Process design methodology for organometallic chemistry in continuous flow systems

Reaction Calorimetry in Continuous Flow Mode: A New Approach for the Thermal Characterization of High Energetic and Fast Reactions

“…Continuous approaches allow chemicals to be rapidly mixed under superior temperature control and unstable intermediates to be instantly produced and selectively transformed. As a result, those processes that need a cryogenic temperature and long dosing time in semibatch could be performed in continuous mode at milder temperatures with residence times of a few seconds and with overall higher efficiency and quality . The archetype sequence of this class of reactions is represented by the lithiation of aryl halides by means of organolithium reagents followed by a quench with electrophiles .…”

Synthesis of a Highly Functionalized Quinazoline Organozinc toward KRAS G12C Inhibitor Divarasib (GDC-6036), Enabled through Continuous Flow Chemistry

“…With kinetics, stability, and calorimetry data in hand, we leveraged process modeling using Dynochem software to apply heat transfer models for standard laboratory-and manufacturing-scale continuous plug flow reactors, allowing us to predict the behavior of this process across different possible set points and equipment scenarios (Figure 4). 15 High rate constants were arbitrarily assigned to the primary Br−Mg exchange and Mg−Zn transmetalation steps due to their rapid observed rates even at low temperature, and reaction enthalpies were included from the RC1 calorimetry experiment. Finally, decomposition and nucleophilic aromatic substitution rates and activation energies were fit based on the observed batch reaction and stability data (Figure 4a).…”