(Hive Addict)
05-13-03 09:30
No 430820
      A look on the patented world of tryptamines
(Rated as: excellent)

The aim of this digest is to give an overview of several possibly interesting patents concerning the synthesis of tryptamine and its analogues. I have a map full with printed versions, and I thought it might be well time to share the information. Many patents are written in German (as many patents are from Switserland), and I shall do my best to condense the content into a text the title translation worthy.
This digest should stimulate the research in the tryptaminopsychedelic field, and should not be abused in your local Bolivian-style drug cartel to cash in on these wonderul substances. I cannot be held responsible for your possible illegal actions resulting from reading this thread, as I have already plenty of things on my mind, as caring about my own clandestine actions crazy.


1. General links concerning tryptamine(s) and its (their) synthesis
2. Patented literature: isolation from plants
3. Patented literature: synthesis of indole and its derivatives
4. Patented literature: synthesis of tryptamine and its derivatives
5. Patented literature: total synthesis of tryptamine and its derivatives

Text in blue italics are personal additions.


*) An online version of TiHKAL (http://www.erowid.org/library/books_online/tihkal/tihkal.shtml) is available at the Erowid website. At least, the synthesis part is... It is strongly advised though to buy your own copy of this magnificent book!

*) The IUPAC (http://www.chem.qmul.ac.uk/iupac/fusedring/app2.html) recommendation for the numbering of indole (cf #39). No more worries about the structure of 2-methyl-4-hydroxy-5-formyl-7-methyl-1H-indole! wink



alfa-methylindoles - Patent GB1098977: Production of alfa-methylindoles. Franz Westphal, Badische Anilin- & Soda-Fabrik AG (Ludwigshafen/Rhein). Anno 1965.
alpha-methylindole - 108 parts of water, 29 parts of phenylhydrazine and 16 parts of acetone are stirred for half an hour at room temperature in a reactor. 10 parts of boric acid is then added and 292 parts of 96% sulphuric acid is allowed to flow in at such rate that the reaction temperature rises to 110C. As soon as the temperature falls, the whole is stirred for two hours at 95 to 100C, then cooled to 20 to 25C and the sulphuric acid solution is allowed to flow into a mixture of 750 parts of ice and 2250 parts of water. The alpha-methylindole thus deposited in crystalline form is suction filtered, washed with water until neutral in reaction and dried at 40C under sub-atmospheric pressure. The yield is 28.5 parts of alpha-methylindole, equivalent to 81% of the theoretical yield. (The patent contains 4 examples, of which 3 for the synthesis of alpha-methylindole, and 1 for the production of 2,5-dimethylindole)

3-(2-ethyl-2-nitrovinyl) indole - Patent GB918055: Upjohn Company. Anno 1961.
3-(2-ethyl-2-nitrovinyl) indole - A mixture of 2.15 g (0.0149 mole) of indole-3-carboxaldehyde, 15 mL (0.169 mole) of 1-nitropropane and 0.43 g (0.0056 mole) of ammonium acetate was placed in a 50 mL 3-necked flask fitted with stirrer and gas inlet and outlet tubes. The outlet tube was provided with a condenser set downward for distillation. Nitrogen was passed through the space above the reaction mixture throughout the reaction at a rate of 110 to 150 mL per minute. The mixture was heated on the steam bath with stirring for 1.25 h. A total of 5.5 mL of distillate was collected during this period. The reaction mixture was then cooled in ice for 0.5 h with occasional stirring. The solid which has separated was then isolated by filtration, washed with three 5 mL portions of water, then with two 10 mL portions of petroleum ether (boiling range 30-60C) before being dried. There was thus obtained 2.3 g of 3-(2-ethyl-2-nitrovinyl) indole having a melting point of 129C to 132C and a purity of 99% as measured by comparison of the extinction coefficient at lambda max = 400 millimicrons with that or a pure specimen of the compound. (6 more examples deal with the same reaction on industrial scale - i.e. up to 60 kg indole-3-carboxaldehyde precursor.)

Indole-3-carboxaldehydes - Patent CH484903: Verfahren zur Herstellung von 3-Indolaldehyden. Georg Gal, Merck & Co Inc (Rahway, NJ). Anno 1964.
2-methyl-5-methoxy-3-indolealdehyde - A three-necked RB flask equipped with magnetic stirbar, thermometer and dropping funnel, is charged with 36.5 g (0.5 mol) anhydrous DMF and cooled down to -5C. 15.3 g (0.1 mol) POCl3 is slowly added while the reaction mixture is stirred. Subsequently, 8.1 g (0.05 mol) 2-methyl-5-methoxyindole was slowly (in several parts) added at 20-25C. After 1 h at room temperature, 20 g anhydrous CaCO3 was added after which the reaction mixture was allowed to react a further hour at 60C. It was then cooled down to 10C en poured into a 30% NaOAc solution, and diluted with 500 mL water. There was added 20 g (0.5 mol) NaOH and the mixture was refluxed for 2 hours. The evolution of dimethylamine was noted. When the reaction mixture was cooled down to 10C, a precipitate was noted. The solids were filtered, washed with water and dried in vacuo.
Other possibilities are: start the reaction for 3 hours at 50C or 1 hour at 75C, use BaCO3 instead of CaCO3 and apply KOH; reflux the reaction mixture for 4 hours. (The patent lists some other indole derivatives which have been tried, but without analytical data, such as mp, yields etc. Also contains procedures for 1-substituted indoles.)

4-methylthio-indole - Patent US3143551: Derivatives of indole. Dr Albert Hofmann and Franz Troxler, Sandoz Ltd (Basel). Anno 1964.
4-methylthio-indole - (a) A mixture of 425 g of 2-nitro-6-aminotoluene, 189 cc of concentrated sulfuric acid, 4 L of water and 2.5 kg of ice are diazotised at 0C by adding a solution of 210 g of sodium nitrite in 350 mL of water dropwise. After 30 min the mixture is brought to a pH value of 6 by the addition of sodium acetate and the solution added at 0C to a mixture of 200 g of sodium hydroxide, 2 L of water, 200 cc of liquid methylmercaptan and 200 g of copper bronze, while stirring. Gaseous methylmercaptan is passed through for a further 15 minutes, 1.5 kg of common salt added and the mixture left to be stirred in an ice bath over night. The mixture is acidified with concentrated HCl, extracted 7 times with 2.5 L of chloroform, the chloroform extract dried over MgSO4 and potash (1:1) and then evaporated. The residue is distilled in a high vacuum. Bp 130/0.2 mmHg. For analysis the mixture is sublimated in a high vacuum at 40-45C. Mp 56-58.
(b) A solution of 9.5 g of the thus obtained 2-nitro-6-methylthio-toluene and 15.3 g of oxalic acid diethyl ester in 50 cc of ether are added dropwise to a solution of potassium ethylate, prepared from 3.53 g of potassium and 16 cc of absolute ethanol in 150 cc of ether, at 0C. After standing for 10 days at room temperature the precipitate is filtered off with suction, washed with ether and then shaken with 100 cc of ether, 150 cc of water and 30 cc of a 2 N sodium hydroxide solution for one hour at room temperature. The ethereal phase is separated, shaken again in 100 cc of water, the aqueous solution filtered through highly purified fuller's earth until clear and slowly acidified with concentrated HCl at 0C. The oily (2-nitro-methylthio-phenyl)pyruvic acid precipitating is extracted with chloroform and crystallizes from benzene in druses having a mp of 107-109C.
(c) 10 g of sodium dithionite are added portionwise to a solution of 6.651 g of (2-nitro-6-methylthio-phenyl)-pyruvic acid in 50 mL of water containing 26 cc of 1 N sodium hydroxide solution while stirring and cooling with ice. A further 20 mL of 1 N sodium hydroxide solution are added, the mixture is filtered through highly purified fuller's earth after 30 minutes and the filtrate slowly acidified with 2 N HCl. The precipitated carboxylic acid is filtered off with suction and recrystallized from EtOH (needles), MeOH/benzene (needles) and from EtOH/GAA (needles). Mp 244-246. Keller's colour reaction: negative. Van Urk's colour reaction: negative.
(d) 4-methylmercapto-indole was prepared by the dearboxylation of 1.2 g of 4-methylthio-indole-2-carboxylic acid in a distillation column at a pressure of 15 mmHg and 260-270. The mixture is subsequently distilled in high vacuum at 0.02 mmHg and 180C. The distillate is taken up in ether, shaken twice with a 10% soda solution and the ethereal solution dried over potash. The evaporation residue of the solution is again distilled at 0.05 mmHg and 145-155. Mp of the solidified distillate 44-47. Keller's colour reaction: brown-violet. Van Urk's colour reaction: blue tinged with violet. (Also contains procedures for 4-benzylthio-indole, 1-methyl-4-benzylthio-indole and 1-benzyl-4-benzylthio-indole. Shulgin reports that the thio analogues are usually weaker then their hydroxy analogues.)


4-hydroxyindole derivatives - Patent CH368802: Verfahren zur Herstellung von neuen hydroxylierten Indol-Derivaten. Dr Albert Hofmann und Dr Franz Troxler, Sandoz AG (Basel). Anno 1963.
The synthesis of new hydroxyindole analogues: This specific patent gives examples of the synthesis of 4-OH-DMT and 4-OH-DET.
4-hydroxy-dimethyltryptamine - 12 g 4-benzyloxyindole is dissolved in 300 mL ether and stirred at a temperature of ca 0-3C. Meanwhile, 9.6 g oxalylchloride is added dropwise. 30 min after total addition of the oxalylchloride, there is added 20 g anhydrous dimethylamine. External ice cooling and slow stirring are necessary. Afterwards, the reaction mixture is stirred at room temperature for several minutes and filtrated. The precipitate is washed well with water and the water-insoluble phase damped in in vacuo. By doing so, a yellowish crystalline powder, which can be recrystallized from benzene/MeOH and addition of petroleum ether, is obtained. mp: 148-150. A solution of 4 g of the so obtained 4-benzyloxy-indolyl-3-glyoxylic acid dimethylamide in 80 mL dioxande is added (dropwise) to a vehemently stirred solution of 5 g LAH in 100 mL dioxane (anhydrous), and the reaction mixture is refluxed for 24 h. Decomposition of the complex and residual LAH is achieved by addition of MeOH and saturated NaSO4. The reaction mixture is filtrated and the filtrate extracted with tartaric acid solution and ether. After isolation of the base, a solidifying oil is obtained. Purification is possible by chromatography of a benzene solution over an aluminium oxide column. This yields a colourless oil, and gives prisms (mp 119-121C) by crystallization from ether/petroleum ether. A solution of 4-benzyloxy-dimethyltryptamine in 100 mL MeOH is mixed with 2 g Pd on aluminium oxide carrier. When the hydrogen gas uptake has stopped, the reaction mixture was filtered and the filtrate freed from solvent. The residue was sublimated in vacuo at 130C, by which a snow-white 4-hydroxy-dimethyltryptamine (mp 166-168) was obtained. Keller spot test: blue
4-hydroxy-diethyltryptamine - 5 g 4-benzyloxyindole is dissolved in 120 mL ether and combined with 4 mL oxalylchloride under stirring and at a temperature of -5 to -7C. The reaction mixture is stirred for another hour at -5C and - at this temperature - 20 mL anhydrous diethylamine in 20 mL is added (dropwise). The precipitate was filtered 2 hours later and washed with water. The water-insoluble phase (4-benzyloxy-indolyl-3-glyoxylic acid diethylamid) was crystallized from EtOH (mp 117-119C). A solution of 6.3 g LAH in 150 mL anhydrous dioxane is added dropwise to a refluxing solution of 4.9 g of the previously described diethylamide and allowed to react (at refluxing temperature) for 24 hours. Decomposition of the complex is achieved with MeOH and saturated sodium sulfate solution; the reaction mixture is filtrated and the filtrate extracted with ether and 0.5N tartaric acid solution. The isolated base is purified on a column of aluminium oxide as a solution in benzene. Recrystallization from benzene, mp 100-101C. The thus obtained 4-benzyloxy-diethyltryptamine (2.8 g) was dissolved in MeOH (50 mL) and reacted with Pd on alumnium oxide carrier. When the uptake of hydrogen gas halted, the mixture was filtered and the filtrate freed from solvent. The residue was distilled (strong vacuum) and the distillate crystallized from ether (mp 99-101C).


5,7-dimethoxytryptamines - Patent US3564012: 5,7-dimethoxytryptamines. James M McManus, Pfizer & Co Inc  (Delaware, NY). Anno 1971
5,7-dimethoxyindole-3-carboxaldehyde - To a solution consisting of 66.0 g (0.370 mole) of 5,7-dimethoxyindole dissolved in 350 mL of DMF that had previously been cooled to 20C, there were added 59.6 g (0.370 mole) of POCl3 in 400 mL of the same said solvent over a period of twenty minutes, while maintaining the temperature of the reaction mixture at 22-28C throughout the course of the addition. The resulting mixture was then allowed to stir at room temperature ( 25C) for a period of one-half hour, followed by the addition of same to a mixture consisting of 6.5 L of ice and water and also containing 148 mL of 20% aqueous NaOH. After stirring for 15 additional minutes and filtering, the filtrate was collected and subsequently adjusted to a pH of 10.5 with 20% aqueous NaOH solution. The resulting yellow precipitate, which formed at this point, was then further stirred in the aqueous alkaline medium for a period of thirty minutes, followed by its subsequent removal by means of suction filtration. After air-drying to constant weight, there was obtained 45.7 g of 5,7-dimethoxyindole-3-carboxaldehyde, mp 128-129C. Recrystallization of the latter material from benzene then raised the melting point to 149-150C. Analysis: Calculated for C11H11O3N (percent): C, 64.39; H, 5.40; N, 6.82. Found (percent): C, 64.44; H, 5.52; N, 6.83.
5,7-dimethoxy-alpha-methyltryptamine - A mixture consisting of 10 g of 5,7-dimethoxyindole-3-carboxaldehyde and 2 g of ammonium acetate in 65 mL of nitroethane was heated on a steam bath for a period of two hours. The reaction mixture was then cooled to room temperature ( 25C) and then added to 300 mL of isopropyl ether, whereupon precipitation of the desired product from solution soon occured. The resulting solids were then collected by suction filtration, washed with water and air-dried to give 7.8 g of 3-(2-methyl-2-nitrovinyl)-5,7-dimethoxyindole, mp 186-188C (mp 186.5-187.5C after recrystallization from toluene). Analysis: calculated for C13H14O4N2 (percent): C, 59.53; H, 5.38. Found (percent): C, 60.07; H, 5.49.
One gram of the above nitrovinylindole compound in 25 mL of THF was then added dropwise to a suspension of 868 mg of LAH in 20 mL of the same said solvent. The resulting mixture was then stirred at room temperature ( 25C) for one hour, followed by careful treatment with water. The solids which formed at this point were then collected by means of suction filtration and the resulting filtrate subsequently concentrated in vacuo to afford a partially crystalline residue. The latter material was then dissolved in diethyl ether and treated with hydrogen chloride in ethyl acetate to give 450 mg of 3-(2-aminopropyl)5,7-dimethoxyindole hydrochloride, mp 271-273C.
5,7-dimethoxy-alpha-ethyltryptamine - The previous procedure (for 5,7-dimethoxy-alpha-MT) was employed once again, only this time using 15.6 g of 5,7-dimethoxyindole-3-carboxaldehyde and 3.2 g of ammonium acetate together with 70 mL of 1-nitropropane. In this particular case, there were obtained 9.8 g of 3-(2-ethyl-nitrovinyl)-5,7-dimethoxyindole, mp 173.5-175C. Analysis: Calculated for C14H16O4N2 (percent): C, 60.86; H, 5.84. Found (percent): C, 60.99; H, 5.61.
Following the procedure of the previous example, the above indolylnitrobutene and 6.6 g LAH in 300 mL of THF reacted to give 5.0 g of 3-(2-aminobutyl)-5,7-dimethoxyindole as the free base, mp 123.5-129C. After one crystallization, from toluene, the mp was raised to 130-131C. Analysis: Calculated for C14H20O2N2 (percent): C, 67.71; H, 8.12; N, 11.28. Found (percent): C, 67.95; H, 7.95; N, 11.44. (The patent contains about 15 examples. The ones presented are those I thought would be the most interesting. As the patent written in English, you shouldn't have to many problems understanding the basics. Post 403060 (Fomalhaut: " ", Russian HyperLab) is something that came in mind when I was reading the patent...)

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