Synthesis method of 4-bromo-2-fluorobiphenyl

Abstract

The invention discloses a synthetic method of 4-bromo-2-fluorobiphenyl, which belongs to the technical field of chemical synthesis and comprises the following steps: adding dichloromethane and tetrabutylammonium bromide into a bromination reaction kettle, cooling, and dropwise adding a mixture of bromine and dichloromethane; dropwise adding o-fluoroaniline, keeping the temperature for 2 hours, sampling and analyzing; then filtering, adding water, benzene and sodium hydroxide into a filter cake for neutralization, washing an oil layer with water, and carrying out azeotropic dehydration to obtain a 2-fluoro-4-bromoaniline benzene solution; the method comprises the following steps: adding anhydrous magnesium sulfate, trifluoroacetic acid and cuprous chloride into a 2-fluoro-4-bromoaniline benzene solution, cooling, dropwise adding isopropyl nitrite, preserving heat, filtering, leaching, washing, neutralizing, separating, distilling under reduced pressure, and rectifying to finally obtain the product. According to the invention, a bromination raw material is changed into bromine, and the price of bromine is far lower than that of a bromination raw material N-bromosuccinimide in the prior art, so that the synthesis cost is reduced; the invention solves the problem of high cost in the existing synthesis method of 4-bromo-2-fluorobiphenyl.

Description

technical field

[0001] The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing 4-bromo-2-fluorobiphenyl. Background technique

[0002] 4-Bromo-2-fluorobiphenyl is stored in a sealed, cool and dry condition. 4-Bromo-2-fluorobiphenyl is used for the preparation of non-steroidal anti-inflammatory drugs and intermediates of other biologically active compounds, and is often used as medicine Intermediate. At present, 4-bromo-2-fluorobiphenyl is usually synthesized by bromination, diazotization and catalytic biphenyl reaction using o-fluoroaniline, and the bromination raw material used is N-bromosuccinimide, which is relatively expensive. SUMMARY OF THE INVENTION

[0003] The technical problem to be solved by the present invention is to provide a method for synthesizing 4-bromo-2-fluorobiphenyl.

[0004] In order to solve the above-mentioned technical problems, the technical scheme adopted in the present invention is as fol...

Examples

Embodiment 1

[0016] Under room temperature conditions, drop into 650kg of methylene chloride, 167.5kg of tetrabutylammonium bromide in the bromination reaction kettle, be cooled to 10~15 ℃, mix 82.5kg of bromine with 65kg of methylene chloride, in this temperature range Carry out dropwise addition, drip at a constant speed for 1 hour, add 56.5kg of o-fluoroaniline dropwise, and drop it at a uniform speed within 30 minutes, keep it in the range of 10 ° C for 2 hours, sample and analyze, the mass fraction of o-fluoroaniline is less than 0.5%, otherwise, continue Insulation, filtration, the filtrate is used for the next batch of recycling, the filter cake is added with 120kg of water, 258kg of benzene, neutralized with 80kg of 30% sodium hydroxide by mass fraction, the pH value of the water phase is required to be 12, layered, and the oil layer is washed with 100kg of water , azeotropic dehydration to obtain 2-fluoro-4-bromoaniline solution.

[0017] In the 2-fluoro-4-bromoaniline solution, a...

Embodiment 2

[0019] Under room temperature, drop into dichloromethane 640kg, tetrabutylammonium bromide 167.5kg in the bromination reactor, be cooled to 15 ℃, 82.3kg bromine is mixed with 65.2kg dichloromethane, carry out in this temperature range Add dropwise, drip at a constant speed in 1 hour, add 55.3kg of o-fluoroaniline dropwise, drip at a constant speed within 30 minutes, keep at 15 °C for 2 hours, sample and analyze, the mass fraction of o-fluoroaniline is less than 0.5%, otherwise, continue to keep warm , filter, the filtrate is used for the next batch of recycling, the filter cake is added with 120kg of water, 258kg of benzene, neutralized with a mass fraction of 30% sodium hydroxide 80kg, the pH value of the water phase is required to be 12, layered, and the oil layer is washed with 100kg of water, Azeotropic dehydration to obtain 2-fluoro-4-bromoaniline solution.

[0020] In 2-fluoro-4-bromoaniline solution, add anhydrous magnesium sulfate 30kg, trifluoroacetic acid 39.2kg, cup...

Embodiment 3

[0022] Under room temperature, drop into dichloromethane 655kg, tetrabutylammonium bromide 167.5kg in the bromination reaction kettle, be cooled to 15 ℃, 82.7kg bromine is mixed with 64.8kg dichloromethane, carry out in this temperature range Dropwise, dripped at a constant speed in 1 hour, dripped 56.9kg of o-fluoroaniline, dripped at a uniform speed within 30 minutes, kept at 15 ° C for 2 hours, sampled and analyzed, the mass fraction of o-fluoroaniline was less than 0.5%, otherwise, continue to keep warm , filter, the filtrate is used for the next batch of recycling, the filter cake is added with 120kg of water, 258kg of benzene, neutralized with a mass fraction of 30% sodium hydroxide 80kg, the pH value of the water phase is required to be 12, layered, and the oil layer is washed with 100kg of water, Azeotropic dehydration to obtain 2-fluoro-4-bromoaniline solution.

[0023] In 2-fluoro-4-bromoaniline solution, add anhydrous magnesium sulfate 30kg, trifluoroacetic acid 39....

technical field

[0001] The invention relates to the technical field of chemical synthesis, in particular to a method for synthesizing 4-bromo-2-fluorobiphenyl. Background technique

[0002] 4-Bromo-2-fluorobiphenyl is stored in a sealed, cool and dry condition. 4-Bromo-2-fluorobiphenyl is used for the preparation of non-steroidal anti-inflammatory drugs and intermediates of other biologically active compounds, and is often used as medicine Intermediate. At present, 4-bromo-2-fluorobiphenyl is usually synthesized by bromination, diazotization and catalytic biphenyl reaction using o-fluoroaniline, and the bromination raw material used is N-bromosuccinimide, which is relatively expensive. SUMMARY OF THE INVENTION

[0003] The technical problem to be solved by the present invention is to provide a method for synthesizing 4-bromo-2-fluorobiphenyl.

[0004] In order to solve the above-mentioned technical problems, the technical scheme adopted in the present invention is as fol...

Examples

Embodiment 1

[0016] Under room temperature conditions, drop into 650kg of methylene chloride, 167.5kg of tetrabutylammonium bromide in the bromination reaction kettle, be cooled to 10~15 ℃, mix 82.5kg of bromine with 65kg of methylene chloride, in this temperature range Carry out dropwise addition, drip at a constant speed for 1 hour, add 56.5kg of o-fluoroaniline dropwise, and drop it at a uniform speed within 30 minutes, keep it in the range of 10 ° C for 2 hours, sample and analyze, the mass fraction of o-fluoroaniline is less than 0.5%, otherwise, continue Insulation, filtration, the filtrate is used for the next batch of recycling, the filter cake is added with 120kg of water, 258kg of benzene, neutralized with 80kg of 30% sodium hydroxide by mass fraction, the pH value of the water phase is required to be 12, layered, and the oil layer is washed with 100kg of water , azeotropic dehydration to obtain 2-fluoro-4-bromoaniline solution.

[0017] In the 2-fluoro-4-bromoaniline solution, a...

Embodiment 2

[0019] Under room temperature, drop into dichloromethane 640kg, tetrabutylammonium bromide 167.5kg in the bromination reactor, be cooled to 15 ℃, 82.3kg bromine is mixed with 65.2kg dichloromethane, carry out in this temperature range Add dropwise, drip at a constant speed in 1 hour, add 55.3kg of o-fluoroaniline dropwise, drip at a constant speed within 30 minutes, keep at 15 °C for 2 hours, sample and analyze, the mass fraction of o-fluoroaniline is less than 0.5%, otherwise, continue to keep warm , filter, the filtrate is used for the next batch of recycling, the filter cake is added with 120kg of water, 258kg of benzene, neutralized with a mass fraction of 30% sodium hydroxide 80kg, the pH value of the water phase is required to be 12, layered, and the oil layer is washed with 100kg of water, Azeotropic dehydration to obtain 2-fluoro-4-bromoaniline solution.

[0020] In 2-fluoro-4-bromoaniline solution, add anhydrous magnesium sulfate 30kg, trifluoroacetic acid 39.2kg, cup...

Embodiment 3

[0022] Under room temperature, drop into dichloromethane 655kg, tetrabutylammonium bromide 167.5kg in the bromination reaction kettle, be cooled to 15 ℃, 82.7kg bromine is mixed with 64.8kg dichloromethane, carry out in this temperature range Dropwise, dripped at a constant speed in 1 hour, dripped 56.9kg of o-fluoroaniline, dripped at a uniform speed within 30 minutes, kept at 15 ° C for 2 hours, sampled and analyzed, the mass fraction of o-fluoroaniline was less than 0.5%, otherwise, continue to keep warm , filter, the filtrate is used for the next batch of recycling, the filter cake is added with 120kg of water, 258kg of benzene, neutralized with a mass fraction of 30% sodium hydroxide 80kg, the pH value of the water phase is required to be 12, layered, and the oil layer is washed with 100kg of water, Azeotropic dehydration to obtain 2-fluoro-4-bromoaniline solution.

[0023] In 2-fluoro-4-bromoaniline solution, add anhydrous magnesium sulfate 30kg, trifluoroacetic acid 39....

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