DMT may bee synthesized by dozens of methods
1 but the the N,N-dimethylation of tryptamine with HCHO
2 is still a very interesting method as all compounds are either commercial available or can be prepared with OTC methods. The reduction agent of choice is Na[BH
3CN] (sodium cyanoborohydride) but this reagent is toxic and therefore quite difficult to purchase for many bees and about 5 times more expensive than NaBH
4 (sodium borohydride).
As the first step of the methylation is the formation of an imine between formaldehyde and tryptamine it is essential that this intermediate is reduced as soon as possible, otherwise it will form a form cyclization product in the so-called Pictet-Spengler reaction. Essential for the formation of the Pictet-Spengler product is the pH of the reaction, usually the Pictet-Spengler is carried in a acidic medium, either by using the hydrochloride salt of the tryptamine, by addition of lewis acids or protic acids
3. Another important reaction condition is the temperature. The Pictet-Spengler product is favored by heating, the dimethylation is carried at room temperature or below. Also two competing reductions take place in this reaction, on the one hand the wanted reduction of the imine and on the other hand the reduction of formaldehyde to methanol, therefore first the imine has to bee formed which has to bee reduced immediately, this is why usually the the reagents are added alternately.
This parameter (not the temperature but the pH) seems to bee neglected when this reaction is discussed. This might explain the poor yields obtained when trying this method
4.
As many N,N-dimethylated tryptamines are important pharmaceutical drugs for the treatment of migraine (the so-called triptanes) it was interesting to see how they are synthesized. Sumatriptan for example is synthesized on a industrial scale by the dimethylation of a 5-substituted tryptamine with HCHO/NaBH
4. Lego had the possibility to talk to a person who is quite experienced in the field of indoles and harmalines and it became clear that the main product depends on carefully selecting the right reaction conditions.
Here are some examples, either from the patent literature or from the scientific literature, in order to show that this method is still worth trying it.
Patent WO0134561
More preferably the reducing agent is present in the range of 0.75-3 molar equivalents with respect to the compound of formula V [
tryptamine derivative].
[...]
Most preferably the formaldehyde equivalent is formaldehyde as an aqeuous solution.
[...]
More preferably the formaldehyde equivalent is present in the range of 1.9-5 molar equivalents with respect to the compound of formula V [
tryptamine derivative].
Suitably the buffer used keeps the pH of the reaction solution between pH 6 and pH 14. Preferably the buffer keeps the pH of the reaction solution between pH 7 and pH 11. More preferably the buffer keeps the pH of the raction between pH 8 and pH 10. Most preferably the buffer is sodium hydrogenphosphate.
Suitably the buffer is present in the range of 0.1-10 molar equivalents with respect to the compound of formula V [
tryptamine derivative]. Preferably the buffer is present in the range of 0.2-5 molar equivalents with respect to the compound of formula V [
tryptamine derivative]. Most preferably the buffer is present in the range of 0.5-3 molar equivalents with respect to the compound of formula V
[
tryptamine derivative].
[...]
Example 53-(2-aminoethyl)-N-1H-indole-5-methanesulphoneamide (5.0 g, 18.7 mmol), prepared by the method of Example 1, and sodium hydrogenphosphate (5.0 g, 35.2 mmol) were heated to 40°C in methanol (50 ml) for 15 minutes and then recooled to room temperature. Solutions of 37% aqueous formaldehyde (5 ml) and sodium borohydride (0.72 g) in water (5 ml stabilised with one drop of 46/48% w/w sodium hydroxide) were added simultaneously over one hour at a room temperature between 17 and 21°C. The mixture was stirred at room temperature for a further 0.5 hours, then filtered and the filter bed wasehd with methanol (10 ml). The combined filtrates were then adjusted to pH 6 by addition of 4M hydrochloric acid, concentrated under reduced pressure (to approximately 20 g) and acidified to pH with more 4M hydrochlorid acid. Ethyl acetate (30 ml) was added and the potassium carbonate was added to give a pH about 11 and the product extracted in a seperating funnel. The aqueous layer was further extracted with ethyl acetate (30 ml) and the combined organic layers dried over sodium sulphate, filtered and concentrated to give sumatriptan free base (4.7 g, 85%, HPLC showed 87% compound).
This material was of suitable quality for conversion into sumatriptan mono-succinate or sumatriptan hemisulphate as described in
Patent GB2162522
and
Patent EP490689
respectively.
[...]
Similiar reaction
without buffering the reaction:
Synthesis of carbon-14 labelled indolic 5HT1 receptor agonistsIan Waterhouse, Karl M. Cable, Ian Fellows, Mark D. Wipperman, Derek R. SutherlandJ. Labelled Compd. Radiopharm., 1996, 38(11), 1021-1030![](https://www.thevespiary.org/rhodium/Rhodium/hive/hiveboard/picproxie_imgs/djvu.gif)
The solid [
1.674 mmol of C-14-labeled sumatriptane freebase, 10b] was dissolved in methanol (25 ml) at 0°. Solutions of sodium borohydride (284 mg, 7.5 mmol) in water (1.7 ml) and of formaldehyde (37% aqueous solution, 2.20 ml, 27 mmol) in methanol (1.93 ml) were prepared. An aliquot (180 µl) of the sodium borohydride solution was added to the solution of
10b in methanol every 4 min, followed each time by an aliquot (410 µl) of the formaldehyde solution. When the additions were complete the reaction was stirred at <5° for 1 h. Sodium borohydride (30 mg, 0.79 mmol) and then 5N hydrochloric acid (3.2 ml) were added and the mixture stirred for 5 min then concentrated under reduced pressure to a volume of 10 ml. Water (45 ml) and 2N hydrochlorid acid (25 ml) were then added and the solution stirred for a a further 10 min. The solution was saturated with solid potassium carbonate and the product extracted into methyl isobutyl ketone (4 x 60 ml). The methyl isobutyl ketone solution was decolourised with charcoal and evaporated under reduced pressure to a volume of 5 ml, cooled to 0° and ether (10 ml) was added. After storing at 0° for 30 min, the resulting solid was recovered by filtration and crystallised from isopropanol-water to give sumatriptan free base (172 mg, 35%).
References1. See for example:
Classical synthesis by reaction of oxalyl chloride on indole, dialkylamide formation and reduction with LAH:
https://www.thevespiary.org/rhodium/Rhodium/chemistry/dmt.det.html
By Fischer indol synthesis:
https://www.thevespiary.org/rhodium/Rhodium/chemistry/dmten.html
By alkylation of indole grignards with 2-(dimethylamino)-ethyl chloride:
https://www.thevespiary.org/rhodium/Rhodium/chemistry/dmt.indole.grignard.html
2.
Post 431982
(Lego: "Article on DMT derivate synths", Tryptamine Chemistry)3. See for example
Post 419132
(pashov: "Different reducing agents", Newbee Forum) and
Post 431982
(Lego: "Article on DMT derivate synths", Tryptamine Chemistry) for a practical example
4.
Post 442894
(BadMad: "Standart method & some troubles", Tryptamine Chemistry)