2-acetyl-5-dimethylaminopentanoic acid ethyl ester | 69472-61-3

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 酮酸及其衍生物
• 英文名称: 2-acetyl-5-dimethylaminopentanoic acid ethyl ester
• 英文别名: ethyl 2-(3-dimethylamino-propyl)-3-oxo-butanoate；ethyl 2-(3-dimethylamino-propyl)-3-oxobutanoate；ethyl-2-(3-dimethylaminopropyl)oxobutanoate；ethyl 2-acetyl-5-(dimethylamino)pentanoate；Pentanoic acid, 2-acetyl-5-(dimethylamino)-, ethyl ester
• CAS: 69472-61-3
• 化学式: C₁₁H₂₁NO₃
• 分子量: 215.293
• InChiKey: UEJVXJPPYYDENA-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  15
• 可旋转键数：
  8
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.82
• 拓扑面积：
  46.6
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  2-acetyl-5-dimethylaminopentanoic acid ethyl ester 在 palladium on activated charcoal titanium(IV) isopropylate 、 盐酸 、 硫酸 、 氢气 、 sodium acetate 、 sodium nitrite 作用下， 以 乙醇 、 乙酸乙酯 为溶剂， 反应 27.75h， 生成 3-<2-(dimethylamino)ethyl>-5-<2-(4,4-diphenyl-2,5-dioxo-1-imidazolidinyl)ethyl>-1H-indole-2-carboxylic acid
  参考文献：
  名称：

  取代的2，N-苄基羧酰胺基-5-（2-乙基-1-二氧代咪唑啉基）-N，N-二甲基色胺衍生物的合成和血清素能活性：血管5-HT（1B）-样受体的新型拮抗剂。

  摘要：

  描述了一系列新的取代的2，N-苄基羧酰胺基-5-（2-乙基-1-二氧代咪唑啉基）-N，N-二甲基色胺衍生物的合成和血管5-HT（1B）-样受体活性。已经研究了对5-乙烯-连接的杂环和2-苄基酰胺侧链上的取代基的修饰。鉴定出几种化合物，它们在pK（B）> 7.0的血管5-HT（1B）样受体上表现出亲和力，选择性比alpha（1）-肾上腺素受体亲和力和5-HT（2A）受体亲和力高100倍，并且表现出良好的药代动力学特征。N-苄基-3- [2-（二甲基氨基）乙基] -5- [2-（4,4-二甲基-2，5-二氧-1-咪唑啉基）乙基] -1H-吲哚-2-羧酰胺（23）被认为是非常有力的 沉默（通过血管紧张素II无法揭露兔股动脉中的5-HT（1B）样受体介导的激动剂活性来判断）和具有血浆消除一半功能的竞争性血管5-HT（1B）样受体拮抗剂犬血浆中约4小时的寿命，并具有良好的口服生物利用度。讨论了该系列

  DOI：

  10.1021/jm9706325
• 作为产物：
  描述：

  N,N-二甲氨基氯丙烷盐酸盐 、 乙酰乙酸乙酯 在 sodium ethanolate 作用下， 生成 2-acetyl-5-dimethylaminopentanoic acid ethyl ester
  参考文献：
  名称：

  一种新型的2,5-取代的色胺衍生物作为血管5HT1B / 1D受体拮抗剂。

  摘要：

  描述了在血管5HT1B样受体上一系列新的2,5-取代的色胺衍生物的设计，合成和活性。在对2-取代基，特别是对亚甲基或乙烯连接的5-侧链进行各种修饰之后，已经提出了5HT1B-样受体的几个重要的辅助结合位点。基于5HT1B样受体的拟药模型对新分子的仔细设计导致发现乙基3- [2-（二甲基氨基）乙基] -5- [2-（2,5-二氧代-1-咪唑啉基] ）[乙基] -1H-吲哚-2-羧酸酯（40），一种高效，沉默，竞争和选择性的拮抗剂，仅对血管5HT1B样受体具有亲和力。2酯取代基大小的变化对5HT1B样受体和其他受体的亲和力有重要影响。在5侧链的杂环中谨慎地放置羰基取代基对于5HT2A和其他受体的良好亲和力和选择性至关重要。确定了几个关键的结构和电子特征，这些特征对基于色胺的系列药物产生拮抗作用至关重要。为了实现拮抗作用，缺电子的吲哚环系统似乎是必不可少的，这是通过在吲哚环的2-位包含吸电子基团

  DOI：

  10.1021/jm9605849

文献信息

• A facile synthesis of 7-chloromethyl-1<i>H</i>-indole-2-carboxylates: Replacement of a sulfonic acid functionality by chlorine
  作者：Béla Pete、Frigyes Varga、János Kovács

  DOI：10.1002/jhet.5570420422

  日期：2005.5

  Valuable new synthetic intermediates, 7-chloromethyl-1H-indole-2-carboxylates (3a-d), were prepared by the facile elimination of sulfur dioxide under the influence of thionyl chloride from 2-ethoxycarbonyl-1H-indole-7-methanesulfonic acids (1a-d), easily accessible by Fischer-type indolisation. The 7-chloromethylindoles easily underwent methanolysis and aminolysis.

  通过在亚硫酰氯的作用下从2-乙氧基羰基-1 H-吲哚-7-容易地消除二氧化硫，制得了有价值的新型合成中间体7-氯甲基-1 H-吲哚-2-羧酸酯（3a-d）甲磺酸（1a-d），很容易通过费歇尔型吲哚酯化获得。7-氯甲基吲哚很容易进行甲醇分解和氨解。
• A facile synthesis of 4-, 5- and 6-chloromethyl-1H-indole-2-carboxylates: replacement of a sulfonic acid functionality by chlorine
  作者：Béla Pete、Gyula Parlagh

  DOI：10.1016/j.tet.2004.07.038

  日期：2004.9

  Valuable new synthetic intermediates, 4-, 5- or 6-chloromethyl-1H-indole-2-carboxylates, were prepared by the facile elimination of SO2 from 2-ethoxycarbonyl-1H-indole-4-, 5- or 6-methanesulfonic acids, respectively, easily accessible by Fischer-type indolization.

  通过从2-乙氧基羰基-1 H-吲哚-4-，5-或6轻松消除SO 2制备了有价值的新型合成中间体4-，5-或6-氯甲基-1 H-吲哚-2-羧酸-甲磺酸分别可以通过费歇尔型吲哚酸容易地获得。
• [EN] NOVEL PROCESS<br/>[FR] NOUVEAU PROCÉDÉ
  申请人：GENERICS UK LTD

  公开号：WO2009016414A1

  公开（公告）日：2009-02-05

  The present invention relates to a novel process for the preparation of almotriptan and pharmaceutically acceptable salts thereof, which affords product conveniently and efficiently with commercially acceptable yields and purity. The present invention also relates to a novel synthetic intermediate used in the process.

  本发明涉及一种用于制备阿莫曲普坦及其药用可接受盐的新型工艺，该工艺以商业上可接受的产量和纯度便捷高效地获得产品。本发明还涉及用于该工艺的一种新型合成中间体。
• Synthese von Derivaten des Indols, des Diindolylmethans und des Indolyl-(tetrahydroindolyl)methans
  作者：Carl Heinz Brieskorn、Günther Wittig

  DOI：10.1002/ardp.19783111110

  日期：——

  3‐Methyl‐2‐(3‐methyl‐2‐indolylmethylen)‐2H‐indoliumbromid (3) und 3‐Methyl‐2‐(3‐methyl‐2‐indolylmethylen)‐4,5,6,7‐tetrahydro‐2H‐indolium‐bromid (14) besitzen das chromophore System, das auch beim Tryptophan‐Nachweis nach Hopkins‐Cole auftritt. Mit bis zu 50 % höherer Ausbeute entsteht es, wenn 3‐Alkyl‐ und 3‐(2‐Aminoäthyl)‐2‐indolmethanole mit den entsprechenden, nur in 3‐Stellung substituierten Indolen

  3-甲基-2-（3-甲基-2-吲哚亚甲基）-2H-溴化吲哚（3）和3-甲基-2-（3-甲基-2-吲哚亚甲基）-4,5,6,7-四氢- 2H 溴化吲哚 (14) 具有发色系统，在 Hopkins-Cole 色氨酸测试中也出现了这种发色系统。当 3-烷基-和 3-（2-氨基乙基）-2-吲哚甲醇与相应的仅在 3-位被取代的吲哚反应时，它的产率可提高 50%。
• Synthesis and serotonergic activity of a series of 2-(N-benzyl)carboxamido-5-substituted-N,N-dimethyltryptamine derivatives: novel antagonists for the vascular 5-HT1B-like receptors
  作者：Gerard P. Moloney、Graeme R. Martin、Neil Mathews、Heather Hobbs、Susan Dodsworth、Pang Yih Sang、Cameron Knight、Miles Maxwell、Robert C. Glen

  DOI：10.1039/a903141c

  日期：——

  The synthesis and vascular 5-HT1B-like receptor activity of a novel series of 2-(N-benzyl)carboxamido-5-substituted-N,N-dimethyltryptamine derivatives is described. Modifications to the 5-ethylene linked heterocycle are explored. Compounds such as N-benzyl-5-[2-(phthalimido)ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-2-carboxamide 22 (pKB = 7.33), the 2-aminobenzyl analogue 24 (pKB = 7.19), which both contain a phthalimide group, and N-benzyl-5-[2-(1-benzyl-2,5-dioxoimidazolidin-4-yl)ethyl]-3-[2-(dimethylamino)ethyl]-1H-indole-2-carboxamide 81 (pKB = 7.05), which incorporates an N-benzylhydantoin moiety, have good 5-HT1B-like affinity and indicate that there may be a hydrophobic binding pocket within the vascular 5-HT1B-like receptor previously not considered. Compounds including N-benzyl-3-[2-(dimethylamino)ethyl]-5-[2-(2,4-dioxo-1,3-thiazolidinyl)ethyl]-1H-indole-2-carboxamide 39 (pKB = 7.35) and the dimethyl analogue 46 (pKB = 7.48) which contain a 2,4-thiazolidinedione moiety have good vascular 5-HT1B-like receptor affinity and show that the sulfur atom is well tolerated. Compound 61 which includes a methylsulfonyl substituent on the 1-nitrogen of the hydantoin ring system has the highest recorded 5-HT1B-like affinity for this series (pKB = 7.54) and it is proposed that this functional group can interact with a secondary hydrogen bonding region within the receptor. Compounds 22, 24, 39, 46, 61 and 81 also exhibited good selectivity over the α1-adrenoceptors. The most selective compound from this series is 46 which contains a 5,5-dimethylthiazolidine-2,4-dione group and which is 66-fold selective over the α1-adrenoceptors. This finding is consistent with the previous discovery that 5,5-dimethyl substitution on the hydantoin group in a related series of compounds afforded superior selectivity for 5-HT1B-like receptors over α1-adrenoceptors and other 5-HT receptors, in particular 5-HT2A receptors, relative to unsubstituted hydantoin analogues. The selectivity of these compounds for the vascular 5-HT1B-like receptor is discussed. Structure–activity relationship indicated a significant steric requirement of the 5-HT1B-like receptor subtype. Potential modes of binding for several of the compounds to a vascular 5-HT1B-like receptor pharmacophore model are also proposed.

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