A green and efficient method for the synthesis of m-trifluoromethylacetophenone oxime

Abstract

This invention belongs to the field of organic synthesis, specifically relating to a green and efficient synthesis method for m-trifluoromethylacetophenone oxime. The specific steps are as follows: first, m-trifluoromethylaniline is added to a nonpolar solvent and reacts with nitrite ester under the action of an organic acid to generate a diazonium salt. Then, under the combined action of a phase transfer catalyst and a copper salt catalyst, it reacts with acetaldehyde oxime to generate m-trifluoromethylacetophenone oxime. After heating and filtering the copper salt catalyst, the mixture is cooled and crystallized to obtain m-trifluoromethylacetophenone oxime with a content of over 98% and a yield of over 90% based on m-trifluoromethylaniline. The above synthesis method generates less waste, has high atom utilization, high reaction yield, simple operation, strong process stability, and is easy for industrial production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and specifically relates to a green and efficient synthesis method for m-trifluoromethylacetophenone oxime. Background Technology

[0002] m-Trifluoromethylacetophenone oxime is a very important pesticide intermediate, mainly used to synthesize the fungicide azoxystrobin. Azoxystrobin has a broad fungicidal spectrum, high cost-effectiveness, high fungicidal activity, and is resistant to rain washout. It is used on many crops such as cereals, soybeans, corn, rice, rapeseed, cotton, and sugar beets to control diseases of Ascomycetes, Deuteromycetes, Basidiomycetes, and Oomycetes, and is particularly effective against Asian rust on soybeans.

[0003] Currently, the main synthetic methods for m-trifluoromethylacetophenone oxime are as follows:

[0004] (1) The first route uses m-trifluoromethylaniline as the starting material and water as the solvent. After diazotization with sulfuric acid and sodium nitrite, it undergoes a coupling reaction with acetaldehyde oxime under copper sulfate catalysis. Then, hydrochloric acid is added to hydrolyze and generate m-trifluoromethylacetophenone. After separation, m-trifluoromethylacetophenone is reacted with hydroxylamine hydrochloride to generate m-trifluoromethylacetophenone oxime, with an overall yield of about 75%. Although this route is currently the main process for industrial production at home and abroad, the reaction steps are complicated, there are many side reactions, poor atom economy, low overall yield, and wastewater consumption is as high as 30% or more, resulting in high production costs for m-trifluoromethylacetophenone oxime.

[0005] The reaction equation is as follows:

[0006]

[0007] (2) The second route uses m-trifluoromethylbromobenzene as the starting material. First, it prepares a Grignard reagent with magnesium, and then reacts with acetic anhydride to generate m-trifluoromethylacetophenone. After purification, m-trifluoromethylacetophenone is reacted with hydroxylamine hydrochloride to generate m-trifluoromethylacetophenone oxime. The total yield is about 65%.

[0008] The reaction equation is as follows:

[0009]

[0010] This route not only has a low overall yield, but also carries a high risk of industrial-scale Grignard reaction, and the raw material, m-trifluoromethylbromobenzene, is expensive, making industrial production less feasible.

[0011] (3) Some literature reports that trifluorotoluene undergoes Friedel-Crafts acylation reaction with acetyl chloride (or acetic anhydride) to directly synthesize m-trifluoromethylacetophenone. The m-trifluoromethylacetophenone is then reacted with hydroxylamine hydrochloride to synthesize m-trifluoromethylacetophenone oxime. This synthetic route is simple, but the yield is extremely low. The aluminum trichloride used in this route will react with trifluorotoluene during the reaction process to generate a large number of cross-linking product impurities. The product yield is less than 5%, and it has no industrial production value.

[0012] The reaction equation is as follows:

[0013]

[0014] The side reaction equation is as follows:

[0015]

[0016] To address the aforementioned issues, it is necessary to develop a new synthetic method for m-trifluoromethylacetophenone oxime that is economical and readily available with minimal waste, high atom economy, high reaction yield, simple operation, and easy for industrial production. Summary of the Invention

[0017] This invention addresses the shortcomings of existing technologies by providing a green and efficient synthesis method for m-trifluoromethylacetophenone oxime. The specific steps involve first adding m-trifluoromethylaniline to a nonpolar solvent, reacting it with nitrite ester under the action of an organic acid to generate a diazonium salt, and then reacting it with acetaldehyde oxime under the combined action of a phase transfer catalyst and a copper salt catalyst to generate m-trifluoromethylacetophenone oxime. After heating and filtering the copper salt catalyst, the mixture is cooled and crystallized to obtain m-trifluoromethylacetophenone oxime with a purity of over 98% and a yield of over 90% based on m-trifluoromethylaniline. This synthesis method generates less waste, has high atom utilization, high reaction yield, simple operation, strong process stability, and is suitable for industrial production.

[0018] The specific technical solution adopted in this invention is as follows:

[0019] A green and efficient method for the synthesis of m-trifluoromethylacetophenone oxime, comprising the following steps:

[0020] A measured amount of m-trifluoromethylaniline and organic acid were added to a nonpolar solvent, and a measured amount of nitrite was slowly added. During the dropwise addition process, the temperature of the reaction system was controlled at 5-10℃, and the dropwise addition time was controlled at 1-2h.

[0021] After the addition of nitrite, the temperature is raised to 15-20℃ and kept at that temperature for 1-3 hours before sampling and testing. After the m-trifluoromethylaniline is completely converted into diazonium salt, the above diazonium salt solution is slowly added dropwise to acetaldehyde oxime containing a phase transfer catalyst and a copper salt catalyst of a certain mesh size. The addition temperature is controlled at 5-10℃ and the addition time is controlled at 2-3 hours. After the diazonium salt is added, the reaction is monitored and found to be qualified. The copper salt catalyst is then filtered, and the filtrate is cooled and crystallized by suction filtration to obtain solid m-trifluoromethylacetophenone oxime.

[0022] Testing revealed that the final obtained m-trifluoromethylacetophenone oxime content reached over 98%, and the yield, calculated based on m-trifluoromethylaniline, reached over 90%.

[0023] The above reaction equation is as follows:

[0024]

[0025] The nonpolar solvent is one or more of petroleum ether, methylcyclohexane, n-hexane, cyclohexane, and pentane; petroleum ether is preferred as the solvent.

[0026] The weight ratio of m-trifluoromethylaniline to solvent is 1:2-10; preferably 1:4.

[0027] The added organic acid has a pH value of 3.0-4.0, and can be selected from one or more of acetic acid, oxalic acid, hydroxysuccinic acid, and 2-hydroxypropyltricarboxylic acid, based on the above; 2-hydroxypropyltricarboxylic acid is preferred.

[0028] The weight ratio of m-trifluoromethylaniline to organic acid is 1:0.05-0.2; preferably 1:0.1.

[0029] The molar ratio of m-trifluoromethylaniline to nitrite and acetaldehyde oxime is 1:1-1.5:1-2.0; preferably 1:1.05:1.1.

[0030] The nitrite is one or more of isopropyl nitrite, n-butyl nitrite, and tert-butyl nitrite; preferably tert-butyl nitrite.

[0031] The phase transfer catalyst is one or more of tetrabutylammonium bromide, methyltrioctylammonium chloride, 18-crown ether-6, and PEG-400; preferably methyltrioctylammonium chloride; the amount of the phase transfer catalyst is 0.1%-3% of the molar amount of m-trifluoromethylaniline; preferably 0.5%.

[0032] The copper salt catalyst is copper acetate or copper sulfate, preferably copper acetate; the catalyst mesh size is 800 mesh or higher, preferably 1000-1200 mesh; the molar ratio of copper salt catalyst to m-trifluoromethylaniline is 0.03-0.2:1; preferably 0.05:1; the copper salt catalyst can be recycled.

[0033] Compared with the prior art, the technical advantages of the present invention are as follows:

[0034] (1) The present invention has a short synthesis step, less waste, and high atom utilization rate. The one-pot two-step reaction method for synthesizing m-trifluoromethylacetophenone oxime shortens the synthesis reaction steps by half compared to the existing first synthetic route for the indirect synthesis of m-trifluoromethylacetophenone oxime; it also eliminates one step compared to the second Grignard reaction route.

[0035] (2) When synthesizing m-trifluoromethyl diazonium salt in an aqueous system, the diazonium salt in the homogeneous system will continue to react with the raw material m-trifluoromethylaniline, resulting in the formation of m-trifluoromethylacetophenone oxime under coupling reaction conditions containing a large amount of m-trifluoromethylacetophenone, m-trifluoromethylphenol, m-trifluoromethylaniline and coupling impurities. The system is dark in color and the product is difficult to separate. Therefore, an indirect method must be used to synthesize m-trifluoromethylacetophenone oxime. The existing side reaction equations for the diazonium salt aqueous phase synthesis system are as follows:

[0036]

[0037] The high selectivity and yield of this invention are due to the use of a non-polar solvent. During the diazotization reaction, the diazonium salt generated precipitates, significantly reducing the chance of further reaction between the diazonium salt and the starting material. This largely controls side reactions and significantly improves reaction selectivity and product yield. The yield of m-trifluoromethylacetophenone oxime reaches over 90%, which is more than 15% higher than the overall yield of the aqueous diazonium salt route and the m-trifluoromethylbromobenzo Grignard process route.

[0038] (3) The process of this invention is simple to operate and has strong process stability. In the existing aqueous synthesis of trifluoromethylacetophenone oxime, during the coupling reaction, a diazonium salt aqueous solution and liquid alkali are simultaneously added dropwise to an acetaldehyde oxime aqueous solution containing a copper salt catalyst. The pH value is adjusted to 3.0-4.0 (the optimal pH range for the coupling reaction) using liquid alkali. However, the pH value adjusted by liquid alkali is unstable. If the pH value is too high, the copper salt catalyst will lose its activity and the diazonium salt will decompose. If the pH value is too low, it will affect the selectivity of the reaction between the diazonium salt and acetaldehyde oxime. Controlling the pH value in the double dropwise operation is difficult. In the process of this invention, because an organic acid with a pH value of 3.0-4.0 is directly added to the reaction system, the process requirements can be met by adding diazonium salt dropwise. The system remains in a stable pH range during the dropwise addition process, which greatly improves the selectivity of the reaction and the stability of the process.

[0039] (4) The post-processing operation of the present invention is simple, and the copper salt catalyst can be recycled, reducing the generation of copper salt wastewater. In the process of the present invention, m-trifluoromethylacetophenone oxime has low solubility in non-polar solvents at room temperature. The reaction solvent is also used as a crystallization solvent. After heating to dissolve m-trifluoromethylacetophenone oxime, the copper salt catalyst can be filtered. The filtrate is cooled and crystallized to obtain the m-trifluoromethylacetophenone oxime product. The recycling of the catalyst reduces the generation of copper salt solid waste and also reduces production costs.

[0040] In summary, the green and efficient synthesis method for m-trifluoromethylacetophenone oxime provided by this invention has a short synthesis step, high atom utilization, high yield, simple operation and strong stability, and produces less waste, which is conducive to large-scale industrial production. Detailed Implementation

[0041] The following detailed description, in conjunction with specific embodiments, further illustrates the above-mentioned content of the present invention. However, it should not be construed as limiting the scope of the subject matter of the present invention to the following examples. All technologies implemented based on the above-mentioned content of the present invention fall within the scope of the present invention. Unless otherwise specified, the raw materials used in the following embodiments are all commercially available products.

[0042] Reagent pretreatment: Purchased copper sulfate was first ground using a grinder and then sieved to obtain a catalyst with a mesh size of 1000-1200 mesh. The recycled catalyst was treated in the same way.

[0043] Example 1

[0044] A green and efficient method for the synthesis of m-trifluoromethylacetophenone oxime is described below:

[0045] At room temperature, 0.2 mol (32.5 g) of m-trifluoromethylaniline and 3.25 g of acetic acid were added to 130 g of petroleum ether. A measured amount of isopropyl nitrite (0.21 mol, 18.7 g) was slowly added. The temperature of the reaction system was controlled at 5-10 °C during the dropwise addition process, and the dropwise addition time was controlled at 1-2 h.

[0046] After the addition of isopropyl nitrite, the temperature is raised to 15-20℃ and held for 2 hours. HPLC analysis is then performed. A concentration of ≤0.1% for m-trifluoromethylaniline is considered the reaction complete, indicating complete conversion to diazonium salt. The diazonium salt solution is then slowly added dropwise to acetaldehyde oxime (0.22mol, 13.0g) containing tetrabutylammonium bromide (0.001mol, 0.32g) and copper sulfate pentahydrate (0.01mol, 2.5g) of 1000-1200 mesh. The addition temperature is controlled at 5-10℃, and the addition time is controlled at 2-3 hours. After the diazonium salt addition is complete, HPLC analysis is performed to check if the diazonium salt concentration is ≤0.1%. Once the reaction is successful, the copper sulfate catalyst is heated and filtered (it can be recycled). The filtrate is then cooled, crystallized, filtered, and dried to obtain 35.62g of solid m-trifluoromethylacetophenone oxime, with a purity of 98.1% and a yield of 86.0% (based on m-trifluoromethylaniline).

[0047] Example 2

[0048] In Example 1, isopropyl nitrite (0.21 mol, 18.7 g) was replaced with n-butyl nitrite (0.21 mol, 21.66 g), and the other conditions were the same as in Example 1.

[0049] Example 3

[0050] The isopropyl nitrite (0.21 mol, 18.7 g) in Example 1 was replaced with tert-butyl nitrite (0.21 mol, 21.66 g), and the other conditions were the same as in Example 1.

[0051] Example 4

[0052] In Example 3, the 1000-1200 mesh copper salt catalyst copper sulfate pentahydrate (0.01 mol, 2.5 g) was replaced with 1000-1200 mesh copper acetate (0.01 mol, 1.8 g), and the other conditions were the same as in Example 3.

[0053] Example 5

[0054] The phase transfer catalyst tetrabutylammonium bromide (0.001 mol, 0.32 g) in Example 4 was replaced with methyltrioctylammonium chloride (0.001 mol, 0.40 g), and the other conditions were the same as in Example 4.

[0055] Example 6

[0056] The phase transfer catalyst tetrabutylammonium bromide (0.001 mol, 0.32 g) in Example 4 was replaced with 18-crown ether-6 (0.001 mol, 0.26 g), and the other conditions were the same as in Example 4.

[0057] Example 7

[0058] The phase transfer catalyst tetrabutylammonium bromide (0.001 mol, 0.32 g) in Example 4 was replaced with PEG-400 (0.001 mol, 0.4 g), and the other conditions were the same as in Example 4.

[0059] Example 8

[0060] In Example 5, acetic acid (3.25 g) was replaced with 2-hydroxypropyltricarboxylic acid (3.25 g), and the other conditions were the same as in Example 5.

[0061] Example 9

[0062] In Example 5, acetic acid (3.25g) was replaced with hydroxysuccinic acid (3.25g), and the other conditions were the same as in Example 5.

[0063] Example 10

[0064] In Example 5, acetic acid (3.25g) was replaced with oxalic acid (3.25g), and the other conditions were the same as in Example 5.

[0065] Example 11

[0066] In Example 8, the 1000-1200 mesh copper acetate (0.01 mol, 1.8 g) was replaced with 500-600 mesh copper acetate (0.01 mol, 1.8 g), and the other conditions were the same as in Example 8.

[0067] Examples 12-14

[0068] In Example 8, the 1000-1200 mesh copper acetate (0.01 mol, 1.8 g) was replaced with the 1000-1200 mesh copper acetate (0.01 mol, 1.8 g) used in Example 8 in a cyclical manner. All other conditions were the same as in Example 8. Examples 12-14 were cyclically used once, twice, and three times, respectively.

[0069] The contents and yields (based on m-trifluoromethylacetophenone oxime) obtained from Examples 1-14 are summarized in the table below:

[0070]

[0071]

[0072] As can be seen from the data in the table above, the reaction conditions in Example 8 were optimal, achieving a content of over 99% for m-trifluoromethylacetophenone oxime and a yield of 93%, which is a significant improvement in yield compared to the traditional aqueous synthesis process. Examples 12-14 show that the copper salt catalyst was recycled once, twice, and three times, respectively. The data shows that recycling the copper salt catalyst has little impact on the final product content and yield, and the copper salt catalyst can be recycled multiple times.

[0073] Meanwhile, the final product obtained in Example 11 had low content and low yield. The inventors believe that this may be due to the large size of the copper salt catalyst particles and the small specific surface area, which affects its catalytic efficiency, resulting in a long reaction cycle. The diazonium salt is unstable and decomposes during the reaction process, resulting in low product content and low yield. It can be seen that the present application has achieved unexpected technical effects by using a catalyst mesh size of 800 mesh or more, preferably 1000-1200 mesh.

[0074] Comparative Example 1 (Direct Synthesis of m-Trifluoromethylacetophenone Oxime via Aqueous Phase Method)

[0075] At room temperature, 0.2 mol (32.5 g) of m-trifluoromethylaniline and 0.21 mol (47.4 g) of 30% sodium nitrite aqueous solution were added to a four-necked flask. 20% sulfuric acid aqueous solution (0.6 mol (294 g) was added dropwise at 0-5℃. After the reaction was completed, a diazonium salt aqueous solution was obtained.

[0076] The above-mentioned diazonium salt solution was slowly added dropwise to a 50% aqueous solution of acetaldehyde oxime (0.22 mol, 26.0 g) containing copper sulfate pentahydrate (0.01 mol, 2.5 g) and acetic acid (4.16 g), while simultaneously adding 20% ​​liquid alkali to control the pH of the system at 3.0-4.0. The double addition temperature was controlled at 5-10℃, and the double addition time was controlled at 2-3 h. After the diazonium salt addition was completed, and the reaction was monitored and found to be qualified, toluene (130 g) was added to extract m-trifluoromethylacetophenone oxime. After the toluene phase was separated into layers and concentrated, it was crystallized by adding (130 g) of petroleum ether at -5-0℃, filtered and dried to obtain 12.63 g of solid m-trifluoromethylacetophenone oxime, with a purity of 98.1% and a yield of 30.5% (based on m-trifluoromethylaniline).

[0077] Comparative Example 2 (Indirect Synthesis of m-Trifluoromethylacetophenone Oxime via Aqueous Phase Method)

[0078] At room temperature, 0.2 mol (32.5 g) of m-trifluoromethylaniline and 0.21 mol (47.4 g) of 30% sodium nitrite aqueous solution were added to a four-necked flask. 20% sulfuric acid aqueous solution (0.6 mol (294 g) was added dropwise at 0-5℃. After the reaction was completed, a diazonium salt aqueous solution was obtained.

[0079] The above-mentioned diazonium salt solution was slowly added dropwise to acetaldehyde oxime (0.22 mol, 13.0 g) of copper sulfate pentahydrate (0.01 mol, 2.5 g) at a mesh size of 1000-1200, while simultaneously adding 20% ​​liquid alkali to control the pH of the system at 3.0-4.0. The double addition temperature was controlled at 5-10℃, and the double addition time was controlled at 2-3 h. After the diazonium salt addition was completed and the reaction was monitored to ensure it was within acceptable limits, 30% hydrochloric acid (0.5 mol, 61.4 g) and toluene (130 g) were added, and the mixture was heated to reflux. After the m-trifluoromethylacetophenone oxime was completely converted to m-trifluoromethylacetophenone, the toluene phase was separated into layers, concentrated, and the m-trifluoromethylacetophenone was separated by distillation under reduced pressure.

[0080] Then, the m-trifluoromethylacetophenone obtained in the previous step and a 20% aqueous solution of hydroxylamine hydrochloride (0.2 mol, 69.5 g) were added to a four-necked flask. The temperature was raised to 50°C and 30% liquid alkali (0.2 mol, 26.67 g) was added dropwise. After the addition was completed, the temperature was maintained for 4 hours, and samples were taken for testing. After the m-trifluoromethylacetophenone was converted to m-trifluoromethylacetophenone oxime, 30% hydrochloric acid (0.2 mol, 24.33 g) was added for acidification. The m-trifluoromethylacetophenone oxime was directly filtered and dried to obtain 31.3 g of solid m-trifluoromethylacetophenone oxime with a content of 97.3% and a yield of 75.0% (based on m-trifluoromethylaniline).

[0081] The comparative examples show that while the aqueous phase method for direct synthesis of m-trifluoromethylacetophenone oxime is relatively simple, it requires recrystallization and generates significant amounts of waste, resulting in a yield of only about 30%, making it unsuitable for industrial application. In contrast, the aqueous phase method for indirect synthesis of m-trifluoromethylacetophenone oxime is more complex, generates similar amounts of waste, but achieves a yield of 75%, higher than the direct aqueous phase method. This process is relatively mature, but still suffers from unsatisfactory yields, large amounts of waste, and high production costs.

[0082] Based on the above comparison, the technical advantages of this invention compared with the prior art are as follows: (1) Shorter synthesis steps, less waste, and higher atom utilization. The one-pot, two-step reaction synthesis of m-trifluoromethylacetophenone oxime shortens the synthesis reaction steps by half compared with the existing more mature aqueous phase synthesis process. (2) Good reaction selectivity, strong process stability, simple operation steps, and the copper salt catalyst can be recycled, reducing pollution from copper heavy metal ions. (3) High reaction yield, which is about 15% higher than the current traditional process, with low production cost and strong feasibility for industrial application.

[0083] For those skilled in the art, the specific embodiments are merely illustrative descriptions of the present invention. Obviously, the specific implementation of the present invention is not limited to the above-described manner. Any non-substantial improvements made using the inventive concept and technical solution of the present invention, or the direct application of the inventive concept and technical solution to other situations without modification, are all within the protection scope of the present invention.

Claims

1. A green and efficient synthesis of m-trifluoromethylacetophenone oxime, characterized in that, The specific steps are as follows: A certain amount of m-trifluoromethylaniline and an organic acid are added into a non-polar solvent, and a certain amount of nitrite ester is slowly added, and the reaction system temperature is controlled to be 5-10 DEG C during the dropwise addition process, and the dropwise addition time is controlled to be 1-2 h; The non-polar solvent is petroleum ether; the weight ratio of m-trifluoromethylaniline to the non-polar solvent is 1:2-10; the organic acid is selected from one or more of acetic acid, oxalic acid, hydroxybutanedioic acid and 2-hydroxytricarballylic acid; After the addition of the nitrite ester is completed, the temperature is increased to 15-20 DEG C for 1-3 h for sampling detection, and after the m-trifluoromethylaniline is completely converted into a diazonium salt, the diazonium salt solution is slowly added into ethyl aldehyde oxime containing a phase transfer catalyst and a copper salt catalyst with a certain mesh, the dropwise addition temperature is controlled to be 5-10 DEG C, the dropwise addition time is controlled to be 2-3 h, after the dropwise addition of the diazonium salt is completed, the reaction is detected and tracked, and after the reaction is qualified, the copper salt catalyst is filtered by increasing the temperature, and the filtrate is cooled and crystallized to obtain solid m-trifluoromethylphenylacetone oxime, and the reaction equation is as follows: ； The copper salt catalyst is copper acetate or copper sulfate, and the mesh of the catalyst is 1000-1200 mesh.

2. The process for green and efficient synthesis of m-trifluoromethylacetophenone oxime as claimed in claim 1, wherein, The mass ratio of m-trifluoromethylaniline to the organic acid is 1:0.05-0.

2.

3. The process for green and efficient synthesis of m-trifluoromethylacetophenone oxime as claimed in claim 1, wherein, The molar ratio of m-trifluoromethylaniline to nitrite ester and ethyl aldehyde oxime is 1:1-1.5:1-2.

0.

4. The green and efficient synthesis of m-trifluoromethylacetophenone oxime according to claim 1 or 3, characterized in that, The nitrite ester is one or more of isopropyl nitrite, n-butyl nitrite and tert-butyl nitrite.

5. The green and efficient synthesis of m-trifluoromethylacetophenone oxime according to claim 1, characterized in that, The phase transfer catalyst is one or more of tetrabutylammonium bromide, methyltrioctylammonium chloride, 18-crown-6 and PEG-400.

6. The green and efficient synthesis of m-trifluoromethylacetophenone oxime according to claim 1 or 5, characterized in that, The amount of the phase transfer catalyst is 0.1%-3% of the molar amount of m-trifluoromethylaniline.

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