Preparation method of novel bactericide pydiflumetofen
By employing techniques such as keratinase catalysis, electrolysis, and photoreduction, the preparation process of fluopyram has been simplified, solving the problems of high energy consumption, significant pollution, and low purity in traditional methods, and achieving a highly efficient and environmentally friendly preparation process.
Patent Information
- Application Number
- CN202511136926.8
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-08-14
- Publication Date
- 2025-11-28
AI Technical Summary
Existing methods for preparing fluopyram have problems such as cumbersome reaction steps, high energy consumption, significant pollution, insufficient purity of intermediate products, and unsatisfactory yield.
The preparation method employs keratinase-catalyzed oxime catalysis, nickel/copper electrode electrolysis, visible light reduction, and substitution reaction in a microchannel reactor, combined with column chromatography purification. The process includes oxime catalysis in phosphate buffer, dimethyl carbonate as the methylating agent, substitution reaction via visible light reduction and a microchannel reactor, and finally, pure product obtained by column chromatography elution.
It reduces energy consumption and pollution, improves the purity and yield of intermediate products, and simplifies the preparation process.
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Figure CN121023533A_ABST
Abstract
Description
Technical Field
[0001] This invention belongs to the field of agricultural chemical preparation technology, specifically relating to a method for preparing a novel fungicide, fluopyram. Background Technology
[0002] In agricultural production, the prevention and control of crop diseases is crucial, and the research and application of fungicides have always been key to ensuring a bumper harvest. Fluopyram, as a highly efficient and broad-spectrum novel fungicide, has shown good results in controlling various crop diseases, playing a significant role in ensuring healthy crop growth and stable yields. Fluopyram is a novel succinate dehydrogenase inhibitor. Its fungicidal mechanism mainly involves specifically interfering with key aspects of pathogen energy metabolism, ultimately leading to pathogen death. The core target of fluopyram is succinate dehydrogenase in the mitochondrial respiratory chain of pathogens. This enzyme is a key component of the tricarboxylic acid cycle and electron transport chain, responsible for catalyzing the oxidation of succinate to fumarate and transferring electrons to coenzyme Q, driving ATP synthesis. Fluopyram specifically binds to the active site of succinate dehydrogenase, blocking its catalytic function, leading to the interruption of the electron transport chain, and preventing pathogens from generating energy through oxidative phosphorylation. Inhibition of succinate dehydrogenase directly prevents the conversion of succinate to fumarate, disrupting the tricarboxylic acid cycle. Pathogens are unable to produce reduced coenzymes, thus affecting the subsequent electron transport chain. With the electron transport function of succinate dehydrogenase inhibited, coenzyme Q cannot accept electrons, the proton gradient across the mitochondrial inner membrane cannot form, ATP synthase loses its driving force, and ultimately the pathogen dies from energy depletion. Fluopyram is effective against a variety of pathogens, including Fusarium, Botrytis, Sclerotinia, and Powdery Mildew, covering more than 30 diseases such as wheat scab, rapeseed sclerotinia rot, and cucumber powdery mildew. To delay resistance development and broaden the fungicidal spectrum, fluopyram is often combined with other fungicides with different mechanisms of action. For example, fluopyram + difenoconazole is used for powdery mildew in watermelon and cucumber, and has been extended to crops such as tomatoes and citrus; fluopyram + azoxystrobin + propiconazole provides multi-mechanism protection against diseases affecting golf course turf. In the preparation of fluopyram, the intermediate 3-difluoromethyl-1-methylpyrazole, generated by a cyclization reaction, exists as an isomer. Impurities must be removed by column chromatography or multiple crystallizations, leading to yield loss and increased costs. Traditional synthesis processes require sodium cyanoborohydride for oxime reduction, which releases highly toxic hydrogen cyanide upon contact with acid.
[0003] Methods for preparing fluopyram often have limitations, such as cumbersome reaction steps, high energy consumption, significant pollution, insufficient purity of intermediate products, and unsatisfactory yields. Therefore, developing efficient methods for the synthesis of fluopyram has become an important research direction. Summary of the Invention
[0004] This invention belongs to the field of pesticide synthesis technology, specifically relating to a method for preparing a novel fungicide, fluopyram. The method comprises five steps: First, in phosphate buffer, 1-(2,4,6-trichlorophenyl)-propyl-2-one is oximated with hydroxylamine using a cutinase catalysis; after the oximation reaction, a nickel / copper electrode is inserted, and electrochemical methylation is performed using dimethyl carbonate as the methylating agent; ethanol and a Pd(OH)2 / C catalyst are added to the methylation product, and photocatalytic reduction is completed under visible light to obtain O-methylN-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine; then, O-methylN-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine undergoes a substitution reaction with 3-difluoromethyl-1-methyl-1H-pyrazole-4-formyl chloride to obtain fluopyram.
[0005] To achieve the above objectives, this application adopts the following technical solution:
[0006] This application provides a novel and highly efficient method for preparing fluopyram, comprising the following steps:
[0007] 1-(2,4,6-trichlorophenyl)-propyl-2-one was reacted with hydroxylamine in a buffer system and catalyzed by keratinase to generate an oxime product;
[0008] The oxime product was electrolyzed in an electrolytic system consisting of a nickel-based anode and a copper-based cathode, using dimethyl carbonate as the methylating agent, to obtain the O-methyl oxime product.
[0009] O-methyl oxime was reduced by visible light irradiation in the presence of ethanol and a palladium-based catalyst to give O-methyl N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine;
[0010] The product of O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine was mixed with 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxyl chloride, and an acid-binding agent was added. The substitution reaction was carried out in a microchannel reactor to obtain fluopyram.
[0011] Fluopyram was purified by column chromatography elution.
[0012] In one feasible implementation, the molar ratio of 1-(2,4,6-trichlorophenyl)-propyl-2-one to hydroxylamine is 1:(1-1.2).
[0013] In one feasible implementation, the buffer system is a phosphate buffer with a pH of 6.5-7.5, the concentration of the keratinase used is 50-150 U / mL, the reaction temperature of the oxime product is 25-35°C, and the reaction time is 1-2 hours.
[0014] In one feasible implementation, the amount of dimethyl carbonate used is 1-1.5 times the volume of the oxime reaction liquid.
[0015] In one feasible implementation, the current density in the electrolysis system is controlled at 3-8 mA / cm². 2 The reaction temperature is maintained at 20-25℃.
[0016] In one feasible implementation, the nitrogen purging time before the reduction reaction is 5-15 minutes, and the gas flow rate is controlled at 30-100 mL / min.
[0017] In one feasible implementation, the palladium-based catalyst is Pd(OH)2 / C, the amount of which is 0.5-5% of the mass of the reaction solution, the reaction is carried out at room temperature for 0.5-1 hours, and the visible light wavelength is 450-600 nm.
[0018] In one feasible implementation, the molar ratio of O-methylN-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine to 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxyl chloride is 1:(1-1.3).
[0019] In one feasible implementation, the acid-binding agent is N,N-diisopropylethylamine, and the substitution reaction temperature is 20°C-25°C.
[0020] In one feasible implementation, the column chromatography elution uses an ethanol / ethyl acetate gradient elution, with the elution ratio gradually adjusted from 15:1 to 2:1, followed by vacuum concentration and crystallization to obtain fluopyram.
[0021] Beneficial technical effects:
[0022] Keratinase achieves highly selective oxime methylation in phosphate buffer, avoiding the high temperature, strong acid and alkali environments of traditional chemical methods, and reducing byproducts and wastewater. Keratinase generates a single-configuration oxime, avoiding material loss during intermediate purification and providing high-purity raw materials for electrolysis. Dimethyl carbonate is used as the methylating agent, and the oxime reaction solution is directly used in the electrolysis reaction, eliminating the need for solvent replacement and achieving methylation. The electrolysis process uses dimethyl carbonate, and visible light reduction eliminates the need for high temperature and pressure. Ethanol, as a solvent, also possesses reducing properties, reducing pollution and energy consumption throughout the process. This invention solves the problems of cumbersome steps, low purity of intermediate products, and high energy consumption in traditional processes through biocatalysis, electromethylation, and photocatalytic reduction reaction processes. Attached Figure Description
[0023] Figure 1This is a schematic diagram of the chemical reaction between O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine and 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxyl chloride. Detailed Implementation
[0024] To make the technical problems, technical solutions, and beneficial effects to be solved by this application clearer, the application will be further described in detail below with reference to embodiments. However, this should not be construed as limiting the scope of this application to the following examples. All other embodiments obtained by those skilled in the art without creative effort without departing from the above-described methodological spirit of this application are within the scope of protection of this application.
[0025] In this application, the terminology used is for the purpose of describing particular embodiments only and is not intended to be limiting of this application.
[0026] The singular forms “for,” “a,” “any one,” and “as described” used in this application are intended to include the plural forms unless the context clearly indicates otherwise.
[0027] Furthermore, the terms "first" and "second" appearing in this application are for descriptive purposes only and should not be construed as indicating or implying relative importance.
[0028] The following will describe in detail, with reference to different embodiments, a highly efficient preparation method of fluopyram hydroxylamine provided in this application.
[0029] Example 1:
[0030] A method for preparing a novel fungicide, fluopyram, includes the following steps:
[0031] 1. In a reactor, 1-(2,4,6-trichlorophenyl)-propyl-2-one, hydroxylamine, and pH 7.0 phosphate buffer were added sequentially, and the mixture was magnetically stirred to initially disperse the substrate. A buffer solution containing 100 U / mL keratinase was slowly added to the reactor, and the mixture was reacted at 30°C with shaking for 1 hour. The molar ratio of 1-(2,4,6-trichlorophenyl)-propyl-2-one to hydroxylamine was 1:1.1.
[0032] 2. Insert the electrolytic cell with nickel-based electrodes (Nifoam electrode for the anode, Cufoil electrode for the cathode), and add dimethyl carbonate (DMC, in a volume 1.2 times the volume of the oxime reaction solution). Connect the constant current power supply and apply 5 mA / cm². 2A constant current density was applied, and the reaction was carried out at room temperature (20°C) for 1 hour, with a stirring rate of 100 rpm maintained throughout the reaction. After the reaction, the solution was transferred to centrifuge tubes and centrifuged at 4°C and 10,000 rpm for 10 minutes. The enzyme precipitate could be recovered and reused, and the supernatant was directly used in the next stage.
[0033] 3. Transfer the methylation supernatant to a photocatalytic reactor, add Pd(OH)₂ / C catalyst (1% of the reaction solution mass), and add ethanol solution (5 times the molar volume of the methylation product). Turn on magnetic stirring. Purge the reactor with nitrogen gas (50 mL / min) for 10 minutes to remove oxygen, and seal the reactor. Irradiate with a visible light source at a wavelength of 525 nm and react at room temperature for 0.5 hours to obtain the reduction product O-methyl N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine, while maintaining stirring.
[0034] 4. Using a plunger pump, the reduction product O-methyl N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine solution was pumped into a microchannel reactor. N,N-diisopropylethylamine (DIPEA) was added, and simultaneously, a dichloromethane solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-formyl chloride was pumped in at an equal volumetric flow rate. The mixture was continuously mixed and reacted within the microchannel. The effluent was concentrated to dryness under reduced pressure at 40°C to obtain crude fluopyram. The molar ratio of the reduction product O-methyl N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine to 3-difluoromethyl-1-methyl-1H-pyrazole-4-formyl chloride was 1:1.2. Figure 1 As shown.
[0035] 5. Crude fluopyram was purified by silica gel column chromatography with gradient elution: ethanol / ethyl acetate (gradually adjusted from 10:1 to 3:1), the target fraction was collected, and concentrated under reduced pressure to obtain white solid fluopyram.
[0036] Example 2:
[0037] A method for preparing a novel fungicide, fluopyram, includes the following steps:
[0038] 1. In a reactor, 1-(2,4,6-trichlorophenyl)-propyl-2-one, hydroxylamine, and pH 6.5 phosphate buffer were added sequentially, and the mixture was magnetically stirred to initially disperse the substrate. A buffer solution containing 100 U / mL keratinase was slowly added to the reactor, and the reaction was carried out at 25°C with shaking for 1 hour. The molar ratio of 1-(2,4,6-trichlorophenyl)-propyl-2-one to hydroxylamine was 1:1.
[0039] 2. Insert the electrolytic cell with nickel-based electrodes (Nifoam electrode for the anode, Cufoil electrode for the cathode), and add dimethyl carbonate (DMC, in a volume 1.0 times the volume of the oxime reaction solution). Connect the constant current power supply and apply 3 mA / cm². 2 A constant current density was applied, and the reaction was carried out at room temperature (20°C) for 1 hour, with a stirring rate of 100 rpm maintained throughout the reaction. After the reaction, the solution was transferred to centrifuge tubes and centrifuged at 4°C and 5000 rpm for 10 minutes. The enzyme precipitate could be recovered and reused, and the supernatant was directly used in the next stage.
[0040] 3. Transfer the methylation supernatant to a photocatalytic reactor, add Pd(OH)₂ / C catalyst (0.5% of the reaction solution mass), and add ethanol solution (5 times the molar volume of the methylation product). Turn on magnetic stirring. Purge the reactor with nitrogen gas (30 mL / min) for 15 minutes to remove oxygen, and seal the reactor. Irradiate with a visible light source at a wavelength of 450 nm and react at room temperature for 0.5 hours to obtain the reduction product O-methyl N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine, while maintaining stirring.
[0041] 4. Using a plunger pump, the reduced product O-methyl N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine solution was pumped into a microchannel reactor. N,N-diisopropylethylamine (DIPEA) was added, and simultaneously, a dichloromethane solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-formyl chloride was pumped in at an equal volumetric flow rate. The mixture was continuously mixed and reacted within the microchannel. The effluent was concentrated to dryness under reduced pressure at 40°C to obtain crude fluopyram. The molar ratio of the reduced product O-methyl N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine to 3-difluoromethyl-1-methyl-1H-pyrazole-4-formyl chloride was 1:1. Figure 1 As shown.
[0042] 5. Crude fluopyram was purified by silica gel column chromatography with gradient elution: ethanol / ethyl acetate (gradually adjusted from 10:1 to 3:1), the target fraction was collected, and concentrated under reduced pressure to obtain white solid fluopyram.
[0043] Example 3:
[0044] A method for preparing a novel fungicide, fluopyram, includes the following steps:
[0045] 1. In a reactor, 1-(2,4,6-trichlorophenyl)-propyl-2-one, hydroxylamine, and pH 7.5 phosphate buffer were added sequentially, and the mixture was magnetically stirred to initially disperse the substrate. A buffer solution containing 150 U / mL keratinase was slowly added to the reactor, and the mixture was reacted at 35°C with shaking for 1 hour. The molar ratio of 1-(2,4,6-trichlorophenyl)-propyl-2-one to hydroxylamine was 1:1.2.
[0046] 2. Insert the electrolytic cell with nickel-based electrodes (Nifoam electrode for the anode, Cufoil electrode for the cathode), and add dimethyl carbonate (DMC, in a volume 1.5 times the volume of the oxime reaction solution). Connect the constant current power supply and apply 8 mA / cm². 2 A constant current density was applied, and the reaction was carried out at room temperature (20°C) for 1 hour, with a stirring rate of 100 rpm maintained throughout the reaction. After the reaction, the solution was transferred to a centrifuge tube and centrifuged at 10°C and 10,000 rpm for 10 minutes. The enzyme precipitate could be recovered and reused, and the supernatant was directly used in the next stage.
[0047] 3. Transfer the methylation supernatant to a photocatalytic reactor, add Pd(OH)₂ / C catalyst (5% of the reaction solution mass), and add ethanol solution (5 times the molar volume of the methylation product). Turn on magnetic stirring. Purge the reactor with nitrogen gas (100 mL / min) for 5 minutes to remove oxygen, and seal the reactor. Irradiate with a visible light source at a wavelength of 600 nm and react at room temperature for 0.5 hours to obtain the reduction product O-methyl N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine, while maintaining stirring.
[0048] 4. Using a plunger pump, the reduced product O-methyl N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine solution was pumped into a microchannel reactor. N,N-diisopropylethylamine (DIPEA) was added, and simultaneously, a dichloromethane solution of 3-difluoromethyl-1-methyl-1H-pyrazole-4-formyl chloride was pumped in at an equal volumetric flow rate. The mixture was continuously mixed and reacted within the microchannel. The effluent was concentrated to dryness under reduced pressure at 40°C to obtain crude fluopyram. The molar ratio of the reduced product O-methyl N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine to 3-difluoromethyl-1-methyl-1H-pyrazole-4-formyl chloride was 1:1.3. Figure 1 As shown.
[0049] 5. Crude fluopyram was purified by silica gel column chromatography with gradient elution: ethanol / ethyl acetate (gradually adjusted from 10:1 to 3:1), the target fraction was collected, and concentrated under reduced pressure to obtain white solid fluopyram.
[0050] Comparative Example 1:
[0051] A method for preparing the fungicide fluopyram includes the following steps:
[0052] 1. Add 1-(2,4,6-trichlorophenyl)-propyl-2-one and [BMIM][BF4] to the reactor and stir until homogeneous. Slowly add pH 7.0 phosphate buffer and stir at room temperature until the substrate is completely dissolved (approximately 15 minutes). Add hydroxylamine hydrochloride in portions, and continue stirring for 1 hour after the addition is complete. After the reaction is complete, transfer the mixture to a separatory funnel, extract with dichloromethane, separate the aqueous phase, dry the organic phase (dichloromethane layer) with anhydrous sodium sulfate, remove dichloromethane by vacuum distillation to obtain the oxime intermediate, add DMF directly to dissolve the residual crude product, add potassium carbonate to the same reaction flask, cool to 0°C in an ice bath, add iodomethane dropwise, and after the addition is complete, warm to room temperature and continue stirring for 2 hours. The molar ratio of 1-(2,4,6-trichlorophenyl)-propyl-2-one to hydroxylamine hydrochloride is 1:1.2, and the molar ratio of the oxime intermediate, potassium carbonate, and iodomethane is 1:1.2:1.1.
[0053] 2. Pour the reaction solution into ice water, extract with dichloromethane, combine the organic phases, wash successively with 10% sodium thiosulfate solution and saturated brine, dry the organic phase with anhydrous sodium sulfate for 30 minutes, filter, concentrate under reduced pressure, dissolve crude O-methyloxime in methanol, add 10% Pd / C to the same reaction flask, evacuate and purge with hydrogen three times, maintaining the pressure of the hydrogen balloon, stir at room temperature for 1 hour. After the reaction is complete, remove the catalyst through diatomaceous earth filtration, wash the filter cake with methanol, concentrate the filtrate under reduced pressure, add anhydrous dichloromethane to dissolve the residual N-methoxyamine. Cool to -10°C in an ice-salt bath. Slowly add triethylamine, keeping the temperature below 0°C, and continue stirring for 10 minutes after the addition is complete. Dissolve 3-difluoromethyl-1-methyl-1H-pyrazole-4-formyl chloride in anhydrous dichloromethane and transfer to a constant pressure dropping funnel. Slowly add at -10-0°C, controlling the dropping rate to about 1 drop / second, observing the gradual formation of a white solid during the addition process. The reaction solution was poured into ice water and stirred for 10 minutes, then transferred to a separatory funnel. The organic phase was washed with 1M hydrochloric acid to remove excess triethylamine. The aqueous phase was back-extracted once with dichloromethane. The combined organic phases were washed successively with saturated sodium bicarbonate solution and saturated brine. The organic phase was dried with anhydrous sodium sulfate for 30 minutes, filtered, and concentrated under reduced pressure to obtain crude fluopyram. The molar ratio of N-methoxyamine, triethylamine, and 3-difluoromethyl-1-methyl-1H-pyrazole-4-formyl chloride was 1:2:1.
[0054] 3. Dissolve crude fluopyram in ethyl acetate, slowly add n-heptane dropwise until the solution becomes slightly turbid, cool to 0°C in an ice bath and stir for 1 hour, collect the crystals by suction filtration, wash the filter cake with n-heptane, and vacuum dry (40°C, oil pump) to constant weight to obtain fluopyram powder.
[0055] Comparative Example 2:
[0056] A method for preparing the fungicide fluopyram includes the following steps:
[0057] 1. Add 1-(2,4,6-trichlorophenyl)-propyl-2-one and [BMIM][BF4] to the reactor and stir until homogeneous. Slowly add pH 7.0 phosphate buffer and stir at room temperature until the substrate is completely dissolved (approximately 15 minutes). Add hydroxylamine hydrochloride in portions, and continue stirring for 1 hour after the addition is complete. After the reaction is complete, transfer the mixture to a separatory funnel, extract with dichloromethane, separate the aqueous phase, dry the organic phase (dichloromethane layer) with anhydrous sodium sulfate, remove dichloromethane by vacuum distillation to obtain the oxime intermediate, add DMF directly to dissolve the residual crude product, add potassium carbonate to the same reaction flask, cool to 0°C in an ice bath, add iodomethane dropwise, and after the addition is complete, warm to room temperature and continue stirring for 2 hours. The molar ratio of 1-(2,4,6-trichlorophenyl)-propyl-2-one to hydroxylamine hydrochloride is 1:1.2, and the molar ratio of the oxime intermediate, potassium carbonate, and iodomethane is 1:1.2:1.1.
[0058] 2. Pour the reaction solution into ice water, extract with dichloromethane, combine the organic phases, wash successively with 10% sodium thiosulfate solution and saturated brine, dry the organic phase with anhydrous sodium sulfate for 30 minutes, filter, concentrate under reduced pressure, dissolve crude O-methyloxime in methanol, add 10% Pd / C to the same reaction flask, evacuate and purge with hydrogen three times, maintaining the pressure of the hydrogen balloon, stir at room temperature for 1 hour. After the reaction is complete, remove the catalyst through diatomaceous earth filtration, wash the filter cake with methanol, concentrate the filtrate under reduced pressure, add anhydrous dichloromethane to dissolve the residual N-methoxyamine. Cool to -10°C in an ice-salt bath. Slowly add triethylamine, keeping the temperature below 0°C, and continue stirring for 10 minutes after the addition is complete. Dissolve 3-difluoromethyl-1-methyl-1H-pyrazole-4-formyl chloride in anhydrous dichloromethane and transfer to a constant pressure dropping funnel. Slowly add at -10-0°C, controlling the dropping rate to about 1 drop / second, observing the gradual formation of a white solid during the addition process. The reaction solution was poured into ice water and stirred for 10 minutes, then transferred to a separatory funnel. The organic phase was washed with 1M hydrochloric acid to remove excess triethylamine. The aqueous phase was back-extracted once with dichloromethane. The combined organic phases were washed successively with saturated sodium bicarbonate solution and saturated brine. The organic phase was dried with anhydrous sodium sulfate for 30 minutes, filtered, and concentrated under reduced pressure to obtain crude fluopyram. The molar ratio of N-methoxyamine, triethylamine, and 3-difluoromethyl-1-methyl-1H-pyrazole-4-formyl chloride was 1:2:1.
[0059] 3. Crude fluopyram was purified by silica gel column chromatography with gradient elution: hexane / ethyl acetate (gradually adjusted from 10:1 to 3:1), the target fraction was collected, and concentrated under reduced pressure to obtain white solid fluopyram.
[0060] The purity of purified fluopyram was determined using gas chromatography. Chromatographic conditions: HP-5 capillary column (30m × 0.32mm × 0.25μm); injection port temperature 250℃; detector temperature 280℃; column temperature program: initial temperature 100℃, increased to 250℃ at 10℃ / min, held for 5 minutes; carrier gas: nitrogen, flow rate 1.0mL / min; injection volume 1μL, split ratio 10:1. The purity of fluopyram was calculated based on the chromatogram.
[0061] Table 1. Test results of fluopyram prepared in the examples and comparative examples.
[0062] Fluopyram (%) Example 1 99.4 Example 2 99.2 Example 3 99.5 Comparative Example 1 95.1 Comparative Example 2 95.5
[0063] The fluopyram prepared in Examples 1-3 had better content than the comparative example. This is because the high selectivity of enzyme catalysis in the oxime reaction reduced the generation of byproducts, providing high-purity raw materials for the subsequent electrolytic reaction. The electrolytic methylation step further reduced side reactions through precise control of current density and temperature.
[0064] The above results demonstrate and describe the basic principles and main features of this application, as well as its advantages.
[0065] Those skilled in the art should understand that this application is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of this application. Various changes and modifications can be made to this application without departing from the spirit and scope thereof, and all such changes and modifications fall within the scope of this application as claimed. The scope of protection of this application is defined by the equivalents of the appended claims.
Claims
1. A method for preparing a novel fungicide, fluopyram, characterized in that, Includes the following steps: 1-(2,4,6-trichlorophenyl)-propyl-2-one was reacted with hydroxylamine in a buffer system via a keratinase-catalyzed reaction to generate an oxime product; The oxime product was electrolyzed in an electrolytic system consisting of a nickel-based anode and a copper-based cathode, using dimethyl carbonate as the methylating agent, to obtain O-methyloxime; O-methyl oxime was reduced by visible light irradiation in the presence of ethanol and a palladium-based catalyst to give O-methyl N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine; The product of O-methyl-N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine was mixed with 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxyl chloride, and an acid-binding agent was added. The substitution reaction was carried out in a microchannel reactor to obtain fluopyram. Fluopyram was purified by column chromatography elution.
2. The preparation method of the novel fungicide fluopyram according to claim 1, characterized in that, The molar ratio of 1-(2,4,6-trichlorophenyl)-propyl-2-one to hydroxylamine is 1:(1-1.2).
3. The preparation method of the novel fungicide fluopyram according to claim 1, characterized in that, The buffer system is a phosphate buffer solution with a pH of 6.5-7.5, the concentration of the keratinase used is 50-150 U / mL, the reaction temperature of the oxime product is 25-35℃, and the reaction time is 1-2 hours.
4. The preparation method of the novel fungicide fluopyram according to claim 1, characterized in that, The amount of dimethyl carbonate used is 1-1.5 times the volume of the oxime reaction liquid.
5. The preparation method of the novel fungicide fluopyram according to claim 1, characterized in that, In the electrolysis system, the current density is controlled at 3-8 mA / cm². 2 The reaction temperature is maintained at 20-25℃.
6. The method for preparing the novel fungicide fluopyram according to claim 1, characterized in that, The nitrogen purging time before the reduction reaction is 5-15 minutes, and the gas flow rate is controlled at 30-100 mL / min.
7. The method for preparing the novel fungicide fluopyram according to claim 1, characterized in that, The palladium-based catalyst is Pd(OH)2 / C, and its amount is 0.5-5% of the mass of the reaction solution. The reaction is carried out at room temperature for 0.5-1 hour, and the visible light wavelength is 450-600nm.
8. The preparation method of the novel fungicide fluopyram according to claim 1, characterized in that, The molar ratio of O-methyl N-[1-methyl-2-(2,4,6-trichlorophenyl)-ethyl]-hydroxylamine to 3-difluoromethyl-1-methyl-1H-pyrazole-4-carboxyl chloride is 1:(1-1.3).
9. The preparation method of the novel fungicide fluopyram according to claim 1, characterized in that, The acid-binding agent is N,N-diisopropylethylamine, and the substitution reaction temperature is 20℃-25℃.
10. The method for preparing the novel fungicide fluopyram according to claim 1, characterized in that, The column chromatography elution was performed using an ethanol / ethyl acetate gradient elution, with the elution ratio gradually adjusted from 15:1 to 2:
1. Fluopyram was obtained by concentration and crystallization under reduced pressure.