New method for prepraring Voriconazole intermediate of antifungal drug

A technology for triazole derivatives and acid addition salts, which is applied in the field of preparation of triazole derivatives or their acid addition salts, and can solve the problems of inability to effectively control the optical purity of the final product and poor stereoselectivity

Inactive Publication Date: 2006-07-05
北京德众万全医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0012] The reaction conditions of this method are relatively mild, and the operation is easy to control, but the stereoselectivity of the reaction is relatively poor.
Inability to effectively control the optical purity of the final product

Method used

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  • New method for prepraring Voriconazole intermediate of antifungal drug
  • New method for prepraring Voriconazole intermediate of antifungal drug
  • New method for prepraring Voriconazole intermediate of antifungal drug

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0019] Preparation of (2R,3S / 2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2, 4-triazol-1-yl)butan-2-ol hydrochloride

[0020] Under nitrogen protection, 32 ml of tetrahydrofuran, 11 g of zinc powder and 0.24 g of lead powder were put into a 200 ml reaction bottle, stirred, and heated to reflux for 3 hours. Cool to room temperature and stir for 16 hours. A solution of 4.4 g of iodine in 13 ml of tetrahydrofuran was added dropwise. After the dropwise addition was completed, the temperature was lowered, and 7.9 grams of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone camphorsulfonate and A solution of 4.2 g of 6-(1-bromoethane)-4-chloro-5-fluoropyrimidine in 32 ml of tetrahydrofuran. After the dropwise addition, the low-temperature reaction was continued for 2 hours, the temperature of the reaction system was warmed to room temperature, 5.2 g of glacial acetic acid and 50 ml of water were added, and stirred. Filter to remove metal residue...

Embodiment 2

[0022] Preparation of (2R,3S / 2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2, 4-triazol-1-yl)butan-2-ol hydrochloride

[0023] Under nitrogen protection, 64 ml of tetrahydrofuran, 22 g of zinc powder and 0.48 g of lead powder were put into a 500 ml reaction bottle, stirred, and heated to reflux for 3 hours. Cool to room temperature and stir overnight. A solution of 9 g of iodine in 25 ml of tetrahydrofuran was added dropwise. After the dropwise addition, the temperature was lowered, and 9.2 grams of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone hydrochloride and 8.5 A solution of 6-(1-bromoethane)-4-chloro-5-fluoropyrimidine in 65 ml THF. After the dropwise addition, continue the reaction at low temperature for 2 hours, warm the temperature of the reaction system to room temperature, add 10 g of glacial acetic acid and 100 ml of water, and stir. Filter to remove metal residues. The organic solvent was removed by rotary evaporation. ...

Embodiment 3

[0025] Preparation of (2R,3S / 2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2, 4-triazol-1-yl)butan-2-ol hydrochloride

[0026] Under nitrogen protection, 48 ml of tetrahydrofuran, 16.5 g of zinc powder and 0.36 g of lead powder were put into a 500 ml reaction bottle, stirred, and heated to reflux for 3 hours. Cool to room temperature and stir overnight. A solution of 6.6 g of iodine in 20 ml of tetrahydrofuran was added dropwise. After the dropwise addition, the temperature was lowered, and 6.8 grams of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone hydrochloride and 6.3 A solution of 6-(1-bromoethane)-4-chloro-5-fluoropyrimidine in 48 ml THF. After the dropwise addition, the low-temperature reaction was continued for 2 hours, and the temperature of the reaction system was warmed to room temperature, 8 g of glacial acetic acid and 75 ml of water were added, and stirred. Filter to remove metal residues. The organic solvent was removed ...

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Abstract

The invention describes a process for preparing the triazole derivatives or acid-addition salts of formula (I). The said compounds can be used to prepare antifungal drugs such as Voriconazole.

Description

field of invention [0001] The invention relates to a preparation method of a triazole derivative or an acid addition salt thereof, and the compound can be used for preparing an antifungal drug voriconazole. Background of the invention [0002] Fungal infection is a common disease, especially due to poor living environment, poor hygiene habits, humid climate, and low quality of life are more likely to occur. [0003] At present, antifungal drugs are developing rapidly, especially in deep fungal diseases. Antifungal drugs can be divided into two categories: antibiotics and synthetic antifungal drugs. Among them, the efficacy of triazole antifungal drugs is even more promising. Voriconazole is a fluorotriazole antifungal drug that can be taken orally. It is considered to have a very broad market prospect because of its unique medicinal characteristics and good clinical application effect. [0004] In the current method for synthesizing voriconazole, most of them are prepare...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D403/06C07D239/30C07D249/08
Inventor 刘昆曲峰
Owner 北京德众万全医药科技有限公司
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