Compositions and methods for the preparation of purified cannabinol and hexahydrocannabinol and their acetate derivatives

Abstract

A method of preparing cannabinol (CBN) and hexahydrocannabinol (HHC) including contacting delta-8-tetrahydrocannabinol (Δ8-THC) with a supported noble metal catalyst under conditions suitable for the dehydrogenation of at least a portion of the Δ8-THC and aromatization of at least a portion of the Δ8-THC to form a product comprising HHC and / or, CBN. Also, a method of preparing CBN and HHC comprising contacting Δ8-THC with a supported noble metal catalyst under conditions suitable for the dehydrogenation of at least a portion of the Δ8-THC and aromatization of at least a portion of the Δ8-THC to form a product comprising HHC and / or CBN; contacting the product with (i) an acetylating agent and (ii) a proton donor under conditions suitable for formation of an acetylated product; and separating the acetylated product to recover an acetylated CBN, an acetylated HHC or combinations thereof.

Description

COMPOSITIONS AND METHODS FOR THE PREPARATION OF PURIFIED CANNABINOL AND HEXAHYDROCANNABINOL AND THEIR ACETATE DERIVATIVESCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application Serial No. 63 / 535,917 filed August 31 , 2023 entitled “COMPOSITIONS AND METHODS FOR THE PREPARATION OF PURIFIED CANNABINOL AND HEXAHYDROCANNABINOL AND THEIR ACETATE DERIVATIVES,” which is incorporated herein by reference in its entirety for all purposes.FIELD

[0002] The present disclosure generally relates to phytocannabinoid compositions and related processes. More particularly, the present disclosure relates to compositions and methods for the production of high purity cannabinol (CBN) and hexahydrocannabinol (HHC), separation of which from a crude mixture may be enabled by acetylation and crystallization.BACKGROUND

[0003] Cannabis sativa is a species of flowering plants in the family Cannabaceae. The number of varieties within the species is sometimes disputed, though three varieties are generally recognized: Cannabis sativa, Cannabis indica, and Cannabis ruderalis. Cannabis sativa with low delta-9-tetrahydrocannabinol (A9-THC) content also known as hemp, refers to varieties of Cannabis cultivated for non-psychotropic use. In the US, “industrial hemp” is classified by the federal government as Cannabis containing no more than 0.3% A9-THC by dry weight. Though they are both members of the same species, hemp and marijuana have differing biochemistries and phenotypes. In particular, the plants differ in their content and distribution of cannabinoids and terpenes.

[0004] Phytocannabinoids and derivatives hold potential as therapeutic agents to address a number of medical conditions. For example, hexahydrocannabinol (HHC) and cannabinol (CBN), which represent two high-value and popular cannabinoids in the cannabis industries, are being investigated fortheir potential to function as antiepileptic, antinociceptive, anti-inflammatory, anxiolytic, anti-depressive, sedative, or neuroprotective agents, among others. For example, regulatory approvals for purifiedcannabidiol, such as for EPIDIOLEX®, a commercially-available purified cannabidiol for use in the treatment of childhood drug-resistant epilepsy, have set a precedent for the use of phytocannabinoids as a prescribed medicine. An ongoing challenge to the utilization of cannabinoids in a medicinal context is the difficulty in providing a sufficient amount of a consistently high purity product for use in carrying out clinical investigations.

[0005] Standard methods for the production of CBN and / or HHC typically include highly hazardous conditions and / or expensive and environmentally harmful reagents. For example, HHC is most commonly produced from delta-8-tetrahydrocannabinol (A8- THC) using high-pressure hydrogenation. This reaction requires handling of pressurized hydrogen gas and has proven hazardous. CBN is often produced from either cannabidiol (CBD) or A8-THC using either stoichiometric iodine or sulfur, respectively. Both of these semi-synthetic routes result in mediocre yields and copious amounts of hazardous by-products that impart unnecessary costs and regulatory compliance obligations. Thus, an ongoing need exists for novel methods and compositions for the efficient synthesis of high purity HHC, CBN, or both.BRIEF DESCRIPTION OF DRAWINGS

[0006] For a detailed description of the aspects of the disclosed processes and systems, reference is made to the accompanying drawings in which:

[0007] Figure 1 depicts the reaction of A8-THCwith a noble metal catalyst to produce CBN and HHC.

[0008] Figure 2 depicts the acetylation of CBN and HHC.

[0009] Figure 3 is an HPLC chromatogram of a crude reaction mixture comprising CBN and HHC as major products.

[0010] Figure 4 is an HPLC chromatogram of CBN-O-acetate.SUMMARY

[0011] Disclosed herein is a method of preparing cannabinol (CBN) and hexahydrocannabinol (HHC). The method may comprise contacting delta-8- tetrahydrocannabinol (A8-THC) with a supported noble metal catalyst under conditions suitable for the dehydrogenation of at least a portion of the A8-THC and aromatization of at least a portion of the A8-THC to form a product comprising HHC, CBN, or combinations thereof.

[0012] Also disclosed herein is a method of preparing cannabinol (CBN) and hexahydrocannabinol (HHC). The method may comprise contacting delta-8-tetrahydrocannabinol (A8-THC) with a supported noble metal catalyst under conditions suitable for the dehydrogenation of at least a portion of the A8-THC and aromatization of at least a portion of the A8-THC to form a product comprising HHC, CBN or combinations thereof. The method may also comprise recovering the product. The method may also comprise contacting the product with (i) an acetylating agent and (ii) a proton donor under conditions suitable for formation of an acetylated product. The method may also comprise separating the acetylated product to recover an acetylated CBN, an acetylated HHC, or combinations thereof.DETAILED DESCRIPTION

[0013] The following discussion is directed to various exemplary aspects. However, one of ordinary skill in the art will understand that the examples disclosed herein have broad application, and that the discussion of any aspect is meant only to be exemplary of that aspect, and not intended to suggest that the scope of the disclosure, including the claims, is limited to that aspect.

[0014] The figures are not necessarily to scale. Certain features and components herein may be shown exaggerated in scale or in somewhat schematic form and some details of conventional elements may not be shown in interest of clarity and conciseness.

[0015] As used herein, the terms “approximately,” “about,” “substantially,” and the like mean within 10% (i.e., plus or minus 10%) of the recited value. Thus, for example, a recited angle of “about 80 degrees” refers to an angle ranging from 72 degrees to 88 degrees.

[0016] Unless the context dictates the contrary, all ranges set forth herein should be interpreted as being inclusive of their endpoints, and open-ended ranges should be interpreted to include only commercially practical values. Similarly, all lists of values should be considered as inclusive of intermediate values unless the context indicates the contrary.

[0017] Disclosed herein are compositions and methods for the production of high- purity HHC. Additionally, or alternatively, in some aspects, methods of the present disclosure comprise the production of high-purity CBN. In some aspects, the compositions and methods disclosed herein result in the concurrent production of HHC and CBN. In an aspect, a method of the present disclosure comprises contacting A8- THC with a supported noble metal catalyst (SNMC) under conditions suitable for theformation of CBN and HHC. Subsequent to contacting with the SNMC, the A8-THC may comprise a product that is a purified highly viscous fluid at room temperature, but becomes non-viscous above 80°C.

[0018] Hereinafter, the disclosure will utilize the term “target product” to refer to the mixture of CBN and HHC. Without wishing to be limited by theory, the reaction mechanisms may involve transferring, via the SNMC, hydrogen from one equivalent of A8-THC to another equivalent of A8-THC (i.e., dehydrogenation of one A8-THC to form CBN and hydrogenation of another A8-THC to form HHC). The removal of 4 hydrogen atoms from A8-THC results in the formation of CBN while the addition of two hydrogen atoms to A8-THC results in the formation of HHC. The simultaneous production of CBN and HHC utilizes two equivalents of hydrogen gas which are liberated from A8-THC to generate CBN, while only 1 equivalent of hydrogen is needed to generate HHC. Therefore, the observed ratio of products is approximately 1 :2 CBN: HHC.

[0019] In one or more aspects, a method for production of the target product comprises contacting A8-THC with a SNMC under conditions suitable for the concomitant production of CBN and HHC. The reaction of A8-THC with a SNMC is depicted schematically in Figure 1 . With reference to Figure 1 , A8-THC is contacted with a SNMC (palladium on alumina) under conditions suitable for the hydrogenation and / or dehydrogenation of A8-THC to produce HHC and CBN, respectively.

[0020] In one or more aspects, the SNMC comprises a platinum group metal. For example, the SNMC can comprise ruthenium, rhodium, palladium, osmium, iridium, platinum, iron, cobalt, gold, titanium, nickel or combinations thereof. In an aspect, the SNMC comprises palladium. The platinum group metal may be present in the SNMC in an amount of from about 0.1 weight percent (0.1 wt.%) to about 10 wt.%, or from about 0.1 wt.% to about 8 wt.% or from about 0.25 wt.% to about 7 wt.% or from about 0.5 wt.% to about 5 wt.% orfrom about 1 wt.% to about 3 wt.% based on the total weight of the SNMC.

[0021] In one or more aspects, the platinum group metal may be associated with a support. It is contemplated that association of the platinum group metal with the support may be carried out using any suitable methodology. For example, a platinum group metal salt may be solubilized and used to impregnate a support material.

[0022] In an aspect, the catalyst support comprises an oxide of a metal or metalloid. In one more aspects, the support comprises elemental carbon. In an aspect, thecatalyst support comprises elemental carbon, silica, titania, alumina, aluminate, or combinations thereof. Nonlimiting examples of materials suitable for use in the catalyst supports of this disclosure include aluminas, silicas, titanias, zirconias, aluminosilicates (e.g., clays, ceramics, and / or zeolites), spinels (e.g., zinc aluminate, zinc titanate, and / or magnesium aluminate), or combinations thereof.

[0023] In an aspect, the catalyst support comprises alumina. For example, the support may comprise, consist of, or consist essentially of an alpha (a)-alumina support. An a-alumina support may be prepared by precipitating sodium aluminate with or without a cation and aluminum to yield an aluminum oxide, with a chemical formula of AI2O3 or aluminum oxide hydroxide (also known as boehmite) with a chemical formula of AIO(OH). The alumina support may include additional components that do not adversely affect the catalyst, such as zirconia, silica, thoria, magnesia, fluoride, sulfate, phosphate, or mixtures thereof.

[0024] The catalyst support (e.g., alumina) may have a surface area ranging from about 100 meters square per gram (m2 / g) to about 1000 m2 / g, or from about 250 m2 / g to about 1000 m2 / g, or from about 500 m2 / g to about 1000 m2 / g. The surface area of the support may be determined using any suitable method. An example of a suitable method includes the Brunauer, Emmett, and Teller (“BET”) method, which measures the quantity of nitrogen adsorbed on the support. Alternatively, the surface area of the support can be measured by a differential mercury intrusion method such as is described in ASTM UOP 578-02, entitled 'Automated Pore Volume and Pore Size Distribution of Porous Substances by MERCURY Porosimetry," which is incorporated herein by reference in its entirety.

[0025] An exemplary SNMC suitable for use in the present disclosure may include 0.5 wt.% palladium on 3.2mm alumina pellets commercially available from Millipore Sigma.

[0026] Advantageously, in some aspects the SNMC may be characterized as reusable. For example, the SNMC (Pd / AI) may be contained within a reactor (e.g., rotating-bed-reactor) and the substrate (e.g., A8-THC) contacted with the SNMC under conditions suitable for the production of a mixture of HHC and CBN. Additionally, or alternatively, a SNMC catalyzes n reactions before the catalyst is deemed a “spent catalyst” where n is equal to or greater than about 100, alternatively equal to or greater than about 500 or alternatively equal to or greater than about 1000. Herein, the termspent catalyst refers to a catalyst whose activity has diminished to a point where it is techno-economically impractical to continue utilizing the catalyst for its purpose as disclosed herein. The value of n refers to the number of catalytic cycles wherein a SNMC effectively achieves an intended catalytic activity, e.g., in catalyzing the (de)hydrogenation of A8-THC under conditions suitable for production of HHC and / or CBN. Each catalytic cycle may involve a set number of substrate molecules (e.g., A8- THC) being contacted with the catalytically active SNMC. Alternatively, each cycle may be characterized by the amount of time needed for a substrate (e.g. , A8-THC) to interact effectively with the SNMC. The methods disclosed herein contemplate replacement or regeneration of the spent catalyst when catalytic activity decreases to some user and / process defined amount. Additionally, or alternatively, the catalyst is cleaned (e.g., washed) after some number, x, of reactions where x may be equal to or greater than about 1 , alternatively equal to or greater than about 5. In one or more aspects, the catalyst is treated while remaining within the reactor.

[0027] Additionally or alternatively, the SNMC is removed from the reactor, regenerated and then returned to the reactor. Catalyst regeneration may be carried out to mitigate contamination of the catalyst by the compounds used or produced during the reaction. The methods disclosed herein contemplate the extensive and easy reuse of expensive palladium catalysts such as the palladium-alumina catalysts of this disclosure.

[0028] In an aspect, the conversion of A8-THC to HHC and CBN occurs in the presence of a catalyst amount ranging from about 1 mol% palladium to about 5 mol% palladium, alternatively from about 0.1 mol% palladium to about 0.9 mol% palladium or alternatively from about 1.1 mol% palladium to about 5 mol% palladium based on the total moles of starting material.

[0029] Generally, the reaction can be carried out the in a medium or diluent of the reaction reagents. In one or more aspects, reaction of A8-THC with the SNMC may be carried out in the presence of a solvent. Nonlimiting examples of solvent classes suitable for use in the present disclosure include alcohols, esters, ethers, hydrocarbons (aliphatic), or hydrocarbons (aromatic). In some aspects, the reaction is carried out in the absence of a solvent.

[0030] Reaction of A8-THC with the SNMC may be carried out under one or more of the following conditions: a temperature ranging from about 150°C to about 210°C,additionally or alternatively, from about 170°C to about 200°C, additionally or alternatively, from about 150°C to about 170°C or, additionally or alternatively, from about 190°C to about 21 C C; a time period of from about 4 hours to about 72 hours, additionally or alternatively, from about 4 hours to about 24 hours, additionally or alternatively, from about 24 hours to about 48 hours or, additionally or alternatively, from about 48 hours to about 72 hours; and under vacuum at pressures ranging from about 20 millibar to about 250 millibar, additionally or alternatively, from about 150 millibar to about 250 millibar, additionally or alternatively, from about 100 millibar to about 150 millibar or, additionally or alternatively, from about 25 millibar to about 100 millibar. In some aspects, the reaction is carried out in the presence of hydrogen at a hydrogen partial pressure of atmospheric, additionally or alternatively, from about 20 millibar to about 250 millibar, additionally or alternatively, from about 40 millibar to about 225 millibar or, additionally or alternatively, from about 50 millibar to about 200 millibar.

[0031] The target product may comprise CBN, HHC, A8-THC or combinations thereof. In one or more aspects, the target product comprises (i) the complete or substantially complete (e.g., greater than 90%) consumption of A8-THC (ii) a product mixture having a ratio of CBN:HHC of about 1 :2 (iii) products in combined yields of -95% or combinations thereof. For example, the reaction product may comprise a yield of CBN of from about 10% to about 35% or from about 15% to about 35%, additionally or alternatively, from about 20% to about 35%, additionally or alternatively, about 15%, about 17.5%, about 20%, about 22.5%, about 25%, about 27.5%, about 30%, about 32.5%, or about 35; a yield of HHC of from about 20% to about 65%, additionally or alternatively, from about 25% to about 55%, additionally or alternatively, from about 30% to about 50% or about 20%, about 22.5%, about 25%, about 27.5%, about 30%, about 32.5%, about 35%, about 37.5%, about 40%, about 42.5%, about 45%, about 47.5%, about 50%, about 52.5%, about 55%, about 57.5%, or about 60 and an unreacted percent of A8-THC of from about 0% to about 10%.

[0032] In an aspect, the reaction disclosed herein results in a target product comprising an approximately 1 :2 ratio of CBN:HHC. In some aspects, the target product may be distilled to form a distilled mixture. Herein distilling the mixture may result in clarification of the target product and removal of any high molecular-weight impurities or suspended catalyst residues. The distilled mixture may be used as a component in aformulation that is a finished good or as a feed to another process. Additionally, or alternatively, the target product may be purified to separate the HHC and CBN.

[0033] In some aspects, a method of the present disclosure further comprises acetylation of at least a portion of the cannabinoids within the target product, for example, at least a portion of the CBN, at least a portion of the HHC, or both. In various aspects, any methodology suitable for acetylation of the target product is contemplated. In an aspect, at least a portion of the target product may be acetylated by contacting the target product with an acetylating agent and an optional proton-donating compound under conditions suitable for the formation of an acetylated CBN (CBN-O-acetate) and an acetylated HHC (HHC-O-acetate).

[0034] In an aspect, the proton-donating compound comprises a mineral acid. Additionally, or alternatively, in an aspect, the proton-donating compound comprises an organosulfur compound. For example, the proton-donating compound may be an organosulfur compound such as, a sulfonic acid, 3-propanedisulfonic acid, ethanedisulfonic acid, ethanesulfonic acid, isethionic acid, methanedisulfonic acid, methanesulfonic acid, camphorsulfonic acid, toluenesulfonic acid, toluenesulfonic acid monohydrate, vinylsulfonic acid, or combinations thereof.

[0035] In an aspect, the acetylating agent is an acetate ester of the enol tautomer of a carbonyl compound (i.e. , enol acetate.) Such acetylating agents may be characterized by the general structures A or B:where R and / or R’ is a Ci-Cx enol group where x ranges from 0 to 5, ethylenyl, propylenyl, isopropenyl, isobutylenyl, or cyclohexenyl derivates. In some aspects, the acetylating agent may comprise a combination of species having multiple R groups as defined herein. An example of an acetylation reaction is schematized in Figure 2.

[0036] In one or more aspects, acetylation of the product mixture is carried out in a solvent chosen to facilitate the reaction. In particular, the use of protic solvents, (e.g., alcohols or water) is not suitable, nor is the use of an aprotic but highly polar organic solvents (e.g., ethyl acetate, dichloromethane, tetrahydrofuran, etc.). In general terms, any solvent that contains a labile H+ is called a protic solvent.

[0037] In aspects, the solvent is a linear or branched hydrocarbon solvent with a boiling point ranging from about 90 °C to about 120 °C. Nonlimiting examples of suitable solvents include hydrocarbons and halogenated hydrocarbons. Nonlimiting examples of suitable solvents include aliphatic hydrocarbons, aromatic hydrocarbons, petroleum distillates, halogenated aliphatic hydrocarbons, halogenated aromatic hydrocarbons, or combinations thereof. Aliphatic hydrocarbons which can be useful as a solvent can include C3 to C20 aliphatic hydrocarbons; or C4 to C15 aliphatic hydrocarbons; or C5 to C10 aliphatic hydrocarbons. The aliphatic hydrocarbons can be linear or branched, unless otherwise specified. Non-limiting examples of suitable acyclic aliphatic hydrocarbon solvents or diluents that can be utilized singly or in any combination can include propane, iso-butane, n-butane, butane (n-butane or a mixture of linear and branched C4 acyclic aliphatic hydrocarbons), pentane (n-pentane or a mixture of linear and branched C5 acyclic aliphatic hydrocarbons), hexane (n-hexane or mixture of linear and branched Ce acyclic aliphatic hydrocarbons), heptane (n-heptane or mixture of linear and branched C7 acyclic aliphatic hydrocarbons), octane (n-octane or a mixture of linear and branched Cs acyclic aliphatic hydrocarbons), or combinations thereof.

[0038] Non-limiting examples of suitable aromatic hydrocarbons that can be utilized singly or in any combination can include benzene, toluene, xylene (including orthoxylene, meta-xylene, para-xylene, or mixtures thereof), and ethylbenzene, or combinations thereof.

[0039] Without wishing to be limited by theory, during acetylation using an acetylating agent of the type disclosed herein (e.g., isopropenyl acetate), acetone is generated upon acetylation of the free phenolic oxygen of the cannabinoids. Acetone produced may be removed from the reaction mixture as the reaction progresses, for example, in order to drive the reaction to completion or substantial completion, for example, by avoiding equilibration between isopropenyl acetate and the reaction products (e.g., acetone).

[0040] The acetylation reaction may be carried out using one or more of the following reaction parameters: an amount of HHC and / or CBN totaling 1 mole equivalent; an amount of acetylating agent from about 0.75 mole equivalent to about 2 mole equivalents; an amount of a proton-donating compound from about 0.1 mole percent to about 5 mole percent; a temperature from about 25 °C to about 65 °C; a time period from about 30 minutes to about 120 minutes, or from about 30 minutes to about 100minutes or from about 30 minutes to about 60 minutes; and an amount of solvent from about 0.5 vol:wt equivalent to about 3 vol:wt equivalent relevant to the amount of HHC and / or CBN starting material to be acetylated.

[0041] In an aspect, the target product once contacted with the acetylating agent and proton-donating compound is converted to an acetylated mixture comprising acetylated CBN (CBN-O-acetate, known colloquially as ‘CBNO’) and acetylated HHC (HHC-O- acetate, known colloquially as ‘HHCO’). For example, in various aspects, at least about90 weight percent (wt.%) of the target product, of the combined CBN and HHC present within the target product, may be converted to HHC-O-Acetate and CBN-O-Acetate, additionally or alternatively, at least 91 %, additionally or alternatively, at least 92%, additionally or alternatively, at least 93%, additionally or alternatively, at least 94%, additionally or alternatively, at least 95%, additionally or alternatively, at least 96%, additionally or alternatively, at least 97%, additionally or alternatively, at least 98%, additionally or alternatively, at least 98.5%, additionally or alternatively, at least 99%, additionally or alternatively, at least 99%, additionally or alternatively, at least 99.5%, additionally or alternatively, at least 99.9%, additionally or alternatively, at least 99.95%, or additionally or alternatively, at least 99.99%. Hereinafter, the target product once subjected to the acetylation reaction is termed the acetylated mixture.

[0042] In an aspect, the acetylated mixture comprising CBN-O-acetate and HHC-O- acetate may be easily separated into its constituents. Not intending to be bound by theory, this separation may be in part to CBN-O-acetate being highly crystalline and will precipitate out of the solution (e.g., heptane solvent) while the HHC-O-acetate is noncrystalline and well-solvated by the same solvent. This separation by crystallization of the acetate derivative avoids the need for chromatography, which is otherwise employed at great expense.

[0043] In an aspect, the CBN-O-Acetate enriched fraction (crystallized) may comprise CBN-O-Acetate present in an amount of equal to or greater than about 85 wt.%, additionally or alternatively, equal to or greater than about 90 wt.% or, additionally or alternatively, equal to or greater than about 95 wt.% based on the total weight of the CBN-O-Acetate-enriched fraction. In an aspect, the HHC-O-Acetate enriched fraction (in solution) has HHC-O-Acetate present in an amount of equal to or greater than about 85 wt.%, additionally or alternatively, equal to or greater than about 90 wt.% or, additionally or alternatively, equal to or greater than about 95 wt.% based on the total weight of the HHC-O-Acetate-enriched fraction.

[0044] Additionally, in some aspects, the CBN-O-Acetate-enriched fraction and / or the HHC-O-Acetate enriched fraction may each be independently deacetylated using any suitable methodology. For example, the aryl acetate may be cleaved in up to quantitative yield by contact with a range of acids and bases in a variety of solvents. Suitable base reaction mixtures may include sodium hydroxide (NaOH) or ammonium acetate in aqueous methanol. Nonlimiting examples of suitable acidic deacetylating conditions may include hydrochloric acid (HCI) in acetone, sulfonic acids in refluxing toluene, AMBERLYST-15 in methanol, and kaolinitic clay in methanol. Deacetylation may also be carried out via enzymatic cleavage using for example porcine pancreatic lipase in a mixture of heptane and butanol. The resulting materials are termed synthetic CBN (designated “sCBN”) and synthetic HHC (designated “sHHC”), respectively.

[0045] In an aspect, the CBN-O-Acetate, HHC-O-Acetate, sCBN, sHHC or combinations thereof may be included in any suitable product, examples of which include an ingestible product such as in a solid dosage forms for oral administration (e.g., capsules, tablets, pills, powders and granules). In such solid dosage forms, the sCBN, the sHHC or both may be mixed with at least one inert, pharmaceutically acceptable excipient or carrier, such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and acacia; c) humectants such as glycerol; d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates and sodium carbonate; e) solution retarding agents such as paraffin; f) absorption accelerators such as quaternary ammonium compounds; g) wetting agents such as cetyl alcohol and glycerol monostearate; h) absorbents such as kaolin and bentonite clay and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof.

[0046] Additionally, or alternatively, in some aspects the CBN-O-Acetate, HHC-O- Acetate, sCBN, sHHC or combinations thereof may be included in an edible product, for example, a food product. Herein "edible" refers to a material that is fit to be eaten as food. "Food" herein refers to any edible product intended for consumption by humans or animals. The term "food" and the term "food and beverage" are used herein interchangeably.

[0047] An advantageous aspect of the presently disclosed methodologies is the reaction pressures utilized are considered moderate and, thus, the reaction does notrequire the use of steel vessels that are typically employed in the production of HHC which is carried out at significantly higher pressures of potentially explosive hydrogen gas. For instance, in some aspects, the relatively low reaction pressure may enable the use of, for instance, glass vessels, thereby avoiding the economic disadvantages of steel vessels. This convenience may translate into the greater utility of this technology in facilities more commonly equipped with jacketed glass reaction vessels.ADDITIONAL DISCLOSURE

[0048] A first aspect which is a method of preparing cannabinol (CBN) and hexahydrocannabinol (HHC) comprising contacting delta-8-tetrahydrocannabinol (A8- THC) with a supported noble metal catalyst under conditions suitable for the dehydrogenation of at least a portion of the A8-THC and aromatization of at least a portion of the A8-THC to form a product comprising HHC, CBN or combinations thereof.

[0049] A second aspect which is the method of claim 1 wherein a ratio of CBN:HHC in the product is about 1 :2.

[0050] A third aspect which is the method of any of the first through second aspects wherein the CBN is recovered in a yield of from about 10% to about 35%.

[0051] A fourth aspect which is the method of any of the first through third aspects wherein the HHC is recovered in a yield of from about 20% to about 65%.

[0052] A fifth aspect which is the method of any of the first through fourth aspects wherein the conditions comprise a reaction temperature of from about 150°C to about 210°C.

[0053] A sixth aspect which is the method of any of the first through fifth aspects wherein the conditions comprise a reaction time of from about 4 hours to about 72 hours.

[0054] A seventh aspect which is the method of any of the first through sixth aspects wherein with the supported noble metal catalyst comprises a platinum group metal and a support.

[0055] An eighth aspect which is the method of the seventh aspect wherein the platinum group metal comprises palladium.

[0056] A ninth aspect which is the method of the seventh aspect wherein the platinum group metal is present in an amount of from about 0.1 wt.% to about 10 wt.% based on the total weight of the supported noble metal catalyst.

[0057] A tenth aspect which is the method of any of the first through ninth aspects wherein the support comprises an oxide of a metal, an oxide of a metalloid or combinations thereof.

[0058] An eleventh aspect which is the method of any of the first through tenth aspects wherein the support comprises silica, titania, alumina, aluminate, or combinations thereof.

[0059] A twelfth aspect which is the method of any of the first through tenth aspects wherein the support comprises alumina.

[0060] A thirteenth aspect which is the method of any of the first through tenth aspects wherein the support comprises carbon.

[0061] A fourteenth aspect which is the method of any of the first through thirteenth aspects further comprising acetylating the product.

[0062] A fifteenth aspect which is the method of the fourteenth aspect wherein acetylating the product comprises contacting the product with (i) a proton-donating compound and (ii) an acetylating agent under conditions suitable for acetylation of one or more compound in the product.

[0063] A sixteenth aspect which is the method of any of the fourteenth through fifteenth aspects wherein the acetylating agents may be characterized by the general structure A or B:where R and / or R’ is a C1-CX enol group where x ranges from 0 to 5, ethylenyl, propylenyl, isopropenyl, isobutylenyl, or cyclohexenyl derivates.

[0064] A seventeenth aspect which is the method of any of the fifteenth through sixteenth aspects wherein the acetylating agent comprises an acetate ester of the enol tautomer of a carbonyl compound.

[0065] An eighteenth aspect which is the method of any of the fifteenth through seventeenth aspects wherein the proton-donating compound comprises a mineral acid.

[0066] A nineteenth aspect which is the method of any of the fifteenth through eighteenth aspects wherein the proton-donating compound comprises an organosulfur compound, a sulfonic acid or combinations thereof.

[0067] A twentieth aspect which is the method of the nineteenth aspect wherein the sulfonic acid comprises 1 ,3-propanedisulfonic acid, ethanedisulfonic acid, ethanesulfonic acid, isethionic acid, methanedisulfonic acid, methanesulfonic acid, tolenesulfonic acid, toluenesulfonic acid monohydrate, camphorsulfonic acid, vinylsulfonic acid or combinations thereof.

[0068] A twenty-first aspect which is the method of any of the fifteenth through twentieth aspects further comprising recovering an acetylated CBN, an acetylated HHC or both.

[0069] A twenty-second aspect which is a method of preparing cannabinol (CBN) and hexahydrocannabinol (HHC) comprising contacting delta-8-tetrahydrocannabinol (A8-THC) with a supported noble metal catalyst under conditions suitable for the dehydrogenation of at least a portion of the A8-THC and aromatization of at least a portion of the A8-THC to form a product comprising HHC, CBN or combinations thereof; recovering the product; contacting the product with (i) an acetylating agent and (ii) a proton donor under conditions suitable for formation of an acetylated product; separating the acetylated product to recover an acetylated CBN, an acetylated HHC or combinations thereof.

[0070] A twenty-third aspect which is the method of the twenty-second aspect further comprising deacetylating the acetylated product.

[0071] A twenty-fourth aspect which is the method of any of the twenty-second through twenty-third aspects wherein the support comprises silica, titania, alumina, aluminate, or combinations thereof.

[0072] A twenty-fifth aspect which is the method of any of the twenty-second through twenty-fourth aspects wherein the support comprises alumina.

[0073] A twenty-sixth aspect which is the method of any of the twenty-second through twenty-fifth aspects wherein the acetylating agents are characterized by the general structure:where R and / or R’ is a C1-CX enol group where x ranges from 0 to 5, ethylenyl, propylenyl, isopropenyl, isobutylenyl, or cyclohexenyl derivates.

[0074] A twenty-seventh aspect which is the method of any of the twenty-second through twenty-sixth aspects wherein the proton-donating compound comprises a mineral acid.

[0075] A twenty-eighth aspect which is the method of any of the twenty-second through twenty-seventh aspects wherein the proton donating compound comprises 1 ,3- propanedisulfonic acid, ethanedisulfonic acid, ethanesulfonic acid, isethionic acid, methanedisulfonic acid, methanesulfonic acid, tolenesulfonic acid, toluenesulfonic acid monohydrate, camphorsulfonic acid, vinylsulfonic acid or combinations thereof.EXAMPLES

[0076] The following examples are given as particular aspects of the present disclosure and to demonstrate the practice and advantages thereof. It is understood that the examples are given by way of illustration and are not intended to limit the specification or the claims to follow in any manner.EXAMPLE 1

[0077] Conversion of A8-THC to a mixture of CBN and HHC was carried out as disclosed herein on a small-scale (less than 500g). The small-scale was not large enough for rotating-bed reactor (greater than 15kg). A8-THC (95% pure, 335g, 1 ,012mol) was heated to about 80 °C and added to a 500 mL jacketed reactor, also held at 80 °C, equipped with a stir shaft. Palladium on alumina (0.5 wt.% Pd) pellets (25.13g, 7.5 wt.% or 0.12 mol% of A8-THC) were then added to the reactor, which was then sealed for application of vacuum. The reactor temperature was brought to 125 °C, the contents allowed to equilibrate, and slow stirring was begun (-150 rpm.) Vacuum was then gradually applied to 75 millibar(mbar) to 150 mbar and the mixture was allowed to degas for 15 minutes. Reactor temperature was then raised to 185 °C and the contents again allowed to equilibrate to this temperature while maintaining vacuum. As the temperature of the reaction mixture was raised to and passed 170 °C, evolution of hydrogen gas was observed from the catalyst pellets, which became more vigorous as the temperature was increased to between 180 °C and 185 °C. These conditions were held for 4 hours, after which the evolution of gas had significantly decreased. A reaction monitor was taken by HPLC analysis, where it was observed there was greater than about 95% consumption of A8-THC and the formation of two distinct products, identified as CBN and HHC in an approximate ratio of 1 :2 (CBN:HHC), reflecting the stoichiometry of 2 equivalents of H2 to form CBN and 1 equivalent of H2 needed to form HHC from A8-THC (Figure 3). The HPLC spectrum indicated 2 major peaks for HHC, which were subsequently confirmed to be diastereomers at the 9-carbon of HHC (dibenzopyran numbering), a new stereocenter created by the hydrogenation of A8-THC. The reaction mixture was then cooled to about 65C, diluted with heptane (about 100mL), and the Pd / AI catalyst recovered by filtration and allowed to soak in additional heptane for regeneration. Example 1 demonstrates a novel, highly efficient and solvent-free use of supported palladium as catalyst for the transfer hydrogenation of A8-THC to produce a mixture of CBN and HHC. This method of transfer hydrogenation exhibits a dramatically improved safety profile, requiring no exogenous source of hydrogen, such as pressurized hydrogen gas or other sacrificial source of hydrogen (e.g. ammonium formate in methanol). The only source of hydrogen in this method is the substrate, A8- THC, whose dehydrogenated product (CBN) and hydrogenated product (HHC) are valuable and otherwise produced at greater expense and hazard.EXAMPLE 2

[0078] Acetylation of a crude mixture of CBN / HHC to isolate crystalline CBN-O- acetate and an oil of HHC-O-acetate was carried out as disclosed herein. Specifically, the crude reaction mixture composed primarily of CBN and HHC (~330g) in heptane (1 vol. / wt. equiv.) was transferred to a 1 L jacketed reactor with jacket temperature at 40°C to 50 °C. The reactor was fitted with a reflux condenser and stir shaft, and sealed with the only outlet being to the reflux condenser. Isopropenyl acetate (1.5 mol. equiv., 175mL) was added and the mixture was homogenized with slow stirring, followed by the addition of beta-camphorsulfonic acid (1 mol%, 2.5g). The reaction vessel jacket was heated to 85C (the solution temp equilibrated to about 70 °C due to evaporative cooling of refluxing acetone, which is produced as a by-product of acetylation with isopropenyl acetate). After 2 hours, the reactor was cooled to 50 °C and water (about 200mL) was added to quench the excess isopropenyl acetate, along with ethyl acetate (about 200m L) to solvate CBN-O-Acetate, which is poorly soluble in heptane. The mixture was stirred for a further 15min, followed by phase separation and draining the aqueous. The reactor was then cooled to ambient (about 25 °C) and the organic phase was sequentially washed with 200mL solutions of 5% citric acid (aq.), 5% sodium bicarbonate (aq.), water and finally brine before drying over MgSO4 and filtering. Solvents were removed from this crude solution, followed by redissolving in hot heptane (about 60 °C), and cooling to ambient with rapid stirring. As the solution cooled,selective crystallization of CBN-O-Acetate occurred, which was filtered and washed with cold heptane. The mother liquor, containing primarily HHC-O-Acetate with 10-20% CBN-O-Acetate in heptane, was then cooled to -20 °C with stirring and a further crop of crystalline CBN-O-Acetate was removed by filtration. These two crystal crops were combined, slurried in fresh heptane, and slowly filtered to remove residual color bodies and any non-crystalline HHC-O-Acetate clinging to the solids. The crystals were then dried in a vacuum oven overnight (65 °C, 1 pm), providing 91 grams (81 % isolated yield of the expected -30% conversion from A8-THC) of CBN-O-Acetate with a purity of 98- 99% (Figure 4) [MP = 85 °C to 87°C],Distillation of HHC-O-Acetate

[0079] The mother liquor from crystallization of CBN-O-Acetate contained HHC-O- Acetate of approx. 85% purity, which was distilled under vacuum (about 125 microns) at temperatures ranging 180 °C to 200 °C. The clear, yellow distillate was comprised of HHC-O-Acetate of approx. 85%-90% purity, with residual CBN-O-Acetate. Example 2 demonstrates the separation of CBN from HHC can be achieved by acetylation of the crude mixture followed by selective crystallization of highly pure, acetylated CBN. The remaining mother liquor containing primarily HHC-O-acetate can then be distilled under vacuum to yield a clarified, homogenous product of non-crystalline HHC-O-acetate of 85% to 90% purity. This method avoids the need for chromatography, which is an expensive and time-consuming alternative to achieve similar results. Example 2 is complementary to Example 1 , making possible the rapid purification of the primary components from a mixture of CBN and HHC via their acetate derivatives, the deacetylation of which is well-known to provide the parent compounds in excellent yields

[0080] While various aspects of the present disclosure have been shown and described, modifications thereof can be made by one skilled in the art without departing from the spirit and teachings of the present disclosure. The aspects of the present disclosure described herein are exemplary only, and are not intended to be limiting. Many variations and modifications of the present disclosure are possible and are within the scope of the present disclosure. Where numerical ranges or limitations are expressly stated, such express ranges or limitations should be understood to include iterative ranges or limitations of like magnitude falling within the expressly stated ranges or limitations (e.g., “from about 1 to about 10” includes, 2, 3, 4, etc.; “greater than 0.10”includes 0.11 , 0.12, 0.13, etc.). Use of the term "optionally" with respect to any element of a claim is intended to mean that the subject element is required, or alternatively, is not required. Both alternatives are intended to be within the scope of the claim. Use of broader terms such as “comprises”, “includes”, “having, etc. should be understood to provide support for narrower terms such as “consisting of’, “consisting essentially of”, “comprised substantially of’, etc.

[0081] Accordingly, the scope of protection is not limited by the description set out above but is only limited by the claims which follow, that scope including all equivalents of the subject matter of the claims. Each and every claim is incorporated into the specification as an aspect of the present disclosure. Thus, the claims are a further description and are an addition to the aspects of the present disclosure. The discussion of a reference in the present disclosure is not an admission that it is prior art to the present disclosure, especially any reference that may have a publication date after the priority date of this application. The present disclosure of all patents, patent applications, and publications cited herein are hereby incorporated by reference, to the extent that they provide exemplary, procedural or other details supplementary to those set forth herein.

[0082] All publications, patent applications, and patents mentioned herein are incorporated by reference in their entirety. In the event of conflict, the present specification, including definitions, is intended to control. With respect to all ranges disclosed herein, such ranges are intended to include any combination of the mentioned upper and lower limits even if the particular combination is not specifically listed.

Claims

CLAIMSWhat is claimed is:

1. A method of preparing cannabinol (CBN) and hexahydrocannabinol (HHC) comprising: contacting delta-8-tetrahydrocannabinol (A8-THC) with a supported noble metal catalyst under conditions suitable for the dehydrogenation of at least a portion of the A8-THC and aromatization of at least a portion of the A8-THC to form a product comprising HHC, CBN, or combinations thereof.

2. The method of claim 1 , wherein a ratio of CBN:HHC in the product is about 1 :2.

3. The method of claim 1 wherein the CBN is recovered in a yield of from about 10% to about 35%.4 The method of claim 1 wherein the HHC is recovered in a yield of from about 20% to about 65%.

5. The method of claim 1 wherein the conditions comprise a reaction temperature of from about 150°C to about 210°C.

6. The method of claim 1 wherein the conditions comprise a reaction time of from about 4 hours to about 72 hours.

7. The method of claim 1 wherein with the supported noble metal catalyst comprises a platinum group metal and a support.

8. The method of claim 7 wherein the platinum group metal comprises palladium.

9. The method of claim 7 wherein the platinum group metal is present in an amount of from about 0.1 wt.% to about 10 wt.% based on the total weight of the supported noble metal catalyst.

10. The method of claim 1 wherein the support comprises an oxide of a metal, an oxide of a metalloid, or combinations thereof.

11. The method of claim 1 wherein the support comprises silica, titania, alumina, aluminate, or combinations thereof.

12. The method of claim 1 wherein the support comprises alumina.

13. The method of claim 1 wherein the support comprises carbon.

14. The method of claim 1 further comprising acetylating the product.

15. The method of claim 14 wherein acetylating the product comprises contacting the product with (i) a proton-donating compound and (ii) an acetylating agentunder conditions suitable for acetylation of one or more compound in the product.

16. The method of claim 14 wherein the acetylating agents may be characterized by the general structure A or B:where R,R’ or both are each independently a Ci-Cx enol group where x ranges from 0 to 5, ethylenyl, propylenyl, isopropenyl, isobutylenyl, or cyclohexenyl derivates.

17. The method of claim 15 wherein the acetylating agent comprises an acetate ester of the enol tautomer of a carbonyl compound.

18. The method of claim 15 wherein the proton-donating compound comprises a mineral acid.

19. The method of claim 15 wherein the proton-donating compound comprises an organosulfur compound, a sulfonic acid or combinations thereof.

20. The method of claim 19 wherein the sulfonic acid comprises 1 ,3- propanedisulfonic acid, ethanedisulfonic acid, ethanesulfonic acid, isethionic acid, methanedisulfonic acid, methanesulfonic acid, tolenesulfonic acid, toluenesulfonic acid monohydrate, camphorsulfonic acid, vinylsulfonic acid or combinations thereof.21 . The method of claim 15 further comprising recovering an acetylated CBN, an acetylated HHC or both.

22. A method of preparing cannabinol (CBN) and hexahydrocannabinol (HHC) comprising: contacting delta-8-tetrahydrocannabinol (A8-THC) with a supported noble metal catalyst under conditions suitable for the dehydrogenation of at least a portion of the A8-THC and aromatization of at least a portion of the A8-THC to form a product comprising HHC, CBN or combinations thereof; recovering the product;contacting the product with (i) an acetylating agent and (ii) a proton donor under conditions suitable for formation of an acetylated product; and separating the acetylated product to recover an acetylated CBN, an acetylated HHC or combinations thereof.

23. The method of claim 22 further comprising deacetylating the acetylated product.

24. The method of claim 22 wherein the support comprises silica, titania, alumina, aluminate, or combinations thereof.

25. The method of claim 22 wherein the support comprises alumina.

26. The method of claim 22 wherein the acetylating agents may be characterized by the general structure A or B:(A) (B) where R, R’ or both are each independently a Ci-Cx enol group where x ranges from 0 to 5, ethylenyl, propylenyl, isopropenyl, isobutylenyl, or cyclohexenyl derivates.

27. The method of claim 22 wherein the proton-donating compound comprises a mineral acid.

28. The method of claim 22 wherein the proton donating compound comprises 1 ,3- propanedisulfonic acid, ethanedisulfonic acid, ethanesulfonic acid, isethionic acid, methanedisulfonic acid, methanesulfonic acid, tolenesulfonic acid, toluenesulfonic acid monohydrate, camphorsulfonic acid, vinylsulfonic acid or combinations thereof.

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