Process development of voriconazole: A novel broad-spectrum triazole antifungal agent
Process development of voriconazole: A novel broad-spectrum triazole antifungal agent
复制标题
DOI：
10.1021/op0000879
复制
发表时间：
2001-01-01
影响因子：
3.4
通讯作者：
Pettman, AJ
中科院分区：
文献类型：
--
作者：
Butters, M;Ebbs, J;Pettman, AJ
在(2R，3S)-2-(2，4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1，2，4-triazol-1-yl)-2-butanol(伏立康唑)的合成中，相对立体化学是在1-(2，4-二氟苯基)-2-(1H-1，2，4-三唑-1-基)-1-乙酮的基础上加成4-(1-金属乙基)-5-氟嘧啶衍生物，通过改变嘧啶取代方式和改变金属化及反应条件来考察该反应的非对映控制。优良的非对映选择性(12：II是使用6-(1-bromoethyl)-4-chloro-5-fluoropyriminidine.的有机锌衍生物获得的提升器去除嘧啶环上的氯？伏立康唑的绝对立体化学是通过使用(1R)-10樟脑磺酸的非对映异构体盐拆分过程建立的。也对通往嘧啶伙伴的合成路线进行了评估。由5-氟尿嘧啶开始的六步合成路线已经被包括3-氧戊酸甲酯氟化和乙酸甲双胺环化的四步合成路线所取代。
In the synthesis of (2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoro-4-pyrimidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (voriconazole), the relative stereochemistry is set in the addition of a 4-(1-metalloethyl)-5-fluoropyrimidine derivative to 1-(2,4-difluorophenyl)-2-(1H-1 ,2,4-triazol-1-yl)-1-ethanone, The diastereo-control of this reaction has been examined by variation of pyrimidine substitution pattern and by changes in the metalation and reaction conditions. Excellent diastereoselection (12: ii is obtained using an organozinc derivative of 6-(1-bromoethyl)-4-chloro-5-fluoropyriminidine. lifter removal cf the chlorine from the pyrimidine ring? the absolute stereochemistry of voriconazole is established via a diastereomeric salt resolution process using (1R)-10 camphorsulfonic acid. Synthetic routes to the pyrimidine partner have also been evaluated. The initial six-step development route from 5-fluorouracil has been superseded by a four-step synthesis involving fluorination of methyl 3-oxopentanoate and cyclisation with formamidine acetate.