Methods for preparing cannabichromene and related cannabinoids

Abstract

A method for producing cannabichromene and related cannabinoid compounds is disclosed. The method includes forming a reaction mixture containing 3,7-dimethylocta-2,6-dienal, a diamine, and olivetol, or a related starting material; and maintaining the reaction mixture under conditions sufficient to form a desired product. The disclosed method can also include a one-pot conversion of the cannabichromene-type product to a cannabinol-type product. TIFF2023508671000022.tif89170

Description

[Technical Field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims priority to U.S. Provisional Patent Application No. 62 / 954,287, filed December 27, 2019, which is incorporated herein by reference in its entirety. [Background technology]

[0002] Background of the Invention Varieties of hemp (Cannabis sativa) are widely cultivated and utilized worldwide for several purposes. The stems, branches, and leaves are used for fiber and fiber-based products; the buds and seeds for food; the seeds for inexpensive oil; the flowers for aromatic, recreational, ceremonial, and medicinal uses; and the flowers and roots for nutritional and additional medical and pharmaceutical uses. Indeed, numerous controlled clinical trials and anecdotal or open-label studies in humans have documented the beneficial effects of both plant extracts and purified hemp plant compounds in a number of human medical conditions. The beneficial activities of the cannabinoid family of compounds described in human studies range from neurological disorders to mood / behavioral disorders, gastrointestinal disorders, and problems with sleep, appetite, and fatigue. Other uses or potential uses include the treatment of various microbial and viral infections and some cancers. Summary of the Invention

[0003] Formula I: Provided herein is a method for preparing the cannabichromene-type compounds of TIFF0007761564000001.tif20128 and salts thereof. 3,7-dimethylocta-2,6-dienal and a diamine with formula II: forming a reaction mixture comprising the compound of formula (I); maintaining the reaction mixture under conditions sufficient to form a compound of formula I. Includes.

[0004] In some embodiments, the compound of formula II is olivetol and the compound of formula I is cannabichromene. In some embodiments, the diamine is N,N'-dimethylethylene-diamine.

[0005] In some embodiments, the method comprises reacting a cannabichromene-type compound of formula I with a compound of formula III: TIFF0007761564000003.tif25128 to a cannabinol-type compound (e.g., in a one-pot reaction).

[0006] Exemplary embodiments provided in accordance with the subject matter disclosed herein include, but are not limited to, the claims and the following embodiments. 1. Formula I: 1. A process for preparing a compound of TIFF0007761564000004.tif20128 or a salt thereof, comprising: The method comprises: 3,7-dimethylocta-2,6-dienal and a diamine with formula II: forming a reaction mixture comprising the compound of formula (I); maintaining said reaction mixture under conditions sufficient to form a compound of formula I. Including, During the ceremony, R 1 However, C1~C 20 Alkyl, C1-C 20 Haloalkyl, C1-C 20 Hydroxyalkyl, deuterated C1-C 20 Alkyl, tritiated C1-C 20 Alkyl, and C2-C 20 alkenyl; R 2 H and -COOR 2a and R 2a is selected from the group consisting of H and C1-C6 alkyl; The method. 2. The method of embodiment 1, wherein the diamine is selected from the group consisting of N,N'-dimethylethylenediamine; N,N-dimethylethylenediamine; N,N-diethylethylenediamine; N,N'-diphenylethylenediamine; N,N'-dibenzylethylenediamine; N,N'-bis(2-hydroxyethyl)ethylenediamine; N,N'-dimethylpropylenediamine; N,N-dimethylpropylenediamine; N,N-diethylpropylenediamine; N,N'-diphenylpropylenediamine; N,N'-dibenzylpropylenediamine; N,N'-bis(2-hydroxyethyl)propylenediamine; 1,2-diaminocyclohexane; N,N'-dimethyl-1,2-diaminocyclohexane; and 1,2-cyclopentanediamine. 3. The method of embodiment 1 or embodiment 2, wherein the reaction mixture contains about 1.1 to 10 molar equivalents of the 3,7-dimethylocta-2,6-dienal relative to the compound of Formula II. 4. The method of embodiment 3, wherein the reaction mixture contains about 1.1 to 2 molar equivalents of the 3,7-dimethylocta-2,6-dienal relative to the compound of formula II. 5. The method of any of embodiments 1-4, wherein the reaction mixture contains about 0.01 to 10 molar equivalents of the diamine relative to the compound of Formula II. 6. The method of embodiment 5, wherein the reaction mixture contains about 0.25 molar equivalents of the diamine relative to the compound of Formula II. 7. The method of any of aspects 1-6, wherein the reaction mixture is maintained at a reaction temperature in the range of about 20°C to about 70°C. 8. The method of embodiment 7, wherein the reaction mixture is maintained at the reaction temperature for a period of time ranging from about 30 minutes to about 24 hours. 9. The method of any of aspects 1-8, wherein the reaction mixture further comprises a solvent. 10. The method of embodiment 9, wherein the solvent is selected from the group consisting of toluene, chloroform, methylene chloride, dichloroethane, ethyl acetate, acetonitrile, acetone, tetrahydrofuran, benzene, ethylbenzene, xylene, diethyl ether, dimethylformamide, dimethyl sulfoxide, petroleum ether, and mixtures thereof. 11. The method of embodiment 9, wherein the solvent is selected from the group consisting of toluene, chloroform, isopropanol, and mixtures thereof. 12. The method of any of aspects 1-11, wherein the 3,7-dimethylocta-2,6-dienal comprises neral, geranial, or a combination thereof. 13. The method of any one of aspects 1-11, wherein the 3,7-dimethylocta-2,6-dienal comprises E,Z-citral. 14. R 2 The method of any of embodiments 1 to 13, wherein 15. R 2 The method of any of embodiments 1 to 13, wherein is —COOH. 16. R 1 The method of any of embodiments 1-15, wherein is n-pentyl. 17. The method of any of embodiments 1-16, wherein the compound of formula II is purified or semi-purified. 18. Reacting a compound of formula I with a compound of formula III: 18. The method of any of embodiments 1-17, further comprising converting to the compound of formula TIFF0007761564000006.tif25128. 19. The method of embodiment 18, wherein the converting step comprises combining the compound of formula I with an iodine source and an oxidizing agent. 20. The method of embodiment 19, wherein the iodine source is selected from the group consisting of sodium iodide, lithium iodide, potassium iodide, magnesium iodide, calcium iodide, ammonium iodide, aluminum iodide, zinc iodide, barium iodide, cesium iodide, N-iodosuccinimide, and combinations thereof. 21. The method of embodiment 18, wherein the converting step comprises combining the compound of formula I with an oxidizing agent. 22. The method of any one of aspects 19-21, wherein the oxidizing agent is selected from the group consisting of potassium peroxymonosulfate, peroxide, 2-iodoxybenzoic acid, sodium hypochlorite, and combinations thereof. 23. The method of embodiment 18, wherein said converting step comprises combining the compound of formula I with sodium iodide and potassium peroxymonosulfate. 24. The method of embodiment 18, wherein the converting step comprises combining the compound of formula I with elemental sulfur. 25. The method of embodiment 18, wherein the converting step comprises combining a compound of formula I with a metal dehydrogenation catalyst. 26. The method of embodiment 25, wherein the metal dehydrogenation catalyst comprises palladium on carbon, platinum on carbon, palladium on alumina, or platinum on alumina. 27. The method of any one of embodiments 18-27, wherein the converting step further comprises combining the compound of Formula I with an acid. 28. The method of embodiment 27, wherein the acid is p-toluenesulfonic acid. 29. The method of any one of embodiments 18-28, wherein the step of converting the compound of Formula I to the compound of Formula III is carried out as a one-pot reaction in the reaction mixture for forming the compound of Formula I. [Brief explanation of the drawings]

[0007] [Figure 1A] 1 shows the proton NMR spectrum recorded for 3,6,6,9-tetramethyl-6H-benzo[c]chromen-1-ol. [Figure 1B] Figure 1 shows a reverse phase chromatogram recorded for 3,6,6,9-tetramethyl-6H-benzo[c]chromen-1-ol. DETAILED DESCRIPTION OF THE INVENTION

[0008] Detailed Description of the Invention Provided herein is a rapid, high-yield method for the preparation of cannabichromene, cannabinol, and related cannabinoids.The method can be used to produce valuable cannabinoids on a kilogram scale and can be carried out by a simple one-pot procedure.As described herein, it has been found that diamine catalysts are particularly advantageous for forming cannabichromene-type products.

[0009] I. Definition The term "cannabichromene" refers to 2-methyl-2-(4-methyl-3-penten-1-yl)-7-pentyl-2H-1-benzopyran-5-ol (CAS Registry Number 20675-51-8). "Cannabichromene analogs" include those analogs that have a C1-C4 alkyl group, a branched C5 alkyl group, a C6-C alkyl group, or a C8-C9 alkyl group at the location of the 7-pentyl in cannabichromene. 20 Alkyl groups, C1-C 20 Haloalkyl groups, C1-C 20 Hydroxyalkyl groups, deuterated C1-C 20 Alkyl groups, tritiated C1-C 20 Alkyl group or C2-C 20 This includes, but is not limited to, compounds in which an alkenyl group is present.

[0010] The term "cannabinol" refers to 6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol (CAS Registry Number 521-35-7). "Cannabinol analogs" include those which have a C1-C4 alkyl group, a branched C5 alkyl group, a C6-C alkyl group, or a C8-C9 alkyl group in place of the 3-pentyl group in cannabinol. 20 Alkyl groups, C1-C 20 Haloalkyl groups, C1-C 20 Hydroxyalkyl groups, deuterated C1-C 20 Alkyl groups, tritiated C1-C 20 Alkyl group or C2-C 20 This includes, but is not limited to, compounds in which an alkenyl group is present.

[0011] The term "diamine" refers to a hydrocarbon compound having two amine substituents of formula -NR2, where each R group is independently selected from the group consisting of hydrogen, alkyl, hydroxyalkyl, aryl, arylalkyl, or acyl. Each amine substituent can independently be a primary amine, where both R groups are hydrogen; a secondary amine, where one R group is hydrogen and one R group is other than hydrogen; or a tertiary amine, where both R groups are other than hydrogen.

[0012] As used herein, the term "iodine source" refers to an inorganic or organic compound that contains at least one iodine atom.

[0013] As used herein, the term "oxidize" refers to the transfer of electron density from a substrate compound to an oxidizing agent. Electron density transfer typically occurs via a process involving the addition of oxygen to or the removal of hydrogen from a substrate compound. The term "oxidizing agent" refers to a reagent capable of accepting electron density from a substrate compound.

[0014] The term "alkyl," by itself or as part of another substituent, means a straight-chain or branched saturated aliphatic group. Alkyl can have any number of carbons, e.g., C 1~2 , C 1~3 , C 1~4 , C 1~5 , C 1~6 , C 1~7 , C 1~8 , C 1~9 , C 1~10 , C 2~3 , C 2~4 , C 2~5 , C 2~6 , C 3~4 , C 3~5 , C 3~6 , C 4~5 , C 4~6 and C 5~6 For example, C 1~6 Alkyl includes, but is not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, etc. Alkyl may also refer to alkyl groups having up to 20 carbons, such as, but not limited to, heptyl, octyl, nonyl, decyl, etc.

[0015] The term "alkenyl," by itself or as part of another substituent, means an alkyl group, as defined herein, having one or more carbon-carbon double bonds. Examples of alkenyl groups include, but are not limited to, vinyl (i.e., ethenyl), crotyl (i.e., but-2-en-1-yl), penta-1,3-dien-1-yl, and the like. Alkenyl moieties may be further substituted, for example, with aryl substituents (e.g., phenyl or hydroxyphenyl in the case of 4-hydroxystyryl).

[0016] The terms "halogen" and "halo," by themselves or as part of another substituent, mean a fluorine, chlorine, bromine, or iodine atom.

[0017] The term "haloalkyl," by itself or as part of another substituent, means an alkyl group in which some or all of the hydrogen atoms have been replaced with halogen atoms. Like alkyl groups, haloalkyl groups can have any suitable number of carbon atoms, e.g., C 1~6 For example, haloalkyl includes trifluoromethyl, fluoromethyl, etc. In some cases, the term "perfluoro" is used to define a compound or group in which all hydrogens have been replaced with fluorine. For example, perfluoromethyl means 1,1,1-trifluoromethyl.

[0018] The term "hydroxyalkyl," by itself or as part of another substituent, means an alkyl group in which some or all of the hydrogen atoms have been replaced with hydroxyl groups (i.e., -OH groups). Similar to alkyl and haloalkyl groups, hydroxyalkyl groups can have any suitable number of carbon atoms, e.g., C 1~6 may have.

[0019] The term "deuterated" refers to the replacement of one or more hydrogen atoms with one or more deuterium atoms (i.e. 2 It means a substituent (such as an alkyl group) having a H atom.

[0020] The term "tritiated" refers to one or more tritium atoms in place of one or more hydrogen atoms (i.e. 3 It means a substituent (such as an alkyl group) having a H atom.

[0021] The term "aryl," used alone or as part of a larger moiety such as "aralkyl," "aralkoxy," or "aryloxyalkyl," refers to a monocyclic or bicyclic ring system having a total of 5 to 14 ring members, wherein at least one ring in the ring system is aromatic and each ring in the ring system contains 3 to 7 ring members. The term "aryl" may be used interchangeably with the term "aryl ring." In certain embodiments of the present invention, "aryl" refers to an aromatic ring system, including, but not limited to, phenyl, biphenyl, naphthyl, anthracyl, and the like, which may bear one or more substituents. Also included within the scope of the term "aryl," as it is used herein, are groups in which an aromatic ring is fused to one or more non-aromatic rings, such as, for example, indanyl, phthalimidyl, naphthimidyl, phenanthridinyl, or tetrahydronaphthyl. The term "aryloxy" refers to the moiety -OR, where R is an aryl group as defined above.

[0022] As used herein, the terms "contacting" and "reacting" refer to the process of bringing at least two separate chemical species into contact so that they can react. However, it should be understood that the resulting reaction product can be produced directly from the reaction between the added reagents or from an intermediate that can be produced from one or more of the added reagents in the reaction mixture.

[0023] As used herein, the term "converting" refers to reacting a starting material with at least one reagent to form an intermediate species or product. Converting can also refer to reacting an intermediate with at least one reagent to form a further intermediate species or product.

[0024] As used herein, the terms "about" and "approximately," when used to modify a particular numerical value, refer to a closed range surrounding that numerical value. For example, if "X" is a value, then "about X" or "approximately X" would refer to a value of 0.9X to 1.1X, such as a value of 0.95X to 1.05X, or a value of 0.98X to 1.02X, or a value of 0.99X to 1.01X. Any reference to "about X" or "approximately X" specifically denotes at least the value X, 0.9X, 0.91X, 0.92X, 0.93X, 0.94X, 0.95X, 0.96X, 0.97X, 0.98X, 0.99X, 1.01X, 1.02X, 1.03X, 1.04X, 1.05X, 1.06X, 1.07X, 1.08X, 1.09X, and 1.1X, as well as values ​​within this range.

[0025] II. Methods for Cannabinoid Synthesis Formula I: Provided herein is a method for preparing the cannabichromene-type compounds of TIFF0007761564000007.tif20128 and salts thereof. 3,7-dimethylocta-2,6-dienal and a diamine with formula II: forming a reaction mixture comprising the compound of formula (I); maintaining the reaction mixture under conditions sufficient to form a compound of formula I. Including, During the ceremony, R 1 is C1~C 20 Alkyl, C1-C 20 Haloalkyl, C1-C 20 Hydroxyalkyl, deuterated C1-C 20 Alkyl, tritiated C1-C 20 Alkyl, and C2-C 20 alkenyl; R 2 H and -COOR 2a and R2a is selected from the group consisting of H and C1-C6 alkyl.

[0026] Isomers of 3,7-dimethylocta-2,6-dienal include (E)-3,7-dimethylocta-2,6-dienal (also known as geranial) and (Z)-3,7-dimethylocta-2,6-dienal (also known as neral).The reaction according to the present disclosure can be carried out using either isomer or a combination thereof; a mixture of geranial and neral is called "citral" and / or "E,Z-citral" and is commercially available from many common suppliers.Therefore, in some embodiments, 3,7-dimethylocta-2,6-dienal includes neral, geranial, or a combination thereof.In some embodiments, 3,7-dimethylocta-2,6-dienal is E,Z-citral.

[0027] The methods provided herein utilize olivetol (R 1 is n-pentyl and R 2 is H), olivetolic acid (R 1 is n-pentyl and R 2 is —COOH), and analogs thereof (compounds of formula II, where R 2 is H or -COOR 2a and R 1 C1-C4 alkyl, branched C5 alkyl, C6-C 20 Alkyl, C1-C 20 Haloalkyl, C1-C 20 Hydroxyalkyl, deuterated C1-C 20 Alkyl, tritiated C1-C 20 Alkyl, or C2-C 20In some embodiments, R in the compounds of Formula I and II can be used. Olivetol, olivetolic acid, and analogs thereof can be prepared as described, for example, in International Patent Application Publication Nos. WO 2018 / 209143, WO 2020 / 092823, and WO 2020 / 102430, which are incorporated herein by reference in their entireties. In some embodiments, R in the compounds of Formula I and II can be used. 2 is H. In some embodiments, R in the compounds of Formula I and Formula II 2 In some embodiments, R in the compounds of Formula I and Formula II is -COOH. 1 is n-pentyl. In some embodiments, R in the compounds of Formula I and Formula II 1 is methyl. In some embodiments, the compound of Formula II is purified or semi-purified. Alternatively, the compound of Formula II (e.g., olivetol) can be used as a crude mixture (e.g., a lysate of yeast cells used for expression of olivetol).

[0028] In some embodiments, the reaction mixture contains a solvent. In some embodiments, the solvent is selected from the group consisting of toluene, chloroform, methylene chloride, dichloroethane, ethyl acetate, acetonitrile, acetone, tetrahydrofuran, benzene, ethylbenzene, xylene, diethyl ether, dimethylformamide, dimethyl sulfoxide, petroleum ether, and mixtures thereof. In some embodiments, the solvent is toluene, chloroform, isopropanol, or a mixture thereof. In some embodiments, the solvent is isopropanol.

[0029] In some embodiments, the diamine is selected from the group consisting of N,N'-dimethylethylenediamine; N,N-dimethylethylenediamine; N,N-diethylethylenediamine; N,N'-diphenylethylenediamine; N,N'-dibenzylethylenediamine; N,N'-bis(2-hydroxyethyl)ethylene-diamine; N,N'-dimethylpropylenediamine; N,N-dimethylpropylenediamine; N,N-diethyl-propylenediamine; N,N'-diphenylpropylenediamine; N,N'-dibenzylpropylenediamine; N,N'-bis(2-hydroxyethyl)propylenediamine; 1,2-diaminocyclohexane; N,N'-dimethyl-1,2-diaminocyclohexane; and 1,2-cyclopentanediamine.

[0030] Generally, the reaction mixture contains 3,7-dimethylocta-2,6-dienal (also referred to herein as "dienal") in an amount ranging from about 0.01 molar equivalent to about 10 molar equivalents relative to the compound of formula II (e.g., olivetol) and / or the diamine. The reaction mixture may contain, for example, about 0.08 molar equivalent to about 1.8 molar equivalents of dienal, or about 1.0 molar equivalent to about 1.5 molar equivalents of dienal, or about 1.05 molar equivalent to about 1.45 molar equivalents of dienal, or about 1.1 molar equivalent to about 1.4 molar equivalents of dienal relative to the compound of formula II. The reaction mixture can contain about 0.01, 0.05, 1.0, 1.1, 1.12, 1.13, 1.14, 1.15, 1.16, 1.17, 1.18, 1.19, 1.2, 1.21, 1.22, 1.23, 1.24, 1.25, 1.26, 1.27, 1.28, 1.29, 1.3, 1.31, 1.32, 1.33, 1.34, 1.35, 1.36, 1.37, 1.38, 1.39, 1.4, 1.45, 1.5, 1.6, 1.7, 1.8, 1.9, or 2.0 molar equivalents of the dienal. In some embodiments, the reaction mixture contains about 1.1 to 10 molar equivalents of the dienal (e.g., E,Z-citral) relative to the compound of Formula II (e.g., olivetol). In some embodiments, the reaction mixture contains about 1.1 to 2 molar equivalents of the dienal (e.g., E,Z-citral) relative to the compound of Formula II (e.g., olivetol).

[0031] The reaction mixture typically contains a diamine (e.g., N,N'-dimethylethylenediamine) in an amount ranging from about 0.01 molar equivalent to about 10 molar equivalents relative to the compound of Formula II (e.g., olivetol) and / or the dienal (e.g., E,Z-citral). The reaction mixture may contain, for example, about 0.05 molar equivalent to about 1 molar equivalent of the diamine, or about 0.1 molar equivalent to about 0.5 molar equivalent of the diamine, or about 0.15 molar equivalent to about 0.4 molar equivalent of the diamine, or about 0.2 molar equivalent to about 0.3 molar equivalent of the diamine relative to the compound of Formula II. The reaction mixture may contain about 0.05, 0.1, 0.15, 0.2, 0.21, 0.22, 0.23, 0.24, 0.25, 0.26, 0.27, 0.28, 0.29, 0.3, 0.35, 0.4, 0.45, or 0.5 molar equivalents of the diamine. In some embodiments, the reaction mixture contains about 0.01 to 10 molar equivalents of the diamine (e.g., N,N'-dimethylethylenediamine) relative to the compound of Formula II (e.g., olivetol). In some embodiments, the reaction mixture contains about 0.25 molar equivalents of the diamine (e.g., N,N'-dimethylethylenediamine) relative to the compound of Formula II (e.g., olivetol).

[0032] The reaction can be carried out at any suitable temperature. Typically, the reaction is carried out at a temperature ranging from about 20°C to about 200°C, e.g., from about 20°C to about 100°C, or from about 20°C to about 80°C, or from about 20°C to about 70°C. The conversion step is carried out for a period of time sufficient to convert the compound of Formula II to the compound of Formula I. Depending on factors such as the particular starting material, the particular diamine, and the particular solvent, the conversion time may range from a few minutes to several hours, or longer. In some embodiments, the reaction mixture is maintained at a reaction temperature ranging from about 20°C to about 100°C (e.g., about 25°C, or about 30°C, or approximately 35°C or about 35°C, or about 40°C, or about 45°C, or about 50°C, or about 55°C, or about 60°C, or about 65°C, or about 70°C, or about 75°C, or about 80°C). In some embodiments, the reaction mixture is maintained at the reaction temperature (e.g., about 60°C) for a time ranging from about 30 minutes to about 24 hours (e.g., about 60 minutes to about 90 minutes). Unexpectedly, it has been found that long reaction times can sometimes result in decomposition of the desired cannabinoid product. However, it has been discovered that short reaction times (e.g., 24 hours or less, or 12 hours or less, or 5 hours or less, or 3 hours or less) can be advantageous to prevent undesired decomposition. The reaction may be carried out under ambient atmosphere or under an inert atmosphere (e.g., argon, nitrogen, etc.).

[0033] In some embodiments, the method comprises reacting a cannabichromene-type compound of formula I with a compound of formula III: TIFF0007761564000009.tif25128 to a cannabinol-type compound.

[0034] Caprioglio et al. (Organic Letters, 2019, 21(15): 6122-6125) recently reported that a one-pot synthesis of CBN is possible using olivetol, citral, and an amine catalyst prior to an iodine-mediated oxidation step. However, this procedure requires an intermediate step to remove the amine catalyst, which reportedly interferes with the subsequent oxidation step involving iodine. Provided herein is a true one-pot procedure that does not require removal of the amine catalyst and does not use DEA-controlled iodine. Rather, the disclosed process uses an iodine source such as NaI and a green oxidant such as oxone, which proceeds cleanly to cannabinol (CBN).

[0035] In some embodiments, the converting step comprises combining the compound of Formula I with an iodine source and an oxidizing agent. Suitable iodine sources include, but are not limited to, sodium iodide, lithium iodide, potassium iodide, magnesium iodide, calcium iodide, ammonium iodide, aluminum iodide, zinc iodide, barium iodide, cesium iodide, N-iodosuccinimide, and combinations thereof. Examples of suitable oxidizing agents include, but are not limited to, potassium peroxymonosulfate, peroxide, 2-iodoxybenzoic acid, sodium hypochlorite, and combinations thereof. In some embodiments, the iodine source is sodium iodide, and the oxidizing agent is potassium peroxymonosulfate (also known as Oxone®).

[0036] The reaction mixture typically contains an iodine source (e.g., sodium iodide) and / or an oxidizing agent (e.g., potassium peroxymonosulfate) in an amount ranging from about 1 molar equivalent to about 10 molar equivalents relative to the compound of Formula II (e.g., olivetol) and / or the compound of Formula I (e.g., cannabichromene). The reaction mixture may contain, for example, from about 1 molar equivalent to about 5 molar equivalents of the iodine source and / or oxidizing agent relative to the compound of Formula II or Formula I, or from about 1 molar equivalent to about 3 molar equivalents of the iodine source and / or oxidizing agent, or from about 1.25 molar equivalents to about 2.75 molar equivalents of the iodine source and / or oxidizing agent, or from about 1.5 molar equivalents to about 2.5 molar equivalents of the iodine source and / or oxidizing agent, or from about 1.8 molar equivalents to about 2.2 molar equivalents of the iodine source and / or oxidizing agent. The reaction mixture can contain about 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2, 2.1, 2.2, 2.3, 2.4, or 2.5 molar equivalents of the iodine source and / or oxidizing agent. In some embodiments, the reaction mixture contains about 1.8 to 2.2 molar equivalents of the iodine source (e.g., sodium iodide) and 1.8 to 2.2 molar equivalents of the oxidizing agent (e.g., potassium peroxymonosulfate) relative to the compound of Formula II (e.g., olivetol). Typically, the reaction to form the compound of formula III is carried out at a temperature ranging from about 20°C to about 200°C (e.g., from about 20°C to about 180°C, or from about 90°C to about 140°C, or from about 100°C to about 120°C) for a time ranging from about 30 minutes to about 24 hours (e.g., from about 60 minutes to about 90 minutes, or from about 60 minutes to about 3.5 hours). Advantageously, the step of converting the compound of formula I to the compound of formula III can be carried out as a one-pot reaction in the reaction mixture. The iodine source and / or oxidizing agent can be added to the reaction mixture in one or more portions without isolating the compound of formula I (e.g., cannabichromene), and other reaction conditions (e.g., reaction temperature, amount of solvent) can be adjusted to promote the formation of the compound of formula III (e.g., cannabinol).

[0037] In some embodiments, an acid may be used with a diamine to convert CBC or its analogs (as an intermediate or starting material) to a mixed intermediate, which is then aromatized to CBN or its analogs using iodine or a metal catalyst as described above. Examples of suitable acids include, but are not limited to, Bronsted acids, such as mineral acids (e.g., hydrochloric acid, sulfuric acid, nitric acid, etc.), sulfonic acids (e.g., p-toluenesulfonic acid, trifluoromethanesulfonic acid, etc.), and carboxylic acids (e.g., trifluoroacetic acid, etc.), as well as Lewis acids, such as copper(I) chloride and boron trifluoride. In some embodiments, the acid is p-toluenesulfonic acid. The reaction mixture may contain, for example, about 0.1 molar equivalent to about 1.1 molar equivalents of acid relative to the diamine, or about 0.5 molar equivalents to about 1 molar equivalent, or about 0.7 molar equivalents to about 0.8 molar equivalents of acid. The reaction mixture may contain about 0.55, 0.6, 0.65, 0.7, 0.71, 0.72, 0.73, 0.74, 0.75, 0.76, 0.77, 0.78, 0.79, 0.8, 0.85, 0.9, or 0.95 molar equivalents of the acid. In some embodiments, the reaction mixture contains about 0.01 to 10 molar equivalents of the diamine (e.g., N,N'-dimethylethylenediamine) relative to the acid (e.g., p-toluenesulfonic acid). In some embodiments, the reaction mixture contains about 1.0 molar equivalent of the diamine (e.g., N,N'-dimethylethylenediamine) relative to the acid (e.g., p-toluenesulfonic acid).

[0038] In addition to the combination of iodine source and oxidizing agent described above, other reagents may also be used to form the compound of Formula III. In some embodiments, the reaction is carried out using an oxidizing agent such as those described above (e.g., potassium peroxymonosulfate, peroxide, 2-iodoxybenzoic acid, or sodium hypochlorite) without an iodine source. In some embodiments, the reaction is carried out using elemental sulfur. In some embodiments, the reaction is carried out using a metal dehydrogenation catalyst. Examples of suitable catalysts include, but are not limited to, palladium phosphine complexes; supported metal catalysts, such as palladium on carbon, palladium hydroxide on carbon, platinum on carbon, palladium on alumina, or platinum on alumina; platinum dioxide; iridium catalysts; rhodium catalysts; Raney nickel; tetra-n-butylammonium decatungstate (TBADT); cobaloxime pyridine chloride (COPC); aerobic palladium catalysts, such as Pd(OAc) / Cu(II) for use with O; and allyl-palladium catalysts, such as Pd(OAc) / NaCO / (allyldiethylphosphate). In some embodiments, the metal dehydrogenation catalyst comprises palladium on carbon, platinum on carbon, palladium on alumina, platinum on alumina, or a combination thereof. The catalyst loading on the support will typically range from about 5% to about 20% by weight. The catalyst can be added in "wet" form (e.g., containing 50% water by weight) or dry form.

[0039] The reaction mixture may contain, for example, about 0.01 to about 0.5 molar equivalents of catalyst relative to the compound of Formula I, or about 0.05 to about 0.25 molar equivalents of catalyst, or about 0.05 to about 0.1 molar equivalents of catalyst. The reaction mixture may contain about 0.05, 0.06, 0.07, 0.08, 0.09, or 0.1 molar equivalents of catalyst. In some embodiments, the reaction mixture contains about 0.01 to 0.1 molar equivalents of catalyst (e.g., 10% Pd / carbon, wet or dry) and about 0.5 to 1.1 molar equivalents of acid (e.g., p-toluenesulfonic acid) relative to the compound of Formula II. Reaction times and temperatures may be varied as described above. For example, the reaction may be carried out at a temperature ranging from about 20° C. to about 200° C. for a time ranging from about 1 hour to about 12 hours (e.g., about 110-125° C. for about 6-10 hours under ambient or inert atmosphere). [Example]

[0040] III. Working Examples Example 1. Preparation of cannabichromene To 0.9 mL of toluene (0.22 M) was added 36 mg (0.2 mmol) of olivetol, followed by 0.038 mL of E,Z-citral (1.15 eq). A 5 μL aliquot of the reaction mixture was diluted into 995 μL of 95% EtOH, and 10 μL of this solution was injected into a Waters 2695 HPLC equipped with a DAD detector monitoring at 230 nm to establish a starting area baseline for olivetol. The reaction was initiated by the addition of 5.5 μL (0.25 eq) of dimethylethylethyenediamine (DMEAD), and subsequent samples were prepared and analyzed by HPLC. The yield was calculated based on the peak area using an extinction coefficient ratio for olivetol / cannabichromene (CBC) of 5.6 at 230 nm, established using a CBC standard (1 mg / mL, obtained from Cerilliant). The reaction was monitored by HPLC for yield at different time points, as summarized in Table 1.

[0041] [Table 1]

[0042] Table 2 shows the effect of solvent, reaction time and temperature, and amine catalyst (DMEAD vs. monoamine) at different reaction times: (E,Z-citral = 1.15 equivalents).

[0043] [Table 2] E,Z-citral = 1.15 eq, solvent concentration = 0.22 M, amine catalyst = 0.25 eq. The yield is based on the extinction coefficient ratio of CBC / olivetol at 230 nm = 5.6. DEMEAD = dimethylethylenediamine, IPA = isopropylamine, IPM = N-isopropyl-N-methylamine, BA = n-butylamine, IPN = i-pentylamine.

[0044] Chlorinated solvents generally resulted in faster reactions, especially with DMEDA. Toluene required higher temperatures but shorter reaction times with DMEDA. DMEDA was the only catalyst to give substantial yields under the initial test conditions, providing significantly higher yields than monoamines. Extended heating times resulted in lower yields with DMEDA, and an increase in impurities was also observed.

[0045] Table 3 shows the effect of solvent, reaction time and temperature, and amine catalyst after different reaction time points.

[0046] [Table 3] E,Z-citral = 1.35 eq, solvent concentration = 0.22 M, amine catalyst = 0.25 eq. The yield is based on the extinction coefficient ratio of CBC / olivetol at 230 nm = 5.6. DEMEDA = dimethylethylenediamine, ED = ethylenediamine, DAC = 1,2-diaminocyclohexane, DP = diaminopropane, TB = t-butylamine.

[0047] DMEDA catalysis was unexpectedly found to be faster than ethylenediamine (ED). DMEDA provided higher yields at extended times at 60°C. Other diamines, such as DAC and DP, also catalyzed the reaction. The decrease in yield at longer reaction times indicates that the product may be sensitive to the equivalent amount of citral used (e.g., 1.35 eq vs. 1.15 eq, compare Table 2).

[0048] The color characteristics of the final purified product, related to trace impurities, are important to the finished distillate product and its acceptability for pharmaceutical-grade compositions. CBC is a clear oil when fully purified by preparative chromatography. In particular, the DMEDA catalyst provides a pale yellow reaction mixture, while the IPA catalyst produces a deep red reaction mixture, which is carried as an orange to orange-red color in the final distillate oil.

[0049] Example 2. Preparation of cannabinol To 9 mL of toluene (0.22 M) was added 360 mg (2 mmol) of olivetol, followed by 0.38 mL of E,Z-citral (1.15 eq) and heated at 60°C for 2 h. To this solution was added 2.4 eq (740 mg) of NaI, followed by 2.1 eq (1.45 g) of Oxone and heated at 110°C for 3 h. The reaction was cooled, filtered through a 5 μm filter, and concentrated in vacuo to yield 660 mg of a dark, sticky oil. HPLC analysis indicated that all CBC had been consumed and the resulting CBN product was identical to a CBN standard (obtained from Cerilliant, 1 mg / mL).

[0050] Acids can also be used to promote the formation of cyclized intermediates for conversion to cannabinol. To 0.9 mL of toluene (0.22 M) was added 36.0 mg (2 mmol) of olivetol, followed by 0.038 mL of E,Z-citral (1.15 eq). The reaction was initiated by the addition of 55 μL (0.25 eq) of DMEAD, and the solution was heated at 110 °C for 2 h. 0.75 equivalents of p-toluenesulfonic acid (3 × 0.25 eq) were added to the reaction to protonate the diamine, and heating was continued for approximately 2 h. NaI / oxone or I2 was added, or the reaction mixture was subjected to dehydrogenation conditions, yielding CBN after 3–4 h at 110 °C. The reaction was cooled, filtered through a 5 μm filter, and concentrated in vacuo to yield CBN as a viscous oil, identical to a CBN standard (obtained from Cerilliant, 1 mg / mL) by HPLC analysis.

[0051] Example 3. Preparation of cannabinol by acid-catalyzed dehydrogenation and metal-catalyzed cyclization of in situ prepared cannabichromene Olivetol (288 mg; 1.6 mmol) was treated with citral (302 μL; 2.0 mmol) and DMEAD (44 μL; 0.25 eq) dissolved in 8 mL xylene (0.2 M) and heated at 60° C. for 2 hours. The reaction mixture was then divided into 500 μL aliquots for use in the reactions summarized in Table 4. The reactions in Table 4 were carried out using 10 mg of TsOH (1 eq) and 5 mg of metal catalyst (A, B, C, D, E, or F). The reactions were heated to 110° C. and monitored by HPLC at different time points as indicated in Table 4. The reaction yield of cannabinol was calculated relative to the maximum yield demonstrated by catalyst B at 48 hours.

[0052] [Table 4] *A= 10% Pd / carbon / wet; B= 5% Pd(OH)2 / carbon; C= 20% Pd(OH)2 / carbon / 50% water; D= 10% Pt / carbon; E= PtO2; F= PtO2.H2O x .

[0053] Example 4. Preparation of the CBN analog 3,6,6,9-tetramethyl-6H-benzo[c]chromen-1-ol To a solution of 5-methyl-benzene-1,3-diol (orcinol; 99 mg; 0.8 mmol) in 1.8 mL of toluene, citral (152 μL, 1.2 eq) was added, followed by DMEAD (22 μL; 0.25 eq) to initiate the reaction. The reaction was stirred for 21 h, heated at 60 °C for 30 min, cooled, and loaded onto a preparative C-18 column eluted with a gradient of 0% to 100% acetonitrile / water / 0.1% formic acid to afford 43 mg (21%) of 2,7-dimethyl-2-(4-methyl-pent-3-enyl)-2H-chromen-5-ol as an oil. The resulting intermediate was treated with 1 eq of TsOH and catalyst A (10% Pd / carbon / wet) in toluene and heated at 120° C. for 8 h. The solution was cooled and purified on a preparative plate TLC followed by C-18 elution with 10% EtOAc to give 5.5 mg of 3,6,6,9-tetramethyl-6H-benzo[c]chromen-1-ol. 99% by HPLC, calculated C 17 H 18 O2254.13, LC-MS / ESI actual value: M+H: 255.10; TIFF0007761564000017.tif11152 This reaction sequence has been found to be particularly useful for obtaining highly pure cannabinoid analogs (e.g., ≥ 99% pure) acceptable for pharmaceutical grade compositions.

[0054] Although the foregoing has been described in some detail by way of illustration and example for purposes of clarity and understanding, those skilled in the art will understand that certain changes and modifications may be practiced within the scope of the appended claims. Furthermore, each reference provided herein is incorporated by reference in its entirety to the same extent as if each reference was individually incorporated by reference.

Claims

1. Formula I: or a salt thereof, comprising: The method comprises: 3,7-dimethylocta-2,6-dienal and a diamine with formula II: forming a reaction mixture comprising a compound of maintaining said reaction mixture under conditions sufficient to form a compound of formula I. Including, During the ceremony, R 1 But C 1 ~C 20 Alkyl, C 1 ~C 20 Haloalkyl, C 1 ~C 20 Hydroxyalkyl, deuterated C 1 ~C 20 Alkyl, tritiated C 1 ~C 20 Alkyl, and C 2 ~C 20 alkenyl; R 2 H and -COOR 2a and R 2a But H and C 1 ~C 6 alkyl, the diamine is selected from the group consisting of N,N'-dimethylethylenediamine; N,N-dimethylethylenediamine; N,N-diethylethylenediamine; N,N'-diphenylethylenediamine; N,N'-dibenzylethylenediamine; N,N'-bis(2-hydroxyethyl)ethylenediamine; N,N'-dimethylpropylenediamine; N,N-dimethylpropylenediamine; N,N-diethylpropylenediamine; N,N'-diphenylpropylenediamine; N,N'-dibenzylpropylenediamine; N,N'-bis(2-hydroxyethyl)propylenediamine; 1,2-diaminocyclohexane; N,N'-dimethyl-1,2-diaminocyclohexane; and 1,2-cyclopentanediamine; The reaction mixture is maintained at a reaction temperature of 20°C to 70°C; and Optionally, the reaction mixture is maintained at the reaction temperature for a time ranging from 27 minutes to 26.4 hours. The method.

2. 2. The method of claim 1, wherein the diamine is selected from the group consisting of N,N'-dimethylethylenediamine; N,N-dimethylethylenediamine; N,N-diethylethylenediamine; N,N'-diphenylethylenediamine; N,N'-dibenzylethylenediamine; N,N'-dimethylpropylenediamine; N,N-dimethylpropylenediamine; N,N-diethylpropylenediamine; N,N'-diphenylpropylenediamine; N,N'-dibenzylpropylenediamine; 1,2-diaminocyclohexane; N,N'-dimethyl-1,2-diaminocyclohexane; and 1,2-cyclopentanediamine.

3. 2. The method of claim 1, wherein the reaction mixture contains 0.99 to 11 molar equivalents of the 3,7-dimethylocta-2,6-dienal relative to the compound of formula II.

4. 4. The method of claim 3, wherein the reaction mixture contains 0.99 to 2.2 molar equivalents of the 3,7-dimethylocta-2,6-dienal relative to the compound of formula II.

5. 10. The method of claim 1, wherein the reaction mixture contains 0.009 to 11 molar equivalents of the diamine relative to the compound of Formula II.

6. 6. The method of claim 5, wherein the reaction mixture contains 0.225 to 0.275 molar equivalents of the diamine relative to the compound of Formula II.

7. 10. The method of claim 1, wherein the reaction mixture is maintained at a reaction temperature in the range of 23°C to 66°C.

8. 8. The process of claim 7, wherein the reaction mixture is maintained at the reaction temperature for a time ranging from 54 minutes to 26.4 hours.

9. The method of claim 1 , wherein the reaction mixture further comprises a solvent.

10. The method of any one of claims 1 to 9, wherein the reaction mixture further comprises a solvent, the solvent being selected from the group consisting of toluene, chloroform, methylene chloride, dichloroethane, ethyl acetate, acetonitrile, acetone, tetrahydrofuran, benzene, ethylbenzene, xylene, diethyl ether, dimethylformamide, dimethyl sulfoxide, petroleum ether, isopropanol, and mixtures thereof.

11. 10. The method of claim 9, wherein the solvent is selected from the group consisting of toluene, chloroform, isopropanol, and mixtures thereof.

12. 2. The method of claim 1, wherein the 3,7-dimethylocta-2,6-dienal comprises neral, geranial, or a combination thereof.

13. 2. The method of claim 1, wherein the 3,7-dimethylocta-2,6-dienal comprises E,Z-citral.

14. R 2 2. The method of claim 1, wherein

15. R 2 2. The method of claim 1, wherein is -COOH.

16. R 1 2. The method of claim 1, wherein is n-pentyl.

17. The compound of formula I may be reacted with a compound of formula III: and further comprising converting the compound of formula (I) into a compound of formula (II) the converting step comprises combining a compound of formula I with an iodine source and an oxidizing agent; the iodine source is selected from the group consisting of sodium iodide, lithium iodide, potassium iodide, magnesium iodide, calcium iodide, ammonium iodide, aluminum iodide, zinc iodide, barium iodide, cesium iodide, and combinations thereof; and the oxidizing agent is selected from the group consisting of potassium peroxymonosulfate, peroxide, 2-iodoxybenzoic acid, sodium hypochlorite, and combinations thereof; or the converting step comprising combining a compound of formula I with a metal dehydrogenation catalyst; 10. The method of claim 1.

18. 18. The method of claim 17, wherein the converting step comprises combining the compound of formula I with an oxidizing agent.

19. 18. The method of claim 17, wherein said converting step comprises combining the compound of formula I with sodium iodide and potassium peroxymonosulfate.

20. 18. The method of claim 17, wherein said converting step comprises combining the compound of formula I with elemental sulfur.

21. 18. The method of claim 17, wherein the metal dehydrogenation catalyst comprises palladium on carbon, palladium hydroxide on carbon, platinum on carbon, platinum dioxide, palladium on alumina, or platinum on alumina.

22. 18. The method of claim 17, wherein the converting step further comprises combining the compound of formula I with an acid.

23. 23. The method of claim 22, wherein the acid is p-toluenesulfonic acid.

24. 24. The method of any one of claims 17 to 23, wherein said step of converting a compound of formula I to a compound of formula III is carried out as a one-pot reaction in said reaction mixture to form a compound of formula I.

25. 18. The method of claim 17, wherein the metal dehydrogenation catalyst comprises a palladium phosphine complex, palladium on carbon, palladium hydroxide on carbon, platinum on carbon, palladium on alumina, platinum on alumina, platinum dioxide, an iridium catalyst, a rhodium catalyst, Raney nickel, tetra-butylammonium decatungstate, cobaloxime pyridine chloride, an aerobic palladium catalyst, or an allyl-palladium catalyst.

26. The metal dehydrogenation catalyst is Pd(OAc) 2 / Cu(II) and / or the allyl-palladium catalyst is Pd(OAc) 2 / NaCO 3 26. The method of claim 25, wherein the phosphate is allyl diethyl phosphate.

27. 18. The method of claim 17, wherein the loading of the metal dehydrogenation catalyst on the support is in the range of 5 wt. % to 20 wt. %, or the metal dehydrogenation catalyst is in wet form containing 50 wt. % water, or in dry form.

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