(R)-carvedilol phosphate

• 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
• 英文名称: (R)-carvedilol phosphate
• 英文别名: (2R)-1-(9H-carbazol-4-yloxy)-3-[2-(2-methoxyphenoxy)ethylamino]propan-2-ol;phosphoric acid
• 化学式: C₂₄H₂₆N₂O₄*H₃O₄P
• 分子量: 504.477
• InChiKey: XCPXNPBILMXKNX-UNTBIKODSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  2.81
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  4.0
• sp3杂化的碳原子比例：
  0.25
• 拓扑面积：
  154
• 氢给体数：
  6
• 氢受体数：
  9

反应信息

• 作为产物：
  描述：

  卡维地洛 在 ChiralPak AD column 作用下， 以 甲醇 、 乙醇 、 正己烷 、 水 、 丙酮 、 三氟乙酸 为溶剂， 反应 1.17h， 生成 (R)-carvedilol phosphate
  参考文献：
  名称：

  Isomorphism, Disorder, and Hydration in the Crystal Structures of Racemic and Single-Enantiomer Carvedilol Phosphate

  摘要：

  Understanding the crystalline structure of racemic carvedilol phosphate hemihydrate presents several challenges that were overcome using a combination of single-crystal X-ray diffraction, solid-state NMR (SSNMR), and other analytical techniques. Initial attempts to obtain a crystal structure were hampered by difficulties with twinning and problematic disorder in the final refinements. Multinuclear SSNMR analysis localized the disorder to portions of the molecule near the chiral center. As a result, single-enantiomer carvedilol phosphate was prepared and was found to crystallize in a phase that was isomorphous with the racemate, while SSNMR spectra of the single enantiomers did not contain the disorder observed in the racemate. The single-crystal X-ray structure of the (R)-enantiomer was solved and used as a starting point to successfully progress the solution of the disordered racemic crystal structure. Thermal analysis and construction of a phase diagram, along with crystallographic and spectroscopic analysis, found the crystal structure of the racemate to be a solid solution of (R)- and (S)-enantiomers, with the conformation of the molecule adjusting to fit. The crystal structures show the stoichiometry of the both the racemate and (R)-enantiomer to be a hemihydrate. The phase isomorphically dehydrates below relative humidity values of 1% and above temperatures of 125 degrees C as assessed by water vapor sorption studies, powder X-ray diffraction, and SSNMR. Single-crystal diffraction detected significant changes in the unit cell dimensions as the phase dehydrated, which was related to the visual appearance of opacity in a single crystal of the (R)-enantiomer. The mechanism of water incorporation was further probed spectroscopically via exchange with deuterium, O-17-, and O-18-labeled water; the results suggest that dehydration and rehydration likely proceed via narrow tunnels in the crystal structure, combined with the formation of fissures in the crystal. H-2 SSNMR experiments showed that the water does not engage in solid-state jump motion even at higher temperatures.

  DOI：

  10.1021/cg100209v

文献信息

• 左旋卡维地洛盐晶型、其制备方法及应用
  申请人：山东创新药物研发有限公司

  公开号：CN110668994A

  公开（公告）日：2020-01-10

  本公开属于医药技术领域，具体涉及左旋卡维地洛盐晶型、其制备方法及应用。本公开涉及左旋卡维地洛在药学上可接受盐类及晶型，连同制备它们的方法，包括它们的药物组合物、以及它们在制备用于治疗不同的病症和/或疾病的药物组合物中的用途。具体的说，本发明涉及左旋卡维地洛磷酸盐、左旋卡维地洛盐酸盐、左旋卡维地洛硫酸盐、左旋卡维地洛富马酸盐、以及左旋卡维地洛酒石酸盐。本公开提供的晶体盐形式显著改善了卡维地洛的溶解效果，并且在防潮性能、稳定性方面也具有显著的提升，对于进一步提高卡维地洛在防治心血管疾病药物中的开发提供了研究方向。
• Isomorphism, Disorder, and Hydration in the Crystal Structures of Racemic and Single-Enantiomer Carvedilol Phosphate
  作者：Frederick G. Vogt、Royston C. B. Copley、Ronald L. Mueller、Grant P. Spoors、Thomas N. Cacchio、Robert A. Carlton、Lee M. Katrincic、James M. Kennady、Simon Parsons、Olga V. Chetina

  DOI：10.1021/cg100209v

  日期：2010.6.2

  Understanding the crystalline structure of racemic carvedilol phosphate hemihydrate presents several challenges that were overcome using a combination of single-crystal X-ray diffraction, solid-state NMR (SSNMR), and other analytical techniques. Initial attempts to obtain a crystal structure were hampered by difficulties with twinning and problematic disorder in the final refinements. Multinuclear SSNMR analysis localized the disorder to portions of the molecule near the chiral center. As a result, single-enantiomer carvedilol phosphate was prepared and was found to crystallize in a phase that was isomorphous with the racemate, while SSNMR spectra of the single enantiomers did not contain the disorder observed in the racemate. The single-crystal X-ray structure of the (R)-enantiomer was solved and used as a starting point to successfully progress the solution of the disordered racemic crystal structure. Thermal analysis and construction of a phase diagram, along with crystallographic and spectroscopic analysis, found the crystal structure of the racemate to be a solid solution of (R)- and (S)-enantiomers, with the conformation of the molecule adjusting to fit. The crystal structures show the stoichiometry of the both the racemate and (R)-enantiomer to be a hemihydrate. The phase isomorphically dehydrates below relative humidity values of 1% and above temperatures of 125 degrees C as assessed by water vapor sorption studies, powder X-ray diffraction, and SSNMR. Single-crystal diffraction detected significant changes in the unit cell dimensions as the phase dehydrated, which was related to the visual appearance of opacity in a single crystal of the (R)-enantiomer. The mechanism of water incorporation was further probed spectroscopically via exchange with deuterium, O-17-, and O-18-labeled water; the results suggest that dehydration and rehydration likely proceed via narrow tunnels in the crystal structure, combined with the formation of fissures in the crystal. H-2 SSNMR experiments showed that the water does not engage in solid-state jump motion even at higher temperatures.