A method for synthesizing 2-amino-N,3-dimethylbenzamide

Abstract

This application relates to the technical field of organic synthesis, and specifically discloses a method for synthesizing 2-amino-N,3-dimethylbenzamide. The specific steps of the method for synthesizing 2-amino-N,3-dimethylbenzamide provided in this application are as follows: Add 2-nitro-N,3-dimethylbenzamide, a solvent, an organic amine auxiliary agent, water, and a noble metal catalyst into a reaction vessel, displace with nitrogen 2 to 3 times, displace with hydrogen 2 to 3 times, after the hydrogen pressure reaches 0.1 to 5 MPa, raise the temperature to 30 to 100 °C for reaction, sample during the reaction process for liquid chromatography detection, and end the reaction until there is no remaining raw material. The reaction solution is obtained after post-treatment. The reaction time of the method for synthesizing 2-amino-N,3-dimethylbenzamide provided in this application is short, and the reaction yield of the 2-amino-N,3-dimethylbenzamide product is high.

Description

Technical Field

[0001] This application relates to the technical field of organic synthesis, and specifically relates to a method for synthesizing 2-amino-N,3-dimethylbenzamide. Background Art

[0002] Chlorantraniliprole is an amide insecticide developed by DuPont. It is safe for mammals and exhibits characteristics such as high efficiency, broad spectrum, and novel action mechanism, with broad market space and prospects. 2-Amino-N,3-dimethylbenzamide, whose structural formula is shown in Formula (2), is a key intermediate for synthesizing chlorantraniliprole;

[0003] Formula (2).

[0004] Currently, the synthesis of 2-amino-N,3-dimethylbenzamide mainly includes the following routes:

[0005] Route 1 is shown in Formula (3). Starting from 2-nitro-3-methylbenzoic acid, it reacts with thionyl chloride (SOCl2) to form an acyl chloride, reacts with methylamine (CH3NH2) to form an N-methylamide, and finally reduces the nitro group with a reducing agent (such as Fe / HCl or SnCl2) to obtain an amino group;

[0006] Formula (3).

[0007] This route uses 2-nitro-3-methylbenzoic acid as a raw material, acyl chlorinates it with thionyl chloride, and then reacts with methylamine to form 2-amino-N,3-dimethylbenzamide. The route is long, the yield is low, and thionyl chloride is a fuming liquid with a strong pungent odor and decomposes rapidly with water, with a relatively high risk factor, making it difficult to scale up production in actual production.

[0008] Route 2 is shown in Formula (4). Starting from 2-amino-3-methylbenzoic acid, it reacts with thionyl chloride (SOCl2) to form an acyl chloride, and reacts with methylamine (CH3NH2) to form the target product;

[0009] Formula (4).

[0010] This route uses 2-amino-3-methylbenzoic acid as a raw material, first reacts with thionyl chloride to form an acyl chloride, and then reacts with methylamine to form 2-amino-N,3-dimethylbenzamide. It is more direct, has fewer steps, and the yield is improved. Although this process seems to have a shorter route and a significantly increased yield, there are still relatively large potential production safety hazards and many uncertain factors in industrial production.

[0011] Therefore, exploring and developing an economically viable and safe production process route for the synthesis of 2-amino-N,3-dimethylbenzamide is of great significance for the industrial production of chlorantraniliprole in China. Summary of the Invention

[0012] To solve the above technical problems, the present application provides a method for synthesizing 2-amino-N,3-dimethylbenzamide.

[0013] The present application provides a method for synthesizing 2-amino-N,3-dimethylbenzamide. The synthesis route is shown in Formula (1), and specifically includes the following steps in sequence:

[0014] Add 2-nitro-N,3-dimethylbenzamide, a solvent, an organic amine auxiliary, water, and a noble metal catalyst into a reaction vessel. Replace with nitrogen 2 to 3 times and replace with hydrogen 2 to 3 times. After the hydrogen pressure reaches 0.1 to 5 MPa, raise the temperature to 30 to 100 °C for reaction. During the reaction process, sample for liquid chromatography detection until there is no remaining raw material, and then end the reaction. The reaction solution is obtained after post-treatment.

[0015] Formula (1).

[0016] Preferably, the solvent is a lower carbon saturated alcohol with 1 to 4 carbon atoms, and the solvent is selected from one or more of methanol, ethanol, and isopropanol; the dosage of the solvent is 1 to 10 times the mass of the raw material.

[0017] Preferably, the solvent is methanol; the dosage of the solvent is 3 to 5 times the mass of the raw material.

[0018] Through experimental analysis of the influence of the solvent type on the synthesis, it can be seen that methanol is the best as the solvent.

[0019] Preferably, the organic amine auxiliary is selected from one or more of ammonia water, monomethylamine solution, and monoethylamine solution; the dosage of the organic amine auxiliary is 0.05 to 0.5% of the mass of the solvent.

[0020] Preferably, the organic amine auxiliary is composed of ammonia water and monoethylamine solution mixed in a weight ratio of 9:1 to 3.

[0021] In a specific embodiment, in the organic amine auxiliary, the weight ratio of ammonia water to monoethylamine solution can be 9:1, 9:2, or 9:3.

[0022] Preferably, the dosage of the organic amine auxiliary is 0.1 to 0.3% of the mass of the solvent.

[0023] In a specific embodiment, the dosage of the organic amine auxiliary can be 0.05%, 0.1%, 0.2%, 0.3%, or 0.5% of the mass of the solvent.

[0024] Through experimental analysis, it can be known that the addition of organic amine additives will reduce the generation of by-products, thereby increasing the yield of 2-amino-N,3-dimethylbenzamide. However, when the amount of organic amine additives is excessive, it will also reduce the synthesis yield of 2-amino-N,3-dimethylbenzamide, and it is likely to produce more by-products in the later application of solvents and catalysts. In this application, ammonia water and monoethylamine solution with the above weight ratio are selected as organic amine additives, and the amount of additives is controlled within the above range, which can further improve the synthesis performance of 2-amino-N,3-dimethylbenzamide.

[0025] Preferably, the amount of water used is 0-50% of the mass of the solvent.

[0026] Preferably, the amount of water used is 0-15% of the mass of the solvent.

[0027] Preferably, the noble metal catalyst is selected from one or more of palladium carbon, platinum carbon, and ruthenium carbon; the dry basis amount of the noble metal catalyst is 0.02-0.5% of the mass of the raw materials.

[0028] Preferably, the noble metal catalyst is a 3-5% palladium carbon catalyst, and the dry basis amount of the noble metal catalyst is 0.05-0.3% of the mass of the raw materials.

[0029] Preferably, the dry basis amount of the noble metal catalyst is 0.05-0.15% of the mass of the raw materials.

[0030] In a specific embodiment, the noble metal catalyst is a 3% palladium carbon catalyst, a 4% palladium carbon catalyst, or a 5% palladium carbon catalyst.

[0031] In a specific embodiment, the dry basis amount of the 5% palladium carbon catalyst is 0.05%, 0.1%, 0.15%, 0.20%, or 0.30% of the mass of the raw materials.

[0032] Through experimental analysis, it can be known that in this application, a 3-5% palladium carbon catalyst is selected and the amount is controlled within the above range, the reaction time is short, the by-products are few, and the product yield is increased.

[0033] Preferably, the reaction hydrogen pressure is 0.6-1.2 MPa, and the reaction temperature is 40°C-80°C.

[0034] In a specific embodiment, the reaction hydrogen pressure can be 0.1 MPa, 0.6 MPa, 1 MPa, 1.2 MPa, 2 MPa, 3 MPa, 4 MPa, or 5 MPa.

[0035] In a specific embodiment, the reaction temperature can be 30°C, 40°C, 50°C, 60°C, 70°C, or 80°C.

[0036] Preferably, the specific steps of the post-treatment are as follows: subject the reaction solution to vacuum filtration to obtain a filtrate and a filter cake. The filter cake is the catalyst for reuse in the next reaction. The filtrate is rotary evaporated to remove the solvent, and then recrystallized and purified with a fresh solvent to obtain the product.

[0037] Preferably, in the specific steps of the post-treatment, in the vacuum filtration, the vacuum degree is -0.1 to -0.05 MPa.

[0038] In the recrystallization, the fresh solvent is the same as the reaction solvent, the dissolution temperature is 60 to 80 °C, the cooling temperature is 0 to 20 °C, and the drying temperature is 60 to 130 °C.

[0039] When the catalyst is reused in the reaction, 0.01% to 0.05% of the raw material mass needs to be supplemented.

[0040] In summary, the technical solution of the present application has the following effects:

[0041] The synthesis method of 2-amino-N,3-dimethylbenzamide provided by the present application has mild reaction conditions, short reaction time, simple process operation, and high product yield.

[0042] The synthesis method of 2-amino-N,3-dimethylbenzamide provided by the present application has high product purity, realizes zero emissions, and is conducive to industrial production.

[0043] The synthesis method of 2-amino-N,3-dimethylbenzamide provided by the present application significantly improves production efficiency, has no dangerous processes, has small production safety hazards, and is suitable for large-scale preparation.

[0044] The synthesis method of 2-amino-N,3-dimethylbenzamide provided by the present application allows the catalyst and solvent to be reused in the reaction, reduces costs, and is suitable for industrial production. Specific Embodiments

[0045] The present application will be further described in detail below in conjunction with examples, comparative examples, and performance detection tests. These examples should not be construed as limiting the scope of protection required by the present application. Examples Example 1

[0046] Example 1 provides a synthesis method of 2-amino-N,3-dimethylbenzamide.

[0047] The synthesis method of 2-amino-N,3-dimethylbenzamide in this example is specifically as follows.

[0048] Add 50 g of 2-nitro-N,3-dimethylbenzamide (purity 99%), 200 g of methanol, 0.4 g of organic amine auxiliary agent (0.2% of the solvent mass, composed of ammonia water and monoethylamine solution mixed in a weight ratio of 9:2), 5 g of water and 0.05 g (dry basis) of 5% palladium-carbon catalyst into the reaction vessel autoclave. Replace with nitrogen 3 times and then with hydrogen 3 times. Raise the hydrogen pressure to 1 MPa and heat up to 60 °C. When the hydrogen pressure drops, replenish hydrogen in a timely manner. Take samples every half hour during the reaction for liquid chromatography detection. After reacting for 3.5 h, there is no remaining raw material (the product yield in the reaction solution detected by liquid chromatography is 99.027%), and end the reaction;

[0049] Vacuum filter the above reaction solution under a vacuum of -0.1 MPa to obtain a filtrate and a filter cake. The filter cake is the catalyst for reuse in the next reaction. Evaporate the solvent from the filtrate by rotary evaporation. Then dissolve the material after rotary evaporation in fresh methanol at 60 °C, and then cool it to 0 - 20 °C for crystallization. Dry the recrystallized material at 90 °C to obtain 41.47 g of high-purity 2-amino-N,3-dimethylbenzamide product with a purity of 99.67% and a yield of 99.18%.

[0050] Examples 2 - 9

[0051] Examples 2 - 9 respectively provide a synthesis method of 2-amino-N,3-dimethylbenzamide.

[0052] The differences between the above examples and Example 1 are as follows: the types and dosages of the organic amine auxiliary agents are different, as shown below.

[0053] In Example 2: The organic amine auxiliary agent is composed of ammonia water and monomethylamine solution mixed in a weight ratio of 9:2.

[0054] In Example 3: The organic amine auxiliary agent is composed of ammonia water and monoethylamine solution mixed in a weight ratio of 2:9.

[0055] In Example 4: The organic amine auxiliary agent is composed of ammonia water and monoethylamine solution mixed in a weight ratio of 9:1.

[0056] In Example 5: The organic amine auxiliary agent is composed of ammonia water and monoethylamine solution mixed in a weight ratio of 9:3.

[0057] In Example 6: The dosage of the organic amine auxiliary agent is 0.1 g (0.05% of the solvent mass).

[0058] In Example 7: The dosage of the organic amine auxiliary agent is 1 g (0.5% of the solvent mass).

[0059] In Example 8: The dosage of the organic amine auxiliary agent is 0.2 g (0.1% of the solvent mass).

[0060] In Example 9: The dosage of the organic amine assistant is 0.6 g (0.3% of the solvent mass).

[0061] In the above examples, other process parameters are the same as those in Example 1.

[0062] Examples 10 - 13

[0063] Examples 10 - 13 respectively provide a method for synthesizing 2 - amino - N,3 - dimethylbenzamide.

[0064] The differences between the above examples and Example 1 are: different types of noble metal catalysts, as shown below.

[0065] In Example 10: The noble metal catalyst is 0.05 g of 5% platinum - carbon catalyst.

[0066] In Example 11: The noble metal catalyst is 0.05 g of 5% ruthenium - carbon catalyst.

[0067] In Example 12: The noble metal catalyst is the palladium - carbon catalyst recovered from Example 1, and 0.025 g (dry - basis equivalent) of 5% palladium - carbon is added.

[0068] In Example 13: The noble metal catalyst is the palladium - carbon catalyst recovered from Example 1, and 0.01 g (dry - basis equivalent) of 5% palladium - carbon is added.

[0069] In the above examples, other process parameters are the same as those in Example 1.

[0070] Examples 14 - 17

[0071] Examples 14 - 17 respectively provide a method for synthesizing 2 - amino - N,3 - dimethylbenzamide.

[0072] The differences between the above examples and Example 1 are: different types of noble metal catalysts, as shown below.

[0073] In Example 14: The reaction temperature is 30 °C.

[0074] In Example 15: The reaction temperature is 40 °C.

[0075] In Example 16: The reaction temperature is 80 °C.

[0076] In Example 17: The reaction temperature is 100 °C.

[0077] In the above examples, other process parameters are the same as those in Example 1. Comparative Examples

[0078] Comparative Examples 1 - 2

[0079] Comparative Example 1-2 provides a method for synthesizing 2-amino-N,3-dimethylbenzamide.

[0080] The differences between the above comparative examples and Example 1 are specifically as follows.

[0081] In Comparative Example 1: No organic amine additive was added.

[0082] In Comparative Example 2: 0.05 g of Raney nickel was used as the catalyst.

[0083] Other process parameters in the above comparative examples were the same as those in Example 1.

[0084] Performance detection test

[0085] Record the reaction time, reaction purity, and yield of the synthesis method of 2-amino-N,3-dimethylbenzamide in the examples and comparative examples.

[0086] Detection results: As shown in Table 1.

[0087] Table 1 Performance detection results of the synthesis method of 2-amino-N,3-dimethylbenzamide in the examples and comparative examples

[0088]

[0089] Combined with Table 1, by comparing the detection results of Examples 1-17 and Comparative Examples 1-2, it can be seen that in Comparative Example 1, no organic amine additive was added, and in Comparative Example 2, Raney nickel was used as the catalyst. The synthesis reaction time of 2-amino-N,3-dimethylbenzamide was longer, and the yield of the product was lower. In contrast, the examples of the present application use an organic amine additive and a noble metal catalyst for synthesizing 2-amino-N,3-dimethylbenzamide, which greatly shortens the synthesis reaction time and improves the yield of the product at the same time.

[0090] By comparing the detection results of Examples 1-9, it can be seen that the present application selects an organic amine additive composed of ammonia water and ethylamine solution mixed in a weight ratio of 1-3 of 9, and controls its dosage to 0.1-0.3% of the solvent mass, which can further improve the synthesis performance of 2-amino-N,3-dimethylbenzamide.

[0091] By comparing the detection results of Examples 1, 10-13, it can be seen that the present application selects a 3%-5% palladium-carbon catalyst, which can further shorten the synthesis time of 2-amino-N,3-dimethylbenzamide and improve the yield of the product at the same time. Moreover, the catalyst and the solvent can be reused in the reaction, reducing the cost and being suitable for industrial production.

[0092] By comparing the detection results of Examples 1, 14 - 17, it can be seen that by controlling the reaction temperature of the present application at 40 - 80 °C, the synthesis performance of 2 - amino - N,3 - dimethylbenzamide can be further improved.

[0093] Although the present invention has been described in detail above with general descriptions and specific embodiments, based on the present invention, some modifications or improvements can be made, which are obvious to those skilled in the art. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection required by the present invention.

Claims

1. A method for synthesizing 2-amino-N,3-dimethylbenzamide, characterized in that: The synthetic route is shown in formula (1), which specifically comprises the following steps in sequence: Add 2-nitro-N,3-dimethylbenzamide, solvent, organic amine auxiliary agent, water and noble metal catalyst into a reaction container, replace with nitrogen 2-3 times, replace with hydrogen 2-3 times, raise the temperature to 40-80°C after the hydrogen pressure reaches 0.1-5MPa, take samples for liquid chromatography detection during the reaction, terminate the reaction after no raw materials remain, and obtain the obtained product after post-treatment of the reaction solution; The solvent is a low-carbon saturated alcohol having 1 to 4 carbon atoms, and the amount of the solvent used is 1 to 10 times the mass of the raw material; The organic amine auxiliary agent is composed of ammonia water and monoethylamine solution mixed in a weight ratio of 9:1-3; the amount of the organic amine auxiliary agent is 0.1-0.3% of the solvent mass; The noble metal catalyst is a 3-5% palladium carbon catalyst, and the dry basis amount of the noble metal catalyst is 0.05-0.3% of the mass of the raw material; 2. The method for synthesizing 2-amino-N,3-dimethylbenzamide according to claim 1, characterized in that: The amount of water used is 0 to 50% of the mass of the solvent.

3. The method for synthesizing 2-amino-N,3-dimethylbenzamide according to claim 1, characterized in that: The reaction hydrogen pressure is 0.6-1.2 MPa.

4. The method for synthesizing 2-amino-N,3-dimethylbenzamide according to claim 1, characterized in that: The specific steps of the post-treatment are: vacuum filtering the reaction liquid to obtain a filtrate and a filter cake, the filter cake is a catalyst to be used in the next reaction, the filtrate is rotary evaporated to remove the solvent, and then recrystallized and purified with a fresh solvent.

5. The method for synthesizing 2-amino-N,3-dimethylbenzamide according to claim 4, characterized in that: In the specific steps of the post-treatment, the vacuum degree in the vacuum filtration is -0.1 to -0.05 MPa; In the recrystallization, the fresh solvent is the same as the reaction solvent, the dissolution temperature is 60-80°C, the cooling temperature is 0-20°C, and the drying temperature is 60-130°C; During the application reaction, the catalyst needs to be supplemented with 0.01% to 0.05% of the mass of the raw material.

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