dimethyl N-benzyl-L-aspartate | 178755-19-6

• 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: dimethyl N-benzyl-L-aspartate
• 英文别名: dimethyl (2S)-2-(benzylamino)butanedioate
• CAS: 178755-19-6
• 化学式: C₁₃H₁₇NO₄
• 分子量: 251.282
• InChiKey: JPJQUMHAJGQHKN-NSHDSACASA-N

物化性质

• 沸点：
  356.4±37.0 °C(Predicted)
• 密度：
  1.137±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  18
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  64.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  dimethyl N-benzyl-L-aspartate 在 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 、 乙腈 为溶剂， 反应 74.5h， 生成 methyl (S)-2-(1-benzyl-4-methyl-3,6-dioxopiperazin-2-yl)acetate
  参考文献：
  名称：

  Synthesis, Pharmacological Evaluation, and σ₁ Receptor Interaction Analysis of Hydroxyethyl Substituted Piperazines

  摘要：

  Starting from (S)- or (R)-aspartate, three synthetic strategies were explored to prepare hydroxyethyl substituted piperazines with different substituents at the N-atoms. sigma receptor affinity was recorded using receptor material from both animal and human origin, sigma(1) affinities determined with guinea pig brain and human RPMI 8226 tumor cell lines differed slightly but showed the same tendency. (S)-2-[4-(Cyclohexylmethyl)-1-(naphthalene-2-ylmethyl)piperazin-2-yliethanol (7c) revealed the highest affinity at human sigma(1) receptors (K-i = 6.8 nM). The potent a, receptor ligand 7c was able to inhibit selectively the growth of three human tumor cell lines with IC50 values in the low micromolar range. The reduced growth of the RPMI-8226 cell line was caused by apoptosis. The interaction of 7c with the a, receptor was analyzed in detail using the 3D homology model of the sigma(1) receptor. The calculated free binding energies of all hydroxyethylpiperazines nicely correlate with their recorded affinities toward the human a, receptor.

  DOI：

  10.1021/jm401707t
• 作为产物：
  描述：

  L-天冬氨酸二甲酯盐酸盐 在 sodium tetrahydroborate 、 sodium sulfate 、 三乙胺 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 16.75h， 生成 dimethyl N-benzyl-L-aspartate
  参考文献：
  名称：

  Synthesis, Pharmacological Evaluation, and σ₁ Receptor Interaction Analysis of Hydroxyethyl Substituted Piperazines

  摘要：

  Starting from (S)- or (R)-aspartate, three synthetic strategies were explored to prepare hydroxyethyl substituted piperazines with different substituents at the N-atoms. sigma receptor affinity was recorded using receptor material from both animal and human origin, sigma(1) affinities determined with guinea pig brain and human RPMI 8226 tumor cell lines differed slightly but showed the same tendency. (S)-2-[4-(Cyclohexylmethyl)-1-(naphthalene-2-ylmethyl)piperazin-2-yliethanol (7c) revealed the highest affinity at human sigma(1) receptors (K-i = 6.8 nM). The potent a, receptor ligand 7c was able to inhibit selectively the growth of three human tumor cell lines with IC50 values in the low micromolar range. The reduced growth of the RPMI-8226 cell line was caused by apoptosis. The interaction of 7c with the a, receptor was analyzed in detail using the 3D homology model of the sigma(1) receptor. The calculated free binding energies of all hydroxyethylpiperazines nicely correlate with their recorded affinities toward the human a, receptor.

  DOI：

  10.1021/jm401707t

文献信息

• Design, Synthesis, and Pharmacological Characterization of a Neutral, Non-Prodrug Thrombin Inhibitor with Good Oral Pharmacokinetics
  作者：Alexander Hillisch、Kersten M. Gericke、Swen Allerheiligen、Susanne Roehrig、Martina Schaefer、Adrian Tersteegen、Simone Schulz、Philip Lienau、Mark Gnoth、Vera Puetter、Roman C. Hillig、Stefan Heitmeier

  DOI：10.1021/acs.jmedchem.0c01035

  日期：2020.11.12

  Despite extensive research on small molecule thrombin inhibitors for oral application in the past decades, only a single double prodrug with very modest oral bioavailability has reached human therapy as a marketed drug. We have undertaken major efforts to identify neutral, non-prodrug inhibitors. Using a holistic analysis of all available internal data, we were able to build computational models and

  尽管在过去的几十年中对口服的小分子凝血酶抑制剂进行了广泛的研究，但只有一种具有非常适度的口服生物利用度的双前药已作为上市药物进入了人类治疗。我们已做出重大努力，以鉴定中性，非前药抑制剂。通过对所有可用内部数据的整体分析，我们能够建立计算模型，并将其用于选择具有最高口服生物利用度可能性的先导系列。在我们的设计中，我们依靠蛋白质结构知识来解决效价问题，并确定了有利理化特性的小窗口以平衡吸收和代谢稳定性。孕烷X受体的蛋白质结构信息有助于克服持续存在的细胞色素P450 3A4诱导问题。通过设计，合成和测试衍生物，将所选化合物系列优化为高效，中性，非前药凝血酶抑制剂。所得的优化化合物BAY1217224已达到首次临床试验，已经证实了所需的药代动力学特性。
• 2-(2-Hydroxyethyl)piperazine derivatives as potent human carbonic anhydrase inhibitors: Synthesis, enzyme inhibition, computational studies and antiglaucoma activity
  作者：Niccolò Chiaramonte、Andrea Angeli、Silvia Sgambellone、Alessandro Bonardi、Alessio Nocentini、Gianluca Bartolucci、Laura Braconi、Silvia Dei、Laura Lucarini、Elisabetta Teodori、Paola Gratteri、Bernhard Wünsch、Claudiu T. Supuran、Maria Novella Romanelli

  DOI：10.1016/j.ejmech.2021.114026

  日期：2022.1

  Targeting Carbonic Anhydrases (CAs) represents a strategy to treat several diseases, from glaucoma to cancer. To widen the structure-activity relationships (SARs) of our series of piperazines endowed with potent human carbonic anhydrase (hCA) inhibition, a new series of chiral piperazines carrying a (2-hydroxyethyl) group was prepared. The Zn-binding function, the 4-sulfamoylbenzoyl moiety, was connected

  靶向碳酸酐酶 (CA) 代表了一种治疗从青光眼到癌症的多种疾病的策略。为了拓宽我们的系列哌嗪的构效关系 (SAR)，这些哌嗪具有有效的人碳酸酐酶 (hCA) 抑制作用，制备了一系列带有 (2-羟乙基) 基团的新手性哌嗪。Zn 结合功能，即 4-氨磺酰基苯甲酰基部分，与一个哌嗪 N 原子相连，而另一个氮被烷基取代基修饰。与用于合成先前报道的系列的方法类似，新化合物的制备从 ( R )- 和 ( S）-天冬氨酸。在合成过程中发生了部分外消旋化。为了克服这个问题，研究了其他化学策略。使用停流CO 2水合酶测定确定新的极性衍生物对四种hCA同工型I、II、IV和IX的抑制活性。一些化合物显示出纳摩尔范围内的效力和抑制 hCA IX 的偏好。
• Rigidity versus Flexibility: Is This an Issue in σ₁ Receptor Ligand Affinity and Activity?
  作者：Frauke Weber、Stefanie Brune、Frederik Börgel、Carsten Lange、Katharina Korpis、Patrick J. Bednarski、Erik Laurini、Maurizio Fermeglia、Sabrina Pricl、Dirk Schepmann、Bernhard Wünsch

  DOI：10.1021/acs.jmedchem.6b00585

  日期：2016.6.9

  chiral-pool synthesis starting from (S)- or (R)-aspartate. The key step in the synthesis was a Dieckmann-analogous cyclization of (dioxopiperazinyl)acetates 8, which involved trapping of the intermediate hemiketal anion with Me3SiCl. The σ1 affinity was tested using membrane preparations from animal (guinea pig) and human origin. The binding of bicyclic compounds was analyzed by molecular dynamics simulations

  从（S）-或（R）-天冬氨酸开始的手性池合成中制备立体异构体2,5-二氮杂双环[2.2.2]辛烷14和15。合成的关键步骤是（二氧杂哌嗪基）乙酸酯8的Dieckmann相似环化反应，该过程涉及用Me 3 SiCl捕获中间的半缩酮阴离子。所述σ 1亲和力使用来自动物（豚鼠）膜制备物和人来源的测试。双环化合物的结合通过分子动力学模拟基于所述σ的3D同源性模型分析1受体。在σ中观察到的K i值之间的良好相关性1种测定法和计算出的自由结合能，再加上对四个关键配体/受体相互作用的鉴定，可以形成结构亲和力关系。在具有七个人类肿瘤细胞系的体外抗肿瘤测定中，双环化合物选择性抑制细胞系A427的生长，这是由于凋亡的诱导所致。在该测定中，所述化合物表现得像已知σ 1受体拮抗剂氟哌啶醇。
• Synthesis of (+)- and (−)-Geissman-Waiss lactone from chiral sulfonium salts
  作者：Ricardo López-González、Dino Gnecco、Jorge R. Juárez、María L. Orea、Victor Gómez-Calvario、Sylvain Bernès、David M. Aparicio、Joel L. Terán

  DOI：10.1016/j.tetlet.2020.151697

  日期：2020.3

  A novel series of chiral cyclic zwitterionic pyrrolidinone type intermediates was prepared via regioselective 5-exo-trig-ring-closure of the corresponding chiral sulfonium salts. This synthetic strategy allowed the rapid non-racemic synthesis of the Geissman-Waiss lactone in six steps and 35% overall yield.

  通过相应手性sulf盐的区域选择性5-外-触发环闭合，制备了一系列新的手性环状两性离子吡咯烷酮型中间体。该合成策略允许分六个步骤快速进行非外消旋的Geissman-Waiss内酯合成，总收率为35％。
• Substrate Engineering in Lipase-Catalyzed Selective Polymerization of <scp>d</scp>-/<scp>l</scp>-Aspartates and Diols to Prepare Helical Chiral Polyester
  作者：Yu Zhang、Bo Xia、Yanyan Li、Xianfu Lin、Qi Wu

  DOI：10.1021/acs.biomac.0c01605

  日期：2021.2.8

  The synthesis of optically pure polymers is one of the most challenging tasks in polymer chemistry. Herein, Novozym 435 (Lipase B from Candida antarctica, immobilized on Lewatit VP OC 1600)-catalyzed polycondensation between d-/l-aspartic acid (Asp) diester and diols for the preparation of helical chiral polyesters was reported. Compared with d-Asp diesters, the fast-reacting l-Asp diesters easily

  光学纯聚合物的合成是聚合物化学中最具挑战性的任务之一。在此，报道了Novozym 435（来自南极假丝酵母的脂肪酶B ，固定在Lewatit VP OC 1600上）催化d / l-天冬氨酸（Asp）二酯和二醇之间的缩聚反应，以制备螺旋型手性聚酯。与d- Asp二酯相比，快速反应的1 - Asp二酯容易与二醇反应，以提供一系列含有N-取代的1- Asp重复单元的手性聚酯。除了氨基酸构型，N还研究和优化了取代基的侧链和二醇的链长。结果发现，像N- Boc和N- Cbz这样的大面积酰基N-取代基比小的基团更有利于该聚合反应，这可能是由于这些小酰基与Novozym 435的活性位点竞争性结合所致。达到39.5×10 3 g / mol（M w，Đ = 1.64）。此外，慢反应d-Asp二酯还通过修饰底物结构成功地聚合，以人工创建“非手性”缩合环境。这些对映体互补手性聚酯具有热稳定性，并具有特定的