Preparation method of high-purity 2-amino-5-chloro-N, 3-dimethyl benzamide

Abstract

The invention relates to the technical field of chemical synthesis, and discloses a preparation method of high-purity 2-amino-5-chloro-N, 3-dimethyl benzamide, which comprises the following steps: S1, adding an organic solvent into a flask, adjusting the temperature, adding a compound shown as a formula I, then starting to dropwise add sulfonyl chloride, after dropwise adding, carrying out heat preservation reaction, and after the reaction is finished, cooling to room temperature to obtain 2-amino-5-chloro-N, 3-dimethyl benzamide; after the reaction is finished, obtaining a compound as shown in a formula II; s2, dropwise adding the compound as shown in the formula II into a light-reinforcing solution, carrying out heating reflux reaction, and after the reaction is finished, carrying out cooling suction filtration to obtain a compound as shown in a formula III; and S3, adding the compound shown in the formula III into an organic solvent, adjusting the temperature, dropwise adding a monomethylamine aqueous solution, carrying out heat preservation reaction after dropwise adding, recovering the solvent under reduced pressure after reaction, adding water for cooling, carrying out suction filtration, and drying to obtain a compound shown in a formula IV. The method has the advantages of high product purity, high yield, simple operation, mild reaction conditions, no high temperature, high pressure and cryogenic process conditions, and suitableness for industrial mass production.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for preparing high-purity 2-amino-5-chloro-N,3-dimethylbenzamide. Background Art

[0002] 2-Amino-5-chloro-N,3-dimethylbenzamide is an important intermediate in the synthesis of chlorantraniliprole. Chlorantraniliprole is a class of insecticides that are safe and environmentally friendly for mammals, exhibits good activity against lepidopteran insects, and exhibits no cross-resistance with other existing insecticides. 2-Amino-5-chloro-N,3-dimethylbenzamide is a key intermediate in the synthesis of chlorantraniliprole, and the development of a competitive, high-quality process is urgent.

[0003] There are many processes reported in the literature for the production of 2-amino-5-chloro-N,3-dimethylbenzamide. Currently, the most common process uses 2-nitro-3-methylbenzoic acid as the raw material: 2-nitro-3-methylbenzoic acid is used as the raw material, and nitro reduction (iron powder, palladium carbon, hydrazine hydrate, etc.) is performed to generate 2-amino-3-methylbenzoic acid, followed by chlorination reaction (sulfonyl chloride, thionyl chloride or hydrochloric acid, hydrogen peroxide) to generate 2-amino-5-chloro-3-methylbenzoic acid, and then cyclization reaction (phosgene, diphosgene or solid light) to generate 6-chloro-8-methylisatoic anhydride, and finally methylation reaction with monomethylamine aqueous solution occurs to generate 2-amino-5-chloro-N,3-dimethylbenzamide.

[0004] In the existing technology, the purity of the product 2-amino-5-chloro-N,3-dimethylbenzamide is not high, generally between 98.0-98.5%, and the external standard content is around 97.0%. It mainly contains three major impurities: ; (1) Impurity 1: 2-amino-N,3-dimethylbenzamide: This impurity is produced by the ring-opening reaction of the compound represented by formula I with solid light and then with monomethylamine. There are two ways of production. One is that during the chlorination reaction, the compound represented by formula I directly reacts with solid light contained in the solvent, and the impurity produced continues to react in the subsequent steps to eventually produce impurity 1; the other is that the chlorination reaction is not complete, and a large amount of the compound represented by formula I remains. During the ring-closure reaction, it reacts with solid light, and the impurity produced continues to react in the subsequent steps to eventually produce impurity 1. (2) Impurity 2: 6-chloro-8-methylisatoic anhydride: This impurity is produced by excess raw materials in the methylamination reaction; (3) Impurity 3: This impurity is produced by the cyclization reaction between the product and solid light. Once generated, it cannot be removed. Summary of the Invention

[0005] In order to solve the above technical problems, the purpose of the present invention is to provide a method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide with high product purity, high yield, mild reaction conditions, simple operation, and suitability for large-scale industrial production.

[0006] To achieve the above object, the present invention provides the following technical solution: The preparation method comprises the following steps: S1. An organic solvent is added to a flask, the temperature is adjusted, and the compound of formula I is added, and then sulfonyl chloride is added dropwise. The addition is completed and the reaction is incubated. The reaction is completed to obtain a compound of formula II; S2. The compound represented by Formula II was added dropwise to the solid light solution, heated to reflux, and after the reaction was completed, cooled and filtered to obtain a compound represented by Formula III; the mother liquor was filtered and the solvent was recovered under normal pressure, and the solvent was applied after removing hydrogen chloride gas and solid light; S3. The compound represented by formula III is added to an organic solvent, and after adjusting the temperature, an aqueous monomethylamine solution is added dropwise, and the reaction is heated to completion. After completion of the reaction, the solvent is recovered under reduced pressure, cooled with water, filtered, and dried to obtain a compound represented by formula IV, ie, the target product; The intermediates of each step are as follows: .

[0007] Preferably, the organic solvent in S1 is dimethyl carbonate, dichloroethane or chloroform.

[0008] Preferably, the temperature for adding sulfonyl chloride in S1 is -5 to 30°C, the insulation temperature is 0 to 50°C, and the insulation time is 1 to 5 hours.

[0009] Preferably, the molar ratio of the sulfonyl chloride in S1 to the compound represented by Formula I is 1 to 3:1.

[0010] Preferably, the molar ratio of the light-fixing solution in S2 to the compound represented by formula II is 0.33-1:1; the reflux temperature is 50-100° C., and the holding time is 6-16 hours.

[0011] Preferably, the filtration temperature in S2 is -5~30°C.

[0012] Preferably, the monomethylamine is added dropwise at a temperature of 0 to 50° C., the insulation temperature is 10 to 60° C., and the insulation time is 2 to 8 hours.

[0013] Preferably, the molar ratio of the monomethylamine aqueous solution in S3 to the compound represented by formula III is 1 to 4:1.

[0014] Preferably, the recovery solvent temperature in S3 is 30-70°C, and the filtration temperature is 0-30°C.

[0015] Compared with the prior art, the present invention has the following beneficial effects: The present invention solves the current technical barriers, reduces impurities and improves purity: (1) Chlorination reaction: by treating the recycled solvent in advance and removing the hydrogen chloride gas and solid light in the solvent, the reaction of the compound shown in formula I with the solid light is avoided, thereby avoiding the formation of impurity 1; at the same time, since the recycled solvent removes the hydrogen chloride gas, the chlorination reaction is more thorough, the residual raw material is less than 0.5%, and the purity of 2-nitro-3-methyl-5-chlorobenzoic acid is increased to more than 99%; (2) Methylation reaction: by studying the reaction temperature, reaction time and the amount of monomethylamine, the reaction is made more thorough, the residual raw material is less than 0.1%, and the problem of excessive impurity 2 is effectively solved; (3) Methylation reaction: by appropriately increasing the amount of monomethylamine, the solid light in the recycled solvent and the compound shown in formula III is destroyed, and the reaction of the solid light with the final product to form impurity 3 is avoided.

[0016] The present invention comprises three reaction steps. The first step, chlorination, and the second step, cyclization, are performed in a one-pot process, resulting in a yield of approximately 90%. The third step, methylamination, achieves a yield of 95%, for a total yield of approximately 85%. The final product has a purity of over 99.5% and is a white to off-white crystal, significantly higher than the approximately 98.5% purity of the currently commercially available beige to pale pink powder. The product of the present invention features high purity, high yield, simple operation, mild reaction conditions, and the absence of high temperature, high pressure, or cryogenic process conditions, making it well-suited for large-scale industrial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0017] Figure 1 The synthetic route of the present invention is shown in FIG.

[0018] Figure 2 The figure is the HPLC spectrum of 2-amino-5-chloro-N,3-dimethylbenzamide of the present invention.

[0019] Figure 3 This is the LC-MS spectrum of impurity 1.

[0020] Figure 4 This is the LC-MS spectrum of impurity 2.

[0021] Figure 5 This is the LC-MS spectrum of impurity 3. DETAILED DESCRIPTION

[0022] The following will clearly and completely describe the technical solutions in the embodiments of the present invention in conjunction with the accompanying drawings. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without making creative efforts are within the scope of protection of the present invention.

[0023] Example 1: 300 g of dichloroethane and 55 g of 2-amino-3-methylbenzoic acid (0.364 mol, 1.0 eq) were added to a 500 mL four-necked flask. The temperature was controlled at about 10 ° C. Sulfuryl chloride (65 g, 0.482 mol, 1.32 eq) was added dropwise. The temperature was controlled at 10-20 ° C during the addition process. After the addition was completed, the temperature was kept at 30-40 ° C for 3 hours. After the reaction was completed, 2-amino-3-methyl-5-chlorobenzoic acid was obtained for stand-by use with a purity of 99.4% and a purity of 0.4% for 2-amino-3-methylbenzoic acid.

[0024] The above 2-amino-3-methyl-5-chlorobenzoic acid solution was continued to be added dropwise with Guguang solution (Guguang: 40 g + dichloroethane: 100 g dissolved). After the addition was completed, the temperature was raised to reflux and the reaction was kept warm for 10 hours. After the reaction was completed, the temperature was lowered to 10-15 ° C, filtered, and dried to obtain 6-chloro-8-methylisatoic anhydride (69.5 g, 0.329 mol) with a purity of 99.5% and a yield of 90.4%.

[0025] The mother liquor was filtered and the solvent was recovered at normal pressure. The recovered solvent was heated and refluxed to remove most of the hydrogen chloride and fixed light. Liquid alkali was then added dropwise to further remove the hydrogen chloride and fixed light. After drying, the solvent was applied to the next batch of chlorination reaction.

[0026] In a 500ml four-necked flask, 6-chloro-8-methylisatoic anhydride (69.5g, 0.329mol) and 200g of dichloroethane were added. The temperature was adjusted to 5-10°C and 40% monomethylamine aqueous solution (38.5g, 0.497mol, 1.51eq) was added dropwise. After the addition was completed, the temperature was raised to 40-50°C and the reaction was maintained for 3 hours. After the reaction was completed, the dichloroethane was recovered by vacuum distillation, and the temperature in the kettle was controlled not to exceed 50°C. After the distillation was completed, 250g of water was added, the temperature was lowered to 15-20°C, and the mixture was filtered and dried to obtain 2-amino-5-chloro-N,3-dimethylbenzamide (62.0g, 0.312mol) with a purity of 99.6% and a yield of 94.9%.

[0027] Example 2: Chloroform: 300 g, 2-amino-3-methylbenzoic acid (55 g, 0.364 mol, 1.0 eq) were added to a 500 mL four-necked flask. The temperature was controlled at about 0°C, and sulfonyl chloride (60 g, 0.444 mol, 1.22 eq) was added dropwise. The temperature was controlled at 0-10°C during the addition process. After the addition was completed, the mixture was kept at 40-50°C for 5 hours. After the reaction was completed, 2-amino-3-methyl-5-chlorobenzoic acid was obtained for standby use with a purity of 99.2%, and 2-amino-3-methylbenzoic acid had a purity of 0.5%.

[0028] The above 2-amino-3-methyl-5-chlorobenzoic acid solution was continued to be added dropwise with Guguang solution (Guguang: 45 g + chloroform: 100 g dissolved). After the addition was completed, the temperature was raised to reflux and the reaction was kept for 8 hours. After the reaction was completed, the temperature was lowered to 20-25 ° C, filtered, and dried to obtain 6-chloro-8-methylisatoic anhydride (70.2 g, 0.332 mol) with a purity of 99.3% and a yield of 91.2%.

[0029] The mother liquor was filtered and the solvent was recovered at normal pressure. The recovered solvent was heated and refluxed to remove most of the hydrogen chloride and fixed light. Liquid alkali was then added dropwise to further remove the hydrogen chloride and fixed light. After drying, the solvent was applied to the next batch of chlorination reaction.

[0030] In a 500 ml four-necked flask, 6-chloro-8-methylisatoic anhydride (70.2 g, 0.332 mol) and chloroform: 200 g were added. The temperature was adjusted to 15-20 ° C and 40% monomethylamine aqueous solution (40 g, 0.516 mol, 1.55 eq) was added dropwise. After the addition was completed, the temperature was raised to 30-40 ° C and the reaction was kept for 5 hours. After the reaction was completed, the chloroform was recovered by vacuum distillation, and the temperature in the kettle was controlled not to exceed 45 ° C. After the distillation was completed, 250 g of water was added, and the temperature was lowered to 20-25 ° C. Filtered and dried to obtain 2-amino-5-chloro-N, 3-dimethylbenzamide (62.7 g, 0.316 eq) with a purity of 99.7% and a yield of 95.2%.

[0031] Example 3: Dimethyl carbonate: 300 g, 2-amino-3-methylbenzoic acid (55 g, 0.364 mol, 1.0 eq) were added to a 500 mL four-necked flask, the temperature was controlled at about 5 ° C, and sulfonyl chloride (70 g, 0.518 mol, 1.42 eq) was added dropwise. The temperature was controlled at 5-10 ° C during the addition process. After the addition was completed, the temperature was kept at 20-30 ° C for 4 hours. After the reaction was completed, 2-amino-3-methyl-5-chlorobenzoic acid was obtained for stand-by use with a purity of 99.6%, and 2-amino-3-methylbenzoic acid had a purity of 0.2%.

[0032] The above 2-amino-3-methyl-5-chlorobenzoic acid solution was continued to be added dropwise with Guguang solution (Guguang: 48 g + dimethyl carbonate: 100 g dissolved). After the addition was completed, the temperature was raised to reflux and the reaction was kept warm for 6 hours. After the reaction was completed, the temperature was lowered to 5~10°C, filtered, and dried to obtain 6-chloro-8-methylisatoic anhydride (69.4 g, 0.328 mol) with a purity of 99.7% and a yield of 90.0%.

[0033] The mother liquor was filtered and the solvent was recovered at normal pressure. The recovered solvent was heated and refluxed to remove most of the hydrogen chloride and fixed light. Liquid alkali was then added dropwise to further remove the hydrogen chloride and fixed light. After drying, the solvent was applied to the next batch of chlorination reaction.

[0034] In a 500 ml four-necked flask, 6-chloro-8-methylisatoic anhydride (69.4 g, 0.328 mol) and dimethyl carbonate: 200 g were added. The temperature was adjusted to 25-30 ° C. and 40% monomethylamine aqueous solution (45 g, 0.581 mol, 1.77 eq) was added dropwise. After the addition was completed, the temperature was raised to 40-50 ° C. and the reaction was kept warm for 3 hours. After the reaction was completed, the dimethyl carbonate was recovered by vacuum distillation, and the temperature in the kettle was controlled not to exceed 60 ° C. After the distillation was completed, water: 250 g was added, the temperature was lowered to 10-15 ° C. Filtered, and dried to obtain 2-amino-5-chloro-N, 3-dimethylbenzamide (62.3 g, 0.314 eq) with a purity of 99.7% and a yield of 95.6%.

[0035] Comparative Example: Methanol: 600 g, 2-nitro-3-methylbenzoic acid: 181 g (1 mol), and 5% palladium carbon: 1.5 g were added to a 1 L autoclave, the autoclave was closed, nitrogen was replaced 3 times, hydrogen was replaced 3 times, and then the hydrogen pressure in the autoclave was maintained at 0.8~1.0 MPa. The temperature was raised to 45~55°C and the reaction was maintained at this temperature and pressure. After the reaction was qualified, it was filtered while hot, and the filtrate was desolvated under reduced pressure to remove methanol: about 250 g, then the temperature was lowered for crystallization, the temperature was lowered to 0~5°C for filtration, and the oven was dried to obtain 2-amino-3-methylbenzoic acid (143.4 g, 0.95 mol).

[0036] In a 500mL four-necked flask, 300g of dichloroethane and 55g of 2-amino-3-methylbenzoic acid (0.364mol, 1.0eq) were added. The temperature was controlled at about 0°C, and 62.9g of 0.466mol, 1.28eq) was added dropwise. The temperature was controlled at 0-5°C during the addition process. After the addition was completed, the temperature was kept at 20-25°C for 5 hours. After the reaction was completed, 2-amino-3-methyl-5-chlorobenzoic acid with a purity of 98.0% was obtained for standby use. The purity of 2-amino-3-methylbenzoic acid was 1.4%.

[0037] The above 2-amino-3-methyl-5-chlorobenzoic acid solution was further added dropwise with Guguang solution (45 g of Guguang dissolved in 100 g of dichloroethane). After the addition was complete, the temperature was raised to reflux and the reaction was maintained for 10 hours. After the reaction was completed, the temperature was lowered to 10-15°C, filtered, and dried to obtain 6-chloro-8-methylisatoic anhydride (65.4 g, 0.310 mol) with a purity of 98.2% and a yield of 85.2%. The mother liquor was filtered and the solvent was recovered at normal pressure and reused for the next batch of chlorination reactions.

[0038] In a 500ml four-necked flask, 6-chloro-8-methylisatoic anhydride (65.4g, 0.310mol) and 200g of dichloroethane were added. The temperature was adjusted to 20-25°C and 40% monomethylamine aqueous solution (28.8g, 0.372mol, 1.2eq) was added dropwise. After the addition was completed, the temperature was raised to 50-55°C and the reaction was carried out for 2 hours. After the reaction was completed, the dichloroethane was recovered by vacuum distillation, and the temperature in the kettle was controlled not to exceed 50°C. After the distillation was completed, 250g of water was added, the temperature was lowered to 15-20°C, and the mixture was filtered and dried to obtain 2-amino-5-chloro-N,3-dimethylbenzamide (56.6g, 0.285mol) with a purity of 98.0% and a yield of 92%.

[0039] In a comparative example, 2-nitro-3-methylbenzoic acid is used as the starting material: a reduction reaction is first performed to obtain 2-amino-3-methylbenzoic acid, followed by a chlorination reaction to obtain 2-amino-3-methyl-5-chlorobenzoic acid; a cyclization reaction is then performed to obtain 6-chloro-8-methylisatoic anhydride, and finally a methylamination reaction is performed with monomethylamine to obtain 2-amino-5-chloro-N,3-dimethylbenzamide. The product obtained according to this process has a purity of only 98.0-98.5%, and the three impurities are relatively large, resulting in a product quality significantly lower than that of the preparation method of the present invention.

[0040] While embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions, and variations may be made to these embodiments without departing from the principles and spirit of the invention, and that the scope of the invention is defined by the appended claims and their equivalents.

Claims

1. A method for preparing high-purity 2-amino-5-chloro-N,3-dimethylbenzamide, characterized in that: The preparation method comprises the following steps: S1. An organic solvent is added to a flask, the temperature is adjusted, and the compound of formula I is added, and then sulfonyl chloride is added dropwise. The addition is completed and the reaction is incubated. The reaction is completed to obtain a compound of formula II; S2. The compound represented by Formula II was added dropwise to the solid light solution, heated to reflux, and after completion of the reaction, cooled and filtered to obtain a compound represented by Formula III; the mother liquor was filtered and the solvent was recovered under normal pressure, and the solvent was applied after removing hydrogen chloride gas and solid light; S3. The compound represented by formula III is added to an organic solvent, and after adjusting the temperature, an aqueous monomethylamine solution is added dropwise, and the reaction is heated to completion. After completion of the reaction, the solvent is recovered under reduced pressure, cooled with water, filtered, and dried to obtain a compound represented by formula IV, ie, the target product; The intermediates of each step are as follows: 。 2. The method for preparing high-purity 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, wherein: The organic solvent in S1 is dimethyl carbonate, dichloroethane or chloroform.

3. The method for preparing high-purity 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, wherein: The temperature for adding sulfonyl chloride in S1 is -5 to 30°C, the temperature for keeping warm is 0 to 50°C, and the time for keeping warm is 1 to 5 hours.

4. The method for preparing high-purity 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, wherein: The molar ratio of the sulfonyl chloride in S1 to the compound represented by formula I is 1 to 3:

1.

5. The method for preparing high-purity 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, wherein: The molar ratio of the light-fixing solution in S2 to the compound represented by formula II is 0.33-1:1; the reflux temperature is 50-100° C., and the holding time is 6-16 hours.

6. The method for preparing high-purity 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, wherein: The filtration temperature in S2 is -5~30℃.

7. The method for preparing high-purity 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, wherein: The monomethylamine dropwise addition temperature in S3 is 0-50° C., the insulation temperature is 10-60° C., and the insulation time is 2-8 hours.

8. The method for preparing high-purity 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, wherein: The molar ratio of the monomethylamine aqueous solution in S3 to the compound represented by formula III is 1-4:

1.

9. The method for preparing high-purity 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, wherein: The recovery solvent temperature in S3 is 30-70°C, and the filtration temperature is 0-30°C.

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