Chapter 18. Analysis of purine drugs

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Purine derivatives have great biological importance in nature. Purine compounds are found in plants and animal tissues in their free form, and are also part of nucleosides, nucleotides and nucleic acids.

The chemical structure of these drugs is based on the bicyclic purine system that exists in the form of two isomers:

Caffeine. Coffeinum 1,3,7-trimethylxanthine monohydrate xanthine: 2,6-dioxopurine

Caffeine-sodium benzoate (Coffeinum-natrii benzoas). A complex salt of sodium benzoate and caffeine:

Theobromine Theobrominum 3,7-dimethylxanthine

Theophylline Theophyllinum 1,3-dimethylxanthine

Aminophylline Euphyllin Aminophyllinum Ethylenediamine salt of theophylline

Physical Properties

All purine compounds are white crystalline powders with characteristic melting points and absorption spectra in the UV and IR regions.

Identification

1. Acid-base properties

Purine is an aromatic system with a strong delocalization of p-electrons that play an important role in the formation of various molecular complexes. It has electron-donating properties and is a weak base soluble in water (pKa = 2.4) that forms fragile salts with acids. At the same time, due to the presence of a mobile hydrogen atom in the NH-group, it exhibits weak acidic properties (pKa = 8.9) and forms salts with metals.

Purine drugs are weak bases that form unstable salts with acids upon protonation of the nitrogen heteroatom in position 9.

As a rule, xanthine derivatives are difficult to dissolve in water, with hot water being more effective. Their ability to form complexes is used to obtain highly soluble drugs.

Caffeine is a weak organic base (pKa = 0.61). It is soluble in mineral acids, but does not form stable salts. It interacts with general alkaloidal precipitating reagents, but reacts with iodine solution only upon acidification (which is typical for such a weak base) with the formation of a precipitate of the periodide Coff ^· HI ^· I₄. With tannin, caffeine forms a precipitate that is soluble in an excess of the reagent. Unlike many other bases, caffeine is not precipitated by Mayer’s reagent, which is used to determine the purity of a substance.

Theobromine and theophylline are amphoteric compounds. Their basic properties are caused by the presence of a lone pair of electrons of the nitrogen atom in position 9. The acidic properties of theobromine (pKa=9.9) are associated with the mobility of the hydrogen atom of the imide group, and those of theophylline (pKa = 8.8) ― with the mobility of the hydrogen atom at the nitrogen heteroatom in position 7. The acidic properties of theophylline are more pronounced than those of theobromine. This is due to the fact that theobromine in alkali solutions only forms the lactimic form, whereas theophylline forms a mesomerically stabilized anion:

Theophylline, possessing more pronounced acidic properties than theobromine, dissolves not only in alkalis, but also in ammonia solution:

Due to their acidic properties, theophylline and theobromine form soluble salts not only with alkalis, but also with organic bases. With salts of heavy metals (Ag⁺, Co²⁺, Cu²⁺), insoluble compounds are formed.

2. Murexide test (group reaction)

The reaction is based on the oxidative-hydrolytic decomposition of substances of the xanthine group to pyrimidine derivatives, in which one or two amino groups condense with each other to form purpuric acid, which results in a red-violet coloration in the form of an ammonium salt. To carry out the reaction, the specimen is evaporated to dryness in a water bath with an oxidizing agent (H₂O₂, Br₂) in an acidic medium. Then ammonia solution is added, and a purple-red color (murexide) appears.

Chemism (using theophylline as an example):

Notably, xanthine drugs are oxidatively decomposed to alloxan and 5-aminobarbituric acid. Then the oxidation product (as a carbonyl compound) condenses with the hydrolysis product to form purple acid, which in the presence of ammonia transforms into a meso-stabilized anion called murexide.

3. Reactions of electrophilic substitution after alkaline hydrolysis

Caffeine, which has weak basic properties, is unstable in an alkaline environment. Above pH 9, the decomposition of caffeine to caffeidine carboxylic acid occurs, which then decomposes to form caffeidine and the corresponding carbonate. Moreover, caffeidine is a caffeine antagonist in terms of its pharmacological action, which can lead to undesirable consequences when using a decomposed drug.

In a sulfuric acid environment, caffeine can decompose to formic acid. Theophylline decomposes similarly to theophyllidine, which can then be identified with a diazonium salt to form an azo dye: