(4S,5R)-tert-butyl 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2,2-dimethyl-5-(((S)-6′-neopentyl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano-[2,3-b]pyridine]-4′-ylamino)methyl)oxazolidine-3-carboxylate | 1373754-61-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡喃吡啶类
• 英文名称: (4S,5R)-tert-butyl 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2,2-dimethyl-5-(((S)-6′-neopentyl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano-[2,3-b]pyridine]-4′-ylamino)methyl)oxazolidine-3-carboxylate
• 英文别名: tert-butyl (4S,5R)-4-(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)-5-[[[(4S)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]methyl]-2,2-dimethyl-1,3-oxazolidine-3-carboxylate
• CAS: 1373754-61-0
• 化学式: C₃₆H₅₁N₃O₆
• 分子量: 621.817
• InChiKey: VBXONBMHBOCOFX-FEVNIDIWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  6.4
• 重原子数：
  45
• 可旋转键数：
  9
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  91.4
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (4S,5R)-tert-butyl 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2,2-dimethyl-5-(((S)-6′-neopentyl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano-[2,3-b]pyridine]-4′-ylamino)methyl)oxazolidine-3-carboxylate 在 盐酸 、 N,N-二异丙基乙胺 作用下， 以 1,4-二氧六环 、 二氯甲烷 为溶剂， 反应 12.0h， 生成 N-[(2S,3R)-1-(2,3-dihydro-1,4-benzodioxin-6-yl)-4-[[(4S)-6-(2,2-dimethylpropyl)spiro[3,4-dihydropyrano[2,3-b]pyridine-2,1'-cyclobutane]-4-yl]amino]-3-hydroxybutan-2-yl]acetamide
  参考文献：
  名称：

  Design and Preparation of a Potent Series of Hydroxyethylamine Containing β-Secretase Inhibitors That Demonstrate Robust Reduction of Central β-Amyloid

  摘要：

  A series of potent hydroxyethyl amine (HEA) derived inhibitors of beta-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS beta-amyloid (A beta) in Sprague-Dawley rats following oral administration.

  DOI：

  10.1021/jm300119p
• 作为产物：
  描述：

  (S)-methyl 2-(tert-butoxycarbonylamino)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)propanoate 在 lithium hydroxide monohydrate 、 camphor-10-sulfonic acid 、 isobutyl chloroformate 、 氢溴酸 、 戴斯-马丁氧化剂 、 lithium tri-t-butoxyaluminum hydride 、 N,N-二异丙基乙胺 、 原甲酸三甲酯 作用下， 以 四氢呋喃 、 甲醇 、 乙醇 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 16.5h， 生成 (4S,5R)-tert-butyl 4-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)methyl)-2,2-dimethyl-5-(((S)-6′-neopentyl-3′,4′-dihydrospiro[cyclobutane-1,2′-pyrano-[2,3-b]pyridine]-4′-ylamino)methyl)oxazolidine-3-carboxylate
  参考文献：
  名称：

  Design and Preparation of a Potent Series of Hydroxyethylamine Containing β-Secretase Inhibitors That Demonstrate Robust Reduction of Central β-Amyloid

  摘要：

  A series of potent hydroxyethyl amine (HEA) derived inhibitors of beta-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS beta-amyloid (A beta) in Sprague-Dawley rats following oral administration.

  DOI：

  10.1021/jm300119p

文献信息

• Design and Preparation of a Potent Series of Hydroxyethylamine Containing β-Secretase Inhibitors That Demonstrate Robust Reduction of Central β-Amyloid
  作者：Matthew M. Weiss、Toni Williamson、Safura Babu-Khan、Michael D. Bartberger、James Brown、Kui Chen、Yuan Cheng、Martin Citron、Michael D. Croghan、Thomas A. Dineen、Joel Esmay、Russell F. Graceffa、Scott S. Harried、Dean Hickman、Stephen A. Hitchcock、Daniel B. Horne、Hongbing Huang、Ronke Imbeah-Ampiah、Ted Judd、Matthew R. Kaller、Charles R. Kreiman、Daniel S. La、Vivian Li、Patricia Lopez、Steven Louie、Holger Monenschein、Thomas T. Nguyen、Lewis D. Pennington、Claire Rattan、Tisha San Miguel、E.Allen Sickmier、Robert C. Wahl、Paul H. Wen、Stephen Wood、Qiufen Xue、Bryant H. Yang、Vinod F. Patel、Wenge Zhong

  DOI：10.1021/jm300119p

  日期：2012.11.8

  A series of potent hydroxyethyl amine (HEA) derived inhibitors of beta-site APP cleaving enzyme (BACE1) was optimized to address suboptimal pharmacokinetics and poor CNS partitioning. This work identified a series of benzodioxolane analogues that possessed improved metabolic stability and increased oral bioavailability. Subsequent efforts focused on improving CNS exposure by limiting susceptibility to Pgp-mediated efflux and identified an inhibitor which demonstrated robust and sustained reduction of CNS beta-amyloid (A beta) in Sprague-Dawley rats following oral administration.