Ethyl (3SR,4aRS,6SR,8aRS)-6-(bromomethyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate

• 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
• 英文名称: Ethyl (3SR,4aRS,6SR,8aRS)-6-(bromomethyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
• 英文别名: 3-O-ethyl 2-O-methyl (3S,4aR,6S,8aR)-6-(bromomethyl)-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2,3-dicarboxylate
• 化学式: C₁₅H₂₄BrNO₄
• 分子量: 362.264
• InChiKey: WFVDYAFZUCGESN-RVMXOQNASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.87
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  Ethyl (3SR,4aRS,6SR,8aRS)-6-(bromomethyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate 在 盐酸 、 三正丁基叠氮化锡 作用下， 反应 1.5h， 生成 (3S,4aR,6S,8aR)-6-(1H-Tetrazol-5-ylmethyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylic acid
  参考文献：
  名称：

  Stereoselective Synthesis of 6-Substituted Decahydroisoquinoline-3-carboxylates: Intermediates for the Preparation of Conformationally Constrained Acidic Amino Acids

  摘要：

  In this article we describe the stereoselective preparation of two 6-(hydroxymethyl) substituted decahydroisoquinoline-3-carboxylates, which are useful in the synthesis of a number of excitatory amino acid antagonists, e.g., (-)-1a (LY235959), (-)-2a (LY202157) and (-)-3a(LY293558). For example, the known ketone 4 was converted to either the (3SR,4aRS,6SR,8aRS)-alcohol 18 or the (3SR,4aRS,6RS,8aRS)-alcohol 21, the former via a stereoselective hydroboration reaction, the latter via a stereoselective enol ether hydrolysis followed by reduction. These C-6 epimeric alcohols were easily converted to a number of useful intermediates, e.g., aldehydes, bromides and iodides. If we used resolved ketone 4, then these intermediates could be obtained in optically active form. In either racemic or non-racemic form, these intermediates provided access to a number of diastereomerically pure amino acids that were difficult to obtain by earlier routes.

  DOI：

  10.1021/jo00104a051
• 作为产物：
  描述：

  Ethyl (3S,4aR,6S,8aR)-6-(hydroxymethyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate 在 吡啶 、 二溴三苯基膦 作用下， 以 二氯甲烷 为溶剂， 反应 1.5h， 以87%的产率得到Ethyl (3SR,4aRS,6SR,8aRS)-6-(bromomethyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
  参考文献：
  名称：

  [Tetrazoyl-11C]LY202157 synthesis forin vivo studies of the NMDA receptor channel complex

  摘要：

  [Tetrazoyl-C-11]LY202157 8 was prepared via a three step synthesis from ethyl (3S,4aR,6S,8aR)-6-bromomethyl-2-methoxycarbonyl 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinol This bromo precursor was reacted with [C-11]hydrogen cyanide affording the corresponding [C-11]nitrile. Conversion to the tetrazole was achieved by treatment with azidotributyltin followed by hydrolysis with 6N hydrochloric acid at 200 degreesC. After HPLC purification and analytical HPLC control, more than 370 MBq (10 mCi) of [tetrazoyl-C-11] LY202157 were obtained after an overall 60 minute synthesis time with 38% yield (EOB) and specific activity of 25.9 GBq/mu mol (700 mCi/mu mol). Ex vivo biological studies showed that the [tetrazoyl-C-11] LY202157 did not cross the brain blood barrier.

  DOI：

  10.1002/1099-1344(200011)43:13<1311::aid-jlcr422>3.0.co;2-b

文献信息

• Structure−Activity Studies of 6-Substituted Decahydroisoquinoline-3-carboxylic Acid AMPA Receptor Antagonists. 2. Effects of Distal Acid Bioisosteric Substitution, Absolute Stereochemical Preferences, and in Vivo Activity
  作者：Paul L. Ornstein、M. Brian Arnold、Nancy K. Allen、Thomas Bleisch、Peter S. Borromeo、Charles W. Lugar、J. David Leander、David Lodge、Darryle D. Schoepp

  DOI：10.1021/jm950913h

  日期：1996.1.1

  the excitatory amino acid antagonist activity in a series of decahydroiso-quinoline-3-carboxyic acids, and within this series found the potent and selective AMPA antagonist (3SR,4aRS,6RS,8aRS)-6-(2-(1H-tetrazol-5-yl )ethyl) decahydroisoquinoline-3-carboxylic acid (1). In this and the preceding paper, we looked at the structure-activity relationships for AMPA antagonist activity in this series of compounds

  我们探索了一系列十氢异喹啉-3-羧酸中的兴奋性氨基酸拮抗剂活性，并在该系列中发现了有效的选择性AMPA拮抗剂（3SR，4aRS，6RS，8aRS）-6-（2-（1H -四唑-5-基）乙基）十氢异喹啉-3-羧酸（1）。在本文中，我们研究了该系列化合物中AMPA拮抗剂活性的构效关系。我们已经表明1具有最佳的立体化学阵列，并且AMPA拮抗剂活性对于将四唑与双环核分开的二碳间隔基而言是最大的。在本文中，我们探讨了改变远端酸的作用以及许多类似物的绝对立体化学偏好。我们研究了各种不同的酸性生物异构体，包括五元杂环酸，例如四唑，1,2,4-三唑和3-异恶唑酮；羧酸，膦酸和磺酸；和酰基磺酰胺。对大鼠皮质组织中的化合物抑制AMPA（[3H] AMPA），NMDA（[3H] CGS 19755）和海藻酸（[3H] kainic acid）受体选择性放射性配体结合的能力及其功能进行了评估抑制由AMPA（40 microM），NMDA（40
• Galea; Ponchant; Bottlaender, Journal of labelled compounds and radiopharmaceuticals, 1999, vol. 42, # SUPPL. 1, p. S369-S371
  作者：Galea、Ponchant、Bottlaender、Coulon、Fuseau、Ottaviani、Crouzel

  DOI：——

  日期：——
• Stereoselective Synthesis of 6-Substituted Decahydroisoquinoline-3-carboxylates: Intermediates for the Preparation of Conformationally Constrained Acidic Amino Acids
  作者：Paul L. Ornstein、Nancy K. Augenstein、M. Brian Arnold

  DOI：10.1021/jo00104a051

  日期：1994.12

  In this article we describe the stereoselective preparation of two 6-(hydroxymethyl) substituted decahydroisoquinoline-3-carboxylates, which are useful in the synthesis of a number of excitatory amino acid antagonists, e.g., (-)-1a (LY235959), (-)-2a (LY202157) and (-)-3a(LY293558). For example, the known ketone 4 was converted to either the (3SR,4aRS,6SR,8aRS)-alcohol 18 or the (3SR,4aRS,6RS,8aRS)-alcohol 21, the former via a stereoselective hydroboration reaction, the latter via a stereoselective enol ether hydrolysis followed by reduction. These C-6 epimeric alcohols were easily converted to a number of useful intermediates, e.g., aldehydes, bromides and iodides. If we used resolved ketone 4, then these intermediates could be obtained in optically active form. In either racemic or non-racemic form, these intermediates provided access to a number of diastereomerically pure amino acids that were difficult to obtain by earlier routes.
• [Tetrazoyl-11C]LY202157 synthesis forin vivo studies of the NMDA receptor channel complex
  作者：M. Ponchant、H. Galéa、M. Bottlaender、C. Coulon、C. Fuseau、M. Ottaviani、C. Crouzel

  DOI：10.1002/1099-1344(200011)43:13<1311::aid-jlcr422>3.0.co;2-b

  日期：2000.11

  [Tetrazoyl-C-11]LY202157 8 was prepared via a three step synthesis from ethyl (3S,4aR,6S,8aR)-6-bromomethyl-2-methoxycarbonyl 1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinol This bromo precursor was reacted with [C-11]hydrogen cyanide affording the corresponding [C-11]nitrile. Conversion to the tetrazole was achieved by treatment with azidotributyltin followed by hydrolysis with 6N hydrochloric acid at 200 degreesC. After HPLC purification and analytical HPLC control, more than 370 MBq (10 mCi) of [tetrazoyl-C-11] LY202157 were obtained after an overall 60 minute synthesis time with 38% yield (EOB) and specific activity of 25.9 GBq/mu mol (700 mCi/mu mol). Ex vivo biological studies showed that the [tetrazoyl-C-11] LY202157 did not cross the brain blood barrier.