Preparing and refining method for hydroxychloroquine and preparation method for sulfate of hydroxychloroquine

A purification method and technology of hydroxychloroquine, applied in the field of preparation and purification of hydroxychloroquine, can solve the problems of unstable impurity control and low purity, and achieve the effects of easy operation, low impurity content and stable impurity content.

Active Publication Date: 2018-10-16
SHANGHAI ZHONGXI SUNVE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The technical problem to be solved by the present invention is to overcome the defects of the existing refining method of hydroxychloroquine, such as low purity

Method used

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  • Preparing and refining method for hydroxychloroquine and preparation method for sulfate of hydroxychloroquine
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  • Preparing and refining method for hydroxychloroquine and preparation method for sulfate of hydroxychloroquine

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Experimental program
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Embodiment 1

[0053] a. Preparation of Hydroxychloroquine

[0054] Add 100g of 4,7-dichloroquinoline and 110g of hydroxychloroquine side chain compound (5-(N-ethyl-N-2-hydroxyethylenediylamino)-2-pentylamine, hereinafter referred to as side chain) into the reactor In the middle, pass nitrogen protection, raise the temperature to 78°C to dissolve 4,7-dichloroquinoline, raise the temperature to 120°C for 20 minutes, raise the temperature to 130°C for 8 hours, cool down (below 80°C) after the reaction, and use sodium hydroxide solution (mass concentration is 7%) to adjust pH>12, extract with dichloromethane, wash with water until neutral, evaporate dichloromethane under reduced pressure to obtain 154 g of crude hydroxychloroquine, yield 90.7%, HPLC purity 92.45%. Add 300g methyl ethyl ketone and 300g ethyl acetate to the full amount of crude hydroxychloroquine, heat at 75°C to dissolve, slowly cool down to 10°C over 4 hours, filter, and wash the filter cake with a mixed solution of methyl ethy...

Embodiment 2

[0057] Embodiment 2: the preparation of hydroxychloroquine sulfate

[0058] a. Preparation of Hydroxychloroquine

[0059] Add 100g of 4,7-dichloroquinoline and 130g of side chains into the reactor, pass through argon protection, raise the temperature to 70°C to dissolve the 4,7-dichloroquinoline, raise the temperature to 115°C for 10 minutes, and raise the temperature to 137°C to react After 10 hours, the temperature was lowered (below 80°C) after the reaction was completed, the pH was adjusted to >12 with sodium hydroxide solution (6% mass concentration), extracted with dichloromethane, washed with water until neutral, dichloromethane was distilled off under reduced pressure to obtain hydroxychloroquine The crude product was 157g, the yield was 92.5%, and the HPLC purity was 93.96%. Add 200 g of acetone and 250 g of methyl acetate to the crude product of hydroxychloroquine, heat to dissolve at 65°C, slowly cool down to 10°C over 4 hours, filter, and wash the filter cake with...

Embodiment 3

[0062] Embodiment 3: the preparation of hydroxychloroquine sulfate

[0063] a. Preparation of Hydroxychloroquine

[0064] Add 100g of 4,7-dichloroquinoline and 130g of side chains into the reactor, pass through helium protection, raise the temperature to 70°C to dissolve the 4,7-dichloroquinoline, raise the temperature to 115°C for 15 minutes, and raise the temperature to 135°C to react After 11 hours, the temperature was lowered (below 80°C) after the reaction was completed, and the pH was adjusted to >12 with sodium hydroxide solution (mass concentration: 10%), extracted with dichloromethane, washed with water until neutral, and dichloromethane was evaporated under reduced pressure to obtain hydroxychloroquine The crude product was 158g, the yield was 93.1%, and the HPLC purity was 93.73%. Add 400g of 2-pentanone and 350g of isopropyl acetate to the crude product of hydroxychloroquine, heat to dissolve at 65°C, slowly cool down to 10°C over 4 hours, filter, and use a mixed ...

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Abstract

The invention discloses a preparing and refining method for hydroxychloroquine and a preparation method for a sulfate of the hydroxychloroquine. The refining method for the hydroxychloroquine comprises the following steps: performing crystallization on a crude product of the hydroxychloroquine in a mixed solvent of a ketone solvent and an ester solvent to obtain a refined product of the hydroxychloroquine, wherein a content of the hydroxychloroquine in the crude product of the hydroxychloroquine is higher than 92%. According to the method disclosed by the invention, purity of the refined product of the hydroxychloroquine prepared by the method can reach 99.9%, a maximum content of a single impurity is controlled within 0.06%, and a total content of other impurities is lower than 0.04%; andpurity of the hydroxychloroquine sulfate prepared from the hydroxychloroquine can reach 99.8%, and a maximum content of a single impurity is controlled within 0.06%.

Description

technical field [0001] The invention relates to a method for preparing and refining hydroxychloroquine and a method for preparing sulfate thereof. Background technique [0002] Hydroxychloroquine Sulfate (Hydroxychloroquine Sulfate), its chemical name is 2-[[4-[(7-chloro-4-quinolyl)amino]pentyl]ethylamino]-ethanol sulfate, CAS number is 747-36- 40. Hydroxychloroquine sulfate was successfully developed by Winthrop Company. It was first listed in the United States in 1956 and has been listed in France, Denmark, Japan, Germany, Finland and other countries and regions. U.S. FDA approved hydroxychloroquine sulfate tablets on May 29, 1998 for the treatment of lupus erythematosus and rheumatoid arthritis. [0003] US2546658 discloses a kind of hydroxychloroquine sulfate synthetic method, and the reaction process of this method is as follows: [0004] [0005] 4,7-dichloroquinoline reacts with 5-(N-ethyl-N-2-hydroxyethylenediylamino)-2-pentylamine (hereinafter referred to as h...

Claims

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Application Information

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IPC IPC(8): C07D215/46
CPCC07D215/46
Inventor 张耀华余坤矫黄启张召群俞伟丁雁卫金强祝鹏程
Owner SHANGHAI ZHONGXI SUNVE PHARMA
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