Preparation method of 3-N-maleimidobenzoic acid
By using tert-butyl 3-aminobenzoate as a raw material, the carboxyl group on the benzene ring is avoided from participating in the ring-closure reaction. A simple hydrolysis step is used to prepare 3-N-maleimide benzoic acid, which solves the problems of low purity and yield in the prior art and achieves the preparation of the target product with high purity.
Patent Information
- Application Number
- CN202511620483.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-11-07
- Publication Date
- 2026-02-10
AI Technical Summary
Existing methods for synthesizing 3-N-maleimide benzoic acid cannot simultaneously achieve high yield and high purity, and also suffer from numerous side reactions.
Using tert-butyl 3-aminobenzoate as a raw material, 1-(3-tert-butyloxycarbonylphenyl)aminomaleic acid is generated by reacting with maleic anhydride. Then, a lactam is formed under the action of a cyclizing reagent, and the protecting group is removed by hydrolysis under acidic conditions to obtain 3-N-maleimide benzoic acid.
The operation process was simplified, the occurrence of side reactions was reduced, and the purity of the product was improved.
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Figure FT_1 
Figure FT_2 
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Abstract
Description
TECHNICAL FIELD
[0001] The application belongs to the technical field of organic synthesis, and more particularly relates to a preparation method of 3-N-maleimide benzoic acid. BACKGROUND
[0002] 3-N-maleimide benzoic acid is an important intermediate of organic compounds, and has wide application in the fields of functional materials, medicine, especially cancer treatment, and targeted drugs. It contains two reactive groups, a carboxyl group and a double bond, and is a typical heterobifunctional crosslinking agent. It can participate in free radical polymerization or thiol addition reaction, and can also react with hydroxyl groups and amino groups through the carboxyl group, thereby connecting two different biological macromolecules or functional materials together to construct complex biomaterials and sensors.
[0003] At present, the methods for synthesizing 3-N-maleimide benzoic acid mainly include the following: One method is to directly react 3-aminobenzoic acid and maleic anhydride to obtain an open-loop intermediate, and then to close the loop to obtain 3-N-maleimide benzoic acid (Russ. J. Bioorg. Chem., 2024, 50, 991-1000). The specific synthesis route is shown in formula (1) as follows.
[0004] (1) However, although this synthesis route has a short step, it cannot balance high yield and high purity. In the ring-closing step, the carboxyl group on the benzene ring also participates in the reaction, resulting in an increase in impurities and a decrease in yield.
[0005] In addition to the above method, a degradable resin can be used to react with 3-nitrobenzoic acid to protect the carboxyl group, and then stannous chloride is used to reduce the nitro group to an amino group, and then the open-loop and ring-closing steps are performed with maleic anhydride, and finally the resin is removed to obtain 3-N-maleimide benzoic acid (Org. Lett., 2001, 3, 22). The specific synthesis route is shown in formula (2) as follows.
[0006] (2) However, although this synthesis route can avoid the interference of the carboxyl group on the benzene ring in the ring-closing step, the synthesis steps are long, and highly dangerous reagents such as stannous chloride are used, which has a high risk coefficient and low synthesis efficiency. SUMMARY
[0007] Therefore, the present application aims to provide a preparation method of 3-N-maleimide benzoic acid, which is simple to operate, has few side reactions, and has high product purity.
[0008] To solve the above technical problems, the technical scheme adopted by the present application is as follows: The preparation method of 3-N-maleimide benzoic acid according to the embodiment of the present application comprises: Step S1, reacting tert-butyl 3-aminobenzoate with maleic anhydride to generate 1-(3-tert-butoxycarbonylphenyl) aminomaleic acid; Step S2, ring-closing reaction of the 1-(3-tert-butoxycarbonylphenyl) aminomaleic acid under the action of a ring-closing reagent to form a lactam, to generate tert-butyl 3-N-maleimide benzoate; Step S3, hydrolysis reaction of the tert-butyl 3-N-maleimide benzoate under acidic conditions to generate 3-N-maleimide benzoic acid.
[0009] According to some embodiments of the present application, the reaction in the step S1 is carried out in a first solvent selected from any one or more of dichloromethane, acetonitrile, acetone, DMF.
[0010] Further, in the step S1, the molar ratio of the tert-butyl 3-aminobenzoate to maleic anhydride is 1:(1.0-1.5), the reaction temperature is 0-40℃, and the reaction time is 1-6 h.
[0011] Further, after the reaction in the step S1 is completed, the system is cooled to 0-5℃, incubated and stirred for 1 h, filtered, the filter cake is washed with cold acetonitrile, and dried to obtain the 1-(3-tert-butoxycarbonylphenyl) aminomaleic acid.
[0012] According to some embodiments of the present application, in the step S2, the ring-closing reagent is a sodium acetate / acetic anhydride system, and the molar ratio of the 1-(3-tert-butoxycarbonylphenyl) aminomaleic acid to sodium acetate to acetic anhydride is 1:(0.05-0.5):(0.5-4.0).
[0013] Further, in the step S2, the reaction temperature of the ring-closing reaction is 0-80℃, and the reaction time is 2-10 h.
[0014] Further, in the step S2, after the reaction is completed, the solvent is removed by concentration under reduced pressure, extracted with dichloromethane, washed with water, dried, and then slurried after distillation under reduced pressure to obtain the tert-butyl 3-N-maleimide benzoate.
[0015] According to some embodiments of the present application, in the step S3, the hydrolysis is carried out in a second solvent in the presence of an acid, the acid is one or more of p-toluenesulfonic acid monohydrate, trifluoroacetic acid, and hydrochloric acid, and the second solvent is any one or more of dichloromethane, 1,4-dioxane, and water.
[0016] Further, in step S3, the molar ratio of tert-butyl 3-N-maleimide benzoate to acid is 1:(0.5~5.0); the reaction temperature is 0~50℃; and the reaction time is 2~12 h.
[0017] Further, in step S3, immediately after the reaction is completed, the phase is extracted and separated with dichloromethane, the aqueous phase is further extracted with dichloromethane, and the organic phases are combined, dried with anhydrous sodium sulfate, and then purified by adding petroleum ether to obtain the 3-N-maleimide benzoic acid.
[0018] The above-described technical solution of the present invention has at least one of the following beneficial effects: According to the method for preparing 3-N-maleimide benzoic acid according to the present invention, by using tert-butyl 3-aminobenzoate as a raw material, the carboxyl group on its benzene ring is in a protected state. Compared with the reaction using 3-aminobenzoic acid as the starting material, the carboxyl group can be prevented from participating in the subsequent ring-closing reaction of maleimide, thereby reducing the occurrence of side reactions and the difficulty of purification, and improving the purity of the product. The method described in this invention is simple to operate, has few side reactions, and produces high product purity. Attached Figure Description
[0019] Figure 1 The liquid phase spectrum of the product obtained in Example 1 is shown; Figure 2 The liquid phase spectrum of the product obtained in Comparative Example 1 is shown. Detailed Implementation
[0020] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the described embodiments of the present invention are within the scope of protection of the present invention.
[0021] The preparation method of 3-N-maleimide benzoic acid according to embodiments of the present invention will be described in detail below.
[0022] The method for preparing 3-N-maleimide benzoic acid according to an embodiment of the present invention includes: Step S1 involves reacting tert-butyl 3-aminobenzoate with maleic anhydride to generate 1-(3-tert-butyloxycarbonylphenyl)aminomaleic acid. Step S2 involves causing the 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid to undergo a ring-closing reaction under the action of a ring-closing reagent to form a lactam, generating tert-butyl 3-N-maleimide benzoate. Step S3 involves hydrolyzing the tert-butyl 3-N-maleimide benzoate under acidic conditions to generate 3-N-maleimide benzoic acid.
[0023] Specifically, the synthesis route is shown in equation (3) below: (3) In other words, according to the preparation method of the present invention, tert-butyl 3-aminobenzoate is selected as the raw material, and the carboxyl group on its benzene ring is in a protected state (i.e. protected by the tert-butyl ester group). Compared with the reaction with 3-aminobenzoic acid as the starting material, the carboxyl group can be avoided from participating in the subsequent ring-closing reaction of maleimide, thereby reducing the occurrence of side reactions and the difficulty of purification, and improving the purity of the product.
[0024] The following section will explain each step in detail.
[0025] (a) React tert-butyl 3-aminobenzoate with maleic anhydride to generate 1-(3-tert-butyloxycarbonylphenyl)aminomaleic acid (i.e., step S1).
[0026] The inventors of this application have fully considered the drawbacks of the prior art, namely, the direct reaction of 3-aminobenzoic acid and maleic anhydride to obtain an open-ring intermediate followed by a ring-closing reaction, and the carboxyl group in the open-ring intermediate will participate in the subsequent reaction to produce side reactions, resulting in a decrease in product purity. Based on this, after repeated research and a large number of experiments, the inventors determined that tert-butyl 3-aminobenzoate is used as the starting material, as shown in the above formula (3). The carboxyl group on the benzene ring is in a protected state (i.e. protected by the tert-butyl ester group) and will not participate in the subsequent ring-closing reaction. The target product can be obtained by simple hydrolysis after the ring-closing reaction.
[0027] According to some embodiments of the present invention, the reaction in step S1 is carried out in a first solvent, which is selected from any one or more of dichloromethane, acetonitrile, acetone, and DMF. Acetonitrile is preferred because the intermediate 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid has low solubility in acetonitrile at low temperatures, and acetonitrile crystallizes more easily than solvents such as dichloromethane, facilitating post-processing.
[0028] Further, in step S1, the molar ratio of tert-butyl 3-aminobenzoate to maleic anhydride is 1:(1.0~1.5), the reaction temperature is 0~40℃, and the reaction time is 1~6 h. Preferably, the molar ratio of tert-butyl 3-aminobenzoate to maleic anhydride is 1:1.1. Maleic anhydride is inexpensive and has high reactivity; a slight excess can ensure complete reaction. The reaction temperature is 20~25℃, and the reaction time is 3 h, indicating high reactivity and eliminating the need for heating to increase the reaction rate.
[0029] Furthermore, after the reaction in step S1 is completed, the system is cooled to 0-5°C, stirred at this temperature for 1 h, filtered, and the filter cake is washed with cold acetonitrile and dried to obtain 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid. In other words, the post-processing is simple and does not require complex purification procedures.
[0030] (ii) Ring-closing reaction (i.e., step S2) That is, after obtaining the intermediate 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid, a cyclization reaction is carried out to form a lactam, generating tert-butyl 3-N-maleimide benzoate.
[0031] According to some embodiments of the present invention, in step S2, the cyclization reagent is a sodium acetate / acetic anhydride system, and the molar ratio of 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid:sodium acetate:acetic anhydride is 1:(0.05~0.5):(0.5~4.0).
[0032] Preferably, the molar ratio of 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid:sodium acetate:acetic anhydride is 1:0.1:1.0.
[0033] Further, in step S2, the ring-closing reaction is carried out at a temperature of 0-80°C for 2-10 hours. Preferably, the reaction temperature is 60°C and the reaction time is 6 hours. Sodium acetate and a higher temperature can promote the ring-closing reaction without causing the decomposition of tert-butyl ester due to excessively high temperatures.
[0034] Furthermore, this step can be carried out in any one or more solvents such as THF, acetonitrile, and DMF. Acetonitrile is preferred because it is highly polar and has a moderate boiling point, which facilitates the reaction and post-processing.
[0035] Further, in step S2, after the reaction is complete, the solvent is removed by vacuum concentration, followed by extraction with dichloromethane, washing with water, drying, vacuum distillation, and pulping to obtain the tert-butyl 3-N-maleimide benzoate. Similarly, by avoiding side reactions, the post-processing becomes simple and easy to operate.
[0036] (iii) Hydrolysis reaction (i.e., step S3) In other words, after obtaining tert-butyl 3-N-maleimide benzoate, the target product can be obtained simply by hydrolyzing to remove the protecting group, namely the tert-butyl ester group.
[0037] According to some embodiments of the present invention, in step S3, hydrolysis is carried out in a second solvent in the presence of an acid, wherein the acid is one or more of p-toluenesulfonic acid monohydrate, trifluoroacetic acid, and hydrochloric acid, and the second solvent is any one or more of dichloromethane, 1,4-dioxane, and water.
[0038] Preferably, the acid is trifluoroacetic acid. The second solvent is dichloromethane. Trifluoroacetic acid can participate well in ester hydrolysis in the organic solvent of dichloromethane, and post-processing is convenient.
[0039] Further, in step S3, the molar ratio of tert-butyl 3-N-maleimide benzoate to acid is 1:(0.5~5.0); the reaction temperature is 0~50℃, and the reaction time is 2~12 h. Preferably, the molar ratio of tert-butyl 3-N-maleimide benzoate to acid is 1:2.0, the reaction temperature is 20~25℃, and the reaction time is 8 h.
[0040] Further, in step S3, immediately after the reaction is completed, the phase is extracted and separated with dichloromethane, the aqueous phase is further extracted with dichloromethane, and the organic phases are combined, dried with anhydrous sodium sulfate, and then purified by adding petroleum ether to obtain the 3-N-maleimide benzoic acid.
[0041] As described above, this invention provides a simple and effective method for preparing 3-N-maleimide benzoic acid. Furthermore, the preparation method of this invention is simple to operate, has few side reactions, and produces high purity.
[0042] The preparation method of 3-N-maleimide benzoic acid of the present invention will be further described in detail below through specific embodiments. Example 1
[0043] (a) Preparation of 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid In a 500 mL three-necked round-bottom flask, add 250 mL of acetonitrile, then add 45 g of tert-butyl 3-aminobenzoate and 25.12 g of maleic anhydride in sequence, and incubate at room temperature (20~25℃) for 3 h.
[0044] Post-processing: The system was cooled to 0-5℃, kept warm and stirred for 1 h, filtered, the filter cake was washed with a small amount of cold acetonitrile, and dried to obtain 61.73 g of 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid, with a yield of 91.0%.
[0045] (II) Preparation of tert-butyl 3-N-maleimide benzoate In a 500 mL three-necked round-bottom flask, 40 g of 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid was added to 200 mL of acetonitrile, followed by the addition of 1.13 g of sodium acetate and 14.02 g of acetic anhydride. The mixture was then heated to 60 °C and kept at that temperature for 6 h.
[0046] Post-processing: The reaction solvent was concentrated under reduced pressure at 40℃, then 150 mL of dichloromethane and 80 mL of water were added, the mixture was extracted and separated, the organic phase was washed with 80 mL of water, dried over anhydrous sodium sulfate, evaporated to dryness, and the crude product was purified by slurrying with petroleum ether to obtain 30.77 g of tert-butyl 3-N-maleimide benzoate, with a yield of 82.0%.
[0047] (III) Preparation of 3-N-maleimide benzoic acid In a 250 mL three-necked round-bottom flask, add 120 mL of dichloromethane, 40 g of tert-butyl 3-N-maleimide benzoate and 33.38 g of trifluoroacetic acid, and react at room temperature (20~25℃) for 8 h.
[0048] Post-processing: Concentrated under reduced pressure, then purified by adding petroleum ether to obtain 29.31 g of 3-N-maleimide benzoic acid, with a yield of 92.2%.
[0049] The NMR data of the product are shown below: 1 H NMR (400 MHz, CDCl3) δ 2.87 – 2.81 (m, 4H), 2.58 (br, 4H), 1.60 (m,1H), 0.48 – 0.37 (m, 4H).
[0050] Data shows that its structure is consistent with the target product 3-N-maleimide benzoic acid. Comparative Example 1
[0051] 3-N-maleimide benzoic acid was synthesized according to the synthetic method described in the literature (Russ. J. Bioorg. Chem., 2024, 50, 991–1000, i.e. the first synthetic route described in the background art).
[0052] The products obtained in Example 1 and Comparative Example 1 were subjected to liquid chromatography to test their purity.
[0053] The liquid phase conditions are shown in Table 1 below:
[0054] The liquid phase spectrum of the product obtained in Example 1 is as follows: Figure 1 As shown. The detection results of the product obtained using this patented method are as follows. Figure 1 As shown. By Figure 1 It can be seen that the purity of 3-N-maleimide benzoic acid, the product obtained by the patented method, is 99.57%.
[0055] Accordingly, the liquid phase spectrum obtained in Comparative Example 1 is as follows: Figure 2 As shown. By Figure 2It can be seen that the purity of the product 3-N-maleimide benzoic acid obtained by this method is 95.61%.
[0056] In summary, the method for synthesizing 3-N-maleimide benzoic acid of the present invention can yield a product with higher purity.
[0057] Example 2 (a) Preparation of 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid In a 500 mL three-necked round-bottom flask, add 250 mL of acetonitrile, then add 45 g of tert-butyl 3-aminobenzoate and 23.98 g of maleic anhydride in sequence, and incubate at room temperature (20~25℃) for 3 h.
[0058] Post-processing: The system was cooled to 0-5℃, kept warm and stirred for 1 h, filtered, the filter cake was washed with a small amount of cold acetonitrile, and dried to obtain 60.51 g of 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid, with a yield of 89.2%.
[0059] (II) Preparation of tert-butyl 3-N-maleimide benzoate In a 500 mL three-necked round-bottom flask, 40 g of 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid was added to 200 mL of acetonitrile, followed by 0.56 g of sodium acetate and 14.02 g of acetic anhydride. The mixture was heated to 60 °C and kept at that temperature for 6 h.
[0060] Post-processing: The reaction solvent was concentrated under reduced pressure at 40℃, then 150 mL of dichloromethane and 80 mL of water were added, the mixture was extracted and separated, the organic phase was washed with 80 mL of water, dried over anhydrous sodium sulfate, evaporated to dryness, and the crude product was purified by slurrying with petroleum ether to obtain 29.46 g of tert-butyl 3-N-maleimide benzoate, with a yield of 78.5%.
[0061] (III) Preparation of 3-N-maleimide benzoic acid In a 250 mL three-necked round-bottom flask, add 120 mL of 50% dioxane aqueous solution, 40 g of tert-butyl 3-N-maleimide benzoate and 2.78 g of p-toluenesulfonic acid monohydrate, and react at room temperature (20~25℃) for 8 h.
[0062] Post-processing: 100 mL of dichloromethane was added for extraction and separation. The aqueous phase was then extracted with 50 mL of dichloromethane. The organic phases were combined, washed with 80 mL of anhydrous sodium sulfate, dried to dryness, and then purified by stirring with petroleum ether to obtain 28.26 g of 3-N-maleimide benzoic acid, with a yield of 88.9%.
[0063] The NMR data of the product are shown below: 1H NMR (400 MHz, CDCl3) δ 2.87 – 2.81 (m, 4H), 2.58 (br, 4H), 1.60 (m, 1H), 0.48 – 0.37 (m, 4H).
[0064] Data shows that its structure is consistent with the target product 3-N-maleimide benzoic acid.
[0065] Example 3 (a) Preparation of 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid In a 500 mL three-necked round-bottom flask, add 250 mL of acetonitrile, then add 45 g of tert-butyl 3-aminobenzoate and 25.12 g of maleic anhydride in sequence, and heat to 40 °C and maintain the temperature for 3 h.
[0066] Post-processing: The system was cooled to 0-5℃, kept warm and stirred for 1 h, filtered, the filter cake was washed with a small amount of cold acetonitrile, and dried to obtain 58.34 g of 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid, with a yield of 86.0%.
[0067] (II) Preparation of tert-butyl 3-N-maleimide benzoate In a 500 mL three-necked round-bottom flask, 40 g of 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid was added to 200 mL of acetonitrile, followed by the addition of 1.13 g of sodium acetate and 14.02 g of acetic anhydride. The mixture was then heated to 80 °C and kept at that temperature for 6 h.
[0068] Post-processing: The reaction solvent was concentrated under reduced pressure at 40℃, then 150 mL of dichloromethane and 80 mL of water were added, the mixture was extracted and separated, the organic phase was washed with 80 mL of water, dried over anhydrous sodium sulfate, evaporated to dryness, and the crude product was purified by slurrying with petroleum ether to obtain 28.22 g of tert-butyl 3-N-maleimide benzoate, with a yield of 75.2%.
[0069] (III) Preparation of 3-N-maleimide benzoic acid In a 250 mL three-necked round-bottom flask, add 120 mL of dichloromethane, 40 g of tert-butyl 3-N-maleimide benzoate and 33.38 g of trifluoroacetic acid, and heat to 40 °C and maintain the temperature for 8 h.
[0070] Post-processing: Concentrated under reduced pressure, then purified by adding petroleum ether to obtain 27.31 g of 3-N-maleimide benzoic acid, with a yield of 85.9%.
[0071] The generated nuclear magnetic resonance data are shown below: 1H NMR (400 MHz, CDCl3) δ 2.87 – 2.81 (m, 4H), 2.58 (br, 4H), 1.60 (m, 1H), 0.48 – 0.37 (m, 4H).
[0072] Data shows that its structure is consistent with the target product 3-N-maleimide benzoic acid.
[0073] Example 4 (a) Preparation of 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid In a 500 mL three-necked round-bottom flask, add 250 mL of dichloromethane, then add 45 g of tert-butyl 3-aminobenzoate and 25.12 g of maleic anhydride in sequence, and incubate at room temperature (20~25℃) for 3 h.
[0074] Post-treatment: Wash with 100 mL of water, dry with anhydrous sodium sulfate, evaporate to dryness to obtain 60.71 g of 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid, yield 89.5%.
[0075] (II) Preparation of tert-butyl 3-N-maleimide benzoate In a 500 mL three-necked round-bottom flask, 40 g of 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid was added to 200 mL of LDM, followed by 1.13 g of sodium acetate and 14.02 g of acetic anhydride. The mixture was heated to 60 °C and kept at that temperature for 6 h.
[0076] Post-processing: The reaction solvent was concentrated under reduced pressure at 70℃, then 150 mL of dichloromethane and 80 mL of water were added, the mixture was extracted and separated, the organic phase was washed with 80 mL of water, dried over anhydrous sodium sulfate, evaporated to dryness, and the crude product was purified by slurrying with petroleum ether to obtain 30.21 g of tert-butyl 3-N-maleimide benzoate, with a yield of 80.5%.
[0077] (III) Preparation of 3-N-maleimide benzoic acid In a 250 mL three-necked round-bottom flask, add 120 mL of dichloromethane, 40 g of tert-butyl 3-N-maleimide benzoate and 16.69 g of trifluoroacetic acid, and react at room temperature (20~25℃) for 8 h.
[0078] Post-processing: Concentrated under reduced pressure, then purified by adding petroleum ether to obtain 26.26 g of 3-N-maleimide benzoic acid, with a yield of 82.6%.
[0079] The NMR data of the product are shown below: 1H NMR (400 MHz, CDCl3) δ 2.87 – 2.81 (m, 4H), 2.58 (br, 4H), 1.60 (m,1H), 0.48 – 0.37 (m, 4H).
[0080] Data shows that its structure is consistent with the target product 3-N-maleimide benzoic acid.
[0081] The above description represents the preferred embodiments of the present invention. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of the present invention, and these improvements and modifications should also be considered within the scope of protection of the present invention.
Claims
1. A method for preparing 3-N-maleimide benzoic acid, characterized in that, include: Step S1 involves reacting tert-butyl 3-aminobenzoate with maleic anhydride to generate 1-(3-tert-butyloxycarbonylphenyl)aminomaleic acid. Step S2 involves causing the 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid to undergo a ring-closing reaction under the action of a ring-closing reagent to form a lactam, generating tert-butyl 3-N-maleimide benzoate. Step S3 involves hydrolyzing the tert-butyl 3-N-maleimide benzoate under acidic conditions to generate 3-N-maleimide benzoic acid.
2. The preparation method according to claim 1, characterized in that, The reaction in step S1 is carried out in a first solvent, which is selected from any one or more of dichloromethane, acetonitrile, acetone, and DMF.
3. The preparation method according to claim 2, characterized in that, In step S1, the molar ratio of tert-butyl 3-aminobenzoate to maleic anhydride is 1:(1.0~1.5), the reaction temperature is 0~40℃, and the reaction time is 1~6 h.
4. The preparation method according to claim 2, characterized in that, After the reaction in step S1 is completed, the system is cooled to 0~5℃, kept warm and stirred for 1 h, filtered, the filter cake is washed with cold acetonitrile, and dried to obtain the 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid.
5. The preparation method according to claim 1, characterized in that, In step S2, the cyclization reagent is a sodium acetate / acetic anhydride system, and the molar ratio of 1-(3-tert-butoxycarbonylphenyl)aminomaleic acid:sodium acetate:acetic anhydride is 1:(0.05~0.5):(0.5~4.0).
6. The preparation method according to claim 4, characterized in that, In step S2, the reaction temperature of the ring-closing reaction is 0~80℃, and the reaction time is 2~10 h.
7. The preparation method according to claim 4, characterized in that, In step S2, after the reaction is complete, the solvent is removed by vacuum concentration, the mixture is extracted with dichloromethane, washed with water, dried, and then pulped after vacuum distillation to obtain the tert-butyl 3-N-maleimide benzoate.
8. The preparation method according to claim 1, characterized in that, In step S3, hydrolysis is carried out in a second solvent in the presence of an acid, wherein the acid is one or more of p-toluenesulfonic acid monohydrate, trifluoroacetic acid, and hydrochloric acid, and the second solvent is any one or more of dichloromethane, 1,4-dioxane, and water.
9. The preparation method according to claim 8, characterized in that, In step S3, the molar ratio of tert-butyl 3-N-maleimide benzoate to acid is 1:(0.5~5.0); the reaction temperature is 0~50℃; and the reaction time is 2~12 h.
10. The preparation method according to claim 9, characterized in that, In step S3, immediately after the reaction is completed, the phase is extracted and separated with dichloromethane. The aqueous phase is further extracted with dichloromethane, and the organic phases are combined. After drying with anhydrous sodium sulfate, petroleum ether is added for slurry purification to obtain the 3-N-maleimide benzoic acid.