A method for the continuous preparation of p-trifluoromethylaniline using a microreactor

Abstract

This invention discloses a method for the continuous preparation of p-trifluoromethylaniline using a microreactor. Aniline, sodium trifluoromethanesulfonate, electrolyte, and additives are dissolved in a solvent to form a homogeneous mixed solution, which is then pumped into an electrochemical microchannel reactor for the first step reaction under electrocatalysis. Subsequently, the reaction solution obtained from the first step reaction is simultaneously reacted with an alkaline aqueous solution in another microchannel reactor for the second step reaction. The effluent is purified to obtain the final product. The method provided by this invention eliminates the need for excess oxidant, effectively avoiding strong exothermic reactions, ensuring high safety, and is environmentally friendly. Furthermore, the microchannel reactor enhances mass and heat transfer processes, thereby increasing the reaction rate and shortening the reaction time. It also enables continuous preparation, is simple to operate, has high yield, and operates under mild reaction conditions, making it valuable for industrial applications.

Description

Technical Field

[0001] This invention belongs to the field of organic chemical synthesis and electrocatalysis, and specifically relates to a method for the continuous preparation of p-trifluoromethylaniline using a microreactor. Background Technology

[0002] p-Trifluoromethylaniline is an important fine chemical product and a crucial intermediate in the manufacturing processes of pharmaceuticals and agrochemicals. In the pharmaceutical field, it is a vital intermediate in the synthesis of drugs for diabetes, skin diseases, and rheumatism. Furthermore, chlorination of p-trifluoromethylaniline yields 2,6-dichloro-p-aminotrifluorotoluene, which is used in the pesticide industry to synthesize highly effective and low-toxicity insecticides such as fipronil, lambda-cyhalothrin, and flufenoxuron, as well as herbicides like etorpheniramine and etorpheniramine. In the pharmaceutical industry, it is used to synthesize novel immunosuppressants such as leflunomide. With the continuous development of green chemical technologies and research into new drugs, new applications are constantly being discovered, making it one of the most important and promising chemical products.

[0003] The main methods for processing trifluoromethylaniline currently include:

[0004] (A) Reduction of p-nitrotrifluorotoluene: p-trifluoromethylaniline is prepared by reducing p-nitrotrifluorotoluene with different catalysts. This method has the following disadvantages: (1) the source of p-nitrotrifluorotoluene is limited and expensive; (2) the catalytic system required for the reaction is complex and difficult to scale up.

[0005] (B) Amination of p-chlorotrifluorotoluene: The commonly used process uses p-chlorotrifluorotoluene as raw material and cuprous chloride and potassium fluoride as catalysts, directly subjected to high-pressure ammonolysis in ethanol, water or other solvents, followed by solvent removal and distillation to obtain p-trifluoromethylaniline. This method has the following disadvantages: (1) poor reaction selectivity, requiring distillation to obtain p-trifluoromethylaniline; (2) high reaction temperature, complicated post-processing, high energy consumption and poor economic efficiency.

[0006] (C) Aniline trifluoromethylation method: This method utilizes the reaction of aniline with a trifluoromethylating agent to prepare the target product. The most frequently reported method involves trifluoroiodomethane, which dissociates under light or heat to generate a trifluoromethyl radical. This trifluoromethyl radical then undergoes a radical substitution reaction with an aromatic ring to generate p-trifluoromethylaniline. However, this method suffers from low conversion rates and high cost of the trifluoromethylating agent. Summary of the Invention

[0007] Purpose of the invention: The technical problem to be solved by the present invention is to provide a method for the continuous preparation of p-trifluoromethylaniline using a microreactor, which addresses the shortcomings of the prior art by providing a method for the continuous preparation of p-trifluoromethylaniline using a microreactor. This method solves the problems of the prior art, such as the need for expensive raw materials, long reaction time, poor selectivity and low yield. It achieves the green preparation of p-trifluoromethylaniline simply and efficiently under mild conditions without the use of oxidants.

[0008] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0009] A method for the continuous preparation of p-trifluoromethylaniline using a microreactor includes the following steps:

[0010] (1) Aniline, sodium trifluoromethanesulfonate, electrolyte and additives are dissolved in a solvent to prepare a homogeneous mixed solution, and then pumped into the electrochemical microchannel reactor in the microreactor to carry out the first step reaction under electrocatalysis;

[0011] (2) The reaction solution obtained from the first step reaction and the alkaline aqueous solution are simultaneously carried out in the second microchannel reactor in the microreactor for the second step reaction. The effluent is purified to obtain the final product.

[0012] Specifically, in step (1), the electrolyte is selected from any one or a combination of two or more of the following: tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium bromide, tetramethylammonium iodide, tetrabutylammonium chloride, tetraethylammonium iodide, tetrabutylammonium iodide, tetraethylammonium perchlorate, tetramethylammonium bromide, tetraethylammonium bromide, ammonium iodide, sodium iodide, ammonium bromide, trifluoroacetic acid, and sodium bromide; preferably, tetrabutylammonium tetrafluoroborate.

[0013] The additive is selected from any one or a combination of two or more of acetic acid, trifluoroacetic acid, phosphoric acid, sulfuric acid, and p-toluenesulfonic acid; acetic acid is preferred.

[0014] The solvent is selected from any one or a combination of two or more of acetonitrile, acetic acid, dichloromethane, 1,2-dichloroethane, trifluoroethanol, hexafluoroisopropanol, methanol, ethanol, and water; preferably, it is a mixed solvent of acetonitrile and water in a volume ratio of 10:1.

[0015] Specifically, in step (1), the concentration of aniline in the homogeneous mixed solution is 0.01 to 0.10 mmol / mL; preferably 0.02 mmol / mL.

[0016] The concentration of sodium trifluoromethanesulfonate in the homogeneous mixed solution is 0.01–0.10 mmol / mL; preferably 0.03 mmol / mL.

[0017] The concentration of the electrolyte in the homogeneous mixed solution is 0.01–0.10 mmol / mL; preferably 0.03 mmol / mL.

[0018] The concentration of the additive in the homogeneous mixed solution is 0.01–0.10 mmol / mL; preferably 0.03 mmol / mL.

[0019] Specifically, in step (1), the microreactor includes an electrochemical microchannel reactor comprising a feed pump, an anode plate, a cathode plate, a first microchannel reactor, and a receiver; wherein, an anode plate and a cathode plate are respectively disposed on both sides of the first microchannel reactor; the feed pump, the first microchannel reactor, and the receiver are connected in series via pipelines. The receiver of the first microchannel reactor is connected in parallel to the feed pump of the alkaline aqueous solution at the front end of the second microchannel reactor.

[0020] The anode sheet is a graphite carbon electrode or a platinum sheet electrode, preferably a graphite carbon electrode.

[0021] The cathode sheet is a nickel electrode or a platinum electrode, preferably a nickel electrode.

[0022] The pipes and other components in the microreactor are made of polytetrafluoroethylene (PTFE).

[0023] Specifically, in step (1), the current introduced into the electrocatalysis in the first step reaction is 3 to 25 mA, preferably 5 mA.

[0024] In step (1), the temperature of the first reaction is controlled at 10-60°C, preferably room temperature; the retention time of the reaction is 0.5-10 min, preferably 4 min.

[0025] In step (2), the alkaline aqueous solution contains an alkali selected from any one or a combination of two or more of sodium hydroxide, potassium hydroxide, potassium phosphate, potassium carbonate, and cesium carbonate, preferably sodium hydroxide; the concentration of the alkaline aqueous solution is 10-40 wt%, preferably 30 wt%.

[0026] Specifically, in step (2), the temperature of the second reaction is controlled at 40 to 100°C, preferably 60°C; the retention time of the reaction is 0.5 to 10 min, preferably 4 min.

[0027] Specifically, in step (2), the purification steps include extraction, vacuum concentration and column chromatography purification in sequence.

[0028] This invention relates to a two-step microreaction method for the continuous preparation of p-trifluoromethylaniline, belonging to the field of organic chemical synthesis and electrocatalysis. The first step involves an electrocatalytic reaction of aniline with sodium trifluoromethanesulfonate in a microchannel reactor, which rapidly and efficiently forms the intermediate 4-trifluoromethylacetaniline. The second step involves alkaline hydrolysis of 4-trifluoromethylacetaniline with an alkaline aqueous solution in a microreactor to obtain p-trifluoromethylaniline.

[0029] Beneficial effects:

[0030] Compared with existing methods, this approach eliminates the need for excessive oxidants, effectively avoiding strong exothermic reactions, ensuring high safety, and is environmentally friendly. Furthermore, the microchannel reaction device enhances mass and heat transfer, thereby increasing the reaction rate and shortening the reaction time. It also enables continuous preparation, is easy to operate, yields high output, and operates under mild conditions, making it highly valuable for industrial applications. Attached Figure Description

[0031] The present invention will be further described in detail below with reference to the accompanying drawings and specific embodiments, and the advantages of the present invention in the above and / or other aspects will become clearer.

[0032] Figure 1 This is a reaction pathway diagram of the present invention.

[0033] Figure 2 The images show the 1H and 1C spectra of p-trifluoromethylaniline synthesized by the method of this invention. Detailed Implementation

[0034] The present invention can be better understood from the following embodiments.

[0035] In the following embodiments, the electrochemical microchannel reactor used in the first step reaction includes a feed pump, a first microchannel reactor, an anode plate, a cathode plate, and a receiver; wherein, an anode plate (graphite carbon plate) and a cathode plate (nickel plate) are respectively provided on both sides of the first microchannel reactor; wherein, the feed pump, the first microchannel reactor, and the receiver are connected in series via pipelines. The second microchannel reactor used in the second step reaction has a similar structure to the microchannel reactor in the first step, but is not equipped with anode and cathode plates.

[0036] The first microchannel reactor has a volume of 2 mL, and the flow rate of the homogeneous solution is 0.1–2 mL / min, preferably 0.5 mL / min. The second microchannel reactor has a volume of 6 mL, and the flow rate of the reaction solution is 0.2–3 mL / min, preferably 1.5 mL / min. The microchannel reactors used in the first and second steps are identical. The name of the microchannel reactor is "the Asia Flux module," manufactured by Syrris Ltd, and its model number is Model No. 2200554.

[0037] Example 1

[0038] 0.2 mmol aniline, 0.3 mmol sodium trifluoromethanesulfonate, 0.3 mmol tetrabutylammonium tetrafluoroborate, and 0.3 mmol acetic acid were dissolved in 10 mL acetonitrile / water (10:1). The resulting homogeneous solution was pumped into an electrochemical microchannel reaction apparatus. The flow rate of the syringe pump was adjusted to 0.5 mL / min, and the current intensity was set to 5 mA. After reacting for 4 min, the solution was mixed with a 30% sodium hydroxide aqueous solution (1 mL / min) and pumped into another microchannel reaction apparatus. The reaction was carried out at 60 °C for 4 min. The reaction solution was collected, extracted, dried, filtered, and separated by column chromatography to obtain p-trifluoromethylaniline with a yield of 91%. The 1H and 1C NMR spectra of the product are shown below. Figure 2 As shown, 1 HNMR(400MHz,Chloroform-d)δ7.40(d,J=8.1Hz,2H),6.68(d,J=7.7Hz,2H),3.95(s,2H)ppm; 13 C NMR (100MHz, Chloroform-d) δ149.5, 129.0, 126.8, 126.7, 126.7, 126.7, 126.3, 123.6, 120.9, 120.0 (q, J = 32.5Hz), 114.2ppm; HRMS (ESI-TOF): m / z calcd for C7H7F3N + [M+H] + 162.0525, found 162.0521.

[0039] Example 2

[0040] 0.3 mmol aniline, 0.2 mmol sodium trifluoromethanesulfonate, 0.3 mmol tetrabutylammonium tetrafluoroborate, and 0.3 mmol acetic acid were dissolved in 10 mL of acetonitrile / water (10:1). The resulting homogeneous solution was pumped into an electrochemical microchannel reaction apparatus. The flow rate of the syringe pump was adjusted to 0.5 mL / min, and the current intensity was set to 5 mA. After reacting for 4 min, the solution was mixed with a 30% sodium hydroxide aqueous solution (1 mL / min) and pumped into another microchannel reaction apparatus. The reaction was carried out at 60 °C for 4 min. The reaction solution was collected, extracted, dried, filtered, and separated by column chromatography to obtain p-trifluoromethylaniline with a yield of 83%.

[0041] Example 3

[0042] 0.2 mmol aniline, 0.3 mmol sodium trifluoromethanesulfonate, 0.3 mmol tetrabutylammonium iodide, and 0.3 mmol acetic acid were dissolved in 10 mL of acetonitrile / water (10:1). The resulting homogeneous solution was pumped into an electrochemical microchannel reaction apparatus. The flow rate of the syringe pump was adjusted to 0.5 mL / min, and the current intensity was set to 5 mA. After reacting for 4 min, the solution was mixed with a 30% sodium hydroxide aqueous solution (1 mL / min) and pumped into another microchannel reaction apparatus. The reaction was carried out at 60 °C for 4 min. The reaction solution was collected, extracted, dried, filtered, and separated by column chromatography to obtain p-trifluoromethylaniline with a yield of 72%.

[0043] Example 4

[0044] 0.2 mmol aniline, 0.3 mmol sodium trifluoromethanesulfonate, 0.3 mmol tetrabutyltetrafluoroborate, and 0.3 mmol trifluoroacetic acid were dissolved in 10 mL of acetonitrile / water (10:1). The resulting homogeneous solution was pumped into an electrochemical microchannel reaction apparatus. The flow rate of the syringe pump was adjusted to 0.5 mL / min, and the current intensity was set to 5 mA. After reacting for 4 min, the solution was mixed with a 30% sodium hydroxide aqueous solution (1 mL / min) and pumped into another microchannel reaction apparatus. The reaction was carried out at 60 °C for 4 min. The reaction solution was collected, extracted, dried, filtered, and separated by column chromatography to obtain p-trifluoromethylaniline with a yield of 72%.

[0045] Example 5

[0046] 0.2 mmol aniline, 0.3 mmol sodium trifluoromethanesulfonate, 0.3 mmol tetrabutylammonium tetrafluoroborate, and 0.3 mmol acetic acid were dissolved in 10 mL of acetonitrile / water (10:1). The resulting homogeneous solution was pumped into an electrochemical microchannel reaction apparatus. The flow rate of the syringe pump was adjusted to 0.5 mL / min, and the current intensity was set to 4 mA. After reacting for 4 min, the solution was mixed with a 30% sodium hydroxide aqueous solution (1 mL / min) and pumped into another microchannel reaction apparatus. The reaction was carried out at 60 °C for 4 min. The reaction solution was collected, extracted, dried, filtered, and separated by column chromatography to obtain p-trifluoromethylaniline with a yield of 80%.

[0047] Example 6

[0048] 0.2 mmol aniline, 0.3 mmol sodium trifluoromethanesulfonate, 0.3 mmol tetrabutylammonium tetrafluoroborate, and 0.3 mmol acetic acid were dissolved in 10 mL acetonitrile / water (10:1). The resulting homogeneous solution was pumped into an electrochemical microchannel reaction apparatus. The flow rate of the syringe pump was adjusted to 1 mL / min, and the current intensity was set to 5 mA. After reacting for 2 min, the solution was mixed with a 30% sodium hydroxide aqueous solution (1 mL / min) and pumped into another microchannel reaction apparatus. The reaction was carried out at 60 °C for 3 min. The reaction solution was collected, extracted, dried, filtered, and separated by column chromatography to obtain p-trifluoromethylaniline with a yield of 65%.

[0049] Example 7

[0050] 0.2 mmol aniline, 0.3 mmol sodium trifluoromethanesulfonate, 0.3 mmol tetrabutylammonium tetrafluoroborate, and 0.3 mmol acetic acid were dissolved in 10 mL of acetonitrile / water (5:1). The resulting homogeneous solution was pumped into an electrochemical microchannel reaction apparatus. The flow rate of the syringe pump was adjusted to 0.5 mL / min, and the current intensity was set to 5 mA. After reacting for 4 min, the solution was mixed with a 30% sodium hydroxide aqueous solution (1 mL / min) and pumped into another microchannel reaction apparatus. The reaction was carried out at 60 °C for 4 min. The reaction solution was collected, extracted, dried, filtered, and separated by column chromatography to obtain p-trifluoromethylaniline with a yield of 66%.

[0051] Example 8

[0052] 0.2 mmol aniline, 0.3 mmol sodium trifluoromethanesulfonate, 0.3 mmol tetrabutylammonium tetrafluoroborate, and 0.3 mmol acetic acid were dissolved in 10 mL of acetonitrile / water (10:1). The resulting homogeneous solution was pumped into an electrochemical microchannel reaction apparatus. The flow rate of the syringe pump was adjusted to 0.5 mL / min, and the current intensity was set to 5 mA. After reacting for 4 min, the solution was mixed with a 30% sodium hydroxide aqueous solution (0.5 mL / min) and pumped into another microchannel reaction apparatus. The reaction was carried out at 60 °C for 6 min. The reaction solution was collected, extracted, dried, filtered, and separated by column chromatography to obtain p-trifluoromethylaniline with a yield of 82%.

[0053] Example 9

[0054] 0.2 mmol aniline, 0.3 mmol sodium trifluoromethanesulfonate, 0.3 mmol tetrabutylammonium tetrafluoroborate, and 0.3 mmol acetic acid were dissolved in 10 mL of acetonitrile / water (10:1). The resulting homogeneous solution was pumped into an electrochemical microchannel reaction apparatus. The flow rate of the syringe pump was adjusted to 0.5 mL / min, and the current intensity was set to 5 mA. After reacting for 4 min, the solution was mixed with a 30% sodium hydroxide aqueous solution (1 mL / min) and pumped into another microchannel reaction apparatus. The reaction was carried out at 50 °C for 4 min. The reaction solution was collected, extracted, dried, filtered, and separated by column chromatography to obtain p-trifluoromethylaniline with a yield of 79%.

[0055] Example 10

[0056] 0.2 mmol aniline, 0.3 mmol sodium trifluoromethanesulfonate, 0.3 mmol tetrabutylammonium tetrafluoroborate, and 0.3 mmol acetic acid were dissolved in 10 mL of acetonitrile / water (10:1). The resulting homogeneous solution was pumped into an electrochemical microchannel reaction apparatus. The flow rate of the syringe pump was adjusted to 0.5 mL / min, and the current intensity was set to 5 mA. After reacting for 4 min, the solution was mixed with a 20% sodium hydroxide aqueous solution (1 mL / min) and pumped into another microchannel reaction apparatus. The reaction was carried out at 60 °C for 4 min. The reaction solution was collected, extracted, dried, filtered, and separated by column chromatography to obtain p-trifluoromethylaniline with a yield of 81%.

[0057] Comparative Example 1

[0058] In a round-bottom flask equipped with a magnetic stirrer, 0.1 mmol of cuprous oxide, 9 mmol of ammonia monohydrate, 1 mmol of p-trifluoromethylphenylboronic acid, and 4 mL of 30% sodium hydroxide solution were added. The pH of the system was 12. The system was left open at 60 °C for 24 h. After the reaction was complete, 1.5 mL of 20% sodium hydroxide solution was added, and the mixture was extracted three times with 10 mL of ethyl acetate each time. The combined organic phases were concentrated, washed, and separated to obtain p-trifluoromethylaniline in a yield of 58%.

[0059] Comparative Example 2

[0060] 1 mmol of 4-trifluoromethylbromobenzene, 15 mmol of ammonia, 0.5 mmol of copper sulfate pentahydrate, 0.5 mmol of sucrose, 1 mmol of sodium phosphate, 0.6 g of PEG-400, and 1.5 mL of water were added to a 10 mL reactor. The reactor was sealed and reacted at 60 °C for 18 h. After the reaction was stopped, the mixture was extracted with ethyl acetate, washed with water and saturated brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was distilled under reduced pressure and separated by column chromatography to obtain p-trifluoromethylaniline in 43% yield.

[0061] This invention provides a method for the continuous preparation of p-trifluoromethylaniline using a microreactor. Many methods and approaches exist for implementing this technical solution; the above description is merely a preferred embodiment. It should be noted that those skilled in the art can make various improvements and modifications without departing from the principles of this invention, and these improvements and modifications should also be considered within the scope of protection of this invention. All components not explicitly stated in this embodiment can be implemented using existing technologies.

Claims

1. A method for the continuous preparation of p-trifluoromethylaniline using a microreactor, characterized in that, Includes the following steps: (1) Aniline, sodium trifluoromethanesulfonate, electrolyte and additives are dissolved in a solvent to prepare a homogeneous mixed solution, which is then pumped into the electrochemical microchannel reactor in the microreactor to carry out the first step reaction under electrocatalysis; (2) The reaction solution obtained from the first step reaction and the alkaline aqueous solution are simultaneously pumped into the second microchannel reactor in the microreactor to carry out the second step reaction. The effluent is purified to obtain the second step reaction. The electrolyte is selected from any one or a combination of two or more of the following: tetrabutylammonium tetrafluoroborate, tetrabutylammonium hexafluorophosphate, tetrabutylammonium bromide, tetramethylammonium iodide, tetrabutylammonium chloride, tetraethylammonium iodide, tetrabutylammonium iodide, tetraethylammonium perchlorate, tetramethylammonium bromide, tetraethylammonium bromide, ammonium iodide, sodium iodide, ammonium bromide, trifluoroacetic acid, and sodium bromide. The additives are selected from any one or a combination of two or more of acetic acid, trifluoroacetic acid, phosphoric acid, sulfuric acid, and p-toluenesulfonic acid; The solvent is selected from any one or a combination of two or more of acetonitrile, acetic acid, dichloromethane, 1,2-dichloroethane, trifluoroethanol, hexafluoroisopropanol, methanol, ethanol, and water; In step (1), the concentration of aniline in the homogeneous mixed solution is 0.01~0.10 mmol / mL; The concentration of sodium trifluoromethanesulfonate in the homogeneous mixed solution is 0.01~0.10 mmol / mL; The concentration of the electrolyte in the homogeneous mixed solution is 0.01~0.10 mmol / mL; The concentration of the additive in the homogeneous mixed solution is 0.01~0.10 mmol / mL; In step (1), the current introduced into the electrocatalysis in the first step reaction is 3~25 mA; In step (1), the temperature of the first reaction is controlled at 10~60 ℃, and the reaction retention time is 0.5~10 min; In the microreactor described above, the electrochemical microchannel reactor includes a feed pump, an anode plate, a cathode plate, a first microchannel reactor, and a receiver; wherein, an anode plate and a cathode plate are respectively arranged on both sides of the first microchannel reactor; the feed pump, the first microchannel reactor, and the receiver are connected in series via pipelines. The anode sheet is a graphite carbon electrode or a platinum sheet electrode; the cathode sheet is a nickel sheet electrode or a platinum sheet electrode. In step (2), the alkali in the alkaline aqueous solution is selected from any one or a combination of two or more of sodium hydroxide, potassium hydroxide, potassium phosphate, potassium carbonate, and cesium carbonate; the concentration of the alkaline aqueous solution is 10~40 wt%. In step (2), the temperature of the second reaction is controlled at 40~100 ℃, and the reaction retention time is 0.5~10 min.

2. The method for continuous preparation of p-trifluoromethylaniline using a microreactor according to claim 1, characterized in that, The connecting pipes in the microreactor are made of polytetrafluoroethylene.

3. The method for continuous preparation of p-trifluoromethylaniline using a microreactor according to claim 1, characterized in that, In step (2), the purification steps include extraction, vacuum concentration and column chromatography purification in sequence.

Images