SYNTHESIS: (from piperonal) To a solution of 15.0 g piperonal in 80 mL glacial acetic acid there was added 15 mL nitroethane followed by 10 g cyclohexylamine. The mixture was held at steam-bath temperature for 6 h, diluted with 10 mL H2O, seeded with a crystal of product, and cooled overnight at 10 °C. The bright yellow crystals were removed by filtration, and air dried to yield 10.7 g of 1-(3,4-methylenedioxyphenyl)-2-nitropropene with a mp of 93-94 °C. This was raised to 97-98 °C by recrystallization from acetic acid. The more conventional efforts of nitrostyrene synthesis using an excess of nitroethane as a solvent and anhydrous ammonium acetate as the base, gives impure product in very poor yields. The nitrostyrene has been successfully made from the components in cold MeOH, with aqueous NaOH as the base.
A suspension of 20 g LAH in 250 mL anhydrous THF was placed under an inert atmosphere and stirred magnetically. There was added, dropwise, 18 g of 1-(3,4-methylenedioxyphenyl)-2-nitropropene in solution in THF and the reaction mixture was maintained at reflux for 36 h. After being brought back to room temperature, the excess hydride was destroyed with 15 mL IPA, followed by 15 mL of 15% NaOH. An additional 50 mL H2O was added to complete the conversion of the aluminum salts to a loose, white, easily filtered solid. This was removed by filtration, and the filter cake washed with additional THF. The combined filtrate and washes were stripped of solvent under vacuum, and the residue dissolved in dilute H2SO4. Washing with 3x75 mL CH2Cl2 removed much of the color, and the aqueous phase was made basic and reextracted with 3x100 mL CH2Cl2. Removal of the solvent yielded 13.0 g of a yellow-colored oil that was distilled. The fraction boiling at 80-90 °C at 0.2 mm weighed 10.2 g and was water-white. It was dissolved in 60 mL of IPA, neutralization with concentrated HCl, and diluted with 120 mL of anhydrous Et2O which produced a lasting turbidity. Crystals formed spontaneously which were removed by filtration, washed with Et2O, and air dried to provide 10.4 g of 3,4-methylenedioxyamphetamine hydrochloride (MDA) with a mp of 187-188 °C.
(from 3,4-methylenedioxyphenylacetone) To a solution of 32.5 g anhydrous ammonium acetate in 120 mL MeOH, there was added 7.12 g 3,4-methylenedioxyphenylacetone (see under MDMA for its preparation) followed by 2.0 g sodium cyanoborohydride. The resulting yellow solution was vigorously stirred, and concentrated HCl was added periodically to keep the pH of the reaction mixture between 6 and 7 as determined by external damp universal pH paper. After several days, undissolved solids remained in the reaction mixture and no more acid was required. The reaction mixture was added to 600 mL of dilute HCl, and this was washed with 3x100 mL CH2Cl2. The combined washes were back-extracted with a small amount of dilute HCl, the aqueous phases combined, and made basic with 25% NaOH. This was then extracted with 3x100 mL CH2Cl2, these extracts combined, and the solvent removed under vacuum to provide 3.8 g of a red-colored residue. This was distilled at 80-90 °C at 0.2 mm/Hg to provide 2.2 g of an absolutely water-white oil. There was no obvious formation of a carbonate salt when exposed to air. This was dissolved in 15 mL IPA, neutralized with 25 drops of concentrated HCl, and diluted with 30 mL anhydrous Et2O. Slowly there was the deposition of white crystals of 3,4-methylenedioxyamphetamine hydrochloride (MDA) which weighed 2.2 g and had a mp of 187-188 °C. The preparation of the formamide (a precursor to MDMA) and the acetamide (a precursor to MDE) are described under those entries.
daarna: (from MDA) A solution of 6.55 g of 3,4-methylenedioxyamphetamine (MDA) as the free base and 2.8 mL formic acid in 150 mL benzene was held at reflux under a Dean Stark trap until no further H2O was generated (about 20 h was sufficient, and 1.4 mL H2O was collected). Removal of the solvent gave an 8.8 g of an amber oil which was dissolved in 100 mL CH2Cl2, washed first with dilute HCl, then with dilute NaOH, and finally once again with dilute acid. The solvent was removed under vacuum giving 7.7 g of an amber oil that, on standing, formed crystals of N-formyl-3,4-methylenedioxyamphetamine. An alternate process for the synthesis of this amide involved holding at reflux for 16 h a solution of 10 g of MDA as the free base in 20 mL fresh ethyl formate. Removal of the volatiles yielded an oil that set up to white crystals, weighing 7.8 g.
A solution of 7.7 g N-formyl-3,4-methylenedioxyamphetamine in 25 mL anhydrous THF was added dropwise to a well stirred and refluxing solution of 7.4 g LAH in 600 mL anhydrous THF under an inert atmosphere. The reaction mixture was held at reflux for 4 days. After being brought to room temperature, the excess hydride was destroyed with 7.4 mL H2O in an equal volume of THF, followed by 7.4 mL of 15% NaOH and then another 22 mL H2O. The solids were removed by filtration, and the filter cake washed with additional THF. The combined filtrate and washes were stripped of solvent under vacuum, and the residue dissolved in 200 mL CH2Cl2. This solution was extracted with 3x100 mL dilute HCl, and these extracts pooled and made basic with 25% NaOH. Extraction with 3x75 mL CH2Cl2 removed the product, and the pooled extracts were stripped of solvent under vacuum. There was obtained 6.5 g of a nearly white residue which was distilled at 100-110 ° C at 0.4 mm/Hg to give 5.0 g of a colorless oil. This was dissolved in 25 mL IPA, neutralized with concentrated HCl, followed by the addition of sufficient anhydrous Et2O to produce a lasting turbidity. On continued stirring, there was the deposition of fine white crystals of 3,4-methylenedioxy-N-methylamphetamine hydrochloride (MDMA) which were removed by filtration, washed with Et2O, and air dried, giving a final weight of 4.8 g.
(from 3,4-methylenedioxyphenylacetone) This key intermediate to all of the MD-series can be made from either isosafrole, or from piperonal via 1-(3,4-methylenedioxyphenyl)-2-nitropropene. To a well stirred solution of 34 g of 30% hydrogen peroxide in 150 g 80% formic acid there was added, dropwise, a solution of 32.4 g isosafrole in 120 mL acetone at a rate that kept the reaction mixture from exceeding 40 ° C. This required a bit over 1 h, and external cooling was used as necessary. Stirring was continued for 16 h, and care was taken that the slow exothermic reaction did not cause excess heating. An external bath with running water worked well. During this time the solution progressed from an orange color to a deep red. All volatile components were removed under vacuum which yielded some 60 g of a very deep red residue. This was dissolved in 60 mL of MeOH, treated with 360 mL of 15% H2SO4, and heated for 3 h on the steam bath. After cooling, the reaction mixture was extracted with 3x75 mL Et2O, the pooled extracts washed first with H2O and then with dilute NaOH, and the solvent removed under vacuum The residue was distilled (at 2.0 mm/108-112 ° C, or at about 160 ° C at the water pump) to provide 20.6 g of 3,4-methylenedioxyphenylacetone as a pale yellow oil. The oxime (from hydroxylamine) had a mp of 85-88 ° C. The semicarbazone had a mp of 162-163 ° C.
An alternate synthesis of 3,4-methylenedioxyphenylacetone starts originally from piperonal. A suspension of 32 g electrolytic iron in 140 mL glacial acetic acid was gradually warmed on the steam bath. When quite hot but not yet with any white salts apparent, there was added, a bit at a time, a solution of 10.0 g of 1-(3,4-methylenedioxyphenyl)-2-nitropropene in 75 mL acetic acid (see the synthesis of MDA for the preparation of this nitrostyrene intermediate from piperonal and nitroethane). This addition was conducted at a rate that permitted a vigorous reaction free from excessive frothing. The orange color of the reaction mixture became very reddish with the formation of white salts and a dark crust. After the addition was complete, the heating was continued for an additional 1.5 h during which time the body of the reaction mixture became quite white with the product appeared as a black oil climbing the sides of the beaker. This mixture was added to 2 L H2O, extracted with 3x100 mL CH2Cl2, and the pooled extracts washed with several portions of dilute NaOH. After the removal of the solvent under vacuum, the residue was distilled at reduced pressure (see above) to provide 8.0 g of 3,4-methylenedioxyphenylacetone as a pale yellow oil.
To 40 g of thin aluminum foil cut in 1 inch squares (in a 2 L wide mouth Erlenmeyer flask) there was added 1400 mL H2O containing 1 g mercuric chloride. Amalgamation was allowed to proceed until there was the evolution of fine bubbles, the formation of a light grey precipitate, and the appearance of occasional silvery spots on the surface of the aluminum. This takes between 15 and 30 min depending on the freshness of the surfaces, the temperature of the H2O, and the thickness of the aluminum foil. (Aluminum foil thickness varies from country to country.) The H2O was removed by decantation, and the aluminum was washed with 2x1400 mL of fresh H2O. The residual H2O from the final washing was removed as thoroughly as possible by shaking, and there was added, in succession and with swirling, 60 g methylamine hydrochloride dissolved in 60 mL warm H2O, 180 mL IPA, 145 mL 25% NaOH, 53 g 3,4-methylenedioxyphenylacetone, and finally 350 mL IPA. If the available form of methylamine is the aqueous solution of the free base, the following sequence can be substituted: add, in succession, 76 mL 40% aqueous methylamine, 180 mL IPA, a suspension of 50 g NaCl in 140 mL H2O that contains 25 mL 25% NaOH, 53 g 3,4-methylenedioxyphenylacetone, and finally 350 mL IPA. The exothermic reaction was kept below 60 ° C with occasional immersion into cold water and, when it was thermally stable, it was allowed to stand until it had returned to room temperature with all the insolubles settled to the bottom as a grey sludge. The clear yellow overhead was decanted and the sludge removed by filtration and washed with MeOH. The combined decantation, mother liquors and washes, were stripped of solvent under vacuum, the residue suspended in 2400 ml of H2O, and sufficient HCl added to make the phase distinctly acidic. This was then washed with 3x75 mL CH2Cl2, made basic with 25% NaOH, and extracted with 3x100 mL of CH2Cl2. After removal of the solvent from the combined extracts, there remained 55 g of an amber oil which was distilled at 100-110 ° C at 0.4 mm/Hg producing 41 g of an off-white liquid. This was dissolved in 200 mL IPA, neutralized with about 17 mL of concentrated HCl, and then treated with 400 mL anhydrous Et2O. After filtering off the white crystals, washing with an IPA/Et2O mixture, (2:1), with Et2O, and final air drying, there was obtained 42.0 g of 3,4-methylenedioxy-N-methylamphetamine (MDMA) as a fine white crystal. The actual form that the final salt takes depends upon the temperature and concentration at the moment of the initial crystallization. It can be anhydrous, or it can be any of several hydrated forms. Only the anhydrous form has a sharp mp; the published reports describe all possible one degree melting point values over the range from 148-153 ° C. The variously hydrated polymorphs have distinct infrared spectra, but have broad mps that depend on the rate of heating.
To a well stirred, cooled mixture of 34g of 30% H202 (hydrogen peroxide) in 150g 80% HCO2H (formic acid) there was added, dropwise, a solution of 32.4g isosafrole in 120ml acetone at a rate that kept the reaction mixture from exceeding 40 deg C. This required a bit over 1 hour, and external cooling was used as necessary. Stirring was continued for 16 hours, and care was taken that the slow exothermic reaction did not cause excess heating. An external bath with running water worked well. During this time the solution progressed from an orange color to a deep red. All volatile components were removed under vacuum which yielded some 60g of a very deep residue. This was dissolved in 60ml of MeOH (methyl alcohol -- methanol), treated with 360ml of 15% H2SO4 (sulfuric acid), and heated for 3 hours on the steam bath. After cooling the mixture was extracted with 3x75ml Et2O (diethyl ether) or C6H6 (benzene). Its recommended that, the pooled extracts can washed -- first with H2O and then with dilute NaOH (sodium hydroxide). Then the solvent is removed under vacuum to afford 20.6g 3,4-methylenedioxyphenylacetone (3,4-methylenedioxybenzyl methyl ketone). The final residue may be distilled at 2.0mm/108-112 deg C, or at about 160 deg C at the water pump.
Add 23g 3,4-methylenedioxyphenylacetone to 65g HCONH2 (formamide) and heat at 190 deg for five hours. Cool, add 100ml H20, extract with C6H6 (benzene) and evaporate in vacuum the extract. Add 8ml MeOH (methyl alcohol -- methanol) and 75ml 15% HCl to residue, heat on water bath two hours and extract in vacuum (or basify with KOH and extract the oil with benzene and dry, evaporate in vacuum) to get 11.7 g 3,4-methylenedioxyamphetamine (MDA).
To produce MDMA substitute N-methylformamide for formamide in the above synthesis.
This is a less yealding method usually producing only MDA. It is a two step procedure first reacting safrole with hydrobromic acid to give 3,4-methylenedi- oxyphenyl-2-bromopropane, and then taking this material and reacting it with either ammonia or methylamine to yield MDA or MDMA respectively. This procedure has the advantages of not being at all sensitive to batch size, nor is it likely to "run away" and produce a tarry mess. It shares with the Ritter reaction the advantage of using cheap, simple, and easily available chemicals.
The sole disadvantage of this method is the need to do the final reaction with ammonia or methylamine inside a sealed pipe. This is because the reaction must be done in the temperature range of 120- 140 C, and the only way to reach this temperature is to seal the reactants up inside of a bomb. This is not particularly dangerous, and is quite safe if some simple precautions are taken.
The first stage of the conversion, the reaction with hydrobromic acid, is quite simple, and produces almost a 100% yield of the bromi- nated product. See the Journal of Biological Chemistry, Volume 108 page 619. The author is H.E. Carter. Also see Chemical Abstracts 1961, column 14350. The following reaction takes place:
To do the reaction, 200 ml of glacial acetic acid is poured into a champagne bottle nestled in ice. Once the acetic acid has cooled down, 300 grams (200 ml) of 48% hydrobromic acid is slowly added with swirling. Once this mixture has cooled down, 100 grarns of safrole is slowly added with swirling. Once the safrole is added, the cheap plastic stopper of the champagne bottle is wired back into place, and the mixture is slowly allowed to come to room temperature with occasional shaking. After about 12 hours the original two layers will merge into a clear red solution. In 24 hours, the reaction is done. The chemist carefully removes the stopper from the bottle, wearing eye protection. Some acid mist may escape from around the stopper.
The reaction mixture is now poured onto about 500 grams of crushed ice in a 1000 or 2000 ml beaker. Once the ice has melted, the red layer of product is separated, and the water is extracted with about l00 ml of petroleum ether or regular ethyl ether. The ether extract is added to the product, and the combined product is washed first with water, and then with a solution of sodium carbonate in water. The purpose of these washings is to remove HBr from the product. One can be sure that all the acid is removed from the product when some fresh carbonate solution does not fizz in contact with the product.
Once all the acid in the product is removed, the ether must be removed from it. This is important because if the ether were allowed to remain in it, too much pressure would be generated in the next stage inside of the bomb. Also, it would interfere with the formation of a solution between the product and methylamine or ammonia. It is not necessary to distill the product because with a yield of over 90%, the crude product is pure enough to feed into the next stage. To remove the ether from the product, the crude product is poured into a flask, and a vacuum is applied to it. This causes the ether to boil off. Some gentle heating with hot water is quite helpful to this process. The yield of crude product is in the neighborhood of 200 grams.
With the bromo compound in hand, it is time to move onto the next step which gives MDA or MDMA. The bromo compound reacts with ammonia or methylamine to give MDA or MDMA.
To do the reaction, 50 grams of the bromo compound is poured into a beaker, and 200 ml of concentrated ammonium hydroxide (28% NH3) or 40% methylamine is added. Next, isopropyl alcohol is added with stirring until a nice smooth solution is formed. It is not good to add too much alcohol because a more dilute solution reacts slower. Now the mixture is poured into a pipe "bomb." This pipe should be made of stainless steel, and have fine threads on both ends. Stainless steel is preferred because the HBr given off in the reaction will rust regular steel. Both ends of the pipe are securely tightened down. The bottom may even be welded into place. Then the pipe is placed into cooking oil heated to around 130 C. This temperature is maintained for about 3 hours or so, then it is allowed to cool. Once the pipe is merely warm, it is cooled down some more in ice, and the cap unscrewed.
The reaction mixture is poured into a distilling flask, the glass- ware rigged for simple distillation, and the isopropyl alcohol and excess ammonia or methylamine is distilled off. When this is done, the residue inside the flask is made acid with hydrochloric acid. If indicating pH paper is available, a pH of about 3 should be aimed for. This converts the MDA to the hydrochloride which is water soluble. Good strong shaking of the mixture ensures that this conversion is complete. The first stage of the purification is to recover unreacted bromo compound. To do this, 200 to 300 ml of ether is added. After some shaking, the ether layer is separated. It contains close to 20 grams of bromo compound which may be used again in later batches.
Now the acid solution containing the MDA is made strongly basic with lye solution. The mixture is shaken for a few minutes to ensure that the MDA is converted to the free base. Upon sitting for a few minutes, the MDA floats on top of the water as a dark colored oily layer. This layer is separated and placed into a distilling flask. Next, the water layer is extracted with some toluene to get out the remaining MDA free base. The toluene is combined with the free base layer, and the toluene is distilled off. Then a vacuum is applied, and the mixture is fractionally distilled. A good aspirator with cold water will bring the MDA off at a temperature of 150 to 160 C. The free base should be clear to pale yellow, and give a yield of about 20 ml. This free base is made into the crystalline hydrochloride by dissolving it in ether and bubbling dry HCl gas through it.
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