7,8-didehydro-6-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4,5-epoxy-17-methyl-(5α,6α)-morphinan-3-amine | 303175-83-9

• 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: 7,8-didehydro-6-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4,5-epoxy-17-methyl-(5α,6α)-morphinan-3-amine
• 英文别名: 3-amino-6-(tert-butyldiphenylsilyl)oxymorphine；(4R,4aR,7S,7aR,12bS)-7-[tert-butyl(diphenyl)silyl]oxy-3-methyl-2,4,4a,7,7a,13-hexahydro-1H-4,12-methanobenzofuro[3,2-e]isoquinolin-9-amine
• CAS: 303175-83-9
• 化学式: C₃₃H₃₈N₂O₂Si
• 分子量: 522.762
• InChiKey: IQKHRCPVBLPKAX-QGLVFQOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.66
• 重原子数：
  38
• 可旋转键数：
  5
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.39
• 拓扑面积：
  47.7
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  7,8-didehydro-6-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4,5-epoxy-17-methyl-(5α,6α)-morphinan-3-amine 在 sodium tetrahydroborate 、 sodium sulfate 作用下， 以 甲醇 为溶剂， 反应 4.0h， 生成 (-)-3-N-(3'-methoxybenzyl)amino-7,8-didehydro-6-(tert-butyldiphenylsilyl)-4,5-epoxy-17-methyl-(5α,6α)-morphinan-6-ol
  参考文献：
  名称：

  Synthesis, Binding Affinity, and Functional in Vitro Activity of 3-Benzylaminomorphinan and 3-Benzylaminomorphine Ligands at Opioid Receptors

  摘要：

  A series of 3-benzylamino-3-desoxymorphinan (I) and 3-benzylamino-3-desoxymorphine (II) derivatives were synthesized and evaluated for their binding affinities, and functional activity data are presented at MOR, KOR, and DOR Some of these ligands were found to have high binding affinity at MOR and KOR and displayed increased selectivity at MOR over KOR and DOR compared to butorphan or cyclorphan. The most selective compound, 3-(3'-hydroxybenzyl)amino-17-methylmorphinan (4g) (24-fold MOR to KOR and 1700-fold MOR to DOR) also showed high binding affinity (0.42 nM to MOR) and was a full agonist in the [S-35]GTP gamma S binding assay. 2-(3'-Hydroxybenzyl)amino-17-cyclopropylmethylmorphinan (17) was found to be a KOR-selective ligand (150-fold over MOR and > 10000-fold over the DORs). Most 3-benzylaminomorphinan derivatives were partial agonists at MOR and full agonists at KOR in the [S-35]GTP gamma S binding assay.

  DOI：

  10.1021/jm3001086
• 作为产物：
  描述：

  吗啡 在 吡啶 、 咪唑 、 1,1'-双(二苯基膦)二茂铁 、 tris(dibenzylideneacetone)dipalladium (0) 、 盐酸羟胺 、 四丁基氟化铵 、 水 、 sodium acetate 、 sodium t-butanolate 作用下， 以 四氢呋喃 、 甲醇 、 二氯甲烷 、 甲苯 为溶剂， 反应 12.5h， 生成 7,8-didehydro-6-[[(1,1-dimethylethyl)diphenylsilyl]oxy]-4,5-epoxy-17-methyl-(5α,6α)-morphinan-3-amine
  参考文献：
  名称：

  吗啡的选择性保护和功能化：3-氨基-3-脱氧吗啡衍生物的合成和阿片样物质受体结合特性。

  摘要：

  作为鉴定新型阿片受体相互作用剂的努力的一部分，我们最近制备了环唑嗪的一系列8-（取代）氨基类似物。我们发现手性8-苯基氨基（NHC（6）H（5））环偶氮衍生物对kappa阿片受体具有亚纳摩尔亲和力，对mu，阿片受体具有较低的2倍亲和力。为了确定（取代）氨基的益处是否可以扩展到吗啡核心结构，我们制备了5个通式5的新颖3-氨基-3-脱氧吗啡衍生物，其中RR'N = H（2）N，CH（ 3）NH，（CH（3））（2）N，C（6）H（5）NH和C（6）H（5）CH（2）NH。相对于吗啡，这些衍生物对mu，delta和kappa类阿片受体的亲和力分别低38-273倍，11-41倍和10-141倍。通过Pd催化的吗啡3-三氟甲基磺酸酯底物的氨化制备目标化合物，其中6-OH基团被叔丁基二苯基甲硅烷基保护。为了选择性地制备6-叔丁基二苯基甲硅烷基氧基吗啡，开发了一种新的高产率方法，其中在正常条件下将吗啡双

  DOI：

  10.1021/jm000119i

文献信息

• 2-Aminothiazole-Derived Opioids. Bioisosteric Replacement of Phenols
  作者：Ao Zhang、Wennan Xiong、James E. Hilbert、Emily K. DeVita、Jean M. Bidlack、John L. Neumeyer

  DOI：10.1021/jm049978n

  日期：2004.4.1

  A series of aminothiazole-derived morphinans, benzomorphans, and morphine were synthesized. Although their affinities were somewhat lower than their phenol prototypes, one compound (9a, ATPM) has been identified possessing high affinity and selectivity at the kappa receptor. Functional assays showed that 9a was a full kappa but partial mu agonist; the efficacy at kappa was significantly greater than at mu receptors. This novel compound may be valuable for the development of long-acting analgesics and drug abuse medication.
• Synthesis, Binding Affinity, and Functional in Vitro Activity of 3-Benzylaminomorphinan and 3-Benzylaminomorphine Ligands at Opioid Receptors
  作者：John L. Neumeyer、Bin Zhang、Tangzhi Zhang、Anna W. Sromek、Brian I. Knapp、Dana J. Cohen、Jean M. Bidlack

  DOI：10.1021/jm3001086

  日期：2012.4.26

  A series of 3-benzylamino-3-desoxymorphinan (I) and 3-benzylamino-3-desoxymorphine (II) derivatives were synthesized and evaluated for their binding affinities, and functional activity data are presented at MOR, KOR, and DOR Some of these ligands were found to have high binding affinity at MOR and KOR and displayed increased selectivity at MOR over KOR and DOR compared to butorphan or cyclorphan. The most selective compound, 3-(3'-hydroxybenzyl)amino-17-methylmorphinan (4g) (24-fold MOR to KOR and 1700-fold MOR to DOR) also showed high binding affinity (0.42 nM to MOR) and was a full agonist in the [S-35]GTP gamma S binding assay. 2-(3'-Hydroxybenzyl)amino-17-cyclopropylmethylmorphinan (17) was found to be a KOR-selective ligand (150-fold over MOR and > 10000-fold over the DORs). Most 3-benzylaminomorphinan derivatives were partial agonists at MOR and full agonists at KOR in the [S-35]GTP gamma S binding assay.
• Selective Protection and Functionalization of Morphine:  Synthesis and Opioid Receptor Binding Properties of 3-Amino-3-desoxymorphine Derivatives^,1
  作者：Mark P. Wentland、Wenhu Duan、Dana J. Cohen、Jean M. Bidlack

  DOI：10.1021/jm000119i

  日期：2000.9.1

  be extended to the morphine core structure, we have made five novel 3-amino-3-desoxymorphine derivatives of general structure 5 where RR'N = H(2)N, CH(3)NH, (CH(3))(2)N, C(6)H(5)NH, and C(6)H(5)CH(2)NH. Relative to morphine, these derivatives had 38-273-fold, 11-41-fold, and 10-141-fold lower affinity for mu, delta, and kappa opioid receptors, respectively. Target compounds were made via Pd-catalyzed

  作为鉴定新型阿片受体相互作用剂的努力的一部分，我们最近制备了环唑嗪的一系列8-（取代）氨基类似物。我们发现手性8-苯基氨基（NHC（6）H（5））环偶氮衍生物对kappa阿片受体具有亚纳摩尔亲和力，对mu，阿片受体具有较低的2倍亲和力。为了确定（取代）氨基的益处是否可以扩展到吗啡核心结构，我们制备了5个通式5的新颖3-氨基-3-脱氧吗啡衍生物，其中RR'N = H（2）N，CH（ 3）NH，（CH（3））（2）N，C（6）H（5）NH和C（6）H（5）CH（2）NH。相对于吗啡，这些衍生物对mu，delta和kappa类阿片受体的亲和力分别低38-273倍，11-41倍和10-141倍。通过Pd催化的吗啡3-三氟甲基磺酸酯底物的氨化制备目标化合物，其中6-OH基团被叔丁基二苯基甲硅烷基保护。为了选择性地制备6-叔丁基二苯基甲硅烷基氧基吗啡，开发了一种新的高产率方法，其中在正常条件下将吗啡双