Method for continuously synthesizing 4-bromo-2-p-chlorophenyl-5-trifluoromethyl pyrrole-3-nitrile by microchannel reactor

Abstract

The invention belongs to the technical field of chemical synthesis, and relates to a method for continuously synthesizing 4-bromo-2-p-chlorophenyl-5-trifluoromethyl pyrrole-3-nitrile by a microchannel reactor, which comprises the following steps: pumping a substrate solution to a first plate type micro-reaction module; respectively pumping the bromination reagent solution to a first plate type micro-reaction module, a second plate type micro-reaction module and a third plate type micro-reaction module to obtain a reaction base solution; the reaction base solution is introduced into a fourth plate type micro-reaction module, n-heptane is pumped to the fourth plate type micro-reaction module and a fifth plate type micro-reaction module, deionized water is pumped to the fourth plate type micro-reaction module and the fifth plate type micro-reaction module, and extract liquor is obtained; and carrying out separation, evaporation recovery and recrystallization to obtain a finished product. Through the multi-stage series design of the micro-channel reactor, catalytic bromination replaces traditional bromine oxidation and reaction-extraction in-situ integration, and the three major problems of low efficiency, serious pollution and poor safety of an intermittent process are solved.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of chemical synthesis, and particularly relates to a method for continuously synthesizing 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile by using a micro-channel reactor. BACKGROUND

[0002] 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile is a key intermediate for synthesizing a new insecticide chlorobromicarbonitrile, and is used for preparing herbicides and insecticides and miticides, and has the characteristics of good thermal stability and coexistence with various antibacterial agents.

[0003] Generally, an intermittent synthesis method is used in industry, and the method has the advantages of simple operation and low cost, but has the disadvantages of slow reaction speed, excessive bromine, more waste acid, and large safety risk. SUMMARY

[0004] In order to solve the problems in the prior art, the application provides a method for continuously synthesizing 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile by using a micro-channel reactor, which has the advantages of fast reaction speed, no waste acid, and green environmental protection.

[0005] To achieve the above-mentioned purpose, the application provides a method for continuously synthesizing 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile by using a micro-channel reactor, which comprises the following steps: 1) preparing a micro-channel reactor, wherein the micro-channel reactor is composed of a first plate-type micro-reaction module, a second plate-type micro-reaction module, a third plate-type micro-reaction module, a fourth plate-type micro-reaction module and a fifth plate-type micro-reaction module in series from left to right; 2) storing n-heptane, deionized water and hydrogen peroxide solution in a third storage tank, a fourth storage tank and a fifth storage tank respectively; 3) dissolving 2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile in acetonitrile / acetic acid mixed solvent, and constant volume to 1L to obtain a substrate solution, wherein the substrate solution passes through a molecular sieve column at 10mL / min, and the water content at the outlet is monitored by a water meter to be less than or equal to 50ppm, and then the substrate solution is transferred into the first storage tank; 4) dissolving copper bromide in acetonitrile solvent, and constant volume to 500mL to obtain a bromination reagent solution, and then the bromination reagent solution is transferred into the second storage tank; 5) Starting the primary feed, the substrate solution in the first storage tank is pumped to the first plate microreactor module at a flow rate of 10 mL / min, the bromination reagent solution in the second storage tank is pumped to the first plate microreactor module, the second plate microreactor module, and the third plate microreactor module at flow rates of 5 mL / min, 2.5 mL / min, and 1 mL / min, respectively, and the hydrogen peroxide solution in the fifth storage tank is pumped to the second plate microreactor module and the third plate microreactor module at flow rates of 1 mL / min and 0.5 mL / min, respectively, to finally obtain the reaction base solution; 6) Starting the secondary feed, the reaction bottom liquid from the third plate microreactor module is introduced into the fourth plate microreactor module, the n-heptane in the third storage tank is pumped into the fourth and fifth plate microreactor modules at flow rates of 15 mL / min and 8 mL / min, respectively, and the deionized water in the fourth storage tank is pumped into the fourth and fifth plate microreactor modules at flow rates of 4 mL / min and 2.5 mL / min, respectively, to finally obtain the extract; 7) The extract is separated into an organic phase and an aqueous phase by a two-stage centrifugal extractor. The organic phase is subjected to a rotary evaporator to recover n-heptane. The evaporation residue is recrystallized from a methanol / water mixed solvent to obtain 4-bromo-2-(p-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile.

[0006] Preferably, the concentration of the substrate solution is 1.2 to 1.8 mol / L, and the concentration of the bromination reagent solution is 0.8 to 1.0 mol / L.

[0007] Preferably, in the acetonitrile / acetic acid mixed solvent, the volume ratio of acetonitrile to acetic acid is 17:3.

[0008] Preferably, in the methanol / water mixed solvent, the volume ratio of methanol to water is 8:2.

[0009] Preferably, the liquid holding capacity of the first plate-type micro-reaction module, the second plate-type micro-reaction module and the third plate-type micro-reaction module is 10 mL, and the liquid holding capacity of the fourth plate-type micro-reaction module and the fifth plate-type micro-reaction module is 15 mL.

[0010] Preferably, the temperature of the first plate-type micro-reaction module is maintained at 45°C, and the temperature of the second plate-type micro-reaction module and the third plate-type micro-reaction module are maintained at 60°C.

[0011] Preferably, the temperature of the fourth plate-type micro-reaction module and the fifth plate-type micro-reaction module is maintained at 40°C.

[0012] Preferably, the mass fraction of the hydrogen peroxide solution is 30%.

[0013] After adopting the above technical solution, the beneficial effects of the present invention are: Through the multi-stage series design of microchannel reactors, catalytic bromination instead of traditional bromine oxidation and in-situ integration of reaction-extraction, the three major pain points of low efficiency, high pollution and poor safety of intermittent processes are solved. It is an efficient, green and environmentally friendly continuous synthesis process of 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile, suitable for large-scale continuous preparation and easy to use in industry. BRIEF DESCRIPTION OF THE DRAWINGS

[0014] In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the following briefly introduces the drawings required for use in the embodiments or the description of the prior art. Obviously, the drawings described below are only some embodiments of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0015] Figure 1 Schematic diagram of the structure of the first plate-type micro-reactor module; Figure 2 Schematic diagram of the reaction process.

[0016] In the figure: 1-first plate type micro-reaction module, 2-reaction chamber, 3-leaf-shaped chamber, 4-flow channel, 5-first material inlet, 6-second material inlet, 7-heat exchange chamber, 8-material outlet, 9-medium inlet, 10-medium outlet, 11-first flow sensor, 12-second flow sensor, 13-second plate type micro-reaction module, 14-third flow sensor, 15-third plate type micro-reaction module, 16-fourth flow sensor, 17-fourth plate type micro-reaction module, 18-fifth plate type micro-reaction module, 19-first metering pump, 20-first storage tank, 21-second storage tank, 22-second metering pump, 23-third metering pump, 24-fourth metering pump, 25-third storage tank, 26-fifth metering pump, 27-sixth metering pump, 28-seventh metering pump, 29-fourth storage tank, 30-eighth metering pump, 31-fifth storage tank, 32-ninth metering pump, 33-tenth metering pump. DETAILED DESCRIPTION

[0017] The features and exemplary embodiments of various aspects of the present invention will be described in detail below. In order to make the objects, technical solutions and advantages of the present invention clearer, the present invention will be further described in detail below in conjunction with specific embodiments. It should be understood that the specific embodiments described herein are only configured to explain the present invention and are not configured to limit the present invention. For those skilled in the art, the present invention can be implemented without the need for some of these specific details. The following description of the embodiments is merely to provide a better understanding of the present invention by illustrating examples of the present invention.

[0018] An embodiment of the present invention provides a microchannel reactor particularly suitable for the large-scale production of 4-bromo-2-(p-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile. The microchannel reactor comprises, from left to right, a first plate-type micro-reactor module 1, a second plate-type micro-reactor module 13, a third plate-type micro-reactor module 15, a fourth plate-type micro-reactor module 17, and a fifth plate-type micro-reactor module 18 connected in series, forming a three-stage reaction system of "premixing-main reaction-extraction."

[0019] The first, second, and third plate-type microreactor modules 1, 13, and 15 all have a single-module liquid holding capacity of 10 mL. The fourth and fifth plate-type microreactor modules 17, 18 each have a single-module liquid holding capacity of 15 mL. The first plate-type microreactor module 1 is equipped with dual material inlets and dual media interfaces. Based on the first plate-type microreactor module 1, the remaining modules are equipped with a third material inlet, forming a three-stream material mixing structure.

[0020] like Figure 1 As shown, the first plate-type microreactor module 1 includes a transparent substrate made of a light-cured perfluoropolyether / olefinic silicone resin composite material. The substrate interior is provided with a tortuous reaction chamber 2 and a heat exchange chamber 7 arranged along the direction of the reaction chamber 2. The heat exchange chamber 7 is adjacent to and parallel to the reaction chamber 2, with a spacing of 3.5 mm between the heat exchange chamber 7 and the reaction chamber 2. One end of the substrate is provided with a first material inlet 5, a second material inlet 6, a material outlet 8, a medium inlet 9, and a medium outlet 10, each connected to the opposite ends of the heat exchange chamber 7. The material outlet 8 is connected to one end of the reaction chamber 2, and the first material inlet 5 and the second material inlet 6 flow into the other end of the reaction chamber 2.

[0021] Reaction chamber 2 features an alternating zigzag structure consisting of "flow channel 4 - lobed chamber 3 - flow channel 4." When the material flows through the narrow slits of flow channel 4, the flow velocity accelerates. Upon entering lobed chamber 3, the channel expands, the flow velocity drops sharply, and the pressure is released. This cyclical change induces intense turbulence, improving mass transfer efficiency and accelerating the reaction.

[0022] Conventional industrial-grade microchannel reactors are mostly constructed of metal materials such as Hastelloy and stainless steel. The manufacturing process relies on precision machining and wire cutting technology, and the key flow channel feature dimensions must achieve a machining accuracy of ±5μm. The contact surface seal adopts a combination of O-rings and mechanical compression, and the flatness of the mating surface needs to be controlled. The geometric reconstruction of the reaction chamber requires the redesign and processing of the entire set of molds, and the modification cycle is as long as 4-6 weeks. The modification of the micro-channel features causes the machining tool path to change completely, and the modification cost is close to that of a new manufacturing. In summary, this type of microchannel reactor is extremely expensive and needs to meet extremely high machining accuracy. It is not suitable for the frequent modification needs of the reaction chamber 2. To this end, this embodiment also provides a method for preparing a microchannel reactor. Taking the first plate-type micro-reaction module 1 as an example, the specific steps are as follows: (1) Using 3D printing or injection molding, paraffin is molded into core molds of the reaction chamber 2 and the heat exchange chamber 7, which are referred to as the reaction core mold and the heat exchange core mold; (2) The reaction core mold and the heat exchange core mold are suspended side by side in the mold cavity, and light-cured perfluoropolyether / olefin silicone resin is injected. After negative pressure exhaust, ultraviolet curing is performed to form a prototype containing the core mold; (3) After the resin is completely cured, it is cut and polished to obtain the required outer contour, and the first material inlet 5, the second material inlet 6, the material outlet 8, the medium inlet 9 and the medium outlet 10 with internal threads are drilled and quick connectors are installed respectively; (4) The processed juveniles are placed in a 75°C water bath, and gas is introduced into the first material inlet 5, the second material inlet 6, and the medium inlet 9. The molten paraffin is discharged under the driving force of the gas pressure to form a complete chamber, thereby obtaining a reaction chamber 2 and a heat exchange chamber 7; (5) Hot water containing silica abrasive particles is pumped into the first material inlet 5, the second material inlet 6, and the medium inlet 9 to polish the inner walls of the reaction chamber 2 and the heat exchange chamber 7, remove residual paraffin and resin burrs, reduce the subsequent material hanging on the wall, and obtain a finished microchannel reactor after cleaning and drying.

[0023] like Figure 2 As shown, the embodiment provides a method for continuously synthesizing 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile in a microchannel reactor. The specific preparation steps and technical details of the preparation method are as follows.

[0024] Example 1 1) Prepare solution 89.3 g of copper bromide was completely dissolved in acetonitrile solvent, and the volume was adjusted to 500 mL to obtain a bromination reagent solution with a concentration of 0.8 mol / L, which was transferred to the first storage tank 20.

[0025] 324.8 g of 2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile was completely dissolved in an acetonitrile / acetic acid mixture and the volume was adjusted to 1 L to obtain a substrate solution with a concentration of 1.2 mol / L. The volume ratio of acetonitrile to acetic acid in the acetonitrile / acetic acid mixture was 17:3. The substrate solution was passed through a molecular sieve column at 10 mL / min. The outlet water content was monitored using a moisture meter to ensure it was ≤50 ppm. The solution was then transferred to a second storage tank 21.

[0026] The n-heptane, deionized water and hydrogen peroxide solution are stored in the third storage tank 25, the fourth storage tank 29 and the fifth storage tank 31 respectively. The mass fraction of the hydrogen peroxide solution is 30%.

[0027] 2) Premixing The first plate-type microreactor module 1, the second plate-type microreactor module 13, the third plate-type microreactor module 15, the fourth plate-type microreactor module 17, and the fifth plate-type microreactor module 18 were connected to a heat exchange system and maintained at specific temperatures. The temperature of the first plate-type microreactor module 1 was maintained at 45°C, the temperature of the second plate-type microreactor module 13 and the third plate-type microreactor module 15 was maintained at 60°C, and the temperature of the fourth plate-type microreactor module 17 and the fifth plate-type microreactor module 18 was maintained at 40°C.

[0028] The first metering pump 19 and the second metering pump 22 were started, and the substrate solution in the first storage tank 20 was pumped to the first material inlet 5 of the first plate-type microreactor module 1 at a flow rate of 10 mL / min. The bromination reagent solution in the second storage tank 21 was pumped to the second material inlet 6 of the first plate-type microreactor module 1 at a flow rate of 5 mL / min. The substrate solution and the bromination reagent solution were instantaneously mixed in the reaction chamber 2 of the first plate-type microreactor module 1, completing preheating and premixing.

[0029] 3) Primary bromination reaction The mixed liquid coming out of the material outlet 8 enters the second plate-type micro-reactor module 13. When the first flow sensor 11 detects the material flow, the third metering pump 23 and the ninth metering pump 32 are started, and the bromination reagent solution in the second storage tank 21 is pumped to the second plate-type micro-reactor module 13 at a flow rate of 2.5 mL / min, and the hydrogen peroxide solution in the fifth storage tank 31 is pumped to the second plate-type micro-reactor module 13 at a flow rate of 1 mL / min.

[0030] Acetic acid maintains a weak acidic environment to prevent excessive protonation of the nitrogen atom of the pyrrole ring. Copper bromide dissociates into Cu in acetonitrile. 2+ and Br - , Br - It is oxidized by hydrogen peroxide to Br2, which reacts with Lewis acid (such as Cu 2+ ) after coordination, they split into Br + , Br +The attack on the pyrrole ring eventually forms the target product (4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile).

[0031] 4) Secondary bromination reaction The mixed solution from the second plate microreaction module 13 enters the third plate microreaction module 15. When the second flow sensor 12 detects the flow, the fourth metering pump 24 and the tenth metering pump 33 are started. The bromination reagent solution in the second storage tank 21 is pumped into the third plate microreaction module 15 at a flow rate of 1 mL / min, and the hydrogen peroxide solution in the fifth storage tank 31 is pumped into the third plate microreaction module 15 at a flow rate of 0.5 mL / min.

[0032] The bromination reagent and hydrogen peroxide are added in stages, which allows the reactants to be contacted and reacted more gradually, helping to avoid the problem of excessive reaction or incomplete reaction caused by the addition of a large amount of reagent at once. After completing the primary bromination, adjustments can be made based on the results of the primary bromination to better adapt to the needs of the secondary bromination, thereby improving the efficiency of the reaction.

[0033] 5) Primary extraction The reaction bottom liquid containing the product flows from the third plate microreaction module 15 to the fourth plate microreaction module 17. When the third flow sensor 14 detects the flow, the fifth metering pump 26 and the seventh metering pump 28 are started simultaneously. The n-heptane in the third storage tank 25 is pumped into the fourth plate microreaction module 17 at a flow rate of 15 mL / min, and the deionized water in the fourth storage tank 29 is pumped into the fourth plate microreaction module 17 at a flow rate of 4 mL / min.

[0034] The purpose of the primary extraction is to quickly capture the organic phase product in the reaction bottom liquid and achieve preliminary separation using solubility differences.

[0035] 6) Secondary extraction The extraction liquid from the fourth plate microreaction module 17 enters the fifth plate microreaction module 18. When the fourth flow sensor 16 detects the flow, the sixth metering pump 27 and the eighth metering pump 30 are started. The n-heptane in the third storage tank 25 is pumped into the fourth plate microreaction module 17 at a flow rate of 8 mL / min, and the deionized water in the fourth storage tank 29 is pumped into the fourth plate microreaction module 17 at a flow rate of 2.5 mL / min.

[0036] The purpose of the secondary extraction is to further purify the product obtained by the primary extraction, remove residual impurities, and improve the purity of the product. After completing the primary extraction, adjustments can be made based on the results of the primary extraction to better adapt to the needs of the secondary extraction, thereby improving the efficiency of the extraction.

[0037] 7) Separation and purification The extract from the fifth plate-type microreactor module 18 was separated into an organic phase and an aqueous phase via a two-stage centrifugal extractor. The organic phase was recovered by rotary evaporation using n-heptane (corresponding to a temperature of 100°C, adsorption dehydration), acetic acid (corresponding to a temperature of 120°C), and acetonitrile (corresponding to a temperature of 85°C). The evaporation residue was recrystallized from a methanol / water mixed solvent (methanol to water volume ratio of 8:2) to obtain 124.7 g of 4-bromo-2-(p-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile, with a content of 99.3%.

[0038] In summary, the present invention adopts a staged continuous process, allowing the reactants to gradually contact and react in multiple stages. Each reaction stage can be independently controlled and optimized, making the process easy to scale up and industrialize, and can meet the needs of large-scale production. The staged continuous process has high flexibility, and the reaction conditions of each stage can be adjusted according to production requirements to adapt to different production scales.

[0039] Example 2 This embodiment provides a method for continuously synthesizing 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile in a microchannel reactor. The specific preparation steps and technical details of the preparation method are as follows.

[0040] 1) Prepare solution 94.92 g of copper bromide was completely dissolved in acetonitrile solvent, and the volume was adjusted to 500 mL to obtain a bromination reagent solution with a concentration of 0.85 mol / L, which was transferred to the first storage tank 20.

[0041] 405.96 g of 2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile was dissolved in an acetonitrile / acetic acid mixed solvent and the volume was adjusted to 1 L to obtain a substrate solution with a concentration of 1.5 mol / L.

[0042] 2) Premixing The first metering pump 19 and the second metering pump 22 were started, and the substrate solution in the first storage tank 20 was pumped to the first material inlet 5 of the first plate-type microreactor module 1 at a flow rate of 10 mL / min. The bromination reagent solution in the second storage tank 21 was pumped to the second material inlet 6 of the first plate-type microreactor module 1 at a flow rate of 5 mL / min. The substrate solution and the bromination reagent solution were instantaneously mixed in the reaction chamber 2 of the first plate-type microreactor module 1, completing preheating and premixing.

[0043] 3) Primary bromination reaction The mixed liquid coming out of the material outlet 8 enters the second plate-type micro-reactor module 13. When the first flow sensor 11 detects the material flow, the third metering pump 23 and the ninth metering pump 32 are started, and the bromination reagent solution in the second storage tank 21 is pumped to the second plate-type micro-reactor module 13 at a flow rate of 2.5 mL / min, and the hydrogen peroxide solution in the fifth storage tank 31 is pumped to the second plate-type micro-reactor module 13 at a flow rate of 1 mL / min.

[0044] 4) Secondary bromination reaction The mixed liquid coming out of the second plate-type micro-reaction module 13 enters the third plate-type micro-reaction module 15. When the second flow sensor 12 detects the material flow, the fourth metering pump 24 and the tenth metering pump 33 are started, and the bromination reagent solution in the second storage tank 21 is pumped to the third plate-type micro-reaction module 15 at a flow rate of 1 mL / min, and the hydrogen peroxide solution in the fifth storage tank 31 is pumped to the third plate-type micro-reaction module 15 at a flow rate of 0.5 mL / min.

[0045] 5) Primary extraction The reaction base liquid containing the product flows from the third plate micro-reaction module 15 to the fourth plate micro-reaction module 17. When the third flow sensor 14 detects the material flow, the fifth metering pump 26 and the seventh metering pump 28 are started synchronously, and the n-heptane in the third storage tank 25 is pumped to the fourth plate micro-reaction module 17 at a flow rate of 15 mL / min, and the deionized water in the fourth storage tank 29 is pumped to the fourth plate micro-reaction module 17 at a flow rate of 4 mL / min.

[0046] 6) Secondary extraction The extract coming out of the fourth plate micro-reactor module 17 enters the fifth plate micro-reactor module 18. When the fourth flow sensor 16 detects the material flow, the sixth metering pump 27 and the eighth metering pump 30 are started, and the n-heptane in the third storage tank 25 is pumped to the fourth plate micro-reactor module 17 at a flow rate of 8 mL / min, and the deionized water in the fourth storage tank 29 is pumped to the fourth plate micro-reactor module 17 at a flow rate of 2.5 mL / min.

[0047] 7) Separation and purification The extract from the fifth plate-type microreactor module 18 was separated into an organic phase and an aqueous phase using a two-stage centrifugal extractor. The organic phase was passed through a rotary evaporator to recover n-heptane. The evaporation residue was recrystallized from a methanol / water mixed solvent (methanol to water volume ratio of 8:2) to obtain 139.6 g of 4-bromo-2-(p-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile, with a content of 99.5%.

[0048] Example 3 This embodiment provides a method for continuously synthesizing 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile in a microchannel reactor. The specific preparation steps and technical details of the preparation method are as follows.

[0049] 1) Preparation of solution Dissolve 111.68 g of copper bromide in acetonitrile solvent, and make up to 500 mL, to obtain a bromination reagent solution with a concentration of 1.0 mol / L, and transfer into the first storage tank 20.

[0050] Dissolve 487.2 g of 2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile in acetonitrile / acetic acid mixed solvent, and make up to 1 L, to obtain a substrate solution with a concentration of 1.8 mol / L.

[0051] 2) Pre-mixing Start the first metering pump 19 and the second metering pump 22, and the substrate solution in the first storage tank 20 is pumped to the first material inlet 5 of the first plate micro-reaction module 1 at a flow rate of 10 mL / min, and the bromination reagent solution in the second storage tank 21 is pumped to the second material inlet 6 of the first plate micro-reaction module 1 at a flow rate of 5 mL / min. The substrate solution and the bromination reagent solution are instantaneously mixed in the reaction chamber 2 of the first plate micro-reaction module 1, and pre-heating and pre-mixing are completed.

[0052] 3) Primary bromination reaction The mixed solution from the material outlet 8 enters the second plate micro-reaction module 13, and when the first flow sensor 11 detects the flow, the third metering pump 23 and the ninth metering pump 32 are started, and the bromination reagent solution in the second storage tank 21 is pumped to the second plate micro-reaction module 13 at a flow rate of 2.5 mL / min, and the hydrogen peroxide solution in the fifth storage tank 31 is pumped to the second plate micro-reaction module 13 at a flow rate of 1 mL / min.

[0053] 4) Secondary bromination reaction The mixed solution from the second plate micro-reaction module 13 enters the third plate micro-reaction module 15, and when the second flow sensor 12 detects the flow, the fourth metering pump 24 and the tenth metering pump 33 are started, and the bromination reagent solution in the second storage tank 21 is pumped to the third plate micro-reaction module 15 at a flow rate of 1 mL / min, and the hydrogen peroxide solution in the fifth storage tank 31 is pumped to the third plate micro-reaction module 15 at a flow rate of 0.5 mL / min.

[0054] 5) Primary extraction The reaction bottom liquid containing the product flows from the third plate micro-reaction module 15 to the fourth plate micro-reaction module 17, and when the third flow sensor 14 detects the flow, the fifth metering pump 26 and the seventh metering pump 28 are started synchronously, and the n-heptane in the third storage tank 25 is pumped to the fourth plate micro-reaction module 17 at a flow rate of 15 mL / min, and the deionized water in the fourth storage tank 29 is pumped to the fourth plate micro-reaction module 17 at a flow rate of 4 mL / min.

[0055] 6) Secondary extraction The extract liquid from the fourth plate micro-reaction module 17 enters the fifth plate micro-reaction module 18. When the fourth flow sensor 16 detects the material flow, the sixth metering pump 27 and the eighth metering pump 30 are started. The n-heptane in the third tank 25 is pumped to the fourth plate micro-reaction module 17 at a flow rate of 8 mL / min, and the deionized water in the fourth tank 29 is pumped to the fourth plate micro-reaction module 17 at a flow rate of 2.5 mL / min.

[0056] 7) Separation and purification The extract liquid from the fifth plate micro-reaction module 18 is separated into an organic phase and an aqueous phase by a two-stage centrifugal extractor. The organic phase is recycled by a rotary evaporator to recover n-heptane. The evaporation residue is recrystallized with a methanol / water mixed solvent (volume ratio of methanol to water is 8:2) to obtain 175.6 g of 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile with a content of 98.9%.

[0057] In accordance with the embodiments of the present application as described above, the embodiments do not describe all the details and are not limited to the specific embodiments. Obviously, many modifications and variations can be made according to the above description. The present description selects and specifically describes these embodiments in order to better explain the principles and practical applications of the present application, so that those skilled in the art can well utilize the present application and make modifications and uses based on the present application. Any modifications, equivalent replacements, improvements, etc. made within the spirit and principles of the present application shall be included in the protection scope of the present application.

Claims

1. A method for continuously synthesizing 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile using a microchannel reactor, characterized in that: The following steps are involved: 1) preparing a microchannel reactor, wherein the microchannel reactor is composed of a first plate-type micro-reaction module (1), a second plate-type micro-reaction module (13), a third plate-type micro-reaction module (15), a fourth plate-type micro-reaction module (17), and a fifth plate-type micro-reaction module (18) connected in series from left to right; 2) storing n-heptane, deionized water, and hydrogen peroxide solution in a third storage tank (25), a fourth storage tank (29), and a fifth storage tank (31), respectively; 3) dissolving 2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile in a mixed solvent of acetonitrile / acetic acid, and adjusting the volume to 1 L to obtain a substrate solution. The substrate solution was passed through a molecular sieve column at a rate of 10 mL / min, and the outlet water content was monitored by a moisture meter to be ≤50 ppm. The substrate solution was then transferred to a first storage tank (20); 4) dissolving copper bromide in acetonitrile solvent and adjusting the volume to 500 mL to obtain a bromination reagent solution, which is transferred to a second storage tank (21); 5) starting the first-stage feed, the substrate solution in the first storage tank (20) is pumped to the first plate micro-reaction module (1) at a flow rate of 10 mL / min, the bromination reagent solution in the second storage tank (21) is pumped to the first plate micro-reaction module (1), the second plate micro-reaction module (13) and the third plate micro-reaction module (15) at flow rates of 5 mL / min, 2.5 mL / min and 1 mL / min, respectively, and the hydrogen peroxide solution in the fifth storage tank (31) is pumped to the second plate micro-reaction module (13) and the third plate micro-reaction module (15) at flow rates of 1 mL / min and 0.5 mL / min, respectively, to finally obtain the reaction base solution; 6) starting the secondary feed, introducing the reaction bottom liquid from the third plate micro-reactor module (15) into the fourth plate micro-reactor module (17), pumping the n-heptane in the third storage tank (25) to the fourth plate micro-reactor module (17) and the fifth plate micro-reactor module (18) at flow rates of 15 mL / min and 8 mL / min, respectively, and pumping the deionized water in the fourth storage tank (29) to the fourth plate micro-reactor module (17) and the fifth plate micro-reactor module (18) at flow rates of 4 mL / min and 2.5 mL / min, respectively, to finally obtain the extract; 7) The extract is separated into an organic phase and an aqueous phase by a two-stage centrifugal extractor. The organic phase is subjected to a rotary evaporator to recover n-heptane. The evaporation residue is recrystallized from a methanol / water mixed solvent to obtain 4-bromo-2-(p-chlorophenyl)-5-trifluoromethylpyrrole-3-carbonitrile.

2. The method for continuously synthesizing 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile in a microchannel reactor according to claim 1, wherein: The concentration of the substrate solution is 1.2-1.8 mol / L, and the concentration of the bromination reagent solution is 0.8-1.0 mol / L.

3. The method for continuously synthesizing 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile in a microchannel reactor according to claim 1, wherein: In the acetonitrile / acetic acid mixed solvent, the volume ratio of acetonitrile to acetic acid is 17:

3.

4. The method for continuously synthesizing 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile in a microchannel reactor according to claim 1, wherein: In the methanol / water mixed solvent, the volume ratio of methanol to water is 8:

2.

5. The method for continuously synthesizing 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile using a microchannel reactor according to claim 1, wherein: The liquid holding capacity of the first plate-type micro-reaction module (1), the second plate-type micro-reaction module (13) and the third plate-type micro-reaction module (15) is 10 mL, and the liquid holding capacity of the fourth plate-type micro-reaction module (17) and the fifth plate-type micro-reaction module (18) is 15 mL.

6. The method for continuously synthesizing 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile using a microchannel reactor according to claim 1, characterized in that: The temperature of the first plate-type micro-reaction module (1) is maintained at 45°C, and the temperature of the second plate-type micro-reaction module (13) and the third plate-type micro-reaction module (15) is maintained at 60°C.

7. The method for continuously synthesizing 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile using a microchannel reactor according to claim 6, characterized in that: The temperature of the fourth plate-type micro-reaction module (17) and the fifth plate-type micro-reaction module (18) is maintained at 40°C.

8. The method for continuously synthesizing 4-bromo-2-p-chlorophenyl-5-trifluoromethylpyrrole-3-carbonitrile using a microchannel reactor according to claim 1, characterized in that: The mass fraction of the hydrogen peroxide solution is 30%.

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