# Fenethylline (Captagon) synthesis



## G.Patton (Jun 5, 2022)

*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:*

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;



​_Fenethylline [3,7-Dihydro-1,3-dimethyl-7-[2-[(1-methyl-2-phenylethyl)amino]ethyl]-1H-purine-2,6-dione]_
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.​
*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 %*.​


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## thedrugdesigner

even better if enantiopure dAMP is used instead of racemic dlAMP 
great post man.


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## cyb3r0

Thank you for the explanation, but is there a video of the process for the benefit of everyone and beginners like me? Thank you


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## quite

G.Patton said:


> *IntroductionView attachment 5168*​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 takes 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.
> 
> ...



G.PattonThanks sir, you are GREAT!


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## G.Patton (Jun 7, 2022)

cyb3r0 said:


> Thank you for the explanation, but is there a video of the process for the benefit of everyone and beginners like me? Thank you



cyb3r0Right now, we don't have a video tutorial, it's not popular synthesis.


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## cyb3r0

THEOPHYLLINE (ANHYDROUS) 99% 100GM/BTL. (C7H8N4O2, 1,3-DIMETHYLXANTHINE)


Is this required?


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## G.Patton

cyb3r0 said:


> THEOPHYLLINE (ANHYDROUS) 99% 100GM/BTL. (C7H8N4O2, 1,3-DIMETHYLXANTHINE)
> 
> 
> Is this required?



cyb3r0CAS 58-55-9


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## cyb3r0

My friend, honestly we haven't understand yet. You mentioned that there are two ways and each way has special reagents.

Are the two methods mandatory to move from the first to the second or are they optional?

And please write the steps in an orderly manner.

And he hates you


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## cyb3r0

cyb3r0 said:


> My friend, honestly we haven't understand yet. You mentioned that there are two ways and each way has special reagents.
> 
> Are the two methods mandatory to move from the first to the second or are they optional?
> 
> ...



cyb3r0Reminder


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## ACAB

cyb3r0 said:


> Reminder



cyb3r0Better you comment the author directly so he gets a message


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## G.Patton

cyb3r0 said:


> And he hates you



cyb3r0Thank you. This method clearly explain that you can choose appropriate method for you in each step. I cannot explain more clearly, maybe you have problem not with my article...
_*Method 1_1 and Method 1_2
or Method 2_1 and Method 2_2
or Method 1_1 and Method 2_2
or Method 2_1 and Method 1_2
Do you understand now???*_​


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## cyb3r0

What are the percentages of reagents in grams?


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## cyb3r0

Can I use any other solvent for this step?
Because the ether is not available to me, there is no suitable alternative that performs the same task. Thank you



G.Patton said:


> taken to dryness filtrate under reduced pressure with petroleum ether or water affords the desired chloroalkyl derivative



G.Patton


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## G.Patton

cyb3r0 said:


> What are the percentages of reagents in grams?



cyb3r0


G.Patton said:


> Theophylline *(1)* (10 mmol)


You can count this by yourself 



cyb3r0 said:


> the ether


It is not diethyl ether, man. *Petroleum ether*. It is affordable everywhere.


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## MadHatter

Thank you for an excellent write-up as usual! 
But I can't really see the point of the drug itself? Why ingest a prodrug that gives you a minor amount of speed and a pretty useless asthma medication? Theophylline has no psychostimulating effects I'm aware of, and I know the medicaton quite well.


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## G.Patton

DocX said:


> Theophylline



DocXTheophylline or Fenethylline?  Fenethylline is works as stimulator but not so potent then amph. Some people ask about this synthesis.


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## MadHatter (Jun 22, 2022)

G.Patton said:


> Theophylline or Fenethylline?  Fenethylline is works as stimulator but not so potent then amph. Some people ask about this synthesis.



G.PattonSorry, i understood from your text that it was a prodrug that metabolized into amphetamine and theophylline?


> 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.



But theophylline is not known for any relevant psychoactive effects. It's an excellent bronchodilator in some cases, but not much else. So the net result would be a weak dose of amphetamine and a little easier breathing, although oral theophylline has only minor short-term effects.


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## cyb3r0

I'm not an expert in chemistry just a hobbyist and I want to know the following ratios how much are they equivalent in grams

Theophylline 10 mmol
Sodium hydroxide 10–20 mmol
aliquat-336 0.6 mmol
1,2-dichloroethane 10–20 ml



G.Patton said:


> 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.



G.PattonAnd the other point here, do you leave it here at a certain temperature?


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## MadHatter

cyb3r0 said:


> I'm not an expert in chemistry just a hobbyist and I want to know the following ratios how much are they equivalent in grams
> 
> Theophylline 10 mmol
> Sodium hydroxide 10–20 mmol
> ...



cyb3r0A hobbyist should know how to google stuff. Otherwise it's impossible to be a hobbyist. Learn to google. 





LMGTFY - Let Me Google That For You


For all those people who find it more convenient to bother you with their question rather than to Google it for themselves.




lmgtfy.app


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## ACAB

cyb3r0 said:


> I'm not an expert in chemistry just a hobbyist and I want to know the following ratios how much are they equivalent in grams



cyb3r0Are the batteries of your calculator also empty? Or do you not know how to convert moles into g?
It's actually quite simple, every substance has a molar mass, you have to search for it, the unit is given in g/mol. Since mmol is given here, you only have to divide it by 1000, the rest is a walk in the park.


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## cyb3r0 (Jun 24, 2022)

G.Patton said:


> 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



G.PattonAnd the other point here, do you leave it here at a certain temperature?


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## G.Patton

cyb3r0 said:


> And the other point here, do you leave it here at a certain temperature?



cyb3r01,2-dichloroethane boiling point (~83 deg C), read topic about Reflux please


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## cyb3r0

G.Patton said:


> 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



G.PattonDoes water or alcohol need to be placed here for the reaction to take place for four hours, or does it react without that and does it need a condenser?


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## G.Patton

cyb3r0 said:


> Does water or alcohol need to be placed here for the reaction to take place for four hours, or does it react without that and does it need a condenser?



cyb3r0You don't need to add anything else. Yes, you have to use reflex condenser.


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## cyb3r0

Thank you so much


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## cyb3r0

In the oil bath, what type of oil is used, and what is the required temperature?


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## G.Patton

cyb3r0 said:


> In the oil bath, what type of oil is used, and what is the required temperature?



cyb3r0


> was heated at 100 °C


Mineral oil for oil bath


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## cyb3r0

G.Patton said:


> 7-(2-Chloroethyl)theophylline *(3)* (0.22 mg, 0.9 mmol) and 1-phenyl-2-aminopropane *(4)* (0.49 g, 3.6 mmol)



G.PattonMy question here is, are the ratios correct here, the kilogram and the milligram for both substances? Thank you


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## G.Patton

cyb3r0 said:


> My question here is, are the ratios correct here, the kilogram and the milligram for both substances? Thank you



cyb3r0These are grams, I fixed it. Also, you could calculate it by moles.


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