6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one | 1354745-69-9

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: 6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one
• 英文别名: ELQ-316；6-fluoro-7-methoxy-2-methyl-3-[4-[4-(trifluoromethoxy)phenoxy]phenyl]-1H-quinolin-4-one
• CAS: 1354745-69-9
• 化学式: C₂₄H₁₇F₄NO₄
• 分子量: 459.397
• InChiKey: SUFFMIUELDDRLM-UHFFFAOYSA-N

物化性质

• 沸点：
  531.8±50.0 °C(Predicted)
• 密度：
  1.345±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  6.3
• 重原子数：
  33
• 可旋转键数：
  5
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.12
• 拓扑面积：
  56.8
• 氢给体数：
  1
• 氢受体数：
  9

反应信息

• 作为反应物：
  描述：

  6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one 在 三氯氧磷 作用下， 以91 %的产率得到4-chloro-6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinoline
  参考文献：
  名称：

  Synthesis of Deuterated Endochin‐Like Quinolones

  摘要：

  Malaria continues to be a serious and debilitating disease. The emergence and spread of high‐level resistance to multiple antimalarial drugs by Plasmodium falciparum has brought about an urgent need for new treatments that will be active against multidrug resistant malaria infections. One such treatment, ELQ‐331 (MMV‐167), an alkoxy carbonate prodrug of 4(1H)‐quinolone ELQ‐300, is currently in preclinical development with the Medicines for Malaria Venture. Clinical development of ELQ‐331 or similar compounds will require the availability of isotopically labeled analogs. Unfortunately, a suitable method for the deuteration of these important compounds was not found in the literature. Here, we describe a facile and scalable method for the deuteration of 4(1H)‐quinolone ELQ‐300, its alkoxycarbonate prodrug ELQ‐331, and their respective N‐oxides using deuterated acetic acid.

  DOI：

  10.1002/jlcr.4092
• 作为产物：
  描述：

  6-fluoro-3-iodo-7-methoxy-2-methylquinolin-4(1H)-one 在 四(三苯基膦)钯 、 氢溴酸 、 potassium carbonate 、 溶剂黄146 作用下， 以 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 50.5h， 生成 6-fluoro-7-methoxy-2-methyl-3-(4-(4-(trifluoromethoxy)phenoxy)phenyl)quinolin-4(1H)-one
  参考文献：
  名称：

  Discovery, Synthesis, and Optimization of Antimalarial 4(1H)-Quinolone-3-Diarylethers

  摘要：

  The historical antimalarial compound endochin served as a structural lead for optimization. Endochin-like quinolones (ELQ) were prepared by a novel chemical route and assessed for in vitro activity against multidrug resistant strains of Plasmodium falciparum and against malaria infections in mice. Here we describe the pathway to discovery of a potent class of orally active antimalarial 4(1H)-quinolone-3-diarylethers. The initial prototype, ELQ-233, exhibited low nanomolar IC50 values against all tested strains including clinical isolates harboring resistance to atovaquone. ELQ-271 represented the next critical step in the iterative optimization process, as it was stable to metabolism and highly effective in vivo. Continued analoging revealed that the substitution pattern on the benzenoid ring of the quinolone core significantly influenced reactivity with the host enzyme. This finding led to the rational design of highly selective ELQs with outstanding oral efficacy against murine malaria that is superior to established antimalarials chloroquine and atovaquone.

  DOI：

  10.1021/jm500147k

文献信息

• New Scalable Synthetic Routes to <b>ELQ-300</b>, <b>ELQ-316</b>, and Other Antiparasitic Quinolones
  作者：Sovitj Pou、Rozalia A. Dodean、Lisa Frueh、Katherine M. Liebman、Rory T. Gallagher、Haihong Jin、Robert T. Jacobs、Aaron Nilsen、David R. Stuart、J. Stone Doggett、Michael K. Riscoe、Rolf W. Winter

  DOI：10.1021/acs.oprd.1c00099

  日期：2021.8.20

  series, a synthetic route needed to be devised, which would lower costs and be amenable to large-scale production. In the new synthetic route described here, a substituted β-keto ester, formed by an Ullmann reaction and subsequent acylation, is reacted with an aniline via a Conrad–Limpach reaction to produce 3-substituted 4(1H)-quinolones such as ELQ-300 and ELQ-316. This synthetic route, the first

  内啡肽样喹诺酮 (ELQ) 化合物类可以为一系列重要的人类和动物疾病提供有效、安全的治疗方法。然而，为了获得该化合物系列的公共卫生潜力，需要设计一种合成路线，该路线将降低成本并适合大规模生产。在这里描述的新合成路线中，通过 Ullmann 反应和随后的酰化形成取代的 β-酮酯，通过 Conrad-Limpach 反应与苯胺反应生成 3-取代的 4( 1H )-喹诺酮类，例如ELQ -300和ELQ-316. 该合成路线首次被描述为真正适合工业规模生产，相对较短（五个反应步骤），不需要钯、色谱分离或保护基化学，并且可以在没有高真空蒸馏的情况下进行。
• [EN] NOVEL INTERMEDIATES AND SYNTHESIS FOR ENDOCHIN-LIKE QUINOLONE COMPOUNDS<br/>[FR] NOUVEAUX INTERMÉDIAIRES ET SYNTHÈSE POUR DES COMPOSÉS DE QUINOLONE DE TYPE ENDOCHINE
  申请人：UNIV OREGON HEALTH & SCIENCE

  公开号：WO2021231335A1

  公开（公告）日：2021-11-18

  The present invention provides synthetic methods and novel intermediates in the preparation of 3-aryl Endochin-like quinolone (ELQ) compounds.

  本发明提供了一种合成方法和新型中间体，用于制备3-芳基内奎诺酮（ELQ）化合物。
• [EN] QUINOLONE-3-DIARYLETHERS<br/>[FR] QUINOLONE-3-DIARYLÉTHERS
  申请人：UNIV OREGON HEALTH & SCIENCE

  公开号：WO2017015360A1

  公开（公告）日：2017-01-26

  Disclosed are derivative compounds of ELQ-300 that include an ester at position 4. These compounds have enhanced properties relative to ELQ-300. Also disclosed are pharmaceutical compositions comprising the compounds and methods of treating and preventing malaria infections involving administering the pharmaceutical compositions to the subject.

  揭示了ELQ-300的衍生化合物，其中在位置4处包含酯基。这些化合物相对于ELQ-300具有增强的性质。还揭示了包括这些化合物的药物组合物以及治疗和预防涉及向受试者施用这些药物组合物的疟疾感染的方法。
• Orally Bioavailable Endochin-Like Quinolone Carbonate Ester Prodrug Reduces Toxoplasma gondii Brain Cysts
  作者：J. Stone Doggett、Tracey Schultz、Alyssa J. Miller、Igor Bruzual、Sovitj Pou、Rolf Winter、Rozalia Dodean、Lev N. Zakharov、Aaron Nilsen、Michael K. Riscoe、Vern B. Carruthers

  DOI：10.1128/aac.00535-20

  日期：2020.8.20

  for T. gondii cytochrome b over human cytochrome b. Despite its oral efficacy, the high crystallinity of ELQ-316 limits oral absorption, plasma concentrations, and therapeutic potential. A carbonate ester prodrug of ELQ-316, ELQ-334, was created to decrease crystallinity and increase oral bioavailability, which resulted in a 6-fold increase in both the maximum plasma concentration (Cmax) and the area

  弓形虫病对免疫功能低下的人和发育中的胎儿来说是一种潜在的致命感染。目前治疗弓形虫病的药物具有很高的不良反应率，会干扰治疗和预防方案。内啡肽样喹诺酮类药物 (ELQ)在体外和急性和潜伏感染动物模型中是刚地弓形虫增殖的有效抑制剂。特别是 ELQ-316 被发现对小鼠急性弓形虫病有效，并且对弓形虫细胞色素b的选择性高于人类细胞色素b. 尽管具有口服功效，但 ELQ-316 的高结晶度限制了口服吸收、血浆浓度和治疗潜力。创建 ELQ-316 的碳酸酯前药 ELQ-334 以降低结晶度并增加口服生物利用度，这导致最大血浆浓度 ( C max) 和 ELQ-316 的曲线下面积 (AUC)。当作为 ELQ-334 给药时，ELQ-316 增加的生物利用度导致对急性弓形虫病的疗效大于等效剂量的 ELQ-316，并且对潜伏弓形虫病的疗效与腹膜内给药的 ELQ-316 相似。用碳酸酯前药治疗是克服 ELQ
• [EN] SYNTHESIS OF ENDOCHIN-LIKE QUINOLONES<br/>[FR] SYNTHÈSE DE QUINOLONES DE TYPE ENDOCHINE
  申请人：UNIV OREGON HEALTH & SCIENCE

  公开号：WO2022197979A1

  公开（公告）日：2022-09-22

  Described herein are new synthetic routes for production of Endochin-Like Quinolone (ELQ) compounds. Synthetic routes to 3-substituted 4(1H)-quinolones are presented that are amenable to industrial scale preparation. One herein presented approach is relatively short, does not require palladium, and involves no chromatographic separation. A second herein presented approach is similarly relatively short, does not require palladium, involves no chromatographic separation, and also avoids high vacuum distillation. Additionally, both approaches require no protecting group chemistry because the insoluble 4(1H)-quinolone is not formed until the final reaction step.

  本文介绍了新的合成路线，用于生产类内酰胺类喹啉酮（ELQ）化合物。介绍了适用于工业规模制备的3-取代4（1H）-喹啉酮的合成路线。其中一个方法相对较短，不需要钯，并且不涉及色谱分离。另一个方法同样相对较短，不需要钯，也不涉及色谱分离，并且避免了高真空蒸馏。此外，这两种方法都不需要保护基化学，因为不溶性的4（1H）-喹啉酮直到最后的反应步骤才形成。