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Synthesis method of 2-bromo-3-fluobenzoic acid

The technology of a kind of fluorobenzoic acid and synthetic method is applied in the field of synthesis of 2-bromo-3-fluorobenzoic acid, which can solve the problems of increased production cost, unfriendly environment, cumbersome steps, etc., and achieve low cost, cheap raw materials, and Easy to get effect

Active Publication Date: 2018-05-08
杭州逸翔化工科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

There are disadvantages in this method: first, the steps are cumbersome and the operation is complicated, and the vacuum distillation of two isomers of 2-bromo-3-fluorobenzotrifluoride and 4-bromo-3-fluorobenzotrifluoride is involved in the process to separate 2-bromo-3-fluorobenzotrifluoride is obtained; second, sulfuric acid is used in multi-step reactions, which produces a large amount of waste acid water, which is not environmentally friendly
The method prepares 1 mole of 2-bromo-3-fluorobenzoic acid, consumes at least 2 moles of isobutyl lithium, and the price of isobutyl lithium is expensive, which greatly increases the production cost

Method used

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  • Synthesis method of 2-bromo-3-fluobenzoic acid

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0029] In the first step, add 160mL tetrahydrofuran and diisopropylamine (24.3g, 0.24mol) to the reaction flask, cool down to -25°C, and add n-butyllithium (96mL, 0.24mol, 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 reaction solution was cooled to -78°C, controlled at -78 to -65°C, o-bromofluorobenzene (35.0 g, 0.2 mol) was added dropwise, kept stirring for 1 hour, and trimethylchlorosilane ( 32.6g, 0.3mol), temperature control -78~-65°C, after dropping, stir at room temperature for 1 hour, dropwise add 1N HCl solution to quench the reaction, control temperature + , used directly in the next step without purification.

[0030] In the second step, 200 mL of tetrahydrofuran and diisopropylamine (21.1 g, 0.209 mol) were added to the reaction flask, the temperature was lowered to -20...

Embodiment 2

[0033] In the first step, 160 mL of cyclopentyl methyl ether and diisopropylamine (22.3 g, 0.22 mol) were added to the reaction flask, the temperature was lowered to -40 ° C, and n-butyllithium (88 mL, 0.22 mol, 2.5mol / 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 cyclopentyl methyl ether solution of lithium diisopropylamide. The reaction solution was cooled to -78°C, controlled at -78 to -40°C, o-bromofluorobenzene (35.0 g, 0.2 mol) was added dropwise, kept stirring for 1 hour, and trimethylchlorosilane ( 43.5g, 0.4mol), temperature control -78~-40°C, after dropping, stir at room temperature for 1 hour, dropwise add 1N HCl solution to quench the reaction, temperature control <20°C, add 160mL n-heptane for layering, organic phase subtraction The solvent was concentrated under reduced pressure to obtain 46.6 g of yellow liquid 3-bromo-2-fluorophenyltrimethylsilane with a purity ...

Embodiment 3

[0037] In the first step, add 160mL 2-methyltetrahydrofuran and diisopropylamine (22.3g, 0.22mol) to the reaction flask, cool down to -40°C, and add n-butyl lithium (88mL, 0.22mol, 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 2-methyltetrahydrofuran. The reaction solution was cooled to -78°C, controlled at -78 to -40°C, o-bromofluorobenzene (35.0 g, 0.2 mol) was added dropwise, kept stirring for 1 hour, and trimethylchlorosilane ( 65.2g, 0.6mol), temperature control -78~-40°C, after dropping, stir at room temperature for 1 hour, dropwise add 1N HCl solution to quench the reaction, control temperature <20°C, add 160mL n-heptane for layering, organic phase subtraction The solvent was concentrated under reduced pressure to obtain 46.7 g of yellow liquid 3-bromo-2-fluorophenyltrimethylsilane with a purity of 94.1%, which was directly...

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Abstract

The invention discloses a synthesis method of 2-bromo-3-fluobenzoic acid. The method comprises the following steps of (1) using o-bromo fluorobenzene as starting raw materials; performing proton abstraction through lithium diisopropylamide; performing reaction with trimethylchlorosilane to generate 3-bromo-2-fluorophenyl trimethylsilane; (2) forming an intermediate of 4-trimethylsilyl-3-bromo-2-bromobenzene lithium saltsby 3-bromo-2-fluorophenyl trimethylsilane under the effect of lithium diisopropylamide; then, performing reaction with carbon dioxide to generate 4-trimethylsilyl-3-bromo-2-bromobenzoic acid; (3) performing reaction on 4-trimethylsilyl-3-bromo-2-bromobenzoic acid and fluorine-containing reagents for desilylation to obtain the 2-bromo-3-fluobenzoic acid. The intermediate obtained by the method does not have isomer; the separation is easy; the obtained product has high purity; a simple and compact path is provided for the synthesis of compounds.

Description

technical field [0001] The invention belongs to the field of organic chemistry, and in particular relates to a synthesis method of 2-bromo-3-fluorobenzoic acid. Background technique [0002] 2-Bromo-3-fluorobenzoic acid is a new type of fluorine-containing drug intermediate, which belongs to a ligand of nicotinic acetylcholine receptor, can reduce the function of cholinergic nervous system, and can be used for the treatment of Alzheimer's disease disease and Parkinson's syndrome and other diseases; it is also a new type of integrin αVβ3 antagonist drug intermediate, which can be used to treat severe ischemic diseases such as myocardial infarction. [0003] The method of the synthetic 2-bromo-3-fluorobenzoic acid that has been reported in existing literature mainly contains following several kinds: [0004] 1) U.S. Patent US2008 / 293708 reported that 2-amino-3-fluorobenzoic acid was used as raw material, diazotized in hydrobromic acid to obtain diazonium salt and then reacted...

Claims

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Application Information

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IPC IPC(8): C07C63/70C07C51/377C07F7/08
CPCC07C51/377C07F7/0827C07C63/70
Inventor 高峰曾赛兰蒋军强张行行
Owner 杭州逸翔化工科技有限公司
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