Method for synthesizing 6-ethyl-5-fluoro-4-hydroxy pyrimidine and intermediate thereof

A technology of hydroxypyrimidine and intermediate, applied in the field of chemical synthesis, can solve the problems of many three wastes, high cost, complicated process and the like

Inactive Publication Date: 2011-05-18
NANTONG FINC PHARMA CHEM
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

This method has lengthy steps, complex process, many wastes and high cost

Method used

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  • Method for synthesizing 6-ethyl-5-fluoro-4-hydroxy pyrimidine and intermediate thereof
  • Method for synthesizing 6-ethyl-5-fluoro-4-hydroxy pyrimidine and intermediate thereof
  • Method for synthesizing 6-ethyl-5-fluoro-4-hydroxy pyrimidine and intermediate thereof

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Experimental program
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Embodiment 1

[0009] Preparation of embodiment 1.2-fluoro-3-oxopentanoic acid ethyl ester

[0010] N 2 Add 1.2 L of isopropyl ether to a 2 L three-necked flask under protection, add about 44 g of sodium hydrogen, and stir evenly at room temperature. 106 g of ethyl fluoroacetate was slowly added dropwise into the reaction bottle, and the dropwise addition was completed within 3 hours. After the reaction system was cooled to 0°C, 95 g of propionyl chloride was slowly added dropwise, and the addition was completed in 3 hours. The temperature was controlled at 0-5°C, and the reaction was completed after stirring at this temperature for about 12 hours. 0.5 L of ice water was added under thorough stirring, the reaction system was adjusted to neutral with 5% NaOH solution, and the mixture was allowed to stand to separate layers. The aqueous phase was extracted three times with 500 ml isopropyl ether, the organic phases were combined, dried over anhydrous sodium sulfate, and the solvent was remov...

Embodiment 2

[0011] The preparation of embodiment 2.6-ethyl-5-fluoro-4-hydroxypyrimidine

[0012] N 2 Add 300ml of methanol to a 1L three-neck flask under protection, and after cooling down to 0°C, put 35g of sodium methoxide into the reaction flask, stir evenly, and keep the temperature in the bottle at 0-5°C. Add 33.4 grams of methyl ether to the bottle, stir at 0-5°C for about 1 hour, then slowly add 52 grams of ethyl 2-fluoro-3-oxopentanoate (dissolved in 20ml of methanol) dropwise into the bottle , The addition is completed within 1 hour, and the temperature in the bottle is maintained at 0-5°C. Remove the ice bath, slowly rise to room temperature, continue to stir and react for 24 hours, then add 15.4 g of glacial acetic acid to the bottle, adjust the pH to 6-6.5, and stir evenly. The solvent methanol was distilled off under reduced pressure to obtain an off-white solid mixture, which was fully extracted 5 times with dichloromethane (100ml×5), the organic phases were combined, the ...

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Abstract

The invention relates to a new concise and efficient method for synthesizing 6-ethyl-5-fluoro-4-hydroxy pyrimidine and an intermediate 2-fluoro-3-oxo ethyl valerate thereof. 6-ethyl-5-fluoro-4-hydroxy pyrimidine is an important intermediate for synthesizing a broad-spectrum antifungal drug voriconazole. At present, the methods for synthesizing 6-ethyl-5-fluoro-4-hydroxy pyrimidine have the defects of more reaction steps, complex processes, more three wastes and high cost and are not favourable for industrial production. To solve the above problems, the method provided by the invention comprises the following reaction steps (see the drawing 1): using ethyl fluoroacetate and propionyl chloride as raw materials under the reaction temperature to synthesize 2-fluoro-3-oxo ethyl valerate under appropriate alkali action; and using 2-fluoro-3-oxo ethyl valerate and formamidine acetate as raw materials under the reaction temperature to synthesize 6-ethyl-5-fluoro-4-hydroxy pyrimidine under appropriate reaction system. The method provided by the invention is safe, environment-friendly, concise and efficient.

Description

technical field [0001] The invention relates to a synthesis method of 6-ethyl-5-fluoro-4-hydroxypyrimidine and an intermediate thereof, belonging to the technical field of chemical synthesis. Background technique [0002] In the past decade, fungal infections, especially deep fungal infections, have increasingly become one of the important reasons that threaten human health. At present, antifungal drugs are developing rapidly. Voriconazole (chemical name: (2R,3S)-3-(5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-(1H-[1,2,4]-triazole -1-yl)butan-2-ol) is a new type of broad-spectrum triazole antifungal drug developed by Pfizer in the United States. Cladomycetes and Fusarium have good antibacterial activity. [0003] 6-Ethyl-5-fluoro-4-hydroxypyrimidine is a key intermediate in the synthesis of voriconazole, and most of the synthetic routes of voriconazole currently go through this intermediate. The world patent WO9706160 provides 5-fluorouracil as the starting material, 6...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D239/36C07C69/716C07C67/343
Inventor 张程亮袁华
Owner NANTONG FINC PHARMA CHEM
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