The active pharmaceutical ingredient sacubitril acts as a neprilysin inhibitor in the body and is administered to patients suffering from high blood pressure and chronic heart failure. In this paper, we report the development of a three-step setup for the synthesis of an advanced sacubitril precursor in continuous flow. The key transformation of our cascade is a Suzuki-Miyaura coupling facilitated by a heterogeneous palladium catalyst. Its implementation in a packed-bed reactor and the application of continuous flow methodologies allow intensification of the cross-coupling reaction compared to batch processing. The subsequent steps for the synthesis of the target molecule involve Boc-deprotection as well as N-succinylation, which have been optimized using the statistical “Design of Experiments” (DoE) approach. In this way, the individual as well as interactive effects of selected parameters on the output of the reactions could be investigated very efficiently. The consecutive performance of the three reaction steps using an integrated setup enabled the synthesis of a late-stage sacubitril precursor in continuous flow with 81% overall yield.

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活性药物成分土必比尔在体内充当中性溶酶抑制剂，并被施用于患有高血压和慢性心力衰竭的患者。在本文中，我们报告了三步装置的发展，该装置用于在连续流动条件下合成高级杀必特林前体。级联反应的关键转变是通过非均相钯催化剂促进的Suzuki-Miyaura偶联。与分批处理相比，它在填充床反应器中的实施以及连续流方法的应用可以增强交叉偶联反应。合成靶分子的后续步骤涉及Boc脱保护以及N-琥珀酰化，已使用统计“实验设计”（DoE）方法进行了优化。这样，可以非常有效地研究所选参数对反应输出的个体以及相互作用的影响。使用集成装置的三个反应步骤的连续执行，可以连续流动的方式合成晚期沙比特利前体，总产率为81％。

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