ethyl 1-(tert-butoxycarbonyl)-4-formylpiperidine-2-carboxylate | 117423-46-8

• 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 1-(tert-butoxycarbonyl)-4-formylpiperidine-2-carboxylate
• 英文别名: 1-(tert-butoxycarbonyl)-2-ethoxycarbonylpiperidine-4-carboxaldehyde；1-O-tert-butyl 2-O-ethyl 4-formylpiperidine-1,2-dicarboxylate
• CAS: 117423-46-8
• 化学式: C₁₄H₂₃NO₅
• 分子量: 285.34
• InChiKey: VVOFSLLZUHOFRC-UHFFFAOYSA-N

物化性质

• 沸点：
  369.6±42.0 °C(Predicted)
• 密度：
  1.162±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  20
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.79
• 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 1-(tert-butoxycarbonyl)-4-formylpiperidine-2-carboxylate 在 sodium tetrahydroborate 、 N-溴代丁二酰亚胺(NBS) 、 正丁基锂 、 乙醇 、 三苯基膦 、 sodium iodide 作用下， 以 二氯甲烷 、 丙酮 为溶剂， 反应 3.17h， 生成
  参考文献：
  名称：

  4-(Phosphonoalkyl)- and 4-(phosphonoalkenyl)-2-piperidinecarboxylic acids: synthesis, activity at N-methyl-D-aspartic acid receptors and anticonvulsant activity

  摘要：

  A series of 4-(phosphonoalkyl)- and 4-(phosphonoalkenyl)-2-piperidinecarboxylic acids were synthesized, and their biological activity was assessed as competitive ligands for the NMDA receptor, both in vitro by using a receptor binding assay ([3H]CGS 19755 binding) and in vivo by using an NMDA seizure model in mice. The analogues were also evaluated in [3H]AMPA and [3H]kainate binding to assess their affinity for non-NMDA excitatory amino acid receptor subtypes. A number of these analogues show potent and selective NMDA antagonistic activity both in vitro and in vivo. Most notable are 4-(phosphonomethyl)-2-piperidinecarboxylic acid (1a) (CGS 19755) and the phosphonopropenyl analogue 1i, both of which show anticonvulsant activity in the 1-2 mg/kg ip range. With the aid of computer-assisted modeling, a putative bioactive conformation for AP-5 is hypothesized from the SAR data presented and a preliminary model for the antagonist-preferring state of the NMDA receptor is presented.

  DOI：

  10.1021/jm00129a025
• 作为产物：
  描述：

  4-吡啶甲醇 在 platinum(IV) oxide 咪唑 、 盐酸 、 氢气 、 sodium 、 三乙胺 、 间氯过氧苯甲酸 、 pyridinium chlorochromate 作用下， 以 二氯甲烷 、 溶剂黄146 、 N,N-二甲基甲酰胺 为溶剂， 25.0~90.0 ℃ 、413.69 kPa 条件下， 反应 99.0h， 生成 ethyl 1-(tert-butoxycarbonyl)-4-formylpiperidine-2-carboxylate
  参考文献：
  名称：

  4-(Phosphonoalkyl)- and 4-(phosphonoalkenyl)-2-piperidinecarboxylic acids: synthesis, activity at N-methyl-D-aspartic acid receptors and anticonvulsant activity

  摘要：

  A series of 4-(phosphonoalkyl)- and 4-(phosphonoalkenyl)-2-piperidinecarboxylic acids were synthesized, and their biological activity was assessed as competitive ligands for the NMDA receptor, both in vitro by using a receptor binding assay ([3H]CGS 19755 binding) and in vivo by using an NMDA seizure model in mice. The analogues were also evaluated in [3H]AMPA and [3H]kainate binding to assess their affinity for non-NMDA excitatory amino acid receptor subtypes. A number of these analogues show potent and selective NMDA antagonistic activity both in vitro and in vivo. Most notable are 4-(phosphonomethyl)-2-piperidinecarboxylic acid (1a) (CGS 19755) and the phosphonopropenyl analogue 1i, both of which show anticonvulsant activity in the 1-2 mg/kg ip range. With the aid of computer-assisted modeling, a putative bioactive conformation for AP-5 is hypothesized from the SAR data presented and a preliminary model for the antagonist-preferring state of the NMDA receptor is presented.

  DOI：

  10.1021/jm00129a025

文献信息

• Certain 2-carboxypiperidyl-alkylene phosphonic acids and esters thereof
  申请人：Ciba-Geigy Corporation

  公开号：US04906621A1

  公开（公告）日：1990-03-06

  The present invention is concerned with the phosphonic acids of formula I ##STR1## wherein one or both of the acidic hydroxy groups of the phosphonic acid moiety may be functionalized in form of pharmaceutically acceptable mono- or di- esters; wherein Y represents optionally substituted 2-carboxypyrrolidinyl, 2-carboxy-2,5-dihydropyrrolyl, 2-carboxy-1,2,3,6-tetrahydropyridinyl, 2-carboxy-1,2,5,6-tetrahydropyridinyl, 2-carboxypiperidinyl, 2-carboxytetrahydroquinolinyl or 2-carboxyperhydroquinolinyl, 2-carboxy-2,3-dihydroindolyl or 2-carboxyperhydroindolyl as described herein, and in each of which the carboxy group may be functionalized in form of a pharmaceutically acceptable ester or amide; A represents a direct bond, lower alkenylene, lower alkylidene or lower alkylene provided that A does not represent a direct bond when Y represents 2-carboxypyrrolidinyl; and pharmaceutically acceptable salts thereof; which are useful for the treatment of nervous system disorders in mammals and as antagonists of the N-methyl-D-aspartate sensitive excitatory amino acid receptor.

  本发明涉及式I的膦酸##STR1##其中膦酸基团的一个或两个酸性羟基可以被功能化为药学上可接受的单酯或二酯形式；其中Y代表可选择地取代的2-羧基吡咯烷基，2-羧基-2,5-二氢吡咯基，2-羧基-1,2,3,6-四氢吡啶基，2-羧基-1,2,5,6-四氢吡啶基，2-羧基哌啶基，2-羧基四氢喹啉基或2-羧基四氢喹啉基，如本文所述的2-羧基-2,3-二氢吲哚基或2-羧基四氢吲哚基，并且其中羧基可以被功能化为药学上可接受的酯或酰胺形式；A代表直接键，低烯基，低烷基亚甲基或低烷基亚烯基，其中A不代表直接键时，Y代表2-羧基吡咯烷基；及其药学上可接受的盐；其用于治疗哺乳动物的神经系统疾病，并作为N-甲基-D-天冬氨酸敏感的兴奋性氨基酸受体的拮抗剂。
• 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
• Certain phosphonic acid quinoline-2-carboxylic acids, esters or amides
  申请人：Ciba-Geigy Corporation

  公开号：US05217963A1

  公开（公告）日：1993-06-08

  The present invention is concerned with the phosphonic acids of formula I ##STR1## wherein one or both of the acidic hydroxy groups of the phosphonic acid moiety may be functionalized in form of pharmaceutically acceptable mono- or di- esters; wherein Y represents optionally substituted 2-carboxytetrahydroquinolinyl or 2-carboxyperhydroquinolinyl, and in each of which the carboxy group may be functionalized in form of a pharmaceutically acceptable ester or amide; A represents a direct bond, lower alkenylene, lower alkylidene or lower alkylene; and pharmaceutically acceptable salts thereof; which are useful for the treatment of nervous system disorders in mammals and as antagonists of the N-methyl-D-aspartate sensitive excitatory amino acid receptor.

  本发明涉及式I的膦酸：##STR1## 其中膦酸基团的一个或两个酸性羟基可以以药学上可接受的单酯或双酯的形式进行官能化；其中Y代表可以选择取代的2-羧基四氢喹啉基或2-羧基戊二氢喹啉基，其中羧基可以以药学上可接受的酯或酰胺的形式进行官能化；A代表直接键，低烯基，低烷基亚甲基或低烷基；以及其药学上可接受的盐；它们对哺乳动物的神经系统疾病治疗和作为N-甲基-D-天门冬氨酸敏感性兴奋性氨基酸受体的拮抗剂是有用的。
• Certain phosphonic acids and derivatives useful for the treatment of
  申请人：Ciba-Geigy Corporation

  公开号：US05057506A1

  公开（公告）日：1991-10-15

  The present invention is concerned with the phosphonic acids of formula I ##STR1## wherein one or both of the acidic hydroxy groups of the phosphonic acid moiety may be functionalized in form of pharmaceutically acceptable mono- or di- esters; wherein Y represent optionally substituted 2-carboxypyrrolidinyl, 2-carboxy-2,5-dihydropyrrolyl, 2-carboxy-1,2,3,6-tetrahydropyridinyl, 2-carboxy-1,2,5,6-tetrahydropyridinyl, 2-carboxypiperidinyl, 2-carboxyetrahydroquinolinyl or 2-carboxyperhydroquinolinyl, 2-carboxyl-2,3-dihydroindolyl or 2-carboxyperhydroindolyl as described herein, and in each of which the carboxy group may be functionalized in form of a pharmaceutical acceptable ester or amide; A represents a direct bond, lower alkenylene, lower alkylidene or lower alkylene provided that A does not represent a direct bond when Y represents 2-carboxypyrolidinyl; and pharmaceutically acceptable salts thereof; which are useful for the treatment of nervous system disorders in mammals and as antagonists of the N-methyl-D-aspartate sensitive excitatory amino acid receptor.

  本发明涉及式I的膦酸，其中膦酸基团中的一个或两个酸性羟基可以以药学上可接受的单酯或二酯的形式进行官能化；其中Y代表可选择取代的2-羧基吡咯烷基，2-羧基-2,5-二氢吡咯基，2-羧基-1,2,3,6-四氢吡啶基，2-羧基-1,2,5,6-四氢吡啶基，2-羧基哌啶基，2-羧基四氢喹啉基或2-羧基过氢喹啉基，2-羧基-2,3-二氢吲哚基或2-羧基过氢吲哚基，如本文所述，在其中羧基可以以药学可接受的酯或酰胺的形式进行官能化；A代表直接键，较低的烯基，较低的烷基亚甲基或较低的烷基，但当Y代表2-羧基吡咯烷基时，A不代表直接键；以及其药学可接受的盐；它们对哺乳动物的神经系统疾病的治疗和作为N-甲基-D-天门冬氨酸敏感性兴奋性氨基酸受体的拮抗剂是有用的。
• Ungesättigte Phosphonsäure und Derivate
  申请人：CIBA-GEIGY AG

  公开号：EP0275820A2

  公开（公告）日：1988-07-27

  Die vorliegende Erfindung bezieht sich auf Verbindungen der Formel I, worin eine oder beide der sauren Hydroxygruppen des Phosphonsäure­teils verethert sein können, m Eins oder Null ist, R¹ Carboxy, verestertes Carboxy oder amidiertes Carboxy bedeutet, der hetero­cyclische Fünf- oder Sechsring zusätzlich am Kohlenstoff und/oder Stickstoff substituiert sein kann, eine Kohlenstoff-Kohlenstoff-­Doppelbindung aufweisen oder mit einem carbocyclischen Sechsring, ausgehend von benachbarten Kohlenstoffatomen, kondensiert sein kann, A für Niederalkenylen steht; sowie Salze davon. Diese Verbindungen eignen sich als Antagonisten des N-Methyl-D-aspartatsensiblen Aminosäurereizrezeptors bei Säugetieren.

  本发明涉及式 I 的化合物、 其中，膦酸分子的一个或两个酸性羟基可被醚化，m 为 1 或 0，R¹ 为羧基、酯化羧基或酰胺化羧基，杂环五环或六环可另外被碳和/或氮取代，可具有碳碳双键或可与从相邻碳原子开始的碳环六环融合，A 为低级烯烃；及其盐类。这些化合物可作为哺乳动物体内 N-甲基-D-天冬氨酸敏感性氨基酸受体的拮抗剂。