Theophylline caffeine synthesis

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. 

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. 

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). 

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. 

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. 

Theophylline occurs in such a low concentration in all xanthine drugs that extraction is not profitable. Theophylline can be produced by demethylation of caffeine or by total synthesis. Theophylline has a spasmolytic effect on smooth muscles, which is apparent in a pronounced bronchodilating action, hence it is used in asthma either on its own or combined with ethylenediamine to produce aminophylline. Furthermore, theophylline has a diuretic action. 

Methylxanthines have a few valid therapeutic uses, including treatment of asthma and relief of dyspnea (see Antiasthmatic agents). The CNS stimulatory effects are also utilized for the treatment of the prolonged apnea that may be observed in premature infants. Theophylline may be combined with doxapram (13) for this use (20). The methylxanthine most widely used therapeutically is theophylline, although caffeine may also be used. For parenteral administration, a salt of theophylline is employed. There are several salts available, including theophylline ethylenediamine (aminophylline [317-34-0]) and oxtriphylline (choline theophyllinate). Other synthetic xanthines that are used include dyphylline [479-18-5] and enprofylline [410784)2-8] (21). Caffeine is obtained in pure form from tea waste, from the manufacture of caffeine coffee, and by total synthesis (22,23). 

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. ... 

Purlnerglc receptors - Receptors for the purines may be divided into P-1 and P-2 subtypes. P-1 receptors are adenosine-sensitive and cyclase-linked, while P-2 receptors are ATP-sensltlve, affect prostaglandin synthesis, and have no effect on cyclic AMP production. Two subtypes of the P-1 receptor exist he A-1 or R1 and A-2 or Ra, which, respectively, inhibit or activate adenylate cyclase. Both A-1 and A-2 receptors are sensitive to blockade by xanthines such as caffeine and theophylline. To date, ligand binding assays have only been described for the A-l and P-2 receptors. Binding studies have led to the description of further subtypes which show species... 

In 1895, Emil Fischer (1852-1919) published what was supposedly the first synthesis of caffeine. [515, 516] However, this was not the case, because the assumed structures of xanthine, theophylline [517] and caffeine were in fact wrong. He had believed, that they were 2,8-dioxopurines. 

It is only necessary to eliminate water from pseudouric acid to form uric acid. Baeyer was unable to do this, but Fischer and Lorenz Ach, by fusing pseudouric acid with anhydrous oxalic acid, obtained uric acid, and Fischer achieved the same result by boiling pseudouric acid with 20 per cent hydrochloric acid. Fischer and Ach then synthesised theophylline, discovered in tea by A. Kossel, from a third dimethyluric acid, and since theophylline forms caffeine on methylation, this is a synthesis of caffeine. 

A. R. Lehmann and S. Kirk-Bell, Effects of caffeine and theophylline on DNA synthesis in unirradiated and UV-irradiated mammalian cells, Mutat. Res. 26, 73-82 (1974). 

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). 

A. xylinum developed faster in black tea infusion than did A. aceti. Cell mass synthesized by A. aceti and A. xylinum increased with incubation time, up to 5 mg % and 22 mg %, respectively, after 25 days as shown in Figure 2. As shown by scaiming electron microscope. Figure 2 shows that some rod-shape A. xylinum cells adhered on the surface of the bacterial cellulose fibrils. Caffeine and theophylline were identified as potent stimulators for bacterial cellulose synthesis in A. xylinum. Methylxanthine probably blocks the action of the specific diguanyl cyclic phosphodiesterase and then avoids or postpones the normal switch off of active cellulose synthase 12). The level of caffeine in the black infusion used in this experiment was determined to be in the range of 2.4 to 3.4 %. This may account for the accumulation of more cell mass in the medium inoculated with A. xylinum rather than in the one with A. aceti. 

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