7-benzyloxy-N-(4-fluorobenzyl)-6,8-dioxo-3,4,6,8,12,12ahexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide | 1229006-36-3

• 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: 7-benzyloxy-N-(4-fluorobenzyl)-6,8-dioxo-3,4,6,8,12,12ahexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide
• 英文别名: 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；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: 1229006-36-3
• 化学式: C₂₆H₂₄FN₃O₅
• 分子量: 477.492
• InChiKey: HYFVURBNORFJON-UHFFFAOYSA-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

• 作为反应物：
  描述：

  7-benzyloxy-N-(4-fluorobenzyl)-6,8-dioxo-3,4,6,8,12,12ahexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide 在 palladium 10% on activated carbon 、 氢气 作用下， 以 甲醇 、 N,N-二甲基甲酰胺 为溶剂， 反应 20.0h， 生成 N-(4-fluorobenzyl)-7-hydroxy-6,8-dioxo-3,4,6,8,12,12ahexahydro-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. 2. Bi- and Tricyclic Derivatives Result in Superior Antiviral and Pharmacokinetic Profiles

  摘要：

  This work is a continuation of our initial discovery of a potent monocyclic carbamoyl pyridone human immunodeficiency virus type-1 (HIV-1) integrase inhibitor that displayed favorable antiviral and pharmacokinetic properties. We report herein a series of bicyclic carbamoyl pyridone analogues to address conformational issues from our initial SAR studies. This modification of the core unit succeeded to deliver low nanomolar potency in standard antiviral assays. An additional hydroxyl substituent on the bicyclic scaffold provides remarkable improvement of antiviral efficacies against clinically relevant resistant viruses. These findings led to additional cyclic tethering of the naked hydroxyl group resulting in tricyclic carbamoyl pyridone inhibitors to address remaining issues and deliver potential clinical candidates. The tricyclic carbamoyl pyridone derivatives described herein served as the immediate leads in molecules to the next generation integrase inhibitor dolutegravir which is currently in late stage clinical evaluation.

  DOI：

  10.1021/jm301550c
• 作为产物：
  描述：

  3-(苄氧基)-2-甲基-4H-吡喃-4-酮 在 selenium(IV) oxide 、 potassium osmate(VI) dihydrate 、 sodium chlorite 、 sodium periodate 、 四(三苯基膦)钯 、 溴苯 、 氨基磺酸 、 溴 、 溶剂黄146 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 N,N-二异丙基乙胺 作用下， 以 甲醇 、 乙醚 、 乙醇 、 氯仿 、 水 、 二甲基亚砜 、 丙酮 、 乙腈 为溶剂， 反应 48.42h， 生成 7-benzyloxy-N-(4-fluorobenzyl)-6,8-dioxo-3,4,6,8,12,12ahexahydro-2H-[1,3]oxazino[3,2-d]pyrido[1,2-a]pyrazine-9-carboxamide
  参考文献：
  名称：

  JP5848595

  摘要：

  公开号：

文献信息

• [EN] PROCESSES AND INTERMEDIATES FOR CARBAMOYLPYRIDONE HIV INTEGRASE INHIBITORS<br/>[FR] PROCÉDÉS ET INTERMÉDIAIRES POUR INHIBITEURS DE LA CARBOMOYLPYRIDONE INTÉGRASE DU HIV
  申请人：GLAXOSMITHKLINE LLC

  公开号：WO2010068262A1

  公开（公告）日：2010-06-17

  Processes are provided which create an aldehyde methylene, or hydrated or hemiacetal methylene attached to a heteroatom of a 6 membered ring without going through an olefinic group and without the necessity of using an osmium reagent. In particular, a comopound of formula (I) can be produced from (II) and avoid the use of an allyl amine: (formulae I and II) where R, P 1 P3, R3 and Rx are as described herein.

  提供了一种方法，可以在不经过烯丙基团的情况下，将醛亚甲基、水合物亚甲基或半缩醛亚甲基连接到6元环的杂原子上，并且无需使用钌试剂。特别地，可以从（II）制备出式（I）的化合物，避免使用烯丙胺：（式I和II），其中R、P1、P3、R3和Rx如本文所述。
• PROCESSES AND INTERMEDIATES FOR CARBAMOYLPYRIDONE HIV INTEGRASE INHIBITORS
  申请人：VIIV Healthcare Company

  公开号：EP3617194A1

  公开（公告）日：2020-03-04

  Processes are provided which create an aldehyde methylene, or hydrated or hemiacetal methylene attached to a heteroatom of a 6 membered ring without going through an olefinic group and without the necessity of using an osmium reagent. In particular, a comopound of formula (I) can be produced from (II) and avoid the use of an allyl amine: where R, P1, P3, R3 and Rx are as described herein.

  本发明提供了无需通过烯烃基团，也无需使用锇试剂，即可生成醛亚甲基，或连接到 6 个成员环的杂原子上的水合亚甲基或半缩醛亚甲基的工艺。特别是可以由(II)制得式(I)的化合物，而无需使用烯丙基胺： 其中 R、P1、P3、R3 和 Rx 如本文所述。
• 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.
• SYNTHESIS OF CARBAMOYLPYRIDONE HIV INTEGRASE INHIBITORS AND INTERMEDIATES
  申请人：Shionogi & Co., Ltd.

  公开号：EP2376080B1

  公开（公告）日：2017-09-13
• JP5848595
  申请人：——

  公开号：——

  公开（公告）日：——