Preparation method of pyraclostrobin intermediate

Abstract

The invention discloses a preparation method of a pyraclostrobin intermediate, and particularly provides a preparation method of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl) phenyl) ethanone. The preparation method provided by the invention has one or more advantages as follows: (1) the used raw materials are mature industrial chemical raw materials and are low in price, low in process cost and relatively strong in market advantage; (2) the process is simple, and the related processes are mature chemical processes; and (3) the reaction mechanism is clear, the reaction yield is high, and the selectivity is good.

Description

Technical Field

[0001] This invention relates to the field of organic chemistry, and specifically to a method for preparing a fluopyram intermediate. Background Technology

[0002] Chlorfenapyr is a triazole fungicide. As a C14-demethylation inhibitor in sterol biosynthesis, it has broad-spectrum, high-efficiency, systemic, eradicative, and protective effects. It exhibits outstanding biological activity, especially against a variety of difficult-to-control fungal diseases, and can significantly enhance the control of diseases in field crops and more than 60 economic crops, such as corn, cereals, soybeans, and other field crops, as well as economic crops such as bell peppers and grapes. It can also be used in lawn and seed treatment.

[0003] Patent WO2013007767A1 discloses a four-step reaction of etherification, acylation, epoxidation and ring-opening substitution to obtain chlorfluazuron from 2-bromo-5-fluoro-trifluorotoluene as the starting material. The intermediate 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)ethyl ketone is the key building block for the synthesis of chlorfluazuron. The starting material 2-bromo-5-fluoro-trifluorotoluene is a fluorobenzene compound, which is difficult to prepare and expensive. Summary of the Invention

[0004] The technical problem this invention aims to solve is to overcome the problems of complex reaction processes and high costs in the preparation of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)ethyl ketone using 2-bromo-5-fluorotrifluorotoluene. This invention provides a method for preparing a fluopyram intermediate, specifically a method for preparing 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)ethyl ketone. This method uses m-trifluoromethylphenol as a raw material. After protecting the phenolic hydroxyl group with acetyl chloride, it is first brominated with a brominating reagent [Br] to generate 4-bromo-3-(trifluoromethyl)phenyl acetate. Then, a Grignard reagent is prepared using magnesium strips, followed by acetylation to generate 4-acetyl-3-(trifluoromethyl)phenyl acetate. Subsequently, deprotection is performed under acidic conditions, and finally, a coupling reaction is carried out with p-dichlorobenzene to generate 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)ethyl ketone. The preparation method provided by the present invention has one or more of the following advantages: (1) The raw materials used are all mature industrial chemical raw materials, which are inexpensive, have low process costs, and have strong market advantages; (2) The process is simple, and the processes involved are all mature chemical processes; (3) The reaction mechanism is clear, the reaction yield is high, and the selectivity is good.

[0005] The present invention solves the above-mentioned technical problems through the following technical solutions.

[0006] This invention provides a method for preparing 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)ethyl ketone, which includes the following steps:

[0007]

[0008] (1) Esterification reaction:

[0009] In organic solvents, acyl chlorides The compound of formula I was prepared by esterification with m-trifluoromethylphenol, wherein R is methyl, phenyl or p-methylphenyl;

[0010] (2) Bromination reaction:

[0011] In an organic solvent, in the presence of a catalyst, the compound of formula I is subjected to a bromination reaction with a brominating reagent [Br] to obtain the compound of formula II;

[0012] (3) Grignard reaction:

[0013] In an organic solvent, in the presence of an initiator, the compound of formula II is subjected to a Grignard reaction with magnesium to prepare the compound of formula III.

[0014] (4) Acetylation reaction:

[0015] Compound III and an acetylation reagent are acetylated in an organic solvent to prepare compound IV;

[0016] (5) Hydrolysis reaction:

[0017] The compound of formula IV was hydrolyzed under the action of acid to obtain 2-trifluoromethyl-4-hydroxyacetophenone;

[0018] (6) Coupling reaction:

[0019] 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)ethyl ketone was prepared by coupling 2-trifluoromethyl-4-hydroxyacetophenone and p-dichlorobenzene in an organic solvent under the conditions of copper catalyst and base.

[0020] In step (1), the acyl chloride is preferably acetyl chloride or benzoyl chloride.

[0021] In step (1), the molar ratio of the acyl chloride to the m-trifluoromethylphenol is preferably (1.0~1.5):1, more preferably (1.0~1.1):1, for example 1.1:1.

[0022] In step (1), the acyl chloride is preferably added dropwise, and the dropwise addition rate is preferably 1~10 g / min, more preferably 2~5 g / min, for example 3 g / min.

[0023] In step (1), the organic solvent can be a commonly used organic solvent for this type of reaction in the art, preferably a halogenated hydrocarbon solvent, more preferably one or more of carbon tetrachloride, chloroform, dichloromethane and 1,2-dichloroethane, and even more preferably carbon tetrachloride.

[0024] In step (1), the volume molar ratio of the organic solvent to the m-trifluoromethylphenol is preferably (200~300 mL):1 mol, more preferably (200~250 mL):1 mol, and even more preferably (200~205 mL):1 mol.

[0025] In step (1), the reaction temperature of the esterification reaction can be the conventional reaction temperature for such reactions in the art, preferably 0~20℃, and more preferably 0~10℃.

[0026] In step (1), the esterification reaction is preferably terminated when 4-chlorotrifluorotoluene disappears, and the reaction time of the esterification reaction is preferably 0.5 to 2 hours, for example 0.9 to 1.1 hours or 1.3 to 1.4 hours.

[0027] In step (1), the esterification reaction preferably includes the following steps: adding acyl chloride dropwise to a mixture of m-trifluoromethylphenol and an organic solvent at 0~20°C, preferably at 0~10°C to carry out the esterification reaction.

[0028] In step (2), the brominating agent [Br] can be a brominating agent conventional for such reactions in the art, preferably one or more of liquid bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin and carbon tetrabromide; more preferably liquid bromine, N-bromosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin.

[0029] In step (2), the molar ratio of the brominating reagent [Br] to the compound of formula I is preferably (0.5~3):1, more preferably (0.8~2):1, and even more preferably (0.8~1.5):1, for example 0.8:1 or 1.5:1.

[0030] In step (2), when the brominating reagent [Br] is liquid bromine, the liquid bromine is preferably added dropwise, and the dropwise addition rate is preferably 0.1~3 g / min, more preferably 0.5~1.5 g / min, for example 1 g / min.

[0031] In step (2), the catalyst may be a conventional catalyst for such reactions in the art, preferably one or both of iron powder and concentrated sulfuric acid.

[0032] In step (2), the molar ratio of the brominating agent [Br] to the catalyst can be a conventional molar ratio for such reactions in the art, preferably (0.25~30):1, more preferably (0.5~20):1, for example 15:1, 1.25:1 or 0.7:1.

[0033] In step (2), the combination of the brominating reagent [Br] and the catalyst in the bromination reaction can be any of the following:

[0034] Combination (1): Liquid bromine and iron powder;

[0035] Combination (2): N-bromosuccinimide and concentrated sulfuric acid;

[0036] Combination (3): 1,3-dibromo-5,5-dimethylhydantoin and concentrated sulfuric acid.

[0037] In step (2), in the combination (1), the molar ratio of the brominating agent [Br] to the catalyst is preferably (10~30):1, more preferably (10~20):1, for example 15:1.

[0038] In step (2), the molar ratio of the brominating agent [Br] to the catalyst in the combination (2) is preferably (1~3):1, more preferably (1~2):1, for example 1.25:1.

[0039] In step (2), in the combination (3), the molar ratio of the brominating agent [Br] to the catalyst is preferably (0.25~1):1, more preferably (0.5~1):1, for example 0.7:1.

[0040] In step (2), the organic solvent can be a commonly used organic solvent for this type of reaction in the art, preferably a halogenated hydrocarbon solvent, more preferably one or more of carbon tetrachloride, chloroform, dichloromethane and 1,2-dichloroethane, and more preferably carbon tetrachloride.

[0041] In step (2), the volume molar ratio of the organic solvent to the compound of formula I is preferably (200~400 mL):1 mol, more preferably (200~300 mL):1 mol, for example (250~260 mL):1 mol.

[0042] In step (2), the reaction temperature of the bromination reaction can be the conventional reaction temperature for this type of reaction in the art, preferably 20℃~60℃, more preferably 40℃~60℃, for example 40℃ or 60℃.

[0043] In step (2), the bromination reaction preferably ends with the disappearance of the compound of formula I.

[0044] Preferably, when the combination of the brominating agent [Br] and the catalyst is combination (1), the reaction time of the bromination reaction is preferably 4 to 12 hours, more preferably 4 to 8 hours, for example 6 hours;

[0045] When the combination of the brominating agent [Br] and the catalyst is combination (2), the reaction time of the bromination reaction is preferably 3 to 8 hours;

[0046] When the combination of the brominating agent [Br] and the catalyst is combination (3), the reaction time of the bromination reaction is preferably 2 to 5 hours.

[0047] In step (2), the bromination reaction is preferably selected from any of the following schemes:

[0048] Scheme 1: Dissolve the catalyst and compound of formula I in an organic solvent, heat to 20℃~60℃, preferably 40℃~60℃, and add brominating reagent [Br] dropwise to carry out bromination reaction;

[0049] Option 2: Dissolve the compound of formula I, the catalyst, and the brominating reagent [Br] in an organic solvent, and heat to 20℃~60℃, preferably 40℃~60℃, to carry out the bromination reaction.

[0050] In step (2), the bromination reaction preferably includes a post-treatment, wherein the post-treatment method is selected from one or more of quenching, filtration, phase separation and distillation.

[0051] Preferably, in step (2), when the combination of the brominating agent [Br] and the catalyst is combination (1), the post-treatment method is quenching, filtration, phase separation, and distillation; in the quenching, the quenching agent is preferably an aqueous sodium sulfite solution. The mass percentage concentration of the aqueous sodium sulfite solution is preferably 5% to 25%, more preferably 5% to 10%, for example, 10%.

[0052] Preferably, in step (2), when the combination of the brominating agent [Br] and the catalyst is combination (2), the post-treatment method is filtration and distillation.

[0053] Preferably, in step (2), when the combination of the brominating agent [Br] and the catalyst is combination (3), the post-treatment method is filtration and distillation.

[0054] In step (3), the molar ratio of magnesium to the compound of formula II is preferably (1.0~2.5):1, more preferably (1.5~2.0):1, for example 1.5:1.

[0055] In step (3), the initiator can be a conventional initiator for such reactions in the art, preferably iodine.

[0056] In step (3), the molar ratio of the initiator to the compound of formula II is preferably (0.1~1):1, more preferably (0.2~0.5):1, for example 0.2:1.

[0057] In step (3), the organic solvent can be a commonly used organic solvent for this type of reaction in the art, preferably an ether solvent, and more preferably one or more of tetrahydrofuran, methyltetrahydrofuran and diethyl ether, such as tetrahydrofuran or methyltetrahydrofuran.

[0058] In step (3), the volume molar ratio of the organic solvent to the compound of formula II is preferably (50~500 mL):1 mol, more preferably (300~500 mL):1 mol, for example 400 mL:1 mol.

[0059] In step (3), the reaction temperature of the Grignard reaction can be the conventional reaction temperature of this type of reaction in the art, preferably 25℃~100℃, more preferably 30℃~80℃, for example 40℃.

[0060] In step (3), the Grignard reaction preferably ends with the disappearance of compound II, and the reaction time is preferably 10 to 20 hours, more preferably 10 to 15 hours, for example 12 hours.

[0061] In step (3), the Grignard reaction preferably includes the following steps: at 25°C to 100°C, preferably at 30°C to 80°C, the compound of formula II, magnesium and initiator are mixed in an organic solvent, and then magnesium and organic solvent are added again to carry out the Grignard reaction.

[0062] In step (3), the concentration of the compound of formula III is preferably 1.0 M to 3.0 M, more preferably 1.5 M to 2.0 M, for example 1.5 M, wherein the concentration is the concentration of the compound of formula III in the organic solvent.

[0063] In step (4), the acetylation reagent can be a conventional acetylation reagent for this type of reaction in the art, preferably one or both of acid anhydride reagents and acyl chloride reagents, and more preferably an acid anhydride reagent. The acid anhydride reagent is preferably acetic anhydride. The acyl chloride reagent is preferably acetyl chloride.

[0064] In step (4), the molar ratio of the acetylation reagent to the compound of formula III is preferably (1.0~2.0):1, more preferably (1.1~1.8):1, for example 1.2:1.

[0065] In step (4), the organic solvent can be a commonly used organic solvent for this type of reaction in the art, preferably an ether solvent, more preferably diethyl ether, 2-methyltetrahydrofuran or tetrahydrofuran, and more preferably tetrahydrofuran.

[0066] In step (4), the volume molar ratio of the organic solvent to the compound of formula III is preferably (50~200 mL):1 mol, more preferably (100~150 mL):1 mol, for example 100 mL:1 mol.

[0067] In step (4), the compound of formula III is preferably added dropwise, and the dropwise addition rate is preferably 0.5~3 mol / h, more preferably 1~2 mol / h.

[0068] In step (4), the reaction temperature of the acetylation reaction is preferably 0℃~30℃, more preferably 5℃~20℃, for example 5℃~10℃.

[0069] In step (4), the acetylation reaction preferably ends with the disappearance of compound III, and the reaction time of the acetylation reaction is preferably 2 to 8 hours, more preferably 2 to 6 hours, for example 3 hours.

[0070] In step (4), the acetylation reaction preferably includes the following steps: adding the compound of formula III dropwise to a mixture of acetylation reagent and organic solvent at 0°C to 30°C, preferably at 5°C to 20°C, to carry out the acetylation reaction.

[0071] In step (4), the acetylation reaction preferably includes post-treatment, and the post-treatment is preferably one or more of quenching, phase separation and distillation, and more preferably quenching, phase separation and distillation.

[0072] In step (4), when the post-processing method is quenching, the quenching agent is preferably water.

[0073] In step (5), the acid may be an acid conventional to such reactions in the art, preferably hydrochloric acid and / or sulfuric acid, and more preferably sulfuric acid.

[0074] In step (5), the acid is preferably added in the form of an aqueous acid solution, and the mass percentage concentration of the acid in the aqueous acid solution is preferably 5% to 36%, more preferably 10% to 25%, for example 10% or 15%.

[0075] In step (5), the molar ratio of the acid to the compound of formula IV is preferably (1.0~2.5):1, more preferably (1.0~2.0):1, for example 1.5:1 or 1.1:1.

[0076] In step (5), the reaction temperature of the hydrolysis reaction is preferably 50℃~150℃, more preferably 70℃~100℃, for example 85℃.

[0077] In step (5), the hydrolysis reaction preferably ends with the disappearance of compound IV, and the reaction time is preferably 3 to 10 hours, more preferably 5 to 8 hours, for example 6 hours.

[0078] In step (5), the hydrolysis reaction preferably includes the following steps: at 50°C to 150°C, preferably at 70°C to 100°C, the compound of formula IV is mixed with an acid and then subjected to a hydrolysis reaction.

[0079] In step (5), the hydrolysis reaction preferably includes post-treatment, and the post-treatment method is preferably one or both of phase separation and distillation.

[0080] In step (6), the copper catalyst can be a conventional copper catalyst for this type of reaction in the art, preferably one or more of cuprous chloride, cuprous iodide, cuprous bromide, cuprous chloride and cuprous bromide, for example, cuprous chloride, cuprous iodide or cuprous bromide.

[0081] In step (6), the molar ratio of the copper catalyst to the 2-trifluoromethyl-4-hydroxyacetophenone is preferably (0.1~0.5):1, more preferably (0.1~0.2):1, for example 0.1:1, 0.15:1, 0.2:1.

[0082] In step (6), the base may be a base conventional to such reactions in the art, preferably one or more of potassium carbonate, sodium acetate, sodium hydroxide and potassium phosphate, such as potassium carbonate or sodium acetate.

[0083] In step (6), the molar ratio of the base to the 2-trifluoromethyl-4-hydroxyacetophenone is preferably (1.0~2.5):1, more preferably (1.5~2.0):1, for example 1.5:1.

[0084] In step (6), the organic solvent can be a conventional organic solvent for this type of reaction in the art, preferably an amide solvent and / or a sulfone solvent. The amide solvent is preferably N,N-dimethylformamide and / or N-methylpyrrolidone, more preferably N,N-dimethylformamide. The sulfone solvent is preferably dimethyl sulfoxide and / or sulfolane, more preferably dimethyl sulfoxide.

[0085] In step (6), the volume molar ratio of the organic solvent to the 2-trifluoromethyl-4-hydroxyacetophenone is preferably (300~500 mL):1 mol, more preferably (350~450 mL):1 mol, for example 400 mL:1 mol.

[0086] In step (6), the reaction temperature of the coupling reaction is preferably 25℃~100℃, more preferably 50℃~80℃, for example 60℃.

[0087] In step (6), the coupling reaction preferably ends with the disappearance of 2-trifluoromethyl-4-hydroxyacetophenone, and the reaction time of the coupling reaction is preferably 2 to 10 hours, more preferably 2 to 5 hours, for example 3 hours.

[0088] In step (6), the coupling reaction preferably includes the following steps: 2-trifluoromethyl-4-hydroxyacetophenone, p-dichlorobenzene, copper catalyst and base are placed in an organic solvent at 25°C to 100°C, preferably 50°C to 80°C, for reaction.

[0089] In step (6), the coupling reaction preferably includes post-treatment, and the post-treatment method is preferably one or both of filtration and distillation.

[0090] The present invention also provides a method for preparing a compound of formula I, comprising the following steps:

[0091] In organic solvents, acyl chlorides The compound of formula I was prepared by esterification with m-trifluoromethylphenol.

[0092] ;

[0093] Where R is methyl, phenyl, or p-methylphenyl;

[0094] The operation and conditions for the esterification reaction are the same as described above.

[0095] The present invention also provides a method for preparing a compound of formula II, comprising the following steps:

[0096] In an organic solvent, in the presence of a catalyst, the compound of formula I is subjected to a bromination reaction with a brominating reagent [Br] to obtain the compound of formula II;

[0097] ;

[0098] Where R is methyl, phenyl, or p-methylphenyl;

[0099] The operation and conditions for the bromination reaction are the same as described above.

[0100] This invention also provides a method for preparing a compound of formula III, comprising the following steps:

[0101] In an organic solvent, in the presence of an initiator, the compound of formula II is subjected to a Grignard reaction with magnesium to prepare the compound of formula III.

[0102] ;

[0103] Where R is methyl, phenyl, or p-methylphenyl;

[0104] The operation and conditions for the Grignard reaction are the same as described above.

[0105] The present invention also provides a method for preparing a compound of formula IV, comprising the following steps:

[0106] Compound III and an acetylation reagent are acetylated in an organic solvent to prepare compound IV;

[0107] ;

[0108] Where R is methyl, phenyl, or p-methylphenyl;

[0109] The operation and conditions for the acetylation reaction are the same as described above.

[0110] The present invention also provides a method for preparing 2-trifluoromethyl-4-hydroxyacetophenone, which includes the following steps:

[0111] The compound of formula IV was hydrolyzed under the action of acid to obtain 2-trifluoromethyl-4-hydroxyacetophenone;

[0112] ;

[0113] Where R is methyl, phenyl, or p-methylphenyl;

[0114] The operation and conditions of the hydrolysis reaction are the same as described above.

[0115] The present invention also provides a method for preparing 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)ethyl ketone, which includes the following steps:

[0116] In the presence of a copper catalyst and a base, 2-trifluoromethyl-4-hydroxyacetophenone and p-dichlorobenzene were coupled together in an organic solvent to prepare 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)acetophenone.

[0117] ;

[0118] The operation and conditions for the coupling reaction are the same as described above.

[0119] Without violating common sense in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0120] The reagents and raw materials used in this invention are all commercially available.

[0121] The positive and progressive effects of this invention are due to one or more of the following:

[0122] 1. The synthesis method provided by this invention uses m-trifluoromethylphenol produced by the enterprise as raw material. The raw material is inexpensive and the process cost is low, giving it a strong market advantage.

[0123] 2. The synthesis method provided by the invention involves 6 steps, including esterification, bromination, Grignard reaction, acetylation, ester hydrolysis and coupling reaction, to prepare high-purity 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)ethyl ketone. All processes involved are mature chemical processes and are simple.

[0124] 3. The reaction mechanism of this invention is clear, the reaction yield is high, and the selectivity is good. Detailed Implementation

[0125] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0126] Example 1

[0127] (1) Esterification reaction

[0128] 162 g (1 mol) of m-trifluoromethylphenol and 324 g (203 mL) of carbon tetrachloride were added to a reaction flask. 86.4 g (1.1 mol) of acetyl chloride was then added dropwise with stirring at 0–10 °C at a rate of 3 g / min. After the addition was complete, the mixture was kept at this temperature and stirred for half an hour. After the reaction was complete, carbon tetrachloride was recovered by distillation under normal pressure. The distillation yielded 198 g of phenyl 3-(trifluoromethyl)acetate, with a GC purity of 99.4% and a yield of 96%. 1 HNMR (CDCl3, 300MHz): 7.50 (d, 2H), 7.38 (s, 1H), 7.31-7.29(m, 1H), 2.32 (s, 3H) ppm.

[0129] (2) Bromination reaction

[0130] 204 g (1 mol) of phenyl 3-(trifluoromethyl)acetate, 5.6 g (0.1 mol) of iron powder, and 408 g (256 mL) of carbon tetrachloride solvent were added to a reaction flask. The mixture was heated to 40 °C, and 240 g (1.5 mol) of liquid bromine was added dropwise with stirring at a rate of 1 g / min (4 h). After the addition was complete, the reaction was continued for 2 hours. After the reaction was complete, the liquid bromine was recovered by distillation at atmospheric pressure. The residue was quenched with 500 g of 10% sodium sulfite, filtered to remove the iron powder, and the filtrate was separated. 221 g of phenyl 4-bromo-3-(trifluoromethyl)acetate was distilled off from the organic phase. The GC purity was 98.6%, and the yield was 78%.

[0131] (3) Grignard reaction

[0132] 283 g (1 mol) of 4-bromo-3-(trifluoromethyl)phenyl acetate, 6 g (0.25 mol) of magnesium ribbon, 0.5 g (0.2 mol) of iodine, and 100 mL of tetrahydrofuran were added to a reaction flask, and the reaction was initiated by stirring at 40 °C. After successful Grignard reaction initiation, 30 g (1.25 mol) of magnesium ribbon and 300 mL of tetrahydrofuran were added to the flask, and the reaction was stirred at 40 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature to obtain the Grignard reagent for later use.

[0133] (4) Acetylation reaction

[0134] 122 g (1.2 mol) of acetic anhydride and 120 mL of tetrahydrofuran solvent were added to a reaction flask. The temperature was lowered to 10 °C, and then the Grignard reagent (1 mol, c = 1.5 M in THF) prepared above was added dropwise to the reaction flask. The reaction temperature was controlled at 5 °C to 10 °C. The Grignard reagent was added dropwise over 1 hour. The reaction was stirred for 2 hours. After the reaction was completed, 100 mL of water was added to quench the reaction. The phases were separated, and the tetrahydrofuran was recovered by distillation of the organic phase, yielding 221 g of 4-acetyl-3-(trifluoromethyl)acetic acid phenyl ester with an LC purity of 97.7% and a yield of 88%.

[0135] (5) Hydrolysis reaction

[0136] 246 g (1 mol) of 4-acetyl-3-(trifluoromethyl)phenyl acetate and 1500 g of 10% (1.5 mol) dilute sulfuric acid were added to a reaction flask, and the mixture was stirred at 85°C for 6 hours. After the reaction was completed, the reaction solution was cooled and the phases were separated. Distillation yielded 200 g of 2-trifluoromethyl-4-hydroxyacetophenone, with a purity of 99.5% and a yield of 98%.

[0137] (6) Coupling reaction

[0138] 400 mL of N,N-dimethylformamide, 19.8 g (0.2 mol) cuprous chloride, 208.5 g (1.5 mol) potassium carbonate, 204 g (1 mol) 2-trifluoromethyl-4-hydroxyacetophenone, and 161.7 g (1.1 mol) p-dichlorobenzene were added to a reaction flask. The mixture was stirred at 80 °C for 3 hours. After the reaction was completed, the reaction solution was cooled and filtered. The solvent and p-dichlorobenzene were recovered from the filtrate to obtain 298.3 g of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)acetophenone, with a purity of 98.6% and a yield of 94%. 1HNMR (CDCl3, 300MHz) δ7.50 (d, 1H) ,7.40-7.35 (m, 2H) ,7.31 (d, 1H) ,7.12(dd, 2.5Hz, 1H) ,7.02-6.98 (m, 2H) ,2.57 (s, 3H).

[0139] Example 2

[0140] (1) Esterification reaction

[0141] 162 g of m-trifluoromethylphenol (1 mol) and 324 g (203 mL) of carbon tetrachloride were added to a reaction flask. 154.6 g (1.1 mol) of benzoyl chloride was then added dropwise with stirring at 0–10 °C at a rate of 3 g / min. After the addition was complete, the mixture was kept at this temperature and stirred for half an hour. After the reaction was complete, carbon tetrachloride was recovered by distillation under normal pressure. The distillation yielded 252.8 g of phenyl 3-(trifluoromethyl)benzoate with a GC purity of 99.2% and a yield of 94%.

[0142] (2) Bromination reaction

[0143] 266 g (1 mol) of phenyl 3-(trifluoromethyl)benzoate, 118 g (1.2 mol) of concentrated sulfuric acid, 267 g (1.5 mol) of N-bromosuccinimide, and 408 g (256 mL) of carbon tetrachloride solvent were added to a reaction flask. The mixture was heated to 60 °C and stirred for 3–8 h. After the reaction was complete, the succinimide was removed by filtration, and 235 g of phenyl 4-bromo-3-(trifluoromethyl)benzoate was distilled off from the filtrate. The GC purity was 99%, and the yield was 67%.

[0144] (3) Grignard reaction

[0145] 345 g (1 mol) of phenyl 4-bromo-3-(trifluoromethyl)benzoate, 6 g (0.25 mol) of magnesium ribbon, 0.5 g (0.2 mol) of iodine, and 100 mL of methyltetrahydrofuran were added to a reaction flask, and the reaction was initiated by stirring at 40 °C. After successful Grignard reaction initiation, 30 g (1.25 mol) of magnesium ribbon and 300 mL of methyltetrahydrofuran were added to the flask, and the reaction was stirred at 40 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature to obtain the Grignard reagent for later use.

[0146] (4) Acetylation reaction

[0147] 122 g (1.2 mol) of acetic anhydride and 120 mL of tetrahydrofuran solvent were added to a reaction flask. The mixture was cooled to 10 °C, and the Grignard reagent (c = 1.5 M in MeTHF) prepared above was added dropwise to the reaction flask. The reaction temperature was controlled at 5 °C to 10 °C. The Grignard reagent was added dropwise over 1 hour. The mixture was stirred and reacted for 2 hours. After the reaction was completed, 100 mL of water was added to quench the reaction. The phases were separated, and the organic phase was distilled to recover methyltetrahydrofuran, yielding 234 g of phenyl 4-acetyl-3-(trifluoromethyl)benzoate. The LC purity was 98.1%, and the yield was 74%.

[0148] (5) Hydrolysis reaction

[0149] 308 g (1 mol) of phenyl 4-acetyl-3-(trifluoromethyl)benzoate and 980 g (1.5 mol) of 15% dilute sulfuric acid were added to a reaction flask, and the mixture was stirred at 85°C for 6 hours. After the reaction was completed, the reaction solution was cooled and separated into phases, and then distilled to obtain 196 g of 2-trifluoromethyl-4-hydroxyacetophenone with a purity of 99.5% and a yield of 96%.

[0150] (6) Coupling reaction

[0151] 400 mL of dimethyl sulfoxide, 28.5 g (0.15 mol) cuprous iodide, 123 g (1.5 mol) sodium acetate, 204 g (1 mol) 2-trifluoromethyl-4-hydroxyacetophenone, and 161.7 g (1.1 mol) p-dichlorobenzene were added to a reaction flask. The mixture was stirred at 60 °C for 3 hours. After the reaction was completed, the reaction solution was cooled and filtered. The solvent and p-dichlorobenzene were recovered from the filtrate, and the solution was further purified by vacuum distillation to obtain 283 g of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)acetophenone, with a purity of 99.5% and a yield of 89%.

[0152] Example 3

[0153] (1) Esterification reaction

[0154] 162 g (1 mol) of m-trifluoromethylphenol and 324 g (203 mL) of carbon tetrachloride were added to a reaction flask. 154.6 g (1.1 mol) of benzoyl chloride was then added dropwise with stirring at 0–10 °C at a rate of 3 g / min. After the addition was complete, the mixture was kept at this temperature and stirred for half an hour. After the reaction was complete, carbon tetrachloride was recovered by distillation under normal pressure. The distillation yielded 247.7 g of phenyl 3-(trifluoromethyl)benzoate with a GC purity of 99.2% and a yield of 92%.

[0155] (2) Bromination reaction

[0156] 266 g (1 mol) of phenyl 3-(trifluoromethyl)benzoate, 118 g (1.2 mol) of concentrated sulfuric acid, 229 g (0.8 mol) of 1,3-dibromo-5,5-dimethylhydantoin, and 408 g (256 mL) of carbon tetrachloride solvent were added to a reaction flask. The mixture was heated to 60 °C and stirred for 2–5 h. After the reaction was complete, the hydantoin was removed by filtration. 258.9 g of phenyl 4-bromo-3-(trifluoromethyl)benzoate was distilled off from the filtrate. GC purity: 98.6%, yield: 74%.

[0157] (3) Grignard reaction

[0158] 345 g (1 mol) of phenyl 4-bromo-3-(trifluoromethyl)benzoate, 6 g (0.25 mol) of magnesium ribbon, 0.5 g (0.2 mol) of iodine, and 100 mL of methyltetrahydrofuran were added to a reaction flask, and the reaction was initiated by stirring at 40 °C. After successful Grignard reaction initiation, 30 g (1.25 mol) of magnesium ribbon and 300 mL of methyltetrahydrofuran were added to the flask, and the reaction was stirred at 40 °C for 12 hours. After the reaction was completed, the mixture was cooled to room temperature to obtain the Grignard reagent for later use.

[0159] (4) Acetylation reaction

[0160] 122 g (1.2 mol) of acetic anhydride and 120 mL of tetrahydrofuran solvent were added to a reaction flask. The mixture was cooled to 10 °C, and the Grignard reagent (c = 1.5 M in MeTHF) prepared above was added dropwise to the reaction flask. The reaction temperature was controlled at 5 °C to 10 °C. The Grignard reagent was added dropwise over 1 hour. The mixture was stirred and reacted for 2 hours. After the reaction was completed, 100 mL of water was added to quench the reaction. The phases were separated, and the organic phase was distilled to recover methyltetrahydrofuran, yielding 234 g of phenyl 4-acetyl-3-(trifluoromethyl)benzoate, with a yield of 76%.

[0161] (5) Hydrolysis reaction

[0162] 308 g (1 mol) of phenyl 4-acetyl-3-(trifluoromethyl)benzoate and 735 g (1.1 mol) of 15% dilute sulfuric acid were added to a reaction flask, and the mixture was stirred at 85°C for 6 hours. After the reaction was completed, the reaction solution was cooled and the phases were separated. Distillation yielded 196 g of 2-trifluoromethyl-4-hydroxyacetophenone, with a purity of 99.3% and a yield of 95%.

[0163] (6) Coupling reaction

[0164] 400 mL of dimethyl sulfoxide, 14.3 g (0.1 mol) cuprous bromide, 123 g (1.5 mol) sodium acetate, 204 g (1 mol) 2-trifluoromethyl-4-hydroxyacetophenone, and 161.7 g (1.1 mol) p-dichlorobenzene were added to a reaction flask. The mixture was stirred at 60 °C for 3 hours. After the reaction was completed, the reaction solution was cooled and filtered. The solvent and p-dichlorobenzene were recovered from the filtrate, and the solution was further purified by vacuum distillation to obtain 276 g of 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)acetophenone, with a purity of 99.5% and a yield of 87%.

Claims

1. A method for preparing 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)ethyl ketone, comprising the following steps: ； (1) Esterification reaction: In organic solvents, acyl chlorides The compound of formula I was prepared by esterification with m-trifluoromethylphenol, wherein R is methyl, phenyl or p-methylphenyl; (2) Bromination reaction: In an organic solvent, in the presence of a catalyst, the compound of formula I is subjected to a bromination reaction with a brominating reagent [Br] to obtain the compound of formula II; (3) Grignard reaction: In an organic solvent, in the presence of an initiator, the compound of formula II is subjected to a Grignard reaction with magnesium to prepare the compound of formula III. (4) Acetylation reaction: Compound III and an acetylation reagent are acetylated in an organic solvent to prepare compound IV; (5) Hydrolysis reaction: The compound of formula IV was hydrolyzed under the action of acid to obtain 2-trifluoromethyl-4-hydroxyacetophenone; (6) Coupling reaction: 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)ethyl ketone was prepared by coupling 2-trifluoromethyl-4-hydroxyacetophenone and p-dichlorobenzene in an organic solvent under the conditions of copper catalyst and base.

2. The preparation method according to claim 1, characterized in that, It meets one or more of the following conditions: (1) In step (1), the acyl chloride is acetyl chloride or benzoyl chloride; (2) In step (1), the molar ratio of the acyl chloride to the m-trifluoromethylphenol is (1.0~1.5):1; (3) In step (1), the acyl chloride is added dropwise at a rate of 1~10 g / min; (4) In step (1), the organic solvent is a halogenated hydrocarbon solvent; (5) In step (1), the volume molar ratio of the organic solvent to the m-trifluoromethylphenol is (200~300 mL):1 mol; (6) In step (1), the reaction temperature of the esterification reaction is 0~20℃; (7) In step (1), the reaction time of the esterification reaction is 0.5 to 2 hours; (8) In step (2), the brominating agent [Br] is one or more of liquid bromine, N-bromosuccinimide, 1,3-dibromo-5,5-dimethylhydantoin and carbon tetrabromide; (9) In step (2), the molar ratio of the brominating reagent [Br] to the compound of formula I is (0.5~3):1; (10) In step (2), the catalyst is one or both of iron powder and concentrated sulfuric acid; (11) In step (2), the molar ratio of the brominating agent [Br] to the catalyst is (0.25~30):1; (12) In step (2), the organic solvent is a halogenated hydrocarbon solvent; (13) In step (2), the volume molar ratio of the organic solvent to the compound of formula I is (200~400 mL):1 mol; (14) In step (2), the reaction temperature of the bromination reaction is 20℃~60℃; (15) In step (3), the molar ratio of magnesium to the compound of formula II is (1.0~2.5):1; (16) In step (3), the initiator is iodine; (17) In step (3), the molar ratio of the initiator to the compound of formula II is (0.1~1):1; (18) In step (3), the organic solvent is an ether solvent; (19) In step (3), the volume molar ratio of the organic solvent to the compound of formula II is (50~500 mL):1 mol; (20) In step (3), the reaction temperature of the Grignard reaction is 25℃~100℃; (21) In step (3), the reaction time of the Grignard reaction is 10 to 20 hours; (22) In step (3), the concentration of the compound of formula III is 1.0 M to 3.0 M, wherein the concentration is the concentration of the compound of formula III in the organic solvent; (23) In step (4), the acetylation reagent is one or both of acid anhydride reagents and acyl chloride reagents, preferably acid anhydride reagents; (24) In step (4), the molar ratio of the acetylation reagent to the compound of formula III is (1.0~2.0):1; (25) In step (4), the organic solvent is an ether solvent; (26) In step (4), the volume molar ratio of the organic solvent to the compound of formula III is (50~200 mL):1 mol; (27) In step (4), the compound of formula III is added dropwise at a rate of 0.5 to 3 mol / h; (28) In step (4), the reaction temperature of the acetylation reaction is 0℃~30℃; (29) In step (4), the reaction time of the acetylation reaction is 2 to 8 hours; (30) In step (5), the acid is hydrochloric acid and / or sulfuric acid; (31) In step (5), the acid is added in the form of an aqueous acid solution, and the mass percentage concentration of the acid in the aqueous acid solution is 5% to 36%; (32) In step (5), the molar ratio of the acid to the compound of formula IV is (1.0~2.5):1; (33) In step (5), the reaction temperature of the hydrolysis reaction is 50℃~150℃; (34) In step (5), the reaction time of the hydrolysis reaction is 3~10h; (35) In step (6), the copper catalyst is one or more of cuprous chloride, cuprous iodide, cuprous bromide, cuprous chloride and copper bromide; (36) In step (6), the molar ratio of the copper catalyst to the 2-trifluoromethyl-4-hydroxyacetophenone is (0.1~0.5):1; (37) In step (6), the alkali is one or more of potassium carbonate, sodium acetate, sodium hydroxide and potassium phosphate; (38) In step (6), the molar ratio of the base to the 2-trifluoromethyl-4-hydroxyacetophenone is (1.0~2.5):1; (39) In step (6), the organic solvent is an amide solvent and / or a sulfone solvent; (40) In step (6), the volume molar ratio of the organic solvent to the 2-trifluoromethyl-4-hydroxyacetophenone is (300~500 mL):1 mol; (41) In step (6), the reaction temperature of the coupling reaction is 25℃~100℃; (42) In step (6), the reaction time of the coupling reaction is 2 to 10 hours.

3. The preparation method according to claim 2, characterized in that, It meets one or more of the following conditions: (1) In step (1), the molar ratio of the acyl chloride to the m-trifluoromethylphenol is (1.0~1.1):1; (2) In step (1), the acyl chloride is added dropwise at a rate of 2-5 g / min; (3) In step (1), the organic solvent is one or more of carbon tetrachloride, chloroform, dichloromethane and 1,2-dichloroethane; (4) In step (1), the volume molar ratio of the organic solvent to the m-trifluoromethylphenol is (200~250 mL):1 mol; (5) In step (1), the reaction temperature of the esterification reaction is 0~10℃; (6) In step (1), the reaction time of the esterification reaction is 0.9~1.1 hours or 1.3~1.4 hours; (7) In step (2), the brominating agent [Br] is liquid bromine, N-bromosuccinimide or 1,3-dibromo-5,5-dimethylhydantoin; (8) In step (2), the molar ratio of the brominating reagent [Br] to the compound of formula I is (0.8~2):1; (9) In step (2), when the brominating reagent [Br] is liquid bromine, the liquid bromine is added dropwise at a rate of 0.1~3 g / min; (10) In step (2), the molar ratio of the brominating agent [Br] to the catalyst is (0.5~20):1; (11) In step (2), the combination of the brominating agent [Br] and the catalyst in the bromination reaction is any one of the following: Combination (1): Liquid bromine and iron powder; Combination (2): N-bromosuccinimide and concentrated sulfuric acid; Combination (3): 1,3-dibromo-5,5-dimethylhydantoin and concentrated sulfuric acid; (12) In step (2), the organic solvent is one or more of carbon tetrachloride, chloroform, dichloromethane and 1,2-dichloroethane; (13) In step (2), the volume molar ratio of the organic solvent to the compound of formula I is (200~300 mL): 1 mol; (14) In step (2), the reaction temperature of the bromination reaction is 40℃~60℃; (15) In step (3), the molar ratio of magnesium to the compound of formula II is (1.5~2.0):1; (16) In step (3), the molar ratio of the initiator to the compound of formula II is (0.2~0.5):1; (17) In step (3), the organic solvent is one or more of tetrahydrofuran, methyltetrahydrofuran and diethyl ether; (18) In step (3), the volume molar ratio of the organic solvent to the compound of formula II is (300~500 mL):1 mol; (19) In step (3), the reaction temperature of the Grignard reaction is 30℃~80℃; (20) In step (3), the reaction time of the Grignard reaction is 10 to 15 hours; (21) In step (3), the concentration of the compound of formula III is 1.5M~2.0M, wherein the concentration is the concentration of the compound of formula III in the organic solvent; (22) In step (4), the acid anhydride reagent is acetic anhydride; (23) In step (4), the acyl chloride reagent is acetyl chloride; (24) In step (4), the molar ratio of the acetylation reagent to the compound of formula III is (1.1~1.8):1; (25) In step (4), the organic solvent is diethyl ether, 2-methyltetrahydrofuran or tetrahydrofuran; (26) In step (4), the volume molar ratio of the organic solvent to the compound of formula III is (100~150 mL):1 mol; (27) In step (4), the compound of formula III is added dropwise at a rate of 1-2 mol / h; (28) In step (4), the reaction temperature of the acetylation reaction is 5℃~20℃; (29) In step (4), the reaction time of the acetylation reaction is 2 to 6 hours; (30) In step (5), the acid is sulfuric acid; (31) In step (5), the mass percentage concentration of the acid in the acidic aqueous solution is 10-25%; (32) In step (5), the molar ratio of the acid to the compound of formula IV is (1.0~2.0):1; (33) In step (5), the reaction temperature of the hydrolysis reaction is 70℃~100℃; (34) In step (5), the reaction time of the hydrolysis reaction is 5~8h; (35) In step (6), the copper catalyst is cuprous chloride, cuprous iodide or cuprous bromide; (36) In step (6), the molar ratio of the copper catalyst to the 2-trifluoromethyl-4-hydroxyacetophenone is (0.1~0.2):1; (37) In step (6), the alkali is potassium carbonate or sodium acetate; (38) In step (6), the molar ratio of the base to the 2-trifluoromethyl-4-hydroxyacetophenone is (1.5~2.0):1; (39) In step (6), the amide solvent is N,N-dimethylformamide and / or N-methylpyrrolidone, preferably N,N-dimethylformamide; (40) In step (6), the sulfone solvent is dimethyl sulfoxide and / or sulfolane, more preferably dimethyl sulfoxide; (41) In step (6), the volume molar ratio of the organic solvent to the 2-trifluoromethyl-4-hydroxyacetophenone is (350~450 mL):1 mol; (42) In step (6), the reaction temperature of the coupling reaction is 50℃~80℃; (43) In step (6), the reaction time of the coupling reaction is 2 to 5 hours.

4. The preparation method according to claim 3, characterized in that, It meets one or more of the following conditions: (1) In step (1), the molar ratio of the acyl chloride to the m-trifluoromethylphenol is 1.1:1; (2) In step (1), the acyl chloride is added dropwise at a rate of 3 g / min; (3) In step (1), the organic solvent is carbon tetrachloride; (4) In step (1), the volume molar ratio of the organic solvent to the m-trifluoromethylphenol is (200~205 mL):1 mol; (5) In step (2), the molar ratio of the brominating reagent [Br] to the compound of formula I is (0.8~1.5):1, for example 0.8:1 or 1.5:1; (6) In step (2), when the brominating reagent [Br] is liquid bromine, the liquid bromine is added dropwise at a rate of 0.5~1.5 g / min, for example, 1 g / min; (7) In step (2), the molar ratio of the brominating agent [Br] to the catalyst is 15:1, 1.25:1 or 0.7:1; (8) In step (2), in the combination (1), the molar ratio of the brominating agent [Br] to the catalyst is (10~30):1, more preferably (10~20):1, for example 15:1; (9) In step (2), the molar ratio of the brominating agent [Br] to the catalyst in the combination (2) is (1~3):1, more preferably (1~2):1, for example 1.25:1; (10) In step (2), in the combination (3), the molar ratio of the brominating agent [Br] to the catalyst is (0.25~1):1, more preferably (0.5~1):1, for example 0.7:1; (11) In step (2), the organic solvent is carbon tetrachloride; (12) In step (2), the volume molar ratio of the organic solvent to the compound of formula I is (250~260 mL):1 mol; (13) In step (2), the reaction temperature of the bromination reaction is 40°C or 60°C; (14) In step (2), when the combination of the brominating agent [Br] and the catalyst is combination (1), the reaction time of the bromination reaction is 4 to 12 hours, more preferably 4 to 8 hours, for example 6 hours; when the combination of the brominating agent [Br] and the catalyst is combination (2), the reaction time of the bromination reaction is 3 to 8 hours; when the combination of the brominating agent [Br] and the catalyst is combination (3), the reaction time of the bromination reaction is 2 to 5 hours. (15) In step (3), the molar ratio of magnesium to the compound of formula II is 1.5:1; (16) In step (3), the molar ratio of the initiator to the compound of formula II is 0.2:1; (17) In step (3), the organic solvent is tetrahydrofuran or methyltetrahydrofuran; (18) In step (3), the volume molar ratio of the organic solvent to the compound of formula II is 400 mL: 1 mol; (19) In step (3), the reaction temperature of the Grignard reaction is 40°C; (20) In step (3), the reaction time of the Grignard reaction is 12 hours; (21) In step (3), the concentration of the compound of formula III is 1.5M, wherein the concentration is the concentration of the compound of formula III in the organic solvent; (22) In step (4), the molar ratio of the acetylation reagent to the compound of formula III is 1.2:1; (23) In step (4), the organic solvent is tetrahydrofuran; (24) In step (4), the volume molar ratio of the organic solvent to the compound of formula III is 100 mL: 1 mol; (25) In step (4), the reaction temperature of the acetylation reaction is 5℃~10℃; (26) In step (4), the reaction time for the acetylation reaction is 3 hours; (27) In step (5), the mass percentage concentration of the acid in the acidic aqueous solution is 10% or 15%; (28) In step (5), the molar ratio of the acid to the compound of formula IV is 1.5:1 or 1.1:1; (29) In step (5), the reaction temperature of the hydrolysis reaction is 85°C; (30) In step (5), the reaction time of the hydrolysis reaction is 6 hours; (31) In step (6), the molar ratio of the copper catalyst to the 2-trifluoromethyl-4-hydroxyacetophenone is 0.1:1, 0.15:1, or 0.2:1; (32) In step (6), the molar ratio of the base to the 2-trifluoromethyl-4-hydroxyacetophenone is 1.5:1; (33) In step (6), the volume molar ratio of the organic solvent to the 2-trifluoromethyl-4-hydroxyacetophenone is 400 mL: 1 mol; (34) In step (6), the reaction temperature of the coupling reaction is 60°C; (35) In step (6), the reaction time of the coupling reaction is 3h.

5. The preparation method according to claim 1, characterized in that, It meets one or more of the following conditions: (1) In step (1), the esterification reaction includes the following steps: at 0~20°C, preferably at 0~10°C, the acyl chloride is added dropwise to a mixture of m-trifluoromethylphenol and an organic solvent to carry out the esterification reaction; (2) In step (2), the bromination reaction is selected from any of the following schemes: Scheme 1: Dissolve the catalyst and compound of formula I in an organic solvent, heat to 20℃~60℃, preferably 40℃~60℃, and add brominating reagent [Br] dropwise to carry out bromination reaction; Option 2: Dissolve the compound of formula I, the catalyst, and the brominating reagent [Br] in an organic solvent, and heat to 20℃~60℃, preferably 40℃~60℃, to carry out the bromination reaction; (3) In step (3), the Grignard reaction includes the following steps: at 25°C to 100°C, preferably at 30°C to 80°C, the compound of formula II, magnesium and initiator are mixed in an organic solvent, and then magnesium and organic solvent are added again to carry out the Grignard reaction; (4) In step (4), the acetylation reaction includes the following steps: at 0°C to 30°C, preferably at 5°C to 20°C, the compound of formula III is added dropwise to a mixture of acetylation reagent and organic solvent to carry out the acetylation reaction; (5) In step (5), the hydrolysis reaction includes the following steps: at 50°C to 150°C, preferably at 70°C to 100°C, the compound of formula IV is mixed with an acid and then subjected to a hydrolysis reaction; (6) In step (6), the coupling reaction includes the following steps: 2-trifluoromethyl-4-hydroxyacetophenone, p-dichlorobenzene, copper catalyst and base are placed in an organic solvent at 25℃~100℃, preferably 50℃~80℃, for reaction.

6. A method for preparing a compound of formula I, comprising the following steps: In organic solvents, acyl chlorides The compound of formula I was prepared by esterification with m-trifluoromethylphenol. ； Where R is methyl, phenyl, or p-methylphenyl; The operation and conditions of the esterification reaction are as described in any one of claims 1-5.

7. A method for preparing a compound of formula II, comprising the following steps: In an organic solvent, in the presence of a catalyst, the compound of formula I is subjected to a bromination reaction with a brominating reagent [Br] to obtain the compound of formula II; ； Where R is methyl, phenyl, or p-methylphenyl; The operation and conditions of the bromination reaction are as described in any one of claims 1-5.

8. A method for preparing a compound of formula III, comprising the following steps: In an organic solvent, in the presence of an initiator, the compound of formula II is subjected to a Grignard reaction with magnesium to prepare the compound of formula III. ； Where R is methyl, phenyl, or p-methylphenyl; The operation and conditions of the Grignard reaction are as described in any one of claims 1-5.

9. A method for preparing a compound of formula IV, comprising the following steps: Compound III and an acetylation reagent are acetylated in an organic solvent to prepare compound IV; ； Where R is methyl, phenyl, or p-methylphenyl; The operation and conditions of the acetylation reaction are as described in any one of claims 1-5.

10. A method for preparing 2-trifluoromethyl-4-hydroxyacetophenone, comprising: The compound of formula IV was hydrolyzed under the action of acid to obtain 2-trifluoromethyl-4-hydroxyacetophenone; ； Where R is methyl, phenyl, or p-methylphenyl; The operation and conditions of the hydrolysis reaction are as described in any one of claims 1-5; Or a method for preparing 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)ethyl ketone, comprising: In the presence of a copper catalyst and a base, 2-trifluoromethyl-4-hydroxyacetophenone and p-dichlorobenzene were coupled together in an organic solvent to prepare 1-(4-(4-chlorophenoxy)-2-(trifluoromethyl)phenyl)acetophenone. ； The operation and conditions of the coupling reaction are as described in any one of claims 1-5.

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