A process for the preparation of 2-amino-5-chloro-N,3-dimethylbenzamide
Patent Information
- Application Number
- CN202611495650.7
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2026-09-24
- Publication Date
- 2026-10-30
AI Technical Summary
[0007]现有技术中，不管采用哪条工艺路线，氯化反应的收率都比较低，只有百分之六七十左右，进而导致总收率偏低；以邻硝基甲苯为原料，需要用到昂贵且不易得到的催化剂，很难应用于工业化生产
本发明共4步反应，第一步还原反应收率在98%左右，第二取代反应和第三步取代反应总收率在90%左右，第四步甲胺化收率96%左右，4步总收率84.7%左右；最终产品纯度99.5%以上，明显高于目前专利工艺98.5%左右的纯度。本发明产品纯度高、收率高、三废大幅减少、操作简单、反应条件温和、无高温高压以及深冷工艺条件，很适合工业化大生产。
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Abstract
Description
Technical Field
[0001] This invention relates to the field of chemical synthesis technology, specifically a method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide. Background Technology
[0002] 2-Amino-5-chloro-N,3-dimethylbenzamide is an important intermediate in the synthesis of chlorantraniliprole. Chlorantraniliprole insecticides are safe and environmentally friendly for mammals, exhibit good activity against lepidopteran insects, and show no cross-resistance with other existing insecticides. Sales of chlorantraniliprole are increasing year by year, indicating a huge market potential. Developing a competitive, high-quality process for synthesizing 2-amino-5-chloro-N,3-dimethylbenzamide is therefore urgently needed.
[0003] Numerous literature reports on the processes for producing 2-amino-5-chloro-N,3-dimethylbenzamide, with the process using 2-nitro-3-methylbenzoic acid and o-nitrotoluene as raw materials being the most common. (1) Using 2-nitro-3-methylbenzoic acid as raw material, it is esterified with methanol under sulfuric acid catalysis to generate methyl 2-nitro-3-methylbenzoate. The ester is methylated with a methylamine methanol solution to generate 2-nitro-N,3-dimethylbenzamide. After nitro reduction (iron powder, palladium on carbon, hydrazine hydrate, etc.), 2-amino-N,3-dimethylbenzamide is generated. Finally, it is chlorinated with sulfonyl chloride or hydrochloric acid and hydrogen peroxide to obtain 2-amino-5-chloro-N,3-dimethylbenzamide.
[0004] (2) Using 3-methylbenzoic acid as raw material, nitric acid as solvent and reactant, nitration reaction is carried out to obtain 2-nitro-3-methylbenzoic acid. Then, nitro reduction is carried out to generate 2-amino-3-methylbenzoic acid, which is then reacted with phosgene (solid phosgene, diphosgene) to form a cyclization compound. Then, it is reacted with methylamine methanol solution for methylation, and finally reacted with sulfonyl chloride or hydrochloric acid and hydrogen peroxide for chlorination to obtain 2-amino-5-chloro-N,3-dimethylbenzamide.
[0005] (3) Using o-nitrotoluene as raw material, a reduction reaction is first carried out to generate o-aminotoluene, and then a chlorination reaction is carried out to generate 2-amino-3,5-dichlorotoluene. Under the action of a catalyst, it reacts with carbon monoxide and monomethylamine to generate 2-amino-5-chloro-N,3-dimethylbenzamide.
[0006] (4) Using o-nitrotoluene as raw material, a reduction reaction is first carried out to generate o-aminotoluene, and then a chlorination reaction is carried out to generate 2-amino-3,5-dichlorotoluene. Under the action of a catalyst, it selectively reacts with sodium cyanide to generate 2-amino-3-cyano-5-chlorotoluene. It then undergoes a hydrolysis reaction to generate 2-amino-3-methyl-5-chlorobenzoic acid. Under the action of a solid light, a cyclization reaction is carried out, and finally it reacts with methylamine methanol to generate 2-amino-5-chloro-N,3-dimethylbenzamide.
[0007] In existing technologies, regardless of the process route used, the yield of the chlorination reaction is relatively low, only about 60% to 70%, which leads to a low overall yield. Using o-nitrotoluene as a raw material requires expensive and hard-to-obtain catalysts, making it difficult to apply to industrial production. Summary of the Invention
[0008] To address the aforementioned technical problems, the present invention aims to provide a method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide with high yield, mild reaction conditions, simple operation, and suitability for large-scale industrial production.
[0009] To achieve the above objectives, the present invention provides the following technical solution: the preparation method includes the following steps: S1. The compound shown in Formula I, organic solvent 1, and catalyst are added to a high-pressure reactor, and hydrogen is introduced to carry out a reduction reaction. After the reaction is completed, the catalyst is recovered by hot filtration. The filtrate is concentrated, cooled, filtered, and washed to obtain the compound shown in Formula II. S2. Add the compound shown in Formula II to organic solvent 2, add sulfonyl chloride dropwise, add water to separate the layers after the reaction is complete, keep the lower layer, and obtain the compound shown in Formula III; S3. Add thionyl chloride and a small amount of DMF to the solution of the compound shown in Formula III to carry out the chlorination reaction. The filtrate is cooled, quenched, separated into layers, and concentrated to obtain the compound shown in Formula IV. S4. Add the compound shown in Formula IV to organic solvent 3, add monomethylamine solution dropwise, and keep the reaction at a constant temperature after the addition is complete. After the reaction is complete, add water and reduce the pressure to recover the organic solvent. After cooling, filtration, rinsing, and drying, obtain the compound shown in Formula V, which is the target product.
[0010] The intermediate components for each step are as follows: .
[0011] Preferably, the heat preservation reaction temperature in S1 is 20~60℃, and the heat preservation reaction pressure is 0~3MPa.
[0012] Preferably, the organic solvent 1 in S1 is methanol, ethanol or isopropanol.
[0013] Preferably, the molar ratio of the sulfonyl chloride and the compound represented by formula II in S2 is 0.5 to 2:1; the dropping temperature of the sulfonyl chloride is -10 to 10°C; the reaction temperature is 10 to 40°C; and the reaction time is 2 to 5 hours.
[0014] Preferably, the organic solvent 2 in S2 is dichloromethane, dichloroethane, or trichloroethylene.
[0015] Preferably, the molar ratio of thionyl chloride and the compound represented by formula III in S3 is 0.5 to 2:1.
[0016] Preferably, the thionyl chloride added in S3 is at a temperature of -10 to 10°C; the reaction temperature is 0 to 20°C; and the reaction time is 2 to 5 hours.
[0017] Preferably, the methylamine in S4 is added at a temperature of 0~20℃, the reaction temperature is maintained at 10~40℃, and the reaction time is maintained at 3~7 hours; the molar ratio of the methylamine to the compound shown in Formula IV is 0.5~2.5:1.
[0018] Preferably, the organic solvent 3 in S4 is dichloromethane, toluene, or ethyl acetate.
[0019] Compared with the prior art, the beneficial effects of the present invention are: This invention involves four reaction steps. The first step, reduction, has a yield of approximately 98%. The second and third steps, substitution, have a combined yield of approximately 90%. The fourth step, methylation, has a yield of approximately 96%, resulting in an overall yield of approximately 84.7%. The final product has a purity of over 99.5%, significantly higher than the approximately 98.5% purity achieved by current patented processes. This invention offers high product purity, high yield, significantly reduced waste, simple operation, mild reaction conditions, and eliminates the need for high-temperature, high-pressure, and cryogenic processes, making it highly suitable for large-scale industrial production. Attached Figure Description
[0020] Figure 1 This is a synthetic route diagram for the present invention.
[0021] Figure 2 The HPLC chromatogram of 2-amino-5-chloro-N,3-dimethylbenzamide of this invention is shown below.
[0022] Figure 3 This is the LC-MS spectrum of 2-amino-5-chloro-N,3-dimethylbenzamide of the present invention. Detailed Implementation
[0023] The technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.
[0024] Example 1: In a 1L autoclave, add the compound shown in I (181.2g, 1mol, 1.0eq), 500g of ethanol, and 4g of 4% palladium on carbon. First, purge with nitrogen three times, then purge with hydrogen three times. Adjust the temperature to 40-60℃ and start the reduction reaction by passing hydrogen gas through the system. Maintain the hydrogen pressure at 1.0-2.0MPa. Continue heating for 1 hour after the reaction stops absorbing hydrogen. Filter the solution, distill off about 300g of ethanol from the filtrate, and cool the remaining solution to 0-5℃. Filter the solution under vacuum and dry it to obtain 148g of the compound shown in II, with a purity of 99.5% and a yield of 98%.
[0025] Add 148g of compound II and 740g of dichloromethane to a 2000mL four-necked flask. Control the temperature at approximately 0-5℃ and begin adding sulfonyl chloride (175.4g, 1.5eq, 1.47mol) dropwise. Control the temperature at -5 to 5℃ during the dropwise addition process. The dropwise addition is completed in about 1 hour. Then, maintain the reaction temperature at 20-30℃ for 5 hours. After the reaction is completed, add 200g of water to the reaction solution for extraction and separation. The organic layer containing the compound shown in formula III is used for the next reaction.
[0026] In a 2000 mL four-necked flask, add approximately 1000 g of a dichloromethane solution of the compound shown in Formula III. Maintain the temperature at approximately -5 to 0 °C. Add DMF (1.85 g, 1%) and begin dropwise addition of thionyl chloride (60.6 g, 1.2 eq, 1.2 mol). Maintain the temperature at -5 to 0 °C during the dropwise addition, continuing for approximately 1 hour. Then, maintain the reaction temperature at 5 to 10 °C for 2 hours. After the reaction is complete, quench the reaction mixture in 500 mL of water, maintaining the temperature at 20 °C. The mixture separates into layers, and the organic phase is concentrated to obtain the compound shown in Formula IV: 182.4 g, purity 98.3%, yield 90%.
[0027] In a 2000 mL four-necked flask, the compound shown in IV (182 g, 0.89 mol, 1.0 eq) and dichloromethane (364 g) were added. A 40% aqueous solution of monomethylamine (100.8 g, 1.3 mol, 1.5 eq) was then added dropwise, with the temperature controlled at 10–15 °C. After the addition was complete, the reaction mixture was kept at 20–30 °C for 5 hours. Then, 800 g of water was added to the reaction mixture. The dichloromethane was then recovered under reduced pressure. After the dichloromethane recovery was complete, the mixture was cooled to 15–25 °C, filtered, washed, and dried to obtain 170.1 g of 2-amino-5-chloro-N,3-dimethylbenzamide (the target product, compound shown in V), with a purity of 99.7% and a yield of 96.0%.
[0028] Example 2: In a 1L autoclave, the compound shown in I (181.2g, 1mol, 1.0eq), methanol (500g), and 4% palladium on carbon (4g) were added. The mixture was first purged with nitrogen three times, then with hydrogen three times. The temperature was then adjusted to 30-40℃, and hydrogen was introduced to carry out the reduction reaction. The hydrogen pressure was maintained at 1.0-1.5MPa. When the reaction no longer absorbed hydrogen, the mixture was kept at this temperature for 1 hour. The mixture was filtered, and approximately 300g of methanol was distilled off from the filtrate. The remaining solution was cooled to 0-5℃, filtered, and dried to obtain 148.5g of the compound shown in II, with a purity of 99.4% and a yield of 98.3%.
[0029] Add 148g of II and 740g of dichloroethane to a 2000mL four-necked flask. Control the temperature at approximately 0-5℃ and begin adding sulfonyl chloride (151.5g, 1.3eq, 1.27mol) dropwise. Control the temperature at -5 to 5℃ during the dropwise addition process. The dropwise addition is completed in about 1 hour. Then, maintain the reaction temperature at 20-30℃ for 5 hours. After the reaction is completed, add 200g of water to the reaction solution for extraction and separation. The organic layer containing the compound shown in Formula III is used for the next reaction.
[0030] Add approximately 1000 g of dichloroethane solution of III to a 2000 mL four-necked flask, maintaining the temperature at approximately -5 to 0 °C. Add DMF (1.85 g, 1%) and begin dropwise addition of thionyl chloride (70.7 g, 1.4 eq, 1.4 mol), maintaining the temperature at -5 to 0 °C throughout the dropwise addition process. The addition is completed in approximately 1 hour, and the reaction is then maintained at 5 to 10 °C for 3 hours. After the reaction is complete, the reaction solution is quenched in 500 mL of water, maintaining the temperature at 20 °C. The mixture separates into layers, and the organic phase is concentrated to obtain compound IV: 184.4 g, purity 98.1%, yield 91%.
[0031] In a 2000 mL four-necked flask, the compound shown in IV (182 g, 0.89 mol, 1.0 eq) and ethyl acetate (364 g) were added. A 40% aqueous solution of monomethylamine (108.5 g, 1.4 mol, 1.6 eq) was then added dropwise, with the temperature controlled at 10–20 °C. After the addition was complete, the reaction mixture was kept at 20–30 °C for 5 hours. Then, 800 g of water was added to the reaction mixture. The ethyl acetate was then recovered under reduced pressure. After the ethyl acetate recovery was complete, the mixture was cooled to 15–20 °C, filtered, washed, and dried to obtain 171.0 g of 2-amino-5-chloro-N,3-dimethylbenzamide (target product, compound shown in V), with a purity of 99.6% and a yield of 96.5%.
[0032] Example 3: In a 1L autoclave, add the compound shown in I (181.2g, 1mol, 1.0eq), 500g of isopropanol, and 4g of 4% palladium on carbon. First, purge with nitrogen three times, then purge with hydrogen three times. Adjust the temperature to 40-50℃ and start the reduction reaction by passing hydrogen gas through the system. Maintain the hydrogen pressure at 1.0-1.7MPa. Continue heating for 1 hour after the reaction stops absorbing hydrogen. Filter the solution, distill off about 300g of isopropanol from the filtrate, and cool the remaining solution to 0-5℃. Filter the solution and dry it to obtain 149g of the compound shown in II, with a purity of 99.1% and a yield of 98.7%.
[0033] Add 148g of compound II and 740g of trichloroethylene to a 2000mL four-necked flask. Control the temperature at approximately 0-5℃ and begin adding sulfonyl chloride (175.4g, 1.4eq, 1.37mol) dropwise. Control the temperature at -5 to 5℃ during the dropwise addition process. The dropwise addition is completed in about 1 hour. Then, maintain the reaction temperature at 20-30℃ for 5 hours. After the reaction is completed, add 200g of water to the reaction solution for extraction and separation. The organic layer containing the compound shown in formula III is used for the next reaction.
[0034] Add approximately 1000 g of trichloroethylene solution (III) to a 2000 mL four-necked flask, maintaining the temperature at approximately -5 to 0 °C. Add DMF (1.85 g, 1%) and begin dropwise addition of thionyl chloride (75.8 g, 1.5 eq, 1.5 mol), maintaining the temperature at -5 to 0 °C throughout the dropwise addition process. The addition is completed in approximately 1 hour, and the reaction is then maintained at 5 to 10 °C for 3 hours. After the reaction is complete, the reaction solution is quenched in 500 mL of water, maintaining the temperature at 20 °C. The mixture separates into layers, and the organic phase is concentrated to obtain compound (IV): 182.4 g, purity 98.3%, yield 90%.
[0035] In a 2000 mL four-necked flask, the compound shown in IV (182 g, 0.89 mol, 1.0 eq) and toluene (364 g) were added. A 40% aqueous solution of monomethylamine (126.7 g, 1.6 mol, 1.9 eq) was then added dropwise, with the temperature controlled at 10–20 °C during the addition. After the addition was completed, the reaction mixture was kept at 20–30 °C for 5 hours. Then, 800 g of water was added to the reaction mixture. Toluene was recovered under reduced pressure from the water-added reaction mixture. After the toluene recovery was completed, the mixture was cooled to 15–20 °C, filtered, washed, and dried to obtain 171.7 g of 2-amino-5-chloro-N,3-dimethylbenzamide (target product, compound shown in V), with a purity of 99.5% and a yield of 96.9%.
[0036] Comparative example: The reduction reaction was carried out using 2-nitro-3-methylbenzoic acid as the initial raw material: In a 1L autoclave, 125g of 2-nitro-3-methylbenzoic acid (0.69mol, 1.0eq), 450g of methanol, 50g of water, and 1g of 5% palladium on carbon were added. The mixture was first purged with nitrogen three times, then with hydrogen three times. The temperature was then adjusted to 50℃, and hydrogen was introduced to carry out the reduction reaction. The hydrogen pressure was maintained at 1.0MPa. When the reaction no longer absorbed hydrogen, the temperature was maintained for another 3 hours. The mixture was filtered, and 50g of 36% hydrochloric acid was added dropwise to the filtrate to adjust the pH to 3-4. The addition time was 40min. After a white solid precipitated, the mixture was filtered, dried, and 96.7g of 2-amino-3-methylbenzoic acid was obtained with a purity of 99.3% and a yield of 92.8%.
[0037] Chlorination and cyclization reaction were carried out using 2-amino-3-methylbenzoic acid as the initial raw material: 2-nitro-3-methylbenzoic acid (55 g, 0.36 mol, 1.0 eq) and ethyl acetate (250 g) were added to a 500 mL four-necked flask. The temperature was lowered to about 0-5 °C, and 65 g of sulfonyl chloride was added dropwise. The temperature was controlled at 0-5 °C during the dropwise addition, which was completed after about 2 hours. The reaction was maintained at this temperature for 4 hours. After the reaction was completed, 32 g of styraxyl chloride was added in batches to carry out the cyclization reaction. The temperature was raised to 50 °C and the reaction was carried out for 7 hours. After the reaction was completed, the temperature was lowered to 0-10 °C, and the mixture was filtered to obtain the cyclized compound 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione: 66.4 g, purity: 97.5%, yield: 87.2%.
[0038] The methylation reaction was carried out with 6-chloro-8-methyl-2H-benzo[d][1,3]oxazine-2,4(1H)-dione: A cyclized compound (66 g, 0.31 mol, 1.0 eq), 150 g of ethyl acetate, and 1.1 g of acetic acid were added to a 500 mL four-necked flask. The temperature was lowered to 15 °C, and 40 g of a 40% aqueous solution of monomethylamine was added dropwise at a controlled temperature of 10–15 °C over 1.5 hours. After the addition was complete, the reaction was maintained at this temperature for 2 hours. After the reaction was complete, 2.2 g of sodium sulfite and 110 g of water were added. The ethyl acetate was distilled off under reduced pressure. After the reduced pressure was removed, 170 g of water was added. At this point, the external temperature was 50 °C. The temperature was lowered to 20–25 °C, and the mixture was filtered to obtain the final target compound, 2-amino-5-chloro-N,3-dimethylbenzamide: 54.4 g, purity 98.3%, yield 88.3%. The overall yield is 71.4%. The reaction requires solidification, which carries the risk of phosgene formation. Furthermore, the final product requires secondary purification, which reduces the yield. This method generates a significant amount of waste, causing severe pollution and resulting in low product purity.
[0039] This invention has the following innovations, which have solved the current technical barriers and improved the purity and yield of the product: (1) Hydrogenation reduction reaction: by selecting a suitable catalyst and determining the appropriate process parameters, the reaction purity is increased to about 99.5% and the yield can reach 98%; (2) Substitution reaction: by selecting a suitable solvent and determining the appropriate process parameters, the reaction selectivity is improved, and the reaction solution can directly carry out the next reaction, reducing reaction loss; (3) After the substitution reaction is completed, the product is more economical and environmentally friendly by layering and washing with water; (4) Methanation reaction: by using the recovered dichloromethane solution, the cost is greatly reduced, and the dichloromethane is conveniently distilled under reduced pressure after the reaction, which improves efficiency and further enhances the product competitiveness.
[0040] This invention addresses the problems of long overall reaction time and low yield by proposing a route that involves chlorination followed by methylation. The two chlorination steps are connected using the same solvent, requiring almost no post-processing, which greatly shortens the time, reduces losses, and significantly improves the yield.
[0041] Although embodiments of the invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made to these embodiments without departing from the principles and spirit of the invention, the scope of which is defined by the appended claims and their equivalents.
Claims
1. A method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide, characterized in that: The preparation method includes the following steps: S1. The compound shown in Formula I, organic solvent 1, and catalyst are added to a high-pressure reactor, and hydrogen is introduced to carry out a reduction reaction. After the reaction is completed, the catalyst is recovered by hot filtration. The filtrate is concentrated, cooled, filtered, and washed to obtain the compound shown in Formula II. S2. Add the compound shown in Formula II to organic solvent 2, add sulfonyl chloride dropwise, add water to separate the layers after the reaction is complete, keep the lower layer, and obtain the compound shown in Formula III; S3. Add thionyl chloride and a small amount of DMF to the solution of the compound shown in Formula III to carry out the chlorination reaction. The filtrate is cooled, quenched, separated into layers, and concentrated to obtain the compound shown in Formula IV. S4. Add the compound shown in Formula IV to organic solvent 3, add monomethylamine solution dropwise, and keep the reaction at a constant temperature after the addition is complete. After the reaction is complete, add water and reduce the pressure to recover the organic solvent. After cooling, filtration, rinsing and drying, the compound shown in V is obtained, which is the target product. The intermediate components for each step are as follows: 。 2. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The heat preservation reaction temperature described in S1 is 20~60℃, and the heat preservation reaction pressure is 0~3MPa.
3. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The organic solvent 1 mentioned in S1 is methanol, ethanol or isopropanol.
4. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The molar ratio of the sulfonyl chloride in S2 to the compound represented by formula II is 0.5 to 2:1; the dropping temperature of the sulfonyl chloride is -10 to 10°C; the reaction temperature is 10 to 40°C; and the reaction time is 2 to 5 hours.
5. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The organic solvent 2 mentioned in S2 is dichloromethane, dichloroethane, or trichloroethylene.
6. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The molar ratio of thionyl chloride described in S3 to the compound shown in Formula III is 0.5 to 2:
1.
7. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The thionyl chloride added in S3 is added at a temperature of -10 to 10°C; the reaction temperature is 0 to 20°C; and the reaction time is 2 to 5 hours.
8. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The methylamine in S4 is added at a temperature of 0~20℃, the reaction temperature is maintained at 10~40℃, and the reaction time is maintained at 3~7 hours; the molar ratio of the methylamine to the compound shown in Formula IV is 0.5~2.5:
1.
9. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The organic solvent 3 mentioned in S4 is dichloromethane, toluene, or ethyl acetate.