Preparation method of 3, 5-diaminobenzoic acid

Abstract

The invention discloses a preparation method of 3, 5-diaminobenzoic acid, which comprises the following steps: by taking parachlorobenzoic acid as a raw material, carrying out amination reaction, selective chlorination and diazotization deamination to obtain a 3, 5-dichlorobenzoic acid intermediate, and finally carrying out amination reaction to obtain the 3, 5-diaminobenzoic acid. The purity of the 3, 5-diaminobenzoic acid solid product obtained in the process is greater than 98%, and the total yield can reach more than 79%. The preparation method of the 3, 5-diaminobenzoic acid is specifically limited, traditional processes such as nitration and hydrogenation are not needed, and on the premise that the high yield is obtained, the whole steps are simple and safe, and industrial implementation is easy.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis and fine chemical industry, and in particular to a preparation method of 3,5-diaminobenzoic acid. BACKGROUND

[0002] As a multifunctional aromatic amine compound, 3,5-diaminobenzoic acid has irreplaceable application value in many high-tech fields. The two amino groups and one carboxyl group in its molecular structure endow it with unique chemical properties, making it a key intermediate in the fields of pharmaceutical synthesis, high-performance polymers, and high-end dyes.

[0003] In the pharmaceutical field, 3,5-diaminobenzoic acid has good antibacterial, anti-inflammatory, and antioxidant activities, has been proven to have significant inhibitory effect on various bacterial strains, and can be used to synthesize contrast agents, sulfonamides, and antitumor compounds, etc., and is an important intermediate for many drugs.

[0004] In the field of electronic materials, 3,5-diaminobenzoic acid is one of the core monomers of high-performance polyimides, and the synthesized materials have high thermal stability and strong mechanical strength, and are widely used in flexible circuit boards, semiconductor devices, photovoltaic components, etc. In addition, 3,5-diaminobenzoic acid also has excellent electron transport performance and can be used as a modification component for OLED, organic solar cell, etc.

[0005] In the dye field, 3,5-diaminobenzoic acid can be used to synthesize various high-grade reactive dyes, such as reactive orange 6R and black series dyes, which have the advantages of bright color and high fastness, and with the development of green printing and dyeing technology, its market demand continues to grow.

[0006] In summary, 3,5-diaminobenzoic acid, as a structurally functional organic compound, has important industrial application value and development potential.

[0007] Currently, the industrial preparation methods of 3,5-diaminobenzoic acid mainly include the following categories:

[0008] (1) Nitration reduction method: taking benzoic acid or its derivatives as raw materials, two nitro groups are introduced through nitration reaction, and then the target product is obtained by catalytic hydrogenation or chemical reduction (such as iron powder-hydrochloric acid method, tin salt reduction, etc.). This method is representative and the reaction route is relatively mature, but it generally has the following problems: site control of dinitration product is difficult, often needs strict cooling conditions; the reduction step uses metal reducing agent or high-cost catalyst such as palladium on carbon, with many side reactions and difficult post-treatment; it is difficult to adapt to continuous production and green process requirements.

[0009] (2) Chlorination hydrolysis of benzonitrile: for example, the halogen is introduced on the benzonitrile, and then the target product is obtained by hydrolysis. A large amount of harmful reagent is used in this process, and a large amount of wastewater difficult to handle is generated in the process of hydrolysis and acidification, which has a certain burden on the environment and equipment.

[0010] (3) Direct multi-site amination of benzene ring: for example, the C-H amination strategy of copper catalysis or palladium catalysis is used to directly construct the diaminobenzene structure, but such methods are currently mostly in the laboratory research stage, and face problems such as harsh catalytic system, poor substrate adaptability, and difficult amplification.

[0011] In summary, the current synthesis routes of 3,5-diaminobenzoic acid generally have problems such as harsh reaction conditions, multiple steps, impurities, and difficult amplification, and there is still a lack of a green, efficient, and scalable preparation process suitable for industrialization. Therefore, it is urgent to develop a 3,5-diaminobenzoic acid preparation method starting from cheap and readily available raw materials, with simple process steps, high yield, mild conditions, and suitable for amplification.

[0012] At present, Chinese patent CN101362705A discloses a preparation method of 3,5-diaminobenzoic acid, which uses 3,5-dinitrobenzoic acid in methanol / ethanol, pressurized hydrogen gas and Ni-Al or Pd / C catalytic hydrogenation to obtain 3,5-diaminobenzoic acid. Although this process solves the pollution and purity problems of the iron powder-hydrochloric acid method, it requires high-pressure equipment and has a high risk of ignition / spontaneous combustion, and the process safety management and drying control requirements are high; 3,5-dinitrobenzoic acid needs to be prepared first (upstream nitration selectivity, purity and cost affect overall economy), nickel catalyst filtration and metal impurity residues need to be controlled in accordance with regulations, and a purification unit operation needs to be added for pharmaceutical grade application. Chinese patent CN105906502A discloses a preparation method of 3,5-diaminobenzoic acid, which starts from the controlled drug o-aminobenzoic acid, and goes through the steps of amino protection, selective 3,5-position chlorination, deprotection, diazotization and deamination to obtain 3,5-dichlorobenzoic acid. Although this process route has high selectivity and good yield, it has high safety and environmental risk: the use of chlorine gas and other high-risk, strong corrosive reagents requires extremely high equipment airtightness, tail gas treatment and anti-leakage measures for scale-up production; the diazotization step has poor thermal stability and has an explosion risk; in addition, the multi-step reaction involves strong acid, strong oxidant and high-salt wastewater, increasing the burden of wastewater treatment and solid waste disposal, and the multi-step separation and purification brings about material loss and increased energy consumption, which poses a high challenge to the safety and environmental management of industrialization. Chinese patent CN103224451B discloses a preparation method of 3,5-diaminobenzoic acid, which uses benzonitrile as raw material, goes through selective chlorination, and then forms acid by water to avoid the diazotization-chlorination process (dangerous and long process) starting from o-aminobenzoic acid, and also discards the direct chlorine gas equipment corrosion and intrinsic safety risk; NaClO or H2O2 / HCl is used as the chlorination system, and the safety and controllability are improved. However, a large amount of chloroform is used in the experiment, which requires solvent recovery and a closed system; concentrated acid, NaClO or H2O2 / HCl is used, and the byproduct contains salt / chlorine oxide-containing wastewater, which needs to be improved by neutralization and oxidation-reduction treatment; improper control may cause over-chlorination / byproducts, and the alkaline hydrolysis and acidification steps will generate mother liquor with high salt load, which requires wastewater treatment and crystallization washing process for scale-up. SUMMARY

[0013] Therefore, in view of the above problems, the present application provides a preparation method of 3,5-diaminobenzoic acid. This method uses inexpensive and readily available p-chlorobenzoic acid as raw material, has a simple route, mild conditions, high yield and environmental friendliness, and is more suitable for industrial production.

[0014] To achieve the above-mentioned purpose, the present application adopts the following technical solutions:

[0015] A preparation method of 3,5-diaminobenzoic acid, comprising the following steps:

[0016] (1) amination of p-chlorobenzoic acid in the presence of a catalyst system and an ammonia source to obtain p-aminobenzoic acid;

[0017] (2) selective chlorination of the p-aminobenzoic acid in the presence of a chlorine source and a metal catalyst to obtain 4-amino-3,5-dichlorobenzoic acid;

[0018] (3) diazotization of the 4-amino-3,5-dichlorobenzoic acid in the presence of a diazotizing agent and an acidic medium, and deamination in the presence of a reducing agent to obtain 3,5-dichlorobenzoic acid;

[0019] (4) amination of the 3,5-dichlorobenzoic acid in the presence of a catalyst system and an ammonia source to obtain the target product 3,5-diaminobenzoic acid;

[0020] The specific synthesis route is as follows:

[0021]

[0022] Further, the catalyst system in steps (1) and (4) independently comprises a copper catalyst, a nitrogen-containing ligand and a base; the copper catalyst is selected from at least one of cuprous chloride, copper chloride, cuprous bromide, copper bromide, cuprous iodide, copper sulfate, copper acetate; the nitrogen-containing ligand is selected from at least one of triethylamine, ethylenediamine, oxalyl diamine, L-proline, 2,2'-bipyridine, 1,10-phenanthroline; the base is selected from at least one of potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate, sodium acetate;

[0023] In step (1), the mass amount ratio of the added copper catalyst, nitrogen-containing ligand and base to p-chlorobenzoic acid is 0.05-0.50:1.0, 0.10-0.80:1.0 and 0.5-3.0:1.0, respectively; in step (4), the mass amount ratio of the added copper catalyst, nitrogen-containing ligand and base to 3,5-dichlorobenzoic acid is 0.05-0.50:1.0, 0.10-0.80:1.0 and 0.5-3.0:1.0, respectively.

[0024] Further, in step (1), the mass amount ratio of the added copper catalyst, nitrogen-containing ligand and base to p-chlorobenzoic acid is 0.1-0.25:1.0, 0.2-0.35:1.0 and 1.0-2.0:1.0, respectively; in step (4), the mass amount ratio of the added copper catalyst, nitrogen-containing ligand and base to 3,5-dichlorobenzoic acid is 0.1-0.25:1.0, 0.2-0.35:1.0 and 1.0-2.0:1.0, respectively.

[0025] Further, the chlorine source in step (2) is a combination of hydrochloric acid and hydrogen peroxide, a combination of sodium hypochlorite and hydrogen peroxide, or N-chlorosuccinimide NCS; the metal catalyst in step (2) is selected from at least one of copper salt or iron salt catalyst; and the metal catalyst is selected from at least one of copper chloride, cuprous chloride, cuprous bromide, cuprous iodide, copper acetate, ferric chloride, and cobalt acetate.

[0026] Further, the diazotization agent in step (3) is sodium nitrite or isoamyl nitrite; the acidic medium is hydrochloric acid or sulfuric acid; and the reaction in step (3) is carried out in an alcohol / water mixed solvent system, and the alcohol is selected from at least one of methanol, ethanol, and isopropanol.

[0027] Further, the reaction in step (3) is carried out in an aqueous solution of hypophosphorous acid or a salt thereof, and the hypophosphorous acid or the salt thereof is selected from at least one of hypophosphorous acid, sodium hypophosphite, potassium hypophosphite, and calcium hypophosphite; and step (3) further comprises adding a copper catalyst to promote the deamination reaction; and the copper catalyst is selected from at least one of copper sulfate pentahydrate, cuprous oxide, copper chloride, and copper acetate.

[0028] Further, the temperature of the amination reaction in steps (1) and (4) is 110-190°C.

[0029] Further, the temperature of the amination reaction is 130-155°C.

[0030] Further, in step (1), the ammonia water is used as both an ammonia source and a solvent, and the volume amount of the ammonia water is 1.0-10.0 mL per 1.0 g of p-chlorobenzoic acid.

[0031] Further, the volume amount of the ammonia water is 2.0-5.0 mL per 1.0 g of p-chlorobenzoic acid.

[0032] By adopting the foregoing technical solutions, the present application has the following beneficial effects:

[0033] 1. The raw materials are inexpensive, and the route is simple: using p-chlorobenzoic acid as a starting material, the complex process of using expensive nitration and hydrogenation or using regulated raw materials is avoided, and the total yield is high.

[0034] 2. The conditions are mild, safe, and environmentally friendly: in step (2), a safe “hydrochloric acid-hydrogen peroxide” compound chlorine source is used to replace the highly toxic chlorine gas, which greatly reduces the equipment requirements and safety risks.

[0035] 3. The reaction efficiency is high, and the post-treatment is simple: in step (3), the diazotization deamination is carried out in an alcohol / water mixed solvent system, the reaction is mild and controllable, the product separation is simple, and the purity is high.

[0036] 4. High efficiency and universality of the catalyst system: the copper-based catalyst system adopted has high efficiency, and can be adapted to different reaction steps through combination of various copper salts and ligands, has wide optional range, and controllable cost.

[0037] 5. Easy industrialization: each step is simple to operate, does not require extreme conditions or special equipment, compared with the traditional process, the method reduces three waste emissions, and is more suitable for scale-up production. BRIEF DESCRIPTION OF DRAWINGS

[0038] Figure 1 is a synthetic route map of the present application. DETAILED DESCRIPTION

[0039] The technical solutions of the present application will be further described below through specific embodiments, and those skilled in the art should understand that the embodiments are only to help understand the present application, and should not be regarded as a specific limitation on the present application.

[0040] The present application will be further described below through specific embodiments.

[0041] A preparation method of 3,5-diaminobenzoic acid, the synthetic route of which is shown in Figure 1 , which is prepared from p-chlorobenzoic acid through an amination reaction, a selective chlorination, a diazotization and deamination, and finally an amination reaction. The specific steps are as follows:

[0042] Amination reaction: p-chlorobenzoic acid, copper chloride, triethylamine, potassium carbonate, and ammonia water are added to an autoclave, which is heated to 145℃ and kept for 21h; after the reaction is completed, it is cooled to 80℃, and a certain amount of activated carbon and sodium sulfide are added, and kept at 80℃ for 30min; the filtrate is adjusted to be acidic, and then filtered to obtain solid p-aminobenzoic acid.

[0043] Selective chlorination reaction: p-aminobenzoic acid, ethyl acetate, and copper chloride are added to a reactor, which is stirred at room temperature; concentrated hydrochloric acid is added dropwise, and after the addition is completed, the reaction is carried out at room temperature for 1h; hydrogen peroxide is added dropwise, and after the addition is completed, the reaction is kept for 30min; after the reaction is completed, the solid 4-amino-3,5-dichlorobenzoic acid is obtained by filtration.

[0044] Diazotization and deamination reaction: 4-amino-3,5-dichlorobenzoic acid, methanol, water, copper sulfate pentahydrate, and hydrochloric acid are added to a reactor, which is heated to 45℃, and sodium nitrite aqueous solution is added dropwise; after the addition is completed, the reaction is kept for 1h; after the reaction is completed, the solid 3,5-dichlorobenzoic acid is obtained by filtration.

[0045] Amination reaction: 3,5-dichlorobenzoic acid, cuprous iodide, 1,10-phenanthroline, ammonia water were added into an autoclave, and the temperature was raised to 170℃, and the reaction was kept for 40h. After the reaction was completed, the temperature was reduced to 80℃, and sodium sulfide nonahydrate and activated carbon were added, and the reaction was kept for 30min at 80℃. After the reaction was completed, the filtrate was obtained by filtration, and the pH was adjusted to 3.0-4.0, and the solid 3,5-diaminobenzoic acid was obtained by filtration.

[0046] Example 1

[0047] A preparation method of 3,5-diaminobenzoic acid, comprising the following preparation steps:

[0048] Step one, amination reaction

[0049] 10.0g p-chlorobenzoic acid, 1.5g copper chloride, 3.0g triethylamine, 13.3g potassium carbonate dissolved in 20.0mL water were added into an autoclave, and finally 30mL ammonia water was added. After the addition was completed, the temperature was raised to 145℃, and the reaction was kept for 21h. After cooling to 80℃, sodium sulfide nonahydrate and 0.5g activated carbon with the same amount of substance as copper chloride were added, and the reaction was kept for 30min. After cooling to room temperature, the insoluble matter was removed by filtration, and hydrochloric acid was added dropwise to the filtrate to adjust the pH to 4.0±0.2. The filter cake was obtained by filtration, and the solid p-aminobenzoic acid 8.4g was obtained by washing with cold water, with a yield of 96% and a purity of 99%.

[0050] Step two, selective chlorination reaction

[0051] 2.0g p-aminobenzoic acid, 0.4g copper chloride, 40.0mL ethyl acetate were added into a reactor, and stirred at room temperature. 8.0mL concentrated hydrochloric acid was slowly added dropwise, and after the dropwise addition was completed, the reaction was kept for 30min. 8.0mL hydrogen peroxide was slowly added dropwise, and gas chromatography (GC) was used for monitoring until the raw material was consumed (<5%). Water was added to quench, and the solid was obtained by filtration. After washing with cold water, the solid 4-amino-3,5-dichlorobenzoic acid 2.67g was obtained, with a yield of 89% and a purity of 100%.

[0052] Step three, diazotization and deamination reaction

[0053] 5.0g 4-amino-3,5-dichlorobenzoic acid, 0.5g copper sulfate pentahydrate, 40mL methanol, 15.0mL water, 10.0mL concentrated hydrochloric acid were added into a reactor, and stirred. The temperature was raised to 45℃, and 1.85g sodium nitrite dissolved in 15.0mL water was added dropwise. GC was used for monitoring until the raw material was consumed (<5%). After cooling, the solid 3,5-dichlorobenzoic acid 4.5g was obtained by filtration, with a yield of 98% and a purity of 100%.

[0054] Step four, amination reaction

[0055] Into an autoclave, 10.0 g of 3,5-dichlorobenzoic acid, 2.1 g of cuprous iodide, 2.0 g of 1,10-phenanthroline, 30 mL of ammonia water were added, and after the addition was completed, the temperature was raised to 170°C, and the reaction was maintained for 40 h. After cooling to 80°C, 0.5 times the amount of sodium sulfide nonahydrate based on the amount of cuprous iodide and 0.5 g of activated carbon were added, and the reaction was maintained for 30 min. After cooling to room temperature, the insoluble matter was removed by filtration, and hydrochloric acid was added to the filtrate to adjust the pH to 4.0±0.2. The filter cake was obtained by filtration, and the solid 3,5-diaminobenzoic acid was obtained by washing with cold water. The yield was 7.6 g, and the purity was 99%.

[0056] Example 2

[0057] A method for preparing 3,5-diaminobenzoic acid, and the specific steps are as follows:

[0058] Step 1, amination reaction

[0059] Into an autoclave, 10.0 g of 3,5-dichlorobenzoic acid, 2.1 g of cuprous iodide, 2.0 g of 1,10-phenanthroline, 30 mL of ammonia water were added, and after the addition was completed, the temperature was raised to 170°C, and the reaction was maintained for 40 h. After cooling to 80°C, 0.5 times the amount of sodium sulfide nonahydrate based on the amount of cuprous iodide and 0.5 g of activated carbon were added, and the reaction was maintained for 30 min. After cooling to room temperature, the insoluble matter was removed by filtration, and hydrochloric acid was added to the filtrate to adjust the pH to 4.0±0.2. The filter cake was obtained by filtration, and the solid 3,5-diaminobenzoic acid was obtained by washing with cold water. The yield was 7.6 g, and the purity was 99%.

[0060] Step 2, selective chlorination reaction

[0061] Into a reactor, 2.0 g of p-aminobenzoic acid, 0.5 g of ferric chloride, and 40.0 mL of ethyl acetate were added, and stirred at room temperature. 8.0 mL of concentrated hydrochloric acid was slowly added dropwise, and after the dropwise addition was completed, the reaction was maintained for 30 min. 8.0 mL of hydrogen peroxide was slowly added dropwise, and GC monitoring was performed until the raw material was consumed (<5%). Water was added to quench the reaction, and the solid was obtained by filtration. After washing with cold water, the solid 4-amino-3,5-dichlorobenzoic acid was obtained. The yield was 2.4 g, and the purity was 100%.

[0062] Step 3, diazotization and deamination reaction

[0063] Into a reactor, 5.0 g of 4-amino-3,5-dichlorobenzoic acid, 0.5 g of copper sulfate pentahydrate, 40 mL of ethanol, 15.0 mL of water, and 10.0 mL of concentrated hydrochloric acid were added, and stirred. 1.85 g of sodium nitrite was dissolved in 15.0 mL of water, and added dropwise. GC monitoring was performed until the raw material was consumed (<5%). After cooling, the solid 3,5-dichlorobenzoic acid was obtained by filtration. The yield was 3.9 g, and the purity was 100%.

[0064] Step four, amination reaction

[0065] Into an autoclave, 10.0 g of 3,5-dichlorobenzoic acid, 1.5 g of copper chloride, 1.7 g of 2,2'-dipyridyl, 30 mL of ammonia water were added, and after the addition was completed, the temperature was raised to 170 DEG C, and the reaction was maintained for 40 h. After cooling to 80 DEG C, the same amount of sodium sulfide nonahydrate as that of copper chloride, and 0.5 g of activated carbon were added, and the reaction was maintained for 30 min. After cooling to room temperature, the insoluble matter was removed by filtration, and to the filtrate, hydrochloric acid was added to adjust the pH to 4.0 ± 0.2. The filter cake was obtained by filtration, and the solid 3,5-diaminobenzoic acid was obtained by washing with cold water. The yield was 6.8 g, and the purity was 99%.

[0066] Example 3

[0067] A method for preparing 3,5-diaminobenzoic acid, and the specific steps are as follows:

[0068] Step one, amination reaction

[0069] Into an autoclave, 10.0 g of 3,5-dichlorobenzoic acid, 1.5 g of copper chloride, 1.7 g of 2,2'-dipyridyl, 30 mL of ammonia water were added, and after the addition was completed, the temperature was raised to 170 DEG C, and the reaction was maintained for 40 h. After cooling to 80 DEG C, the same amount of sodium sulfide nonahydrate as that of copper chloride, and 0.5 g of activated carbon were added, and the reaction was maintained for 30 min. After cooling to room temperature, the insoluble matter was removed by filtration, and to the filtrate, hydrochloric acid was added to adjust the pH to 4.0 ± 0.2. The filter cake was obtained by filtration, and the solid 3,5-diaminobenzoic acid was obtained by washing with cold water. The yield was 6.8 g, and the purity was 99%.

[0070] Step two, selective chlorination reaction

[0071] Into a reactor, 2.0 g of p-aminobenzoic acid, 0.5 g of ferric chloride, and 40.0 mL of acetic acid were added, and stirred at room temperature. 8.0 mL of concentrated hydrochloric acid was slowly added dropwise, and after the dropwise addition was completed, the reaction was maintained for 30 min. 8.0 mL of hydrogen peroxide was slowly added dropwise, and GC monitoring was performed until the raw material was consumed (<5%). Water was added for quenching, and the solid was obtained by filtration. After washing with cold water, the solid 4-amino-3,5-dichlorobenzoic acid was obtained. The yield was 2.3 g, and the purity was 100%.

[0072] Step three, diazotization and deamination reaction

[0073] Into a reactor, 5.0 g of 4-amino-3,5-dichlorobenzoic acid, 0.5 g of copper sulfate pentahydrate, 40 mL of isopropyl alcohol, and 10.0 mL of concentrated hydrochloric acid were added, and stirred. The temperature was raised to 80 DEG C, and 1.85 g of sodium nitrite was dissolved in 15.0 mL of water and added dropwise. GC monitoring was performed until the raw material was consumed (<5%). After cooling, the solid 3,5-dichlorobenzoic acid was obtained by filtration. The yield was 4.4 g, and the purity was 100%.

[0074] Step four, amination reaction

[0075] Into an autoclave, 10.0 g of 3,5-dichlorobenzoic acid, 1.5 g of copper chloride, 3 g of triethylamine, 30 mL of ammonia water were added, and after the addition was completed, the temperature was raised to 155°C, and the reaction was maintained for 25 h; cooled to 80°C, added with sodium sulfide nonahydrate in the same amount as the copper chloride, 0.5 g of activated carbon, and maintained for 30 min; cooled to room temperature, filtered to remove insoluble matter, hydrochloric acid was added to the filtrate to adjust to pH = 4.0 ± 0.2, and the filter cake was obtained by filtration, and washed with cold water to obtain solid 3,5-diaminobenzoic acid 7.1 g, yield 91%, purity 99%.

[0076] Example 4

[0077] A method for preparing 3,5-diaminobenzoic acid, the specific steps are as follows:

[0078] Step one, amination reaction

[0079] Into an autoclave, 10.0 g of 3,5-dichlorobenzoic acid, 1.5 g of copper chloride, 3 g of triethylamine, 30 mL of ammonia water were added, and after the addition was completed, the temperature was raised to 155°C, and the reaction was maintained for 25 h; cooled to 80°C, added with sodium sulfide nonahydrate in the same amount as the copper chloride, 0.5 g of activated carbon, and maintained for 30 min; cooled to room temperature, filtered to remove insoluble matter, hydrochloric acid was added to the filtrate to adjust to pH = 4.0 ± 0.2, and the filter cake was obtained by filtration, and washed with cold water to obtain solid 3,5-diaminobenzoic acid 7.1 g, yield 91%, purity 99%.

[0080] Step two, selective chlorination reaction

[0081] Into a reactor, 2.0 g of p-aminobenzoic acid, 0.5 g of cobalt acetate, 40.0 mL of DCE were added, stirred at room temperature, 8.0 mL of concentrated hydrochloric acid was slowly added dropwise, after the dropwise addition was completed, the reaction was carried out for 30 min, 8.0 mL of hydrogen peroxide was slowly added dropwise, GC monitoring was carried out until the raw material was consumed (<5%), water was added to quench, and the solid was obtained by filtration, and after washing with cold water, solid 4-amino-3,5-dichlorobenzoic acid 2.1 g was obtained, yield 71%, purity 100%.

[0082] Step three, diazotization and deamination reaction

[0083] Into a reactor, 5.0 g of 4-amino-3,5-dichlorobenzoic acid, 10.0 mL of concentrated hydrochloric acid, 20 mL of water were added, stirred, cooled to 5°C, 1.85 g of sodium nitrite was dissolved in 15 mL of water and added dropwise, keeping the temperature at 5°C during the process, after dropping, 0.16 g of copper oxide was added, 1.65 g of sodium hypophosphite was dissolved in 15 mL of water and added dropwise, keeping the temperature at 5°C during the process, after dropping, it was reacted at room temperature for 1-2 h, then the temperature was raised to 60°C and kept for 1 h, GC monitoring was performed until the raw material was consumed (<5%), then it was cooled, filtered, and 3.2 g of solid 3,5-dichlorobenzoic acid was obtained, with a yield of 70% and a purity of 100%.

[0084] Step four, amination reaction

[0085] Into an autoclave, 10.0 g of 3,5-dichlorobenzoic acid, 1.5 g of copper chloride, 3 g of triethylamine, 20 g of cesium carbonate dissolved in 20 mL of water were added, and then 30 mL of ammonia water was added, after the addition was completed, the temperature was raised to 160°C and kept for 25 h; cooled to 80°C, added with sodium sulfide nonahydrate with the same amount of substance as copper chloride, 0.5 g of activated carbon, kept for 30 minutes; cooled to room temperature, removed the insoluble matter by filtration, added hydrochloric acid to the filtrate to adjust the pH to 4.0±0.2, filtered to obtain the filter cake, washed with cold water to obtain 7.0 g of solid 3,5-diaminobenzoic acid, with a yield of 90% and a purity of 99%.

[0086] Example 5

[0087] A preparation scheme of 3,5-diaminobenzoic acid is as follows:

[0088] Step one, amination reaction:

[0089] Into an autoclave, 800.0 g of p-chlorobenzoic acid, 120.0 g of copper chloride, 240.0 g of triethylamine, 1 kg of potassium carbonate dissolved in 1.6 L of water were added, and finally 2.6 L of ammonia water was added, after the addition was completed, the temperature was raised to 145°C and kept for 21 h; cooled to 80°C, added with 214.3 g of sodium sulfide nonahydrate, 50 g of activated carbon, kept for 30 minutes; cooled to room temperature, removed the insoluble matter by filtration, added hydrochloric acid to the filtrate to adjust the pH to 4.0±0.2, filtered to obtain the filter cake, washed with cold water to obtain 658.2 g of solid p-aminobenzoic acid, with a yield of 94% and a purity of 98%.

[0090] Step two, selective chlorination reaction

[0091] Into the reactor, 500.0 g of p-aminobenzoic acid, 20.0 g of copper chloride, 12 L of ethyl acetate were added, stirred at room temperature, 1.8 L of concentrated hydrochloric acid was slowly added dropwise, after dropping, the reaction was carried out for 30 minutes, 1.5 L of hydrogen peroxide was slowly added dropwise, GC monitoring was carried out until the raw material was consumed (<5%), water was added to quench, filtration was carried out to obtain a solid, after cold water washing, solid 4-amino-3,5-dichlorobenzoic acid 637.5 g was obtained, the yield was 85%, and the purity was 100%.

[0092] Step three, diazotization deamination reaction

[0093] Into the reactor, 400.0 g of 4-amino-3,5-dichlorobenzoic acid, 30.0 g of copper sulfate pentahydrate, 3 L of methanol, 1.2 L of water, 800.0 mL of concentrated hydrochloric acid were added, stirred, heated to 45 DEG C, 220.0 g of sodium nitrite was dissolved in 1.2 L of water and added dropwise, GC monitoring was carried out until the raw material was consumed (<5%), cooled, filtered, and 352.0 g of solid 3,5-dichlorobenzoic acid was obtained, the yield was 95%, and the purity was 100%.

[0094] Step four, amination reaction

[0095] Into the autoclave, 500.0 g of 3,5-dichlorobenzoic acid, 70.0 g of cuprous iodide, 100.0 g of 1,10-phenanthroline, 1.5 L of ammonia water were added, after the addition was completed, the temperature was increased to 170 DEG C, and the reaction was carried out for 40 h; cooled to 80 DEG C, 88.3 g of sodium sulfide nonahydrate and 30 g of activated carbon were added, and the reaction was carried out for 30 minutes; cooled to room temperature, insoluble substances were removed by filtration, hydrochloric acid was added to the filtrate to adjust to pH = 4.0 ± 0.2, the filter cake was filtered, and cold water was washed to obtain solid 3,5-diaminobenzoic acid 355.0 g, the yield was 89.1%, and the purity was 98%.

[0096] The applicant declares that the above is only a specific embodiment of the present application, but the protection scope of the present application is not limited thereto, and persons skilled in the art should understand that any changes or replacements within the technical scope disclosed by the present application can be easily thought of by any person skilled in the art, and all fall within the protection scope and disclosure scope of the present application.

Claims

1. A method for preparing 3,5-diaminobenzoic acid, characterized by, The method comprises the following steps: (1) performing an amination reaction on p-chlorobenzoic acid in the presence of a catalyst system and an ammonia source to obtain p-aminobenzoic acid; (2) performing a selective chlorination reaction on the p-aminobenzoic acid in the presence of a chlorine source and a metal catalyst to obtain 4-amino-3,5-dichlorobenzoic acid; (3) performing diazotization on the 4-amino-3,5-dichlorobenzoic acid in the presence of a diazotization reagent and an acidic medium, and performing a deamination reaction in the presence of a reducing agent to obtain 3,5-dichlorobenzoic acid; (4) performing an amination reaction on the 3,5-dichlorobenzoic acid in the presence of a catalyst system and an ammonia source to obtain the target product 3,5-diaminobenzoic acid; The specific synthesis route is as follows:

2. The process for the preparation of 3,5-diaminobenzoic acid as claimed in claim 1, wherein: The catalyst system in steps (1) and (4) independently comprises a copper catalyst, a nitrogen-containing ligand and a base; the copper catalyst is selected from at least one of cuprous chloride, copper chloride, cuprous bromide, copper bromide, cuprous iodide, copper sulfate and copper acetate; the nitrogen-containing ligand is selected from at least one of triethylamine, ethylenediamine, oxalyl diamine, L-proline, 2,2'-bipyridine and 1,10-phenanthroline; and the base is selected from at least one of potassium hydroxide, potassium carbonate, sodium carbonate, cesium carbonate and sodium acetate. In step (1), the mass ratio of the amounts of the copper catalyst, the nitrogen-containing ligand and the base to the p-chlorobenzoic acid is 0.05-0.50:1.0, 0.10-0.80:1.0 and 0.5-3.0:1.0, respectively; and in step (4), the mass ratio of the amounts of the copper catalyst, the nitrogen-containing ligand and the base to the 3,5-dichlorobenzoic acid is 0.05-0.50:1.0, 0.10-0.80:1.0 and 0.5-3.0:1.0, respectively.

3. A process for the preparation of 3,5-diaminobenzoic acid according to claim 2, characterized in that: In step (1), the mass ratio of the amounts of the copper catalyst, the nitrogen-containing ligand and the base to the p-chlorobenzoic acid is 0.1-0.25:1.0, 0.2-0.35:1.0 and 1.0-2.0:1.0, respectively; and in step (4), the mass ratio of the amounts of the copper catalyst, the nitrogen-containing ligand and the base to the 3,5-dichlorobenzoic acid is 0.1-0.25:1.0, 0.2-0.35:1.0 and 1.0-2.0:1.0, respectively.

4. The method for preparing 3,5-diaminobenzoic acid according to claim 1, characterized in that, The chlorine source in step (2) is a combination of hydrochloric acid and hydrogen peroxide, a combination of sodium hypochlorite and hydrogen peroxide, or N-chlorosuccinimide NCS; the metal catalyst in step (2) is selected from a copper salt or an iron salt catalyst; and the metal catalyst is selected from at least one of copper chloride, cuprous chloride, cuprous bromide, cuprous iodide, copper acetate, iron chloride and cobalt acetate.

5. The method for preparing 3,5-diaminobenzoic acid according to claim 1, characterized in that, The diazotization reagent in step (3) is sodium nitrite or isoamyl nitrite; the acidic medium is hydrochloric acid or sulfuric acid; and the reaction in step (3) is performed in an alcohol / water mixed solvent system, and the alcohol is selected from at least one of methanol, ethanol and isopropanol.

6. The method for preparing 3,5-diaminobenzoic acid according to claim 1, characterized in that, The reaction in step (3) is carried out in an aqueous solution of hypophosphorous acid or a salt thereof, which is at least one selected from hypophosphorous acid, sodium hypophosphite, potassium hypophosphite, calcium hypophosphite; step (3) further comprises adding a copper catalyst to promote the deamination reaction; the copper catalyst is at least one selected from copper sulfate pentahydrate, cuprous oxide, copper chloride, copper acetate.

7. The method for preparing 3,5-diaminobenzoic acid according to claim 1, characterized in that, The temperature of the amination reaction in steps (1) and (4) is 110-190℃.

8. The method for preparing 3,5-diaminobenzoic acid according to claim 7, characterized in that, The temperature of the amination reaction is 130-155℃.

9. The method for preparing 3,5-diaminobenzoic acid according to claim 1, characterized in that, In step (1), the ammonia water is used as both an ammonia source and a solvent, and the volume amount is 1.0-10.0 mL per 1.0 g of p-chlorobenzoic acid.

10. The method for preparing 3,5-diaminobenzoic acid according to claim 9, characterized in that, The volume amount of the ammonia water is 2.0-5.0 mL per 1.0 g of p-chlorobenzoic acid.

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