funnel to obtain the organic phase and aqueous phase, extract the aqueous phase twice with dichloromethane (100 mL of dichloromethane was used for each extraction), combine the extracted dichloromethane phase and the organic phase, wash the combined organic phase twice with sodium bicarbonate aqueous solution (the concentration of the sodium bicarbonate aqueous solution was 0.5 N, and the amount of sodium bicarbonate aqueous solution used per wash was 100 mL), then wash the organic phase twice with water (100 mL of water was used per wash), and finally wash the organic phase once with saturated saline solution (saturated saline solution). The amount used was 100 mL. The organic phase after washing was dried with sodium sulfate, the solvent was removed by rotary evaporator, and the residue was separated by column chromatography (stationary phase was silica gel, eluent was petroleum ether:ethyl acetate in a volume ratio of 10:1) to obtain 7.26 g of product. The product was identified as 1,4-diethoxy-2-nitrobenzene by nuclear magnetic resonance and measured by high-performance liquid chromatography. The purity of 1,4-diethoxy-2-nitrobenzene was 99.5%, and the yield was 86%.

[0065] The nuclear magnetic resonance (NMS) identification results for 1,4-diethoxy-2-nitrobenzene were as follows: 1 H NMR(600MHz,CDCl3)δ 7.34(d,J=3.2Hz,1H),7.07(dd,J=9.2,3.2Hz,1H),7.00(d,J=9.2Hz,1H),4.12(q,J=6.8Hz,2H),4.02(q,J=7.2Hz,2H),1.46-1.38(m,6H). 13 C NMR(150MHz,CDCl3)δ 152.9,147.4,139.5,121.0,115.1,110.0,64.6,64.1,15.2,15.0.

[0066] (2) Add 1,4-diethoxy-2-nitrobenzene (7.26 g, 34.4 mmol) to a 150 mL three-necked flask, then add 50 mL of methanol and 1 g of Pd / C, and allow to react for 6 hours with hydrogen flow. After the reaction is complete, remove the solid by filtration to obtain a filtrate, and purify the filtrate by column chromatography (stationary phase is silica gel, eluent is petroleum ether:ethyl acetate in volume ratio = 10:1) to obtain 5.73 g of a yellow solid, which was identified as 2,5-diethoxyaniline by nuclear magnetic resonance, and measured by high-performance liquid chromatography. The purity of 2,5-diethoxyaniline was 99%, and the yield was 92%.

[0067] The nuclear magnetic resonance (NMS) identification results for 2,5-diethoxyaniline were as follows: 1 H NMR(600MHz,CDCl3)δ 6.70(d,J=8.7Hz,1H),6.35(d,J=2.9Hz,1H),6.24(dd,J=8.7,2.9Hz,1H),4.00(m,4H),3.70(s,2H),1.40(m,6H). 13 C NMR(150MHz,CDCl3)δ 153.6,141.0,137.4,112.7,102.9,102.6,64.5,63.7,15.1,14.9.

[0068] (3) 2,5-diethoxyaniline (5.73 g, 31.6 mmol) was dissolved in chloroform (50 mL), and the alkaline reagent triethylamine (4.80 g, 47.4 mmol) was added. The mixture was cooled in an ice bath at 0°C, and a chloroform solution of benzoyl chloride (5.34 g, 38 mmol) (20 mL) was slowly added. The mixture was stirred at room temperature for 12 hours, then separated using a separatory funnel to obtain an organic phase and an aqueous phase. The organic phase was washed twice with water (50 mL of water used each time), and then once with saturated brine (50 mL of brine used). The washed organic phase was dried over sodium sulfate, and the solvent was removed using a rotary evaporator to obtain a solid. This solid was recrystallized with ethyl acetate to obtain a white solid (7.67 g), which was identified as N-(2,5-diethoxyphenyl)benzamide by nuclear magnetic resonance. The product purity was measured by high-performance liquid chromatography, and the yield was 99% and 85%.

[0069] The nuclear magnetic resonance results for N-(2,5-diethoxyphenyl)benzamide were as follows: 1 H NMR(600MHz,CDCl3)δ 8.59(br s,1H),8.27(d,J=3.2Hz,1H),7.83(d,J=6.8Hz,2H),7.56-7.45(m,3H),6.79(d,J =8.9Hz,1H),6.60(dd,J=3.0Hz,8.9Hz,1H),4.20-4.02(m,4H),1.50-1.41(m,6H). 13 C NMR(150MHz,CDCl3)δ 165.3,154.1,142.5,135.3,131.9,128.9,128.6,127.2,110.9,109.1,106.0,64.9,64.0,15.4,15.1.

[0070] (4) Add N-(2,5-diethoxyphenyl)benzamide (7.67 g, 26.9 mmol) to a 250 mL reaction flask, add chloroform (60 mL) and acetic acid (30 mL), cool in an ice bath at 0°C, add fuming nitric acid (98%, 18 mL) dropwise, stir for 1 hour, and after the reaction is complete, pour the reaction solution into ice water (100 mL). Next, separate the organic phase and aqueous phase using a separatory funnel, extract the aqueous phase twice with chloroform (50 mL of chloroform was used each time), combine the extracted chloroform phase and the organic phase, wash the combined organic phase twice with sodium bicarbonate aqueous solution (the concentration of the sodium bicarbonate aqueous solution was 0.5 N, and the amount of sodium bicarbonate aqueous solution used each time), then wash the organic phase twice with water (50 mL of water was used each time), and then wash once with saturated saline solution (saturated saline solution) (50 mL of brine was used), the organic phase after washing was dried with sodium sulfate, and the solvent was removed by evaporator. The residue was separated by column chromatography (stationary phase: silica gel, eluent: petroleum ether:ethyl acetate, volume ratio = 3:1) to obtain 6.90 g of product. The product was identified as N-(2,5-diethoxy-4-nitrophenyl)benzamide by nuclear magnetic resonance and measured by high-performance liquid chromatography. The purity of the product was 98% and the yield was 78%.

[0071] The nuclear magnetic resonance (NMRI) identification results for N-(2,5-diethoxy-4-nitrophenyl)benzamide were as follows: 1 H NMR(600MHz,CDCl3)δ 8.68(s,1H),8.49(s,1H),7.89(d,J=6.9Hz,2H),7.60-7.53(m,3H),7.02(s,1H),4.24-4.05(m,4H),1.56-1.47(m,6H). 13 C NMR(150MHz,CDCl3)δ 165.72,157.25,141.57,134.42,133.56,132.59,129.14,127.21,116.97,113.52,103.32,64.72,64.01,15.55,15.15.

[0072] (5) N-(2,5-diethoxy-4-nitrophenyl)benzamide (6.90 g, 20.9 mmol) and stannous chloride monohydrate (13.7 g, 66 mmol) were added to ethyl acetate (100 mL), and the mixture was stirred and reacted under reflux for 6 hours. Next, the mixture was cooled to room temperature, saturated sodium bicarbonate aqueous solution was added dropwise until the pH reached 8, and the solid was removed by filtration through diatomaceous earth. The filtrate was separated using a separatory funnel to obtain an organic phase and an aqueous phase. The aqueous phase was extracted with ethyl acetate (80 mL), and the extracted ethyl acetate phase and the organic phase were combined. The combined organic phase was washed twice with water (80 mL each time), and then once with saturated saline solution (80 mL). After washing, the organic phase was dried with sodium sulfate, and the solvent was removed using a rotary evaporator. Finally, the residue was separated by column chromatography (stationary phase: silica gel, eluent: petroleum ether:ethyl acetate volume ratio = 2:1) to obtain 5.02 g of product. The product was identified as Fast Blue BB Salt by nuclear magnetic resonance and measured by high-performance liquid chromatography. The purity of the obtained Fast Blue BB Salt was 99%, the yield was 80%, and the total yield was 41.9%.

[0073] The nuclear magnetic resonance (NRS) identification results for Fast Blue BB salt were as follows: 1 H NMR(600MHz,CDCl3)δ 8.44(s,1H),8.18(s,1H),7.87(d,J=7.2Hz,2H),7.56-7.46(m,3H),6.39(s,1H),4.18-3.97(m,4H),3.67(br,2H),1.49-1.37(m,6H). 13 C NMR(151MHz,CDCl3)δ 164.44,142.11,140.14,135.51,132.39,131.44,128.77,126.83,119.27,105.75,100.47,64.99,64.70,15.10,15.07.

[0074] This invention synthesizes N-(4-amino-2,5-diethoxyphenyl)benzamide using 1,4-diethoxybenzene as a starting material and a four-step reaction involving bromination, two amidations, and hydrolysis. This method fundamentally avoids highly hazardous and polluting reactions such as nitration, and offers advantages such as a short reaction pathway, mild reaction conditions, high process safety, and environmental friendliness, thus meeting the demands for greening and safe development.

[0075] Comparing Example 4 and Example 5, Example 4, which used toluene as the first organic solvent to prepare N-(4-bromo-2,5-diethoxyphenyl)benzamide, yielded a higher yield. Comparing Example 4 and Example 6, when prepared with a catalyst amount of 5% and a ligand amount of 10%, the yield of N-(4-bromo-2,5-diethoxyphenyl)benzamide was higher.

[0076] A comparison of Examples 10, 11, and 13 revealed that Example 10, which used 1,4-dioxane as the second organic solvent to produce Fast Blue BB salt, yielded a higher yield.

[0077] Comparative Example 12 and 13 Compared to Example 1 0 is By selecting specific raw materials and parameters in the process, the total yield of the resulting Fastblue BB salt was found to far exceed the yield of the Fastblue BB salt produced by Comparative Example 1. In particular, the total yield of the Fastblue BB salt produced in Example 12 reached 61.2%, significantly higher than the 41.9% of Comparative Example 1. This approach achieves fewer reaction steps, greener and safer reaction processes, improved yield of the target product (Fastblue BB salt), and a substantial reduction in production costs for businesses.

[0078] Finally, I would like to add that the above preferred embodiments are for illustrating the technical solutions of the present invention and are not limiting. While the above preferred embodiments describe the present invention in detail, it will be understood by those skilled in the art that various changes can be made to the formal details without departing from the scope limited by the claims of the present invention.

[0079] (Note) (Note 1) (1) The step of obtaining 1,4-dibromo-2,5-diethoxybenzene by a bromination reaction of 1,4-diethoxybenzene, (2) In the presence of an alkaline reagent, a copper salt catalyst, its ligand and additives, the 1,4-dibromo-2,5-diethoxybenzene prepared in step (1) and benzamide are reacted in a first organic solvent to obtain N-(4-bromo-2,5-diethoxyphenyl)benzamide. (3) In the presence of an alkaline reagent, a copper salt catalyst, its ligand and additives, react the N-(4-bromo-2,5-diethoxyphenyl)benzamide prepared in step (2) with trifluoroacetamide in a second organic solvent to obtain N-(2,5-diethoxy-4-(2,2,2-trifluoroacetylamino)phenyl)benzamide, A method for synthesizing N-(4-bromo-2,5-diethoxyphenyl)benzamide, characterized by comprising the step of (4) obtaining N-(4-amino-2,5-diethoxyphenyl)benzamide by hydrolysis of N-(2,5-diethoxy-4-(2,2,2-trifluoroacetylamino)phenyl)benzamide prepared in step (3).

[0080] (Note 2) The synthesis method described in Appendix 1, characterized in that the bromination reaction is carried out by adding a brominating reagent to a mixed solution of 1,4-diethoxybenzene and a third organic solvent under the protection of an inert gas, preferably with a reaction temperature of -10 to 10°C, and more preferably with a reaction time of 2 to 10 hours.

[0081] (Note 3) The brominating reagent is selected from one or more of bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium bromideperbromide, carbon tetrabromide, 1,3-dibromo-1,3,5-triazine-2,4,6-trione, N-bromophthalimide, and N-bromosaccharin, preferably bromine. Preferably, the molar ratio of bromine element to 1,4-diethoxybenzene in the brominating reagent is 2 to 6:1. Preferably, the third organic solvent is selected from one or more of acetic acid, dichloromethane, chloroform, or carbon tetrachloride, preferably dichloromethane or chloroform, and more preferably the weight of the third organic solvent is 1 to 20 times the weight of 1,4-diethoxybenzene, characterized in that, the synthesis method according to Appendix 2.

[0082] (Note 4) The copper salt catalyst described in step (2) and step (3) is independently selected from one or more of the following: cuprous iodide, cuprous chloride, cuprous oxide, cuprous acetate, copper sulfate, copper trifluoromethanesulfonate, cupric chloride, cupric bromide, and cupric oxide, and preferably cuprous iodide and / or cupric chloride. Preferably, the amount of the copper salt catalyst described in step (2) used is 0.2 to 10% of 1,4-dibromo-2,5-diethoxybenzene on a molar basis, preferably 0.5 to 5%, more preferably 1 to 5%, and / or, the amount of the copper salt catalyst described in step (3) used is 1 to 10% of N-(4-bromo-2,5-diethoxyphenyl)benzamide on a molar basis, preferably 1 to 5%, characterized in that the synthesis method according to any one of the appendices 1 to 3.

[0083] (Note 5) The ligands of the catalyst described in step (2) and step (3) are independently selected from one or more of proline, tetramethylethylenediamine, N,N'-dimethylethylenediamine, bipyridine, 1,10-phenanthroline, triphenylphosphine, and tricyclohexylphosphine, respectively, preferably N,N'-dimethylethylenediamine and / or proline. Preferably, the amount of the catalyst ligand described in step (2) used is 1 to 20% of 1,4-dibromo-2,5-diethoxybenzene on a molar basis, preferably 1 to 10%, more preferably 5 to 10%, and / or, the amount of the ligand described in step (3) used is 1 to 20% of N-(4-bromo-2,5-diethoxyphenyl)benzamide on a molar basis, preferably 5 to 10%, characterized in that the synthesis method according to any one of the appendices 1 to 4.

[0084] (Note 6) The alkaline reagents described in step (2) and step (3) are each independently selected from sodium carbonate, potassium carbonate, sodium acetate, sodium bicarbonate, potassium phosphate, triethylamine, and pyridine, and are preferably potassium carbonate and / or potassium phosphate. Preferably, the molar ratio of the alkaline reagent described in step (2) to 1,4-dibromo-2,5-diethoxybenzene is 1 to 3:1, and / or the molar ratio of the alkaline reagent described in step (3) to N-(4-bromo-2,5-diethoxyphenyl)benzamide is 1 to 3:1, characterized in that the synthesis method according to any one of the appendices 1 to 5.

[0085] (Note 7) The additives described in step (2) and step (3) are each independently selected from sodium iodide, lithium iodide, potassium iodide, and tetrabutylammonium iodide, and preferably sodium iodide. Preferably, the amount of the additive described in step (2) used is 1 to 20% of 1,4-dibromo-2,5-diethoxybenzene on a molar basis, preferably 1 to 10%, more preferably 5 to 10%, and / or, the amount of the additive described in step (3) used is 1 to 300% of N-(4-bromo-2,5-diethoxyphenyl)benzamide on a molar basis, preferably 50 to 200%, the synthesis method according to any one of the appendices 1 to 6.

[0086] (Note 8) The first organic solvent and the second organic solvent are each independently selected from toluene, tetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate, dimethyl sulfoxide, and N,N-dimethylformamide, and preferably toluene and / or 1,4-dioxane. Preferably, the mass ratio of the first organic solvent described in step (2) to 1,4-dibromo-2,5-diethoxybenzene is 1 to 10:1, and more preferably, the first organic solvent is toluene and / or The synthesis method according to any one of the appendices 1 to 7, characterized in that the mass ratio of the second organic solvent described in step (3) to N-(4-bromo-2,5-diethoxyphenyl)benzamide is 1 to 10:1, and more preferably the second organic solvent is 1,4-dioxane.

[0087] (Note 9) The synthesis method according to any one of the appendices 1 to 8, characterized in that the molar ratio of 1,4-dibromo-2,5-diethoxybenzene to benzamide described in step (2) is 1:1 to 2, preferably 1:1 to 1.5.

[0088] (Note 10) The synthesis method according to any one of the appendices 1 to 9, characterized in that the molar ratio of N-(4-bromo-2,5-diethoxyphenyl)benzamide to trifluoroacetamide described in step (3) is 1:1 to 3, preferably 1:1.5 to 2.

[0089] (Note 11) The synthesis method according to any one of the appendices 1 to 10, characterized in that the reaction temperature for both the reaction described in step (2) and step (3) is 60 to 140°C, and preferably the reaction time for both is 20 to 40 hours.

[0090] (Note 12) The hydrolysis reaction described in step (4) is carried out in water or an aqueous solution of alcohol, preferably an aqueous solution of alcohol, more preferably the aqueous solution of alcohol is one of an aqueous methanol solution, an aqueous ethanol solution, or an aqueous propanol solution, and preferably the volume ratio of alcohol to water in the aqueous solution of alcohol is 1:1 to 4. The synthesis method according to any one of the appendices 1 to 11, characterized in that the temperature of the hydrolysis reaction described in step (4) is 50 to 80°C, and preferably the duration of the hydrolysis reaction is 4 to 10 hours.

Claims

1. (1) A step of separating and purifying the reaction product by a bromination reaction of 1,4-diethoxybenzene to obtain 1,4-dibromo-2,5-diethoxybenzene, (2) In the presence of an alkaline reagent, a copper salt catalyst, its ligand and additives, the 1,4-dibromo-2,5-diethoxybenzene prepared in step (1) and benzamide are reacted in a first organic solvent to obtain N-(4-bromo-2,5-diethoxyphenyl)benzamide. (3) In the presence of an alkaline reagent, a copper salt catalyst, its ligand and additives, the N-(4-bromo-2,5-diethoxyphenyl)benzamide prepared in step (2) and trifluoroacetamide are reacted in a second organic solvent to obtain N-(2,5-diethoxy-4-(2,2,2-trifluoroacetylamino)phenyl)benzamide, A method for synthesizing N-(4-amino-2,5-diethoxyphenyl)benzamide, characterized by comprising the step of (4) obtaining N-(4-amino-2,5-diethoxyphenyl)benzamide by hydrolysis of N-(2,5-diethoxy-4-(2,2,2-trifluoroacetylamino)phenyl)benzamide prepared in step (3).

2. The synthesis method according to claim 1, characterized in that the bromination reaction is carried out by adding a brominating reagent to a mixed solution of 1,4-diethoxybenzene and a third organic solvent under the protection of an inert gas.

3. The synthesis method according to claim 2, characterized in that the reaction temperature is -10 to 10°C and / or the reaction time is 2 to 10 hours.

4. The synthesis method according to claim 2, characterized in that the brominating reagent is selected from one or more of bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin, pyridinium bromideperbromide, carbon tetrabromide, 1,3-dibromo-1,3,5-triazine-2,4,6-trione, N-bromophthalimide, and N-bromosaccharin, and the third organic solvent is selected from one or more of acetic acid, dichloromethane, chloroform, or carbon tetrachloride.

5. The synthesis method according to claim 2, characterized in that the molar ratio of bromine element to 1,4-diethoxybenzene in the brominating reagent is 2 to 6:

1.

6. The synthesis method according to claim 2, characterized in that the weight of the third organic solvent is 1 to 20 times the weight of 1,4-diethoxybenzene.

7. The copper salt catalyst described in step (2) and step (3) is independently selected from one or more of the following: cuprous iodide, cuprous chloride, cuprous oxide, cuprous acetate, copper sulfate, copper trifluoromethanesulfonate, cupric chloride, cupric bromide, and cupric oxide. And / or, The ligands of the catalyst described in step (2) and step (3) are independently selected from one or more of the following: proline, tetramethylethylenediamine, N,N'-dimethylethylenediamine, bipyridine, 1,10-phenanthroline, triphenylphosphine, and tricyclohexylphosphine. And / or, The alkaline reagents described in step (2) and step (3) are independently selected from sodium carbonate, potassium carbonate, sodium acetate, sodium bicarbonate, potassium phosphate, triethylamine, and pyridine, one or more of these, respectively. And / or, The synthesis method according to claim 1, characterized in that the additives described in step (2) and step (3) are independently selected from sodium iodide, lithium iodide, potassium iodide, and tetrabutylammonium iodide, one or more of them.

8. The amount of copper salt catalyst used in step (2) is 0.2 to 10% of 1,4-dibromo-2,5-diethoxybenzene, and / or the amount of copper salt catalyst used in step (3) is 1 to 10% of N-(4-bromo-2,5-diethoxyphenyl)benzamide, based on a mole percentage. And / or, On a molar basis, the amount of the catalyst ligand described in step (2) used is 1 to 20% of 1,4-dibromo-2,5-diethoxybenzene, and / or, on a molar basis, the amount of the ligand described in step (3) used is 1 to 20% of N-(4-bromo-2,5-diethoxyphenyl)benzamide. And / or, The molar ratio of the alkaline reagent described in step (2) to 1,4-dibromo-2,5-diethoxybenzene is 1 to 3:1, and / or the molar ratio of the alkaline reagent described in step (3) to N-(4-bromo-2,5-diethoxyphenyl)benzamide is 1 to 3:

1. And / or, The synthesis method according to claim 7, characterized in that, on a molar basis, the amount of the additive described in step (2) used is 1 to 20% of 1,4-dibromo-2,5-diethoxybenzene, and / or, on a molar basis, the amount of the additive described in step (3) used is 1 to 300% of N-(4-bromo-2,5-diethoxyphenyl)benzamide.

9. On a molar basis, the amount of the copper salt catalyst used in step (2) is 0.5 to 5% of 1,4-dibromo-2,5-diethoxybenzene, and / or, on a molar basis, the amount of the copper salt catalyst used in step (3) is 1 to 5% of N-(4-bromo-2,5-diethoxyphenyl)benzamide. And / or, On a molar basis, the amount of the catalyst ligand described in step (2) used is 1 to 10% of 1,4-dibromo-2,5-diethoxybenzene, and / or, on a molar basis, the amount of the ligand described in step (3) used is 5 to 10% of N-(4-bromo-2,5-diethoxyphenyl)benzamide. And / or, The synthesis method according to claim 8, characterized in that, on a molar basis, the amount of the additive described in step (2) used is 1 to 10% of 1,4-dibromo-2,5-diethoxybenzene, and / or, on a molar basis, the amount of the additive described in step (3) used is 50 to 200% of N-(4-bromo-2,5-diethoxyphenyl)benzamide.

10. The amount of copper salt catalyst used in step (2) is 1 to 5% of 1,4-dibromo-2,5-diethoxybenzene, based on mole percentage. And / or, On a molar basis, the amount of catalyst ligand used in step (2) is 5-10% of 1,4-dibromo-2,5-diethoxybenzene. And / or, The synthesis method according to claim 9, characterized in that, on a molar basis, the amount of the additive described in step (2) used is 5 to 10% of 1,4-dibromo-2,5-diethoxybenzene.

11. The copper salt catalyst described in step (2) and step (3) is independently selected from one or more of the following: cuprous iodide, cuprous chloride, cuprous oxide, cuprous acetate, copper sulfate, copper trifluoromethanesulfonate, cupric chloride, cupric bromide, and cupric oxide. And / or, The ligands of the catalyst described in step (2) and step (3) are independently selected from one or more of the following: proline, tetramethylethylenediamine, N,N'-dimethylethylenediamine, bipyridine, 1,10-phenanthroline, triphenylphosphine, and tricyclohexylphosphine. And / or, The alkaline reagents described in step (2) and step (3) are independently selected from sodium carbonate, potassium carbonate, sodium acetate, sodium bicarbonate, potassium phosphate, triethylamine, and pyridine, one or more of these, respectively. And / or, The synthesis method according to claim 2, characterized in that the additives described in step (2) and step (3) are independently selected one or more from sodium iodide, lithium iodide, potassium iodide, and tetrabutylammonium iodide, respectively.

12. The synthesis method according to claim 1, characterized in that the first organic solvent and the second organic solvent are each independently selected from toluene, tetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate, dimethyl sulfoxide, and N,N-dimethylformamide, one or more of these.

13. The mass ratio of the first organic solvent described in step (2) to 1,4-dibromo-2,5-diethoxybenzene is 1 to 10:1 and / or The synthesis method according to claim 12, characterized in that the mass ratio of the second organic solvent described in step (3) to N-(4-bromo-2,5-diethoxyphenyl)benzamide is 1 to 10:

1.

14. The synthesis method according to claim 7, characterized in that the first organic solvent and the second organic solvent are independently selected from toluene, tetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate, dimethyl sulfoxide, and N,N-dimethylformamide, one or more of these.

15. The mass ratio of the first organic solvent and 1,4-dibromo-2,5-diethoxybenzene described in step (2) is 1 to 10:1 and / or, The synthesis method according to claim 14, characterized in that the mass ratio of the second organic solvent described in step (3) to N-(4-bromo-2,5-diethoxyphenyl)benzamide is 1 to 10:

1.

16. The molar ratio of 1,4-dibromo-2,5-diethoxybenzene to benzamide described in step (2) is 1:1 to 2. And / or, The synthesis method according to claim 1, characterized in that the molar ratio of N-(4-bromo-2,5-diethoxyphenyl)benzamide to trifluoroacetamide described in step (3) is 1:1 to 3.

17. The synthesis method according to claim 1, characterized in that the reaction temperature of the reaction described in step (2) and step (3) is 60 to 140°C and / or the reaction time is 20 to 40 hours.

18. The hydrolysis reaction described in step (4) is carried out in water or an aqueous solution of alcohol. The synthesis method according to any one of claims 1 to 17, characterized in that the temperature of the hydrolysis reaction described in step (4) is 50 to 80°C, and the duration of the hydrolysis reaction is 4 to 10 hours.

19. The synthesis method according to claim 18, characterized in that the alcohol aqueous solution is one of methanol aqueous solution, ethanol aqueous solution, or propanol aqueous solution.

20. The synthesis method according to claim 19, characterized in that the volume ratio of alcohol to water in the alcohol aqueous solution is 1:1 to 4.

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