1-benzyl-5′-methoxy-4′,5′-dihydrospiro[piperidine-4,7′-thieno-[2,3-c]pyran] | 1398399-90-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 1-benzyl-5′-methoxy-4′,5′-dihydrospiro[piperidine-4,7′-thieno-[2,3-c]pyran]
• 英文别名: 1-benzyl-5'-methoxy-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]；1'-Benzyl-5-methoxyspiro[4,5-dihydrothieno[2,3-c]pyran-7,4'-piperidine]
• CAS: 1398399-90-0
• 化学式: C₁₉H₂₃NO₂S
• 分子量: 329.463
• InChiKey: QQTHDTCMPMXZHM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  23
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.47
• 拓扑面积：
  49.9
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  3-碘吡啶 、 1-benzyl-5′-methoxy-4′,5′-dihydrospiro[piperidine-4,7′-thieno-[2,3-c]pyran] 在 2,2'-联吡啶 、 silver carbonate 、 palladium dichloride 作用下， 以 间二甲苯 为溶剂， 反应 12.5h， 以14%的产率得到1-benzyl-5'-methoxy-2'-(3-pyridyl)-4',5'-dihydrospiro[piperidine-4,7'-thieno[2,3-c]pyran]
  参考文献：
  名称：

  Pd-Catalyzed Direct C–H Bond Functionalization of Spirocyclic σ₁ Ligands: Generation of a Pharmacophore Model and Analysis of the Reverse Binding Mode by Docking into a 3D Homology Model of the σ₁ Receptor

  摘要：

  To explore the hydrophobic binding region of the sigma(1) receptor protein, regioisomeric spirocyclic thiophenes 9-11 were developed as versatile building blocks. Regioselective alpha- and beta-arylation using the catalyst systems PdCl2/bipy/Ag2CO3 and PdCl2/P[OCH(CF3)(2)](3)/Ag2CO3 allowed the introduction of various aryl moieties at different positions in the last step of the synthesis. The increasing sigma(1) affinity in the order 4 < 5/6 < 7/8 indicates that the positions of the additional aryl moiety and the S atom in the spirocyclic thiophene systems control the sigma(1) affinity. The main features of the pharmacophore model developed for this class of sigma(1) ligands are a positive ionizable group, a H-bond acceptor group, two hydrophobic moieties, and one hydrophobic aromatic group. Docking of the ligands into a sigma(1) 3D homology model via molecular mechanics/Poisson-Boltzmann surface area calculations led to a very good correlation between the experimentally determined and estimated free energy of receptor binding. These calculations support the hypothesis of a reverse binding mode of ligands bearing the aryl moiety at the "top" (compounds 2, 3, 7, and 8) and "left" (compounds 4, 5, and 6) positions, respectively.

  DOI：

  10.1021/jm300894h
• 作为产物：
  描述：

  2-(4-bromothiophen-3-yl)acetaldehyde dimethyl acetal 在 正丁基锂 、 对甲苯磺酸 作用下， 以 四氢呋喃 、 甲醇 、 正己烷 为溶剂， 反应 27.25h， 生成 1-benzyl-5′-methoxy-4′,5′-dihydrospiro[piperidine-4,7′-thieno-[2,3-c]pyran]
  参考文献：
  名称：

  Pd-Catalyzed Direct C–H Bond Functionalization of Spirocyclic σ₁ Ligands: Generation of a Pharmacophore Model and Analysis of the Reverse Binding Mode by Docking into a 3D Homology Model of the σ₁ Receptor

  摘要：

  To explore the hydrophobic binding region of the sigma(1) receptor protein, regioisomeric spirocyclic thiophenes 9-11 were developed as versatile building blocks. Regioselective alpha- and beta-arylation using the catalyst systems PdCl2/bipy/Ag2CO3 and PdCl2/P[OCH(CF3)(2)](3)/Ag2CO3 allowed the introduction of various aryl moieties at different positions in the last step of the synthesis. The increasing sigma(1) affinity in the order 4 < 5/6 < 7/8 indicates that the positions of the additional aryl moiety and the S atom in the spirocyclic thiophene systems control the sigma(1) affinity. The main features of the pharmacophore model developed for this class of sigma(1) ligands are a positive ionizable group, a H-bond acceptor group, two hydrophobic moieties, and one hydrophobic aromatic group. Docking of the ligands into a sigma(1) 3D homology model via molecular mechanics/Poisson-Boltzmann surface area calculations led to a very good correlation between the experimentally determined and estimated free energy of receptor binding. These calculations support the hypothesis of a reverse binding mode of ligands bearing the aryl moiety at the "top" (compounds 2, 3, 7, and 8) and "left" (compounds 4, 5, and 6) positions, respectively.

  DOI：

  10.1021/jm300894h

文献信息

• Late-Stage C-H Bond Arylation of Spirocyclic σ₁Ligands for Analysis of Complementary σ₁Receptor Surface
  作者：Christina Meyer、Dirk Schepmann、Shuichi Yanagisawa、Junichiro Yamaguchi、Kenichiro Itami、Bernhard Wünsch

  DOI：10.1002/ejoc.201200837

  日期：2012.10

  Direct C–H bond arylation in the α- and β-positions of spirocyclic thiophenes containing various functional groups (amine, ether, acetal, lactone) was accomplished. Selective phenylation in the α-position of the thiophene ring was achieved by using the catalytic system PdCl2/bipy/Ag2CO3. The introduction of phenyl moieties to the β-position was performed with the catalytic system PdCl2/P[OCH(CF3)2]3/Ag2CO3

  在含有各种官能团（胺、醚、缩醛、内酯）的螺环噻吩的 α-和 β-位直接进行 C-H 键芳基化。通过使用催化体系 PdCl2/bipy/Ag2CO3 实现了噻吩环 α 位的选择性苯基化。使用催化系统 PdCl2/P[OCH(CF3)2]3/Ag2CO3 将苯基部分引入 β-位。甚至具有直接连接到噻吩环的吸电子羰基部分的五元内酯 10 也被芳基化。在位置 A（顶部）或 B（左侧位置）被苯基部分取代的螺环噻吩显示低纳摩尔 σ1 亲和力（例如，4a：Ki = 1.6 nM；5a：Ki = 2.4 nM），表明在互补的σ1受体蛋白。σ1 受体不耐受 C 位（底部位置）的苯基部分（例如，12：Ki = 483 nM）。然而，A 位的额外苯基部分能够至少部分补偿 C 位苯基部分的不利影响。
• Pd-Catalyzed Direct C–H Bond Functionalization of Spirocyclic σ₁ Ligands: Generation of a Pharmacophore Model and Analysis of the Reverse Binding Mode by Docking into a 3D Homology Model of the σ₁ Receptor
  作者：Christina Meyer、Dirk Schepmann、Shuichi Yanagisawa、Junichiro Yamaguchi、Valentina Dal Col、Erik Laurini、Kenichiro Itami、Sabrina Pricl、Bernhard Wünsch

  DOI：10.1021/jm300894h

  日期：2012.9.27

  To explore the hydrophobic binding region of the sigma(1) receptor protein, regioisomeric spirocyclic thiophenes 9-11 were developed as versatile building blocks. Regioselective alpha- and beta-arylation using the catalyst systems PdCl2/bipy/Ag2CO3 and PdCl2/P[OCH(CF3)(2)](3)/Ag2CO3 allowed the introduction of various aryl moieties at different positions in the last step of the synthesis. The increasing sigma(1) affinity in the order 4 < 5/6 < 7/8 indicates that the positions of the additional aryl moiety and the S atom in the spirocyclic thiophene systems control the sigma(1) affinity. The main features of the pharmacophore model developed for this class of sigma(1) ligands are a positive ionizable group, a H-bond acceptor group, two hydrophobic moieties, and one hydrophobic aromatic group. Docking of the ligands into a sigma(1) 3D homology model via molecular mechanics/Poisson-Boltzmann surface area calculations led to a very good correlation between the experimentally determined and estimated free energy of receptor binding. These calculations support the hypothesis of a reverse binding mode of ligands bearing the aryl moiety at the "top" (compounds 2, 3, 7, and 8) and "left" (compounds 4, 5, and 6) positions, respectively.