A method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone

Abstract

This invention discloses a method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone, comprising the following steps: Step (1): using 2-trifluoromethylaniline as the starting material, a chlorination reaction is carried out under the action of a chlorinating agent to generate 2-trifluoromethyl-4-chloroaniline; Step (2): the 2-trifluoromethyl-4-chloroaniline obtained in step (1) is placed under acidic conditions and reacted with nitrous acid or nitrous ester to generate a diazonium salt, and then catalytically coupled with acetaldehyde oxime under the action of a catalyst to obtain 2-trifluoromethyl-4-chloroacetophenone; Step (3): the 2-trifluoromethyl-4-chloroacetophenone obtained in step (2) is etherified with p-chlorophenol in a polar solvent in the presence of an acid-binding agent to generate 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone; This invention selects readily available 2-trifluoromethylaniline as the starting material, uses chlorine gas, and achieves high regioselectivity of catalysis to obtain 4-chloro-2-trifluoromethylaniline in a yield of 96%.

Description

Technical Field

[0001] This invention relates to the field of the synthesis technology of the fungicide mefentrifluconazole, specifically a method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone. Background Technology

[0002] Chlorfenapyr is a novel triazole fungicide developed by BASF and officially launched in 2019. Its structure incorporates an isopropanol group, allowing it to freely rotate from its free state and bind to the target, thereby reducing pathogen mutations and delaying the development and progression of resistance. Therefore, it remains highly effective against a variety of resistant strains.

[0003] Chlorfluazuron belongs to the sterol demethylation inhibitors. It inhibits cell growth by blocking the biosynthesis of ergosterol, thereby altering the structure and function of the fungal cell membrane.

[0004] Chlorflufenicol can solve the resistance problem that conventional triazole fungicides cannot address, giving it superior performance compared to other triazole fungicides. Chlorflufenicol has excellent systemic conductivity, providing protective, curative, and eradicative effects against diseases, resulting in thorough treatment and a long-lasting effect. It exhibits outstanding biological activity against a wide range of difficult-to-control fungal diseases, especially those affecting already infected plants, demonstrating excellent control efficacy against more than 60 diseases such as anthracnose, brown spot, blight, corn leaf blight, rice blast, wheat powdery mildew, and sheath blight.

[0005] Chlorfluazuron has low toxicity to mammals and bees, and is highly safe, without causing acute or long-term toxicity, thus overcoming the potential harm to humans and animals posed by traditional triazole fungicides.

[0006]

[0007] Mefentrifluconazole

[0008] 1-(4-(4-chlorophenoxy)-2-trifluoromethylphenyl)ethan-1-one 4-(4-Chlorophenoxy)-2-trifluoromethylacetophenone Several methods for producing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone have been reported so far. WO2013 / 007767 A1 BASF uses the intermediate 2-bromo-5-fluoro(or chloro)-trifluorotoluene By docking with p-chlorochlorobenzene, bromine is converted to acetyl groups via a Grignard reaction to yield 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone.

[0009] Where X represents F or Cl.

[0010] The intermediate 2-bromo-5-fluoro(or chloro)-trifluorotoluene is not readily available, the Grignard reaction requires stringent reaction conditions, is difficult to operate, and is relatively expensive.

[0011] WO 2019 / 016115 This patented method uses the intermediate 2-halo-5-fluoro-trifluorotoluene to convert the halogen into an acetyl group via a Heck coupling reaction, and then docks it with p-chlorochlorobenzene to obtain 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone.

[0012] Where X represents Br, Cl, or I; R1 represents alkoxy or secondary amino groups.

[0013] The intermediate 2-halo-5-fluoro-trifluorotoluene is not readily available in this method, requiring expensive metal catalysts and an additional acidification step, which increases production costs.

[0014] CN 114539041 A This patented method uses formula A as a raw material and docks it with p-chlorophenol or 1,4-dichlorobenzene to obtain 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone through oxidative de-CN method.

[0015] The patented method involves oxygen oxidation to remove cyanide while simultaneously etherifying the cyanide. This process is difficult to control safely and results in highly toxic cyanide-containing wastewater that is difficult to treat, making it unsuitable for large-scale production.

[0016] US 2025 / 0059132 A1 This patent provides a method for preparing the above compound A by coupling 3-cyano-2-alkylpropionate with an aromatic haloalkane, and provides a method for oxidative catalytic decyanation under alkaline conditions, followed by docking with p-chlorophenol to prepare 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone.

[0017]

[0018] R1 is an alkyl group.

[0019] The intermediate 2-bromo-5-nitrotrifluorotoluene is difficult to obtain in this patented method. The first step of the reaction has poor yield due to excessive steric hindrance. The second step of decyanation is even more difficult to control and results in wastewater containing highly toxic cyanide and nitro groups, leading to high production costs.

[0020] To address the shortcomings of existing technologies that are either uncommercializable or have high production costs, this invention analyzes the characteristics of each group in the target product and proposes a process route for commercial production, along with a series of specific operating methods and steps. Summary of the Invention

[0021] The purpose of this invention is to provide a method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone, so as to solve the problems mentioned in the background art.

[0022] To achieve the above objectives, the present invention provides the following technical solution: a method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone, wherein the reaction route is as follows:

[0023] Specifically, the following steps are included: Step (1): Using 2-trifluoromethylaniline as the starting material, a chlorination reaction is carried out under the action of a chlorinating agent to generate 2-trifluoromethyl-4-chloroaniline; Step (2): The 2-trifluoromethyl-4-chloroaniline obtained in step (1) is placed under acidic conditions and reacted with nitrous acid or nitrous ester to generate a diazonium salt. Then, it undergoes a catalytic coupling reaction with acetaldehyde oxime under the action of a catalyst to obtain 2-trifluoromethyl-4-chloroacetophenone. Step (3): The 2-trifluoromethyl 4-chloroacetophenone obtained in step (2) is etherified with p-chlorophenol in a polar solvent in the presence of an acid-binding agent to generate 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone.

[0024] Furthermore, the chlorination reagent mentioned in step (1) is NCS, chlorine, methanesulfonyl chloride, dichlorohydantoin, ZrCl4, or R3N. + One or more combinations of Cl; the reaction solvent in step (1) is one of trifluoroacetic acid, dichloromethane, 1,2-dichloroethane, and carbon tetrachloride, preferably dichloromethane; when chlorine is used as the chlorinating agent, the reaction temperature is -10℃ to 30℃, the reaction time is 1 to 6h, the volume ratio of dichloromethane to 2-trifluoromethylaniline is 3 to 10:1, the molar ratio of chlorine to 2-trifluoromethylaniline is 0.9 to 1.6:1, and the molar ratio of ZrCl4 to 2-trifluoromethylaniline is 0.02 to 1.1:1.

[0025] Furthermore, in step (1), the reaction temperature of chlorine gas is -2℃ to 10℃, the reaction time is 3 to 4h, the volume ratio of dichloromethane to 2-trifluoromethylaniline is 3 to 5:1, the molar ratio of chlorine gas to 2-trifluoromethylaniline is 1.05 to 1.15:1, and the molar ratio of ZrCl4 to 2-trifluoromethylaniline is 0.05 to 0.1:1.

[0026] Furthermore, the catalyst mentioned in step (2) is one or more combinations of ketone salts, iron salts, nickel salts, manganese salts, and cobalt salts; the temperature at which sodium nitrite aqueous solution is added to the reaction system is -5℃ to 15℃, the addition time is 1 to 6 hours, and the reaction is kept at the temperature for 1 hour after the addition is completed; the coupling reaction temperature after adding cuprous acetate and acetaldehyde oxime is 30℃ to 120℃, and the reaction time is 1 to 6 hours; the molar ratio of hydrochloric acid to 2-trifluoromethyl-4-chloroaniline hydrochloride is 1 to 2:1, the molar ratio of sodium nitrite to 2-trifluoromethyl-4-chloroaniline hydrochloride is 0.8 to 2:1, and the molar ratio of acetaldehyde oxime to 2-trifluoromethyl-4-chloroaniline hydrochloride is 1 to 1.6:1.

[0027] Furthermore, in step (2), the temperature at which the sodium nitrite aqueous solution is added is 0℃~10℃, and the addition time is 3~4h; the coupling reaction temperature after adding cuprous acetate and acetaldehyde oxime is 60℃~80℃, and the reaction time is 3~4h; the molar ratio of hydrochloric acid to 2-trifluoromethyl-4-chloroaniline hydrochloride is 1.2~1.5:1, the molar ratio of sodium nitrite to 2-trifluoromethyl-4-chloroaniline hydrochloride is 1.0~1.2:1, and the molar ratio of acetaldehyde oxime to 2-trifluoromethyl-4-chloroaniline hydrochloride is 1.05~1.15:1.

[0028] Furthermore, the acid-binding agent in step (3) is one or a combination of sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium tert-butoxide, and sodium tert-butoxide; the polar solvent is one of tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone, formamide, and N,N-dimethylformamide, preferably N,N-dimethylformamide; the etherification reaction temperature is 80℃~160℃, the reaction time is 4~12h, and the volume ratio of N,N-dimethylformamide to 2-trifluoromethyl4-chloroacetophenone is 1~7:1.

[0029] Furthermore, in step (3), the etherification reaction temperature is 110℃~130℃, the reaction time is 7~9h, the volume ratio of N,N-dimethylformamide to 2-trifluoromethyl4-chloroacetophenone is 1.8~2.5:1, the molar ratio of p-chlorophenol to 2-trifluoromethyl4-chloroacetophenone is 0.8~2:1, and the molar ratio of sodium methoxide to 2-trifluoromethyl4-chloroacetophenone is 1~2.5:1.

[0030] Furthermore, in step (3), the molar ratio of p-chlorophenol to 2-trifluoromethyl-4-chloroacetophenone is 1.0 to 1.1:1, and the molar ratio of sodium methoxide to 2-trifluoromethyl-4-chloroacetophenone is 1.5 to 1.8:1.

[0031] Compared with the prior art, the beneficial effects of the present invention are: This invention selects readily available 2-trifluoromethylaniline as the starting material and uses chlorine gas for catalysis with high regioselectivity to obtain 4-chloro-2-trifluoromethylaniline in 96% yield. Using a mature industrial diazotization reaction with a simple acetaldehyde oxime reagent, the amino group is converted to an acetyl group in a one-pot process, yielding 2-trifluoromethyl-4-chloroacetophenone in greater than 85% yield. Finally, it is docked with p-chlorophenol to obtain the target product 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone in greater than 96% yield. Attached Figure Description

[0032] Figure 1 This is a gas chromatogram of 2-trifluoromethyl-4-chloro-aniline.

[0033] Figure 2 This is a gas chromatogram of 2-trifluoromethyl-4-chloro-acetophenone.

[0034] Figure 3 This is the gas chromatogram of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone; The above gas chromatography separation methods: Instrument: GC-2014 (Shimadzu), Column: HP-5, Injection volume: 1uL, Vaporization chamber temperature: 280℃, Detector temperature: 280℃, Column temperature: 70℃, Retention time: 2min, Rate: 20℃ / min to 280℃, Retention time: 4min, Column flow rate: 4.50ml / min, Split ratio: 30:1.

[0035] Figure 4 This is a liquid chromatography chromatogram of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone.

[0036] Figure 5 This is the 1H NMR spectrum of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone. Detailed Implementation

[0037] The technical solutions of the present invention will be clearly and completely described below with reference to the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of protection of the present invention.

[0038] Please see Figure 1-5 This invention provides a method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone, the reaction route being as follows:

[0039] Specifically, the following steps are included: Step (1): Using 2-trifluoromethylaniline as the starting material, a chlorination reaction is carried out under the action of a chlorinating agent to generate 2-trifluoromethyl-4-chloroaniline; Step (2): The 2-trifluoromethyl-4-chloroaniline obtained in step (1) is placed under acidic conditions and reacted with nitrous acid or nitrous ester to generate a diazonium salt. Then, it undergoes a catalytic coupling reaction with acetaldehyde oxime under the action of a catalyst to obtain 2-trifluoromethyl-4-chloroacetophenone. Step (3): The 2-trifluoromethyl 4-chloroacetophenone obtained in step (2) is etherified with p-chlorophenol in a polar solvent in the presence of an acid-binding agent to generate 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone.

[0040] The chlorination reagents in step (1) are NCS, chlorine gas, methanesulfonyl chloride, dichlorohydantoin, ZrCl4, and R3N. + One or more combinations of Cl; the reaction solvent in step (1) is one of trifluoroacetic acid, dichloromethane, 1,2-dichloroethane, and carbon tetrachloride, preferably dichloromethane; when chlorine is used as the chlorinating agent, the reaction temperature is -10℃ to 30℃, the reaction time is 1 to 6h, the volume ratio of dichloromethane to 2-trifluoromethylaniline is 3 to 10:1, the molar ratio of chlorine to 2-trifluoromethylaniline is 0.9 to 1.6:1, and the molar ratio of ZrCl4 to 2-trifluoromethylaniline is 0.02 to 1.1:1.

[0041] In step (1), the reaction temperature of chlorine gas is -2℃ to 10℃, the reaction time is 3 to 4h, the volume ratio of dichloromethane to 2-trifluoromethylaniline is 3 to 5:1, the molar ratio of chlorine gas to 2-trifluoromethylaniline is 1.05 to 1.15:1, and the molar ratio of ZrCl4 to 2-trifluoromethylaniline is 0.05 to 0.1:1.

[0042] In step (2), the catalyst is one or more combinations of ketone salts, iron salts, nickel salts, manganese salts, and cobalt salts; the temperature at which sodium nitrite aqueous solution is added to the reaction system is -5℃ to 15℃, the addition time is 1 to 6 hours, and the reaction is kept at the temperature for 1 hour after the addition is completed; the coupling reaction temperature after adding cuprous acetate and acetaldehyde oxime is 30℃ to 120℃, and the reaction time is 1 to 6 hours; the molar ratio of hydrochloric acid to 2-trifluoromethyl-4-chloroaniline hydrochloride is 1 to 2:1, the molar ratio of sodium nitrite to 2-trifluoromethyl-4-chloroaniline hydrochloride is 0.8 to 2:1, and the molar ratio of acetaldehyde oxime to 2-trifluoromethyl-4-chloroaniline hydrochloride is 1 to 1.6:1.

[0043] In step (2), the temperature at which sodium nitrite aqueous solution is added is 0℃~10℃, and the addition time is 3~4h; the coupling reaction temperature after adding cuprous acetate and acetaldehyde oxime is 60℃~80℃, and the reaction time is 3~4h; the molar ratio of hydrochloric acid to 2-trifluoromethyl-4-chloroaniline hydrochloride is 1.2~1.5:1, the molar ratio of sodium nitrite to 2-trifluoromethyl-4-chloroaniline hydrochloride is 1.0~1.2:1, and the molar ratio of acetaldehyde oxime to 2-trifluoromethyl-4-chloroaniline hydrochloride is 1.05~1.15:1.

[0044] In step (3), the acid-binding agent is one or a combination of sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium tert-butoxide, and sodium tert-butoxide; the polar solvent is one of tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone, formamide, and N,N-dimethylformamide, preferably N,N-dimethylformamide; the etherification reaction temperature is 80℃~160℃, the reaction time is 4~12h, and the volume ratio of N,N-dimethylformamide to 2-trifluoromethyl4-chloroacetophenone is 1~7:1.

[0045] In step (3), the etherification reaction temperature is 110℃~130℃, the reaction time is 7~9h, the volume ratio of N,N-dimethylformamide to 2-trifluoromethyl4-chloroacetophenone is 1.8~2.5:1, the molar ratio of p-chlorophenol to 2-trifluoromethyl4-chloroacetophenone is 0.8~2:1, and the molar ratio of sodium methoxide to 2-trifluoromethyl4-chloroacetophenone is 1~2.5:1.

[0046] In step (3), the molar ratio of p-chlorophenol to 2-trifluoromethyl-4-chloroacetophenone is 1.0 to 1.1:1, and the molar ratio of sodium methoxide to 2-trifluoromethyl-4-chloroacetophenone is 1.5 to 1.8:1. Detailed Implementation

[0047] The method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone of the present invention is based entirely on the reaction apparatus and operating procedures commonly used in industrial production. The specific implementation steps are as follows: Step (1): Preparation of 2-trifluoromethyl-4-chloroaniline: A 250ml four-necked reaction flask was selected as the reaction vessel, equipped with an ice-water bath, thermometer, magnetic stirrer, and PTFE three-way valve. 32.2g of 2-trifluoroaniline and 3g of zirconium tetrachloride were weighed into the reaction flask, and 128ml of dichloromethane was added to the reaction flask. The magnetic stirrer was turned on to dilute and dissolve the materials. The airtightness of the reaction system was checked to ensure that there was no leakage. The reaction system was then cooled to 0-5℃ (the preferred reaction temperature in step 1).

[0048] After evacuating the reaction flask using a tetrafluoromethane three-way valve, 16g of chlorine gas was slowly introduced into the flask using a double-walled balloon. Stirring was then initiated, and the reaction was maintained at 0-5°C for 2 hours. After the reaction, the reaction solution was filtered to obtain 37.96g of 2-trifluoromethyl-4-chloroaniline hydrochloride. The yield of this step was 96%, and the purity of the product was determined by gas chromatography. Figure 1 The success rate reached 99.677%.

[0049] Step (2): Preparation of 2-trifluoromethyl-4-chloroacetophenone: A 250ml four-necked reaction flask was selected as the reaction vessel, equipped with an ice-water bath, thermometer, magnetic stirrer, spherical condenser, constant pressure dropping funnel, and tail gas absorption device. 23.2g of 2-trifluoromethyl-4-chloroaniline hydrochloride obtained in step (1) was weighed into the reaction flask, and 9.2ml of concentrated hydrochloric acid (mass fraction 36.5%) was measured and diluted to 50ml. The diluted hydrochloric acid solution was added into the reaction flask and the magnetic stirrer was turned on.

[0050] Weigh 7.6g of sodium nitrite, dissolve it in 7.6g of water and stir until clear. Add the sodium nitrite aqueous solution to a constant pressure dropping funnel. Cool the reaction system to 0-5℃ (preferred dropping temperature in step 2), slowly add the sodium nitrite aqueous solution, and continue stirring the reaction at this temperature for 30 minutes after the addition is complete.

[0051] 0.5 g of cuprous acetate and 6.5 g of acetaldehyde oxime were added to the reaction system, and then the reaction system was heated to 60 °C (preferably the coupling reaction temperature in step 2) and kept at this temperature for 4 h. After the reaction was completed, methyl tert-butyl ether was added to the reaction solution for extraction. After extraction, the organic phase was subjected to solvent removal to obtain 19.4 g of 2-trifluoromethyl-4-chloroacetophenone. The yield of this step was greater than 85%, and the purity of the product was determined by gas chromatography. Figure 2 It meets the requirements for subsequent reactions.

[0052] Step (3): Preparation of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone: A 250ml four-necked reaction flask was selected as the reaction vessel, equipped with a magnetic stirrer, an oil bath, a thermometer, and a spherical condenser. 11.13g of 2-trifluoromethyl-4-chloroacetophenone and 4.05g of sodium methoxide obtained in step (2) were weighed into the reaction flask. 23ml of N,N-dimethylformamide was added into the reaction flask, and the magnetic stirrer was turned on to mix the materials evenly.

[0053] The reaction system was heated to 120℃ (the preferred etherification reaction temperature in step 3) and maintained at this temperature for 8 hours. After the reaction, 100 ml of water was added to the reaction solution for dilution, followed by extraction with methyl tert-butyl ether. The extracted organic phase was then subjected to solvent removal and crystallization to obtain 15.1 g of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone. The yield of this step was greater than 96%. The product was analyzed by gas chromatography (GC). Figure 3 ), liquid chromatography-mass spectrometry (LC-MS) Figure 4 ), 1H NMR spectrum ( Figure 5 The test results showed that the structure and purity met the raw material requirements for the synthesis of chlorfluazuron.

[0054] Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art can still modify the technical solutions described in the foregoing embodiments or make equivalent substitutions for some of the technical features. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone, characterized in that, The reaction route is as follows: Specifically, the following steps are included: Step (1): Using 2-trifluoromethylaniline as the starting material, a chlorination reaction is carried out under the action of a chlorinating agent to generate 2-trifluoromethyl-4-chloroaniline; Step (2): The 2-trifluoromethyl-4-chloroaniline obtained in step (1) is placed under acidic conditions and reacted with nitrous acid or nitrous ester to generate a diazonium salt. Then, it undergoes a catalytic coupling reaction with acetaldehyde oxime under the action of a catalyst to obtain 2-trifluoromethyl-4-chloroacetophenone. Step (3): The 2-trifluoromethyl 4-chloroacetophenone obtained in step (2) is etherified with p-chlorophenol in a polar solvent in the presence of an acid-binding agent to generate 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone.

2. The method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone according to claim 1, characterized in that, The chlorination reagents mentioned in step (1) are NCS, chlorine, methanesulfonyl chloride, dichlorohydantoin, ZrCl4, and R3N. + One or more combinations of Cl; the reaction solvent in step (1) is one of trifluoroacetic acid, dichloromethane, 1,2-dichloroethane, and carbon tetrachloride, preferably dichloromethane; when chlorine is used as the chlorinating agent, the reaction temperature is -10℃ to 30℃, the reaction time is 1 to 6h, the volume ratio of dichloromethane to 2-trifluoromethylaniline is 3 to 10:1, the molar ratio of chlorine to 2-trifluoromethylaniline is 0.9 to 1.6:1, and the molar ratio of ZrCl4 to 2-trifluoromethylaniline is 0.02 to 1.1:

1.

3. The method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone according to claim 2, characterized in that, In step (1), the reaction temperature of chlorine gas is -2℃ to 10℃, the reaction time is 3 to 4h, the volume ratio of dichloromethane to 2-trifluoromethylaniline is 3 to 5:1, the molar ratio of chlorine gas to 2-trifluoromethylaniline is 1.05 to 1.15:1, and the molar ratio of ZrCl4 to 2-trifluoromethylaniline is 0.05 to 0.1:

1.

4. The method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone according to claim 1, characterized in that, The catalyst mentioned in step (2) is one or more combinations of ketone salts, iron salts, nickel salts, manganese salts, and cobalt salts; the temperature at which sodium nitrite aqueous solution is added dropwise to the reaction system is -5℃ to 15℃, the dropwise addition time is 1 to 6 hours, and the reaction is kept at the temperature for 1 hour after the dropwise addition is completed; the coupling reaction temperature after adding cuprous acetate and acetaldehyde oxime is 30℃ to 120℃, and the reaction time is 1 to 6 hours; the molar ratio of hydrochloric acid to 2-trifluoromethyl-4-chloroaniline hydrochloride is 1 to 2:1, the molar ratio of sodium nitrite to 2-trifluoromethyl-4-chloroaniline hydrochloride is 0.8 to 2:1, and the molar ratio of acetaldehyde oxime to 2-trifluoromethyl-4-chloroaniline hydrochloride is 1 to 1.6:

1.

5. The method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone according to claim 4, characterized in that, In step (2), the temperature at which sodium nitrite aqueous solution is added is 0℃~10℃, and the addition time is 3~4h; the coupling reaction temperature after adding cuprous acetate and acetaldehyde oxime is 60℃~80℃, and the reaction time is 3~4h; the molar ratio of hydrochloric acid to 2-trifluoromethyl-4-chloroaniline hydrochloride is 1.2~1.5:1, the molar ratio of sodium nitrite to 2-trifluoromethyl-4-chloroaniline hydrochloride is 1.0~1.2:1, and the molar ratio of acetaldehyde oxime to 2-trifluoromethyl-4-chloroaniline hydrochloride is 1.05~1.15:

1.

6. The method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone according to claim 1, characterized in that, The acid-binding agent in step (3) is one or a combination of sodium carbonate, potassium carbonate, potassium hydroxide, sodium hydroxide, sodium methoxide, potassium tert-butoxide, and sodium tert-butoxide; the polar solvent is one of tetrahydrofuran, dimethyl sulfoxide, N-methylpyrrolidone, formamide, and N,N-dimethylformamide, preferably N,N-dimethylformamide; the etherification reaction temperature is 80℃~160℃, the reaction time is 4~12h, and the volume ratio of N,N-dimethylformamide to 2-trifluoromethyl4-chloroacetophenone is 1~7:

1.

7. The method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone according to claim 6, characterized in that, In step (3), the etherification reaction temperature is 110℃~130℃, the reaction time is 7~9h, the volume ratio of N,N-dimethylformamide to 2-trifluoromethyl4-chloroacetophenone is 1.8~2.5:1, the molar ratio of p-chlorophenol to 2-trifluoromethyl4-chloroacetophenone is 0.8~2:1, and the molar ratio of sodium methoxide to 2-trifluoromethyl4-chloroacetophenone is 1~2.5:

1.

8. The method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone according to claim 7, characterized in that, In step (3), the molar ratio of p-chlorophenol to 2-trifluoromethyl-4-chloroacetophenone is 1.0 to 1.1:1, and the molar ratio of sodium methoxide to 2-trifluoromethyl-4-chloroacetophenone is 1.5 to 1.8:1.

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