Prepn process and intermediate for voriconazole

A technology for triazoles and compounds, applied in the field of compounds and their preparation, can solve the problems of difficult separation, low enantiomeric yield, unsuitable for large-scale economical production and the like

Inactive Publication Date: 2006-08-02
JIANGSU HANSOH PHARMA CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

The two groups of enantiomers (2R, 3S / 2S, 3R) and (2R, 3R / 2S, 3S) obtained by this method are in the same ratio, and the separation is difficult, which requires column chromatography to separate, and the desired (2R, 3S / 2S, 3R) enantiomer yield is relatively low, only 12%, not suitable for large-scale economical production

Method used

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  • Prepn process and intermediate for voriconazole
  • Prepn process and intermediate for voriconazole
  • Prepn process and intermediate for voriconazole

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0049] 1. Synthesis of 1-(2,4-difluorophenyl)-2-(3,5-dibromo-1H-[1,2,4]triazol-1-yl)ethanone

[0050]In a 500ml three-necked flask, add 2'-chloro-2,4-difluoroacetophenone (27.3g, 0.14mol), 3,5-dibromo-1H-[1,2,4]triazole ( 34.0g, 0.15mol), potassium carbonate (27.6g, 0.2mol), tetrabutylammonium bromide (2.0g) and dichloromethane (300ml), stirred at reflux for 8h. Cool, filter, filter cake with CH 2 Cl 2 Wash, combine the organic layers, wash with water, dry, concentrate to dryness, and recrystallize with petroleum ether / ethyl acetate (1 / 1, 200ml) to obtain 35.0g of light yellow solid with a yield of 65.6%.

[0051] 2. (2R, 3S / 2S, 3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(3,5-di Synthesis of bromo-1H-[1,2,4]-triazol-1-yl)butan-2-ol

[0052] Under nitrogen, 2.5M hexane solution of n-butyl lithium (80ml, 0.2mol) was added in the three-necked flask, and a tetrahydrofuran (100ml) solution of diisopropylamine (20.0g, 0.2mol) was added dropwise under an ice...

Embodiment 2

[0058] 1. (2R, 3S / 2S, 3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(3,5-di Preparation of bromo-1H-[1,2,4]-triazol-1-yl)butan-2-ol

[0059] Under nitrogen, 2.5M hexane solution of n-butyl lithium (80ml, 0.2mol) was added in the three-necked flask, and a tetrahydrofuran (100ml) solution of diisopropylamine (20.0g, 0.2mol) was added dropwise under an ice-water bath, Stir for 30 min, cool to -78°C, add dropwise 4-chloro-5-fluoro-6-ethylpyrimidine (32.1 g, 0.2 mol) in tetrahydrofuran (300 ml), and stir at this temperature for 3 h. Add 1-(2,4-difluorophenyl)-2-(3,5-dibromo-1H-[1,2,4]triazol-1-yl)ethanone (76.2 g, 0.2 mol) THF (500ml) solution, stirred at -78°C for 2h, slowly warmed to -20°C, continued to stir for 2h, cooled to -50°C, added a solution of glacial acetic acid (12.0g) in water (100ml) to stop the reaction, and heated to At room temperature, separate the organic layer, extract the aqueous layer with ethyl acetate (50ml×2), combine the organic layer...

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Abstract

The present invention relates to 3-(4-chloro-5-fluoropyrimidyl-6-yl)-2-(2ú¼4-diflurophenyl)-1-(3ú¼5-dibromo-1H-[1ú¼2ú¼4]-triazolyl-1-yl)butyl-2-alcohol, as the intermediate for voriconazole, ad its preparation process and the voriconazole preparing process therewith.

Description

technical field [0001] The present invention relates to a compound (I) and a preparation method thereof, and a method for preparing voriconazole using the compound as an intermediate. Background technique [0002] In the past decade, the incidence of invasive fungal infections has continued to rise and has become one of the leading causes of infectious disease-related deaths worldwide. The existing antifungal drugs are not only limited in number, but also have problems such as narrow antifungal activity spectrum, poor pharmacokinetic properties, safety and drug interactions, which lead to the increasing attention of people to the treatment of fungal infections. Voriconazole (chemical name: (2R,3S)-3-(5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-[1,2,4]- Triazol-1-yl)butan-2-ol) is a new type of broad-spectrum triazole antifungal drug developed by Pfizer, which is effective against acute invasive Aspergillus and fluconazole-resistant severe invasive Candida Bacteria...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06C07D239/00C07D249/10
Inventor 岑均达
Owner JIANGSU HANSOH PHARMA CO LTD
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