Purification method of hydroxychloroquine sulfate

A technology of hydroxychloroquine sulfate and purification method, which is applied in the field of purification of hydroxychloroquine sulfate, and can solve the problems of no suitable method for finished product control, clarity, acidity and unqualified crystal form, etc.

Inactive Publication Date: 2020-07-07
CINKATE PHARMA INTERMEDIATES +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Quality control is only controlled from the source, and there is no suitable method for finished product control. It is difficult to fully meet the requirements of GMP in the preparation process, and hydroxychloroquine sulfate is prone to abnormalities such as related substances, clarity, acidity and unqualified crystal form. , for these abnormal situations, there are no related solutions reported in the literature

Method used

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  • Purification method of hydroxychloroquine sulfate
  • Purification method of hydroxychloroquine sulfate

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0069] Preparation of crude hydroxychloroquine sulfate:

[0070] Put 0.91Kg of 4,7-dichloroquinoline, 0.9kg of phenol and 10g of potassium iodide into a 20L reactor, stir and heat to 120°C, and slowly add 5-(N-ethyl-N-2-hydroxyethylamino)-2 - Pentylamine 1.32Kg, after dropping, continue stirring at 125-130°C for 18 hours. Cool to room temperature, add 20% sodium hydroxide lye to adjust to pH 12, extract with toluene three times, concentrate under reduced pressure to remove toluene, dissolve the residue in 1.5L absolute alcohol, cool to room temperature, slowly add concentrated sulfuric acid, adjust pH to 6-7.5, stirring, crystallization slowly. Store at 5°C for more than 6 hours. Filter to obtain the wet product of hydroxychloroquine sulfate crude product. Vacuum dried at 80°C for 4 hours. Obtained 0.89kg crude product of hydroxychloroquine sulfate, purity 95%, mp235-240 ℃, yield 45.76%.

Embodiment 2

[0072] Add 600g of crude hydroxychloroquine sulfate, 600ml of water and 1200ml of ethanol into a 10L round-bottomed three-neck flask respectively, then stir and heat to 70°C, continue to insulate and stir until completely dissolved, slowly add 6L of ethanol, then heat to reflux (78-80 ℃), refluxing and crystallizing for 1 hour, then stirring to lower the temperature to 30-40 ℃, continuing to stir for 1 hour, filtering, rinsing with a small amount of ethanol, and drying the filter cake to obtain 578.5 g of white solid with a yield of 96.41%. High performance liquid chromatography purity 99.85%, the largest single impurity 0.05%, particle size D x (90) is 339 μm. The main characteristic peaks measured by the 2θ reflection angle in the X-ray powder diffraction pattern: 12.95°, 17.10°, 17.21°, 17.47°, 19.90°, 21.15°, 23.5±0.2°, 23.9±0.2°, 26.7±0.2°.

Embodiment 3

[0074] Add 80g of crude hydroxychloroquine sulfate, 40ml of water and 120ml of ethanol into a 1L round-bottomed three-necked flask, then stir and heat to reflux, continue to reflux for 0.5h, slowly add 640ml of ethanol, stir and crystallize under reflux for 0.5, then stir and cool down to 40°C , continue to stir for 3 hours, filter, rinse with a small amount of ethanol, and dry the filter cake to obtain 70.1 g of white solid, with a yield of 87.67%. The purity by high performance liquid chromatography is 99.58%, the maximum single impurity is 0.09%, and the particle size Dx(90) is 259 μm. The main characteristic peaks determined by the 2θ reflection angle in the X-ray powder diffraction pattern: 12.87°, 16.85°, 17.11°, 17.45°, 19.84°, 21.25°, 23.52°, 23.90°, 26.64°.

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Abstract

The invention discloses a purification method of hydroxychloroquine sulfate, which comprises the following steps: (1) dissolving a hydroxychloroquine sulfate crude product in water or a mixed solventof water and a first solvent to obtain a mixed solution I; (2) adding a second solvent into the mixed solution I, and carrying out reflux crystallization; and (3) cooling the reaction product, and filtering and drying the reaction product to obtain a fine hydroxychloroquine sulfate product. The method is excellent in purification effect, so that hydroxychloroquine sulfate with the purity of 99.5%or above and the particle size Dx (90) larger than or equal to 200 microns is prepared. The method is easy and convenient to operate, low in cost, safe, environmentally friendly and suitable for large-scale production.

Description

technical field [0001] The invention belongs to the field of medicinal chemistry, in particular to a method for purifying hydroxychloroquine sulfate. Background technique [0002] Hydroxychloroquine sulfate has the following structural formula, its chemical name is (±)-2[[4-[(7-chloro-4-quinolyl)amino]pentyl]-ethylamino]ethanol sulfate, and its CAS number is 747 -36-4, the molecular formula is C 18 h 26 ClN 3 O·H 2 SO 4 . Hydroxychloroquine sulfate was synthesized by Surrey and Hammer in 1946 and was first listed in the United States in 1956 as an antimalarial drug. On May 29, 1998, the US FDA approved hydroxychloroquine sulfate tablets for the treatment of lupus erythematosus and rheumatoid arthritis. Hydroxychloroquine sulfate is more and more widely used in the rheumatic field because of its unique mechanism of action and better safety. After the 1990s, the clinical treatment of more than 90% of rheumatic diseases all selects hydroxychloroquine sulfate. Its structu...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/46
CPCC07D215/46
Inventor 文勇罗军王果马玉涛仇波肖飞
Owner CINKATE PHARMA INTERMEDIATES
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