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

Abstract

The invention belongs to the technical field of chemical synthesis, and discloses a preparation method of 2-amino-5-chloro-N, 3-dimethyl benzamide, which comprises the following steps: taking a formula I as a raw material, and carrying out cyclization reaction on the raw material and solid light to generate a compound as shown in a formula II; carrying out nitration reaction on the compound as shown in the formula II, fuming nitric acid and concentrated sulfuric acid to generate a compound as shown in a formula III; then carrying out reduction reaction on the compound shown in the formula III and hydrogen under the catalysis of raney nickel to generate a compound shown in a formula IV; carrying out diazotization reaction on the compound as shown in the formula IV, sodium nitrite and hydrochloric acid, and generating a compound as shown in a formula V under the catalysis of cuprous chloride dehydrate; and reacting the compound as shown in the formula V with monomethylamine to generate a compound as shown in the formula VI. The preparation method provided by the invention has the advantages of high product purity, high yield, mild reaction conditions and simple operation, and is suitable for industrial mass production.

Description

Technical Field

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

[0002] 2-Amino-5-chloro-N,3-dimethylbenzamide is an important intermediate of chlorantraniliprole. Chlorantraniliprole is a type of insecticide that is safe and environmentally friendly to mammals, has good activity against lepidopteran insects, and has no cross-resistance with other existing insecticides. The sales volume of chlorantraniliprole is increasing year by year, and the market potential is huge.

[0003] There are many processes reported in the literature for the production of 2-amino-5-chloro-N,3-dimethylbenzamide, among which the process using 2-nitro-3-methylbenzoic acid and o-nitrotoluene as raw materials is the most common:

[0004] (1) 2-nitro-3-methylbenzoic acid is used as a raw material, and is subjected to an esterification reaction with methanol under the catalysis of sulfuric acid to generate 2-nitro-3-methylbenzoic acid methyl ester, and the ester is subjected to a methylamination reaction with a methanol solution of monomethylamine to generate 2-nitro-N,3-dimethylbenzamide, which is then subjected to nitro reduction (iron powder, palladium carbon, hydrazine hydrate, etc.) to generate 2-amino-N,3-dimethylbenzamide, and finally chlorinated with sulfuryl chloride or hydrochloric acid or hydrogen peroxide to obtain 2-amino-5-chloro-N,3-dimethylbenzamide.

[0005] (2) Using 3-methylbenzoic acid as a raw material, nitric acid as a solvent and reactants to undergo a nitration reaction to obtain 2-nitro-3-methylbenzoic acid, followed by nitro reduction to generate 2-amino-3-methylbenzoic acid, followed by reacting with phosgene (solid light, diphosgene) to generate a cyclized compound, followed by methylation with a methanol solution of monomethylamine, and finally chlorination with sulfonyl chloride or hydrochloric acid, hydrogen peroxide to obtain 2-amino-5-chloro-N,3-dimethylbenzamide.

[0006] (3) Taking o-nitrotoluene as the raw material, firstly reducing it to generate o-aminotoluene, then chlorinating it to generate 2-amino-3,5-dichlorotoluene, and then reacting it with carbon monoxide and monomethylamine in the presence of a catalyst to generate 2-amino-5-chloro-N,3-dimethylbenzamide.

[0007] (4) Taking o-nitrotoluene as the raw material, firstly a reduction reaction is carried out to generate o-aminotoluene, then a chlorination reaction is carried out to generate 2-amino-3,5-dichlorotoluene, then a selective reaction is carried out with sodium cyanide under the action of a catalyst to generate 2-amino-3-cyano-5-chlorotoluene, then a hydrolysis reaction is carried out to generate 2-amino-3-methyl-5-chlorobenzoic acid, then a cyclization reaction is carried out under the action of fixed light, and finally a reaction is carried out with monomethylamine methanol to generate 2-amino-5-chloro-N,3-dimethylbenzamide.

[0008] In the prior art, no matter which process route is adopted, the yield of the chlorination reaction is relatively low, only about 60 to 70 percent, which leads to a low overall yield; using o-nitrotoluene as a raw material requires expensive and difficult-to-obtain catalysts, which makes it difficult to apply to industrial production. Summary of the invention

[0009] The object of the present invention is to provide a method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide, so as to solve the problems of low raw material utilization and high cost proposed in the above background technology.

[0010] To achieve the above object, the present invention provides the following technical solution: a method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide, the method comprising the following steps:

[0011] S1. The compound represented by formula I is put into an organic solvent, and a light-fixing solution is added dropwise, and the reaction is heated to a stop. After the reaction is completed, part of the solvent is recovered under reduced pressure, and the compound represented by formula II is obtained by cooling, filtering, and rinsing;

[0012] S2. The compound of formula II is added to dichloroethane, fuming nitric acid and concentrated sulfuric acid are added dropwise, the reaction is completed and the layers are separated, the lower layer of mixed acid is to be applied, the upper layer of the material is added with water, cooled, filtered, and rinsed to obtain the compound of formula III;

[0013] S3. The compound represented by formula III, ethanol and Raney nickel are added to an autoclave, and hydrogen is passed through for reduction reaction. After the reaction is completed, the catalyst is recovered by hot filtration, and the filtrate is concentrated, cooled, filtered and rinsed to obtain a compound represented by formula IV;

[0014] S4. The compound represented by formula IV is added with hydrochloric acid, and an aqueous sodium nitrite solution is added dropwise to obtain a diazonium salt; the diazonium salt is then added dropwise to a solution containing cuprous chloride dihydrate and hydrochloric acid to carry out a heat-insulated reaction, and after the reaction is completed, the temperature is lowered, the solution is filtered, and the solution is rinsed to obtain a compound represented by formula V;

[0015] S5. The compound represented by formula V is added to an organic solvent, and an aqueous solution of monomethylamine is added dropwise, and the reaction is continued by incubation. After the reaction is completed, water is added to recover the organic solvent under reduced pressure, and the compound represented by formula VI is obtained by cooling, filtering, rinsing, and drying, i.e., the target product;

[0016] The intermediates of the above steps are as follows:

[0017]

[0018] Preferably, the organic solvent in S1 is butyl acetate, dimethyl carbonate or diethyl carbonate; the dropping temperature is 30-60° C.; the insulation reaction temperature is 40-80° C., and the insulation reaction time is 3-12 hours.

[0019] Preferably, the molar ratio of the light-fixing agent contained in the light-fixing solution in S1 to the compound represented by formula I is 0.35 to 0.6:1.

[0020] Preferably, the molar ratio of the concentrated sulfuric acid, fuming nitric acid and the compound represented by formula II in S2 is 0.3-0.5:1.1-1.4:1.

[0021] Preferably, the dropping temperature in S2 is -5 to 20°C; the insulation reaction temperature is 20 to 50°C, and the insulation reaction time is 1 to 5 hours.

[0022] Preferably, the insulation reaction temperature in S3 is 20-60° C., and the insulation reaction pressure is 1-2 MPa.

[0023] Preferably, the molar ratio of the sodium nitrite to the compound shown in formula IV in S4 is 1.1 to 1.5:1; the molar ratio of cuprous chloride dihydrate to the compound shown in formula IV is 0.1 to 0.2:1; the molar ratio of hydrochloric acid to the compound shown in formula IV during the diazotization reaction is 3.5 to 5.5:1, the molar ratio of hydrochloric acid to the compound shown in formula IV during the chlorination reaction is 1 to 2:1, and the concentration of hydrochloric acid is 31% to 36%.

[0024] Preferably, the reaction temperature of the compound represented by Formula IV in S4 and hydrochloric acid to form a salt is 20 to 60°C; the temperature of adding the sodium nitrite aqueous solution is -10 to 10°C; the temperature of the cuprous chloride catalytic reaction is 20 to 60°C, and the insulation reaction time is 1 to 5 hours.

[0025] Preferably, the monomethylamine aqueous solution is added dropwise at a temperature of 5 to 40° C., the insulation reaction temperature is 20 to 60° C., and the insulation reaction time is 1 to 6 hours.

[0026] Preferably, the molar ratio of the monomethylamine aqueous solution to the compound represented by formula V in S5 is 1 to 2:1.

[0027] Compared with the prior art, the invention has the following beneficial effects: the preparation method of 2-amino-5-chloro-N,3-dimethylbenzamide,

[0028] (1) Photocatalytic cyclization reaction: by selecting a suitable solvent and determining appropriate process parameters, the reaction yield is increased to about 98%;

[0029] (2) Nitration reaction: by selecting a suitable solvent and determining suitable process parameters, the reaction selectivity is improved and the yield is greatly increased to about 95%;

[0030] (3) After the nitration reaction is completed, the unreacted sulfuric acid and nitric acid are separated by stratification for application, which greatly reduces wastewater discharge and is more economical and environmentally friendly;

[0031] (4) The chlorination on the benzene ring is obtained by diazotization of amino groups and catalysis by cuprous chloride dihydrate. The total yield of amino groups converted to chlorine is about 95%, which is much higher than the 60-70% yield of chlorination by sulfonyl chloride and hydrogen peroxide hydrochloric acid;

[0032] (5) In the hydrogenation reduction reaction, the Raney nickel catalyst is used instead of the palladium carbon catalyst, which greatly reduces the catalyst cost and improves the product competitiveness. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 It is a schematic diagram of the preparation process route of the present invention. DETAILED DESCRIPTION

[0034] The following will be combined with the drawings in the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. 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 creative work are within the scope of protection of the present invention.

[0035] See also Figure 1 The present invention provides a technical solution: a method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide, the method comprising the following steps:

[0036] S1. Add the compound represented by formula I into an organic solvent, add the light-fixing solution dropwise, terminate the heat preservation reaction by adding dropwise, recover part of the solvent under reduced pressure after the reaction is completed, and obtain the compound represented by formula II by cooling, filtering and rinsing; wherein the organic solvent is butyl acetate, dimethyl carbonate or diethyl carbonate; the dropping temperature is 30-60°C; the heat preservation reaction temperature is 40-80°C, and the heat preservation reaction time is 3-12 hours. The molar ratio of light-fixing contained in the light-fixing solution in S1 to the compound represented by formula I is 0.35-0.6:1.

[0037] S2. Add the compound represented by formula II into dichloroethane, and drop fuming nitric acid and concentrated sulfuric acid. After the reaction is completed, separate the layers. The lower mixed acid layer is to be used, and water is added to the upper material. The mixture is cooled, filtered, and rinsed to obtain the compound represented by formula III. The molar ratio of concentrated sulfuric acid, fuming nitric acid and the compound represented by formula II is 0.3-0.5:1.1-1.4:1, and the dropping temperature is -5-20°C. The insulation reaction temperature is 20-50°C, and the insulation reaction time is 1-5 hours.

[0038] S3. Add the compound represented by formula III, ethanol and Raney nickel into an autoclave, pass hydrogen to carry out reduction reaction, filter and recover the catalyst while hot after the insulation reaction is completed, concentrate the filtrate, cool it, filter it and rinse it to obtain the compound represented by formula IV; wherein the insulation reaction temperature is 20-60°C, and the insulation reaction pressure is 1-2MPa.

[0039] S4. Add hydrochloric acid to the compound shown in formula IV, and dropwise add sodium nitrite aqueous solution to obtain a diazonium salt; then dropwise add the diazonium salt into a solution containing dihydrate cuprous chloride and hydrochloric acid for a heat-insulating reaction, cool down after the reaction, filter, and rinse to obtain a compound shown in formula V; wherein, the molar ratio of sodium nitrite to the compound shown in formula IV is 1.1 to 1.5:1; the molar ratio of dihydrate cuprous chloride to the compound shown in formula IV is 0.1 to 0.2:1; during the diazotization reaction, the molar ratio of hydrochloric acid to the compound shown in formula IV is 3.5 to 5.5:1, during the chlorination reaction, the molar ratio of hydrochloric acid to the compound shown in formula IV is 1 to 2:1, the concentration of hydrochloric acid is 31% to 36%, and the salt-forming reaction temperature of the compound shown in formula IV and hydrochloric acid is 20 to 60°C; the temperature of the sodium nitrite aqueous solution is -10 to 10°C; the temperature of the cuprous chloride catalytic reaction is 20 to 60°C, and the heat-insulating reaction time is 1 to 5 hours.

[0040] S5. Add the compound represented by formula V to an organic solvent, add monomethylamine aqueous solution dropwise, and terminate the heat preservation reaction by adding dropwise. After the reaction is completed, add water and reduce the pressure to recover the organic solvent. After cooling, filtering, rinsing and drying, the compound represented by formula VI, i.e., the target product, is obtained; wherein, the monomethylamine aqueous solution is added dropwise at a temperature of 5 to 40°C, the heat preservation reaction temperature is 20 to 60°C, the heat preservation reaction time is 1 to 6 hours, and the molar ratio of the monomethylamine aqueous solution to the compound represented by formula V is 1 to 2:1.

[0041] The intermediates of the above steps are as follows:

[0042]

[0043] Embodiment 1: add dimethyl carbonate: 750g, 2-amino-3-methylbenzoic acid (151g, 1mol, 1.0eq) in 2000mL four-necked flask, control temperature about 30 ℃, begin to drip dissolved solid light solution (solid light: 120g, 0.404mol, 0.4eq, dimethyl carbonate: 250g), drip process control temperature 30~40 ℃, about 1 hour dripping finishes, then at 50~60 ℃ insulation reaction 10 hours, reaction finishes reduced pressure recovery dimethyl carbonate: about 300g, recovery finishes cooling to 5~10 ℃ suction filtration, filter cake is rinsed with dimethyl carbonate: 100g, dry, obtain the compound shown in formula II: 173.5g, purity 99.3%, yield 98%;

[0044] In a 2000mL four-necked flask, add 850g of dichloroethane and the compound shown in Formula II (173.5g, 0.98mol, 1.0eq), control the temperature at -5 to 0°C, start to dropwise add 98% fuming nitric acid (78.8g, 1.225mol, 1.25eq) and 98% concentrated sulfuric acid (30g, 0.3mol, 0.306eq), control the temperature at 0 to 10°C during the dropwise addition process, and add for about 2 hours. The mixture was heated to 20-30°C for 4 hours, and then allowed to stand for stratification after the reaction was completed. The excess mixed acid in the lower layer was removed for standby use. The upper layer was poured into a 2000 mL flask filled with 800 g of water, and then reduced pressure distillation was started to recover dichloroethane. After the recovery of dichloroethane was completed, the temperature was lowered to 10-15°C and filtered. The filter cake was rinsed with water until the pH of the rinse filtrate was 6-7, and dried to obtain 206.7 g of the compound represented by formula III, with a purity of 99.0% and a yield of 95%.

[0045] In a 1L autoclave, add the compound represented by formula III (206.7g, 0.931mol, 1.0eq), ethanol: 500g, Raney nickel: 5.4g, replace with nitrogen 3 times, then replace with hydrogen 3 times, then adjust the temperature to 20-30°C and start to pass hydrogen for reduction reaction, the hydrogen pressure is maintained at 1.0-1.2MPa, and keep warm for 1 hour when the reaction no longer absorbs hydrogen, filter, evaporate ethanol from the filtrate: about 300g, cool the remaining material to 0-5°C, filter, and dry to obtain the compound represented by formula IV: 175.2g, purity 99.6%, yield 98%;

[0046] In a 1000ml four-necked flask, add the compound represented by formula IV (175.2g, 0.912mol, 1.0eq) and 31% hydrochloric acid (536.9g, 4.56mol, 5.0eq) and stir at 20-25°C for 0.5 hour, then cool to about -10°C and dropwise add the prepared sodium nitrite aqueous solution: 178.7g (sodium nitrite: (78.7g, 1.14mol, 1.25eq) + water: 100g), maintain the temperature at -10--5°C during the dropwise addition, and stir at this temperature for 0.5 hour after the dropwise addition is completed; In another 1000ml four-necked flask, add 31% hydrochloric acid: (134.2g, 1.14mol, 1.25eq)) and cuprous chloride dihydrate (14.9g, 0.11mol, 0.12eq) and adjust the temperature to 30°C, then drop the above diazonium salt reaction material into the flask, maintain the temperature at 30-40°C during the dropwise addition, keep the temperature at 30-40°C for 3 hours after the dropwise addition, cool to 5-10°C after the reaction, filter, rinse, and dry to obtain 183.3g of the compound represented by formula V, with a purity of 99.1% and a yield of 95%;

[0047] In a 2000ml four-necked flask, add the compound represented by formula V (183.3g, 0.866mol, 1.0eq) and dimethyl carbonate: 650g, adjust the temperature to 10-15°C and start to dropwise add 40% monomethylamine aqueous solution (90.7g, 1.17mol, 1.35eq), control the temperature at 10-25°C during the dropping process, keep the reaction at 20-30°C for 5 hours after the dropping is completed, then add water: 800g and start to reduce the pressure to recover ethyl acetate, cool to 15-25°C after the recovery is completed, filter, rinse, and dry to obtain 2-amino-5-chloro-N,3-dimethylbenzamide (target product, compound represented by formula VI): 165.0g, purity 99.3%, yield 96.0%.

[0048] Embodiment 2: add diethyl carbonate: 750g, 2-amino-3-methylbenzoic acid (151g, 1mol, 1.0eq) in 2000mL four-necked flask, control temperature about 40 ℃, begin to drip dissolved solid light solution (solid light: 133.6g, 0.45mol, 0.45eq, diethyl carbonate: 250g), drip process control temperature 40~50 ℃, about 1 hour dripping finishes, then at 60~70 ℃ insulation reaction 7 hours, reaction finishes reduced pressure recovery diethyl carbonate: about 300g, recovery finishes cooling to 5~10 ℃ suction filtration, filter cake is rinsed with diethyl carbonate: 100g, dry, obtain the compound shown in formula II: 173.8g, purity 99.1%, yield 98.2%;

[0049] Add 850 g of dichloroethane and the compound of formula II (173.8 g, 0.982 mol, 1.0 eq) into a 2000 mL four-necked flask, control the temperature at 0-5 °C, start dripping 98% fuming nitric acid (72.6 g, 1.129 mol, 1.15 eq) and 98% concentrated sulfuric acid (35 g, 0.35 mol, 0.356 eq) mixed evenly, control the temperature at 5-15 °C during the dripping process, and finish the dripping in about 2 hours. , then keep the temperature at 30-40°C for 2 hours, stand for stratification after the reaction, remove the excess mixed acid in the lower layer for standby use, pour the upper layer material into a 2000mL flask filled with 800g of water, and then start to distill under reduced pressure to recover dichloroethane. After the recovery of dichloroethane, cool to 10-15°C and filter, rinse the filter cake with water until the pH of the rinse filtrate is 6-7, and dry to obtain 206.0g of the compound shown in formula III, with a purity of 99.2% and a yield of 94.5%;

[0050] In a 1L autoclave, add the compound represented by formula III (206.0g, 0.928mol, 1.0eq), ethanol: 500g, Raney nickel: 5.4g, replace with nitrogen 3 times, then replace with hydrogen 3 times, then adjust the temperature to 30-40°C and start to pass hydrogen for reduction reaction, the hydrogen pressure is maintained at 1.2-1.5MPa, and keep warm for 1 hour when the reaction no longer absorbs hydrogen, filter, evaporate ethanol from the filtrate: about 300g, cool the remaining material to 0-5°C, filter, and dry to obtain the compound represented by formula IV: 175.5g, purity 99.3%, yield 98.5%;

[0051] In a 1000ml four-necked flask, add the compound represented by formula IV (175.5g, 0.914mol, 1.0eq) and 31% hydrochloric acid (430.5g, 3.656mol, 4.0eq) and stir at 30-35°C for 0.5 hour, then cool to about -5°C and dropwise add the prepared sodium nitrite aqueous solution: 185.1g (sodium nitrite: 85.1g, 1.233mol, 1.35eq) + water: 100g), maintain the temperature at -5-0°C during the dropwise addition, and stir at this temperature for 0.5 hour after the dropwise addition is completed; In another 1000ml four-necked flask, 31% hydrochloric acid (161.4g, 1.371mol, 1.5eq) and cuprous chloride dihydrate (18.6g, 0.137mol, 0.15eq) were added. When the temperature was adjusted to 40°C, the above diazonium salt reaction material was added dropwise to the flask. During the addition, the temperature was maintained at 40-55°C. After the addition was completed, the temperature was kept at 40-55°C for 2 hours. After the reaction was completed, the temperature was lowered to 5-10°C, filtered, rinsed, and dried to obtain 182.7g of the compound represented by formula V, with a purity of 99.0% and a yield of 94.5%.

[0052] In a 2000ml four-necked flask, add the compound represented by formula V (182.7g, 0.864mol, 1.0eq) and diethyl carbonate: 650g, adjust the temperature to 5-10°C and start to dropwise add 40% monomethylamine aqueous solution (83.7g, 1.08mol, 1.25eq), control the temperature at 5-15°C during the dropping process, keep the reaction at 30-40°C for 3 hours after the dropping is completed, then add water: 800g and start to recover diethyl carbonate under reduced pressure, cool to 15-25°C after the recovery is completed, filter, rinse, and dry to obtain 2-amino-5-chloro-N,3-dimethylbenzamide (target product, compound represented by formula VI): 165.5g, purity 99.2%, yield 96.5%.

[0053] Embodiment 3: add butyl acetate: 750g, 2-amino-3-methylbenzoic acid (151g, 1mol, 1.0eq) in 2000mL four-necked flask, control temperature about 50 ℃, begin to drip dissolved solid light solution (solid light: 112.9g, 0.38mol, 0.38eq, butyl acetate: 250g), drip process control temperature 50~55 ℃, drip end about 1 hour, then keep warm at 70~75 ℃ and react for 5 hours, after reaction, reduce pressure and recycle butyl acetate: about 300g, after recycle, cool to 5~10 ℃ and filter, rinse filter cake with butyl acetate: 100g, dry, obtain compound shown in formula II: 174.4g, purity 99.5%, yield 98.5%;

[0054] Add 850 g of dichloroethane and the compound shown in Formula II (174.4 g, 0.985 mol, 1.0 eq) into a 2000 mL four-necked flask, control the temperature at -5 to 0 ° C, and start adding a uniform mixture of 98% fuming nitric acid (76.0 g, 1.182 mol, 1.2 eq) and 98% concentrated sulfuric acid (40 g, 0.40 mol, 0.406 eq). Control the temperature at -5 to 5 ° C during the addition process. The addition is completed in about 2 hours. , then keep the temperature at 25-35°C for 3 hours, stand for stratification after the reaction, remove the excess mixed acid in the lower layer for standby use, pour the upper layer material into a 2000mL flask filled with 800g of water, and then start to distill under reduced pressure to recover dichloroethane. After the recovery of dichloroethane, cool to 10-15°C and filter, rinse the filter cake with water until the pH of the rinse filtrate is 6-7, and dry to obtain 208.8g of the compound shown in formula III, with a purity of 99.3% and a yield of 95.5%;

[0055] In a 1L autoclave, add the compound shown in formula III (208.8g, 0.940mol, 1.0eq), ethanol: 500g, Raney nickel: 5.4g, replace with nitrogen 3 times, then replace with hydrogen 3 times, then adjust the temperature to 40-50°C and start to pass hydrogen for reduction reaction, the hydrogen pressure is maintained at 1.5-1.8MPa, and keep warm for 1 hour when the reaction no longer absorbs hydrogen, filter, evaporate ethanol from the filtrate: about 300g, cool the remaining material to 0-5°C, filter, and dry to obtain the compound shown in IV: 176.9g, purity 99.3%, yield 98.0%;

[0056] In a 1000ml four-necked flask, add the compound represented by formula IV (176.9g, 0.921mol, 1.0eq) and 31% hydrochloric acid (487.9g, 4.144mol, 4.5eq) and stir at 40-50°C for 0.5 hour, then cool to about -5°C and dropwise add the prepared sodium nitrite aqueous solution: 182.6g (sodium nitrite: 82.6g, 1.197mol, 1.30eq) + water: 100g), maintain the temperature at -5-0°C during the dropwise addition, and keep stirring at this temperature for 0.5 hour after the dropwise addition is completed; In another 1000ml four-necked flask, 31% hydrochloric acid (161.4g, 1.371mol, 1.5eq) and cuprous chloride dihydrate (24.9g, 0.184mol, 0.20eq) were added, and the temperature was adjusted to 40°C. The above diazonium salt reaction material was added dropwise to the flask. The temperature was maintained at 40-50°C during the addition. After the addition was completed, the mixture was kept at 40-50°C for 2 hours. After the reaction was completed, the temperature was lowered to 5-10°C, filtered, rinsed, and dried to obtain 186.0g of the compound shown in V, with a purity of 99.2% and a yield of 95.5%;

[0057] In a 2000ml four-necked flask, add the compound represented by formula V (186.0g, 0.879mol, 1.0eq) and butyl acetate: 650g, adjust the temperature to 20-30°C and start to dropwise add 40% monomethylamine aqueous solution (95.3g, 1.23mol, 1.40eq), control the temperature at 20-30°C during the dropping process, keep the reaction at 40-50°C for 2 hours after the dropping is completed, then add water: 800g and start to recover butyl acetate under reduced pressure, cool to 15-25°C after the recovery is completed, filter, rinse, and dry to obtain 2-amino-5-chloro-N,3-dimethylbenzamide (target product, compound represented by formula VI): 167.5g, purity 99.4%, yield 96.0%.

[0058] Comparative Example: 3-methylbenzoic acid is used as the initial raw material: firstly, nitration reaction is carried out to obtain 2-nitro-3-methylbenzoic acid, followed by esterification reaction and methylamination reaction to obtain 2-nitro-N, 3-dimethylbenzamide; then, iron powder reduction reaction and sulfonyl chloride chlorination reaction are carried out to obtain 2-amino-5-chloro-N, 3-dimethylbenzamide. According to literature reports: the yield of the nitration step is 45-50%, the reaction selectivity is poor, and a large amount of waste acid is produced; the total yield of the subsequent esterification, methylamination, reduction, and chlorination is only 69-82%, the product purity is 98.5%, and the total yield based on 3-methylbenzoic acid is only 31%-41%. This method produces a lot of three wastes, serious pollution, and low product purity.

[0059] As shown in Examples 1-3, the preparation method of 2-amino-5-chloro-N, 3-dimethylbenzamide is divided into 5 steps of reaction, the first step of solid light ring formation reaction yield is about 98%, the second step of nitration reaction yield is about 95%, the third step of reduction reaction yield is about 98%, the fourth step of diazotization and chlorination yield is about 95%, the fifth step of methyl amination reaction yield is about 96%, and the total yield of 5 steps is about 83%; the purity of the final product is more than 99.2%, which is significantly higher than the purity of about 98.5% of the current process in the comparative example. The product of the present invention has high purity, high yield, greatly reduced three wastes, simple operation, mild reaction conditions, no high temperature and high pressure and deep cold process conditions, and is very suitable for large-scale industrial production.

[0060] Although 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 the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention 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 comprises the following steps: S1. The compound represented by formula I is put into an organic solvent, and a light-fixing solution is added dropwise, and the reaction is heated to a stop. After the reaction is completed, part of the solvent is recovered under reduced pressure, and the compound represented by formula II is obtained by cooling, filtering, and rinsing; S2. The compound of formula II is added to dichloroethane, fuming nitric acid and concentrated sulfuric acid are added dropwise, the reaction is completed and the layers are separated, the lower layer of mixed acid is to be applied, the upper layer of the material is added with water, cooled, filtered, and rinsed to obtain the compound of formula III; S3. The compound represented by formula III, ethanol and Raney nickel are added to an autoclave, and hydrogen is passed through for reduction reaction. After the reaction is completed, the catalyst is recovered by hot filtration, and the filtrate is concentrated, cooled, filtered and rinsed to obtain a compound represented by formula IV; S4. The compound represented by formula IV is added with hydrochloric acid, and an aqueous sodium nitrite solution is added dropwise to obtain a diazonium salt; the diazonium salt is then added dropwise to a solution containing cuprous chloride dihydrate and hydrochloric acid to carry out a heat-insulated reaction, and after the reaction is completed, the temperature is lowered, the solution is filtered, and the solution is rinsed to obtain a compound represented by formula V; S5. The compound represented by formula V is added to an organic solvent, and an aqueous solution of monomethylamine is added dropwise, and the reaction is continued by incubation. After the reaction is completed, water is added to recover the organic solvent under reduced pressure, and the compound represented by formula VI is obtained by cooling, filtering, rinsing, and drying, i.e., the target product; The intermediates of the above steps are as follows:

2. A method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The organic solvent in S1 is butyl acetate, dimethyl carbonate or diethyl carbonate; the dropping temperature is 30-60° C.; the insulation reaction temperature is 40-80° C., and the insulation reaction time is 3-12 hours.

3. A method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The molar ratio of the solid light contained in the solid light solution in S1 to the compound represented by formula I is 0.35 to 0.6:

1.

4. A method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The molar ratio of the concentrated sulfuric acid, fuming nitric acid and the compound represented by formula II in S2 is 0.3-0.5:1.1-1.4:

1.

5. A method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The dropping temperature in S2 is -5 to 20°C; the insulation reaction temperature is 20 to 50°C, and the insulation reaction time is 1 to 5 hours.

6. A method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The insulation reaction temperature in S3 is 20-60° C., and the insulation reaction pressure is 1-2 MPa.

7. A method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The molar ratio of sodium nitrite to the compound shown in formula IV in S4 is 1.1 to 1.5:1; the molar ratio of cuprous chloride dihydrate to the compound shown in formula IV is 0.1 to 0.2:1; the molar ratio of hydrochloric acid to the compound shown in formula IV during the diazotization reaction is 3.5 to 5.5:1, the molar ratio of hydrochloric acid to the compound shown in formula IV during the chlorination reaction is 1 to 2:1, and the concentration of hydrochloric acid is 31% to 36%.

8. A method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The reaction temperature of the compound represented by Formula IV in S4 and hydrochloric acid to form a salt is 20 to 60°C; the temperature of adding the sodium nitrite aqueous solution is -10 to 10°C; the temperature of the cuprous chloride catalytic reaction is 20 to 60°C, and the insulation reaction time is 1 to 5 hours.

9. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The monomethylamine aqueous solution in S5 is added dropwise at a temperature of 5 to 40° C., the heat preservation reaction temperature is 20 to 60° C., and the heat preservation reaction time is 1 to 6 hours.

10. The method for preparing 2-amino-5-chloro-N,3-dimethylbenzamide according to claim 1, characterized in that: The molar ratio of the monomethylamine aqueous solution in S5 to the compound represented by formula V is 1 to 2:1.

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