[4-¹³C]-(2S)-isopropyl 2-(((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-trideuteromethyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate | 1256490-44-4

• 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: [4-¹³C]-(2S)-isopropyl 2-(((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-trideuteromethyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate
• 英文别名: (S)-isopropyl 2-((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-¹³C-perdeuteriomethyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphorylamino)propanoate；Propan-2-yl (2S)-2-[[[(2R,3R,4R,5R)-5-(2,4-dioxopyrimidin-1-yl)-4-fluoro-3-hydroxy-4-(trideuterio(113C)methyl)oxolan-2-yl]methoxy-phenoxyphosphoryl]amino]propanoate
• CAS: 1256490-44-4
• 化学式: C₂₂H₂₉FN₃O₉P
• 分子量: 533.424
• InChiKey: TTZHDVOVKQGIBA-SBMHIBAOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  36
• 可旋转键数：
  11
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  153
• 氢给体数：
  3
• 氢受体数：
  11

反应信息

• 作为反应物：
  描述：

  [4-¹³C]-(2S)-isopropyl 2-(((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-trideuteromethyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate 在 三乙胺 作用下， 以 水 为溶剂， 反应 30.0h， 以83%的产率得到(2S)-2-(((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-¹³C-perdeuteriomethyltetrahydrofuran-2-yl)methoxy)(hydroxy)phosphoryl)amino)propanoic acid
  参考文献：
  名称：

  [EN] N- [ (2 ' R) -2 ' -DEOXY-2 ' -FLUORO-2 ' -METHYL-P-PHENYL-5 ' -URIDYLYL] -L-ALANINE 1-METHYLETHYL ESTER AND PROCESS FOR ITS PRODUCTION
  [FR] ESTER DE N-[(2 ' R) -2' -DÉSOXY-2' -FLUORO-2' -MÉTHYL-P-PHÉNYL-5' -URIDYLYL]-L-ALANINE 1-MÉTHYLÉTHYLE ET SON PROCÉDÉ DE PRODUCTION

  摘要：

  本文披露了化学式4的核苷酸磷酰胺及其作为治疗病毒性疾病的药物的用途。这些化合物是RNA依赖性5RNA病毒复制的抑制剂，可作为HCV NS5B聚合酶的抑制剂，HCV复制的抑制剂以及哺乳动物丙型肝炎感染的治疗药物。还披露了一种制备化合物4的方法：（化学式4），其中P*代表手性磷原子，包括：a）反应异丙基-丙氨酸酯（化学式A）、二-X'-苯基磷酸酯（化学式B）、2'-脱氧-2f-氟-2'-C-甲基尿嘧啶（化学式3）和碱以获得含有4的第一混合物；其中X是酸的共轭碱基，n为0或1，X'是卤素；b）将第一混合物与保护化合物反应以获得含有4的第二混合物；c）可选地将第二混合物经结晶、色谱或萃取处理以获得4。

  公开号：

  WO2010135569A1
• 作为产物：
  描述：

  3',5'-O-(1,1,3,3-四异丙基-1,3-二硅氧烷)尿苷 在 吡啶 、 N-甲基咪唑 、 二甲氨基三氟化硫 、 magnesium 、 二甲基亚砜 、 正丁胺 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 乙醚 、 正己烷 、 二氯甲烷 为溶剂， 反应 46.5h， 生成 [4-¹³C]-(2S)-isopropyl 2-(((((2R,3R,4R,5R)-5-(2,4-dioxo-3,4-dihydropyrimidin-1(2H)-yl)-4-fluoro-3-hydroxy-4-trideuteromethyltetrahydrofuran-2-yl)methoxy)(phenoxy)phosphoryl)amino)propanoate
  参考文献：
  名称：

  Synthesis of Stable Isotope Labeled Analogs of the Anti-Hepatitis C Virus Nucleotide Prodrugs PSI-7977 and PSI-352938

  摘要：

  In order to support bioanalytical LC/MS method development and plasma sample analysis in preclinical and clinical studies of the anti-hepatitis C-virus nucleotides, PSI-7977 and PSI-352938, the corresponding stable isotope labeled forms were prepared. These labeled compounds were prepared by addition reaction of the freshly prepared Grignard reagent (CD3MgI)-C-13 to the corresponding 2'-ketone nucleosides followed by fluorination of the resulting carbinol with DAST. As expected, these 2'-C-(trideuterated-C-13-methyl) nucleotide prodrugs showed similar anti-HCV activity to that of the corresponding unlabeled ones.

  DOI：

  10.1080/15257770.2011.614308

文献信息

• NUCLEOSIDE PHOSPHORAMIDATES
  申请人：Ross Bruce S.

  公开号：US20110251152A1

  公开（公告）日：2011-10-13

  Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.

  本文披露了核苷酸磷酰胺及其作为治疗病毒性疾病的药物的用途。这些化合物是RNA依赖性RNA病毒复制的抑制剂，可用作HCV NS5B聚合酶的抑制剂，用于抑制HCV复制并治疗哺乳动物的丙型肝炎感染。
• [EN] N- [ (2 ' R) -2 ' -DEOXY-2 ' -FLUORO-2 ' -METHYL-P-PHENYL-5 ' -URIDYLYL] -L-ALANINE 1-METHYLETHYL ESTER AND PROCESS FOR ITS PRODUCTION<br/>[FR] ESTER DE N-[(2 ' R) -2' -DÉSOXY-2' -FLUORO-2' -MÉTHYL-P-PHÉNYL-5' -URIDYLYL]-L-ALANINE 1-MÉTHYLÉTHYLE ET SON PROCÉDÉ DE PRODUCTION
  申请人：PHARMASSET INC

  公开号：WO2010135569A1

  公开（公告）日：2010-11-25

  Disclosed herein are nucleoside phosphoramidates of formula 4 and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent 5 RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals. Disclosed is also a process for preparing compound represented by formula 4: (Formula 4) wherein P* represents a chiral phosphorus atom, which comprises: a) reacting an isopropyl-alanate, (Formula A), a di-X'-phenylphosphate, (Formula B), 2'-deoxy-2f-fluoro-2'-C-methyluridine, (Formula 3), and a base to obtain a first mixture comprising 4; wherein X is a conjugate base of an acid, n is 0 or 1, and X' is a halogen, b) reacting the first mixture with a protecting compound to obtain a second mixture comprising 4; and c) optionally subjecting the second mixture to crystallization, chromatography or extraction in order to obtain 4.

  本文披露了化学式4的核苷酸磷酰胺及其作为治疗病毒性疾病的药物的用途。这些化合物是RNA依赖性5RNA病毒复制的抑制剂，可作为HCV NS5B聚合酶的抑制剂，HCV复制的抑制剂以及哺乳动物丙型肝炎感染的治疗药物。还披露了一种制备化合物4的方法：（化学式4），其中P*代表手性磷原子，包括：a）反应异丙基-丙氨酸酯（化学式A）、二-X'-苯基磷酸酯（化学式B）、2'-脱氧-2f-氟-2'-C-甲基尿嘧啶（化学式3）和碱以获得含有4的第一混合物；其中X是酸的共轭碱基，n为0或1，X'是卤素；b）将第一混合物与保护化合物反应以获得含有4的第二混合物；c）可选地将第二混合物经结晶、色谱或萃取处理以获得4。
• Synthesis of Stable Isotope Labeled Analogs of the Anti-Hepatitis C Virus Nucleotide Prodrugs PSI-7977 and PSI-352938
  作者：Byoung-Kwon Chun、Jinfa Du、Hai-Ren Zhang、Wonsuk Chang、Bruce S. Ross、Ying Jiang、Donghui Bao、Christine L. Espiritu、Meg Keilman、Holly M. Micolochick Steuer、Phillip A. Furman、Michael J. Sofia

  DOI：10.1080/15257770.2011.614308

  日期：2011.11

  In order to support bioanalytical LC/MS method development and plasma sample analysis in preclinical and clinical studies of the anti-hepatitis C-virus nucleotides, PSI-7977 and PSI-352938, the corresponding stable isotope labeled forms were prepared. These labeled compounds were prepared by addition reaction of the freshly prepared Grignard reagent (CD3MgI)-C-13 to the corresponding 2'-ketone nucleosides followed by fluorination of the resulting carbinol with DAST. As expected, these 2'-C-(trideuterated-C-13-methyl) nucleotide prodrugs showed similar anti-HCV activity to that of the corresponding unlabeled ones.