System and method for continuously preparing bixafen

Abstract

The invention provides a system and a method for continuously preparing bixafen. The system comprises a first reaction unit and a second reaction unit, and the first reaction unit is composed of a first feeding module, a first reaction module and a first purification module which are sequentially connected; the second reaction unit consists of a second feeding module, a second reaction module and a second purification module which are connected in sequence; and a discharge port of the first purification module is connected with a feed port of the second feed module. By adopting the continuous synthesis system to prepare bixafen, automatic control can be realized, the labor is saved, the production time is saved, and the production cost is effectively reduced; meanwhile, the production efficiency can be improved, and the product yield is increased.

Description

Technical Field

[0001] The present invention relates to the technical field of chemical synthesis, and in particular to a system and method for continuously preparing bixafen. Background Art

[0002] Bixafen, English common name: bixafen, Chinese chemical name: N-(3',4'-dichloro-5-fluorobiphenyl-2-yl)-3-(difluoromethyl)-1-methylpyrazole-4-amide. A pyrazole chemicalbookamide fungicide developed by Bayer CropScience, it is an important member of the fastest growing succinate dehydrogenase inhibitor (SDHI) fungicide class. It was disclosed in 2006, first registered in 2010, and launched in 2011. It is produced by Bayer.

[0003] Bixafen acts on succinate dehydrogenase (SDH), one of the hubs connecting oxidative phosphorylation and electron transfer in bacteria, leading to chemical blockage of tricarboxylic acid cycle, hindering its energy metabolism, and then inhibiting the growth of pathogens, leading to their death, thereby achieving the purpose of disease prevention and control. Bixafen is highly effective, broad-spectrum, long-lasting, highly selective, and has excellent systemic conductivity. It has both preventive and therapeutic effects and can inhibit spore germination, mycelial growth and spore formation.

[0004] There are two main existing synthetic routes for bixafen. Among them, the patent application document CN110117256A discloses the following process route:

[0005]

[0006] Using 3,4-dichloroaniline as raw material, a diazotization reaction is carried out under the action of hydrochloric acid and sodium nitrite to generate the corresponding diazonium salt, and the diazonium salt is further reduced under the condition of sodium bisulfite to generate the corresponding hydrazine, and then under the condition of hydrochloric acid to form a hydrazine salt, and the hydrazine salt and p-fluoroaniline are coupled under air conditions to generate intermediate 1; intermediate 1 and intermediate 2 are condensed under the alkaline condition of triethylamine to generate bixafen. The diazotization reaction of this method is a high-risk reaction, with large and intense reaction heat release, inaccurate process parameter control, easy to exceed the limit, and the feeding method of the intermittent process is easy to cause material exposure, aggravating the dangerous risk level of the production site operation environment, and the process risk is high.

[0007] Japan Fankem Company announced the following process route:

[0008]

[0009] Raw materials 1 and 2 are subjected to amine ester reaction under alkaline conditions, and intermediate 1 is obtained after post-treatment such as crystallization and filtration, and Suzuki coupling is carried out with intermediate 2 in the presence of a palladium catalyst, and bixafen is obtained after post-treatment. This route performs deacetylation protection in the first step, and the atomic utilization rate is low. In the second step, hazardous materials such as sodium ethoxide are used, which is highly dangerous during the preparation of the compound and does not conform to the green trend of chemical reactions. Summary of the invention

[0010] The main purpose of the present invention is to provide a system and method for continuously preparing bixafen, so as to solve the problem of low yield of bixafen in the prior art.

[0011] In order to achieve the above-mentioned object, according to a first aspect of the present invention, a system for continuously preparing bixafen is provided, comprising: a first reaction unit, the first reaction unit consisting of a first feeding module, a first reaction module and a first purification module connected in sequence; a second reaction unit, the second reaction unit consisting of a second feeding module, a second reaction module and a second purification module connected in sequence; the discharge port of the first purification module is connected to the feed port of the second feeding module.

[0012] Furthermore, the first purification module includes a first separation module and a second separation module connected in sequence, and the feed port of the first separation module is connected to the discharge port of the first reaction module; the second purification module includes an extraction module, a concentration module and a third separation module connected in sequence, and the feed port of the extraction module is connected to the discharge port of the second reaction module.

[0013] Furthermore, the outside of the first reaction module, the first separation module and the second separation module are each independently provided with a jacket for passing a medium substance for temperature adjustment; the outside of the second reaction module, the extraction module, the concentration module and the third separation module are each independently provided with a jacket for passing a medium substance for temperature adjustment.

[0014] Furthermore, the medium material includes: silicon heat-conducting oil or circulating water.

[0015] Furthermore, the first reaction module includes 1-5 first reactors connected in series, the second reaction module includes 1-3 second reactors connected in series, and the types of the first reactor and the second reactor include: a continuous dynamic tubular reactor, and a mixing core structure is arranged inside the continuous dynamic tubular reactor.

[0016] In order to achieve the above-mentioned object, according to a second aspect of the present invention, a method for continuously preparing bixafen is provided, wherein the system for continuously preparing bixafen is used to continuously synthesize bixafen, and the method comprises: adding a solution of a first raw material, a solution of a second raw material and a first alkaline solution to a first reaction module through a first feeding module for a first reaction, and a product of the first reaction enters a first purification module for a first purification treatment to obtain a first intermediate; adding a solution of the first intermediate, a solution of the second intermediate, a second alkaline solution and a catalyst to a second reaction module through a second feeding module for a second reaction, and a product of the second reaction enters a second purification module for a second purification treatment to obtain bixafen;

[0017] Wherein, the first raw material is a compound as shown in formula I Formula Ⅰ; the second raw material is a compound as shown in Formula Ⅱ Formula II; the first intermediate is a compound as shown in Formula III Formula III; the second intermediate is a compound shown in Formula IV Formula IV.

[0018] Furthermore, the first raw material and the second raw material are respectively dissolved in a first solvent to obtain a solution of the first raw material and a solution of the second raw material, and the first solvent is selected from one or more of the following: dichloromethane, 1,2-dichloroethane, chloroform and tetrahydrofuran; the molar ratio of the first raw material to the second raw material is 1:0.9-8.

[0019] Furthermore, the first intermediate and the second intermediate are respectively dissolved in a second solvent to obtain a solution of the first intermediate and a solution of the second intermediate, and the second solvent is selected from one or more of the following: toluene, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, ethanol, ethylene glycol dimethyl ether and water; the molar ratio of the first intermediate to the second intermediate is 1:1-5.

[0020] Furthermore, the catalyst is selected from any one or more of the following: PdCl2, Pd(pph3)4, Pd(OAc)2, Pd(dppf)Cl2, Pd2(dba)3, Pd(dba)2, NiCl2 and Ni(dppf)Cl2; the molar ratio of the first intermediate to the catalyst is 1:0.0005-0.2.

[0021] Furthermore, the first alkaline solution is selected from any one or more of the following: triethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, diethylamine, ethylenediamine and N,N-diisopropylethylamine; the molar ratio of the first raw material to the first alkaline solution is 1:0.5-5; the second alkaline solution is selected from any one or more of the following: triethylamine, pyridine, potassium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, cesium carbonate, lithium carbonate and sodium carbonate; the molar ratio of the first intermediate to the second alkaline solution is 1:3-15.

[0022] By applying the technical solution of the present invention, the synthesis system capable of continuously performing the first reaction and the second reaction is adopted to prepare bixafen, and the whole process from the first reaction reactant to finally obtaining bixafen can be realized. The substances in the system are not in contact with the outside world, and automatic control is realized, which saves labor, saves production time, and effectively reduces production costs; at the same time, the production efficiency can be improved and the product yield can be improved. BRIEF DESCRIPTION OF THE DRAWINGS

[0023] 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:

[0024] Figure 1 A schematic diagram of a system for continuous preparation of bixafen in the examples of the present application is shown;

[0025] The above drawings include the following reference numerals:

[0026] 101: first raw material feeding module; 102: second raw material feeding module; 103: first alkaline solution feeding module; 201: first reaction module; 301: first separation module; 302: second separation module; 401: first intermediate feeding module; 402: second intermediate feeding module; 403: second alkaline solution feeding module; 404: catalyst feeding module; 501: second reaction module; 601: extraction module; 602: concentration module; 603: third separation module. DETAILED DESCRIPTION

[0027] 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 with reference to the accompanying drawings and in combination with the embodiments.

[0028] As described in the background technology, the existing production of bixafen is mostly intermittent operation, which has low heat exchange efficiency and low production efficiency, resulting in decreased reaction effect and yield; and some reactions such as diazotization reaction are high-risk reactions, with large and intense reaction heat release, inaccurate process parameter control, and high production environmental risks. Therefore, the present application intends to provide a bixafen preparation device and method that is simple to operate and has a high yield.

[0029] In the first typical embodiment of the present application, a system for continuously preparing bixafen is provided, the system comprising: a first reaction unit and a second reaction unit, wherein the first reaction unit is composed of a first feed module, a first reaction module 201 and a first purification module connected in sequence; the second reaction unit is composed of a second feed module, a second reaction module 501 and a second purification module connected in sequence; the discharge port of the first purification module is connected to the feed port of the second feed module. The above-mentioned continuous system can integrate the feeding, reaction and product purification, can timely control the reaction conditions for preparing bixafen, avoids material loss and inconvenience in operation in the intermittent process, and further improves the yield of bixafen.

[0030] In order to further industrialize the process of preparing bixafen, the configuration and mixing of the solution materials for the reaction are also carried out in the above-mentioned continuous system. In a preferred embodiment, the first feeding module includes: a first raw material feeding module 101, a second raw material feeding module 102 and a first alkaline solution feeding module 103, and the outlets of the first raw material feeding module 101, the second raw material feeding module 102 and the first alkaline solution feeding module 103 are respectively connected to the inlet of the first reaction module 201. In a preferred embodiment, the second feeding module includes: a first intermediate feeding module 401, a second intermediate feeding module 402, a second alkaline solution feeding module 403, and a catalyst feeding module 404, and the outlet of the first purification module is connected to the inlet of the first intermediate feeding module 401, and the outlets of the first intermediate feeding module 401, the second intermediate feeding module 402, the second alkaline solution feeding module 403, and the catalyst feeding module 404 are respectively connected to the inlet of the second reaction module 501.

[0031] In a preferred embodiment, the inlets of the batching kettles in the first raw material feeding module 101, the second raw material feeding module 102, the first alkaline solution feeding module 103, the first intermediate feeding module 401, the second intermediate feeding module 402, the second alkaline solution feeding module 403 and the catalyst feeding module 404 are respectively connected to the outlets of their respective material storage tanks. Among them, the outlets of the material storage tanks of the first raw material and the first solvent are respectively connected to the inlet of the batching kettle in the first raw material feeding module 101, the outlets of the material storage tanks of the second raw material and the first solvent are respectively connected to the inlet of the batching kettle in the second raw material feeding module 102, and the outlets of the material storage tanks of the first alkaline solution and the first solvent are respectively connected to the inlet of the batching kettle in the first alkaline solution feeding module 103; the outlet of the material storage tank of the second separation module 302 and the second solvent is connected to the inlet of the batching kettle. They are respectively connected to the inlet of the batching kettle in the first intermediate feeding module 401, the outlets of the material storage tanks of the second intermediate and the second solvent are respectively connected to the inlet of the batching kettle in the second intermediate feeding module 402, the outlets of the material storage tanks of the second alkaline solution and the second solvent are respectively connected to the inlet of the batching kettle in the second alkaline solution feeding module 403, and the outlets of the material storage tanks of the catalyst and the second solvent are connected to the inlet of the batching kettle in the catalyst feeding module 404.

[0032] For example, the first raw material and the first solvent are introduced from their respective material storage tanks into the batching kettle in the first raw material feeding module 101 for mixing, and then enter the first reaction module 201 to participate in the first reaction; the first intermediate and the second solvent are introduced from the discharge port of the first purification module and the material storage tank of the second solvent into the batching kettle in the first intermediate feeding module 401 for mixing, and then enter the second reaction module 501 to participate in the second reaction. In a preferred embodiment, the feed port of the second intermediate feeding module 402 is provided with an interface connected to a nitrogen protection device for nitrogen protection of the material (second intermediate) in the second intermediate feeding module 402.

[0033] In order to further complete the second reaction with a higher yield and obtain a pyraclostrobin product with a higher purity, a purification device for the reaction product is set in the continuous system. In a preferred embodiment, the first purification module includes a first separation module 301 and a second separation module 302 connected in sequence, and the feed inlet of the first separation module 301 is connected to the discharge port of the first reaction module 201; the second purification module includes an extraction module 601, a concentration module 602 and a third separation module 603 connected in sequence, and the feed inlet of the extraction module 601 is connected to the discharge port of the second reaction module 501. Among them, the first separation module 301 is used to separate the solid-liquid product of the first reaction. In a preferred embodiment, the first separation module 301 includes 1-3 separators, preferably 1-2; the second separation module 302 is used to crystallize and filter the separated liquid reactant to obtain a first intermediate; the extraction module 601 is used to continuously extract and separate the product of the second reaction. In a preferred embodiment, the extraction module 601 includes 1-3 centrifugal extractors, preferably 1-2. After the organic phase is concentrated by the concentration module 602, it is crystallized and filtered in the third separation module 603 to obtain the bifenthrin product.

[0034] In order to further efficiently control the reaction temperature of the first reaction and the second reaction in the continuous system, in a preferred embodiment, the first reaction module 201, the first separation module 301 and the second separation module 302 are each independently provided with a jacket on the outside for passing a medium substance for temperature adjustment; the second reaction module 501, the extraction module 601, the concentration module 602 and the third separation module 603 are each independently provided with a jacket on the outside for passing a medium substance for temperature adjustment. During the preparation process, the temperature change in the reaction module is monitored in real time, and the temperature of the substance in the jacket is adjusted.

[0035] To further improve the reaction efficiency of the first reaction and the second reaction, in a preferred embodiment, the temperature of the first reaction module 201 is -5~25°C, the temperature of the first separation module 301 is -5~25°C, and the temperature of the second separation module 302 is -20~-10°C; preferably, the temperature of the second reaction module 501 is 30~120°C, the temperature of the extraction module 601 is 15~45°C; the temperature of the third separation module 603 is -20~10°C. To effectively adjust the temperature in the reaction module, in a preferred embodiment, the medium material includes: silicon heat transfer oil or circulating water.

[0036] In order to further fully carry out the first reaction and the second reaction, in a preferred embodiment, the first reaction module 201 includes 1-5 first reactors connected in series, preferably 1-2 first reactors connected in series, and the second reaction module 501 includes 1-3 second reactors connected in series; preferably, the types of the first reactor and the second reactor include: a continuous dynamic tubular reactor, and a mixing core structure is arranged inside the continuous dynamic tubular reactor. Among them, the second reactor selects a continuous dynamic tubular reactor, and a mixing core structure is arranged therein, which improves the mixing of materials in the pipeline, such as the reaction system of toluene and a solvent with poor water solubility, increases the mixing state of liquid-liquid heterogeneous materials, further shortens the reaction time, improves the reaction efficiency, and avoids the generation of some side reactions.

[0037] In a second typical embodiment of the present application, a method for continuously preparing bixafen is provided, and the above-mentioned system for continuously preparing bixafen is used to continuously synthesize bixafen, and the method comprises: adding a solution of a first raw material, a solution of a second raw material, and a first alkaline solution to a first reaction module 201 through a first feeding module for a first reaction, and a product of the first reaction enters a first purification module for a first purification treatment to obtain a first intermediate; adding a solution of the first intermediate, a solution of the second intermediate, a second alkaline solution, and a catalyst to a second reaction module 501 through a second feeding module for a second reaction, and a product of the second reaction enters a second purification module for a second purification treatment to obtain bixafen;

[0038] Wherein, the first raw material is a compound as shown in formula I Formula Ⅰ; the second raw material is a compound as shown in Formula Ⅱ Formula II; the first intermediate is a compound as shown in Formula III Formula III; the second intermediate is a compound shown in Formula IV Formula IV.

[0039] In order to further efficiently carry out the first reaction, in a preferred embodiment, the first raw material and the second raw material are dissolved respectively in a first solvent to obtain a solution of the first raw material and a solution of the second raw material, and the first solvent is selected from one or more of the following: dichloromethane, 1,2-dichloroethane, chloroform and tetrahydrofuran, preferably dichloromethane and chloroform; preferably, the molar ratio of the first raw material and the second raw material is 1:1.05-8, preferably 1:0.95-1.3; preferably, the mass ratio of the first raw material to the first solvent is 1:2-30; preferably, the mass ratio of the second raw material to the first solvent is 1:1-20; preferably, the mass ratio of the first alkaline solution to the first solvent is 1:3-7. In a preferred embodiment, the temperature of the first reaction is -10~25°C, and the time of the first reaction is 5-120min, preferably 20-90min.

[0040] In order to further obtain a first reaction product with better purity, in a preferred embodiment, the first purification treatment includes: the product of the first reaction sequentially enters the first separation module 301 for first solid-liquid separation, and the second separation module 302 for first crystallization and filtration. In a preferred embodiment, the temperature of the first solid-liquid separation is -10~25°C, and the temperature of the first crystallization is -25~-15°C.

[0041] In order to further efficiently carry out the second reaction, in a preferred embodiment, the first intermediate and the second intermediate are respectively dissolved in a second solvent to obtain a solution of the first intermediate and a solution of the second intermediate, and the second solvent is selected from one or more of the following: toluene, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, ethanol, ethylene glycol dimethyl ether and water; preferably, the molar ratio of the first intermediate to the second intermediate is 1:1-5. Preferably, the mass ratio of the first intermediate to the second solvent is 1:2-20, preferably, the mass ratio of the second intermediate to the second solvent is 1:1-5; preferably, the mass ratio of the second alkaline solution to the second solvent is 1:2-6; preferably, the mass ratio of the catalyst to the second solvent is 1:8-14. In a preferred embodiment, the temperature of the second reaction is 30-150°C, preferably 60-120°C, and the time of the second reaction is 30-120min, preferably 40-90min.

[0042] In a preferred embodiment, the catalyst is selected from any one or more of the following: PdCl2, Pd(PPh3)4, Pd(OAc)2, Pd(dppf)Cl2, Pd2(dba)3, Pd(dba)2, NiCl2 and Ni(dppf)Cl2; preferably, the molar ratio of the first intermediate to the catalyst is 1:0.0005-0.2.

[0043] In a preferred embodiment, the first alkaline solution is selected from any one or more of the following: triethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, diethylamine, ethylenediamine and N,N-diisopropylethylamine, preferably triethylamine, diethylamine and ethylenediamine; the molar ratio of the first raw material to the first alkaline solution is 1:0.5-5; the second alkaline solution is selected from any one or more of the following: triethylamine, pyridine, potassium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, cesium carbonate, lithium carbonate and sodium carbonate; the molar ratio of the first intermediate to the second alkaline solution is 1:3-15.

[0044] 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.

[0045] The beneficial effects of the present application will be further described below in conjunction with specific embodiments. It should be noted that the equipment used in the following embodiments is as follows: Figure 1 shown.

[0046] Example 1

[0047] 1. First Response

[0048] 1. Solution preparation: The first raw material and the first solvent are introduced from their respective material storage tanks into the batching kettle in the first raw material feeding module 101 for mixing, wherein the first solvent is dichloromethane, and the mass ratio of the first raw material to the first solvent is 1:2; the second raw material and the first solvent are introduced from their respective material storage tanks into the batching kettle in the second raw material feeding module 102 for mixing, wherein the first solvent is dichloromethane, and the mass ratio of the second raw material to the first solvent is 1:3; the first alkaline solution and the first solvent are introduced from their respective material storage tanks into the batching kettle in the first alkaline solution feeding module 103 for mixing, wherein the first alkaline solution is triethylamine, the first solvent is dichloromethane, and the mass ratio of the first alkaline solution to the first solvent is 1:1. The mixed first raw material, the second raw material and the first alkaline solution are prepared for use in the first raw material feeding module 101, the second raw material feeding module 102 and the first alkaline solution feeding module 103, respectively.

[0049] 2. Cooling: The reactor in the first reaction module 201 is cooled by introducing refrigerant circulating water into the interlayer of the first reactor to reduce the temperature inside the reactor to -5°C.

[0050] 3. Carry out the first reaction: start the delivery pumps in the first raw material feeding module 101, the second raw material feeding module 102 and the first alkaline solution feeding module 103, wherein the feed flow rate of the first raw material is 2.0 g / min, the feed flow rate of the second raw material is 3.0 g / min, and the feed flow rate of the triethylamine solution is 1.5 g / min, and the three streams of materials are simultaneously pumped into the first reactor in the first reaction module 201, and the first reactor is a continuous dynamic tubular reactor. Among them, the molar ratio of the first raw material to the second raw material is 1:1.46; the molar ratio of the first raw material to the triethylamine solution is 1:0.75.

[0051] The first raw material, the second raw material and triethylamine are subjected to a first reaction in the first reactor. The temperature of the first reaction is maintained at -5~5°C throughout the whole process. The first reaction time is 90 minutes, and then the first reaction product overflows into the first separation module 301.

[0052] 4. Post-treatment of the first reaction product: The first reaction product overflows into the first separation module 301 for solid-liquid separation, and the temperature is maintained at -10~-5°C throughout the process. The filtrate obtained enters the second separation module 302, where it is cooled and crystallized, and the temperature is controlled at -20~-15°C. After crystallization, it is further filtered, and the obtained filter cake is the first intermediate.

[0053] 2. Second reaction

[0054] 1. Solution preparation: The first intermediate and the second solvent are respectively introduced from the second separation module 302 and the second solvent material storage tank into the batching kettle in the first intermediate feeding module 401 for mixing, wherein the second solvent is toluene, and the mass ratio of the first intermediate to the second solvent is 1:2; the second intermediate and the second solvent are respectively introduced from their respective material storage tanks into the batching kettle in the second intermediate feeding module 402 for mixing, wherein the second solvent is toluene, and the mass ratio of the second intermediate to the second solvent is 1:2; the second alkaline solution and the second solvent are introduced from their respective material storage tanks into the batching kettle in the second alkaline solution feeding module 403 for mixing. The catalyst and the second solvent are introduced from their respective material storage tanks into a batching kettle in a catalyst feeding module 404 for mixing, wherein the catalyst is Pd(OAc)2, the second solvent is toluene, and the mass ratio of the catalyst to the second solvent is 1:0.5; the mixed first intermediate, second intermediate, catalyst and second alkaline solution are prepared for use in the first intermediate feeding module 401, the second intermediate feeding module 402, the second alkaline solution feeding module 403 and the catalyst feeding module 404, respectively.

[0055] 2. Heating: The reactor in the second reaction module 501 is heated, and heat medium silicon heat transfer oil is introduced into the interlayer of the second reactor to raise the temperature in the reactor to 80°C.

[0056] 3. Carry out the second reaction: start the respective delivery pumps in the first intermediate feed module 401, the second intermediate feed module 402, the second alkali solution feed module 403 and the catalyst feed module 404, wherein the feed flow rate of the first intermediate is 1.0 g / min, the feed flow rate of the second intermediate is 1.2 g / min, the feed flow rate of the cesium carbonate solution is 3.0 g / min, and the feed flow rate of the Pd(OAc)2 solution is 0.3 g / min, and the four streams of materials are simultaneously pumped into the second reactor in the second reaction module 501, and the second reactor is a continuous dynamic tubular reactor. Among them, the molar ratio of the first intermediate to the second intermediate is 1:2.2; the molar ratio of the first intermediate to the Pd(OAc)2 solution is 1:0.1; and the molar ratio of the first intermediate to the cesium carbonate solution is 1:3.1.

[0057] The first intermediate, the second intermediate, and the cesium carbonate solution undergo a second reaction in the second reactor under the catalysis of Pd(OAc)2. The temperature of the second reaction is maintained at 75-85°C throughout the process. The second reaction time is 60 minutes, and then the second reaction product overflows into the extraction module 601.

[0058] 4. Post-treatment of the second reaction product: The second reaction product overflows into the extraction module 601 for liquid separation, the organic phase enters the concentration module 602 for solvent concentration, and the concentrated system enters the third separation module 603 for crystallization. After crystallization, it is further filtered to obtain a filter cake of bixafen with a yield of 92%.

[0059] Example 2

[0060] Except that the type and amount of the first alkaline solution are different from those in Example 1, the other operations in this example are the same. The specific effects of the type and amount of the first alkaline solution on the products obtained by the reaction are shown in Table 1 below, wherein the system liquid phase purity in the example is the real-time sampling detection of the liquid phase material in the second reactor:

[0061] Table 1:

[0062]

[0063] Example 3

[0064] Except that the type and amount of the first solvent in this embodiment are different from those in Example 1, the other operations are the same. The specific effects of the type and amount of the first solvent on the product obtained by the reaction are shown in Table 2 below:

[0065] Table 2:

[0066]

[0067] Example 4

[0068] Except that the type and amount of the second alkaline solution in this embodiment are different from those in Example 1, the other operations are the same. The specific effects of the type and amount of the second alkaline solution on the products obtained by the reaction are shown in Table 3 below:

[0069] Table 3:

[0070]

[0071] Example 5

[0072] Except for the type and amount of catalyst used in this embodiment being different from those in Embodiment 1, the other operations are the same. The effects of the type and amount of catalyst used on the products obtained by the reaction are shown in Table 4 below:

[0073] Table 4:

[0074]

[0075] Comparative Example 1

[0076] Except that the molar ratio of the first raw material to the second raw material is different from that in Example 1, the other operations are the same. The effects of the specific molar ratio on the products obtained by the reaction are shown in Table 5 below:

[0077] Table 5:

[0078]

[0079] Comparative Example 2

[0080] This comparative example uses the reactor mentioned in Example 1 and three other different types of reactors to carry out the first reaction and the second reaction, and the first reactor and the second reactor are of the same type. Except for the type of reactor, the other operations are the same as in Example 1. The specific results of the effect of the type of reactor on the products obtained by the reaction are shown in Table 6 below:

[0081] Table 6:

[0082]

[0083] From the above description, it can be seen that the above embodiments of the present invention achieve the following technical effects: the use of the above continuous synthesis system to prepare bixafen can realize automated control, save labor, save production time, and effectively reduce production costs; at the same time, it can improve production efficiency and product yield.

[0084] 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 system for continuously preparing bixafen, characterized in that: include: A first reaction unit, the first reaction unit is composed of a first feed module, a first reaction module (201) and a first purification module which are connected in sequence; A second reaction unit, the second reaction unit is composed of a second feed module, a second reaction module (501) and a second purification module connected in sequence; The outlet of the first purification module is connected to the inlet of the second feeding module.

2. The system according to claim 1, characterized in that The first purification module comprises a first separation module (301) and a second separation module (302) which are connected in sequence, and an inlet of the first separation module (301) is connected to an outlet of the first reaction module (201); The second purification module comprises an extraction module (601), a concentration module (602) and a third separation module (603) which are connected in sequence, and the feed inlet of the extraction module (601) is connected to the feed outlet of the second reaction module (501).

3. The system according to claim 2, characterized in that The first reaction module (201), the first separation module (301) and the second separation module (302) are each independently provided with a jacket on the outside for passing a medium substance for temperature regulation; The second reaction module (501), the extraction module (601), the concentration module (602) and the third separation module (603) are each independently provided with a jacket on the outside for passing a medium substance for temperature regulation.

4. The system according to claim 3, characterized in that The medium material includes: silicon heat-conducting oil or circulating water.

5. The system according to claim 1, characterized in that The first reaction module (201) comprises 1 to 5 first reactors connected in series, and the second reaction module (501) comprises 1 to 3 second reactors connected in series. The types of the first reactor and the second reactor include continuous dynamic tubular reactors, and a mixing core structure is arranged inside the continuous dynamic tubular reactor.

6. A method for continuously preparing bixafen, characterized in that: The system for continuously preparing bixafen as claimed in any one of claims 1 to 5 is used to continuously synthesize bixafen, the method comprising: The solution of the first raw material, the solution of the second raw material and the first alkaline solution are added to the first reaction module (201) through the first feeding module to perform a first reaction, and the product of the first reaction enters the first purification module for a first purification treatment to obtain a first intermediate; The solution of the first intermediate, the solution of the second intermediate, the second alkaline solution and the catalyst are added to a second reaction module (501) through a second feeding module to carry out a second reaction, and the product of the second reaction enters the second purification module for a second purification treatment to obtain the bixafen; Wherein, the first raw material is a compound as shown in formula I Formula I; The second raw material is a compound as shown in formula II Formula II; The first intermediate is a compound as shown in formula III Formula III; The second intermediate is a compound shown in formula IV Formula IV.

7. The method according to claim 6, characterized in that Dissolving the first raw material and the second raw material respectively by using a first solvent to obtain a solution of the first raw material and a solution of the second raw material, wherein the first solvent is selected from one or more of the following: dichloromethane, 1,2-dichloroethane, chloroform and tetrahydrofuran; The molar ratio of the first raw material to the second raw material is 1:0.9-8.

8. The method according to claim 6, characterized in that Dissolving the first intermediate and the second intermediate in a second solvent to obtain a solution of the first intermediate and a solution of the second intermediate, wherein the second solvent is selected from one or more of the following: toluene, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, tetrahydrofuran, acetonitrile, ethanol, ethylene glycol dimethyl ether and water; The molar ratio of the first intermediate to the second intermediate is 1:1-5.

9. The method according to claim 6, characterized in that The catalyst is selected from any one or more of the following: PdCl2, Pd(pph3)4, Pd(OAc)2, Pd(dppf)Cl2, Pd2(dba)3, Pd(dba)2, NiCl2 and Ni(dppf)Cl2; The molar ratio of the first intermediate to the catalyst is 1:0.0005-0.

2.

10. The method according to claim 6, characterized in that The first alkaline solution is selected from any one or more of the following: triethylamine, potassium carbonate, sodium carbonate, sodium bicarbonate, diethylamine, ethylenediamine and N,N-diisopropylethylamine; The molar ratio of the first raw material to the first alkaline solution is 1:0.5-5; The second alkaline solution is selected from any one or more of the following: triethylamine, pyridine, potassium carbonate, potassium phosphate, sodium hydroxide, potassium hydroxide, cesium carbonate, lithium carbonate and sodium carbonate; The molar ratio of the first intermediate to the second alkaline solution is 1:3-15.

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