(3R,11aR)-11a-methyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one | 1061681-28-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯氮卓类
• 英文名称: (3R,11aR)-11a-methyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one
• 英文别名: (3R,11aR)-11a-methyl-3-phenyl-2,3,6,11-tetrahydro-[1,3]oxazolo[2,3-b][3]benzazepin-5-one
• CAS: 1061681-28-4
• 化学式: C₁₉H₁₉NO₂
• 分子量: 293.365
• InChiKey: CTQNCACBTMJCTE-PKOBYXMFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  22
• 可旋转键数：
  1
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.32
• 拓扑面积：
  29.5
• 氢给体数：
  0
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  (3R,11aR)-11a-methyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one 在 盐酸 、 aluminum (III) chloride 、 lithium aluminium tetrahydride 、 palladium 10% on activated carbon 、 氢气 、 lithium hexamethyldisilazane 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 7.0h， 生成 (1S,4S)-1,4-dimethyl-2,3,4,5-tetrahydro-1H-3-benzazepine
  参考文献：
  名称：

  Asymmetric synthesis of enantiomerically pure 1,4-di- and 1,1,4-trisubstituted tetrahydro-1H-3-benzazepines

  摘要：

  A four step asymmetric synthesis of 1,4-di- and 1,1,4-trisubstituted enantiomerically pure tetrahydro-3-benzazepines is described. Tricyclic oxazolobenzazepinones trans-9 and cis-10 allow the introduction of different alkyl groups (methyl, ethyl, allyl) with high diastereoselectivity (dr > 99:1). The relative configuration of the new stereogenic center was determined by NOE experiments. Tricyclic lactams trans-9 and cis-10 were also used for the introduction of two substituents and, moreover, the establishment of spiro-cyclic rings. Reduction of the substitution products 11 and 12 with AlCl3/LiAlH4 (1:3) took place with retention of configuration and the final hydrogenolytic removal of the N-(2-hydroxy-1-phenylethyl) residue provided enantiomerically pure 1,4-di- and 1,1,4-trisubstituted tetrahydro-3-benzazepines 17 and ent-17. In receptor binding studies with radioligands, the 3-benzazepines 17a-g and ent-17a-g did not show any interactions with cri, sigma(1), sigma(2) or NMDA receptors. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetasy.2011.07.027
• 作为产物：
  描述：

  1,2-苯二乙酸 以 四氢呋喃 、 甲苯 为溶剂， 反应 24.0h， 生成 (3R,11aR)-11a-methyl-3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b][3]benzazepin-5(6H)-one
  参考文献：
  名称：

  Asymmetric synthesis of enantiomerically pure 1,4-di- and 1,1,4-trisubstituted tetrahydro-1H-3-benzazepines

  摘要：

  A four step asymmetric synthesis of 1,4-di- and 1,1,4-trisubstituted enantiomerically pure tetrahydro-3-benzazepines is described. Tricyclic oxazolobenzazepinones trans-9 and cis-10 allow the introduction of different alkyl groups (methyl, ethyl, allyl) with high diastereoselectivity (dr > 99:1). The relative configuration of the new stereogenic center was determined by NOE experiments. Tricyclic lactams trans-9 and cis-10 were also used for the introduction of two substituents and, moreover, the establishment of spiro-cyclic rings. Reduction of the substitution products 11 and 12 with AlCl3/LiAlH4 (1:3) took place with retention of configuration and the final hydrogenolytic removal of the N-(2-hydroxy-1-phenylethyl) residue provided enantiomerically pure 1,4-di- and 1,1,4-trisubstituted tetrahydro-3-benzazepines 17 and ent-17. In receptor binding studies with radioligands, the 3-benzazepines 17a-g and ent-17a-g did not show any interactions with cri, sigma(1), sigma(2) or NMDA receptors. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetasy.2011.07.027

文献信息

• Asymmetric Synthesis of Enantiomerically Pure 2-Substituted Tetrahydro-3-benzazepines and Their Affinity to σ₁ Receptors
  作者：Syed Masood Husain、Roland Fröhlich、Dirk Schepmann、Bernhard Wünsch

  DOI：10.1021/jo900087e

  日期：2009.4.3

  pairs of enantiomerically pure 2-substituted tetrahydro-3-benzazepines 12a−d and ent-12a−d, which were tested for their σ1, σ2, and NMDA receptor affinities. The 2-butyl and the 2-phenyl derivatives 12c and 12d show very high σ1 affinity with Ki values of 16 and 50 nM, respectively. The eudismic ratios are greater than 50, reflecting highly stereoselective interaction with the σ1 receptor. Both σ1

  描述了对映体纯的2-取代的四氢-3-苯并ze庚因的非常短的不对称合成。首先，合成3-苯基-2,3,11,11a-四氢[1,3]恶唑并[2,3- b ] [3]苯并ze庚因-5（6 H）-酮3a - d和4a - d。的缩合2-（2-氧代）苯基乙酸1A - d与（[R）-phenylglycinol（2）。除11a-苯基衍生物3d / 4d（比例为91：9）外，非对映体11a-烷基衍生物3a - c / 4a - c的比例差不多是50:50。通过NOE实验以及X射线晶体结构分析证明了在11a位新形成的手性中心的构型。恶唑并[2,3-的减少b ] [3]苯并吖庚因5（6 ħ） -酮的反式- 3和顺式- 4与的AlCl 3 /的LiAlH 4（1：3）发生了与配置的保留，并且得到2,3-二取代的四氢-3-苯并ze庚因10和11。在最后一步中，从10和11中除去N-（2-羟基-1-苯乙基）残基通过
• Asymmetric synthesis and σ receptor affinity of enantiomerically pure 1,4-disubstituted tetrahydro-1H-3-benzazepines
  作者：Syed Masood Husain、Marie Theres Heim、Dirk Schepmann、Bernhard Wünsch

  DOI：10.1016/j.tetasy.2009.05.017

  日期：2009.7

  A very short (three steps) asymmetric synthesis of enantiomerically pure 1,4-disubstituted tetrahydro-1H-3-benzazepines 14 has been elaborated upon, starting from the trans- and cis-configured 11a-substituted 3-phenyl-2,3,11,11a-tetrahydro[1,3]oxazolo[2,3-b]-[3]-benzazepin-5(6H)-ones 6 and 7. The stereoisomerically pure lactams 6 and 7 were benzylated to give 6-benzyl-substituted products 8 and 9.

  非常短的（三步）不对称对映体纯的1,4-二取代四氢-1的合成ħ -3-苯并吖庚因14已被详细阐述，从起始的反式-和顺-型11a的取代的3-苯基-2,3- ，11，11a-四氢[1，3]恶唑并[2，3- b ]-[3] -苯并ze庚因-5（6 H）-一个6和7。将立体异构纯的内酰胺6和7苄基化，得到6-苄基取代的产物8和9。NOE实验显示反苄基残基和11a-位残基的-构型表明苄基化反应的立体化学受11a-位的立体中心控制。用AlCl 3 / LiAlH 4（1/3）还原苄基化的三环苯并内酰胺8和9，得到1,3,4-三取代的3-苯并pine庚因12和13，它们立体选择性地形成并保留构型。最后，通过氢解裂解去除N-（2-羟基-1-苯乙基）残基，形成对映体纯的1,4-二取代的3-苯并ze庚因14。的σ 1，σ 2对映体纯3-苯并ze庚因14和eNT - 14的NMDA受体亲和力已在竞争性受体结合研究中进行了研究。丁基衍生物ENT
• Enantioselective Synthesis of a 2,2-Disubstituted Tetrahydro-3- benzazepine as Novel NMDA Receptor Antagonist
  作者：Syed Masood Husain、Roland Fröhlich、Dirk Schepmann、Bernhard Wünsch

  DOI：10.1515/znb-2010-0216

  日期：2010.2.1

  The tricyclic oxazolidines trans-4 and cis-4 were interconverted upon treatment with allyltrimethylsilane/ TiCl₄. The oxazolidine trans-4 was diastereoselectively reacted with PhMgBr to yield the 4,4-disubstituted 3-benzazepinone 6, along with two side products. An X-ray crystal structure analysis of 6 proved the (R)-configuration of the stereogenic center C-4 and thus the retention of configuration. Reduction of 6 with AlCl₃/LiAlH₄ (1/3) followed by hydrogenolysis with H₂, Pd/C resulted in the formation of enantiomerically pure 2-methyl-2-phenyl-tetrahydro-3-benzazepine 11 which has a moderate affinity (K_i = 496 nM) to the PCP binding site of the NMDA receptor.

  三环氧氮杂环化合物trans-4和cis-4在与丙烯基三甲基硅烷/TiCl4反应后互相转化。氧氮杂环化合物trans-4与苯基镁溴反应，选择性地生成4,4-二取代的3-苯并环己酮6，同时伴随着两个副产物。化合物6的X射线晶体结构分析证实了手性中心C-4的(R)-构型，并因此保留了构型。将6还原为2-甲基-2-苯基-四氢-3-苯并环己烷11，再用氢气、Pd/C进行氢解，得到对映纯的化合物11，其对NMDA受体的PCP结合位点具有适度的亲和力(Ki = 496 nM)。
• A very short asymmetric synthesis of enantiomerically pure methyl substituted tetrahydro-3-benzazepines
  作者：S. Masood Husain、Roland Fröhlich、Bernhard Wünsch

  DOI：10.1016/j.tetasy.2008.06.016

  日期：2008.7

  12. Reduction of the diastereomeric pairs 6, 7 and 11, 12 with LiAlH4/AlCl3 (3:1) occurred under retention of configuration yielding tetrahydro-3-benzazepines 8 and 9 with de >98%, as well as 13 and 14 with complete diastereoselectivity. Hydrogenolytic cleavage of the N-substituent led to the enantiomerically pure 2-methyltetrahydro-3-benzazepines (R)-10 and (S)-10 and 1-benzyl-4-methyltetrahydro-3-benzazepines

  在很短的反应过程之后，已经详细阐述了甲基四氢-3-苯并ze庚因10和15的两种对映体的有效合成。两个非对映体唑并[3] benzazepinones 6和7通过的酮酸缩合制备4用（- [R）-phenylglycinol 5。新建立的N / O-乙缩醛立体生成中心控制6和7的苯甲酰化，生成产物11和12。非对映体对减少6，7和11，12LiAlH 4 / AlCl 3（3：1）在保留构型的情况下发生，产生de> 98％的四氢-3-苯并ze庚因8和9，以及具有完全非对映选择性的13和14。N取代基的氢解裂解产生对映体纯的2-甲基四氢-3-苯并ze庚因（R）-10和（S）-10和1-苄基-4-甲基四氢-3-苯并ze庚因（R，R）-15和（小号，小号） - 15。从3-苯并ze庚因14 ·HCl的X射线晶体结构分析推导出了形成产物的相对和绝对构型，但在N取代基中仍带有原始的立体化学信息。