Process for producing 2-amino-5-chloro-n,3-dimethylbenzamide

Abstract

Disclosed in the present invention is a process for producing 2-amino-5-chloro-N,3-dimethylbenzamide. Regioselective chlorination at the 5-position of a benzene ring is achieved by using 2-amino-N,3-dimethylbenzamide as a starting material, 10-Cl-9-acridone as a chlorinating agent and 1-butyl-3-methyl-1H-imidazol-3-ium tetrachloroferrate as a catalyst. By systematically optimizing reaction parameters including key factors such as the reaction temperature, the reaction time and the stoichiometric ratio of reagents, the technical problems of excessive chlorination, by-product formation, etc., in a traditional synthesis route are successfully solved. Under optimal conditions, the isolated yield of the target product is stably maintained at 90% or higher, and the process has the significant characteristics of mild reaction conditions, being simple and convenient to operate, etc. The process of the present invention involves a simple process flow, requires no special reaction devices, and can significantly reduce production costs.

Description

A process for producing 2-amino-5-chloro-N,3-dimethylbenzamide Technical Field

[0001] This invention belongs to the field of fine chemical technology, specifically relating to a production process for 2-amino-5-chloro-N,3-dimethylbenzamide. Background Technology

[0002] 2-Amino-5-chloro-N,3-dimethylbenzamide, a key intermediate in the production of chlorantraniliprole, plays a vital role in the pesticide industry. However, with increasingly stringent industry standards, the production processes of chlorantraniliprole intermediates and o-formamide series products face numerous challenges. Therefore, developing clean and efficient production processes to increase yield and reduce energy consumption has become an urgent technical challenge.

[0003] Traditional synthetic routes mainly involve hydrogenation, cyclization, aminolysis, and chlorination. Among these, the chlorination step is crucial for the synthesis of 2-amino-5-chloro-N,3-dimethylbenzamide. Existing processes primarily include the hydrogen peroxide method, hypohalous acid catalysis, iodine catalysis, and sulfonyl chloride method. The hydrogen peroxide method uses hydrochloric acid as the chlorine source, and the protic acid readily competes with the amino group, complicating subsequent steps. In the hypohalous acid catalysis method, the hydrochloric acid produced inhibits the reaction process. While the iodine catalysis method offers the advantage of recycling, its industrial-scale application can create an environmental burden. The sulfonyl chloride method is prone to hydrolysis during the reaction, producing hydrochloric acid and sulfuric acid, which not only reduces reaction efficiency but also increases equipment corrosion requirements and processing costs.

[0004] The invention patent with publication number CN101492387B discloses a method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide, using sulfonyl chloride as the chlorine source and controlling the reaction conditions through an ice-water bath to suppress the formation of byproducts. However, the industrialization process still faces problems such as equipment corrosion and high energy consumption, necessitating the development of new green processes.

[0005] In recent years, green catalytic technologies based on organic bases have been widely used in the organic synthesis industry, among which the triethylamine catalytic synthesis technology has become a research hotspot. Based on this, this invention develops a novel catalytic system for the synthesis of 2-amino-5-chloro-N,3-dimethylbenzamide from the target product. Summary of the Invention

[0006] To address the shortcomings of existing technologies, this invention provides a process for producing 2-amino-5-chloro-N,3-dimethylbenzamide. The 2-amino-N,3-dimethylbenzamide raw material used in this invention is readily available and inexpensive, 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-mentioned technical problems, the present invention provides the following technical solution:

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

[0009] The preparation process of the 2-amino-5-chloro-N,3-dimethylbenzamide includes the following steps:

[0010] Using 2-amino-N,3-dimethylbenzamide as the starting material, triethylamine as a co-catalyst, 10-Cl-9-acridone as a chlorinating agent, 1-butyl-3-methyl-1H-imidazolium-3-onium tetrachloroferrate as a catalyst, and a reaction solvent, 2-amino-N,3-dimethylbenzamide and 10-Cl-9-acridone underwent a chlorination reaction. After the reaction was completed, the reaction mixture was extracted and separated, and the combined organic phases were concentrated under reduced pressure to obtain a crude product. The crude product was then distilled to obtain 2-amino-5-chloro-N,3-dimethylbenzamide.

[0011] Preferably, the preparation process of the 10-Cl-9-acridone is as follows:

[0012] Acridinone and anhydrous dichloromethane were used as solvents and cooled to 0°C in an ice bath. Tert-butyl hypochlorite was added dropwise with constant stirring, while maintaining the reaction temperature below 5°C. After the addition was complete, the reaction system was removed from the ice bath and stirred at room temperature for 4 hours. After the reaction was completed, saturated sodium bicarbonate solution was added for quenching, and the organic phase was extracted with dichloromethane. The organic phases were combined and dried successively with saturated brine and anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was separated and purified to obtain a pale yellow solid, 10-Cl-9-acridone.

[0013] Preferably, the molar ratio of acridinone to tert-butyl hypochlorite is 1:1.5 to 2.

[0014] Preferably, the preparation process of the 1-butyl-3-methyl-1H-imidazolium-3-onium tetrachloroferrate is as follows:

[0015] 1-Methylimidazolium and 1-chlorobutane were refluxed in ethyl acetate for 24 hours to obtain 1-butyl-3-methylimidazolium chloride. Subsequently, anhydrous ferric chloride and 1-butyl-3-methylimidazolium chloride were reacted in ethanol solution at room temperature with stirring for 4 hours. During the reaction, the solution gradually changed from light yellow to dark reddish-brown. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was recrystallized from dichloromethane to finally obtain 1-butyl-3-methyl-1H-imidazolium-3-onium tetrachloroferrate.

[0016] Preferably, the molar ratio of 1-methylimidazole, 1-chlorobutane, and anhydrous ferric chloride is 1:1:1.

[0017] Preferably, the amount of the reaction solvent is 1 L per kilogram of 2-amino-N,3-dimethylbenzamide.

[0018] Preferably, the mass of the 1-butyl-3-methyl-1H-imidazolium-3-onium tetrachloroferrate is 0.1 to 0.15 times that of 2-amino-N,3-dimethylbenzamide.

[0019] Preferably, the mass of the triethylamine is 0.1 to 0.2 times that of 2-amino-N,3-dimethylbenzamide.

[0020] Preferably, the mass of the 10-Cl-9-acridone is 1.0 to 1.5 times that of 2-amino-N,3-dimethylbenzamide.

[0021] Preferably, the reaction solvent is anhydrous acetonitrile.

[0022] Compared with the prior art, the present invention has the following beneficial effects:

[0023] (1) This invention uses 1-butyl-3-methyl-1H-imidazolium-3-onium tetrachloroferrate as a catalyst, which can significantly improve the catalytic efficiency of the chlorination reaction and greatly shorten the reaction time compared with traditional catalysts. Simultaneously, this catalyst achieves high-efficiency catalysis at lower temperatures and under milder conditions, significantly increasing the yield of 2-amino-5-chloro-N,3-dimethylbenzamide to over 90%. This gain helps reduce energy consumption and costs, improving the economics of industrial production.

[0024] (2) The 1-butyl-3-methyl-1H-imidazolium-3-onium tetrachloroferrate catalyst in this invention also exhibits good chemoselectivity, effectively suppressing side reactions and improving the purity of the target product 2-amino-5-chloro-N,3-dimethylbenzamide. Furthermore, the reaction conditions of this catalyst are easily controlled, allowing for optimization of chlorination reaction parameters for different substrates and reaction systems, thereby achieving a highly selective and controllable synthesis process and further improving product quality and consistency.

[0025] (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. Attached Figure Description

[0026] Figure 1 is a schematic diagram comparing the chlorination reaction results of different chlorination reagents and catalysts of the present invention. Detailed Implementation

[0027] The preferred embodiments of the present invention will be described below with reference to the accompanying drawings. It should be understood that the preferred embodiments described herein are for illustration and explanation only and are not intended to limit the present invention.

[0028] Example 1: Production process steps of 10-Cl-9-acridone.

[0029] 10 mmol of acridinone and 50 mL of anhydrous dichloromethane were added to a dry 250 mL three-necked flask as solvents, and the mixture was cooled to 0 °C in an ice bath. 12 mmol of tert-butyl hypochlorite was added dropwise with constant stirring, while maintaining the reaction temperature below 5 °C. After the addition was complete, the reaction mixture was removed from the ice bath and stirred at room temperature for 4 hours. After the reaction was complete, 20 mL of saturated sodium bicarbonate solution was added for quenching, and the organic phase was extracted with dichloromethane (3 × 30 mL). The organic phases were combined, dried successively with saturated brine and anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v 10:1) to give 110-Cl-9-acridone (yield 92%).

[0030] Example 2: Production process steps of 1-butyl-3-methyl-1H-imidazol-3-onium tetrachloroferrate.

[0031] 1-Methylimidazolium was refluxed with 1-chlorobutane in ethyl acetate for 24 hours to give 1-butyl-3-methylimidazolium chloride. Subsequently, anhydrous ferric chloride was reacted with 1-butyl-3-methylimidazolium chloride in ethanol solution at room temperature with stirring for 4 hours. During the reaction, the solution gradually changed from light yellow to dark reddish-brown. After the reaction was complete, the solvent was removed by rotary evaporation, and the product was recrystallized from dichloromethane to finally give 1-butyl-3-methyl-1H-imidazolium-3-onium tetrachloroferrate (yield 96%).

[0032] Example 3: Production process steps of 2-amino-5-chloro-N,3-dimethylbenzamide.

[0033] In a 1L round-bottom flask, 0.5 kg of 3-amino-N,3-dimethylbenzamide, 0.5 kg of 1-butyl-3-methyl-1H-imidazolium-3-onium tetrachloroferrate (catalyst), 0.5 kg of triethylamine (acid scavenger), 0.6 kg of 10-chloro-9-acridone (chlorinating agent), and 0.5 L of anhydrous acetonitrile were added sequentially as the reaction solvent. After thorough mixing at room temperature, the mixture was stirred for another 2 hours, with periodic sampling to monitor the reaction progress (HPLC). After the reaction was complete, the solvent was removed by concentration under reduced pressure to obtain the crude product. The crude product was purified by distillation to finally obtain 2-amino-5-chloro-N,3-dimethylbenzamide, with a yield of 93.0% and a purity of 99.3% (purity determined by HPLC).

[0034] Example 4: Production process steps of 2-amino-5-chloro-N,3-dimethylbenzamide.

[0035] In a 10L round-bottom flask, 5 kg of 3-amino-N,3-dimethylbenzamide, 5 kg of 1-butyl-3-methyl-1H-imidazolium-3-onium tetrachloroferrate (catalyst), 5 kg of triethylamine (acid scavenger), 6 kg of 10-chloro-9-acridone (chlorination reagent), and 5 L of anhydrous acetonitrile were added sequentially as the reaction solvent. After thorough mixing at room temperature, the mixture was stirred and reacted for 2 hours, with periodic sampling to monitor the reaction progress (HPLC). After the reaction was complete, the solvent was removed by concentration under reduced pressure to obtain the crude product. The crude product was purified by distillation to finally obtain 2-amino-5-chloro-N,3-dimethylbenzamide, with a yield of 90.2% and a purity of 99.3% (purity determined by HPLC).

[0036] The chlorination reactions of 2-amino-N,3-dimethylbenzamide with a series of chlorinating reagents and catalysts were then systematically investigated. The reaction products were qualitatively and quantitatively analyzed by gas chromatography. The experimental results showed significant differences in reactivity, selectivity, and yield among different chlorinating reagents. Specific experimental data and reaction conditions are shown in Table 1 and Figure 1.

[0037] Table 1: Chlorination reaction results with different chlorination reagents and catalysts.

[0038] Based on the comprehensive analysis of the above experimental results, the following conclusions are drawn: the catalytic system of 1-butyl-3-methyl-1H-imidazolium-3-onium tetrachloroferrate with triethylamine (TEA) exhibits excellent chemoselectivity and regioselectivity. This reaction not only demonstrates high atom economy but also offers simple product separation and purification. Notably, in a series of control experiments, the catalytic system used in this application outperformed traditional methods in both reaction activity and selectivity. This 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 highly economical. Furthermore, the catalytic effect of 1-butyl-3-methyl-1H-imidazolium-3-onium tetrachloroferrate significantly improves the regioselectivity of the reaction and effectively suppresses the occurrence of side reactions. This process is characterized by its simplicity, high atom economy, and environmental friendliness, aligning with the development concept of green chemistry.

[0039] Finally, it should be noted that the above descriptions are merely 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 make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within 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 includes the following steps: Using 2-amino-N,3-dimethylbenzamide as the starting material, triethylamine as a co-catalyst, 10-Cl-9-acridone as a chlorinating agent, 1-butyl-3-methyl-1H-imidazolium-3-onium tetrachloroferrate as a catalyst, and a reaction solvent, 2-amino-N,3-dimethylbenzamide and 10-Cl-9-acridone underwent a chlorination reaction. After the reaction was completed, the reaction mixture was extracted and separated, and the combined organic phases were concentrated under reduced pressure to obtain a crude product. The crude product was then distilled to obtain 2-amino-5-chloro-N,3-dimethylbenzamide.

2. The process for the production 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: Acridinone and anhydrous dichloromethane were used as solvents and cooled to 0°C in an ice bath. Tert-butyl hypochlorite was added dropwise with constant stirring, while maintaining the reaction temperature below 5°C. After the addition was complete, the reaction system was removed from the ice bath and stirred at room temperature for 4 hours. After the reaction was completed, saturated sodium bicarbonate solution was added for quenching, and the organic phase was extracted with dichloromethane. The organic phases were combined and dried successively with saturated brine and anhydrous sodium sulfate, filtered, and the solvent was removed by vacuum distillation. The crude product was separated and purified to obtain a pale yellow solid, 10-Cl-9-acridone.

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

4. The process for the production 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-imidazolium-3-onium tetrachloroferrate is as follows: 1-Methylimidazolium and 1-chlorobutane were refluxed in ethyl acetate for 24 hours to obtain 1-butyl-3-methylimidazolium chloride. Subsequently, anhydrous ferric chloride and 1-butyl-3-methylimidazolium chloride were reacted in ethanol solution at room temperature with stirring for 4 hours. During the reaction, the solution gradually changed from light yellow to dark reddish-brown. After the reaction was completed, the solvent was removed by rotary evaporation, and the product was recrystallized from dichloromethane to finally obtain 1-butyl-3-methyl-1H-imidazolium-3-onium tetrachloroferrate.

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

1.

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

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

8. The process for the production 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 the production of 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 production process of 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that, The reaction solvent is anhydrous acetonitrile.

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