Production process of 2-amino-5-chloro-N, 3-dimethyl benzamide

Abstract

The invention discloses a production process of 2-amino-5-chloro-N, 3-dimethyl benzamide, and relates to the technical field of organic synthesis. According to the present invention, 2-amino-N, 3-dimethyl benzamide is adopted as a starting material, 10-Cl-9-acridone is adopted as a chlorination reagent, and 1-butyl-3-methyl-1H-imidazole-3-onium tetrachloroferrate is adopted as a catalyst, such that the regioselective chlorination of the benzene ring site 5 is achieved; by systematically optimizing reaction parameters including key factors such as reaction temperature, time, reagent stoichiometric ratio and the like, the technical problems of excessive chlorination, by-product formation and the like in a traditional synthesis path are successfully solved. Under the optimal condition, the separation yield of the target product is stably maintained at 90% or above, and the method has the remarkable characteristics of mild reaction conditions, simplicity and convenience in operation and the like. The process flow is simple, a special reaction device is not needed, and the production cost can be remarkably reduced.

Description

Technical Field

[0001] The present invention belongs to the technical field of fine chemical industry, and particularly relates to a production process of 2-amino-5-chloro-N,3-dimethylbenzamide. Background Art

[0002] As a key intermediate of chlorantraniliprole, 2-amino-5-chloro-N,3-dimethylbenzamide plays an important role in the pesticide industry. With the increasingly strict industry standards, the production processes of chlorantraniliprole intermediates and o-formylaminobenzamide series products face many challenges. Therefore, developing a clean and efficient production process to achieve yield improvement and energy consumption reduction has become a technical problem to be solved urgently.

[0003] The traditional synthesis route mainly includes processes such as hydrogenation, cyclization, aminolysis, and chlorination. Among them, the chlorination step is the key link in the synthesis of 2-amino-5-chloro-N,3-dimethylbenzamide. The existing processes mainly include the hydrogen peroxide method, the hypohalous acid catalysis method, the iodine catalysis method, and the sulfonyl chloride method. In the hydrogen peroxide method, hydrochloric acid is used as the chlorine source, and the protonic acid is prone to competitive reaction with the amino group, resulting in the complication of subsequent processes; in the hypohalous acid catalysis method, the hydrochloric acid generated by the reaction will inhibit the reaction process; although the iodine catalysis method has the advantage of recycling, its industrial-scale use is likely to cause an environmental burden; in the sulfonyl chloride method, hydrolysis is likely to occur during the reaction, generating hydrochloric acid and sulfuric acid, which not only reduces the reaction efficiency but also increases the equipment anti-corrosion requirements and treatment costs.

[0004] The invention patent with the publication number CN101492387B discloses a preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide, which uses sulfonyl chloride as the chlorine source and controls the reaction conditions through an ice-water bath to inhibit the generation of by-products. However, problems such as equipment corrosion and high energy consumption still exist in the industrialization process, and there is an urgent need to develop a new type of green process.

[0005] In recent years, the green catalytic technology catalyzed by organic bases has been widely used in the organic synthesis industry, and among them, the triethylamine catalytic synthesis technology has become a research hotspot. Based on this, the present invention develops a new catalytic system for the synthesis of the target product 2-amino-5-chloro-N,3-dimethylbenzamide. Summary of the Invention

[0006] To solve the defects existing in the prior art, the present invention provides a production process of 2-amino-5-chloro-N,3-dimethylbenzamide. The raw materials of 2-amino-N,3-dimethylbenzamide in the present invention are easily available and have a low price. The yield of 2-amino-5-chloro-N,3-dimethylbenzamide is high, and the preparation process is green and environmentally friendly.

[0007] To solve the above technical problems, the present invention provides the following technical solutions:

[0008] The present invention provides a production process of 2-amino-5-chloro-N,3-dimethylbenzamide, and the preparation route of the 2-amino-5-chloro-N,3-dimethylbenzamide is as follows:

[0009]

[0010] The preparation process of the 2-amino-5-chloro-N,3-dimethylbenzamide includes the following steps:

[0011] Using 2-amino-N,3-dimethylbenzamide as the starting material, triethylamine as the co-catalyst, 10-Cl-9-acridone as the chlorinating reagent, 1-butyl-3-methyl-1H-imidazol-3-ium tetrachloroferrate as the catalyst, and adding a reaction solvent, the chlorination reaction of 2-amino-N,3-dimethylbenzamide and 10-Cl-9-acridone is carried out. After the reaction is completed, the reaction mixture is extracted and separated, and the organic phases are combined and concentrated under reduced pressure to obtain a crude product. The crude product is rectified to obtain 2-amino-5-chloro-N,3-dimethylbenzamide.

[0012] Preferably, the preparation process of the 10-Cl-9-acridone is as follows:

[0013] Taking acridone and anhydrous dichloromethane as the solvent, cooling it to 0 °C in an ice bath; slowly dropping tert-butyl hypochlorite while continuously stirring, and at the same time keeping the reaction temperature not exceeding 5 °C; after the dropping is completed, removing the reaction system from the ice bath and continuing to stir the reaction at room temperature for 4 hours; after the reaction is completed, adding saturated sodium bicarbonate solution for quenching, and extracting the organic phase with dichloromethane; after combining the organic phases, drying them successively with saturated brine and anhydrous sodium sulfate, filtering, and distilling off the solvent under reduced pressure; separating and purifying the crude product to obtain light yellow solid 10-Cl-9-acridone.

[0014] Preferably, the molar ratio of acridone to tert-butyl hypochlorite is 1:1.5 - 2.

[0015] Preferably, the preparation process of the 1-butyl-3-methyl-1H-imidazol-3-ium tetrachloroferrate is as follows:

[0016] Refluxing 1-methylimidazole and 1-chlorobutane in ethyl acetate solvent for 24 hours to obtain 1-butyl-3-methylimidazole chloride; then stirring anhydrous ferric chloride and 1-butyl-3-methylimidazole chloride in ethanol solution at room temperature for 4 hours, and the solution gradually changes from light yellow to dark red-brown during the reaction; after the reaction is completed, rotary evaporating the solvent, and recrystallizing the obtained product with dichloromethane to finally obtain 1-butyl-3-methyl-1H-imidazol-3-ium tetrachloroferrate.

[0017] Preferably, the molar ratio of 1-methylimidazole, 1-chlorobutane, and anhydrous iron(III) chloride is 1:1:1.

[0018] Preferably, the amount of the reaction solvent is 1 L of solvent per kilogram of 2-amino-N,3-dimethylbenzamide.

[0019] Preferably, the mass of 1-butyl-3-methyl-1H-imidazol-3-ium tetrachloroferrate(III) is 0.1 - 0.15 times that of 2-amino-N,3-dimethylbenzamide.

[0020] Preferably, the mass of triethylamine is 0.1 - 0.2 times that of 2-amino-N,3-dimethylbenzamide.

[0021] Preferably, the mass of 10-Cl-9-acridone is 1.0 - 1.5 times that of 2-amino-N,3-dimethylbenzamide.

[0022] Preferably, the reaction solvent is anhydrous acetonitrile.

[0023] The present invention has the following beneficial effects compared with the prior art:

[0024] (1) The present invention uses 1-butyl-3-methyl-1H-imidazol-3-ium tetrachloroferrate(III) as a catalyst, which can significantly improve the catalytic efficiency of the chlorination reaction. Compared with traditional catalysts, the reaction time is greatly shortened. At the same time, this catalyst can achieve efficient catalysis at lower temperatures and milder conditions, resulting in a significantly increased yield of 2-amino-5-chloro-N,3-dimethylbenzamide, reaching over 90%. This beneficial effect helps to reduce energy consumption and costs, and improve the economic efficiency of industrial production.

[0025] (2) The 1-butyl-3-methyl-1H-imidazol-3-ium tetrachloroferrate(III) catalyst in the present invention also has good chemoselectivity, which can effectively inhibit the occurrence of side reactions and improve the purity of the target product, 2-amino-5-chloro-N,3-dimethylbenzamide. At the same time, the reaction conditions of this catalyst are easy to control, and it can optimize the chlorination reaction parameters for different substrates and reaction systems, thus achieving a highly selective and highly controllable synthesis process, further improving the product quality and consistency.

[0026] (3) The present invention uses 10-chloro-9-acridone to replace traditional chlorine sources (such as liquid chlorine, hydrochloric acid, sulfonyl chloride, etc.), which is not only environmentally friendly but also has high economic benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0027] Figure 1 is a comparative schematic diagram of the chlorination reaction results of different chlorinating reagents and catalysts of the present invention. DETAILED DESCRIPTION OF THE INVENTION

[0028] The preferred embodiments of the present invention will be described below in conjunction with the accompanying drawings. It should be understood that the preferred embodiments described herein are only for illustrating and explaining the present invention, and are not used to limit the present invention.

[0029] Example 1: Process steps for the production of 10-Cl-9-acridone.

[0030] Add 10 mmol of acridone and 50 mL of anhydrous dichloromethane as a solvent into a dry 250 mL three-necked flask, and cool it to 0 °C in an ice bath. Slowly add dropwise 12 mmol of tert-butyl hypochlorite while continuously stirring, and at the same time keep the reaction temperature not exceeding 5 °C. After the addition is complete, remove the reaction system from the ice bath and continue to stir the reaction at room temperature for 4 hours. After the reaction is completed, add 20 mL of saturated sodium bicarbonate solution for quenching, and extract the organic phase with dichloromethane (3 × 30 mL). After combining the organic phases, dry them successively with saturated brine and anhydrous sodium sulfate, filter, and remove the solvent by rotary evaporation under reduced pressure. The crude product is separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate, volume ratio 10:1) to obtain 10-Cl-9-acridone (yield 92%).

[0031] Example 2: Process steps for the production of 1-butyl-3-methyl-1H-imidazol-3-ium tetrachloroferrate.

[0032] Reflux 1-methylimidazole and 1-chlorobutane in ethyl acetate solvent for 24 hours to obtain 1-butyl-3-methylimidazole chloride; then stir 1-butyl-3-methylimidazole chloride and anhydrous ferric chloride in ethanol solution at room temperature for 4 hours, and the solution gradually changes from light yellow to dark red-brown during the reaction. After the reaction is completed, remove the solvent by rotary evaporation, and recrystallize the obtained product with dichloromethane to finally obtain 1-butyl-3-methyl-1H-imidazol-3-ium tetrachloroferrate (yield 96%).

[0033] Example 3: Process steps for the production of 2-amino-5-chloro-N,3-dimethylbenzamide.

[0034] In a 1 L round-bottom flask, 3-amino-N,3-dimethylbenzamide (0.5 kg), 1-butyl-3-methyl-1H-imidazol-3-ium tetrachloroferrate (0.5 kg, catalyst), triethylamine (0.5 kg, acid scavenger), 10-chloro-9-acridone (0.6 kg, chlorinating reagent), and 0.5 L of anhydrous acetonitrile as the reaction solvent were added in sequence. After stirring and mixing evenly at room temperature, the reaction was continued with stirring for 2 hours, and samples were taken regularly to detect the reaction progress (HPLC). After the reaction was completed, the solvent was removed by reduced pressure concentration to obtain the crude product. After purification by distillation, 2-amino-5-chloro-N,3-dimethylbenzamide was finally obtained with a yield of 93.0% and a purity of 99.3% (purity detected by HPLC).

[0035] Example 4: Process steps for the production of 2-amino-5-chloro-N,3-dimethylbenzamide.

[0036] In a 10 L round-bottom flask, 3-amino-N,3-dimethylbenzamide (5 kg), 1-butyl-3-methyl-1H-imidazol-3-ium tetrachloroferrate (5 kg, catalyst), triethylamine (5 kg, acid scavenger), 10-chloro-9-acridone (6 kg, chlorinating reagent), and 5 L of anhydrous acetonitrile as the reaction solvent were added in sequence. After stirring and mixing evenly at room temperature, the reaction was continued with stirring for 2 hours, and samples were taken regularly to detect the reaction progress (HPLC). After the reaction was completed, the solvent was removed by reduced pressure concentration to obtain the crude product. After purification by distillation, 2-amino-5-chloro-N,3-dimethylbenzamide was finally obtained with a yield of 90.2% and a purity of 99.3% (purity detected by HPLC).

[0037] Subsequently, a systematic investigation was carried out on the chlorination reaction of a series of chlorinating reagents, catalysts with 2-amino-N,3-dimethylbenzamide. The reaction products were qualitatively and quantitatively analyzed by gas chromatography. The experimental results showed that there were significant differences in the reaction activity, selectivity and yield of different chlorinating reagents. The specific experimental data and reaction conditions are shown in Table 1 and Figure 1 as follows.

[0038] Table 1: Chlorination reaction results of different chlorinating reagents and catalysts.

[0039]

[0040]

[0041] Based on the comprehensive analysis of the above experimental results, the following conclusions are drawn: The catalytic system of 1-butyl-3-methyl-1H-imidazol-3-ium tetrachloroferrate and triethylamine (TEA) exhibits excellent chemoselectivity and regioselectivity. This reaction not only shows a high atom economy, but also has a simple operation for product separation and purification. It is worth noting that in a series of control experiments, the catalytic system adopted in this application is superior to the traditional methods in terms of reaction activity and selectivity. The present invention uses 10-chloro-9-acridone to replace the traditional chlorine sources (such as liquid chlorine, hydrochloric acid, sulfonyl chloride, etc.), which is not only environmentally friendly but also has high economic benefits. In addition, the catalytic effect of 1-butyl-3-methyl-1H-imidazol-3-ium tetrachloroferrate significantly improves the regioselectivity of the reaction and effectively inhibits the occurrence of side reactions. This process has the characteristics of simple operation, high atom economy, and environmental friendliness, which conforms to the development concept of green chemistry.

[0042] Finally, it should be noted that the above are only the preferred embodiments of the present invention and are not intended to limit the present invention. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments, or perform equivalent replacements for some of the technical features. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A process for producing 2-amino-5-chloro-N,3-dimethylbenzamide, characterized in that: The preparation route of the 2-amino-5-chloro-N,3-dimethylbenzamide is as follows: The preparation process of the 2-amino-5-chloro-N,3-dimethylbenzamide comprises the following steps: With 2-amino-N,3-dimethylbenzamide as a starting material, triethylamine as a co-catalyst, 10-Cl-9-acridone as a chlorination reagent, 1-butyl-3-methyl-1H-imidazol-3-ium tetrachloroferrate as a catalyst, and a reaction solvent added, 2-amino-N,3-dimethylbenzamide and 10-Cl-9-acridone undergo a chlorination reaction, after the reaction is completed, the reaction mixture is extracted and separated, the organic phases are combined and concentrated under reduced pressure to obtain a crude product, and the crude product is distilled to obtain 2-amino-5-chloro-N,3-dimethylbenzamide.

2. The production process of 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The preparation process of the 10-Cl-9-acridone is as follows: Acridone and anhydrous dichloromethane were used as solvents and placed in an ice bath to cool to 0°C; tert-butyl hypochlorite was added dropwise with continuous stirring while maintaining the reaction temperature not exceeding 5°C; after the addition was completed, the reaction system was removed from the ice bath and continued to react at room temperature with stirring for 4 hours; after the reaction was completed, a saturated sodium bicarbonate solution was added for quenching, and the organic phase was extracted with dichloromethane; the organic phases were combined, dried with saturated brine and anhydrous sodium sulfate in turn, filtered, and the solvent was removed by distillation under reduced pressure; the crude product was separated and purified to obtain a light yellow solid 10-Cl-9-acridone.

3. The production process of 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 2, characterized in that: The molar ratio of the acridone to tert-butyl hypochlorite is 1:1.5-2.

4. The production process of 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The preparation process of the 1-butyl-3-methyl-1H-imidazol-3-ium tetrachloroferrate is as follows: 1-Methylimidazole and 1-chlorobutane are refluxed in an ethyl acetate solvent for 24 hours to obtain 1-butyl-3-methylimidazole chloride; then anhydrous ferric chloride and 1-butyl-3-methylimidazole chloride are stirred in an ethanol solution at room temperature for 4 hours, and the solution gradually changes from light yellow to dark red brown during the reaction; after the reaction is completed, the solvent is removed by rotary evaporation, and the obtained product is recrystallized with dichloromethane to finally obtain 1-butyl-3-methyl-1H-imidazole-3-ium tetrachloroferrate.

5. The production process of 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 4, characterized in that: The molar ratio of the 1-methylimidazole, 1-chlorobutane and anhydrous ferric chloride is 1:1:

1.

6. The production process of 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The amount of the reaction solvent is 1 L per kilogram of 2-amino-N,3-dimethylbenzamide.

7. The production process of 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The mass of the 1-butyl-3-methyl-1H-imidazol-3-ium tetrachloroferrate is 0.1 to 0.15 times that of 2-amino-N,3-dimethylbenzamide.

8. The production process of 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The mass of the triethylamine is 0.1 to 0.2 times that of 2-amino-N,3-dimethylbenzamide.

9. The process for producing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The mass of the 10-Cl-9-acridone is 1.0 to 1.5 times that of 2-amino-N,3-dimethylbenzamide.

10. The process for producing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The reaction solvent is anhydrous acetonitrile.

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