A process for the preparation of clocanide

Abstract

The application discloses a method for preparing cymiazole based on ionic liquid catalysis, and belongs to the technical field of pesticide synthesis. The method uses a functionalized acidic ionic liquid as a catalyst and a reaction medium at the same time, and catalyzes direct reaction of an intermediate in formula (I) and tert-pentanoic acid to synthesize cymiazole. The ionic liquid is preferably [BMIM][H2PO4] or [BMIM][HSO4]. The method completely abandons tert-pentanoyl chloride and triethylamine used in a traditional process, and eliminates high-risk reagents, corrosive gases, viscous amine salt waste residues and amine-containing wastewater from the source. The reaction condition is mild, the selectivity is high, the post-treatment only needs simple extraction, and the ionic liquid can be recycled for more than 5 times. The method has the outstanding advantages of high atomic economy, simplified process flow, reduced production cost, environmental friendliness and the like, and provides a new scheme for green industrial production of cymiazole.

Description

Technical Field

[0001] This invention belongs to the field of chemical synthesis and pesticide preparation technology, specifically relating to a method for preparing the acaricide cyenopyrafen, and particularly to a method for preparing cyenopyrafen efficiently and selectively using a functionalized acidic ionic liquid as a catalyst and reaction medium. Background Technology

[0002] Cyenopyrafen is a novel acrylonitrile acaricide with a unique mechanism of action, successfully developed by Nissan Chemical Industries, Ltd. in the early 21st century. It is primarily used to control mites on fruits, vegetables, and other crops, and is relatively safe for non-target organisms. Its chemical name is (E)-2-(4-tert-butylphenyl)-2-cyano-1-(1,3,4-trimethylpyrazol-5-yl)vinyl-2,2-dimethylpropionate. It is low in toxicity, requires low dosage, has a broad acaricidal spectrum, and exhibits no cross-resistance with existing mainstream acaricides. After metabolic activation, it inhibits mitochondrial respiratory chain complex II (succinate dehydrogenase), disrupting energy metabolism. The pure product is a white to grayish-white crystal with a melting point of approximately 93-108℃. The tertivalyl chloride route is currently the classic method for the industrial production of cyenopyrafen. However, it has the following inherent drawbacks: pivaloyl chloride is a highly reactive acylation reagent with extremely high reactivity. In the presence of a catalytic amount of triethylamine, it reacts with the intermediate...

[0003] While the enol hydroxyl reaction is rapid, it is also prone to side reactions with trace amounts of other nucleophilic impurities (such as water and alcohols) present in the system, leading to reagent waste and increased purification difficulty. Furthermore, the significant steric hindrance of pivaloyl chloride, while imparting good product stability, may also make the reaction sensitive to the steric environment, potentially affecting the reaction rate and yield. Pivaloyl chloride is expensive and extremely sensitive to moisture, requiring stringent storage and use conditions, increasing production costs and operational complexity. The reaction quantitatively produces highly corrosive hydrogen chloride gas. Although triethylamine can be used as an acid-binding agent to convert it to triethylamine hydrochloride, triethylamine hydrochloride forms a viscous solid or precipitate in tetrahydrofuran, increasing the difficulty of stirring and mass transfer; after the reaction, the salt and excess triethylamine must be removed by washing and extraction, a cumbersome process that generates amine-containing wastewater, increasing the environmental burden. Triethylamine is consumed as a stoichiometric base in this reaction, becoming a waste salt that cannot be recycled, resulting in poor atom economy.

[0004] Ionic liquids, especially functionalized acidic ionic liquids, offer solutions for the above reactions through the flexible design of their anions and cations.

[0005] Functionalized ionic liquids can provide moderately strong and programmable Brønsted acidity. Compared to the aggressive approach of pentanoyl chloride, this acidic environment can more gently and specifically activate carboxylic acids, promoting transesterification reactions and effectively suppressing side reactions caused by highly reactive acyl chlorides, potentially improving reaction selectivity.

[0006] Ionic liquids can form specific microenvironments through structural design, and may enable reactions to take place in a more ordered and lower-energy state through weak interactions of reactant molecules such as hydrogen bonds and ion pairs, thereby further improving regioselectivity or chemoselectivity.

[0007] Ionic liquids can serve as homogeneous catalysts. After the reaction, the product can be separated from the ionic liquid by simply adding water or changing the temperature. Alternatively, the non-volatile nature of the ionic liquid allows for direct recovery of the product through vacuum distillation. This completely avoids the need for extensive water washing and the generation of triethylamine hydrochloride waste.

[0008] The separated ionic liquids can be directly recycled multiple times. Studies have shown that many acidic ionic liquids can be recycled 5-10 times or more in esterification reactions without a significant decrease in activity, which greatly reduces reagent costs and waste emissions.

[0009] Ionic liquids can simultaneously act as catalysts and reaction media, thereby reducing or even eliminating the use of volatile organic solvents (such as THF), making the process safer and greener. Replacing the pentanoyl chloride / triethylamine system with ionic liquids can transform a stoichiometric reaction into a catalytic reaction, requiring only a catalytic amount of ionic liquid to drive the reaction, resulting in high atom utilization and conforming to the principles of green chemistry.

[0010] Therefore, developing a new green synthesis method for pyridaben that can avoid the use of pentanoyl chloride, reduce or eliminate the generation of waste at the source, and maintain or improve reaction efficiency and selectivity has become a technical problem that urgently needs to be solved in this field. Summary of the Invention

[0011] (a) Technical problems to be solved

[0012] The present invention aims to overcome the above-mentioned defects of the existing pentanoyl chloride route and provide a novel strategy for the synthesis of pyridaben.

[0013] (II) Technical Solution

[0014] This invention provides a method for preparing cypermethrin as shown in formula (I).

[0015] ,

[0016] The method is characterized by comprising: reacting the intermediate shown in formula (I) with tervastatin in the presence of a functionalized acidic ionic liquid, and separating the pyridaben after the reaction is completed. The functionalized acidic ionic liquid serves simultaneously as a catalyst and a reaction medium for the reaction.

[0017] The functionalized acidic ionic liquid is a Brønsted acidic ionic liquid, and its anion is selected from dihydrogen phosphate (H2PO4). - ), hydrogen sulfate (HSO4) - ), p-Toluenesulfonate (TsO) - ), trifluoromethanesulfonate (CF3SO3) - At least one of the following: its cation is selected from at least one of imidazoles, pyridines, quaternary ammonium salts or quaternary phosphonium salts.

[0018] The functionalized acidic ionic liquid is preferably 1-butyl-3-methylimidazolium dihydrogen phosphate ([BMIM][H2PO4]) or 1-butyl-3-methylimidazolium hydrogen sulfate ([BMIM][HSO4]). After the reaction is completed, the product and ionic liquid are separated by the following steps: a) an organic extractant immiscible with water is added to the reaction mixture to extract the organic phase containing cyproterone; b) the organic phase is separated, dried, and concentrated to obtain a crude product; c) the crude product is purified to obtain pure cyproterone.

[0019] The organic extractant mentioned in step a) is diethyl ether, ethyl acetate, dichloromethane, methyl tert-butyl ether, or n-hexane; the purification method in step c) is recrystallization or column chromatography.

[0020] After separating the organic phase, the remaining ionic liquid phase is dried and / or distilled under reduced pressure to remove trace impurities and moisture, and then directly recycled for the next reaction.

[0021] The use of a functionalized acidic ionic liquid as a catalyst and reaction medium in the catalytic synthesis of pyridaben; said functionalized acidic ionic liquid is a Brønsted acidic ionic liquid, and its anion is selected from dihydrogen phosphate (H2PO4). - ), hydrogen sulfate (HSO4) - ), p-Toluenesulfonate (TsO) - ), trifluoromethanesulfonate (CF3SO3) - At least one of the following: its cation is selected from at least one of imidazoles, pyridines, quaternary ammonium salts or quaternary phosphonium salts.

[0022] The functionalized acidic ionic liquid is 1-butyl-3-methylimidazolium dihydrogen phosphate ([BMIM][H2PO4]) or 1-butyl-3-methylimidazolium hydrogen sulfate ([BMIM][HSO4]). The core concept of this invention is to abandon traditional highly reactive acyl chloride reagents and instead utilize terpentine as an inexpensive acyl donor, and to simultaneously activate carboxylic acids and provide an optimal reaction environment through a carefully designed functionalized acidic ionic liquid. This ionic liquid plays a triple role in this process:

[0023] 1. Acidic catalyst: Its acidic sites mildly and effectively activate the carboxyl group of pivalic acid, making it readily esterified / transesterified with the enol hydroxyl group of the intermediate of formula (I). This catalytic mode is more specific than the strong electrophilic attack of pivaloyl chloride, and can greatly suppress various side reactions caused by the high activity of acyl chloride.

[0024] 2. Advanced Reaction Media: Ionic liquids, through their designable cation and anion structures, create a solubility environment and microreaction field for reactants. Their polarity, hydrogen bonding ability, and steric properties can stabilize the reaction transition state through weakly interacting reactants, thereby thermodynamically and kinetically promoting the target reaction and enhancing selectivity.

[0025] 3. Separation aid: After the reaction is complete, the product pyridaben and the ionic liquid are significantly different in physical properties, and the product can be separated efficiently and cleanly by simple liquid-liquid extraction, while the ionic liquid phase is easy to recover.

[0026] As a preferred embodiment of the present invention:

[0027] The functionalized acidic ionic liquid is a Brønsted acidic ionic liquid, and its anion is selected from dihydrogen phosphate (H2PO4). - ), hydrogen sulfate (HSO4) - ), p-Toluenesulfonate (TsO) - ), trifluoromethanesulfonate (CF3SO3) - At least one of the following: its cation is selected from at least one of imidazoles, pyridines, quaternary ammonium salts or quaternary phosphonium salts.

[0028] More preferably, the ionic liquid is 1-butyl-3-methylimidazolium dihydrogen phosphate ([BMIM][H2PO4]) or 1-butyl-3-methylimidazolium hydrogen sulfate ([BMIM][H2PO4]).

[0029] The reaction is carried out without the addition of any external organic solvent, using only the functionalized acidic ionic liquid as the reaction medium. An inert organic solvent (such as toluene or xylene) may also be added as an aid, depending on the circumstances.

[0030] The reaction temperature is 60°C to 120°C, preferably 80°C to 100°C; the reaction time is 1 hour to 15 hours, preferably 2-10 hours.

[0031] The molar ratio of the intermediate of formula (I) to pivalic acid is 1:1 to 1:1.5. The amount of the functionalized acidic ionic liquid is 50% to 300% of the total mass of the reaction raw materials (the intermediate of formula I and pivalic acid), preferably 100% to 200%.

[0032] The separation process includes: adding an organic extractant that is immiscible with water to the mixture after the reaction is completed for extraction, and separating the organic phase containing pyridoxine; the organic extractant is preferably diethyl ether, ethyl acetate, dichloromethane, methyl tert-butyl ether or n-hexane.

[0033] After the organic phase is separated, the remaining ionic liquid phase, after drying and / or vacuum distillation, can be directly recycled for the next reaction. Preferably, the ionic liquid can be recycled more than 5 times without a significant decrease in activity. This invention provides a novel use of the functionalized acidic ionic liquid as a catalyst and reaction medium in the catalytic synthesis of cyproterone. Specifically, it is used to catalyze the reaction of the intermediate of formula (I) with terpentine to prepare cyproterone.

[0034] (III) Beneficial Effects

[0035] Compared with the prior art, the present invention has the following outstanding advantages:

[0036] 1. It fundamentally achieves greening by completely eliminating the high-risk and expensive pentanoyl chloride and stoichiometric organic bases, thereby eliminating the generation of HCl gas, viscous amine salt waste residue and amine-containing wastewater at the source, and significantly improving atom economy.

[0037] 2. The mild acidic catalysis and unique microenvironment provided by ionic liquids enhance reaction specificity and reduce byproducts. Examples show that product yields are consistently above 92%, and HPLC purity is greater than 99%, comparable to or even superior to existing processes.

[0038] 3. The process flow is greatly simplified. The reaction is homogeneous catalysis, and the post-treatment only requires simple extraction. This eliminates the cumbersome neutralization, water washing, and desalination steps in traditional processes, making operation simple and improving production efficiency.

[0039] 4. Ionic liquids can be efficiently recovered and recycled multiple times (>5 times), significantly reducing catalyst costs and waste disposal expenses per batch. Using inexpensive pentaponic acid instead of pentaponicoyl chloride further reduces raw material costs.

[0040] 5. It avoids the use of water-repellent reagents and the release of corrosive gases, reducing the requirements for production equipment and protection levels, and making the production environment safer. Attached Figure Description

[0041] Figure 1 This is a process flow diagram for the synthesis of pyridaben using tervastatin in this application;

[0042] Figure 2 HPLC analysis of the cyprodinil prepared in Example 3 of this application;

[0043] Figure 3 HPLC of cypermethrin prepared in Example 4 of this application. Detailed Implementation

[0044] To make the objectives, technical solutions, and advantages of this invention clearer, the embodiments of this invention will be described in detail below with reference to the examples. However, the scope of protection of this invention is not limited to the following embodiments.

[0045] To make the objectives, technical solutions, and advantages of the embodiments of this application clearer, the technical solutions in the embodiments of this application will be clearly and completely described below. Unless otherwise specified in the embodiments, the conditions shall be performed according to conventional conditions or conditions recommended by the manufacturer. Unless otherwise specified, the reagents or instruments used are all conventional products that can be purchased commercially. The intermediate of formula (I) is prepared by a preparation method known in the prior art (see Cheng Yan, Wu Hongfei, Luo Yanmei, et al. Synthesis and acaricidal activity of cyenopyrafen [J]. Modern Pesticides, 2019, 18(03):9-11).

[0046] Example 1: Preparation of Functionalized Acidic Ionic Liquid [BMIM][H2PO4]

[0047] Under nitrogen protection, 50.0 g of 1-methylimidazole and 100.1 g of 1-bromobutane were added to a dry reaction vessel. The temperature was controlled at 35±2℃, and the reaction was stirred continuously for 24 hours. After the reaction was completed, the mixture was transferred to a separatory funnel, washed thoroughly with 3×150 mL of anhydrous diethyl ether, and separated. The lower viscous liquid was collected and dried in a vacuum drying oven at 60℃ for 24 hours to obtain a pale yellow viscous [BMIM]Br intermediate.

[0048] Accurately weigh 110.0 g of the dried [BMIM]Br intermediate from the previous step and add it along with 35.3 g of deionized water to another reaction flask equipped with a condenser. Stir until completely dissolved. While stirring, slowly add 58.0 g of 85% phosphoric acid aqueous solution. After the addition is complete, raise the temperature to 90±2℃ and continue stirring for 36 hours. After the reaction is complete, transfer the product to a petri dish and dry it in a vacuum drying oven at 60℃ for 24 hours to remove residual water, obtaining a pale yellow to colorless transparent viscous liquid, which is the target ionic liquid [BMIM][[H2PO4].

[0049] Example 2: Preparation of Functionalized Acidic Ionic Liquid [BMIM][HSO4]

[0050] Under nitrogen protection, 41.0 g (0.50 mol) of 1-methylimidazolium and 50.9 g (0.55 mol) of n-chlorobutane were added to a dry 500 mL three-necked flask. A condenser and stirrer were installed, and the mixture was stirred until homogeneous. The mixture was then refluxed at 80 °C for 48 hours. After the reaction was complete, the flask was cooled to room temperature and allowed to stand for 12 hours to allow crystals to fully separate. The unreacted upper layer was carefully decanted. 160 mL of ethyl acetate was added to the remaining lower solid (or viscous substance), and the mixture was thoroughly washed and the washings were decanted. This washing operation was repeated twice (160 mL each time). The washed wet solids were combined and the residual ethyl acetate was removed by rotary evaporation at 80 °C to obtain a milky white to pale yellow solid. The solid was transferred to a vacuum drying oven and dried at 70 °C for 24 hours to obtain a high-purity 1-butyl-3-methylimidazolium chloride ([BMIM]Cl) intermediate.

[0051] The dried [BMIM]Cl intermediate (0.475 mol) was transferred entirely to a 250 mL single-necked flask. The flask was placed in an ice-water bath to cool. With vigorous stirring, approximately 25.3 mL (0.475 mol) of concentrated sulfuric acid was slowly added dropwise using a constant-pressure funnel. The dropping rate was controlled to ensure the temperature of the reaction mixture remained below 30°C. After the addition was complete, the ice-water bath was removed, and the reaction mixture was allowed to continue stirring at room temperature for 8 hours. The product obtained after the reaction was complete was the target ionic liquid, 1-butyl-3-methylimidazolium hydrogen sulfate ([BMIM][HSO4]).

[0052] Example 3: Synthesis of cypermethrin using [BMIM][H2PO4] catalysis

[0053] In a dry 100 mL round-bottom flask, accurately weigh 10.0 mmol (2.30 g) of compound (I) and 12 mmol (1.225 g) of pivalic acid. Then add 5.29 g of [BMIM][H2PO4] as a catalyst and medium. Place the flask on a magnetic stirrer, connect a condenser, start stirring, and heat in an oil bath to 80 °C.

[0054] The reaction was carried out under constant temperature reflux at 80°C. Capillary samples were taken every 2 hours, and the reaction progress was monitored by thin-layer chromatography (TLC) with petroleum ether:ethyl acetate = 3:1 as the developing solvent. The reaction was considered complete when the starting material spot essentially disappeared.

[0055] Turn off the heat and allow the reaction mixture to cool naturally to room temperature (25°C). Add 30 mL of diethyl ether to the cooled reaction mixture, shake thoroughly to extract, and allow to stand for separation. Transfer the upper ether phase to a separatory funnel. Repeat this extraction process twice, using 30 mL of diethyl ether each time. Combine the ether extracts.

[0056] Add an appropriate amount of anhydrous magnesium sulfate to the combined ether phases and dry for about 10 minutes. Filter to remove the drying agent. Distill the filtrate under reduced pressure on a rotary evaporator to remove the ether and obtain the crude product.

[0057] The crude product was purified by recrystallization to obtain high-purity pyridaben. The product mass was 2.76 g, with a yield of 92%. A small amount of the pure product was analyzed by high-performance liquid chromatography (HPLC), and the purity was greater than 99%.

[0058] The lower [BMIM][H2PO4] ionic liquid phase remaining after extraction was dried with a small amount of anhydrous magnesium sulfate and then filtered. It was then distilled under reduced pressure for 1-2 hours to remove trace organic impurities and water. The resulting clear [BMIM][H2PO4] ionic liquid was recovered.

[0059] The recovered [BMIM][H2PO4] ionic liquid was directly used in the next batch of cyproterone synthesis. This ionic liquid can be recycled more than 5 times, with the cyproterone yield remaining between 90% and 92% in each reaction and an HPLC purity >99%, demonstrating its excellent catalytic stability and recyclability.

[0060] Example 4: Synthesis of cyproterone acetate using [BMIM][HSO4] catalysis and ionic liquid cycling

[0061] Take 20 mL of [BMIM][HSO4] ionic liquid, add 10 g of 4 Å molecular sieve, seal, and bubble and stir with nitrogen for 48 hours for deep dehydration. Then, distill under reduced pressure at 60 °C for 1 hour to further remove trace amounts of water, ensuring that the water content is below 0.1%.

[0062] In a dry 100 mL three-necked flask, add 20 mL of the pretreated [BMIM][HSO4] ionic liquid. Then, add 21.6 g (0.094 mol) of compound (I) and 11.23 g (0.110 mol, molar ratio approximately 1:1.17) of pentovalinic acid sequentially. Stir and heat in an oil bath to 80 °C to initiate the reaction. During the reaction, take samples for TLC monitoring; the disappearance of the starting material spot indicates the reaction is complete. Cool the reaction solution to room temperature and transfer it to a 250 mL separatory funnel. Add 30 mL of diethyl ether, shake thoroughly, and allow to separate the layers. Separate the ether layer. Repeat the extraction with 30 mL of diethyl ether twice more. Combine all the ether extracts.

[0063] The combined ether extracts were dried with anhydrous magnesium sulfate for 10 minutes, filtered, and the ether was removed by vacuum distillation to obtain crude cypermethrin.

[0064] The crude product was purified by recrystallization to obtain high-purity cypermethrin. The product mass was 24 g, with a yield of 85.1%. A small amount of the pure product was analyzed by high-performance liquid chromatography (HPLC), and the purity was greater than 97%.

[0065] Referring to the classic method reported in the literature: In dry THF solvent, the intermediate of formula (I) and triethylamine are added, and tervapotranol chloride is slowly added dropwise under ice bath cooling. After the addition is complete, the reaction is brought to room temperature. During the reaction, a large amount of white fumes are produced, and a viscous white precipitate gradually forms, making stirring difficult. After the reaction is complete, a large amount of ice water needs to be added to quench the reaction, followed by washing with dilute hydrochloric acid, and then repeated washing of the organic phase with saturated sodium bicarbonate solution and water to remove triethylamine and its salts. The post-processing is cumbersome and generates a large amount of alkaline wastewater. Finally, after drying, concentration, and purification, the yield of pyridaben is approximately 85-88%, and the product purity often requires more refined purification due to byproducts.

[0066] The above examples and comparative examples fully demonstrate that the method for synthesizing pyridaben based on functionalized acidic ionic liquids provided by this invention not only meets industrial requirements in terms of product yield and purity (yield ≥ 92%, purity > 99%), but also achieves a qualitative leap in terms of safety, environmental friendliness, atom economy, and ease of operation in the production process. It successfully transforms a classical stoichiometric reaction with inherent defects into a highly efficient and green catalytic process, possessing significant industrial application value and environmental significance.

Claims

1. A method for preparing cypermethrin, characterized in that, Includes the following steps: In the presence of a functionalized acidic ionic liquid, the intermediate shown in formula (I) is reacted with tervastatin to obtain the pyridoxine; the functionalized acidic ionic liquid is 1-butyl-3-methylimidazolium dihydrogen phosphate ([BMIM][H2PO4]).

2. The method according to claim 1, characterized in that, The reaction temperature is 60°C to 120°C, and the reaction time is 2 to 15 hours.

3. The method according to claim 2, characterized in that, The molar ratio of the intermediate of formula (I) to tervastatin is 1:1 to 1:1.5; the amount of the functionalized acidic ionic liquid is 50% to 1000% of the total mass of the reaction raw materials.

4. The method according to claim 1, characterized in that, After the reaction is complete, the product and ionic liquid are separated by the following steps: a) an organic extractant that is immiscible with water is added to the reaction mixture to extract the organic phase containing cyproterone; b) the organic phase is separated, dried, and concentrated to obtain a crude product; c) the crude product is purified to obtain pure cyproterone.

5. The method according to claim 4, characterized in that, The organic extractant mentioned in step a) is diethyl ether, ethyl acetate, dichloromethane, methyl tert-butyl ether, or n-hexane; the purification method in step c) is recrystallization or column chromatography.

6. The method according to claim 4, characterized in that, After separating the organic phase, the remaining ionic liquid phase is dried and / or distilled under reduced pressure to remove trace impurities and moisture, and then directly recycled for the next reaction.

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