Introduction.
Everybody whoever tried knows that synthesizing tryptamines is a real pain and needs lots of know-how and experience. Mostly, DMT itself is notorious for being very tough to obtain in pure form. The classical oxalylchloride route is only for skillful chemists. The final reduction step needs to be so drastic that the final product is extremely hard to purify. You should have a sublimation apparatus at hand for purification.
It is the reason why I looked into alternative methods, and re-found the old route by Fish starting from indoleacetic acid (IAA). IAA is used in agriculture/horticulture as a plant grow hormone, which would make it an affordable and obtainable precursor. It can be bought in chemical market without problems or synthesize for large-scale production.
In the first step, the ether is converted to the amine. This stage works well in 40% aqueous solution of dimethylamine, using 0.5-1% conc. H2SO4 as a catalyst. The reaction takes place at room temperature, but is slow, allow 48h for completion. It is easily monitored by TLC, using ethylacetate with a hint of MeOH or something polar like this. After completion an acid base extraction is necessary to remove the catalyst, and the crude product is evaporated to give a reddish thick oil. This can be recrystallized from ethyl acetate. Yield is approximately 50% from this crystallization. Amide breaks down while crystallizing. This is evident by TLC, two spots appears, one above and one below the amide, none of them is the starting material (IAA). When too much junk is in the solution, no crystallization occurs anymore. This is strange, cause the raw- product of the substitution is quite pure. But not pure enough to reduce it directly in the next step, recrystallization is essential.
Other strange things: IAA has been totally inert towards dipropylamine under otherwise identical conditions. The junky mother liquor can be chromatographed to obtain pure amide, again. Trying to crystallize this stuff again leads to the same 50% yield in solid material.
The reduction of this amide is performed with LiAlH4, or better with NaAlH4. I know the sodium stuff is much less common, and available usually only in tech (90% pure) grade, but the workup is much easier, as it aggregates much better during workup. As with all hydride reductions, an overhead mechanical stirrer is very much preferred over a magnetic stirrer. It just works better. The organic solution can easily be decanted. Reduction is performed in THF during 4 hours (or diethyl ether). Use no more than 1.5 ml water per gram of used hydride to hydrolize the cooled solution. The decanted or filtered solution is remarkable colorless (but only if you listened earlier and used only crystalline amide in the reduction step.) It is important that the next steps are performed fast. Not in a hurry, not with haste, but fast. If you used THF, add enough ether to get a good separation of phases, and do an acid base extraction so that you end up with the base (tryptamine) in an ether solution. During the extraction, the solution will turn more and more reddish (it is not so good). When you find a method to avoid this, please let me know. After evaporation, the crude tryptamine is dissolved in boiling hexane (cyclohexane would be better).
This is very difficult, and after a while you may add ethylacetate dropwise to get all in solution, but not too much. It must be around 30 ml hexane per gram of tryptamine. Keep it boiling! On cooling down, usually an oil will separate. This is ok, as this oil is deeply colored, leaving a much less colored solution. After a while decant from the oil, which either collects at the bottom or sticks to the walls, in to a clean flask. This flask is cold, so a lot more oils out, reheat to reflux until all is in solution, and clean the first flask while the second cools down. Decant from oils again. Repeat as often as you feel it is needed. One can end up with a perfectly clear solution this way, and be careful with the ethylacetate. Not too much. If the solution is clean enough, seed it with a crystal and set it in the freezer. Without a seed, the task is kind of hopeless. If you really don't have one, dissolve the oil you decanted from earlier and let it evaporate in a Petri dish or so. This can yield a semisolid material which may be good enough for seeding, but doesn't match my demands on the final product. If the seed dissolves, the solution you made is a way to dilute, evaporate a bit and try again. With this method, DMT crystals that are only slightly yellowish can be obtained. The real clear stuff is only obtainable by sublimation.
What I offer is no breakthrough, but obviously author spends some time in the purification process. Unfortunately, the material does not survive a column chromatography. It's really important to work quick and to know what you are doing, fooling around with tryptamines is not a good idea, they are unforgiving. Trying to purify a dirty product makes things only worse, and that's why it is important to start with a pretty pure product to begin with. The gentler conditions of reducing a simple amide instead of a glyoxylamide provides a much cleaner crude product.
Perhaps most importantly, IAA is probably available to those that are willing to spend some effort, and the first step is as easy as it gets in organic chemistry. TLC is essential during the whole process to control how things are going.
It is the reason why I looked into alternative methods, and re-found the old route by Fish starting from indoleacetic acid (IAA). IAA is used in agriculture/horticulture as a plant grow hormone, which would make it an affordable and obtainable precursor. It can be bought in chemical market without problems or synthesize for large-scale production.
In the first step, the ether is converted to the amine. This stage works well in 40% aqueous solution of dimethylamine, using 0.5-1% conc. H2SO4 as a catalyst. The reaction takes place at room temperature, but is slow, allow 48h for completion. It is easily monitored by TLC, using ethylacetate with a hint of MeOH or something polar like this. After completion an acid base extraction is necessary to remove the catalyst, and the crude product is evaporated to give a reddish thick oil. This can be recrystallized from ethyl acetate. Yield is approximately 50% from this crystallization. Amide breaks down while crystallizing. This is evident by TLC, two spots appears, one above and one below the amide, none of them is the starting material (IAA). When too much junk is in the solution, no crystallization occurs anymore. This is strange, cause the raw- product of the substitution is quite pure. But not pure enough to reduce it directly in the next step, recrystallization is essential.
Other strange things: IAA has been totally inert towards dipropylamine under otherwise identical conditions. The junky mother liquor can be chromatographed to obtain pure amide, again. Trying to crystallize this stuff again leads to the same 50% yield in solid material.
The reduction of this amide is performed with LiAlH4, or better with NaAlH4. I know the sodium stuff is much less common, and available usually only in tech (90% pure) grade, but the workup is much easier, as it aggregates much better during workup. As with all hydride reductions, an overhead mechanical stirrer is very much preferred over a magnetic stirrer. It just works better. The organic solution can easily be decanted. Reduction is performed in THF during 4 hours (or diethyl ether). Use no more than 1.5 ml water per gram of used hydride to hydrolize the cooled solution. The decanted or filtered solution is remarkable colorless (but only if you listened earlier and used only crystalline amide in the reduction step.) It is important that the next steps are performed fast. Not in a hurry, not with haste, but fast. If you used THF, add enough ether to get a good separation of phases, and do an acid base extraction so that you end up with the base (tryptamine) in an ether solution. During the extraction, the solution will turn more and more reddish (it is not so good). When you find a method to avoid this, please let me know. After evaporation, the crude tryptamine is dissolved in boiling hexane (cyclohexane would be better).
This is very difficult, and after a while you may add ethylacetate dropwise to get all in solution, but not too much. It must be around 30 ml hexane per gram of tryptamine. Keep it boiling! On cooling down, usually an oil will separate. This is ok, as this oil is deeply colored, leaving a much less colored solution. After a while decant from the oil, which either collects at the bottom or sticks to the walls, in to a clean flask. This flask is cold, so a lot more oils out, reheat to reflux until all is in solution, and clean the first flask while the second cools down. Decant from oils again. Repeat as often as you feel it is needed. One can end up with a perfectly clear solution this way, and be careful with the ethylacetate. Not too much. If the solution is clean enough, seed it with a crystal and set it in the freezer. Without a seed, the task is kind of hopeless. If you really don't have one, dissolve the oil you decanted from earlier and let it evaporate in a Petri dish or so. This can yield a semisolid material which may be good enough for seeding, but doesn't match my demands on the final product. If the seed dissolves, the solution you made is a way to dilute, evaporate a bit and try again. With this method, DMT crystals that are only slightly yellowish can be obtained. The real clear stuff is only obtainable by sublimation.
What I offer is no breakthrough, but obviously author spends some time in the purification process. Unfortunately, the material does not survive a column chromatography. It's really important to work quick and to know what you are doing, fooling around with tryptamines is not a good idea, they are unforgiving. Trying to purify a dirty product makes things only worse, and that's why it is important to start with a pretty pure product to begin with. The gentler conditions of reducing a simple amide instead of a glyoxylamide provides a much cleaner crude product.
Perhaps most importantly, IAA is probably available to those that are willing to spend some effort, and the first step is as easy as it gets in organic chemistry. TLC is essential during the whole process to control how things are going.
Equipment and glassware:
- Three naked round bottom flask 200 ml;
- Beaker 100 ml (x2);
- Reflux condenser;
- Magnetic stirrer with heater;
- TLC kit (SiO2/EtOAc/MeOH);
- Rotavap machine with water bath;
- Aspirator;
- Laboratory grade thermometer (-20 °C to 200 °C) with three-necked flask adapter;
- Small conventional funnel (d 10 cm);
- Erlenmeyer flask 200 ml (x2);
- Buchner flask and funnel;
- Laboratory scale (0.1 g-100 g is suitable);
- Evaporation flask, 100 ml;
- Filter paper;
- Retort stand and clamp for securing apparatus;
- Ice bath (0 °C);
- Vacuum desiccator;
- Measuring cylinder for 100 ml and 20 ml.
Reagents:
- 1 g Indole-3-acetic;
- 0.5 l MeOH;
- 100ml EtOAc;
- 10 ml Concentrated H2SO4;
- 50 g CaCO3 (NaHCO3);
- ~5-6 l distilled water to filling rotavap machine bath;
- 20 ml Dimethylamine (DMA) 40% aqueous solution;
- 1 g LiAlH4;
- 50 ml THF (tetrahydrofuran);
- 50 ml DCM (dichloromethane);
- 200 g Anhydrous MgSO4;
Safety note: you have to use chemical glass, gloves, chemical coat and respirator.
Procedure.
Methyl Indole-3-Acetate (1) (IAA).A solution of 1 g (5.3 mmol) of indole-3-acetic acid in 70 ml of MeOH with a few drops of concentrated sulfuric acid (98.3% H2SO4) was heated under reflux for two hours until complete disappearance of the indoleacetic acid, as checked by TLC on alumina plates using ethylacetate (EtOAc), Rf indoleacetic acid (acid) 0.1, Rf Methyl Indole-3-Acetate(1) 0.9. The solution was neutralized with CaCO3 (NaHCO3), filtered and the solvent was evaporated under reduced pressure in a rotavap machine. The crude product was crystallised from methanol to give 0.95 g (5.0 mmol, 95%), melting point (mp) 48-48.5 °C.
2-(3-Indolyl)-N,N-dimethylacetamide (2).
The Indole-3-Acetate(1) was dissolved in 20 ml of dimethylamine (DMA) 40% aqueous solution. It was stirred at 20 °C for 40 hrs, the reaction was tested by TLC [SiO2/EtOAc], Rf 2-(3-Indolyl)-N, N-dimethylacetamide(2) 0.5; Rf Indole-3-Acetate(1) 0.8. The excess of DMA was evaporated at 20 °C under reduced pressure to avoid amide hydrolysis. The product was filtered and purified by sublimation under reduced pressure to give 0.8 g (4 mmol, 80%), mp 119-120 °C.
The Indole-3-Acetate(1) was dissolved in 20 ml of dimethylamine (DMA) 40% aqueous solution. It was stirred at 20 °C for 40 hrs, the reaction was tested by TLC [SiO2/EtOAc], Rf 2-(3-Indolyl)-N, N-dimethylacetamide(2) 0.5; Rf Indole-3-Acetate(1) 0.8. The excess of DMA was evaporated at 20 °C under reduced pressure to avoid amide hydrolysis. The product was filtered and purified by sublimation under reduced pressure to give 0.8 g (4 mmol, 80%), mp 119-120 °C.
N,N-Dimethyltryptamine (3).
To a stirred suspension of LiAlH4 (0.4 g, 10.5 mmol) in dry THF (15 ml), 2-(3-Indolyl)-N, N-dimethylacetamide(2) (0.4 g, 1.98 mmol), which was dissolved in dry dichloromethane (25 ml), was added slowly. The mixture was stirred for 48 hrs at room temperature under nitrogen atmosphere until complete disappearance of the amide(2) was achieved as checked by TLC, silicagel/methanol, Rf DMT(3) 0.2, Rf 2-(3-Indolyl)-N, N-dimethylacetamide(2) 0.8. The mixture was cooled in an ice bath, and treated with several drops of water to decompose the excess of LiAlH4 reagent. The reaction mixture was vacuum filtered with help of a Buchner flask to remove any remaining solids, dried over anhydrous MgSO4 in vacuum desiccator, and solvents removed. The yield was 76% (0.28 g, 1.5 mmol) of a colorless oil which crystallized in the freezer (-20 °C) in one week, mp 44-45 °C (Oxalate, mp 151-151 °C).
To a stirred suspension of LiAlH4 (0.4 g, 10.5 mmol) in dry THF (15 ml), 2-(3-Indolyl)-N, N-dimethylacetamide(2) (0.4 g, 1.98 mmol), which was dissolved in dry dichloromethane (25 ml), was added slowly. The mixture was stirred for 48 hrs at room temperature under nitrogen atmosphere until complete disappearance of the amide(2) was achieved as checked by TLC, silicagel/methanol, Rf DMT(3) 0.2, Rf 2-(3-Indolyl)-N, N-dimethylacetamide(2) 0.8. The mixture was cooled in an ice bath, and treated with several drops of water to decompose the excess of LiAlH4 reagent. The reaction mixture was vacuum filtered with help of a Buchner flask to remove any remaining solids, dried over anhydrous MgSO4 in vacuum desiccator, and solvents removed. The yield was 76% (0.28 g, 1.5 mmol) of a colorless oil which crystallized in the freezer (-20 °C) in one week, mp 44-45 °C (Oxalate, mp 151-151 °C).
Methyl Indole-3-Acetate (1) (IAA) synthesis from Indole.
This step is described to large-scale manufacturing IAA but in the same time you can decrease batch and use smaller equipment. Very important that you have to use metal equipment because glassware will be damaged by alkali in high-temperature and long exposure terms.
Procedure.
Stainless steel, rocking autoclave is charged with 270 g (4.1 moles) of 85% potassium hydroxide and 351 g (3.00 moles) of indole, and then 360 g (3.3 moles) of 70% aqueous glycolic acid is added gradually. If the reactants are added in this order, with the glycolic acid being introduced over a 5–10-minute period, there is no violent heating because the heat of neutralization is used to melt the indole. An equivalent amount of anhydrous glycolic acid may be used, but this offers no special advantage. The autoclave is closed and rocked at 250 °C for about 18 hours. These limits are not critical, but they are probably optimum. Reaction times of 24–30 hours are not particularly detrimental, and high yields of product can be obtained within 12 hours. The temperature can range from 230 °C to 270 °C with but slight effect on the yield of product. The reaction mixture is cooled to below 50 °C, 500 ml. of water is added, and the autoclave is rocked at 100 °C for 30 minutes to dissolve the potassium indole-3-acetate.
Procedure.
Stainless steel, rocking autoclave is charged with 270 g (4.1 moles) of 85% potassium hydroxide and 351 g (3.00 moles) of indole, and then 360 g (3.3 moles) of 70% aqueous glycolic acid is added gradually. If the reactants are added in this order, with the glycolic acid being introduced over a 5–10-minute period, there is no violent heating because the heat of neutralization is used to melt the indole. An equivalent amount of anhydrous glycolic acid may be used, but this offers no special advantage. The autoclave is closed and rocked at 250 °C for about 18 hours. These limits are not critical, but they are probably optimum. Reaction times of 24–30 hours are not particularly detrimental, and high yields of product can be obtained within 12 hours. The temperature can range from 230 °C to 270 °C with but slight effect on the yield of product. The reaction mixture is cooled to below 50 °C, 500 ml. of water is added, and the autoclave is rocked at 100 °C for 30 minutes to dissolve the potassium indole-3-acetate.
The aqueous solution is cooled to 25 °C and removed from the autoclave, the autoclave is rinsed out well with water, and water is added until the total volume of solution is 3 L. The solution is extracted with 500 ml. of ether (this extraction may be omitted. It does, however, remove traces of neutral material and consequently gives a product with greater color stability). The aqueous phase is acidified at 20–30 °C with concentrated hydrochloric acid (HCl aq) and then is cooled to 10 °C.
This operation is most conveniently conducted in a flask equipped with a stirrer. The indole-3-acetic acid that precipitates is collected on a Büchner funnel, washed with copious amounts of cold water, and dried in air or a vacuum desiccator out of direct light. The product dries slowly, and several days in air or 24 hours in a vacuum desiccator is usually required. Considerable coloration will result if this is done in direct light. Drying in a heated oven or removing the water as a benzene azeotrope is not satisfactory because of some decarboxylation to skatole. The product should be stored in a dark bottle away from direct sunlight.; weight 455–490 g. (87–93%); m.p. 163–165 °C.
The indole-3-acetic acid, which is cream-colored, is of high purity. If further purification is desired, it may be done conveniently by recrystallization from water. One liter of water is used for 30 g. of acid, with 10 g. of decolorizing carbon added. Recovery is about 22 g. of a nearly colorless product, m.p. 164–166 °C.
The indole-3-acetic acid, which is cream-colored, is of high purity. If further purification is desired, it may be done conveniently by recrystallization from water. One liter of water is used for 30 g. of acid, with 10 g. of decolorizing carbon added. Recovery is about 22 g. of a nearly colorless product, m.p. 164–166 °C.
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