Preparation method of 2-amino-3-methyl-5-chlorobenzoic acid

Abstract

The invention provides a synthesis method of 2-amino-3-methyl-5-chlorobenzoic acid, which comprises the following steps: respectively pumping m-xylene and liquid chlorine into a microchannel reactor for reaction, and purifying to obtain 2-chloro m-xylene; s2, adding a catalyst into the 2-chloro-m-xylene obtained in the step S1, introducing the mixture into a micro-channel reactor, introducing an oxidizing reagent, carrying out a reaction, and purifying a product to obtain 2-chloro-3-methyl benzoic acid; s2, dissolving the 2-chloro-3-methyl benzoic acid obtained in the step S2 and alkali in a solvent 1, introducing ammonia gas, reacting under the pressure condition, and purifying a product to obtain 2-amino-3-methyl benzoic acid; and S3, diluting the 2-amino-3-methyl benzoic acid obtained in S3 with a solvent 2, pumping the diluted 2-amino-3-methyl benzoic acid into a tubular reactor, introducing liquid chlorine for reaction, and purifying the product to obtain the 2-amino-3-methyl-5-chlorobenzoic acid. Ammonia gas is adopted as a nucleophilic reagent to avoid nitration reaction, so that the amount of acid wastewater can be reduced from the source, hydrogenation reduction is not needed, and the route atom utilization rate is greatly increased.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for preparing 2-amino-3-methyl-5-chlorobenzoic acid. Background Art

[0002] The synthesis of chlorfenapyr technical involves two core intermediates. Therefore, in-depth analysis of the intermediate synthesis process and research and development of cheaper and greener synthesis routes are of great significance for implementing strategies such as energy conservation and consumption reduction and green production.

[0003] The product synthesis route is as follows:

[0004] Synthesis route of chlorantraniliprole technical In the production process of the above-mentioned technical, domestic enterprises are relatively mature in the synthesis process of pyrazole acid, and the production cost is roughly the same, but there are multiple synthesis routes for 2-amino-3-methyl-5-chlorobenzoic acid. Based on the existing production routes, the present invention develops a synthesis method with lower cost. The production process does not involve nitration reaction, the process is safer and controllable, and does not produce a large amount of acidic wastewater, does not involve hydrogenation reduction, and does not require the participation of precious metals. The overall production cost advantage is obvious, which is of great significance to the cost control of the chlorantraniliprole industry chain.

[0005] Route 1:

[0006] Route 2:

[0007] Industrialization and self-developed synthesis routes Route 1 is the existing production route of most domestic enterprises. The process involves nitration and hydrogenation reactions, both of which are extremely dangerous operation units. The former produces a large amount of acidic wastewater during the reaction process, and the latter is extremely easy to burn and explode during the post-treatment process. Expensive precious metal catalysts are involved in the production, resulting in high overall production costs. There are also technologies that disclose new synthetic routes, such as patent CN115417781B discloses a method for converting halogens into amides under palladium catalysis, but the raw materials are expensive and involve precious metal catalysts to participate in the reaction; patent CN110845341 discloses using o-toluidine as a raw material, first selectively chlorinating, then selectively cyanating, and finally hydrolyzing to obtain the target product. Although the conditions of this route are mild, it involves multiple chemical selectivities in the route, which will produce more low-value by-products. At the same time, the source of cyano is expensive, and the overall advantage is not obvious.

[0008] Based on the above situation, the present invention has developed a more environmentally friendly and low-cost method for synthesizing 2-amino-3-methyl-5-chlorobenzoic acid. The present invention preferably uses a microchannel reactor or a dynamic tubular reactor to replace the traditional reactor, which can greatly transfer the reaction heat and reduce the reaction risk. At the same time, cheap chlorine, air or oxygen, and ammonia are used as reaction auxiliary materials, which greatly reduces the production cost. Summary of the invention

[0009] In order to solve the problem that the existing production process of this product involves nitration and subsequent hydrogenation reduction operations, avoid the generation of large amounts of acidic wastewater, while improving atomic utilization and reducing production costs.

[0010] The technical scheme of the present invention uses m-xylene as a starting material, reacts with chlorine in a microchannel to obtain 2-chloro-1,3-xylene, catalytically oxidizes the obtained product to obtain 2-chloro-3-methylbenzoic acid, then performs a substitution reaction under alkaline conditions to prepare 2-amino-3-methylbenzoic acid, and finally performs chlorination in a tubular reactor to obtain 2-amino-3-methyl-5-chlorobenzoic acid.

[0011] A method for synthesizing 2-amino-3-methyl-5-chlorobenzoic acid comprises the following steps: S1: Pumping meta-xylene and liquid chlorine into a microchannel reactor for reaction, and purifying the obtained product to obtain 2-chloro-meta-xylene; S2: adding a catalyst to the 2-chloro-meta-xylene obtained in S1 and then passing it into a microchannel reactor again, introducing an oxidizing agent to react, and obtaining 2-chloro-3-methylbenzoic acid after purification; S3: adding solvent 1 to dissolve the 2-chloro-3-methylbenzoic acid and alkali obtained in S2, introducing ammonia gas, reacting under pressure conditions, and obtaining 2-amino-3-methylbenzoic acid after purification; S4: The 2-amino-3-methylbenzoic acid obtained in S3 is diluted with solvent 2 and pumped into a tubular reactor, and liquid chlorine is introduced to react, and 2-amino-3-methyl-5-chlorobenzoic acid is obtained after purification.

[0012] In some embodiments, a post-processing refining step is also included, which has the following: In some embodiments, the 2-chlorometa-xylene-containing product obtained in S1 is subjected to heating distillation to purify 2-chlorometa-xylene.

[0013] In some embodiments, the 2-chloro-3-methylbenzoic acid product obtained from S2 is first dissolved in liquid alkali and then extracted to remove impurities. The solid is precipitated from the aqueous phase after extraction in concentrated hydrochloric acid, and the 2-chloro-3-methylbenzoic acid is purified by suction filtration and drying.

[0014] In some embodiments, the 2-amino-3-methylbenzoic acid product obtained in S3 is dissolved in water, and acid is added to adjust the pH to 5-6. The obtained solid is filtered and dried to obtain 2-amino-3-methylbenzoic acid.

[0015] In some embodiments, the 2-amino-3-methyl-5-chlorobenzoic acid product obtained in S4 is desolvated and 5-10% liquid alkali is added to adjust the pH value to 5-6, and a solid product is precipitated. After filtration and drying, 2-amino-3-methyl-5-chlorobenzoic acid is obtained.

[0016] It is understood by those skilled in the art that the above post-treatment purification step can achieve a more complete next step reaction.

[0017] The plunger pump used in this embodiment is JJRZ-S-1K505S, the microchannel is an ordinary polytetrafluoroplastic tube with a size of Φ=1.58*3.17mm, and the channel length is about 20 meters.

[0018] In step S1, the flow rate of m-xylene is 30-50 mL / min; the flow rate of liquid chlorine is 30-100 mL / min; the reaction temperature is 0-50°C, and the system pressure is 0.12-0.2 MPa.

[0019] In step S2, the catalyst includes any one of zinc naphthenate, copper naphthenate, cobalt naphthenate, nickel naphthenate, and molybdenum naphthenate, and the amount used is 0.5-3% of the molar amount of 2-chloro-meta-xylene; The oxidant is air or oxygen, and the flow rate is set to 30-200 mL / min.

[0020] In step S2, after adding the catalyst to 2-chlorometa-xylene, the mixture is introduced into the microchannel reactor at a flow rate of 5-15 mL / min, the reaction temperature is 120-180° C., the product mother liquor is collected at the bottom of the reactor, and the product mother liquor is purified.

[0021] In step S3, the base added to the reaction is sodium hydroxide, sodium carbonate, pyridine or triethylamine, and the added amount is 2.0-5.0 equivalents of 2-chloro-3-methylbenzoic acid.

[0022] The solvent 1 includes one or a mixed solvent of methanol, ethanol, n-butanol and water.

[0023] In step S3, the reaction under pressure conditions refers to the reaction at 30-70° C. and 1-3 MPa. During the process, if the pressure gauge is stable for 10-20 minutes without changing, it indicates that the reaction is completed.

[0024] The S3 step inevitably includes replacing the air inside the autoclave, using nitrogen and / or ammonia to replace the oxygen in the autoclave, and then introducing ammonia to maintain the pressure in the autoclave at 1-3 MPa for reaction.

[0025] In step S4, 2-amino-3-methylbenzoic acid is diluted with solvent 2 and then pumped into the tubular reactor at a flow rate of 10-50 mL / min; liquid chlorine is pumped into the tubular reactor at a flow rate of 30-100 mL / min, and the reaction is carried out at 10-50° C. The reaction time in the tubular reactor is 10-20 min.

[0026] Solvent 2 includes one or a mixed solvent selected from the group consisting of dichloromethane, dichloroethane, ethyl acetate, acetonitrile, water, and N,N-dimethylformamide.

[0027] The tubular reactor used in the present invention was purchased from Shenzhen Yizheng Technology Co., Ltd. The specific model is a continuous oscillation tubular reactor OAR-300 with a size of Φ=30*500mm.

[0028] Technical Effects This route is a new synthesis method for 2-amino-3-methyl-5-chlorobenzoic acid. Compared with the existing route, it is more reasonable. The nucleophilic substitution reaction of ammonia on chlorobenzene can avoid the tedious steps of nitration and then reduction, and the atomic utilization rate of the route is higher. The overall advantages of the reaction are summarized as follows: 1. The designed 2-amino-3-methyl-5-chlorobenzoic acid production technology is different from the existing route. There are fewer by-products in the production process, and the main raw materials used are all bulk cheap chemicals, which has a lower overall cost; 2. Using ammonia as a nucleophilic reagent to avoid nitration reaction can reduce the amount of acidic wastewater at the source, and at the same time, no hydrogenation reduction is required, and the atomic utilization rate of the route is greatly improved; 3. All hazardous chemical processes are carried out using microchannel or tubular reactors, which can significantly reduce the potential risks of the reaction and is in line with existing policy guidance. DETAILED DESCRIPTION

[0029] Example 1 Step 1, preparation of 2-chloro-meta-xylene: 5 kg of meta-xylene was measured, and the flow rate of the plunger pump was set to 50 mL / min. The flow rate of the liquid chlorine cylinder was adjusted to 40 mL / min after decompression. The two were mixed evenly in a mixer and passed into a coil of about 20 m in length at an external temperature of 30°C. The system was pressurized to 0.15 MPa. After the reaction liquid was collected, it was heated and distilled to obtain about 5.9 kg of 2-chloro-meta-xylene, with a yield of 89.4% and a content of 96.2%; Step 2, preparation of 2-chloro-3-methylbenzoic acid: weigh about 5 kg of 2-chloro-meta-xylene, add about 140 g of catalyst cobalt naphthenate, stir evenly, set the plunger pump flow rate to 10 mL / min, the air flow rate to 150 mL / min, the reaction system temperature to 150 ° C, collect the reaction solution, first add 5% liquid alkali to dissolve and then extract to remove impurities, finally add 37% hydrochloric acid to the aqueous phase to adjust the pH to about 1, precipitate a large amount of white solid, filter and dry to obtain about 5.5 kg of 2-chloro-3-methylbenzoic acid, with a yield of 90.8% and a content of 98.3%; Step 3, preparation of 2-amino-3-methylbenzoic acid: weigh 2kg of the product in step 2 and 1.2kg of caustic soda flakes into a high-pressure reactor, add 10L of methanol and stir to mix. The system is replaced with nitrogen and ammonia three times respectively, and ammonia is introduced to maintain the system pressure at 2Mpa. The system temperature is controlled at 60°C. When the system pressure does not change within 20 minutes, it indicates that the reaction is over. After the reaction solution is desolventized, water is added to dissolve it, and acid is added to adjust the pH to 5-6. The solid is filtered and dried to obtain about 1.5kg of 2-amino-3-methylbenzoic acid, with a yield of 86.3% and a content of 98.5%; Step 4, preparation of 2-amino-3-methyl-5-chlorobenzoic acid: weigh about 3.0 kg of the product in step 3 and add 10 L of dichloroethane to fully dissolve it. Set the flow rate of the tubular reactor to 50 mL / min and the temperature to 35 ° C. After the liquid chlorine cylinder is depressurized, the chlorine flow rate is set to 40 mL / min. The material stays in the system for about 20 min. After the reaction is completed, desolventizing is added with 5% liquid alkali to adjust the pH to 5-6 to precipitate a large amount of light yellow to white powder. Filter and dry to obtain about 3.4 kg of the product, with a yield of 91.2% and a content of 96.3%.

[0030] Example 2 Step 1, preparation of 2-chloro-meta-xylene: 5 kg of meta-xylene was measured, and the flow rate of the plunger pump was set to 50 mL / min. The flow rate of the liquid chlorine cylinder was adjusted to 55 mL / min after decompression. The two were mixed evenly in a mixer and passed into a coil with an external temperature of 50°C and a length of about 20 m. The system was kept at a pressure of 0.15 MPa. After the reaction liquid was collected and heated and distilled, about 5.9 kg of 2-chloro-meta-xylene was obtained, with a yield of 89.2% and a content of 96.5%; Step 2: Preparation of 2-chloro-3-methylbenzoic acid: weigh about 5 kg of 2-chloro-meta-xylene, add about 120 g of catalyst copper cyclohexane, stir evenly, set the plunger pump flow rate to 10 mL / min, the air flow rate to 140 mL / min, and the reaction system temperature to 160°C. After the reaction liquid is collected, first add 5% liquid alkali to dissolve and then extract to remove impurities. Finally, add 37% hydrochloric acid to the aqueous phase to adjust the pH to about 1, and a large amount of white solid is precipitated. Filter and dry to obtain about 5.5 kg of 2-chloro-3-methylbenzoic acid, with a yield of 90.8% and a content of 98.5%; Step 3, preparation of 2-amino-3-methylbenzoic acid: weigh 2kg of the product in step 2 and 3.8kg of sodium carbonate into a high-pressure reactor, add 8L of methanol and 2L of water and stir to mix. The system is replaced with nitrogen and ammonia three times respectively, and ammonia is introduced to maintain the system pressure at 2Mpa. The system temperature is controlled at 60°C. When the system pressure does not change within 20 minutes, it indicates that the reaction is over. After the reaction solution is desolventized, water is added to dissolve it, and acid is added to adjust the pH to 5-6. The solid is filtered and dried to obtain about 1.5kg of 2-amino-3-methylbenzoic acid, with a yield of 85.2% and a content of 97.6%; Step 4, preparation of 2-amino-3-methyl-5-chlorobenzoic acid: weigh about 3.0 kg of the product in step 3 and add 10 L of ethyl acetate to fully dissolve, set the flow rate of the tubular reactor to 50 mL / min, the temperature to 20 ° C, and set the chlorine flow rate to 55 mL / min after the liquid chlorine cylinder is depressurized. The material stays in the system for about 20 min. After the reaction is completed, 5% liquid alkali is added to adjust the pH to 5-6 to precipitate a large amount of light yellow powder. Filter and dry to obtain about 3.3 kg of the product, with a yield of 90.2% and a content of 96.9%.

[0031] Example 3 Step 1 Preparation of 2-chloro-meta-xylene: 5 kg of meta-xylene was measured, and the flow rate of the plunger pump was set to 50 mL / min. The flow rate of the liquid chlorine cylinder was adjusted to 70 mL / min after decompression. The two were mixed evenly in a mixer and passed into a coil with an external temperature of 10°C and a length of about 20 m. The system was kept at a pressure of 0.14 MPa. After the reaction liquid was collected and heated and distilled, about 5.8 kg of 2-chloro-meta-xylene was obtained, with a yield of 88.3% and a content of 95.7%; Step 2: Preparation of 2-chloro-3-methylbenzoic acid: weigh about 5 kg of 2-chloro-meta-xylene, add about 125 g of catalyst nickel cyclohexane, stir evenly, set the plunger pump flow rate to 10 mL / min, the air flow rate to 180 mL / min, and the reaction system temperature to 170°C. After the reaction liquid is collected, first add 5% liquid alkali to dissolve and then extract to remove impurities. Finally, add 37% hydrochloric acid to the aqueous phase to adjust the pH to about 1, and a large amount of white solid is precipitated. Filter and dry to obtain about 5.5 kg of 2-chloro-3-methylbenzoic acid, with a yield of 90.2% and a content of 97.8%; Step 3, preparation of 2-amino-3-methylbenzoic acid: weigh 2kg of the product in step 2 and 2.6kg of triethylamine into a high-pressure reactor, add 8L of ethanol and stir to mix. The system is replaced with nitrogen and ammonia three times respectively, and ammonia is introduced to maintain the system pressure at 1.5Mpa. The system temperature is controlled at 50°C. When the system pressure does not change within 20 minutes, it indicates that the reaction is over. After the reaction solution is desolventized, water is added to dissolve it, and acid is added to adjust the pH to 5-6. The solid is filtered and dried to obtain about 1.5kg of 2-amino-3-methylbenzoic acid, with a yield of 83.8% and a content of 96.4%; Step 4, preparation of 2-amino-3-methyl-5-chlorobenzoic acid: weigh about 3.0 kg of the product in step 3 and add 10 L of acetonitrile to fully dissolve, set the flow rate of the tubular reactor to 50 mL / min, the temperature to 20 ° C, and set the chlorine flow rate to 65 mL / min after the liquid chlorine cylinder is depressurized. The material stays in the system for about 20 minutes. After the reaction is completed, 5% liquid alkali is added to adjust the pH to 5-6 to precipitate a large amount of light yellow powder. Filter and dry to obtain about 3.4 kg of the product, with a yield of 91.2% and a content of 97.4%.

[0032] Example 4 Step 1, preparation of 2-chloro-meta-xylene: 5 kg of meta-xylene was measured, and the flow rate of the plunger pump was set to 50 mL / min. The flow rate of the liquid chlorine cylinder was adjusted to 40 mL / min after decompression. The two were mixed evenly in a mixer and passed into a coil of about 20 m in length at an external temperature of 40°C. The system was kept at a pressure of 0.2 MPa. After the reaction liquid was collected and heated and distilled, about 5.8 kg of 2-chloro-meta-xylene was obtained, with a yield of 89.1% and a content of 95.9%; Step 2: Preparation of 2-chloro-3-methylbenzoic acid: weigh about 5 kg of 2-chloro-meta-xylene, add about 125 g of catalyst nickel cyclohexane, stir evenly, set the plunger pump flow rate to 10 mL / min, set the oxygen flow rate to 50 mL / min, and the reaction system temperature to 150°C. After the reaction solution is collected, first add 5% liquid alkali to dissolve and then extract to remove impurities. Finally, add 37% hydrochloric acid to the aqueous phase to adjust the pH to about 1, and a large amount of white solid is precipitated. Filter and dry to obtain about 5.4 kg of 2-chloro-3-methylbenzoic acid, with a yield of 88.9% and a content of 95.4%; Step 3, preparation of 2-amino-3-methylbenzoic acid: weigh 2kg of the product in step 2 and 1.4kg of caustic soda flakes into a high-pressure reactor, add 10L of methanol and stir to mix. The system is replaced with nitrogen and ammonia three times respectively, and ammonia is introduced to maintain the system pressure at 2.0Mpa. The system temperature is controlled at 60°C. When the system pressure does not change within 20 minutes, it indicates that the reaction is over. After the reaction solution is desolventized, water is added to dissolve it, and acid is added to adjust the pH to 5-6. The solid is filtered and dried to obtain about 1.5kg of 2-amino-3-methylbenzoic acid, with a yield of 85.2% and a content of 96.9%; Step 4, preparation of 2-amino-3-methyl-5-chlorobenzoic acid: weigh about 3.0 kg of the product in step 3 and add 10 L of dichloromethane to fully dissolve it. Set the flow rate of the tubular reactor to 50 mL / min and the temperature to 20 ° C. After the liquid chlorine cylinder is depressurized, the chlorine flow rate is set to 35 mL / min. The material stays in the system for about 20 min. After the reaction is completed, 5% liquid alkali is added to adjust the pH to 5-6 to precipitate a large amount of light yellow powder. Filter and dry to obtain about 3.4 kg of the product, with a yield of 91.8% and a content of 97.6%.

Claims

1. A method for synthesizing 2-amino-3-methyl-5-chlorobenzoic acid, characterized in that: The following steps are involved: S1: Pumping meta-xylene and liquid chlorine into a microchannel reactor for reaction, and obtaining 2-chloro-meta-xylene after purification; S2: adding a catalyst to the 2-chloro-meta-xylene obtained in S1 and passing it into a microchannel reactor, and then introducing an oxidizing agent to react, and the product is purified to obtain 2-chloro-3-methylbenzoic acid; S3: adding solvent 1 to dissolve the 2-chloro-3-methylbenzoic acid and alkali obtained in S2, introducing ammonia gas, and reacting under pressure conditions, and the product is purified to obtain 2-amino-3-methylbenzoic acid; S4: The 2-amino-3-methylbenzoic acid obtained in S3 is diluted with solvent 2 and pumped into a tubular reactor, and liquid chlorine is introduced to react. The product is purified to obtain 2-amino-3-methyl-5-chlorobenzoic acid.

2. The method for synthesizing 2-amino-3-methyl-5-chlorobenzoic acid according to claim 1, characterized in that: In step S1, the flow rate of m-xylene is 30-50 mL / min; the flow rate of liquid chlorine is 30-100 mL / min; the reaction temperature is 0-50°C, and the system pressure is 0.12-0.2 MPa.

3. The method for synthesizing 2-amino-3-methyl-5-chlorobenzoic acid according to claim 1, characterized in that: In step S2, the catalyst includes any one of zinc naphthenate, copper naphthenate, cobalt naphthenate, nickel naphthenate, and molybdenum naphthenate, and the amount used is 0.5-3% of the molar amount of 2-chloro-meta-xylene; The oxidant is air or oxygen, and the flow rate is set to 30-200 mL / min.

4. The method for synthesizing 2-amino-3-methyl-5-chlorobenzoic acid according to claim 1, characterized in that: In step S2, after adding the catalyst to 2-chloro-meta-xylene, the 2-chloro-meta-xylene is introduced into the microchannel reactor at a flow rate of 5-15 mL / min, and the reaction temperature is 120-180°C.

5. The method for synthesizing 2-amino-3-methyl-5-chlorobenzoic acid according to claim 1, characterized in that: In step S3, the base added to the reaction is sodium hydroxide, sodium carbonate, pyridine or triethylamine, and the added amount is 2.0-5.0 equivalents of the amount of 2-chloro-3-methylbenzoic acid fed.

6. The method for synthesizing 2-amino-3-methyl-5-chlorobenzoic acid according to claim 1, characterized in that: The solvent 1 includes one or a mixed solvent of methanol, ethanol, n-butanol and water.

7. The method for synthesizing 2-amino-3-methyl-5-chlorobenzoic acid according to claim 1, characterized in that: In step S3, the reaction under pressure conditions refers to the reaction at 30-70° C. and 1-3 MPa.

8. The method for synthesizing 2-amino-3-methyl-5-chlorobenzoic acid according to claim 1, characterized in that: In step S4, 2-amino-3-methylbenzoic acid is diluted with solvent 2 and then pumped into the tubular reactor at a flow rate of 10-50 mL / min; liquid chlorine is pumped into the tubular reactor at a flow rate of 30-100 mL / min, and the reaction is carried out at 10-50°C.

9. The method for synthesizing 2-amino-3-methyl-5-chlorobenzoic acid according to claim 8, characterized in that: Solvent 2 includes one or a mixed solvent selected from the group consisting of dichloromethane, dichloroethane, ethyl acetate, acetonitrile, water, and N,N-dimethylformamide.

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