Synthesis method of hydroxychloroquine sulfate

Abstract

The invention provides a preparation method of hydroxychloroquine sulfate 2-((4-((7-chloro-4-quinolyl)amino)amyl)ethylamino)-ethanol sulfate. The method provided by the invention has the advantages of cheap and easily available raw materials, short reaction steps, high yield, simple overall process, strong operability, environmental friendliness and the like, reduces the cost, and is suitable for large-scale industrial production.

Description

technical field [0001] The invention relates to the field of medicinal chemistry, in particular to the preparation of hydroxychloroquine sulfate for treating malaria, rheumatoid arthritis and systemic lupus erythematosus. Background technique [0002] Hydroxychloroquine is a 4-aminoquinone compound with a chemical name of 2-((4-((7-chloro-4-quinolyl)amino)pentyl)ethylamino)-ethanol, and its chemical structure is as follows: [0003] [0004] In 1951, Winthrop successfully developed hydroxychloroquine for the treatment of malaria, and in 1955 for the treatment of systemic lupus erythematosus. 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 terms of safety. It can not only improve the symptoms of arthritis in patients, but also resist oxidation and blood lipids, avoid a large number of platelet aggregation, reduce the blood sugar level of patients, a...

AI Technical Summary

Problems solved by technology

[0009] This method has three obvious disadvantages: 1. A large amount of phenol is used as a reaction solvent. Because phenol is toxic and corrosive, it is harmful to the human body, and the waste liquid containing phenol increases the difficulty of waste disposal, which is extremely unfriendly to the environment; 2. Phenol is solid (42 DEG C of melting point) at normal temperature, needs heating and dissolving during use and can carry out feeding, and operation is loaded down with trivial details when enlarging production; Three, adopted hydroxychloroquine side chain (formula II) to make raw material, and this side chain existing preparation The route steps are cumbersome and expensive, which is not conducive to the control of product costs

[0012] This method has two obvious deficiencies: one, adopted hydroxychloroquine side chain (formula II) to make raw material, and the existing preparation route step of this side chain is loaded down with trivial details, the cost is expensive, is unfavorable for the control of product cost; Two, reaction time is up to 20 -24h, not only increases the production cost, but also easily leads to the increase of impurity content

[0015] This method has three obvious defects: one, adopted hydroxychloroquine side chain (formula II) as raw material, and the existing preparation route step of this side chain is loaded down with trivial details, and the cost is expensive, is unfavorable for the control of product cost; Two, adopt pressurized condition to react , has high requirements for equipment, and there is a certain risk in scale-up production; 3. The use of chloroform, a highly toxic class II solvent, as the extraction solvent is extremely harmful to humans and the environment

[0021] This method is the same as the method disclosed in the patent WO2019165337A1. There are also intermediates that do not absorb ultraviolet rays and are mostly liquids. It is difficult to detect and purify. At the same time, the reaction is carried out under pressurized conditions, which requires high equipment. There is a certain risk in scale-up production. The finished product high cost and other disadvantages

[0022] In summary, the existing technology for preparing hydroxychloroquine sulfate has high cost of raw materials, long reaction time, large energy consumption and large environmental pollution. Therefore, it is urgent to find an environmentally friendly, cost-controllable, industrialized New Technology

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