3-descladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-(oxycarbonyl-(1-((3-hydroxy-[1,5]naphthyridin-4-yl)-methyl)-azetidin-3-yl)-imino)-erythromycin A tosylate | 1192256-10-2

• 分子结构分类: 有机化合物 - 有机氧化合物
• 英文名称: 3-descladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-(oxycarbonyl-(1-((3-hydroxy-[1,5]naphthyridin-4-yl)-methyl)-azetidin-3-yl)-imino)-erythromycin A tosylate
• 英文别名: (1S,2R,5R,7R,8R,9R,11R,13R,14R)-8-[(2S,3R,4S,6R)-4-(dimethylamino)-3-hydroxy-6-methyloxan-2-yl]oxy-2-ethyl-15-[1-[(3-hydroxy-1,5-naphthyridin-4-yl)methyl]azetidin-3-yl]-9-methoxy-1,5,7,9,11,13-hexamethyl-3,17-dioxa-15-azabicyclo[12.3.0]heptadecane-4,6,12,16-tetrone;4-methylbenzenesulfonic acid
• CAS: 1192256-10-2
• 化学式: C₇H₈O₃S*C₄₃H₆₃N₅O₁₁
• 分子量: 998.205
• InChiKey: ZPXURQOHDXXKFI-MFUKWFAJSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  4.97
• 重原子数：
  70
• 可旋转键数：
  9
• 环数：
  7.0
• sp3杂化的碳原子比例：
  0.64
• 拓扑面积：
  253
• 氢给体数：
  3
• 氢受体数：
  18

反应信息

• 作为产物：
  描述：

  (3-methoxy[1,5]naphthyridin-4-yl)methyl bromide 在 potassium acetate 、 三乙酰氧基硼氢化钠 、 三乙胺 、 lithium chloride 、 2-碘酰基苯甲酸 作用下， 以 四氢呋喃 、 乙酸乙酯 、 N,N-二甲基甲酰胺 、 丙酮 、 乙腈 为溶剂， 反应 27.5h， 生成 3-descladinosyl-11,12-dideoxy-6-O-methyl-3-oxo-12,11-(oxycarbonyl-(1-((3-hydroxy-[1,5]naphthyridin-4-yl)-methyl)-azetidin-3-yl)-imino)-erythromycin A tosylate
  参考文献：
  名称：

  Process Development of a Novel Azetidinyl Ketolide Antibiotic

  摘要：

  Process development and the multikilogram synthesis of a novel azetidinyl ketolide antibiotic is described. Starting with clarithromycin, the eight-step synthesis features several telescoped operations and direct isolations, which results in a significant improvement in throughput and a major reduction in solvent usage and waste stream volume over the first scale-up campaign. Particular highlights of this effort include the development of an efficient synthesis of 3-hydroxy-1,5-naphthyridine-4-carbaldehyde via a Skraup process and engineering a robust final API synthesis. We also discovered a crystalline monotosylate salt that addressed significant formulation and degradation issues experienced when using the noncrystalline freebase.

  DOI：

  10.1021/op300064b

文献信息

• Discovery of Azetidinyl Ketolides for the Treatment of Susceptible and Multidrug Resistant Community-Acquired Respiratory Tract Infections
  作者：Thomas V. Magee、Sharon L. Ripp、Bryan Li、Richard A. Buzon、Lou Chupak、Thomas J. Dougherty、Steven M. Finegan、Dennis Girard、Anne E. Hagen、Michael J. Falcone、Kathleen A. Farley、Karl Granskog、Joel R. Hardink、Michael D. Huband、Barbara J. Kamicker、Takushi Kaneko、Michael J. Knickerbocker、Jennifer L. Liras、Andrea Marra、Ivy Medina、Thuy-Trinh Nguyen、Mark C. Noe、R. Scott Obach、John P. O’Donnell、Joseph B. Penzien、Usa Datta Reilly、John R. Schafer、Yue Shen、Gregory G. Stone、Timothy J. Strelevitz、Jianmin Sun、Amelia Tait-Kamradt、Alfin D. N. Vaz、David A. Whipple、Daniel W. Widlicka、Donn G. Wishka、Joanna P. Wolkowski、Mark E. Flanagan

  DOI：10.1021/jm900729s

  日期：2009.12.10

  Respiratory tract bacterial strains are becoming increasingly resistant to currently marketed macrolide antibiotics. The current alternative telithromycin (1) from the newer ketolide class of macrolides addresses resistance but is hampered by serious safety concerns, hepatotoxicity in particular. We have discovered a novel series of azetidinyl ketolides that focus on mitigation of hepatotoxicity by minimizing hepatic turnover and time-dependent inactivation of CYP3A isoforms in the liver without compromising the potency and efficacy of 1.