Mephedrone Synthesis: Step-by-Step Guide & Crystallization Techniques

Mephedrone Synthesis: Step-by-Step Guide & Crystallization Techniques

Reaction scheme:

Reagents:

1. 4'-Methylpropiophenone (cas 5337-93-9) 1 kg;
2. Hydrobromic acid 48% 1300 ml;
3. Hydrogen peroxide 35% 750 ml;
4. Sodium/potassium hydroxide 25% (NaOH/KOH) aqueous solution;
5. Distilled water;
6. Ethyl acetate 6 l;
7. Methylamine 40% aq - 2 l;
8. Acetone - 8 l;
9. Hydrochloric acid (HCl 38%) 500 ml;
10. Isopropyl alcohol;

Equipment and glassware:

1. Scales;
2. Jacketed 10 L reactor equipped with reflux condenser, drip funnel, thermometer, top stirrer and temperature control system;
3. Heating pump;
3. Chiller pump;
4. Vacuum source;
5. Buckets;
6. Freezer;
7. Pyrex dishes;
8. Nutsche filter;
9. pH indicator papers;

Stage 1. Halogenation

1. 4'-Methylpropiophenone 1000 g is added into a 10 L reactor flask.

2. Hydrobromic (HBr) acid 1300 g 48% is poured into the flask and stirred for 5 min.

3. Hydrogen peroxide 750 g 35% is added into a drip funnel 1 l.

4. Hydrogen peroxide is added dropwise to the stirred reaction mixture.

5. Bromine is released during hydrogen peroxide addition to the mixture, dissolved in solution and reacted.

6. Hydrogen peroxide must be added at an appropriate rate so that the reaction mixture becomes colorless.

7. Reaction mixture temperature have to be kept less than 65 °C. An external cooling is applied in case of overheating. If reaction temperature is higher, hydrogen peroxide addition is stopped.

8. The second part of discoloration reaction can be conducted for longer time. Hydrogen peroxide is added according with reaction temperature.

9. Reaction mixture is left for a 12 h with a constant stirring at room temperature as soon as all hydrogen peroxide is added.

10. After 12 h precipitate is formed.

11. Sodium bicarbonate aq solution is added to the reaction mixture to reach neutral pH 6-7, stir it well. The mixture with 2-bromo-4'-methylpropiophenone is filtered through a Buchner funnel. Product is washed with small amount of distilled water.

12. Crude 2-bromo-4'-methylpropiophenone (cas 1451-82-7) is used for further reactions. Theoretical yield up to 1530 g. Practice yield is almost quantitative (video yield 94%).

13. The resulting product is left in the reactor.

Stage 2. Methamination.

1. Ethyl acetate 6 l is poured into the reactor.

2. Reaction mixture is stirred and heated in Jacketed reactor up to 30 °C with help of heating system.

3. The mixture is stirred until complete amount of 2-bromo-4'-methylpropiophenone (cas 1451-82-7) is dissolved.

4. The stirring is stopped. The reaction mixture is left for layer separations. A bottom layer is drained through a bottom reactor tap.

5. The stirrer is turned on and methylamine 40% aq 2 l is added at once.

6. The mixture is stirred for 20 min, temperature is kept below 65 °C.

7. Repeat step 4.

8. After that, the mixture is heated up to 55 °C and reactor vacuum pump is turned on. The reactor condenser chiller pump is turned on as well.

9. All amount of ethyl acetate or the biggest part of it is distilled off.

10. Vacuum pump is turned off. Acetone is added to the reactor with a constant stirring.

11. Hydrochloric acid (500 ml) is placed into the drip funnel and the funnel is installed onto the reactor neck.

12. Hydrochloric acid is added dropwise to reach pH 5 with constant stirring. A small amount (~2-5 ml) of reaction mixture is drained from the bottom reactor tap in order to check pH by pH indicator stripe. The sample is poured back into the reaction mixture.

13. After that, the mixture is poured into a bucket and the bucket is put into a freezer for 12 h.

Stage 3. Filtration

1. A vacuum filtration system (Nutsche filter, filter cloth, vacuum pump) is assembled and installed.

2. The vacuum pump is turned on.

3. A bucket content from step 13 stage 2 is poured to the Nutsche filter.

4. The mixture is filtered and pressed until the funnel content is become solid.

5. A cold dry acetone is poured onto the solid product in the funnel in several small portions during filtration.

6. Acetone is filtered. Step 5 is repeated, if the solid is not white.

7. White solid 4-MMC product is moved into a Pyrex dish for a drying after filtration procedure.

8. Pyrex dish with 4-MMC is placed into a dry well ventilated warm room.

9. 4-MMC product is dried to a constant mass. Product is mixed and grinded periodically in order to increase drying speed.

Stage 4. Recrystallisation

4-Methylmethcathinone crystallization conditions:

• - Constant temperature 22-24 ºC;
• - Dry air (<40% relative humidity);
• - Container volume;

Simple method

Isopropyl alcohol (IPA) or ethanol solution with water is prepared in ratio 30/70, 50/50, 70/30. Proportions are adjusted according with a tasks and a crystallization container volume. Time of crystallization and crystal size depend on amount of water in solution. The more water, the bigger the crystals and longer crystallization procedure. Average proportion of mephedrone hydrochloride to water is 1 g per 2-3 ml of solvent. The solution is heated to a light boiling (small bubbles). Then mephedrone hydrochloride is added in portions so that it has time to dissolve. Next, the product is dissolved, boil for a couple minutes and the solution is poured into a crystallization dish. Plastic and glass dishes are mostly used. The solution layer with height 1-2 cm height gives a fraction with a sugar crystals size. The solution layer 3-5 cm height gives an up to 5 mm fraction. Air-conditioned boxes, fume hoods and air dryers can be used for this procedure. Wet crystals are obtained after solvent evaporation, which are well dried under dry air flow, infrared radiation (IR lamp or IR heater) or in a vacuum desiccator.

Gradual cooling method

Сrystallization centers are formed in the solution, when solution is evaporated for 50% or more. To accelerate the crystallization process, the mixture is gradually cooled. A crystallization dish is placed into a refrigerator (4 ºC) for 8-12 h, then it is moved into a freezer (-17-20 ºC) for 8-12 h.

Rotary evaporator crystallization technique (fine fraction)

Mephedrone hydrochloride is dissolved in a solvent in the proportion of 1 g per 1 ml. The solution is placed in the rotary evaporator flask and distilled. The deeper vacuum, the lower the boiling point of the solution. Large amount of fine crystals are obtained by this way.

It is possible to evaporate the solution with a hot air fan from a crystallization dish in the rotary evaporator absence case. In this case, glass or ceramic heat-resistant glassware is used. It is important to prevent overheating of the product and, as a result, its deterioration.

Crystallization technique with rapid cooling

Mephedrone salt is dissolved in hot water in the proportion 1 g per 1 ml in a boiling hot water. Ethanol 0.5 l or other polar organic solvent is added after complete dissolving. The hot solution is poured into a plastic containers to fill ½ or 2/3 volume, sealed and cooled in a freezer at -17-20 ºC. There is a chance that the product will not precipitate out. In this case crystals are filtered and the solution is additionally evaporated.

Сrystallization method in brine solution

Sodium chloride (NaCl) 23 g is dissolved in distilled water (H2O) 100 ml. Mephedrone hydrochloride 100 g is dissolved in this brine solution, the solution should be heated for better solubility. The solution is poured into a plastic container to fill ½ or 2/3 volume and sealed tightly. Crystals are grown at low temperature -18 ºC. If the temperature is cooled below -18 ºC, the brine solution is frozen.