tert-butyl 3-(acetoxymethyl)-7α-methoxy-8-oxo-5-thia-1-azabicyclo<4.2.0>oct-2-ene-2-carboxylate 5,5-dioxide | 95671-97-9

• 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: tert-butyl 3-(acetoxymethyl)-7α-methoxy-8-oxo-5-thia-1-azabicyclo<4.2.0>oct-2-ene-2-carboxylate 5,5-dioxide
• 英文别名: 4-tert-butoxycarbonyl-7α-methoxy-3-acetoxymethyl-3-cephem-1,1-dioxide；t-butyl 3-acetoxymethyl-7α-methoxy-3-cephem-4-carboxylate 1,1-dioxide；tert-butyl 7α-methoxycephalosporanate 1,1-dioxide；tert-butyl 1,1-dioxo-trans-7-methoxycephalosporanate；tert-butyl 3-(acetoxymethyl)-7α-methoxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate 5,5-dioxide；3-Acetoxymethyl-7-methoxy-5,5,8-trioxo-5lambda*6*-thia-1-aza-bicyclo[4.2.0]oct-2-ene-2-carboxylic acid tert-butyl ester；tert-butyl (6R,7S)-3-(acetyloxymethyl)-7-methoxy-5,5,8-trioxo-5λ6-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate
• CAS: 95671-97-9
• 化学式: C₁₅H₂₁NO₈S
• 分子量: 375.4
• InChiKey: NBHAMBQTQHPTSS-WCQYABFASA-N

物化性质

• 熔点：
  129-130 °C
• 沸点：
  587.2±50.0 °C(Predicted)
• 密度：
  1.39±0.1 g/cm3(Temp: 20 °C; Press: 760 Torr)(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  -0.8
• 重原子数：
  25
• 可旋转键数：
  7
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.67
• 拓扑面积：
  125
• 氢给体数：
  0
• 氢受体数：
  8

反应信息

• 作为反应物：
  描述：

  tert-butyl 3-(acetoxymethyl)-7α-methoxy-8-oxo-5-thia-1-azabicyclo<4.2.0>oct-2-ene-2-carboxylate 5,5-dioxide 在 N-甲基吗啉 、 茴香硫醚 、 1-羟基苯并三唑 、 O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium tetrafluoroborate 、 三氟乙酸 作用下， 以 N,N-二甲基甲酰胺 为溶剂， 反应 7.5h， 生成 9H-fluoren-9-ylmethyl (2S)-2-[[(6R,7S)-3-(acetyloxymethyl)-7-methoxy-5,5,8-trioxo-5lambda6-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carbonyl]amino]-3-(1H-indol-3-yl)propanoate
  参考文献：
  名称：

  新型人白细胞弹性蛋白酶β-内酰胺抑制剂的合成与评价

  摘要：

  合成并测试了一系列 β-内酰胺衍生物，以确定抑制人类白细胞弹性蛋白酶 (HLE) 的构效关系，HLE 是一种参与多种退行性肺和组织疾病的丝氨酸蛋白酶。使用中性疏水性 7α-甲氧基头孢烷酸衍生物获得最有效的 IC50 值。7α-甲氧基头孢烷酸的色氨酸-9-芴基甲酯和 N-二苯甲基哌嗪衍生物是两种新型 HLE 抑制剂，作用持续时间超过 24 小时。

  DOI：

  10.1139/v01-062
• 作为产物：
  描述：

  7-氨基头孢烷酸 在 辛酸铑 sodium tungstate 、 亚硝酸异丙酯 、 硫酸 、 双氧水 、 三乙胺 、 三氟乙酸 作用下， 以 1,4-二氧六环 、 二氯甲烷 、 乙酸乙酯 为溶剂， 反应 25.25h， 生成 tert-butyl 3-(acetoxymethyl)-7α-methoxy-8-oxo-5-thia-1-azabicyclo<4.2.0>oct-2-ene-2-carboxylate 5,5-dioxide
  参考文献：
  名称：

  新型人白细胞弹性蛋白酶β-内酰胺抑制剂的合成与评价

  摘要：

  合成并测试了一系列 β-内酰胺衍生物，以确定抑制人类白细胞弹性蛋白酶 (HLE) 的构效关系，HLE 是一种参与多种退行性肺和组织疾病的丝氨酸蛋白酶。使用中性疏水性 7α-甲氧基头孢烷酸衍生物获得最有效的 IC50 值。7α-甲氧基头孢烷酸的色氨酸-9-芴基甲酯和 N-二苯甲基哌嗪衍生物是两种新型 HLE 抑制剂，作用持续时间超过 24 小时。

  DOI：

  10.1139/v01-062

文献信息

• Synthesis and evaluation of new elastase inhibitors. I. 1,1-Dioxocephem-4-thiolesters
  作者：M Alpegiani、A Baici、P Bissolino、P Carminati、G Cassinelli、S Del Nero、G Franceschi、P Orezzi、E Perrone、V Rizzo、N Sacchi

  DOI：10.1016/0223-5234(92)90019-w

  日期：1992.12

  Several 7alpha-chloro and 7alpha-methoxy cephalosporin thiolester sulphones variously substituted at the C-3' position were synthesized from 7-amino-3-deacetoxycephalosporanic acid (7-ADCA). The compounds are time-dependent inhibitors of human leukocyte elastase (HLE) with effective K(i) ranging from micro- to nanomolar values, and second order rate constant reaching 10(6) M-1s-1; they also inhibit porcine pancreatic elastase with similar, though not identical efficiency. Compared to the corresponding cephem esters, the thiolesters of the 7-Cl series inhibit HLE up to 10 times as fast. Complete enzyme inactivation is achieved when a leaving group at C-3' (OAc or S-Het) is present, at the expense however of stability towards hydrolytic beta-lactam cleavage. In the 7-OMe series the thiolester compounds are far more stable and retain good efficiency for irreversible enzyme inhibition, superior to that displayed by the corresponding ester compounds. Three representative compounds (including one ester and two thiolesters) are shown to be effective inhibitors of HLE in the presence of insoluble elastin.
• Inhibition of human leukocyte elastase. 2. Inhibition by substituted cephalosporin esters and amides
  作者：Paul E. Finke、Bonnie M. Ashe、Wilson B. Knight、Alan L. Maycock、Manuel A. Navia、Shrenik K. Shah、Kevan R. Thompson、Dennis J. Underwood、Hazel Weston

  DOI：10.1021/jm00171a029

  日期：1990.9

  A variety of 7 alpha-methoxycephalosporin ester and amide sulfones were prepared and tested to determine the structure-activity relations for inhibition of human leukocyte elastase (HLE), a serine protease which has been implicated in several degenerative lung and tissue diseases. The most potent IC50 values were obtained with neutral, lipophilic derivatives, with the esters being more active than the amides. However, the best time-dependent inhibition in this series was observed with the p- and m-carboxybenzyl esters 7b and 7c. These results are discussed in terms of the proposed mechanism of inhibition as well as a molecular modeling study using the recently solved X-ray crystal structure of HLE.
• Inhibition of human leukocyte elastase. 1. Inhibition by C-7-substituted cephalosporin tert-butyl esters
  作者：James B. Doherty、Bonnie M. Ashe、Peter L. Barker、Thomas J. Blacklock、John W. Butcher、Gilbert O. Chandler、M. Ellen Dahlgren、Philip Davies、Conrad P. Dorn

  DOI：10.1021/jm00171a028

  日期：1990.9

  Time-dependent inhibitors of the enzyme human leukocyte elastase have been developed based on the cephem nucleus. A series of cephalosporin tert-butyl esters has been examined, and the activity of these compounds has been found to be very sensitive to C-7 substituents, with small, alpha-oriented, electron-withdrawing groups showing greatest activity. Additionally, the oxidation state of the sulfur atom has been found to play a role in potency, with sulfones showing considerably greater activity than the corresponding sulfides or beta-sulfoxides. The alpha-sulfoxides were inactive.
• Inhibition de l'élastase leucocytaire humaine: inhibition par des céphalosporines sulfones substituées sur le C-2
  作者：W Hagmann

  DOI：10.1016/0223-5234(89)90027-5

  日期：1989.12
• A versatile synthesis of 1,1-dioxo 7-substituted cephems: preparation of the human leukocyte elastase (HLE) inhibitor 1,1-dioxo-trans-7-methoxycephalosporanic acid tert-butyl ester
  作者：Thomas J. Blacklock、John W. Butcher、Paul Sohar、Theresa Rothauser Lamanec、Edward J. J. Grabowski

  DOI：10.1021/jo00277a030

  日期：1989.8