Development of a Practical and Greener Process for
the Dual Leucine Zipper Kinase Inhibitor GDC-0134 Comprising Two SNAr Reactions, Oxidation and Suzuki Coupling
posted on 2022-01-20, 21:14authored byFabienne Hoffmann-Emery, Katrin Niedermann, Pankaj D. Rege, Manuel Konrath, Christian Lautz, Anne Katrin Kraft, Carine Steiner, Fritz Bliss, André Hell, Rolf Fischer, Diane E. Carrera, Danial Beaudry, Remy Angelaud, Sushant Malhotra, Francis Gosselin
A sustainable
second-generation process for GDC-0134 was developed
with a particular focus on safety and greenness, while complying with
strong specifications to supply pivotal clinical studies. Through
these efforts, we discovered solvents to replace the solvents classified
as substances of very high concern by the REACH regulation in two
SNAr steps. We further established a safer and faster way
to oxidize the sulfanyl to the sulfonyl intermediate by dosing H2O2 at higher temperatures, reducing accumulation
while minimizing uncontrolled H2O2 decomposition.
The reaction conditions for the Suzuki coupling and the second SNAr were modified to increase the selectivity in these two
steps. A change in the solvent for the final crystallization allowed
operation at higher concentrations and delivery of a highly pure active
pharmaceutical ingredient (API). The new improved process reduced
the process mass intensity by approximately 40% and was successfully
used to produce 150 kg of GDC-0134.