Synthesis of Paraxanthine and Isoparaxanthine Analogs (1,7- and 1,9-Substituted Xanthine Derivatives)

A general, convenient method for the preparation of 1,7- and 1,9-disubstituted xanthine derivatives (paraxanthine and isoparaxanthine analogs) was developed starting from 6-amino-2- methoxypyrimidin-4-one. Alkylation with alkyl halides in ace- tone/potassium carbonate in the presence of a phase-transfer cata- lyst (PTC) yielded an equimolar mixture of N3- and O 4 -alkylated products, which could be separated by dry column chromatogra- phy. The N3-alkylated uracil derivatives were converted to the corresponding 1-alkyl-2-methoxypurin-6-ones by standard proce- dures. PTC alkylation yielded an equimolar mixture of 7- and 9- alkylated isomers, which were again conveniently separated by dry column chromatography. The title compounds were obtained after acid hydrolysis of the 2-methoxy group in satisfactory yields.