ANTITUMOR IMIDAZOTETRAZINES .35. NEW SYNTHETIC ROUTES TO THE ANTITUMOR DRUG TEMOZOLOMIDE

Three new pathways to the antitumor drug temozolomide (4) have been ex plored via intermediates 3, 6, and 7. The key intermediate amino-1-(N- methylcarbamoyl)imidazole-4-carboxamide (6) has been successfully conv erted to 4 in 45% yield by employing sodium nitrite in aqueous tartari c acid at 0-5 degrees C, Compound 6 is prepared from nitrophenyl carba mate 14a and methylamine or directly from 5-aminoimidazole-4-carboxami de (13) and either methyl isocyanate or N-methylcarbamoyl chloride. Te mozolomide (4) is also prepared from -3-methylimidazo[5,1-d]-1,2,3,5-t etrazin-4(3H)-one (7) by hydrolysis to the hydrochloride salt of 4 in 10 M hydrochloric acid. Compound 7 is prepared from either 5-diazoimid azole-4-carbonitrile (28) and methyl isocyanate or by diazotization of mino-1-(N-methylcarbamoyl)imidazole-4-carbonitrile (25). Attempts to cyclize 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (3) with phosg ene or phosgene equivalents were unsuccessful: only 2-azahypoxanthine (11) was isolated.