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Method for preparing a-fluoro-propionyl acetate

A technology of fluoropropionyl acetate and chloropropionyl acetate, which is applied in the field of synthesis of voriconazole intermediate a-fluoropropionyl acetate, which can solve unfavorable industrial production, high equipment requirements, and safety Low-level problems, to achieve the effect of safe production process, simple operation and high yield

Active Publication Date: 2015-06-03
广东方盛健盟药业有限公司
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0011] The purpose of the present invention is to provide a method for preparing α-fluoropropionoacetate, so as to solve the problem of low safety, high equipment requirements and unfavorable industrial production in the method for synthesizing α-fluoropropionoacetate in the prior art. technical problem

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  • Method for preparing a-fluoro-propionyl acetate
  • Method for preparing a-fluoro-propionyl acetate
  • Method for preparing a-fluoro-propionyl acetate

Examples

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Embodiment 1

[0025] In a 2L reaction flask, add 78.0g (0.599mol) of methyl propionoacetate and 500ml of dichloromethane, stir and dissolve at room temperature, slowly add 93.5g (0.693mol) of sulfonyl chloride dropwise, and stir at room temperature for 2 -3h, after the reaction, lower the temperature to 0-5°C, add 200ml of water and stir for 20min, extract the aqueous phase with 100ml of dichloromethane once, combine the organic phase, and use 10% sodium carbonate solution (200ml) and saturated saline for the organic phase in turn (200ml) was washed, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain 96g of methyl α-chloropropionoacetate with a yield of 98%.

[0026] In a 1L reaction flask, add 90.0g (0.547mol) of methyl α-chloropropionoacetate, 300ml of DMF, 35.0g (0.602mol) of potassium fluoride, 2.25g of polyethylene glycol 600, stir under nitrogen protection, and heat Raise the temperature to 130°C, react for 10 hours, after the reaction is completed,...

Embodiment 2

[0028] In a 2L reaction flask, add 78.0g of ethyl propionoacetate and 500ml of n-hexane, stir and dissolve at room temperature, slowly add 93.5g of sulfonyl chloride dropwise, and stir at room temperature for 2-3h after the dropwise completion. After the reaction, cool down to 0-5°C, add 200ml of water and stir for 20min, extract the aqueous phase with 100ml of dichloromethane once, combine the organic phase with 200ml of 10% sodium carbonate solution, wash with 200ml of saturated saline, dry the organic phase with anhydrous sodium sulfate, and concentrate under reduced pressure 94.1 g of ethyl α-chloropropionoacetate was obtained, with a yield of 97.0%.

[0029] In a 1L reaction flask, add 90.0g (0.541mol) ethyl α-chloropropionoacetate, 350ml N,N-dimethylacetamide, 34.66g (0.595mol) potassium fluoride, 4.5g polyethylene glycol 600, stirred under the protection of nitrogen, heated to 130°C, reacted for 10h, after the reaction was completed, cooled to room temperature, filtered...

Embodiment 3

[0031] In a 1L reaction flask, sequentially add 90.0g (0.547mol) methyl α-chloropropionoacetate, 300mL DMF, 34.96g (0.602mol) potassium fluoride, 2.25g polyethylene glycol 800, stir under nitrogen protection, and heat Raise the temperature to 130°C and react for 10 hours. After the reaction is completed, cool to room temperature and filter. The filtrate is concentrated under reduced pressure. The residue is added to 200ml of water and stirred for 15min. (200mlx2), the organic phase was dried with anhydrous sodium sulfate, filtered, concentrated under reduced pressure to remove the solvent, and the residue was rectified under reduced pressure to obtain 73.17g methyl a-fluoropropionoacetate, light yellow liquid, 85-90°C / 10mmHg, yield 90.3%.

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Abstract

The invention relates to a method for preparing a-fluoro-propionyl acetate. The method comprises the following steps: 1) reacting propionyl acetate with sulfuryl chloride to generate a-chloro-propionyl acetate; 2) at the presence of polyethylene glycol and a polar aprotic solvent, substituting chlorinum in a-chloro-propionyl acetate with a fluorinating agent to obtain a-fluoro-propionyl acetate. Potassium fluoride or sodium fluoride is optimally used as the fluorinating agent, and polyethylene glycol 400, polyethylene glycol 600, polyethylene glycol 800 and polyethylene glycol 1000 can be used as the polyethylene glycol, wherein the polyethylene glycol is optimally the polyethylene glycol 800. The method has the advantages that the production process is safe, reaction conditions are mild, and meanwhile, the product yield is increased.

Description

technical field [0001] The present invention relates to a method for synthesizing voriconazole intermediate a-fluoropropionyl acetate. Background technique [0002] Voriconazole is a derivative of fluconazole and a new type of second-generation triazole antifungal drug. It is currently one of the most effective drugs for the treatment of severe fungal infections such as Aspergillus. The drug has high curative effect and small side effects , good tolerance, and has the advantages of drug resistance. [0003] The synthesis of voriconazole (compound I) requires the key intermediate 6-ethyl-5-fluoro-4-hydroxypyrimidine (compound II), and the synthesis of the latter requires the use of a-fluoropropanoyl acetate (compound III). [0004] [0005] Chinese patent application CN200310108345 discloses a preparation method of α-fluoropropionyl acetate: taking 2,3,3,3-tetrafluoropropionate methyl ester as raw material, through multi-step reactions such as alcoholysis, saponification,...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07C67/307C07C69/716
CPCC07C67/307C07C69/716
Inventor 张庆华徐广宇陈波
Owner 广东方盛健盟药业有限公司
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