Process for the one-pot preparation of 4-nitro-n-phenylbenzamide

Abstract

The application relates to the technical field of organic synthesis, in particular to a method for preparing 4-nitro-N-phenyl benzamide through one-pot reaction, and the preparation method is as follows: under the protection of inert gas, inert solvent, p-nitrobenzoic acid and a composite catalyst are added into a reactor and heated and dissolved, wherein the composite catalyst comprises NFM and TPPO; a small amount of thionyl chloride is slowly added into the reaction system to perform acylation reaction; then, aniline is slowly added into the reaction system to perform condensation reaction; after the reaction is completed, 4-nitro-N-phenyl benzamide is obtained through post-treatment. The method can realize one-pot reaction, and a high-risk intermediate does not need to be separated. NFM in the composite catalyst can efficiently catalyze acyl chloride, TPPO can stabilize the acyl chloride intermediate and promote condensation, so that the reaction is efficiently, stably and highly selectively performed, the product has high yield and high purity. Moreover, the catalyst is easy to recycle and use, the process is green, safe and economical, and is suitable for industrial production.

Description

Technical Field

[0001] This invention relates to a one-pot method for preparing 4-nitro-N-phenylbenzamide, belonging to the field of organic synthesis technology. Background Technology

[0002] 4-Nitro-N-phenylbenzanilide, with the chemical formula C 13 H 10 N2O3, structural formula is .

[0003] 4-Nitro-N-phenylbenzamide is a high-performance monomer used to prepare 2-(4-aminophenyl)-5-aminobenzimidazole (APBIA). APBIA plays a crucial role in the preparation of polymers such as aramid fibers, polyimide films, and polyaminoimides. Through the amino and imidazole rings in its molecular structure, APBIA can undergo condensation polymerization with various monomers to form high-performance polymer chain structures. This structure endows the materials with excellent mechanical properties, thermal stability, and chemical stability, making them widely used in aerospace, electronics, automotive, and protective equipment industries. The introduction of APBIA not only improves the performance of materials but also enhances their processing properties, demonstrating significant application value and market potential. Furthermore, it can be used as a pharmaceutical intermediate in pharmaceutical synthesis.

[0004] Patent application US20220177416A1 discloses a method for preparing 4-nitro-N-phenylbenzamide by reacting 3-nitrobenzaldehyde with aniline. However, this method has a low yield of only 66%. Furthermore, directly reacting p-nitrobenzoic acid with aniline to prepare 4-nitro-N-phenylbenzamide often requires high reaction temperatures (≥200℃), resulting in high energy consumption and unsuitability for industrial applications. The preparation method of 4-nitro-N-phenylbenzamide disclosed in patent application US20160136166A1 is as follows: 4-nitrobenzoic acid is added to dichloromethane, and ClCOCOCl is added. N,N-dimethylformamide is added dropwise under stirring. After stirring at room temperature, the mixture is concentrated under vacuum. A dichloromethane solution of PhNH is added to the residue. Then, triethylamine is added dropwise at 0°C under stirring. The resulting solution is stirred overnight at room temperature. The resulting mixture is washed with HC solution and brine, dried with anhydrous sodium sulfate, and concentrated under vacuum. The residue is diluted with a mixed solvent of petroleum ether and ethyl acetate. The solid is collected by filtration to obtain the 4-nitro-N-phenylbenzamide product. However, this preparation process has a low product yield (only 85%), and the preparation process is complicated and the reaction efficiency is low.

[0005] Therefore, developing a method for preparing 4-nitro-N-phenylbenzamide that is simple, has a high yield, produces a high-purity product, and can achieve a one-pot preparation is of great value. Summary of the Invention

[0006] This invention addresses the shortcomings of existing technologies by providing a one-pot method for preparing 4-nitro-N-phenylbenzamide. This method is simple to operate and produces a high yield and high purity of the target product, 4-nitro-N-phenylbenzamide, making it suitable for industrial applications.

[0007] The technical solution of the present invention to solve the above-mentioned technical problems is as follows:

[0008] A one-pot method for preparing 4-nitro-N-phenylbenzamide is as follows:

[0009] S1. Under inert gas protection, an inert solvent, p-nitrobenzoic acid, and a composite catalyst are added to the reactor and heated to dissolve them, wherein the composite catalyst includes NFM and TPPO;

[0010] S2. Slowly add thionyl chloride to the reaction system to carry out the acylation reaction;

[0011] S3. Slowly add aniline to the reaction system to carry out the condensation reaction;

[0012] S4. After the reaction is complete, 4-nitro-N-phenylbenzamide is obtained through post-treatment.

[0013] Furthermore, the inert solvent is at least one selected from tetrachloroethylene, dichloromethane, dichloroethane, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0014] Furthermore, in step S1, the heating and dissolution temperature is 35-55℃, and the inert solvent is 5-8 times the mass of p-nitrobenzoic acid.

[0015] Furthermore, the mass ratio of NFM to TPPO in the composite catalyst is 1:(0.2~0.5).

[0016] Furthermore, the total amount of the composite catalyst is 1.5%-4% of the mass of p-nitrobenzoic acid.

[0017] Furthermore, the molar ratio of thionyl chloride to p-nitrobenzoic acid is (1-2):1; the molar ratio of aniline to p-nitrobenzoic acid is (0.8-1.5):1.

[0018] Furthermore, in step S2, thionyl chloride is slowly added to the reaction system under the heating and dissolution temperature conditions, and the temperature is raised to 70-85°C at a rate of 8-12°C / 30min to carry out the acylation reaction. The reaction time of the acylation reaction is 2h-4h.

[0019] Furthermore, in step S3, the condensation reaction temperature is 100-120℃, and the reaction time is 2h-4h.

[0020] Furthermore, in step S4, after the reaction is complete, methanol is added to quench the reaction, followed by solid-liquid separation, washing, and vacuum drying at 50-60℃ to obtain 4-nitro-N-phenylbenzamide.

[0021] Furthermore, the mother liquor obtained from the solid-liquid separation is subjected to vacuum distillation to recover methanol and inert solvent, and TPPO and NFM-containing concentrate are obtained through crystallization and solid-liquid separation. The recovered methanol, inert solvent, TPPO and NFM-containing concentrate are recycled in the preparation process of 4-nitro-N-phenylbenzamide.

[0022] The beneficial effects of this invention are:

[0023] In the one-pot method for preparing 4-nitro-N-phenylbenzamide described in this invention, NFM and TPPO in the composite catalyst exhibit synergistic catalytic efficiency: NFM acts as a highly efficient acyl chloride catalyst, while TPPO acts as an acyl chloride stabilizer. Together, they achieve the dual functions of "activation and stabilization," resulting in a reaction conversion rate ≥99%, a yield ≥97%, and a 4-nitro-N-phenylbenzamide product purity ≥99.5%. Furthermore, the composite catalyst can be efficiently recovered from the reaction mother liquor and recycled through a simple distillation-crystallization process, significantly reducing production costs and emissions of waste, which aligns with the principles of green chemistry.

[0024] The one-pot method for preparing 4-nitro-N-phenylbenzamide described in this invention utilizes low-temperature feeding control, a gradient temperature program, and a solvent-catalyst synergistic system to achieve efficient integration of acylation and condensation reactions without separating the intermediate product p-nitrobenzoyl chloride, thus synthesizing 4-nitro-N-phenylbenzamide in a single pot. The resulting product is obtained after washing and drying with methanol, achieving a yield ≥97%, a purity ≥99.5%, a scale-up yield ≥95%, and a thionyl chloride residue ≤0.03%. The core of this process lies in employing a composite catalyst system composed of N-formylmorpholine (NFM) and triphenylphosphine oxide (TPPO), enabling efficient, stable, and continuous acylation and condensation reactions in the same reactor without separating the intermediate p-nitrobenzoyl chloride.

[0025] The composite catalytic mechanism employed in this invention is as follows: NFM reacts with thionyl chloride to generate a highly active Vilsmeier-Haack reagent, which efficiently catalyzes the conversion of p-nitrobenzoic acid into an acyl chloride intermediate and undergoes its own regeneration. TPPO reversibly coordinates with the carbonyl group of the acyl chloride intermediate through its phosphorus-oxygen bond (P=O bond), forming a stable complex, thereby significantly inhibiting side reactions such as hydrolysis and dimerization of the acyl chloride. This ensures a safe and stable reaction process, and the combination of low-temperature feeding and slow temperature rise control strategies effectively suppresses violent exothermic reactions, making the process easy to control and ensuring high production safety.

[0026] The preparation method of this invention avoids the separation of highly hazardous intermediates. The preparation process does not require the separation, purification, storage, or transfer of p-nitrobenzoyl chloride, greatly reducing safety and environmental exposure risks during operation and minimizing the waste generated from intermediate handling. It is both environmentally friendly and economical. Moreover, it simplifies the process flow by integrating the two-step reaction into a single reactor, reducing investment in production equipment, simplifying operation steps, improving production efficiency, and making it more suitable for industrial applications. Attached Figure Description

[0027] Figure 1 The carbon NMR spectrum of 4-nitro-N-phenylbenzamide prepared in Example 1;

[0028] Figure 2 The liquid chromatogram of 4-nitro-N-phenylbenzamide prepared in Example 1;

[0029] Figure 3 The liquid chromatogram of 4-nitro-N-phenylbenzamide prepared in Example 2;

[0030] Figure 4 The liquid chromatogram of 4-nitro-N-phenylbenzamide prepared in Example 3;

[0031] Figure 5 The liquid chromatogram of 4-nitro-N-phenylbenzamide prepared in Comparative Example 1 is shown.

[0032] Figure 6 The liquid chromatogram of 4-nitro-N-phenylbenzamide prepared in Comparative Example 2 is shown below.

[0033] Figure 7 The liquid chromatogram of 4-nitro-N-phenylbenzamide prepared in Comparative Example 3 is shown below.

[0034] Figure 8 The image shows the liquid chromatogram of 4-nitro-N-phenylbenzamide prepared in Comparative Example 4. Detailed Implementation

[0035] 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.

[0036] 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.

[0037] A one-pot method for preparing 4-nitro-N-phenylbenzamide is as follows:

[0038] ;

[0039] S1. Under inert gas protection, an inert solvent, p-nitrobenzoic acid, and a composite catalyst are added to the reactor and heated to dissolve them, wherein the composite catalyst includes NFM and TPPO;

[0040] S2. Slowly add thionyl chloride to the reaction system to carry out the acylation reaction;

[0041] S3. Slowly add aniline to the reaction system to carry out the condensation reaction;

[0042] S4. After the reaction is complete, 4-nitro-N-phenylbenzamide is obtained through post-treatment.

[0043] Specifically, the inert solvent is at least one of tetrachloroethylene, dichloromethane, dichloroethane, N,N-dimethylformamide, and N,N-dimethylacetamide.

[0044] Specifically, in step S1, the heating and dissolution temperature is 35-55℃, and the inert solvent is 5-8 times the mass of p-nitrobenzoic acid.

[0045] Specifically, the mass ratio of NFM to TPPO in the composite catalyst is 1:(0.2~0.5).

[0046] Specifically, the total amount of the composite catalyst is 1.5%-4% of the mass of p-nitrobenzoic acid.

[0047] Specifically, the molar ratio of thionyl chloride to p-nitrobenzoic acid is (1-2):1; the molar ratio of aniline to p-nitrobenzoic acid is (0.8-1.5):1.

[0048] Specifically, in step S2, thionyl chloride is slowly added to the reaction system under the heating and dissolution temperature conditions, and the temperature is raised to 70-85°C at a rate of 8-12°C / 30 min to carry out the acylation reaction. The reaction time of the acylation reaction is 2-4 h.

[0049] Specifically, in step S3, the condensation reaction temperature is 100-120℃ and the reaction time is 2h-4h.

[0050] Specifically, in step S4, after the reaction is complete, methanol is added to quench the reaction, followed by solid-liquid separation, washing, and vacuum drying at 50-60℃ to obtain 4-nitro-N-phenylbenzamide.

[0051] Specifically, the mother liquor obtained from the solid-liquid separation is subjected to vacuum distillation to recover methanol and inert solvent, and TPPO and NFM-containing concentrate are obtained through crystallization and solid-liquid separation. The recovered methanol, inert solvent, TPPO and NFM-containing concentrate are recycled in the preparation process of 4-nitro-N-phenylbenzamide.

[0052] Specifically, steps S1-S3 are all carried out under mechanical stirring conditions, where the mechanical stirring speed is 100~300 r / min.

[0053] Example 1

[0054] A method for preparing 4-nitro-N-phenylbenzamide, the method is as follows:

[0055] Nitrogen gas was introduced into a reaction flask equipped with a mechanical stirrer, thermometer, reflux condenser, and constant-pressure dropping funnel to replace the air. Then, 150.36 g of tetrachloroethylene, 25.07 g of p-nitrobenzoic acid, 0.38 g of N-formylmorpholine (NFM), and 0.12 g of triphenylphosphine oxide (TPPO) were added sequentially, and the mixture was heated to 50 °C and stirred until dissolved.

[0056] At 50 °C, 21.76 g of thionyl chloride (n(p-nitrobenzoic acid):n(thionyl chloride) = 1:1.22) was slowly added dropwise over 1 hour through a constant-pressure dropping funnel. After the addition was complete, the temperature was increased to 80 °C at a rate of 10 °C / 30 min, and the reaction was allowed to proceed for 3 hours. The acyl chloride reaction was confirmed to be complete by TLC monitoring.

[0057] The reaction system was cooled to 50 °C, and 15.35 g of aniline (n(p-nitrobenzoic acid):n(aniline) = 1:1.1) was slowly added dropwise over 30 min through a constant pressure dropping funnel. After the addition was complete, the temperature was raised to 115 °C and the reaction was carried out for 2.5 h.

[0058] The reaction was quenched with methanol, and the product was washed, filtered, and dried in a vacuum oven at 50°C. The obtained product, 4-nitro-N-phenylbenzamide, had a yield of 97.78%, a purity of 99.84% as determined by liquid chromatography, and a carbon NMR spectrum as shown below. Figure 1 As shown, the liquid chromatography detection results are as follows: Figure 2 As shown in Table 1, the liquid chromatography detection data are as follows.

[0059] Table 1. Liquid chromatography detection data of Example 1

[0060]

[0061] Example 2

[0062] A method for preparing 4-nitro-N-phenylbenzamide, the method is as follows:

[0063] The mother liquor after filtration in Example 1 was collected and subjected to vacuum distillation to recover the mixed solvent of methanol and most of tetrachloroethylene.

[0064] The remaining small amount of viscous material was cooled to 5°C, and a white solid precipitated out with stirring. After filtration, 0.10 g of recovered triphenylphosphine oxide (TPPO) was obtained. The filtrate (mainly NFM and a small amount of high-boiling solvent) was weighed directly and used as the "recovered catalyst concentrate".

[0065] When conducting the next batch of reaction, take 90% of the total amount of fresh catalyst from the previous batch of "recovered catalyst concentrate", and replenish the lost TPPO and 10% of fresh NFM, and repeat the operation of Example 1.

[0066] The yield of the obtained product was 96.1%, and the purity was 99.47%. The liquid chromatography results are as follows: Figure 3 As shown in Table 2, the specific results are as follows. After repeating this process three times, the average yield was ≥95%, and the purity was ≥99%.

[0067] Table 2. Liquid chromatography detection data of Example 2

[0068]

[0069] Example 3

[0070] A method for preparing 4-nitro-N-phenylbenzamide, the method is as follows:

[0071] Nitrogen gas was introduced to purge air from a reaction flask equipped with a mechanical stirrer, thermometer, reflux condenser, and constant-pressure dropping funnel. Then, 2005.44 g of tetrachloroethylene, 334.24 g of p-nitrobenzoic acid, 4.94 g of N-formylmorpholine (NFM), and 1.56 g of triphenylphosphine oxide (TPPO) were added sequentially. The mixture was heated to 50°C and stirred until dissolved.

[0072] At 50 °C, 290.29 g of thionyl chloride was slowly added dropwise over 2 h using a constant-pressure dropping funnel. After the addition was complete, the temperature was increased to 80 °C at a rate of 10 °C / 30 min, and the reaction was allowed to proceed for 4 hours. The acyl chloride reaction was confirmed to be complete by TLC monitoring.

[0073] The reaction system was cooled to 50 °C, and 204.88 g of aniline was slowly added dropwise over 1 h using a constant-pressure dropping funnel. After the addition was complete, the temperature was raised to 115 °C, and the reaction was allowed to proceed for 5 h.

[0074] The reaction was quenched with methanol, and the product was washed, filtered, and dried in a vacuum oven at 50°C. The yield of the product, 4-nitro-N-phenylbenzamide, was 95.49%, and the purity according to liquid chromatography was 99.50%. The results are as follows: Figure 4 As shown in Table 3, the specific results are as follows.

[0075] Table 3. Liquid chromatography detection data of Example 3

[0076]

[0077] Example 4

[0078] A method for preparing 4-nitro-N-phenylbenzamide, the method is as follows:

[0079] Nitrogen gas was introduced to replace the air in a reaction flask equipped with a mechanical stirrer, thermometer, reflux condenser, and constant-pressure dropping funnel. 200 g of N,N-dimethylformamide, 25.07 g of p-nitrobenzoic acid, 0.38 g of N-formylmorpholine (NFM), and 0.19 g of triphenylphosphine oxide (TPPO) were added sequentially, and the mixture was heated to 35 °C and stirred until dissolved.

[0080] At 35 °C, 17.85 g of thionyl chloride (n(p-nitrobenzoic acid):n(thionyl chloride) = 1:1) was slowly added dropwise over 1 hour through a constant-pressure dropping funnel. After the addition was complete, the temperature was increased to 70 °C at a rate of 8 °C / 30 min, and the reaction was allowed to proceed for 4 hours. The acyl chloride reaction was confirmed to be complete by TLC monitoring.

[0081] The reaction system was cooled to 35 °C, and 20.93 g of aniline (n(p-nitrobenzoic acid):n(aniline) = 1:1.5) was slowly added dropwise through a constant pressure dropping funnel over 30 min. After the addition was complete, the temperature was raised to 120 °C and the reaction was carried out for 2 h.

[0082] The reaction was quenched with methanol, and the product was washed, filtered, and dried in a vacuum oven at 60°C. The yield of the product, 4-nitro-N-phenylbenzamide, was 97.59%, and the purity was 99.65% as determined by liquid chromatography.

[0083] Example 5

[0084] A method for preparing 4-nitro-N-phenylbenzamide, the method is as follows:

[0085] Nitrogen gas was introduced to replace the air in a reaction flask equipped with a mechanical stirrer, thermometer, reflux condenser, and constant-pressure dropping funnel. 125.35 g of N,N-dimethylacetamide, 25.07 g of p-nitrobenzoic acid, 0.83 g of N-formylmorpholine (NFM), and 0.17 g of triphenylphosphine oxide (TPPO) were added sequentially, and the mixture was heated to 55 °C and stirred until dissolved.

[0086] At 55 °C, 35.69 g of thionyl chloride (n(p-nitrobenzoic acid):n(thionyl chloride) = 1:2) was slowly added dropwise over 1 hour through a constant-pressure dropping funnel. After the addition was complete, the temperature was increased to 85 °C at a rate of 12 °C / 30 min, and the reaction was allowed to proceed for 2 hours. The acyl chloride reaction was confirmed to be complete by TLC monitoring.

[0087] The reaction system was cooled to 55 °C, and 16.76 g of aniline (n(p-nitrobenzoic acid):n(aniline) = 1:1.2) was slowly added dropwise over 30 min through a constant pressure dropping funnel. After the addition was complete, the temperature was raised to 100 °C and the reaction was carried out for 4 h.

[0088] The reaction was quenched with methanol, and the product was washed, filtered, and dried in a vacuum oven at 60°C. The yield of the product, 4-nitro-N-phenylbenzamide, was 97.50%, and its purity was 99.62% as determined by liquid chromatography.

[0089] Comparative Example 1

[0090] 4-Nitro-N-phenylbenzamide was prepared using the same method as in Example 1, except that triphenylphosphine oxide (TPPO) was not added in Comparative Example 1. The specific preparation process is as follows:

[0091] Nitrogen gas was introduced to purge the air from the reaction flask, which was equipped with a mechanical stirrer, thermometer, reflux condenser, and constant-pressure dropping funnel. Then, 150.36 g of tetrachloroethylene, 25.07 g of p-nitrobenzoic acid, and 0.5 g of N-formylmorpholine (NFM) were added sequentially. The mixture was heated to 50 °C and stirred until dissolved.

[0092] At 50 °C, 21.76 g of thionyl chloride was slowly added dropwise over 1 hour through a constant-pressure dropping funnel. After the addition was complete, the temperature was increased to 80 °C at a rate of 10 °C / 30 min, and the reaction was allowed to proceed for 3 hours.

[0093] The reaction system was cooled to 50 °C, and 15.35 g of aniline was slowly added dropwise over 30 min through a constant-pressure dropping funnel. After the addition was complete, the temperature was raised to 115 °C, and the reaction was allowed to proceed for 2.5 h.

[0094] The reaction was quenched with methanol, and the product was washed, filtered, and dried in a vacuum oven at 50°C. The yield of the product, 4-nitro-N-phenylbenzamide, was 95.21%, and the purity according to liquid chromatography was 99.38%. The results are as follows: Figure 5 As shown in Table 4 below.

[0095] Table 4. Liquid chromatography detection data of Comparative Example 1

[0096]

[0097] Comparative Example 2

[0098] 4-Nitro-N-phenylbenzamide was prepared using the same method as in Example 1, except that N-formylmorpholine (NFM) was not added in Comparative Example 2. The specific preparation process is as follows:

[0099] Nitrogen gas was introduced to purge the air from the reaction flask, which was equipped with a mechanical stirrer, thermometer, reflux condenser, and constant-pressure dropping funnel. Then, 150.36 g of tetrachloroethylene, 25.07 g of p-nitrobenzoic acid, and 0.5 g of triphenylphosphine oxide (TPPO) were added sequentially. The mixture was heated to 50 °C and stirred until dissolved.

[0100] At 50 °C, 21.76 g of thionyl chloride was slowly added dropwise over 1 hour through a constant-pressure dropping funnel. After the addition was complete, the temperature was increased to 80 °C at a rate of 10 °C / 30 min, and the reaction was allowed to proceed for 3 hours.

[0101] The reaction system was cooled to 50 °C, and 15.35 g of aniline was slowly added dropwise over 30 min through a constant-pressure dropping funnel. After the addition was complete, the temperature was raised to 115 °C, and the reaction was allowed to proceed for 2.5 h.

[0102] The reaction was quenched with methanol, and the product was washed, filtered, and dried in a vacuum oven at 50°C. The yield of the product, 4-nitro-N-phenylbenzamide, was 94.27%, and the purity was 99.23%. The test results are as follows: Figure 6 As shown in Table 5 below, the relevant test data are as follows.

[0103] Table 5. Liquid chromatography detection data of Comparative Example 2

[0104]

[0105] Comparative Example 3

[0106] 4-Nitro-N-phenylbenzamide was prepared using the same method as in Example 1, except that N-formylmorpholine (NFM) and triphenylphosphine oxide (TPPO) were not added in Comparative Example 3; instead, DMF was used as the catalyst. The specific preparation process is as follows:

[0107] Nitrogen gas was introduced to purge the air from the reaction flask, which was equipped with a mechanical stirrer, thermometer, reflux condenser, and constant-pressure dropping funnel. Then, 150.36 g of tetrachloroethylene, 25.07 g of p-nitrobenzoic acid, and 0.73 g of N,N dimethylformamide (DMF) were added sequentially. The mixture was heated to 50 °C and stirred until dissolved.

[0108] At 50 °C, 21.76 g of thionyl chloride was slowly added dropwise over 1 hour using a constant-pressure dropping funnel. After the addition was complete, the temperature was increased to 80 °C at a rate of 10 °C / 30 min, and the reaction was allowed to proceed for 3 hours. The acyl chloride reaction was confirmed to be complete by TLC monitoring.

[0109] The reaction system was cooled to 50 °C, and 15.35 g of aniline was slowly added dropwise over 30 min through a constant-pressure dropping funnel. After the addition was complete, the temperature was raised to 115 °C, and the reaction was allowed to proceed for 2.5 h.

[0110] The reaction was quenched with methanol, and the product was washed, filtered, and dried in a vacuum oven at 50°C. The yield of the product, 4-nitro-N-phenylbenzamide, was 97.28%, and the purity was 99.14%. The test results are as follows: Figure 7 As shown in Table 6 below, the relevant test data are as follows.

[0111] Table 6. Liquid Chromatography Detection Data of Comparative Example 3

[0112]

[0113] Comparative Example 4

[0114] 4-Nitro-N-phenylbenzamide was prepared using the same method as in Example 1, except that a one-pot method was not used in Comparative Example 4; instead, the intermediate was separated. The specific preparation process is as follows:

[0115] Nitrogen gas was introduced to purge the air from the reaction flask, which was equipped with a mechanical stirrer, thermometer, reflux condenser, and constant-pressure dropping funnel. Then, 150.36 g of tetrachloroethylene, 25.07 g of p-nitrobenzoic acid, 0.38 g of N-formylmorpholine (NFM), and 0.12 g of triphenylphosphine oxide (TPPO) were added sequentially. The mixture was heated to 50 °C and stirred until most of the solids dissolved.

[0116] At 50 °C, 21.76 g of thionyl chloride was slowly added dropwise over 1 hour through a constant-pressure dropping funnel. After the addition was complete, the temperature was increased to 80 °C at a rate of 10 °C / 30 min, and the reaction was allowed to proceed for 3 hours.

[0117] After the reaction was complete, the reaction system was cooled to room temperature. A vacuum distillation apparatus was set up, and excess thionyl chloride and most of the solvent tetrachloroethylene were removed by vacuum distillation at a water bath temperature of 65 °C and a vacuum degree of -0.08 MPa. The residue in the flask was a pale yellow viscous liquid or a eutectic, which was the crude p-nitrobenzoyl chloride.

[0118] The crude p-nitrobenzoyl chloride was dissolved in anhydrous petroleum ether and purified by recrystallization to obtain light yellow needle-like crystals. 25.72 g of the crystals were weighed, yielding a yield of 92.39%. The crystals were sealed and stored in a desiccator for later use.

[0119] Take another reaction flask, add 25.72 g of purified p-nitrobenzoyl chloride obtained above and 50 g of fresh tetrachloroethylene, and stir to dissolve.

[0120] At 50 °C, a solution of 12.91 g aniline dissolved in 20 g tetrachloroethylene was slowly added dropwise over 30 min through a constant-pressure dropping funnel. After the addition was complete, the temperature was raised to 115 °C, and the reaction was allowed to proceed for 2.5 h.

[0121] The reaction was quenched with methanol, and the product was washed, filtered, and dried in a vacuum oven at 50°C. The yield of the product, 4-nitro-N-phenylbenzamide, was 82.15%, with a purity of 98.3%. Liquid chromatography analysis showed the following results. Figure 8 The relevant test data are shown in Table 7 below.

[0122] Table 7. Liquid chromatography detection data of Comparative Example 4

[0123]

[0124] Comparative Example 5

[0125] 4-Nitro-N-phenylbenzamide was prepared using the same method as in Example 1, except that the heating rate during the acyl chloride reaction in Comparative Example 5 was 20°C / 30 min (higher than the heating rate specified in this invention). The specific preparation process is as follows:

[0126] Nitrogen gas was introduced into a reaction flask equipped with a mechanical stirrer, thermometer, reflux condenser, and constant-pressure dropping funnel to replace the air. Then, 150.36 g of tetrachloroethylene, 25.07 g of p-nitrobenzoic acid, 0.38 g of N-formylmorpholine (NFM), and 0.12 g of triphenylphosphine oxide (TPPO) were added sequentially, and the mixture was heated to 50 °C and stirred until dissolved.

[0127] At 50 °C, 21.76 g of thionyl chloride (n(p-nitrobenzoic acid):n(thionyl chloride) = 1:1.22) was slowly added dropwise over 1 hour through a constant-pressure dropping funnel. After the addition was complete, the temperature was increased to 80 °C at a rate of 20 °C / 30 min, and the reaction was allowed to proceed for 3 hours.

[0128] The reaction system was cooled to 50 °C, and 15.35 g of aniline (n(p-nitrobenzoic acid):n(aniline) = 1:1.1) was slowly added dropwise over 30 min through a constant pressure dropping funnel. After the addition was complete, the temperature was raised to 115 °C and the reaction was carried out for 2.5 h.

[0129] The reaction was quenched with methanol, and the product was washed, filtered, and dried in a vacuum oven at 50°C. The yield of the product, 4-nitro-N-phenylbenzamide, was 86.11%, and the purity was 99.01% as determined by liquid chromatography.

[0130] A comparison of the experimental results from Example 1 and Comparative Examples 1 and 2 shows that in the one-pot preparation method of 4-nitro-N-phenylbenzamide, the composite catalyst NFM efficiently catalyzes acylation, while TPPO stabilizes the acylation intermediate and promotes condensation. Their synergistic effect enables the reaction to proceed efficiently, stably, and with high selectivity, resulting in high product yield and high purity. The synergistic effect of NFM and TPPO is beneficial to the preparation of 4-nitro-N-phenylbenzamide.

[0131] A comparison of the experimental results of Example 1 and Comparative Example 3 shows that the composite catalyst used in the preparation method of the present invention is significantly superior to the traditional DMF catalytic system and is more conducive to obtaining high yield and high purity of 4-nitro-N-phenylbenzamide.

[0132] A comparison of the experimental results of Example 1 and Comparative Example 4 shows that the one-pot method for preparing 4-nitro-N-phenylbenzamide in the present invention can greatly simplify the process and improve the yield of the target product.

[0133] A comparison of the experimental results of Example 1 and Comparative Example 5 shows that if the heating rate is too fast during the preparation process, the yield and purity of the target product 4-nitro-N-phenylbenzamide will decrease. This is because an excessively fast heating rate will cause some of the raw materials in the system to not react fully, resulting in the volatilization of thionyl chloride, which ultimately affects the yield and purity of the target product.

[0134] In summary, this invention discloses a one-pot synthesis of 4-nitro-N-phenylbenzamide, avoiding the separation of highly active intermediates; and the NFM+TPPO composite catalyst system used is significantly superior to single catalysts or traditional DMF catalytic systems in terms of yield, purity and catalyst recyclability, demonstrating outstanding synergistic effects and technical advantages.

[0135] 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.

[0136] For those skilled in the art, various modifications and improvements can be made without departing from the concept of the present invention, and these modifications and improvements are all 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 4-nitro-N-phenylbenzamide in a one-pot process, characterized in that, The preparation method is as follows: S1. Under inert gas protection, an inert solvent, p-nitrobenzoic acid, and a composite catalyst are added to the reactor and heated to dissolve them. The composite catalyst is NFM and TPPO. The mass ratio of NFM to TPPO in the composite catalyst is 1:(0.2~0.5). S2. Under the conditions of heating and dissolving temperature, thionyl chloride is slowly added to the reaction system, and the temperature is raised to 70-85℃ at a rate of 8-12℃ / 30min to carry out the acylation reaction. S3. Slowly add aniline to the reaction system to carry out the condensation reaction; S4. After the reaction is complete, 4-nitro-N-phenylbenzamide is obtained through post-treatment.

2. The method for preparing 4-nitro-N-phenylbenzamide in a one-pot process according to claim 1, characterized in that, The inert solvent is at least one of tetrachloroethylene, dichloromethane, dichloroethane, N,N-dimethylformamide, and N,N-dimethylacetamide.

3. The method for preparing 4-nitro-N-phenylbenzamide in a one-pot process according to claim 1, characterized in that, In step S1, the heating and dissolution temperature is 35-55℃, and the inert solvent is 5-8 times the mass of p-nitrobenzoic acid.

4. The method for preparing 4-nitro-N-phenylbenzamide in a one-pot process according to claim 1, characterized in that, The total amount of the composite catalyst is 1.5%-4% of the mass of p-nitrobenzoic acid.

5. The method for preparing 4-nitro-N-phenylbenzamide in a one-pot process according to claim 1, characterized in that, The molar ratio of thionyl chloride to p-nitrobenzoic acid is (1-2):1; the molar ratio of aniline to p-nitrobenzoic acid is (0.8-1.5):

1.

6. The method for preparing 4-nitro-N-phenylbenzamide in a one-pot process according to claim 1, characterized in that, In step S2, the reaction time for the acylation reaction is 2h-4h.

7. The method for preparing 4-nitro-N-phenylbenzamide in a one-pot process according to claim 1, characterized in that, In step S3, the condensation reaction temperature is 100-120℃ and the reaction time is 2h-4h.

8. The method for preparing 4-nitro-N-phenylbenzamide in a one-pot process according to claim 1, characterized in that, In step S4, after the reaction is complete, methanol is added to quench the reaction. After solid-liquid separation and washing, the product is vacuum dried at 50-60℃ to obtain 4-nitro-N-phenylbenzamide.

9. The method for preparing 4-nitro-N-phenylbenzamide in a one-pot process according to claim 8, characterized in that, The mother liquor obtained from the solid-liquid separation is subjected to vacuum distillation to recover methanol and inert solvent, and TPPO and NFM-containing concentrate are obtained through crystallization and solid-liquid separation. The recovered methanol, inert solvent, TPPO and NFM-containing concentrate are recycled in the preparation process of 4-nitro-N-phenylbenzamide.

Images