title: Antitumor Imidazotetrazines. 35. New Synthetic Routes to the Antitumor Drug Temozolomide.
abstract: Three new pathways to the antitumor drug temozolomide (4) have been explored via intermediates 3, 6, and 7. The key intermediate 5-amino-1-(N-methylcarbamoyl)imidazole-4-carboxamide (6) has been successfully converted to 4 in 45% yield by employing sodium nitrite in aqueous tartaric acid at 0-5 degrees C. Compound 6 is prepared from nitrophenyl carbamate 14a and methylamine or directly from 5-aminoimidazole-4-carboxamide (13) and either methyl isocyanate or N-methylcarbamoyl chloride. Temozolomide (4) is also prepared from 8-cyano-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one (7) by hydrolysis to the hydrochloride salt of 4 in 10 M hydrochloric acid. Compound 7is prepared from either 5-diazoimidazole-4-carbonitrile (28) and methyl isocyanate or by diazotization of 5-amino-1-(N-methylcarbamoyl)imidazole-4-carbonitrile (25). Attempts to cyclize 5-(3-methyltriazen-1-yl)imidazole-4-carboxamide (3) with phosgene or phosgene equivalents were unsuccessful: only 2-azahypoxanthine (11) was isolated.
authors.affiliation: Aston Molecules Ltd, 10 Holt Court, Aston Science Park, Birmingham, B7 4EJ, UK.
authors.forename: Yongfeng
authors.initials: Y
authors.lastname: Wang
authors.forename: Malcolm F. G.
authors.initials: MF
authors.lastname: Stevens
authors.forename: Tze-ming
authors.lastname: Chan Tm
authors.forename: Donald
authors.initials: D
authors.lastname: DiBenedetto
authors.forename: Zhe-xing
authors.lastname: Ding Zx
authors.forename: Dinesh
authors.initials: D
authors.lastname: Gala
authors.forename: Donald
authors.initials: D
authors.lastname: Hou
authors.forename: Max
authors.initials: M
authors.lastname: Kugelman
authors.forename: William
authors.initials: W
authors.lastname: Leong
authors.forename: Shen-chun
authors.lastname: Kuo Sc
authors.forename: Janet L.
authors.initials: JL
authors.lastname: Mas
authors.forename: Doris P.
authors.initials: DP
authors.lastname: Schumacher
authors.forename: Bruce P.
authors.initials: BP
authors.lastname: Shutts
authors.forename: Lyman
authors.initials: L
authors.lastname: Smith
authors.forename: Zheng-Yun J.
authors.initials: ZY
authors.lastname: Zhan
authors.forename: William T.
authors.initials: WT
authors.lastname: Thomson