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Chiral chloroquine, hydroxychloroquine and derivatives thereof as well as preparation method and application of chiral chloroquine, hydroxychloroquine and derivatives thereof

A compound, polymorphic technology, applied in the field of chiral chloroquine, hydroxychloroquine and derivatives thereof and their preparation, can solve problems such as toxicity not being reported

Active Publication Date: 2020-09-04
SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although the racemic mixture of chloroquine exhibited some anti-coronavirus activity (EC 50 =1.13μM in VeroE6cells), the efficacy and possible toxicity of each isomer has not been reported

Method used

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  • Chiral chloroquine, hydroxychloroquine and derivatives thereof as well as preparation method and application of chiral chloroquine, hydroxychloroquine and derivatives thereof
  • Chiral chloroquine, hydroxychloroquine and derivatives thereof as well as preparation method and application of chiral chloroquine, hydroxychloroquine and derivatives thereof
  • Chiral chloroquine, hydroxychloroquine and derivatives thereof as well as preparation method and application of chiral chloroquine, hydroxychloroquine and derivatives thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0164] Preparation of Chiral Chloroquine by Chiral High Performance Liquid Chromatography

[0165] The racemic chloroquine phosphate 7 purchased from the market was converted into free racemic chloroquine 8 under alkaline conditions.

[0166]

[0167] At 0°C, 13.0 grams of chloroquine phosphate was dissolved in 75 milliliters of water, followed by the addition of 50 milliliters of 12% NaOH aqueous solution. After stirring for half an hour, 25 milliliters of ethyl acetate was added, and the stirring was continued for half an hour. The reaction solution was naturally raised to room temperature, extracted three times with 100 ml of ethyl acetate, combined the organic phases, washed with 150 ml of saturated brine and water, dried by adding anhydrous sodium sulfate, and filtered to remove sodium sulfate. The organic solvent was removed with a rotary evaporator to obtain 7.6 grams of free chloroquine in the form of light yellow viscous liquid, with a yield of 94%.

[0168] 1 H ...

Embodiment 2

[0172] Preparation of Optically Pure Chloroquine Phosphate

[0173] R and S Free State Chloroquine Converted to Optically Pure Chloroquine Phosphate

[0174]

[0175] Dissolve 640 mg of (S)-chloroquine 9 in 4 mL of ethanol and heat to reflux. 0.25 milliliters of 85% phosphoric acid was added dropwise to the above solution, and the reaction was refluxed for two hours, at which time a large amount of white solids were precipitated. After the reaction solution was cooled to room temperature, it was filtered, and the filter cake was washed three times with 1 milliliter of ethanol to obtain 868 mg of white (S)-chloroquine phosphate 10 solids, with a yield of 84%, [α] D 27.8 =79.7 (c=0.5,H 2 O).

[0176]

[0177] Dissolve 640 mg of (R)-chloroquine 11 in 4 mL of ethanol and heat to reflux. 0.25 ml of 85% phosphoric acid was added dropwise to the above solution, and the reaction was refluxed for two hours, at which time a large amount of white solids were precipitated. The...

Embodiment 3

[0179] Preparation of Chiral Hydroxychloroquine by Chiral High Performance Liquid Chromatography

[0180] Racemic hydroxychloroquine sulfate 1 purchased from the market is converted into free racemic hydroxychloroquine 2 under alkaline conditions.

[0181]

[0182] At 0°C, 10.9 grams of hydroxychloroquine sulfate was dissolved in 75 milliliters of water, then 25 milliliters of 12% NaOH aqueous solution was added, after stirring for half an hour, 25 milliliters of ethyl acetate was added, and stirring was continued for half an hour. The reaction solution was naturally raised to room temperature, extracted three times with 100 ml of ethyl acetate, combined the organic phases, washed with 150 ml of saturated brine and water, dried by adding anhydrous sodium sulfate, and filtered to remove sodium sulfate. The organic solvent was removed with a rotary evaporator to obtain 7.7 grams of free hydroxychloroquine in the form of light yellow viscous liquid, with a yield of 91%.

[01...

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Abstract

The invention belongs to the field of drug synthesis, and discloses a compound with a structure as shown in a formula I (See the specification) and pharmaceutically acceptable salt, tautomer, polymorphic substance, isomer and solvate thereof. Secondly, the invention discloses a method for preparing chiral chloroquine and hydroxychloroquine through chiral high performance liquid chromatography. Finally, the invention discloses application of chiral chloroquine, hydroxychloroquine and salt derivatives thereof in preparation of drugs for treating novel coronavirus pneumonia.

Description

technical field [0001] The invention belongs to the field of drug synthesis, and specifically relates to chiral chloroquine, hydroxychloroquine and derivatives thereof, their preparation method and application. Background technique [0002] 2019 Novel Coronavirus (2019 Novel Coronavirus, 2019-nCoV), also known as Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), has the characteristics of strong infectivity and long incubation period. Common signs after virus infection include respiratory symptoms, fever, cough, shortness of breath, and dyspnea, etc., which cause severe acute respiratory syndrome and other serious diseases and have a high mortality rate, and are highly pathogenic viruses. On March 11, the World Health Organization declared that the 2019 coronavirus outbreak constituted a global pandemic. As of May 6, 2020, more than 3.66 million people in 187 countries around the world have been infected with the new coronavirus, and the death toll has exceeded ...

Claims

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Application Information

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IPC IPC(8): C07D215/46A61K31/4706A61P31/14
CPCC07D215/46A61P31/14C07B2200/07Y02A50/30
Inventor 李官官史永杰李迎君张绪穆
Owner SOUTH UNIVERSITY OF SCIENCE AND TECHNOLOGY OF CHINA
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