他达那非杂质B | 951661-82-8

• 分子结构分类: 有机化合物 - 生物碱及其衍生物 - 哈马拉生物碱
• 中文名称: 他达那非杂质B
• 英文名称: (1R,3R)-1-(benzo[d][1,3]dioxol-5-yl)-N-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide
• 英文别名: (1R,3R)-1-(1,3-benzodioxol-5-yl)-N-methyl-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide
• CAS: 951661-82-8
• 化学式: C₂₀H₁₉N₃O₃
• 分子量: 349.389
• InChiKey: QWRJNDUNSMFZTP-CRAIPNDOSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.4
• 重原子数：
  26
• 可旋转键数：
  2
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  75.4
• 氢给体数：
  3
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  他达那非杂质B 在 lithium aluminium tetrahydride 作用下， 以 四氢呋喃 为溶剂， 反应 24.0h， 以37%的产率得到(+/-) cis-[1-(1,3-benzodioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-yl]-N-methylmethanamine
  参考文献：
  名称：

  The Discovery of Tadalafil:  A Novel and Highly Selective PDE5 Inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1‘,2‘:1,6]pyrido[3,4-b]indole-1,4-dione Analogues

  摘要：

  Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC50 = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1.12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/> 7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).

  DOI：

  10.1021/jm0300577
• 作为产物：
  描述：

  (R)-2-Amino-5-oxo-pentanoic acid 在 aluminum oxide 、 溶剂黄146 、 N,N'-二环己基碳二亚胺 、 三氟乙酸 作用下， 以 乙醇 、 二氯甲烷 、 乙腈 为溶剂， 反应 18.5h， 生成 他达那非杂质B
  参考文献：
  名称：

  一种他达拉非制备方法

  摘要：

  本发明公开了一种他达拉非制备方法。该方法采用化合物Ⅰ为起始物料，先后经过缩合、Fisher吲哚合成反应、Pictet‑Spengler反应、酰化与关环五步反应得到他达拉非，关环时不使用危险性试剂(正丁基锂等)。该反应路线简单，且反应条件温和，纯度高，成本相对较低，操作简便，易于工业化生产。

  公开号：

  CN114213414A

文献信息

• WO2007/110734
  申请人：——

  公开号：——

  公开（公告）日：——
• [EN] PROCESS FOR THE PREPARATION OF TADALAFIL<br/>[FR] PROCEDE DE PREPARATION DE TADALAFIL
  申请人：GLENMARK PHARMACEUTICALS LTD

  公开号：WO2007110734A1

  公开（公告）日：2007-10-04

  [EN] The present invention provides novel intermediates of tadalafil and processes for their preparation. The present invention also provides for the preparation of tadalafil or a pharmaceutically acceptable salt or solvate thereof using the intermediates.
  [FR] La présente invention concerne des intermédiaires innovants du tadalafil et leurs procédés de préparation. L'invention concerne également la préparation du tadalafil ou d'un de ses sels ou solvates pharmaceutiquement acceptable en utilisant les intermédiaires.
• WO2023/235719
  申请人：——

  公开号：——

  公开（公告）日：——
• The Discovery of Tadalafil:  A Novel and Highly Selective PDE5 Inhibitor. 2: 2,3,6,7,12,12a-hexahydropyrazino[1‘,2‘:1,6]pyrido[3,4-<i>b</i>]indole-1,4-dione Analogues
  作者：Alain Daugan、Pascal Grondin、Cécile Ruault、Anne-Charlotte Le Monnier de Gouville、Hervé Coste、Jean Michel Linget、Jorge Kirilovsky、François Hyafil、Richard Labaudinière

  DOI：10.1021/jm0300577

  日期：2003.10.1

  Modification of the hydantoin ring in the previously described lead compound 2a has led to the discovery of compound 12a, tadalafil, a highly potent and highly selective PDE5 inhibitor. The replacement of the hydantoin in compound 2a by a piperazinedione ring led to compound cis-11a which showed similar PDE5 inhibitory potency. Introduction of a 3,4-methylenedioxy substitution on the phenyl ring in position 6 led to a potent PDE5 inhibitor cis-11c with increased cellular potency. Optimization of the chain on the piperazinedione ring led to the identification of the racemic cis-N-methyl derivative 11i. High diastereospecificity for PDE5 inhibition was observed in the piperazinedione series with the cis-(6R,12aR) enantiomer displaying the highest PDE5 inhibitory activity. The piperazinedione 12a, tadalafil (GF196960), has been identified as a highly potent PDE5 inhibitor (IC50 = 5 nM) with high selectivity for PDE5 vs PDE1-4 and PDE6. Compound 12a displays 85-fold greater selectivity vs PDE6 than sildenafil 1.12a showed profound and long-lasting blood pressure lowering activity (30 mmHg/> 7 h) in the spontaneously hypertensive rat model after oral administration (5 mg/kg).
• 一种他达拉非制备方法
  申请人：山东安信制药有限公司

  公开号：CN114213414A

  公开（公告）日：2022-03-22

  本发明公开了一种他达拉非制备方法。该方法采用化合物Ⅰ为起始物料，先后经过缩合、Fisher吲哚合成反应、Pictet‑Spengler反应、酰化与关环五步反应得到他达拉非，关环时不使用危险性试剂(正丁基锂等)。该反应路线简单，且反应条件温和，纯度高，成本相对较低，操作简便，易于工业化生产。