2(2R)-methyl-[1,3'(3'R)]bipyrrolidinyl dihydrochloride

• 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: 2(2R)-methyl-[1,3'(3'R)]bipyrrolidinyl dihydrochloride
• 英文别名: (2R,3'R)-2-methyl-[1,3']bipyrrolidinyl dihydrochloride；(2R)-2-methyl-1-[(3R)-pyrrolidin-3-yl]pyrrolidine;hydrochloride
• 化学式: C₉H₁₈N₂*2ClH
• 分子量: 227.177
• InChiKey: GHRAFEBOJNAWNT-VTLYIQCISA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.25
• 重原子数：
  12
• 可旋转键数：
  1
• 环数：
  2.0
• sp3杂化的碳原子比例：
  1.0
• 拓扑面积：
  15.3
• 氢给体数：
  2
• 氢受体数：
  2

反应信息

• 作为反应物：
  描述：

  2(2R)-methyl-[1,3'(3'R)]bipyrrolidinyl dihydrochloride 在 N-甲基吗啉 、 palladium 10% on activated carbon 、 氢气 、 potassium carbonate 、 1-羟基苯并三唑 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 甲醇 、 二氯甲烷 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 4.0h， 生成 (2R,3'R)-5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3']bipyrrolidinyl-1'-yl) phenyl]benzamide
  参考文献：
  名称：

  Synthesis, characterization, and biological assessment of the four stereoisomers of the H3 receptor antagonist 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3′]bipyrrolidinyl-1′-yl)phenyl]benzamide

  摘要：

  This Letter describes the asymmetric synthesis of the four stereoisomers (8a-8d) of a potent and highly selective histamine H-3 receptor (H3R) antagonist, 5-fluoro-2-methyl-N-[2-methyl-4-(2methyl[1,3']bipyrrolidinyl-1'-yl)phenyl]benzamide (1). The physico-chemical properties, in vitro H3R affinities and ADME of 8a-8d were determined. Stereoisomer 8c (2S, 3'S) displayed superior in vitro H3R affinity over other three stereoisomers and was selected for further profiling in in vivo PK and drug safety. Compound 8c exhibited excellent PK properties with high exposure, desired brain to plasma ratio and reasonable brain half life. However, all stereoisomers showed similar unwanted hERG affinities. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.05.068
• 作为产物：
  描述：

  2-(2R)-methyl-[1,3'(3'R)]bipyrrolidinyl-1'-carboxylic acid tert-butyl ester 在 盐酸 作用下， 以 1,4-二氧六环 为溶剂， 以100%的产率得到2(2R)-methyl-[1,3'(3'R)]bipyrrolidinyl dihydrochloride
  参考文献：
  名称：

  Synthesis, characterization, and biological assessment of the four stereoisomers of the H3 receptor antagonist 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3′]bipyrrolidinyl-1′-yl)phenyl]benzamide

  摘要：

  This Letter describes the asymmetric synthesis of the four stereoisomers (8a-8d) of a potent and highly selective histamine H-3 receptor (H3R) antagonist, 5-fluoro-2-methyl-N-[2-methyl-4-(2methyl[1,3']bipyrrolidinyl-1'-yl)phenyl]benzamide (1). The physico-chemical properties, in vitro H3R affinities and ADME of 8a-8d were determined. Stereoisomer 8c (2S, 3'S) displayed superior in vitro H3R affinity over other three stereoisomers and was selected for further profiling in in vivo PK and drug safety. Compound 8c exhibited excellent PK properties with high exposure, desired brain to plasma ratio and reasonable brain half life. However, all stereoisomers showed similar unwanted hERG affinities. (C) 2013 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2013.05.068

文献信息

• Synthesis, characterization, and biological assessment of the four stereoisomers of the H3 receptor antagonist 5-fluoro-2-methyl-N-[2-methyl-4-(2-methyl[1,3′]bipyrrolidinyl-1′-yl)phenyl]benzamide
  作者：Zhongli Gao、William J. Hurst、Etienne Guillot、Raisa Nagorny、Marie-Pierre Pruniaux、James A. Hendrix、Pascal G. George

  DOI：10.1016/j.bmcl.2013.05.068

  日期：2013.7

  This Letter describes the asymmetric synthesis of the four stereoisomers (8a-8d) of a potent and highly selective histamine H-3 receptor (H3R) antagonist, 5-fluoro-2-methyl-N-[2-methyl-4-(2methyl[1,3']bipyrrolidinyl-1'-yl)phenyl]benzamide (1). The physico-chemical properties, in vitro H3R affinities and ADME of 8a-8d were determined. Stereoisomer 8c (2S, 3'S) displayed superior in vitro H3R affinity over other three stereoisomers and was selected for further profiling in in vivo PK and drug safety. Compound 8c exhibited excellent PK properties with high exposure, desired brain to plasma ratio and reasonable brain half life. However, all stereoisomers showed similar unwanted hERG affinities. (C) 2013 Elsevier Ltd. All rights reserved.