合成路线1

3,5-Dihydroxybenzoic acid (I) was carboxylated under CO2-pressure in aqueous KOH solution. Acidification in situ directly precipitated 2,6-dihydroxyterephthalic acid (II), which was per-ethylated with diethyl sulfate in acetone to afford diethyl 2,6-diethoxyterephthalate (III). The sterically more hindered 1-ester group of di-ester (III) underwent Lossen rearrangement upon treatment with hydroxylamine sulfate in polyphosphoric acid. The resulting ethyl 4-amino-3,5-diethoxybenzoate (IV) was condensed with 2,5-dimethoxytetrahydrofuran in hexane under acetic acid catalysis and water removal yielding ethyl 3,5-diethoxy-4-(pyrrol-1-yl)benzoate (V), which was reduced with diisobutylaluminum hydride in toluene. The intermediate benzyl alcohol was oxidized in situ with activated manganese(IV) oxide to yield 3,5-diethoxy-4-(pyrrol-1-yl)benzaldehyde (VI). The following steps achieved the construction of the 2,4-diaminopyrimidine moiety of the title drug and reflect well established methodology. The benzaldehyde (VI) was condensed with 3-morpholinopropionitrile under potassium tert-butylate catalysis in N,N-dimethylformamide. The crude acrylonitrile intermediate was treated with aniline hydrochloride in 2-propanol in order to provide a better leaving group for the final cyclization, which was carried out by heating with an excess of guanidine in methyl sulfoxide.