Patent ID: 7470791
Filing Date: 2008-12-30
Classification: A61K,A61P,C07D

Abstract:
1. A process for the preparation of roflumilast by reacting an anion of 4-amino-3,5-dichloropyridine (1) in which A + is a potassium cation, with an activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2), in which LG is a suitable leaving group selected from a chlorine atom, a bromine atom or a radical of the formula OC(O)-1-4C-alkyl, wherein (a) the molar ratio of the employed anion of 4-amino-3,5-dichloropyridine (1) to the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is at least 1.8 and at most 2.7, (b) the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out in a solvent selected from dimethylformamide or N-methylpyrrolidone, (c) the reaction of the anion of 4-amino-3,5-dichloropyridine (1) with the activated derivative of 3-cyclopropylmethoxy-4-difluoromethoxybenzoic acid (2) is carried out at a temperature between 0° C. and the boiling point of the solvent used, and (d) KOtBu is used to prepare the anion of 4-amino-3,5-dichloropyridine (1).