Process Development for the Manufacture of the Antimalarial Amodiaquine Dihydrochloride Dihydrate

A robust process technology for the manufacture of the active pharmaceutical ingredient (API) amodiaquine dihydrochloride dihydrate (ADQ, 3), an important antimalarial, is reported. The process consists of a three-step synthetic route that involves a Mannich reaction, condensation with 4,7-dichloroquinoline (DCQ, 5) and rehydration. Additionally, a cost-competitive process for the production of DCQ (5) is also reported wherein DCQ (5) was prepared in four steps from meta-chloroaniline (7). 4-Amido-2-(diethylaminomethyl)phenol (14), DCQ (5), and ADQ (3) were obtained in yields of 92, 89 and 90% respectively.