Interquim, S.a.

Josep Salaet Ferre

Francisco Marquillas Olondriz

The invention relates to a process for the preparation of Roflumilast by reaction of an activated form of 3-(cyclopropylmethoxy)-4-(difluoromethoxy)-benzoic acid with an activating agent selected from (a) carbonyldiimidazole (CDI), (b) 1,1'-carbonyl-di-(1,2,4-triazol) (CDT), (c) 1,1&#x2032;-carbonyl-bis-(2-methylimidazol), (d), 1&#x2032;-carbonyl-dipyperidin, (e) N,N&#x2032;-dicyclohexylcarbodiimide (DCC), (f) N,N&#x2032;-diisopropylcarbodiimide (DIC), (g) 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) and a combination of one of the previous (a)-(g) with (h) N-hydroxysuccinimide or (i) N-hydroxyphthalimide, and the subsequent reaction with 3,5-dichloropyridine-4-amine in the presence of an inorganic base. The invention also relates to the synthesis intermediates.

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Sant Cugat del Vallés-Barcelona, Spain

Josep Salaet Ferre