Aminopyrine nitrosation

These seemingly anomalous results suggest that the formation and fragmentation of a-amino nitrite esters could be playing a central role in the nitrosation of aminopyrine. The characterization of both fast and slow reactions, as well as the identification of two pH optima, imply that more than one kinetically significant pathway is involved in the overall transformation. The mechanism of Fig. 5a could well be the first order component the kinetic studies show to be operative under some conditions. It is noteworthy that this pathway also leads directly in its final step to the keto-enol derivative IV, which Mirvish et al. have identified as a by-product of aminopyrine nitrosation. 

Figure 5. Possible mechanisms of aminopyrine nitrosation (a) as proposed by Keefer and Roller (6) (b) as postulated by Mirvish et al. (12) (c) an alternative...

An apparent order in nitrite of 3 or more would also be consistent with a-amino nitrite fragmentation mechanisms if one assumes that nitrite is preferentially consumed in redox or nitrosation reactions elsewhere in the molecule which compete with nitrosation of the dimethylamino group. One such possibility was suggested by Dr. R.N. Loeppky (private communication), as shown in Fig. 6. This mechanism, which postulates the intermediacy of two different o-amino nitrites, le and If, should obey third order kinetics, since dimethylnitrosamine is produced only after aminopyrine reacts with the third mole of nitrite. Moreover, this pathway offers a mechanistic explanation for the direct production of nitrosohydrazide V, which has also been reported to be a product of aminopyrine nitrosation (12.17). 

Figure 6. Possible mechanism of aminopyrine nitrosation, proposed by R. N. Loeppky (private communication)...

Ascorbic acid has been found to be the most effective and useful inhibitor of amine nitrosation [23]. Ascorbic acid inhibits the formation of DMN from oxytetracycline and nitrite, and also from aminophenazone (aminopyrine) and nitrite. Tannins are present in a variety of foods, competing with secondary amines for nitrite and thus leading to a reduction in the amount of nitrosamine formed [24]. 

Mirvish. later investigated the nitrosation of aminopyrine in considerable detail (12), proposing the alternative pathway shown in Fig. 5b, but presenting evidence that the mechanism is actually a great deal more complex than that. Firstly, they identified both a "fast" initial reaction, which was essentially complete within 2-5 min., and a "slow" reaction, which proceeded at a nearly constant rate for 15 min. Secondly, they found that the pH rate profile had maxima at both pH 2.0 and pH 3.1. Thirdly, they reported an apparent kinetic order for nitrite which varied considerably under some conditions from the value of 2 required by the mechanism of Fig. 5b, ranging from cleanly first order for the "slow" reaction at pH 2 to as high as 3-4 for the initial reaction at low nitrite concentration (l-6mM). 

Many pharmaceutical products on the market contain primary, secondary, and/or tertiary amines or amine derivatives, and several drugs have been shown to readily form N-nitroso compounds when nitrosated in vitro and/or in vivo (27-33). With the exception of aminopyrine in Germany (23) and the antibiotic studied by Schoenhard et, (26), there appears to be no information available with regard to the possible presence of N-nitroso impurities present in pharmaceutical products. 

If k2 >> k, then reaction (4) is mostly complete before (3) starts. Large doses of vitamin C have been observed to protect rats from liver tumors induced by aminopyrine and sodium nitrite (26). This inhibition is thought to result, in part, from blockage of in vivo nitrosation, which forms dimethylnitrosamine. 

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