(S)-2-{[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy](phenoxy)phosphorylamino}propionic acid ethyl ester | 1064684-30-5

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘧啶核苷
• 英文名称: (S)-2-{[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy](phenoxy)phosphorylamino}propionic acid ethyl ester
• 英文别名: Ethyl ((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)-L-alaninate；ethyl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyloxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate
• CAS: 1064684-30-5
• 化学式: C₂₁H₂₇FN₃O₉P
• 分子量: 515.432
• InChiKey: HRGZELWFPQCNNG-LHGNKGQLSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.6
• 重原子数：
  35
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.48
• 拓扑面积：
  153
• 氢给体数：
  3
• 氢受体数：
  11

反应信息

• 作为产物：
  描述：

  1-((2R,3R,4R,5R)-5-(((tert-butyldimethylsilyl)oxy)methyl)-3-fluoro-4-hydroxy-3-methyltetrahydrofuran-2-yl)pyrimidin-2,4(1H,3H)dione 在 N-甲基咪唑 、 4-二甲氨基吡啶 、 1,4-环己二烯 、 palladium 10% on activated carbon 、 triethylamine tris(hydrogen fluoride) 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 为溶剂， 反应 3.0h， 生成 (S)-2-{[(2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-4-fluoro-3-hydroxy-4-methyltetrahydrofuran-2-ylmethoxy](phenoxy)phosphorylamino}propionic acid ethyl ester
  参考文献：
  名称：

  Efficient synthesis of nucleoside aryloxy phosphoramidate prodrugs utilizing benzyloxycarbonyl protection

  摘要：

  An efficient method for the synthesis of nucleoside phosphoramidates prodrugs (6a-f) has been developed that employs a simple protection/deprotection sequence of the nucleoside with benzyloxycarbonyl (Cbz). The coupling reaction of Cbz-protected derivatives (5a-f) with phenyl-(ethoxy-L-alaninyl)-phosphorochloridate (7), followed by Cbz group removal by hydrogenolysis provided the phenyl phosphoramidate ProTides (6a-f) in excellent overall yields. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tet.2011.05.046

文献信息

• Discovery of a β-<scp>d</scp>-2′-Deoxy-2′-α-fluoro-2′-β-<i>C</i>-methyluridine Nucleotide Prodrug (PSI-7977) for the Treatment of Hepatitis C Virus
  作者：Michael J. Sofia、Donghui Bao、Wonsuk Chang、Jinfa Du、Dhanapalan Nagarathnam、Suguna Rachakonda、P. Ganapati Reddy、Bruce S. Ross、Peiyuan Wang、Hai-Ren Zhang、Shalini Bansal、Christine Espiritu、Meg Keilman、Angela M. Lam、Holly M. Micolochick Steuer、Congrong Niu、Michael J. Otto、Phillip A. Furman

  DOI：10.1021/jm100863x

  日期：2010.10.14

  Hepatitis C virus (HCV) is a global health problem requiring novel approaches for effective treatment of this disease. The HCV NS5B polymerase has been demonstrated to be a viable target for the development of HCV therapies. β-d-2′-Deoxy-2′-α-fluoro-2′-β-C-methyl nucleosides are selective inhibitors of the HCV NS5B polymerase and have demonstrated potent activity in the clinic. Phosphoramidate prodrugs

  丙型肝炎病毒 (HCV) 是一个全球性的健康问题，需要新的方法来有效治疗这种疾病。HCV NS5B 聚合酶已被证明是开发 HCV 疗法的可行靶标。β- d -2'-Deoxy-2'-α-fluoro-2'-β- C-甲基核苷是 HCV NS5B 聚合酶的选择性抑制剂，并已在临床上显示出有效的活性。制备了 β- d -2'-deoxy-2'-α-fluoro-2'-β- C-甲基尿苷核苷的 5'-磷酸衍生物的氨基磷酸酯前药，并在 HCV 亚基因组复制子测定中显示出显着的效力（< 1 μM）并产生高水平的三磷酸盐6当体内给药时，在原代肝细胞和大鼠、狗和猴子的肝脏中。使非对映体混合物14的单一非对映体51结晶，确定X射线结构，将氨基磷酸酯立体化学建立为S p ，从而首次将氨基磷酸酯前药的立体化学与生物活性相关联。51（PSI-7977）被选为临床开发候选者。
• NUCLEOSIDE PHOSPHORAMIDATE PRODRUGS
  申请人：SOFIA MICHAEL JOSEPH

  公开号：US20100016251A1

  公开（公告）日：2010-01-21

  Disclosed herein are phosphoramidate prodrugs of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomer, salt (acid or basic addition salt), hydrate, solvate, or crystalline form thereof, represented by the following structure: Also disclosed are methods of treatment, uses, and processes for preparing each of which utilize the compound represented by formula I.

  本文披露了用于治疗哺乳动物病毒感染的核苷类衍生物的磷酰胺酯前药，该前药是一种化合物，其立体异构体、盐（酸性或碱性加合盐）、水合物、溶剂合物或结晶形式，由以下结构表示：同时还披露了治疗方法、用途和制备过程，每种方法均利用由式I表示的化合物。
• Nucleoside phosphoramidate prodrugs
  申请人：Gilead Pharmasset LLC

  公开号：EP2801580A1

  公开（公告）日：2014-11-12

  Disclosed herein are phosphoramidate prodrugs of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound or its stereoisomer, represented by the following structure: Also disclosed are uses and processes for preparing the compound represented by formula I.

  本文公开了用于治疗哺乳动物病毒感染的核苷衍生物磷酰胺原药，它是由以下结构表示的化合物或其立体异构体： 还公开了制备式 I 所表示的化合物的用途和工艺。
• US8334270B2
  申请人：——

  公开号：US8334270B2

  公开（公告）日：2012-12-18
• [EN] NUCLEOSIDE PHOSPHORAMIDATE PRODRUGS<br/>[FR] PROMÉDICAMENTS DE PHOSPHORAMIDATE DE NUCLÉOSIDE
  申请人：PHARMASSET INC

  公开号：WO2008121634A2

  公开（公告）日：2008-10-09

  [EN] Disclosed herein are phosphoramidate prodrugs of nucleoside derivatives for the treatment of viral infections in mammals, which is a compound, its stereoisomer, salt (acid or basic addition salt), hydrate, solvate, or crystalline form thereof, represented by the following structure: Also disclosed are methods of treatment, uses, and processes for preparing each of which utilize the compound represented by formula (I).
  [FR] L'invention concerne des promédicaments de phosphoramidate de dérivés de nucléoside pour le traitement d'infections virales chez les mammifères, qui sont un composé, son stéréo-isomère, un sel (sel d'addition acide ou basique), un hydrate, un solvate, ou une forme cristalline de celui-ci, représentés par la structure suivante : l'invention concerne également des procédés de traitement, des utilisations et des processus de préparation utilisant chacun le composé représenté par la formule (I).