Process for continuously synthesizing m-trifluoromethyl acetophenone oxime by adopting micro-channel reactor

Abstract

The invention discloses a process for continuously synthesizing m-trifluoromethyl acetophenone oxime by adopting a microchannel reactor. The process comprises the following steps: reacting m-trifluoromethyl aniline with sodium nitrite and sulfuric acid to obtain a diazonium salt solution; the method comprises the following steps: adding a copper salt catalyst, acetaldoxime, sodium acetate and water into a temperature-controlled stirring kettle as an initial circular reaction solution, and regulating the pH value of the circular reaction solution in real time by adding alkali liquor; the method comprises the following steps: quickly mixing a diazonium salt solution, an organic extraction solvent and a circular reaction solution through a micro-mixer, carrying out reaction and product in-situ extraction on the obtained mixed solution in a micro-channel reactor, and then separating through a phase splitter to obtain a water phase and an organic phase; the water phase returns to the temperature control reaction kettle for continuous recycling, and the organic phase is subjected to post-treatment to obtain the m-trifluoromethyl acetophenone oxime. The method disclosed by the invention is simple in process, continuous in operation, short in reaction period, high in safety controllability and high in production efficiency, and effectively solves the problems in the intermittent kettle type process for preparing the m-trifluoromethyl acetophenone oxime by utilizing the m-trifluoromethyl aniline at present.

Description

Technical Field

[0001] The invention belongs to the technical field of fine chemical raw material synthesis, and particularly relates to a process for continuously synthesizing m-trifluoromethylacetophenone oxime by using a microchannel reactor. Background Art

[0002] 3-Trifluoromethylacetophenone oxime (CAS: 99705-50-7) is widely used in pesticides, medicines and other fields. It is a key intermediate for the synthesis of strobilurin fungicides such as trifloxystrobin and oxime phenylglyoxylic acid derivatives. It can also be used as a fluorination agent for fluorinated organic compounds.

[0003] The preparation of m-trifluoromethyl acetophenone oxime by using m-trifluoromethyl aniline as raw material, reacting the diazonium salt generated in situ by diazotization reaction with acetaldehyde oxime has a high cost advantage and is the mainstream route of industrial production at present (CN 103193611 A, US 6211413 B1). The reaction of the diazonium salt with acetaldehyde oxime in the latter step is the key. This step of the reaction is usually catalyzed by copper salt, which is sensitive to the pH of the reaction solution and requires the introduction of a buffer system. The reaction releases a large amount of gas, which poses a certain safety risk. Due to the cascade side reaction of the product and the diazonium salt, the reaction usually has only a 50-70% yield (Tetrahedron, 2004, 60, 4361; Journal of Organic Chemistry, 2000, 65, 432). Moreover, due to the disadvantages of low heat and mass transfer efficiency, insufficient mixing, and poor process controllability, conventional intermittent reactors have problems such as unstable product quality, poor reaction selectivity, low production efficiency, obvious amplification effect, and complex operation procedures that are difficult to solve when using the above route to prepare trifluoromethylacetophenone oxime.

[0004] The present invention proposes a new cyclic micro-reaction process, which realizes the rapid reaction of diazonium salt and the in-situ large-phase extraction of generated products in a microchannel through mass transfer enhancement, greatly reduces the series side reactions of the products and improves the reaction selectivity. Summary of the invention

[0005] The present invention aims to provide a process for continuously synthesizing m-trifluoromethylacetophenone oxime by using a microchannel reactor, aiming to solve the problems of unstable product quality, poor reaction selectivity, low production efficiency, obvious amplification effect, complicated operation flow, etc. in the process of preparing m-trifluoromethylacetophenone oxime by the existing kettle production process, improve production efficiency and process controllability, and reduce process risks.

[0006] The specific technical solutions are as follows:

[0007] A process for continuously synthesizing m-trifluoromethylacetophenone oxime using a microchannel reactor comprises the following steps:

[0008] (1) using m-trifluoromethylaniline as a raw material, reacting with sodium nitrite and sulfuric acid to obtain a diazonium salt aqueous solution as feed liquid A;

[0009] (2) selecting an organic solvent as feed liquid B;

[0010] (3) mixing a copper salt catalyst, acetaldehyde oxime, acetic acid and water in a certain proportion in a temperature-controlled stirring kettle to serve as an initial circulating reaction liquid;

[0011] (4) by dropping the feed liquid C containing the alkaline substance, the pH of the circulating reaction liquid in the temperature-controlled stirring tank is stabilized within a certain range;

[0012] (5) Feed liquid A, feed liquid B and circulating reaction liquid are respectively transported into the micro mixer under the action of pumps, wherein feed liquid A and feed liquid B are sheared phases and the circulating reaction liquid is the shearing phase;

[0013] (6) the mixed liquid flowing out of the micro mixer enters a microchannel reactor for reaction to obtain an oil-water mixed liquid with gas, and after passing through a gas-liquid-liquid phase separator, the aqueous phase enters a temperature-controlled stirring tank to mix with the circulating reaction liquid, and the organic phase is collected and post-processed to obtain the product m-trifluoromethylacetophenone oxime;

[0014] The post-treatment is preferably washing, solvent recovery, and recrystallization;

[0015] (7) The circulating reaction liquid in the temperature-controlled stirring tank is circulated until the prepared feed liquid A is reacted completely and the batch reaction is finished.

[0016] The molar ratio of m-trifluoromethylaniline, sodium nitrite and sulfuric acid used to prepare the feed liquid A in step (1) is 1:(1-1.2):(2-4), the reaction temperature is -5-5°C; the concentration of the diazonium salt in the feed liquid A is 5-20%.

[0017] The organic solvent in step (2) is one of inert organic solvents immiscible with water, such as aromatic hydrocarbon solvents, alkane solvents, halogenated hydrocarbon solvents, and is preferably one of toluene, xylene, n-hexane, cyclohexane, dichloromethane, and dichloroethane.

[0018] The copper salt catalyst in the initial circulating reaction liquid of step (3) is one of cupric chloride, cuprous chloride, copper sulfate and copper acetate, more preferably copper sulfate, and the molar ratio of the copper salt catalyst to the intermediate trifluoromethylaniline in step (1) is 0.05-0.2:1; the concentration of acetaldehyde oxime in the initial circulating reaction liquid of step (3) is 2-10%, and the molar ratio of acetaldehyde oxime to the intermediate trifluoromethylaniline in step (1) is (1-3):1; the molar ratio of acetic acid in the initial circulating reaction liquid of step (3) to the intermediate trifluoromethylaniline in step (1) is (0.2-0.5):1; the temperature of the temperature-controlled stirring kettle is 10-30°C.

[0019] In the step (4), the feed liquid C is one of a sodium hydroxide aqueous solution and a sodium carbonate aqueous solution, with a concentration of 10-50%, and the pH range of the circulating reaction liquid is 4-5.

[0020] In the step (5), the micromixer is a membrane dispersion microreactor or a microsieve reactor, wherein the diameter of the microsieve is 0.1 to 1.0 mm, the number of sieve holes is at least 1, and the average pore size of the dispersion membrane is 0.1 to 100 μm; the mass flow ratio of the feed liquid A, feed liquid B and circulating reaction liquid introduced into the micromixer is 1:(0.5 to 2):(5 to 20).

[0021] The characteristic size of the microchannel reactor in step (6) is 0.5-5 mm, the reaction temperature is 20-60° C., the residence time is 0.5-10 min, and the pressure is 0-1 MPa (gauge pressure). Preferably, the characteristic size of the microchannel reactor is 2-4 mm, the reaction temperature is 30-40° C., the residence time is 3-5 min, and the pressure is 0.5-1 MPa (gauge pressure).

[0022] Compared with the prior art, the present invention has the following advantages and outstanding technical effects:

[0023] The present invention utilizes micro-reaction technology to achieve rapid mixing of multiple streams of liquid, effectively avoiding side reactions such as decomposition of diazonium salts caused by insufficient mixing of materials. In the microchannel, nitrogen generated by the reaction is used to form a gas-liquid-liquid Taylor flow. On the one hand, the back-mixing phenomenon of the reaction liquid is effectively avoided through the partition effect of the gas, and the side reaction between the product and the diazonium salt is reduced; on the other hand, the formation of the Taylor flow can effectively strengthen the circulation in the liquid column, improve the mass transfer effect between the liquid and liquid phases, and efficiently achieve large-phase extraction of oil and water. In the cyclic micro-reaction process, the side reaction between the product and the subsequently added diazonium salt can be greatly reduced by extracting the product in situ and removing the organic phase in time; at the same time, the addition process of the alkali solution is separated from the addition process of the diazonium salt, which can effectively reduce the effect of the large amount of heat released by the acid-base neutralization reaction on the reaction process. The method of the present invention has a simple process, continuous operation, short reaction cycle, high safety and controllability, and high production efficiency, and effectively solves the problems in the intermittent reactor process of preparing m-trifluoromethylacetophenone oxime using m-trifluoromethylaniline. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 The present invention is a continuous synthesis process flow chart of trifluoromethylacetophenone oxime. DETAILED DESCRIPTION

[0025] The present invention provides a continuous synthesis process of m-trifluoromethylacetophenone oxime, which is further described below in conjunction with embodiments.

[0026] Example 1

[0027] Add 40g 20% ​​sulfuric acid solution and 4.02g m-trifluoromethylaniline in a three-necked flask, heat to 60℃ to dissolve completely, then cool to -5℃ and start to drop 5.42g 35% sodium nitrite aqueous solution, control the reaction temperature to -5~0℃, keep warm and stir for 1 hour after the dropwise addition, and obtain a diazonium salt clarified liquid as feed liquid A. Toluene is selected as feed liquid B. Add 60g water, 0.5g acetic acid, 0.4g copper sulfate and 5.9g 50% acetaldehyde oxime aqueous solution in a 25℃ temperature-controlled stirring kettle in turn as the initial circulation reaction liquid. Connect the temperature-controlled stirring kettle to a pH meter to monitor the pH of the circulation reaction liquid in real time, and add 40% sodium hydroxide aqueous solution (feed liquid C) through a peristaltic pump to control the pH of the circulation reaction liquid between 4.5 and 4.7. Three horizontal flow pumps were used to transport feed liquid A, feed liquid B and circulating reaction liquid into a micro mixer (membrane dispersion microreactor, dispersion membrane average pore size of 10 μm, main channel size of 250 μm) at a flow rate of 1 g / min, 1 g / min, and 10 g / min, respectively. The resulting mixed solution was passed into a microchannel reactor (Hastelloy alloy, inner diameter 2 mm, temperature 30 ° C, residence time 5 min, pressure 0.5 MPa). The reaction liquid flowing out of the microchannel reactor entered a continuous gas-liquid-liquid phase separator, and the aqueous phase entered a temperature-controlled stirring kettle to mix with the circulating reaction liquid. The organic phase was collected, washed with 5% ammonia water until neutral, dried over anhydrous sodium sulfate, the solvent was recovered, and the resulting crude product was recrystallized from petroleum ether to obtain 4.53 g of white solid trifluoromethylacetophenone oxime, which was detected by GC with a purity of 99.2% and a yield of 88.7%.

[0028] Example 2

[0029] Add 40g 20% ​​sulfuric acid solution and 4.02g m-trifluoromethylaniline in a three-necked flask, heat to 60℃ to dissolve completely, then cool to -5℃ and start to drop 5.42g 35% sodium nitrite aqueous solution, control the reaction temperature to -5~0℃, keep warm and stir for 1 hour after the dropwise addition, and obtain a diazonium salt clarified liquid as feed liquid A. Toluene is selected as feed liquid B. Add 30g water, 0.5g acetic acid, 0.4g copper sulfate and 5.9g 50% acetaldehyde oxime aqueous solution in a 25℃ temperature-controlled stirring kettle in turn as the initial circulation reaction liquid. Connect the temperature-controlled stirring kettle to a pH meter to monitor the pH of the circulation reaction liquid in real time, and add 40% sodium hydroxide aqueous solution (feed liquid C) through a peristaltic pump to control the pH of the circulation reaction liquid between 4.5 and 4.7. Three horizontal flow pumps were used to transport feed liquid A, feed liquid B and circulating reaction liquid into a micro mixer (membrane dispersion microreactor, dispersion membrane average pore size of 10 μm, main channel size of 250 μm) at a flow rate of 1 g / min, 1 g / min, and 5 g / min, respectively. The resulting mixed solution was passed into a microchannel reactor (Hastelloy alloy, inner diameter 2 mm, temperature 30 ° C, residence time 5 min, pressure 0.5 MPa). The reaction liquid flowing out of the microchannel reactor entered a continuous gas-liquid-liquid phase separator, and the aqueous phase entered a temperature-controlled stirring kettle to mix with the circulating reaction liquid. The organic phase was collected, washed with 5% ammonia water until neutral, dried over anhydrous sodium sulfate, the solvent was recovered, and the resulting crude product was recrystallized from petroleum ether to obtain 4.24 g of white solid trifluoromethylacetophenone oxime, which was detected by GC with a purity of 99.0% and a yield of 82.8%.

[0030] Example 3

[0031] Add 40g 20% ​​sulfuric acid solution and 4.02g m-trifluoromethylaniline in a three-necked flask, heat to 60℃ to dissolve completely, then cool to -5℃ and start to drop 5.42g 35% sodium nitrite aqueous solution, control the reaction temperature to -5~0℃, keep warm and stir for 1 hour after the dropwise addition, and obtain a diazonium salt clarified liquid as feed liquid A. Dichloromethane is selected as feed liquid B. Add 60g water, 0.5g acetic acid, 0.4g copper sulfate and 5.9g 50% acetaldehyde oxime aqueous solution in a 25℃ temperature-controlled stirring kettle in turn as the initial circulation reaction liquid. Connect the temperature-controlled stirring kettle to a pH meter to monitor the pH of the circulation reaction liquid in real time, and add 40% sodium hydroxide aqueous solution (feed liquid C) through a peristaltic pump to control the pH of the circulation reaction liquid between 4.5 and 4.7. Three horizontal flow pumps were used to transport feed liquid A, feed liquid B and circulating reaction liquid into a micro mixer (membrane dispersion microreactor, dispersion membrane average pore size of 10 μm, main channel size of 250 μm) at a flow rate of 1 g / min, 1 g / min, and 10 g / min, respectively. The resulting mixed solution was passed into a microchannel reactor (Hastelloy alloy, inner diameter 2 mm, temperature 40 ° C, residence time 3 min, pressure 0.5 MPa). The reaction liquid flowing out of the microchannel reactor entered a continuous gas-liquid-liquid phase separator, and the aqueous phase entered a temperature-controlled stirring kettle to mix with the circulating reaction liquid. The organic phase was collected, washed with 5% ammonia water until neutral, dried over anhydrous sodium sulfate, the solvent was recovered, and the resulting crude product was recrystallized from petroleum ether to obtain 3.89 g of white solid trifluoromethylacetophenone oxime, which was detected by GC with a purity of 98.2% and a yield of 75.4%.

[0032] Example 4

[0033] Add 40g 20% ​​sulfuric acid solution and 4.02g m-trifluoromethylaniline in a three-necked flask, heat to 60℃ to dissolve completely, then cool to -5℃ and start to drop 5.42g 35% sodium nitrite aqueous solution, control the reaction temperature to -5~0℃, keep warm and stir for 1 hour after the dropwise addition, and obtain a diazonium salt clarified liquid as feed liquid A. Toluene is selected as feed liquid B. Add 60g water, 0.5g acetic acid, 0.4g copper sulfate and 5.9g 50% acetaldehyde oxime aqueous solution in a 25℃ temperature-controlled stirring kettle in sequence as the initial circulation reaction liquid. Connect the temperature-controlled stirring kettle to a pH meter to monitor the pH of the circulation reaction liquid in real time, and add 40% sodium hydroxide aqueous solution (feed liquid C) through a peristaltic pump to control the pH of the circulation reaction liquid between 4 and 4.2. Three horizontal flow pumps were used to transport feed liquid A, feed liquid B and circulating reaction liquid into a micro mixer (membrane dispersion microreactor, dispersion membrane average pore size of 10 μm, main channel size of 250 μm) at a flow rate of 1 g / min, 1 g / min, and 10 g / min, respectively. The resulting mixed solution was passed into a microchannel reactor (Hastelloy alloy, inner diameter 2 mm, temperature 30 ° C, residence time 5 min, pressure 0.5 MPa). The reaction liquid flowing out of the microchannel reactor entered a continuous gas-liquid-liquid phase separator, and the aqueous phase entered a temperature-controlled stirring kettle to mix with the circulating reaction liquid. The organic phase was collected, washed with 5% ammonia water until neutral, dried over anhydrous sodium sulfate, the solvent was recovered, and the resulting crude product was recrystallized from petroleum ether to obtain 4.18 g of white solid trifluoromethylacetophenone oxime, which was detected by GC with a purity of 98.7% and a yield of 81.4%.

[0034] Example 5

[0035] Add 40g 20% ​​sulfuric acid solution and 4.02g m-trifluoromethylaniline in a three-necked flask, heat to 60℃ to dissolve completely, then cool to -5℃ and start to drop 5.42g 35% sodium nitrite aqueous solution, control the reaction temperature to -5~0℃, keep warm and stir for 1 hour after the dropwise addition, and obtain a diazonium salt clarified liquid as feed liquid A. Toluene is selected as feed liquid B. Add 60g water, 0.5g acetic acid, 0.4g copper sulfate and 5.9g 50% acetaldehyde oxime aqueous solution in a 25℃ temperature-controlled stirring kettle in turn as the initial circulation reaction liquid. Connect the temperature-controlled stirring kettle to a pH meter to monitor the pH of the circulation reaction liquid in real time, and add 40% sodium hydroxide aqueous solution (feed liquid C) through a peristaltic pump to control the pH of the circulation reaction liquid between 4.5 and 4.7. Three horizontal flow pumps were used to transport feed liquid A, feed liquid B and circulating reaction liquid into a micro mixer (membrane dispersion microreactor, dispersion membrane average pore size of 10 μm, main channel size of 250 μm) at a flow rate of 1 g / min, 1 g / min, and 10 g / min, respectively. The resulting mixed solution was passed into a microchannel reactor (Hastelloy alloy, inner diameter 4 mm, temperature 30 ° C, residence time 5 min, pressure 0.5 MPa). The reaction liquid flowing out of the microchannel reactor entered a continuous gas-liquid-liquid phase separator, and the aqueous phase entered a temperature-controlled stirring kettle to mix with the circulating reaction liquid. The organic phase was collected, washed with 5% ammonia water until neutral, dried over anhydrous sodium sulfate, the solvent was recovered, and the resulting crude product was recrystallized from petroleum ether to obtain 4.12 g of white solid trifluoromethylacetophenone oxime, which was detected by GC with a purity of 98.9% and a yield of 80.4%.

[0036] Comparative Example 1

[0037] In a 100mL three-necked flask, add 40g of 20% sulfuric acid solution and 4.02g of m-trifluoromethylaniline in sequence, heat to 60℃ to dissolve completely, then cool to -5℃ and start dripping 5.42g of 35% sodium nitrite aqueous solution, control the reaction temperature to -5~0℃, keep warm and stir for 1 hour after the dripping, and obtain the diazonium salt clear solution for standby use. In a 500mL four-necked flask, add 50g of water, 0.5g of acetic acid, 0.4g of copper sulfate, 5.9g of 50% acetaldehyde oxime aqueous solution, and add 50g of toluene. Connect a pH meter to the side port, and control the pH at 4.5~4.7 by dripping 40% NaOH aqueous solution. Use a horizontal flow pump to slowly add the clarified diazo solution to the above solution, maintain the temperature at 15-20°C, and complete the addition within 30 minutes. Continue stirring for 2 hours, separate the phases, wash the organic phase with 5% ammonia water until neutral, dry over anhydrous sodium sulfate, recover the solvent, and recrystallize the crude product from petroleum ether to obtain 2.84 g of white solid trifluoromethylacetophenone oxime. GC detection showed a purity of 98.1% and a yield of 55.0%.

[0038] The above embodiments describe the technical solutions of the present invention in detail. Obviously, the present invention is not limited to the described embodiments. Based on the embodiments of the present invention, people familiar with the technical field can also make various changes accordingly, but any changes that are equivalent or similar to the present invention belong to the scope of protection of the present invention.

Claims

1. A process for continuously synthesizing m-trifluoromethylacetophenone oxime using a microchannel reactor, characterized in that: The following steps are involved: (1) using m-trifluoromethylaniline as a raw material, reacting with sodium nitrite and sulfuric acid to obtain a diazonium salt solution as feed solution A; (2) selecting an organic solvent as feed liquid B; (3) mixing a copper salt catalyst, acetaldehyde oxime, acetic acid and water in a temperature-controlled stirring kettle to serve as an initial circulating reaction solution; (4) stabilizing the pH of the circulating reaction liquid in the temperature-controlled stirring tank by dropwise adding a liquid C containing an alkaline substance; (5) Feed liquid A, feed liquid B and circulating reaction liquid are respectively transported into the micro mixer under the action of pumps, wherein feed liquid A and feed liquid B are sheared phases and the circulating reaction liquid is the shearing phase; (6) the mixed liquid flowing out of the micro mixer enters a microchannel reactor for reaction to obtain an oil-water mixed liquid with gas, and after passing through a gas-liquid-liquid phase separator, the aqueous phase enters a temperature-controlled stirring tank to mix with the circulating reaction liquid, and the organic phase is collected and post-processed to obtain the product m-trifluoromethylacetophenone oxime; (7) The circulating reaction liquid in the temperature-controlled stirring tank is circulated until the prepared feed liquid A is reacted completely and the batch reaction is finished.

2. The process according to claim 1, characterized in that The molar ratio of m-trifluoromethylaniline, sodium nitrite and sulfuric acid used to prepare the feed liquid A in step (1) is 1:(1-1.2):(2-4), and the reaction temperature is -5-5°C; the concentration of the diazonium salt in the feed liquid A is 5-20wt%.

3. The process according to claim 1, characterized in that The organic solvent in step (2) is an inert organic solvent that is immiscible with water, and is one of an aromatic hydrocarbon solvent, an alkane solvent, and a halogenated hydrocarbon solvent.

4. The process according to claim 3, characterized in that The organic solvent is one of toluene, xylene, n-hexane, cyclohexane, dichloromethane and dichloroethane.

5. The process according to claim 1, characterized in that The copper salt catalyst in the initial circulating reaction liquid of step (3) is one of cupric chloride, cuprous chloride, copper sulfate and copper acetate, and the molar ratio of the copper salt catalyst to the intermediate trifluoromethylaniline in step (1) is (0.05-0.2):1; The concentration of acetaldehyde oxime in the initial circulating reaction liquid of step (3) is 2-10 wt %, and the molar ratio of acetaldehyde oxime to the intermediate trifluoromethylaniline of step (1) is (1-3):1; The molar ratio of acetic acid in the initial circulating reaction liquid of step (3) to the intermediate trifluoromethylaniline of step (1) is (0.2-0.5):

1.

6. The process according to claim 1, characterized in that The temperature of the temperature-controlled stirring kettle in step (3) is 10-30°C.

7. The process according to claim 1, characterized in that The feed liquid C in step (4) is one of a sodium hydroxide aqueous solution and a sodium carbonate aqueous solution, with a concentration of 10 to 50 wt%, and the pH range of the circulating reaction liquid is controlled to be 4 to 5.

8. The process according to claim 1, characterized in that The micromixer in step (5) is a membrane dispersion microreactor or a microsieve reactor, wherein the diameter of the microsieve is 0.1 to 1.0 mm, the number of sieve holes is at least 1, and the average pore size of the dispersion membrane is 0.1 to 100 μm.

9. The process according to claim 1, characterized in that In step (5), the mass flow ratio of the feed liquid A, feed liquid B and circulating reaction liquid introduced into the micro mixer is 1:(0.5-2):(5-20).

10. The process according to claim 1, characterized in that The characteristic size of the microchannel reactor in step (6) is 0.5-5 mm, the reaction temperature is 20-60° C., the residence time is 0.5-10 min, and the pressure is 0-1 MPa (gauge pressure).

Images