Synthesis of DOC - 4-Chloro-2,5-dimethoxyamphetamine

Translation and Comments by Rhodium
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A german research team wanted to create a better synthesis of DOC than the procedure featured in Pihkal #64 as they thought it was cumbersome to generate the liquid chlorine required for that synthesis, and analysis of the resulting chlorinated 2,5-DMA indicated that the product consisted of 35% monochlorinated, 35% dichlorinated and 5% trichlorinated product (the rest was unreacted starting material). They concluded that the use of elemental chlorine was not suitable for the selective 4-chlorination of 2,5-DMA. Instead they turned to the use of the Sandmeyer reaction to incorporate the chlorine, as made in Canadian Journal of Chemistry, 1402-1409 (1973). The synthesis is longer than the one in Pihkal, lower yielding, but it produces only the desired product. Reaction schemes, NMR, MS, IR and UV spectrums can be found in the original german reference, Synthese von DOC.



A solution of 75g 2,5-dimethoxybenzaldehyde in 375ml glacial acetic acid was mixed with 49ml nitroethane and 31.2 g anhydrous ammonium acetate. The mixture was refluxed for 3h at an oil bath temperature of 135°C, and the solvents removed by vacuum distillation. The residue was suspended in water and extracted with chloroform. After evaporation of the chloroform, and recrystallization from methanol, 2,5-dimethoxyphenyl- 2-nitropropene was isolated in 50.6% yield, mp 72-75°C.

2,5-dimethoxyamphetamine (2,5-DMA)

A solution of 17g 2,5-dimethoxyphenyl-2-nitropropene in 500ml diethyl ether was added dropwise to a well-stirred suspension of 12g Lithium Aluminum Hydride in 700ml anhydrous ether, and the mixture refluxed for 20h. The mixture was cooled in an ice-bath and the excess hydride decomposed carefully by the addition of 500ml water. 300g potassium sodium tartrate (Rochelle salt) was dissolved in the mixture, and the aqueous phase was drawn off and extracted with 3x100ml diethyl ether. The combined ether phases was washed with brine, and dried over anhydrous Na2SO4. The drying agent was filtered off, and the solvent was distilled off on a water bath. The residue consisted of 2,5-DMA as a light brown oil in a yield of 82.5%.


200ml acetic anhydride was added to a solution of 24.5 g 2,5-DMA and 122.5g Sodium acetate in 1500ml water, and the mixture shaken vigorously until the exothermic reaction had subsided. After standing in the fridge fro three days the precipitate was filtered off and recrystallized from ethanol. N-acetyl-2,5-dimethoxy- amphetamine was isolated in 25% yield with a mp of 104°C.


A solution of 10ml 70% HNO3 and 72ml water was added to a solution of 7.3g N-acetyl-2,5-dimethoxy- amphetamine, 0.1g NaNO2 and 73ml glacial acetic acid. The mixture was refluxed for 4h in a 125°C oil bath, cooled to room temperature, and diluted with 73ml water. N-acetyl-4-nitro-2,5-dimethoxyamphetamine precipitated from the solution as yellow needles after several days in the fridge. The yield was 32%, mp 165-168°C


A solution of 2.7g N-acetyl-4-nitro-2,5-dimethoxyamphetamine in 400ml ethanol was hydrogenated for three days using 0.1g 10% Pd/C [No H2 pressure indicated]. The catalyst was filtered off and the filtrate concentrated under vacuum. The residue was suspened in 30ml 5% aqueous NaOH and extracted with 3x100ml chloroform. The combined organic phases was washed with brine and dried over anhydrous Na2SO4, filtered and the solvents evaporated under vacuum. After recrystallization of the residue from ethanol, N-acetyl-4-amino-2,5-dimethoxyamphetamine was isolated in 67% yield, mp 183-186°C.


A solution of 1.6 g N-acetyl-4-amino-2,5-dimethoxyamphetamine in 5.5ml concentrated HCl and 11ml water was cooled to -6°C in an ice/salt bath. To this mixture was added a solution of 0.5g NaNO2 (cooled to 0°C) slowly added with good stirring. To this cooled diazonium salt solution, under constant stirring, was added a solution of 0.1g Copper(I)chloride in 3.3ml conc. HCl (cooled to -8°C with an ice/salt bath). The stirred solution was allowed to return to room temperature, then heated to 70°C and held there for 60min, and then cooled to room temperature. The white precipitate was filtered with suction, washed with a little ice-cold water and recrystallized from ethanol. Yield 75.5%, mp 148°C.

4-chloro-2,5-dimethoxyamphetamine (DOC)

0.9g N-acetyl-4-chloro-2,5-dimethoxyamphetamine was refluxed for 22h in i solution of 3g NaOH in 15ml water and 30 ml ethylene glycol at an oil bath temperature of 140°C. After cooling, the solution was extracted with 3x100ml chloroform, the combined organic phases washed with brine and dried over Na2SO4, filtered and the filtrate concentrated under vacuum. 4-chloro-2,5-dimethoxyamphetamine (DOC) was isolated in 93% yield, mp 95-102°C.

4-chloro-2,5-dimethoxyamphetamine Hydrochloride

A solution of 0.7 g 4-chloro-2,5-dimethoxyamphetamine in 300ml anhydrous ether was bubbled with anhydrous HCl gas, the solution evaporated to dryness in a rotary evaporator, and the residue dissolved in 1.5ml ether/ethanol (50/50). After standing in the fridge for two days, the precipitate was filtered off with suction and washed with ice-cold ether/ethanol (50/50). 4-chloro-2,5-dimethoxyamphetamine Hydrochloride was isolated in 70.3% yield, mp 188-192°C.

Reference: Synthese von DOC (PDF in German)