A process for the preparation of 2-amino-5-chloro-N,3-dimethylbenzamide

Abstract

The application provides a preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide, which comprises the following steps: dissolving 2-amino-N,3-dimethylbenzamide in a polar solvent, introducing hydrogen chloride to make the hydrogen chloride react with the 2-amino-N,3-dimethylbenzamide to form a first product, introducing chlorine to make the chlorine react with the first product to obtain a second product, and adjusting the pH value of the second product to obtain 2-amino-5-chloro-N,3-dimethylbenzamide. According to the application, the amino group on the aromatic ring is protected by salifying the raw material and hydrogen chloride before the chlorosubstitution reaction, so that the product yield is greatly improved, and meanwhile, the product color can be improved.

Description

Technical Field

[0001] This invention relates to the industrialization of the K-amine process, specifically to a method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide. Background Technology

[0002] Chlorantraniliprole is a novel, highly effective, and low-toxicity o-formamide insecticide widely used for pest control in crops. Since its market launch, chlorantraniliprole has received widespread acclaim, with sales increasing year by year, demonstrating broad application prospects and a huge market potential.

[0003] 2-Amino-5-chloro-N,3-dimethylbenzamide is an important intermediate in the preparation of chlorantraniliprole. Industrially, it can be synthesized by chlorination using the hydrochloric acid-hydrogen peroxide method or the sulfonyl chloride method.

[0004] Patent application publication (CN115594608A) discloses a method for obtaining 2-amino-5-chloro-3-cyanotoluene from 2-amino-3-methylbenzonitrile as a starting material via a hydrochloric acid and hydrogen peroxide system, followed by the addition of hydrochloric acid to obtain 2-amino-5-chloro-3-methylbenzoic acid, ultimately yielding 2-amino-5-chloro-N,3-dimethylbenzamide. Patent application publication (CN101492387A) discloses a method for preparing the product by chlorination using 2-amino-3-methylbenzoylmethylamine as a starting material, acetonitrile as a solvent, and 1.2 equivalents of sulfonyl chloride as a chlorine source.

[0005] Of the methods described above, the former requires a large amount of hydrochloric acid, generating highly concentrated acidic wastewater that cannot be recycled, while the latter uses sulfonyl chloride, which also produces acidic tail gas requiring large amounts of liquid alkali for neutralization. Furthermore, sulfonyl chloride has a strong odor and is environmentally unfriendly. Both of these mainstream industrial methods suffer from low yields and low production capacity.

[0006] Patent application publication (CN11 8439967A) discloses a method for producing the product by chlorination of 2-amino-3-methylbenzoylmethylamine using dichloromethane or dichloroethane as a solvent, followed by extraction with dichloromethane. However, this method requires a high temperature for the chlorination reaction, which increases side reactions and results in a poor-looking 2-amino-5-chloro-N,3-dimethylbenzamide product, which is detrimental to subsequent production.

[0007] In actual production, in addition to the problem of poor product color caused by increased side reactions, the higher chlorine substitution temperature will cause a certain degree of corrosion to the production equipment. Therefore, it is essential to find a way to produce at a relatively low temperature while obtaining a high product yield.

[0008] Given the numerous problems existing in the current technology, there is an urgent need to improve and break through the process to reduce the reaction temperature while ensuring product yield. Summary of the Invention

[0009] To address the problems existing in the prior art, the present invention provides a method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide, the method comprising the following steps:

[0010] Hydrogen chloride gas is introduced to react with 2-amino-N,3-dimethylbenzamide to form the first product.

[0011] Chlorine gas is introduced to react with the first product in a chlorine substitution reaction.

[0012] Furthermore, before introducing hydrogen chloride gas to form the first product with 2-amino-N,3-dimethylbenzamide, 2-amino-N,3-dimethylbenzamide is dissolved in a polar solvent.

[0013] Furthermore, after chlorine gas is introduced to react with the first product in a chlorine substitution reaction, a nonpolar solvent is added to precipitate the second product.

[0014] Further, the pH of the second product was adjusted to alkaline to obtain 2-amino-5-chloro-N,3-dimethylbenzamide.

[0015] Specifically, the polar solvent is selected from at least one of acetic acid, tetrahydrofuran, dioxane, methyl tert-butyl ether, MDF, DMSO, dichloroethane, and dichloromethane.

[0016] Specifically, the nonpolar solvent is selected from at least one of cyclohexane, alkanes with 6 to 10 carbon atoms, toluene, xylene, trimethylbenzene, and 60-90% petroleum ether.

[0017] Furthermore, the first product includes an ammonium salt formed at the 2-amino position on the benzene ring of 2-amino-N,3-dimethylbenzamide.

[0018] Furthermore, the first product is shown in formula (I) below.

[0019]

[0020] Where R stands for Cl.

[0021] Furthermore, the second product includes a chlorine substitution at the 5-position of the benzene ring of 2-amino-N,3-dimethylbenzamide.

[0022] Furthermore, the second product is shown in formula (II) below.

[0023]

[0024] Where R stands for Cl.

[0025] Furthermore, the weight ratio of the polar solvent to 2-amino-N,3-dimethylbenzamide is greater than or equal to 7:1, and more preferably 7-8:1.

[0026] Further, the weight ratio of hydrogen chloride to 2-amino-N,3-dimethylbenzamide is greater than or equal to 0.3:1, and more preferably 0.3-0.4:1.

[0027] Furthermore, the temperature for the chlorine substitution reaction is 15-30°C, preferably 15-25°C.

[0028] The time for introducing chlorine gas to carry out the chlorine substitution reaction is adjusted according to the amount of raw materials.

[0029] In the technical solution provided by this invention, the raw material 2-amino-N,3-dimethylbenzamide and hydrogen chloride are salted before the chlorination reaction. This step protects the amino group on the aromatic ring. Then, chlorine gas, which is cheap and readily available, is used for the chlorination reaction, which reduces the cost. The use of concentrated hydrochloric acid is eliminated, thus avoiding high-concentration hydrochloric acid wastewater products. At the same time, the use of environmentally unfriendly and expensive sulfonyl chloride is eliminated, which reduces a large amount of acidic tail gas. The product yield of the preparation method described in this invention is significantly improved. Attached Figure Description

[0030] Figure 1 The images show actual products of 2-amino-5-chloro-N,3-dimethylbenzamide obtained using the methods of Examples 1, 13-16, and Comparative Examples 1-2. Detailed Implementation

[0031] Specific embodiments of the present application will now be described in more detail with reference to the accompanying drawings. While specific embodiments of the present application are shown in the drawings, it should be understood that the present application can be implemented in various forms and should not be limited to the embodiments set forth herein. Rather, these embodiments are provided to enable a more thorough understanding of the present application and to fully convey the scope of the present application to those skilled in the art.

[0032] It should be noted that certain terms are used in the specification and claims to refer to specific components. Those skilled in the art will understand that different terms may be used to refer to the same component. This specification and claims do not distinguish components based on differences in terminology, but rather on differences in function. The terms "comprising" or "including" used throughout the specification and claims are open-ended and should be interpreted as "comprising but not limited to." The following descriptions in the specification are preferred embodiments for carrying out this application; however, these descriptions are for the purpose of understanding the general principles of the specification and are not intended to limit the scope of this application. The scope of protection of this application shall be determined by the appended claims.

[0033] This invention provides a method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide, the method comprising the following steps:

[0034] 2-Amino-N,3-dimethylbenzamide is dissolved in a polar solvent selected from at least one of acetic acid, tetrahydrofuran, dioxane, methyl tert-butyl ether, DMF, DMSO, dichloroethane, and dichloromethane.

[0035] In some embodiments, the polar solvent is selected from acetic acid, tetrahydrofuran, dichloroethane, or dichloromethane.

[0036] Specifically, when acetic acid is selected as the polar solvent, the weight ratio of the polar solvent to 2-amino-N,3-dimethylbenzamide is greater than or equal to 7:1. For example, it can be selected as 7:1, 7.5:1, 8:1, 8.5:1, 9:1, 9.5:1, or 10:1.

[0037] After the raw material is completely dissolved, hydrogen chloride is added to the solution, causing 2-amino-N,3-dimethylbenzamide to react with hydrogen chloride to form the first product. Specifically, the first product includes an ammonium salt formed at the 2-amino position on the benzene ring of 2-amino-N,3-dimethylbenzamide, as shown in formula (I), where R is Cl.

[0038]

[0039] 2-Amino-N,3-dimethylbenzamide reacts with hydrogen chloride to form an ammonium salt, which can protect the amine group on the aromatic ring.

[0040] Specifically, hydrogen chloride gas is added to the solution, wherein the weight ratio of the hydrogen chloride to 2-amino-N,3-dimethylbenzamide is 0.1 to 0.5:1, for example, 0.1:1, 0.2:1, 0.3:1, 0.4:1, or 0.5:1.

[0041] In some embodiments, the weight ratio of 2-amino-N,3-dimethylbenzamide to hydrogen chloride is 0.2:1, 0.3:1, 0.32:1, 0.38:1, or 0.4:1.

[0042] After 2-amino-N,3-dimethylbenzamide reacts with hydrogen chloride to form an ammonium salt, chlorine gas is introduced into the solution to carry out a chlorination reaction.

[0043] During the above chlorine substitution reaction, the reaction temperature is controlled within the range of 15-30℃, for example, 15℃, 16℃, 17℃, 18℃, 19℃, 20℃, 21℃, 22℃, 23℃, 24℃, 25℃, 26℃, 27℃, 28℃, 29℃, and 30℃.

[0044] The reaction solution of the above chlorination reaction was sampled and analyzed. When the mass fraction of the starting material 2-amino-N,3-dimethylbenzamide was ≤1%, the chlorine gas flow was stopped, and the chlorination reaction was considered complete. In the above chlorination reaction, the time for chlorine gas flow to carry out the chlorination reaction can be adjusted according to the amount of starting material.

[0045] After the chlorine substitution reaction is complete, the reaction solution is stirred and centrifuged, and then a nonpolar solvent is added to precipitate the second product.

[0046] Specifically, the second product includes a chlorine substitution at the 5-position of the benzene ring of 2-amino-N,3-dimethylbenzamide, as shown in formula (II), where R is Cl.

[0047]

[0048] Specifically, the nonpolar solvent is selected from at least one of the following: cyclohexane, alkanes with 6 to 10 carbon atoms, toluene, xylene, trimethylbenzene, etc. Among these, alkanes with 6 to 10 carbon atoms may include hexane, n-heptane, n-octane, n-nonane, and n-decane.

[0049] After the above precipitation process is completed, alkali is added to the second product to adjust the pH of the second product. When the pH value is alkaline, centrifugation, filtration and drying are performed to finally obtain 2-amino-5-chloro-N,3-dimethylbenzamide.

[0050] Example

[0051] Unless otherwise specified, the experimental methods used in the following examples are conventional methods.

[0052] Unless otherwise specified, all materials and reagents used in the following examples are commercially available.

[0053] Example 1

[0054] 50g of 2-amino-N,3-dimethylbenzamide was dissolved in 375g of acetic acid. After complete dissolution, 16g of hydrogen chloride was introduced into the solution, maintaining the reaction temperature at 20℃. After the 2-amino-N,3-dimethylbenzamide reacted with hydrogen chloride for 25 minutes, chlorine gas was introduced into the solution to carry out a chlorination reaction, maintaining the reaction temperature at 20℃. The reaction solution was sampled and analyzed. When the mass fraction of 2-amino-N,3-dimethylbenzamide was ≤1%, the introduction of chlorine gas was stopped. 375g of cyclohexane was added to the reaction solution to lower the temperature. When the temperature dropped to 10-15℃, the mixture was stirred for 0.5 hours and centrifuged. 75g of cyclohexane was added to wash the reactants, and the filter cake was dried. Add 250g of water to the dried filter cake and stir for 0.5h. While continuing to stir, add 60g of 30% liquid alkali dropwise, keeping the temperature ≤25℃. When the pH of the reaction solution is alkaline, reduce the temperature of the reactor to 10-15℃, discharge the material and centrifuge. Send the filtrate to the wastewater tank and dry the remaining filter cake until the moisture content is ≤0.3%. Finally, the product 2-amino-5-chloro-N,3-dimethylbenzamide is obtained.

[0055] The yield of the product 2-amino-5-chloro-N,3-dimethylbenzamide in Example 1 is shown in Table 1.

[0056] The difference between Examples 2-4 and Example 1 is that the types of polar solvents are different, while all other parameters are the same. The parameters are shown in Table 1.

[0057] Table 1 shows the effect of using solvents of different polarities on the yield.

[0058] Polar solvents Product yield Example 1 Acetic acid 98％ Example 2 Tetrahydrofuran 92％ Example 3 dichloromethane 93％ Example 4 dichloroethane 97％

[0059] The data in Table 1 show that the products have high yields when using the polar solvents described in the table. Comparing the data in Table 1 and Table 6, it can be seen that adding polar solvents and carrying out the salt formation process can greatly improve the product yield.

[0060] The difference between Examples 5-8 and Example 1 is that the weight ratio of the polar solvent to 2-amino-N,3-dimethylbenzamide is different, while all other parameters are the same. The parameters are shown in Table 2.

[0061] Table 2. Effect of the weight ratio of polar solvent to 2-amino-N,3-dimethylbenzamide on feed conversion and product yield.

[0062]

[0063]

[0064] The data in Table 2 show that if the weight ratio of the polar solvent to 2-amino-N,3-dimethylbenzamide is too low, the raw material is difficult to convert completely, resulting in some waste. When the weight ratio of the polar solvent to 2-amino-N,3-dimethylbenzamide is greater than or equal to 7:1, the conversion rate of the raw material and the product yield are both high. However, further increases in the weight of the polar solvent do not have a greater impact on the conversion rate of the raw material or the product yield.

[0065] Therefore, the present application can be realized with a weight ratio of polar solvent to 2-amino-N,3-dimethylbenzamide greater than or equal to 7:1. From the perspective of saving raw materials and costs, a weight ratio of polar solvent to 2-amino-N,3-dimethylbenzamide of 7-8:1 is preferred.

[0066] The difference between Examples 9-12 and Example 1 is that the weight ratio of hydrogen chloride to 2-amino-N,3-dimethylbenzamide is different, while other parameters are the same. All parameters are shown in Table 3.

[0067] Table 3. Effect of the weight ratio of hydrogen chloride to 2-amino-N,3-dimethylbenzamide on product yield.

[0068]

[0069] According to the data in Tables 3 and 6, Comparative Examples 1 and 2 did not have the aforementioned salt-forming step, and their product yields were 85% or less. Examples 9-12 added a salt-forming step, and the product yields all reached 95% or more. That is to say, when the chlorine substitution reaction is carried out under relatively low temperature conditions, adding the step of salt formation between the raw materials and hydrogen chloride can improve the product yield. In other words, under relatively low temperature reaction conditions, the salt-forming step described in this application is a key link in improving the product yield.

[0070] When the weight ratio of hydrogen chloride to 2-amino-N,3-dimethylbenzamide is too low, only a portion of the raw materials can form a salt with hydrogen chloride. The amino groups in the unsalted portion of the raw materials are not fully protected, resulting in a low reaction yield. Further increasing the proportion of raw materials forming a salt can continue to improve the product yield until all the raw materials are salted, reaching the maximum product yield. Further increasing the amount of hydrogen chloride introduced does not further improve the product yield. Through extensive experiments, the inventors discovered that when the weight ratio of hydrogen chloride to 2-amino-N,3-dimethylbenzamide is 0.3-0.4:1, all the raw materials can form a salt with hydrogen chloride, the amino groups are fully protected, side reactions are reduced, and the product yield is consistently high. Further increasing the amount of hydrogen chloride does not significantly affect the product yield, and introducing excessive hydrogen chloride is wasteful.

[0071] The data in the table shows that a weight ratio of hydrogen chloride to 2-amino-N,3-dimethylbenzamide of 0.3:1 or greater is sufficient to achieve the present application. Furthermore, considering cost and environmental factors, a weight ratio of hydrogen chloride to 2-amino-N,3-dimethylbenzamide of 0.3-0.4:1 is preferred.

[0072] The inventors further discovered that adding salt during the production process also improves the color of the product. Figure 1 As can be seen, Comparative Examples 1 and 2 both obtained without the salt-forming step, and their products exhibit varying shades of pink, which is highly detrimental to their subsequent use. In other words, the addition of the salt-forming step not only increased the product yield but also further improved the product's color, changing it from pink to white.

[0073] The difference between Examples 13-16 and Example 1 is that the temperature at which the chlorine substitution reaction occurs is different, while all other parameters are the same. The parameters of the compositions are shown in Table 4.

[0074] Table 4. Effect of Chlorination Reaction Temperature on Product Yield

[0075] Temperature of chlorine substitution reaction Product yield Example 13 15℃ 97％ Example 1 20℃ 98％ Example 14 25℃ 96％ Example 15 30℃ 95％ Example 16 35℃ 90％

[0076] The data in Table 4 show that relatively low temperatures can improve product yield. When the chlorination temperature is between 15-25℃, the product yield is relatively high. As the temperature continues to rise, side reactions increase, and the product yield decreases. (Appendix) Figure 1 The images show the products obtained from the embodiments described in Table 4. As can be seen from the images, the product obtained under low temperature conditions is relatively white. However, as the reaction temperature increases, the side reactions increase, the product yield decreases, and the color of the product also deteriorates, gradually changing from white to a slightly grayish color. In actual production, this kind of product greatly affects subsequent use and is very unfavorable.

[0077] The difference between Examples 17-22 and Example 1 is that the type of nonpolar solvent added when precipitating the second product is different after the chlorine substitution reaction is completed. All other parameters are the same. The parameters of the composition are shown in Table 5.

[0078] Table 5. Effect of the type of nonpolar solvent on product yield

[0079]

[0080]

[0081] The data in Table 5 show that the choice of non-polar solvent has a certain impact on the yield. Products obtained using the above-mentioned types of non-polar solvents all have high yields.

[0082] Comparative Example 1

[0083] The difference between Comparative Example 1 and Example 1 is that, in the Comparative Example, hydrogen chloride was not introduced before the chlorination reaction to form a salt with the raw material 2-amino-N,3-dimethylbenzamide. All other parameters are the same, and the parameters are shown in Table 6.

[0084] Specifically:

[0085] 50g of 2-amino-N,3-dimethylbenzamide was dissolved in 375g of acetic acid. After complete dissolution, chlorine gas was introduced into the solution, and the reaction temperature was controlled at 20℃. The reaction solution was sampled and analyzed. When the mass fraction of 2-amino-N,3-dimethylbenzamide was ≤1%, the chlorine gas introduction was stopped. 375g of cyclohexane was added to the reaction solution to lower the temperature. When the temperature reached 10-15℃, the mixture was stirred for 0.5h and centrifuged. 75g of cyclohexane was added to wash the reactants, and the filter cake was dried. Add 250g of water to the dried filter cake and stir for 0.5h. While continuing to stir, add 60g of 30% liquid alkali dropwise, keeping the temperature ≤25℃. When the pH of the reaction solution is alkaline, reduce the temperature of the reactor to 10-15℃, discharge the material and centrifuge. Send the filtrate to the wastewater tank and dry the remaining filter cake until the moisture content is ≤0.3%. Finally, the product 2-amino-5-chloro-N,3-dimethylbenzamide is obtained.

[0086] Comparative Example 2

[0087] The difference between Comparative Example 2 and Comparative Example 1 is that the polar solvent used to dissolve the raw material 2-amino-N,3-dimethylbenzamide is dichloroethane. All other parameters are the same, and the parameters are shown in Table 6.

[0088] Table 6

[0089] Whether it becomes salt Product yield Example 1 yes 98％ Comparative Example 1 no 85％ Comparative Example 2 no 83％

[0090] As shown in Table 6, the data and photographs of the samples demonstrate that the salt formation of the raw material 2-amino-N,3-dimethylbenzamide and hydrogen chloride before the chlorination reaction protects the amino group on the aromatic ring, significantly increasing the product yield and improving its appearance, which is highly beneficial for subsequent use. Furthermore, production at relatively low temperatures reduces side reactions, avoids corrosion of production equipment, and further saves costs, which is extremely advantageous in actual production.

[0091] The technical features of the above embodiments can be combined in any way. For the sake of brevity, not all possible combinations of the technical features in the above embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0092] The embodiments described above are merely illustrative of several implementation methods of this application, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of this application. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of this application, and these all fall within the protection scope of this application. Therefore, the protection scope of this patent application should be determined by the appended claims.

Claims

1. A method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide, characterized in that, The method includes: Hydrogen chloride gas is introduced to react with 2-amino-N,3-dimethylbenzamide to form the first product. Chlorine gas is introduced to react with the first product in a chlorine substitution reaction.

2. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that, Before introducing hydrogen chloride gas to form the first product with 2-amino-N,3-dimethylbenzamide, 2-amino-N,3-dimethylbenzamide is dissolved in a polar solvent.

3. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that, After chlorine gas is introduced to react with the first product in a chlorine substitution reaction, a nonpolar solvent is added to precipitate the second product.

4. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 3, characterized in that, The pH of the second product was adjusted to alkaline to give 2-amino-5-chloro-N,3-dimethylbenzamide.

5. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to any one of claims 1 to 2, characterized in that, The polar solvent is selected from at least one of acetic acid, tetrahydrofuran, dioxane, methyl tert-butyl ether, MDF, DMSO, dichloroethane, and dichloromethane.

6. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 3, characterized in that, The nonpolar solvent is selected from at least one of cyclohexane, alkanes with 6 to 10 carbon atoms, toluene, xylene, trimethylbenzene, and 60-90% petroleum ether.

7. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that, The first product comprises an ammonium salt formed at the 2-amino position on the benzene ring of 2-amino-N,3-dimethylbenzamide.

8. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 7, characterized in that, The first product is shown in formula (I). Where R stands for Cl.

9. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 3, characterized in that, The second product includes a chlorine substitution at the 5-position of the benzene ring of 2-amino-N,3-dimethylbenzamide.

10. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 9, characterized in that, The second product is shown in formula (II). Where R stands for Cl.

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