Continuous Manufacturing of Active Pharmaceutical Ingredients Using Organometallic Heterogeneous Catalysis

Continuous manufacturing of active pharmaceutical ingredients (APIs) is becoming increasingly important as there are many advantages, such as better control of process conditions, elimination of batch-to-batch variability, and the lack of scale-up problems, since even bench-top continuous systems can produce the desired quantities required in the pharmaceutical or fine-chemicals industry. We present the development of continuous processes for the synthesis of APIs using heterogeneous organometallic catalysts. The catalysts (heterogeneous titanocenes and Pd-complexes) are covalently attached to different solid supports in order to prevent metal leaching into the product. For this purpose we developed novel methods for catalyst immobilization [1, 2] that allow a precise control of the location and dispersion of the catalytic sites on the surface of the solid supports as well as the preparation of multifunctional catalysts. The novel materials were tested for the synthesis of chiral amines and substituted biphenyls [3] and were implemented in different lab-scale continuous flow systems, e.g., packed bed reactors, monolithic structures and microfluidic devices, which allow online analysis of the reaction processes. Preliminary results show that the developed setups lead to improved practicability and flexibility of the processes. Thus, these novel reaction systems constitute promising alternatives to existing batch applications.