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Preparation method of ethyl 5-chloro-2-fluoro-3-hydroxybenzoate

A technology of ethyl hydroxybenzoate and concentrated sulfuric acid, which is applied to the preparation of carboxylic acid esters, the preparation of organic compounds, chemical instruments and methods, etc., which can solve the problems of long reaction steps, inability to achieve amplification, complex post-processing, and operational uncertainty and other issues, to achieve the effect of simple operation

Pending Publication Date: 2021-11-02
CHEMSHUTTLE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

This method has the disadvantages of long reaction steps, harsh conditions, inability to achieve further amplification and complicated post-treatment. In the nitration reaction, there is uncertainty of isomers.
The diazonium salt generated during the diazotization reaction is unstable, so that the post-reaction treatment requires operation below zero, making the operation uncertain

Method used

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  • Preparation method of ethyl 5-chloro-2-fluoro-3-hydroxybenzoate
  • Preparation method of ethyl 5-chloro-2-fluoro-3-hydroxybenzoate
  • Preparation method of ethyl 5-chloro-2-fluoro-3-hydroxybenzoate

Examples

Experimental program
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Effect test

Embodiment 1

[0025] A kind of preparation method of 5-chloro-2-fluoro-3-hydroxybenzoic acid ethyl ester, described preparation method comprises the steps:

[0026] (1) Dissolve 2-chloro-5-fluorobenzoic acid (65g, 0.37mol) in solvent ethanol (650mL), slowly add concentrated sulfuric acid (65mL) dropwise at room temperature, heat to reflux and stir for 18h, After the reaction is complete, pour the reaction solution into crushed ice and keep stirring, then use 15% NaOH aqueous solution to adjust the pH value to greater than 7, then extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate and concentrate 47 g of ethyl 5-chloro-2-fluorobenzoate was obtained as a yellow oil, with a yield of 63% and a content of 96%.

[0027] (2) Ethyl 5-chloro-2-fluorobenzoate (20g, 99mmol), 4,4'-di-tert-butyl-2,2'-dipyridine and (0.8g, 3mmol), methoxy ( Cyclooctadiene) iridium dimer (0.98g, 1.5mmol) and diboronic acid pinacol ester (28g, 108mmol) were added to ...

Embodiment 2

[0032] A kind of preparation method of 5-chloro-2-fluoro-3-hydroxybenzoic acid ethyl ester, described preparation method comprises the steps:

[0033] (1) Dissolve 2-chloro-5-fluorobenzoic acid (65g, 0.37mol) in solvent ethanol (650mL), slowly add concentrated sulfuric acid (325mL) dropwise at room temperature, heat to reflux and stir for 18h, After the reaction is complete, pour the reaction solution into crushed ice and keep stirring, then use 15% NaOH aqueous solution to adjust the pH value to greater than 7, then extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate and concentrate , 50 g of ethyl 5-chloro-2-fluorobenzoate was obtained as a yellow oil, with a yield of 67% and a content of 96%.

[0034] (2) Ethyl 5-chloro-2-fluorobenzoate (20g, 99mmol), 4,4'-di-tert-butyl-2,2'-dipyridine and (5.3g, 20mmol), methoxy ( Cyclooctadiene) iridium dimer (6.5g, 9.9mmol) and diboronic acid pinacol ester (50.9g, 196mmol) were adde...

Embodiment 3

[0037] A kind of preparation method of 5-chloro-2-fluoro-3-hydroxybenzoic acid ethyl ester, described preparation method comprises the steps:

[0038](1) Dissolve 2-chloro-5-fluorobenzoic acid (65g, 0.37mol) in solvent ethanol (650mL), slowly add concentrated sulfuric acid (162mL) dropwise at room temperature, heat to reflux and stir for 18h, After the reaction is complete, pour the reaction solution into crushed ice and keep stirring, then use 15% NaOH aqueous solution to adjust the pH value to greater than 7, then extract with ethyl acetate, wash the organic phase with saturated brine, dry over anhydrous sodium sulfate and concentrate 47 g of ethyl 5-chloro-2-fluorobenzoate was obtained as a yellow oil, with a yield of 63% and a content of 96%.

[0039] (2) Ethyl 5-chloro-2-fluorobenzoate (20g, 99mmol), 4,4'-di-tert-butyl-2,2'-bipyridine and (2.7g, 10mmol), methoxy ( Cyclooctadiene) iridium dimer (3.3g, 5mmol) and diboronic acid pinacol ester (25.5g, 98mmol) were added to t...

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Abstract

The invention discloses a preparation method of ethyl 5-chloro-2-fluoro-3-hydroxybenzoate. The preparation method comprises the following steps of: (1) carrying out an esterification reaction on a compound 1 to obtain a compound 2; (2) carrying out a hydrocarbon boronation reaction on the compound 2 under the catalytic action of iridium to obtain a compound 3; and (3) carrying out a boric acid ester oxidation reaction on the compound 3 to obtain ethyl 5-chloro-2-fluoro-3-hydroxybenzoate. The method has the advantages of easily available raw materials, simple operation and high yield, and a single-target configuration product is obtained.

Description

technical field [0001] The invention relates to the technical field of synthesis of pharmaceutical intermediates, in particular to a preparation method of ethyl 5-chloro-2-fluoro-3-hydroxybenzoate. Background technique [0002] The introduction of fluorine atoms or fluorine-containing groups into drug molecules can change the permeability and metabolic stability of drug molecules, adjust their pKa and lipid solubility, and affect the absorption, distribution and interaction with biological targets of drug molecules. This has gradually become a common means of drug screening. However, with the development and popularization of fluorine-containing drugs, people also need to consider their chemical stability in the human body and the impact of metabolites produced under the action of enzymes on the human body. The safety issues during drug treatment are also the same. Need to draw people's attention. Recently, Dr. Yue Pan from the Novartis Institute for Biomedical Research (N...

Claims

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Application Information

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IPC IPC(8): C07C67/31C07C69/84
CPCC07C67/31C07C67/08C07F5/025C07C69/84C07C69/76
Inventor 李欢
Owner CHEMSHUTTLE
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