Hydroxychloroquine sulfate and preparation method thereof

A technology of hydroxychloroquine sulfate and hydroxychloroquine, applied in the field of chemistry or medicinal chemistry, can solve the problems of long production time, cumbersome process, unfriendly environment, etc., and achieve the effects of reducing pollution and consumption, avoiding high pollution, and simple and rapid operation.

Pending Publication Date: 2021-07-30
JIANGXI GUOYAO PHARMA LLC +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Potassium / sodium alkoxide used is toxic, its vapor, mist, and dust are irritating and corrosive, and it is inconvenient to store and prone to deliquescence and combustion
[0012] In the preparation method of hydroxychloroquine sulfate disclosed above, there are some insufficient factors, or unfriendly to the environment, or the complex and loaded down with trivial details production time is long, is unfavorable for suitability for industrialized production

Method used

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  • Hydroxychloroquine sulfate and preparation method thereof
  • Hydroxychloroquine sulfate and preparation method thereof
  • Hydroxychloroquine sulfate and preparation method thereof

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preparation example Construction

[0036] A kind of preparation method of hydroxychloroquine sulfate is characterized in that, comprises the following steps:

[0037] (1) Synthesis of hydroxychloroquine: after mixing 4,7-dichloroquinoline with hydroxychloroquine side chain (i.e. 5-(N-ethyl-N-2-hydroxyethylamine)-2-pentylamine), in Heat and condense under an organic base catalyst, add water solution, cool down and crystallize to obtain hydroxychloroquine, the HPLC purity of hydroxychloroquine is ≥96.50%, and the maximum simple impurity content is <0.10%. Wherein, the molar ratio of 4,7-dichloroquinoline, hydroxychloroquine side chain, and base catalyst is 1:0.8-1.3:0.8-1.3; the mass ratio of 4,7-dichloroquinoline to water is 1:1-6; the reaction The temperature is 80-130°C, and the reaction time is 13-40h; the organic base catalyst is selected from one or more of triethylamine, ethanolamine, and pyridine; when adding water, keep the temperature not lower than 85°C, and discard the organic base in the lower layer....

Embodiment 1

[0040] (1) Synthesis of Hydroxychloroquine:

[0041] In a 500mL three-necked flask, add 4,7-dichloroquinoline: 100.0g (0.51mol) and hydroxychloroquine side chain: 70.0g, add 0.8eq (0.51mol) of triethylamine (29.8g) and heat up to 80°C, React for 40 hours, HPLC monitors that the content of 4,7-dichloroquinoline is less than 2.5%, add 100g of water, separate the phases, keep the water phase, cool down to room temperature, keep warm for crystallization, drop to 0°C, keep warm for crystallization, suction filter, filter The cake was vacuum-dried to obtain about 144.5 g of hydroxychloroquine, with a yield of 85.20%, an HPLC purity of 96.59%, and a maximum impurity content of 0.08%.

[0042] (2) the synthesis of hydroxychloroquine sulfate:

[0043] Take 50.0g of hydroxychloroquine and add it to a 1000mL four-neck flask, add 50mL of ethyl acetate and 250mL of ethanol, heat up and stir to dissolve, wait until it is completely dissolved, add 11.7g of concentrated sulfuric acid dropwis...

Embodiment 2

[0045] (1) Synthesis of Hydroxychloroquine:

[0046]In a 500mL three-necked flask, add 4,7-dichloroquinoline: 100.0g (0.51mol) and hydroxychloroquine side chain: 79.0g, add 0.9eq of ethanolamine (28.3g) and raise the temperature to 90°C, react for 30h, and monitor by HPLC to The content of 4,7-dichloroquinoline is less than 2.5%, add 200g of water, separate the phases, keep the water phase, cool down to room temperature, keep warm for crystallization, drop to 2°C, keep warm for crystallization, filter with suction, and dry the filter cake in vacuum to obtain hydroxyl Chlorine is about 146.4g, the yield is 86.32%, the HPLC purity is 97.24%, and the maximum simple impurity content is 0.07%.

[0047] (2) the synthesis of hydroxychloroquine sulfate:

[0048] Take 50.0g of hydroxychloroquine refined product and add it to a 1000mL four-neck flask, add 100mL ethyl acetate and 300mL ethanol, heat up and stir to dissolve, wait until it is completely dissolved, add 13.2g of concentrate...

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Abstract

The invention discloses hydroxychloroquine sulfate and a preparation method thereof, and relates to the technical field of medicinal chemistry. The preparation method comprises the steps of mixing 4, 7-dichloroquinoline with a hydroxychloroquine side chain, carrying out heating condensation in the presence of an organic base catalyst, adding water and liquid, and carrying out cooling crystallization to obtain hydroxychloroquine; and dissolving hydroxychloroquine in an ethyl acetate and ethanol aqueous solution, heating, dissolving and clarifying, dropwise adding concentrated sulfuric acid, cooling, crystallizing, filtering and drying to obtain hydroxychloroquine sulfate. The method has the beneficial effects that a solvent-free reaction is used, and a catalyst is added, so that high pollution is avoided, the reaction process is accelerated, and the operation is simple; and meanwhile, the HPLC purity of the obtained hydroxychloroquine refined product is not less than 96.50%, the maximum single impurity content is less than 0.10%, the yield can reach 85%, the HPLC purity of hydroxychloroquine sulfate is not less than 98.00%, the maximum single impurity content is less than 0.10%, and the yield can reach 90%.

Description

technical field [0001] The invention belongs to the field of chemistry or medicinal chemistry, and in particular relates to a hydroxychloroquine sulfate and an industrial preparation method thereof. Background technique [0002] Hydroxychloroquine Sulfate (Hydroxychloroquine Sulfate), its chemical name is 2-[[4-[(7-chloro-4-quinolyl)amino]pentyl]ethylamino]-ethanol sulfate. 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] U.S. Patent US2546658A discloses a kind of synthetic method of hydroxychloroquine sulfate, and this method is reported in 1951, and this patent adopts 4,7-dichloroquinoline and 5-(N-ethyl-N-2-hydroxyethylenediylamino)- 2-pentylamine (hereinafter referred to as hydroxychloro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/46
CPCC07D215/46
Inventor 姚文涛双亚中杨明孟周钧
Owner JIANGXI GUOYAO PHARMA LLC
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