Continuous Production of the Diazomethane Precursor N-Methyl-N-nitroso-p-toluenesulfonamide: Batch Optimization and Transfer into a Microreactor Setup

The goal of this study was to develop a continuous multistep synthesis for the preparation of N-methyl-N-nitroso-p-toluene-sulfonamide (3, MNTS, Diazald) starting from p-toluenesulfonyl chloride W. making use of microreaction technology (MRT). MNTS is an important precursor for diazomethane, a highly reactive and selective reagent for the production of pharmaceuticals and fine chemicals. We to the properties of the successive reaction steps (exothermic reactions, use of toxic and highly reactive reagents), if was envisaged that MRT could provide advantages when compared to its hatch-wise preparation. The research strategy included preliminary batch investigations, in which the effects of the solvent system, reed concentration, relative molar ratio. temperature, and residence time were established. Starting front these results. the reactions were translated into tire MRT setup As a result, the amidation of 1 to N-methyl-p-toluenesulfonamide (2) its the first reaction step is performed continuously in >90% yield and maximum space-lime yields of up to 75 kg L-1 h(-1). By making use of salting-out effects, the product separates nearly quantitatively in high concentrations in organic solution from the saline-waste stream. It is continuously converted to 3 by addition of NaNO2 with quantitative conversions: yields of >90% and maximum space-time yields of tip to 9 kg L-1 h(-1). The method presented allows for [fie connection of the diazomethane precursor preparation to its continuous liberation by addition of a base, and conversion with a substrate, as previously demonstrated using MRT (Struempel, M.; On. druschka, B.; Daute, R.; Stark, A. Green Chem. 2008, 10, 41).