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Preparation method and application of impurities of 4-aminoquinoline compounds

A technology of hydroxyquinoline and mixture, applied in the field of organic chemical synthesis, can solve the problem of difficulty in obtaining high-purity LKL-4 isomers and the like

Inactive Publication Date: 2020-09-18
珠海润都制药股份有限公司 +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Since LKL-4 isomers have very similar physical and chemical properties to LKL-4, and LKL-4 is only soluble in DMF or DMSO, it is insoluble in methanol, dichloromethane, and ethyl acetate, and it is insoluble in water. It has a certain solubility, so it is difficult to obtain high-purity LKL-4 isomers by recrystallization using solvents based on the solubility difference between LKL-4 and LKL-4 isomers. Similarly, it is also difficult to obtain high-purity LKL-5 pure products Obtained by solvent recrystallization

Method used

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  • Preparation method and application of impurities of 4-aminoquinoline compounds
  • Preparation method and application of impurities of 4-aminoquinoline compounds
  • Preparation method and application of impurities of 4-aminoquinoline compounds

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0040] Preparation of 5-chloro-4-hydroxy-3-quinolinecarboxylic acid (LKL-5 isomer)

[0041] Dissolve 3 g of mixture 1 (the purity of 5-chloro-4-hydroxy-3-quinoline carboxylic acid is 8.5%) in dimethyl sulfoxide to prepare a solution with a concentration of 150 mg / ml, and separate by preparative liquid chromatography , the chromatographic conditions are as follows:

[0042] The chromatographic column is a C18 column with isocratic elution, and the mobile phase is acetonitrile-phosphate aqueous solution (pH=4.5), where the volume ratio of acetonitrile and phosphate aqueous solution is 1:4, the flow rate is 30ml / min, and the column temperature is 30°C , the injection volume is 3ml. 5-Chloro-4-hydroxy-3-quinolinecarboxylic acid was collected by elution with a purity of 99.21%.

Embodiment 2

[0044] Preparation of 5-chloro-4-hydroxy-3-quinolinecarboxylic acid (LKL-5 isomer)

[0045] Mix and stir 3g (0.01mol) of LKL-3 and 10ml of paraffin oil, add 2.94g (0.03mol) of concentrated sulfuric acid once at 20~30°C, continue to stir and heat to 100°C for 2h. Cool to 20~30°C, filter under reduced pressure to obtain a brownish-yellow solid, wash the filter cake with 10ml water, 10ml chloroform and 10ml ethanol in sequence, and continue to filter for 10min, the obtained off-white solid mixture 2 (LKL-4 isomer purity 70.4%). The above-mentioned LKL-4 isomer was directly mixed with 10ml of 25% aqueous sodium hydroxide solution, stirred at 20~30°C for 2h, the reaction solution was filtered under reduced pressure and washed with 5ml of ethanol, dried to obtain off-white solid mixture 1 (LKL -5 isomer purity 75.3%). The above mixture 1 was dissolved in dimethyl sulfoxide to form a solution with a concentration of 120 mg / ml, and separated by liquid phase preparative chromatograph...

Embodiment 3

[0050] Preparation of 5-chloro-4-hydroxy-3-quinolinecarboxylic acid (LKL-5 isomer)

[0051] Mix and stir 3g (0.01mol) of LKL-3 and 18ml of paraffin oil, add 4.45g (0.045mol) of concentrated sulfuric acid once at 20~30°C, continue to stir and heat to 90°C for 2.5h. Cool to 20~30°C, filter under reduced pressure to obtain a brownish-yellow solid, wash the filter cake with 10ml water, 10ml chloroform and 10ml ethanol in sequence, and continue to filter for 10min, the obtained off-white solid mixture 2 (LKL-4 isomer purity 72.2%). The above-mentioned LKL-4 isomer was directly mixed with 10ml of 30% potassium hydroxide aqueous solution, stirred at 20~30°C for 2h, the reaction solution was filtered under reduced pressure and washed with 5ml of ethanol, dried to obtain off-white solid mixture 1 (LKL -5 isomer purity 76.1%). The above mixture 1 was dissolved in dimethyl sulfoxide to prepare a solution with a concentration of 150 mg / ml, and separated by preparative liquid chromatogra...

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Abstract

The invention discloses a preparation method and application of impurities of 4-aminoquinoline compounds, and concretely discloses a preparation method of 5-chloro-4-hydroxyl-3-quinolinecarboxylic acid (LKL-5 isomer). The preparation method is characterized in that the 5-chloro-4-hydroxyl-3-quinolinecarboxylic acid is separated from a mixture 1 containing the 5-chloro-4-hydroxyl-3-quinolinecarboxylic acid and 7-chloro-4-hydroxyl-3-quinolinecarboxylic acid by adopting a liquid phase method. Preferably, the mixture 1 is obtained by reacting diethyl m-chloroaniline methylene malonate (LKL-3) under the conditions of mineral oil and concentrated sulfuric acid, post-treating after the reaction is completed to obtain a mixture 2, hydrolyzing the mixture 2 under an alkaline condition, and post-treating to obtain the mixture 1. The purity of the 5-chloro-4-hydroxy-3-quinolinecarboxylic acid is greater than 99%, and preferably greater than 99.5%, the 5-chloro-4-hydroxy-3-quinolinecarboxylic acidcan be used for synthesizing subsequent products, and the 5-chloro-4-hydroxy-3-quinolinecarboxylic acid and the synthesized subsequent products can be used for impurity reference substances of 4-aminoquinoline compounds and can be used for quality control of related raw material medicines.

Description

technical field [0001] The invention belongs to the technical field of organic chemical synthesis, and relates to a method for preparing impurities of 4-aminoquinoline compounds and its use. The impurities include ethyl 5-chloro-4-hydroxy-3-quinolinecarboxylate, 5-chloroquinoline -4-hydroxy-3-quinolinecarboxylic acid, 5-chloro-4-hydroxyquinoline, 4,5-dichloroquinoline, etc. Background technique [0002] 4,7-Dichloroquinoline is the preparation of 4-aminoquinoline compounds Hydroxy Chloroquine (Hydroxy Chloroquine), Chloroquine (Chloroquine), Amodiaquine (Amodiaquine), Glafenine (Glafenine) and pharmaceutically available salts Key intermediates, among which the structural formulas of Hydroxy Chloroquine, Chloroquine, Amodiaquine and Glafenine are shown in Formula I, Formula II, Formula III and Formula IV respectively. In the prior art, a synthetic route of 4,7-dichloroquinoline uses m-chloroaniline (LKL-1) and diethyl ethoxymethylene malonate (LKL-2) as reactants to obtain m...

Claims

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Application Information

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IPC IPC(8): C07D215/56C07D215/233C07D215/18C07D215/46C07D215/44
CPCC07D215/56C07D215/233C07D215/18C07D215/46C07D215/44
Inventor 阎智勇刘杰顾克利徐甜陶少君焦慎超
Owner 珠海润都制药股份有限公司
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