Synthesis method of 2-amino-N, 3-dimethyl benzamide

Abstract

The invention relates to the technical field of organic synthesis, and particularly discloses a synthetic method of 2-amino-N, 3-dimethyl benzamide. The synthesis method of 2-amino-N, 3-dimethyl benzamide comprises the following specific steps: adding 2-nitro-N, 3-dimethyl benzamide, a solvent, an organic amine auxiliary agent, water and a noble metal catalyst into a reaction container, carrying out nitrogen replacement for 2-3 times, carrying out hydrogen replacement for 2-3 times, raising the temperature to 30-100 DEG C after the hydrogen pressure is 0.1-5 MPa, carrying out a reaction, and cooling to room temperature to obtain the 2-amino-N, 3-dimethyl benzamide. And sampling in the reaction process, carrying out liquid chromatography detection, ending the reaction until no raw material is left, and carrying out post-treatment on the reaction liquid. According to the synthesis method of the 2-amino-N, 3-dimethyl benzamide, provided by the invention, the reaction time is short, and the reaction yield of the 2-amino-N, 3-dimethyl benzamide product is high.

Description

Technical Field

[0001] The present application relates to the technical field of organic synthesis, and in particular 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 has the characteristics of high efficiency, broad spectrum, and novel mechanism of action. It has broad market space and prospects. 2-Amino-N,3-dimethylbenzamide, with the structural formula shown in formula (2), is a key intermediate in the synthesis of chlorantraniliprole; Formula (2).

[0003] At present, the synthesis of 2-amino-N,3-dimethylbenzamide mainly includes the following routes: Route 1 is shown in formula (3), using 2-nitro-3-methylbenzoic acid as the starting material, reacting with thionyl chloride (SOCl2) to generate acyl chloride, reacting with methylamine (CH3NH2) to generate N-methylamide, and finally using a reducing agent (such as Fe / HCl or SnCl2) to reduce the nitro group to obtain the amino group; Formula (3).

[0004] This route uses 2-nitro-3-methylbenzoic acid as a raw material, chlorinates it with thionyl chloride, and then reacts with methylamine to generate 2-amino-N,3-dimethylbenzamide. The route is long and the yield is low. In addition, thionyl chloride is a fuming liquid with a strong irritating odor and decomposes rapidly with water. The risk factor is relatively high and it is difficult to scale up production in actual production.

[0005] Route 2 is shown in formula (4), using 2-amino-3-methylbenzoic acid as the starting material, reacting with thionyl chloride (SOCl2) to generate an acyl chloride, and reacting with methylamine (CH3NH2) to generate the target product; Formula (4).

[0006] This route uses 2-amino-3-methylbenzoic acid as raw material, which first reacts with thionyl chloride to form acyl chloride, and then reacts with methylamine to form 2-amino-N,3-dimethylbenzamide. It is more direct, has fewer steps, and has a higher yield. Although the process seems to shorten the route and significantly increase the yield, there are still major production safety risks, and there are also many uncertain factors in industrial production.

[0007] Therefore, exploring and developing an economically feasible and safe production process 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

[0008] In order to solve the above technical problems, the present application provides a method for synthesizing 2-amino-N,3-dimethylbenzamide.

[0009] The present application provides a method for synthesizing 2-amino-N,3-dimethylbenzamide. 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 30-100°C to react after the hydrogen pressure reaches 0.1-5MPa, take samples during the reaction for liquid chromatography detection, terminate the reaction until there is no raw material left, and obtain the obtained product after post-treatment of the reaction solution; Formula (1).

[0010] Preferably, the solvent is a low-carbon saturated alcohol having 1 to 4 carbon atoms, and the solvent is selected from one or more of methanol, ethanol, and isopropanol; the amount of the solvent used is 1 to 10 times the mass of the raw material.

[0011] Preferably, the solvent is methanol; the amount of the solvent used is 3 to 5 times the mass of the raw material.

[0012] Through experimental analysis of the effect of solvent type on synthesis, it was found that methanol is the best solvent.

[0013] Preferably, the organic amine auxiliary agent is selected from one or more of ammonia water, monomethylamine solution, and monoethylamine solution; the dosage of the organic amine auxiliary agent is 0.05-0.5% of the mass of the solvent.

[0014] Preferably, the organic amine auxiliary agent is composed of a mixture of ammonia water and monoethylamine solution in a weight ratio of 9:1-3.

[0015] In a specific embodiment, in the organic amine auxiliary agent, the weight ratio of ammonia water to monoethylamine solution can be 9:1, 9:2, or 9:3.

[0016] Preferably, the amount of the organic amine auxiliary agent is 0.1-0.3% of the mass of the solvent.

[0017] In a specific embodiment, the amount of the organic amine auxiliary agent can be 0.05%, 0.1%, 0.2%, 0.3%, or 0.5% of the mass of the solvent.

[0018] Through experimental analysis, it is known that the addition of organic amine auxiliary agents will reduce the generation of by-products, thereby increasing the yield of 2-amino-N,3-dimethylbenzamide products. However, when the amount of organic amine auxiliary agents is too much, the synthesis yield of 2-amino-N,3-dimethylbenzamide will also be reduced, and it is easy to produce more by-products in the subsequent use of solvents and catalysts. The present application selects ammonia water and monoethylamine solution in the above weight ratio as organic amine auxiliary agents, and controls the amount of the auxiliary agents within the above range, which can further improve the synthesis performance of 2-amino-N,3-dimethylbenzamide.

[0019] Preferably, the amount of water used is 0 to 50% of the mass of the solvent.

[0020] Preferably, the amount of water used is 0-15% of the solvent mass.

[0021] 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 to 0.5% of the mass of the raw material.

[0022] 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 material.

[0023] Preferably, the dry amount of the noble metal catalyst is 0.05-0.15% of the mass of the raw material.

[0024] In a specific embodiment, the noble metal catalyst is 3% palladium carbon catalyst, 4% palladium carbon catalyst, or 5% palladium carbon catalyst.

[0025] In a specific embodiment, the dry basis dosage of the 5% palladium carbon catalyst is 0.05%, 0.1%, 0.15%, 0.20%, or 0.30% of the mass of the raw material.

[0026] Through experimental analysis, it can be known that the present application selects 3-5% palladium carbon catalyst and controls the dosage within the above range, the reaction time is shorter, the by-products are less, and the product yield is improved.

[0027] Preferably, the reaction hydrogen pressure is 0.6-1.2 MPa, and the reaction temperature is 40°C-80°C.

[0028] 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.

[0029] In a specific embodiment, the reaction temperature can be 30°C, 40°C, 50°C, 60°C, 70°C, or 80°C.

[0030] Preferably, 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; Preferably, in the specific step of 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 above-mentioned application reaction, the catalyst needs to be supplemented with 0.01% to 0.05% of the mass of the raw material.

[0031] In summary, the technical solution of this application has the following effects: The present application provides a method for synthesizing 2-amino-N,3-dimethylbenzamide, which has mild reaction conditions, short reaction time, simple process operation and high product yield.

[0032] The 2-amino-N,3-dimethylbenzamide synthesis method provided in the present application has high product purity, achieves zero emission, and is conducive to industrial production.

[0033] The 2-amino-N,3-dimethylbenzamide synthesis method provided in the present application has significantly improved production efficiency, has no hazardous processes, has little production safety hazard, and is suitable for large-scale preparation.

[0034] The 2-amino-N,3-dimethylbenzamide synthesis method provided in the present application can use catalysts and solvents for repeated reactions, thereby reducing costs and being suitable for industrial production. DETAILED DESCRIPTION

[0035] The present application is further described in detail below in conjunction with examples, comparative examples and performance testing experiments. These examples should not be construed as limiting the scope of protection claimed in the present application. Example Example 1

[0036] Example 1 provides a method for synthesizing 2-amino-N,3-dimethylbenzamide.

[0037] The specific synthesis method of 2-amino-N,3-dimethylbenzamide in this embodiment is as follows.

[0038] Add 50g 2-nitro-N,3-dimethylbenzamide (purity of 99%), 200g methanol, 0.4g organic amine auxiliary agent (0.2% of the mass of the solvent, composed of ammonia water and monoethylamine solution mixed in a weight ratio of 9:2), 5g water and 0.05g (on a dry basis) of 5% palladium carbon catalyst into the reaction vessel autoclave, replace with nitrogen 3 times, replace with hydrogen 3 times, increase the hydrogen pressure to 1MPa, raise the temperature to 60°C, add hydrogen in time when the hydrogen pressure decreases, take samples every half an hour during the reaction process for liquid chromatography detection, and no raw materials remain after 3.5h of reaction (the product yield in the reaction liquid is 99.027% by liquid chromatography detection), and terminate the reaction; The reaction liquid was vacuum filtered under a vacuum degree of -0.1 MPa to obtain a filtrate and a filter cake. The filter cake was used as a catalyst for the next reaction. The filtrate was rotary evaporated to remove the solvent. The material after rotary evaporation was dissolved in fresh solvent methanol at 60°C, and then cooled to 0-20°C for crystallization. The recrystallized material was dried 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%. Embodiment 2-9

[0039] Examples 2-9 respectively provide a method for synthesizing 2-amino-N,3-dimethylbenzamide.

[0040] The difference between the above embodiment and embodiment 1 is that the type and amount of the organic amine auxiliary agent are different, as shown below.

[0041] In Example 2, the organic amine auxiliary agent is composed of ammonia water and monomethylamine solution mixed in a weight ratio of 9:2.

[0042] In Example 3, the organic amine auxiliary agent is composed of ammonia water and monoethylamine solution mixed in a weight ratio of 2:9.

[0043] In Example 4, the organic amine auxiliary agent is composed of ammonia water and monoethylamine solution mixed in a weight ratio of 9:1.

[0044] In Example 5, the organic amine auxiliary agent is composed of ammonia water and monoethylamine solution mixed in a weight ratio of 9:3.

[0045] In Example 6, the amount of the organic amine auxiliary agent used is 0.1 g (0.05% of the mass of the solvent).

[0046] In Example 7, the amount of the organic amine auxiliary agent used is 1 g (0.5% of the mass of the solvent).

[0047] In Example 8, the amount of the organic amine auxiliary agent used is 0.2 g (0.1% of the mass of the solvent).

[0048] In Example 9, the amount of the organic amine auxiliary agent used is 0.6 g (0.3% of the mass of the solvent).

[0049] The other process parameters in the above embodiment are the same as those in embodiment 1. Examples 10-13

[0050] Examples 10-13 respectively provide a method for synthesizing 2-amino-N,3-dimethylbenzamide.

[0051] The difference between the above embodiment and embodiment 1 is that the types of precious metal catalysts are different, as shown below.

[0052] In Example 10: the noble metal catalyst is 0.05 g of 5% platinum-carbon catalyst.

[0053] In Example 11: the precious metal catalyst is 0.05 g of 5% ruthenium carbon catalyst.

[0054] In Example 12: The palladium carbon catalyst recovered from the noble metal catalyst Example 1 was supplemented with 0.025 g (on a dry basis) of 5% palladium carbon.

[0055] In Example 13: The palladium carbon catalyst recovered from the noble metal catalyst Example 1 was supplemented with 0.01 g (on a dry basis) of 5% palladium carbon.

[0056] The other process parameters in the above embodiment are the same as those in embodiment 1. Examples 14-17

[0057] Examples 14-17 respectively provide a method for synthesizing 2-amino-N,3-dimethylbenzamide.

[0058] The difference between the above embodiment and embodiment 1 is that the types of precious metal catalysts are different, as shown below.

[0059] In Example 14: the reaction temperature is 30°C.

[0060] In Example 15: the reaction temperature is 40°C.

[0061] In Example 16: the reaction temperature is 80°C.

[0062] In Example 17: the reaction temperature is 100°C.

[0063] The other process parameters in the above embodiment are the same as those in embodiment 1. Comparative Example Comparative Example 1-2

[0064] This comparative example 1-2 provides a method for synthesizing 2-amino-N,3-dimethylbenzamide.

[0065] The differences between the above comparative example and Example 1 are specifically as follows.

[0066] In Comparative Example 1: no organic amine auxiliary agent was added.

[0067] In Comparative Example 2, 0.05 g of Raney nickel was used as a catalyst.

[0068] The other process parameters in the above comparative example are the same as those in Example 1. Performance testing

[0069] The reaction time, reaction purity and yield of the 2-amino-N,3-dimethylbenzamide synthesis method in the examples and comparative examples were recorded.

[0070] Test results: as shown in Table 1.

[0071] Table 1 Performance test results of the synthesis method of 2-amino-N,3-dimethylbenzamide in the examples and comparative examples

[0072] In combination with Table 1, by comparing the test results of Examples 1-17 with Comparative Examples 1-2, it can be seen that in Comparative Example 1, no organic amine auxiliary agent is added, and in Comparative Example 2, Raney nickel is used as a catalyst, and the synthesis reaction time of 2-amino-N, 3-dimethylbenzamide is long, and the yield of the product is low; in contrast, the embodiment of the present application uses an organic amine auxiliary agent and a precious metal catalyst for synthesizing 2-amino-N, 3-dimethylbenzamide, which greatly shortens the synthesis reaction time and improves the yield of the product.

[0073] By comparing the test results of Examples 1-9, it can be seen that the present application selects an organic amine auxiliary agent composed of ammonia water and monoethylamine 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.

[0074] By comparing the test results of Examples 1 and 10-13, it can be seen that the selection of 3% to 5% palladium-carbon catalyst in the present application can further shorten the synthesis time of 2-amino-N,3-dimethylbenzamide, while improving the yield of the product; and the catalyst and solvent can be repeatedly used in the reaction, reducing costs and being suitable for industrial production.

[0075] By comparing the test results of Examples 1 and 14-17, it can be seen that the present application controls the reaction temperature to 40-80° C., which can further improve the synthesis performance of 2-amino-N,3-dimethylbenzamide.

[0076] Although the present invention has been described in detail above with general descriptions and specific embodiments, it is obvious to those skilled in the art that some modifications or improvements may be made thereto based on the present invention. Therefore, these modifications or improvements made without departing from the spirit of the present invention all fall within the scope of protection claimed 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 30-100°C to react after the hydrogen pressure reaches 0.1-5MPa, take samples during the reaction for liquid chromatography detection, terminate the reaction until there is no raw material left, and obtain the obtained product after post-treatment of the reaction solution; Formula (1).

2. The method for synthesizing 2-amino-N,3-dimethylbenzamide according to claim 1, characterized in that: The solvent is a low-carbon saturated alcohol with 1 to 4 carbon atoms, and the solvent is selected from one or more of methanol, ethanol, and isopropanol; the amount of the solvent used is 1 to 10 times the mass of the raw material.

3. The method for synthesizing 2-amino-N,3-dimethylbenzamide according to claim 1, characterized in that: The organic amine auxiliary agent is selected from one or more of ammonia water, monomethylamine solution and monoethylamine solution; the dosage of the organic amine auxiliary agent is 0.05-0.5% of the mass of the solvent.

4. The method for synthesizing 2-amino-N,3-dimethylbenzamide according to claim 3, characterized in that: The organic amine auxiliary agent is composed of ammonia water and monoethylamine solution mixed in a weight ratio of 9:1-3.

5. 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 solvent mass.

6. The method for synthesizing 2-amino-N,3-dimethylbenzamide according to claim 1, characterized in that: The noble metal catalyst is selected from one or more of palladium carbon, platinum carbon, and ruthenium carbon; the dry basis dosage of the noble metal catalyst is 0.02-0.5% of the raw material mass.

7. The method for synthesizing 2-amino-N,3-dimethylbenzamide according to claim 6, characterized in that: The noble metal catalyst is a 3-5% palladium carbon catalyst, and the dry basis dosage of the noble metal catalyst is 0.05-0.3% of the raw material mass.

8. 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, and the reaction temperature is 40°C-80°C.

9. 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.

10. The method for synthesizing 2-amino-N,3-dimethylbenzamide according to claim 9, 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 above-mentioned 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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