((R)-8-bromo-5-methyl-1,2,3,4-tetrahydronaphthalen-2-yl)-(S)-1-(phenylethyl)amine | 951155-03-6

• 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
• 英文别名: (2R)-8-bromo-5-methyl-N-[(1S)-1-phenylethyl]-1,2,3,4-tetrahydronaphthalen-2-amine
• CAS: 951155-03-6
• 化学式: C₁₉H₂₂BrN
• 分子量: 344.294
• InChiKey: OUPOSQGNHCKNAT-GOEBONIOSA-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

• 作为反应物：
  描述：

  ((R)-8-bromo-5-methyl-1,2,3,4-tetrahydronaphthalen-2-yl)-(S)-1-(phenylethyl)amine 在 palladium diacetate 、 1,3-双(二苯基膦)丙烷 potassium carbonate 、 三乙胺 、 potassium iodide 作用下， 以 N,N-二甲基甲酰胺 、 乙腈 为溶剂， 反应 22.0h， 生成 methyl (7R)-7-{benzyl[(1S)-1-phenylethyl]amino}-4-methyl-5,6,7,8-tetrahydronaphthalene-1-carboxylate
  参考文献：
  名称：

  WO2008/130319

  摘要：

  公开号：
• 作为产物：
  描述：

  ((R)-8-bromo-5-methyl-1,2,3,4-tetrahydronaphthalen-2-yl)-(S)-1-(phenylethyl)amine hydrochloride 在 sodium hydroxide 作用下， 以 水 、 甲苯 为溶剂， 以99.7%的产率得到((R)-8-bromo-5-methyl-1,2,3,4-tetrahydronaphthalen-2-yl)-(S)-1-(phenylethyl)amine
  参考文献：
  名称：

  可循环利用的NHC催化剂，用于开发通用的连续Buchwald-Hartwig反应和后处理方法

  摘要：

  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

  DOI：

  10.1021/acs.oprd.5b00349

文献信息

• A microfluidic approach for flexible and efficient operation of a cross-coupling reactive flow
  作者：A. Perazzo、G. Tomaiuolo、L. Sicignano、G. Toscano、R. E. Meadows、S. P. Nolan、S. Guido

  DOI：10.1039/c5ra10971j

  日期：——

  In this work, a flexible and efficient flow microreactor has been developed for the synthesis of an aromatic amine via a Buchwald–Hartwig reaction, a key bond-forming reaction in the synthesis of a wide range of naturally-occurring and pharmaceutically active targets. The microreactor, coupled with a highly active palladium N-heterocyclic carbene (NHC) catalyst, enabled the full conversion of the reagents within twenty minutes, even at very low catalyst concentrations. In addition to the classical two-feed design, a novel, more flexible four-feed flow system was developed with a configuration optimised to avoid clogging, which is one of the main problems in microreactors and in continuous flow reactive systems in general. We report the effect of flow rate, temperature and catalyst loading on conversion degree. In particular, a slight increase in temperature allowed faster conversion even at low catalyst loadings, likely due to the highly efficient heat transfer provided by the confined microreactor geometry.

  这项研究开发了一种灵活高效的流动微反应器，用于通过布赫瓦尔德-哈特维格反应合成芳香胺，布赫瓦尔德-哈特维格反应是合成多种天然存在和具有制药活性的目标物的关键成键反应。微反应器与高活性钯 N-杂环碳烯 (NHC) 催化剂相结合，即使催化剂浓度很低，也能在二十分钟内实现试剂的完全转化。除了经典的双进料设计外，我们还开发了一种新颖、更灵活的四进料流动系统，其配置经过优化，可避免堵塞，而堵塞是微反应器和一般连续流反应系统的主要问题之一。我们报告了流速、温度和催化剂负载对转化率的影响。特别是，即使催化剂负载量较低，温度略微升高也能加快转化速度，这可能是由于密闭微反应器的几何形状提供了高效的热传导。
• 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.
• 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.
• A General Liquid–Liquid Partitioning Equation and Its Consequences: Learning from the pH Dependent Extraction of a Pharmaceutical Intermediate
  作者：Ian W. Ashworth、Rebecca E. Meadows

  DOI：10.1021/acs.joc.8b00309

  日期：2018.4.6

  We observed that the product of a Buchwald-Hartwig coupling reaction extracted from the organic phase easily, relative to the starting aryl bromide as the pH was lowered. This was surprising given the similarity of their pK(a)'s. The product's extraction curve was also significantly steeper than expected. A consideration of the relevant equilibria, including all three of the product's pK(a)'s, led to a general model for the liquid-liquid extraction behavior of ionizable molecules. This model predicts the observed, useful extraction behavior.