Antitumour imidazotetrazines. Part 33. New syntheses of the antitumour drug temozolomide using ‘masked’ methyl isocyanates

Abstract

Ethyl 8-carbamoyl-4-oxo-3,4-dihydroimidazo[5,1-d]-1,2,3,5-tetrazin-3-ylacetate 6a can be prepared by treating 5-diazoimidazole-4-carboxamide 3 with ethyl isocyanatoacetate or by diazotisation of N-(5-amino-4-carbamoylimidazol-1-ylcarbonyl)glycine ethyl ester 5. Barton radical decarboxylation of the tetrazin-3-ylacetic acid 6b affords temozolomide 1(26%) whereas deprotection of the 3-trimethylsilylmethyl-imidazotetrazine 6g with TBAF in acetonitrile–acetic acid yields 1 in 78% yield. 3-Benzylimidazotetrazinones 10a–c are stable to hydrogenolytic or oxidative debenzylation reactions.