PREPARATION OF ASYMMETRIC CYCLIC UREAS THROUGH A MONOACYLATED DIAMINE INTERMEDIATE

• Main Author: ROBERT E. WALTERMIRE
• Format: Patent
• Language: English
• Published: 31.10.1999
• Edition: 6
• Subjects: CHEMISTRY; HETEROCYCLIC COMPOUNDS; METALLURGY; ORGANIC CHEMISTRY

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.