2-oxo-3-((2’-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylic acid

• 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: 2-oxo-3-((2’-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylic acid
• 英文别名: 2-oxo-3-[[2'-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)biphenyl-4-yl]methyl]2,3-dihydro-1H-benzimidazole-4-carboxylic acid；1-[[2′-(4,5-dihydro-5-oxo-4H-1,2,4-oxadiazol-3-yl)-biphenyl-4-yl]methyl]-2-oxo-1H-benzimidazole-7-carboxylic acid；O-Desethyl Azilsartan；2-oxo-3-[[4-[2-(5-oxo-4H-1,2,4-oxadiazol-3-yl)phenyl]phenyl]methyl]-1H-benzimidazole-4-carboxylic acid
• 化学式: C₂₃H₁₆N₄O₅
• 分子量: 428.404
• InChiKey: LLINNBQUGIKCPM-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.9
• 重原子数：
  32
• 可旋转键数：
  5
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.04
• 拓扑面积：
  120
• 氢给体数：
  3
• 氢受体数：
  6

反应信息

• 作为产物：
  描述：

  阿齐沙坦 在 盐酸 作用下， 以 乙醇 、 水 为溶剂， 反应 3.0h， 以60%的产率得到2-oxo-3-((2’-(5-oxo-4,5-dihydro-1,2,4-oxadiazol-3-yl)-[1,1’-biphenyl]-4-yl)methyl)-2,3-dihydro-1H-benzo[d]imidazole-4-carboxylic acid
  参考文献：
  名称：

  Preparation, Crystal Structures and Hirshfeld Surface Analyses of Two Impurities of Azilsartan

  摘要：

  两种阿齐沙坦杂质(1·EtOH和2)已被制备出来，并通过1H-NMR、IR和单晶X射线衍射技术鉴定了它们的结构。杂质1·EtOH（C25H22N4O6，Mr=474.46）为三斜晶系，空间群P-1，晶胞参数为a=9.0425(15) Å，b=10.5498(18) Å，c=12.826(2) Å，α=76.329(3)°，β=79.086(3)°，γ=76.763(3)°，V=1145.4(3) ų，Z=2，F(000)=496，Dc=1.376 g/cm³，μ=0.100 mm−1。杂质2（C25H20N4O5，Mr=456.45）也是三斜晶系，空间群P-1，晶胞参数为a=9.356(7) Å，b=9.490(8) Å，c=13.562(10) Å，α=72.173(13)°，β=73.864(12)°，γ=82.628(15)°，V=1099.9(15) ų，Z=2，F(000)=476，Dc=1.378 g/cm³，μ=0.098 mm−1。1·EtOH通过两个N–H···O氢键形成异核R 2 2 (8)二聚体结构，由一个1,2,4-恶二唑和一个2-氧代苯并咪唑构成，乙醇分子通过O–H···O氢键连接。杂质2通过两个同核R 2 2 (8) N–H···O氢键形成一维链状结构，分别由两个1,2,4-恶二唑和两个2-氧代苯并咪唑构成。Hirshfeld表面分析表明氢键对稳定构象至关重要。两种阿齐沙坦杂质(1 EtOH和2)已被制备出来，它们的晶体结构显示出不同的分子构型和组装方式，主要通过经典的氢键以及C–H···N和C–H···O相互作用来稳定。

  DOI：

  10.1007/s10870-018-0754-y

文献信息

• [EN] AN IMPROVED PROCESS FOR THE PREPARATION OF SUBSTANTIALLY PURE AZILSARTAN<br/>[FR] PROCÉDÉ AMÉLIORÉ POUR LA PRÉPARATION D'AZILSARTAN SENSIBLEMENT PUR
  申请人：SMILAX LABORATORIES LTD

  公开号：WO2016147120A1

  公开（公告）日：2016-09-22

  The present invention relates to an improved process for the preparation of substantially pure compound of 2-Ethoxy-1-[[2'-(2,5-dihydro-5-oxo-1,2,4-oxadiazol- 3-yl)biphenyl-4-yl]methyl]benzimidazole-7-carboxylic acid (Azilsartan) of Formula I, with a reduced content of desethyl impurity less than 0.1% and an efficient, commercially viable process for the preparation of pure intermediates of Azilsartan.

  本发明涉及一种改进的工艺，用于制备公式I的2-乙氧基-1-[[2'-(2,5-二氢-5-氧代-1,2,4-噁二唑-3-基)联苯-4-基]甲基]苯并咪唑-7-羧酸（阿利沙坦）的基本纯化合物，其去乙基杂质含量低于0.1%，以及一种高效、商业可行的制备阿利沙坦纯中间体的工艺。
• 一种阿齐沙坦杂质标准品的制备方法
  申请人：合肥久诺医药科技有限公司

  公开号：CN106279140A

  公开（公告）日：2017-01-04

  本发明公开了一种阿齐沙坦杂质标准品的制备方法，是以阿齐沙坦为原料，经无机酸水解制得粗品，粗品经精制而得2‑氧代‑3‑[[2'‑(5‑氧代‑4,5‑二氢‑1,2,4‑噁二唑‑3‑基)双苯基‑4‑基]甲基]‑2,3‑二氢‑1H‑苯并咪唑‑4‑羧酸纯品。本发明提供的杂质制备方法原料廉价易得、工艺简捷、制备周期短，经标定产品含量大于98.5％。本发明提供的阿齐沙坦杂质可作为杂质标准品，应用于阿齐沙坦原料及其制剂杂质的定性、定量研究和检测。
• Liquid chromatography/tandem mass spectrometry study of forced degradation of azilsartan medoxomil potassium
  作者：Debasish Swain、Prinesh N. Patel、Ilayaraja Palaniappan、Gayatri Sahu、Gananadhamu Samanthula

  DOI：10.1002/rcm.7235

  日期：2015.8.15

  Azilsartan medoxomil potassium (AZM) is a new antihypertensive drug introduced in the year 2011. The presence of degradation products not only affects the quality, but also the safety aspects of the drug. Thus, it is essential to develop an efficient analytical method which could be useful to selectively separate and identify the degradation products of azilsartan medoxomil potassium.

  Azilsartan medoxomil钾（AZM）是一种于2011年推出的新型降压药。降解产物的存在不仅影响药物的质量，还影响其安全性。因此，至关重要的是开发一种有效的分析方法，该方法可用于选择性地分离和鉴定阿齐沙坦美多西莫钾的降解产物。
• Preparation, Crystal Structures and Hirshfeld Surface Analyses of Two Impurities of Azilsartan
  作者：Liping Zhou、Rongkai Du、Xianrui Zhang、Hua Chen、Su Guan、Jing Li、Lei Zhang

  DOI：10.1007/s10870-018-0754-y

  日期：2019.3

  Two impurities of azilsartan (1·EtOH and 2) have been prepared and the structures have been identified by 1H-NMR, IR and single crystal X-ray diffraction. Impurity 1·EtOH (C25H22N4O6, Mr = 474.46) crystallizes in triclinic, space group P-1 with a = 9.0425(15), b = 10.5498(18), c = 12.826(2) Å, α = 76.329(3), β = 79.086(3), γ = 76.763(3)°, V = 1145.4(3) Å3, Z = 2, F(000) = 496, Dc = 1.376 g/cm3, and µ = 0.100 mm− 1. Impurity 2 (C25H20N4O5, Mr = 456.45) is triclinic space group P-1 with a = 9.356(7), b = 9.490(8), c = 13.562(10) Å, α = 72.173(13), β = 73.864(12), γ = 82.628(15)°, V = 1099.9(15) Å3, Z = 2, F(000) = 476, Dc = 1.378 g/cm3, and µ = 0.098 mm−1. 1·EtOH shows a heteronuclear R 2 2 (8) dimeric structure through two N–H···O hydrogen bonds constructed by one 1,2,4-oxadiazol and one 2-oxo-benzimidazole groups, and ethanol molecule is attached by O–H···O hydrogen bond. Impurity 2 shows one-dimensional chain structure through two homonuclear R 2 2 (8) N–H···O hydrogen bonds constructed by two 1,2,4-oxadiazols and by two 2-oxo-benzimidazoles, respectively. Hirshfeld surface analysis shows that the hydrogen bonds are important to stabilize the conformation. Two impurities of azilsartan (1 EtOH and 2) have been prepared and the crystal structures show different molecular configurations and assembly which are predominantly stabilized by the classical hydrogen bonds as well as C–H···N and C–H···O interactions.

  两种阿齐沙坦杂质(1·EtOH和2)已被制备出来，并通过1H-NMR、IR和单晶X射线衍射技术鉴定了它们的结构。杂质1·EtOH（C25H22N4O6，Mr=474.46）为三斜晶系，空间群P-1，晶胞参数为a=9.0425(15) Å，b=10.5498(18) Å，c=12.826(2) Å，α=76.329(3)°，β=79.086(3)°，γ=76.763(3)°，V=1145.4(3) ų，Z=2，F(000)=496，Dc=1.376 g/cm³，μ=0.100 mm−1。杂质2（C25H20N4O5，Mr=456.45）也是三斜晶系，空间群P-1，晶胞参数为a=9.356(7) Å，b=9.490(8) Å，c=13.562(10) Å，α=72.173(13)°，β=73.864(12)°，γ=82.628(15)°，V=1099.9(15) ų，Z=2，F(000)=476，Dc=1.378 g/cm³，μ=0.098 mm−1。1·EtOH通过两个N–H···O氢键形成异核R 2 2 (8)二聚体结构，由一个1,2,4-恶二唑和一个2-氧代苯并咪唑构成，乙醇分子通过O–H···O氢键连接。杂质2通过两个同核R 2 2 (8) N–H···O氢键形成一维链状结构，分别由两个1,2,4-恶二唑和两个2-氧代苯并咪唑构成。Hirshfeld表面分析表明氢键对稳定构象至关重要。两种阿齐沙坦杂质(1 EtOH和2)已被制备出来，它们的晶体结构显示出不同的分子构型和组装方式，主要通过经典的氢键以及C–H···N和C–H···O相互作用来稳定。