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Preparation method of chloroquine phosphate

A technology of chloroquine phosphate and phosphoric acid, applied in the fields of medicine and chemical industry, can solve the problems of uneven mixing, toxic and corrosive phenol, inconvenient use and the like

Pending Publication Date: 2021-05-25
CHONGQING KANGLE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] This process uses a large amount of phenol as a solvent and catalyst, and a large amount of sodium phenate wastewater is produced after alkalization extraction, which is difficult for industrial treatment; there is no solvent in the condensation reaction, resulting in uneven mixing and poor appearance of the product; The bottom is solid, which must be heated to liquid before use, which is inconvenient for industrial use; phenol is easily oxidized to benzoquinone at a higher temperature, which is condensed with 2-amino-5-diethylaminopentane to form an imine, which is refined by adding chloroquine phosphate Difficulty of purification

Method used

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  • Preparation method of chloroquine phosphate
  • Preparation method of chloroquine phosphate

Examples

Experimental program
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Effect test

Embodiment 1

[0030] The preparation of embodiment 1 chloroquine phosphate formula I

[0031] Condensation reaction:

[0032] Add 103.0 g of 4,7-dichloroquinoline, 3.3 g of sodium sulfite, 24.2 g of N,N-diisopropylethylamine, and 600.0 g of isopropanol into the reaction flask, start stirring, and heat up to 4,7-dichloroquinoline to dissolve ; Add 95.5 g of 2-amino-5-diethylaminopentane dropwise; slowly heat up, and the isopropanol is evaporated. When the internal temperature rises to 133.0°C; start the timing reaction. The internal temperature of the reaction was controlled at 133.0°C to 138.0°C, and the heat preservation reaction was carried out for a total of 10 hours.

[0033] Alkaline Extraction:

[0034] Add 100.0g of drinking water to the alkalization bottle, start stirring; slowly pour the reaction solution into the alkalization bottle, add sodium hydroxide, adjust the pH of the water layer to 12; minutes, the alkalization is completed; the feed liquid is cooled to 70.0°C. 300.0 ...

Embodiment 2

[0039] The preparation of embodiment 2 chloroquine phosphate formula I

[0040] Condensation reaction:

[0041] Add 103.0 g of 4,7-dichloroquinoline, 13.1 g of sodium sulfite, 11.4 g of N,N-diisopropylethylamine, and 600.0 g of isopropanol into the reaction flask, start stirring, and heat up to 4,7-dichloroquinoline to dissolve ; Add 83.1 g of 2-amino-5-diethylaminopentane dropwise; slowly heat up, and the isopropanol is evaporated. When the internal temperature rises to 133.0°C; start the timing reaction. The inner temperature of the reaction was controlled at 133.0°C to 138.0°C, and the heat preservation reaction was carried out for a total of 12 hours.

[0042] Alkaline Extraction:

[0043] Add 100.0g of drinking water to the alkalization bottle, start stirring; slowly pour the reaction solution into the alkalization bottle, add sodium hydroxide, adjust the pH of the water layer to 11; minutes, the alkalization is completed; the feed liquid is cooled to 70.0°C. 300.0 g ...

Embodiment 3

[0048] The preparation of embodiment 3 chloroquine phosphate formula I

[0049] Condensation reaction:

[0050] Add 103.0 g of 4,7-dichloroquinoline, 6.5 g of sodium sulfite, 16.1 g of N,N-diisopropylethylamine, and 600.0 g of isopropanol into the reaction flask, start stirring, and heat up to 4,7-dichloroquinoline to dissolve ; Add 87.5 g of 2-amino-5-diethylaminopentane dropwise; slowly raise the temperature, and when the isopropanol is evaporated, the internal temperature rises to 133.0°C; start the timing reaction. The inner temperature of the reaction was controlled at 133.0°C to 138.0°C, and the heat preservation reaction was carried out for a total of 12 hours.

[0051] Alkaline Extraction:

[0052]Add 100.0g of drinking water into the alkalization bottle, start stirring; slowly pour the reaction solution into the alkalization bottle, add sodium hydroxide, adjust the pH of the water layer to 12; minutes, the alkalization is completed; the feed liquid is cooled to 70....

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Abstract

The invention discloses a preparation method of chloroquine phosphate, namely 7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline diphosphate. The preparation method comprises the following steps: (1) carrying out a condensation reaction on 4,7-dichloroquinoline and 2-amino-5-diethylaminopentane, and carrying out alkalization extraction, concentration and crystallization to obtain chloroquine; and (2) salifying the chloroquine obtained in the step (1) and phosphoric acid to obtain chloroquine phosphate. The method avoids the use of phenol, is simple in reaction, and is beneficial to industrial production; and the chloroquine is crystallized to improve the purity and then salified with the phosphoric acid, so product appearance is good, the purity of the produced chloroquine phosphate is greater than or equal to 99.5%, and a single impurity is less than 0.1% (according to an HPLC area normalization method).

Description

technical field [0001] The invention belongs to the technical field of medicine and chemical industry, and in particular relates to the preparation method and application of chloroquine phosphate, 7-chloro-4-(4-diethylamino-1-methylbutylamino)quinoline diphosphate. Background technique [0002] Chloroquine Phosphate (Chloroquine Phosphate), chemical name: 7-chloro-4-(4-diethylamino-1-methylbutylamino) quinoline diphosphate, used to treat chloroquine-sensitive P. falciparum and vivax malaria, etc. Malaria; it can also be used to treat parenteral amoebiasis; it also has anti-rheumatic effects, etc.; it also has a certain effect on new coronary pneumonia. [0003] The preparation method of the currently disclosed chloroquine phosphate is as Ji Zhizhong. Chemical Pharmaceutical Technology [M]. Chemical Industry Press, 2001; P183~P187 use 4,7-dichloroquinoline, phenol (solvent and catalyst), 2-amino -5-Diethylaminopentane. The process is a condensation reaction of 4,7-dichloroq...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/46
CPCC07D215/46
Inventor 杨忠鑫宋金铼蔡中文余文杰
Owner CHONGQING KANGLE PHARMA
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