4’-叔-丁基二甲基硅烷基-6-羟基雷洛昔芬 | 174264-46-1

• 分子结构分类: 有机化合物 - 有机氧化合物
• 中文名称: 4’-叔-丁基二甲基硅烷基-6-羟基雷洛昔芬
• 英文名称: 2-[4-[[(1,1-dimethylethyl)dimethylsilyl]oxy]phenyl]-6-hydroxybenzo[b]thiophen-3-yl 4-[2-(1-piperidinyl)ethoxy]phenyl ketone
• 英文别名: [2-[4-(t-Butyldimethylsilyloxy)phenyl]-6-hydroxybenzo[b]thien-3-yl] [4-[2-(1-piperidinyl)ethoxy]phenyl]methanone；(2-(4-(tert-butyldimethylsilyloxy)phenyl)-6-hydroxybenzo[b]thiophen-3-yl)(4-(2-(piperidin-1-yl)ethoxy)phenyl)methanone；[2-[4-(t-Butyldimethylsilyloxy)phenyl]-6-hydroxybenzo[b]thien-3-yl][4-[2-(1-piperidinyl)ethoxy]phenyl]methanone；4'-tert-Butyldimethylsilyl-6-hydroxy Raloxifene；[2-[4-[tert-butyl(dimethyl)silyl]oxyphenyl]-6-hydroxy-1-benzothiophen-3-yl]-[4-(2-piperidin-1-ylethoxy)phenyl]methanone
• CAS: 174264-46-1
• 化学式: C₃₄H₄₁NO₄SSi
• 分子量: 587.855
• InChiKey: YYSIXGNGLSNJGQ-UHFFFAOYSA-N

物化性质

• 溶解度：
  可溶于丙酮、氯仿、二氯甲烷、乙醇、甲醇

计算性质

• 辛醇/水分配系数(LogP)：
  8.75
• 重原子数：
  41
• 可旋转键数：
  10
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  87.2
• 氢给体数：
  1
• 氢受体数：
  6

制备方法与用途

生物活性

4'-叔丁基二甲基硅基-6-羟基Raloxifene（化合物4）是Raloxifene与叔丁基二甲基硅基氯反应的产物。该化合物可用于合成Raloxifene 6-葡萄糖苷。

体外研究

Raloxifene 6-葡萄糖苷的制备包括以下步骤：

1. 将Raloxifene与叔丁基二甲基硅基氯反应，生成一种色谱可分离的混合物，包含化合物3和4'-叔丁基二甲基硅基-6-羟基Raloxifene（化合物4）。
2. 使用路易斯酸催化酚4'-叔丁基二甲基硅基-6-羟基Raloxifene与甲基1,2,3,4-四-O-乙酰-D-葡糖醛酸的偶联，生成单一产品（化合物6），并具有期望的第一手性中心。
3. 将化合物6在二氧六环中加热至60°C并与锂氢氧化物反应，随后使用四丁基氨氟化物脱保护，最终得到Raloxifene 6-葡萄糖苷。

反应信息

• 作为反应物：
  描述：

  4’-叔-丁基二甲基硅烷基-6-羟基雷洛昔芬 在 palladium diacetate 盐酸 、 ammonium hydroxide 、 三乙胺 作用下， 以 四氢呋喃 、 甲醇 、 1,1-二氯乙烷 、 二氯甲烷 、 N,N-二甲基甲酰胺 为溶剂， 生成 2-(4-hydroxyphenyl)-3-[4-[2-(1-piperidinyl)ethoxy]benzoyl]benzo[b]thiophene-6-carboxylic acid methyl ester
  参考文献：
  名称：

  Antithrombotic diamines

  摘要：

  该应用涉及将I式中所定义的二胺用作凝血酶抑制剂、凝血抑制剂和血栓栓塞性疾病药剂。它还提供了I式的新化合物，其制备方法和中间体，以及包含这些新化合物的药物配方。

  公开号：

  US06025382A1
• 作为产物：
  描述：

  雷洛昔芬 、 叔丁基二甲基氯硅烷 在 4-二甲氨基吡啶 作用下， 生成 6-叔-丁基二甲基硅烷基-4’-羟基雷洛昔芬 、 4’-叔-丁基二甲基硅烷基-6-羟基雷洛昔芬
  参考文献：
  名称：

  Structure−Activity Relationships of Selective Estrogen Receptor Modulators:  Modifications to the 2-Arylbenzothiophene Core of Raloxifene

  摘要：

  The 8-arylbenzothiophene raloxifene, 1, is a selective estrogen receptor modulator which is currently under clinical evaluation for the prevention and treatment of postmenopausal osteoporosis. A series of raloxifene analogs which contain modifications to the 2-arylbenzothiophene core have been prepared and evaluated for the ability to bind to the estrogen receptor and inhibit MCF-7 breast cancer cell proliferation in vitro. Their ability to function as tissue-selective estrogen agonists in vivo has been assayed in a short-term, ovariectomized (OVX) rat model with end points of serum cholesterol lowering, uterine weight gain, and uterine eosinophil peroxidase activity. These studies have demonstrated that (1) the 6-hydroxy and, to a lesser extent, the 4'-hydroxy substituents of raloxifene are important for receptor binding and in vitro activity, (2) small, highly electronegative 4'-substituents such as hydroxy, fluoro, and chloro are preferred both in vitro and in vivo, (3) increased steric bulk at the 4'-position leads to increased uterine stimulation in, vivo, and (4) additional substitution of the 2-aryl moiety is tolerated while additional substitution at the 4-, 5-, or 7-position of the benzothiophene results in reduced biological activity. In addition, compounds in which the 2-aryl group is replaced by alkyl, cycloalkyl, and naphthyl substituents maintain a profile of in vitro and in vivo biological activity qualitatively similar to that of raloxifene. Several novel structural variants including 2-cyclohexyl, 2-naphthyl, and 6-carbomethoxy analogs also demonstrated efficacy in preventing bone loss in a chronic OVX rat model of postmenopausal osteopenia, at doses of 0.1-10 mg/kg.

  DOI：

  10.1021/jm9606352

文献信息

• Benzo[b]thiophene compounds, intermediates, formulations, and methods
  申请人：Eli Lilly and Company

  公开号：US06017914A1

  公开（公告）日：2000-01-25

  This invention relates to the field of pharmaceutical and organic chemistry and provides benzothiophene compounds, intermediates, formulations, and methods.

  本发明涉及制药和有机化学领域，提供苯并噻吩化合物、中间体、配方和方法。
• Versatile raloxifene triflates
  作者：Michael J. Martin、Timothy A. Grese、Andrew L. Glasebrook、Ken Matsumoto、Lewis D. Pennington、D.Lynn Phillips、Lorri L. Short

  DOI：10.1016/s0960-894x(97)00130-3

  日期：1997.1

  Methodology has been employed that permits the differentiation of the phenols of raloxifene. Transition metal mediated transformations of raloxifene triflates have subsequently provided a number of analogs that were evaluated further in two in vitro models predictive of estrogen receptor mediated biological activity. (C) 1997 Elsevier Science Ltd.
• Synthesis and estrogen receptor binding affinities of the major human metabolites of raloxifene (LY139481)
  作者：Jeffrey A. Dodge、Charles W. Lugar、Stephen Cho、John J. Osborne、David L. Phillips、Andrew L. Glasebrook、Charles A. Frolik

  DOI：10.1016/s0960-894x(97)00142-x

  日期：1997.4

  Glucuronide conjugates 1 and 2, the major metabolites of raloxifene, have been prepared and their molecular interactions with the estrogen receptor determined. (C) 1997 Elsevier Science Ltd.
• Benzo [b] thiophene compounds, intermediates, formulations, and methods
  申请人：ELI LILLY AND COMPANY

  公开号：EP0835871B1

  公开（公告）日：2006-03-01
• Benzo (b) thiophene compounds, intermediates, formulations, and methods
  申请人：ELI LILLY AND COMPANY

  公开号：EP0835878B1

  公开（公告）日：2002-12-11