1-benzyl 4-tert-butyl 5-methyl-1,4-diazepane-1,4-dicarboxylate | 1030377-24-2

• 分子结构分类: 有机化合物 - 苯类化合物 - 苯和取代衍生物
• 英文名称: 1-benzyl 4-tert-butyl 5-methyl-1,4-diazepane-1,4-dicarboxylate
• 英文别名: 1-O-benzyl 4-O-tert-butyl 5-methyl-1,4-diazepane-1,4-dicarboxylate
• CAS: 1030377-24-2
• 化学式: C₁₉H₂₈N₂O₄
• 分子量: 348.442
• InChiKey: XLSSEJRFMLKZQO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.1
• 重原子数：
  25
• 可旋转键数：
  5
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.58
• 拓扑面积：
  59.1
• 氢给体数：
  0
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  1-benzyl 4-tert-butyl 5-methyl-1,4-diazepane-1,4-dicarboxylate 在 N-甲基吗啉 、 盐酸 、 N-羟基-7-氮杂苯并三氮唑 、 20 wt.% Pd(OH)2 on activated carbon 、 氢气 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 甲醇 、 乙酸乙酯 、 N,N-二甲基甲酰胺 为溶剂， 20.0 ℃ 、101.33 kPa 条件下， 反应 46.0h， 生成 (7-methyl-1,4-diazepan-1-yl)(5-methyl-2-(2H-1,2,3-triazol-2-yl)phenyl)methanone
  参考文献：
  名称：

  使用2,2,6,6-四甲基哌啶-N-氧铵四氟硼酸铵作为有机氧化剂对苯并恶唑和1,3,4-恶二唑进行胺化

  摘要：

  没有过渡金属是必要通过正式直接C（2）使用-amination到tetramethylpiperidine-苯并恶唑和1,3,4-恶二唑转化成相应的药理学上感兴趣的2-胺化杂环Ñ -oxoammonium四氟硼酸盐（TEMPO + BF 4 - ），为氧化剂（参见方案; TEMP = 2,2,6,6-四甲基哌啶; TfOH =三氟甲磺酸）。

  DOI：

  10.1002/anie.201104735
• 作为产物：
  描述：

  5-甲基-1,4-二氮杂烷-1-羧酸苄酯 生成 1-benzyl 4-tert-butyl 5-methyl-1,4-diazepane-1,4-dicarboxylate
  参考文献：
  名称：

  Substituted diazepan orexin receptor antagonists

  摘要：

  本发明涉及替代二氮平化合物，其是促进素受体拮抗剂，可用于治疗或预防神经系统和精神疾病，以及其中促进素受体参与的疾病。本发明还涉及包含这些化合物的药物组合物以及这些化合物和组合物在预防或治疗促进素受体参与的疾病中的用途。

  公开号：

  US20080132490A1

文献信息

• [EN] CHIRAL RESOLUTION OF AN INTERMEDIATE OF SUVOREXANT AND COCRYSTALS THEREOF<br/>[FR] RÉSOLUTION CHIRALE D'UN INTERMÉDIAIRE DU SUVOREXANT ET CO-CRISTAUX CORRESPONDANTS
  申请人：ENANTIA S L

  公开号：WO2017211733A1

  公开（公告）日：2017-12-14

  Relating to processes for preparing suvorexant or its pharmaceutically acceptable salts through the formation of a cocrystal of (R)-benzyl 5-methyl-1,4-diazepane-1-carboxylate hydrochloridewith (R)-(+)-1,1,2-triphenyl-1,2-ethanediol ((R)-TED). This cocrystal provides the resolution of an intermediate of suvorexant, in particular, of(rac)-benzyl5-methyl-1,4-diazepane-1-carboxylateor a hydrochloride salt thereof. It also relates to a new cocrystal useful in such preparation processes.

  与通过(R)-苄基5-甲基-1,4-二氮杂环-1-羧酸盐与(R)-(+)-1,1,2-三苯基-1,2-乙二醇((R)-TED)的共晶形成来制备苏维雷沙或其药用可接受盐的过程相关。这种共晶提供了苏维雷沙的中间体的分离，特别是(rac)-苄基5-甲基-1,4-二氮杂环-1-羧酸盐或其盐酸盐。它还涉及一种在这种制备过程中有用的新共晶。
• Substituted diazepan orexin receptor antagonists
  申请人：Bergman Jeffrey M.

  公开号：US20080132490A1

  公开（公告）日：2008-06-05

  The present invention is directed to substituted diazepan compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

  本发明涉及替代二氮杂环丙烷化合物，其为促进睡眠蛋白受体的拮抗剂，可用于治疗或预防神经和精神疾病，以及涉及促进睡眠蛋白受体的疾病。该发明还涉及包含这些化合物的药物组合物，以及利用这些化合物和组合物在预防或治疗涉及促进睡眠蛋白受体的疾病中的用途。
• [EN] PROCESS FOR THE PREPARATION OF AN OREXIN RECEPTOR ANTAGONIST<br/>[FR] PROCÉDÉ DE PRÉPARATION D'UN ANTAGONISTE DES RÉCEPTEURS DES OREXINES
  申请人：MERCK SHARP & DOHME

  公开号：WO2012148553A1

  公开（公告）日：2012-11-01

  The present invention is directed to processes for preparing a diazepane compound which is an antagonist of orexin receptors, and which is useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The present invention is further directed to crystalline forms of this diazepane compound and pharmaceutical compositions thereof.

  本发明涉及制备一种二氮平化合物的方法，该化合物是促进睡眠的荷尔蒙受体的拮抗剂，可用于治疗或预防神经和精神疾病，以及涉及荷尔蒙受体的疾病。本发明还涉及该二氮平化合物的晶体形式及其制药组合物。
• Substituted diazepan compounds as orexin receptor antagonists
  申请人：Merck Sharp & Dohme Corp.

  公开号：EP2392572A1

  公开（公告）日：2011-12-07

  The present invention is directed to substituted diazepan compounds which are antagonists of orexin receptors, and which are useful in the treatment or prevention of neurological and psychiatric disorders and diseases in which orexin receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which orexin receptors are involved.

  本发明涉及取代的二氮杂环庚烷化合物，它们是奥曲肽受体的拮抗剂，可用于治疗或预防涉及奥曲肽受体的神经和精神紊乱及疾病。本发明还涉及包含这些化合物的药物组合物，以及这些化合物和组合物在预防或治疗涉及奥曲肽受体的此类疾病中的用途。
• Discovery of the Dual Orexin Receptor Antagonist [(7<i>R</i>)-4-(5-Chloro-1,3-benzoxazol-2-yl)-7-methyl-1,4-diazepan-1-yl][5-methyl-2-(2<i>H</i>-1,2,3-triazol-2-yl)phenyl]methanone (MK-4305) for the Treatment of Insomnia
  作者：Christopher D. Cox、Michael J. Breslin、David B. Whitman、John D. Schreier、Georgia B. McGaughey、Michael J. Bogusky、Anthony J. Roecker、Swati P. Mercer、Rodney A. Bednar、Wei Lemaire、Joseph G. Bruno、Duane R. Reiss、C. Meacham Harrell、Kathy L. Murphy、Susan L. Garson、Scott M. Doran、Thomayant Prueksaritanont、Wayne B. Anderson、Cuyue Tang、Shane Roller、Tamara D. Cabalu、Donghui Cui、George D. Hartman、Steven D. Young、Ken S. Koblan、Christopher J. Winrow、John J. Renger、Paul J. Coleman

  DOI：10.1021/jm100541c

  日期：2010.7.22

  Despite increased understanding of the biological basis for sleep control in the brain, few novel mechanisms for the treatment of insomnia have been identified in recent years. One notable exception is inhibition of the excitatory neuropeptides orexins A and B by design of orexin receptor antagonists. Herein, we describe how efforts to understand the origin of poor oral pharmacokinetics in a leading HTS-derived diazepane orexin receptor antagonist led to the identification of compound 10 with a 7-methyl substitution on the diazepane core. Though 10 displayed good potency, improved pharmacokinetics, and excellent in vivo efficacy, it formed reactive metabolites in microsomal incubations. A mechanistic hypothesis coupled with an in vitro assay to assess bioactivation led to replacement of the fluoroquina-zoline ring of 10 with a chlorobenzoxazole to provide 3 (MK-4305), a potent dual orexin receptor antagonist that is currently being tested in phase III clinical trials for the treatment of primary insomnia.