4-bromo-2, 6-dimethyl fluorobenzene and preparation method thereof

Abstract

The invention discloses 4-bromo-2, 6-dimethyl fluorobenzene and a preparation method thereof, and belongs to the technical field of organic synthesis. The method provided by the invention comprises the following steps: reacting 4-bromo-2, 6-dimethylaniline, a boron trifluoride ether complex and nitrite ester in a reaction system in the presence of an organic solvent at the temperature of 75-105 DEG C to obtain a material containing 4-bromo-2, 6-dimethyl fluorobenzene; wherein the weight ratio of the 4-bromine-2, 6-dimethylaniline to the boron trifluoride ether complex to the nitrite ester is 1: (0.93 to 1.75): (0.58 to 0.88). According to the reaction method, an unstable intermediate fluoborate does not need to be separated, the safety is high, the large-scale production yield is stable, the purity is high, and the amount of three wastes is low.

Description

Technical Field

[0001] This application relates to the technical field of organic synthesis, and more particularly, to a 4-bromo-2,6-dimethylfluorobenzene and a method for preparing the same. Background Art

[0002] Dimethylfluorobenzene compounds, as very important raw materials, are mainly concentrated in the fields of organic synthesis intermediates, pharmaceutical chemistry, and functional materials, and have a wide range of uses.

[0003] The prior art discloses a method for synthesizing dimethylfluorobenzene or trimethylfluorobenzene by an anhydrous diazotization method, which uses pyridine hydrofluoride or triethylamine hydrofluoride as a reaction reagent. The yield of such a reaction is about 80%, but pyridine hydrofluoride or triethylamine hydrofluoride is relatively expensive, and has high corrosivity and toxicity, is not friendly to the environment, and is not easy to produce on a large scale.

[0004] Currently, the process route for synthesizing 4-bromo-2,6-dimethylfluorobenzene mainly uses a wet diazotization method, which uses sulfuric acid or hydrochloric acid or directly uses fluoboric acid as the bottom acid. After the fluoborate is formed by the reaction, the fluoborate needs to be separated, and after the fluoborate is dried to remove water, it is then pyrolyzed to obtain the fluorinated product; the fluoborate formed by the reaction has poor stability, is extremely easy to decompose, and needs to be dehydrated after separation before it can be used in subsequent reactions, resulting in a high safety risk after scale-up, being difficult to industrialize and having a low yield. Summary of the Invention

[0005] The main object of this application is to provide a 4-bromo-2,6-dimethylfluorobenzene and a method for preparing the same, so as to solve the problems of complex process, poor safety, inability to stably produce on a large scale, high three wastes, and low yield in the prior art when using the wet diazotization method to synthesize 4-bromo-2,6-dimethylfluorobenzene.

[0006] To achieve the above object, according to one aspect of this application, a method for preparing 4-bromo-2,6-dimethylfluorobenzene is provided, including: reacting 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex, and nitrite in a reaction system in the presence of an organic solvent at a temperature of 75 °C to 105 °C to obtain a material containing 4-bromo-2,6-dimethylfluorobenzene; wherein, the weight ratio of 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex, and nitrite is 1:(0.93 - 1.75):(0.58 - 0.88).

[0007] Further, the reaction temperature is 85 °C to 105 °C.

[0008] Further, the reaction time is at least 2 h or more.

[0009] Further, the weight ratio of 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex and nitrite is 1:(1.05 - 1.40):(0.58 - 0.70).

[0010] Further, the weight ratio of 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex, nitrite and organic solvent is 1:(0.93 - 1.75):(0.58 - 0.88):(6 - 18).

[0011] Further, the weight ratio of 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex, nitrite and organic solvent is 1:(1.05 - 1.40):(0.58 - 0.70):(8 - 15).

[0012] Further, the boron trifluoride ether complex is selected from at least one of boron trifluoride tetrahydrofuran, boron trifluoride methyl ether, boron trifluoride ethyl ether, boron trifluoride dimethyl sulfide and boron trifluoride.

[0013] Further, the nitrite is tert-butyl nitrite and / or isoamyl nitrite.

[0014] Further, the organic solvent is selected from at least one of alkane solvents, acetate solvents, ether solvents and aromatic hydrocarbon solvents.

[0015] Further, the organic solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, heptane, n-hexane, cyclohexane, petroleum ether, ethyl acetate, isopropyl acetate, tetrahydrofuran, isopropyl ether, 1,4-dioxane, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene and acetonitrile.

[0016] Further, the organic solvent is selected from at least one of heptane, cyclohexane, dichloroethane, isopropyl acetate, 1,4-dioxane, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene and acetonitrile.

[0017] Further, the reaction process specifically includes: 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex and nitrite in a reaction system with an organic solvent are first kept at a temperature of -20 to 30 °C for at least 2 h or more; after the heat preservation is completed, then kept at a temperature of 75 to 105 °C for at least 2 h or more to obtain a material containing 4-bromo-2,6-dimethylfluorobenzene.

[0018] Further, the reaction process specifically includes: 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex and nitrite in a reaction system with an organic solvent are first kept at a temperature of -10 to 20 °C for 2 to 24 h; after the heat preservation is completed, then kept at a temperature of 85 to 105 °C for 2 to 24 h to obtain a material containing 4-bromo-2,6-dimethylfluorobenzene.

[0019] Further, the reaction process specifically includes: 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex, and nitrite are in a reaction system in the presence of a first organic solvent. First, it is kept warm at a temperature of -20 to 30 °C for at least 2 h or more; after the heat preservation ends, the reaction system is added to a second organic solvent at a temperature of 75 to 105 °C and kept warm for at least 2 h or more to obtain a material containing 4-bromo-2,6-dimethylfluorobenzene.

[0020] Further, the reaction process specifically includes: 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex, and nitrite are in a reaction system in the presence of a first organic solvent. First, it is kept warm at a temperature of -10 to 20 °C for 2 to 24 h; after the heat preservation ends, the reaction system is added to a second organic solvent at a temperature of 85 to 105 °C and kept warm for 2 to 24 h to obtain a material containing 4-bromo-2,6-dimethylfluorobenzene.

[0021] Further, the reaction process specifically includes a first reaction process and a second reaction process that are carried out in sequence; First reaction process: 4-bromo-2,6-dimethylaniline and a first organic solvent are mixed at a temperature of 15 to 35 °C, then the temperature of the mixed system is controlled to -20 to 30 °C, boron trifluoride ether complex is added dropwise thereto, and after the addition ends, nitrite is added dropwise; then, the reaction system is kept warm at a temperature of -20 to 30 °C for 2 to 24 h to obtain an intermediate product; Second reaction process: First, the second organic solvent is heated to a temperature of 75 to 105 °C, and then the intermediate product is added dropwise to the second organic solvent and kept warm for 2 to 24 h to obtain a material containing 4-bromo-2,6-dimethylfluorobenzene.

[0022] Further, the reaction process specifically includes a first reaction process and a second reaction process that are carried out in sequence; First reaction process: 4-bromo-2,6-dimethylaniline and a first organic solvent are mixed at a temperature of 15 to 35 °C, then the temperature of the mixed system is controlled to -10 to 20 °C, boron trifluoride ether complex is added dropwise thereto, and after the addition ends, nitrite is added dropwise; then, the reaction system is kept warm at a temperature of -10 to 20 °C for 2 to 5 h to obtain an intermediate product; Second reaction process: First, the second organic solvent is heated to a temperature of 85 to 105 °C, and then the intermediate product is added dropwise to the second organic solvent and kept warm for 2 to 5 h to obtain a material containing 4-bromo-2,6-dimethylfluorobenzene.

[0023] Further, the first organic solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, heptane, n-hexane, cyclohexane, petroleum ether, ethyl acetate, isopropyl acetate, tetrahydrofuran, isopropyl ether, 1,4-dioxane, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, and acetonitrile.

[0024] Further, the second organic solvent is selected from at least one of heptane, cyclohexane, dichloroethane, isopropyl acetate, 1,4-dioxane, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, and acetonitrile.

[0025] Further, the weight ratio of 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex, nitrite, and the first organic solvent is 1:(0.93 - 1.75):(0.58 - 0.88):(6 - 13).

[0026] Further, the weight ratio of 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex, nitrite, and the first organic solvent is 1:(1.05 - 1.40):(0.58 - 0.70):(7 - 11).

[0027] Further, the reaction system further comprises a catalyst; the catalyst is selected from at least one of metal oxides, metal halides, metal sulfates, and metal powders.

[0028] Further, the metal oxide is selected from at least one of magnesium oxide, manganese dioxide, copper oxide, cuprous oxide, zinc oxide, and iron oxide.

[0029] Further, the metal halide is selected from at least one of nickel fluoride, nickel chloride, nickel bromide, cuprous iodide, copper bromide, cuprous bromide, copper chloride, cuprous chloride, zinc iodide, zinc bromide, zinc chloride, and iron chloride.

[0030] Further, the metal sulfate is at least one of copper sulfate, magnesium sulfate, nickel sulfate, iron sulfate, manganese sulfate, and zinc sulfate.

[0031] Further, the metal powder is at least one of copper powder, zinc powder, iron powder, and manganese powder.

[0032] Further, the weight ratio of 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex, nitrite, and the catalyst is 1:(0.93 - 1.75):(0.58 - 0.88):(0.01 - 0.10).

[0033] Further, the weight ratio of 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex, nitrite, and the catalyst is 1:(1.05 - 1.40):(0.58 - 0.70):(0.02 - 0.05).

[0034] Further, the preparation method further includes adding sulfite to the material containing 4-bromo-2,6-dimethylfluorobenzene after the reaction to form a product system, and purifying the product system; the purification process sequentially includes: adjusting the product system to be alkaline, washing with water, concentrating under reduced pressure, and rectifying to obtain 4-bromo-2,6-dimethylfluorobenzene.

[0035] Further, the sulfite is sodium sulfite.

[0036] Further, the pH value of the product system is 7-9.

[0037] Further, the temperature of vacuum concentration is ≤70 °C, and the pressure is ≤ -0.09 MPa.

[0038] Further, the temperature of rectification is 70-140 °C, and the vacuum degree is 5-15 mmHg.

[0039] According to the second aspect of the present application, a 4-bromo-2,6-dimethylfluorobenzene is provided, which is prepared by the above preparation method.

[0040] Applying the technical solution of the present application, a preparation method of 4-bromo-2,6-dimethylfluorobenzene is provided. For the first time, anhydrous diazotization is used to directly react 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex and nitrite under specific conditions to obtain 4-bromo-2,6-dimethylfluorobenzene products, without separating unstable intermediate fluoroborate; the product yield is at least 10% higher than that of the traditional technology and the purity is high, the amount of three wastes generated by the reaction is greatly reduced, the safety is good, and the product yield is stable in large-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0041] The specification drawings forming a part of the present application are used to provide a further understanding of the present application. The schematic embodiments and descriptions thereof of the present application are used to explain the present application and do not constitute an improper limitation to the present application. In the drawings:

[0042] Figure 1 is the process route diagram for preparing 4-bromo-2,6-dimethylfluorobenzene in the embodiment of the present application;

[0043] Figure 2 is the nuclear magnetic resonance hydrogen spectrum diagram of 4-bromo-2,6-dimethylfluorobenzene prepared in Example 1 of the present application;

[0044] Figure 3 is the liquid chromatography diagram of 4-bromo-2,6-dimethylfluorobenzene prepared in Example 1 of the present application. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0045] It should be noted that, without conflict, the embodiments in the present application and the features in the embodiments can be combined with each other. The present application will be described in detail below with reference to the embodiments.

[0046] As mentioned in the background art, the traditional technology for synthesizing 4-bromo-2,6-dimethylfluorobenzene is the aqueous diazotization method. This process is complex, requires separating unstable intermediates, has poor stability in large-scale production, high safety risks, low yield, and high generation of three wastes.

[0047] To solve the above problems, according to one aspect of the present application, a method for preparing 4-bromo-2,6-dimethylfluorobenzene is provided, including:

[0048] Reacting 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex and nitrite in a reaction system in the presence of an organic solvent at a temperature of 75°C to 105°C to obtain a material containing 4-bromo-2,6-dimethylfluorobenzene; wherein, the weight ratio of 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex and nitrite is 1:(0.93 to 1.75):(0.58 to 0.88).

[0049] The 4-bromo-2,6-dimethylaniline selected in the present application provides the main structure for the reaction product, such as the benzene ring, bromine element, and methyl group; the boron trifluoride ether complex selected provides the fluorine element for the reaction product, and the nitrite selected is used to generate diazonium salt. In this reaction process, there is no need to separate the intermediate fluoroborate, and it can be directly reacted to obtain 4-bromo-2,6-dimethylfluorobenzene; the selected organic solvent ensures that the reaction system is carried out under anhydrous conditions.

[0050] The reaction temperature in the present application is any value among 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C or the range value between any two of them; among the above reactants, the weight ratio of 4-bromo-2,6-dimethylaniline and boron trifluoride ether complex is, for example, any value among 1:0.93, 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.20, 1:1.25, 1:1.30, 1:1.35, 1:1.40, 1:1.45, 1:1.50, 1:1.55, 1:1.60, 1:1.65, 1:1.75 or the range value between any two of them; the weight ratio of 4-bromo-2,6-dimethylaniline and nitrite is, for example, any value among 1:0.58, 1:0.60, 1:0.62, 1:0.65, 1:0.68, 1:0.70, 1:0.72, 1:0.75, 1:0.78, 1:0.80, 1:0.82, 1:0.85, 1:0.88 or the range value between any two of them. By adopting the above reaction temperature and raw material ratio, the product purity and yield can be improved, side reactions can be reduced, and the amount of three wastes can be reduced.

[0051] The present application first uses anhydrous diazotization to directly react 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex and nitrite under specific conditions to obtain 4-bromo-2,6-dimethylfluorobenzene products, without separating the unstable intermediate fluoroborate; the product yield is at least 10% higher than that of the traditional technology, the purity is at least over 95%, the safety is good, the product yield is stable in large-scale production, and the amount of three wastes generated by the reaction is greatly reduced.

[0052] In some embodiments, the temperature of the anhydrous diazotization reaction is 85°C to 105°C, and the reaction time is at least 2 h or more; for example, the reaction temperature is 90 to 100°C, and the reaction time is 2 to 48 h; for another example, 2 to 24 h, 2 to 10 h, or 2 to 5 h. By further optimizing the reaction temperature and controlling the reaction time, the reaction by-products can be reduced, and the purity and yield of the 4-bromo-2,6-dimethylfluorobenzene product can be improved.

[0053] In some embodiments, the weight ratio of 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex, and nitrite ester is 1:(1.05 to 1.40):(0.58 to 0.70); for another example, 1:(1.05 to 1.20):(0.60 to 0.65). Further, the weight ratio of 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex, nitrite ester, and organic solvent is 1:(0.93 to 1.75):(0.58 to 0.88):(6 to 18); for example, 1:(1.05 to 1.40):(0.58 to 0.70):(7 to 15); for another example, 1:(1.05 to 1.30):(0.58 to 0.65):(10 to 14); for another example, 1:(1.05 to 1.20):(0.60 to 0.65):(7 to 13). By gradually optimizing the reaction raw material ratio, side reactions can be further reduced, which is more conducive to improving the product purity and yield and reducing the amount of three wastes.

[0054] In some embodiments, the boron trifluoride ether complex is selected from at least one of boron trifluoride tetrahydrofuran, boron trifluoride methyl ether, boron trifluoride ethyl ether, boron trifluoride dimethyl sulfide, and boron trifluoride; preferably boron trifluoride tetrahydrofuran; the nitrite ester is tert-butyl nitrite and / or isoamyl nitrite. The above raw materials are easily obtained and have good safety, and have good effects in the anhydrous diazotization reaction.

[0055] In some embodiments, the organic solvent is selected from at least one of alkane solvents, acetate solvents, ether solvents, and aromatic hydrocarbon solvents. For example, at least one of dichloromethane, dichloroethane, chloroform, heptane, n-hexane, cyclohexane, petroleum ether, ethyl acetate, isopropyl acetate, tetrahydrofuran, isopropyl ether, 1,4-dioxane, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, and acetonitrile; further, at least one of heptane, cyclohexane, dichloroethane, isopropyl acetate, 1,4-dioxane, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, and acetonitrile. The above solvents can provide anhydrous diazotization reaction conditions for the reaction, adapt to the reaction temperature, are beneficial to the progress of the reaction, and promote the product yield and purity.

[0056] In some embodiments, such as Figure 1As shown, the reaction process specifically includes: 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex and nitrite ester in a reaction system with an organic solvent. First, it is kept at a temperature of -20 to 30 °C for at least 2 h or more, then the temperature is further -10 to 20 °C and the holding time is further 2 to 24 h; after the holding is completed, it is then kept at a temperature of 75 to 105 °C for at least 2 h or more, the temperature is further 85 to 105 °C and the holding time is further 2 to 24 h, and finally a material containing 4-bromo-2,6-dimethylfluorobenzene is obtained. Using a relatively low temperature can ensure the smooth formation of the intermediate product and the intermediate product is relatively stable at this low temperature, and the intermediate product does not need to be separated at low temperature; at the same time, it can promote the reaction selectivity, reduce side reactions, and improve the product yield and purity.

[0057] In some embodiments, the reaction process specifically includes: 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex and nitrite ester in a reaction system with a first organic solvent. First, it is kept at a temperature of -20 to 30 °C for at least 2 h or more, and further kept at -10 to 20 °C for 2 to 24 h; after the holding is completed, the reaction system is then added to a second organic solvent at a temperature of 75 to 105 °C and kept at least 2 h or more, and further kept at 85 to 105 °C for 2 to 24 h; finally, a material containing 4-bromo-2,6-dimethylfluorobenzene is obtained. By quickly adding the intermediate product in the low-temperature reaction stage to the second solvent that has been heated to a high temperature, the intermediate product can immediately react, promoting the reaction rate, reducing side reactions, improving the reaction selectivity, and improving the product yield and purity.

[0058] In some embodiments, the reaction process specifically includes a first reaction process and a second reaction process carried out in sequence; First reaction process: Mix 4-bromo-2,6-dimethylaniline and a first organic solvent at a temperature of 15 to 35 °C, then control the temperature of the mixed system to -20 to 30 °C, add boron trifluoride ether complex dropwise thereto, and after the addition is completed, add nitrite ester dropwise; then, control the reaction system to be kept at a temperature of -20 to 30 °C for 2 to 24 h, and further kept at -10 to 20 °C for 2 to 5 h to obtain an intermediate product; Second reaction process: First heat the second organic solvent to a temperature of 75 to 105 °C, and further heat to 85 to 105 °C, then add the intermediate product dropwise to the second organic solvent at a temperature of 75 to 105 °C (or 85 to 105 °C) and keep it for 2 to 24 h, and further keep it for 2 to 5 h, and finally obtain a material containing 4-bromo-2,6-dimethylfluorobenzene.

[0059] In some embodiments, the first organic solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, heptane, n-hexane, cyclohexane, petroleum ether, ethyl acetate, isopropyl acetate, tetrahydrofuran, isopropyl ether, 1,4-dioxane, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, and acetonitrile. The above solvents have good solubility for raw materials, provide an anhydrous reaction condition for the reaction, adapt to the reaction temperature, are beneficial to the progress of the reaction and promote the product yield and purity.

[0060] In some embodiments, the second organic solvent is selected from at least one of heptane, cyclohexane, dichloroethane, isopropyl acetate, 1,4-dioxane, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, and acetonitrile. The above solvents have a wide range of applications, can be applied to reactions in the low-temperature stage and the high-temperature stage, and are beneficial to convenient operation.

[0061] In some embodiments, the weight ratio of 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex, nitrite, and the first organic solvent is 1:(0.93 - 1.75):(0.58 - 0.88):(6 - 13); further 1:(1.05 - 1.40):(0.58 - 0.70):(7 - 11). Using the above ratio is more beneficial to the anhydrous diazotization reaction, promotes the reaction rate and selectivity, and improves the product yield and purity.

[0062] In some embodiments, the reaction system further contains a catalyst, which is selected from at least one of metal oxides, metal halides, metal sulfates, and metal powders; for example, the metal oxides are selected from at least one of magnesium oxide, manganese dioxide, copper oxide, cuprous oxide, zinc oxide, and iron oxide; the metal halides are selected from at least one of nickel fluoride, nickel chloride, nickel bromide, cuprous iodide, copper bromide, cuprous bromide, copper chloride, cuprous chloride, zinc iodide, zinc bromide, zinc chloride, and iron chloride; the metal sulfate is at least one of copper sulfate, magnesium sulfate, nickel sulfate, iron sulfate, manganese sulfate, and zinc sulfate; the metal powder is at least one of copper powder, zinc powder, iron powder, and manganese powder. By adding a catalyst to the reaction system, the reaction activity and reaction rate can be improved, the reaction time can be shortened, and the yield can be increased.

[0063] In some embodiments, the weight ratio of 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex, nitrite, and catalyst is 1:(0.93 to 1.75):(0.58 to 0.88):(0.01 to 0.10); for example, 1:(1.05 to 1.40):(0.58 to 0.70):(0.02 to 0.05). Further, the weight ratio of 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex, nitrite, organic solvent, and catalyst is 1:(0.93 to 1.75):(0.58 to 0.88):(6 to 18):(0.01 to 0.10); for example, 1:(1.05 to 1.40):(0.58 to 0.70):(8 to 15):(0.02 to 0.05); and for another example, 1:(1.05 to 1.20):(0.60 to 0.65):(8 to 13):(0.02 to 0.04). By further optimizing the amount of catalyst used, while ensuring the premise of improving the reaction efficiency, the amount of catalyst used is controlled to save costs.

[0064] In some embodiments, the feeding order of each raw material in the reaction system is as follows: First, mix 4-bromo-2,6-dimethylaniline and the first organic solvent at room temperature (15 to 35 °C), control the temperature of the reaction system to -20 to 30 °C, then add boron trifluoride ether complex dropwise to the mixed system. After the addition is completed, then add nitrite dropwise to the reaction system. After the addition is completed, keep the temperature for at least 2 h or more; heat the second solvent and the optional catalyst to 75 to 105 °C to form a mixed system; add the above reaction system dropwise to the mixed system that has been heated to 75 to 105 °C, continue the reaction, keep the temperature for at least 2 h or more, and finally cool down to room temperature (15 to 35 °C). Adjust the pH to 7 to 9 using an aqueous sodium carbonate solution, and then successively carry out purification processes such as washing the organic phase with water, concentrating under reduced pressure, and rectification. Finally, the product yield reaches 78%, and the purity reaches 99.5%. During the above anhydrous diazotization reaction process, the feeding order is optimized, and the rapid dropping timing of the reaction system in the second solvent is optimized to further promote the reaction rate and improve the product yield. The reaction time can be adjusted according to the actual situation.

[0065] In some embodiments, the preparation method further includes adding sulfite to the material containing 4-bromo-2,6-dimethylfluorobenzene after the reaction ends to form a product system, and purifying the product system; the purification process sequentially includes: adjusting the product system to be alkaline, washing the organic phase with water, concentrating the organic phase under reduced pressure to remove toluene until no distillate comes out, transferring the material to a distillation still for distillation to obtain 4-bromo-2,6-dimethylfluorobenzene; wherein, the sulfite is sodium sulfite; the pH value of the product system can be adjusted to 7-9 with an aqueous sodium carbonate solution; the temperature of concentration under reduced pressure is ≤70°C, and the pressure is ≤ -0.09 MPa; for example, the temperature of concentration under reduced pressure is ≤60°C, and the pressure is ≤ -0.08 MPa; the temperature of distillation is 70-140°C, and the vacuum degree of distillation is 5-15 mmHg; for example, the temperature of distillation is 100-135°C, and the vacuum degree of distillation is 8-12 mmHg; adding sulfite to the product system is used to quench the oxidizing property of the reaction, which is more conducive to the subsequent purification process, and the product purity can be further improved through concentration under pressure and distillation.

[0066] According to the second aspect of the present application, there is provided a 4-bromo-2,6-dimethylfluorobenzene, which is prepared by the above preparation method. The purity of the 4-bromo-2,6-dimethylfluorobenzene prepared by the above method reaches 99.5%, and the product yield reaches 78%.

[0067] The following further describes the present application in detail with specific embodiments, and these embodiments should not be construed as limiting the scope claimed by the present application.

[0068] The raw materials used in the following examples of the present application are all prior arts and are commercially available.

[0069] Example 1

[0070] At room temperature, add 180 g of 4-bromo-2,6-dimethylaniline (CAS No.: 24596-19-8) and 1559 g of toluene to reaction flask 1. Cool the temperature to -5°C, and while controlling the temperature at -5°C, dropwise add 207.7 g of boron trifluoride tetrahydrofuran (CAS No.: 462-34-0) to the reaction system. After the addition is complete, then dropwise add 110.7 g of isoamyl nitrite (CAS No.: 110-46-3). After the addition is complete, keep the reaction at a constant temperature for 2 h. Add 467.6 g of toluene and 3.6 g of copper(I) iodide to reaction flask 2, and heat up to 100°C; dropwise add the reaction system in reaction flask 1 to reaction flask 2. After the addition is complete, keep the reaction at a constant temperature for 3 h, and then cool down to room temperature to form a product system; dissolve 3.6 g of sodium sulfite in 180 g of water to prepare a sodium sulfite solution, and add the sodium sulfite solution to the above product system; dropwise add an aqueous sodium carbonate solution (10 wt%) to the product system to adjust the pH value of the reaction system to 8; perform liquid separation on the product system (separate the organic phase and the aqueous phase); wash the organic phase with 360 g of tap water, and concentrate the organic phase under reduced pressure (temperature is 60°C, pressure is -0.08 MPa) until toluene stops distilling, and transfer the bottom to a distillation still (temperature is 130°C, vacuum degree is 10 mmHg), and distill to obtain 140.6 g of product; detect that the product structure is 4-bromo-2,6-difluorobenzene, and its nuclear magnetic resonance hydrogen spectrum is as Figure 2 shown, and the product yield is 77%; use liquid phase analysis method to detect that the product purity reaches 99.5%, and the HPLC is as Figure 3 shown.

[0071] Example 2 (industrial scale)

[0072] At room temperature, 3062 kg of toluene was added to an 8000 L enamel reactor 1, and then 352 kg of 4-bromo-2,6-dimethylaniline (CAS No.: 24596-19-8) was added. The temperature was lowered to -5°C, and while controlling the temperature at -5°C, 406.1 kg of boron trifluoride tetrahydrofuran (CAS No.: 462-34-0) was added dropwise to the system. After the dropwise addition was completed, 216.3 kg of isoamyl nitrite (CAS No.: 110-46-3) was added dropwise. After the dropwise addition was completed, the reaction was carried out under insulation for 2 h. 918.7 Kg of toluene and 7.04 kg of cuprous iodide were added to an 8000 L enamel reactor 2, and the temperature was raised to 100°C; the reaction system in reactor 1 was transferred to reactor 2 through a pipeline. After the transfer was completed, the reaction was carried out under insulation for 3 h, and then the temperature was lowered to room temperature to form a product system; 7.04 kg of sodium sulfite was dissolved in 352 kg of water to prepare a sodium sulfite solution, and the sodium sulfite solution was added to the above product system; an aqueous sodium carbonate solution (10 wt%) was added dropwise to the product system to adjust the pH value of the system to 8, and the product system was separated by liquid separation (separating the organic phase and the aqueous phase); the organic phase was washed with 704 kg of tap water, and after the organic phase was concentrated under reduced pressure (temperature: 60°C, pressure: -0.08 MPa) to remove toluene, the bottom was transferred to a distillation kettle (temperature: 130°C, vacuum degree: 10 mmHg), and 278.6 kg of product was obtained by distillation; the structure of the product was detected to be 4-bromo-2,6-difluorobenzene, and its nuclear magnetic resonance hydrogen spectrum was Figure 2 similar, and the product yield was 78%; the purity of the product was detected by liquid phase analysis to reach 99.5%, and it was Figure 3 similar to HPLC.

[0073] Example 3

[0074] At room temperature, 100 g of 4-bromo-2,6-dimethylaniline (CAS No.: 24596-19-8) and 860 g of toluene were added to reaction flask 1. The temperature was lowered to -10°C, and while controlling the temperature at -5°C, 93.0 g of boron trifluoride tetrahydrofuran (CAS No.: 462-34-0) was added dropwise to the reaction system. After the addition was complete, 58 g of isoamyl nitrite (CAS No.: 110-46-3) was added dropwise. After the addition was complete, the reaction was carried out under insulation for 4 h. 173.2 g of toluene and 2.0 g of copper(I) iodide were added to reaction flask 2, and the temperature was raised to 95°C; the reaction system in reaction flask 1 was added dropwise to reaction flask 2. After the addition was complete, the reaction was carried out under insulation for 3 h, and then the temperature was lowered to room temperature to form a product system; 2.0 g of sodium sulfite was dissolved in 100 g of water to prepare a sodium sulfite solution, and the sodium sulfite solution was added to the above product system; an aqueous sodium carbonate solution (10 wt%) was added dropwise to the product system to adjust the pH value of the reaction system to 8; the product system was separated by liquid-liquid extraction (separating the organic phase and the aqueous phase); the organic phase was washed with 100 g of tap water, and the organic phase was concentrated under reduced pressure (temperature: 50°C, pressure: -0.07 MPa) to remove toluene until no distillate came out. The bottom product was transferred to a distillation still (temperature: 70°C, vacuum: 5 mmHg), and 66 g of the product was obtained by distillation; the structure of the product was detected to be 4-bromo-2,6-dimethylfluorobenzene, and the product yield was 65%; the purity of the product was detected by liquid phase analysis to reach 98%.

[0075] Example 4

[0076] At room temperature, 100 g of 4-bromo-2,6-dimethylaniline (CAS No.: 24596-19-8) and 1299 g of toluene were added to reaction flask 1. The temperature was lowered to -10°C, and while controlling the temperature at -5°C, 175 g of boron trifluoride tetrahydrofuran (CAS No.: 462-34-0) was added dropwise to the reaction system. After the addition was complete, 88 g of isoamyl nitrite (CAS No.: 110-46-3) was added dropwise. After the addition was complete, the reaction was carried out under insulation for 4 h. 260 g of toluene and 5.0 g of copper(I) iodide were added to reaction flask 2, and the temperature was raised to 95°C; the reaction system in reaction flask 1 was added dropwise to reaction flask 2. After the addition was complete, the reaction was carried out under insulation for 3 h, and then the temperature was lowered to room temperature to form a product system; 2.0 g of sodium sulfite was dissolved in 100 g of water to prepare a sodium sulfite solution, and the sodium sulfite solution was added to the above product system; an aqueous sodium carbonate solution (10 wt%) was added dropwise to the product system to adjust the pH value of the reaction system to 8; the product system was separated by liquid-liquid extraction (separating the organic phase and the aqueous phase); the organic phase was washed with 100 g of tap water, and the organic phase was concentrated under reduced pressure (temperature: 50°C, pressure: -0.07 MPa) to remove toluene until no distillate came out. The bottom product was transferred to a distillation still (temperature: 70°C, vacuum: 5 mmHg), and 71.0 g of the product was obtained by distillation; the structure of the product was detected to be 4-bromo-2,6-dimethylfluorobenzene, and the product yield was 70%; the purity of the product was detected by liquid phase analysis to reach 96%.

[0077] Example 5

[0078] Add 100 g of 4-bromo-2,6-dimethylaniline (CAS No.: 24596-19-8) and 779 g of toluene to reaction flask 1 at room temperature. Cool the temperature to -10°C, and while controlling the temperature at -5°C, dropwise add 105 g of boron trifluoride tetrahydrofuran (CAS No.: 462-34-0) to the reaction system. After the addition is complete, dropwise add 61 g of isoamyl nitrite (CAS No.: 110-46-3). After the addition is complete, keep the reaction at a constant temperature for 4 h. Add 260 g of toluene and 2.0 g of cuprous iodide to reaction flask 2, and raise the temperature to 100°C; dropwise add the reaction system in reaction flask 1 to reaction flask 2. After the addition is complete, keep the reaction at a constant temperature for 3 h, and then cool to room temperature to form a product system; dissolve 2.0 g of sodium sulfite in 100 g of water to prepare a sodium sulfite solution, and add the sodium sulfite solution to the above product system; dropwise add an aqueous sodium carbonate solution (10 wt%) to the product system to adjust the pH value of the reaction system to 8; perform liquid separation on the product system (separate the organic phase and the aqueous phase); wash the organic phase with 100 g of tap water, and concentrate the organic phase under reduced pressure (temperature is 50°C, pressure is -0.07 MPa) until toluene stops distilling, transfer the bottom liquid to a distillation kettle (temperature is 70°C, vacuum degree is 5 mmHg), and distill to obtain 75.1 g of the product; detect that the product structure is 4-bromo-2,6-dimethylfluorobenzene, the product yield is 74%; use liquid phase analysis method to detect that the product purity reaches 98%.

[0079] Example 6

[0080] At room temperature, 100 g of 4-bromo-2,6-dimethylaniline (CAS No.: 24596-19-8) and 866 g of toluene were added to reaction flask 1. The temperature was lowered to -10 °C, and while controlling the temperature at -5 °C, 140 g of boron trifluoride tetrahydrofuran (CAS No.: 462-34-0) was added dropwise to the reaction system. After the addition was complete, 70 g of isoamyl nitrite (CAS No.: 110-46-3) was added dropwise. After the addition was complete, the reaction was carried out under heat preservation for 4 h. 260 g of toluene and 5 g of copper(I) iodide were added to reaction flask 2, and the temperature was raised to 100 °C; the reaction system in reaction flask 1 was added dropwise to reaction flask 2. After the addition was complete, the reaction was carried out under heat preservation for 3 h, and then the temperature was lowered to room temperature to form a product system; 2.0 g of sodium sulfite was dissolved in 100 g of water to prepare a sodium sulfite solution, and the sodium sulfite solution was added to the above product system; an aqueous sodium carbonate solution (10 wt%) was added dropwise to the product system to adjust the pH value of the reaction system to 8; the product system was separated by liquid separation (separating the organic phase and the aqueous phase); the organic phase was washed with 100 g of tap water, and the organic phase was concentrated under reduced pressure (temperature: 50 °C, pressure: -0.07 MPa) until toluene stopped distilling, and the bottom product was transferred to a distillation still (temperature: 70 °C, vacuum degree: 5 mmHg), and 76.1 g of the product was obtained by distillation; the structure of the product was detected to be 4-bromo-2,6-dimethylfluorobenzene, and the product yield was 75%; the purity of the product was detected by liquid phase analysis to reach 98%.

[0081] Example 7

[0082] The difference between Example 7 and Example 1 is that boron trifluoride tetrahydrofuran was replaced by boron trifluoride dimethyl ether.

[0083] Example 8

[0084] The difference between Example 8 and Example 1 is that boron trifluoride tetrahydrofuran was replaced by boron trifluoride diethyl ether.

[0085] Example 9

[0086] The difference between Example 9 and Example 1 is that boron trifluoride tetrahydrofuran was replaced by boron trifluoride dimethyl sulfide.

[0087] Example 10

[0088] The difference between Example 10 and Example 1 is that isoamyl nitrite was replaced by tert-butyl nitrite.

[0089] Example 11

[0090] The difference between Example 11 and Example 1 is that the solvent toluene was replaced by heptane.

[0091] Example 12

[0092] The difference between Example 12 and Example 1 is that the solvent toluene was replaced by isopropyl acetate.

[0093] Example 13

[0094] The difference between Example 13 and Example 1 is that the solvent toluene is replaced by 1,4 - dioxane.

[0095] Example 14

[0096] The difference between Example 14 and Example 1 is that no catalyst is added during the reaction process.

[0097] Comparative Example 1

[0098] The difference between Comparative Example 1 and Example 1 is that the reaction temperature of the second reaction stage, which is 100 °C, is replaced by 65 °C.

[0099] Comparative Example 2

[0100] The difference between Comparative Example 2 and Example 1 is that the weight of boron trifluoride tetrahydrofuran is replaced by 144 g.

[0101] Comparative Example 3

[0102] The difference between Comparative Example 3 and Example 1 is that the weight of boron trifluoride tetrahydrofuran is replaced by 342 g.

[0103] Comparative Example 4

[0104] The difference between Comparative Example 4 and Example 1 is that the weight of isoamyl nitrite is replaced by 72 g.

[0105] Comparative Example 5

[0106] The difference between Comparative Example 5 and Example 1 is that the weight of isoamyl nitrite is replaced by 180 g.

[0107] Table 1

[0108]

[0109]

[0110] As can be seen from the detection data in Table 1, in Examples 1 to 14 of the present application, 4-bromo-2,6-dimethylfluorobenzene products are obtained by carrying out an anhydrous diazotization reaction on 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex and nitrite under specific conditions; this method realizes that there is no need to separate the unstable intermediate fluoroborate during the reaction process, simplifies the process, is convenient to operate, especially has high safety during large-scale production, stable yield, and greatly reduces the amount of three wastes generated by this anhydrous diazotization reaction. Further, by adopting a two-step reaction process, first reacting at a low temperature to keep the structure of the intermediate product stable, and then reacting at a high temperature, the reaction selectivity can be promoted, and the yield of 4-bromo-2,6-dimethylfluorobenzene reaches more than 70%, and the purity reaches more than 98%. Furthermore, by optimizing the raw material ratio and reaction temperature, the product purity is as high as 99.5%, and the product yield is as high as 78%.

[0111] Although Comparative Examples 1 to 5 adopt the synthesis process of the present application, the control of the raw material ratio and reaction temperature is inappropriate, resulting in various problems; in Comparative Example 1, Comparative Example 2 and Comparative Example 4, the raw material ratio or reaction temperature is inappropriate, resulting in side reactions, low product yield, low purity, long reaction time or raw material residue; although the product yields in Comparative Example 3 and Comparative Example 5 are good, the raw materials are in excessive amounts, resulting in an increase in impurities in the reaction system, poor product purity, and waste of raw materials.

[0112] It should be noted that the terms "first", "second", etc. in the specification and claims of the present application are used to distinguish similar objects, and do not necessarily have to be used to describe a specific order or sequence. It should be understood that such terms can be interchanged under appropriate circumstances so that the embodiments of the present application described herein can be implemented in an order other than those described herein, for example.

[0113] The above are only the preferred embodiments of the present application and are not used to limit the present application. For those skilled in the art, the present application can have various changes and modifications. Any modification, equivalent replacement, improvement, etc. made within the spirit and principle of the present application shall be included within the protection scope of the present application.

Claims

1. A method for preparing 4-bromo-2,6-dimethylfluorobenzene, characterized in that, The preparation method includes: 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex and nitrite are reacted in a reaction system in the presence of an organic solvent at a temperature of 75°C to 105°C to obtain a material containing 4-bromo-2,6-dimethylfluorobenzene; wherein, the weight ratio of the 4-bromo-2,6-dimethylaniline, the boron trifluoride ether complex and the nitrite is 1: (0.93～1.75):(0.58～0.88)。 2. The preparation method of 4-bromo-2,6-dimethylfluorobenzene according to claim 1, characterized in that, The temperature of the reaction is 85°C to 105°C; and / or, the reaction time is at least 2 h or more; and / or, the weight ratio of the 4-bromo-2,6-dimethylaniline, the boron trifluoride ether complex and the nitrite is 1:(1.05 to 1.40):(0.58 to 0.70); and / or, the weight ratio of the 4-bromo-2,6-dimethylaniline, the boron trifluoride ether complex, the nitrite and the organic solvent is 1:(0.93 to 1.75):(0.58 to 0.88):(6 to 18); Preferably, the weight ratio of the 4-bromo-2,6-dimethylaniline, the boron trifluoride ether complex, the nitrite and the organic solvent is 1:(1.05 to 1.40):(0.58 to 0.70):(8 to 15).

3. The preparation method of 4-bromo-2,6-dimethylfluorobenzene according to claim 1 or 2, characterized in that, The boron trifluoride ether complex is selected from at least one of boron trifluoride tetrahydrofuran, boron trifluoride methyl ether, boron trifluoride ethyl ether, boron trifluoride dimethyl sulfide and boron trifluoride; and / or, the nitrite is tert-butyl nitrite and / or isoamyl nitrite; and / or, the organic solvent is selected from at least one of alkane solvents, acetate solvents, ether solvents and aromatic hydrocarbon solvents; Preferably, the organic solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, heptane, n-hexane, cyclohexane, petroleum ether, ethyl acetate, isopropyl acetate, tetrahydrofuran, isopropyl ether, 1,4-dioxane, toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene and acetonitrile; more preferably at least one of heptane, cyclohexane, dichloroethane, isopropyl acetate, 1,4-dioxane, toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene and acetonitrile.

4. The preparation method of 4-bromo-2,6-dimethylfluorobenzene according to any one of claims 1 to 3, characterized in that, The process of the reaction specifically includes: 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex and nitrite in the reaction system in the presence of the organic solvent are first kept at a temperature of -20 to 30°C for at least 2 h or more; after the heat preservation is completed, then kept at a temperature of 75 to 105°C for at least 2 h or more to obtain the material containing 4-bromo-2,6-dimethylfluorobenzene; Preferably, the process of the reaction specifically includes: 4-bromo-2,6-dimethylaniline, boron trifluoride ether complex and nitrite in the reaction system in the presence of the organic solvent are first kept at a temperature of -10 to 20°C for 2 to 24 h; after the heat preservation is completed, then kept at a temperature of 85 to 105°C for 2 to 24 h to obtain the material containing 4-bromo-2,6-dimethylfluorobenzene.

5. The preparation method of 4-bromo-2,6-dimethylfluorobenzene according to any one of claims 1 to 4, characterized in that, The process of the reaction specifically includes: in a reaction system in the presence of a first organic solvent, the 4-bromo-2,6-dimethylaniline, the boron trifluoride ether complex, and the nitrite ester are first kept warm at a temperature of -20 to 30 °C for at least 2 h or more; after the heat preservation ends, the reaction system is then added to a second organic solvent at a temperature of 75 to 105 °C and kept warm for at least 2 h or more to obtain the material containing 4-bromo-2,6-dimethylfluorobenzene; Preferably, the process of the reaction specifically includes: in a reaction system in the presence of the first organic solvent, the 4-bromo-2,6-dimethylaniline, the boron trifluoride ether complex, and the nitrite ester are first kept warm at a temperature of -10 to 20 °C for 2 to 24 h; after the heat preservation ends, the reaction system is added to a second organic solvent at a temperature of 85 to 105 °C and kept warm for 2 to 24 h to obtain the material containing 4-bromo-2,6-dimethylfluorobenzene; Preferably, the process of the reaction specifically includes a first reaction process and a second reaction process that are carried out in sequence; The first reaction process: The 4-bromo-2,6-dimethylaniline and the first organic solvent are mixed at a temperature of 15 to 35 °C, then the temperature of the mixed system is controlled to -20 to 30 °C, the boron trifluoride ether complex is added dropwise thereto, and after the dropwise addition ends, the nitrite ester is added dropwise; then, the reaction system is controlled to be kept warm at a temperature of -20 to 30 °C for 2 to 24 h to obtain an intermediate product; The second reaction process: First, the second organic solvent is heated to a temperature of 75 to 105 °C, and then the intermediate product is added dropwise to the second organic solvent and kept warm for 2 to 24 h to obtain the material containing 4-bromo-2,6-dimethylfluorobenzene; Preferably, the process of the reaction specifically includes a first reaction process and a second reaction process that are carried out in sequence; The first reaction process: The 4-bromo-2,6-dimethylaniline and the first organic solvent are mixed at a temperature of 15 to 35 °C, then the temperature of the mixed system is controlled to -10 to 20 °C, the boron trifluoride ether complex is added dropwise thereto, and after the dropwise addition ends, the nitrite ester is added dropwise; then, the reaction system is controlled to be kept warm at a temperature of -10 to 20 °C for 2 to 5 h to obtain an intermediate product; The second reaction process: First, the second organic solvent is heated to a temperature of 85 to 105 °C, and then the intermediate product is added dropwise to the second organic solvent and kept warm for 2 to 5 h to obtain the material containing 4-bromo-2,6-dimethylfluorobenzene.

6. The preparation method of 4-bromo-2,6-dimethylfluorobenzene according to claim 5, characterized in that, The first organic solvent is selected from at least one of dichloromethane, dichloroethane, chloroform, heptane, n-hexane, cyclohexane, petroleum ether, ethyl acetate, isopropyl acetate, tetrahydrofuran, isopropyl ether, 1,4-dioxane, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, and acetonitrile; And / or, the second organic solvent is selected from at least one of heptane, cyclohexane, dichloroethane, isopropyl acetate, 1,4-dioxane, toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, and acetonitrile; And / or, the weight ratio of the 4-bromo-2,6-dimethylaniline, the boron trifluoride ether complex, the nitrite ester, and the first organic solvent is 1:(0.93 to 1.75):(0.58 to 0.88):(6 to 13); Preferably, the weight ratio of the 4-bromo-2,6-dimethylaniline, the boron trifluoride ether complex, the nitrite ester, and the first organic solvent is 1:(1.05 to 1.40):(0.58 to 0.70):(7 to 11).

7. The preparation method of 4-bromo-2,6-dimethylfluorobenzene according to any one of claims 1 to 6, characterized in that, The reaction system further comprises a catalyst; the catalyst is selected from at least one of metal oxides, metal halides, metal sulfates, and metal powders; Preferably, the metal oxide is selected from at least one of magnesium oxide, manganese dioxide, copper oxide, cuprous oxide, zinc oxide, and iron oxide; Preferably, the metal halide is selected from at least one of nickel fluoride, nickel chloride, nickel bromide, cuprous iodide, copper bromide, cuprous bromide, copper chloride, cuprous chloride, zinc iodide, zinc bromide, zinc chloride, and iron chloride; Preferably, the metal sulfate is at least one of copper sulfate, magnesium sulfate, nickel sulfate, iron sulfate, manganese sulfate, and zinc sulfate; Preferably, the metal powder is at least one of copper powder, zinc powder, iron powder, and manganese powder.

8. The preparation method of 4-bromo-2,6-dimethylfluorobenzene according to claim 7, characterized in that, The weight ratio of the 4-bromo-2,6-dimethylaniline, the boron trifluoride ether complex, the nitrite ester, and the catalyst is 1:(0.93 to 1.75): (0.58～0.88):(0.01～0.10)； Preferably, the weight ratio of the 4-bromo-2,6-dimethylaniline, the boron trifluoride ether complex, the nitrite ester, and the catalyst is 1:(1.05 to 1.40):(0.58 to 0.70):(0.02 to 0.05).

9. The preparation method of 4-bromo-2,6-dimethylfluorobenzene according to any one of claims 1 to 8, characterized in that, The preparation method further comprises adding a sulfite to the material containing 4-bromo-2,6-dimethylfluorobenzene after the reaction to form a product system, and purifying the product system; The purification process sequentially includes: adjusting the product system to be alkaline, washing with water, concentrating under reduced pressure, and rectifying to obtain the 4-bromo-2,6-dimethylfluorobenzene; Preferably, the sulfite is sodium sulfite; Preferably, the pH value of the product system is 7 to 9; Preferably, the temperature of the concentration under reduced pressure is ≤70°C, and the pressure is ≤ -0.09 MPa; Preferably, the temperature of the rectification is 70 to 140°C, and the vacuum degree is 5 to 15 mmHg.

10. A 4-bromo-2,6-dimethylfluorobenzene, characterized in that, It is prepared by using the preparation method according to any one of claims 1 to 9.

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