Process for the preparation of N-(4-nitrophenyl)-4-nitrobenzamide

Abstract

This invention relates to the field of organic synthesis technology, specifically to a method for preparing N-(4-nitrophenyl)-4-nitrobenzamide. The method comprises: S1, dissolving p-nitrobenzoyl chloride in an inert compound solvent under inert gas conditions; the inert compound solvent includes an aprotic main solvent and a weakly polar co-solvent; S2, under controlled temperature conditions, slowly adding a portion of p-nitroaniline to the system from step S1 to form a seed reaction solution; S3, slowly adding the remaining p-nitroaniline to the seed reaction solution from step S2, and heating and maintaining the temperature for reaction; S4, after the reaction is complete, post-treatment yields N-(4-nitrophenyl)-4-nitrobenzamide. The preparation process requires no additional catalyst, effectively suppresses side reactions, ensures a safe and stable production process, significantly improves product yield and purity, and is more suitable for industrial applications.

Description

Technical Field

[0001] This invention relates to a method for preparing N-(4-nitrophenyl)-4-nitrobenzamide, belonging to the field of organic synthesis technology. Background Technology

[0002] N-(4-nitrophenyl)-4-nitrobenzamide (chemical formula C) 13 H9N3O6 is an important high-performance material monomer whose molecular structure contains two nitro groups and one amide bond, as shown in the following structural formula: .

[0003] This compound is the core raw material for the preparation of 2-(4-aminophenyl)-5-aminobenzimidazole (APBIA). APBIA has wide applications in polymer materials such as aramid fibers, polyimide films, and polyaminoimides. The amino and imidazole rings in its molecule can undergo condensation reactions with various monomers to form polymer chain structures with excellent mechanical properties, thermal stability, and chemical stability. These materials are widely used in aerospace, electronics, automotive, and protective equipment industries. Furthermore, APBIA can also be used as a pharmaceutical intermediate in drug synthesis, demonstrating significant application value and market potential.

[0004] Currently, the existing synthetic methods for N-(4-nitrophenyl)-4-nitrobenzamide involve reacting aniline with p-nitrobenzoic acid to prepare 4-nitro-N-phenylbenzamide, followed by a nitration reaction to obtain N-(4-nitrophenyl)-4-nitrobenzamide. This requires at least two steps to obtain the target product, making the process complex. Furthermore, traditional synthetic routes often require the addition of catalysts such as organic bases or Lewis acids, increasing catalyst residue and subsequent waste treatment burden, as well as raising production costs and process complexity. There is a lack of a green synthetic method that requires no catalyst, is simple to operate, has high yield, good purity, and is suitable for industrial production.

[0005] Therefore, developing an efficient, low-cost, easily scalable, and environmentally friendly process for preparing N-(4-nitrophenyl)-4-nitrobenzamide is of great significance for improving the production efficiency and quality of downstream high-performance material monomers APBIA and promoting the development of related polymer materials industries.

[0006] It should be noted that the information disclosed in the background section above is only used to enhance the understanding of the background of this disclosure, and therefore may include information that does not constitute prior art known to those skilled in the art. Summary of the Invention

[0007] This invention addresses the shortcomings of existing technologies by providing a method for preparing N-(4-nitrophenyl)-4-nitrobenzamide. It solves the core problems in the condensation reaction of dinitro compounds, such as insufficient driving force, numerous side reactions, low yield and purity, large post-processing losses, and poor product powder characteristics. This method achieves efficient directional synthesis without a catalyst, simplifies the nitration step in the subsequent preparation of APBIA, improves the industrial adaptability of the process and the compatibility with downstream products, and reduces the total production cost.

[0008] The technical solution of this invention to solve the above-mentioned technical problems is as follows: a method for preparing N-(4-nitrophenyl)-4-nitrobenzamide, wherein the preparation method is as follows: S1. Under inert gas conditions, p-nitrobenzoyl chloride is dissolved in an inert compound solvent; the inert compound solvent includes an aprotic main solvent and a weakly polar co-solvent. S2. Controlling the temperature conditions, a portion of p-nitroaniline is slowly added to the system in step S1 to form a seed reaction solution after mixing. S3. Slowly add the remaining p-nitroaniline to the seed reaction solution from step S2, and heat and maintain the temperature for reaction; S4. After the reaction is complete, N-(4-nitrophenyl)-4-nitrobenzamide is obtained through post-treatment.

[0009] Furthermore, by mass percentage, the inert compound solvent comprises 80%-90% of the aprotic main solvent and 10%-20% of the weakly polar co-solvent.

[0010] Furthermore, the aprotic primary solvent is at least one of tetrachloroethylene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and chlorobenzene; The weakly polar co-solvent is isopropyl acetate.

[0011] Furthermore, the inert compound solvent used in step S1 is dehydrated, and the water content in the dehydrated inert compound solvent is ≤0.01%; and before adding p-nitrobenzoyl chloride, anhydrous sodium sulfate is added to the system and dispersed and dissolved.

[0012] Further, in step S2, the system temperature is controlled at 40~60℃, and a portion of p-nitroaniline is slowly added and stirred for 30-40 minutes to form a seed reaction solution.

[0013] Furthermore, the mass ratio of p-nitroaniline added in step S2 to p-nitroaniline added in step S3 is 1:(2-3).

[0014] Further, in step S3, the remaining p-nitroaniline is slowly added to the seed reaction solution at a rate of 0.5~1 g / min, and then the temperature is increased to the reflux temperature at a rate of 8~10℃ / 30min, and the reaction is maintained at this temperature for 2~5h.

[0015] Furthermore, the post-processing method for step S4 is as follows: Slowly cool to 55-60℃, add some methanol to the system and stir to perform mild in-situ quenching. After slowly cooling to 0-5℃, add another part of methanol to completely quench. Then perform solid-liquid separation, washing and drying to obtain N-(4-nitrophenyl)-4-nitrobenzamide.

[0016] Furthermore, in the post-treatment process, the total amount of methanol added is 1.1-1.3 times the remaining mass of reactants in the system, and the ratio of the mass of methanol added during mild quenching to the mass of methanol added during complete quenching is 1:(1-1.5).

[0017] Furthermore, after mild in-situ quenching, the temperature is controlled at a rate of 3-5℃ / 20min to slowly cool down to 0~5℃; the drying process is a gradient cooling drying.

[0018] The beneficial effects of this invention are: The preparation method described in this invention employs a compound design of "main inert solvent + weakly polar co-solvent" without adding any catalyst. This not only improves the solubility of the dinitro base compound and achieves molecular-level dispersion, avoiding side reactions caused by excessively high local concentrations, but also slightly reduces the viscosity of the system, improves mass transfer efficiency, and shortens the reaction time by more than 30%. Furthermore, the compound solvent can be recovered and reused by distillation with a recovery rate of ≥96%, significantly reducing solvent costs.

[0019] In the preparation method described in this invention, the combination of "small-batch activation to form seed liquid + slow addition of remaining substrate" utilizes the generated amide bond product as a molecular template and pre-organizes the subsequent substrate through weak interactions, effectively reducing the reaction activation energy, thereby achieving efficient reaction initiation and complete conversion under catalyst-free conditions.

[0020] More specifically, the preparation method of the present invention combines a temperature control design of low-temperature feeding at 40~60℃, heating rate of 8~10℃ / 30min, and low-temperature crystallization at 0~5℃ to suppress localized violent exothermic reactions; and with a completely inert environment, it eliminates amino oxidation caused by trace amounts of oxygen, resulting in a product HPLC purity ≥99%, which is higher than that of conventional processes.

[0021] In the post-processing of the preparation method described in this invention, quenching and crystallization are coupled. First, light quenching is performed, followed by low-temperature crystallization. The characteristic of the target product's low-temperature solubility drops sharply is used to achieve directional crystallization, forming large-particle crystals. This avoids the loss of fine crystals with the filtrate, and the yield is increased from the conventional ≤90% to ≥96%. Moreover, only one washing is required after crystallization, reducing the post-processing time by 50%. No additional crystallization vessel is required, reducing equipment investment and making it suitable for industrial continuous production.

[0022] In the post-processing of the preparation method described in this invention, gradient cooling drying is used instead of conventional constant temperature drying, allowing the product crystals to dehydrate slowly, avoiding agglomeration and clumping. After drying, the crystals are loose and fine, requiring no additional crushing. The solubility in downstream APBIA preparation is increased by more than 30%. Combined with solvent pre-dehydration and anhydrous sodium sulfate-assisted dehydration, the hydrolysis of acyl chloride is completely eliminated, further reducing impurities and substrate loss, without increasing process time and complexity.

[0023] The preparation method described in this invention does not involve the addition of any organic bases, Lewis acids, or other catalysts throughout the process, resulting in no catalyst residue and no associated waste treatment pressure. It employs conventional reactors and mechanical stirring equipment, ensuring controllable process parameters and minimal scale-up effects. The post-processing steps are simple, and the raw materials are readily available, enabling green, safe, and low-cost industrial-scale production. This provides a replicable process template for the synthesis of similar strongly electron-withdrawing substituted amide compounds. The obtained N-(4-nitrophenyl)-4-nitrobenzamide product yield is ≥96%, with HPLC purity ≥99%. The product is a loose, fine-crystal form without agglomeration or clumping. Attached Figure Description

[0024] Figure 1 The HCl spectrum of N-(4-nitrophenyl)-4-nitrobenzamide prepared in Example 1; Figure 2 The C-chromatogram of N-(4-nitrophenyl)-4-nitrobenzamide prepared in Example 1 is shown below. Figure 3 The image shows the HPLC chromatogram of N-(4-nitrophenyl)-4-nitrobenzamide prepared in Example 1. Detailed Implementation

[0025] The specific embodiments of the present invention will be described in detail below. The present invention can be implemented in many other ways different from those described herein, and those skilled in the art can make similar modifications without departing from the spirit of the present invention. Therefore, the present invention is not limited to the specific embodiments disclosed.

[0026] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains. The terminology used is for describing particular embodiments only and is not intended to limit the invention.

[0027] A method for preparing N-(4-nitrophenyl)-4-nitrobenzamide, wherein the preparation method comprises: ; S1. Under inert gas conditions, p-nitrobenzoyl chloride is dissolved in an inert compound solvent; the inert compound solvent includes an aprotic main solvent and a weakly polar co-solvent. S2. Controlling the temperature conditions, a portion of p-nitroaniline is slowly added to the system in step S1 to form a seed reaction solution after mixing. S3. Slowly add the remaining p-nitroaniline to the seed reaction solution from step S2, and heat and maintain the temperature for reaction; S4. After the reaction is complete, N-(4-nitrophenyl)-4-nitrobenzamide is obtained through post-treatment.

[0028] Specifically, by mass percentage, the inert compound solvent comprises 80%-90% of the aprotic main solvent and 10%-20% of the weakly polar co-solvent.

[0029] Specifically, the aprotic main solvent is at least one of tetrachloroethylene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and chlorobenzene; The weakly polar co-solvent is isopropyl acetate.

[0030] Specifically, the inert compound solvent used in step S1 is dehydrated, and the water content in the dehydrated inert compound solvent is ≤0.01%; and before adding p-nitrobenzoyl chloride, anhydrous sodium sulfate is added to the system and dispersed and dissolved.

[0031] More specifically, the dehydration treatment method is as follows: an inert compound solvent is added to a reaction vessel and vacuum micro-extraction pre-dehydration treatment is performed. The process parameters for vacuum micro-extraction pre-dehydration are: vacuum degree -0.05~-0.08MPa, temperature 50~60℃, stirring time 30~40min, and the water content of the solvent after dehydration is ≤0.01%.

[0032] The total mass of the inert compound solvent is 8 to 12 times the mass of p-nitrobenzoyl chloride. Before adding p-nitrobenzoyl chloride, 0.5% to 1% (relative to the mass of p-nitrobenzoyl chloride) of anhydrous sodium sulfate can be added to the inert compound solvent. After stirring and dissolving, the substrate can be dissolved to further adsorb any trace amounts of water that may remain in the system after pre-dehydration, inhibit the hydrolysis side reaction of p-nitrobenzoyl chloride, thereby reducing the formation of carboxylic acid impurities and improving the purity of the product.

[0033] After adding p-nitrobenzoyl chloride, heat to 30~50℃ and mechanically stir to dissolve. The stirring speed is 50~200r / min, and the stirring method is uniform stirring throughout the process.

[0034] Specifically, in step S2, the system temperature is controlled at 40~60℃, and a portion of p-nitroaniline is slowly added and stirred for 30-40 minutes to form a seed reaction solution.

[0035] Specifically, the mass ratio of p-nitroaniline added in step S2 to p-nitroaniline added in step S3 is 1:(2-3).

[0036] Specifically, in step S3, the remaining p-nitroaniline is slowly added to the seed reaction solution at a rate of 0.5~1 g / min, and then the temperature is increased to the reflux temperature at a rate of 8~10℃ / 30min, and the reaction is maintained at this temperature for 2~5h.

[0037] Preferably, the reflux temperature is 110-115℃.

[0038] Specifically, the molar ratio of p-nitrobenzoyl chloride to p-nitroaniline is 1:(0.8~1.5).

[0039] Specifically, the post-processing method for step S4 is as follows: Slowly cool to 55-60℃, add some methanol to the system and stir to perform mild in-situ quenching, then slowly cool to 0-5℃ to allow the target product to crystallize slowly in situ; after crystallization, add another part of methanol to completely quench; then perform solid-liquid separation, washing and drying to obtain N-(4-nitrophenyl)-4-nitrobenzamide.

[0040] Specifically, in the post-treatment process, the total amount of methanol added is 1.1-1.3 times the remaining mass of reactants in the system. The ratio of the mass of methanol added during mild quenching to the mass of methanol added during complete quenching is 1:(1-1.5). When p-nitroaniline is in excess, the purpose of adding methanol is to wash away the excess p-nitroaniline; when p-nitrobenzoyl chloride is in excess, it is to wash away p-nitrobenzoyl chloride.

[0041] Specifically, the cooling rate is controlled at 3-5℃ / 20min to slowly cool down to 55~60℃, and after slight in-situ quenching, the cooling rate is controlled at 3-5℃ / 20min to slowly cool down to 0~5℃; the drying process is a gradient cooling drying.

[0042] More specifically, after complete quenching, the solid obtained by vacuum filtration is washed with pure water, or washed once with a 5% sodium bicarbonate aqueous solution and then washed once with pure water. The washed wet product is subjected to gradient cooling and drying in a vacuum drying oven at a vacuum degree of -0.08~-0.05MPa. First, it is dried at 55-60℃ for 1-1.5h, then cooled to 45-50℃ at a rate of 5-10℃ / h for 1-2h, and finally cooled to room temperature to obtain N-(4-nitrophenyl)-4-nitrobenzamide product.

[0043] Example 1: A method for preparing N-(4-nitrophenyl)-4-nitrobenzamide, wherein the preparation method is as follows: Under nitrogen protection, 50g of an inert compound solvent consisting of 80% tetrachloroethylene and 20% isopropyl acetate by mass percentage was added to the reactor. Mechanical stirring was started (100r / min), and pre-dehydration was carried out under vacuum at -0.06MPa and 55℃ for 35min. After dehydration, 0.5% (relative to the mass of p-nitrobenzoyl chloride) of anhydrous sodium sulfate was added, and after stirring to dissolve, 5g of p-nitrobenzoyl chloride was added. The temperature was raised to 50℃ and stirred until the solid was completely dissolved.

[0044] Maintaining the system temperature at 55°C, first slowly add 1 / 3 molar of p-nitroaniline (1.30 g) to the solution and stir for 30 min to form a seed reaction solution; then slowly add the remaining 2 / 3 molar of p-nitroaniline (2.61 g) at a rate of 0.8 g / min. After the addition is complete, purge with nitrogen to replace the air. The molar ratio of p-nitrobenzoyl chloride to p-nitroaniline is 1:1.05.

[0045] The system was heated to the reflux temperature at a gradient rate of 10℃ / 30min, and the reaction was maintained at this temperature for 5h. TLC monitoring showed that the reaction of p-nitrobenzoyl chloride was complete.

[0046] The temperature was lowered to 60℃ at a rate of 5℃ / 20min, and 0.15mL of methanol was added for mild in-situ quenching. The mixture was stirred for 10min. The temperature was then lowered to 0℃ at a rate of 5℃ / 20min to allow the product to crystallize slowly in situ. After crystallization, 0.15mL of methanol was added for complete quenching.

[0047] The sample was filtered under reduced pressure, and the filtered solid was washed once with 20 mL of pure water. The washed wet sample was placed in a vacuum drying oven and dried at 60 °C for 1 h under a vacuum of -0.06 MPa, then cooled to 50 °C at a rate of 10 °C / h and dried for 2 h, finally cooled to room temperature and discharged. The obtained product was a pale yellow, loose, fine-crystalline N-(4-nitrophenyl)-4-nitrobenzamide, with a yield of 96.83% and an HPLC purity of 99.56%. The relevant NMR spectra are shown below. Figure 1 and Figure 2 As shown, the HPLC spectrum is as follows: Figure 3 As shown in Table 1, the HPLC chromatographic data are as follows.

[0048] Table 1 HPLC Chromatographic Data

[0049] Example 2: A method for preparing N-(4-nitrophenyl)-4-nitrobenzamide, wherein the preparation method is as follows: Under nitrogen protection, 50g of an inert compound solvent consisting of 85% chlorobenzene and 15% isopropyl acetate by mass percentage was added to the reactor. Mechanical stirring was started (speed 120r / min), and pre-dehydration was carried out under vacuum micro-extraction for 30min at a vacuum degree of -0.08MPa and a temperature of 60℃. After dehydration, 1% (relative to the mass of p-nitrobenzoyl chloride) of anhydrous sodium sulfate was added, and after stirring to dissolve, 5g of p-nitrobenzoyl chloride was added. The temperature was raised to 45℃ and stirred until the solid was completely dissolved.

[0050] Maintaining the system temperature at 60°C, first slowly add 1 / 3 molar of p-nitroaniline (1.30 g) to the solution and stir for 30 min to form a seed reaction solution; then slowly add the remaining 2 / 3 molar of p-nitroaniline (2.61 g) at a rate of 1.0 g / min. After the addition is complete, purge with nitrogen to replace the air. The molar ratio of p-nitrobenzoyl chloride to p-nitroaniline is 1:1.05.

[0051] The system was heated to the reflux temperature at a rate of 8℃ / 30min, and the reaction was maintained at this temperature for 4h. TLC monitoring showed that the reaction of p-nitrobenzoyl chloride was complete.

[0052] The temperature was lowered to 60°C at a rate of 5°C / 20 min, and 0.15 mL of methanol was added for mild in-situ quenching. The mixture was stirred for 10 min. Then the temperature was lowered to 5°C at a rate of 5°C / 20 min to allow the product to crystallize slowly in situ. After crystallization, 0.15 mL of methanol was added for complete quenching.

[0053] The solid was filtered under reduced pressure. It was first washed once with 20 mL of 5% sodium bicarbonate aqueous solution, and then once with 20 mL of pure water. The washed wet product was placed in a vacuum drying oven and dried at -0.08 MPa at 60°C for 1 hour, then cooled to 50°C at a rate of 10°C / hour and dried for another 1.5 hours. Finally, it was cooled to room temperature and discharged. The yield was 96.21%, the HPLC purity was 99.52%, and the product was in the form of loose, fine crystals.

[0054] Example 3: A method for preparing N-(4-nitrophenyl)-4-nitrobenzamide, wherein the preparation method is as follows: Under nitrogen protection, 60g of an inert compound solvent consisting of 90% N,N-dimethylformamide and 10% isopropyl acetate by mass percentage was added to the reactor. Mechanical stirring was started (120 r / min), and pre-dehydration was carried out under vacuum at -0.08 MPa and 60℃ for 30 min. After dehydration, 0.8% (relative to the mass of p-nitrobenzoyl chloride) of anhydrous sodium sulfate was added, and after stirring to dissolve, 5g of p-nitrobenzoyl chloride was added. The temperature was raised to 35℃ and stirred until the solid was completely dissolved.

[0055] Maintaining the system temperature at 40°C, first slowly add 1 / 4 mole of p-nitroaniline (1.30 g) to the solution and stir for 40 min to form a seed reaction solution; then slowly add the remaining 3 / 4 mole of p-nitroaniline (3.90 g) at a rate of 0.5 g / min. After the addition is complete, purge with nitrogen to replace the air. The molar ratio of p-nitrobenzoyl chloride to p-nitroaniline is 1:1.40.

[0056] The system was heated to the reflux temperature at a rate gradient of 10℃ / 30min, and the reaction was maintained at this temperature for 3h. TLC monitoring showed that the reaction of p-nitrobenzoyl chloride was complete.

[0057] The temperature was lowered to 60°C at a rate of 3°C / 20 min, and 1 mL of methanol was added for mild in-situ quenching. The mixture was stirred for 10 min. Then the temperature was lowered to 0°C at a rate of 3°C / 20 min to allow the product to crystallize slowly in situ. After crystallization, 1.25 mL of methanol was added for complete quenching.

[0058] The solid was filtered under reduced pressure. It was first washed once with 20 mL of 5% sodium bicarbonate aqueous solution, and then once with 20 mL of pure water. The washed wet product was placed in a vacuum drying oven and dried at -0.08 MPa at 60°C for 1 h, then cooled to 50°C at a rate of 10°C / h and dried for 1.5 h. Finally, it was cooled to room temperature and discharged. The yield was 96.00%, and the HPLC purity was 99.41%.

[0059] Example 4: A method for preparing N-(4-nitrophenyl)-4-nitrobenzamide, wherein the preparation method is as follows: Under nitrogen protection, 60g of an inert compound solvent consisting of 80% N-methylpyrrolidone and 20% isopropyl acetate by mass percentage was added to the reactor. Mechanical stirring was started (120r / min), and pre-dehydration was carried out under vacuum at -0.08MPa and 60℃ for 40min. After dehydration, 1% (relative to the mass of p-nitrobenzoyl chloride) of anhydrous sodium sulfate was added, and after stirring to dissolve, 5g of p-nitrobenzoyl chloride was added. The temperature was raised to 50℃ and stirred until the solid was completely dissolved.

[0060] Maintaining the system temperature at 60°C, first slowly add 1 / 3 molar of p-nitroaniline (1.30 g) to the solution and stir for 40 min to form a seed reaction solution; then slowly add the remaining 2 / 3 molar of p-nitroaniline (2.61 g) at a rate of 0.5 g / min. After the addition is complete, purge with nitrogen to replace the air. The molar ratio of p-nitrobenzoyl chloride to p-nitroaniline is 1:1.05.

[0061] The system was heated to the reflux temperature at a rate gradient of 10℃ / 30min, and the reaction was maintained at this temperature for 3h. TLC monitoring showed that the reaction of p-nitrobenzoyl chloride was complete.

[0062] The temperature was lowered to 60°C at a rate of 5°C / 20 min, and 0.15 mL of methanol was added for mild in-situ quenching. The mixture was stirred for 10 min. Then the temperature was lowered to 0°C at a rate of 5°C / 20 min to allow the product to crystallize slowly in situ. After crystallization, 0.15 mL of methanol was added for complete quenching.

[0063] The sample was filtered under reduced pressure. The filtered solid was washed once with 20 mL of pure water. The washed wet sample was placed in a vacuum drying oven and dried at 60 °C for 1.5 h under a vacuum of -0.05 MPa. Then, the temperature was lowered to 45 °C at a rate of 5 °C / h and dried for 1.0 h. Finally, the sample was cooled to room temperature and discharged. The yield was 96.12%, and the HPLC purity was 99.50%.

[0064] Comparative Example 1: N-(4-nitrophenyl)-4-nitrobenzamide was prepared using the same method as in Example 1, except that a single solvent was used in Comparative Example 1 (without dehydration treatment), and the p-nitroaniline was not added in batches during the feeding process. The post-treatment process was directly carried out using conventional post-treatment. The specific preparation process is as follows: Under nitrogen protection, add 50g of tetrachloroethylene to the reactor, turn on mechanical stirring (100r / min), add 5g of p-nitrobenzoyl chloride, heat to 50℃ and stir until the solid is completely dissolved.

[0065] Maintaining the system temperature at 55°C, p-nitroaniline (3.9 g) was slowly added at a rate of 0.8 g / min. After the addition was complete, nitrogen gas was purged to replace the air. The molar ratio of p-nitrobenzoyl chloride to p-nitroaniline was 1:1.05.

[0066] The system was rapidly heated to the reflux temperature and kept at that temperature for 5 hours. TLC monitoring showed that the reaction of p-nitrobenzoyl chloride was complete.

[0067] The temperature was lowered to 60°C at a rate of 5°C / 20 min, and 0.30 mL of methanol was added for mild in-situ quenching. The mixture was stirred for 10 min. Then the temperature was lowered to 0°C at a rate of 5°C / 20 min to allow the product to crystallize slowly in situ. After crystallization was complete, the product was allowed to crystallize.

[0068] The solid was filtered under reduced pressure and washed twice with 20 mL of pure water. The washed wet product was then vacuum dried at 50 °C for 3 h. The yield was 85.41%, the HPLC purity was 91.36%, and the product state was agglomerated solid.

[0069] A comparison of the experimental results of Comparative Example 2 and Example 1 shows that the preparation method described in this invention is more conducive to obtaining N-(4-nitrophenyl)-4-nitrobenzamide products with high yield and high purity.

[0070] Comparative Example 2: N-(4-nitrophenyl)-4-nitrobenzamide was prepared using the same method as in Example 1, except that a single solvent was used in Comparative Example 2. The specific preparation process is as follows: Under nitrogen protection, 50g of tetrachloroethylene was added to the reactor, and mechanical stirring was started (100r / min). Vacuum micro-extraction was performed for pre-dehydration for 35min at a vacuum degree of -0.06MPa and a temperature of 55℃. After dehydration, 0.5% (relative to the mass of p-nitrobenzoyl chloride) of anhydrous sodium sulfate was added, and after stirring to dissolve, 5g of p-nitrobenzoyl chloride was added. The temperature was raised to 50℃ and stirred until the solid was completely dissolved.

[0071] Maintaining the system temperature at 55°C, first slowly add 1 / 3 molar of p-nitroaniline (1.30 g) to the solution and stir for 30 min to form a seed reaction solution; then slowly add the remaining 2 / 3 molar of p-nitroaniline (2.61 g) at a rate of 0.8 g / min. After the addition is complete, purge with nitrogen to replace the air. The molar ratio of p-nitrobenzoyl chloride to p-nitroaniline is 1:1.05.

[0072] The system was heated to the reflux temperature at a gradient rate of 10℃ / 30min, and the reaction was maintained at this temperature for 5h. TLC monitoring showed that the reaction of p-nitrobenzoyl chloride was complete.

[0073] The temperature was lowered to 60℃ at a rate of 5℃ / 20min, and 0.15mL of methanol was added for mild in-situ quenching. The mixture was stirred for 10min. Then the temperature was lowered to 0℃ at a rate of 5℃ / 20min to allow the product to crystallize slowly in situ. After crystallization, 0.15mL of methanol was added for complete quenching.

[0074] The sample was filtered under reduced pressure, and the filtered solid was washed once with 20 mL of pure water. The washed wet sample was placed in a vacuum drying oven and dried at 60 °C for 1 h under a vacuum of -0.06 MPa. Then, the temperature was lowered to 50 °C at a rate of 10 °C / h and dried for another 2 h. Finally, the sample was cooled to room temperature and discharged. The yield was 92.58%, the HPLC purity was 97.34%, and the product was in the form of fine crystals with a slight tendency to agglomerate.

[0075] A comparison of the experimental results of Comparative Example 2 and Example 1 shows that if a single solvent is used in the reaction system without the addition of a weakly polar co-solvent, the yield and purity of the product will decrease significantly (the yield will decrease by about 4.2 percentage points and the purity will decrease by about 2.2 percentage points), and the powder properties of the product will deteriorate.

[0076] Comparative Example 3: N-(4-nitrophenyl)-4-nitrobenzamide was prepared using the same method as in Example 1, except that p-nitroaniline was not added in batches during the feeding process in Comparative Example 3. The specific preparation process is as follows: Under nitrogen protection, 50g of an inert compound solvent consisting of 80% tetrachloroethylene and 20% isopropyl acetate by mass percentage was added to the reactor. Mechanical stirring was started (100r / min), and pre-dehydration was carried out under vacuum at -0.06MPa and 55℃ for 35min. After dehydration, 0.5% (relative to the mass of p-nitrobenzoyl chloride) of anhydrous sodium sulfate was added, and after stirring to dissolve, 5g of p-nitrobenzoyl chloride was added. The temperature was raised to 50℃ and stirred until the solid was completely dissolved.

[0077] Maintaining the system temperature at 55°C, p-nitroaniline (3.91 g) was slowly added at a rate of 0.8 g / min. After the addition was complete, nitrogen gas was purged to replace the air. The molar ratio of p-nitrobenzoyl chloride to p-nitroaniline was 1:1.05.

[0078] The system was heated to the reflux temperature at a gradient rate of 10℃ / 30min, and the reaction was maintained at this temperature for 5h. TLC monitoring showed that the reaction of p-nitrobenzoyl chloride was complete.

[0079] The temperature was lowered to 60℃ at a rate of 5℃ / 20min, and 0.15mL of methanol was added for mild in-situ quenching. The mixture was stirred for 10min. Then the temperature was lowered to 0℃ at a rate of 5℃ / 20min to allow the product to crystallize slowly in situ. After crystallization, 0.15mL of methanol was added for complete quenching.

[0080] The product was filtered under reduced pressure, and the filtered solid was washed once with 20 mL of pure water. The washed wet product was placed in a vacuum drying oven and dried at 60 °C for 1 h under a vacuum of -0.06 MPa, then cooled to 50 °C at a rate of 10 °C / h and dried for 2 h. Finally, it was cooled to room temperature and discharged. The yield was 94.67%, the HPLC purity was 96.16%, and the product was in the form of fine crystals with slight agglomeration.

[0081] A comparison of the experimental results of Comparative Example 3 and Example 1 shows that if p-nitroaniline is not added in batches during the feeding process, the yield decreases by approximately 6 percentage points, and the purity decreases by approximately 3 percentage points. In the preparation method described in this invention, p-nitroaniline is added in batches. A small amount of p-nitroaniline is added first to form a seed reaction solution. The already generated amide bond product is used as a molecular template, and subsequent substrates are pre-organized through weak interactions, effectively reducing the reaction activation energy and resulting in a higher degree of reaction. This allows for the acquisition of high-yield, high-purity N-(4-nitrophenyl)-4-nitrobenzamide products within the same production cycle.

[0082] Comparative Example 4: N-(4-nitrophenyl)-4-nitrobenzamide was prepared using the same method as in Example 1, except that in the post-treatment process of Comparative Example 4, methanol was added in one step to directly and completely quench the reaction before crystallization. The specific preparation process is as follows: Under nitrogen protection, 50g of an inert compound solvent consisting of 80% tetrachloroethylene and 20% isopropyl acetate by mass percentage was added to the reactor. Mechanical stirring was started (100r / min), and pre-dehydration was carried out under vacuum at -0.06MPa and 55℃ for 35min. After dehydration, 0.5% (relative to the mass of p-nitrobenzoyl chloride) of anhydrous sodium sulfate was added, and after stirring to dissolve, 5g of p-nitrobenzoyl chloride was added. The temperature was raised to 50℃ and stirred until the solid was completely dissolved.

[0083] Maintaining the system temperature at 55°C, first slowly add 1 / 3 molar of p-nitroaniline (1.30 g) to the solution and stir for 30 min to form a seed reaction solution; then slowly add the remaining 2 / 3 molar of p-nitroaniline (2.61 g) at a rate of 0.8 g / min. After the addition is complete, purge with nitrogen to replace the air. The molar ratio of p-nitrobenzoyl chloride to p-nitroaniline is 1:1.05.

[0084] The system was heated to the reflux temperature at a gradient rate of 10℃ / 30min, and the reaction was maintained at this temperature for 5h. TLC monitoring showed that the reaction of p-nitrobenzoyl chloride was complete.

[0085] The temperature was lowered to 60℃ at a rate of 5℃ / 20min, and the reaction was quenched by adding 0.30mL of methanol and stirring for 10min. Then, the temperature was lowered to 0℃ at a rate of 5℃ / 20min to allow the product to crystallize slowly. After crystallization, the product was filtered under reduced pressure, and the filtered solid was washed once with 20mL of pure water. The washed wet product was placed in a vacuum drying oven and dried at 60℃ for 1h under a vacuum of -0.06MPa, then cooled to 50℃ at a rate of 10℃ / h and dried for 2h, finally cooled to room temperature before being discharged. The yield was 91.86%, the HPLC purity was 96.78%, and the product was a fine powder with obvious agglomeration.

[0086] A comparison of the experimental results of Comparative Example 4 and Example 1 shows that if the quenching process is not carried out in steps, the product yield decreases by about 5 percentage points, the purity decreases by about 2.8 percentage points, and the powder characteristics of the product deteriorate. In the preparation method described in this invention, quenching and crystallization are coupled. First, mild quenching is carried out, followed by low-temperature crystallization. The characteristic of the target product's low-temperature solubility drops sharply is used to achieve directional crystallization, forming large-particle crystals. This avoids the loss of fine crystals with the filtrate, and is more conducive to obtaining a high-yield, high-quality target product.

[0087] Comparative Example 5: N-(4-nitrophenyl)-4-nitrobenzamide was prepared using the same method as in Example 1, except that a slow heating process was not performed during the preparation of Comparative Example 5. The specific preparation process is as follows: Under nitrogen protection, 50g of an inert compound solvent consisting of 80% tetrachloroethylene and 20% isopropyl acetate by mass percentage was added to the reactor. Mechanical stirring was started (100r / min), and pre-dehydration was carried out under vacuum at -0.06MPa and 55℃ for 35min. After dehydration, 0.5% (relative to the mass of p-nitrobenzoyl chloride) of anhydrous sodium sulfate was added, and after stirring to dissolve, 5g of p-nitrobenzoyl chloride was added. The temperature was raised to 50℃ and stirred until the solid was completely dissolved.

[0088] Maintaining the system temperature at 55°C, first slowly add 1 / 3 molar of p-nitroaniline (1.30 g) to the solution and stir for 30 min to form a seed reaction solution; then slowly add the remaining 2 / 3 molar of p-nitroaniline (2.61 g) at a rate of 0.8 g / min. After the addition is complete, purge with nitrogen to replace the air. The molar ratio of p-nitrobenzoyl chloride to p-nitroaniline is 1:1.05.

[0089] The system was rapidly heated to the reflux temperature (heating rate of approximately 50°C / 30 min), and the reaction was maintained at this temperature for 5 h. TLC monitoring showed that the reaction of p-nitrobenzoyl chloride was complete.

[0090] The temperature was lowered to 60℃ at a rate of 5℃ / 20min, and 0.15mL of methanol was added for mild in-situ quenching. The mixture was stirred for 10min. Then the temperature was lowered to 0℃ at a rate of 5℃ / 20min to allow the product to crystallize slowly in situ. After crystallization, 0.15mL of methanol was added for complete quenching.

[0091] The solid was filtered under reduced pressure and washed once with 20 mL of pure water. The washed wet product was placed in a vacuum drying oven and dried at 60°C for 1 hour under a vacuum of -0.06 MPa. Then, it was cooled to 50°C at a rate of 10°C / h and dried for 2 hours. Finally, it was cooled to room temperature and discharged.

[0092] The yield was 93.45%, the HPLC purity was 97.12%, and the product was in the form of fine crystals with slight agglomeration.

[0093] Comparison of the experimental results of Comparative Example 5 and Example 1 shows that if the heating rate is too fast, the yield and purity of the product will decrease. This is because the condensation reaction of p-nitrobenzoyl chloride and p-nitroaniline is an exothermic reaction. Rapid heating will cause the system to accumulate a large amount of reaction heat in a short time, resulting in local overheating and causing the following adverse consequences: (1) The local temperature is too high, which accelerates the side reactions (such as the trace hydrolysis of acyl chloride, amino oxidation, etc.) and generates impurities that are difficult to separate; (2) The violent exothermic reaction destroys the molecular template effect formed by the "seed reaction solution", making it impossible for the subsequent substrate to be pre-organized in an orderly manner, and the reaction selectivity decreases.

[0094] This invention employs a gradient heating method of 8-10℃ / 30min, which allows for the stable release of reaction heat, uniform and controllable system temperature, effectively suppresses the occurrence of side reactions, and ensures product yield and purity.

[0095] Comparative Example 6: N-(4-nitrophenyl)-4-nitrobenzamide was prepared using the same method as in Example 1, except that anhydrous sodium sulfate was not added during the preparation of Comparative Example 6. The specific preparation process is as follows: Under nitrogen protection, 50g of an inert compound solvent consisting of 80% tetrachloroethylene and 20% isopropyl acetate by mass percentage was added to the reactor. Mechanical stirring was started (100r / min), and pre-dehydration was carried out under vacuum at -0.06MPa and 55℃ for 35min. After dehydration, 5g of p-nitrobenzoyl chloride was added after stirring and dissolving, and the temperature was raised to 50℃ and stirred until the solid was completely dissolved.

[0096] Maintaining the system temperature at 55°C, first slowly add 1 / 3 molar of p-nitroaniline (1.30 g) to the solution and stir for 30 min to form a seed reaction solution; then slowly add the remaining 2 / 3 molar of p-nitroaniline (2.61 g) at a rate of 0.8 g / min. After the addition is complete, purge with nitrogen to replace the air. The molar ratio of p-nitrobenzoyl chloride to p-nitroaniline is 1:1.05.

[0097] The system was heated to the reflux temperature at a gradient rate of 10℃ / 30min, and the reaction was maintained at this temperature for 5h. TLC monitoring showed that the reaction of p-nitrobenzoyl chloride was complete.

[0098] The temperature was lowered to 60℃ at a rate of 5℃ / 20min, and 0.15mL of methanol was added for mild in-situ quenching. The mixture was stirred for 10min. Then the temperature was lowered to 0℃ at a rate of 5℃ / 20min to allow the product to crystallize slowly in situ. After crystallization, 0.15mL of methanol was added for complete quenching.

[0099] The solid was filtered under reduced pressure and washed once with 20 mL of pure water. The washed wet product was placed in a vacuum drying oven and dried at 60 °C for 1 h under a vacuum of -0.06 MPa, then cooled to 50 °C at a rate of 10 °C / h and dried for another 2 h. Finally, it was cooled to room temperature and discharged. The yield was 95.82%, the HPLC purity was 97.91%, and the product was in the form of loose, fine crystals.

[0100] A comparison of the experimental results of Comparative Example 6 and Example 1 shows that without the addition of anhydrous sodium sulfate, the product yield and purity decreased. This is because although the inert compound solvent underwent vacuum micro-extraction pre-dehydration treatment (moisture content ≤0.01%), the system could still adsorb trace amounts of moisture from the environment during operations such as feeding, stirring, and dissolving. Anhydrous sodium sulfate, as a highly efficient desiccant, can continuously adsorb these trace amounts of moisture in the liquid phase, thereby further inhibiting the hydrolysis side reaction of p-nitrobenzoyl chloride and reducing the formation of the corresponding nitrobenzoic acid impurities. The data from Comparative Example 6 indicate that even if the solvent has undergone rigorous pre-dehydration treatment, the additional addition of anhydrous sodium sulfate for auxiliary dehydration still helps improve product purity, demonstrating the technical advantage of the "pre-dehydration + in-situ auxiliary dehydration" dual moisture control strategy of this invention.

[0101] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are exhaustively listed. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0102] For those skilled in the art, various modifications and improvements can be made without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention. The scope of protection of the present invention is defined by the appended claims.

Claims

1. A method for preparing N-(4-nitrophenyl)-4-nitrobenzamide, characterized in that, The preparation method is as follows: S1. Under inert gas conditions, p-nitrobenzoyl chloride is dissolved in an inert compound solvent; the inert compound solvent includes an aprotic main solvent and a weakly polar co-solvent. S2. Controlling the temperature conditions, a portion of p-nitroaniline is slowly added to the system in step S1 to form a seed reaction solution after mixing. S3. Slowly add the remaining p-nitroaniline to the seed reaction solution from step S2, and heat and maintain the temperature for reaction; S4. After the reaction is complete, N-(4-nitrophenyl)-4-nitrobenzamide is obtained through post-treatment.

2. The method for preparing N-(4-nitrophenyl)-4-nitrobenzamide according to claim 1, characterized in that, The inert compound solvent comprises 80%-90% aprotic main solvent and 10%-20% weakly polar co-solvent by mass percentage.

3. The method for preparing N-(4-nitrophenyl)-4-nitrobenzamide according to claim 1, characterized in that, The aprotic primary solvent is at least one of tetrachloroethylene, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone, and chlorobenzene; The weakly polar co-solvent is isopropyl acetate.

4. The method for preparing N-(4-nitrophenyl)-4-nitrobenzamide according to claim 1, characterized in that, The inert compound solvent used in step S1 is dehydrated, and the water content in the dehydrated inert compound solvent is ≤0.01%; and before adding p-nitrobenzoyl chloride, anhydrous sodium sulfate is added to the system and dispersed and dissolved.

5. The method for preparing N-(4-nitrophenyl)-4-nitrobenzamide according to claim 1, characterized in that, In step S2, the system temperature is controlled at 40~60℃, and a portion of p-nitroaniline is slowly added and stirred for 30-40 minutes to form a seed reaction solution.

6. The method for preparing N-(4-nitrophenyl)-4-nitrobenzamide according to claim 1, characterized in that, The mass ratio of p-nitroaniline added in step S2 to p-nitroaniline added in step S3 is 1:(2-3).

7. The method for preparing N-(4-nitrophenyl)-4-nitrobenzamide according to claim 1, characterized in that, In step S3, the remaining p-nitroaniline is slowly added to the seed reaction solution at a rate of 0.5~1 g / min, and then the temperature is increased to the reflux temperature at a rate of 8~10℃ / 30min, and the reaction is maintained at this temperature for 2~5h.

8. The method for preparing N-(4-nitrophenyl)-4-nitrobenzamide according to claim 1, characterized in that, The post-processing method for step S4 is as follows: Slowly cool to 55-60℃, add some methanol to the system and stir to perform mild in-situ quenching. After slowly cooling to 0-5℃, add another part of methanol to completely quench. Then perform solid-liquid separation, washing and drying to obtain N-(4-nitrophenyl)-4-nitrobenzamide.

9. The method for preparing N-(4-nitrophenyl)-4-nitrobenzamide according to claim 8, characterized in that, During the post-treatment process, the total amount of methanol added is 1.1-1.3 times the remaining mass of reactants in the system. The ratio of the mass of methanol added during mild quenching to the mass of methanol added during complete quenching is 1:(1-1.5).

10. The method for preparing N-(4-nitrophenyl)-4-nitrobenzamide according to claim 8, characterized in that, After mild in-situ quenching, the temperature is slowly reduced to 0~5℃ at a rate of 3-5℃ / 20min; the drying process is a gradient cooling drying process.

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