Stage 1. Bromination of propiophenone
The bromination of propiophenone occurs according to Scheme 1.
Scheme 1
Starting reagents and materials
- 50 ml propiophenone
- 40 ml HBr (1,3 g/ml)
- 55 ml H2O2 35%
- 150 ml dichloromethane (DCM)
- 2000-2500 ml H2O
- 250 ml 5% Na2S2O3 (12.5 g and 238 ml H2O)
- 250 ml 5% Na2CO3 (12.5 g and 238 ml H2O)
- 100 ml 15% Na2CO (15 g and 85 ml H2O)
- pH indicator paper
- 3-necked flask, 1000 ml
- 125 ml dropping funnel
- Thermometer
- Reflux condenser
- Magnetic stirrer
- Beakers
- Funnel
- Vacuum pump
Fig 1
In a 1000 ml flask, 50 ml of propiophenone, 40 ml of HBr, and 100 ml of water are placed. A reflux condenser and a thermometer are attached to the flask. Hydrogen peroxide is poured into the dropping funnel. Fig 2
Fig 2
Gentle stirring is initiated, and hydrogen peroxide is added dropwise until an orange color appears. The process proceeds with the generation of heat! The temperature is maintained in the range of 30-40°C. Fig 3
Fig 3
When the orange color disappeared over time, additional portions of hydrogen peroxide are added. Fig 4
Fig 4
Upon adding new portions of hydrogen peroxide, free bromine is generated, which is necessary for the bromination process. Bromination is carried out until the color ceases to disappear, and orange bromine vapors are formed. Fig 5
Fig 5
To the formed bromopropiophenone, 150 ml of DCM added. Fig 6
Fig 6
DCM extracts bromopropiophenone (which is a lachrymator) and separates it under the aqueous layer. The upper aqueous layer exhibits an acidic reaction due to the presence of residual acid. Fig 7
Fig 7
Next, the DCM layer is washed with water until a neutral reaction is achieved. Then, a water solution of 250 ml of 5% Na2S2O3 is added. Fig 8
Fig 8
Despite thorough washing until a neutral reaction is achieved, the addition of sodium thiosulfate solution leads to the precipitation of free sulfur. Therefore, further use of thiosulfate as an anti-bromine agent is not recommended. Fig 9
Fig 9
Next, the mixture was washed with four portions of water. The subsequent washing was carried out with 250 ml of a 5% sodium carbonate solution, which was slowly added dropwise to the stirred mixture. Fig 10
Fig 10
After the addition of the 5% water solution sodium carbonate, the mixture was stirred for 20-30 minutes. Subsequently, portions of a 15% sodium carbonate water solution were added. If the flask volume was insufficient, some of the aqueous layer was aspirated and discarded. Fig 11
Fig 11
After removing as much of the aqueous layer as possible, DCM was washed with two portions of water, each with a volume of 250 ml. Following the carbonate washes, the DCM layer becomes significantly lighter in color. Fig 12
Fig 12
Stage 2. Synthesis and Purification of methcathinone hydrochloride
Stage 2. Synthesis and Purification of methcathinone hydrochloride
The interaction with methylamine proceeds according to Scheme 2.
Scheme 2
Starting reagents and materials
- The solution of bromopropiophenone in DCM under the water layer from Stage 1
- 70 ml 35-40% methylamine water solution
- 2000 ml H2O
- 40-50 ml 14% HCl
- 20 ml DCM
- 25 ml ethylacetate
- 10 ml acetone
- 40-50 ml acetone with temperature -5℃
- 3-necked flask, 1000 ml
- 125 ml dropping funnel
- 250 ml separating funnel
- Thermometer
- Reflux condenser
- Magnetic stirrer
- Filtration setup
- Beakers
- Funnel
- Vacuum pump
Methylamine is added dropwise to the obtained and purified solution of bromopropiophenone in DCM with vigorous stirring. The reflux condenser should also be in operation during this process. Fig 13
Fig 13
The addition of the all volume of methylamine is carried out over a period of 12 hours. The temperature is maintained at around 27°C due to the heat generated by the reaction. Fig 14
Fig 14
After the addition of the all volume of methylamine, the mixture is stirred for 24 hours. During this time, the color changes to amber. Fig 15
Fig 15
The resulting methcathinone is washed with water to remove methylamine. Fig 16
Fig 16
Complete washing to neutral pH is impossible, so residual alkalinity in the washing water is normal. Fig 17
Fig 17
The aqueous washing layer may not be entirely removed.
To convert methcathinone into the water-soluble hydrochloride, hydrochloric acid is added. Fig 18
Fig 18
Hydrochloric acid is added from a dropping funnel to DCM for convert methcathinone into the hydrochloride, achieving a slightly acidic pH. The temperature should not exceed 30°C. Added 40-45 ml of 14% HCl. Fig 19
Fig 19
The DCM layer is separated and washed in a 1:1 volume ratio, additionally with a portion of water containing 1.5-2 ml of hydrochloric acid. If the pH of the aqueous layer is alkaline, diluted hydrochloric acid (1.5-2 ml) is added to achieve an acidic pH. The DCM layer is discarded, and the aqueous layers are combined. Fig 20
Fig 20
To the aqueous layers, 20 ml of pure DCM is added to purify it from organic impurities. Fig 21
Fig 21
The aqueous solution of methcathinone hydrochloride is evaporated to crystallization. Fig 22
Fig 22
The crystallization of methcathinone hydrochloride is shown in Fig 23.
Fig 23
The fully crystallized methcathinone hydrochloride is shown in Fig 24.
Fig 24
First wash: A mixture of 25 ml of ethyl acetate and 10 ml of acetone is added to the crystallized solution. The mixture is well stirred and then filtered. The wash with ethyl acetate on the filter does not completely wash out the product. Fig 25
Fig 25
The product after the first wash is shown in Fig 26.
Fig 26
Second wash: The obtained product is thoroughly ground into a powder. 20-40 ml of ice-cold acetone is added, and the mixture is then filtered. Fig 27
Fig 27
The purity of the obtained methcathinone hydrochloride is sufficient for further synthesis of ephedrine. Fig 28
Fig 28
With additional recrystallization from alcohol, a pure white product is obtained. Fig 29
Fig 29
Raman spectra for some base starting reagents and the obtained product.
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