A method for synthesizing N-methylene-2-(trifluoromethyl)benzamide

Abstract

This invention discloses a method for synthesizing N-methylene-2-(trifluoromethyl)benzamide, which is prepared by ring-opening reaction using 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine as a starting material. In this invention, 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine has a unique structure that significantly alters the electron cloud density and reactivity of the aziridine ring. Therefore, N-methylene-2-(trifluoromethyl)benzamide can be prepared by ring-opening reaction with a purity of up to 98% and a yield of up to 85%. Furthermore, the synthesis method of this invention has advantages such as simple process, convenient operation, mild reaction conditions, easy separation and purification, high purity, and high yield. It solves the problems of difficult separation of intermediate products and cumbersome steps in existing synthetic routes, facilitating large-scale industrial production and application.

Description

Technical Field

[0001] This invention belongs to the field of pesticide preparation technology and relates to a method for synthesizing a fluopyram intermediate, specifically a method for synthesizing N-methylene-2-(trifluoromethyl)benzamide. Background Technology

[0002] Fluopyram, chemical name: N-[2-[3-chloro-5-(trifluoromethyl)-2-pyridine]ethyl]-2-(trifluoromethyl)benzamide, molecular formula: C 16 H 11 ClF6N2O has the following structural formula: .

[0003] Fluopyram is a fungicide with low toxicity, high efficacy, strong systemic properties, and environmental friendliness. It can treat a variety of diseases caused by Sclerotinia sclerotiorum, Platycodon grandiflorus, powdery mildew, and gray mold, and has a very promising application prospect.

[0004] To date, based on domestic and international literature reports, there are two main synthetic routes for fluopyram.

[0005] Route 1: .

[0006] In Route 1 described above, 2,3-dichloro-5-trifluoromethylpyridine is used as a raw material. It is condensed with ethyl cyanoacetate and hydrolyzed to obtain 2-cyanomethyl-3-chloro-5-trifluoromethylpyridine, which is then hydrogenated and reduced by palladium on carbon to give 2-aminoethyl-3-chloro-5-trifluoromethylpyridine hydrochloride. Finally, it is amidated with o-trifluoromethylbenzoyl chloride to obtain fluopyram technical. This route is relatively lengthy, the condensation intermediates are difficult to separate, the cyano hydrogenation step uses the noble metal palladium on carbon catalysis, resulting in relatively high costs and demanding reaction conditions.

[0007] Route 2: .

[0008] In Route 2 described above, 2,3-dichloro-5-trifluoromethylpyridine, diethyl malonate, and o-trifluoromethylbenzoic acid are used as starting materials, and the final product fluopyram is obtained through 7 steps. This route involves many synthetic steps, harsh reaction conditions, and the esterification intermediates are difficult to separate and purify, resulting in a large number of byproducts, making it unsuitable for large-scale industrial production.

[0009] Therefore, obtaining a synthetic method for fluopyram intermediates that is simple in process, convenient in operation, mild in reaction conditions, easy to separate and purify, and has high purity and high yield is of great significance for promoting the industrial production of fluopyram. Summary of the Invention

[0010] The technical problem to be solved by the present invention is to overcome the shortcomings of the prior art and provide a method for synthesizing N-methylene-2-(trifluoromethyl)benzamide that is simple in process, convenient in operation, mild in reaction conditions, easy to separate and purify, has high purity and high yield.

[0011] To solve the above-mentioned technical problems, the present invention adopts the following technical solution.

[0012] A method for synthesizing N-methylene-2-(trifluoromethyl)benzamide, wherein the method uses 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine as a starting material to prepare N-methylene-2-(trifluoromethyl)benzamide by a ring-opening reaction.

[0013] The above-mentioned synthesis method, further improved, includes the following steps: S1. A ring-opening reaction is carried out by mixing 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine, an oxidant and a solvent; S2. Wash and dry the reaction solution obtained after the ring-opening reaction in step S1 to remove the solvent and obtain N-methylene-2-(trifluoromethyl)benzamide.

[0014] In a further improvement to the above synthesis method, in step S1, the molar ratio of 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine to the oxidant is 1:1.04 to 1.20.

[0015] In a further improvement to the above synthesis method, in step S1, the oxidant is m-chloroperoxybenzoic acid (mCPBA).

[0016] In a further improvement to the above synthesis method, in step S1, the solvent is at least one of dichloromethane, chlorobenzene, and dichloroethane.

[0017] In a further improvement to the above synthesis method, in step S1, the ring-opening reaction is carried out at a temperature of 40℃ to 150℃; and the time of the ring-opening reaction is 10 min to 40 min.

[0018] In a further improvement to the above synthesis method, in step S2, the reaction solution obtained after the ring-opening reaction in step S1 is washed with an alkaline solution; the alkaline solution is at least one of a saturated sodium bicarbonate solution, a saturated sodium carbonate solution, and a saturated sodium hydroxide solution.

[0019] In a further improvement to the above synthesis method, in step S2, anhydrous magnesium sulfate is used to dry the washed organic phase.

[0020] In a further improvement to the above synthesis method, step S2 involves removing the solvent from the dried product using vacuum distillation.

[0021] In a further improvement to the above synthesis method, in step S2, the purity of the N-methylene-2-(trifluoromethyl)benzamide is 97%–98%, and the yield is 75%–85%.

[0022] In a further improvement to the above synthesis method, in step S2, N-methylene-2-(trifluoromethyl)benzamide is used as an intermediate to prepare fluopyram.

[0023] In this invention, the method for preparing fluopyram uses N-methylene-2-(trifluoromethyl)benzamide as an intermediate, reacts it with dimethyl 2,3-dichloro-5-trifluoromethylpyridinemalonic acid, and generates fluopyram through hydrolysis and decarboxylation.

[0024] In this invention, the reaction equations for the synthesis of N-methylene-2-(trifluoromethyl)benzamide and the synthesis of fluopyram based on N-methylene-2-(trifluoromethyl)benzamide as an intermediate are as follows: .

[0025] In the above reaction equation, fluopyram intermediate I is N-methylene-2-(trifluoromethyl)benzamide, which is to be synthesized in this invention.

[0026] Compared with the prior art, the advantages of the present invention are as follows: (1) In this invention, 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine is used as a raw material. It has a special structure. The strong electron-withdrawing trifluoromethyl (-CF3) group adjacent to the aziridine ring in its molecule will significantly change the electron cloud density and reactivity of the aziridine ring. Therefore, N-methylene-2-(trifluoromethyl)benzamide can be prepared by ring-opening reaction. The purity of N-methylene-2-(trifluoromethyl)benzamide can reach up to 98%, and the yield can reach up to 85%.

[0027] (2) In this invention, 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine is used as a raw material. A ring-opening reaction is carried out under the action of an oxidant, followed by washing, drying, and solvent removal to rapidly prepare N-methylene-2-(trifluoromethyl)benzamide with high purity and high yield. The synthesis method of this invention does not require expensive catalysts such as palladium on carbon, and the obtained N-methylene-2-(trifluoromethyl)benzamide is easy to process and separate, avoiding losses during processing. It has advantages such as simple process, convenient operation, mild reaction conditions, easy separation and purification, high purity, and high yield. It solves the problems of difficult separation of intermediate products and cumbersome steps in existing synthetic routes, facilitating large-scale industrial production and application.

[0028] (3) In this invention, by optimizing the molar ratio of 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine to the oxidant to 1:1.04-1.20, side reactions can be reduced, the amount of oxidant used can be reduced, and the post-processing cost can be reduced. In particular, in this invention, m-chloroperoxybenzoic acid is used as the oxidant, which can effectively avoid the presence of water or water participation in the ring-opening reaction, thereby more effectively reducing the formation of impurities and facilitating the acquisition of high-purity products.

[0029] (4) In this invention, the ring-opening reaction is carried out at a temperature of 40℃~150℃ for 10 min~40 min. By increasing the temperature, the reaction time can be reduced, the reaction cycle can be significantly shortened, the yield can be increased, and the cost can be reduced. Detailed Implementation

[0030] The present invention will be further described below with reference to specific preferred embodiments, but this does not limit the scope of protection of the present invention. All materials and instruments used in the following embodiments are commercially available.

[0031] Example 1 A method for synthesizing N-methylene-2-(trifluoromethyl)benzamide, specifically using 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine as a starting material, involves a ring-opening reaction to prepare N-methylene-2-(trifluoromethyl)benzamide, comprising the following steps: 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine (10.0 g, 46.5 mmol) and m-chloroperoxybenzoic acid (8.5 g, 48.8 mmol) were dissolved in 100 mL of chlorobenzene, and the mixture was heated to 132 °C and refluxed for 30 min to complete the oxidative ring-opening reaction. After the reaction was complete, the reaction solution was washed with saturated sodium bicarbonate solution (2 × 100 mL) to remove m-chlorobenzoic acid generated after the reaction with m-chloroperoxybenzoic acid. The chlorobenzene phase was dried over anhydrous magnesium sulfate to remove residual water from the washing process, and the solvent was removed by vacuum distillation to obtain 8.2 g of fluopyram intermediate I (N-methylene-2-(trifluoromethyl)benzamide) with a purity of 97% and a yield of 85%.

[0032] Example 2 A method for synthesizing N-methylene-2-(trifluoromethyl)benzamide, specifically using 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine as a starting material, involves a ring-opening reaction to prepare N-methylene-2-(trifluoromethyl)benzamide, comprising the following steps: 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine (10.0 g, 46.5 mmol) and m-chloroperoxybenzoic acid (8.5 g, 48.8 mmol) were dissolved in 100 mL of dichloromethane and refluxed at 40 °C for 25 min. After the reaction was complete, the reaction solution was washed with saturated sodium bicarbonate solution (2 × 100 mL), the chlorobenzene phase was dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation to obtain 7.9 g of fluopyram intermediate I (N-methylene-2-(trifluoromethyl)benzamide) with a purity of 97% and a yield of 82%.

[0033] Example 3 A method for synthesizing N-methylene-2-(trifluoromethyl)benzamide, specifically using 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine as a starting material, involves a ring-opening reaction to prepare N-methylene-2-(trifluoromethyl)benzamide, comprising the following steps: 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine (15.0 g, 69.8 mmol) and m-chloroperoxybenzoic acid (13.5 g, 79.3 mmol) were dissolved in 50 mL of chlorobenzene and heated to 80 °C for 20 min. After the reaction was complete, the reaction solution was washed with saturated sodium carbonate solution (2 × 100 mL), the organic phase was dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation to obtain 10.8 g of N-methylene-2-(trifluoromethyl)benzamide with a purity of 97% and a yield of 75%.

[0034] Example 4 A method for synthesizing N-methylene-2-(trifluoromethyl)benzamide, specifically using 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine as a starting material, involves a ring-opening reaction to prepare N-methylene-2-(trifluoromethyl)benzamide, comprising the following steps: 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine (20.33 g, 100 mmol) and m-chloroperoxybenzoic acid (21.07 g, 120 mmol) were added to 500 mL of dichloroethane as solvent. The mixture was stirred and heated to 83 °C, and the reaction was maintained at this temperature for 20 min. After the reaction was complete, the reaction solution was washed with saturated sodium bicarbonate solution (2 × 100 mL), the chlorobenzene phase was dried over anhydrous magnesium sulfate, and the solvent was removed by vacuum distillation to obtain 16.27 g of fluopyram intermediate I (N-methylene-2-(trifluoromethyl)benzamide) with a purity of 97% and a yield of 80%.

[0035] Example 5 A method for synthesizing N-methylene-2-(trifluoromethyl)benzamide, specifically using 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine as a starting material, involves a ring-opening reaction to prepare N-methylene-2-(trifluoromethyl)benzamide, comprising the following steps: 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine (10.0 g, 46.5 mmol) and m-chloroperoxybenzoic acid (8.5 g, 48.8 mmol) were dissolved in 120 mL of chlorobenzene and refluxed at 135 °C for 30 min to complete the oxidative ring-opening reaction. After the reaction was complete, the reaction solution was washed with saturated sodium bicarbonate solution (2 × 100 mL) to remove m-chlorobenzoic acid generated after the reaction with m-chloroperoxybenzoic acid. The chlorobenzene phase was dried over anhydrous magnesium sulfate to remove residual water from the washing process. The solvent was removed by vacuum distillation to obtain 8.0 g of fluopyram intermediate I (N-methylene-2-(trifluoromethyl)benzamide) with a purity of 98% and a yield of 84%.

[0036] As can be seen from the above results, the present invention uses 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine as a raw material, which has a special structure. The strongly electron-withdrawing trifluoromethyl (-CF3) group adjacent to the aziridine ring in its molecule significantly changes the electron cloud density and reactivity of the aziridine ring. Therefore, N-methylene-2-(trifluoromethyl)benzamide can be prepared by ring-opening reaction. The purity of N-methylene-2-(trifluoromethyl)benzamide can reach up to 98%, and the yield can reach up to 85%. At the same time, the synthesis method of the present invention does not require the use of expensive catalysts such as palladium on carbon, and the obtained N-methylene-2-(trifluoromethyl)benzamide is easy to process and separate, avoiding losses in post-processing. It has the advantages of simple process, convenient operation, mild reaction conditions, easy separation and purification, high purity, and high yield. It solves the problems of difficult separation of intermediate products and cumbersome steps in existing synthesis routes, which facilitates large-scale industrial production and application.

[0037] The above description is merely a preferred embodiment of the present invention and is not intended to limit the present invention in any way. Although the present invention has been disclosed above with reference to preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make many possible variations and modifications to the technical solutions of the present invention using the methods and techniques disclosed above, or modify them into equivalent embodiments with equivalent changes, without departing from the spirit and technical essence of the present invention. Therefore, any simple modifications, equivalent substitutions, equivalent changes, and modifications made to the above embodiments based on the technical essence of the present invention without departing from the content of the technical solutions of the present invention shall still fall within the protection scope of the technical solutions of the present invention.

Claims

1. A method for the synthesis of N-methylene-2-(trifluoromethyl)benzamide, characterized in that, The synthesis method uses 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine as a raw material to prepare N-methylene-2-(trifluoromethyl)benzamide through a ring-opening reaction.

2. The method of synthesis of claim 1, wherein, Includes the following steps: S1. A ring-opening reaction is carried out by mixing 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine, an oxidant and a solvent; S2. Wash and dry the reaction solution obtained after the ring-opening reaction in step S1 to remove the solvent and obtain N-methylene-2-(trifluoromethyl)benzamide.

3. The method of synthesis of claim 2, wherein, In step S1, the molar ratio of 2-(2-trifluoromethyl-2,4-cyclopentadien-1-yl)aziridine to the oxidant is 1:1.04 to 1.

20.

4. The synthesis method according to claim 3, characterized in that, In step S1, the oxidant is m-chloroperoxybenzoic acid.

5. The synthesis method according to claim 2, characterized in that, In step S1, the solvent is at least one of dichloromethane, chlorobenzene, and dichloroethane.

6. The synthesis method according to claim 2, characterized in that, In step S1, the ring-opening reaction is carried out at a temperature of 40℃ to 150℃; the time of the ring-opening reaction is 10 min to 40 min.

7. The synthesis method according to any one of claims 2 to 6, characterized in that, In step S2, the reaction solution obtained after the ring-opening reaction in step S1 is washed with an alkaline solution; the alkaline solution is at least one of saturated sodium bicarbonate solution, saturated sodium carbonate solution, and saturated sodium hydroxide solution.

8. The synthesis method according to any one of claims 2 to 6, characterized in that, In step S2, anhydrous magnesium sulfate is used to dry the washed organic phase; The solvent in the dried product was removed by vacuum distillation.

9. The synthesis method according to any one of claims 2 to 6, characterized in that, In step S2, the purity of the N-methylene-2-(trifluoromethyl)benzamide is 97%–98%, and the yield is 75%–85%.

10. The synthesis method according to claim 9, characterized in that, In step S2, the N-methylene-2-(trifluoromethyl)benzamide is used as an intermediate to prepare fluopyram.