(8S,9R,11R)-2-tert-butyldimethylsilyl-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo[a,g]cycloocta[cde]trinden-1-one | 222992-61-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (8S,9R,11R)-2-tert-butyldimethylsilyl-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo[a,g]cycloocta[cde]trinden-1-one
• CAS: 222992-61-2
• 化学式: C₃₃H₃₅N₃O₅Si
• 分子量: 581.744
• InChiKey: SHAGVOKZTJUHNQ-CLJJQJHESA-N

物化性质

• 沸点：
  641.5±55.0 °C(Predicted)
• 密度：
  1.38±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.37
• 重原子数：
  42.0
• 可旋转键数：
  2.0
• 环数：
  8.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  85.93
• 氢给体数：
  1.0
• 氢受体数：
  7.0

反应信息

• 作为反应物：
  描述：

  (8S,9R,11R)-2-tert-butyldimethylsilyl-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo[a,g]cycloocta[cde]trinden-1-one 在 锂硼氢 、 sodium hydride 作用下， 以 四氢呋喃 为溶剂， 生成
  参考文献：
  名称：

  Synthesis, Modeling, and In Vitro Activity of (3‘S)-epi-K-252a Analogues. Elucidating the Stereochemical Requirements of the 3‘-Sugar Alcohol on trkA Tyrosine Kinase Activity

  摘要：

  Utilizing our recently published semisynthetic approach to the (3'S)-K-252a diastereomer, we report the first synthesis of the (3'R)-10 diastereomer and a set of related epimers, with the goal of defining the stereochemical role of the 3'-sugar hydroxyl group on trkA tyrosine kinase activity and selectivity. (3'R)-10 displayed potent trkA inhibitory activity with an IC50 value of 4 nM. The corresponding deshydroxy epimer (3'S)-14 was 7-fold more potent than its 3'R counterpart (natural stereochemistry) with a trkA IC50 value of 3 nM and demonstrated > 280-fold selectivity over PKC (IC50 = 850 nM). In cells, (3'S)-14 displayed potent inhibition of trkA autophosphorylation with an IC50 < 10 nM. Molecular modeling studies revealed that the X-OH, due to the inverted geometry, forms significant H-bonding interactions with Glu27 and Arg195, an interaction that is not attainable with the natural isomers.

  DOI：

  10.1021/jm040178m
• 作为产物：
  描述：

  来他替尼 以90的产率得到(8S,9R,11R)-2-tert-butyldimethylsilyl-9-hydroxy-9-methoxycarbonyl-8-methyl-2,3,9,10-tetrahydro-8,11-epoxy-1H,8H,11H-2,7b,11a-triazadibenzo[a,g]cycloocta[cde]trinden-1-one
  参考文献：
  名称：

  Org. Process Res. Dev. 1999, 3, 131-134

  摘要：

  DOI：

文献信息

• Synthetic Process Development of Antitumor Agent KT6587, an Indolocarbazole Alkaloid K252a Derivative
  作者：Masahiko Kinugawa、Yukiteru Mimura、Yoshiaki Masuda、Chikara Murakata、Takehiro Ogasa、Masaji Kasai

  DOI：10.1021/op980087x

  日期：1999.3.1

  A facile and large-scale preparation process of an antitumor. agent KT6587 (2), derived from an indolocarbazole alkaloid K252a (1), has been developed, The new synthetic process requires four steps: (i) selective N-silylation of the amide group of 1 with tert-butyldimethylsilyl chloride, (ii) methylation of the hydroxy group, (iii) deprotection under aqueous acidic conditions to afford 3, and (iv) reduction of the methoxycarbonyl group to obtain 2, The key strategic improvement is to obtain fine quality of the intermediate 3 in a reasonable yield with reproducibility. This new process improves the overall yield from 33% to 70% without tedious chromatographic separations and hazardous conditions, Multikilogram quantities of KT6587 (2) for early clinical evaluation have been obtained by this method.