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Synthesis of ephedrine from propiophenone


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Jul 5, 2021
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The mechanism of these reactions is well known:
- at the first stage, bromine is attached to propiophenone in benzene, alpha-bromine-propiophenone is obtained;
- at the second stage, bromine is replaced by an amino group, cathinone is obtained (if ammonia is taken as an amine) or methcathinone (if methylamine is used);
- reduce sodium borohydride to phenylpropanolamine (PPA) or ephedrine.
This article describes the synthesis and isolation of ephedrine.


To a solution of 30.8 ml (0.234 mol, 31.4 g, MW = 134.2) of propiophenone in 120 ml of benzene in a liter flat-bottom flask closed with a reverse refrigerator (running water is not needed), add drop by drop 12.0 ml (0.234 mol, 37.4 g, MW = 159.8) bromine at such a speed that the mass has time to discolor (first add a few drops, wait until it discolors, if this does not happen, the mass is slightly heated). The reaction is exothermic, the addition should be made at such a pace that the temperature does not exceed 35...40 degrees. As the bromine is added, the color becomes slightly yellowish, an ominous kind of smoke spreads from the flask. It's the most tear gas!

After adding all the bromine, the solution is stirred for another 30 minutes, after which the alkalis' solution is carefully added until the foaming stops. In this case, the mixture is slightly heated, and the color is much lighter. Immediately add about 100...200 ml of water, all thoroughly mixed (washed), the water layer (bottom) is separated and discarded, benzene solution of alpha-bromine-propiophenone is used in the second stage in the form in which it turned out. The yield of the product, if you allocate - about 95%.

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In a flask with a benzene solution of alpha-bromine-propiophenone, 50 ml of water is added (as an option - not fully select water from washing after the first stage) and within twelve hours, in three to four doses - an aqueous solution of methylamine. Methylamine is enough 1.5...2 equivalent (with these tabs - about 0.4 mol), so the amount is as follows: 40 ml of a 40% solution or 50 ml of a 30% solution. If there is no aqueous methylamine, then instead of water, an aqueous solution of methylamine hydrochloride taken in an amount of 27 g (0.4 mol, MW = 67.5) is poured, and in the reaction process an aqueous solution of alkalis is added: 16 g (0.4 mol, MW = 40.0) NaOH or 22.5 g KOH (0.4 mol, MW = 56.1), taken equimolarily with methylamine hydrochloride.

All the reaction time, the mixture is stirred so that the layers do not separate, while the flask must be closed with a cork to prevent the leakage of methylamine. The temperature is maintained slightly above the room temperature, about 30 degrees. At the same time, the color slowly changes to a more yellow, at the end acquiring orange shades. After this time, the cork is replaced with a reverse refrigerator, an aqueous solution of 10...12 g of NaOH (or 14...16 g of KOH) is added, and the mixture is heated once to 70 degrees. In this case, the alkalis displaces excess methylamine, the color becomes more saturated, the solution is no longer a lacrimator.

The solution is cooled, the water layer (bottom) is separated and thrown away. The benzene solution is washed once with a weak aqueous solution of table salt and once with water taken approximately by the volume of benzene, and sent, in the form in which it turned out, to the next stage of the process. Those who wish can allocate methcathinone.

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In the benzene solution of methcathinone, obtained at the previous stage, with intensive stirring in small portions, add 18 g (0.476 mol, MW = 37.8) of carefully crushed sodium borohydride (NaBH4). When adding each portion after about 5 to 10 minutes, exotherm and foaming begin, so the addition is carried out slowly, taking into account this factor. When the addition is finished, the flask is closed with a reverse refrigerator and the resulting suspension is left to stir intensively at room temperature throughout the day. At the end, the solution is heated once to 30...50 degrees, kept at this temperature for three hours and cooled. The color of the mixture remains unchanged for a long time, at the end it becomes lighter, orange shades disappear.

A concentrated aqueous alkalochi solution (KOH or NaOH) is added to the mixture to facilitate the filtration of borohydride suspension. The addition is carried out in small portions, while the suspension for 10...15 minutes reacts, swells and settles to the bottom. If you add too much - then the suspension dissolves, which is undesirable. After the filtered mass is formed at the bottom, the liquid is filtered, the residue is rinsed with a small amount of benzene. Organic phases are combined, washed once with cold water, then acetic acid is added when stirring drop-by-drop (vinegar 70% is suitable). In this case, the remains of borohydride disintegrate with gas release noticeable to the eye. Borane, a poisonous gas, is released, be careful. The addition of acetic acid is completed, when the gas release stops, the mixture is stirred for another 30 minutes, and the product begins to be released.

The yield of this stage - about 75%.

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The allocation is standard: acid-base extraction, salt planting, washing - and here it is, crystalline powder. A weak aqueous solution of hydrochloric acid in a volume of about a quarter of the volume of benzene is thoroughly mixed with a cooled benzene solution from the previous stage. If after stirring, the solution has not become slightly acidic, then add more acids and mix again. At the same time, the volume of the benzene layer decreases, and the volume of the water layer increases: this ephedrine passes into salt and goes into water. The water layer is separated (it is from below), the benzene is washed two more times with slightly acidic water in portions of a quarter of the volume of benzene. Benzene is thrown out, the aqueous fractions are combined, washed once with a small amount of benzene (the benzene layer will be on top) and once with a portion of dichloromethane (the dichloromethane layer will be from below) 20...30 ml. Solvents are thrown out, the aqueous solution, which has become lighter, is left.

After washing with solvents, ephedrine hydrochloride is added in small portions to the alkalis in dry form and dissolved during cooling (exotherm). At the same time, the color lightens, the mixture becomes cloudy, and with a sufficiently alkaline reaction (pH>11), ephedrine is separated - the base in the form of yellow oil and suspension. The base of ephedrine is extracted in three portions of dichloromethane (the first - 50 ml, the second and third - 20 ml each), with the formation of an emulsion at the border of the layers, it is broken by passing through the filter. The aqueous layer is thrown out, organic extracts are combined, washed once with a weak solution of table salt and once with water, dichloromethane is distilled, preferably with reduced pressure. The residue is dissolved in 50 ml of isopropyl alcohol (IPA), the kobla is rinsed with 20 ml of IPA, alcohol solutions are combined. Drop-by-drop and stirring, concentrated hydrochloric acid (at least 35%) is added until a barely noticeable acidic reaction is achieved. The color of the solution does not change significantly, remaining yellow.

Alcohol is evaporated in a water bath, the remaining thick viscous mass is diluted with a new portion of IPA 20...40 ml, dissolved and evaporated to dry. At the end of the procedure, the product is tried to crystallize, evenly distributed over the evaporation bowl, cooling and supplying a stream of fresh air. It crystallizes without problems, forming a noticeably lightened crust of almost white or light beige color. After crystallization, the bowl with the contents is heated in a water bath for 30 minutes to remove the remnants of moisture, then cooled, the resulting mass is separated with a blade and crushed, preparing for washing.

Pre-prepared acetone is cooled to the lowest possible temperature, and with a small amount grind the resulting product in a mortar. Acetone is filtered. As a rule, this produces a perfectly white powder, which is rinsed directly in the filter with a small amount of acetone, acetone is filtered, the resulting product is dried in a water bath for at least an hour, in the process of drying grinding lumps (while there is a characteristic "creaking").

The yield of this stage is about 80%.

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Uncle Lee

Jan 1, 2022
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I wish I could have seen this article years ago, I have a lot of experience with this reaction.

I have tried many wrong methods, because almost all the Russian and Chinese literature is wrong about this reaction. In a more moderate scale production, it is safer to use potassium borohydride to reduce ephedrone freebase in a common polar solvent, and the reaction time will be reduced and the operation will be much easier, I will summarize my method and publish it when I have time


New member
Jan 11, 2022
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Is it viable ti grow and extract ephedra plant what scale and what chemicals would be used and is this the only synthasis

William Dampier

Well-known member
Jul 19, 2021
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Is it viable ti grow and extract ephedra plant what scale and what chemicals would be used and is this the only synthasis
Easier to take synthetic propiophenone, for ordinary chemist. Industrial production is also chemically
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