(S)-7-(benzyloxy)-N-(4-fluorobenzyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]-oxazine-9-carboxamide | 1447310-90-8

• 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
• 英文名称: (S)-7-(benzyloxy)-N-(4-fluorobenzyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]-oxazine-9-carboxamide
• 英文别名: (12aS)-N-[(4-fluorophenyl)methyl]-6,8-dioxo-7-[(phenylmethyl)oxy]-3,4,6,8,12,12ahexahydro-2H-pyrido[1',2':4,5]pyrazino[2,1-b][1,3]oxazine-9-carboxamide；(3S)-N-[(4-fluorophenyl)methyl]-9,12-dioxo-11-phenylmethoxy-4-oxa-1,8-diazatricyclo[8.4.0.03,8]tetradeca-10,13-diene-13-carboxamide
• CAS: 1447310-90-8
• 化学式: C₂₆H₂₄FN₃O₅
• 分子量: 477.492
• InChiKey: HYFVURBNORFJON-NRFANRHFSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  3.2
• 重原子数：
  35
• 可旋转键数：
  6
• 环数：
  5.0
• sp3杂化的碳原子比例：
  0.27
• 拓扑面积：
  88.2
• 氢给体数：
  1
• 氢受体数：
  7

反应信息

• 作为产物：
  描述：

  methyl 3-benzyloxy-5-(4-fluorobenzylcarbamoyl)-4-oxo-1-(2-oxoethyl)-1,4-dihydropyridine-2-carboxylate 、 3-氨基-1-丙醇 在 溶剂黄146 作用下， 以33 mg的产率得到(R)-7-(benzyloxy)-N-(4-fluorobenzyl)-6,8-dioxo-3,4,6,8,12,12a-hexahydro-2H-pyrido[1′,2′:4,5]pyrazino[2,1-b][1,3]-oxazine-9-carboxamide
  参考文献：
  名称：

  Carbamoyl Pyridone HIV-1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744)

  摘要：

  We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the integrase catalytic active site. Structure-activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereo-selective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of 3 and 4, which are currently in clinical development.

  DOI：

  10.1021/jm400645w

文献信息

• Carbamoyl Pyridone HIV-1 Integrase Inhibitors 3. A Diastereomeric Approach to Chiral Nonracemic Tricyclic Ring Systems and the Discovery of Dolutegravir (S/GSK1349572) and (S/GSK1265744)
  作者：Brian A. Johns、Takashi Kawasuji、Jason G. Weatherhead、Teruhiko Taishi、David P. Temelkoff、Hiroshi Yoshida、Toshiyuki Akiyama、Yoshiyuki Taoda、Hitoshi Murai、Ryuichi Kiyama、Masahiro Fuji、Norihiko Tanimoto、Jerry Jeffrey、Scott A. Foster、Tomokazu Yoshinaga、Takahiro Seki、Masanori Kobayashi、Akihiko Sato、Matthew N. Johnson、Edward P. Garvey、Tamio Fujiwara

  DOI：10.1021/jm400645w

  日期：2013.7.25

  We report herein the discovery of the human immunodeficiency virus type-1 (HIV-1) integrase inhibitors dolutegravir (S/GSK1349572) (3) and S/GSK1265744 (4). These drugs stem from a series of carbamoyl pyridone analogues designed using a two-metal chelation model of the integrase catalytic active site. Structure-activity studies evolved a tricyclic series of carbamoyl pyridines that demonstrated properties indicative of once-daily dosing and superior potency against resistant viral strains. An inherent hemiaminal ring fusion stereocenter within the tricyclic carbamoyl pyridone scaffold led to a critical substrate controlled diastereo-selective synthetic strategy whereby chiral information from small readily available amino alcohols was employed to control relative and absolute stereochemistry of the final drug candidates. Modest to extremely high levels of stereochemical control were observed depending on ring size and position of the stereocenter. This approach resulted in the discovery of 3 and 4, which are currently in clinical development.