Antitumour imidazotetrazines. Synthesis and chemistry of 4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (nor-temozolomide): an intermediate for the preparation of the antitumour drugtemozolomide and analogues, avoiding the use of isocyanates

Abstract

An efficient synthesis of 4-oxo-3,4-dihydroimidazo[5,1-d][1,2,3,5]tetrazine-8-carboxamide (nor-temozolomide) and in situ generation of the anion of nor-temozolomide from an N-3-hydroxymethyl derivative of temozolomide are reported. Alkylation of the anion of nor-temozolomide with methyl iodide gave a new route to temozolomide avoiding the use of methyl isocyanate. A series of new 3-substituted analogues of temozolomide were also prepared by electrophilic substitution of the nor-temozolomide anion but this approach is so far restricted to certain electrophiles.