Preparation method of methyl 3, 4-diaminobenzoate

Abstract

The invention provides a method for preparing 3, 4-diaminobenzoic acid methyl ester, which comprises the following steps: preparing 3, 4-diaminobenzoic acid from 3, 4-dichlorobenzoic acid by using a metal catalyst and a ligand catalyst; and preparing methyl 3, 4-diaminobenzoate by using the 3, 4-diaminobenzoic acid. The method provided by the invention has the advantages of easily available raw materials, simple process route, no dangerous reaction, no use of expensive heavy metal catalysts, yield and product purity which are equivalent to or superior to those in the prior art, and easiness in large-scale production.

Description

TECHNICAL FIELD

[0001] The present application relates to the field of organic synthesis, in particular to a preparation method of methyl 3,4-diaminobenzoate. BACKGROUND

[0002] Methyl 3,4-diaminobenzoate is a white, yellow or pink solid with a pungent odor, easily soluble in methanol, ethanol, ethyl acetate, dichloromethane and other organic solvents, and is a key intermediate for the synthesis of Danuglipron. Danuglipron is a GLP-1 receptor agonist (GLP-1R agonist) and an oral small molecule drug. No serious adverse reactions were found in the clinical study of treating type 2 diabetes patients. Danuglipron, as a new type of hypoglycemic drug, shows good safety, and methyl 3,4-diaminobenzoate, as a key intermediate of Danuglipron, is essential.

[0003] The literature "Venter, Jana; Perez, Concepcion; van Otterlo, Willem A.L; Martinez, Ana; Blackie; Margaret A.L. [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, # 13, p. 1597 - 1600]" reports that methyl 4-aminobenzoate is used as a raw material, reacts with acetic anhydride in dichloromethane solvent to obtain methyl 4-acetylamino benzoate, then undergoes nitration reaction to obtain methyl 4-acetylamino-3-nitrobenzoate, and then hydrolyzes in dilute sulfuric acid to remove the acetyl group to obtain methyl amino-3-nitrobenzoate, and finally undergoes palladium-carbon catalytic hydrogenation reaction to obtain methyl 3,4-diaminobenzoate. The route has a long step and complicated operation. The nitration reaction is a dangerous reaction, and a large amount of acidic wastewater is difficult to treat, and the industrial production is also dangerous. In addition, the hydrogenation reaction uses a noble metal catalyst, palladium-carbon, which increases the cost of raw materials, thus limiting the industrial production.

[0004] Patent CN116332779A reports that 4-chloro-3-nitrobenzoic acid methyl ester and dibenzylamine are subjected to condensation reaction to obtain 3-nitro-4-dibenzylamino benzoic acid methyl ester, and then subjected to palladium-carbon catalytic hydrogenation to reduce the nitro group and remove the benzyl group to obtain 3,4-diamino benzoic acid methyl ester. The raw material is difficult to obtain in this route, and the nucleophilic substitution reaction on the benzene ring is carried out using dibenzylamine to generate 3-nitro-4-dibenzylamino benzoic acid methyl ester, and then hydrogenation is carried out to remove two benzene rings, which produces a large amount of waste solvent, and the atom economy is poor. In addition, the amino group generated in the hydrogenation reaction easily poisons the catalyst palladium-carbon, making it difficult for the raw material to react completely, affecting the quality and yield of the product, and the problem of expensive noble metal palladium-carbon also makes this route not suitable for industrial production.

[0005] Therefore, there is an urgent need in the art to develop a preparation method of 3,4-diamino benzoic acid methyl ester, which is easy to obtain raw materials, simple process route, does not go through dangerous reactions, is easy to scale up production, and does not need to use expensive heavy metal catalysts. SUMMARY

[0006] In view of the problems in the prior art, the present application provides a preparation method of 3,4-diamino benzoic acid methyl ester.

[0007] The specific technical scheme of the present application is as follows: 1. A method for preparing 3,4-diamino benzoic acid methyl ester, comprising: using a metal catalyst and a ligand catalyst to prepare 3,4-diamino benzoic acid from 3,4-dichlorobenzoic acid; and using 3,4-diamino benzoic acid to prepare 3,4-diamino benzoic acid methyl ester.

[0008] 2. The method of item 1, wherein the method comprises refluxing 3,4-diamino benzoic acid, sulfuric acid in methanol to prepare 3,4-diamino benzoic acid methyl ester.

[0009] 3. The method of item 2, characterized in that after the refluxing reaction, the system is concentrated, deionized water is added, a base is added to adjust the system to a given pH, and then 3,4-diamino benzoic acid methyl ester is obtained by cooling, filtering and drying.

[0010] 4. The method of item 2, characterized in that the molar ratio of 3,4-diamino benzoic acid to sulfuric acid is 1:(0.1-0.3).

[0011] 5. The method of item 2, characterized in that the mass ratio of 3,4-diamino benzoic acid to methanol is 1:(6-10).

[0012] 6. The method of item 2, characterized in that the reaction time of the refluxing reaction is 5-10 h; and the given pH is 6-8.

[0013] 7. The method according to item 3, wherein the mass ratio of the 3,4-diaminobenzoic acid to the deionized water is 1: (4-7).

[0014] 8. The method according to item 3, wherein the base is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium hydroxide, sodium hydroxide, and preferably is sodium carbonate.

[0015] 9. The method according to item 1, wherein the preparation of the 3,4-diaminobenzoic acid from the 3,4-dichlorobenzoic acid further comprises mixing the 3,4-dichlorobenzoic acid, aqueous ammonia, a metal catalyst, and a ligand catalyst, reacting at a given temperature for a given time, then concentrating to remove most of the aqueous ammonia, adding an acid to adjust the system to a given pH, and then obtaining the 3,4-diaminobenzoic acid by cooling and purification.

[0016] 10. The method according to item 9, wherein the molar ratio of the 3,4-dichlorobenzoic acid to the aqueous ammonia is 1: (4-6).

[0017] 11. The method according to item 9, wherein the molar ratio of the 3,4-dichlorobenzoic acid, the metal catalyst, and the ligand catalyst is 1: (0.01-0.05): (0.01-0.05).

[0018] 12. The method according to item 9, wherein the metal catalyst is selected from one or more of cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, and cuprous cyanide, and preferably is cuprous chloride.

[0019] 13. The method according to item 9, wherein the ligand catalyst is selected from one or more of 2-methylpyridine, 3-methylpyridine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 4,7-dimethoxy-1,10-phenanthroline, 2,2'-bipyridine, 4,4-di-tert-butyl-2,2'-bipyridine, 1,10-phenanthroline, and 3,4,7,8-tetramethyl-1,10-phenanthroline, and preferably is 4,7-dimethoxy-1,10-phenanthroline.

[0020] 14. The method according to item 9, wherein the given temperature is 130-150 °C, the given time is 10-16 h, and the given pH is 4-7.

[0021] 15. The method according to item 9, wherein the acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, and citric acid, and preferably is hydrochloric acid.​​

[0022] 16. Methyl 3,4-diaminobenzoate and / or 3,4-diaminobenzoic acid prepared by the method according to any one of claims 1 to 15.

[0023] 17. The method according to any one of claims 1 to 15, or the methyl 3,4-diaminobenzoate and / or 3,4-diaminobenzoic acid according to claim 16, in the field of organic synthesis.

[0024] 18. Use of metal catalysts and ligand catalysts in the preparation of 3,4-diaminobenzoic acid from 3,4-dichlorobenzoic acid.

[0025] The method provided in this application uses readily available raw materials, has a simple process route, does not involve dangerous reactions, and does not require expensive heavy metal catalysts. At the same time, it has yields and product purity that are comparable to or better than existing technologies, and is easy to scale up for production. Detailed Implementation

[0026] Specific embodiments of this application will now be described in more detail. While specific embodiments of this application have been described, it should be understood that this application can be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided to enable a more thorough understanding of this application and to fully convey the scope of this application to those skilled in the art.

[0027] It should be noted that certain terms are used in the specification and claims to refer to specific components. Those skilled in the art will understand that different terms may be used to refer to the same component. This specification and claims do not distinguish components based on differences in terminology, but rather on differences in function. The use of "comprising" or "including" throughout the specification and claims is an open-ended term and should be interpreted as "comprising but not limited to." The following descriptions in the specification are preferred embodiments for carrying out this application; however, these descriptions are for the purpose of understanding the general principles of the specification and are not intended to limit the scope of this application. The scope of protection of this application shall be determined by the appended claims.

[0028] This application provides a method for preparing methyl 3,4-diaminobenzoate, comprising: 3,4-Diaminobenzoic acid was prepared from 3,4-dichlorobenzoic acid using metal catalysts and ligand catalysts; and methyl 3,4-diaminobenzoate was prepared using 3,4-diaminobenzoic acid.

[0029] In one embodiment of this application, the method comprises adding 3,4-diaminobenzoic acid and sulfuric acid to methanol and refluxing to prepare methyl 3,4-diaminobenzoate.

[0030] In one embodiment of this application, the reaction system is concentrated after the reflux reaction.

[0031] In one embodiment of this application, the system is concentrated to a viscous state by the reflux reaction, deionized water is added, alkali is added to adjust the system to a given pH, and then methyl 3,4-diaminobenzoate is obtained by cooling, filtration, and drying.

[0032] In this application, "viscous state" refers to a liquid or semi-fluid substance having a high concentration and viscosity, and poor fluidity. Those skilled in the art can accurately understand its meaning upon seeing this term, and it should not be construed as a limitation of this application.

[0033] In this application, "system" refers to the sum of factors such as the environment, substances, containers, and conditions in which a chemical reaction occurs. Those skilled in the art can accurately understand its meaning upon seeing this term, and it should not be construed as a limitation of this application.

[0034] The molar ratio of 3,4-diaminobenzoic acid to sulfuric acid is 1:(0.1-0.3); for example, it can be 1:0.1, 1:0.15, 1:0.2, 1:0.25, or 1:0.3. It should be understood that the sulfuric acid should be in solution form. Those skilled in the art can easily determine the molar amount of sulfuric acid added to the system based on the concentration and volume of the sulfuric acid solution. Therefore, in the embodiments, 0.2 mol of sulfuric acid should be understood as the presence of 0.2 mol of sulfuric acid in the system by adding a certain volume of sulfuric acid solution of a certain concentration. Therefore, this should not be construed as a limitation of this application.

[0035] In one embodiment of this application, sulfuric acid serves to catalyze the methyl esterification reaction of 3,4-diaminobenzoic acid. In another embodiment, the mass ratio of the 3,4-diaminobenzoic acid, the methanol, and the deionized water is 1:(6-10):(4-7). The molar ratio of the 3,4-diaminobenzoic acid to the methanol is 1:(6-10); for example, it can be 1:6, 1:6.1, 1:6.2, 1:6.3, 1:6.4, 1:6.5, 1:6.4, 1:6.7, 1:6.8, 1:6.9, 1:7, 1:7.1, 1:7.2, 1:7.3, 1:7.4, 1:7.5, 1:7.6, 1: 7.7, 1:7.8, 1:7.9, 1:8, 1:8.1, 1:8.2, 1:8.3, 1:8.4, 1:8.5, 1:8.6, 1:8.7, 1:8.8, 1:8.9, 1:9, 1:9.1, 1:9.2, 1:9.3, 1:9.4, 1:9.5, 1:9.6, 1:9.7, 1:9.8, 1:9.9, 1:10. The molar ratio of 3,4-diaminobenzoic acid to deionized water is 1:(4-7), for example, it can be 1:4, 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9, 1:5, 1:5.1, 1:5.2, 1:5.3, 1:5.4, 1:5.5, 1:5.6, 1:5.7, 1:5.8, 1:5.9, 1:6, 1:6.1, 1:6.2, 1:6.3, 1:6.4, 1:6.5, 1:6.6, 1:6.7, 1:6.8, 1:6.9, or 1:7.

[0036] In one embodiment of this application, in the reflux reaction, the alkali is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium hydroxide, and sodium hydroxide, preferably sodium carbonate. It should be understood that the form of the alkali is not limited in this application; for example, it can be in solid or solution form. Those skilled in the art can choose according to actual conditions, only needing to adjust the pH value to a suitable range. In the reflux reaction, the given pH is 6-8, for example, it can be 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, 7, 7.1, 7.2, 7.3, 7.4, 7.5, 7.6, 7.7, 7.8, 7.9, or 8. In one embodiment of this application, in the reflux reaction, the given time is 5-10 hours, for example, it can be 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, or 10 hours.

[0037] In one embodiment of this application, the preparation of 3,4-diaminobenzoic acid from 3,4-dichlorobenzoic acid further comprises mixing 3,4-dichlorobenzoic acid, ammonia, a metal catalyst and a ligand catalyst, reacting at a given temperature for a given time, then concentrating to remove most of the ammonia, adding acid to adjust the system to a given pH, and then cooling and purifying to obtain 3,4-diaminobenzoic acid.

[0038] In one embodiment of this application, the mixing of 3,4-dichlorobenzoic acid, ammonia, metal catalyst, and ligand catalyst can be performed by mixing the above-mentioned raw materials in a high-pressure reactor.

[0039] In one embodiment of this application, a "ligand catalyst" refers to a molecule or ion that binds to a metal center in a catalytic reaction, regulating the electronic and spatial environment of the metal center through coordination, thereby affecting catalytic activity and selectivity. Ligands not only stabilize the metal center during catalysis but also modulate the reaction pathway and alter reaction efficiency through their electronic effects (such as electron-donating or electron-withdrawing capabilities) and steric effects (such as steric hindrance). A "metal catalyst" refers to a solid catalyst with a metal as the main active component, whose active components include noble metals (such as platinum and palladium) and transition elements such as iron, cobalt, nickel, and copper. Metal catalysts achieve catalytic activity through the energy and steric adaptation of the metal component with reactant molecules.

[0040] In one embodiment of this application, the molar ratio of 3,4-dichlorobenzoic acid, ammonia, metal catalyst, and ligand catalyst is 1:(4-6):(0.01-0.05):(0.01-0.05).

[0041] In one embodiment of this application, the ammonia water should be in solution form. Those skilled in the art can easily determine the molar amount of ammonia water added to the system by the concentration and volume of the ammonia water solution. Therefore, in the embodiment, 5 mol of ammonia water should be understood as the presence of 5 mol of ammonia water in the system by adding a certain volume of ammonia water solution of a certain concentration to the system. Therefore, this should not be construed as a limitation of this application.

[0042] In one embodiment of this application, the ammonia solution may be an ammonia solution prepared at a certain mass concentration, such as ammonia solution with a mass concentration of 10 wt%, 15 wt%, or 20 wt%. Here, wt% refers to mass concentration in this application.

[0043] The molar ratio of 3,4-dichlorobenzoic acid to ammonia is 1:(4-6). For example, the molar ratio of 3,4-dichlorobenzoic acid to ammonia can be 1:4.0, 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9, 1:5.0, 1:5.1, 1:5.2, 1:5.3, 1:5.4, 1:5.5, 1:5.6, 1:5.7, 1:5.8, 1:5.9, or 1:6.0.

[0044] The molar ratio of 3,4-dichlorobenzoic acid to the ligand catalyst can be, for example, 1.0:0.01, 1.0:0.02, 1.0:0.03, 1.0:0.04, or 1.0:0.05. The molar ratio of 3,4-dichlorobenzoic acid to the metal catalyst can also be, for example, 1.0:0.01, 1.0:0.02, 1.0:0.03, 1.0:0.04, or 1.0:0.05.

[0045] In one embodiment of this application, the metal catalyst is selected from one or more of cuprous chloride, cuprous bromide, cuprous iodide, cuprous oxide, and cuprous cyanide, preferably cuprous chloride.

[0046] In one embodiment of this application, the ligand catalyst is selected from one or more of 2-methylpyridine, 3-methylpyridine, 1,8-diazabispiro[5.4.0]undec-7-ene (DBU), 4,7-dimethoxy-1,10-phenanthroline, 2,2'-bipyridine, 4,4'-di-tert-butyl-2,2'-bipyridine, 1,10-o-phenanthroline, and 3,4,7,8-tetramethyl-1,10-phenanthroline, preferably 4,7-dimethoxy-1,10-phenanthroline.

[0047] In one embodiment of this application, the given temperature is 100-200℃, preferably 100-200℃. For example, it can be 100℃, 110℃, 120℃, 130℃, 140℃, 150℃, 160℃, 170℃, 180℃, 190℃, or 200℃, preferably 130℃-150℃. In one embodiment of this application, the given time is 8-20 hours, for example, it can be 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, or 20h, preferably 10-16 hours.

[0048] In one embodiment of this application, the acid is selected from one or more of hydrochloric acid, sulfuric acid, phosphoric acid, and citric acid, preferably hydrochloric acid. It should be understood that the form of the acid is not limited in this application; for example, it can be in solid or solution form. Those skilled in the art can choose according to the actual situation, only needing to adjust the pH value to a suitable range. The given pH is 4-7; for example, the pH can be 4, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 5, 5.1, 5.2, 5.3, 5.4, 5.5, 5.6, 5.7, 5.8, 5.9, 6, 6.1, 6.2, 6.3, 6.4, 6.5, 6.6, 6.7, 6.8, 6.9, or 7.

[0049] In one embodiment of this application, the use of metal catalysts and ligand catalysts for the preparation of 3,4-diaminobenzoic acid from 3,4-dichlorobenzoic acid is also provided.

[0050] In one embodiment of this application, 3,4-diaminobenzoic acid may be synthesized first using 3,4-dichlorobenzoic acid in the manner described above, and then methyl 3,4-diaminobenzoate may be synthesized using 3,4-diaminobenzoic acid.

[0051] This application also provides methyl 3,4-diaminobenzoate prepared by the method described in any of the above-mentioned methods.

[0052] This application also provides 3,4-diaminobenzoic acid prepared by the method described in any of the above-mentioned methods.

[0053] This application also provides the application of methyl 3,4-diaminobenzoate and / or 3,4-diaminobenzoic acid prepared by the methods described in any of the preceding claims, and the methyl 3,4-diaminobenzoate and / or 3,4-diaminobenzoic acid described in any of the preceding claims, in the field of organic synthesis. The field of organic synthesis refers to the field of transforming simple organic compounds (raw materials) into structurally complex organic molecules (such as drug molecules, material monomers, natural products, etc.) with specific functions through the design of reasonable chemical reaction pathways. Specifically, this application also provides the application of the methods described in any of the preceding claims, and the methyl 3,4-diaminobenzoate and / or 3,4-diaminobenzoic acid prepared by any of the preceding claims, in the pharmaceutical field, especially in the field related to dangalidomide.

[0054] In addition, this application also provides the application of the method described in this application in the preparation of dangalidomide.

[0055] Example The following description, in conjunction with specific embodiments, illustrates the content of this application, but the scope of this application is not limited thereto. Unless otherwise specified, the reagents and instruments used in the following embodiments are all conventional reagents and instruments in the art and can be obtained commercially. The methods used are all conventional experimental methods, and those skilled in the art can undoubtedly implement the described schemes and obtain corresponding results based on the embodiments.

[0056] The products obtained in the examples were characterized by liquid chromatography using an Agilent Technologies 1260 Infinity II liquid chromatograph.

[0057] Those skilled in the art can convert various units of various substances according to the actual situation to obtain various substances that conform to the unit parameters in the embodiments.

[0058] Example 1 1) Add 1.0 mol of 3,4-dichlorobenzoic acid, 5.0 mol of ammonia, 0.02 mol of cuprous chloride and 0.02 mol of 4,7-dimethoxy-1,10-phenanthroline to a high-pressure reactor, control the temperature to 140℃, react for 10 hours, then heat to remove most of the ammonia, add hydrochloric acid solution to adjust the pH of the system to 5, cool the system to 10℃, filter, dry, and obtain 3,4-diaminobenzoic acid and weigh it.

[0059] 2) Add the 3,4-diaminobenzoic acid prepared in 1) and 0.2 mol of sulfuric acid to methanol (7 times the mass of 3,4-diaminobenzoic acid, which has been weighed in step 1). Reflux the reaction for 7 hours, then concentrate the system to a viscous state. Add deionized water (6 times the mass of 3,4-diaminobenzoic acid, which has been weighed in step 1). Adjust the pH of the system to 8 with sodium carbonate solution, gradually cool to 10°C, filter the experimental system, and dry it to obtain methyl 3,4-diaminobenzoate.

[0060] Collect and weigh methyl 3,4-diaminobenzoate, calculate the yield and purity according to the following formula and method, and record the weighing results, yield and purity of methyl 3,4-diaminobenzoate in Table 1.

[0061] Yield calculation formula: Yield of methyl 3,4-diaminobenzoate = 1.15 × M1 ÷ M0 × 100% in, M0 is the mass (grams) of the product methyl 3,4-diaminobenzoate under ideal conditions. M1 is the mass (grams) of the product methyl 3,4-diaminobenzoate. It should be understood that the 3,4-diaminobenzoic acid obtained in step 1) will be used entirely in the preparation of methyl 3,4-diaminobenzoate in step 2). Therefore, the yield of methyl 3,4-diaminobenzoate can be calculated solely by the mass of the raw materials and the product.

[0062] It should be understood that the molecular weight of the raw material 3,4-dichlorobenzoic acid is 191.01, and the molecular weight of the product methyl 3,4-diaminobenzoate is 166.18. Therefore, when 1 mol of 3,4-dichlorobenzoic acid (191.01 g) is fed, under ideal conditions, the mass of the product methyl 3,4-diaminobenzoate obtained in 100% yield is 166.18 g.

[0063] Purity calculation method: Purity of methyl 3,4-diaminobenzoate = A1 ÷ A0 × 100% in, A0 is the total area of ​​the absorption peaks of all substances (mAU·min); A1 represents the absorption peak area of ​​methyl 3,4-diaminobenzoate (mAU·min). The absorption peak areas can be obtained directly using an Agilent Technologies 1260 Infinity II liquid chromatograph, and purity should be understood as the percentage of absorption peak area.

[0064] Example 2 1) Add 1.0 mol of 3,4-dichlorobenzoic acid, 5.0 mol of ammonia, 0.02 mol of cuprous bromide and 0.02 mol of 4,7-dimethoxy-1,10-phenanthroline to a high-pressure reactor, control the temperature to 140℃, react for 10 hours, then heat to remove most of the ammonia, add hydrochloric acid solution to adjust the pH of the system to 5, cool the system to 10℃, filter, dry, and obtain 3,4-diaminobenzoic acid and weigh it.

[0065] 2) Add the 3,4-diaminobenzoic acid prepared in 1) and 0.2 mol of sulfuric acid to methanol (7 times the mass of 3,4-diaminobenzoic acid, which has been weighed in step 1). Reflux the reaction for 7 hours, then concentrate the system to a viscous state. Add 6 times the mass of 3,4-diaminobenzoic acid (3,4-diaminobenzoic acid, which has been weighed in step 1) of deionized water. Adjust the pH of the system to 8 with sodium carbonate solution. Gradually cool the system to 10°C, filter the experimental system, and dry it to obtain methyl 3,4-diaminobenzoate.

[0066] Methyl 3,4-diaminobenzoate was collected and weighed. The yield and purity were calculated according to the formula and method in Example 1. The weighing results, yield and purity of methyl 3,4-diaminobenzoate were statistically summarized in Table 1.

[0067] Example 3 1) Add 1.0 mol of 3,4-dichlorobenzoic acid, 5.0 mol of ammonia, 0.02 mol of cuprous iodide and 0.02 mol of 4,7-dimethoxy-1,10-phenanthroline to a high-pressure reactor, control the temperature to 140℃, react for 10 hours, then heat to remove most of the ammonia, add hydrochloric acid solution to adjust the pH of the system to 5, cool the system to 10℃, filter, dry, and obtain 3,4-diaminobenzoic acid and weigh it.

[0068] 2) Add the 3,4-diaminobenzoic acid prepared in 1) and 0.2 mol of sulfuric acid to methanol (7 times the mass of 3,4-diaminobenzoic acid, which has been weighed in step 1). Reflux the reaction for 7 hours, then concentrate the system to a viscous state. Add 6 times the mass of 3,4-diaminobenzoic acid (3,4-diaminobenzoic acid, which has been weighed in step 1) of deionized water. Adjust the pH of the system to 8 with sodium carbonate solution. Gradually cool the system to 10°C, filter the experimental system, and dry it to obtain methyl 3,4-diaminobenzoate.

[0069] Methyl 3,4-diaminobenzoate was collected and weighed. The yield and purity were calculated according to the formula and method in Example 1. The weighing results, yield and purity of methyl 3,4-diaminobenzoate were statistically summarized in Table 1.

[0070] Example 4 1) Add 1.0 mol of 3,4-dichlorobenzoic acid, 5.0 mol of ammonia, 0.02 mol of cuprous oxide and 0.02 mol of 4,7-dimethoxy-1,10-phenanthroline to a high-pressure reactor, control the temperature to 140℃, react for 10 hours, then heat to remove most of the ammonia, add hydrochloric acid solution to adjust the pH of the system to 5, cool the system to 10℃, filter, dry, and obtain 3,4-diaminobenzoic acid and weigh it.

[0071] 2) Add the 3,4-diaminobenzoic acid prepared in 1) and 0.2 mol of sulfuric acid to methanol (7 times the mass of 3,4-diaminobenzoic acid, which has been weighed in step 1). Reflux the reaction for 7 hours, then concentrate the system to a viscous state. Add deionized water (6 times the mass of 3,4-diaminobenzoic acid, which has been weighed in step 1). Adjust the pH of the system to 8 with sodium carbonate solution, gradually cool to 10°C, filter the experimental system, and dry it to obtain methyl 3,4-diaminobenzoate.

[0072] Methyl 3,4-diaminobenzoate was collected and weighed. The yield and purity were calculated according to the formula and method in Example 1. The weighing results, yield and purity of methyl 3,4-diaminobenzoate were statistically summarized in Table 1.

[0073] Example 5 1) 1.0 mol of 3,4-dichlorobenzoic acid, 5.0 mol of ammonia, 0.02 mol of cuprous cyanide and 0.02 mol of 4,7-dimethoxy-1,10-phenanthroline were added to a high-pressure reactor, the temperature was controlled at 140℃, and the reaction was carried out for 10 hours. Then, most of the ammonia was removed by thermal concentration, hydrochloric acid solution was added to adjust the pH of the system to 5, the system was cooled to 10℃, filtered, and dried to obtain 3,4-diaminobenzoic acid.

[0074] 2) Add the 3,4-diaminobenzoic acid prepared in 1) and 0.2 mol of sulfuric acid to methanol (7 times the mass of 3,4-diaminobenzoic acid, which has been weighed in step 1). Reflux the reaction for 7 hours, then concentrate the system to a viscous state. Add 6 times the mass of 3,4-diaminobenzoic acid (3,4-diaminobenzoic acid, which has been weighed in step 1) of deionized water. Adjust the pH of the system to 8 with sodium carbonate solution. Gradually cool the system to 10°C, filter the experimental system, and dry it to obtain methyl 3,4-diaminobenzoate.

[0075] Methyl 3,4-diaminobenzoate was collected and weighed. The yield and purity were calculated according to the formula and method in Example 1. The weighing results, yield and purity of methyl 3,4-diaminobenzoate were statistically summarized in Table 1.

[0076] Example 6 1) Add 1.0 mol of 3,4-dichlorobenzoic acid, 5.0 mol of ammonia, 0.02 mol of cuprous chloride and 0.02 mol of 2-methylpyridine to a high-pressure reactor, control the temperature to 140℃, react for 10 hours, then heat to remove most of the ammonia, add hydrochloric acid solution to adjust the pH of the system to 5, cool the system to 10℃, filter, and dry to obtain 3,4-diaminobenzoic acid.

[0077] 2) Add the 3,4-diaminobenzoic acid prepared in 1) and 0.2 mol of sulfuric acid to methanol (7 times the mass of 3,4-diaminobenzoic acid, which has been weighed in step 1). Reflux the reaction for 7 hours, then concentrate the system to a viscous state. Add 6 times the mass of 3,4-diaminobenzoic acid (3,4-diaminobenzoic acid, which has been weighed in step 1) of deionized water. Adjust the pH of the system to 8 with sodium carbonate solution. Gradually cool the system to 10°C, filter the experimental system, and dry it to obtain methyl 3,4-diaminobenzoate.

[0078] Methyl 3,4-diaminobenzoate was collected and weighed. The yield and purity were calculated according to the formula and method in Example 1. The weighing results, yield and purity of methyl 3,4-diaminobenzoate were statistically summarized in Table 1.

[0079] Example 7 1) Add 1.0 mol of 3,4-dichlorobenzoic acid, 5.0 mol of ammonia, 0.02 mol of cuprous chloride and 0.02 mol of 3-methylpyridine to a high-pressure reactor, control the temperature to 140℃, react for 10 hours, then heat to remove most of the ammonia, add hydrochloric acid solution to adjust the pH of the system to 5, cool the system to 10℃, filter, and dry to obtain 3,4-diaminobenzoic acid.

[0080] 2) Add the 3,4-diaminobenzoic acid prepared in 1) and 0.2 mol of sulfuric acid to methanol (7 times the mass of 3,4-diaminobenzoic acid, which has been weighed in step 1). Reflux the reaction for 7 hours, then concentrate the system to a viscous state. Add 6 times the mass of 3,4-diaminobenzoic acid (3,4-diaminobenzoic acid, which has been weighed in step 1) of deionized water. Adjust the pH of the system to 8 with sodium carbonate solution. Gradually cool the system to 10°C, filter the experimental system, and dry it to obtain methyl 3,4-diaminobenzoate.

[0081] Methyl 3,4-diaminobenzoate was collected and weighed. The yield and purity were calculated according to the formula and method in Example 1. The weighing results, yield and purity of methyl 3,4-diaminobenzoate were statistically summarized in Table 1.

[0082] Example 8 1) 1.0 mol of 3,4-dichlorobenzoic acid, 5.0 mol of ammonia, 0.02 mol of cuprous chloride and 0.02 mol of 1,8-diazobisspirocyclic [5.4.0]undecyl-7-ene (DBU) were added to a high-pressure reactor, the temperature was controlled at 140℃, and the reaction was carried out for 10 hours. Then, most of the ammonia was removed by thermal concentration, hydrochloric acid solution was added to adjust the pH of the system to 5, the system was cooled to 10℃, filtered, and dried to obtain 3,4-diaminobenzoic acid.

[0083] 2) Add the 3,4-diaminobenzoic acid prepared in 1) and 0.2 mol of sulfuric acid to methanol (7 times the mass of 3,4-diaminobenzoic acid, which has been weighed in step 1). Reflux the reaction for 7 hours, then concentrate the system to a viscous state. Add 6 times the mass of 3,4-diaminobenzoic acid (3,4-diaminobenzoic acid, which has been weighed in step 1) of deionized water. Adjust the pH of the system to 8 with sodium carbonate solution. Gradually cool the system to 10°C, filter the experimental system, and dry it to obtain methyl 3,4-diaminobenzoate.

[0084] Methyl 3,4-diaminobenzoate was collected and weighed. The yield and purity were calculated according to the formula and method in Example 1. The weighing results, yield and purity of methyl 3,4-diaminobenzoate were statistically summarized in Table 1.

[0085] Example 9 1) Add 1.0 mol of 3,4-dichlorobenzoic acid, 5.0 mol of ammonia, 0.02 mol of cuprous chloride and 0.02 mol of 2,2'-bipyridine to a high-pressure reactor, control the temperature to 140℃, react for 10 hours, then heat to remove most of the ammonia, add hydrochloric acid solution to adjust the pH of the system to 5, cool the system to 10℃, filter, and dry to obtain 3,4-diaminobenzoic acid.

[0086] 2) Add the 3,4-diaminobenzoic acid prepared in 1) and 0.2 mol of sulfuric acid to methanol (7 times the mass of 3,4-diaminobenzoic acid, which has been weighed in step 1). Reflux the reaction for 7 hours, then concentrate the system to a viscous state. Add 6 times the mass of 3,4-diaminobenzoic acid (3,4-diaminobenzoic acid, which has been weighed in step 1) of deionized water. Adjust the pH of the system to 8 with sodium carbonate solution. Gradually cool the system to 10°C, filter the experimental system, and dry it to obtain methyl 3,4-diaminobenzoate.

[0087] Methyl 3,4-diaminobenzoate was collected and weighed. The yield and purity were calculated according to the formula and method in Example 1. The weighing results, yield and purity of methyl 3,4-diaminobenzoate were statistically summarized in Table 1.

[0088] Example 10 1) 1.0 mol of 3,4-dichlorobenzoic acid, 5.0 mol of ammonia, 0.02 mol of cuprous chloride and 0.02 mol of 4,4'-di-tert-butyl-2,2'-bipyridine were added to a high-pressure reactor, the temperature was controlled at 140°C, and the reaction was carried out for 10 hours. Then, most of the ammonia was removed by thermal concentration, hydrochloric acid solution was added to adjust the pH of the system to 5, the system was cooled to 10°C, filtered, and dried to obtain 3,4-diaminobenzoic acid.

[0089] 2) Add the 3,4-diaminobenzoic acid prepared in 1) and 0.2 mol of sulfuric acid to methanol (7 times the mass of 3,4-diaminobenzoic acid, which has been weighed in step 1). Reflux the reaction for 7 hours, then concentrate the system to a viscous state. Add 6 times the mass of 3,4-diaminobenzoic acid (3,4-diaminobenzoic acid, which has been weighed in step 1) of deionized water. Adjust the pH of the system to 8 with sodium carbonate solution. Gradually cool the system to 10°C, filter the experimental system, and dry it to obtain methyl 3,4-diaminobenzoate.

[0090] Methyl 3,4-diaminobenzoate was collected and weighed. The yield and purity were calculated according to the formula and method in Example 1. The weighing results, yield and purity of methyl 3,4-diaminobenzoate were statistically summarized in Table 1.

[0091] Example 11 1) Add 1.0 mol of 3,4-dichlorobenzoic acid, 5.0 mol of ammonia, 0.02 mol of cuprous chloride and 0.02 mol of 1,10-o-phenanthroline to a high-pressure reactor, control the temperature to 140℃, react for 10 hours, then heat to remove most of the ammonia, add hydrochloric acid solution to adjust the pH of the system to 5, cool the system to 10℃, filter, and dry to obtain 3,4-diaminobenzoic acid.

[0092] 2) Add the 3,4-diaminobenzoic acid prepared in 1) and 0.2 mol of sulfuric acid to methanol (7 times the mass of 3,4-diaminobenzoic acid, which has been weighed in step 1). Reflux the reaction for 7 hours, then concentrate the system to a viscous state. Add 6 times the mass of 3,4-diaminobenzoic acid (3,4-diaminobenzoic acid, which has been weighed in step 1) of deionized water. Adjust the pH of the system to 8 with sodium carbonate solution. Gradually cool the system to 10°C, filter the experimental system, and dry it to obtain methyl 3,4-diaminobenzoate.

[0093] Methyl 3,4-diaminobenzoate was collected and weighed. The yield and purity were calculated according to the formula and method in Example 1. The weighing results, yield and purity of methyl 3,4-diaminobenzoate were statistically summarized in Table 1.

[0094] Example 12 1) Add 1.0 mol of 3,4-dichlorobenzoic acid, 5.0 mol of ammonia, 0.02 mol of cuprous chloride and 0.02 mol of 3,4,7,8-tetramethyl-1,10-phenanthroline to a high-pressure reactor, control the temperature to 140℃, react for 10 hours, then heat to remove most of the ammonia, add hydrochloric acid solution to adjust the pH of the system to 5, cool the system to 10℃, filter, and dry to obtain 3,4-diaminobenzoic acid.

[0095] 2) Add the 3,4-diaminobenzoic acid prepared in 1) and 0.2 mol of sulfuric acid to methanol (7 times the mass of 3,4-diaminobenzoic acid, which has been weighed in step 1). Reflux the reaction for 7 hours, then concentrate the system to a viscous state. Add 6 times the mass of 3,4-diaminobenzoic acid (3,4-diaminobenzoic acid, which has been weighed in step 1) of deionized water. Adjust the pH of the system to 8 with sodium carbonate solution. Gradually cool the system to 10°C, filter the experimental system, and dry it to obtain methyl 3,4-diaminobenzoate.

[0096] Methyl 3,4-diaminobenzoate was collected and weighed. The yield and purity were calculated according to the formula and method in Example 1. The weighing results, yield and purity of methyl 3,4-diaminobenzoate were statistically summarized in Table 1.

[0097] Comparative Example 1 Example 1 of patent CN116332779 discloses the condensation reaction of methyl 4-chloro-3-nitrobenzoate and dibenzylamine in dimethyl sulfoxide to obtain methyl 3-nitro-4-dibenzylaminobenzoate; methyl 3-nitro-4-dibenzylaminobenzoate is then subjected to nitro reduction and debenzylation in a one-pot cooking under Pt / C catalysis and hydrogenation conditions to obtain methyl 3,4-diaminobenzoate. The yield and purity results are summarized in Table 1.

[0098] Comparative Example 2 The literature “Venter, Jana; Perez, Concepción; van Otterlo, Willem AL; Martínez, Ana; Blackie; Margaret AL [Bioorganic and Medicinal Chemistry Letters, 2019, vol. 29, #13, p. 1597-1600]” reports that methyl 4-aminobenzoate was used as a raw material and reacted with acetic anhydride in dichloromethane solvent to obtain methyl 4-acetaminobenzoate. Then, nitration was carried out to obtain methyl 4-acetamino-3-nitrobenzene. The acetyl group was removed by hydrolysis in dilute sulfuric acid to obtain methyl amino-3-nitrobenzene. Finally, methyl 3,4-diaminobenzoate was obtained by palladium-catalyzed hydrogenation. The yield and purity results are summarized in Table 1.

[0099] Comparative Example 3 Example 10 of CN117776942 discloses the reaction of 3,4-dinitrobenzoic acid, methanol, and a strong acid sulfonic acid resin at reflux temperature until the feedstock no longer decreases. The system is then cooled to room temperature, and methanol is evaporated. The remaining material is washed with purified water and dried to obtain methyl 3,4-dinitrobenzoate. Then, methyl 3,4-dinitrobenzoate, methanol, and a Pt / C catalyst are added to a hydrogenation reactor. Hydrogenation is carried out until the methyl 3,4-dinitrobenzoate is essentially eliminated. The Pt / C catalyst is filtered off while hot, and the filtrate is concentrated, washed with purified water, and dried to obtain methyl 3,4-diaminobenzoate. The yield and purity results are summarized in Table 1. The method in Comparative Example 3 uses multiple steps; the yield calculation results in the table are the product of the yields of each step.

[0100] Comparative Example 4 1) Add 1.0 mol of 3,4-dichlorobenzoic acid, 5.0 mol of ammonia water, and 0.04 mol of cuprous chloride to a high-pressure reactor, control the temperature to 140℃, react for 10 hours, then heat to concentrate to remove most of the ammonia water, add hydrochloric acid solution to adjust the pH of the system to 5, cool the system to 10℃, filter, dry, and obtain 3,4-diaminobenzoic acid and weigh it.

[0101] 2) Add the 3,4-diaminobenzoic acid prepared in 1) and 0.2 mol of sulfuric acid to methanol (7 times the mass of 3,4-diaminobenzoic acid, which has been weighed in step 1). Reflux the reaction for 7 hours, then concentrate the system to a viscous state. Add deionized water (6 times the mass of 3,4-diaminobenzoic acid, which has been weighed in step 1). Adjust the pH of the system to 8 with sodium carbonate solution, gradually cool to 10°C, filter the experimental system, and dry it to obtain methyl 3,4-diaminobenzoate.

[0102] Methyl 3,4-diaminobenzoate was collected and weighed. The yield and purity were calculated according to the formula and method in Example 1. The weighing results, yield and purity of methyl 3,4-diaminobenzoate were statistically summarized in Table 1.

[0103] Comparative Example 5 1) Add 1.0 mol of 3,4-dichlorobenzoic acid, 5.0 mol of ammonia water, and 0.04 mol of 4,7-dimethoxy-1,10-phenanthroline to a high-pressure reactor, control the temperature to 140℃, react for 10 hours, then heat to remove most of the ammonia water, add hydrochloric acid solution to adjust the pH of the system to 5, cool the system to 10℃, filter, dry, and obtain 3,4-diaminobenzoic acid and weigh it.

[0104] 2) Add the 3,4-diaminobenzoic acid prepared in 1) and 0.2 mol of sulfuric acid to methanol (7 times the mass of 3,4-diaminobenzoic acid, which has been weighed in step 1). Reflux the reaction for 7 hours, then concentrate the system to a viscous state. Add deionized water (6 times the mass of 3,4-diaminobenzoic acid, which has been weighed in step 1). Adjust the pH of the system to 8 with sodium carbonate solution, gradually cool to 10°C, filter the experimental system, and dry it to obtain methyl 3,4-diaminobenzoate.

[0105] Methyl 3,4-diaminobenzoate was collected and weighed. The yield and purity were calculated according to the formula and method in Example 1. The weighing results, yield and purity of methyl 3,4-diaminobenzoate were statistically summarized in Table 1.

[0106] Table 1

[0107] In both Comparative Examples 1 and 3, raw materials containing nitrobenzene functional groups were used, and Pt / C was used for the hydrogenation step. Due to the instability of the nitrobenzene functional group, the cost of the raw materials is high, and the palladium-carbon catalyst used in the hydrogenation step is also expensive. Furthermore, the reaction process poses potential hazards; in the hydrogenation step, the generated amino groups can easily poison the palladium-carbon catalyst, making it difficult for the raw materials to react completely, affecting the quality and yield of the product. In addition, the hydrogenation process is a hazardous process under key national regulation and is not suitable for industrial production.

[0108] In Comparative Example 2, the route steps are long and the operation is complicated. The nitration reaction is also a dangerous process under key national supervision. In addition, this preparation method will generate a large amount of acidic wastewater. Furthermore, the hydrogenation reaction also uses the precious metal catalyst palladium on carbon, which increases the cost of raw materials, thus limiting industrial production.

[0109] As can be seen from the table, the highest yield of this application, 98.3%, was obtained when using cuprous chloride and 4,7-dimethoxy-1,10-phenanthroline as catalysts. When using other metal catalysts and ligand catalysts, the yields were all above 95%, and the purity was all above 99%, achieving technical effects comparable to existing technologies. In some examples (e.g., Examples 1, 2, and 6), the yields and purity were even superior to existing technologies.

[0110] The synthetic route will also react with only cuprous chloride catalyst, but the yield and purity of methyl 3,4-diaminobenzoate will be greatly reduced in this case. When only 4,7-dimethoxy-1,10-phenanthroline is used as catalyst, the final product cannot be obtained.

[0111] The synthetic route for methyl 3,4-diaminobenzoate presented in this application uses readily available and safe raw materials, has a simple process, does not require expensive heavy metal catalysts, and the product can be synthesized in a one-pot reaction. The synthetic route does not contain dangerous reactions (i.e., no hydrogenation or nitration reactions), has a relatively low overall cost, and is easy to scale up for production.

[0112] 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 described. 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.

[0113] The embodiments described above are merely illustrative of several implementation methods of this application, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of this application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this patent application should be determined by the appended claims.

Claims

1. A method for preparing methyl 3,4-diaminobenzoate, comprising: 3,4-Diaminobenzoic acid was prepared from 3,4-dichlorobenzoic acid using metal catalysts and ligand catalysts; as well as Methyl 3,4-diaminobenzoate was prepared using 3,4-diaminobenzoic acid.

2. The method according to claim 1, wherein, The method comprises adding 3,4-diaminobenzoic acid and sulfuric acid to methanol and refluxing to prepare methyl 3,4-diaminobenzoate.

3. The method according to claim 2, characterized in that, After the reflux reaction, the system was concentrated, deionized water was added, and alkali was added to adjust the system to a given pH. Then, by cooling, filtration, and drying, methyl 3,4-diaminobenzoate was obtained.

4. The method according to claim 2, characterized in that, The molar ratio of 3,4-diaminobenzoic acid to sulfuric acid is 1:(0.1-0.3).

5. The method according to claim 2, characterized in that, The mass ratio of 3,4-diaminobenzoic acid to methanol is 1:(6-10).

6. The method according to claim 2, characterized in that, The reflux reaction time is 5-10 h; the given pH is 6-8.

7. The method according to claim 3, characterized in that, The mass ratio of the 3,4-diaminobenzoic acid to the deionized water is 1:(4-7).

8. The method according to claim 3, characterized in that, The alkali is selected from one or more of sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium hydroxide, and sodium hydroxide, preferably sodium carbonate.

9. The method according to claim 1, characterized in that, The preparation of 3,4-diaminobenzoic acid from 3,4-dichlorobenzoic acid further includes mixing 3,4-dichlorobenzoic acid, ammonia, a metal catalyst and a ligand catalyst, reacting at a given temperature for a given time, then concentrating to remove most of the ammonia, adding acid to adjust the system to a given pH, and then obtaining 3,4-diaminobenzoic acid by cooling and purification.

10. The method according to claim 9, characterized in that, The molar ratio of 3,4-dichlorobenzoic acid to ammonia is 1:(4-6).

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