A process for preparing clofodoxaflutamide in a continuous flow microchannel

Abstract

The invention discloses a process method for preparing clofoconazole through a continuous flow microchannel, comprising four steps of etherification and acylation to prepare 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone, epoxidation to prepare 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane and ring-opening substitution to prepare clofoconazole. The process of the invention has key and dangerous process steps, and is prepared by using a continuous flow microreactor, has the advantages of good atom economy, high yield and preparation efficiency, and greatly improves the intrinsic safety of the process.

Description

Technical Field

[0001] The invention belongs to the technical field of pesticide technical preparation process, and particularly relates to a process for preparing clofodoxiconazole in a continuous flow microchannel. Background Art

[0002] Mefentrifluconazole (common name: Mefentrifluconazole, trade name: ) is a triazole fungicide developed by BASF. It is a C14-demethylation inhibitor in sterol biosynthesis and a new product of BASF with epoch-making significance. It has a broad spectrum, high efficiency, systemic, eradication and protection effect, especially has outstanding biological activity against a variety of fungal diseases that are difficult to control. It can significantly enhance the prevention and control of more than 60 field and economic crop diseases, such as field crops such as corn, grains, and soybeans, as well as economic crops such as green peppers and grapes. It can also be used for lawn and seed treatment. Compared with other fungicides, it not only has higher biological activity, but also has good environmental characteristics and is highly safe for mammals, bees, etc. Experiments show that the combination of clofoconazole and SDHI fungicides can delay fungicide resistance, such as the prevention and control of difficult-to-treat diseases on wheat, such as diseases caused by Septoria and yellow rust; in addition, clofoconazole is better than prothioconazole and fluphenazine, and has better environmental characteristics. BASF has submitted registration information for clofotriazole to 50 relevant agencies in Brazil, the United States, Canada, the European Union and Mexico.

[0003] The synthesis of chlorfluanidazole uses 2-bromo-4-fluoro-trifluorotoluene and 2-iodo-4-bromo-trifluorotoluene as starting materials, respectively. However, due to the relatively high price of 2-iodo-4-bromo-trifluorotoluene, 2-bromo-4-fluoro-trifluorotoluene is generally used as the starting material, and the target product is obtained through etherification, acylation, epoxidation and ring-opening substitution in four steps [patent: WO2013007767, CN103649057A, EP2731935 (A1)]. The target product chlorfluanidazole is synthesized by ring-opening substitution reaction of 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane and triazole as raw materials, and the equation is as follows:

[0004]

[0005] Among them: the intermediate 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane is the key intermediate for synthesizing chlorfluanidazole, trimethylsulfonium iodide and acetyl chloride are used in the synthesis process, and the synthesis method uses 2-bromo-5-fluoro-trifluorotoluene and 4-chlorophenol as starting materials to prepare 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene, and then uses 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene and acetyl chloride as intermediates to prepare 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone through acylation reaction, and then undergoes epoxidation reaction with trimethylsulfonium iodide reagent to obtain the target key intermediate 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane, and the specific reaction equation is as follows:

[0006]

[0007] Continuous flow micro-reaction technology is a multidisciplinary frontier in modern chemical engineering. Due to the miniaturization of its characteristic scale, it has the following advantages: (1) small equipment size, low liquid holding volume, and high equipment safety; (2) large specific surface area and high mass and heat transfer efficiency; (3) easy and precise control, which can realize continuous operation and direct scale-up, and is particularly suitable for rapid and highly exothermic reactions.

[0008] Based on the above reasons, existing literature reports that the key and dangerous process steps of chlorfluazol are intermittent synthesis processes. For example, the acylation and epoxidation reactions have large exothermicity and poor selectivity for ring-opening substitution, which results in the traditional industrialized and literature-reported process routes having problems such as poor process atom economy and selectivity, low yield and preparation efficiency, high inventory of reaction liquid in the process, and poor intrinsic safety of the process. The use of continuous flow micro-reaction technology can effectively solve the above problems. Summary of the invention

[0009] In view of the defects and shortcomings in the existing process technology, the purpose of the present invention is to provide a process for preparing clofothiazolin in a continuous flow microchannel, which can realize the precise and controllable continuous preparation of epoxidation, ring-opening substitution and acylation processes, and has the advantages of high intrinsic safety, good atom economy, high yield and preparation efficiency.

[0010] To achieve the above object, the present invention adopts the following technical scheme:

[0011] A process for preparing clofodoxiconazole in a continuous flow microchannel comprises etherification, acylation, epoxidation and ring-opening substitution reactions, specifically comprising the following steps:

[0012] Step 1: 2-bromo-5-fluoro-trifluorotoluene, 4-chlorophenol and an acid-binding agent are refluxed and heated to 70-150° C. in an organic solvent for reaction for 1-20 hours, and 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene is obtained by post-treatment, with a yield of ≥91% and a content of ≥95%;

[0013] Step 2: The organic solution of 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene and the organic solution of acetyl chloride obtained in step 1 are respectively introduced into a microchannel preheating module by metering pumps and heated to 10-50° C. The mass percentage concentration of the two solutions is 40%-90%, and the residence time is 10-30 seconds. The preheated raw materials are then introduced into a microchannel reaction module for reaction, the reaction temperature is 10-90° C., the residence time is 20-50 seconds, and the outflowing reaction liquid is post-treated to obtain the intermediate 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone;

[0014] Step 3: The organic solution of 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone with a mass percentage concentration of 10% to 70% and the trimethylsulfonium iodide solution with a mass percentage concentration of 10% to 50% obtained in step 2 are respectively introduced into a microchannel preheating module by a metering pump, the temperature is controlled at 0 to 20° C., and the residence time is 10 to 20 seconds; then the two are introduced into a microchannel reaction module for reaction, the residence time is 5 to 20 seconds, and the reaction temperature is 0 to 20° C. After the reaction is completed, the reaction liquid is continuously quenched with ammonium chloride in a microchannel quenching module, the temperature is controlled at 0 to 20° C., and the residence time is 5 to 15 seconds. After post-treatment, the quenched reaction liquid is subjected to an oily substance 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane;

[0015] Step 4: preheating a 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane solution with a mass percentage concentration of 10% to 90% and a triazole salt solution with a mass percentage concentration of 10% to 50% in a microchannel preheating module, the preheating temperature is 20 to 90° C., the residence time is 2 to 60 seconds, and the reaction continues to enter the next stage microchannel reactor, the reaction temperature is 40 to 150° C., the residence time is 5 to 60 seconds, the reaction is completed, and white solid chlorfenapyr is obtained through post-treatment.

[0016] Optionally, the acid binding agent in step 1 is selected from at least one of sodium hydroxide, sodium carbonate, metallic sodium, potassium carbonate, potassium hydroxide and sodium hydride;

[0017] The organic solvent is selected from at least one of acetone, toluene, dichloromethane, cyclohexane, ethanol, chlorobenzene, DMF, tetrahydrofuran, methyltetrahydrofuran, xylene and chloroform;

[0018] The molar ratio of 2-bromo-5-fluoro-trifluorotoluene: 4-chlorophenol and acid binding agent is 1: (1-1.5): (1-2.5).

[0019] Optionally, in step 2, the molar ratio of 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene to acetyl chloride is 1:(1.05-3);

[0020] The organic solvent is selected from at least one of ethyl acetate, toluene, dichloromethane, cyclohexane, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, dimethyl sulfoxide, xylene and chloroform.

[0021] Optionally, in step 3, the molar ratio of 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone, trimethylsulfonium iodide and ammonium chloride is 1:(1.2-2):(1.5-3); and the solvent is selected from at least one of dimethyl sulfoxide, tetrahydrofuran, methyltetrahydrofuran, DMF and water.

[0022] Optionally, in the step 4, the triazole salt solution is generated by reacting triazole and an acid binding agent in an organic solvent; the molar ratio of 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane:triazole:acid binding agent is 1:(1.1-1.5):(1.1-2.7); the acid binding agent is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydride and metallic sodium; the organic solvent is selected from at least one of ethyl acetate, toluene, dichloromethane, cyclohexane, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, dimethyl sulfoxide, xylene and chloroform; the solvent of the 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane solution in the step 4 is selected from at least one of DMF, DMSO, tetrahydrofuran, methyltetrahydrofuran, methylpyrrolidone, acetone, water, ethanol and methanol or a mixed solution thereof.

[0023] Compared with the prior art, the present invention has the following beneficial technical effects:

[0024] The device and process for preparing clofoconazole in a continuous flow microchannel of the present invention have the advantages of precise and controllable continuous preparation of etherification, acylation, epoxidation and ring-opening substitution process. The present invention realizes the continuous flow microchannel synthesis preparation of acylation, epoxidation and ring-opening substitution, and has the advantages of high intrinsic safety of the process, good atomic economy, high yield and preparation efficiency. BRIEF DESCRIPTION OF THE DRAWINGS

[0025] The accompanying drawings are used to provide a further understanding of the present disclosure and constitute a part of the specification. Together with the following specific embodiments, they are used to explain the present disclosure but do not constitute a limitation of the present disclosure. In the accompanying drawings:

[0026] Figure 1 Reaction process flow chart for preparing clofothiazolin in continuous flow microchannel. DETAILED DESCRIPTION

[0027] In summary of the above technical solutions, specific embodiments of the present invention are given below. It should be noted that the present invention is not limited to the following specific embodiments, and all equivalent changes made on the basis of the technical solutions of this application fall within the protection scope of the present invention.

[0028] Combination Figure 1 The process for preparing clofodoxiconazole in a continuous flow microchannel of the present invention comprises etherification, acylation, epoxidation and ring-opening substitution reactions, and comprises the following steps:

[0029] Step 1: 2-bromo-5-fluoro-trifluorotoluene, 4-chlorophenol and an acid-binding agent are refluxed in an organic solvent and heated to 70-150° C. for reaction for 1-20 hours to obtain 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene with a yield of ≥91% and a content of ≥95%;

[0030] Step 2: The organic solution of 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene and the organic solution of acetyl chloride obtained in step 1 are respectively introduced into a microchannel preheating module by a metering pump and heated to 10-50° C., the mass fraction of the organic solution is 40%-90% respectively, and the residence time is 10-30s. The preheated raw materials are then introduced into a microchannel reaction module for reaction, the reaction temperature is 10-90° C., the residence time is 20-50s, and the outflowing reaction liquid is post-treated to obtain the intermediate 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone, the yield is ≥92%, and the content is ≥95%;

[0031] Step 3: The organic solution of 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone (mass fraction of 10% to 70%) and the solution of trimethylsulfonium iodide (mass fraction of 10% to 50%) obtained in step 2 are respectively introduced into a microchannel preheating module by metering pumps, the temperature is controlled at 0 to 20° C., and the residence time is 10 to 20 seconds; then the two are introduced into a microchannel reaction module for reaction, the residence time is 5 to 20 seconds, and the reaction temperature is 0 to 20° C. After the reaction, the reaction liquid is continuously quenched with ammonium chloride in a microchannel quenching module, the temperature is controlled at 0 to 20° C., the residence time is 5 to 15 seconds, and the quenched reaction liquid is post-treated to obtain an oily substance 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane, with a yield of ≥92% and a content of ≥95%;

[0032] Step 4: preheating a 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane solution with a mass fraction of 10% to 90% and a triazole salt solution with a mass fraction of 10% to 50% (triazole and an acid binding agent react in an organic solvent to generate a salt solution) in a microchannel preheating module, the preheating temperature is 20 to 90° C., the residence time is 2 to 60 seconds, and the reaction continues to enter the next stage microchannel reactor for reaction, the reaction temperature is 40 to 150° C., the residence time is 5 to 60 seconds, the reaction is completed, and a white solid chlorfenapyr is obtained after post-treatment, the product yield is ≥91%, and the content is ≥97%;

[0033] In an embodiment of the present disclosure, in step 1, the acid binding agent is selected from at least one of sodium hydroxide, sodium carbonate, metallic sodium, potassium carbonate, potassium hydroxide and sodium hydride; the organic solvent is selected from at least one of acetone, toluene, dichloromethane, cyclohexane, ethanol, chlorobenzene, DMF, tetrahydrofuran, methyltetrahydrofuran, xylene and chloroform; the molar ratio of 2-bromo-5-fluoro-trifluorotoluene: 4-chlorophenol and the acid binding agent is: 1: (1 to 1.5): (1 to 2.5).

[0034] In an embodiment of the present disclosure, the molar ratio of 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene to acetyl chloride in step 2 is 1:(1.05-3); the organic solvent is selected from at least one of ethyl acetate, toluene, dichloromethane, cyclohexane, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, dimethyl sulfoxide, xylene and chloroform;

[0035] In an embodiment of the present disclosure, the molar ratio of 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone, trimethylsulfonium iodide and ammonium chloride in step 3 is 1:(1.2-2):(1.5-3); the solvent is selected from at least one of dimethyl sulfoxide, tetrahydrofuran, methyltetrahydrofuran, DMF and water.

[0036] In an embodiment of the present disclosure, in step 4, the molar ratio of 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane solution: triazole: acid binding agent is: 1:(1.1-1.5):(1.1-2.7); the solvent of the 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane solution in step 4 is selected from at least one of DMF, DMSO, tetrahydrofuran, methyltetrahydrofuran, methylpyrrolidone, acetone, water, ethanol and methanol, or a mixed solution thereof; the acid binding agent is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydride and metallic sodium.

[0037] Embodiment 1:

[0038] This embodiment provides a process for preparing clofoconazole in a continuous flow microchannel. The process is implemented by the following process route, comprising four steps of etherification and acylation to prepare 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone, cyclization to prepare 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane, and ring-opening substitution to prepare clofoconazole, specifically comprising the following steps:

[0039] Step 1: 2-bromo-5-fluoro-trifluorotoluene, 4-chlorophenol and potassium carbonate are refluxed and heated at 70°C in acetone for 4 hours, wherein the molar ratio of 2-bromo-5-fluoro-trifluorotoluene: 4-chlorophenol: potassium carbonate and acetone is 1:1.2:1.3. After the reflux reaction is completed, the intermediate 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene is obtained by post-treatment such as concentration, washing and drying, with a yield of 91% and a content of 96%.

[0040] Step 2: The n-hexane solutions of 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene and acetyl chloride obtained in step 1 are respectively introduced into a microchannel preheating module by a metering pump and heated to 40° C., the mass content of the organic solution is 40% and the residence time is 20 seconds. The preheated raw materials are then introduced into a microchannel reaction module for reaction at a reaction temperature of 90° C. and a residence time of 30 seconds, wherein the molar ratio of 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene to acetyl chloride is 1:1.5; the reaction liquid flowing out of the microchannel reaction module is post-treated to obtain an intermediate 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone, with a yield of 94% and a content of 96%;

[0041] Step 3: The dimethyl sulfoxide solution (mass content 20%) of 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone and the dimethyl sulfoxide solution (mass content 35%) of trimethylsulfonium iodide obtained in step 2 are respectively introduced into the microchannel preheating module by metering pumps, the temperature is controlled at 15°C, the residence time is 15s, and then the two are introduced into the microchannel reaction module for reaction, the residence time is 20s, the reaction temperature is 17°C, and after the reaction, the reaction solution is continuously reacted with methyl The ammonium chloride solution of tert-butyl ether is quenched in a microchannel quenching module, the temperature is controlled at 0°C, the residence time is 10s, and the quenched reaction solution is post-treated to obtain an oily substance 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane, wherein the molar ratio of 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone: trimethylsulfonium iodide and ammonium chloride is 1:1.5:2, the yield is 92.7%, and the content is 93%;

[0042] Step 4: preheating 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane methylpyrrolidone (mass content 50%) and triazole salt solution (methylpyrrolidone solution of triazole and potassium hydroxide, mass content 15%) in a microchannel preheating module, the preheating temperature is 70°C, the residence time is 5s, and then continuing to enter the next stage microchannel reactor for reaction, the reaction temperature is 100°C, the residence time is 10s, the reaction is completed, and white solid chlorfluanidazole is obtained by post-treatment, wherein the molar ratio of 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane: triazole and potassium carbonate is 1:1.3:1.5, the yield is 93%, and the content is 98%.

[0043] Embodiment 2:

[0044] This embodiment provides a process for preparing clofoconazole in a continuous flow microchannel. The process is implemented by the following process route, comprising four steps of etherification and acylation to prepare 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone, cyclization to prepare 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane, and ring-opening substitution to prepare clofoconazole, specifically comprising the following steps:

[0045] Step 1: 2-bromo-5-fluoro-trifluorotoluene, 4-chlorophenol and potassium carbonate are refluxed and heated at 80°C in acetone for 3 hours, wherein the molar ratio of 2-bromo-5-fluoro-trifluorotoluene: 4-chlorophenol: potassium carbonate and methyltetrahydrofuran is 1:1.1:1.3. After the reflux reaction is completed, the intermediate 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene is obtained by post-treatment such as concentration, washing and drying, with a yield of 92.4% and a content of 97%;

[0046] Step 2: The methyltetrahydrofuran solutions of 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene and acetyl chloride obtained in step 1 are respectively introduced into a microchannel preheating module by a metering pump and heated to 50° C., the mass content of the organic solution is 20% and the residence time is 30 seconds. The preheated raw materials are then introduced into a microchannel reaction module for reaction at a reaction temperature of 80° C. and a residence time of 40 seconds, wherein the molar ratio of 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene to acetyl chloride is 1:1.5, and the reaction liquid flowing out of the microchannel reaction module is post-treated to obtain an intermediate 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone, with a yield of 93% and a content of 95%;

[0047] Step 3: The dimethyl sulfoxide solution (mass content 20%) of 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone and the dimethyl sulfoxide solution (mass content 30%) of trimethylsulfonium iodide obtained in step 2 are respectively introduced into the microchannel preheating module by metering pumps, the temperature is controlled at 10°C, the residence time is 20s, and then the two are introduced into the microchannel reaction module for reaction, the residence time is 20s, the reaction temperature is 20°C, and after the reaction, the reaction solution is continued to react with The ammonium chloride solution of methyl tert-butyl ether is quenched in a microchannel quenching module, the temperature is controlled at 5°C, the residence time is 10s, and the quenched reaction solution is post-treated to obtain an oily substance 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane, wherein the molar ratio of 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone: trimethylsulfonium iodide and ammonium chloride is 1:1.5:2, the yield is 92.3%, and the content is 95%

[0048] Step 4: preheating 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane in DMF (50% by mass) and triazole salt solution (methylpyrrolidone solution of triazole and potassium hydroxide, 20% by mass) in a microchannel preheating module at a preheating temperature of 90° C. and a residence time of 20 s, and then continuing to enter the next stage microchannel reactor for reaction at a reaction temperature of 110° C. and a residence time of 15 s. After the reaction is completed, a white solid chlorfluanidazole is obtained after post-treatment, wherein the molar ratio of 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane: triazole and sodium carbonate is 1:1.3:1.5, the yield is 91.9%, and the content is 97%.

[0049] Embodiment 3:

[0050] This embodiment provides a process for preparing clofoconazole in a continuous flow microchannel. The process is implemented by the following process route, comprising four steps of etherification and acylation to prepare 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone, cyclization to prepare 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane, and ring-opening substitution to prepare clofoconazole, specifically comprising the following steps:

[0051] Step 1: 2-bromo-5-fluoro-trifluorotoluene, 4-chlorophenol and potassium carbonate are refluxed and heated at 75°C in tetrahydrofuran for 6 hours, wherein the molar ratio of 2-bromo-5-fluoro-trifluorotoluene: 4-chlorophenol and potassium carbonate is 1:1.1:1.5. After the reflux reaction is completed, the intermediate 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene is obtained by post-treatment such as concentration, washing and drying, with a yield of 91% and a content of 95.7%;

[0052] Step 2: The tetrahydrofuran solutions of 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene and acetyl chloride obtained in step 1 are respectively introduced into a microchannel preheating module by a metering pump and heated to 40°C, the mass content of the organic solution is 25%, and the residence time is 30s. The preheated raw materials then enter the microchannel reaction module for reaction, the reaction temperature is °C, the residence time is 35s, wherein the molar ratio of 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene and acetyl chloride is: 1:1.5, and the reaction liquid flowing out of the microchannel reaction module is post-treated to obtain the intermediate 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone, the yield is 92%, and the content is 96%;

[0053] Step 3: The dimethyl sulfoxide solution (mass content 30%) of 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone and the dimethyl sulfoxide solution (mass content 20%) of trimethylsulfonium iodide obtained in step 2 are respectively introduced into the microchannel preheating module by metering pumps, the temperature is controlled at 15°C, the residence time is 20s, and then the two are introduced into the microchannel reaction module for reaction, the residence time is 20s, the reaction temperature is 20°C, and after the reaction, the reaction solution is continuously reacted with methyl The ammonium chloride solution of tert-butyl ether is quenched in a microchannel quenching module, the temperature is controlled at 5°C, the residence time is 10s, and the quenched reaction solution is post-treated to obtain an oily substance 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane, wherein the molar ratio of 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone: trimethylsulfonium iodide and ammonium chloride is: 1:1.7:2.3, the yield is 92.3%, and the content is 95%

[0054] Step 4: preheating 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane in DMSO (50% by mass) and triazole salt solution (methylpyrrolidone solution of triazole and potassium hydroxide, 20% by mass) in a microchannel preheating module at a preheating temperature of 70°C and a residence time of 20s, and then continuing to enter the next-stage microchannel reactor for reaction at a reaction temperature of 110°C and a residence time of 20s. After the reaction is completed, post-treatment is performed to obtain white solid chlorfluanidazole, wherein the molar ratio of 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane: triazole and sodium carbonate is 1:1.4:2, the yield is 93%, and the content is 97.8%.

[0055] Embodiment 4:

[0056] This embodiment provides a process for preparing clofoconazole in a continuous flow microchannel. The process is implemented by the following process route, comprising four steps of etherification and acylation to prepare 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone, cyclization to prepare 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane, and ring-opening substitution to prepare clofoconazole, specifically comprising the following steps:

[0057] Step 1: heating 2-bromo-5-fluoro-trifluorotoluene, 4-chlorophenol and potassium carbonate in acetone at 70°C for 10 hours, wherein the molar ratio of 2-bromo-5-fluoro-trifluorotoluene: 4-chlorophenol and potassium carbonate is 1:1.1:2.5. After the reflux reaction is completed, the intermediate 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene is obtained by post-treatment such as concentration, washing and drying, with a yield of 93% and a content of 95.7%;

[0058] Step 2: The dichloromethane solutions of 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene and acetyl chloride obtained in step 1 are respectively introduced into a microchannel preheating module by a metering pump and heated to 40°C, the mass content of the organic solution is 25%, and the residence time is 30s. The preheated raw materials then enter the microchannel reaction module for reaction, the reaction temperature is °C, the residence time is 35s, wherein the molar ratio of 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene and acetyl chloride is: 1:2, and the reaction liquid flowing out of the microchannel reaction module is post-treated to obtain the intermediate 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone, the yield is 94%, and the content is 95%;

[0059] Step 3: The dimethyl sulfoxide solution (mass content 30%) of 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone and the dimethyl sulfoxide solution (mass content 20%) of trimethylsulfonium iodide obtained in step 2 are respectively introduced into the microchannel preheating module by metering pumps, the temperature is controlled at 20°C, the residence time is 20s, and then both are introduced into the microchannel reaction module for reaction, the residence time is 15s, the reaction temperature is 20°C, and after the reaction, the reaction solution is continued to react with The ammonium chloride solution of methyl tert-butyl ether is quenched in a microchannel quenching module, the temperature is controlled at 15°C, the residence time is 15s, and the quenched reaction solution is post-treated to obtain an oily substance 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane, wherein the molar ratio of 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone: trimethylsulfonium iodide and ammonium chloride is: 1:2:2.3, the yield is 93%, and the content is 96%

[0060] Step 4: preheating 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane in DMF (40% by mass) and triazole salt solution (methylpyrrolidone solution of triazole and sodium hydroxide, 20% by mass) in a microchannel preheating module at a preheating temperature of 90° C. and a residence time of 60 s, and then continuing to react in the next microchannel reactor at a reaction temperature of 110° C. and a residence time of 50 s. After the reaction is completed, a white solid chlorfluanidazole is obtained after post-treatment, wherein the molar ratio of 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane: triazole and sodium carbonate is 1:1.5:2.5, the yield is 92%, and the content is 98%.

[0061] Embodiment 5:

[0062] This embodiment provides a process for preparing clofoconazole in a continuous flow microchannel. The process is implemented by the following process route, comprising four steps of etherification and acylation to prepare 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone, cyclization to prepare 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane, and ring-opening substitution to prepare clofoconazole, specifically comprising the following steps:

[0063] Step 1: heating 2-bromo-5-fluoro-trifluorotoluene, 4-chlorophenol and potassium carbonate in acetone at 70°C for 10 hours, wherein the molar ratio of 2-bromo-5-fluoro-trifluorotoluene: 4-chlorophenol and potassium carbonate is 1:1.05:2. After the reflux reaction is completed, the intermediate 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene is obtained by post-treatment such as concentration, washing and drying, with a yield of 91% and a content of 95%;

[0064] Step 2: The dichloromethane solutions of 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene and acetyl chloride obtained in step 1 are respectively introduced into a microchannel preheating module by a metering pump and heated to 40°C, wherein the mass content of the organic solution is 25% and the residence time is 30s. The preheated raw materials are then introduced into a microchannel reaction module for reaction, the reaction temperature is °C, the residence time is 35s, wherein the molar ratio of 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene to acetyl chloride is 1:1.2, and the reaction liquid flowing out of the microchannel reaction module is post-treated to obtain an intermediate 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone, with a yield of 92% and a content of 95%;

[0065] Step 3: The dimethyl sulfoxide solution (mass content 30%) of 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone and the dimethyl sulfoxide solution (mass content 20%) of trimethylsulfonium iodide obtained in step 2 are respectively introduced into the microchannel preheating module by metering pumps, the temperature is controlled at 20°C, the residence time is 20s, and then both are introduced into the microchannel reaction module for reaction, the residence time is 15s, the reaction temperature is 20°C, and after the reaction, the reaction solution is continuously reacted with methyl The ammonium chloride solution of tert-butyl ether was quenched in a microchannel quenching module, the temperature was controlled at 15°C, the residence time was 15s, and the quenched reaction solution was post-treated to obtain an oily substance 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane, wherein the molar ratio of 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone: trimethylsulfonium iodide and ammonium chloride was 1:1.2:1.5, the yield was 92%, and the content was 96.1%

[0066] Step 4: preheating 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane in DMF (40% by mass) and triazole salt solution (methylpyrrolidone solution of triazole and sodium hydroxide, 20% by mass) in a microchannel preheating module at a preheating temperature of 90° C. and a residence time of 60 s, and then continuing to react in a next-stage microchannel reactor at a reaction temperature of 110° C. and a residence time of 50 s. After the reaction is completed, post-treatment is performed to obtain a white solid chlorfluanidazole, wherein the molar ratio of 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane: triazole and sodium carbonate is 1:1.1:1.1, the yield is 92%, and the content is 97%.

[0067] Embodiment 6:

[0068] This embodiment provides a process for preparing clofoconazole in a continuous flow microchannel. The process is implemented by the following process route, comprising four steps of etherification and acylation to prepare 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone, cyclization to prepare 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane, and ring-opening substitution to prepare clofoconazole, specifically comprising the following steps:

[0069] Step 1: heating 2-bromo-5-fluoro-trifluorotoluene, 4-chlorophenol and potassium carbonate in acetone at 70°C for 20 hours, wherein the molar ratio of 2-bromo-5-fluoro-trifluorotoluene: 4-chlorophenol and potassium carbonate is 1:1.1:2.5. After the reflux reaction is completed, the intermediate 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene is obtained by post-treatment such as concentration, washing and drying, with a yield of 94% and a content of 96%.

[0070] Step 2: The dichloromethane solutions of 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene and acetyl chloride obtained in step 1 are respectively introduced into a microchannel preheating module by a metering pump and heated to 40°C, wherein the mass content of the organic solution is 25% and the residence time is 30s. The preheated raw materials are then introduced into a microchannel reaction module for reaction, the reaction temperature is °C, the residence time is 50s, wherein the molar ratio of 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene to acetyl chloride is 1:2, and the reaction liquid flowing out of the microchannel reaction module is post-treated to obtain an intermediate 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone, with a yield of 92% and a content of 97.1%;

[0071] Step 3: The dimethyl sulfoxide solution (mass content 30%) of 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone and the dimethyl sulfoxide solution (mass content 50%) of trimethylsulfonium iodide obtained in step 2 are respectively introduced into the microchannel preheating module by metering pumps, the temperature is controlled at 15°C, the residence time is 20s, and then the two are introduced into the microchannel reaction module for reaction, the residence time is 15s, the reaction temperature is 20°C, and after the reaction, the reaction solution is continuously reacted with methyl The ammonium chloride solution of tert-butyl ether is quenched in a microchannel quenching module, the temperature is controlled at 15°C, the residence time is 15s, and the quenched reaction solution is post-treated to obtain an oily substance 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane, wherein the molar ratio of 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone: trimethylsulfonium iodide and ammonium chloride is: 1:2:2.1, the yield is 93%, and the content is 95.1%

[0072] Step 4: preheating 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane in DMF (40% by mass) and triazole salt solution (methylpyrrolidone solution of triazole and sodium hydroxide, 20% by mass) in a microchannel preheating module at a preheating temperature of 90° C. and a residence time of 60 s, and then continuing to react in the next microchannel reactor at a reaction temperature of 130° C. and a residence time of 50 s. After the reaction is completed, a white solid chlorfluanidazole is obtained after post-treatment, wherein the molar ratio of 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane: triazole and sodium carbonate is 1:1.5:2.3, the yield is 94%, and the content is 98%.

[0073] The preferred embodiments of the present disclosure are described in detail above; however, the present disclosure is not limited to the specific details in the above embodiments. Within the technical concept of the present disclosure, a variety of simple modifications can be made to the technical solution of the present disclosure, and these simple modifications all fall within the protection scope of the present disclosure.

[0074] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present disclosure will not further describe various possible combinations.

[0075] In addition, various embodiments of the present disclosure may be arbitrarily combined, and as long as they do not violate the concept of the present disclosure, they should also be regarded as the contents disclosed by the present disclosure.

Claims

1. A process for preparing clofodoxiconazole in a continuous flow microchannel, comprising etherification, acylation, epoxidation and ring-opening substitution reactions, characterized in that: The specific steps include: Step 1: 2-bromo-5-fluoro-trifluorotoluene, 4-chlorophenol and an acid-binding agent are refluxed and heated to 70-150° C. in an organic solvent for reaction for 1-20 hours, and 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene is obtained by post-treatment, with a yield of ≥91% and a content of ≥95%; Step 2: The organic solution of 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene and the organic solution of acetyl chloride obtained in step 1 are respectively introduced into a microchannel preheating module by metering pumps and heated to 10-50° C. The mass percentage concentration of the two solutions is 40%-90%, and the residence time is 10-30 seconds. The preheated raw materials are then introduced into a microchannel reaction module for reaction, the reaction temperature is 10-90° C., the residence time is 20-50 seconds, and the outflowing reaction liquid is post-treated to obtain the intermediate 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone; Step 3: The organic solution of 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone with a mass percentage concentration of 10% to 70% and the trimethylsulfonium iodide solution with a mass percentage concentration of 10% to 50% obtained in step 2 are respectively introduced into a microchannel preheating module by a metering pump, the temperature is controlled at 0 to 20° C., and the residence time is 10 to 20 seconds; then the two are introduced into a microchannel reaction module for reaction, the residence time is 5 to 20 seconds, and the reaction temperature is 0 to 20° C. After the reaction is completed, the reaction liquid is continuously quenched with ammonium chloride in a microchannel quenching module, the temperature is controlled at 0 to 20° C., and the residence time is 5 to 15 seconds. After post-treatment, the quenched reaction liquid is subjected to an oily substance 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane; Step 4: preheating a 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane solution with a mass percentage concentration of 10% to 90% and a triazole salt solution with a mass percentage concentration of 10% to 50% in a microchannel preheating module, the preheating temperature is 20 to 90° C., the residence time is 2 to 60 seconds, and the reaction continues to enter the next stage microchannel reactor, the reaction temperature is 40 to 150° C., the residence time is 5 to 60 seconds, the reaction is completed, and a white solid chlorfenapyr is obtained through post-treatment; In the step 1, the acid binding agent is selected from at least one of sodium hydroxide, sodium carbonate, metallic sodium, potassium carbonate, potassium hydroxide and sodium hydride; the organic solvent is selected from at least one of acetone, toluene, dichloromethane, cyclohexane, ethanol, chlorobenzene, DMF, tetrahydrofuran, methyltetrahydrofuran, xylene and chloroform; the molar ratio of 2-bromo-5-fluoro-trifluorotoluene: 4-chlorophenol and the acid binding agent is: 1: (1-1.5): (1-2.5); In the step 2, the molar ratio of 1-bromo-4-(4-chlorophenoxy)-2-(trifluoromethyl)benzene to acetyl chloride is 1:(1.05-3); the organic solvent is selected from at least one of ethyl acetate, toluene, dichloromethane, cyclohexane, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, dimethyl sulfoxide, xylene and chloroform; In the step 3, the molar ratio of 1-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]ethanone, trimethylsulfonium iodide and ammonium chloride is 1:(1.2-2):(1.5-3); the solvent is selected from at least one of dimethyl sulfoxide, tetrahydrofuran, methyltetrahydrofuran, DMF and water; In the step 4, the triazole salt solution is generated by reacting triazole and an acid binding agent in an organic solvent; the molar ratio of 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane:triazole:acid binding agent is 1:(1.1-1.5):(1.1-2.7); the acid binding agent is selected from at least one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, potassium bicarbonate, sodium hydride and metallic sodium; the organic solvent is selected from at least one of ethyl acetate, toluene, dichloromethane, cyclohexane, chlorobenzene, tetrahydrofuran, methyltetrahydrofuran, dimethyl sulfoxide, xylene and chloroform; the solvent of the 2-[4-(4-chlorophenoxy)-2-trifluoromethylphenyl]-2-methyloxirane solution in the step 4 is selected from at least one of DMF, DMSO, tetrahydrofuran, methyltetrahydrofuran, methylpyrrolidone, acetone, water, ethanol and methanol or a mixed solution thereof.

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