N-Phenyl-1,2-phenylenediamine (I) was alkylated with bromoacetanilide (II) in the presence of potassium carbonate in DMF, and the resulting alkylated phenylenediamine (III) was condensed with diacid chloride (IV) in THF to afford dioxobenzodiazepine (V). Reduction of the hydrazone function with zinc-acetic acid provided amine (VI) (1). Urea (VIII) was then prepared by treatment of amine (VI) with isocyanate (VII) in dichloromethane, and finally, ethyl ester was hydrolyzed on treatment with K2CO3 in a refluxing mixture of methanol and THF.
2-nitroaniline (III) was prepared by reaction of an excess of cyclohexylamine (II) with either 2-chloronitrobenzene (Ia) in the presence of CuI and K2CO3 at 150 C or 2-fluoronitrobenzene (Ib) in chloroform. Catalytic hydrogenation gave phenylenediamine (IV), which was selectively alkylated on the primary N atom with bromoacetylpyrrolidine (V) in the presence of K2CO3 in DMF. Condensation of the resulting (VI) with the malonic acid dichloride (VII) yielded benzodiazepine (VIII). Hydrazone function was then reduced with zinc dust in acetic acid to provide amine (IX). Separation of the racemic mixture was performed by treatment with the chiral carbonic acid derivative (X), followed by chromatographic separation to give the desired (S)-isomer (XI). Cleavage of the carbamate group of (XI) was effected by hydrogenolysis to afford chiral amine (XII). The target urea was then prepared by reaction of (XII) with 4-fluorophenylisocyanate (XIII) in dichloromethane.