Kinetics of the nitrosation of aminopyrine to give dimethylnitrosamine

Abstract

The initial rate of nitrosation of aminopyrine (AP, Pyramidon) to give dimethyl nitrosamine (DMN) showed maxima at pH 2.0 and 3.1. At pH 2, initial rate was proportional to nitrite concentration squared down to 6 mM, below which it decreased rapidly. The rate was independent of AP concentration at pH 2 but proportional to AP concentration at pH 0.5, indicating that nitrous anhydride formation was rate-limiting at pH 2. DMN was detected after 5 seconds reaction under "normal" conditions. The stoichiometric rate constant at pH 2 and 0° was 80 M-2 sec-1, higher than that for all secondary amines previously studied, except N-methylaniline. In addition to the "initial reaction", a second slow reaction giving DMN was observed. When 20 mM AP was reacted for 1 hr with 25-100 μM nitrite at 37°, >90% of the nitrite reacted to give DMN. Ascorbate blocked DMN formation from AP efficiently under various conditions. We confirmed Bockmühl's finding that the other main product of AP nitrosation is 1-diketo-butyryl-1-phenyl-2-methyl-2-nitrosohydrazide hydrate (DPMN). The unusual ease of reaction is attributed to the enamine structure of AP. The possibility of intragastric nitrosation of AP is considered to present a hazard to people ingesting this analgesic drug, which is widely used in Europe. © 1974 Springer-Verlag.