Preparation method of hydroxychloroquine and sulfate thereof

A technology of hydroxychloroquine and hydroxychloroquine sulfate, applied in organic chemistry methods, organic chemistry, etc., can solve the problems of unstable impurity control and low purity

Inactive Publication Date: 2018-10-23
SHANGHAI ZHONGXI SUNVE PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The technical problem to be solved by the present invention is that the existing hydroxychloroquine preparation method has def

Method used

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  • Preparation method of hydroxychloroquine and sulfate thereof
  • Preparation method of hydroxychloroquine and sulfate thereof
  • Preparation method of hydroxychloroquine and sulfate thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1～8

[0090] The preparation of step (1), hydroxychloroquine crude product

[0091] Add 4,7-dichloroquinoline (100g) and side chains into the reaction flask, under nitrogen protection, stir, rise to a certain temperature, react, until HPLC detects that the content of 4,7-dichloroquinoline is below 6%, stop For the reaction, quench the reaction with a quenching liquid, extract with an organic solvent, wash the extract with purified water until the pH is 7-8, and distill under reduced pressure to obtain crude hydroxychloroquine.

[0092] Table 1. Preparation of hydroxychloroquine crude product

[0093]

[0094] The preparation of step (2), hydroxychloroquine fine product

[0095] Add the mixed solvent to the crude product obtained in step (1), heat to 70±5°C to dissolve, then lower the temperature, cool to 10°C, add seed crystals, crystallize, suction filter, and dry the filter cake to obtain fine hydroxychloroquine.

[0096] Table 2. Preparation of Hydroxychloroquine Essence

[0...

Embodiment 1 and comparative Embodiment 3

[0121] Embodiment 1 and comparative example 3,4 compare

[0122] Table 3. Comparison of products and impurities in crude hydroxychloroquine

[0123]

[0124] Table 4. Comparison of products and impurities in hydroxychloroquine boutique

[0125]

[0126]

[0127] Note: The relative retention time is compared with the HPLC retention time of hydroxychloroquine; that is, a relative retention time of "1" means hydroxychloroquine, and other relative retention times are impurities.

[0128] After refining, in Example 1, the content of impurity 1 is controlled at 0.1% unqualified in the subsequent storage process.

Embodiment 9～17 and comparative Embodiment 9～11

[0130] Preparation of hydroxychloroquine sulfate-salt crystallization

[0131] Hydroxychloroquine fine product (50g; obtained by Example 1) was dissolved in an alcoholic solvent, and sulfuric acid aqueous solution was added dropwise at 20 to 35° C. until turbidity, and the dropwise addition was stopped, and the temperature was raised to 35 to 55° C., and the heat preservation reaction was carried out for more than 5 hours. After the reaction is completed, the temperature is lowered to 0-20° C., kept for 1 hour, filtered with suction, and the filter cake is dried to obtain the finished product.

[0132] Table 5. Preparation of hydroxychloroquine sulfate

[0133]

[0134]

[0135] Wherein, the HPLC data analysis of embodiment 11 and comparative example 9 is as follows:

[0136] Table 6. Comparison of products and impurities in hydroxychloroquine sulfate

[0137]

[0138] Note: The relative retention time is compared with the HPLC retention time of hydroxychloroquine s...

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Abstract

The invention discloses a preparation method of hydroxychloroquine and sulfate thereof. The preparation method of the hydroxychloroquine comprises the following steps of step (1), under the inert gasprotection atmosphere, enabling 4,7-dichloroquine and hydroxychloroquine side chain compounds to react at the temperature of 134 to 144 DEG C until the content of 4,7-dichloroquine is smaller than orequal to 10%, so as to obtain a crude product of the hydroxychloroquine, wherein the content of the hydroxychloroquine in the crude product of the hydroxychloroquine is greater than 92%; step (2), recrystallizing the obtained crude product of the hydroxychloroquine in step (1) in a mixed solvent of alcohol solvent and ester solvent, so as to obtain a refined product of the hydroxychloroquine. Thepurity of the refined product of the hydroxychloroquine can reach 99.9%, the maximum content of single impurity is controlled within 0.06%, and the total content of other impurities is smaller than 0.04%.

Description

technical field [0001] The invention relates to a preparation method of hydroxychloroquine and sulfate thereof. Background technique [0002] Hydroxychloroquine Sulfate (Hydroxychloroquine Sulfate), its chemical name is 2-[[4-[(7-chloro-4-quinolyl)amino]pentyl]ethylamino]-ethanol sulfate, CAS number is 747-36- 40. 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 and other countries and regions. U.S. FDA approved hydroxychloroquine sulfate tablets on May 29, 1998 for the treatment of lupus erythematosus and rheumatoid arthritis. [0003] US2546658 discloses a kind of hydroxychloroquine sulfate synthetic method, and the reaction process of this method is as follows: [0004] [0005] 4,7-dichloroquinoline reacts with 5-(N-ethyl-N-2-hydroxyethylenediylamino)-2-pentylamine (hereinafter referred to as hydroxychloroquine side chain compou...

Claims

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Application Information

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IPC IPC(8): C07D215/46
CPCC07B2200/13C07D215/46
Inventor 李晓东颜国明卫金强祝鹏程余坤矫丁云晖俞伟丁雁
Owner SHANGHAI ZHONGXI SUNVE PHARMA
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