A preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide

Abstract

The present invention discloses a preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide, belonging to the technical field of organic synthesis. Specifically, o-toluidine is used as a raw material, and after chlorination, Friedel-Crafts acylation, oxidative ring opening and formamidation, 2-amino-5-chloro-N,3-dimethylbenzamide is obtained. The method of the present invention has easily available raw materials, simple process operation, mild reaction conditions, high product yield and less three-waste emissions, and is suitable for industrial production.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide. Background Art

[0002] Chlorantraniliprole is an amide insecticide developed by DuPont. It is safe for mammals and exhibits characteristics such as high efficiency, broad spectrum, and novel action mechanism, having broad market space and prospects. 2-Amino-5-chloro-N,3-dimethylbenzamide, with the structural formula , abbreviated as K amine, is a key intermediate for the synthesis of chlorantraniliprole.

[0003] Currently, the synthesis of 2-amino-5-chloro-N,3-dimethylbenzamide mainly includes the following routes:

[0004] Route 1:

[0005]

[0006] Patent CN202210355074 reports that using o-toluidine as a raw material, through reaction with trichloroacetaldehyde and hydroxylamine hydrochloride, and then using concentrated sulfuric acid for ring closure to prepare 7-methylisatin, followed by oxidative ring opening under the action of sodium hydroxide and hydrogen peroxide, and finally carrying out chlorination and formamidation reactions to prepare 2-amino-5-chloro-N,3-dimethylbenzamide. This synthesis route has problems such as high raw material cost of trichloroacetaldehyde, low yield of the ring closure reaction using concentrated sulfuric acid, and a large amount of waste salt, making it difficult to scale up production in actual industry.

[0007] Route 2:

[0008]

[0009] Patent CN111517975A reports that using m-methylbenzoic acid as a raw material, through nitration, reduction, chlorination, and formamidation to obtain 2-amino-5-chloro-N,3-dimethylbenzamide. Although this process seems to have a shorter route, the selectivity of the nitration reaction is relatively low, resulting in a reaction yield of about 35% for the entire process. Moreover, there are potential production safety hazards during the hydrogenation reduction process, and there are also uncertain factors in industrial production.

[0010] Patent CN101492387B discloses the production process of 2-amino-5-chloro-N,3-dimethylbenzamide. Methyl 3-methyl-2-nitrobenzoate and methylamine are heated and reacted in a lower alcohol to obtain 3-methyl-2-nitrobenzamide, and then it is heated and reacted with iron powder and acid in water to obtain 3-methyl-2-aminobenzamide. In the chlorination step, sulfonyl chloride is selected as the chlorine source to prepare 2-amino-5-chloro-N,3-dimethylbenzamide. However, the reaction uses catalysts such as iron powder, resulting in a large amount of solid waste. Regarding the chlorination step patent (CN110845341A), it also mentions that dilute hydrochloric acid reacts with hydrogen peroxide to obtain the electrophilic reagent chloride ion, and then an electrophilic reaction occurs to obtain the chlorinated product. The introduction of hydrochloric acid requires higher requirements for production equipment, and the reaction route is not suitable for large-scale production. Therefore, exploring and developing an economically feasible and safe production process route for 2-amino-5-chloro-N,3-dimethylbenzamide is of great significance for the industrial production of chlorantraniliprole in China. Summary of the Invention

[0011] To solve the above problems, the purpose of the present invention is to provide a preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide. The method has mild reaction conditions, a simple operation process, and a high reaction yield.

[0012] To achieve the above object, the present invention is realized through the following technical solutions:

[0013] A preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide, the synthesis route is as follows:

[0014] 。

[0015] The preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide includes the following steps:

[0016] 1) At 20 - 50 °C, o-toluidine and hydrochloric acid are added to a reactor and mixed evenly. Hydrogen peroxide 1 is added dropwise thereto. After the addition of hydrogen peroxide 1 is completed, the reaction continues. The reaction process is tracked by liquid phase. After the o-toluidine reaction is complete, the reaction is terminated. The obtained reaction solution is extracted with organic solvent 1, the organic phase is separated out, anhydrous sodium sulfate is added thereto to remove the residual moisture in the organic phase, filtered, and the obtained filtrate is distilled under reduced pressure to remove the solvent to obtain 2-methyl-4-chloro-aniline;

[0017] The molar ratio of the o-toluidine, hydrochloric acid, and hydrogen peroxide 1 is 1:1 - 10:1 - 5;

[0018] The mass concentration of the hydrochloric acid is 10 - 30%;

[0019] The mass concentration of the hydrogen peroxide 1 is 10 - 30%;

[0020] The organic solvent 1 is one or a combination of two of dichloromethane, ethyl acetate, and toluene;

[0021] The mass ratio of the organic solvent 1 to o-toluidine is 3 - 5:1;

[0022] The dropping rate of the hydrogen peroxide 1 is 7 - 35 g / min;

[0023] 2) Dissolve the 2-methyl-4-chloroaniline prepared in step 1) in an organic solvent 2, and dropwise add oxalyl chloride thereto, controlling the temperature during the dropping process to be 0 - 10°C. After the dropping is completed, add a catalyst, and raise the temperature to 10 - 80°C to continue the reaction. Track the reaction process by liquid phase. After the 2-methyl-4-chloroaniline reacts completely, end the reaction to obtain a reaction solution. Add the obtained reaction solution to ice water containing hydrochloric acid for quenching, separate the organic phase, add anhydrous sodium sulfate thereto to remove the residual moisture in the organic phase, filter, and distill the obtained filtrate under reduced pressure to remove the solvent to obtain 5-chloro-7-methylisatin;

[0024] The molar ratio of the 2-methyl-4-chloroaniline, oxalyl chloride, and the catalyst is 1:1 - 1.2:0.0001 - 0.005;

[0025] The dropping rate of the oxalyl chloride is 2.5 - 5 g / min;

[0026] The organic solvent 2 is dichloromethane, dichloroethane, toluene, or ethyl acetate;

[0027] The mass ratio of the organic solvent 2, the ice water containing hydrochloric acid, and the 2-methyl-4-chloroaniline is 2 - 3:5 - 10:1;

[0028] The catalyst is one or a combination of two of aluminum trichloride, stannic chloride, ferric chloride, and polyphosphoric acid;

[0029] The mass concentration of hydrochloric acid in the ice water containing hydrochloric acid is 0.1 - 5%;

[0030] 3) Add the 5-chloro-7-methylisatin obtained in step 2) into an aqueous sodium hydroxide solution. After stirring and dissolving it at 20~50°C, add hydrogen peroxide 2 dropwise thereto, control the temperature of the reaction system at 50~70°C, track the reaction process by liquid phase. After the reaction of 5-chloro-7-methylisatin is complete, end the reaction to obtain a reaction solution. Adjust the pH of the reaction solution to 2~5 with 0.5~5% hydrochloric acid, filter, wash the obtained filter cake with ice water, and dry it to obtain 5-chloro-2-amino-3-methyl-benzoic acid. Add the obtained 5-chloro-2-amino-3-methyl-benzoic acid and thionyl chloride into a reactor, stir and mix them evenly, then heat to 50~100°C for reaction, track the reaction process by liquid phase. After the reaction of 5-chloro-2-amino-3-methyl-benzoic acid is complete, end the reaction to obtain a reaction solution. Distill off thionyl chloride in the reaction solution under reduced pressure. Add an organic solution of methylamine dropwise to the obtained residue. After the addition is complete, distill off the solvent under reduced pressure to obtain 2-amino-5-chloro-N,3-dimethylbenzamide;

[0031] The mass concentration of the aqueous sodium hydroxide solution is 5~20%;

[0032] The mass concentration of the hydrogen peroxide 2 is 10~30%;

[0033] The dropping rate of the hydrogen peroxide 2 is 2.5~12 g / min;

[0034] The molar ratio of 5-chloro-7-methylisatin, sodium hydroxide and hydrogen peroxide 2 is 1:1~10:1~5;

[0035] The molar ratio of 5-chloro-2-amino-3-methyl-benzoic acid, thionyl chloride and methylamine is 1:1~5:1~1.2;

[0036] A drying tube is added to the reactor, and the reduced pressure drying temperature is 10~30°C;

[0037] The organic solution of methylamine is obtained by mixing methylamine and organic solvent 3 in a mass ratio of 1:1~5, where the organic solvent 3 is one or a combination of two of dichloromethane, dichloroethane, dioxane and tetrahydrofuran;

[0038] The dropping rate of the organic solution of methylamine is 1~2 g / min.

[0039] Preferably, in step 1), the reaction temperature is 20~30°C, the molar ratio of o-toluidine, hydrochloric acid and hydrogen peroxide 1 is 1:2~5:1~3, the mass concentration of the hydrochloric acid is 10~20%, and the mass concentration of the hydrogen peroxide 1 is 10~20%.

[0040] Preferably, in step 1), the dropping rate of the hydrogen peroxide 1 is 15 g / min, and the organic solvent 1 is dichloromethane.

[0041] Preferably, in step (2), the temperature during the dropping process is 0-5°C, the organic solvent 2 is dichloroethane, and the dropping rate of oxalyl chloride is 3.5 g / min.

[0042] Preferably, the catalyst in step (2) is aluminum trichloride, tin tetrachloride or polyphosphoric acid, and the molar ratio of 2-methyl-4-chloroaniline to the catalyst is 1:0.0005-0.002; the temperature for heating up is 50-80°C, and the mass concentration of hydrochloric acid in the ice water containing hydrochloric acid is 0.1-1%.

[0043] Preferably, in step (3), the temperature for stirring and dissolving is 20-30°C, the mass concentration of the sodium hydroxide aqueous solution is 5-15%, the mass concentration of hydrogen peroxide 2 is 10-20%, and the dropping rate of hydrogen peroxide 2 is 7.5 g / min.

[0044] Preferably, in step (3), the reaction system is controlled at 50-60°C, the molar ratio of 5-chloro-7-methylisatin, sodium hydroxide and hydrogen peroxide 2 is 1:1-5:1-2, the mass concentration of hydrochloric acid is 0.5-2%, and the pH of the reaction solution is adjusted to 3-5.

[0045] Preferably, in step (3), the heating temperature is 50-80°C, the molar ratio of 5-chloro-2-amino-3-methylbenzoic acid to thionyl chloride is 1:1-2, the temperature for drying under reduced pressure is 10-20°C, the organic solution of methylamine is obtained by mixing methylamine and organic solvent 3 in a mass ratio of 1:1-3, where the organic solvent 3 is one or a combination of two of dichloromethane, dichloroethane, dioxane and tetrahydrofuran, and the dropping rate of the organic solution of methylamine is 1.5 g / min.

[0046] The present invention has the following advantages compared with the prior art:

[0047] (1) For the preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide of the present invention, the reaction conditions are mild, the process operation is simple, and the product yield is significantly improved.

[0048] (2) For the preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide of the present invention, the product has high purity, less three-waste emissions, low raw material cost, and is conducive to industrial production.

[0049] (3) For the preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide of the present invention, the production efficiency is significantly improved, there is no dangerous process, and the production safety hazard is small, which is suitable for large-scale preparation. Detailed implementation manners

[0050] To better understand the technical solution of the present invention, the following provides a further detailed description of the above content of the present invention in the form of specific embodiments, but this should not be construed as limiting the scope of the above subject matter of the present invention to the following examples. Any technology implemented based on the above content of the present invention belongs to the scope of the present invention.

[0051] Example 1: At 20 °C, 0.1 kg of o-toluidine and 0.34 kg of hydrochloric acid with a mass concentration of 10% were added to a reactor and mixed evenly. 0.32 kg of hydrogen peroxide with a mass concentration of 10% was added dropwise thereto, and the dropping rate of hydrogen peroxide was 7 g / min. After the dropping of hydrogen peroxide was completed, the reaction continued. The reaction process was tracked by liquid phase. After the o-toluidine reacted completely, the reaction was terminated. The obtained reaction solution was extracted with 0.3 kg of dichloromethane, and the organic phase was separated. Anhydrous sodium sulfate was added thereto to remove the residual moisture in the organic phase, and then filtered. The obtained filtrate was distilled under reduced pressure to remove the solvent, and 0.123 kg of 2-chloro-4-methylaniline was obtained, with a yield of 93.0% and a purity of 99.2%.

[0052] 0.1 kg of 2-chloro-4-methylaniline was dissolved in 0.2 kg of dichloromethane, and 0.09 kg of oxalyl chloride was added dropwise thereto. The dropping rate of oxalyl chloride was 2.5 g / min, and the temperature during the dropping process was controlled at 0 °C. After the dropping was completed, 0.009 g of aluminum trichloride was added, and the temperature was raised to 10 °C to continue the reaction. The reaction process was tracked by liquid phase. After the 2-chloro-4-methylaniline reacted completely, the reaction was terminated to obtain a reaction solution. The obtained reaction solution was added to 0.5 kg of hydrochloric acid-ice water with a mass concentration of 0.1% for quenching, and the organic phase was separated. Anhydrous sodium sulfate was added thereto to remove the residual moisture in the organic phase, and then filtered. The obtained filtrate was distilled under reduced pressure to remove the solvent, and 0.123 kg of 5-chloro-7-methylisatin was obtained, with a yield of 89.1% and a purity of 99.5%.

[0053] 0.1 kg of 5-chloro-7-methylisatin was added to 0.4 kg of an aqueous sodium hydroxide solution with a mass concentration of 5%. After stirring and dissolving at 20 °C, 0.17 kg of hydrogen peroxide with a mass concentration of 10% was added dropwise thereto. The dropping rate of hydrogen peroxide was 2.5 g / min, and the temperature of the reaction system was controlled at 50 °C. The reaction process was tracked by liquid phase. After the 5-chloro-7-methylisatin reacted completely, the reaction was terminated to obtain a reaction solution. The pH of the reaction solution was adjusted to 2 with 0.5% hydrochloric acid, and then filtered. The obtained filter cake was washed with ice water and dried to obtain 0.083 kg of 5-chloro-2-amino-3-methylbenzoic acid, with a yield of 87.6% and a purity of 99%.

[0054] 0.08 kg of 5-chloro-2-amino-3-methylbenzoic acid and 0.05 kg of thionyl chloride were added to a reactor. After stirring and dissolving, the mixture was heated to 50 °C for reaction. A drying tube was added to the reactor, and the vacuum drying temperature was 10 °C. The reaction progress was tracked by liquid phase. After the reaction of 5-chloro-2-amino-3-methylbenzoic acid was complete, the reaction was terminated to obtain a reaction solution. Thionyl chloride in the reaction solution was removed by vacuum distillation. An organic solution of 0.027 kg of methylamine, which was obtained by mixing methylamine and dichloromethane in a mass ratio of 1:1, was added dropwise to the obtained residue at a dropping rate of 1 g / min. After the dropping was completed, the solvent was removed by vacuum distillation to obtain 0.078 kg of 2-amino-5-chloro-N,3-dimethylbenzamide with a yield of 91.3% and a purity of 99.5%.

[0055] Example 2: At 30 °C, 0.1 kg of o-toluidine and 0.68 kg of 10% hydrochloric acid by mass concentration were added to a reactor and mixed evenly. 0.32 kg of 10% hydrogen peroxide by mass concentration was added dropwise thereto at a dropping rate of 9 g / min. After the addition of hydrogen peroxide was completed, the reaction continued. The reaction progress was tracked by liquid phase. After the reaction of o-toluidine was complete, the reaction was terminated. The obtained reaction solution was extracted with 0.3 kg of dichloromethane, and the organic phase was separated. Anhydrous sodium sulfate was added thereto to remove the residual moisture in the organic phase, and then filtered. The solvent in the obtained filtrate was removed by vacuum distillation to obtain 0.125 kg of 2-methyl-4-chloroaniline with a yield of 94.7% and a purity of 99.2%.

[0056] 0.1 kg of 2-methyl-4-chloroaniline was dissolved in 0.2 kg of dichloroethane. 0.1 kg of oxalyl chloride was added dropwise thereto at a dropping rate of 3 g / min, and the temperature was controlled at 0 °C during the dropping process. After the dropping was completed, 0.09 g of stannic chloride was added, and the temperature was raised to 50 °C for continued reaction. The reaction progress was tracked by liquid phase. After the reaction of 2-methyl-4-chloroaniline was complete, the reaction was terminated to obtain a reaction solution. The obtained reaction solution was quenched into 0.6 kg of 0.1% hydrochloric acid-ice water, and the organic phase was separated. Anhydrous sodium sulfate was added thereto to remove the residual moisture in the organic phase, and then filtered. The solvent in the obtained filtrate was removed by vacuum distillation to obtain 0.125 kg of 5-chloro-7-methylisatin with a yield of 90.3% and a purity of 99.5%.

[0057] 0.1 kg of 5-chloro-7-methylisatin was added to 0.8 kg of an aqueous sodium hydroxide solution with a mass concentration of 5%. After stirring and dissolving at 25°C, 0.21 kg of an aqueous hydrogen peroxide solution with a mass concentration of 12% was added dropwise thereto. The dropping rate of the hydrogen peroxide was 3.5 g / min, and the temperature of the reaction system was controlled at 50°C. The reaction process was tracked by liquid phase. After the reaction of 5-chloro-7-methylisatin was complete, the reaction was terminated to obtain a reaction solution. The pH of the reaction solution was adjusted to 3 with 0.5% hydrochloric acid, filtered, and the obtained filter cake was washed with ice water and dried to obtain 0.0852 kg of 5-chloro-2-amino-3-methylbenzoic acid, with a yield of 89.9% and a purity of 99%.

[0058] 0.08 kg of 5-chloro-2-amino-3-methylbenzoic acid and 0.06 kg of thionyl chloride were added to a reactor. After stirring and dissolving, the mixture was heated to 60°C for reaction. A drying tube was added to the reactor, and the vacuum drying temperature was 12°C. The reaction process was tracked by liquid phase. After the reaction of 5-chloro-2-amino-3-methylbenzoic acid was complete, the reaction was terminated to obtain a reaction solution. Thionyl chloride in the reaction solution was removed by vacuum distillation. 0.032 kg of an organic solution of methylamine, which was obtained by mixing methylamine and tetrahydrofuran in a mass ratio of 1:1, was added dropwise to the obtained residue. The dropping rate was 1.1 g / min. After the dropping was complete, the solvent was removed by vacuum distillation to obtain 0.0784 kg of 2-amino-5-chloro-N,3-dimethylbenzamide, with a yield of 91.9% and a purity of 99.5%.

[0059] In Example 3, at 20°C, 0.1 kg of o-toluidine and 0.85 kg of hydrochloric acid with a mass concentration of 20% were added to a reactor and mixed evenly. 0.48 kg of an aqueous hydrogen peroxide solution with a mass concentration of 20% was added dropwise thereto. The dropping rate of the hydrogen peroxide was 12 g / min. After the dropping of the hydrogen peroxide was complete, the reaction continued. The reaction process was tracked by liquid phase. After the reaction of o-toluidine was complete, the reaction was terminated. The obtained reaction solution was extracted with 0.5 kg of dichloromethane, and the organic phase was separated. Anhydrous sodium sulfate was added thereto to remove the residual water in the organic phase. After filtration, the solvent in the obtained filtrate was removed by vacuum distillation to obtain 0.126 kg of 2-methyl-4-chloroaniline, with a yield of 95.0% and a purity of 99.2%.

[0060] Dissolve 0.1 kg of 2-methyl-4-chloroaniline in 0.25 kg of toluene, and dropwise add 0.1 kg of oxalyl chloride to it at a dropping rate of 3.5 g / min. Control the temperature during the dropping process at 5 °C. After the dropping is completed, add 0.48 g of polyphosphoric acid, heat up to 80 °C and continue the reaction. Track the reaction process by liquid phase. After the reaction of 2-methyl-4-chloroaniline is complete, end the reaction to obtain a reaction solution. Add the obtained reaction solution to 0.8 kg of 1% hydrochloric acid-ice water for quenching, separate the organic phase, add anhydrous sodium sulfate to remove the residual water in the organic phase, filter, and distill the obtained filtrate under reduced pressure to remove the solvent to obtain 0.124 kg of 5-chloro-7-methylisatin, with a yield of 90.2% and a purity of 99.5%.

[0061] Add 0.1 kg of 5-chloro-7-methylisatin to 0.67 kg of 15% sodium hydroxide aqueous solution, stir and dissolve it at 35 °C, then dropwise add 0.17 kg of 20% hydrogen peroxide at a dropping rate of 5 g / min. Control the temperature of the reaction system at 60 °C. Track the reaction process by liquid phase. After the reaction of 5-chloro-7-methylisatin is complete, end the reaction to obtain a reaction solution. Adjust the pH of the reaction solution to 5 with 2% hydrochloric acid, filter, wash the obtained filter cake with ice water, and dry it to obtain 0.0853 kg of 5-chloro-2-amino-3-methylbenzoic acid, with a yield of 90% and a purity of 99%.

[0062] Add 0.08 kg of 5-chloro-2-amino-3-methylbenzoic acid and 0.1 kg of thionyl chloride to a reactor, stir and dissolve them, then heat up to 80 °C for reaction. Add a drying tube to the reactor, and the reduced pressure drying temperature is 20 °C. Track the reaction process by liquid phase. After the reaction of 5-chloro-2-amino-3-methylbenzoic acid is complete, end the reaction to obtain a reaction solution. Distill the thionyl chloride in the reaction solution under reduced pressure, and dropwise add 0.06 kg of an organic solution of methylamine to the obtained residue. The organic solution of methylamine is obtained by mixing methylamine and dioxane in a mass ratio of 1:3 at a dropping rate of 1.2 g / min. After the dropping is completed, distill the solvent under reduced pressure to obtain 0.0786 kg of 2-amino-5-chloro-N,3-dimethylbenzamide, with a yield of 92.1% and a purity of 99.5%.

[0063] Example 4: At 25 °C, 0.1 kg of o-toluidine and 0.68 kg of hydrochloric acid with a mass concentration of 15% were added to a reactor and mixed evenly. Then, 0.43 kg of hydrogen peroxide with a mass concentration of 15% was added dropwise thereto at a dropping rate of 15 g / min. After the addition, the reaction was continued, and the reaction process was tracked by liquid phase. After the o-toluidine was completely reacted, the reaction was terminated. The obtained reaction solution was extracted with 0.4 kg of dichloromethane, and the organic phase was separated. Anhydrous sodium sulfate was added thereto to remove the residual moisture in the organic phase. After filtration, the solvent in the obtained filtrate was removed by vacuum distillation to obtain 0.127 kg of 2-methyl-4-chloroaniline with a yield of 96.2% and a purity of 99.2%.

[0064] 0.1 kg of 2-methyl-4-chloroaniline was dissolved in 0.25 kg of dichloroethane, and 0.11 kg of oxalyl chloride was added dropwise thereto at a dropping rate of 3.5 g / min. The temperature was controlled at 3 °C during the dropping process. After the addition, 0.09 g of aluminum trichloride was added, and the temperature was raised to 70 °C for continuous reaction. The reaction process was tracked by liquid phase. After the 2-methyl-4-chloroaniline was completely reacted, the reaction was terminated to obtain a reaction solution. The obtained reaction solution was added to 0.9 kg of hydrochloric acid-ice water with a mass concentration of 0.5% for quenching, and the organic phase was separated. Anhydrous sodium sulfate was added thereto to remove the residual moisture in the organic phase. After filtration, the solvent in the obtained filtrate was removed by vacuum distillation to obtain 0.125 kg of 5-chloro-7-methylisatin with a yield of 90.8% and a purity of 99.5%.

[0065] 0.1 kg of 5-chloro-7-methylisatin was added to 0.8 kg of an aqueous sodium hydroxide solution with a mass concentration of 10%, and the mixture was stirred and dissolved at 35 °C. Then, 0.17 kg of hydrogen peroxide with a mass concentration of 15% was added dropwise thereto at a dropping rate of 7.5 g / min. The temperature of the reaction system was controlled at 55 °C, and the reaction process was tracked by liquid phase. After the 5-chloro-7-methylisatin was completely reacted, the reaction was terminated to obtain a reaction solution. The pH of the reaction solution was adjusted to 4 with 1.5% hydrochloric acid, and the mixture was filtered. The obtained filter cake was washed with ice water and dried to obtain 0.0855 kg of 5-chloro-2-amino-3-methylbenzoic acid with a yield of 90.2% and a purity of 99%.

[0066] 0.08 kg of 5-chloro-2-amino-3-methylbenzoic acid and 0.08 kg of thionyl chloride were added to a reactor. After stirring and dissolving, the mixture was heated to 70 °C for reaction. A drying tube was added to the reactor, and the vacuum drying temperature was 15 °C. The reaction progress was tracked by liquid phase. After the reaction of 5-chloro-2-amino-3-methylbenzoic acid was complete, the reaction was terminated to obtain a reaction solution. Thionyl chloride in the reaction solution was removed by vacuum distillation. An organic solution of 0.044 kg of methylamine was added dropwise to the obtained residue. The organic solution of methylamine was obtained by mixing methylamine and dichloromethane in a mass ratio of 1:2. The dropping rate was 1.5 g / min. After the dropping was completed, the solvent was removed by vacuum distillation to obtain 0.0790 kg of 2-amino-5-chloro-N,3-dimethylbenzamide, with a yield of 92.5% and a purity of 99.5%.

[0067] Example 5: At 40 °C, 0.1 kg of o-toluidine and 1.09 kg of hydrochloric acid with a mass concentration of 25% were added to a reactor and mixed evenly. 0.51 kg of hydrogen peroxide with a mass concentration of 25% was added dropwise thereto. The dropping rate of hydrogen peroxide was 25 g / min. After the dropping of hydrogen peroxide was completed, the reaction continued. The reaction progress was tracked by liquid phase. After the reaction of o-toluidine was complete, the reaction was terminated. The obtained reaction solution was extracted with 0.5 kg of ethyl acetate, and the organic phase was separated. Anhydrous sodium sulfate was added thereto to remove the residual moisture in the organic phase. After filtration, the solvent in the obtained filtrate was removed by vacuum distillation to obtain 0.125 kg of 2-methyl-4-chloroaniline, with a yield of 94.4% and a purity of 99.2%.

[0068] 0.1 kg of 2-methyl-4-chloroaniline was dissolved in 0.2 kg of dichloromethane. 0.1 kg of oxalyl chloride was added dropwise thereto. The dropping rate of oxalyl chloride was 4 g / min. The temperature was controlled at 8 °C during the dropping process. After the dropping was completed, 0.32 g of aluminum trichloride was added, and the temperature was raised to 30 °C for continued reaction. The reaction progress was tracked by liquid phase. After the reaction of 2-methyl-4-chloroaniline was complete, the reaction was terminated to obtain a reaction solution. The obtained reaction solution was quenched into 0.5 kg of hydrochloric acid-ice water with a mass concentration of 2.5%, and the organic phase was separated. Anhydrous sodium sulfate was added thereto to remove the residual moisture in the organic phase. After filtration, the solvent in the obtained filtrate was removed by vacuum distillation to obtain 0.124 kg of 5-chloro-7-methylisatin, with a yield of 90% and a purity of 99.5%.

[0069] Add 0.1 kg of 5-chloro-7-methylisatin to 0.89 kg of an aqueous sodium hydroxide solution with a mass concentration of 18%. After stirring and dissolving at 40 °C, add dropwise 0.27 kg of hydrogen peroxide with a mass concentration of 25% thereto. The dropping rate of hydrogen peroxide is 10 g / min, and the temperature of the reaction system is controlled at 65 °C. Track the reaction process by liquid phase. After the reaction of 5-chloro-7-methylisatin is complete, end the reaction to obtain a reaction solution. Adjust the pH of the reaction solution to 2.5 with 3.5% hydrochloric acid, filter, wash the obtained filter cake with ice water, and dry to obtain 0.0841 kg of 5-chloro-2-amino-3-methylbenzoic acid, with a yield of 88.8% and a purity of 99%.

[0070] Add 0.08 kg of 5-chloro-2-amino-3-methylbenzoic acid and 0.2 kg of thionyl chloride to a reactor. After stirring and dissolving, heat to 90 °C for reaction. Add a drying tube to the reactor, and the vacuum drying temperature is 25 °C. Track the reaction process by liquid phase. After the reaction of 5-chloro-2-amino-3-methylbenzoic acid is complete, end the reaction to obtain a reaction solution. Distill off thionyl chloride in the reaction solution under reduced pressure. Add dropwise 0.074 kg of an organic solution of methylamine to the obtained residue. The organic solution of methylamine is obtained by mixing methylamine and dichloromethane in a mass ratio of 1:4. The dropping rate is 1.8 g / min. After the dropping is complete, distill off the solvent under reduced pressure to obtain 0.0784 kg of 2-amino-5-chloro-N,3-dimethylbenzamide, with a yield of 91.8% and a purity of 99.5%.

[0071] In Example 6, at 50 °C, add 0.1 kg of o-toluidine and 1.13 kg of hydrochloric acid with a mass concentration of 30% to a reactor and mix evenly. Add dropwise 0.53 kg of hydrogen peroxide with a mass concentration of 30% thereto. The dropping rate of hydrogen peroxide is 35 g / min. After the dropping of hydrogen peroxide is complete, continue the reaction. Track the reaction process by liquid phase. After the reaction of o-toluidine is complete, end the reaction. Extract the obtained reaction solution with 0.5 kg of toluene, separate the organic phase, add anhydrous sodium sulfate to remove the residual water in the organic phase, filter, and distill off the solvent from the obtained filtrate under reduced pressure to obtain 0.124 kg of 2-methyl-4-chloroaniline, with a yield of 93.5% and a purity of 99.2%.

[0072] Dissolve 0.1 kg of 2-methyl-4-chloroaniline in 0.3 kg of ethyl acetate, and add 0.11 kg of oxalyl chloride dropwise thereto at a dropping rate of 5 g / min. Control the temperature during the dropping process to be 10 °C. After the dropping is completed, add 0.57 g of ferric chloride, heat up to 80 °C and continue the reaction. Track the reaction process by liquid phase. After the reaction of 2-methyl-4-chloroaniline is complete, end the reaction to obtain a reaction solution. Add the obtained reaction solution to 1 kg of hydrochloric acid-ice water with a mass concentration of 5% for quenching, separate out the organic phase, add anhydrous sodium sulfate thereto to remove the residual moisture in the organic phase, filter, and distill the obtained filtrate under reduced pressure to remove the solvent to obtain 0.124 kg of 5-chloro-7-methylisatin, with a yield of 89.6% and a purity of 99.5%.

[0073] Add 0.08 kg of 5-chloro-7-methylisatin to 1 kg of an aqueous sodium hydroxide solution with a mass concentration of 20%. Stir and dissolve it at 50 °C, and then add 0.29 kg of hydrogen peroxide with a mass concentration of 30% dropwise thereto at a dropping rate of 12 g / min. Control the temperature of the reaction system to be 70 °C. Track the reaction process by liquid phase. After the reaction of 5-chloro-7-methylisatin is complete, end the reaction to obtain a reaction solution. Adjust the pH of the reaction solution to 5 with 5% hydrochloric acid, filter, wash the obtained filter cake with ice water, and dry it to obtain 0.0836 kg of 5-chloro-2-amino-3-methylbenzoic acid, with a yield of 88.2% and a purity of 99%.

[0074] Add 0.08 kg of 5-chloro-2-amino-3-methylbenzoic acid and 0.264 kg of thionyl chloride to a reactor, stir and dissolve them, heat up to 100 °C for reaction, add a drying tube to the reactor, and the reduced pressure drying temperature is 30 °C. Track the reaction process by liquid phase. After the reaction of 5-chloro-2-amino-3-methylbenzoic acid is complete, end the reaction to obtain a reaction solution. Distill the thionyl chloride in the reaction solution under reduced pressure, and add 0.096 kg of an organic solution of methylamine dropwise to the obtained residue. The organic solution of methylamine is obtained by mixing methylamine and dichloroethane in a mass ratio of 1:5 at a dropping rate of 2 g / min. After the dropping is completed, distill the solvent under reduced pressure to obtain 0.0782 kg of 2-amino-5-chloro-N,3-dimethylbenzamide, with a yield of 91.5% and a purity of 99.5%.

[0075] Although the specific embodiments of the present invention are described above, they are not limitations on the protection scope of the present invention. Based on the technical solutions of the present invention, various modifications or deformations that can be made by those skilled in the art without creative efforts are still within the protection scope of the present invention.

Claims

1. A preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide, characterized in that: The synthetic route is as follows: ； It includes the following steps: 1) At 20~50°C, add o-toluidine and hydrochloric acid into a reactor and mix evenly. Then, dropwise add hydrogen peroxide 1. After the addition of hydrogen peroxide 1 is completed, continue the reaction. Track the reaction process by liquid phase. When the o-toluidine reaction is complete, end the reaction. Extract the obtained reaction solution with organic solvent 1, separate the organic phase, add anhydrous sodium sulfate to remove the residual moisture in the organic phase, filter, and distill the obtained filtrate under reduced pressure to remove the solvent to obtain 2-methyl-4-chloroaniline; The molar ratio of the o-toluidine, hydrochloric acid and hydrogen peroxide 1 is 1:1~10:1~5; The mass concentration of the hydrochloric acid is 10~30%; The mass concentration of the hydrogen peroxide 1 is 10~30%; The organic solvent 1 is one or a combination of two of dichloromethane, ethyl acetate and toluene; The mass ratio of the organic solvent 1 to the o-toluidine is 3~5:1; The dropping rate of the hydrogen peroxide 1 is 7~35 g / min; 2) Dissolve the 2-methyl-4-chloroaniline prepared in step 1) in organic solvent 2, dropwise add oxalyl chloride, control the temperature during the dropping process to be 0~10°C. After the addition is completed, add a catalyst, and raise the temperature to 10~80°C to continue the reaction. Track the reaction process by liquid phase. When the 2-methyl-4-chloroaniline reaction is complete, end the reaction to obtain a reaction solution. Quench the obtained reaction solution into ice water containing hydrochloric acid, separate the organic phase, add anhydrous sodium sulfate to remove the residual moisture in the organic phase, filter, and distill the obtained filtrate under reduced pressure to remove the solvent to obtain 5-chloro-7-methylisatin; The molar ratio of the 2-methyl-4-chloroaniline, oxalyl chloride and the catalyst is 1:1~1.2:0.0001~0.005; The dropping rate of the oxalyl chloride is 2.5~5 g / min; The organic solvent 2 is dichloromethane, dichloroethane, toluene or ethyl acetate; The mass ratio of the organic solvent 2, ice water containing hydrochloric acid and 2-methyl-4-chloroaniline is 2~3:5~10:1; The catalyst is one or a combination of two of aluminum trichloride, tin tetrachloride, ferric trichloride and polyphosphoric acid; The mass concentration of hydrochloric acid in the ice water containing hydrochloric acid is 0.1~5%; ​ 3) Add the 5-chloro-7-methylisatin obtained in step 2) into an aqueous sodium hydroxide solution, stir and dissolve it at 20-50 °C, then dropwise add hydrogen peroxide 2 thereto, control the temperature of the reaction system at 50-70 °C, track the reaction process by liquid phase, and end the reaction after the 5-chloro-7-methylisatin reacts completely to obtain a reaction solution. Adjust the pH of the reaction solution to 2-5 with 0.5-5% hydrochloric acid, filter, wash the obtained filter cake with ice water, and dry it to obtain 5-chloro-2-amino-3-methylbenzoic acid. Add the obtained 5-chloro-2-amino-3-methylbenzoic acid and thionyl chloride into a reactor, stir and mix evenly, then heat to 50-100 °C for reaction, track the reaction process by liquid phase, and end the reaction after the 5-chloro-2-amino-3-methylbenzoic acid reacts completely to obtain a reaction solution. Distill off thionyl chloride in the reaction solution under reduced pressure, dropwise add an organic solution of methylamine to the obtained residue, and after the addition is completed, distill off the solvent under reduced pressure to obtain 2-amino-5-chloro-N,3-dimethylbenzamide; The mass concentration of the aqueous sodium hydroxide solution is 5-20%; The mass concentration of the hydrogen peroxide 2 is 10-30%; The dropping rate of the hydrogen peroxide 2 is 2.5-12 g / min; The molar ratio of the 5-chloro-7-methylisatin, sodium hydroxide and hydrogen peroxide 2 is 1:1-10:1-5; The molar ratio of the 5-chloro-2-amino-3-methylbenzoic acid, thionyl chloride and methylamine is 1:1-5:1-1.2; A drying tube is added to the reactor, and the reduced pressure drying temperature is 10-30 °C; The organic solution of methylamine is obtained by mixing methylamine and organic solvent 3 in a mass ratio of 1:1-5, wherein the organic solvent 3 is one or a combination of two of dichloromethane, dichloroethane, dioxane and tetrahydrofuran; The dropping rate of the organic solution of methylamine is 1-2 g / min.

2. The preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide as described in claim 1, characterized in that: In step 1), the reaction temperature is 20-30 °C, the molar ratio of o-toluidine, hydrochloric acid and hydrogen peroxide 1 is 1:2-5:1-3, the mass concentration of the hydrochloric acid is 10-20%, and the mass concentration of the hydrogen peroxide 1 is 10-20%.

3. The preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide as described in claim 1, characterized in that: In step 1), the dropping rate of the hydrogen peroxide 1 is 15 g / min, and the organic solvent 1 is dichloromethane.

4. The preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide as described in claim 1, characterized in that: In step 2), the temperature during the dropping process is controlled at 0-5 °C, the organic solvent 2 is dichloroethane, and the dropping rate of oxalyl chloride is 3.5 g / min.

5. The preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide as described in claim 1, characterized in that: The catalyst described in step 2) is aluminum trichloride, stannic chloride or polyphosphoric acid, and the molar ratio of 2-methyl-4-chloroaniline to the catalyst is 1:0.0005 - 0.002; the temperature increase is 50 - 80°C, and the mass concentration of hydrochloric acid in the ice water containing hydrochloric acid is 0.1 - 1%.

6. The preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide as described in claim 1, characterized in that: the stirring and dissolving temperature in step 3) is 20 - 30°C, the mass concentration of the sodium hydroxide aqueous solution is 5 - 15%, the mass concentration of hydrogen peroxide 2 is 10 - 20%, and the dropping rate of hydrogen peroxide 2 is 7.5 g / min.

7. The preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide as described in claim 1, characterized in that: in step 3), the reaction system is controlled at 50 - 60°C, the molar ratio of 5-chloro-7-methylisatin, sodium hydroxide and hydrogen peroxide 2 is 1:1 - 5:1 - 2, the mass concentration of hydrochloric acid is 0.5 - 2%, and the pH of the reaction solution is adjusted to 3 - 5.

8. The preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide as described in claim 1, characterized in that: the heating temperature in step 3) is 50 - 80°C, the molar ratio of 5-chloro-2-amino-3-methylbenzoic acid to thionyl chloride is 1:1 - 2, the vacuum drying temperature is 10 - 20°C, the organic solution of methylamine is obtained by mixing methylamine and organic solvent 3 in a mass ratio of 1:1 - 3, where organic solvent 3 is one or a combination of two of dichloromethane, dichloroethane, dioxane and tetrahydrofuran, and the dropping rate of the organic solution of methylamine is 1.5 g / min.

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