tert-butyl ((1R,2S)-2-amino-1,2-bis(4-chlorophenyl)ethyl)carbamate | 1353891-88-9

• 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: tert-butyl ((1R,2S)-2-amino-1,2-bis(4-chlorophenyl)ethyl)carbamate
• 英文别名: tert-butyl N-[(1R,2S)-2-amino-1,2-bis(4-chlorophenyl)ethyl]carbamate
• CAS: 1353891-88-9
• 化学式: C₁₉H₂₂Cl₂N₂O₂
• 分子量: 381.302
• InChiKey: WIPFVAZZRHSNTE-DLBZAZTESA-N

物化性质

• 沸点：
  511.0±50.0 °C(Predicted)
• 密度：
  1.242±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  25
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  64.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  tert-butyl ((1R,2S)-2-amino-1,2-bis(4-chlorophenyl)ethyl)carbamate 在 4-二甲氨基吡啶 、 三氟甲磺酸酐 、 potassium carbonate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 三氟乙酸 、 三苯基氧化膦 、 sodium iodide 作用下， 以 二氯甲烷 、 丙酮 为溶剂， 反应 27.5h， 生成 3-(4-(3-(4-((4S,5R)-2-(4-(tert-butyl)-2-ethoxyphenyl)-4,5-bis(4-chlorophenyl)-4,5-dihydro-1H-imidazole-1-carbonyl)piperazin-1-yl)prop-1-yn-1-yl)-1-oxoisoindolin-2-yl)piperidine-2,6-dione
  参考文献：
  名称：

  [EN] BIFUNCTIONAL NUTLIN-LENALIDOMIDE DERIVATIVES ((4,5-DIHYDRO-1H-IMIDAZOLE-1-CARBONYL)PIPERAZIN-1-YL-[LINKER]-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE DERIVATIVES) AS MDM2 DEGRADERS AND MDM2-P53 INHIBITORS FOR USE IN CANCER THERAPY
  [FR] DÉRIVÉS BIFONCTIONNELS DE NUTLINE-LÉNALIDOMIDE (DÉRIVÉS DE LA (4,5-DIHYDRO-1H-IMIDAZOLE-1-CARBONYL)PIPÉRAZIN-1-YL-[LIEUR]-1-OXOISOINDOLIN-2-YL)PIPÉRIDINE-2,6-DIONE) UTILISÉS COMME AGENTS DE DÉGRADATION DE MDM2 ET COMME INHIBITEURS DE MDM2-P53 DESTINÉS À ÊTRE UTILISÉS DANS LE TRAITEMENT DU CANCER

  摘要：

  双功能nutlin-lenalidomide衍生物((4,5-二氢-lH-咪唑-1-羰基)哌嗪-1-基-[连接剂]-1-氧代异吲哚-2-基)哌啶-2,6-二酮衍生物)的化学式(I)，作为MDM2 (murine double minute 2)降解剂和MDM2-p53相互作用抑制剂，用于抑制肿瘤细胞生长和癌症治疗。

  公开号：

  WO2020232115A1
• 作为产物：
  描述：

  N-(tert-butoxycarbonyl)-α-(phenylsulfonyl)-4-chlorobenzylamine 在 光气 、 sodium tetrahydroborate 、 (1R,2R)-N₁,N₂-bis(8-methoxy-4-(pyrrolidin-1-yl)quinolin-2-yl)cyclohexane-1,2-diamine 、 potassium carbonate 、 sodium sulfate 作用下， 以 四氢呋喃 、 甲醇 、 甲苯 为溶剂， 反应 28.75h， 生成 tert-butyl ((1R,2S)-2-amino-1,2-bis(4-chlorophenyl)ethyl)carbamate
  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。
• Efficient Reactivation of p53 in Cancer Cells by a Dual MdmX/Mdm2 Inhibitor
  作者：Lingyun Qin、Fei Yang、Cindy Zhou、Yao Chen、Huashan Zhang、Zhengding Su

  DOI：10.1021/ja509223m

  日期：2014.12.31

  between p53 and Mdm2/MdmX is an attractive target for cancer drug discovery because the overexpression of Mdm2 and/or MdmX ultimately impairs the function of p53 in approximately half of all human cancers. Recent studies have shown that inhibition of both Mdm2 and MdmX is more efficient than that of a single target in promoting cellular apoptosis in cancers. In this study, we demonstrate that a dual small-molecule

  p53 和 Mdm2/MdmX 之间的异常相互作用是癌症药物发现的一个有吸引力的目标，因为 Mdm2 和/或 MdmX 的过度表达最终会损害 p53 在大约一半的人类癌症中的功能。最近的研究表明，抑制 Mdm2 和 MdmX 在促进癌症细胞凋亡方面比抑制单一靶点更有效。在这项研究中，我们证明了 Mdm2/MdmX 的双重小分子拮抗剂可以有效地重新激活过表达 MdmX 和/或 Mdm2 的模型癌细胞中的 p53 通路。双重拮抗剂是基于 MdmX N 端结构域的节段突变分析和 Mdm2 N 端结构域与 nutlin-3a（Mdm2 特异性抑制剂）复合物的晶体结构合理设计的。
• [EN] BIFUNCTIONAL NUTLIN-LENALIDOMIDE DERIVATIVES ((4,5-DIHYDRO-1H-IMIDAZOLE-1-CARBONYL)PIPERAZIN-1-YL-[LINKER]-1-OXOISOINDOLIN-2-YL)PIPERIDINE-2,6-DIONE DERIVATIVES) AS MDM2 DEGRADERS AND MDM2-P53 INHIBITORS FOR USE IN CANCER THERAPY<br/>[FR] DÉRIVÉS BIFONCTIONNELS DE NUTLINE-LÉNALIDOMIDE (DÉRIVÉS DE LA (4,5-DIHYDRO-1H-IMIDAZOLE-1-CARBONYL)PIPÉRAZIN-1-YL-[LIEUR]-1-OXOISOINDOLIN-2-YL)PIPÉRIDINE-2,6-DIONE) UTILISÉS COMME AGENTS DE DÉGRADATION DE MDM2 ET COMME INHIBITEURS DE MDM2-P53 DESTINÉS À ÊTRE UTILISÉS DANS LE TRAITEMENT DU CANCER
  申请人：WISCONSIN ALUMNI RES FOUND

  公开号：WO2020232115A1

  公开（公告）日：2020-11-19

  Bifunctional nutlin-lenalidomide derivatives ((4,5-dihydro-lH- imidazole-l-carbonyl) piperazin-l-yl-[linker]-l-oxoisoindolin-2-yl) piperidine-2, 6-dione derivatives) of the formula (I),as MDM2 (murine double minute 2) degraders and MDM2-p53 interaction inhibitors for use in inhibiting neoplastic cell growth and cancer therapy

  双功能nutlin-lenalidomide衍生物((4,5-二氢-lH-咪唑-1-羰基)哌嗪-1-基-[连接剂]-1-氧代异吲哚-2-基)哌啶-2,6-二酮衍生物)的化学式(I)，作为MDM2 (murine double minute 2)降解剂和MDM2-p53相互作用抑制剂，用于抑制肿瘤细胞生长和癌症治疗。
• 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.