Introduction
Fenethylline (BAN, USAN) is a codrug of amphetamine and theophylline and a prodrug to both. It is also spelled phenethylline and fenetylline (INN); other names for it are amphetaminoethyltheophylline and amfetyline. The drug was marketed for use as a psychostimulant under the brand names Captagon, Biocapton, and Fitton.
Synthesis of Fenethylline is quite simple and doesn't take elaborated expensive glassware. In this topic, you can find two-step synthesis of this substance, each step presented by two different methods, which have some features.
One of the main advantages of fenethylline was 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. Fenethylline is metabolized by the body to form two drugs amphetamine (24.5% of oral dose) and theophylline (13.7% of oral dose), both of which are active stimulants themselves. The physiological effects of fenethylline therefore result from a combination of all three drugs.
Difficulty rating: 4/10
Equipment and glassware:Synthesis of Fenethylline is quite simple and doesn't take elaborated expensive glassware. In this topic, you can find two-step synthesis of this substance, each step presented by two different methods, which have some features.
One of the main advantages of fenethylline was 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. Fenethylline is metabolized by the body to form two drugs amphetamine (24.5% of oral dose) and theophylline (13.7% of oral dose), both of which are active stimulants themselves. The physiological effects of fenethylline therefore result from a combination of all three drugs.
Difficulty rating: 4/10
- Magnetic stirrer with heater;
- Filter paper;
- pH Indicator paper;
- Vacuum source;
- Buchner flask and funnel [Schott filter may be used for small quantities];
- Reflux condenser;
- Oil bath;
- Funnel;
- 250 or 500 mL Separatory funnel;
- Laboratory scale (0.01-100 g is suitable) [depends on synthesis load];
- Retort stand and clamp for securing apparatus;
- [Method 1_1]
- 50 mL Round-bottom flask (RBF);
- [Method 2_1]
- 1 L Round-bottom flask (RBF);
- [Method 1_2]
- 1 L Round-bottom flask (RBF);
- [Method 2_2]
- 5 mL Pear shaped flask;
- Flash chromatography kit
Reagents:
- Theophylline (1);
- 1,2-dichloroethane (2);
- Distilled water;
- 1-phenyl-2-aminopropane (4);
- Sodium sulfate (Na2SO4) anhydrous;
- [Method 1_1]
- Aliquat-336 or TEBA (BTEAC) or TBAB (catalyst);
- Petroleum ether;
- [Method 2_1]
- Sodium hydroxide;
- i-Propanol (IPA);
- Chloroform;
- Ethanol (EtOH);
- [Method 1_2]
- Alcohol (EtOH) or toluene;
- Hydrochloric acid (HCl) alcoholic solution;
- [Method 2_2]
- Sodium bicarbonate (aq. solution);
- Dichloromethane;
- Ethyl acetate;
Boiling Point: 563.8 °C at 760 mm Hg;
Melting Point: 227–229 °C;
Molecular Weight: 341.41 g/mol;
Density: 1.26±0.1 g/cm3;
CAS Number: 3736-08-1.
7-(2-Chloroethyl)theophylline from Theophylline
Method 1_1
Theophylline (1) (10 mmol), finely ground sodium (potassium) hydroxide (10–20 mmol) and aliquat-336 (0.6 mmol) are suspended in 1,2-dichloroethane (2) (10–20 ml) in 50 mL Round-bottom flask (RBF) with reflux condenser. 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 the taken to dryness filtrate under reduced pressure with petroleum ether or water affords the desired chloroalkyl derivative (3) in crystalline form in 99 % yield from the theoretical. The compound (3) obtained are then recrystallized from ethanol.
Aliquat-336, TEBA (BTEAC) and TBAB show similar catalytic activities.
Method 2_1
Theophylline (1) (150.0 mmol, 29.70 g) was added to a solution of sodium hydroxide (150.0 mmol, 6.0 g) in 200 ml water in 1 L Round-bottom flask (RBF). 1,2-Dichloroethane (1.20 mol, 118.66 g) in 300 ml i-propanol was then added with stirring. The mixture was heated under reflux at 78–80 °C for 76.5 h. After filtration and removal of the solvent, the residual solid was extracted with chloroform (3 x 200 ml). Combined chloroform extracts were dried over anhydrous sodium sulfate and after filtration the solvent was removed. The product (3) crystallized from ethanol in 90 % yield, m.p.: 120–122 °C.
Theophylline (1) (10 mmol), finely ground sodium (potassium) hydroxide (10–20 mmol) and aliquat-336 (0.6 mmol) are suspended in 1,2-dichloroethane (2) (10–20 ml) in 50 mL Round-bottom flask (RBF) with reflux condenser. 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 the taken to dryness filtrate under reduced pressure with petroleum ether or water affords the desired chloroalkyl derivative (3) in crystalline form in 99 % yield from the theoretical. The compound (3) obtained are then recrystallized from ethanol.
Aliquat-336, TEBA (BTEAC) and TBAB show similar catalytic activities.
Method 2_1
Theophylline (1) (150.0 mmol, 29.70 g) was added to a solution of sodium hydroxide (150.0 mmol, 6.0 g) in 200 ml water in 1 L Round-bottom flask (RBF). 1,2-Dichloroethane (1.20 mol, 118.66 g) in 300 ml i-propanol was then added with stirring. The mixture was heated under reflux at 78–80 °C for 76.5 h. After filtration and removal of the solvent, the residual solid was extracted with chloroform (3 x 200 ml). Combined chloroform extracts were dried over anhydrous sodium sulfate and after filtration the solvent was removed. The product (3) crystallized from ethanol in 90 % yield, m.p.: 120–122 °C.
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)
Method 1_2
1 mol of 7-(2-Chloroethyl)theophylline (3) and 2.5 mols of 1-phenyl-2-aminopropane (4) are heated for 6 hours in an oil bath in 1 L Round-bottom flask (RBF), if necessary with addition of alcohol or toluene. The reaction mixture is diluted with alcohol and acidified with alcoholic hydrochloric acid. The crystalline mass formed is filtered with suction and extracted by boiling with alcohol. A product having a melting point of 237 to 239 °C is formed. With prolonged extraction by boiling with alcohol, the melting point of the mass falls, preferably due to a change in modification, to 227 to 229 °C. However, analysis shows that both products are the pure condensation product. Instead of the chloroethyl theophylline, it is also possible to use the corresponding bromine derivative. It was found that in this way the process is facilitated, and the yield is improved.
Method 2_2
A mixture of 7-(2-Chloroethyl)theophylline (3) (0.22 g, 0.9 mmol) and 1-phenyl-2-aminopropane (4) (0.49 g, 3.6 mmol) was heated at 100 °C for 17 h in 5 mL pear shaped flask. After cooling to room temperature, the saturated aqueous solution of sodium bicarbonate was added to basify the reaction mixture to a pH of 8. The aqueous phase was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. Filtration and concentration yielded a residue, which was purified by flash column chromatography using silica gel as the stationary phase and ethyl acetate as the mobile phase to produce compound (5) (0.15 g, 0.4 mmol). Yield: 48 %.
1 mol of 7-(2-Chloroethyl)theophylline (3) and 2.5 mols of 1-phenyl-2-aminopropane (4) are heated for 6 hours in an oil bath in 1 L Round-bottom flask (RBF), if necessary with addition of alcohol or toluene. The reaction mixture is diluted with alcohol and acidified with alcoholic hydrochloric acid. The crystalline mass formed is filtered with suction and extracted by boiling with alcohol. A product having a melting point of 237 to 239 °C is formed. With prolonged extraction by boiling with alcohol, the melting point of the mass falls, preferably due to a change in modification, to 227 to 229 °C. However, analysis shows that both products are the pure condensation product. Instead of the chloroethyl theophylline, it is also possible to use the corresponding bromine derivative. It was found that in this way the process is facilitated, and the yield is improved.
Method 2_2
A mixture of 7-(2-Chloroethyl)theophylline (3) (0.22 g, 0.9 mmol) and 1-phenyl-2-aminopropane (4) (0.49 g, 3.6 mmol) was heated at 100 °C for 17 h in 5 mL pear shaped flask. After cooling to room temperature, the saturated aqueous solution of sodium bicarbonate was added to basify the reaction mixture to a pH of 8. The aqueous phase was extracted with dichloromethane, and the organic phase was dried over anhydrous sodium sulfate. Filtration and concentration yielded a residue, which was purified by flash column chromatography using silica gel as the stationary phase and ethyl acetate as the mobile phase to produce compound (5) (0.15 g, 0.4 mmol). Yield: 48 %.
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