Synthesis of Labeled Caffeine - Caffeine: Chemistry, Analysis, Function and Effects - page 77

d n 0 t 2 n g | 2

Scheme 5.4 Synthesis of [2- 14 C]caffeine from [2- 14 C]xanthine. [2- 14 C]caffeine (18)

waspreparedwithhighchem cal purity by methylation of
[2- 14 C]xanthine (17) with dimethylsulfate in aqueous sodium hydroxide
solution.

1971; Suzuki and Waller 1984) (Scheme 5.4). The labeled caffeine was purified
by repeated paper chromatography and TLC (Suzuki and Waller 1984).
[1- 14 CH 3 ]caffeine (19) was prepared by the action of a labeled methylating
agent on 3,7-dimethylxanthine (7) (Carr et al 2010; Kalberer 1964). In the same
way, [7- 14 CH 3 ]caffeine (20) was prepared from 1,3-dimethylxanthine (9) by N-
7 methylation with [ 14 C]H 3 I (Kalberer 1964) (Scheme 5.5).
Labeled methyl iodide is one of the most convenient reagents for the
preparation of labeled compounds, but it is toxic and volatile. Furthermore,
the shelf life of [ 14 C]H 3 I is limited due to its autoradiolyse and its shipping by
air is restricted by safety regulations. Therefore new 14 C labeled methylating
agents were developed. The synthesis of [ 14 C-methyl]-methyl nosylate
(Figure 5.1) offered a valuable alternative to the use of [ 14 C]H 3 I (Carr et al
2010).
[1- 14 CH 3 ]Caffeine (19) was prepared by the action of [ 14 C-methyl]-methyl
nosylate on 3,7-dimethylxanthine (7) in the presence of sodium hydrogencar-
bonate in DMF-ACN mixture (Carr et al 2010).

Scheme 5.5 Syntheses of [ 14 C]caffeine from theobromine and theophylline.

[1- 14 CH 3 ]Caffeine (19) and [7- 14 CH 3 ]caffeine (20) were prepared by
the

action of a labeled methylating agent respectively on 3,7-

dimethylxanthine (7) and on 1,3-dimethylxanthine (9).