SYNTHESIS : (from indole) To a well-stirred solution of 1.6 gindole in 30 mL anhydrous Et2O there was added, dropwise over thecourse of 30 min, a solution of 3.8 g (2.6 mL) oxalyl chloride in 30mL anhydrous Et2O. Stirring was continued for an additional 15 minduring which time there was the separation of indol-3-ylglyoxylchloride as a yellow crystalline solid. This intermediate was removedby filtration and washed with Et2O. It was used directly in thefollowing step. This solid acid chloride was added to 3.6 g anhydrousethyl amine in Et2O and stirred until the color had largelyfaded. Then there was added 100 mL of 2 N HCl. The mixture was cooled,and the resulting product N-ethyl-3-ylglyoxamide was removed byfiltration. The air-dried product was obtained in a 67% yield (mp208-210 °C from benzene).
A solution of 1.6 g N-ethyl-3-ylglyoxylamide in 50 mL anhydrous THFwas added, dropwise, to 1.5 g LAH in 50 mL anhydrous THF which waswell-stirred and under an inert atmosphere. This was brought to refluxand held there for 3 h. The reaction mixture was cooled, and theexcess hydride destroyed by the cautious addition of wet THF. A 15%NaOH solution was then added until the solids had a loose whitecottage cheese character to them, and the mobile phase tested basic byexternal damp pH paper. These formed solids were removed byfiltration, washed with first THF and then MeOH. The filtrate andwashings were combined, dried over anhydrous MgSO4, and the solventremoved under vacuum. The residue set up to a crystalline mass. Thiswas converted to the hydrochloride salt (mp 188-190 °C frombenzene/methanol) in a 35% yield.
(from tryptamine) To a well-stirred solution of 16.0 g tryptamine basein 25 g triethylamine, there was added dropwise 11.2 g aceticanhydride. The mixture was heated on the steam bath overnight, thenthe volatiles were removed under vacuum. The residue was dissolved in100 mL CH2Cl2 and washed with 100 mL dilute aqueous HCl. The waterphase was extracted twice with additional CH2Cl2, the organic phaseswere combined, washed with aqueous NaHCO3 solution, and the solventremoved under vacuum. The resulting residue (12.5 g of a dark viscousoil) was distilled at the KugelRohr to give N-acetyltryptamine as aviscous amber oil boiling at 185-200 °C, which set to a fused glassat room temperature. It weighed 9.45 g, for a yield of 47% oftheory. This glass ground under hexane had a mp of 70-73 °C andformed white crystal from toluene, with a mp 73-74 °C. IR(in cm-1)756, 810, 1022, 1073, 1103, C=O at 1640. MS (in m/z): indolemethylene+130 (100%); 143 (86%); parent ion 202 (7%).
A solution of 2.31 g of N-acetyltryptamine in 30 mL anhydrous THF wasadded dropwise to 60 mL of 1 M LAH in THF, held at a reflux underargon. After 12 h reflux, the reaction was returned to roomtemperature and the excess hydride destroyed by the addition of 20 mLof 50% aqueous THF. The mixture was filtered through paper, washedwith 3x25 mL THF, and the combined filtrates and washings stripped ofvolatiles under vacuum. The remaining pale cream-colored oil wasdistilled at 0.1 mm/Hg to give a white oil, bp 125-135 °C, 1.58 gfor a yield of 73%. This free-base product spontaneously crystallizedto a white waxy solid, with a mp of 80-81 °C. IR (in cm-1): 751,887, 940, 1021, 1051, 1118. MS (in m/z): C3H8N+ 58 (100%);indolemethylene+ 131, 130 (48%, 33%); parent ion 188(2%). N-ethyltryptamine base, dissolved in 5x its weight ofisopropanol, acidified with concentrated HCl, and Et2O added dropwise,yields the hydrochloride salt, N-ethyltryptamine hydrochloride or NET,with a melting point of 181-182 °C. IR (in cm-1); 750, 761, 825,1020, 1108, 1142.
NIPT
TRYPTAMINE, N-ISOPROPYL; INDOLE, N ISOPROPYLTRYPTAMINE;3-[2-(ISOPROPYLAMINE)ETHYL]INDOLESYNTHESIS : To a solution of 3.2 g tryptamine base (20 mMol) in 25 mLisopropanol there was added 6.8 g isopropyl iodide and the solutionwas held at reflux for 36 h. All volatiles were removed under vacuum,and the residue suspended in dilute aqueous NaOH and extracted threetimes with 40 mL portions of CH2Cl2. These extracts were pooled and,after removal of the solvent, yielded 2.19 g of a dark oil whichcrystallized on standing. This was distilled at the KugelRohr at130-150 °C at 0.08 mm/Hg to give 1.51 g of a white oil that set toa solid in the receiver. An analytical sample was recrystallized fromisopropanol, and had an mp 94-95 °C. A solution of the free base in10 mL warm isopropanol was treated with concentrated HCl dropwiseuntil the solution was red to external damp pH paper. The spontaneouscrystals that formed were diluted, with stirring, with 20 mL anhydrousEt2O, the resulting curdy crystalline mass removed by filtration,washed with additional Et2O, and air dried to constant weight. Thusthere was obtained 1.58 g N-isopropyltryptamine hydrochloride (NIPT)as fine white crystals, with a mp of 224-227 °C. MS (in m/z):C4H10N+ 72 (100%); indolemethylene+ 131,130 (50%, 35%); parent ion 202(2%). IR (in cm-1): 751, 860, 1024, 1036, 1112.
EXTENSIONS AND COMMENTARY : Why two complete recipes, for twomonoalkyltryptamines which have received only modest human trials butwhich have yet to have any active levels discovered? For several verygood reasons.
Firstly, these two monosubstituted tryptamines are described here areeasily made as pure entities, in acceptable yields.
Secondly, they are prepared here by completely different processes,each of which is amenable to modification to other, potentially usefulmono-substituted tryptamines (NRT'S, where the R is a sizable alkylgroup). There is the oxalylamine route (used here with ethylamine forNET) and the alkyl halide route (used here with isopropyliodide forNIPT but which proved to be rather useless in making NET where themajor product was the quaternary salt). With these two proceduresavailable, there is almost no limit to the potential identity of thatmono-group on the nitrogen atom of tryptamine. Quite a few havealready been made. Let me list some examples.
The normal-propylamine NPT has been made by the oxalylamide route,with the amide with a mp 179-181 °C (75%) from benzene and NPThydrochloride mp 186-187 °C (33%) from MeOH/benzene. An attempt tomake NPT by the alkyl halide procedure failed. Using these same ratiosof reactants, there was the formation of a sizable quantity of DPTwith appreciable unreacted tryptamine presence (T:NPT:DPT/1:5:4). Arecycling under the same conditions gave T:NPT:DPT/0:3:7) and a thirdcycle gave only DPT, but with a loss of almost 90% of the materialpresumably to quaternary salt formation. Interestingly NPT is lesstoxic than DPT in experimental mice, but has not been assayed yet inman.
NBT (N-butyltryptamine) is also an oxalylamide product. The amide witha mp 167-169° C (81%) from benzene and NBT hydrochloride with mp203-205 °C (13%) from benzene/methanol
The two geometric isomers, mono-isobutyl and mono-sec-butyltryptamines are best called NIBT and NSBT. They also have been made bythe oxalylamide route and the hydrochloride salts melt at 150-151°C and 175-177 °C resp. Interestingly, NSBT is one of the twomono-substituted tryptamines that just might have CNS activity. It hasshown a generalized and somewhat diffuse intoxication with severalstudies covering the 25 to 75 milligram range. Short lived,intellectual excitement with some modest sensoryenhancements. Promising, and a lot of erotic horniness, but no plusthrees, yet.
The tertiary-butyl analogue, NTBT, is the remaining mono-substitutedtryptamine that just might have psychotropic potential. In the 5 to 20milligram area, there is a light-headed intoxication that is a totallypleasant buzz, but nothing more profound than that. Wouldn't it befascination of it turned out that all of the mono-tryptamines (theNRT's) were GHB-like intoxicants, and totally devoid of psychedelicactivity. That would be a true challenge to the SAR crowd. I was toldmany years ago that NTBT was extremely potent when smoked, but I neverreceived any particulars, and I must leave that as a baselessrumor.
Both the mono-amyl and the mono-hexylamines have been described (NATand NHT), both having been made by the glyoxylamide process. These,too, as has been mentioned above, it appears to be inactive in man, asreported by Stephen Szara at the famous Ethnopharmacologic Search forPsychoactive Drugs conference, organized by the late Dan Efron of theNational Institute of Mental Health, in San Francisco, in 1967.
Thirdly, this is where the staggering potential power of this recipecomes into focus. One can make, easily, pure mono-ethyl, mono-propyl,mono-isopropyl, mono-n-, s-, i- and t-NBT's. And using thesedirections, one can systematically react these mono's with everydifferent alkyl halide. Thus, there suddenly becomes available a"this" times "that" squared possibilities of new tryptamines, everyone easily made, every one potentially psychoactive, and almost everyone totally unknown to the scientific literature. The oxalylamideprocess goes out to lunch when one considered the unlikelihood offinding N-s-butyl-N-i-butyl amine as a commercially availableproduct. It is no longer required. Make IBSBT (how would you everencode that product) by the simple treatment of one of these mono'swith an appropriate alkyl halide, and clean up the mess with a dash ofacetic anhydride.
Fourthly, and most important, every one of these adventures has anexact counterpart with the inclusion of that magical 5-methoxygroup. Whatever is found with the 5-H archetype is certain to be morepotent, and correspondingly unpredictable, with a5-methoxy-substituent. Some have already been made. Most havenot. This is open territory. Go west, young man.
Back to the mundane. I really have to justify the "N" in the NET. Iwill try to hold to the convention that is expanded on at length inthe recipe for DBT, that if there is one alkyl group (a monoalkyltryptamine) then it is N-alkyl-tryptamine, with the reserving the Mfor methyl rather than for mono, even in the case ofmonomethyltryptamine. There is wide use of MMT formonomethyltryptamine in the literature, but the ambiguity comes fromthe higher mono-substituted homologues, and this makes NMT a muchsafer name. As there can be several places for the ethyl group,perhaps it is best to give the location as a number or letter, such as1, 2, a (for alpha) or N.
A detail for spectroscopists amongst us. With the mono-N-substitutedtryptamines, there is always a 131 e/m mass peak, larger than the 130e/m mass peak. This peak is a minor one with the disubstitutedanalogue. The same relationship exists with the 5-methoxy analogues,where N-monosubstituted compounds have a 161/160 m/e fragment (the5-methoxymethylene indole fragment, with the 161 m/e peak always thelarger. The primary amine shows this same character. Thedisubstituted analogue has only the 160 m/e fragment.
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