(2R)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid methyl ester | 363138-97-0

• 分子结构分类: 有机化合物 - 有机杂环化合物 - 苯二氮卓类
• 英文名称: (2R)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid methyl ester
• 英文别名: methyl 2-[(2R)-4-methyl-3-oxo-2,5-dihydro-1H-1,4-benzodiazepin-2-yl]acetate
• CAS: 363138-97-0
• 化学式: C₁₃H₁₆N₂O₃
• 分子量: 248.282
• InChiKey: OCJURJNFLYOSLL-LLVKDONJSA-N

物化性质

• 沸点：
  437.7±38.0 °C(Predicted)
• 密度：
  1.154±0.06 g/cm3(Predicted)

计算性质

• 辛醇/水分配系数(LogP)：
  0.9
• 重原子数：
  18
• 可旋转键数：
  3
• 环数：
  2.0
• sp3杂化的碳原子比例：
  0.38
• 拓扑面积：
  58.6
• 氢给体数：
  1
• 氢受体数：
  4

反应信息

• 作为反应物：
  描述：

  (2R)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid methyl ester 在 sodium methylate 、 碳酸二甲酯 作用下， 以 甲醇 为溶剂， 反应 4.0h， 以87%的产率得到(4-methyl-3-oxo-2,3,4-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)-acetic acid methyl ester
  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
• 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 、 氨 、 氢气 、 sodium methylate 、 叔丁醇 作用下， 以 甲醇 、 水 为溶剂， 50.0~65.0 ℃ 、413.68 kPa 条件下， 生成 (2R)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid methyl ester
  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

• Synthesis of SB-214857 using Copper Catalysed Amination of Arylbromides with l-Aspartic Acid
  作者：Jean-Baptiste Clement、Jerome F. Hayes、Helen M. Sheldrake、Peter W. Sheldrake、Andrew S. Wells

  DOI：10.1055/s-2001-16780

  日期：——

  An efficient synthesis of a 1,4-benzodiazepine was accomplished using copper catalysed amination of an arylbromide with the soluble bis-tetrabutylammonium salt of l-aspartic acid as a key step.

  通过铜催化芳基溴化物与可溶性双四丁基铵盐的氨基化反应，实现了1,4-苯并二氮杂卓的高效合成，其中l-天冬氨酸是关键步骤。
• 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.