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CN117486800A - Synthesis method of fipronil intermediate - Google Patents

Synthesis method of fipronil intermediate Download PDF

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Publication number
CN117486800A
CN117486800A CN202311392013.3A CN202311392013A CN117486800A CN 117486800 A CN117486800 A CN 117486800A CN 202311392013 A CN202311392013 A CN 202311392013A CN 117486800 A CN117486800 A CN 117486800A
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fipronil
synthesizing
reaction
compound iii
substitution reaction
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Inventor
何昆仑
张彥祥
李兰杰
赵能选
朱加权
闫磊
方亚虹
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Zhejiang Avilive Chemical Co ltd
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Zhejiang Avilive Chemical Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/14—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D231/44—Oxygen and nitrogen or sulfur and nitrogen atoms
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The invention discloses a method for synthesizing a fipronil intermediate, which is characterized in that a compound 5-amino-1- (2, 6-dichloro-4- (trifluoromethyl) phenyl) -4- ((trichloromethyl) sulfur) -1H-pyrazole-3-carbonitrile III is taken as a raw material, an intermediate IV is synthesized through a fluorination reaction, the fluorination reagent is anhydrous HF or an Olah reagent (Pyridine.3-10 HF) with the HF content of 40-70%, and the addition amount of the Olah reagent or HF relative to the compound III is 3-50 equivalent in terms of effective HF, the reaction temperature is not higher than 30 ℃, the reaction temperature is reduced, the target intermediate IV is singly obtained, and the reaction selectivity is greatly improved.

Description

Synthesis method of fipronil intermediate
Technical Field
The invention relates to a method for synthesizing polysubstituted pyrazoles, in particular to a method for synthesizing fipronil intermediates.
Background
Fipronil (I) is a novel pyrazole broad-spectrum pesticide, developed successfully by the company ronafalack in 1989, and marketed in europe under the trade name Goliath et al in 1996. The current commercial production methods mainly comprise three methods, namely, taking 5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carbonitrile (a formula II, hereinafter referred to as a pyrazole compound) as a starting material, wherein a pyrazole compound reacts with trifluoromethylthio haloalkane, trifluoromethylthio is introduced, and metachloroperoxybenzoic acid is oxidized to obtain fipronil (Liu Yang, li Chunren, xu Guhua, tao Jingchao, etc.. A novel efficient pesticide fipronil preparation technology [ J ]. Applied chemical engineering, 2006,35 (7): 561-563, 568.); route 2 is that a pyrazole compound is firstly prepared into dithio compound, and is oxidized with trifluorobromomethane to obtain fipronil, and the technical scheme refers to patent document CN 102690232A; route 3 is a one-step synthesis of a pyrazole compound reacted with a sulfinyl substituent to give fipronil, technical scheme is referred to patent document CN 104557713 B,CN101578270A.
Regarding fluorine element introduction during synthesis, schemes 1 and 3 have been realized in substitution reactions, and the trifluorobromomethane used in scheme 2 is extremely damaging to the ozone layer, in the list of controlled use listed in China. Direct fluorination of pyrazole ring substituents has been less studied, and only patent document US06316636B1 discloses a reaction in which halogen on a pyrazole compound substituent is substituted with fluorine, but this method is poor in selectivity, and the resultant product is a mixture.
Regarding the substitution reaction of the pyrazole compound at the 4-position during synthesis, reagent CF used in scheme 1 3 SCl is gas at normal temperature and normal pressure, has high toxicity and is easy to cause safety accidents, and the route is eliminated. The key reagent used in the route 3, namely the trifluoromethyl sulfinyl chloride, is difficult to control in the sulfoxide stage, a large amount of waste acid is generated, the waste acid cannot be used, great difficulty is brought to terminal treatment, and the trifluoromethyl sulfinyl chloride has low boiling point and unstable property and is not suitable for transportation or long-term storage.
Disclosure of Invention
The invention aims to: the invention aims to provide a method for synthesizing a fipronil intermediate with high selectivity.
The technical scheme is as follows: the invention relates to a method for synthesizing a fipronil intermediate, which is characterized in that a compound III (5-amino-1- (2, 6-dichloro-4- (trifluoromethyl) phenyl) -4- ((trichloromethyl) sulfur) -1H-pyrazole-3-carbonitrile) is taken as a raw material, and an intermediate IV is synthesized through a fluorination reaction:
the fluoridation reagent is anhydrous HF or an Olah reagent (Pyridine.3-10 HF) with the content of 40-70%, the addition amount of the Olah reagent or HF relative to the compound III is 3-50 equivalents based on effective HF, and when the ratio of the HF is less than 3 times of equivalents, the solid cannot be fully infiltrated, and the reaction cannot be completed. The reaction temperature is not higher than 30 ℃, the reaction selectivity can be effectively improved, and the reaction does not need any solvent or pressurization. Other fluorinating agents such as triethylamine hydrofluoride (TEA.3HF), KF, KHF 2 、KBF 4 And the like, only partial fluorination occurs even at high temperatures, with other impurities being formed.
Preferably, the addition amount of the Olah reagent or the HF relative to the compound III is 15-30 equivalents based on the effective HF, when the ratio of the HF is lower than 15 times of equivalents, the solid in the reaction system is more, the stirring difficulty in the early stage of the reaction is higher, but the solid gradually decreases until the solid is dissolved and becomes more viscous liquid along with the progress of the reaction; when HF is more than 30 times equivalent, the reaction itself is not adversely affected, but an increase in volume and unnecessary energy consumption in the subsequent treatment are caused.
Preferably, the reaction temperature is-10 to 30 ℃, and when the temperature is lower than-10 ℃, the reaction hardly occurs or the reaction is extremely slow; above 30 ℃, the occurrence of obvious byproducts is detected, more preferably, the reaction temperature is 10-20 ℃, the reaction time is 2-20 h, and the selectivity and the reaction time are balanced.
Preferably, the post-treatment mode of the fluorination reaction is as follows: evaporating excessIs collected by condensation and can be used for the next reaction. The residue after evaporation of HF was slurried with a suitable aqueous diluted alkaline solution, filtered, washed continuously with clean water to ph=7-8 to give intermediate IV wet product which was used directly in the next step without drying. Or dissolving the residue with an organic solvent, washing with a dilute alkali solution until the pH value is=6-8, concentrating to remove the solvent, and obtaining a concentrate which is the intermediate IV and can be directly used in the next step. The selected dilute aqueous alkali solution is prepared from NaOH, KOH, na 2 CO 3 、K 2 CO 3 、NaHCO 3 And the like or any mixture thereof with water, and the concentration of the solution is 0.5-30 percent. The selected organic solvent is ethyl acetate, isopropyl acetate, methylene dichloride and the like or any combination thereof, but is not limited to the listed solvents, and the yield of the step is 94-98% (dry basis) and the purity is more than 98%.
In the reaction, the synthesis method of the compound III comprises the following steps: with 5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ]]-1H-pyrazole-3-carbonitrile II and perchloromethyl mercaptan as substrates, and carrying out substitution reaction under the conditions of alkaline additive and organic solvent to obtain a compound III: 5-amino-1- (2, 6-dichloro-4- (trifluoromethyl) phenyl) -4- ((trichloromethyl) thio) -1H-pyrazole-3-carbonitrile. Taking the raw material II as a reference, adding 1-2 equivalents of perchloromethyl mercaptan; the alkaline additive is added with 1 to 3 equivalents, and the substitution reaction temperature is 0 to 60 ℃. The possible mechanism of this reaction is: perchloromethyl mercaptan may react with the amino group at the 5-position of the pyrazole compound, followed by a Thia-Fries rearrangement, to finally give 4-trichloromethylthiopyrazole compound III. The perchloromethyl mercaptan used is commercially available or is prepared from carbon disulphide, chlorine and water, and has a GC purity of greater than 96%. The reaction promotes substitution reaction by adding an alkaline additive which is soluble in an organic solvent, and simultaneously serves as an acid binding agent of the reaction, so that the reaction yield is improved. Perchloromethyl mercaptan (CCl) 3 SCl) and trifluoromethyl sulfanyl Chloride (CF) 3 SCl) are high toxic compounds, but the perchloromethyl mercaptan has a boiling point of about 147 ℃ and a normal temperature and pressure, the compound is liquid, is convenient to be added into a reaction system, is safer, and the trichloromethyl mercaptan has a boiling point of about 0 ℃ and a normal temperature and pressure, and is gas, so that the perchloromethyl mercaptan is inconvenient to be added into the reaction systemIn the method, gas is easy to escape and leak, and safety accidents are easy to cause, so that relatively safe perchloromethyl mercaptan is selected as a reactant. However, perchloromethyl mercaptan has low reactivity compared to trifluoromethylthiochloride, directly with 5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ]]The reaction of the-1H-pyrazole-3-formonitrile (II) has extremely low yield of the compound III, so that the invention introduces an alkaline additive into a reaction system to promote the reaction of the compound III and the alkaline additive also serves as an acid-binding agent because hydrogen chloride is generated in the reaction process.
Preferably, the alkaline additive is an organic amine compound; the alkaline additive is one or more of triethylamine, dimethylamine salt, diisopropylethylamine, pyridine and N, N-dimethylaminopyridine, but is not limited to the listed alkaline additives.
Preferably, the addition amount of the perchloromethyl mercaptan is as follows: 1.05 to 1.5eq, and the addition amount of the alkaline additive is as follows: 1.05 to 1.7eq, the reaction temperature is 10 to 30 ℃, under the reaction condition, the yield of the purified product can reach more than 90 percent, and the purity is more than 98 percent.
Preferably, the organic solvent is an aprotic solvent, and the organic solvent is one or more of dichloromethane, 1, 2-dichloroethane, 1, 2-trichloroethane, chloroform, carbon tetrachloride, chlorobenzene, tetrahydrofuran, dioxane, methyl tertiary butyl ether, but is not limited to the listed solvents.
Preferably, the substitution reaction post-treatment mode is as follows: adding a proper amount of water for washing, layering, concentrating an organic phase to form a part, crystallizing, carrying out suction filtration and drying to obtain the compound III, wherein the yield of the step is 90-97%, and the purity is more than 98%.
The intermediate IV can be used for synthesizing fipronil, and the synthesis steps are as follows: the intermediate IV is used as a raw material, a second organic solvent is used as a reaction medium, the fipronil product is produced through oxidation, the oxidant is hydrogen peroxide with the content of 20-40%, the additive is trichloroacetic acid, the adding mole ratio of the trichloroacetic acid is 5-10 equivalents based on the intermediate IV, the adding mole ratio of the hydrogen peroxide is 2-10 equivalents, the reaction temperature is 15-25 ℃, and the second organic solvent is one or more of toluene, benzene, chlorobenzene, xylene and trimethylbenzene.
The beneficial effects are that: compared with the prior art, the invention has the following remarkable advantages: 1. the reaction condition is mild, and the safety is high; 2. the post-treatment is simple; 3. the product selectivity is high.
Drawings
FIG. 1 is a schematic diagram of the synthetic route of the present invention.
Fig. 2 is a High Performance Liquid Chromatography (HPLC) of intermediate IV of the present invention.
FIG. 3 is a mass spectrum of compound III of the present invention.
Detailed Description
The technical scheme of the invention is further described below with reference to the accompanying drawings. Unless otherwise indicated, the reagents used in the examples below were all analytically pure commercial reagents and were used without purification.
Example 1: synthesis of Compound III
32.1g (0.1 mol, HPLC purity is more than or equal to 99.0%) of pyrazole compound II,300ml of dichloroethane and 15.2g (0.15 mol) of triethylamine are sequentially added into a 500ml reaction bottle, stirring is started, the temperature is reduced to below 10 ℃, 22.4g (0.12 mol, GC purity is more than or equal to 96%) of perchloromethyl mercaptan is slowly added, reaction is carried out for 16h at 15-20 ℃, TLC detection is carried out, the reaction of raw materials is confirmed to be complete, 50ml of water is added for washing, an organic phase is concentrated to about 200ml of solvent, the concentrate is cooled to-5-0 ℃, the temperature is stirred for 2h, suction filtration is carried out, and a filter cake is dried to obtain 44.5g of compound III, the yield is 93.7%, and the purity is 98.5%. Compound III was a yellowish to white solid powder characterized by LC-MS, found (ES-API): m-1:468.6 (100%), 470.6 (67%), 466.6 (60%), theory MS:469.85 (100%), 471.85 (66.9%), 467.86 (60.8%) were found to be in agreement with theory, as demonstrated in FIG. 3, compound III was 5-amino-1- (2, 6-dichloro-4- (trifluoromethyl) phenyl) -4- ((trichloromethyl) thio) -1H-pyrazole-3-carbonitrile.
Example 2: synthesis of Compound III
32.1g (0.1 mol, HPLC purity is more than or equal to 99.0%) of pyrazole compound II,320ml of dichloromethane and 18.1g (0.14 mol) of diisopropylethylamine are sequentially added into a 500ml reaction bottle, stirring is started, the temperature is reduced to below 10 ℃, 24.2g (0.13 mol) of perchloromethyl mercaptan is slowly added, reaction is carried out for 13h at 20-25 ℃, TLC detection is carried out, the reaction of raw materials is confirmed to be complete, 50ml of water is added for washing, an organic phase is concentrated to about 210ml of solvent, the concentrate is cooled to-2 ℃, pumping filtration is carried out after stirring for 2h, and a filter cake is dried to obtain 43.1g of compound III, the yield is 91.7%, and the purity is 98.1%.
Example 3: synthesis of Compound III
160.5g of pyrazole compound II with the purity of (0.5 mol) being more than or equal to 99.0 percent by HPLC, 63.1g (0.62 mol) of triethylamine with the purity of 1500ml of dichloroethane are sequentially added into a 2L reaction bottle, stirring is started, the temperature is reduced to below 5 ℃, 112g (0.6 mol) of perchloromethyl mercaptan is slowly added, the reaction is carried out for 16 hours at the temperature of 12-18 ℃, TLC detection is carried out, the reaction of the raw materials is confirmed to be complete, 200ml of water is added for washing, the organic phase is concentrated (40 ℃) to obtain about 1000ml of solvent, the concentrate is cooled to-5 to-2 ℃, the temperature is reduced to-2 ℃, suction filtration is carried out after stirring is carried out for 2 hours, a filter cake is dried, and 226.0g of a compound III is obtained, the yield is 96.1%, and the purity is 98.8%.
Example 4: intermediate IV synthesis
0.470g (0.001 mol) of compound III was added to a 4ml plastic test tube, 1.0ml (1.100 g,70%,0.0385 mol) of Olah reagent was added at 10℃and sealed, and placed on a shaker at 20℃with the reaction system being a solid-liquid mixture, and the system gradually dissolved as the reaction proceeded. After 4h of reaction, sample TLC was used to check the reaction, after evaporation of HF, 2ml isopropyl acetate and 0.5ml 5% aqueous sodium carbonate solution were added, after disappearance of the air bubbles, the aqueous layer was separated, then aqueous sodium carbonate solution was added until no air bubbles were generated, the aqueous layer was separated, and the organic phase was concentrated to give 0.40g of Compound IV in 95% yield and 98.5% purity. Instrument: LC-10AT/SPD-10AvP, acetonitrile: methanol: water = 15:60:25 is used as a mobile phase, the product is compared with a standard substance, the peak time of the product and the standard substance are consistent, and the product, namely the target compound IV, is proved, and the result is shown in figure 2.
Example 5: intermediate IV synthesis
0.470g (0.001 mol) of Compound III was added to a 4ml plastic test tube, 1.0ml (1.0 g,0.0186 mol) of TEA.3HF was added at 10℃and after 4 hours of reaction as in example four, the reaction was performed by sampling TLC, and monofluorinated and difluorinated products were produced, and no perfluorinated substituted products were produced. The reaction was carried out again for 2h at 35℃and the product IV was approximately 10%, starting material approximately 50% and impurity spots were more marked by TLC.
Example 6: intermediate IV synthesis
200g of HF (10 mol,5 ℃) were introduced into a 500ml tetrafluoro-reactor equipped with magnetic stirring, thermometer probe, condenser, the temperature was controlled below 10℃and 94.1g (0.2 mol) of Compound III was added in portions, and the tail gas absorption and personal protection were achieved. After reaction at 5-15 ℃ for 5h, detection by sampling TLC, confirming that reaction is complete, evaporating off HF, adding saturated sodium bicarbonate aqueous solution, stirring for 0.5h until no bubbles are generated, confirming that pH=7-8, suction filtering, and washing with water to obtain 81.0g of compound IV (dried), yield 96.2%, purity 98.7%.
Example 7: intermediate IV synthesis
180g of HF (9.0 mol,5 ℃ C.) are introduced into a 500ml tetrafluoro-reactor equipped with a mechanical stirrer, thermometer probe, condenser, the temperature is controlled below 10 ℃ and 141g (0.3 mol) of compound III are added in portions, over about 1 hour, and the tail gas absorption and personal protection are achieved. After reaction at 10-19 ℃ for 4h, detection by sampling TLC, confirming that reaction is complete, evaporating off HF, adding 5% potassium carbonate aqueous solution until no bubbles are generated, stirring for 0.5h, confirming that pH=7-8, suction filtering, and washing with water to obtain 122.6g of compound IV (dried), wherein the yield is 97.0%, and the purity is 98.8%.
Example 8: intermediate IV synthesis
90g of HF (4.5 mol,5 ℃ C.) are introduced into a 500ml tetrafluoro-reactor equipped with a mechanical stirrer, thermometer probe, condenser, at a temperature below 10 ℃ C. 141g (0.3 mol) of Compound III are added in portions, the system is visually examined for substantial melting before each addition, about 1.5 hours are consumed, 124.0g of Compound IV (dried) is obtained, the yield is 98.1%, and the purity is 98.3%.
Example 9: fipronil I synthesis
5.47g of compound IV,19.11g of trichloroacetic acid, 90ml of toluene are put into a 250ml flask, 10ml of 30% hydrogen peroxide is dripped at 10-20 ℃ for about 30min, after the reaction is completed at 15-20 ℃ for 16h, the HPLC detection shows that the conversion rate of the product is 95.2% and the sulfone is 1.8%. Filtering, recrystallizing the obtained solid with 95% ethanol, filtering, and oven drying to obtain fipronil 4.91g with 86.1% yield, 98.0% purity, and sulfone impurity 0.5%.

Claims (10)

1. A method for synthesizing a fipronil intermediate is characterized in that a compound III is used as a raw material, and an intermediate IV is synthesized through a fluorine substitution reaction:
the fluoridation reagent used in the fluoridation reaction is anhydrous HF or an Olah reagent with the content of 40-70 percent, the molar ratio of the Olah reagent or the HF to the addition of the compound III is 3-50 equivalents based on the effective HF, and the reaction temperature is not higher than 30 ℃.
2. The method for synthesizing fipronil intermediate IV according to claim 1, wherein the molar ratio of the Olah reagent or anhydrous HF to the addition of the compound III is 15 to 30 equivalents based on the effective HF.
3. The method for synthesizing fipronil intermediate IV according to claim 1, wherein the fluorine substitution reaction temperature is-10-30 ℃.
4. The method for synthesizing fipronil intermediate IV according to claim 1, wherein the fluorine substitution reaction temperature is 10-30 ℃.
5. The method for synthesizing fipronil intermediate IV according to claim 1, wherein the fluorine substitution reaction is a solvent-free reaction.
6. The method for synthesizing fipronil intermediate IV according to claim 1, wherein the method for synthesizing the compound III is as follows: taking 5-amino-1- [2, 6-dichloro-4- (trifluoromethyl) phenyl ] -1H-pyrazole-3-carbonitrile II and perchloromethyl mercaptan as raw materials, and carrying out substitution reaction under the condition of an alkaline additive and an aprotic solvent organic solvent to obtain a compound III, wherein the adding molar ratio of the perchloromethyl mercaptan is 1-2 equivalents based on the raw material II; the addition mole ratio of the alkaline additive is 1-3 equivalent, and the substitution reaction temperature is 0-60 ℃.
7. The method for synthesizing fipronil intermediate IV according to claim 6, wherein the total amount of perchloromethyl mercaptan added is 1.05 to 1.5 equivalents, the amount of alkaline additive added is 1.05 to 1.7 equivalents, and the substitution reaction temperature is 10 to 30 ℃.
8. The method for synthesizing fipronil intermediate IV according to claim 6, wherein the basic additive is an organic amine compound.
9. The method for synthesizing fipronil intermediate IV according to claim 6 or 8, wherein the basic additive is one or more of triethylamine, dimethylamine salt, diisopropylethylamine, pyridine, N-dimethylaminopyridine.
10. The method for synthesizing fipronil intermediate IV according to claim 6, wherein the organic solvent is one or more of dichloromethane, 1, 2-dichloroethane, 1, 2-trichloroethane, chloroform, carbon tetrachloride, chlorobenzene, tetrahydrofuran, dioxane, and methyl tert-butyl ether.
CN202311392013.3A 2023-10-25 2023-10-25 Synthesis method of fipronil intermediate Pending CN117486800A (en)

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