Introduction
Difluoromethylenedioxymethamphetamine (DFMDMA, DiFMDMA) is a substituted derivative of 3,4-methylenedioxyamphetamine (MDMA), which was developed along with the corresponding fluorinated derivatives of MDA, MDEA, BDB and MBDB, with the aim of finding a non-neurotoxic drug able to be used as a less harmful substitute for entactogenic drugs such as MDMA. Since a major route of the normal metabolism of these compounds is scission of the methylenedioxy ring, producing neurotoxic metabolites such as alpha-methyldopamine, it was hoped that the difluoromethylenedioxy bioisostere would show increased metabolic stability and less toxicity.
Difluoro Methylenedioxymethamphetamine Hydrochloride (DFMDMA, DiFMDMA)
This MDMA analogue can be synthesized from legal available precursors, such as 5-bromo-2,2-difluorobenzodioxole the nearest one to the end product.
Difficulty rating: 6/10
Equipment and glassware:
- 1 L round-bottom flask;
- Funnel;
- Vacuum distillation setup;
- Reflux condenser;
- Vacuum pump;
- Buchner flask and funnel;
- Laboratory grade thermometer (20 °C to 200 °C) with flask adapter;
- Magnetic stirrer with a heating plate;
- Retort stand and clamp for securing apparatus;
- Laboratory scale (0.1 g-1 kg is suitable);
- HCl gas generator (optional);
- Separation funnel 1 L x2 (+ 0.5 L optional);
- Crystallizing dish;
- Beakers 1 L x2; 500 ml x4; 100 ml x3;
- Measuring cylinder 100 ml and 20 ml;
- Plastic or glass syringe 10 ml;
- Cotton or filtr paper;
- Dimethyl sulfoxide (DMSO) 310 ml;
- 5-Bromo-2,2-difluorobenzodioxole (1) [CAS 33070-32-5] 25 g;
- Acetylacetone 31.7 g;
- Potassium phosphate trihydrate (H3PO4 • 3H2O) 84.3g;
- Copper(1) iodide 6 g;
- Nitrogen balloon 10 L;
- Hydrobromic acid 210 ml 2M (16% HBr);
- Ethyl acetate (EtOAc; EA) 320 ml;
- Sodium sulphate Na2SO4;
- Distilled water;
- Sodium metabisulfite (Na2S2O5)
- Ethanol (EtOH);
- DCM ~185 ml;
- Sodium hydroxide NaOH;
- Methanol (MeOH) 50 ml;
- Methylamine 40% aq (it’s better to use alcohol solution) solution 14.2 ml;
- Sodium borohydride 1.43 g;
- Hydrochloric acid 6M (HCl ~20 %);
- Diethyl ether (Et2O) ~30-40 ml;
- HCl 1,4-dioxane solution or HCl gas generator;
Procedures:
1-(2,2-difluorobenzo[1,3]dioxol-5-yl)propan-2-one (2) Synthesis
1. Dimethyl sulfoxide (DMSO) 250 ml is placed into 1 L round-bottom flask following by 5-bromo-2,2-difluorobenzodioxole (1) 25 g, acetylacetone 31.7 g, potassium phosphate trihydrate (H3PO4 • 3H2O) 84.3g, and copper(1) iodide 6 g, which turns mixture green, blue and finally very dark purplish color. After all, dimethyl sulfoxide (DMSO) 60 ml is used to wash off the leftovers.
2. Nitrogen balloon is attached to an end hole of the reflux condenser to avoid a catalyst oxidation.
3. The mixture is stirred at 110℃ for 16 hours.
4. Hydrobromic acid 210 ml 2M (16% HBr) is added after 16h. The flask is shaken in order to loosen the solids formed during the reaction.
5. Ethyl acetate (EtOAc; EA) is added ~150-200 ml for an extraction of the product, the solution is filtred on a Buchner flask and funnel and filtered precipitate is additionally washed with portion of methyl acetate (or ethyl acetate).
6. The extract is separated in the separation funnel 1 L from water. An addition portion of cold fresh water is added in the funnel in order to wash it from precipitates. The solution turned milky color.
7. More EA is added; layers are separated. Extracts are combined.
8. Na2SO4 is added to remove water remainings. After, dessicant is removed by filtration into distillation flask.
9. Extract is vacuum distilled to remove solvents. As the result, the flask contained a mixture of the product with DMSO and side products.
10. The mixture is purified via bisulfite adduct to get only ketone product. Some water is added to an empty round bottom flask (about 70-100 ml) and a bunch of sodium metabisulfite (Na2S2O5) is also poured there and stirred until a complete dissolution.
11. The reaction mixture after distillation is added to the saturated sodium metabisulfite water solution and stirred overnight (~12 h). Ketone adduct is precipitated after 12 h stirring and looks gummy.
12. Some ethanol is added and shaken in order to loosen it all. The mixture is stirred for 1h.
13. About 70 ml DCM is added in order to dissolve impurities but not the product.
14. The mixture is vacuum filtered on a Buchner funnel and washed with addition amount of DCM.
15. To a 1L separating funnel, the products is moved and some water and DCM (as an extraction solvent) are added. Then some amount of NaOH aq solution is added in the mixture to convert the bisulfite adduct to the ketone. The mixture is shaken and mixed well, got it all to react.
16. DCM layer is separated and saved, water layer extracted by two ~35 ml portions of fresh ethyl acetate. Extracts are combined and dried over anhydrous Na2SO4.
17. The dried extract is filtered via cotton into the round-bottom distillation flask. Solvents are distilled off, the product is vacuum distilld as well in a different reciver flask. The yield of target 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)propan-2-one (2) is 6.81 g (30%) as a slightly yellow liquid.
2. Nitrogen balloon is attached to an end hole of the reflux condenser to avoid a catalyst oxidation.
3. The mixture is stirred at 110℃ for 16 hours.
4. Hydrobromic acid 210 ml 2M (16% HBr) is added after 16h. The flask is shaken in order to loosen the solids formed during the reaction.
5. Ethyl acetate (EtOAc; EA) is added ~150-200 ml for an extraction of the product, the solution is filtred on a Buchner flask and funnel and filtered precipitate is additionally washed with portion of methyl acetate (or ethyl acetate).
6. The extract is separated in the separation funnel 1 L from water. An addition portion of cold fresh water is added in the funnel in order to wash it from precipitates. The solution turned milky color.
7. More EA is added; layers are separated. Extracts are combined.
8. Na2SO4 is added to remove water remainings. After, dessicant is removed by filtration into distillation flask.
9. Extract is vacuum distilled to remove solvents. As the result, the flask contained a mixture of the product with DMSO and side products.
10. The mixture is purified via bisulfite adduct to get only ketone product. Some water is added to an empty round bottom flask (about 70-100 ml) and a bunch of sodium metabisulfite (Na2S2O5) is also poured there and stirred until a complete dissolution.
11. The reaction mixture after distillation is added to the saturated sodium metabisulfite water solution and stirred overnight (~12 h). Ketone adduct is precipitated after 12 h stirring and looks gummy.
12. Some ethanol is added and shaken in order to loosen it all. The mixture is stirred for 1h.
13. About 70 ml DCM is added in order to dissolve impurities but not the product.
14. The mixture is vacuum filtered on a Buchner funnel and washed with addition amount of DCM.
15. To a 1L separating funnel, the products is moved and some water and DCM (as an extraction solvent) are added. Then some amount of NaOH aq solution is added in the mixture to convert the bisulfite adduct to the ketone. The mixture is shaken and mixed well, got it all to react.
16. DCM layer is separated and saved, water layer extracted by two ~35 ml portions of fresh ethyl acetate. Extracts are combined and dried over anhydrous Na2SO4.
17. The dried extract is filtered via cotton into the round-bottom distillation flask. Solvents are distilled off, the product is vacuum distilld as well in a different reciver flask. The yield of target 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)propan-2-one (2) is 6.81 g (30%) as a slightly yellow liquid.
Difluoromethylenedioxymethamphetamine (DFMDMA, DiFMDMA) Hydrochloride Synthesis
19. A small round-bottom flask immersed in ice water bath filled with 50 ml of methanol (MeOH) and 6.8 g of the cold last reaction ketone product (2). Methylamine 40% aq (better to use alcohol solution of methylamine) solution 14.2 ml is also added in the flask.
20. Reaction mixture is stirred for 30 min.
21. Sodium borohydride 1.43 g is added into the flask. The reaction is stirred for 2 h.
22. The flask is connected to a distillation apparatus and solvent is vacuum distilled off.
23. After complete solvent removal, hydrochloric acid 6M (HCl ~20 %) is added to slightly acidic pH 6.
24. A bunch of DCM (about 20 ml) is added into the flask, 20 ml water is also added there.
25. The mixture is moved and separated in the separating funnel. DCM is drained and disposed of. Water layer is extracted with two additional portions of 10 ml DCM.
26. Water layer is basified with 6M 24% NaOH aq solution to pH 14 in order to make free base of amine.
27. The free base is extracted from the mixture by DCM 3 x 15 ml.
28. The combined extract is dried over anhydrous Na2SO4 and filtered into a vacuum distillation flask.
29. DCM is distilled off to get yellow oily product.
30. The product is dissolved in diethyl ether (about 7-10 ml).
31. The mixture is filtered through a cotton filter into a crystallizing dish. The mixture is rinsed from the flask by addition portion of ether (~5 ml).
32. HCl 1,4-dioxane solution is added to make neutral pH. HCl gas bubbling is also suitable for this acidification process. White precipitate is formed.
33. Some ether is added and the precipitate is vacuum filtered with yield 1.68 g (25%) of (3) 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)-N-methylpropan-2-amine hydrochloride or difluoromethylenedioxymethamphetamine (DFMDMA, DiFMDMA) hydrochloride.
20. Reaction mixture is stirred for 30 min.
21. Sodium borohydride 1.43 g is added into the flask. The reaction is stirred for 2 h.
22. The flask is connected to a distillation apparatus and solvent is vacuum distilled off.
23. After complete solvent removal, hydrochloric acid 6M (HCl ~20 %) is added to slightly acidic pH 6.
24. A bunch of DCM (about 20 ml) is added into the flask, 20 ml water is also added there.
25. The mixture is moved and separated in the separating funnel. DCM is drained and disposed of. Water layer is extracted with two additional portions of 10 ml DCM.
26. Water layer is basified with 6M 24% NaOH aq solution to pH 14 in order to make free base of amine.
27. The free base is extracted from the mixture by DCM 3 x 15 ml.
28. The combined extract is dried over anhydrous Na2SO4 and filtered into a vacuum distillation flask.
29. DCM is distilled off to get yellow oily product.
30. The product is dissolved in diethyl ether (about 7-10 ml).
31. The mixture is filtered through a cotton filter into a crystallizing dish. The mixture is rinsed from the flask by addition portion of ether (~5 ml).
32. HCl 1,4-dioxane solution is added to make neutral pH. HCl gas bubbling is also suitable for this acidification process. White precipitate is formed.
33. Some ether is added and the precipitate is vacuum filtered with yield 1.68 g (25%) of (3) 1-(2,2-difluorobenzo[1,3]dioxol-5-yl)-N-methylpropan-2-amine hydrochloride or difluoromethylenedioxymethamphetamine (DFMDMA, DiFMDMA) hydrochloride.
Sources
- Chemiolis, Making Fluorinated Empathogens (RC, Designer)
- Trachsel, Daniel, Marcel Hadorn, and Franz Baumberger. "Synthesis of fluoro analogues of 3, 4‐(methylenedioxy) amphetamine (MDA) and its derivatives." Chemistry & biodiversity 3.3 (2006): 326-336. https://onlinelibrary.wiley.com/doi/10.1002/cbdv.200690035
- He, Chuan, et al. "Copper catalyzed arylation/C− C bond activation: an approach toward α-aryl ketones." Journal of the American Chemical Society 132.24 (2010): 8273-8275. https://pubs.acs.org/doi/10.1021/ja1033777
