4-cyclobutyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂卓
• 英文名称: 4-cyclobutyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester
• 英文别名: tert-butyl 4-(cyclobutyl)-hexahydro-1H-1,4-diazepine-1-carboxylate；N-Boc-N'-cyclobutyl-homopiperazine；1-tert-butyl-4-(cyclobutyl)-hexahydro-1H-1,4-diazepine-1-carboxylate；tert-butyl 4-cyclobutyl-1,4-diazepane-1-carboxylate
• 化学式: C₁₄H₂₆N₂O₂
• 分子量: 254.373
• InChiKey: NWPZHAZJADHBJO-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.2
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.93
• 拓扑面积：
  32.8
• 氢给体数：
  0
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  4-cyclobutyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester 在 盐酸 、 caesium carbonate 、 sodium hydroxide 作用下， 以 1,4-二氧六环 、 甲醇 、 N,N-二甲基乙酰胺 、 醋酸异丙酯 为溶剂， 反应 30.5h， 生成 (4-cyclobutyl-1,4-diazepan-1-yl)[6-(4-fluorophenoxy)pyridin-3-yl]methanone
  参考文献：
  名称：

  First, Second, and Third Generation Scalable Syntheses of Two Potent H₃ Antagonists

  摘要：

  Our teams have recently completed scale-up campaigns for two structurally similar H-3 receptor antagonists. The first and second generation processes were developed for the synthesis of 107 and 125 g batches of (4-cyclobutyl-1,4-diazepan-1-yl)(6-(4-fluorophenoxy)pyridin-3-yl)methanone center dot HCl (1 center dot HCl). A third generation process was utilized for production of 104 g of 3-((5-(4-cyclobutyl-1,4-diazepane-1-carbonyl)pyridin-2-yl)oxy)benzonitrile center dot HCl (2 center dot HCl). The evolution from first to second generation process was driven by a desire to minimize cost of goods through employment of symmetrical homopiperazine rather than a more expensive monoprotected variant. Project demands for a late stage intermediate that could provide 1 or 2 led to additional route scouting and the ultimate determination of a third scalable synthesis for these types of molecules. The use of a lithium alkoxide for Lewis base catalysis of an ester to amide transformation represents a key improvement for the third generation synthesis.

  DOI：

  10.1021/op200005e
• 作为产物：
  描述：

  环丁酮 、 1,4-二氮杂环庚烷-1-甲酸叔丁酯 在 sodium tetrahydroborate 作用下， 以 2-甲基四氢呋喃 为溶剂， 反应 27.0h， 以100%的产率得到4-cyclobutyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester
  参考文献：
  名称：

  组胺H 3受体拮抗剂的合成-羟脯氨酸立体化学的处理，高哌嗪的不对称化和非萃取性三乙酰氧基硼氢化钠反应后处理

  摘要：

  我们最近完成了羟基脯氨酸1- [2-（4-环丁基-[1,4]二氮杂-1-羰基）-4-（3-氟-苯氧基）-吡咯烷-1-基]-乙酮的合成的H 3受体拮抗剂，量为100 g。合成过程通过四个步骤进行，并且路线选择是由将商品成本降至最低的愿望所驱动的。选择天然存在的反式-4-羟基-L-脯氨酸作为靶标核心的前体，这需要在两个立体发生中心进行反转。通过策略性使用La Rosa的内酯和后期的Mitsunobu反应来完成反演。使用N的第一代合成-Boc-高哌嗪在第二代方法中得到了改进，其中高哌嗪直接去对称。最后，关键中间体的水溶性使得必须开发用于三乙酰氧基硼氢化钠还原的非萃取性后处理。

  DOI：

  10.1021/jo100629z

文献信息

• [EN] AZETIDINES AND CYCLOBUTANES AS HISTAMINE H3 RECEPTOR ANTAGONISTS<br/>[FR] AZÉTIDINES ET CYCLOBUTANES COMME ANTAGONISTES DES RÉCEPTEURS H3 DE L'HISTAMINE
  申请人：EVOTEC NEUROSCIENCES GMBH

  公开号：WO2009135842A1

  公开（公告）日：2009-11-12

  The invention relates to compounds of formula (I) wherein R, R0, R1, m, n and X1 to X4 have the meaning as cited in the description and the claims. Said compounds are useful as Histamine H3 receptor antagonists. The invention also relates to pharmaceutical compositions, the preparation of such compounds as well as the production and use as medicament.

  本发明涉及具有式(I)的化合物，其中R，R0，R1，m，n和X1至X4如描述和权利要求中所引述的含义。所述化合物作为组胺H3受体拮抗剂是有用的。本发明还涉及药物组合物，以及此类化合物的制备以及作为药品的生产和使用。
• [EN] NOVEL COMPOUNDS<br/>[FR] DERIVES DE DIAZEPINE 1-BENZOYLE SUBSTITUES EN TANT QU'AGONISTES DE RECEPTEUR D'HISTAMINE SELECTIVE H3
  申请人：GLAXO GROUP LTD

  公开号：WO2005040144A1

  公开（公告）日：2005-05-06

  The present invention relates to novel diazepanyl derivatives of formula (I) having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurological and psychiatric disorders.

  本发明涉及具有药理活性的新型二氮杂环庚基衍生物（I）的公式，其制备方法，含有它们的组合物以及它们在治疗神经和精神障碍中的用途。
• [EN] PYRROLIDINE DERIVATIVES AS HISTAMINE RECEPTORS LIGANDS<br/>[FR] LIGANDS DE RECEPTEURS HISTAMINIQUES A BASE DE DERIVES PYRROLIDINIQUES
  申请人：GLAXO GROUP LTD

  公开号：WO2006040192A1

  公开（公告）日：2006-04-20

  The present invention relates to pyrrolidine derivatives of formula (I) having pharmacological activity, processes for their preparation, to compositions containing them and to their use in the treatment of neurological and psychiatric disorders.

  本发明涉及具有药理活性的吡咯烷衍生物公式(I)，它们的制备方法，含有它们的组合物及其在治疗神经和精神障碍中的用途。
• Spirocyclobutyl Piperidine Derivatives
  申请人：Bernstein Peter

  公开号：US20100130477A1

  公开（公告）日：2010-05-27

  Disclosed herein is at least one spirocyclobutyl piperidine derivative, at least one pharmaceutical composition comprising at least one spirocyclobutyl piperidine derivative disclosed herein, and at least one method of using at least one spirocyclobutyl piperidine derivative disclosed herein for treating at least one histamine H3 receptor associated condition therewith.

  披露至少一种螺环环丁基哌啶衍生物，至少一种包含本文披露的至少一种螺环环丁基哌啶衍生物的药物组合物，以及至少一种使用本文披露的至少一种螺环环丁基哌啶衍生物治疗至少一种组胺H3受体相关状况的方法。
• [EN] DIAZEPANES AS HISTAMINE H3 RECEPTOR ANTAGONISTS<br/>[FR] DIAZÉPANES, ANTAGONISTES DU RÉCEPTEUR H3 DE L'HISTAMINE
  申请人：EVOTEC NEUROSCIENCES GMBH

  公开号：WO2009095394A1

  公开（公告）日：2009-08-06

  The invention relates to compounds of formula (I) wherein R1 to R8 and X1, X2 have the meaning as cited in the description and the claims. Said compounds are useful as Histamine H3 receptor antagonists. The invention also relates to pharmaceutical compositions, the preparation of such compounds as well as the production and use as medicament.

  该发明涉及式(I)的化合物，其中R1至R8和X1、X2的含义如描述和权利要求中所述。所述化合物可用作组胺H3受体拮抗剂。该发明还涉及制药组合物，制备此类化合物以及作为药物的生产和使用。