Liquizald─Thermally Stable N-Nitrosamine Precursor for Diazomethane

Abstract

N-Methyl-N-nitroso-p-toluenesulfonamide (Diazald) and N-nitroso-β-methylaminoisobutyl methyl ketone (Liquizald) were compared in this study as diazomethane precursors for process scale-up. Thermal assessment flagged Diazald for explosion propagation and impact sensitivity using the Yoshida methodology, while Liquizald only indicated potential for impact sensitivity under more conservative Pfizer correlations. A higher onset temperature of Liquizald at 170 °C was determined. Compared to the onset temperature for Diazald (80 °C), Liquizald made a favorable candidate for exploitation of increased reaction rates at high temperatures using microreactor technologies. New kinetic parameters of decomposition were further used to study the potential for process intensification and identify the microreactor channel sizing for thermally stable and near-isothermal reactor operation.

Highlights of the Recent Patent Literature: Continuous Chemistry in the Pharmaceutical Industry

“…Several N -alkyl- N -nitroso compounds have been developed as precursors of diazomethane. N -Nitroso-β-methylaminoisobutyl methyl ketone (“Liquizald”), which is prepared from mesityl oxide, has emerged as one of the optimal precursors due to improved stability, cost, and availability . The preparation of diazomethane from an appropriate precursor in flow mode was described by Poechlauer and co-workers, wherein diazomethane is continuously formed in a flow reactor and then transferred through a hydrophobic membrane into a second reactor containing the substrate .…”