diethyl (1,4-dioxa-8-azaspiro[4.5]dec-8-yl)methylphosphonate | 1159216-37-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 氮杂螺癸烷衍生物
• 英文名称: diethyl (1,4-dioxa-8-azaspiro[4.5]dec-8-yl)methylphosphonate
• 英文别名: 8-(Diethoxyphosphorylmethyl)-1,4-dioxa-8-azaspiro[4.5]decane
• CAS: 1159216-37-1
• 化学式: C₁₂H₂₄NO₅P
• 分子量: 293.3
• InChiKey: TVLOELRMHKGIEE-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  0.3
• 重原子数：
  19
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  57.2
• 氢给体数：
  0
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  3-吡啶甲醛 、 diethyl (1,4-dioxa-8-azaspiro[4.5]dec-8-yl)methylphosphonate 在 三氟化硼乙醚 作用下， 以34%的产率得到(3E,5E)-1-[(diethoxyphosphoryl)methyl]-4-oxo-3,5-bis(3-pyridinylmethylene)piperidinium tetrafluoroborate
  参考文献：
  名称：

  Structure–cytotoxicity relationship in a series of N-phosphorus substituted E,E-3,5-bis(3-pyridinylmethylene)- and E,E-3,5-bis(4-pyridinylmethylene)piperid-4-ones

  摘要：

  In order to give further insight on the influence of the aromatic ring nature and the presence of the phosphorus substituent at the piperidone nitrogen atom of E,E-3,5-bis((hetero)arylidene)piperid-4-ones on their antitumor properties, a series of phosphorus substituted E,E-3,5-bis(pyridinylmethylene) piperid-4-ones bearing either 3-pyridine or 4-pyridine rings was obtained. Novel NH-3,5-bis(pyridinylmethylene)piperid-4-ones 1a,b were converted into the corresponding N-phosphorylated derivatives 3a-c, 4a-c differing in the substitution at the phosphorus atom (amidophosphates and amidophosphonates), via direct phosphorylation while N-(omega-phosphorylalkyl)-substituted compounds 8a-c were obtained via aldol-crotonic condensation of preformed N-phosphorylalkyl substituted piperidones with the corresponding pyridinecarboxaldehyde. The cytotoxicity screen has revealed that phosphorylated compounds based on E,E-3,5-bis(4-pyridinylmethylene)piperid-4-one framework displayed higher inhibitory properties toward Caov3, A549, KB 3-1 and KB 8-5 human carcinoma cell lines comparing with their analogues with 3-pyridine rings. Introduction of the phosphorus moiety substantially increased the antitumor properties in the case of E,E-3,5-bis(3-pyridinylmethylene)piperid-4-ones derivatives but this influence less pronounced for more active analogues bearing 4-pyridinyl rings. Most of the compounds tested are potent against multi-drug resistant cell line KB 8-5 affording some guidelines for the search of perspective drug-candidates among phosphorus substituted E,E-3,5-bis ((hetero)arylidene)piperid-4-ones. (C) 2010 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2010.09.058
• 作为产物：
  描述：

  聚合甲醛 、 二乙基亚磷酸氢酯 、 4-哌啶酮缩乙二醇 以 甲醇 、 水 为溶剂， 反应 72.0h， 生成 diethyl (1,4-dioxa-8-azaspiro[4.5]dec-8-yl)methylphosphonate
  参考文献：
  名称：

  新型N-磷酰基烷基取代的E，E -3,5-双（亚芳基）哌啶-4-酮的设计，细胞毒性和荧光性质

  摘要：

  通过芳族醛与ω-氨基膦酸酯5a - c和6a，b带有哌啶酮或a的缩合反应，制得一系列E，E - N-磷酰基亚烷基-3,5-双（亚芳基）哌啶-4-酮7a - k。保护的哌啶酮部分。起始氨基膦酸酯5a – c和6a，b的合成路线因亚烷基链中亚甲基的数量而异，包括Kabachnik-Fields反应（n  = 1），aza-Michael反应（n ＝ 2）或在相转移催化条件下用ω-溴代烷基膦酸二乙酯将4-哌啶酮盐酸盐烷基化（n  ＝ 3，4）。芳基环对位上带有硝基和氟原子的磷酰基取代的3,5-双（亚芳基）哌啶-4-酮7b，c，e，f，h，i，k对人癌细胞具有细胞毒性低摩尔浓度的CaOv3，Scov3，PC3和A549系，而其具有对二甲氨基的类似物的IC 50值大于50μM。相比之下，只有我2N-取代的膦酸酯7g，j（n  ＝ 3和4）和Me 2 N-取代的膦酸10c，f（n  ＝ 2和3）的盐显示荧光。

  DOI：

  10.1016/j.ejmech.2008.10.019

文献信息

• Synthetic Approaches to Cytotoxic Amidophosphates, Aminophosphonates, and Aminobisphosphonates with 3,5-Bis(arylidene)piperid-4-one Framework
  作者：Mikhail V. Makarov、Evgenia S. Leonova、Ekaterina V. Matveeva、Ekaterina Yu. Rybalkina、Gerd-Volker Röschenthaler、Tatiana V. Timofeeva、Irina L. Odinets

  DOI：10.1080/10426507.2010.514308

  日期：2011.3.31

  bisphosphonates having a 3,5-bis(arylidene)piperid-4-one backbone have been elaborated starting from piperid-4-ones functionalized with phosphorus motives followed by aldol-crotonic condensation with a range of (hetero)aromatic aldehydes or via introduction of the corresponding phosphorus function into the preformed NH-3,5-bis(arylidene)piperid-4-ones. Combination of phosphorus-containing moieties possessing inherent

  摘要 一些新型酰胺磷酸酯、ω-氨基膦酸酯和具有 3,5-双（亚芳基）哌啶-4-one 骨架的双膦酸酯的简便合成方法已经从用磷动机功能化的哌啶-4-酮开始阐述，然后是醛醇-巴豆与一系列（杂）芳香醛缩合或通过将相应的磷官能团引入预先形成的 NH-3,5-双（亚芳基）哌啶-4-酮。具有固有生物活性和细胞毒性 3,5-双（亚芳基）哌啶-4-one 部分的含磷部分的组合导致化合物对人癌细胞系 Caov3、A549、Scov3、PC3、KB 3-1 具有高抗肿瘤活性和 KB 8-5（IC50 在 1-80 μM 范围内）。
• Synthesis, characterization and structure–activity relationship of novel N-phosphorylated E,E-3,5-bis(thienylidene)piperid-4-ones
  作者：Michael V. Makarov、Evgeniya S. Leonova、Ekaterina Yu. Rybalkina、Paul Tongwa、Victor N. Khrustalev、Tatiana V. Timofeeva、Irina L. Odinets

  DOI：10.1016/j.ejmech.2009.11.041

  日期：2010.3

  In order to design the agents with improved antitumor activity of 3,5-bis(thienylidene)piperid-4-one type, E,E-N-phosphoryl-3,5-bis(thienylidene)piperid-4-ones 6a-c and E,E-N-omega-phosphorylalkyl-3,5-bis-(thienylidene)piperid-4-ones 7a-c were obtained via the direct phosphorylation of the parent NH-3,5-bis(thienylidene)piperid-4-one and by condensation of preformed N-phosphorylalkyl substituted piperidones with thiophene 2-carbaldehyde, respectively. The structures of the compounds were elucidated by H-1, P-31 C-13 NMR along with a single crystal X-ray diffraction analysis. Under the action of visible light thermodynamically more stable E,E-isomers slowly undergo photochemical conversion in CDCl3 solution to the corresponding E,Z-isomers and E,Z-N-methyl-3,5-bis(thienylidene)piperid-4-one 5 was isolated in individual state. The importance of phosphorylation for cytotoxic properties of 3,5bis(thienylidene)piperid-4-ones towards human carcinoma cell lines Caov3, Scov3, and A549 and influence of olefin configuration on antitumor activity were demonstrated. (C) 2009 Elsevier Masson SAS. All rights reserved.
• Design, cytotoxic and fluorescent properties of novel N-phosphorylalkyl substituted E,E-3,5-bis(arylidene)piperid-4-ones
  作者：Michael V. Makarov、Ekaterina Yu. Rybalkina、Gerd-Volker Röschenthaler、Kurt W. Short、Tatiana V. Timofeeva、Irina L. Odinets

  DOI：10.1016/j.ejmech.2008.10.019

  日期：2009.5

  prepared via the condensation of aromatic aldehydes with ω-aminophosphonates 5a–c and 6a,b bearing piperidone or a protected piperidone moiety, respectively. The synthetic routes to the starting aminophosphonates 5a–c and 6a,b varied depending on the number of methylene groups in the alkylene chain and comprised the Kabachnik–Fields reaction (n = 1), the aza-Michael reaction (n = 2) or alkylation of 4-piperidone

  通过芳族醛与ω-氨基膦酸酯5a - c和6a，b带有哌啶酮或a的缩合反应，制得一系列E，E - N-磷酰基亚烷基-3,5-双（亚芳基）哌啶-4-酮7a - k。保护的哌啶酮部分。起始氨基膦酸酯5a – c和6a，b的合成路线因亚烷基链中亚甲基的数量而异，包括Kabachnik-Fields反应（n  = 1），aza-Michael反应（n ＝ 2）或在相转移催化条件下用ω-溴代烷基膦酸二乙酯将4-哌啶酮盐酸盐烷基化（n  ＝ 3，4）。芳基环对位上带有硝基和氟原子的磷酰基取代的3,5-双（亚芳基）哌啶-4-酮7b，c，e，f，h，i，k对人癌细胞具有细胞毒性低摩尔浓度的CaOv3，Scov3，PC3和A549系，而其具有对二甲氨基的类似物的IC 50值大于50μM。相比之下，只有我2N-取代的膦酸酯7g，j（n  ＝ 3和4）和Me 2 N-取代的膦酸10c，f（n  ＝ 2和3）的盐显示荧光。
• Structure–cytotoxicity relationship in a series of N-phosphorus substituted E,E-3,5-bis(3-pyridinylmethylene)- and E,E-3,5-bis(4-pyridinylmethylene)piperid-4-ones
  作者：Evgeniya S. Leonova、Michael V. Makarov、Ekaterina Yu. Rybalkina、Shravana L. Nayani、Paul Tongwa、Alexander Fonari、Tatiana V. Timofeeva、Irina L. Odinets

  DOI：10.1016/j.ejmech.2010.09.058

  日期：2010.12

  In order to give further insight on the influence of the aromatic ring nature and the presence of the phosphorus substituent at the piperidone nitrogen atom of E,E-3,5-bis((hetero)arylidene)piperid-4-ones on their antitumor properties, a series of phosphorus substituted E,E-3,5-bis(pyridinylmethylene) piperid-4-ones bearing either 3-pyridine or 4-pyridine rings was obtained. Novel NH-3,5-bis(pyridinylmethylene)piperid-4-ones 1a,b were converted into the corresponding N-phosphorylated derivatives 3a-c, 4a-c differing in the substitution at the phosphorus atom (amidophosphates and amidophosphonates), via direct phosphorylation while N-(omega-phosphorylalkyl)-substituted compounds 8a-c were obtained via aldol-crotonic condensation of preformed N-phosphorylalkyl substituted piperidones with the corresponding pyridinecarboxaldehyde. The cytotoxicity screen has revealed that phosphorylated compounds based on E,E-3,5-bis(4-pyridinylmethylene)piperid-4-one framework displayed higher inhibitory properties toward Caov3, A549, KB 3-1 and KB 8-5 human carcinoma cell lines comparing with their analogues with 3-pyridine rings. Introduction of the phosphorus moiety substantially increased the antitumor properties in the case of E,E-3,5-bis(3-pyridinylmethylene)piperid-4-ones derivatives but this influence less pronounced for more active analogues bearing 4-pyridinyl rings. Most of the compounds tested are potent against multi-drug resistant cell line KB 8-5 affording some guidelines for the search of perspective drug-candidates among phosphorus substituted E,E-3,5-bis ((hetero)arylidene)piperid-4-ones. (C) 2010 Elsevier Masson SAS. All rights reserved.