4-(N-tert-butoxycarbonyl)aminomethyl-3-Z-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine | 197143-34-3

• 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: 4-(N-tert-butoxycarbonyl)aminomethyl-3-Z-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine
• 英文别名: 1-(N-t-butoxycarbonyl)-4-(t-butoxycarbonylaminomethyl) pyrrolidin-3-methoxime；1-(N-t-butoxycarbonyl)-4-(t-butoxycarbonylaminomethyl)pyrrolidin-3-methoxime；1-Pyrrolidinecarboxylic acid, 3-[[[(1,1-dimethylethoxy)carbonyl]amino]methyl]-4-(methoxyimino)-, 1,1-dimethylethyl ester, (4Z)-；tert-butyl (3Z)-3-methoxyimino-4-[[(2-methylpropan-2-yl)oxycarbonylamino]methyl]pyrrolidine-1-carboxylate
• CAS: 197143-34-3
• 化学式: C₁₆H₂₉N₃O₅
• 分子量: 343.423
• InChiKey: QPBOYTCMSYULGM-LDADJPATSA-N

物化性质

• 密度：
  1.14±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  2
• 重原子数：
  24
• 可旋转键数：
  7
• 环数：
  1.0
• sp3杂化的碳原子比例：
  0.81
• 拓扑面积：
  89.5
• 氢给体数：
  1
• 氢受体数：
  6

反应信息

• 作为反应物：
  描述：

  4-(N-tert-butoxycarbonyl)aminomethyl-3-Z-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine 在 甲醇 、 1,8-二氮杂双环[5.4.0]十一碳-7-烯 、 乙酰氯 作用下， 以 乙腈 为溶剂， 反应 1.33h， 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 sodium tetrahydroborate 、 lithium aluminium tetrahydride 、 乙醇 、 盐酸羟胺 、 sodium ethanolate 、 三氧化硫吡啶 、 碳酸氢钠 、 二甲基亚砜 、 三乙胺 作用下， 以 四氢呋喃 、 1,4-二氧六环 、 乙醇 、 水 为溶剂， 反应 6.5h， 生成 4-(N-tert-butoxycarbonyl)aminomethyl-3-Z-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine
  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

文献信息

• Intermediates for the production of quinolone carboxylic acid derivatives
  申请人：SB Pharmco Puerto Rico Inc. of the United States Corporation Company

  公开号：US06703512B1

  公开（公告）日：2004-03-09

  Chemical intermediates which are of use in the production of quinolone carboxylic acid derivatives having antibacterial activity.

  化学中间体，用于生产具有抗菌活性的喹诺酮羧酸衍生物。
• Synthesis of the Intermediate of Gemifloxacin by the Chemoselective Hydrogenation of 4-Cyano-3-methoxyimino-1-(<i>N</i>-<i>tert</i>-butoxycarbonyl)pyrrolidine. Part 1. Screening of Metal Catalysts
  作者：Hyun Kuk Noh、Jae Sung Lee、Yeongdae Kim、Jay Hyok Chang、Hyunik Shin、Do Hyun Nam、Kyung Hee Lee

  DOI：10.1021/op049913u

  日期：2004.9.1

  methanesulfonate (AMPM), the key intermediate of gemifloxacin, based on chemoselective hydrogenation of the cyano group in 4-cyano-3-methoxyimino-1-(N-tert-butoxycarbonyl)pyrrolidine (CMBP) with minimum reduction of the methyloxime group employing (t-Boc)2O (BOC) as in situ protecting agent. Over Raney nickel or cobalt catalysts, without in situ BOC protection of amine, the side reaction to 4-amino

  基于 4-cyano-3-methoxyimino-1-(N-tert) 中氰基的化学选择性加氢，设计了吉米沙星的关键中间体 4-aminomethyl-3-Z-methoxyiminopyrrolidine methanesulfonate (AMPM) 的新合成路线。 -丁氧基羰基）吡咯烷（CMBP），使用（t-Boc）2O（BOC）作为原位保护剂，甲基肟基团的还原最少。在阮内镍或钴催化剂上，在没有胺的原位 BOC 保护的情况下，通过甲基肟和氰基的同时氢化，生成 4-氨基甲基-3-氨基-1-(N-叔丁氧基羰基)吡咯烷 (AABP) 的副反应是广泛的CMBP 中的基团，导致所需中间体 4-氨基甲基-3-Z-甲氧基亚氨基 1-(N-叔丁氧基羰基)吡咯烷 (Z-AMBP) 一直过度还原为 AABP。当进行原位 BOC 保护时，
• 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.
• PROCESS FOR PRODUCTION OF NAPHTHYRIDINE-3-CARBOXYLIC ACID DERIVATIVES
  申请人：LG Life Sciences, Ltd.

  公开号：EP1214321B1

  公开（公告）日：2004-07-14
• US7232907B2
  申请人：——

  公开号：US7232907B2

  公开（公告）日：2007-06-19