Dimethyl sulfate Caffeine

Caffeine (128) and dimethyl sulfate in nitrobenzene give the fully methylated dioxo compound 129. In the same way that 2,4-dialk-oxypyrimidines give unstable quaternary salts which decompose to the N-alkyl oxo compounds even at room temperature, the action of... 

Further methylation of theobromine readily produces caffeine (31MI40900). Similarly, 1-methylxanthine is methylated by dimethyl sulfate in alkaline solution to furnish 1,3-dimethylxanthine (theophylline) which is further converted into caffeine (31MI40900). Scheme 18 outlines the major stages of xanthine alkylation. 

Caffeine occurs in both tea (3.5%) and coffee and is normally manufactured from coffee and tea dust and similarly theobromine is the main purine of the cocoa bean from which it may be prepared. Caffeine has also been manufactured from guanine by hydrolysis to xanthine followed by methylation with methyl acetate or dimethyl sulfate (46USP2509084). 

Starting material for the industrial synthesis of caffeine is dimethylurea as well. Reaction with cyanoacetic acid leads to dimethylaminouracil, which upon reaction with nitrous acid, reduction, and condensation with formic acid gives theophyUine. Methylation with methyl chloride or dimethyl sulfate finally leads to caffeine. 

StUl noteworthy is the elegant two-stage synthesis of caffeine, which Hellmut Bredereck (1904-1981) published in 1950. [521] Thereby, uric acid - as a matter of choice, the excrement of snakes may be used as weU - is heated to reflux in formamide. The precipitated xanthine is dissolved in aqueous sodium hydroxide, purified with activated charcoal, and fmaUy methylated with dimethyl sulfate. With pure uric acid, the overall yield of caffeine is 60 %, and in the case of... 

Caffeine, mp 263 °C, sublimes on heating and is more soluble than dimethybcanthines. Caffeine has a stimulating effect on the central nervous system. It is extracted from green coffee beans with hquid CO2 [283]. Caffeine is synthesized by methylation of xanthine, theophylline, or theobromine with methyl iodide or dimethyl sulfate [258]. 

Precolumn Lichrosorb RP2 10 pm (40x2.1 mm ID), column Ultrasphere ODS 5 pm (250x4.6 mm ID), mobile phase gradient with solvent A 0.01 M sodium acetate and 0.005 M tetrabutylammonium hydrogen sulfate in water (pH 4.9), solvent B same salt concentrations in 50% methanol (pH 4.8). Gradient 0-7.5 min 0 B, 7.5-15 min 0-T5% B, 15-25 min 15-30% B, 25-33 min 30-32% B, 33-38 min 32-45% B and 38-41 min 45-0% 6. Detection UV 280 nm. Peaks 1, xanthine 2, uric acid 3, 3-methyluric acid 4, 7-methyl xanthine 5, 3-methyl xanthine 6, 1-methylxanthine 7, theobromine 8, 3,7-dimethyl uric acid 9, 7-methyluric acid 10, 1-methyluric acid 11, 1,3-dimethyluric acid 12, 1,7-dimethyl xanthine 13, theophylline 14, e-hydroxyethyltheophylline (internal standard) 15, 1,7-dimethyluric acid 16, 1,3,7-trimethyluric acid 17, caffeine, (reproduced with permission from ref. 192, by the courtesy of Journal Chromatographic Science)... 

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