(1R,3S,5R,6R,7S,11R,14S,15S,16S,17R,18S,19S,20E,22RS,25S,28S,31S,33R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-16,17,19-tris{[tert-butyl(dimethyl)silyl]oxy}-22-hydroxy-6-methoxy-33-methyl-27,34-bis(methylene)-4,35,36,37,38-pentaoxahexacyclo[29.3.1.111,15.114,18.125,28.03,7]octatriacont-20-en-9-one | 253128-13-1

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: (1R,3S,5R,6R,7S,11R,14S,15S,16S,17R,18S,19S,20E,22RS,25S,28S,31S,33R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-16,17,19-tris{[tert-butyl(dimethyl)silyl]oxy}-22-hydroxy-6-methoxy-33-methyl-27,34-bis(methylene)-4,35,36,37,38-pentaoxahexacyclo[29.3.1.111,15.114,18.125,28.03,7]octatriacont-20-en-9-one
• 英文别名: (1R,3S,5R,6R,7S,11R,14S,15S,16S,17R,18S,19S,20E,25S,28S,31S,33R)-5-[(2S)-2,3-bis[[tert-butyl(dimethyl)silyl]oxy]propyl]-16,17,19-tris[[tert-butyl(dimethyl)silyl]oxy]-22-hydroxy-6-methoxy-33-methyl-27,34-dimethylidene-4,35,36,37,38-pentaoxahexacyclo[29.3.1.111,15.114,18.125,28.03,7]octatriacont-20-en-9-one
• CAS: 253128-13-1
• 化学式: C₇₀H₁₃₂O₁₃Si₅
• 分子量: 1322.24
• InChiKey: OPIRHZLSIAZMNY-DAIZTQJSSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  16.97
• 重原子数：
  88
• 可旋转键数：
  19
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.9
• 拓扑面积：
  139
• 氢给体数：
  1
• 氢受体数：
  13

反应信息

• 作为反应物：
  描述：

  (1R,3S,5R,6R,7S,11R,14S,15S,16S,17R,18S,19S,20E,22RS,25S,28S,31S,33R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-16,17,19-tris{[tert-butyl(dimethyl)silyl]oxy}-22-hydroxy-6-methoxy-33-methyl-27,34-bis(methylene)-4,35,36,37,38-pentaoxahexacyclo[29.3.1.111,15.114,18.125,28.03,7]octatriacont-20-en-9-one 在 四丁基氟化铵 、 咪唑盐酸盐 、 戴斯-马丁氧化剂 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 生成 (1R,3S,5R,6R,7S,11R,14S,15R,16R,17S,18S,19S,20E,25S,28S,31S,33R)-5-[(2S)-2,3-dihydroxypropyl]-16,17,19-trihydroxy-6-methoxy-33-methyl-27,34-dimethylidene-4,35,36,37,38-pentaoxahexacyclo[29.3.1.111,15.114,18.125,28.03,7]octatriacont-20-ene-9,22-dione
  参考文献：
  名称：

  Macrocyclic ketone analogues of halichondrin B

  摘要：

  Structurally simplified macrocyclic ketone analogues of halichondrin B were prepared by total synthesis and found to retain the potent cell growth inhibitory activity in vitro, stability in mouse serum, and in vivo efficacy of the natural product. (C) 2004 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2004.08.069
• 作为产物：
  描述：

  3-{(2S,5S)-5-[2-((2S,4R,6R)-6-{[(2S,3S,4R,5R)-3-[(1RS)-3-[(2R,4aS,6S,7R,8S,8aS)-7,8-bis{[tertbutyl(dimethyl)silyl]oxy}-6-((1S,2E)-1-{[tert-butyl(dimethyl)silyl]oxy}-3-iodoprop-2-en-1-yl)octahydropyrano[3,2-b]pyran-2-yl]-2-oxo-propyl]-5-((2S)-2,3-bis{[tertbutyl(dimethyl)silyl]oxy}propyl)-4-methoxytetrahydrofuran-2-yl]methyl}-4-methyl-5-methylenetetrahydro-2H-pyran-2-yl)ethyl]-4-methylenetetrahydrofuran-2-yl}propanal 在 chromium dichloride 、 三乙胺 、 nickel dichloride 、 艾日布林S-甲基配体 作用下， 以 四氢呋喃 、 乙腈 为溶剂， 生成 (1R,3S,5R,6R,7S,11R,14S,15S,16S,17R,18S,19S,20E,22RS,25S,28S,31S,33R)-5-((2S)-2,3-bis{[tert-butyl(dimethyl)silyl]oxy}propyl)-16,17,19-tris{[tert-butyl(dimethyl)silyl]oxy}-22-hydroxy-6-methoxy-33-methyl-27,34-bis(methylene)-4,35,36,37,38-pentaoxahexacyclo[29.3.1.111,15.114,18.125,28.03,7]octatriacont-20-en-9-one
  参考文献：
  名称：

  Commercial Manufacture of Halaven®: Chemoselective Transformations En Route to Structurally Complex Macrocyclic Ketones

  摘要：

  The evolution of the synthesis of Halaven (R) (E7389, INN eribulin mesylate) from a medicinal chemistry process to the execution of the final process on pilot scale is described. The completion of the synthesis of Halaven (R) from C1-C13 ester and C14-C35 sulfone alcohol involves a series of chemo-, regio-, and stereoselective transformations. Furthermore, a high-dilution macrocyclization presented a number of challenges for industrial-scale manufacture (throughput, processing time, and side reactions). This paper describes studies at Eisai leading to an understanding, optimization, and control of the chemistry that realized the reproducible commercial production of Halaven (R).

  DOI：

  10.1055/s-0032-1318026

文献信息

• [EN] MACROCYCLIZATION REACTIONS AND INTERMEDIATES USEFUL IN THE SYNTHESIS OF ANALOGS OF HALICHONDRIN B<br/>[FR] RÉACTIONS DE MACROCYCLISATION ET INTERMÉDIAIRES UTILES DANS LA SYNTHÈSE D'ANALOGUES DE L'HALICHONDRINE B
  申请人：EISAI R&D MAN CO LTD

  公开号：WO2015066729A1

  公开（公告）日：2015-05-07

  The invention provides methods for the synthesis of eribulin or a pharmaceutically acceptable salt thereof (e.g., eribulin mesylate) through a macrocyclization strategy. The macrocyclization strategy of the present invention involves subjecting a non-macrocyclic intermediate to a carbon-carbon bond-forming reaction (e.g., an olefination reaction (e.g., Horner-Wadsworth-Emmons olefination), Dieckmann reaction, catalytic Ring-Closing Olefin Metathesis, or Nozaki-Hiyama-Kishi reaction) to afford a macrocyclic intermediate. The invention also provides compounds useful as intermediates in the synthesis of eribulin or a pharmaceutically acceptable salt thereof and methods for preparing the same.

  该发明提供了一种通过大环化策略合成厄立宾或其药用可接受盐（例如，厄立宾甲磺酸盐）的方法。本发明的大环化策略涉及将非大环中间体经过碳-碳键形成反应（例如，烯化反应（例如，Horner-Wadsworth-Emmons烯化反应）、迪克曼反应、催化环闭合烯烃交换反应，或Nozaki-Hiyama-Kishi反应）以获得大环中间体。该发明还提供了在合成厄立宾或其药用可接受盐时作为中间体有用的化合物以及制备这些化合物的方法。
• Commercial Manufacture of Halaven®: Chemoselective Transformations En Route to Structurally Complex Macrocyclic Ketones
  作者：Francis Fang、Brian Austad、Trevor Calkins、Charles Chase、Thomas Horstmann、Yongbo Hu、Bryan Lewis、Xiang Niu、Thomas Noland、John Orr、Matthew Schnaderbeck、Huiming Zhang、Naoki Asakawa、Naoki Asai、Hiroyuki Chiba、Takashi Hasebe、Yorihisa Hoshino、Hiroyuki Ishizuka、Takashi Kajima、Akio Kayano、Yuki Komatsu、Manabu Kubota、Hirofumi Kuroda、Mamoru Miyazawa、Katsuya Tagami、Tomohiro Watanabe

  DOI：10.1055/s-0032-1318026

  日期：——

  The evolution of the synthesis of Halaven (R) (E7389, INN eribulin mesylate) from a medicinal chemistry process to the execution of the final process on pilot scale is described. The completion of the synthesis of Halaven (R) from C1-C13 ester and C14-C35 sulfone alcohol involves a series of chemo-, regio-, and stereoselective transformations. Furthermore, a high-dilution macrocyclization presented a number of challenges for industrial-scale manufacture (throughput, processing time, and side reactions). This paper describes studies at Eisai leading to an understanding, optimization, and control of the chemistry that realized the reproducible commercial production of Halaven (R).
• Macrocyclic ketone analogues of halichondrin B
  作者：Wanjun Zheng、Boris M. Seletsky、Monica H. Palme、Paul J. Lydon、Lori A. Singer、Charles E. Chase、Charles A. Lemelin、Yongchun Shen、Heather Davis、Lynda Tremblay、Murray J. Towle、Kathleen A. Salvato、Bruce F. Wels、Kimberley K. Aalfs、Yoshito Kishi、Bruce A. Littlefield、Melvin J. Yu

  DOI：10.1016/j.bmcl.2004.08.069

  日期：2004.11

  Structurally simplified macrocyclic ketone analogues of halichondrin B were prepared by total synthesis and found to retain the potent cell growth inhibitory activity in vitro, stability in mouse serum, and in vivo efficacy of the natural product. (C) 2004 Elsevier Ltd. All rights reserved.