Synthesis of 4‐substituted 1,4‐benzodiazepine‐3,5‐diones

Synthetic routes leading to the preparation of 4‐substituted 1,4‐benzodiazepine‐3,5‐diones are described. Thus, 2‐carbobenzoxyaminobenzoic acid was converted to its p ‐nitrobenzyl ester (I) and the decarbobenzoxylated product (II) gave, with ethyl α‐bromoacetate, N ‐(2‐carboxy p ‐nitrobenzylate)phenylglycine ethyl ester (III). The latter was hydrogenolyzed to N ‐(2‐car‐boxy)phenylglycine ethyl ester (IV), which was coupled with benzylamine to give N ‐(2‐carboxy‐benzylamido)phenylglycine ethyl ester (VIa). Saponification of VIa afforded N ‐(2‐carboxy‐benzylamido)phenylglycine (VIIa) which was cyclized with DCCI to produce 4‐benzyl‐2 H ‐1,4‐benzodiazepine‐3,5(l H ,4 H )dione (VIIIa). Alternatively, 2‐nitro‐ N ‐phenylbenzamide (Xb) was reduced to 2‐amino‐ N ‐phenylbenzamide (XIb) which was converted to N ‐(2‐carboxanih'do)‐phenylglycine ethyl ester (VIb). The latter was converted to 4‐phenyl‐2 H ‐1,4‐benzodiazepine‐3,5(1 H ,4 H )dione (VIIIb) in an analogous fashion described for VIIIa.