Synthesis of Labeled Caffeine - Caffeine: Chemistry, Analysis, Function and Effects - page 76

The purification of the [ 11 C]caffeine was performed by HPLC (Denutte et al
1982) or semi preparative HPLC (Funaki et al 1992).

5.3.3 Syntheses of [ 13 C]Caffeine
[ 13 C]caffeine was prepared by partial synthesis, starting from xanthine and 3-
methylxanthine (Scheme 5.3).

d n 0 t 2 n g | 2

Scheme 5.3 Syntheses of [ 13 C]caffeine from xanthine and 3-methylxanthine.

[ 13 C]caffeine was prepared by partial synthesis, starting from xanthine
and 3-methylxanthine, by the action of [ 13 C]H 3 I in aqueous sodium
hydroxide or methanolic potassium hydroxide solution.

Xanthine (13) was methylated by the action of [ 13 C]H 3 I in aqueous sodium
hydroxide [1,3,7- 13 CH 3 ]caffeine

to afford (14). The labeled caffeine was

purified by column chromatography (Arnaud et al 1980).
In the same way, [1,7- 13 CH 3 ]caffeine (16) was prepared from 3-methyl-
xanthine (15) by the action of [ 13 C]H 3 I in a methanolic potassium hydroxide
solution. After 24 h stirring at room temperature and liquid-liquid extraction,
pure [1,7- 13 CH 3 ]caffeine (16) was obtained with 82% yield (Pierce et al 1984).

5.3.4 Syntheses of [ 14 C]Caffeine
Synthesis of [ 14 C]caffeine was extensively investigated since it has been the
most widely used in metabolic studies.
Numerous strategies were set up, both by partial and total synthesis.

5.3.4.1 Syntheses of [ 14 C]Caffeine by Partial Synthesis
Two strategies were investigated for this purpose: the methylation of a labeled
xanthine derivative with unlabeled methylating agent and the methylation of
an unlabeled xanthine derivative with a labeled methylating agent.
[2- 14 C]xanthine (17) was methylated with DMS in aqueous sodium
hydroxide to give [2- 14 C]caffeine (18) with high chemical purity (Heftmann