4-(1-bromoethyl)-2-chloro-5-fluoropyrimidine | 188416-46-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二嗪类
• 英文名称: 4-(1-bromoethyl)-2-chloro-5-fluoropyrimidine
• 英文别名: 6-(1-bromoethyl)-2-chloro-5-fluoropyrimidine
• CAS: 188416-46-8
• 化学式: C₆H₅BrClFN₂
• 分子量: 239.475
• InChiKey: HNRVNZSHWCXVSQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  11
• 可旋转键数：
  1
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  25.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-(1-bromoethyl)-2-chloro-5-fluoropyrimidine 、 2'4'-二氟-2-[1-(1H-1,2,4-三唑基)]苯乙酮 在 lead 、 锌 作用下， 以 四氢呋喃 为溶剂， 以6%的产率得到(2R,3S)-3-(2-chloro-5-fluoropyrimidin-4-yl)-2-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl)butan-2-ol
  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 The initial six-step development route from 5-fluorouracil has been superseded by a four-step synthesis involving fluorination of methyl 3-oxopentanoate and cyclisation with formamidine acetate.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
• 作为产物：
  描述：

  2-(2-氯-5-氟嘧啶-4-基)-2-甲基丙二酸二乙酯 在 盐酸 、 N-溴代丁二酰亚胺(NBS) 、 偶氮二异丁腈 、 溶剂黄146 作用下， 以 三氯乙烷 、 水 为溶剂， 反应 46.0h， 生成 4-(1-bromoethyl)-2-chloro-5-fluoropyrimidine
  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：——

  公开号：US20030181720A1

  公开（公告）日：2003-09-25

  The invention provides a process for the preparation of a compound of the formula: 1 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; R 1 is C 1 -C 6 alkyl; and “Het” is pyrimidinyl optionally substituted by 1 to 3 substituents each independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, halo, oxo, benzyl and benzyloxy, comprising reaction of a compound of the formula: 2 wherein R is as previously defined for a compound of the formula (I), with a compound of the formula: 3 wherein R 1 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.

  本发明提供了一种制备式1化合物或其酸加成物或碱盐的方法，其中R是苯基，可选地被1至3个取代基独立选择的卤素和三氟甲基取代；R1是C1-C6烷基；而“Het”是嘧啶基，可选地被1至3个取代基独立选择的C1-C4烷基，C1-C4烷氧基，卤素，氧代，苄基和苄氧基所取代。该方法包括将式2化合物与式3化合物在锌、碘和/或路易斯酸和无水有机溶剂的存在下反应，其中R1和“Het”与式1化合物中定义的相同，X为氯、溴或碘。该方法可随后将式1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：EP0871625B1

  公开（公告）日：2003-12-17
• US6586594B1
  申请人：——

  公开号：US6586594B1

  公开（公告）日：2003-07-01
• US6946555B2
  申请人：——

  公开号：US6946555B2

  公开（公告）日：2005-09-20