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Synthesis method of 3-bromine-2-fluorobenzoic acid

A technology of fluorobenzoic acid and a synthesis method, which is applied in the synthesis field of 3-bromo-2-fluorobenzoic acid, can solve problems such as poor selectivity, low yield, application limitation, etc. good effect

Active Publication Date: 2018-05-29
烟台市蓬莱区融欣化工有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

The biggest disadvantage of the above method is: the selectivity is very poor when the raw material o-fluorobromobenzene is deprotonated, and the ratio of the two isomers of 3-bromo-2-fluorobenzoic acid and 3-fluoro-2-bromobenzoic acid usually obtained is nearly 3 :1-4:1, which brings difficulty to the separation and purification of the product, and the separation yield is usually around 55%.
[0004] The products of the prior art are difficult to purify, and the defect of low yield restricts the scale-up synthesis of this type of compound, and the application is limited

Method used

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  • Synthesis method of 3-bromine-2-fluorobenzoic acid

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Experimental program
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Effect test

Embodiment 1

[0027] The first step, add 200mL tetrahydrofuran and diisopropylamine (30.4g, 0.3mol) to the reaction flask, cool down to -25°C, and add n-butyllithium (120mL, 0.3mol, 2.5mol / L) dropwise under nitrogen protection , the temperature is controlled not to exceed -10°C, after the drop is completed, the solution is kept and stirred for 30 minutes to obtain a tetrahydrofuran solution of lithium diisopropylamide. The temperature of the reaction solution was lowered to -78°C, the temperature was controlled at -78 to -65°C, fluorobenzene (28.8g, 0.3mol) was added dropwise, kept stirring for 1 hour, and trimethylchlorosilane (32.6g , 0.3mol), temperature control -78 ~ -65 ℃, dropwise, stirring at room temperature for 1 hour, dropwise adding saturated ammonium chloride solution to quench the reaction, temperature control + ), used directly in the next step without purification.

[0028] The second step, add 200mL tetrahydrofuran and diisopropylamine (29.3g, 0.29mol) to the reaction flask,...

Embodiment 2

[0031] The first step, add 200mL 2-methyltetrahydrofuran and diisopropylamine (33.4g, 0.33mol) to the reaction flask, cool to -40 ℃, under the protection of nitrogen, add dropwise n-butyllithium (126mL, 0.315mol, 2.5mol / L), the temperature is controlled not to exceed -10°C, after dropping, keep stirring for 30 minutes to obtain a 2-methyltetrahydrofuran solution of lithium diisopropylamide. The temperature of the reaction solution was lowered to -78°C, the temperature was controlled at -78 to -40°C, fluorobenzene (28.8g, 0.3mol) was added dropwise, kept stirring for 1 hour, and trimethylchlorosilane (34.2g , 0.315mol), temperature control -78 ~ -40 ℃, dropwise, stirring at room temperature for 1 hour, dropwise adding saturated ammonium chloride solution to quench the reaction, temperature control <25 ℃, adding 200mL n-heptane layering, organic phase subtraction The solvent was concentrated under reduced pressure to obtain 49.0 g of light yellow liquid 2-fluorophenyltrimethyls...

Embodiment 3

[0035]The first step, add 200mL diethoxymethane and diisopropylamine (31.8g, 0.315mol) to the reaction flask, cool down to -20°C, and add n-butyl lithium (126mL, 0.315mol, 2.5 mol / L), the temperature was controlled not to exceed -10°C, after the drop was completed, the solution was kept and stirred for 30 minutes to obtain a solution of lithium diisopropylamide in diethoxymethane. The temperature of the reaction solution was lowered to -70°C, the temperature was controlled at -70 to -40°C, fluorobenzene (28.8g, 0.3mol) was added dropwise, kept stirring for 1 hour, and trimethylchlorosilane (34.2g , 0.315mol), temperature control -70 ~ -40 ℃, after dropping, stirring at room temperature for 1 hour, dropwise adding saturated ammonium chloride solution to quench the reaction, temperature control < 25 ℃, adding 200mL n-heptane layering, organic phase subtraction The solvent was concentrated under reduced pressure to obtain 49.1 g of light yellow liquid 2-fluorophenyltrimethylsilan...

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Abstract

The invention discloses a synthesis method of 3-bromine-2-fluorobenzoic acid, and belongs to the field of organic synthesis. The synthesis method of the 3-bromine-2-fluorobenzoic acid comprises the following steps: taking fluorobenzene as a starting material, deprotonating lithium diisopropylamide, carrying out a reaction with trimethylchlorosilane to generate 2-fluorophenyl trimethylsilane, forming an intermediate 3-trimethyl silicon-2-fluorinated phenyl lithium salt, carrying out a reaction with carbon dioxide to generate 3-trimethyl silicon-2-fluorobenzoic acid, and carrying out a reactionwith a bromide reagent to obtain the 3-bromine-2-fluorobenzoic acid. The intermediate obtained by the method avoids separation of an isomer, the obtained product has high purity, and a concise approach is provided for synthesis of the compound.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis, and in particular relates to a synthesis method of 3-bromo-2-fluorobenzoic acid. Background technique [0002] 3-Bromo-2-fluorobenzoic acid is an important intermediate in organic synthesis and drug synthesis, and is the main raw material for the synthesis of anticancer drug dabrafenib and receptor agonist propargylphenoxyacetic acid compounds. It has broad market prospects. High demand and high added value. [0003] The existing synthetic method of 3-bromo-2-fluorobenzoic acid mainly takes o-fluorobromobenzene as raw material, reacts with diisopropylamine or 2,2,6,6-tetramethylpiperidine, butyllithium to remove After the proton, carbon dioxide was used to introduce the carboxyl group to give 3-bromo-2-fluorobenzoic acid (US2009197871 and Tetrahedron Letters, 1995, 36, 881-884). The biggest disadvantage of the above method is: the selectivity is very poor when the raw material o-f...

Claims

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Application Information

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IPC IPC(8): C07C51/363C07C63/70C07F7/08
CPCC07C51/363C07F7/0827C07F7/083C07C63/70
Inventor 高峰曾赛兰蒋军强张行行
Owner 烟台市蓬莱区融欣化工有限公司
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