Process Development for the Manufacture of the Antimalarial Amodiaquine Dihydrochloride Dihydrate.

A robust process for the manufacture of the active pharmaceutical ingredient (API) amodiaquine dihydrochloride dihydrate (ADQ, ), 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, ), and rehydration. Additionally, a cost-competitive process for the production of 4,7-DCQ () is also reported wherein 4,7-DCQ () was prepared in four steps from -chloroaniline (). 4-Acetamido-2-(diethylaminomethyl)phenol (), 4,7-DCQ (), and ADQ () were obtained in yields of 92, 89, and 90%, respectively. Costing and process mass intensities of 4,7-DCQ and ADQ are also reported.