Abstract

Multistep Synthesis of API Precursors in Continuous Flow Involving Heterogeneous Palladium Catalysis

Katharina Hiebler, Project Assistant, TU Graz

According to the World Health Organization (WHO), cardiovascular diseases are the number one cause of death globally. Regarding the treatment of hypertension and chronic heart failure, the combination drug Entresto^® (Novartis) is considered to be superior to other medication options. It comprises the two active pharmaceutical ingredients (APIs) valsartan, a non-peptide angiotensin II receptor blocker, and the neprilysin-inhibitor prodrug sacubitril. Owing to the numerous benefits of continuous processing, the synthesis of active pharmaceutical ingredients (APIs) in continuous flow has gained increasing attention in the past couple of years. Within the framework of the ONE-FLOW project, we have developed multi-step routes for the synthesis of late-stage precursors of these two APIs in continuous flow. The key step of both cascades, achieving formation of the biphenyl motif, is a Suzuki-Miyaura cross-coupling reaction facilitated by heterogeneous Pd-substituted cerium-tin-oxides. Using a combination of coil and packed-bed reactors, the target compounds could be obtained in high yields and in moderate enantiomeric excess. The authors kindly acknowledge the funding by the H2020-FETOPEN-2016-2017 programme of the European commission (Grant agreement number: 737266-ONE FLOW).