(7-碘-4-甲基-3-氧代-2,3,4,5-四氢-1H-1,4-苯并二氮杂卓-2-基)乙酸 | 210288-67-8

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 中文名称: (7-碘-4-甲基-3-氧代-2,3,4,5-四氢-1H-1,4-苯并二氮杂卓-2-基)乙酸
• 英文名称: (2S)-2,3,4,5-tetrahydro-7-iodo-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid
• 英文别名: SB 240093；2-[(2S)-7-iodo-4-methyl-3-oxo-2,5-dihydro-1H-1,4-benzodiazepin-2-yl]acetic acid
• CAS: 210288-67-8
• 化学式: C₁₂H₁₃IN₂O₃
• 分子量: 360.151
• InChiKey: USQCSFAOCPKJQV-JTQLQIEISA-N

物化性质

• 沸点：
  577.0±50.0 °C(Predicted)
• 密度：
  1.699±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  1.2
• 重原子数：
  18
• 可旋转键数：
  2
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.33
• 拓扑面积：
  69.6
• 氢给体数：
  2
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (7-碘-4-甲基-3-氧代-2,3,4,5-四氢-1H-1,4-苯并二氮杂卓-2-基)乙酸 在 bis-triphenylphosphine-palladium(II) chloride 、 palladium 10% on activated carbon 、 氢气 、 苯甲醚 、 二环己胺 作用下， 以 水 、 异丙醇 为溶剂， 75.0~109.0 ℃ 、413.7 kPa 条件下， 反应 10.0h， 生成 洛曲非班
  参考文献：
  名称：

  The Development of a Manufacturing Route for the GPIIb/IIIa Receptor Antagonist SB-214857-A. Part 2:  Conversion of the Key Intermediate SB-235349 to SB-214857-A

  摘要：

  The process development to the manufacturing route to (2S)-7-([4,4'-bipiperidin]-1-ylcarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid hydrochloride (SB214857-A, lotrafiban) is described. The starting point is the previously reported intermediate (2RS)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid methyl ester. The first stage is a lipase-catalysed resolution of the racemic ester to (2S)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid and subsequent iodination using a pyridine iodine monochloride complex to give (2S)-2,3,4,5-tetrahydro-7-iodo-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid. The unreacted (R)-enantiomer of the starting ester is recovered and recycled to the racemate by treatment with sodium methoxide. The next stage describes the palladium-catalysed aminocarbonylation of the aryl iodide with 4,4'-pyridylpiperidine to give (2S)-2,3,4,5-tetrahydro-4-methyl-3-oxo-7-[[4-(4-pyridinyl)-1-piperidinyl]carbonyl]-1H-1,4-benzodiazepine-2-acetic acid dihydrate. The third stage is the hydrogenation of the pyridine subunit over palladium on charcoal to obtain the zwitterionic (2S)-7-([4,4'-bipiperidin]-1-ylcarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid hexahydrate. The final stage is the formation of the hydrochloride salt to afford the drug substance.

  DOI：

  10.1021/op034023k
• 作为产物：
  描述：

  3-methyl-2-methoxycarbonyl-2-(methoxycarbonylmethyl)-1,2,3,4-tetrahydroquinazoline 在 palladium on activated charcoal Candida antarctica lipase B 、 sodium hydroxide 、 C₅H₅N*ClH*I₂ 、 氨 、 氢气 、 sodium methylate 、 叔丁醇 作用下， 以 甲醇 、 水 为溶剂， 10.0~65.0 ℃ 、413.68 kPa 条件下， 生成 (7-碘-4-甲基-3-氧代-2,3,4,5-四氢-1H-1,4-苯并二氮杂卓-2-基)乙酸
  参考文献：
  名称：

  A new synthesis of the GPIIb/IIIa receptor antagonist SB-214857-A

  摘要：

  A new synthesis of lotrafiban SB-214857-A is reported. The key steps are the preparation of racemic (4-melhyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,4]diazepin-2-yl)-acid methyl ester from 2-nitrobenzyl alcohol, a resolution using an immobilised lipase enzyme and a palladium-catalysed aminocarbonylation reaction. (C) 2001 Elsevier Science Ltd. All rights reserved.

  DOI：

  10.1016/s0040-4039(01)00843-7

文献信息

• Polymer-Supported Catalase: A Green Approach to the Removal of Hydrogen Peroxide from Reaction Mixtures
  作者：Mark Alston、Andy Willetts、Andy Wells

  DOI：10.1021/op0255074

  日期：2002.7.1

  During a programme of work directed at developing a manufacturing route for SB 214857, Lotrafiban, the need arose to find methodology for efficiently destroying hydrogen peroxide in aqueous solutions of the penultimate intermediate, SB 270051. Whilst this was initially achieved using a chemical process, a biotransformation process has now been developed that utilises a polymer-supported catalase enzyme to remove peroxide from reaction mixtures. The biocatalytic approach provides an economic and environmentally friendly solution to peroxide removal when compared to the chemical process.
• ENZYMATIC RESOLUTION OF BENZODIAZEPINE-ACETIC ACID ESTERS WITH A LIPASE
  申请人：SMITHKLINE BEECHAM PLC

  公开号：EP0964928A1

  公开（公告）日：1999-12-22
• [EN] ENZYMATIC RESOLUTION OF BENZODIAZEPINE-ACETIC ACID ESTERS WITH A LIPASE<br/>[FR] RESOLUTION ENZYMATIQUE D'ESTERS D'ACIDE ACETIQUE DE BENZODIAZEPINE PAR UNE LIPASE
  申请人：SMITHKLINE BEECHAM PLC

  公开号：WO1998029561A1

  公开（公告）日：1998-07-09

  (EN) The present invention involves enantiomerically pure benzodiazepine acetic acid esters and methods of preparing them by resolving a racemic mixture utilizing a lipase.(FR) L'invention concerne des esters d'acide acétique de benzodiazépine pure sur le plan énantiomère, ainsi que des procédés servant à les préparer par résolution d'un mélange racémique au moyen d'une lipase.
• A new synthesis of the GPIIb/IIIa receptor antagonist SB-214857-A
  作者：Ian P Andrews、Richard J Atkins、Neil F Badham、Richard K Bellingham、Gary F Breen、John S Carey、Stephen K Etridge、Jerome F Hayes、Nigel Hussain、David O Morgan、Andrew C Share、Stephen A.C Smith、Timothy C Walsgrove、Andrew S Wells

  DOI：10.1016/s0040-4039(01)00843-7

  日期：2001.7

  A new synthesis of lotrafiban SB-214857-A is reported. The key steps are the preparation of racemic (4-melhyl-3-oxo-2,3,4,5-tetrahydro-1H-benzo[c][1,4]diazepin-2-yl)-acid methyl ester from 2-nitrobenzyl alcohol, a resolution using an immobilised lipase enzyme and a palladium-catalysed aminocarbonylation reaction. (C) 2001 Elsevier Science Ltd. All rights reserved.
• The Development of a Manufacturing Route for the GPIIb/IIIa Receptor Antagonist SB-214857-A. Part 2:  Conversion of the Key Intermediate SB-235349 to SB-214857-A
  作者：Richard J. Atkins、Adam Banks、Richard K. Bellingham、Gary F. Breen、John S. Carey、Stephen K. Etridge、Jerome F. Hayes、Nigel Hussain、David O. Morgan、Paul Oxley、Stephen C. Passey、Timothy C. Walsgrove、Andrew S. Wells

  DOI：10.1021/op034023k

  日期：2003.9.1

  The process development to the manufacturing route to (2S)-7-([4,4'-bipiperidin]-1-ylcarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid hydrochloride (SB214857-A, lotrafiban) is described. The starting point is the previously reported intermediate (2RS)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid methyl ester. The first stage is a lipase-catalysed resolution of the racemic ester to (2S)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid and subsequent iodination using a pyridine iodine monochloride complex to give (2S)-2,3,4,5-tetrahydro-7-iodo-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid. The unreacted (R)-enantiomer of the starting ester is recovered and recycled to the racemate by treatment with sodium methoxide. The next stage describes the palladium-catalysed aminocarbonylation of the aryl iodide with 4,4'-pyridylpiperidine to give (2S)-2,3,4,5-tetrahydro-4-methyl-3-oxo-7-[[4-(4-pyridinyl)-1-piperidinyl]carbonyl]-1H-1,4-benzodiazepine-2-acetic acid dihydrate. The third stage is the hydrogenation of the pyridine subunit over palladium on charcoal to obtain the zwitterionic (2S)-7-([4,4'-bipiperidin]-1-ylcarbonyl)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid hexahydrate. The final stage is the formation of the hydrochloride salt to afford the drug substance.