A method for synthesizing fipronil sulfone

Abstract

The present invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing fipronil sulfone. Using hydrogen peroxide as an oxidant, under the action of a catalyst, fipronil is oxidized to fipronil sulfone. The by-product of this method is water, and the whole reaction process is green and environmentally friendly, avoiding unstable strong oxidants such as peroxyacids, potassium permanganate, and persulfates. The addition of the catalyst enables the reaction to proceed safely, smoothly, and efficiently. The method is simple and safe. At the same time, a product with high yield and high purity can be obtained by the method of the present invention.

Description

Technical Field

[0001] The present invention belongs to the field of organic synthesis, and particularly relates to a method for synthesizing fipronil sulfone. Background Art

[0002] Fipronil, also known as Regent, with the English common name Fipronil and the trade name Regent, has the chemical name 5-amino-3-cyano-1-(2,6-dichloro-4-trifluoromethylphenyl)-4-trifluoromethylsulfinylpyrazole. It is a broad-spectrum phenylpyrazole insecticide first produced by Rhone-Poulenc Company in France in 1989. It mainly acts on pests through stomach poisoning, and also has contact killing and certain systemic effects. Its mechanism of action is to hinder the chloride metabolism controlled by γ-aminobutyric acid in insects. Therefore, it has high insecticidal activity against important pests such as aphids, leafhoppers, planthoppers, lepidopteran larvae, flies, and coleoptera, and has no phytotoxicity to crops.

[0003] Fipronil sulfone is a metabolite of fipronil in animals and is listed as a compound "moderately toxic to humans" by the World Health Organization. A study on fipronil metabolism shows that its main metabolite, fipronil sulfone, has a much longer retention time in the human body than the fipronil parent, and fipronil sulfone is more destructive to the thyroid gland. In the rat brain nerve membrane blocking experiment, the toxicity of fipronil sulfone is 9 times higher than that of the fipronil parent. After the "fipronil in eggs incident" in Europe in 2017, China also urgently formulated the detection method GB 23200.115–2018 for fipronil and its metabolites in eggs. Based on toxicity research and regulatory requirements, the demand for fipronil sulfone has increased significantly.

[0004]

[0005] Ri-Yuan Tang et al. published a method for synthesizing fipronil sulfone from fipronil ether (Journal of Fluorine Chemistry 127(2006)948–953). First, trifluoroperacetic acid is prepared by reacting hydrogen peroxide with trifluoroacetic acid, and then fipronil ether is oxidized to obtain fipronil sulfone. Fipronil sulfone can also be obtained by oxidizing fipronil ether with trichloroisocyanuric acid, and then purified by silica gel preparative thin-layer chromatography. The operation is complex, difficult to scale up production, and the yield is only 25%.

[0006]

[0007] Dominik Hainzl et al. disclosed a method for synthesizing fipronil sulfone (Chemical Research in Toxicology (1998), 11(12), 1529-1535), which oxidizes fipronil ether with m-chloroperbenzoic acid or potassium permanganate to obtain fipronil sulfone. Both m-chloroperbenzoic acid and potassium permanganate are dangerous substances prone to explosion and difficult to be industrially produced and applied. Summary of the Invention

[0008] To solve the existing technical problems, the present invention provides a method for synthesizing fipronil sulfone. This method uses hydrogen peroxide as an oxidant under the action of a catalyst to oxidize fipronil to synthesize fipronil sulfone, and the by-product is water, which is a safe, environmentally friendly and green synthesis process.

[0009] The technical solution of the present invention is as follows:

[0010] A method for synthesizing fipronil sulfone, using hydrogen peroxide as an oxidant, under the action of a catalyst, oxidizes fipronil to fipronil sulfone, and the reaction is as follows:

[0011]

[0012] Preferably, after fipronil is dissolved in a solvent, it reacts with hydrogen peroxide under the action of a catalyst; the solvent is one or several of water, methanol, ethanol, n-propanol, isopropanol, butanol, acetone, butanone, acetonitrile, propionitrile, butyronitrile.

[0013] Further preferably, the molar ratio of fipronil to hydrogen peroxide is 1:2 - 1:15, the mass-volume ratio of fipronil to the solvent is 1:3 - 1:20 (g / mL), and the addition amount of the catalyst is 0.5% - 2% of the mass of fipronil.

[0014] Preferably, the catalyst is a main catalyst or a combination of a main catalyst and a co-catalyst, the mass-volume ratio of the main catalyst to the co-catalyst is 1:1 - 1:12 (g / mL), the main catalyst is tungstic acid or tungstate, and the co-catalyst is one of sulfuric acid, phosphoric acid, hydrochloric acid, formic acid, acetic acid, propionic acid, butyric acid. Further preferably, the main catalyst is one of tungstic acid, lithium tungstate, sodium tungstate, potassium tungstate, rubidium tungstate, cesium tungstate, magnesium tungstate, calcium tungstate, strontium tungstate, barium tungstate, ammonium tungstate, cobalt tungstate, cadmium tungstate, ferrous tungstate, zinc tungstate.

[0015] Preferably, the reaction is a continuous reaction or a batch reaction; when it is a batch reaction, the reaction temperature is 40 - 90 °C and the reaction time is 1 - 10 h; when it is a continuous reaction, the reaction temperature is 70 - 150 °C and the reaction time is 10 - 150 s.

[0016] Preferably, the batch reaction is applicable to batch reactors, such as the most common batch reaction devices in fine chemical production, like flasks and reaction kettles, while the continuous reaction is applicable to continuous microreactors, such as tubular reactors like microchannel reactors.

[0017] Preferably, after the reaction is completed, the temperature is lowered, crystallization is carried out, and filtration is performed to obtain the purified product; more preferably, the temperature for lowering the temperature and crystallization is 5 - 35 °C.

[0018] The beneficial effects of the present invention are as follows: Under the action of a catalyst, hydrogen peroxide is used as an oxidant to oxidize fipronil to synthesize fipronil sulfone, and the by-product is water. The whole reaction process is green and environmentally friendly, avoiding unstable strong oxidants such as peroxyacids, potassium permanganate, and persulfates. The addition of the catalyst enables the reaction to proceed safely, smoothly, and efficiently. The method is simple and safe. At the same time, through the method of the present invention, products with high yield and high purity can be obtained. BRIEF DESCRIPTION OF THE DRAWINGS

[0019] In order to more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the following will briefly introduce the drawings required for use in the description of the embodiments or the prior art. Obviously, for those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings.

[0020] Figure 1 It is the HPLC chromatogram of the product prepared in Example 6;

[0021] Figure 2 It is the positive ion scanning LC / MS chromatogram of the product prepared in Example 6;

[0022] Figure 3 It is the negative ion scanning LC / MS chromatogram of the product prepared in Example 6;

[0023] Figure 4 It is the 1H NMR spectrum of the product prepared in Example 6. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0024] In order to enable those skilled in the art to better understand the technical solutions in the present invention, the following will clearly and completely describe the technical solutions in the embodiments of the present invention with reference to the accompanying drawings in the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, rather than all the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative efforts shall fall within the protection scope of the present invention.

[0025] By mass fraction, the concentration of concentrated sulfuric acid is 98% in the following, the concentration of concentrated hydrochloric acid is 37%, and the concentration of concentrated phosphoric acid is 85%.

[0026] Example 1

[0027] A method for synthesizing fipronil sulfone:

[0028]

[0029] Add fipronil (43.7 g, 0.1 mol, 1.0 eq.), sodium tungstate (0.5 g, catalytic amount), concentrated sulfuric acid (1 mL, catalytic amount) and ethanol (250 mL) into a four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, constant pressure dropping funnel and oil bath heating device. Heat and stir to reflux, and add hydrogen peroxide (30 wt%, 30 mL, 0.3 mol, 3.0 eq.) dropwise to the four-necked flask. After refluxing for 2 h, the reaction is completed. Then add deionized water (500 mL), stir and keep warm at 80 °C for 1 h, cool down to 20 - 25 °C, stir and keep warm for 1 h, and filter to obtain a white solid product with a weight of 42.1 g, a purity of 98.6%, and a yield of 92.9%.

[0030] Example 2

[0031] A method for synthesizing fipronil sulfone:

[0032]

[0033] Add fipronil (43.7 g, 0.1 mol, 1.0 eq.), sodium tungstate (0.5 g, catalytic amount) and ethanol (250 mL) into a four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, constant pressure dropping funnel and oil bath heating device. Heat and stir to reflux, and add hydrogen peroxide (30 wt%, 60 mL, 0.6 mol, 6.0 eq.) dropwise to the four-necked flask. After refluxing for 5 h, the reaction is completed. Then add deionized water (450 mL), stir and keep warm at 80 °C for 1 h, cool down to 20 - 25 °C, stir and keep warm for 1 h, and filter to obtain a white solid product with a weight of 39.4 g, a purity of 98.1%, and a yield of 87.0%.

[0034] Example 3

[0035] A method for synthesizing fipronil sulfone:

[0036]

[0037] In a four-necked flask equipped with a mechanical stirrer, a thermometer, a reflux condenser, a constant-pressure dropping funnel, and an oil bath heating device, add fipronil (43.7 g, 0.1 mol, 1.0 eq.), tungstic acid (0.5 g, catalytic amount), concentrated phosphoric acid (2 mL, catalytic amount), and isopropanol (250 mL). Heat with stirring to reflux, and dropwise add hydrogen peroxide (30 wt%, 40 mL, 0.4 mol, 4.0 eq.). After refluxing for 1.5 h, the reaction is completed. Then dropwise add deionized water (450 mL), stir and keep warm at 80 °C for 1 h, cool down to 25 - 30 °C, stir and keep warm for 1 h, and filter to obtain a white solid product with a weight of 40.5 g, a purity of 99.1%, and a yield of 89.4%.

[0038] Example 4

[0039] A method for synthesizing fipronil sulfone:

[0040]

[0041] In a four-necked flask equipped with a mechanical stirrer, a thermometer, a reflux condenser, a constant-pressure dropping funnel, and an oil bath heating device, add fipronil (43.7 g, 0.1 mol, 1.0 eq.), potassium tungstate (0.5 g, catalytic amount), acetic acid (5 mL), and acetone (200 mL). Heat with stirring to reflux, and dropwise add hydrogen peroxide (30 wt%, 40 mL, 0.4 mol, 4.0 eq.) to the four-necked flask. After refluxing for 2 h, the reaction is completed. Then dropwise add deionized water (450 mL), stir and keep warm at 80 °C for 1 h, cool down to 15 - 20 °C, stir and keep warm for 1 h, and filter to obtain a white solid product with a weight of 39.8 g, a purity of 98.3%, and a yield of 87.6%.

[0042] Example 5

[0043] A method for synthesizing fipronil sulfone:

[0044]

[0045] In a four-necked flask equipped with a mechanical stirrer, a thermometer, a reflux condenser, a constant-pressure dropping funnel, and an oil bath heating device, add fipronil (43.7 g, 0.1 mol, 1.0 eq.), barium tungstate (0.5 g, catalytic amount), concentrated hydrochloric acid (2 mL), and acetonitrile (200 mL). Heat with stirring to reflux, and dropwise add hydrogen peroxide (30 wt%, 50 mL, 0.5 mol, 5.0 eq.) to the four-necked flask. After refluxing for 2.5 h, the reaction is completed. Then dropwise add deionized water (400 mL), stir and keep warm at 80 °C for 1 h, cool down to 10 - 15 °C, stir and keep warm for 1 h, and filter to obtain a white solid product with a weight of 41.6 g, a purity of 98.2%, and a yield of 91.8%.

[0046] Example 6

[0047] A method for synthesizing fipronil sulfone:

[0048]

[0049] Add fipronil (43.7 g, 0.1 mol, 1.0 eq.) and ethanol (500 mL) to mixing tank 1, heat to 70 °C for mixing and dissolution, and keep at 70 °C for standby; add sodium tungstate (0.5 g, catalytic amount), concentrated sulfuric acid (1 mL, catalytic amount) and hydrogen peroxide (30 wt%, 100 mL, 1.0 mol, 10.0 eq.) to another mixing tank 2 for mixing and dissolution, and cool to 5 °C for standby. Pump the liquid materials in mixing tanks 1 and 2 into a microchannel reactor (Corning microchannel reactor). The specific conditions are as follows: the flow rate of the fipronil ethanol solution is 50 mL / min, the feeding temperature is 70 °C, the flow rate of sodium tungstate sulfuric acid hydrogen peroxide is 10 mL / min, the feeding temperature is 5 °C, the temperature of the reaction system is 130 °C, adjust the back pressure valve to make the pressure of the reaction system 1.0 MPa, the reaction time is 40 s. The reaction module of the microchannel reactor used is made of glass, with an inner heart-shaped reaction material mixing and heat exchange channel. After the reaction material flows through the microchannel reactor, it is cooled to 80 °C and the pressure is reduced to atmospheric pressure, and the reaction liquid is received with a receiving tank. After the reaction is completed, transfer the reaction liquid in the receiving tank to a four-necked flask equipped with a mechanical stirrer, a thermometer, a reflux condenser, a constant pressure dropping funnel and an oil bath heating device. Then add deionized water (1000 mL), stir and keep warm at 80 °C for 1 h, cool to 20 - 25 °C, stir and keep warm for 1 h, filter to obtain a white solid product, with a weight of 37.4 g, a purity of 99.6%, and a yield of 82.6%. LC / MS, +ESI: [M+H] + 452.94 / 454.93; [M+H 2 O] + 469.96 / 471.96; LC / MS, -ESI: [M-H] - 450.92 / 452.92, 1 H NMR (400 MHz, DMSO-d 6 ) δ 8.33 (s, 2H), 8.04 (s, 2H).

[0050] Example 7

[0051] A method for synthesizing fipronil sulfone:

[0052]

[0053] Add fipronil (43.7 g, 0.1 mol, 1.0 eq.) and ethanol (500 mL) to mixing tank 1, heat to 70 °C and mix until dissolved, and keep at 70 °C for standby; add sodium tungstate (0.5 g, catalytic amount), concentrated sulfuric acid (1 mL, catalytic amount) and hydrogen peroxide (30 wt%, 100 mL, 1.0 mol, 10.0 eq.) to another mixing tank 2, mix and dissolve, and cool to 5 °C for standby; use two peristaltic pumps to transport the feed liquid to the tubular reactor. The specific conditions are as follows: the flow rate of the fipronil ethanol solution is 50 mL / min, the feed temperature is 70 °C, the flow rate of the sodium tungstate sulfuric acid hydrogen peroxide is 10 mL / min, the feed temperature is 5 °C, the temperature of the reaction system is 130 °C, adjust the back pressure valve to make the pressure of the reaction system 1.0 MPa, the reaction time is 77 s, the cross-sectional diameter of the reaction channel of the tubular reactor is 1.4 mm, the flow path length is 50 m. After the material flows through the tubular reactor, cool to 80 °C and reduce the pressure to atmospheric pressure, and receive the reaction liquid with a receiving tank. After the reaction is completed, transfer the reaction liquid to a four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, constant pressure dropping funnel and oil bath heating device, then add deionized water (1000 mL), stir and keep warm at 80 °C for 1 h, cool to 20 - 25 °C, stir and keep warm for 1 h, filter to obtain a white solid product with a weight of 35.7 g, a purity of 99.4%, and a yield of 78.8%.

[0054] Comparative Example 1

[0055] A method for synthesizing fipronil sulfone:

[0056]

[0057] Add fipronil ether (42.0 g, 0.1 mol, 1.0 eq.), trifluoroacetic acid (100 mL) and dichloromethane (500 mL) to a four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, constant pressure dropping funnel and oil bath heating device, control the temperature at 10 - 12 °C, dropwise add hydrogen peroxide (30 wt%, 20 mL, 0.2 mol, 2.0 eq.), in-situ generate trifluoroperacetic acid to oxidize fipronil ether, continue to stir for 3 h after dropping, add dichloromethane (1000 mL), then add sodium bisulfite to quench the residual oxidant, stir the reaction mixture at 12 °C for 1 h, add deionized water (2000 mL) to the reaction system, extract the product with dichloromethane (1000 mL * 3), combine the organic phases, add anhydrous magnesium sulfate for drying, remove the solvent under reduced pressure to obtain a crude product, and purify by column chromatography, elute with a petroleum ether / ethyl acetate (volume ratio 7:3) system, and remove the eluent by distillation under reduced pressure to obtain a white solid product with a weight of 11.7 g, a purity of 95.1%, and a yield of 25.8%.

[0058] Compared with Comparative Example 1, the method of the present invention has a greatly increased yield and does not require complex treatment steps such as extraction and column chromatography.

[0059] Comparative Example 2

[0060] A method for synthesizing fipronil sulfone:

[0061]

[0062] Add fipronil ether (42.0 g, 0.1 mol, 1.0 eq.), magnesium sulfate (34 g), acetone (600 mL) and water (100 mL) into a four-necked flask equipped with a mechanical stirrer, thermometer, reflux condenser, constant pressure dropping funnel and oil bath heating device. While stirring vigorously, add a solution of potassium permanganate (47.4 g, 0.3 mol, 3.0 eq.) in acetone-water (1:1, 200 mL). After the addition is complete, continue stirring at room temperature overnight. Add hydrochloric acid to quench the excess oxidant, then extract with ether, dry with sodium sulfate, and remove the organic solvent under reduced pressure to obtain a crude product. Recrystallize with hexane / chloroform (volume ratio 2:1) to obtain a white solid product with a weight of 36.7 g, a purity of 97.4%, and a yield of 81.0%.

[0063] Comparative Example 2 uses very dangerous oxidants such as potassium permanganate, as well as inorganic salts such as magnesium sulfate and sodium sulfate, which are prone to explosion, and a large amount of three wastes are generated. The post-treatment requires processes such as extraction and recrystallization, which is relatively cumbersome. In contrast, the present invention uses hydrogen peroxide as an oxidant to oxidize fipronil to synthesize fipronil sulfone under the action of a catalyst, and the by-product is water. The whole reaction process is green and environmentally friendly, avoiding unstable strong oxidants such as peroxyacids, potassium permanganate, and persulfates. The addition of the catalyst enables the reaction to proceed safely, smoothly and efficiently. The method is simple and safe. At the same time, high-yield and high-purity products can be obtained by the method of the present invention.

Claims

1. A method for synthesizing fipronil sulfone, characterized in that, using hydrogen peroxide as an oxidant, under the action of a catalyst, fipronil is oxidized to fipronil sulfone, and the reaction is as follows: After the fipronil is dissolved in a solvent, it reacts with hydrogen peroxide under the action of a catalyst; the solvent is one or several of water, methanol, ethanol, n-propanol, isopropanol, butanol, acetone, butanone, acetonitrile, propionitrile, butyronitrile; The catalyst is a main catalyst or a combination of a main catalyst and a co-catalyst. The main catalyst is tungstic acid or tungstate, and the co-catalyst is one of sulfuric acid, phosphoric acid, hydrochloric acid, formic acid, acetic acid, propionic acid, butyric acid.

2. The method for synthesizing fipronil sulfone according to claim 1, characterized in that, The molar ratio of fipronil to hydrogen peroxide is 1:2 - 1:15, the mass-volume ratio of fipronil to the solvent is 1:3 - 1:20, and the addition amount of the catalyst is 0.5% - 2% of the mass of fipronil.

3. The method for synthesizing fipronil sulfone according to claim 1, characterized in that, The main catalyst is one of tungstic acid, lithium tungstate, sodium tungstate, potassium tungstate, rubidium tungstate, cesium tungstate, magnesium tungstate, calcium tungstate, strontium tungstate, barium tungstate, ammonium tungstate, cobalt tungstate, cadmium tungstate, ferrous tungstate, zinc tungstate.

4. The method for synthesizing fipronil sulfone according to claim 1, characterized in that, The mass-volume ratio of the main catalyst to the co-catalyst is 1:1 - 1:

12.

5. The method for synthesizing fipronil sulfone according to claim 1, characterized in that, The reaction is a continuous reaction or a batch reaction.

6. The method for synthesizing fipronil sulfone according to claim 5, characterized in that, In the batch reaction, the reaction temperature is 40 - 90 °C and the reaction time is 1 - 10 h; in the continuous reaction, the reaction temperature is 70 - 150 °C and the reaction time is 10 - 150 s.

7. The method for synthesizing fipronil sulfone according to claim 1, characterized in that, After the reaction is completed, the temperature is lowered, crystallization is carried out, and filtration is carried out to obtain a purified product.

8. The method for synthesizing fipronil sulfone according to claim 7, characterized in that, The temperature of the crystallization is 5 - 35 °C.

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