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Introduction
Fenethylline (Captagon), CAS 3736-08-1 is a synthetic compound combining molecules of amphetamine and theophylline. Originally developed in the 1960s as a therapeutic agent, fenethylline was marketed under the trade name Captagon and widely prescribed for various medical conditions, including ADHDs, narcolepsy, and mild depression. The compound’s dual-action pharmacology, leveraging the stimulant effects of amphetamine and the bronchodilator properties of theophylline. One of the main advantages of fenethylline that it does not tend to increase blood pressure to the same extent as amphetamines, and so it could be used in patients with cardiovascular conditions.
Despite its initial success, fenethylline as a pharmaceutical agent was short-lived, largely due to its misuse and dependency. By the 1980s, its widespread recreational use and abuse, prompting its classification as a controlled substance under international conventions. This ended its legal production and medical use, though its legacy persists in the form of drugs, particularly in the Middle East.
This article reviews fenetylline, delving into its physical and chemical properties, historical context, health effects, and uses. Its synthesis and reactions intention to provide an overview of this compound.

History of Captagon
Fenethylline CAS 3736-08-1 was first synthesized in 1961 by the German pharmaceutical company Degussa AG, which aimed to create a compound combining the stimulant properties of amphetamines with the mild bronchodilator effects of theophylline. This dual-action mechanism was intended to offer therapeutic benefits, particularly for conditions such as attention deficit disorders, narcolepsy, and asthma. During its early years, fenethylline gained popularity as a prescription medication under the trade name Captagon, widely prescribed across Europe and parts of the Middle East.
By the 1970s, fenethylline was recognized for its efficacy in treating both psychological and physical conditions, such as depression and fatigue, and its relatively mild side effect profile compared with pure amphetamines. Its use extended to individuals seeking improved cognitive and physical performance, making it a popular medication among students and professionals.
In the 1980s, increased reports of fenethylline misuse as a recreational drug. Its ability to metabolize into amphetamine and theophylline contributed to its appeal among illicit users, who sought its stimulating and euphoric effects. Consequently, many countries began to restrict or ban its production and distribution. In 1986, fenethylline was classified as a controlled substance under the Convention on Psychotropic Substances, effectively halting its legal medical use in most regions.
Despite its ban, illicit production of fenethylline persists, particularly in the Middle East, where it is commonly associated with the counterfeit drug trade. Often marketed as Captagon, these counterfeit tablets frequently contain a mixture of amphetamines and other stimulants rather than genuine fenethylline.

Physical and Chemical Properties of Captagon
Fenethylline, [3,7-Dihydro-1,3-dimethyl-7-[2-[(1-methyl-2-phenylethyl)amino]ethyl]-1H-purine-2,6-dione], CAS 3736-08-1, is a synthetic compound belonging to the phenethylamine group, structurally, it combines the phenethylamine with a theophylline. The molecular formula of fenethylline is C18H23N5O2, and its molecular weight is 341.41 g/mol. Fenethylline hydrochloride typically appears as a white or off-white crystalline powder, highly soluble in polar solvents such as water and ethanol, but sparingly soluble in nonpolar solvents like hexane. Fenethylline melting point is 227–229 °C and boiling point is 563.8 °C at 760 mmHg. Density of fenethylline is 1.26±0.1 g/cm3.
Fenethylline is characterized by its dual-action mechanism, attributed to the metabolic liberation of amphetamine and theophylline. This chemical decomposition underscores its relevance as a prodrug, as its physiological activity largely stems from its breakdown products. The compound is relatively stable under standard storage conditions, maintaining its integrity in tightly sealed containers at room temperature. However, it is sensitive to acidic and alkaline hydrolysis, leading to degradation products that include phenylacetone derivatives.
Synthesis of Captagon
The synthesis of fenethylline, CAS 3736-08-1 involves the chemical reaction of two main components: theophylline and phenethylamine derivatives. This process typically starts with the preparation of 7-(2-chloroethyl) theophylline.
The usual method for synthesizing fenethylline begins with theophylline, finely ground sodium (potassium) hydroxide and aliquat-336 are suspended in 1,2-dichloroethane in flask with reflux condenser. Aliquat-336, TEBA (BTEAC) and TBAB show similar catalytic activities. Reaction can go without catalysator, but it takes more time. The reaction mixture is stirred under reflux for 4 hours, filtered while hot and the precipitate dissolved in distilled water and the solution neutralized to pH 7 to give the unreacted theophylline and the synthesized symmetric 1,2-bis(7-theophyllinyl)ethane. Trituration of filtrate under reduced pressure with petroleum ether or water affords 7-(2-Chloroethyl)theophylline.

The second stage of preparing fenethylline is heating 7-(2-chloroethyl)theophylline and 1-phenyl-2-aminopropane for 6 hours on an oil bath, if necessary with the addition of alcohol or toluene. The reaction mixture is diluted with alcohol and acidified with alcoholic hydrochloric acid. The resulting crystalline mass is filtered with suction and extracted by boiling with alcohol. Instead of chloroethyl theophylline, the corresponding bromine derivative can also be used.
![Synthesis of 1,3-dimethyl-7-[2-(1-phenylpropan-2-ylamino)ethyl]purine-2,6-dione (fenethylline) from 7-(2-Chloroethyl)theophylline and 1-Phenyl-2-aminopropane (amphetamine).](https://safrole.com/wp-content/uploads/3-2-1-1024x231.png)

Chemical Reactions of Captagon
Fenethylline CAS 3736-08-1 undergoes a variety of chemical reactions, both under physiological conditions and in laboratory settings, owing to its functional groups and structural composition. One of its most reactions is enzymatic hydrolysis, which occurs in the human body. This reaction cleaves the bond between the phenethylamine and theophylline units, yielding amphetamine and theophylline as primary metabolites. This hydrolysis is catalyzed by esterases in the liver, representing the compound’s prodrug nature.

Captagon can form salts with various acids. For example the synthesis of captagon hydrochloride involves dissolving fenethylline in solvent like ethanol, followed by the slow addition of gaseous or concentrated HCl to protonate the amine group in the amphetamine moiety, forming the hydrochloride salt. The reaction mixture is cooled to promote crystallization, and the resulting fenethylline HCl precipitate is collected by filtration. Proper control of acid concentration and reaction conditions is crucial to prevent hydrolysis and degradation.

Synthesis of captagon hydrochloride from fenethylline
In alkaline environments, fenethylline undergoes base-catalyzed hydrolysis, leading to the formation of phenylacetone and aminoethyltheophylline. This reaction is due to the nucleophilic attack of hydroxide ions (OH⁻) on the ethylamine bond.

Under acidic conditions, captagon decomposes into its active metabolites via a hydrolytic pathway similar to enzymatic hydrolysis. This reaction is facilitated by the presence of protons (H⁺), which weaken the bond between the phenethylamine and theophylline units.

Reacting fenetylline with oxidizing agents such as potassium permanganate (KMnO₄) results in oxidative cleavage of the molecule. This reaction breaks the compound down into smaller fragments, including amphetamine and hydroxyethyltheophylline.

Applications of Captagon
Captagon (fenethylline, CAS 3736-08-1) during its time as a legally marketed pharmaceutical, served a variety of therapeutic purposes due to its combined stimulant and bronchodilator effects. One of its primary medical applications was the treatment of attention deficit hyperactivity disorder (ADHD) and narcolepsy.
Patients with these conditions benefited from fenethylline’s ability to enhance focus and reduce fatigue without the pronounced jitteriness often associated with pure amphetamines. For example, a prescribed dosage of Captagon was commonly used in European clinical settings to manage excessive daytime sleepiness in narcoleptic patients. Another notable application was in the treatment of mild to moderate depression and chronic fatigue. Fenethylline’s stimulant properties provided an energy boost and mood elevation, making it a useful adjunct for individuals experiencing lethargy and reduced motivation. In cases of asthma or other respiratory conditions, fenethylline’s bronchodilator effects, derived from its theophylline component, made it effective in improving airflow and reducing respiratory distress.
In the military and professional domains, fenethylline was employed as a performance-enhancing drug. Similarly, professionals and students used it to sustain productivity and concentration.
Despite its therapeutic potential, fenethylline is now primarily recognized for its illicit use. Counterfeit versions labeled as Captagon are widely trafficked in regions like the Middle East, often consumed for recreational purposes due to their stimulating and euphoric effects.

Health Effects of Captagon
The health effects of fenethylline, CAS 3736-08-1 have been studied extensively in laboratory settings to understand its pharmacological and toxicological properties.
Laboratory experiments on animal models have demonstrated that fenethylline enhances dopamine and norepinephrine release in the brain, leading to increased alertness, reduced fatigue, and elevated mood.
Toxicological studies have revealed dose-dependent adverse effects associated with fenethylline. At therapeutic doses, laboratory data show minimal toxicity; however, higher concentrations lead to symptoms such as hyperactivity, tachycardia, and hypertension.
Chronic exposure in animal studies has indicated potential neurotoxic effects, including alterations in dopaminergic pathways and oxidative stress, which are linked to long-term cognitive and behavioral changes. Repeated high doses resulted in decreased memory retention and increased anxiety-like behaviors.

Safety Precautions
The handling of fenethylline, CAS 3736-08-1 in laboratory settings requires safety precautions to prevent accidental exposure.
Personal protective equipment (PPE), including lab coats, gloves, and safety goggles, is mandatory when working with fenethylline. In case of accidental skin contact, the affected area should be immediately washed with soap and water, and any contaminated clothing should be removed. For eye exposure, thorough rinsing with water for at least 15 minutes is recommended, followed by medical consultation.
Fenethylline should be stored in a secure, well-ventilated location, away from sources of heat, moisture, and direct sunlight. It is advisable to use airtight, chemically resistant containers to maintain the compound’s stability and prevent degradation.
Conclusion
Fenethylline, CAS 3736-08-1 a synthetic prodrug combining a phenethylamine with a theophylline, exemplifies the intricate chemistry of bioactive compounds. Its molecular structure facilitates enzymatic hydrolysis, yielding amphetamine and theophylline as active metabolites, which mediate its stimulant and bronchodilator effects. It is currently banned and used recreationally, mainly in the Middle East.

Bibliography
- Fenethylline (Captagon) synthesis. https://bbgate.com/threads/fenethylline-captagon-synthesis.2173/post-78647
- Katselou, M., Papoutsis, I., Nikolaou, P., Qammaz, S., Spiliopoulou, C., & Athanaselis, S. (2016). Fenethylline (captagon) abuse–local problems from an old drug become universal. Basic & clinical pharmacology & toxicology, 119(2), 133-140 https://doi.org/10.1111/bcpt.12584
- Alabdalla, M. A. (2005). Chemical characterization of counterfeit captagon tablets seized in Jordan. Forensic science international, 152(2-3), 185-188 https://doi.org/10.1016/j.forsciint.2004.08.004
- Crosby, M. M., & Moore, K. A. (2020). Amphetamines/sympathomimetic amines. Principles of forensic toxicology, 449-466 https://doi.org/10.1007/978-3-030-42917-1_25