(5R,6R,7R)-6,7-dihydroxy-5-(hydroxymethyl)-2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,2-a]pyridazine-1,3-dione

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 唑类
• 英文名称: (5R,6R,7R)-6,7-dihydroxy-5-(hydroxymethyl)-2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,2-a]pyridazine-1,3-dione
• 化学式: C₁₃H₁₅N₃O₅
• 分子量: 293.279
• InChiKey: QCFVUBRTICHOCC-GMTAPVOTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  -0.5
• 重原子数：
  21
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  105
• 氢给体数：
  3
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (5R,6R,7R)-6,7-dihydroxy-5-(hydroxymethyl)-2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,2-a]pyridazine-1,3-dione 在 二乙胺基三氟化硫 作用下， 以 二氯甲烷 为溶剂， 反应 1.0h， 以59%的产率得到(1R,8R,11R)-11-Hydroxy-4-phenyl-9-oxa-2,4,6-triaza-tricyclo[6.2.1.0^2,6]undecane-3,5-dione
  参考文献：
  名称：

  Synthetic studies of fluorinated analogues of 1-azafagomine: Remarkable nucleophilic substitution of fluorine by hydrazine

  摘要：

  (+/-)-5-氟-4-羟基-3-羟甲基六氢吡啶嗪(7)及其他一些aza-扇贝啶类似物的合成目的是比较它们对糖苷酶的抑制作用与(+/-)-4,5-二羟基-3-羟甲基六氢吡啶嗪(1-aza-扇贝啶)。在合成7以及尝试合成4,5-二羟基-3-氟甲基六氢吡啶嗪的过程中，在最终的去保护步骤中观察到了显著的氟被肼的亲核取代反应。氟类似物7的糖苷酶抑制作用比1弱得多，表明1中的3-OH在结合中起作用，作为氢键供体。 (C) 1997 Elsevier Science Ltd.

  DOI：

  10.1016/s0040-4020(97)00588-7
• 作为产物：
  描述：

  (+/-)-2-hydroxymethyl-8-phenyl-1,6,8-triazabicyclo[4.3.0]non-3-ene-7,9-dione 在 Oxone 、 高氯酸 、 1,1,1-三氟丙酮 、 碳酸氢钠 作用下， 以 乙腈 为溶剂， 反应 23.0h， 生成 (5R,6R,7R)-6,7-dihydroxy-5-(hydroxymethyl)-2-phenyl-5,6,7,8-tetrahydro-[1,2,4]triazolo[1,2-a]pyridazine-1,3-dione
  参考文献：
  名称：

  1-Azafagomine: A Hydroxyhexahydropyridazine That Potently Inhibits Enzymatic Glycoside Cleavage

  摘要：

  Abstract(3,4‐trans‐4,5‐trans)‐4,5‐dihydroxy‐3‐hydroxymethylhexahydropyrida‐zine (16) was synthesized in four steps from 2,4‐pentadienol (22) and 4‐phenyl‐triazolin‐3,5‐dione (18) in an overall yield of 32%. In the first step a Diels‐Alder reaction between 18 and 22 gave (π)‐2‐hydroxymethyl‐8‐phenyl‐1,6,8‐triazabicyclo[4.3.0]non‐3‐ene‐7,9‐dione (23c) in 88% yield. Epoxidation of 23c with trifluoromethyl(methyl)dioxirane, generated in situ, gave the trans epoxide 24c in 62% yield. Hydrolysis of the epoxide with perchloric acid gave stereoselectively (2,3‐trans‐3,4‐trans)‐3,4‐dihydroxy‐2‐hydroxy‐methyl‐8‐phenyl‐1,6,8‐triazabicyclo[4.3.0]‐nonane‐7,9‐dione (26) in 73% yield. In the fourth and final step, hydrazinolysis of 26 gave 16 in 84% yield. Pyridazine 16 was found to be a potent inhibitor of α‐and β‐glucosidase, isomaltase and glyco‐gen phosphorylase, while galactosidases and α‐mannosidase were not inhibited. The inhibition of β‐glucosidase is independent of pH, and was found to be due to unprotonated 16.

  DOI：

  10.1002/chem.19970030616

文献信息

• Advances in the Synthesis of Homochiral (−)-1-Azafagomine and (+)-5-<i>epi</i>-1-Azafagomine. 1-<i>N</i>-Phenyl Carboxamide Derivatives of both Enantiomers of 1-Azafagomine: Leads for the Synthesis of Active α-Glycosidase Inhibitors.
  作者：M. José Alves、Flora T. Costa、Vera C. M. Duarte、Antonio Gil Fortes、José A. Martins、Nuno M. Micaelo

  DOI：10.1021/jo201486q

  日期：2011.12.2

  for functionalizing alkenes into molecules bearing a glucosyl framework. Homochiral (+)-5-epi-1-azafagomine was synthetized for the first time. Partial reductive cleavage of the phenyltriazolidinone moiety afforded new homochiral 1-N-phenyl carboxamide derivatives of 1-azafagomine. Both enantiomers of these derivatives were synthetized and tested, displaying a very good enzymatic inhibition toward baker's

  已经设计了一种新的快速制备手性同位（-）-1-氮杂胺和（+）-5-表位-1-氮杂胺的方法。Stoodley将带有2,3,4,6-四乙酰基葡萄糖基手性助剂的二烯的非对映选择性环加成到4-苯基-1,2,4-三唑-3,5-二酮与Bols协议合并，将烯烃官能化为带有葡萄糖基的分子框架。首次合成了手性（+）-5-表位-1-氮杂胺。苯基三唑烷酮部分的部分还原性裂解得到1-氮杂花果胺的新的同手性1- N-苯基羧酰胺衍生物。合成并测试了这些衍生物的两种对映异构体，显示出对面包酵母酵母α-葡萄糖苷酶的很好的酶抑制作用。1-的分子识别机理通过分子模拟研究了来自面包酵母的1-氮杂谷氨酰胺的N-苯基羧酰胺衍生物。将1- N-苯基羧酰胺基团的芳香环有效填充到酶活性位点的疏水亚位点（口袋）中，似乎是导致与未衍生化的（-）-1-azafagomine和（ +）-1-氮杂胺。
• 1-Azafagomine: A Hydroxyhexahydropyridazine That Potently Inhibits Enzymatic Glycoside Cleavage
  作者：Mikael Bols、Rita G. Hazell、Ib B. Thomsen

  DOI：10.1002/chem.19970030616

  日期：1997.6

  Abstract(3,4‐trans‐4,5‐trans)‐4,5‐dihydroxy‐3‐hydroxymethylhexahydropyrida‐zine (16) was synthesized in four steps from 2,4‐pentadienol (22) and 4‐phenyl‐triazolin‐3,5‐dione (18) in an overall yield of 32%. In the first step a Diels‐Alder reaction between 18 and 22 gave (π)‐2‐hydroxymethyl‐8‐phenyl‐1,6,8‐triazabicyclo[4.3.0]non‐3‐ene‐7,9‐dione (23c) in 88% yield. Epoxidation of 23c with trifluoromethyl(methyl)dioxirane, generated in situ, gave the trans epoxide 24c in 62% yield. Hydrolysis of the epoxide with perchloric acid gave stereoselectively (2,3‐trans‐3,4‐trans)‐3,4‐dihydroxy‐2‐hydroxy‐methyl‐8‐phenyl‐1,6,8‐triazabicyclo[4.3.0]‐nonane‐7,9‐dione (26) in 73% yield. In the fourth and final step, hydrazinolysis of 26 gave 16 in 84% yield. Pyridazine 16 was found to be a potent inhibitor of α‐and β‐glucosidase, isomaltase and glyco‐gen phosphorylase, while galactosidases and α‐mannosidase were not inhibited. The inhibition of β‐glucosidase is independent of pH, and was found to be due to unprotonated 16.
• Synthetic studies of fluorinated analogues of 1-azafagomine: Remarkable nucleophilic substitution of fluorine by hydrazine
  作者：Ib Thomsen、Bettina V. Ernholt、Mikael Bols

  DOI：10.1016/s0040-4020(97)00588-7

  日期：1997.7

  (+/-)-5-fluoro-4-hydroxy-3-hydroxymethylhexahydropyridazine (7) and some other azafagomine analogues were synthesised with the aim of comparing their glycosidase inhibition to that of (+/-)-4,5-dihydroxy-3-hydroxymethylhexahydropyridazine (1-azafagomine). Both in the synthesis of 7 and in the attempted synthesis of 4,5-dihydroxy-3-fluoromethylhexahydropyridazine, a remarkable degree of nucleophilic substitution of fluorine by hydrazine was observed in the final deprotection step involving hydrazinolysis. Fluorine analogue 7 was a considerably weaker glycosidase inhibitor than I, suggesting that the 3-OH of 1 play a role in its binding by acting as a hydrogen bond donator. (C) 1997 Elsevier Science Ltd.

  (+/-)-5-氟-4-羟基-3-羟甲基六氢吡啶嗪(7)及其他一些aza-扇贝啶类似物的合成目的是比较它们对糖苷酶的抑制作用与(+/-)-4,5-二羟基-3-羟甲基六氢吡啶嗪(1-aza-扇贝啶)。在合成7以及尝试合成4,5-二羟基-3-氟甲基六氢吡啶嗪的过程中，在最终的去保护步骤中观察到了显著的氟被肼的亲核取代反应。氟类似物7的糖苷酶抑制作用比1弱得多，表明1中的3-OH在结合中起作用，作为氢键供体。 (C) 1997 Elsevier Science Ltd.