2-isobutyl-1-oxo-3-(thiophen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 异喹啉及其衍生物
• 英文名称: 2-isobutyl-1-oxo-3-(thiophen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid
• 英文别名: (3R*,4R*)-2-isobutyl-1-oxo-3-(thiophen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid；(3R,4R)-2-(2-methylpropyl)-1-oxo-3-thiophen-2-yl-3,4-dihydroisoquinoline-4-carboxylic acid
• 化学式: C₁₈H₁₉NO₃S
• 分子量: 329.42
• InChiKey: FLMAYNNKDFXEDI-CVEARBPZSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.77
• 重原子数：
  23.0
• 可旋转键数：
  4.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  57.61
• 氢给体数：
  1.0
• 氢受体数：
  3.0

反应信息

• 作为反应物：
  描述：

  2-isobutyl-1-oxo-3-(thiophen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid 、 3-三氟甲氧基苯胺 在 1-丙基磷酸酐 、 三乙胺 作用下， 以 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 16.0h， 生成
  参考文献：
  名称：

  Hit-to-Lead Studies for the Antimalarial Tetrahydroisoquinolone Carboxanilides

  摘要：

  Phenotypic whole-cell screening in erythrocytic cocultures of Plasmodium falciparum identified a series of dihydroisoquinolones that possessed potent antimalarial activity against multiple resistant strains of P. falciparum in vitro and show no cytotoxicity to mammalian cells. Systematic structure activity studies revealed relationships between potency and modifications at N-2, C-3, and C-4. Careful structure property relationship studies, coupled with studies of metabolism, addressed the poor aqueous solubility and metabolic vulnerability, as well as potential toxicological effects, inherent in the more potent primary screening hits such as 10b. Analogues 13h and 13i, with structural modifications at each site, were shown to possess excellent antimalarial activity in vivo. The (+)-(35,4S) enantiomer of 13i and similar analogues were identified as the more potent. On the basis of these studies, we have selected (+)-13i for further study as a preclinical candidate.

  DOI：

  10.1021/acs.jmedchem.6b00752
• 作为产物：
  描述：

  2-噻吩甲醛 在 溶剂黄146 作用下， 以 甲醇 为溶剂， 反应 20.0h， 生成 2-isobutyl-1-oxo-3-(thiophen-2-yl)-1,2,3,4-tetrahydroisoquinoline-4-carboxylic acid
  参考文献：
  名称：

  Hit-to-Lead Studies for the Antimalarial Tetrahydroisoquinolone Carboxanilides

  摘要：

  Phenotypic whole-cell screening in erythrocytic cocultures of Plasmodium falciparum identified a series of dihydroisoquinolones that possessed potent antimalarial activity against multiple resistant strains of P. falciparum in vitro and show no cytotoxicity to mammalian cells. Systematic structure activity studies revealed relationships between potency and modifications at N-2, C-3, and C-4. Careful structure property relationship studies, coupled with studies of metabolism, addressed the poor aqueous solubility and metabolic vulnerability, as well as potential toxicological effects, inherent in the more potent primary screening hits such as 10b. Analogues 13h and 13i, with structural modifications at each site, were shown to possess excellent antimalarial activity in vivo. The (+)-(35,4S) enantiomer of 13i and similar analogues were identified as the more potent. On the basis of these studies, we have selected (+)-13i for further study as a preclinical candidate.

  DOI：

  10.1021/acs.jmedchem.6b00752

文献信息

• <i>N</i>-Methylimidazole Promotes the Reaction of Homophthalic Anhydride with Imines
  作者：Jian Liu、Zheng Wang、Aaron Levin、Thomas J. Emge、Paul R. Rablen、David M. Floyd、Spencer Knapp

  DOI：10.1021/jo501316m

  日期：2014.8.15

  pyridine-3-carboxaldehyde-N-trifluoroethylimine (9) reduces the amount of elimination byproduct and improves the yield of the formal cycloadduct, tetrahydroisoquinolonic carboxylate 10. Carboxanilides of such compounds are of interest as potential antimalarial agents. A mechanism that rationalizes the role of NMI is proposed, and a gram-scale procedure for the synthesis and resolution of 10 is also described.

  将N-甲基咪唑 (NMI) 添加到同邻苯二甲酸酐与亚胺如吡啶-3-甲醛-N-三氟乙基亚胺( 9 ) 的反应中减少了消除副产物的量并提高了缩甲醛环加合物四氢异喹诺酮羧酸酯10的产率。这些化合物的羧酰苯胺作为潜在的抗疟剂是令人感兴趣的。提出了一种合理化 NMI 作用的机制，并描述了10的合成和分辨率的克级程序。
• Stereochemical Aspects of T3P Amidations
  作者：Zheng Wang、Robert D. Barrows、Thomas J. Emge、Spencer Knapp

  DOI：10.1021/acs.oprd.7b00046

  日期：2017.3.17

  Propanephosphonic acid anhydride (T3P) is a process-friendly commercial reagent that is useful for direct carboxamide formation from the carboxylic acid and amine components. For amidation reactions of certain tetrahydroisoquinolonic carboxylic acids and electron-poor anilines, the phosphonate carboxylate mixed anhydride intermediate evidently eliminates under basic conditions to give a ketene, whose

  丙膦酸酐（T3P）是一种易处理的商业试剂，可用于由羧酸和胺成分直接形成羧酰胺。对于某些四氢异喹啉代羧酸和贫电子苯胺的酰胺化反应，膦酸酯羧酸盐混合酸酐中间体在碱性条件下明显消除，得到乙烯酮，其加成反应又导致非对映异构酰胺产物的混合物。例如，用作碱的1,4-二氮杂双环[2,2,2]辛烷主要提供3,4-顺式产物，而N-甲基咪唑可有效地产生3,4-反式产物。提供了机理学原理以及有关中间烯酮的令人信服的证据，以及有效的T3P介导的羧酰胺作为活性抗疟疾药物的有效制备方法的几个实例。
• Hit-to-Lead Studies for the Antimalarial Tetrahydroisoquinolone Carboxanilides
  作者：David M. Floyd、Philip Stein、Zheng Wang、Jian Liu、Steve Castro、Julie A. Clark、Michele Connelly、Fangyi Zhu、Gloria Holbrook、Amy Matheny、Martina S. Sigal、Jaeki Min、Rajkumar Dhinakaran、Senthil Krishnan、Sridevi Bashyum、Spencer Knapp、R. Kiplin Guy

  DOI：10.1021/acs.jmedchem.6b00752

  日期：2016.9.8

  Phenotypic whole-cell screening in erythrocytic cocultures of Plasmodium falciparum identified a series of dihydroisoquinolones that possessed potent antimalarial activity against multiple resistant strains of P. falciparum in vitro and show no cytotoxicity to mammalian cells. Systematic structure activity studies revealed relationships between potency and modifications at N-2, C-3, and C-4. Careful structure property relationship studies, coupled with studies of metabolism, addressed the poor aqueous solubility and metabolic vulnerability, as well as potential toxicological effects, inherent in the more potent primary screening hits such as 10b. Analogues 13h and 13i, with structural modifications at each site, were shown to possess excellent antimalarial activity in vivo. The (+)-(35,4S) enantiomer of 13i and similar analogues were identified as the more potent. On the basis of these studies, we have selected (+)-13i for further study as a preclinical candidate.