Epiroprim, Ro-11-8958

依匹普林Chemical Name: 5-(3,5-Diethoxy-4-pyrrolidinobenzyl)pyrimidine-2,4-diamine
CAS No. 73090-70-7
项目整合开发状态: Phase I
项目研究机构: Roche (Originator)
合成路线: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.