A continuous preparation process of 3-methyl-2-nitrobenzoic acid

Abstract

The present invention belongs to the field of synthesis of organic chemical intermediates, and specifically provides a continuous preparation process of 3-methyl-2-nitrobenzoic acid. This preparation process mainly includes nitration reaction, product separation, product purification, and waste liquid recovery. The preparation process of 3-methyl-2-nitrobenzoic acid provided by the present invention solves the problems of high cost, low yield, and low purity in the existing continuous preparation process.

Description

Technical Field

[0001] The present invention belongs to the field of synthesis of organic chemical intermediates, and particularly relates to a continuous preparation process of 3-methyl-2-nitrobenzoic acid. Background Art

[0002] 3-Methyl-2-nitrobenzoic acid is an important class of fine chemicals. In recent years, with the increasing development of the fine chemical industry, the application scope of 3-methyl-2-nitrobenzoic acid in pharmaceutical products, bioengineering, reactive dyes, polyester compounds and pesticides has been continuously expanding, and the demand has been increasing year by year. In addition, in accordance with the "Notice on Issuing the Key Points of Hazardous Chemicals Safety Supervision Work in 2023 and 11 Work Plans such as the Safety Rectification and Improvement of Chemical Industrial Parks" (YuYingJiBan

[2023] No. 21) issued by the Henan Provincial Emergency Management Bureau, requirements for continuous production have been put forward for nitrification production enterprises. Therefore, it is of great significance to optimize the production process of 3-methyl-2-nitrobenzoic acid.

[0003] Patent CN115784893A provides a continuous production method of 3-methyl-2-nitrobenzoic acid. After continuous nitration reaction of fuming nitric acid with a mass fraction of 98% and 3-methylbenzoic acid in a reactor, filtration and washing can obtain the target product. Although the production conditions of this method are simple, there is a problem of acid recovery in the later stage, which is not environmentally friendly. The synthesis method of 3-methyl-2-nitrobenzoic acid provided by Patent CN114560772B, although avoiding the generation of a large amount of nitric acid wastewater during the production process, this synthesis can only be achieved under the conditions of inorganic base, catalyst, ozone and light. For industrial production, the equipment requirements and upfront investment are relatively high, and it is not suitable for large-scale promotion.

[0004] Therefore, there is an urgent need in the market for a continuous preparation process of 3-methyl-2-nitrobenzoic acid with low cost, environmental friendliness, high selectivity and high purity. Summary of the Invention

[0005] Aiming at the problems existing in the prior art, the present invention selects a special catalyst to activate the target substitution site, reduces the generation of side reactions, and solves the problems of high cost, low yield and low purity in the existing continuous preparation process of 3-methyl-2-nitrobenzoic acid.

[0006] In order to achieve the above object, the technical solutions adopted by the present invention are as follows:

[0007] On the one hand, the present invention provides a continuous preparation process of 3-methyl-2-nitrobenzoic acid, which comprises the following steps: adding m-toluic acid and a catalyst into concentrated nitric acid respectively, carrying out a nitration reaction at -10 to 0 °C, then filtering the product to obtain a filtrate and a filter cake; separating the catalyst and concentrated nitric acid from the filtrate by rectification and continuing to feed them into the reaction; washing, purifying and drying the filter cake to obtain the 3-methyl-2-nitrobenzoic acid.

[0008] In some embodiments, the nitration reaction time is 120 to 180 s.

[0009] In some embodiments, the molar ratio of m-toluic acid to concentrated nitric acid is 1:(3.0 to 5.0).

[0010] In some embodiments, the mass ratio of m-toluic acid to the catalyst is 1:(0.32 to 0.48).

[0011] In some embodiments, the feeding rate of m-toluic acid and the catalyst is 5.5 to 7.0 g / min.

[0012] In the nitration reaction, nitric acid will be protonated first, and then nitronium cation NO2 + , NO2 + collides with the aromatic hydrocarbon molecule, and a collision complex is formed due to ion-dipole interaction. The formed complex obeys the traditional electrophilic substitution rule, first undergoes single-electron transfer, and then deprotonates to generate the nitration product.

[0013] The benzene ring of m-toluic acid contains a carboxyl group, and the carboxyl group is an electron-withdrawing group. Therefore, the carbon atom connected to the carboxyl group on the benzene ring bears partial positive charge. Since the electron clouds of each carbon atom on the benzene ring are evenly distributed on the benzene ring, according to the conjugation effect, these positive charges will be distributed on the whole benzene ring, which reduces the charge density on the benzene ring and deactivates the reaction activity of the benzene ring; at the same time, according to the resonance theory, the distribution of positive charges on the benzene ring is not uniform, but more distributed at the 2nd, 4th and 6th positions, which makes the nitronium cation more likely to react at these positions, resulting in side reactions when nitrating m-toluic acid. The present invention provides a continuous production process of 3-methyl-2-nitrobenzoic acid. Compared with the traditional batch kettle method, the reaction temperature of this method is closer to normal temperature, the reaction conditions are easier to control, and by optimizing the preparation process, the occurrence of side reactions is reduced to a certain extent, and the yield of 3-methyl-2-nitrobenzoic acid is improved.

[0014] In some embodiments, the preparation method of the catalyst comprises the following steps:

[0015] S1. Stir PEG, pyridine, and toluene evenly at 80 - 90 °C, add thionyl chloride, stir for 15 - 20 h, cool to room temperature, add hydrochloric acid until solids appear, let it stand, take the upper layer after stratification, extract the lower layer, combine the obtained extraction product with the upper layer, and rotary evaporate to constant weight to obtain reactant 1;

[0016] S2. Stir sodium ethoxide, absolute ethanol, and imidazole at 60 - 70 °C for 7 - 8 h, then add reactant 1 obtained in step S1, stir for 15 - 20 h, filter, take the filtrate, add 1,3 - propane sultone, stir at 40 - 60 °C for 8 - 12 h, add hydrochloric acid, raise the temperature to 65 - 75 °C and stir for 2.5 - 3.5 h, wash and rotary evaporate to constant weight to obtain reactant 2;

[0017] S3. Under nitrogen protection, add stannic chloride pentahydrate to reactant 2 obtained in step S2, then stir at 85 - 100 °C for 2 - 4 h, rotary evaporate, and vacuum dry to constant weight to obtain the catalyst.

[0018] In some embodiments, the molar ratio of PEG, pyridine, and thionyl chloride in step S1 is 1:(2 - 3):(2 - 3).

[0019] In some embodiments, the molar ratio of sodium ethoxide, imidazole to thionyl chloride in step S1 in step S2 is (1.2 - 1.5):(1.2 - 1.5):1.

[0020] In some embodiments, the molar ratio of stannic chloride pentahydrate to 1,3 - propane sultone in step S2 in step S3 is (1.0 - 1.3):1.

[0021] The present invention further improves the yield of the product by adding a catalyst. On the one hand, the catalyst has certain ions. During nitration, the nitronium cation may form an ion pair with the ions on the catalyst, thereby increasing the volume of the attacking reagent and making the reaction selectivity increase; or, the catalyst changes the reaction selectivity through steric hindrance effects. On the other hand, the catalyst presents a highly dispersed droplet shape in the reaction system and has good contact with the reactants to be catalyzed. On the third hand, this catalyst can be separated by simple filtration, and the separated catalyst can be reused in the reaction without complex treatment, simplifying the reaction process.

[0022] In some embodiments, the yield of 3 - methyl - 2 - nitrobenzoic acid prepared by the preparation process described in the above technical solution is 77% - 83%, and the product purity is greater than 99.3%.

[0023] Compared with the prior art, the present invention has the following beneficial effects:

[0024] (1) The present invention provides a continuous preparation process of 3-methyl-2-nitrobenzoic acid. By activating the target substitution site with a special catalyst, the generation of side reactions is reduced, and the problems of high cost, low yield, and low purity in the existing continuous preparation process of 3-methyl-2-nitrobenzoic acid are solved.

[0025] (5) The yield of 2-acetylpyridine obtained by the preparation process of the present invention is 77% - 83%, and the product purity is greater than 99.3%. Specific Embodiments

[0026] The present invention will be described below in conjunction with specific embodiments. It should be noted that the following examples are examples of the present invention, only for illustrating the present invention, and not for limiting the present invention. Without departing from the gist or scope of the present invention, other combinations and various improvements within the concept of the present invention can be made.

[0027] For the convenience of those skilled in the art to implement the present invention, some raw materials and manufacturers of the examples and comparative examples are described as follows:

[0028] PEG-400 is purchased from Jiangsu Dena Chemical Co., Ltd.

[0029] Preparation Example 1

[0030] The preparation steps of catalyst-A are as follows:

[0031] S1. Stir 1 mol of PEG-400, 2.5 mol of pyridine, and 800 mL of toluene evenly at 85 °C, add 2.5 mol of thionyl chloride, stir for 16 h, cool to room temperature, add hydrochloric acid with a concentration of 30 wt% until a solid appears, let it stand, take the upper layer after layering, extract the lower layer, combine the lower layer extraction product with the upper layer, and rotary evaporate to constant weight to obtain reactant 1;

[0032] S2. Stir 3.25 mol of sodium ethoxide, 1000 mL of absolute ethanol, and 3.25 mol of imidazole at 65 °C for 7.5 h, then add the reactant 1 obtained in step S1, stir for 16 h, filter, take the filtrate, add 3.25 mol of 1,3-propane sultone, stir at 50 °C for 10 h, add 3250 mL of hydrochloric acid with a concentration of 1 M, heat up to 70 °C and stir for 3 h, wash with petroleum ether 3 times, and rotary evaporate to constant weight to obtain reactant 2;

[0033] S3. Under nitrogen protection, add 3.5 mol of stannic chloride pentahydrate to the reactant 2 obtained in step S2, then stir at 90 °C for 3 h, rotary evaporate, and vacuum dry at 80 °C to constant weight to obtain catalyst-A.

[0034] Preparation Example 2

[0035] The preparation steps of Catalyst-B are as follows:

[0036] S1. Mix 1 mol of PEG-400, 2.5 mol of pyridine, and 800 mL of toluene evenly by stirring at 85 °C. Add 2.5 mol of thionyl chloride and stir for 16 h. Cool to room temperature. Add hydrochloric acid with a concentration of 30 wt% until a solid appears. Let it stand. After layering, take the upper layer, extract the lower layer, combine the lower-layer extraction product with the upper layer, and rotary evaporate until constant weight to obtain Reactant 1;

[0037] S2. Stir 3.25 mol of sodium ethoxide, 1000 mL of absolute ethanol, and 3.25 mol of imidazole at 65 °C for 7.5 h. Then add Reactant 1 obtained in Step S1 and stir for 16 h. Filter and take the filtrate. Add 3.25 mol of 1,3-propane sultone and stir at 50 °C for 10 h. Add 3250 mL of hydrochloric acid with a concentration of 1 M, raise the temperature to 70 °C and stir for 3 h. Wash with petroleum ether three times, rotary evaporate, and vacuum dry at 80 °C until constant weight to obtain Catalyst-B;

[0038] Preparation Example 3

[0039] The preparation steps of Catalyst-C are as follows:

[0040] S1. Stir 3.25 mol of imidazole and 3.25 mol of 1,3-propane sultone at 50 °C for 10 h. Add 3250 mL of hydrochloric acid with a concentration of 1 M, raise the temperature to 70 °C and stir for 3 h. Wash with petroleum ether three times, rotary evaporate until constant weight to obtain Reactant 1;

[0041] S2. Under nitrogen protection, add 3.5 mol of stannous chloride pentahydrate to Reactant 1 obtained in Step S1, then stir at 90 °C for 3 h, rotary evaporate, and vacuum dry at 80 °C until constant weight to obtain Catalyst-C.

[0042] Example 1

[0043] A continuous preparation process of 3-methyl-2-nitrobenzoic acid includes the following steps: Add 1 mol of m-methylbenzoic acid and 55 g of Catalyst-A to 4 mol of concentrated nitric acid with a concentration of 98 wt% at a rate of 6.2 g / min respectively, carry out a nitration reaction at -5 °C for 150 s, then filter the product to obtain a filtrate and a filter cake; The filtrate is separated by distillation to obtain the catalyst and concentrated nitric acid, and continue to feed them into the reaction; The filter cake is washed, purified, and dried to obtain 3-methyl-2-nitrobenzoic acid.

[0044] Example 2

[0045] A continuous preparation process of 3-methyl-2-nitrobenzoic acid, comprising the following steps: adding 1 mol of m-methylbenzoic acid and 44 g of catalyst-A into 3 mol of concentrated nitric acid with a concentration of 98 wt% at a rate of 5.5 g / min respectively, carrying out a nitration reaction at 0 °C for 120 s, then filtering the product to obtain a filtrate and a filter cake; separating the catalyst and the concentrated nitric acid from the filtrate by rectification and continuing to feed them into the reaction; washing, purifying and drying the filter cake to obtain 3-methyl-2-nitrobenzoic acid.

[0046] Example 3

[0047] A continuous preparation process of 3-methyl-2-nitrobenzoic acid, comprising the following steps: adding 1 mol of m-methylbenzoic acid and 65 g of catalyst-A into 5 mol of concentrated nitric acid with a concentration of 98 wt% at a rate of 7.0 g / min respectively, carrying out a nitration reaction at -10 °C for 180 s, then filtering the product to obtain a filtrate and a filter cake; separating the catalyst and the concentrated nitric acid from the filtrate by rectification and continuing to feed them into the reaction; washing, purifying and drying the filter cake to obtain 3-methyl-2-nitrobenzoic acid.

[0048] Example 4

[0049] The present invention provides a continuous preparation process of 3-methyl-2-nitrobenzoic acid. The specific implementation manner is the same as that of Example 1, except that the dosage of catalyst-A is 40 g.

[0050] Example 5

[0051] The present invention provides a continuous preparation process of 3-methyl-2-nitrobenzoic acid. The specific implementation manner is the same as that of Example 1, except that the dosage of catalyst-A is 70 g.

[0052] Example 6

[0053] The present invention provides a continuous preparation process of 3-methyl-2-nitrobenzoic acid. The specific implementation manner is the same as that of Example 1, except that catalyst-A is replaced by an equal amount of catalyst-B.

[0054] Example 7

[0055] The present invention provides a continuous preparation process of 3-methyl-2-nitrobenzoic acid. The specific implementation manner is the same as that of Example 1, except that catalyst-A is replaced by an equal amount of catalyst-C.

[0056] Comparative Example 1

[0057] A continuous preparation process of 3-methyl-2-nitrobenzoic acid, comprising the following steps: adding 1 mol of m-methylbenzoic acid to 4 mol of concentrated nitric acid with a concentration of 98 wt% at a rate of 6.2 g / min, carrying out a nitration reaction at -5°C for 150 s, and then filtering the product to obtain a filtrate and a filter cake; separating the concentrated nitric acid from the filtrate by distillation and continuing to feed it into the reaction; washing, purifying, and drying the filter cake to obtain 3-methyl-2-nitrobenzoic acid.

[0058] Performance test

[0059] The yields and purities of 3-methyl-2-nitrobenzoic acid obtained in Examples 1-7 and Comparative Example 1 above were tested by HPLC method, and the test results are shown in Table 1.

[0060] Table 1

[0061]

[0062]

[0063] It can be seen from the data in Table 1 that 3-methyl-2-nitrobenzoic acid in Examples 1-3 of the present invention has the characteristics of high yield and high purity, indicating that fewer side reactions occur in the preparation processes of these three examples. Compared with Example 1, in Examples 4-5, the amount of catalyst used in the preparation process was changed, which may be unfavorable for the formation of an ion pair between the nitronium cation and the ions on the catalyst, or may affect the steric effect in the reaction, resulting in a decrease in both the yield and purity of 3-methyl-2-nitrobenzoic acid; compared with Example 1, in Examples 6-7, the synthesis steps of the catalyst were changed, which is not conducive to the formation of the target structure of the catalyst, resulting in a decrease in the yield. It can be seen from Example 1 and Comparative Example 1 that the addition of the catalyst effectively increases the yield of the product.

[0064] The above embodiments are only used to illustrate the technical concept and characteristics of the present invention, and the purpose is to enable those familiar with this technology to understand the content of the present invention and implement it, and it cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit and essence of the present invention should be covered within the protection scope of the present invention.

Claims

1. A continuous preparation process for 3-methyl-2-nitrobenzoic acid, characterized in that: The following steps are involved: The m-toluic acid and the catalyst are added to concentrated nitric acid respectively, and a nitration reaction is carried out at -10 to 0°C, and then the product is filtered to obtain a filtrate and a filter cake; the filtrate is subjected to rectification to separate the catalyst and concentrated nitric acid, and then further subjected to the reaction; the filter cake is washed, purified, and dried to obtain the 3-methyl-2-nitrobenzoic acid; The preparation method of the catalyst comprises the following steps: S1. Stir PEG, pyridine and toluene at 80-90°C, add thionyl chloride, stir for 15-20h, cool to room temperature, add hydrochloric acid until solid appears, let stand, take the upper layer after separation, extract the lower layer, combine the obtained extract with the upper layer, and rotary evaporate to constant weight to obtain reactant 1; S2, stirring sodium ethoxide, anhydrous ethanol and imidazole at 60-70° C. for 7-8 h, then adding the reactant 1 obtained in step S1, stirring for 15-20 h, filtering, taking the filtrate, adding 1,3-propane sultone, stirring at 40-60° C. for 8-12 h, adding hydrochloric acid, heating to 65-75° C., stirring for 2.5-3.5 h, washing, and rotary evaporating to constant weight to obtain reactant 2; S3. Under nitrogen protection, add tin chloride pentahydrate to the reactant 2 obtained in step S2, then stir at 85-100° C. for 2-4 hours, rotary evaporate, and vacuum dry to constant weight to obtain the catalyst.

2. The continuous preparation process of 3-methyl-2-nitrobenzoic acid according to claim 1, characterized in that: The nitration reaction time is 120 to 180 seconds.

3. The continuous preparation process of 3-methyl-2-nitrobenzoic acid according to claim 1, characterized in that: The molar ratio of the m-toluic acid to the concentrated nitric acid is 1:(3.0-5.0).

4. The continuous preparation process of 3-methyl-2-nitrobenzoic acid according to claim 1, characterized in that: The mass ratio of the m-toluic acid to the catalyst is 1:(0.32-0.48).

5. The continuous preparation process of 3-methyl-2-nitrobenzoic acid according to claim 4, characterized in that: The rate of adding the m-toluic acid and the catalyst is 5.5-7.0 g / min.

6. The continuous preparation process of 3-methyl-2-nitrobenzoic acid according to claim 1, characterized in that: In step S1, the molar ratio of PEG, pyridine and dithionyl chloride is 1:(2-3):(2-3).

7. The continuous preparation process of 3-methyl-2-nitrobenzoic acid according to claim 1, characterized in that: In step S2, the molar ratio of the sodium ethoxide, imidazole and the dithionyl chloride in step S1 is (1.2-1.5):(1.2-1.5):

1.

8. The continuous preparation process of 3-methyl-2-nitrobenzoic acid according to claim 1, characterized in that: In step S3, the molar ratio of the tin chloride pentahydrate to the 1,3-propane sultone in step S2 is (1.0-1.3):1.

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