Process Optimization for GSK369796 (N-tert-Butyl Isoquine)

An improved process to the novel 4-aminoquinoline antimalarial GSK369796 is described. Although the initial synthetic route consisted of only two steps from readily available starting materials, the product isolated via the key Mannich reaction was hampered by both low yields and low purity. In addition to instability under the reaction conditions used for the Mannich reaction, the drug substance was found to decompose during attempts to purify by recrystallisation. Reaction conditions were developed that resolved these issues, culminating in the successful production of multi-kg quantities of GSK369796 in >98% a/a purity and in 57% overall yield.