Chlor-bis(pyrrolidino)carbeniumchlorid | 101373-58-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: Chlor-bis(pyrrolidino)carbeniumchlorid
• 英文别名: Chlorbis(1-pyrrolidinyl)carbenium-chlorid；1-(chloro(pyrrolidin-1-yl)methylene)pyrrolidinium chloride；1-(chloro(pyrrolidine-1-yl)methylene)pyrrolidine-1-ium chloride；1-[Chloro(pyrrolidin-1-yl)methylidene]pyrrolidin-1-ium chloride；1-[chloro(pyrrolidin-1-ium-1-ylidene)methyl]pyrrolidine;chloride
• CAS: 101373-58-4
• 化学式: C₉H₁₆ClN₂*Cl
• 分子量: 223.145
• InChiKey: NYPPZXFHFBBWJR-UHFFFAOYSA-M

计算性质

• 辛醇/水分配系数(LogP)：
  -1.51
• 重原子数：
  13
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.89
• 拓扑面积：
  6.2
• 氢给体数：
  0
• 氢受体数：
  1

反应信息

• 作为反应物：
  描述：

  Chlor-bis(pyrrolidino)carbeniumchlorid 在 sodium perchlorate 、 三乙胺 作用下， 以 乙腈 为溶剂， 反应 2.0h， 生成 Tris(pyrrolidino)carbenium-perchlorat
  参考文献：
  名称：

  Orthoamide. IL. Umsetzungen von Orthoamid-Derivaten mit Schwefel und Selen, Synthesen von 1,3-Thiazol- und 1,3-Selenazolderivaten

  摘要：

  N,N-Dimethylformamide acetal reacts with elemental selenium to give a mixture of selenocarbonic acid derivatives 2 and 3, which can be converted to the pure N,N-dimethylcarbamidic acid Se-methylester 2 by treatment with methyl iodide. Analogously from the orthoformic acid derivatives 5 and 6 and selenium the N,N,N',N'-tetramethyl-selenurea 7 can be prepared. In the reaction of 12 with elemental sulfur and selenium the amidines 14 and 15, respectively, are formed. By treatment of 14 and 15 with alpha-halogenated carbonyl compounds and triethylamine the 1,3-thiazoles 18 and 1,3-selenazoles 19 can be prepared. The synthesis of the propynoic acid orthoamide 26b is described. 26b reacts with the guanidinium salt 24b to give the bis-orthoamide of butynedioic acid 20b. Other orthoamides of butynedioic acid 20b-20e can be synthesized from the orthoamide 20a by transamination. The thiolation of the orthoamides affords the bis-amidinium-dithiolates 21a-c, which can be alkylated to give the bis-amidinium salts 27. By treatment with alpha-halogene carbonyl compounds and triethylamine the dithiolates 21a-e are cyclized to give thieno [3,2b] thiophenes 28a-n. The quadrupoles 21 undergo cycloadditions with dimethyl-butynedioate which afford the bis(3H-thiophene-2 ylidenes) 29a-c. Treatment of 29a with methyl tosylate gives rise to the dithiophene 30a. The dithiophene 30b can be obtained by heating 21b with dimethylbutynedionate.

  DOI：

  10.1002/prac.19963380180
• 作为产物：
  描述：

  1,1’-羰基二吡咯烷 在 草酰氯 作用下， 以 二氯甲烷 为溶剂， 反应 5.0h， 以160 g的产率得到Chlor-bis(pyrrolidino)carbeniumchlorid
  参考文献：
  名称：

  Impact of guanidine-containing backbone linkages on stereopure antisense oligonucleotides in the CNS

  摘要：

  在任何药物发现计划中，获得足够的组织暴露在作用部位，以实现对目标的期望药效是一个重要的决定因素，对于在中枢神经系统深处的寡核苷酸来说尤其具有挑战性。在这里，我们报告了立体纯的含磷酸鸟嘌呤骨架连接（PN连接）对通过RNase H介导机制作用的寡核苷酸的合成和影响，以Malat1和C9orf72为基准。我们发现，将各种类型的PN连接纳入立体纯的寡核苷酸骨架中，与类似修改的立体纯磷硫酸酯（PS）和磷酸二酯（PO）基分子相比，在自由吸收条件下可以使培养神经元的沉默效果提高10倍。其中一种骨架类型称为PN-1，在小剂量下也可以在小鼠的大脑和脊髓中产生深远的沉默效果，在难以到达的脑组织中特别提高了反应的效力和持久性。鉴于这些在临床前模型中的优势，将PN连接纳入带有嵌合骨架修饰的立体纯寡核苷酸中，有可能使脊髓以外的大脑区域更易受到寡核苷酸的影响，从而也可能扩大适用于寡核苷酸治疗的神经学指示的范围。

  DOI：

  10.1093/nar/gkac037

文献信息

• Catalytic Enantioselective Nucleophilic Addition to Arynes by a New Quaternary Guanidinium Salt-Based Phase-Transfer Catalyst
  作者：Guihua Pan、Maoping Pu、Hongyu Wang、Meijia Ying、Yi Li、Shunxi Dong、Xiaoming Feng、Xiaohua Liu

  DOI：10.1021/jacs.3c09594

  日期：2023.12.6

  in situ generated fluoride-based chiral phase-transfer catalyst. In this study, we present a catalytic enantioselective nucleophilic addition reaction involving arynes, utilizing an amino amide-based guanidinium salt QG•X. Furthermore, we demonstrate the broad compatibility of this reaction with various arynes and cyclic/acyclic β-keto amides, leading to the creation of diverse α-aryl quaternary stereocenters

  由于芳炔的生成方法温和，在合成化学中得到了广泛的应用。然而，用芳烃实现不对称有机催化反应仍然是一个艰巨且罕见的挑战，主要是因为这些中性和瞬态物质往往会自发猝灭。为了解决这个问题，设计了一种固液相转移策略，其中芳炔的生成速度可以通过原位生成的氟化物基手性相转移催化剂来控制。在这项研究中，我们利用基于氨基酰胺的胍盐QG •X，提出了一种涉及芳烃的催化对映选择性亲核加成反应。此外，我们证明了该反应与各种芳烃和环状/无环β-酮酰胺的广泛相容性，从而产生具有良好立体选择性的多种α-芳基季立体中心。机理研究发现，在QG ·X 和 CsF 之间的离子交换过程中，手性分子内阳离子-阴离子对和 HF 可能参与亲核试剂活化和芳基生成。此外，DFT 计算表明，观察到的高水平对映选择性可归因于空间排斥以及催化剂和底物之间累积的非共价相互作用。
• Kantlehner, Willi; Greiner, Ulrich, Liebigs Annalen der Chemie, 1990, # 10, p. 965 - 973
  作者：Kantlehner, Willi、Greiner, Ulrich

  DOI：——

  日期：——
• KANTEHNER, WILLI;GREINER, ULRICH, LIEBIGS ANN. CHEM.,(1990) N0, C. 965-973
  作者：KANTEHNER, WILLI、GREINER, ULRICH

  DOI：——

  日期：——
• Orthoamide. IL. Umsetzungen von Orthoamid-Derivaten mit Schwefel und Selen, Synthesen von 1,3-Thiazol- und 1,3-Selenazolderivaten
  作者：W. Kantlehner、Michael Hauber、Markus Vettel

  DOI：10.1002/prac.19963380180

  日期：——

  N,N-Dimethylformamide acetal reacts with elemental selenium to give a mixture of selenocarbonic acid derivatives 2 and 3, which can be converted to the pure N,N-dimethylcarbamidic acid Se-methylester 2 by treatment with methyl iodide. Analogously from the orthoformic acid derivatives 5 and 6 and selenium the N,N,N',N'-tetramethyl-selenurea 7 can be prepared. In the reaction of 12 with elemental sulfur and selenium the amidines 14 and 15, respectively, are formed. By treatment of 14 and 15 with alpha-halogenated carbonyl compounds and triethylamine the 1,3-thiazoles 18 and 1,3-selenazoles 19 can be prepared. The synthesis of the propynoic acid orthoamide 26b is described. 26b reacts with the guanidinium salt 24b to give the bis-orthoamide of butynedioic acid 20b. Other orthoamides of butynedioic acid 20b-20e can be synthesized from the orthoamide 20a by transamination. The thiolation of the orthoamides affords the bis-amidinium-dithiolates 21a-c, which can be alkylated to give the bis-amidinium salts 27. By treatment with alpha-halogene carbonyl compounds and triethylamine the dithiolates 21a-e are cyclized to give thieno [3,2b] thiophenes 28a-n. The quadrupoles 21 undergo cycloadditions with dimethyl-butynedioate which afford the bis(3H-thiophene-2 ylidenes) 29a-c. Treatment of 29a with methyl tosylate gives rise to the dithiophene 30a. The dithiophene 30b can be obtained by heating 21b with dimethylbutynedionate.
• Impact of guanidine-containing backbone linkages on stereopure antisense oligonucleotides in the CNS
  作者：Pachamuthu Kandasamy、Yuanjing Liu、Vincent Aduda、Sandheep Akare、Rowshon Alam、Amy Andreucci、David Boulay、Keith Bowman、Michael Byrne、Megan Cannon、Onanong Chivatakarn、Juili Dilip Shelke、Naoki Iwamoto、Tomomi Kawamoto、Jayakanthan Kumarasamy、Sarah Lamore、Muriel Lemaitre、Xuena Lin、Kenneth Longo、Richard Looby、Subramanian Marappan、Jake Metterville、Susovan Mohapatra、Bridget Newman、Ik-Hyeon Paik、Saurabh Patil、Erin Purcell-Estabrook、Mamoru Shimizu、Pochi Shum、Stephany Standley、Kris Taborn、Snehlata Tripathi、Hailin Yang、Yuan Yin、Xiansi Zhao、Elena Dale、Chandra Vargeese

  DOI：10.1093/nar/gkac037

  日期：2022.6.10

  Attaining sufficient tissue exposure at the site of action to achieve the desired pharmacodynamic effect on a target is an important determinant for any drug discovery program, and this can be particularly challenging for oligonucleotides in deep tissues of the CNS. Herein, we report the synthesis and impact of stereopure phosphoryl guanidine-containing backbone linkages (PN linkages) to oligonucleotides acting through an RNase H-mediated mechanism, using Malat1 and C9orf72 as benchmarks. We found that the incorporation of various types of PN linkages to a stereopure oligonucleotide backbone can increase potency of silencing in cultured neurons under free-uptake conditions 10-fold compared with similarly modified stereopure phosphorothioate (PS) and phosphodiester (PO)-based molecules. One of these backbone types, called PN-1, also yielded profound silencing benefits throughout the mouse brain and spinal cord at low doses, improving both the potency and durability of response, especially in difficult to reach brain tissues. Given these benefits in preclinical models, the incorporation of PN linkages into stereopure oligonucleotides with chimeric backbone modifications has the potential to render regions of the brain beyond the spinal cord more accessible to oligonucleotides and, consequently, may also expand the scope of neurological indications amenable to oligonucleotide therapeutics.

  在任何药物发现计划中，获得足够的组织暴露在作用部位，以实现对目标的期望药效是一个重要的决定因素，对于在中枢神经系统深处的寡核苷酸来说尤其具有挑战性。在这里，我们报告了立体纯的含磷酸鸟嘌呤骨架连接（PN连接）对通过RNase H介导机制作用的寡核苷酸的合成和影响，以Malat1和C9orf72为基准。我们发现，将各种类型的PN连接纳入立体纯的寡核苷酸骨架中，与类似修改的立体纯磷硫酸酯（PS）和磷酸二酯（PO）基分子相比，在自由吸收条件下可以使培养神经元的沉默效果提高10倍。其中一种骨架类型称为PN-1，在小剂量下也可以在小鼠的大脑和脊髓中产生深远的沉默效果，在难以到达的脑组织中特别提高了反应的效力和持久性。鉴于这些在临床前模型中的优势，将PN连接纳入带有嵌合骨架修饰的立体纯寡核苷酸中，有可能使脊髓以外的大脑区域更易受到寡核苷酸的影响，从而也可能扩大适用于寡核苷酸治疗的神经学指示的范围。