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Hydroxychloroquine sulfate as well as crystal form and preparation method of enantiomer of hydroxychloroquine sulfate

A technology of hydroxychloroquine sulfate and hydroxychloroquine is applied in the crystal field of S-hydroxychloroquine sulfate, R-hydroxychloroquine sulfate and hydroxychloroquine sulfate, and can solve the problems of low yield, complicated operation and the like

Pending Publication Date: 2020-10-20
珠海润都制药股份有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0009] S-hydroxychloroquine or R-hydroxychloroquine is generally composed of (S)-2-[(4-aminopentyl)ethylamino]ethanol or (R)-2-[(4-aminopentyl)ethylamino]ethanol and 4,7-dichloroquinoline are prepared by condensation reaction, and (S)-2-[(4-aminopentyl)ethylamino]ethanol or (R)-2-[(4-aminopentyl)ethyl Amino]ethanol prior art can adopt (±)-2-[(4-aminopentyl)ethylamino]ethanol and chiral resolution reagent L-(+)-mandelic acid (ie S-(+)- Mandelic acid) or D-(-)-mandelic acid (i.e. R-(-)-mandelic acid) is prepared by resolution, the disclosed resolution method requires multiple resolutions and crystallization, cumbersome operation, yield Low

Method used

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  • Hydroxychloroquine sulfate as well as crystal form and preparation method of enantiomer of hydroxychloroquine sulfate
  • Hydroxychloroquine sulfate as well as crystal form and preparation method of enantiomer of hydroxychloroquine sulfate
  • Hydroxychloroquine sulfate as well as crystal form and preparation method of enantiomer of hydroxychloroquine sulfate

Examples

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Embodiment 1

[0116] The preparation of embodiment 1 hydroxychloroquine

[0117] Weigh 100g of 4,7-dichloroquinoline, 105.6g of hydroxychloroquine side chain, and 25g of isopropanol in a 500ml three-neck flask, raise the temperature to 90°C and keep it for 30min, then raise the temperature to 95°C for 24h; cool down to 70°C, drop 5% sodium hydroxide solution (prepared from 13g of sodium hydroxide and 247g of water), add 350g of dichloromethane and stir for 5min, let stand for liquid separation, concentrate the dichloromethane layer under reduced pressure; add 450g of ethyl acetate and 50g of isocyanate to the concentrate Propanol, stirred and dissolved, crystallized at 20-30°C for 6h, suction filtered, and the filter cake was dried at 55-65°C for 6h, and 118g of hydroxychloroquine was obtained with a purity of 99.5%.

Embodiment 2

[0118] The preparation of embodiment 2 hydroxychloroquine sulfate

[0119] Add 118g of hydroxychloroquine obtained in Example 1 into a 1000ml three-neck bottle, then add absolute ethanol with a weight ratio of 4 times, stir to dissolve, add sulfuric acid solution (mass fraction concentration: 47%) dropwise at 15-25°C, and adjust pH=2 , after stirring for 3 hours, slowly cooling down to 10-15°C to crystallize for 6 hours, filtering, and placing the wet product in a vacuum drying oven at 60°C for 8 hours to obtain 122 g of hydroxychloroquine sulfate with a purity of 99.81%, and no hydroxychloroquine nitrogen oxide was detected.

Embodiment 3

[0120] The preparation of embodiment 3 hydroxychloroquine

[0121] Weigh 100g of 4,7-dichloroquinoline, 110g of hydroxychloroquine side chain, and 30g of isopropanol in a 500ml three-necked flask, raise the temperature to 90°C and keep it for 30min, then raise the temperature to 100°C for 24h; cool down to 80°C, drop 5 % sodium hydroxide solution (prepared from 13g of sodium hydroxide and 247g of water), add 350g of dichloromethane and stir for 5min, let stand to separate the liquid, concentrate the dichloromethane layer under reduced pressure; add 500g of ethyl acetate and 50g of isopropyl to the concentrate Alcohol, stirred and dissolved, crystallized at 20-30°C for 6h, suction filtered, and the filter cake was dried at 55-65°C for 6h, and 123g of hydroxychloroquine was obtained with a purity of 99.7%.

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Abstract

The invention relates to hydroxychloroquine sulfate as well as a crystal form and a preparation method of an enantiomer of hydroxychloroquine sulfate. The invention provides a crystal form A hydroxychloroquine sulfate. An X-ray powder diffraction pattern of the crystal form A hydroxychloroquine sulfate has characteristic peaks at 10.8 degrees, 13.0 degrees, 13.3 degrees, 16.9 degrees, 17.2 degrees, 17.5 degrees, 19.9 degrees, 21.3 degrees, 23.5 degrees, 24.0 degrees and 26.7 degrees + / -0.2 degrees, and does not contain hydroxychloroquine nitrogen oxide; the invention provides a hydroxychloroquine crystal, the X-ray powder diffraction pattern has characteristic peaks at 7.5 degrees, 14.9 degrees, 16.5 degrees, 19.2 degrees, 19.6 degrees, 22.8 degrees, 23.6 degrees and 26.7 degrees+ / -0.2 degree; the invention provides an S-hydroxychloroquine sulfate monohydrate, the X-ray powder diffraction pattern has characteristic peaks at 12.2 degrees, 13.0 degrees, 14.9 degrees, 17.8 degrees, 22.7 degrees, 23.3 degrees, 25.0 degrees and 26.2 degrees + / -0.2 degrees; the invention also provides R-hydroxychloroquine sulfate, the X-ray powder diffraction pattern has characteristic peaks at 12.2 degrees, 13.0 degrees, 14.9 degrees, 17.8 degrees, 22.7 degrees, 23.3 degrees, 25.0 degrees and 26.2 degrees + / -0.2 degrees.

Description

technical field [0001] The invention relates to hydroxychloroquine sulfate crystals and a preparation method thereof, in particular to crystals of S-hydroxychloroquine sulfate, R-hydroxychloroquine sulfate and hydroxychloroquine sulfate. Background technique [0002] Hydroxychloroquine Sulfate (Hydroxychloroquine Sulfate), chemically named as 2-[[4-[(7-chloro-4-quinolyl)amino]pentyl]ethylamino]-ethanol sulfate, the chemical structure is shown in formula I, hydroxy Chloroquine is its free base, , Clinically used for rheumatoid arthritis, juvenile chronic arthritis, discoid lupus erythematosus and systemic lupus erythematosus, and skin lesions caused or exacerbated by sunlight. [0003] S-Hydroxychloroquine sulfate, chemically named as (S)-(+)-2-[[4-[(7-chloro-4-quinolyl)amino]pentyl]ethylamino]-ethanol sulfate, chemical Structure as shown in formula II, S-hydroxychloroquine is its free base, , R-hydroxychloroquine sulfate, chemically named as (R)-(-)-2-[[4-[(7-chloro-4-q...

Claims

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Application Information

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IPC IPC(8): C07D215/46C07C213/08C07C215/14C07C51/41C07C59/50
CPCC07D215/46C07C213/08C07C51/412C07B2200/13C07B2200/07C07C215/14C07C59/50
Inventor 李光辉覃志俊莫泽艺董雪林吴挺强胡双龙蔡强焦慎超
Owner 珠海润都制药股份有限公司
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