ethyl (3R)-(7-fluoro-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate | 800377-03-1

• 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: ethyl (3R)-(7-fluoro-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate
• 英文别名: ethyl 2-[(3R)-7-fluoro-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl]acetate
• CAS: 800377-03-1
• 化学式: C₁₅H₁₆FNO₂
• 分子量: 261.296
• InChiKey: DUDTZVCHBINVOE-SECBINFHSA-N

物化性质

• 沸点：
  394.6±37.0 °C(Predicted)
• 密度：
  1.248±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  19
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.4
• 拓扑面积：
  42.1
• 氢给体数：
  1
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  ethyl (3R)-(7-fluoro-1,2,3,4-tetrahydrocyclopenta[b]indol-3-yl)acetate 在 sodium hydroxide 作用下， 生成 拉罗皮兰
  参考文献：
  名称：

  An efficient enzyme-catalyzed kinetic resolution: large-scale preparation of an enantiomerically pure indole-ethyl ester derivative, a key component for the synthesis of a prostaglandin D2 receptor antagonist, an anti-allergic rhinitis drug candidate

  摘要：

  Three racemic esters including indole-ethyl ester I as well as its related derivatives 3 and 4 in Scheme 1, all synthetic intermediates for the preparation of chiral compound 5, were used as substrates to evaluate the catalytic potentials of a panel of commercial enzymes for asymmetric hydrolysis. After an extensive evaluation of the conversion rates (C), enantiomeric excesses (ee) and enantioselectivity determination (E), lipase from Pseudomonas fluorescens was identified. This lipase catalyzed the asymmetric hydrolysis of racemic indole-ethyl ester I affording the desired enantiomerically pure intermediate 1 with 97% ee and an E value of 425. Indole-ethyl ester 1, with the following attributes: being early in the synthetic scheme, showing resistance to racemization in the later chemical reactions as well as the possibility of the recycling of the unwanted enantiomer, was therefore selected for optimization and establishment of an enzyme-catalyzed reaction for the industrial-scale synthesis of the compound 5, a drug candidate for the treatment of allergic rhinitis. (C) 2005 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.tetasy.2005.08.021
• 作为产物：
  描述：

  7-氟-5-溴-1,2,3,4-四氢乙酯 在 pseudomonas fluorescens lipase AK-AF 作用下， 以 DMF (N,N-dimethyl-formamide) 为溶剂， 反应 38.0h， 以99%的产率得到
  参考文献：
  名称：

  [EN] FLUORO-METHANESULFONYL-SUBSTITUTED CYCLOALKANOINDOLES AND THEIR USE AS PROSTAGLANDIN D2 ANTAGONISTS
  [FR] FLUORO-METHANESULFONYL- CYCLOALKANOINDOLES SUBSTITUES ET LEUR UTILISATION EN TANT QU'ANTAGONISTES DE PROSTAGLANDINE D2

  摘要：

  化合物(I)的新型环烷基吲哚衍生物是前列腺素拮抗剂，因此对于治疗前列腺素介导的疾病是有用的。

  公开号：

  WO2004103970A1

文献信息

• Optimization and Scale-Up of a Lipase-Catalyzed Enzymatic Resolution of an Indole Ester Intermediate for a Prostaglandin D₂ (DP) Receptor Antagonist Targeting Allergic Rhinitis
  作者：Matthew D. Truppo、Michel Journet、Ali Shafiee、Jeffrey C. Moore

  DOI：10.1021/op050261z

  日期：2006.5.1

  Pseudomonas fluorescens lipase was found to catalyze the asymmetric hydrolysis of racemic indole-ethyl ester 1.1 The lipase converted the undesired ( S) enantiomer to its corresponding acid, while leaving the desired ( R) enantiomer untouched, yielding optically enhanced (R)-ester with an ee of 95%(1) at 48% conversion. The original process conditions for this resolution contained a second-phase immiscible organic solvent to solubilize the substrate, and required 128 g/L enzyme for a 100 g/L substrate charge (Shafiee, A.; Upadhyay, V.; Corley, E.; Biba, M.; Zhao, D.; Marcoux, J.-F.; Campos, K.; Journet, M.; King, A.; Larsen, R.; Grabowski, E.; Volante, R.; Tillyer, R. Tetrahedron Asymmetry 2005, 16, 3094). A study of substrate solubility and phase-partitioning behavior in a wide range of miscible and immiscible solvent concentrations demonstrated that the presence of the immiscible organic solvent caused the reaction to reach a mass transfer limited regime at conversions > 40%. Process optimization led to the elimination of the second-phase immiscible organic solvent, a greater than 4-fold reduction in enzyme charge, and an increased product ee of > 99%. The optimized process has been demonstrated at scale on two 40-kg batches and has resulted in product ester ee of 99.75% at 50% conversion.