Valsartan is a potent, orally active angiotensin II receptor blocker and is widely used in the treatment of hypertension and chronic heart failure. Herein, we present an approach for the continuous synthesis of a late-stage precursor of valsartan in three steps. The applied synthetic route involves N-acylation, Suzuki-Miyaura cross-coupling and methyl ester hydrolysis. After optimization of the individual steps in batch, they were successfully transferred to continuous flow processes employing different reactor designs. The first step of the synthetic route (N-acylation) as well as the third step (methyl ester hydrolysis) are performed in coil reactor setups. The key step of the reaction cascade (Suzuki-Miyaura cross-coupling) is catalyzed by a heterogeneous palladium-substituted cerium-tin-oxide with the molecular formula Ce_0.20Sn_0.79Pd_0.01O_2-δ. The catalyst particles are implemented in an in-house developed packed-bed reactor, which features an HPLC column as fixed-bed. The combination of the individual reaction modules facilitates the consecutive performance of the three reaction steps. Using the developed multistep continuous setup, the targeted valsartan precursor was obtained with up to 96% overall yield.

Graphical abstract

缬沙坦是一种有效的口服活性血管紧张素II受体阻滞剂，被广泛用于治疗高血压和慢性心力衰竭。在这里，我们提出了一种在三个步骤中连续合成缬沙坦后期前体的方法。所应用的合成途径包括N-酰化，Suzuki-Miyaura交叉偶联和甲酯水解。在分批优化各个步骤后，它们已成功转移到采用不同反应器设计的连续流工艺中。合成路线的第一步（N-酰化反应）以及第三步（甲酯水解）均在盘管反应器中进行。反应级联的关键步骤（Suzuki-Miyaura交叉偶联）由分子式为Ce _0.20 Sn _0.79 Pd _0.01 O2 _-δ的多相钯取代的铈锡氧化物催化。催化剂颗粒在内部开发的填充床反应器中实施，该反应器以HPLC色谱柱为固定床。各个反应模块的组合促进了三个反应步骤的连续进行。使用开发的多步连续设置，可以以高达96％的总收率获得目标缬沙坦前体。

图形概要