Methanesulfonic acid (R)-(6-methoxy-quinolin-4-yl)-((1S,2R,4S,5R)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl ester

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 金鸡纳生物碱
• 英文名称: Methanesulfonic acid (R)-(6-methoxy-quinolin-4-yl)-((1S,2R,4S,5R)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl ester
• 英文别名: [(R)-[(2R,4S,5R)-5-ethenyl-1-azabicyclo[2.2.2]octan-2-yl]-(6-methoxyquinolin-4-yl)methyl] methanesulfonate
• 化学式: C₂₁H₂₆N₂O₄S
• 分子量: 402.514
• InChiKey: XZMSYNFHZBKDFN-VUEDXXQZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3
• 重原子数：
  28
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  77.1
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  Methanesulfonic acid (R)-(6-methoxy-quinolin-4-yl)-((1S,2R,4S,5R)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl ester 在 sodium azide 、 copper(ll) sulfate pentahydrate 、 sodium ascorbate 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 18.0h， 生成
  参考文献：
  名称：

  Synthesis and systemic toxicity assessment of quinine-triazole scaffold with antiprotozoal potency

  摘要：

  A series of hybrid antiprotozoal compounds with quinine-triazolyl scaffold were prepared by copper catalyzed Huisgen 1,3-dipolar cycloaddition via O-mesylation with mesyl chloride followed by azide displacement. The synthesized azide derivative was made to react with various aromatic and aliphatic alkynes. The triazolyl-linked quinine scaffolds were synthesized under solvent-free mechanochemical ball milling conditions. Products (6a-s) were screened for in-vitro antimalarial and antileishmanial activity. Screening results indicated that out of the synthesized series of 19 products, compounds 6d, 6h, 6l, 6m, and 6n showed significant antimalarial (P. falciparum) and antileishmanial activities (L. donavani) with IC50 values 0.28, 0.28, 0.25, 0.33, 0.76 mu M and 8.26, 4.4, 1.78, 3.95, and 4.06 mu M, respectively. Further toxicological analysis established the Median lethal dose (LD50), No observed adverse effect level (NOAEL) and human equivalent dose (HED) of the most potent compounds by acute and sub acute toxicity studies performed in rodent animal model. The studies revealed that compounds (6d, 6h, 6l and 6m) did not reveal any toxic manifestation at dose 1000 mg/Kg and from which the corresponding HED was calculated to be 13.84 mg/kg.

  DOI：

  10.1016/j.bioorg.2019.102939
• 作为产物：
  描述：

  甲基磺酰氯 、 表奎宁定 在 三乙胺 作用下， 以 四氢呋喃 为溶剂， 反应 2.0h， 生成 Methanesulfonic acid (R)-(6-methoxy-quinolin-4-yl)-((1S,2R,4S,5R)-5-vinyl-1-aza-bicyclo[2.2.2]oct-2-yl)-methyl ester
  参考文献：
  名称：

  不对称有机催化和连续化学制备普瑞巴林的高效且具有成本竞争力的过程

  摘要：

  在此，我们介绍了普瑞巴林的创新合成工艺的放大开发。该过程由对其成功至关重要的两项支持技术提供支持；连续化学允许安全和清洁生产硝基烯烃，不对称有机催化使手性中间体以对映体富集形式获得。该工艺成功的关键是精心开发了硝基烯烃的连续工艺以及有机催化剂和反应条件的优化，以在催化不对称反应中获得非常高的转换频率。还开发了有机催化剂的成功回收，以实现具有成本竞争力的过程。

  DOI：

  10.1021/acs.oprd.1c00394

文献信息

• The First and Second <i>Cinchona</i> Rearrangement. Two Fundamental Transformations of Alkaloid Chemistry
  作者：M. Heiko Franz、Stefanie Röper、Rudolf Wartchow、H. M. R. Hoffmann

  DOI：10.1021/jo030363s

  日期：2004.4.1

  Stereochemistry, products, and driving forces of the “first and second Cinchona rearrangement” have been investigated and a unified theory is presented. The first cage expansion affords [3.2.2]azabicyclic α-amino ether and is formulated via a configurationally stable bridgehead iminium ion and quasiequatorial nucleophilic attack. The second cage expansion affords β-functionalized [3.2.2]azabicycles

  研究了“第一和第二次金鸡纳重排”的立体化学，产物和驱动力，并提出了统一的理论。第一次笼扩展提供了[3.2.2]氮杂双环α-氨基醚，并通过构型稳定的桥头亚胺离子和准四亲核攻击进行配制。第二个笼扩展提供了β-官能化的[3.2.2]氮杂双环。在这种情况下，假定存在非经典的氮桥阳离子，以说明保持构型和保持架扩展的潜在可逆性。第二种重新排列因所谓的肚带而受到青睐在三氟乙醇中的碱（6'-R = H）。在所有情况下，立体电子因素，C9处的电子需求，基态构型和溶剂类型都是至关重要的。描述了从9- nat前体制备9-表位构型的金鸡纳生物碱的两步方案。
• Fused Triazoles via Tandem Reactions of Activated <i>Cinchona</i> Alkaloids with Azide Ion. Second <i>Cinchona</i> Rearrangement Exemplified
  作者：S. Röper、M. H. Franz、R. Wartchow、H. M. R. Hoffmann

  DOI：10.1021/ol034719y

  日期：2003.8.1

  [reaction: see text] Intramolecular 1,3-dipolar cycloadditions of cinchona azides to the C10-C11 alkyne and C10-C11 olefin unit of the alkaloid have been designed via tandem strategy. A variety of fused triazoles and triazolines with a bis-azahomotwistane skeleton have been prepared. In trifluoroethanol, O-mesylcinchonidine 7-OMs and NaN(3) furnish triazole 8 as well as cage-expanded 1,5-diazatricyclo[4

  [反应：见正文]通过串联策略设计了金鸡纳叠氮化物的分子内1,3-偶极环加成反应到生物碱的C10-C11炔烃和C10-C11烯烃单元上。已经制备了具有双氮杂高硫烷骨架的各种稠合的三唑和三唑啉。在三氟乙醇中，O-甲磺酰基可可宁7-OMs和NaN（3）提供三唑8以及笼扩展的1,5-二氮杂三环[4.4.1.0（3,8）]十一烷衍生物10。形成了稠合的三唑8和10。分别保留了C9和C3的配置。1-氮杂双环[3.2.2]笼的扩展被证明是可逆的。
• Clickable 9-azido-(9-deoxy)-Cinchona alkaloids: synthesis and conformation
  作者：Karol Kacprzak、Błażej Gierczyk

  DOI：10.1016/j.tetasy.2010.10.023

  日期：2010.11

  The synthesis and conformational preferences of 9-azido-(9-deoxy)-Cinchona alkaloids constituting a novel class of Cinchona alkaloid derivatives of both natural and 9-epi configurations are described One and two-step preparative syntheses of 9-azido-(9-deoxy)-Cinchona alkaloids have been developed allowing for their easy access on a multigram scale The stereochemical integrity of these azides has been confirmed from their circular dichroism and specific rotation data The conformations of the 9-azido Cinchona alkaloids deduced from both H-1 NMR and DFT calculations show that this class of Cinchona derivatives largely reflect the conformational preferences of the corresponding Cinchona bases this strategy therefore offers a defined chiral and clickable scaffold (C) 2010 Elsevier Ltd All rights reserved
• Synthesis and systemic toxicity assessment of quinine-triazole scaffold with antiprotozoal potency
  作者：Adarsh Sahu、Ram Kishore Agrawal、RajKishor Pandey

  DOI：10.1016/j.bioorg.2019.102939

  日期：2019.7

  A series of hybrid antiprotozoal compounds with quinine-triazolyl scaffold were prepared by copper catalyzed Huisgen 1,3-dipolar cycloaddition via O-mesylation with mesyl chloride followed by azide displacement. The synthesized azide derivative was made to react with various aromatic and aliphatic alkynes. The triazolyl-linked quinine scaffolds were synthesized under solvent-free mechanochemical ball milling conditions. Products (6a-s) were screened for in-vitro antimalarial and antileishmanial activity. Screening results indicated that out of the synthesized series of 19 products, compounds 6d, 6h, 6l, 6m, and 6n showed significant antimalarial (P. falciparum) and antileishmanial activities (L. donavani) with IC50 values 0.28, 0.28, 0.25, 0.33, 0.76 mu M and 8.26, 4.4, 1.78, 3.95, and 4.06 mu M, respectively. Further toxicological analysis established the Median lethal dose (LD50), No observed adverse effect level (NOAEL) and human equivalent dose (HED) of the most potent compounds by acute and sub acute toxicity studies performed in rodent animal model. The studies revealed that compounds (6d, 6h, 6l and 6m) did not reveal any toxic manifestation at dose 1000 mg/Kg and from which the corresponding HED was calculated to be 13.84 mg/kg.
• Asymmetric Organocatalysis and Continuous Chemistry for an Efficient and Cost-Competitive Process to Pregabalin
  作者：Armando Carlone、Luca Bernardi、Peter McCormack、Tony Warr、Srinivas Oruganti、Christopher J. Cobley

  DOI：10.1021/acs.oprd.1c00394

  日期：2021.12.17

  innovative synthetic process to pregabalin. The process is underpinned by two enabling technologies critical to its success; continuous chemistry allowed a safe and clean production of nitroalkene, and asymmetric organocatalysis gave access to the chiral intermediate in an enantioenriched form. Crucial to the success of the process was the careful development of a continuous process to nitroalkene and

  在此，我们介绍了普瑞巴林的创新合成工艺的放大开发。该过程由对其成功至关重要的两项支持技术提供支持；连续化学允许安全和清洁生产硝基烯烃，不对称有机催化使手性中间体以对映体富集形式获得。该工艺成功的关键是精心开发了硝基烯烃的连续工艺以及有机催化剂和反应条件的优化，以在催化不对称反应中获得非常高的转换频率。还开发了有机催化剂的成功回收，以实现具有成本竞争力的过程。