Aryl amines, acid/base hydrolysis

Acid/base stress testing is performed to force the degradation of a drug substance to its primary degradation products by exposure to acidic and basic conditions over time. Functional groups likely to introduce acid/base hydrolysis are amides (lactams), esters (lactones), carbamates, imides, imines, alcohols (epimerization for chiral centers), and aryl amines. 

A new spray reagent, dapsone, was described for the detection of baygon, carbaryl, and carbofuran. ITie detection was based on the alkaline hydrolysis of the carbamates forming the corresponding phenols, which can be reacted in the para position with the diazotized aryl amines. The sensitivities of several diazotized anilines, sulfanilic acid, p-toluidine were compared with dapsone. The limits of the detection were about 0.1 pg range (72e) (Table 4). 

While aryl phosphoramidates based on amino acids are by far the most common examples of this class, further variations in the ester and amine components certainly are known [142]. For example, in place of an aryl ester, a 3-acyloxymethoxypropyl group has been studied (e.g., 65), and hydrolysis of the ester was found to be 20 times faster than the corresponding phenyl phosphoramidate [131]. In this work, small differences in the reactivity of the Rp and Sp isomers were noted, but it was not possible to identify which was the more reactive (Fig. 14). 

The a-keto amides are less susceptible to hydrolysis and preparation of a-keto esters and acids are preferable for synthesizing various derivatives thereof. Various aryl iodides and bromides can be converted into a-keto esters on reactions with alcohols and carbon monoxide in the presence of a base such as tertiary amines or potassium acetate with catalytic amounts of tertiary phosphine-coordinated palladium complexes (Eq. 11).[42]-[46] jjjgjj yields of a-keto esters can be achieved only when iodide substrates are used. Double carbonylation of aryl bromides to a-keto esters can be accomplished with difficulty at much slower rates. Alkyl and benzyl iodides give no double carbonylation products. 

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