Preparation method of fosfluconazole

A technology of fosfluconazole and fluconazole, which is applied in the field of drug synthesis, can solve the problems of excessive organic waste, environmental pollution, and low yield, and achieve the effects of reducing organic impurities, improving purity, and increasing yield

Active Publication Date: 2020-05-19
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, an

Method used

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  • Preparation method of fosfluconazole
  • Preparation method of fosfluconazole
  • Preparation method of fosfluconazole

Examples

Experimental program
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Effect test

experiment example 1

[0069] Group 1-1

[0070] Under the protection of nitrogen, control the temperature at -10°C, slowly add 76.7g of phosphorus oxychloride dropwise to 300ml of 3.33mol / L triethylamine in dichloromethane solution, after the drop, maintain the temperature at -10°C and stir for 1 hour, slowly Add 1L of 0.5mol / L fluconazole dichloromethane solution dropwise, and monitor by TLC (mobile phase ethyl acetate:petroleum ether=2:1 mixed solution) the reaction is complete; maintain the temperature at -10°C, add 650ml of water and stir for 30 minutes, Sodium hydroxide was added until the pH of the aqueous phase was 10, and the layers were allowed to stand to separate. The upper aqueous phase was separated, and the organic phase was evaporated to remove the solvent under reduced pressure to obtain solid fluconazole dichlorophosphate.

[0071] Group 1-2

[0072] Under the protection of nitrogen, control the temperature at -5°C, slowly add 161.0 g of phosphorus oxychloride dropwise to 600ml of...

experiment example 2

[0087] Group 3-1

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

[0089] Group 3-2

[0090] Under nitrogen protection, control the temperature at 0°C, and slowly add 50.6g of phosphorus oxychloride dropwise to 200ml of 3.3mol / L triethylamine in dichloromethane solution. 0.5mol / L fluconazole dichloromethane solution 600ml, TLC monitoring (mobile phase ethyl acet...

experiment example 3

[0093] Group 4-1

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

[0095] Group 4-2

[0096] Under nitrogen protection, control the temperature at 0°C, slowly add 50.6 g of phosphorus oxychloride dropwise to 200 ml of a 3.3 mol / L N,N-diisopropylethylamine (DIEA) solution in dichloromethane, and maintain the temperature after the drop is comple...

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Abstract

The invention provides a preparation method of fosfluconazole. The method comprises the following steps: preparing fluconazole dichlorophosphate: under the protection of nitrogen, controlling the temperature to be-10 DEG C to 0 DEG C, slowly dropwise adding phosphorus oxychloride into a dichloromethane solution of triethylamine, maintaining the temperature to be-10 DEG C to 0 DEG C, performing stirring for 1 hour, slowly dropwise adding a dichloromethane solution of fluconazole, and monitoring the completion of the reaction by TLC; maintaining temperature between-10 DEG C and 0 DEG C, adding water and stirring for 30 minutes, adding inorganic base until the pH value of the water phase is at least 8; and performing standing stratification, separating out the fluconazole, wherein the organicphase contains the fluconazole dichlorophosphate, the fluconazole is prepared through the fluconazole-fluconazole dichlorophosphate-fluconazole dibenzyl phosphate-fosfluconazole ammonium salt-fosfluconazole process, the yield is increased, all intermediates are controllably prepared, the raw materials can be recycled, and raw material waste and organic waste pollution are reduced.

Description

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

Claims

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Application Information

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IPC IPC(8): C07F9/6518
CPCC07F9/6518Y02A50/30
Inventor 韩明娣薛霞
Owner BEIJING FOUR RINGS BIOPHARM
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