Novel indole-based intermediates and processes for their production

Abstract

The application describes novel indole-based intermediates, and processes for their production. The intermediates can in turn be used in new processes to prepare the serotonin agonists psilocin and psilocybin.

Description

[0001] Novel indole-based intermediates and processes for their production Related Application This application claims priority to Australian provisional application no. 2023903039 (filed 21 September 2023), the entire contents of which is incorporated herein by reference. Field of the invention The application describes novel intermediates, and processes using those intermediates, in preparing psilocin and psilocybin. Background of the invention The last two decades have witnessed a renewed interest in the clinical study of serotonin agonists (colloquially referred to as psychedelics) for the potential treatment of a range of mental illnesses, including major depressive disorder, treatment-resistant depression, end-of-life anxiety, obsessive-compulsive disorder, and addiction disorders. The serotonergic agonist agent psilocybin has been designated a Breakthrough Therapy by the FDA for the treatment of major depressive disorder and treatment- resistant depression. Furthermore, in Australia, the Therapeutic Goods Administration (TGA) has permitted the prescribing of psilocybin for treatment-resistant depression. Psilocybin is an indole-based secondary metabolite produced by numerous species of mushrooms. Psilocybin functions as a prodrug that is dephosphorylated to psilocin by the enzyme alkaline phosphate when ingested. Studies have shown that psychedelic drugs, including psilocybin, have both rapid onset and persisting effects on brain and mood function long after their acute effects. The long lasting effects have been attributed to their unique receptor affinities, which ultimately improves neuroplasticity and neuroprotection, promotes cell survival and modulates brain neuroimmune systems. To date, several synthesises of psilocybin (the prodrug version of psilocin) or psilocin have been reported. However, these approaches are limited by the need for expensive, corrosive and potentially explosive reagents and pharmaceutically undesirable solvents. Furthermore, difficulties in removing salt by-products and the need

[0002] 1 1005377547 for chromatographic purification make these approaches undesirable for commercial scale syntheses. For example, one route to provide kilogram amounts of psilocybin in a good manufacturing practice (GMP) process uses LiAlH4 is used. But there is an inherent danger and difficulty associated with handling and using this reagent as it is explosive upon contact with water, and it is difficult and impractical to remove aluminium salts on an industrial scale. This process was initially published in 1959 (Helv. Chim. Acta.42, (1959), 1557-1572) and subsequent variations were also published, but all processes relied on using expensive and corrosive reagents and pharmaceutically undesirable solvents. Summary of the invention In one aspect of the invention there is provided a novel compound that can be utilised as an intermediate in a process to synthesise psilocin. In a first embodiment of this aspect of the invention there is provided a compound of formula (A), or a pharmaceutically acceptable salt and / or solvate thereof, wherein Z is selected from Z1or Z2: Z1Z2R1is H or a carboxyl protecting group; X is an amine protecting group; and Y is a hydroxyl protecting group.

[0003] 2 1005377547 Preferably the carboxyl protecting group is C1-6 alkyl or C2-6 alkenyl; the amine protecting group is selected from SO2R3, CO2R5, benzyl carbamate or C1-6alkyl; and the hydroxyl protecting group is selected from alkylaryl, Si(R4)3, COR5, CH2OCH2CH2Si(CH3)3, and OCH2OCH3; wherein R3is selected from C1-6 alkyl or aryl, and R4and R5is C1-6alkyl. In one preferred embodiment, the compound of formula (A) is a compound of formula (I): or a pharmaceutically acceptable salt and / or solvate thereof, wherein X is an amine protecting group; and Y is a hydroxyl protecting group. In another preferred embodiment, the compound of formula (A) is a compound of formula (Ia): or a pharmaceutically acceptable salt and / or solvate thereof, wherein X is an amine protecting group; and Y is a hydroxyl protecting group. In another aspect of the invention there is provided a method for preparing a compound of formula (A), or a pharmaceutically acceptable salt and / or solvate thereof,

[0004] 3 1005377547 wherein R1is H, methyl or ethyl; X is an amine protecting group; and Y is a hydroxyl protecting group the method comprising contacting a compound of formula (Ib), or a pharmaceutically acceptable salt and / or solvate thereof, with: i. a 1,3-dicarbonyl compound; ii. a base; and iii. a reducing agent. In this embodiment: - the 1,3-dicarbonyl compound is preferably selected from 2,2-dimethyl-1,3- dioxane-4,6-dione, malonic acid, dimethyl malonate and diethyl malonate; - the base is preferably selected from D-proline, piperidine, pyridine, L-tyrosine, and 4,4′-trimethylenedipiperidine; and - the reducing agent is preferably selected is sodium borohydride, Pd / C, Ra-Ni, PtO2, H2NNH2, Pd(OAc)2 and zinc. In these embodiments X is an amine protecting group; and Y is a hydroxyl protecting group.

[0005] 4 1005377547 When the 1,3-dicarbonyl compound is 2,2-dimethyl-1,3-dioxane-4,6-dione, a compound of formula Ia, or a pharmaceutically acceptable salt and / or solvate thereof, is produced: When the 1,3-dicarbonyl is malonic acid a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, is produced: wherein: R1is H; and X is an amine protecting group; and Y is a hydroxyl protecting group. A compound of formula (Ia) can also be utilised in a method to produce a compound of formula (I). Accordingly, there is provided a method of preparing the compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, wherein: R1is H; and

[0006] 5 1005377547 X is an amine protecting group; and Y is a hydroxyl protecting group; the method comprising contacting a compound of formula (Ia), or a pharmaceutically acceptable salt and / or solvate thereof, with an acid and water. A compound of formula (I) is an intermediate useful in the synthesis of psilocin, and its subsequent modification to the prodrug psilocybin. In one embodiment there is provided a method for preparing a compound of formula (Ie), or a pharmaceutically acceptable salt and / or solvate thereof, the method comprising contacting a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, with: i. an azide source; ii. a base; and iii. an acid;

[0007] 6 1005377547 wherein X is an amine protecting group; and Y is a hydroxyl protecting group. The method further comprises contacting the compound of formula (Ie), or a pharmaceutically acceptable salt and / or solvate thereof, with: i. formaldehyde; ii. formic acid; and iii. a reducing agent to produce a compound of formula (If), or a pharmaceutically acceptable salt and / or solvate thereof: The method further comprises contacting a compound of formula (If) with reagents to remove X to produce a compound of formula (Ig) or a pharmaceutically acceptable salt and / or solvate thereof, - contacting a compound of formula (Ig) with Pd / C under an atmosphere of hydrogen to produce psilocin: , or a pharmaceutically acceptable salt and / or solvate thereof.

[0008] 7 1005377547 Further aspects of the present invention and further embodiments of the aspects described in the preceding paragraphs will become apparent from the following description, given by way of example and with reference to the accompanying drawings. Brief description of the drawings Figures 1 and 2: Synthetic process for psilocin (compound 13) including all of the developmental steps. Figure 2: The optimised synthetic process for psilocin (compound 13). Definitions As used herein, except where the context requires otherwise, the term "comprise" and variations of the term, such as "comprising", "comprises" and "comprised", are not intended to exclude further additives, components, integers or steps. It must be noted that as used herein and in the appended claims, the singular forms “a”, “an” and “the” include plural reference unless the context clearly dictates otherwise. Thus, for example, a reference to “a salt” may include a plurality of salts and a reference to “at least one heteroatom” may include one or more heteroatoms, and so forth. The term “and / or” means “and” or “or”. The term “(s)” following a noun contemplates the singular or plural form, or both. Psilocybin ((O-phosphoryl-4-hydroxy-N) functions as a prodrug that is dephosphorylated to psilocin (4-hydroxy-N,N-dimethyl-tryptamine). As used herein, unless the distinction between the prodrug and the metabolite is relevant, the names may be used interchangeably. For example, the schemes throughout the specification illustrate psilocin. However as would be appreciated by the skilled person, psilocin is not orally bioavailable, and any psilocin produced from the schemes of the invention will then be subjected to known methods to add a prodrug moiety. The term “serotonin agonists” is used interchangeably with psychedelics and serotonergic psychedelics. The term “C1-6 alkyl” refers to optionally substituted straight chain or branched chain hydrocarbon groups having from 1 to 6 carbon atoms. Examples include methyl

[0009] 8 1005377547 (Me), ethyl (Et), propyl (Pr), isopropyl (i-Pr), butyl (Bu), isobutyl (i-Bu), sec-butyl (s-Bu), tert-butyl (t-Bu), pentyl, neopentyl, hexyl and the like. Unless the context requires otherwise, the term “C1-6alkyl” also encompasses alkyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. “C1-4alkyl” and “C1-3alkyl” including methyl, ethyl, propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and tert-butyl are preferred with methyl being particularly preferred. The term “C2-6 alkenyl” refers to optionally substituted straight chain or branched chain hydrocarbon groups having at least one double bond of either E or Z stereochemistry where applicable and 2 to 6 carbon atoms. Examples include vinyl, 1- propenyl, 1- and 2-butenyl and 2-methyl-2-propenyl. Unless the context requires otherwise, the term “C2-6alkenyl” also encompasses alkenyl groups containing one less hydrogen atom such that the group is attached via two positions i.e. divalent. “C2-4 alkenyl” and “C2-3 alkenyl” including ethenyl, propenyl and butenyl are preferred with ethenyl being particularly preferred. The term “aryl” refers to a carbocyclic (non-heterocyclic) aromatic ring or mono-, bi- or tri-cyclic ring system. Poly-cyclic ring systems may be referred to as “aryl” provided at least 1 of the rings within the system is aromatic. The aromatic ring or ring system is generally composed of 6 to 10 carbon atoms. Examples of aryl groups include but are not limited to phenyl, biphenyl, naphthyl and tetrahydronaphthyl.6-membered aryls such as phenyl are preferred. The term “alkylaryl” refers to C1-6alkylaryl such as benzyl. The terms “hydroxy” and “hydroxyl” refer to the group -OH. The term “oxo” refers to the group =O. The terms “cyano” and “nitrile” refer to the group -CN. The term “nitro” refers to the group -NO2. The term “amino” refers to the group -NH2. The term “aldehyde” refers to the group -C(=O)H. The terms “acyl” and “acetyl” refers to the group –C(O)CH3.

[0010] 9 1005377547 The term “ketone” refers to a carbonyl group which may be represented by –C(O). The term “tosyl” refers to a group –SO2-C6H5-CH3. The term “substituted ketone” refers to a ketone group covalently linked to at least one further group, for example, a C1-6 alkyl group (“C1-6 alkylacyl” or “alkylketone” or “ketoalkyl”), an aryl group (“arylketone”), an aralkyl group (“aralkylketone) and so on. C1- 3alkylacyl groups are preferred. The term “halo” refers to fluoro, chloro, bromo or iodo. It will be understood that suitable derivatives of aromatic heterocycles containing nitrogen include N-oxides thereof. In the case of hybrid naming of substituent radicals describing two moieties that may both form a bond attaching the radical to the rest of the compound, such as alkylamino and alkylaryl, no direction in the order of groups is intended, so the point of attachment may be to any of the moieties included in the hybrid radical. For example, the terms “alkylaryl” and “arylalkyl”, are intended to refer to the same group and the point of attachment may be via the alkyl or the aryl moiety (or both in the case of diradical species). The direction of attachment of such a hybrid radical may be denoted by inclusion of a bond, for example, “-alkylaryl” or “arylalkyl-” denotes that the point of attachment of the radical to the rest of the compound is via the alkyl moiety, and “alkylaryl-“ or “-arylalkyl” denotes that the point of attachment is via the aryl moiety. The term "carboxyl protecting group" as used herein is intended to mean a group that is capable of being readily removed to provide the OH group of a carboxyl group and protects the carboxyl group against undesirable reaction during synthetic procedures. Such protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999) and 'Amino Acid-Protecting Groups' by Fernando Albericio (with Albert Isidro-Llobet and Mercedes Alvarez) Chemical Reviews 2009 (109) 2455-2504. Examples include, but are not limited to, alkyl and silyl groups, for example methyl, ethyl, tert-butyl, methoxymethyl, 2,2,2-trichloroethyl, benzyl, diphenylmethyl, trimethylsilyl, and tert-butyldimethylsilyl, and the like.

[0011] 10 1005377547 The term "hydroxyl protecting group" as used herein is intended to mean a group that is capable of being readily removed to provide the OH group of a hydroxyl group against undesirable reaction during synthetic procedures. Such protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999) and 'Amino Acid-Protecting Groups' by Fernando Albericio (with Albert Isidro-Llobet and Mercedes Alvarez) Chemical Reviews 2009 (109) 2455-2504. Examples include, but are not limited to, alkyl and silyl groups, for example substituted ketone, methoxymethyl, benzyl, trimethylsilyl, and tert-butyldimethylsilyl, and the like The term "amine protecting group" as used herein is intended to mean a group that is capable of being readily removed to provide the NH2 group of an amine group and protects the amine group against undesirable reaction during synthetic procedures. Such protecting groups are described in Protective Groups in Organic Synthesis edited by T. W. Greene et al. (John Wiley & Sons, 1999) and 'Amino Acid-Protecting Groups' by Fernando Albericio (with Albert Isidro-Llobet and Mercedes Alvarez) Chemical Reviews 2009 (109) 2455-2504. Examples include, but are not limited to, acyl and acyloxy groups, for example acetyl, chloroacetyl, trichloroacetyl, o-nitrophenylacetyl, o-nitrophenoxy- acetyl, trifluoroacetyl, acetoacetyl, 4-chlorobutyryl, isobutyryl, picolinoyl, aminocaproyl, benzoyl, methoxy-carbonyl, 9-fluorenylmethoxycarbonyl (fmoc), 2,2,2- trifluoroethoxycarbonyl, 2-trimethylsilylethoxy-carbonyl, tert-butyloxycarbonyl (BOC), allyloxycarbonyl (alloc), benzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2,4-dichloro- benzyloxycarbonyl, and the like. Further examples include Cbz (carboxybenzyl), Nosyl (o- or p-nitrophenylsulfonyl), Bpoc (2-(4-biphenyl)isopropoxycarbonyl) and Dde (1-(4,4- dimethyl-2,6-dioxohexylidene)ethyl). Various features of the invention are described with reference to a certain value, or range of values. These values are intended to relate to the results of the various appropriate measurement techniques, and therefore should be interpreted as including a margin of error inherent in any particular measurement technique. Where values referred to herein are denoted by the term “about” to at least in part account for this variability. The term “about”, when used to describe a value, may mean an amount within ±5%, ±1% or ±0.1% of that value.

[0012] 11 1005377547 Detailed description of the embodiments The present invention is directed to novel intermediates, and processes for preparing them. The intermediates prepared can then be used in a new process for synthesising psilocin, and ultimately psilocybin. The invention seeks to overcome one or more problems with existing processes, including using benign reagents rather than explosive and corrosive agents, avoiding pharmaceutically undesirable solvents, preferably relying on pharmaceutically acceptable class 2 and 3 solvents, the starting materials and reagents being cost effective and readily available, the process being scalable and not requiring chromatography or special handling conditions. Compounds In a first aspect of the invention, there is provided a compound of formula (A): (A), or a pharmaceutically acceptable salt and / or solvate thereof, wherein: Z is selected from Z1or Z2: Z1Z2R1is H or a carboxyl protecting group; X is an amine protecting group; and Y is a hydroxyl protecting group.

[0013] 12 1005377547 In some embodiments, R1is selected from H, C1-6 alkyl or C2-6 alkenyl. In some embodiments the amine protecting group X is selected from SO2R3, CO2R5, benzyl carbamate or C1-6 alkyl; preferably X is SO2R3; more preferably X is tosyl; wherein R3is selected from C1-6 alkyl or aryl, and R5is C1-6alkyl. In some embodiments the hydroxyl protecting group Y is selected from alkylaryl, Si(R4)3, COR5, CH2OCH2CH2Si(CH3)3, OCH2OCH3; preferably Y is benzyl; wherein R4and R5are C1-6 alkyl. In one embodiment of this aspect of the invention there is provided a compound of formula (I): or a pharmaceutically acceptable salt and / or solvate thereof, wherein R1, X and Y are as defined for formula (A). In another embodiment of this aspect of the invention there is provided a compound of formula (Ia): or a pharmaceutically acceptable salt and / or solvate thereof, wherein X and Y are as defined for formula (A). The term “pharmaceutically acceptable” may be used to describe any salt, solvate, tautomer, N-oxide and / or stereoisomer thereof, or any other compound which upon administration to a subject, is capable of providing (directly or indirectly) a

[0014] 13 1005377547 compound of formula (I), or an active metabolite or residue thereof and typically that is not deleterious to the subject. Suitable pharmaceutically acceptable salts include, but are not limited to, salts of pharmaceutically acceptable inorganic acids such as hydrochloric, sulphuric, phosphoric, nitric, carbonic, boric, sulfamic, and hydrobromic acids, or salts of pharmaceutically acceptable organic acids such as acetic, propionic, butyric, tartaric, maleic, hydroxymaleic, fumaric, malic, citric, lactic, mucic, gluconic, benzoic, succinic, oxalic, phenylacetic, methanesulphonic, toluenesulphonic, benzenesulphonic, salicylic, sulphanilic, aspartic, glutamic, edetic, stearic, palmitic, oleic, lauric, pantothenic, tannic, ascorbic and valeric acids. Base salts include, but are not limited to, those formed with pharmaceutically acceptable cations, such as sodium, potassium, lithium, calcium, magnesium, zinc, ammonium, alkylammonium such as salts formed from triethylamine, alkoxyammonium such as those formed with ethanolamine and salts formed from ethylenediamine, choline or amino acids such as arginine, lysine or histidine. General information on types of pharmaceutically acceptable salts and their formation is known to those skilled in the art and is as described in general texts such as “Handbook of Pharmaceutical salts” P.H.Stahl, C.G.Wermuth, 1st edition, 2002, Wiley-VCH. In the case of compounds that are solids, it will be understood by those skilled in the art that the inventive compounds, agents and salts may exist in different crystalline or polymorphic forms, all of which are intended to be within the scope of the present invention and specified formulae. Formula (A), and all formulas within the scope of formula (A), is intended to cover, where applicable, solvated as well as unsolvated forms of the compounds. Thus, formula (I) includes compounds having the indicated structures, including the hydrated or solvated forms, as well as the non-hydrated and non-solvated forms. The compounds of formula (A), or salts, tautomers, N-oxides or polymorphs thereof may be provided in the form of solvates. Solvates contain either stoichiometric or non-stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, alcohols such as methanol, ethanol or isopropyl alcohol, DMSO, acetonitrile, dimethyl formamide

[0015] 14 1005377547 (DMF), acetic acid, and the like with the solvate forming part of the crystal lattice by either non-covalent binding or by occupying a hole in the crystal lattice. Hydrates are formed when the solvent is water, alcoholates are formed when the solvent is alcohol. Solvates of the compounds of the present invention can be conveniently prepared or formed during the processes described herein. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the invention. Basic nitrogen-containing groups may be quarternised with such agents as C1- 6alkyl halide, such as methyl, ethyl, propyl, and butyl chlorides, bromides and iodides; dialkyl sulfates like dimethyl and diethyl sulfate; and others. Nitrogen containing groups may also be oxidised to form an N-oxide. The compound of formula (A), or salts, tautomers, N-oxides and / or solvates thereof that form crystalline solids may demonstrate polymorphism. All polymorphic forms of the compounds, salts, tautomers, N-oxides and / or solvates are within the scope of the invention. The compound of formula (A), may demonstrate tautomerism. Tautomers are two interchangeable forms of a molecule that typically exist within an equilibrium. Any tautomers of the compounds of formula (I) are to be understood as being within the scope of the invention. Synthesis of compounds Preferably, a Knoevenagel condensation is used whereby an aldehyde is condensed with a 1,3-dicarbonyl compound. As would be understood by the skilled person, many 1,3-dicarbonyl compounds for a Knoevenagel condensation reaction are known in the art, and the skilled person can make an appropriate choice. For example, those described in Jones. G., 'The Knoevenagel Condensation', in Organic Reactions p 204-599. The below embodiments are therefore not to taken as limiting. In accordance with this preference there is further provided a method of preparing a compound of formula (A), or a pharmaceutically acceptable salt and / or solvate thereof,

[0016] 15 1005377547 wherein R1is H, methyl or ethyl; X is an amine protecting group; and Y is a hydroxyl protecting group the method comprising contacting a compound of formula (Ib), or a pharmaceutically acceptable salt and / or solvate thereof, with: a 1,3-dicarbonyl compound; a base; and a reducing agent. In some embodiments, the 1,3-dicarbonyl compound is selected from 2,2- dimethyl-1,3-dioxane-4,6-dione, malonic acid, dimethyl malonate or diethyl malonate; preferably the 1,3-dicarbonyl compound is 2,2-dimethyl-1,3-dioxane-4,6-dione. In some embodiments, the base is selected from D-proline, piperidine, pyridine, L- tyrosine, 4,4′-trimethylenedipiperidine; preferably the base is D-proline.

[0017] 16 1005377547 In some embodiments, the reducing agent is selected is sodium borohydride, Pd / C, Ra-Ni, PtO2, H2NNH2, Pd(OAc)2 or zinc; preferably the reducing agent is sodium borohydride. In the above embodiments, when the 1,3-dicarbonyl is malonic acid the method will give rise to a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, wherein R1is H, and X and Y are protecting groups as described herein. When the 1,3-dicarbonyl compound is dimethyl malonate or diethyl malonate and the reducing agent is selected is Pd / C, PtO2, H2NNH2 or Pd(OAc)2, the method will give rise to a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, wherein R1is methyl or ethyl and X and Y are protecting groups as described herein. When the 1,3-dicarbonyl compound is 2,2-dimethyl-1,3-dioxane-4,6-dione, the method will rise to a compound of formula (Ia), or a pharmaceutically acceptable salt and / or solvate thereof,

[0018] 17 1005377547 and X and Y are protecting groups as described herein. The compound of formula (Ia) can be utilised to prepare a compound of formula (I). In one embodiment of this aspect of the invention, there is provided a method for preparing a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, wherein: R1is H; X is an amine protecting group; Y is a hydroxyl protecting group; the method comprising contacting a compound of Formula (Ia), or a pharmaceutically acceptable salt and / or solvate thereof, with an acid and water.

[0019] 18 1005377547 In some embodiments, the acid is selected from HCl, HBr, H2SO4, H3PO4, CH3COOH, MeSO3H, CF3SO3H or HOC(CH₂CO₂H)₂; preferably the acid is HOC(CH₂CO₂H)₂. Other suitable acids known in the art are contemplated. Optionally DMSO can be utilised as a co-solvent with water. In a preferred embodiment, the method for preparing a compound of formula (A), or a pharmaceutically acceptable salt and / or solvate thereof, may include a precursor step of preparing the compound of formula (Ib), or a pharmaceutically acceptable salt and / or solvate thereof. Accordingly, there is also provided a method of preparing a compound of Formula (Ib), or a pharmaceutically acceptable salt and / or solvate thereof, the method comprising contacting a compound of formula (Ic), or a pharmaceutically acceptable salt and / or solvate thereof, with: i. a base; and ii. a protecting group precursor wherein: X is an amine protecting group; and Y is a hydroxyl protecting group.

[0020] 19 1005377547 In some embodiments, the base is selected from pyridine, Et3N, 4- dimethylaminopyridine, K2CO3, sodium hydride; preferably the base is 4- dimethylaminopyridine or Et3N. Other suitable bases known in the art are contemplated. In some embodiments, the protecting group precursor is selected from, tosyl chloride, methanesulfonyl chloride, benzyl chloroformate, di-tert-butyl dicarbonate; preferably the protecting group precursor is tosyl chloride. In a preferred embodiment, the method for preparing a compound of formula (Ib), or a pharmaceutically acceptable salt and / or solvate thereof, may include a precursor step of preparing the compound of formula (Ic), or a pharmaceutically acceptable salt and / or solvate thereof. Accordingly, there is also provided a method of preparing a compound of formula (Ic), or a pharmaceutically acceptable salt and / or solvate thereof, the method comprising contacting a compound of formula (Id), or a pharmaceutically acceptable salt and / or solvate thereof, i. a formylating agent; and ii. a base; wherein Y is a hydroxyl protecting group. In some embodiments, the formylating agent is selected from phosphorus oxychloride with DMF, hexamethylenetetramine or formic acid.

[0021] 20 1005377547 In some embodiments, the base is selected from NaOAc, NaOH, KOH; preferably the base is NaOH. In each of the above embodiments the amine protecting group X is selected from SO2R3, CO2R5, benzyl carbamate or C1-6alkyl; preferably SO2R3; more preferably tosyl. In these embodiments R3is selected from C1-6alkyl or aryl; R5is C1-6alkyl. In each of the above embodiments, the hydroxyl protecting group Y is selected from CH2Ar, Si(R4)3, COR5, CH2OCH2CH2Si(CH3)3, OCH2OCH3; preferably Y is CH2aryl. In these embodiments R4and R5are C1-6alkyl. Use of the compounds of formula (I) The compounds of formula (I) can be utilised as an intermediate in a process to synthesise psilocin, and the prodrug version of psilocin, psilocybin. In a first step, a Curtius rearrangement reaction is conducted whereby an acyl azide undergoes rearrangement to form a primary amine. Specifically, in this aspect of the invention, there is provided a method of preparing a compound of formula (Ie), or a pharmaceutically acceptable salt and / or solvate thereof, via an acyl azide intermediate (Ii), the method comprising contacting a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof,

[0022] 21 1005377547 with: iv. an azide source; v. a base; and vi. an acid; wherein R1is H and X is an amine protecting group; and Y is a hydroxyl protecting group. In some embodiments, the azide source is trimethylsilyl azide, sodium azide or diphenyl phosphoryl azide; preferably the azide source is diphenyl phosphoryl azide. In some embodiments, the base is a nitrogen containing base; preferably the base is selected from triethylamine, diisopropylamine, N,N-diisopropylethylamine or 4- dimethylaminopyridine; more preferably the base is triethylamine. In another embodiment, the acid is selected from HCl, HBr, H2SO4, H3PO4, CH3COOH, MeSO3H or CF3SO3H; preferably the acid is HCl. The compound of formula (Ie), or a pharmaceutically acceptable salt and / or solvate thereof, can subsequently be used in a method of preparing a compound of formula (If), or a pharmaceutically acceptable salt and / or solvate thereof. In one embodiment, there is provide a method of preparing a compound of formula (If), or a pharmaceutically acceptable salt and / or solvate thereof, wherein: X is an amine protecting group; and Y is a hydroxyl protecting group; the method comprising contact a compound of formula (Ie), or a pharmaceutically acceptable salt and / or solvate thereof,

[0023] 22 1005377547 with reagents for methylation of –NH2, to yield the compound of formula (If). In an alternative embodiment, the method comprises contacting a compound of formula (Ie), or a pharmaceutically acceptable salt and / or solvate thereof, with: iv. formaldehyde; v. formic acid; and vi. a reducing agent. In some embodiments; the reducing agent is selected from sodium triacetoxyborohydride, sodium cyanoborohydride, sodium borohydride or any suitable hydride donor. In yet another embodiment, the method comprises contacting a compound of formula (Ie), or a pharmaceutically acceptable salt and / or solvate thereof, i. a methylating agent; and ii. a trialkyl base. In some embodiments; the methylating agent is methyl iodide and a trialkyl base is triethylamine. The compound of formula (If), or a pharmaceutically acceptable salt and / or solvate thereof can subsequently be used in a method of preparing a compound of formula (Ig), or a pharmaceutically acceptable salt and / or solvate thereof. In one embodiment, there

[0024] 23 1005377547 is provided a method of preparing a compound of formula (Ig), or a pharmaceutically acceptable salt and / or solvate thereof, wherein: X is an amine protecting group; and Y is a hydroxyl protecting group; the method comprising contact a compound of formula (If) with reagents to remove X, yielding the compound of formula (Ig), or a pharmaceutically acceptable salt and / or solvate thereof. In an embodiment where X is tosyl, the method comprises contacting a compound of Formula (If) with Cs2CO3 as the reagent to remove X. Preparation of psilocin The compound of formula (Ig), or a pharmaceutically acceptable salt and / or solvate thereof, can subsequently be used in a method of preparing psilocin, or a pharmaceutically acceptable salt and / or solvate thereof. In one embodiment, there is provide a method of preparing psilocin, ,

[0025] 24 1005377547 or a pharmaceutically acceptable salt and / or solvate thereof, wherein the method comprises contacting a compound of Formula (Ig) with reagents to remove Y. In the embodiment where Y is alkylaryl, the method comprises contacting a compound of formula (Ig) with Pd / C under an atmosphere of hydrogen. In each of the above embodiments the amine protecting group X is selected from SO2R3, CO2R5, benzyl carbamate or C1-6alkyl; preferably SO2R3; more preferably tosyl. In these embodiments R3is selected from C1-6alkyl or aryl; R5is C1-6alkyl. In each of the above embodiments, the hydroxyl protecting group Y is selected from alkylaryl, Si(R4)3, COR5, CH2OCH2CH2Si(CH3)3, OCH2OCH3; preferably Y is benzyl. In these embodiments R4and R5are C1-6alkyl. Preparation of psilocybin Psilocin, or a pharmaceutically acceptable salt and / or solvate thereof, can subsequently be used in a method of preparing psilocybin, or a pharmaceutically acceptable salt and / or solvate thereof. In one embodiment, there is provided a method of preparing psilocybin, , psilocybin or a pharmaceutically acceptable salt and / or solvate thereof, wherein the method comprises contacting psilocin, or a pharmaceutically acceptable salt and / or solvate thereof,

[0026] 25 1005377547 , psilocin with a phosphorylating agent and a base; preferably the phosphorylating agent is phosphorus oxychloride and the base is triethylamine. Although as would be understood by the skilled person, many other methods for phosphorylation of aromatic alcohols are known in the art, and the skilled person can make an appropriate choice. For example, the method described in Kozak, Witold, Rachon, Janusz, et al., 'Selected Methods for the Chemical Phosphorylation and Thiophosphorylation of Phenols', Asian Journal of Organic Chemistry, 7 (2018), 314-23. Alternatively, psilocin, or a pharmaceutically acceptable salt and / or solvate thereof, can subsequently be used in a method of preparing psilocybin, the method comprising the steps of: a) preparing a compound of formula (Ih), or a pharmaceutically acceptable salt and / or solvate thereof by contacting psilocin, or a pharmaceutically acceptable salt and / or solvate thereof, , psilocin with a benzyl protected phosphate precursor and a base; and

[0027] 26 1005377547 b) contacting a compound of formula (Ih), or a pharmaceutically acceptable salt and / or solvate thereof, with Pd / C under an atmosphere of H2 to yield psilocybin. Preferably, in step (a) the benzyl protected phosphate precursor is tetrabenzyl pyrophosphate and the base is n-butyllithium. In another embodiment there is provided a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt and / or solvate thereof, the method comprising: Step i: contacting a compound of formula (Id), or a pharmaceutically acceptable salt and / or solvate thereof with a formylating agent to provide a compound of formula (Ic); Step ii: contacting the compound of formula (Ic) of step i with a protecting group precursor and a base to provide a compound of formula (Ib); Step iiia: contacting the compound of formula (Ib) of step ii with 2,2-dimethyl-1,3- dioxane-4,6-dione, a base and a reducing agent to provide a compound of formula (Ia); and contacting the compound of formula (Ia) with an acid and water to provide a compound of formula (I); or Step iiib: contacting the compound of formula (Ib) of step ii with malonic acid, a base and a reducing agent to provide a compound of (I). In another embodiment there is provided a method of preparing psilocin, or a pharmaceutically acceptable salt and / or solvate thereof, the method comprising: Step iv: contacting a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof, with an azide source, a base and an acid to provide a compound of formula (Ie) via an acyl azide intermediate (Ii); Step v: contacting the compound of formula (Ie) of step iv with formaldehyde, formic acid and a reducing agent or a methylation agent and a trialkyl base to provide a compound of formula (If); Step vi: contacting the compound of formula (If) of step v with a reagent to remove X to provide a compound of formula (Ig); and

[0028] 27 1005377547 Step vii: contacting the compound of formula (Ig) of step vi with a reagent to remove Y, to provide psilocin. In these 2 methods, X and Y are protecting groups as defined herein; all compounds may also be the pharmaceutically acceptable salt and / or solvate thereof. Steps i to vii may also optionally be combined as a single method to prepare psilocin, where the compound of formula (I) from either step iiia or step iiib is used in step iv. It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention. Examples The following examples are provided solely to illustrate the present invention and are not intended to limit the scope of the invention, as described herein. Scheme 1: Synthetic process leading to compound 13 All of the below development steps are shown collectively in Figures 1 and 2. The initial approach involved converting the aldehyde 2 to the Knoevenagel product 3 using malonic acid in accordance with Bioorg. Med. Chem.22 (2014), 3096– 3104 and the conditions shown below. Surprisingly, subsequent attempts to convert to the amine 4 via Curtius rearrangement resulted in a number of products with very little formation of 4 and a degree of reversion to compound 2.

[0029] 28 1005377547 From compound 2, the one pot process via Knoevenagel condensation with Meldrum’s acid and subsequent reduction of the alkylidene intermediate with NaBH4 provided compound 6. Decarboxylation of compound 6 to compound 7 was trialled under various known conditions including DMF / H2O (in accordance with Tetrahedron.65 (2009), 5161–5167), FeCl3 (in accordance with Org. Lett. 15 (2013), 4564-4567) and Toluene / Pyridine (in accordance with J. Org. Chem.73, (2008), 1639-1642), but all only with varying success, and not to levels necessary for large scale production. It was found that heating compound 6 in a mixture of DMSO and 10% citric acid solution (internal temperature 105-110 °C) conveniently and cleanly provided compound 7. Unfortunately, the Curtius rearrangement of compound 7 provided the unexpected compound 8 via electrophilic aromatic substitution. In order to avoid the formation of compound 8, it was deduced protection of the indole nitrogen with an electron withdrawing substituent was required. From compound 2, tosylation occurred to provide compound 1 which was then subjected to the same

[0030] 29 1005377547 conditions for the Knoevenagel condensation with 2,2-dimethyl-1,3-dioxane-4,6-dione and subsequent reduction of the alkylidene to provide 5 and subsequent decarboxylation to compound 9. The Curtius rearrangement to compound 10 used concentrated HCl. Initially, the Curtis arrangement from compound 9 to compound 10 also gave a dimerized side structure (compound 17). It was determined that acidic water was needed to suppress the formation of compound 17. Several approaches to psilocin (compound 13) were trialled and initially, tosyl removal from compound 10 to form compound 11 proceeded smoothly but reductive amination exclusively formed the product of a Pictet-Spengler-like reaction product compound 12.

[0031] 30 1005377547

[0032] Reductive amination directly from 10 provided exclusively compound 15. From compound 15 two routes to psilocin (13) were explored. Firstly, hydrogenolysis of compound 15 to compound 14 proceeded smoothly but surprisingly the attempted removal of the tosyl group to form 13 using the well-known conditions of Cs2CO3 in methanol provided an intractable tar. Unexpectedly, it was found that reordering these steps successfully led to the product. Performing the tosyl removal from compound 15 to produce compound 16 followed by hydrogenolysis to psilocin (compound 13) was determined to be the most effective route.

[0033] 31 1005377547

[0034] Scheme 2: Synthetic process to intermediate 5 and psilocin All of the below steps are shown collectively in Figure 2. Synthetic process to intermediate 5 This scheme mostly uses benign reagents, mostly pharmaceutically acceptable solvents and cost effective and readily available reagents and starting materials. The process is scalable and does not require chromatography or special handling conditions and all intermediates up to compound 5 are solids. Step 1

[0035] 32 1005377547 4-Benzyloxyindole (55.83 g, 250 mmol) was placed in an oven dried 3-neck 1L round-bottom flask fitted with a N2 inlet and flushed with N2. The reaction mixture was placed in an ice bath while flushing with N2 and then fitted with a rubber septum and stopper. To the above mixture was added anhydrous N,N-dimethylformamide (DMF) (96.8 mL) and stirred until solids dissolved. POCl3 (28.0 mL) was added dropwise via syringe pump over 30 min. After the addition, the mixture was stirred with heating at 40 °C for 2h in which time a bright yellow precipitate formed.2M sodium hydroxide (1.5L) was slowly added and the mixture stirred while heating to 90 °C while gently purging with N2 overnight in which time a fine precipitate resulted. The mixture was allowed to cool to room temperature; the solid was filtered and washed with plenty of water and dried to provide 60.6g of the compound 2 as a light brown solid 96% yield. 1H NMR (400 MHz, CDCl3) δ 10.52 (d, J = 0.7 Hz, 1H), 8.86 (s, 1H), 7.94 (d, J = 3.0 Hz, 1H), 7.51 – 7.47 (m, 2H), 7.44 – 7.31 (m, 3H), 7.21 (t, J = 8.0 Hz, 1H), 7.10 (dd, J = 8.1, 0.7 Hz, 1H), 6.83 – 6.78 (m, 1H), 5.27 (s, 1H). Step 2 Compound 2 (60g, 238.8mmol) was placed in a two neck 2L flask fitted with a N2 inlet and rubber septum. To this was added dichloromethane (DCM) (600mL) followed by N,N-dimethylaminopyridine (DMAP) (1.68g, 13.75mmol), triethylamine (58.3mL, 418mmol) and the mixture was cooled on an ice bath then tosyl chloride (51.0g, 267.5mmol) was added and the reaction was left to stir without recharging the ice bath for 2h after which time LCMS showed complete reaction. The solution was concentrated to a semi-solid mass and then triturated with stirring with 90% MeOH-H2O (360mL) until a fine uniform precipitated resulted (overnight). The crude solid was filtered and washed with 200mL of 90%MeOH-H2O in portions until the filtrate was colourless and the filter

[0036] 33 1005377547 cake was dried to provide 90.52g of the compound 3 as a peach-coloured powder 93% yield. 1H NMR (400 MHz, Chloroform-d) δ 10.48 (s, 1H), 8.25 (s, 1H), 7.84 (d, J = 8.4 Hz, 2H), 7.63 (dd, J = 8.4, 0.6 Hz, 1H), 7.44–7.26 (m, 8H), 6.86 (dd, J = 8.1, 0.6 Hz, 1H), 5.20 (s, 2H), 2.37 (s, 3H). Step 3 The compound 3 (90g, 221.96mmol) was placed in a 3L rb and meldrum’s acid (41.6g, 288.55mmol) was added followed by EtOH (1125mL) and D-proline (2.56g, 22.2mmol) and then heated with stirring at 60-65 °C for 2h after which time LCMS showed approx.7% starting material remaining. The heat was removed and the reaction mixture allowed to cool to approx.40 °C and then placed in an ice bath until the internal temp reached 3-4 °C. To the ice-cooled solution was then added NaBH4 (18.57g, 490.88mmol) portion-wise so as to maintain the internal temperature at or below 10 °C and the mixture was left to stir overnight without recharging the ice bath. After this time, LCMS showed complete conversion. The mixture was then diluted with water (1L) and stirred for 1h, filtered to a clear solution then acidified with dropwise addition of 2M HCl with stirring until the pH was approximately 2-3 and the resulting precipitate was stirred for 1h. The solid was filtered, washed with water and then EtOH (2 x 50mL, 1 x 100mL) then Et2O 3 x 100mL. The cake was taken up in 50:50 EtOH:Et2O (500mL) and stirred at room temperature overnight. The solid was filtered and washed with 50:50 EtOH:Et2O until a colourless filtrate was observed and then Et2O to provide compound5 as an off-white solid (99.25g, 84% yield) with HPLC purity 96.5%.

[0037] 34 10053775471H NMR (400 MHz, Chloroform-d) δ 7.77 (d, J = 8.4 Hz, 2H), 7.61 (dd, J = 8.4, 0.6 Hz, 1H), 7.50 (s, 1H), 7.41 – 7.34 (m, 5H), 7.24 – 7.17 (m, 3H), 6.75 (dd, J = 8.1, 0.6 Hz, 1H), 5.09 (s, 2H), 4.14 (t, J = 6.3 Hz, 1H), 3.46 (dd, J = 6.4, 1.0 Hz, 2H), 2.33 (s, 3H), 1.63 (d, J = 0.8 Hz, 3H), 1.37 (d, J = 0.7 Hz, 3H). Synthetic process from intermediate 5 to psilocin The steps from intermediate 5 to psilocin could also be performed in a continuously flowing stream in addition to batch production. Step 4 The compound 5 (90g, 168.67mmol) was placed in a 3L 3-neck flask then dimethylsulfoxide (DMSO) (900mL) was added followed by 10% citric acid (200mL) and stirred with heating to maintain an internal temperature of 105-110 °C for 16h after which time LCMS showed complete reaction. The heat was turned off and to the mixture was slowly added water (1.2L) (after approximately 300mL was added a precipitate started to form, the suspension was allowed to stir several minutes and the remaining water added slowly) then allowed to slowly cool to room temperature. The solid was filtered and washed thoroughly with water, then EtOH (2 X 100mL) and Et2O to provide compound 9 as an off-white crystalline solid 74.5g, 98% yield and >99% purity by HPLC and NMR. 1H NMR (400 MHz, DMSO-d6) δ 7.78 (d, J = 8.4 Hz, 2H), 7.50 – 7.42 (m, 3H), 7.42 – 7.27 (m, 6H), 7.23 (t, J = 8.2 Hz, 1H), 6.87 (d, J = 8.1 Hz, 1H), 5.17 (s, 2H), 2.98 (t, J = 7.4 Hz, 2H), 2.55 (t, J = 7.5 Hz, 2H), 2.31 (s, 3H).Step 5

[0038] 35 1005377547

[0039] Compound 9 (1g, 2.225mmol) was placed in a two-neck 25 mL round bottom flask and 4Å molecular sieves (300mg) was added followed by anhydrous acetonitrile (10 mL) and triethylamine (Et3N) (0.375mL, 2.686mmol) and the mixture stirred at room temperature for 30-45 minutes under N2. Diphenylphosphoryl azide (DPPA) was added neat and then heated to 50 °C with stirring for 3h and then 37% HCl was added and continued stirring at 50 °C for 2h and then stirring at room temperature overnight. Insoluble precipitate were filtered and washed with acetonitrile (5 mL). The filtrate was diluted with ethyl acetate (20mL) and then washed with twice with 1N NaOH(aq) and once with brine, dried over MgSO4, filtered and then concentrated to a foam providing crude compound 10 as a foam 850mg and used directly in the next step. Step 6 Crude compound 10 (820mg, 1.95mmol) was dissolved in methanol and 37% formaldehyde solution (0.697 mL) was added followed by acetic acid (0.12 mL) and allowed to stir for 5-10 minutes before sodium triacetoxyborohydride (1.33g, 6.272mmol) was added portion wise over 20-30 minutes and stirred at room temperature overnight.

[0040] 36 1005377547 The mixture was diluted with ethyl acetate and 1M NaOH (30mL) was added and the mixture stirred for 1h. The aqueous layer was removed and the organic layer washed with water and brine, filtered and dried under MgSO4, filtered and concentrated to provide compound 16 as an amber resin to provide 762mg. 1H NMR (400 MHz, CDCl3) δ 7.74 (d, J = 8.4 Hz, 2H), 7.58 (dd, = 8.3, 0.7 Hz, 1H), 7.48 – 7.30 (m, 5H), 7.25 – 7.14 (m, 4H), 6.68 (d, J = 8.0 Hz, 1H), 5.12 (s, 2H), 3.01 – 2.92 (m, 2H), 2.57 – 2.49 (m, 2H), 2.34 (s, 3H), 2.12 (s, 6H). Step 7 Crude compound 15 (100mg, 0.223mmol) was taken up in methanol (3 mL and Cs2CO3 (600 mg) was added and heated at 65 °C with stirring for 16h. The cooled mixture was diluted with ethyl acetate (10 mL) and washed with twice with water and once with brine, dried over MgSO4, filtered and concentrated to provide compound 16 as a resin 72mg. A small portion was purified by high-performance liquid chromatography (HPLC) for analytical purposes. 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 7.53 – 7.45 (m, 2H), 7.40 – 7.26 (m, 3H), 7.03 (t, J = 8.0 Hz, 1H), 6.92 (dd, J = 8.2, 0.7 Hz, 1H), 6.83 (d, J = 2.2 Hz, 1H), 6.53 (d, J = 7.6 Hz, 1H), 5.17 (s, 2H), 3.09 – 2.96 (m, 2H), 2.67 – 2.57 (m, 2H), 2.14 (s, 6H). Step 8

[0041] 37 1005377547 Crude compound 16 (50mg, 0.17mmol) in methanol (10mL) and 10% Pd / C (20mg) was added and the mixture hydrogenated under a hydrogen atmosphere at ambient temperature overnight. The mixture was filtered and concentrated to a brown oil that was purified on reverse phase HPLC C18 eluting with an isocratic solvent at 68% MeOH / H2O to provide 20mg of compound 13 as a resin. 1H NMR (401 MHz, MeOD) δ 6.86 (d, J = 8.7 Hz, 2H), 6.82 (d, J = 0.9 Hz, 1H), 6.33 (dd, J = 7.4, 0.9 Hz, 1H), 3.01 (t, J = 6.7 Hz, 2H), 2.73 (t, J = 6.7 Hz, 2H), 2.35 (s, 6H). As would be understood by the skilled person, steps 2-5 could be applied a range of aldehydes to access the corresponding amine. Further exemplary amines prepared by the steps similar to that described above are detailed in Table 1. Table 1. Entry Compound Name Structure1H NMR data 1 2-(7- (400 MHz, MeOD) δ 6.48 (d, methoxybenzo[d][1,3]dioxol- J = 10.4 Hz, 2H), 5.92 (s, 5-yl)ethan-1-amine 2H), 3.89 (s, 3H), 3.12 (s, 2H), 2.84 (s, 2H). 2 2-(2,2- (400 MHz, MeOD) δ 6.48 (d, difluorobenzo[d][1,3]dioxol-5- J = 10.4 Hz, 2H), 5.92 (s, yl)ethan-1-amine 2H), 3.89 (s, 3H), 3.12 (s, 2H), 2.84 (s, 2H).

[0042] 38 1005377547 3 2-(1-tosyl-1H-indol-5- (400 MHz, MeOD) δ 7.96 (d, yl)ethan-1-amine J = 8.5 Hz, 1H), 7.80 (d, J = 8.4 Hz, 2H), 7.67 (d, J = 3.7 Hz, 1H), 7.46 (s, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.23 (dd, J = 8.6, 1.5 Hz, 1H), 6.71 (dd, J = 3.7, 0.7 Hz, 1H), 3.18 (t, J = 7.6 Hz, 2H), 3.00 (t, J = 7.5 Hz, 2H), 2.34 (s, 3H). 4 2-(1-tosyl-1H-indol-7- (400 MHz, MeOD) δ 7.76 (d, yl)ethan-1-amine J = 3.8 Hz, 1H), 7.51 (dd, J = 15.9, 8.1 Hz, 3H), 7.29 (d, J = 8.0 Hz, 2H), 7.23 (t, J = 7.5 Hz, 1H), 7.15 (d, J = 7.5 Hz, 1H), 6.82 (d, J = 3.8 Hz, 1H), 3.46 (d, J = 8.5 Hz, 2H), 3.25 (d, J = 7.0 Hz, 2H), 2.35 (s, 3H). 5 2-phenylethan-1-amine (400 MHz, MeOD) δ 7.27 (d, J = 7.2 Hz, 2H), 7.20 (d, J = 7.2 Hz, 3H), 3.35 (t, J = 7.2 Hz, 2H), 2.83 – 2.67 (m, 2H). 6 2-(thiophen-2-yl)ethan-1- (400 MHz, MeOD) δ 7.32 amine (dd, J = 5.0, 1.3 Hz, 1H), 6.99 (dd, J = 7.8, 2.7 Hz, 2H), 3.22 (m, 4H).

[0043] 39 1005377547 7 2-(5-methylthiophen-2- (400 MHz, CDCl3) δ 6.62 – yl)ethan-1-amine 6.50 (m, 2H), 3.38 (dd, J = 12.5, 6.4 Hz, 1H), 2.92 (dt, J = 9.1, 5.9 Hz, 3H), 2.60 (br s, 1H), 2.41 (s, 3H). 8 2-(4- (400 MHz, CDCl3) δ 7.23 (d, (methylthio)phenyl)ethan-1- J = 8.3 Hz, 2H), 7.14 (d, J = amine8.5 Hz, 2H), 3.51 (t, J = 6.9 Hz, 2H), 2.86 (t, J = 6.9 Hz, 2H), 2.47 (d, J = 3.3 Hz, 3H). 9 2-(4- (400 MHz, CDCl3) δ 7.90 – (methylsulfonyl)phenyl)ethan- 7.84 (m, 2H), 7.39 (m, J = 8.1 1-amine Hz, 2H), 3.47 (t, J = 6.8 Hz, 2H), 3.06 ( s, 3H), 2.92 (m, J = 2.4 Hz, 2H). 10 2-(2- (400 MHz, MeOD) δ 8.01 (methylsulfonyl)phenyl)ethan- (dd, J = 7.9, 1.1 Hz, 1H), 1-amine 7.68 – 7.61 (m, 1H), 7.48 (dd, J = 13.9, 7.2 Hz, 2H), 3.44 (m, 2H), 3.24 – 3.16 (m, 5H). 11 2-(3,4,5- (400 MHz, MeOD) δ 6.60 (d, trimethoxyphenyl)ethan-1- J = 1.3 Hz, 2H), 3.85 (s, 6H), amine 3.74 (s, 3H), 3.32 (s, 2H), 2.91 (s, 2H). 12 2-cyclohexylethan-1-amine (400 MHz, CDCl3) δ 3.32 – 3.20 (m, 1H), 3.19 – 3.13 (m, 1H), 1.72 – 1.59 (m, 6H), 1.28 – 1.08 (m, 5H), 0.89 (dd, J = 8.3, 3.3 Hz, 2H).

[0044] 40 1005377547 13 2-cyclopentylethan-1-amine (400 MHz, MeOD) δ 2.91 (d, J = 8.0 Hz, 2H), 1.89 – 1.80 (m, 3H), 1.71 – 1.58 (m, 6H), 1.16 (d, J = 7.3 Hz, 2H). 14 2-cyclopropylethan-1- (400 MHz, MeOD) δ 3.19 amine (t, J = 7.1 Hz, 2H), 1.42 – 1.32 (m, 2H), 0.69 (m, 1H), 0.44 (m, 2H), 0.06 (m, 2H).

[0045] 41 1005377547

Claims

CLAIMS 1. A compound of formula (A), or a pharmaceutically acceptable salt and / or solvate thereof,wherein Z is selected from Z1or Z2: Z1Z2R1is H or a carboxyl protecting group; X is an amine protecting group; and Y is a hydroxyl protecting group.

2. A compound according to claim 1, or a pharmaceutically acceptable salt and / or solvate thereof, wherein the carboxyl protecting group is C1-6 alkyl or C2-6 alkenyl.

3. A compound according to claim 1 or 2, or a pharmaceutically acceptable salt and / or solvate thereof, wherein X is selected from SO2R3, CO2R5, benzyl carbamate or C1-6 alkyl, wherein R3is selected from C1-6 alkyl or aryl, and R5is C1-6alkyl 4. A compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt and / or solvate thereof, wherein Y is selected from beznyl, Si(R4)3, COR5, CH2OCH2CH2Si(CH3)3, and OCH2OCH3, wherein R4and R5are C1-6 alkyl.

5. A compound according to claim 1 of formula (I):42 1005377547or a pharmaceutically acceptable salt and / or solvate thereof.

6. A compound according to claim 1 of formula (Ia):or a pharmaceutically acceptable salt and / or solvate thereof.

7. A compound according to any one of claims 1 to 6, or a pharmaceutically acceptable salt and / or solvate thereof, wherein X is SO2R3, wherein R3is selected from C1-6 alkyl or aryl.

8. A compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt and / or solvate thereof, wherein Y is benzyl.

9. A method for preparing a compound of formula (A), or a pharmaceutically acceptable salt and / or solvate thereof,wherein43 1005377547R1is H, methyl or ethyl; and X is an amine protecting group; and Y is a hydroxyl protecting group; the method comprising contacting a compound of formula (Ib), or a pharmaceutically acceptable salt and / or solvate thereof,iv. a 1,3-dicarbonyl compound; v. a base; and vi. a reducing agent.

10. The method according to claim 9 wherein: the 1,3-dicarbonyl compound is selected from 2,2-dimethyl-1,3-dioxane-4,6-dione, malonic acid, dimethyl malonate and diethyl malonate; the base is selected from D-proline, piperidine, pyridine, L-tyrosine, and 4,4′- trimethylenedipiperidine; and the reducing agent is selected is sodium borohydride, Pd / C, Ra-Ni, PtO2, H2NNH2, Pd(OAc)2 and zinc.

11. The method according to claim 9 or 10 wherein the 1,3-dicarbonyl compound is 2,2-dimethyl-1,3-dioxane-4,6-dione, to produce a compound of formula Ia, or a pharmaceutically acceptable salt and / or solvate thereof,44 100537754712. The method according to claim 11, further comprising a step of preparing the compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof,wherein: R1is H; X is an amine protecting group; and Y is a hydroxyl protecting group; the method comprising contacting a compound of formula (Ia), or a pharmaceutically acceptable salt and / or solvate thereof,with an acid and water.

13. The method according to claim 9 further comprising a step of preparing the compound of formula (Ib), or a pharmaceutically acceptable salt and / or solvate thereof, the method comprising contacting a compound of formula (Ic), or a pharmaceutically acceptable salt and / or solvate thereof,ii. a protecting group precursor.45 100537754714. The method according to claim 13 wherein the base is selected from pyridine, Et3N, 4-dimethylaminopyridine, K2CO3, and sodium hydride; and the protecting group precursor is selected from trimethylsilylethoxymethyl chloride, tosyl chloride, methanesulfonyl chloride, di-tert-butyl dicarbonate, benzyl bromide, and trimethylsilyl chloride.

15. The method according to claim 13 or 14 further comprising a step of preparing the compound of formula (Ic), or a pharmaceutically acceptable salt and / or solvate thereof, the method comprising contacting a compound of formula (Id), or a pharmaceutically acceptable salt and / or solvate thereof,with: iii. a formylating agent; and iv. a base.

16. The method according to claim 15 wherein the formylating agent is selected from phosphorus oxychloride with DMF, hexamethylenetetramine and formic acid; and the base is selected from NaOAc, NaOH, and KOH.

17. A method for preparing a compound of formula (Ie), or a pharmaceutically acceptable salt and / or solvate thereof,46 1005377547the method comprising contacting a compound of formula (I), or a pharmaceutically acceptable salt and / or solvate thereof,with: i. an azide source; ii. a base; and iii. an acid; wherein X is an amine protecting group; and Y is a hydroxyl protecting group.

18. The method according to claim 17 wherein the azide source is selected from trimethylsilyl azide, sodium azide and diphenyl phosphoryl azide; the base is a nitrogen containing base; preferably the base is selected from triethylamine, diisopropylamine, N,N-diisopropylethylamine and 4-dimethylaminopyridine; and the acid is selected from HCl, HBr, H2SO4, H3PO4, CH3COOH, MeSO3H and CF3SO3H.

19. The method according to claim 18, further comprising contacting the compound of formula (Ie),or a pharmaceutically acceptable salt and / or solvate thereof, with: i. formaldehyde; ii. formic acid; and47 1005377547iii. a reducing agent to produce a compound of formula (If), or a pharmaceutically acceptable salt and / or solvate thereof:

20. The method of claim 19 further comprising - contacting a compound of formula (If), or a pharmaceutically acceptable salt and / or solvate thereof, with reagents to remove X to produce a compound of formula (Ig) or a pharmaceutically acceptable salt and / or solvate thereof,contacting a compound of formula (Ig) with Pd / C under an atmosphere of hydrogen to produce psilocin:, or a pharmaceutically acceptable salt and / or solvate thereof.

21. The method according to any one of claims 9 to 20, wherein X is selected from SO2R3, CO2R5, benzyl carbamate or C1-6alkyl; and / or Y is selected from benzyl, Si(R4)3, COR5, CH2OCH2CH2Si(CH3)3, OCH2OCH3; wherein R3is selected from C1-6alkyl or aryl; and R4and R5are C1-6alkyl.48 1005377547

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