A process for the preparation of 3-amino-4-methoxy-N-phenylbenzamide

Abstract

The application discloses a preparation method of 3-amino-4-methoxy-N-phenyl benzamide. The method comprises the following steps: taking p-hydroxybenzoic acid as raw material, carrying out amidation reaction, diazotization and reduction reaction to obtain 3-amino-4-hydroxy-N-phenyl benzamide intermediate, and finally carrying out methylation reaction to obtain 3-amino-4-methoxy-N-phenyl benzamide. The solid product of 3-amino-4-methoxy-N-phenyl benzamide obtained by the preparation method has a purity greater than 97%, the overall step operation is simple under the premise of obtaining high yield, three waste emissions are reduced, and the method is more suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the fields of organic synthesis and fine chemicals, specifically to a method for preparing 3-amino-4-methoxy-N-phenylbenzamide. Background Technology

[0002] 3-Amino-4-methoxy-N-phenylbenzamide, also known as red-based KD, is a type of chromophore and a relatively new product that has been put into production in China in recent years, with an annual output exceeding 100 tons and a large market demand. The unique molecular structure of 3-amino-4-methoxy-N-phenylbenzamide endows it with unique properties, and it is mainly used in dyes or pigments, pharmaceutical and pesticide intermediates, and new material intermediates.

[0003] In the field of dyes and pigments, red-based KD is a high-fastness dyeing agent among ice-dyeing dyes, mainly used for dyeing and printing cotton, rayon, and linen fibers. It is also an important intermediate in the synthesis of organic pigments; organic pigments synthesized using this intermediate include Pigment Red 31, 32, 146, 147, 150, 176, 261, and Pigment Violet 43. In the pharmaceutical and pesticide intermediate field, this structure can be used to synthesize certain bioactive molecules, such as kinase inhibitors, antibacterial agents, or anti-inflammatory drugs, with amino and amide groups providing key sites for interaction with biological targets. Similarly, this compound can also serve as an intermediate in the synthesis of certain herbicides, fungicides, or insecticides. In the field of new material intermediates, this compound can be used to synthesize high-performance polymers, such as polyamides or polyimides, by introducing specific side-chain groups to adjust the polymer's thermal properties, solubility, or optical properties.

[0004] Therefore, red-based KD is a typical aromatic amine fine chemical intermediate. Due to its aromatic amino groups and highly stable amide backbone, it is an excellent precursor for the synthesis of azo dyes and pigments. At the same time, it also has the potential to serve as a structural unit in the fields of pharmaceutical and pesticide research and development.

[0005] Currently, the industrial preparation methods for red-based KD mainly include the following categories: (1) It is prepared from o-nitroanisole as a raw material by chloromethylation, hydrolysis, oxidation, amidation, condensation and reduction. The reaction route is as follows:

[0006] However, the above routes are lengthy, have low yields, high costs, and generate a lot of waste, causing serious pollution.

[0007] (2) In 1996, Lü Yuzhi et al. disclosed in “Exploration of New Synthesis Process of Red-Based KD” that red-based KD was obtained by using p-chlorobenzoic acid as raw material through etherification, nitration, condensation of thionyl chloride and reduction with sodium hydrosulfide.

[0008] (3) In 2003, Ma Ying et al. disclosed in “Research on New Process of Red-Based KD” that red-based KD was obtained by using p-chlorobenzoic acid as raw material through four steps: nitration, etherification, amidation and reduction.

[0009] The existing traditional synthesis process uses mixed acid (concentrated nitric acid-concentrated sulfuric acid) nitration as the core step. This nitration process is highly exothermic, and improper temperature control can easily lead to material spillage and explosions, posing a high safety risk. Furthermore, the raw materials and products contain amino and nitro groups, resulting in poor thermal stability and further exacerbating production safety hazards. In addition, the traditional process generates significant pollution from wastewater, producing large amounts of highly acidic wastewater with high color, COD, and nitrogen content, as well as containing toxic organic impurities, making treatment difficult and costly. The nitration reaction releases toxic and corrosive nitrogen oxides, easily inducing acid rain pollution. Simultaneously, the sulfuric acid consumed in the process produces large amounts of waste sulfuric acid and sulfate residue. Moreover, traditional nitration easily generates various nitro isomers as byproducts. Due to the similar physicochemical properties of these isomers, separation and purification are difficult, requiring multiple recrystallizations for refining. This results in low product purity, dull appearance, and impure color, affecting subsequent dyeing applications. Furthermore, side reactions and material losses during separation also lead to low overall product yield and significant raw material waste. Finally, the above process is lengthy, involving multiple steps such as nitration, dilution, neutralization, recrystallization, solid-liquid separation, and drying, resulting in a large equipment footprint and high energy and labor costs.

[0010] In summary, there is an urgent need to develop a simple, mild, high-yield, environmentally friendly method for preparing 3-amino-4-methoxy-N-phenylbenzamide that is more suitable for industrial production. Summary of the Invention

[0011] The purpose of this invention is to provide a method for preparing 3-amino-4-methoxy-N-phenylbenzamide, thereby overcoming the shortcomings of existing preparation methods. The preparation method of this invention uses readily available and inexpensive p-hydroxybenzoic acid as a raw material, and features a simple route, mild conditions, high yield, and environmental friendliness, making it more suitable for industrial production.

[0012] To achieve the above objectives, the present invention adopts the following technical solution: A method for preparing 3-amino-4-methoxy-N-phenylbenzamide includes the following steps: (1) In the presence of a catalyst and aniline, p-hydroxybenzoic acid was amidated to obtain 4-hydroxy-N-phenylbenzamide; (2) In the presence of a diazotizing agent and an acidic medium, 4-hydroxy-N-phenylbenzamide was coupled to prepare 4-hydroxy-N-phenyl-3-(phenylazo)benzamide; (3) In the presence of a catalyst and a reducing agent, 4-hydroxy-N-phenyl-3-(benzoazo)benzamide was reduced to obtain 3-amino-4-hydroxy-N-phenylbenzamide; (4) In the presence of an alkaline source and a methylating agent, 3-amino-4-hydroxy-N-phenylbenzamide is subjected to a methylation reaction to obtain 3-amino-4-methoxy-N-phenylbenzamide; The specific synthesis route is as follows: .

[0013] Furthermore, the above preparation method specifically includes the following steps: (1) Amide reaction: p-hydroxybenzoic acid, aniline and catalyst are mixed and subjected to an amidation reaction to obtain 4-hydroxy-N-phenylbenzamide; (2) Preparation of azo compounds: Aniline was mixed with 0.355 mol / L sodium carbonate aqueous solution under ice bath, and diazotizing reagent and acidic medium were added dropwise in sequence. The reaction was kept at the temperature for 0.5~1.5h to obtain a diazonium salt solution. 4-hydroxy-N-phenylbenzamide, sodium hydroxide aqueous solution, sodium carbonate and water were mixed evenly and then slowly added dropwise to the above diazonium salt solution at the same temperature. The reaction was carried out for 2~4h. The reaction solution was purified to obtain azo compounds. (3) Reduction reaction: 4-hydroxy-N-phenyl-3-(benzoazo)benzamide, catalyst and solvent were subjected to hydrogenation reduction reaction at room temperature to obtain 3-amino-4-hydroxy-N-phenylbenzamide; (4) Methylation: 3-amino-4-hydroxy-N-phenylbenzamide, solvent and base source are mixed and heated to 40~60℃. Methylation reagent is added and the temperature is raised to carry out methylation reaction. After the reaction is completed, the resulting reaction solution is purified to obtain 3-amino-4-methoxy-N-phenylbenzamide.

[0014] Furthermore, the catalyst mentioned in step (1) is at least one of tetrabutyl titanate and antimony fluoride, and the mass ratio of hydroxybenzoic acid, aniline and catalyst is (2-15):(1.5-11.25):(0.3-1).

[0015] Furthermore, the amidation reaction in step (1) is carried out at a temperature of 160℃-180℃ for a time of 4-8h.

[0016] Furthermore, in step (2), the diazotizing agent is sodium nitrite; the acidic medium is hydrochloric acid; and the ratio of the amount of aniline, sodium carbonate aqueous solution, diazotizing reagent, acidic medium and 4-hydroxy-N-phenylbenzamide is (0.58g-2.32g): (8.5mL-34mL): (0.45g-1.8g): (1.7mL-6.4mL): (1.06g-4.24g).

[0017] Furthermore, the catalyst in step (3) is at least one of platinum-carbon catalyst and Raney nickel; the solvent is at least one of methanol, anhydrous ethanol and ethyl acetate.

[0018] Furthermore, in step (3), the ratio of 4-hydroxy-N-phenyl-3-(benzoazo)benzamide, catalyst and solvent is 2-4g:0.2g:20-40mL.

[0019] Furthermore, in step (4), the alkali source is at least one of potassium carbonate, sodium carbonate, and cesium carbonate; the methylating agent is dimethyl carbonate; and the solvent is at least one of DMF and DMSO.

[0020] Furthermore, in step (4), the molar ratio of 3-amino-4-hydroxy-N-phenylbenzamide, methylating agent and base source is 1:1.0-1.5:0.5-1.

[0021] Furthermore, the temperature in the methylation reaction described in step (4) is 130℃-150℃.

[0022] The beneficial effects of this invention are as follows: (1) Economically feasible: Using inexpensive tetrabutyl titanate as a catalyst, the reaction can be carried out under solvent-free conditions.

[0023] (2) Environmentally friendly: The diazotization process replaces the traditional nitration process, reducing the discharge of waste gas, wastewater and solid waste and the corrosion of equipment.

[0024] (3) Safe and reliable: Use more green and safe dimethyl carbonate instead of highly toxic dimethyl sulfate.

[0025] (4) Easy to industrialize: Each step is simple to operate and does not require extreme conditions or special equipment. Compared with traditional processes, the preparation method of the present invention reduces the emission of three wastes and is more suitable for large-scale production. Attached Figure Description

[0026] Figure 1 This is a synthetic route diagram of the present invention.

[0027] Figure 2 The hydrogen spectrum of 4-amino-4-hydroxy-N-phenylbenzamide.

[0028] Figure 3 The hydrogen spectrum of 3-amino-4-methoxy-N-phenylbenzamide. Detailed Implementation

[0029] The present invention will be further described below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the invention and should not be considered as limiting the invention.

[0030] The preparation method of 3-amino-4-methoxy-N-phenylbenzamide, and its synthetic route, can be found in [link to relevant documentation]. Figure 1 Using p-hydroxybenzoic acid as a raw material, the final product 3-amino-4-methoxy-N-phenylbenzamide is obtained through amidation, diazotization, and finally methylation. The following examples illustrate this process.

[0031] Example 1

[0032] Step 1, amidation reaction 2 g of p-hydroxybenzoic acid, 1.5 g of aniline, and 3.4 g of tetrabutyl titanate (GR, ≥99%, Shanghai Maclean Biochemical Technology Co., Ltd., hereinafter the same) were added to a 100 mL three-necked flask. Stirring was started, and the temperature was raised to 180 °C for reaction. Gas phase monitoring was performed every 1 hour, and the reaction was complete after 6 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the resulting solid was dissolved in a 20 wt% sodium hydroxide aqueous solution to adjust the pH to 12-13. The solution was then extracted with ethyl acetate (3 × 25 mL) to remove excess aniline. The aqueous phase was collected, and concentrated hydrochloric acid (37%) was added to adjust the pH to 6-7. After the solid precipitated, it was filtered and dried to obtain a white solid, 4-hydroxy-N-phenylbenzamide, with a yield of 91% and a purity of 98%.

[0033] Step 2, Preparation of azo compounds Dissolve 0.32 g Na₂CO₃ in 8.5 mL of water to obtain an aqueous sodium carbonate solution. Take 0.58 g aniline in a 250 mL three-necked flask, add the aqueous sodium carbonate solution, and slowly add sodium nitrite solution (0.45 g NaNO₂ dissolved in 1.1 mL of water) dropwise under ice bath conditions (0-5℃). Then slowly add 1.7 mL of concentrated hydrochloric acid (37%). React for 1 h to obtain an orange-yellow diazonium salt solution. Prepare another 250 mL three-necked flask, add 1.06 g 4-hydroxy-N-phenylbenzamide, 1.6 mL of 20 wt% NaOH aqueous solution, 0.44 g Na₂CO₃, and 5 mL of water. Mix well and slowly add to the diazonium salt solution under the same ice bath conditions. After reacting for 3 h, filter. Wash the resulting precipitate twice with ice water, then add 20 wt% sodium hydroxide solution to adjust the pH to 12-13, and then extract with dichloromethane (3 × 20 mL). The aqueous phase was collected, and concentrated hydrochloric acid (37%) was added dropwise to slowly acidify the aqueous phase to a pH of 6-7. After the solid precipitated, it was filtered and dried in a vacuum oven at 50 °C for 12 h to obtain a brown solid, 4-hydroxy-N-phenyl-3-(phenylazo)benzamide. The yield was 71%, and the purity was 97.5%.

[0034] Step 3, reduction reaction 2 g of 4-hydroxy-N-phenyl-3-(phenylazo)benzamide was added to a 100 mL round-bottom flask, along with 20 mL of methanol and 0.2 g of 5% platinum-carbon catalyst (purchased from Shanghai Haohong Biomedical Technology Co., Ltd.). The reaction was carried out at room temperature using a hydrogen generator for 20 h. After the reaction was complete, the 5% platinum-carbon catalyst was recovered by filtration under normal pressure, and the filter cake was washed repeatedly with methanol. The filtrate was concentrated under reduced pressure to remove the solvent. The product was then adjusted to pH 12-13 with 20 wt% sodium hydroxide solution, followed by extraction with dichloromethane (3 × 20 mL) to remove aniline. The aqueous phase was collected, and concentrated hydrochloric acid (37%) was added dropwise to slowly acidify the pH to 6-7, precipitating a solid. The solid was filtered, and the filter cake was washed twice with ice water and then dried in a vacuum oven at 50 ℃ for 12 h to obtain the product 3-amino-4-hydroxy-N-phenylbenzamide. The yield was 91%, and the purity was 98%. Its NMR data are as follows: 1 H NMR (600 MHz, DMSO) δ 9.86 (s, 1H), 9.71 (s, 1H), 7.75 (d, J = 8.7Hz, 2H), 7.31 (t, J = 8.0 Hz, 2H), 7.23 (d, J = 2.4 Hz, 1H), 7.12 (dd, J =8.2, 2.3 Hz, 1H), 7.05 (t, J = 7.9 Hz, 1H), 6.74 (d, J = 8.2 Hz, 1H), 4.73(s, 2H).

[0035] 13 C NMR (151 MHz, DMSO) δ 166.00, 147.30, 139.70, 136.44, 128.52(2C), 126.31, 123.09, 120.18(2C), 116.70, 113.94, 113.40.

[0036] Step 4, methylation reaction 2 g of 3-amino-4-hydroxy-N-phenylbenzamide, 20 mL of DMF, and 1 g of potassium carbonate were added to a three-necked flask. The mixture was heated to 50 °C, and then 1 g of dimethyl carbonate was slowly added dropwise. The temperature was then raised to 140 °C, and the reaction was allowed to proceed for 10 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was extracted with ethyl acetate (3 × 25 mL). The combined organic phases were washed with brine (3 × 500 mL) to ensure complete removal of DMF. The obtained organic phase was concentrated under reduced pressure to obtain a crude solid. 2 mL of concentrated hydrochloric acid (37%) and 5 mL of water were added to the crude solid. After the solid was fully dissolved, ethyl acetate was added for extraction (3 × 25 mL) to remove organic impurities. The aqueous phase was collected, and 20 wt% sodium hydroxide solution was added to adjust the pH to 8-9. The solid product precipitated, was filtered, and dried to obtain the target product 3-amino-4-methoxy-N-phenylbenzamide, with a yield of 80% and a purity of 97.5%. The 1H NMR spectrum is shown below. Figure 3 .

[0037] Example 2

[0038] Step 1, amidation reaction 2 g of p-hydroxybenzoic acid, 1.5 g of aniline, and 0.02 g of tetrabutyl titanate catalyst were added to a 100 mL three-necked flask. Stirring was started, and the temperature was raised to 170 °C for the reaction. Gas phase monitoring was performed every 1 hour until the reaction was complete after 6 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the resulting solid was dissolved in a 20 wt% sodium hydroxide solution to adjust the pH to 12-13. The solution was then extracted with ethyl acetate (3 × 25 mL) to remove excess aniline. The aqueous phase was collected, and concentrated hydrochloric acid (37%) was added to adjust the pH to 6-7, precipitating a solid. After filtration and drying, a white solid, 4-hydroxy-N-phenylbenzamide, was obtained with a yield of 85% and a purity of 98%.

[0039] Step 2, Preparation of azo compounds Dissolve 0.64 g Na₂CO₃ in 17 mL of water to obtain an aqueous sodium carbonate solution. Take 1.16 g aniline in a 250 mL three-necked flask, add the aqueous sodium carbonate solution, and slowly add sodium nitrite solution (0.9 g NaNO₂ dissolved in 2.2 mL of water) dropwise under ice bath conditions (0-5℃). Then slowly add 3.2 mL of concentrated hydrochloric acid (37%). React for 1 h to obtain an orange-yellow diazonium salt solution. Prepare another 250 mL three-necked flask, add 2.12 g 4-hydroxy-N-phenylbenzamide, 2.4 mL of 20 wt% NaOH aqueous solution, 0.88 g Na₂CO₃, and 5 mL of water. Mix well, and then slowly add this mixture to the diazonium salt solution under the same ice bath conditions. After reacting for 3 h, filter. Wash the resulting precipitate twice with ice water, then add 20 wt% sodium hydroxide solution to adjust the pH to 12-13, and then extract with dichloromethane (3 × 20 mL). The aqueous phase was collected, and concentrated hydrochloric acid (37%) was added dropwise to slowly acidify the aqueous phase to a pH of 6-7. After the solid precipitated, it was filtered and dried in a vacuum oven at 50 °C for 12 h to finally obtain a brown solid, 4-hydroxy-N-phenyl-3-(benzano)benzamide. The yield was 70%, and the purity was 97.5%.

[0040] Step 3, reduction reaction 4 g of 4-hydroxy-N-phenyl-3-(phenylazo)benzamide was added to a 100 mL round-bottom flask, along with 40 mL of methanol and 0.4 g of 5% platinum-carbon catalyst. The reaction was carried out at room temperature using a hydrogen generator for 20 h. After the reaction was complete, the 5% platinum-carbon catalyst was recovered by filtration under normal pressure, and the filter cake was washed repeatedly with methanol. The filtrate was concentrated under reduced pressure to remove the solvent. The product was then adjusted to pH 12-13 with 20 wt% sodium hydroxide solution, followed by extraction with dichloromethane (3 × 20 mL) to remove aniline. The aqueous phase was collected, and concentrated hydrochloric acid (37%) was added dropwise to slowly acidify the phase to pH 6-7, precipitating a solid. The solid was filtered, and the filter cake was washed twice with ice water and then dried in a vacuum oven at 50 ℃ for 12 h to obtain 3-amino-4-hydroxy-N-phenylbenzamide with a yield of 91% and a purity of 98%.

[0041] Step 4, methylation reaction 4 g of 3-amino-4-hydroxy-N-phenylbenzamide was added to a three-necked flask, followed by 40 mL of DMF and 2 g of potassium carbonate. The temperature was raised to 50 °C, and then 2 g of dimethyl carbonate was slowly added dropwise. After the addition was complete, the temperature was raised to 140 °C, and the reaction was allowed to proceed for 10 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was extracted with ethyl acetate (3 × 25 mL). The combined organic phases were washed with brine (3 × 500 mL) to ensure complete removal of DMF. The obtained organic phase was concentrated under reduced pressure to obtain a crude solid. 2 mL of concentrated hydrochloric acid (37%) and 5 mL of water were added to the crude solid. After the solid was fully dissolved, ethyl acetate was added for extraction (3 × 25 mL) to remove organic impurities. The aqueous phase was collected, and 20 wt% sodium hydroxide solution was added to adjust the pH to 8-9. The solid product precipitated out, was filtered, and dried to obtain the target product 3-amino-4-methoxy-N-phenylbenzamide, with a yield of 79% and a purity of 97.5%.

[0042] Example 3

[0043] Step 1, amidation reaction 2 g of p-hydroxybenzoic acid, 1.5 g of aniline, and 0.4 g of tetrabutyl titanate catalyst were added to a 100 mL three-necked flask. Stirring was started, and the temperature was raised to 160 °C for the reaction. Gas phase monitoring was performed every 1 hour, and the reaction was carried out for 6 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the solid was dissolved in a 20 wt% sodium hydroxide aqueous solution to adjust the pH to 12-13. The solution was then extracted with ethyl acetate (3 × 25 mL) to remove excess aniline. The aqueous phase was collected, and concentrated hydrochloric acid (37%) was added to adjust the pH to 6-7, precipitating a solid. After filtration and drying, a white solid, 4-hydroxy-N-phenylbenzamide, was obtained with a yield of 78% and a purity of 98%.

[0044] Step 2, Preparation of azo compounds Dissolve 0.64 g Na₂CO₃ in 17 mL of water to obtain an aqueous sodium carbonate solution. Take 1.16 g aniline in a 250 mL three-necked flask, add the aqueous sodium carbonate solution, and slowly add sodium nitrite solution (0.9 g NaNO₂ dissolved in 2.2 mL of water) dropwise under ice bath conditions (0-5℃). Then slowly add 3 mL of concentrated hydrochloric acid (37%), reacting for 1 h to obtain an orange-yellow diazonium salt solution. Prepare another 250 mL three-necked flask, add 2.12 g 4-hydroxy-N-phenylbenzamide, 2.4 mL of 20 wt% NaOH aqueous solution, 0.88 g Na₂CO₃, and 5 mL of water. Mix well, and then slowly add this mixture dropwise to the diazonium salt solution under the same ice bath conditions. After reacting for 3 h, filter, wash the resulting precipitate twice with ice water, then add 20 wt% sodium hydroxide solution to adjust the pH to 12-13, and then extract with dichloromethane (3 × 20 mL). The aqueous phase was collected, and concentrated hydrochloric acid (37%) was added dropwise to slowly acidify it to a pH of 6-7. After the solid precipitated, it was filtered and dried in a vacuum oven at 50 °C for 12 h to finally obtain a brown solid, 4-hydroxy-N-phenyl-3-(phenylazo)benzamide. The yield was 67%, and the purity was 97%.

[0045] Step 3, reduction reaction 2 g of 4-hydroxy-N-phenyl-3-(phenylazo)benzamide was added to a 100 mL round-bottom flask, along with 20 mL of methanol and 0.2 g of Raney nickel. The reaction was carried out at room temperature using a hydrogen generator for 20 h. After the reaction was complete, the Raney nickel catalyst was recovered by filtration under normal pressure. The filter cake was washed repeatedly with methanol, keeping it moist throughout the process to prevent spontaneous combustion of the Raney nickel in air due to excessive water loss. The filtrate was concentrated under reduced pressure to remove the solvent. The product was adjusted to pH 12-13 with 20 wt% sodium hydroxide solution and extracted with dichloromethane (3 × 20 mL) to remove aniline. The aqueous phase was collected, and concentrated hydrochloric acid (37%) was slowly added dropwise to acidify it to pH 6-7, precipitating a solid. The solid was filtered, and the filter cake was washed twice with ice water and then dried in a vacuum oven at 50 ℃ for 12 h to obtain a black crystalline solid, 3-amino-4-hydroxy-N-phenylbenzamide, with a yield of 90% and a purity of 98%.

[0046] Step 4, methylation reaction 2 g of 3-amino-4-hydroxy-N-phenylbenzamide was added to a three-necked flask, followed by 20 mL of DMF and 1 g of potassium carbonate. The temperature was raised to 50 °C, and 1 g of dimethyl carbonate was slowly added dropwise. After the addition was complete, the temperature was raised to 130 °C, and the reaction was allowed to proceed for 10 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was extracted with ethyl acetate (3 × 25 mL). The combined organic phases were washed with brine (3 × 500 mL) to ensure complete removal of DMF. The obtained organic phase was concentrated under reduced pressure to obtain a crude solid. 2 mL of concentrated hydrochloric acid (37%) and 5 mL of water were added to the crude solid. After the solid was fully dissolved, ethyl acetate was added for extraction (3 × 25 mL) to remove organic impurities. The aqueous phase was collected, and 20 wt% sodium hydroxide solution was added to adjust the pH to 8-9. The solid product precipitated, was filtered, and dried to obtain the target product 3-amino-4-methoxy-N-phenylbenzamide, with a yield of 72% and a purity of 97.5%.

[0047] Example 4

[0048] Step 1, amidation reaction 10 g of p-hydroxybenzoic acid, 7.5 g of aniline, and 1 g of tetrabutyl titanate catalyst were added to a 100 mL three-necked flask. Stirring was started, and the temperature was raised to 180 °C for the reaction. The gas phase was monitored every 1 hour, and the reaction was completed in 6 hours. After the reaction was complete, the mixture was cooled to room temperature, filtered, and the resulting solid was dissolved in a 20 wt% sodium hydroxide aqueous solution to adjust the pH to 12-13. The solution was then extracted with ethyl acetate (3 × 25 mL) to remove excess aniline. The aqueous phase was collected, and concentrated hydrochloric acid (37%) was added to adjust the pH to 6-7, precipitating a solid. After filtration and drying, a white solid, 4-hydroxy-N-phenylbenzamide, was obtained with a yield of 90% and a purity of 98%.

[0049] Step 2, Preparation of azo compounds Dissolve 0.64 g Na₂CO₃ in 17 mL of water to obtain an aqueous sodium carbonate solution. Take 1.16 g aniline in a 250 mL three-necked flask, add the aqueous sodium carbonate solution, and slowly add sodium nitrite solution (0.9 g NaNO₂ dissolved in 2.2 mL of water) dropwise under ice bath conditions (0-5℃). Then slowly add 2.8 mL of concentrated hydrochloric acid (37%). React for 1 h to obtain an orange-yellow diazonium salt solution. Prepare another 250 mL three-necked flask, add 2.12 g 4-hydroxy-N-phenylbenzamide, 2.4 mL of 20% NaOH aqueous solution, 0.88 g Na₂CO₃, and 5 mL of water. Mix well, and then slowly add this mixture to the diazonium salt solution under the same ice bath conditions. After reacting for 3 h, filter. Wash the resulting precipitate twice with ice water, then add 20 wt% sodium hydroxide solution to adjust the pH to 12-13, and then extract with dichloromethane (3 × 20 mL). The aqueous phase was collected, and concentrated hydrochloric acid (37%) was added dropwise to slowly acidify it to a pH of 6-7. After the solid precipitated, it was filtered and dried in a vacuum oven at 50 °C for 12 h to finally obtain a brown solid, 4-hydroxy-N-phenyl-3-(phenylazo)benzamide. The yield was 65%, and the purity was 97%.

[0050] Step 3, reduction reaction 4 g of 4-hydroxy-N-phenyl-3-(phenylazo)benzamide was added to a 100 mL round-bottom flask, along with 40 mL of methanol and 0.2 g of Raney nickel. The reaction was carried out at room temperature using a hydrogen generator for 20 h. After the reaction was complete, the Raney nickel catalyst was recovered by filtration under normal pressure. The filter cake was washed repeatedly with methanol, keeping it moist throughout to prevent spontaneous combustion of the Raney nickel in air due to excessive water loss. The filtrate was concentrated under reduced pressure to remove the solvent. The product was adjusted to pH 12-13 with 20 wt% sodium hydroxide solution, followed by extraction with dichloromethane (3 × 20 mL) to remove aniline. The aqueous phase was collected, and concentrated hydrochloric acid (37%) was slowly added dropwise to acidify it to pH 6-7, precipitating a solid. The solid was filtered, and the filter cake was washed twice with ice water and then dried in a vacuum oven at 50 ℃ for 12 h to obtain 3-amino-4-hydroxy-N-phenylbenzamide with a yield of 90% and a purity of 98%.

[0051] Step 4, methylation reaction 2 g of 3-amino-4-hydroxy-N-phenylbenzamide was added to a three-necked flask, followed by 20 mL of DMF and 1 g of sodium carbonate. The temperature was raised to 50 °C, and 1 g of dimethyl carbonate was slowly added dropwise. After the addition was complete, the temperature was raised to 140 °C, and the reaction was allowed to proceed for 10 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was extracted with ethyl acetate (3 × 25 mL). The combined organic phases were washed with brine (3 × 500 mL) to ensure complete removal of DMF. The obtained organic phase was concentrated under reduced pressure to obtain a crude solid. 2 mL of concentrated hydrochloric acid (37%) and 5 mL of water were added to the crude solid. After the solid was fully dissolved, ethyl acetate was added for extraction (3 × 25 mL) to remove organic impurities. The aqueous phase was collected, and 20 wt% sodium hydroxide solution was added to adjust the pH to 8-9. The solid product precipitated out, was filtered, and dried to obtain the target product 3-amino-4-methoxy-N-phenylbenzamide, with a yield of 58% and a purity of 97.5%.

[0052] Example 5

[0053] Step 1, amidation reaction 15 g of p-hydroxybenzoic acid, 11.25 g of aniline, and 1 g of tetrabutyl titanate catalyst were added to a 100 mL three-necked flask. Stirring was started, and the temperature was raised to 180 °C for the reaction. The gas phase was monitored every 1 hour, and the reaction was completed in 6 hours. After the reaction was complete, the mixture was cooled to room temperature and filtered. The resulting solid was dissolved in a 20 wt% sodium hydroxide aqueous solution to adjust the pH to 12-13, and then extracted with ethyl acetate (3 × 25 mL) to remove excess aniline. The aqueous phase was collected, and concentrated hydrochloric acid (37%) was added to adjust the pH to 6-7, precipitating a solid. After filtration and drying, a white solid, 4-hydroxy-N-phenylbenzamide, was obtained with a yield of 90% and a purity of 98%.

[0054] Step 2, Preparation of azo compounds Dissolve 1.28 g Na₂CO₃ in 34 mL of water to obtain an aqueous sodium carbonate solution. Take 2.32 g aniline in a 250 mL three-necked flask, add the aqueous sodium carbonate solution, and slowly add sodium nitrite solution (1.8 g NaNO₂ dissolved in 4.4 mL of water) dropwise under ice bath conditions (0-5℃). Then slowly add 6.4 mL of concentrated hydrochloric acid (37%). React for 1 h to obtain an orange-yellow diazonium salt solution. Prepare another 250 mL three-necked flask, add 4.24 g 4-hydroxy-N-phenylbenzamide, 4.8 mL of 20wt% NaOH aqueous solution, 1.76 g Na₂CO₃, and 10 mL of water. Mix well, and then slowly add this mixture to the diazonium salt solution under the same ice bath conditions. After reacting for 3 h, filter. Wash the resulting precipitate twice with ice water, then add 20wt% sodium hydroxide solution to adjust the pH to 12-13, and then extract with dichloromethane (3 × 20 mL). The aqueous phase was collected, and concentrated hydrochloric acid (37%) was added dropwise to slowly acidify it to a pH of 6-7. After the solid precipitated, it was filtered and dried in a vacuum oven at 50 °C for 12 h to finally obtain a brown solid, 4-hydroxy-N-phenyl-3-(phenylazo)benzamide. The yield was 69%, and the purity was 97.5%.

[0055] Step 3, reduction reaction 2 g of 4-hydroxy-N-phenyl-3-(phenylazo)benzamide was added to a 100 mL round-bottom flask, along with 20 mL of anhydrous ethanol and 0.2 g of Raney nickel. The reaction was carried out at room temperature using a hydrogen generator for 20 h. After the reaction was complete, the Raney nickel catalyst was recovered by filtration under normal pressure. The filter cake was washed repeatedly with methanol, keeping it moist throughout the process to prevent spontaneous combustion of the Raney nickel in air due to excessive water loss. The filtrate was concentrated under reduced pressure to remove the solvent. The product was adjusted to pH 12-13 with 20 wt% sodium hydroxide solution and extracted with dichloromethane (3 × 20 mL) to remove aniline. The aqueous phase was collected, and concentrated hydrochloric acid (37%) was slowly added dropwise to acidify it to pH 6-7, precipitating a solid. The solid was filtered, and the filter cake was washed twice with ice water and then dried in a vacuum oven at 50 ℃ for 12 h to obtain 3-amino-4-hydroxy-N-phenylbenzamide. The yield was 86%, and the purity was 98%.

[0056] Step 4, methylation reaction 2 g of 3-amino-4-hydroxy-N-phenylbenzamide was added to a three-necked flask, followed by 20 mL of DMF and 1 g of potassium carbonate. The temperature was raised to 50 °C, and 1 g of dimethyl carbonate was slowly added dropwise. After the addition was complete, the temperature was raised to 150 °C, and the reaction was allowed to proceed for 10 h. After the reaction was complete, the mixture was cooled to room temperature, and the reaction solution was extracted with ethyl acetate (3 × 25 mL). The combined organic phases were washed with brine (3 × 500 mL) to ensure complete removal of DMF. The obtained organic phase was concentrated under reduced pressure to obtain a crude solid. 2 mL of concentrated hydrochloric acid (37%) and 5 mL of water were added to the crude solid. After the solid was fully dissolved, ethyl acetate was added for extraction (3 × 25 mL) to remove organic impurities. The aqueous phase was collected, and 20 wt% sodium hydroxide solution was added to adjust the pH to 8-9. The solid product precipitated, was filtered, and dried to obtain the target product, 3-amino-4-methoxy-N-phenylbenzamide. The yield was 78%, and the purity was 97.5%.

[0057] The above description is only a preferred embodiment of the present invention. All equivalent changes and modifications made within the scope of the claims of the present invention should be included in the scope of the present invention.

Claims

1. A method for preparing 3-amino-4-methoxy-N-phenylbenzamide, characterized in that: Includes the following steps: (1) In the presence of a catalyst and aniline, p-hydroxybenzoic acid was amidated to obtain 4-hydroxy-N-phenylbenzamide; (2) In the presence of a diazotizing agent and an acidic medium, 4-hydroxy-N-phenylbenzamide was coupled to prepare 4-hydroxy-N-phenyl-3-(phenylazo)benzamide; (3) In the presence of a catalyst and a reducing agent, 4-hydroxy-N-phenyl-3-(benzoazo)benzamide was reduced to obtain 3-amino-4-hydroxy-N-phenylbenzamide; (4) In the presence of an alkaline source and a methylating agent, 3-amino-4-hydroxy-N-phenylbenzamide is subjected to a methylation reaction to obtain 3-amino-4-methoxy-N-phenylbenzamide.

2. The preparation method according to claim 1, characterized in that: Specifically, the steps include the following: (1) Amide reaction: p-hydroxybenzoic acid, aniline and catalyst are mixed and subjected to an amidation reaction to obtain 4-hydroxy-N-phenylbenzamide; (2) Preparation of azo compounds: Aniline was mixed with 0.355 mol / L sodium carbonate aqueous solution under ice bath, and diazotizing reagent and acidic medium were added dropwise in sequence. The reaction was kept at the temperature for 0.5~1.5h to obtain a diazonium salt solution. 4-hydroxy-N-phenylbenzamide, sodium hydroxide aqueous solution, sodium carbonate and water were mixed evenly and then slowly added dropwise to the above diazonium salt solution at the same temperature. The reaction was carried out for 2~4h. The reaction solution was purified to obtain 4-hydroxy-N-phenyl-3-(phenylazo)benzamide. (3) Reduction reaction: 4-hydroxy-N-phenyl-3-(benzoazo)benzamide, catalyst and solvent were subjected to hydrogenation reduction reaction at room temperature to obtain 3-amino-4-hydroxy-N-phenylbenzamide; (4) Methylation: 3-amino-4-hydroxy-N-phenylbenzamide, solvent and base source are mixed and heated to 40~60℃. Methylation reagent is added and the temperature is raised to carry out methylation reaction. After the reaction is completed, the resulting reaction solution is purified to obtain 3-amino-4-methoxy-N-phenylbenzamide.

3. The preparation method according to claim 2, characterized in that: The catalyst mentioned in step (1) is at least one of tetrabutyl titanate and antimony fluoride, and the mass ratio of hydroxybenzoic acid, aniline and catalyst is (2-15):(1.5-11.25):(0.3-1).

4. The preparation method according to claim 2, characterized in that: The temperature of the amidation reaction in step (1) is 160℃-180℃ and the time is 4~8h.

5. The preparation method according to claim 2, characterized in that: The diazotizing agent in step (2) is sodium nitrite; the acidic medium is hydrochloric acid; and the ratio of the amount of aniline, sodium carbonate aqueous solution, diazotizing reagent, acidic medium and 4-hydroxy-N-phenylbenzamide is (0.58g-2.32g): (8.5mL-34mL): (0.45g-1.8g): (1.7mL-6.4mL): (1.06g-4.24g).

6. The preparation method according to claim 2, characterized in that: The catalyst mentioned in step (3) is at least one of platinum-carbon catalyst and Raney nickel; the solvent is at least one of methanol, anhydrous ethanol and ethyl acetate.

7. The preparation method according to claim 2, characterized in that: In step (3), the ratio of 4-hydroxy-N-phenyl-3-(benzoazo)benzamide, catalyst and solvent is 2-4g:0.2g:20-40mL.

8. The preparation method according to claim 2, characterized in that: The alkali source in step (4) is at least one of potassium carbonate, sodium carbonate, and cesium carbonate; the methylation reagent is dimethyl carbonate; and the solvent is at least one of DMF and DMSO.

9. The preparation method according to claim 2, characterized in that: The molar ratio of 3-amino-4-hydroxy-N-phenylbenzamide, methylation reagent and base source in step (4) is 1:1.0-1.5:0.5-1.

10. The preparation method according to claim 2, characterized in that: The temperature in the methylation reaction described in step (4) is 130℃-150℃.

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