(1S,3S)-1-(1,3-苯并二氧戊环-5-基)-2-(2-氯乙酰基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯 | 629652-42-2

• 物质功能分类: 有机原料 - 羧酸类化合物及衍生物
• 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: (1S,3S)-1-(1,3-苯并二氧戊环-5-基)-2-(2-氯乙酰基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯
• 中文别名: 他达那非中间体异构体杂质
• 英文名称: methyl (1S,3S)-1-(benzo[d][1,3]dioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate
• 英文别名: (1S,3S)-1-(1,3-Benzodioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylic Acid Methyl Ester；methyl (1S,3S)-1-(1,3-benzodioxol-5-yl)-2-(2-chloroacetyl)-1,3,4,9-tetrahydropyrido[3,4-b]indole-3-carboxylate
• CAS: 629652-42-2
• 化学式: C₂₂H₁₉ClN₂O₅
• 分子量: 426.856
• InChiKey: JUKHNCNDFOAFLT-KKSFZXQISA-N

物化性质

• 熔点：
  208-210oC
• 溶解度：
  可溶于二甲基亚砜、甲醇

计算性质

• 辛醇/水分配系数(LogP)：
  3.5
• 重原子数：
  30
• 可旋转键数：
  4
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  80.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  (1S,3S)-1-(1,3-苯并二氧戊环-5-基)-2-(2-氯乙酰基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯 在 氨 作用下， 以50%的产率得到(+/-) cis-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione
  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：

  甲基色氨酸 在 碳酸氢钠 、 三氟乙酸 作用下， 以 二氯甲烷 、 氯仿 为溶剂， 反应 25.0h， 生成 (1S,3S)-1-(1,3-苯并二氧戊环-5-基)-2-(2-氯乙酰基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚-3-羧酸甲酯
  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

文献信息

• Design, Synthesis, and Biological Evaluation of Orally Available First-Generation Dual-Target Selective Inhibitors of Acetylcholinesterase (AChE) and Phosphodiesterase 5 (PDE5) for the Treatment of Alzheimer’s Disease
  作者：Fei Mao、Huan Wang、Wei Ni、Xinyu Zheng、Manjiong Wang、Keting Bao、Dazheng Ling、Xiaokang Li、Yixiang Xu、Haiyan Zhang、Jian Li

  DOI：10.1021/acschemneuro.7b00345

  日期：2018.2.21

  drug discovery strategies of repurposing and redeveloping existing drugs, a series of novel tadalafil derivatives were rationally designed, synthesized, and evaluated to seek dual-target AChE/PDE5 inhibitors as good candidate drugs for Alzheimer’s disease (AD). Among these derivatives, 1p and 1w exhibited excellent selective dual-target AChE/PDE5 inhibitory activities and improved blood-brain barrier

  通过重新利用和重新开发现有药物的药物发现策略，合理地设计，合成和评估了一系列新型他达拉非衍生物，以寻找双靶点AChE / PDE5抑制剂作为阿尔茨海默氏病（AD）的良好候选药物。在这些衍生物中，1p和1w表现出优异的选择性双靶AChE / PDE5抑制活性和改善的血脑屏障（BBB）渗透性。重要的是1w·Cit（柠檬酸盐为1w）可以逆转东pol碱诱导的AD小鼠的认知功能障碍，并在增强体内cAMP反应元件结合蛋白（CREB）磷酸化方面表现出优异的作用，这是记忆形成和突触可塑性的关键因素。此外，与hAChE和hPDE5A的1w分子对接模拟证实了我们的设计策略是合理的。总而言之，我们的研究提供了一种潜在的选择性双靶AChE / PDE5抑制剂，作为治疗AD的良好候选药物，它也可以被视为小分子探针，以验证体内新颖的AD治疗方法。
• 一种他达拉非异构体的制备方法
  申请人：珠海联邦制药股份有限公司

  公开号：CN107973796B

  公开（公告）日：2020-05-26

  本发明公开了一种他达拉非异构体的制备方法，属于药物合成技术领域。本发明的制备方法包括将他达拉非置于非质子强极性溶剂中，利用有机碱进行部分消旋得到异构体I；以L‑色氨酸为原料，通过四步反应全合成得到异构体II；将异构体II置于非质子强极性溶剂中，利用有机碱进行部分消旋得到异构体III；并对以上三个异构体进行了结构确证。本发明所提供的制备方法工序简单、收率高，后处理简单、易于纯化。
• [EN] TADALAFIL SYNTHESIS METHOD<br/>[FR] MÉTHODE DE SYNTHÈSE DE TADALAFIL
  申请人：OBSHESTVO S OGRANICHENNOY OTVETSTVENNOSTUY BALTFARMA

  公开号：WO2020218941A1

  公开（公告）日：2020-10-29

  The invention relates to a new one-pot continuous method for the synthesis of tadalafil from methyl (1R,3R)-1-(1,3-benzodioxol-5-yl)-2-(chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate and methylamine in aprotic solvent. The method allows to obtain high-quality tadalafil (I) with the high yield at low temperature in a short time.

  该发明涉及一种新的一锅连续法合成他达拉非，该法使用无极性溶剂中的甲胺和甲基（1R,3R）-1-（1,3-苯并二氧杂环[5,6]戊-5-基）-2-（氯乙酰基）-2,3,4,9-四氢-1H-吡啶[3,4-b]吲哚-3-羧酸甲酯。该方法在低温下短时间内高收率地得到高质量的他达拉非（I）。
• Diastereospecific Synthesis of Tetrahydroisoquinolines via Radical Cyclization: Application in the Synthesis of ent‐Tadalafil
  作者：Wei‐Jung Chiu、Yan‐Liang Lin、Indrajeet J. Barve、Chung‐Ming Sun

  DOI：10.1002/adsc.202100506

  日期：2021.8.13

  An enantioselective synthesis of 1-substituted tetrahydroisoquinolines from L–Dopa methyl ester through intramolecular aryl radical cyclization is demonstrated. The strategy consists of bromination of (S)-2-amino-3-(2-bromo-4,5-dimethoxyphenyl)propanoate followed by condensation with various aldehydes to afford bromoimidate ester. Aryl radicals generated from bromoimidate ester under the radical generating

  证明了通过分子内芳基环化从 L-多巴甲酯中对映选择性合成 1-取代的四氢异喹啉。该策略包括（S）-2-氨基-3-（2-溴-4,5-二甲氧基苯基）丙酸酯的溴化，然后与各种醛缩合得到溴亚胺酸酯。在自由基生成条件 ( n Bu 3 SnH/AIBN)下由溴亚胺酯生成的芳基通过6-内模式环化，以 99% ee 独家提供顺式-1-取代的四氢异喹啉。该合成方案的效用在 (6 S , 12a S) 他达拉非（5 步，21%，99% ee）。
• PROCESS FOR THE PREPARATION OF AN INTERMEDIATE OF TADALAFIL
  申请人：RANBAXY LABORATORIES LIMITED

  公开号：US20140142309A1

  公开（公告）日：2014-05-22

  The present invention relates to a process for the preparation of a cis-intermediate compound of Formula II which is a useful synthetic intermediate for the preparation of tadalafil of Formula I—a potent, selective, and reversible inhibitor of cyclic guanosine 3′,5′-monophosphate specific phosphodiesterase type 5 enzyme having phosphodiesterase inhibitory activity.

  本发明涉及一种制备II式顺式中间体化合物的方法，该化合物是制备I式他达拉非的有用合成中间体，该化合物是一种强效、选择性和可逆的环磷鸟苷3′，5′-单磷酸特异性磷酸二酯酶5型抑制剂，具有磷酸二酯酶抑制活性。