FIELD

[0001] This invention relates to the preparation of cannabinol. In particular, the invention relates to methods of preparing cannabinol from cannabis extracts comprising hydrocannabinols or from one or more than one synthetic hydrocannabinols comprising double bond positional and stereo isomers thereof.

BACKGROUND

[0002] Cannabinol (CBN) is a valuable biologically active cannabinoid present in cannabis plants. This cannabinoid may have prophylactic and/or therapeutic application in the treatment of sleep disorders. In addition to being used as a sleep aid, CBN may also act as a pain reliever, an antibacterial agent, an anti-inflammatory agent, an anti- convulsive agent, an appetite stimulant, a bone cell growth stimulant or an eye pressure reliever as well as other possible uses. However, CBN is present in low quantities in cannabis plants and extracts compared to other cannabinoids such as D ⁹ - tetrahydrocannabinol (A ⁹ -THC), tetrahydrocannabinolic acid (THCA), cannabidiol (CBD) and cannabidiolic acid (CBDA). The limited availability of CBN has hindered its use.

[0003] CBN has been chemically synthesized using a number of different multi-step routes (see, for example, R. Adams, B.R. Baker and R.B. Wearn, J. Am. Chem. Soc., (1940), 62, 2204-2207; R. Ghosh, A.R. Todd and S. Wilkinson, J. Am. Chem. Soc., (1940), 62, 1393-1396; P.R. Nandaluru and G.J. Bodwell, Org. Lett., (2012), 14 (1 ), 310-313; Y. Li, Y. Ding, J. Wang, Y. Su and X. Wang, Org. Lett., (2013), 15(11 ), 2574- 2577; J. Novak and C.A. Salemink, Tetrahedron Letters, (1982), 23 (2), 253-254; and F. Fan, J. Dong, J. Wang, L. Song, C. Song and J. Chang, Advanced Syn. and Cat.,

(2014), 6, 356). However, these methods utilize expensive, toxic and hazardous chemicals and are generally not suitable for commercial applications due to their low yield.

[0004] Other methods of synthesizing CBN have used cannabis extracts containing A ⁹ -THC as the starting material (see, for example, K.P. Bastola, A. Hazekamp and R. Verpoorte, Planta Medica, (2007), 73: 273-275, US9,763,991 and US9,867,859). CBN has been obtained by cooking cannabis extracts at very high temperatures for prolonged periods of time. This approach results in low yields of CBN due to the decomposition of most of the A ⁹ -THC in the extract. Exposing A ⁹ -THC-containing cannabis oil to air or light over a period of time is another method to make CBN from a cannabis extract. In this method, A ⁹ -THC to CBN oxidation is extremely slow and provides a very low yield of product.

[0005] Thus, there remains a need for an effective method to produce CBN with suitable yield for commercial applications.

SUMMARY

[0006] In one aspect, the present disclosure provides a method of preparing cannabinol (CBN) using cannabis extracts comprising hydrocannabinols or one or more than one synthetic hydrocannabinols comprising double bond positional and stereo isomers thereof.

[0007] Various aspects of the present disclosure provide a method of preparing CBN from a cannabis extract comprising hydrocannabinols or from one or more than one synthetic hydrocannabinols comprising double bond positional and stereo isomers thereof by reacting the cannabis extract comprising hydrocannabinols or the one or more than one synthetic hydrocannabinols comprising double bond positional and stereo isomers thereof with a catalyst to aromatize hydrocannabinols and double bond positional and stereo isomers thereof in the cannabis extract comprising

hydrocannabinols or the one or more than one synthetic hydrocannabinols comprising double bond positional and stereo isomers thereof to CBN; and isolating a reaction product comprising CBN.

[0008] In various embodiments, the hydrocannabinols in the cannabis extract comprise A ⁹ -tetrahydrocannabinol (A ⁹ -THC) and double bond positional isomers thereof.

[0009] Various aspects of the present disclosure also provide a method of preparing CBN from a cannabis extract comprising hydrocannabinols or from one or more than one synthetic hydrocannabinols comprising double bond positional and stereo isomers thereof by reacting the cannabis extract comprising hydrocannabinols or the one or more than one synthetic hydrocannabinols comprising double bond positional and stereo isomers thereof with a heterogeneous catalyst at elevated temperature to aromatize the hydrocannabinols and double bond positional and stereo isomers thereof in the cannabis extract comprising hydrocannabinols or the one or more synthetic hydrocannabinols comprising double bond positional and stereo isomers thereof to CBN; and isolating a reaction product comprising CBN.

[0010] In various embodiments, the hydrocannabinols in the cannabis extract comprise A ⁹ -tetrahydrocannabinol (A ⁹ -THC) and double bond positional isomers thereof.

[0011] Other aspects and features of the present invention will become apparent to those of ordinary skill in the art upon review of the following description of specific embodiments of the invention in conjunction with the accompanying claims.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012] In drawings which illustrate embodiments of the disclosure,

[0013] Figure 1 shows HPLC chromatograms of distilled cannabis extract from Example 1 (Figure 1 (A)) and the reaction product obtained after aromatization in

Example 2 (Figure 1 (B)).

DETAILED DESCRIPTION

[0014] In the context of the present disclosure, various terms are used in accordance with what is understood to be the ordinary meaning of those terms.

[0015] In various embodiments, the disclosure provides methods of preparing cannabinol (CBN) (1) from a cannabis extract comprising hydrocannabinols or from one or more than one synthetic hydrocannabinols comprising double bond positional and stereo isomers thereof. In various embodiments, the cannabis extract comprises one or more than one hydrocannabinols and double bond positional and stereo isomers thereof. The cannabis extract also comprises other oily resins, fats and oils. In various embodiments, the hydrocannabinols, whether synthetic or as part of the cannabis extract, may comprise one or more than one of dihydrocannabinol,

tetrahydrocannabinol, hexahydrocannabinol, octahydrocannabinol,

decahydrocannabinol, dodecahydrocannabinol, and double bond positional and stereo isomers thereof. In various embodiments, the hydrocannabinol, whether synthetic or as part of the cannabis extract, comprises A ⁹ -tetrahydrocannabinol (A ⁹ -THC) (2) and double bond positional and stereo isomers thereof. CBN possesses a structural skeleton similar to A ⁹ -THC but is more aromatic in nature.

[0016] The term“synthetic hydrocannabinol” refers to a hydrocannabinol which is prepared by reaction of other compounds. For example, A ⁹ -THC can be prepared from cannabidiol (CBD) using known synthetic reactions. Methods of preparing synthetic cannabinoid mixtures, including synthetic hydrocannabinols, are known to one of ordinary skill in the art, for example B.M. Trost and K. Dogra, Org. Lett., (2007), 9 (5), 861 -863; L.J. Cheng, J.H. Xie, Y. Chen, L.X. Wang and Q.L. Zhou, Org. Lett., (2013), 15 (4), 764-767; K.E. Fahrenholtz, M. Lurie and R.W. Kierstead, J. Am. Chem. Soc., (1967), 89 (23), 5934-5941 ; R. Mechoulam and Y. Gaoni, J. Am. Chem. Soc., (1965), 87 (14), 3273-3275. These methods are carried out using readily available starting materials. However, these methods can result in the preparation of the desired compound(s) with other by-products, such as biologically inactive isomers. In other embodiments, the methods can result in preparation of an isomerically pure

hydrocannabinol.

[0017] The term“hydrocannabinol” refers to a compound, whether synthetic or as part of the cannabis extract, having the following general formula (3):

wherein:

cycle C is aromatic and cycle A contains two double bonds;

cycle A is aromatic and cycle C contains two double bonds;

cycle C is aromatic and cycle A contains one double bonds;

cycle A is aromatic and cycle C contains one double bonds;

cycle C contain two double bonds and cycle A contains two double bonds;

cycle C is aromatic and cycle A is saturated;

cycle A is aromatic and cycle C is saturated;

cycle C contain two double bonds and cycle A contains one double bonds;

cycle A contain two double bonds and cycle C contains one double bonds;

cycle C contain two double bonds and cycle A is saturated;

cycle A contain two double bonds and cycle C is saturated;

cycle C contain one double bonds and cycle A contains one double bonds;

cycle C contain one double bonds and cycle A is saturated;

cycle A contain one double bonds and cycle C is saturated; and

cycles A and B are saturated.

[0018] The term“saturated” refers to a moiety of a compound in which the atoms are linked by single bonds.

[0019] The term“stereo isomers” refers to isomeric compounds differing only in the spacial arrangement of their atoms.

[0020] The term“double bond positional isomers” refers to constitutional isomers that have the same carbon skeleton and the same functional groups but differ from each other in the location of the one or more double bonds in the compounds. [0021] For example, double bond positional isomers of A ⁹ -THC are shown in Formula (4):

wherein

cycle A is aromatic and cycle C contains one double bond,

cycle C is aromatic and cycle A contains one double bond, or

cycles A and C each contain two double bonds.

[0022] In various embodiments, the hydrocannabinols comprise (- )-trans- ⁹ - tetrahydrocannabinol, (+)-frans-A ⁹ -tetrahydrocannabinol, (-)-c/s-A ⁹ - tetrahydrocannabinol, (+)-c/s-A ⁹ -tetrahydrocannabinol, (- )-trans- ⁸ - tetrahydrocannabinol, (+)-frans-A ⁸ -tetrahydrocannabinol, (-)-c/s-A ⁸ - tetrahydrocannabinol, (+)-c/s-A ⁸ -tetrahydrocannabinol or any combination thereof.

[0023] In various embodiments, the hydrocannabinols comprise (- )-trans- ⁹ - tetrahydrocannabinol, (-)-frans-A ⁸ -tetrahydrocannabinol or any combination thereof. In various embodiments, the hydrocannabinols comprise (- )-trans- ⁹ - tetrahydrocannabinol.

[0024] In various embodiments, cannabinol is prepared from an isomerically pure synthetic hydrocannabinol. In various embodiments, the one or more than one synthetic hydrocannabinols comprising double bond positional and stereo isomers thereof is part of a mixture with other synthetic cannabinoids.

[0025] The cannabis extract comprising hydrocannabinols may be obtained from the extraction of cannabis flowers. The extraction of cannabis flowers may comprise supercritical CO2 extraction or solvent extraction to form the cannabis extract.

Preferably, the cannabis extract is obtained by supercritical CO2 extraction. [0026] The cannabis extract may then be refined by fractional distillation under reduced pressure to obtain the cannabis extract comprising hydrocannabinols and double bond positional and stereo isomers thereof and other oily resins, fats and oils which have a similar boiling point. In various embodiments, the hydrocannabinols comprise one or more of dihydrocannabinol, tetrahydrocannabinol,

hexahydrocannabinol, octahydrocannabinol, decahydrocannabinol,

dodecahydrocannabinol, and double bond positional and stereo isomers thereof. In various embodiments, the hydrocannabinols comprise A ⁹ -THC and double bond positional isomers thereof.

[0027] Extracts prepared by solvent extraction of cannabis flowers may contain more complicated mixtures of compounds and lower proportion of A ⁹ -THC and double bond positional isomers thereof. Reaction products from these starting materials may require additional purification.

[0028] In various embodiments, cannabis extracts made from some cannabis strains contain a high proportion of A ⁹ -THC and double bond positional isomers thereof such that the cannabis extract may be used without the fractional distillation step.

[0029] In various embodiments, the hydrocannabinols and double bond positional and stereo isomers thereof are naturally occurring in cannabis plants or may be formed as by-products during the extraction and/or distillation steps. For example, the hydrocannabinols, including A ⁹ -THC, and double bond positional and stereo isomers thereof, may be formed by thermal rearrangement, or double bond formation or migration during distillation of the cannabis extract at elevated temperatures.

[0030] The cannabis extract comprising hydrocannabinols or the one or more than one synthetic hydrocannabinols comprising double bond positional and stereo isomers thereof is reacted with a catalyst to form a reaction product comprising CBN. In various embodiments, the reaction is conducted at elevated temperature. In various

embodiments, the reaction is conducted at atmospheric pressure. During the reaction, the hydrocannabinols and double bond positional and stereo isomers thereof undergo aromatization to form CBN. The rate of reaction may depend on the composition of the catalyst and the reaction conditions. [0031] The catalyst may be a heterogeneous catalyst such as a transition metal deposited onto an inert solid support. The transition metal may, for example, be palladium, platinum, gold, ruthenium or nickel. The inert solid support may, for example, be carbon, silica, alumina, calcium carbonate, barium sulfate or a polymeric fiber support. Preferably, the heterogenous catalyst is palladium or platinum deposited on carbon. In some embodiments, a homogeneous catalyst may be used, however, a homogeneous catalyst may increase the complexity of purifying the reaction product comprising CBN.

[0032] The rate of aromatization of the hydrocannabinols and double bond positional and stereo isomers thereof to CBN may be dependent on the percentage of the metal in the catalyst. For example, the heterogenous catalyst may contain about 5% (w/w) to about 20% (w/w) metal, about 5% (w/w) to about 10% (w/w) metal or any amount therebetween. In various embodiments, the heterogeneous catalyst is 10% (w/w) palladium on carbon.

[0033] In various embodiments, the amount of heterogeneous catalyst used for reaction may be about 3% (w/w) to about 1 % (w/w) based on the weight of the one or more than one hydrocannabinols and double bond positional and stereo isomers thereof. If too little heterogenous catalyst is used, the rate of reaction may be slow and decomposition of the hydrocannabinols and double bond positional and stereo isomers thereof may occur. The use of excess catalyst may only improve the rate of reaction slightly and result in a reaction mixture comprising large amounts of dark carbon, and increased reaction costs.

[0034] In various embodiments, the naturally occurring oily resins, fats and oils in the cannabis extract may act as the solvent or medium for the reaction. In various embodiments, no other high boiling solvent is required for the reaction. If the one or more than one synthetic hydrocannabinols comprising double bond positional and stereo isomers thereof is used for the reaction, a high boiling (boiling point greater than about 300°C) inert solvent may be used as the reaction medium.

[0035] In various embodiments, the elevated temperature is greater than about 100°C. In various embodiments, the elevated temperature is between about 200°C and about 300°C, or any temperature therebetween. For example, the temperature may be maintained at 300°C for the entire duration of the reaction. If the reaction temperature is too low for a particular catalyst, the rate of reaction for the aromatization of the cannabinols and double bond positional and stereo isomers thereof may slow down and the reaction mixture will be exposed to the reaction conditions for a longer period of time. This may result in a reduced yield of CBN as a result of the decomposition of the one or more than one hydrocannabinols and double bond positional and stereo isomers thereof.

[0036] In various embodiments, the reaction is complete in about 20 minutes to about 45 minutes, about 25 minutes to about 40 minutes, about 30 minutes to about 35 minutes, or any time therebetween.

[0037] A reaction product comprising CBN can then be isolated. As the

heterogeneous catalyst is a solid, insoluble in the reaction medium and particulate in nature, it can be removed by filtration following dilution of the reaction product with a diluent. In various embodiments, the diluent is an organic solvent which can dissolve the organic matter present in the reaction product but does not dissolve the

heterogeneous catalyst. The solvent may be a low boiling solvent such as methanol, ethanol, hexanes, pentane, toluene, petroleum ether, chloroform, dichloromethane, diethyl ether, ethyl acetate or any combination thereof. The solvent may be 95% ethanol. The use of ethanol may prevent the reaction product from being contaminated with petroleum-based organic solvent residues, particularly if the reaction product is to be used for human consumption and not subject to further purification.

[0038] Filtration may be done by passing the diluted reaction product through a silica gel bed or analytical grade filter by applying medium pressure or suction. Due to the viscosity of the diluted reaction product, sufficient quantities of solvent may be used to ensure that the CBN passes through the filter, thereby increasing the yield of CBN in the reaction product. The filtrate is then concentrated by removing the solvent to form the reaction product comprising CBN.

[0039] In various embodiments, the reaction product comprising CBN may be ready for use, including consumer product preparation and consumption, without requiring further purification. In various embodiments, the reaction product comprising CBN may be produced free from any foreign reagents, including solvent and heavy metals, after filtration. Alternatively, the reaction product comprising CBN may be purified using, for example, medium-pressure chromatography using silica-gel as the stationary phase and pentane/hexane and ether as the mobile phase. Chromatography can also be done using RP-C18 silica-gel column with ethanol/methanol and water as eluent.

Alternatively, the reaction product may be purified by vacuum distillation or

crystallization, amongst other techniques known to a person of ordinary skill in the art.

[0040] In various embodiments, the cannabis extract comprising hydrocannabinols or the one or more than one synthetic hydrocannabinols comprising double bond positional and stereo isomers thereof may be part of a mixture which may contain other cannabinoids such as cannabidiol (CBD), cannabidivarin (CBDV) and

tetrahydrocannabivarin (THCV). These other cannabinoids may undergo aromatization with the catalyst. The reaction product comprising CBN may be contaminated with these other cannabinoids or reaction products thereof. If such contamination is present, the reaction product comprising CBN may be purified by, for example, chromatography, amongst other techniques known to a person of ordinary skill in the art.

[0041] In various embodiments, CBN is obtained in about 95% yield, about 96% yield, about 97% yield, about 98% yield or about 99% yield or greater after the filtration and concentration steps. In various embodiments, the conversion of the

hydrocannabinol and double bond positional and stereo isomers thereof to CBN is near quantitative, indicating minimal thermal decomposition of the hydrocannabinol and double bond positional and stereo isomers thereof during aromatization. In various embodiments, CBN is produced with a purity of about 98% or greater or about 99% or greater, after chromatography. CBN may be the only cannabinoid present in the reaction product with no other intermediate compounds or decomposed impurities produced.

EXAMPLES

[0042] These examples illustrate various aspects of the invention, evidencing a variety of conditions for preparing CBN from a cannabis extract comprising

hydrocannabinols or from one or more than one synthetic hydrocannabinols comprising double bond positional and stereo isomers thereof. Selected examples are illustrative of advantages that may be obtained compared to alternative methods, and these advantages are accordingly illustrative of particular embodiments and not necessarily indicative of the characteristics of all aspects of the invention.

[0043] As used herein, the term“about” refers to an approximately +/-10% variation from a given value. It is to be understood that such a variation is always included in any given value provided herein, whether or not it is specifically referred to.

Example 1 : Preparation of a cannabis extract

[0044] Cannabis extract prepared from supercritical CO2 extraction of Cannabis sativa flowers was used as raw material for the synthesis. This extract was prepared from a high A ⁹ -THC-strain of Cannabis sativa and contained A ⁹ -THC as the major cannabinoid.

[0045] The extract was distilled by fractional distillation under reduced pressure to obtain the cannabis extract. The vacuum pressure was maintained at 0.07-0.1 mm/Hg. Vapour distilled out at about 155°C to about 165°C was collected into one pot which contained most of the A ⁹ -THC, other hydrocannabinols and double bond positional and stereo isomers thereof. Analysis of this cannabis extract by HPLC (Figure 1 (A)) showed A ⁹ -THC (25.40% (w/w)), CBN (4.0% (w/w)) and other hydrocannabinols and double bond positional and stereo isomers thereof (29.88% (w/w)).

Example 2: Preparation of CBN

[0046] The cannabis extract from Example 1 (30.0 g) was reacted with 10% (w/w) palladium on carbon (0.16 g) (Aldrich) catalyst. The mixture was refluxed at about 300°C for 35 min while stirring. The mixture was cooled and diluted with 95% ethanol (250 ml_). The diluted reaction product was filtered and concentrated using a rotary evaporator to a constant weight. Analysis of the reaction product comprising CBN by HPLC (Figure 1 (B)) showed that the sample contained CBN (59.20% (w/w)). This data indicates that almost all hydrocannabinols present in the cannabis extract from Example 1 were converted to CBN (total % of A ⁹ -THC (25.40%) + CBN (4.0%) + other

hydrocannabinols and double bond positional and stereo isomers thereof (29.88%) = 59.28% (w/w)). [0047] A sample of the reaction product (3.0 g) was chromatographed on medium pressure RP-C18-silica-gel (250 g) (silicycle) column using ethanol-water (70:30) as eluent. Fractions with CBN were combined and concentrated to obtain 1.4 g of reaction product with approximately 99% purity by HPLC.

[0048] This method was replicated using several different batches of cannabis extracts. Each replicate showed near quantitative conversion of A ⁹ -THC and other hydrocannabinols and double bond positional and stereo isomers thereof to CBN, supporting the reproducibility of this method.

[0049] Although various embodiments of the invention are disclosed herein, many adaptations and modifications may be made within the scope of the invention in accordance with the common general knowledge of those skilled in this art. Such modifications include the substitution of known equivalents for any aspect of the invention in order to achieve the same result in substantially the same way. Numeric ranges are inclusive of the numbers defining the range. The word "comprising" is used herein as an open-ended term, substantially equivalent to the phrase "including, but not limited to", and the word "comprises" has a corresponding meaning. As used herein, the singular forms "a", "an" and "the" include plural referents unless the context clearly dictates otherwise. Thus, for example, reference to "a thing" includes more than one such thing. Citation of references herein is not an admission that such references are prior art to the present invention. Any priority document(s) and all publications, including but not limited to patents and patent applications, cited in this specification are incorporated herein by reference as if each individual publication were specifically and individually indicated to be incorporated by reference herein and as though fully set forth herein. The invention includes all embodiments and variations substantially as hereinbefore described and with reference to the examples and drawings.