((S)-8-bromo-5-methyl-1,2,3,4-tetrahydronaphthalen-2-yl)-(S)-1-(phenylethyl)amine | 1381802-56-7

• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 英文名称: ((S)-8-bromo-5-methyl-1,2,3,4-tetrahydronaphthalen-2-yl)-(S)-1-(phenylethyl)amine
• 英文别名: (2S)-8-bromo-5-methyl-N-[(1S)-1-phenylethyl]-1,2,3,4-tetrahydronaphthalen-2-amine
• CAS: 1381802-56-7
• 化学式: C₁₉H₂₂BrN
• 分子量: 344.294
• InChiKey: OUPOSQGNHCKNAT-HOCLYGCPSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.2
• 重原子数：
  21
• 可旋转键数：
  3
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  12
• 氢给体数：
  1
• 氢受体数：
  1

反应信息

• 作为产物：
  描述：

  2-溴-5-甲基苯乙酸 在 甲醇 、 aluminum (III) chloride 、 sodium tetrahydroborate 、 氯化亚砜 、 对甲苯磺酸 、 N,N-二甲基甲酰胺 作用下， 以 水 、 1,2-二氯乙烷 、 异丙醇 、 甲苯 为溶剂， 反应 14.5h， 生成 ((R)-8-bromo-5-methyl-1,2,3,4-tetrahydronaphthalen-2-yl)-(S)-1-(phenylethyl)amine 、 ((S)-8-bromo-5-methyl-1,2,3,4-tetrahydronaphthalen-2-yl)-(S)-1-(phenylethyl)amine
  参考文献：
  名称：

  Optimization and Scale-up of a Pd-Catalyzed Aromatic C−N Bond Formation: A Key Step in the Synthesis of a Novel 5-HT_1B Receptor Antagonist

  摘要：

  Searching for the best synthetic route for a given target molecule is a complex task and, by the same token, a key deliverable from a process R&D department. In this vein the challenge for our group was to identify a sustainable manufacturing process for a chiral compound, AR-A2, to be developed for the treatment of certain neurological disorders. Besides designing a method for assembling the core (R)-2-aminotetralin nucleus, a key feature in the overall synthesis was to provide a robust procedure for creating a new C-N bond between an aromatic ring and a heterocyche moiety. The methodology employed a Buchwald-Hartwig coupling, and a highly efficient catalytic process was developed using Pd(OAc)(2) as precatalyst, with loadings as low as 0.47 mol % (in laboratory trials one order of magnitude lower) together with (R)BINAP as ligand. Optimizing the reaction conditions allowed a virtually quantitative conversion of the brominated aromatic substrate after heating to 110-115 degrees C in toluene for 4 h. Telescoping this step with a succeeding catalytic hydrogenation to effect an N-debenzylation, followed by precipitation of the benzoate salt offered an overall yield for the two consecutive steps of 88% at 125-kg batch size, combined with excellent stereochemical product purity of 98% ee.

  DOI：

  10.1021/op8000146

文献信息

• Optimization and Scale-up of a Pd-Catalyzed Aromatic C−N Bond Formation: A Key Step in the Synthesis of a Novel 5-HT_1B Receptor Antagonist
  作者：Hans-Jürgen Federsel、Martin Hedberg、Fredrik R. Qvarnström、Wei Tian

  DOI：10.1021/op8000146

  日期：2008.5.1

  Searching for the best synthetic route for a given target molecule is a complex task and, by the same token, a key deliverable from a process R&D department. In this vein the challenge for our group was to identify a sustainable manufacturing process for a chiral compound, AR-A2, to be developed for the treatment of certain neurological disorders. Besides designing a method for assembling the core (R)-2-aminotetralin nucleus, a key feature in the overall synthesis was to provide a robust procedure for creating a new C-N bond between an aromatic ring and a heterocyche moiety. The methodology employed a Buchwald-Hartwig coupling, and a highly efficient catalytic process was developed using Pd(OAc)(2) as precatalyst, with loadings as low as 0.47 mol % (in laboratory trials one order of magnitude lower) together with (R)BINAP as ligand. Optimizing the reaction conditions allowed a virtually quantitative conversion of the brominated aromatic substrate after heating to 110-115 degrees C in toluene for 4 h. Telescoping this step with a succeeding catalytic hydrogenation to effect an N-debenzylation, followed by precipitation of the benzoate salt offered an overall yield for the two consecutive steps of 88% at 125-kg batch size, combined with excellent stereochemical product purity of 98% ee.
• Regioisomerism in the Synthesis of a Chiral Aminotetralin Drug Compound: Unraveling Mechanistic Details and Diastereomer-Specific In-Depth NMR Investigations
  作者：Peter Schuisky、Hans-Jürgen Federsel、Wei Tian

  DOI：10.1021/jo300277y

  日期：2012.7.6

  During chemical process development of a novel 2-aminotetralin derivative intended for use as an antidepressant, scrutiny of the byproduct present in the drug molecule revealed a set of regioisomers. Detailed studies showed that this impurity issue originated from an early synthetic step in which a brominated tetralone motif was generated in a ring-closing protocol. It was found that this reaction was accompanied by a migration of the aromatic bromo substituent via different bromonium species along two discrete pathways. This example of the halogen dance reaction resulted in the formation of a series of tetralone impurities with a bromine distributed across all available aromatic positions of the tetralin nucleus. Subsequently, when subjected to reductive amination conditions, each of these tetralones gave rise to pairs of aminotetralins in a diastereomeric relationship. NMR investigations revealed that the alicyclic portion of the compounds thus formed displayed very complex signal patterns, which required further in-depth studies using a variety of sophisticated techniques. As a result, a deep insight into the structural features of the current 2-aminotetralin family was obtained, which is emphasized by the definition of a novel "0.2 ppm rule" allowing the absolute configuration at tetralin C-2 to be determined.