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Optically active chloroquine and hydroxychloroquine and analogues thereof, and preparation method, composition and application of optically active chloroquine and hydroxychloroquine

A compound, chiral separation technology, applied in the fields of organic active ingredients, organic chemistry, pharmaceutical formulations, etc., can solve problems such as retinal damage

Pending Publication Date: 2021-03-09
瀚海新拓(杭州)生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

Hydroxychloroquine is a commonly used drug for chronic diseases such as rheumatoid arthritis and systemic lupus erythematosus. Long-term or high-dose administration is prone to irreversible retinal damage

Method used

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  • Optically active chloroquine and hydroxychloroquine and analogues thereof, and preparation method, composition and application of optically active chloroquine and hydroxychloroquine
  • Optically active chloroquine and hydroxychloroquine and analogues thereof, and preparation method, composition and application of optically active chloroquine and hydroxychloroquine
  • Optically active chloroquine and hydroxychloroquine and analogues thereof, and preparation method, composition and application of optically active chloroquine and hydroxychloroquine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0134] Embodiment 1: prepare the L-malate of (R)-hydroxychloroquine

[0135] Dissolve racemic hydroxychloroquine (5 g, 14.88 mol) in ethanol / ethyl acetate (v / v=1:2, 30 mL), and dissolve L-malic acid (6 g, 44.64 mol) in ethanol / ethyl acetate Ester (v / v=1:2, 15 mL), at 0°C, slowly dropwise add L-malic acid in ethanol / ethyl acetate solution to the above racemate in ethanol / ethyl acetate solution. When the temperature was raised to 5° C., reacted for 30 minutes, until the reaction was complete, most of the salts of the L-malic acid of (S)-hydroxychloroquine were dissolved in the ethanol / ethyl acetate mixed solution, while the salts of the L-malic acid of (R)-hydroxychloroquine The acid salt was precipitated, and the L-malate crude product (5.2 g) of (R)-hydroxychloroquine was obtained by suction filtration.

Embodiment 2

[0136] Embodiment 2: the L-malate recrystallization purification of (R)-hydroxychloroquine

[0137] The L-malate crude product (5.2 g) of (R)-hydroxychloroquine was suspended in 10 mL of ethanol / ethyl acetate (v / v=1:2), heated to reflux until completely dissolved, slowly cooled to room temperature, and Keep stirring for 1-2 hours, and continue to cool down to 5-10° C., stir for 30 minutes, and filter with suction to obtain (R)-hydroxychloroquine L-malate (4.3 g) with an optical purity of 87.8% ee. Then, according to the above recrystallization method, the L-malate of (R)-hydroxychloroquine obtained above was recrystallized once to obtain the L-malate of (R)-hydroxychloroquine with an optical purity of 98.8% ee. (3.8g).

Embodiment 3

[0138] Embodiment 3: the preparation of (R)-hydroxychloroquine

[0139]

[0140] Sodium methoxide (1g, 20.24mol) was added in batches to 10ml of anhydrous methanol. After stirring for about 10min at 0°C, the system became clear, and (R)-hydroxychloroquine L-malate (3.8g , 5.06mmol), stirred at room temperature for 30min, concentrated under reduced pressure to remove methanol. Add 20ml of ethyl acetate, stir at room temperature for 1 hour, desalt by suction filtration, concentrate the ethyl acetate mother liquor under reduced pressure to obtain (R)-hydroxychloroquine (1.6g), purity>99%, chiral purity>99.92%, yield 64%.

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Abstract

The invention provides a rapid and simple method for preparing optically active chloroquine, hydroxychloroquine and analogues thereof, which comprises the following steps: reacting racemates of chloroquine, hydroxychloroquine and analogues thereof with an acidic chiral resolution reagent to generate corresponding salts, and separating and purifying to obtain optically pure salts of chloroquine, hydroxychloroquine and analogues thereof, and reacting with alkali to obtain (R)- or (S)- chloroquine with high optical purity and (R)- or (S)- hydroxychloroquine and analogues thereof. The method is simple and convenient to operate and low in cost, the enantiomer purity can reach 99.9% ee, and industrial production of chloroquine, hydroxychloroquine and analogues thereof with single chiral configuration is easy to realize. The invention also provides (R)- or (S)- chloroquine and (R)- or (S)- hydroxychloroquine and analogues thereof, pharmaceutical compositions and uses thereof, optically activechloroquine and hydroxychloroquine and analogues thereof reduce toxic and side effects, and have better treatment effects on coronavirus, influenza virus and autoimmune diseases.

Description

technical field [0001] The invention belongs to the technical field of medicinal chemistry, in particular to optically pure (S)-chloroquine, (S)-hydroxychloroquine and analogs thereof, (R)-chloroquine, (R)-hydroxychloroquine and analogs thereof and preparation methods thereof, Its medicinal composition and use. Background technique [0002] Chloroquine and hydroxychloroquine are antimalarial drugs that have received much attention for nearly 50 years. At present, the sulfate form of hydroxychloroquine, that is, hydroxychloroquine sulfate, is currently one of the most commonly used drugs for the clinical treatment of rheumatic diseases, especially systemic lupus erythematosus and rheumatoid arthritis. In related mechanism research experiments, it has been shown that hydroxychloroquine has anti-inflammatory and immunomodulatory activities. Chloroquine has a long half-life, and continuous administration is prone to cumulative toxicity. When the plasma concentration (trough co...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/46A61K31/4706A61P31/14A61P31/16A61P31/18A61P31/20A61P31/22
CPCA61P31/14A61P31/16A61P31/18A61P31/20A61P31/22C07D215/46Y02A50/30
Inventor 张霁蒋晟
Owner 瀚海新拓(杭州)生物医药有限公司
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