A process for the preparation of 2-amino-3,5-dichloro-N-methylbenzamide
The preparation process of 2-amino-3,5-dichloro-N-methylbenzamide was simplified by reacting methyl anthranilate with chlorinating and amination agents, solving the problems of low yield and high cost in the prior art and realizing efficient and low-cost production.
Patent Information
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- SHENYANG SINOCHEM AGROCHEMICALS R&D CO LTD
- Filing Date
- 2022-07-20
- Publication Date
- 2026-07-21
AI Technical Summary
Existing technologies for preparing 2-amino-3,5-dichloro-N-methylbenzamide suffer from problems such as long reaction steps, low yield, large amounts of waste, and high costs.
Methyl anthranilate was reacted with a chlorinating agent to produce methyl 2-amino-3,5-dichlorobenzoate, which was then reacted with an amination agent to produce 2-amino-3,5-chloro-N-methylbenzamide. Using conventional chemical raw materials and mild reaction conditions, the product quality and yield were improved by recrystallization purification.
It simplifies the synthesis process, improves product quality and yield, reduces production costs, and reduces the amount of waste.
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Abstract
Description
Technical Field
[0001] This invention relates to the field of organic synthesis, and more specifically, to a method for preparing 2-amino-3,5-dichloro-N-methylbenzamide. Background Technology
[0002] The Shenyang Chemical Research Institute has developed 3-bromo-N-(2,4-dichloro-6-(methanoyl)phenyl)-1-(3,5-dichloro-2-pyridinyl)-1H-pyrazole-5-carboxamide (internationally known as tetrachlorantraniliprole), which has high insecticidal activity and has been developed into an insecticide.
[0003] As shown in the following formula: .
[0004] 2-Amino-3,5-dichloro-N-methylbenzamide is a key intermediate in the synthesis of tetrachlorantraniliprole. Its synthesis is disclosed in CN110526863. It involves first cyclizing 2-amino-3,5-dichlorobenzoic acid with triphosgene to prepare 3,5-dichloroindocyanine anhydride, and then reacting it with monomethylamine to obtain tetrachlorantraniliprole. This method has a long reaction time, low yield, large amount of waste, and high cost.
[0005] The reaction formula is as follows: .
[0006] WO2020177778 discloses the preparation of 2-amino-3,5-dichlorobenzoyl chloride by reacting 2-amino-3,5-dichlorobenzoic acid with thionyl chloride, followed by reaction with a substituted amine analog of 2-amino-3,5-dichloro-N-methylbenzamide in tetrahydrofuran solvent. This method also suffers from problems such as long reaction steps, large amounts of waste, and high cost.
[0007] The reaction formula is as follows: .
[0008] CN104003976 discloses the preparation of the corresponding benzoyl isopropylamine by reacting methyl 2-amino-3,5-dichlorobenzoate with isopropylamine, but does not provide a detailed description of the preparation of 2-amino-3,5-dichloro-N-methylbenzamide by reacting methyl 2-amino-3,5-dichlorobenzoate with monomethylamine.
[0009] The reaction formula is as follows: .
[0010] CN112142620 discloses a method for preparing 2-amino-N-methylbenzamide by reacting indigo anhydride with monomethylamine, and for preparing 2-amino-3,5-dichloro-N-methylbenzamide by reacting 2-amino-N-methylbenzamide with trichloroisocyanuric acid. This method uses indigo anhydride as a starting material, which is expensive, and uses trichloroisocyanuric acid for chlorination, producing isocyanuric acid as a byproduct. It also has low atom utilization and generates a large amount of waste.
[0011] Iscience23(5),101072;2020 reported the preparation of methyl 2-amino-3,5-dichlorobenzoate by chlorination reaction in acetonitrile solvent in the presence of hydrogen peroxide, acetic acid and strontium chloride. The solvent and raw materials used were expensive and used in large quantities, and the yield was only 59%.
[0012] The reaction formula is as follows: .
[0013] The above methods all have drawbacks such as high cost and large amount of waste. How to develop a synthesis method more suitable for industrial production is a problem that urgently needs to be solved by those skilled in the art. Summary of the Invention
[0014] The purpose of this invention is to provide a simpler and more efficient method for preparing 2-amino-3,5-dichloro-N-methylbenzamide.
[0015] To achieve the above objectives, the technical solution provided by the present invention is as follows: A method for preparing 2-amino-3,5-chloro-N-methylbenzamide: The reaction formula is as follows: .
[0016] The compound methyl anthranilate shown in formula (I) undergoes a chlorination reaction with a chlorinating agent to produce the compound methyl 2-amino-3,5-dichlorobenzoate shown in formula (II); the compound methyl 2-amino-3,5-dichlorobenzoate shown in formula (II) undergoes an amination reaction with an amination agent to obtain 2-amino-3,5-chloro-N-methylbenzamide shown in formula (III).
[0017] In the chlorination reaction, the molar ratio of the compound shown in formula (I) to the chlorinating agent is 1:2 to 10, and the reaction is carried out at 20 to 100°C for 0.5 to 48 hours. The chlorinating agent is selected from hydrochloric acid and hydrogen peroxide, NCS, chlorine, dichlorohydantoin, or sulfonyl chloride. The molar ratio of hydrochloric acid to hydrogen peroxide is 1.3:1. The preferred chlorinating agent is sulfonyl chloride, hydrochloric acid and hydrogen peroxide, or chlorine.
[0018] In the chlorination reaction, the molar ratio of the compound shown in formula (I) to the chlorinating agent is 1:2 to 5, and the reaction is carried out at 40 to 80°C for 2 to 10 hours.
[0019] The chlorination reaction is carried out in the presence of an organic solvent and water (the amount of water may be added according to experimental requirements), or in the presence of an organic solvent, wherein the solvent may be selected from halogenated alkane organic compounds or lower ester organic solvents, and the amount of solvent used is 1 to 10 times the weight of the compound shown in formula (I).
[0020] Among them are halogenated alkane organic compounds such as dichloroethane, dichloromethane, chloroform, toluene, and xylene, and lower esters such as ethyl acetate, methyl acetate, and butyl acetate.
[0021] The preferred solvent can be selected from dichloroethane, dichloromethane, chloroform, methyl acetate, ethyl acetate, or butyl acetate.
[0022] The compound shown in formula (II) is mixed with the amination agent in a molar ratio of 1:1 to 10 in an amination reaction solvent and reacted at -20 to 150°C for 0.5 to 48 hours; wherein the amination agent is an aqueous solution of monomethylamine, a methanol solution of monomethylamine, an ethanol solution of monomethylamine, or a gas of monomethylamine, preferably a methanol solution of monomethylamine, an ethanol solution of monomethylamine, or a gas of monomethylamine.
[0023] The compound shown in formula (II) is mixed with the amination agent in a molar ratio of 1:1 to 8 in the amination reaction solvent and reacted at 30 to 110°C for 2 to 12 hours.
[0024] The amination reaction solvent is selected from one or more of haloalkanes, aromatics, and lower alcohols, and the substances can be mixed in any proportion. The amount of the amination reaction solvent used is 1-10 times the weight of the compound shown in formula (II).
[0025] The halogenated alkane organic compounds include dichloroethane, dichloromethane, and chloroform; lower alcohols include methanol, ethanol, propanol, and isopropanol; aromatic organic compounds include toluene, xylene, acetonitrile, and DMF.
[0026] The product obtained by the amination reaction was purified by recrystallization to obtain 2-amino-3,5-chloro-N-methylbenzamide of formula (III) with a purity of more than 98%.
[0027] The solvent used for recrystallization is methanol, ethanol, or isopropanol, or an aqueous solution of the aforementioned solvent and water, or dichloroethane; the amount of recrystallization solvent used is 0.5 to 10 times the weight ratio of the compound shown in formula (II).
[0028] Advantages of this invention: The synthesis process of this invention is short and simple. Using the above preparation method helps improve the product quality and yield of 2-amino-3,5-dichloro-N-methylbenzamide and reduces process costs. Specifically: 1. The chlorinating agent used in this invention is a conventional chemical raw material with a moderate price; 2. The reaction conditions of this invention are mild, without high temperature or high pressure; 3. This invention generates relatively little waste, and the solvent and reaction raw materials can be recycled and reused; 4. The product prepared by this invention has high yield and content, and reduces production costs. Detailed Implementation
[0029] It should be noted that, unless otherwise specified, the embodiments and features described in this application can be combined with each other. The present invention will now be described in detail with reference to the embodiments.
[0030] The method of this invention solves the problems of low product yield, large amount of waste, and high manufacturing cost that exist when preparing methyl 2-amino-3,5-dichlorobenzoate and 2-amino-3,5-dichloro-N-methylbenzamide compounds using existing methods.
[0031] The reaction formula is as follows: .
[0032] Example 1
[0033] Preparation of methyl 2-amino-3,5-dichlorobenzoate Methyl anthranilate (15.2 g, 0.1 mol) and dichloroethane (150 ml) were added to a reaction flask. The mixture was cooled to -5°C in a cold bath, and sulfonyl chloride (34.1 g, 0.25 mol) was added dropwise. The reaction was slightly exothermic. The dropping rate was controlled to maintain the temperature between 0 and 5°C, and the addition was completed in about 2 hours. The reaction was maintained at this temperature for 4 hours, and TLC was monitored until the reaction was complete. The reaction solution was poured into ice water, and the layers separated. The organic layer was washed again with cold water, allowed to stand, and separated. The organic layer was desolventized under reduced pressure to obtain 21.0 g of methyl 2-amino-3,5-dichlorobenzoate, a light yellow solid with a purity of 94.5% and a yield of 90.2% (based on methyl anthranilate). The recovered solvent was anhydrous and reused.
[0034] Example 2 Preparation of methyl 2-amino-3,5-dichlorobenzoate Add methyl anthranilate (15.2 g, 0.1 mol), chloroform (100 ml), and water (40 g) to a reaction flask. Heat to 40°C and add hydrochloric acid (29.6 g, 37%, 0.3 mol) dropwise. The reaction is exothermic and takes about 0.5 h to complete. Heat to 50°C and begin adding hydrogen peroxide (56.7 g, 30%, 0.5 mol) dropwise. The reaction is exothermic. Control the temperature at 55-61°C and add the hydrogen peroxide dropwise over about 2 h. Maintain this temperature for 2 h and monitor the reaction until complete using TLC. Cool the reaction solution to room temperature, allow it to stand, and allow it to separate into layers. Add water (50 ml) and sodium sulfite (0.5 g) to the organic layer, stir at room temperature for 2 h, and allow it to stand and separate into layers. Desolventize the organic layer under reduced pressure to obtain methyl 2-amino-3,5-dichlorobenzoate, a light yellow solid, 22.0 g, with a purity of 95.5% and a yield of 95.4% (based on methyl anthranilate).
[0035] Example 3 Preparation of methyl 2-amino-3,5-dichlorobenzoate Add methyl anthranilate (15.2 g, 0.1 mol) and chloroform (100 ml) to the reaction flask, heat to 45-50°C, and purge with chlorine gas (14.8 g, 99%, 0.206 mol). The hydrogen chloride gas produced as a reaction byproduct is absorbed by water, and the purging is completed in about 4 hours. Maintain the reaction at this temperature for 2 hours, and monitor the reaction until it is complete using TLC. Heat the reaction solution to 55-61°C and maintain the temperature for 1 hour to fully expel the hydrogen chloride gas. Cool to below 50°C, add 20 g of water and 2.5 g of 30% alkali solution, heat to 40-45°C, stir for 1 hour, and then allow to stand and separate into layers. Desolventize the organic layer under reduced pressure to obtain methyl 2-amino-3,5-dichlorobenzoate, a light yellow solid, 22.2 g, with a purity of 93.5% and a yield of 94.4% (based on methyl anthranilate).
[0036] Example 4 Preparation of 2-amino-3,5-dichloro-N-methylbenzamide The methyl 2-amino-3,5-dichlorobenzoate (21.5 g, 95.5%, 0.093 mol), monomethylamine methanol solution (31.0 g, 30%, 0.3 mol), and 50 g of methanol prepared in Example 2 were added to the reaction flask. The temperature was raised to 40°C, and the reaction was maintained at this temperature for 8 hours. The reaction was monitored by TLC until complete. The monomethylamine methanol solution was recovered by atmospheric distillation and reused in the next batch of reaction. 60 g of methanol was added to the reaction solution, the temperature was lowered to 0°C, and the mixture was filtered. The filter cake was washed with a small amount of methanol and dried to obtain 19.7 g of grayish-white crystalline solid with a purity of 99.0% and a yield of 95.8%.
[0037] Example 5 Preparation of 2-amino-3,5-dichloro-N-methylbenzamide The difference from Example 4 is that monomethylamine ethanol solution (31.0 g, 30%, 0.3 mol) was used instead of monomethylamine methanol solution, and ethanol was used instead of methanol. The rest was the same as in Example 4, and a grayish-white crystalline solid with a content of 99.2% and a yield of 94.7% was obtained.
[0038] Example 6
[0039] Preparation of 2-amino-3,5-dichloro-N-methylbenzamide The methyl 2-amino-3,5-dichlorobenzoate (21.5 g, 93.5%, 0.091 mol), monomethylamine methanol solution (12.4 g, 30%, 0.12 mol), and 50 g of toluene prepared in Example 3 were added to the reaction flask. The temperature was raised to 45°C and maintained at this temperature for 20 h. The reaction was monitored by TLC until complete. The monomethylamine methanol solution and toluene were recovered by atmospheric distillation and reused in the next batch of reaction. 60 g of methanol was added to the reaction solution, the temperature was lowered to 0-5°C, and the mixture was filtered. The filter cake was washed with a small amount of methanol and dried to obtain 19.1 g of product with a purity of 98.5% and a yield of 94.5%.
[0040] Example 7 The methyl 2-amino-3,5-dichlorobenzoate (21.5 g, 95.5%, 0.093 mol) prepared in Example 2, the recovered monomethylamine methanol solution (31.0 g, 30%, 0.3 mol), and 50 g of methanol were added to the reaction flask. The temperature was raised to 40°C, and the reaction was maintained at this temperature for 8 hours. The reaction was monitored by TLC until complete. The monomethylamine methanol solution was recovered by atmospheric distillation and reused in the next batch of reaction. 60 g of methanol was added to the reaction solution, the temperature was lowered to 0°C, and the mixture was filtered. The filter cake was washed with a small amount of methanol and dried to obtain 19.6 g of grayish-white crystalline solid with a purity of 98.7% and a yield of 95.0%.
[0041] As can be seen from the above description, the embodiments of the present invention achieve the following technical effects: methyl 2-amino-3,5-dichlorobenzoate is prepared based on methyl anthranilate, with a product content of 93-96% and a yield of 90-96%; 2-amino-3,5-dichloro-N-methylbenzamide is prepared based on methyl 2-amino-3,5-dichlorobenzoate, with a product content of 98-99% and a yield of 94-95%. These results are far superior to those in the literature, and the operation is simple, with few byproducts and low cost.
[0042] As is known from the background technology, the preparation of methyl 2-amino-3,5-dichlorobenzoate by formula (II) has a low yield, uses a lot of raw materials, produces a lot of by-products, and has a high cost; the preparation of 2-amino-3,5-dichloro-N-methylbenzamide by formula (III) uses expensive raw materials, has low reaction atom utilization, produces a lot of by-products, and has a high cost.
[0043] As can be seen from Examples 1 to 7 above, the yield of methyl 2-amino-3,5-dichlorobenzoate shown in Formula (II) is greater than 93%; the yield of 2-amino-3,5-dichloro-N-methylbenzamide shown in Formula (III) is greater than 94%, and the product content is 98-99%. It can be seen that the preparation method provided in this application can greatly improve the yield of methyl 2-amino-3,5-dichlorobenzoate and 2-amino-3,5-dichloro-N-methylbenzamide.
[0044] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.
Claims
1. A method for preparing 2-amino-3,5-dichloro-N-methylbenzamide, characterized in that: The reaction formula is ； The compound methyl anthranilate shown in formula (I) undergoes a chlorination reaction with a chlorinating agent to produce the compound methyl 2-amino-3,5-dichlorobenzoate shown in formula (II); the compound methyl 2-amino-3,5-dichlorobenzoate shown in formula (II) undergoes an amination reaction with an amination agent to obtain the 2-amino-3,5-dichloro-N-methylbenzamide shown in formula (III); The chlorinating agent is selected from a mixture of hydrochloric acid and hydrogen peroxide or chlorine gas; The amination agent is a methylamine methanol solution or a methylamine ethanol solution; during the chlorination reaction, the molar ratio of the compound shown in formula (I) to the chlorinating agent is 1:2 to 5, and the reaction is carried out at 40 to 80°C for 2 to 10 hours. The chlorination reaction is carried out in the presence of an organic solvent and water, or in the presence of an organic solvent, wherein the organic solvent is selected from dichloroethane or chloroform, and the amount of the organic solvent used is 1 to 10 times the weight of the compound shown in formula (I). The compound of formula (II) is mixed with the amination agent in a molar ratio of 1:1 to 8 in an amination reaction solvent and reacted at 30 to 110°C for 2 to 12 hours. The amination reaction solvent is selected from one or more of chloroform, methanol, and toluene; the amount of the amination reaction solvent used is 1-10 times the weight of the compound of formula (II).
2. The preparation method according to claim 1, characterized in that: The product obtained by the amination reaction was purified by recrystallization to obtain 2-amino-3,5-dichloro-N-methylbenzamide of formula (III) with a purity of more than 98%.
3. The preparation method according to claim 2, characterized in that: The solvent used for recrystallization is methanol, ethanol or isopropanol; the amount of recrystallization solvent used is 0.5 to 10 times the weight of the compound shown in formula (II).