N-((1S,2R)-2-amino-1,2-bis(4-chlorophenyl)ethyl)-2-isopropoxy-4-methoxybenzamide | 1353891-92-5

• 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: N-((1S,2R)-2-amino-1,2-bis(4-chlorophenyl)ethyl)-2-isopropoxy-4-methoxybenzamide
• 英文别名: N-[(1S,2R)-2-amino-1,2-bis(4-chlorophenyl)ethyl]-4-methoxy-2-propan-2-yloxybenzamide
• CAS: 1353891-92-5
• 化学式: C₂₅H₂₆Cl₂N₂O₃
• 分子量: 473.399
• InChiKey: ITAFVKOGQVRPPK-RPWUZVMVSA-N

物化性质

• 沸点：
  624.9±55.0 °C(Predicted)
• 密度：
  1.251±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  32
• 可旋转键数：
  8
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.24
• 拓扑面积：
  73.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-((1S,2R)-2-amino-1,2-bis(4-chlorophenyl)ethyl)-2-isopropoxy-4-methoxybenzamide 在 三氟甲磺酸酐 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 N,N'-羰基二咪唑 、 三苯基氧化膦 、 potassium hydroxide 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 异丙醇 为溶剂， 反应 53.0h， 生成 N-(6-(2-(2-(2-(adamantan-1-yl)acetamido)ethoxy)ethoxy)hexyl)-6-(4-((4S,5R)-4,5-bis(4-chlorophenyl)-2-(2-isopropoxy-4-methoxyphenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)-2-oxopiperazin-1-yl)hexanamide
  参考文献：
  名称：

  The hydrophobically-tagged MDM2–p53 interaction inhibitor Nutlin-3a-HT is more potent against tumor cells than Nutlin-3a

  摘要：

  疏水标记的MDM2-p53相互作用抑制剂Nutlin-3a-HT在p53重新激活时降低MDM2水平，对肿瘤细胞的作用比Nutlin-3a更强。

  DOI：

  10.1039/c9cc07795b
• 作为产物：
  描述：

  4-甲氧基水杨酸 在 4-二甲氨基吡啶 、 potassium carbonate 、 1,2-二氯乙烷 、 三氟乙酸 、 potassium hydroxide 作用下， 以 乙醇 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 反应 93.25h， 生成 N-((1S,2R)-2-amino-1,2-bis(4-chlorophenyl)ethyl)-2-isopropoxy-4-methoxybenzamide
  参考文献：
  名称：

  The hydrophobically-tagged MDM2–p53 interaction inhibitor Nutlin-3a-HT is more potent against tumor cells than Nutlin-3a

  摘要：

  疏水标记的MDM2-p53相互作用抑制剂Nutlin-3a-HT在p53重新激活时降低MDM2水平，对肿瘤细胞的作用比Nutlin-3a更强。

  DOI：

  10.1039/c9cc07795b

文献信息

• Chiral synthesis method for producing cis-imidazoline compounds for pharmaceutical use
  申请人：Unity Biotechnology, Inc.

  公开号：US09988368B1

  公开（公告）日：2018-06-05

  This invention provides a method for enantioselective synthesis of cis-imidazolines and related structures through chiral resolution. A chiral acid is used to separate enantiomeric precursors of the cis-imidazolines from a racemic mixture by selective crystallization. Both enantiomers can be cyclized into the desired cis-imidazoline by complementary pathways. Compounds can be synthesized according to the invention with an enantiomeric excess as high as 99%. Cis-imidazolines such as Nutlin-3a prepared according to this invention may be used for treating cancer, killing senescent cells, or treating senescence-associated conditions.

  这项发明提供了一种通过手性分辨法合成顺式咪唑啉和相关结构的方法。使用手性酸将顺式咪唑啉的对映体前体从混合物中分离出来，通过选择性结晶进行分离。两种对映体可以通过互补途径环化成所需的顺式咪唑啉。根据该发明合成的化合物的对映体过量可以高达99%。根据这项发明制备的Nutlin-3a等顺式咪唑啉可用于治疗癌症、杀死衰老细胞或治疗与衰老相关的疾病。
• STEREOSELECTIVE METHODS, CATALYSTS AND INTERMEDIATES FOR THE SYNTHESIS OF (-)-NUTLIN-3 AND RELATED COMPOUNDS
  申请人：Johnston Jeffrey N.

  公开号：US20120088915A1

  公开（公告）日：2012-04-12

  The present invention provides methods and intermediates are provided for the preparation of (−)-Nutlin-3. Methods and intermediates are also provided for the enantioselective addition of aryl nitromethanes to aldimines. Bis(amidine) catalysts for the use in these and other reactions are also provided.

  本发明提供了用于制备(−)-Nutlin-3的方法和中间体。还提供了用于对芳基硝基甲烷与醛亚胺进行对映选择性加成的方法和中间体。此外，还提供了用于这些及其他反应中使用的双(胺基)催化剂。
• Organocatalytic, Diastereo- and Enantioselective Synthesis of Nonsymmetric <i>cis</i>-Stilbene Diamines: A Platform for the Preparation of Single-Enantiomer <i>cis</i>-Imidazolines for Protein–Protein Inhibition
  作者：Brandon A. Vara、Anand Mayasundari、John C. Tellis、Michael W. Danneman、Vanessa Arredondo、Tyler A. Davis、Jaeki Min、Kristin Finch、R. Kiplin Guy、Jeffrey N. Johnston

  DOI：10.1021/jo501003r

  日期：2014.8.1

  The finding by scientists at Hoffmann-La Roche that cis-imidazolines could disrupt the protein-protein interaction between p53 and MDM2, thereby inducing apoptosis in cancer cells, raised considerable interest in this scaffold over the past decade. Initial routes to these small molecules (i.e., Nutlin-3) provided only the racemic form, with enantiomers being enriched by chromatographic separation using high-pressure liquid chromatography (HPLC) and a chiral stationary phase. Reported here is the first application of an enantioselective aza-Henry approach to nonsymmetric cis-stilbene diamines and cis-imidazolines. Two novel mono(amidine) organocatalysts (MAM) were discovered to provide high levels of enantioselection (>95% ee) across a broad range of substrate combinations. Furthermore, the versatility of the aza-Henry strategy for preparing nonsymmetric cis-imidazolines is illustrated by a comparison of the roles of aryl nitromethane and aryl aldimine in the key step, which revealed unique substrate electronic effects providing direction for aza-Henry substrate-catalyst matching. This method was used to prepare highly substituted cis-4,5-diaryl imidazolines that project unique aromatic rings, and these were evaluated for MDM2-p53 inhibition in a fluorescence polarization assay. The diversification of access to cis-stilbene diamine-derived imidazolines provided by this platform should streamline their further development as chemical tools for disrupting protein-protein interactions.
• Preparation of (−)-Nutlin-3 Using Enantioselective Organocatalysis at Decagram Scale
  作者：Tyler A. Davis、Anna E. Vilgelm、Ann Richmond、Jeffrey N. Johnston

  DOI：10.1021/jo401321a

  日期：2013.11.1

  Chiral nonracemic cis-4,5-bis(aryl)imidazolines have emerged as a powerful platform for the development of cancer chemotherapeutics, stimulated by the Hoffmann-La Roche discovery that Nutlin-3 can restore apoptosis in cells with wild-type p53. The lack of efficient methods for the enantioselective synthesis of cis-imidazolines, however, has limited their more general use. Our disclosure of the first enantioselective synthesis of (-)-Nutlin-3 provided a basis to prepare larger amounts of this tool used widely in cancer biology. Key to the decagram-scale synthesis described here was the discovery of a novel bis(amidine) organocatalyst that provides high enantioselectivity at warmer reaction temperature (-20 degrees C) and low catalyst loadings. Further refinements to the procedure led to the synthesis of (-)-Nutlin-3 in a 17 g batch and elimination of all but three chromatographic purifications.
• CHIRAL SYNTHESIS METHOD FOR PRODUCING CIS-IMIDAZOLINE COMPOUNDS FOR PHARMACEUTICAL USE
  申请人：Unity Biotechnology, Inc.

  公开号：US20180362510A1

  公开（公告）日：2018-12-20

  This invention provides a method for enantioselective synthesis of cis-imidazolines and related structures through chiral resolution. A chiral acid is used to separate enantiomeric precursors of the cis-imidazolines from a racemic mixture by selective crystallization. Both enantiomers can be cyclized into the desired cis-imidazoline by complementary pathways. Compounds can be synthesized according to the invention with an enantiomeric excess as high as 99%. Cis-imidazolines such as Nutlin-3a prepared according to this invention may be used for treating cancer, killing senescent cells, or treating senescence-associated conditions.