tert-butyl N-[2-[[6-(aminomethyl)pyridin-2-yl]methylamino]ethyl]-N-(3-hydroxypropyl)carbamate | 192379-43-4

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 英文名称: tert-butyl N-[2-[[6-(aminomethyl)pyridin-2-yl]methylamino]ethyl]-N-(3-hydroxypropyl)carbamate
• CAS: 192379-43-4
• 化学式: C₁₇H₃₀N₄O₃
• 分子量: 338.45
• InChiKey: XDBFEBKVZVFIKV-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.3
• 重原子数：
  24
• 可旋转键数：
  11
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.65
• 拓扑面积：
  101
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  tert-butyl N-[2-[[6-(aminomethyl)pyridin-2-yl]methylamino]ethyl]-N-(3-hydroxypropyl)carbamate 在 potassium carbonate 、 三氟乙酸 作用下， 以 氯仿 、 乙腈 为溶剂， 反应 4.0h， 生成 3-[2-[[6-[[Bis[(3-fluorophenyl)methyl]amino]methyl]-2-pyridyl]methyl-[(3-fluorophenyl)methyl]amino]ethylamino]propan-1-ol
  参考文献：
  名称：

  Discovery of Novel Pyridinopolyamines with Potent Antimicrobial Activity:  Deconvolution of Mixtures Synthesized by Solution-Phase Combinatorial Chemistry

  摘要：

  A 1638-member pyridinopolyamine library, consisting of 13 sublibraries of 126 members prepared by a solution-phase approach, was completely deconvoluted from orthogonally protected intermediates by a combination of iterative and positional scanning procedures. Antibacterial assays against Streptococcus pyogenes and Escherichia coli imp(-) and a Candida albicans yeast specificity assay were employed to follow the activity of sublibraries. Screening of the 13 sublibraries, which were prepared by a synthetic method that places the differentiating functionality in a selected position A (secondary amine), at the end of the synthesis (fix last), provided several first-round actives. Subsequently, six single pyridinopolyamines (2-7) were prepared where the first-round winner, a hydrogen atom, is in the first deconvoluted position and the remaining three positions contained the same functionalities. The range of antibacterial and yeast activities of these single compounds suggested that a more active and selective compound may be discovered by completely deconvoluting the first-round active sublibraries. Pyridinopolyamine positions B (secondary benzylamine) and C (primary benzylamine) were then sequentially positionally scanned with a set of six meta-substituted benzyl functionalities to generate two sets of second/third-round sublibraries, containing 21 or 36 compounds in each sublibrary, respectively. High-throughput screening yielded sublibraries 15, 18, and 21 with MICs of 1-5 mu M against S. pyogenes and E. coli imp(-). Using rounds 1 and 2/3 screening data, two sets of single compounds (22-27) and (28-32) with the combination of m-(trifluoromethyl)benzyl group at position C and m-(trifluoromethyl)benzyl or m-methylbenzyl group at position B with position D (primary benzylamine) fixed were synthesized in the fourth round deconvolution. Subsequently, broader screening of deconvoluted compounds against a tier II panel of wild-type bacteria identified eight compounds (5, 7, 27, and 29-32) with approximately 100-fold greater selectivity for Gram-positive than Gram-negative bacteria, Thus, S. pyogenes, S. pyogenes (wild-type), Streptomyces aureus, and Enterococcus faecalis were inhibited at MICs of 1-12 mu M, whereas MICs for E. coli, Klebsiella pneumoniae, Proteus vulgaris, and Pseudomonas aeruginosa were >100 mu M. These eight compounds were not active (>100 mu M) against fungus C. albicans.

  DOI：

  10.1021/jm970598u
• 作为产物：
  描述：

  2,6-双(溴甲基)吡啶 在 potassium carbonate 、 苯硫酚 、 肼 作用下， 以 二氯甲烷 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 75.0h， 生成 tert-butyl N-[2-[[6-(aminomethyl)pyridin-2-yl]methylamino]ethyl]-N-(3-hydroxypropyl)carbamate
  参考文献：
  名称：

  Solution Phase Combinatorial Chemistry. Synthesis of Novel Linear Pyridinopolyamine Libraries with Potent Antibacterial Activity

  摘要：

  Novel linear pyridinopolyamine derivatives 1-3, 7, and 8 have been synthesized as scaffolds for combinatorial drug discovery. The mono-t-Boc- and monotosyl-protected linear scaffolds 1 and 2 were obtained by a Schiff base type cyclization of 2,6-pyridinedicarboxaldehyde (24) with monoprotected triamines 22 and 23 using Ni2+ as a metal template, followed by reductive cleavage and decomplexation in a one-pot procedure. The unprotected linear scaffold 3 was obtained by treating 1 with TFA, Scaffold 1 was also synthesized from the orthogonally protected pyridinopolyamine 7 which was constructed from 2,6-bis(bromomethylipyridine (29) in four steps. Selective deprotection of the key intermediate 7 afforded 8, which was further selectively deprotected to give scaffold 1. A combinatorial chemistry strategy involving solution phase simultaneous addition of functionalities (SPSAF) is described. Thirteen high-purity tertiary amine libraries 19-21) (total 1638 compounds) were synthesized by the SPSAF and fix last methodologies from linear polyamine scaffolds 1 and 2. All libraries were examined by TLC, purified by chromatographic techniques, and characterized by H-1 NMR and ESI RIS spectral data. A fur last methodology was utilized to minimize chemical reactions and perform SAR studies directly on libraries. Several first-round sublibraries of scaffold 1 containing 126 compounds each, exhibited potent antibacterial activity with MICs of 1-12 mu M against Streptococcus pyogenes and Escherichia coli imp(-).

  DOI：

  10.1021/jo970535j

文献信息

• Discovery of Novel Pyridinopolyamines with Potent Antimicrobial Activity:  Deconvolution of Mixtures Synthesized by Solution-Phase Combinatorial Chemistry
  作者：Haoyun An、Becky D. Haly、P. Dan Cook

  DOI：10.1021/jm970598u

  日期：1998.2.1

  A 1638-member pyridinopolyamine library, consisting of 13 sublibraries of 126 members prepared by a solution-phase approach, was completely deconvoluted from orthogonally protected intermediates by a combination of iterative and positional scanning procedures. Antibacterial assays against Streptococcus pyogenes and Escherichia coli imp(-) and a Candida albicans yeast specificity assay were employed to follow the activity of sublibraries. Screening of the 13 sublibraries, which were prepared by a synthetic method that places the differentiating functionality in a selected position A (secondary amine), at the end of the synthesis (fix last), provided several first-round actives. Subsequently, six single pyridinopolyamines (2-7) were prepared where the first-round winner, a hydrogen atom, is in the first deconvoluted position and the remaining three positions contained the same functionalities. The range of antibacterial and yeast activities of these single compounds suggested that a more active and selective compound may be discovered by completely deconvoluting the first-round active sublibraries. Pyridinopolyamine positions B (secondary benzylamine) and C (primary benzylamine) were then sequentially positionally scanned with a set of six meta-substituted benzyl functionalities to generate two sets of second/third-round sublibraries, containing 21 or 36 compounds in each sublibrary, respectively. High-throughput screening yielded sublibraries 15, 18, and 21 with MICs of 1-5 mu M against S. pyogenes and E. coli imp(-). Using rounds 1 and 2/3 screening data, two sets of single compounds (22-27) and (28-32) with the combination of m-(trifluoromethyl)benzyl group at position C and m-(trifluoromethyl)benzyl or m-methylbenzyl group at position B with position D (primary benzylamine) fixed were synthesized in the fourth round deconvolution. Subsequently, broader screening of deconvoluted compounds against a tier II panel of wild-type bacteria identified eight compounds (5, 7, 27, and 29-32) with approximately 100-fold greater selectivity for Gram-positive than Gram-negative bacteria, Thus, S. pyogenes, S. pyogenes (wild-type), Streptomyces aureus, and Enterococcus faecalis were inhibited at MICs of 1-12 mu M, whereas MICs for E. coli, Klebsiella pneumoniae, Proteus vulgaris, and Pseudomonas aeruginosa were >100 mu M. These eight compounds were not active (>100 mu M) against fungus C. albicans.
• Solution Phase Combinatorial Chemistry. Synthesis of Novel Linear Pyridinopolyamine Libraries with Potent Antibacterial Activity
  作者：Haoyun An、Becky D. Haly、Allister S. Fraser、Charles J. Guinosso、P. Dan Cook

  DOI：10.1021/jo970535j

  日期：1997.7.1

  Novel linear pyridinopolyamine derivatives 1-3, 7, and 8 have been synthesized as scaffolds for combinatorial drug discovery. The mono-t-Boc- and monotosyl-protected linear scaffolds 1 and 2 were obtained by a Schiff base type cyclization of 2,6-pyridinedicarboxaldehyde (24) with monoprotected triamines 22 and 23 using Ni2+ as a metal template, followed by reductive cleavage and decomplexation in a one-pot procedure. The unprotected linear scaffold 3 was obtained by treating 1 with TFA, Scaffold 1 was also synthesized from the orthogonally protected pyridinopolyamine 7 which was constructed from 2,6-bis(bromomethylipyridine (29) in four steps. Selective deprotection of the key intermediate 7 afforded 8, which was further selectively deprotected to give scaffold 1. A combinatorial chemistry strategy involving solution phase simultaneous addition of functionalities (SPSAF) is described. Thirteen high-purity tertiary amine libraries 19-21) (total 1638 compounds) were synthesized by the SPSAF and fix last methodologies from linear polyamine scaffolds 1 and 2. All libraries were examined by TLC, purified by chromatographic techniques, and characterized by H-1 NMR and ESI RIS spectral data. A fur last methodology was utilized to minimize chemical reactions and perform SAR studies directly on libraries. Several first-round sublibraries of scaffold 1 containing 126 compounds each, exhibited potent antibacterial activity with MICs of 1-12 mu M against Streptococcus pyogenes and Escherichia coli imp(-).