isopropyl ((S)-(((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate | 1334513-09-5

• 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: isopropyl ((S)-(((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
• 英文别名: (S)-isopropyl 2-(((S)-(((3aR,4R,6R,6aR)-6-(6-amino-0H-purin-9-yl)-2,2-dimethyltetrahydrofuro-[3,4-d]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)amino)propionoate；propan-2-yl (2S)-2-[[[(3aR,4R,6R,6aR)-4-(6-aminopurin-9-yl)-2,2-dimethyl-3a,4,6,6a-tetrahydrofuro[3,4-d][1,3]dioxol-6-yl]methoxy-phenoxyphosphoryl]amino]propanoate
• CAS: 1334513-09-5
• 化学式: C₂₅H₃₃N₆O₈P
• 分子量: 576.546
• InChiKey: BRTZIROJDXGPAR-BVJSHOCJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.7
• 重原子数：
  40
• 可旋转键数：
  11
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.52
• 拓扑面积：
  171
• 氢给体数：
  2
• 氢受体数：
  13

反应信息

• 作为产物：
  描述：

  二氯磷酸苯酯 在 叔丁基氯化镁 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 4.88h， 生成 isopropyl ((S)-(((3aR,4R,6R,6aR)-6-(6-amino-9H-purin-9-yl)-2,2-dimethyltetrahydrofuro[3,4-d][1,3]dioxol-4-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate
  参考文献：
  名称：

  Synthesis of Diastereomerically Pure Nucleotide Phosphoramidates

  摘要：

  Prodrugs of therapeutic nucleoside monophosphates masked as phosphoramidate derivatives have become an increasingly important class of antiviral drugs in pharmaceutical research for delivering nucleotides in vitro and in vivo. Conventionally, phosphoramidate derivatives are prepared as a mixture of two diastereomers. We report a class of stable phosphoramidating reagents containing an amino acid ester and two phenolic groups, one unsubstituted and the other with electron-withdrawing substituents. The reagents can be isolated as single diastereomers and reacted with the 5'-hydroxyl group of nucleosides through selective nucleophilic displacement of the substituted phenol to prepare single diastereomer phosphoramidate products. This method has been used to prepare the HCV clinical candidate PSI-7977 in high yield and high diastereomeric purity.

  DOI：

  10.1021/jo201492m

文献信息

• Mechanism-Based Solution to the ProTide Synthesis Problem: Selective Access to Sofosbuvir, Acelarin, and INX-08189
  作者：Bryon Simmons、Zhuqing Liu、Artis Klapars、Ana Bellomo、Steven M. Silverman

  DOI：10.1021/acs.orglett.7b00469

  日期：2017.5.5

  A general and efficient method for the synthesis of pronucleotide (ProTide) 5'-phosphoramidate monoesters is :reported. This method consists of a highly stereoselective 5'-phosphorylation mediated by dimethylaluminum chloride to afford the desired target ProTides in excellent yields without employing, 3'-protection strategies. The application of this methodology to the synthesis of a number of pharmaceutically relevant compounds currently marketed or under investigation in clinical research is demonstrated.
• Synthesis of Diastereomerically Pure Nucleotide Phosphoramidates
  作者：Bruce S. Ross、P. Ganapati Reddy、Hai-Ren Zhang、Suguna Rachakonda、Michael J. Sofia

  DOI：10.1021/jo201492m

  日期：2011.10.21

  Prodrugs of therapeutic nucleoside monophosphates masked as phosphoramidate derivatives have become an increasingly important class of antiviral drugs in pharmaceutical research for delivering nucleotides in vitro and in vivo. Conventionally, phosphoramidate derivatives are prepared as a mixture of two diastereomers. We report a class of stable phosphoramidating reagents containing an amino acid ester and two phenolic groups, one unsubstituted and the other with electron-withdrawing substituents. The reagents can be isolated as single diastereomers and reacted with the 5'-hydroxyl group of nucleosides through selective nucleophilic displacement of the substituted phenol to prepare single diastereomer phosphoramidate products. This method has been used to prepare the HCV clinical candidate PSI-7977 in high yield and high diastereomeric purity.