By cyclization of 5-diazoimidazole-4-carboxamide (I) with 2-chloroethyl isocyanate (II) in dichloromethane.
By reaction of 5-diazoimidazole-4-carboxamide (II), prepared by diazotization of 5-aminoimidazole-4-carboxamide (I) with nitrous acid, with methylisocyanate (III) either alone or in dichloromethane.
The synthesis of several forms of [13C]- and [15N]-labeled temozolomide has been reported: 1) The diazotation of 3-aminopyrazole-4-carboxamide (I) with [15N]-labeled sodium nitrite and HCl gives the corresponding labeled diazonium salt (II), which is cyclized with methyl isocyanate (II) at room temperature, yielding temozolomide labeled at the N in the 2-position.
2) The condensation of N,N-diphenylcarbamoyl chloride (IV) with [13C]-labeled methylamine (V) gives the corresponding urea (VI), which by heating at 240 C is converted to the [13C]-labeled methyl isocyanate (VII). Finally, this compound is cyclized with the diazonium salt (VIII) (obtained by diazotation of 3-aminopyrazole-4-carbonitrile with NaNO2-HCl in the usual way) to afford temozolomide labeled at the methyl in the 3-position. 3) The preceding sequence performed with [15N]-labeled methylamine (X) gives urea (XI), isocyanate (XII) and finally temozolomide labeled at the N in the 3-position.
Further nitration of the nitroimidazole (I) with HNO3, Ac2O gives the 1,4-dinitroimidazole (II), which is treated with KCN and NaHCO3 in methanol/water to yield 5-nitro-1H-imidazole-4-carbonitrile (III). The reaction of (III) with dihydropyran and Ts-OH in ethyl acetate affords the N-protected imidazole (IV). The reduction of (IV) with H2 over Pt/C in ethyl acetate provides the hydroxylamine (V), which is oxidized with NaIO4 in ethyl acetate/water to give the nitroso derivative (VI). The condensation of (VI) with phenyl 2-methylcarbazate (VII) by means of HOAc and TFA yields the triazene (VIII), which is treated with conc. HCL in ethyl acetate to afford the carboxamide (IX). Finally, this compound is cyclized to the target imidazo-tetrazinone by irradiation with daylight in acetone/MeOH, most probably through the non isolated cis intermediate (X).
This compound has been obtained by two related ways: 1. The reaction of 5-diazoimidazole (I) with methylamine gives the triazene (II), which is then cyclized with 11C-phosgene (III) to yield the target 11C-carbonyl labeled compound. 2. The cyclization of 5-diazoimidazole-4-carboxamide (I) with 11C-carbonyl labeled methyl isocyanate (IV) gives the target 11C carbonyl labeled compound.
The cyclization of 5-diazoimidazole-4-carboxamide (I) with 11C-methyl isocyanate (II) gives the target 11C methyl labelled compound.