(-)-(4,5α-epoxy-3,6-dimethoxy-17-methyl-6α,14α-ethenoisomorphinan-7α)methanol | 47518-94-5

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 吗啡烷
• 英文名称: (-)-(4,5α-epoxy-3,6-dimethoxy-17-methyl-6α,14α-ethenoisomorphinan-7α)methanol
• 英文别名: (4,5α-epoxy-3,6-dimethoxy-17-methyl-6α,14α-etheno-morphinan-7α-yl)-methanol；[(1R,2S,6R,14R,15R,16R)-11,15-dimethoxy-5-methyl-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11,18-tetraen-16-yl]methanol
• CAS: 47518-94-5
• 化学式: C₂₂H₂₇NO₄
• 分子量: 369.461
• InChiKey: LFXDNMUTEKCZOC-GEAUKGQYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.9
• 重原子数：
  27
• 可旋转键数：
  3
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  51.2
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (-)-(4,5α-epoxy-3,6-dimethoxy-17-methyl-6α,14α-ethenoisomorphinan-7α)methanol 在 lithium aluminium tetrahydride 作用下， 以 吡啶 、 乙醚 、 二氯甲烷 为溶剂， 生成 N-Cyan-6,14-endo-etheno-7α-methyl-tetrahydro-northebain
  参考文献：
  名称：

  吗啡-蒂巴因组的新型镇痛药和分子重排。第八部分 7-烷基-6,14-内-乙炔四氢蒂巴因及其相关化合物

  摘要：

  描述了6，14-内-乙炔四氢蒂巴因和6，14-内-乙炔四氢-奥巴韦的7-烷基衍生物的制备，包括N-烷基，N-烯基和N-环丙基甲基类似物。

  DOI：

  10.1039/j39690000826
• 作为产物：
  描述：

  (-)-ethyl 4,5α-epoxy-3,6-dimethoxy-17-methyl-6α,14α-ethenoisomorphinan-7α-carboxylate 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 以77%的产率得到(-)-(4,5α-epoxy-3,6-dimethoxy-17-methyl-6α,14α-ethenoisomorphinan-7α)methanol
  参考文献：
  名称：

  chemistry of opium alkaloids. part 44: Synthesis and opioid receptor binding profile of substituted ethenoisomorphinans and ethenomorphinans 1Part XLIII. Baas, J. M. A.; Woudenberg, R. H.; Maat, L. Liebigs Ann./Recueil 1997, 13. 1

  摘要：

  7- And 8-substituted 6 alpha,14 alpha-ethenoisomorphinans were synthesized by reaction of properly substituted morpkinan-6,8-dienes (analogues of thebaine) with methyl vinyl ketone or ethyl acrylate. Reaction with the appropriate Grignard reagent gave the 7- and 8-dialkylmethanols, respectively. Cleavage of the 3-methyl ether with KOH/glycol or boron tribromide afforded the 3-hydroxyl derivatives. In general, the compounds with the ethoxycarbonyl or dimethylmethanol substituent at the 8 alpha-position showed lower affinity for the mu, kappa, and delta opioid receptor subtypes than the corresponding 7 alpha- and 7 beta-substituted compounds. Introduction of a chloro substituent in position 18 increased the potency significantly. The 7-substituent could be connected to the 18-position without loss of affinity. 5 beta-alkyl substitution of 6 alpha, 14 alpha-ethenoisomorphinans led to a decrease in affinity for the three opioid receptor subtypes. In the 5 beta-methyl series the affinity for the mu and delta receptors increased from 7 alpha-dimethylmethanol to 7 alpha-methylhexylmethanol. In the 5 beta-alkyl series, the affinity for the mu-receptor could be increased by connecting the 5- and 7-substituents, yielding a compound with high mu-selectivity. The new 6 beta,14 beta-ethenomorphinans did not show affinity for any of the opioid receptors, in accordance with the inactivity earlier found in in vivo experiments. (C) 1999 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0968-0896(98)00267-3

文献信息

• Novel analgesics and molecular rearrangements in the morphine-thebaine group. III. Alcohols of the 6,14-endo-ethenotetrahydrooripavine series and derived analogs of N-allylnormorphine and -norcodeine
  作者：Kenneth W. Bentley、Denis G. Hardy

  DOI：10.1021/ja00989a032

  日期：1967.6

  affected only the meth-oxy1 group attached to (2-3, that at C-6 remaining undisturbed. From the point of view of analgesic activity , however, the retention of the C-6 methoxyl group is advantageous, since methylation of the hy-droxyl group at this position in morphine and codeine enhances the activity. The demethylation of the C-3 methoxyl group in the codeine-thebaine group under alkaline conditions

  通式结构 IV 和 V 的仲醇和叔醇是通过本系列第 I1 部分中描述的相应碱 I 和 I1 的脱甲基化制备的。如此获得的酚类是具有极高效力的镇痛剂，其强度是吗啡的 12,000 倍，这是史无前例的。该系列和更早系列的碱已通过 N-氰基化合物和新的 N，N'-亚甲基双化合物 XI11 转化为通式结构 XI 和 XI1 的 N-烯丙基诺吗啡和 N-烯丙基诺可待因的类似物。 I和I1与偶氮二羧酸甲酯。XI1 系列的某些碱基是具有前所未有效力的吗啡拮抗剂，高达 N-烯丙基吗啡的 150 倍。在之前的论文中，报道了通式结构 I 和 I1 的两个系列 I 可待因衍生物的制备，其中许多成员作为镇痛剂的活性比以前在吗啡-蒂巴因组中制备的任何碱都要高得多。由于可待因衍生物去甲基化为相应的吗啡衍生物几乎总是导致镇痛活性显着增加，因此结构 I 和 I1 的大部分醇都转化为相关的酚类。由于醇非常容易进行酸催化重排
• Novel analgesics and molecular rearrangements in the morphine-thebaine group. II. Alcohols derived from 6,14-endo-etheno- and 6,14-endo-ethanotetrahydrothebaine
  作者：Kenneth W. Bentley、Denis G. Hardy、B. Meek

  DOI：10.1021/ja00989a031

  日期：1967.6
• 6-O-Demethylation of the Thevinols with Lithium Aluminium Hydride: Selective Demethylation of a Tertiary Alkyl Methyl Ether in the Presence of an Aryl Methyl Ether
  作者：Simon W. Breeden、Andrew Coop、Stephen M. Husbands、John W. Lewis

  DOI：10.1002/(sici)1522-2675(19991110)82:11<1978::aid-hlca1978>3.0.co;2-q

  日期：1999.11.10

  In the pursuit of ring-constrained analogues of buprenorphine, we wished to prepare 6-O-demethylated analogues of the thevinols and orvinols. Previously it had been disclosed that lithium aluminum hydride (LAH) in THF containing a chlorinated solvent could achieve this transformation. Here we report the results of our work with LAH in the non-coordinating solvent toluene. In refluxing toluene, the selective 6-O-demethylation of thevinols could be achieved with no 3-O-demethylation being observed. It appears that a C(20)-OH or C(2O)-NH2 group is needed on the substrate for this hydrogenolysis to proceed.
• chemistry of opium alkaloids. part 44: Synthesis and opioid receptor binding profile of substituted ethenoisomorphinans and ethenomorphinans 1Part XLIII. Baas, J. M. A.; Woudenberg, R. H.; Maat, L. Liebigs Ann./Recueil 1997, 13. 1
  作者：Leendert Maat、Richard H. Woudenberg、Gerrit J. Meuzelaar、Joannes T.M. Linders

  DOI：10.1016/s0968-0896(98)00267-3

  日期：1999.3

  7- And 8-substituted 6 alpha,14 alpha-ethenoisomorphinans were synthesized by reaction of properly substituted morpkinan-6,8-dienes (analogues of thebaine) with methyl vinyl ketone or ethyl acrylate. Reaction with the appropriate Grignard reagent gave the 7- and 8-dialkylmethanols, respectively. Cleavage of the 3-methyl ether with KOH/glycol or boron tribromide afforded the 3-hydroxyl derivatives. In general, the compounds with the ethoxycarbonyl or dimethylmethanol substituent at the 8 alpha-position showed lower affinity for the mu, kappa, and delta opioid receptor subtypes than the corresponding 7 alpha- and 7 beta-substituted compounds. Introduction of a chloro substituent in position 18 increased the potency significantly. The 7-substituent could be connected to the 18-position without loss of affinity. 5 beta-alkyl substitution of 6 alpha, 14 alpha-ethenoisomorphinans led to a decrease in affinity for the three opioid receptor subtypes. In the 5 beta-methyl series the affinity for the mu and delta receptors increased from 7 alpha-dimethylmethanol to 7 alpha-methylhexylmethanol. In the 5 beta-alkyl series, the affinity for the mu-receptor could be increased by connecting the 5- and 7-substituents, yielding a compound with high mu-selectivity. The new 6 beta,14 beta-ethenomorphinans did not show affinity for any of the opioid receptors, in accordance with the inactivity earlier found in in vivo experiments. (C) 1999 Elsevier Science Ltd. All rights reserved.
• Novel analgesics and molecular rearrangements in the morphine–thebaine group. Part VIII. 7-Alkyl-6,14-endo-ethenotetrahydrothebaine and related compounds
  作者：K. W. Bentley、D. G. Hardy、J. W. Lewis、M. J. Readhead、W. I. Rushworth

  DOI：10.1039/j39690000826

  日期：——

  The preparation of 7-alkyl derivatives of 6,14-endo-ethenotetrahydrothebaine and 6,14-endo-ethenotetrahydro-oripavine, including N-alkyl, N-alkenyl, and N-cyclopropylmethyl analogues, is described.

  描述了6，14-内-乙炔四氢蒂巴因和6，14-内-乙炔四氢-奥巴韦的7-烷基衍生物的制备，包括N-烷基，N-烯基和N-环丙基甲基类似物。