2-[(2-氨基乙氧基)甲基]-4-(2-氯苯基)-1,4-二氢-6-甲基-3,5-吡啶二甲酸二乙酯 | 140171-65-9

• 物质功能分类: 分析化学 - 对照品
• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡啶及其衍生物
• 中文名称: 2-[(2-氨基乙氧基)甲基]-4-(2-氯苯基)-1,4-二氢-6-甲基-3,5-吡啶二甲酸二乙酯
• 中文别名: 氨氯地平杂质E
• 英文名称: 2-(2-Amino-ethoxymethyl)-4-(2-chloro-phenyl)-6-methyl-1,4-dihydro-pyridine-3,5-dicarboxylic acid diethyl ester
• 英文别名: diethyl 2-((2-aMinoethoxy)Methyl)-4-(2-chlorophenyl)-6-Methyl-1,4-dihydropyridine-3,5-dicarboxylate；diethyl 2-(2-aminoethoxymethyl)-4-(2-chlorophenyl)-6-methyl-1,4-dihydropyridine-3,5-dicarboxylate
• CAS: 140171-65-9
• 化学式: C₂₁H₂₇ClN₂O₅
• 分子量: 422.909
• InChiKey: BGGLOZPVAWMSEB-UHFFFAOYSA-N

物化性质

• 熔点：
  106-108°C
• 沸点：
  537.8±50.0 °C(Predicted)
• 密度：
  1.209±0.06 g/cm3(Predicted)
• 溶解度：
  可溶于氯仿（少许）、DMSO（少许）、甲醇（少许）

计算性质

• 辛醇/水分配系数(LogP)：
  3.4
• 重原子数：
  29
• 可旋转键数：
  11
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.43
• 拓扑面积：
  99.9
• 氢给体数：
  2
• 氢受体数：
  7

安全信息

• WGK Germany：
  3

制备方法与用途

用途

氨氯地平杂质E 用于含量测定、鉴别、药理实验及活性筛选等方面。

反应信息

• 作为产物：
  描述：

  Diethyl 4-(2-chlorophenyl)-2-{[2-(1.3-dioxo-1.3-dihydro-2H-isoindol-2-yl) ethoxy] methyl}-6-methyl-1.4-dihydro-3.5-pyridine dicarboxylate 在 甲胺 作用下， 以94%的产率得到2-[(2-氨基乙氧基)甲基]-4-(2-氯苯基)-1,4-二氢-6-甲基-3,5-吡啶二甲酸二乙酯
  参考文献：
  名称：

  Long-acting dihydropyridine calcium antagonists. 9. Structure activity relationships around amlodipine

  摘要：

  The preparation of a range of 1,4-dihydropyridine analogues of amlodipine has been undertaken and their calcium antagonist activities on rat aorta have been evaluated. Increasing the size of the C5 ester group dramatically reduces calcium antagonist activity, a trend which would be compatible with the carbonyl group of that ester binding to the DHP receptor. Amlodipine analogues with extended C3 ester substituents also have lower potency than amlodipine, possibly because of disruption of a favourable interaction between the protonated amino group on the 2-substituent and the DHP receptor. Replacement of the 6-methyl substituent in amlodipine by alkoxyalkyl groups or electron-withdrawing groups is also detrimental to calcium antagonist activity.

  DOI：

  10.1016/0223-5234(91)90132-7

文献信息

• PROCESS FOR MAKING AMLODIPINE, DERIVATIVES THEREOF, AND PRECURSORS THEREFOR
  申请人：Slanina Pavel

  公开号：US20080070789A1

  公开（公告）日：2008-03-20

  Impurities associated with the commercial production of amlodipine are identified along with methods of assaying the same.

  商业生产氨氯地平时发现了杂质，并提出了检测方法。
• [EN] A PROCESS FOR THE PREPARATION OF AMLODIPINE BENZENESULFONATE<br/>[FR] PROCÉDÉ DE PRÉPARATION DE BENZÈNESULFONATE D'AMLODIPINE
  申请人：LEK PHARMACEUTICALS

  公开号：WO2007131759A1

  公开（公告）日：2007-11-22

  [EN] The present invention relates to novel alkyl 2-(2-chlorobenzylidene)-4-(2- tritylaminoethoxy) acetoacetate, wherein alkyl represents C₁C₄ alkyl group, preferably ethyl 2-(2-chlorobenzylidene)-4-(2-tritylaminoethoxy) acetoacetate, as useful intermediate in the novel process for the preparation of amlodipine benzenesulfonate in high overall yield and high purity, containing substantially less then 0.1 Area % of 3,5-diethyl (±)-2-[(2-aminoethoxy)-methyl]-4-(2-chlorophenyl)-1,4- dihydro-6-methyl-3,5-pyridinedicarboxylate as the single remaining impurity. No other impurities are contained in obtained pure crystalline amlodipine benzenesulfonate. Preferably, 2-chlorobenzaldehyde is contacted with ethyl-4-[2-(N- tritylamino)ethoxy]acetoacetate in an organic solvent, preferably ethanol, to form ethyl-2-(2-chlorobenzylidene)-4-(2-tritylaminoethoxy) acetoacetate, which is converted without isolation from the reaction mixture, preferably with methyl (E)-3- aminocrotonate to form 3-ethyl 5-methyl (±)-2-[2-(N-tritylamino)ethoxymethyl]-4-(2- chlorophenyl)-1,4-dihydro-6-methyl-3,5-pyridinedicarboxylate ("tritylamlodipine"), which is converted without isolation from the reaction mixture with benzenesulfonic acid in an organic solvent, preferably ethanol, followed by isolation and purification of amlodipine benzenesulfonate. C₁-C₄ alkyl alcohols, especially methanol, ethanol, isopropanol and mixtures thereof, are used as an organic solvent. Amlodipine benzenesulfonate (besylate) is useful as antiishemic and antihypertensive agent.
  [FR] La présente invention concerne un nouvel alkyl-2-(2-chlorobenzylidène)-4-(2- tritylaminoéthoxy)-acétoacétate, dans lequel alkyle représente un groupe alkyle C₁-C₄, de préférence un éthyl-2-(2-chlorobenzylidène)-4-(2-tritylaminoéthoxy)-acétoacétate, utile comme produit intermédiaire dans un nouveau procédé de préparation de benzènesulfonate d'amlodipine avec un rendement total élevé et une haute pureté, et contenant sensiblement moins de 0,1% en surface de 3,5-diéthyl (±)-2-[(2-aminoéthoxy)-méthyl]-4-(2-chlorophényl)-1,4- dihydro-6-méthyl-3,5-pyridinedicarboxylate comme unique impureté restante. Aucune autre impureté n'est contenue dans le benzènesulfonate d'amlodipine cristallin pur obtenu. De préférence, du 2-chlorobenzaldéhyde est mis en contact avec de l'éthyl-4-[2-(N-tritylamino)-thoxy]acétoacétate dans un solvant organique, de préférence de l'éthanol, pour former de l'éthyl-2-(2-chlorobenzylidène)-4-(2-tritylaminoéthoxy)-acetoacétate, lequel est converti sans isolement à partir du mélange réactionnel, de préférence avec du méthyl-(E)-3-aminocrotonate, pour former du 3-éthyl 5-méthyl (±)-2-[2-(N-tritylamino)éthoxyméthyl]-4-(2- chlorophényl)-1,4-dihydro-6-méthyl-3,5-pyridinedicarboxylate ("tritylamlodipine"), lequel est converti sans isolement à partir du mélange réactionnel avec de l'acide benzènesulfonique dans un solvant organique, de préférence de l'éthanol, le benzènesulfonate d'amlodipine étant alors isolé et purifié. Des alcools d'alkyle C₁-C₄, et notamment du méthanol, de l'éthanol, de l'isopropanol et des mélanges de ceux-ci, sont utilisés comme solvant organique. Le benzènesulfonate d'amlodipine (bésylate) est utile comme agent anti-ischémique et anti-hypertenseur.
• Long-acting dihydropyridine calcium antagonists. 9. Structure activity relationships around amlodipine
  作者：D Alker、JE Arrowsmith、SF Campbell、PE Cross

  DOI：10.1016/0223-5234(91)90132-7

  日期：1991.12

  The preparation of a range of 1,4-dihydropyridine analogues of amlodipine has been undertaken and their calcium antagonist activities on rat aorta have been evaluated. Increasing the size of the C5 ester group dramatically reduces calcium antagonist activity, a trend which would be compatible with the carbonyl group of that ester binding to the DHP receptor. Amlodipine analogues with extended C3 ester substituents also have lower potency than amlodipine, possibly because of disruption of a favourable interaction between the protonated amino group on the 2-substituent and the DHP receptor. Replacement of the 6-methyl substituent in amlodipine by alkoxyalkyl groups or electron-withdrawing groups is also detrimental to calcium antagonist activity.