Theobromine caffeine synthesis

Ai,A/-bis(hydroxymethyl) formamide [6921-98-8] (21), which in solution is in equiUbrium with the monomethylol derivative [13052-19-2] and formaldehyde. With ben2aldehyde in the presence of pyridine, formamide condenses to yield ben2yhdene bisformamide [14328-12-2]. Similar reactions occur with ketones, which, however, requite more drastic reaction conditions. Formamide is a valuable reagent in the synthesis of heterocycHc compounds. Synthetic routes to various types of compounds like imida2oles, oxa2oles, pyrimidines, tria2ines, xanthines, and even complex purine alkaloids, eg, theophylline [58-55-9] theobromine [83-67-0], and caffeine [58-08-2], have been devised (22). 

Seasonal variations in the metabolic fate of adenine nucleotides prelabelled with [8—1-4C] adenine were examined in leaf disks prepared at 1-month intervals, over the course of 1 year, from the shoots of tea plants (Camellia sinensis L. cv. Yabukita) which were growing under natural field conditions by Fujimori et al.33 Incorporation of radioactivity into nucleic acids and catabolites of purine nucleotides was found throughout the experimental period, but incorporation into theobromine and caffeine was found only in the young leaves harvested from April to June. Methy-lation of xanthosine, 7-methylxanthine, and theobromine was catalyzed by gel-filtered leaf extracts from young shoots (April to June), but the reactions could not be detected in extracts from leaves in which no synthesis of caffeine was observed in vivo. By contrast, the activity of 5-phosphoribosyl-1-pyrophosphate synthetase was still found in leaves harvested in July and August. 

Mazzafera, P, Wingsle, G., Olsson, O., Sandberg, G., S-adensoyl-L-methionine theobromine 1-N-methyltranferase, a enzyme catalyzing the synthesis of caffeine in coffee Phytochemistry 37 1577 1994... 

Caffeine and theobromine may be obtained in large quantities from natural sources, or they may be obtained by total or partial synthesis. Theophylline is usually produced by total synthesis. 

Caffeine is used medicinally as a CNS stimulant, usually combined with another therapeutic agent, as in compound analgesic preparations. Theobromine is of value as a diuretic and smooth muscle relaxant, but is not now routinely used. Theophylline is an important smooth muscle relaxant for relief of bronchospasm, and is frequently dispensed in slow-release formulations to reduce side-effects. It is also available as aminophylline (a more soluble preparation containing theophylline with ethylenediamine) and choline theophyllinate (theophylline and choline). The alkaloids may be isolated from natural sources, or obtained by total or partial synthesis. 

Caffeine is also manufactured synthetically by, for instance, the methy-lation of theobromine and also total synthesis by methylation and other reactions based upon urea. 

MAZZAFERA, P., WINGSLE, G., OLSSON, O., SANDBERG, G S-Adenosyl-L-methionine theobromine 1-jV-methyltransferase, an enzyme catalyzing the synthesis of caffeine in coffee. Phytochemistry, 1994,37,1577-1584. 

S3mthesis of Xanthine.— The synthesis of xanthine which is the immediate mother substance of theobromine, theophylline and caffeine has been accomplished as follows Starting with urea or carbamide, this is treated with cyano acetic acid in the presence of phosphorus oxychloride whereby the cyan acetyl radical is introduced into urea. The cyan acetyl urea by treatment with sodium hydroxide yields an isomeric imino compound. 

By starting this synthesis with mono-methyl urea and introducing another methyl radical into the new amine groups of the di-amine the product is theobromine, f.e., 3-7-di-methyl xanthine. Similarly di-methyl urea without further methylation yields theophylline which is therefore 1-3-di-methyl xanthine. Caffeine is obtained by starting with di-methyl urea and later introducing a third methyl radical in the same position as in theophylline. Caffeine is therefore i-3-7-tri-methyl xanthine. 

Theobromine has been converted in three steps into 2,6,8-trichloro-7-methyl-purine (28). A safe and improved procedure for the preparation of 2-amino-6-chloropurine has been developed." Treatment of 8-nitro-caffeine and -theophylline with liquid HF provides the corresponding 8-fluoro-derivatives. The synthesis of the tritium-labelled kinetin (29) has been accomplished. ... 

Triacanthine (17) has been isolated from Holarrhena mitis Details on the structure and total synthesis of eritadenine (18), a hypocholesterolemic alkaloid from Lentinus edodes, have been reported.An unsuccessful attempt to improve the imidazole ring-closure reaction in a total synthesis of eritadenine, which has been previously discussed, was also reported in this study. Concentrations of both caffeine and theobromine in the cocoa bean were shown to increase most markedly in the time period from flowering to harvest. ... 

Historical The term A. was introduced by the apothecary C. F. W. Meissner in 1819 for alkali-like plant substances. The development of A. chemistry is illustrated by some dates and names morphine (1803 or 1816 Sertiimer), strychnine (1818 Pelletier and Caven-tou), solanine (1820 Desfosses), caffeine (1820 Runge), quinine (1820 Pelletier and Caventou), nicotine (1828 Posselt and Reimann), atropine (1831 Mein), codeine (1832 Robiquet), theobromine (1842 Woskresensky), cocaine (1860 Wohler), ephedrine (1887 Nagai), scopolamine (1881 Ladenburg and 1888 E. Schmidt), mescaline (1896 Heffter). The first A. synthesis was realized in 1886 by Ladenburg (coniine). In the 20th century A. chemistry is especially associated with the names Willstatter, Woodward, Schopf,... 

The first correct synthesis of caffeine was achieved by Wilhelm Traube (1866-1942) in 1900. [519] In spite of some modifications that were introduced over the years, Traube s procedure stUl serves today as the basis for the industrial synthesis of caffeine, theobromine and theophyUine. 

The first example, depicted in Fig. 6, describes the synthesis and evaluation of a polymer imprinted with the bronchodilating drug theophylline, which is used in the treatment of asthma. Originally published in the journal Nature [2], this work drew considerable attention to the field of molecular imprinting because it was the first study to show that an MIP could be substituted for a natural antibody in a standard clinical assay. The MIP and antibody-based assays exhibit similar selectivities, and both can discriminate between theophylline and structurally related compounds. An equilibrium binding assay is described which uses radiolabeled theophylline as a marker. Data are presented for which nonradioactive theophylline, caffeine, and theobromine are used in competitive binding assays. These assays provide valuable information about the capacity and selectivity of the MIP. 

Uric acid and xanthines are markers for metabolic disorders such as gout, Lesch—Nyman syndrome, and xanthinuria. Measurements of urinary excretion of purine metabolites, among them uric acid and xanthine, have been proposed as a marker for microbial protein synthesis. Their simultaneous determination is useful for diagnosis and treatment of hyperuricemia. In addition to xanthine and hypoxanthine, notable members of the xanthine class include caffeine, theophylhne, and theobromine. ... 

Whether this second mode of synthesis of caffeine, theobromine, and theophyllin actually occurs in nature is rather doubtful. There are, however, other purine derivatives, the cytokinins, which show close relationships to tRNA and are of great interest to physiologists. They are a group of phytohormones, of which isopentenyl adenine (IPA) is an example. Several investigations have shown that the isopentenyl unit is built on to an adenine residue, which is already incorporated in a tRNA molecule (also cf page 209). 

In addition to natural caffeine obtained by the industrial decaffeination process, caffeine can also be obtained by the methylation of theobromine and also by total chemical synthesis using dimethyl-carbamide and malonic acid. 

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