14-acetoxy-3-<(tert-butyldimethylsilyl)oxy>-17-(cyclopropylmethyl)-4,5α-epoxymorphinan-6-one | 96453-54-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 菲及其衍生物
• 英文名称: 14-acetoxy-3-<(tert-butyldimethylsilyl)oxy>-17-(cyclopropylmethyl)-4,5α-epoxymorphinan-6-one
• 英文别名: 4,5α-epoxy-3-<(tert-butyldimethylsilyl)oxy>-6-oxo-14-acetoxy-17-(cyclopropylmethyl)morphinan；14-acetoxy-3-[(tert-butyldimethylsilyl)oxy]-17-(cyclopropylmethyl)-4,5α-epoxymorphinan-6-one；[(4R,4aS,7aR,12bS)-9-[tert-butyl(dimethyl)silyl]oxy-3-(cyclopropylmethyl)-7-oxo-2,4,5,6,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-4a-yl] acetate
• CAS: 96453-54-2
• 化学式: C₂₈H₃₉NO₅Si
• 分子量: 497.707
• InChiKey: GENFGMWUNYPNIZ-CGNDNVFTSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.77
• 重原子数：
  35.0
• 可旋转键数：
  5.0
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.71
• 拓扑面积：
  65.07
• 氢给体数：
  0.0
• 氢受体数：
  6.0

反应信息

• 作为反应物：
  描述：

  14-acetoxy-3-<(tert-butyldimethylsilyl)oxy>-17-(cyclopropylmethyl)-4,5α-epoxymorphinan-6-one 在 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 反应 4.0h， 生成 4,5α-epoxy-3,14-dihydroxy-6-methylene-17-(cyclopropylmethyl)morphinan 6α-oxide
  参考文献：
  名称：

  Opioid agonists and antagonists. 6-Desoxy-6-substituted lactone, epoxide, and glycidate ester derivatives of naltrexone and oxymorphone

  摘要：

  Synthesis and opioid radioreceptor assay data on analogues closely related to 6-desoxy-6-spiro-alpha-methylene-gamma-lactone 5a, a compound with irreversible activity in this assay, are reported. Saturated lactones (7a,b), endocyclic alpha, beta-unsaturated gamma-lactones (8a,b and 9a), and 6 alpha,7 alpha-fused alpha-methylene-gamma-lactones (10a and 11a) were prepared. Related 6-desoxy-6-methylene 6 beta- and 6 alpha-oxides (12a,b and 13a) and glycidate esters 14a,b and 15a,b were also prepared with use of naltrexone (1a) and oxymorphone (1b) as starting material. Compounds in the N-cyclopropylmethyl (N-CPM) series were more potent than those in the N-Me series in displacing [3H]naltrexone in the opioid radioreceptor assay, usually by 2-16-fold in the absence of Na ion. The most potent N-CPM analogues were epoxides 12a and 13a and glycidate esters 14a and 15a, showing IC50's of 2-6 nM, similar to that of 5a. Of the N-Me analogues, 6 beta-oxide 12b was most active, with an IC50 of 8 nM in the absence of Na ion. For the N-CPM analogues, the Na ion ratios were generally less than 1, with two exceptions. The N-Me analogues showed expected larger Na ion effects of 7 or greater. None of the lactone analogues had irreversible effects when preincubated in the rat brain membrane preparation, even at 37 degrees C for 30 min, i.e., washing restored [3H]naltrexone binding to control levels. These results clearly show that the alpha-methylene-gamma-lactone moiety of 5a is required for irreversible effects, consistent with it serving as a conjugate addition acceptor of a nucleophilic group from a ligand at or near the receptor. The epoxides and glycidate esters also had no irreversible activity, indicating more electrophilic functional groups are needed and/or these electrophiles are not properly aligned to react with nucleophilic groups at or near the opioid receptor.

  DOI：

  10.1021/jm00145a018
• 作为产物：
  描述：

  纳曲酮 在 咪唑 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 3.5h， 生成 14-acetoxy-3-<(tert-butyldimethylsilyl)oxy>-17-(cyclopropylmethyl)-4,5α-epoxymorphinan-6-one
  参考文献：
  名称：

  Opioid agonists and antagonists. 6-Desoxy-6-substituted lactone, epoxide, and glycidate ester derivatives of naltrexone and oxymorphone

  摘要：

  Synthesis and opioid radioreceptor assay data on analogues closely related to 6-desoxy-6-spiro-alpha-methylene-gamma-lactone 5a, a compound with irreversible activity in this assay, are reported. Saturated lactones (7a,b), endocyclic alpha, beta-unsaturated gamma-lactones (8a,b and 9a), and 6 alpha,7 alpha-fused alpha-methylene-gamma-lactones (10a and 11a) were prepared. Related 6-desoxy-6-methylene 6 beta- and 6 alpha-oxides (12a,b and 13a) and glycidate esters 14a,b and 15a,b were also prepared with use of naltrexone (1a) and oxymorphone (1b) as starting material. Compounds in the N-cyclopropylmethyl (N-CPM) series were more potent than those in the N-Me series in displacing [3H]naltrexone in the opioid radioreceptor assay, usually by 2-16-fold in the absence of Na ion. The most potent N-CPM analogues were epoxides 12a and 13a and glycidate esters 14a and 15a, showing IC50's of 2-6 nM, similar to that of 5a. Of the N-Me analogues, 6 beta-oxide 12b was most active, with an IC50 of 8 nM in the absence of Na ion. For the N-CPM analogues, the Na ion ratios were generally less than 1, with two exceptions. The N-Me analogues showed expected larger Na ion effects of 7 or greater. None of the lactone analogues had irreversible effects when preincubated in the rat brain membrane preparation, even at 37 degrees C for 30 min, i.e., washing restored [3H]naltrexone binding to control levels. These results clearly show that the alpha-methylene-gamma-lactone moiety of 5a is required for irreversible effects, consistent with it serving as a conjugate addition acceptor of a nucleophilic group from a ligand at or near the receptor. The epoxides and glycidate esters also had no irreversible activity, indicating more electrophilic functional groups are needed and/or these electrophiles are not properly aligned to react with nucleophilic groups at or near the opioid receptor.

  DOI：

  10.1021/jm00145a018

文献信息

• The facility of formation of a .DELTA.6 bond in dihydromorphinone and related opiates
  作者：Hiroshi Nagase、Akira Abe、Philip S. Portoghese

  DOI：10.1021/jo00278a025

  日期：1989.8
• NAGASE, HIROSHI;ABE, AKIRA;PORTOGHESE, PHILIP S., J. ORG. CHEM., 54,(1989) N7, C. 4120-4125
  作者：NAGASE, HIROSHI、ABE, AKIRA、PORTOGHESE, PHILIP S.

  DOI：——

  日期：——