Synthesis method of 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 to related applications) This application claims the priority of a prior application with the application number 202311439148.0 filed in China on October 31, 2023, and it is incorporated herein by reference in its entirety.

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

Background Art

[0003] N-(4 - amino - 2,5 - diethoxyphenyl)benzamide, also known as Fast Blue BB Salt, with the English name Fast Blue BB and the Color Index number 37175, is a dye and a developer that can be used for the dyeing and printing of cotton, viscose, and silk fabrics. Currently, the synthesis of this product is mainly carried out by a reaction with five steps: nitration, reduction, acylation, re - nitration, and re - reduction of 1,4 - diethoxybenzene. In the nitration step, concentrated nitric acid needs to be used, which requires high - level equipment, is prone to corrosion, and has a great safety risk. Also, due to the long synthesis route, the overall efficiency is low, and the energy consumption and cost in the synthesis are high, so the production cost is increasing.

[0004] Therefore, developing a more efficient, greener, and safer new synthesis method has become a practical need in the production and use of Fast Blue BB Salt.

Summary of the Invention

Problems to be Solved by the Invention

[0005] Regarding the above problems, the technical problem to be solved by the present invention is to provide a new synthesis method for Fast Blue BB Salt with fewer reaction steps, higher yield, more green, and safer.

Means for Solving the Problem

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

[0007] In some embodiments of the present application, the bromination reaction described in step (1) is to add a bromination reagent to a mixed solution of 1,4-diethoxybenzene and a third organic solvent and react under the protection of an inert gas. Preferably, the reaction temperature is -10 to 10 °C, and more preferably, the reaction time is 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, and carbon tetrachloride, and preferably, it is dichloromethane or chloroform. 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 steps (2) and (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 0.5-5%, and more preferably 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 1-5%.

[0010] In some embodiments of the present application, the ligands of the catalysts described in steps (2) and (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 usage 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 usage 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, they are 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, it is sodium iodide. Preferably, based on mole percentage, the usage 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 usage 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 one or more of toluene, tetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate, dimethyl sulfoxide, and N,N-dimethylformamide, and preferably, they are 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, and preferably, it is 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, and preferably, it is 1:1.5 to 2.

[0016] In some embodiments of the present application, the reaction temperatures of the reactions described in steps (2) and (3) are both 60 to 140 °C, and preferably, the reaction times are both 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 alcohol aqueous solution, preferably in an alcohol aqueous solution, and more preferably, the alcohol aqueous solution is one of a methanol aqueous solution, an ethanol aqueous solution, or a propanol aqueous solution, and preferably, the volume ratio of alcohol to water in the alcohol aqueous solution is 1:1 to 4. And / or, the temperature of the hydrolysis reaction described in step (4) is 50 to 80 °C, preferably, the time of the hydrolysis reaction is 4 to 10 hours.

Advantages of the Invention

[0018] The beneficial effects of the present invention are as follows. The present invention provides a novel synthetic route for N-(4-amino-2,5-diethoxyphenyl)benzamide. The synthetic route consists of only four steps, and by performing the reactions of four steps including bromination, two amidations and hydrolysis, it fundamentally avoids highly dangerous and highly polluting reactions such as nitration. It has the advantages of short reaction route, mild reaction conditions, high process safety, environmental friendliness, etc., and meets the requirements of green and safe development.

Embodiments for Carrying out the Invention

[0019] In the present invention, unless otherwise specified in a specific context, the numerical ranges shown in this specification include the upper and lower limit values, and "above" and "below" 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 in this specification is an inclusive term. For example, "A and / or B" refers to the case where only A exists, or only B exists, or both A and B exist.

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

Chemical Formula

[0021] The design principle of the synthetic 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 an electrophilic bromination reaction with a bromination reagent, then obtains N - (4 - bromo - 2,5 - diethoxyphenyl)benzamide by amidation with benzamide under a copper catalyst, and finally realizes amidation with trifluoroacetamide by a copper catalyst and obtains the product N - (4 - amino - 2,5 - diethoxyphenyl)benzamide by hydrolysis.

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

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

[0024] In some embodiments of the present application, the bromination 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 preferably, it is bromine. Considering various factors such as cost, efficiency, yield, and purity of the product comprehensively, the molar ratio of bromine element in the bromination reagent to 1,4-diethoxybenzene is preferably 2-6:1. In some embodiments of the present application, the molar ratio of bromine element in the bromination reagent to 1,4-diethoxybenzene may be 2:1, 3:1, 4:1, 5:1 or 6:1, or within the numerical range formed by taking 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, provided that N-(4-amino-2,5-diethoxyphenyl)benzamide of the present application can be obtained.

[0025] The reaction solvent has a great influence on whether the bromination reaction proceeds smoothly. An appropriate reaction solvent can improve the selectivity of the bromination reaction, suppress the occurrence of dibromination side reactions, reduce the usage amount of the bromination reagent, and improve the purity of the product. The third organic solvent described in the present application is selected from one or more of acetic acid, dichloromethane, chloroform, and carbon tetrachloride, and preferably, it is chloroform or dichloromethane. If the usage amount of the solvent is too much or too little, it will have an adverse effect on the reaction. Preferably, the usage amount of the third organic solvent is 1-20 times that of 1,4-diethoxybenzene, the reaction raw material, more preferably 5-15 times, still more preferably 6-11 times, and even more preferably 5-7 times.

[0026] The gas generated in step (1) is passed through an aqueous solution of Na2SO3 and / or NaHCO3 for treatment, and after the reaction is completed, the reaction is quenched with a saturated aqueous solution of Na2SO3.

[0027] This application further includes a 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 this application, the copper salt catalysts described in steps (2) and (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, preferably cuprous iodide and / or cupric chloride, and more preferably cuprous iodide. Based on molar percentage, the amount of the 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%. Based on molar percentage, the amount of the 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 this application, the amount of the copper salt catalyst used in step (2) described above may be 0.2 to 10%, 0.2 to 9%, 0.2 to 8%, 0.2 to 7%, 0.2 to 6%, 0.2 to 5%, 0.2 to 4%, 0.2 to 3%, 0.2 to 2%, 0.2 to 1%, 0.5 to 10%, 1 to 10%, 2 to 10%, 3 to 10%, 4 to 10%, 5 to 10%, 6 to 10%, 7 to 10%, 8 to 10%, or 9 to 10% of the raw material 1,4-dibromo-2,5-diethoxybenzene. In some embodiments, the amount of the copper salt catalyst used in step (2) described 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 the numerical range formed by taking two of the 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, provided that the fast blue BB salt of the present invention can be obtained.

[0030] In some embodiments of the present application, the amount of the copper salt catalyst described 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 the copper salt catalyst described 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 formed by taking 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, provided that the fast blue BB salt of the present invention can be obtained.

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

[0032] In some embodiments of the present application, the amount of the ligand described in step (2) above may be 1 to 20%, 1 to 19%, 1 to 18%, 1 to 17%, 1 to 16%, 1 to 15%, 1 to 14%, 1 to 13%, 1 to 12%, 1 to 11%, 1 to 10%, 2 to 20%, 3 to 20%, 4 to 20%, 5 to 20%, 6 to 20%, 7 to 20%, 8 to 20%, 9 to 20% or 10 to 20% of the raw material 1,4-dibromo-2,5-diethoxybenzene. In some embodiments, the amount of the copper salt catalyst described 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 formed by taking 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, provided that the fast blue BB salt of the present invention can be obtained.

[0033] In some embodiments of the present application, the amount of the ligand described in step (3) above may be 1 to 20%, 1 to 19%, 1 to 18%, 1 to 17%, 1 to 16%, 1 to 15%, 1 to 14%, 1 to 13%, 1 to 12%, 1 to 11%, 1 to 10%, 2 to 20%, 3 to 20%, 4 to 20%, 5 to 20%, 6 to 20%, 7 to 20%, 8 to 20%, 9 to 20% or 10 to 20% of the raw material N-(4-bromo-2,5-diethoxyphenyl)benzamide. In some embodiments, the amount of the copper salt catalyst described 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 formed by taking 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, provided that the fast blue BB salt of the present invention can be obtained.

[0034] 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, they are 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 raw 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 one or more of sodium iodide, lithium iodide, potassium iodide, and tetrabutylammonium iodide, and preferably, it is sodium iodide. By exchanging halogen ions, an aromatic iodine compound with higher activity in situ is generated to promote the conversion of the bromide of the raw material.

[0036] Preferably, based on the molar percentage, the usage 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 the molar percentage, the usage amount of the additive described in step (3) 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 the additive described in step (2) above may be 1 to 20%, 1 to 19%, 1 to 18%, 1 to 17%, 1 to 16%, 1 to 15%, 1 to 14%, 1 to 13%, 1 to 12%, 1 to 11%, 1 to 10%, 2 to 20%, 3 to 20%, 4 to 20%, 5 to 20%, 6 to 20%, 7 to 20%, 8 to 20%, 9 to 20% or 10 to 20% of the raw material 1,4-dibromo-2,5-diethoxybenzene. In some embodiments, the amount of the additive described 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 the numerical range formed by taking 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, provided that the fast blue BB salt of the present invention can be obtained.

[0038] In some embodiments of the present application, the amount of the additive used in step (3) above may be 1 to 10%, 1 to 20%, 1 to 30%, 1 to 40%, 1 to 50%, 1 to 60%, 1 to 70%, 1 to 80%, 1 to 90%, 1 to 100%, 1 to 200%, 1 to 250%, 1 to 300%, 10 to 300%, 20 to 300%, 30 to 300%, 40 to 300%, 50 to 300%, 60 to 300%, 70 to 300%, 80 to 300%, 90 to 300%, 100 to 300% or 200 to 300% of N-(4-bromo-2,5-diethoxyphenyl)benzamide. In some embodiments, the amount of the 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 the numerical range formed by taking 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, provided that the fast blue BB salt of the present invention can be obtained.

[0039] To mitigate the occurrence of side reactions, the reaction needs to be carried out in a suitable solvent. Each of the first organic solvent and the second organic solvent is independently selected from one or more of toluene, tetrahydrofuran, 1,4 - dioxane, acetonitrile, ethyl acetate, dimethyl sulfoxide, and N,N - dimethylformamide, preferably toluene and / or 1,4 - dioxane. Adding the solvent is mainly to dissolve and disperse the reaction raw materials, put the raw materials in a good dispersion state, and facilitate the reaction. If the amount of the solvent used is too much or too little, it will have an adverse effect on the reaction. Preferably, the amount of the first organic solvent used is 1 to 10 times that of 1,4 - dibromo - 2,5 - diethoxybenzene of the reaction raw materials. More preferably, the first organic solvent is toluene. Even more preferably, the amount of the second organic solvent used is 1 to 10 times that of N-(4 - bromo - 2,5 - diethoxyphenyl)benzamide of the reaction raw materials. More preferably, the second organic solvent is 1,4 - dioxane.

[0040] The selection of the reaction temperature is related to the solvent used. To accelerate the reaction rate, the reaction temperature can be appropriately increased so as to reach the boiling point of the solvent used, that is, the reaction system reacts in a reflux state. When the reaction temperature is increased, the reaction rate can be accelerated. However, if the reaction temperature is too high, side reactions will become active, which is disadvantageous for improving the product purity. If the reaction temperature is too low, the reaction rate will be very slow and the production efficiency will decrease. Therefore, preferably, the reaction temperatures in both step (2) and step (3) are both 60 to 140 °C, and preferably, the reaction times are both 20 to 40 hours. More preferably, the reaction temperature of the reaction described in step (2) is 100 to 120 °C. Even more preferably, the reaction temperature of the reaction described in step (2) is 100 to 140 °C, 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 meet the reaction conditions. If the amount of benzamide is too large, the diamination side reaction is likely to occur, which is disadvantageous 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, appropriately increasing the amount of trifluoroacetamide used is advantageous for the progress of the reaction.

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

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

[0045] The synthetic route for producing Fast Blue BB Salt according to the following examples is as follows.

Chemical formula

[0046] The raw materials or reagents used in the present invention are purchased from major market manufacturers. Those without specified manufacturers or concentrations are all analytically pure raw materials or reagents that can be obtained through normal procurement routes, and are not particularly limited as long as they can achieve the desired effects. The devices and equipment used in this example are all purchased from major market manufacturers and are not particularly limited as long as they can achieve the desired effects. When the technology or conditions are not specifically specified in this example, they are carried out according to the technologies or conditions described in the literature in this field or the product manuals.

[0047] The provision of each reagent and device used in the following examples is as shown in Table 1. Table 1: Information on the 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 stir bar. CHCl3 (90 mL) was added as a 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. The addition was completed in 25 minutes, and the gas generated in the reaction was treated with an aqueous solution of Na2SO3 and NaHCO3. After the addition was completed, timing was started. After reacting for 3 hours, the reaction was quenched with a saturated aqueous solution of Na2SO3 and stirred until it became colorless. Liquid - liquid separation was carried out with a separatory funnel to obtain an organic phase and an aqueous phase. The aqueous phase was extracted twice with dichloromethane (using 100 mL of dichloromethane for each extraction). The extracted dichloromethane phase and the organic phase were combined. The organic phase was further washed once with water and once with saturated brine, dried over anhydrous magnesium sulfate, and then the solvent was removed by a rotary evaporator to obtain a white solid. Finally, recrystallization was carried out with a mixed solvent of methanol and dichloromethane (the volume ratio of methanol to dichloromethane was 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 measured by high - performance liquid chromatography was 99%, and the yield was 90%.

[0049] The identification result of 1,4 - dibromo - 2,5 - diethoxybenzene by nuclear magnetic resonance was 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 stir bar. Dichloromethane (100 mL) was added as a solvent. Under the protection of an inert gas, bromine (195 mmol) was added, and the addition was completed in 25 minutes. An aqueous solution of Na2SO3 and NaHCO3 was used to treat the gas generated in the reaction. The reaction was carried out at 10 °C. After the addition was completed, the timing was started. After reacting for 2 hours, the reaction was quenched with a saturated aqueous solution of Na2SO3 and stirred until it became colorless. Liquid - liquid separation was carried out with a separatory funnel to obtain an organic phase and an aqueous phase. The aqueous phase was extracted twice with dichloromethane (100 mL of dichloromethane was used for each extraction). The extracted dichloromethane phase and the organic phase were combined, and the organic phase was washed once with water and once with saturated brine respectively. After the organic phase was dried over magnesium sulfate, the solvent was removed by a rotary evaporator to obtain a white solid. Finally, recrystallization was carried out with a mixed solvent of methanol and dichloromethane (the volume ratio of methanol to dichloromethane was 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%. When 1,4 - dibromo - 2,5 - diethoxybenzene was analyzed by nuclear magnetic resonance, the following results were obtained. 1 H NMR (600 MHz, CDCl3) δ 7.09 (s, 2H), 4.03 (q, J = 7.0 Hz, 4H), 1.44 (t, J = 7.0 Hz, 6H). 13 C NMR (151 MHz, 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 stir bar, and CHCl3 (100 mL) was added as a 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 a saturated aqueous Na2SO3 solution. Liquid - liquid separation was carried out with a separatory funnel to obtain an organic phase and an aqueous phase. The aqueous phase was extracted twice with dichloromethane (using 100 mL of dichloromethane for each extraction). The extracted dichloromethane phase and the organic phase were combined, and the organic phase was washed once with water and once with saturated brine. After drying the organic phase over anhydrous magnesium sulfate, the solvent was removed by a rotary evaporator to obtain a solid. Finally, chromatography was carried out 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%. When 1,4 - dibromo - 2,5 - diethoxybenzene was analyzed by nuclear magnetic resonance, the following results were obtained. 1 H NMR (600 MHz, CDCl3) δ 7.09 (s, 2H), 4.03 (q, J = 7.0 Hz, 4H), 1.44 (t, J = 7.0 Hz, 6H). 13 C NMR (151 MHz, CDCl3) δ 149.99, 118.61, 111.17, 65.93, 14.77.

[0052] Example 4: 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 toluene (2 mL) was added to the tube reactor. After sealing the tube reactor, it was heated to 110 °C and reacted with stirring for 24 hours. After completion of the reaction, saturated brine was added for quenching, ethyl acetate was added for dilution and dissolution, and then separated with a separatory funnel to obtain an organic phase. The organic phase was dried over anhydrous magnesium sulfate, the solvent was removed from the organic phase by a rotary evaporator, 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) to obtain a white solid product. 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 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=7.5Hz,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.

[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 (stationary phase: silica gel, eluent: volume ratio of DCM (dichloromethane):PE (petroleum ether) = 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 (600 MHz, CDCl3) δ 8.60 (s, 1H), 8.40 (s, 1H), 7.91 - 7.85 (m, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.09 (s, 1H), 4.16 (q, J = 7.0 Hz, 2H), 4.10 (q, J = 7.0 Hz, 2H), 1.50 - 1.44 (m, 6H). 13 C NMR (151 MHz, 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 1,4-Dibromo-2,5-diethoxybenzene (324 mg, 1 mmol) prepared in Example 1, 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) were weighed and placed in a tube reactor equipped with a stir bar. Solvent toluene (2 mL) was added to the tube reactor. After sealing the tube reactor, it was heated to 110 °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, the organic phase was separated with a separatory funnel, 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 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=7.5Hz,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.

[0055] Example 7: 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 phosphate (424 mg, 2 mmol) were weighed and placed in a tube reactor equipped with a stir bar. Solvent toluene (2 mL) was added to the tube reactor. After sealing the tube reactor, it was heated to 110 °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, the organic phase was separated with a separatory funnel, 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 (stationary phase: silica gel, eluent: volume ratio of DCM (dichloromethane):PE (petroleum ether) = 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 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=7.5Hz,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.

[0056] Example 8: Preparation of N-(4-bromo-2,5-diethoxyphenyl)benzamide 1,4-Dibromo-2,5-diethoxybenzene (324 mg, 1 mmol) prepared in Example 2, 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) were weighed and placed in a tube reactor equipped with a stir bar. Solvent 1,4-dioxane (3 mL) was added to the tube reactor. After sealing the tube reactor, it was heated to 100 °C and reacted with stirring for 30 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 54%, and the nuclear magnetic resonance results were as follows. 1 H NMR (600 MHz, CDCl3) δ 8.60 (s, 1H), 8.40 (s, 1H), 7.91 - 7.85 (m, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.09 (s, 1H), 4.16 (q, J = 7.0 Hz, 2H), 4.10 (q, J = 7.0 Hz, 2H), 1.50 - 1.44 (m, 6H). 13 C NMR (151 MHz, 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) prepared in Example 3, 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) were weighed and placed in a tube reactor equipped with a stir bar. Dimethyl sulfoxide (1 mL) was added to the tube reactor. After sealing the tube reactor, it was heated to 120 °C and reacted with stirring for 20 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 (stationary phase: silica gel, eluent: volume ratio of DCM (dichloromethane):PE (petroleum ether) = 1:2). A white solid product was obtained. The purity of N-(4-bromo-2,5-diethoxyphenyl)benzamide measured by high performance liquid chromatography was 99%, and the yield was 60%. The product was analyzed by nuclear magnetic resonance and identified as N-(4-bromo-2,5-diethoxyphenyl)benzamide. The nuclear magnetic resonance results were as follows. 1 H NMR (600 MHz, CDCl3) δ 8.60 (s, 1H), 8.40 (s, 1H), 7.91 - 7.85 (m, 2H), 7.57 (t, J = 7.4 Hz, 1H), 7.52 (t, J = 7.5 Hz, 2H), 7.09 (s, 1H), 4.16 (q, J = 7.0 Hz, 2H), 4.10 (q, J = 7.0 Hz, 2H), 1.50 - 1.44 (m, 6H). 13 C NMR (151 MHz, 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 N-(4-Bromo-2,5-diethoxyphenyl)benzamide (364 mg, 1 mmol) prepared in Example 4, 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 stir bar. Solvent 1,4-dioxane (1 mL) was added, and after sealing the tube reactor, it was heated to 100 °C and reacted with stirring for 24 hours. After completion of the reaction, a methanol / H2O (4 mL:4 mL) mixture was added, and the reaction was carried out with stirring at 60 °C for 6 hours. After completion of the reaction, water and ethyl acetate (the volume ratio of water to ethyl acetate was 1:3) were added for extraction. Separation was carried out 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 EA (ethyl acetate):PE (petroleum ether) with a volume ratio = 1:2) to obtain a light 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%, the total yield was 50%, and the nuclear magnetic resonance results were as follows. 1 H NMR (600 MHz, CDCl3) δ 8.44 (s, 1H), 8.18 (s, 1H), 7.87 (d, J = 7.2 Hz, 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 (151 MHz, 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 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 5 of the solid reagent were weighed and placed in a tube reactor equipped with a stir bar. Toluene (1 mL) was added, and after sealing the tube reactor, it was heated to 110°C and stirred for 24 hours. After completion of the reaction, a methanol / H2O (4 mL:4 mL) mixture was added, and the reaction was carried out with stirring at 60°C for 6 hours. After completion of the reaction, water and ethyl acetate were added for extraction. Separation was carried out 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 (eluent: volume ratio of EA (ethyl acetate):PE (petroleum ether) = 1:2) to obtain a light 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%, the total yield was 38%, and 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: Preparation of Fast Blue BB Salt Weighed 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) prepared in Example 6 of the solid reagent, and placed them in a tube reactor equipped with a stir bar. Added the solvent 1,4-dioxane (1 mL), sealed the tube reactor, then heated it to 100 °C and reacted for 36 hours with stirring. After the reaction was completed, a methanol / H2O (4 mL:4 mL) mixture was added and stirred at 60 °C for 6 hours. After completion, water and ethyl acetate (the volume ratio of water to ethyl acetate was 1:3) were added for extraction. Separated with a separatory funnel to obtain an organic phase, and dried the organic phase with anhydrous magnesium sulfate. Removed the solvent from the organic phase by rotary evaporation, and further purified the product by chromatography (the stationary phase was silica gel, and the eluent was EA (ethyl acetate):PE (petroleum ether) with a volume ratio = 1:2) to obtain a light 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%, the total yield was 61.2%, and 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: Preparation of Fast Blue BB Salt N-(4-Bromo-2,5-diethoxyphenyl)benzamide (364 mg, 1 mmol) prepared in Example 7, 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 stir bar. Xylene (1 mL) was added, and after sealing the tube reactor, it was heated to 140 °C and reacted with stirring for 24 hours. After completion of the reaction, a methanol / H2O (4 mL:4 mL) mixture was added, and the reaction was carried out with stirring at 60 °C for 6 hours. After completion, water and ethyl acetate (the volume ratio of water to ethyl acetate was 1:3) were added for extraction. The organic phase was separated with a separatory funnel and 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 EA (ethyl acetate):PE (petroleum ether) with a volume ratio = 1:2) to obtain a light 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%, the total yield was 44%, and 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). 1313C NMR (151 MHz, 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 N-(4-Bromo-2,5-diethoxyphenyl)benzamide (364 mg, 1 mmol) prepared in Example 8, 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) were weighed and placed in a tube reactor equipped with a stir bar. Tetrahydrofuran (4 mL) was added, the tube reactor was sealed, and then heated to 60 °C and reacted with stirring for 30 hours. After completion of the reaction, an ethanol / H2O (2 mL:4 mL) mixture was added and reacted with stirring at 50 °C for 10 hours. After completion, water and ethyl acetate (volume ratio of water to ethyl acetate is 1:3) were added for extraction. The organic phase was separated with a separatory funnel and 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 is silica gel, eluent is EA (ethyl acetate):PE (petroleum ether) volume ratio = 1:2) to obtain a light 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%, the total yield was 22.3%, and the nuclear magnetic resonance results were as follows. 1 1H NMR (600 MHz, CDCl3) δ 8.44 (s, 1H), 8.18 (s, 1H), 7.87 (d, J = 7.2 Hz, 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). 1313C NMR (151 MHz, 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 Weighed 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, placed them in a tube reactor equipped with a stir bar, added dimethyl sulfoxide (2 mL), sealed the tube reactor, then heated it to 120 °C and reacted with stirring for 20 hours. After the reaction was completed, a propanol / H2O (1 mL:4 mL) mixture was added and reacted with stirring at 60 °C for 6 hours. After the reaction was completed, water and ethyl acetate (the volume ratio of water to ethyl acetate was 1:3) were added for extraction. 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 EA (ethyl acetate):PE (petroleum ether) volume ratio = 1:2) to obtain a light 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%, the total yield was 23.8%, and the nuclear magnetic resonance results were as follows. 1 1H NMR (600 MHz, CDCl3) δ 8.44 (s, 1H), 8.18 (s, 1H), 7.87 (d, J = 7.2 Hz, 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 13C NMR (151 MHz, 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 of Comparative Example 1 was as shown below. [Chemical Structure] The specific synthesis steps based on the above synthesis route were as follows. (1) 1,4 - Diethoxybenzene (6.64 g, 40 mmol) was added to a 250 mL reaction flask, dichloromethane (100 mL) and acetic acid (50 mL) were added, and the mixture was cooled in an ice bath at 0 °C. Fuming nitric acid (98%, 25 mL) was added dropwise, and the mixture was stirred for 2 hours. After the reaction was completed, the reaction solution was poured into ice water (200 mL). The organic and aqueous phases were obtained by liquid separation using a separating funnel. The aqueous phase was extracted twice with dichloromethane (100 mL of dichloromethane was used for each extraction). The extracted dichloromethane phase was combined with the organic phase. The combined organic phase was washed twice with an aqueous sodium bicarbonate solution (the concentration of the aqueous sodium bicarbonate solution was 0.5 N, and 100 mL of the aqueous sodium bicarbonate solution was used for each wash), then the organic phase was washed twice with water (100 mL of water was used for each wash), and then the organic phase was washed once with saturated brine (100 mL of saturated brine was used). The washed organic phase was dried over sodium sulfate, and the solvent was removed using a rotary evaporator. The residue was separated by column chromatography (the stationary phase was silica gel, and the eluent was petroleum ether:ethyl acetate volume ratio = 10:1) to obtain 7.26 g of the product. The product was identified as 1,4 - diethoxy - 2 - nitrobenzene by nuclear magnetic resonance. Measured by high - performance liquid chromatography, the purity of 1,4 - diethoxy - 2 - nitrobenzene was 99.5% and the yield was 86%.

[0065] The identification results of 1,4 - diethoxy - 2 - nitrobenzene by nuclear magnetic resonance 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, pass hydrogen through, and react for 6 hours. After the reaction is completed, remove the solid by filtration to obtain a filtrate. The filtrate is purified by column chromatography (the stationary phase is silica gel, and the eluent is petroleum ether:ethyl acetate volume ratio = 10:1) to obtain 5.73 g of a yellow solid, which is identified as 2,5 - diethoxyaniline by nuclear magnetic resonance. Measured by high - performance liquid chromatography, the purity of 2,5 - diethoxyaniline is 99%, and the yield is 92%.

[0067] The identification results of 2,5 - diethoxyaniline by nuclear magnetic resonance 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 triethylamine (4.80 g, 47.4 mmol), an alkaline reagent, was added. It was cooled in an ice bath at 0 °C, and a chloroform (20 mL) solution of benzoyl chloride (5.34 g, 38 mmol) was slowly added. The mixture was stirred at room temperature for 12 hours, then separated with a separatory funnel to obtain an organic phase and an aqueous phase. The organic phase was washed twice with water (the amount of water used each time was 50 mL), and then washed once with saturated brine (the amount used was 50 mL). The washed organic phase was dried over sodium sulfate, and after removing the solvent with a rotary evaporator, a solid was obtained and recrystallized with ethyl acetate to obtain a white solid (7.67 g). It was identified as N-(2,5 - diethoxyphenyl)benzamide by nuclear magnetic resonance. Measured by high-performance liquid chromatography, the purity of the product was 99% and the yield was 85%.

[0069] The nuclear magnetic resonance results of 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) N-(2,5-Diethoxyphenyl)benzamide (7.67 g, 26.9 mmol) was added to a 250 mL reaction flask, chloroform (60 mL) and acetic acid (30 mL) were added, and the mixture was cooled in an ice bath at 0 °C. Fuming nitric acid (98%, 18 mL) was added dropwise, and the mixture was stirred for 1 hour. After the reaction was completed, the reaction solution was poured into ice water (100 mL). Next, liquid separation was performed with a separatory funnel to obtain an organic phase and an aqueous phase. The aqueous phase was extracted twice with chloroform (the amount of chloroform used each time was 50 mL). The extracted chloroform phase and the organic phase were combined. The combined organic phase was washed twice with an aqueous sodium bicarbonate solution (the concentration of the aqueous sodium bicarbonate solution was 0.5 N, and the amount of the aqueous sodium bicarbonate solution used each time was 50 mL). Next, the organic phase was washed twice with water (the amount of water used each time was 50 mL), and then washed once with saturated brine (the amount of saturated brine used was 50 mL). The washed organic phase was dried over sodium sulfate, and after removing the solvent with an evaporator, the residue was separated by column chromatography (the stationary phase was silica gel, and the eluent was petroleum ether:ethyl acetate volume ratio = 3:1) to obtain 6.90 g of the product. The product was identified as N-(2,5-diethoxy-4-nitrophenyl)benzamide by nuclear magnetic resonance. Measured by high-performance liquid chromatography, the purity of the product was 98%, and the yield was 78%.

[0071] The identification result of N-(2,5-diethoxy-4-nitrophenyl)benzamide by nuclear magnetic resonance was 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, it was cooled to room temperature, and a saturated aqueous sodium bicarbonate solution was added dropwise until pH = 8. The solid formed by filtration through diatomaceous earth was removed, and the filtrate was separated by liquid separation using a separatory funnel to obtain an organic phase and an aqueous phase. The aqueous phase was extracted with ethyl acetate (80 mL), the extracted ethyl acetate phase was combined with the organic phase, the combined organic phase was washed twice with water (80 mL each time), and then washed once with saturated brine (80 mL). After drying the washed organic phase with sodium sulfate, the solvent was removed by a rotary evaporator. Finally, the residue was separated by column chromatography (the stationary phase was silica gel, and the eluent was petroleum ether:ethyl acetate volume ratio = 2:1) to obtain 5.02 g of the product. The product was identified as Fast Blue BB Salt by nuclear magnetic resonance. 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 identification result of Fast Blue BB Salt by nuclear magnetic resonance was as follows. 1 H NMR (600 MHz, CDCl3) δ 8.44 (s, 1H), 8.18 (s, 1H), 7.87 (d, J = 7.2 Hz, 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 (151 MHz, 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 application synthesizes N-(4-amino-2,5-diethoxyphenyl)benzamide using 1,4-diethoxybenzene as the starting material and utilizing reactions in four steps: bromination, two amidations, and hydrolysis. It fundamentally avoids highly dangerous and highly polluting reactions such as nitration. It has advantages such as a short reaction route, mild reaction conditions, high process safety, and environmental friendliness, meeting the requirements of green and safe development.

[0075] When comparing Example 4 and Example 5, Example 4 prepared N-(4-bromo-2,5-diethoxyphenyl)benzamide using toluene as the first organic solvent and had a higher yield. When comparing Example 4 and Example 6, when the catalyst usage amount was 5% and the ligand usage amount was 10%, the yield of N-(4-bromo-2,5-diethoxyphenyl)benzamide was higher.

[0076] When comparing Example 10, 11, and 13, Example 10 manufactured Fast Blue BB Salt using 1,4-dioxane as the second organic solvent and had a higher yield.

[0077] When comparing with Comparative Example 1, it was found that Examples 10, 12, and 13, by selecting specific raw materials and parameters in the process, had a total yield of the obtained Fast Blue BB Salt far exceeding that of the Fast Blue BB Salt produced by Comparative Example 1. Among them, the total yield of the Fast Blue BB Salt produced in Example 12 reached 61.2%, much higher than 41.9% of Comparative Example 1. It can achieve fewer reaction steps, greening and safety in the reaction process, improve the yield of the target product Fast Blue BB Salt, and significantly reduce the production cost of the manufacturer.

[0078] Finally, it should be added that the above preferred embodiments are for explaining the technical solutions of the present invention and are not intended to limit it. Although the present invention has been described in detail with the above preferred embodiments, those skilled in the art will understand that various formal and detailed changes may be made without departing from the scope defined by the claims of the present invention.

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

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

[0081] (Supplementary Note 3) 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, preferably 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 dichloromethane or chloroform, and more preferably, the weight of the third organic solvent is 1-20 times the weight of 1,4-diethoxybenzene, which is characterized in that the synthesis method according to Supplementary Note 2.

[0082] (Supplementary Note 4) 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, preferably cuprous iodide and / or cupric chloride, preferably, based on 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 0.5-5%, more preferably 1-5%, and / or, based on 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 1-5%, which is characterized in that the synthesis method according to any one of Supplementary Notes 1-3.

[0083] (Supplementary Note 5) 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, preferably N,N'-dimethylethylenediamine and / or proline, Preferably, based on molar percentage, the usage amount of the ligand of the catalyst described in step (2) is 1-20% of 1,4-dibromo-2,5-diethoxybenzene, preferably 1-10%, more preferably 5-10%, and / or, based on molar percentage, the usage amount of the ligand described in step (3) is 1-20% of N-(4-bromo-2,5-diethoxyphenyl)benzamide, preferably 5-10%. The synthesis method according to any one of supplementary notes 1-4 is characterized by this.

[0084] (Supplementary note 6) 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, 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 1-3:1, and / or the molar ratio of the alkaline reagent described in step (3) to N-(4-bromo-2,5-diethoxyphenyl)benzamide is 1-3:1. The synthesis method according to any one of supplementary notes 1-5 is characterized by this.

[0085] (Supplementary note 7) 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, preferably sodium iodide, Preferably, based on mole percentage, the usage amount of the additive described in step (2) is 1 to 20% of 1,4-dibromo-2,5-diethoxybenzene, preferably 1 to 10%, more preferably 5 to 10%, and / or, based on mole percentage, the usage amount of the additive described in step (3) is 1 to 300% of N-(4-bromo-2,5-diethoxyphenyl)benzamide, preferably 50 to 200%, and the synthesis method according to any one of supplementary notes 1 to 6 is characterized in that.

[0086] (Supplementary note 8) The first organic solvent and the second organic solvent are each independently selected from one or more of toluene, tetrahydrofuran, 1,4-dioxane, acetonitrile, ethyl acetate, dimethyl sulfoxide and N,N-dimethylformamide, 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, 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, more preferably, the second organic solvent is 1,4-dioxane, and the synthesis method according to any one of supplementary notes 1 to 7 is characterized in that.

[0087] (Supplementary note 9) 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, and the synthesis method according to any one of supplementary notes 1 to 8 is characterized in that.

[0088] (Supplementary note 10) 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, and the synthesis method according to any one of supplementary notes 1 to 9 is characterized in that.

[0089] (Appendix 11) The reaction temperatures of the reactions described in step (2) and step (3) are both 60 to 140 °C, and preferably, the reaction times are both 20 to 40 hours. The synthesis method according to any one of Appendices 1 to 10 is characterized by this.

[0090] (Appendix 12) The hydrolysis reaction described in step (4) is carried out in water or an alcohol aqueous solution, preferably in an alcohol aqueous solution. More preferably, the alcohol aqueous solution is one of a methanol aqueous solution, an ethanol aqueous solution, or a propanol aqueous solution. Preferably, the volume ratio of alcohol to water in the alcohol aqueous solution 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 hydrolysis reaction time is 4 to 10 hours. The synthesis method according to any one of Appendices 1 to 11 is characterized by this.

Claims

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

2. The bromination reaction is carried out by adding a bromination reagent to a mixed solution of 1,4-diethoxybenzene and a third organic solvent under the protection of an inert gas. Preferably, the reaction temperature is -10 to 10 °C, and more preferably, the reaction time is 2 to 10 hours. The synthesis method according to Claim 1, characterized by the above.

3. 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. Preferably, it is bromine. Preferably, the molar ratio of bromine element in the bromination reagent to 1,4-diethoxybenzene 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. The synthesis method according to claim 2 is characterized by this.

4. 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, preferably cuprous iodide and / or cupric chloride. Preferably, based on mole percentage, the amount of the copper salt catalyst used in step (2) is 0.2 to 10% of 1,4 - dibromo - 2,5 - diethoxybenzene, preferably 0.5 to 5%, more preferably 1 to 5%, and / or, based on mole percentage, the amount of the copper salt catalyst used in step (3) is 1 to 10% of N-(4 - bromo - 2,5 - diethoxyphenyl)benzamide, preferably 1 to 5%. The synthesis method according to any one of claims 1 to 3 is characterized by this.

5. 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, preferably N,N’ - dimethylethylenediamine and / or proline. Preferably, based on mole percentage, the amount of the ligand of the catalyst used in step (2) is 1 to 20% of 1,4 - dibromo - 2,5 - diethoxybenzene, preferably 1 to 10%, more preferably 5 to 10%, and / or, based on mole percentage, the amount of the ligand used in step (3) is 1 to 20% of N-(4 - bromo - 2,5 - diethoxyphenyl)benzamide, preferably 5 to 10%. The synthesis method according to any one of claims 1 to 4 is characterized by this.

6. 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, 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. The synthesis method according to any one of claims 1 to 5, characterized in that.

7. 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, preferably sodium iodide, Preferably, based on the molar percentage, the amount of the additive described in step (2) used is 1 to 20% of 1,4-dibromo-2,5-diethoxybenzene, preferably 1 to 10%, more preferably 5 to 10%, and / or based on the molar percentage, the amount of the additive described in step (3) used is 1 to 300% of N-(4-bromo-2,5-diethoxyphenyl)benzamide, preferably 50 to 200%. The synthesis method according to any one of claims 1 to 6, characterized in that.

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

9. 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. The synthesis method according to any one of claims 1 to 8, characterized by this.

10. 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. The synthesis method according to any one of claims 1 to 9, characterized by this.

11. The reaction temperature of the reactions described in steps (2) and (3) is both 60 to 140°C, preferably the reaction time is both 20 to 40 hours. The synthesis method according to any one of claims 1 to 10, characterized by this.

12. The hydrolysis reaction described in step (4) is carried out in water or an alcohol aqueous solution, preferably in an alcohol aqueous solution. More preferably, the alcohol aqueous solution is one of a methanol aqueous solution, an ethanol aqueous solution, or a propanol aqueous solution. Preferably, the volume ratio of alcohol to water in the alcohol aqueous solution is 1:1 to 4. And / or, the temperature of the hydrolysis reaction described in step (4) is 50 to 80°C, preferably the time of the hydrolysis reaction is 4 to 10 hours. The synthesis method according to any one of claims 1 to 11, characterized by this.

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