Synthesis method of 1, 5-dibromo-3-fluoro-2, 4-xylene

Abstract

The invention provides a synthesis method of 1, 5-dibromo-3-fluoro-2, 4-xylene, and belongs to the field of synthesis of fine chemical intermediates. According to the method, 2-fluorine-m-xylene is taken as a starting raw material, and 1, 5-dibromo-3-fluoro-2, 4-xylene is obtained through two steps of bromination and reduction. According to the synthesis method, the problem that accurate bromination positioning cannot be realized is solved by optimizing reaction raw materials and operation steps, so that the purity and yield of the product are greatly improved. The synthesis method is simple and stable, and has great industrial production value.

Description

Technical Field

[0001] This invention discloses a method for synthesizing 1,5-dibromo-3-fluoro-2,4-dimethylbenzene, which belongs to the field of fine chemical intermediate synthesis. Background Technology

[0002] 1,5-Dibromo-3-fluoro-2,4-xylene is an important raw material for the preparation of organic light-emitting diodes (OLEDs). Currently, there are very few published domestic documents on the preparation methods of this compound; the main routes are as follows:

[0003] A. Kyulux Corporation of Japan reported a method for direct bromination using 2-fluoro-m-xylene as a raw material and iodine as a catalyst (JP202332402). Although this process is simple, it cannot accurately locate the position of bromine.

[0004] B. Changzhou Beidijiaer Biotechnology Co., Ltd. publicly reported a method using 3,5-dimethyl-4-fluoroaniline as raw material, bromination with NBS reagent, and diazotization and deamination of the intermediate after separation and purification (CN118388315). Although this process can solve the positioning problem, the reaction steps are long and complex, the diazotization reaction produces a large amount of wastewater that is difficult to treat, and there are significant safety hazards.

[0005] Therefore, it is still necessary to conduct in-depth research to find a suitable method for synthesizing 1,5-dibromo-3-fluoro-2,4-xylene under high bromination orientation. Summary of the Invention

[0006] The purpose of this invention is to provide a low-cost, high-yield, environmentally friendly, and easily industrially scalable method for preparing 1,5-dibromo-3-fluoro-2,4-xylene, addressing the shortcomings of existing technologies. Using 2-fluoro-m-xylene as a raw material, the invention overcomes the problem of precise localization during bromination through a two-step reaction involving bromination and reduction. Furthermore, it utilizes the ease of removal at the para position during dehalogenation reduction to synthesize 1,5-dibromo-3-fluoro-2,4-xylene. This synthetic method has not been publicly reported to date.

[0007] The process route for 1,5-dibromo-3-fluoro-2,4-xylene in this invention is represented by the following reaction equation:

[0008]

[0009] The method for synthesizing 1,5-dibromo-3-fluoro-2,4-xylene according to the present invention includes the following steps:

[0010] A. Using 2-fluoro-m-xylene as a starting material, 1,2,3-tribromo-5-fluoro-4,6-xylene is obtained by reacting it with a brominating agent in the presence of a Lewis acid catalyst.

[0011] B. 1,2,3-tribromo-5-fluoro-4,6-dimethylbenzene reacts with a reducing agent to give 1,5-dibromo-3-fluoro-2,4-dimethylbenzene.

[0012] Furthermore, in the above technical solution, the reaction steps are specifically as follows:

[0013] (1) Mix 2-fluoro-m-xylene with an organic solvent, add a Lewis acid catalyst, and add a brominating reagent dropwise to brominate the mixture and obtain a reaction solution.

[0014] (2) Quenching the reaction solution to separate it into layers yields 1,2,3-tribromo-5-fluoro-4,6-xylene;

[0015] (3) 1,2,3-tribromo-5-fluoro-4,6-dimethylbenzene was reacted with a reducing agent under acidic conditions to obtain crude 1,5-dibromo-3-fluoro-2,4-dimethylbenzene;

[0016] (4) The crude 1,5-dibromo-3-fluoro-2,4-dimethylbenzene was recrystallized to obtain 1,5-dibromo-3-fluoro-2,4-dimethylbenzene.

[0017] Furthermore, in step (1) of the above technical solution, the organic solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, and DMF; the mass ratio of the organic solvent to 2-fluoro-m-xylene is 1-5:1.

[0018] Furthermore, in step (1) of the above technical solution, the Lewis acid catalyst is selected from ferric chloride, aluminum chloride, ferric bromide, and iron powder; the weight ratio of the Lewis acid catalyst to 2-fluoro-m-xylene is 0.005-0.05:1.

[0019] Furthermore, in step (1) of the above technical solution, the brominating reagent is selected from bromine or N-bromosuccinimide; the molar ratio of the brominating reagent to 2-fluoro-m-xylene is 1-4:1.

[0020] Furthermore, in step (1) of the above technical solution, the reaction temperature is 0-85℃ and the reaction time is 10-30h; in step (3), the reaction temperature is 60-80℃ and the reaction time is 10-15h.

[0021] Furthermore, in step (2) of the above technical solution, sodium sulfite, sodium bisulfite, sodium bicarbonate or sodium carbonate are used for quenching, and the quenching temperature is 10-30℃.

[0022] Furthermore, in step (3) of the above technical solution, the reducing agent is selected from iron powder or zinc powder; the molar ratio of the reducing agent to 1,2,3-tribromo-5-fluoro-4,6-xylene is 1-3:1.

[0023] Furthermore, in step (3) of the above technical solution, the acid is selected from one or two of ammonium chloride, ammonium bromide, hydrochloric acid, and sulfuric acid; the molar ratio of the acidic reagent to 1,2,3-tribromo-5-fluoro-4,6-xylene is 0.5-2.5:1.

[0024] Furthermore, in step (4) of the above technical solution, the recrystallization uses one or two of methylcyclohexane, cyclohexane, ethanol, toluene, dichloromethane, and ethyl acetate.

[0025] Further, in the above technical solution, the typical operating steps are as follows: Add the raw material 2-fluoro-m-xylene to the reactor, and add the corresponding organic solvent at a raw material mass ratio of 1-1.5:1; add a Lewis acid catalyst at 0.5-5% of the mass of 2-fluoro-m-xylene; then slowly add the brominating reagent at a 2-fluoro-m-xylene molar ratio of 1:1-4, with the reaction temperature at 0-85℃ and the reaction time at 10-30 h. The brominating reagents used are: bromine, N-bromosuccinimide (NBS); the organic solvents are: dichloromethane, 1,2-dichloroethane, chloroform, DMF; and the Lewis acid catalysts are: ferric chloride, aluminum trichloride, and ferric tribromide.

[0026] The bromination reaction was controlled by gas chromatography (GC). After the reaction was completed, the reaction solution was quenched using solvents including sodium sulfite, sodium bisulfite, sodium bicarbonate, and sodium carbonate, at temperatures ranging from 10 to 30 °C. After post-treatment, 1,2,3-tribromo-5-fluoro-4,6-xylene was obtained with a conversion rate of 85% and a molar yield exceeding 90%.

[0027] Add 1,2,3-tribromo-5-fluoro-4,6-xylene to the reaction vessel, along with an acidic reagent at a molar ratio of 1:0.5-2.5; add a reducing agent at a molar ratio of 1:1-3. The acidic reagent may be ammonium chloride, ammonium bromide, hydrochloric acid, or sulfuric acid; the reducing agent may be iron powder or zinc powder; the reaction temperature is 60–80℃, and the reaction time is 10–15 h.

[0028] The final product, 1,5-dibromo-3-fluoro-2,4-xylene, is a colorless solid or a white crystalline solid, which can be purified by one or more recrystallization solvents. Recrystallization solvents include methylcyclohexane, cyclohexane, ethanol, toluene, dichloromethane, and ethyl acetate. The product was confirmed by 1H NMR spectroscopy. 1 H NMR (400M Hz, DMSO-d6) δ7.72 (d, J = 1.8 Hz, 1H), 2.22 (d, J = 2.7 Hz, 6H). Detailed Implementation

[0029] The following non-limiting embodiments are intended to enable those skilled in the art to more fully understand the invention, but do not limit the invention in any way.

[0030] Unless otherwise specified, the experimental methods described in the following examples are conventional methods; the reagents and materials described are commercially available unless otherwise specified.

[0031] Example 1

[0032] The organic solvent is dichloromethane, the Lewis acid catalyst is iron powder, the brominating reagent is bromine, the reducing agent is iron powder, and the acidic reagent is hydrochloric acid.

[0033] 1) Add 200g of 2-fluoro-m-xylene and 600g of dichloromethane to the reactor, stir and add 4g of iron powder. Control the reactor temperature at 0-10℃, and slowly add 386.1g of excess bromine dropwise over 8 hours. After the bromine is added, slowly raise the reactor temperature to 40℃ and continue the reaction at 40℃ for 3 hours. Monitor the reaction by gas chromatography (GC) during the reaction. The reaction is considered complete when the 2-fluoro-m-xylene content is ≤0.5%. An 8% sodium bisulfite and sodium bicarbonate aqueous solution was added dropwise to the reactor until the solution changed from reddish-brown to light yellow. The amount added was 167.6 g. The mixture was stirred for 2 hours, filtered under reduced pressure, and dried to obtain 377.8 g of the intermediate 1,2,3-tribromo-5-fluoro-4,6-xylene with a purity of 76% and a yield of 65%. Part of the raw material was converted into 1,2-dibromo-4-fluoro-3,5-xylene with a purity of 24%. The raw material reacted completely. Even after adding bromine, it was still impossible to completely convert 1,2-dibromo-4-fluoro-3,5-xylene into 1,2,3-tribromo-5-fluoro-4,6-xylene.

[0034] 2) Add 377.8 g of the above intermediate 1,2,3-tribromo-5-fluoro-4,6-xylene and 377.8 g of dichloromethane to the reactor. Add 216.4 g of 15% hydrochloric acid dropwise. After the solution is completely added, slowly raise the reactor temperature to 40°C. Add 117.2 g of iron powder in batches over 6 hours, maintaining the temperature for 4 hours. Monitor the reaction by gas chromatography (GC). The reaction is considered complete when the concentration of 1,2,3-tribromo-5-fluoro-4,6-xylene is ≤0.5%. Filter the reaction solution under reduced pressure, allow it to stand and separate into layers. After removing the aqueous layer, concentrate the organic phase to obtain 306.1 g of crude 1,5-dibromo-3-fluoro-2,4-xylene with a purity of 64.7%.

[0035] 3) Crude methylcyclohexane of 1,5-dibromo-3-fluoro-2,4-dimethylbenzene and ethyl acetate (mass ratio 1:1 = 612.2 g) were recrystallized to obtain 258.9 g of white solid with a purity of 69% and a molar yield of 57%.

[0036] Example 2

[0037] The organic solvent is DMF, the Lewis acid catalyst is ferric bromide, the brominating reagent is bromine, the reducing agent is iron powder, and the acidic reagent is sulfuric acid.

[0038] 2) 1) Add 200g of 2-fluoro-m-xylene and 600g of DMF to the reactor, stir and add 4g of ferric tribromide. Control the reactor temperature at 0-10℃, and slowly add 386.1g of excess bromine dropwise over 8 hours. After the bromine is added, slowly raise the reactor temperature to 70℃ and continue the reaction at 70℃ for 3 hours. Monitor the reaction by gas chromatography (GC) during the reaction. The reaction is considered complete when the 2-fluoro-m-xylene content is ≤0.5%. An 8% sodium bisulfite and sodium bicarbonate aqueous solution was added dropwise to the reactor until the solution changed from reddish-brown to light yellow. The amount added was 167.6 g. The mixture was stirred for 2 hours, filtered under reduced pressure, and dried to obtain 395.3 g of intermediate 1,2,3-tribromo-5-fluoro-4,6-xylene with a purity of 80% and a yield of 68%. Part of the raw material was converted into 1,2-dibromo-4-fluoro-3,5-xylene with a purity of 20%. The raw material reacted completely. Even after adding bromine, it was still impossible to completely convert 1,2-dibromo-4-fluoro-3,5-xylene into 1,2,3-tribromo-5-fluoro-4,6-xylene.

[0039] 2) Add 395.3 g of the above intermediate 1,2,3-tribromo-5-fluoro-4,6-xylene and 395.3 g of DMF to the reactor. Add 290.7 g of 15% sulfuric acid dropwise. After the solution is completely added, slowly raise the reactor temperature to 60°C. Add 117.2 g of iron powder in batches over 6 hours, maintaining the temperature for 4 hours. Monitor the reaction by gas chromatography (GC). The reaction is considered complete when the concentration of 1,2,3-tribromo-5-fluoro-4,6-xylene is ≤0.5%. Filter the reaction solution under reduced pressure, allow it to stand and separate into layers. After removing the aqueous layer, concentrate the organic phase to obtain 346.3 g of crude 1,5-dibromo-3-fluoro-2,4-xylene with a purity of 69%.

[0040] 3) The crude methylcyclohexane of 1,5-dibromo-3-fluoro-2,4-dimethylbenzene was recrystallized and purified with ethyl acetate (mass ratio 1:1 = 692.6 g) to obtain 277 g of white solid with a purity of 73% and a molar yield of 61%.

[0041] Example 3

[0042] The organic solvent is 1,2-dichloroethane, the Lewis acid catalyst is ferric chloride, the brominating reagent is bromine, the reducing agent is zinc powder, and the acidic reagent is ammonium chloride.

[0043] 1) Add 200g of 2-fluoro-m-xylene and 600g of 1,2-dichloroethane to a reactor, stir, and add 4g of ferric chloride. Control the reactor temperature at 0-10℃, and slowly add 386.1g of excess bromine dropwise over 8 hours. After the bromine addition is complete, slowly raise the reactor temperature to 70℃ and continue the reaction at 70℃ for 3 hours. Monitor the reaction by gas chromatography (GC). The reaction is considered complete when the 2-fluoro-m-xylene content is ≤0.5%. Add 167.6g of 8% sodium bisulfite aqueous solution dropwise to the reactor until the solution changes from reddish-brown to light yellow. Stir for 2 hours, filter under reduced pressure, and dry to obtain 523.1g of intermediate 1,2,3-tribromo-5-fluoro-4,6-xylene with a purity of 99% and a yield of 90%.

[0044] 2) Add 523.1 g of the above intermediates 1,2,3-tribromo-5-fluoro-4,6-xylene and 523.1 g of 1,2-dichloroethane to the reactor. Add 516.9 g of a 15% ammonium chloride aqueous solution dropwise. After the solution is added, slowly raise the reactor temperature to 60°C. Add 95.8 g of zinc powder in batches over 6 hours, maintaining the reaction temperature for 4 hours. Monitor the reaction by gas chromatography (GC). The reaction is considered complete when the concentration of 1,2,3-tribromo-5-fluoro-4,6-xylene is ≤0.5%. Filter the reaction solution under reduced pressure, allow it to stand and separate into layers. After removing the aqueous layer, concentrate the organic phase to obtain 482.6 g of crude 1,5-dibromo-3-fluoro-2,4-xylene with a purity of 95.2%.

[0045] 3) The crude ethanol (965.2 g) of 1,5-dibromo-3-fluoro-2,4-dimethylbenzene) was recrystallized and purified to obtain 440.5 g of white solid with a purity of 99% and a molar yield of 97%.

[0046] Example 4

[0047] The solvent is chloroform, the Lewis acid catalyst is aluminum trichloride, the brominating reagent is bromine, the reducing agent is zinc powder, and the acidic reagent is ammonium bromide.

[0048] 1) Add 200g of 2-fluoro-m-xylene and 600g of chloroform to a reactor, stir, and add 4g of aluminum trichloride. Control the reactor temperature at 0-10℃, and slowly add 386.1g of excess bromine dropwise over 8 hours. After the bromine addition is complete, slowly raise the reactor temperature to 60℃ and continue the reaction at 60℃ for 3 hours. Monitor the reaction by gas chromatography (GC). The reaction is considered complete when the 2-fluoro-m-xylene content is ≤0.5%. Add 167.6g of 8% sodium bisulfite aqueous solution dropwise to the reactor until the solution changes from reddish-brown to light yellow. Stir for 2 hours, filter under reduced pressure, and dry to obtain 499.8g of intermediate 1,2,3-tribromo-5-fluoro-4,6-xylene with a purity of 95% and a yield of 86%.

[0049] 2) Add 499.8 g of the above intermediate 1,2,3-tribromo-5-fluoro-4,6-xylene and 499.8 g of chloroform to the reactor. Add 742.1 g of a 15% ammonium bromide aqueous solution dropwise. After the solution is added, slowly raise the reactor temperature to 60°C. Add 95.8 g of zinc powder in batches over 6 hours, maintaining the temperature for 4 hours. Monitor the reaction by gas chromatography (GC). The reaction is considered complete when the concentration of 1,2,3-tribromo-5-fluoro-4,6-xylene is ≤0.5%. Filter the reaction solution under reduced pressure, allow it to stand and separate into layers. After removing the aqueous layer, concentrate the organic phase to obtain 469.5 g of crude 1,5-dibromo-3-fluoro-2,4-xylene with a purity of 90%.

[0050] 3) The crude ethanol (879 g) of 1,5-dibromo-3-fluoro-2,4-dimethylbenzene was recrystallized and purified to obtain 431.4 g of white solid with a purity of 97% and a molar yield of 95%.

[0051] Example 5

[0052] The organic solvent is dichloromethane, the Lewis acid catalyst is iron powder, the brominating reagent is NBS; the reducing agent is iron powder, and the acidic reagent is hydrochloric acid.

[0053] 1) Add 200g of 2-fluoro-m-xylene and 600g of dichloromethane to the reactor, stir and add 4g of iron powder. Control the reactor temperature at 0-10℃, and slowly add 286.7g of NBS in batches over 5 hours. After the NBS is added, slowly raise the reactor temperature to 40℃ and continue the reaction at 40℃ for 3 hours. Monitor the reaction by gas chromatography (GC) during the reaction. The reaction is considered complete when the 2-fluoro-m-xylene content is ≤0.5%. An 8% sodium bisulfite aqueous solution was added dropwise to the reactor until the solution changed from reddish-brown to light yellow. The amount added was 167.6 g. The mixture was stirred for 2 hours, filtered under reduced pressure, and dried to obtain 308 g of intermediate 1,2,3-tribromo-5-fluoro-4,6-xylene with a purity of 58% and a yield of 53%. Part of the raw material was converted into 1,2-dibromo-4-fluoro-3,5-xylene with a purity of 42%. The raw material reacted completely. Even after adding bromine, it was still impossible to completely convert 1,2-dibromo-4-fluoro-3,5-xylene into 1,2,3-tribromo-5-fluoro-4,6-xylene.

[0054] 2) Add 308g of the above intermediate 1,2,3-tribromo-5-fluoro-4,6-xylene and 308g of dichloromethane to the reactor. Add 176.2g of 15% hydrochloric acid dropwise. After the solution is completely added, slowly raise the reactor temperature to 40℃. Add 117.2g of iron powder in batches over 6 hours, maintaining the temperature for 4 hours. Monitor the reaction using gas chromatography (GC). The reaction is considered complete when the concentration of 1,2,3-tribromo-5-fluoro-4,6-xylene is ≤0.5%. Filter the reaction solution under reduced pressure, allow it to stand and separate into layers. After removing the aqueous layer, concentrate the organic phase to obtain 293.3g of crude 1,5-dibromo-3-fluoro-2,4-xylene with a purity of 50%.

[0055] 3) The crude ethanol (586.6 g) of 1,5-dibromo-3-fluoro-2,4-dimethylbenzene) was recrystallized and purified to obtain 222.5 g of white solid with a purity of 55% and a molar yield of 49%.

[0056] Example 6

[0057] The organic solvent is DMF, the Lewis acid catalyst is ferric bromide, the brominating reagent is NBS; the reducing agent is iron powder, and the acidic reagent is sulfuric acid.

[0058] 1) Add 200g of 2-fluoro-m-xylene and 600g of DMF to a reactor, stir, and add 4g of ferric bromide. Control the reactor temperature at 0-10℃, and slowly add 286.7g of NBS in batches over 5 hours. After the NBS addition is complete, slowly raise the reactor temperature to 70℃ and continue the reaction at 70℃ for 3 hours. Monitor the reaction by gas chromatography (GC). The reaction is considered complete when the 2-fluoro-m-xylene content is ≤0.5%. Add 167.6g of 8% sodium bisulfite aqueous solution dropwise to the reactor until the solution changes from reddish-brown to light yellow. Stir for 2 hours, filter under reduced pressure, and dry to obtain 302.2g of intermediate 1,2,3-tribromo-5-fluoro-4,6-xylene with a purity of 61% and a yield of 52%. A portion of the raw materials were converted into 1,2-dibromo-4-fluoro-3,5-xylene with a purity of 39%. The raw materials reacted completely, but even after adding NBS, it was still impossible to completely convert 1,2-dibromo-4-fluoro-3,5-xylene into 1,2,3-tribromo-5-fluoro-4,6-xylene.

[0059] 2) Add 302.2 g of the above intermediates 1,2,3-tribromo-5-fluoro-4,6-xylene and DMF to the reactor. Add 232.3 g of 15% sulfuric acid dropwise. After the solution is added, slowly raise the reactor temperature to 60°C. Add 117.2 g of iron powder in batches over 6 hours, maintaining the temperature for 4 hours. Monitor the reaction by gas chromatography (GC). The reaction is considered complete when the concentration of 1,2,3-tribromo-5-fluoro-4,6-xylene is ≤0.5%. Filter the reaction solution under reduced pressure, allow it to stand and separate into layers. After removing the aqueous layer, concentrate the organic phase to obtain 288.8 g of crude 1,5-dibromo-3-fluoro-2,4-xylene with a purity of 56.8%.

[0060] 3) The crude methylcyclohexane of 1,5-dibromo-3-fluoro-2,4-dimethylbenzene was recrystallized and purified with ethyl acetate (mass ratio 1:1 = 577.6 g) to obtain 236.1 g of white solid with a purity of 60% and a molar yield of 52%.

[0061] Example 7

[0062] The organic solvent is 1,2-dichloroethane, the Lewis acid catalyst is ferric chloride, the brominating reagent is NBS, the reducing agent is zinc powder, and the acidic reagent is ammonium chloride.

[0063] 1) Add 200g of 2-fluoro-m-xylene and 600g of 1,2-dichloroethane to a reactor, stir, and add 4g of ferric chloride. Control the reactor temperature at 0-10℃, and slowly add 286.7g of NBS in batches over 5 hours. After the NBS addition is complete, slowly raise the reactor temperature to 70℃ and continue the reaction at 70℃ for 3 hours. Monitor the reaction by gas chromatography (GC). The reaction is considered complete when the 2-fluoro-m-xylene content is ≤0.5%. Add 167.6g of 8% sodium bisulfite aqueous solution dropwise to the reactor until the solution changes from reddish-brown to light yellow. Stir for 2 hours, filter under reduced pressure, and dry to obtain 511.5g of intermediate 1,2,3-tribromo-5-fluoro-4,6-xylene with a purity of 98% and a yield of 88%.

[0064] 2) Add 511.5 g of the above intermediates 1,2,3-tribromo-5-fluoro-4,6-xylene and 511.5 g of 1,2-dichloroethane to the reactor. Add 336.8 g of a 15% ammonium chloride aqueous solution dropwise. After the solution is added, slowly raise the reactor temperature to 60°C. Add 95.8 g of zinc powder in batches over 6 hours, maintaining the temperature for 4 hours. Monitor the reaction by gas chromatography (GC). The reaction is considered complete when the concentration of 1,2,3-tribromo-5-fluoro-4,6-xylene is ≤0.5%. Filter the reaction solution under reduced pressure, allow it to stand and separate into layers. After removing the aqueous layer, concentrate the organic phase to obtain 477.3 g of crude 1,5-dibromo-3-fluoro-2,4-xylene with a purity of 92%.

[0065] 3) The crude ethanol (954.6 g) of 1,5-dibromo-3-fluoro-2,4-dimethylbenzene) was recrystallized and purified to obtain 436 g of white solid with a purity of 98% and a molar yield of 96%.

[0066] Example 8

[0067] The organic solvent is chloroform, the Lewis acid catalyst is aluminum trichloride, the brominating reagent is NBS, the reducing agent is zinc powder, and the acidic reagent is ammonium bromide.

[0068] 1) Add 200g of 2-fluoro-m-xylene and 600g of chloroform to the reactor, stir and add 4g of aluminum trichloride. Control the reactor temperature at 0-10℃, and slowly add 286.7g of NBS in batches over 5 hours. After the NBS is added, slowly raise the reactor temperature to 60℃ and continue the reaction at 60℃ for 3 hours. Monitor the reaction by gas chromatography (GC) during the reaction. The reaction is considered complete when the 2-fluoro-m-xylene content is ≤0.5%. An 8% sodium bisulfite aqueous solution was added dropwise to the reactor until the solution changed from reddish-brown to light yellow. The amount added was 167.6 g. The mixture was stirred for 2 hours, filtered under reduced pressure, and dried to obtain 377.8 g of intermediate 1,2,3-tribromo-5-fluoro-4,6-xylene with a purity of 73% and a yield of 65%. Part of the raw material was converted into 1,2-dibromo-4-fluoro-3,5-xylene with a purity of 27%. The reaction of the raw material was complete. Even after adding NBS, it was still impossible to completely convert 1,2-dibromo-4-fluoro-3,5-xylene into 1,2,3-tribromo-5-fluoro-4,6-xylene.

[0069] 2) Add 377.8 g of the above intermediate 1,2,3-tribromo-5-fluoro-4,6-xylene and 377.8 g of chloroform to the reactor. Add 678.7 g of a 15% ammonium bromide aqueous solution dropwise. After the solution is added, slowly raise the reactor temperature to 60°C. Add 95.8 g of zinc powder in batches over 6 hours, maintaining the temperature for 4 hours. Monitor the reaction by gas chromatography (GC). The reaction is considered complete when the concentration of 1,2,3-tribromo-5-fluoro-4,6-xylene is ≤0.5%. Filter the reaction solution under reduced pressure, allow it to stand and separate into layers. After removing the aqueous layer, concentrate the organic phase to obtain 328.9 g of crude 1,5-dibromo-3-fluoro-2,4-xylene with a purity of 61%.

[0070] 3) The crude methylcyclohexane of 1,5-dibromo-3-fluoro-2,4-dimethylbenzene was recrystallized and purified with ethyl acetate (mass ratio 1:1 = 577.6 g) to obtain 272.5 g of white solid with a purity of 67% and a molar yield of 60%.

[0071] The above embodiments describe the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the present invention. Various changes and modifications can be made to the present invention without departing from its principles, and all such changes and modifications fall within the scope of protection of the present invention.

Claims

1. A method for synthesizing 1,5-dibromo-3-fluoro-2,4-xylene, characterized in that, Includes the following steps: 1,2,3-tribromo-5-fluoro-4,6-xylene was obtained by reacting 2-fluoro-m-xylene with a brominating agent in the presence of a Lewis acid catalyst; then, it was reacted with a reducing agent to obtain 1,5-dibromo-3-fluoro-2,4-xylene.

2. The method for synthesizing 1,5-dibromo-3-fluoro-2,4-xylene according to claim 1, characterized in that, The specific reaction steps are as follows: (1) Mix 2-fluoro-m-xylene with an organic solvent, add a Lewis acid catalyst, and add a brominating reagent dropwise to brominate the mixture and obtain a reaction solution. (2) Quenching the reaction solution to separate it into layers yields 1,2,3-tribromo-5-fluoro-4,6-xylene; (3) 1,2,3-tribromo-5-fluoro-4,6-dimethylbenzene was reacted with a reducing agent under acidic conditions to obtain crude 1,5-dibromo-3-fluoro-2,4-dimethylbenzene; (4) The crude 1,5-dibromo-3-fluoro-2,4-dimethylbenzene was recrystallized to obtain 1,5-dibromo-3-fluoro-2,4-dimethylbenzene.

3. The method for synthesizing 1,5-dibromo-3-fluoro-2,4-xylene according to claim 2, characterized in that: In step (1), the organic solvent is selected from dichloromethane, 1,2-dichloroethane, chloroform, and DMF; the mass ratio of the organic solvent to 2-fluoro-m-xylene is 1-5:

1.

4. The method for synthesizing 1,5-dibromo-3-fluoro-2,4-xylene according to claim 2, characterized in that: In step (1), the Lewis acid catalyst is selected from ferric chloride, aluminum chloride, ferric bromide, and iron powder; the weight ratio of the Lewis acid catalyst to 2-fluoro-m-xylene is 0.005-0.05:

1.

5. The method for synthesizing 1,5-dibromo-3-fluoro-2,4-xylene according to claim 2, characterized in that: In step (1), the brominating reagent is selected from bromine or N-bromosuccinimide; the molar ratio of the brominating reagent to 2-fluoro-m-xylene is 1-4:

1.

6. The method for synthesizing 1,5-dibromo-3-fluoro-2,4-xylene according to claim 2, characterized in that: In step (1), the reaction temperature is 0-85℃ and the reaction time is 10-30h; in step (3), the reaction temperature is 60-80℃ and the reaction time is 10-15h.

7. The method for synthesizing 1,5-dibromo-3-fluoro-2,4-xylene according to claim 2, characterized in that: In step (2), sodium sulfite, sodium bisulfite, sodium bicarbonate or sodium carbonate are used for quenching, and the quenching temperature is 10-30℃.

8. The method for synthesizing 1,5-dibromo-3-fluoro-2,4-xylene according to claim 2, characterized in that: In step (3), the reducing agent is selected from iron powder or zinc powder; the molar ratio of the reducing agent to 1,2,3-tribromo-5-fluoro-4,6-xylene is 1-3:

1.

9. The method for synthesizing 1,5-dibromo-3-fluoro-2,4-xylene according to claim 2, characterized in that: In step (3), the acid is selected from one or two of ammonium chloride, ammonium bromide, hydrochloric acid, and sulfuric acid; the molar ratio of the acidic reagent to 1,2,3-tribromo-5-fluoro-4,6-xylene is 0.5-2.5:

1.

10. The method for synthesizing 1,5-dibromo-3-fluoro-2,4-xylene according to claim 2, characterized in that: In step (4), the recrystallization uses one or two of the following: methylcyclohexane, cyclohexane, ethanol, toluene, dichloromethane, and ethyl acetate.

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