Preparation method of zidovudine and intermediate thereof

Abstract

The invention discloses a preparation method of zidovudine and an intermediate thereof. The intermediate is a zidovudine azide compound. The method comprises the steps of: (1) a dissolution reaction: dissolving a zidovudine oxygen bridge compound in an organic solvent, adding an azidation reagent and a catalyst inorganic acid salt or a small molecular organic acid salt, and reacting and insulating at 90-115 DEG C for 12-48 h; (2) distilling filtration: cooling, filtering, conducting reduced pressure distillation on the filtrate and recovering an organic solvent; and (3) extraction concentration: extracting and washing the above obtained product and concentrating to obtain the zidovudine azide compound. Compared with the prior art, the whole process has the advantages of easily available raw materials, low cost, environment friendliness, and high recovery rate of solvent. The preparation process of the intermediate zidovudine azide compound uses inorganic acid salt and small molecular organic acid catalytic reaction, effectively reduces the azidation reaction temperature, shortens the reaction time, and is conducive to process production. The obtained product has less impurities, good state; and the zidovudine crude refining process is simple, and high in yield.

Description

technical field [0001] The invention relates to a method for preparing zidovudine and an intermediate thereof, belonging to the technical field of pharmaceutical chemical synthesis. Background technique [0002] Zidovudine is an antiviral drug for the treatment of AIDS or AIDS-related syndrome patients and human immunodeficiency virus (HIV) infection. Zidovudine is the world's first anti-AIDS drug approved by the US FDA. Because of its definite curative effect, it has become the most basic component of the "cocktail" therapy. [0003] The method for producing zidovudine at present is mainly reported in U.S. Patent US 5124442A, [0004] [0005] Wherein, in the process of converting compound (III) into (IV), an oxygen bridge compound is formed by intramolecular dehydration through Mitsunobu reaction, and triphenylphosphine and diisopropyl azodicarboxylate (DIAD) are used as raw materials, Not conducive to industrialization. The azidation reaction temperature is high, an...

AI Technical Summary

Problems solved by technology

[0005] Wherein, in the process of converting compound (III) into (IV), an oxygen bridge compound is formed by intramolecular dehydration through Mitsunobu reaction, and triphenylphosphine and diisopropyl azodicarboxylate (DIAD) are used as raw materials, not conducive to industrialization

The azidation reaction temperature is high, and the production process has a potential explosion hazard

[0006] Simultaneously, 10%-15% of 3',5'-dihydroxy protection products will inevitably be produced when selectively protecting the 5'-hydroxyl of the raw material β-thymidine (II) in this production process, and this by-product makes Zidovudine is difficult to purify in the later refining process, and the total yield is difficult to further improve

In order to solve this defect, patent 201180002520.0 discloses a method for preparing zidovudine and its intermediates, which can effectively reduce the content of 3',5'-dihydroxy protected compounds, but the raw materials of this method use halogenated Thymidine requires further dehalogenation during the preparation process, and the operation process is cumbersome

The halogenated hydrocarbon solvent used to protect the 3’-hydroxyl group is highly volatile, highly toxic, difficult to recycle, and not conducive to environmental protection. The entire process conditions and safety requirements are relatively strict

[0007] In view of the problems of low yield, high cost of raw materials, and high requirements on production equipment and process conditions in the current patented and reported synthetic processes, it is very necessary to develop a synthetic method with simple process, high yield, and less pollution

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