Theobromine sodium

A solution of 35.4 g of 1 -bromohexanone-5 in 200 ml of ethanol was gradually mixed at the reflux temperature with vigorous stirring with 39.7 g of theobromine-sodium in 100 ml of water. After 3 hours reflux the unreacted theobromine was filtered off with suction, the fil-trete was evaporated to dryness, the residue was dissolved in water and the solution was extracted with chloroform. The chloroform was distilled off and 1-(5 -oxohexyl)-3,7-dimethyl-xanthine was obtained as residue after recrystellization from isopropanol, it melted at 102°C to 103°C (about 25% yield, calculated on the reacted theobromine). 

C7HJN4O2 83-67-0) see Pentifylline Protheobromine theobromine sodium sait (C7H7N4Na02 1010-59-9) see Pentoxifylline theophyiiine... 

The mixture 25 g theobromine, 38 ml 4 N sodium hydroxide, 60 ml isopropanol, and 17 g n-hexyl chloride were heated 24 hours to 100°C in autoclave. The solvent was removed and the residual alkaline solution was extracted with chloroform, water layer was acidified. Yield of l-hexyl-3,7-dimethylxanthine was 88% MP 82°-83°C. The product may be prepared from theobromine sodium. 20.2 g theobromine sodium, 20 n-hexyl bromide and 100 ml toluene were ground 10 hours at 100°C in a ball mill. After above written treatment 22.3 g (84.5%) 1-hexyltheobromine was prepared MP 84°C. 

Note Thephorin was formerly used to designate theobromine sodium formate. 

CHI3, theobromine, sodium salicylate, mercaptobenzothiazole, potassium ethylxanthate, organic acids... 

Apart from the possible prevention of unwanted physiological effects, hydrotropes can have a direct action on efficacy. Theobromine is soluble in water to the extent of 1 in 2000 an equimolar mixture with sodium acetate has a solubility of 1 in 1.5, and a mixture with sodium salicylate, 1 in 1. Clinical evaluation of various theophylline and theobromine preparations in the treatment of angina pectoris [288] showed a theobromine-sodium acetate mixture to be the most effective. Ergotamine levels have been shown to be enhanced when the drug is administered in combination with caffeine, which increases the solubility and rate of solution of the ergotamine [289]. 

C7H9N402- M.p. 337 C, an alkaloid obtained from cacao seeds or prepared synthetically. Constitutionally it is similar to caffeine, and is also a weak base. It is usually administered as the sodium compound combined with either sodium ethanoate or sodium salicylate, and is employed almost entirely as a diuretic. Physiologically theobromine resembles caffeine, but its effect on the central nervous system is less, while its action on the kidneys, is more pronounced. 

The effect of concentration of cationic (cetylpyridinium chloride, CPC), anionic (sodium dodecylsulfate, SDS) and nonionic (Twin-80) surfactants as well as effect of pH value on the characteristics of TLC separ ation has been investigated. The best separ ation of three components has been achieved with 210 M CPC and LIO M Twin-80 solutions, at pH 7 (phosphate buffer). Individual solution of SDS didn t provide effective separation of caffeine, theophylline, theobromine, the rate of separ ation was low. The separ ation factor and rate of separ ation was increase by adding of modifiers - alcohol 1- propanol (6 % vol.) or 1-butanol (0.1 % vol.) in SDS solution. The optimal concentration of SDS is 210 M. 

Only theophylline yields an intensely fluorescent derivative under long-wavelength UV light when treated with chloramine T — sodium hydroxide reagent. The purine derivatives caffeine and theobromine investigated at the same time fluoresce very weakly or not at all. 

Some patents describe alkylation of theobromine derivatives under phase transfer conditions. l-(5-Oxohexyl)theobromine (104) has been prepared by alkylating the sodium salt in the presence of TBAB and toluene.163 Theobromine (not its Na+ salt), and other xanthines have also been alkylated, according to Philipossian and Enslen164 using NaOH and TBAHS04. 

FIGURE 7-5. A 0 to 10% gradient separation of polar compounds. Components (1.0 p.g each) (1) uracil, (2) hypoxanthine, (3) 3-methyl xanthine, (4) theobromine, (5) theophylline, and (6) /3-hydroxyethyl theophylline. Solvent A 0.01 M sodium ace-tate/water. Solvent B acetonitrile. Flow rate 2.0 mL/min. Gradient 0-10% solvent B using a linear shape (top line). Run time 50 min. Injection volume 15 p.L. Column Radial-Pak Resolve Cig (10 /xm) 8 mm ID x 10 cm. Detector UV at 254 nm, 0.1 AUFS. (Reproduced from reference 1 with permission.)... 

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. 

Incompatible with alkalis, heavy metal ions, especially copper and iron, oxidizing materials, methenamine, phenylephrine hydrochloride, pyrilamine maleate, salicylamide, sodium nitrite, sodium salicylate, theobromine salicylate, and picot-amide. Additionally, ascorbic acid has been found to interfere with certain colorimetric assays by reducing the intensity of the color produced. ... 

Nishijo J, Yonetani I. Interaction of theobromine with sodium benzoate. J Pharm Sci 1982 71 354—356. 

Electrophilic N-aminations have been performed with hydroxylamine-O-sulfonic acid (HOSA)," O-(2,4-dinitrophenyl)hydroxylamine and C>-mesitylenesulfonylhydroxylamine. The use of HOSA is mainly restricted to aqueous reaction media. Imide sodium salts of some heterocycles such as theobromine (88) can be converted to hydrazine derivatives by treatment with 0-(diphenylphosphinyl)hydroxylamine (equation 35)." This reaction has been extended to synthesis of N-arylhyd ines, where R and R are hydrogen, alkyl or aryl (equation 36)." Similarly, trisubstituted hydrazines can be prepared by the use of N-aryl-O-acetylhy oxylamines and secondary amines." A recent publication" concerning the synthesis of l-acyl-2-dkylhydrazines from hydroxamic acids and amines in the presence of activating agents has been found to be erroneous no N—N bond formation occurs under these conditions." ... 

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)... 

Dimethylxanthine (theobromine) as the sodium salt is smoothly aminated by DPPH (82S592) or HOSA (81 Mil) affording the 1-aminoderivative in good yield. There is no information about N-amination of xanthine itself. 

Other compounds with relatively mild diuretic properties are the xanthines, theobromine and theophylline the former usually as a soluble complex with sodium benzoate, the latter with ethylene diamine (aminophylline). Theophyline s present use is primarily as an antiasthmatic (see Chapter 9). 

Caffeine, theobromine, theophylline and xanthine. Ion-exchange Zipax SAX 0.01M sodium borate... 

Pharmaceutical Incompat. Alcohol, iodide, cyanide, permanganate, borax, alkali hydroxides and carbonates, lead acetate, monobromated camphor, Diuretin, acetophenctidin, quinine sulfate, salol, theobromine sodiosalicylate, sodium phosphate, urea, urethane. 

Sodium acetate, Aguritt, Thesodate. Equimolar mixture of sodium theobromine and sodium acetate, containing IH O. Theobromine 59.6%, anhydr sodium acetate 27,1%, White, odorless or almost odorless, hygroscopic powder. Absorbs COz from the air becoming incompletely sol. Very sol io water, sparingly sol jn cold alcohol the solus are strongly alkaline. pH about 10. Keep tightly closed. 

Monosodium Glutamate N,N-Diethyl-3-Methyl-henzamide Niacin Nicotine Nitric Acid Nitric Oxide Nitrogen Dioxide Nitroglycerin Nylon 6 and Nylon 66 Penicillin Polyurethane Potassium Nitrate Pyridoxine Riboflavin Saccharin Silver Nitrate Sodium Cyclamate Theobromine Thiamine Triclocarban Urea... 

Calcium Hydroxide Magnesium Hydroxide Potassium Hydroxide Sodium Hydroxide Theobromine... 

Methylation According to Reaction (1). Phenyltrimethylammonium chloride is an excellent methylating compound not only for morphine but for a number of other compounds such as antipyrine and theobromine. It is prepared and used according to the method of Schwyzer by wanning dimethylaniline with methyl chloride- in absolute alcohol in a 100-liter stirred autoclave provided with an enameled liner. The sodium ethylate is prepared by dissolving metallic sodium in absolute alcohol. Schwyzer... 

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