A process for the preparation of 2-amino-3-methylbenzoic acid

Abstract

The application discloses a preparation method of 2-amino-3-methylbenzoic acid, and particularly relates to the technical field of organic compound synthesis, and comprises the following steps: (1) a carboxylation step: adding o-cresol and a Lewis base into a closed pressure-resistant reactor, introducing CO2, heating, pressurizing and stirring to react, and after the reaction is completed, the crude product is subjected to acidification, solid-liquid separation and recrystallization purification to obtain 2-hydroxy-3-methylbenzoic acid; (2) an amination step: adding the obtained 2-hydroxy-3-methylbenzoic acid into a closed pressure-resistant reactor, heating, pressurizing and reacting under the ammonia condition provided by ammonia water and in the presence of a Lewis acid, so that the phenolic hydroxyl group in the 2-hydroxy-3-methylbenzoic acid is converted into an amino group, the amination reaction is completed, and 2-amino-3-methylbenzoic acid is obtained; the method has the advantages of simple process route, safe operation, industrial feasibility and high product purity, and meanwhile, the use of nitro or halogenated intermediates and noble metal catalysts is avoided, so that the raw material cost and environmental burden are reduced.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, specifically relating to a method for preparing 2-amino-3-methylbenzoic acid. Background Technology

[0002] 2-Amino-3-methylbenzoic acid is an important organic intermediate that can be widely used in pharmaceuticals, pesticides and fine chemicals. The choice of its preparation method has a significant impact on product quality, production cost and industrialization feasibility.

[0003] In existing technologies, the main methods for synthesizing 2-amino-3-methylbenzoic acid include nitration-reduction, halogenation-ammonolysis, and transition metal catalytic coupling. The nitration-reduction method typically involves multiple reaction steps and strong acid nitration and reduction, resulting in harsh reaction conditions, numerous byproducts, and significant environmental burden. The halogenation-ammonolysis method often relies on halogenated raw materials and metal catalysts, leading to high raw material costs and potential metal residues or solid waste, which are detrimental to green production and industrial scale-up. While some transition metal catalytic routes exhibit high reactivity, they require strict control over the catalytic system and reaction conditions, and their process stability and scale-up adaptability still need improvement.

[0004] Therefore, developing a method for preparing 2-amino-3-methylbenzoic acid that uses readily available raw materials, has a simple reaction route, allows for controllable conditions, and is suitable for industrial production remains of significant practical importance. Summary of the Invention

[0005] To address the above problems, the present invention provides a method for preparing 2-amino-3-methylbenzoic acid.

[0006] To achieve the above objectives, the technical solution of the present invention is as follows:

[0007] A method for preparing 2-amino-3-methylbenzoic acid includes the following steps:

[0008] (1) Carboxylation step: o-cresol and Lewis base are added to a closed pressure-resistant reactor, CO2 is introduced, heated and pressurized and stirred to react. After the reaction is completed, the crude product is purified by acidification, solid-liquid separation and recrystallization to obtain 2-hydroxy-3-methylbenzoic acid;

[0009] (2) Amination step: The obtained 2-hydroxy-3-methylbenzoic acid is added to a closed pressure-resistant reactor and heated and pressurized under the ammonia conditions provided by ammonia water and in the presence of Lewis acid to convert the phenolic hydroxyl group in 2-hydroxy-3-methylbenzoic acid into amino group, thus completing the amination reaction. After the reaction is completed, the solid-liquid mixture is post-treated to obtain 2-amino-3-methylbenzoic acid.

[0010] As a preferred technical solution of the present invention, the Lewis base in step (1) is one or more of potassium hydroxide and potassium carbonate.

[0011] As a preferred embodiment of the present invention, when the Lewis base is potassium hydroxide, the amount of potassium hydroxide used is 2.5 times the molar amount of o-cresol; when the Lewis base is potassium carbonate, the amount of potassium carbonate used is 1.25 times the molar amount of o-cresol.

[0012] As a preferred technical solution of the present invention, the Lewis acid in step (2) is one or more of zinc chloride and calcium chloride.

[0013] As a preferred embodiment of the present invention, the amount of Lewis acid used is 0.64 times the molar amount of 2-hydroxy-3-methylbenzoic acid.

[0014] As a preferred technical solution of the present invention, the molar ratio of 2-hydroxy-3-methylbenzoic acid to ammonium ions in ammonia water in step (2) is 1:10-11.

[0015] As a preferred technical solution of the present invention, the molar ratio of 2-hydroxy-3-methylbenzoic acid to ammonium ions in ammonia water in step (2) is 1:10.69.

[0016] As a preferred technical solution of the present invention, the reaction temperature in step (1) is 150 °C, the reaction pressure is 3.0 MPa, and the reaction time is 6 h.

[0017] As a preferred technical solution of the present invention, the reaction temperature of step (2) is 150-200 °C, the reaction pressure is 1.5-3.5 MPa, and the reaction time is 24-48h.

[0018] As a preferred embodiment of the present invention, the post-processing step of the solid-liquid mixture in step (2) is as follows:

[0019] S1. Add hydrochloric acid to the solid-liquid mixture to acidify and boil, filter and collect the filtrate, repeat the above operation several times, and after cooling the filtrate of the last time, filter and collect to obtain 2-amino-3-methylbenzoate precipitate.

[0020] S2. Dissolve the 2-amino-3-methylbenzoate precipitate in deionized water, and add NaOH to the solution to adjust the pH to 10-11. Heat the solution to 85 °C, filter while hot to remove a small amount of insoluble matter, and collect the filtrate.

[0021] S3. Add hydrochloric acid to the filtrate obtained in S2 to adjust the pH to 6-7. After stirring for 15 min, adjust the system to near neutral with 10% sodium acetate solution. A large amount of precipitate will precipitate out. Filter while hot and collect the solid. Wash the solid with hot water and dry to obtain 2-amino-3-methylbenzoic acid.

[0022] The beneficial effects of this invention are as follows:

[0023] The preparation method of this invention uses o-cresol as the starting material, first preparing 2-hydroxy-3-methylbenzoic acid through carboxylation, and then obtaining 2-amino-3-methylbenzoic acid through amination and post-treatment. This method has the advantages of simple process route, safe operation, industrial feasibility, and high product purity. It also avoids the use of nitro or halogenated intermediates and precious metal catalysts, thereby reducing raw material costs and environmental burden, making the process safer and more reliable. In the carboxylation step, this method uses a potassium salt (potassium hydroxide or potassium carbonate) as the reaction base, combined with acidification and recrystallization separation and purification steps, which is beneficial for obtaining the target intermediate 2-hydroxy-3-methylbenzoic acid. The amination step does not require a precious metal catalyst, and the reaction conditions are controllable, showing potential for further scale-up production. In the amination step, by controlling the reaction temperature to be no lower than 150 °C and no higher than 200 °C and maintaining sufficient reaction pressure, side reactions can be effectively suppressed, improving amination selectivity and target product purity. By reasonably controlling the temperature, pressure, and catalyst, high-purity products can be obtained, meeting the needs of subsequent applications or further purification. Attached Figure Description

[0024] Figure 1 The NMR spectrum of the product obtained by the carboxylation step in Example 1 of this invention is shown below.

[0025] Figure 2 This is an HPLC chromatogram of the product obtained in the carboxylation step of Example 1 of the present invention;

[0026] Figure 3 The nuclear magnetic resonance H-spectrum of the product obtained in the post-processing step of Example 1 of this invention;

[0027] Figure 4 This is an HPLC chromatogram of the product obtained in the post-processing step of Example 1 of the present invention. Detailed Implementation

[0028] The present invention will be further illustrated below with reference to the accompanying drawings and specific embodiments. It should be understood that the following specific embodiments are for illustrative purposes only and are not intended to limit the scope of the invention.

[0029] In the following examples, the room temperature is 25 ~ 30 ℃.

[0030] Example 1

[0031] I. Carboxylation Step

[0032] 145.0 g (1.34 mol) of o-cresol and 188.0 g (3.35 mol) of dry potassium hydroxide were added to a sealed, pressure-resistant reactor and stirred thoroughly. Dry carbon dioxide gas with a purity of 99.9% was introduced at room temperature to a pressure of 2.0–2.2 MPa, and then the temperature was increased and maintained at 3.0 MPa and 150 °C for 6 h.

[0033] After the reaction was completed, the mixture was cooled to room temperature. About 1000 mL of deionized water was added to the reaction mixture and stirred for 30 min. Then, 300 mL of 37% concentrated hydrochloric acid was slowly added to acidify the system to adjust the pH to 2. The precipitated solid was collected by filtration and washed with deionized water until the filtrate was close to neutral to obtain the crude carboxylated product.

[0034] The crude product was added to a mixed solvent of ethanol / water at a volume ratio of 1:3, and heated to reflux to dissolve completely. The solution was then filtered while hot to remove insoluble matter. The filtrate was slowly cooled to room temperature and then allowed to stand at 0–5 °C for 2 h to precipitate crystals. The crystals were collected by vacuum filtration, washed with a small amount of cold ethanol / water mixed solvent, and dried at 50 °C to constant weight to obtain 150.1 g of a white to light yellow crystalline powder, with a yield of 73.6%. Figure 1 and 2 As shown, the main component of the obtained product was 2-hydroxy-3-methylbenzoic acid, with a purity greater than 90%, as determined by nuclear magnetic resonance spectroscopy and HPLC.

[0035] II. Amination Step

[0036] 135.0 g (0.89 mol) of 2-hydroxy-3-methylbenzoic acid obtained from the above carboxylation step, 77.6 g (0.57 mol) of zinc chloride, and 643 mL (9.52 mol NH3) of approximately 28% ammonia water were slowly added sequentially to a sealed pressure-resistant reactor.

[0037] After shutting off the reactor, the system was gradually heated under continuous stirring until it reached 165°C within 3 hours. This temperature was then maintained at 165°C and a pressure of 2.7–2.8 MPa for 36 hours. After the reaction was complete, the system was stirred continuously and allowed to cool naturally to room temperature. The reactor lid was then opened, and the solid adhering to the walls was scraped off and transferred along with the reaction liquid to a 5 L container. The reactor walls were rinsed twice with 700 mL of water, and the rinsed water was added to the reaction liquid to form a solid-liquid mixture.

[0038] III. Post-processing steps

[0039] Add 550 mL of 37% concentrated hydrochloric acid to the solid-liquid mixture formed above (including the water used to rinse the reactor), boil for 30 min, and filter while hot. The resulting filter cake is boiled again with 500 mL of water and 30 mL of 37% concentrated hydrochloric acid for 30 min, and then filtered again.

[0040] The filtrates from the two filtrations were combined and cooled to obtain 2-amino-3-methylbenzoate precipitate, which was collected by vacuum filtration. The wet solid obtained from the precipitation was placed in a container, 1.3 L of deionized water was added, and 40% NaOH solution was slowly added to adjust the pH to 10-11. The solution was heated to 85 °C, and filtered while hot to remove a small amount of insoluble matter, and the filtrate was collected.

[0041] The filtrate was acidified to pH 6-7 with 37% concentrated hydrochloric acid. After stirring for 15 min, the system was adjusted to near neutral with 10% sodium acetate solution, resulting in the precipitation of a large amount of precipitate. The precipitate was filtered while hot, and the solid was collected using a Buchner funnel and washed with 400 mL of hot water. The wet solid was dried at 50 °C to constant weight to give 88.5 g of a white to pale yellow powder, with a yield of 66.0%. Figure 3 and 4 As shown, the main component of the obtained product was 2-amino-3-methylbenzoic acid, with a purity greater than 90%, as determined by nuclear magnetic resonance spectroscopy and HPLC.

[0042] Example 2

[0043] Repeat the steps of Example 1, except that:

[0044] 1. In the carboxylation step, dry potassium hydroxide was replaced with dry potassium carbonate. The amount of potassium carbonate used was 231.5 g (1.68 mol). The product obtained from the carboxylation step was 143.7 g of 2-hydroxy-3-methylbenzoic acid, with a yield of 70.5%, and the properties of the product were similar to those in Example 1.

[0045] 2. In the amination step, zinc chloride is replaced with anhydrous calcium chloride. The amount of calcium chloride used is 63.3 g (0.57 mol).

[0046] 3. In the amination step, the reaction temperature was 165 °C. The system was heated to 165 °C within 3 h and maintained at 165 °C for 48 h. The product obtained was 84.3 g of 2-amino-3-methylbenzoic acid, with a yield of about 62.9%. The properties of the product were similar to those in Example 1.

[0047] Example 3

[0048] Repeat the steps of Example 1, except that:

[0049] 1. In the amination step, the reaction temperature was 150 °C. The system was heated to 150 °C within 3 h and maintained at 150 °C for 48 h. The reaction pressure was 1.5 MPa. The product obtained was 78.5 g of 2-amino-3-methylbenzoic acid, with a yield of about 58.5%. The properties of the product were similar to those in Example 1.

[0050] Example 4

[0051] Repeat the steps of Example 1, except that:

[0052] 1. In the amination step, the reaction temperature was 200 °C. The system was heated to 200 °C within 3 h and maintained at 200 °C for 48 h. The reaction pressure was 3.5 MPa. The product obtained was 75.4 g of 2-amino-3-methylbenzoic acid, with a yield of about 56.2%. The product was a light yellow powder.

[0053] It should be noted that the above content merely illustrates the technical concept of the present invention and should not be construed as limiting the scope of protection of the present invention. For those skilled in the art, various improvements and modifications can be made without departing from the principle of the present invention, and all such improvements and modifications fall within the scope of protection of the claims of the present invention.

Claims

1. A method for preparing 2-amino-3-methylbenzoic acid, characterized in that, Includes the following steps: (1) Carboxylation step: o-cresol and Lewis base are added to a closed pressure-resistant reactor, CO2 is introduced, heated and pressurized and stirred to react. After the reaction is completed, the crude product is purified by acidification, solid-liquid separation and recrystallization to obtain 2-hydroxy-3-methylbenzoic acid; (2) Amination step: The obtained 2-hydroxy-3-methylbenzoic acid is added to a closed pressure-resistant reactor and heated and pressurized under the ammonia conditions provided by ammonia water and in the presence of Lewis acid to convert the phenolic hydroxyl group in 2-hydroxy-3-methylbenzoic acid into amino group, thus completing the amination reaction. After the reaction is completed, the solid-liquid mixture is post-treated to obtain 2-amino-3-methylbenzoic acid.

2. The method for preparing 2-amino-3-methylbenzoic acid according to claim 1, characterized in that, The Lewis base in step (1) is one or more of potassium hydroxide and potassium carbonate.

3. The method for preparing 2-amino-3-methylbenzoic acid according to claim 2, characterized in that, When the Lewis base is potassium hydroxide, the amount of potassium hydroxide used is 2.5 times the molar amount of o-cresol; when the Lewis base is potassium carbonate, the amount of potassium carbonate used is 1.25 times the molar amount of o-cresol.

4. The method for preparing 2-amino-3-methylbenzoic acid according to claim 1, characterized in that, The Lewis acid in step (2) is one or more of zinc chloride and calcium chloride.

5. The method for preparing 2-amino-3-methylbenzoic acid according to claim 1, characterized in that, The amount of Lewis acid used is 0.64 times the molar amount of 2-hydroxy-3-methylbenzoic acid.

6. The method for preparing 2-amino-3-methylbenzoic acid according to claim 1, characterized in that, In step (2), the molar ratio of 2-hydroxy-3-methylbenzoic acid to ammonium ions in ammonia water is 1:10-11.

7. The method for preparing 2-amino-3-methylbenzoic acid according to claim 6, characterized in that, In step (2), the molar ratio of 2-hydroxy-3-methylbenzoic acid to ammonium ions in ammonia water is 1:10.

69.

8. The method for preparing 2-amino-3-methylbenzoic acid according to claim 1, characterized in that, The reaction temperature in step (1) is 150 °C, the reaction pressure is 3.0 MPa, and the reaction time is 6 h.

9. The method for preparing 2-amino-3-methylbenzoic acid according to claim 1, characterized in that, The reaction temperature in step (2) is 150-200 °C, the reaction pressure is 1.5-3.5 MPa, and the reaction time is 24-48 h.

10. The method for preparing 2-amino-3-methylbenzoic acid according to claim 1, characterized in that, The post-processing steps for the solid-liquid mixture in step (2) are as follows: S1. Add hydrochloric acid to the solid-liquid mixture to acidify and boil, filter and collect the filtrate, repeat the above operation several times, and after cooling the filtrate of the last time, filter and collect to obtain 2-amino-3-methylbenzoate precipitate. S2. Dissolve the 2-amino-3-methylbenzoate precipitate in deionized water, and add NaOH to the solution to adjust the pH to 10-11. Heat the solution to 85 °C, filter while hot to remove a small amount of insoluble matter, and collect the filtrate. S3. Add hydrochloric acid to the filtrate obtained in S2 to adjust the pH to 6-7. After stirring for 15 min, adjust the system to near neutral with 10% sodium acetate solution. A large amount of precipitate will precipitate out. Filter while hot and collect the solid. Wash the solid with hot water and dry to obtain 2-amino-3-methylbenzoic acid.

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