(2S)-1,3-benzodioxol-5-yl{6-[(benzyloxy)carbonyl]-1-methyl-1H-indol-3-yl}ethanoic acid | 370104-34-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 英文名称: (2S)-1,3-benzodioxol-5-yl{6-[(benzyloxy)carbonyl]-1-methyl-1H-indol-3-yl}ethanoic acid
• 英文别名: (2S)-2-(1,3-benzodioxol-5-yl)-2-(1-methyl-6-phenylmethoxycarbonylindol-3-yl)acetic acid
• CAS: 370104-34-0
• 化学式: C₂₆H₂₁NO₆
• 分子量: 443.456
• InChiKey: MOUKNWCLEPMCJE-DEOSSOPVSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.3
• 重原子数：
  33
• 可旋转键数：
  7
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.15
• 拓扑面积：
  87
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (2S)-1,3-benzodioxol-5-yl{6-[(benzyloxy)carbonyl]-1-methyl-1H-indol-3-yl}ethanoic acid 在 N-羟基-7-氮杂苯并三氮唑 、 5%-palladium/activated carbon 、 氢气 、 sodium hexamethyldisilazane 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 水 为溶剂， -60.0 ℃ 、413.7 kPa 条件下， 反应 2.17h， 生成 3-((1S)-1-(1,3-benzodioxol-5-yl)-2-{[(2-methoxy-4-methylphenyl)sulfonyl]amino}-2-oxoethyl)-1-methyl-1H-indole-6-carboxylic acid
  参考文献：
  名称：

  An Efficient and Scalable Synthesis of the Endothelin Antagonists UK-350,926 and UK-349,862 Using a Dynamic Resolution Process

  摘要：

  The development and scale-up of a potential manufacturing route to the endothelin antagonists UK-350,926 1 and UK-349,862 2 are described. A key synthetic challenge in designing an efficient route to these molecules was the optical lability of the stereogenic centre during the construction of the acylsulfonamide functionality. In the discovery synthesis of UK-350,926 the chiral centre was introduced by classical resolution and the acylsulfonamide functionality synthesized by construction of the N-sulfonyl bond. An alternative more efficient process route was developed involving the preparation of racemic UK-350,926 and final step dynamic resolution with (S)-(-)-1-phenylethylamine as the key step. The process route prepared the acylsulfonamide by construction of the N-carbonyl bond, eliminates a cryogenic reaction and a hazardous intermediate from the synthesis, improves the overall process yield, and allows access to both endothelin antagonists from common intermediates without the need for purification by chromatography. Full experimental details of the new five-step process to prepare UK-349,862 from commercially available starting materials are given for the first time.

  DOI：

  10.1021/op050102f
• 作为产物：
  描述：

  2-(1,3-benzodioxol-5-yl)-2-bromoacetic acid 在 盐酸 、 R(+)-alpha-甲基苄胺 作用下， 以 水 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 (2S)-1,3-benzodioxol-5-yl{6-[(benzyloxy)carbonyl]-1-methyl-1H-indol-3-yl}ethanoic acid
  参考文献：
  名称：

  An Efficient and Scalable Synthesis of the Endothelin Antagonists UK-350,926 and UK-349,862 Using a Dynamic Resolution Process

  摘要：

  The development and scale-up of a potential manufacturing route to the endothelin antagonists UK-350,926 1 and UK-349,862 2 are described. A key synthetic challenge in designing an efficient route to these molecules was the optical lability of the stereogenic centre during the construction of the acylsulfonamide functionality. In the discovery synthesis of UK-350,926 the chiral centre was introduced by classical resolution and the acylsulfonamide functionality synthesized by construction of the N-sulfonyl bond. An alternative more efficient process route was developed involving the preparation of racemic UK-350,926 and final step dynamic resolution with (S)-(-)-1-phenylethylamine as the key step. The process route prepared the acylsulfonamide by construction of the N-carbonyl bond, eliminates a cryogenic reaction and a hazardous intermediate from the synthesis, improves the overall process yield, and allows access to both endothelin antagonists from common intermediates without the need for purification by chromatography. Full experimental details of the new five-step process to prepare UK-349,862 from commercially available starting materials are given for the first time.

  DOI：

  10.1021/op050102f

文献信息

• The Design and Synthesis of a Novel, Orally Active, Selective ETA Antagonist
  作者：David J. Rawson、Kevin N. Dack、Roger P. Dickinson、Kim James、Clive Long、Don Walker

  DOI：10.1007/s00044-004-0021-y

  日期：2004.4

  potency and pharmacokinetic properties of an indole-based series of endothelin antagonists have been optimised using in vitro, in silico and in vivo methods. Compound 8 is oxidised in vivo to the active metabolite 7 and has been highlighted as an orally active agent suitable for further profiling. A synthesis of the active enantiomer of the lead compound (8a) and its metabolite (7a) has been developed

  已使用体外、计算机和体内方法优化了基于吲哚的系列内皮素拮抗剂的效力和药代动力学特性。化合物 8 在体内被氧化为活性代谢物 7，并被强调为适合进一步分析的口服活性剂。开发了先导化合物 (8a) 及其代谢物 (7a) 的活性对映异构体的合成方法，并介绍了 8a 的药代动力学和药理学特征。
• Racemisation-free synthesis of chiral acylsulfonamides
  作者：David Ellis

  DOI：10.1016/s0957-4166(01)00259-2

  日期：2001.7

  The development and application of a synthesis of acylsulfonamide A avoiding racemisation of the labile benzylic stereogenic centre is described. (C) 2001 Elsevier Science Ltd. All rights reserved.
• An Efficient and Scalable Synthesis of the Endothelin Antagonists UK-350,926 and UK-349,862 Using a Dynamic Resolution Process
  作者：Christopher P. Ashcroft、Stephen Challenger、David Clifford、Andrew M. Derrick、Yousef Hajikarimian、Keith Slucock、Terry V. Silk、Nicholas M. Thomson、John R. Williams

  DOI：10.1021/op050102f

  日期：2005.9.1

  The development and scale-up of a potential manufacturing route to the endothelin antagonists UK-350,926 1 and UK-349,862 2 are described. A key synthetic challenge in designing an efficient route to these molecules was the optical lability of the stereogenic centre during the construction of the acylsulfonamide functionality. In the discovery synthesis of UK-350,926 the chiral centre was introduced by classical resolution and the acylsulfonamide functionality synthesized by construction of the N-sulfonyl bond. An alternative more efficient process route was developed involving the preparation of racemic UK-350,926 and final step dynamic resolution with (S)-(-)-1-phenylethylamine as the key step. The process route prepared the acylsulfonamide by construction of the N-carbonyl bond, eliminates a cryogenic reaction and a hazardous intermediate from the synthesis, improves the overall process yield, and allows access to both endothelin antagonists from common intermediates without the need for purification by chromatography. Full experimental details of the new five-step process to prepare UK-349,862 from commercially available starting materials are given for the first time.