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Synthesis method of 4,7-dichloroquinoline

A technology of dichloroquinoline and synthetic methods, applied in 4 fields, can solve the problems of expensive raw materials, unfavorable industrial production, high cost of raw materials, etc., and achieve the effects of low cost, good product quality and good purity

Inactive Publication Date: 2020-07-03
CHONGQING MEDICAL & PHARMA COLLEGE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] Patent documents CN201310680605 and CN1847226A are synthesized by using ethyl 7-chloro-4-hydroxyquinoline 3-carboxylate and diethyl ethoxymethylene malonate as starting materials respectively, and the raw materials are expensive and difficult to obtain, which is not conducive to industrial production
[0004] CN104447534A and "Process Research on Antimalarial Intermediate 4,7-Dichloroquinoline" (Zhongnan Pharmacy, Volume 4, Phase 1, February 2006), discloses the preparation method of 4,7-dichloroquinoline, using m-chloroaniline Diethyl ethoxymethine malonate is used as raw material to form a ring through condensation, then decarboxylation and chlorination to obtain 4,7-dichloroquinoline, and the cost of raw materials is high

Method used

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  • Synthesis method of 4,7-dichloroquinoline

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0021] Synthesis and condensation of diethyl 2-[[(3-chlorophenyl)amino]methylene]malonate (5)

[0022] Add m-chloroaniline (101.6g, 0.8mol), triethyl orthoformate (118.4g, 0.8mol), diethyl malonate (128g, 0.8mol) in a reaction vessel equipped with a stirring and distillation device, without Mix ferric chloride (0.10g) with water evenly. After the addition, the temperature was raised to 110° C. and the reaction was kept for 2 hours. During the reaction, ethanol would evaporate, and after 2 hours, triethyl orthoformate (88.8 g, 0.6 mol) was added dropwise to the reaction system. After adding the material, raise the temperature to 130-140°C, keep the temperature for 5 hours, and then use vacuum distillation to remove the residual ethanol after the reaction. The crude oily product remains, and the crude product directly enters the next step of cyclization.

[0023] Synthesis of Ethyl 7-Chloro-4-Hydroxy-3-quinolinecarboxylate (6) and 4-Hydroxy-7-Chloroquinolinic Acid (7) (one-pot ...

Embodiment 2

[0030] Synthesis and condensation of diethyl 2-[[(3-chlorophenyl)amino]methylene]malonate (5)

[0031] Add m-chloroaniline (101.6g, 0.8mol), trimethyl orthoformate 0.8mol, diethyl malonate (128g, 0.8mol) and anhydrous iron trichloride in a reaction vessel equipped with a stirring and distillation device (0.10g) and mix well. After the feeding is completed, raise the temperature to 120°C and keep it warm for 3 hours. Methanol will evaporate during the reaction. After 3 hours, add 0.8 mol of trimethyl orthoformate dropwise to the reaction system. After adding the material, raise the temperature to 130-140°C, keep it warm for 4 hours, and then use vacuum distillation to remove the residual methanol after the reaction. The crude oily product remains, and the crude product directly enters the next step of cyclization.

[0032] Synthesis of Ethyl 7-Chloro-4-Hydroxy-3-quinolinecarboxylate (6) and 4-Hydroxy-7-Chloroquinolinic Acid (7) (one-pot method of ring closure and hydrolysis) ...

Embodiment 3

[0039]Synthesis and condensation of diethyl 2-[[(3-chlorophenyl)amino]methylene]malonate (5)

[0040] Add m-chloroaniline (101.6g, 0.8mol), triethyl orthoformate (118.4g, 0.8mol), diethyl malonate (128g, 0.8mol) in a reaction vessel equipped with a stirring and distillation device, without Mix ferric chloride (0.15g) with water evenly. After the addition, the temperature was raised to 100° C. and the reaction was kept for 1 hour. During the reaction, ethanol would evaporate, and after 1 hour, triethyl orthoformate (71 g, 0.48 mol) was added dropwise to the reaction system. After adding the material, raise the temperature to 130-140°C, keep the temperature for 5 hours, and then use vacuum distillation to remove the residual ethanol after the reaction. The crude oily product remains, and the crude product directly enters the next step of cyclization.

[0041] Synthesis of Ethyl 7-Chloro-4-Hydroxy-3-quinolinecarboxylate (6) and 4-Hydroxy-7-Chloroquinolinic Acid (7) (one-pot meth...

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Abstract

The invention discloses a synthesis method of 4,7-dichloroquinoline. The synthesis method is characterized by comprising the following steps: synthesizing 7-chloro-4-hydroxylquinoline-3-carboxylic acid by using a one-pot method, and carrying out decarboxylation and chlorination on the 7-chloro-4-hydroxylquinoline-3-carboxylic acid to obtain 4,7-dichloroquinoline. The step of synthesizing the 7-chloro-4-hydroxylquinoline-3-carboxylic acid by the one-pot method comprises the following sub-steps: with m-chloroaniline, triethyl orthoformate or trimethyl orthoformate and diethyl malonate as raw materials, carrying out condensation under the catalysis of anhydrous ferric trichloride to obtain diethyl 2-[[(3-chlorophenyl)amino]methylene]malonate, directly adding a condensation reaction solution into an organic solvent, carrying out heating cyclization to obtain 7-chloro-4-hydroxylquinoline-3-carboxylic acid ethyl ester, and after the cyclization reaction is completed, adding sodium hydroxidefor hydrolysis to obtain 7-chloro-4-hydroxylquinoline-3-carboxylic acid. Although the whole process comprises five reactions, intermediate products are good enough in purity and can be directly synthesized into a target product without purification, so operation is easy and convenient and industrialization is facilitated; and raw materials are easily available, and pollution is small.

Description

technical field [0001] The invention relates to a synthesis method of 4,7-dichloroquinoline, which belongs to the technical field of organic synthesis. Background technique [0002] Chloroquine is an antimalarial drug and an effective drug for the treatment of new coronary pneumonia, and 4,7-dichloroquinoline is an important intermediate for its synthesis. 4,7-Dichloroquinoline, as the mother nucleus of chloroquine and hydroxychloroquine, is in short supply in the current market. However, the old process of producing 4,7-dichloroquinoline has high production cost, harsh conditions and long production cycle, which cannot meet the market demand. It is of great significance to find the production process suitable for the moment as soon as possible. [0003] Patent documents CN201310680605 and CN1847226A are synthesized by using ethyl 7-chloro-4-hydroxyquinoline 3-carboxylate and diethyl ethoxymethylene malonate as starting materials respectively, and the raw materials are exp...

Claims

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Application Information

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IPC IPC(8): C07D215/18
CPCC07D215/18
Inventor 刘殿卿郭胜超谭文龙何东贤
Owner CHONGQING MEDICAL & PHARMA COLLEGE
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