rac-4-{[(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carbonyl]amino}-3-methoxybenzoic acid

• 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: rac-4-{[(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carbonyl]amino}-3-methoxybenzoic acid
• 英文别名: (±)-4-{[(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carbonyl]amino}-3-methoxybenzoic acid；rac-4-((2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-neopentyl-2-oxospiro[indoline-3,3'-pyrrolidine]-5'-carboxamido)-3-methoxybenzoic acid；rac-4-((2’S,3’R,4’S,5’R)-6-chloro-4’-(3-chloro-2-fluorophenyl)-2’-neopentyl-2-oxospiro[indoline-3,3’-pyrrolidine]-5’-carboxamido)-3-methoxybenzoic acid；4-[[(2'S,3S,3'R,5'R)-6-chloro-3'-(3-chloro-2-fluorophenyl)-5'-(2,2-dimethylpropyl)-2-oxospiro[1H-indole-3,4'-pyrrolidine]-2'-carbonyl]amino]-3-methoxybenzoic acid
• 化学式: C₃₁H₃₀Cl₂FN₃O₅
• 分子量: 614.501
• InChiKey: LLUVUTBCUVPUNF-JXFSROLISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  42
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  117
• 氢给体数：
  4
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  rac-4-{[(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carbonyl]amino}-3-methoxybenzoic acid 在 ammonium hydroxide 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， 反应 4.0h， 生成 (2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carboxylic acid (4-carbamoyl-2-methoxyphenyl)amide
  参考文献：
  名称：

  Synthesis of a Spiroindolinone Pyrrolidinecarboxamide MDM2 Antagonist

  摘要：

  A practical synthesis of a spiroindolinone pyrrolidinecarboxamide MDM2 antagonist 2 is reported. Cycloaddition of dipolarophile 3 with imine 30 afforded a complex mixture of diastereomers that were isomerized to the desired stereoisomer 31 by heating the mixture in the presence of DBU. After hydrolysis, the resulting product was resolved with a chiral amine to give an enantiopure acid which was converted to the target product 2. The process has been scaled up to a multihundred-gram scale. In addition, an asymmetric synthesis of 31 catalyzed by AgOAc and a chiral phosphine ligand was developed to give enantiomerically enriched 31, which was also converted to enantiopure 2.

  DOI：

  10.1021/op3003213
• 作为产物：
  描述：

  3,3-二甲基丁醛 在 水 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 三乙胺 、 lithium hydroxide 作用下， 以 四氢呋喃 、 甲基叔丁基醚 、 甲苯 为溶剂， 反应 11.0h， 生成 rac-4-{[(2'S,3'R,4'S,5'R)-6-chloro-4'-(3-chloro-2-fluorophenyl)-2'-(2,2-dimethylpropyl)-2-oxo-1,2-dihydrospiro[indole-3,3'-pyrrolidine]-5'-carbonyl]amino}-3-methoxybenzoic acid
  参考文献：
  名称：

  螺环吲哚酮聚乙二醇碳酸酯类化合物和其组 合物、制备方法及用途

  摘要：

  本发明涉及螺环吲哚酮聚乙二醇碳酸酯类化合物、其组合物、制备方法以及其具有抗肿瘤活性而作为抗癌药物的用途。所述螺环吲哚酮聚乙二醇碳酸酯类化合物结构式如下，其具有优异的肿瘤抑制活性，水溶解性好，毒性低，可用于静脉注射剂型。

  公开号：

  CN107698598B

文献信息

• 螺环吲哚酮聚乙二醇碳酸酯类化合物和其组 合物、制备方法及用途
  申请人：肖飞

  公开号：CN107698598B

  公开（公告）日：2019-06-21

  本发明涉及螺环吲哚酮聚乙二醇碳酸酯类化合物、其组合物、制备方法以及其具有抗肿瘤活性而作为抗癌药物的用途。所述螺环吲哚酮聚乙二醇碳酸酯类化合物结构式如下，其具有优异的肿瘤抑制活性，水溶解性好，毒性低，可用于静脉注射剂型。
• SPIROINDOLINONE PYRROLIDINES
  申请人：Bartkovitz David Joseph

  公开号：US20110130398A1

  公开（公告）日：2011-06-02

  There are provided compounds of the formula wherein X, Y and R 1 to R 8 are described herein along with the enantiomers, pharmaceutically acceptable salts and esters thereof. The compounds are useful as anticancer agents.

  提供了以下式中的化合物，其中X、Y和R1至R8如本文所述，以及其对映体、药用可接受的盐和酯。这些化合物可用作抗癌药物。
• EP3498712
  申请人：——

  公开号：——

  公开（公告）日：——
• US8088815B2
  申请人：——

  公开号：US8088815B2

  公开（公告）日：2012-01-03
• Discovery of potent and selective spiroindolinone MDM2 inhibitor, RO8994, for cancer therapy
  作者：Zhuming Zhang、Qingjie Ding、Jin-Jun Liu、Jing Zhang、Nan Jiang、Xin-Jie Chu、David Bartkovitz、Kin-Chun Luk、Cheryl Janson、Christian Tovar、Zoran M. Filipovic、Brian Higgins、Kelli Glenn、Kathryn Packman、Lyubomir T. Vassilev、Bradford Graves

  DOI：10.1016/j.bmc.2014.05.072

  日期：2014.8

  The field of small-molecule inhibitors of protein-protein interactions is rapidly advancing and the specific area of inhibitors of the p53/MDM2 interaction is a prime example. Several groups have published on this topic and multiple compounds are in various stages of clinical development. Building on the strength of the discovery of RG7112, a Nutlin imidazoline-based compound, and RG7388, a pyrrolidine-based compound, we have developed additional scaffolds that provide opportunities for future development. Here, we report the discovery and optimization of a highly potent and selective series of spiroindolinone small-molecule MDM2 inhibitors, culminating in RO8994. (C) 2014 Elsevier Ltd. All rights reserved.