N-(tert-Butyloxycarbonyl)-4-(methoxymethoxy)-2-naphthylamine | 198708-95-1

• 分子结构分类: 有机化合物 - 苯类化合物 - 萘
• 英文名称: N-(tert-Butyloxycarbonyl)-4-(methoxymethoxy)-2-naphthylamine
• 英文别名: tert-butyl N-[4-(methoxymethoxy)naphthalen-2-yl]carbamate
• CAS: 198708-95-1
• 化学式: C₁₇H₂₁NO₄
• 分子量: 303.358
• InChiKey: KHJOMZLZPDSZAP-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.7
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.35
• 拓扑面积：
  56.8
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  N-(tert-Butyloxycarbonyl)-4-(methoxymethoxy)-2-naphthylamine 在 盐酸 、 四氯化碳 、 正丁基锂 、 1-氯-2-碘乙烷 、 四甲基乙二胺 、 三正丁基氢锡 、 sodium hydride 、 碳酸氢钠 、 三苯基膦 、 锌 作用下， 以 四氢呋喃 、 二氯甲烷 、 水 、 溶剂黄146 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 苯 为溶剂， 反应 11.25h， 生成 methyl 3-(chloromethyl)-4-hydroxy-2,3-dihydrobenzo[f]indole-1-carboxylate
  参考文献：
  名称：

  Synthesis and Evaluation of CC-1065 and Duocarmycin Analogues Incorporating the Iso-CI and Iso-CBI Alkylation Subunits:  Impact of Relocation of the C-4 Carbonyl

  摘要：

  The synthesis of 2-(tert-Butyloxycarbonyl)-1, 2, 9, 9a-tetrahydrocyclopropa[c]benzo[f]indol-8-one (31, N-BOC-iso-CBI) and 1-(tert-Butyloxycarbonyl)-4-hydroxy-3-[[(methanesulfonyl)oxy]methyl]-2, 3-dihydroindole (19, seco-N-BOC-iso-CI) containing an isomeric structural modification in the CC-1065 and duocarmycin alkylation subunits and their incorporation into analogues of the natural products are detailed. The approach was based on a directed ortho metalation of an appropriately functionalized benzene (13) or naphthalene (24) precursor to regiospecifically install iodine at the C-2 position. Conversion of these respective intermediates to the dihydroindole skeleton utilized an established 5-exo-trig aryl radical cyclization onto an unactivated alkene with subsequent TEMPO trap or the more recent 5-exo-trig aryl radical cyclization onto a vinyl chloride for direct synthesis of the immediate precursors. Closure of the activated cyclopropane to complete the iso-CBI nucleus was accomplished by a selective ortho spirocyclization. The evaluation of the iso-CBI-based agents revealed a significant stability comparable to that of CC-1065 and duocarmycin A, but that it is more reactive than duocarmycin SA (6 - 7x) or the direct comparison CBI-based agents (5x) for which X-ray structure comparisons served to establish the basis for their inherent reaction regioselectivity and reactivity. Resolution and synthesis of a full set of natural product analogues and subsequent evaluation of their DNA alkylation properties revealed that the iso-CBI analogues, even with the relocation of the C-4 carbonyl and the most substantial structural modifications to the alkylation subunit to date, reacted at comparable rates and retain the identical and characteristic sequence selectivity of CC-1065 and the duocarmycins. This observation is inconsistent with the proposal that a sequence-dependent C-4 carbonyl protonation by strategically located DNA backbone phosphates controls the DNA alkylation selectivity but is consistent with the proposal that it is determined by the AT-rich noncovalent binding selectivity of the agents and the steric accessibility of the N3 alkylation site. Confirmation that the DNA alkylation reaction is derived from adenine N3 addition to the least substituted carbon of the activated cyclopropane, and its quantitation (95%) was established by isolation and characterization of the depurination adenine N3 adduct. Consistent with past studies and despite the deep-seated structural change in the alkylation subunit, the agents were found to exhibit potent cytotoxic activity that correlates with their inherent reactivity.

  DOI：

  10.1021/jo971686p
• 作为产物：
  描述：

  氯甲基甲基醚 、 3-(叔丁氧基羰基)-Α-萘酚 在 N,N-二异丙基乙胺 作用下， 以 二氯甲烷 为溶剂， 以58%的产率得到N-(tert-Butyloxycarbonyl)-4-(methoxymethoxy)-2-naphthylamine
  参考文献：
  名称：

  [EN] CONJUGATES FOR TREATING DISEASES
  [FR] CONJUGUÉS POUR LE TRAITEMENT DE MALADIES

  摘要：

  本公开涉及吡咯苯并二氮杂环（PBD）前药及其结合物。本公开还涉及所述结合物的药物组合物，制备方法和使用方法。

  公开号：

  WO2016148674A1

文献信息

• ISO-CBI and ISO-CI analogs of CC-1065 and the duocarmycins
  申请人：The Scripps Research Institute

  公开号：US06262271B1

  公开（公告）日：2001-07-17

  A series of bioactive analogs of (+)-CC-1065 (1) and the duocarmycins 2 and 3 are synthesized. The bioactive analogs include either iso-CI or iso-CBI (6 and 7) as a DNA alkylation subunit. Conjugated to the DNA alkylating subunits are a variety of DNA binding subunits. The bioactive analogs maintain their DNA selectivity and display enhanced reactivity.

  合成了一系列生物活性类似物(+)-CC-1065 (1)和duocarmycins 2和3。这些生物活性类似物包括iso-CI或iso-CBI (6和7)作为DNA烷基化亚基。与DNA烷基化亚基结合的是各种DNA结合亚基。这些生物活性类似物保持其DNA选择性并显示出增强的反应性。
• Synthesis and Evaluation of a Series of C3-Substituted CBI Analogues of CC-1065 and the Duocarmycins
  作者：Dale L. Boger、Steven R. Brunette、Robert M. Garbaccio

  DOI：10.1021/jo010309g

  日期：2001.7.1

  proved remarkably reactive toward solvolysis even at pH 7, where the reaction is uncatalyzed and the reactivity order (I > Br > Cl > F > H) follows a trend consistent with the extent of vinylogous amide conjugation and stabilization. The implications of these observations on the source of catalysis for the DNA alkylation reaction of the natural products are discussed.

  详细介绍了CC-1065和Duocarmycin烷基化亚基的一系列C3取代的1,2,9,9a-四氢环丙烷[c]苯并[e]吲哚-4-酮（CBI）类似物的合成和评估，包括甲基以及全系列的卤素。关键取代基的引入是通过对seco-CBI核进行定向金属化，然后使所得的芳基锂与适当的亲电试剂反应完成的。仅使用新型卤素源（1-溴-和1-碘苯基乙炔）将C3-溴和碘取代基有效地安装在受阻芳基锂中间体上，这在我们描述的研究范围之外通常应被证明是有用的。该系列的X射线晶体结构由于C3取代基和N（2）-氨基甲酸酯之间不利的空间相互作用而在乙烯基酰胺中显示出明显的变形。在卤素系列中，N2-C2a键长和扭转角chi（1）随C3取代基尺寸的增加而平稳增加，这表明整个系列中乙烯基酰胺键的结合减少（H> F> Cl> Br> I）。与N-Boc-CBI不同，该系列的取代CBI类似物甚至在pH 7时也表现出对溶剂分解的显着反
• iso-CBI and iso-CI analogs of CC-1065 duocarmycins
  申请人：The Scripps Research Institute

  公开号：US20020049335A1

  公开（公告）日：2002-04-25

  A series of bioactive analogs of (+)-CC-1065 ( 1 ) and the duocarmycins 2 and 3 are synthesized. The bioactive analogs include either iso-CI or iso-CBI ( 6 and 7 ) as a DNA alkylation subunit. Conjugated to the DNA alkylating subunits are a variety of DNA binding subunits. The bioactive analogs maintain their DNA selectivity and display enhance reactivity.

  合成了一系列活性类似物，包括(+)-CC-1065 (1)和duocarmycins2和3。这些活性类似物包括iso-CI或iso-CBI (6和7)作为DNA烷基化亚基。与DNA烷基化亚基结合的是各种DNA结合亚基。这些活性类似物保持其DNA选择性并显示增强的反应性。
• iso-CBI AND iso-CI ANALOGS OF CC-1065 AND THE DUOCARMYCINS
  申请人：The Scripps Research Institute

  公开号：EP1042285A1

  公开（公告）日：2000-10-11
• EP1042285A4
  申请人：——

  公开号：EP1042285A4

  公开（公告）日：2002-11-20