Preparation method of hydroxychloroquine sulfate

Abstract

The invention provides a preparation method of hydroxychloroquine sulfate, specifically a preparation method of hydroxychloroquine sulfate. The method comprises the following steps: (1) preparation of hydroxychloroquine: (1.1) in a first solvent, in the presence of KI and an antioxidant, reacting 4, 7-dichloroquinoline (formula I) with an amino side chain as shown in a formula II to obtain a reaction mixture containing hydroxychloroquine (formula III); and (1.2) separating the hydroxychloroquine from the reaction mixture containing the hydroxychloroquine; and (2) preparation of hydroxychloroquine sulfate: (2.1) in a second inert solvent, reacting the hydroxychloroquine obtained in the step (1) with sulfuric acid to form a salt so as to obtain the hydroxychloroquine sulfate (formula IV).

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a preparation method of hydroxychloroquine sulfate. Background technique [0002] Hydroxychloroquine sulfate, its structural formula is as follows, its chemical name is (±)-2-[[4-[(7-chloro-4-quinolyl) amino] pentyl] ethylamino] ethanol sulfate, CAS number is 747 -36-4, the molecular formula is C 18 h 26 ClN 3 O·H 2 SO 4 . [0003] [0004] 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. [0005] Patent US2546658 discloses a synthetic method of hydroxychloroquine phosphate, the reaction process is as follows: [0006] [0007] This process uses potassium iodide as a catalyst to react at 125-130°C for 18 hour...

AI Technical Summary

Problems solved by technology

[0010] However, the process introduces new impurities that are difficult to remove (hydroxychloroquine deethylated)

In order to remove the deethylated impurities of hydroxychloroquine, the process reacts it with acetic anhydride to obtain acetylated derivatives, which are removed through further post-treatment, resulting in cumbersome steps and a long time for the process, which is not conducive to industrial production, and the final purity is low

[0011] In addition, the reaction under solvent-free conditions is also disclosed in the prior art, but this type of method also has the following disadvantages: for example, for solvent-free reactions, high pressure conditions (> 5bar pressure) are required, and the requirements for equipment are harsh. It is difficult to realize in industry and the safety risk is high, and 1,2-dichloroethane (a class of solvent) is required for crystallization; or the post-treatment needs to be acidified and then alkalized to discard the water phase, and then add an organic solvent to crystallize. This method easily causes a large amount of inorganic bases or salts to be included in the organic solvent and to be separated out together with the hydroxychloroquine crystallization process, resulting in difficult product quality assurance, and the purity of the finished product is not satisfactory

[0012] The prior art also discloses the preparation of hydroxychloroquine by gradually increasing the temperature for a long time to carry out condensation reaction to control the formation of impurities, but this type of method requires a cumbersome process of gradually increasing the temperature to evaporate the solvent to carry out the reaction, resulting in the overall reaction process taking too long and Requires a lot of solvent and requires a lot of solvent for extraction or washing

[0013] Generally speaking, the current method for synthesizing hydroxychloroquine sulfate has the disadvantages of harsh reaction conditions, long reaction time, large amount of solvent used for reaction or post-treatment, unenvironmental protection, and complicated process operations.

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