Side chain, synthesis method thereof, and method for synthesizing hydroxychloroquine sulfate from side chain

Abstract

The invention discloses a side chain, a synthesis method thereof, and a method for synthesizing hydroxychloroquine sulfate from the side chain. The synthesis method of the side chain comprises the following steps: 1, condensing N-ethylethanolamine and 5-chloro-2-pentanone to obtain a condensation product; 2, esterifying the condensation product and an acetyl reagent to obtain an esterification product; 3, reducing the esterification product to obtain a reduction product; and 4, reacting the reduction product with a halogenating agent to obtain the side chain. The synthesis method of the hydroxychloroquine sulfate comprises the following steps: 1, reacting 4-amino-7-chloroquinoline with paratoluensulfonyl chloride to obtain 4-Tos-amino-7-chloroquinoline; 2, reacting the side chain with the 4-Tos-amino-7-chloroquinoline to obtain a hydroxyquine base; and 3, reacting the hydroxyquine base with sulfuric acid to obtain the hydroxychloroquine sulfate. The synthesis method of the new side chain avoids the ammonification process and the catalytic hydrogenation process, and is safe and environmentally friendly, and the hydroxychloroquine sulfate can be obtained through low-temperature condensation of the side chain, so the quality of the above products is remarkably improved, and the production flow is simplified.

Description

technical field [0001] The invention belongs to the field of medicine and chemical industry, and in particular relates to a side chain and a synthesis method thereof, and a method for synthesizing hydroxychloroquine sulfate by using the side chain. Background technique [0002] Hydroxychloroquine sulfate, chemical name 2-4-(7-chloro-4-quinolyl) aminopentylethylamino-ethanol sulfate, English name: Hydroxychloroquine Sulfate, chemical structural formula is as follows: [0003] [0004] Hydroxychloroquine (Hydroxychloroquine, HCQ) is an antimalarial drug composed of 4-aminoquinoline compounds. Hydroxychloroquine sulfate was synthesized by Surrey and Hammer in 1946. It is clinically used to treat discoid lupus erythematosus and systemic lupus erythematosus, and has also been widely used in rheumatism-related diseases. [0005] Discoid lupus erythematosus (DLE) is a relatively common skin and mucous membrane connective tissue disease, 25%-35% have oral lesions, which can be s...

AI Technical Summary

Problems solved by technology

[0025] In summary, the current synthetic route of hydroxychloroquine sulfate mainly has two unfavorable factors: one is the preparation of the side chain of hydroxychloroquine: it needs to use ammonia gas or high-concentration liquid ammonia, which has a heavy odor and has a bad impact on the environment. High-pressure hydrogenation is required to reduce to amino groups, which has a high safety risk; the second is the preparation of hydroxychloroquine base: due to the relatively low activity of the 4-position chlorine of 4,7-dichloroquinoline, it is impossible to use only catalysts such as potassium bromide, potassium iodide, etc. , so it needs to be reacted under high temperature conditions. During the high temperature reaction, the terminal -NH of the hydroxychloroquine side chain 2 and -OH are easily oxidized, dehydrated, condensed, etc. Therefore, to ensure product quality, it is necessary to adopt a relatively cumbersome post-treatment process and use a large amount of organic solvents

In addition, the existing synthetic routes still have the defects of long production cycle, high impurity content, low yield and high cost of raw materials

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