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Preparation method of 5-fluoro-6-ethyl-4-hydroxypyrimidine intermediate and Voriconazole

A technology of hydroxypyrimidine and ethyl, which is applied in the field of chemical drug synthesis, can solve the problems of low yield, unfavorable industrial production, and high cost, and achieve mild and easy-to-control reaction conditions, cheap and easy-to-obtain reaction reagents, convenient purification and intermediate control Effect

Active Publication Date: 2013-05-22
ZHEJIANG HISOAR PHARMA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] Therefore, the object of the present invention is to solve the problems of high cost, low yield and unfavorable industrialized production of the method for synthesizing voriconazole intermediate 5-fluoro-6-ethyl-4-hydroxypyrimidine in the prior art

Method used

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  • Preparation method of 5-fluoro-6-ethyl-4-hydroxypyrimidine intermediate and Voriconazole
  • Preparation method of 5-fluoro-6-ethyl-4-hydroxypyrimidine intermediate and Voriconazole
  • Preparation method of 5-fluoro-6-ethyl-4-hydroxypyrimidine intermediate and Voriconazole

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Embodiment 1

[0038] 137g (1.02mol) of SO 2 Cl 2 Slowly added dropwise to a chloroform solution (125ml) of 130g methyl propionoacetate, and the dropwise was completed in 3 hours. It was slightly exothermic during the dropwise addition (about 32°C, room temperature 20°C), and stirred overnight at room temperature. Then the organic layer was washed with 200 ml of water, neutralized to neutral with a saturated aqueous sodium bicarbonate solution, separated, the organic layer was dried with anhydrous magnesium sulfate, and filtered. The solvent is recovered under normal pressure. The 66°C-70°C fraction (4mmHg) was collected by distillation under reduced pressure to obtain 158g of methyl α-chloropropionoacetate, the mass percentage was 86% as measured by GC, and the yield was 83%.

Embodiment 2

[0040] Under the condition of nitrogen protection, add 132g (0.8mol) methyl α-chloropropanoylacetate successively, 160ml acetonitrile, 258g (1.6mol) Et 3 N·3HF salt, and then 80 g (0.8 mol) of triethylamine was added dropwise to the system. Raise the temperature to 90°C and reflux for 21 hours, concentrate under reduced pressure, and then add 70ml of water to dissolve the formed triethylamine salt (the triethylamine hydrochloride can also be filtered out first). Extract with dichloromethane (100ml×3), combine the organic phases, wash the organic phase with saturated sodium bicarbonate solution until neutral, wash with saturated brine, dry over anhydrous magnesium sulfate, and filter. Dichloromethane was recovered under reduced pressure, and the 54°C-58°C fraction (4mmHg) was collected by vacuum distillation to obtain 83.4g of methyl α-fluoropropionoacetate. The mass percentage was 85% as measured by GC, and the yield was 60%. .

Embodiment 3

[0042] Under the condition of nitrogen protection, 400ml of anhydrous ether and 22.44g (0.34mol) of sodium ethoxide were added to the three-necked flask, and ethyl α-fluoroacetate was slowly added dropwise at room temperature. After the dropwise addition, the reaction was carried out for 3h. Dissolve 22.44g (0.34mol) of propionyl chloride in 50ml of anhydrous diethyl ether, slowly add dropwise to the above reaction solution under ice bath, heat and reflux for 4h, pour the reaction solution into ice water, separate the liquids, dry the organic phase, and filter , remove the solvent, and distill under reduced pressure to obtain 35.1 g of ethyl α-fluoropropionoacetate as an anhydrous liquid with a yield of 65%.

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Abstract

The invention discloses a preparation method of a 5-fluoro-6-ethyl-4-hydroxypyrimidine intermediate and Voriconazole, which comprises the following steps: (1) introducing ammonia gas into alpha-fluoro-propionylmethyl acetate or alpha-fluoro-propionylethyl acetate which is selectively dissolved in a solvent, thereby obtaining a propionyl-carbonyl enaminated product; (2) cyclizing the enaminated product obtained in the step (1) with formamide under the action of alkali to obtain the 5-fluoro-6-ethyl-4-hydroxypyrimidine; and chlorinating the hydroxy group on the 5-fluoro-6-ethyl-4-hydroxypyrimidine with phosphorus oxychloride, brominating the alpha position of the ethyl group of the pyrimidine ring with NBS (N-bromosuccinimide) to obtain a brominated product, and reacting the brominated product with 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl-1-yl)acetophenone to obtain the Voriconazole racemate. The method disclosed by the invention has the advantages of cheap and accessible reaction reagents, and mild and controllable reaction conditions in the whole process, and is especially suitable for industrial production.

Description

technical field [0001] The invention relates to the field of chemical drug synthesis, more specifically, to a 5-fluoro-6-ethyl-4-hydroxypyrimidine intermediate and a preparation method of voriconazole. Background technique [0002] Voriconazole is a derivative of fluconazole, which belongs to triazole antifungal agents. It is a new type of antifungal drug with broad antibacterial spectrum and strong antibacterial efficacy. The U.S. is listed first. It is mainly used clinically for the treatment of acute or chronic deep fungal infections. [0003] Voriconazole is used as a chemotherapeutic agent in humans and animals, it is effective in the treatment of infections caused by a variety of bacteria, and it is also used in the preservation of materials. Its molecular formula is shown in formula (I), and the important intermediate 5-fluoro-6-ethyl-4-hydroxypyrimidine must be used in its synthesis is shown in formula (II). [0004] [0005] Regarding the synthesis method of t...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D239/36C07D403/06
Inventor 潘仙华欧文华张群辉何明炬
Owner ZHEJIANG HISOAR PHARMA
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