顺式-ent-他达拉非 | 171596-28-4

• 物质功能分类: 分析化学 - 标准品
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吲哚及其衍生物
• 中文名称: 顺式-ent-他达拉非
• 中文别名: 他达拉非EP杂质C；他达拉非EP杂质C(CIS- ENT-他达拉非)；他达拉非EP杂质C(CIS-ENT-他达拉非)
• 英文名称: (6S,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,12,12a tetrahydropyrazino [1',2':1,6] pyrido[3,4b] indole1,4(6H,7H)-dione
• 英文别名: (6S,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,12,12a-tetrahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4(6H,7H)-dione；(6S,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione；(6S,12aR)-6-(1,3-benzodioxol-5-yl)-2,3,6,7,12,12a-hexahydro-2-methyl-pyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione；(6S,12aR)-6-benzo[1,3]dioxol-5-yl-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione；trans-6-benzo[1,3]dioxol-4-yl-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione；(6S,12aR)-tadalafil；cis-ent-Tadalafil；(2S,8R)-2-(1,3-benzodioxol-5-yl)-6-methyl-3,6,17-triazatetracyclo[8.7.0.03,8.011,16]heptadeca-1(10),11,13,15-tetraene-4,7-dione
• CAS: 171596-28-4
• 化学式: C₂₂H₁₉N₃O₄
• 分子量: 389.411
• InChiKey: WOXKDUGGOYFFRN-IERDGZPVSA-N

物化性质

• 熔点：
  287-289 °C(Solv: toluene (108-88-3))
• 沸点：
  679.1±55.0 °C(Predicted)
• 密度：
  1.51±0.1 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、DMSO（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  2.3
• 重原子数：
  29
• 可旋转键数：
  1
• 环数：
  6.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  74.9
• 氢给体数：
  1
• 氢受体数：
  4

安全信息

• 储存条件：
  2-8°C

制备方法与用途

该产品是他达拉非的杂质，主要用于杂质标准品和对照品。

上下游信息

• 上游原料

  中文名称	英文名称	CAS号	化学式	分子量
  ENT-他达拉非	(+/-) cis-6-(1,3-benzodioxol-5-yl)-2-methyl-2,3,6,7,12,12a-hexahydropyrazino[1',2':1,6]pyrido[3,4-b]indole-1,4-dione	629652-72-8	C22H19N3O4	389.411
  ——	(+/-) trans-methyl 1-(1,3-benzodioxol-5-yl)-2-(chloroacetyl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylate	629652-42-2	C22H19ClN2O5	426.856
  (1S,3R)-甲基-1,2,3,4-四氢-1-(3,4-亚甲二氧基苯基)-9H-吡啶并[3,4-b]吲哚-3-羧酸酯	(1S,3R)-1-(benzo[1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline-3-carboxylic acid methyl ester	171596-42-2	C20H18N2O4	350.374

• 下游产品

  中文名称	英文名称	CAS号	化学式	分子量
  ——	(6S,12aR)-6-(benzo[d][1,3]dioxol-5-yl)-2,7-dimethyl-2,3,12,12a-tetrahydropyrazino[1',2':1,6] pyrido[3,4-b]indole-1,4(6H,7H)dione	1370438-55-3	C23H21N3O4	403.437
  ——	(1S,3R)-1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide	1370438-58-6	C19H17N3O3	335.362

反应信息

• 作为反应物：
  描述：

  顺式-ent-他达拉非 在 ammonium hydroxide 作用下， 以 1,4-二氧六环 为溶剂， 生成 (1S,3R)-1-(benzo[d][1,3]dioxol-5-yl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxamide
  参考文献：
  名称：

  Synthesis and evaluation of human phosphodiesterases (PDE) 5 inhibitor analogs as trypanosomal PDE inhibitors. Part 2. Tadalafil analogs

  摘要：

  In this Letter we describe our ongoing target repurposing efforts focused on discovery of inhibitors of the essential trypanosomal phosphodiesterase TbrPDEB1. This enzyme has been implicated in virulence of Trypanosoma brucei, the causative agent of human African trypanosomiasis (HAT). We outline the synthesis and biological evaluation of analogs of tadalafil, a human PDE5 inhibitor currently utilized for treatment of erectile dysfunction, and report that these analogs are weak inhibitors of TbrPDEB1. (C) 2012 Elsevier Ltd. All rights reserved.

  DOI：

  10.1016/j.bmcl.2012.01.118
• 作为产物：
  描述：

  D-色氨酸甲酯 在 碳酸氢钠 、 三氟乙酸 作用下， 以 乙醇 、 二氯甲烷 、 氯仿 为溶剂， 生成 顺式-ent-他达拉非
  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

• Highly stereoselective one-pot construction of trisubstituted tetrahydro-β-carboline-fused diketopiperazines: a synthetic route towards cialis analogues
  作者：Mouhamad Jida、Dirk Tourwé、Steven Ballet

  DOI：10.1039/c4ra05981f

  日期：——

  A facile and efficient synthetic method for the stereoselective preparation of trisubstituted tetrahydro-β-carboline-fused diketopiperazine derivatives is reported.

  一种简便高效的合成方法用于立体选择性制备三取代四氢-β-咔啉融合二酮肽衍生物。
• First highly stereocontrolled synthesis of tetrahydro trans-β-carboline derivatives by exploiting the influence of a cyclic amide
  作者：Ravindra Vedantham、Sakthivel Shanmugam、Prasadaraju V.N.K.V. Vetukuri、Mukkanti Khaggab、Rakeshwar Bandichhor

  DOI：10.3998/ark.5550190.0014.204

  日期：——

  Stereocontrolled synthesis of trans-β-carboline derivatives by employing amidation strategy is presented.

  提出了采用酰胺化策略立体控制合成反式-β-咔啉衍生物。
• An Efficient and General Method for the Stereodivergent Syntheses of Tadalafil-Like Tetracyclic Compounds
  作者：Sen Xiao、Xiao-Xin Shi、Feng Ni、Jing Xing、Jing-Jing Yan、Shi-Ling Liu

  DOI：10.1002/ejoc.200901378

  日期：2010.3

  A clean and general DBU-catalyzed epimerization at C-12a position of the tadalafil-like tetracyclic compounds has been fully studied. In addition, by using this clean epimerization as the key step, four stereomers of 6-d 1 -tadalafil were stereo-divergently synthesized from both L - and D -tryptophan methyl ester hydrochlorides and deuterated piperonal.

  他达拉非样四环化合物的 C-12a 位的清洁和通用 DBU 催化差向异构化已得到充分研究。此外，通过使用这种干净的差向异构化作为关键步骤，从 L - 和 D - 色氨酸甲酯盐酸盐和氘代胡椒醛立体发散合成了 6-d 1 - 他达拉非的四种立体异构体。
• Microwave-Assisted Synthesis of Tetracyclic 2,5-Diketopiperazines on a Soluble Polymer Support: A Structural Analogue of Tadalafil
  作者：Wong-Jin Chang、Kaushik Chanda、Chung-Ming Sun

  DOI：10.1071/ch08334

  日期：——

  Structural analogues of tadalafil that contain two diversity points have been synthesized from a soluble polymer support employing a Pictet–Spengler reaction using focussed microwave irradiation. Polymer-bound deprotected tryptophan reacts with various aldehydes to generate the tetrahydro-β-carbolines on the support. Subsequently immobilized tetrahydro-β-carboline underwent a highly efficient intramolecular N-heterocyclization in a traceless fashion from various in-situ generated α-alkyl and heteroalkyl amides in two steps to generate tetracyclic 2,5-diketopiperazines in high purity. All the compounds were isolated as cis and trans isomers with good yields.

  利用聚焦微波辐照技术，通过皮克泰-斯彭勒反应，从可溶性聚合物载体中合成了含有两个多样性点的他达拉非结构类似物。聚合物结合的脱保护色氨酸与各种醛类发生反应，在支撑物上生成四氢-β-咔啉。随后，固定化的四氢-β-咔啉与各种原位生成的α-烷基和杂烷基酰胺以无痕方式进行了高效的分子内 N-异环化反应，分两步生成了高纯度的四环 2,5-二酮哌嗪。所有化合物都以顺式和反式异构体的形式分离出来，而且收率很高。
• Two Concise Syntheses of Cialis via the<i>N</i>-Acyliminium Pictet-Spengler Reaction
  作者：A. Ganesan、Jefferson D. Revell、Natarajan Srinivasan

  DOI：10.1055/s-2004-825625

  日期：——

  The imine derived from piperonal and d-tryptophan ­methyl ester underwent N-acyliminium Pictet-Spengler reaction with either Fmoc-sarcosyl chloride or chloroacetyl chloride. The products were readily converted to the drug Cialis.

  从胡椒醛和D-色氨酸甲酯衍生的亚胺与Fmoc-肌氨酸氯或氯乙酰氯发生N-酰亚胺Pictet-Spengler反应。产物很容易转化为药物西力士。