Preparation method of 3, 5-dichloro-2-aminobenzoyl isopropylamine

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a preparation method of 3, 5-dichloro-2-aminobenzoyl isopropylamine, o-nitrobenzoic acid is taken as an initial raw material, 80% hydrazine hydrate is dropwise added, a catalyst prepared in advance is matched, o-aminobenzoic acid is prepared, then the o-aminobenzoic acid is dissolved in dichloroethane to react with sulfuryl chloride, and 3, 5-dichloro-2-aminobenzoyl isopropylamine is prepared. The preparation method comprises the following steps: reacting 3, 5-dichloro-2-aminobenzoic acid with triphosgene under an alkaline condition to generate 3, 5-dichloro-2-aminobenzoyl chloride, and reacting the 3, 5-dichloro-2-aminobenzoyl chloride with isopropanolamine to obtain the final product 3, 5-dichloro-2-aminobenzoyl isopropylamine. By reasonably controlling the raw material ratio and reaction conditions in each step, the reaction in each step is sufficient, the obtained 3, 5-dichloro-2-aminobenzoyl isopropylamine is high in purity and yield, the used raw materials are cheap and easy to obtain, the requirements on production equipment are low, the process conditions are simple, the labor and energy consumption are greatly reduced and saved, the cost is low, and industrial production is easy.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a preparation method of 3,5-dichloro-2-aminobenzoyl isopropylamine. Background Art

[0002] 3,5-dichloro-2-aminobenzoyl isopropylamine, also known as ethyl forin, is mainly used to treat diseases such as attention deficit hyperactivity disorder (ADHD) and narcolepsy, and improves attention and alertness by regulating the balance of chemicals in the brain. At the same time, it is also a pesticide intermediate and can be used to synthesize compounds such as 3,5-dichloro-2-aminobenzoylthioisopropylamine, which plays a role in insecticide, weed control or regulating plant growth in agricultural production. At present, although the production process of 3,5-dichloro-2-aminobenzoyl isopropylamine is becoming more and more mature, there are still problems such as insufficient reaction, long time consumption, expensive raw materials, low purity and complex process in the production process. Therefore, it is necessary to develop a new preparation method for 3,5-dichloro-2-aminobenzoyl isopropylamine with high quality, safety, environmental protection and low cost. Summary of the invention

[0003] In view of the above defects or improvement needs of the prior art, the present invention provides a method for preparing 3,5-dichloro-2-aminobenzoyl isopropylamine. The raw materials of the preparation method are cheap and easily available, the requirements for production equipment are low, the process conditions are simple, there is no safety risk, it has obvious cost advantages, and it is easy to industrialize production.

[0004] In order to achieve the above object, the present invention provides a method for preparing 3,5-dichloro-2-aminobenzoyl isopropylamine, which comprises the following steps: (1) Preparation of catalyst: Add water to an enameled reactor and start the stirring device. Then add ferric chloride hexahydrate in batches. After stirring until it is completely dissolved, add activated carbon. Then, add sodium hydroxide solution dropwise at room temperature. After the addition is complete, stir at 25-35°C for 1 hour. After filtering, rinse the residue with water for 1-3 times and set aside. (2) Preparation of o-aminobenzoic acid: prepare a clean enameled glass kettle, add water, start the stirring device, add sodium hydroxide in batches, stir until completely dissolved, add o-nitrobenzoic acid, continue to stir until completely dissolved, add the catalyst prepared in step (1), raise the temperature to between 80-90°C, add 80% hydrazine hydrate dropwise, keep warm and stir to react after the addition, filter while hot, wash the obtained filter cake with alkaline water 1-3 times and filter, combine the filtrate and transfer it to another enameled reaction kettle, cool to room temperature, adjust the pH to 3-4 with hydrochloric acid, add dichloroethane and stir to react, solid crystals precipitate, remove the water phase, add dichloroethane again to the initial amount, raise the temperature to perform azeotropic separation until the water is completely separated, and set aside; wherein the reaction formula of this step is as follows: .

[0005] In this step, by strictly controlling the reaction temperature after adding the catalyst, the normal progress of the reaction can be effectively promoted. If the temperature is lower than 80°C, the reaction cannot proceed, and if the temperature is higher than 90°C, other impurities will be produced, affecting the normal progress of the reaction. Controlling the pH at 3-4 with hydrochloric acid can effectively prevent the formation of anthranilate.

[0006] (3) Preparation of 3,5-dichloro-2-aminobenzoic acid: In a clean enameled reactor, turn on the stirring device, add the anthranilic acid obtained in step (2) and dichloroethane, control the reaction temperature to 25-35°C, then add sulfuryl chloride dropwise, keep warm and stir for 3-5 hours, add a proper amount of water at this temperature, after stirring, lower the temperature to between 10-15°C (to prevent dechlorination), add sodium hydroxide aqueous solution dropwise, adjust the pH to 6-7, then heat the reaction solution to 70-75°C, keep warm and stand for 20 minutes, extract the upper aqueous phase, reflux the organic phase, dehydrate it, add dichloroethane to the initial amount and set aside; wherein the reaction formula of this step is as follows: .

[0007] (4) Preparation of 3,5-dichloro-2-aminobenzoyl isopropylamine: put the reaction solution obtained in step (3) into a clean enamel reactor, turn on the stirring device, heat it to 50-55°C, add sodium bicarbonate in batches, keep the temperature at 50-55°C and drop triphosgene dichloroethane solution, keep it warm and stir for 1-2 hours after dropping, cool it to 10-15°C (to prevent isopropylamine from volatilizing), then add isopropanolamine dropwise, and control the dropping to be completed within 1 hour, then heat it to 25-35°C and keep it warm and stir for 1-2 hours, then add water in batches under stirring, dichloroethane is distilled off under reduced pressure, finally cool it to 25-35°C and add methanol and keep it warm and stir for 2-3 hours, filter, and rinse the filter cake with water 1-2 times to obtain the target product. The reaction formula of this step is as follows: .

[0008] The invention creatively uses o-nitrobenzoic acid as a starting raw material, and can obtain a target product through three steps. The raw materials used are simple and easy to obtain, and the requirements for production equipment are not high. The process can be completed in a conventional enamel reactor, and no excessive high-temperature reaction is required. The energy consumption is low, the cost advantage is obvious, and no sewage is generated, which is safe and environmentally friendly. At the same time, the invention adds the raw materials in a dropwise manner for multiple times, and the reaction is more complete. Water or other solvents are added before the reaction to make the raw materials in a dissolved state. At the same time, by strictly controlling the temperature of each reaction, the reaction is faster and more complete, and the waste of raw materials can be reduced. The invention has simple process conditions and is easy for industrial production.

[0009] Furthermore, in step (1) of the above technical solution, the molar ratio of ferric chloride hexahydrate to sodium hydroxide is 1:3-3.2; and the mass ratio of ferric chloride hexahydrate to activated carbon is 1:1.

[0010] Furthermore, in step (1) of the above technical solution, the particle size of the activated carbon is 100-120 mesh; the mass concentration of the sodium hydroxide solution is 14-15%; and the obtained catalyst should be stored in a moist and sealed state because it absorbs a large amount of water.

[0011] Furthermore, in step (2) of the above technical solution, the molar ratio of o-nitrobenzoic acid, sodium hydroxide and 80% hydrazine hydrate is 1:0.5-0.55:1-1.1; and the amount of catalyst added is 25-30% of the mass of o-nitrobenzoic acid.

[0012] Furthermore, in step (2) of the above technical solution, the stirring reaction is stopped when the raw material is less than 0.5%; the alkaline water used is a 1.5-2% sodium hydroxide solution; the mass concentration of the hydrochloric acid is 36%; and the initial amount of the dichloroethane is 2.5-6.25 times the mass of the o-nitrobenzoic acid.

[0013] Furthermore, in step (3) of the above technical solution, the mass ratio of anthranilic acid to ethylene dichloride is 1:11-12; the molar ratio of anthranilic acid to sulfonyl chloride is 1:1.1-1.5; when the raw material is detected to be less than 5% before adding water, the reaction is terminated and the detection is carried out by HPLC method.

[0014] Furthermore, in step (4) of the above technical solution, the molar ratio of 3,5-dichloro-2-aminobenzoic acid, sodium bicarbonate, triphosgene and isopropylamine is 1:1.4-3:0.3-0.5:1.1-1.5.

[0015] Furthermore, in step (4) of the above technical solution, the triphosgene dichloroethane solution is a mixture of solid triphosgene and dichloroethane in a mass ratio of 0.5:1; when the raw material is detected to be less than 0.5% before adding water, the reaction is terminated; and the reduced pressure distillation temperature does not exceed 65°C.

[0016] Compared with the prior art, the present invention has the following beneficial effects: 1. The present invention uses o-nitrobenzoic acid as a starting material, drips 80% hydrazine hydrate and simultaneously uses a pre-prepared catalyst to prepare o-aminobenzoic acid, then dissolves the o-nitrobenzoic acid in dichloroethane and reacts with sulfuryl chloride to prepare 3,5-dichloro-2-aminobenzoic acid, then reacts with triphosgene under alkaline conditions to first generate 3,5-dichloro-2-aminobenzoyl chloride, and finally reacts with isopropanolamine to obtain the final product 3,5-dichloro-2-aminobenzoyl isopropylamine. The preparation method of the present invention is a brand-new preparation process of 3,5-dichloro-2-aminobenzoyl isopropylamine, which can provide a basis for the production of 3,5-dichloro-2-aminobenzoyl isopropylamine and related products.

[0017] 2. No irritating gas is generated during the preparation process of the present invention, and the pollution is small; the preparation temperature is low, there is no explosion risk, and the safety factor is high; the catalyst used is simple, easy to obtain, and low in cost, the raw materials used are cheap and easy to obtain, the requirements for production equipment are low, the process conditions are simple, and the steps of drying materials and loading and unloading solid materials are greatly reduced, saving labor and energy consumption, low cost, and easy industrial production.

[0018] 3. The present invention reasonably controls the raw material ratio and reaction conditions of each step, and each step reacts fully. The yield of the obtained 3,5-dichloro-2-aminobenzoyl isopropylamine is above 95% and the purity is above 99.5%. Compared with the old process, the raw material cost can be saved by about 70%, which has obvious cost advantages. DETAILED DESCRIPTION

[0019] The experimental methods in the following examples are conventional methods unless otherwise specified. The raw materials involved in the following examples are common commercial products and can be purchased from the market unless otherwise specified.

[0020] The above-mentioned technical features of the present invention and the technical features specifically described below (such as implementation cases) can be combined with each other to form a new or preferred technical solution.

[0021] Example 1: Preparation of Catalyst Add 320kg of water to a clean 1-ton enamel reactor and turn on the stirring device. Then add 5kg of ferric chloride hexahydrate (37mol) in batches. Stir for 1h until it is completely dissolved, then add 5kg of activated carbon. Add sodium hydroxide solution (111mol, obtained by 40kg of water + 7kg of sodium hydroxide) dropwise at room temperature (25-35℃). After the addition is completed, keep warm and stir at 25-35℃ for 1h. After filtering, rinse the filter residue with 500mL of water for 1-3 times to obtain 23kg of catalyst, which is stored in a wet sealed container.

[0022] Example 2: Preparation of anthranilic acid Prepare a clean 1-ton enamel reactor, add 360 kg of water, turn on the stirring device, add 10 kg of sodium hydroxide solid (250 mol) in batches, stir for 30 min until completely dissolved, add 80 kg of o-nitrobenzoic acid (479.04 mol), continue stirring for 1 h until completely dissolved, add the catalyst prepared in Example 1, heat to 80 ° C, add 24 kg of 80% hydrazine hydrate (480 mol), keep stirring at 80 ° C after the dripping, and terminate the reaction when the raw material is <0.5% by HPLC. Filter while hot, wash the resulting filter cake with sodium hydroxide solution (800 g of sodium hydroxide, 40 kg of water) 3 times and filter, combine the filtrate and transfer it to another clean 1-ton enamel reactor, then cool to room temperature (25-35 ° C) and use about 12 kg The pH value was adjusted to 3-4 with 36% hydrochloric acid, and 200 kg of dichloroethane was added to react by stirring. Solid crystals were precipitated, and the aqueous phase was removed. Dichloroethane was added again to the initial amount (dichloroethane was continuously added to the initial amount during the process), and the temperature was raised to perform azeotropic water separation until the water was completely separated to obtain an anthranilic acid dichloroethane solution (containing 64.9 kg of anthranilic acid).

[0023] Example 3: Preparation of anthranilic acid Prepare a clean 1-ton enamel reactor, add 360 kg of water, turn on the stirring device, add 10 kg of sodium hydroxide solid (250 mol) in batches, stir for 30 min until completely dissolved, add 80 kg of o-nitrobenzoic acid (479.04 mol), continue stirring for 1 h until completely dissolved, add the catalyst prepared in Example 1, heat to 90 ° C, add 24 kg of 80% hydrazine hydrate (480 mol), keep stirring at 90 ° C after the dropwise reaction, terminate the reaction when the raw material is <0.5% by HPLC, filter while hot, wash the obtained filter cake with sodium hydroxide solution (800 g of sodium hydroxide, 40 kg of water) twice and filter, combine the filtrate and transfer it to another clean 1-ton enamel reactor, then cool to room temperature (25-35 ° C) and use about 12 kg The pH value was adjusted to 3-4 with 36% hydrochloric acid, and 200 kg of dichloroethane was added to react with stirring. Solid crystals were precipitated, and the aqueous phase was removed. Dichloroethane was added again to the initial amount (dichloroethane was continuously added to the initial amount during the process), and the temperature was raised to perform azeotropic water separation until the water was completely separated to obtain an anthranilic acid dichloroethane solution (containing 65.03 kg of anthranilic acid).

[0024] Example 4: Preparation of 3,5-dichloro-2-aminobenzoic acid In a clean 1-ton enamel reactor, the stirring device was turned on, the anthranilic acid dichloroethane solution obtained in Example 2 was added, and the reaction temperature was controlled to be 25-35°C, and then 75kg of sulfuryl chloride (555.5mol) was added dropwise. After the addition, the mixture was kept warm and stirred for 4h. When the raw material was detected by HPLC <4%, the reaction was terminated, and 300kg of water was added dropwise at this temperature. After stirring, the temperature was lowered to 15°C, and an aqueous sodium hydroxide solution (1800mol, 72kg of sodium hydroxide and 200kg of water were added to form a solution and then cooled to room temperature) was added dropwise. The pH was adjusted to 6-7, and the reaction solution was heated to 70°C, kept warm and allowed to stand for 20min, the upper aqueous phase was extracted, and the organic phase was refluxed and dehydrated, and then dichloroethane was added to the initial amount to obtain a 3,5-dichloro-2-aminobenzoic acid dichloroethane solution (containing 97.05kg of 3,5-dichloro-2-aminobenzoic acid).

[0025] Example 5: Preparation of 3,5-dichloro-2-aminobenzoic acid In a clean 1-ton enamel reactor, the stirring device was turned on, and the dichloroethane solution of anthranilic acid obtained in Example 3 was added, and the reaction temperature was controlled to be 25-35°C, and then 75kg of sulfuryl chloride (555.5mol) was added dropwise. After the addition, the mixture was kept warm and stirred for 5h. When the raw material was detected by HPLC and the content was <4%, the reaction was terminated, and 300kg of water was added dropwise at this temperature. After stirring, the temperature was lowered to 15°C, and an aqueous sodium hydroxide solution (1800mol, 72kg of sodium hydroxide and 200kg of water were added to form a solution and then cooled to room temperature) was added dropwise. The pH was adjusted to 6-7, and the reaction solution was heated to 75°C, kept warm and allowed to stand for 20min, the upper aqueous phase was extracted, and the organic phase was refluxed and dehydrated, and dichloroethane was added to the initial amount to obtain a dichloroethane solution of 3,5-dichloro-2-aminobenzoic acid (containing 96.76kg of 3,5-dichloro-2-aminobenzoic acid).

[0026] Example 6: Preparation of 3,5-dichloro-2-aminobenzoyl isopropylamine The 3,5-dichloro-2-aminobenzoic acid dichloroethane solution obtained in Example 4 was put into a clean 1-ton enamel reactor, the stirring device was turned on, the temperature was raised to 55°C, 72kg of sodium bicarbonate solid (857.1mol) was added in batches, the temperature was maintained at 55°C and triphosgene dichloroethane solution (189.2mol, 65.6kg of triphosgene dissolved in 130kg of dichloroethane) was added dropwise, the temperature was kept at 55°C, and the mixture was stirred for 1-2h after the addition was completed. When the raw material was detected by HPLC and was less than 1%, the temperature was lowered to 15°C and 21.8kg of isopropanolamine (70 3.2mol), and control the dripping within 1h, then heat to 25-35℃ and keep warm and stir for 1-2h. When the intermediate raw material is <0.5% by HPLC, the reaction is terminated, and then 392kg of water is added in batches under stirring, and dichloroethane is distilled off under reduced pressure (the temperature does not exceed 65%). Finally, after cooling to 25-35℃, 96k methanol is added and kept warm and stirred for 2-3h. After filtration, the filter cake is rinsed with 160kg of water 1-2 times to obtain 114.1kg of the target product (molar yield is 95.88%, purity is 99.65%).

[0027] Example 7: Preparation of 3,5-dichloro-2-aminobenzoyl isopropylamine The 3,5-dichloro-2-aminobenzoic acid dichloroethane solution obtained in Example 5 was put into a clean 1-ton enamel reactor, the stirring device was turned on, the temperature was raised to 50°C, 72kg of sodium bicarbonate solid (857.1mol) was added in batches, the temperature was maintained at 50°C and triphosgene dichloroethane solution (189.1mol, 65.6kg of triphosgene dissolved in 130kg of dichloroethane) was added dropwise, the temperature was kept at 50°C, and the mixture was stirred for 1-2h after the addition was completed. When the raw material was detected by HPLC and was less than 1%, the temperature was lowered to 10°C and 21.8kg of isopropanolamine (703 .2mol), and control the dripping within 1h, then raise the temperature to 25℃-35℃ and keep stirring for 1-2h. When the intermediate raw material is <0.5% by HPLC, the reaction is terminated, and then 392kg of water is added in batches under stirring, and dichloroethane is distilled off under reduced pressure (the temperature does not exceed 65%). Finally, after cooling to 25℃-35℃, 96k methanol is added and kept stirring for 2-3h. After filtration, the filter cake is rinsed with 160kg of water 1-2 times to obtain 113.8kg of the target product (molar yield is 95.63%, purity is 99.52%).

[0028] Comparative Example 1: Preparation of o-aminobenzyl isopropylamide Add 500kg purified water and 100kg ethyl acetate into a 1000L reactor, start stirring and add 80kg isocyanic anhydride; transport 44kg isopropylamine to the high-level tank and add it dropwise at 0-5℃; after the addition is completed, keep warm for 2h and take samples for testing. When the raw material is less than 1%, filter press, take samples after keeping warm and filter press if qualified, rinse the filter cake with 500L water, press dry the material and dry it to obtain 79.8kg of finished product (o-aminobenzyl isopropylamide).

[0029] Comparative Example 2: Preparation of o-aminobenzyl isopropylamide Add 500kg purified water and 100kg ethyl acetate into a 1000L reactor, start stirring and add 80kg isocyanic anhydride; transport 44kg isopropylamine to the high-level tank and add it dropwise at 0-5℃; after the addition is completed, keep warm for 2h and take samples for testing. When the raw material is less than 1%, filter press, take samples after keeping warm and filter press if qualified, rinse the filter cake with 500L water, press dry the material and dry it to obtain 80.24kg of finished product (o-aminobenzyl isopropylamide).

[0030] Comparative Example 3: Preparation of 3,5-dichloro-2-aminobenzoyl isopropylamine The wet product of o-aminobenzyl isopropylamide obtained in Comparative Example 1 is put into a 1000L reactor, 900L butyl acetate is added, stirred, heated and dehydrated, sampled and tested, the moisture content is qualified, and heating is stopped. 190kg of sulfuryl chloride is transported to the high-level tank, and sulfuryl chloride is dripped when the temperature drops to about 35°C, and the temperature is controlled to be dripped between 30-40°C, and the dripping time is controlled between 10-12h, and the dripping is completed, and the temperature is kept warm for 4h, and the temperature is controlled between 30-40°C. After the insulation is completed, sampling and analysis (HPLC) are performed, and the amide is ≤4% that is qualified, and the temperature is lowered. After the temperature drops to 5°C, the material is discharged and filtered, and after being pressed dry, it is rinsed once with 20L butyl acetate mother liquor, and then pressed dry, the mother liquor is recycled and applied, and the filter cake is discharged and put into the acid-base neutralization reaction in the neutralization kettle (there is a pungent smell when discharging, and personal protection is done well); 200kg of water is put into the 2000L kettle, stirred, and then the whole batch of materials is put into. Control the water temperature to be within 50℃ and distill under reduced pressure to remove the residual butyl acetate in the kettle; transport 32kg of liquid alkali to the high-level tank, cool to 25-35℃ and add liquid alkali, stop adding when the pH is between 8-9, stir for 30min, and re-measure the pH between 8-9. Discharge the material and filter, wash with 200kg of purified water after pressing dry, and recycle the water; add 500L of methanol to the 1000L kettle, stir, and add the whole batch of crude products; heat to 60-70℃, keep warm and stir under reflux for 2h. After the insulation is finished, cool to 0-5℃, discharge the material and filter, press dry, and obtain 69.7kg of finished product (molar yield is 57.12%, purity is 98.33%).

[0031] Comparative Example 4: Preparation of 3,5-dichloro-2-aminobenzoyl isopropylamine The wet product of o-aminobenzyl isopropylamide obtained in comparative example 2 is put into a 1000L reactor, 900L butyl acetate is added, stirred, heated and dehydrated, sampled and tested, the moisture content is qualified, and heating is stopped. 190kg of sulfuryl chloride is transported to the high-level tank, and sulfuryl chloride is dripped when the temperature drops to about 35°C, and the temperature is controlled to be dripped between 30-40°C, and the dripping time is controlled between 10-12h, and the dripping is completed, and the temperature is kept warm for 4h, and the temperature is controlled between 30-40°C. After the insulation is completed, sampling and analysis (HPLC) are performed, and the amide is ≤4%, that is, qualified, and the temperature is lowered. After the temperature drops to 10°C, the material is discharged and filtered, and after being pressed dry, 20L butyl acetate mother liquor is used for leaching once, and then pressed dry, the mother liquor is recycled and applied, and the filter cake is discharged and put into the acid-base neutralization reaction in the neutralization kettle (there is a pungent smell when discharging, and personal protection is done well); 200kg of water is put into the 2000L kettle, stirred, and then the whole batch of materials is put into. Control the water temperature to be within 50℃ and distill under reduced pressure to remove the residual butyl acetate in the kettle; transport 32kg of liquid alkali to the high-level tank, cool to 25-35℃ and add liquid alkali, stop adding when the pH is between 8-9, stir for 30min, and re-measure the pH between 8-9. Discharge the material and filter, wash with 200kg of purified water after pressing dry, and recycle the water; add 500L of methanol to the 1000L kettle, stir, and add the whole batch of crude products; heat to 60-70℃, keep warm and stir under reflux for 2h. After the insulation is finished, cool to 0-5℃, discharge the material and filter, press dry, and obtain 70.5kg of finished product (molar yield is 57.78%, purity is 98.46%).

[0032] It can be seen from the above embodiments and comparative examples that the molar yield of 3,5-dichloro-2-aminobenzoyl isopropylamine prepared by the present invention is above 95% and the purity is above 99.5%, while the molar yield of the old process is less than 60% and the purity is no more than 98.5%. It needs to be refined again to reach above 99.0% before it can be used, and the process is more complicated. At the same time, statistics of two different preparation methods to produce 100kg3,5-dichloro-2-aminobenzoyl isopropylamine show that the raw material cost used in the method of the present invention is 19729.8 yuan and the energy consumption cost is 7825 yuan, while the raw material cost used by the old process (Comparative Examples 1-4) is 66154 yuan and the energy consumption cost is 16630 yuan. The preparation method of the present invention has obvious cost advantages.

[0033] In summary, the newly developed method for preparing 3,5-dichloro-2-aminobenzoyl isopropylamine of the present invention uses o-nitrobenzoic acid as a starting material, and the target product can be obtained through three steps. Meanwhile, the intermediate product is directly dissolved in a solvent to participate in the lower reaction, which not only makes the operation simpler, but also reduces the drying step and the waste in the process. The obtained 3,5-dichloro-2-aminobenzoyl isopropylamine has high yield and purity. Compared with the old process, the process conditions are simpler, the raw materials are easily available and non-toxic, the operation is safer, the raw material waste is less, the cost is low, and it is of great significance for industrial production.

[0034] Finally, it should be emphasized that the above is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various changes and modifications. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for preparing 3,5-dichloro-2-aminobenzoyl isopropylamine, characterized in that: The preparation method comprises the following steps: (1) Preparation of catalyst: Add water to an enameled reactor and start the stirring device. Then add ferric chloride hexahydrate in batches. After stirring until it is completely dissolved, add activated carbon. Then, add sodium hydroxide solution dropwise at room temperature. After the addition is complete, stir at 25-35°C for 1 hour. After filtering, rinse the residue with water for 1-3 times and set aside. (2) Preparation of o-aminobenzoic acid: prepare a clean enameled glass kettle, add water, start the stirring device, add sodium hydroxide in batches, stir until completely dissolved, add o-nitrobenzoic acid, continue to stir until completely dissolved, add the catalyst prepared in step (1), raise the temperature to 80-90°C, add 80% hydrazine hydrate dropwise, keep warm and stir to react after the addition, filter while hot, wash the obtained filter cake with alkaline water 1-3 times and filter, combine the filtrate and transfer it to another enameled reaction kettle, cool to room temperature, adjust the pH to 3-4 with hydrochloric acid, add dichloroethane and stir to react, solid crystals precipitate, remove the water phase, add dichloroethane again to the initial amount, raise the temperature to perform azeotropic separation until the water is completely separated, and set aside; (3) Preparation of 3,5-dichloro-2-aminobenzoic acid: In a clean enameled reactor, turn on the stirring device, add the anthranilic acid obtained in step (2) and ethylene dichloride, control the reaction temperature to 25-35°C, then add sulfuryl chloride dropwise, keep warm and stir for 3-5 hours, add a proper amount of water at this temperature, lower the temperature to between 10-15°C after stirring, add sodium hydroxide aqueous solution dropwise, adjust the pH to 6-7, then heat the reaction solution to 70-75°C, keep warm and stand for 20 minutes, extract the upper aqueous phase, reflux the organic phase, dehydrate it, add ethylene dichloride to the initial amount and set aside; (4) Preparation of 3,5-dichloro-2-aminobenzoyl isopropylamine: The reaction solution obtained in step (3) is placed in a clean enameled reactor, the stirring device is turned on, the temperature is raised to 50-55°C, sodium bicarbonate is added in batches, the temperature is maintained at 50-55°C and triphosgene dichloroethane solution is added dropwise, and the temperature is kept warm and stirred for 1-2 hours. After the temperature is lowered to 10-15°C, isopropanolamine is added dropwise, and the temperature is controlled to be completed within 1 hour. The temperature is then raised to 25-35°C and the temperature is kept warm and stirred for 1-2 hours. Water is then added in batches under stirring, and dichloroethane is distilled off under reduced pressure. Finally, the temperature is lowered to 25-35°C, methanol is added, and the temperature is kept warm and stirred for 2-3 hours. After filtering, the filter cake is rinsed with water 1-2 times to obtain the target product.

2. A method for preparing 3,5-dichloro-2-aminobenzoyl isopropylamine according to claim 1, characterized in that: In step (1), the molar ratio of ferric chloride hexahydrate to sodium hydroxide is 1:3-3.2; the mass ratio of ferric chloride hexahydrate to activated carbon is 1:

1.

3. A method for preparing 3,5-dichloro-2-aminobenzoyl isopropylamine according to claim 1, characterized in that: In step (1), the particle size of the activated carbon is 100-120 mesh; the mass concentration of the sodium hydroxide solution is 14-15%; and the obtained catalyst should be stored in a moist and sealed manner.

4. A method for preparing 3,5-dichloro-2-aminobenzoyl isopropylamine according to claim 1, characterized in that: In step (2), the molar ratio of o-nitrobenzoic acid, sodium hydroxide and 80% hydrazine hydrate is 1:0.5-0.55:1-1.1; and the amount of catalyst added is 25-30% of the mass of o-nitrobenzoic acid.

5. A method for preparing 3,5-dichloro-2-aminobenzoyl isopropylamine according to claim 1, characterized in that: In step (2), the reaction is stirred until the raw material is less than 0.5% and then stopped; the alkaline water used is a 1.5-2% sodium hydroxide solution; the mass concentration of the hydrochloric acid is 36%; and the initial amount of the dichloroethane is 2.5-6.25 times the mass of the o-nitrobenzoic acid.

6. The method for preparing 3,5-dichloro-2-aminobenzoyl isopropylamine according to claim 1, characterized in that: In step (3), the mass ratio of anthranilic acid to ethylene dichloride is 1:11-12; the molar ratio of anthranilic acid to sulfonyl chloride is 1:1.1-1.5; when the raw material is detected to be less than 5% before adding water, the reaction is terminated.

7. A method for preparing 3,5-dichloro-2-aminobenzoyl isopropylamine according to claim 1, characterized in that: In step (4), the molar ratio of 3,5-dichloro-2-aminobenzoic acid, sodium bicarbonate, triphosgene and isopropylamine is 1:1.4-3:0.3-0.5:1.1-1.

5.

8. A method for preparing 3,5-dichloro-2-aminobenzoyl isopropylamine according to claim 1, characterized in that: In step (4), the triphosgene dichloroethane solution is a mixture of solid triphosgene and dichloroethane in a mass ratio of 0.5:1; when the raw material is detected to be less than 0.5% before adding water, the reaction is terminated; and the reduced pressure distillation temperature does not exceed 65°C.