A kind of industrialized preparation method of hydroxychloroquine sulfate

A technology of hydroxychloroquine sulfate and hydroxychloroquine sulfate, which is applied in the field of preparation of hydroxychloroquine sulfate, can solve problems such as unfavorable recycling and environmental protection, increase production costs, and cumbersome production processes, so as to save extraction agent and labor costs, and save production Cost, the effect of reducing environmental pollution

Active Publication Date: 2016-05-25
WUHAN WUYAO PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, this method uses a large amount of organic solvents for extraction and crystallization in the production process, which increases the cost of the product on the one hand, and is not conducive to recycling and environmental protection on the other hand.
[0015] In general, most of the current methods for producing hydroxychloroquine sulfate use toxic catalysts or solvents, which are unfriendly to the environment and increase production costs; in addition, the production process is more cumbersome, and the production time is longer, which is not conducive to industrialization

Method used

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  • A kind of industrialized preparation method of hydroxychloroquine sulfate
  • A kind of industrialized preparation method of hydroxychloroquine sulfate
  • A kind of industrialized preparation method of hydroxychloroquine sulfate

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Effect test

Embodiment 1

[0033] Embodiment 1: the preparation of hydroxychloroquine

[0034] Add 20g of side chains and 22.4g of 4.7-dichloroquinoline into a three-necked flask, protect it with argon, raise the temperature to 100°C, stir for 1h, then raise the temperature to 120-130°C for 20h. After the reaction is complete, lower the temperature slightly, add 40g of water to the reaction solution, then add 20g of concentrated sulfuric acid, add 80g of liquid caustic soda after stirring, stir for 30min to separate the liquid, discard the water phase; add 60g of ethyl acetate to the organic phase, and wait for the organic phase to The phase was dissolved, then cooled to 0-10°C, kept warm for 2h, filtered with suction, and dried to obtain 34g of crude hydroxychloroquine, with a yield of 89% and HPLC ≥ 95%.

Embodiment 2

[0035] Embodiment 2: the preparation of hydroxychloroquine

[0036] Add 20g of side chains and 22.4g of 4.7-dichloroquinoline into a three-necked flask, protect it with nitrogen, raise the temperature to 100°C, stir for 1h, then raise the temperature to 120-130°C for 20h. After completion of the reaction, lower the temperature slightly, add 20 g of water to the reaction solution, then add 40 g of concentrated hydrochloric acid, add 80 g of liquid caustic soda after stirring, stir for 30 min to separate the liquid, discard the water phase; add 60 g of ethyl acetate to the organic phase, and wait for the organic phase to phase was dissolved, then cooled to 0-10°C, kept warm for 2h, filtered with suction, and dried to obtain 33.6g of crude hydroxychloroquine, with a yield of 88%, HPLC≥96%

Embodiment 3

[0037] Embodiment 3: the preparation of hydroxychloroquine

[0038] Add 20g of side chains and 22.4g of 4.7-dichloroquinoline into a three-necked flask, protect it with carbon dioxide, raise the temperature to 100°C, stir for 1h, then raise the temperature to 120-130°C for 20h. After the reaction is complete, lower the temperature slightly, add 20g of water to the reaction solution, then add 40g of concentrated hydrochloric acid, add 80g of liquid caustic soda after stirring, stir for 30min to separate the liquid, discard the water phase; add 60g of 1.2-dichloroethane to the organic phase Alkanes, to be dissolved in the organic phase, then lower the temperature to 0 ~ 10 ° C, heat preservation 2h, suction filtration, drying, to obtain crude hydroxychloroquine 33.8g, yield 89%, HPLC ≥ 96%

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Abstract

The invention provides an industrial production method for hydroxychloroquine sulfate, which includes the following steps: enabling 4.7-dichloroquinoxaline and 5-(N-ethyl-N-ethoxyl)-2-amino pentane to react under gas shield for 13-24 h at a gradually increased temperature of 120-130 DEG C to obtain hydroxychloroquine; preparing the hydroxychloroquine sulfate after the reaction between the hydroxychloroquine and an alcohol sulfate solution at the temperature of 20-30 DEG C. According to the method, the yield of the obtained crude product of the hydroxychloroquine is not smaller than 85%, the yield of the obtained hydroxychloroquine sulfate is not smaller than 85%, the yield of the obtained hydroxychloroquine sulfate HPLC is not smaller than 99.5%, the yield of single impurity is not larger than 0.1%, so that requirements of United States Pharmacopeia is met; the novel method is simple in procedure, is environment-friendly and easy in industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to the preparation of hydroxychloroquine sulfate for treating discoid lupus erythematosus and systemic lupus erythematosus. Background technique [0002] The chemical name of hydroxychloroquine sulfate is 2-[[4-[(7-chloro-4-quinolyl)amino]pentyl]ethylamino]-ethanol sulfate, and its chemical structure is as follows: [0003] [0004] Hydroxychloroquine sulfate was successfully developed by Winthrop Company and was first listed in the United States in 1956. It has been listed in France, Denmark, Japan, Germany, Finland and other countries and regions. The U.S. FDA approved Chlorine Sulfate Tablets on May 29, 1998 for the treatment of lupus erythematosus and rheumatoid arthritis. [0005] US2546658 discloses a kind of hydroxychloroquine sulfate synthetic method, and the reaction process of this method is as follows: [0006] [0007] This patent was reported in 1951, and the ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/46
CPCC07D215/46
Inventor 皮金红丁友友岳荣耀魏金维潘文清谢国范
Owner WUHAN WUYAO PHARMA
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