The Synthesis and Hazards of 1,7-Dimethylxanthine

General Description

1,7-Dimethylxanthine, widely recognized under the moniker paraxanthine, is identified as a naturally occurring compound within the alkaloid category, specifically falling under the xanthine class. This compound emerges as a derivative of xanthine, showcasing a close kinship to other notable compounds such as caffeine and theobromine. Paraxanthine's presence is noted across a variety of plant species, encompassing tea, coffee, and cacao plants, among others. It is distinguished by its physiological effects, which mirror those of caffeine, notably acting as a stimulant to the central nervous system. This stimulation results in heightened alertness and a diminution in drowsiness, alongside its diuretic characteristics, which enhance urine production.

In the human body, paraxanthine undergoes primary metabolism within the liver, facilitated by the enzyme cytochrome P450 1A2 (CYP1A2). This metabolic process further breaks down paraxanthine into various compounds, including 5-acetylamino-6-formylamino-3-methyluracil (AFMU) and 7-methylxanthine (7-MX). The exploration of 1,7-dimethylxanthine's health implications is an ongoing field of research. Preliminary studies have posited that moderate intake of beverages containing paraxanthine, such as coffee and tea, may confer beneficial impacts on cognitive functions and metabolic processes. Nonetheless, it is imperative to acknowledge that excessive consumption harbors the potential to induce adverse health consequences, including insomnia, heightened nervousness, and gastrointestinal disturbances.

Synthesis

The synthesis of 1,7-dimethylxanthine involves several steps, as illustrated in Figure 1:

Fig. 1 The synthesis route of 1,7-DIMETHYLXANTHINE

Scheme 1: Stir equimolar amounts of 2-chloro-6-alkoxy-7-methylpurine (5 mmol) and sodium alkoxide in 30 ccm of anhydrous alcohol at 60 °C for 2 hours. Distill off the alcohol in a vacuum. Treat the residue with 40 ccm of water. Neutralize the mixture with diluted hydrochloric acid. Extract the resultant mixture with chloroform (3 x 15 ccm). Dry the extracts with anhydrous sodium sulfate. Evaporate the solvent under vacuum at water bath temperature.

Scheme 2: Reflux 2-alkoxy-1,7-dialkyl hypoxanthine (5 mmol) with 10 ccm of 18% HCl aqueous in an oil bath at 125-130 °C for 1.5 hours. Evaporate the mixture under a vacuum to dryness. Suspend the residue in water. Neutralize the residue with concentrated NH3 aqueous. Filter off the residue.

Scheme 3: Add 6.5 g (55 mmol) of dimethyl sulfate and 5.5 ccm (55 mmol) of a 20% aqueous solution of potassium hydroxide dropwise to a solution of 2-chloro-6-oxo-1,6-dihydro-7-methylpurine (50 mmol) in 100 ccm of a 50% water-methanol solution at 30 °C. Keep the pH value at 9. Stir the mixture continuously for 1 hour. Filter off the product.

Hazards

1,7-Dimethylxanthine is present in beverages such as tea, coffee, and some soft drinks. Although structurally similar to caffeine, its effects on the body may differ and may be harmful when consumed in excess:

Cardiovascular Effects: Excessive intake can lead to increased heart rate, palpitations, and even irregular heart rhythms (arrhythmias), particularly dangerous for individuals with pre-existing heart conditions.

Central Nervous System Stimulation: Overstimulation can lead to restlessness, anxiety, and insomnia. Prolonged or excessive consumption may also contribute to tolerance and dependence.

Gastrointestinal Distress: It can irritate the gastrointestinal tract, leading to symptoms such as nausea, vomiting, and stomach cramps, and may exacerbate conditions like gastritis or acid reflux.

Diuretic Effects: Like caffeine, it has diuretic properties, which can increase urine production and contribute to dehydration if not compensated for by adequate fluid intake.

Interaction with Medications: It can interact with certain medications, including those for heart conditions, psychiatric disorders, and asthma, altering their effectiveness or side effects.

Moderate consumption of beverages containing 1,7-dimethylxanthine is generally considered safe for most individuals, but excessive intake can lead to a range of adverse health effects. It is important to consume such beverages in moderation and be aware of their potential hazards, especially for individuals with underlying health conditions or those taking medications that may interact with paraxanthine. Understanding the risks associated with 1,7-dimethylxanthine can help individuals make informed decisions about their consumption and minimize it.

References

[1]Klemmer, I., Yagi, S., & Gressner, O. A. (2011). Oral application of 1, 7‐dimethylxanthine (paraxanthine) attenuates the formation of experimental cholestatic liver fibrosis. Hepatology Research, 41(11), 1094-1109.

[2]Kowalska, Alicja; et al. "2,6-Dialkoxy-7-methylpurines." Monatshefte fuer Chemie (1985), 116(3), 341-51.

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