Process Development of the Synthetic Route to (R)-6-Amino-1-ethyl-4-methylhexahydro-1,4-diazepine

The optically active (R)-6-amino-1-ethyl-4-methylhexahydro-1,4-diazepine (1) is the amine moiety of a novel and potent dopamine (D2 and D3) and 5-HT3 receptors antagonist AS-8112, which is a clinical candidate expected to be a broad antiemetic agent. Process development of an effective synthetic route to the optically active amine 1 from N-Cbz- and N-Ts-l-serine methyl esters was undertaken. In two potential scale-up processes, the route from N-Ts-l-serine methyl ester (21) was chosen because of its better overall yield (>30% yield for seven steps) and handling. The optically active amine 1 with high purity (>99.5% ee) was prepared via the reaction of the key intermediate N-Ts-aziridine 23 with EtNH2 and successive LiAlH4 reduction without racemization. Moderate scale-up synthesis of the amine 1 and AS-8112 by condensation of 1 and 5-bromo-2-methoxy-6-methylaminopyridine-3-carboxylic acid is described.