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, 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.