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Synthesis method of high-purity chloroquine phosphate

A technology of chloroquine phosphate and a synthesis method, applied in directions such as organic chemistry, can solve problems such as high reaction temperature and uneconomical production, and achieve the effects of lowering reaction temperature, reducing side reactions, and reducing waste

Active Publication Date: 2021-02-02
ZHANG JIA GANG VINSCE BIO PHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The condensation reaction temperature of this process is too high, and the production is uneconomical

Method used

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  • Synthesis method of high-purity chloroquine phosphate
  • Synthesis method of high-purity chloroquine phosphate
  • Synthesis method of high-purity chloroquine phosphate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0044] (1) prepare chloroquine,

[0045] Mix 198g of 4,7-dichloroquinoline (1mol) and 94g (1mol) of phenol evenly, raise the temperature of the system to 70-80°C, and slowly add 332g of 2-amino-5-diethylaminopentyl under the pressure of 1.7atm alkanes (2.1 mol) and 100 g of di-n-butylamine (0.77 mol). After the reaction was complete, add 600 mL of toluene to dilute, add a mass fraction of 10% sodium carbonate solution to adjust the pH of the system to 8-9, separate liquids, wash with water (200 mL*3), and concentrate the organic phase to dryness to obtain 436.2 g of crude chloroquine. Save the aqueous phase for later use.

[0046] (2) Refined Chloroquine

[0047] Add 150ml sherwood oil in 436.2g of chloroquine crude product, heat and dissolve clear, stir and crystallize in ice-water bath, filter, dry to obtain 294.2g chloroquine. Molar yield: 90.55%, liquid chromatography purity (HPLC): 98.42%. The mother liquor of petroleum ether was reserved for future use.

[0048] (3)...

Embodiment 2

[0054] (1) prepare chloroquine,

[0055] Mix 178.2g (0.9mol) of 4,7-dichloroquinoline and 84.6g of phenol (0.9mol) evenly, raise the temperature of the system to 80-90°C, and slowly add 300.6g of 2-amino-5-diethylaminopentane (1.9mol) and 80g of di-n-propylamine (0.80mol), react under the pressure of 1.4atm, add 600mL of dichloromethane to dilute after the reaction is complete, add 10% sodium hydroxide solution to adjust the pH of the system to 8-9, separate liquid, wash with water (Totally 540mL three times), concentrated to dryness to obtain 396.0 grams of chloroquine crude product. Save the aqueous phase for later use.

[0056] (2) Refined Chloroquine

[0057] Add 120ml sherwood oil in 396.0g of chloroquine crude product, heat and dissolve clear, stir and crystallize in ice-water bath, filter, dry to obtain product 265.2g chloroquine. Molar yield: 90.32%, purity: 98.17%. The mother liquor of petroleum ether was reserved for future use.

[0058] (3) prepare chloroquine ...

Embodiment 3

[0063] (1) prepare chloroquine,

[0064] Mix 227.7g of 4,7-dichloroquinoline (1.15mol) and 108.1g of phenol (1.15mol) uniformly, heat up the system to 90-100°C, and slowly add 397g of 2-amino-5-diethylaminopentane ( 2.5mol) and 70g of diethylamine (0.96mol), under 1.5atm pressure, heat preservation reaction. After the reaction was complete, 600 mL of chloroform was added for dilution, and 10% potassium hydroxide solution was added to adjust the pH to 8-9, separated, washed with water (570 mL three times), and concentrated to dryness to obtain 522.9 g of crude chloroquine. Save the aqueous phase for later use.

[0065] (2) Refined Chloroquine

[0066] Add 200ml sherwood oil heating to dissolve clear in 522.9g of chloroquine crude product, stir and crystallize in ice-water bath, filter, dry to obtain product 338.5g chloroquine. Molar yield: 90.72%, purity: 98.55%. The mother liquor of petroleum ether was reserved for future use.

[0067] (3) prepare chloroquine phosphate

...

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Abstract

The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of chloroquine phosphate, and particularly provides a synthesis method of high-purity chloroquine phosphate. The synthesis method comprises the following steps: (1) condensation: reacting 4, 7-dichloroquinoline with 2-amido-5-diethylamine pentane to obtain a chloroquine crude product; and (2) refining: recrystallizing to obtain chloroquine with higher purity. (3) salifying: stirring and crystallizing the refined chloroquine and phosphoric acid for 2-3 hours, and filtering to obtain a chloroquine phosphate crude product; and (4) purification: recrystallizing the chloroquine phosphate crude product to obtain high-purity chloroquine phosphate. The method is high in atom utilization rate, high in yield, high in product purity, less in solid waste, beneficial to environmental protection and convenient for industrial application, and has a relatively good industrial prospect.

Description

technical field [0001] The invention relates to the technical field of medicine synthesis, in particular to a synthesis method of chloroquine phosphate. Background technique [0002] Chloroquine phosphate has an effect on the schizont in the erythrocytes of Plasmodium, which may interfere with the replication and transcription process of Plasmodium schizont DNA or hinder its endocytosis, so that the parasite dies due to the lack of amino acids. For the treatment of chloroquine-sensitive falciparum malaria, vivax malaria and malaria malaria. And can be used for the suppressive prevention of malaria symptoms. It can also be used to treat parenteral amoebiasis, connective tissue disease, photosensitivity disease, etc. Therefore a high-efficiency, low-cost, high-purity chloroquine phosphate synthesis process has great significance. [0003] Chinese patent CN 111662229 A discloses a preparation process of chloroquine phosphate. The preparation technology of described chloroqu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/46
CPCC07D215/46Y02A50/30
Inventor 彭学东张梅赵金召
Owner ZHANG JIA GANG VINSCE BIO PHARM
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