(2S,3R)-2-hydroxymethyl-3-p-tolyl-pyrrolidine-1-carboxylic acid tert-butyl ester | 1344158-17-3

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: (2S,3R)-2-hydroxymethyl-3-p-tolyl-pyrrolidine-1-carboxylic acid tert-butyl ester
• CAS: 1344158-17-3
• 化学式: C₁₇H₂₅NO₃
• 分子量: 291.39
• InChiKey: KNQVNVWAIXLNGQ-HUUCEWRRSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.08
• 重原子数：
  21.0
• 可旋转键数：
  2.0
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.59
• 拓扑面积：
  49.77
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  (2S,3R)-2-hydroxymethyl-3-p-tolyl-pyrrolidine-1-carboxylic acid tert-butyl ester 在 chromium(VI) oxide 、 硫酸 、 水 、 sodium carbonate 、 N,N-二异丙基乙胺 、 Methanaminium,N-[(dimethylamino)(3H-1,2,3-triazolo[4,5-b]pyridin-3-yloxy)methylene]-N-methyl-, hexafluorophosphate(1-) 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 水 、 N,N-二甲基甲酰胺 、 丙酮 为溶剂， 反应 44.75h， 生成 (S)-3-((S)-2-acetamido-3-methylbutanamido)-4-(((S)-1-((2S,3R)-2-(((3S)-2-hydroxy-5-oxotetrahydrofuran-3-yl)carbamoyl)-3-(p-tolyl)pyrrolidin-1-yl)-3-methyl-1-oxobutan-2-yl)amino)-4-oxobutanoic acid
  参考文献：
  名称：

  Exploiting differences in caspase-2 and -3 S2 subsites for selectivity: Structure-based design, solid-phase synthesis and in vitro activity of novel substrate-based caspase-2 inhibitors

  摘要：

  Several caspases have been implicated in the pathogenesis of Huntington's disease (HD); however, existing caspase inhibitors lack the selectivity required to investigate the specific involvement of individual caspases in the neuronal cell death associated with HD. In order to explore the potential role played by caspase-2, the potent but non-selective canonical Ac-VDVAD-CHO caspase-2 inhibitor 1 was rationally modified at the P-2 residue in an attempt to decrease its activity against caspase-3. With the aid of structural information on the caspase-2, and -3 active sites and molecular modeling, a 3-(S)-substituted-L-proline along with four additional scaffold variants were selected as P-2 elements for their predicted ability to clash sterically with a residue of the caspase-3 S-2 pocket. These elements were then incorporated by solid-phase synthesis into pentapeptide aldehydes 33a-v. Proline-based compound 33h bearing a bulky 3-(S)-substituent displayed advantageous characteristics in biochemical and cellular assays with 20- to 60-fold increased selectivity for caspase-2 and similar to 200-fold decreased caspase-3 potency compared to the reference inhibitor 1. Further optimization of this prototype compound may lead to the discovery of valuable pharmacological tools for the study of caspase-2 mediated cell death, particularly as it relates to HD. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.08.020
• 作为产物：
  描述：

  (2S,3R)-2-(tert-butyl-diphenyl-silanyloxymethyl)-5-oxo-3-p-tolyl-pyrrolidine-1-carboxylic acid tert-butyl ester 在 dimethyl sulfide borane 、 四丁基氟化铵 作用下， 以 四氢呋喃 为溶剂， 反应 25.0h， 生成 (2S,3R)-2-hydroxymethyl-3-p-tolyl-pyrrolidine-1-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  Exploiting differences in caspase-2 and -3 S2 subsites for selectivity: Structure-based design, solid-phase synthesis and in vitro activity of novel substrate-based caspase-2 inhibitors

  摘要：

  Several caspases have been implicated in the pathogenesis of Huntington's disease (HD); however, existing caspase inhibitors lack the selectivity required to investigate the specific involvement of individual caspases in the neuronal cell death associated with HD. In order to explore the potential role played by caspase-2, the potent but non-selective canonical Ac-VDVAD-CHO caspase-2 inhibitor 1 was rationally modified at the P-2 residue in an attempt to decrease its activity against caspase-3. With the aid of structural information on the caspase-2, and -3 active sites and molecular modeling, a 3-(S)-substituted-L-proline along with four additional scaffold variants were selected as P-2 elements for their predicted ability to clash sterically with a residue of the caspase-3 S-2 pocket. These elements were then incorporated by solid-phase synthesis into pentapeptide aldehydes 33a-v. Proline-based compound 33h bearing a bulky 3-(S)-substituent displayed advantageous characteristics in biochemical and cellular assays with 20- to 60-fold increased selectivity for caspase-2 and similar to 200-fold decreased caspase-3 potency compared to the reference inhibitor 1. Further optimization of this prototype compound may lead to the discovery of valuable pharmacological tools for the study of caspase-2 mediated cell death, particularly as it relates to HD. (C) 2011 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmc.2011.08.020

文献信息

• 一种合成(2S,3R)-3-取代苯基吡咯烷-2-羧酸 的中间体及其制备方法和应用
  申请人：浙江晖石药业有限公司

  公开号：CN110498808B

  公开（公告）日：2021-11-05

  本发明涉及一种(2S,3R)‑3‑取代苯基吡咯烷‑2‑羧酸的中间体及其制备方法和应用，主要解决目前(2S,3R)‑3‑取代苯基吡咯烷‑2‑羧酸没有适合工业化合成方法的技术问题。本发明以化合物II和卤代苯为原料，在有机金属试剂作用下，依次经过Michael加成反应、还原反应、脱苄基保护基反应、Boc保护反应、氧化和脱Boc保护基等反应步骤制备得到化合物I((2S,3R)‑3‑取代苯基吡咯烷‑2‑羧酸)。本方法操作方便，收率稳定，适合大规模生产。