A process for the preparation of 5-amino-2-nitrobenzoic acid

Abstract

The application provides a preparation method of 5-amino-2-nitrobenzoic acid, which comprises the following steps: (1) mixing and reacting p-phenylenediamine with an acylating agent to obtain an intermediate 1; (2) mixing and reacting the intermediate 1 with a Lewis acid and dichloromethyl methyl ether to obtain an intermediate 2; (3) mixing and reacting the intermediate 2 with an oxidizing agent and an acid catalyst to obtain an intermediate 3; (4) mixing and reacting the intermediate 3 with an acylating agent to obtain an intermediate 4; and (5) mixing and reacting the intermediate 4 with a base and an oxidizing agent to obtain the 5-amino-2-nitrobenzoic acid. The preparation method provided by the application overcomes the problems of the traditional preparation method, such as the need to use a large amount of sulfuric acid, nitric acid and strong oxidant potassium permanganate, and has the advantages of easy availability of raw materials, low cost, mild reaction condition and high yield.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for preparing 5-amino-2-nitrobenzoic acid, and more particularly to a low-cost method for preparing 5-amino-2-nitrobenzoic acid. Background Technology

[0002] γ-Glutamine-3-carboxy-4-nitroaniline monoammonium salt (Glupa-C) is an important substrate for the determination of transpeptidase and has significant clinical applications. 5-Amino-2-nitrobenzoic acid is an important intermediate in the preparation of Glupa-C, and currently, the synthesis of 5-amino-2-nitrobenzoic acid is mostly carried out using isophenyl compounds as starting materials.

[0003] In 1992, China Pharmaceutical University, in conjunction with Livzon Pharmaceutical Group Co., Ltd., disclosed a synthetic route for 5-amino-2-nitrobenzoic acid in CN1076688A: using m-toluidine as a raw material, the product was prepared through amide condensation, nitration, potassium permanganate oxidation, and amide hydrolysis. This method requires harsh reaction conditions, including sulfuric acid, nitric acid, and the strong oxidant potassium permanganate. The oxidation reaction poses high safety risks, and the potassium permanganate treatment is cumbersome, resulting in high levels of heavy metal residues, making it unsuitable for industrial production.

[0004] CN116283629A discloses a method for preparing 5-amino-2-nitrobenzoic acid, comprising the following steps: 1) using m-aminobenzoic acid as the starting material and glacial acetic acid as the solvent, controlling the reaction temperature below 35°C, adding acetic anhydride dropwise; after the reaction is complete, controlling the reaction temperature below 35°C, adding concentrated sulfuric acid dropwise; after the addition is complete, the solid dissolves, and fuming nitric acid is added dropwise while maintaining the temperature at 20-35°C; after the addition is complete, the reaction continues until the reaction is complete to obtain crude 5-acetamino-2-nitrobenzoic acid; 2) recrystallizing the crude 5-acetamino-2-nitrobenzoic acid in anhydrous ethanol; 3) hydrolyzing to obtain 5-amino-2-nitrobenzoic acid. This invention prepares 5-acetamino-2-nitrobenzoic acid in a one-pot process, avoiding the trouble and risks of post-processing the intermediate m-acetaminobenzoic acid, and then obtaining the product through hydrolysis. However, it still uses a large amount of concentrated sulfuric acid and fuming nitric acid as raw materials, increasing the risk of the production process.

[0005] Currently, there is no effective and safe method for synthesizing 5-amino-2-nitrobenzoic acid. Therefore, providing a safe, efficient, and low-cost method for preparing 5-amino-2-nitrobenzoic acid has become an urgent problem to be solved. Summary of the Invention

[0006] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing 5-amino-2-nitrobenzoic acid, and more particularly, a low-cost method for preparing 5-amino-2-nitrobenzoic acid. The preparation method provided by this invention overcomes the problems of traditional methods requiring large amounts of sulfuric acid, nitric acid, and the strong oxidant potassium permanganate. The raw materials are readily available, the cost is low, the reaction conditions are mild, and the yield is high.

[0007] To achieve this objective, the present invention adopts the following technical solution:

[0008] This invention provides a method for preparing 5-amino-2-nitrobenzoic acid, the method comprising the following steps:

[0009] (1) The reaction of p-phenylenediamine with an acylation reagent yields intermediate 1;

[0010] (2) Intermediate 1 was mixed with Lewis acid and dichloromethyl methyl ether and reacted to obtain intermediate 2;

[0011] (3) Intermediate 2 is mixed with an oxidant and an acid catalyst to react and obtain intermediate 3;

[0012] (4) Intermediate 3 is mixed with an acylation reagent and reacted to obtain intermediate 4;

[0013] (5) Intermediate 4 is mixed with alkali and oxidant to react and obtain the 5-amino-2-nitrobenzoic acid.

[0014] The reaction route is as follows:

[0015]

[0016] R1 and R2 are independently selected from methyl, ethyl, or propyl.

[0017] The above preparation method, by employing specific starting materials and reaction routes, can overcome the problem that traditional preparation methods require the use of large amounts of sulfuric acid, nitric acid, and strong oxidant potassium permanganate. It has the advantages of readily available raw materials, low cost, mild reaction conditions, and high yield.

[0018] Preferably, the acylation reagent in step (1) includes any one or a combination of at least two of acetyl chloride, propionyl chloride, butyryl chloride, acetic anhydride, propionic anhydride or butyryl anhydride, with acetyl chloride being the most preferred.

[0019] The aforementioned specific acylation reagents can effectively improve the efficiency of acylation and increase the reaction yield.

[0020] Preferably, the molar ratio of p-phenylenediamine to acylation reagent in step (1) is 1:(1-10), such as 1:1, 1:2, 1:3, 1:4, 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0021] Preferably, the reaction temperature in step (1) is 0-40℃ and the time is 2-12h. The temperature can be 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, 30℃, 35℃ or 40℃, etc., and the time can be 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h or 12h, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0022] Preferably, the Lewis acid in step (2) includes any one or a combination of at least two of aluminum trichloride, boron trifluoride, tin tetrachloride or ferric bromide, with aluminum trichloride being the most preferred.

[0023] The aforementioned Lewis acids can effectively improve the efficiency of substitution and increase the yield of the reaction.

[0024] Preferably, the molar ratio of intermediate 1 in step (2) to Lewis acid and dichloromethyl methyl ether is 1:(2-10):(2-10), wherein the number of Lewis acid components can be 2, 3, 4, 5, 6, 7, 8, 9 or 10, and the number of dichloromethyl methyl ether components can be 2, 3, 4, 5, 6, 7, 8, 9 or 10, but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0025] Preferably, the reaction temperature in step (2) is 0-25℃ and the time is 0.5-4h. The temperature can be 0℃, 5℃, 10℃, 15℃, 20℃ or 25℃, etc., and the time can be 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h or 4h, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0026] Preferably, the acid catalyst in step (3) includes any one or a combination of at least two of hydrochloric acid, phosphoric acid, sulfuric acid or acetic acid.

[0027] Preferably, the molar ratio of intermediate 2 to oxidant and acid catalyst in step (3) is 1:(1-10):(0.001-0.1), wherein the number of parts of oxidant can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, etc., and the number of parts of acid catalyst can be 0.001, 0.002, 0.003, 0.005, 0.01, 0.02, 0.03, 0.05 or 0.1, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0028] Preferably, the reaction temperature in step (3) is 25-100℃ and the time is 12-36h. The temperature can be 25℃, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃ or 100℃, etc., and the time can be 12h, 14h, 16h, 18h, 20h, 22h, 24h, 26h, 28h, 30h, 32h, 34h or 36h, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0029] Preferably, the acylation reagent in step (4) includes any one or a combination of at least two of acetyl chloride, propionyl chloride, butyryl chloride, acetic anhydride, propionic anhydride, or butyryl anhydride.

[0030] Preferably, the molar ratio of intermediate 3 to acylation reagent in step (4) is (1-3):1, such as 1:1, 1.5:1, 2:1, 2.5:1 or 3:1, but not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0031] Preferably, the reaction temperature in step (4) is 0-40℃ and the time is 1-6h. The temperature can be 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, 30℃, 35℃ or 40℃, etc., and the time can be 1h, 2h, 3h, 4h, 5h or 6h, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0032] Preferably, the alkali in step (5) includes any one or a combination of at least two of sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, diethylamine or pyridine.

[0033] Preferably, the molar ratio of intermediate 4 to alkali and oxidant in step (5) is 1:(0.5-5):(1-10), wherein the amount of alkali can be 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5 or 5, and the amount of oxidant can be 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10, but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0034] Preferably, the reaction temperature in step (5) is 0-40℃ and the time is 0.5-4h. The temperature can be 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, 30℃, 35℃ or 40℃, etc., and the time can be 0.5h, 1h, 0.5h, 2h, 2.5h, 3h, 3.5h or 4h, etc., but is not limited to the values ​​listed above. Other unlisted values ​​within the above range are also applicable.

[0035] Preferably, the oxidant includes any one or a combination of at least two of urea oxychloride, hydrogen peroxide, or dimethyl sulfoxide.

[0036] Compared with the prior art, the present invention has the following beneficial effects:

[0037] This invention provides a method for preparing 5-amino-2-nitrobenzoic acid. By using specific starting materials and reaction routes, it can overcome the problem that traditional preparation methods require the use of large amounts of sulfuric acid, nitric acid, and strong oxidant potassium permanganate. It has the advantages of readily available raw materials, low cost, mild reaction conditions, and high yield. Detailed Implementation

[0038] To further illustrate the technical means and effects of the present invention, the following describes the technical solution of the present invention in conjunction with preferred embodiments of the present invention. However, the present invention is not limited to the scope of the embodiments.

[0039] Example 1

[0040] This embodiment provides a method for preparing 5-amino-2-nitrobenzoic acid, the specific steps of which are as follows:

[0041] (1) 2 mol of pyridine and 1 mol of p-phenylenediamine were added to 50 mL of THF solution, and then 2 mol of acetyl chloride was added dropwise to the above solution. The mixture was stirred at 20 °C for 4 hours. After the reaction was completed, the solvent was removed by rotary evaporation. The residue was dissolved in water and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous MgSO4, filtered, and the solvent was removed to give intermediate 1 in 90% yield.

[0042] (2) Intermediate 1 (3.5 g, 18 mmol), AlCl3 (7.3 g, 45 mmol) and dry CH2Cl2 (30 mL) were added to a reaction flask. Dichloromethyl methyl ether (5.2 g, 45 mmol) was added dropwise to the reaction solution. The mixture was then reacted in an ice-water bath for 0.5 hours. Finally, the mixture was stirred at 20 °C for 0.5 hours to obtain a crude product. Intermediate 2 was obtained by silica gel column chromatography with a yield of 70%.

[0043] (3) Add 25g of intermediate 2 to the reaction flask, add 40mL of 30% hydrogen peroxide and 100μL of concentrated sulfuric acid, and react at 60℃ for 24h to obtain crude product. Intermediate 3 is obtained by silica gel column chromatography with a yield of 85%.

[0044] (4) Add 1 mol of pyridine and 1 mol of intermediate 3 to 50 mL of THF solution, then add 1 mol of acetyl chloride dropwise to the above solution, and stir the reaction at 20 °C for 4 hours. After the reaction is complete, remove the solvent by rotary evaporation. Dissolve the residue in water and then extract with ethyl acetate. Combine the organic phases, dry with anhydrous MgSO4, filter, remove the solvent, and obtain the crude product. Separate intermediate 4 by silica gel column chromatography, with a yield of 70%.

[0045] (5) 1 mmol of intermediate 4 and 1 mmol of potassium carbonate were added to a 50% H2O2 aqueous solution (3 mmol), followed by 3 mL of CH3CN. The mixture was stirred at 20 °C for 10 minutes, the solvent was evaporated, and the mixture was extracted three times with ethyl acetate. The organic phase was then washed with brine and dried with anhydrous Na2SO4. The solvent was removed by evaporation, and the mixture was recrystallized from a hexane / ethyl acetate mixture to give 5-amino-2-nitrobenzoic acid in 70% yield. Characterization data are as follows: H-NMR (DMSO-d6, ppm): 13.2 (broadpeak, 1H, COOH), 7.8 (S, 1H, ArH), 6.8 (S, 2H, NH2), 6.5 (m, 2H, ArH).

[0046] Example 2

[0047] This embodiment provides a method for preparing 5-amino-2-nitrobenzoic acid. Except for step (1) as follows, the other steps are the same as in Example 1.

[0048] (1) 2 mol of pyridine and 1 mol of p-phenylenediamine were added to 50 mL of THF solution, and then 2 mol of acetic anhydride were added dropwise to the above solution. The mixture was stirred at 20 °C for 4 hours. After the reaction was completed, the solvent was removed by rotary evaporation. The residue was dissolved in water and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous MgSO4, filtered, and the solvent was removed to give intermediate 1 in 80% yield.

[0049] Example 3

[0050] This embodiment provides a method for preparing 5-amino-2-nitrobenzoic acid. Except for step (1) as follows, the other steps are the same as in Example 1.

[0051] (1) 2 mol of pyridine and 1 mol of p-phenylenediamine were added to 50 mL of THF solution, and then 2 mol of propionic anhydride were added dropwise to the above solution. The mixture was stirred at 20 °C for 4 hours. After the reaction was completed, the solvent was removed by rotary evaporation. The residue was dissolved in water and then extracted with ethyl acetate. The organic phases were combined, dried over anhydrous MgSO4, filtered, and the solvent was removed to give intermediate 1 in 75% yield.

[0052] Example 4

[0053] This embodiment provides a method for preparing 5-amino-2-nitrobenzoic acid. Except for step (2) as follows, the other steps are the same as in Example 1.

[0054] (2) Intermediate 1 (3.5 g, 18 mmol), SnCl4 (45 mmol) and dry CH2Cl2 (30 mL) were added to a reaction flask. Dichloromethyl methyl ether (5.2 g, 45 mmol) was added dropwise to the reaction solution. The mixture was then reacted in an ice-water bath for 0.5 hours. Finally, the mixture was stirred at 20 °C for 0.5 hours to obtain a crude product. Intermediate 2 was obtained by silica gel column chromatography with a yield of 50%.

[0055] Example 5

[0056] This embodiment provides a method for preparing 5-amino-2-nitrobenzoic acid. Except for step (2) as follows, the other steps are the same as in Example 1.

[0057] (2) Intermediate 1 (3.5 g, 18 mmol), BF3 (45 mmol) and dry CH2Cl2 (30 mL) were added to a pressure vessel. Dichloromethyl methyl ether (5.2 g, 45 mmol) was added dropwise to the reaction solution. The mixture was then reacted in an ice-water bath for 0.5 hours. Finally, the mixture was stirred at 20 °C for 0.5 hours to obtain a crude product. Intermediate 2 was obtained by silica gel column chromatography with a yield of 45%.

[0058] Test case

[0059] The overall yields of the preparation methods in Examples 1-5 were calculated, and the results are as follows:

[0060] Group Example 1 Example 2 Example 3 Example 4 Example 5 Overall yield (%) 26.2 23.3 21.9 18.7 16.9

[0061] The results above show that, compared with the prior art, the preparation method provided by the present invention does not require the use of large amounts of sulfuric acid and strong oxidant potassium permanganate, which reduces the safety risks of preparation, reduces costs, and provides milder reaction conditions. Comparing Examples 1-5, it can be seen that the present invention can effectively promote the reaction and improve the overall yield by selecting specific acylation reagents and Lewis acids.

[0062] The applicant declares that the present invention illustrates the preparation method of 5-amino-2-nitrobenzoic acid through the above embodiments, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

[0063] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0064] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

Claims

1. A method for preparing 5-amino-2-nitrobenzoic acid, characterized in that, The preparation method includes the following steps: (1) The reaction of p-phenylenediamine with an acylation reagent yields intermediate 1; (2) Intermediate 1 was mixed with Lewis acid and dichloromethyl methyl ether and reacted to obtain intermediate 2; (3) Intermediate 2 is mixed with an oxidant and an acid catalyst to react and obtain intermediate 3; (4) Intermediate 3 is mixed with an acylation reagent and reacted to obtain intermediate 4; (5) Intermediate 4 is mixed with a base and an oxidizing agent and reacted to obtain the 5-amino-2-nitrobenzoic acid; The reaction route is as follows: R1 and R2 are independently selected from methyl, ethyl, or propyl.

2. The preparation method according to claim 1, characterized in that, The acylation reagent in step (1) includes any one or a combination of at least two of acetyl chloride, propionyl chloride, butyryl chloride, acetic anhydride, propionic anhydride, or butyryl anhydride.

3. The preparation method according to claim 2, characterized in that, The acylation reagent in step (1) is acetyl chloride.

4. The preparation method according to claim 1, characterized in that, The molar ratio of p-phenylenediamine to the acylation reagent in step (1) is 1:(1-10).

5. The preparation method according to claim 1, characterized in that, The reaction in step (1) is carried out at a temperature of 0-40℃ for 2-12 hours.

6. The preparation method according to claim 1, characterized in that, The Lewis acid in step (2) includes any one or a combination of at least two of aluminum trichloride, boron trifluoride, tin tetrachloride or ferric bromide.

7. The preparation method according to claim 6, characterized in that, The Lewis acid mentioned in step (2) is aluminum trichloride.

8. The preparation method according to claim 1, characterized in that, In step (2), the molar ratio of intermediate 1 to Lewis acid and dichloromethyl methyl ether is 1:(2-10):(2-10).

9. The preparation method according to claim 1, characterized in that, The reaction in step (2) is carried out at a temperature of 0-25℃ for 0.5-4h.

10. The preparation method according to claim 1, characterized in that, The acid catalyst in step (3) includes any one or a combination of at least two of hydrochloric acid, phosphoric acid, sulfuric acid or acetic acid.

11. The preparation method according to claim 1, characterized in that, The molar ratio of intermediate 2 to oxidant and acid catalyst in step (3) is 1:(1-10):(0.001-0.1).

12. The preparation method according to claim 1, characterized in that, The reaction in step (3) is carried out at a temperature of 25-100℃ for 12-36 hours.

13. The preparation method according to claim 1, characterized in that, The acylation reagent in step (4) includes any one or a combination of at least two of acetyl chloride, propionyl chloride, butyryl chloride, acetic anhydride, propionic anhydride, or butyryl anhydride.

14. The preparation method according to claim 1, characterized in that, The molar ratio of intermediate 3 to acylation reagent in step (4) is (1-3):

1.

15. The preparation method according to claim 1, characterized in that, The reaction in step (4) is carried out at a temperature of 0-40℃ for 1-6 hours.

16. The preparation method according to claim 1, characterized in that, The base in step (5) includes any one or a combination of at least two of sodium carbonate, potassium carbonate, sodium bicarbonate, triethylamine, diethylamine or pyridine.

17. The preparation method according to claim 1, characterized in that, In step (5), the molar ratio of intermediate 4 to alkali and oxidant is 1:(0.5-5):(1-10).

18. The preparation method according to claim 1, characterized in that, The reaction in step (5) is carried out at a temperature of 0-40℃ for 0.5-4h.

19. The preparation method according to claim 1, characterized in that, The oxidant includes any one or a combination of at least two of urea oxychloride, hydrogen peroxide, or dimethyl sulfoxide.

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