Preparation method of dinotefuran

Abstract

The invention provides a preparation method of dinotefuran, and belongs to the technical field of pesticide pharmacy. The preparation method of the dinotefuran provided by the invention comprises the following step: enabling 3-aminomethyl tetrahydrofuran and 1, 3-dimethyl-2-nitroisourea to react in an alkaline environment under the condition of a catalyst to obtain the dinotefuran. According to the catalyst provided by the invention, 1, 3-dimethyl-2-nitroisourea and 3-aminomethyl tetrahydrofuran molecules can be aggregated on the catalyst, and a by-product methanol is dispersed, so that the forward proceeding of a condensation reaction is facilitated, and the yield of dinotefuran is improved; and the organic benzene is used as the solvent, the dinotefuran can be generated at normal temperature, and the operation is simple. Meanwhile, the synthesis steps are few, and the pollutant emission is less; and the synthesis period is short, and production processing and industrial use are facilitated.

Description

Technical Field

[0001] This invention belongs to the field of pesticide manufacturing, and specifically relates to a method for preparing fipronil. Background Technology

[0002] Dinotefuran is a third-generation neonicotinoid insecticide developed by Mitsui Chemicals, Inc. of Japan. It primarily kills pests such as cockroaches and is characterized by high efficiency and low toxicity. It is environmentally friendly and poses minimal harm to humans. Its chemical structure differs significantly from existing neonicotinoid insecticides; its tetrahydrofuran group replaces the previous chloropyridinyl and chlorothiazolyl groups, and it does not contain halogens. Furthermore, its performance characteristics also differ from those of neonicotinoids.

[0003] Among the existing synthetic methods, 1,3-dimethyl-2-nitroisourea is reacted with 3-aminomethyltetrahydrofuran to prepare fipronil. However, the yield of fipronil prepared by this method is low, usually ≤75%. Therefore, it is urgent to improve the yield of fipronil prepared by this synthetic route. Summary of the Invention

[0004] The purpose of this invention is to provide a method for preparing fipronil. This invention uses 1,3-dimethyl-2-nitroisourea and 3-aminomethyltetrahydrofuran as reaction raw materials, and reacts them under benzene solvent and catalyst conditions to obtain fipronil. The yield of fipronil is relatively high.

[0005] To achieve the objectives of this invention, the following technical solutions are provided: A method for preparing fipronil includes the following steps: 1,3-Dimethyl-2-nitroisourea, a base reagent, an organic base catalyst, and a first organic solvent are mixed to obtain a premix; the temperature of the first mixing is 20~50℃. 3-Aminomethyltetrahydrofuran, a second organic solvent, and the premixed solution were mixed and subjected to a condensation reaction to obtain the fipronil. The first and second organic solvents are benzene-based solvents; the organic base catalyst is one or more of trimethylamine, triethylamine, 4-dimethylaminopyridine, and N,N-dimethylformamide.

[0006] Preferably, the benzene solvent is one of toluene, xylene, and pseudotrimethylbenzene.

[0007] Preferably, the alkaline reagent is one or more of alkali metal alkoxides, alkali metal hydroxides, and alkali metal carbonates.

[0008] Preferably, the molar ratio of 1,3-dimethyl-2-nitroisourea and 3-aminomethyltetrahydrofuran is 1:0.99~1.03.

[0009] Preferably, the mass ratio of the 1,3-dimethyl-2-nitroisourea to the catalyst is 1:0.01~0.10.

[0010] Preferably, the mass concentration of 1,3-dimethyl-2-nitroisourea in the premix is ​​0.2~0.4 g / mL.

[0011] Preferably, the mass ratio of the 1,3-dimethyl-2-nitroisourea to the alkaline reagent is 1:1 to 1.3.

[0012] Preferably, the volume ratio of the first organic solvent to the second organic solvent is 1.5 to 2.5:1.

[0013] Preferably, the condensation reaction is carried out at a temperature of 30-50°C for 3-5 hours.

[0014] Preferably, the process further includes washing the resulting condensation reaction system; the solvent used for washing is a benzene-based solvent.

[0015] This invention provides a method for preparing fipronil, comprising the following steps: firstly mixing 1,3-dimethyl-2-nitroisourea, a base reagent, an organic base catalyst, and a first organic solvent to obtain a premix; the temperature of the first mixing is 20-50°C; secondly mixing 3-aminomethyltetrahydrofuran, a second organic solvent, and the premix to carry out a condensation reaction to obtain fipronil; the first and second organic solvents are benzene-based solvents; the organic base catalyst is one or more of trimethylamine, triethylamine, 4-dimethylaminopyridine, and N,N-dimethylformamide. In the method provided by this invention, an organic base is used as a catalyst, which allows 1,3-dimethyl-2-nitroisourea and 3-aminomethyltetrahydrofuran molecules to aggregate onto the catalyst, while the byproduct methanol is dispersed, which is beneficial for the forward condensation reaction and improves the yield of fipronil. Example results show that the yield of fipronil in this invention reaches 83%, and the purity is above 95%; furthermore, this invention uses organic benzene as a solvent, and fipronil can be generated at room temperature, making the operation simple. Meanwhile, the present invention has fewer synthesis steps and less pollution emissions; and the synthesis cycle is short, making it convenient for production, processing and industrial use. Detailed Implementation

[0016] This invention provides a method for preparing fipronil, comprising the following steps: 1,3-Dimethyl-2-nitroisourea, a base reagent, an organic base catalyst, and a first organic solvent are mixed to obtain a premix; the temperature of the first mixing is 20~50℃. 3-Aminomethyltetrahydrofuran, a second organic solvent, and the premixed solution were mixed and subjected to a condensation reaction to obtain the fipronil. The first and second organic solvents are benzene-based solvents; the organic base catalyst is one or more of trimethylamine, triethylamine, 4-dimethylaminopyridine, and N,N-dimethylformamide.

[0017] In this invention, unless otherwise specified, all raw materials used in the preparation are commercially available products well known to those skilled in the art.

[0018] This invention involves first mixing 1,3-dimethyl-2-nitroisourea, an alkaline reagent, an organic base catalyst, and a portion of an organic solvent to obtain a premixed solution. In this invention, the benzene solvent is one of toluene, xylene, and pseudotrimethylbenzene; in specific embodiments, pseudotrimethylbenzene may be used. This invention uses organic benzene as a solvent, which can generate fipronil at room temperature. The operation is simple, and the raw materials have low pollution and low toxicity. Furthermore, the benzene solvent is easily separated and recovered, and can be reused multiple times, thereby improving the yield. In addition, the mother liquor of the benzene solvent has a significantly higher solubility for impurities than the product, which is beneficial for improving purity.

[0019] In specific embodiments of the present invention, the organic base catalyst can be triethylamine, triethylamine, and N,N-dimethylformamide. When the catalyst is triethylamine and DMF, the molar ratio of triethylamine to DMF is 1:3~5. The present invention uses one or more of trimethylamine, triethylamine, 4-dimethylaminopyridine (DMAP), and N,N-dimethylformamide (DMF) as a catalyst, which allows 1,3-dimethyl-2-nitroisourea and 3-aminomethyltetrahydrofuran molecules to aggregate onto the catalyst. This is similar to the presence of a closed or semi-open cell within the reaction system, where the reagent reaction occurs inside the 'cell,' the product is released, and the reaction continues in the forward direction. Furthermore, the byproduct methanol is dispersed, which also facilitates the forward condensation reaction, thus increasing the yield of fipronil.

[0020] In this invention, the alkaline reagent is one or more selected from alkali metal alkoxides, alkali metal hydroxides, and alkali metal carbonates; the alkali metal alkoxide can be sodium methoxide, sodium ethoxide, or potassium tert-butoxide; the alkali metal hydroxide can be sodium hydroxide or potassium hydroxide; and the alkali metal carbonate can be sodium carbonate or potassium carbonate. The alkaline reagent of this invention can provide an alkaline environment. This invention places the reaction system in a strongly alkaline environment with a pH value > 12 using the alkaline reagent.

[0021] In this invention, the molar ratio of 1,3-dimethyl-2-nitroisourea and 3-aminomethyltetrahydrofuran is 1:0.99~1.03, and in specific embodiments it can be 1:1.0 or 1:1.01.

[0022] In this invention, the mass ratio of 1,3-dimethyl-2-nitroisourea to the catalyst is 1:0.01~0.10, and in specific embodiments it can be 1:0.03, 1:0.05 or 1:0.08.

[0023] In this invention, the ratio of 1,3-dimethyl-2-nitroisourea to organic solvent is 1g:3~5mL, and in a specific embodiment it can be 1g:4mL.

[0024] In this invention, the mass ratio of 1,3-dimethyl-2-nitroisourea to the base reagent is 1:1 to 1.3, and in a specific embodiment it can be 1:1.2.

[0025] This invention involves a first mixing of 1,3-dimethyl-2-nitroisourea, an alkaline reagent, a catalyst, and a portion of an organic solvent to obtain a premixed solution. The temperature of the first mixing is 20-50°C. The first mixing is carried out under stirring conditions, and the stirring rate is not specifically limited in this invention. This invention controls the temperature of the first mixing within the above range. Under alkaline conditions, the higher the temperature, the faster the reaction rate (including the rate of side reactions). When the temperature is too high, the product continues to react with 3-aminomethyltetrahydrofuran to generate impurities (dimer impurities, i.e., one molecule of isourea reacts with two molecules of trimethylamine). When the temperature is too low (e.g., 0°C), the reaction rate is slower, resulting in a lower isourea conversion rate in the same amount of time.

[0026] After obtaining the premixed solution, the present invention further mixes 3-aminomethyltetrahydrofuran, a second organic solvent, and the premixed solution to carry out a condensation reaction to obtain the fipronil. The present invention first mixes 3-aminomethyltetrahydrofuran and the remaining organic solvent, and then adds the resulting mixture dropwise to the premixed solution to carry out the condensation reaction. In the present invention, the volume ratio of the first organic solvent to the second organic solvent is 1.5~2.5:1, and in a specific embodiment, it can be 2:4; the dropwise addition time is 0.5~1.5 h, and in a specific embodiment, it can be 1.0 h. The present invention initially adds the first organic solvent as a reaction solvent mixed with isourea, and the second organic solvent is mixed with 3-aminomethyltetrahydrofuran and added dropwise into the system. If the organic solvents are added together, and only 3-aminomethyltetrahydrofuran is added dropwise, the impurities will be too large, affecting the yield.

[0027] In this invention, the temperature of the condensation reaction is 30~50℃, and in a specific embodiment it can be 35 or 40℃. The time is 3~5h, and in a specific embodiment it can be 3.5 or 4h.

[0028] After the condensation reaction is completed, the present invention further includes cooling and filtering the obtained condensation reaction system, and washing and drying the obtained filter cake; the present invention does not have any special limitations on cooling and filtering; the reagent used for washing in the present invention is the above-mentioned organic solvent, and the amount of organic solvent used for washing is 50 to 150% of the amount of organic solvent used in the condensation reaction.

[0029] To further illustrate the present invention, the preparation method of fipronil provided by the present invention will be described in detail below with reference to the embodiments, but these should not be construed as limiting the scope of protection of the present invention.

[0030] Example 1 1 mol of 1,3-dimethyl-2-nitroisourea, 1 mol of potassium hydroxide, 0.05 mol of catalyst (DMF and triethylamine in a mass ratio of 1:5) and 540 mL of pseudotrimethylbenzene were added to a reaction vessel and stirred for 1 h at 30 °C. Then, a mixture of 0.99 mol of 3-aminomethyltetrahydrofuran and 270 mL of pseudotrimethylbenzene was added dropwise over a time of 90 min. After the addition was completed, the temperature was raised to 50 °C and the condensation reaction was carried out at 50 °C for 6 h (the content of 1,3-dimethyl-2-nitroisourea was <0.5% as determined by liquid chromatography). The condensation reaction system was cooled and filtered. The resulting filter cake was washed once with 810 mL of pseudotrimethylbenzene and dried at 80 °C to obtain fipronil. The molar yield was calculated to be 83%, and the purity was 97.5% as determined by HPLC.

[0031] Example 2 1 mol of 1,3-dimethyl-2-nitroisourea, 1 mol of potassium hydroxide, 0.05 mol of catalyst (DMF and triethylamine in a mass ratio of 1:1) and 540 mL of pseudotrimethylbenzene were added to a reaction vessel and stirred for 1 h at 30 °C. Then, a mixture of 0.99 mol of 3-aminomethyltetrahydrofuran and 270 mL of pseudotrimethylbenzene was added dropwise over a time of 90 min. After the addition was completed, the temperature was raised to 50 °C and the condensation reaction was carried out at 50 °C for 6 h. The condensation reaction system was cooled and filtered. The resulting filter cake was washed once with 810 mL of pseudotrimethylbenzene and dried at 80 °C to obtain fipronil. The molar yield was calculated to be 85%, and the purity was 98% as determined by HPLC.

[0032] Example 3 1 mol of 1,3-dimethyl-2-nitroisourea, 1 mol of potassium hydroxide, 0.05 mol of DMF, and 540 mL of pseudotrimethylbenzene were added to a reaction vessel and stirred for 1 h at 30 °C. Then, a mixture of 0.99 mol of 3-aminomethyltetrahydrofuran and 270 mL of pseudotrimethylbenzene was added dropwise over a period of 90 min. After the addition was completed, the temperature was raised to 50 °C, and the condensation reaction was carried out at 50 °C for 6 h. The condensation reaction system was cooled and filtered. The resulting filter cake was washed once with 810 mL of pseudotrimethylbenzene and dried at 80 °C to obtain fipronil. The molar yield was calculated to be 85.5%, and the purity was 97.5% as determined by HPLC.

[0033] Example 4 1 mol of 1,3-dimethyl-2-nitroisourea, 1 mol of potassium carbonate, 0.05 mol of catalyst (DMF and triethylamine in a mass ratio of 1:5) and 540 mL of pseudotrimethylbenzene were added to a reaction vessel and stirred for 1 h at 30 °C. Then, a mixture of 0.99 mol of 3-aminomethyltetrahydrofuran and 270 mL of pseudotrimethylbenzene was added dropwise over a time of 90 min. After the addition was completed, the temperature was raised to 50 °C and the condensation reaction was carried out at 50 °C for 6 h. The condensation reaction system was cooled and filtered. The resulting filter cake was washed once with 810 mL of pseudotrimethylbenzene and dried at 80 °C to obtain fipronil. The molar yield was calculated to be 94.4%, and the purity was 98.1% as determined by HPLC.

[0034] Example 5 1 mol of 1,3-dimethyl-2-nitroisourea, 1 mol of potassium hydroxide, 0.05 mol of catalyst (DMF and triethylamine in a mass ratio of 1:5) and 540 mL of pseudotrimethylbenzene were added to a reaction vessel and stirred for 1 h at 20 °C. Then, a mixture of 0.99 mol of 3-aminomethyltetrahydrofuran and 270 mL of pseudotrimethylbenzene was added dropwise over a time of 90 min. After the addition was completed, the temperature was raised to 50 °C and the condensation reaction was carried out at 50 °C for 6 h. The condensation reaction system was cooled and filtered. The resulting filter cake was washed once with 810 mL of pseudotrimethylbenzene and dried at 80 °C to obtain fipronil. The molar yield was calculated to be 83%, and the purity was 96.5% as determined by HPLC.

[0035] Comparative Example 1 1 mol of 1,3-dimethyl-2-nitroisourea, 1 mol of potassium hydroxide, 0.05 mol of catalyst (DMF and triethylamine in a mass ratio of 1:5) and 540 mL of water were added to a reaction vessel and stirred for 1 h at 30 °C. Then, a mixture of 0.99 mol of 3-aminomethyltetrahydrofuran and 270 mL of water was added dropwise over a period of 90 min. After the addition was completed, the temperature was raised to 50 °C and the condensation reaction was carried out at 50 °C for 6 h. The condensation reaction system was cooled and filtered. The resulting filter cake was washed once with 810 mL of pseudotrimethylbenzene and dried at 80 °C to obtain fipronil. The molar yield was calculated to be 75%, and the purity was 96.9% as determined by HPLC.

[0036] Comparative Example 2 1 mol of 1,3-dimethyl-2-nitroisourea, 1 mol of potassium hydroxide, 0.05 mol of catalyst (DMF and triethylamine in a mass ratio of 1:5) and 540 mL of pseudotrimethylbenzene were added to a reaction vessel and stirred for 1 h at 60 °C. Then, a mixture of 0.99 mol of 3-aminomethyltetrahydrofuran and 270 mL of pseudotrimethylbenzene was added dropwise over a time of 90 min. After the addition was completed, the temperature was raised to 50 °C and the condensation reaction was carried out at 50 °C for 6 h. The condensation reaction system was cooled and filtered. The resulting filter cake was washed once with 810 mL of pseudotrimethylbenzene and dried at 80 °C to obtain fipronil. The molar yield was calculated to be 44.5%, and the purity was 72.1% as determined by HPLC.

[0037] Comparative Example 3 1 mol of 1,3-dimethyl-2-nitroisourea, 1 mol of potassium hydroxide, 0.05 mol of catalyst (DMF and triethylamine in a mass ratio of 1:5) and 540 mL of pseudotrimethylbenzene were added to a reaction vessel and stirred for 1 h at 80 °C. Then, a mixture of 0.99 mol of 3-aminomethyltetrahydrofuran and 270 mL of pseudotrimethylbenzene was added dropwise over a time of 90 min. After the addition was completed, the temperature was raised to 50 °C and the condensation reaction was carried out at 50 °C for 6 h. The condensation reaction system was cooled and filtered. The resulting filter cake was washed once with 810 mL of pseudotrimethylbenzene and dried at 80 °C to obtain fipronil. The molar yield was calculated to be 23.2%, and the purity was 76.1% as determined by HPLC.

[0038] Comparative Example 4 1 mol of 1,3-dimethyl-2-nitroisourea, 1 mol of potassium hydroxide, 0.05 mol of catalyst (DMF and triethylamine in a mass ratio of 1:5) and 540 mL of pseudotrimethylbenzene were added to a reaction vessel and stirred for 1 h at 0 °C. Then, a mixture of 0.99 mol of 3-aminomethyltetrahydrofuran and 270 mL of pseudotrimethylbenzene was added dropwise over a time of 90 min. After the addition was completed, the temperature was raised to 50 °C and the condensation reaction was carried out at 50 °C for 6 h. The condensation reaction system was cooled and filtered. The resulting filter cake was washed once with 810 mL of pseudotrimethylbenzene and dried at 80 °C to obtain fipronil. The molar yield was calculated to be 73.2%, and the purity was 97.5% as determined by HPLC.

[0039] Comparative Example 5 1 mol of 1,3-dimethyl-2-nitroisourea, 1 mol of potassium hydroxide, and 540 mL of pseudotrimethylbenzene were added to a reaction vessel and stirred for 1 h at 30 °C. Then, a mixture of 0.99 mol of 3-aminomethyltetrahydrofuran and 270 mL of pseudotrimethylbenzene was added dropwise over a period of 90 min. After the addition was completed, the temperature was raised to 50 °C and the condensation reaction was carried out at 50 °C for 6 h (the content of 1,3-dimethyl-2-nitroisourea was <0.5% as determined by liquid chromatography). The condensation reaction system was cooled and filtered. The resulting filter cake was washed once with 810 mL of pseudotrimethylbenzene and dried at 80 °C to obtain fipronil. The molar yield was calculated to be 25%, and the purity was 95% as determined by HPLC.

[0040] Although the above embodiments have provided a detailed description of the present invention, they are only some embodiments of the present invention, and not all embodiments. People can obtain other embodiments based on these embodiments without creative effort, and these embodiments all fall within the protection scope of the present invention.

Claims

1. A process for the preparation of dinotefuran, characterized in that, The method comprises the following steps: mixing 1,3-dimethyl-2-nitroisourea, a base reagent, an organic base catalyst and a first organic solvent to obtain a premix; the first mixing is carried out at a temperature of 20-50℃; mixing 3-aminomethyltetrahydrofuran, a second organic solvent and the premix to carry out a condensation reaction to obtain the dinotefuran; the first and second organic solvents are benzene solvents; the organic base catalyst is one or more of trimethylamine, triethylamine, 4-dimethylaminopyridine and N,N-dimethylformamide.

2. The production method according to claim 1, characterized by, the benzene solvent is one of toluene, xylene and pseudocumene.

3. The production method according to claim 1, characterized by, the base reagent is one or more of alkali metal alkoxide, alkali metal hydroxide and alkali metal carbonate.

4. The method of claim 1, wherein, the molar ratio of 1,3-dimethyl-2-nitroisourea to 3-aminomethyltetrahydrofuran is 1:0.99-1.

03.

5. The preparation method according to claim 1, characterized in that, the mass ratio of 1,3-dimethyl-2-nitroisourea to catalyst is 1:0.01-0.

10.

6. The method of claim 1, wherein, the mass concentration of 1,3-dimethyl-2-nitroisourea in the premix is 0.2-0.4g / mL.

7. The production method according to claim 1 or 3, characterized by, the mass ratio of 1,3-dimethyl-2-nitroisourea to base reagent is 1:1-1.

3.

8. The method of claim 1, wherein, the volume ratio of the first organic solvent to the second organic solvent is 1.5-2.5:

1.

9. The method of claim 1, wherein, the condensation reaction is carried out at a temperature of 30-50℃ for 3-5h.

10. The method of claim 1, wherein, the obtained condensation reaction system is further washed; the washing solvent is a benzene solvent.