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

Abstract

This invention relates to the field of organic synthesis technology, and in particular to a method for preparing 3-nitro-2-methylbenzoic acid. The method involves mixing o-methylbenzoic acid with an organic solvent and a sulfonating agent, followed by sulfonation to obtain 3-carboxy-4-methylbenzenesulfonic acid; then mixing 3-carboxy-4-methylbenzenesulfonic acid with an organic solvent and a nitrating agent, followed by nitration to obtain a suspension containing 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid; finally, mixing the suspension containing 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid with an acid reagent, followed by hydrolysis to obtain 3-nitro-2-methylbenzoic acid. The synthetic route of this invention for synthesizing 2-methyl-3-nitrobenzoic acid uses a novel intermediate, offering advantages such as inexpensive raw materials, a short synthetic route, mild reaction conditions, and high yield (over 80%).

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for preparing 3-nitro-2-methylbenzoic acid. Background Technology

[0002] 3-Nitro-2-methylbenzoic acid is a key raw material for the preparation of methoxyfenozide intermediate 2-methyl-3-methoxybenzoic acid. Currently, there are several main routes for the preparation of 3-nitro-2-methylbenzoic acid.

[0003] Route 1: CN109824517, 2019, A Synthesis Route:

[0004]

[0005] The preparation method uses o-nitroxylene as raw material and oxidizes it with dilute nitric acid under the catalysis of transition metal salt. During the reaction, the raw material is not completely reacted and a large amount of brown nitrogen oxide gas is generated. The yield is low and there are environmental and safety hazards.

[0006] Route 2: Synthetic route of chemische Berichte 1884 vol 17, P161:

[0007]

[0008] The preparation method uses o-methylbenzoic acid as raw material and directly nitrates it with nitric acid. However, during the nitration reaction, there are two groups of products, ortho and para, resulting in low reaction selectivity, difficulty in separation, and low yield.

[0009] Route 3: CN111718264.2020.A Synthesis Route:

[0010]

[0011] This preparation method uses 2-methyl-3-nitrobenzoate as raw material, and the product is obtained through ester hydrolysis. In industry, acid products are generally used as raw materials to prepare esters. Summary of the Invention

[0012] To address the aforementioned problems, this invention provides a method for preparing 3-nitro-2-methylbenzoic acid. The synthetic route of this invention uses a novel intermediate for the synthesis of 2-methyl-3-nitrobenzoic acid, which features inexpensive raw materials, a short synthetic route, mild reaction conditions, and high yield.

[0013] To achieve the above objectives, the present invention provides the following technical solution:

[0014] This invention provides a method for preparing 3-nitro-2-methylbenzoic acid, comprising the following steps:

[0015] 1) o-Toluic acid is mixed with an organic solvent and a sulfonating agent and then subjected to a sulfonation reaction to obtain 3-carboxy-4-methylbenzenesulfonic acid;

[0016] 2) The 3-carboxy-4-methylbenzenesulfonic acid obtained in step 1) is mixed with an organic solvent and a nitrating agent and then subjected to a nitration reaction to obtain a suspension containing 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid;

[0017] 3) The suspension containing 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid obtained in step 2) is mixed with an acid reagent and then subjected to a hydrolysis reaction to obtain 3-nitro-2-methylbenzoic acid.

[0018] Preferably, the conditions for the sulfonation reaction in step 1) include: a temperature of 0-5°C and a time of 5 hours.

[0019] Preferably, the mass ratio of o-methylbenzoic acid to organic solvent is 1:10;

[0020] The molar ratio of o-methylbenzoic acid to the sulfonating agent is 1:1.1 to 1.7.

[0021] Preferably, the sulfonating agent includes one or more of concentrated sulfuric acid, sulfur trioxide, chlorosulfonic acid, and fuming sulfuric acid.

[0022] Preferably, the sulfonation reaction further includes: obtaining an organic layer, mixing the organic layer with water, recovering the organic solvent, filtering and drying to obtain 3-carboxy-4-methylbenzenesulfonic acid.

[0023] Preferably, the conditions for the nitration reaction in step 2) include: a temperature of 40-60°C and a time of 10 hours.

[0024] Preferably, in step 2), the mass ratio of 3-carboxy-4-methylbenzenesulfonic acid to the organic solvent is 1:5;

[0025] The molar ratio of 3-carboxy-4-methylbenzenesulfonic acid to the nitrating agent is 1:1.2.

[0026] Preferably, the organic reagents in steps 1) and 2) include one or more of dichloromethane, dichloroethane, trichloromethane, carbon tetrachloride, methylcyclohexane, and tetrahydrofuran.

[0027] Preferably, the conditions for the hydrolysis reaction in step 3) include: a temperature of 80-85°C and a time of 8-20 hours.

[0028] Preferably, in step 3), the acid reagent is three times the molar amount of 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid, in terms of the molar amount of hydrogen ions.

[0029] The acid reagent includes one or more of concentrated sulfuric acid, sulfuric acid solution, and hydrochloric acid solution;

[0030] The sulfuric acid solution has a mass percentage of 50%.

[0031] The hydrochloric acid solution has a mass percentage of 15-30%.

[0032] The beneficial effects of this invention are as follows:

[0033] The synthetic route for 2-methyl-3-nitrobenzoic acid in this invention uses a novel intermediate, which has the advantages of inexpensive raw materials, a short synthetic route, mild reaction conditions, and high yield (over 80%). Detailed Implementation

[0034] This invention provides a method for preparing 3-nitro-2-methylbenzoic acid, comprising the following steps:

[0035] 1) o-Toluic acid is mixed with an organic solvent and a sulfonating agent and then subjected to a sulfonation reaction to obtain 3-carboxy-4-methylbenzenesulfonic acid;

[0036] 2) The 3-carboxy-4-methylbenzenesulfonic acid obtained in step 1) is mixed with an organic solvent and a nitrating agent and then subjected to a nitration reaction to obtain a suspension containing 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid;

[0037] 3) The 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid suspension obtained in step 2) is mixed with an acid reagent and then subjected to a hydrolysis reaction to obtain 3-nitro-2-methylbenzoic acid.

[0038] This invention involves mixing o-methylbenzoic acid with an organic solvent and a sulfonating agent, followed by a sulfonation reaction to obtain 3-carboxy-4-methylbenzenesulfonic acid. Preferably, the o-methylbenzoic acid is mixed with the organic solvent and the sulfonating agent under nitrogen protection. More preferably, the o-methylbenzoic acid is mixed with the organic solvent, stirred at 0°C for 30 min, and then mixed with the sulfonating agent.

[0039] In this invention, the sulfonation reaction conditions preferably include: a temperature of 0–5°C and a time of 5 hours. In this invention, the sulfonation reaction is preferably carried out under stirring; however, there are no particular limitations on the stirring method, and conventional methods can be used by those skilled in the art. In this invention, the mass ratio of o-methylbenzoic acid to the organic solvent is 1:10; the molar ratio of o-methylbenzoic acid to the sulfonating reagent is 1:1.1–1.7. In this invention, the sulfonating reagent preferably includes one or more of concentrated sulfuric acid, sulfur trioxide, chlorosulfonic acid, and fuming sulfuric acid. In this invention, the sulfonation reaction preferably further includes: obtaining an organic layer, mixing the organic layer with water, recovering the organic solvent, filtering, and drying to obtain 3-carboxy-4-methylbenzenesulfonic acid. In this invention, the organic reagent preferably includes one or more of dichloromethane, dichloroethane, trichloromethane, carbon tetrachloride, methylcyclohexane, and tetrahydrofuran.

[0040] In this invention, 3-carboxy-4-methylbenzenesulfonic acid is mixed with an organic solvent and a nitrating agent and then subjected to a nitrification reaction to obtain a suspension containing 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid.

[0041] In this invention, the preferred conditions for the nitration reaction include a temperature of 40–60°C and a time of 10 h. In this invention, the mass ratio of 3-carboxy-4-methylbenzenesulfonic acid to the organic solvent is 1:5; the molar ratio of 3-carboxy-4-methylbenzenesulfonic acid to the nitrating agent is 1:1.2. In this invention, the organic reagent preferably includes one or more of dichloromethane, dichloroethane, trichloromethane, carbon tetrachloride, methylcyclohexane, and tetrahydrofuran. In this invention, the 3-carboxy-4-methylbenzenesulfonic acid is preferably mixed with the organic solvent and the nitrating agent at 20–25°C, and the mixture is kept at this temperature for 30 min before the nitration reaction. In this invention, the nitration reaction preferably further includes: obtaining an organic layer, mixing the organic layer with water, recovering the organic reagent, and obtaining a suspension containing 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid.

[0042] This invention involves hydrolyzing a suspension containing 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid with an acid reagent to obtain 3-nitro-2-methylbenzoic acid. Preferably, the hydrolysis reaction conditions include a temperature of 80–85°C and a time of 8–20 hours. The acid reagent is three times the molar amount of 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid (based on the molar amount of hydrogen ions). The acid reagent preferably includes one or more of concentrated sulfuric acid, sulfuric acid solution, and hydrochloric acid solution. The sulfuric acid solution preferably has a mass percentage of 50%. The hydrochloric acid solution preferably has a mass percentage of 15–30%.

[0043] To further illustrate the present invention, the following detailed description is provided in conjunction with embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0044] Example 1

[0045] Under nitrogen protection, 27.2 g of o-methylbenzoic acid was added to 272 g of dichloromethane. The mixture was cooled to 0°C and stirred for 30 minutes. 24 g of concentrated sulfuric acid was then added dropwise to the suspension. After the addition was complete, the mixture was stirred for another 5 hours, maintaining the temperature at 0-5°C. The organic layer was collected as a control. After the reaction was complete, water was added dropwise to quench the reaction. The aqueous layer was separated, and 100 g of water was added to the organic layer. Dichloromethane was recovered under normal pressure to obtain a suspension of 3-carboxy-4-methylbenzenesulfonic acid and water. The suspension was filtered, dried, and 41.04 g of 3-carboxy-4-methylbenzenesulfonic acid was obtained. Chromatographic analysis showed a purity of 95% (same peak time as the standard), with a yield of 91.16%.

[0046] Example 2

[0047] Under nitrogen protection, 27.2 g of o-methylbenzoic acid was added to 272 g of dichloroethane. The mixture was cooled to 0°C and stirred for 30 minutes. 24 g of concentrated sulfuric acid was then added dropwise to the suspension. After the addition was complete, the mixture was stirred for another 5 hours, maintaining the temperature at 0-5°C. The organic layer was collected as a control. After the reaction was complete, water was added dropwise to quench the reaction. The aqueous layer was separated, and 100 g of water was added to the organic layer. Dichloroethane was recovered under normal pressure to obtain a suspension of 3-carboxy-4-methylbenzenesulfonic acid and water. The suspension was filtered, dried, and 42.1 g of 3-carboxy-4-methylbenzenesulfonic acid was obtained. Chromatographic analysis showed a purity of 94% (same peak time as the standard), with a yield of 92.53%.

[0048] Example 3

[0049] Under nitrogen protection, 27.2 g of o-methylbenzoic acid was added to 272 g of chloroform. The mixture was cooled to 0°C, and 24 g of concentrated sulfuric acid was added dropwise to the suspension. After the addition was complete, the mixture was stirred for 5 hours while maintaining the temperature at 0-5°C. The organic layer was collected as a control. After the reaction was complete, water was added dropwise to quench the reaction. The aqueous layer was separated, and 100 g of water was added to the organic layer. Chloroform was recovered under normal pressure to obtain a suspension of 3-carboxy-4-methylbenzenesulfonic acid and water. The suspension was filtered, dried, and 41 g of 3-carboxy-4-methylbenzenesulfonic acid was obtained. Chromatographic analysis showed a purity of 94% (same peak time as the standard), with a yield of 90.11%.

[0050] Example 4

[0051] Under nitrogen protection, 27.2 g of o-methylbenzoic acid was added to 272 g of dichloroethane. The mixture was cooled to 0°C and stirred for 30 minutes. 28 g of chlorosulfonic acid was then added dropwise to the suspension. After the addition was complete, the mixture was stirred for another 5 hours, maintaining the temperature at 0-5°C. The organic layer was collected as a control. After the reaction was complete, water was added dropwise to quench the reaction. The aqueous layer was separated, and 100 g of water was added to the organic layer. Dichloroethane was recovered under normal pressure to obtain a suspension of 3-carboxy-4-methylbenzenesulfonic acid and water. The suspension was filtered, dried, and 41.5 g of 3-carboxy-4-methylbenzenesulfonic acid was obtained. Chromatographic analysis showed a purity of 97% (same peak time as the standard), with a yield of 94.12%.

[0052] Example 5

[0053] Under nitrogen protection, 27.2 g of o-methylbenzoic acid was added to 272 g of carbon tetrachloride. The mixture was cooled to 0°C and stirred for 30 minutes. 28 g of chlorosulfonic acid was then added dropwise to the suspension. After the addition was complete, the mixture was stirred for another 5 hours, maintaining the temperature at 0-5°C. The organic layer was collected as a control. After the reaction was complete, water was added dropwise to quench the reaction. The aqueous layer was separated, and 100 g of water was added to the organic layer. Carbon tetrachloride was recovered under normal pressure to obtain a suspension of 3-carboxy-4-methylbenzenesulfonic acid and water. The suspension was filtered, dried, and 42 g of 3-carboxy-4-methylbenzenesulfonic acid was obtained. Chromatographic analysis showed a purity of 94% (same peak time as the standard), with a yield of 92.31%.

[0054] Example 6

[0055] 42g of 3-carboxy-4-methylbenzenesulfonic acid was added to 210g of dichloroethane, the temperature was lowered to 23℃, and 14.25g of fuming nitric acid was added dropwise. After the addition was complete, the temperature was maintained for 30 minutes, and then the temperature was raised to 58℃ and the reaction was maintained for 10 hours. A sample was taken and the organic layer was taken as control. After the reaction was complete, 100g of water was added, and dichloroethane was recovered under normal pressure to obtain a suspension containing 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid.

[0056] Example 7

[0057] 42g of 3-carboxy-4-methylbenzenesulfonic acid was added to 210g of dichloromethane, the temperature was lowered to 23℃, and 14.25g of fuming nitric acid was added dropwise. After the addition was complete, the temperature was maintained for 30 minutes, and then the temperature was raised to 40℃ and the reaction was maintained for 10 hours. A sample was taken and the organic layer was taken as control. After the reaction was complete, 100g of water was added, and the dichloromethane was recovered under normal pressure to obtain a suspension containing 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid.

[0058] Example 8

[0059] 42g of 3-carboxy-4-methylbenzenesulfonic acid was added to 210g of chloroform, the temperature was lowered to 23℃, and 14.25g of fuming nitric acid was added dropwise. After the addition was complete, the temperature was maintained for 30 minutes, and then the temperature was raised to 58℃ and the reaction was maintained for 10 hours. A sample was taken and the organic layer was taken as control. After the reaction was complete, 100g of water was added, and the chloroform was recovered under normal pressure to obtain a suspension containing 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid.

[0060] Example 9

[0061] 42g of 3-carboxy-4-methylbenzenesulfonic acid was added to 210g of tetrahydrofuran. The mixture was cooled to 23℃, and 14.25g of fuming nitric acid was added dropwise. After the addition was complete, the mixture was kept at this temperature for 30 minutes, and then the temperature was raised to 58℃ and the reaction was maintained for 10 hours. A sample was taken from the organic layer. After the reaction was complete, 100g of water was added, and tetrahydrofuran was recovered under normal pressure to obtain a suspension containing 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid.

[0062] Example 10

[0063] A certain amount of concentrated sulfuric acid (with a hydrogen ion molar amount three times that of 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid) was added to the suspension containing 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid obtained in Example 6. The mixture was then heated to 80-85°C and kept at that temperature for 8 hours. Samples were taken for monitoring. After the reaction was complete, the mixture was cooled to 0-5°C, filtered, washed with water, and dried to obtain 2-methyl-3-nitrobenzene acid: 28.2 g; chromatographic content 98% (same peak time as the standard); two-step yield: 83.54%.

[0064] Example 11

[0065] A certain amount of 50% sulfuric acid solution (with a hydrogen ion molar amount three times that of 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid) was added to the suspension containing 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid obtained in Example 7. The mixture was then heated to 80-85°C and kept at that temperature for 10 hours. Samples were taken for monitoring. After the reaction was complete, the mixture was cooled to 0-5°C, filtered, washed with water, and dried to obtain 2-methyl-3-nitrobenzene acid: 29.1 g; chromatographic content 98.5% (same peak time as the standard); two-step yield: 86.65%.

[0066] Example 12

[0067] A certain amount of 30% hydrochloric acid solution (with a hydrogen ion molar amount three times that of 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid) was added to the suspension containing 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid obtained in Example 8. The mixture was then heated to 80-85°C and kept at that temperature for 10 hours. Samples were taken for monitoring. After the reaction was complete, the mixture was cooled to 0-5°C, filtered, washed with water, and dried to obtain 2-methyl-3-nitrobenzene acid: 28.5 g; chromatographic content 99% (same peak time as the standard); two-step yield: 85.29%.

[0068] Example 13

[0069] A certain amount of 15% hydrochloric acid solution (with a hydrogen ion molar amount three times that of 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid) was added to the suspension containing 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid obtained in Example 9. The mixture was then heated to 80-85°C and kept at that temperature for 20 hours. Samples were taken for monitoring. After the reaction was complete, the mixture was cooled to 0-5°C, filtered, washed with water, and dried to obtain 2-methyl-3-nitrobenzene acid: 29.3 g; chromatographic content 98% (same peak time as the standard); two-step yield: 86.8%.

[0070] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A method for preparing 3-nitro-2-methylbenzoic acid, characterized in that, Includes the following steps: 1) o-Toluic acid is mixed with an organic solvent and a sulfonating agent and then subjected to a sulfonation reaction to obtain 3-carboxy-4-methylbenzenesulfonic acid; 2) The 3-carboxy-4-methylbenzenesulfonic acid obtained in step 1) is mixed with an organic solvent and a nitrating agent and then subjected to a nitration reaction to obtain a suspension containing 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid; 3) The suspension containing 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid obtained in step 2) is mixed with an acid reagent and then subjected to a hydrolysis reaction to obtain 3-nitro-2-methylbenzoic acid; The conditions for the sulfonation reaction in step 1) include: a temperature of 0–5°C and a time of 5 hours; The mass ratio of o-methylbenzoic acid to organic solvent is 1:10; The molar ratio of o-methylbenzoic acid to the sulfonating agent is 1:1.1 to 1.7; The sulfonating agent is selected from one or more of concentrated sulfuric acid, sulfur trioxide, chlorosulfonic acid, and fuming sulfuric acid; The sulfonation reaction further includes: obtaining an organic layer, mixing the organic layer with water, recovering the organic solvent, filtering and drying to obtain 3-carboxy-4-methylbenzenesulfonic acid; The conditions for the nitration reaction in step 2) include: a temperature of 40–60°C and a time of 10 h; the nitrifying agent is fuming nitric acid. In step 2), the mass ratio of 3-carboxy-4-methylbenzenesulfonic acid to the organic solvent is 1:5; The molar ratio of 3-carboxy-4-methylbenzenesulfonic acid to the nitrating agent is 1:1.2; The conditions for the hydrolysis reaction in step 3) include: a temperature of 80-85°C and a time of 8-20 hours; In step 3), the acid reagent is three times the molar amount of 3-carboxy-4-methyl-5-nitrobenzenesulfonic acid, measured by the molar amount of hydrogen ions. The acid reagent is selected from one or more of concentrated sulfuric acid, sulfuric acid solution and hydrochloric acid solution; The sulfuric acid solution has a mass percentage of 50%. The hydrochloric acid solution has a mass percentage of 15-30%.

2. The preparation method according to claim 1, characterized in that, The organic solvents used in steps 1) and 2) are selected from one or more of dichloromethane, dichloroethane, trichloromethane, carbon tetrachloride, methylcyclohexane, and tetrahydrofuran.

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