1-BOC-4-氧代哌啶-2-甲酸乙酯 | 125545-98-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 中文名称: 1-BOC-4-氧代哌啶-2-甲酸乙酯
• 英文名称: 1-(tert-butyl) 2-ethyl 4-oxopiperidine-1,2-dicarboxylate
• 英文别名: ethyl 2SR-4-oxo-N-(t-butoxycarbonyl)piperidine-2-carboxylate；1-Tert-butyl 2-ethyl 4-oxopiperidine-1,2-dicarboxylate；1-O-tert-butyl 2-O-ethyl 4-oxopiperidine-1,2-dicarboxylate
• CAS: 125545-98-4
• 化学式: C₁₃H₂₁NO₅
• 分子量: 271.313
• InChiKey: YAVQLRUBKDCOCI-UHFFFAOYSA-N

物化性质

• 沸点：
  364.6±42.0 °C(Predicted)
• 密度：
  1.152±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  19
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.77
• 拓扑面积：
  72.9
• 氢给体数：
  0
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-BOC-4-氧代哌啶-2-甲酸乙酯 在 palladium on activated charcoal 甲酸 、 氢气 、 sodium hydride 、 三氟乙酸 作用下， 以 乙醇 、 二氯甲烷 、 水 为溶剂， 25.0~80.0 ℃ 、413.69 kPa 条件下， 反应 10.0h， 生成 ethyl 4-(cyanomethyl)-N-methylpiperidine-2-carboxylate
  参考文献：
  名称：

  4-(Tetrazolylalkyl)piperidine-2-carboxylic acids. Potent and selective N-methyl-D-aspartic acid receptor antagonists with a short duration of action

  摘要：

  We have prepared a series of cis-4-(tetrazolylalkyl)piperidine-2-carboxylic acids as potent and selective N-methyl-D-aspartic acid (NMDA) receptor antagonists. NMDA antagonists may prove to be useful therapeutic agents, for instance, as anticonvulsants, in the treatment of neurodegenerative disorders such as Alzheimer's disease and in the prevention of neuronal damage that occurs during cerebral ischemia. The compounds prepared were evaluated in vitro in both receptor binding assays ([H-3]CGS-19755, [H-3]AMPA, and [H-3]kainic acid) and in a cortical-wedge preparation (versus NMDA, quisqualic acid, and kainic acid) to determine affinity, potency, and selectivity. The new amino acids were also evaluated in vivo for their ability to block NMDA-induced convulsions in neonatal rats and NMDA-induced lethality in mice. The most potent compound of this series, 15 (LY233053), selectively displaced [H-3]CGS-19755 binding with an IC50 of 107 +/- 7 nM and selectively antagonized responses due to NMDA in a cortical-wedge preparation with an IC50 of 4.2 +/- 0.4-mu-M. Compound 15 blocked both NMDA-induced convulsions in neonatal rats (minimum effective dose (MED) = 20 mg/kg ip) and NMDA-induced lethality in mice (MED = 5 mg/kg ip). This is the first example of an NMDA receptor antagonist that incorporates a tetrazole moiety as an omega-acid bioisostere. These amino acid antagonists are also unique from their phosphonic acid counterparts in that they have a shorter duration of action in vivo. For the treatment of acute disorders such as stroke, where an NMDA antagonist would be administered parenterally, the shorter duration of action may be beneficial, e.g., allowing for better dosage control. The combination of potent NMDA receptor antagonism and a short duration of action may make these compounds useful therapeutic agents in the treatment of a variety of neurological disorders.

  DOI：

  10.1021/jm00105a016
• 作为产物：
  描述：

  4-甲氧基吡啶-2-甲腈 在 Rh/Al₂O₃ 盐酸 、 4 A molecular sieve 、 氢溴酸 、 氢气 、 N,N-二异丙基乙胺 、 pyridinium chlorochromate 作用下， 以 乙醇 、 二氯甲烷 为溶剂， 25.0~100.0 ℃ 、6.89 MPa 条件下， 反应 84.0h， 生成 1-BOC-4-氧代哌啶-2-甲酸乙酯
  参考文献：
  名称：

  4-(Tetrazolylalkyl)piperidine-2-carboxylic acids. Potent and selective N-methyl-D-aspartic acid receptor antagonists with a short duration of action

  摘要：

  We have prepared a series of cis-4-(tetrazolylalkyl)piperidine-2-carboxylic acids as potent and selective N-methyl-D-aspartic acid (NMDA) receptor antagonists. NMDA antagonists may prove to be useful therapeutic agents, for instance, as anticonvulsants, in the treatment of neurodegenerative disorders such as Alzheimer's disease and in the prevention of neuronal damage that occurs during cerebral ischemia. The compounds prepared were evaluated in vitro in both receptor binding assays ([H-3]CGS-19755, [H-3]AMPA, and [H-3]kainic acid) and in a cortical-wedge preparation (versus NMDA, quisqualic acid, and kainic acid) to determine affinity, potency, and selectivity. The new amino acids were also evaluated in vivo for their ability to block NMDA-induced convulsions in neonatal rats and NMDA-induced lethality in mice. The most potent compound of this series, 15 (LY233053), selectively displaced [H-3]CGS-19755 binding with an IC50 of 107 +/- 7 nM and selectively antagonized responses due to NMDA in a cortical-wedge preparation with an IC50 of 4.2 +/- 0.4-mu-M. Compound 15 blocked both NMDA-induced convulsions in neonatal rats (minimum effective dose (MED) = 20 mg/kg ip) and NMDA-induced lethality in mice (MED = 5 mg/kg ip). This is the first example of an NMDA receptor antagonist that incorporates a tetrazole moiety as an omega-acid bioisostere. These amino acid antagonists are also unique from their phosphonic acid counterparts in that they have a shorter duration of action in vivo. For the treatment of acute disorders such as stroke, where an NMDA antagonist would be administered parenterally, the shorter duration of action may be beneficial, e.g., allowing for better dosage control. The combination of potent NMDA receptor antagonism and a short duration of action may make these compounds useful therapeutic agents in the treatment of a variety of neurological disorders.

  DOI：

  10.1021/jm00105a016

文献信息

• Synthesis of 8-aminomorphans with high KOR affinity
  作者：Hendrik Jonas、Daniele Aiello、Dirk Schepmann、Patrizia Diana、Bernhard Wünsch

  DOI：10.1016/j.ejmech.2021.114079

  日期：2022.2

  (morphans) with a (3,4-dichlorophenyl)acetyl group at 2-position and a pyrrolidino moiety at 8-position were designed as conformationally restricted analogs of piperidine-based KOR agonists. The synthesis started with 4-oxopiperidine-2-carboxylic acid comprising 13 reaction steps. At first the ketone 10 was transformed into diester 7 bearing a propionate side chain. Dieckmann condensation of diester 7

  2-氮杂双环[3.3.1]壬烷（吗啡）在 2 位具有 (3,4-二氯苯基) 乙酰基，在 8 位具有吡咯烷基部分，被设计为基于哌啶的 KOR 激动剂的构象受限类似物。合成从 4-氧代哌啶-2-羧酸开始，包括 13 个反应步骤。首先，酮10被转化为带有丙酸酯侧链的二酯7 。二酯7的Dieckmann 缩合得到双环烯醇酯14和随后的 Krapcho 脱乙氧基羰基化是合成的关键步骤。对映体吡咯烷 (1 S ,5 R ,8 R )- 5a和 (1 R ,5S ,8 S )- 5a通过手性 HPLC 分离。Eutomer (1 S ,5 R ,8 R ) -5a显示出高 KOR 亲和力 ( K i  = 18 nM) 和对 MOR、DOR 和 σ 2受体的选择性。得出的结论是，(1 S ,5 R ,8 R ) -5a (68°)的 KOR 药效团 N(pyrrolididine)-CCN(acyl) 的二面角接近于柔性
• Tetrazole excitatory amino acid receptor antagonists
  申请人：Eli Lilly and Company

  公开号：US04968678A1

  公开（公告）日：1990-11-06

  The present invention provides novel tetrazole derivatives useful as excitatory amino acid receptor antagonists and in treating a variety of associated nervous system disorders.

  本发明提供了一种新型四唑衍生物，可用作兴奋性氨基酸受体拮抗剂，并用于治疗各种相关的神经系统疾病。
• Effects of five-membered ring conformation on bioreceptor recognition: identification of 3R-amino-1-hydroxy-4R-methylpyrrolidin-2-one (L-687,414) as a potent glycine/N-methyl-D-aspartate receptor antagonist
  作者：Paul D. Leeson、Brian J. Williams、Raymond Baker、Tamara Ladduwahetty、Kevin W. Moore、Michael Rowley

  DOI：10.1039/c39900001578

  日期：——

  Syntheses of the 4-methyl (2 and 3) and [3.2.1]bicyclo (4 and 5) analogues of the glycine/N-methyl-D-aspartate (NMDA) antagonist 3-amino-1-hydroxypyrrolidin-2-one (HA-966, 1) provide evidence that glycine receptor recogntion requires the energetically less favoured 3-pseudoaxial conformation of the pyrrolidone ring, resulting in a 5–10 fold improvement in activity with the 3R-amino, 4R-methyl derivative

  甘氨酸/ N-甲基-D-天门冬氨酸（NMDA）拮抗剂3-氨基-1-羟基吡咯烷-2-酮的4-甲基（2和3）和[3.2.1]双环（4和5）类似物的合成（HA-966，1）提供的证据表明甘氨酸受体recogntion要求吡咯烷酮环的能量少青睐3- pseudoaxial构象，导致5-10倍的提高的活性与3 - [R -氨基，4 - [R -甲基衍生物（2a，L-687414）。
• Heteroatom-substitution as a strategy for increasing the potency of competitive NMDA antagonists
  作者：Paul L. Ornstein、M.Brian Arnold、William H.W. Lunn、Lawrence J. Heinz、J.David Leander、David Lodge、Darryle D. Schoepp

  DOI：10.1016/s0960-894x(98)00038-9

  日期：1998.2

  We report the synthesis and characterization of compounds that are competitive NMDA receptor antagonists. Significant increases in affinity and potency were obtained by incorporation of a heteroatom into the substructure of the tetrazole-substituted amino acid LY233053. (C) 1998 Elsevier Science Ltd. All rights reserved.
• ORNSTEIN, PAUL L.;SCHOEPP, DARRYLE D.;ARNOLD, M. BRIAN;LEANDER, J. DAVID;+, J. MED. CHEM., 34,(1991) N, C. 90-97
  作者：ORNSTEIN, PAUL L.、SCHOEPP, DARRYLE D.、ARNOLD, M. BRIAN、LEANDER, J. DAVID、+

  DOI：——

  日期：——