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Industrial preparation method of 4,7-dichloroquinoline

A technology of dichloroquinoline and chloroquinoline, which is applied in the field of preparation of pharmaceutical intermediate 4,7-dichloroquinoline, and achieves the effects of high yield, high product purity and simple process

Inactive Publication Date: 2014-03-12
WUHAN WUYAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] This patent uses ethyl 4-hydroxy-7-chloro-quinoline-3-carboxylate as a raw material to obtain 4,7-dichloroquinoline through a three-step reaction, which has not been reported in China

Method used

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  • Industrial preparation method of 4,7-dichloroquinoline
  • Industrial preparation method of 4,7-dichloroquinoline
  • Industrial preparation method of 4,7-dichloroquinoline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0017] a, the preparation of compound 4-hydroxyl-7 chloro-quinoline-3-carboxylic acid

[0018] Add 50g of ethyl 4-hydroxy-7-chloro-quinoline-3-carboxylate into a 250mL single-necked bottle, then add 120g of 10% NaOH solution, stir and heat to 90-100°C to dissolve, then add activated carbon for half an hour to decolorize, and filter with suction , the filtrate was adjusted to PH to 3-4 with 10% HCl solution, and a large amount of solids were precipitated, cooled to room temperature, filtered with suction, washed with water, and dried to obtain 40.87 g of the product, with a yield of 92%

[0019] B, the preparation of compound 4-hydroxyl-7-chloroquinoline

[0020] Add 120 mL of paraffin oil into a 250 mL three-necked flask, stir, and add 40 g of 4-hydroxy-7-chloro-quinoline-3 carboxylic acid. Heat to raise the temperature to 230-250 and react for 30 minutes. After the reaction, cool to room temperature and suction filter, wash and dry with toluene to obtain 31.5 g of 7-chloro-4...

Embodiment 2

[0024] a, the preparation of compound 4-hydroxyl-7 chloro-quinoline-3-carboxylic acid

[0025] Add 50g of ethyl 4-hydroxy-7-chloro-quinoline-3-carboxylate into a 250mL single-necked bottle, then add 120g of 10% NaOH solution, stir and heat to 90-100°C to dissolve, then add activated carbon for half an hour to decolorize, and filter with suction , the filtrate was adjusted to PH to 3-4 with 10% HCl solution, and a large amount of solids were precipitated, cooled to room temperature, filtered with suction, washed with water, and dried to obtain 42.2 g of the product, with a yield of 95%

[0026] B, the preparation of compound 4-hydroxyl-7-chloroquinoline

[0027] Add 120 mL of paraffin oil into a 250 mL three-necked flask, stir, and add 40 g of 4-hydroxy-7-chloro-quinoline-3 carboxylic acid. Heat to raise the temperature to 230-250°C, react for 30 minutes, cool to room temperature after the reaction, filter the toluene with suction to wash the filter cake, and dry to obtain 32....

Embodiment 3

[0031] a, the preparation of compound 4-hydroxyl-7 chloro-quinoline-3-carboxylic acid

[0032] Add 50g of ethyl 4-hydroxy-7-chloro-quinoline-3-carboxylate into a 250mL single-necked bottle, then add 120g of 10% NaOH solution, stir and heat to 90-100°C to dissolve, then add activated carbon for half an hour to decolorize, and filter with suction , the filtrate was adjusted to PH with 10% HCl solution until the Congo red test paper turned blue, and a large amount of solid was precipitated, cooled to room temperature, filtered with suction, washed with water, and dried to obtain 41.32 g of the product, with a yield of 93%

[0033] B, the preparation of compound 4-hydroxyl-7-chloroquinoline

[0034] Add 120 mL of paraffin oil into a 250 mL three-necked flask, stir, and add 40 g of 4-hydroxy-7-chloro-quinoline-3-carboxylic acid. Heat to raise the temperature to 230-250 and react for 30 minutes. After the reaction, cool to room temperature and suction filter, wash and dry with tolu...

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Abstract

The invention relates to a preparation method of a medical intermediate 4,7-dichloroquinoline. The 4,7-dichloroquinoline is an important intermediate of a medicine hydroxychloroquine sulfate for treating discoid lupus erythematosus and systemic lupus erythematosus. The preparation method comprises the following steps: performing hydrolysis and acid adjustment on 4-hydroxyl-7-chlorine-quinoline-3-carboxylic acid ethyl ester by using 10% sodium hydroxide solution to prepare 4-hydroxyl-7-chlorine-quinoline-3-carboxylic acid; performing decarboxylation to produce 4-hydroxyl-7-chloroquinoline; and chlorinating the 4-hydroxyl-7-chloroquinoline by using phosphorus oxychloride to obtain 4,7-dichloroquinoline crude products; and performing one-step refining to obtain the products. The purity of the prepared products is more than or equal to 99% and the total yield of the products is more than or equal to 70%; raw materials are easily available; the process is simple; the yield and the purity are high in each step; and the preparation method is suitable for industrialized production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, and in particular relates to a preparation method of a pharmaceutical intermediate 4,7-dichloroquinoline. Background technique [0002] 4,7-Dichloroquinoline is a white needle-like crystalline solid with a chemical formula of C9H5Cl2N, a molecular weight of 198.05, and a melting point of 84-86°C. It is an important pharmaceutical intermediate and is used for the synthesis and treatment of discoid lupus erythematosus and systemic Raw material of hydroxychloroquine sulfate, a drug for lupus erythematosus. [0003] The application number is 200510063145.7, and a patent document whose publication number is CN1847226A discloses a kind of synthetic method of 4-hydroxyl-7-chloro-quinoline-3-carboxylic acid ethyl ester. Diethyl ester and m-chloroaniline are used as starting materials, 3-chloroanilino methylene malonate diethyl ester prepared by heating in toluene at 100°C, and then 3-chloroanilino met...

Claims

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Application Information

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IPC IPC(8): C07D215/18
CPCC07D215/18
Inventor 皮金红丁友友尹冬魏金维潘文清谢国范
Owner WUHAN WUYAO PHARMA
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