EP-4735428-A1 - METHODS OF PREPARING CANNABINOIDS OR DERIVATIVES THEREOF

Abstract

Provided are methods of preparing cannabinol from cannabidiol and/ or tetrahydrocannabinol and for preparing cannabinol acetate. The methods comprise using catalytic molecular halogen in the presence of an oxidant.

Inventors

• JENSEN, Robert Paul
• HARTUNG, VAUGHN

Assignees

• Florascience Inc.

Dates

Publication Date

20260506

Application Date

20240103

Claims (1)

1. Attorney Docket No.: 54679-0004WO1 CLAIMS What is claimed is: 1. A method of preparing cannabinol, or a pharmaceutically acceptable salt thereof, the method comprising: admixing a catalyst, cannabidiol, and an oxidizing agent to form cannabinol, or a pharmaceutically acceptable salt thereof, wherein the catalyst is I 2 , Br 2 , or Cl 2 . 2. The method of claim 1, wherein the admixing comprises: (a) reacting the catalyst and the cannabidiol to form tetrahydrocannabinol; and (b) reacting the tetrahydrocannabinol, the catalyst, and the oxidizing agent to form the cannabinol, or a pharmaceutically acceptable salt thereof. 3. The method of claim 1, wherein the catalyst is I2. 4. The method of claim 2, wherein reacting the catalyst and the cannabidiol is performed at a temperature of about 35°C to about 200°C, about 50°C to about 150°C, about 50°C to about 100°C, or less than about 100°C. 5. The method of claim 1, wherein the admixing is done in the presence of a solvent. 6. The method of claim 5, wherein the solvent comprises one or more of benzene, toluene, xylenes, mesitylene, anisole, acetonitrile, acetic acid, acetic anhydride, heptane, cyclohexane, pyridine, chloroform, isopropyl acetate, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and chlorobenzene. 7. The method of claim 1, wherein the catalyst is present in an amount of about 10 mol% or less, about 5 mol% or less, or about 1 mol% or less, based on the total mols of cannabidiol. 8. The method of claim 2, wherein the reacting the tetrahydrocannabinol, the catalyst, and the oxidizing agent is performed at a temperature in a range of about 50°C to about 250°C, about 75°C to about 200°C, about 120°C to about 170°C, or less than about 150°C. Attorney Docket No.: 54679-0004WO1 9. The method of claim 1, wherein the oxidizing agent comprises one or more of O2, S8, benzoquinone, chloranil, hydrogen peroxide, peracetic acid, diacetyl peroxide, ditertbutyl peroxide, dicumyl peroxide, peroxybenzoic acid, benzoyl peroxide, and dimethyl sulfoxide. 10. The method of claim 1, wherein the oxidizing agent comprises O2 and an inert gas. 11. The method of claim 1, wherein the oxidizing agent comprises O2 and N2. 12. The method of claim 1, wherein the oxidizing agent comprises O2 and the O2 is present in an amount of less than about 25 wt%, less than about 20 wt%, less than about 15 wt%, about 10 wt% to about 20 wt%, or about 1 wt% to about 10 wt%, based on the total weight of the oxidizing agent. 13. The method of claim 2, wherein step (a) and step (b) are performed in situ. 14. The method of claim 1, wherein the method is performed in a single vessel. 15. The method of claim 1, wherein the method further forms cannabifuran, and wherein the cannabifuran is formed in an amount of less than about 5 mol%, based on the total mols of cannabinol, or a pharmaceutically acceptable salt thereof. 16. The method of claim 1, comprising crystallizing the cannabinol, or a pharmaceutically acceptable salt thereof. 17. The method of claim 1, wherein the cannabinol, or a pharmaceutically acceptable salt thereof, has a purity of about 90% or more, about 95% or more, or about 99% or more. 18. The method of claim 1, wherein the cannabinol, or a pharmaceutically acceptable salt thereof, is substantially free of Δ (9,10) -tetrahydrocannabinol. 19. The method of claim 1, wherein the cannabinol, or a pharmaceutically acceptable salt thereof, is substantially free of Δ (8,9) -tetrahydrocannabinol and Δ (9,10) -tetrahydrocannabinol. 20. The method of claim 1, further comprising: Attorney Docket No.: 54679-0004WO1 admixing the cannabinol, or a pharmaceutically acceptable salt thereof, with a dehydrating agent and acetic acid to form a mixture comprising acetylcannabinol, or a pharmaceutically acceptable salt thereof. 21. The method of claim 20, wherein the dehydrating agent comprises one or more of acetic anhydride, phosphoric acid, sulfuric acid, sodium bisulfite, phosphorus pentoxide, and polyphosphoric acid. 22. The method of claim 20, wherein the mixture further forms acetylcannabifuran, or a pharmaceutically acceptable salt thereof, wherein the acetylcannabifuran, or a pharmaceutically acceptable salt thereof, is formed in an amount of less than about 5 mol%, based on the total mols of acetylcannabinol. 23. A method of preparing cannabinol, or a pharmaceutically acceptable salt thereof, the method comprising: admixing a catalyst, an oxidizing agent, and tetrahydrocannabinol to form cannabinol, or a pharmaceutically acceptable salt thereof, wherein the catalyst is I2, Br2, or Cl2. 24. The method of claim 23, wherein the tetrahydrocannabinol is prepared by a process comprising: admixing the catalyst and cannabidiol to form the tetrahydrocannabinol. 25. The method of 24, wherein admixing the catalyst and the cannabidiol is performed at a temperature of about 35°C to about 200°C, about 50°C to about 150°C, about 50°C to about 100°C, or about less than about 100°C. 26. A method of preparing cannabinol, or a pharmaceutically acceptable salt thereof, the method comprising: (a) admixing cannabidiol and a catalyst to form a mixture of Δ (8,9) - tetrahydrocannabinol and Δ (9,10) -tetrahydrocannabinol; and (b) admixing the mixture and an oxidizing agent to form the cannabinol, or a pharmaceutically acceptable thereof, Attorney Docket No.: 54679-0004WO1 wherein the catalyst is I2 and the I2 is present in an amount of less than about 5 mol%, based on the total mols of the cannabidiol. 27. The method of claim 26, wherein the catalyst is present in an amount of less than about 1 mol%, based on the total mols of the cannabidiol. 28. The method of claim 26, wherein the cannabinol has a purity of about 90% or more, about 95% or more, or about 99% or more. 29. A method of preparing acetylcannabinol, or a pharmaceutically acceptable salt thereof, the method comprising: admixing cannabidiol, an oxidizing agent, I 2 , and acetic acid to form a mixture comprising cannabinol, or a pharmaceutically acceptable salt thereof, wherein the I2 is present in an amount of less than about 5 mol%, based on the total mols of cannabidiol; and admixing the mixture with a dehydrating agent to form acetylcannabinol, or a pharmaceutically acceptable salt thereof. 30. The method of claim 29, wherein the I2 is present in an amount of less than about 1 mol%, based on the total mols of cannabidiol.

Description

Attorney Docket No.: 54679-0004WO1 METHODS OF PREPARING CANNABINOIDS OR DERIVATIVES THEREOF TECHNICAL FIELD [0001] This disclosure relates to methods of preparing cannabinoids or derivatives thereof and compositions including two or more cannabinoids or derivatives thereof. BACKGROUND [0002] Many cannabinoids are produced via metabolic processes of the cannabis plant; however, cannabinol (CBN) is different. CBN is not produced by the metabolic processes of the cannabis plant, as there is no enzyme that can produce CBN in a high-fidelity transformation. It has been understood since 1944 that CBN is produced naturally by non- enzymatic oxidation of tetrahydrocannabinol (THC) (Levine, J. Am. Chem. Soc.1944, 66 (11), 1868–1870), a process that is slow and cannot generate CBN in high enough abundance to become the dominant cannabinoid in biomass. Thus, while some cultivars of Cannabis sativa can produce extracts and distillates with very high levels of cannabidiol (CBD) and THC, it is not feasible to do so with CBN. Traditional horticultural methods of optimizing cannabinoid expression are not practically useful for cannabinoids such as CBN, cannabinodiol (CBND), and cannabifuran (CBF) which are not made by enzymatic processes. While THC can transform into CBN, the lack of any enzyme known to catalyze the transformation also means that traditional industrial biosynthesis approaches are not practical methods of generating CBN in high purity. One of the ways that CBN can be generated in high yield and with high purity is by beginning with a purified cannabinoid as a starting material and performing a synthetic oxidation reaction, a method sometimes referred to as “partial synthesis.” In the chemical literature there exist at least six examples of CBN being generated by a controlled synthetic oxidation of a cannabinoid compound (see, e.g., Adams et al., J. Am. Chem. Soc. (1940) 62(9):2402–2405; Ghosh et al., J. Chem. Soc. Resumed (1940) No.0:1393–1396; Mechoulam et al., J. Am. Chem. Soc. (1968) 90(9):2418– 2420; Meltzer et al., Improv. Synth. Cannabinol Cannabiorcol (1981); Pollastro et al., J. Nat. Prod. (2018) 81(3):630–633; and Caprioglio et al., Org. Lett. (2019) 21(15):6122–6125. However, none of these methods constitute a scalable means of producing CBN due to a variety of reasons including their use of toxic solvents, formation of undesirable byproducts, high temperatures, expensive reagents, or other peculiarities which limit the practicality of these methods to below the kilogram scale. Attorney Docket No.: 54679-0004WO1 SUMMARY [0003] Provided in the present disclosure are methods of preparing cannabinoids and cannabinoid derivatives, and compositions thereof. [0004] Provided is a method of preparing cannabinol, or a pharmaceutically acceptable salt thereof, the method comprising admixing a catalyst, cannabidiol, and an oxidizing agent to form cannabinol, or a pharmaceutically acceptable salt thereof, wherein the catalyst is I2, Br2, or Cl2. [0005] In some embodiments, the admixing comprises (a) reacting the catalyst and the cannabidiol to form tetrahydrocannabinol; and (b) reacting the tetrahydrocannabinol, the catalyst, and the oxidizing agent to form the cannabinol, or a pharmaceutically acceptable salt thereof. [0006] In some embodiments, the catalyst is I2. [0007] In some embodiments, reacting the catalyst and the cannabidiol is performed at a temperature of about 35°C to about 200°C, about 50°C to about 150°C, about 50°C to about 100°C, or less than about 100°C. [0008] In some embodiments, the admixing is done in the presence of a solvent. [0009] In some embodiments, the solvent comprises one or more of benzene, toluene, xylenes, mesitylene, anisole, acetonitrile, acetic acid, acetic anhydride, heptane, cyclohexane, pyridine, chloroform, isopropyl acetate, dimethyl sulfoxide, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and chlorobenzene. [0010] In some embodiments, the catalyst is present in an amount of about 10 mol% or less, about 5 mol% or less, or about 1 mol% or less, based on the total mols of cannabidiol. [0011] In some embodiments, the reacting the tetrahydrocannabinol, the catalyst, and the oxidizing agent is performed at a temperature in a range of about 50°C to about 250°C, about 75°C to about 200°C, about 120°C to about 170°C, or less than about 150°C. [0012] In some embodiments, the oxidizing agent comprises one or more of O2, S8, benzoquinone, chloranil, hydrogen peroxide, peracetic acid, diacetyl peroxide, ditertbutyl peroxide, dicumyl peroxide, peroxybenzoic acid, benzoyl peroxide, and dimethyl sulfoxide. In some embodiments, the oxidizing agent comprises O2 and an inert gas. In some embodiments, the oxidizing agent comprises O2 and N2. In some embodiments, the oxidizing agent comprises O2 and the O2 is present in an amount of less than about 25 wt%, less than about 20 wt%, less than about 15 wt%, about 10 wt% to about 20 wt%, or about 1 wt% to about 10 wt%, based o