Fremstilling av asymmetriske sykliske ureaforbindelser via et monoacylert diaminintermediat

Foreliggende oppfinnelse angår en forbedret fremgangsmåte for fremstilling av asymmetriske sykliske ureaforbindelser så vel som intermediater ved fremstillingen av asymmetriske sykliske ureaforbindelser. I fremgangsmåten kan et diamin med formel (I- a) selektivt monoacyleres og gi et asymmetrisk monoacylert diamin som kan omdannes til asymmetriske intermediater. Asymmetriske intermediater kan videre alkyleres, sykliseres og/eller modifiseres og gi forbindelser som er anvendelige som HJV protease inhibitorer for behandling av HIV-infeksjon. Oppfinnelsen muliggjør storskala fremstilling av et bredt spekter av asymmetriske sykliske ureaforbindelser. A process for the preparation of asymmetric cyclic ureas of Formula (VI) starting from the diamine of Formula (I). In the process, a compound of Formual (I), wherein G is a group selected from -C(-CH2CH2CH2CH2CH2-)-, -C(CH2CH3)2-, -C(CH3)(CH2CH3)-, -C(CH2CH2CH2CH3)2-, -C(CH3)(CH2CH(CH3)CH3)-, -CH(phenyl)-, -CH2-, -C(CH3)2-, and -C(OCH3)(CH2CH2CH3)-, is selectively monoacylated with an acylating agent to give an asymmetric monoacylated diamine, 2) the asymmetric monoacylated diamine is contacted with an aldehdye and a reducing agent to form a monoalkylated monoacylated diamine, 3) the monoalkylated monoacylated diamine is contacted with a strong base to form a monoalkylated de-acylated diamine, 4) the monoalkylated de-acylated diamine is contacted with 3-cyano-4-fluoro-benzaldehyde and a reducing agent to form a dialkylated diamine, and 5) the dialkylated diamine is contacted with phosgene in the presence of a base to form a compound of Formula (VI). The invention allows for scalable preparation of a wide variety of asymmetrical cyclic ureas useful as HIV protease inhibitors for the treatment of HIV infection.