Dimethyl methyl xanthine

Reaction of xanthine with triethylsilylamine gives 0, 0 ,A -tris(triethylsilyl)xanthine which can be methylated with iodomethane at room temperature to give bis-silylated 7-methyl-xanthine (33). At 60 "C, alkylation leads to the 0 -monosilylated 3,7-dimethyl derivative 34. Hydrolysis yields 7-methylxanthine or theobromine. 

Fig. 11.1. Separation of some xanthine derivatives Column pBondapak C18 (300x4 rim ID), mobile phase acetonitrile - 0.01 M sodium acetate buffer (pH 4.0) (7 93), flow rate 2.0 ml/min, detection UV 254 nm. Peaks 1, 1-methyluric acid 2, 3-methyl xanthine 3, 1,3-dimethyl-uric acid 4, theobromine 5, theophylline 6, B-hydroxy-ethyltheophylline 7, phenobarbital 8, caffeine 9, 8--chlorotheophyl1ine. (reproduced with permission from ref. 56, by the courtesy of Clinical Chemistry)...

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)... 

Synthesis of l,8-dimethyl-3-(2-methyl-l-butyl)xanthine included 7 steps ... 

The naturally occurring purines fall into 4 main groups. (1) Simple substituted derivatives of purine (1) such as adenine (2) and various 6-AT-substituted derivatives. (2) Monoxo-dihydropurines such as hypoxanthine (3), guanine (4), and isoguanine (5). f3) Dioxotetra-hydropurines such as xanthine (6) and methylated derivatives including the 3,7-dimethyl derivative theobromine (7), 1,3-dimethylxanthine or theophylline f8), and 1,3,7-trimethylxanthine or caffeine (9). (4) Trioxohexahydropurines such as uric acid (10). 

In alkaline solutions, xanthine alkylates on nitrogen in the order N-3, N-7, N-1, i.e. in decreasing order of acidity, and substitution is easier when the first position has been alkylated so to this extent dialkyl derivatives tend to be most easily produced. Thus 3,7-dimethylxanthine (theobromine) is produced by methylation of xanthine or 3-methylxanthine with methyl iodide and barium carbonate (33JCS662) or dimethyl sulfate in potassium hydroxide at 60 °C (50CB201). However when the oxygen functions are blocked by trimethylsilylation, alkylation occurs at N-7 (64CB934). 

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. 

Under acidic or neutral conditions methylation of xanthine proceeds at N-7 or N-9. Thus with methyl iodide the 7,9-dimethylxanthine betaine (107) results after heating in a sealed tube at 150 °C for 5 h. In solvents such ag DMSO or dimethylacetamide using dimethyl sulfate or methyl p-toluenesulfonate, better yields may be obtained (62CB1812). The same betaine is also produced by similar methylation of 9-methylxanthine (62JA1914,61LA(647)l6l). 

In contrast to xanthine the isomeric 2,8- and 6,8-dioxo compounds have been little studied. However the presence of an oxo function in the imidazole ring ensures that alkylation will very readily and rapidly occur in that ring, followed generally by alkylation elsewhere. Thus in alkaline solution dimethyl sulfate converts 2,8-dioxo-l,2,7,8-tetra-hydropurine into a mixture of the 1,7- and the 1,9-dimethyl derivatives (111) and (112), respectively, in 10 minutes at room temperature, the former compound predominating (i4JBC07)i). Further alkylation then affords the 1,7,9-trimethylpurine (113). Similar products are formed with methyl iodide under more forcing conditions (100 °C, 1 h) and the latter also produces the 3,7,9-trimethyl derivative (114) from the 3-methyl-2,8-dioxo derivatives (i899CB272i). 

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). 

Caffeine, mp 263°C, sublimes on heating and is more soluble than dimethylxanthines. Caffeine has a stimulating effect on the central nervous system. It is extracted from green coffee beans with liquid CO2 [151]. Caffeine is synthesized by methylation of xanthine, theophylline or theobromine with methyl iodide or dimethyl sulphate [149]. 

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... 

Plasma and urine metabolites of isbufylline were extracted from samples and analyzed on a C g column (2 = 280nm). Plasma metabolites (l-methyl-7-[2-hydroxy-2-methylpropyl]xanthine, 3-dimethyl-7-[2-hydroxy-2-methylpropyl]-xanthine) were separated in 12 min using a 20/80 acetonibile/water (0.5% acetic acid) mobile phase [1538]. Three urine metabolites were sqiarated using a 40-min 5/95 -> 40/60 acetonitrile/water) 0.1 M ammoniiun acetate buffer pH 3.7) gradient. Compounds of interest were well resolved and separated from other extracted components for both methods. 

Dimethyl-7 - [2 -(l"-methyl-2"-phenyl-ethylamino)-ethyl]-xanthine... 

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