tert-butyl 3-(tert-butoxycarbonyl)aminomethyl-4-oxopyrrolidine-1-carboxylate | 175463-35-1

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 吡咯烷类
• 英文名称: tert-butyl 3-(tert-butoxycarbonyl)aminomethyl-4-oxopyrrolidine-1-carboxylate
• 英文别名: tert-Butyl 3-(((tert-butoxycarbonyl)amino)methyl)-4-oxopyrrolidine-1-carboxylate；tert-butyl 3-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]-4-oxopyrrolidine-1-carboxylate
• CAS: 175463-35-1
• 化学式: C₁₅H₂₆N₂O₅
• 分子量: 314.382
• InChiKey: UXKMYLZTGJCBKD-UHFFFAOYSA-N

物化性质

• 沸点：
  435.4±30.0 °C(Predicted)
• 密度：
  1.125±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  22
• 可旋转键数：
  6
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.8
• 拓扑面积：
  84.9
• 氢给体数：
  1
• 氢受体数：
  5

反应信息

• 作为反应物：
  描述：

  tert-butyl 3-(tert-butoxycarbonyl)aminomethyl-4-oxopyrrolidine-1-carboxylate 在 甲醇 、 盐酸羟胺 、 碳酸氢钠 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 乙酰氯 作用下， 以 四氢呋喃 、 乙醇 、 乙腈 为溶剂， 反应 2.33h， 生成 gemifloxacin
  参考文献：
  名称：

  Novel Fluoroquinolone Antibacterial Agents Containing Oxime-Substituted (Aminomethyl)pyrrolidines:  Synthesis and Antibacterial Activity of 7-(4-(Aminomethyl)-3-(methoxyimino)pyrrolidin-1-yl)-1-cyclopropyl-6-fluoro- 4-oxo-1,4-dihydro[1,8]naphthyridine-3-carboxylic Acid (LB20304)^,1

  摘要：

  New pyrrolidine derivatives, which bear an alkyloxime substituent in the 4-position and an aminomethyl substituent in the 3-position of the pyrrolidine ring, have been synthesized and coupled with various quinolinecarboxylic acids to produce a series of new fluoroquinolone antibacterials. These fluoroquinolones were found to possess potent antimicrobial activity against both Gram-negative and Gram-positive organisms, including methicillin resistant Staphylococcus aureus (MRSA). Variations at the C-8 position of the quinolone nucleus included fluorine, chlorine, nitrogen, methoxy, and hydrogen atom substitution. The activity imparted to the substituted quinolone nucleus by the C-8 substituent was in the order F (C-5-NH2) > F (C-5-H) > naphthyridine > Cl = OMe = H against Gram-positive organisms. In the case of Gram-negative strains, activity was in the order F (C-5-NH2) > naphthyridine = F (C-5-H) > H > Cl > OMe. The advantages provided by the newly introduced oxime group of the quinolones were clearly demonstrated by their comparison to a desoximino compound 30. In addition, the oxime moiety greatly improved the pharmacokinetic parameters of the novel quinolones. Among these compounds, compound 20 (LB20304) showed the best in vivo efficacy and pharmacokinetic profile in animals, as well as good physical properties. The MICs (mu g/mL) of LB20304, compound 30, and ciprofloxacin against several test organisms are as follows: S. aureus 6538p (0.008, 0.031, and 0.13), methicillin resistant S. aureus 241 (4, 16, and 128), Streptococcus epidermidis 887E (0.008, 0.016, and 0.13), methicillin resistant S. epidermidis 178 (4, 32, and 128), Enterococcus faecalis 29212 (0.063, 0.13, and 1), Pseudomonas aeruginosa 1912E (0.25, 0.5, and 0.13), Escherichia coli 3190Y (0.008, 0.016, and 0.008), Enterobacter cloacae P99 (0.008, 0.031, and 0.008), Acinobacter calcoaceticus 15473 (0.063, 0.13, and 0.25). On the basis of these promising results, LB20304 was selected as a candidate for further evaluation.

  DOI：

  10.1021/jm970202e
• 作为产物：
  描述：

  N-tert-butoxycarbonyl-2-(2-cyanoethyl)aminoacetic acid ethyl ester 在 Jones reagent 、 palladium 10% on activated carbon 、 氢气 、 sodium 作用下， 以 甲醇 、 乙醇 、 丙酮 为溶剂， 50.0 ℃ 、4.0 MPa 条件下， 反应 19.5h， 生成 tert-butyl 3-(tert-butoxycarbonyl)aminomethyl-4-oxopyrrolidine-1-carboxylate
  参考文献：
  名称：

  一种吉米沙星中间体的制备方法

  摘要：

  本发明涉及医药及相关领域，特别涉及一种吉米沙星中间体的制备方法，以丙烯睛和甘氨酸乙酯盐酸盐为起始原料，经过亲核加成反应、氨基保护、缩合、还原保护、氧化、肟化、脱去保护基得到吉米沙星支链中间体4‑氨甲基吡咯烷‑3‑酮‑O‑甲基肟二盐酸盐，路线简单，节省了两步反应，原料价廉易得，产物收率较高，且该路线无需进行柱层析分离，为工业化生产提供了一条可行的合成路线。

  公开号：

  CN105585518B

文献信息

• Novel quinoline carboxylic acid derivatives having 7-(4-amino-methyl-3-oxime) pyrrolidine substituents and processes for their preparation
  申请人：LG Chemical Limited

  公开号：EP0688772A1

  公开（公告）日：1995-12-27

  The present invention relates to a novel quinolone compound having an excellent antibacterial activity. More specifically, the present invention relates to a novel quinoline(naphthyridine)carboxylic acid derivative represented by the following formula (I), which has an 4-aminomethyl-3-oximepyrrolidine substituent on 7-position of the quinolone nucleus and shows a superior antibacterial activity in contrast to the known quinolone antibactrial agents having a weak activity against gram-positive bacterial strains and also has a broad antibacterial spectrum and a highly improved pharmacokinetic property : wherein R, R₁, R₂, R₃, R₄ and Q are defined as described in the specification.

  本发明涉及一种具有优异抗菌活性的新型喹诺酮化合物。更具体地说，本发明涉及一种由下式（I）表示的新型喹啉（萘啶）羧酸衍生物，该衍生物在喹诺酮核的 7 位上具有 4-氨基甲基-3-氧亚甲基吡咯烷取代基，与对革兰氏阳性细菌菌株活性较弱的已知喹诺酮类抗菌剂相比，显示出更优越的抗菌活性，并且具有广泛的抗菌谱和高度改进的药代动力学特性： 其中 R、R₁、R₂、R₃、R₄ 和 Q 的定义如说明书所述。
• Synthesis and in vitro antibacterial activity of gemifloxacin derivatives containing a substituted benzyloxime moiety
  作者：Lianshun Feng、Kai Lv、Mingliang Liu、Shuo Wang、Jing Zhao、Xuefu You、Sujie Li、Jue Cao、Huiyuan Guo

  DOI：10.1016/j.ejmech.2012.07.010

  日期：2012.9

  A series of novel gemifloxacin (GMFX) derivatives containing a substituted benzyloxime moiety with remarkable improvement in lipophilicity were synthesized. The target compounds evaluated for their in vitro antibacterial activity against representative strains. Our results reveal that most of the target compounds have considerable potency against all of the tested Gram-positive strains including MRSA and MRSE (MIC: <0.008-8 mu g/mL), although they are generally less active than the references against the Gram-negative strains. In particular, compound 111 (MIC: <0.008-4 mu g/mL) was found to be 8-2048 and 2-128 times more potent than levofloxacin (LVFX) and GMFX against the Gram-positive strains, respectively. Moreover, against MRSA clinical isolates, 111 (MIC90: 1 mu g/mL) is 8-fold more active than GMFX, and 2-fold more active than GMFX and moxifloxacin against MRSE clinical isolates (MIC90: 4 mu g/mL). Crown Copyright (C) 2012 Published by Elsevier Masson SAS. All rights reserved.
• Quinoline carboxylic acid derivatives having 7-(4-amino-methyl-3-oxime) pyrrolidine substituents and processes for their preparation
  申请人：LG Chemical Limited

  公开号：EP0688772B1

  公开（公告）日：1999-05-06
• Discovery of gemifloxacin (Factive, LB20304a): a quinolone of new a generation
  作者：Chang Yong Hong

  DOI：10.1016/s0014-827x(01)01017-5

  日期：2001.3

  Novel quinolone antibacterials, which bear an alkyloxime substituent in the 4-position and an aminomethyl substituent in the 3-position of the pyrrolidine ring, have been designed and synthesized. These fluoroquinolones were found to possess extremely potent antimicrobial activity against Gram-positive organisms including resistant strains such as methicillin-resistant Staphylococcus aureus (MRSA). Among these compounds our development candidate, Gemifloxacin (Factive, LB20304a), showed the best in vivo efficacy and pharmacokinetic profile in animals, as well as good safety pharmacological properties. Gemifloxacin was found to be especially effective against respiratory tract infections that account for over 70% of all infections. With once-a-day dosage, potency against respiratory tract infections such as chronic bronchitis and pneumonia was ensured without any significant side effect. In December 1999, Gemifloxacin filed a NDA for marketing approval to the US Food and Drug Administration. (C) 2001 Elsevier Science S.A. All rights reserved.
• Synthesis and antibacterial activity of naphthyridone derivatives containing mono/difluoro-methyloxime pyrrolidine scaffolds
  作者：Kai Lv、Ming-Liang Liu、Lian-Shun Feng、Lan-Ying Sun、Ye-Xin Sun、Zeng-Quan Wei、Hui-Quan Guo

  DOI：10.1016/j.ejmech.2011.10.048

  日期：2012.1

  A series of novel naphthyridone derivatives containing mono/difluoro-methyloxime pyrrolidine scaffolds were designed and synthesized. These derivatives were initially evaluated for their in vitro antibacterial activity and compounds 13a1, b1 were chosen for further evaluation their in vivo activity against systemic infections in mice. The results indicate that all of the target compounds have considerable in vitro antibacterial activity. In the in vivo experiments, 13b1 was found to be more effective than the parent drug gemifloxacin against the tested five strains, and especially its activity (ED50:21.27 mg/kg) is 5.2-6.1 times more potent than gemifloxacin and ciprofloxacin against clinically important Gram-negative pathogen Pseudomonas aeruginosa. (C) 2011 Elsevier Masson SAS. All rights reserved.