(3R,5R,6R)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one

• 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: (3R,5R,6R)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one
• 英文别名: (3R,5R,6R)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyloxan-2-one
• 化学式: C₁₈H₁₆Cl₂O₂
• 分子量: 335.23
• InChiKey: QNQSZYRUBCVBEK-LQAWEQHXSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.3
• 重原子数：
  22
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.28
• 拓扑面积：
  26.3
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为产物：
  描述：

  间氯溴苯 在 lithium hydroxide monohydrate 、 硫酸 、 RuCl[(S)-1-isopropyl-2,2-bis(4-methoxyphenyl)ethylenediamine][(S)-2,2'-bis[di(3,5-xylyl)phosphino]-1,1'-binaphthyl] 、 potassium tert-butylate 、 氢气 、 palladium diacetate 、 N,N'-羰基二咪唑 、 4,5-双二苯基膦-9,9-二甲基氧杂蒽 、 sodium t-butanolate 作用下， 以 四氢呋喃 、 水 、 异丙醇 、 甲苯 为溶剂， 10.0~85.0 ℃ 、275.8 kPa 条件下， 反应 73.0h， 生成 (3S,5R,6R)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one 、 (3R,5R,6R)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-3-methyltetrahydro-2H-pyran-2-one
  参考文献：
  名称：

  鲁棒性高选择性Ru（II）催化动力学动力学拆分技术的开发，用于制造AMG 232

  摘要：

  我们在本文中描述了可扩展的Noyori还原动态动力学分辨率的发展，以制造DLAC，这是活性药物成分AMG 232的Δ-内酯前体。这项工作的中心是鉴定钌双环复合物RuCl [（S）-daipena] [ （S）-xylBINAP]（（S）-RUCY-xylBINAP），其在底物与催化剂的负载量（S / C）为2000：1时提供具有> 98：2对映体比率的产物。通过在氢化之前进行酯交换反应生成位阻更大的异丙酯，我们能够抑制酯的意外还原。在最终烷基化步骤中形成DLAC的碱当量的优化防止产品降解。经过优化的工艺可扩展到> 200 kg，从而以5％的总收率提供147 kg DLAC，光学纯度为99.9％。

  DOI：

  10.1021/acs.oprd.9b00427

文献信息

• PROCESSES OF MAKING AND CRYSTALLINE FORMS OF A MDM2 INHIBITOR
  申请人：AMGEN INC.

  公开号：US20140364455A1

  公开（公告）日：2014-12-11

  The present invention provides processes for making 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid as well as intermediates and processes for making the intermediates. Also provided are crystalline forms of the compound and the intermediates.

  本发明提供了制备2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙磺酰基)-3-甲基丁烷-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸的方法，以及制备中间体和制备中间体的方法。还提供了该化合物和中间体的晶型形式。
• BENZOIC ACID DERIVATIVE MDM2 INHIBITOR FOR THE TREATMENT OF CANCER
  申请人：AMGEN INC.

  公开号：US20140243372A1

  公开（公告）日：2014-08-28

  The present invention provides a MDM2 inhibitor compound, or a pharmaceutically acceptable salt thereof, which compound is useful as a therapeutic agent, particularly for the treatment of cancers. The present invention also relates to pharmaceutical compositions that contains the MDM2 inhibitor.

  本发明提供了一种MDM2抑制剂化合物，或其药用可接受的盐，该化合物可作为治疗剂，特别是用于癌症治疗。本发明还涉及含有MDM2抑制剂的药物组合物。
• CRYSTALLINE SYNTHETIC INTERMEDIATE USEFUL IN PROCESSES FOR MAKING A MDM2 INHIBITOR
  申请人：Amgen Inc.

  公开号：EP3805232A1

  公开（公告）日：2021-04-14

  The present invention provides the crystalline form of an intermediate useful in processes for making 2-((3R,5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)-1-((S)-1-(isopropylsulfonyl)-3-methylbutan-2-yl)-3-methyl-2-oxopiperidin-3-yl)acetic acid as well as processes for making the intermediate.

  本发明提供了在制造 2-((3R,5R,6S)-5-(3-氯苯基)-6-(4-氯苯基)-1-((S)-1-(异丙基磺酰基)-3-甲基丁-2-基)-3-甲基-2-氧代哌啶-3-基)乙酸的工艺中有用的中间体的结晶形式以及制造该中间体的工艺。
• Combination therapy including an MDM2 inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers
  申请人：AMGEN INC.

  公开号：US10881648B2

  公开（公告）日：2021-01-05

  The present invention provides combination therapy that includes an MDM2 inhibitor and one or more additional pharmaceutically active agents, particularly for the treatment of cancers. The invention also relates to pharmaceutical compositions that contain an MDM2 inhibitor and one or more additional pharmaceutically active agents for the treatment of cancers.

  本发明提供了包括MDM2抑制剂和一种或多种额外的药学活性剂的组合疗法，特别是用于治疗癌症的组合疗法。 本发明还涉及用于治疗癌症的包含 MDM2 抑制剂和一种或多种额外药学活性剂的药物组合物。
• Discovery of AM-7209, a Potent and Selective 4-Amidobenzoic Acid Inhibitor of the MDM2–p53 Interaction
  作者：Yosup Rew、Daqing Sun、Xuelei Yan、Hilary P. Beck、Jude Canon、Ada Chen、Jason Duquette、John Eksterowicz、Brian M. Fox、Jiasheng Fu、Ana Z. Gonzalez、Jonathan Houze、Xin Huang、Min Jiang、Lixia Jin、Yihong Li、Zhihong Li、Yun Ling、Mei-Chu Lo、Alexander M. Long、Lawrence R. McGee、Joel McIntosh、Jonathan D. Oliner、Tao Osgood、Anne Y. Saiki、Paul Shaffer、Yu Chung Wang、Sarah Wortman、Peter Yakowec、Qiuping Ye、Dongyin Yu、Xiaoning Zhao、Jing Zhou、Julio C. Medina、Steven H. Olson

  DOI：10.1021/jm501550p

  日期：2014.12.26

  Structure-based rational design and extensive structure-activity relationship studies led to the discovery of AMG 232 (1), a potent piperidinone inhibitor of the MDM2-p53 association, which is currently being evaluated in human clinical trials for the treatment of cancer. Further modifications of 1, including replacing the carboxylic acid with a 4-amidobenzoic acid, afforded AM-7209 (25), featuring improved potency (K-D from ITC competition was 38 pM, SJSA-1 EdU IC50 = 1.6 nM), remarkable pharmacokinetic properties, and in vivo antitumor activity in both the SJSA-1 osteosarcoma xenograft model (ED50 = 2.6 mg/kg QD) and the HCT-116 colorectal carcinoma xenograft model (ED50 = 10 mg/kg QD). In addition, 25 possesses distinct mechanisms of elimination compared to 1.