(4-methyl-3-oxo-2,3,4-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)-acetic acid methyl ester | 193077-87-1

• 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: (4-methyl-3-oxo-2,3,4-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)-acetic acid methyl ester
• 英文别名: methyl 2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetate；2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid methyl ester；(2RS)-2,3,4,5-tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-acetic acid methyl ester；Methyl 2,3,4,5-tetrahydro-3-oxo-4-methyl-1H-1,4-benzodiazepine-2-acetate；methyl 2-(4-methyl-3-oxo-2,5-dihydro-1H-1,4-benzodiazepin-2-yl)acetate
• CAS: 193077-87-1
• 化学式: C₁₃H₁₆N₂O₃
• 分子量: 248.282
• InChiKey: OCJURJNFLYOSLL-UHFFFAOYSA-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：

  (4-methyl-3-oxo-2,3,4-tetrahydro-1H-benzo[e][1,4]diazepin-2-yl)-acetic acid methyl ester 在 bis-triphenylphosphine-palladium(II) chloride 、 novozyme 435 、 氨 、 碘化吡啶单盐酸盐 、 苯甲醚 、 二环己胺 、 sodium hydroxide 作用下， 以 水 、 叔丁醇 为溶剂， 109.0 ℃ 、103.42 kPa 条件下， 反应 13.5h， 生成 (2S)-2,3,4,5-tetrahydro-4-methyl-3-oxo-7-[[4-(4-pyridinyl)-1-piperidinyl]carbonyl]-1H-1,4-benzodiazepine-2-acetic acid
  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 sodium tetrahydroborate 、 palladium 10% on activated carbon 、 sodium methylate 、 sodium hydroxide 作用下， 以 甲醇 、 水 为溶剂， 反应 5.67h， 生成 (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：

  GPIIb/IIIa 受体拮抗剂 SB-214857-A 制造路线的开发。第 1 部分：关键中间体 2,3,4,5-Tetrahydro-4-methyl-3-oxo-1H-1,4-benzodiazepine-2-乙酸甲酯的合成，SB-235349

  摘要：

  开发合成关键中间体 2,3,4,5-四氢-4-甲基-3-氧代-1H-1,4-苯二氮卓-2-乙酸甲酯 SB-235349 的高效制造路线描述了lotrafiban。合成以甲磺酸化的 2-硝基苯甲醇开始，与甲胺反应，然后与二甲基乙炔二羧酸酯反应，然后还原硝基。所得苯胺用酸处理得到中间体喹唑啉，其在用碱处理时重排，得到1，4-苯二氮平。环外双键的还原得到 SB-235349。该过程可以在不分离任何中间体的情况下运行，并已用于制备数吨 SB-235349。

  DOI：

  10.1021/op034024c

文献信息

• Process for the aminocarbonylation of benzazepines and benzodiazepines
  申请人：SmithKline Beecham plc

  公开号：US06225465B1

  公开（公告）日：2001-05-01

  A new process for preparing substituted 7-aminocarbonyl-3-oxo-2,3,4,5-tetrahydro-1H-1,4-benzodiazepines is disclosed.

  揭示了一种制备取代的7-氨基甲酰基-3-酮基-2,3,4,5-四氢-1H-1,4-苯二氮䓬的新工艺。
• Process for obtaining enantiomerically enriched pyrazole derivatives
  申请人：Laboratorios Del. Dr. Esteve, S.A.

  公开号：EP2196458A1

  公开（公告）日：2010-06-16

  The present invention is directed to a process for the enantioselective hydrolysis of an ester of formula (I), which comprises reacting a mixture of C4-enantiomers of esters of formula (I), or salts thereof, with an esterase enzyme in the presence of a solvent. The invention is further directed to the transformation of said esters of formula (I) into enantiomerically enriched pyrazoles.

  本发明涉及一种对映体选择性水解式（I）酯的工艺，该工艺包括在溶剂存在下，使式（I）酯或其盐的 C4-对映体混合物与酯酶反应。本发明进一步涉及将所述式（I）酯转化为对映体富集的吡唑。
• 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.
• A New and Convergent Synthesis of (2<i>S</i>)-7-(4,4‘-Bipiperidinylcarbonyl)-2,3,4,5- tetrahydro-4-methyl-3-oxo-1<i>H</i>-1,4-benzodiazepine-2-acetic Acid Using a Palladium-Catalysed Aminocarbonylation Reaction
  作者：Stephen K. Etridge、Jerome F. Hayes、Timothy C. Walsgrove、Andrew S. Wells

  DOI：10.1021/op980068n

  日期：1999.1.1
• Org. Process Res. Dev. 2003, 7, 663-675
  作者：

  DOI：——

  日期：——