A process for the continuous synthesis of 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-carbonitrile in a microchannel reactor

Abstract

This invention provides a method for the continuous synthesis of 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile using a microchannel reactor. Using 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one as a raw material, a mixed solution is prepared with 2-chloroacrylonitrile. This solution, along with an acid-binding accelerator solution, is simultaneously introduced into microreactor 1. A cyclization reaction is completed via a series reaction module to generate the intermediate 2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile. The obtained intermediate is then simultaneously introduced into microreactor 2 with a solution of 1,3-dibromo-5,5-dimethylhydantoin. A bromination reaction is completed via a series reaction module to obtain the target product. The overall yield of this process reaches 90.3%, and the product purity reaches 98%. Compared with existing technologies, this invention features a continuous and simple process flow, short reaction time, easy process control, high safety, and fewer by-products with a high yield.

Description

Technical Field

[0001] This invention relates to a method for the continuous synthesis of 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile using a microchannel reactor. Background Technology

[0002] 4-Bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile is an important intermediate in the aryl pyrrole insecticide chlorfenapyr. Its main synthetic method involves cyclizing 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one with 2-chloroacrylonitrile to obtain the intermediate 2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile, followed by bromination with a brominating agent. Industrially, this reaction is generally carried out using a batch synthesis method. This process has the advantages of simple operation and low cost, but it also has disadvantages such as slow reaction rate, excessive raw material consumption, and relatively high safety risks.

[0003] A microreactor, also known as a microchannel reactor, is a small-scale reaction system manufactured using microfabrication and precision machining techniques. Its "micro" characteristic is mainly reflected in the tiny scale of the process fluid channels, rather than in the "small" size of the equipment or the product output.

[0004] Microreaction technology is a novel chemical technology based on continuous flow processes, replacing traditional batch reactors with microchannel reactors. This technology offers significant advantages such as high mixing efficiency, excellent mass and heat transfer performance, and strong reaction process safety, making it suitable for chemical reaction processes requiring precise control.

[0005] Therefore, it is necessary to provide a new continuous synthesis method for 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-nitrile to solve the above problems. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to overcome the shortcomings of the existing batch synthesis technology and provide a method for continuous synthesis of 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile using a microchannel reactor.

[0007] To solve the above-mentioned technical problems, the technical solution adopted by the present invention is as follows:

[0008] A method for the continuous synthesis of 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile using a microchannel reactor includes the following steps: a mixed solution of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile, along with an acid-binding accelerator solution, is simultaneously and continuously introduced into a microchannel reactor 1 for a cyclization reaction to obtain an intermediate solution; then, the intermediate solution and a solution of 1,3-dibromo-5,5-dimethylhydantoin are simultaneously and continuously introduced into a microchannel reactor 2 for a bromination reaction; after the reaction is completed, post-treatment yields 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile.

[0009] Furthermore, both the microchannel reactor 1 and the microchannel reactor 2 are composed of multiple reaction modules connected in series; the microchannel reactor 1 contains 10 reaction modules connected in series, with each module holding 20-40 mL of liquid; the microchannel reactor 2 contains 10 reaction modules connected in series, with each module holding 40-80 mL of liquid.

[0010] Furthermore, the molar ratio of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one to 2-chloroacrylonitrile is 1:1.05~1.1; the molar ratio of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one to the acid accelerator is 1:1.0~1.1; and the molar ratio of the intermediate to 1,3-dibromo-5,5-dimethylhydantoin is 1:0.5~0.55.

[0011] Furthermore, in the mixed solution of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile, the mass content of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one is 1.3%~20%, and the mass content of 2-chloroacrylonitrile is 0.8%~7.5%; the solvent of the mixed solution of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile is acetonitrile.

[0012] Furthermore, the acid-binding accelerator is triethylamine; the solvent of the acid-binding accelerator solution is acetonitrile, and the mass content of triethylamine in the solution is 1.0%~11%.

[0013] Furthermore, the intermediate 2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-nitrile solution is obtained by filtering the cyclization reaction effluent, with acetonitrile as the solvent, wherein the intermediate mass content is 1.4%~20%.

[0014] Furthermore, the solvent of the 1,3-dibromo-5,5-dimethylhydantoin solution is acetonitrile, and the mass content of 1,3-dibromo-5,5-dimethylhydantoin in the solution is 0.7%~9%.

[0015] Furthermore, the feed flow rate of the mixed solution of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile is 3-20 mL / min; the feed flow rate of the acid-binding accelerator solution is 5-12 mL / min; the feed flow rate of the intermediate solution is 3-20 mL / min; and the feed flow rate of the 1,3-dibromo-5,5-dimethylhydantoin solution is 3-20 mL / min.

[0016] Furthermore, the reaction temperature of the microchannel reactor 1 is 50~65℃; the reaction temperature of the microchannel reactor 2 is 60~81℃.

[0017] Furthermore, the post-treatment involves removing the solvent by vacuum distillation.

[0018] Compared with the prior art, the advantages of the present invention are as follows:

[0019] (1) This invention provides a novel method for the continuous synthesis of 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile. A mixed solution of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile, along with an acid-binding accelerator solution, are simultaneously and continuously introduced into a microreactor 1 to react and obtain an intermediate solution of 2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile. This intermediate solution is then simultaneously and continuously introduced into a microreactor 2 with a solution of 1,3-dibromo-5,5-dimethylhydantoin to react and obtain a solution of 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile. Finally, the solvent and low-boiling-point impurities are removed by vacuum distillation to obtain the target product, thereby achieving the continuous preparation of 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile.

[0020] (2) In this invention, each microchannel reactor is composed of 10 reaction modules connected in series with microfluidic circuits. It has excellent mass transfer and heat transfer efficiency, which can make the solutions of each component mix quickly and evenly, and can strictly control the feed flow rate and reaction ratio. It has advantages such as fast reaction speed, high raw material conversion rate and good operation safety. It is suitable for large-scale continuous preparation and is easy to promote and apply in industrial applications.

[0021] (3) Compared with the traditional batch synthesis method, the reaction of this invention is carried out in a microchannel all-liquid phase environment without free gas phase space, which fundamentally eliminates the generation and accumulation of irritating fumes in the batch reactor and solves the main safety and environmental hazards in the traditional process. At the same time, the ultra-fast mixing at the microscale can make the reactants contact each other instantaneously and uniformly at the molecular scale, effectively avoiding the problems of local overheating or local high concentration, greatly suppressing the occurrence of side reactions and significantly improving the purity of the product. Attached Figure Description

[0022] Figure 1 This is a process flow diagram for the synthesis of 4-bromo-2-(p-chlorophenyl)-5-trifluoromethylpyrrole-3-onitrile according to the present invention.

[0023] Figure 2 The reaction equation for the synthesis of 4-bromo-2-(p-chlorophenyl)-5-trifluoromethylpyrrole-3-onitrile in this invention is shown below. Specific implementation methods

[0024] To make the content of this invention easier to understand, the technical solution of this invention will be further described below with reference to specific embodiments, but this invention is not limited thereto.

[0025] Example 1:

[0026] A method for the continuous synthesis of 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile using a microchannel reactor includes the following steps:

[0027] (1) A mixed solution of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile was prepared by dissolving 26.4 g of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile in 200 mL of acetonitrile. A solution of acid-binding accelerator was prepared by dissolving 11.1 g of triethylamine in 200 mL of acetonitrile. A solution of 1,3-dibromo-5,5-dimethylhydantoin was prepared by dissolving 14.3 g of 1,3-dibromo-5,5-dimethylhydantoin in 400 mL of acetonitrile.

[0028] (2) The microchannel reactor 1 adopts a multi-module structure, with the modules connected in series. There are 10 modules, and each module has a liquid holding capacity of 40 mL. A mixed solution of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile, as well as an acid-binding promoter solution, are simultaneously and continuously pumped into the first series reaction module of the microchannel reactor 1 at a flow rate of 10 mL / min. The temperature of each series reaction module is controlled at 55 °C by a temperature control module. After the material flows through all series reaction modules (total residence time is 20 min), it is discharged through a 0.3 MPa back pressure valve. The discharged liquid is filtered to remove the triethylamine hydrochloride solid generated in the reaction, and a clear intermediate 2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-nitrile solution is collected.

[0029] (3) The microchannel reactor 2 adopts a multi-module structure, with the modules connected in series. There are 10 modules, and each module has a liquid holding capacity of 80 mL. The intermediate 2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-nitrile solution and the 1,3-dibromo-5,5-dimethylhydantoin solution are simultaneously and continuously pumped into the first series reaction module of the microchannel reactor 2 at a flow rate of 10 mL / min. The temperature of each series reaction module is controlled at 65℃ by the temperature control module. After the material flows through all series reaction modules (total residence time is 40 min), it is discharged through a 0.3 MPa back pressure valve. The discharged liquid is filtered to remove the triethylamine hydrochloride solid generated in the reaction, and a clear intermediate 2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-nitrile solution is collected.

[0030] (4) The solvent in the 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile solution was removed by vacuum distillation under water bath conditions of 80℃ and -0.03MPa to obtain 31.4g of the product 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile, and the product content was found to be 97.9%.

[0031] Example 2:

[0032] A method for the continuous synthesis of 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile using a microchannel reactor includes the following steps:

[0033] (1) A mixed solution of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile was prepared by dissolving 26.4 g of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile in 200 mL of acetonitrile. A solution of acid-binding accelerator was prepared by dissolving 10.1 g of triethylamine in 200 mL of acetonitrile. A solution of 1,3-dibromo-5,5-dimethylhydantoin was prepared by dissolving 14.3 g of 1,3-dibromo-5,5-dimethylhydantoin in 400 mL of acetonitrile.

[0034] (2) The microchannel reactor 1 adopts a multi-module structure, with the modules connected in series. There are 10 modules, and each module has a liquid holding capacity of 40 mL. A mixed solution of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile, as well as an acid-binding promoter solution, are simultaneously and continuously pumped into the first series reaction module of the microchannel reactor 1 at a flow rate of 12 mL / min. The temperature of each series reaction module is controlled at 55 °C by a temperature control module. After the material flows through all series reaction modules (total residence time is 16.7 min), it is discharged through a 0.3 MPa back pressure valve. The discharged liquid is filtered to remove the triethylamine hydrochloride solid generated in the reaction, and a clear intermediate 2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-nitrile solution is collected.

[0035] (3) The microchannel reactor 2 adopts a multi-module structure, with the modules connected in series. There are 10 modules, and each module has a liquid holding capacity of 80 mL. The intermediate 2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-nitrile solution and the 1,3-dibromo-5,5-dimethylhydantoin solution are simultaneously and continuously pumped into the first series reaction module of the microchannel reactor 2 at a flow rate of 12 mL / min. The temperature of each series reaction module is controlled at 65℃ by the temperature control module. After the material flows through all the series reaction modules (total residence time is 33.4 min), it is discharged through a 0.3 MPa back pressure valve to obtain a 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-nitrile solution.

[0036] (4) The solvent in the 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile solution was removed by vacuum distillation under water bath conditions of 80℃ and -0.03MPa to obtain 31.2g of the product 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile, and the product content was found to be 98.0%.

[0037] Example 3:

[0038] A method for the continuous synthesis of 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile using a microchannel reactor includes the following steps:

[0039] (1) A mixed solution of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile was prepared by dissolving 26.4 g of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile in 100 mL of acetonitrile. A solution of acid-binding accelerator was prepared by dissolving 10.1 g of triethylamine in 100 mL of acetonitrile. A solution of 1,3-dibromo-5,5-dimethylhydantoin was prepared by dissolving 14.3 g of 1,3-dibromo-5,5-dimethylhydantoin in 200 mL of acetonitrile.

[0040] (2) The microchannel reactor 1 adopts a multi-module structure, with the modules connected in series. There are 10 modules, and each module has a liquid holding capacity of 20 mL. A mixed solution of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile, as well as an acid-binding promoter solution, are simultaneously and continuously pumped into the first series reaction module of the microchannel reactor 1 at a flow rate of 5 mL / min. The temperature of each series reaction module is controlled at 50 °C by a temperature control module. After the material flows through all series reaction modules (total residence time is 20 min), it is discharged through a 0.3 MPa back pressure valve. The discharged liquid is filtered to remove the triethylamine hydrochloride solid generated in the reaction, and a clear intermediate 2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-nitrile solution is collected.

[0041] (3) The microchannel reactor 2 adopts a multi-module structure, with the modules connected in series. There are 10 modules, and each module has a liquid holding capacity of 40 mL. The intermediate 2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-nitrile solution and the 1,3-dibromo-5,5-dimethylhydantoin solution are simultaneously and continuously pumped into the first series reaction module of the microchannel reactor 2 at a flow rate of 5 mL / min. The temperature of each series reaction module is controlled at 65℃ by the temperature control module. After the material flows through all the series reaction modules (total residence time is 40 min), it is discharged through a 0.3 MPa back pressure valve to obtain a 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-nitrile solution.

[0042] (4) The solvent in the 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile solution was removed by vacuum distillation under water bath conditions of 80℃ and -0.03MPa to obtain 31.2g of the product 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile, and the product content was found to be 98.0%.

[0043] Example 4:

[0044] (1) A mixed solution of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile was prepared by dissolving 26.4 g of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile in 100 mL of acetonitrile. A solution of acid-binding accelerator was prepared by dissolving 11.1 g of triethylamine in 100 mL of acetonitrile. A solution of 1,3-dibromo-5,5-dimethylhydantoin was prepared by dissolving 14.3 g of 1,3-dibromo-5,5-dimethylhydantoin in 200 mL of acetonitrile.

[0045] (2) The microchannel reactor 1 adopts a multi-module structure, with the modules connected in series. There are 10 modules, and each module has a liquid holding capacity of 20 mL. A mixed solution of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile, as well as an acid-binding promoter solution, are simultaneously and continuously pumped into the first series reaction module of the microchannel reactor 1 at a flow rate of 10 mL / min. The temperature of each series reaction module is controlled at 55 °C by a temperature control module. After the material flows through all series reaction modules (total residence time is 10 min), it is discharged through a 0.3 MPa back pressure valve. The discharged liquid is filtered to remove the triethylamine hydrochloride solid generated in the reaction, and a clear intermediate 2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-nitrile solution is collected.

[0046] (3) The microchannel reactor 2 adopts a multi-module structure, with the modules connected in series. There are 10 modules, and each module has a liquid holding capacity of 40 mL. The intermediate 2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-nitrile solution and the 1,3-dibromo-5,5-dimethylhydantoin solution are simultaneously and continuously pumped into the first series reaction module of the microchannel reactor 2 at a flow rate of 10 mL / min. The temperature of each series reaction module is controlled at 65℃ by the temperature control module. After the material flows through all the series reaction modules (total residence time is 20 min), it is discharged through a 0.3 MPa back pressure valve to obtain a 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-nitrile solution.

[0047] (4) The solvent in the 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile solution was removed by vacuum distillation under water bath conditions of 80℃ and -0.03MPa to obtain 31.5g of the product 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile, and the product content was found to be 98.0%.

Claims

1. A process for the continuous synthesis of 4-bromo-2-(p-chlorophenyl)-5- trifluoromethyl-pyrrole-3-carbonitrile in a microchannel reactor characterized by: The process includes the following steps: a mixed solution of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile, along with an acid-binding accelerator solution, is continuously fed into a microchannel reactor 1 to carry out a cyclization reaction, yielding an intermediate 2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile solution; then, the intermediate 2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile solution and a 1,3-dibromo-5,5-dimethylhydantoin solution are continuously fed into a microchannel reactor 2 to carry out a bromination reaction; after the reaction is completed, post-treatment yields 4-bromo-2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-onitrile.

2. The method according to claim 1, characterized in that: Both the microchannel reactor 1 and the microchannel reactor 2 are composed of multiple reaction modules connected in series; the microchannel reactor 1 contains 10 reaction modules connected in series, and the liquid holding capacity of each module is 20~40mL; the microchannel reactor 2 contains 10 reaction modules connected in series, and the liquid holding capacity of each module is 40~80mL.

3. The method according to claim 1, characterized in that: The molar ratio of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one to 2-chloroacrylonitrile is 1:1.05~1.1; the molar ratio of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one to the acid accelerator is 1:1.0~1.1; and the molar ratio of the intermediate to 1,3-dibromo-5,5-dimethylhydantoin is 1:0.5~0.

55.

4. The method according to claim 1, characterized in that: In the mixed solution of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile, the mass content of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one is 1.3%~20%, and the mass content of 2-chloroacrylonitrile is 0.8%~7.5%; the solvent of the mixed solution of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile is acetonitrile.

5. The method according to claim 1, characterized in that: The acid-binding accelerator is triethylamine; the solvent of the acid-binding accelerator solution is acetonitrile, and the mass content of triethylamine in the solution is 1.0%~11%.

6. The method according to claim 1, characterized in that: The intermediate 2-(p-chlorophenyl)-5-trifluoromethyl-pyrrole-3-nitrile solution was obtained by filtering the cyclization reaction effluent, with acetonitrile as the solvent, and the intermediate mass content was 1.4%~20%.

7. The method according to claim 1, characterized in that: The solvent of the 1,3-dibromo-5,5-dimethylhydantoin solution is acetonitrile, and the mass content of 1,3-dibromo-5,5-dimethylhydantoin in the solution is 0.7%~9%.

8. The method according to claim 1, characterized in that: The feed flow rate of the mixed solution of 4-(4-chlorophenyl)-2-trifluoromethyl-3-oxazol-5-one and 2-chloroacrylonitrile is 3-20 mL / min; the feed flow rate of the acid-binding accelerator solution is 5-12 mL / min; the feed flow rate of the intermediate solution is 3-20 mL / min; and the feed flow rate of the 1,3-dibromo-5,5-dimethylhydantoin solution is 3-20 mL / min.

9. The method according to claim 1, characterized in that: The reaction temperature of the microchannel reactor 1 is 50~65℃; the reaction temperature of the microchannel reactor 2 is 60~81℃.

10. The method according to claim 1, characterized in that: The post-treatment involves removing the solvent by vacuum distillation.

Images