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Fosfluconazole refining method

A technique for the purification of fosfluconazole and a refining method, which is applied in the field of refining known chemical drugs, can solve the problems of poor removal of water-insoluble impurities and the like, and achieve the effects of low production cost, pure product, and high purity of the finished product

Active Publication Date: 2015-09-23
HEFEI JIUNUO MEDICAL TECH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0010] There are few literature reports on the refining method of fosfluconazole. CN1210540A adds sulfuric acid dropwise to the alkaline hydrogenation reaction solution to precipitate the solid of fosfluconazole. This method has a good effect on removing water-soluble impurities (impurity C, impurity D) Poor removal of impurities (impurity A, impurity B and fluconazole)

Method used

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  • Fosfluconazole refining method
  • Fosfluconazole refining method
  • Fosfluconazole refining method

Examples

Experimental program
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Effect test

Embodiment 1

[0040] Stir and disperse 10 g of fosfluconazole crude product in 30 ml of water, add dropwise 2 mol / L sodium hydroxide aqueous solution to adjust the pH to 6.0, add 35 ml of ethyl acetate, stir and wash for 15 min, discard the organic layer, and adjust the aqueous layer with 1 mol / L sulfuric acid aqueous solution pH to 1-3, filter, wash the filter cake with ethanol, dry the solid at 30-35°C under reduced pressure (vacuum degree ≥ 0.08MPa) for 12h, and obtain 8.3g of the finished product of fluconazole, with a yield of 83% and a purity of 100.0% ( HPLC detection).

Embodiment 2

[0042] Stir and disperse 10 g of fosfluconazole crude product in 30 ml of water, add dropwise 1.5 mol / L sodium carbonate aqueous solution to adjust the pH to 6.5, add 35 ml of isopropyl ether, stir and wash for 15 min, discard the organic layer, and adjust the aqueous layer with 2 mol / L acetic acid aqueous solution pH to 1-3, filter, the filter cake is washed with acetone, and the solid is dried at 30-35°C under reduced pressure (vacuum degree ≥ 0.08MPa) for 8 hours to obtain 8.5g of fluconazole finished product, the yield is 85%, and the purity is 100.0% (HPLC detection).

Embodiment 3

[0044] Stir and disperse 10 g of fosfluconazole crude product in 30 ml of water, add dropwise 2.5 mol / L sodium bicarbonate aqueous solution to adjust the pH to 6.7, add 35 ml of ethyl acetate, stir and wash for 15 min, discard the organic layer, and wash the aqueous layer with 3 mol / L hydrochloric acid aqueous solution Adjust the pH to 1-3, filter, wash the filter cake with an appropriate amount of methanol, and dry the solid at 30-35°C under reduced pressure (vacuum degree ≥ 0.08MPa) for 8 hours to obtain 8.3g of forsi fluconazole, with a yield of 83% and a purity of 100.0 % (HPLC detection).

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Abstract

The present invention discloses a fosfluconazole refining method, a fosfluconazole crude product is dispersed in water, the temperature is controlled at 0-15 DEG C, the pH is adjusted with an aqueous solution of an inorganic base to 6-7, a water-insoluble solvent is added for washing at least once, the organic layer is removed, the aqueous layer temperature is controlled at-5-10 DEG C, the pH is adjusted with a protonic acid solution to 1 to 3, the aqueous layer is filtered, the filter cake is washed with a water-soluble organic solvent, and dried to obtain a pure fosfluconazole product. The method has the advantages of simple operation, high yield, product purity, and the like, the total yield is over 80%, the purity of the pure fosfluconazole product is more than 99.95% (by HPLC detection), and the single impurity peak drops from 0.5% to 0.1% or less.

Description

1. Technical field [0001] The invention relates to a method for refining known chemical drugs, in particular to a method for refining fosfluconazole, a phosphodiesterase inhibitor. 2. Background technology [0002] Fosfluconazole (Fosfluconazole, formula (I)), the chemical name is 2,4-difluoro-α,α-bis(1-hydrogen-1,2,4-triazol-1-ylmethyl)benzyl alcohol Dihydrogen phosphate, the chemical structural formula is the following formula (I): [0003] [0004] Fluconazole fos is the monophosphate prodrug of fluconazole (Fluconazole, formula (II)), which is hydrolyzed into fluconazole by alkaline phosphatase in vivo. Compared with fluconazole, fosfluconazole has good water solubility, is more suitable for injection administration, has good safety and less side effects. Fos fluconazole injection was developed by Pfizer and launched in Japan in 2003 under the trade name Prodif, which is used to treat deep fungal infections of the respiratory tract, esophagus, and urinary tract. ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F9/6518
Inventor 吴标凌林
Owner HEFEI JIUNUO MEDICAL TECH