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Preparation method of hydroxychloroquine sulfate

A technology of hydroxychloroquine sulfate and hydroxychloroquine hydrochloride, applied in organic chemistry and other directions, can solve problems such as unfavorable industrial production, large amount of solvent, low solubility, etc., to avoid the risk of toxic substances, good product crystallinity, and reduced labor intensity. Effect

Inactive Publication Date: 2019-01-29
SHANGHAI INST OF TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

In comparison, the operation method described in this patent is more convenient, and its main disadvantage is that the solubility of hydroxychloroquine in acetate solvents is small, and the required solvent for extracting hydroxychloroquine with acetate solvents is used in post-treatment. huge amount
[0005] In the preparation method of the above-disclosed hydroxychloroquine sulfate, all have some insufficient factors, are unfavorable for suitability for suitability for industrialized production

Method used

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  • Preparation method of hydroxychloroquine sulfate

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Embodiment 1

[0028] The synthesis of embodiment 1 hydroxychloroquine

[0029] In a 500mL four-necked flask, add 4,7-dichloroquinoline: 100g (0.51mol) and hydroxychloroquine side chain: 89g (0.51mol), heat up to 110°C for 1 hour, then heat up to 120°C for 24 hours , point the board to monitor until 4,7-dichloroquinoline basically disappears, cool slightly, add anhydrous methanol (600mL), stir to dissolve, add 1.0eq sodium methoxide (27.5g) in batches, stir for 2h, filter to remove insoluble matter, the filtrate Concentrate under reduced pressure to dryness, then add methyl acetate (300 mL) to make a slurry, and filter to obtain 169 g of crude hydroxychloroquine.

[0030] Add the above-mentioned crude hydroxychloroquine to a mixed solvent of methanol-methyl acetate (1:4, v / v, 600mL), heat to dissolve, then naturally cool to room temperature, stir and crystallize for 5h, filter, and the filter cake is moistened with methyl acetate. Wash, dry at 50 DEG C with forced air to constant weight, an...

Embodiment 2

[0031] The synthesis of embodiment 2 hydroxychloroquine

[0032] In a 500mL four-necked flask, add 4,7-dichloroquinoline: 100g (0.51mol) and hydroxychloroquine side chain: 92g (0.53mol), heat up to 110°C for 1 hour, then heat up to 125°C for 20 hours , point the plate to monitor until 4,7-dichloroquinoline disappears substantially, cool to room temperature, add ethanol (800mL) to dissolve, add 1.1eq sodium ethoxide (38.15g) in batches, stir for 1-2h, filter to remove insoluble matter, and the filtrate reduces Concentrate under pressure to dryness, add isopropyl acetate to make a slurry, and filter to obtain crude hydroxychloroquine (168 g).

[0033] Add the above crude hydroxychloroquine to a mixed solvent of ethanol-ethyl acetate (1:5, v / v, 800mL), heat to dissolve, then naturally cool to room temperature, stir and crystallize for 8h, filter, and filter the cake with isopropyl acetate After rinsing, air-drying at 50°C to constant weight, about 146 g of refined hydroxychloroq...

Embodiment 3

[0034] The synthesis of embodiment 3 hydroxychloroquine

[0035] In a 500mL four-necked flask, add 4,7-dichloroquinoline: 100g (0.51mol) and hydroxychloroquine side chain: 95g (0.55mol), heat up to 110°C for 1 hour, then heat up to 130°C for 18 hours , point the plate to monitor until 4,7-dichloroquinoline disappears, cool to room temperature, add absolute ethanol to dissolve (1000mL), add 1.05eq of potassium tert-butoxide (59.9g) in batches, stir for 1-2h, filter to remove insoluble The filtrate was concentrated to dryness under reduced pressure, and ethyl acetate was added to make a slurry, and filtered to obtain 167.9 g of crude hydroxychloroquine.

[0036] Add the above crude hydroxychloroquine to a mixed solvent of ethanol-ethyl acetate (1:6, v / v, 1000mL), heat to dissolve, then naturally cool to room temperature, stir and crystallize for 6h, filter, and the filter cake is moistened with ethyl acetate. Wash, dry at 50 DEG C with forced air to constant weight, and obtain ...

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Abstract

The invention discloses a preparation method of high-purity hydroxychloroquine sulfate. The method uses 4,7-dichloroquinoline and hydroxychloroquine side chain as raw materials to directly prepare hydroxychloroquine hydrochloride, hydroxychloroquine hydrochloride is neutralized with sodium alcoholate or potassium alcoholate, filtered, concentrated, beaten and crystallized to obtain hydroxychloroquine refined product, and the hydroxychloroquine refined product finally is subjected to salifying reaction with sulfuric acid in a certain proportion of pure aqueous solution to obtain hydroxychloroquine sulfate. The method avoids the use of phenol or its catalyst in the process of preparing hydroxychloroquine, avoids the extraction operation in the post-treatment, has high product purity, and basically does not generate waste water in the production process. The method is convenient to operate and has high yield, the HPLC purity of prepared hydroxychloroquine sulfate is more than or equal to99.6%, and maximum single impurity is less than or equal to 0.1%, and that method is more suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, and in particular relates to a preparation method of hydroxychloroquine sulfate. Background technique [0002] Hydroxychloroquine Sulfate (Hydroxychloroquine Sulfate), the chemical name is 2-[[4-[(7-chloro-4-quinolyl)amino]pentyl]ethylamino]-ethanol sulfate is a quinoline drug, clinical For rheumatoid arthritis, juvenile chronic arthritis, discoid and systemic lupus erythematosus, and skin lesions caused or exacerbated by sunlight. [0003] Chinese patent CN 103724261B discloses an industrialized method of hydroxychloroquine sulfate: directly add 4,7-dichloroquinoline and hydroxychloroquine side chains under the protection of an inert gas, and then heat up the reaction, and gradually heat up to 120-130°C during the reaction process. After 13-24 hours, the reaction is completed, the temperature is lowered, water is added to the reaction system to acidify and dissolve, and then alkaliz...

Claims

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Application Information

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IPC IPC(8): C07D215/46
CPCC07D215/46
Inventor 黄金文李中原冉剑雄汪忠华汪泽东吴范宏
Owner SHANGHAI INST OF TECH
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