CN117658763A - Preparation method of 5-bromo-1, 2-dichloro-3-fluorobenzene - Google Patents

Preparation method of 5-bromo-1, 2-dichloro-3-fluorobenzene Download PDF

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CN117658763A
CN117658763A CN202311643900.3A CN202311643900A CN117658763A CN 117658763 A CN117658763 A CN 117658763A CN 202311643900 A CN202311643900 A CN 202311643900A CN 117658763 A CN117658763 A CN 117658763A
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bromo
dichloro
fluorobenzene
acid
fluoroaniline
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鲁东飞
卢坦钦
李显跃
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Bangnuo Suzhou New Materials Co ltd
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/093—Preparation of halogenated hydrocarbons by replacement by halogens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C17/00—Preparation of halogenated hydrocarbons
    • C07C17/38—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C209/00—Preparation of compounds containing amino groups bound to a carbon skeleton
    • C07C209/68—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton
    • C07C209/74—Preparation of compounds containing amino groups bound to a carbon skeleton from amines, by reactions not involving amino groups, e.g. reduction of unsaturated amines, aromatisation, or substitution of the carbon skeleton by halogenation, hydrohalogenation, dehalogenation, or dehydrohalogenation

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Abstract

The application relates to the technical field of organic materials, and particularly discloses a preparation method of 5-bromo-1, 2-dichloro-3-fluorobenzene, which comprises the following steps: mixing o-fluoroaniline with an organic solvent A, cooling, adding a brominating reagent, heating to react, pouring the reaction solution into ice water, extracting, concentrating under reduced pressure to obtain p-bromo-o-fluoroaniline; mixing and cooling para-bromo-o-fluoroaniline and a solvent B, adding an acid A and an oxidant, heating for reaction, standing for layering, washing an organic phase by using an alkali solution, and concentrating under reduced pressure to obtain 4-bromo-2-fluoro-6-chloroaniline; mixing 4-bromo-2-fluoro-6-chloroaniline with acid B, heating to react, cooling, dropwise adding nitrite aqueous solution to react, dropwise adding the reaction solution into a mixed solution containing halogenated copper salt aqueous solution and solvent C, reacting, extracting, washing with water, concentrating under reduced pressure, and rectifying under high vacuum to obtain the aqueous solution; the method has the advantages of simple and easily obtained raw materials, low cost, simple post-treatment, high product purity and convenience in industrialized amplification.

Description

Preparation method of 5-bromo-1, 2-dichloro-3-fluorobenzene
Technical Field
The application relates to the technical field of organic materials, in particular to a preparation method of 5-bromo-1, 2-dichloro-3-fluorobenzene.
Background
5-bromo-1, 2-dichloro-3-fluorobenzene has received much attention as an intermediate for chemical synthesis in various industries, such as in the biomedical field, a novel drug Kv1.3 synthesized from 5-bromo-1, 2-dichloro-3-fluorobenzene as a raw material by U.S. Xiao Er institute (WO 2021071806A 1) has a good therapeutic effect as an immunosuppressant or an immune system regulator potential therapeutic agent by synthesizing a channel blocker arylmethylene compound. In the technical field of photoelectric materials, for example, CN114195813a, JP6880352B1 discloses that materials prepared from 5-bromo-1, 2-dichloro-3-fluorobenzene compounds as starting materials obtain good device performance as functional materials in devices.
The prior art discloses a synthesis method of 5-bromo-1, 2-dichloro-3-fluorobenzene, which takes o-fluoroaniline as a raw material, prepares a target product through bromination, NCS (chlorosuccinimide) chlorination and diazonium, and comprises the following synthesis lines:
specifically, NCS is taken as a chlorinating agent, acetonitrile is taken as a solvent, and an intermediate 4-bromo-2-fluoro-6-chloroaniline is synthesized; diazotizing with tert-butyl nitrite and chloridizing with copper chloride to obtain the target product. The intermediate 4-bromo-2-fluoro-6-chloroaniline obtained by the method has low purity and low yield, and the refining process is complex, the production cost is high and the industrialization degree is poor; the use of the tert-butyl nitrite has high cost and poor safety. Therefore, the active research of a method for preparing 5-bromo-1, 2-dichloro-3-fluorobenzene with high efficiency and high yield is of great significance.
Disclosure of Invention
In order to solve the defects of low purity, low yield, complicated refining process, high production cost, poor industrialization degree and the like of 5-bromo-1, 2-dichloro-3-fluorobenzene prepared by the prior art, the application provides a preparation method of 5-bromo-1, 2-dichloro-3-fluorobenzene.
The application provides a preparation method of 5-bromo-1, 2-dichloro-3-fluorobenzene, which adopts the following technical scheme:
a process for the preparation of 5-bromo-1, 2-dichloro-3-fluorobenzene comprising the steps of:
step I: mixing o-fluoroaniline and an organic solvent A, cooling to 0-5 ℃, adding a bromination reagent, heating to 20-25 ℃, carrying out heat preservation reaction, pouring the reaction liquid into ice water after the reaction is finished, extracting, and concentrating under reduced pressure to obtain p-bromo-o-fluoroaniline;
step II: mixing para-bromo-o-fluoroaniline and a solvent B, cooling to 0-5 ℃, adding an acid A and an oxidant, heating to 45-50 ℃, carrying out heat preservation reaction, standing for layering after the reaction is finished, washing an organic phase by using an alkali solution, and concentrating under reduced pressure to obtain 4-bromo-2-fluoro-6-chloroaniline;
step III: mixing 4-bromo-2-fluoro-6-chloroaniline and acid B, heating to 50-55 ℃, carrying out heat preservation reaction, cooling to 0-5 ℃ after the reaction is finished, dropwise adding nitrite aqueous solution, carrying out heat preservation reaction, dropwise adding the reaction solution into a mixed solution containing halogenated copper salt aqueous solution and solvent C at 50-55 ℃, carrying out heat preservation reaction after the dropwise adding is finished, extracting, washing, concentrating under reduced pressure and rectifying under high vacuum to obtain a pure 5-bromo-1, 2-dichloro-3-fluorobenzene product.
Preferably, the organic solvent A in the step I is at least one of N, N-dimethylformamide, acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, dimethyl sulfoxide and 1, 4-dioxane.
Preferably, the organic solvent a in the step I is at least one of N, N-dimethylformamide, acetone, methanol, and ethanol.
Preferably, the molar ratio of the o-fluoroaniline to the brominating reagent in the step I is 1:0.9-1.1.
Preferably, the molar ratio of the o-fluoroaniline to the brominating reagent in the step I is 1:1.
Preferably, the brominating reagent is at least one of 1, 3-dibromo-5, 5-dimethylhydantoin, 3-pyridylmethylamine bromine, carbon tetrabromide, 5-dibromo-2, 2-dimethyl-4, 6-dione-1, 3-dioxane, tetrabromo-o-benzoquinone, 1,3, 5-tribromo-1, 3, 5-thiazinane-2, 4, 6-trione, N-bromophthalimide, N-bromosuccinimide and ferric bromide.
Preferably, the brominating reagent is at least one of 1, 3-dibromo-5, 5-dimethylhydantoin, carbon tetrabromide, 1,3, 5-tribromo-1, 3, 5-thiazinane-2, 4, 6-trione, N-bromosuccinimide and ferric bromide.
Preferably, the solvent B in the step II is at least one of dichloromethane, dichloroethane, ethyl acetate, toluene, chlorobenzene, xylene, decalin and cyclohexane.
Preferably, the solvent B in the step II is at least one of ethyl acetate, xylene, decalin and cyclohexane.
Preferably, the dosage mole ratio of the para-bromo-o-fluoroaniline to the acid A in the step II is 1:1-3.
Preferably, the molar ratio of the p-bromo-o-fluoroaniline to the acid A in the step II is 1:1.5-2.5.
Preferably, the dosage mole ratio of the para-bromo-o-fluoroaniline to the acid A in the step II is 1:2.
Preferably, the acid A is at least one of hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, perchloric acid and hydroiodic acid.
Preferably, the acid A is at least one of hydrochloric acid, sulfuric acid, trifluoroacetic acid and acetic acid.
Preferably, the dosage mole ratio of the para-bromo-o-fluoroaniline to the oxidant in the step II is 1:1-4.
Preferably, the dosage mole ratio of the para-bromo-o-fluoroaniline to the oxidant in the step II is 1:1.5-3.5.
Preferably, the dosage mole ratio of the para-bromo-o-fluoroaniline to the oxidant in the step II is 1:2.5.
Preferably, the oxidant is at least one of hydrogen peroxide, potassium permanganate, carbamide peroxide, sodium peroxide and periodic acid.
Preferably, the oxidant is at least one of hydrogen peroxide, potassium permanganate and sodium peroxide.
Preferably, the solvent C in the step III is at least one of methanol, ethanol, tetrahydrofuran and dioxane.
Preferably, the solvent C in the step III is methanol and/or ethanol.
Preferably, the molar ratio of the 4-bromo-2-fluoro-6-chloroaniline to the nitrite in the step III is 1:1.0-2.5.
Preferably, the molar ratio of the 4-bromo-2-fluoro-6-chloroaniline to the nitrite in the step III is 1:1.8.
Preferably, the nitrite is at least one of sodium nitrite, potassium nitrite, ferric nitrite and copper nitrite.
Preferably, the nitrite is sodium nitrite and/or potassium nitrite.
Preferably, the molar ratio of the 4-bromo-2-fluoro-6-chloroaniline to the amount of the halogenated copper in the step III is 1:1-4.
Preferably, the molar ratio of the 4-bromo-2-fluoro-6-chloroaniline to the amount of the halogenated copper in the step III is 1:2.5.
Preferably, the halogenated copper is at least one of cuprous bromide, cuprous iodide, cuprous chloride, cupric bromide and cupric chloride.
Preferably, the halogenated copper is at least one of cuprous bromide, cupric bromide and cupric chloride.
Preferably, the high vacuum in the step III is 10-30Kpa.
Preferably, the high vacuum in the step III is 14-17Kpa.
In summary, the present application has the following beneficial effects:
the application provides a preparation method of 5-bromo-1, 2-dichloro-3-fluorobenzene, which has the advantages of simple and easily obtained raw materials, high intermediate yield, simple post-treatment, high product yield and high purity, and is convenient for industrialized amplification.
Detailed Description
The present application is described in further detail below with reference to examples.
Examples 1-7 provide a process for the preparation of 5-bromo-1, 2-dichloro-3-fluorobenzene which is synthesized as follows:
example 1
A preparation method of 5-bromo-1, 2-dichloro-3-fluorobenzene comprises the following steps:
step I: o-fluoroaniline (11.1 g,100 mmol) and DMF (100 ml) are sequentially added into a reaction bottle, after a low-temperature bath is cooled to 0 ℃,1, 3-dibromo-5, 5-dimethylhydantoin (11.1 g,100 mmol) dissolved by DMF (100 ml) is dropwise added, the dropwise adding time is controlled to be 3 hours, the reaction temperature is kept to be 0 ℃, after the dropwise adding is finished, the temperature is increased to 25 ℃ at a heating rate of 10 ℃/h, the temperature is kept for 3 hours, the sampling is controlled in a central mode, the content of o-fluoroaniline is less than 0.3%, and the reaction is stopped; the reaction solution was slowly poured into vigorously stirred ice water (1L), stirred for 10min, extracted with ethyl acetate (300 ml each time, 2 times of extraction), the organic phases were combined, extracted once again with 5% aqueous sodium hydroxide solution (200 ml each time, 2 times of extraction) and water (500 ml each time, the organic phases were taken and dried over anhydrous sodium sulfate, concentrated under reduced pressure to give p-bromo-o-fluoroaniline as a pale yellow solid (17.57 g, yield 93.8%, purity 97.0%);
step II: to a glass reaction flask, p-bromo-o-fluoroaniline (17.57 g,93 mmol) and methylene dichloride (100 ml) are sequentially added, 30% hydrochloric acid (22.84 ml, 216 mmol) is cooled to 0 ℃ in a low-temperature bath, 30% hydrogen peroxide (10.54 g, 100.8 mmol) is dropwise added, a small amount of heat is released in the dropwise adding process, the dropwise adding time is controlled to be 2h, after the dropwise adding is finished, the temperature is slowly increased to 50 ℃, the temperature is kept for 2h, sampling is centrally controlled until the p-bromo-o-fluoroaniline is reacted, the reaction is stopped, the temperature is reduced to room temperature, the mixture is kept stand for layering, the upper layer is water phase 1, and the lower layer is organic phase 1 (methylene dichloride). The obtained organic phase 1 was stirred with 10% aqueous sodium hydroxide (100 ml) for 1 hour, and the mixture was allowed to stand again for delamination, wherein the upper layer was aqueous phase 2, and the lower layer was organic phase 2 (dichloromethane phase). Then 2 drops of the water phase are taken and put on starch potassium iodide test paper to show no color change. The organic phase 2 was extracted with water (100 ml each time, 2 times of extraction), dried over anhydrous sodium sulfate and concentrated to give 4-bromo-2-fluoro-6-chloroaniline as a reddish brown solid (18.33 g, yield 88%, purity 95.2%).
Step III: adding hydrochloric acid (11.23 ml) with the mass fraction of 30% into a glass reaction bottle in sequence, adding 4-bromo-2-fluoro-6-chloroaniline (11.22 g,50mmol,5.61 g/time, 10 minutes each time interval) in two batches, heating to 50 ℃, preserving heat for 1h, cooling to-5 ℃ at the cooling rate of 20 ℃/h, separating out a large amount of solid, dropwise adding 30% sodium nitrite aqueous solution (150 g, wherein each 11.5g of sodium nitrite aqueous solution contains 3.45g and 50 mmol) at the temperature, controlling the dropwise adding time to be 1h, and preserving heat for 30min at the temperature after the dropwise adding is finished to prepare a nitrogen-containing mixture; adding 30% hydrochloric acid (100 ml), cuprous chloride (4.95 g,50 mmol), water (50 ml) and ethanol (30 ml) into the other reaction bottle, stirring at a rotating speed of 300r/min, heating to 50 ℃, dropwise adding the prepared nitrogen-containing mixture, discharging a large amount of gas in the dropwise adding process, controlling the dropwise adding time to be 2h, preserving heat for 1h after dropwise adding, heating to 70 ℃ at a heating rate of 10 ℃/h, and preserving heat for 3h continuously; cooling the reaction solution to room temperature, extracting the reaction solution by using ethyl acetate (200 ml), washing an organic phase by using water (200 ml each time, extracting for 2 times), extracting, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product of 5-bromo-1, 2-dichloro-3-fluorobenzene; the crude product obtained was rectified in high vacuum under a controlled pressure of 15kpa and the fraction at 80 c was collected to obtain colorless liquid 5-bromo-1, 2-dichloro-3-fluorobenzene (11.18 g, yield 92%, purity 98.9%).
Example 2
Compared with the example 1, only the brominating reagent in the step I is changed to be selected, specifically, 1, 3-dibromo-5, 5-dimethyl hydantoin is changed to be N-bromo-o-sulfonyl benzene imide, and the rest steps are unchanged, so as to obtain light yellow solid p-bromo-o-fluoroaniline (16.927 g, yield 89% and purity 98.0%); finally, colorless liquid 5-bromo-1, 2-dichloro-3-fluorobenzene (11.20 g, yield 92.2%, purity 99.1%) was obtained.
Example 3
Compared with the example 1, only the brominating reagent in the step I is changed to be selected, specifically, 1, 3-dibromo-5, 5-dimethyl hydantoin is changed to N-bromosuccinimide, and the rest steps are unchanged, so that light yellow solid para-bromo-o-fluoroaniline (18.24 g, yield 96% and purity 97.0%) is obtained; finally, colorless liquid 5-bromo-1, 2-dichloro-3-fluorobenzene (11.17 g, yield 91.9%, purity 98.7%) was obtained.
Example 4
Compared with example 3, the molar ratio of the o-fluoroaniline to the brominating reagent in the step I is changed from 1:1 to 1:0.98, and the rest steps are unchanged, so that the light yellow solid p-bromoo-fluoroaniline (18 g, yield 94.6% and purity 97.7%) is obtained; finally, colorless liquid 5-bromo-1, 2-dichloro-3-fluorobenzene (11.42 g, yield 94%, purity 98.9%) was obtained.
Example 5
Compared with the example 1, only the organic solvent A in the step I is changed, specifically, N-dimethylformamide is changed into dimethyl sulfoxide, and the other steps are unchanged, so that para-bromo-o-fluoroaniline (16.73 g, yield 88% and purity 97.9%) is obtained; finally, colorless liquid 5-bromo-1, 2-dichloro-3-fluorobenzene (10.93 g, yield 90%, purity 98.6%) was obtained.
Example 6
Compared with example 5, only the organic solvent A in the step I is changed, specifically, dimethyl sulfoxide is changed into a mixed solution of N, N-dimethylformamide and dichloromethane (v/v=1:1), and the other steps are unchanged, so that p-bromo-o-fluoroaniline (16.92 g, yield 89% and purity 98.3%) is obtained; finally, colorless liquid 5-bromo-1, 2-dichloro-3-fluorobenzene (11.31 g, yield 93.1%, purity 98.3%) was obtained.
Example 7
Compared with the example 1, only the selection of the acid A in the step II is changed, specifically, 30% of hydrochloric acid is changed into trifluoroacetic acid, and the rest steps are unchanged, so that 4-bromo-2-fluoro-6-chloroaniline (17.33 g, yield 83% and purity 94.1%) is obtained; finally, colorless liquid 5-bromo-1, 2-dichloro-3-fluorobenzene (11.27 g, yield 92.7%, purity 93%) was obtained.
Example 8
Compared with the example 7, only the molar ratio of the bromoo-fluoroaniline to the acid A in the step II is changed from 1:2.3 to 1:1.8, and the other steps are unchanged, so that 4-bromo-2-fluoro-6-chloroaniline (16.70 g, yield 80% and purity 95.2%) is obtained; finally, colorless liquid 5-bromo-1, 2-dichloro-3-fluorobenzene (11.08 g, yield 91.2%, purity 97%) was obtained.
Example 9
Compared with the example 1, only the selection of the oxidant in the step II is changed, specifically, 30% hydrogen peroxide is changed into sodium peroxide, and the rest steps are unchanged, so that 4-bromo-2-fluoro-6-chloroaniline (17.74 g, yield 85% and purity 92.1%) is obtained; finally, colorless liquid 5-bromo-1, 2-dichloro-3-fluorobenzene (10.93 g, yield 90%, purity 94.3%) was obtained.
Example 10
Compared with the example 1, only the oxidant in the step II is changed, specifically, 30% hydrogen peroxide is changed into carbamide peroxide, and the rest steps are unchanged, so that 4-bromo-2-fluoro-6-chloroaniline (18.58 g, yield 89%, purity 96.3%) is obtained; finally, colorless liquid 5-bromo-1, 2-dichloro-3-fluorobenzene (11.10 g, yield 93%, purity 98%) was obtained.
Example 11
Compared with the example 10, only the molar ratio of the p-bromo-o-fluoroaniline to the oxidant in the step II is changed from 1:1.0839 to 1:2.4, and the other steps are unchanged, so as to obtain 4-bromo-2-fluoro-6-chloroaniline (18.79 g, yield 90%, purity 96.1%); finally, colorless liquid 5-bromo-1, 2-dichloro-3-fluorobenzene (11.21 g, yield 92.2%, purity 98.3%) was obtained.
Example 12
Compared with the example 11, only the selection of the solvent B in the step II is changed, and the specific change of dichloromethane into decalin is carried out, and the rest steps are unchanged, so that 4-bromo-2-fluoro-6-chloroaniline (16.70 g, yield 80% and purity 93.1%) is obtained; finally, colorless liquid 5-bromo-1, 2-dichloro-3-fluorobenzene (11.06 g, yield 91%, purity 97%) was obtained.
Example 13
Compared with the example 1, only the selection of the solvent B in the step II is changed, and the specific method is that dichloromethane is changed into a mixed solvent of dichloromethane and toluene (v/v=2:1), and the rest steps are unchanged, so that 4-bromo-2-fluoro-6-chloroaniline (17.74 g, yield 85% and purity 96.6%) is obtained; finally, colorless liquid 5-bromo-1, 2-dichloro-3-fluorobenzene (11.05 g, yield 90.9%, purity 97.6%) was obtained.
Example 14
Compared with example 1, only the selection of nitrite in the step III is changed, specifically, sodium nitrite is changed into ferric nitrite, and the other steps are unchanged, so that 5-bromo-1, 2-dichloro-3-fluorobenzene (10.12 g, yield 83% and purity 97.1%) is obtained.
Example 15
Compared with example 1, the method only changes the selection of halogenated copper in the step III, specifically changes cuprous chloride into cuprous bromide, and the other steps are unchanged, so as to obtain 5-bromo-1, 2-dichloro-3-fluorobenzene (11.10 g, yield 90% and purity 98.4%).
Example 16
Compared with example 1, only the selection of the solvent C in the step III is changed, the ethanol is specifically changed into acetone, and the rest steps are unchanged, so that 5-bromo-1, 2-dichloro-3-fluorobenzene (10.49 g, 86% yield and 97.7% purity) is obtained.
Example 17
Compared with example 14, only the molar ratio of the 4-bromo-2-fluoro-6-chloroaniline to the nitrite in the step III is changed from 1:1 to 1:1.8, and the other steps are unchanged, so that 5-bromo-1, 2-dichloro-3-fluorobenzene (10.61 g, yield 87% and purity 98.1%) is obtained.
Example 18
Compared with the example 1, only the molar ratio of the 4-bromo-2-fluoro-6-chloroaniline to the halogenated copper in the step III is changed from 1:1 to 1:2.0, and the other steps are unchanged, so that 5-bromo-1, 2-dichloro-3-fluorobenzene (11.29 g, yield 92.5% and purity 98.3%) is obtained.
Example 19
In comparison with example 1, only the pressure of reduced pressure distillation in step III was changed from 15kpa to 10kpa, and the remaining steps were unchanged, to obtain 5-bromo-1, 2-dichloro-3-fluorobenzene (10.97 g, yield 90%, purity 97.2%).
Comparative example 1
Compared with the example 1, only the selection of the brominating reagent in the step I is changed, 1, 3-dibromo-5, 5-dimethyl hydantoin is changed into N-bromosuccinimide, and the other steps are unchanged, so that p-bromo-o-fluoroaniline (15.21 g, yield 80% and purity 92.6%) is obtained; finally, colorless liquid 5-bromo-1, 2-dichloro-3-fluorobenzene (10.57 g, yield 87%, purity 92%) was obtained.
Comparative example 2
Compared with the example 1, only the selection of the acid A and the oxidant in the step II is changed, 30% of hydrochloric acid and 30% of hydrogen peroxide are changed into chlorosuccinimide, and the other steps are unchanged, so that 4-bromo-2-fluoro-6-chloroaniline (16.07 g, yield 77% and purity 90.9%) is obtained; finally, colorless liquid 5-bromo-1, 2-dichloro-3-fluorobenzene (10.69 g, yield 88%, purity 90%) was obtained.
Comparative example 3
In comparison with example 1, only step III was modified, the specific procedure being as follows:
step III: adding 30% hydrochloric acid (11.23 ml) into a glass reaction bottle in sequence, adding 4-bromo-2-fluoro-6-chloroaniline (11.22 g,50mmol,5.61 g/time, 10 minutes each time interval) in two batches, heating to 50 ℃, preserving heat for 1h, slowly cooling to-5 ℃, separating out a large amount of solid, dropwise adding 30% sodium nitrite aqueous solution (150 g, wherein each 11.5g of sodium nitrite aqueous solution contains 3.45g and 50 mmol) at the temperature, controlling the dropwise adding time to be 1h, and preserving heat for 30min at the temperature after the dropwise adding is finished to prepare a nitrogen-containing mixture; adding 30% hydrochloric acid (100 ml), cuprous chloride (4.95 g,50 mmol), water (50 ml) and ethanol (30 ml) into the other reaction bottle, stirring at a rotating speed of 300r/min, heating to 50 ℃, dropwise adding the prepared nitrogen-containing mixture, discharging a large amount of gas in the dropwise adding process, controlling the dropwise adding time to be 2h, preserving heat for 1h after dropwise adding, slowly heating to 70 ℃, and preserving heat for 3h; cooling the reaction solution to room temperature, extracting the reaction solution by using ethyl acetate (200 ml), washing an organic phase by using water (200 ml each time, extracting for 2 times), extracting, drying by using anhydrous sodium sulfate, and concentrating under reduced pressure to obtain a crude product of 5-bromo-1, 2-dichloro-3-fluorobenzene; the crude product obtained was rectified in high vacuum under a controlled pressure of 15kpa and the fraction at 80 c was collected to obtain 5-bromo-1, 2-dichloro-3-fluorobenzene (9.54 g, yield 78%, purity 88%) as a colorless liquid.
Comparative example 4
In comparison with example 1, only the pressure of reduced pressure distillation in step III was changed from 15kpa to 8kpa, and the remaining steps were unchanged, to obtain 5-bromo-1, 2-dichloro-3-fluorobenzene (3.65 g, yield 30%, purity 70%).
Comparative example 5
In comparison with example 1, only the pressure of reduced pressure distillation in step III was changed from 15kpa to 25kpa, and the remaining steps were unchanged, so that 5-bromo-1, 2-dichloro-3-fluorobenzene could not be collected.
The present embodiment is merely illustrative of the present application and is not intended to be limiting, and those skilled in the art, after having read the present specification, may make modifications to the present embodiment without creative contribution as required, but is protected by patent laws within the scope of the claims of the present application.

Claims (10)

1. The preparation method of the 5-bromo-1, 2-dichloro-3-fluorobenzene is characterized by comprising the following steps:
step I: mixing o-fluoroaniline and an organic solvent A, cooling to 0-5 ℃, adding a bromination reagent, heating to 20-25 ℃, carrying out heat preservation reaction, pouring the reaction liquid into ice water after the reaction is finished, extracting, and concentrating under reduced pressure to obtain p-bromo-o-fluoroaniline;
step II: mixing para-bromo-o-fluoroaniline and a solvent B, cooling to 0-5 ℃, adding an acid A and an oxidant, heating to 45-50 ℃, carrying out heat preservation reaction, standing for layering after the reaction is finished, washing an organic phase by using an alkali solution, and concentrating under reduced pressure to obtain 4-bromo-2-fluoro-6-chloroaniline;
step III: mixing 4-bromo-2-fluoro-6-chloroaniline and acid B, heating to 50-55 ℃, carrying out heat preservation reaction, cooling to 0-5 ℃ after the reaction is finished, dropwise adding nitrite aqueous solution, carrying out heat preservation reaction, dropwise adding the reaction solution into a mixed solution containing halogenated copper salt aqueous solution and solvent C at 50-55 ℃, carrying out heat preservation reaction after the dropwise adding is finished, extracting, washing, concentrating under reduced pressure and rectifying under high vacuum to obtain a pure 5-bromo-1, 2-dichloro-3-fluorobenzene product.
2. The method for preparing 5-bromo-1, 2-dichloro-3-fluorobenzene according to claim 1, wherein the organic solvent a in the step I is at least one of N, N-dimethylformamide, acetone, tetrahydrofuran, dichloromethane, methanol, ethanol, dimethyl sulfoxide and 1, 4-dioxane.
3. The method for preparing 5-bromo-1, 2-dichloro-3-fluorobenzene according to claim 1, wherein the molar ratio of o-fluoroaniline to brominating agent in the step I is 1:0.9-1.1; the brominating reagent is at least one of 1, 3-dibromo-5, 5-dimethyl hydantoin, 3-pyridine methylamine bromine, carbon tetrabromide, 5-dibromo-2, 2-dimethyl-4, 6-diketone-1, 3-dioxane, tetrabromo-o-benzoquinone, 1,3, 5-tribromo-1, 3, 5-thiazine-2, 4, 6-trione, N-bromo-o-sulfonyl benzene imide, N-bromo-succinimide and ferric bromide.
4. The method for preparing 5-bromo-1, 2-dichloro-3-fluorobenzene according to claim 1, wherein the solvent B in the step II is at least one of dichloromethane, dichloroethane, ethyl acetate, toluene, chlorobenzene, xylene, decalin and cyclohexane.
5. The method for preparing 5-bromo-1, 2-dichloro-3-fluorobenzene according to claim 1, wherein the molar ratio of the amount of p-bromo-o-fluoroaniline to the amount of acid a in the step II is 1:1-3; the acid A is at least one of hydrochloric acid, sulfuric acid, trifluoroacetic acid, acetic acid, perchloric acid and hydroiodic acid.
6. The method for preparing 5-bromo-1, 2-dichloro-3-fluorobenzene according to claim 1, wherein the molar ratio of the p-bromo-o-fluoroaniline to the oxidant in the step II is 1:1-4; the oxidant is at least one of hydrogen peroxide, potassium permanganate, carbamide peroxide, sodium peroxide and periodic acid.
7. The method for preparing 5-bromo-1, 2-dichloro-3-fluorobenzene according to claim 1, wherein the solvent C in the step III is at least one of methanol, ethanol, tetrahydrofuran and dioxane.
8. The method for preparing 5-bromo-1, 2-dichloro-3-fluorobenzene according to claim 1, wherein the molar ratio of 4-bromo-2-fluoro-6-chloroaniline to nitrite in step III is 1:1.0-2.5; the nitrite is at least one of sodium nitrite, potassium nitrite, ferric nitrite and copper nitrite.
9. The method for preparing 5-bromo-1, 2-dichloro-3-fluorobenzene according to claim 1, wherein the molar ratio of 4-bromo-2-fluoro-6-chloroaniline to the amount of halogenated copper in step III is 1:1-4; the halogenated copper is at least one of cuprous bromide, cuprous iodide, cuprous chloride, cupric bromide and cupric chloride.
10. The method for preparing 5-bromo-1, 2-dichloro-3-fluorobenzene according to claim 1, wherein the high vacuum in the step III is 10-30Kpa.
CN202311643900.3A 2023-12-04 2023-12-04 Preparation method of 5-bromo-1, 2-dichloro-3-fluorobenzene Pending CN117658763A (en)

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