6-amino-9-<5-O-(tert-butyldimethylsilyl)-2-deoxy-2-fluoro-β-D-arabinofuranosyl>-9H-purine | 111727-03-8

• 分子结构分类: 有机化合物 - 核苷、核苷酸和类似物 - 嘌呤核苷
• 英文名称: 6-amino-9-<5-O-(tert-butyldimethylsilyl)-2-deoxy-2-fluoro-β-D-arabinofuranosyl>-9H-purine
• 英文别名: 9-<2-deoxy-2-fluoro-5-O-(tert-butyldimethylsilyl)-β-D-arabinofuranosyl>adenine；9-[5-O-(tert-butyldimethylsilyl)-2-deoxy-2-fluoro-β-D-arabinofuranosyl]adenine；9-(5-O-tert-Butyldimethylsilyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)adenine；6-amino-9-[5-O-(tert-butyldimethylsilyl)-2-deoxy-2-fluoro-β-D-arabinofuranosyl]-9H-purine；(2R,3R,4S,5R)-5-(6-aminopurin-9-yl)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-fluorooxolan-3-ol
• CAS: 111727-03-8
• 化学式: C₁₆H₂₆FN₅O₃Si
• 分子量: 383.498
• InChiKey: ZHFRTBXCDTYQLG-KVQFHVITSA-N

物化性质

• 熔点：
  185 °C
• 沸点：
  531.8±60.0 °C(Predicted)
• 密度：
  1.37±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.03
• 重原子数：
  26
• 可旋转键数：
  5
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.69
• 拓扑面积：
  108
• 氢给体数：
  2
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  6-amino-9-<5-O-(tert-butyldimethylsilyl)-2-deoxy-2-fluoro-β-D-arabinofuranosyl>-9H-purine 在 对甲苯磺酸 、 triethylamine tris(hydrogen fluoride) 作用下， 以 四氢呋喃 、 1,4-二氧六环 为溶剂， 反应 0.5h， 生成 9-(2-deoxy-2-fluoro-3-O-tetrahydropyranyl-β-D-arabinofuranosyl)adenine
  参考文献：
  名称：

  Synthesis of Nonhydrolyzable Analogues of Thiazole-4-carboxamide and Benzamide Adenine Dinucleotide Containing Fluorine Atom at the C2‘ of Adenine Nucleoside: Induction of K562 Differentiation and Inosine Monophosphate Dehydrogenase Inhibitory Activity

  摘要：

  Thiazole-4-carboxamide adenine dinucleotide (TAD) analogue 7 containing a fluorine atom at the C2' arabino configuration of the adenine nucleoside moiety was found to be a potent inducer of differentiation of K562 erythroid leukemia cells. This finding prompted us to synthesize its hydrolysis-resistant methylenebis(phosphonate) and difluoromethylenebis(phosphonate) analogues 8 and 9, respectively. Since both TAD and benzamide adenine dinucleotide (BAD) are potent inhibitors of inosine monophosphate dehydrogenase (IMPDH), the corresponding fluorine-substituted methylenebis(phosphonate) analogue 12 of BAD was also synthesized. Thus, 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine (13) was converted in five steps into the corresponding methylenebis( phosphonate) analogue 18. Dehydration of 18 with DCC led to the formation of the bicyclic trisanhydride intermediate 19a, which upon reaction with 2',3'-O-isopropylidenetiazofurin (20) or -benzamide riboside (21) followed by hydrolysis and deprotection afforded the desired methylene-bridged dinucleotides 8 and 12, respectively. The similar displacement of the 5'-mesyl function of 2',3'-O-isopropylidene-5'-O-mesyltiazofuin (24) with the difluoromethylenebis(phosphonic acid) derivative gave the phosphonate 25 which was coupled with 13 to afford 26. The desired difluoromethylenebis (phosphonate) analogue 9 was obtained by deprotection with Dowex 50/H+. This compound as well as beta-CF2-TAD (4) showed improved differentiation-inducing activity over beta-CH2-TAD (3), whereas analogues containing the -CH2- linkage (8 and 12) were inactive.

  DOI：

  10.1021/jm970247f
• 作为产物：
  描述：

  6-chloro-9-(3-O-acetyl-5-O-benzoyl-2-deoxy-2-fluoro-β-D-arabinofuranosyl)-9H-purine 在 咪唑 、 氨 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 84.0h， 生成 6-amino-9-<5-O-(tert-butyldimethylsilyl)-2-deoxy-2-fluoro-β-D-arabinofuranosyl>-9H-purine
  参考文献：
  名称：

  Acid-stable 2'-fluoro purine dideoxynucleosides as active agents against HIV

  摘要：

  2',3'-Dideoxy purine nucleosides have anti-HIV activity in vitro and the inosine analogue is being clinically evaluated. The instability of these compounds toward acidic conditions complicates oral administration. The effect of the addition of a fluorine atom to the 2'-position was investigated by preparing the fluorine-containing 2'-erythro and 2'-threo isomers of ddA and the threo isomer of ddI. All fluorine-containing compounds were indefinitely stable to acidic conditions which completely decomposed ddI (1) and ddA (2) in minutes. While the fluorine-containing erythro isomer, 5, was inactive, the threo isomers, 2'-F-dd-ara-A (3) and 2'-F-dd-ara-I (4), were just as potent and active in protecting CD4+ ATH8 cells from the cytopathogenic effects of HIV-1 as the parent drugs. Exposure to pH 1 at 37 degrees C prior to testing destroyed the activity of ddA and ddI but left the anti-HIV properties of 3 and 4 unchanged. The fluorinated analogues also protected cells exposed to HIV-2 and inhibited gag gene product expression but not as effectively as the parent compounds. The fluorine-containing analogues appear to be somewhat more toxic in vitro to the antigen- and mitogen-driven proliferation of immunocompetent cells than their corresponding parent compounds.

  DOI：

  10.1021/jm00165a015

文献信息

• The β-Fluorine Effect. Electronic Versus Steric Effects in Radical Deoxygenations of Fluorine-Containing Pentofuranose Nucleosides
  作者：Stanislaw F. Wnuk、Dania R. Companioni、Vladimir Neschadimenko、Morris J. Robins

  DOI：10.1021/jo020428b

  日期：2002.12.1

  Stereoselective pyramidalization of free radicals by a vicinal fluorine substituent, the beta-fluorine effect, was invoked to rationalize a 77:23 anti/syn ratio of 2-deuterio-1-fluorocyclopentanes obtained by radical reduction of trans-2-fluoro-1-bromocyclopentane with tributyltin deuteride (Dolbier, W. R., Jr.; Bartberger, M. D. J. Org. Chem. 1995, 60, 4984-4985). We have evaluated analogous reductions

  借助邻位氟取代基对自由基进行立体选择性锥体化，即β-氟效应，以合理化通过反式-2-氟-1-基的自由基还原而获得的2-氘-1-氟环戊烷的77:23反/同比例。溴环戊烷和氘化三丁基锡（Dolbier，WR，Jr .; Bartberger，MDJ Org.Chem。1995，60，4984-4985）。我们已经评估了某些腺嘌呤2'（3'）-氟-3'（2'）-O-苯氧基硫羰基核苷衍生物的四种可能的立体异构体的类似还原。在所有情况下，腺嘌呤在β面上的立体作用都将氘从锡烷转移到呋喃糖环的α面上的C2'（C3'）。然而，β-氟效应增加了氘转移与邻位氟取代基的比率。
• Deoxyfluoronucleoside process
  申请人：Bristol-Myers Squibb Company

  公开号：EP0428109A3

  公开（公告）日：1991-09-11

  There is disclosed a process for synthesizing 2′-­fluoro-2′,3′-dideoxyarabinofuranose derivatives of inosine and adenine on a large scale which involves coupling of a fluorosugar derivative and a purine reactant to provide a purine nucleoside intermediate which is then deoxygenated. 6-Chloro or 6-benzamidopurine and 1,3,5-tri-O-benzoyl-2-­deoxy-2-fluoroarabinofuranose are used as starting materials.

  揭示了一种合成肌苷和腺嘌呤的2'-氟-2',3'-二去氧阿拉伯呋喃糖衍生物的大规模过程，涉及将氟糖衍生物和嘌呤试剂偶联以提供嘌呤核苷中间体，然后对其进行脱氧。6-氯或6-苯甲酰基嘌呤和1,3,5-三-O-苯甲酰-2-脱氧-2-氟阿拉伯呋喃糖被用作起始物质。
• MARQUEZ, VICTOR E.;TSENG, CHRISTOPHER K. -H.;MITSUYA, HIROAKI;AOKI, SHIZU+, J. MED. CHEM., 33,(1990) N, C. 978-985
  作者：MARQUEZ, VICTOR E.、TSENG, CHRISTOPHER K. -H.、MITSUYA, HIROAKI、AOKI, SHIZU+

  DOI：——

  日期：——
• Acid-stable 2'-fluoro purine dideoxynucleosides as active agents against HIV
  作者：Victor E. Marquez、Christopher K. H. Tseng、Hiroaki Mitsuya、Shizuko Aoki、James A. Kelley、Harry Ford、Jeri S. Roth、Samuel Broder、David G. Johns、John S. Driscoll

  DOI：10.1021/jm00165a015

  日期：1990.3

  2',3'-Dideoxy purine nucleosides have anti-HIV activity in vitro and the inosine analogue is being clinically evaluated. The instability of these compounds toward acidic conditions complicates oral administration. The effect of the addition of a fluorine atom to the 2'-position was investigated by preparing the fluorine-containing 2'-erythro and 2'-threo isomers of ddA and the threo isomer of ddI. All fluorine-containing compounds were indefinitely stable to acidic conditions which completely decomposed ddI (1) and ddA (2) in minutes. While the fluorine-containing erythro isomer, 5, was inactive, the threo isomers, 2'-F-dd-ara-A (3) and 2'-F-dd-ara-I (4), were just as potent and active in protecting CD4+ ATH8 cells from the cytopathogenic effects of HIV-1 as the parent drugs. Exposure to pH 1 at 37 degrees C prior to testing destroyed the activity of ddA and ddI but left the anti-HIV properties of 3 and 4 unchanged. The fluorinated analogues also protected cells exposed to HIV-2 and inhibited gag gene product expression but not as effectively as the parent compounds. The fluorine-containing analogues appear to be somewhat more toxic in vitro to the antigen- and mitogen-driven proliferation of immunocompetent cells than their corresponding parent compounds.
• Synthesis of Nonhydrolyzable Analogues of Thiazole-4-carboxamide and Benzamide Adenine Dinucleotide Containing Fluorine Atom at the C2‘ of Adenine Nucleoside: Induction of K562 Differentiation and Inosine Monophosphate Dehydrogenase Inhibitory Activity
  作者：Krystyna Lesiak、Kyoichi A. Watanabe、Alokes Majumdar、Michael Seidman、Kristen Vanderveen、Barry M. Goldstein、Krzysztof W. Pankiewicz

  DOI：10.1021/jm970247f

  日期：1997.8.1

  Thiazole-4-carboxamide adenine dinucleotide (TAD) analogue 7 containing a fluorine atom at the C2' arabino configuration of the adenine nucleoside moiety was found to be a potent inducer of differentiation of K562 erythroid leukemia cells. This finding prompted us to synthesize its hydrolysis-resistant methylenebis(phosphonate) and difluoromethylenebis(phosphonate) analogues 8 and 9, respectively. Since both TAD and benzamide adenine dinucleotide (BAD) are potent inhibitors of inosine monophosphate dehydrogenase (IMPDH), the corresponding fluorine-substituted methylenebis(phosphonate) analogue 12 of BAD was also synthesized. Thus, 9-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl)adenine (13) was converted in five steps into the corresponding methylenebis( phosphonate) analogue 18. Dehydration of 18 with DCC led to the formation of the bicyclic trisanhydride intermediate 19a, which upon reaction with 2',3'-O-isopropylidenetiazofurin (20) or -benzamide riboside (21) followed by hydrolysis and deprotection afforded the desired methylene-bridged dinucleotides 8 and 12, respectively. The similar displacement of the 5'-mesyl function of 2',3'-O-isopropylidene-5'-O-mesyltiazofuin (24) with the difluoromethylenebis(phosphonic acid) derivative gave the phosphonate 25 which was coupled with 13 to afford 26. The desired difluoromethylenebis (phosphonate) analogue 9 was obtained by deprotection with Dowex 50/H+. This compound as well as beta-CF2-TAD (4) showed improved differentiation-inducing activity over beta-CH2-TAD (3), whereas analogues containing the -CH2- linkage (8 and 12) were inactive.