(R)-N-(tert-butoxycarbonyl)-α-methylproline ethyl ester | 619307-07-2

• 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: (R)-N-(tert-butoxycarbonyl)-α-methylproline ethyl ester
• 英文别名: N-Boc-α-methyl-proline ethyl ester；1-(1,1-dimethylethyl) 2-ethyl (2R)-2-methylpyrrolidine-1,2-dicarboxylate；1-(tert-Butyl) 2-ethyl (R)-2-methylpyrrolidine-1,2-dicarboxylate；1-O-tert-butyl 2-O-ethyl (2R)-2-methylpyrrolidine-1,2-dicarboxylate
• CAS: 619307-07-2
• 化学式: C₁₃H₂₃NO₄
• 分子量: 257.33
• InChiKey: APLKPAQPQLXCRO-CYBMUJFWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  18
• 可旋转键数：
  5
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.85
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (R)-N-(tert-butoxycarbonyl)-α-methylproline ethyl ester 在 吡啶 、 4-二甲氨基吡啶 、 锂硼氢 、 sodium hydride 、 苯甲醚 、 三氟乙酸 作用下， 以 四氢呋喃 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 (1R,5S,6R,7R,10R,11R,14R,15S,20R,21R)-5,7,10,15-tetramethyl-7-[(2R)-3-methylbutan-2-yl]-21-[[(2R)-2-methylpyrrolidin-2-yl]methoxy]-20-(5-pyridin-4-yl-1,2,4-triazol-1-yl)-17-oxapentacyclo[13.3.3.01,14.02,11.05,10]henicos-2-ene-6-carboxylic acid
  参考文献：
  名称：

  Synthesis and biological evaluation of antifungal derivatives of enfumafungin as orally bioavailable inhibitors of β-1,3-glucan synthase

  摘要：

  Orally bioavailable inhibitors of beta-(1,3)-D-glucan synthase have been pursued as new, broad-spectrum fungicidal therapies suitable for treatment in immunocompromised patients. Toward this end, a collaborative medicinal chemistry program was established based on semisynthetic derivatization of the triterpenoid glycoside natural product enfumafungin in order to optimize in vivo antifungal activity and oral absorption properties. In the course of these studies, it was hypothesized that the pharmacokinetic properties of the semisynthetic enfumafungin analog 3 could be improved by tethering the alkyl groups proximal to the basic nitrogen of the C3-aminoether side chain into an azacyclic system, so as to preclude oxidative N-demethylation. The results of this research effort are disclosed herein. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.05.031
• 作为产物：
  描述：

  (S)-N-(3-bromopropyl)-N-(tert-butoxycarbonyl)alanine ethyl ester 在 双(三甲基硅烷基)氨基钾 作用下， 以 N,N-dimethyl-d₆-formamide 为溶剂， 反应 0.5h， 以96%的产率得到(R)-N-(tert-butoxycarbonyl)-α-methylproline ethyl ester
  参考文献：
  名称：

  Synthesis and biological evaluation of antifungal derivatives of enfumafungin as orally bioavailable inhibitors of β-1,3-glucan synthase

  摘要：

  Orally bioavailable inhibitors of beta-(1,3)-D-glucan synthase have been pursued as new, broad-spectrum fungicidal therapies suitable for treatment in immunocompromised patients. Toward this end, a collaborative medicinal chemistry program was established based on semisynthetic derivatization of the triterpenoid glycoside natural product enfumafungin in order to optimize in vivo antifungal activity and oral absorption properties. In the course of these studies, it was hypothesized that the pharmacokinetic properties of the semisynthetic enfumafungin analog 3 could be improved by tethering the alkyl groups proximal to the basic nitrogen of the C3-aminoether side chain into an azacyclic system, so as to preclude oxidative N-demethylation. The results of this research effort are disclosed herein. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.05.031

文献信息

• [EN] ANTIFUNGAL AGENTS<br/>[FR] AGENTS ANTIFONGIQUES
  申请人：MERCK SHARP & DOHME

  公开号：WO2010019204A1

  公开（公告）日：2010-02-18

  Novel derivatives of enfumafungin are disclosed herein, along with their pharmaceutically acceptable salts, hydrates and prodrugs. Also disclosed are compositions comprising such compounds, methods of preparing such compounds and methods of using such compounds as antifungal agents and/or inhibitors of (l,3)-β-D-glucan synthase. The disclosed compounds, their pharmaceutically acceptable salts, hydrates and prodrugs,,as well as compositions comprising such compounds, salts, hydrates and prodrugs, are useful for treating and/or preventing fungal infections and associated diseases and conditions.

  本文披露了恩富马富金的新颖衍生物，以及它们的药用盐、水合物和前药。还披露了包含这些化合物的组合物、制备这些化合物的方法以及将这些化合物用作抗真菌剂和/或（1,3）-β-D-葡聚糖合酶抑制剂的方法。所披露的化合物、它们的药用盐、水合物和前药，以及包含这些化合物、盐、水合物和前药的组合物，可用于治疗和/或预防真菌感染及相关疾病和症状。
• Asymmetric Cyclization via Memory of Chirality:  A Concise Access to Cyclic Amino Acids with a Quaternary Stereocenter
  作者：Takeo Kawabata、Shimpei Kawakami、Swapan Majumdar

  DOI：10.1021/ja0378299

  日期：2003.10.1

  N-(omega-Bromoalkyl)-amino acid derivatives, readily prepared from natural alpha-amino acids, gave cyclic amino acids with a quaternary stereocenter by treatment with potassium hexamethyldisilazaide in DMF. The chirality of parent amino acids was almost completely preserved during an enolate-formation and cyclization process, giving aza-cyclic amino acids in up to 98% ee in retention of configuration

  N-(ω-溴烷基)-氨基酸衍生物，很容易从天然α-氨基酸制备，通过在DMF中用六甲基二硅氮杂钾处理得到具有季立体中心的环状氨基酸。在烯醇化物形成和环化过程中，亲本氨基酸的手性几乎完全保留，使氮杂环氨基酸的构型保留率高达 98% ee。该方法适用于氮杂环丁烷、吡咯烷、哌啶和氮杂环庚烷衍生物的不对称合成。不对称环化似乎是通过轴向手性烯醇中间体而不是通过协调一致的 SEi 过程进行的。
• 光学活性環状アミノ酸誘導体、その中間体及びそれらの製造方法
  申请人：東ソー株式会社

  公开号：JP2005082572A

  公开（公告）日：2005-03-31

  PROBLEM TO BE SOLVED: To provide a new cyclic amino acid derivative useful as a synthetic intermediate for drugs and agricultural chemicals, its intermediate, and a method of manufacturing the compound having high general-purpose properties which can be applied to 4- to 6-membered rings and can obtain a target product with an extremely high optical selectivity.

  SOLUTION: The optically active amino acid derivative represented by formula (1) is obtained by derivatizing an optically active amino acid represented by formula (3) as a raw material to an N-haloalkylamino acid derivative represented by formula (2) and reacting the compound with a base.

  COPYRIGHT: (C)2005,JPO&NCIPI

  要解决的问题：提供一种新的环状氨基酸衍生物，可用作药物和农业化学品的合成中间体，其中间体，以及一种制造具有高通用性能的化合物的方法，该方法可应用于4-至6-成员环，并且可以获得具有极高光学选择性的目标产品。 解决方案：通过将公式（3）表示的光学活性氨基酸作为原料衍生为公式（2）表示的N-卤代烷基氨基酸衍生物，然后将化合物与碱反应，得到公式（1）表示的光学活性氨基酸衍生物。 版权所有：（C）2005，JPO&NCIPI
• Stereochemical Diversity in Asymmetric Cyclization via Memory of Chirality
  作者：Takeo Kawabata、Seiji Matsuda、Shimpei Kawakami、Daiki Monguchi、Katsuhiko Moriyama

  DOI：10.1021/ja0670761

  日期：2006.12.1

  potassium amide bases in DMF, cyclization proceeds with retention of configuration, while inversion of configuration was observed with lithium amide bases in THF. Chirality of the parent amino acids was preserved during enolate formation and cyclization to give aza-cyclic amino acids in up to 98% ee with retention of configuration or inversion of configuration, depending on the reaction conditions. Thus, both

  已开发出 N-Boc-N-ω-溴烷基-α-氨基酸衍生物的对映发散不对称环化。在 DMF 中使用氨基钾碱时，环化在构型保留的情况下进行，而在 THF 中使用氨基化锂碱时观察到构型反转。在烯醇化物形成和环化过程中保留了母体氨基酸的手性，以产生高达 98% ee 的氮杂环氨基酸，并保留构型或反转构型，这取决于反应条件。因此，具有四取代立体中心的环状氨基酸的两种对映异构体均以高对映异构纯度从容易获得的l-α-氨基酸制备。该协议也适用于α-氨基酸衍生物的螺环化和分子内共轭添加，
• Antifungal agents
  申请人：Greenlee Mark L.

  公开号：US20100113439A1

  公开（公告）日：2010-05-06

  Novel derivatives of enfumafungin are disclosed herein, along with their pharmaceutically acceptable salts, hydrates and prodrugs. Also disclosed are compositions comprising such compounds, methods of preparing such compounds and methods of using such compounds as antifungal agents and/or inhibitors of (1,3)-β-D-glucan synthase. The disclosed compounds, their pharmaceutically acceptable salts, hydrates and prodrugs, as well as compositions comprising such compounds, salts, hydrates and prodrugs, are useful for treating and/or preventing fungal infections and associated diseases and conditions.

  本文披露了恩福马富金的新型衍生物，以及它们的药用盐、水合物和前药。还公开了包含这些化合物的组合物、制备这些化合物的方法以及将这些化合物用作抗真菌剂和/或(1,3)-β-D-葡聚糖合酶抑制剂的方法。这些公开的化合物、它们的药用盐、水合物和前药，以及包含这些化合物、盐、水合物和前药的组合物，可用于治疗和/或预防真菌感染及相关疾病和病况。