Continuous preparation process of 3-methyl-2-nitrobenzoic acid

Abstract

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

Description

Technical Field

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

[0002] 3-Methyl-2-nitrobenzoic acid (methyl-2-nitric acid) is an important type of fine chemicals. In recent years, with the growing 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 continued to expand, and the demand has increased year by year. In addition, according to the "Notice on Issuing 11 Work Plans including the Key Points of Dangerous Chemical Safety Supervision Work and Safety Improvement of Chemical Parks in 2023" issued by the Henan Provincial Emergency Management Bureau (Henan Emergency Office

[2023] No. 21), continuous production requirements are proposed for nitration 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, which is to carry out continuous nitration reaction of 98% fuming nitric acid and 3-methylbenzoic acid in a reactor, and then filter and wash to 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. Patent CN114560772B provides a synthesis method of 3-methyl-2-nitrobenzoic acid, which avoids the generation of a large amount of nitric acid wastewater during the production process, but the synthesis can only be achieved under the conditions of inorganic base, catalyst, ozone and light. For industrial production, the equipment requirements and initial investment are high, which is not suitable for large-scale promotion.

[0004] Therefore, there is an urgent need on the market for a low-cost, environmentally friendly, highly selective and high-purity continuous preparation process of 3-methyl-2-nitrobenzoic acid. Summary of the invention

[0005] In view of the problems existing in the prior art, the present invention selects a specially prepared catalyst to activate the target substitution site, reduces the occurrence 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 solution adopted by the present invention is as follows:

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

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

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

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

[0012] In the nitration reaction, nitric acid is first protonated and then produces nitroxyl cation NO2 + , NO2 + It collides with aromatic molecules and forms a collision complex due to ion-dipole interaction. The formed complex obeys the traditional electrophilic substitution rules, first undergoes single electron transfer, and then deprotonates to generate nitration products.

[0013] The benzene ring of m-toluic acid contains a carboxyl group, wherein the carboxyl group is an electron-withdrawing group, therefore, the carbon atom connected to the benzene ring and the carboxyl group is partially positively charged, and since the electron cloud of each carbon atom on the benzene ring is evenly distributed on the benzene ring, according to the conjugation effect, these positive charges will be distributed on the entire benzene ring, which reduces the charge density on the benzene ring and passivates the reactivity of the benzene ring; at the same time, according to the resonance theory, the distribution of positive charges on the benzene ring is not even, but more distributed on the 2nd, 4th and 6th positions, which makes the nitroxyl cation more likely to react at these positions, thereby causing side reactions when nitrating m-toluic acid. The present invention provides a continuous production process of 3-methyl-2-nitrobenzoic acid, and compared with the traditional kettle batch method, the reaction temperature of the method is closer to room 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 method for preparing the catalyst comprises the following steps:

[0015] 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;

[0016] 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;

[0017] 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 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 and imidazole in step S2 to thionyl chloride in step S1 is (1.2-1.5):(1.2-1.5):1.

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

[0021] The present invention further improves the yield of the product by adding a catalyst. Firstly, the catalyst carries certain ions. During nitration, the nitroxyl cation may form ion pairs with the ions on the catalyst, thereby increasing the volume of the attacking reagent and increasing the selectivity of the reaction. Alternatively, the catalyst changes the selectivity of the reaction through a steric effect. Secondly, the catalyst is in the form of highly dispersed droplets in the reaction system and has good contact with the catalyzed reactants. Thirdly, the catalyst can be separated by simple filtration, and the separated catalyst can be put back into the reaction without complicated treatment, thereby 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% to 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 for 3-methyl-2-nitrobenzoic acid, which activates the target substitution site through a specially prepared catalyst, reduces the occurrence of side reactions, and solves the problems of high cost, low yield and low purity in the existing continuous preparation process for 3-methyl-2-nitrobenzoic acid.

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

[0026] The present invention will be described below in conjunction with specific embodiments. It should be noted that the following embodiments are examples of the present invention and are only used to illustrate the present invention, but not to limit the present invention. Other combinations and various modifications within the concept of the present invention may be performed without departing from the spirit or scope of the present invention.

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

[0028] PEG-400 was 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 PEG-400, 2.5 mol pyridine and 800 mL toluene at 85°C, add 2.5 mol thionyl chloride, stir for 16 h, cool to room temperature, add 30 wt% hydrochloric acid until solid appears, let stand, take the upper layer after stratification, extract the lower layer, combine the extract of the lower layer with the upper layer, and rotary evaporate to constant weight to obtain reactant 1;

[0032] S2, 3.25 mol of sodium ethoxide, 1000 mL of anhydrous ethanol and 3.25 mol of imidazole were stirred at 65°C for 7.5 h, then reactant 1 obtained in step S1 was added, stirred for 16 h, filtered, the filtrate was taken, 3.25 mol of 1,3-propane sultone was added, stirred at 50°C for 10 h, 3250 mL of 1 M hydrochloric acid was added, the temperature was raised to 70°C and stirred for 3 h, petroleum ether was washed 3 times, and rotary evaporated to constant weight to obtain reactant 2;

[0033] S3. Under nitrogen protection, add 3.5 mol of tin 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. Stir 1 mol PEG-400, 2.5 mol pyridine and 800 mL toluene at 85°C, add 2.5 mol thionyl chloride, stir for 16 h, cool to room temperature, add 30 wt% hydrochloric acid until solid appears, let stand, take the upper layer after stratification, extract the lower layer, combine the extract product of the lower layer with the upper layer, and rotary evaporate to constant weight to obtain reactant 1;

[0037] S2, 3.25 mol of sodium ethoxide, 1000 mL of anhydrous ethanol and 3.25 mol of imidazole were stirred at 65°C for 7.5 h, then reactant 1 obtained in step S1 was added, stirred for 16 h, filtered, the filtrate was taken, 3.25 mol of 1,3-propane sultone was added, stirred at 50°C for 10 h, 3250 mL of 1 M hydrochloric acid was added, the temperature was raised to 70°C and stirred for 3 h, petroleum ether was washed 3 times, rotary evaporated, and vacuum dried at 80°C to constant weight to obtain catalyst-B;

[0038] Preparation Example 3

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

[0040] S1, 3.25 mol of imidazole and 3.25 mol of 1,3-propane sultone were stirred at 50°C for 10 h, 3250 mL of 1 M hydrochloric acid was added, the temperature was raised to 70°C and stirred for 3 h, petroleum ether was washed 3 times, and the mixture was rotary evaporated to constant weight to obtain reactant 1;

[0041] S2. Under nitrogen protection, add 3.5 mol of tin chloride pentahydrate to the reactant 1 obtained in step S1, then stir at 90° C. for 3 h, rotary evaporate, and vacuum dry at 80° C. to constant weight to obtain catalyst-C.

[0042] Example 1

[0043] A continuous preparation process of 3-methyl-2-nitrobenzoic acid comprises the following steps: adding 1 mol of m-methylbenzoic acid and 55 g of catalyst-A into 4 mol of concentrated nitric acid with a concentration of 98 wt% at a rate of 6.2 g / min, respectively, performing nitration reaction at -5 DEG C for 150 seconds, and then filtering the product to obtain a filtrate and a filter cake; separating the catalyst and concentrated nitric acid from the filtrate through rectification, and continuing to feed the reaction; and washing, purifying and drying the filter cake to obtain 3-methyl-2-nitrobenzoic acid.

[0044] Example 2

[0045] A continuous preparation process of 3-methyl-2-nitrobenzoic acid comprises 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, performing nitration reaction at 0 DEG C for 120 seconds, and then filtering the product to obtain a filtrate and a filter cake; separating the catalyst and concentrated nitric acid from the filtrate through rectification, and continuing to feed 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 comprises 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, performing nitration reaction at -10 DEG C for 180 seconds, and then filtering the product to obtain a filtrate and a filter cake; separating the catalyst and concentrated nitric acid from the filtrate through rectification, and continuing to feed the reaction; and 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, and the specific implementation manner is the same as that of Example 1, except that the amount of catalyst-A used is 40 g.

[0050] Example 5

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

[0052] Example 6

[0053] The present invention provides a continuous preparation process of 3-methyl-2-nitrobenzoic acid. The specific implementation method 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 method 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 for 3-methyl-2-nitrobenzoic acid comprises 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 DEG C for 150 seconds, filtering the product to obtain a filtrate and a filter cake; separating the concentrated nitric acid from the filtrate through rectification and continuing to feed the reaction; and washing, purifying and drying the filter cake to obtain 3-methyl-2-nitrobenzoic acid.

[0058] Performance Testing

[0059] The yield and purity of 3-methyl-2-nitrobenzoic acid obtained in Examples 1-7 and Comparative Example 1 were tested by HPLC. The test results are shown in Table 1.

[0060] Table 1

[0061]

[0062]

[0063] As can be seen from the data in Table 1, 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 embodiments. Compared with Example 1, Examples 4-5 change the amount of catalyst used in the preparation process, which may be unfavorable for the formation of ion pairs between nitroxyl cations and ions on the catalyst, or affect the steric effect in the reaction, resulting in a decrease in the yield and purity of 3-methyl-2-nitrobenzoic acid; Compared with Example 1, Examples 6-7 change the synthesis steps of the catalyst, which is not conducive to the formation of the target structure of the catalyst, resulting in a decrease in yield. As can be seen from Example 1 and Comparative Example 1, the addition of the catalyst effectively increases the yield of the product.

[0064] The above implementation modes are only for illustrating the technical concept and features of the present invention, and their purpose is to enable people familiar with this technology to understand the content of the present invention and implement it, and they cannot be used to limit the protection scope of the present invention. Any equivalent changes or modifications made according to the spirit of the present invention should be included in 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 respectively added to concentrated nitric acid, 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.

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: 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.

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

8. The continuous preparation process of 3-methyl-2-nitrobenzoic acid according to claim 6, 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.

9. The continuous preparation process of 3-methyl-2-nitrobenzoic acid according to claim 6, 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.

10. The continuous preparation process of 3-methyl-2-nitrobenzoic acid according to any one of claims 1 to 9, characterized in that: The yield of the prepared 3-methyl-2-nitrobenzoic acid is 77% to 83%, and the product purity is greater than 99.3%.

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