2,2-dimethylpropionic acid 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxy-4-oxo-4H-quinazolin-3-ylmethyl ester | 1444000-03-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 二氮杂萘
• 英文名称: 2,2-dimethylpropionic acid 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxy-4-oxo-4H-quinazolin-3-ylmethyl ester
• 英文别名: [2-[4-(2-Hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-4-oxoquinazolin-3-yl]methyl 2,2-dimethylpropanoate；[2-[4-(2-hydroxyethoxy)-3,5-dimethylphenyl]-5,7-dimethoxy-4-oxoquinazolin-3-yl]methyl 2,2-dimethylpropanoate
• CAS: 1444000-03-6
• 化学式: C₂₆H₃₂N₂O₇
• 分子量: 484.549
• InChiKey: APMRBTSTJMTNSK-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.9
• 重原子数：
  35
• 可旋转键数：
  10
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.42
• 拓扑面积：
  107
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  2,2-dimethylpropionic acid 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxy-4-oxo-4H-quinazolin-3-ylmethyl ester 在 sodium methylate 、 silver(l) oxide 作用下， 以 甲醇 、 二氯甲烷 为溶剂， 反应 72.0h， 生成 6-(2-(4-(5,7-dimethoxy-4-oxo-3,4-dihydroquinazolin-2-yl)-2,6-dimethylphenoxy)ethoxy)-3,4,5-trihydroxytetrahydropyran-2-carboxylic acid
  参考文献：
  名称：

  In vitro biosynthesis, isolation, and identification of predominant metabolites of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208)

  摘要：

  The structures of the two predominant metabolites (M4 and M5) of RVX-208, observed both in in vitro human and animal liver microsomal incubations, as well as in plasma from animal in vivo studies, were determined. A panel of biocatalytic systems was tested to identify biocatalysts suitable for milligram scale production of metabolite M4 from RVX-208. Rabbit liver S9 fraction was selected as the most suitable system, primarily based on pragmatic metrics such as catalyst cost and estimated yield of M4 (similar to 55%). Glucuronidation of RVX-208 catalyzed by rabbit liver S9 fraction was optimized to produce M4 in amounts sufficient for structural characterization. Structural studies using LC/MS/MS analysis and H-1 NMR spectroscopy showed the formation of a glycosidic bond between the primary hydroxyl group of RVX-208 and glucuronic acid. NMR results suggested that the glycosidic bond has the beta-anomeric configuration. A synthetic sample of M4 confirmed the proposed structure. Metabolite M5, hypothesized to be the carboxylate of RVX-208, was prepared using human liver microsomes, purified by HPLC, and characterized by LC/MS/MS and H-1 NMR. The structure was confirmed by comparison to a synthetic sample. Both samples confirmed M5 as a product of oxidation of primary hydroxyl group of RVX-208 to carboxylic acid. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.03.062
• 作为产物：
  描述：

  特戊酸氯甲酯 、 2-(4-(2-羟基乙氧基)-3,5-二甲基苯基)-5,7-二甲氧基喹唑啉-4(3H)-酮 在 sodium hydride 作用下， 以 N,N-二甲基甲酰胺 、 mineral oil 为溶剂， 反应 25.0h， 以56%的产率得到2,2-dimethylpropionic acid 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxy-4-oxo-4H-quinazolin-3-ylmethyl ester
  参考文献：
  名称：

  In vitro biosynthesis, isolation, and identification of predominant metabolites of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208)

  摘要：

  The structures of the two predominant metabolites (M4 and M5) of RVX-208, observed both in in vitro human and animal liver microsomal incubations, as well as in plasma from animal in vivo studies, were determined. A panel of biocatalytic systems was tested to identify biocatalysts suitable for milligram scale production of metabolite M4 from RVX-208. Rabbit liver S9 fraction was selected as the most suitable system, primarily based on pragmatic metrics such as catalyst cost and estimated yield of M4 (similar to 55%). Glucuronidation of RVX-208 catalyzed by rabbit liver S9 fraction was optimized to produce M4 in amounts sufficient for structural characterization. Structural studies using LC/MS/MS analysis and H-1 NMR spectroscopy showed the formation of a glycosidic bond between the primary hydroxyl group of RVX-208 and glucuronic acid. NMR results suggested that the glycosidic bond has the beta-anomeric configuration. A synthetic sample of M4 confirmed the proposed structure. Metabolite M5, hypothesized to be the carboxylate of RVX-208, was prepared using human liver microsomes, purified by HPLC, and characterized by LC/MS/MS and H-1 NMR. The structure was confirmed by comparison to a synthetic sample. Both samples confirmed M5 as a product of oxidation of primary hydroxyl group of RVX-208 to carboxylic acid. (C) 2013 Elsevier Masson SAS. All rights reserved.

  DOI：

  10.1016/j.ejmech.2013.03.062

文献信息

• In vitro biosynthesis, isolation, and identification of predominant metabolites of 2-(4-(2-hydroxyethoxy)-3,5-dimethylphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (RVX-208)
  作者：Yuri L. Khmelnitsky、Vadim V. Mozhaev、Ian C. Cotterill、Peter C. Michels、Sihem Boudjabi、Vladimir Khlebnikov、M. Madhava Reddy、Gregory S. Wagner、Henrik C. Hansen

  DOI：10.1016/j.ejmech.2013.03.062

  日期：2013.6

  The structures of the two predominant metabolites (M4 and M5) of RVX-208, observed both in in vitro human and animal liver microsomal incubations, as well as in plasma from animal in vivo studies, were determined. A panel of biocatalytic systems was tested to identify biocatalysts suitable for milligram scale production of metabolite M4 from RVX-208. Rabbit liver S9 fraction was selected as the most suitable system, primarily based on pragmatic metrics such as catalyst cost and estimated yield of M4 (similar to 55%). Glucuronidation of RVX-208 catalyzed by rabbit liver S9 fraction was optimized to produce M4 in amounts sufficient for structural characterization. Structural studies using LC/MS/MS analysis and H-1 NMR spectroscopy showed the formation of a glycosidic bond between the primary hydroxyl group of RVX-208 and glucuronic acid. NMR results suggested that the glycosidic bond has the beta-anomeric configuration. A synthetic sample of M4 confirmed the proposed structure. Metabolite M5, hypothesized to be the carboxylate of RVX-208, was prepared using human liver microsomes, purified by HPLC, and characterized by LC/MS/MS and H-1 NMR. The structure was confirmed by comparison to a synthetic sample. Both samples confirmed M5 as a product of oxidation of primary hydroxyl group of RVX-208 to carboxylic acid. (C) 2013 Elsevier Masson SAS. All rights reserved.