WO2023044577A1 - Recovery method for tryptamines - Google Patents

Abstract

A recovery method for tryptamines of formula (I) and/or indolealkylamines of formula (II). The method incorporates an aluminum binding agent which is added prior to, during or following quenching of the reduction reaction. This allows for greater recovery of said tryptamines and/or indolealkylamines. The binding agents can be selected from a Lewis base (e.g. fluoride) or a chelating agent (e.g. triethanolamine).

Description

RECOVERY METHOD FOR TRYPTAMINES

CROSS-REFERENCE TO RELATED APPLICATION

[0001] This Patent Application claims priority from United States Provisional patent Application No. 63/247,845, filed September 24, 2021 and entitled RECOVERY METHOD FOR TRYPTAMINES, the entirety of which is hereby incorporated by reference.

FIELD

[0002] The present disclosure relates to recovery of tryptamines.

BACKGROUND

[0003] Psilocin and other tryptamines may be prepared synthetically from indole compounds, such as 4-hydroxy indole, which may be used to synthesize psilocin. When psilocin or other tryptamines are prepared from indole compounds, a glyoxylamide intermediate may be prepared from 4-acetyl indole or other indole compounds. The glyoxylamide intermediate may be reduced to form psilocin. Psilocin is unstable in oxygen and yield of psilocybin or other downstream tryptamines may be limited by breakdown of psilocin after reduction of a glyoxylamide intermediate.

[0004] Syntheses of psilocybin by a method including reduction with LiAIH4 in tetrahydrofuran (“THF”) or 2-methyl-tetrahydrofuran (“2-Me-THF”) has been undertaken by a number of researchers. US Patent Nos. 10,519,175; 10,947,257 and 10,954,259, each to Londesbrough, each provide a method that includes destruction of excess hydride by addition of an acetone quench, and cake formation by the addition of 20% citric acid in H2O, followed by cake extraction and wash with THF to recover the product. A method published by Shirota, 2003 further includes quenching with a saturated aqueous Na2SO4, cake formation with anhydrous Na2SO4, followed by cake extraction and wash with ethyl acetate to recover the product. A method published by the Usona Institute further includes quenching with a THF/H2O solution, followed by cake formation with silica gel and anhydrous Na2SO4. Cake extraction and wash was performed with dichloromethane (“DCM”) mixed with methanol (“MeOH”), followed by recovery in the resultant DCM/MeOH/THF/2-Me-THF solution. An alternative method published by Sherwood and Karbo further includes quenching with Na2SO4*10 H2O, a filtration of the solution through silica gel and a washing of the silica gel with DCM/MeOH, followed by compound recovery in the DCM/MeOH/2-Me-THF solution.

SUMMARY

[0005] In view of the shortcomings of previous approaches to recovery of tryptamines, there is motivation to provide an improved method. In some cases, psilocin, other tryptamines or other indolealkylamines may be unstable and prone to degradation prior to recovery where the tryptamines or other indolealkylamines are recovered slowly from reduction reactions during workup.

[0006] A method for synthesis and recovery of tryptamines is described herein. Following reduction, such as with LiAIF , the workup used in the method includes addition of an aluminum binding compound. Addition of the aluminum binding compound may facilitate recovery of labile compounds that adhere to the AI(OH)3 cake. Such labile compounds may be found in a reductive reaction mixture produced during synthesis of tryptamines or other indolealkylamines near the end of a synthetic plan that includes reduction of a glyoxylamide to a tryptamine, or other indoleketoalkylamides to other indolealkylamines (e.g. 3-aminopropylindole, 3-aminobutylindole, 3-aminopentylindole, 3-aminohexylindole, 3-aminoheptylindole, 3-aminooctylindole, etc.).

[0007] Triethanolamine or other chelating agents may be included in workup of reductive reaction mixtures to capture Al³⁺ and facilitate recovery of amino alcohols from LiAIF reductions. Fluoride may alternatively or also be included in workup of reductive reaction mixtures to bind and capture Al³⁺. Fluoride may also facilitate removal of contaminants including [3-hydroxy-tryptamines. Both triethanolamine and fluoride facilitate migration of the tryptamine from the filter cake to the mother liquor. Reduction synthesis using LiAIF of Psilocin or other tryptamines that are amino alcohols, or that are amines with other functional groups that may bind Al³⁺, may adhere to a cake through interactions with aluminum or other by-products of the reaction following reduction of a glyoxylamide to psilocin, other tryptamines with hydroxyl substitution on the indole ring, other tryptamines with ligands other than alcohol that bind Al³⁺ on the indole ring, or other indolealkylamines that bind Al³⁺ may also benefits from application of the method described herein. Interaction between tryptamines and Al³⁺ may be particularly strong where the tryptamine is a 4-substituted tryptamine and where the substituent on the ring is suitable for binding metal ions. Interaction between tryptamines and Al³⁺ may be particularly strong where the tryptamine has relatively little steric hinderance on the amine group, such as dimethylated, diethylated, methylethylated, methylated, ethylated, or amines that are not alkylated (i.e. primary amines). Physical manipulation of the cake to break the cake up following quenching with water or another hydride target may be unnecessary where fluoride is added to the cake prior to quenching.

[0008] Adding fluoride to a reductive reaction mixture may increase the potential recoverable amount of a tryptamine by reducing the time spent in contact with oxygen during workup of a reductive reaction mixture. Adding fluoride to a reductive reaction mixture may also facilitate recovery of a greater percentage of the recoverable tryptamine. Without being bound by any particular theory, fluoride may reduce time spent in contact with oxygen during workup by binding and sequestering Al³⁺, displacing the tryptamine from binding with Al³⁺ and facilitating more rapid recovery of the tryptamine than without the fluoride. Without being bound by any theory, fluoride may also react with and degrade [3-hydroxy tryptamine contaminants that sometimes result from incomplete reduction of glyoxylamides. Fluoride may be provided to the reductive reaction mixture paired with Li⁺, Na⁺, K⁺, Be²⁺, Mg²⁺, Ca²⁺ or any suitable cation that will dissociate from F- in solution at the prevailing conditions in the reductive reaction mixture.

[0009] Adding triethanolamine or other chelating agents to a reductive reaction mixture may increase the potential recoverable amount of a tryptamine by reducing the time spent in contact with oxygen during workup of a reductive reaction mixture. Without being bound by any particular theory, a chelating agent may reduce time spent in contact with oxygen during workup by binding and sequestering Al³⁺, displacing the tryptamine from binding with Al³⁺ and facilitating more rapid recovery of the tryptamine than without the chelating agent. Without being bound by any particular theory, triethanolamine or other chelating agents are unlikely to facilitate degradation of [3-hydroxy tryptamine contaminants.

[0010] The method may be applied to tryptamines or other indole alkylamines that are substituted at the 4-position of the indole ring, substituted at the 5-position of the indole ring, substituted at other indole ring positions or unsubstituted on the indole ring. Substituents on the indole ring may include acetyl, hydroxy, alkoxyl, benzyloxy, chloride, fluoride or any suitable functional group that is likely to resist degradation during reduction of a glyoxylamide to a tryptamine or other indolealkylamine.

[0011] The terminal nitrogen of the tryptamine or other indolealkylamine may be a primary, secondary, tertiary or quaternary nitrogen. Substituents on the terminal nitrogen may include H, any alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, n- pentyl, 2-isopentyl, 3-isopentyl, n-hexyl, 2-isohexyl, 3-isohexyl, etc), cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), aromatic (e.g. benzyl, etc.) or functionalized groups, ranging in size from Ci to Ce. The substituents on the terminal amine nitrogen may include two identical substituents, two distinct substituents, three identical substituents, two identical substituents and one distinct substituent, or three distinct substituents. Single-chain cyclic groups on the terminal N may include the amine within the cyclized single-chain group (e.g. piperidinyl glyoxylamide, pyrrolidinyl glyoxylamide, azetidinyl glyoxylamide, piperidinyl indoleketoalkylamide, pyrrolidinyl indoleketoalkylamide, azetidinyl indoleketoalkylamide, etc.).

[0012] In a first aspect, herein provided is a recovery method for tryptamines or other indolealkylamines. A reductive reaction mixture including ionic aluminum and a tryptamine product is provided. An aluminum binding agent is added to the reaction mixture prior to, during or following quenching with of the reduction reaction. Quenching of the reaction mixture results in formation of a cake including ionic aluminum, which may bind with tryptamines, slowing and reducing potential recovery of the tryptamines. The aluminum binding agent may preferentially bind with aluminum, displacing tryptamines bound to the aluminum and facilitating recovery of the tryptamines. The aluminum binding agent may be a Lewis base such as fluoride. The aluminum binding agent may a chelating agent such as triethanolamine. The tryptamine may include psilocin, DMT, 5- MeO-DMT or other tryptamines, and the method may be applied to indolealkylamines other than tryptamines.

[0013] In a further aspect, herein provided is a method of recovering a tryptamine comprising: providing a reductive reaction mixture comprising the tryptamine and Al³⁺ ions; combining an aluminum binding agent with the reaction mixture; combining a quenching agent with the reaction mixture; combining a recovery solvent with the reaction mixture; and recovering the tryptamine in the recovery solvent.

[0014] In some embodiments, the tryptamine has the following structure (I):

(I) wherein: R1 comprises H, or an alkyl, cycloalkyl or aromatic group ranging in size from Ci to Ce; R2 comprises H, or an alkyl, cycloalkyl or aromatic group ranging in size from Ci to Ce; R3 comprises H, hydroxyl, benzyloxy, alkoxy, chloride or fluoride; R4 comprises H or hydroxyl, benzyloxy, alkoxy, chloride or fluoride; Rs comprises H, hydroxyl, benzyloxy, alkoxy, chloride or fluoride; Re comprises H or hydroxyl, benzyloxy, alkoxy, chloride or fluoride; and R7 comprises H or hydroxyl, benzyloxy, alkoxy, chloride or fluoride. In some embodiments, R1 and R2 are together a single cycloalkyl group that includes a tertiary amine nitrogen N within the single cycloalkyl group. In some embodiments, providing the reductive reaction mixture comprises combining a reagent with LiAIH4. In some embodiments, the reductive reaction mixture comprises byproducts of reduction of the reagent with LiAIH4. In some embodiments, the reductive reaction mixture comprises byproducts of reduction of a reagent with LiAIH4. In some embodiments, the aluminum binding agent comprises a Lewis base. In some embodiments, the Lewis base is selected from the group consisting of F-, RH2O, ROH, NH₃, SO4²; CO, PR3, Ch, Br, I; NO3; RSH, R2S and ON’. In some embodiments, the aluminum binding agent comprises a chelating agent. In some embodiments, the chelating agent comprises a compound selected from the group consisting of triethanolamine, 1 ,2-ethanediamine, acetylacetonate ion, oxalate or ethanedioate ion, N,N,N',N'-ethylenediaminetetraacetate ion (“EDTA”), ethylene glycol- bis([3-aminoethyl ether)-N,N,N',N'-tetraacetic acid (“EGTA”), trans-1 ,2- diaminocyclohexane-N,N,N'N'-tetraacetic acid (“CDTA”), L-glutamic acid N,N-diacetic acid, tetrasodium salt (“GLDA”), methylglycinediacetic acid (“MGDA”), nitrilotriacetic acid (“NTA”), hydroxyethyl ethylenediamine triacetic acid trisodium salt (“HEDTA”), diethylenetriamene pentaacetatic acid (“DTPA”), oxalic acid, malic acid and tartaric acid. In some embodiments, combining the quenching agent with the reaction mixture comprises combining the quenching agent with the reaction mixture after combining the aluminum binding agent with the reaction mixture. In some embodiments, combining the quenching agent with the reaction mixture comprises combining the quenching agent with the reaction mixture concomitantly with combining the aluminum binding agent with the reaction mixture.

[0015] In a further aspect, herein provided is a method of recovering an indolealkylamine comprising: providing a reductive reaction mixture comprising the indolealkylamine and Al³⁺ ions; combining an aluminum binding agent with the reaction mixture; combining a quenching agent with the reaction mixture; combining a recovery solvent with the reaction mixture; and recovering the indolealkylamine in the recovery solvent. In some embodiments, the indolealkylamine has the following structure (II):

wherein:-n is an integer from 1 to 6; R1 comprises H, or an alkyl, cycloalkyl or aromatic group ranging in size from Ci to Ce; R2 comprises H, or an alkyl, cycloalkyl or aromatic group ranging in size from Ci to Ce; R3 comprises H, hydroxyl, benzyloxy, alkoxy, chloride or fluoride; R4 comprises H or hydroxyl, benzyloxy, alkoxy, chloride or fluoride; Rs comprises H, hydroxyl, benzyloxy, alkoxy, chloride or fluoride; Re comprises H or hydroxyl, benzyloxy, alkoxy, chloride or fluoride; and R7 comprises H or hydroxyl, benzyloxy, alkoxy, chloride or fluoride. In some embodiments, R1 and R2 are together a single cycloalkyl group that includes a tertiary amine nitrogen N within the single cycloalkyl group. In some embodiments, providing the reductive reaction mixture comprises combining a reagent with LiAIH4. In some embodiments, the reductive reaction mixture comprises byproducts of reduction of the reagent with LiAIH4. In some embodiments, the reductive reaction mixture comprises byproducts of reduction of a reagent with LiAIH4. In some embodiments, the reagent comprises an indoleketoalkylamides. In some embodiments, the aluminum binding agent comprises a Lewis base. In some embodiments, the Lewis base is selected from the group consisting of F-, RH₂O, ROH, NH₃, SO4²; CO, PR3, Ch, Br, I; NO3; RSH, R2S and CN^_. In some embodiments, the aluminum binding agent comprises a chelating agent. In some embodiments, the chelating agent comprises a compound selected from the group consisting of triethanolamine, 1 ,2-ethanediamine, acetylacetonate ion, oxalate or ethanedioate ion, N,N,N',N'-ethylenediaminetetraacetate ion (“EDTA”), ethylene glycol- bis([3-aminoethyl ether)-N,N,N',N'-tetraacetic acid (“EGTA”), trans-1 ,2- diaminocyclohexane-N,N,N'N'-tetraacetic acid (“CDTA”), L-glutamic acid N,N-diacetic acid, tetrasodium salt (“GLDA”), methylglycinediacetic acid (“MGDA”), nitrilotriacetic acid (“NTA”), hydroxyethyl ethylenediamine triacetic acid trisodium salt (“HEDTA”), diethylenetriamene pentaacetatic acid (“DTPA”), oxalic acid, malic acid and tartaric acid. In some embodiments, combining the quenching agent with the reaction mixture comprises combining the quenching agent with the reaction mixture after combining the aluminum binding agent with the reaction mixture. In some embodiments, combining the quenching agent with the reaction mixture comprises combining the quenching agent with the reaction mixture concomitantly with combining the aluminum binding agent with the reaction mixture.

[0016] Other aspects and features of the present disclosure will become apparent to those ordinarily skilled in the art upon review of the following description of specific embodiments in conjunction with the accompanying figures.

DETAILED DESCRIPTION

[0017] Generally, the present disclosure provides a method for synthesis and recovery of tryptamines. The present method may also be applied to other indolealkylamines, such as indolealkylamines with a side chain longer than two carbons (e.g. 3-aminopropylindole, 3-aminobutylindole, 3-aminopentylindole, 3-aminohexylindole, 3-aminoheptylindole, 3-aminooctylindole, etc.).

[0018] During synthesis of psilocybin, other tryptamines that are phosphorylated on the indole ring, other indole-substituted tryptamines with functional group at the 4 position or other indolealkylamines with a functional group at the 4 position, a 4- hydroxylated tryptamine (e.g. 4-hydroxy-N,N-dimethyltryptamine (“4-OH-DMT” or psilocin), 4-hydroxy-N,N-diethyltryptamine (“4-OH-DET”), 4-hydroxy-N,N- dipropyltryptamine (“4-OH-DPT”), 4-hydroxy-N,N-diisopropyltryptamine (“4-OH-DiPT”), 4-hydroxy-N-methyl-N-ethyltryptamine (“4-OH-MET”), 4-hydroxy-N-methyl-N- propyltryptamine (“4-OH-MPT”), 4-hydroxy-N-methyl-N-isopropyltryptamine (“4-OH- MiPT”), 4-hydroxy-N-ethyl-N-propyltryptamine (“4-OH-EPT”), 4-hydroxy-N-ethyl-N- isopropyltryptamine (“4-OH-EiPT”), 4-hydroxy-N-propyl-N-isopropyltryptamine (“4-OH- PiPT”), etc.), or other 4-hydroxylated indolealkylamine, such as any of the foregoing 4- OH N-alkylation patterns on indolealkylamines with a side chain longer than two carbons (e.g. 3-aminopropylindole, 3-aminobutylindole, 3-aminopentylindole, 3-aminohexylindole, 3-aminoheptylindole, 3-aminooctylindole, etc.), may be an intermediate prior to substitution of the hydroxyl with phosphate or another functional group. End products may also include 4-hydroxylated tryptamines or other 4-hydroxylated indolealkylamines. [0019] In some cases, a 4-substituted-glyoxylamide (I) is reduced to the intermediate 4-hydroxy tryptamine (II) with a reducing agent, as shown in Eq. 1 :

[0020] In Eq. 1 , a generalized substitution pattern on the amine group is shown. Each of Ri and R2 may independently include H, any alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, n-pentyl, 2-isopentyl, 3-isopentyl, n-hexyl, 2-isohexyl, 3- isohexyl, etc), cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), aromatic (e.g. benzyl, etc.) or functionalized groups, ranging in size from Ci to Ce. R1 and R2 may be identical to each other or may be distinct. Single-chain cyclic groups on the terminal N may include the both R1 and R2 as points of connection between the amine nitrogen and a cyclized single-chain group (e.g. piperidinyl glyoxylamide, pyrrolidinyl glyoxylamide, azetidinyl glyoxylamide, piperidinyl indoleketoalkylamide, pyrrolidinyl indoleketoalkylamide, azetidinyl indoleketoalkylamide, etc.). R3 may be acetyl or any suitable functional group that may be reduced to a hydroxyl group.

[0021] In the case of psilocybin synthesis, the intermediate 4-hydroxy tryptamine (II) of Eq. 1 is psilocin, both R1 and R2 are methyl groups and the R3 group is typically an acetyl group, as shown below in Eq. 2. The functional group R3 at position 4 may be any suitable functional group for the end product being synthesized. The functional group at position 4 may be further derivatized to other functional groups, for example to phosphate when producing psilocybin or other phosphorylated tryptamines.

[0022] Equation 2 shows synthesis of psilocin (IV) by reduction. In Eq. 2, N,N- dimethyl-4-acetoxy-indole-3-yl-glyoxylamide (III) is the 4-substituted glyoxylamide and psilocin (IV) is the 4-hydroxylated tryptamine:

[0023] A standard approach to reducing a 4-substituted N-alkylated glyoxylamide intermediate as in Eqs. 1 and 2 is to use LiAIH4. Where the 4-substituted glyoxylamide carries a functional group that can also be reduced by using LiAIF , reduction results in production of a 4-hydroxylated tryptamine, as is shown in both Eq. 1 and Eq. 2. Formation of a cake of AI(OH)s accompanies reduction of the glyoxylamide.

[0024] The method may facilitate improved yield or other benefits when producing tryptamines or other indolealkylamines, including tryptamines or other indolealkylamines that are substituted at position 4 or elsewhere on the indole ring with a hydroxyl group or other functional group that may bind with Al³⁺. The terminal amine group on the side chain of tryptamine, or on indolealkylamines with longer side chains, may also bind with Al³⁺. In tryptamines, the side chain amine may coordinate with Al³⁺ bound to the 4- position, forming a stronger bidentate bond. In other indolealkylamines bidentate bonds may also be possible with 5, 6 or 7-substituted tryptamines. Binding of Al³⁺ to the terminal amine may be particularly likely where the terminal amine group is a primary or secondary amine, or where the terminal amine group is alkylated or otherwise derivatized with smaller substituents that present minimal steric hinderance to binding with Al³⁺.

[0025] The method may be applied to produce unsubstituted tryptamines, which do not include functional groups on the indole ring (e.g. N,N-dimethyltryptamine (“DMT” or psilocin), N,N-diethyltryptamine (“DET”), N,N-dipropyltryptamine (“DPT”), N,N- diisopropyltryptamine (“DiPT”), N-methyl-N-ethyltryptamine (“MET”), N-methyl-N- propyltryptamine (“MPT”), N-methyl-N-isopropyltryptamine (“MiPT”), N-ethyl-N- propyltryptamine (“EPT”), N-ethyl-N-isopropyltryptamine (“EiPT”), N-propyl-N- isopropyltryptamine (“PiPT”), etc.), or other indolealkylamines that are unsubstituted, which do not include functional groups on the indole ring, such as any of the foregoing unsubstituted N-alkylation patterns on indolealkylamines with a side chain longer than two carbons (e.g. 3-aminopropylindole, 3-aminobutylindole, 3-aminopentylindole, 3- aminohexylindole, 3-aminoheptylindole, 3-aminooctylindole, etc.), as shown in Eq. 3:

[0026] In Eq. 3, a generalized substitution pattern on the amine group is shown in both the glyoxylamide (V) and the tryptamine (VI). Each of Ri and R2 may independently include H, any alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, n-pentyl, 2- isopentyl, 3-isopentyl, n-hexyl, 2-isohexyl, 3-isohexyl, etc), cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), aromatic (e.g. benzyl, etc.) or functionalized groups, ranging in size from Ci to Ce. R1 and R2 may be identical to each other or may be distinct. Single-chain cyclic groups on the terminal N may include the both R1 and R2 as points of connection between the amine nitrogen and a cyclized single-chain group (e.g. piperidinyl glyoxylamide, pyrrolidinyl glyoxylamide, azetidinyl glyoxylamide, piperidinyl indoleketoalkylamide, pyrrolidinyl indoleketoalkylamide, azetidinyl indoleketoalkylamide, etc.). [0027] The method may be applied to produce 5-hydroxylated tryptamines (e.g. 5- hydroxy-N,N-dimethyltryptamine (“5-OH-DMT” or psilocin), 5-hydroxy-N,N- diethyltryptamine (“5-OH-DET”), 5-hydroxy-N,N-dipropyltryptamine (“5-OH-DPT”), 5- hydroxy-N,N-diisopropyltryptamine (“5-OH-DiPT”), 5-hydroxy-N-methyl-N- ethyltryptamine (“5-OH-MET”), 5-hydroxy-N-methyl-N-propyltryptamine (“5-OH-MPT”), 5- hydroxy-N-methyl-N-isopropyltryptamine (“5-OH-MiPT”), 5-hydroxy-N-ethyl-N- propyltryptamine (“5-OH-EPT”), 5-hydroxy-N-ethyl-N-isopropyltryptamine (“5-OH-EiPT”), 5-hydroxy-N-propyl-N-isopropyltryptamine (“5-OH-PiPT”), etc.), or other 5-hydroxylated indolealkylamine, such as any of the foregoing 5-OH N-alkylation patterns on indolealkylamines with a side chain longer than two carbons (e.g. 3-aminopropylindole, 3-aminobutylindole, 3-aminopentylindole, 3-aminohexylindole, 3-aminoheptylindole, 3- aminooctylindole, etc.), may be an intermediate prior to substitution of the hydroxyl with phosphate or another functional group. End products may also include 5-hydroxylated tryptamines or other 5-hydroxylated indolealkylamines, as shown in Eq. 4:

[0028] In Eq. 4, a generalized substitution pattern on the amine group is shown in both the glyoxylamide (VII) and the tryptamine (VIII). Each of Ri and R2 may independently include H, any alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, n-pentyl, 2-isopentyl, 3-isopentyl, n-hexyl, 2-isohexyl, 3-isohexyl, etc), cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), aromatic (e.g. benzyl, etc.) or functionalized groups, ranging in size from Ci to Ce. R1 and R2 may be identical to each other or may be distinct. Single-chain cyclic groups on the terminal N may include the both R1 and R2 as points of connection between the amine nitrogen and a cyclized singlechain group (e.g. piperidinyl glyoxylamide, pyrrolidinyl glyoxylamide, azetidinyl glyoxylamide, piperidinyl indoleketoalkylamide, pyrrolidinyl indoleketoalkylamide, azetidinyl indoleketoalkylamide, etc.). R3 may be acetyl or any suitable functional group that may be reduced to a hydroxyl group. [0029] The method may be applied to produce tryptamines or other indolealkylamines that are substituted with a methoxy group on the indole ring at position 4 (e.g. 4-methoxy-N,N-dimethyltryptamine (“4-MeO-DMT” or psilocin), 4-methoxy-N,N- diethyltryptamine (“4-MeO-DET”), 4-methoxy-N,N-dipropyltryptamine (“4-MeO-DPT”), 4- methoxy-N,N-diisopropyltryptamine (“4-MeO-DiPT”), 4-methoxy-N-methyl-N- ethyltryptamine (“4-MeO-MET”), 4-methoxy-N-methyl-N-propyltryptamine (“4-MeO- MPT”), 4-methoxy-N-methyl-N-isopropyltryptamine (“4-MeO-MiPT”), 4-methoxy-N-ethyl- N-propyltryptamine (“4-MeO-EPT”), 4-methoxy-N-ethyl-N-isopropyltryptamine (“4-MeO- EiPT”), 4-methoxy-N-propyl-N-isopropyltryptamine (“4-MeO-PiPT”), etc.), or other 4- methoxylated indolealkylamine, such as any of the foregoing 4-MeO N-alkylation patterns on indolealkylamines with a side chain longer than two carbons (e.g. 3-aminopropylindole, 3-aminobutylindole, 3-aminopentylindole, 3-aminohexylindole, 3-aminoheptylindole, 3- aminooctylindole, etc.), or substituted on the indole ring at position 4 with other groups that remain after reduction with LiAIH4, as shown in Eq. 5:

[0030] In Eq. 5, a generalized substitution pattern on the amine group is shown in both the glyoxylamide (IX) and the tryptamine (X). Each of Ri and R2 may independently include H, any alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, n-pentyl, 2- isopentyl, 3-isopentyl, n-hexyl, 2-isohexyl, 3-isohexyl, etc), cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), aromatic (e.g. benzyl, etc.) or functionalized groups, ranging in size from Ci to Ce. R1 and R2 may be identical to each other or may be distinct. Single-chain cyclic groups on the terminal N may include the both R1 and R2 as points of connection between the amine nitrogen and a cyclized single-chain group (e.g. piperidinyl glyoxylamide, pyrrolidinyl glyoxylamide, azetidinyl glyoxylamide, piperidinyl indoleketoalkylamide, pyrrolidinyl indoleketoalkylamide, azetidinyl indoleketoalkylamide, etc.). R3 may be any alkoxyl, benzyloxy, chloride, fluoride or any other suitable group that would not be reduced by LiAIH4.

[0031] The method may be applied to produce tryptamines or other indolealkylamines that are substituted with a methoxy group on the indole ring at position 5 (e.g. 5-methoxy-N,N-dimethyltryptamine (“5-MeO-DMT” or psilocin), 5-methoxy-N,N- diethyltryptamine (“5-MeO-DET”), 5-methoxy-N,N-dipropyltryptamine (“5-MeO-DPT”), 5- methoxy-N,N-diisopropyltryptamine (“5-MeO-DiPT”), 5-methoxy-N-methyl-N- ethyltryptamine (“5-MeO-MET”), 5-methoxy-N-methyl-N-propyltryptamine (“5-MeO- MPT”), 5-methoxy-N-methyl-N-isopropyltryptamine (“5-MeO-MiPT”), 5-methoxy-N-ethyl- N-propyltryptamine (“5-MeO-EPT”), 5-methoxy-N-ethyl-N-isopropyltryptamine (“5-MeO- EiPT”), 5-methoxy-N-propyl-N-isopropyltryptamine (“5-MeO-PiPT”), etc.), or other 5- methoxylated indolealkylamine, such as any of the foregoing 5-MeO N-alkylation patterns on indolealkylamines with a side chain longer than two carbons (e.g. 3-aminopropylindole, 3-aminobutylindole, 3-aminopentylindole, 3-aminohexylindole, 3-aminoheptylindole, 3- aminooctylindole, etc.), or substituted on the indole ring at position 5 with other groups that remain after reduction with LiAIH4, as shown in Eq. 6:

[0032] In Eq. 6, a generalized substitution pattern on the amine group is shown in both the glyoxylamide (XI) and the tryptamine (XII). Each of Ri and R2 may independently include H, any alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, n-pentyl, 2- isopentyl, 3-isopentyl, n-hexyl, 2-isohexyl, 3-isohexyl, etc), cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), aromatic (e.g. benzyl, etc.) or functionalized groups, ranging in size from Ci to Ce. R1 and R2 may be identical to each other or may be distinct. Single-chain cyclic groups on the terminal N may include the both R1 and R2 as points of connection between the amine nitrogen and a cyclized single-chain group (e.g. piperidinyl glyoxylamide, pyrrolidinyl glyoxylamide, azetidinyl glyoxylamide, piperidinyl indoleketoalkylamide, pyrrolidinyl indoleketoalkylamide, azetidinyl indoleketoalkylamide, etc.). R3 may be any alkoxyl, benzyloxy, chloride, fluoride or any other suitable group that would not be reduced by LiAIH4.

[0033] In addition the tryptamines shown in Egs. 1 to 6, other ring-substituted tryptamines may be synthesized from glyoxylamides that are substituted on positions 2, 6 or 7 of the indole ring, either in addition to substitution at positions 4, 5 or both, or instead of substitution at positions 4, 5 or both. Such additional indole ring substitution positions may carry any alkoxyl, benzyloxy, chloride, fluoride or any other suitable group that would not be reduced by LiAIH4.

[0034] Other examples of indolealkylamines that may be synthesized using reduction with LiAIH4 include indolealkylamines reduced from indoleketoalkylamides with more than two carbons between the indole ring and the terminal amine. For example, reaction of diacylchlorides other than oxalyl chloride are with indole compounds may result in indoleketoalkylamides with more than two carbons between the indole ring and the terminal amine, which may in turn be reduced with LiAIF , as shown in Eq. 7.

Eq. 7 [0035] In Eq. 7, a generalized substitution pattern on the amine group is shown in both the indoleketoalkylamide (XII) and the indolealkylamine (XIII). The interger n may be any value from 1 to 6, providing side chains between three and eight carbons in length and corresponding to 3-aminopropylindole, 3-aminobutylindole, 3-aminopentylindole, 3- aminohexylindole, 3-aminoheptylindole and 3-aminooctylindole compounds. Each of R1 and R2 may independently include H, any alkyl (e.g. methyl, ethyl, n-propyl, isopropyl, n- butyl, iso-butyl, n-pentyl, 2-isopentyl, 3-isopentyl, n-hexyl, 2-isohexyl, 3-isohexyl, etc), cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), aromatic (e.g. benzyl, etc.) or functionalized groups, ranging in size from Ci to Ce. R1 and R2 may be identical to each other or may be distinct. Single-chain cyclic groups on the terminal N may include the both Ri and R2 as points of connection between the amine nitrogen and a cyclized single-chain group (e.g. piperidinyl glyoxylamide, pyrrolidinyl glyoxylamide, azetidinyl glyoxylamide, piperidinyl indoleketoalkylamide, pyrrolidinyl indoleketoalkylamide, azetidinyl indoleketoalkylamide, etc.). R3 may be any alkoxyl, benzyloxy, chloride, fluoride or any other suitable group that would not be reduced by LiAIH4. R4 may be any alkoxyl, benzyloxy, chloride, fluoride or any other suitable group that would not be reduced by LiAIH4. Rs may be any alkoxyl, benzyloxy, chloride, fluoride or any other suitable group that would not be reduced by LiAIH4. Re may be any alkoxyl, benzyloxy, chloride, fluoride or any other suitable group that would not be reduced by LiAIH₄.

[0036] The reactions shown in Eqs. 1 to 7 each include reduction of a glyoxylamide or other indoleketoalkylamide with excess LiAIH4. During workup, water, acetone or another oxidizing agent may be added to quench any remaining active FT. This leaves LiOH and AI(OH)3, both of which precipitate. Addition of the oxidizing agent modifies the mechanical characteristics of the resultant filter cake. The AI(OH)s precipitate may form the filter cake, which may have a colloidal form with low porosity that complicates filtration. [0037] 4-substituted-tryptamines, unsubstituted tryptamines and 5-substituted- tryptamines may adhere to the AI(OH)s cake through binding with the Al³⁺.

[0038] 4-hydroxy tryptamines and 5-hydroxy-tryptamines may bind to the AI(OH)s cake through coordination between the electron-rich hydroxyl group on the indole ring, the electron-rich nitrogen group and the Al³⁺.

[0039] Tryptamines or other indolealkylamines that lack a functional group on the ring, such as DMT and DET, may bind to Al³⁺ and adhere to the cake without coordinate binding. With these molecules lacking a functional group on the ring, mechanical washing may be effective to remove mother liquor and product from the cake. Binding of ring- substituted tryptamines or other indolealkylamines to Al³⁺ or another metal ion, particularly with 4-substituted tryptamines or other indolealkylamines, requires much more vigorous washing of the cake with larger volumes of solvent and physical agitation of the cake in the extraction solvent.

[0040] Bidentate binding of ring-substituted tryptamines or other indolealkylamines may occur through coordination of Al³⁺ between both hydroxyl groups on the indole ring and the amine on the side chain. Other tryptamines and other indolealkylamines, regardless of whether substituted on the indole ring, may also adhere to the Al³⁺ cake. Adhering of the tryptamines or other indolealkylamines may with the cake may decrease recovery of tryptamines or other indolealkylamines by washing the cake. A result of one or both of binding between the Al³⁺, and the tryptamines or other indolealkylamines, is to limit the speed at which tryptamines or other indolealkylamines may be recovered from the cake. For any tryptamines or other indolealkylamines that are susceptible to oxidative degradation, such as psilocin, longer residence time on the cake may result in greater amounts of the tryptamine or other indolealkylamine being degraded.

[0041] During manipulation of certain tryptamines or other indolealkylamines while on the cake, the tryptamines or other indolealkylamines may oxidize and break down. This is particularly evident with psilocin and other 4-hydroxylated tryptamines or other indolealkylamines. Breakdown due to oxidation reduces the total recoverable material. Further, binding between 4-hydroxylated tryptamines or other indolealkylamines and the Al³⁺ reduces the amount of tryptamine or other indolealkylamine that may be recovered from the total recoverable product present.

[0042] Psilocin is a 4-hydroxylated tryptamine of particular interest in certain applications, both as a precursor to psilocybin and as an end product. Recovery of psilocin following quenching of the LiAIF after reduction may present a significant bottleneck in production of psilocin. Coordination between psilocin and Al³⁺ sequesters psilocin in the AI(OH)3 filter cake, reducing total potential recovery as a result of some psilocin tightly binding with the Al³⁺. In addition, due to coordinate binding and other adhering to the Al³⁺, the psilocin that is eluted from the cake may spend a greater amount of time in the presence of oxygen than would be the case without binding or adhering to the Al³⁺. The greater time spent in oxygen may result in a greater degree of oxidative decomposition, reducing total potential yield. Eluting as much product as possible, and as fast as possible, into the mother liquor from the cake, may mitigate the impact of oxidation, polymerization and other reactions that lower potential yield.

[0043] The AI(OH)3 cake retains a significant amount of psilocin. Visual observation of a sheen of organic solvents entrained in the cake suggests that the cake is not sufficiently porous for free flow of recovery solvents, or is otherwise blocking flow of solvents through the cake. This appearance is in contrast with a large-grained, grey plug having a dry and flaky appearance that would be expected if the cake were filtering in a manner that would be typically expected for a cake resulting from LiAIH4 reduction without binding or adhering of reaction products to the cake.

[0044] The cake may include supports (e.g. celite, silica, other inert material, etc.) that bind with impurities or provide a matrix to facilitate filtration. When water is used to quench the reduction reaction without such supports, the cake may include Al⁺³ bound to psilocin, and the quality of the cake becomes similar to clay - very densely packed and not conducive to effective filtration. The supports may mitigate this dense packing in close proximity to the supports but are unlikely to provide a complete solution to the dense packing that may result from tryptamines or indolealkylamines binding to Al³⁺ and impeding recovery of the tryptamines or indolealkylamines and adhering to the cake. The supports may also conversely retard the speed of filtration by increasing the bulk of the cake, further prolonging time that psilocin is exposed to oxygen.

[0045] Triethanolamine, fluoride or both may be added to the cake to displace tryptamines or other indolealkylamines from the AI(OH)s cake. Fluoride and triethanolamine each disrupt binding between Al⁺³ and the tryptamines or other indolealkylamines. Fluoride may bind preferentially to Al⁺³ over psilocin due to high electronegativity of F displacing the tryptamine or other indolealkylamine from the AI(OH)3. Triethanolamine may bind preferentially to Al⁺³, mitigating coordinating with the psilocin through chelation of Al³⁺ by psilocin. Both fluoride and triethanolamine may be used together because each provides the advantage of disrupting coordinate bonds between Al⁺³ and the tryptamines through different mechanisms of action. With use of triethanolamine alone or fluoride and triethanolamine, some triethanolamine may be reduced to an amine by hydride. Any such amine, and any triethanolamine that does not react with hydride, would be recovered from the reaction mixture as a contaminant. In contrast, fluoride is likely to ionize and the F- form crystals or other complexes with Al³⁺, including AIF²⁺, AIF2⁺ or AIF3. The complexes may form part of the cake, allowing the tryptamine or other indolealkylamine to be recovered by redissolution.

[0046] Examples of reduction workup including fluoride, triethanolamine or NH4CI being added to the workup following synthesis of have been assayed for psilocin, 4-OH- MET, DMT, 5-MeO-DMT and 5-MeO-MiPT. DMT, 5-MeO-DMT and 5-MeO-MiPT in some cases filtered slowly through the cake, but psilocin and 4-OH-MET were in some casesa observed to elute more slowly from the cake. Without being bound by any theory, the relative differences between psilocin and 4-OH-MET on the one hand, and DMT, 5-MeO- DMT and 5-MeO-MiPT on the other, may be due to the absence of structural features on

DMT, 5-MeO-DMT and 5-MeO-MiPT that would support bidentate chemical binding, alongside the side chain amine, with the Al⁺³. Psilocin, 4-OH-MET or other 4-hydroxylated tryptamines may be more likely to form bidentate bonds between a single tryptamine molecule and a single Al³⁺ ion. The slowdown in filtration after quenching in the absence of triethanolam ine or fluoride was not as pronounced with DMT, 5-MeO-DMT and 5-MeO-

MiPT as with psilocin or with 4-OH-MET. In addition, there is oxidative degradation of DMT is less likely than oxidative degradation with psilocin. 4-substituted tryptamines that are bidentate may bind to Al³⁺ and other metals with greater affinity than tryptamines without phenolic substituents on the indole ring. [0047] In addition to triethanolamine, other chelating agents may be applied, including the chelating agents listed in the below Table of Chelating Agents.

Table of Chelating Agents

[0048] Fluoride salts may be added neat to the completed reduction mix. The fluoride salts may not dissolve in the THF and may be dispersed in the reaction mixture as a solid. When the water is added and the cake is formed, the fluoride salts dissolves and the Al³⁺ becomes bound to fluoride ions. As a result of the Al³⁺ being bound to fluoride ions, the tryptamine or other indolealkylamine being synthesized will have a smaller abundance of free Al⁺³ with which to bind. Fluoride may be provided to the reductive reaction mixture paired with Li⁺, Na⁺, K⁺, Be²⁺, Mg²⁺, Ca²⁺ or any suitable cation, as LiF, NaF, KF, BeF2, MgF2, CaF2, or any suitable salt, that will dissociate from F- in solution at the conditions in the reductive reaction mixture.

[0049] Synthesis of substituted and unsubstituted tryptamines may result in a [3- hydroxy contaminant formed during reduction. The [3-hydroxy contaminant has the following general formula (XV):

[0050] In formula (XV), each of Ri and R2 may independently include H, any alkyl

(e.g. methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, n-pentyl, 2-isopentyl, 3- isopentyl, n-hexyl, 2-isohexyl, 3-isohexyl, etc), cycloalkyl (e.g. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, etc.), aromatic (e.g. benzyl, etc.) or functionalized groups, ranging in size from Ci to Ce. R1 and R2 may be identical to each other or may be distinct. Single-chain cyclic groups on the terminal N may include the both Ri and R2 as points of connection between the amine nitrogen and a cyclized single-chain group (e.g. piperidinyl glyoxylamide, pyrrolidinyl glyoxylamide, azetidinyl glyoxylamide, piperidinyl indoleketoalkylamide, pyrrolidinyl indoleketoalkylamide, azetidinyl indoleketoalkylamide, etc.). R3 may be H, acetyl, alkoxy, benzyloxy or any suitable functional group, whether or not the functional group may be reduced to a hydroxyl group. R4 may be H, acetyl, alkoxy, benzyloxy or any suitable functional group, whether or not the functional group may be reduced to a hydroxyl group. Where synthesizing psilocin, R1 and R2 are methyl groups, R3 is hydroxyl and R4 is H.

[0051] Reduction of glyoxylamides with LiAIH4 in some cases does not proceed to completion, which has been observed with the glyoxylamide used to make DMT, psilocin, 4-OH-MET, 5-MeO-DMT, 5-MeO-MiPT and other tryptamines. As a result of this incomplete reaction, a [3-hydroxy contaminant may remain after reduction. Fluoride may react with and destroy the [3-hydroxy contaminant.

[0052] The [3-hydroxy contaminants resulting from psilocin synthesis, 2- dimethylamino-1 -(4-hydroxy-indol-3-yl)-ethanol, or similar compounds from other 4- substituted tryptamine syntheses, are unstable and the reaction during quenching of remaining LiAIFk may generate double bonded intermediates that in turn polymerize with the product tryptamine, further decreasing yield. The [3-hydroxy contaminant of 5- substituted tryptamines and unsubstituted tryptamines are each more stable than the corresponding [3-hydroxy contaminants of 4-OH-substituted tryptamines or other 4- substituted tryptamines that would remain in solution after reduction of a glyoxylamide with LiAIFU. Fluoride may facilitate decomposition of these unsubstituted or 5-substituted [3-hydroxy-tryptamine contaminants. After decomposition, the unsubstituted or 5- substituted tryptamine contaminants can be removed by purification methods such as chromatography, crystallization or distillation. The [3-hydroxy intermediate of 2- alkylamino-1 -(4-hydroxy-indol-3-yl)-ethanol compounds (also referred to herein as 4- hydroxy-[3-hydroxy-tryptamines) may be broken down by triethanolamine or other chelating agents. The [3-hydroxy intermediate of unsubstituted or 5-substituted [3- hydroxy-tryptamine contaminants are less likely to break down by triethanolamine or other chelating agents than 4-substituted examples. Addition of NH4OIO H2O in combination with the quench may facilitate breakdown of the 4-hydroxy-[3-hydroxy-tryptamines.

[0053] LiAIH4 reductions are usually carried out in ethereal solvents, since LiAIH4 forms a coordinate with the ether, facilitating the reduction. Toluene mixed with THF may also be used as a solvent, in which case the THF forms the coordinate with LiAIH4. Dichloromethane is not stable in the presence of LiAIH4 in solution. 2-methyl THF has a higher boiling point than THF, giving advantages in terms of reaction speed over THF. Chlorinated solvents may have an interaction with the cake, particularly where the chlorinated solvent includes a protic co-solvent like methanol, that results in formation of a gel, which may complicate identifying when all solvents are removed from the cake.

[0054] A sterically hindered basic nitrogen in the amine group may mitigate a bidentate interaction with a tryptamine relative to the interaction between Al⁺³ and psilocin, other dimethylated tryptamines or other tryptamines with relatively low steric hinderance at the amine group (e.g. N-methyl,N-ethyl, N,N-diethyl, N-methyl,N-isopropyl, N-methyl,N-propyl, etc.). Production of the dibenzyl precursor to norpsilocin (norpsilocin being 4-hydroxytryptamine and its precursor being 4-hydroxy-N,N, -dibenzyltryptamine) does not suffer the same decrease in yield as psilocin, which may be as a result of 4- hydroxy-N,N, -dibenzyltryptamine binding to Al⁺³ less tightly than psilocin. However, psilocin or any other 4-OH substituted tryptamines with relatively lower steric hinderance on the amine group are more likely to strongly bind Al³⁺. Like psilocin, norpsilocin synthesized from a singly N-methylated glyoxylamide would bind to Al³⁺ and be difficult to recover from the cake.

[0055] Residing on the cake during workup may result in a significant amount of decomposition. Participation of the alkyl amine groups may accelerate oxidation of psilocin on the solid support of the filter cake. Migliaccio et al (1980) discusses rotamers of psilocin, and while there is no data in Migliaccio about coordination of metal ions, it is clear that coordination between the sterically unhindered amine and the 4-OH group could coordinate a metal ion. A cis-rotamer of psilocin at the side chain toward the indole ring allows formation of a six-membered ring in with the sidechain and the 4-OH group participate. Configuration as the cis-rotamer allows psilocin base to be purified by chromatography. It is more difficult to purify 5-OH-DMT base than psilocin by chromatography as 5-OH-DMT is much more polar than psilocin due to an absence of conformational isomers in 5-OH-DMT that facilitate a bidentate bond of both the amine and the ring hydroxyl group with a cation.

[0056] In addition to F; additional Lewis bases that may be used to displace Al³⁺ include RHO, ROH, NH₃, SO4²; CO, PR3, Ch, Br, L, NO3; RSH, R2S and CN’. Where NH₃ is used, the NH₃ may be provided as NH4H2PO3, (NH₄)₂HPO3, NH₄CI, (NH₄)₂SO4 or any other suitable source of ammonia.

[0057] The chelating agent or the Lewis base may be added to the reaction mixture before or during addition of a quenching agent, such as acetone or water. A recovery solvent, such as THF, may be added to the reaction mixture after quenching.

[0058] Seven examples of tryptamines prepared in the presence of different aluminum binding agents are described below. In Example I, 4-OH-MET was synthesized with fluoride applied as the aluminum binding agent. In Example II, DMT was synthesized with fluoride applied as the aluminum binding agent. In Example III, 4-OH-MET was synthesized with NH4CI applied as the aluminum binding agent. In Example IV, psilocin was synthesized with triethanolamine as the aluminum binding agent. In Example V, psilocin was synthesized with fluoride applied as the aluminum binding agent. In Example VI, 5-MeO-DMT was synthesized with fluoride applied as the aluminum binding agent. In Example VII, 5-MeO-DiPT was synthesized with fluoride applied as the aluminum binding agent.

[0059] Mitigating binding of the tryptamine or other indolealkylamine sticking with the Al³⁺ cake is a benefit that applied primarily to 4-substituted tryptamines or other 4- substituted indolealkylamines. Eliminating the beta-hydroxy contaminant is a benefit to synthesis of tryptamines or other indolealkylamines more broadly.

[0060] Example I

[0061] Reduction of N-methyl,N-ethyl-4-acetoxy-indole-3-yl-glyloxylamide was completed at a 10-gram scale with a NaF I deionized H2O quench to synthesize 4-OH- MET. The reagents and solvents used in Example I are listed in Table 1 .

Table 1 : Reagents and Solvents Used in Example I

[0062] Anhydrous 2-methyl THF (130mL) was placed in a 3 neck 500mL round bottom flask equipped with mechanical stirring. A thermometer and an ice-salt bath were used for temperature monitoring and control. A 125mL pressure equalizing addition funnel was connected with the round bottom flask.

[0063] LiAIH4 pellets (4.22g, 0.111 mol, 3.2 eq) were added to the round bottom flask all at once accompanied by vigorous stirring. The mixture was cooled to 10 °C in the ice-salt bath after the dissolution of the pellets.

[0064] Solid N-methyl,N-ethyl-4-acetoxy-indole-3-yl-glyloxylamide (10.0 g, 0.0347 Mols) was added portionwise with a spoon. The reaction temperature was maintained below 30 °C by varying the addition rate.

[0065] After the addition of the N-methyl,N-ethyl-4-acetoxy-indole-3-yl- glyloxylamide, an efficient condenser was fitted and the reaction was heated at reflux to 82 °C, utilizing a heating mantle, for 12 hours.

[0066] Once thin layer chromatography showed that the reaction was complete, the round bottom flask was cooled to 5 °C in the ice-salt bath.

[0067] After the temperature of the reaction was cooled to 5 °C, powdered NaF (13.98 g, 0.333 M, 3 eq. LiAIF ) was added all at once with vigorous stirring. No visible reaction occurred upon addition of NaF.

[0068] The reaction was quenched with deionized water in THF after addition of NaF. Deionized H2O (6.0 g, 0.333 M, 3 eq. UAIH4) in THF (40 mL) was added dropwise, keeping the temperature under 15 °C by cooling in an ice bath. The reaction was stirred for 40 minutes and allowed to warm to 25 °C. Gas evolution was monitored to maintain safe reaction conditions and to determine when all H2O was added to ensure complete reaction of H2O with the LiAIH4. [0069] Ethyl acetate (120 mL) was added all at once and the stirring continued for 30 additional minutes. The resultant cake of AI(OH)s white solids was isolated onto filter paper placed over a bed of Celite in a Buchner fritted glass funnel.

[0070] The AI(OH)s cake was washed with ethyl acetate (150 mL) on the filter followed by resuspension of the AI(OH)s cake in ethyl acetate (200 mL). The mixture was stirred and the AI(OH)s cake refiltered. To refilter the AI(OH)s cake, the AI(OH)s cake was again washed with ethyl acetate (150 mL) on the filter followed again by resuspension of the AI(OH)3 cake in ethyl acetate (200 mL).

[0071] The filtrates were combined and concentrated by rotary evaporation to provide a yield of 6.7 g (0.0307 M, 88.4% of theoretical maximum recovery). Losses from quantitative recovery are likely due to destruction of the [3-hydroxy intermediate of 4-OH MET. The 4-OH MET base was further purified by trituration and recrystallization.

[0072] Example

[0073] Reduction of N-methyl,N-ethyl-4-acetoxy-indole-3-yl-glyloxylamide was completed at a 10-gram scale with a NH4CI I deionized H2O quench to synthesize 4-OH- MET. The reagents and solvents used in Example II are listed in Table 2.

Table 2: Reagents and Solvents Used in Example II

[0074] Anhydrous 2-methyl THF (130mL) was placed in a 3 neck 500mL round bottom flask equipped with mechanical stirring. A thermometer and an ice-salt bath were used for temperature monitoring and control. A 125mL pressure equalizing addition funnel was connected with the round bottom flask.

[0075] LiAIH4 pellets (4.22 g, 0.111 mol, 3.2 eq) were added to the round bottom flask all at once accompanied by vigorous stirring. The mixture was cooled to 10 °C in the ice-salt bath after the dissolution of the pellets. [0076] Solid N-methyl,N-ethyl-4-acetoxy-indole-3-yl-glyloxylamide (10.0 g, 0.0347 Mols) was added portionwise with a spoon. The reaction temperature was maintained below 30 °C by varying the addition rate.

[0077] After the addition of the N-methyl,N-ethyl-4-acetoxy-indole-3-yl- glyloxylamide, an efficient condenser was fitted and the reaction was heated at reflux to 82 °C, utilizing a heating mantle, for 12 hours.

[0078] Once thin layer chromatography showed that the reaction was complete, the round bottom flask was cooled to 5 °C in the ice-salt bath.

[0079] After the temperature of the reaction was cooled to 5 °C, the reaction was quenched with NH4CI solution followed by deionized water in THF. NH4CI (17.8 g, 0.333 Mols) in H2O (6.0 mL) was added dropwise with vigorous stirring, keeping the reaction temperature under 23 °C in an ice bath. Gas evolution was monitored to maintain safe reaction conditions and to determine when all the NH4CI has reacted with the LiAIH4 residue. After addition of the NH4CI, the temperature was raised to 30 °C by use of a water bath. The temperature was held at 30 °C for 1 hour to ensure complete reaction of NH4CI with the LiAIH₄.

[0080] Deionized H2O (6.0 g, 0.333 M, 3 eq/LiAIH4) in THF (40 mL) was added dropwise, keeping the temperature under 15 °C by cooling in an ice bath. Gas evolution was monitored to maintain safe reaction conditions and to when the quench was complete after addition of the deionized H2O. The reaction was stirred for 40 minutes and allowed to warm to 25 °C. Gas evolution was monitored to determine when the quench was complete.

[0081] Ethyl acetate (120 mL) was added all at once and the stirring continued for 30 additional minutes. The resultant cake of AI(OH)s gray solids and ammonium complexes were isolated onto filter paper and placed over a bed of Celite in a Buchner fritted glass funnel.

[0082] The AI(OH)s cake was washed with ethyl acetate (150 mL) on the filter followed by resuspension of the AI(OH)s cake in ethyl acetate (200 mL). The mixture was stirred and the AI(OH)s cake refiltered. To refilter the AI(OH)s cake, the AI(OH)s cake was again washed with ethyl acetate (150 mL) on the filter followed again by resuspension of the AI(OH)3 cake in ethyl acetate (200 mL). [0083] The filtrates were combined and concentrated by rotary evaporation to provide a yield of 6.06 g (0.0278 M, 80% of theoretical maximum recovery). Losses from quantitative recovery are likely due to destruction of the [3-hydroxy intermediate of 4-OH MET. The 4-OH MET base was further purified by trituration and recrystallization.

[0084] Example III

[0085] Reduction of N,N-dimethyl-3-indole glyoxylamide was completed at a 5- gram scale with a NaF I H2O quench to synthesize DMT. The reagents and solvents used in Example III are listed in Table 3.

Table 3: Reagents and Solvents Used in Example III

[0086] N,N-dimethyl-3-indole glyoxylamide (5.0 g, 0.0231 Mols) was placed in a 3 neck 500m L round bottom flask equipped with mechanical stirring. A thermometer and an ice-salt bath were used for temperature monitoring and control. A 125mL pressure equalizing addition funnel was connected with the round bottom flask.

[0087] THF (75 mL) was added all at once to the round bottom flask and the N,N- dimethyl-3-indole glyoxylamide dissolved in the THF. The mixture was cooled to 0 °C in the ice-salt bath.

[0088] 1.0M LiAIH4 solution (75 mL, 3.25 eq) was transferred via cannula to the addition funnel. The LiAIH4 solution was added dropwise, maintaining the reaction temperature below 20 °C by varying the addition rate. After addition of the LiAIH4 solution, the reaction was allowed to warm to 25 °C.

[0089] After the the reaction warmed to 25 °C, an efficient condenser was fitted and the reaction was heated to reflux at 66 °C, utilizing a heating mantle, for 12 hours.

[0090] Once thin layer chromatography showed that the reaction was complete, the round bottom flask was cooled to 5 °C in the ice-salt bath. [0091] After the temperature of the reaction was cooled to 5 °C, powdered NaF (9.44 g, 0.225 M, 3 eq. LiAIF ) was added portionwise with a spoon and vigorous stirring. No visible reaction occurred upon addition of NaF.

[0092] Deionized H₂O (4.0 g, 0.225 M, 3 eq. LiAIH₄) in THF (20 mL) was added dropwise, keeping the temperature under 15 °C by cooling in an ice bath. The reaction was stirred for 40 minutes and allowed to warm to 25 °C. Gas evolution was monitored to determine when the quench was complete.

[0093] Ethyl acetate (50 mL) was added all at once and the stirring continued for 30 additional minutes. The resultant cake of AI(OH)3 white solids was isolated onto filter paper and placed over a bed of Celite in a Buchner fritted glass funnel.

[0094] The AI(OH)3 cake was washed with ethyl acetate (75 mL) on the filter followed by resuspension of the AI(OH)s cake in ethyl acetate (100 mL). The mixture was stirred and the AI(OH)s cake refiltered. To refilter the AI(OH)s cake, the AI(OH)s cake was again washed with ethyl acetate (75 mL) on the filter followed again by resuspension of the AI(OH)3 cake in ethyl acetate (100 mL).

[0095] The filtrates were combined and concentrated by rotary evaporation to provide a yield of 4.06 g (0.0216 M, 92% of theoretical maximum recovery). Losses from quantitative recovery are likely due to destruction of the [3-hydroxy intermediate of DMT. The DMT base was further purified by trituration and recrystallization.

[0096] Example IV

[0097] Reduction of N,N-dimethyl-4-acetoxy-indole-3-yl-glyloxylamide was completed at a 10-gram scale with a triethanolamine quench to synthesize psilocin. The reagents and solvents used in Example IV are listed in Table 4.

Table 4: Reagents and Solvents Used in Example IV

[0098] N,N-dimethyl-4-acetoxy-indole-3-yl-glyoxylamide (5 g, 0.0182 Mols) was placed in a 3 neck 500m L round bottom flask equipped with mechanical stirring. A thermometer and an ice-salt bath were used for temperature monitoring and control. A 125mL pressure equalizing addition funnel was connected with the round bottom flask. [0099] Dioxane (50 mL) was added all at once to the round bottom flask. The mixture was cooled to 0 °C in the ice-salt bath.

[0100] 1.0M LiAIH4 solution (58 mL, 3.2 eq) was transferred via cannula to the addition funnel. The LiAIH4 solution was added dropwise, maintaining the reaction temperature below 20 °C by varying the addition rate.

[0101] After addition of the LiAIH4 solution, an efficient condenser was fitted and the reaction was refluxed at 80 °C, utilizing a heating mantle, for 12 hours.

[0102] Once thin layer chromatography showed that the reaction was complete, the round bottom flask was cooled to 5 °C in the ice-salt bath.

[0103] After the temperature of the reaction was cooled to 5 °C, triethanolamine (8.20 g, 0.055 M, 0.93 eq. LiAIH4) in THF (75 mL) was added dropwise with vigorous stirring. Gas evolution was monitored to maintain safe reaction conditions and to determine when all the triethanolamine has reacted with the LiAIH4 residue. After addition of the triethanolamine, the temperature was raised to 30 °C by use of a water bath. The temperature was held at 30 °C for 1 hour to ensure complete reaction of triethanolamine with the LiAIH4.

[0104] Powdered Na2SO4*10 H2O (11 .3 g, 0.036 M, 0.6 eq.) was added portionwise with a spoon, keeping the temperature under 20 °C by cooling in an ice bath. The reaction was stirred for one hour and allowed to warm to 25 °C. Gas evolution was monitored to maintain safe reaction conditions and to when the quench was complete after addition of the deionized H2O. After the addition, the temperature was raised to 30 °C by use of a water bath. The temperature was held at 30 °C for 1 hour to insure the complete reaction of the Na2SO4*10 H2O with the LiAIH4. The reaction was stirred for 40 minutes and allowed to warm to 25 °C. Gas evolution was monitored to determine when the quench was complete.

[0105] Ethyl acetate (50 mL) was added all at once and the stirring continued for 30 additional minutes. Silica gel (2.5 g) was added to remove the blue decomposing beta hydroxy psilocin. The resultant cake of grey AI(OH)s was were isolated onto filter paper and placed over a bed of Celite in a Buchner fritted glass funnel. The AI(OH)s cake was washed with ethyl acetate (75 mL) on the filter.

[0106] The mother liquor included 58 mL THF from the LiAIH4 solution, 50 mL dioxane, 75 mL THF from the triethanolamine solution and 50 mL ethyl acetate from the wash. The mother liquor was combined with the ethyl acetate wash (75 mL), resulting in a 308 mL solution that contained a crude yield of 87% of the psilocin product.

[0107] The cake was transferred from the Buchner fritted glass funnel to a flask. In the flask, the AI(OH)s cake was resuspended in ethyl acetate (100 mL) by stirring, resulting in a mixture. The mixture was placed in a Buchner fritted glass funnel and vacuum applied to remove the ethyl acetate from the cake. This process was repeated one additional time for a total of twice. The resulting 200 mL of ethyl acetate was kept as product and the psilocin in the ethyl acetate was also quantified, in addition to the psilocin from the mother liquor.

[0108] The filtrates were combined and concentrated by rotary evaporation to provide a yield of 3.49 g (0.017 M, 94% of theoretical maximum recovery). Losses from quantitative recovery are likely due to destruction of the [3-hydroxy intermediate of psilocin. The psilocin base was further purified by trituration and recrystallization.

[0109] Example V

[0110] Reduction of N,N-dimethyl-4-acetoxy-indole-3-yl-glyoxylamide was completed at a 38.25-gram scale with a NaF I deionized H2O quench to synthesize psilocin. The reagents and solvents used in Example V are listed in Table 5.

Table 5: Reagents and Solvents Used in Example V

[0111] Anhydrous 2-methyl THF (765 mL) was placed in a 3 neck 3 L round bottom flask equipped with mechanical stirrer, powder addition funnel, and a thermometer for temperature monitoring and control. The reaction set up was placed in a heating mantle. [0112] LiAIH4 pellets (16.41 g, 0.432 mol, 3.1 eq) were added to the round bottom flask all at once accompanied by vigorous stirring. The mixture was heated to 40 to 50 °C for the dissolution of the pellets.

[0113] Solid N,N-dimethyl-4-acetoxy-indole-3-yl-glyoxylamide (38.25 g, 0.140 mol) was added portion wise through the powder addition funnel and the reaction temperature was maintained 40 to 50 °C by varying the addition rate.

[0114] After the addition of the N,N-dimethyl-4-acetoxy-indole-3-yl-glyoxylamide, an efficient condenser was fitted and the reaction was heated at reflux (80 °C), utilizing a heating mantle (for about 8 h).

[0115] Once thin layer chromatography showed that the reaction was complete, heating was stopped and the reaction mixture allowed to cool slowly to 23 ± 2 °C. Stirring was continued overnight under N2 atmosphere.

[0116] After cooling, the reaction mixture was diluted by adding 75 mL of THF to the reaction flask with continued stirring.

[0117] Thirty minutes after adding the THF, the reaction mixture was cooled to 5 °C, and powdered NaF (54.46 g, 1.30 mol, 3.0 eq. wrt LiAIH4) was added all at once with vigorous stirring. No visible reaction occurred upon addition of NaF.

[0118] The reaction was quenched with deionized water in THF (after addition of NaF). Deionized H2O (24 mL, 1.30 mol, 3.0 eq. wrt LiAIH4) in THF (60 mL, 2.5 volumes wrt water) was added dropwise, keeping the temperature under 20 °C. The reaction was stirred for 1 h and allowed to warm to 25 °C. Gas evolution was monitored to maintain safe reaction conditions and cessation of H2 gas evolution was a prompt for the next step. [0119] Ethyl acetate (155 mL) was added all at once and the stirring continued for 30 additional minutes. The resulting slurry was filtered onto filter paper placed over a bed of Celite in a Buchner fritted glass funnel, resulting in a cake of AI(OH)s bound with psilocin.

[0120] The solid cake was washed with ethyl acetate (60 mL) on the filter followed by resuspension of the filter cake in ethyl acetate (270 mL). The mixture was stirred, and the slurry was re-filtered. The re-filtered solid cake was again washed with ethyl acetate (60 mL) and then solid cake was discarded.

[0121] The filtrates were combined and concentrated by rotary evaporation to provide a white solid of psilocin (23.15 g, 0.113 mol, Crude yield: 81 % of theoretical maximum recovery). Losses from quantitative recovery may be due to destruction of a [3-hydroxy intermediate of psilocin.

[0122] The psilocin base was further purified by trituration from tert-butyl methyl ether and Isopropyl acetate to obtain pure Psilocin (98 to 99 % by HPLC, 21.3 g, 75 % yield).

[0123] Example VI

[0124] Reduction of N,N-dimethyl-5-methoxy-indole-3-yl-glyloxylamide was completed at a 500-gram scale with a NaF I deionized H2O quench to synthesize 5-MeO- DMT. The reagents and solvents used in Example VI are listed in Table 6.

Table 6: Reagents and Solvents Used in Example VI

[0125] Anhydrous 2-methyl THF (4.20 L) was placed in a 3 neck 12 L round bottom flask equipped with mechanical stirring. A 500 mL pressure equalizing addition funnel was connected with the round bottom flask. [0126] LiAIH4 pellets (238.9 g, 6.30 Mols, 3.2 eq to glyoxylamide) were added to the round bottom flask all at once accompanied by vigorous stirring. The mixture was cooled to 20 °C in the ice-salt bath after the dissolution of the pellets.

[0127] Solid N,N-dimethyl-5-methoxy-indole-3-yl-glyloxylamide (500 g, 2.03 Mols) was added portionwise. The reaction temperature was maintained at between 20 and 25 °C during addition of the N,N-dimethyl-5-methoxy-indole-3-yl-glyloxylamide.

[0128] After the addition of the N,N-dimethyl-5-methoxy-indole-3-yl-glyloxylamide, an efficient condenser was fitted and the reaction was heated at reflux to between 80 and 85 °C, utilizing a heating mantle, for 18 hours.

[0129] Once thin layer chromatography showed that the reaction was complete, the round bottom flask was cooled to 5 to 10 °C.

[0130] After the temperature of the reaction was cooled to 5 °C, powdered NaF (793 g, 18.89 Mols, 3.0 eq. LiAIFU) was added all at once with vigorous stirring. No visible reaction occurred upon addition of NaF.

[0131] The reaction was quenched with deionized water in THF after addition of NaF. Deionized H₂O (340 mL, 18.9 Mols, 3.0 eq. LiAIH₄) in THF (2.92 L) was added dropwise, keeping the temperature under 20 °C. The reaction was stirred for 210 minutes and allowed to warm to 20 °C. Gas evolution was monitored to maintain safe reaction conditions and to determine when all H2O was added to ensure complete reaction of H2O with the LiAIH₄.

[0132] Ethyl acetate was added and stirring continued for 60 additional minutes. The resultant cake of AI(OH)s white solids was isolated onto filter paper placed over a bed of Celite in a Buchner fritted glass funnel. The AI(OH)s cake was washed with additional ethyl acetate on the filter followed by resuspension of the AI(OH)s cake in additional ethyl acetate. The mixture was stirred and the AI(OH)s cake refiltered. To refilter the AI(OH)s cake, the AI(OH)s cake was again washed with ethyl acetate on the filter followed again by resuspension of the AI(OH)s cake in ethyl acetate. A total of 11 .25 L of ethyl acetate was used and recovered as filtrate.

[0133] The filtrates were combined and concentrated by rotary evaporation to provide a yield of 323.7 g (1.48 Mols, 73 % of theoretical maximum recovery of 443.21 g). Losses from quantitative recovery are likely due to destruction of the [3-hydroxy intermediate of 5-MeO-DMT. The 5-MeO-DMT base was further purified by trituration and recrystallization.

[0134] Example VII

[0135] Reduction of N, methyl, N-isopropyl-5-methoxy-indole-3-yl-glyloxylamide was completed at a 25-gram scale with a NaF I deionized H2O quench to synthesize 5- MeO-DiPT. The reagents and solvents used in Example VII are listed in Table 7.

Table 7: Reagents and Solvents Used in Example VII

[0136] Anhydrous 2-methyl THF (260 mL) was placed in a 3 neck 3 L round bottom flask equipped with mechanical stirring. A 250 mL pressure equalizing addition funnel was connected with the round bottom flask.

[0137] LiAIF pellets (11.3 g, 0.30 Mols, 3.2 eq) were added to the round bottom flask all at once accompanied by vigorous stirring. The mixture was cooled to 20 °C in the ice-salt bath after the dissolution of the pellets.

[0138] Solid N, methyl, N-isopropyl-5-methoxy-indole-3-yl-glyloxylamide (25.9 g, 0.094 Mols) was added portionwise. The reaction temperature was maintained at between 20 and 25 °C during addition of N, methyl, N-isopropyl-5-methoxy-indole-3-yl- glyloxylamide.

[0139] After the addition of the N, methyl, N-isopropyl-5-methoxy-indole-3-yl- glyloxylamide, an efficient condenser was fitted and the reaction was heated at reflux to between 80 and 85 °C, utilizing a heating mantle, for 18 hours.

[0140] Once thin layer chromatography showed that the reaction was complete, the round bottom flask was cooled to 10 °C. [0141] After the temperature of the reaction was cooled to 5 °C, powdered NaF (37.5 g, 0.89 Mols, 3.0 eq. LiAIF ) was added all at once with vigorous stirring. No visible reaction occurred upon addition of NaF.

[0142] The reaction was quenched with deionized water in THF after addition of NaF. Deionized H2O (16.2 mL, 0.9 M, 3.0 eq. LiAIFU) in THF (275 mL) was added dropwise, keeping the temperature under 20 to 25 °C. The reaction was stirred for 105 minutes and allowed to warm to 23 °C. Gas evolution was monitored to maintain safe reaction conditions and to determine when all H2O was added to ensure complete reaction of H2O with the LiAIH4.

[0143] Ethyl acetate was added and stirring continued for 20 additional minutes. The resultant cake of AI(OH)s white solids was isolated onto filter paper placed over a bed of Celite in a Buchner fritted glass funnel. The AI(OH)s cake was washed with additional ethyl acetate on the filter followed by resuspension of the AI(OH)s cake in additional ethyl acetate. The mixture was stirred and the AI(OH)s cake refiltered. To refilter the AI(OH)s cake, the AI(OH)s cake was again washed with ethyl acetate on the filter followed again by resuspension of the AI(OH)s cake in ethyl acetate. A total of 325 mL of ethyl acetate was used and recovered as filtrate.

[0144] The filtrates were combined and concentrated by rotary evaporation to provide a yield of 17.77 g (0.072 Mols, 76% of theoretical maximum recovery of 23.26 g). Losses from quantitative recovery are likely due to destruction of the [3-hydroxy intermediate of 5-MeO-DiPT. The 5-MeO-DiPT base was further purified by trituration and recrystallization.

[0145] References

[0146] J. Powell, N. James and S. J. Smith, 1986 (4), Synthesis, 338-340

[0147] Migliaccio et al J. Med. Chem, 1981 , 24206-209

[0148] Shirota, 2003, J.Nat.Prod.,QQ, 885

[0149] H. Yamamoto and K. Maruoka, 1981 , JACS 103, 4186-4194

[0150] Examples Only

[0151] In the preceding description, for purposes of explanation, numerous details are set forth in order to provide a thorough understanding of the embodiments. However, it will be apparent to one skilled in the art that these specific details are not required. [0152] The above-described embodiments are intended to be examples only. Alterations, modifications and variations can be effected to the particular embodiments by those of skill in the art. The scope of the claims should not be limited by the particular embodiments set forth herein, but should be construed in a manner consistent with the specification as a whole.

Claims

1 . A method of recovering a tryptamine comprising: providing a reductive reaction mixture comprising the tryptamine and Al³⁺ ions; combining an aluminum binding agent with the reaction mixture; combining a quenching agent with the reaction mixture; combining a recovery solvent with the reaction mixture; and recovering the tryptamine in the recovery solvent.

2. The method of claim 1 wherein the tryptamine has the following structure (I):

wherein:

Ri comprises H, or an alkyl, cycloalkyl or aromatic group ranging in size from Ci to C₆;

R2 comprises H, or an alkyl, cycloalkyl or aromatic group ranging in size from Ci to C₆;

Rs comprises H, hydroxyl, benzyloxy, alkoxy, chloride or fluoride;

R4 comprises H or hydroxyl, benzyloxy, alkoxy, chloride or fluoride;

Rs comprises H, hydroxyl, benzyloxy, alkoxy, chloride or fluoride;

Re comprises H or hydroxyl, benzyloxy, alkoxy, chloride or fluoride; and

R? comprises H or hydroxyl, benzyloxy, alkoxy, chloride or fluoride.

3. The method of claim 2 wherein Ri and R2 are together a single cycloalkyl group that includes a tertiary amine nitrogen N within the single cycloalkyl group.

4. The method of any one of claims 1 to 3 wherein providing the reductive reaction mixture comprises combining a reagent with LiAIH4.

- 36 -

5. The method of claim 4 wherein the reductive reaction mixture comprises byproducts of reduction of the reagent with LiAIH4.

6. The method of any one of claims 1 to 3 wherein the reductive reaction mixture comprises byproducts of reduction of a reagent with LiAIH4.

7. The method of any one of claims 4 to 6 wherein the reagent comprises a glyoxylamide.

8. The method of any one of claims 1 to 7 wherein the aluminum binding agent comprises a Lewis base.

9. The method of claim 8 wherein the Lewis base is selected from the group consisting of F; RH₂O, ROH, NH₃, SO₄ ² CO, PR₃, Cl; Br, I; NO₃ RSH, R2S and CN’.

10. The method of any one of claims 1 to 9 wherein the aluminum binding agent comprises a chelating agent.

11 . The method of claim 10 wherein the chelating agent comprises a compound selected from the group consisting of triethanolamine, 1 ,2-ethanediamine, acetylacetonate ion, oxalate or ethanedioate ion, N,N,N',N'-ethylenediaminetetraacetate ion (“EDTA”), ethylene glycol-bis([3-aminoethyl ether)-N,N,N',N'-tetraacetic acid (“EGTA”), trans-1 ,2-diaminocyclohexane-N,N,N'N'-tetraacetic acid (“CDTA”), L-glutamic acid N,N-diacetic acid, tetrasodium salt (“GLDA”), methylglycinediacetic acid (“MGDA”), nitrilotriacetic acid (“NTA”), hydroxyethyl ethylenediamine triacetic acid trisodium salt (“HEDTA”), diethylenetriamene pentaacetatic acid (“DTPA”), oxalic acid, malic acid and tartaric acid.

12. The method of any one of claims 1 to 11 wherein combining the quenching agent with the reaction mixture comprises combining the quenching agent with the reaction mixture after combining the aluminum binding agent with the reaction mixture.

13. The method of any one of claims 1 to 12 wherein combining the quenching agent with the reaction mixture comprises combining the quenching agent with the reaction

- 37 - mixture concomitantly with combining the aluminum binding agent with the reaction mixture.

14. A method of recovering an indolealkylamine comprising: providing a reductive reaction mixture comprising the indolealkylamine and Al³⁺ ions; combining an aluminum binding agent with the reaction mixture; combining a quenching agent with the reaction mixture; combining a recovery solvent with the reaction mixture; and recovering the indolealkylamine in the recovery solvent.

15. The method of claim 14 wherein the indolealkylamine has the following structure (II):

wherein:- n is an integer from 1 to 6;

Ri comprises H, or an alkyl, cycloalkyl or aromatic group ranging in size from Ci to C₆;

R2 comprises H, or an alkyl, cycloalkyl or aromatic group ranging in size from Ci to C₆;

Rs comprises H, hydroxyl, benzyloxy, alkoxy, chloride or fluoride;

R4 comprises H or hydroxyl, benzyloxy, alkoxy, chloride or fluoride;

Rs comprises H, hydroxyl, benzyloxy, alkoxy, chloride or fluoride;

Re comprises H or hydroxyl, benzyloxy, alkoxy, chloride or fluoride; and

R? comprises H or hydroxyl, benzyloxy, alkoxy, chloride or fluoride.

16. The method of claim 15 wherein Ri and R2 are together a single cycloalkyl group that includes a tertiary amine nitrogen N within the single cycloalkyl group

17. The method of any one of claims 14 to 16 wherein providing the reductive reaction mixture comprises combining a reagent with LiAIH4.

18. The method of claim 17 wherein the reductive reaction mixture comprises byproducts of reduction of the reagent with LiAIH4

19. The method of any one of claims 14 to 16 herein the reductive reaction mixture comprises byproducts of reduction of a reagent with LiAIH4.

20. The method of any one of claims 17 to 19 wherein the reagent comprises an indoleketoalkylam ides.

21 . The method of any one of claims 14 to 20 wherein the aluminum binding agent comprises a Lewis base.

22. The method of claim 21 wherein the Lewis base is selected from the group consisting of F; RH₂O, ROH, NH₃, SO4²; CO, PR₃, Ch, Br, I; NO3; RSH, R2S and ON’.

23. The method of any one of claims 14 to 22 wherein the aluminum binding agent comprises a chelating agent.

24. The method of claim 23 wherein the chelating agent comprises a compound selected from the group consisting of triethanolamine, 1 ,2-ethanediamine, acetylacetonate ion, oxalate or ethanedioate ion, N,N,N',N'-ethylenediaminetetraacetate ion (“EDTA”), ethylene glycol-bis([3-aminoethyl ether)-N,N,N',N'-tetraacetic acid (“EGTA”), trans-1 ,2-diaminocyclohexane-N,N,N'N'-tetraacetic acid (“CDTA”), L-glutamic acid N,N-diacetic acid, tetrasodium salt (“GLDA”), methylglycinediacetic acid (“MGDA”), nitrilotriacetic acid (“NTA”), hydroxyethyl ethylenediamine triacetic acid trisodium salt (“HEDTA”), diethylenetriamene pentaacetatic acid (“DTPA”), oxalic acid, malic acid and tartaric acid.

25. The method of any one of claims 14 to 24 wherein combining the quenching agent with the reaction mixture comprises combining the quenching agent with the reaction mixture after combining the aluminum binding agent with the reaction mixture.

26. The method of any one of claims 14 to 25 wherein combining the quenching agent with the reaction mixture comprises combining the quenching agent with the reaction mixture concomitantly with combining the aluminum binding agent with the reaction mixture.