Preparation method of zidovudine and intermediate thereof

A technology of zidovudine and intermediates, applied in the field of pharmaceutical chemical synthesis, can solve the problems of high reaction temperature, high cost of raw materials, cumbersome operation process, etc., to reduce the azidation reaction temperature, facilitate process production, and solvent recovery rate high effect

Inactive Publication Date: 2015-08-19
XENOAH PHARMA INC
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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 ...

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  • Preparation method of zidovudine and intermediate thereof
  • Preparation method of zidovudine and intermediate thereof
  • Preparation method of zidovudine and intermediate thereof

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Embodiment Construction

[0038] The present invention will be described below in conjunction with specific embodiments. The given embodiments are only general examples of the products or methods of the present invention, which help to better understand the present invention, but do not limit the scope of the present invention.

[0039] Synthesis of Zidovudine Oxygen Bridge Compound (d)

[0040] Add β-thymidine (f, 100.0 g, 0.41 mol) and pyridine (400 mL) into the reaction flask, stir, and slowly raise the temperature to 30-60° C. to dissolve. After complete dissolution, triphenylchloromethane (125.5 g, 1.1 eq) was added, and the reaction was maintained at 30-60° C. for 16 hours, and the end point was controlled by TLC. After confirming the completion of the reaction, cool down and slowly add methanesulfonyl chloride (49.3g, 1.05eq) dropwise under stirring at 0-5°C. After the dropwise addition, it is naturally raised to room temperature and reacted for 2-8 hours, and the end point is controlled by TLC....

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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...

Claims

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Application Information

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IPC IPC(8): C07H19/073C07H1/00C07H9/06
CPCC07H19/073C07H1/00C07H9/06
Inventor 王亚农戈平张鲁岩
Owner XENOAH PHARMA INC
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