Catalytic Cannabinol Synthesis and Precursors

Abstract

Cannabinol (CBN) is a minor cannabinoid found in the cannabis plant, and there has been considerable interest in investigating CBN for pharmaceutical applications. It is currently being investigated to treat glaucoma, sleep disorders, and skin inflammation. Several synthetic approaches for CBN have been described in the prior art, however, the methods are still limited in scope due to harsh reaction conditions, the number of steps involved, low yields, and the extensive purification generally required. The present disclosure relates to novel cannabinol precursor compounds and processes for preparing cannabinol compounds. The disclosure also relates to the use of catalysts and catalytic processes for the preparation of cannabinol compounds from cannabinol precursors.

Description

[Technical Field]

[0001] Related applications This application claims the benefit of U.S. Provisional Application No. 63 / 159,568, filed on 11 March 2021 (the entire contents of which are incorporated herein by reference).

[0002] Areas of disclosure This disclosure relates to cannabinol precursor compounds and the use of these compounds for the preparation of cannabinol and its analogues. This disclosure also relates to the use of catalysts and catalytic processes for the preparation of cannabinol and its analogues using cannabinol precursor compounds. [Background technology]

[0003] Cannabinol (CBN) is a trace cannabinoid found in the cannabis plant. It has been reported to be non-psychoactive or slightly psychoactive. CBN is usually extracted from mature cannabis, and the main pathway is the oxidation of tetrahydrocannabinol (THC), which is accelerated by light and high temperatures during storage of harvested cannabis. It is not economically feasible to extract CBN directly from the plant for pharmaceutical purposes.

[0004] CBN is more chemically stable than CBD and THC under external stresses such as heat and light. This characteristic of CBN allows for a longer shelf life, which is an important pharmaceutical parameter. Therefore, there is considerable interest in investigating CBN for pharmaceutical applications. Currently, it is being studied for the treatment of glaucoma, sleep disorders, skin inflammation, and other conditions.

[0005] The supply of pure CBN for pharmaceuticals, nutritional supplements, and recreational products is complicated by the limited supply from natural sources and the demand for more abundant main components (CBD and THC) from the cannabis plant. In addition, extracted cannabis resin contains over 150 cannabinoid products, in addition to terpenes and other compounds present in the plant. Isolating pure CBN from extracted and matured cannabis resin is laborious, time-consuming, and results in low yields. Therefore, there is a demand for a high-purity, commercially viable supply of CBN.

[0006] Several synthetic approaches for CBN have been described in the prior art. These include the use of a high-pressure Diels-Alder reaction to prepare 6,6-dialkyl-benzo[c]chromene, e.g., CBN (L. Minuti et al., J. Org. Chem. 2012, 77, 7923-7931). In another approach, Appendino and collaborators reported the use of iodine for the aromatization of CBD and THC (F. Pollastro et al., J. Nat. Prod. 2018, 81, 630-633). However, these and other methods are still limited in scope due to harsh reaction conditions, number of steps, low yields, and the large-scale purification generally required.

[0007] Furthermore, there are essentially no practical routes for isolating the rare cannabinoid CBN derivatives THCV, THCB, and THCP from cannabis plants. Unlike THC, these analogues are either rare in cannabis plants or only detectable in minute quantities.

[0008] Prior art reflects the challenges associated with developing reliable and commercially viable pathways for synthetic CBN and its analogues. [Overview of the project]

[0009] This disclosure describes a novel approach to the synthesis of cannabinols and their analogues, focusing in several aspects on the use of novel, stable precursors that can be converted on demand to desired cannabinol products. The precursors are derived from commercially available chemicals.

[0010] In various embodiments, this disclosure relates to the preparation of novel cannabinol precursor compounds for the preparation of cannabinols and their analogues and derivatives using catalysts and catalytic processes. The precursors can be prepared, purified, and subsequently converted to desired cannabinol products. The precursors are air-stable, well-storage-stable compounds that can be stored, transported, and converted to desired cannabinol products on demand.

[0011] Therefore, in some embodiments, the present disclosure relates to cannabinol precursors of formula (I): [ka] During the ceremony, LG is any suitable leaving group, and R2 represents hydrogen, a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, a substituted aryl group, a substituted heteroaryl group, or a substituted acyl group, where one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or acyl group of R2 are optionally replaced by heteroatoms selected from the group consisting of O, S, N, P, and Si, which are optionally substituted by one or more groups, if possible.

[0012] In one embodiment, the leaving group is a halo group, a sulfonate, or a boronate.

[0013] In another embodiment, the boronic acid leaving group is -B(OR)2, where R is H, (C1-C 20)-alkyl group, (C2-C 20 )-alkenyl group, (C2-C 20 )-alkynyl group, (C3-C 20 )-cycloalkyl group, or (C6-C 14 )-aryl group. In another embodiment, the boronic acid leaving group is -B(OR)2, where R is H, (C1-C 20 )-alkyl group (e.g., (C1-C 10 )-alkyl group) or (C6-C 14 )-aryl group (e.g., (C6-C 10 )-aryl group). In another embodiment, the boronic acid leaving group is -BF3K.

[0014] In another embodiment, the leaving group is a sulfonate of the following formula:

Chemical formula

[0015] In one embodiment, the sulfonic acid leaving group is a triflate, mesylate or tosylate group.

[0016] Generally, the compounds of formula (I) can be prepared, isolated, and then used.

[0017] In some other embodiments, the present disclosure relates to cannabinol sulfonates of formula (II): [ka] During the ceremony, R1 can be a hydrogen atom, a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, a substituted aryl group, a substituted heteroaryl group, or a substituted OR c Base or NR c Represents two groups, and the non-restrictive substituents that can be R1 are halogen atoms, OR d , or NR d There are two units, R c or R d is a hydrogen atom or a cyclic, linear or branched alkyl, aryl or alkenyl group; and R2 represents a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, a substituted aryl group, a substituted heteroaryl group, or a substituted acyl group, wherein one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or acyl group of R2 are optionally replaced with heteroatoms selected from the group consisting of O, S, N, P, and Si, which are optionally replaced with one or more groups, if possible.

[0018] Generally, compounds of formula (II) can be prepared, isolated, and then used.

[0019] In some embodiments, the present disclosure relates to cannabinol sulfonates of formula (III): [ka] During the ceremony, R1 can be a hydrogen atom, a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, a substituted aryl group, a substituted heteroaryl group, or a substituted OR c Base or NR c Represents two groups, and the non-restrictive substituents that can be R1 are halogen atoms, OR d , or NR d There are two units, R c or R d is a hydrogen atom or a cyclic, linear, or branched alkyl, aryl, or alkenyl group.

[0020] Generally, compounds of formula (III) can be prepared, isolated, and then used.

[0021] In some other embodiments, the disclosure also relates to a cannabinol precursor of formula (IV): [ka]

[0022] In some other embodiments, the disclosure also relates to cannabinol precursors of formulas (I) to (IV), wherein one or more hydrogen atoms are replaced with deuterium.

[0023] In some other embodiments, the disclosure also relates to cannabinol precursors of formulas (I) to (IV), wherein one or more carbon-12 atoms are replaced with carbon-13 atoms.

[0024] In another embodiment, the present disclosure relates to a cannabinol precursor of formula (V): [ka] During the ceremony, One or more hydrogen atoms are replaced by deuterium, and / or one or more carbon-12 atoms are replaced by carbon-13; R2 represents a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, a substituted aryl group, a substituted heteroaryl group, or a substituted acyl group, wherein one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or acyl group of R2 are optionally replaced by heteroatoms selected from the group consisting of O, S, N, P, and Si, which are optionally substituted with one or more groups if possible; and R3 and R4 represent a hydrogen atom, a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, or a substituted aryl group.

[0025] In another embodiment, the present disclosure relates to a cannabinol precursor of formula (VI): [ka] During the ceremony, One or more hydrogen atoms are replaced by deuterium, and / or one or more carbon-12 atoms are replaced by carbon-13; R2 represents a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, a substituted aryl group, a substituted heteroaryl group, or a substituted acyl group, wherein one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or acyl group of R2 are optionally replaced by heteroatoms selected from the group consisting of O, S, N, P, and Si, which are optionally substituted with one or more groups if possible; and R3 represents a hydrogen atom, a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, or a substituted aryl group.

[0026] In another embodiment, the present disclosure relates to a cannabinol compound of formula (VII): [ka] During the ceremony, One or more hydrogen atoms in the p-cymene fragment of the molecule are replaced by deuterium, and / or one or more carbon-12 atoms in the p-cymene fragment of the molecule are replaced by carbon-13; R2 represents hydrogen, a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, a substituted aryl group, a substituted heteroaryl group, or a substituted acyl group, where one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or acyl group of R2 are optionally replaced by heteroatoms selected from the group consisting of O, S, N, P, and Si, which are optionally substituted with one or more groups if possible; and R3 represents a hydrogen atom, a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, or a substituted aryl group.

[0027] In various embodiments of this disclosure, transformations to which the compounds of the disclosure can be applied include, but are not limited to, catalyzed and uncatalyzed carbon-carbon bond formation reactions, including the Ullman, Suzuki-Miyaura, Negishi, Kumada, Sonogashira, and Stille reactions. Such carbon-carbon bond formation reactions involve the use of the compounds of the disclosure, and one or more cannabinol compounds selected from the group consisting of: Formula (VII): [ka] and Formula (VIII): [ka] During the ceremony, R2 represents a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, a substituted aryl group, a substituted heteroaryl group, or a substituted acyl group, wherein one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or acyl group of R2 are optionally replaced by heteroatoms selected from the group consisting of O, S, N, P, and Si, which are optionally substituted with one or more groups if possible; and R3 represents a hydrogen atom, a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, or a substituted aryl group.

[0028] In some other embodiments, the disclosure also relates to the preparation of cannabinol compounds of formula (VII) and formula (VIII), wherein one or more hydrogen atoms are replaced with deuterium.

[0029] In some other embodiments, the disclosure also relates to the preparation of cannabinol compounds of formula (VII) and formula (VIII), wherein one or more carbon-12 atoms are replaced with carbon-13 atoms.

[0030] In some other embodiments, the disclosure also relates to the preparation of cannabinol compounds of formula (VII) and formula (VIII), wherein one or more hydrogen atoms of the p-cymene fragment of the molecule are replaced with deuterium.

[0031] In some other embodiments, the disclosure also relates to the preparation of cannabinol compounds of formula (VII) and formula (VIII), wherein one or more carbon-12 atoms of the p-cymene fragment of the molecule are replaced with carbon-13 atoms.

[0032] In some other aspects of the disclosure, the present disclosure provides methods for the synthesis of one or more of the following cannabinol products: [ka]

[0033] In some other aspects of the disclosure, the present disclosure provides methods for the synthesis of one or more of the following deuterated cannabinol products: [ka]

[0034] In some other aspects of the disclosure, the present disclosure provides methods for the synthesis of one or more of the following carbon-13 cannabinol products: [ka]

[0035] In some embodiments, this disclosure provides a process for the catalytic preparation of compounds of formula (VII) and formula (VIII).

[0036] In some other embodiments, this disclosure provides a process for the non-catalytic preparation of compounds of formula (VII) and formula (VIII) from compounds of formula (I) to formula (VI).

[0037] In various embodiments, the process for preparing the compounds of formula (VII) and (VIII) from the compounds of formula (I) to (VI) is, according to the disclosure, to use a boron-containing compound, such as R3-B(OH)2, R3-B(OR)2, or R3-BF3K.

[0038] In some other aspects of the disclosure process, a Grignard compound such as R3-MgX is used to prepare the compounds of formula (VII) and formula (VIII).

[0039] In yet another aspect of the disclosure process, an organozinc compound such as R3-ZnX is used to prepare the compounds of formula (VII) and formula (VIII).

[0040] The disclosure also includes compositions, methods for producing compounds, and kits comprising compositions containing the compounds of the disclosure, one or more of the aforementioned components, along with instructions for optionally producing or using them, and the use of any of the aforementioned.

[0041] Other features and advantages of this disclosure will become apparent from the detailed description below. However, it should be understood that the detailed description and specific examples, while illustrating preferred embodiments of this disclosure, are provided only as examples, for various changes and modifications within the spirit and scope of this disclosure will become apparent to those skilled in the art from this detailed description.

[0042] This disclosure is described in more detail with reference to the drawings below, which are intended to be illustrative of certain embodiments of the disclosure and not to limit the scope of the disclosure. [Brief explanation of the drawing]

[0043] [Figure 1]A scheme for the preparation of cannabinol (CBN) in one embodiment of this disclosure is shown. [Figure 2] The X-ray crystal structure of methyl 2',4',6'-trimethoxy-5-methylbiphenyl-2-carboxylate in one embodiment of this disclosure is shown. [Figure 3] The X-ray crystal structure of 2-(2',4',6'-trimethoxy-5-methylbiphenyl-2-yl)propan-2-ol in one embodiment of this disclosure is shown. [Figure 4] The X-ray crystal structure of 6,6,9-trimethyl-6H-benzo[c]chromene-1,3-diol in one embodiment of this disclosure is shown. [Figure 5] The X-ray crystal structure of 1-hydroxy-6,6,9-trimethyl-6H-benzo[c]chromen-3-yltrifluoromethanesulfonate in one embodiment of this disclosure is shown. [Figure 6] The 1H NMR spectrum of methyl 2',4',6'-trimethoxy-5-methylbiphenyl-2-carboxylate in one embodiment of this disclosure is shown. [Figure 7] The 1H NMR spectrum of 2-(2',4',6'-trimethoxy-5-methylbiphenyl-2-yl)propan-2-ol in one embodiment of this disclosure is shown. [Figure 8] The 1H NMR spectrum of 6,6,9-trimethyl-6H-benzo[c]chromene-1,3-diol in one embodiment of this disclosure is shown. [Figure 9] The 1H NMR spectrum of 1-hydroxy-6,6,9-trimethyl-6H-benzo[c]chromen-3-yltrifluoromethanesulfonate in one embodiment of this disclosure is shown. [Figure 10] The 1H NMR spectrum of 6,6,9-trimethyl-1-(trimethylsilyloxy)-6H-benzo[c]chromen-3-yltrifluoromethanesulfonate in one embodiment of this disclosure is shown. [Figure 11]The 1H NMR spectrum of cannabinol-C1 (CBN-C1) in one embodiment of this disclosure is shown. [Figure 12] The 1H NMR spectrum of cannabinol-C2 (CBN-C2) in one embodiment of this disclosure is shown. [Figure 13] The 1H NMR spectrum of cannabivarin (CBNV) in one embodiment of this disclosure is shown. [Figure 14] The 1H NMR spectrum of cannabibutol (CBNB) in one embodiment of this disclosure is shown. [Figure 15] The 1H NMR spectrum of cannabinol (CBN) in one embodiment of this disclosure is shown. [Figure 16] The 1H NMR spectrum of cannabihexol (CBNH) in one embodiment of this disclosure is shown. [Figure 17] The 1H NMR spectrum of cannabiphorol (CBNP) in one embodiment of this disclosure is shown. [Figure 18] The 1H NMR spectrum of benzyl-cannabinol in one embodiment of this disclosure is shown. [Modes for carrying out the invention]

[0044] (I) Definition (C1-C m The term "-alkyl" as used herein means a linear and / or branched saturated alkyl radical containing one or more carbon atoms, including methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, 2,2-dimethylbutyl, n-pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-hexyl, etc., depending on what "m" is, where the variable "m" indicates the maximum number of carbon atoms.

[0045] (C2-C mThe term "-alkenyl" as used herein means a linear and / or branched, unsaturated alkyl radical containing two or more carbon atoms and one to three double bonds, including vinyl, allyl, 2-methylprop-1-enyl, buto-1-enyl, buto-2-enyl, buto-3-enyl, 2-methylbuto-1-enyl, 2-methylpento-1-enyl, 4-methylpento-1-enyl, 4-methylpento-2-enyl, 2-methylpento-2-enyl, 4-methylpenta-1,3-dienyl, hexen-1-yl, etc., where the variable "m" indicates the maximum number of carbon atoms.

[0046] (C1-C m The term "(-alkynyl)" as used herein means a linear and / or branched, unsaturated alkyl radical containing two or more carbon atoms and one to three triple bonds, including acetylinyl, propynyl, buto-1-inyl, buto-2-inyl, buto-3-inyl, 3-methylbuto-1-enyl, 3-methylpento-1-inyl, 4-methylpento-1-inyl, 4-methylpento-2-inyl, penta-1,3-di-inyl, hexyn-1-yl, etc., depending on what "m" is, where the variable "m" indicates the maximum number of carbon atoms.

[0047] The term "alkoxy" as used herein means a linear and / or branched alkoxy group comprising one or more carbon atoms, including (by identity) methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy, heptoxy, and the like.

[0048] (C3C m The term "-cycloalkyl" as used herein means a monocyclic, dicyclic, or tricyclic saturated carbocyclic group containing three or more carbon atoms, including cyclopropyl, cyclobutyl, cyclopentyl, cyclodecyl, etc. (depending on what "m" is), where the variable "m" indicates the maximum number of carbon atoms.

[0049] (C6C mThe term "-aryl" as used herein means a monocyclic, dicyclic, or tricyclic aromatic ring system comprising at least one aromatic ring and six or more carbon atoms, including phenyl, naphthyl, anthracenyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, etc., where the variable "m" indicates the maximum number of carbon atoms.

[0050] (C5C m The term "-heteroaryl" as used herein means a monocyclic, dicyclic, or tricyclic system comprising one or two aromatic rings and five or more atoms, of which, unless otherwise specified, one, two, three, four, or five are heteromotors independently selected from N, NH, N(alkyl), O, and S, including thienyl, furyl, pyrrolyl, pyrididyl, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl, etc., where the variable "m" indicates the maximum number of carbon atoms.

[0051] In this specification, "leaving group" or "LG" refers to a group that can be readily substituted by a nucleophile, for example, under nucleophilic substitution reaction conditions.

[0052] The terms "halo" or "halogen" as used herein mean chloro, fluoro, bromo, or iodine.

[0053] The term "fluorosubstitution" as used herein means that at least one (or all) of the hydrogen atoms on the group in question have been replaced by fluorine.

[0054] The subscript "en" attached to any of the above groups indicates that the group is divalent, meaning it is inserted between two other groups.

[0055] The term "ring system" as used herein refers to a ring system containing carbon, which includes monocyclic, fused dicyclic and polycyclic rings, bridging rings and metallocenes. Where specified, carbon atoms within a ring may or may not be substituted with heteroatoms.

[0056] In understanding the scope of this disclosure, the term “equipped with” and its derivatives are intended herein to be unrestricted terms that identify the presence of expressed features, elements, components, bases, integers, and / or steps, but do not exclude the presence of other unexpressed features, elements, components, bases, integers, and / or steps. The foregoing also applies to similarly meaning words such as “contains,” “has,” and their derivatives. For example, “contains” also encompasses “contains, but is not limited to them.” Finally, terms of degree, such as “substantially,” “about,” and “approximately,” mean herein a reasonable amount of deviation from the modified term such that the final result is not substantially altered. These terms of degree should be interpreted as including a deviation of at least ±5% from the modified term, provided that this deviation does not invalidate the meaning of the word it modifies.

[0057] (II) Disclosed Compounds This disclosure relates to a cannabinol precursor of formula (I): [ka] During the ceremony, LG is any suitable leaving group, and R2 represents hydrogen, a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, a substituted aryl group, a substituted heteroaryl group, or a substituted acyl group, where one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or acyl group of R2 are optionally replaced by heteroatoms selected from the group consisting of O, S, N, P, and Si, which are optionally substituted by one or more groups, if possible.

[0058] In one embodiment, LG is an anionic group (after elimination), such as a sulfonate, halide, or boronate; or MX nThe group (M=Li, Mg, Zn, Sn, B, Si; X is a halide, OH, OR, (in the formula, R is (C1-C) 20 )-alkyl, (C2-C 20 )-alkenyl group, (C2-C 20 )-Alkynyl group, (C3-C 20 )-cycloalkyl group, or (C6-C 20 )-aryl; n=0~3). In another embodiment, (C1-C 20 )-alkyl is (C1-C 10 )-alkyl, or (C1-C6)-alkyl; (C2-C 20 )-Alkenyl group is (C2-C 10 )-alkenyl group or (C2-C6)-alkenyl group; (C2-C 20 )-Alkynyl group is (C2-C 10 )-alkynyl group or (C2-C6)-alkynyl group; (C3-C 20 )-Cycloalkyl groups are (C3-C 10 )-cycloalkyl group or (C3-C6)-cycloalkyl group; as well as (C6-C 20 )-Aryl is (C6-C 14 )-aryl or (C6-C 10 It is )-aryl or (C6)-aryl.

[0059] In one embodiment, the leaving group is a halo group, a sulfonate, or a boronate.

[0060] In another embodiment, the boronic acid leaving group is -B(OR)2, where R is H, (C1-C 20 )-alkyl group, (C2-C 20 )-alkenyl group, (C2-C 20 )-Alkynyl group, (C3-C 20 )-cycloalkyl group, or (C6-C 14 )-aryl group. In another embodiment, the boronic acid leaving group is -B(OR)2, where R is H, (C1-C 20 )-alkyl group (e.g., (C1-C 10 )-alkyl group or (C1-C6)-alkyl group) or (C6-C14 )-aryl group (e.g. (C6-C) 10 It is a (C6)-aryl group or (C6)-aryl group.

[0061] In another embodiment, the boronic acid leaving group is -BF3K.

[0062] In another embodiment, the leaving group is a sulfonate of the following formula: [ka] During the ceremony, R t is a hydrogen atom, a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, a substituted aryl group, a substituted heteroaryl group, or a substituted OR c Base or NR c There are two units, R t Possible non-limiting substituents include halogen atoms, OR c , or NR c There are two units, R c is a hydrogen atom or a cyclic, linear, or branched alkyl, aryl, or alkenyl group.

[0063] In another embodiment, R t This is a hydrogen atom, optionally substituted (C1-C 20 )-alkyl group, optionally substituted (C2-C 20 )-alkenyl group, optionally substituted (C2-C 20 )-alkynyl group, optionally substituted (C3-C 20 )-cycloalkyl group, optionally substituted (C6-C 14 )-aryl group, optionally substituted (C5-C 14 )-heteroaryl group, OR c Base or NR c It has two groups, and optional substituents are halogen atoms, OR d , or NR d There are two units, Rc or R d is a hydrogen atom, a (C1-C 20 )-alkyl group, a (C2-C 20 )-alkenyl group, a (C2-C 20 )-alkynyl group, a (C3-C 20 )-cycloalkyl group, or a (C6-C 14 )-aryl group.

[0064] In another embodiment, R t is a hydrogen atom, an optionally substituted (C1-C 10 )-alkyl group, an optionally substituted (C2-C 10 )-alkenyl group, an optionally substituted (C2-C 10 )-alkynyl group, an optionally substituted (C3-C 10 [[ID=);-cycloalkyl group, an optionally substituted (C6-C 10 )-aryl group. In another embodiment, R[[ID=,0]] t is a hydrogen atom, an optionally substituted (C1-C6)-alkyl group, an optionally substituted (C2-C6)-alkenyl group, an optionally substituted (C2-C6)-alkynyl group, an optionally substituted (C3-C6)-cycloalkyl group, an optionally substituted (C6)-aryl group. In another embodiment, any of the alkyl groups is fluorine-substituted, for example, a fluorine-substituted (C1-C6)-alkyl group, for example CF3.

[0065] In another embodiment, the optional substituent is a (C1-C 10 )-alkyl group, a (C2-C 10 )-alkenyl group, a (C2-C 10 )-alkynyl group, a (C3-C 10 )-cycloalkyl group, or a (C6-C 10 )-aryl group. In another embodiment, it is a (C1-C6)-alkyl group, a (C2-C6)-alkenyl group, a (C2-C6)-alkynyl group, a (C3-C6)-cycloalkyl group, or a (C6)-aryl group.

[0066] In one embodiment, the sulfonic acid leaving group is a triflate, mesylate or tosylate group.

[0067] In one embodiment, R2 is (C1-C 20 )-alkyl group, (C2-C 20 )-alkenyl group, (C2-C 20 )-Alkynyl group, (C3-C 20 )-Cycloalkyl group, -Si[(C1-C 20 )-alkyl]3 groups, (C6-C 14 )-aryl group, or (C5-C 14 )-heteroaryl group or acyl group-C(=O)-R' represents (C1-C 20 )-alkyl group, each group optionally contains one or more halogen atoms (F, Cl, Br or I), (C1-C 20 )-alkyl group, (C2-C 20 )-alkenyl group, (C2-C 20 )-alkynyl group, -OR d , or -NR d Substituted with 2, R c and R d Independently or simultaneously, hydrogen, (C1-C 20 )-alkyl, (C2-C 20 )-alkenyl, or (C2-C 20 )-Alkynyl, where one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl group of R2 are optionally replaced by heteroatoms selected from the group consisting of O, S, N, P and Si, and it is optionally one or more halogens (F, Cl, Br or I) or -(C1-C 20 )- Replaced with an alkyl group.

[0068] In one embodiment, R2 is (C1-C 10 )-alkyl group, (C2-C 10 )-alkenyl group, (C2-C 10 )-Alkynyl group, (C3-C 10 )-Cycloalkyl group, -Si[(C1-C 10 )-alkyl]3 groups, (C6-C 10 )-aryl group, or (C5-C 10)-heteroaryl group or acyl group-C(=O)-R' represents (C1-C 10 )-alkyl group, each group optionally contains one or more halogen atoms (F, Cl, Br or I), -(C1-C 10 )-alkyl group, (C2-C 10 )-alkenyl group, (C2-C 10 )-alkynyl group, -OR d , or -NR d Substituted with 2, R c and R d Hydrogen, (C1-C) independently or simultaneously 10 )-alkyl, (C2-C 10 )-alkenyl, or (C2-C 10 )-Alkynyl, where one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl group of R2 are optionally replaced by heteroatoms selected from the group consisting of O, S, N, P and Si, and it is optionally one or more halogens (F, Cl, Br or I) or -(C1-C 10 )- Replaced with an alkyl group.

[0069] In one embodiment, R2 represents a (C1-C6)-alkyl group, a (C2-C6)-alkenyl group, a (C2-C6)-alkynyl group, a (C3-C6)-cycloalkyl group, a -Si[(C1-C6)-alkyl]3 group, a phenyl group, or a (C5-C6)-heteroaryl group, or an acyl group -C(=O)-R', where R' is a (C1-C6)-alkyl group, each group optionally consisting of one or more halogen atoms (F, Cl, Br, or I), -(C1-C6)-alkyl group, (C2-C6)-alkenyl group, (C2-C6)-alkynyl group, -OR d , or -NR d Substituted with 2, R c and R dR2 is independently or simultaneously hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, and one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or acyl group of R2 are optionally replaced by heteroatoms selected from the group consisting of O, S, N, P, and Si, which are optionally substituted with one or more halogens (F, Cl, Br, or I) or -(C1-C6)-alkyl groups, if possible.

[0070] In one embodiment, R2 represents a (C1-C6)-alkyl group, a -Si[(C1-C6)-alkyl]3 group, or a phenyl group.

[0071] In one embodiment, R2 represents three -Si[(C1-C6)-alkyl] groups. In one embodiment, R2 represents three -Si[(C1-C3)-alkyl] groups. In one embodiment, R2 represents three -Si(CH3) groups.

[0072] This disclosure also relates to cannabinol sulfonate esters of formula (II): [ka] During the ceremony, R1 is a hydrogen atom, a substituted linear or branched alkyl group of any length, or a substituted alkenyl group of any length, or a substituted alkynyl group, or a substituted cycloalkyl group, or a substituted aryl group, or a substituted heteroaryl group, or a substituted OR c Base or NR c Represents two groups, and the non-restrictive substituents that can be R1 are halogen atoms, OR c , or NR c There are two units, R c is a hydrogen atom or a cyclic, linear or branched alkyl, aryl or alkenyl group; and R2 is defined above for formula (I) and represents hydrogen, a substituted linear or branched alkyl group of any length, or a substituted alkenyl group, a substituted alkynyl group, a substituted cycloalkyl group, a substituted alkyl-substituted silyl group, an substituted aryl group, a substituted heteroaryl group, or an substituted acyl group of any length, wherein one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or acyl group of R2 are optionally replaced by heteroatoms selected from the group consisting of O, S, N, P, and Si, which are optionally replaced by one or more groups if possible.

[0073] In another embodiment, R1 is a hydrogen atom, optionally substituted (C1-C 20 )-alkyl group, optionally substituted (C2-C 20 )-alkenyl group, optionally substituted (C2-C 20 )-alkynyl group, optionally substituted (C3-C 20 )-cycloalkyl group, optionally substituted (C6-C 14 )-aryl group, optionally substituted (C5-C 14 )-heteroaryl group, OR c Base or NR c It has two groups, and optional substituents are halogen atoms, OR d , or NR d There are two units, R c or R d (C1-C) 20 )-alkyl group, (C2-C 20 )-alkenyl group, (C2-C 20 )-Alkynyl group, (C3-C 20 )-cycloalkyl group, or (C6-C 14 It is an aryl group.

[0074] In another embodiment, R1 is a hydrogen atom, optionally substituted (C1-C 10 )-alkyl group, optionally substituted (C2-C10 )-alkenyl group, optionally substituted (C2-C 10 )-alkynyl group, optionally substituted (C3-C 10 )-cycloalkyl group, optionally substituted (C6-C 10 )-aryl group. In another embodiment, R t The alkyl group is a hydrogen atom, an optionally substituted (C1-C6)-alkyl group, an optionally substituted (C2-C6)-alkenyl group, an optionally substituted (C2-C6)-alkynyl group, an optionally substituted (C3-C6)-cycloalkyl group, or an optionally substituted (C6)-aryl group. In another embodiment, one of the alkyl groups is fluorosubstituted, for example, a fluorosubstituted (C1-C6)-alkyl group, e.g., CF3.

[0075] In another embodiment, an optional substituent is (C1-C 10 )-alkyl group, (C2-C 10 )-alkenyl group, (C2-C 10 )-Alkynyl group, (C3-C 10 )-cycloalkyl group, or (C6-C 10 It is a (C1-C6)-aryl group. In another embodiment, it is a (C1-C6)-alkyl group, a (C2-C6)-alkenyl group, a (C2-C6)-alkynyl group, a (C3-C6)-cycloalkyl group, or a (C6)-aryl group.

[0076] In another embodiment, R1 is CF3, CH3, mesityl, or toryl.

[0077] Generally, compounds of formula (III) can be prepared, isolated, and then used.

[0078] In another embodiment, R1 in the compound of formula (II) is as defined in all embodiments for the compound of formula (I).

[0079] In one embodiment, R2 is (C1-C 20 )-alkyl group, (C2-C 20 )-alkenyl group, (C2-C 20)-Alkynyl group, (C3-C 20 )-Cycloalkyl group, -Si[(C1-C 20 )-alkyl]3 groups, (C6-C 14 )-aryl group, or (C5-C 14 )-heteroaryl group or acyl group-C(=O)-R' represents (C1-C 20 )-alkyl group, each group optionally contains one or more halogen atoms (F, Cl, Br or I), (C1-C 20 )-alkyl group, (C2-C 20 )-alkenyl group, (C2-C 20 )-alkynyl group, -OR d , or -NR d Substituted with 2, R c and R d Independently or simultaneously, hydrogen, (C1-C 20 )-alkyl, (C2-C 20 )-alkenyl, or (C2-C 20 )-Alkynyl, where one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl group of R2 are optionally replaced by heteroatoms selected from the group consisting of O, S, N, P and Si, and it is optionally one or more halogens (F, Cl, Br or I) or -(C1-C 20 )- Replaced with an alkyl group.

[0080] In one embodiment, R2 is (C1-C 10 )-alkyl group, (C2-C 10 )-alkenyl group, (C2-C 10 )-Alkynyl group, (C3-C 10 )-Cycloalkyl group, -Si[(C1-C 10 )-alkyl]3 groups, (C6-C 10 )-aryl group, or (C5-C 10 )-heteroaryl group or acyl group-C(=O)-R' represents (C1-C 10 )-alkyl group, each group optionally contains one or more halogen atoms (F, Cl, Br or I), -(C1-C 10)-alkyl group, (C2-C 10 )-alkenyl group, (C2-C 10 )-alkynyl group, -OR d , or -NR d Substituted with 2, R c and R d Hydrogen, (C1-C) independently or simultaneously 10 )-alkyl, (C2-C 10 )-alkenyl, or (C2-C 10 )-Alkynyl, where one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl group of R2 are optionally replaced by heteroatoms selected from the group consisting of O, S, N, P and Si, and it is optionally one or more halogens (F, Cl, Br or I) or -(C1-C 10 )- Replaced with an alkyl group.

[0081] In one embodiment, R2 represents a (C1-C6)-alkyl group, a (C2-C6)-alkenyl group, a (C2-C6)-alkynyl group, a (C3-C6)-cycloalkyl group, a -Si[(C1-C6)-alkyl]3 group, a phenyl group, or a (C5-C6)-heteroaryl group, or an acyl group -C(=O)-R', where R' is a (C1-C6)-alkyl group, each group optionally consisting of one or more halogen atoms (F, Cl, Br, or I), -(C1-C6)-alkyl group, (C2-C6)-alkenyl group, (C2-C6)-alkynyl group, -OR d , or -NR d Substituted with 2, R c and R d R2 is independently or simultaneously hydrogen, (C1-C6)-alkyl, (C2-C6)-alkenyl, or (C2-C6)-alkynyl, and one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or acyl group of R2 are optionally replaced by heteroatoms selected from the group consisting of O, S, N, P, and Si, which are optionally substituted with one or more halogens (F, Cl, Br, or I) or -(C1-C6)-alkyl groups, if possible.

[0082] In one embodiment, R2 represents a (C1-C6)-alkyl group, a -Si[(C1-C6)-alkyl]3 group, or a phenyl group.

[0083] In one embodiment, R2 represents three -Si[(C1-C6)-alkyl] groups. In one embodiment, R2 represents three -Si[(C1-C3)-alkyl] groups. In one embodiment, R2 represents three -Si(CH3) groups.

[0084] This disclosure also relates to cannabinol sulfonate esters of formula (III): [ka] During the ceremony, R1 is a hydrogen atom, a substituted linear or branched alkyl group of any length, or a substituted alkenyl group of any length, or a substituted alkynyl group, or a substituted cycloalkyl group, or a substituted aryl group, or a substituted heteroaryl group, or a substituted OR c Base or NR c Represents two groups, and the non-restrictive substituents that can be R1 are halogen atoms, OR c , or NR c There are two units, R c is a hydrogen atom or a cyclic, linear, or branched alkyl, aryl, or alkenyl group.

[0085] Generally, compounds of formula (III) can be prepared, isolated, and then used.

[0086] In one embodiment, R1 is a hydrogen atom, -OR c , -NR c 2. Fluorosubstituted (C1-C 20 )-alkyl, (C1-C 20 )-alkyl group, (C2-C 20 )-alkenyl group, (C2-C 20 )-Alkynyl group, (C3-C20 )-Cycloalkyl group, (C6-C 14 )-aryl group, or (C5-C 14 )- represents a heteroaryl group, where the latter six groups each optionally consist of one or more halogen atoms (F, Cl, Br, or I), -(C1-C 20 )-alkyl, (C2-C 20 )-alkenyl group, (C2-C 20 )-alkynyl group, -OR d , or -NR d Substituted with 2, R c and R d Hydrogen, (C1-C) independently or simultaneously 20 )-alkyl, (C2-C 20 )-alkenyl, or (C2-C 20 )-Alkinyl.

[0087] In another embodiment, R1 is a hydrogen atom, fluorosubstituted -(C1-C 20 )-alkyl, (C1-C 20 )-alkyl group, (C2-C 20 )-alkenyl group, (C2-C 20 )-Alkynyl group, (C3-C 20 )-Cycloalkyl group, (C6-C 14 )-aryl group, (C5-C 14 )- represents a heteroaryl group, where the latter six groups each optionally consist of one or more halogen atoms (F, Cl, Br, or I), -(C1-C 20 )-alkyl, (C2-C 20 )-alkenyl group, (C2-C 20 )-alkynyl group, -OR d , or -NR d Substituted with 2, R c and R d Hydrogen, (C1-C) independently or simultaneously 20 )-alkyl, (C2-C 20 )-alkenyl, or (C2-C 20 )-Alkinyl.

[0088] In another embodiment, R1 is a hydrogen atom, fluorosubstituted -(C1-C 10)-alkyl, (C1-C 10 )-alkyl group, (C2-C 10 )-alkenyl group, (C2-C 10 )-Alkynyl group, (C3-C 10 )-Cycloalkyl group, (C6-C 10 )-aryl group, (C5-C 10 )- represents a heteroaryl group, where the latter six groups each optionally consist of one or more halogen atoms (F, Cl, Br, or I), -(C1-C 20 )-alkyl, (C2-C 20 )-alkenyl group, or (C2-C 20 It is substituted with an alkynyl group.

[0089] In another embodiment, R1 represents a hydrogen atom, a fluorosubstituted -(C1-C6)-alkyl, (C1-C6)-alkyl, (C2-C6)-alkenyl group, (C2-C6)-alkynyl group, (C3-C6)-cycloalkyl, (C6)-aryl group, or (C5-C6)-heteroaryl group, where each of the latter six groups can optionally contain one or more halogen atoms (F, Cl, Br, or I), or -(C1-C 20 )-substituted with alkyl.

[0090] In another embodiment, R1 represents a hydrogen atom, a fluorosubstituted -(C1-C6)-alkyl, (C1-C6)-alkyl, or phenyl group, where the latter two groups each optionally consist of one or more halogen atoms (F, Cl, Br, or I), or -(C1-C 10 )-substituted with alkyl.

[0091] In another embodiment, R1 is a hydrogen atom, -CF3, [ka] or [ka] It represents.

[0092] In one embodiment, the compound of formula (III) has one of the following structures: [ka]

[0093] This disclosure relates to a cannabinol precursor of formula (IV): [ka]

[0094] The disclosure also relates to the cannabinol precursor of formula (IV), wherein one or more hydrogen atoms are replaced with deuterium.

[0095] The disclosure also relates to the cannabinol precursor of formula (IV), wherein one or more carbon-12 atoms are replaced with carbon-13 atoms.

[0096] In another embodiment, the present disclosure relates to a cannabinol precursor of formula (V): [ka] During the ceremony, One or more hydrogen atoms are replaced by deuterium, and / or one or more carbon-12 atoms are replaced by carbon-13; R2 is as defined in any of the embodiments above, and represents a substituted linear or branched alkyl group of any length, or a substituted alkenyl group, or a substituted alkynyl group, or a substituted cycloalkyl group, or a substituted aryl group, or a substituted heteroaryl group, or an substituted acyl group of any length, wherein one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or acyl group of R2 are optionally replaced with heteroatoms selected from the group consisting of O, S, N, P, and Si, which are optionally replaced with one or more groups if possible; and R3 and R4 represent a hydrogen atom, a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, or a substituted aryl group.

[0097] In one embodiment, R3 and R4 are hydrogen atoms, (C1-C 20 )-alkyl group, (C2-C 20 )-alkenyl group, (C2-C 20 )-Alkynyl group, (C3-C 20 )-Cycloalkyl group, (C6-C 14 )-aryl group, or (C5-C 14 )- represents a heteroaryl group, where the latter six groups each optionally consist of one or more halogen atoms (F, Cl, Br, or I), or -(C1-C 20 )-substituted with alkyl.

[0098] In one embodiment, R3 and R4 are hydrogen atoms, (C1-C 10 )-alkyl group, (C2-C 10 )-alkenyl group, (C2-C 10 )-Alkynyl group, (C3-C 10 )-Cycloalkyl group, (C6-C 10 )-aryl group, or (C5-C 10 )- represents a heteroaryl group, where the latter six groups each optionally consist of one or more halogen atoms (F, Cl, Br, or I), or -(C1-C 10 )-substituted with alkyl.

[0099] In one embodiment, R3 and R4 represent a hydrogen atom, a (C1-C6)-alkyl group, a (C2-C6)-alkenyl group, a (C2-C6)-alkynyl group, a (C3-C6)-cycloalkyl group, a (C6)-aryl group, or a (C5-C6)-heteroaryl group, where each of the latter six groups is optionally substituted with one or more halogen atoms (F, Cl, Br, or I) or -(C1-C6)-alkyl groups.

[0100] In another embodiment, the present disclosure relates to a cannabinol precursor of formula (VI): [ka] During the ceremony, One or more hydrogen atoms are replaced by deuterium, and / or one or more carbon-12 atoms are replaced by carbon-13; In any embodiment, R2 is as defined above, and represents a substituted linear or branched alkyl group of any length, or a substituted alkenyl group, or a substituted alkynyl group, or a substituted cycloalkyl group, or a substituted aryl group, or a substituted heteroaryl group, or an substituted acyl group of any length, wherein one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl group of R2 are optionally replaced with heteroatoms selected from the group consisting of O, S, N, P and Si, which are optionally replaced with one or more groups if possible; and R3 is as defined above in any embodiment and represents a hydrogen atom, a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, or a substituted aryl group.

[0101] In another embodiment, the present disclosure relates to a cannabinol compound of formula (VII): [ka] During the ceremony, One or more hydrogen atoms in the p-cymene fragment of the molecule are replaced by deuterium, and / or one or more carbon-12 atoms in the p-cymene fragment of the molecule are replaced by carbon-13; R2 is as defined above in any embodiment, and represents hydrogen, a substituted linear or branched alkyl group of any length, or a substituted alkenyl group, or a substituted alkynyl group, or a substituted cycloalkyl group, or a substituted aryl group, or a substituted heteroaryl group, or an substituted acyl group, where one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl group of R2 are optionally replaced by heteroatoms selected from the group consisting of O, S, N, P and Si, which are optionally replaced by one or more groups if possible; and R3 is as defined above in any embodiment and represents a hydrogen atom, a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, or a substituted aryl group.

[0102] The compounds disclosed may be used in transformations that include, but are not limited to, catalytic and non-catalytic carbon-carbon bond formation reactions, such as the Ullman, Suzuki-Miyaura, Negishi, Kumada, Sonogashira, and Stille reactions. Such carbon-carbon bond formation reactions are represented by formula (VII): [ka] and formula (VIII): [ka] The disclosure includes the use of the compounds for preparing cannabinol compounds. During the ceremony, R2 is as defined above in any embodiment, and represents hydrogen, a substituted linear or branched alkyl group of any length, or a substituted alkenyl group, or a substituted alkynyl group, or a substituted cycloalkyl group, or a substituted aryl group, or a substituted heteroaryl group, or an substituted acyl group, where one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl group of R2 are optionally replaced by heteroatoms selected from the group consisting of O, S, N, P and Si, which are optionally replaced by one or more groups if possible; and R3 is as defined in the above-mentioned optional embodiments and represents a hydrogen atom, a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, or a substituted aryl group.

[0103] In one embodiment, R2 in the compounds of formulas (VII) and (VIII) is as defined in each embodiment for the compounds of formulas (I) to (VI).

[0104] In one embodiment, R3 is a hydrogen atom, (C1-C 20 )-alkyl group, (C2-C 20 )-alkenyl group, (C2-C 20 )-Alkynyl group, (C3-C 20 )-Cycloalkyl group, (C6-C 14 )- Represents an aryl group, and the latter five groups each optionally consist of one or more halogen atoms (F, Cl, Br, or I), -(C1-C 20 )-alkyl, (C2-C 20 )-alkenyl group, (C2-C 20 )-Alkynyl group, (C6-C 14 )-aryl group, -OR d , or -NR d Substituted with 2, Rc and R d is independently or simultaneously hydrogen, (C1-C 20 )-alkyl, (C2-C 20 )-alkenyl, or (C2-C 20 )-alkynyl.

[0105] In one embodiment, R3 is a hydrogen atom, a (C1-C 20 )-alkyl group, a (C2-C 20 )-alkenyl group, a (C6-C 14 )-aryl group, and the latter three groups are each optionally substituted with one or more halogen atoms (F, Cl, Br or I), -(C1-C 10 )-alkyl, (C2-C 10 )-alkenyl group, (C2-C 10 )-alkynyl group, or (C6-C 10 )-aryl group.

[0106] In one embodiment, R3 is a hydrogen atom, a (C1-C 20 )-alkyl group, a (C6-C 10 )-aryl group, and the latter two groups are each optionally substituted with one or more phenyl groups.

[0107] In one embodiment, R3 represents a hydrogen atom or a (C1-C 20 )-alkyl group optionally substituted with a phenyl group.

[0108] In some other aspects, the present disclosure also relates to the preparation of cannabinol compounds of formula (VII) and formula (VIII), wherein one or more of the hydrogen atoms are replaced by deuterium.

[0109] In some other aspects, the present disclosure also relates to the preparation of cannabinol compounds of formula (VII) and formula (VIII), wherein one or more of the carbon-12 atoms are replaced by carbon-13 atoms.

[0110] In some other embodiments, the disclosure also relates to the preparation of cannabinol compounds of formula (VII) and formula (VIII), wherein one or more hydrogen atoms of the p-cymene fragment of the molecule are replaced with deuterium.

[0111] In some other embodiments, the disclosure also relates to the preparation of cannabinol compounds of formula (VII) and formula (VIII), wherein one or more carbon-12 atoms of the p-cymene fragment of the molecule are replaced with carbon-13 atoms.

[0112] (III) Disclosure process This disclosure also relates to a process for producing the compound of formula (IV), first the compound of formula (IX). [ka] and compounds of formula (X) [ka] This involves contacting the two substances in the presence of a catalyst to form a compound of formula (XI). [ka]

[0113] Next, compound (XI) is converted to compound (IV) by contacting the compound of formula (XI) with methylmagnesium Grignard, followed by the removal of the R2 group and ring closure.

[0114] Next, compound (IV) is converted to compound (III) by contacting the compound of formula (IV) in the presence of a sulfonating agent and a base.

[0115] Next, compound (III) is converted to compound (II) by contacting the compound of formula (III) in the presence of a suitable reagent and a base.

[0116] In some embodiments, the conversion of compound (IX) and compound (X) to compound (XI) requires a suitable catalyst. Suitable catalysts include, but are not limited to, transition metal salts and complexes, such as compounds of palladium, nickel, iron, ruthenium, cobalt, rhodium, iridium, and copper.

[0117] This disclosure also relates to processes for the catalytic and non-catalytic use of compounds of formula (I), formula (II), and formula (III) for the preparation of cannabinol compounds of formula (VII) and formula (VIII): [ka] and formula (VIII): [ka] During the ceremony, R2 represents hydrogen, a substituted linear or branched alkyl group of any length, or a substituted alkenyl group of any length, or a substituted alkynyl group, or a substituted cycloalkyl group, or a substituted aryl group, or a substituted heteroaryl group, or an substituted acyl group, where one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or acyl group of R2 are optionally replaced by heteroatoms selected from the group consisting of O, S, N, P, and Si, which are optionally replaced by one or more groups if possible; and R3 represents a hydrogen atom, a substituted linear or branched alkyl group of any length, a substituted alkenyl group of any length, a substituted alkynyl group, a substituted cycloalkyl group, or a substituted aryl group.

[0118] In one embodiment, R2 in the compounds of formulas (VII) and (VIII) is as defined in each embodiment for the compounds of formulas (I) to (VI).

[0119] In one embodiment, R3 represents a hydrogen atom, a (C1-C 20 )-alkyl group, a (C2-C 20 )-alkenyl group, a (C2-C 20 )-alkynyl group, a (C3-C 20 )-cycloalkyl group, a (C6-C 14 )-aryl group, and the latter five groups are each optionally substituted with one or more halogen atoms (F, Cl, Br or I), -(C1-C 20 )-alkyl, (C2-C 20 )-alkenyl group, (C2-C 20 )-alkynyl group, (C6-C 14 )-aryl group, -OR d , or -NR d 2, where R c and R d are independently or simultaneously hydrogen, (C1-C 20 )-alkyl, (C2-C 20 )-alkenyl, or (C2-C 20 )-alkynyl.

[0120] In one embodiment, R3 represents a hydrogen atom, a (C1-C 20 )-alkyl group, a (C2-C 20 )-alkenyl group, a (C6-C 14 )-aryl group, and the latter three groups are each optionally substituted with one or more halogen atoms (F, Cl, Br or I), -(C1-C 10 )-alkyl, (C2-C 10 〚修正:(C2-Cに修正)〛 )-alkenyl group, (C2-C 10 )-alkynyl group, or (C6-C 10 )-aryl group.

[0121] In one embodiment, R3 represents a hydrogen atom, a (C1-C 20 )-alkyl group, a (C6-C 10 )-aryl group, and the latter two groups are each optionally substituted with one or more phenyl groups.

[0122] In one embodiment, R3 is substituted with a hydrogen atom or optionally a phenyl group (C1-C 20 )- Represents an alkyl group.

[0123] In some other embodiments, the disclosure also relates to the preparation of cannabinol compounds of formula (VII) and formula (VIII), wherein one or more hydrogen atoms are replaced with deuterium.

[0124] In some other embodiments, the disclosure also relates to the preparation of cannabinol compounds of formula (VII) and formula (VIII), wherein one or more carbon-12 atoms are replaced with carbon-13 atoms.

[0125] In some other embodiments, the disclosure also relates to the preparation of cannabinol compounds of formula (VII) and formula (VIII), wherein one or more hydrogen atoms of the p-cymene fragment of the molecule are replaced with deuterium.

[0126] Carbon-carbon bond formation reactions for the preparation of cannabinol compounds of formulas (VII) and (VIII) include, but are not limited to, the catalytic and uncatalytic Ullman, Suzuki-Miyaura, Negishi, Kumada, Sonogashira, and Stille reactions.

[0127] In some embodiments of the disclosure, a compound of formula (I), formula (II), or formula (III) is contacted with a nucleophilic R3 group, R3-W (wherein R3 is as defined above and is nucleophilic, and W is an electrophilic group), for example, a boron-containing compound, for example R3-B(OH)2, R3-B(OR)2, or R3-BF3K; or a Grignard compound, for example R3-MgX; or an organozinc compound, for example R3-ZnX, in the presence or absence of a catalyst, to produce a compound of formula (VII) or formula (VIII).

[0128] In one embodiment, the compound of formula (I) is prepared as shown in the following example: [ka]

[0129] This disclosure also first describes the compound of formula (IX). [ka] and compounds of formula (XII) [ka] The present invention relates to a process for producing a compound of formula (V), comprising contacting the compound of formula (V) in the presence of a catalyst to form a compound of formula (V). [ka] .

[0130] Next, compound (V) is converted to compound (VI) by contacting the compound of formula (V) with methylmagnesium Grignard: [ka] .

[0131] Compound (VI) is converted to a cannabinol compound by removal of the R2 group and ring closure.

[0132] In some embodiments of the disclosure, the catalytic system characterizing the process of the disclosure may include a base. In some embodiments, the base may be any conventional base. In some embodiments, non-limiting examples include: organic non-coordinating bases, e.g., DBU; alkali or alkaline earth metal carbonates; carboxylates, e.g., sodium or potassium acetate; or alkoxides or hydroxides. Preferred bases are alkoxides or hydroxides selected from the group consisting of compounds of formula (RO)2M' and ROM'', where M' is an alkaline earth metal, M'' is an alkali metal, and R represents hydrogen or a linear or branched alkyl group.

[0133] The catalyst can be added to the reaction medium at a wide range of concentrations. In non-limiting examples, catalyst concentrations can range from 0.001% to 50% relative to the amount of substrate, thus representing substrate / catalyst (S / cat) ratios of 100,000 to 2, respectively. Preferably, the complex concentration is 0.01% to 10%, i.e., within S / cat ratios of 10,000 to 10, respectively. In some preferred embodiments, concentrations in the range of 0.1% to 5% (corresponding to S / cat ratios of 1000 to 20, respectively) are used.

[0134] If necessary, the useful amount of base added to the reaction mixture can be included in a relatively wide range. In some embodiments, non-limiting examples include: a range of 1 to 100 molar equivalents relative to the substrate. However, it should be noted that it is also possible to add small amounts of base (e.g., base / substrate = 1:3) to achieve high yields.

[0135] In the processes of this disclosure, the catalytic reaction may be carried out in the presence or absence of a solvent. Where a solvent is required or used for practical reasons, then any solvent currently used in a catalytic reaction may be used for the purposes of this disclosure. Non-limiting examples include aromatic solvents, e.g., benzene, toluene, or xylene; hydrocarbon solvents, e.g., hexane or cyclohexane; ethers, e.g., tetrahydrofuran; or even primary or secondary alcohols; or water; or mixtures thereof. Those skilled in the art will be able to select the most advantageous solvent in each case to optimize the catalytic reaction.

[0136] The temperature range in which the catalytic reaction can be carried out is -30°C to 200°C, more preferably 0°C to 100°C. Of course, those skilled in the art can also select a preferred temperature.

[0137] Standard catalytic conditions, as used herein, typically mean a mixture of the substrate with or without a base, and optionally in the presence of a solvent, which is then treated with the desired reactants at a selected temperature in air or under an inert atmosphere of nitrogen or argon gas. Varying the reaction conditions, including, for example, the catalyst, temperature, solvent, and reagents, to optimize the yield of the desired product will be well within the capabilities of those skilled in the art.

[0138] The present disclosure is described in the following examples, which are provided to aid in understanding the disclosure and should not be construed in any way as limiting the scope of the present disclosure as defined in the claims that follow.

[0139] (IV) Benzylcannabinol This disclosure also includes benzylcannabinol having the following structure and all its isomers, and their salts: [ka] During the ceremony, R2 is defined above in any paragraph for compounds of formulas (III) to (VII); R5 and R6 are one or more substituents, hydrogen, halo, -OR c , -NR c 2. Carboxylate (-COOR, where R is H or (C1-C6)-alkyl), phosphate, sulfate, (C1-C 20 )-alkyl group, (C2-C 20 )-alkenyl group, (C2-C 20 )-Alkynyl group, (C3-C 20 )-Cycloalkyl group, (C6-C 14 )-aryl group, or (C5-C 14 )-heteroaryl group, R c and R d Hydrogen, (C1-C) independently or simultaneously 20 )-alkyl, (C2-C 20 )-alkenyl, or (C2-C 20)-Alkinyl; X is (C1-C 10 -alkylene) or (C2-C 10 -Alkenylene)

[0140] In one embodiment, R5 and R6 are one or more substituents, such as hydrogen, halo, (C1-C 10 )-alkyl group, or (C6-C 10 It is an aryl group. In one embodiment, R5 and R6 are one or more substituents, which are hydrogen, a halo, a (C1-C6)-alkyl group, or a phenyl group.

[0141] In one embodiment, X is (C1-C6-alkylene) or (C2-C6-alkenylene). In another embodiment, X is (C1-C2-alkylene) or (C2-alkenylene).

[0142] In one embodiment, the compound of formula (X) is one of the following compounds: [ka]

[0143] Examples The disclosure is described in further detail below by the following examples. Temperatures are given in Celsius, and abbreviations have their usual meanings in this art.

[0144] All procedures described herein were performed under an inert atmosphere unless otherwise specified. All preparations and operations under air-free conditions were carried out in a dry, oxygen-free solvent using standard Schlenk, vacuum line, and glove box techniques under an N2 or Ar atmosphere. The deuterated solvent was degassed and dried on an activated molecular sieve. NMR spectra were recorded on a 400 MHz spectrometer. 1 H is 400MHz, 13 Regarding C, 100MHz, 19 Regarding F, 376MHz and 31 P is 162MHz). All 31The P chemical shift was measured relative to 85% H3PO4 as an external standard. 1 H and 13 The 1C chemical shift was measured against the partially deuterated solvent peak, but this has been reported for tetramethylsilane.

[0145] Example 1. Preparation of methyl 2',4',6'-trimethoxy-5-methylbiphenyl-2-carboxylate [ka] Anhydrous THF (12 ml) was added to 1,3,5-trimethoxybenzene (5.35 g, 32 mmol) under argon. A solution of n-butyllithium (20 ml, 1.6 M hexane solution, 32 mmol) was added, and the mixture was refluxed at 40°C for 2 hours. The solvent was removed under reduced pressure, anhydrous THF (20 ml) was added, and the resulting yellow solution was cooled to 0°C. Solid ZnBr2 (7.22 g, 32 mmol) was added under argon flow. The mixture spontaneously boiled. Stirring was continued for 30 minutes. Catalyst PdCl2 (dppf) (0.35 g, 0.48 mmol) was added, followed by methyl 2-bromo-4-methylbenzoate (7.10 g, 31 mmol), and the mixture was heated at 70°C for 72 hours. The reaction was stopped with water, followed by ammonium chloride solution. The aqueous layer was extracted with CH2Cl2 (3 × 50 ml), the organic fraction was combined, dried (MgSO4), filtered, and evaporated to dryness. The product was purified by column chromatography (EA / hexane, 1:4) to obtain a crystalline white solid. Yield = 7.20 g.

[0146] Example 2. Preparation of 2-(2',4',6'-trimethoxy-5-methylbiphenyl-2-yl)propan-2-ol [ka] A solution of MeMgBr (35 ml, 3M ether solution, 105 mmol) was added under argon to a solution of THF (60 ml) containing methyl 2',4',6'-trimethoxy-5-methylbiphenyl-2-carboxylate (7.2 g, 23 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction was stopped with water, followed by ammonium chloride solution. The aqueous layer was extracted with CH2Cl2 (3 × 50 ml), the organic fractions were combined, dried (MgSO4), filtered, and evaporated to dryness. Yield = 7.18 g.

[0147] Example 3. Preparation of 6,6,9-trimethyl-6H-benzo[c]chromene-1,3-diol [ka] Pyridinium bromide (25.5 g, 159 mmol), hydrobromic acid (48%, 13.4 g, 79.5 mmol), and acetic anhydride (30 ml) were added to 2-(2',4',6'-trimethoxy-5-methylbiphenyl-2-yl)propan-2-ol (5.0 g, 15.9 mmol), and the mixture was heated at 115°C for 18 hours. It was cooled to room temperature and diluted with water. It was neutralized with NaOH solution to approximately pH 6 and then extracted with CH2Cl2 (3 × 50 ml). The organic fraction was dried with (MgSO4), then filtered, and evaporated to dryness. The residue was suspended in a mixture of H2SO4 (2 M, 25 ml) and ethanol (25 ml) and stirred for 18 hours. It was neutralized with NaOH solution to approximately pH 6 and then extracted with CH2Cl2 (3 × 50 ml). The organic fraction was dried (MgSO4), filtered, and evaporated to dryness. The product was obtained as a white crystalline solid by recrystallization from hexane. Yield = 3.30 g.

[0148] Example 4. Preparation of 1-hydroxy-6,6,9-trimethyl-6H-benzo[c]chromen-3-yltrifluoromethanesulfonate [ka] Triethylamine (5.1 g, 50.4 mmol) was added to a solution of dichloromethane (50 ml) containing 6,6,9-trimethyl-6H-benzo[c]chromene-1,3-diol (4.31 g, 16.8 mmol), and the mixture was cooled to 0°C. Solid N-phenyl-bis(trifluoromethanesulfonimide) (6.30 g, 17.7 mmol) was added over 30 minutes, and the mixture was stirred overnight at room temperature. The reaction was stopped with water (50 ml), and the phases were separated. The aqueous layer was extracted with dichloromethane (3 × 25 ml), and the organic layers were combined and dried (MgSO4). This was filtered through a short pad of silica gel, and the solvent was removed under reduced pressure. The product was obtained as a crystalline white solid by chromatography using hexane / EA(15 / 1). Yield = 4.32 g.

[0149] Example 5. Preparation of 6,6,9-trimethyl-1-(trimethylsilyloxy)-6H-benzo[c]chromen-3-yltrifluoromethanesulfonate [ka] TMSCl (1.45 g, 13.4 mmol) was added at room temperature to a mixture of CH2Cl2 (25 ml) containing 1-hydroxy-6,6,9-trimethyl-6H-benzo[c]chromen-3-yltrifluoromethanesulfonate (2.6 g, 6.67 mmol) and NEt3 (1.35 g, 13.4 mmol). The mixture was stirred overnight, then filtered, and the solid was washed with dichloromethane. Volatile substances were removed from the combined filtrate under reduced pressure. The residue was suspended in hexane (25 ml) and stirred at room temperature for 2 hours. The mixture was filtered, and the solvent was removed. The residue was dried under vacuum, and the product was obtained as a viscous yellow oil. Yield = 2.98 g.

[0150] Example 6. Preparation of 6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol (cannabinol, CBN) [ka] A solution of n-pentyl zinc bromide (5.56 ml of 0.5 M THF solution, 2.82 mmol) was added to a mixture of THF (4 ml) containing 6,6,9-trimethyl-1-(trimethylsilyloxy)-6H-benzo[c]chromen-3-yltrifluoromethanesulfonate (1.0 g, 2.17 mmol) and PdCl2 (dppf) (40 mg, 0.054 mmol). The mixture was stirred under argon at 45°C for 18 hours. It was cooled to room temperature, water (10 ml) was added, followed by 2 M H2SO4 (10 ml), and the mixture was stirred at room temperature for 1 hour. The phases were separated, and the aqueous layer was extracted with ether (3 × 10 ml). The organic layers were combined and dried (MgSO4), filtered, and evaporated to dryness. The residue was dissolved in hexane and filtered through a short pad of silica gel. Silica was washed with hexane, the filtrates were combined, and the mixture was evaporated to dryness to obtain the product as a pale yellow oil. Yield = 0.65 g.

[0151] Example 7. Preparation of 6,6,9-trimethyl-3-propyl-6H-benzo[c]chromen-1-ol (cannabivarin, CBNV) [ka] This was prepared using n-propyl zinc bromide according to the procedure described in Example 6. The product was isolated as a pale yellow oil. Yield = 0.58 g.

[0152] Example 8. Preparation of 3-heptyl-6,6,9-trimethyl-6H-benzo[c]chromen-1-ol (cannabiphorol, CBNP) [ka] This was prepared using n-heptyl zinc bromide according to the procedure described in Example 6. The product was isolated as a pale yellow oil. Yield = 0.72 g.

[0153] Example 9. Preparation of 6,6,9-trimethyl-3-phenethyl-6H-benzo[c]chromen-1-ol [ka] This was prepared using phenethyl zinc bromide according to the procedure described in Example 6. The product was isolated as a pale yellow oil. Yield = 0.74 g.

[0154] Example 10. Preparation of 3-butyl-6,6,9-trimethyl-6H-benzo[c]chromen-1-ol (cannabibutol, CBNB) [ka] This was prepared using butyl zinc bromide according to the procedure described in Example 6. The product was isolated as a pale yellow oil. Yield = 0.62 g.

[0155] Example 11. Preparation of 3-hexyl-6,6,9-trimethyl-6H-benzo[c]chromen-1-ol (cannabihexol, CBNH) [ka] This was prepared using hexyl zinc bromide according to the procedure described in Example 6. The product was isolated as a pale yellow oil. Yield = 0.67 g.

[0156] Example 12. Preparation of 3-ethyl-6,6,9-trimethyl-6H-benzo[c]chromen-1-ol [ka] A solution of ethylmagnesium bromide (5.2 ml of 1.0 M THF solution, 5.2 mmol) was added to zinc bromide (1.17 g, 5.21 mmol). The resulting solution was added under argon to a mixture of THF (4 ml) containing 6,6,9-trimethyl-1-(trimethylsilyloxy)-6H-benzo[c]chromen-3-yltrifluoromethanesulfonate (0.8 g, 1.74 mmol) and PdCl2 (dppf) (32 mg, 0.043 mmol). The mixture was stirred under argon at 45°C for 18 hours. It was cooled to room temperature, water (10 ml) was added, followed by 2 M H2SO4 (10 ml), and the mixture was stirred at room temperature for 1 hour. The phases were separated, and the aqueous layer was extracted with ether (3 × 10 ml). The organic layers were combined and dried (MgSO4), filtered, and evaporated to dryness. The residue was dissolved in hexane and filtered through a short pad of silica gel. The silica was washed with hexane, the filtrates were combined, and the mixture was evaporated to dryness to obtain the product as a pale yellow oil. Yield = 0.38 g.

[0157] Example 13. Preparation of 3,6,6,9-tetramethyl-6H-benzo[c]chromen-1-ol [ka] This was prepared using methylmagnesium bromide according to the procedure described in Example 12. The product was isolated as a pale yellow oil. Yield = 0.37 g.

[0158] Example 14. Preparation of 2-(2',4',6'-trimethoxy-5-methyl-[1,1'-biphenyl]-2-yl)propan-1,1,1,3,3,3-d6-2-ol [ka] This was prepared using CD3MgBr according to the procedure described in Example 2.

[0159] Example 15. Preparation of 9-methyl-6,6-bis(methyl-d3)-6H-benzo[c]chromene-1,3-diol [ka] This was prepared using the procedure described in Example 3.

[0160] Example 16. Preparation of 1-hydroxy-9-methyl-6,6-bis(methyl-d3)-6H-benzo[c]chromen-3-yltrifluoromethanesulfonate [ka] This was prepared using the procedure described in Example 4.

[0161] Example 17. Preparation of 9-methyl-6,6-bis(methyl-d3)-1-((trimethylsilyl)oxy)-6H-benzo[c]chromen-3-yltrifluoromethanesulfonate [ka] This was prepared using the procedure described in Example 5.

[0162] Example 18. Preparation of 9-methyl-6,6-bis(methyl-d3)-3-pentyl-6H-benzo[c]chromen-1-ol [ka] This was prepared using the procedure described in Example 6.

[0163] Example 19.2-(2',4',6'-trimethoxy-5-methyl-[1,1'-biphenyl]-2-yl)propan-2-ol-1,3- 13 Preparation of C2 [ka] This can be done using the procedure described in Example 2. 13 It was prepared using CH3MgBr.

[0164] Example 20. 9-methyl-6,6-di(methyl- 13Preparation of C)-6H-benzo[c]chromene-1,3-diol [ka] This was prepared using the procedure described in Example 3.

[0165] Example 21. 1-Hydroxy-9-methyl-6,6-di(methyl- 13 Preparation of C)-6H-benzo[c]chromen-3-yltrifluoromethanesulfonate [ka] This was prepared using the procedure described in Example 4.

[0166] Example 22. 9-methyl-6,6-di(methyl- 13 Preparation of C)-1-((trimethylsilyl)oxy)-6H-benzo[c]chromen-3-yltrifluoromethanesulfonate [ka] This was prepared using the procedure described in Example 5.

[0167] Example 23. 9-methyl-6,6-di(methyl- 13 Preparation of C)-3-pentyl-6H-benzo[c]chromen-1-ol [ka] This was prepared using the procedure described in Example 6.

[0168] Example 24. Preparation of 1-methoxy-6,6,9-trimethyl-6H-benzo[c]chromen-3-yltrifluoromethanesulfonate [ka] Anhydrous acetonitrile (10 ml) was added to a mixture of 1-hydroxy-6,6,9-trimethyl-6H-benzo[c]chromen-3-yltrifluoromethanesulfonate (1.0 g, 2.57 mmol), methyl iodide (0.44 g, 3.1 mmol), and potassium carbonate (0.31 g, 3.1 mmol). The suspension was vigorously stirred under argon for 12 hours at room temperature. The mixture was evaporated to dryness, and the residue was extracted with ether. The ether extract was washed with water and dried (MgSO4). It was filtered, and the solvent was removed under reduced pressure. The residue was dried under vacuum, and the product was obtained as a pale yellow oil. Yield = 1.02 g.

[0169] Example 25. Preparation of methylmethyl 2',6'-dimethoxy-5-methyl-4'-pentylbiphenyl-2-carboxylate [ka] Anhydrous THF (12 ml) was added to 1,3-dimethoxy-5-pentylbenzene (6.66 g, 32 mmol) under argon. A solution of n-butyllithium (20 ml, 1.6 M hexane solution, 32 mmol) was added, and the mixture was refluxed at 40°C for 2 hours. The solvent was removed under reduced pressure, anhydrous THF (20 ml) was added, and the resulting yellow solution was cooled to 0°C. Solid ZnBr2 (7.22 g, 32 mmol) was added under argon flow. The mixture spontaneously boiled. Stirring was continued for 30 minutes. Catalyst PdCl2 (dppf) (0.35 g, 0.48 mmol) was added, followed by methyl 2-bromo-4-methylbenzoate (7.10 g, 31 mmol), and the mixture was heated at 70°C for 72 hours. The reaction was stopped with water, followed by ammonium chloride solution. The aqueous layer was extracted with CH2Cl2 (3 × 50 ml), the organic fraction was combined, dried (MgSO4), filtered, and evaporated to dryness. The product was purified by column chromatography (EA / hexane, 1:20) to obtain a crystalline white solid. Yield = 7.30 g.

[0170] Example 26. Preparation of 2-(2',6'-dimethoxy-5-methyl-4'-pentylbiphenyl-2-yl)propan-2-ol [ka] A solution of MeMgBr (35 ml, 3M ether solution, 105 mmol) was added under argon to a solution of THF (60 ml) containing methyl 2',6'-dimethoxy-5-methyl-4'-pentylbiphenyl-2-carboxylate (7.2 g, 20.2 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction was stopped with water, followed by ammonium chloride solution. The aqueous layer was extracted with CH2Cl2 (3 × 50 ml), the organic fractions were combined, dried (MgSO4), filtered, and evaporated to dryness. Yield = 7.15 g.

[0171] Example 27. Preparation of 6,6,9-trimethyl-3-pentyl-6H-benzo[c]chromen-1-ol (cannabinol) [ka] Pyridinium bromide (13.73 g, 85.6 mmol), hydrobromic acid (48%, 3.48 g, 42.9 mmol), and acetic anhydride (16 ml) were added to 2-(2',6'-dimethoxy-5-methyl-4'-pentylbiphenyl-2-yl)propan-2-ol (2.7 g, 8.59 mmol), and the mixture was heated at 115°C for 18 hours. It was cooled to room temperature and diluted with water. It was neutralized with NaOH solution to approximately pH 6, and then extracted with CH2Cl2 (3 × 50 ml). The organic fraction was dried over (MgSO4), then filtered, and evaporated to dryness. The residue was suspended in a mixture of H2SO4 (2 M, 25 ml) and ethanol (25 ml) and stirred for 18 hours. The solution was neutralized with NaOH to approximately pH 6, and then extracted with CH2Cl2 (3 × 50 ml). The organic fraction was dried with (MgSO4), filtered, and evaporated to dryness. The residue was dissolved in hexane and filtered through a short silica gel pad. The filtrate was evaporated to dryness, and the product was obtained as a pale yellow oil. Yield = 1.81 g.

[0172] Example 28. Preparation of 2-(2',6'-dimethoxy-5-methyl-4'-pentyl-[1,1'-biphenyl]-2-yl)propan-1,1,1,3,3,3-d6-2-ol [ka] This was prepared using CD3MgBr according to the procedure described in Example 26.

[0173] Example 29. 2-(2',6'-dimethoxy-5-methyl-4'-pentyl-[1,1'-biphenyl]-2-yl)propan-2-ol-1,3- 13 Preparation of C2 [ka] This can be done using the procedure described in Example 26. 13 It was prepared using CH3MgBr.

[0174] While the foregoing disclosure has been described in some detail for clarity and understanding, those skilled in the art will recognize by reading this disclosure that various modifications in form and detail are possible without departing from the true scope of this disclosure in the attached claims.

[0175] All publications, patents, and patent applications are incorporated herein by reference in the same way that each individual publication, patent, and patent application is specifically and individually incorporated by reference in whole.

Claims

1. Equation (I): 【Chemistry 1】 A compound of which, in the formula, LG is a sulfonate, halide, boronate, or MXn, where M is Li, Mg, Zn, Sn, B, or Si, X is a halide, OH, or OR, R is (C1-C20)-alkyl, (C2-C20)-alkenyl, (C2-C20)-alkynyl, (C3-C20)-cycloalkyl, or (C6-C20)-aryl, and n is 0, 1, 2, or 3; R ２ is hydrogen, (C1-C20)-alkyl group, (C2-C20)-alkenyl group, (C2-C20)-alkynyl group, (C3-C20)-cycloalkyl group, -Si[(C1-C20)-alkyl]3 group, (C6-C14)-aryl group, or (C5-C14)-heteroaryl group, or acyl group -C(=O)-R', where R' is (C1-C20)-alkyl group, and each group is either unsubstituted or has one or more halogen atoms (F, Cl, Br, or I), (C1-C20)-alkyl group, (C2-C20)-alkenyl group, (C2-C20)-alkynyl group, or -ORd , or is substituted with -NRd2, where Rc and Rd are independently or simultaneously hydrogen, (C1-C20)-alkyl, (C2-C20)-alkenyl, or (C2-C20)-alkynyl, R ２ One or more carbon atoms in the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group, or acyl group may be replaced by heteroatoms selected from the group consisting of O, S, N, P, and Si, which, if possible, are unsubstituted or substituted with one or more halogen atoms (F, Cl, Br, or I) or (C1-C20)-alkyl groups. compound.

2. X is a halide, OH, or OR, and R is (C １ -C ６ )-alkyl, (C ２ -C ６ )-alkenyl group, (C ２ -C ６ )-alkynyl group, (C ３ -C ６ )-cycloalkyl group, or (C ６ )-aryl group, the compound of formula (I) according to claim 1.

3. The compound of formula (I) according to claim 1 or 2, wherein LG is a halide, sulfonate, or boronate.

4. The boronate leaving group is -B (OR) ２ And R is H, (C １ -C ２０ )-alkyl group, (C ２ -C ２０ )-alkenyl group, (C ２ -C ２０ )-Alkynyl group, (C ３ -C ２０ )-cycloalkyl group, or (C ６ -C １４ A compound of formula (I) according to claim 3, wherein the compound is an aryl group.

5. Boronate leaving group is BF ３ A compound of formula (I) according to claim 3, wherein K.

6. The sulfonate group is of formula: 【Chemistry 2】 It is, and in the formula, R ｔ This includes hydrogen atoms, linear or branched unsubstituted or substituted (C1-C20) alkyl groups, unsubstituted or substituted (C2-C20) alkenyl groups, unsubstituted or substituted (C2-C20) alkynyl groups, unsubstituted or substituted (C3-C20) cycloalkyl groups, unsubstituted or substituted (C6-C14) aryl groups, unsubstituted or substituted (C5-C14) heteroaryl groups, OR ｃ Base or NR ｃ ２ The group is such that the substituent is a halogen atom, ORd, or NRd. ２ It is a base, R ｃ The compound of formula (I) according to claim 3, wherein R d is a hydrogen atom, a (C1-C20)-alkyl group, a (C2-C20)-alkenyl group, a (C2-C20)-alkynyl group, a (C3-C20)-cycloalkyl group, or a (C6-C14)-aryl group.

7. R ｔ (C) is a hydrogen atom, either unsubstituted or substituted. １ -C １０ )-alkyl group, unsubstituted or substituted (C ２ -C １０ )-Alkenyl group, unsubstituted or substituted (C ２ -C １０ )-Alkynyl group, unsubstituted or substituted (C ３ -C １０ )-cycloalkyl group, or unsubstituted or substituted (C ６ -C １０ A compound of formula (I) according to claim 6, wherein the compound is an aryl group.

8. The compound of formula (I) according to claim 6, wherein the sulfonate group is a triflate group, a mesylate group, or a tosylate group.

9. R ２ is (C １ -C ６ )-alkyl group, (C ２ -C ６ )-alkenyl group, (C ２ -C ６ )-Alkynyl group, (C ３ -C ６ )-cycloalkyl group,-Si[(C １ -C ６ ) - alkyl] ３ group, phenyl group, or (C ５ -C ６ ) represents a heteroaryl group or acyl group -C(=O)-R', where R' is (C １ -C ６ ) - Alkyl alkyl group, each group is either unsubstituted or has one or more halogen atoms (F, Cl, Br, or I), - (C １ -C ６ )-alkyl group, (C ２ -C ６ )-alkenyl group, (C ２ -C ６ ) -Alkynyl group, -OR ｄ , or -NR ｄ ２ It is replaced with R ｃ and R ｄ Hydrogen, (C) independently or simultaneously １ -C ６ )-alkyl, (C ２ -C ６ )-Alkenyl, or (C ２ -C ６ ) - Alkinyl, R ２ One or more carbon atoms in the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group, or acyl group may be replaced by a heteroatom selected from the group consisting of O, S, N, P, and Si, which may, if possible, be unsubstituted or have one or more halogens (F, Cl, Br, or I), or -(C). １ -C ６ A compound of formula (I) according to claim 1, which is substituted with an alkyl group.

10. Formula (II): 【Transformation 3】 A compound of formula (I) according to claim 1, wherein, R １ Rc or Rd is a hydrogen atom, an unsubstituted or substituted (C1-C20)-alkyl group, an unsubstituted or substituted (C2-C20)-alkenyl group, an unsubstituted or substituted (C2-C20)-alkynyl group, an unsubstituted or substituted (C3-C20)-cycloalkyl group, an unsubstituted or substituted (C6-C14)-aryl group, an unsubstituted or substituted (C5-C14)-heteroaryl group, an OR c group, or an NR c2 group, where the substituent is a halogen atom, an OR d, or an NR d2 group, and Rc or Rd is a hydrogen atom, an (C1-C20)-alkyl group, an (C2-C20)-alkenyl group, an (C2-C20)-alkynyl group, or a (C3 (C20)-cycloalkyl group, or (C6-C14)-aryl group; R ２ is represented by hydrogen, (C1-C20)-alkyl group, (C2-C20)-alkenyl group, (C2-C20)-alkynyl group, (C3-C20)-cycloalkyl group, -Si[(C1-C20)-alkyl]3 group, (C6-C14)-aryl group, or (C5-C14)-heteroaryl group, or acyl group -C(=O)-R', where R' is (C1-C20)-alkyl group, and each group is either unsubstituted or contains one or more halogen atoms (F, Cl, Br or I), (C1-C20)-alkyl group, (C2-C20)-alkenyl group, (C2-C20)-alkynyl group, or -OR d is substituted with -NRd2, where Rc and Rd are independently or simultaneously hydrogen, (C1-C20)-alkyl, (C2-C20)-alkenyl, or (C2-C20)-alkynyl, and one or more carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, or acyl group of R2 may be replaced with a heteroatom selected from the group consisting of O, S, N, P, and Si, which, if possible, is unsubstituted or substituted with one or more halogen atoms (F, Cl, Br, or I) or (C1-C20)-alkyl groups. compound.

11. R １ (C) is a hydrogen atom, either unsubstituted or substituted. １ -C ６ )-alkyl group, unsubstituted or substituted (C ２ -C ６ )-Alkenyl group, unsubstituted or substituted (C ２ -C ６ )-Alkynyl group, unsubstituted or substituted (C ３ -C ６ )-cycloalkyl group, or unsubstituted or substituted (C ６ A compound of formula (II) according to claim 10, wherein the compound is an aryl group.

12. R １ is CF ３ , CH ３ , mesityl or tolyl, the compound of formula (II) according to claim 11.

13. R ２ is a (C １ -C ６ )-alkyl group, a (C ２ -C ６ )-alkenyl group, a (C ２ -C ６ )-alkynyl group, a (C ３ -C ６ )-cycloalkyl group, -Si[(C １ -C ６ )-alkyl] ３ group, a phenyl group, or a (C ５ -C ６ )-heteroaryl group, or an acyl group -C(=O)-R', where R' is a (C １ -C ６ )-alkyl group, and each group is independently either unsubstituted or substituted with one or more halogen atoms, -(C １ -C ６ )-alkyl group, a (C ２ -C ６ )-alkenyl group, a (C ２ -C ６ )-alkynyl group, -OR ｄ , or -NR ｄ ２ , and R ｃ and R ｄ are independently or simultaneously hydrogen, (C １ -C ６ )-alkyl, (C ２ -C ６ )-alkenyl, or (C ２ -C ６ )-alkynyl, and one or more of the carbon atoms in the alkyl group, alkenyl group, alkynyl group, cycloalkyl group, aryl group, heteroaryl group or acyl group of R ２ may be replaced by a heteroatom selected from the group consisting of O, S, N, P and Si, and it is, if possible, either unsubstituted or substituted with one or more halogens, or a -(C １ -C ６ )-alkyl group, the compound of formula (II) according to claim 10.

14. R ２ is -Si[(C １ -C ６ ) - alkyl] ３ A compound of formula (II) according to claim 13, representing a group.

15. Formula (III): 【Chemistry 4】 A compound of formula (I) according to claim 1, wherein, R １ Rc represents a hydrogen atom, -OR c, -NR c2, a fluorosubstituted -(C1-C20)-alkyl, (C1-C20)-alkyl, (C2-C20)-alkenyl group, (C2-C20)-alkynyl group, (C3-C20)-cycloalkyl, (C6-C14)-aryl group, or (C5-C14)-heteroaryl group, and the last six groups are each unsubstituted or substituted with one or more halogen atoms (F, Cl, Br, or I), (C1-C20)-alkyl, (C2-C20)-alkenyl group, (C2-C20)-alkynyl group, -OR d, or -NR d2, and R c and R d is independently or simultaneously hydrogen, (C1-C20)-alkyl, (C2-C20)-alkenyl, or (C2-C20)-alkynyl. compound.

16. R １ is a hydrogen atom, fluorosubstituted - (C １ -C ６ )-alkyl, (C １ -C ６ ) - Represents an alkyl group or a phenyl group, where the last two groups are either unsubstituted or have one or more halogen atoms, or - (C １ -C １０ A compound of formula (III) according to claim 15, which is substituted with an alkyl group.

17. The compound of formula (I) described in claim 1 is as follows: 【Transformation 5】

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