Process for Preparing 4-Halo-2-(Trifluoromethyl)Acetophenone

Abstract

The present invention relates to the field of preparation of an intermediate of metconazole, and discloses a method for preparing 4-halo-2-trifluoromethylacetophenone, comprising: (1A) in the presence of a first solvent, subjecting the compound represented by formula (II) to a substitution reaction with N,N-dimethylformamide dimethyl acetal, and then obtaining the compound represented by formula (III) through a hydrolysis reaction; (2A) in the presence of a third solvent, subjecting the compound represented by formula (III) to a reaction with hydroxylamine, and then contacting with a dehydrating agent to obtain the compound represented by formula (V); (3) subjecting the compound represented by formula (V) to a methylation reaction to obtain the compound represented by formula (VI), and then obtaining the compound represented by formula (I) through an oxidation reaction, wherein X in formula (I)-formula (VI) is the same and is selected from one of F, Cl, Br and I. The method provided by the present invention has the advantages of low cost, mild conditions and high yield.

Description

Technical Field

[0001] The present invention relates to the field of preparation of mefentrifluconazole intermediates, and particularly to a method for preparing 4-halo-2-trifluoromethylacetophenone. Background Art

[0002] Mefentrifluconazole (common name) is a triazole fungicide of epoch-making significance newly developed by BASF. It was officially launched in 2019, and the future market is expected to exceed $1 billion annually. Mefentrifluconazole has broad-spectrum, high-efficiency, systemic, eradicating and protecting effects. In particular, it has outstanding biological activity against a variety of difficult-to-control fungal diseases, and can significantly enhance the control of more than 60 crop diseases, such as field crops like corn, cereals, soybeans, and cash crops like green peppers, grapes, etc. It can also be used for lawn and seed treatment, etc. It not only has higher biological activity, but also has good environmental characteristics, low toxicity to mammals, bees, etc., and high safety.

[0003] 4-Halo-2-trifluoromethylacetophenone is a key intermediate for synthesizing the mefentrifluconazole intermediate 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone.

[0004] Currently, the technologies used for producing 4-halo-2-trifluoromethylacetophenone and 4-(4-chlorophenoxy)-2-trifluoromethylacetophenone mostly refer to the steps disclosed in existing technologies such as CN103649057A, EP3670491A1, and US6229051B1.

[0005] For example:

[0006]

[0007] In the above process routes, Grignard reaction is required, the conditions are relatively harsh, and a large amount of magnesium-containing wastewater is generated after the reaction, which is difficult to treat. When preparing 4-halo-2-trifluoromethylacetophenone, there are disadvantages such as high cost and poor production environment.

[0008] Therefore, it is necessary to seek a method for preparing 4-halo-2-trifluoromethylacetophenone with lower cost and milder conditions. Summary of the Invention

[0009] The object of the present invention is to overcome the technical problems existing in the prior art, such as high production cost and harsh conditions, and provide a new method for preparing 4-halo-2-trifluoromethylacetophenone. This method has the advantages of low cost, mild conditions, and high yield.

[0010] To achieve the above object, the present invention provides a method for preparing 4-halo-2-trifluoromethylacetophenone, the method comprising steps (1A), (2A), (3), or the method comprising (1B), (2B), (3):

[0011]

[0012] (1A) In the presence of a first solvent, subject the compound represented by formula (II) to a substitution reaction with N,N-dimethylformamide dimethyl acetal, and then obtain the compound represented by formula (III) through a hydrolysis reaction;

[0013]

[0014] (1B) In the presence of a second solvent and a first halogenating reagent, subject the compound represented by formula (II) to a halogenation reaction to obtain the compound represented by formula (IV);

[0015]

[0016] (2A) In the presence of a third solvent, subject the compound represented by formula (III) to a reaction with hydroxylamine, and then contact with a dehydrating agent to obtain the compound represented by formula (V);

[0017]

[0018] (2B) Subject the compound represented by formula (IV) to a cyanation reaction with a cyanide to obtain the compound represented by formula (V);

[0019] (3) Subject the compound represented by formula (V) to a methylation reaction to obtain the compound represented by formula (VI), and then obtain the compound represented by formula (I) through an oxidation reaction,

[0020]

[0021] wherein, X in formula (I) - formula (VI) is the same and is selected from one of F, Cl, Br, and I; in formula (IV), Y is selected from one of F, Cl, Br, and I.

[0022] Through the above technical solution, the present invention provides a new method for preparing 4-halo-2-trifluoromethylacetophenone. Using the compound represented by formula (II) as the starting material, the compound represented by formula (V) (benzyl cyanide) is obtained through two different paths, and then the final target compound is obtained through a methylation reaction and an oxidation reaction. Compared with the prior art, the method provided by the present invention has a low preparation cost, a high yield, and mild reaction conditions in the whole process route, which is conducive to industrialization. Detailed implementation mode

[0023] The endpoints and any values in the ranges disclosed herein are not limited to the exact ranges or values, and these ranges or values should be understood to include values close to these ranges or values. For numerical ranges, the endpoint values of each range, between the endpoint values of each range and individual point values, and between individual point values can be combined with each other to obtain one or more new numerical ranges, and these numerical ranges should be regarded as specifically disclosed herein.

[0024] The present invention provides a method for preparing 4-halo-2-trifluoromethylacetophenone, the method comprising steps (1A), (2A), (3), or the method comprising (1B), (2B), (3):

[0025]

[0026] (1A) In the presence of a first solvent, subject the compound represented by formula (II) to a substitution reaction with N,N-dimethylformamide dimethyl acetal (DMF-DMA), and then obtain the compound represented by formula (III) through a hydrolysis reaction;

[0027]

[0028] (1B) In the presence of a second solvent and a first halogenating reagent, subject the compound represented by formula (II) to a halogenation reaction to obtain the compound represented by formula (IV);

[0029]

[0030] (2A) In the presence of a third solvent, subject the compound represented by formula (III) to a reaction with hydroxylamine, and then contact with a dehydrating agent to obtain the compound represented by formula (V);

[0031]

[0032] (2B) Subject the compound represented by formula (IV) to a cyanation reaction with a cyanide to obtain the compound represented by formula (V);

[0033] (3) Subject the compound represented by formula (V) to a methylation reaction to obtain the compound represented by formula (VI), and then obtain the compound represented by formula (I) through an oxidation reaction,

[0034]

[0035] wherein, X in formula (I)-formula (VI) is the same and is selected from one of F, Cl, Br, and I; in formula (IV), Y is selected from one of F, Cl, Br, and I.

[0036] In the present invention, the compound represented by the formula (II) can be obtained commercially or prepared by referring to the conventional methods in the art. For example, it can be prepared by reacting o-methylbenzotrifluoride with a second halogenating reagent at 80-150 °C for 2-8 h. Among them, the second halogen reagent can be selected from one of hydrogen fluoride, chlorine, bromine, iodine, NCS (N-chlorosuccinimide), NBS (N-bromosuccinimide), and is preferably NCS (N-chlorosuccinimide) or chlorine.

[0037] According to some embodiments of the present invention, in step (1A), the conditions for the substitution reaction may include: the temperature is 70-150 °C, preferably 80-110 °C; the time is 4-12 h, preferably 8-9 h.

[0038] According to some embodiments of the present invention, relative to 1 mol of the compound represented by the formula (II), the amount of N,N-dimethylformamide dimethyl acetal used can be 0.8-2 mol, preferably 0.9-1.2 mol.

[0039] According to some embodiments of the present invention, the first solvent can be selected from at least one of acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone; preferably N,N-dimethylformamide.

[0040] According to a preferred embodiment of the present invention, relative to each gram of the compound represented by the formula (II), the amount of the first solvent used can be 1-20 mL, preferably 2-10 mL.

[0041] According to some embodiments of the present invention, in step (1A), the hydrolysis reaction is carried out in the presence of an acid, and the acid can be selected from at least one of hydrochloric acid, sulfuric acid, and phosphoric acid, preferably selected from hydrochloric acid and / or sulfuric acid.

[0042] According to some embodiments of the present invention, the conditions for the hydrolysis reaction may include: the temperature is 40-100 °C, preferably 50-70 °C, and the time is 1-10 h, preferably 2-5 h.

[0043] According to a preferred embodiment of the present invention, relative to 1 mol of the compound represented by the formula (II), the amount of the acid used can be 0.02-0.5 mol, preferably 0.05-0.1 mol.

[0044] In the present invention, preferably, in step (1A), before obtaining the compound represented by formula (III), it may further include post-treatment of the material containing the compound represented by formula (III). The present invention has no particular limitation on the post-treatment in step (1A), and it can be carried out with reference to the conventional methods in the art. For example, it may include the following steps: by removing the first solvent, a residue containing the compound represented by formula (III) is obtained, then a non-polar solvent such as toluene is added, and the pH is adjusted to 7-8 with a 5-30 wt% aqueous sodium hydroxide solution, followed by liquid separation, discarding the aqueous phase, and removing the non-polar solvent.

[0045] According to some embodiments of the present invention, in step (1B), the conditions for the halogenation reaction may include: the temperature is 80-150 °C, preferably 130-140 °C; the time is 2-8 h, preferably 3-5 h.

[0046] According to some embodiments of the present invention, the first halogenating reagent may be selected from one of hydrogen fluoride, chlorine, bromine, iodine, NCS (N-chlorosuccinimide), NBS (N-bromosuccinimide), and preferably NCS (N-chlorosuccinimide) or chlorine.

[0047] According to a preferred embodiment of the present invention, relative to 1 mol of the compound represented by formula (II), the amount of the first halogenating reagent used may be 0.8-3.5 mol, preferably 1.9-2.2 mol.

[0048] According to some embodiments of the present invention, the second solvent may be selected from at least one of p-chlorobenzotrifluoride, 2,4-dichlorobenzotrifluoride, and 3,4-dichlorobenzotrifluoride, and preferably p-chlorobenzotrifluoride.

[0049] According to some embodiments of the present invention, relative to each gram of the compound represented by formula (II), the amount of the second solvent used may be 1-20 mL, preferably 2-10 mL.

[0050] In the present invention, preferably, in step (1B), before obtaining the compound represented by formula (IV), it may further include post-treatment of the material containing the compound represented by formula (IV). The present invention has no particular limitation on the post-treatment in step (3), and it can be carried out with reference to the conventional methods in the art. For example, it may include the following steps: by removing the solvent, a residue containing the compound represented by formula (IV) is obtained, then a non-polar solvent such as 1,2-dichloroethane (DCE) is added, and the pH is adjusted to 7-8 with a 5-30 wt% aqueous sodium hydroxide solution, followed by liquid separation, discarding the aqueous phase, and removing the non-polar solvent.

[0051] According to some embodiments of the present invention, in step (2A), the conditions for the reaction of the compound represented by formula (III) with hydroxylamine may include: the temperature is 60 - 150 °C, preferably 80 - 100 °C; the time is 2 - 6 h, preferably 3 - 4 h.

[0052] According to a preferred embodiment of the present invention, relative to 1 mol of the compound represented by formula (III), the amount of hydroxylamine used may be 0.9 - 2.5 mol, preferably 1 - 1.5 mol. Preferably, the hydroxylamine is selected from hydroxylamine hydrochloride and / or hydroxylamine sulfate, more preferably hydroxylamine hydrochloride.

[0053] According to some embodiments of the present invention, the third solvent may be selected from at least one of acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, and N,N-dimethylacetamide, preferably N,N-dimethylformamide.

[0054] According to some embodiments of the present invention, relative to each gram of the compound represented by formula (III), the amount of the third solvent used may be 1 - 20 mL, preferably 3 - 6 mL.

[0055] According to some embodiments of the present invention, in step (2A), the conditions for the contact may include: the temperature is 20 - 100 °C, preferably 40 - 80 °C; the time is 2 - 5 h, preferably 3 - 4 h.

[0056] According to some embodiments of the present invention, the dehydrating agent may be selected from at least one of phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, ammonium acetate, and acetic anhydride, preferably acetic anhydride.

[0057] According to a preferred embodiment of the present invention, relative to 1 mol of the compound represented by formula (III), the amount of the dehydrating agent used may be 1 - 15 mol, preferably 5 - 10 mol.

[0058] In the present invention, the contact may also be carried out in the presence of a fourth solvent, and the fourth solvent may be selected from at least one of ethyl acetate, dichloromethane, dichloroethane, tetrahydrofuran, dioxane, and acetic anhydride. Preferably, relative to 1 mol of the compound represented by formula (III), the amount of the fourth solvent used may be 1 - 20 mL, preferably 3 - 6 mL.

[0059] In the present invention, when the dehydrating agent is acetic anhydride, acetic anhydride may serve as both a raw material and a fourth solvent.

[0060] In the present invention, preferably, in step (2A), before obtaining the compound represented by formula (V), it may further include post-treatment of the material containing the compound represented by formula (V). The present invention has no particular limitation on the post-treatment in step (2), and it can be carried out according to the conventional methods in the art. For example, it may include the following steps: removing the fourth solvent to obtain a residue containing the compound represented by formula (V), then adding a non-polar solvent such as toluene, and adjusting the pH to 7-8 with a 5-30 wt% aqueous sodium hydroxide solution, separating the layers, discarding the aqueous phase, and removing the non-polar solvent.

[0061] According to some embodiments of the present invention, in step (2B), the conditions for the cyanation reaction may include: the temperature is 100-180 °C, preferably 130-150 °C; the time is 6-12 h, preferably 7-9 h.

[0062] According to some embodiments of the present invention, the cyanide may be selected from at least one of sodium cyanide, potassium cyanide, and cuprous cyanide, preferably sodium cyanide.

[0063] According to a preferred embodiment of the present invention, relative to 1 mol of the compound represented by formula (IV), the amount of the cyanide used is 0.8-1.5 mol, preferably 0.9-1.2 mol.

[0064] In the present invention, the cyanation reaction may also be carried out in the presence of a fifth solvent. The fifth solvent may be selected from at least one of N,N-dimethylformamide (DMF), N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone, preferably N,N-dimethylformamide.

[0065] In the present invention, preferably, relative to each gram of the compound represented by formula (IV), the amount of the fifth solvent used is 1-20 mL, preferably 2-10 mL.

[0066] In the present invention, preferably, in step (2B), before obtaining the compound represented by formula (V), it may further include post-treatment of the material containing the compound represented by formula (V). The present invention has no particular limitation on the post-treatment in step (2B), and it can be carried out according to the conventional methods in the art. For example, it may include the following steps: removing the solvent to obtain a residue containing the compound represented by formula (V), then adding a non-polar solvent such as 1,2-dichloroethane (DCE), and adjusting the pH to 7-8 with a 5-30 wt% aqueous sodium hydroxide solution, separating the layers, discarding the aqueous phase, and removing the non-polar solvent.

[0067] According to some embodiments of the present invention, in step (3), the methylation reaction can be carried out in an alkaline condition in the presence of a methylation reagent. The alkaline condition is provided by a base and / or a salt that is alkaline when dissolved in water, preferably provided by at least one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide, and sodium ethoxide, and preferably provided by sodium methoxide; the methylation reagent can be selected from at least one of methyl iodide, ethyl iodide, dimethyl sulfate, and dimethyl carbonate; preferably selected from dimethyl sulfate and / or dimethyl carbonate.

[0068] According to some embodiments of the present invention, the conditions for the methylation reaction can include: the temperature is 20 - 150 °C, preferably 60 - 80 °C; the time is 1 - 10 h, preferably 2 - 5 h.

[0069] According to some embodiments of the present invention, relative to 1 mol of the compound represented by formula (V), the amounts of the base and / or salt and the methylation reagent can be 0.8 - 2.5 mol and 0.8 - 2.5 mol respectively, preferably 1 - 1.5 mol and 1 - 1.5 mol respectively.

[0070] According to some embodiments of the present invention, the methylation reaction can also be carried out in the presence of a sixth solvent, and the sixth solvent can be selected from one of acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and N-methylpyrrolidone; preferably tetrahydrofuran.

[0071] According to some embodiments of the present invention, relative to each gram of the compound represented by formula (V), the amount of the sixth solvent can be 1 - 20 mL, preferably 2 - 10 mL.

[0072] According to some embodiments of the present invention, the oxidation reaction is carried out in the presence of a catalyst and oxygen. The catalyst is selected from soluble copper salts and / or soluble cobalt salts, preferably selected from at least one of cobalt chloride, cobalt bromide, cobalt iodide, cuprous chloride, cuprous bromide, and cuprous iodide, and more preferably selected from cuprous chloride and / or cuprous bromide.

[0073] According to some embodiments of the present invention, the conditions for the oxidation reaction include: the temperature is 50 - 220 °C, preferably 80 - 110 °C; the time is 4 - 12 h, preferably 6 - 8 h;

[0074] and / or, relative to 1 mol of the compound represented by formula (V), the amounts of the catalyst and oxygen are 0.05 - 1.5 mol and 1 - 4 mol respectively, preferably 0.1 - 1.1 mol and 2 - 3 mol respectively.

[0075] In the present invention, preferably, in step (3), before obtaining the compound represented by formula (I), it may further include post-treatment of the material containing the compound represented by formula (I). The present invention has no particular limitation on the post-treatment in step (3), and it can be carried out by referring to the conventional methods in the art. For example, it may include the following steps: removing the solvent to obtain a residue containing the compound represented by formula (I), then adding a non-polar solvent, such as 1,2-dichloroethane (DCE), and adjusting the pH to 7-8 with 5-30 wt% aqueous hydrochloric acid solution, separating the layers, discarding the aqueous phase, and removing the non-polar solvent.

[0076] The present invention will be described in detail below through examples.

[0077] In the following examples, the purity was measured by liquid chromatography (Agilent HPLC 1260). Unless otherwise specified, the raw materials used were all commercially available products. The reaction products of each step were verified by 1 1H-NMR (400M) to detect and verify the structure.

[0078] The yield of each step = actual yield / theoretical yield × 100%, where the "yield of each step" was calculated based on the starting materials of each step (such as the compounds represented by formula (II), (III), (IV), (V)).

[0079] Preparation Example

[0080] This preparation example is used for the preparation of the compound of formula (II)

[0081] X = Cl;

[0082] In a 2 L four-necked flask, 163 g (1 mol, 98%) of o-methylbenzotrifluoride was added, and then NCS (1.2 mol, 90 wt%) was added in batches. It took 2 h to add all, and the reaction was carried out at 100 °C for 4 h. After the reaction was monitored by HPLC to be completed; 200 mL of DCE and 10 wt% sodium hydroxide solution were added to the reaction system to adjust the pH to 7, and the mixture was allowed to stand and separate the layers. The organic solvent was removed to obtain the compound represented by formula (II), which was directly used for the next step.

[0083] Example 1

[0084] (1A) In a 2 L four-necked flask, successively add the compound shown in formula (II) obtained in the preparation example (1 mol, 98 wt%) and 600 mL of DMF. Dropwise add 145.7 g (1.2 mol, 98 wt%) of DMF-DMA. After dropping for 2 h, carry out a substitution reaction at 100 °C. After 6 h, HPLC detects that the raw materials are completely reacted. Add 5 g of 50 wt% sulfuric acid and carry out a hydrolysis reaction at 60 °C for 2 h. HPLC detects that the raw materials are completely reacted. Recover the solvent DMF. Then add 200 mL of toluene and a 10 wt% aqueous sodium hydroxide solution to adjust the pH to 7. Let it stand for layering, discard the aqueous phase, and remove toluene from the organic layer to obtain 204 g of the compound shown in formula (III), with a purity of 98 wt% and a yield of 90%. Among them, in formula (III), X = Cl.

[0085] (2A) In a 2 L four-necked flask, successively add 22.8 g (0.1 mol, 98 wt%) of the compound shown in formula (III) and 100 mL of DMF. Then add 8.3 g of hydroxylamine hydrochloride (0.12 mol, 98 wt%). After reacting at 100 °C for 6 h, HPLC detects that the raw materials are completely reacted. Remove the solvent. Then add 100 mL of acetic anhydride and react at 50 °C for 3 h. HPLC detects that the raw materials are completely reacted. Recover acetic anhydride. Then add 200 mL of toluene and a 10 wt% sodium hydroxide solution to adjust the pH to 7. Let it stand for layering, discard the aqueous phase, and remove toluene to obtain 20.4 g of the compound shown in formula (V), with a purity of 98 wt% and a yield of 91%. Among them, in formula (V), X = Cl.

[0086] (3) In a 2 L four-necked flask, successively add 22.3 g (0.1 mol, 98 wt%) of the compound shown in formula (V), 200 mL of tetrahydrofuran, and 6 g of sodium methoxide. Reflux at 80 °C, dropwise add 12.6 g of dimethyl sulfate over 1 h. After dropping, reflux and react for 3 h. After the reaction is complete, continue to add 0.5 g of copper chloride and pass air for 4 h (containing 0.2 mol of oxygen). Oxidize at 80 °C for 3 h. Monitor the end of the reaction by HPLC. Remove tetrahydrofuran. Add 200 mL of DCE and a 10 wt% hydrochloric acid solution to the remaining system to adjust the pH to 7. Let it stand for layering. Remove the solvent from the organic layer to obtain 18.2 g of 4-chloro-2-(trifluoromethyl)acetophenone, with a purity of 98 wt% and a yield of 80.3%.

[0087] Example 2

[0088] (1B) In a 2 L four-necked flask, successively add the compound shown in formula (II) obtained in the Preparation Example (1 mol, 98 wt%), 600 mL of p-chlorobenzotrifluoride, and then add NCS (1.2 mol, 90 wt%) in batches. It takes 3 h to add all. After carrying out the halogenation reaction at 130 °C for 3 h, monitor the end of the reaction by HPLC; add 200 mL of DCE to the reaction system, adjust the pH to 7 with 10 wt% sodium hydroxide solution, let it stand for stratification, and remove the organic solvent to obtain 226 g of the compound shown in formula (IV) with a purity of 98 wt% and a yield of 97%. Among them, in formula (IV), X = Cl, Y = Cl.

[0089] (2B) In a 2 L four-necked flask, successively add 23 g (0.1 mol, 98 wt%) of the compound shown in formula (IV), 100 mL of DMF, and 5.9 g of sodium cyanide. After carrying out the cyanation reaction at 130 °C for 8 h, monitor the end of the reaction by HPLC; remove the solvent, add 200 mL of DCE to the reaction system, adjust the pH to 7 with 10 wt% sodium hydroxide solution, let it stand for stratification, and remove the organic solvent to obtain 20.1 g of the compound shown in formula (V) with a purity of 98 wt% and a yield of 90%. Among them, in formula (V), X = Cl.

[0090] (3) In a 2 L four-necked flask, successively add 22.3 g (0.1 mol, 98 wt%) of the compound shown in formula (Ⅴ), 200 mL of tetrahydrofuran, 6 g of sodium methoxide, reflux at 80 °C, dropwise add 12.6 g of dimethyl sulfate, finish dropping in 1 h, reflux and react for 3 h. After the reaction is completed, continue to add 0.5 g of copper chloride, pass air for 4 h (containing 0.2 mol of oxygen), oxidize at 80 °C for 3 h, monitor the end of the reaction by HPLC, remove tetrahydrofuran, add 200 mL of DCE to the remaining system, adjust the pH to 7 with 10 wt% hydrochloric acid solution, let it stand for stratification, and remove the solvent from the organic layer to obtain 18.2 g of 4-chloro-2-(trifluoromethyl)acetophenone with a purity of 98 wt% and a yield of 80.3%.

[0091] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited thereto. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention, including any other suitable combination of each technical feature. These simple modifications and combinations should also be regarded as the content disclosed by the present invention and all fall within the protection scope of the present invention.

Claims

1. A method for preparing 4-halo-2-trifluoromethylacetophenone, characterized in that, The method comprises steps (1A), (2A), (3), or the method comprises (1B), (2B), (3): (1A) In the presence of a first solvent, subject the compound represented by formula (II) to a substitution reaction with N,N-dimethylformamide dimethyl acetal, and then obtain the compound represented by formula (III) through a hydrolysis reaction; (1B) In the presence of a second solvent and a first halogenating reagent, subject the compound represented by formula (II) to a halogenation reaction to obtain the compound represented by formula (IV); (2A) In the presence of a third solvent, subject the compound represented by formula (III) to a reaction with hydroxylamine, and then contact with a dehydrating agent to obtain the compound represented by formula (V); (2B) Subject the compound represented by formula (IV) to a cyanation reaction with a cyanide to obtain the compound represented by formula (V); (3) Subject the compound represented by formula (V) to a methylation reaction to obtain the compound represented by formula (VI), the methylation reaction is carried out under basic conditions in the presence of a methylation reagent, the methylation reagent is selected from at least one of methyl iodide, ethyl iodide, dimethyl sulfate and dimethyl carbonate; and then obtain the compound represented by formula (I) through an oxidation reaction, the oxidation reaction is carried out in the presence of a catalyst and oxygen, the catalyst is selected from soluble copper salts and / or soluble cobalt salts; Wherein, X in formula (I)-formula (VI) is the same and is selected from one of F, Cl, Br and I; in formula (IV), Y is selected from one of F, Cl, Br and I.

2. The method according to claim 1, wherein, In step (1A), the conditions of the substitution reaction include: the temperature is 70-150 °C and the time is 4-12 h; And / or, relative to 1 mol of the compound represented by formula (II), the amount of N,N-dimethylformamide dimethyl acetal used is 0.8-2 mol; And / or, the first solvent is selected from at least one of acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide and N-methylpyrrolidone; And / or, relative to each gram of the compound represented by formula (II), the amount of the first solvent used is 1-20 mL.

3. The method according to claim 1 or 2, wherein, The conditions of the substitution reaction include: the temperature is 80-110 °C and the time is 8-9 h; And / or, relative to 1 mol of the compound represented by formula (II), the amount of N,N-dimethylformamide dimethyl acetal used is 0.9-1.2 mol; And / or, the first solvent is N,N-dimethylacetamide; And / or, relative to each gram of the compound represented by formula (II), the amount of the first solvent used is 2-10 mL.

4. The method according to claim 1, wherein, In step (1A), the hydrolysis reaction is carried out in the presence of an acid, the acid is selected from at least one of hydrochloric acid, sulfuric acid and phosphoric acid; And / or, the conditions of the hydrolysis reaction include: the temperature is 40-100 °C and the time is 1-10 h; And / or, relative to 1 mol of the compound represented by formula (II), the amount of the acid used is 0.02-0.5 mol.

5. The method according to claim 4, wherein The acid is hydrochloric acid and / or sulfuric acid; And / or, the conditions of the hydrolysis reaction include: the temperature is 50-70 °C and the time is 2-5 h; And / or, relative to 1 mol of the compound represented by formula (II), the amount of the acid used is 0.05 - 0.1 mol.

6. The method according to claim 1, wherein In step (1B), the conditions for the halogenation reaction include: the temperature is 80 - 150 °C and the time is 2 - 8 h; And / or, the first halogenating reagent is selected from one of hydrogen fluoride, chlorine, bromine, iodine, N-chlorosuccinimide, and N-bromosuccinimide; And / or, relative to 1 mol of the compound represented by formula (II), the amount of the first halogenating reagent used is 0.8 - 3.5 mol; And / or, the second solvent is selected from at least one of p-chlorobenzotrifluoride, 2,4-dichlorobenzotrifluoride, and 3,4-dichlorobenzotrifluoride; And / or, relative to each gram of the compound represented by formula (II), the amount of the second solvent used is 1 - 20 mL.

7. The method according to claim 1 or 6, wherein The conditions for the halogenation reaction include: the temperature is 130 - 140 °C and the time is 3 - 5 h; And / or, the first halogenating reagent is N-chlorosuccinimide or chlorine; And / or, relative to 1 mol of the compound represented by formula (II), the amount of the first halogenating reagent used is 1.9 - 2.2 mol; And / or, the second solvent is p-chlorobenzotrifluoride; And / or, relative to each gram of the compound represented by formula (II), the amount of the second solvent used is 2 - 10 mL.

8. The method according to claim 1, wherein In step (2A), the conditions for the reaction of the compound represented by formula (III) with hydroxylamine include: the temperature is 60 - 150 °C and the time is 2 - 6 h; And / or, relative to 1 mol of the compound represented by formula (III), the amount of hydroxylamine used is 0.9 - 2.5 mol; And / or, the hydroxylamine is selected from hydroxylamine hydrochloride and / or hydroxylamine sulfate; And / or, the third solvent is selected from at least one of acetonitrile, tetrahydrofuran, dioxane, N,N-dimethylformamide, and N,N-dimethylacetamide; And / or, relative to each gram of the compound represented by formula (III), the amount of the third solvent used is 1 - 20 mL.

9. The method according to claim 1 or 8, wherein The conditions for the reaction of the compound represented by formula (III) with hydroxylamine include: the temperature is 80 - 100 °C and the time is 3 - 4 h; And / or, relative to 1 mol of the compound represented by formula (III), the amount of hydroxylamine used is 1 - 1.5 mol; And / or, the hydroxylamine is hydroxylamine hydrochloride; And / or, the third solvent is N,N-dimethylformamide; And / or, relative to each gram of the compound represented by formula (III), the amount of the third solvent used is 3 - 6 mL.

10. The method according to claim 1, wherein, In step (2A), the conditions for the contact include: the temperature is 20 - 100 °C and the time is 2 - 5 h; And / or, the dehydrating agent is selected from at least one of phosphorus oxychloride, phosphorus pentachloride, thionyl chloride, ammonium acetate, and acetic anhydride; And / or, relative to 1 mol of the compound represented by formula (III), the amount of the dehydrating agent used is 1 - 15 mol.

11. The method according to claim 1 or 10, wherein, The conditions for the contact include: the temperature is 40 - 80 °C and the time is 3 - 4 h; And / or, the dehydrating agent is acetic anhydride; And / or, relative to 1 mol of the compound represented by formula (III), the amount of the dehydrating agent used is 5 - 10 mol.

12. The method according to claim 1, wherein In step (2B), the conditions for the cyanidation reaction include: temperature is 100 - 180 °C, time is 6 - 12 h; and / or, the cyanide is selected from at least one of sodium cyanide, potassium cyanide and cuprous cyanide; and / or, relative to 1 mol of the compound shown in formula (IV), the dosage of the cyanide is 0.8 - 1.5 mol.

13. The method according to claim 1 or 12, wherein, The conditions for the cyanidation reaction include: temperature is 130 - 150 °C, time is 7 - 9 h; and / or, the cyanide is sodium cyanide; and / or, relative to 1 mol of the compound shown in formula (IV), the dosage of the cyanide is 0.9 - 1.2 mol.

14. The method according to claim 1, wherein, In step (3), the basic condition is provided by a base and / or a salt that is alkaline in water, and is provided by at least one of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, sodium methoxide and sodium ethoxide; and / or, the conditions for the methylation reaction include: temperature is 20 - 150 °C, time is 1 - 10 h; and / or, relative to 1 mol of the compound shown in formula (V), the dosages of the base and / or salt and the methylation reagent are 0.8 - 2.5 mol and 0.8 - 2.5 mol respectively.

15. The method according to claim 1 or 14, wherein The basic condition is provided by sodium methoxide; and / or, the methylation reagent is selected from dimethyl sulfate and / or dimethyl carbonate; and / or, the conditions for the methylation reaction include: temperature is 20 - 150 °C, time is 1 - 10 h; and / or, relative to 1 mol of the compound shown in formula (V), the dosages of the base and / or salt and the methylation reagent are 1 - 1.5 mol and 1 - 1.5 mol respectively.

16. The method according to claim 1, wherein In step (3), the methylation reaction is further carried out in the presence of a sixth solvent, and the sixth solvent is selected from one of acetonitrile, tetrahydrofuran, dioxane, N,N - dimethylformamide, N,N - dimethylacetamide, dimethyl sulfoxide and N - methylpyrrolidone; and / or, relative to each gram of the compound shown in formula (V), the dosage of the sixth solvent is 1 - 20 mL.

17. The method according to claim 16, wherein, The sixth solvent is tetrahydrofuran; and / or, relative to each gram of the compound shown in formula (V), the dosage of the sixth solvent is 2 - 10 mL.

18. The method according to claim 1, wherein In step (3), the catalyst is selected from at least one of cobalt chloride, cobalt bromide, cobalt iodide, cuprous chloride, cuprous bromide and cuprous iodide; and / or, the conditions for the oxidation reaction include: temperature is 50 - 220 °C, time is 4 - 12 h; and / or, relative to 1 mol of the compound shown in formula (V), the dosages of the catalyst and oxygen are 0.05 - 1.5 mol and 1 - 4 mol respectively.

19. The method according to claim 1 or 18, wherein The catalyst is selected from cuprous chloride and / or cuprous bromide; and / or, the conditions for the oxidation reaction include: temperature is 80 - 110 °C, time is 6 - 8 h; and / or, relative to 1 mol of the compound shown in formula (V), the dosages of the catalyst and oxygen are 0.1 - 1.1 mol and 2 - 3 mol respectively.

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