Synthesis of 2,5-Dimethoxy-4-methylamphetamine (STP, DOM)IntroductionThe preparation of STP (DOM) in Pihkal suffers from a very bad yield of the intermediate aldehyde and its tedious workup. This synthesis is easier and has much improved yield (88% compared to 25% in Pihkal). 2,5-Dimethoxytoluene [1]
1000ml of water was poured into a wide-mouthed 2000 ml flask, and magnetic stirring was initiated. In sequence, there was added 62 g toluhydroquinone, 160 ml 25% NaOH solution and finally 126 g of dimethyl sulfate. The flask was covered with aluminum foil and stirred for a few days. The brown solution was poured into 2500ml water, and the resulting solution was extracted with 3x100ml of CH2Cl2 and the pooled extracts was stripped of solvent under vacuum. The residue was distilled at about 70°C at 0.5 mmHg to give 49 grams (64%) of 2,5-dimethoxytoluene as a white liquid, which turns orange under several years storage. 2,5-Dimethoxy-4-methylbenzaldehyde [2]
40ml POCl3 and 45ml N-methylformanilide was stirred at room temp for 50 min to give a nice orange solution of the Vilsmeyer complex. 15.2g (0.1 mole) 2,5-dimethoxytoluene was then added in one portion, and the reaction mixture was heated to 70°C, during which time the reaction mixture became dark red. The heat source was then removed, and the exothermic reaction, which evolved large amounts of HCl gas, was allowed to go on until the mixture cooled down and solidified. The flask was then heated on the steam bath for 2 hours, and the warm reaction mixture poured into 2 liters of ice water, and was stirred until all the ice had melted. The ice-cold solution was filtered, and the crude aldehyde was collected as a red solid. This was suspended in 50ml of boiling petroleum ether and was decanted. The procedure was repeated two more times with 50ml of petroleum ether each. This left a small amount of red goo on the bottom of the flask. The solution was allowed to crystallize in the fridge for an hour and was then filtered. The mother liquor was concentrated to 25% of the original volume, again cooled in the fridge and filtered. The orange-brown precipitate was then recrystallized from 50 ml 80% aqueous MeOH to give 14.6g (88%) of 2,5-dimethoxy-4-methylbenzaldehyde as orange crystals. 2,5-dimethoxy-4-methylphenyl-2-nitropropene
To 50 ml glacial acetic acid in a 100ml flask there was added 10.8 g of 4-methyl-2,5-dimethoxybenzaldehyde, 7.5 g nitroethane, 4 g ammonium acetate and 2 ml of acetic anhydride. The solution was heated on a water bath for 3h, whereupon the solvent was removed under vacuum. The residue was mixed with 100 ml H2O and extracted with 2x50ml CH2Cl2. The organic phase was washed with 50ml 10% NaHSO3 followed by 50ml H2O. The pooled aqueous phases was extracted with 50 ml CH2Cl2, the organic phases dried over MgSO4, and the solvent was evaporated under vacuum. The residue was dissolved in 50ml IPA and was allowed to precipitate in the freezer to give 8.15 g of orange crystals (69%). 2,5-Dimethoxy-4-methylamphetamine [3]
In a two-necked round-bottomed flask, equipped with a reflux condenser and a calcium chloride drying tube, a suspension of 9.5 g LAH in 750 mL well stirred anhydrous Et2O was brought to a boil, and a THF solution of 9.5 g 2,5-dimethoxy-4-methylphenyl-2-nitropropene was added dropwise through an addition funnel. After the addition of the nitrostyrene was complete, the stirred suspension was maintained at reflux for an additional 4 h with a water bath, then allowed to cool to room temperature and the stirring was continued overnight. The excess hydride was destroyed by the addition of 750 mL 8% H2SO4, cautiously, until the hydrogen evolution ceased, then at a speed that allowed the formed solids to disperse. The phases were separated, the aqueous phase washed once with Et2O, treated with 225 g potassium sodium tartrate, and finally made basic (pH >9) with 5% NaOH. This was extracted with 3x150 mL CH2Cl2, the extracts pooled, and the solvent removed under vacuum. The residue was 9.6 g of a clear oil which spontaneously formed crystals with a mp of 60.5-61°C from hexane. These solids were dissolved in 150 mL anhydrous Et2O, and saturated with anhydrous HCl gas. After standing at room temperature for 2 h, the crystalline 2,5-dimethoxy-4-methylamphetamine hydrochloride (DOM) was removed by filtration, washed with Et2O, and air dried to constant weight. There was obtained 8.25g (84%) of glistening white crystals that had a mp of 190.5-191.5°C. References [1] Shulgin & Shulgin, Pihkal #23, p 511
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