Optimization and scale-up of a Pd-catalyzed aromatic C-N bond formation:: A key step in the synthesis of a novel 5-HT1B receptor antagonist
Optimization and scale-up of a Pd-catalyzed aromatic C-N bond formation:: A key step in the synthesis of a novel 5-HT1B receptor antagonist
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DOI：
10.1021/op8000146
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发表时间：
2008-05-01
影响因子：
3.4
通讯作者：
Tian, Wei
中科院分区：
文献类型：
--
作者：
Federsel, Hans-Juergen;Hedberg, Martin;Tian, Wei
为给定的目标分子寻找最佳的合成路线是一项复杂的任务，同样，这也是工艺研发部门的关键成果。在这种情况下，我们小组面临的挑战是为一种手性化合物AR-A2确定一种可持续的制造工艺，用于治疗某些神经系统疾病。除了设计了一种组装核心(R)-2-氨基四肽核的方法外，整个合成的一个关键特征是提供了一种在芳环和杂环段之间建立新的C-N键的稳健程序。该方法采用Buchwald-Hartwig偶联，以Pd(OAc)(2)为预催化剂，以(R)BINAP为配体，负载低至0.47 mol %（在实验室试验中低一个数量级），开发了高效的催化过程。优化反应条件后，在甲苯中加热至110-115℃4小时后，溴化芳香族底物几乎可以定量转化。将这一步骤与随后的催化加氢进行n -脱苄基化，然后沉淀苯甲酸盐，在125 kg的批量下，连续两步的总收率为88%，并结合了优异的立体化学产品纯度98% ee。
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.