4-formyl-1'-(tert-butoxycarbonyl)-4'-methyl-1,4'-bipiperidine | 305794-51-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 哌啶类
• 英文名称: 4-formyl-1'-(tert-butoxycarbonyl)-4'-methyl-1,4'-bipiperidine
• 英文别名: Tert-butyl 4-(4-formylpiperidin-1-yl)-4-methylpiperidine-1-carboxylate
• CAS: 305794-51-8
• 化学式: C₁₇H₃₀N₂O₃
• 分子量: 310.437
• InChiKey: OSJZKZQESQHCDX-UHFFFAOYSA-N

物化性质

• 沸点：
  398.1±42.0 °C(Predicted)
• 密度：
  1.105±0.06 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.8
• 重原子数：
  22
• 可旋转键数：
  4
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.88
• 拓扑面积：
  49.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  4-formyl-1'-(tert-butoxycarbonyl)-4'-methyl-1,4'-bipiperidine 在 正丁基锂 、 N-甲基吲哚酮 、 四丙基高钌酸铵 、 sodium acetate 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 为溶剂， 反应 27.33h， 生成 tert-butyl 4-[4-[(Z)-N-ethoxy-C-[4-(trifluoromethoxy)phenyl]carbonimidoyl]piperidin-1-yl]-4-methylpiperidine-1-carboxylate
  参考文献：
  名称：

  Synthesis, SAR, and Biological Evaluation of Oximino-Piperidino-Piperidine Amides. 1. Orally Bioavailable CCR5 Receptor Antagonists with Potent Anti-HIV Activity

  摘要：

  We previously reported the discovery of 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1'-[(2,4-dimethyl-3-pyridinyl)carbonyl] -4'-methyl-1,4'-bipiperidine N-oxide 1 (SCH 351125) as an orally bioavailable human CCR5 antagonist for the treatment of HIV-1 infection. Herein, we describe in detail the discovery of 1 from our initial lead compound as well as the synthesis and SAR studies directed toward optimization of substitution at the phenyl, oxime, and right-hand side amide groups in the oximino-piperidino-piperidine series. Substitutions (4-Br, 4-CF3, 4-OCF3, 4-SO2Me, and 4-Cl) at the phenyl group are well-tolerated, and small alkyl substitutions (Me, Et, Pr-n, Pr-i, and cyclopropyl methyl) at the oxime moiety are preferred for CCR5 antagonism. The 2,6-dimethylnicotinamide N-oxide moiety is the optimal choice for the right-hand side. Several compounds in this series, including compound 1, exhibited excellent antiviral activity in vitro. Compound 1, which has a favorable pharmacokinetic profile in rodents and primates, excellent oral bioavailability, and potent antiviral activity against a wide range of primary HIV-1 isolates, is a potentially promising new candidate for treatment of HIV-1 infection.

  DOI：

  10.1021/jm0200815
• 作为产物：
  描述：

  Tert-butyl 4-(hydroxymethyl)-4'-methyl-1,4'-bipiperidine-1'-carboxylate 在 四丙基高钌酸铵 N-甲基吗啉氧化物 作用下， 以 二氯甲烷 为溶剂， 反应 3.0h， 以53%的产率得到4-formyl-1'-(tert-butoxycarbonyl)-4'-methyl-1,4'-bipiperidine
  参考文献：
  名称：

  PIPERIDINE DERIVATIVES USEFUL AS CCR5 ANTAGONISTS

  摘要：

  公开号：

  EP1175402B1

文献信息

• PIPERIDINE DERIVATIVES USEFUL AS CCR5 ANTAGONISTS
  申请人：SCHERING CORPORATION

  公开号：EP1175402B1

  公开（公告）日：2005-07-20
• CCR5 antagonists useful for treating aids
  申请人：Schering Corporation

  公开号：EP1591444B1

  公开（公告）日：2010-04-28
• Synthesis, SAR, and Biological Evaluation of Oximino-Piperidino-Piperidine Amides. 1. Orally Bioavailable CCR5 Receptor Antagonists with Potent Anti-HIV Activity
  作者：Anandan Palani、Sherry Shapiro、Hubert Josien、Thomas Bara、John W. Clader、William J. Greenlee、Kathleen Cox、Julie M. Strizki、Bahige M. Baroudy

  DOI：10.1021/jm0200815

  日期：2002.7.1

  We previously reported the discovery of 4-[(Z)-(4-bromophenyl)(ethoxyimino)methyl]-1'-[(2,4-dimethyl-3-pyridinyl)carbonyl] -4'-methyl-1,4'-bipiperidine N-oxide 1 (SCH 351125) as an orally bioavailable human CCR5 antagonist for the treatment of HIV-1 infection. Herein, we describe in detail the discovery of 1 from our initial lead compound as well as the synthesis and SAR studies directed toward optimization of substitution at the phenyl, oxime, and right-hand side amide groups in the oximino-piperidino-piperidine series. Substitutions (4-Br, 4-CF3, 4-OCF3, 4-SO2Me, and 4-Cl) at the phenyl group are well-tolerated, and small alkyl substitutions (Me, Et, Pr-n, Pr-i, and cyclopropyl methyl) at the oxime moiety are preferred for CCR5 antagonism. The 2,6-dimethylnicotinamide N-oxide moiety is the optimal choice for the right-hand side. Several compounds in this series, including compound 1, exhibited excellent antiviral activity in vitro. Compound 1, which has a favorable pharmacokinetic profile in rodents and primates, excellent oral bioavailability, and potent antiviral activity against a wide range of primary HIV-1 isolates, is a potentially promising new candidate for treatment of HIV-1 infection.