Preparation method of 4-(4-chlorophenoxy)-2-trifluoromethyl acetophenone

Abstract

The invention provides a preparation method of 4-(4-chlorophenoxy)-2-trifluoromethyl acetophenone, which is characterized in that o-trifluoromethyl aniline is used as a raw material, and the 4-(4-chlorophenoxy)-2-trifluoromethyl acetophenone is obtained through amino protection, bromination reaction, protecting group removal, diazotization reaction, coupling reaction, hydrolysis reaction and etherification reaction. The raw materials of the preparation method are cheap and easy to obtain and are supplied in large scale in China; an acetyl group is obtained by diazotization, coupling and hydrolysis processes, a Grignard reagent and a Grignard reaction are not needed, dangerous reagents, harsh reaction conditions, fluoride-free cracking and other processes are avoided, special equipment is not needed, and magnesium-containing, fluorine-containing and other difficult-to-treat wastewater cannot be generated. The preparation method has the advantages of cheap and easily available raw materials, simple process, mild reaction conditions, safe and controllable preparation process and higher industrial application value, and all reactions can be carried out under normal pressure.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis technology and relates to the preparation technology of chlorfluazuron intermediates, specifically to a method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone. Background Technology

[0002] Mefentrifluconazole (common name: BASF) is the first novel isopropanol triazole fungicide discovered and developed by BASF. It filled the gap in the market for new triazole fungicides since the introduction of siloxyfenozide in 2002. Structurally different from other triazole fungicides, it is a completely new type of fungicide with no cross-resistance with other fungicides, making it a preferred agent for disease resistance management. Mefentrifluconazole has excellent systemic conductivity, providing excellent protective, curative, and eradicative effects against diseases, resulting in thorough treatment and a long-lasting effect. It exhibits outstanding biological activity, particularly against a variety of difficult-to-control fungal diseases. It can be used to control more than 60 crop diseases, including apple anthracnose, brown spot, tomato early blight, and corn leaf blight. It boasts higher biological activity, better environmental characteristics, lower toxicity to mammals and bees, and a high safety profile.

[0003] 4-(4-Chlorophenoxy)-2-trifluoromethylacetophenone is a key intermediate in the synthesis of chlorfluazuron, and its structural formula is as follows: Currently, there are many reported methods for preparing this intermediate. Among them, BASF patents CN105152899A, CN105050406A, and CN105829274A disclose two methods for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone:

[0004] (1) Using 2-bromo-5-fluorotrifluorotoluene as a raw material, it is first reacted with p-chlorophenol to synthesize 2-bromo-5-(4-chlorophenoxy)-trifluorotoluene, and then subjected to Grignard-acetylation reaction to generate 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone. The synthetic reaction formula is as follows:

[0005]

[0006] (2) Using 2-bromo-5-fluorotrifluorotoluene as a raw material, 4-fluoro-2-trifluoromethylacetophenone is generated by Grignard-acetylation reaction, and then reacted with p-chlorophenol to synthesize 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone. The synthetic reaction formula is as follows:

[0007]

[0008] Both of the above process routes involve Grignard reactions, which pose a high risk for industrial scale-up and generate large amounts of magnesium-containing wastewater, significantly increasing the difficulty of waste treatment. Furthermore, the 2-bromo-5-fluorotrifluorotoluene raw material used in these routes is difficult to obtain (it cannot be purchased in bulk; currently, only a small quantity is available at 900 yuan / kg), and the preparation route is often lengthy and costly. For example, CN104447183A discloses a method for preparing 2-bromo-5-fluorotrifluorotoluene, using m-trifluoromethylaniline as a raw material, through amino protection, bromination, deamination, diazotization, fluorination, and cracking to synthesize 2-bromo-5-fluorotrifluorotoluene. The synthesis reaction formula is as follows:

[0009]

[0010] The process for preparing 2-bromo-5-fluorotrifluorotoluene using the route described in CN104447183A involves as many as six steps. Because it involves fluorination cracking, it requires high-performance industrial equipment and carries significant risks. Furthermore, it generates a large amount of wastewater containing fluorine and boron, which is difficult and costly to treat.

[0011] Therefore, there is an urgent need in this field to develop a method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone, an intermediate of chlorfluazuril, which has low production costs, mild reaction conditions, and a safe preparation process. Summary of the Invention

[0012] To address the shortcomings of existing technologies, the present invention aims to provide a method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone. The method uses o-trifluoromethylaniline as the starting material, which is inexpensive and readily available. The reaction conditions are mild, the process is simple, and no hazardous reagents or special equipment are required. The preparation process is safe and controllable, and no difficult-to-treat waste liquid is generated. It has broad prospects for industrial application.

[0013] To achieve this objective, the present invention adopts the following technical solution:

[0014] In a first aspect, the present invention provides a method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone, comprising the following steps:

[0015] (S1) o-Trifluoromethylaniline reacts with an amino protecting agent to give compound 1;

[0016] (S2) Compound 1 obtained in step (S1) undergoes a bromination reaction with a brominating reagent to obtain compound 2;

[0017] (S3) Compound 2 obtained in step (S2) undergoes a deprotection reaction to obtain compound 3;

[0018] (S4) Compound 3 obtained in step (S3) undergoes a diazotization reaction with nitrite to obtain compound 4;

[0019] (S5) Compound 4 obtained in step (S4) undergoes a coupling reaction with acetaldehyde oxime to obtain compound 5;

[0020] (S6) The compound 5 obtained in step (S5) is subjected to a hydrolysis reaction to obtain compound 6;

[0021] (S7) Compound 6 obtained in step (S6) is etherified with p-chlorophenol to obtain 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone;

[0022] The reaction formula is as follows:

[0023]

[0024] R1 represents an amino protecting group.

[0025] The preparation method provided by this invention uses o-trifluoromethylaniline as the starting material, which is inexpensive and readily available, and is supplied on a large scale in China (it can be purchased in tonnes: 30,000-40,000 RMB / ton). The o-trifluoromethylaniline is synthesized into 2-trifluoromethyl-4-bromoaniline (compound 3) through amino protection, bromination, and deamination, without the need for Grignard reagents and Grignard reactions, thus avoiding harsh reaction conditions and the problem of difficult treatment of magnesium-containing wastewater. Then, 2-trifluoromethyl-4-bromoacetophenone (compound 6) is synthesized through diazotization, coupling, and hydrolysis; finally, it undergoes an etherification reaction with p-chlorophenol to obtain 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone. The preparation method uses inexpensive and readily available raw materials, has a simple process, mild reaction conditions, and all reactions can be carried out under normal pressure. The preparation process is safe and controllable, without fluorination cracking or other processes, requires no special equipment, and does not generate difficult-to-treat wastewater containing magnesium or fluorine. It has low production costs and broad prospects for industrial application.

[0026] The following are preferred technical solutions of the present invention, but are not intended to limit the technical solutions provided by the present invention. The purpose and beneficial effects of the present invention can be better achieved and realized through the following preferred technical solutions.

[0027] In this invention, R1 represents an amino protecting group, which includes, but is not limited to, acyl (-COR), tert-butoxycarbonyl (Boc), etc.; based on raw material cost considerations, acyl is preferred.

[0028] Preferably, the amino protecting agent includes any one of acyl chloride compounds and acid anhydride compounds.

[0029] Preferably, compound 1 is R2 is selected from any one of straight-chain or branched alkyl or benzyl groups from C1 to C6 (e.g., C1, C2, C3, C4, C5, C6).

[0030] Preferably, the amino protecting agent includes acetyl chloride, benzoyl chloride, acetic anhydride or succinic anhydride, and more preferably acetyl chloride.

[0031] Preferably, the molar ratio of the amino protecting agent to o-trifluoromethylaniline is (1-2):1, for example, it can be 1.05:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, etc., more preferably (1.02-1.1):1, and even more preferably 1.05:1.

[0032] Preferably, the reaction in step (S1) is carried out in the absence of solvent or in the presence of solvent.

[0033] In a preferred embodiment, the reaction in step (S1) is carried out in the presence of a solvent, which includes any one or a combination of at least two of aliphatic hydrocarbon solvents, halogenated aliphatic hydrocarbon solvents, alicyclic hydrocarbon solvents, and aromatic hydrocarbon solvents. Exemplary examples include, but are not limited to, any one or a combination of at least two of 1,2-dichloroethane, dichloromethane, cyclohexane, toluene, and xylene, with 1,2-dichloroethane being more preferred.

[0034] Preferably, step (S1) specifically includes: mixing o-trifluoromethylaniline with a solvent, adding an amino protecting agent dropwise, reacting, and obtaining compound 1.

[0035] Preferably, the reaction temperature in step (S1) is 10-90°C, for example, it can be 15°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C or 85°C, as well as specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. More preferably, it is 75-85°C, and more preferably 80°C.

[0036] Preferably, the reaction time in step (S1) is 1-6 hours, for example, it can be 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours or 5.5 hours, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0037] Preferably, the brominating agent includes any one or a combination of at least two of bromine, hydrogen bromide, sodium bromide, and N-bromosuccinimide (NBS), with bromine being more preferred.

[0038] Preferably, the molar ratio of bromine in the brominating reagent to compound 1 is (1-1.5):1, for example, it can be 1.05:1, 1.1:1, 1.15:1, 1.2:1, 1.25:1, 1.3:1, 1.35:1, 1.4:1 or 1.45:1, etc.

[0039] Preferably, the bromination reaction is carried out in the presence of an oxidizing agent.

[0040] Preferably, the oxidant includes any one or a combination of at least two of hydrogen peroxide, sodium chlorate, and sodium hypochlorite, with hydrogen peroxide being more preferred.

[0041] Preferably, the hydrogen peroxide is added to the reaction system in step (S2) in the form of hydrogen peroxide.

[0042] Preferably, the molar ratio of the oxidant to the brominating reagent is (0.9-1.2):1, for example, it can be 0.92:1, 0.95:1, 0.98:1, 1:1, 1.02:1, 1.05:1, 1.08:1, 1.1:1, 1.12:1, 1.15:1 or 1.18:1, etc.

[0043] Preferably, step (S2) specifically includes: heating the product obtained in step (S1) to 40-80°C (e.g., 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, etc.), adding a brominating agent and an oxidizing agent thereto, and carrying out a bromination reaction to obtain compound 2.

[0044] Preferably, the brominating reagent and oxidizing agent are slowly added (e.g., dropwise) to the reaction system over a period of 1-5 hours, such as 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, or 4.5 hours.

[0045] Preferably, the temperature of the bromination reaction in step (S2) is 40-80°C, for example, it can be 45°C, 50°C, 55°C, 60°C, 65°C, 70°C or 75°C, as well as specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0046] Preferably, the bromination reaction time in step (S2) is 2-12 hours, for example, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours, 10.5 hours, or 11 hours, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0047] Preferably, after the bromination reaction in step (S2) is completed, a reducing agent is added to the system to make the system non-oxidizing.

[0048] Preferably, the reducing agent comprises sodium bisulfite, and more preferably it is added to the system in the form of an aqueous solution.

[0049] Preferably, the deprotection reaction in step (S3) is carried out in the presence of an alkaline substance.

[0050] Preferably, the alkaline substance includes any one or a combination of at least two of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, and sodium ethoxide, with sodium hydroxide being more preferred.

[0051] In step (S3), the alkaline substance (e.g., sodium hydroxide) may be used in the form of a solid or an aqueous solution thereof.

[0052] Preferably, the mass percentage of alkaline substance in the aqueous solution of the alkaline substance is 10-50%, for example, it can be 15%, 20%, 25%, 30%, 35%, 40% or 45%, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. More preferably, it is 28-32%, and more preferably 30%.

[0053] Preferably, the molar ratio of the alkaline substance to compound 2 is (1-2):1, for example, it can be 1.05:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, etc., more preferably (1.05-1.15):1, and even more preferably 1.1:1.

[0054] Preferably, the deprotection reaction in step (S3) is carried out in the presence of a solvent.

[0055] Preferably, the solvent includes an alcohol solvent, more preferably any one or a combination of at least two of methanol, ethanol, propanol, and ethylene glycol, and more preferably ethanol.

[0056] Preferably, step (S3) specifically includes: mixing compound 2 with a solvent and an alkaline substance, and then carrying out a deprotection reaction to obtain compound 3.

[0057] Preferably, the temperature of the deprotection reaction in step (S3) is 40-90°C, for example, it can be 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C or 85°C, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. More preferably, it is 60-80°C, and more preferably 70°C.

[0058] Preferably, the deprotection reaction time in step (S3) is 2-10 hours, for example, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours or 9 hours, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0059] Preferably, after compound 3 undergoes a salt-forming reaction with an acid, it is then subjected to a diazotization reaction with a nitrite to obtain compound 4.

[0060] Preferably, the acid includes sulfuric acid or hydrochloric acid; since diazonium salts of hydrochloric acid contain many impurities, sulfuric acid is further preferred.

[0061] Preferably, the sulfuric acid reacts with compound 3 in the form of a sulfuric acid solution to form a salt.

[0062] Preferably, the sulfuric acid solution contains 30-80% sulfuric acid by mass, for example, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list all the specific values ​​included in the range. More preferably, it is 40-60%, and more preferably, it is 50%.

[0063] Preferably, the molar ratio of the acid to compound 3 is (1.5-4):1, for example, it can be 1.8:1, 2:1, 2.2:1, 2.5:1, 2.8:1, 3:1, 3.2:1, 3.5:1, 3.8:1, etc., and more preferably 2:1.

[0064] Preferably, the nitrite comprises sodium nitrite and / or potassium nitrite.

[0065] Preferably, the molar ratio of the nitrite to compound 3 is (1.01-1.1):1, for example, it can be 1.02:1, 1.03:1, 1.04:1, 1.05:1, 1.06:1, 1.07:1, 1.08:1, 1.09:1, etc., more preferably (1.04-1.08):1, and even more preferably 1.06:1.

[0066] Preferably, the nitrite is introduced into the reaction system of step (S4) in the form of a nitrite solution.

[0067] Preferably, the nitrite solution contains 10-50% by mass, for example, 15%, 20%, 25%, 30%, 35%, 40% or 45%, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. More preferably, it is 25-35%, and more preferably 30%.

[0068] Preferably, step (S4) specifically includes: first adding compound 3 to (preferably adding dropwise) a sulfuric acid solution to carry out a salt formation reaction, and then adding (preferably adding dropwise) a nitrite solution to carry out a diazotization reaction to obtain compound 4.

[0069] Preferably, the temperature of the salt formation reaction is 20-60℃, for example, it can be 25℃, 28℃, 30℃, 32℃, 35℃, 38℃, 40℃, 42℃, 45℃, 48℃, 50℃, 52℃, 55℃ or 58℃, as well as specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. More preferably, it is 40-60℃, and more preferably 50℃.

[0070] Preferably, the salt formation reaction time is 0.5-5h, for example, it can be 0.8h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h or 4.5h, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0071] Preferably, the temperature of the diazotization reaction in step (S4) is -20°C to 5°C, for example, it can be -15°C, -12°C, -10°C, -8°C, -5°C, -2°C, 0°C, 2°C or 4°C, as well as specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. More preferably, it is -5°C to 2°C, and more preferably, it is 0°C.

[0072] Preferably, the diazotization reaction time in step (S4) is 0.5-5h, for example, it can be 0.8h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h or 4.5h, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0073] Preferably, the molar ratio of acetaldehyde oxime to compound 3 is (1.05-1.8):1, for example, it can be 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, etc., more preferably (1.4-1.6):1, and even more preferably 1.5:1.

[0074] Preferably, the acetaldehyde oxime is introduced into the reaction system of step (S5) in the form of an aqueous solution of acetaldehyde oxime.

[0075] Preferably, the acetaldehyde oxime aqueous solution contains 30-70% by mass, for example, 35%, 40%, 42%, 45%, 48%, 50%, 52%, 55%, 58%, 60%, or 65%, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, this invention will not exhaustively list all the specific values ​​included in the range.

[0076] Preferably, the coupling reaction in step (S5) is carried out in the presence of a copper salt catalyst.

[0077] Preferably, the copper salt catalyst comprises any one or a combination of at least two of copper sulfate, copper chloride, cuprous chloride, and copper acetate.

[0078] Preferably, the molar ratio of the copper salt catalyst to compound 3 is (0.05-0.15):1, for example, it can be 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.1:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, etc., more preferably (0.08-0.12):1, and even more preferably 0.1:1.

[0079] Preferably, the copper salt catalyst is introduced into the reaction system of step (S5) in the form of an aqueous solution of the copper salt catalyst.

[0080] Preferably, the mass percentage of copper salt catalyst in the aqueous solution of the copper salt catalyst is 5-20%, for example, it can be 6%, 8%, 10%, 12%, 15% or 18%, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0081] Preferably, the coupling reaction in step (S5) is carried out in the presence of an acid-binding agent, which can form a buffer system in the system, which is beneficial for reaction control.

[0082] Preferably, the acid-binding agent includes any one or a combination of at least two of alkali metal formate, alkali metal acetate, alkali metal phosphate, alkali metal hydrogen phosphate, and alkali metal dihydrogen phosphate.

[0083] Preferably, the alkali metal includes any one of Na and K; preferably, the acid-binding agent includes any one or a combination of at least two of sodium formate, sodium acetate, sodium phosphate, sodium hydrogen phosphate, and sodium dihydrogen phosphate.

[0084] Preferably, the molar ratio of the acid-binding agent to compound 3 is (1-5):1, for example, it can be 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, etc.

[0085] Preferably, the coupling reaction in step (S5) is carried out in the presence of a solvent.

[0086] Preferably, the solvent for the coupling reaction in step (S5) includes any one or a combination of at least two of water, aromatic hydrocarbon solvent, aliphatic hydrocarbon solvent, and halogenated aliphatic hydrocarbon solvent, more preferably any one or a combination of at least two of water, dichloroethane, toluene, and xylene, and more preferably a mixture of water and toluene.

[0087] Preferably, step (S5) specifically includes: placing acetaldehyde oxime, solvent, copper salt catalyst aqueous solution and acid-binding agent in a reaction apparatus, and adding (preferably dropwise) compound 4 (its aqueous solution) obtained in step (S4) to it to carry out a coupling reaction to obtain compound 5.

[0088] It should be noted that the order of addition in step (S5) is not mandatory. For example, acetaldehyde oxime, solvent, copper salt catalyst aqueous solution, and acid-binding agent can all be added dropwise to obtain the product, but the yield will fluctuate. It is preferred to add the aqueous solution of compound 4 dropwise.

[0089] Preferably, the temperature of the coupling reaction in step (S5) is from -10°C to 50°C, for example, it can be -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C or 45°C, as well as specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range, and 0-20°C is further preferred.

[0090] Preferably, the coupling reaction time in step (S5) is 1-10 hours, for example, it can be 1.5 hours, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours or 9.5 hours, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0091] Preferably, the coupling reaction further includes a post-processing step, which includes: allowing the product obtained from the coupling reaction to stand and separate into layers, and the resulting organic phase is the organic phase solution of compound 5, which directly enters the next step of hydrolysis reaction.

[0092] Preferably, the hydrolysis reaction is carried out in the presence of an acidic substance.

[0093] Preferably, the acidic substance includes hydrochloric acid and / or sulfuric acid.

[0094] Preferably, the H in the acidic substance + The molar ratio of compound 3 to compound 3 is (1-3.2):1, for example, it can be 1.2:1, 1.5:1, 1.8:1, 2:1, 2.2:1, 2.5:1, 2.8:1, 3:1, etc.

[0095] Preferably, the acidic substance is sulfuric acid, and the molar ratio of sulfuric acid to compound 3 is (0.5-1.6):1, for example, it can be 0.6:1, 0.7:1, 0.8:1, 1:1, 1.1:1, 1.2:1 or 1.5:1, etc.

[0096] Preferably, the acidic substance is hydrochloric acid, and the molar ratio of hydrochloric acid to compound 3 is (1-3.2):1, for example, it can be 1.2:1, 1.5:1, 1.8:1, 2:1, 2.2:1, 2.5:1, 2.8:1, 3:1, etc.

[0097] Preferably, step (S6) specifically includes: mixing the organic phase solution of compound 5 obtained in step (S5) with an acidic substance, and carrying out a hydrolysis reaction under stirring conditions to obtain compound 6.

[0098] Preferably, the temperature of the hydrolysis reaction in step (S6) is 60-100℃, for example, it can be 65℃, 70℃, 75℃, 80℃, 85℃, 90℃ or 95℃, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0099] Preferably, the hydrolysis reaction time in step (S6) is 1-6 hours, for example, it can be 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours or 5.5 hours, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0100] Preferably, in step (S7), the p-chlorophenol undergoes a salt-forming reaction with an alkaline substance, and after removing the aqueous azeotrope, it undergoes an etherification reaction with compound 6 to obtain the 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone; or, the p-chlorophenol, the alkaline substance, and compound 6 undergo an etherification reaction (one-pot etherification reaction) to obtain the 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone.

[0101] Preferably, the molar ratio of p-chlorophenol to compound 6 is (0.8-1.5):1, for example, it can be 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1 or 1.4:1, etc., more preferably (0.95-1.15):1, and even more preferably 1:1.

[0102] Preferably, the alkaline substance includes any one or a combination of at least two of alkali metal hydroxides, alkali metal carbonates, and alkali metal bicarbonates.

[0103] Preferably, the alkali metal includes any one of Na and K; preferably, the alkaline substance includes any one or a combination of at least two of sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate, and more preferably sodium hydroxide.

[0104] Preferably, the molar ratio of the alkaline substance to compound 6 is (1-1.2):1, for example, it can be 1.02:1, 1.05:1, 1.08:1, 1.1:1, 1.12:1, 1.15:1, 1.18:1, etc., more preferably (1.01-1.1):1, and even more preferably 1.05:1.

[0105] Preferably, the temperature for the salt formation reaction of p-chlorophenol with the alkaline substance is 80-130°C, for example, it can be 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C or 125°C, as well as specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0106] Preferably, the time for the salt formation reaction of p-chlorophenol with the alkaline substance is 0.5-3 hours, for example, 0.8 hours, 1 hour, 1.2 hours, 1.5 hours, 1.8 hours, 2.2 hours, 2.5 hours or 2.8 hours, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0107] Preferably, the method for removing aqueous azeotropes includes removing aqueous azeotropes using negative pressure.

[0108] Preferably, the etherification reaction in step (S7) is carried out in the presence of a phase transfer catalyst or without the use of a phase transfer catalyst; the phase transfer catalyst does not affect the yield but can increase the reaction rate.

[0109] Preferably, the etherification reaction in step (S7) is carried out in the presence of a phase transfer catalyst.

[0110] Preferably, the phase transfer catalyst comprises any one or a combination of at least two of tetramethylammonium chloride, tetrabutylammonium bromide, and 18-crown ether-6.

[0111] Preferably, based on the mass of compound 6 as 100%, the mass of the phase transfer catalyst is 0.1-5%, for example, 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4% or 4.5%, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. More preferably, it is 0.8-1.2%, and more preferably, it is 1%.

[0112] Preferably, the etherification reaction (and optionally the salt formation reaction) in step (S7) is carried out in the presence of a polar aprotic solvent.

[0113] Preferably, the polar aprotic solvent includes any one or a combination of at least two of acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, and N-methylpyrrolidone, with dimethyl sulfoxide being more preferred.

[0114] Preferably, the temperature of the etherification reaction in step (S7) is 90-200°C, for example, it can be 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, 170°C, 180°C or 190°C, as well as specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. More preferably, it is 115-145°C, and more preferably, it is 130°C.

[0115] Preferably, the etherification reaction time in step (S7) is 1-10 hours, for example, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours or 9 hours, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. More preferably, it is 2-5 hours, and more preferably, it is 3 hours.

[0116] Preferably, after the etherification reaction in step (S7) is completed, a post-processing step is further included, which includes: cooling the product obtained from the etherification reaction to room temperature and filtering it, and distilling the filtrate under reduced pressure to obtain 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone.

[0117] Secondly, the present invention provides another method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone, the method comprising the following steps:

[0118] (1) o-Trifluoromethylaniline reacts with an amino protecting agent to give compound 1;

[0119] (2) Compound 1 obtained in step (1) undergoes a bromination reaction with a brominating reagent to obtain compound 2;

[0120] (3) Compound 2 obtained in step (2) undergoes a deprotection reaction to obtain compound 3; compound 3 undergoes an etherification reaction with p-chlorophenol to obtain compound 8;

[0121] Alternatively, compound 2 obtained in step (2) undergoes an etherification reaction with p-chlorophenol to obtain compound 7; compound 7 undergoes a deprotection reaction to obtain compound 8;

[0122] (4) Compound 8 obtained in step (3) undergoes a diazotization reaction with nitrite to obtain compound 9;

[0123] (5) Compound 9 obtained in step (4) is coupled with acetaldehyde oxime to obtain compound 10;

[0124] (6) The compound 10 obtained in step (5) is subjected to a hydrolysis reaction to obtain the 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone;

[0125] The reaction formula is as follows:

[0126]

[0127] R1 represents an amino protecting group.

[0128] This invention provides another preparation method using o-trifluoromethylaniline as the starting material, which is inexpensive, readily available, and supplied on a large scale domestically. The o-trifluoromethylaniline undergoes amino protection, bromination, deamination, and etherification reactions to obtain 4-(4-chlorophenoxy)-2-trifluoromethylaniline (compound 8); subsequently, diazotization, coupling, and hydrolysis are used to obtain 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone. This preparation method eliminates the need for Grignard reagents and Grignard reactions, as well as fluorination cracking processes, avoiding harsh reaction conditions and specialized equipment. It also avoids the generation of difficult-to-treat wastewater containing magnesium or fluorine. The raw materials used in this preparation method are inexpensive and readily available, the process is simple, the reaction conditions are mild, all reactions can be carried out under normal pressure, the preparation process is safe and controllable, and the production cost is low, making it promising for broad industrial applications.

[0129] In this invention, steps (1) and (S1) have the same materials, parameters and routes, and steps (2) and (S2) have the same materials, parameters and routes. For the sake of brevity, they will not be described in detail.

[0130] In the preparation method, step (3) includes two parallel technical solutions: Solution ①: Compound 2 undergoes a deprotection reaction to obtain Compound 3; Compound 3 undergoes an etherification reaction with p-chlorophenol to obtain Compound 8; Solution ②: Compound 2 undergoes an etherification reaction with p-chlorophenol to obtain Compound 7; Compound 7 undergoes a deprotection reaction to obtain Compound 8.

[0131] Specifically, the scheme ① includes the following steps: the compound 2 undergoes a deprotection reaction to obtain the compound 3; the p-chlorophenol undergoes a salt formation reaction with a basic substance, and after removing the aqueous azeotrope, it undergoes an etherification reaction with the compound 3 to obtain the compound 8; or, the p-chlorophenol, the basic substance, and the compound 3 undergo an etherification reaction to obtain the compound 8.

[0132] In scheme ①, the preparation of compound 3 has the same materials, parameters and route as step (S3), and for the sake of simplicity, it will not be described again.

[0133] In scheme ①, the p-chlorophenol undergoes a salt-forming reaction with an alkaline substance, and after removing the aqueous azeotrope, it undergoes an etherification reaction with compound 3 to obtain compound 8; or, the p-chlorophenol, alkaline substance, and compound 3 undergo an etherification reaction (one-pot reaction) to obtain compound 8.

[0134] Preferably, in scheme ①, the molar ratio of p-chlorophenol to compound 3 is (0.8-1.5):1, for example, it can be 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1 or 1.4:1, etc., further preferably (0.95-1.15):1, more preferably 1:1.

[0135] Preferably, in scheme ①, the alkaline substance includes any one or a combination of at least two of alkali metal hydroxides, alkali metal carbonates, and alkali metal bicarbonates.

[0136] Preferably, the alkali metal includes any one of Na and K; preferably, in scheme ①, the alkaline substance includes any one or a combination of at least two of sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate, and more preferably sodium hydroxide.

[0137] Preferably, in scheme ①, the molar ratio of the alkaline substance to compound 3 is (1-1.2):1, for example, it can be 1.02:1, 1.05:1, 1.08:1, 1.1:1, 1.12:1, 1.15:1, 1.18:1, etc., further preferably (1.01-1.1):1, and more preferably 1.05:1.

[0138] Preferably, in scheme ①, the temperature for the salt formation reaction of p-chlorophenol with the alkaline substance is 80-130℃, for example, it can be 85℃, 90℃, 95℃, 100℃, 105℃, 110℃, 115℃, 120℃ or 125℃, as well as specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0139] Preferably, in scheme ①, the time for the salt formation reaction of p-chlorophenol with the alkaline substance is 0.5-3h, for example, it can be 0.8h, 1h, 1.2h, 1.5h, 1.8h, 2.2h, 2.5h or 2.8h, as well as specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0140] Preferably, in scheme ①, the method for removing aqueous azeotropic substances includes removing aqueous azeotropic substances using negative pressure.

[0141] Preferably, in scheme ①, the etherification reaction is carried out in the presence of a copper-based catalyst.

[0142] Preferably, in Scheme ①, the copper-based catalyst includes any one or a combination of at least two of copper powder, cuprous chloride, cuprous bromide, cuprous iodide, copper chloride, copper sulfate, cuprous oxide, copper oxide, and ketone acetate, with cuprous chloride being more preferred.

[0143] Preferably, in scheme ①, based on the mass of compound 3 as 100%, the mass of the copper-based catalyst is 1-5%, for example, it can be 1.2%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4% or 4.5%, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. More preferably, it is 1.8-2.2%, and more preferably, it is 2%.

[0144] Preferably, in scheme ①, the etherification reaction is carried out in the presence of a phase transfer catalyst or without the use of a phase transfer catalyst; the phase transfer catalyst does not affect the yield, but can increase the reaction rate.

[0145] Preferably, in scheme ①, the etherification reaction is carried out in the presence of a phase transfer catalyst.

[0146] Preferably, in scheme ①, the phase transfer catalyst includes any one or a combination of at least two of tetramethylammonium chloride, tetrabutylammonium bromide, and 18-crown ether-6.

[0147] Preferably, in scheme ①, based on the mass of compound 3 as 100%, the mass of the phase transfer catalyst is 0.1-5%, for example, it can be 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4% or 4.5%, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range, but is further preferred to be 0.8-1.2%, and more preferably 1%.

[0148] Preferably, in scheme ①, the etherification reaction (and optionally the salt formation reaction) is carried out in the presence of a polar aprotic solvent.

[0149] Preferably, in scheme ①, the polar aprotic solvent includes any one or a combination of at least two of acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, and N-methylpyrrolidone, with dimethyl sulfoxide being more preferred.

[0150] Preferably, in scheme ①, the temperature of the etherification reaction is 90-200℃, for example, it can be 100℃, 110℃, 120℃, 130℃, 140℃, 150℃, 160℃, 170℃, 180℃ or 190℃, as well as specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. Further preferred is 115-145℃, more preferably 130℃.

[0151] Preferably, in scheme ①, the etherification reaction time is 1-10h, for example, it can be 2h, 3h, 4h, 5h, 6h, 7h, 8h or 9h, as well as specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. More preferably, it is 2-5h, and more preferably, it is 3h.

[0152] Preferably, in scheme ①, after the etherification reaction is completed, a post-processing step is further included, which includes: cooling the product obtained from the etherification reaction to room temperature and filtering it, and distilling the filtrate under reduced pressure to obtain compound 8.

[0153] Specifically, scheme ② includes the following steps: the p-chlorophenol undergoes a salt-forming reaction with an alkaline substance, and after removing the aqueous azeotrope, it undergoes an etherification reaction with compound 2 to obtain compound 7; or, the p-chlorophenol, the alkaline substance, and compound 2 undergo an etherification reaction to obtain compound 7; and compound 7 undergoes a deprotection reaction to obtain compound 8.

[0154] Preferably, in scheme ②, the p-chlorophenol undergoes a salt-forming reaction with an alkaline substance, and after removing the aqueous azeotrope, it undergoes an etherification reaction with compound 2 to obtain compound 7; or, the p-chlorophenol, the alkaline substance, and compound 2 undergo an etherification reaction (one-pot reaction) to obtain compound 7.

[0155] Preferably, in scheme ②, the molar ratio of p-chlorophenol to compound 2 is (0.8-1.5):1, for example, it can be 0.9:1, 1:1, 1.1:1, 1.2:1, 1.3:1 or 1.4:1, etc., further preferably (0.95-1.15):1, more preferably 1:1.

[0156] Preferably, in scheme ②, the alkaline substance includes any one or a combination of at least two of alkali metal hydroxides, alkali metal carbonates, and alkali metal bicarbonates.

[0157] Preferably, the alkali metal includes any one of Na and K; preferably, in scheme ②, the alkaline substance includes any one or a combination of at least two of sodium hydroxide, potassium hydroxide, sodium carbonate, and sodium bicarbonate, and more preferably sodium hydroxide.

[0158] Preferably, in scheme ②, the molar ratio of the alkaline substance to compound 2 is (1-1.2):1, for example, it can be 1.02:1, 1.05:1, 1.08:1, 1.1:1, 1.12:1, 1.15:1, 1.18:1, etc., further preferably (1.01-1.1):1, and more preferably 1.05:1.

[0159] Preferably, in scheme ②, the temperature for the salt formation reaction of p-chlorophenol with the alkaline substance is 80-130℃, for example, it can be 85℃, 90℃, 95℃, 100℃, 105℃, 110℃, 115℃, 120℃ or 125℃, as well as specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0160] Preferably, in scheme ②, the time for the salt formation reaction of p-chlorophenol with the alkaline substance is 0.5-3h, for example, it can be 0.8h, 1h, 1.2h, 1.5h, 1.8h, 2.2h, 2.5h or 2.8h, as well as specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0161] Preferably, in scheme ②, the method for removing aqueous azeotropic substances includes removing aqueous azeotropic substances using negative pressure.

[0162] Preferably, in scheme ②, the etherification reaction is carried out in the presence of a copper-based catalyst.

[0163] Preferably, in Scheme ②, the copper-based catalyst includes any one or a combination of at least two of copper powder, cuprous chloride, cuprous bromide, cuprous iodide, copper chloride, copper sulfate, cuprous oxide, copper oxide, and ketone acetate, with cuprous chloride being more preferred.

[0164] Preferably, in scheme ②, based on the mass of compound 2 as 100%, the mass of the copper-based catalyst is 1-5%, for example, it can be 1.2%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4% or 4.5%, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. More preferably, it is 1.8-2.2%, more preferably 2%.

[0165] Preferably, in scheme ②, the etherification reaction is carried out in the presence of a phase transfer catalyst or without the use of a phase transfer catalyst; the phase transfer catalyst does not affect the yield, but can increase the reaction rate.

[0166] Preferably, in scheme ②, the etherification reaction is carried out in the presence of a phase transfer catalyst.

[0167] Preferably, in scheme ②, the phase transfer catalyst includes any one or a combination of at least two of tetramethylammonium chloride, tetrabutylammonium bromide, and 18-crown ether-6, with tetramethylammonium chloride being more preferred.

[0168] Preferably, in scheme ②, based on the mass of compound 2 as 100%, the mass of the phase transfer catalyst is 0.1-5%, for example, it can be 0.5%, 1%, 1.5%, 2%, 2.5%, 3%, 3.5%, 4% or 4.5%, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range, but is further preferred to be 0.8-1.2%, and more preferably 1%.

[0169] Preferably, in scheme ②, the etherification reaction (and optionally the salt formation reaction) is carried out in the presence of a polar aprotic solvent.

[0170] Preferably, in scheme ②, the polar aprotic solvent includes any one or a combination of at least two of acetonitrile, dimethyl sulfoxide, N,N-dimethylformamide, and N-methylpyrrolidone, with dimethyl sulfoxide being more preferred.

[0171] Preferably, in scheme ②, the temperature of the etherification reaction is 90-200℃, for example, it can be 100℃, 110℃, 120℃, 130℃, 140℃, 150℃, 160℃, 170℃, 180℃ or 190℃, as well as specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. Further preferred is 115-145℃, more preferably 130℃.

[0172] Preferably, in scheme ②, the etherification reaction time is 1-10h, for example, it can be 2h, 3h, 4h, 5h, 6h, 7h, 8h or 9h, as well as specific point values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific point values ​​included in the range. More preferably, it is 2-5h, and more preferably, it is 3h.

[0173] Preferably, in scheme ②, after the etherification reaction is completed, a post-processing step is further included, which includes: cooling the product obtained from the etherification reaction to room temperature and filtering it, and distilling the filtrate under reduced pressure to obtain compound 7.

[0174] Preferably, in scheme ②, the deprotection reaction of compound 7 is carried out in the presence of a basic substance.

[0175] Preferably, the alkaline substance in the deprotection reaction includes any one or a combination of at least two of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, and sodium ethoxide, with sodium hydroxide being more preferred.

[0176] In Scheme ②, the alkaline substance (e.g., sodium hydroxide) used in the deprotection reaction can be used in solid form or in aqueous solution form.

[0177] Preferably, the mass percentage of alkaline substance in the aqueous solution of the alkaline substance is 10-50%, for example, it can be 15%, 20%, 25%, 30%, 35%, 40% or 45%, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. More preferably, it is 28-32%, and more preferably 30%.

[0178] Preferably, in scheme ②, the molar ratio of the basic substance to compound 7 in the deprotection reaction is (1-2):1, for example, it can be 1.05:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, etc., further preferably (1.05-1.15):1, and more preferably 1.1:1.

[0179] Preferably, in scheme ②, the deprotection reaction is carried out in the presence of a solvent.

[0180] Preferably, in scheme ②, the solvent for the deprotection reaction includes an alcohol solvent, more preferably any one or a combination of at least two of methanol, ethanol, propanol, and ethylene glycol, and more preferably ethanol.

[0181] Preferably, the preparation method of compound 8 in scheme ② specifically includes: mixing compound 7 with a solvent (preferably an alcohol) and an alkaline substance, and then carrying out a deprotection reaction to obtain compound 8.

[0182] Preferably, in scheme ②, the temperature of the deprotection reaction is 40-90℃, for example, it can be 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃ or 85℃, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. More preferably, it is 60-80℃, and more preferably 70℃.

[0183] Preferably, in scheme ②, the deprotection reaction time is 2-10h, for example, it can be 3h, 4h, 5h, 6h, 7h, 8h or 9h, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific point values ​​included in the range.

[0184] Preferably, after compound 8 undergoes a salt-forming reaction with an acid, it is then subjected to a diazotization reaction with a nitrite to obtain compound 9.

[0185] Preferably, the acid includes sulfuric acid or hydrochloric acid; since diazonium salts of hydrochloric acid contain many impurities, sulfuric acid is further preferred.

[0186] Preferably, the sulfuric acid reacts with compound 8 in the form of a sulfuric acid solution to form a salt.

[0187] Preferably, the sulfuric acid solution contains 30-80% sulfuric acid by mass, for example, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, or 75%, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list all the specific values ​​included in the range. More preferably, it is 40-60%, and more preferably, it is 50%.

[0188] Preferably, the molar ratio of the acid to compound 8 is (1.5-4):1, for example, it can be 1.8:1, 2:1, 2.2:1, 2.5:1, 2.8:1, 3:1, 3.2:1, 3.5:1, 3.8:1, etc., and more preferably 2:1.

[0189] Preferably, the nitrite comprises sodium nitrite and / or potassium nitrite.

[0190] Preferably, the molar ratio of the nitrite to compound 8 is (1.01-1.1):1, for example, it can be 1.02:1, 1.03:1, 1.04:1, 1.05:1, 1.06:1, 1.07:1, 1.08:1, 1.09:1, etc., more preferably (1.04-1.08):1, and even more preferably 1.06:1.

[0191] Preferably, the nitrite is introduced into the reaction system of step (4) in the form of a nitrite solution.

[0192] Preferably, the nitrite solution contains 10-50% by mass, for example, 15%, 20%, 25%, 30%, 35%, 40% or 45%, and specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. More preferably, it is 25-35%, and more preferably 30%.

[0193] Preferably, step (4) specifically includes: first adding compound 8 to (preferably adding dropwise) sulfuric acid solution to carry out a salt formation reaction, and then adding (preferably adding dropwise) nitrite solution to carry out a diazotization reaction to obtain compound 9.

[0194] Preferably, the temperature of the salt formation reaction is 20-60℃, for example, it can be 25℃, 28℃, 30℃, 32℃, 35℃, 38℃, 40℃, 42℃, 45℃, 48℃, 50℃, 52℃, 55℃ or 58℃, as well as specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. More preferably, it is 40-60℃, and more preferably 50℃.

[0195] Preferably, the salt formation reaction time is 0.5-5h, for example, it can be 0.8h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h or 4.5h, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0196] Preferably, the temperature of the diazotization reaction in step (4) is -20°C to 5°C, for example, it can be -15°C, -12°C, -10°C, -8°C, -5°C, -2°C, 0°C, 2°C or 4°C, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range. It is further preferred to be -5°C to 2°C, and more preferably 0°C.

[0197] Preferably, the diazotization reaction time in step (4) is 0.5-5h, for example, it can be 0.8h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h or 4.5h, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0198] Preferably, the molar ratio of acetaldehyde oxime to compound 8 is (1.05-1.8):1, for example, it can be 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, etc., further preferably (1.4-1.6):1, and more preferably 1.5:1.

[0199] Preferably, the acetaldehyde oxime is introduced into the reaction system of step (5) in the form of an aqueous solution of acetaldehyde oxime.

[0200] Preferably, the acetaldehyde oxime aqueous solution contains 30-70% by mass, for example, 35%, 40%, 42%, 45%, 48%, 50%, 52%, 55%, 58%, 60%, or 65%, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, this invention will not exhaustively list all the specific values ​​included in the range.

[0201] Preferably, the coupling reaction in step (5) is carried out in the presence of a copper salt catalyst.

[0202] Preferably, the copper salt catalyst comprises any one or a combination of at least two of copper sulfate, copper chloride, cuprous chloride, and copper acetate;

[0203] Preferably, the molar ratio of the copper salt catalyst to compound 8 is (0.05-0.15):1, for example, it can be 0.06:1, 0.07:1, 0.08:1, 0.09:1, 0.1:1, 0.11:1, 0.12:1, 0.13:1, 0.14:1, etc., more preferably (0.08-0.12):1, and even more preferably 0.1:1.

[0204] Preferably, the copper salt catalyst is introduced into the reaction system of step (5) in the form of an aqueous solution of the copper salt catalyst.

[0205] Preferably, the mass percentage of copper salt catalyst in the aqueous solution of the copper salt catalyst is 5-20%, for example, it can be 6%, 8%, 10%, 12%, 15% or 18%, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0206] Preferably, the coupling reaction in step (5) is carried out in the presence of an acid-binding agent.

[0207] Preferably, the acid-binding agent comprises any one or a combination of at least two of alkali metal formate, alkali metal acetate, alkali metal phosphate, alkali metal hydrogen phosphate, and alkali metal dihydrogen phosphate; the acid-binding agent can form a buffer system in the system, which is beneficial for reaction control.

[0208] Preferably, the alkali metal includes any one of Na and K; preferably, the acid-binding agent includes any one or a combination of at least two of sodium formate, sodium acetate, sodium phosphate, sodium hydrogen phosphate, and sodium dihydrogen phosphate.

[0209] Preferably, the molar ratio of the acid-binding agent to compound 8 is (1-5):1, for example, it can be 1.5:1, 2:1, 2.5:1, 3:1, 3.5:1, 4:1, 4.5:1, etc.

[0210] Preferably, the coupling reaction in step (5) is carried out in the presence of a solvent.

[0211] Preferably, the solvent for the coupling reaction in step (5) includes any one or a combination of at least two of water, aromatic hydrocarbon solvent, aliphatic hydrocarbon solvent, and halogenated aliphatic hydrocarbon solvent, more preferably any one or a combination of at least two of water, dichloroethane, toluene, and xylene, and more preferably a mixture of water and toluene.

[0212] Preferably, step (5) specifically includes: placing acetaldehyde oxime, solvent, copper salt catalyst aqueous solution and acid-binding agent in a reaction apparatus, and adding (preferably dropwise) compound 9 (its aqueous solution) obtained in step (4) to carry out a coupling reaction to obtain compound 10.

[0213] It should be noted that the order of addition in step (5) is not mandatory. For example, acetaldehyde oxime, solvent, copper salt catalyst aqueous solution, and acid-binding agent can all be added dropwise and the product can be obtained, but the yield will fluctuate. It is preferred to add the aqueous solution of compound 9 dropwise.

[0214] Preferably, the temperature of the coupling reaction in step (5) is from -10°C to 50°C, for example, it can be -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C or 45°C, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range, and 0-20°C is further preferred.

[0215] Preferably, the coupling reaction time in step (5) is 1-10h, for example, it can be 1.5h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h or 9.5h, as well as specific point values ​​between the above point values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific point values ​​included in the range.

[0216] Preferably, the coupling reaction further includes a post-processing step, which includes: allowing the product obtained from the coupling reaction to stand and separate into layers, and the resulting organic phase is the organic phase solution of compound 10, which directly enters the next step of hydrolysis reaction.

[0217] Preferably, the hydrolysis reaction is carried out in the presence of an acidic substance.

[0218] Preferably, the acidic substance includes hydrochloric acid and / or sulfuric acid.

[0219] Preferably, the H in the acidic substance + The molar ratio of compound 8 to compound 8 is (1-3.2):1, for example, it can be 1.2:1, 1.5:1, 1.8:1, 2:1, 2.2:1, 2.5:1, 2.8:1, 3:1, etc.

[0220] Preferably, the acidic substance is sulfuric acid, and the molar ratio of sulfuric acid to compound 8 is (0.5-1.6):1, for example, it can be 0.6:1, 0.7:1, 0.8:1, 1:1, 1.1:1, 1.2:1 or 1.5:1, etc.

[0221] Preferably, the acidic substance is hydrochloric acid, and the molar ratio of hydrochloric acid to compound 8 is (1-3.2):1, for example, it can be 1.2:1, 1.5:1, 1.8:1, 2:1, 2.2:1, 2.5:1, 2.8:1, 3:1, etc.

[0222] Preferably, step (6) specifically includes: mixing the organic phase solution of compound 10 obtained in step (5) with an acidic substance and carrying out a hydrolysis reaction under stirring conditions to obtain the 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone.

[0223] Preferably, the temperature of the hydrolysis reaction in step (6) is 60-100℃, for example, it can be 65℃, 70℃, 75℃, 80℃, 85℃, 90℃ or 95℃, and specific values ​​between the above points. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0224] Preferably, the hydrolysis reaction time in step (6) is 1-6 hours, for example, it can be 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, 4 hours, 4.5 hours, 5 hours or 5.5 hours, as well as specific values ​​between the above values. Due to space limitations and for the sake of brevity, the present invention will not exhaustively list the specific values ​​included in the range.

[0225] Preferably, after the hydrolysis reaction in step (6) is completed, a post-treatment step is also included. The post-treatment method includes: allowing the product obtained from the hydrolysis reaction to stand and separate into layers, washing the upper organic phase with a weakly alkaline aqueous solution until neutral, removing the solvent, and then distilling under reduced pressure to obtain the 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone.

[0226] Compared with the prior art, the present invention has the following beneficial effects:

[0227] The preparation method provided by this invention uses o-trifluoromethylaniline as the starting material, which is inexpensive, readily available, and supplied on a large scale domestically. The acetyl group is obtained through diazotization, coupling addition, and hydrolysis, eliminating the need for Grignard reagents and Grignard reactions, thus avoiding hazardous reagents and harsh reaction conditions. It also avoids fluorination cracking and other processes, requiring no special equipment and producing wastewater containing magnesium, fluorine, or boron, which is difficult to treat. The preparation method utilizes inexpensive and readily available raw materials, has a simple process, mild reaction conditions, and all reactions can be carried out under normal pressure. The preparation process is safe and controllable, making it highly valuable for industrial applications. Detailed Implementation

[0228] The technical solution of the present invention will be further illustrated below through specific embodiments. Those skilled in the art should understand that the embodiments described are merely illustrative of the present invention and should not be construed as limiting the invention in any way.

[0229] In one specific embodiment, the preparation method uses o-trifluoromethylaniline as a raw material, and proceeds through amino protection (amidation reaction), bromination reaction, deprotection reaction, diazotization reaction, coupling reaction, hydrolysis reaction, and etherification reaction to obtain 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone, as shown in the following reaction formula:

[0230]

[0231] In another specific embodiment, the preparation method uses o-trifluoromethylaniline as a raw material, and proceeds through amino protection (amidation reaction), bromination reaction, deprotection reaction, etherification reaction, diazotization reaction, coupling reaction and hydrolysis reaction to obtain 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone, as shown in the following reaction formula:

[0232]

[0233] In another specific embodiment, the preparation method uses o-trifluoromethylaniline as a raw material, and proceeds through amino protection (amidation reaction), bromination reaction, etherification reaction, deprotection reaction, diazotization reaction, coupling reaction and hydrolysis reaction to obtain 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone, as shown in the following reaction formula:

[0234]

[0235]

[0236] In the following specific embodiments of the present invention, all raw materials for which preparation methods are not provided were purchased from the market; the reaction conversion rate was determined by high performance liquid chromatography (HPLC) normalization method, the purity (content) of all products was determined by HPLC external standard method, and the yield was mass yield. The molecular structure of each product was determined by ultra-high performance liquid chromatography-mass spectrometry (UHPLC-MS) and / or nuclear magnetic resonance (NMR) spectroscopy. 1 Characterized and confirmed by H-NMR.

[0237] Example 1

[0238] A method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone includes the following steps:

[0239] (1) Synthesis of compound 1 (2-acetamido-trifluorotoluene)

[0240] 164.4 g of o-trifluoromethylaniline (98% purity, 1 mol) and 1000 g of 1,2-dichloroethane were added to a reaction flask. The mixture was heated to 80 °C, and 84.1 g of acetyl chloride (98% purity, 1.05 mol) was added dropwise over 1 hour with stirring. After the addition was complete, the mixture was kept at 80 °C for 1 hour. The reaction conversion rate reached over 99.5%, with no obvious impurities, yielding compound 1. UHPLC-MS (m / z, ESI): 204.0627 (M+H) + Theoretical value: 204.0631.

[0241] (2) Synthesis of compound 2 (2-acetamido-5-bromotrifluorotoluene)

[0242] The reaction solution in step (1) (compound 1, calculated as 1 mol) was heated to 50°C. Simultaneously, 96.9 g of bromine (99% purity, 0.6 mol) and 68 g of hydrogen peroxide (30% H2O2 concentration, 0.6 mol) were added dropwise over 2 hours. After the addition was complete, the reaction was maintained at this temperature for 3 hours. After cooling, a certain amount of sodium bisulfite aqueous solution was added dropwise until the system was free of oxidizing agents (the absence of oxidizing agents is indicated by the absence of blackening on KI starch test paper). The mixture was then stirred at 20°C for 1 hour, and the solvent was removed under negative pressure while maintaining the temperature below 60°C. 100 g of water was added to the reaction flask, stirred thoroughly, and filtered to obtain 324.5 g of wet 2-acetamido-5-bromotrifluorotoluene with a purity of 81.9% and a yield of 94.2% (based on o-trifluoromethylaniline). UHPLC-MS (m / z, ESI): 281.9733 (M+H) + Theoretical value: 281.9736. 0.1g of wet sample was dried and the NMR data were measured. 1 H-NMR (DMSO, 400MHz) δ (ppm): 2.052 (s, 3H, CH3); 7.466 (d, J=8.4Hz, 1H, ArH); 7.866~7.905 (m, 2H, ArH); 9.629 (s, 1H, NH).

[0243] (3) Synthesis of compound 3 (2-trifluoromethyl-4-bromoaniline)

[0244] 324.5 g of the wet product 2-acetamido-5-bromotrifluorotoluene (purity 81.9%, 0.94 mol) obtained in step (2), 470 g of ethanol, and 137.3 g of sodium hydroxide aqueous solution (NaOH mass concentration 30%, 1.03 mol) were added to the reaction flask. The temperature was raised to 70 °C, and the reaction was carried out for 3 h. The solvent was removed under negative pressure while maintaining the temperature below 70 °C. 94 g of water was added to the reaction flask and stirred until the layers were separated. The lower oil phase of 237.2 g, namely 2-trifluoromethyl-4-bromoaniline, with a purity of 93.2% and a yield of 98.0%, was separated. UHPLC-MS (m / z, ESI): 289.9627 (M+H) + Theoretical value: 289.9630.

[0245] (4) Synthesis of compound 4 (2-trifluoromethyl-4-bromoaniline diazonium salt)

[0246] Add 100g of water and 100g of concentrated sulfuric acid (H2SO4 mass concentration of 98%, 1mol) to the reaction flask, then add 128.8g of 2-trifluoromethyl-4-bromoaniline (purity of 93.2%, 0.5mol) dropwise. Raise the temperature to 60℃ and keep it at that temperature for 1h, then cool it to 0℃. Add 121.9g of sodium nitrite aqueous solution (NaNO2 mass concentration of 30%, 0.53mol) dropwise, and keep the temperature at 0℃ with stirring for 1h. Then add 18g of urea aqueous solution (urea mass concentration of 10%, 0.03mol) dropwise to destroy the residual nitrite. Finally, a pale yellow diazonium salt clear solution is obtained and stored at 0℃ for later use.

[0247] (5) Synthesis of compound 5 (2-trifluoromethyl-4-bromoacetophenone oxime)

[0248] Add 88.6 g of acetaldehyde oxime aqueous solution (C2H5NO mass concentration 50%, 0.75 mol), 180 g of water, 66.7 g of copper sulfate solution (CuSO4 mass concentration 12%, 0.05 mol), and 132.5 g of sodium acetate (purity 99%, 1.6 mol) to the reaction flask. Control the temperature at about 10℃ and add the clear diazonium salt solution obtained in step (4) dropwise over about 3 hours. After the addition is complete, control the temperature at 10℃ and keep the reaction at this temperature for 2 hours. After the reaction is complete, add 150 g of toluene to extract the product, then allow it to stand and separate the layers. Separate the organic phase, which is the toluene solution of 2-trifluoromethyl-4-bromoacetophenone oxime. UHPLC-MS (m / z, ESI): 281.9734 (M+H) + Theoretical value: 281.9736.

[0249] (6) Synthesis of compound 6 (2-trifluoromethyl-4-bromoacetophenone)

[0250] The organic phase solution obtained in step (5) was added to a reaction flask, and 127.8 g of dilute hydrochloric acid (HCl mass concentration of 20%, 0.7 mol) was added. The temperature was raised to 85℃ and kept at that temperature for 4 h. After hydrolysis, the mixture was allowed to stand and separate into layers. The upper organic phase was washed with sodium bicarbonate aqueous solution until neutral. After solvent removal, the mixture was distilled under reduced pressure (2 kPa, 76-78℃) to obtain 114.4 g of a pale yellow liquid, which is 2-trifluoromethyl-4-bromoacetophenone with a purity of 97.0%. The yield of the three-step reaction (diazotization reaction-coupling reaction-hydrolysis reaction) in steps (4)-(6) was 83.1%. UHPLC-MS (m / z, ESI): 266.9625 (M+H) + Theoretical value: 266.9627.

[0251] (7) Synthesis of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone

[0252] 39.0 g of p-chlorophenol (99% purity, 0.3 mol), 13.1 g of sodium hydroxide (96% purity, 0.315 mol), and 300 g of dimethyl sulfoxide were added to a reaction flask. The mixture was heated to 110 °C and kept at this temperature for 1 h. Then, 92.5 g of the aqueous azeotrope was removed under negative pressure. After cooling, 82.6 g of 2-trifluoromethyl-4-bromoacetophenone (97.0% purity, 0.3 mol) and 0.83 g of tetramethylammonium chloride (99% purity) were added to the reaction flask. The mixture was heated to 130 °C and reacted for 2 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was then subjected to vacuum distillation (0.4 kPa, 120-122 °C) to obtain 88.9 g of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone with a purity of 99.3% and a yield of 93.5%. UHPLC-MS(m / z, ESI): 315.0390(M+H) + Theoretical value: 315.0394. 1 H-NMR (CDCl3, 400MHz) δ (ppm): 2.576 (s, 3H, CH3); 7.001 (d, J=7.6Hz, 2H, ArH); 7.121 (d, J=8Hz, 1H, ArH); 7.308 (s, 1H, ArH); 7.371 (d, J=6.8Hz, 2H, ArH); 7.50 (d, J=8Hz, 1H, ArH).

[0253] Example 2

[0254] A method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone includes the following steps:

[0255] (1) Synthesis of compound 1 (2-acetamido-trifluorotoluene): Same as step (1) of Example 1.

[0256] (2) Synthesis of compound 2 (2-acetamido-5-bromotrifluorotoluene)

[0257] The reaction solution from step (1) (compound 1, calculated as 1 mol) was heated to 50-60℃. Simultaneously, 202.5 g of HBr aqueous solution (HBr mass concentration 48%, HBr 1.2 mol) and 136 g of hydrogen peroxide (H2O2 mass concentration 30%, H2O2 1.2 mol) were added dropwise over 2-4 hours. The reaction was maintained at this temperature for 3 hours. After cooling, a certain amount of sodium bisulfite aqueous solution was added dropwise until the system was free of oxidizing agents (the absence of oxidizing agents is indicated by the KI starch test paper not turning black). The mixture was stirred at 20-30℃ for 1 hour, and the solvent was removed under negative pressure while maintaining the temperature below 60℃. 100 g of water was added to the reaction flask, stirred thoroughly, and filtered to obtain 327.9 g of wet product 2-acetamido-5-bromotrifluorotoluene, with a purity of 80.4% and a yield of 93.5%. UHPLC-MS (m / z, ESI): 281.9733 (M+H) + Theoretical value: 281.9736.

[0258] (3) Synthesis of compound 3 (2-trifluoromethyl-4-bromoaniline)

[0259] 327.9 g of the wet product 2-acetamido-5-bromotrifluorotoluene (purity 80.4%, 0.93 mol), 465 g of ethanol, and 136 g of sodium hydroxide aqueous solution (NaOH mass concentration 30%, 1.02 mol) obtained in step (2) were added to the reaction flask. The temperature was raised to 70 °C, and the reaction was carried out for 3 h. The solvent was removed under negative pressure while maintaining the temperature below 70 °C. 93 g of water was added to the reaction flask and stirred until the layers were separated. The lower oil phase of 234.4 g, namely 2-trifluoromethyl-4-bromoaniline, with a purity of 93.5% and a yield of 98.2%, was separated. UHPLC-MS (m / z, ESI): 289.9627 (M+H) + Theoretical value: 289.9630.

[0260] (4) Synthesis of compound 4 (2-trifluoromethyl-4-bromoaniline diazonium salt)

[0261] Add 100g of water and 100g of concentrated sulfuric acid (H2SO4 mass concentration of 98%, 1mol) to the reaction flask, then add 128.4g of 2-trifluoromethyl-4-bromoaniline (purity of 93.5%, 0.5mol) dropwise. Raise the temperature to 60℃ and keep it at that temperature for 1h, then cool it to 0℃. Add 121.9g of sodium nitrite aqueous solution (NaNO2 mass concentration of 30%, 0.53mol) dropwise, and keep the temperature at 0℃ with stirring for 1h. Then add 18g of urea aqueous solution (urea mass concentration of 10%, 0.03mol) dropwise to destroy the residual nitrite. Finally, a pale yellow diazonium salt clear solution is obtained and stored at 0℃ for later use.

[0262] (5) Synthesis of compound 5 (2-trifluoromethyl-4-bromoacetophenone oxime)

[0263] Add 88.6 g of acetaldehyde oxime aqueous solution (C2H5NO mass concentration 50%, 0.75 mol), 180 g of water, 66.7 g of copper sulfate solution (CuSO4 mass concentration 12%, 0.05 mol), and 132.5 g of sodium acetate (purity 99%, 1.6 mol) to the reaction flask. Control the temperature at about 10℃ and add the clear diazonium salt solution obtained in step (4) dropwise over about 3 hours. After the addition is complete, control the temperature at 10℃ and keep the reaction at this temperature for 2 hours. After the reaction is complete, add 150 g of toluene to extract the product, then allow it to stand and separate the layers. Separate the organic phase, which is the toluene solution of 2-trifluoromethyl-4-bromoacetophenone oxime. UHPLC-MS (m / z, ESI): 281.9734 (M+H) + Theoretical value: 281.9736.

[0264] (6) Synthesis of compound 6 (2-trifluoromethyl-4-bromoacetophenone)

[0265] The organic phase solution obtained in step (5) was added to a reaction flask, and 127.8 g of dilute hydrochloric acid (HCl mass concentration of 20%, 0.7 mol) was added. The temperature was raised to 85 °C and kept at that temperature for 4 h. After hydrolysis, the mixture was allowed to stand and separate into layers. The upper organic phase was washed with sodium bicarbonate aqueous solution until neutral. After solvent removal, the mixture was distilled under reduced pressure (2 kPa, 76-78 °C) to obtain 114.5 g of a pale yellow liquid, which is 2-trifluoromethyl-4-bromoacetophenone with a purity of 97.3%. The yield of the three-step reaction (diazotization reaction-coupling reaction-hydrolysis reaction) in steps (4)-(6) was 83.4%. UHPLC-MS (m / z, ESI): 266.9625 (M+H) + Theoretical value: 266.9627.

[0266] (7) Synthesis of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone

[0267] 39.0 g of p-chlorophenol (99% purity, 0.3 mol), 13.1 g of sodium hydroxide (96% purity, 0.315 mol), and 300 g of dimethyl sulfoxide were added to a reaction flask. The mixture was heated to 110 °C and held at this temperature for 1 h. Then, 90.3 g of the aqueous azeotrope was removed under negative pressure. After cooling, 82.3 g of 2-trifluoromethyl-4-bromoacetophenone (97.3% purity, 0.3 mol) and 0.83 g of tetramethylammonium chloride (99% purity) were added to the reaction flask. The mixture was heated to 130 °C and reacted for 2 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was then subjected to vacuum distillation (0.8 kPa, 144-146 °C) to obtain 89.1 g of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone with a purity of 99.4% and a yield of 93.8%.

[0268] Example 3

[0269] A method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone includes the following steps:

[0270] Steps (1)-(4) are the same as in Example 1, yielding compound 4 (2-trifluoromethyl-4-bromoaniline diazonium salt), which is stored at 0°C for later use.

[0271] (5) Synthesis of compound 5 (2-trifluoromethyl-4-bromoacetophenone oxime)

[0272] Add 88.6 g of acetaldehyde oxime aqueous solution (C2H5NO mass concentration 50%, 0.75 mol), 180 g of water, 150 g of toluene, 66.7 g of copper sulfate solution (CuSO4 mass concentration 12%, 0.05 mol), and 114.7 g of disodium hydrogen phosphate (purity 99%, 0.8 mol) to the reaction flask. Control the temperature at about 20℃ and add the clear diazonium salt solution obtained in step (4) dropwise over about 3 hours. After the addition is complete, control the temperature at 20℃ and keep the reaction at this temperature for 2 hours. After the reaction is complete, allow the mixture to stand and separate the layers. Separate the organic phase, which is the toluene solution of 2-trifluoromethyl-4-bromoacetophenone oxime. UHPLC-MS (m / z, ESI): 281.9734 (M+H) + Theoretical value: 281.9736.

[0273] (6) Synthesis of compound 6 (2-trifluoromethyl-4-bromoacetophenone)

[0274] The organic phase solution obtained in step (5) was put into a reaction flask and 127.8g of dilute hydrochloric acid (HCl mass concentration of 20%, 0.7mol) was added. The temperature was raised to 85℃ and kept at that temperature for 4h. After hydrolysis was completed, the mixture was allowed to stand and separate into layers. The upper organic phase was washed with sodium bicarbonate aqueous solution until neutral. After desolvation, it was distilled under reduced pressure (2kPa, 76-78℃) to obtain 111.5g of pale yellow liquid, which is 2-trifluoromethyl-4-bromoacetophenone with a purity of 97.2%. The yield of the three-step reaction (3)-(6) of diazotization, coupling and hydrolysis was 81.2%.

[0275] (7) Synthesis of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone

[0276] 82.4 g of 2-trifluoromethyl-4-bromoacetophenone (97.2% purity, 0.3 mol), 39.0 g of p-chlorophenol (99% purity, 0.3 mol), 13.1 g of sodium hydroxide (96% purity, 0.315 mol), 0.82 g of tetramethylammonium chloride (99% purity) and 210 g of dimethyl sulfoxide were added to a reaction flask. The mixture was heated to 130 °C and reacted for 2 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was then subjected to vacuum distillation (0.4 kPa, 120-122 °C) to obtain 87.5 g of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone with a purity of 98.8% and a yield of 91.6%.

[0277] Example 4

[0278] A method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone includes the following steps:

[0279] Steps (1)-(3) are the same as in Example 1, yielding compound 3 (2-trifluoromethyl-4-bromoaniline);

[0280] (4) Synthesize compound 8(4-(4-chlorophenoxy)-2-trifluoromethylaniline)

[0281] 77.9 g of p-chlorophenol (99% purity, 0.6 mol), 26.2 g of sodium hydroxide (96% purity, 0.63 mol), and 600 g of dimethyl sulfoxide were added to a reaction flask. The mixture was heated to 110 °C and held at this temperature for 1 h. Then, 189.4 g of the aqueous azeotrope was removed under negative pressure. After cooling, 154.5 g of 2-trifluoromethyl-4-bromoaniline (93.2% purity, 0.6 mol) and 3.1 g of cuprous chloride (99% purity) were added to the reaction flask. The mixture was heated to 130 °C and reacted for 3 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was then subjected to vacuum distillation (0.3 kPa, 101-103 °C) to obtain 162.1 g of 4-(4-chlorophenoxy)-2-trifluoromethylaniline with a purity of 98.5% and a yield of 92.5%. UHPLC-MS(m / z, ESI): 288.0399(M+H) + Theoretical value: 288.0398.

[0282] (5) Synthesize compound 9 (4-(4-chlorophenoxy)-2-trifluoromethylaniline diazonium salt)

[0283] Add 76.8g of water and 80g of concentrated sulfuric acid (H2SO4 mass concentration of 98%, 0.8mol) to the reaction flask, then add 116.8g of 4-(4-chlorophenoxy)-2-trifluoromethylaniline (purity of 98.5%, 0.4mol) dropwise. Raise the temperature to 60℃ and keep it at that temperature for 1h, then cool it to 0℃. Add 96.6g of sodium nitrite aqueous solution (NaNO2 mass concentration of 30%, 0.42mol) dropwise, and keep the temperature at 0℃ with stirring for 1h. Then add 12g of urea aqueous solution (urea mass concentration of 10%, 0.02mol) dropwise to destroy the residual nitrite. Finally, a pale yellow diazonium salt clear solution is obtained and stored at 0℃ for later use.

[0284] (6) Synthesis of compound 10 (4-(4-chlorophenoxy)-2-trifluoromethylacetophenone oxime):

[0285] Add 70.9 g of acetaldehyde oxime solution (C2H5NO mass concentration 50%, 0.6 mol), 144 g of water, 53.3 g of copper sulfate solution (CuSO4 mass concentration 12%, 0.04 mol), and 106.0 g of sodium acetate (purity 99%, 1.28 mol) to the reaction flask. Control the temperature at about 10℃ and add the clear diazonium salt solution obtained in step (5) dropwise over about 3 hours. After the addition is complete, control the temperature at 10℃ and keep the reaction at this temperature for 2 hours. After the reaction is complete, add 120 g of toluene to extract the product, then allow it to stand and separate into layers. Separate the organic phase, which is a toluene solution of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone oxime. UHPLC-MS (m / z, ESI): 330.0490 (MH) - Theoretical value: 330.0503.

[0286] (7) Synthesis of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone

[0287] The organic phase solution obtained in step (6) was added to a reaction flask, and 102.2 g of dilute hydrochloric acid (HCl mass concentration of 20%, 0.56 mol) was added. The temperature was raised to 85℃ and kept at that temperature for 4 h. After hydrolysis, the mixture was allowed to stand and separate into layers. The upper organic phase was washed with sodium bicarbonate aqueous solution until neutral. After solvent removal, the mixture was distilled under reduced pressure (0.4 kPa, 120-122℃) to obtain 107 g of a pale yellow liquid, which is 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone with a purity of 97.5%. The yield of the three-step reaction (diazotization, coupling, and hydrolysis) in steps (5)-(7) was 82.9%. UHPLC-MS (m / z, ESI): 315.0390 (M+H) + Theoretical value: 315.0394. 1 H-NMR (CDCl3, 400MHz) δ (ppm): 2.576 (s, 3H, CH3); 7.001 (d, J=7.6Hz, 2H, ArH); 7.121 (d, J=8Hz, 1H, ArH); 7.308 (s, 1H, ArH); 7.371 (d, J=6.8Hz, 2H, ArH); 7.50 (d, J=8Hz, 1H, ArH).

[0288] Example 5

[0289] A method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone includes the following steps:

[0290] Steps (1)-(3) are the same as in Example 1, yielding compound 3 (2-trifluoromethyl-4-bromoaniline);

[0291] (4) Synthesize compound 8(4-(4-chlorophenoxy)-2-trifluoromethylaniline)

[0292] 154.5 g of 2-trifluoromethyl-4-bromoaniline (93.2% purity, 0.6 mol), 77.9 g of p-chlorophenol (99% purity, 0.6 mol), 88.8 g of potassium carbonate (98% purity, 0.63 mol), 3.1 g of cuprous chloride, and 420 g of dimethyl sulfoxide were added to a reaction flask. The mixture was heated to 130 °C and reacted for 2 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was then subjected to vacuum distillation (0.3 kPa, 101-103 °C) to obtain 162.5 g of 4-(4-chlorophenoxy)-2-trifluoromethylaniline with a purity of 99% and a yield of 93.2%.

[0293] (5) Synthesize compound 9 (4-(4-chlorophenoxy)-2-trifluoromethylaniline diazonium salt)

[0294] Add 76.8g of water and 80g of concentrated sulfuric acid (H2SO4 mass concentration of 98%, 0.8mol) to the reaction flask, then add 116.2g of 4-(4-chlorophenoxy)-2-trifluoromethylaniline (purity of 99%, 0.4mol) dropwise. Raise the temperature to 60℃ and keep it at that temperature for 1h, then cool it to 0℃. Add 96.6g of sodium nitrite aqueous solution (NaNO2 mass concentration of 30%, 0.42mol) dropwise, and keep the temperature at 0℃ with stirring for 1h. Then add 12g of urea aqueous solution (urea mass concentration of 10%, 0.02mol) dropwise to destroy the residual nitrite. Finally, a pale yellow diazonium salt clear solution is obtained and stored at 0℃ for later use.

[0295] (6) Synthesis of compound 10 (4-(4-chlorophenoxy)-2-trifluoromethylacetophenone oxime):

[0296] Add 70.9 g of acetaldehyde oxime solution (C2H5NO mass concentration 50%, 0.6 mol), 144 g of water, 120 g of toluene, 53.3 g of copper sulfate solution (CuSO4 mass concentration 12%, 0.04 mol), and 106.0 g of sodium acetate (purity 99%, 1.28 mol) to the reaction flask. Control the temperature at about 20℃ and add the clear diazonium salt solution obtained in step (5) dropwise over about 3 hours. After the addition is complete, control the temperature at 20℃ and maintain the reaction for 2 hours. After the reaction is complete, allow it to stand and separate the layers. Separate the organic phase, which is the toluene solution of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone oxime. UHPLC-MS (m / z, ESI): 330.0490 (MH) - Theoretical value: 330.0503.

[0297] (7) Synthesis of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone

[0298] The organic phase solution obtained in step (6) was put into a reaction flask and 102.2 g of dilute hydrochloric acid (HCl mass concentration of 20%, 0.56 mol) was added. The temperature was raised to 85℃ and kept at that temperature for 4 h. After hydrolysis was completed, the mixture was allowed to stand and separate into layers. The upper organic phase was washed with sodium bicarbonate aqueous solution until neutral. After desolvation, it was distilled under reduced pressure (0.4 kPa, 120-122℃) to obtain 107 g of pale yellow liquid, which is 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone with a purity of 97.5%. The yield of the three steps of diazotization reaction-coupling reaction-hydrolysis reaction in steps (5)-(7) was 82.9%.

[0299] Example 6

[0300] A method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone includes the following steps:

[0301] Step (1) is the same as in Example 1, yielding compound 1 (2-acetamido-trifluorotoluene);

[0302] (2) Synthesis of compound 2 (2-acetamido-5-bromotrifluorotoluene)

[0303] The reaction solution in step (1) (compound 1 is calculated as 1 mol) was heated to 50℃. At the same time, 96.9 g of bromine (purity 99%, 0.6 mol) and 68 g of hydrogen peroxide (H2O2 mass concentration 30%, 0.6 mol) were added dropwise to the system for 2 h. The reaction was kept at this temperature for 3 h. After cooling, a certain amount of sodium bisulfite aqueous solution was added dropwise to the reaction solution until the system was free of oxidizing properties (the system was free of oxidizing properties as long as KI starch test paper did not turn black). The solution was stirred at 20℃ for 1 h. The solvent was removed under negative pressure while maintaining the temperature below 60℃. 100 g of water was added to the reaction flask, stirred evenly, filtered, and dried to obtain 287.9 ​​g of 2-acetamido-5-bromo-trifluorotoluene with a purity of 91.8% and a yield of 93.7%.

[0304] (3) Synthesis of compound 7 (2-acetamido-5-(4-chlorophenoxy)-trifluorotoluene)

[0305] 77.9 g of p-chlorophenol (99% purity, 0.6 mol), 26.2 g of sodium hydroxide (96% purity, 0.63 mol), and 600 g of dimethyl sulfoxide were added to a reaction flask. The mixture was heated to 110 °C and kept at this temperature for 1 h. Then, 195.3 g of the aqueous azeotrope was removed under negative pressure. After cooling, 184.4 g of 2-acetamido-5-bromo-trifluorotoluene (91.8% purity, 0.6 mol) and 3.7 g of cuprous chloride (99% purity) were added to the reaction flask. The mixture was heated to 130 °C and reacted for 2 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was then subjected to vacuum distillation (0.2 kPa, 145-147 °C) to obtain 184.0 g of 2-acetamido-5-(4-chlorophenoxy)-trifluorotoluene with a purity of 98.9% and a yield of 92%. UHPLC-MS(m / z, ESI): 328.0358(MH) - Theoretical value: 328.0357.

[0306] (4) Synthesize compound 8(4-(4-chlorophenoxy)-2-trifluoromethylaniline)

[0307] 166.7 g of 2-acetamido-5-(4-chlorophenoxy)-trifluorotoluene (98.9% purity, 0.5 mol), 250 g of ethanol, and 73.3 g of sodium hydroxide aqueous solution (30% NaOH, 0.55 mol) were added to a reaction flask. The temperature was raised to 70 °C, and the reaction was carried out for 3 h. The solvent was removed under negative pressure while maintaining the temperature below 70 °C. 50 g of water was added to the reaction flask, and after stirring until homogeneous, the layers separated. The lower oil phase, 150 g, containing 4-(4-chlorophenoxy)-2-trifluoromethylaniline, with a purity of 93.1% and a yield of 97.1%, was separated. UHPLC-MS (m / z, ESI): 288.0399 (M+H) + Theoretical value: 288.0398.

[0308] (5) Synthesize compound 9 (4-(4-chlorophenoxy)-2-trifluoromethylaniline diazonium salt)

[0309] Add 76.8g of water and 80g of concentrated sulfuric acid (H2SO4 mass concentration of 98%, 0.8mol) to the reaction flask, then add 123.6g of 4-(4-chlorophenoxy)-2-trifluoromethylaniline (purity of 93.1%, 0.4mol) dropwise. Raise the temperature to 60℃ and keep it at that temperature for 1h, then cool it to 0℃. Add 96.6g of sodium nitrite aqueous solution (NaNO2 mass concentration of 30%, 0.42mol) dropwise, and keep the temperature at 0℃ with stirring for 1h. Then add 12g of urea aqueous solution (urea mass concentration of 10%, 0.02mol) dropwise to destroy the residual nitrite. Finally, a pale yellow diazonium salt clear solution is obtained and stored at 0℃ for later use.

[0310] (6) Synthesis of compound 10 (4-(4-chlorophenoxy)-2-trifluoromethylacetophenone oxime):

[0311] Add 70.9g of acetaldehyde oxime solution (C2H5NO mass concentration of 50%, 0.6mol), 144g of water, 120g of toluene, 53.3g of copper sulfate solution (CuSO4 mass concentration of 12%, 0.04mol), and 87.9g of sodium formate (purity of 99%, 1.28mol) to the reaction flask. Control the temperature at about 30℃ and add the clear diazonium salt solution obtained in step (5) dropwise over about 3 hours. After the addition is complete, control the temperature at 30℃ and keep the reaction at this temperature for 2 hours. After the reaction is complete, let it stand and separate into layers. Separate the organic phase, which is the toluene solution of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone oxime.

[0312] (7) Synthesis of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone

[0313] The organic phase solution obtained in step (6) was put into a reaction flask and 102.2 g of dilute hydrochloric acid (HCl mass concentration of 20%, 0.56 mol) was added. The temperature was raised to 85℃ and kept at that temperature for 4 h. After hydrolysis was completed, the mixture was allowed to stand and separate into layers. The upper organic phase was washed with sodium bicarbonate aqueous solution until neutral. After desolvation, it was distilled under reduced pressure (0.4 kPa, 120-122℃) to obtain 106 g of pale yellow liquid, which is 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone with a purity of 96.5%. The yield of the three steps of diazotization reaction-coupling reaction-hydrolysis reaction in steps (5)-(7) was 81.3%.

[0314] Example 7

[0315] A method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone includes the following steps:

[0316] Steps (1)-(2) are the same as in Example 6, yielding compound 2 (2-acetamido-5-bromotrifluorotoluene).

[0317] (3) Synthesis of compound 7 (2-acetamido-5-(4-chlorophenoxy)-trifluorotoluene)

[0318] 184.4 g of 2-acetamido-5-bromo-trifluorotoluene (91.8% purity, 0.6 mol), 77.9 g of p-chlorophenol (99% purity, 0.6 mol), 88.8 g of potassium carbonate (98% purity, 0.63 mol), 3.7 g of cuprous chloride (99% purity) and 420 g of dimethyl sulfoxide were added to a reaction flask. The mixture was heated to 130 °C and reacted for 2 h. After the reaction was completed, the mixture was cooled to room temperature and filtered. The filtrate was then subjected to vacuum distillation (0.2 kPa, 145-147 °C) to obtain 184.8 g of 2-acetamido-5-(4-chlorophenoxy)-trifluorotoluene with a purity of 98.8% and a yield of 92.3%.

[0319] (4) Synthesize compound 8(4-(4-chlorophenoxy)-2-trifluoromethylaniline)

[0320] 166.9 g of 2-acetamido-5-(4-chlorophenoxy)-trifluorotoluene (purity 98.8%, 0.5 mol), 250 g of ethanol, and 73.3 g of sodium hydroxide aqueous solution (NaOH mass concentration 30%, 0.55 mol) were added to a reaction flask. The temperature was raised to 70 °C, and the reaction was carried out for 3 h. The solvent was removed under negative pressure while maintaining the temperature below 70 °C. 97.8 g of water was added to the reaction flask and stirred until homogeneous. After separation, the lower oil phase of 150.0 g, namely 4-(4-chlorophenoxy)-2-trifluoromethylaniline, with a purity of 93.1% and a yield of 97.1%, was separated.

[0321] (5) Synthesize compound 9 (4-(4-chlorophenoxy)-2-trifluoromethylaniline diazonium salt)

[0322] Add 80g of water and 80g of concentrated sulfuric acid (H2SO4 mass concentration of 98%, 0.8mol) to the reaction flask, then add 123.6g of 4-(4-chlorophenoxy)-2-trifluoromethylaniline (purity of 93.1%, 0.4mol) dropwise. Raise the temperature to 60℃ and keep it at that temperature for 1h, then cool it to 0℃. Add 96.6g of sodium nitrite aqueous solution (NaNO2 mass concentration of 30%, 0.42mol) dropwise, and keep the temperature at 0℃ with stirring for 1h. Then add 12g of urea solution (urea mass concentration of 10%, 0.02mol) dropwise to destroy the nitrite. Finally, a pale yellow diazonium salt clear solution is obtained and stored at 0℃ for later use.

[0323] (6) Synthesis of compound 10(4-(4-chlorophenoxy)-2-trifluoromethylacetophenone oxime)

[0324] Add 70.9 g of acetaldehyde oxime aqueous solution (C2H5NO mass concentration 50%, 0.6 mol), 144 g of water, 120 g of toluene, 53.3 g of copper sulfate solution (CuSO4 mass concentration 12%, 0.04 mol), and 106.0 g of sodium acetate (purity 99%, 1.28 mol) to the reaction flask. Control the temperature at about 15℃ and add the clear diazonium salt solution obtained in step (5) dropwise over about 2 hours. After the addition is complete, control the temperature at 15℃ and maintain the reaction for 2 hours. After the reaction is complete, allow the mixture to stand and separate the layers. Separate the organic phase, which is a toluene solution of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone oxime. UHPLC-MS (m / z, ESI): 330.0490 (MH) - Theoretical value: 330.0503.

[0325] (7) Synthesis of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone

[0326] The organic phase solution obtained in step (6) was put into a reaction flask and 117.6 g of sulfuric acid aqueous solution (H2SO4 mass concentration of 20%, 0.24 mol) was added. The temperature was raised to 85℃ and kept at that temperature for 4 h. After hydrolysis was completed, the mixture was allowed to stand and separate into layers. The upper organic phase was washed with sodium bicarbonate aqueous solution until neutral. After desolvation, it was distilled under reduced pressure (0.4 kPa, 120-122℃) to obtain 106.5 g of pale yellow liquid, which is 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone with a purity of 97.5%. The yield of the three steps of diazotization reaction-coupling reaction-hydrolysis reaction in steps (5)-(7) was 82.5%.

[0327] Example 8

[0328] A method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone includes the following steps:

[0329] Steps (1)-(5) are the same as in Example 7, yielding compound 9 (4-(4-chlorophenoxy)-2-trifluoromethylaniline diazonium salt), which is stored at 0°C for later use.

[0330] (6) Synthesize compound 10(4-(4-chlorophenoxy)-2-trifluoromethylacetophenone oxime)

[0331] Add 70.9g of acetaldehyde oxime aqueous solution (C2H5NO mass concentration of 50%, 0.6mol), 144g of water, 120g of toluene and 106.0g of sodium acetate (purity of 99%, 1.28mol) to the reaction flask, control the temperature at about 15℃, and add the clear diazonium salt obtained in step (5) and 53.3g of copper sulfate solution (CuSO4 mass concentration of 12%, 0.04mol) dropwise over about 2 hours. After the addition is complete, control the temperature at 20℃ and keep the reaction at this temperature for 2 hours. After the reaction is complete, let it stand and separate into layers, and separate the organic phase, namely the toluene solution of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone oxime.

[0332] (7) Synthesis of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone

[0333] The organic phase solution obtained in step (6) was put into a reaction flask and 117.6 g of sulfuric acid aqueous solution (H2SO4 mass concentration of 20%, 0.24 mol) was added. The temperature was raised to 85℃ and kept at that temperature for 4 h. After hydrolysis was completed, the mixture was allowed to stand and separate into layers. The upper organic phase was washed with sodium bicarbonate aqueous solution until neutral. After desolvation, it was distilled under reduced pressure (0.4 kPa, 120-122℃) to obtain 105.9 g of pale yellow liquid, which is 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone with a purity of 97.0%. The yield of the three steps of diazotization reaction-coupling reaction-hydrolysis reaction in steps (5)-(7) was 81.6%.

[0334] The applicant declares that the present invention illustrates the preparation method of 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone through the above embodiments, but the present invention is not limited to the above embodiments, that is, it does not mean that the present invention must rely on the above embodiments to be implemented. Those skilled in the art should understand that any improvements to the present invention, equivalent substitutions of the raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone, characterized in that, The preparation method includes the following steps: (S1) o-Trifluoromethylaniline reacts with an amino protecting agent to give compound 1; (S2) Compound 1 obtained in step (S1) undergoes a bromination reaction with a brominating reagent to obtain compound 2; (S3) Compound 2 obtained in step (S2) undergoes a deprotection reaction to obtain compound 3; (S4) Compound 3 obtained in step (S3) undergoes a diazotization reaction with nitrite to obtain compound 4; (S5) Compound 4 obtained in step (S4) undergoes a coupling reaction with acetaldehyde oxime to obtain compound 5; (S6) The compound 5 obtained in step (S5) is subjected to a hydrolysis reaction to obtain compound 6; (S7) Compound 6 obtained in step (S6) is etherified with p-chlorophenol to obtain 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone; The reaction formula is as follows: R1 represents an amino protecting group.

2. The preparation method according to claim 1, characterized in that, The amino protecting agent includes any one of acyl chloride compounds and acid anhydride compounds; Preferably, compound 1 is R2 is selected from any one of C1-C6 straight-chain or branched alkyl groups and benzyl groups; Preferably, the amino protecting agent includes acetyl chloride, benzoyl chloride, acetic anhydride or succinic anhydride, and more preferably acetyl chloride; Preferably, the molar ratio of the amino protecting agent to o-trifluoromethylaniline is (1-2):1; Preferably, the temperature of the reaction in step (S1) is 10-90°C; Preferably, the reaction time in step (S1) is 1-6 hours; Preferably, the brominating agent includes any one or a combination of at least two of bromine, hydrogen bromide, sodium bromide, and N-bromosuccinimide; Preferably, the molar ratio of bromine in the brominating reagent to compound 1 is (1-1.5):1; Preferably, the bromination reaction is carried out in the presence of an oxidizing agent; Preferably, the oxidant includes any one or a combination of at least two of hydrogen peroxide, sodium chlorate, and sodium hypochlorite; Preferably, the molar ratio of the oxidizing agent to the brominating agent is (0.9-1.2):1; Preferably, the temperature of the bromination reaction in step (S2) is 40-80°C; Preferably, the bromination reaction in step (S2) takes 2-12 hours; Preferably, the deprotection reaction in step (S3) is carried out in the presence of an alkaline substance; Preferably, the alkaline substance includes any one or a combination of at least two of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, and sodium ethoxide. Preferably, the molar ratio of the alkaline substance to compound 2 is (1-2):1; Preferably, the temperature of the deprotection reaction in step (S3) is 40-90°C; Preferably, the deprotection reaction in step (S3) takes 2-10 hours.

3. The preparation method according to claim 1 or 2, characterized in that, Compound 3 undergoes a salt-forming reaction with an acid, followed by a diazotization reaction with a nitrite to obtain compound 4. Preferably, the acid includes sulfuric acid or hydrochloric acid, and more preferably sulfuric acid; Preferably, the molar ratio of the acid to compound 3 is (1.5-4):1; Preferably, the temperature of the salt-forming reaction is 20-60℃; Preferably, the salt-forming reaction takes 0.5-5 hours; Preferably, the molar ratio of the nitrite to compound 3 is (1.01-1.1):1; Preferably, the temperature of the diazotization reaction in step (S4) is -20°C to 5°C; Preferably, the diazotization reaction in step (S4) takes 0.5-5 hours.

4. The preparation method according to any one of claims 1-3, characterized in that, The molar ratio of acetaldehyde oxime to compound 3 is (1.05-1.8):1; Preferably, the coupling reaction in step (S5) is carried out in the presence of a copper salt catalyst; Preferably, the copper salt catalyst comprises any one or a combination of at least two of copper sulfate, copper chloride, cuprous chloride, and copper acetate; Preferably, the molar ratio of the copper salt catalyst to compound 3 is (0.05-0.15):1; Preferably, the coupling reaction in step (S5) is carried out in the presence of an acid-binding agent; Preferably, the acid-binding agent includes any one or a combination of at least two of alkali metal formate, alkali metal acetate, alkali metal phosphate, alkali metal hydrogen phosphate, and alkali metal dihydrogen phosphate. Preferably, the molar ratio of the acid-binding agent to compound 3 is (1-5):1; Preferably, the temperature of the coupling reaction in step (S5) is from -10°C to 50°C; Preferably, the coupling reaction in step (S5) takes 1-10 hours.

5. The preparation method according to any one of claims 1-4, characterized in that, The hydrolysis reaction is carried out in the presence of an acidic substance; Preferably, the acidic substance includes hydrochloric acid and / or sulfuric acid; Preferably, the H in the acidic substance + The molar ratio of compound 3 to compound 4 is (1-3.2):1; Preferably, the temperature of the hydrolysis reaction in step (S6) is 60-100°C; Preferably, the hydrolysis reaction in step (S6) takes 1-6 hours.

6. The preparation method according to any one of claims 1-5, characterized in that, The 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone is obtained by reacting p-chlorophenol with an alkaline substance to form a salt, excluding the aqueous azeotrope, and then by reacting p-chlorophenol with compound 6 to form an etherification reaction. Alternatively, the 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone is obtained by reacting p-chlorophenol, an alkaline substance, and compound 6 to form an etherification reaction. Preferably, the molar ratio of p-chlorophenol to compound 6 is (0.8-1.5):1; Preferably, the alkaline substance includes any one or a combination of at least two of alkali metal hydroxides, alkali metal carbonates, and alkali metal bicarbonates; Preferably, the molar ratio of the alkaline substance to compound 6 is (1-1.2):1; Preferably, the temperature for the salt-forming reaction of p-chlorophenol with the alkaline substance is 80-130°C; Preferably, the time for the salt-forming reaction of p-chlorophenol with the alkaline substance is 0.5-3 hours; Preferably, the etherification reaction in step (S7) is carried out in the presence of a phase transfer catalyst; Preferably, the phase transfer catalyst comprises any one or a combination of at least two of tetramethylammonium chloride, tetrabutylammonium bromide, and 18-crown ether-6; Preferably, the phase transfer catalyst comprises 0.1-5% of the total mass of compound 6 (100% by mass); Preferably, the temperature of the etherification reaction in step (S7) is 90-200°C; Preferably, the etherification reaction in step (S7) takes 1-10 hours.

7. A method for preparing 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone, characterized in that, The preparation method includes the following steps: (1) o-Trifluoromethylaniline reacts with an amino protecting agent to give compound 1; (2) Compound 1 obtained in step (1) undergoes a bromination reaction with a brominating reagent to obtain compound 2; (3) Compound 2 obtained in step (2) undergoes a deprotection reaction to obtain compound 3; compound 3 undergoes an etherification reaction with p-chlorophenol to obtain compound 8; Alternatively, compound 2 obtained in step (2) undergoes an etherification reaction with p-chlorophenol to obtain compound 7; compound 7 undergoes a deprotection reaction to obtain compound 8; (4) Compound 8 obtained in step (3) undergoes a diazotization reaction with nitrite to obtain compound 9; (5) Compound 9 obtained in step (4) is coupled with acetaldehyde oxime to obtain compound 10; (6) The compound 10 obtained in step (5) is subjected to a hydrolysis reaction to obtain the 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone; The reaction formula is as follows: R1 represents an amino protecting group.

8. The preparation method according to claim 7, characterized in that, Step (3) includes either option ① or option ②; Scheme ① includes the following steps: compound 2 undergoes a deprotection reaction to obtain compound 3; p-chlorophenol undergoes a salt-forming reaction with a basic substance, and after removing the aqueous azeotrope, it undergoes an etherification reaction with compound 3 to obtain compound 8; or, p-chlorophenol, a basic substance, and compound 3 undergo an etherification reaction to obtain compound 8. Scheme ② includes the following steps: the p-chlorophenol undergoes a salt-forming reaction with an alkaline substance to remove the aqueous azeotrope, and then undergoes an etherification reaction with compound 2 to obtain compound 7; or, the p-chlorophenol, the alkaline substance, and compound 2 undergo an etherification reaction to obtain compound 7; and compound 7 undergoes a deprotection reaction to obtain compound 8. Preferably, in scheme ①, the molar ratio of p-chlorophenol to compound 3 is (0.8-1.5):1; Preferably, in scheme ①, the molar ratio of the alkaline substance to compound 3 is (1-1.2):1; Preferably, in scheme ②, the molar ratio of p-chlorophenol to compound 2 is (0.8-1.5):1; Preferably, in scheme ②, the molar ratio of the alkaline substance to compound 2 is (1-1.2):1; Preferably, in Scheme ① and Scheme ②, the temperature at which p-chlorophenol reacts with the alkaline substance to form a salt is independently 80-130℃. Preferably, in schemes ① and ②, the time for the salt-forming reaction of p-chlorophenol with the alkaline substance is independently 0.5-3 hours. Preferably, the etherification reaction in step (3) is carried out in the presence of a copper-based catalyst; Preferably, the copper-based catalyst comprises any one or a combination of at least two of the following: copper powder, cuprous chloride, cuprous bromide, cuprous iodide, copper chloride, copper sulfate, cuprous oxide, copper oxide, and ketone acetate. Preferably, in scheme ①, the mass of the copper-based catalyst is 1-5% based on the mass of compound 3 being 100%; Preferably, in scheme ②, the mass of the copper-based catalyst is 1-5% based on the mass of compound 2 being 100%; Preferably, the etherification reaction in step (3) is carried out in the presence of a phase transfer catalyst; Preferably, the phase transfer catalyst comprises any one or a combination of at least two of tetramethylammonium chloride, tetrabutylammonium bromide, and 18-crown ether-6; Preferably, in scheme ①, based on the mass of compound 3 being 100%, the mass of the phase transfer catalyst is 0.1-5%; Preferably, in scheme ②, the mass of the phase transfer catalyst is 0.1-5% based on the mass of compound 2 being 100%; Preferably, the temperature of the etherification reaction in step (3) is 90-200℃; Preferably, the etherification reaction in step (3) takes 1-10 hours; Preferably, the deprotection reaction in step (3) is carried out in the presence of an alkaline substance; Preferably, the alkaline substance in the deprotection reaction includes any one or a combination of at least two of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium methoxide, and sodium ethoxide. Preferably, in scheme ②, the molar ratio of the basic substance in the deprotection reaction to compound 7 is (1-2):1; Preferably, the temperature of the deprotection reaction in step (3) is 40-90℃; Preferably, the deprotection reaction in step (3) takes 2-10 hours.

9. The preparation method according to claim 7 or 8, characterized in that, In step (4), compound 8 undergoes a salt formation reaction with an acid, and then undergoes a diazotization reaction with a nitrite to obtain compound 9; Preferably, the acid includes sulfuric acid or hydrochloric acid, and more preferably sulfuric acid; Preferably, the molar ratio of the acid to compound 8 is (1.5-4):1; Preferably, the temperature of the salt-forming reaction is 20-60℃; Preferably, the salt-forming reaction takes 0.5-5 hours; Preferably, the molar ratio of the nitrite to compound 8 is (1.01-1.1):1; Preferably, the temperature of the diazotization reaction in step (4) is -20°C to 5°C; Preferably, the diazotization reaction in step (4) takes 0.5-5 hours; Preferably, the molar ratio of acetaldehyde oxime to compound 8 is (1.05-1.8):1; Preferably, the coupling reaction in step (5) is carried out in the presence of a copper salt catalyst; Preferably, the copper salt catalyst comprises any one or a combination of at least two of copper sulfate, copper chloride, cuprous chloride, and copper acetate; Preferably, the molar ratio of the copper salt catalyst to compound 8 is (0.05-0.15):1; Preferably, the coupling reaction in step (5) is carried out in the presence of an acid-binding agent; Preferably, the acid-binding agent includes any one or a combination of at least two of alkali metal formate, alkali metal acetate, alkali metal phosphate, alkali metal hydrogen phosphate, and alkali metal dihydrogen phosphate. Preferably, the molar ratio of the acid-binding agent to compound 8 is (1-5):1; Preferably, the temperature of the coupling reaction in step (5) is -10°C to 50°C; Preferably, the coupling reaction in step (5) takes 1-10 hours.

10. The preparation method according to any one of claims 7-9, characterized in that, The hydrolysis reaction described in step (6) is carried out in the presence of an acidic substance; Preferably, the acidic substance includes hydrochloric acid and / or sulfuric acid; Preferably, the H in the acidic substance + The molar ratio of compound 8 to compound 8 is (1-3.2):1; Preferably, the temperature of the hydrolysis reaction in step (6) is 60-100℃; Preferably, the hydrolysis reaction in step (6) takes 1-6 hours.

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