[(1R)-1-(benzoyl)oxy]ethyl (2S,5R,6R)-3,3-dimethyl-6-(hydroxymethyl)-7-oxo-4-thia-1-azabicyclo-[3.2.0]heptane-2-carboxylate-4,4-dioxide | 666174-87-4

• 分子结构分类: 有机化合物 - 有机酸及其衍生物 - 羧酸及其衍生物
• 英文名称: [(1R)-1-(benzoyl)oxy]ethyl (2S,5R,6R)-3,3-dimethyl-6-(hydroxymethyl)-7-oxo-4-thia-1-azabicyclo-[3.2.0]heptane-2-carboxylate-4,4-dioxide
• 英文别名: [(1R)-1-(benzoyl)oxy]ethyl(2S,5R,6R)-3,3-dimethyl-6-(hydroxymethyl)-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate-4,4-dioxide；4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylic acid, 6-(hydroxymethyl)-3,3-dimethyl-7-oxo-, (1R)-1-(benzoyloxy)ethyl ester, 4,4-dioxide, (2S,5R,6R)；[(1R)-1-benzoyloxyethyl] (2S,5R,6R)-6-(hydroxymethyl)-3,3-dimethyl-4,4,7-trioxo-4lambda6-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate；[(1R)-1-benzoyloxyethyl] (2S,5R,6R)-6-(hydroxymethyl)-3,3-dimethyl-4,4,7-trioxo-4λ6-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate
• CAS: 666174-87-4
• 化学式: C₁₈H₂₁NO₈S
• 分子量: 411.433
• InChiKey: WIMLUYVKJJGUNJ-IKVITTDRSA-N

物化性质

• 沸点：
  672.9±55.0 °C(Predicted)
• 密度：
  1.47±0.1 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.3
• 重原子数：
  28
• 可旋转键数：
  7
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.5
• 拓扑面积：
  136
• 氢给体数：
  1
• 氢受体数：
  8

反应信息

• 作为产物：
  描述：

  benzyl (2S,5R,6S)-6-bromo-3,3-dimethyl-6-hydroxymethyl-7-oxo-4-thia-1-azabicyclo[3.2.0]heptane-2-carboxylate-4,4-dioxide 在 N-甲基吡咯烷酮 、 palladium on activated charcoal 、 氢气 、 N,N-二异丙基乙胺 、 sodium 2-ethylhexanoic acid 作用下， 以 乙酸乙酯 、 异丙醇 为溶剂， 25.0~52.0 ℃ 、700.01 kPa 条件下， 反应 26.0h， 生成 [(1R)-1-(benzoyl)oxy]ethyl (2S,5R,6R)-3,3-dimethyl-6-(hydroxymethyl)-7-oxo-4-thia-1-azabicyclo-[3.2.0]heptane-2-carboxylate-4,4-dioxide
  参考文献：
  名称：

  Process Enabling and the Scale-Up of 6β-Hydroxymethylsulbactam and Its Esters

  摘要：

  The optimization of the synthesis of 6 beta-hydroxymethylsulbactam is described. The primary challenge in this synthesis is the installation of the 6 beta-hydroxymethyl group with the proper stereochemistry. Engineering challenges associated with the addition of gaseous formaldehyde to a Grignard reagent at low temperature and a number of approaches to achieving the appropriate beta-stereochemistry are presented.

  DOI：

  10.1021/op050047a

文献信息

• [EN] BETA-LACTAMASE INHIBITOR PRODRUG<br/>[FR] PROMEDICAMENT INHIBITEUR DE BETA-LACTAMASE
  申请人：PFIZER PROD INC

  公开号：WO2004018484A1

  公开（公告）日：2004-03-04

  Prodrugs of 6-ß-hydroxymethylpenicillanic acid sulfone having the structure wherein R is H or methyl, and solvates thereof, are disclosed. Also disclosed are pharmaceutical compositions comprising a prodrug of the present invention, or a solvate thereof, an optional beta-lactam antibiotic and at least one pharmaceutically acceptable carrier. Further disclosed is a method for increasing the therapeutic effectiveness of a beta-lactam antibiotic in a mammal by administering an effective amount of a betalactam antibiotic and an effectiveness-increasing amount of a prodrug of the present invention, or a solvate thereof. Additionally disclosed is a method for treating a bacterial infection in a mammal by administering a therapeutically effective amount of a pharmaceutical composition of the present invention to a mammal in need thereof.

  6-ß-羟甲基青霉烷酸磺酸酯的前药具有结构，其中R为H或甲基，并公开其溶剂合物。还公开了包括本发明的前药或其溶剂合物、可选的β-内酰胺类抗生素和至少一种药用载体的药物组合物。进一步公开了通过给哺乳动物投予β-内酰胺类抗生素的有效量和本发明的前药或其溶剂合物的增效量来增加β-内酰胺类抗生素的治疗效果的方法。此外，还公开了通过给需要的哺乳动物投予本发明的药物组合物的治疗有效量来治疗哺乳动物的细菌感染的方法。
• A New Efficient Stereoselective Debromination Reaction with Trialkylgermanium Hydrides Useful in the Design of Short Synthetic Routes to β-Lactamase Inhibitor Prodrugs
  作者：Timothy Norris、Christian Dowdeswell、Natalka Johnson、Dan Daia

  DOI：10.1021/op050151s

  日期：2005.11.1

  suitable for prodrug use in high yields. The bromine abstraction usually results in favoured formation of the 6-β-hydroxymethyl epimer relative to the 6-α-hydroxymethyl epimer in ratios that exceed 97:3. Reaction of pure 6-α-hydroxymethyl-6-β-bromo-penicillate-1,1-dioxide ester results in almost exclusive formation of 6-β-hydroxymethylsulbactam ester. This methodology conserves the C−C bond formation at C-6

  从β内酰胺酶抑制剂6-β-hydroxymethylsulbactam衍生的前药能够有效地在三个步骤通过使利用三的高度立体选择性的自由基脱溴使用合成Ñ-丁基氢化锗。该试剂能够从高产率的适合于前药使用的差向异构体6-羟基甲基-6-溴青霉酸酯-1,1-二氧化物酯和官能化酯对的C-6位置提取溴。相对于6-α-羟甲基差向异构体，比率超过97∶3，溴的提取通常导致6-β-羟甲基差向异构体的有利形成。纯的6-α-羟甲基-6-β-溴青霉酸酯-1,1-二氧化物酯的反应导致几乎完全形成6-β-羟甲基舒巴坦酯。该方法通过利用甲酰化反应产生的两种差向异构体来保护C-6处的C-C键形成，这在β-羟甲基舒巴坦前药合成中既困难又非立体选择性。
• Process Enabling and the Scale-Up of 6β-Hydroxymethylsulbactam and Its Esters
  作者：Timothy Norris、David H. Brown Ripin、Paul Ahlijanian、Brian M. Andresen、Mark T. Barrila、Roberto Colon-Cruz、Michel Couturier、Joel M. Hawkins、Ioulia V. Loubkina、Jennifer Rutherford、Kurt Stickley、Lulin Wei、Roel Vollinga、Robert de Pater、Peter Maas、Ben de Lange、Dominique Callant、Jeroen Konings、Jean Andrien、Jos Versleijen、Jos Hulshof、Elena Daia、Natalka Johnson、David W. L. Sung

  DOI：10.1021/op050047a

  日期：2005.7.1

  The optimization of the synthesis of 6 beta-hydroxymethylsulbactam is described. The primary challenge in this synthesis is the installation of the 6 beta-hydroxymethyl group with the proper stereochemistry. Engineering challenges associated with the addition of gaseous formaldehyde to a Grignard reagent at low temperature and a number of approaches to achieving the appropriate beta-stereochemistry are presented.