A method for synthesizing fipronil

Abstract

The present invention relates to a method for efficiently synthesizing fipronil, belonging to the field of pesticide synthesis. The present invention utilizes an anhydrous solid base to catalyze hydrogen peroxide in a milling system to oxidize sulfide, thereby improving stirring and mixing efficiency, shortening reaction time, and thereby reducing the content of peroxide impurities (sulfones). High-content fipronil can be obtained without requiring multiple crystallizations. The method has a short reaction time, low raw material costs, is environmentally friendly, and has high product purity and yield, making it easy to industrialize.

Description

Technical Field

[0001] The present invention relates to the field of pesticide synthesis, and in particular to a method for efficiently synthesizing fipronil. Background Art

[0002] Fipronil, commonly known as fipronil in English, and trade names Regent and Fipronil, is a phenylpyrazole broad-spectrum veterinary insecticide with high insecticidal activity and no cross-resistance with existing insecticides. In recent years, global sales have remained between US$400 million and US$500 million.

[0003] The common synthetic routes of fipronil are as follows:

[0004] (1) 5-amino-1-(2,6-dichloro-4-trifluoromethyl)-3-cyanopyrazole reacts with trifluoromethylsulfenyl chloride to obtain the product. This process is simple to operate and has fewer steps, but the preparation of trifluorosulfenyl chloride is difficult, the production cost is high, it is easy to absorb moisture at room temperature, and the reaction conditions are harsh, so this method is not suitable for large-scale industrial production.

[0005]

[0006] (2). 5-amino-1-(2,6-dichloro-4-trifluoromethyl)-3-cyanopyrazole reacts with sulfur chloride to generate the corresponding disulfide. The disulfide reacts with trifluorobromomethane in the presence of a weak base and a reducing agent to obtain 5-amino-1-(2,6-dichloro-4-trifluoromethyl)-3-cyano-4-trifluoromethylthiopyrazole, which is then oxidized to obtain fipronil. Although this route has two more steps, its safety is improved and it has become the preferred route for the industrial production of fipronil. However, in addition to fipronil (sulfoxide), the oxidation product of the sulfide in this route also produces peroxidized impurities (sulfone). How to control the selective oxidation of the sulfide is the key to improving the yield of fipronil.

[0007]

[0008] European Patent EP1222173 describes a method for synthesizing fipronil by oxidation using DOF in a CF3COOH / H2O2 system, achieving an 89% yield. This method uses a large amount of trifluoroacetic acid (14 eq) as a solvent. In industrial production, this solvent can cause severe corrosion to both glass-lined and stainless steel equipment. While the patent mentions the addition of boric acid to suppress corrosion, this method still does not fundamentally address the problem. Furthermore, trifluoroacetic acid is expensive, has a low boiling point, and is difficult to recycle, significantly limiting its use.

[0009]

[0010] U.S. Patent WO2007 / 122440 introduces the use of a trichloroacetic acid / H2O2 system, and Patent WO2012 / 007398 introduces the use of a dichloroacetic acid / H2O2 system. These systems solve the corrosion problem to a certain extent and improve the synthesis yield to a certain extent. However, the reaction time is too long and the production efficiency is low, making industrial production impossible.

[0011] Chinese patent CN103360316A introduces a composite catalyst / H2O2 system using trifluoroacetic acid, which requires the use of an excess of solvent and has complex post-processing operations involving multiple crystallizations and mother liquor recycling. The reaction yield, efficiency, and product purity need to be further improved.

[0012] Therefore, it is necessary to find a synthesis method for fipronil with simple production process, low production cost, environmental friendliness, higher product purity and yield, and easy industrial production. Summary of the Invention

[0013] The present invention aims to provide a method for efficiently synthesizing fipronil, which has the advantages of short reaction time, low raw material cost, environmental friendliness, high product purity and yield, and is easy for industrial production.

[0014] To achieve the above-mentioned purpose, the present invention provides the following technical solutions:

[0015] 5-amino-1-(2,6-dichloro-4-trifluoromethyl)-3-cyano-4-trifluoromethylthiopyrazole is mixed with an organic solvent, and an anhydrous solid base catalyst is added to form a suspension;

[0016] The suspension is continuously stirred and ground, and at the same time, 50% hydrogen peroxide is added dropwise to react. After the sulfone content (peroxide impurity) is detected to be ≥1%, the reaction is stopped to obtain the fipronil.

[0017] In some embodiments, the organic solvent is selected from one or both of n-pentanol and isopentanol.

[0018] In some embodiments, the catalyst is selected from any one or more of sodium carbonate, potassium carbonate, cesium carbonate, and sodium bicarbonate.

[0019] In some embodiments, the mass ratio of the 5-amino-1-(2,6-dichloro-4-trifluoromethyl)-3-cyano-4-trifluoromethylthiopyrazole to the organic solvent is 1:1 to 1:4.

[0020] In some embodiments, the molar ratio of the 5-amino-1-(2,6-dichloro-4-trifluoromethyl)-3-cyano-4-trifluoromethylthiopyrazole to the catalyst is 100:1 to 20:1.

[0021] In some embodiments, the molar ratio of the 5-amino-1-(2,6-dichloro-4-trifluoromethyl)-3-cyano-4-trifluoromethylthiopyrazole to the hydrogen peroxide is 1:1 to 1:2.

[0022] In some embodiments, the reaction temperature is 10-30° C., and the reaction time is 4-10 h.

[0023] In some embodiments, the continuous cycle stirring and grinding includes a stirring step, a grinding step, and a step of circulating the suspension between the reactor and a sand mill connected to the reactor by a pneumatic pump.

[0024] In some embodiments, the sand mill is equipped with high-purity zirconium oxide beads to grind the suspension to a fineness of 3 to 5 μm.

[0025] In some embodiments, the following steps are further included:

[0026] After the reaction stops, a sodium sulfite aqueous solution is added to the reaction system to quench excess hydrogen peroxide until the starch KI test paper does not turn blue, and 5-15% hydrochloric acid is added to the quenched reaction solution to adjust the pH to 6-8. The reaction solution is heated to 50-55° C., the layers are separated, the aqueous layer is discarded, the organic layer is concentrated, the temperature is lowered to 0-5° C., crystallized, and filtered. The solid obtained after filtration is recrystallized with dichloroethane and dried to obtain the fipronil.

[0027] Compared with the prior art, the present invention has the following advantages:

[0028] 1. The creative point of the present invention is that the catalyst is replaced by a weakly alkaline solid base instead of an expensive strongly acidic reagent, thereby avoiding corrosion of equipment and reducing production costs, which is conducive to industrial production.

[0029] 2. Another innovative feature of the present invention is that an external sand mill is used to achieve continuous cyclic stirring and grinding of the suspension, thereby improving the stirring and mixing efficiency, shortening the reaction time by two-thirds, reducing the content of peroxide impurities (sulfones), simplifying the post-processing operation, and obtaining a high content of fipronil without multiple recrystallizations. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 This is the HPLC spectrum of fipronil in Example 1 of the present invention;

[0031] Figure 2 This is the HPLC spectrum of fipronil in Example 2 of the present invention;

[0032] Figure 3 This is the HPLC spectrum of fipronil in Comparative Example 2 of the present invention;

[0033] Figure 4This is the HPLC spectrum of fipronil in Comparative Example 3 of the present invention; DETAILED DESCRIPTION

[0034] In order to better understand the essence of the present invention, the contents of the present invention are further illustrated in conjunction with the embodiments below, but they should not be regarded as limiting the present invention. The following description is only used to explain the present invention. Any modifications, replacements or improvements made without departing from the spirit and principles of the present invention are within the scope of protection claimed by the present invention.

[0035] Example 1

[0036] Into a 500 L stainless steel reactor, 100 kg (236.3 mol) of 5-amino-1-(2,6-dichloro-4-trifluoromethyl)-3-cyano-4-trifluoromethylthiopyrazole, 5.0 kg (47.3 mol) of sodium carbonate, and 300 kg of isoamyl alcohol were added, stirred and mixed to obtain a suspension, and the system was cooled to 10-20°C.

[0037] Start stirring and external grinding equipment, circulate the suspension between the reactor and the sand mill through a pneumatic pump, pass chilled water through the sand mill jacket and the reactor jacket, maintain the temperature of the reaction system between 10 and 20 ° C, slowly add 17.7 kg of 50% hydrogen peroxide (259.9 mol) dropwise into the reactor for 5 hours. After the addition is completed, keep warm for 2 hours. Sampling is performed to detect the sulfone content (peroxide impurity) ≥1%, and the external grinding equipment is stopped.

[0038] Add 10% sodium sulfite aqueous solution to the reactor to quench excess hydrogen peroxide until the starch KI test paper does not turn blue. Add 5% hydrochloric acid to the quenched reaction solution to adjust the pH to 6-8. Heat to 50-55°C, separate the layers, discard the aqueous layer, concentrate the organic layer, cool it to 0-5°C, crystallize and filter it. Add 5 times the weight ratio of dichloroethane to the solid obtained after filtration, heat it to 75-80°C, then slowly cool it to 0-5°C and recrystallize it twice. Dry it to obtain the fipronil, weighing 97.2 kg. Figure 1 The HPLC content shown was 98.08% and the yield was 92.3%.

[0039] Example 2

[0040] Into a 500 L stainless steel reactor, 100 kg (236.3 mol) of 5-amino-1-(2,6-dichloro-4-trifluoromethyl)-3-cyano-4-trifluoromethylthiopyrazole, 5.0 kg (47.3 mol) of sodium carbonate, and 300 kg of n-pentanol were added, stirred and mixed to obtain a suspension, and the system was cooled to 10-20°C.

[0041] Start stirring and external grinding equipment, circulate the suspension between the reactor and the sand mill through a pneumatic pump, pass chilled water through the sand mill jacket and the reactor jacket, maintain the temperature of the reaction system between 10 and 20 ° C, slowly add 17.7 kg of 50% hydrogen peroxide (259.9 mol) dropwise into the reactor for 5 hours. After the addition is completed, keep warm for 2 hours. Sampling is performed to detect the sulfone content (peroxide impurity) ≥1%, and the external grinding equipment is stopped.

[0042] Add 10% sodium sulfite aqueous solution to the reactor to quench excess hydrogen peroxide until the starch KI test paper does not turn blue. Add 5% hydrochloric acid to the quenched reaction solution to adjust the pH to 6-8. Heat to 50-55°C, separate the layers, discard the aqueous layer, concentrate the organic layer, cool it to 0-5°C, crystallize and filter it. Add 5 times the weight ratio of dichloroethane to the solid obtained after filtration, heat it to 75-80°C, then slowly cool it to 0-5°C and recrystallize it twice. Dry it to obtain the fipronil, weighing 97.4 kg. Figure 2 The HPLC content shown was 97.84% and the yield was 92.3%.

[0043] Example 3

[0044] Into a 500 L stainless steel reactor, 100 kg (236.3 mol) of 5-amino-1-(2,6-dichloro-4-trifluoromethyl)-3-cyano-4-trifluoromethylthiopyrazole, 5.0 kg (59.1 mol) of sodium bicarbonate, and 300 kg of n-pentanol were added, stirred and mixed to obtain a suspension, and the system was cooled to 10-20°C.

[0045] Start stirring and external grinding equipment, circulate the suspension between the reactor and the sand mill through a pneumatic pump, pass chilled water through the sand mill jacket and the reactor jacket, maintain the temperature of the reaction system between 10 and 20 ° C, slowly add 17.7 kg of 50% hydrogen peroxide (259.9 mol) dropwise into the reactor for 5 hours. After the addition is completed, keep warm for 2 hours. Sampling is performed to detect the sulfone content (peroxide impurity) ≥1%, and the external grinding equipment is stopped.

[0046] A 10% aqueous sodium sulfite solution was added to the reactor to quench excess hydrogen peroxide until the starch KI test paper did not turn blue. 5% hydrochloric acid was added to the quenched reaction solution to adjust the pH to 6-8. The reaction solution was heated to 50-55°C, separated, and the aqueous layer was discarded. The organic layer was concentrated and then cooled to 0-5°C for crystallization and filtration. The solid obtained after filtration was added with 5 times the weight ratio of dichloroethane, heated to 75-80°C, and then slowly cooled to 0-5°C for recrystallization twice. The solid was dried to obtain the fipronil, weighing 97.0 kg, with a content of 97.68% and a yield of 91.7%.

[0047] Comparative Example 1:

[0048] Into a 500L Hastelloy reaction kettle, 100kg (236.3mol) of 5-amino-1-(2,6-dichloro-4-trifluoromethyl)-3-cyano-4-trifluoromethylthiopyrazole, 6.0kg (52mol) of trifluoroacetic acid, 12.0kg (122mol) of 98% concentrated sulfuric acid, and 450kg of dichloroethane were added, stirred and mixed to obtain a mixed solution, and the system was cooled to 10-20°C.

[0049] Start stirring and external grinding equipment, circulate the suspension between the reactor and the sand mill through a pneumatic pump, pass chilled water through the sand mill jacket and the reactor jacket, maintain the temperature of the reaction system between 10 and 20 ° C, slowly add 17.7 kg of 50% hydrogen peroxide (259.9 mol) dropwise into the reactor for 5 hours. After the addition is completed, keep warm for 2 hours. Sampling is performed to detect the sulfone content (peroxide impurity) ≥1%, and the external grinding equipment is stopped.

[0050] A 10% aqueous sodium sulfite solution was added to the reactor to quench excess hydrogen peroxide until the starch KI test paper did not turn blue. A 12% by mass sodium hydroxide solution was added to the quenched reaction solution to adjust the pH to 6-8. The reaction solution was heated to 50-55°C, separated, the aqueous layer was discarded, and the organic layer was concentrated and then cooled to 0-5°C for crystallization and filtration. The solid obtained after filtration was added with 5 times the weight ratio of dichloroethane, heated to 75-80°C, and then slowly cooled to 0-5°C for recrystallization twice. The solid was dried to obtain the fipronil, weighing 97.7 kg, with a content of 98.0% and a yield of 92.3%.

[0051] Compared with Example 1, Comparative Example 1 uses a strong acidic reagent as a catalyst, and the purity and yield of fipronil obtained are comparable to those in Example 1. However, this method uses expensive and environmentally polluting catalysts such as trifluoroacetic acid and concentrated sulfuric acid.

[0052] Comparative Example 2:

[0053] Into a 500 L stainless steel reactor, 100 kg (236.3 mol) of 5-amino-1-(2,6-dichloro-4-trifluoromethyl)-3-cyano-4-trifluoromethylthiopyrazole, 50 kg (47.3 mol) of a 10% aqueous sodium carbonate solution, and 300 kg of isoamyl alcohol were added, stirred and mixed to obtain a suspension, and the system was cooled to 10-20°C.

[0054] Start stirring and external grinding equipment, circulate the suspension between the reactor and the sand mill through a pneumatic pump, pass chilled water through the sand mill jacket and the reactor jacket, maintain the temperature of the reaction system between 10 and 20 ° C, slowly add 17.7 kg of 50% hydrogen peroxide (259.9 mol) to the reactor, and add it dropwise for 5 hours. After the addition is completed, keep the reaction warm for 3.5 hours until the sulfone content (peroxide impurity) is ≥1% when sampling and testing, and stop the external grinding equipment.

[0055] Add 10% sodium sulfite aqueous solution to the reactor to quench excess hydrogen peroxide until the starch KI test paper does not turn blue. Add 5% hydrochloric acid to the quenched reaction solution to adjust the pH to 6-8. Heat to 50-55°C, separate the layers, discard the aqueous layer, concentrate the organic layer, cool it to 0-5°C, crystallize and filter it. Add 5 times the weight ratio of dichloroethane to the solid obtained after filtration, heat it to 75-80°C, then slowly cool it to 0-5°C and recrystallize it three times. Dry it to obtain the fipronil, weighing 88.5 kg. Figure 3 The HPLC content shown was 97.09% and the yield was 83.2%.

[0056] Compared with Example 1, Comparative Example 2 uses an aqueous solution of a weakly alkaline catalyst as a catalyst. The purity of the obtained fipronil is slightly lower than that of Example 1, but the yield is significantly lower than that of Example 1.

[0057] Comparative Example 3:

[0058] Into a 500 L stainless steel reactor, 100 kg (236.3 mol) of 5-amino-1-(2,6-dichloro-4-trifluoromethyl)-3-cyano-4-trifluoromethylthiopyrazole, 5.0 kg (47.3 mol) of sodium carbonate, and 300 kg of isoamyl alcohol were added, stirred and mixed to obtain a suspension, and the system was cooled to 10-20°C.

[0059] Maintaining the reaction system temperature at 10-20°C, slowly add 17.7 kg of 50% hydrogen peroxide (259.9 mol) to the reactor under stirring for 5 hours. Keep warm and stir the reaction for 5 hours until the sulfone content (peroxide impurity) is ≥1% when sampling and testing. Stop stirring.

[0060] Add 10% sodium sulfite aqueous solution to the reactor to quench excess hydrogen peroxide until the starch KI test paper does not turn blue. Add 5% hydrochloric acid to the quenched reaction solution to adjust the pH to 6-8. Heat to 50-55°C, separate the layers, discard the aqueous layer, concentrate the organic layer, cool it to 0-5°C, crystallize and filter it. Add 5 times the weight ratio of dichloroethane to the solid obtained after filtration, heat it to 75-80°C, then slowly cool it to 0-5°C and recrystallize it three times. Dry it to obtain the fipronil, weighing 86.3 kg. Figure 4 The HPLC content shown was 95.93% and the yield was 80.2%.

[0061] Compared with Example 1, Comparative Example 3 did not use continuous circulation stirring and grinding to treat the suspension, resulting in a prolonged reaction time. The purity and yield of the obtained fipronil were significantly lower than those in Example 1.

[0062] In summary:

[0063] 1. The creative point of the embodiment of the present invention is that the catalyst is replaced by a weakly alkaline solid base instead of an expensive strongly acidic reagent, thereby avoiding corrosion of equipment and reducing production costs, which is conducive to industrial production.

[0064] 2. Another innovative feature of the embodiment of the present invention is that an external sand mill is used to achieve continuous cyclic stirring and grinding of the suspension, thereby improving the stirring and mixing efficiency, shortening the reaction time by two-thirds, reducing the content of peroxide impurities (sulfones), simplifying the post-processing operation, and obtaining a high content of fipronil without multiple crystallizations.

[0065] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the scope of protection of the present invention.

Claims

1. A method for synthesizing fipronil, characterized in that: The following steps are involved: Mixing 5-amino-1-(2,6-dichloro-4-trifluoromethyl)-3-cyano-4-trifluoromethylthiopyrazole with an organic solvent, adding an anhydrous solid base catalyst, wherein the anhydrous solid base catalyst is selected from sodium carbonate or sodium bicarbonate, to form a suspension; The suspension is continuously stirred and ground, and at the same time, 50% hydrogen peroxide is added dropwise to react. After the sulfone content is detected to be ≥1%, the reaction is stopped to obtain the fipronil.

2. The method according to claim 1, wherein The organic solvent is selected from one or both of n-amyl alcohol and isoamyl alcohol.

3. The method according to claim 1, wherein The mass ratio of the 5-amino-1-(2,6-dichloro-4-trifluoromethyl)-3-cyano-4-trifluoromethylthiopyrazole to the organic solvent is 1:1 to 1:

4.

4. The method according to claim 1, wherein The molar ratio of the 5-amino-1-(2,6-dichloro-4-trifluoromethyl)-3-cyano-4-trifluoromethylthiopyrazole to the catalyst is 100:1 to 20:

1.

5. The method according to claim 1, wherein The molar ratio of the 5-amino-1-(2,6-dichloro-4-trifluoromethyl)-3-cyano-4-trifluoromethylthiopyrazole to the hydrogen peroxide is 1:1 to 1:

2.

6. The method according to claim 1, wherein The reaction temperature is 10-30° C., and the reaction time is 4-10 hours.

7. The method according to claim 1, wherein The continuous cycle stirring and grinding includes a stirring step, a grinding step, and a step of circulating the suspension between the reactor and a sand mill connected to the reactor by a pneumatic pump.

8. The method according to claim 7, wherein The sand mill is equipped with high-purity zirconium oxide beads to grind the suspension to a fineness of 3 to 5 μm.

9. The method according to any one of claims 1 to 8, characterized in that The following steps are also included: After the reaction stops, a sodium sulfite aqueous solution is added to the reaction system to quench excess hydrogen peroxide until the starch KI test paper does not turn blue, and 5-15% hydrochloric acid is added to the quenched reaction solution to adjust the pH to 6-8. The reaction solution is heated to 50-55° C., the layers are separated, the aqueous layer is discarded, the organic layer is concentrated, the temperature is lowered to 0-5° C., crystallized, and filtered. The solid obtained after filtration is recrystallized with dichloroethane and dried to obtain the fipronil.

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