3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride
• 英文别名: (2S,3S)-3-(6-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl)butan-2-ol;hydrochloride
• 化学式: C₁₆H₁₃ClF₃N₅O*ClH
• 分子量: 420.221
• InChiKey: ISUMRMYBGZGUMY-SCKAJQSLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.25
• 重原子数：
  27
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  76.7
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride 、 camphor-10-sulfonic acid 在 钯 ammonium formate 作用下， 以 甲醇 、 二氯甲烷 、 水 、 异丙醇 为溶剂， 生成 (2R,3S/2S,3R)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol R-(-)-10-camphorsulphonate
  参考文献：
  名称：

  Preparation of triazoles by organometallic addition to ketones and intermediates therefor

  摘要：

  该方法用于制备以下化合物：或其酸加合物或碱盐，其中R是苯基，可以选择地被1至3个取代基取代，每个取代基独立地选自卤素和三氟甲基；R1是C1-C6烷基；“Het”是嘧啶基，可以选择地被1至3个取代基取代，每个取代基独立地选自C1-C4烷基、C1-C4烷氧基、卤素、氧代基、苄基和苄氧基，包括将以下化合物与以下化合物反应：其中X是氯、溴或碘，在锌的存在下进行反应；至少使用碘或路易斯酸；和无水有机溶剂：可选择进一步将所得化合物与酸或碱反应，形成相应的酸加合物或碱盐。

  公开号：

  US06586594B1
• 作为产物：
  描述：

  6-乙基-5-氟嘧啶-4(3H)-酮 在 lead 、 N-溴代丁二酰亚胺(NBS) 、 偶氮二异丁腈 、 三乙胺 、 锌 、 三氯氧磷 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 21.0h， 生成 3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride 、 3-(6-chloro-5-fluoro-4-pyrimidinyl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol hydrochloride
  参考文献：
  名称：

  Process Development of Voriconazole:  A Novel Broad-Spectrum Triazole Antifungal Agent

  摘要：

  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.

  DOI：

  10.1021/op0000879

文献信息

• [EN] PREPARATION OF TRIAZOLES BY ORGANOMETALLIC ADDITION TO KETONES AND INTERMEDIATES THEREFOR<br/>[FR] PREPARATION DE TRIAZOLES PAR ADDITION DE REACTIFS ORGANOMETALLIQUES A DES CETONES ET INTERMEDIAIRES PREVUS A CET EFFET
  申请人：PFIZER RESEARCH AND DEVELOPMENT COMPANY, N.V./S.A.

  公开号：WO1997006160A1

  公开（公告）日：1997-02-20

  (EN) The invention provides a process for the preparation of a compound of formula (I), or an acid addition or base salt thereof, wherein R is phenyl optionally substituted by 1 to 3 substituents each independently selected from halo and trifluoromethyl; R1 is C1-C6 alkyl; and 'Het' is pyrimidinyl optionally substituted by 1 to 3 substituents each independently selected from C1-C4 alkyl, C1-C4 alkoxy, halo, oxo, benzyl and benzyloxy, comprising reaction of a compound of formula (II), wherein R is as previously defined for a compound of formula (I), with a compound of formula (III), wherein R1 and 'Het' are as previously defined for a compound of the formula (I) and X is chloro, bromo or iodo, in the presence of zinc, iodine and/or a Lewis acid and an aprotic organic solvent: said process being optionally followed by conversion of the compound of the formula (I) to an acid addition or base salt thereof.(FR) L'invention porte sur un procédé de préparation d'un composé de formule (I), ou d'un sel d'addition d'acide ou de base de celui-ci, où R représente phényle éventuellement substitué par 1 à 3 substituants choisis indépendamment parmi halo et trifluorométhyle; R1 représente alkyle C1-C6; et 'Het' représente pyrimidinyle éventuellement substitué par 1 à 3 substituants choisis indépendamment parmi alkyle C1-C4, alcoxy C1-C4, halo, oxo, benzyle et benzyloxy. Le procédé comprend également la mise en réaction d'un composé de formule (II), où R est comme défini ci-dessus pour un composé de formule (I), avec un composé de formule (III), où R1 et 'Het' sont comme défini ci-dessus pour un composé de formule (I), et X représente chloro, bromo ou iodo, en présence de zinc, d'iode et/ou d'un acide de Lewis et un solvant organique aprotique. Ledit procédé est éventuellement suivi par la conversion du composé de formule (I) en sel d'addition d'acide ou sel de base de celui-ci.

  本发明提供了一种制备公式（I）化合物或其酸加成物或碱盐的过程，其中R是苯基，可选地被1至3个取代基独立地选择自卤素和三氟甲基取代; R1是C1-C6烷基; 'Het'是嘧啶基，可选地被1至3个取代基独立地选择自C1-C4烷基，C1-C4烷氧基，卤素，氧代和苄基和苄氧基，包括将公式（II）化合物与公式（III）化合物反应，其中R如上所述为公式（I）化合物的定义，R1和'Het'如上所述为公式（I）的定义，X是氯，溴或碘，在锌，碘和/或路易斯酸和无水有机溶剂的存在下：该过程可以随后将公式（I）化合物转化为其酸加成物或碱盐。
• PREPARATION OF TRIAZOLES BY ORGANOMETALLIC ADDITION TO KETONES AND INTERMEDIATES THEREFOR
  申请人：Pfizer Research and Development Company, N.V./S.A.

  公开号：EP0871625A1

  公开（公告）日：1998-10-21
• Process Development of Voriconazole:  A Novel Broad-Spectrum Triazole Antifungal Agent
  作者：Mike Butters、Julie Ebbs、Stuart P. Green、Julie MacRae、Matthew C. Morland、Charles W. Murtiashaw、Alan J. Pettman

  DOI：10.1021/op0000879

  日期：2001.1.1

  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.
• Preparation of triazoles by organometallic addition to ketones and intermediates therefor
  申请人：Pfizer, Inc.

  公开号：US06586594B1

  公开（公告）日：2003-07-01

  A process for the preparation of a compound of the formula: or an acid addition or base salt thereof, wherein R is phenyl optionally substituted by 1 to 3 substituents each independently selected from halo and trifluoromethyl; R1 is C1-C6 alkyl; and “Het” is pyrimidinyl optionally substituted by 1 to 3 substituents each independently selected from C1-C4 alkyl, C1-C4 alkoxy, halo, oxo, benzyl and benzyloxy, comprising reacting a compound of the formula: with a compound of the formula wherein X is chloro, bromo or iodo, the reaction taking place in the presence of zinc; at least one of iodine or a Lewis acid; and an aprotic organic solvent: optionally further reacting the resulting compound with an acid or base to form the corresponding acid addition or base salt thereof.

  该方法用于制备以下化合物：或其酸加合物或碱盐，其中R是苯基，可以选择地被1至3个取代基取代，每个取代基独立地选自卤素和三氟甲基；R1是C1-C6烷基；“Het”是嘧啶基，可以选择地被1至3个取代基取代，每个取代基独立地选自C1-C4烷基、C1-C4烷氧基、卤素、氧代基、苄基和苄氧基，包括将以下化合物与以下化合物反应：其中X是氯、溴或碘，在锌的存在下进行反应；至少使用碘或路易斯酸；和无水有机溶剂：可选择进一步将所得化合物与酸或碱反应，形成相应的酸加合物或碱盐。