Novel method for producing voriconazole

A technology of voriconazole and fluoropyrimidine, applied in the field of voriconazole, can solve the problems of poor safety, unfavorable industrial production, many steps and the like

Active Publication Date: 2012-06-27
北京联本医药化学技术有限公司 +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0038] The purpose of the present invention is to provide an improved method for preparing optically pure voriconazole with high yield, so as to solve the p...

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  • Novel method for producing voriconazole
  • Novel method for producing voriconazole
  • Novel method for producing voriconazole

Examples

Experimental program
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Effect test

Embodiment 1

[0095] Example 1 (2R, 3S)-3-(5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl-1-(1H-1,2,4-triazole-1- Base)-2-Butanol R-(-)-Camphorsulfonate Preparation

[0096] In the presence of nitrogen, 37.9 grams of zinc powder and 1.89 grams of lead powder were added to 180 ml of tetrahydrofuran solution, heated to reflux for 3 hours, cooled to room temperature, and 100 ml of tetrahydrofuran solution containing 29.4 grams of iodine was added dropwise within 20 minutes, and the temperature was raised to 45°C, after the addition, cool to -5 to 0°C, dropwise add 25.9 g of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl) 110 ml of a tetrahydrofuran solution of acetone and 110 ml of a tetrahydrofuran solution containing 27.8 grams of 4-chloro-6-(1-bromoethyl)-5-fluoropyrimidine, kept the temperature below 5°C during the addition, and stirred at 0 to 10°C for 3 Hours, raised to room temperature, left overnight; kept at 25 ° C, within 30 minutes, dropwise added an acid solution consisting of 34....

Embodiment 2

[0097] Example 2 (2R, 3S)-3-(5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1 Preparation of -yl)-2-butanol R-(-)-camphorsulfonate

[0098] In the presence of nitrogen, add 37.9 grams of zinc powder and 1.89 grams of lead powder to 180 ml of tetrahydrofuran solution, heat to reflux for 3 hours, cool to room temperature, and within 20 minutes, add 100 ml of tetrahydrofuran solution containing 29.4 grams of iodine, and heat up to 45 ° C during the addition process , Cool to -5 to 0°C after addition, dropwise add 25.9 grams of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone 110ml of tetrahydrofuran solution and 110ml of tetrahydrofuran solution containing 27.7 grams of 4-chloro-6-(1-bromoethyl)-5-fluoropyrimidine, keep the temperature below 5°C during the addition process, and stir at 0 to 10°C for 3 hours, Warm to room temperature and let stand overnight. Keep at 25°C, within 30 minutes, add dropwise an acid solution consisting of 57.2 grams of co...

Embodiment 3

[0099] Example 3 (2R, 3S)-3-(-5-fluoropyrimidin-4-yl-2-(2,4-difluorophenyl-1-(1H-1,2,4-triazole-1- base)-2-butanol preparation

[0100](2R,3S)-3-(-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl-1-(1H-1,2,4-triazol-1-yl) 19.1 g of -2-butanol R-(-)-camphorsulfonate was dissolved in a solution composed of 92 ml of dichloromethane and 100 ml of water, and the pH value was adjusted to about 11 with 40% NaOH solution, and the solution was layered and separated. The aqueous phase was extracted with 25ml of dichloromethane, and the organic layers were combined, washed with water 3×100ml, concentrated under reduced pressure and evaporated to remove the solvent. Add 30ml of isopropanol, heat to 45°C, evaporate 8ml of isopropanol under reduced pressure, and cool to 0°C, stirred for 1 hour, added a little seed crystal, filtered the precipitated solid, washed the solid with 5ml of cooled isopropanol, and dried to obtain 10.5 g of white solid, yield 91.5%, melting point 126-127°C, optical p...

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Abstract

The invention provides an improved preparation method of (2R,3S)-3-(5-fluoropyrimidine-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-yl)-2-butanol(voriconazole), comprising the following steps: preparing a mixture of four enantiomers by using Reformatsky coupling reaction, then in the presence of residual zinc dust after the reaction, directly adding proper amount of acid to carry out hydrogenolysis dechlorination; splitting by directly using chiral acid to obtain chiral acid addition salts of a target compound with (2R,3S) configuration, and dissociating under alkaline conditions to obtain high-yield high-optical purity voriconazole. The method is safe, convenient and efficient, can fully utilize the residual zinc dust of the coupling reaction, and can save the steps of separating the enantiomers through hydrochloride production, alkalization, palladium-carbon catalytic hydrogenation dechlorination, thus the production process is greatly simplified, the product yield and production safety are raised, and simultaneously the production cost is greatly reduced.

Description

technical field [0001] The invention relates to an improved industrialized and low-cost production of (2R,3S)-3-(5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1 , a new method for 2,4-triazol-1-yl)-2-butanol (voriconazole) to obtain voriconazole with an optical purity greater than 99.9% and impurities less than 0.5%. Background technique [0002] Voriconazole, namely (2R,3S)-3-(5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2 , 4-triazol-1-yl)-2-butanol is a triazole antifungal drug developed by Pfizer and listed in the United States in 2002. The listed strengths include lyophilized powder for intravenous injection, film-coated tablet for oral administration and oral suspension. The mechanism of action of voriconazole is to inhibit the demethylation of 14α-sterol mediated by cytochrome P450 in fungi, thereby inhibiting the biosynthesis of ergosterol. In vitro tests have shown that voriconazole has a broad-spectrum antifungal effect, and it is used for the t...

Claims

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Application Information

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IPC IPC(8): C07D403/06
Inventor 郭荣耀吕关峰刘贵斌
Owner 北京联本医药化学技术有限公司
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