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Preparation method of hydroxychloroquine

A technology of hydroxychloroquine and hydroxyquinoline, which is applied in the field of preparation of hydroxychloroquine, can solve the problems affecting the final quality of the product, unfavorable industrial application, high cost, etc., and is beneficial to large-scale production, prevents the generation of isomers, and is not easy to produce. The effect of side effects

Active Publication Date: 2020-09-08
北京成宇化工有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The existence of this impurity will undoubtedly cause great pressure on the production process of hydroxychloroquine, and will also affect the final quality of the product
Although the product can be further purified by some purification means (CN109928925A, CN103626699A), it is also difficult to ensure the high quality of the intermediate 4,7-dichloroquinoline required for the preparation of hydroxychloroquine chloride
[0034] The organic solvents used in large quantities in the chemical and chemical production process not only cause environmental pollution, but also are expensive and difficult to recycle, which is not conducive to industrial applications. Therefore, the development of non-toxic and cheap green solvents is a very important issue for the chemical industry

Method used

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  • Preparation method of hydroxychloroquine
  • Preparation method of hydroxychloroquine
  • Preparation method of hydroxychloroquine

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0066] In the deep eutectic solvent (200g) that choline chloride and urea (molar ratio 1:2) form, add 7-chloro-4-hydroxyquinoline p-toluenesulfonate (333.0g, 1.0mol) and Hydroxychloroquine side chain (182.7g, 1.05mol) was subjected to a constant temperature reaction at 80° C. for 9 hours, and TLC detected that the reaction was complete.

[0067] Cool down to 25°C, add ethyl acetate (300 mL), add cold water (500 mL) while fully stirring, let stand for 2 hours, separate the ethyl acetate solution, wash with water, and concentrate to obtain a crude product. Isopropanol was recrystallized to obtain off-white crystals (289 g), with a yield of 86%. Melting point: 91-92°C.

[0068] The content of hydroxychloroquine analyzed by liquid chromatography was 99.54%.

[0069] The preparation of hydroxychloroquine sulfate

[0070] Under ice-water cooling, the concentrated sulfuric acid (20g) is slowly added in the solution of isopropanol (80g), and is slowly dropped in the solution of hyd...

Embodiment 2

[0073] In the deep eutectic solvent (50g) that choline chloride and urea (molar ratio 1:2) form, add 7-chloro-4-hydroxyquinoline p-toluenesulfonate (33.3g, 0.1mol) and Hydroxychloroquine side chain (17.4 g, 0.1 mol) was reacted at a constant temperature of 85° C. for 8 hours, and the reaction was detected by TLC.

[0074] Cool down to 25°C, add ethyl acetate (50 mL), add cold water (100 mL) while fully stirring, let stand for 2 hours, separate the ethyl acetate solution, wash with water, and concentrate to obtain a crude product. Isopropanol was recrystallized to obtain off-white crystals (30 g) with a yield of 91%. Melting point: 91-92°C.

[0075] The content of hydroxychloroquine analyzed by liquid chromatography was 99.62%.

[0076] The preparation of hydroxychloroquine sulfate

[0077] According to the preparation process described in Example 1, hydroxychloroquine sulfate was obtained, with a melting point of 239° C. to 241° C.

[0078] HPLC purity 99.79%, the largest s...

Embodiment 3

[0080] In the deep eutectic solvent (50g) that choline chloride and urea (molar ratio 1:2) are formed, add 7-chloro-4-hydroxyquinoline trifluoromethanesulfonate (32.7g, 0.1mol) and hydroxyl Chloroquine side chains (20.9 g, 0.12 mol) were subjected to a constant temperature reaction at 70° C. for 5 hours, and TLC detected that the reaction was complete.

[0081] Cool down to 25°C, add ethyl acetate (50 mL), add cold water (100 mL) while fully stirring, let stand for 2 hours, separate the ethyl acetate solution, wash with water, and concentrate to obtain a crude product. Isopropanol was recrystallized to obtain off-white crystals (32.3 g), with a yield of 96%. Melting point: 91-92°C.

[0082] The content of hydroxychloroquine analyzed by liquid chromatography was 99.69%.

[0083] The preparation of hydroxychloroquine sulfate

[0084] According to the preparation process described in Example 1, hydroxychloroquine sulfate was obtained, with a melting point of 239° C. to 241° C. ...

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Abstract

The invention belongs to the technical field of medicine and chemical engineering, and particularly relates to a hydroxychloroquine preparation method. The method comprises: carrying out a condensation reaction on a quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate and a hydroxychloroquine side chain in a eutectic solvent to obtain a target product, wherein the preparation method of thequinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate comprises the following steps: (1) by taking 4-chloro-2-nitrobenzoic acid as a raw material, carrying out a chlorination reaction to prepare acyl chloride, condensing the acyl chloride with Meldrum's acid, and hydrolyzing to obtain 4-chloro-2-nitroacetophenone; and (2) carrying out condensation reaction, nitro reduction cyclization andhydroxyl protection reaction on the 4-chloro-2-nitroacetophenone and N,N-dimethylformamide methylal to obtain the quinoline intermediate 7-chloro-4-hydroxyquinoline sulfonate. The method has the advantages of easily available raw materials, mild reaction conditions, difficulty in side reaction, avoidance of high-temperature production conditions, reduction of risks, good intermediate stability, high yield and good purity of the obtained hydroxychloroquine, and facilitation of large-scale production.

Description

technical field [0001] The invention belongs to the technical fields of medicine and chemical industry, and in particular relates to a preparation method of hydroxychloroquine. Background technique [0002] Hydroxychloroquine is a 4-aminoquinoline derivative, and its sulfate, namely hydroxychloroquine sulfate, is used clinically. [0003] The chemical name of hydroxychloroquine sulfate (Hydroxychloroquine Sulfate) is 2-[[4-[(7-chloro-4-quinolyl)amino]pentyl]ethylamino]-ethanol sulfate, and its CAS number is 747-36-4. The chemical structural formula is as follows: [0004] [0005] Hydroxychloroquine sulfate was successfully developed by Winthrop Company. It was first listed in the United States in 1956, and then listed in France, Denmark, Japan, Germany, Finland and other countries and regions. U.S. FDA approved hydroxychloroquine sulfuric acid tablets on May 29, 1998 for the treatment of lupus erythematosus and rheumatoid arthritis. Compared with other similar drugs, ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D215/46C07D215/233
CPCC07D215/46C07D215/233Y02P20/55
Inventor 宋也
Owner 北京成宇化工有限公司
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