7-氰基-4-(苯基甲氧基)-2-萘羧酸 | 178877-05-9

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 中文名称: 7-氰基-4-(苯基甲氧基)-2-萘羧酸
• 英文名称: 4-benzyloxy-7-cyano-2-naphthalenecarboxylic acid
• 英文别名: 2-Naphthalenecarboxylic acid, 7-cyano-4-(phenylmethoxy)-；7-cyano-4-phenylmethoxynaphthalene-2-carboxylic acid
• CAS: 178877-05-9
• 化学式: C₁₉H₁₃NO₃
• 分子量: 303.317
• InChiKey: MXQJMTWAPVELKQ-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.05
• 拓扑面积：
  70.3
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  7-氰基-4-(苯基甲氧基)-2-萘羧酸 在 palladium on activated charcoal 四氯化碳 、 N-碘代丁二酰亚胺 、 叠氮磷酸二苯酯 、 氢气 、 三正丁基氢锡 、 sodium hydride 、 碳酸氢钠 、 对甲苯磺酸 、 溶剂黄146 、 三乙胺 、 三苯基膦 、 锌 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 水 、 乙酸乙酯 、 苯 为溶剂， 反应 40.42h， 生成 tert-butyl (1R,13S)-4-cyano-8-oxo-11-azatetracyclo[8.4.0.01,13.02,7]tetradeca-2(7),3,5,9-tetraene-11-carboxylate
  参考文献：
  名称：

  Synthesis, Chemical Properties, and Preliminary Evaluation of Substituted CBI Analogs of CC-1065 and the Duocarmycins Incorporating the 7-Cyano-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one Alkylation Subunit:  Hammett Quantitation of the Magnitude of Electronic Effects on Functional Reactivity

  摘要：

  The synthesis of 7-cyano-1,2,9,9a-tetrahydrocyclopropa[c]benz[e]indol-4-one (CCBI), a substituted CBI derivative bearing a C7 cyano group, is described in efforts that establish the magnitude of potential electronic effects on the functional reactivity of the agents. The CCBI alkylation subunit was prepared by a modified Stobbe condensation/Friedel-Crafts acylation for generation of the appropriately functionalized naphthalene precursors followed by 5-exo-trig aryl radical-alkene cyclization for synthesis of the 1,2-dihydro-3H-benz[e]indole skeleton and final Ar-3' alkylation for introduction of the activated cyclopropane. The most concise approach provided the CCBI subunit and its immediate precursor in 14-15 steps in superb overall conversions (15-20%). Resolution of an immediate CCBI precursor and its incorporation into both enantiomers of 34-39, analogs of CC-1065 and the duocarmycins, are detailed. A study of the solvolysis reactivity and regioselectivity of N-BOC-CCBI (25) revealed that introduction of the C7 nitrile slowed the rate of solvolysis but only to a surprisingly small extent. Classical Hammett quantitation of the effect provided a remarkably small rho (-0.3), indicating an exceptionally small C7 substituent electronic effect on functional reactivity. Additional kinetic studies of acid-catalyzed nucleophilic addition proved inconsistent with C4 carbonyl protonation as the slow and rate-determining step but consistent with a mechanism in which protonation is rapid and reversible followed by slow and rate-determining nucleophilic addition to the cyclopropane requiring both the presence and assistance of a nucleophile (S(N)2 mechanism). No doubt this contributes to the DNA alkylation selectivity of this class of agents and suggests that the positioning of an accessible nucleophile (adenine N3) and not C4 carbonyl protonation is the rate-determining step controlling the sequence selectivity of the DNA alkylation reaction, This small electronic effect on the solvolysis rate had no impact on the solvolysis regioselectivity, and stereoelectronically-controlled nucleophilic addition to the least substituted carbon of the activated cyclopropane was observed exclusively. Consistent with past studies, a direct relationship between solvolysis stability and cytotoxic potency was observed with the CCBI-derived agents providing the most potent analogs in the CBI series, and these observations were related to the predictable Hammett substituent effects. For the natural enantiomers, this unusually small electronic effect on functional reactivity had no perceptible effect on their DNA alkylation selectivity. Similar effects of the C7 cyano substituent on the unnatural enantiomers were observed, and they proved to be 4-10x more effective than the corresponding CBI-based unnatural enantiomers and 4-70x less potent than the CCBI natural enantiomers.

  DOI：

  10.1021/jo9605298
• 作为产物：
  描述：

  7-氰基-4-(苯基甲氧基)-2-萘羧酸乙酯 在 lithium hydroxide monohydrate 、 盐酸 作用下， 以 四氢呋喃 、 甲醇 、 水 为溶剂， 反应 2.0h， 以87%的产率得到7-氰基-4-(苯基甲氧基)-2-萘羧酸
  参考文献：
  名称：

  基于细胞毒性抗生素 Duocarmycin 的荧光标记糖苷前药的合成

  摘要：

  描述了在2中芳族A环的不同位置用不同荧光染料标记的糖苷前药(1S)-30a、(1S,10R)-30b和(1S,10R)-32的合成；这些化合物在结构上基于细胞毒性抗生素 duocarmycin SA。为了结合，氨基化合物(1S)-3a和(1S，10R)-3b分别用染料5-SFX (29)和D10162 (31)的市售琥珀酰亚胺处理。

  DOI：

  10.1002/ejoc.201000966

文献信息

• Analogs of CC-1065 and the duocarmycins
  申请人：The Scripps Research Institute

  公开号：US06060608A1

  公开（公告）日：2000-05-09

  Analogs of antitumor antibiotics CC-1065 and the duocarmycins are synthesized which possess systematic and extensive modifications in the DNA binding subunits attached to a 1,2,9,9a-tetra-hydro-cyclo-propa[c]benz[e]indol-4-one (CBI) alkylation subunit. The analogs have potent cytotoxic activity and are efficacious antitumor compounds.

  合成了抗肿瘤抗生素CC-1065和二元环四氢-环丙基[c]苯并[e]吲哚-4-酮（CBI）烷基化亚基附着的DNA结合亚基系统和广泛的修饰的类似物。这些类似物具有强效的细胞毒性活性，并且是有效的抗肿瘤化合物。
• EP0934269A4
  申请人：——

  公开号：EP0934269A4

  公开（公告）日：2000-01-12
• ANALOGS OF CC-1065 AND THE DUOCARMYCINS
  申请人：The Scripps Research Institute

  公开号：EP0934269A1

  公开（公告）日：1999-08-11
• US6060608A
  申请人：——

  公开号：US6060608A

  公开（公告）日：2000-05-09
• [EN] ANALOGS OF CC-1065 AND THE DUOCARMYCINS<br/>[FR] ANALOGUES DE CC-1065 ET DUOCARMYCINES
  申请人：——

  公开号：WO1997045411A1

  公开（公告）日：1997-12-04

  [EN] Analogs of antitumor antibiotics CC-1065 and the duocarmycins are synthesized which possess systematic and extensive modifications in the DNA binding subunits attached to a 1,2,9,9a-tetra-hydro-cyclo-propa[c]benz[e]indol-4-one (CBI) alkylation subunit. The analogs have potent cytotoxic activity and are efficacious antitumor compounds.
  [FR] Cette invention se rapporte à la synthèse d'analogues d'antibiotiques antitumoraux CC-1065 et de duocarmycines qui possèdent des modifications systématiques et étendues au niveau des sous-unités de liaison à l'ADN attachées à une sous-unité d'alkylation 1,2,9,9a-tétra-hydro-cyclo-propa[c]benz[e]indol-4-one (CBI). Ces analogues possèdent une puissante activité cytotoxique et sont des composés antitumoraux efficaces.