Antitumor Imidazotetrazines. 35. New Synthetic Routes to the Antitumor Drug Temozolomide.
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.
Wang
Yongfeng
Y
Aston Molecules Ltd, 10 Holt Court, Aston Science Park, Birmingham, B7 4EJ, UK.
Stevens
Malcolm F. G.
MF
Chan Tm
Tze-ming
DiBenedetto
Donald
D
Ding Zx
Zhe-xing
Gala
Dinesh
D
Hou
Donald
D
Kugelman
Max
M
Leong
William
W
Kuo Sc
Shen-chun
Mas
Janet L.
JL
Schumacher
Doris P.
DP
Shutts
Bruce P.
BP
Smith
Lyman
L
Zhan
Zheng-Yun J.
ZY
Thomson
William T.
WT