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Continuous manufacturing in the pharmaceutical industry: 
an enabling technology for the utilization of thermally unstable organolithium intermediates

Novartis Pharma AG, Fabrikstrasse 14, 4002 Basel, Switzerland


The benefit of rapid generation and consumption of reactive or unstable intermediates under flow conditions (flash chemistry) has been proven to be a valuable addition to traditional batch chemistry. In this context a continuous flow process for the synthesis of highly functionalized benzoxazoles utilizing unstable reaction intermediates avoiding cryogenic reaction conditions has been developed.


Over recent years, continuous manufacturing has emerged as a complementary tool to traditional batch chemistry with numerous applications in both academia and industry (1). This new aspect of process development is often linked with distinctive benefits such as increased process safety and accurate control of reaction parameters as well as enhanced robustness and reproducibility of chemical processes (2). Furthermore, the enlarged operational window (e.g. high temperatures and pressures, minimized residence times) and additional benefits such as improved throughput, minimization of footprint, handling of hazardous intermediates/reagents in closed reactor systems and sustainability as well as cost-efficiency are strong drivers for the application of flow technology in large scale manufacturing (1a, 3).

Continuous manufacturing technology is of particular interest when dealing with rapid and strongly exothermic transformations, as well as handling of highly reactive, short-lived reaction intermediates. Organolithium species which serve as valuable synthons in organic synthesis (4) often fall into this specific category. Lithiumbase med ...