1,1-dimethylethyl ((2R)-2-(3-chlorophenyl)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)[(1R)-1-methyl-2-oxoethyl]carbamate | 174891-03-3

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 1,1-dimethylethyl ((2R)-2-(3-chlorophenyl)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)[(1R)-1-methyl-2-oxoethyl]carbamate
• 英文别名: tert-butyl (2R)-2-{[tert-butyl(dimethyl)silyl]oxy}-2-(3-chlorophenyl)ethyl[(1R)-1-methyl-2-oxoethyl]carbamate；[2R-(tert-butoxycarbonyl)-[2R-(tert-butyldimethylsilyloxy)-2-(3-chlorophenyl)ethyl]amino]propionaldehyde；Carbamic acid, N-[(2R)-2-(3-chlorophenyl)-2-[[(1,1-dimethylethyl)dimethylsilyl]oxy]ethyl]-N-[(1R)-1-methyl-2-oxoethyl]-, 1,1-dimethylethyl ester；tert-butyl N-[(2R)-2-[tert-butyl(dimethyl)silyl]oxy-2-(3-chlorophenyl)ethyl]-N-[(2R)-1-oxopropan-2-yl]carbamate
• CAS: 174891-03-3
• 化学式: C₂₂H₃₆ClNO₄Si
• 分子量: 442.071
• InChiKey: LIJBUAMKBRDYED-APWZRJJASA-N

物化性质

• 沸点：
  477.0±45.0 °C(Predicted)
• 密度：
  1.060±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.23
• 重原子数：
  29
• 可旋转键数：
  10
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  55.8
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1,1-dimethylethyl ((2R)-2-(3-chlorophenyl)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)[(1R)-1-methyl-2-oxoethyl]carbamate 在 三乙酰氧基硼氢化钠 、 溶剂黄146 、 三氟乙酸 作用下， 以 二氯甲烷 为溶剂， 反应 16.75h， 生成 (1R)-2-[[(2R)-1-anilinopropan-2-yl]amino]-1-(3-chlorophenyl)ethanol
  参考文献：
  名称：

  Synthesis and Evaluation of Potent and Selective β₃ Adrenergic Receptor Agonists Containing Acylsulfonamide, Sulfonylsulfonamide, and Sulfonylurea Carboxylic Acid Isosteres

  摘要：

  Starting from phenethanolamine aniline leads 3a and 3b, we have identified a series of functionally potent and selective beta(3) adrenergic receptor (AR) agonists containing acylsulfonamide, sulfonylsulfonamide, or sulfonylurea groups within the aniline phenethanolamine series. In beta(3) beta(2), and beta(1) AR cAMP functional assays, 3a and other right-hand side (RHS) carboxylate analogues were found to be full agonists that were modestly selective against beta(1) or beta(2) ARs, while analogues lacking RHS acid functionality were active at beta(3) AR but not selective. Replacement of the carboxylate with acylthiazole and acylmethylsulfone gave potent, but only modestly selective, compounds. Increasing the size of the RHS sulfonamide substituent with phenyl or p-toluene afforded compounds with good potency and functional selectivity (beta(3) AR pEC(50) greater than 8; beta(1) and beta(2) AR selectivity greater than 40- and 500-fold, respectively). Our SAR studies suggest that the potency and selectivity profile of the best analogues reported here is a result of both the steric bulk and acidity of the RHS sulfonamide NH group. Although all of the analogues had a pharmacokinetic half-life of less than 2 h, acylsulfonamides 43 and 44 did show moderately low clearance in dogs. These two compounds were further evaluated by thermographic imaging in mice and were found to produce a robust thermogenic response via oral administration.

  DOI：

  10.1021/jm0101500
• 作为产物：
  描述：

  (R)-(-)-methyl 2-(3-chlorophenyl)-2-hydroxyacetate 在 咪唑 、 二异丁基氢化铝 作用下， 以 乙醚 、 N,N-二甲基甲酰胺 、 甲苯 为溶剂， 反应 11.75h， 生成 1,1-dimethylethyl ((2R)-2-(3-chlorophenyl)-2-{[(1,1-dimethylethyl)(dimethyl)silyl]oxy}ethyl)[(1R)-1-methyl-2-oxoethyl]carbamate
  参考文献：
  名称：

  Synthesis and Evaluation of Potent and Selective β₃ Adrenergic Receptor Agonists Containing Acylsulfonamide, Sulfonylsulfonamide, and Sulfonylurea Carboxylic Acid Isosteres

  摘要：

  Starting from phenethanolamine aniline leads 3a and 3b, we have identified a series of functionally potent and selective beta(3) adrenergic receptor (AR) agonists containing acylsulfonamide, sulfonylsulfonamide, or sulfonylurea groups within the aniline phenethanolamine series. In beta(3) beta(2), and beta(1) AR cAMP functional assays, 3a and other right-hand side (RHS) carboxylate analogues were found to be full agonists that were modestly selective against beta(1) or beta(2) ARs, while analogues lacking RHS acid functionality were active at beta(3) AR but not selective. Replacement of the carboxylate with acylthiazole and acylmethylsulfone gave potent, but only modestly selective, compounds. Increasing the size of the RHS sulfonamide substituent with phenyl or p-toluene afforded compounds with good potency and functional selectivity (beta(3) AR pEC(50) greater than 8; beta(1) and beta(2) AR selectivity greater than 40- and 500-fold, respectively). Our SAR studies suggest that the potency and selectivity profile of the best analogues reported here is a result of both the steric bulk and acidity of the RHS sulfonamide NH group. Although all of the analogues had a pharmacokinetic half-life of less than 2 h, acylsulfonamides 43 and 44 did show moderately low clearance in dogs. These two compounds were further evaluated by thermographic imaging in mice and were found to produce a robust thermogenic response via oral administration.

  DOI：

  10.1021/jm0101500

文献信息

• Biarylaniline Phenethanolamines as Potent and Selective β₃ Adrenergic Receptor Agonists
  作者：David E. Uehling、Barry G. Shearer、Kelly H. Donaldson、Esther Y. Chao、David N. Deaton、Kim K. Adkison、Kathleen K. Brown、Neal F. Cariello、Walter L. Faison、Mary E. Lancaster、Jasmine Lin、Robert Hart、Tula O. Milliken、Mark A. Paulik、Bryan W. Sherman、Elizabeth E. Sugg、Conrad Cowan

  DOI：10.1021/jm0509445

  日期：2006.5.1

  substituted at the meta position with a benzoic acid or a pyridyl carboxylate is described. Several of the analogues (e.g., 34, 36-38, 40, and 44) have high beta(3) adrenergic receptor (AR) potency and selectivity against beta(1) and beta(2) ARs in Chinese hamster ovary (CHO) cells expressing beta ARs. The dog pharmacokinetic profile of some of these analogues showed >25% oral bioavailability and po half-lives

  描述了一系列苯乙醇胺苯胺激动剂的合成，该苯乙醇胺苯胺激动剂在分子的右侧含有在苯甲基或苯吡啶羧酸酯的间位取代的苯胺环。几种类似物（例如34、36-38、40和44）在中国仓鼠卵巢（CHO）中具有较高的beta（3）肾上腺素受体（AR）效能和对beta（1）和beta（2）AR的选择性。表达βAR的细胞。其中一些类似物的狗药代动力学特征显示，其口服生物利用度> 25％，半衰期至少为1.5小时。在本文所述的化合物中，3，3'-联芳基苯胺羧酸酯衍生物36、38和苯基吡啶基衍生物44表现出优异的体外性质和合理的狗药代动力学特征。这三个类似物在小鼠中也显示出剂量依赖性β（3）AR介导的反应。化合物38相对于化合物44的合成容易性和优越的狗药代动力学，再加上其体外特性，使我们选择该化合物作为治疗2型糖尿病的候选药物。
• Synthesis and evaluation of potent and selective β3 adrenergic receptor agonists containing heterobiaryl carboxylic acids
  作者：Barry G. Shearer、Esther Y. Chao、David E. Uehling、David N. Deaton、Conrad Cowan、Bryan W. Sherman、Tula Milliken、Walter Faison、Kathleen Brown、Kimberly K. Adkison、Frank Lee

  DOI：10.1016/j.bmcl.2007.05.069

  日期：2007.8

  The design, synthesis, and SAR of a novel series of heterobiaryl phenethanolamine beta(3) adrenergic receptor agonists are described. The furan analogue 49 was shown to elicit a significant dose-dependent lowering of plasma glucose in a rodent model of type 2 diabetes. (c) 2007 Elsevier Ltd. All rights reserved.