1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione | 351367-87-8

• 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: 1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
• 英文别名: 1-cyclopropyl-6,7-difluoro-8-methoxyquinazoline-2,4-dione
• CAS: 351367-87-8
• 化学式: C₁₂H₁₀F₂N₂O₃
• 分子量: 268.22
• InChiKey: BCZJHULRTYMTDK-UHFFFAOYSA-N

物化性质

• 熔点：
  233-234 °C(Solv: 1,4-dioxane (123-91-1); heptane (142-82-5))
• 密度：
  1.526±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.4
• 重原子数：
  19
• 可旋转键数：
  2
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione 在 potassium carbonate 、 四甲基胍 作用下， 以 1,4-二氧六环 、 二甲基亚砜 、 N,N-二甲基甲酰胺 为溶剂， 反应 35.0h， 生成 {(S)-1-[(R)-1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)pyrrolidin-3-yl]ethyl}carbamic acid tert-butyl ester
  参考文献：
  名称：

  The Preparation of Two, Preclinical Amino-quinazolinediones as Antibacterial Agents

  摘要：

  This paper describes the synthesis of two amino-quinazolinediones which are potent gyrase/topoisomerase inhibitors and useful as antibacterial agents. The early scale-up work to prepare a chiral side chain on multigram scale and two different amino-quinazolinedione cores is detailed. The enabling synthesis for the side chain employed a previously reported Michael addition of MeNO2 to an enantiomerically enriched delta-amino-enoate and a two-step de-oxygenation of a lactam. Key synthetic steps for core preparation and completion of the amino-quinazolinediones include dianion-promoted cyclization via intramolecular, nucleophilic aromatic substitution, electrophilic amination, nucleophilic aromatic substitution of the side chain to the core, deprotection and isolation of the hydrochloride salt in acceptable yield.

  DOI：

  10.1021/op7000639
• 作为产物：
  描述：

  在 双(三甲基硅烷基)氨基钾 作用下， 以 四氢呋喃 、 1,4-二氧六环 为溶剂， 反应 3.67h， 生成 1-cyclopropyl-6,7-difluoro-8-methoxy-1H-quinazoline-2,4-dione
  参考文献：
  名称：

  5，6-二氢吡唑并[1,5-c]喹唑啉-1-羧酸乙酯作为DNA促旋酶的催化抑制剂的鉴定。

  摘要：

  氟喹诺酮类是临床上用于治疗多种细菌感染和靶向细菌II型拓扑异构酶（DNA促旋酶和拓扑异构酶IV）的一类抗菌剂。然而，氟喹诺酮类药物很强效，长时间使用对细菌具有抵抗力，这限制了它们在临床上的使用。喹唑啉-2,4-二酮也靶向细菌II型拓扑异构酶，与氟喹诺酮类相似，对细菌的耐药性不敏感，但是，与氟喹诺酮类相比，它们的药效低下。为了满足对抗菌素开发的不断增长的需求，开发了九种修饰的喹唑啉-2,4-二酮，以探测喹唑啉-2,4-二酮的结构修饰，以寻找与细菌II型拓扑异构酶，DNA促旋酶的新结合接触。化合物对DNA促旋酶超螺旋活性的抑制作用评估显示，新型的5,6-二氢吡唑并[1,5-c]喹唑啉-1-羧酸乙酯衍生物是DNA促旋酶的适度抑制剂，IC50为3.5μM。但是，这种5,6-二氢吡唑并[1,5-c]喹唑啉-1-羧酸乙酯不能像氟喹诺酮或典型的喹唑啉-2,4-二酮那样捕获催化中间体。因此，在这项工作中发现的5

  DOI：

  10.1016/j.bmc.2020.115439

文献信息

• QUINAZOLINE-2,4-DIONE DERIVATIVES
  申请人：Hubschwerlen Christian

  公开号：US20140171425A1

  公开（公告）日：2014-06-19

  The invention relates to antibacterial compounds of formula (I), wherein R 1 is H, halogen, (C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxy; R 2 is H, halogen, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy or pyrrolidin-1-yl; R 3 is H, halogen, (C 1 -C 3 )alkyl, (C 1 -C 3 )alkoxy, vinyl or 2-methoxycarbonyvinyl or R 2 and R 3 together with the two carbon atoms which bear them form a phenyl ring; R 4 is H, halogen, (C 1 -C 3 )alkyl or (C 1 -C 3 )alkoxy; and R 5 is H, (C 1 -C 3 )alkyl or cyclopropyl, or R 4 and R 5 form together a —CH 2 CH 2 CH 2 — group; A is the divalent group —CH 2 —, —CH 2 CH 2 —, #—CH(OH)CH 2 —*, #—CH 2 N(R 6 )—* and —CH 2 NHCH 2 —, wherein # indicates the point of attachment to the optionally substituted (quinazoline-2,4-dione-3-yl)methyl residue and * represents the point of attachment to the substituted (oxazolidinon-4-yl)methyl residue; R 6 is H or acetyl; Y is CH or N; and Q is O or S; and salts of such compounds.

  该发明涉及式(I)的抗菌化合物，其中R1为H、卤素、(C1-C3)烷基或(C1-C3)氧烷；R2为H、卤素、(C1-C3)烷基、(C1-C3)氧烷或吡咯烷-1-基；R3为H、卤素、(C1-C3)烷基、(C1-C3)氧烷、乙烯基或2-甲氧羰基乙烯基，或R2和R3与携带它们的两个碳原子一起形成苯环；R4为H、卤素、(C1-C3)烷基或(C1-C3)氧烷；R5为H、(C1-C3)烷基或环丙基，或R4和R5一起形成一个—CH2CH2CH2—基团；A为二价基团—CH2—、—CH2CH2—、#—CH(OH)CH2—*、#—CH2N(R6)—*和—CH2NHCH2—，其中#表示可选择取代的(喹唑啉-2,4-二酮-3-基)甲基残基的连接点，*表示取代的(噁唑烷酮-4-基)甲基残基的连接点；R6为H或乙酰基；Y为CH或N；Q为O或S；以及这类化合物的盐。
• [EN] QUINAZOLINE-2,4-DIONE DERIVATIVES<br/>[FR] DÉRIVÉS DE QUINAZOLINE-2,4-DIONE
  申请人：ACTELION PHARMACEUTICALS LTD

  公开号：WO2013021363A1

  公开（公告）日：2013-02-14

  The invention relates to antibacterial compounds of formula (I), wherein R1 is H, halogen, (C1-C3)alkyl or (C1-C3)alkoxy; R2 is H, halogen, (C1-C3)alkyl, (C1-C3)alkoxy or pyrrolidin-l-yl; R3 is H, halogen, (C1-C3)alkyl, (C1-C3)alkoxy, vinyl or 2-methoxycarbonylvinyl or R2 and R3 together with the two carbon atoms which bear them form a phenyl ring; R4 is H, halogen, (C1-C3)alkyl or (C1-C3)alkoxy and R5 is H, (C1-C3)alkyl or cyclopropyl, or R4 and R5 form together a -CH2CH2CH2- group; A is the divalent group -CH2-, -CH2CH2-, #-CH(OH)CH2-*, #-CH2N(R6)-* or -CH2NHCH2-, wherein # indicates the point of attachment to the optionally substituted (quinazoline-2,4-dione-3-yl)methyl residue and * represents the point of attachment to the substituted (oxazolidinon-4-yl)methyl residue; R6 is H or acetyl; Y is CH or N; and Q is O or S; and salts of such compounds.

  该发明涉及式(I)的抗菌化合物，其中R1为H、卤素、(C1-C3)烷基或(C1-C3)氧烷基；R2为H、卤素、(C1-C3)烷基、(C1-C3)氧烷基或吡咯烷-1-基；R3为H、卤素、(C1-C3)烷基、(C1-C3)氧烷基、乙烯基或2-甲氧羰基乙烯基，或者R2和R3与它们所连接的两个碳原子一起形成苯环；R4为H、卤素、(C1-C3)烷基或(C1-C3)氧烷基，R5为H、(C1-C3)烷基或环丙基，或者R4和R5一起形成一个-CH2CH2CH2-基团；A为二价基团-CH2-、-CH2CH2-、#-CH(OH)CH2-*、#-CH2N(R6)-*或-CH2NHCH2-，其中#表示可选择取代的(喹唑啉-2,4-二酮-3-基)甲基残基的连接点，*表示取代的(噁唑烷酮-4-基)甲基残基的连接点；R6为H或乙酰基；Y为CH或N；Q为O或S；以及这类化合物的盐。
• Antibacterial agents
  申请人：——

  公开号：US20030114666A1

  公开（公告）日：2003-06-19

  The present invention provides compounds of formula (I): 1 wherein R 1 -R 6 and J and K have any of the values defined in the specification, and pharmaceutically acceptable salt thereof, that are useful as antibacterial agents. Also disclosed are pharmaceutical compositions comprising one or more compounds of formula I, processes for preparing compounds of formula I, and intermediates useful for preparing compounds of formula I.

  本发明提供了化合物(I)的公式：1其中R1-R6和J和K具有规范中定义的任何值，以及其药学上可接受的盐，可用作抗菌剂。还揭示了包含一个或多个公式I化合物的制药组合物，制备公式I化合物的过程以及制备公式I化合物有用的中间体。
• A facile synthesis of substituted 3-amino-1<i>H</i>-quinazoline-2,4-diones
  作者：Tuan P. Tran、Edmund L. Ellsworth、Brian M. Watson、Joseph P. Sanchez、H. D. Hollis Showalter、John R. Rubin、Michael A. Stier、Judy Yip、Dai Q. Nguyen、Paul Bird、Rajeshwar Singh

  DOI：10.1002/jhet.5570420428

  日期：2005.5

  1H-quinazoline-2,4-dione 10 was made starting with fluorobenzoic acid in three high yielding steps. The key step of this synthesis involved the generation of the dianion of urea 7 and the subsequent intramolecular nucleophilic displacement of the 2-fluoro to form the quinazolinedione ring. The 3-amino moiety was incorporated using (2,4-dinitro-phenyl)-hydroxylamine as the aminating reagent.

  描述了一系列3-氨基-1 H-喹唑啉-2,4-二酮的新合成。从氟苯甲酸开始，在三个高产率步骤中制备1 H-喹唑啉-2,4-二酮10。该合成的关键步骤涉及尿素7的二价阴离子的产生和随后的2-氟分子内亲核取代以形成喹唑啉二酮环。使用（2，4-二硝基-苯基）-羟胺作为胺化试剂并入3-氨基部分。
• Electrophilic <i>N</i>-Amination of Two Quinazoline-2,4-diones Using Substituted (Nitrophenyl)hydroxylamines
  作者：David C. Boyles、Timothy T. Curran、Parlett、Mark Davis、Frank Mauro

  DOI：10.1021/op010239f

  日期：2002.5.1

  The preparation of a few (nitrophenyl)hydroxylamines and reaction with two quinazoline-2,4-diones is described. The electrophilic aminating agents were assessed in terms of yield for the N-amination of two quinazoline-2,4-diones and safety considerations for rapid scale-up. For the amination of the described system, the best yield and the highest onset temperature were found in the same aminating agent

  描述了几种（硝基苯基）羟胺的制备和与两种喹唑啉-2,4-二酮的反应。根据两种喹唑啉-2,4-二酮的 N-胺化的产率和快速放大的安全考虑来评估亲电胺化剂。对于所述体系的胺化，在相同的胺化剂中发现了最好的产率和最高的起始温度，特别是（4-硝基苯基）羟胺。