[1(R)-methyl-3-[(phenylmethyl)amino]propyl]carbamic acid, 1,1-dimethylethyl ester | 170367-70-1

• 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(R)-methyl-3-[(phenylmethyl)amino]propyl]carbamic acid, 1,1-dimethylethyl ester
• 英文别名: 3-(R)-tert-butoxycarbonylamino-N-benzylbutylamine；Carbamic acid, [(1R)-1-methyl-3-[(phenylmethyl)amino]propyl]-, 1,1-dimethylethyl ester；tert-butyl N-[(2R)-4-(benzylamino)butan-2-yl]carbamate
• CAS: 170367-70-1
• 化学式: C₁₆H₂₆N₂O₂
• 分子量: 278.395
• InChiKey: CCZUYJZXWSXNJJ-CYBMUJFWSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.8
• 重原子数：
  20
• 可旋转键数：
  8
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.56
• 拓扑面积：
  50.4
• 氢给体数：
  2
• 氢受体数：
  3

反应信息

• 作为反应物：
  描述：

  [1(R)-methyl-3-[(phenylmethyl)amino]propyl]carbamic acid, 1,1-dimethylethyl ester 在 镍 氨 、 氢气 、 sodium carbonate 、 potassium iodide 作用下， 以 乙醇 、 正丁醇 为溶剂， 20.0 ℃ 、600.0 kPa 条件下， 反应 35.0h， 生成 3-[(4-aminobutyl)(phenylmethyl)amino-1(R)-methylpropyl]carbamic acid, 1,1-dimethylethyl ester
  参考文献：
  名称：

  Structure−Immunosuppressive Activity Relationships of New Analogues of 15-Deoxyspergualin. 2. Structural Modifications of the Spermidine Moiety

  摘要：

  A series of new analogues of 15-deoxyspergualin (DSG), an immunosuppressive agent commercialized in Japan, was synthesized and tested in a graft-versus-host disease (GVHD) model in mice. Various substitutions of the spermidine "D" region were made in order to determine its optimum structure in terms of in vivo immunosuppressive activity. Various positions of methylation were first investigated leading to the discovery of the monomethylated malonic derivative 56h in which the pro-R hydrogen of the methylene a to the primary amine of the spermidine moiety has been replaced by a methyl group. Synthesis of the similarly methylated analogue of the previously reported glycolic derivative LF 08-0299 afforded 60e which demonstrated a powerful activity at a dose as low as 0.3 mg/kg in the GVHD model and was much more potent than DSG in the demanding heart allotransplantation model in rats. The improvement of in vivo activity was supposed to be related to an increase of the metabolic stability of the methylated analogues compared to the parent molecules. Due to its very low active dose, compatible with a subcutaneous administration in humans, and its favorable pharmacological and toxicological profile, 60e was selected as a candidate for clinical evaluation.

  DOI：

  10.1021/jm991043x
• 作为产物：
  描述：

  (R)-3-N-叔丁氧羰基氨基丁胺 在 sodium tetrahydroborate 、 3 A molecular sieve 作用下， 以 乙醚 、 乙醇 为溶剂， 反应 23.0h， 生成 [1(R)-methyl-3-[(phenylmethyl)amino]propyl]carbamic acid, 1,1-dimethylethyl ester
  参考文献：
  名称：

  Structure−Immunosuppressive Activity Relationships of New Analogues of 15-Deoxyspergualin. 2. Structural Modifications of the Spermidine Moiety

  摘要：

  A series of new analogues of 15-deoxyspergualin (DSG), an immunosuppressive agent commercialized in Japan, was synthesized and tested in a graft-versus-host disease (GVHD) model in mice. Various substitutions of the spermidine "D" region were made in order to determine its optimum structure in terms of in vivo immunosuppressive activity. Various positions of methylation were first investigated leading to the discovery of the monomethylated malonic derivative 56h in which the pro-R hydrogen of the methylene a to the primary amine of the spermidine moiety has been replaced by a methyl group. Synthesis of the similarly methylated analogue of the previously reported glycolic derivative LF 08-0299 afforded 60e which demonstrated a powerful activity at a dose as low as 0.3 mg/kg in the GVHD model and was much more potent than DSG in the demanding heart allotransplantation model in rats. The improvement of in vivo activity was supposed to be related to an increase of the metabolic stability of the methylated analogues compared to the parent molecules. Due to its very low active dose, compatible with a subcutaneous administration in humans, and its favorable pharmacological and toxicological profile, 60e was selected as a candidate for clinical evaluation.

  DOI：

  10.1021/jm991043x

文献信息

• 手性高哌嗪环的制备方法
  申请人：华润双鹤药业股份有限公司

  公开号：CN105367506B

  公开（公告）日：2021-02-05

  本发明涉及(R)‑I所示手性高哌嗪环化合物的制备方法，该方法包括还原式Int所示化合物，得到式(R)‑I所示化合物。本发明还涉及式Int所示的新的中间体化合物。(R)‑I所示手性高哌嗪环化合物是合成用于治疗睡眠障碍的药物Suvorexant的重要中间体。本发明的制备方法从起始原料即引入手性中心，在整个反应过程中，未采用会影响手性中心的反应和试剂，避免了手性拆分或手性催化剂等成本较高、收率较低的方法，工艺过程中无手性参与的反应，保证了产品的手性的纯度，仅使用常规的方法和设备，操作简单，条件温和，路线短，产率高，适合于工业化生产，