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A kind of preparation method of forsefluconazole

A technology for forsifluconazole and fluconazole, applied in the field of drug synthesis, can solve the problems of low yield, many organic wastes, environmental pollution and the like, and achieve the effects of improving purity, improving yield and reducing waste of raw materials

Active Publication Date: 2022-07-12
BEIJING FOUR RINGS BIOPHARM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the yield of present fos fluconazole is not high, and there are many organic wastes, which pollute the environment

Method used

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  • A kind of preparation method of forsefluconazole
  • A kind of preparation method of forsefluconazole
  • A kind of preparation method of forsefluconazole

Examples

Experimental program
Comparison scheme
Effect test

experiment example 1

[0069] Group 1-1

[0070] Under nitrogen protection, the temperature was controlled at -10 °C, and 76.7 g of phosphorus oxychloride was slowly added dropwise to 300 ml of 3.33 mol / L triethylamine in dichloromethane solution. After dropping, the temperature was maintained at -10 °C and stirred for 1 hour. 1L of 0.5mol / L fluconazole in dichloromethane solution was added dropwise, TLC monitoring (mobile phase ethyl acetate:petroleum ether=2:1 mixed solution) was completed; the temperature was maintained at -10°C, 650ml of water was added and stirred for 30 minutes, Sodium hydroxide was added until the pH of the aqueous phase was 10, the layers were left to stand, the upper aqueous phase was separated, and the organic phase was evaporated under reduced pressure to remove the solvent to obtain solid fluconazole dichlorophosphate.

[0071] Group 1-2

[0072] Under nitrogen protection, the temperature was controlled at -5 °C, and 161.0 g of phosphorus oxychloride was slowly added dr...

experiment example 2

[0087] Group 3-1

[0088] Under nitrogen protection, the temperature was controlled at 0 °C, and 50.6 g of phosphorus oxychloride was slowly added dropwise to 200 ml of 3.3 mol / L triethylamine in dichloromethane solution. After dropping, the temperature was maintained at 0 °C and stirred for 1 hour. 600ml of 0.5mol / L fluconazole solution in dichloromethane, monitored by TLC (mobile phase ethyl acetate:petroleum ether=2:1 mixed solution), the reaction was completed; maintain the temperature at 0°C, add 400ml of water and stir for 30 minutes, then add hydroxide Potassium to the pH of the aqueous phase is 8, stand for stratification, separate the upper aqueous phase, and evaporate the organic phase to remove the solvent under reduced pressure to obtain solid fluconazole dichlorophosphate.

[0089] Group 3-2

[0090] Under nitrogen protection, the temperature was controlled at 0 °C, and 50.6 g of phosphorus oxychloride was slowly added dropwise to 200 ml of 3.3 mol / L triethylamin...

experiment example 3

[0093] Group 4-1

[0094] Under nitrogen protection, the temperature was controlled at 0 °C, and 50.6 g of phosphorus oxychloride was slowly added dropwise to 200 ml of a 3.3 mol / L pyrimidine solution in dichloromethane. After dropping, the temperature was maintained at 0 °C and stirred for 1 hour, and 0.5 mol of / L fluconazole in dichloromethane solution 600ml, TLC monitoring (mobile phase ethyl acetate:petroleum ether=2:1 mixed solution) the reaction is complete; maintain the temperature at 0 ℃, add 400ml water and stir for 30 minutes, add sodium hydroxide to The pH of the aqueous phase is 8, and the layers are left to stand, the upper aqueous phase is separated, and the organic phase is evaporated under reduced pressure to remove the solvent to obtain solid fluconazole dichlorophosphate.

[0095] Group 4-2

[0096] Under nitrogen protection, the temperature was controlled at 0 °C, and 50.6 g of phosphorus oxychloride was slowly added dropwise to 200 ml of a dichloromethane...

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Abstract

The invention provides a preparation method of forsifluconazole, comprising the following steps: preparing fluconazole dichlorophosphate: under nitrogen protection, at a temperature of ‑10 to 0 DEG C, adding a solution of triethylamine in dichloromethane Phosphorus oxychloride was slowly added dropwise, after the dropping was completed, the temperature was maintained at -10 to 0 °C and stirred for 1 hour, the dichloromethane solution of fluconazole was slowly added dropwise, and the reaction was monitored by TLC; the temperature was maintained at -10 to 0 °C, and water was added. Stir for 30 minutes, add an inorganic base until the pH of the aqueous phase is at least 8, stand for stratification, separate the upper aqueous phase, the organic phase contains fluconazole dichlorophosphate, pass through fluconazole-fluconazole dichlorophosphate ‑Fluconazole dibenzyl phosphate ‑ Forse fluconazole ammonium salt ‑ Forse fluconazole process to prepare forse fluconazole, improve yield, controllable preparation of intermediates, raw materials can be recycled and reused, reduce raw material waste and Organic waste pollution.

Description

technical field [0001] The invention relates to the field of drug synthesis, in particular to a preparation method of forsefluconazole. Background technique [0002] Fosfluconazole (Fosfluconazole, formula (1)), chemical name 2,4-difluoro-α,α-bis(1-hydro-1,2,4-triazol-1-ylmethyl)benzyl alcohol Dihydrogen phosphate is a monophosphate prodrug of fluconazole (Fluconazole, formula (2)), which is hydrolyzed into fluconazole by alkaline phosphatase in the body, such as figure 1 shown. [0003] Fluconazole is a triazole antifungal drug used clinically to treat deep-seated infections caused by Candida, Cryptococcus and other opportunistically pathogenic yeast or fungi. Forsefluconazole is a phosphate prodrug of fluconazole, with good water solubility, which can reduce the infusion volume and reduce the burden on the circulatory system. After intravenous administration, it is hydrolyzed into fluconazole and phosphoric acid by alkaline phosphatase in vivo. Forsfluconazole maintain...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07F9/6518
CPCC07F9/6518Y02A50/30
Inventor 韩明娣薛霞
Owner BEIJING FOUR RINGS BIOPHARM
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