Industrial preparation method of hydroxychloroquine sulfate

Abstract

The invention relates to an industrial preparation method of hydroxychloroquine sulfate, which comprises heating 4, 7-dichloroquinoline and hydroxychloroquine side chain at refluxing temperature to 120-125 DEG C, allowing reaction to obtain hydroxychloroquine, and reacting with sulfuric acid to obtain hydroxychloroquine sulfate. The method can obtain high-purity hydroxychloroquine sulfate with single impurity less than or equal to 0.1% and purity higher than or equal to 99.5%; and has less preparation procedures, simple process, high product yield, good quality, low environmental pollution, no use of highly toxic solvent, and is easy for industrial production.

Description

technical field [0001] The invention belongs to the field of chemistry or pharmaceutical chemistry, and specifically relates to an industrialized preparation method of hydroxychloroquine sulfate, which involves heating 4,7-dichloroquinoline and the side chain of hydroxychloroquine at reflux temperature and slowly raising the temperature to 120°C-125°C for reaction Hydroxychloroquine is prepared, and then reacted with sulfuric acid to obtain hydroxychloroquine sulfate. The method can obtain high-purity hydroxychloroquine sulfate with a single impurity ≤ 0.1% and a purity ≥ 99.5%. Background technique [0002] The structure of hydroxychloroquine sulfate is shown below, its chemical name is 2-[[4-[(7-chloro-4-quinolyl)amino]pentyl]ethylamino]-ethanol sulfate, and its CAS number is 747-36- 4. Hydroxychloroquine sulfate was successfully developed by Winthrop Company. It was first listed in the United States in 1956 and has been listed in France, Denmark, Japan, Germany, Finland ...

AI Technical Summary

Problems solved by technology

[0017] According to the three methods disclosed above, the method of CA2561987 has certain advantages in terms of environmental protection and reaction conditions compared with other methods, and no toxic reagents and high pressure are used. However, since the reaction is kept at 120-130 ° C, the reaction time is as long as 20 -24h, the impurity content in the crude product will still be high, increasing the post-processing pressure, and there are also the following outstanding shortcomings:

[0019] 2. The consumption of 5-(N-ethyl-N-2-hydroxyethylamino)-2-pentylamine (referred to as "hydroxychloroquine side chain" in the present invention) is large, and the consumption of hydroxychloroquine side chain is 4, 2-3 times that of 7-dichloroquinoline, so that the side chain of hydroxychloroquine occupies a large proportion in the cost, resulting in too high production cost

[0020] 3. In order to remove 7-chloro-4-(4-N-hydroxyethyl-1-methyl tertiary amino) quinoline in the post-treatment process of the reaction, the higher price of methyl isobutyl ketone was adopted, and The steps are complicated and increase the production cost

[0021] 4. There are many overnight treatment operations in the post-processing, and there will be uncertainty in the operation time when it is applied to production, resulting in production deviations

[0022] Generally speaking, the current method for synthesizing hydroxychloroquine sulfate has the use of highly toxic catalysts and solvents, lengthy synthetic route, poor reaction selectivity, long reaction cycle, special pressure-resistant equipment, cumbersome post-reaction treatment, difficult operation, and high production costs , high impurity content in the product, etc.

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