(R)-1-(6,8-difluorochroman-3-yl)-2-thioxohexahydropyrrolo[2,3-d]imidazole-4-carboxylic acid tert-butyl ester

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯并吡喃
• 英文名称: (R)-1-(6,8-difluorochroman-3-yl)-2-thioxohexahydropyrrolo[2,3-d]imidazole-4-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl 1-[(3R)-6,8-difluoro-3,4-dihydro-2H-chromen-3-yl]-2-sulfanylidene-3a,5,6,6a-tetrahydro-3H-pyrrolo[2,3-d]imidazole-4-carboxylate
• 化学式: C₁₉H₂₃F₂N₃O₃S
• 分子量: 411.473
• InChiKey: VPDQCJZMLHZBQI-XEBKBJJBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  28
• 可旋转键数：
  3
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  86.1
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  (R)-1-(6,8-difluorochroman-3-yl)-2-thioxohexahydropyrrolo[2,3-d]imidazole-4-carboxylic acid tert-butyl ester 在 盐酸 作用下， 以 水 、 乙酸乙酯 为溶剂， 反应 2.0h， 以90%的产率得到依他米司特盐酸盐
  参考文献：
  名称：

  Process Research for Multikilogram Production of Etamicastat: A Novel Dopamine β-Hydroxylase Inhibitor

  摘要：

  In order to develop a manufacturing route to etamicastat, three synthetic approaches to the pivotal chiral 3-aminochroman intermediate have been studied as well as four methods for the construction of the 2-aminoethyl imidazolethione fragment. The evolution of the synthetic strategy based on the early discovery route was described. By focusing on the use of readily available starting materials it was possible to avoid chromatography steps and expensive reagents, bringing about significant improvements in cost and throughput. The best route involves construction of the chiral centre by asymmetric hydrogenation.

  DOI：

  10.1021/op300012d
• 作为产物：
  描述：

  6,8-difluoro-2H-chromene-3-carbonitrile 在 sodium hypochlorite 、 硫酸 、 水 、 氢气 、 溶剂黄146 、 potassium hydroxide 、 sodium hydroxide 作用下， 以 甲醇 、 溶剂黄146 、 乙酸乙酯 为溶剂， 25.0~100.0 ℃ 、3.0 MPa 条件下， 反应 76.0h， 生成 (R)-1-(6,8-difluorochroman-3-yl)-2-thioxohexahydropyrrolo[2,3-d]imidazole-4-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Process Research for Multikilogram Production of Etamicastat: A Novel Dopamine β-Hydroxylase Inhibitor

  摘要：

  In order to develop a manufacturing route to etamicastat, three synthetic approaches to the pivotal chiral 3-aminochroman intermediate have been studied as well as four methods for the construction of the 2-aminoethyl imidazolethione fragment. The evolution of the synthetic strategy based on the early discovery route was described. By focusing on the use of readily available starting materials it was possible to avoid chromatography steps and expensive reagents, bringing about significant improvements in cost and throughput. The best route involves construction of the chiral centre by asymmetric hydrogenation.

  DOI：

  10.1021/op300012d

文献信息

• Synthesis and Biological Evaluation of Novel, Peripherally Selective Chromanyl Imidazolethione-Based Inhibitors of Dopamine β-Hydroxylase
  作者：Alexandre Beliaev、David A. Learmonth、Patricio Soares-da-Silva

  DOI：10.1021/jm051051f

  日期：2006.2.1

  A novel series of dopamine beta-hydroxylase (DBH) inhibitors was designed and synthesized incorporating modifications to the core structure of nepicastat 3, with the principal aim of discovering potent DBH inhibitors exerting minimal effects on dopamine (DA) and noradrenaline (NA) levels in the central nervous system. This study resulted in the identification of a potent, peripherally selective DBH inhibitor, (R)-5-(2-aminoethyl)-1-(6,8-difluorochroman-3-yl)-1,3-dihydroimidazole-2-thione hydrochloride 54 (BIA 5-453). In experiments in mice and rats at T-max (9 h after administration), 54 reduced NA levels in a dose-dependent manner in both the left atrium and the left ventricle, with the maximal inhibitory effect attained at a dose of 100 mg/kg. In contrast to that found in the heart, 54 failed to affect NA tissue levels in the brain. Compound 54 is thus presented as a candidate for clinical evaluation for the treatment of chronic heart failure and hypertension.
• Process Research for Multikilogram Production of Etamicastat: A Novel Dopamine β-Hydroxylase Inhibitor
  作者：Alexandre Beliaev、Jorge Wahnon、Domenico Russo

  DOI：10.1021/op300012d

  日期：2012.4.20

  In order to develop a manufacturing route to etamicastat, three synthetic approaches to the pivotal chiral 3-aminochroman intermediate have been studied as well as four methods for the construction of the 2-aminoethyl imidazolethione fragment. The evolution of the synthetic strategy based on the early discovery route was described. By focusing on the use of readily available starting materials it was possible to avoid chromatography steps and expensive reagents, bringing about significant improvements in cost and throughput. The best route involves construction of the chiral centre by asymmetric hydrogenation.