N-triflylglycine methyl ester

• 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: N-triflylglycine methyl ester
• 英文别名: methyl 2-(trifluoromethylsulfonylamino)acetate；(Trifluoromethylsulfonylamino)acetic acid methyl ester
• 化学式: C₄H₆F₃NO₄S
• 分子量: 221.157
• InChiKey: ZAUVQXFGHAGOAM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.5
• 重原子数：
  13
• 可旋转键数：
  4
• 环数：
  0.0
• sp3杂化的碳原子比例：
  0.75
• 拓扑面积：
  80.8
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  苯乙醇 、 N-triflylglycine methyl ester 在 三苯基膦 、 偶氮二甲酸二异丙酯 作用下， 以 四氢呋喃 为溶剂， 反应 16.25h， 以92%的产率得到methyl 2-[N-(2-phenylethyl)-N-(1-(trifluoromethylsulfonyl)amino)]acetate
  参考文献：
  名称：

  Role of the phenolic OH moiety of GluN2B-selective NMDA antagonists with 3-benzazepine scaffold

  摘要：

  In order to analyze the role of the phenolic OH moiety of ifenprodil (1) and 3-benzazepin-1,7-diol 2 for the affinity and selectivity at GluN2B subunit containing NMDA receptors, the 3-benzazepin-1-ols 3 were designed, synthesized and pharmacologically evaluated and furthermore, the molecular interactions of the phenylbutyl derivative 3c with the GluN2B receptor were investigated. In order to avoid decarbonylation during the intramolecular Friedel-Crafts acylation of 11, the N-atom has to be protected with a trifluoromethylsulfonyl group. The second key step of the synthesis was the removal of the N-triflyl group, which was realized by K2CO3 induced elimination of trifluoromethanelsulfinate (F3CSO2-). In receptor binding studies with the radioligand [3H] ifenprodil the 3-benzazepin-1-ol 3c revealed a GluN2B affinity of 73 nM indicating that the phenolic OH moiety of 1 and 2 is not essential but favorable for high GluN2B affinity. In docking studies 3-benzazepin-1-ol 3c shows the same binding pose as ifenprodil-keto 1A in the X-ray crystal structure. H-bond interactions and lipophilic interactions of 3c and 1A are very similar. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.12.067
• 作为产物：
  描述：

  三氟甲磺酸酐 、 甘氨酸甲酯盐酸盐 在 三乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 16.25h， 以70%的产率得到N-triflylglycine methyl ester
  参考文献：
  名称：

  Role of the phenolic OH moiety of GluN2B-selective NMDA antagonists with 3-benzazepine scaffold

  摘要：

  In order to analyze the role of the phenolic OH moiety of ifenprodil (1) and 3-benzazepin-1,7-diol 2 for the affinity and selectivity at GluN2B subunit containing NMDA receptors, the 3-benzazepin-1-ols 3 were designed, synthesized and pharmacologically evaluated and furthermore, the molecular interactions of the phenylbutyl derivative 3c with the GluN2B receptor were investigated. In order to avoid decarbonylation during the intramolecular Friedel-Crafts acylation of 11, the N-atom has to be protected with a trifluoromethylsulfonyl group. The second key step of the synthesis was the removal of the N-triflyl group, which was realized by K2CO3 induced elimination of trifluoromethanelsulfinate (F3CSO2-). In receptor binding studies with the radioligand [3H] ifenprodil the 3-benzazepin-1-ol 3c revealed a GluN2B affinity of 73 nM indicating that the phenolic OH moiety of 1 and 2 is not essential but favorable for high GluN2B affinity. In docking studies 3-benzazepin-1-ol 3c shows the same binding pose as ifenprodil-keto 1A in the X-ray crystal structure. H-bond interactions and lipophilic interactions of 3c and 1A are very similar. (C) 2015 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2015.12.067

文献信息

• Strategic use of amino acid N-substituents to limit α-carbon-centered radical formation and consequent loss of stereochemical integrity
  作者：Anna K. Croft、Christopher J. Easton、Katherine Kociuba、Leo Radom

  DOI：10.1016/s0957-4166(03)00542-1

  日期：2003.10

  amino acid radicals. Optimized structures of glycine derivatives and related substituted methanes, and the corresponding radicals, were determined with B3-LYP/6-31G(d). Single-point RMP2/6-31G(d) calculations on these structures were then used to obtain radical stabilization energies, which were compared with the relative rates of formation of the same or closely similar radicals in reactions with N-bromosuccinimde

  从头算开始已经用于研究N-取代基对以α-碳为中心的氨基酸自由基的稳定性的影响。用B3-LYP / 6-31G（d）确定了甘氨酸衍生物和相关取代的甲烷的最佳结构以及相应的基团。然后将这些结构的单点RMP2 / 6-31G（d）计算用于获得自由基稳定能，并将其与在与N-溴代琥珀酰亚胺反应中形成相同或相似自由基的相对速率进行比较。这些研究表明，ñ酰化和磺化降低了α-碳中心自由基的稳定性和易形成性。氟代酰基，氟代烷基磺酰基和亚氨基基团看到了更大的作用。酰亚胺基和氟代烷基磺酰基的作用程度是，使N-邻苯二甲酰基和三氟甲磺酰基保护的氨基酸通过从侧链的氢原子抽象反应，从而避免在手性α-中心反应并保持其立体化学完整性。研究了这些取代基效应的起源。
• Synthesis of oxazolo‐annulated 3‐benzazepines designed by merging two negative allosteric NMDA receptor modulators
  作者：Alexander Markus、Dirk Schepmann、Bernhard Wünsch

  DOI：10.1002/ardp.202200020

  日期：2022.6

  4-(2-hydroxyethyl)phenol (8). Mitsunobu reaction of primary alcohol 7 with N-sulfonylated glycine esters established the necessary side chain. The intramolecular Friedel–Crafts acylation of acid 12a containing the N-tosyl protective group led upon decarbonylation exclusively to the tricyclic tetrahydroisoquinoline 14. Protection of the amino moiety by the stronger electron-withdrawing triflyl group resulted in the

  为了提高艾芬地尔 ( 1 ) 的代谢稳定性和受体选择性，将 besonprodil ( 2 ) 的苯并恶唑酮部分和 WMS-1410 ( 3 )的 3-苯并氮杂酮部分合并以获得4型恶唑并苯并氮杂。代表第一个关键中间体的 5-(羟乙基)苯并恶唑酮7从 4-(2-羟乙基)苯酚 ( 8 ) 开始分四步制备。伯醇7与 N-磺酰化甘氨酸酯的 Mitsunobu 反应建立了必要的侧链。含有N的酸12a的分子内 Friedel-Crafts 酰化-甲苯磺酰基保护基团在脱羰后专门生成三环四氢异喹啉14。由更强的吸电子三氟甲酰基团保护氨基部分产生所需的 3-苯并氮杂15，而不会形成类似的异喹啉。通过 K 2 CO 3诱导的三氟甲亚磺酸盐消除将三氟甲酰基保护基团裂解掉。在一锅三步程序中，获得了各种恶唑并苯并氮杂二酮15，将其还原以提供所需的仲醇18。
• Phenol—Benzoxazolone bioisosteres: Synthesis and biological evaluation of tricyclic GluN2B‐selective <i>N</i> ‐methyl‐ <scp>d</scp> ‐aspartate receptor antagonists
  作者：Alexander Markus、Julian A. Schreiber、Gunnar Goerges、Bastian Frehland、Guiscard Seebohm、Dirk Schepmann、Bernhard Wünsch

  DOI：10.1002/ardp.202200147

  日期：2022.9

  reduced with NaBH4 to yield the aminoalcohol 20, which was alkylated or reductively alkylated to form tertiary amines 21f–21r. In the last step, the allyl protective group of 21 was removed with RhCl3 and HCl to obtain oxazolones 22. In receptor binding studies using [3H]ifenprodil as radioligand ketone, 22m showed the highest GluN2B affinity (Ki = 88 nM). However, a reduced affinity toward GluN2B subunit-containing

  三环四氢恶唑并[4,5 - h ]-[3]苯并氮杂-9-醇22被设计为四氢-3-苯并氮杂-1,7-二醇的苯酚生物等排体。该合成的关键特征是在杂环 N 原子上引入了三氟甲基磺酰基和烯丙基保护基团。开发了两种方法来将三氟甲酰基保护的酮16转化为带有各种 N-取代基的三环醇21 。根据第一种方法，通过K 2 CO 3去除三氟甲亚磺酸盐。在用 NaBH(OAc) 3选择性还原17的亚氨基部分后，得到氨基酮18，其被还原烷基化和还原。根据第二种方法，亚胺酮17的亚胺和酮均被 NaBH 4还原，得到氨基醇20，其被烷基化或还原烷基化形成叔胺21f-21r。最后一步用RhCl 3和HCl除去21的烯丙基保护基，得到恶唑酮22。在使用 [ 3 H]ifenprodil 作为放射性配体酮的受体结合研究中， 22m显示出最高的 GluN2B 亲和力（K i  = 88 nM）。然而，对含 GluN2B 亚基的N的亲和力降低与生物等排的
• Role of the phenolic OH moiety of GluN2B-selective NMDA antagonists with 3-benzazepine scaffold
  作者：Sougata Dey、Dirk Schepmann、Bernhard Wünsch

  DOI：10.1016/j.bmcl.2015.12.067

  日期：2016.2

  In order to analyze the role of the phenolic OH moiety of ifenprodil (1) and 3-benzazepin-1,7-diol 2 for the affinity and selectivity at GluN2B subunit containing NMDA receptors, the 3-benzazepin-1-ols 3 were designed, synthesized and pharmacologically evaluated and furthermore, the molecular interactions of the phenylbutyl derivative 3c with the GluN2B receptor were investigated. In order to avoid decarbonylation during the intramolecular Friedel-Crafts acylation of 11, the N-atom has to be protected with a trifluoromethylsulfonyl group. The second key step of the synthesis was the removal of the N-triflyl group, which was realized by K2CO3 induced elimination of trifluoromethanelsulfinate (F3CSO2-). In receptor binding studies with the radioligand [3H] ifenprodil the 3-benzazepin-1-ol 3c revealed a GluN2B affinity of 73 nM indicating that the phenolic OH moiety of 1 and 2 is not essential but favorable for high GluN2B affinity. In docking studies 3-benzazepin-1-ol 3c shows the same binding pose as ifenprodil-keto 1A in the X-ray crystal structure. H-bond interactions and lipophilic interactions of 3c and 1A are very similar. (C) 2015 Elsevier Ltd. All rights reserved.