Deep eutectic solvent (DES) enables drastic increase in substrate solubility and solvent compatibility of a chemo-enzymatic two-step flow process combining enzymatic decarboxylation and Pd-catalyzed Heck coupling.

Advances in flow chemistry to produce active pharmaceutical ingredients (APIs) require performing reactions in tailor-made equipment as complexity of the planned setups increases. To react quickly and with low costs to these demanding reactions, additive manufacturing, also known as 3D printing, is a preferred way for the production of customized reactors. This work presents three examples of 3D printed reactors and their application for the synthesis of API precursors in continuous flow. The first case deals with an aerobic oxidation of Grignard reagents to the corresponding phenols by molecular oxygen. Here, a design concept was utilized; various stainless steel reactors were tested, and their performances were evaluated in continuous flow. Next, another stainless steel reactor was applied for achieving fast mixing in a cascade, leading to a valsartan precursor. The third and final case employed a continuous stirred tank reactor (CSTR) made of a UV-curable resin. It was used for the first step of a multiphase enzymatic decarboxylation followed by a Heck cross-coupling reaction, leading to resveratrol derivatives.

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 palladiumsubstituted cerium-tin-oxide with the molecular formula Ce 0.20 Sn 0.79 Pd 0.01 O 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.