(-)-ethyl 9,10-difluoro-2,3-dihydro-3-hydroxymethyl-7-oxo-7H-pyrido<1,2,3-de><1,4>benzoxazine-6-carboxylate | 100986-87-6

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 喹啉及其衍生物
• 英文名称: (-)-ethyl 9,10-difluoro-2,3-dihydro-3-hydroxymethyl-7-oxo-7H-pyrido<1,2,3-de><1,4>benzoxazine-6-carboxylate
• 英文别名: ethyl (3S)-9,10-difluoro-2,3-dihydro-3-hydroxymethyl-7-oxo-7H-pyrido[1,2,3-de]benzoxazine-6-carboxylate；(3S)-9,10-difluoro-2,3-dihydro-3-hydroxymethyl-7-oxo-7H-pyrido[1,2,3-d,e][1,4]benzoxazine-6-carboxylic acid ethyl ester；ethyl (2S)-6,7-difluoro-2-(hydroxymethyl)-10-oxo-4-oxa-1-azatricyclo[7.3.1.05,13]trideca-5(13),6,8,11-tetraene-11-carboxylate
• CAS: 100986-87-6
• 化学式: C₁₅H₁₃F₂NO₅
• 分子量: 325.269
• InChiKey: JMLQHHMFVZKRSL-ZETCQYMHSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  1.1
• 重原子数：
  23
• 可旋转键数：
  4
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  76.1
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  (-)-ethyl 9,10-difluoro-2,3-dihydro-3-hydroxymethyl-7-oxo-7H-pyrido<1,2,3-de><1,4>benzoxazine-6-carboxylate 在 二乙胺基三氟化硫 作用下， 以 四氢呋喃 为溶剂， 反应 0.5h， 以65%的产率得到(+)-ethyl 9,10-difluoro-3-fluoromethyl-2,3-dihydro-7-oxo-7H-pyrido<1,2,3-de><1,4>benzoxazine-6-carboxylate
  参考文献：
  名称：

  Synthesis and Antibacterial Activity of Novel Pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic Acid Derivatives Carrying the 3-Cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl Group as a C-10 Substituent

  摘要：

  Novel pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid derivatives 5-9 carrying a 3-cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl moiety at the C-10 position were synthesized and their in vitro antibacterial activity, intravenous single-dose toxicity, convulsion inductive ability, and phototoxicity were evaluated. It appeared evident that compounds 5a, 6a, 8a, and 9a, which have a cis-oriented 4-methyl or 4-fluoro-3-cyclopropylaminomethyl-1-pyrrolidinyl moiety at the C-10 position, exhibited 2- to 16-fold more potent in vitro antibacterial activity than clinafloxacin against quinolone-resistant Gram-positive clinical isolates. Furthermore, it was obvious that introduction of a fluorine atom to the C-4 position of the 3-cyclopropylaminomethyl-1-pyrrolidinyl moiety reduced intraveneous single-dose acute toxicity and the convulsion inductive ability, and introduction of a fluorine atom to the C-3 methyl group of the pyridobenzoxazine nucleus eliminated the phototoxicity.

  DOI：

  10.1021/jm701428b
• 作为产物：
  描述：

  (+/-)-ethyl 9,10-difluoro-2,3-dihydro-3-(3,5-dinitrobenzoyloxy)methyl-7-oxo-7H-pyrido<1,2,3-de><1,4>benzoxazine-6-carboxylate 在 碳酸氢钠 作用下， 以 乙醇 为溶剂， 反应 2.0h， 生成 (-)-ethyl 9,10-difluoro-2,3-dihydro-3-hydroxymethyl-7-oxo-7H-pyrido<1,2,3-de><1,4>benzoxazine-6-carboxylate
  参考文献：
  名称：

  synthesis and antibacterial activities of optically active ofloxacin and its fluoromethyl derivative.

  摘要：

  氧氟沙星（1）[(±) -ofloxacin; DL-8280；(±)-9-氟-2, 3-二氢-3-甲基-10- (4-甲基-1-哌嗪基) -7-氧代-7H-吡啶并[1, 2, 3-de] [1, 4] 苯并恶嗪-6-羧酸]及其氟甲基衍生物 (14a 和 14b)是通过使用高效液相色谱法 (HPLC) 解析其光学活性中间体而制备的。通过苯并恶嗪（17）与 L-脯氨酰氯反应制备的非对映异构体（18、19）的分离，也可以通过另一种途径有效地获得异构体（13a 和 13b）。1 的 (-) - 异构体及其氟甲基衍生物 (2) 的活性大约是相应外消旋体的两倍，而 (+) - 异构体的活性则大大低于外消旋体。通过对 (-) - 苯并恶嗪衍生物 (15b) 的盐酸盐进行 X 射线分析，证实了一系列 (-) - 化合物 (b) 中恶嗪环 C3 位置的绝对构型为 S。

  DOI：

  10.1248/cpb.35.1896

文献信息

• 10-(3-cyclopropylaminomethyl-1-pyrrolidinyl)pyridobenzoxazinecarboxylic acid derivative effective against resistant bacterium
  申请人：Asahina Yoshikazu

  公开号：US20050182052A1

  公开（公告）日：2005-08-18

  A compound as represented by the general formula (I) shown below exhibits high antibacterial activity against gram-positive bacteria, in particular, such drug-resistant bacteria as mRNA, PRSP and VRE: wherein R1 is a methyl group, a fluoromethyl group, a methoxymethyl group, an acetoxymethyl group, a hydroxymethyl group or a methylene; R2 is a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, or a pharmaceutically acceptable cation and an ester of a prodrug; R3 is a hydrogen atom or a halogen atom; R4 is a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, a fluoromethyl group, a trifluoromethyl group or a fluorine atom; and R5 is a hydrogen atom or a fluorine atom, with exceptions where R1 is a methyl group, R4 and R5 are at the same time a hydrogen atom, and R3 is a fluorine atom.

  下列通式（I）所代表的化合物对革兰氏阳性细菌表现出高度的抗菌活性，特别是对那些耐药菌如mRNA、PRSP和VRE： 其中，R1是甲基、氟甲基、甲氧甲基、乙酰氧甲基、羟甲基或亚甲基；R2是氢原子、具有1至3个碳原子的低烷基或药学上可接受的阳离子和前药的酯；R3是氢原子或卤素原子；R4是氢原子、具有1至3个碳原子的低烷基、氟甲基、三氟甲基或氟原子；R5是氢原子或氟原子，除非R1是甲基、R4和R5同时为氢原子，且R3是氟原子的情况。
• 10-(3-CYCLOPROPYLAMINOMETHYL-1-PYRROLIDINYL)PYRIDOBENZOXAZINECARBOXYLIC ACID DERIVATIVE EFFECTIVE AGAINST RESISTANT BACTERIUM
  申请人：Kyorin Pharmaceutical Co., Ltd.

  公开号：EP1486500A1

  公开（公告）日：2004-12-15

  A compound as represented by the general formula (I) shown below exhibits high antibacterial activity against gram-positive bacteria, in particular, such drug-resistant bacteria as MRNA, PRSP and VRE: wherein R1 is a methyl group, a fluoromethyl group, a methoxymethyl group, an acetoxymethyl group, a hydroxymethyl group or a methylene; R2 is a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, or a pharmaceutically acceptable cation and an ester of a prodrug; R3 is a hydrogen atom or a halogen atom; R4 is a hydrogen atom, a lower alkyl group having 1 to 3 carbon atoms, a fluoromethyl group, a trifluoromethyl group or a fluorine atom; and R5 is a hydrogen atom or a fluorine atom, with exceptions where R1 is a methyl group, R4 and R5 are at the same time a hydrogen atom, and R3 is a fluorine atom.

  下图所示通式(I)代表的化合物对革兰氏阳性菌，特别是 MRNA、PRSP 和 VRE 等耐药菌具有很强的抗菌活性： 其中 R1 是甲基、氟甲基、甲氧基甲基、乙酰氧甲基、羟甲基或亚甲基；R2 是氢原子、具有 1 至 3 个碳原子的低级烷基或药学上可接受的阳离子和原药的酯类；R3 是氢原子或卤素原子；R4 是氢原子、1-3 个碳原子的低级烷基、氟甲基、三氟甲基或氟原子；R5 是氢原子或氟原子，但 R1 是甲基、R4 和 R5 同时是氢原子和 R3 是氟原子的情况除外。
• 10-(3-CYCLOPROPYLAMINOMETHYL-1-PYRROLIDINYL)PYRIDOBENZOXAZINECARBOXYLIC ACID DERIVATIVE EFFECTIVE AGAINST RESISTANT BACTERIA
  申请人：Kyorin Pharmaceutical Co., Ltd.

  公开号：EP1486500B1

  公开（公告）日：2009-09-16
• US7153851B2
  申请人：——

  公开号：US7153851B2

  公开（公告）日：2006-12-26
• Synthesis and Antibacterial Activity of Novel Pyrido[1,2,3-<i>de</i>][1,4]benzoxazine-6-carboxylic Acid Derivatives Carrying the 3-Cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl Group as a C-10 Substituent
  作者：Yoshikazu Asahina、Masaya Takei、Tetsuya Kimura、Yasumichi Fukuda

  DOI：10.1021/jm701428b

  日期：2008.6.1

  Novel pyrido[1,2,3-de][1,4]benzoxazine-6-carboxylic acid derivatives 5-9 carrying a 3-cyclopropylaminomethyl-4-substituted-1-pyrrolidinyl moiety at the C-10 position were synthesized and their in vitro antibacterial activity, intravenous single-dose toxicity, convulsion inductive ability, and phototoxicity were evaluated. It appeared evident that compounds 5a, 6a, 8a, and 9a, which have a cis-oriented 4-methyl or 4-fluoro-3-cyclopropylaminomethyl-1-pyrrolidinyl moiety at the C-10 position, exhibited 2- to 16-fold more potent in vitro antibacterial activity than clinafloxacin against quinolone-resistant Gram-positive clinical isolates. Furthermore, it was obvious that introduction of a fluorine atom to the C-4 position of the 3-cyclopropylaminomethyl-1-pyrrolidinyl moiety reduced intraveneous single-dose acute toxicity and the convulsion inductive ability, and introduction of a fluorine atom to the C-3 methyl group of the pyridobenzoxazine nucleus eliminated the phototoxicity.