(2R,3R)-3-(4-(4-cyanophenyl)-thiazol-2-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-((di-tert-butylphosphonpxy)-methoxy)-butane | 351227-63-9

• 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: (2R,3R)-3-(4-(4-cyanophenyl)-thiazol-2-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-((di-tert-butylphosphonpxy)-methoxy)-butane
• 英文别名: di-tert-butyl-[{(1R,2R)-2-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-1-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-ylmethyl)propyl}-oxy]methyl phosphate；ditert-butyl [(2R,3R)-3-[4-(4-cyanophenyl)-1,3-thiazol-2-yl]-2-(2,4-difluorophenyl)-1-(1,2,4-triazol-1-yl)butan-2-yl]oxymethyl phosphate
• CAS: 351227-63-9
• 化学式: C₃₁H₃₆F₂N₅O₅PS
• 分子量: 659.694
• InChiKey: XYIRIEAMRPBUKG-JCOAXYOVSA-N

物化性质

• 沸点：
  745.9±70.0 °C(Predicted)
• 密度：
  1.28±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.4
• 重原子数：
  45
• 可旋转键数：
  14
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  150
• 氢给体数：
  0
• 氢受体数：
  12

反应信息

• 作为反应物：
  描述：

  (2R,3R)-3-(4-(4-cyanophenyl)-thiazol-2-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-((di-tert-butylphosphonpxy)-methoxy)-butane 在 叔丁胺 作用下， 以 乙酸乙酯 为溶剂， 反应 1.0h， 生成 (2R,3R)-3-(4-(4-cyanophenyl)-thiazol-2-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-((dihydrogenphosphonoxy)methoxy)butane, tert-butylamine salt
  参考文献：
  名称：

  WO2006/118351

  摘要：

  公开号：
• 作为产物：
  描述：

  磷酸二叔丁基酯四正丁基铵盐 在 碘 、 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 生成 (2R,3R)-3-(4-(4-cyanophenyl)-thiazol-2-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-((di-tert-butylphosphonpxy)-methoxy)-butane
  参考文献：
  名称：

  Phosphonooxymethyl prodrugs of the broad spectrum antifungal azole, ravuconazole: Synthesis and biological properties

  摘要：

  Synthesis of phosphonooxymethyl derivatives of ravuconazole, 2 (BMS-379224) and 3 (BMS-315801) and their biological evaluation as potential water-soluble prodrugs of ravuconazole are described. The phosphonooxymethyl ether analogue 2 (BMS-379224) and N-phosphonooxymethyl triazolium salt 3 (BMS-315801) were both prepared from ravuconazole (1) and bis-tert-butyl chloromethyl phosphate, but under two different conditions. Both derivatives were highly soluble in water and converted to the parent in alkaline phosphatase, and also in vivo (rat). However, BMS-315801 was found to be less stable than BMS-379224 in water at neutral pH. BMS-379224 (2) has proved to be one of the most promising prodrugs of ravuconazole that we tested, and it is currently in clinical evaluation as an intravenous formulation of the broad spectrum antifungal azole, ravuconazole. (C) 2003 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2003.08.029

文献信息

• COMPOSITION CONTAINING STABILITY-IMPROVED CHLOROMETHYL PHOSPHATE DERIVATIVE AND PROCESS FOR PRODUCING SAME
  申请人：Sato Keizo

  公开号：US20100094001A1

  公开（公告）日：2010-04-15

  The present invention provides a process or the like which is employed for producing chloromethyl phosphate derivatives that are useful for producing water-soluble prodrugs, and which are excellent from the points of view of workability, operativity and energy saving. According to the present invention, there is provided a process for producing a composition containing a compound represented by the following formula (I) and a tertiary amine, (wherein R1 and R2 are identical or different from each other, and represent a C1-C6 alkyl group, a C2-C6 alkenyl group or a C6-C14 aryl C1-C6 alkyl group which may have a substituent, and R1 and R2 may together form a ring), the process comprising the step of adding the tertiary amine having a boiling point at 1 atmosphere of 150° C. or higher to the compound represented by formula (I).

  本发明提供了一种用于制备氯甲基磷酸酯衍生物的工艺或类似工艺，该工艺用于制备水溶性前药，从操作性、可操作性和节能性等角度来看都非常优秀。根据本发明，提供了一种制备含有化合物(I)和三级胺的组合物的工艺，其中化合物(I)的结构式如下：（其中R1和R2相同或不同，分别代表C1-C6烷基，C2-C6烯基或C6-C14芳基C1-C6烷基，其上可能带有取代基，且R1和R2可以形成环），该工艺包括将具有1大气压下沸点高于150℃的三级胺加入化合物(I)的步骤。
• STABILIZED PHARMACEUTICAL COMPOSITION
  申请人：Eisai R&D Management Co., Ltd.

  公开号：EP1987830B1

  公开（公告）日：2010-09-29
• PROCESS FOR PRODUCTION OF WATER-SOLUBLE AZOLE PRODRUG
  申请人：Eisai R&D Management Co., Ltd.

  公开号：EP1964843B1

  公开（公告）日：2013-08-28
• IMPROVED PROCESS FOR THE PREPARATION OF WATER-SOLUBLE O-PHOSPHONOOXYMETHYL PRODRUGS
  申请人：Eisai Co., Ltd.

  公开号：EP1345915B1

  公开（公告）日：2007-01-31
• Composition Containing Stability-Improved Chloromethyl Phosphate Derivatve and Process for Producing Same
  申请人：Negi Shigeto

  公开号：US20090114877A1

  公开（公告）日：2009-05-07

  The present invention provides a production process or the like, which is a process for producing a chloromethyl phosphate derivative useful for producing a water-soluble prodrug, and which is excellent from the points of view of workability, operativity and energy saving. According to the present invention, there is provided a process for producing a composition containing a compound represented by the following Formula (I) and a tertiary amine, (wherein R1 and R2 are identical or different from each other, and represent a C1-C6 alkyl group, a C2-C6 alkenyl group or a C6-C14 aryl C1-C6 alkyl group which may have a substituent, and R1 and R2 may together form a ring), the process comprising adding the tertiary amine to the compound represented by Formula (I).