((R)-8-bromo-5-methyl-1,2,3,4-tetrahydronaphthalen-2-yl)-(S)-1-(phenylethyl)amine hydrochloride | 1394290-38-0

• 分子结构分类: 有机化合物 - 苯类化合物 - 四氢化萘
• 英文名称: ((R)-8-bromo-5-methyl-1,2,3,4-tetrahydronaphthalen-2-yl)-(S)-1-(phenylethyl)amine hydrochloride
• 英文别名: (R)-(8-bromo-5-methyl-1,2,3,4-tetrahydronaphthalen-2-yl)-(S)-(1-phenylethyl)amine hydrochloride
• CAS: 1394290-38-0
• 化学式: C₁₉H₂₂BrN*ClH
• 分子量: 380.755
• InChiKey: VVPJBTVMBUUKMR-KUARMEPBSA-N

计算性质

• 辛醇/水分配系数(LogP)：
  5.39
• 重原子数：
  22.0
• 可旋转键数：
  3.0
• 环数：
  3.0
• sp3杂化的碳原子比例：
  0.37
• 拓扑面积：
  12.03
• 氢给体数：
  1.0
• 氢受体数：
  1.0

反应信息

• 作为反应物：
  描述：

  ((R)-8-bromo-5-methyl-1,2,3,4-tetrahydronaphthalen-2-yl)-(S)-1-(phenylethyl)amine hydrochloride 在 盐酸 、 sodium hydroxide 作用下， 以 异丙醇 、 甲苯 为溶剂， 反应 4.0h， 生成 ((R)-5-methyl-1,2,3,4-tetrahydronaphthalen-2-yl)-(S)-1-(phenylethyl)amine hydrochloride
  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
• 作为产物：
  描述：

  在 盐酸 作用下， 以 乙酸乙酯 为溶剂， 生成 ((R)-8-bromo-5-methyl-1,2,3,4-tetrahydronaphthalen-2-yl)-(S)-1-(phenylethyl)amine hydrochloride
  参考文献：
  名称：

  Regioisomerism in the Synthesis of a Chiral Aminotetralin Drug Compound: Unraveling Mechanistic Details and Diastereomer-Specific In-Depth NMR Investigations

  摘要：

  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.

  DOI：

  10.1021/jo300277y

文献信息

• Recyclable NHC Catalyst for the Development of a Generalized Approach to Continuous Buchwald–Hartwig Reaction and Workup
  作者：Anthony Chartoire、Carmen Claver、Martin Corpet、Jamin Krinsky、Julie Mayen、David Nelson、Steven P. Nolan、Itziar Peñafiel、Robert Woodward、Rebecca E. Meadows

  DOI：10.1021/acs.oprd.5b00349

  日期：2016.2.19

  3-bis(2,6-bis(diphenylmethyl)-4-methylphenyl)imidazol-2-ylidene; cin = η3-cinnamyl) is an excellent choice for continuous Buchwald–Hartwig reactions, due to its inherent high activity and stability. In preparation for running this reaction in flow (published concurrently), a detailed study has been carried out into its water stability, ultimately allowing the recycling of the catalyst in the organic phase

  通过结合以下三个关键因素，报告了一种用于优化和实施布赫瓦尔德-哈特维希反应的通用方法：高活性钯催化剂，连续后处理和纯化的通用方法以及催化剂回收和再利用的方法。钯N-杂环卡宾（NHC）预催化剂[Pd（IPr *）（cin）Cl] 4（IPr * = 1,3-双（2,6-双（二苯基甲基）-4-甲基苯基）咪唑-2-亚烷基; CIN =η 3-肉桂酸）由于其固有的高活性和稳定性，是连续Buchwald-Hartwig反应的绝佳选择。为了使该反应在流动中进行（同时出版），已经对其水的稳定性进行了详细的研究，最终使催化剂在有机相中以批处理方式循环使用多达三次。还开发了“一次正确的”后处理方法，从而产生了一种通用协议，该协议允许将Buchwald-Hartwig产品作为盐选择性萃取到水流中，同时将芳基溴化物的起始原料保留在有机流中。用催化剂，因此不需要进一步纯化。因此，设想该方法将特别适合于制药工业中的开发。经过优化的