Ethyl (3SR,4aRS,6SR,8aRS)-6-formyl-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-formyl-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-formyl-3,4,4a,5,6,7,8,8a-octahydro-1H-isoquinoline-2,3-dicarboxylate
• 化学式: C₁₅H₂₃NO₅
• 分子量: 297.351
• InChiKey: OPNBVGGPCMCEEX-RVMXOQNASA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  21
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.8
• 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：

  Ethyl (3SR,4aRS,6SR,8aRS)-6-formyl-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate 在 palladium on activated charcoal 草酰氯 、 dimethyl sulfide borane 、 氢气 、 sodium hydride 、 magnesium 、 三乙胺 作用下， 以 四氢呋喃 、 乙酸乙酯 为溶剂， -78.0~25.0 ℃ 、413.69 kPa 条件下， 反应 18.5h， 生成 (3S,4aR,6S,8aR)-6-(4-Cyano-butyl)-octahydro-isoquinoline-2,3-dicarboxylic acid dimethyl ester
  参考文献：
  名称：

  6-（四唑基烷基）取代的十氢异喹啉-3-羧酸AMPA受体拮抗剂的结构活性研究。1.立体化学，链长和链取代的影响。

  摘要：

  制备了一系列6-取代的十氢异喹啉-3-羧酸作为兴奋性氨基酸（EAA）受体拮抗剂。这些化合物是配体门控离子通道（离子型）的N-甲基-D-天冬氨酸（NMDA）和2-氨基-3-（5-甲基-3-羟基异恶唑-4-基）丙酸（AMPA）亚类的拮抗剂。 EAA受体。（3S，4aR，6R，8aR）-6-（2-（1H-四唑-5-基）乙基）-1,2,3,4,4a，5,6,7,8,8,8a-十氢异喹啉-3 -羧酸（9）是有效的，选择性的和内在活性的AMPA拮抗剂。该系列的其他类似物，包括（3S，4aR，6S，8aR）-6-（（（1H-四唑-5-基）甲基）-1,2,3,4,4a，5,6,7,8， 8a-十氢异喹啉-3-羧酸（32）和（3S，4aR，6S，8aR）-6-（膦酰基甲基）-1,2,3,4,4a，5,6,7,8,8,8a-十氢异喹啉- 3-ca rboxylic acid（61）是有效的，选择性的和内吸性的

  DOI：

  10.1021/jm950912p
• 作为产物：
  描述：

  Ethyl (3SR,4aRS,6RS,8aRS)-6-(hydroxymethyl)-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate 在 咪唑 、 sodium hydroxide 、 草酰氯 、 dimethyl sulfide borane 、 双氧水 、 碘 、 二甲基亚砜 、 三乙胺 、 三苯基膦 作用下， 以 二氯甲烷 为溶剂， 反应 10.75h， 生成 Ethyl (3SR,4aRS,6SR,8aRS)-6-formyl-2-(methoxycarbonyl)-1,2,3,4,4a,5,6,7,8,8a-decahydroisoquinoline-3-carboxylate
  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

文献信息

• [EN] ISOQUINOLINE-3-CARBOXYLIC ACID DERIVATIVES AS EXCITATORY AMINO ACID RECEPTOR ANTAGONISTS<br/>[FR] DERIVES D'ACIDE ISOQUINOLINE-3-CARBOXYLIQUE EN TANT QU'ANTAGONISTES DU RECEPTEUR D'ACIDE AMINE EXCITATEUR
  申请人：LILLY CO ELI

  公开号：WO2003082856A1

  公开（公告）日：2003-10-09

  The present invention provides a compound of Formula I, or a pharmaceutically acceptable salt thereof, pharmaceutical compositions comprising an effective amount of a compound of Formula I in combination with a suitable carrier, diluent, or excipient, and methods for treating neurological disorders and neurodegenerative diseases comprising administering to a patient in need thereof an effective amount of a compound of Formula I.

  本发明提供了一种化合物I的化合物，或其药用可接受的盐，包含化合物I的有效量与适当载体、稀释剂或赋形剂结合的药物组合物，以及治疗神经系统疾病和神经退行性疾病的方法，包括向需要的患者施用化合物I的有效量。
• (3SR,4aRS,6SR,8aRS)-6-(1H-Tetrazol-5-yl)decahydroisoquinoline-3-carboxylic Acid, a Novel, Competitive, Systemically Active NMDA and AMPA Receptor Antagonist
  作者：Paul L. Ornstein、M. Brian Arnold、Nancy K. Allen、J. David Leander、Joseph P. Tizzano、David Lodge、Darryle D. Schoepp

  DOI：10.1021/jm00025a005

  日期：1995.12

  corresponding isomers of 7. The compound displaces both NMDA and AMPA receptor binding and antagonizes depolarizations in cortical slices evoked by both NMDA and AMPA. In mice and pigeons, the compound showed antagonism of responses mediated through NMDA and AMPA receptors. Using the resolved optical isomers of 6, both NMDA and AMPA antagonist activities were found to reside in a single isomer, (-)-6.

  我们报告的合成和表征6（LY246492），这是一种竞争性的N-甲基-D-天冬氨酸（NMDA）和2-氨基-3-（3-羟基-5-甲基异恶唑-4-基）丙酸（AMPA） ）受体拮抗剂。用最近描述的醛7分四个步骤制备四唑取代的氨基酸6。使用7的相应异构体，从相同的反应序列中获得旋光异构体（-）-6和（+）-6。 NMDA和AMPA受体结合均能拮抗NMDA和AMPA诱发的皮质切片的去极化作用。在小鼠和鸽子中，该化合物显示出对通过NMDA和AMPA受体介导的反应的拮抗作用。使用6的拆分的旋光异构体，发现NMDA和AMPA拮抗剂活性均位于单个异构体（-）-6中。
• (3SR,4aRS,6RS,8aRS)-6-[2-(1H-Tetrazol-5-yl)ethyl]decahydroisoquinoline-3-carboxylic acid: a structurally novel, systemically active, competitive AMPA receptor antagonist
  作者：Paul L. Ornstein、M. Brian Arnold、Nancy K. Augenstein、David Lodge、J. David Leander、Darryle D. Schoepp

  DOI：10.1021/jm00066a016

  日期：1993.7
• Structure−Activity Studies of 6-(Tetrazolylalkyl)-Substituted Decahydroisoquinoline-3-carboxylic Acid AMPA Receptor Antagonists. 1. Effects of Stereochemistry, Chain Length, and Chain Substitution
  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/jm950912p

  日期：1996.1.1

  subsequent publication look at the AMPA antagonist aspects of this SAR. Herein we report the effects of varying stereochemistry around the hydroisoquinoline ring; of tetrahydro-versus decahydroisoquinoline; of having the carboxylic acid at C-1 versus C-3; of varying the length of the carbon chain connecting a tetrazole to the bicyclic nucleus; and of holding the connecting chain constant at two atoms

  制备了一系列6-取代的十氢异喹啉-3-羧酸作为兴奋性氨基酸（EAA）受体拮抗剂。这些化合物是配体门控离子通道（离子型）的N-甲基-D-天冬氨酸（NMDA）和2-氨基-3-（5-甲基-3-羟基异恶唑-4-基）丙酸（AMPA）亚类的拮抗剂。 EAA受体。（3S，4aR，6R，8aR）-6-（2-（1H-四唑-5-基）乙基）-1,2,3,4,4a，5,6,7,8,8,8a-十氢异喹啉-3 -羧酸（9）是有效的，选择性的和内在活性的AMPA拮抗剂。该系列的其他类似物，包括（3S，4aR，6S，8aR）-6-（（（1H-四唑-5-基）甲基）-1,2,3,4,4a，5,6,7,8， 8a-十氢异喹啉-3-羧酸（32）和（3S，4aR，6S，8aR）-6-（膦酰基甲基）-1,2,3,4,4a，5,6,7,8,8,8a-十氢异喹啉- 3-ca rboxylic acid（61）是有效的，选择性的和内吸性的
• 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.