5,6-dichloro-1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)benzimidazole | 194159-89-2

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并咪唑类
• 英文名称: 5,6-dichloro-1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)benzimidazole
• 英文别名: 5,6-Dichloro-1-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)benzimidazole；(2R,3R,4R,5R)-5-(5,6-dichlorobenzimidazol-1-yl)-4-fluoro-2-(hydroxymethyl)oxolan-3-ol
• CAS: 194159-89-2
• 化学式: C₁₂H₁₁Cl₂FN₂O₃
• 分子量: 321.135
• InChiKey: HDPMPBRZXGHRAC-DDHJBXDOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.1
• 重原子数：
  20
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  67.5
• 氢给体数：
  2
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  5,6-dichloro-1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)benzimidazole 在 吡啶 、 N-溴代丁二酰亚胺(NBS) 作用下， 以 1,4-二氧六环 为溶剂， 反应 0.17h， 生成 2-bromo-5,6-dichloro-1-(2-deoxy-3,5-di-O-acetyl-2-fluoro-β-D-ribofuranosyl)benzimidazole
  参考文献：
  名称：

  Synthesis of Fluorosugar Analogues of 2,5,6-Trichloro-1-(β-d-ribofuranosyl)benzimidazole as Antivirals with Potentially Increased Glycosidic Bond Stability

  摘要：

  The metabolic instability in vivo of the glycosidic bond of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) prompted us to design and synthesize the hitherto unreported fluorinated benzimidazole nucleosides 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole, 2,5,6-trichloro-1-(3-deoxy-3-fluoro-beta-D-ribofuranosyl)benzimidazole, and 2-bromo-5,6-dichloro-1-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)benzimidazole. TCRB was converted into the 2',5'-ditrityl and 3'5'-dinitryl derivatives, which were fluorinated with DAST and deprotected to yield 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) and 2,5,6-trichloro-1(3-deoxy-3-fluoro-beta-D-xylofuranosyl)benzimidazole. The resulting low over yield (5%) of 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole encouraged us to develop an alternative route. The heterocycle 2,5,6-trichlorobenzimidazole was condensed with 1-bromo-3,5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranose to give, after deprotection, 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole in a 50% overall yield. The 2'-deoxy-2'-fluoro-beta-D-ribofuranosyl compounds were prepared using 2'-deoxy-2'-fluorouridine, N-deoxyribofuranosyl transferase, and 5,6-dichlorobenzimidazole. Functionalization of the C2 position then gave the desired derivatives. Antiviral and cytotoxicity testing revealed that the deoxy fluoro arabinofuranosyl, xylofuranosyl, and ribofuranosyl derivatives were less active against human cytomegalovirus and more cytotoxic than TCRB.

  DOI：

  10.1021/jm990219s
• 作为产物：
  描述：

  5-甲基苯并咪唑 、 2'-氟-2'-脱氧尿苷 在 citrate buffer 、 N-deoxyribofuranosyl transferase 作用下， 以67%的产率得到5,6-dichloro-1-(2-deoxy-2-fluoro-β-D-ribofuranosyl)benzimidazole
  参考文献：
  名称：

  Synthesis of Fluorosugar Analogues of 2,5,6-Trichloro-1-(β-d-ribofuranosyl)benzimidazole as Antivirals with Potentially Increased Glycosidic Bond Stability

  摘要：

  The metabolic instability in vivo of the glycosidic bond of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) prompted us to design and synthesize the hitherto unreported fluorinated benzimidazole nucleosides 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole, 2,5,6-trichloro-1-(3-deoxy-3-fluoro-beta-D-ribofuranosyl)benzimidazole, and 2-bromo-5,6-dichloro-1-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)benzimidazole. TCRB was converted into the 2',5'-ditrityl and 3'5'-dinitryl derivatives, which were fluorinated with DAST and deprotected to yield 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) and 2,5,6-trichloro-1(3-deoxy-3-fluoro-beta-D-xylofuranosyl)benzimidazole. The resulting low over yield (5%) of 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole encouraged us to develop an alternative route. The heterocycle 2,5,6-trichlorobenzimidazole was condensed with 1-bromo-3,5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranose to give, after deprotection, 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole in a 50% overall yield. The 2'-deoxy-2'-fluoro-beta-D-ribofuranosyl compounds were prepared using 2'-deoxy-2'-fluorouridine, N-deoxyribofuranosyl transferase, and 5,6-dichlorobenzimidazole. Functionalization of the C2 position then gave the desired derivatives. Antiviral and cytotoxicity testing revealed that the deoxy fluoro arabinofuranosyl, xylofuranosyl, and ribofuranosyl derivatives were less active against human cytomegalovirus and more cytotoxic than TCRB.

  DOI：

  10.1021/jm990219s

文献信息

• Modified benzimidazole nucleosides as antiviral agents
  申请人：The Regents of the University of Michigan

  公开号：US05840743A1

  公开（公告）日：1998-11-24

  This invention pertains to nucleoside analogs which have antiviral activity and improved metabolic stability. More specifically, this invention pertains to modified sugar benzimidazole nucleosides, as exemplified by compounds such as benzimidazole nucleosides possessing a fluorinated sugar-like moiety (for example, a 2'-fluoro-furanosyl moiety or a 3'-fluoro-furanosyl moiety), and may be represented by the following formula, ##STR1## wherein R.sup.1 is a fluorinated sugar-like moiety; and R.sup.2, R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are benzimidazole substituents, such as --H, halogens (e.g., --F, --Cl, --Br, --I), --NO.sub.2, --NR.sub.2 (where R is independently --H or an alkyl group having 1-6 carbon atoms), --OR (where R is --H or an alkyl group having 1-6 carbon atoms), --SR (where R is --H or a hydrocarbyl of 1-10 carbon atoms), and --CF.sub.3. In one embodiment, R.sup.1 is 2'-fluoro-furanosyl or 3'-fluoro-furanosyl; R.sup.2 is --H, --F, --Cl, --Br, --I, or --NR.sub.2, wherein R is independently --H or an alkyl group having 1-6 carbon atoms; R.sup.4, R.sup.5, R.sup.6 and R.sup.7 are independently --H, --F, --Cl, --Br, or --I.

  这项发明涉及具有抗病毒活性和改进的代谢稳定性的核苷类似物。更具体地说，这项发明涉及经改造的糖苯并咪唑核苷，例如具有类似于氟代糖的基团（例如，2'-氟基呋喃糖基团或3'-氟基呋喃糖基团）的苯并咪唑核苷，可以用以下公式表示，其中R.sup.1是类似于氟代糖的基团；R.sup.2、R.sup.4、R.sup.5、R.sup.6和R.sup.7是苯并咪唑取代基，例如--H、卤素（例如，--F、--Cl、--Br、--I）、--NO.sub.2、--NR.sub.2（其中R独立地是--H或具有1-6个碳原子的烷基基团）、--OR（其中R是--H或具有1-6个碳原子的烷基基团）、--SR（其中R是--H或具有1-10个碳原子的烃基）、和--CF.sub.3。在一个实施例中，R.sup.1是2'-氟基呋喃糖基团或3'-氟基呋喃糖基团；R.sup.2是--H、--F、--Cl、--Br、--I或--NR.sub.2，其中R独立地是--H或具有1-6个碳原子的烷基基团；R.sup.4、R.sup.5、R.sup.6和R.sup.7独立地是--H、--F、--Cl、--Br或--I。
• US5840743A
  申请人：——

  公开号：US5840743A

  公开（公告）日：1998-11-24
• Synthesis of Fluorosugar Analogues of 2,5,6-Trichloro-1-(β-<scp>d</scp>-ribofuranosyl)benzimidazole as Antivirals with Potentially Increased Glycosidic Bond Stability
  作者：Kristjan S. Gudmundsson、George A. Freeman、John C. Drach、Leroy B. Townsend

  DOI：10.1021/jm990219s

  日期：2000.6.1

  The metabolic instability in vivo of the glycosidic bond of 2,5,6-trichloro-1-(beta-D-ribofuranosyl)benzimidazole (TCRB) prompted us to design and synthesize the hitherto unreported fluorinated benzimidazole nucleosides 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole, 2,5,6-trichloro-1-(3-deoxy-3-fluoro-beta-D-ribofuranosyl)benzimidazole, and 2-bromo-5,6-dichloro-1-(2-deoxy-2-fluoro-beta-D-ribofuranosyl)benzimidazole. TCRB was converted into the 2',5'-ditrityl and 3'5'-dinitryl derivatives, which were fluorinated with DAST and deprotected to yield 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) and 2,5,6-trichloro-1(3-deoxy-3-fluoro-beta-D-xylofuranosyl)benzimidazole. The resulting low over yield (5%) of 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole encouraged us to develop an alternative route. The heterocycle 2,5,6-trichlorobenzimidazole was condensed with 1-bromo-3,5-di-O-benzoyl-2-deoxy-2-fluoro-alpha-D-arabinofuranose to give, after deprotection, 2,5,6-trichloro-1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)benzimidazole in a 50% overall yield. The 2'-deoxy-2'-fluoro-beta-D-ribofuranosyl compounds were prepared using 2'-deoxy-2'-fluorouridine, N-deoxyribofuranosyl transferase, and 5,6-dichlorobenzimidazole. Functionalization of the C2 position then gave the desired derivatives. Antiviral and cytotoxicity testing revealed that the deoxy fluoro arabinofuranosyl, xylofuranosyl, and ribofuranosyl derivatives were less active against human cytomegalovirus and more cytotoxic than TCRB.