3-benzoyl-1-((6aR,8R,9aS)-2,2,4,4-tetraisopropyl-9-methylenetetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrimidine-2,4(1H,3H)-dione | 156900-02-6

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 3-benzoyl-1-((6aR,8R,9aS)-2,2,4,4-tetraisopropyl-9-methylenetetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrimidine-2,4(1H,3H)-dione
• 英文别名: N³-benzoyl-2'-deoxy-2'-methylidene-3',5'-O-(tetraisopropyldisiloxane-1,3-diyl)uridinr；1-[(6aR,8R,9aS)-9-methylidene-2,2,4,4-tetra(propan-2-yl)-6a,9a-dihydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl]-3-benzoylpyrimidine-2,4-dione
• CAS: 156900-02-6
• 化学式: C₂₉H₄₂N₂O₇Si₂
• 分子量: 586.833
• InChiKey: GHPWSJJUNPOKHX-MAARLIENSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.11
• 重原子数：
  40
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.55
• 拓扑面积：
  94.6
• 氢给体数：
  0
• 氢受体数：
  7

反应信息

• 作为反应物：
  描述：

  3-benzoyl-1-((6aR,8R,9aS)-2,2,4,4-tetraisopropyl-9-methylenetetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrimidine-2,4(1H,3H)-dione 在 四丁基氟化铵 、 三乙胺 作用下， 以 四氢呋喃 、 二氯甲烷 为溶剂， 反应 18.17h， 生成 N3-benzoyl-2'-deoxy-2'-methylidene-5'-O-trityluridine
  参考文献：
  名称：

  Nucleosides and Nucleotides. 125. Synthesis and Biological Evaluation of 2′,3′-Dideoxy-3′-fluoro-2′-methylidene Pyrimidine Nucleosides

  摘要：

  Reaction of 2'-deoxy-2'-methylidene-5'-O-trityluridine (1) with diethylamino-sulfur trifluoride (DAST) in CH2Cl2 resulted in the formation of a mixture of (3'R)-2',3'-dideoxy-3'-fluoro-2'-methylidene derivative 3 and 2',3'-didehydro-2',3'-dideoxy-2'-fluoromethyl derivative 4 (3:4 = 1:1.5) in 65% yield. A similar treatment of 1-(2-deoxy-2-methylidene-5-O-trityl-beta-D-threo-pentofuranosyl)uracil (19) with DAST in CH2Cl2 afforded (3'S)-2',3'-dideoxy-3'-fluoro-2'-methylidene derivatives 20 and 4 in 38% and 17% yields respectively. Transformation of the uracil nucleosides 4, 12, and 20 into cytosines followed by deprotection furnished the corresponding cytidine derivatives 29, 18, and 25, respectively. The corresponding thymidine congener 27 was also synthesized in a similar manner. All of the newly synthesized nucleosides were evaluated for their inhibitory activities against HIV and for their antiproliferative activities against L1210 and KB cells.

  DOI：

  10.1080/15257779408013235
• 作为产物：
  描述：

  1-((6aR,8R,9aS)-2,2,4,4-tetraisopropyl-9-methylenetetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrimidine-2,4(1H,3H)-dione 、 苯甲酰氯 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 反应 12.0h， 以86%的产率得到3-benzoyl-1-((6aR,8R,9aS)-2,2,4,4-tetraisopropyl-9-methylenetetrahydro-6H-furo[3,2-f][1,3,5,2,4]trioxadisilocin-8-yl)pyrimidine-2,4(1H,3H)-dione
  参考文献：
  名称：

  2′-Deoxy-2′-spirocyclopropylcytidine Revisited: A New and Selective Inhibitor of the Hepatitis C Virus NS5B Polymerase

  摘要：

  The current therapy for hepatitis C virus (HCV) infection has limited efficacy, in particular against the genotype 1 virus, and a range of side effects. In this context of high unmet medical need, more efficacious drugs targeting HCV nonstructural proteins are of interest. Here we describe 2'-deoxy-2'-spirocyclo-propylcytidine (5) as a new inhibitor of the HCV NS5B RNA-dependent RNA polymerase, displaying an EC50 of 7.3 mu M measured in the Huh7-Rep cell line and no associated cytotoxicity (CC50 > 98.4 mu M). Computational results indicated high similarity between 5 and related HCV inhibiting nucleosides. A convenient synthesis was devised, facilitating synthesis of multigram quantities of 5. As the exposure measured after oral administration of 5 was found to be limited, the 3'-mono- and 3',5'-diisobutyryl ester prodrugs 20 and 23, respectively, were evaluated, The oral dosing of 23 led to substantially increased exposure to 5 in both rats and dogs.

  DOI：

  10.1021/jm101050a

文献信息

• Cyclopropyl polymerase inhibitors
  申请人：Janssen Products, L.P.

  公开号：EP2141172B1

  公开（公告）日：2012-10-24
• Nucleic acid and related compounds. 75. Synthesis and radical-induced ring-opening reactions of 2'-deoxyadenosine-2'-spirocyclopropane and its uridine analogs. Mechanistic probes for ribonucleotide reductases
  作者：Vicente Samano、Morris J. Robins

  DOI：10.1021/ja00036a077

  日期：1992.5