4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino}-3-methoxybenzoic acid methyl ester | 1229705-05-8

• 分子结构分类: 有机化合物 - 苯丙烷和聚酮 - 二苯乙烯类
• 英文名称: 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino}-3-methoxybenzoic acid methyl ester
• 英文别名: methyl 4-((2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-neopentylpyrrolidine-2-carboxamido)-3-methoxybenzoate；Benzoic acid, 4-[[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-diMethylpropyl)-2-pyrrolidinyl]carbonyl]aMino]-3-Methoxy-, Methyl ester；methyl 4-[[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino]-3-methoxybenzoate
• CAS: 1229705-05-8
• 化学式: C₃₂H₃₁Cl₂F₂N₃O₄
• 分子量: 630.519
• InChiKey: LCHHDUKJFGKTCK-ULWUHOHFSA-N

物化性质

• 沸点：
  720.4±60.0 °C(Predicted)
• 密度：
  1.35±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.9
• 重原子数：
  43
• 可旋转键数：
  9
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.34
• 拓扑面积：
  100
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino}-3-methoxybenzoic acid methyl ester 在 水 、 sodium hydroxide 作用下， 以 四氢呋喃 、 乙醇 为溶剂， 反应 18.0h， 以118 mg的产率得到Idasanutlin（4-（（2R,3S,4R,5S）-3-（3-氯-2-氟苯基）-4-（4-氯-2-氟苯基）-4-氰基-5-新戊基吡咯烷-2-甲酰胺）-3-甲氧基苯甲酸;）
  参考文献：
  名称：

  Photoactivation of MDM2 Inhibitors: Controlling Protein–Protein Interaction with Light

  摘要：

  Selectivity remains a major challenge in anticancer therapy, which potentially can be overcome by local activation of a cytotoxic drug. Such triggered activation can be obtained through modification of a drug with a photoremovable protecting group (PPG), and subsequent irradiation in the chosen place and time. Herein, the design, synthesis and biological evaluation is described of a photoactivatable MDM2 inhibitor, PPG-idasanutlin, which exerts no functional effect on cellular outgrowth, but allows for the selective, noninvasive activation of antitumor properties upon irradiation visible light, demonstrating activation with micrometer, single cell precision. The generality of this method has been demonstrated by growth inhibition of multiple cancer cell lines showing p53 stabilization and subsequent growth inhibition effects upon irradiation. Light activation to regulate protein-protein interactions between MDM2 and p53 offers exciting opportunities to control a multitude of biological processes and has the potential to circumvent common selectivity issues in antitumor drug development.

  DOI：

  10.1021/jacs.8b04870
• 作为产物：
  描述：

  3-甲氧基-4-氨基苯甲酸甲酯 在 氨 、 copper (I) acetate 、 magnesium sulfate 、 (R)-2,2'-bis(diphenylphosphanyl)-1,1'-binaphthyl 、 三乙胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 为溶剂， 反应 5.75h， 生成 4-{[(2R,3S,4R,5S)-3-(3-chloro-2-fluorophenyl)-4-(4-chloro-2-fluorophenyl)-4-cyano-5-(2,2-dimethylpropyl)pyrrolidine-2-carbonyl]amino}-3-methoxybenzoic acid methyl ester
  参考文献：
  名称：

  Photoactivation of MDM2 Inhibitors: Controlling Protein–Protein Interaction with Light

  摘要：

  Selectivity remains a major challenge in anticancer therapy, which potentially can be overcome by local activation of a cytotoxic drug. Such triggered activation can be obtained through modification of a drug with a photoremovable protecting group (PPG), and subsequent irradiation in the chosen place and time. Herein, the design, synthesis and biological evaluation is described of a photoactivatable MDM2 inhibitor, PPG-idasanutlin, which exerts no functional effect on cellular outgrowth, but allows for the selective, noninvasive activation of antitumor properties upon irradiation visible light, demonstrating activation with micrometer, single cell precision. The generality of this method has been demonstrated by growth inhibition of multiple cancer cell lines showing p53 stabilization and subsequent growth inhibition effects upon irradiation. Light activation to regulate protein-protein interactions between MDM2 and p53 offers exciting opportunities to control a multitude of biological processes and has the potential to circumvent common selectivity issues in antitumor drug development.

  DOI：

  10.1021/jacs.8b04870

文献信息

• SUBSTITUTED HEXAHYDROPYRROLO[1,2-C]IMIDAZOLONES
  申请人：Chu Xin-Jie

  公开号：US20120065210A1

  公开（公告）日：2012-03-15

  There are provided compounds of formula I or a pharmaceutically acceptable salt thereof, wherein X, Y, R 1 , R 1′ , R 2 , R 2′ , R 3 , R 4 , R 5 are as defined herein. The compounds exhibit activity as anticancer agents.

  提供的化合物具有以下式I的结构 或其药学上可接受的盐， 其中X，Y，R 1 ，R 1′ ，R 2 ，R 2′ ，R 3 ，R 4 ，R 5 如本文所定义。这些化合物表现出抗癌剂的活性。
• N-SUBSTITUTED PYRROLIDINES
  申请人：Chu Xin-Jie

  公开号：US20120010235A1

  公开（公告）日：2012-01-12

  Compounds of formula and enantiomers and pharmaceutically acceptable salts thereof are described, as well as the pharmaceutical compositions containing said compounds and their pharmaceutically acceptable salts, and the use of said compounds and pharmaceutical compositions for the treatment, control, amelioration or prevention of cancer.

  描述了公式的化合物及其对映体和药用可接受的盐，以及含有该化合物及其药用可接受的盐的药物组合物，以及该化合物和药物组合物用于治疗、控制、改善或预防癌症的用途。
• Practical Synthesis of MDM2 Antagonist RG7388. Part 2: Development of the Cu(I) Catalyzed [3 + 2] Asymmetric Cycloaddition Process for the Manufacture of Idasanutlin
  作者：Gösta Rimmler、Andre Alker、Marcello Bosco、Ralph Diodone、Dan Fishlock、Stefan Hildbrand、Bernd Kuhn、Christian Moessner、Carsten Peters、Pankaj D. Rege、Markus Schantz

  DOI：10.1021/acs.oprd.6b00319

  日期：2016.12.16

  A concise catalytic asymmetric synthesis of idasanutlin (1) was developed in which the key pyrrolidine core, containing four contiguous stereocenters, was constructed via a Ag/MeOBIPHEP promoted [3 + 2] cycloaddition reaction. Further development of the [3 + 2] cycloaddition reaction resulted in an improvement in diastereoselectivity and enantioselectivity by changing the catalyst system to Cu(I)/BINAP

  开发了简明的催化不对称合成依沙替林（1），其中通过Ag / MeOBIPHEP促进的[3 + 2]环加成反应构建了包含四个连续立体中心的关键吡咯烷核。通过将催化剂体系更改为Cu（I）/ BINAP，[3 + 2]环加成反应的进一步发展导致非对映选择性和对映选择性的提高。在生产同等质量的API时，铜（I）催化的工艺不仅提高了总产量，而且在循环时间，废物流和可加工性方面也表现出了优势。优化的铜（I）催化工艺已用于制备超过1500 kg的依地那林（1）。
• MRNA-BASED GENE EXPRESSION FOR PERSONALIZING PATIENT CANCER THERAPY WITH AN MDM2 ANTAGONIST
  申请人：Hoffmann-La Roche Inc.

  公开号：US20150211073A1

  公开（公告）日：2015-07-30

  Use of at least an MDM2 gene panel, preferably a four gene MDM2 gene panel, as a biomarker for predicting the response to a MDM2 antagonist.

  至少使用一个MDM2基因面板，最好是一个四基因MDM2基因面板，作为预测对MDM2拮抗剂反应的生物标志物。
• Substituted Pyrrolidine-2-Carboxamides
  申请人：Bartkovitz David Joseph

  公开号：US20100152190A1

  公开（公告）日：2010-06-17

  There are provided compounds of the formula wherein X, Y, R 1 , R 2 , R 3 , R 3 , R 4 , R 5 , R 6 and R 7 are as described herein and enantiomers and pharmaceutically acceptable salts and esters thereof. The compounds are useful as anticancer agents.

  提供了以下公式的化合物，其中X、Y、R1、R2、R3、R4、R5、R6和R7如本文所述，并且其对映体和药学上可接受的盐和酯。这些化合物可用作抗癌剂。