Introduction
Bupropion, sold as Wellbutrin (in sustained-release, immediate-release, or extended-release form), Zyban, and known also as amfebutamone, is a cathinone medication used on-label for major depressive disorder and smoking cessation. Bupropion is also used off-label for seasonal affective disorder and ADHD. Bupropion is also taken recreationally for its deliriant-like and stimulant effects. It is a norepinephrine-dopamine reuptake inhibitor (NDRI) and nicotinic acetylcholine receptor antagonist. It may exert its deliriant-like actions through antagonism of the nicotinic acetylcholine receptors.
This manual represents simple synthesis of this substance with detailed explanation of each step of the method. This method doesn't take a lot of chemicals, glassware and skills and has quite good yield. Also, you can find synthesis video tutorial at the end of this topic.
Bupropion, is a molecule of the cathinone class with substituted a chlorine atom at R3 of its phenyl ring, and a tert-btylamine at the amino group. Cathinones are a sub-category of amphetamines, sharing the core amphetamine structure of a phenyl ring bound to an amino (NH2) group through an ethyl chain and an additional methyl substitution at Rα. Bupropion and other cathinones are differentiated by their ketone substitution on the beta carbon of the amphetamine skeleton, meaning they are β-keto-amphetamines.
Difficulty rating: 4/10This manual represents simple synthesis of this substance with detailed explanation of each step of the method. This method doesn't take a lot of chemicals, glassware and skills and has quite good yield. Also, you can find synthesis video tutorial at the end of this topic.
Bupropion, is a molecule of the cathinone class with substituted a chlorine atom at R3 of its phenyl ring, and a tert-btylamine at the amino group. Cathinones are a sub-category of amphetamines, sharing the core amphetamine structure of a phenyl ring bound to an amino (NH2) group through an ethyl chain and an additional methyl substitution at Rα. Bupropion and other cathinones are differentiated by their ketone substitution on the beta carbon of the amphetamine skeleton, meaning they are β-keto-amphetamines.
Equipment and glassware:
- 50 mL Round-bottom flask (RBF);
- Magnetic stirrer with heater;
- Retort stand and clamp for securing apparatus;
- 50 mL Pressure-equalizing dropping funnel;
- Water bath with ice;
- Rotovap machine;
- Vacuum source;
- Funnel;
- 250 or 500 mL Separatory funnel;
- Buchner flask and funnel [Schott filter may be used for small quantities];
- Laboratory scale (0.01-100 g is suitable) [depends on synthesis load];
- Laboratory grade thermometer (10°C to 100°C);
- 500 mL x2; 100 mL x2 Beakers;
- 250 mL x2 Erlenmeyer flasks;
- Filter paper;
- pH Indicator paper;
- Pasteur pipet (medium);
- Glass rod and spatula;
Reagents:
- 1.0 g (5.9 mmol) 3'-Chloropropiophenone (1);
- 5.0 mL Dichloromethane (CH2Cl2);
- 6.0 mL (6.0 mmol) 1.0 M Bromine solution (Br2) in dichloromethane;
- 5 mL t-Butylamine;
- 5 mL N-methylpyrrolidinone (NMP);
- ~250 mL Distilled water;
- 75 mL Diethyl ether (or petroleum ether);
- ~100 g Potassium carbonate anhydrous (K2CO3) [or MgSO4, Na2SO4];
- ~50 mL Hydrochloric acid conc. (HCl:isopropyl alcohol 20:100 v:v) solution;
Bupropion hydrochloride [2-(tert-Butylamino)-1-(3-chlorophenyl)propan-1-one hydrochloride]
Boiling Point: 334.8 °C at 760 mm Hg;
Melting Point: 233-234°C;
Molecular Weight: 276.2 g/mol;
Density: N/D;
CAS Number: 31677-93-7 [34911-55-2 free base].
Procedure
3'-Chloropropiophenone (1) to 2-bromo-3'-chloropropiophenone (2)
Put 1.0 g (5.9 mmol) 3'-chloropropiophenone (1), in a 50 mL round-bottom flask (RBF), add 5.0 mL dichloromethane (CH2Cl2) and a magnetic stirbar and stir until the solid is dissolved. Clamp the flask in the hood and attach a 50 mL pressure-equalizing dropping funnel. Put 6.0 mL (6.0 mmol) of a 1.0 M solution of Br2 in CH2Cl2 in the funnel and add a few drops to the RBF. If the reaction does not begin immediately (as judged by the disappearance of the color of the bromine), warm the flask briefly with your hand or a warm-water bath. Once the reaction begins, the color of the bromine will rapidly disappear, and the RBF should be placed in an ice bath. The bromine solution can now be added dropwise to the flask with stirring; add the bromine solution just rapidly enough so that the color of the bromine has disappeared before the next drop is added. After all the bromine has been added, remove the dropping funnel and insert a simple distillation apparatus or rotovap machine. Distill the solvent from the reaction mixture by placing the stirred RBF in a heated (55-60°С) water bath. When all the dichloromethane has distilled over (a little less than 10 mL will be collected due to evaporative loses) the temperature of the distillate should rise to 40 °С (the b.p. of dichloromethane), remove the distillation apparatus.
Put 1.0 g (5.9 mmol) 3'-chloropropiophenone (1), in a 50 mL round-bottom flask (RBF), add 5.0 mL dichloromethane (CH2Cl2) and a magnetic stirbar and stir until the solid is dissolved. Clamp the flask in the hood and attach a 50 mL pressure-equalizing dropping funnel. Put 6.0 mL (6.0 mmol) of a 1.0 M solution of Br2 in CH2Cl2 in the funnel and add a few drops to the RBF. If the reaction does not begin immediately (as judged by the disappearance of the color of the bromine), warm the flask briefly with your hand or a warm-water bath. Once the reaction begins, the color of the bromine will rapidly disappear, and the RBF should be placed in an ice bath. The bromine solution can now be added dropwise to the flask with stirring; add the bromine solution just rapidly enough so that the color of the bromine has disappeared before the next drop is added. After all the bromine has been added, remove the dropping funnel and insert a simple distillation apparatus or rotovap machine. Distill the solvent from the reaction mixture by placing the stirred RBF in a heated (55-60°С) water bath. When all the dichloromethane has distilled over (a little less than 10 mL will be collected due to evaporative loses) the temperature of the distillate should rise to 40 °С (the b.p. of dichloromethane), remove the distillation apparatus.
2-Bromo-3'-chloropropiophenone (2) to Bupropion free base (3)
The small amount of dense liquid remaining in the flask at this stage is 2-bromo-3'-chloropropiophenone (2), which is a mild lachrymator (see Precautions above). Using a funnel, add to the flask 10 mL of a 50:50 mixture of t-butylamine and N-methylpyrrolidinone (NMP), and heat the (unstoppered) flask in a 55-60°С (water bath with stirring for 10 minutes). The flask now contains (3), the free base form of bupropion. [Although most of the lachrymatory (2) has been consumed in forming (3), you should continue to work in the hood.] There are two other substances besides (3) in the flask: the excess t-butylamine and the NMP solvent. All three substances are soluble in ether, but the last two are also soluble in water, while (3) as the free base is not. We will take advantage of these solubility differences to isolate our product in pure form. Transfer the contents of the flask to a separatory funnel, add 25 mL distilled water and extract the mixture 3 times with 25 mL portions of ether (or petroleum ether), collecting and combining the ether extracts in a beaker. Remember to shake the separatory funnel well during each extraction and to wait for the layers to fully separate. [Caution! Ether is very volatile and pressure will develop!] The ether layer(s) will be on top and contain your product (3), while the aqueous layer will be at the bottom. The water layer contains the NMP solvent and excess t-butylamine; discard this layer, rinse the funnel with distilled water, and return the combined ether extracts to the separatory funnel. Shake the ether solution five times with 25 mL portions of water, allowing the layers to separate each time and then discarding the water layer. Transfer the ether solution to a clean, dry Erlenmeyer flask and remove any remaining water by stirring it in the beaker with anhydrous K2CO3 (or MgSO4, Na2SO4). You should add K2CO3 until new material swirls freely in the solvent without clumping. Average yield 75-85%.
The small amount of dense liquid remaining in the flask at this stage is 2-bromo-3'-chloropropiophenone (2), which is a mild lachrymator (see Precautions above). Using a funnel, add to the flask 10 mL of a 50:50 mixture of t-butylamine and N-methylpyrrolidinone (NMP), and heat the (unstoppered) flask in a 55-60°С (water bath with stirring for 10 minutes). The flask now contains (3), the free base form of bupropion. [Although most of the lachrymatory (2) has been consumed in forming (3), you should continue to work in the hood.] There are two other substances besides (3) in the flask: the excess t-butylamine and the NMP solvent. All three substances are soluble in ether, but the last two are also soluble in water, while (3) as the free base is not. We will take advantage of these solubility differences to isolate our product in pure form. Transfer the contents of the flask to a separatory funnel, add 25 mL distilled water and extract the mixture 3 times with 25 mL portions of ether (or petroleum ether), collecting and combining the ether extracts in a beaker. Remember to shake the separatory funnel well during each extraction and to wait for the layers to fully separate. [Caution! Ether is very volatile and pressure will develop!] The ether layer(s) will be on top and contain your product (3), while the aqueous layer will be at the bottom. The water layer contains the NMP solvent and excess t-butylamine; discard this layer, rinse the funnel with distilled water, and return the combined ether extracts to the separatory funnel. Shake the ether solution five times with 25 mL portions of water, allowing the layers to separate each time and then discarding the water layer. Transfer the ether solution to a clean, dry Erlenmeyer flask and remove any remaining water by stirring it in the beaker with anhydrous K2CO3 (or MgSO4, Na2SO4). You should add K2CO3 until new material swirls freely in the solvent without clumping. Average yield 75-85%.
Bupropion free base (3) to Bupropion hydrochloride (4)
At this point, your beaker contains a solution of the free base of bupropion, (3), in ether. Like most amines, the free base of this compound is soluble in ether and insoluble in water. But when (3) is reacted with an acid, it will form a salt which will have opposite solubility properties, being insoluble in ether but soluble in water. Most pharmaceuticals are amines like bupropion, and they are nearly always marketed and administered in their salt form, usually the chloride. Following an ancient convention, amine chlorides in pharmacy and medicine are referred to as the “hydrochloride”: e.g., morphine hydrochloride, fluoxetine (Prozac) hydrochloride. We will form the hydrochloride salt in a solvent mixture consisting mostly of ether so that it will precipitate out in crystalline form. Decant the ether solution through a funnel loosely plugged with cotton into a dry beaker chilled in an ice bath. The white powder remaining behind is the drying agent, K2CO3. Stir this powder with enough fresh ether to cover it, allow it to settle, and decant the ether through the same cotton-plugged funnel (or use simple filter paper) into the beaker in the ice bath. You can then discard the cotton plug and the K2CO3 desiccant. Using a Pasteur pipet, add a 20:100 v:v solution of conc. HCl:isopropyl alcohol dropwise with manual stirring to the chilled ether solution until the contents of the beaker are acid to pH paper. A few pipets-full will be needed; test the pH by touching a stirring rod moistened with the solution to a small piece of pH paper moistened with water. About halfway to the equivalence point, sparkling white crystals of bupropion hydrochloride, (4), will begin to form in the beaker. When the pH of the beaker is < 3 enough acid has been added. Cover the beaker loosely with a watch glass, and allow it to chill thoroughly for 5-10 minutes in the ice bath. Collect the crystals by gentle vacuum filtration, wash them twice with small portions of ether, and let them air dry. [Do not force a rapid stream of air through the crystals during vacuum filtration; if you do, they may develop a static electric charge, and when approached with a spatula will leap around the bench like Mexican jumping beans.]
Synthesis video tutorial
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