The condensation between 2-fluorobenzonitrile (I) and ethyl isonipecotate (II) produced the piperidino benzonitrile (III). Reduction of nitrile and ester functions of (III) to afford the intermediate amino alcohol (IV) was accomplished using either LiAlH4 or, in a more practical, scalable procedure, using NaBH4/ZnCl2.
Quinazolinone (VI) was prepared by condensation of 4-chloroanthranilic acid (V) with hot formamide. Subsequent electrophilic nitration of (VI) provided the 6-nitroquinazolinone (VII) as the major regioisomer. Displacement of the 7-chloro of (VII) upon heating with ethylamine in a sealed tube gave rise to the nitro amine (VIII). The 4-chloroquinazoline derivative (IX) was then obtained by chlorination of (VIII) with phosphorus oxychloride. Condensation of (IX) with the intermediate benzylamine (IV) furnished adduct (X). The nitro group of (X) was then reduced by catalytic hydrogenation to yield the phenylenediamine derivative (XI). Finally, condensation of phenylenediamine (XI) with carbon disulfide in the presence of Et3N generated the target imidazoquinazoline, which was isolated as the dihydrochloride salt.
In an improved procedure, commercial 7-chloroquinazolinedione (XII) was nitrated to (XIII) using 60% HNO3 in the presence of H2SO4. Subsequent chloro displacement in (XIII) with ethylamine in hot DMSO furnished nitro amine (XIV). Chlorination of quinazolinedione (XIV) to the dichloro derivative (XV) was carried out by means of POCl3 in the presence of diisopropylethylamine in hot toluene. The 4-chloro group of (XV) was regioselectively displaced by the intermediate benzylamine (IV) yielding (XVI). Simultaneous reduction of the nitro and chloro groups of (XVI) by transfer hydrogenation provided the phenylenediamine (XI). The imidazothione ring was finally constructed by condensation of (XI) with phenyl isothiocyanate.