Protecting moieties nitro

Melphalan and the racemic analog have been prepared by two general routes (Scheme I). In Approach (A) the amino acid function is protected, and the nitrogen mustard moiety is prepared by conventional methods from aromatic nitro-derivatives. Thus, the ethyl ester of N-phthaloyl-phenylalanine was nitrated and reduced catalytically to amine I. Compound I was reacted with ethylene oxide to form the corresponding bis(2-hydroxyethyl)amino derivative II, which was then treated with phosphorus oxychloride or thionyl chloride. The blocking groups were removed by acidic hydrolysis. Melphalan was precipitated by addition of sodium acetate and was recrystallized from methanol. No racemization was detected [10,28—30]. The hydrochloride was obtained in pure form from the final hydrolysis mixture by partial neutralization to pH 0.5 [31]. Variants of this approach, used for the preparation of the racemic compound, followed the same route via the a-acylamino-a-p-aminobenzyl malonic ester III [10,28—30,32,33] or the hydantoin IV [12]. 

The synthetic importance of reaction (a) ° comes from the fact that it reduces to one step the pathway for conversion of an acid chloride into a nitrile (instead of the classical and rather inconvenient two-step route via an acid amide). Reaction is an example of a new transformation for aliphatic amines. Previously, there were no methods available for the direct transformation of an amino into a nitro group and the stepwise procedures were too cumbersome to be of practical use. Transformation of a nitro group into a carbonyl is a well-known reaction. Its modification, shown in reaction represents a welcome opportunity to obtain a protected carbonyl group as the immediate result of such a transformation. The viability of the sequential reactions (b) plus (c) enables the employment of a > CHNH2 moiety as a synthetic equivalent to a protected carbonyl group. A one-pot sequence of imine formation and its reduction with sodium triacetoxyborohydride represents a convenient... 

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