Continuous production system and continuous production method of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole

Abstract

The invention provides a continuous production system of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole and a continuous production method of the 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole. The continuous production system comprises a continuous cyclization reaction unit, a continuous difluoromethylation reaction unit and a continuous chloromethylation reaction unit. The continuous cyclization reaction unit is used for carrying out continuous cyclization reaction on ethyl trifluoroacetoacetate and a methylhydrazine aqueous solution under the catalysis of a first catalyst; the continuous difluoromethylation reaction unit is used for carrying out continuous difluoromethylation reaction on the cyclization reaction product and monochlorodifluoromethane in a solvent under the catalysis of a second catalyst; and the continuous chloromethylation reaction unit is used for carrying out continuous chloromethylation reaction on the difluoromethylation product, hydrochloric acid and a formaldehyde aqueous solution under the catalysis of a third catalyst to obtain a target product. By adopting the continuous production system, the feasibility of a continuous process can be improved, and the production efficiency and the production safety can be improved.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a continuous production system and a continuous production method of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole. Background Art

[0002] 5-(Difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole (CAS: 656825-76-2), with a molecular formula of C7H6ClF5N2O, is an oily liquid at room temperature, with low water solubility and good solubility in organic solvents (such as ether, ketone and alcohol), and also has certain chemical stability. This compound is an important intermediate for the synthesis of sulfone pyrazole.

[0003] Patent WO2020240392A1 discloses a synthetic route for 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole, which is prepared from ethyl trifluoroacetoacetate by cyclization reaction, hydroxymethylation reaction, difluoromethoxylation reaction and chlorination reaction. The preparation process has four steps, especially in step 4, thionyl chloride is used as a chlorination reagent. Thionyl chloride will release polluting gases such as sulfur dioxide, and the release of a large amount of acidic gas will increase the safety risk of the reaction system; and although the above production process uses a continuous reactor, it does not describe the post-reaction treatment method and the connection between multiple continuous reaction steps. If the post-treatment still uses a batch process, the labor intensity is high, the production efficiency is low, and the equipment utilization rate is low, which cannot be applied to large-scale production.

[0004] Patent IN202141025919A discloses a process for preparing 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole, which uses ethyl trifluoroacetoacetate as a raw material and is prepared by cyclization reaction, difluoromethoxylation reaction and chloromethylation reaction in sequence. However, the difluoromethylation step in this route uses sodium 2,2-difluoro-2-chloroacetate as a difluoromethylation reagent, which is expensive. Therefore, this synthetic route has no practical application value for the large-scale production of pesticide products, and the yield of its chloromethylation step is low, only 82%.

[0005] In addition, intermittent reactions usually require excess raw materials to ensure the main reaction, thereby increasing raw material consumption and production costs. At the same time, due to the low heat exchange efficiency of the intermittent reactor, the reaction conditions cannot be accurately controlled, which can easily lead to side reactions, thereby reducing the yield and purity of the target product; in particular, the above-mentioned synthesis route involves the use of a variety of hazardous chemicals (such as thionyl chloride, methylhydrazine aqueous solution, sulfuric acid, hydrochloric acid, etc.), and batch processing of these hazardous chemicals is likely to cause safety hazards.

[0006] In summary, a continuous production system and a continuous production method of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole with high production efficiency, low material cost, few side reactions, high degree of automation, high equipment utilization and high safety have been studied and developed, which is of great significance to the industrial production and application of sulfone pyrazole. Summary of the invention

[0007] The main purpose of the present invention is to provide a continuous production system and a continuous production method of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole, so as to solve the problems of low production efficiency, low equipment utilization, poor safety and low yield due to poor heat exchange efficiency and many side reactions in the production process of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole in the prior art.

[0008] In order to achieve the above-mentioned object, the present invention provides a continuous production system of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole on the one hand, wherein the continuous production system comprises: a continuous cyclization reaction unit, a continuous difluoromethylation reaction unit and a continuous chloromethylation reaction unit. The continuous cyclization reaction unit is used to cause ethyl trifluoroacetoacetate and a methylhydrazine aqueous solution to undergo a continuous cyclization reaction under the catalysis of a first catalyst to obtain a first product system containing a cyclization reaction product, and the first product system is sequentially subjected to continuous quenching, a first continuous concentration and a first continuous solid-liquid separation to obtain a cyclization reaction product; the continuous cyclization reaction unit comprises a first continuous feeding module, a continuous cyclization reaction device, a continuous quenching device, a first continuous concentration device and a first continuous solid-liquid separation device which are connected in sequence; the first continuous solid-liquid separation device is provided with a cyclization reaction product outlet; the continuous difluoromethylation reaction unit is used to cause the cyclization reaction product and monochlorodifluoromethane to undergo a continuous difluoromethylation reaction in a solvent under the catalysis of a second catalyst to obtain a second product system containing a difluoromethylated product, and the second product system is sequentially subjected to a second continuous solid-liquid separation and a second continuous concentration to obtain a difluoromethylated product; the continuous difluoromethylation reaction unit comprises a second continuous feeding module, a continuous difluoromethylation reaction device, a second continuous A solid-liquid separation device and a second continuous concentration device; the inlet of the second continuous feeding module is connected to the outlet of the cyclization reaction product; the second continuous concentration device is provided with a difluoromethylation product outlet; the continuous chloromethylation reaction unit is used to cause the difluoromethylation product, hydrochloric acid and formaldehyde aqueous solution to undergo continuous chloromethylation reaction under the catalysis of a third catalyst to obtain a third product system containing a target product, and the third product system is subjected to a first continuous liquid separation, a continuous water washing and a second continuous liquid separation in sequence to obtain 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole; the continuous chloromethylation reaction unit comprises a third continuous feeding module, a continuous chloromethylation reaction device, a first continuous liquid separation device, a continuous water washing device and a second continuous liquid separation device connected in sequence; the inlet of the third continuous feeding module is connected to the outlet of the difluoromethylation product; the second continuous liquid separation device is provided with a target product outlet for discharging 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole.

[0009] In order to achieve the above-mentioned purpose, another aspect of the present invention further provides a continuous production method of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole, and the above-mentioned continuous production system provided by the present application is used to continuously produce 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole. The continuous production method comprises: step S1, using a first continuous feeding module to pass ethyl trifluoroacetoacetate, a first catalyst and a methylhydrazine aqueous solution into a continuous cyclization reaction device for continuous cyclization reaction to obtain a first product system containing a cyclization reaction product; sequentially using a continuous quenching device, a first continuous concentrating device and a first continuous solid-liquid separation device to continuously quench, first continuously concentrate and first continuously solid-liquid separate the first product system to obtain a cyclization reaction product; step S2, using a second continuous feeding module to pass the cyclization reaction product, a second catalyst, a solvent and monochlorodifluoromethane into a continuous difluoromethylation reaction device for continuous difluoromethylation reaction to obtain a second product system containing a difluoromethylation reaction product. system; sequentially using a second continuous solid-liquid separation device and a second continuous concentration device to perform a second continuous solid-liquid separation and a second continuous concentration on the second product system to obtain a difluoromethylation reaction product; step S3, using a third continuous feeding module to pass the difluoromethylation reaction product, a third catalyst, hydrochloric acid and a formaldehyde aqueous solution into a continuous chloromethylation reaction device for continuous chloromethylation reaction to obtain a third product system containing a target product; sequentially using a first continuous liquid separation device, a continuous water washing device and a second continuous liquid separation device to perform a first continuous liquid separation, a continuous water washing and a second continuous liquid separation on the third product system to obtain 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole.

[0010] By using the technical solution of the present invention, compared with the prior art of preparing 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole by four-step reaction, the above-mentioned continuous production system provided by the present application can reduce the synthesis route to three steps, which can improve production efficiency, and avoid the use of highly polluting thionyl chloride as a chlorination reagent, which is more environmentally friendly and safer. Compared with the three-step synthesis route reported, the advantage of the present application is reflected in the control of cost, that is, the use of cheaper monochlorodifluoromethane as a difluoromethylation reagent, which reduces the production cost on the one hand, and improves the yield of continuous difluoromethylation reaction and continuous chloromethylation reaction on the other hand.

[0011] The setting of the continuous ring-closing reaction unit can continuously and accurately control the reaction conditions and post-treatment process of the continuous ring-closing reaction, thereby suppressing the occurrence of side reactions, improving reaction efficiency, and improving the yield and purity of the ring-closing reaction product. The reaction system of the continuous difluoromethylation reaction is complex in phase, involving the three phases of "solid-liquid-gas", and the complex phase of the system makes its continuous process development extremely challenging. The inventors have continuously improved and processed the reaction equipment through a large number of experimental tests, while optimizing the process conditions, matching the process and equipment with each other, and finally developed a continuous difluoromethylation reaction process, and connected with the two steps before and after. On the other hand, the continuous difluoromethylation reaction unit can improve the reaction efficiency, reduce the amount of auxiliary materials, and improve the utilization rate of raw materials. On the other hand, it can improve the utilization rate of equipment and production capacity. The setting of the continuous chloromethylation reaction unit can make the difluoromethylation product, hydrochloric acid and formaldehyde aqueous solution undergo continuous chloromethylation reaction under the catalysis of the third catalyst, and carry out continuous post-treatment at the same time, so as to obtain the target product, and the acidic aqueous phase obtained by the continuous post-treatment can be applied back to the reaction process by simple post-treatment, and almost no three wastes are produced.

[0012] The above-mentioned continuous production system of the present application covers the entire process from raw material feeding to product output, realizing the full continuous process from continuous feeding to continuous reaction to continuous post-processing. The highly integrated automated operating system improves the accuracy of feeding, the accuracy of temperature control, the high uniformity of products, and the safety of production. The automated material post-processing and transportation process reduces the labor input and the risk of material exposure, while reducing the risk of leakage of toxic and hazardous waste.

[0013] In summary, the application of the above-mentioned continuous production system of the present application for production can improve the overall production efficiency, reduce energy loss and raw material waste, and reduce production costs; the above-mentioned continuous equipment has high heat exchange efficiency and can accurately control the reaction conditions, thereby suppressing the occurrence of side reactions and improving the yield and purity of the target product; at the same time, continuous operation can, on the one hand, reduce the safety hazards caused by long-term storage of large amounts of highly reactive materials, and on the other hand, can significantly reduce the labor intensity of operators and reduce their frequency of contact with hazardous materials, thereby significantly improving production safety. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] The drawings constituting a part of the present application are used to provide a further understanding of the present invention. The exemplary embodiments of the present invention and their descriptions are used to explain the present invention and do not constitute an improper limitation of the present invention. In the drawings:

[0015] Figure 1 A schematic structural diagram of a continuous production system of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole in one embodiment of the present application is shown;

[0016] Figure 2 A schematic structural diagram of a continuous production system of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole in another embodiment of the present application is shown.

[0017] The above drawings include the following reference numerals:

[0018] 100, continuous cyclization reaction unit; 110, first continuous feeding module; 120, continuous cyclization reaction device; 130, continuous quenching device; 140, first continuous concentration device; 150, first continuous solid-liquid separation device; 160, first temperature control device; 170, first tail gas absorption device; 180, explosion venting device; 111, continuous ethyl trifluoroacetoacetate feeding device; 112, continuous first catalyst feeding device; 113, continuous methylhydrazine aqueous solution feeding device; 114, first continuous mixing device; 115, second continuous mixing device;

[0019] 200, continuous difluoromethylation reaction unit; 210, second continuous feeding module; 220, continuous difluoromethylation reaction device; 230, second continuous solid-liquid separation device; 240, second continuous concentration device; 250, second temperature control device; 260, second tail gas absorption device; 270, first inert gas supply device; 211, continuous liquid phase feeding device; 212, continuous gas feeding device;

[0020] 300, continuous chloromethylation reaction unit; 310, third continuous feeding module; 320, continuous chloromethylation reaction device; 330, first continuous liquid separation device; 340, continuous water washing device; 350, second continuous liquid separation device; 360, third temperature control device; 370, third tail gas absorption device; 380, second inert gas supply device; 311, continuous difluoromethylation product feeding device; 312, continuous third catalyst feeding device; 313, continuous hydrochloric acid feeding device; 314, continuous formaldehyde aqueous solution feeding device; 315, third continuous mixing device; 316, fourth continuous mixing device; 317, fifth continuous mixing device. DETAILED DESCRIPTION

[0021] It should be noted that, in the absence of conflict, the embodiments and features in the embodiments of the present application can be combined with each other. The present invention will be described in detail below in conjunction with the embodiments.

[0022] As described in the background technology, the existing production process of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole has the problems of low production efficiency, low equipment utilization, poor safety, and low yield due to poor heat exchange efficiency and many side reactions. In order to solve the above technical problems, the first aspect of the present application provides a continuous production system of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole, such as Figure 1 As shown, the continuous production system includes a continuous cyclization reaction unit 100, a continuous difluoromethylation reaction unit 200 and a continuous chloromethylation reaction unit 300. The continuous cyclization reaction unit 100 is used to cause ethyl trifluoroacetoacetate and a methylhydrazine aqueous solution to undergo a continuous cyclization reaction under the catalysis of a first catalyst to obtain a first product system containing a cyclization reaction product, and the first product system is sequentially subjected to continuous quenching, a first continuous concentration and a first continuous solid-liquid separation to obtain a cyclization reaction product; the continuous cyclization reaction unit 100 includes a first continuous feeding module 110, a continuous cyclization reaction device 120, a continuous quenching device 130, a first continuous concentration device 140 and a first continuous solid-liquid separation device 150 which are connected in sequence; the first The continuous solid-liquid separation device 150 is provided with an outlet for the cyclization reaction product; the continuous difluoromethylation reaction unit 200 is used to cause the cyclization reaction product and chlorodifluoromethane to undergo a continuous difluoromethylation reaction in a solvent under the catalysis of a second catalyst to obtain a second product system containing a difluoromethylation product, and the second product system is sequentially subjected to a second continuous solid-liquid separation and a second continuous concentration to obtain a difluoromethylation product; the continuous difluoromethylation reaction unit 200 comprises a second continuous feeding module 210, a continuous difluoromethylation reaction device 220, a second continuous solid The liquid separation device 230 and the second continuous concentration device 240; the inlet of the second continuous feeding module 210 is connected to the outlet of the cyclization reaction product; the second continuous concentration device 240 is provided with a difluoromethylation product outlet; the continuous chloromethylation reaction unit 300 is used to cause the difluoromethylation product, hydrochloric acid and formaldehyde aqueous solution to undergo continuous chloromethylation reaction under the catalysis of a third catalyst to obtain a third product system containing the target product, and the third product system is sequentially subjected to a first continuous liquid separation, a continuous water washing and a second continuous liquid separation to obtain 5-(difluoromethoxy)-4-chloromethyl- 1-methyl-3-(trifluoromethyl)-1H-pyrazole; the continuous chloromethylation reaction unit 300 includes a third continuous feeding module 310, a continuous chloromethylation reaction device 320, a first continuous liquid separation device 330, a continuous water washing device 340 and a second continuous liquid separation device 350 which are connected in sequence; the inlet of the third continuous feeding module 310 is connected to the difluoromethylation product outlet; the second continuous liquid separation device 350 is provided with a target product outlet for discharging 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole.

[0023] It should be noted that the target product in the present application refers to 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole.

[0024] Compared with the prior art that uses intermittent equipment to prepare 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole through four-step reactions, the application of the above-mentioned continuous production system provided by the present application can reduce the synthesis route to three steps, thereby improving production efficiency and improving the feasibility of the continuous process. The setting of the continuous cyclization reaction unit 100 can continuously and accurately control the reaction conditions and post-treatment process of the continuous cyclization reaction, thereby suppressing the occurrence of side reactions, improving reaction efficiency, and improving the yield and purity of the cyclization reaction product. The reaction system of the continuous difluoromethylation reaction has a complex phase state, involving the three phases of "solid-liquid-gas". The setting of the continuous difluoromethylation reaction unit 200 can improve the reaction efficiency, reduce the amount of auxiliary materials, and improve the utilization rate of raw materials on the one hand, and on the other hand, it can improve the utilization rate of equipment and production capacity. The setting of the continuous chloromethylation reaction unit 300 can cause the difluoromethylation product, hydrochloric acid and formaldehyde aqueous solution to undergo continuous chloromethylation reaction under the catalysis of the third catalyst, and simultaneously carry out continuous post-treatment to obtain the target product. The acidic aqueous phase obtained by the continuous post-treatment can be applied back to the reaction process through simple post-treatment, and almost no three wastes are generated.

[0025] The above-mentioned continuous production system of the present application covers the entire process from raw material feeding to product output, realizing the full continuous process from continuous feeding to continuous reaction to continuous post-processing. The highly integrated automated operating system improves the accuracy of feeding, the accuracy of temperature control, the high uniformity of products, and the safety of production. The automated material post-processing and transportation process reduces the labor input and the risk of material exposure, while reducing the risk of leakage of toxic and hazardous waste.

[0026] In summary, the application of the above-mentioned continuous production system of the present application for production can improve the overall production efficiency, reduce energy loss and raw material waste, and reduce production costs; the above-mentioned continuous equipment has high heat exchange efficiency and can accurately control the reaction conditions, thereby suppressing the occurrence of side reactions and improving the yield and purity of the target product; at the same time, continuous operation can, on the one hand, reduce the safety hazards caused by long-term storage of large amounts of highly reactive materials, and on the other hand, can significantly reduce the labor intensity of operators and reduce their frequency of contact with hazardous materials, thereby significantly improving production safety.

[0027] In a preferred embodiment, the continuous cyclization reaction device 120 includes but is not limited to a microchannel tubular reactor, a continuous overflow reactor, a dynamic tubular reactor, a vertical tubular reactor, a tubular reactor, a coil reactor, a U-shaped tubular reactor, or a horizontal tubular reactor. Compared with other types, the use of the above-mentioned type of continuous cyclization reaction device 120 is conducive to more accurately controlling the reaction conditions of the continuous cyclization reaction, thereby facilitating the suppression of the occurrence of side reactions, facilitating the improvement of the reaction efficiency of the continuous cyclization reaction, and further facilitating the improvement of the yield of the cyclization reaction product. At the same time, the above-mentioned type of continuous cyclization reaction device 120 has a higher heat exchange efficiency, thereby facilitating the improvement of the safety of the continuous cyclization reaction and the improvement of the utilization rate of the equipment.

[0028] In order to further improve the heat exchange efficiency of the continuous cyclization reaction device 120, further improve the reaction efficiency and safety of the continuous cyclization reaction, and further improve the utilization rate of the equipment, preferably, the material of the continuous cyclization reaction device 120 includes but is not limited to 316L stainless steel, 304 stainless steel, Hastelloy A, Hastelloy B or Hastelloy C; more preferably, the material of the continuous cyclization reaction device 120 is 304 stainless steel.

[0029] In order to more accurately control the temperature in the continuous ring-closure reaction device 120, thereby further improving the reaction efficiency of the continuous ring-closure reaction, in a preferred embodiment, Figure 2 As shown, the continuous cyclization reaction unit 100 further includes a first temperature control device 160, which is electrically connected to the continuous cyclization reaction device 120 and adjusts the temperature in the continuous cyclization reaction device 120 through negative feedback.

[0030] In a preferred embodiment, Figure 2 As shown, the continuous cyclization reaction device 120 also has a first tail gas outlet, and the continuous cyclization reaction unit 100 also includes a first tail gas absorption device 170, which is used to absorb the tail gas generated during the continuous cyclization reaction, and the inlet of the first tail gas absorption device 170 is connected to the first tail gas outlet. The tail gas generated during the continuous cyclization reaction includes nitrogen and water vapor generated by the thermal decomposition of the methylhydrazine aqueous solution, acidic or alkaline gas formed by the volatilization of the first catalyst, and volatile gas of the byproduct ethanol generated during the reaction. The provision of the first tail gas absorption device 170 is conducive to improving the absorption efficiency of the above-mentioned gases (except nitrogen), thereby helping to reduce the potential safety hazards caused by the above-mentioned gases and improve the safety of production. On the other hand, it is conducive to controlling the emission of the above-mentioned gases, thereby helping to suppress the pollution of the above-mentioned gases to the environment.

[0031] In order to further improve the absorption efficiency of the tail gas generated during the continuous cyclization reaction, preferably, the first tail gas absorption device 170 includes but is not limited to a packed tower, a spray tower or a Venturi absorber.

[0032] In order to improve the safety of the continuous ring-closure reaction process, thereby facilitating the continuous ring-closure reaction to be carried out stably, in a preferred embodiment, Figure 2 As shown, the continuous cyclization reaction unit 100 further includes an explosion relief device 180 for releasing the pressure in the continuous cyclization reaction device 120. The explosion relief device 180 is connected to the continuous cyclization reaction device 120 through an explosion relief pipeline, and the explosion relief device 180 is equipped with an explosion relief sheet.

[0033] In order to more accurately supply the various reaction raw materials required for the continuous ring-closure reaction to the continuous ring-closure reaction device 120, improve the reaction efficiency of the continuous ring-closure reaction, and at the same time improve the utilization rate of the equipment and the production efficiency, in a preferred embodiment, as Figure 2 As shown, the first continuous feeding module 110 includes: a continuous ethyl trifluoroacetoacetate feeding device 111 , a continuous first catalyst feeding device 112 , a continuous methylhydrazine aqueous solution feeding device 113 , a first continuous mixing device 114 and a second continuous mixing device 115 .

[0034] In a preferred embodiment, Figure 2 As shown, the inlet of the first continuous mixing device 114 is connected to the outlet of the continuous ethyl trifluoroacetoacetate feeding device 111 and the outlet of the continuous first catalyst feeding device 112; the first continuous mixing device 114 is used to mix ethyl trifluoroacetoacetate with the first catalyst to obtain a first mixed solution. The provision of the first continuous mixing device 114 is conducive to improving the dispersibility of ethyl trifluoroacetoacetate and the first catalyst, thereby facilitating the reaction efficiency of the subsequent continuous cyclization reaction, and the continuous mixing operation is conducive to improving production efficiency.

[0035] In a preferred embodiment, Figure 2 As shown, the inlet of the second continuous mixing device 115 is connected to the outlet of the continuous methylhydrazine aqueous solution feeding device 113 and the outlet of the first continuous mixing device 114, and the outlet of the second continuous mixing device 115 is connected to the inlet of the continuous cyclization reaction device 120; the second continuous mixing device 115 is used to mix the methylhydrazine aqueous solution with the first mixed solution to obtain a second mixed solution, and the second mixed solution is sent to the continuous cyclization reaction device 120 for continuous cyclization reaction. The provision of the second continuous mixing device 115 is conducive to improving the dispersibility of the methylhydrazine aqueous solution and the first mixed solution, thereby facilitating the improvement of the reaction efficiency of the subsequent continuous cyclization reaction, and the continuous mixing operation is conducive to improving production efficiency.

[0036] In a preferred embodiment, the first continuous mixing device 114 and the second continuous mixing device 115 independently include but are not limited to a microchannel silicon carbide mixer, a Kenics static mixer, an SMX static mixer, an SMXL static mixer, an SMV static mixer or an SK static mixer. Compared with other types, the use of the first continuous mixing device 114 and the second continuous mixing device 115 of the above type is conducive to improving the dispersibility of the above raw materials, improving the mixing efficiency, more accurately controlling the material residence time and mixing degree of the mixing process, and inhibiting the deterioration of the above raw materials, thereby improving the reaction efficiency of the subsequent continuous cyclization reaction.

[0037] In order to more accurately control the feed amount and feed rate of ethyl trifluoroacetoacetate, the first catalyst and methylhydrazine aqueous solution, and improve production efficiency and production safety, in a preferred embodiment, the first continuous feeding module 110 also includes a first metering device, a second metering device and a third metering device; the first metering device is electrically connected to the continuous ethyl trifluoroacetoacetate feeding device 111, the second metering device is electrically connected to the continuous first catalyst feeding device 112, and the third metering device is electrically connected to the continuous methylhydrazine aqueous solution feeding device 113; the first metering device, the second metering device and the third metering device adjust the feed amount of the continuous ethyl trifluoroacetoacetate feeding device 111, the continuous first catalyst feeding device 112 and the continuous methylhydrazine aqueous solution feeding device 113 through negative feedback.

[0038] In a preferred embodiment, the continuous cyclization reaction unit 100 further includes a continuous quenching agent feeding device for supplying a quenching agent to the continuous quenching device 130; the continuous quenching agent feeding device is connected to the continuous quenching device 130 via a quenching agent delivery pipeline.

[0039] In order to more accurately control the feed amount and feed rate of the quencher and further improve production efficiency and production safety, preferably, a fourth metering device is provided on the quencher delivery pipeline; the fourth metering device is electrically connected to the continuous quencher feeding device, and the feed amount of the continuous quencher feeding device is adjusted by negative feedback.

[0040] In a preferred embodiment, the continuous difluoromethylation reaction device 220 includes but is not limited to a dynamic tubular reactor or a continuous overflow reactor. Compared with other types, the continuous difluoromethylation reaction device 220 of the above type is conducive to more accurately controlling the reaction conditions of the continuous difluoromethylation reaction, suppressing the occurrence of side reactions, and improving the reaction efficiency and raw material conversion rate of the continuous difluoromethylation reaction, thereby reducing the use of auxiliary materials and improving the utilization rate of raw materials; on the other hand, the continuous difluoromethylation reaction device 220 of the above type has a higher heat exchange efficiency, which is conducive to improving the safety of the continuous difluoromethylation reaction and improving the utilization rate of the equipment.

[0041] In order to further improve the heat exchange efficiency of the continuous difluoromethylation reaction device 220, further improve the reaction efficiency and safety of the continuous difluoromethylation reaction, and further improve the utilization rate of the equipment, preferably, the material of the continuous difluoromethylation reaction device 220 includes but is not limited to high carbon steel (carbon content is 0.6-1.7wt%), 304 stainless steel, 316L stainless steel, Hastelloy alloy, and plastic fluorine-lined high carbon steel, preferably plastic fluorine-lined high carbon steel.

[0042] In a preferred embodiment, a gas distributor is provided at the bottom of the continuous difluoromethylation reaction device 220. The provision of the gas distributor is conducive to uniformly distributing the chlorodifluoromethane into the continuous difluoromethylation reaction device 220, thereby facilitating the mass transfer efficiency between the gas phase material (i.e. the introduced chlorodifluoromethane) and the liquid phase material, facilitating the reaction efficiency of the continuous difluoromethylation reaction, facilitating the utilization rate of chlorodifluoromethane, and also facilitating the suppression of potential safety hazards caused by gas accumulation, thereby improving production safety.

[0043] In order to distribute chlorodifluoromethane more evenly in the continuous difluoromethylation reaction unit 220, thereby further improving the mass transfer efficiency between the gas phase material (chlorodifluoromethane) and the liquid phase material, and further improving the reaction efficiency of the continuous difluoromethylation reaction, preferably, the gas distributor is selected from a plate gas distributor or a tubular gas distributor.

[0044] In order to more accurately supply the various reaction raw materials required for the continuous difluoromethylation reaction to the continuous difluoromethylation reaction device 220, improve the reaction efficiency of the continuous difluoromethylation reaction, and at the same time improve the equipment utilization rate and production efficiency, in a preferred embodiment, as Figure 2 As shown, the second continuous feeding module 210 includes a continuous liquid phase feeding device 211 and a continuous gas feeding device 212; the outlet of the continuous liquid phase feeding device 211 is used to discharge the liquid phase material containing the cyclization reaction product, the second catalyst and the solvent, and the outlet of the continuous gas feeding device 212 is used to supply monochlorodifluoromethane.

[0045] In order to more accurately control the feed amount and feed rate of the liquid phase material containing the cyclization reaction product, the second catalyst and the solvent, and monochlorodifluoromethane, and further improve production efficiency and production safety, preferably, the second continuous feeding module 210 also includes a fifth metering device and a sixth metering device; the fifth metering device is electrically connected to the continuous liquid phase feeding device 211, and the sixth metering device is electrically connected to the continuous gas feeding device 212; the fifth metering device and the sixth metering device respectively adjust the feed amount of the continuous liquid phase feeding device 211 and the continuous gas feeding device 212 through negative feedback.

[0046] In order to more accurately control the temperature in the continuous difluoromethylation reaction device 220, thereby further improving the reaction efficiency of the continuous difluoromethylation reaction, in a preferred embodiment, Figure 2 As shown, the continuous difluoromethylation reaction unit 200 further includes a second temperature control device 250 , which is electrically connected to the continuous difluoromethylation reaction device 220 and adjusts the temperature in the continuous difluoromethylation reaction device 220 through negative feedback.

[0047] In a preferred embodiment, the continuous difluoromethylation reaction device 220 also has a second tail gas outlet, and the continuous difluoromethylation reaction unit 200 also includes a second tail gas absorption device 260 for absorbing the tail gas generated during the continuous difluoromethylation reaction, and the inlet of the second tail gas absorption device 260 is connected to the second tail gas outlet. The tail gas generated during the continuous difluoromethylation reaction includes unreacted chlorodifluoromethane gas, inert gas introduced during the reaction, hydrogen chloride gas generated during the reaction, and formaldehyde gas. The setting of the second tail gas absorption device 260 is conducive to improving the absorption efficiency of the above-mentioned gas (except inert gas), thereby helping to reduce the potential safety hazards caused by the above-mentioned gas and improve the safety of production. On the other hand, it is conducive to controlling the emission of the above-mentioned gas, thereby helping to suppress the pollution of the above-mentioned gas to the environment.

[0048] In order to further improve the absorption efficiency of the tail gas generated during the continuous difluoromethylation reaction, preferably, the second tail gas absorption device 260 includes but is not limited to a packed tower, a spray tower or a venturi absorber.

[0049] In a preferred embodiment, Figure 2As shown, the continuous difluoromethylation reaction unit 200 further includes a first inert gas supply device 270 for supplying an inert gas to the continuous difluoromethylation reaction device 220, and the outlet of the first inert gas supply device 270 is connected to the inlet of the continuous difluoromethylation reaction device 220. The provision of the first inert gas supply device 270 is beneficial to providing an inert gas environment for the continuous difluoromethylation reaction, thereby facilitating the suppression of the occurrence of side reactions, facilitating the improvement of the stability and selectivity of the continuous difluoromethylation reaction, and further facilitating the improvement of the yield of the difluoromethylation reaction product, and also facilitating the improvement of production safety.

[0050] In order to further provide an inert gas environment for the continuous difluoromethylation reaction, thereby further suppressing the occurrence of side reactions and further improving the stability and selectivity of the continuous difluoromethylation reaction, preferably, the inert gas in the first inert gas supply device 270 includes but is not limited to nitrogen and / or helium.

[0051] In a preferred embodiment, the continuous chloromethylation reaction device 320 includes but is not limited to a microchannel tubular reactor, a continuous overflow reactor, a dynamic tubular reactor, a vertical tubular reactor, a tubular reactor, a coil reactor, a U-shaped tubular reactor, or a horizontal tubular reactor. Compared with other types, the continuous chloromethylation reaction device 320 of the above type is conducive to more accurately controlling the reaction conditions of the continuous chloromethylation reaction, thereby helping to suppress the occurrence of side reactions, helping to improve the reaction efficiency of the continuous chloromethylation reaction, and then helping to improve the yield of the target product. At the same time, the continuous chloromethylation reaction device 320 of the above type has a higher heat exchange efficiency, thereby helping to improve the safety of the continuous cyclization reaction and also helping to improve the utilization rate of the equipment.

[0052] In order to further improve the heat exchange efficiency of the continuous chloromethylation reaction device 320, further improve the reaction efficiency and safety of the continuous chloromethylation reaction, and further improve the utilization rate of the equipment, preferably, the material of the continuous chloromethylation reaction device 320 is Hastelloy B.

[0053] In order to more accurately control the temperature in the continuous chloromethylation reaction unit 300, thereby further improving the reaction efficiency of the continuous chloromethylation reaction, in a preferred embodiment, Figure 2 As shown, the continuous chloromethylation reaction unit 300 further includes a third temperature control device 360, which is electrically connected to the continuous chloromethylation reaction device 320 and adjusts the temperature in the continuous chloromethylation reaction device 320 through negative feedback.

[0054] In a preferred embodiment, Figure 2As shown, the continuous chloromethylation reaction device 320 also has a third tail gas outlet, and the continuous chloromethylation reaction unit 300 also includes a third tail gas absorption device 370, which is used to absorb the tail gas generated during the continuous chloromethylation reaction, and the inlet of the third tail gas absorption device 370 is connected to the third tail gas outlet. The tail gas generated during the continuous chloromethylation reaction includes hydrogen chloride gas volatilized by the heat of hydrochloric acid, inert gas introduced during the reaction, and formaldehyde gas generated during the reaction. The setting of the third tail gas absorption device 370 is conducive to improving the absorption efficiency of the above-mentioned gases (except inert gases), thereby helping to reduce the potential safety hazards caused by the above-mentioned gases and improve the safety of production. On the other hand, it is conducive to controlling the emission of the above-mentioned gases, thereby helping to suppress the pollution of the above-mentioned gases to the environment.

[0055] In order to further improve the absorption efficiency of the tail gas generated during the continuous chloromethylation reaction, preferably, the third tail gas absorption device 370 includes but is not limited to a packed tower, a spray tower or a Venturi absorber.

[0056] In a preferred embodiment, Figure 2 As shown, the continuous chloromethylation reaction unit 300 further includes a second inert gas supply device 380 for supplying an inert gas to the continuous chloromethylation reaction device 320, and the outlet of the second inert gas supply device 380 is connected to the inlet of the continuous chloromethylation reaction device 320. The provision of the second inert gas supply device 380 is beneficial to providing an inert gas environment for the continuous chloromethylation reaction, thereby facilitating the suppression of the occurrence of side reactions, improving the stability and selectivity of the continuous chloromethylation reaction, and thus facilitating the improvement of the yield of the target product, and also facilitating the improvement of production safety.

[0057] In order to further provide an inert gas environment for the continuous chloromethylation reaction, thereby further suppressing the occurrence of side reactions and further improving the stability and selectivity of the continuous chloromethylation reaction, preferably, the inert gas in the second inert gas supply device 380 includes but is not limited to nitrogen and / or helium.

[0058] In order to more accurately supply the various reaction raw materials required for the continuous chloromethylation reaction to the continuous chloromethylation reaction device 320, improve the reaction efficiency of the continuous chloromethylation reaction, and at the same time improve the equipment utilization rate and production efficiency, in a preferred embodiment, as Figure 2 As shown, the third continuous feeding module 310 includes: a continuous difluoromethylation product feeding device 311, a continuous third catalyst feeding device 312, a continuous hydrochloric acid feeding device 313, a continuous formaldehyde aqueous solution feeding device 314, a third continuous mixing device 315, a fourth continuous mixing device 316 and a fifth continuous mixing device 317.

[0059] In a preferred embodiment, Figure 2 As shown, the inlet of the third continuous mixing device 315 is connected to the outlet of the continuous difluoromethylation product feeding device 311 and the outlet of the continuous third catalyst feeding device 312; the third continuous mixing device 315 is used to mix the difluoromethylation product with the third catalyst to obtain a third mixed liquid. The provision of the third continuous mixing device 315 is conducive to improving the dispersibility of the difluoromethylation product and the third catalyst, thereby facilitating the improvement of the reaction efficiency of the subsequent continuous chloromethylation reaction, and the continuous mixing operation is conducive to improving production efficiency.

[0060] In a preferred embodiment, Figure 2 As shown, the fourth continuous mixing device 316 is used to mix hydrochloric acid with the formaldehyde aqueous solution to obtain a fourth mixed solution; the inlet of the fourth continuous mixing device 316 is connected to the outlet of the continuous hydrochloric acid feeding device 313 and the outlet of the continuous formaldehyde aqueous solution feeding device 314; the fourth continuous mixing device 316 is used to mix hydrochloric acid with the formaldehyde aqueous solution to obtain a fourth mixed solution. The setting of the fourth continuous mixing device 316 is conducive to improving the dispersibility of hydrochloric acid and formaldehyde aqueous solution, thereby facilitating the reaction efficiency of the subsequent continuous chloromethylation reaction, and the continuous mixing operation is conducive to improving production efficiency.

[0061] In a preferred embodiment, Figure 2 As shown, the inlet of the fifth continuous mixing device 317 is connected to the outlet of the third continuous mixing device 315 and the outlet of the fourth continuous mixing device 316; the fifth continuous mixing device 317 is used to mix the third mixed liquid with the fourth mixed liquid to obtain a fifth mixed liquid, and send the fifth mixed liquid to the continuous chloromethylation reaction device 320 for continuous chloromethylation reaction. The setting of the fifth continuous mixing device 317 is conducive to improving the dispersibility of the third mixed liquid and the fourth mixed liquid, thereby facilitating the improvement of the reaction efficiency of the subsequent continuous chloromethylation reaction, and the continuous mixing operation is conducive to improving production efficiency.

[0062] In a preferred embodiment, the third continuous mixing device 315, the fourth continuous mixing device 316 and the fifth continuous mixing device 317 independently include but are not limited to a microchannel silicon carbide mixer, a Kenics type static mixer, an SMX type static mixer, an SMXL type static mixer, an SMV type static mixer or an SK type static mixer. Compared with other types, the third continuous mixing device 315, the fourth continuous mixing device 316 and the fifth continuous mixing device 317 of the above type are beneficial to improving the dispersibility of each reaction raw material of the continuous chloromethylation reaction, improving the mixing efficiency, more accurately controlling the material residence time and mixing degree of the mixing process, and inhibiting the deterioration of the above raw materials, thereby improving the reaction efficiency of the subsequent continuous chloromethylation reaction.

[0063] In order to more accurately control the feed amount and feed rate of the difluoromethylation product, the third catalyst, hydrochloric acid and formaldehyde aqueous solution, and improve production efficiency and production safety, in a preferred embodiment, the third continuous feeding module 310 also includes a seventh metering device, an eighth metering device, a ninth metering device and a tenth metering device; the seventh metering device is electrically connected to the continuous difluoromethylation product feeding device 311, the eighth metering device is electrically connected to the continuous third catalyst feeding device 312, the ninth metering device is electrically connected to the continuous hydrochloric acid feeding device 313, and the tenth metering device is electrically connected to the continuous formaldehyde aqueous solution feeding device 314; the seventh metering device, the eighth metering device, the ninth metering device and the tenth metering device respectively adjust the feed amount of the continuous difluoromethylation product feeding device 311, the continuous third catalyst feeding device 312, the continuous hydrochloric acid feeding device 313 and the continuous formaldehyde aqueous solution feeding device 314 through negative feedback.

[0064] In a second aspect, the present application further provides a method for continuously producing 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole, wherein the continuous production system provided by the present application is used to continuously produce 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole. The continuous production method comprises: step S1, using a first continuous feeding module 110 to pass ethyl trifluoroacetoacetate, a first catalyst and a methylhydrazine aqueous solution into a continuous cyclization reaction device 120 for continuous cyclization reaction to obtain a first product system containing a cyclization reaction product; sequentially using a continuous quenching device 130, a first continuous concentrating device 140 and a first continuous solid-liquid separation device 150 to continuously quench, perform a first continuous concentrating and a first continuous solid-liquid separation on the first product system to obtain a cyclization reaction product; step S2, using a second continuous feeding module 210 to pass the cyclization reaction product, the second catalyst, The solvent and chlorodifluoromethane are introduced into the continuous difluoromethylation reaction device 220 for continuous difluoromethylation reaction to obtain a second product system containing a difluoromethylation reaction product; the second continuous solid-liquid separation device 230 and the second continuous concentration device 240 are used in sequence to perform a second continuous solid-liquid separation and a second continuous concentration on the second product system to obtain a difluoromethylation reaction product; step S3, the difluoromethylation reaction product, the third catalyst, hydrochloric acid and formaldehyde aqueous solution are introduced into the continuous chloromethylation reaction device 320 by using the third continuous feeding module 310 for continuous chloromethylation reaction to obtain a third product system containing a target product; the first continuous liquid separation device 330, the continuous water washing device 340 and the second continuous liquid separation device 350 are used in sequence to perform a first continuous liquid separation, a continuous water washing and a second continuous liquid separation on the third product system to obtain 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole.

[0065] The synthetic route of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole in this application is as follows:

[0066] .

[0067] Compared with the prior art that adopts four-step intermittent reaction to prepare 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole, the above-mentioned continuous production method provided by the present application can reduce the synthesis route to three steps, thereby improving production efficiency and the feasibility of the continuous process. Step S1 can make ethyl trifluoroacetoacetate and methylhydrazine aqueous solution undergo continuous cyclization reaction under the catalysis of the first catalyst, and sequentially perform continuous quenching, first continuous concentration and first continuous solid-liquid separation to obtain the cyclization reaction product. The above-mentioned continuous method can inhibit the occurrence of side reactions, improve reaction efficiency, realize instant quenching of the reaction and separation of the cyclization reaction product, thereby improving the yield and purity of the cyclization reaction product. The reaction system of the continuous difluoromethylation reaction is complex in phase state, involving the three phases of "solid-liquid-gas". Step S2 can reduce the generation of by-products and reduce the amount of auxiliary materials by accurately controlling the reaction conditions on the one hand, and can improve the utilization rate of monochlorodifluoromethane gas on the other hand, thereby improving the reaction efficiency and the yield of the difluoromethylation product. Step S3 enables the difluoromethylated product, hydrochloric acid and formaldehyde aqueous solution to undergo continuous chloromethylation reaction under the catalysis of the third catalyst, and improves the yield and purity of the target product 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole by sequentially performing the first continuous liquid separation, the continuous water washing and the second continuous liquid separation.

[0068] In summary, the above-mentioned continuous production method of the present application can improve the overall production efficiency, reduce energy loss and raw material waste, and reduce production costs; at the same time, continuous operation can more accurately control the reaction conditions, inhibit the occurrence of side reactions, and improve the yield and purity of the target product; on the other hand, it can achieve instant quenching of the reaction and instant separation of the product, thereby reducing the safety hazards caused by long-term storage of large amounts of highly reactive materials. At the same time, it can also significantly reduce the labor intensity of operators and reduce their frequency of contact with hazardous materials, thereby improving production safety.

[0069] In a preferred embodiment, the reaction temperature of the continuous ring-closure reaction is 80-110° C., and the material residence time is 30-130 min. The temperature and material residence time of the continuous ring-closure reaction include but are not limited to the above ranges, and limiting them within the above ranges is conducive to improving the selectivity and reaction efficiency of the continuous ring-closure reaction, and is conducive to inhibiting the occurrence of side reactions, thereby facilitating the improvement of the yield of the ring-closure reaction product, and further facilitating the improvement of the yield of the subsequent preparation of the target product.

[0070] In order to improve the dispersibility of ethyl trifluoroacetoacetate and the first catalyst, thereby facilitating improving the reaction efficiency of the subsequent continuous cyclization reaction, in a preferred embodiment, a first continuous mixing device 114 is used to mix ethyl trifluoroacetoacetate and the first catalyst to obtain a first mixed solution.

[0071] In a preferred embodiment, the feed rate ratio of ethyl trifluoroacetoacetate to the first catalyst is (1-2): (0.7-3.2). The feed rate ratio of ethyl trifluoroacetoacetate to the first catalyst includes but is not limited to the above range. Limiting it within the above range is beneficial to improving the utilization rate of the above raw materials on the one hand, and on the other hand, it is beneficial to improving the dispersibility and mixing efficiency of the above raw materials, and is beneficial to improving the selectivity and reaction efficiency of the subsequent continuous ring-closure reaction, and is beneficial to suppressing the occurrence of side reactions, thereby helping to improve the yield of the continuous ring-closure reaction product.

[0072] In order to further improve the dispersibility and mixing efficiency of ethyl trifluoroacetoacetate and the first catalyst, thereby further improving the production efficiency, preferably, the residence time of ethyl trifluoroacetoacetate and the first catalyst is independently 0.01 to 0.05 min.

[0073] In order to improve the catalytic efficiency of the first catalyst, thereby improving the reaction efficiency of the continuous cyclization reaction, in a preferred embodiment, the first catalyst includes but is not limited to one or more of acetic acid, triethylamine, and pyridine.

[0074] In order to improve the dispersibility of the methylhydrazine aqueous solution and the first mixed solution, thereby improving the reaction efficiency of the subsequent continuous cyclization reaction, in a preferred embodiment, the methylhydrazine aqueous solution is mixed with the first mixed solution by a second continuous mixing device 115 to obtain a second mixed solution.

[0075] In a preferred embodiment, the feed rate ratio of the methylhydrazine aqueous solution to the first mixed solution is (0.36-1): (0.5-1). The feed rate ratio of the methylhydrazine aqueous solution to the first mixed solution includes but is not limited to the above range, and limiting it within the above range is conducive to improving the dispersibility and mixing efficiency of the two, thereby facilitating the improvement of the selectivity and reaction efficiency of the subsequent continuous ring-closure reaction, and is conducive to suppressing the occurrence of side reactions, thereby facilitating the improvement of the yield of the continuous ring-closure reaction product.

[0076] In order to further improve the dispersibility and mixing efficiency of the methylhydrazine aqueous solution and the first mixed solution, thereby further improving the production efficiency, preferably, the residence time of the methylhydrazine aqueous solution and the first mixed solution is independently 0.01 to 0.05 min.

[0077] In a preferred embodiment, in the second mixed solution, the weight ratio of ethyl trifluoroacetoacetate, the first catalyst and the methylhydrazine aqueous solution is 1: (0.4-3): (0.5-1.2). The weight ratio of ethyl trifluoroacetoacetate, the first catalyst and the methylhydrazine aqueous solution includes but is not limited to the above range. Limiting it within the above range is beneficial to improving the utilization rate of the above raw materials on the one hand, and on the other hand, it is beneficial to improving the selectivity and reaction efficiency of the continuous cyclization reaction, and is beneficial to suppressing the occurrence of side reactions, thereby facilitating improving the yield of the continuous cyclization reaction product.

[0078] It should be noted that the flow rate in this application refers to the length per unit area of ​​the cross section of the reactor that the material passes through per unit time. In a preferred embodiment, the flow rate of the second mixed liquid is 44 to 100 cm·cm -2 ·min -1 The flow rate of the second mixed liquid includes but is not limited to the above range, and limiting it within the above range is beneficial to improving the reaction efficiency of the continuous cyclization reaction.

[0079] In a preferred embodiment, the reaction temperature of the continuous difluoromethylation reaction is 0 to 40° C., and the material residence time is 20 to 100 min. The reaction temperature and material residence time of the continuous difluoromethylation reaction include but are not limited to the above ranges, and limiting them within the above ranges is beneficial to improving the selectivity and reaction efficiency of the continuous difluoromethylation reaction, and is beneficial to suppressing the occurrence of side reactions, thereby facilitating improving the yield of the continuous difluoromethylation reaction product, and further facilitating improving the yield of the subsequent preparation of the target product.

[0080] In order to improve the dispersibility of the cyclization reaction product, the second catalyst and the solvent, thereby improving the reaction efficiency of the subsequent continuous difluoromethylation reaction, in a preferred embodiment, the cyclization reaction product, the second catalyst and the solvent are mixed using a continuous liquid phase feeding device 211 to obtain a liquid phase material.

[0081] In a preferred embodiment, the feed rate ratio of the cyclization reaction product, the second catalyst and the solvent is 1: (0.3-1): (2-5). The feed rate ratio of the cyclization reaction product, the second catalyst and the solvent includes but is not limited to the above range. Limiting it within the above range is beneficial to improving the dispersibility and mixing efficiency of the above raw materials, and is beneficial to improving the reaction efficiency of the subsequent continuous difluoromethylation reaction, thereby helping to improve the yield of the difluoromethylation product, and is also beneficial to improving the utilization rate of the above raw materials and reducing production costs.

[0082] In order to further improve the dispersibility and mixing efficiency of the cyclization reaction product, the second catalyst and the solvent, thereby further improving the production efficiency, preferably, the residence time of the cyclization reaction product, the second catalyst and the solvent is independently 0.01 to 0.05 min.

[0083] In order to improve the catalytic efficiency of the second catalyst, thereby improving the reaction efficiency of the continuous difluoromethylation reaction, in a preferred embodiment, the second catalyst includes but is not limited to one or more of potassium hydroxide, sodium hydroxide and triethylamine.

[0084] In order to further improve the dispersibility of the cyclization reaction product and the second catalyst, in a preferred embodiment, the solvent includes but is not limited to one or more of acetonitrile, methanol and ethanol.

[0085] In a preferred embodiment, the weight ratio of the cyclization reaction product, chlorodifluoromethane, the second catalyst and the solvent is 1: (0.5-1): (0.3-2): (1-3). The weight ratio of the cyclization reaction product, the second catalyst and the solvent includes but is not limited to the above range. Limiting it within the above range is beneficial to improving the selectivity and reaction efficiency of the continuous difluoromethylation reaction, and is beneficial to suppressing the occurrence of side reactions, thereby facilitating improving the purity and yield of the difluoromethylation product.

[0086] In a preferred embodiment, in the continuous difluoromethylation reaction device 220, the feed rate ratio of the liquid phase material to the monochlorodifluoromethane is 3.5:(0.6-2). The feed rate ratio of the liquid phase material to the monochlorodifluoromethane includes but is not limited to the above range, and limiting it within the above range is conducive to improving the selectivity and reaction efficiency of the continuous difluoromethylation reaction, thereby facilitating improving the yield of the continuous cyclization reaction product.

[0087] In a preferred embodiment, the reaction temperature of the continuous chloromethylation reaction is 90-120° C., and the material residence time is 20-120 min. The reaction temperature and material residence time of the continuous chloromethylation reaction include but are not limited to the above ranges, and limiting them within the above ranges is conducive to improving the selectivity and reaction efficiency of the continuous chloromethylation reaction, and is conducive to suppressing the occurrence of side reactions, thereby helping to improve the yield of the target product.

[0088] In order to improve the dispersibility of the difluoromethylation product and the third catalyst, thereby facilitating improving the reaction efficiency of the subsequent continuous chloromethylation reaction, in a preferred embodiment, the difluoromethylation product and the third catalyst are mixed by a third continuous mixing device 315 to obtain a third mixed liquid.

[0089] In a preferred embodiment, the feed rate ratio of the difluoromethylation product to the third catalyst is 1:(0.5-2). The feed rate ratio of the difluoromethylation product to the third catalyst includes but is not limited to the above range, and limiting it within the above range is conducive to improving the dispersibility and mixing efficiency of the two, and is conducive to improving the reaction efficiency of the subsequent continuous chloromethylation reaction, thereby helping to improve the yield of the target product, and is also conducive to improving the utilization rate of raw materials and reducing production costs.

[0090] In order to further improve the dispersibility and mixing efficiency of the difluoromethylation product and the third catalyst, thereby further improving the production efficiency, preferably, the residence time of the difluoromethylation product and the third catalyst is independently selected to be 0.01 to 0.05 min.

[0091] In order to improve the dispersibility of hydrochloric acid and formaldehyde aqueous solution, thereby facilitating improving the reaction efficiency of the subsequent continuous chloromethylation reaction, in a preferred embodiment, a fourth continuous mixing device 316 is used to mix hydrochloric acid and formaldehyde aqueous solution to obtain a fourth mixed solution.

[0092] In order to further improve the dispersibility of hydrochloric acid and formaldehyde aqueous solution and further improve the reaction efficiency of the continuous chloromethylation reaction, preferably, the mass concentration of the formaldehyde aqueous solution is 37-40wt%; the mass concentration of the hydrochloric acid is 36-38wt%.

[0093] In a preferred embodiment, the feed rate ratio of hydrochloric acid to formaldehyde aqueous solution is 1:(0.3-1.5). The feed rate ratio of hydrochloric acid to formaldehyde aqueous solution includes but is not limited to the above range, and limiting it within the above range is conducive to improving the dispersibility and mixing efficiency of the two, and is conducive to improving the reaction efficiency of the subsequent continuous chloromethylation reaction, thereby helping to improve the yield of the target product.

[0094] In order to further improve the dispersibility and mixing efficiency of hydrochloric acid and formaldehyde aqueous solution, thereby further improving production efficiency, preferably, the residence time of hydrochloric acid and formaldehyde aqueous solution is independently 0.01 to 0.05 min.

[0095] In order to improve the dispersibility of the third mixed liquid and the fourth mixed liquid, thereby facilitating improving the reaction efficiency of the subsequent continuous chloromethylation reaction, in a preferred embodiment, a fifth continuous mixing device 317 is used to mix the third mixed liquid with the fourth mixed liquid to obtain a fifth mixed liquid.

[0096] In a preferred embodiment, the feed rate ratio of the third mixed liquid to the fourth mixed liquid is 1:(1-1.5). The feed rate ratio of the third mixed liquid to the fourth mixed liquid includes but is not limited to the above range, and limiting it within the above range is conducive to improving the dispersibility and mixing efficiency of the two, and is conducive to improving the reaction efficiency of the continuous chloromethylation reaction, thereby helping to improve the yield of the target product.

[0097] In order to further improve the dispersibility and mixing efficiency of the third mixed liquid and the fourth mixed liquid, thereby further improving the production efficiency, preferably, the residence time of the third mixed liquid and the fourth mixed liquid is independently 0.01 to 0.05 min.

[0098] In a preferred embodiment, in the fifth mixed solution, the weight ratio of the difluoromethylation reaction product, the third catalyst, hydrochloric acid and the formaldehyde aqueous solution is 1: (0.1-2): (0.5-5): (0.3-1). The weight ratio of the difluoromethylation reaction product, the third catalyst, hydrochloric acid and the formaldehyde aqueous solution includes but is not limited to the above range. Limiting it within the above range is beneficial to improving the selectivity and reaction efficiency of the continuous chloromethylation reaction, and is beneficial to suppressing the occurrence of side reactions, thereby facilitating the improvement of the yield of the target product, and is also beneficial to improving the utilization rate of raw materials and reducing production costs.

[0099] In order to improve the catalytic efficiency of the third catalyst, thereby improving the reaction efficiency of the continuous chloromethylation reaction, in a preferred embodiment, the third catalyst includes but is not limited to one or more of sulfuric acid, acetic acid and sulfate. There is no particular restriction on the type of sulfate in the present application, and sulfates commonly used in the art can be selected.

[0100] In order to improve the reaction efficiency of the continuous chloromethylation reaction, in a preferred embodiment, the flow rate of the fifth mixed liquid is 200 to 500 cm·cm -2 ·min -1 .

[0101] The present application is further described in detail below in conjunction with specific embodiments. These embodiments should not be construed as limiting the scope of protection claimed in the present application.

[0102] (I) Influence of the Type of Continuous Cyclization Reaction Device 120 on the Continuous Cyclization Reaction

[0103] Examples 1 to 5

[0104] Use Figure 2The continuous production system of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole shown in the figure is continuously synthesized, comprising the following steps: ethyl trifluoroacetoacetate and acetic acid are introduced into a first microchannel silicon carbide mixer (refer to Chinese patent application CN202230000540.5) at a rate of 2.2 kg / h and 1 kg / h, respectively, and mixed for 0.01 min to obtain a first mixed solution; the first mixed solution and a methylhydrazine aqueous solution (mass concentration of 40wt%) are introduced into a second microchannel silicon carbide mixer (the same model as the first microchannel silicon carbide mixer) at a rate of 3.1 kg / h and 1.32 kg / h, respectively, and mixed for 0.01 min to obtain a second mixed solution; the second mixed solution is introduced into different types of continuous cyclization reaction devices 120 (specific types are shown in Table 1) at a rate of 4.42 kg / h for continuous cyclization reaction to obtain a first product system containing a cyclization reaction product, and the flow rate of the second mixed solution is set to 44 cm·cm -2 ·min -1 The temperature of the continuous cyclization reaction was 95°C, and the material residence time was 130 min. The first product system was introduced into a continuous quenching reactor, quenched continuously with tap water, and then continuously concentrated with a first thin film evaporator (Shanghai Deda Tianyi Chemical, DEA-BML-10). After continuous solid-liquid separation with a horizontal screw centrifuge (Germany Lemitec, MD60), the cyclization reaction product 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole was obtained.

[0105] The purity and yield of the cyclization reaction products obtained in Examples 1 to 5 and the residual amount of ethyl trifluoroacetoacetate are shown in Table 1. The purity of the cyclization reaction products obtained in Examples 1 to 5 and the residual amount of ethyl trifluoroacetoacetate were detected by gas chromatograph (Agilent, 8890).

[0106] Table 1

[0107]

[0108] It can be seen from Table 1 that the residual amount of ethyl trifluoroacetoacetate in Example 4 is small, and the purity and yield of the cyclization reaction product are high. Therefore, compared with other types of reactors, when the continuous cyclization reaction device 120 is a coil reactor (Example 4), the purity and yield of the cyclization reaction product are higher.

[0109] (II) Effect of the feed rate of each reactant in the continuous cyclization reaction on the continuous cyclization reaction

[0110] Examples 6 to 10

[0111] Use Figure 2The continuous production system of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole shown in the embodiment is continuously synthesized, comprising the following steps: introducing ethyl trifluoroacetoacetate and acetic acid into a first microchannel silicon carbide mixer at different feed rates and mixing for 0.01 min to obtain a first mixed solution; introducing the first mixed solution and a methylhydrazine aqueous solution into a second microchannel silicon carbide mixer and mixing for 0.01 min to obtain a second mixed solution, wherein the feed rates of ethyl trifluoroacetoacetate, the methylhydrazine aqueous solution and the acetic acid are shown in Table 2; introducing the second mixed solution into a coil reactor (the same as the reactor in Example 4) at a rate of 4.42 kg / h for continuous cyclization reaction to obtain a first product system containing a cyclization reaction product, and setting the flow rate of the second mixed solution to 44 cm·cm -2 ·min -1 The temperature of the continuous cyclization reaction is 95° C., and the material residence time is 130 min. The first product system is passed into a continuous quenching reactor, and is continuously quenched with tap water. Then, the first thin film evaporator is used for continuous concentration, and a horizontal screw centrifuge is used for continuous solid-liquid separation to obtain the cyclization reaction product 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole.

[0112] The purity and yield of the cyclization reaction products obtained in Examples 4, 6 to 10 and the residual amount of ethyl trifluoroacetoacetate are shown in Table 2. The purity of the cyclization reaction products obtained in Examples 4, 6 to 10 and the residual amount of ethyl trifluoroacetoacetate were detected by gas chromatograph.

[0113] Table 2

[0114]

[0115] It can be seen from Table 2 that when the feed rates of ethyl trifluoroacetoacetate, methylhydrazine aqueous solution and acetic acid are 2.2 kg / h, 1.32 kg / h and 0.9 kg / h respectively (Example 6), the purity and yield of the cyclization reaction product are higher.

[0116] (III) Effect of the Type of Continuous Difluoromethylation Reaction Unit 220 on the Continuous Difluoromethylation Reaction

[0117] Examples 11 and 12

[0118] Use Figure 2 The continuous production system of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole shown in the invention is continuously synthesized, comprising the following steps:

[0119] (1) Ethyl trifluoroacetoacetate and acetic acid were introduced into a first microchannel silicon carbide mixer at a rate of 2.2 kg / h and 0.9 kg / h, respectively, and mixed for 0.01 min to obtain a first mixed solution; the first mixed solution and a methylhydrazine aqueous solution were introduced into a second microchannel silicon carbide mixer at a rate of 3.1 kg / h and 1.32 kg / h, respectively, and mixed for 0.01 min to obtain a second mixed solution; the second mixed solution was introduced into a coil reactor (the same as the reactor in Example 4) at a rate of 4.42 kg / h for continuous cyclization reaction to obtain a first product system containing a cyclization reaction product, and the flow rate of the second mixed solution was set to 44 cm·cm -2 ·min -1 , the temperature of the continuous cyclization reaction is 95° C., and the material residence time is 130 min; the first product system is passed into a continuous quenching reactor, and is continuously quenched with tap water, and then continuously concentrated with a first thin film evaporator, and continuously separated solid from liquid with a horizontal screw centrifuge to obtain a cyclization reaction product 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole;

[0120] (2) The cyclization reaction product, potassium hydroxide and acetonitrile were introduced into a continuous liquid feeder at a rate of 1 kg / h, 0.6 kg / h and 2 kg / h, respectively, and mixed for 0.01 min to obtain a liquid phase material; the liquid phase material and monochlorodifluoromethane were introduced into different types of continuous difluoromethylation reaction devices 220 (specific types are shown in Table 3) at a rate of 3.5 kg / h and 0.6 kg / h, respectively, for continuous difluoromethylation reaction to obtain a second product system containing a difluoromethylation product, and the temperature of the continuous difluoromethylation reaction was set to 30° C. and the material residence time was 90 min; the second product system was continuously solid-liquid separated by a twin-screw solid-liquid separator, and then continuously concentrated by a second thin film evaporator to obtain a difluoromethylation product 5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole.

[0121] The purity and yield of the difluoromethylation products obtained in Examples 11 and 12 and the remaining amount of the cyclization product are shown in Table 3. The purity of the difluoromethylation products obtained in Examples 11 and 12 and the remaining amount of the cyclization product were detected by liquid chromatograph (Thermo Fisher, U-3000).

[0122] Table 3

[0123]

[0124] It can be seen from Table 3 that the residual amount of the cyclization reaction product in Example 11 is small, and the purity and yield of the difluoromethylation product are high. Therefore, compared with the continuous overflow reactor, when the continuous difluoromethylation reaction device 220 is a dynamic tubular reactor (Example 11), the residual amount of the cyclization reaction product is lower, and the purity and yield of the difluoromethylation product are higher.

[0125] 4. Effect of the Feed Rate of Each Reaction Material on the Continuous Difluoromethylation Reaction

[0126] Examples 13 to 18

[0127] Use Figure 2 The continuous production system of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole shown in the invention is continuously synthesized, comprising the following steps:

[0128] (1) Ethyl trifluoroacetoacetate and acetic acid were introduced into a first microchannel silicon carbide mixer at a rate of 2.2 kg / h and 0.9 kg / h, respectively, and mixed for 0.01 min to obtain a first mixed solution; the first mixed solution and a methylhydrazine aqueous solution were introduced into a second microchannel silicon carbide mixer at a rate of 3.1 kg / h and 1.32 kg / h, respectively, and mixed for 0.01 min to obtain a second mixed solution; the second mixed solution was introduced into a coil reactor (the same as the reactor in Example 4) at a rate of 4.42 kg / h for continuous cyclization reaction to obtain a first product system containing a cyclization reaction product, and the flow rate of the second mixed solution was set to 44 cm·cm -2 ·min -1 , the temperature of the continuous cyclization reaction is 95° C., and the material residence time is 130 min; the first product system is passed into a continuous quenching reactor, and is continuously quenched with tap water, and then continuously concentrated with a first thin film evaporator, and continuously separated solid from liquid with a horizontal screw centrifuge to obtain a cyclization reaction product 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole;

[0129] (2) The cyclization reaction product, potassium hydroxide and acetonitrile were introduced into a continuous liquid phase feeder at different feed rates and mixed for 0.01 min to obtain a liquid phase material; the liquid phase material and chlorodifluoromethane were introduced into a dynamic tubular reactor (the same as the reactor in Example 11) for continuous difluoromethylation reaction to obtain a second product system containing a difluoromethylation product, wherein the feed rates of the cyclization reaction product, potassium hydroxide, acetonitrile and chlorodifluoromethane are shown in Table 4; the temperature of the continuous difluoromethylation reaction was set to 30° C. and the material residence time was 90 min; the second product system was continuously solid-liquid separated by a twin-screw solid-liquid separator, and then continuously concentrated by a second thin film evaporator to obtain a difluoromethylation product 5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole.

[0130] The purity and yield of the difluoromethylation products obtained in Examples 13 to 18 and the remaining amount of the cyclization product are shown in Table 4. The purity of the difluoromethylation products obtained in Examples 13 to 18 and the remaining amount of the cyclization product were detected by liquid chromatography.

[0131] Table 4

[0132]

[0133] It can be seen from Table 4 that when the feed rate of potassium hydroxide is 0.6 kg / h or 0.7 kg / h (Example 17 and Example 18), the residual amount of the cyclization reaction product is lower, and the purity and yield of the difluoromethylation product are higher.

[0134] (V) Effect of the Type of Continuous Chloromethylation Reaction Unit 320 on the Continuous Chloromethylation Reaction

[0135] Examples 19 to 23

[0136] Use Figure 2 The continuous production system of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole shown in the invention is continuously synthesized, comprising the following steps:

[0137] (1) Ethyl trifluoroacetoacetate and acetic acid were introduced into a first microchannel silicon carbide mixer at a rate of 2.2 kg / h and 0.9 kg / h, respectively, and mixed for 0.01 min to obtain a first mixed solution; the first mixed solution and a methylhydrazine aqueous solution were introduced into a second microchannel silicon carbide mixer at a rate of 3.1 kg / h and 1.32 kg / h, respectively, and mixed for 0.01 min to obtain a second mixed solution; the second mixed solution was introduced into a coil reactor (the same as the reactor in Example 4) at a rate of 4.42 kg / h for continuous cyclization reaction to obtain a first product system containing a cyclization reaction product, and the flow rate of the second mixed solution was set to 44 cm·cm -2·min -1 , the temperature of the continuous cyclization reaction is 95° C., and the material residence time is 130 min; the first product system is passed into a continuous quenching reactor, and is continuously quenched with tap water, and then continuously concentrated with a first thin film evaporator, and continuously separated solid from liquid with a horizontal screw centrifuge to obtain a cyclization reaction product 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole;

[0138] (2) introducing the cyclization reaction product, potassium hydroxide and acetonitrile into a continuous liquid feeder at a rate of 1 kg / h, 0.6 kg / h and 2 kg / h, respectively, and mixing for 0.01 min to obtain a liquid phase material; introducing the liquid phase material and chlorodifluoromethane into a dynamic tubular reactor (the same as the reactor in Example 11) at a rate of 3.5 kg / h and 0.6 kg / h, respectively, to carry out a continuous difluoromethylation reaction to obtain a second product system containing a difluoromethylated product, wherein the temperature of the continuous difluoromethylation reaction is set to 30° C. and the material residence time is 90 min; performing continuous solid-liquid separation on the second product system using a twin-screw solid-liquid separator, and then continuously concentrating it using a second thin film evaporator to obtain a difluoromethylated product 5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole;

[0139] (3) The difluoromethylation product and sulfuric acid were introduced into a third microchannel silicon carbide mixer at a rate of 1 kg / h and 0.5 kg / h, respectively, and mixed for 0.01 min to obtain a third mixed solution; hydrochloric acid (mass concentration of 36 wt%) and formaldehyde aqueous solution (mass concentration of 37 wt%) were introduced into a fourth microchannel silicon carbide mixer at a rate of 1.2 kg / h and 0.5 kg / h, respectively, and mixed for 0.01 min to obtain a fourth mixed solution; the third mixed solution and the fourth mixed solution were introduced into a fifth microchannel silicon carbide mixer at a rate of 1.5 kg / h and 1.7 kg / h, respectively, and mixed for 0.01 min to obtain a fifth mixed solution; the fifth mixed solution was introduced into different types of continuous chloromethylation reaction devices 320 (specific types are shown in Table 5) at a rate of 3.2 kg / h for continuous chloromethylation reaction to obtain a third product system containing the target product, and the flow rate of the fifth mixed solution was set to 400 cm·cm -2 ·min -1 The temperature of the continuous chloromethylation reaction is 110°C, and the material residence time is 120min; the third product system is passed into the first continuous centrifuge for continuous liquid separation, and then a continuous overflow reactor (refer to Chinese patent application CN202223253379.6) is used for continuous water washing, and a second continuous centrifuge is used for continuous liquid separation again to obtain the target product 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole.

[0140] The purity and yield of the target products obtained in Examples 19 to 23 and the remaining amount of the difluoromethylated product are shown in Table 5. The purity of the target products obtained in Examples 19 to 23 and the remaining amount of the difluoromethylated product were detected by liquid chromatography.

[0141] Table 5

[0142]

[0143] It can be seen from Table 5 that when the continuous chloromethylation reaction device 320 is a coil reactor (Example 22), the residual amount of the difluoromethylation product is less, and the purity and yield of the target product are higher.

[0144] (VI) Effect of the Feed Rate of Each Reaction Material on the Continuous Chloromethylation Reaction

[0145] Examples 24 to 27

[0146] Use Figure 2 The continuous production system of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole shown in the invention is continuously synthesized, comprising the following steps:

[0147] (1) Ethyl trifluoroacetoacetate and acetic acid were introduced into a first microchannel silicon carbide mixer at a rate of 2.2 kg / h and 0.9 kg / h, respectively, and mixed for 0.01 min to obtain a first mixed solution; the first mixed solution and a methylhydrazine aqueous solution were introduced into a second microchannel silicon carbide mixer at a rate of 3.1 kg / h and 1.32 kg / h, respectively, and mixed for 0.01 min to obtain a second mixed solution; the second mixed solution was introduced into a coil reactor (the same as the reactor in Example 4) at a rate of 4.42 kg / h for continuous cyclization reaction to obtain a first product system containing a cyclization reaction product, and the flow rate of the second mixed solution was set to 44 cm·cm -2 ·min -1 , the temperature of the continuous cyclization reaction is 95° C., and the material residence time is 130 min; the first product system is passed into a continuous quenching reactor, and is continuously quenched with tap water, and then continuously concentrated with a first thin film evaporator, and continuously separated solid from liquid with a horizontal screw centrifuge to obtain a cyclization reaction product 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole;

[0148] (2) introducing the cyclization reaction product, potassium hydroxide and acetonitrile into a continuous liquid feeder at a rate of 1 kg / h, 0.6 kg / h and 2 kg / h, respectively, and mixing for 0.01 min to obtain a liquid phase material; introducing the liquid phase material and chlorodifluoromethane into a dynamic tubular reactor (the same as the reactor in Example 11) at a rate of 3.5 kg / h and 0.6 kg / h, respectively, to carry out a continuous difluoromethylation reaction to obtain a second product system containing a difluoromethylated product, wherein the temperature of the continuous difluoromethylation reaction is set to 30° C. and the material residence time is 90 min; performing continuous solid-liquid separation on the second product system using a twin-screw solid-liquid separator, and then continuously concentrating it using a second thin film evaporator to obtain a difluoromethylated product 5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole;

[0149] (3) The difluoromethylation product and sulfuric acid were introduced into a third microchannel silicon carbide mixer at different feed rates and mixed for 0.01 min to obtain a third mixed solution; hydrochloric acid and formaldehyde aqueous solution were introduced into a fourth microchannel silicon carbide mixer and mixed for 0.01 min to obtain a fourth mixed solution; the third mixed solution and the fourth mixed solution were introduced into a fifth microchannel silicon carbide mixer and mixed for 0.01 min to obtain a fifth mixed solution; the fifth mixed solution was introduced into a coil reactor (the same as the reactor in Example 22) at a rate of 3.2 kg / h for continuous chloromethylation reaction to obtain a third product system containing the target product, wherein the feed rates of the difluoromethylation product, sulfuric acid, hydrochloric acid and formaldehyde aqueous solution are shown in Table 6; the flow rate of the fifth mixed solution was set to 400 cm·cm -2 ·min -1 The temperature of the continuous chloromethylation reaction is 110°C, and the material residence time is 120 min; the third product system is passed into the first continuous centrifuge for continuous liquid separation, and then continuously washed with water using a continuous overflow reactor, and then continuously separated again using a second continuous centrifuge to obtain the target product 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole.

[0150] The purity and yield of the target products obtained in Examples 24 to 27 and the remaining amount of the difluoromethylated product are shown in Table 6. The purity of the target products obtained in Examples 24 to 27 and the remaining amount of the difluoromethylated product were detected by liquid chromatography.

[0151] Table 6

[0152]

[0153] It can be seen from Table 6 that when the feed rate of hydrochloric acid is 1.2 kg / h (Example 22), the remaining amount of difluoromethylation product is less, and the purity and yield of the target product are higher.

[0154] Comparative Example 1

[0155] A batch preparation method of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole comprises the following steps:

[0156] (1) In a 250 mL four-necked bottle, 20 g of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole and 10 mL of acetic acid were mixed to obtain a mixed solution, 7.5 g of methylhydrazine aqueous solution was slowly dropped into the mixed solution, and the mixture was reacted at 95° C. for 120 min. After solid-liquid separation and concentration, the intermediate 5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole was obtained; the residual amount of 5-hydroxy-1-methyl-3-trifluoromethyl-1H-pyrazole was measured by liquid chromatography to be 0.5%, the purity of the intermediate was 99.5%, and the yield of the intermediate was 83%;

[0157] (2) In a 250 mL four-necked flask, 20 g of the intermediate 5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole, 25 g of potassium hydroxide and 0.5 g of acetonitrile were mixed to obtain a mixed solution. 25 g of monochlorodifluoromethane was slowly introduced into the mixed solution at 30°C, and the mixture was reacted at 30°C for 140 min. After separation, washing with water and separation again, the product 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole was obtained. The residual amount of 5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole was measured by liquid chromatography to be 1%. After the reaction was extended for 40 min and tested again, the residual amount of 5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole was 0%, the product purity was 98%, and the product yield was 94%.

[0158] In Comparative Example 1, the yield of the intermediate 5-(difluoromethoxy)-1-methyl-3-(trifluoromethyl)-1H-pyrazole is lower than that of Examples 17 and 18 under the optimal conditions in the examples of the present application; the yield of the target product 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole is lower than that of Example 22 under the optimal conditions in the examples of the present application.

[0159] From the above description, it can be seen that the above embodiments of the present invention achieve the following technical effects:

[0160] By comparing the embodiments of the present application with comparative example 1, it can be seen that the application of the above-mentioned continuous production system of the present application for production can improve the overall production efficiency, reduce energy loss and raw material waste, and reduce production costs; the above-mentioned continuous equipment of the present application has high heat exchange efficiency and can accurately control the reaction conditions, thereby being able to suppress the occurrence of side reactions and improve the yield and purity of the target product; at the same time, the continuous operation can, on the one hand, realize the immediate quenching of the reaction and the immediate separation of the product, thereby reducing the safety hazards caused by the long-term storage of a large amount of highly reactive materials, and on the other hand, can significantly reduce the labor intensity of operators and reduce the frequency of their contact with hazardous materials, thereby significantly improving production safety.

[0161] By comparing Examples 1 to 5, it can be seen that, compared with other types, the use of the above-mentioned type of continuous cyclization reaction device 120 is conducive to more accurate control of the reaction conditions of the continuous cyclization reaction, thereby helping to suppress the occurrence of side reactions, helping to improve the reaction efficiency of the continuous cyclization reaction, and further helping to improve the yield of the cyclization reaction product. At the same time, the above-mentioned type of continuous cyclization reaction device 120 has a higher heat exchange efficiency, thereby helping to improve the safety of the continuous cyclization reaction and also helping to improve the utilization rate of the equipment.

[0162] Comparing Examples 4, 6 to 10, it can be seen that, compared with other ranges, limiting the feed rate ratio of ethyl trifluoroacetoacetate, methylhydrazine aqueous solution and the first catalyst within the above range of the present application is beneficial to improving the dispersibility and mixing efficiency of the above raw materials, improving the selectivity and reaction efficiency of the continuous cyclization reaction, and suppressing the occurrence of side reactions, thereby helping to improve the purity and yield of the continuous cyclization reaction product.

[0163] By comparing Examples 11 and 12, it can be seen that, compared with other types, the above-mentioned type of continuous difluoromethylation reaction device 220 is beneficial to more accurately control the reaction conditions of the continuous difluoromethylation reaction, suppress the occurrence of side reactions, and improve the reaction efficiency and raw material conversion rate of the continuous difluoromethylation reaction, thereby reducing the use of auxiliary materials and improving the utilization rate of raw materials; on the other hand, the above-mentioned type of continuous difluoromethylation reaction device 220 has a higher heat exchange efficiency, which is beneficial to improve the safety of the continuous difluoromethylation reaction and improve the utilization rate of the equipment.

[0164] By comparing Examples 13 to 18, it can be seen that, compared with other ranges, limiting the feed rate ratio of the cyclization reaction product, the second catalyst, the solvent and CHF2Cl within the above-mentioned range of the present application is beneficial to improving the dispersibility and mixing efficiency of the above-mentioned raw materials, and is beneficial to improving the reaction efficiency of the continuous difluoromethylation reaction, and is beneficial to suppressing the occurrence of side reactions, and is beneficial to improving the selectivity and raw material conversion rate of the continuous difluoromethylation reaction, thereby helping to improve the purity and yield of the difluoromethylation product.

[0165] Comparing Examples 19 to 23, it can be seen that, compared with other types, the above-mentioned type of continuous chloromethylation reaction device 320 is conducive to more accurate control of the reaction conditions of the continuous chloromethylation reaction, thereby helping to suppress the occurrence of side reactions, and helping to improve the reaction efficiency of the continuous chloromethylation reaction, thereby helping to improve the yield of the target product. At the same time, the above-mentioned type of continuous chloromethylation reaction device 320 has a higher heat exchange efficiency, thereby helping to improve the safety of the continuous cyclization reaction and also helping to improve the utilization rate of the equipment.

[0166] By comparing Examples 22, 24 to 27, it can be seen that, compared with other ranges, limiting the feed rate ratio of the difluoromethylation product, the third catalyst, hydrochloric acid and the formaldehyde aqueous solution within the above-mentioned range of the present application is beneficial to improving the dispersibility and mixing efficiency of the above-mentioned raw materials, improving the reaction efficiency of the continuous chloromethylation reaction, suppressing the occurrence of side reactions, and improving the selectivity and raw material conversion rate of the continuous chloromethylation reaction, thereby helping to improve the purity and yield of the target product.

[0167] It should be noted that the terms "first", "second", etc. in the specification and claims of the present application are used to distinguish similar objects, and are not necessarily used to describe a specific order or sequence. It should be understood that the terms used in this way can be interchangeable where appropriate, so that the embodiments of the present application described herein can be implemented in an order other than those described herein, for example.

[0168] The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. For those skilled in the art, the present invention may have various modifications and variations. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A continuous production system of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole, characterized in that: The continuous production system comprises: A continuous cyclization reaction unit (100) is used to cause ethyl trifluoroacetoacetate and a methylhydrazine aqueous solution to undergo a continuous cyclization reaction under the catalysis of a first catalyst to obtain a first product system containing a cyclization reaction product, and to sequentially perform continuous quenching, first continuous concentration, and first continuous solid-liquid separation on the first product system to obtain a cyclization reaction product; the continuous cyclization reaction unit (100) comprises a first continuous feeding module (110), a continuous cyclization reaction device (120), a continuous quenching device (130), a first continuous concentration device (140), and a first continuous solid-liquid separation device (150) which are connected in sequence; the first continuous solid-liquid separation device (150) is provided with a cyclization reaction product outlet; A continuous difluoromethylation reaction unit (200) is used to cause the cyclization reaction product and chlorodifluoromethane to undergo a continuous difluoromethylation reaction in a solvent under the catalysis of a second catalyst to obtain a second product system containing a difluoromethylation product, and to sequentially perform a second continuous solid-liquid separation and a second continuous concentration on the second product system to obtain a difluoromethylation product; the continuous difluoromethylation reaction unit (200) comprises a second continuous feeding module (210), a continuous difluoromethylation reaction device (220), a second continuous solid-liquid separation device (230) and a second continuous concentration device (240) which are connected in sequence; the inlet of the second continuous feeding module (210) is connected to the outlet of the cyclization reaction product; and the second continuous concentration device (240) is provided with an outlet for the difluoromethylation product; The continuous chloromethylation reaction unit (300) is used to cause the difluoromethylation product, hydrochloric acid and formaldehyde aqueous solution to undergo a continuous chloromethylation reaction under the catalysis of a third catalyst to obtain a third product system containing a target product, and to sequentially perform a first continuous liquid separation, a continuous water washing and a second continuous liquid separation on the third product system to obtain the 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole. The continuous chloromethylation reaction unit (300) comprises a third continuous feeding module (310), a continuous chloromethylation reaction device (320), a first continuous liquid separation device (330), a continuous water washing device (340) and a second continuous liquid separation device (350) which are connected in sequence. The inlet of the third continuous feeding module (310) is connected to the difluoromethylation product outlet. The second continuous liquid separation device (350) is provided with a target product outlet for discharging the 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole.

2. The continuous production system according to claim 1, characterized in that: The continuous cyclization reaction device (120) is selected from a microchannel tubular reactor, a continuous overflow reactor, a dynamic tubular reactor, a vertical tubular reactor, a tubular reactor, a coil reactor, a U-shaped tubular reactor, or a horizontal tubular reactor.

3. The continuous production system according to claim 1, characterized in that: The continuous cyclization reaction device (120) further comprises a first tail gas outlet, and the continuous cyclization reaction unit (100) further comprises: A first temperature control device (160), the first temperature control device (160) being electrically connected to the continuous cyclization reaction device (120) and regulating the temperature in the continuous cyclization reaction device (120) through negative feedback; A first tail gas absorption device (170) is used to absorb tail gas generated during the continuous cyclization reaction, and an inlet of the first tail gas absorption device (170) is connected to the first tail gas outlet; The explosion relief device (180) is used to release the pressure in the continuous cyclization reaction device (120); the explosion relief device (180) is connected to the continuous cyclization reaction device (120) via an explosion relief pipeline; the explosion relief device (180) is equipped with an explosion relief sheet.

4. The continuous production system according to claim 1, characterized in that: The first continuous feeding module (110) comprises: a continuous ethyl trifluoroacetoacetate feeding device (111), a continuous first catalyst feeding device (112), a continuous methylhydrazine aqueous solution feeding device (113), a first continuous mixing device (114) and a second continuous mixing device (115); wherein: The inlet of the first continuous mixing device (114) is connected to the outlet of the continuous ethyl trifluoroacetoacetate feeding device (111) and the outlet of the continuous first catalyst feeding device (112); the first continuous mixing device (114) is used to mix the ethyl trifluoroacetoacetate with the first catalyst to obtain a first mixed liquid; The inlet of the second continuous mixing device (115) is connected to the outlet of the continuous methylhydrazine aqueous solution feeding device (113) and the outlet of the first continuous mixing device (114), and the outlet of the second continuous mixing device (115) is connected to the inlet of the continuous cyclization reaction device (120); the second continuous mixing device (115) is used to mix the methylhydrazine aqueous solution with the first mixed solution to obtain a second mixed solution, and feed the second mixed solution into the continuous cyclization reaction device (120) to carry out the continuous cyclization reaction.

5. The continuous production system according to claim 4, characterized in that: The first continuous mixing device (114) and the second continuous mixing device (115) are each independently selected from a microchannel silicon carbide mixer, a Kenics type static mixer, an SMX type static mixer, an SMXL type static mixer, an SMV type static mixer or an SK type static mixer.

6. The continuous production system according to claim 1, characterized in that: The continuous difluoromethylation reaction device (220) is selected from a dynamic tubular reactor or a continuous overflow reactor.

7. The continuous production system according to claim 6, characterized in that: A gas distributor is provided at the bottom of the continuous difluoromethylation reaction device (220).

8. The continuous production system according to claim 1, characterized in that: The second continuous feeding module (210) comprises a continuous liquid phase feeding device (211) and a continuous gas feeding device (212); the outlet of the continuous liquid phase feeding device (211) is used to discharge the liquid phase material containing the cyclization reaction product, the second catalyst and the solvent, and the outlet of the continuous gas feeding device (212) is used to supply the monochlorodifluoromethane.

9. The continuous production system according to claim 1, characterized in that: The continuous difluoromethylation reaction device (220) further comprises a second tail gas outlet, and the continuous difluoromethylation reaction unit (200) further comprises: A second temperature control device (250), the second temperature control device (250) being electrically connected to the continuous difluoromethylation reaction device (220) and regulating the temperature in the continuous difluoromethylation reaction device (220) through negative feedback; A second tail gas absorption device (260) is used to absorb tail gas generated during the continuous difluoromethylation reaction, and an inlet of the second tail gas absorption device (260) is connected to the second tail gas outlet; The first inert gas supply device (270) is used to supply inert gas to the continuous difluoromethylation reaction device (220), and the outlet of the first inert gas supply device (270) is connected to the inlet of the continuous difluoromethylation reaction device (220).

10. The continuous production system according to claim 1, characterized in that: The continuous chloromethylation reaction device (320) is selected from a microchannel tubular reactor, a continuous overflow reactor, a dynamic tubular reactor, a vertical tubular reactor, a tubular reactor, a coil reactor, a U-shaped tubular reactor, or a horizontal tubular reactor.

11. The continuous production system according to claim 1, characterized in that: The continuous chloromethylation reaction device (320) further has a third tail gas outlet. The continuous chloromethylation reaction unit (300) further comprises: a third temperature control device (360), the third temperature control device (360) being electrically connected to the continuous chloromethylation reaction device (320) and regulating the temperature in the continuous chloromethylation reaction device (320) through negative feedback; A third tail gas absorption device (370) is used to absorb tail gas generated during the continuous chloromethylation reaction, and the inlet of the third tail gas absorption device (370) is connected to the third tail gas outlet; The second inert gas supply device (380) is used to supply inert gas to the continuous chloromethylation reaction device (320), and the outlet of the second inert gas supply device (380) is connected to the inlet of the continuous chloromethylation reaction device (320).

12. The continuous production system according to claim 1, characterized in that: The third continuous feeding module (310) comprises: a continuous difluoromethylation product feeding device (311), a continuous third catalyst feeding device (312), a continuous hydrochloric acid feeding device (313), a continuous formaldehyde aqueous solution feeding device (314), a third continuous mixing device (315), a fourth continuous mixing device (316) and a fifth continuous mixing device (317); wherein, The inlet of the third continuous mixing device (315) is connected to the outlet of the continuous difluoromethylation product feeding device (311) and the outlet of the continuous third catalyst feeding device (312); the third continuous mixing device (315) is used to mix the difluoromethylation product with the third catalyst to obtain a third mixed liquid; The inlet of the fourth continuous mixing device (316) is connected to the outlet of the continuous hydrochloric acid feeding device (313) and the outlet of the continuous formaldehyde aqueous solution feeding device (314); the fourth continuous mixing device (316) is used to mix the hydrochloric acid and the formaldehyde aqueous solution to obtain a fourth mixed solution; The inlet of the fifth continuous mixing device (317) is connected to the outlet of the third continuous mixing device (315) and the outlet of the fourth continuous mixing device (316); the fifth continuous mixing device (317) is used to mix the third mixed liquid with the fourth mixed liquid to obtain a fifth mixed liquid, and send the fifth mixed liquid to the continuous chloromethylation reaction device (320) to perform the continuous chloromethylation reaction.

13. The continuous production system according to claim 12, characterized in that: The third continuous mixing device (315), the fourth continuous mixing device (316) and the fifth continuous mixing device (317) are each independently selected from a microchannel silicon carbide mixer, a Kenics type static mixer, an SMX type static mixer, an SMXL type static mixer, an SMV type static mixer or an SK type static mixer.

14. A method for continuous production of 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole, characterized in that: 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole is continuously produced using the continuous production system according to any one of claims 1 to 13, and the continuous production method comprises: Step S1, using a first continuous feeding module (110) to pass ethyl trifluoroacetoacetate, a first catalyst and a methylhydrazine aqueous solution into a continuous cyclization reaction device (120) for continuous cyclization reaction to obtain a first product system containing a cyclization reaction product; sequentially using a continuous quenching device (130), a first continuous concentrating device (140) and a first continuous solid-liquid separation device (150) to continuously quench, first continuously concentrate and first continuously solid-liquid separate the first product system to obtain the cyclization reaction product; Step S2, using a second continuous feeding module (210) to introduce the cyclization reaction product, a second catalyst, a solvent and monochlorodifluoromethane into a continuous difluoromethylation reaction device (220) for continuous difluoromethylation reaction to obtain a second product system containing a difluoromethylation reaction product; sequentially using a second continuous solid-liquid separation device (230) and a second continuous concentration device (240) to perform second continuous solid-liquid separation and second continuous concentration on the second product system to obtain the difluoromethylation reaction product; Step S3, using a third continuous feeding module (310) to pass the difluoromethylation reaction product, a third catalyst, hydrochloric acid and a formaldehyde aqueous solution into a continuous chloromethylation reaction device (320) for continuous chloromethylation reaction to obtain a third product system containing the target product; and using a first continuous liquid separation device (330), a continuous water washing device (340) and a second continuous liquid separation device (350) in sequence to perform a first continuous liquid separation, a continuous water washing and a second continuous liquid separation on the third product system to obtain the 5-(difluoromethoxy)-4-chloromethyl-1-methyl-3-(trifluoromethyl)-1H-pyrazole.

15. The continuous production method according to claim 14, characterized in that: The reaction temperature of the continuous cyclization reaction is 80-110° C., and the material residence time is 30-130 min.

16. The continuous production method according to claim 14, characterized in that: The ethyl trifluoroacetoacetate and the first catalyst are mixed by a first continuous mixing device (114) to obtain a first mixed solution; the feed rate ratio of the ethyl trifluoroacetoacetate to the first catalyst is (1-2): (0.7-3.2); the residence time of the ethyl trifluoroacetoacetate and the first catalyst is independently 0.01-0.05 min; and / or, The methylhydrazine aqueous solution is mixed with the first mixed solution by a second continuous mixing device (115) to obtain a second mixed solution; the feed rate ratio of the methylhydrazine aqueous solution to the first mixed solution is (0.36-1):(0.5-1); and the residence time of the methylhydrazine aqueous solution and the first mixed solution is independently 0.01-0.05 min.

17. The continuous production method according to claim 16, characterized in that: In the second mixed solution, the weight ratio of the ethyl trifluoroacetoacetate, the first catalyst and the methylhydrazine aqueous solution is 1:(0.4-3):(0.5-1.2); and / or, The flow rate of the second mixed liquid is 44 to 100 cm·cm -2 ·min -1 .

18. The continuous production method according to claim 14, characterized in that: The reaction temperature of the continuous difluoromethylation reaction is 0-40° C., and the material residence time is 20-100 min.

19. The continuous production method according to claim 14, characterized in that: The cyclization reaction product, the second catalyst and the solvent are mixed by a continuous liquid phase feeding device (211) to obtain a liquid phase material; the feed rate ratio of the cyclization reaction product, the second catalyst and the solvent is 1:(0.3-1):(2-5); the residence time of the cyclization reaction product, the second catalyst and the solvent is independently 0.01-0.05 min.

20. The continuous production method according to claim 19, characterized in that: The weight ratio of the cyclization reaction product, the monochlorodifluoromethane, the second catalyst and the solvent is 1:(0.5-1):(0.3-2):(1-3); and / or, In the continuous difluoromethylation reaction device (220), the feed rate ratio of the liquid phase material to the chlorodifluoromethane is 3.5:(0.6-2).

21. The continuous production method according to claim 14, characterized in that: The reaction temperature of the continuous chloromethylation reaction is 90-120° C., and the material residence time is 20-120 min.

22. The continuous production method according to claim 14, characterized in that: The difluoromethylation product and the third catalyst are mixed by a third continuous mixing device (315) to obtain a third mixed solution; the feed rate ratio of the difluoromethylation product to the third catalyst is 1:(0.5-2); the residence time of the difluoromethylation product and the third catalyst is independently 0.01-0.05 min; and / or, The hydrochloric acid and the formaldehyde aqueous solution are mixed by a fourth continuous mixing device (316) to obtain a fourth mixed solution; the mass concentration of the formaldehyde aqueous solution is 37-40wt%; the mass concentration of the hydrochloric acid is 36-38wt%; the feed rate ratio of the hydrochloric acid to the formaldehyde aqueous solution is 1:(0.3-1.5); the residence time of the hydrochloric acid and the formaldehyde aqueous solution is independently 0.01-0.05min; and / or, The third mixed liquid and the fourth mixed liquid are mixed by a fifth continuous mixing device (317) to obtain a fifth mixed liquid; the feed rate ratio of the third mixed liquid to the fourth mixed liquid is 1:(1-1.5); the residence time of the third mixed liquid and the fourth mixed liquid is independently 0.01-0.05 min.

23. The continuous production method according to claim 22, characterized in that: In the fifth mixed solution, the weight ratio of the difluoromethylation reaction product, the third catalyst, the hydrochloric acid and the formaldehyde aqueous solution is 1:(0.1-2):(0.5-5):(0.3-1); and / or, The flow rate of the fifth mixed liquid is 200 to 500 cm·cm -2 ·min -1 .

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