Hydroxychloroquine synthetic method

Abstract

The invention provides a hydroxychloroquine synthetic method, including the steps of mixing 4,7-dichloroquinoline, 2-[(4-aminopentyl)(ethyl)amino]ethanol and N,N-diisopropylethylamine, reacting under protective gas, and after the reaction, performing extraction, concentration and purification to obtain the hydroxychloroquine. By using the synthetic method provided by the invention, N,N-diisopropylethylamine is used as both an acid-binding and a solvent to promote smooth reaction, the amount is small (only theoretical amount), and the consumption is low; the reaction time is short, alkalization is not needed after treatment, the hydroxychloroquine can be obtained by just the operations of extraction and recrystallization, and the operation is simple; the extraction solvent and the recrystallization solvent may be the same solvent, which is beneficial to the recovery and utilization of the solvent, and the production cost is reduced; the total recovery is increased from 45.9% to 74.7%, the product quality is increased from 99.0% to 99.8% or above (HPLC purity), and single impurity being less than or equal to 0.1%.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to the preparation of hydroxychloroquine for treating malaria, rheumatoid arthritis and systemic lupus erythematosus. Background technique [0002] Hydroxychloroquine (hydroxychloroquine, 1) is a 4-aminoquinone compound with a chemical name of 2-[[4-[(7-chloro-4-quinolyl)amino]pentyl]ethylamino]-ethanol, chemical structure as follows: [0003] [0004] In 1951, hydroxychloroquine was successfully developed by Winthrop Company. It was initially used to treat malaria. It was used to treat systemic lupus erythematosus in 1955. It was first listed in the United States in 1956. After that, it was successively used in Japan, France, Denmark, Finland, Germany and other countries. Listed in countries and regions. In 1998, the US FDA approved hydroxychloroquine for the treatment of rheumatoid arthritis and lupus erythematosus. Compared with other similar drugs, it has an advantage in...

AI Technical Summary

Problems solved by technology

[0008] The method mainly has the following deficiencies: i) phenol is used as a solvent for the reaction, and phenol is highly toxic and corrosive, which is extremely harmful to personnel and the environment, and is converted into sodium phenate aqueous solution to form harmful phenolic waste water in the aftertreatment process, Increased the difficulty of the three wastes treatment; ii) the condensation reaction time is 18h, the long-time reaction will not only increase the production cost, but also lead to the increase of the content and quantity of impurities, especially the long-time high-temperature reaction, which will increase the amount of deethylated impurities and this impurity is difficult to remove; iii) Phosphoric acid is used to remove impurities in the reaction process, resulting in a large amount of phosphorus-containing wastewater, which further increases the pressure on environmental protection; iv) The extraction solvent chloroform is a class of solvent, carcinogenic, and environmentally unfriendly; v) The recrystallization solvent diethyl ether is flammable and explosive, and has great safety hazards; vi) The steps are long, the operation is cumbersome, and the total yield is very low, only 18.6%.

[0020] This method uses carcinogenic chloroform as a solvent, and the amount is very large, which is extremely harmful to personnel and the environment; N,N-dimethylformamide with a high boiling point is used as a solvent, which is difficult to recycle and causes great harm when it enters the waste water. environmental protection pressure; the route is long and complicated, and the operation is cumbersome; the price of raw materials is expensive and the cost is high

[0021] All of the above-mentioned routes have disadvantages such as long reaction time, high toxicity of reagents, cumbersome operation, environmental pollution, high production cost, and poor product quality.

Especially with the increase of production capacity, the cost of environmental protection has risen sharply. Therefore, it is urgent to study a green synthesis route suitable for industrial production, with the purpose of solving the problems of low green degree, low yield and low product purity in the current process.

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