Nonpeptide HIV Protease Inhibitors. Differential Introduction of Alkylamino Groups into the Two Aryl Rings of Haloperidol

Abstract

In efforts to synthesize haloperidol analogues with improved properties as HIV protease inhibitors, methods were sought to introduce mono- and dialkylamino groups into the two aromatic rings of the parent structure. We report here that the reaction of haloperidol with alkylamines in the presence of a strong base (NaNH) regiospecifically introduces the alkylamino group into the chlorophenyl ring, whereas the same reaction in the presence of a weak base (KCO) results in exclusive replacement of the fluorine of the fluorophenyl ring. Different amine functions can be introduced at the two rings by sequential reactions in the presence of, respectively, a strong and a weak base. The reaction catalyzed by NaNH involves, at least in part, benzyne formation, whereas the reaction catalyzed by KCO involves direct nucleophilic addition to the aromatic ring. The regiospecificity of the reaction is due to conjugation of the fluorophenyl ring to a ketone group. The fluorophenyl ring is activated by the ketone towards nucleophilic aromatic substitution but is deactivated by the same function when it is converted by strong base to the enolate anion. Carbonyl conjugation of one of two haloaryl groups appears to be a general strategy for regiospecific introduction of alkylamino functions into complex aromatic molecules. The alkylamino derivatives actually prepared are comparable to haloperidol as inhibitors of the HIV-1 protease.