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A method for synthesizing 2-fluoro-4-trifluoromethylbenzoic acid

A technology of trifluoromethylbenzoic acid and tetramethylpiperidine, which is applied in the field of fine chemical intermediate synthesis, can solve the problems of no disclosed process method, limited key starting materials, etc., and achieves a highly innovative, simple and effective method. , the effect of mild reaction conditions

Active Publication Date: 2018-05-25
CANGZHOU PURUI DONGFANG SCI & TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] Although the application of this compound has been increasing, so far, no effective process for synthesizing this compound has been disclosed, which directly limits its subsequent clinical research as a key starting material for potential drug candidates

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0016] In the first step, under nitrogen protection, mix 55 ml of tetrahydrofuran and 2,2,6,6-tetramethylpiperidine (15.5 g, 0.11 mol) and cool to -20 o C, followed by temperature control -25 o C to -20 o C. Start to add 2M isopropylmagnesium chloride tetrahydrofuran solution (53 ml, 0.105 mol) dropwise, and stir the reaction for half an hour. The above reaction solution was cooled to -78 o C, followed by temperature control -78 o C to -65 o C, add m-chlorotrifluoromethylbenzene (18.1 g, 0.1 mol) dropwise, keep stirring and react for 1 hour, then feed carbon dioxide gas into the system until the reaction is no longer absorbed, after the detection reaction is complete, quench with 10% hydrochloric acid To quench the reaction, add 150 milliliters of ethyl acetate for layering, and after the organic layer was evaporated to dryness, it was directly used in the next reaction;

[0017] In the second step, the product obtained in the first step was added to 110 ml of dioxane, an...

Embodiment 2

[0019] In the first step, under nitrogen protection, mix 65 ml of cyclopentyl methyl ether and 2,2,6,6-tetramethylpiperidine (16.9 g, 0.12 mol) and cool to -20 o C, followed by temperature control -25 o C to -20 o C. Start to add 2.5M n-butyllithium hexane solution (44 ml, 0.11 mol) dropwise, and stir the reaction for half an hour. The above reaction solution was cooled to -70 o C, followed by temperature control -70 o C to -60 o C, add m-chlorotrifluoromethylbenzene (18.1 g, 0.1 mol) dropwise, keep stirring and react for 1 hour, then feed carbon dioxide gas into the system until the reaction is no longer absorbed, after the detection reaction is complete, quench with 10% hydrochloric acid To quench the reaction, add 180 milliliters of ethyl acetate for layering, and after the organic layer was evaporated to dryness, it was directly used in the next reaction;

[0020] In the second step, add the product obtained in the first step to 140 ml of dimethyl sulfoxide, mix evenl...

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PUM

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Abstract

The invention discloses a method for synthesizing 2-fluoro-4-trifluoromethylbenzoic acid. After chlorobenzotrifluoride serves as a raw material and undergoes selective proton abstraction together with 2,2,6,6-tetramethyl piperidine magnesium chloride or 2,2,6,6-lithium tetramethylpiperidide, carbon dioxide is led in to generate 2-fluoro-4-trifluoromethylbenzoic acid, and then 2-fluoro-4-trifluoromethylbenzoic acid is obtained after potassium fluoride nucleophilic substitution. In the method, the raw materials are easy to obtain, the steps are short, the reaction selectivity is high, and the method has potential industrialized amplification prospect.

Description

technical field [0001] The invention relates to a method for synthesizing 2-fluoro-4-trifluoromethylbenzoic acid, which belongs to the field of synthesis of fine chemical intermediates. Background technique [0002] 2-Fluoro-4-trifluoromethylbenzoic acid, as a fluorine-containing carboxylic acid compound, can be used as a synthetic structural unit to construct a variety of complex drugs with specific uses. According to the Reaxys data retrieval results, as of August 2016, there were 15 published patents using 2-fluoro-4-trifluoromethylbenzoic acid, involving BoehringerIngelheim, SumitomoChemical, Bayer Pharma, Merck Sharp&Dohme, Eisai and other internationally renowned pharmaceutical company. [0003] Although the application of this compound has been increasing, so far, no effective process for synthesizing this compound has been disclosed, which directly limits its subsequent clinical research as a key starting material for a potential drug candidate. Contents of the in...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C51/363C07C63/70
CPCC07C51/15C07C51/363C07C63/70
Inventor 冷延国王栋召刘增仁
Owner CANGZHOU PURUI DONGFANG SCI & TECH