(3R,4R)-3-amino-4-hydroxyazepane-1-carboxylic acid tert butyl ester | 198419-15-7

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂环庚烷
• 英文名称: (3R,4R)-3-amino-4-hydroxyazepane-1-carboxylic acid tert butyl ester
• 英文别名: tert-butyl (3R,4R)-3-amino-4-hydroxy-azepan-1-carboxylate；(3R,4R)-tert-Butyl 3-amino-4-hydroxyazepane-1-carboxylate；tert-butyl (3R,4R)-3-amino-4-hydroxyazepane-1-carboxylate
• CAS: 198419-15-7
• 化学式: C₁₁H₂₂N₂O₃
• 分子量: 230.307
• InChiKey: LWINOKVVXXXYPN-RKDXNWHRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.1
• 重原子数：
  16
• 可旋转键数：
  2
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.91
• 拓扑面积：
  75.8
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (3R,4R)-3-amino-4-hydroxyazepane-1-carboxylic acid tert butyl ester 在 sodium hydroxide 、 三乙胺 作用下， 以 二氯甲烷 为溶剂， 生成 (3R,4R)-tert-butyl-3-(4-(benzyloxy)benzamido)-4-(3,5-bis(benzyloxy)-4-(2-(benzyloxy)-6-(benzyloxycarbonyl)benzoyl)benzoyloxy)azepane-1-carboxylate
  参考文献：
  名称：

  Total Synthesis of (-)-Balanol

  摘要：

  (-)-Balanol是一种具有强效蛋白激酶C抑制活性的真菌 metabolite，我们已通过全合成方法成功制备。该合成方法采用了阴离子同系Fries重排策略来构建苯丙酮（benzophenone）部分，同时将叠氮（azepane）部分由(2S,3R)-3-羟基赖氨酸（3-hydroxylysine）获取。

  DOI：

  10.1021/jo00097a014
• 作为产物：
  描述：

  (2S,3R)-1-allylamino-3-benzyloxy-pent-4-en-2-ol 在 palladium on activated charcoal 三氟甲磺酸 、 Mo(CHCMe2Ph)2 、 叠氮磷酸二苯酯 、 氢气 、 三乙胺 、 三苯基膦 、 偶氮二甲酸二乙酯 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 32.5h， 生成 (3R,4R)-3-amino-4-hydroxyazepane-1-carboxylic acid tert butyl ester
  参考文献：
  名称：

  （-）-balanol的正式合成：基于RCM的六氢氮杂segment片段的简洁方法。

  摘要：

  描述了（-）-balanol 1的六氢氮杂moiety部分13的简明合成，该合成仅包括八个步骤，并且明显短于所有先前报道的对该特定化合物的所有方法。二乙烯基甲醇4的无锐环氧化和用于形成杂环支架9的闭环烯烃复分解（RCM）反应构成了该序列的关键转化。最近报道的催化量的茚茚亚钌络合物18是最好的反应。此外，证明了只要施罗克的钼亚烷基络合物Mo（= NAr）（= CHCMe2Ph）[OC（Me）（CF3）2] 2（Ar = 2），即使存在叠氮基功能，RCM也可以成功进行。 （6-二异丙基苯基）用作预催化剂。

  DOI：

  10.1021/jo991611g

文献信息

• Total Synthesis of (-)-Balanol
  作者：John W. Lampe、Philip F. Hughes、Christopher K. Biggers、Shelley H. Smith、Hong Hu

  DOI：10.1021/jo00097a014

  日期：1994.9

  (-)-Balanol, a fungal metabolite with potent protein kinase C inhibitory properties, has been prepared in a total synthesis which makes use of an anionic homo-Fries rearrangement approach to the benzophenone subunit and in which the azepane subunit is obtained from (2S,3R)-3-hydroxylysine.

  (-)-Balanol是一种具有强效蛋白激酶C抑制活性的真菌 metabolite，我们已通过全合成方法成功制备。该合成方法采用了阴离子同系Fries重排策略来构建苯丙酮（benzophenone）部分，同时将叠氮（azepane）部分由(2S,3R)-3-羟基赖氨酸（3-hydroxylysine）获取。
• Assymetric synthesis of azepines
  申请人：Hoffmann-La Roche Inc.

  公开号：US05902882A1

  公开（公告）日：1999-05-11

  A novel process for the manufacture of compounds of the formula ##STR1## wherein R.sup.1 and R.sup.2 independently represent aroyl. The present invention also concerns novel intermediates used in the novel process for making compounds of formula I.

  一种新型工艺用于制造公式 ##STR1## 中R.sup.1和R.sup.2独立地代表芳酰基的化合物。本发明还涉及用于制造公式I化合物的新型中间体。
• Asymmetric synthesis of azepines
  申请人：Hoffmann-La Roche Inc.

  公开号：US06069245A1

  公开（公告）日：2000-05-30

  A novel process for the manufacture of compounds of the formula ##STR1## wherein R.sup.1 and R.sup.2 independently represent aroyl. The present invention also concerns novel intermediates used in the novel process for making compounds of formula I.

  一种新型的制备式为##STR1##其中R.sup.1和R.sup.2分别表示芳酰基的化合物的制备工艺。本发明还涉及用于制备式I化合物的新型中间体。
• Asymmetric synthesis process
  申请人：Matzinger Peter Karl

  公开号：US06914140B1

  公开（公告）日：2005-07-05

  A novel process for the manufacture of compounds of the formula wherein R 1 and R 2 independently represent aroyl. The present invention also concerns novel intermediates used in the novel process for making compounds of formula I.

  一种制造化合物的新工艺，其化学式为其中R1和R2独立地代表芳酰基。本发明还涉及用于制造式I化合物的新中间体。
• Structure-Based Optimization of Novel Azepane Derivatives as PKB Inhibitors
  作者：Christine B. Breitenlechner、Thomas Wegge、Laurent Berillon、Klaus Graul、Klaus Marzenell、Walter-Gunar Friebe、Ulrike Thomas、Ralf Schumacher、Robert Huber、Richard A. Engh、Birgit Masjost

  DOI：10.1021/jm0310479

  日期：2004.3.1

  Novel azepane derivatives were prepared and evaluated for protein kinase B (PKB-alpha) and protein kinase A (PKA) inhibition. The original (-)-balanol-derived lead structure (4R)-4-(2fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoic acid (3R)-3-[(pyridine-4-carbonyl)aminol-azepan4-yl ester (1) (IC50 (PKB-alpha.) = 5 nM) which contains an ester moiety was found to be plasma unstable and therefore unsuitable as a drug. Based upon molecular modeling studies using the crystal structure of the complex between PKA and 1, the five compounds N-(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzoylamino]-azepan-3-yl}-isonicotinamide (4), (3R,4R)-N-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzyloxy]-azepan-3-yl}-isonicotinamide (5), N-(3R,4S)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-phenylamino]-methyl}-azepan-3-yl)-isonicotinamide (6), N-(3R,4R)-4-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-benzylamino]-azepan-3-yl}-isonicotinamide (7), and N-(3R,4S)-4-(4-trans-2-[4-(2-fluoro-6-hydroxy-3-methoxy-benzoyl)-phenyl] -vinyl}-azepan-3-yl)-isonicotinamide (8) with linkers isosteric to the ester were designed, synthesized, and tested for in vitro inhibitory activity against PKA and PKB-alpha and for plasma stability in mouse plasma.(1)Compound 4 was found to be plasma stable and highly active (IC50 (PKB-alpha) = 4 nM). Cocrystals with PKA were obtained for 4, 5, and 8 and analyzed for binding interactions and conformational changes in the ligands and protein in order to rationalize the different activities of the molecules.