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A kind of preparation method of 4,7-dichloroquinoline

A technology of dichloroquinoline and hydroxyquinoline, which is applied in the field of medicine, can solve problems such as danger and impact, and achieve the effect of quality assurance

Active Publication Date: 2022-03-15
JIANGSU TIANHE PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Its shortcoming is: the 4,7-dichloroquinoline that this technical route makes can have about 10% isomer 4,5-dichloroquinoline, has had a strong impact on the quality and yield of 4,7-dichloroquinoline rate, and after further reaction, it will become the isomer impurity in hydroxychloroquine sulfate, and there is a certain potential danger after the human body takes it

Method used

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  • A kind of preparation method of 4,7-dichloroquinoline
  • A kind of preparation method of 4,7-dichloroquinoline
  • A kind of preparation method of 4,7-dichloroquinoline

Examples

Experimental program
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Effect test

Embodiment 1

[0024] Add 240g of toluene, 90g of ethoxymethylenemalonate diethyl ester, 60g of 2-amino-6-chlorobenzoic acid into a 500mL four-necked reaction flask, stir and heat up to 60°C for 6 hours, when the reaction is complete, add 12g FeCl 3 , continue to heat up and reflux for 24 hours, and when the reflux is over, evaporate toluene under reduced pressure to dryness, then add 300ml of drinking water to the reaction bottle, stir and break up, transfer the feed solution to a 1L four-necked flask, and then add 300ml of drinking water and 56g caustic soda, stir and heat up to reflux for 6 hours, cool to 50-60°C, adjust pH to about 3 with hydrochloric acid, continue to cool down to below 20°C, filter, wash the solid with water, and dry to obtain intermediate V.

[0025] Put the tide product of intermediate Ⅴ into a 500ml four-necked reaction bottle, dry fry at 250°C for 4 hours, then cool down to about 60°C, add 240g of fresh phosphorus oxychloride, heat up and reflux for 5 hours, and th...

Embodiment 2

[0027] Add 360g of xylene, 90g of diethyl ethoxymethylenemalonate, 60g of 2-amino-6-chlorobenzoic acid into a 1L four-necked reaction flask, stir and raise the temperature to about 80°C for 4 hours. After the reaction is complete, add 10g FeCl 3 , continue to heat up and reflux for 16 hours, reflux is over, distill off xylene under reduced pressure to dryness, then add 800ml of drinking water and 84g of caustic soda to the reaction bottle, stir and heat up to reflux for 2 hours, cool to 50-60°C, use Adjust the pH to about 2 with hydrochloric acid, continue to cool down to below 20°C, filter, wash the solid with water, and dry to obtain intermediate V.

[0028] Put the tide product of intermediate Ⅴ into a 500ml four-necked reaction bottle, dry-fry at 300°C for 2 hours, then cool down to about 60°C, add 480g of fresh phosphorus oxychloride, heat up and reflux for 1 hour, and then change to vacuum distillation to excess Phosphorus oxychloride, after distillation, slowly pour th...

Embodiment 3

[0030] Add 480g of chlorobenzene, 90g of ethoxymethylenemalonate diethyl ester, 60g of 2-amino-6-chlorobenzoic acid into a 1L four-necked reaction flask, stir and raise the temperature to about 70°C for 5 hours. After the reaction is complete, add 6g FeCl 3 , continue to heat up and reflux for 12 hours, reflux is over, decompress and evaporate chlorobenzene to dryness, then add 700ml of drinking water and 75g of caustic soda to the reaction bottle, stir and heat up to reflux for 4 hours, cool to 50-60°C, use Adjust the pH to about 2 with hydrochloric acid, continue to cool down to below 20°C, filter, wash the solid with water, and dry to obtain intermediate V.

[0031] Put the tide product of intermediate Ⅴ into a 500ml four-necked reaction bottle, dry fry at 270°C for 3 hours, then cool down to about 60°C, add 360g of fresh phosphorus oxychloride, heat up and reflux for 3 hours, then change to vacuum distillation to excess Phosphorus oxychloride, after distillation, slowly p...

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Abstract

The invention relates to a preparation method of 4,7-dichloroquinoline in the technical field of medicine, which uses 2-amino-6-chlorobenzoic acid (I) as a starting material, and ethoxymethine in an organic solvent Diethyl malonate (II) undergoes condensation reaction to obtain (Ⅲ), III undergoes cyclization, hydrolysis, and acidification to obtain hydroxyquinoline dicarboxylic acid (V), V undergoes high-temperature decarboxylation to obtain hydroxyquinoline (VI), and VI undergoes Chlorination of phosphorus oxychloride gives 4,7-dichloroquinoline. The 4,7-dichloroquinoline prepared by the method of the present invention does not have the isomer 4,5-dichloroquinoline, and the temperature of the condensation reaction under the catalysis of the catalyst is low, which improves the yield of the reaction and avoids the generation of impurities , and reduce energy consumption, improve the economic benefits of the product.

Description

technical field [0001] The invention relates to a preparation method of 4,7-dichloroquinoline, which belongs to the technical field of medicine. Background technique [0002] 4,7-dichloroquinoline, CAS number: 86-98-6, molecular formula: C 9 h 5 Cl 2 N, is the main intermediate in the production of hydroxychloroquine sulfate. Hydroxychloroquine sulfate is the most commonly used drug in clinical treatment of rheumatic diseases, especially systemic lupus erythematosus and rheumatoid arthritis. [0003] 4,7-Dichloroquinoline is usually prepared from m-chloroaniline and diethyl ethoxymethylenemalonate through condensation, cyclization, hydrolysis, acidification, decarboxylation, and finally chlorination. Its shortcoming is: the 4,7-dichloroquinoline that this technical route makes can have about 10% isomer 4,5-dichloroquinoline, has had a strong impact on the quality and yield of 4,7-dichloroquinoline rate, and after further reaction, it will become the isomer impurity in h...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/18
CPCC07D215/18
Inventor 刘磊赵云德张来平黄正帅陈浩
Owner JIANGSU TIANHE PHARMA CO LTD
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