Mustards, aniline nitrogen

In Approach (B), aniline is converted into the corresponding nitrogen mustard, which is formylated to the benzaldehyde nitrogen mustard V. The alanine moiety is constructed via the Erlenmeyer reaction with hippuric acid, reduction, and hydrolysis [23,34—38]. 

Anti-cancer drugs such as cyclophosphamide (15), aniline mustard, and nitrosoureas are transformed to reactive metabolites which are the toxic species required for their anti-cancer activity. Experiments with selectively deuterated analogs of these drugs has distinguished which pathway, among several alternative pathways of metabolism, is responsible for antitumor activity. For example, a deuterium isotope effect was observed for the formation of 4-ketocyclophosphamide (16), formed by the oxidation of the carbon alpha to the phosphoramide nitrogen, but there was no Isotope effect on the anti-tumor activity. However, there was a marked effect on the subsequent -elimination reaction and consequent decrease in anti-tumor activity by deuterium substitution at C-5. Thus, the formation of acrolein and phosphoramide mustard is rate determining for the anti-tumor activity of cyclophosphamide. 

Krentzkamp, N., and Cordes, G., Carbonyl- and cyanophosphonic acid esters. Part 6. a-Substimted benzylphosphonic acid and its derivatives. Arch. Pharm. Ber. Dtsch Pharm. Ges., 295, 276, 1962. Schulze, W., WiUitzer, H., and Fritzsche, H., Nitrogen mustard derivatives by the reaction of N,N-iiw(P-chloroethyl)-p-(tricyanovinyl)aniline with the sodium salts of OH, NH, PH, and SH acidic compounds, Chem. Ber., 100, 2640, 1967,... 

It is well-established that the reactivity of aromatic nitrogen mustards in hydrolysis reactions correlates positively with the degree of electron release to the nitrogen (7). The rate constants for alkaline hydrolysis of a series of aniline mustards correlate well with a, as shown by Equation 1 (equation 23 of ref. 8). 

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