tert-butyl (1R,2S,5R)-2-(benzyloxycarbonylamino)-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate | 746670-91-7

• 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: tert-butyl (1R,2S,5R)-2-(benzyloxycarbonylamino)-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate
• 英文别名: (1R, 2S, 5R)-2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylic acid tert-butyl ester；(1R,2S,5R)-tert-butyl 2-(benzyloxycarbonylamino)-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate；(1R,2S,5R)-Tert-butyl 2-benzyloxycarbonylamino-7-oxo-6-aza-bicyclo[3.2.1]octane-6-carboxylate；tert-butyl (1R,2S,5R)-7-oxo-2-(phenylmethoxycarbonylamino)-6-azabicyclo[3.2.1]octane-6-carboxylate
• CAS: 746670-91-7
• 化学式: C₂₀H₂₆N₂O₅
• 分子量: 374.437
• InChiKey: HGNXRTOUUOHZEO-OAGGEKHMSA-N

物化性质

• 熔点：
  96.9 °C(Solv: ethyl acetate (141-78-6); hexane (110-54-3))
• 沸点：
  562.5±39.0 °C(Predicted)
• 密度：
  1.24±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  84.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl (1R,2S,5R)-2-(benzyloxycarbonylamino)-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate 在 lithium hydroxide monohydrate 、 碘苯二乙酸 、 palladium 10% on activated carbon 、 氢气 、 sodium acetate 、 sodium cyanoborohydride 、 1-羟基苯并三唑 、 caesium carbonate 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 、 N,N-二异丙基乙胺 、 三氟乙酸 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 二甲基亚砜 、 乙酸乙酯 、 乙腈 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 112.33h， 生成 benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(isopropylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate
  参考文献：
  名称：

  Use of a Conformational-Switching Mechanism to Modulate Exposed Polarity: Discovery of CCR2 Antagonist BMS-741672

  摘要：

  We encountered a dilemma in the course of studying a series of antagonists of the G-protein coupled receptor CC chemokine receptor-2 (CCR2): compounds with polar C3 side chains exhibited good ion channel selectivity but poor oral bioavailability, whereas compounds with lipophilic C3 side chains exhibited good oral bioavailability in preclinical species but poor ion channel selectivity. Attempts to solve this through the direct modulation of physicochemical properties failed. However, the installation of a protonation-dependent conformational switching mechanism resolved the problem because it enabled a highly selective and relatively polar molecule to access a small population of a conformer with lower polar surface area and higher membrane permeability. Optimization of the overall properties in this series yielded the CCR2 antagonist BMS-741672 (7), which embodied properties suitable for study in human clinical trials.

  DOI：

  10.1021/acsmedchemlett.8b00439
• 作为产物：
  描述：

  (1R,2S,4S,5S)-tert-butyl 2-(benzyloxycarbonylamino)-4-iodo-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate 在 偶氮二异丁腈 、 三正丁基氢锡 作用下， 以 苯 为溶剂， 反应 0.66h， 以168 mg的产率得到tert-butyl (1R,2S,5R)-2-(benzyloxycarbonylamino)-7-oxo-6-azabicyclo[3.2.1]octane-6-carboxylate
  参考文献：
  名称：

  以碘内酰胺化为关键步骤对苯甲酸（1 S，2 R，4 R）-4-（叔丁氧基羰基氨基）-2-（羟甲基）环己基氨基甲酸酯的对映选择性合成

  摘要：

  描述了有效的对映选择性合成苄基（1 S，2 R，4 R）-4-（叔丁氧基羰基氨基）-2-（羟甲基）环己基氨基甲酸酯2的方法，该中间体是一系列有效CCR2拮抗剂的重要中间体。序列中的关键步骤是碘化内酰胺化，以生成高度官能化的（1 R，2 S，4 S，5 S）-叔丁基2-（苄氧基羰基氨基）-4-碘-7-氧代-6-氮杂双环[3.2 .1] -6-羧酸辛烷酯11。在两步碘化内酰胺化序列中对反应机理的检查导致发现效率提高的单罐转化。

  DOI：

  10.1021/jo9011249

文献信息

• Cyclic derivatives as modulators of chemokine receptor activity
  申请人：Carter H. Percy

  公开号：US20050054627A1

  公开（公告）日：2005-03-10

  The present application describes modulators of MCP-1 of formula (I): or pharmaceutically acceptable salt forms thereof, useful for the treatment of rheumatoid arthritis, multiple sclerosis, atherosclerosis and asthma.

  当前申请描述了MCP-1的调节剂，其化学公式为(I):或其药用可接受的盐形式，用于治疗类风湿性关节炎、多发性硬化症、动脉粥样硬化和哮喘。
• Substituted cycloalkylamine derivatives as modulators of chemokine receptor activity
  申请人：Carter H. Percy

  公开号：US20050054626A1

  公开（公告）日：2005-03-10

  The present application describes modulators of MCP-1 of formula (I): or pharmaceutically acceptable salt forms thereof, useful for the prevention of asthma, multiple sclerosis, artherosclerosis, and rheumatoid arthritis.

  本申请描述了MCP-1的调节剂，化学式为(I)：或其药用可接受的盐形式，用于预防哮喘、多发性硬化症、动脉粥样硬化和类风湿性关节炎。
• CYCLIC DERIVATIVES AS MODULATORS OF CHEMOKINE RECEPTOR ACTIVITY
  申请人：Carter Percy H.

  公开号：US20080027080A1

  公开（公告）日：2008-01-31

  This invention relates generally to modulators of chemokine receptor activity having unexpected combination of desirable pharmacological properties. Pharmaceutical compositions containing the same, and methods of using the same as agents for treatment and prevention of inflammatory, allergic, autoimmune, metabolic, cancer and/or cardiovascular diseases, particularly diabetes, Crohn's disease, atherosclerosis, and multiple sclerosis, along with methods of preparing compounds and intermediates therefor. Metabolites of active compounds are also provided herein, pharmaceutical compositions and use thereof are also provided.

  这项发明涉及具有意想不到的理想药理特性组合的趋化因子受体活性调节剂。包含这些化合物的药物组合物，以及将其用作治疗和预防炎症、过敏、自身免疫、代谢、癌症和/或心血管疾病的药剂，特别是糖尿病、克罗恩病、动脉粥样硬化和多发性硬化症，以及制备化合物和中间体的方法。此外，还提供了活性化合物的代谢产物，以及药物组合物和其使用方法。
• Discovery of a Potent and Orally Bioavailable Dual Antagonist of CC Chemokine Receptors 2 and 5
  作者：Percy H. Carter、Gregory D. Brown、Robert J. Cherney、Douglas G. Batt、Jing Chen、Cheryl M. Clark、Mary Ellen Cvijic、John V. Duncia、Soo S. Ko、Sandhya Mandlekar、Ruowei Mo、David J. Nelson、Jian Pang、Anne V. Rose、Joseph B. Santella、Andrew J. Tebben、Sarah C. Traeger、Songmei Xu、Qihong Zhao、Joel C. Barrish

  DOI：10.1021/ml500505q

  日期：2015.4.9

  We describe the hybridization of our previously reported acyclic and cyclic CC chemokine receptor 2 (CCR2) antagonists to lead to a new series of dual antagonists of CCR2 and CCRS. Installation of a gamma-lactam as the spacer group and a quinazoline as a benzamide mimetic improved oral bioavailability markedly. These efforts led to the identification of 13d, a potent and orally bioavailable dual antagonist suitable for use in both murine and monkey models of inflammation.
• Processes for preparing cyclic derivatives which are modulators of chemokine receptor activity
  申请人：Bristol-Myers Squibb Company

  公开号：EP2098508B1

  公开（公告）日：2012-06-20