A kind of preparation method of hydroxychloroquine sulfate

A technology of hydroxychloroquine sulfate and hydroxychloroquine, which is applied in the fields of medicine and chemical industry, can solve the problems of producing dimethyl sulfate and diethyl sulfate, being unsuitable for industrialized production, and not being able to achieve them, so as to reduce the number of washings and avoid toxic Substance risk, easy operation effect

Active Publication Date: 2017-02-01
TSINGHUA TONGFANG CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0013] In the preparation method of above-disclosed hydroxychloroquine sulfate, all have some insufficient factors, are not suitable for realizing suitability for industrialized production; The product contains chloroform, dichloroethane and other halogenated hydrocarbon genotoxic impurities, which cannot meet the requirements of ICH's "Guidelines for Residual Solvents"
When hydroxychloroquine is converted into sulfate, most of the processes use concentrated sulfuric acid under the condition of absolute alcohol, which may cause the risk of producing dimethyl sulfate and diethyl sulfate

Method used

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  • A kind of preparation method of hydroxychloroquine sulfate
  • A kind of preparation method of hydroxychloroquine sulfate
  • A kind of preparation method of hydroxychloroquine sulfate

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Embodiment 1

[0033] The preparation of embodiment 1 hydroxychloroquine sulfate

[0034] 1.1 The preparation of hydroxychloroquine

[0035]In a three-neck round bottom flask, add 4,7-dichloroquinoline (198.0g, 1.0mol), hydroxychloroquine side chain (182.7g, 1.05mol) and isopropyl acetate 1089g, slowly add sodium ethoxide (13.6g, 0.2mol), slowly heat up to reflux under stirring conditions, then distill out isopropyl acetate, gradually heat up to 110°C over 9 hours, then heat up to 120°C~122°C in 10 hours, and finally keep warm at 120°C~122°C for reaction After 4 hours, after the reaction is complete, cool the reaction liquid to 90°C-100°C, directly add 5% sodium hydroxide solution, and alkalinize to pH=9-10. The distilled isopropyl acetate is divided into two extractions of the reaction solution, layered, and 500 g of drinking water is added to the combined organic phase for washing, layered, and the above operations are repeated until the pH value of the washing water is 7. After washing,...

Embodiment 2

[0038] The preparation of embodiment 2 hydroxychloroquine sulfate

[0039] 2.1 Preparation of hydroxychloroquine

[0040] According to embodiment 1.1 as the basis, change catalyst type, do not change the reaction effect after consumption, other conditions are constant, the result obtained is as follows:

[0041] table 2-1

[0042] sequence Catalyst type yield HPLC purity largest single impurity 1 Sodium methoxide 85.1% 99.0% ＜0.1％ 2 Sodium tert-butoxide 85.4% 99.1% ＜0.1％ 3 Sodium tert-amylate 86.0% 99.0% ＜0.1％

[0043] 2.2 Preparation of hydroxychloroquine sulfate

[0044] Based on Example 1.2, the hydroxychloroquine obtained in Example 2.1 is used to carry out the salt-forming reaction, and other conditions are constant, and the results are as follows:

[0045] Table 2-2

[0046]

Embodiment 3

[0047] The preparation of embodiment 3 hydroxychloroquine sulfate

[0048] 3.1 Preparation of hydroxychloroquine

[0049] In a three-neck round bottom flask, add 4,7-dichloroquinoline (198.0g, 1.0mol), hydroxychloroquine side chain (182.7g, 1.05mol) and tert-butyl acetate 1089g, slowly add sodium ethoxide (13.6g, 0.2mol), slowly heat up to reflux under stirring conditions, then distill off tert-butyl acetate, gradually heat up to 110°C over 9 hours, then heat up to 120°C~122°C in 10 hours, and finally keep warm at 120°C~122°C for reaction After 4 hours, after the reaction is complete, cool the reaction solution to 90°C-100°C, add 5% sodium hydroxide solution, and alkalize to pH=9-10. The distilled tert-butyl acetate was divided into two extractions of the reaction solution, layered, and 500 g of drinking water was added to the combined organic phase for washing, layered, and the above operations were repeated until the pH value of the washing water was 7. After washing, cont...

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Abstract

The invention discloses a preparation method of hydroxychloroquine sulfate. The preparation method is characterized by comprising the following steps: condensing 4,7-dichloroquinoline serving as an initial raw material and a hydroxychloroquine side chain under the action of a catalyst, so as to obtain hydroxychloroquine; and reacting hydroxychloroquine with sulfuric acid, so as to prepare the hydroxychloroquine sulfate. According to the method disclosed by the invention, the defects in the prior art are overcome. The method has the advantages that the yield of the prepared hydroxychloroquine sulfate crude product is greater than or equal to 85%, the yield of hydroxychloroquine sulfate is greater than or equal to 94%; the total yield is greater than or equal to 80%; the purity of the prepared hydroxychloroquine sulfate HPLC is greater than or equal to 99.6%; the maximum single impurity is smaller than 0.1%; the method accords with the requirements of United States pharmacopeia, is short in reaction step, and simple in the whole technological operation; and the obtained product is high in quality, high in yield, and relatively suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical fields of medicine and chemical industry, in particular to hydroxychloroquine sulfate for treating discoid lupus erythematosus and systemic lupus erythematosus. Background technique [0002] Hydroxychloroquine Sulfate (Hydroxychloroquine Sulfate) chemical name is 2-[[4-[(7-chloro-4-quinolyl)amino]pentyl]ethylamino]-ethanol sulfate, CAS number is 747-36-4, The chemical structural formula is as follows: [0003] [0004] 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. [0005] US2546658 discloses a kind of synthetic method of hydroxychloroquine sulfate, and the reaction process of this method is as follow...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D215/46
CPCC07D215/46
Inventor 唐明龚大勇杨忠鑫刘英超杨继斌蔡中文查正华王亚川
Owner TSINGHUA TONGFANG CO LTD
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