WO2025169153A1 - Making 5-methoxy-n,n-dimethyltryptamine and bufotenin - Google Patents

Abstract

Disclosed is a process for, starting from melatonin, the synthesis of 2-(5-methoxy-lH-indol-3-yl)-N,Ndimethylethan-l-amine (MeO-DMT) or a bufotenin salt, said process involving nucleophilic de-acetylation, contacting the resulting 2-(5-methoxy-lH-indol-3-yl)ethan-l-amine with an aryloxy or alkoxy-carbonylation reagent to form a first carbamate, reducing the carbamate, adding a second aryloxy or alkoxy carbonylation reagent to form a second carbamate and reducing said second carbamate to form MeO-DMT followed by the addition of boron tribromide to MeO-DMT in dichloromethane to form bufotenin hydrobromide.

Description

Making 5-Methoxy-N,N-Dimethyltryptamine and Bufotenin 407-P014PCT REFERENCE TO RELATED APPLICATIONS [0001] This application claims the benefits of US provisional patent application number 63/550,907 filed on 7 February 2024. FIELD OF THE INVENTION [0002] The inventions relates to the synthesis of a bufotenin salt which is useful as a platform for the synthesis of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT), bufotenin, and derivatives thereof. BACKGROUND OF THE INVENTION [0003] Every fifth resident of Canada is affected annually by a mental disorder. Moreover, upon reaching the age of 40, one in two Canadians has either faced or is currently grappling with one of these illnesses. In Ontario alone, the collective impact of mental illness and substance use carries a disease burden 1.5 times greater than that of all cancers combined, and over 7 times that of all infectious diseases. This includes years lived with diminished functionality and years lost to premature death. The yearly economic impact of mental illness in Canada surpasses $50 billion, including expenses related to healthcare, diminished productivity, and declines in health-related quality of life. [0004] In recent years there has been growing interest and research focus on the potential use of psychedelics in the treatment of mental illnesses. Administered within controlled environments and under the supervision of trained professional therapists, patients can get these substances as part of a structured psychotherapeutic process. Clinical trials involving psychedelics have revealed enhancements in psychological well-being and reductions in depressive symptoms. These findings suggest that psychedelics can assist individuals in addressing fears and breaking free from addictive behavioral patterns by promoting introspection. Another area where psychedelics show promise is in pain relief, a field that is currently under active development. Currently, some of the most potent pain relievers belong to the opioid class of drugs; unfortunately, they can be addictive, which reduces the potential of their use. [0005] Bufotenin is a naturally occurring psychedelic compound found in several species of the Bufo genus of toads. Bufotenin, along with many other toxins, is produced in the parotoid glands on their backs to protect them from predators. As the natural extract, it has been used by traditional communities in both Mesoamerica and East Asia as a treatment for hemorrhages, bites and stings, cancers, skin and stomach conditions, and infection. [0006] Bufotenin is closely related to its O-methylated analogue, 5- methoxy-N,N-dimethyltryptamine 1a (5-MeO-DMT, also known as O- methylbufotenin or mebufotenin). Both are Schedule 1 drugs in the United States; however, regulation on these molecules in other jurisdictions is highly variable. With the significant cultural changes around reversing the 20th century’s prohibition of psychoactives currently underway around the world, there is a renewed interest in the potential medical benefits of tryptamines and other serotonin analogues. This has led to an explosion in interest in obtaining these materials. As they are highly and, most importantly, regulated differently, their commercial availability lags even in jurisdictions where they are not controlled. This has forced both academic and industrial scientists to develop new routes for synthesis of these molecules. [0007] Bufotenin is a particularly interesting psychedelic compound because it has one of the simplest chemical structures among psychedelics, with only 13 heavy atoms and no stereocenters. Also, the therapeutic potential of bufotenine is much less studied than that of MDMA and psilocybin even though its serotoninergic activity and psychedelic effects suggest it may hold promise for various mental health conditions. [0008] The salts of bufotenin are suitable for the synthesis of various derivatives of bufotenin. An especially preferred salt is the hydrobromide salt because it is more stable and easier to obtain than the free base form of bufotenin. Free-basing other bufotenin salts (i.e. not the bromide) has previously been done in the literature, but because of the instability of bufotenin itself, it is not commonly done as a preparative step. The hydrobromide salt is free-based in situ during a reaction or the salt form is used in a formulation. At physiological pH, bufotenin hydrobromide exists as a bufotenin cation, and the bromide is naturally substituted with other more common counterions present in the body by a process known as salt metathesis. [0009] It would be desirable to have a commercially viable method of making bufotenin as well as derivatives and analogs thereof. [0010] 5-Methoxy-N,N-dimethyltryptamine is a promising molecule for the treatment of mental distress. It is the O-methylated analogue of bufotenin and can share a common synthesis. Bufotenin is an active metabolite of 5- MeO-DMT, although both have psychoactive/physiological effects. [0011] It would be desirable to have a commercially viable method of making 5-MeO-DMT as well as derivatives and analogues thereof. SUMMARY OF THE INVENTION [0012] It is an object of the invention to provide a process of making bufotenin. [0013] In accordance with this and other objectives of the invention that will become apparent from the description herein, a process according to the invention comprises: a. contacting melatonin in a polar solvent (such as a protic solvent, e.g., a lower alkyl alcohol like methanol) with a nucleophilic de- acetylation reagent, preferably a mineral base (such as sodium hydroxide), to form 2-(5-methoxy-1H-indol-3-yl)ethan-1-amine, b. contacting said 2-(5-methoxy-1H-indol-3-yl)ethan-1-amine with an aryloxy or alkoxy-carbonylation reagent, such as di-tert-butyl dicarbonate to form a first carbamate, such as tert-butyl (2-(5- methoxy-1H-indol-3-yl)-ethyl)-carbamate, c. adding the first carbamate in an aprotic solvent, such as tetrahydrofuran, to a reducing agent, such as a hydride reagent (preferably lithium aluminum hydride) in an aprotic solvent (e.g., diethyl ether) to form 2-(5-methoxy-1H-indol-3-yl)-N- methylethan-1-amine, d. adding an aryloxy or alkoxy-carbonylation reagent (e.g., di-tert- butyl-dicarbonate) to 2-(5-methoxy-1H-indol-3-yl)-N- methylethan-1-amine in an aprotic solvent (e.g., dichloromethane) to produce a second carbamate (e.g., tert- butyl (2-(5-methoxy-1H-indol-3-yl)ethyl)(methyl)carbamate), e. adding the second carbamate to a reducing agent to form a precipitate comprising 2-(5-methoxy-1H-indol-3-yl)-N,N- dimethylethan-1-amine, and f. adding a demethylating agent (e.g., boron tribromide) to the 2- (5-methoxy-1H-indol-3-yl)-N,N-dimethylethan-1-amine in a solvent (e.g., dichloromethane) to form a bufotenin salt, e.g., bufotenin hydrobromide). [0014] The synthesis method of the invention has a number of advantages over the prior art that make it commercially viable. For example: [0015] a. The synthesis route starts from melatonin, which is one of the cheapest possible precursors to bufotenin. Melatonin is manufactured worldwide at a scale of about 4000 tons in 2019. Melatonin is highly unlikely to experience supply shortages. [0016] b. Three stages out of six (hydrolysis A, and Boc-protection steps B and D) are among simplest, easiest to carry out reactions in organic synthesis. [0017] c. The Boc-protection steps B, D are fast, taking about 1 hour total from initiating the reaction to the product being ready for the next step. [0018] d. The proposed synthesis route also gives access to 5-MeO-DMT (intermediate 6), which is known to be a potent psychedelic that may have its own therapeutic applications. [0019] e. The yields are reasonably high. The overall yield to 5-MeO- DMT is about 76%. The overall yield of the route to bufotenin hydrobromide is about 38% [0020] f. All stages except the last are very easily scalable. We have performed the final conversion in stage F to the bromide salt on a scale that gave 22 g of product in one run. 5-MeO-DMT was obtained in 64 g scale in one run. [0021] h. All stages except the last do not require laborious purification. All reactions give products of enough purity to be used in subsequent steps without chromatographic purification. If, for any reason higher purity material is required, in all cases (except for the bufotenin hydrobromide 7) this can be done with simple crystallization. No column chromatography purifications are required. Only the bufotenin hydrobromide 7 step is filtered through silica gel, but that is not a full scale chromatographic purification. [0022] i. None of the steps is particularly sensitive to the quality of the reagents. All solvents used were reagent grade. [0023] j. The synthesis route of the invention does not involve any particularly hazardous materials or use of reagents or catalysts which contain heavy toxic elements. [0024] k. The synthesis route of the invention can be modified to obtain analogs of bufotenin with longer alkyl substituents on aliphatic nitrogen atom, different from current methyl groups, which would allow to do fine tuning of physicochemical properties of the product as well as biological activity and metabolic stability. This modification involves the simple substitution of the alkoxycarbonylation reagents in steps B and D with acylation reagents. [0025] l. The bufotenin obtained through the present process is very conveniently obtained as an HBr salt (product 7) after quenching and working up the reaction mixture on step F. [0026] m. The HBr salt of bufotenin is a form of bufotenin which is much more stable to degradation by mild heating or exposure to light or atmospheric oxygen than free base bufotenin. As such, the HBr salt is a valuable intermediate for the manufacture of the final bufotenin as well as a platform for making analogs and derivatives having activities similar to bufotenin. BRIEF DESCRIPTION OF THE DRAWINGS [0027] Figure 1 shows a process for making bufotenin hydrobromide salt and its use to make the derivative octanoyl bufotenin. DETAILED DESCRIPTION [0028] The synthesis of 5-methoxy-N,N-dimethyltryptamine starts with melatonin. Melatonin is a natural indoleamine hormone secreted in the human brain during the night. It plays a crucial role in regulating the sleep- wake cycle. In vertebrates, melatonin's functions extend to synchronizing sleep-wake cycles, encompassing sleep-wake timing and blood pressure regulation, as well as controlling seasonal rhythmicity, which includes reproduction, fattening, molting, and hibernation. In plants and bacteria, melatonin primarily serves as a defense mechanism against oxidative stress, indicating its evolutionary significance. [0029] The first step in the process of the present invention is contacting melatonin with a nucleophilic de-acetylation reagent to form 2-(5-methoxy- 1H-indol-3-yl)ethan-1-amine. Preferably, the melatonin is in a polar solvent, such as a protic solvent, preferably a lower alkyl alcohol like methanol. A preferred nucleophilic de-acetylation reagent for the present process is a mineral base such as sodium hydroxide. [0030] The second step involves contacting said 2-(5-methoxy-1H- indol-3-yl)ethan-1-amine with an aryloxy or alkoxy-carbonylation reagent to form a first carbamate. A preferred reagent for this purpose is a di-tert- butyl dicarbonate, and especially preferred is tert-butyl (2-(5-methoxy-1H- indol-3-yl)-ethyl)-carbamate. [0031] The third step is adding the first carbamate to a reducing agent to form 2-(5-methoxy-1H-indol-3-yl)-N-methylethan-1-amine. Preferably, the first carbamate is in an aprotic solvent, such as tetrahydrofuran. The reducing agent is preferably in a hydride reagent in an aprotic solvent (e.g., diethyl ether). Lithium aluminum hydride is an especially preferred hydride reagent. [0032] The fourth step includes adding an aryloxy or alkoxy- carbonylation reagent to 2-(5-methoxy-1H-indol-3-yl)-N-methylethan-1- amine to produce a second carbamate. A preferred second carbamate for the present invention is tert-butyl (2-(5-methoxy-1H-indol-3- yl)ethyl)(methyl)carbamate). [0033] Preferably the carbonylation reagent for the fourth step is an aryloxy or alkoxy-carbonylation reagent, such as di-tert-butyl dicarbonate). Preferably, the reaction is carried out in an aprotic solvent, such as dichloromethane. [0034] The fifth step involves adding the second carbamate to a reducing agent to form a precipitate comprising 2-(5-methoxy-1H-indol-3- yl)-N,N-dimethylethan-1-amine (MeO-DMT). This product can be recovered at this point for its other uses. [0035] If not recovered as an interim product, the MeO-DMT is contacted with a demethylating agent to form a bufotenin salt (e.g., bufotenin hydrobromide). Preferably, the contact occurs in a suitable solvent, such as dichloromethane. [0036] Suitable demethylating agents include Lewis acids, Lewis bases, or combinations of a Lewis acid and a Lewis base. Suitable Lewis acids include boron tribromide, boron trichloride, aluminum chloride, aluminum bromide, diethylaluminum chloride, and diethyl aluminum iodide. Suitable Lewis bases include sodium methanethiolate, sodium ethanethiolate, sodium propanethiolate, sodium tert-butylthiolate, dimethyl sulfide, diethyl sulfide, ethanethiol, hexane thiol, and dodecanethiol, thiolane. [0037] The following manufacturing steps represent a preferred embodiment for making MeO-DMT, the hydrobromide salt of bufotenin hydrobromide from MeO-DMT and, optionally, octanoyl bufotenin from the bufotenin salt. The steps described herein are illustrated in the process flowchart depicted in Figure 1. [0038] Step A. 2-(5-Methoxy-1H-indol-3-yl)ethan-1-amine. [0039] To a solution of melatonin (110 g, 474 mmol, 1 eq), in MeOH (600 mL) that solution of NaOH (341 g, 8.52 mol, 18 eq) in H₂O (600 mL) was added in one portion and the mixture was set to reflux for 2 days until NMR analysis showed that the reaction was complete. The reaction mixture was cooled to room temperature, and MeOH was removed under reduced pressure (approximately half the volume). [0040] The residual mixture was diluted with H₂O (300 mL) and extracted with 2-methyl-tetrahydrofuran (“2-Me-THF”) (500 mL). The organic extract was washed with brine (50 mL), dried over MgSO₄ and evaporated under reduced pressure to give Intermediate 2 (94% purity by NMR analysis, 91.5 g, 90% yield) as a yellow solid, which was used in the next step without purification. [0041] The product of step A (Intermediate 2: 2-(5-Methoxy-1H-indol-3- yl)ethan-1-amine) shows the following characteristics: [0042] ¹H NMR (300 MHz, DMSO-d₆) δ 10.63 (s, 1H), 7.22 (d, J = 8.7 Hz, 1H), J = 2.2 Hz, 1H), 6.70 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, 3H), 2.81 (dd, J = 10.9, 4.3 Hz, 2H), 2.72 (dd, J = 10.9, 4.3 Hz, 2H), 1.46 (s, 2H). [0043] ¹³C NMR (76 MHz, DMSO-d₆) δ 152.89, 131.42, 127.65, 123.27, 112.37, 111.93, 110.94, 100.18, 55.34, 42.67, 29.60. [0044] Melting Point: 115.2 – 119.4 °C [0045] Step B. tert-butyl (2-(5-methoxy-1H-indol-3-yl)ethyl)carbamate. [0046] To a stirred suspension of 2-(5-methoxy-1H-indol-3-yl)ethan-1- amine (Intermediate 2) in a purity of (94%, 85.1 g, 421 mmol, 1 eq) in dichloromethane (“DCM”) (500 mL) and liquid di-tert-butyl dicarbonate (“Boc2O”) (101 g, 462 mmol, 1.1 eq; kept above 25 °C) was added dropwise. The mixture was stirred at room temperature for 1 h, solvent removed under reduced pressure, and dried in vacuum to give Intermediate 3 (92% purity by NMR analysis, 130 g, 412 mmol, 98% yield) as light brown crystalline solid, which was used in the next step without purification. [0047] Intermediate 3 from step B (tert-butyl (2-(5-methoxy-1H-indol-3- yl)ethyl)carbamate) has the following characteristics: [0048] ¹H NMR (300 MHz, DMSO-d₆) δ 10.61 (s, 1H), 7.21 (d, J = 8.7 Hz, 1H), 1H), 6.85 (t, J = 5.2 Hz, 1H), 6.71 (dd, J = 8.7, 2.4 Hz, 1H), 3.75 (s, J = 2.6 Hz, 3H), 3.19 (dd, J = 13.8, 6.5 Hz, 2H), 2.75 (t, J = 7.5 Hz, 2H), 1.37 (s, 9H). [0049] ¹³C NMR (76 MHz, DMSO-d₆) δ 155.57, 152.95, 131.38, 127.58, 123.21, 111.93, 111.61, 110.93, 100.26, 77.39, 55.36, 40.71, 28.28, 25.57. [0050] Melting Point: 120.9 – 122.2 °C [0051] Step C. 2-(5-Methoxy-1H-indol-3-yl)-N-methylethan-1-amine. [0052] To a suspension of LiAlH₄ (31.4 g, 827 mmol, 3 eq) in tetrahydrofuran (“THF”) (1.6 L) stirred at 50°C under an inert atmosphere (e.g. nitrogen) was added the solution of tert-butyl (2-(5-methoxy-1H-indol- 3-yl)ethyl)carbamate (Intermediate 3) (92%, 87 g, 276 mmol, 1 eq) in THF (260 mL) dropwise over 20 minutes at a rate sufficient to keep the reaction mixture temperature between 50 °C and gentle reflux. The resulting mixture heated at reflux overnight. After the reaction mixture was cooled down to room temperature H₂O (31 mL) was added dropwise with rapid hydrogen gas evolution, followed by aqueous NaOH (10%, 31 mL; and again H₂O (93 mL). The resulting suspension was stirred at room temperature for 30 min before diethyl ether (“Et₂O”) (500 mL) was added in one portion and the mixture was stirred for another 10 min. The precipitate was filtered out and washed with THF (200 mL) and the filtrate was concentrated in vacuum. The residue was dissolved in DCM (400 mL), the solution was dried with Na₂SO₄ and concentrated again to give Intermediate 4 (90% purity by NMR, 58.7 g, 259 mmol, 94% yield) as a light brown viscous oil, which solidified upon standing at room temperature and was used in the next step without purification. [0053] Please note that a pure sample of the product was obtained from the corresponding hydrochloride salt (Intermediate 4s), which was prepared from Intermediate 4 by addition of excess 1 M HCl at room followed by evaporation of water under reduced pressure. The salt (Intermediate 4s) was then recrystallized from EtOH/dioxane; it was then dissolved in water and basified with Na₂CO₃ solution. The resulting mixture was extracted with DCM, the organic phase was dried with Na₂SO₄ and the solvent removed under reduced pressure to provide pure Intermediate 4. [0054] The non-salt (“free base”) and salt versions of Intermediate 4s/4 have the following properties: [0055] Free base version: [0056] ¹H NMR (300 MHz, DMSO-d₆) δ 10.63 (s, 1H), 7.22 (d, J = 8.7 Hz, 1H), J = 2.3 Hz, 1H), 6.71 (dd, J = 8.7, 2.3 Hz, 1H), 3.76 (s, 3H), 2.79 (dd, J = 11.1, 4.3 Hz, 2H), 2.73 (dd, J = 11.0, 4.3 Hz, 2H), 2.32 (s, 3H), 2.20 – 1.69 (s, 1H). [0057] ¹³C NMR (76 MHz, DMSO-d₆) δ 152.90, 131.41, 127.60, 123.22, 112.42, 111.95, 110.92, 100.16, 55.34, 52.32, 36.12, 25.25. [0058] Melting Point: 101.3 – 103.7 °C [0059] 2-(5-Methoxy-1H-indol-3-yl)-N-methylethan-1-amine hydrochloride (hydrochloride salt form, 4s): ¹H NMR (300 MHz, DMSO-d₆) δ 10.85 (s, 1H), 9.11 (s, 2H), 7.25 (d, J = 8.7 Hz, 1H), 7.18 (d, J = 2.2 Hz, 1H), 7.13 (d, J = 2.2 Hz, 1H), 6.73 (dd, J = 8.7, 2.3 Hz, 1H), 3.77 (s, 3H), 3.19 – 2.98 (m, 4H), 2.55 (t, J = 5.3 Hz, 3H). [0060] ¹³C NMR (76 MHz, DMSO-d₆) δ 153.14, 131.41, 127.13, 123.88, 112.16, 111.28, 109.04, 100.26, 55.49, 48.55, 32.27, 21.65. [0061] Melting Point: 168 – 170.6 °C [0062] Step D. tert-Butyl (2-(5-methoxy-1H-indol-3- yl)ethyl)(methyl)carbamate (Intermediate 5). [0063] To a stirred solution of 2-(5-methoxy-1H-indol-3-yl)-N- methylethan-1-amine (intermediate 4) (90%, 72.2 g, 318 mmol, 1 eq) in DCM (350 mL), liquid Boc2O (76.3 g, 350 mmol, 1.1 eq; kept above 25 °C) was added dropwise. The mixture was stirred at room temperature for 1 h, solvent removed under reduced pressure, and dried in vacuum to give intermediate 5 (91% purity by NMR, 102.1 g, 305 mmol, 96% yield) as a light brown oil which solidified upon standing at room temperature and was used in the next step without purification. [0064] Note: A pure sample was obtained as off-white crystalline powder by crystallization from Et₂O/hexane. [0065] ¹H NMR (300 MHz, DMSO-d₆) δ 10.64 (s, 1H), 7.22 (d, J = 8.7 Hz, 1H), J = 8.7, 1.9 Hz, 1H), 3.76 (s, 3H), 3.41 (t, J = 7.1 Hz, 2H), 2.83 (t, J = 7.1 Hz, 2H), 2.78 (s, 3H), 1.40 (s, 3H), 1.23 (s, 6H). [0066] ¹³C NMR (76 MHz, DMSO-d₆) δ 154.71, 152.98, 131.44, 127.56, 123.63, 111.96, 111.16, 110.94, 100.14, 77.98, 55.36, 49.10, 33.63, 27.86, 23.44. [0067] Melting Point: 91.5 – 93.5 °C [0068] Step E. 2-(5-Methoxy-1H-indol-3-yl)-N,N-dimethylethan-1-amine, 5-MeO-DMT (intermediate 6). [0069] To a suspension of LiAlH₄ (33.7 g, 887 mmol, 3 eq) in THF (1.7 L) stirred at 50 °C under nitrogen atmosphere was added a solution of tert- butyl (2-(5-methoxy-1H-indol-3-yl)ethyl)(methyl)carbamate (intermediate 5) (91%, 98.9 g, 295 mmol, 1 eq) in THF (300 mL) dropwise over 15 min at a rate sufficient to keep the reaction mixture temperature between 50 °C and gentle reflux. The resulting mixture was refluxed overnight. The reaction mixture was cooled down to room temperature, and then H₂O (34 mL) was added dropwise with the rapid evolution of hydrogen gas, followed by aqueous NaOH (10%, 34 mL) and H2O (100 mL). [0070] The resulting suspension was stirred at room temperature for 30 min before Et₂O (600 mL) was added in one portion and the mixture was stirred for another 10 minutes. The precipitate was filtered out and washed with THF (200 mL) and the filtrate was concentrated in vacuum. The residue was dissolved in DCM (400 mL), the solution was dried with Na₂SO₄ and concentrated again to give intermediate 6 (95% purity by NMR, 64.2 g, 280 mmol, 95% yield) as light brown viscous oil, which solidified upon standing at room temperature. [0071] Note: A pure sample of the product was obtained by crystallization from Et2O/hexanes. [0072] ¹H NMR (300 MHz, DMSO-d₆) δ 10.60 (s, 1H), 7.22 (d, J = 8.7 Hz, 1H), J = 2.3 Hz, 1H), 6.71 (dd, J = 8.7, 2.3 Hz, 1H), 3.76 (s, 3H), 2.78 (dd, J = 8.3, 7.3 Hz, 2H), 2.50 (dd, J = 8.3, 7.3 Hz, 2H), 2.22 (s, 6H). [0073] ¹³C NMR (76 MHz, DMSO-d₆) δ 152.88, 131.34, 127.55, 123.11, 112.37, 111.92, 110.86, 100.15, 59.94, 55.34, 45.20, 23.11. [0074] Melting Point: 61.7 – 64.8 °C [0075] Step F. 3-(2-(Dimethylamino)ethyl)-1H-indol-5-ol hydrobromide, bufotenin hydrobromide (product 7). [0076] To a solution of 2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethan-1- amine (intermediate 6) (22 g, 101 mmol, 1 eq) in DCM (2 L) at −50 °C boron tribromide (75.7 g, 302 mmol, 3 eq) was added portionwise, while maintaining the temperature between −50 and −40 °C. After the addition was complete, the reaction mixture was allowed to warm to 10 °C and was stirred at this temperature for 20 min. After the NMR showed complete conversion of the starting material, the reaction mixture was cooled back down to −10 °C and cold aqueous NaOH solution (2 M, 500 mL) was added in one portion, while the mixture was stirred vigorously. [0077] The reaction mixture was allowed to warm up to 20 °C and was titrated slowly by addition of cold aqueous 1 M NaOH until the aqueous phase was consistently pH 7. Additional water was added to make the total volume of the aqueous phase about 800 mL, after which the mixture was stirred for another 5 min. The aqueous phase was then separated and concentrated under reduced pressure, after which the solid residue was dispersed in cold MeOH (200 mL). The precipitate was filtered off, washed with 50 mL of cold MeOH and the solid discarded. The filtrate had its solvent removed under reduced pressure, and the residue was then dried under vacuum. This procedure was then repeated using: 1) cold anhydrous EtOH; and then 2) 1:1 EtOH/IPA mixture. The residue after solvent evaporation was dissolved in MeOH (800 mL) and celite (150 g) was added. The resulting slurry was dried in vacuum and transferred onto a filter that had been loaded with a 300 g plug of silica gel. The material was eluted with 1:9 IPA/MeCN mixture (5 L) and collected in 300 mL fractions. The fractions containing pure product by NMR, were combined, solvent removed under reduced pressure and dried under vacuum to give intermediate 7 (95% purity by NMR, 22.5 g, 74.9 mmol, 51% yield) as a yellow viscous gum. [0078] The resulting bufotenin hydrobromide had the following characteristics: [0079] ¹H NMR (300 MHz, DMSO-d₆) δ 10.68 (s, 1H), 9.62 (s, 1H), 8.64 (s, 1H), = 7.14 1H), 6.89 (s, 1H), 6.65 (d, J = 7.5 Hz, 1H), – , – (m, 2H), 2.85 (s, 6H). [0080] ¹³C NMR (76 MHz, DMSO-d₆) δ 150.38, 130.78, 127.42, 123.67, 111.83, 111.64, 107.79, 102.22, 56.68, 42.18, 20.20. [0081] Melting Point: 99.6 – 105.8 °C [0082] Step G. 3-(2-(Dimethylamino)ethyl)-1H-indol-5-yl octanoate, octanoyl bufotenin (Derivative product 8). [0083] To a solution of bufotenin hydrobromide 7 (10 g, 35.1 mmol, 1 eq) in pyridine (100 mL) Et3N (14.7 mL, 105 mmol, 3 eq) was added in one portion, followed by portionwise addition of octanoyl chloride (8.56 g, 52.6 mmol, 1.5 eq). After stirring overnight at room temperature MeOH (5 mL) was added in one portion and the resulting mixture was evaporated in vacuum. The residue was partitioned between 1:1 Hexanes/MTBE (200 mL) and aq Na2CO3 (5%, 200 mL). The organic phase was washed with H2O (2 × 100 mL), brine, dried over sodium sulfate and evaporated in vacuum. The residue was purified by column chromatography on basic alumina (100% EtOAc, Rf = 0.5) to give product 8 (6.1 g, 18.5 mmol, 53% yield) as yellow oil. [0084] The resulting octanoyl bufotenin had the following characteristics: [0085] ¹H NMR (300 MHz, CDCl₃) δ 8.59 (s, 1H), 7.25 (d, J = 2.1 Hz, 1H), 7.18 1H), 6.84 (dd, J = 8.7, 2.1 Hz, 1H), 2.94 – 2.79 (m, 2H), 2.66 – 2.52 (m, 4H), 2.33 (s, 6H), 1.79 (p, J = 7.3 Hz, 2H), 1.52 – 1.27 (m, 8H), 0.91 (t, J = 6.3 Hz, 3H). [0086] ¹³C NMR (76 MHz, CDCl₃) δ 173.54, 144.02, 134.27, 127.83, 123.19, 115.94, 114.36, 111.66, 110.77, 60.25, 45.49, 34.61, 31.78, 29.24, 29.05, 25.19, 23.70, 22.71, 14.18. [0087] Melting Point: 48.3 – 50.2 °C.

Claims

Claims 1. A process for making 2-(5-methoxy-1H-indol-3-yl)-N,N- dimethylethan-1-amine that comprises: a. contacting melatonin with a nucleophilic de-acetylation reagent to form 2-(5-methoxy-1H-indol-3-yl)ethan-1-amine, b. contacting said 2-(5-methoxy-1H-indol-3-yl)ethan-1-amine with an aryloxy or alkoxy-carbonylation reagent to form a first carbamate, c. adding the first carbamate to a reducing agent to form 2-(5- methoxy-1H-indol-3-yl)-N-methylethan-1-amine, d. adding an aryloxy or alkoxy carbonylation reagent to said 2-(5- methoxy-1H-indol-3-yl)-N-methylethan-1-amine to produce a second carbamate, e. adding the second carbamate to a reducing agent to form a precipitate comprising 2-(5-methoxy-1H-indol-3-yl)-N,N- dimethylethan-1-amine (MeO-DMT).

2. A process according to claim 1 wherein said carbonylation reagent comprises a di-tert-butyl dicarbonate.

3. A process according to claim 2 wherein said carbonylation reagent comprises tert-butyl (2-(5-methoxy-1H-indol-3-yl)-ethyl)-carbamate.

4. A process according to claim 1 wherein the first carbamate is in an aprotic solvent.

5. A process according to claim 1 wherein the reducing agent is a hydride reagent.

6. A process according to claim 5 wherein said hydride reagent comprises lithium aluminum hydride.

7. A process according to claim 1 wherein said second carbamate comprises tert-butyl (2-(5-methoxy-1H-indol-3- yl)ethyl)(methyl)carbamate).

8. A process according to claim 1 further comprising: (f) adding a demethylating reagent to said 2-(5-methoxy-1H-indol-3-yl)-N,N- dimethylethan-1-amine to form a bufotenin salt.

9. A process according to claim 8 wherein said demethylating agent is a Lewis Acid, a Lewis base, or a combination of a Lewis acid and a Lewis base.

10. 2-(5-methoxy-1H-indol-3-yl)-N,N-dimethylethan-1-amine.

11. A process for making a bufotenin salt with steps that comprise: a. contacting melatonin with a base to form 2-(5-methoxy-1H- indol-3-yl)ethan-1-amine, b. contacting said 2-(5-methoxy-1H-indol-3-yl)ethan-1-amine with di-tert-butyl dicarbonate to form tert-butyl (2-(5-Methoxy-1H- indol-3-yl)-ethyl)-carbamate, c. adding the tert-butyl (2-(5-methoxy-1H-indol-3- yl)ethyl)carbamate in tetrahydrofuran to lithium aluminum hydride and diethyl ether to form 2-(5-Methoxy-1H-indol-3-yl)- N-methylethan-1-amine, d. adding di-tert-butyl dicarbonate to 2-(5-Methoxy-1H-indol-3-yl)- N-methylethan-1-amine in dichloromethane to produce tert- Butyl (2-(5-methoxy-1H-indol-3-yl)ethyl)(methyl)carbamate, e. adding tert-butyl (2-(5-methoxy-1H-indol-3- yl)ethyl)(methyl)carbamate to lithium aluminum hydride then water, followed by an aqueous solution comprising NaOH and diethyl ether to form a precipitate comprising 2-(5-Methoxy-1H- indol-3-yl)-N,N-dimethylethan-1-amine, and f. adding boron tribromide to 2-(5-methoxy-1H-indol-3-yl)-N,N- dimethylethan-1-amine in dichloromethane to form bufotenin hydrobromide.