Shulgin

Synthesis

• From safrole (with aqueous HBr) to 5-(2-bromopropyl)benzo-1,3-dioxole; (with methyl­ amine in EtOH) to MDMA (Merck, 1912; Bineicki and Krajewski, 1960).
• From 3,4-methylenedioxyphenylacetone (aka: piperonylacetone; with methylamine, sodium cyanoborohydride) to MDMA (Braun et al., 1980).
• From MDA (with formic acid or ethyl formate) to N-formyl-3,4-methylenedioxy­ amphetamine; (with LAH) to MDMA (Shulgin and Shulgin, 1991)
• From isosafrole (with formic acid, H₂0₂) to 3,4-methylenedioxyphenylacetone; (with Al, HgCl₂, CH₃NH₂) to MDMA (Shulgin and Shulgin, 1991).
• (For the optical isomers) from piperonylacetone (with R-(-)- (or S-(+)-) α-methylbenzyl­ amine, Raney Ni) to R,R- (or S,S) N-α-methylbenzyl-MOA; (with Pd, H₂) to R-(-)- (or S-(+)-) MDA; (with methyl formate) to R-(+)- (or S-(-) N-formamido-MDA; (with LAH) to R-(-)­ (or S-(+)-) MDMA (Anderson et al., 1978a).

M. Swist, J. Wilamowski, A. Parczewski

The following procedures are extracted from (Swist, Wilamowski, Parczewski; 2004).^[1]

Chemicals and reagents

In the synthesis of MDMA, the following reagents were used:

• formic acid (98%)
• hydrochloric acid (36–38%)
• methylene chloride
• sodium hydroxide
• acetic acid (99.5%)
• acetone
• diethyl ether
• toluene
• isopropanol
• hydrogen peroxide (~33%)
• sulfuric acid (95%) (all POCh, Poland, analytical grade)
• piperonal (99%, Aldrich, for synthesis)
• isosafrole (97%, Aldrich, for synthesis)
• safrole (97%, Aldrich, for synthesis)
• nitroethane (96%, Aldrich, for synthesis)
• cyclohexylamine (99%, Aldrich, for synthesis)
• ethyl formate (97%, Aldrich, for synthesis)
• hydrobromic acid (62%, Aldrich, analytical grade)
• methylamine solution (33% in abs. ethyl alcohol, Aldrich, analytical grade)
• methylamine aqueous solution (40%, Aldrich, analytical grade)
• diethyl ether (anhydrous, >99%, Aldrich, A.C.S. Reagent)
• methanol (Merck, HPLC grade)
• NaBH₄ (Aldrich, for synthesis)
• NaBH₃(CN) (Aldrich, for synthesis).

In impurity profiling experiments, the following reagents were used:

• carbonate buffer, pH 10 (10.7 ml, 0.1 M NaOH; 50 ml, 0.05 M NaHCO₃; 39.3 ml H₂O)
• n-heptane (Aldrich, HPLC grade)
• phosphate buffer, pH 7 (Merck)
• diphenylamine (Supelco, used as internal standard).

Synthesis

3,4-Methylenedioxyphenyl-2-propanone (MDP-2-P) was synthesized by two different routes, i.e. by oxidation of isosafrole in an acid medium and by reduction of 1-(3,4-methylenedioxyphenyl)-2-nitropropene which was previously prepared by condensation of piperonal and nitroethane. The syntheses were performed according to the procedures described by Shulgin and Shulgin.^[2] Subsequently, MDP-2-P, prepared by the oxidation of isosafrole, was used in Leuckart reaction, cyanoborohydride reduction, dissolving metal reduction and borohydride reduction in low temperature. MDP-2-P prepared by the reduction of 1-(3,4-methylenedioxyphenyl)-2-nitropropene was only subjected to borohydride reduction in low temperature.

Leuckart method was performed according to the modified MDA synthesis procedure described by Elks and Hey.^[3] Safrole bromination was carried out according to the procedure described by Biniecki and Krajewski.^[4] Cyanoborohydride reduction (NaBH₄CN) was performed according to the modified MDA synthesis procedure described by Shulgin and Shulgin.^[2] Dissolving metal reduction (aluminium–mercury amalgam) was performed according to the procedure described by Shulgin and Shulgin.^[2] Borohydride reduction (NaBH₄) was performed as follows: aqueous solution (40%) of methylamine (2 ml) was added to a cold mixture of MDP-2-P (1.51 g) in MeOH (5 ml). The mixture was cooled to -20°C and then NaBH₄ (30 mg) was slowly added. After dissolving of the reductive agent, the reaction mixture was left at -20°C for two hours. The addition of NaBH₄ was repeated three times, in portions of 30, 30 and 40 mg, and the reaction mixture was left at -20°C for 24 h. Methanol was evaporated, 10% HCl (10 ml) was added to a residue, and the solution was washed with CH2Cl2 (3 ml x 8 ml). The organic solution was extracted with 10% HCl, combined aqueous layers were alkalized with 25% NaOH (~10 ml) and extracted with CH₂Cl₂ (3 ml x 10 ml). Combined extracts were dried over MgSO4, evaporated, a residue was dissolved in Et₂O (18 ml), and dry HCl was passed through the solution. The precipitate of MDMA HCl was filtered off, dried and homogenized before analysis.

Extraction of impurities

Two hundred milligrams of MDMA HCl was dissolved in 2 ml of buffer. Two different buffers, phosphate buffer, pH 7, and carbonate buffer, pH 10, were tested. The suspension was vigorously shaken (25 min) following by the addition of 200 ml of n-heptane, containing diphenylamine as an internal standard, and then again shaken (25 min). The extracts were subjected to GC/MS analysis, and impurity profiles were obtained.

External links

• MDMA (PiHKAL: A Chemical Love Story)

References