MDMA Synthesis from Vanillin

Fully Validated, Multi-Kilogram cGMP Synthesis of MDMA

Steps

1. Vanillin → Guaiacol
2. Guaiacol → Catechol
3. Catechol → 1,3-Benzodioxole
4. 1,3-Benzodioxole → 5-Bromo-1,3-Benzodioxole
5. 5-Bromo-1,3-Benzodioxole → 1-(3,4-Methylenedioxyphenyl)-2-propanol
6. 1-(3,4-Methylenedioxyphenyl)-2-propanol → 1-(3,4-Methylenedioxyphenyl)-propan-2-one
7. 1-(3,4-Methylenedioxyphenyl)-propan-2-one → 3,4-methylenedioxymethamphetamine Hydrochloride

1. Vanillin → Guaiacol (Reduction of Aldehyde to Methyl)

Reagents & equipment:

• Vanillin (C₈H₈O₃) – 1 mol
• Zinc powder (Zn) or Sodium Borohydride (NaBH₄) – 1.2 mol
• Hydrochloric Acid (HCl) or Acetic Acid – catalytic
• Methanol (MeOH) or Ethanol (EtOH) – solvent
• Water bath at 40°C

Procedure:

1. Dissolve 1 mol of Vanillin in 100 mL of MeOH or EtOH.
2. Add 1.2 mol of Zn powder (or NaBH₄ for milder conditions) slowly while stirring.
3. Add HCl dropwise until the solution turns slightly acidic.
4. Stir the mixture at 40°C for 2–3 hours.
5. Quench the reaction with water, then extract with ethyl acetate.
6. Dry the organic layer with MgSO₄, filter, and evaporate the solvent.
7. Purify by recrystallization (hexane/ethyl acetate mix).

Yield: ~80% of Guaiacol (C₇H₈O₂).

2. Guaiacol → Catechol (Demethylation)

Reagents & equipment:

• Guaiacol (C₇H₈O₂) – 1 mol
• Hydroiodic Acid (HI, 57%) or Hydrobromic Acid (HBr, 48%) – 1.2 mol
• Red Phosphorus (P, catalytic)
• Toluene or Diethyl Ether – extraction solvent
• Reflux apparatus (130°C)

Procedure:

1. Add 1 mol of Guaiacol and 1.2 mol of HI (or HBr) into a round-bottom flask.
2. Add a trace amount of red phosphorus (P) to enhance reactivity.
3. Heat under reflux (~130°C) for 4–5 hours.
4. Cool, then extract with toluene or diethyl ether.
5. Wash with Na₂S₂O₃ solution to remove iodine residues.
6. Evaporate the solvent and recrystallize the crude Catechol (C₆H₆O₂) using hexane/ethyl acetate.

Yield: ~80% of Catechol.

3. Catechol → 1,3-Benzodioxole (Methylenation)

Reagents & equipment:

• Catechol (C₆H₆O₂) – 1 mol
• Dichloromethane (CH₂Cl₂) or Paraformaldehyde (CH₂O)n – 1.2 mol
• Potassium Carbonate (K₂CO₃) or NaOH – 1.5 mol
• Toluene or Acetonitrile (CH₃CN) – solvent
• Reflux apparatus (80°C)

Procedure:

1. Dissolve 1 mol of Catechol in 100 mL of toluene.
2. Add 1.5 mol of K₂CO₃ and stir.
3. Slowly add 1.2 mol of CH₂Cl₂ (or Paraformaldehyde + acid catalyst).
4. Reflux at 80°C for 5 hours.
5. Cool and extract with ethyl acetate.
6. Wash with water and brine, then dry over MgSO₄.
7. Evaporate the solvent and distill under vacuum.

Yield: ~80% of 1,3-Benzodioxole (C₇H₆O₂).

4. 1,3-Benzodioxole → 5-Bromo-1,3-Benzodioxole (Bromination)

Reagents & equipment:

• 1,3-Benzodioxole (C₇H₆O₂) – 1 mol
• Bromine (Br₂) or NBS (N-Bromosuccinimide) – 1.2 mol
• Glacial Acetic Acid or Chloroform – solvent
• Reflux setup (50–60°C)

Procedure:

1. Dissolve 1 mol of 1,3-Benzodioxole in 100 mL of Acetic Acid or Chloroform.
2. Slowly add 1.2 mol of Br₂ or NBS, stirring at 50–60°C for 2 hours.
3. Cool and quench with sodium bisulfite (NaHSO₃) solution.
4. Extract with ethyl acetate, wash with water, dry with MgSO₄.
5. Purify via column chromatography (silica gel, hexane/ethyl acetate mix).

Yield: ~85% of 5-Bromo-1,3-Benzodioxole (C₇H₅BrO₂).

5. 5-Bromo-1,3-Benzodioxole → 1-(3,4-Methylenedioxyphenyl)-2-propanol

Reagents & equipment:

• Magnesium turnings
• THF
• 5-Bromo-1,3-benzodioxole
• Copper(I) iodide
• (±)-Propylene oxide
• THF
• 10% (w/w) Sodium chloride solution
• Acetic acid
• n-Heptane
• PEG400

Procedure:

Grignard Formation

1. Charge magnesium turnings into a dry reaction vessel under stirring.
2. Add dry THF and heat to gentle reflux.
3. Add a small initial portion of 5-bromo-1,3-benzodioxole and stir at reflux until initiation is observed.
4. Add the remaining 5-bromo-1,3-benzodioxole dropwise while maintaining reflux.
5. Stir at reflux, then cool the Grignard solution to ambient temperature.

Scale-Up Grignard Initiation

6. Charge magnesium turnings and THF into a larger reaction vessel and heat to gentle reflux.
7. Add a portion of 5-bromo-1,3-benzodioxole followed by a seed amount of the previously prepared Grignard solution to initiate the reaction.
8. Once initiation is confirmed, add the remaining 5-bromo-1,3-benzodioxole while maintaining reflux.
9. Stir at gentle reflux to complete Grignard formation.

Addition to Propylene Oxide

10. Cool the Grignard solution to low temperature.
11. Add copper iodide to the reaction mixture.
12. Add a solution of propylene oxide in THF while maintaining low temperature.
13. Rinse the addition vessel with THF and add the rinse to the reaction.
14. Stir at controlled temperature until reaction completion is confirmed.

Workup

15. Divide the reaction mixture into portions for workup.
16. Add aqueous sodium chloride solution followed by acetic acid while controlling temperature.
17. Transfer each portion into the reaction vessel and stir at elevated temperature.
18. Adjust the pH to acidic using additional acetic acid.
19. Allow phase separation and remove the aqueous layer.
20. Add n-heptane and additional sodium chloride solution, stir, and separate layers again.
21. Filter the organic layer through a fine filter.
22. Combine organic fractions and remove solvent under reduced pressure.

Purification

23. Add PEG-400 to the crude product and mix until homogeneous.
24. Distill the mixture under reduced pressure using a wiped-film evaporator.
25. Collect the purified product as a pale yellow oil.

6. 1-(3,4-Methylenedioxyphenyl)-2-propanol → 1-(3,4-Methylenedioxyphenyl)-propan-2-one

Reagents & equipment:

• Crude 1-(3,4-methylenedioxyphenyl)-2-propanol
• Dichloromethane
• Potassium bromide
• TEMPO (2,2,6,6-Tetramethylpiperidin-1-yloxyl)
• Oxidizing Solution: A pre-mixed solution of Sodium hydrogen carbonate in diluted bleach (12.5% w/v sodium hypochlorite). Total volume used: ~9720 mL (7280 mL initial + 4 x 610 mL aliquots).
• Aqueous sodium hydrosulfite solution (12% w/w, 4890 mL)
• Aqueous sodium hydroxide solution (0.5 M, freshly prepared, 4900 mL)
• Aqueous sodium chloride solution (11% w/w, 2 x 4900 mL)
• Concentrated hydrochloric acid (36% w/w, 98 mL)
• Saturated aqueous sodium chloride solution (4900 mL)

Procedure:

Oxidation (TEMPO / Bleach System)

1. Charge crude 1-(3,4-methylenedioxyphenyl)-2-propanol into a reaction vessel.
2. Add dichloromethane and initiate stirring at ambient temperature.
3. Add potassium bromide followed by TEMPO.
4. Cool the reaction mixture to low temperature.
5. Add a sodium hydrogen carbonate / bleach solution dropwise while maintaining sub-ambient temperature.
6. Withdraw samples periodically and monitor reaction progress by HPLC.
7. Continue incremental additions of the oxidant solution until conversion criteria are met.
8. Stop stirring and allow the reaction mixture to settle.
9. Separate the layers and retain the organic phase.

Workup

10. Cool the organic layer to low temperature.
11. Add aqueous sodium hydrosulfite while maintaining controlled temperature.
12. Warm the mixture to ambient temperature and stir.
13. Separate the layers and retain the organic phase.
14. Add aqueous sodium hydroxide and stir.
15. Separate the layers and retain the organic phase.
16. Add aqueous sodium chloride solution followed by hydrochloric acid.
17. Stir at ambient temperature, then separate the layers.
18. Wash the organic layer with additional sodium chloride solution.
19. Perform a final wash with saturated sodium chloride solution.
20. Filter the organic layer through a Buchner funnel, rinsing with dichloromethane.
21. Transfer the filtrate to a rotary evaporator and remove solvent under reduced pressure.

7. 1-(3,4-Methylenedioxyphenyl)-propan-2-one → 3,4-methylenedioxymethamphetamine Hydrochloride

Reagents & equipment:

For the Reductive Amination Reaction:

• Crude 1-(3,4-methylenedioxyphenyl)-propan-2-one from Step 2 (2963.9 g)
• Methanol (31170 mL)
• 40% (w/w) aqueous methylamine (3520 mL, 102 mol)
• Sodium borohydride (NaBH₄, 286.4 g)
• Sodium hydroxide (NaOH, 40.4 g)
• Purified Water (for reagent preparation and quench: 630 mL + 9640 mL)

For Workup and Liquid-Liquid Extractions:

• tert-Butyl methyl ether (TBME) (12,100 mL + 2400 mL + 12,000 mL + 12,000 mL)
• 2.0 M Hydrochloric acid (HCl, 12,000 mL)
• 5.4 M aqueous Sodium hydroxide (NaOH, 6000 mL)
• Rochelle salt (Potassium sodium tartrate tetrahydrate, 1589.6 g)

For Final Salt Formation and Purification:

• Isopropanol (2-propanol, 2400 mL)
• 2-Propanol (20,280 mL)
• 5.4 M HCl in 2-propanol (2435 mL)

Procedure:

1. Add crude material and methanol to the reaction vessel and cool to 5 °C.
2. Add aqueous methylamine dropwise and cool the batch to −10 °C.
3. Add NaOH and NaBH₄ in purified water over 120 minutes.
4. Warm the solution and stir.
5. Take a sample and analyze by HPLC to confirm reaction completion.
6. Add purified water portionwise while maintaining temperature.
7. Transfer the mixture to a rotary evaporator and remove methanol under vacuum.
8. Take a sample and analyze by ¹H NMR for residual methanol.
9. Return the crude product to the reaction vessel and stir with TBME.
10. Separate layers and wash the aqueous layer with additional TBME.
11. Combine organic layers and add aqueous HCl portionwise, then stir.
12. Separate layers and return the aqueous layer to the reaction vessel.
13. Wash the aqueous layer with TBME.
14. Stir the aqueous layer with aqueous NaOH.
15. Add TBME and Rochelle salt and stir.
16. Separate the organic layer and wash the aqueous layer again with TBME.
17. Combine organic layers and remove solvent by rotary evaporation.
18. Add isopropanol to the residue and remove by rotary evaporation.
19. Record crude product weight and purity.
20. Return the crude product to the reaction vessel with 2-propanol and initiate stirring.
21. Add HCl in 2-propanol dropwise.
22. Stir the mixture at room temperature.
23. Collect the precipitate by vacuum filtration.
24. Wash the filter cake with 2-propanol.
25. Dry the product under vacuum.
26. Record final product weight and purity.