Method for continuously preparing m-trifluoromethyl acetophenone oxime

Abstract

The invention discloses a method for continuously preparing 3-(trifluoromethyl) acetophenone oxime, which belongs to the technical field of organic synthesis and comprises the following specific steps: diazotizing 3-(trifluoromethyl) aniline serving as an initial raw material, adding fluoboric acid to prepare tetrafluoroborate diazonium salt, drying the tetrafluoroborate diazonium salt, dissolving the dried tetrafluoroborate diazonium salt in a polar organic solvent, and reacting to obtain 3-(trifluoromethyl) acetophenone oxime. The preparation method comprises the following steps: dissolving a copper salt catalyst in water, uniformly mixing the copper salt catalyst with acetaldehyde oxime, and proportionally feeding the two materials into a micro-channel reactor for reaction to generate 3-(trifluoromethyl) acetophenone oxime; the total yield of the m-trifluoromethyl acetophenone oxime prepared by the method is 92% or above, and the content is 99% or above; the method has the advantages of simple preparation conditions, high yield and less pollution, and can realize continuous production.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a method for continuously preparing m-trifluoromethylacetophenone oxime. Background Art

[0002] 3-Trifluoromethylacetophenoneoxime, English name 3-Trifluoromethylacetophenoneoxime, molecular formula is C 9 H 8 F 3 NO, melting point 56 ~ 62 ℃, white needle-shaped crystals, it is the key intermediate for the synthesis of methoxypropylene ester compound trifloxystrobin (trade name Flint), and is also an important raw material for the synthesis of medicines and dyes. Its key downstream product trifloxystrobin is a new type of efficient, safe and broad-spectrum fungicide, which has special effects on powdery mildew and leaf spot, and also has good activity against rust, downy mildew, damping-off disease, apple scab, etc. It has low toxicity to mammals, bees, birds, fish, insects, etc., and has fast environmental metabolism, so it is safe for the environment, has no teratogenic, carcinogenic, mutagenic effects, and has no adverse effects on genetics. Therefore, the study of its synthesis process is of great practical significance.

[0003] At present, the synthesis methods of m-trifluoromethylacetophenone oxime mainly include the following routes: (1) m-trifluoromethylaniline is used as the starting material, and after nitrogenation, it is coupled with acetaldehyde oxime under the catalysis of copper sulfate to generate m-trifluoromethylacetophenone oxime. The m-trifluoromethylacetophenone oxime thus generated has low purity and cannot be used directly. It needs to be hydrolyzed into m-trifluoromethylacetophenone and then reacted with hydroxylamine hydrochloride to generate m-trifluoromethylacetophenone oxime. This route is the main process for industrial production at home and abroad. However, this route has complicated reaction steps, many side reactions, large amount of solvent, wastewater consumption of more than 30, low production capacity and high production cost. (2) Using m-trifluoromethylaniline as the starting material, in a non-polar solvent, it first reacts with nitrite under the action of organic acid to form diazonium salt, and then reacts with acetaldehyde oxime under the action of phase transfer catalyst and copper salt catalyst to form m-trifluoromethylacetophenone oxime, with a yield of about 90%. However, this route uses expensive nitrite, which is dangerous, and also requires the addition of a phase transfer catalyst, resulting in a high production cost. (3) Using m-trifluoromethylacetophenone as the starting material, it reacts with hydroxylamine hydrochloride to form m-trifluoromethylacetophenone oxime, with a yield of more than 95%. The starting materials used in this method are expensive, and the industrialization cost is high.

[0004] Therefore, it is of great significance to provide a method for synthesizing m-trifluoromethylacetophenone oxime with low raw material consumption, small amount of three wastes generated, high production capacity and simple process route. Summary of the invention

[0005] In order to solve the problems of long process route, large raw material consumption and large amount of waste salt generated in the reaction process of the above-mentioned traditional synthesis process of trifluoromethylacetophenone oxime, the present invention aims to provide a method for continuously preparing trifluoromethylacetophenone oxime. The method has the advantages of simple operation, high safety, short reaction time, low production cost, high product purity and continuous production.

[0006] In order to achieve the above object, the present invention is implemented through the following technical solutions:

[0007] A method for continuously preparing m-trifluoromethylacetophenone oxime, comprising the following steps:

[0008] 1) Add m-trifluoromethylaniline and dilute acid into a reactor, heat to 65-70°C to dissolve, cool to 0-5°C, dropwise add a 30% sodium nitrite aqueous solution, and control the system temperature at 0-10°C. After the dropwise addition, stir and react for 0.5-1h, then add a 40% fluoroboric acid aqueous solution, continue to stir and react for 0.5-1h, filter, wash the filter cake with water 1-2 times, and dry to obtain tetrafluoroborate diazonium salt;

[0009] 2) dissolving the tetrafluoroborate diazonium salt obtained in step 1) in a polar organic solvent to obtain solution 1; adding a copper salt catalyst into water, stirring and dissolving, then adding an acetaldehyde oxime aqueous solution with a mass concentration of 50%, stirring and mixing evenly to obtain solution 2; respectively pumping solution 1 and solution 2 into a microchannel reactor through a metering pump, and performing a coupling reaction at a pressure of 0.2 to 0.4 MPa and a temperature of 20 to 40° C. for a residence time of 6 to 10 seconds to obtain a reaction solution;

[0010] 3) The reaction solution obtained in step 2) is transferred to a crystallization kettle, purified water is added, and the temperature is lowered to 0-5° C. for crystallization for 1-2 hours to obtain a crystallization liquid; the obtained crystallization liquid is filtered, and the obtained filter cake is washed with water 1-2 times, and then dried under reduced pressure at 40-50° C. for 6-10 hours to obtain m-trifluoromethylacetophenone oxime.

[0011] The molar ratio of the dilute acid, sodium nitrite, fluoroboric acid and m-trifluoromethylaniline in step 1) is 2.5-4.0:1.05-1.1:1.1-1.2:1.

[0012] The dilute acid in step 1) is one or two of dilute hydrochloric acid, dilute sulfuric acid and dilute hydrobromic acid.

[0013] The polar organic solvent in step 2) is one or two of methanol, ethanol, isopropanol, acetone, tetrahydrofuran and acetonitrile.

[0014] The copper salt catalyst in step 2) is copper sulfate, copper acetate, copper chloride or cuprous chloride; the mass ratio of the copper salt catalyst to the added water is 1:5-8.

[0015] The molar ratio of the copper salt catalyst, acetaldehyde oxime in step 2) to the intermediate trifluoromethylaniline in step 1) is 0.07-0.13:1.4-1.8:1.

[0016] The amount of the polar organic solvent added in step 2) is 2 to 3 times the total volume of water in the water and acetaldehyde oxime aqueous solution.

[0017] The amount of purified water added in step 3) is 0.5 to 1 times the volume of the polar organic solvent in step 2).

[0018] Preferably, the dilute acid in step 1) is dilute hydrochloric acid; the polar organic solvent in step 2) is acetone; and the copper salt catalyst in step 2) is copper sulfate.

[0019] Preferably, the temperature of the coupling reaction in step 2) is 30-40° C. It should be noted that if the temperature is too low, the reaction will be incomplete and the yield will be reduced; if the temperature is too high, the side reactions will increase and the product content will decrease.

[0020] The synthetic route of m-trifluoromethylacetophenone oxime of the present invention is:

[0021]

[0022] Compared with the prior art, the present invention has the following advantages:

[0023] The method for continuously preparing meta-trifluoromethylacetophenone oxime of the present invention prepares diazonium tetrafluoroborate from diazonium salt, and obtains solid from dilute acid. Firstly, it avoids introducing a large amount of dilute acid into the next step reaction, and a large amount of dilute acid needs to be neutralized by adding alkali in the next step, and the dilute acid can be further recovered and reused, which greatly reduces the generation of waste water and waste salt; secondly, the preparation of diazonium tetrafluoroborate greatly improves the stability of the diazonium salt, reduces the occurrence of side reactions, and improves the reaction selectivity and product yield.

[0024] The method for continuously preparing m-trifluoromethylacetophenone oxime of the present invention uses a microchannel reactor for reaction, the reaction substrate is not back-mixed during the reaction process, the reaction time is short, the activity of the diazonium salt is relatively high, and side reactions are prone to occur, so the probability of the diazonium salt side reactions occurring can be effectively reduced; the microchannel reactor also has efficient mass transfer and heat transfer effects, which can further reduce the occurrence of side reactions; and continuous production can be realized to improve production efficiency.

[0025] The method for continuously preparing m-trifluoromethylacetophenone oxime of the present invention has the advantages of simple operation, short reaction time, low production cost, high product purity, less waste water and continuous production, and the total yield of generated m-trifluoromethylacetophenone oxime is above 92%, and the content is above 99%. BRIEF DESCRIPTION OF THE DRAWINGS

[0026] Figure 1 The present invention is a process flow chart for continuously preparing m-trifluoromethylacetophenone oxime. DETAILED DESCRIPTION

[0027] In order to better understand the technical solution of the present invention, the above content of the present invention is further described in detail below through specific implementation methods in the form of embodiments, but this should not be understood as the scope of the above subject matter of the present invention being limited to the following examples. All technologies realized based on the above content of the present invention belong to the scope of the present invention.

[0028] Example 1 Process flow Figure 1 As shown, 64.45g of m-trifluoromethylaniline and 218.76g of hydrochloric acid with a mass concentration of 20% are added to a reactor, heated to 68°C for dissolution, cooled to 3°C, 96.6g of a 30% sodium nitrite aqueous solution is added dropwise thereto, and the system temperature is controlled at 5°C. After the addition is complete, the mixture is stirred and reacted for 0.7h at the temperature, and then 96.6g of a 40% fluoroboric acid aqueous solution is added, and the mixture is stirred and reacted for 0.7h at the temperature, filtered, and the filter cake is washed once with water and dried to obtain tetrafluoroborate diazonium salt;

[0029] The prepared tetrafluoroborate diazonium salt was dissolved in 200 mL of acetone to obtain solution 1; 9.98 g of copper sulfate pentahydrate catalyst was added to 60 g of water, stirred to dissolve, and then 75.6 g of acetaldehyde oxime aqueous solution with a mass concentration of 50% was added, and stirred to mix evenly to obtain solution 2; solution 1 and solution 2 were respectively pumped into a microchannel reactor through a metering pump, and a coupling reaction was carried out at a pressure of 0.3 MPa and a temperature of 30° C. The residence time was 8 s to obtain a reaction solution;

[0030] The obtained reaction solution was transferred to a crystallization kettle, and 100 g of purified water was added, and the temperature was lowered to 3° C. for crystallization. The crystallization time was 1 h to obtain a crystallization liquid; the obtained crystallization liquid was filtered, and the obtained filter cake was washed with water twice, and then dried under reduced pressure at 45° C. for 8 h to obtain 76.54 g of m-trifluoromethylacetophenone oxime, with a product content of 99.50% and a yield of 94.19%.

[0031] Example 2 64.45 g of m-trifluoromethylaniline and 470.78 g of sulfuric acid with a mass concentration of 25% were added to a reactor, heated to 65°C for dissolution, cooled to 2°C, 98 g of a 30% aqueous sodium nitrite solution was added dropwise thereto, and the system temperature was controlled at 5°C. After the addition was complete, the mixture was stirred and reacted for 0.6 h at room temperature, and then 100 g of a 40% aqueous fluoroboric acid solution was added, and the mixture was stirred and reacted for 0.7 h at room temperature, filtered, and the filter cake was washed twice with water and dried to obtain diazonium tetrafluoroborate;

[0032] The prepared tetrafluoroborate diazonium salt was dissolved in 200 mL of acetone to obtain solution 1; 8.98 g of copper sulfate pentahydrate catalyst was added to 60 g of water, stirred to dissolve, and then 80 g of acetaldehyde oxime aqueous solution with a mass concentration of 50% was added, and stirred to mix evenly to obtain solution 2; solution 1 and solution 2 were respectively pumped into a microchannel reactor through a metering pump, and a coupling reaction was carried out at a pressure of 0.3 MPa and a temperature of 30° C. The residence time was 9 s to obtain a reaction solution;

[0033] The obtained reaction solution was transferred to a crystallization kettle, and 120 g of purified water was added, and the temperature was lowered to 3° C. for crystallization. The crystallization time was 1.8 h to obtain a crystallization liquid. The obtained crystallization liquid was filtered, and the obtained filter cake was washed once with water, and then dried under reduced pressure at 45° C. for 7 h to obtain 76.80 g of m-trifluoromethylacetophenone oxime, with a product content of 99.34% and a yield of 94.51%.

[0034] Example 3 64.45 g of m-trifluoromethylaniline and 230 g of hydrochloric acid with a mass concentration of 20% were added to a reactor, heated to 66°C for dissolution, cooled to 4°C, 100 g of a 30% aqueous sodium nitrite solution was added dropwise thereto, and the system temperature was controlled at 0°C. After the addition was complete, the mixture was stirred and reacted for 0.8 h, and then 98.5 g of a 40% aqueous fluoroboric acid solution was added, and the mixture was stirred and reacted for 0.6 h. The mixture was filtered, and the filter cake was washed twice with water and dried to obtain diazonium tetrafluoroborate.

[0035] The prepared tetrafluoroborate diazonium salt was dissolved in 220 mL of ethanol to obtain solution 1; 7.5 g of copper sulfate pentahydrate catalyst was added to 60 g of water, stirred to dissolve, and then 72.5 g of acetaldehyde oxime aqueous solution with a mass concentration of 50% was added, and stirred to mix evenly to obtain solution 2; solution 1 and solution 2 were respectively pumped into a microchannel reactor through a metering pump, and a coupling reaction was carried out at a pressure of 0.2 MPa and a temperature of 35° C. The residence time was 8 s to obtain a reaction solution;

[0036] The obtained reaction solution was transferred to a crystallization kettle, and 140 g of purified water was added, and the temperature was lowered to 4° C. for crystallization. The crystallization time was 1.4 h to obtain a crystallization liquid. The obtained crystallization liquid was filtered, and the obtained filter cake was washed twice with water, and then dried under reduced pressure at 40° C. for 10 h to obtain 74.96 g of m-trifluoromethylacetophenone oxime, with a product content of 99.23% and a yield of 92.24%.

[0037] Example 4 64.45 g of m-trifluoromethylaniline and 530.5 g of hydrobromic acid with a mass concentration of 20% were added to a reactor, heated to 68° C. to dissolve, then cooled to 3° C., 98.6 g of a 30% aqueous sodium nitrite solution was added dropwise thereto, and the system temperature was controlled at 8° C. After the addition was complete, the mixture was stirred and reacted for 0.8 h, and then 102.8 g of a 40% aqueous fluoroboric acid solution was added, and the mixture was stirred and reacted for 0.8 h, filtered, and the filter cake was washed twice with water and dried to obtain diazonium tetrafluoroborate;

[0038] The prepared tetrafluoroborate diazonium salt was dissolved in 200 mL of methanol to obtain solution 1; 5.5 g of copper chloride catalyst was added to 40 g of water, stirred to dissolve, and then 82.5 g of acetaldehyde oxime aqueous solution with a mass concentration of 50% was added, and stirred to mix evenly to obtain solution 2; solution 1 and solution 2 were respectively pumped into a microchannel reactor through a metering pump, and a coupling reaction was carried out at a pressure of 0.3 MPa and a temperature of 25° C. The residence time was 9 s to obtain a reaction solution;

[0039] The obtained reaction solution was transferred to a crystallization kettle, and 200 g of purified water was added, and the temperature was lowered to 5° C. for crystallization. The crystallization time was 1.2 h to obtain a crystallization liquid; the obtained crystallization liquid was filtered, and the obtained filter cake was washed with water twice, and then dried under reduced pressure at 48° C. for 6.5 h to obtain 75.52 g of m-trifluoromethylacetophenone oxime, with a product content of 99.35% and a yield of 92.93%.

[0040] Example 5 64.45 g of m-trifluoromethylaniline and 182.5 g of hydrochloric acid with a mass concentration of 20% were added to a reactor, heated to 65°C for dissolution, cooled to 0°C, 96.6 g of a 30% aqueous sodium nitrite solution was added dropwise thereto, and the system temperature was controlled at 0°C. After the addition was complete, the mixture was stirred and reacted for 0.5 h, and then 96.6 g of a 40% aqueous fluoroboric acid solution was added, and the mixture was stirred and reacted for 1 h, filtered, and the filter cake was washed twice with water and dried to obtain diazonium tetrafluoroborate;

[0041] The prepared tetrafluoroborate diazonium salt was dissolved in 110 mL of tetrahydrofuran to obtain solution 1; 2.8 g of cuprous chloride catalyst was added to 20 g of water, stirred to dissolve, and then 66.2 g of acetaldehyde oxime aqueous solution with a mass concentration of 50% was added, and stirred to mix evenly to obtain solution 2; solution 1 and solution 2 were respectively pumped into a microchannel reactor through a metering pump, and a coupling reaction was carried out at a pressure of 0.2 MPa and a temperature of 40° C. The residence time was 6 s to obtain a reaction solution;

[0042] The obtained reaction solution was transferred to a crystallization kettle, and 55 g of purified water was added, and the temperature was lowered to 0°C for crystallization. The crystallization time was 1 h to obtain a crystallization liquid; the obtained crystallization liquid was filtered, and the obtained filter cake was washed once with water, and then dried under reduced pressure at 40°C for 10 h to obtain 75.90 g of m-trifluoromethylacetophenone oxime, with a product content of 99.28% and a yield of 93.40%.

[0043] Example 6 64.45 g of m-trifluoromethylaniline and 292 g of hydrochloric acid with a mass concentration of 20% were added to a reactor, heated to 70°C for dissolution, cooled to 5°C, 101.2 g of a 30% aqueous sodium nitrite solution was added dropwise thereto, and the system temperature was controlled at 10°C. After the addition was complete, the mixture was stirred and reacted for 1 h, and then 105.4 g of a 40% aqueous fluoroboric acid solution was added, and the mixture was stirred and reacted for 0.5 h. The mixture was filtered, and the filter cake was washed twice with water and dried to obtain diazonium tetrafluoroborate.

[0044] The prepared tetrafluoroborate diazonium salt was dissolved in 370 mL of acetonitrile to obtain solution 1; 10.4 g of copper acetate monohydrate catalyst was added to 83 g of water, stirred to dissolve, and then 85 g of acetaldehyde oxime aqueous solution with a mass concentration of 50% was added, and stirred to mix evenly to obtain solution 2; solution 1 and solution 2 were respectively pumped into a microchannel reactor through a metering pump, and a coupling reaction was carried out at a pressure of 0.4 MPa and a temperature of 20° C. The residence time was 10 s to obtain a reaction solution;

[0045] The obtained reaction solution was transferred to a crystallization kettle, and 370 g of purified water was added, and the temperature was lowered to 5° C. for crystallization. The crystallization time was 2 h to obtain a crystallization liquid; the obtained crystallization liquid was filtered, and the obtained filter cake was washed with water twice, and then dried under reduced pressure at 50° C. for 6 h to obtain 75.42 g of m-trifluoromethylacetophenone oxime, with a product content of 99.17% and a yield of 92.81%.

[0046] Although the above describes the specific implementation methods of the present invention, it does not limit the scope of protection of the present invention. Based on the technical solution of the present invention, various modifications or variations that can be made by those skilled in the art without creative work are still within the scope of protection of the present invention.

Claims

1. A method for continuously preparing m-trifluoromethylacetophenone oxime, characterized in that: The specific steps include: 1) Add m-trifluoromethylaniline and dilute acid into a reactor, heat to 65-70°C to dissolve, cool to 0-5°C, dropwise add a 30% sodium nitrite aqueous solution, and control the system temperature at 0-10°C. After the dropwise addition, stir and react for 0.5-1h, then add a 40% fluoroboric acid aqueous solution, continue to stir and react for 0.5-1h, filter, wash the filter cake with water 1-2 times, and dry to obtain tetrafluoroborate diazonium salt; 2) dissolving the tetrafluoroborate diazonium salt obtained in step 1) in a polar organic solvent to obtain solution 1; adding a copper salt catalyst into water, stirring and dissolving, then adding an acetaldehyde oxime aqueous solution with a mass concentration of 50%, stirring and mixing evenly to obtain solution 2; respectively pumping solution 1 and solution 2 into a microchannel reactor through a metering pump, and performing a coupling reaction at a pressure of 0.2 to 0.4 MPa and a temperature of 20 to 40° C. for a residence time of 6 to 10 seconds to obtain a reaction solution; 3) The reaction solution obtained in step 2) is transferred to a crystallization kettle, purified water is added, and the temperature is lowered to 0-5° C. for crystallization for 1-2 hours to obtain a crystallization liquid; the obtained crystallization liquid is filtered, and the obtained filter cake is washed with water 1-2 times, and then dried under reduced pressure at 40-50° C. for 6-10 hours to obtain m-trifluoromethylacetophenone oxime.

2. The method for continuously preparing m-trifluoromethylacetophenone oxime according to claim 1, characterized in that: The molar ratio of the dilute acid, sodium nitrite, fluoroboric acid and m-trifluoromethylaniline in step 1) is 2.5-4.0:1.05-1.1:1.1-1.2:

1.

3. The method for continuously preparing m-trifluoromethylacetophenone oxime according to claim 1, characterized in that: The dilute acid in step 1) is one or two of dilute hydrochloric acid, dilute sulfuric acid and dilute hydrobromic acid.

4. The method for continuously preparing m-trifluoromethylacetophenone oxime according to claim 1, characterized in that: The polar organic solvent in step 2) is one or two of methanol, ethanol, isopropanol, acetone, tetrahydrofuran and acetonitrile.

5. The method for continuously preparing m-trifluoromethylacetophenone oxime according to claim 1, characterized in that: The copper salt catalyst in step 2) is copper sulfate, copper acetate, copper chloride or cuprous chloride; the mass ratio of the copper salt catalyst to the added water is 1:5-8.

6. The method for continuously preparing m-trifluoromethylacetophenone oxime according to claim 1, characterized in that: The molar ratio of the copper salt catalyst, acetaldehyde oxime in step 2) to the intermediate trifluoromethylaniline in step 1) is 0.07-0.13:1.4-1.8:

1.

7. The method for continuously preparing m-trifluoromethylacetophenone oxime according to claim 1, characterized in that: The amount of the polar organic solvent added in step 2) is 2 to 3 times the total volume of water in the water and acetaldehyde oxime aqueous solution.

8. The method for continuously preparing m-trifluoromethylacetophenone oxime according to claim 1, characterized in that: The amount of purified water added in step 3) is 0.5 to 1 times the volume of the polar organic solvent in step 2).

9. The method for continuously preparing m-trifluoromethylacetophenone oxime according to claim 1, characterized in that: The dilute acid in step 1) is dilute hydrochloric acid; the polar organic solvent in step 2) is acetone; and the copper salt catalyst in step 2) is copper sulfate.

10. The method for continuously preparing m-trifluoromethylacetophenone oxime according to claim 1, characterized in that: The temperature of the coupling reaction in step 2) is 30-40°C.

Images