PURINES .70. AN EXTENSION OF THE PHENACYLAMINE ROUTE TO THE SYNTHESESOF THE 7-N-OXIDES OF 6-MERCAPTOPURINE AND 6-METHYLTHIOPURINE, AND ANTILEUKEMIC ACTIVITY OF SOME PURINE N-OXIDES

A full account is given of the first syntheses of 6-mercaptopurine 7-N -oxide (4) and 6-methylthiopurine 7-N-oxide (5), The synthesis of 4 fo llowed a ''phenacylamine route'', which started from condensation of 4 ,6-dichloro-5-nitropyrimidine (15) with N-(4-methoxybenzyl)phenacylami ne to form the phenacylaminopyrimidine derivative (11) and proceeded t hrough conversion into the mercapto derivative, intramolecular cycliza tion between the NO2 nitrogen atom and the phenacyl carbanion to give 6-mercapto-9-(4-methoxybenzyl)purine 7-N-oxide (12), and removal of th e 4-methoxybenzyl group, S-Methylation of 12 and removal of the 4-meth oxybenzyl group afforded 5, The location of the oxygen function in 4, 5, and 12 was confirmed by X-ray crystallographic analysis of 5 . H2O, which was shown to exist in the N(7)-OH form (19), A UV spectroscopic approach suggested that the neutral species of 4 exists in H2O as the N(7)-OH tautomer (21), whereas that of 5 exists as an equilibrated mi xture of the N(7)-oxide (5) and the N(7)-OH (19) tautomers, In the in vitro bioassay of antileukemic activity against murine L5178Y cells, t he N-oxides 4 and 12 were found to be weakly cytotoxic.