methyl 5-benzyloxy-6-hydroxymethyl-4-oxo-1,4-dihydropyridine-3-carboxylate | 906658-35-3

• 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: methyl 5-benzyloxy-6-hydroxymethyl-4-oxo-1,4-dihydropyridine-3-carboxylate
• 英文别名: 5-Benzyloxy-4-hydroxy-6-hydroxymethyl-nicotinic acid methyl ester；methyl 6-(hydroxymethyl)-4-oxo-5-phenylmethoxy-1H-pyridine-3-carboxylate
• CAS: 906658-35-3；906658-57-9
• 化学式: C₁₅H₁₅NO₅
• 分子量: 289.288
• InChiKey: PGFZURCHGNIEMW-UHFFFAOYSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1
• 重原子数：
  21
• 可旋转键数：
  6
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.2
• 拓扑面积：
  84.9
• 氢给体数：
  2
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  methyl 5-benzyloxy-6-hydroxymethyl-4-oxo-1,4-dihydropyridine-3-carboxylate 在 manganese(IV) oxide 、 potassium osmate(VI) dihydrate 、 sodium chlorite 、 sodium periodate 、 氨基磺酸 、 1-羟基苯并三唑 、 caesium carbonate 、 溶剂黄146 、 盐酸-N-乙基-Nˊ-(3-二甲氨基丙基)碳二亚胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 二氯甲烷 、 氯仿 、 水 、 N,N-二甲基甲酰胺 为溶剂， 反应 13.5h， 生成 1-benzyloxy-6-methyl-2,11-dioxo-2,5a,6,7,8,9,10,11-octahydro-5H-4a,6,10a-triazacyclohepta[b]naphthalene-3-carboxylic acid 4-fluorobenzylamide
  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 N-溴代丁二酰亚胺(NBS) 、 1,3-双(二苯基膦)丙烷 、 氨 、 sodium methylate 、 palladium diacetate 、 三乙胺 、 间氯过氧苯甲酸 、 sodium hydroxide 作用下， 以 甲醇 、 乙醇 、 氯仿 、 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 24.0h， 生成 methyl 5-benzyloxy-6-hydroxymethyl-4-oxo-1,4-dihydropyridine-3-carboxylate
  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

文献信息

• Bicyclic Carbamoylpyridone Derivative Having Hiv Integrase Inhibitory Activity
  申请人：Yoshida Hiroshi

  公开号：US20080161271A1

  公开（公告）日：2008-07-03

  [Object] Is to provide a novel compound having an anti-viral activity, particularly a HIV integrase inhibitory activity, and an agent, particularly an anti-HIV agent. [Solving means] A compound represented by the formula: (wherein Z 1 is NR 4 (R 4 is hydrogen, optionally substituted lower alkyl etc.), O or CH 2 ; Z 2 is optionally substituted lower alkylene or optionally substituted lower alkenylene, each may be intervened by a heteroatom group selected from group consisting O, S, SO, SO 2 , NR 5 (R 5 is selected independently from the same substituent group of R 4 )—N═ and ═N—; R 1 is hydrogen or lower alkyl; X is a single bond, a heteroatom group selected from O, S, SO, SO 2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group; R 2 is optionally substituted aryl; R 3 is hydrogen, halogen, hydroxy, optionally substituted alkyl group etc.)

  [目的]提供一种具有抗病毒活性，特别是HIV整合酶抑制活性的新化合物和一种药剂，特别是抗HIV药剂。 [解决方法]一种由以下公式表示的化合物： （其中Z1为NR4（R4为氢，可选择性取代的低碳基等），O或CH2； Z2为可选择性取代的低位撑链或可选择性取代的低位烯链，每个可以由从O，S，SO，SO2，NR5（R5为独立选择自R4的相同取代基团）-N═和═N-组成的杂原子基团隔开； R1为氢或低碳基； X为单键，从O，S，SO，SO2和NH中选择的杂原子基团，或者可选择性被杂原子基团隔开的低位撑链或低位烯链； R2为可选择性取代的芳基； R3为氢，卤素，羟基，可选择性取代的烷基等。
• Bicyclic carbamoylpyridone derivative having HIV integrase inhibitory activity
  申请人：Shionogi & Co., Ltd.

  公开号：US07858788B2

  公开（公告）日：2010-12-28

  Is to provide a novel compound having an anti-viral activity, particularly a HIV integrase inhibitory activity, and an agent, particularly an anti-HIV agent. A compound represented by the formula: (wherein Z1 is NR4 (R4 is hydrogen, optionally substituted lower alkyl etc.), O or CH2; Z2 is optionally substituted lower alkylene or optionally substituted lower alkenylene, each may be intervened by a heteroatom group selected from group consisting O, S, SO, SO2, NR5 (R5 is selected independently from the same substituent group of R4) —N═ and ═N—; R1 is hydrogen or lower alkyl; X is a single bond, a heteroatom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group; R2 is optionally substituted aryl; R3 is hydrogen, halogen, hydroxy, optionally substituted alkyl group etc.)

  提供一种具有抗病毒活性，特别是HIV整合酶抑制活性的新型化合物和制剂，特别是抗HIV制剂。该化合物的表示式为：（其中Z1为NR4（R4为氢，可选取取代基较低的烷基等），O或CH2; Z2为可选取取代基较低的亚烷基或可选取取代基较低的烯基，每个均可由从O、S、SO、SO2、NR5（R5从与R4相同的取代基群中独立选择）-N═和═N-组成的杂原子基团中介；R1为氢或较低的烷基；X为单键，从O、S、SO、SO2和NH中选择的杂原子基团，或可选取取代基较低的亚烷基或可选取取代基较低的烯基，每个均可由杂原子基团中介；R2为可选取取代基的芳基；R3为氢，卤素，羟基，可选取取代基的烷基等。
• An improved process for the preparation of Dolutegravir
  申请人：Aurobindo Pharma Ltd.

  公开号：US20160108058A1

  公开（公告）日：2016-04-21

  The present invention provides (R)-3-Amino-1-butanol (D)-tartarate (IIb); process for its preparation and its conversion to Dolutegravir. The present invention also provides an improved process for the preparation of Dolutegravir (I) or pharmaceutically acceptable salts wherein compound (XVI) is reacted with an optically active acid addition salt of (R)-3-amino-1-butanol (IIa).

  本发明提供(R)-3-氨基-1-丁醇(D)-酒石酸盐(IIb)；其制备方法以及其转化为多糖格拉韦的方法。本发明还提供了一种改进的多糖格拉韦(I)或药学上可接受的盐的制备方法，其中化合物(XVI)与(R)-3-氨基-1-丁醇(IIa)的光学活性酸盐进行反应。
• BICYCLIC CARBAMOYLPYRIDONE DERIVATIVE HAVING HIV INTEGRASE INHIBITING ACTIVITY
  申请人：Shionogi Co., Ltd.

  公开号：EP1852434A1

  公开（公告）日：2007-11-07

  [Object] Is to provide a novel compound having an anti-viral activity, particularly a HIV integrase inhibitory activity, and an agent, particularly an anti-HIV agent. [Solving means] A compound represented by the formula: (wherein Z1 is NR4 (R4 is hydrogen, optionally substituted lower alkyl etc.), O or CH2; Z2 is optionally substituted lower alkylene or optionally substituted lower alkenylene, each may be intervened by a heteroatom group selected from group consisting O, S, SO, SO2, NR5 (R5 is selected independently from the same substituent group of R4) -N= and =N-; R1 is hydrogen or lower alkyl; X is a single bond, a heteroatom group selected from O, S, SO, SO2 and NH, or lower alkylene or lower alkenylene each may be intervened by the heteroatom group; R2 is optionally substituted aryl; R3 is hydrogen, halogen, hydroxy, optionally substituted alkyl group etc.)

  [目的]提供一种具有抗病毒活性，特别是抑制HIV整合酶活性的新型化合物，以及一种制剂，特别是抗HIV制剂。 [解决手段] 一种由式表示的化合物： 其中 Z1 是 NR4（R4 是氢、任选取代的低级烷基等）、O 或 CH2； Z2 是任选取代的低级亚烷基或任选取代的低级烯基，每个亚烷基和低级烯基之间可以有一个杂原子基团，该杂原子基团选自 O、S、SO、SO2、NR5（R5 独立地选自 R4 的相同取代基）-N= 和 =N-； R1 是氢或低级烷基； X 是单键、选自 O、S、SO、SO2 和 NH 的杂原子基团或低级亚烷基或低级亚烯基，每个杂原子基团之间可以有一个杂原子基团； R2 是任选取代的芳基； R3 是氢、卤素、羟基、任选取代的烷基等）。
• PROCESS FOR PREPARING COMPOUND HAVING HIV INTEGRASE INHIBITORY ACTIVITY
  申请人：SHIONOGI & CO., LTD

  公开号：EP3127908A2

  公开（公告）日：2017-02-08

  A process for preparing a compound represented by formula (Y1) or (Y2) [wherein Rx is an optionally substituted carbocyclyl lower alkyl, or the like] or a salt thereof, using a novel process for preparing a pyridone derivative represented by formula (X4) [wherein R1d is hydrogen, halogen, or the like; R2d is hydrogen, a lower alkyl optionally substituted with substituent E, or the like; R4d is a lower alkyl optionally substituted with substituent E, or the like; and R6d is a lower alkyl group optionally substituted with substituent group E].

  一种制备式(Y1)或(Y2)代表的化合物[其中Rx为任选取代的羰基低级烷基或类似物]或其盐的工艺，该工艺采用了制备式(X4)代表的吡啶酮衍生物的新工艺[其中R1d为氢、卤素或类似物；R2d为氢、任选被取代基E取代的低级烷基或类似物；R4d为任选被取代基E取代的低级烷基或类似物；R6d为任选被取代基E取代的低级烷基]。