ethyl c-(1,3-benzodioxol-5-yl)-r-2-(4-methoxyphenyl)pyrrolidine-t-3-carboxylate | 403614-48-2

• 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: ethyl c-(1,3-benzodioxol-5-yl)-r-2-(4-methoxyphenyl)pyrrolidine-t-3-carboxylate
• 英文别名: 2293Fyc2PW；ethyl (2S,3S,4R)-4-(1,3-benzodioxol-5-yl)-2-(4-methoxyphenyl)pyrrolidine-3-carboxylate
• CAS: 403614-48-2
• 化学式: C₂₁H₂₃NO₅
• 分子量: 369.417
• InChiKey: SUCOGDSEXBRYSF-FFZOFVMBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  27
• 可旋转键数：
  6
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  66
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  ethyl c-(1,3-benzodioxol-5-yl)-r-2-(4-methoxyphenyl)pyrrolidine-t-3-carboxylate 在 盐酸 、 lithium hydroxide 、 sodium hydroxide 、 正丁基锂 、 双氧水 、 三甲基乙酰氯 、 三乙胺 、 N,N-二异丙基乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 乙腈 为溶剂， 反应 1.5h， 生成 阿曲生坦
  参考文献：
  名称：

  2,4-Diarylpyrrolidine-3-carboxylic AcidsPotent ET_A Selective Endothelin Receptor Antagonists. 1. Discovery of A-127722

  摘要：

  We have discovered a novel class of endothelin (ET) receptor antagonists through pharmacophore analysis of the existing non-peptide ET antagonists. On the basis of this analysis, we determined that a pyrrolidine ring might replace the indan ring in SE 209670. The resultant compounds were readily prepared and amenable to extensive SAR studies. Thus a series of N-substituted trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl) pyrrolidine-3-carboxylic acids (8) have been synthesized and evaluated for binding at ET(A) and ET(B) receptors. Compounds with N-acyl and simple N-alkyl substituents had weak activity. Compounds with N-alkyl substituents containing ethers, sulfoxides, or sulfones showed increased activity. Much improved activity resulted from compounds where the N-substituents were acetamides. Compound 17u (A-127722) with the N,N-dibutylacetamide substituent is the best of the series. It has an IC50 = 0.36 nM for inhibition of ET-1 radioligand binding at the ETA(A) receptor, with a 1000-fold selectivity for the ET(A) vs the ET(B) receptor. It is also a potent inhibitor (IC50 = 0.16 nM) of phosphoinositol hydrolysis stimulated by ET-1, and it antagonized the ET-l-induced contraction of the rabbit aorta with a pA(2) = 9.20. The compound has 70% oral bioavailability in rats.

  DOI：

  10.1021/jm9505369
• 作为产物：
  描述：

  4-溴-1,2-亚甲二氧基苯 在 palladium on activated charcoal 氢气 、 叔丁基锂 、 三氟乙酸 作用下， 以 四氢呋喃 、 乙醇 、 二氯甲烷 、 乙酸乙酯 、 正戊烷 为溶剂， 反应 74.5h， 生成 ethyl c-(1,3-benzodioxol-5-yl)-r-2-(4-methoxyphenyl)pyrrolidine-t-3-carboxylate
  参考文献：
  名称：

  通过 1,2-恶嗪对映选择性合成内皮素拮抗剂 ABT-627（Atrasentan）的吡咯烷核心

  摘要：

  介绍了内皮素拮抗剂 ABT-627 (Atrasentan) 的吡咯烷核心 6a 的非对映选择性合成，作为外消旋混合物或对映体纯化合物。这些合成的关键步骤是利用 1,3-苯并二氧杂环己烷-5-基锂与外消旋 6H-1,2-恶嗪 3 或对映体纯 6H-1,2-恶嗪 7 或 8 的高度非对映选择性共轭加成，然后用乙基捕获氰基甲酸酯（曼德试剂）。得到的 5,6-二氢-4H-1,2-恶嗪转化为 2,3,4-三取代的吡咯烷 6a。(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)

  DOI：

  10.1002/ejoc.200300234

文献信息

• Enantioselective Michael Reactions of Chiral Secondary Enaminoesters with 2-Substituted Nitroethylenes. Syntheses of <i>trans,trans</i>-2,4-Disubstituted Pyrrolidine-3-carboxylates
  作者：Gilbert Revial、Sethy Lim、Bernard Viossat、Pascale Lemoine、Alain Tomas、Arthur F. Duprat、Michel Pfau

  DOI：10.1021/jo000206i

  日期：2000.7.1

  The Michael reaction of chiral 3-substituted secondary enaminoesters with 2-substituted nitroethylenes leads to (Z)-adducts, with good to excellent diastereoselectivity. The nitro group of these adducts was catalytically reduced to give, after cyclization and chiral amine elimination, pyrrolines or pyrrolidines after further reduction. In particular, the syntheses of ethyl (2R,3S,4S)-2,4-dimethylp

  手性3-取代的仲烯氨基酯与2-取代的硝基乙烯的迈克尔反应导致（Z）-加合物，具有良好至优异的非对映选择性。这些加合物的硝基被催化还原，在环化和手性胺消除后，进一步还原后得到吡咯啉或吡咯烷。特别是（2R，3S，4S）-2,4-二甲基吡咯烷-3-羧酸乙酯和（2R，3R，4S）-2-（4-甲氧基苯基）-4-（3,4-（描述了亚甲基二氧基）苯基）吡咯烷-3-羧酸酯。
• Enantioselective Synthesis of the Pyrrolidine Core of Endothelin Antagonist ABT-627 (Atrasentan) via 1,2-Oxazines
  作者：Monika Buchholz、Hans-Ulrich Reißig

  DOI：10.1002/ejoc.200300234

  日期：2003.9

  Diastereoselective syntheses of the pyrrolidine core 6a of the endothelin antagonist ABT-627 (Atrasentan) either as a racemic mixture or as an enantiopure compound are presented. The crucial steps of these syntheses utilized the highly diastereoselective conjugate addition of 1,3-benzodioxol-5-yllithium to racemic 6H-1,2-oxazine 3 or enantiopure 6H-1,2-oxazines 7 or 8, followed by trapping with ethyl

  介绍了内皮素拮抗剂 ABT-627 (Atrasentan) 的吡咯烷核心 6a 的非对映选择性合成，作为外消旋混合物或对映体纯化合物。这些合成的关键步骤是利用 1,3-苯并二氧杂环己烷-5-基锂与外消旋 6H-1,2-恶嗪 3 或对映体纯 6H-1,2-恶嗪 7 或 8 的高度非对映选择性共轭加成，然后用乙基捕获氰基甲酸酯（曼德试剂）。得到的 5,6-二氢-4H-1,2-恶嗪转化为 2,3,4-三取代的吡咯烷 6a。(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2003)
• 2,4-Diarylpyrrolidine-3-carboxylic AcidsPotent ET_A Selective Endothelin Receptor Antagonists. 1. Discovery of A-127722
  作者：Martin Winn、Thomas W. von Geldern、Terry J. Opgenorth、Hwan-Soo Jae、Andrew S. Tasker、Steven A. Boyd、Jeffrey A. Kester、Robert A. Mantei、Radhika Bal、Bryan K. Sorensen、Jinshyun R. Wu-Wong、William J. Chiou、Douglas B. Dixon、Eugene I. Novosad、Lisa Hernandez、Kennan C. Marsh

  DOI：10.1021/jm9505369

  日期：1996.1.1

  We have discovered a novel class of endothelin (ET) receptor antagonists through pharmacophore analysis of the existing non-peptide ET antagonists. On the basis of this analysis, we determined that a pyrrolidine ring might replace the indan ring in SE 209670. The resultant compounds were readily prepared and amenable to extensive SAR studies. Thus a series of N-substituted trans,trans-2-(4-methoxyphenyl)-4-(1,3-benzodioxol-5-yl) pyrrolidine-3-carboxylic acids (8) have been synthesized and evaluated for binding at ET(A) and ET(B) receptors. Compounds with N-acyl and simple N-alkyl substituents had weak activity. Compounds with N-alkyl substituents containing ethers, sulfoxides, or sulfones showed increased activity. Much improved activity resulted from compounds where the N-substituents were acetamides. Compound 17u (A-127722) with the N,N-dibutylacetamide substituent is the best of the series. It has an IC50 = 0.36 nM for inhibition of ET-1 radioligand binding at the ETA(A) receptor, with a 1000-fold selectivity for the ET(A) vs the ET(B) receptor. It is also a potent inhibitor (IC50 = 0.16 nM) of phosphoinositol hydrolysis stimulated by ET-1, and it antagonized the ET-l-induced contraction of the rabbit aorta with a pA(2) = 9.20. The compound has 70% oral bioavailability in rats.