Process Development for the Manufacture of the Antimalarial Amodiaquine Dihydrochloride Dihydrate

Abstract

A robust process 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, substitution with 4,7-dichloroquinoline (4,7-DCQ, 5), and rehydration. Additionally, a cost-competitive process for the production of 4,7-DCQ (5) is also reported wherein 4,7-DCQ (5) was prepared in four steps from meta-chloroaniline (7). 4-Acetamido-2-(diethylaminomethyl)phenol (14), 4,7-DCQ (5), and ADQ (3) were obtained in yields of 92, 89, and 90%, respectively. Costing and process mass intensities of 4,7-DCQ and ADQ are also reported.