Synthesis of cannabidiol and its analogues, as well as related compounds, formulations, and methods of use.

Abstract

This invention provides methods for the synthesis of cannabidiol and its analogues, as well as related compounds, formulations, and methods of use. [Solution] Methods are provided for the synthesis of oliveitol, oliveitol analogs, cannabidiol (CBD), CBD analogs, and other cannabinoids. One method uses phloroglucinol or phloroglucinol analogs as starting materials. The synthesis is stereospecific, efficient, selective, cost-effective, and THC((-)-trans-Δ 9 There is little to no possibility of generating (tetrahydro-cannabinol) or any other psychoactive by-products. Shortened synthesis is also provided, as well as new cannabinoids, pharmaceutical formulations, and methods of use.

Description

[Technical Field]

[0001] Technical field This invention generally relates to methods for chemically synthesizing cannabidiol (CBD) and its analogs, compounds and compositions used in the synthesis and produced by the synthesis, and methods for synthesizing the reactants used. This invention has utility in the fields of pharmaceuticals, medical chemistry, therapeutics, and the manufacture of chemicals and pharmaceuticals. [Background technology]

[0002] background Medical cannabis and individual cannabinoids, e.g., THC(--trans-Δ 9 CBD (cannabidiol), also known as tetrahydrocannabinol, is gaining increasing attention in the media and scientific literature. In particular, CBD, the second most abundant component of the Cannabis sativa (C. Sativa) plant, is a non-psychoactive plant-derived cannabinoid known for its several beneficial properties and potential for a wide range of therapeutic uses. Antioxidant, anti-inflammatory, and neuroprotective effects are among the most documented properties of CBD, and established and proposed uses range from pain and anxiety relief to the treatment of cancer, neurodegenerative diseases, and paroxysmal disorders. CBD has also been suggested to have the potential to mitigate the side effects of other medications, including chemotherapy drugs. The significant physiological significance of CBD has generated substantial interest in its potential for pharmacotherapy.

[0003] CBD is a chiral 21-carbon terpenophenolic cannabinoid biosynthesized in plants by the decarboxylation of its direct precursor, cannabidiolic acid. The term "cannabidiol" is commonly used to refer to the (-)-enantiomer, i.e., (-)-cannabidiol, as shown below: [ka]

[0004] A 2018 critical review by the World Health Organization ("WHO") reported that pure CBD, even at high doses, showed no evidence of potential abuse or dependence and was well within the bounds of a good safety profile.

[0005] CBD and CBD analogs are primarily obtained by extraction, isolation, and purification from C. Sativa and industrial hemp, varieties used for fiber and oilseed production. However, this has proven difficult. The main reason is that the isolation of CBD from C. Sativa and cannabis is a complex process due to the chemical and physical similarities among the many plant cannabinoids present in natural sources, leading to quality control issues in commercial production. See Lo et al. (2019) Nature 567: 123-126.

[0006] To ensure a reliable supply of CBD with consistent quality and to avoid contamination of the product by impurities and toxins absorbed from the soil, scientists have explored the possibility of chemically synthesizing CBD and its analogues. One of the earliest reported synthetic strategies for the preparation of racemic CBD (i.e., +CBD) is the strategy of Mechoulam et al. (1965) J. Am. Chem. Soc. 87: 3273-75, which is a multi-step method that begins with the electrophilic addition of citral A to 1,3-dimethoxy-oliveitol and ends with high-temperature demethylation of the two methoxy groups in the second-to-last intermediate to obtain CBD as a racemic mixture of enantiomers.

[0007] The first direct, stereoselective synthesis of the desired enantiomer, (-)-CBD, was carried out by Petrzilka et al. (1967) Helv. Chim. Acta 50: 719-23. This was reported by Petrzilka et al. (1967) Helv. Chim. Acta 50: 2111-13), and it is that olivetor and optically pure Δ 9This involves electrophilic aromatic substitution reactions with -2,8-mentadiene-1-ol. These reactants are expensive to obtain, resulting in a very costly synthetic process. Furthermore, as can be seen below, the reaction exhibited weak regioselectivity, with two reaction sites on the olivetol ring yielding a mixture of three products, of which only 25% consisted of (-)-CBD.

[0008] Reactants by Petrzilka et al.: Olivetor (2): [ka] Δ-2,8-mentadiene-1-ol(3): [ka]

[0009] Composition of the reaction products by Petrzilka et al.:

[0010] (-)-CBD, 25%

[0011] Unreacted oliveitol, 30%,

[0012] Abnormal CBD (Abn-CBD), 35% Abn-CBD(4): [ka] and

[0013] The following (-)-2,4-disubstituted olivetol products (5), 5% (sometimes referred to herein as "bis"): [ka]

[0014] For a discussion of Petrzilka et al. (1967), see Jung et al. (2019), "Synthetic Strategies for (-)-Cannabidiol and Its Structural Analogs," Chem. Asian J. 14: 3749-62.

[0015] Subsequent attempts to improve the synthesis of these two types continued, including by Razdan et al. (1974) J. Am. Chem. Soc. 98:5860-65, Rickards et al. (1984) J. Org. Chem. 49: 572-3 and Baek et al. (1985) Tetrahedron: Asymmetry 26: 1083-86 Boron trifluoride-catalyzed synthesis; Kobayashi et al. (2006) Org. Lett. 8: 2699-702 S N 2 and 1,4-addition methods (also Kobayashi et al. (2002) J. Org.) Chem. 67:8771-82; and Kobayashi et al. (2001) Org. Lett. 3:2017-20 as well. See reference); the complex, multifaceted approach described in Shultz et al. (2018) Org. Lett. 20:381-84 combines enzyme-catalyzed synthesis and racemic product resolution, enantioselective enone reduction, stereospecific rearrangement, and ruthenium-catalyzed ring-closing metathesis reactions. Furthermore, a more recent synthesis is proposed in International Patent Publication WO2019 / 046806A1 by Bencivenga et al., which describes a Lewis acid-catalyzed reaction between oliveitol and mentadienol, exposure of the reaction mixture to a second reaction mixture containing terpenes, and phase separation to produce the desired product. In U.S. Patent No. 10,059,683, Dialer et al. also describe a CBD synthesis similar to the method of Petrzilka et al. between oliveitol and mentadienol, but requiring the use of a dihalogenated oliveitol compound as a starting material.

[0016] Efficient, cost-effective, and stereoselective synthesis of cannabinoids, such as CBD and CBD analogs, remains a need in this field. Ideal stereospecific synthesis offers several advantages compared to cannabinoid synthesis methods developed to date. In particular, ideal synthesis...

[0017] The present invention provides a reaction product composition having a high percentage of the desired cannabinoid and minimizing the presence of other reaction products.

[0018] Enables direct separation of the desired product.

[0019] To provide the desired product in high yield.

[0020] It allows the use of mild reaction conditions without requiring harsh reagents or special precautions.

[0021] Without requiring many or time-consuming reaction steps, intermediate steps between steps It is efficient without requiring the isolation and purification of the body.

[0022] Eliminate or significantly reduce any accidental production of THC. CBD itself, CBD analogues, and other cannabinoids are easily adapted to produce them, as It is economical by using low-cost, commercially available reactants or by including cost-effective methods for the chemical synthesis of reactants. [Prior art documents] [Patent Documents]

[0023] [Patent Document 1] International Publication No. 2019 / 046806A1 [Patent Document 2] U.S. Patent No. 10,059,683 [Non-patent literature]

[0024] [Non-Patent Document 1] Lo et al. (2019) Nature 567: 123-126 [Non-Patent Document 2] Mechoulam et al. (1965) J. Am. Chem. Soc. 87: 3273-75 [Non-Patent Document 3] Petrzilka et al. (1967) Helv. Chim. Acta 50: 719-23 [Non-Patent Document 4] Petrzilka et al. (1967) Helv. Chim. Acta 50: 2111-13 [Non-Patent Document 5] Jung et al. (2019), "Synthetic Strategies for (-)-Cannabidiol and Its Structural Analogs," Chem. Asian J. 14: 3749-62 [Non-Patent Document 6] Razdan et al. (1974) J. Am. Chem. Soc. 98:5860-65 [Non-Patent Document 7] Rickards et al. (1984) J. Org. Chem. 49: 572-3 [Non-Patent Document 8] Baek et al. (1985) Tetrahedron: Asymmetry 26: 1083-86 [Non-Patent Document 9] Kobayashi et al. (2006) Org. Lett. 8:2699-702 [Non-Patent Document 10] Kobayashi et al. (2002) J. Org. Chem. 67:8771-82 [Non-Patent Document 11] Kobayashi et al. (2001) Org. Lett. 3:2017-20 [Non-Patent Document 12] Shultz et al. (2018) Org. Lett. 20:381-84 [Overview of the Initiative] [Means for solving the problem]

[0025] Summary of the Invention The present invention addresses the above-mentioned needs of the art and provides a method for synthesizing cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), tetrahydrocannabivarin (THCV), their analogues, and synthetic precursors. The method is efficient, cost-effective, has little to no accidental production of THC or other psychoactive by-products, and is readily adaptable to produce CBD, CBD precursors, or numerous analogues. In one embodiment, the present invention provides a method for synthesizing oliveitol from phloroglucinol. The method also extends to the synthesis of oliveitol analogs from appropriately substituted phloroglucinol reactants, namely the structure of formula (AA). [ka] [In the formula, m is either zero or 1. n is zero, 1, or 2. R 1 C1~C 12Hydrocarbyl, substituted C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, and substituted heteroatom-containing C1-C 12 Selected from hydrocarbyl, R 2 is C1-C 12 Hydrocarbyl, substituted C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Hydrocarbyl, and a functional group, and when n is 2, R 2 may be the same or different, and any R on adjacent carbon atoms 2 may be linked to form a cyclic structure], and a compound having the same is synthesized. The method is (a) A structure of formula (AA-1)

Chemical formula

Chemical formula

Chemical formula

[0026] In related embodiments, a method for synthesizing tetrahydrocannabivarin (THCV) or an analog thereof is provided. The method involves R such that compound (AA) is optionally substituted divalinol. 1The reaction proceeds as described above, provided that (CC) is n-propyl. Divalinol is used as the first reactant to produce a compound of formula (CC) where (CC) is n-propyl. The compound is then cyclized to obtain THCV or its substituted analogues.

[0027] In other embodiments, methods for synthesizing cannabinol (CBN), cannabichromene (CBC), CBN analogs, and CBC analogs are also provided.

[0028] In further embodiments, the structure of formula (EE) [ka] [In the formula, q1 is zero or 1, and q2 is zero, 1, or 2. R 11 C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Hydrocarbyl and selected from functional groups, if n is 2, R 11 The R atoms may be the same or different, and any two R atoms bonded to adjacent carbon atoms. 11 They may combine to form a cyclic structure selected from 5-membered and 6-membered rings, which may be condensed as needed into an additional 5-membered or 6-membered ring, and the ring may be aromatic, alicyclic, heteroaromatic, or heteroalicyclic, having zero to 4 nonhydrogen substituents and zero to 3 heteroatoms. R 12 This is H, carboxyl, C2-C6 acyloxy, C2-C6 alkoxycarbonyl, C1-C6 alkyl, or a C1-C6 alkyl substituted with hydroxyl, carboxyl, or halo. R 13 and R 14 These are H, C1~C independently. 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12Hydrocarbyl, substituted heteroatom-containing C1-C 12 Selected from hydrocarbyl and functional groups, R 15 These are methyl, hydroxymethyl, or halomethyl, R 16 (a)-(CO)-NR 28 -R 29 (In the formula, R 28 is H or C1~C 12 Hydrocarbil, R 29 is C1~C 12 (b)-NR (hydrocarbyl) 30 -R 31 (In the formula, R 30 is H or C1~C 12 Hydrocarbil, R 31 is C6~C 12 Hydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbil, C1-C 12 Heterohydrocarbyl, or C1-C1 substituted with at least one functional group 12 (It is a heterohydrocarbyl), (c)-(SO2)-R 32 (In the formula, R 32 is H or C1~C 12 Heterohydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbyl, or C1-C1 substituted with at least one functional group 12 (It is a heterohydrocarbyl), (d)-(SO2)-NR 33 R 34 (In the formula, R 33 is H or C1~C 12 Hydrocarbil, R 34 is H or C1~C 12 (It is hydrocarbyl.) [ka] (In the formula, L 1 (which is a C1-C6 alkyl group) 18 Alkyl, C2~C 18 Alkenyl, or C2~C 18It is either alkinyl or R 16 Additional C1~C 12 C1-C substituted with hydrocarbyl oxy 12 A cannabidiol analog having [hydrocarbyl oxy] is provided.

[0029] In additional embodiments, the structure of formula (FF) [ka] [In the formula, q3 is zero or 1, and q4 is zero, 1 or 2. R 17 C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Hydrokalbi R is selected from the functional groups, and if n is 2, 17 The R atoms may be the same or different, and any two R atoms bonded to adjacent carbon atoms. 17 They may combine to form a cyclic structure selected from 5-membered and 6-membered rings, which may be condensed as needed into an additional 5-membered or 6-membered ring, and the ring may be aromatic, alicyclic, heteroaromatic, or heteroalicyclic, having zero to 4 nonhydrogen substituents and zero to 3 heteroatoms. R 18 This is H, carboxyl, C2-C6 acyloxy, C2-C6 alkoxycarbonyl, C1-C6 alkyl, or a C1-C6 alkyl substituted with hydroxyl, carboxyl, or halo. R 19 and R 20 These are H, C1~C independently. 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Selected from hydrocarbyl and functional groups, R 21is methyl, hydroxymethyl, or halomethyl, R 22 is (a) -(CO)-NR 35 -R 36 (wherein R 35 is H or C1-C 12 hydrocarbyl, and R 36 is C1-C 12 hydrocarbyl), (b) -NR 37 -R 38 (wherein R 37 is H or C1-C 12 hydrocarbyl, and R '<s 38 is C6-C 12 hydrocarbyl, C1-C 12 hydrocarbyl substituted with at least one functional group, C1-C 12 heterohydrocarbyl, or C1-C 12 heterohydrocarbyl substituted with at least one functional group), (c) -(SO2)-R 39 (wherein R 39 is H or C1-C 12 heterohydrocarbyl, C1-C 12 hydrocarbyl substituted with at least one functional group, or C1-C 12 heterohydrocarbyl substituted with at least one functional group), (d) -(SO2)-NR 40 R 41 (wherein R 42 is H or C1-C 12 hydrocarbyl, and R 43 is H or C1-C 12 hydrocarbyl),

Chemical formula

[0030] In further embodiments, the structure of formula (GG) [ka] [In the formula, q5 is zero or 1, q6 is zero, 1 or 2, and the sum of q5 and q6 is not greater than 2. R 23 C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Hydrocarbyl and selected from functional groups, if n is 2, R 23 The R atoms may be the same or different, and any two R atoms bonded to adjacent carbon atoms. 23 These elements combine to form a cyclic structure, selected from 5-membered and 6-membered rings, which are condensed as needed into additional 5-membered or 6-membered rings. The ring may be aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and may have zero to 4n3on-hydrogen substituents and zero to 3 heteroatoms. R 24 is a C1-C6 alkyl group substituted with H, C1-C6 alkyl, or hydroxyl, carboxyl, or halo. R 25 H, C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Hydrocarbyl, or a functional group, R 26 These are methyl, hydroxymethyl, or halomethyl, R 27 (a)-(CO)-NR 42 R 43 (In the formula, R42 is H or C1~C 12 Hydrocarbil, R 43 is C1~C 12 (b)-NR (hydrocarbyl) 44 R 45 (In the formula, R 44 is H or C1~C 12 Hydrocarbil, R 45 is C6~C 12 Hydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbil, C1-C 12 Heterohydrocarbyl, or C1-C1 substituted with at least one functional group 12 (It is a heterohydrocarbyl), (c)-(SO2)-R 46 (In the formula, R 46 is H or C1~C 12 Heterohydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbyl, or C1-C1 substituted with at least one functional group 12 (It is a heterohydrocarbyl), (d)-(SO2)-NR 47 R 48 (In the formula, R 47 is H or C1~C 12 Hydrocarbil, R 48 is H or C1~C 12 (It is hydrocarbyl.) [ka] (In the formula, L 1 is C 1 ~C 6 C1-C (which are alkyl) 18 Alkyl or C2-C 18 It is an alkenyl, or R 27 Additional C1~C 12 C1-C substituted with hydrocarbyl oxy 12 A cannabichromene analog (GG) having hydrocarbyl oxy is provided.

[0031] In further embodiments, the structure (HH) [ka] [In the formula, q7 is either zero or 1. R 53 C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Selected from hydrocarbyl and functional groups, R 49 This is H, carboxyl, C2-C6 acyloxy, C2-C6 alkoxycarbonyl, C1-C6 alkyl, or a C1-C6 alkyl substituted with hydroxyl, carboxyl, or halo. R 50 and R 51 These are H, C1~C independently. 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Selected from hydrocarbyl and functional groups, R 52 These are methyl, hydroxymethyl, or halomethyl, R 54 (a)-(CO)-NR 55 R 56 (In the formula, R 55 is H or C1~C 12 Hydrocarbil, R 56 is C1~C 12 (b)-NR (hydrocarbyl) 57 R 58 (In the formula, R 57 is H or C1~C 12 Hydrocarbil, R 58 is C6~C 12 Hydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbil, C1-C 12 Heterohydrocarbyl, or C1-C1 substituted with at least one functional group12 (It is a heterohydrocarbyl), (c)-(SO2)-R 59 (In the formula, R 59 is H or C1~C 12 Heterohydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbyl, or C1-C1 substituted with at least one functional group 12 (It is a heterohydrocarbyl), (d)-(SO2)-NR 60 R 61 (In the formula, R 60 is H or C1~C 12 Hydrocarbil, R 61 is H or C1~C 12 (It is hydrocarbyl.) [ka] (In the formula, L 1 (where C1-C6 alkyl is substituted with C1-C6 18 Alkyl, C2~C 18 Alkenyl, or C2~C 18 It is either alkinyl or R 16 is C1~C 12 C1-C substituted with hydrocarbyl oxy 12 A tetrahydrocannabivarin analog having hydrocarbyloxy is provided.

[0032] The cannabinoid analogs of the present invention can be used for any purpose for which known cannabinoids are used, or for any purpose for which such purposes may be discovered in the future.

[0033] A pharmaceutical formulation comprising a cannabinoid analog of the present invention in combination with a pharmaceutical excipient suitable for a selected mode of administration is also provided, wherein the cannabinoid is present in an effective amount. The formulation may contain a certain amount of additional activator such that the amounts of cannabinoid and additional activator together constitute an effective amount. Any additional activator is usually, but not necessarily, used for the same purpose as the selected cannabinoid analog, and the additional activator in the formulation may or may not be an additional cannabinoid. The formulation is usually provided as a unit dosage form for the administration of the activator(s) to a subject.

[0034] Another embodiment provides a method for treating a subject affected by a condition, disorder, or disease that responds to cannabinoid administration, comprising administering an effective amount of the cannabinoid analog of the present invention to the subject. The administration may be performed once, on a required basis or in connection with an ongoing dosing regimen. Indications for which the cannabinoids of the present invention are useful are described in detail in the following sections. [Modes for carrying out the invention]

[0035] Detailed explanation I. Definitions and Nomenclature: A. Overview:

[0036] Unless otherwise defined, all technical and scientific terms used herein have meanings commonly understood by those skilled in the art in the field to which this invention relates. Specific terms of particular importance to the description of this invention are defined below.

[0037] In this specification and the appended claims, the singular "one (a)", "one ( The pronouns "an" and "the" refer to multiple objects unless the context explicitly indicates otherwise. For example, a reference to "catalyst" can refer not only to a single catalyst but also to a combination of two or more different catalysts, and "reagent" can refer to a single reagent or a combination of reagents.

[0038] B. Chemical terminology:

[0039] As used herein, the phrases “having a formula” or “having a structure” are not intended to be limiting and are used in the same way as the term “including” is commonly used.

[0040] The term "hydrocarbyl" refers to a hydrocarbyl group or linkage containing 1 to about 18 carbon atoms, usually 1 to 12 carbon atoms, including linear, branched, cyclic, saturated, and unsaturated species, such as alkyl groups, alkenyl groups, and aryl groups. "Substitutable hydrocarbyl" refers to a hydrocarbyl that is substituted with one or more substituents, and the term "heteroatom-containing hydrocarbyl" refers to a hydrocarbyl in which at least one carbon atom is replaced by a heteroatom. Unless otherwise noted, the term "hydrocarbyl" should be interpreted as including substituted and / or heteroatom-containing hydrocarbyl moieties.

[0041] The term "alkyl," as used herein, typically contains, but not necessarily, 1 to about 18 carbon atoms, including branched or unbranched saturated hydrocarbon groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and cycloalkyl groups such as cyclopentyl, cyclohexyl, and cycloalkyl groups. Generally, and again not necessarily, alkyl groups as used herein contain 1 to 12 carbon atoms, such as 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms, or 1 to 3 carbon atoms. "Substituted alkyl" means an alkyl group substituted with one or more substituents, and the terms "heteroatom-containing alkyl" and "heteroalkyl" mean an alkyl group in which at least one carbon atom is replaced by a heteroatom, as further detailed below. Unless otherwise indicated, the term "alkyl" includes linear, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkyl groups.

[0042] The term "alkenyl," as used herein, refers to a linear, branched, or cyclic hydrocarbon group containing at least one double bond and comprising 2 to about 18 carbon atoms, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicocenyl, tetracocenyl, etc. The alkenyl groups herein typically contain 2 to 12 carbon atoms, for example, 2 to 12 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 3 carbon atoms. The term "cycloalkenyl" typically refers to a cyclic alkenyl group having 5 to 8 carbon atoms. The term "substituted alkenyl" refers to an alkenyl substituted with one or more substituents, and the terms "heteroatom-containing alkenyl" and "heteroalkenyl" refer to an alkenyl in which at least one carbon atom is replaced by a heteroatom. Unless otherwise indicated, the term “alkenyl” includes linear, branched, cyclic, unsubstituted, substituted, and / or heteroatom-containing alkenyls.

[0043] The term "alkynyl," as used herein, refers to a linear or branched hydrocarbon group of 2 to 18 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, etc. Generally, and not necessarily in this case either, the alkynyl group as used herein has 2 to 12 carbon atoms, for example, 2 to 12 carbon atoms, 2 to 10 carbon atoms. Contains atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms, or 2 to 3 carbon atoms. The term "substituted alkynyl" refers to an alkynyl substituted with one or more substituents, while the terms "heteroatom-containing alkynyl" and "heteroalkynyl" refer to an alkynyl in which at least one carbon atom is replaced by a heteroatom. Unless otherwise indicated, the term "alkynyl" includes linear, branched, unsubstituted, substituted, and / or heteroatom-containing alkynyls.

[0044] As used herein, the term "alkoxy" refers to a single alkyl group linked via a terminal ether linkage. That is, an "alkoxy" group can be represented as -O-alkyl, where alkyl is as defined above. Thus, alkoxy groups include C1-C6 alkoxy groups, such as methoxy, ethoxy, n-propoxy, isopropoxy, t-butyloxy, etc. The terms "alkenyloxy" and "alkynyloxy" are defined similarly.

[0045] The term "aryl," as used herein and unless otherwise specified, refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are condensed, directly linked, or indirectly linked (so that different aromatic rings are bonded to a common group, e.g., a methylene or ethylene moiety). Preferred aryl groups contain 5 to 18 carbon atoms, and particularly preferred aryl groups contain 5 to 14 carbon atoms. Exemplary aryl groups contain one aromatic ring or two condensed or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenyl ether, diphenylamine, benzophenone, etc. "Substitutable aryl" refers to an aryl moiety substituted with one or more substituents, and the terms "heteroatom-containing aryl" and "heteroaryl" refer to an aryl substituent in which at least one carbon atom is replaced by a heteroatom, as further described below. Unless otherwise indicated, the term "aryl" includes unsubstituted, substituted, and / or heteroatom-containing aromatic substituents.

[0046] The term "aryloxy," as used herein, refers to a single aryl group linked via a terminal ether linkage, where "aryl" is as defined above. An "aryloxy" group can be represented as -O-aryl, where "aryl" is as defined above. Preferred aryloxy groups contain 5 to 18 carbon atoms, and particularly preferred aryloxy groups contain 5 to 14 carbon atoms. Examples of aryloxy groups, without limitation, include phenoxy, o-halo-phenoxy, m-halo-phenoxy, p-halo-phenoxy, o-methoxy-phenoxy, m-methoxy-phenoxy, p-methoxy-phenoxy, 2,4-dimethoxy-phenoxy, and 3,4,5-trimethoxy-phenoxy.

[0047] The term "alkalil" refers to an aryl substituent substituted with an alkyl group, and the term "aralkyl" refers to an alkyl substituent substituted with an aryl group, where "aryl" and "alkyl" are as defined above. Preferred alkalil and aralkyl groups contain 6 to 18 carbon atoms, and particularly preferred aralkyl groups contain 6 to 16 carbon atoms. For example, examples of alkalil groups include p-methylphenyl, 2,4-dimethylphenyl, p-cyclohexylphenyl, 2,7-dimethylnaphthyl, 7-cyclooctylnaphthyl, and 3-ethyl-cyclopenta-1,4-diene. Examples of aralkyl groups, without limitation, include benzyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl, 4-phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl, and 4-benzylcyclohexylmethyl. The terms "alkalyloxy" and "aralkyloxy" refer to substituents of formula -OR (wherein R is alkalyl or aralkyl, respectively, as defined immediately above).

[0048] The term "acyl" refers to a substituent having the formula -(CO)-alkyl, -(CO)-aryl, or -(CO)-aralkyl, and the term "acyloxy" refers to a substituent having the formula -O(CO)-alkyl, -O(CO)-aryl, or -O(CO)-aralkyl, where "alkyl," "aryl," and "aralkyl" are as defined above.

[0049] The term "cyclic" refers to alicyclic or aromatic substituents that may or may not be substituted and / or contain heteroatoms, and may be monocyclic, bicyclic, or polycyclic.

[0050] The term "alicyclic" is used in its traditional sense to refer to the aliphatic cyclic part, in contrast to the aromatic cyclic part, and may be monocyclic, bicyclic, or polycyclic, and may be cross-linked.

[0051] The terms "halo" and "halogen" are used in their traditional sense to refer to chloro, bromo, fluoro, or iodo substituents.

[0052] The term "heteroatom-containing" refers to a molecule, linkage, or substituent in which one or more carbon atoms are replaced by an atom other than carbon, such as nitrogen, oxygen, sulfur, phosphorus, or silicon, usually nitrogen, oxygen, or sulfur, preferably nitrogen or oxygen, as in the case of a "heteroatom-containing alkyl group" (also called a "heteroalkyl" group) or a "heteroatom-containing aryl group" (also called a "heteroaryl" group). Similarly, the term "heteroalkyl" refers to an alkyl substituent containing a heteroatom, the term "heterocyclic" refers to a cyclic substituent containing a heteroatom, and the terms "heteroaryl" and "heteroaromatic" refer to "aryl" and "aromatic" substituents containing a heteroatom, respectively. Examples of heteroalkyl groups include alkoxyaryls, alkylsulfanyl-substituted alkyls, and N-alkylated aminoalkyls. Examples of heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, and tetrazolyl. Examples of heteroatom-containing alicyclic groups include pyrrolidino, morpholino, piperazino, and piperidino.

[0053] The term "substituted," as in "substituted alkyl" and "substituted aryl," means, as implied in part of the definition above, that in the alkyl, aryl, or other moiety, at least one hydrogen atom bonded to a carbon (or other) atom is replaced by one or more non-hydrogen substituents. Examples of such substituents include functional groups and hydrocarbyl moieties.

[0054] Functional groups that can represent the substituted molecular structure and substituents within its segments are, without restriction, halos, hydroxyls, sulfhydryls, and C1-C12 18 Alkoxy, C2~C 18 Alkoxyalkyl, C2-C 18 Alkenyloxy, C2~C 18 Alkynyloxy, C5~C 18 Aryloxy, Acyl (C2~C 18Alkylcarbonyl (-CO-alkyl) and C6~C 18 Arylcarbonyl (-CO-aryl), acyloxy (-O-acyl), C2~C 18 Alkoxycarbonyl (-(CO)-O-alkyl), C6~C 18 Aryloxycarbonyl (-(CO)-O-aryl), Halocarbonyl (-CO)-X (where X is a halo)), C2~C 18 Alkylcarbonato (-O-(CO)-O-alkyl), C6~C 18 Arylcarbonato (-O-(CO)-O-aryl), Carboxylate (-COOH), Carboxylato (-COO-), Carbamoyl (-(CO)-NH2), Mono-(C1~C) 18 Alkyl)-substituted carbamoyl(-( CO)-NH(C1~C 18 Alkyl)), di-(C1~C 18 Alkyl)-substituted carbamoyl (-(CO)-N(C1~C 18 Alkyl)2), Mono-(C5~C) 18 Aryl)-substituted carbamoyl(-(CO)-NH-aryl), di-(C5~C 18 aryl)-substituted carbamoyl(-(CO)-N(aryl)2), di-N-(C1~C 18 Alkyl), N-(C5~C 18 Aryl)-substituted carbamoyl, thiocarbamoyl (-(CS)-NH2), carbamide (-NH-(CO)-NH2), cyano(-C≡N), isocyano(-N + ≡C - -), cyanato(-OC≡N), isocyanato(-ON) + ≡C - -), isothiocyanates (-SC≡N), azides (-N=N) + ≡N - ), formyl(-(CO)-H), thioformyl(-(CS)-H), amino(-NH2), mono-(C1~C) 18 Alkyl)-substituted amino, di-(C1~C 18 Alkyl)-substituted amino, mono-(C5~C) 18 Aryl)-substituted amino, di-(C5~C 18Aryl)-substituted amino, C2~C 18 Alkylamide (-NH-(CO)-alkyl), C6~C 18 Arylamide (-NH-(CO)-aryl), imino (-CR=NH (where R = hydrogen), C1~C 18 Alkyl, C5~C 18 Aryl, C6~C 18 Alkali, C6~C 18 Aralkyl (e.g., aralkyl), alkylimino (-CR=N(alkyl), (where R=hydrogen), C1~C 18 Alkyl, C5~C 18 Aryl, C6~C 18 Alkali, C6~C 18 Aralkyls, etc.), aryliminos (-CR=N(aryl), (where R=hydrogen), C1~C 18 Alkyl, C5~C 18 Aryl, C6~C 18 Alkali, C6~C 18 (Aralkyl, etc.), nitro(-NO2), nitroso(-NO), sulfo(-SO2-OH), sulfonate(-SO2-O-), C1~C 18 Alkylsulfanyl (-S-alkyl; also called "alkylthio"), arylsulfanyl (-S-aryl; also called "arylthio"), C1-C 18 Alkylsulfinyl (-(SO)-alkyl), C5~C 18 Aryl sulfinyl (-(SO)-aryl), C1~C 18 Alkylsulfonyl (-SO2-alkyl), C5~C 18 Examples include arylsulfonyl (-SO2-aryl), phosphono (-P(O)(OH)2), phosphonato (-P(O)(O-)2), phosphinato (-P(O)(O-)), phospho (-PO2), and phosphino (-PH2). Typically, the hydrocarbyl portion of the above functional groups has 1 to 12 carbon atoms if it is acyclic, and 5 to 16 carbon atoms if it is cyclic.

[0055] The functional groups described above may be further substituted with one or more additional functional groups or one or more hydrocarbyl moieties, for example, those specifically listed above, where permitted by the particular group; the term “functional group” encompasses all such cases.

[0056] When the term “substituted” appears before a list of possible substituted groups, the term is intended to apply to all members of that group. For example, the phrase “substituted alkyl, alkenyl, and aryl” should be interpreted as “substituted alkyl, substituted alkenyl, and substituted aryl.” Similarly, when the term “heteroatom-containing” appears before a list of possible heteroatom-containing groups, the term is intended to apply to all members of that group. For example, the phrase “heteroatom-containing alkyl, alkenyl, and aryl” should be interpreted as “heteroatom-containing alkyl, substituted alkenyl, and substituted aryl.”

[0057] Some of the compounds described herein contain one or more chiral centers, which can result in enantiomers, diastereomers, or other stereoisomeric forms. Such compounds may be a single stereoisomer, i.e., a "stereoisomerically pure" form, or they may be contained in two or more stereoisomers, e.g., two diastereomers, a mixture of two enantiomers, or a mixture of two diastereomers and two enantiomers. However, cannabidiols and their analogues referred to herein are in a (-)- configuration and not a (+)-racemic mixture unless otherwise specified (including numbering rules): [ka] See Lago Fernandez et al. (2017), "New Methods for the Synthesis of Cannabidiol Derivatives," Methods Enzymol. 593: 237-257. For ease of use, in the description of the various types of analogs described herein, a phenyl group having carbon atoms 1' to 6' is sometimes referred to herein as a “phloroglucinol ring,” while a cyclohexene ring having carbon atoms 1 to 6 is sometimes referred to herein as a “mentadienol ring.” The above numbering rules are also used herein for other cannabinoids, including cannabinol, cannabichromene, and tetrahydrocannabivarin.

[0058] C. Pharmaceutical Terminology:

[0059] Sometimes, the term "pharmacological activator," as simply referred to herein, encompasses not only identified cannabinoids or other molecular entities, but also, but not limited to, salts, esters, prodrugs, conjugates, active metabolites, crystalline forms, enantiomers, stereoisomers, and other such derivatives, analogs, and related compounds, including their pharmaceutically acceptable analogs and derivatives.

[0060] "Pharmacologically acceptable" means that a material is not biologically or otherwise undesirable; that is, the material can be incorporated into a pharmaceutical formulation or dosage form administered to a subject without causing any undesirable biological effects or interacting in a harmful manner with any of the other components of the composition in which it is contained. When the term "pharmaceutically acceptable" is used to refer to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient meets the required standards of toxicological and manufacturing testing and / or is included in the Inactive Ingredients Guide created by the U.S. Food and Drug Administration.

[0061] The terms “to treat” and “treatment,” as used herein, refer to a reduction in the severity and / or frequency of symptoms, the disappearance of symptoms and / or underlying causes, and improvement or correction of damage, for example, a reduction in the number and / or range of menopausal symptoms in a patient who has been administered hormone replacement therapy using the drug delivery system of the present invention. Unless otherwise noted, the terms “to treat” and “treatment,” as used herein, also encompass the prevention of symptoms.

[0062] The terms “effective dose” and “therapeutic dose” for an activator or pharmaceutical preparation refer to the amount that is non-toxic to the target and effective in producing a therapeutic effect. “Effective dosage” and “unit dosage” result in the “effective dose” of an activator.

[0063] As used herein, “subject,” “individual,” or “patient” refers to any living individual to whom the therapy is desired, and to the recipient of the therapy to be carried out in accordance with the present invention.

[0064] "As needed" or "as required" means that the following situation may or may not occur, and therefore the description includes cases in which the situation occurs and cases in which it does not. For example, the phrase "co-administered with ~ as required" refers to the administration of the activator to a target, and includes the administration of the activator in the context of monotherapy, as well as co-administration with a second compound of the activator. In another context, the phrase "substituted as required" means that the non-hydrogen substituent may or may not be present on a given atom, and therefore the description includes structures in which the non-hydrogen substituent is present and structures in which the non-hydrogen substituent is absent. II. Synthesis of Olivetor and its analogs:

[0065] In the first embodiment, the present invention provides a method for synthesizing a compound useful as a synthetic precursor into cannabinoids described herein, including CBD and CBD analogs, wherein the synthetic precursor has the structure of formula (AA). [ka] [In the formula,

[0066] m is either zero or 1.

[0067] n is zero, 1, or 2.

[0068] R 1 C1~C 18 Hydrocarbyl, substitution C1-C 18 Hydrocarbyl, heteroatom-containing C1-C 18 Hydrocarbyl and substituted heteroatom-containing C1-C 18 Selected from hydrocarbil,

[0069] R 2 C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Hydrocarbyl and selected from functional groups, if n is 2, R 2 They may be the same or different, and any R bonded to an adjacent carbon atom. 2 The method provides a cyclic structure which may be formed by combining and optionally condensing to an additional five- or six-membered ring, wherein the ring is aromatic, alicyclic, heteroaromatic, or heteroalicyclic and has zero to four nonhydrogen substituents and zero to three heteroatoms.

[0070] R 1 As mentioned above, these are substituted as needed, and contain heteroatoms as needed (C1-C). 18 This is the hydrocarbyl portion. In one embodiment, R 1 These are substituted as needed, and contain heteroatoms as needed (C1-C). 12The hydrocarbyl moiety is a C1-C8 hydrocarbyl moiety that is substituted as needed and may contain heteroatoms as needed. When heteroatoms are present, there are generally four or fewer, usually two or fewer, for example, in the range of 1-4, and the heteroatoms are usually selected from O, N, and S. Nitrogen heteroatoms may be contained in primary, secondary, or tertiary amino groups or linkages, in functional groups, for example, in amides or sulfonamides, or in aromatic or alicyclic rings, such as pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, morpholino, piperazino, and piperidino. Oxygen heteroatoms may be contained in hydroxyl groups, alkoxy groups, carbonyl moieties (e.g., ester or amide linkages), ether linkages, or in furanyl, tetrahydrofuranyl, pyranyl, tetrahydropyranyl, dioxanyl, or morpholino rings. Sulfur heteroatoms are linked by thioethers, forming sulfonates. It may be located within a linkage, sulfonate group, etc. Hydrocarbyl or heteroatom-containing hydrocarbyl moiety R 1 If substituted, the non-hydrogen substituent is generally selected from the functional groups defined in the “substituted” part (I) of this section. Typical substituents include, without limitation, halo, carboxyl, alkoxy, amide, amino, sulfonamide, alicyclic, and aromatic groups. For example, R 1 These include halo, hydroxyl, carboxyl, C1-C8 alkoxy, C2-C8 acyloxy, C2-C8 alkoxycarbonyl, amino, mono-(C1-C8 alkyl)-substituted amino, di-(C1-C8 alkyl)-substituted amino, C2-C8 alkylamide, mono-(C1-C8 alkyl)-substituted carbamoyl, di-(C1-C8 alkyl)-substituted carbamoyl, and C1-C8 substituted with zero to three functional groups selected from combinations thereof. 18 Alkyl, C2~C 18 Alkenyls, and C2~C 18 Alkinyl may also be selected.

[0071] R1 As some examples, without restrictions:

[0072] C1~C 18 Alkyl (for example, C1~C 12 Alkyl, C1-C 10 Alkyl, or C1-C8 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, cyclohexyl, etc.)

[0073] C2~C 18 Alkenyl (for example, C2~C 12 Alkenyl, C2~C 10 Alkenyls or C2-C8 alkenyls)

[0074] C2~C 18 Alkinyl (for example, C2~C 12 Alkinyl, C2~C 10 Alkinyl or C2-C8 alkynyl),

[0075] C6~C 18 Aralkyl (for example, C5-C6 aryl substitution C1-C) 12 Alkyl or C5-C6 aryl-substituted C1-C8 alkyl),

[0076] C4~C 16 Heteroaralkyl (e.g., C3-C6 heteroaryl substitution C1-C) 10 Alkyl or C3-C6 heteroaryl-substituted C1-C8 alkyl) (where the heteroaryl substituent may be saturated or unsaturated),

[0077] C1~C 18 Haloalkyl (for example, C1-C) 12 Chloroalkyl, C1-C 10 Chloroalkyl, C1-C8 chloroalkyl, C1-C 12 Fluoroalkyl, C1-C 10 Fluoroalkyl, or C1-C8 fluoroalkyl,

[0078] C1~C18 Hydroxyalkyl (for example, C1-C 12 Hydroxyalkyl, C1-C 10 Hydroxyalkyl, or C1-C8 hydroxyalkyl,

[0079] C2~C 18 Haloalkenyls (e.g., C2~C) 12 Chloroalkenyl, C2~C 10 Chloroalkenyl, C2-C8 chloroalkenyl, C2-C 12 Fluoroalkenyl, C2~C 10 Fluoroalkenyls or C2-C6 fluoroalkenyls),

[0080] C2~C 18 Haloalkynyl (for example, C2~C 12 Chloroalkynyl, C2~C 10 Chloroalkynyl, C2-C8 chloroalkynyl, C2-C 12 Fluoroalkynyl, C2~C 10 Fluoroalkynyl or C2-C6 fluoroalkynyl),

[0081] C2~C 18 Alkoxyalkyl (e.g., (C1-C8 alkoxy)-substituted C1-C 12 Alkyl or (C1-C8 alkoxy)-substituted C1-C8 alkyl), unsubstituted, or with additional C2-C 18 Substituted with alkoxyalkyl groups,

[0082] C2~C 18 Alkoxyalkenyl (e.g., (C1-C8 alkoxy)-substituted C2-C) 12 Alkenyl or (C1-C8 alkoxy)-substituted C2-C8 alkenyl),

[0083] C2~C 12 Alkoxyalkynyl (e.g., (C1~C8 alkoxy)-substituted C2~C 12 Alkynyl or (C1-C8 alkoxy)-substituted C2-C8 alkynyl),

[0084] C2~C 18 Carboxyalkyl (for example, C2~C 12 Carboxyalkyl, C2~C 10 Carboxyalkyl, or C2-C8 carboxyalkyl),

[0085] C3~C 18 Carboxyalkenyl (e.g., C3-C3) 12 Carboxyalkenyl, C3~C 10 Carboxyalkenyl, or C3-C8 carboxyalkenyl)

[0086] C1~C 18 C1~C8 alkyl, for example, mono-(C1~C8 alkyl)-substituted carbamoyl (-(CO)-NH(C1~C8 alkyl)) or di-(C1~C8 alkyl)-substituted carbamoyl (-(CO)-N(C1~C8 alkyl)2) 12 Alkyl,

[0087] C2~C 18 Alkenyls, for example, mono-(C1~C8 alkyl)-substituted carbamoyl (-(CO)-NH(C1~C8 alkyl)) or di-(C1~C8 alkyl)-substituted carbamoyl (-(CO)-N(C1~C 12 C2~C substituted with alkyl)2) 12 Alkenil,

[0088] C1~C 18 C1-C8 alkylamides (-NH-(CO)-alkyl) are substituted with alkyl groups. 12 Alkyl,

[0089] C2~C 18 C2-C8 alkylamides substituted with alkenyls, for example, C2-C8 alkylamides (-NH-(CO)-alkenyls) 12 Alkenil,

[0090] C1~C 18 C1~C8 alkyl groups, for example, C1~C8 alkyl groups substituted with -NH-(C1~C8 alkyl) or -N(C1~C8 alkyl)2.12 Alkyl,

[0091] C2~C 18 Alkenyls, for example, C2-C2 substituted with -NH-(C1-C8 alkyl) or -N(C1-C8 alkyl)2. 12 Alkenil,

[0092] C1~C 18 Alkyl, for example, C1-C8 alkylsulfonyl (-SO2-alkyl) substituted C1-C8 12 Alkyl,

[0093] C2~C 18 Alkenyls, for example, C2-C8 alkylsulfonyl (-SO2-alkyl) substituted with C1-C8 alkylsulfonyl (-SO2-alkyl) 12 Alkenil,

[0094] C1~C 18 C1-C1 substituted with alkyl groups, for example, C0-C8 sulfonamides (-SO2-NH2 or -SO2-N alkyl groups) 12 Alkyl,

[0095] C2~C 18 C2-C2 substituted with alkenyls, for example, C0-C8 sulfonamides (-SO2-NH2 or -SO2-N alkyl). 12 Alkenil,

[0096] C1~C 18 Alkyls, such as morpholino and diazinyl, are generally C1-C2 molecules where the nitrogen atom of the nitrogen heterocycle is substituted with oxanyl, morpholino, or diazinyl. 12 Alkyl, or

[0097] C2~C 18 Alkenyls, such as morpholino and diazinyl, are generally C2-C2 carbon atoms in which the nitrogen atom of a nitrogen heterocycle is substituted with oxanyl, morpholino, or diazinyl. 12 Alkenil These are some examples.

[0098] The aforementioned representative R 1 Any of the substituents may be further substituted with one or more additional substituents, which may or may not be the same as the substituents identified above. Such R 1 Examples of substituents include C1-C11, which are disubstituted with Cl or F. 18 Alkyl groups (for example, C1-C) 12 Alkyl group C1~C 10 Alkyl, or C1-C8 alkyl group); one or more C2-C 18 C2-C substituted with alkoxyalkyl groups 18 Alkoxyalkyl groups, for example, structure (C1-C6 alkoxy)-substituted C1-C 12 C2-C having alkyl 12 Alkylalkyl groups (where C1~C 12 Alkyl is an additional C2-C 12 Examples include those substituted with alkoxyalkyl groups.

[0099] R 1 Specific examples of substituents are as follows: [ka]

[0100] R 2 R 1 With respect to this, it may be any of the groups and substituents identified above, and in addition, it may be a functional group selected from those described in Part (I) of this detailed explanation. Therefore, R 2 Examples of functional groups that can function as substituents include, without limitation, halos, carboxyls, and C1-C12 12 Alkoxy, C1-C 12 Alkyl sulfanyl, C2~C 12 Ashiru, C2~C 12 Acyloxy, C2~C 12 Alkoxycarbonyl, and C6~C 18 Examples include aryloxycarbonyl (-(CO)-O-aryl).

[0101] R 2If it is anything other than H, it is usually C1 to C 12 Alkyl (e.g., C1-C8 alkyl), C1-C 12 Alkoxy (e.g., C1-C8 alkoxy), C2-C 12 It is an alkoxyalkyl (e.g., C2-C8 alkoxyalkyl) or a halo.

[0102] Halo (Br and Cl are generally preferred),

[0103] From the above description and substituent definitions, it can be inferred that many compounds can be produced using the method of the present invention. One example of a compound of formula (AA) is olivetol. That is, the compound is R 1 If is n-pentyl, m is 1, n is zero, and the substituents are in a 1,3,5 configuration, then it is oliveitol. As another example, compound (AA) is R 1 If n is n-propyl, and as in the case of oliveitol, m is 1, n is zero, and the phenyl ring is 1,3,5-trisubstituted, then it is divalinol. [ka]

[0104] Step 1:

[0105] The synthesis of a compound having the structure of formula (AA) is first performed using the structure of formula (AA-1). [ka] Starting materials having the structure of formula (AA-2) are used with an electron-withdrawing hydroxyl protecting reagent. [ka] (wherein m, n, and R 2The reaction proceeds by carrying out the reaction under conditions effective for obtaining a hydroxyl-protected intermediate having (as previously defined, where PR represents an electron-withdrawing hydroxyl protecting group). The starting material (AA-1) can be obtained commercially or synthesized using procedures known to those skilled in the art or readily available.

[0106] The electron-withdrawing protecting group PR can be one of any number of electron-withdrawing protecting groups. In one embodiment, -O-PR represents a sulfonic acid ester. In some embodiments, -O-PR is -O-(SO2)-R 3 (In the formula, R 3 The C1-C atoms are optionally substituted with one or more non-hydrogen substituents and optionally contain at least one heteroatom. 12 Hydrocarbyl; C1~C 12 It can be expressed as perfluorocarbyl (selected from fluoro). Examples of such protecting groups include tosylate, mesylate, triflate (trifluoromethanesulfonate), benzyl sulfonate, 2-[(4-nitrophenyl)ethyl)sulfonate, and fluorosulfate, which correspond to the -O-PR portion below: [ka]

[0107] It should be understood that the above -O-PR portion is intended to be a representative and non-limiting example of an electron-withdrawing protecting group useful in carrying out the present invention.

[0108] Suitable electron-withdrawing hydroxyl protecting reagents for performing hydroxyl group protection as -O-PR are known to those skilled in the art or can be found in relevant texts and literature where the reaction conditions are commonly used. For example, the hydroxyl group of compound (AA-1) can be protected by treatment of (AA-1) using an electron-withdrawing hydroxyl protecting reagent as follows:

[0109] (AA-1) is treated with approximately equimolar amounts of p-toluenesulfonyl chloride (Ts-Cl) in a suitable solvent, such as aqueous tetrahydrofuran (THF), aqueous toluene, dichloromethane (DCM), or pyridine, in the presence of a base, such as triethylamine, pyridine, dimethylaminopyridine (DMAP), sodium carbonate [NaHCO3], sodium hydroxide, potassium hydroxide, or any combination thereof, at a temperature in the range of about 10°C to about 40°C, preferably about 30°C to about 40°C, and for a reaction time of about 0.5 hours to about 5 hours, to obtain (AA-2), in which -O-PR is a tosylate ester.

[0110] (AA-1) is treated with methanesulfonyl chloride ("mesyl chloride") or methanesulfonic anhydride in the presence of a base and in a suitable solvent (both usually selected from those exemplified for tosylation) to obtain (AA-2), in which -O-PR is the mesylate.

[0111] (AA-1) is treated with trifluoromethanesulfonic anhydride in the presence of a base and in a suitable solvent (as before) to obtain (AA-2), in which -O-PR is triflate.

[0112] (AA-1) is treated with benzenesulfonyl chloride or nitrobenzylsulfonyl chloride in the presence of a base and in a suitable solvent (as before) to obtain (AA-2), where -O-PR is benzenesulfonate or nitrobenzylsulfonate, respectively.

[0113] (AA-1) is treated with 2-[(4-nitrophenyl)ethyl)sulfonyl chloride in the presence of a base and in a suitable solvent (as before) to obtain (AA-2), in which -O-PR is 2-[(4-nitrophenyl)ethyl)sulfonate, or

[0114] (AA-1) is treated with sulfuryl fluoride (as before) in the presence of a base and in a suitable solvent to obtain (AA-2), in which -O-PR is a fluorosulfate ester (Lekkala et al.) See al. (2019) Organic Chemistry Frontiers 6: 3490-3516.

[0115] The hydroxyl-protected compound (AA-2) may or may not be isolated and purified at this point. In some cases, it may be preferable for the reaction to proceed as a "one-pot" reaction without isolating (AA-2) before continuing the reaction. For example, the synthesis of (AA) may be carried out in a flow reactor in which the starting materials are introduced from the first inlet and the final product is obtained downstream without isolating any intermediates in between.

[0116] Step 2:

[0117] Next, in the presence of a catalyst to promote the cross-coupling reaction, the hydroxyl-protected intermediate (AA-2) and reactant R 1 -M(here, R 1 As previously defined, it undergoes a cross-coupling reaction with (where M contains a metallic element) to form the structure of formula (AA-3). [ka] To obtain a compound having the following properties.

[0118] The reaction is R 1 Since the reaction involves the coupling of compound (AA-3) to the aromatic ring of -M, it is recognized as an sp2-sp3 cross-coupling reaction. As is well known in the art, cross-coupling reactions conventionally involve the metal-catalyzed coupling of an sp2-hybridized substituted aryl electrophile with an organometallic nucleophile, the aryl electrophile may be a phenol derivative or an aryl halide. Many techniques are suitable for performing this step and are described in the literature. These cross-coupling techniques include:

[0119] Negishi cross-coupling. Co-reactant R 1-M (i.e., the reactant that cross-couples with (AA-2)) is usually R 1 The compound is -Zn-X (where X is a halo), and the catalyst used is usually palladium or nickel (Negishi et al. (1977)). See J. Org. Chem. 42(10): 1821-23.

[0120] Suzuki-Miyaura cross-coupling. Co-reactant R 1 -M is the organoboron reagent R 1 -B(OH)2 or R 1 The formula is -B(OR)2 (where R is hydrocarbyl), the catalyst is generally palladium or nickel, as in the case of the Negishi cross-coupling reaction, and the reaction proceeds in the presence of a base (Miyaura et al. (1995)). Chem. Rev. 95: 2457-83 and Minard et al. (2014) Eur. J. Org. Chem. See pages 2942-55).

[0121] Furstner cross-coupling. Co-reactant R 1 -M is structure R 1 -A Grignard reagent containing MgBr, using an iron-based catalyst, i.e., a salt or iron-containing organometallic complex (e.g., FeCl2, FeCl3, Fe(acac)2, or Fe(acac)3 (where "acac" is an acetylacetonate ligand) (see Furstner et al. (2002) J. Am. Chem. Soc. 124(46): 13856-63),

[0122] Kumada cross-coupling. Co-reactant R 1 -M is Grignard reagent R 1 -MgBr, and the catalyst is generally a palladium, nickel, or iron catalyst (Tamao et al.). (1976) Bull. Chem. Soc. Jpn. 49:1958 and Jiro (1992) J. Synth. Org. Chem. 50(12): 1125-30), and

[0123] Corey-House synthesis. Co-reactant R 1 -M is (R 1 )2CuLi or R 1 -MgBr is the catalyst, and Cu catalysts are commonly used (see Posner et al. (1975) Organic Reactions 22: 253-400).

[0124] The aforementioned publications are incorporated herein by reference with respect to disclosed reactants, procedures, and reaction conditions that can be used in connection with the present invention to obtain compound (AA-3).

[0125] Preferred cross-coupling reactions described herein are carried out at reaction temperatures below about 25°C, for example, below about 15°C, below about 5°C, below about -5°C. For example, the cross-coupling reaction temperature may be in the range of about -25°C to about 25°C, for example, about -20°C to about 20°C, about -15°C to about 15°C, about -10°C to about 10°C, about -15°C to about 5°C, about -15°C to about 0°C, about -15°C to about -10°C, about -5°C to about 5°C, about -25°C to about 5°C, about -25°C to about -5°C, or about -10°C.

[0126] Negishi, Suzuki-Miyaura, and Furstner cross-couplings are generally preferred herein, and iron-catalyzed Furstner couplings are particularly preferred, insofar as the reaction can be carried out under relatively mild conditions and iron catalysts tend to be low-cost, non-toxic, and selective.

[0127] In one embodiment, R 1 The substituent is introduced using the Furstner reaction, with approximately 1 to 1.5 equivalents of Grignard reagent R 1-MgBr is used. The reaction temperature is maintained in the range of about -15°C to about -5°C, preferably in the range of about -15°C to about -10°C. Either ferric chloride or ferric acetylacetone (Fe(acac)3) is used to catalyze the reaction. The catalyst packing amount is in the range of about 5 mol% to about 10 mol%, and the reaction is carried out in a solvent such as THF or a THF / toluene mixture, with additives that promote cross-coupling with the iron salt (e.g., Neidig et al. (2019), "Development and Evolution of Mechanistic See "Understanding in Iron-Catalyzed Cross-Coupling," Acc Chem Res 52(1): 140-150. For example, this is carried out in the presence of N-methylpyrrolidone (NMP), tetramethylethylenediamine (TMEDA), N,N'-dimethylethyleneurea (DMEU), and N,N'-dimethylpropyleneurea (DMPU). See, for example, Examples 1 and 3 of this specification.

[0128] R 1 -M reagent is a variety of R 1 Substituent (R 1 It will be noted that it is possible to select to obtain an AA-3 intermediate having (as previously defined in this section).

[0129] Compound (AA-3) can be isolated and purified at this point, but if desired, the next step in the synthesis, deprotection, can be carried out in the same reaction vessel without isolation and purification, as described for the first reaction step and intermediate (AA-2).

[0130] A compound having the structure of formula (AA-3) is considered to be a novel chemical component and is therefore claimed herein. In one embodiment, m is 1, n is zero, and R 1 It is n-pentyl, and the ring is 1,3,5-trisubstituted, thus the compound has structure (AA-4): [ka] It has.

[0131] Step 3:

[0132] In the final step of this synthesis, compound (AA-3) is deprotected to obtain the desired final product, compound (AA). The deprotection reagents and reaction conditions for removing the hydroxyl protecting group are known to those skilled in the art and are described throughout relevant texts. For example, see Greene et al., "Protective Groups in Organic Synthesis," 3rd Ed. (New York: John Wiley & Sons, 1999). For example, the tosyl group is Na / NH Greene states that the tosyl group can be removed by reductive cleavage using 3 or by treatment with sodium borohydride or lithium aluminum hydride. In this method, the tosyl group is preferably removed with potassium hydroxide, sodium hydroxide, isobutyl alcohol, or t-butyl alcohol. The benzyl sulfonate can be cleaved with sodium amide, while the mesylate group can be removed by photolysis in the presence of potassium iodide, the triflate group can be removed by acid and hydrolysis, and the fluorosulfate protecting group can be removed with a strong aqueous base or under hydride conditions. After deprotection, the reaction product can be isolated and then purified by any suitable means or combination thereof, for example, by filtration, extraction, crystallization or recrystallization, or by chromatographic means. Alternatively, the reaction product can be used without purification in subsequent synthesis, i.e., in a "one-pot" reaction. For example, the reaction product can be used immediately in the synthesis of CBD or its analogues, as described in Part VII of this detailed description. See also Example 28 relating to the synthesis of oliveitol via a shortened reaction.

[0133] In one embodiment, n is zero, and therefore the starting compound of formula (AA-1) is dihydroxy- or trihydroxybenzene. If m is also zero, compound (AA-1) will be recognized as dihydroxybenzene, i.e., 1,2-dihydroxybenzene, 1,3-dihydroxybenzene, or 1,4-dihydroxybenzene. If n is zero and m is 1, compound (AA-1) is trihydroxybenzene, usually 1,2,4-trihydroxybenzene or 1,3,5-trihydroxybenzene. The latter compound is also known as phloroglucinol.

[0134] The starting material compound (AA-1) is phloroglucinol, and R 1 -M co-reactant R 1 If n-pentyl is present, the reaction product (AA) is oliveitol: [ka] Therefore, in one embodiment, the present invention provides a method for synthesizing olivetol and its analogues, which yields highly pure reaction products and does not produce harmful byproducts, and which can be scaled up to an efficient and economical process.

[0135] The purified reaction products include compound (AA), as well as compounds whose reaction products have the structure of formula (AA-5) and compound (AA-6). [ka] [In the formula,

[0136] n is zero, 1, or 2.

[0137] R 1 and R 2 This is as previously defined for compounds of formula (AA),

[0138] If n is 2, then R 2 [They can be the same or different.] The composition may include additional compounds in which cross-coupling occurs at two ring hydroxyl sites instead of one, such as including the above.

[0139] The molar ratio of (AA-5) to (AA-6) in the purified reaction product can vary. Generally, (AA-6) corresponds to a maximum of approximately 2 mol% of the (AA-5) and (AA-6) combination, while (AA-5) corresponds to a corresponding amount of over 98 mol% of (AA-5) plus (AA-6), thus the molar ratio of (AA-5) to (AA-6) is at least approximately 49:1. More typically, (AA-6) corresponds to a maximum of approximately 0.1 mol% of the (AA-5) and (AA-6) combination, while (AA-5) corresponds to a corresponding amount of over 99.9 mol% of (AA-5) plus (AA-6). In one embodiment, (AA-6) corresponds to a maximum of approximately 0.01 mol% of the combination of (AA-5) and (AA-6), while (AA-5) corresponds to approximately 99.99 mol% or more of (AA-5) plus (AA-6). In another embodiment, (AA-6) corresponds to a range of approximately 0.001 mol% to approximately 2 mol% of the combination of (AA-5) and (AA-6), while (AA-5) corresponds to approximately 98 mol% to approximately 99.999 mol% of the combination of (AA-5) plus (AA-6).

[0140] If the starting material (AA-1) is phloroglucinol, then compounds (AA-5) and (AA-6) have the structures of compounds (AA-7) and (AA-8), respectively. [ka]

[0141] Substituent R 1 This is as previously defined for compounds having structure (AA).

[0142] Typical (AA) reactants:

[0143] It will be recognized that various compounds are included in (AA) and can be synthesized using the methods described above. These include the following compounds, collectively referred to herein as “(AA) type reactants”:

[0144] At position 5, substituted or unsubstituted C1-C containing zero to three heteroatoms. 12 Alkyl, substituted or unsubstituted C2-C containing zero to three heteroatoms 12 Alkenyls, substituted or unsubstituted C2-C atoms containing zero to three heteroatoms 12 Alkynyl-substituted 1,3-dihydroxybenzene, 1,2-dihydroxybenzene, or 1,4-dihydroxybenzene, which include linear, branched, and cyclic portions that may be substituted or unsubstituted and / or contain heteroatoms.

[0145] Substituted or unsubstituted C1-C atoms containing zero to three heteroatoms 12 Alkyl, substituted or unsubstituted C2-C containing zero to three heteroatoms 12 Alkenyls, substituted or unsubstituted C2-C atoms containing zero to three heteroatoms 12 Phenolic compounds that are ortho, para, or meta-substituted with alkynyl groups, which may be substituted or unsubstituted and / or contain heteroatoms, and which include linear, branched, and cyclic groups, as well as

[0146] Same or different, substituted or unsubstituted C1-C containing zero to three heteroatoms 12 Alkyl, substituted or unsubstituted C2-C containing zero to three heteroatoms 12 Alkenyls, substituted or unsubstituted C2-C atoms containing zero to three heteroatoms 12 Phenols that are ortho- and meta-disubstituted, ortho- and para-disubstituted, or meta- and para-disubstituted with two substituents selected from alkynyls, including linear, branched, and cyclic moies that may be substituted or unsubstituted and / or contain heteroatoms.

[0147] For example, R 1 The substituents are -(CH2)-(CO)-NHCH3, -(CH2)-(CO)-NHCH2CH3, -(CH2)-(CO)-NH-(CH2)2CH3, -(CH2)-(CO)-NH-(CH2)3CH3, -(CH2)-(CO)-NH-(CH2)4CH3, -(CH2)2-(CO)-NHCH3, -(CH2)2-(CO)-NHCH2CH3, -(CH2)2-(CO)-NH-(CH2)2CH3, -(CH2)2-(CO)-NH-(CH2)3CH3, -(CH2)2-(CO)-NH-(CH2)4CH3, -(CH2)3-(CO)-NHCH3, -(CH2)3-(CO)-NHCH2CH3, -(CH2)3-(CO)-NH-(CH2)2CH3, -(CH2)3-(CO)-NH-(CH2)3CH3, -(CH2)3-(CO)-NH-(CH2)3CH3, -(CH2)-NHCH3, -(CH2)-NHCH2CH3, -(CH2)-NH-(CH2)2CH3, -(CH2)-NH-(CH2)3CH3, -(CH2)2-NHCH3, -(CH2)2-NHCH2CH3, -(CH2)2-NH-(CH2)2CH3, -(CH2)2-NH-(CH2)3CH3, -(CH2)3-NHCH3, -(CH2)3-NHCH2CH3, -(CH2)3-NH-(CH2)2CH3, -(CH2)3-NH-(CH2)3CH3, -(CH2)3-NH-(CH2)4CH3, -(CH2)-(SO2)-CH3, -(CH2)-(SO2)-CH2CH3, -(CH2)-(SO)2-(CH2)3CH3, -(CH2)-(SO2)-(CH2)4CH3, -(CH2)2-(SO2)-CH3, -(CH2)2-(SO2)-CH2CH3, -(CH2)2-(SO2)-(CH2)3CH3, -(CH2)2-(SO2)-(CH2)4 CH3, -(CH2)3-(SO2)-CH3, -(CH2)3-(SO2)-CH2CH3, -(CH2)3-(SO2)-(CH2)3CH3, -(CH2)3-(SO2)-(CH2)4CH3, -(CH2)-(SO2)-NH-CH3, -(CH2)-(SO2)-NH-CH2CH3, -(CH2)-(SO2)-NH-(CH2)2CH3, -(CH2)-(SO2)-NH-(CH2)4CH3, -(CH2)2-(SO2)-NH-CH3, -(CH2)2-(SO2)-NH-CH2CH3, -(CH2)2-(SO2)-NH -(CH2)2CH3, -(CH2)2-(SO2)-NH-(CH2)4CH3, -(CH2)3-(SO2)-NH-CH3, -(CH2)3-(SO2)-NH-CH2CH3, -(CH2)3-(SO2)-NH-(CH2)2CH3, -(CH2)3-(SO2)-NH-(CH2)4CH3, -CH2-O-CH3, -CH2-O-CH2CH3, -CH2-O-(CH2)2CH3, -CH2-O-(CH2)3CH3, -CH2-O-(CH2)4CH3, -(CH2)2-O-CH3, -(CH2)2-O-CH2CH3, -(C H2)2-O-(CH2)2CH3、-(CH2)2-O-(CH2)3CH3、-(CH2)2-O-(CH2)4CH3、-(CH 2)3-O-CH3、-(CH2)3-O-CH2CH3、-(CH2)3-O-(CH2)2CH3、-(CH2)3-O-(CH2) 3CH3、-(CH2)3-O-(CH2)4CH3、-O-CH3、-O-CH2CH3、-O-(CH2)2CH3、-O-(CH2 )3CH3、-O-(CH2)4CH3、-O-CH2-O-CH3、-O-(CH2)2-OCH3、-O-(CH2)3-OCH3、-O-(CH2)3-OCH3, -O-CH2-O-CH2CH3, -O-(CH2)2-CH2CH3, -O-(CH2)3-OCH2CH3, -O-(CH2)3-OCH2C H3, -O-CH2-O-(CH2)2CH3, -O-(CH2)2-O-(CH2)2CH3, -O-(CH2)3-O(CH2)2CH3, -O-(CH2)3-O(CH2) 2CH3, -O-CH2-O-(CH2)2CH3, -O-(CH2)2-O-(CH2)2CH3, -O-(CH2)3-O(CH2)2CH3, -O-(CH2)3-O(CH 2)2CH3, -CH2-O-CH2-O-CH3, -CH2-O-(CH2)2-OCH3, -CH2-O-(CH2)3-OCH3, -CH2-O-(CH2)3-OCH3, [ka] That's fine. III. Synthesis of CBD and CBD Analogues:

[0148] A. Synthesis of CBD and CBD analogs from compound (AA):

[0149] In another embodiment, a method is provided for synthesizing cannabidiol or an analogue of it from a compound synthesized in a preceding section, namely, a compound (AA) which may itself be olivetol, as previously described. Compound (AA) may be isolated and purified before use in this synthesis using conventional means or methods readily apparent to those skilled in the art. However, compound (AA) can be used in the present synthesis as prepared, without isolation and purification.

[0150] In this embodiment, the method is the structure of formula (CC) [ka] [In the formula,

[0151] m is either zero or 1.

[0152] n is zero, 1, or 2.

[0153] R 1 and R 2 It is defined similarly to the compound of formula (AA),

[0154] R 5 This is H, carboxyl, C2-C6 acyloxy, C2-C6 alkoxycarbonyl, C1-C6 alkyl, or a C1-C6 alkyl substituted with hydroxyl, carboxyl, or halo.

[0155] R 6 and R 7 These are, independently, C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Selected from hydrocarbyl and functional groups,

[0156] R 8 This results in the synthesis of compounds having methyl, hydroxymethyl, or halomethyl compounds.

[0157] In one embodiment,

[0158] R 1 teeth,

[0159] C1~C 18 Alkyl (for example, C1~C 12 Alkyl, C1-C 10 Alkyl, or C1-C8 alkyl, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, n-pentyl, cyclohexyl, etc.)

[0160] C2~C 18 Alkenyl (for example, C2~C 12 Alkenyl, C2~C 10 Alkenyls or C2-C8 alkenyls)

[0161] C2~C18 Alkinyl (for example, C2~C 12 Alkinyl, C2~C 10 Alkinyl or C2-C8 alkynyl),

[0162] C6~C 18 Aralkyl (for example, C5-C6 aryl substitution C1-C) 12 Alkyl or C5-C6 aryl-substituted C1-C8 alkyl),

[0163] C4~C 16 Heteroaralkyl (e.g., C3-C6 heteroaryl substitution C1-C) 10 Alkyl or C3-C6 heteroaryl-substituted C1-C8 alkyl, (where the heteroaryl substituent may be saturated or unsaturated),

[0164] C1~C 18 Haloalkyl (for example, C1-C) 12 Chloroalkyl, C1-C 10 Chlorine Alkyl, C1-C8 chloroalkyl, C1-C 12 Fluoroalkyl, C1-C 10 Fluoroalkyl, or C1-C8 fluoroalkyl,

[0165] C1~C 18 Hydroxyalkyl (for example, C1-C 12 Hydroxyalkyl, C1-C 10 Hydroxyalkyl, or C1-C8 hydroxyalkyl,

[0166] C2~C 18 Haloalkenyls (e.g., C2~C) 12 Chloroalkenyl, C2~C 10 Chloroalkenyl, C2-C8 chloroalkenyl, C2-C 12 Fluoroalkenyl, C2~C 10 Fluoroalkenyls or C2-C6 fluoroalkenyls),

[0167] C2~C 18Haloalkynyl (for example, C2~C 12 Chloroalkynyl, C2~C 10 Chloroalkynyl, C2-C8 chloroalkynyl, C2-C 12 Fluoroalkynyl, C2~C 10 Fluoroalkynyl or C2-C6 fluoroalkynyl),

[0168] C2~C 18 Alkoxyalkyl (e.g., (C1-C8 alkoxy)-substituted C1-C 12 Alkyl or (C1-C8 alkoxy)-substituted C1-C8 alkyl),

[0169] C2~C 18 Alkoxyalkenyl (e.g., (C1-C8 alkoxy)-substituted C2-C) 12 Alkenyl or (C1-C8 alkoxy)-substituted C2-C8 alkenyl),

[0170] C2~C 12 Alkoxyalkynyl (e.g., (C1~C8 alkoxy)-substituted C2~C 12 Alkynyl or (C1-C8 alkoxy)-substituted C2-C8 alkynyl),

[0171] C2~C 18 Carboxyalkyl (for example, C2~C 12 Carboxyalkyl, C2~C 10 Carboxyalkyl, or C2-C8 carboxyalkyl),

[0172] C3~C 18 Carboxyalkenyl (e.g., C3-C3) 12 Carboxyalkenyl, C3~C 10 Carboxyalkenyl, or C3-C8 carboxyalkenyl)

[0173] C1~C 18C1~C8 alkyl, for example, mono-(C1~C8 alkyl)-substituted carbamoyl (-(CO)-NH(C1~C8 alkyl)) or di-(C1~C8 alkyl)-substituted carbamoyl (-(CO)-N(C1~C8 alkyl)2) 12 Alkyl,

[0174] C2~C 18 Alkenyls, for example, mono-(C1~C8 alkyl)-substituted carbamoyl (-(CO)-NH(C1~C8 alkyl)) or di-(C1~C8 alkyl)-substituted carbamoyl (-(CO)-N(C1~C 12 C2~C substituted with alkyl)2) 12 Alkenil,

[0175] C1~C 18 C1-C8 alkylamides (-NH-(CO)-alkyl) are substituted with alkyl groups. 12 Alkyl,

[0176] C2~C 18 C2-C8 alkylamides substituted with alkenyls, for example, C2-C8 alkylamides (-NH-(CO)-alkenyls) 12 Alkenil,

[0177] C1~C 18 C1~C8 alkyl groups, for example, C1~C8 alkyl groups substituted with -NH-(C1~C8 alkyl) or -N(C1~C8 alkyl)2. 12 Alkyl,

[0178] C2~C 18 Alkenyls, for example, C2-C2 substituted with -NH-(C1-C8 alkyl) or -N(C1-C8 alkyl)2. 12 Alkenil,

[0179] C1~C 18 Alkyl, for example, C1-C8 alkylsulfonyl (-SO2-alkyl) substituted C1-C8 12 Alkyl,

[0180] C2~C 18Alkenyls, for example, C2-C8 alkylsulfonyl (-SO2-alkyl) substituted with C1-C8 alkylsulfonyl (-SO2-alkyl) 12 Alkenil,

[0181] C1~C 18 C1-C1 substituted with alkyl groups, for example, C0-C8 sulfonamides (-SO2-NH2 or -SO2-N alkyl groups) 12 Alkyl,

[0182] C2~C 18 C2-C2 substituted with alkenyls, for example, C0-C8 sulfonamides (-SO2-NH2 or -SO2-N alkyl). 12 Alkenil,

[0183] C1~C 18 Alkyl compounds, such as morpholino and diazinyl, generally have the nitrogen atom of a nitrogen heterocycle substituted with oxanyl, morpholino, or diazinyl, resulting in C1-C1 rings. 12 Alkyl, or

[0184] C2~C 18 Alkenyls, such as morpholino and diazinyl, generally refer to C2-C carbon atoms where the nitrogen atom of a nitrogen heterocycle is substituted with oxanyl, morpholino, or diazinyl. 12 Alkenil Selected from.

[0185] As mentioned earlier, the representative R 1 Any of the substituents may be further substituted with one or more additional substituents, which may or may not be the same as the substituents identified above. Such R 1 Examples of substituents include C1-C11, which are disubstituted with Cl or F. 18 Alkyl groups (for example, C1-C) 12 Alkyl alkyl groups, C1-C 10 Alkyl, or C1-C8 alkyl group); one or more C2-C 18 C2-C substituted with alkoxyalkyl groups 18Alkoxyalkyl groups, for example, structure (C1-C6 alkoxy)-substituted C1-C 12 C2-C having alkyl 12 Alkylalkyl groups (where C1~C 12 Alkyl is an additional C2-C 12 (substituted with alkoxyalkyl groups), if present, C2-C2 atoms are typically substituted with one or more heterocyclic substituents, e.g., oxanyl, morpholino, or diazinyl, by linking to the nitrogen atom within the heterocycle. 18 Examples include alkoxyalkyl groups.

[0186] In this embodiment, compound (AA), which can be commercially obtained or used as-synthesized as described in Section II, has the structure of formula (CC-1). [ka] [In the formula, L is a leaving group, for example, hydroxyl, triflate, Br, Cl, etc., and hydroxyl is preferred, R 5 ~R 8 A Lewis acid-catalyzed coupling reaction is carried out with a second reactant having [as defined above]. The reaction produces the reaction product (CC). [ka] This results in...

[0187] Compound (AA) has structure (AA-9) [ka] If it has the structure (CC-1), the reaction product (CC) is structure (CC-1) [ka] It has.

[0188] If L is hydroxyl, then R 5 and R 8 is methyl, and R 6 and R7 is H, and the reactant of formula (CC-1) is the structure of formula (3) (Δ-2,8-mentadiene-1-ol) (sometimes referred to herein as "(+)-mentadienol"). [ka] It has, and therefore the reaction product with (AA-9) has structure (CC-2) [ka] It has.

[0189] When n is zero, the reaction product has the structure of formula (CC-3). [ka] It has.

[0190] R of reactant (AA) 1 By changing the position at 4', (R 1 Many different CBD analogs can be obtained by substituting (the position of the substituent). 1 If n-pentyl, then the compound of formula (CC-3) is CBD, and R 1 It will be understood that if n-propyl is present and cyclization is performed, the compound of formula (CC-3) is THCV. The cyclization of the second-to-last intermediate in the synthesis of THCV can be carried out using methods known to those skilled in the art, and / or described in relevant texts and literature concerning the synthesis of either THCV or THC.

[0191] Coupling reactions require Lewis acid catalysts. As is understood in the art, Lewis acid catalysts are based on metals, such as aluminum, boron, silicon, tin, titanium, iron, copper, zinc, and palladium, with aluminum and boron catalysts being the most common and generally preferred herein. An exemplary Lewis acid catalyst for cross-coupling reactions is boron trifluoride (BF3), which may be in the form of an organic complex, such as BF3 etherate (BF3·Et2O), and may be used in conjunction with a metal oxide support, such as zeolite or alumina, as needed.

[0192] The coupling of the two reactants is carried out in a suitable organic solvent, such as heptane, dichloroethane (DCE), dichloromethane (DCM), N-methylpyrrolidone (NMP), chlorobenzene, in an inert atmosphere (e.g., under argon), typically not necessarily under reflux, at high temperatures in the range of about 30°C to about 140°C, or about 30°C to about 130°C, or about 35°C to about 100°C, e.g., 35°C, 40°C, 65°C, 80°C, 85°C, or 90°C. The reaction is quenched with sodium bisulfate or another suitable base, and the product is extracted with diethyl ether or another organic solvent effective in extracting the desired product. See Examples 4 and 5. To reduce the presence of one or more contaminants in the synthesis of CBD, such as abn-CBD and tetrahydrocannabinol (THC), an excess amount of (AA) reactant may sometimes be desired. The reaction yield is in the range of approximately 30% to 60%, and the desired reaction product (CC-1) is obtained with a purity of at least approximately 95%.

[0193] After the synthesis is complete, the reaction product obtained can be modified to obtain other desired analogs, as described in Part III of this section.

[0194] As can be inferred from Examples 4-20, by changing the selected solvent, reaction temperature, catalyst packing, and stoichiometry, the composition of the reaction product can be optimized and the yield maximized, for example, by reducing the presence of contaminants. The use of molecular sieves can also be advantageous in minimizing the accidental formation of contaminants, particularly THC.

[0195] The reactants of formula (AA) have the structure of formula (AA-8). [ka] If the oliveitol has the substituted or unsubstituted properties of formula (CC-4A) and (CC-4B), the reaction products have the structures of formula (CC-4A) and (CC-4B): [ka] It contains a mixture of two positional isomers having the same properties.

[0196] R 5 and R 8 is methyl, and R 6 and R 7 When is H, the reactant of formula (CC-1) has the structure (3) as described above, and therefore the isomers of formula (CC-4A) and formula (CC-4B) ​​have the structures of formula (CC-5A) and formula (CC-5B), respectively: [ka] It has.

[0197] The composition of the reaction product generally includes at least about 98 mol% of compound (CC-5), for example, at least about 99.9 mol% of compound (CC-5), or at least about 99.999 mol% of compound (CC-5). In one embodiment, at least one additional compound selected from (CC-5A), (CC-5B), and (CC-5C) corresponds to a range of about 0.001 mol% to about 2 mol% of the composition.

[0198] It should be understood that the mentadienol ring of the synthesized CBD analog (CC-1), as described above, may be substituted in different ways, and the substituents have different possible configurations depending on the selected specific (AA) type reactant. See "Typical (AA) Reactants" in Section II.

[0199] B. Synthesis of CBD analogs from compound (AB):

[0200] In a variation of the method in Part A, the starting material that reacts with reactant (CC-4) is compound (AB-1). [ka] (where n, R 1 , and R 2 As previously defined, R A The compound is generally a C1-C4 alkyl group (e.g., methyl or ethyl). Suitable solvents, reaction temperatures, and Lewis acid catalysts are as described in Part A. The coupling reaction produces product (AB-2). [ka] This results in...

[0201] If the co-reactant (CC-1) has structure (3), the reaction product has the structure of formula (CC-6). [ka] It should be recognized that it possesses this characteristic. A typical reaction is included in Example 20 of this specification. Similar to the cross-coupling reactions described in Part A, various analogs can be synthesized in this manner by selecting appropriately substituted reactants. For example, an analog of CBD having a modification at the 4' position can be synthesized with the desired R 1 It can be prepared by starting with a substituted reactant (AB-1).

[0202] C. Synthesis of CBD and CBD analogs via the ketone pathway:

[0203] In another embodiment of the present invention, the synthesis relies on a ketone intermediate, starting with hydroxyl-protected 3,5-dihydroxybenzoic acid (DD-1), which is optionally substituted, as a starting material, and the structure of formula (DD) [ka] An alternative method for synthesizing CBD or its analogs is provided. [ka]

[0204] In the above molecular structure:

[0205] s is zero, 1, or 2.

[0206] R 1 and R 2 This is as previously defined in the preceding section, except that if s is 2, R 2 They may be the same or different.

[0207] R 5 is H, carboxyl, C2-C6 acyloxy, C2-C6 alkoxycarbonyl, C1-C6 alkyl, or a C1-C6 alkyl substituted with hydroxyl, carboxyl, or halo.

[0208] R 6 and R 7 These are, independently, C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Selected from hydrocarbyl and functional groups,

[0209] R 8These are methyl, hydroxymethyl, or halomethyl,

[0210] R 9 C1~C 11 Hydrocarbyl, substitution C1-C 11 Hydrocarbyl, heteroatom-containing C1-C 11 Hydrocarbyl and substituted heteroatom-containing C1-C 11 Selected from hydrocarbil,

[0211] PR is an electron-withdrawing hydroxyl protecting group as previously described herein.

[0212] The starting material is commercially available, for example, as benzyloxy-protected 3,5-dihydroxybenzoic acid, and one or more R 2 It can be modified to include substituents, or the desired R 2 You can also purchase the replaced analog and use it without modification.

[0213] The first step of the synthesis is to reduce (DD-1) under reducing conditions, R 9 -When reacted with Li, the structure of formula (DD-2) is obtained. [ka] This involves obtaining a hydroxyl-protected ketone intermediate having [a specific characteristic].

[0214] This is obtained by treating a carboxylic acid (DD-1) with sodium hydride, followed by a appropriately substituted lithium reagent, i.e., R as specified herein, as is known in the art. 9 This can be achieved by reacting with -Li. Then, the hydroxyl-protected ketone (DD-2) is deprotected to generate a free hydroxyl group and obtain the ketone intermediate (DD-3). . [ka]

[0215] When a benzyloxy protecting group is used, i.e., when the hydroxyl group of the starting compound (DD-1) is benzyloxy protected, deprotection can be readily achieved by hydrogenation using a Pd / C catalyst. The deprotection reaction is known in the art and is discussed in Section II concerning the deprotection of compound (AA-4).

[0216] In the next step, the intermediate (DD-3) is converted to compound (CC-1), namely (+)-mentadienol or its analogue. [ka] An electrophilic addition reaction is carried out, and in the presence of a Lewis acid catalyst, compound (CC-1) is added to the 4-position of (DD-3), thereby producing a direct precursor to compound (DD), i.e., compound (DD-4): [ka] The compound (DD-4) is then decarbonylated using conventional means to obtain the desired product (DD-3).

[0217] Similar to the synthesis described in Parts A and B of this section, this method is efficient and economical, allows the use of mild reaction conditions without requiring harsh reagents or special precautions, is readily adaptable to produce CBD analogs and CBD itself, and has little to no chance of accidental THC production.

[0218] D.CBD and CBD analog alternative synthesis:

[0219] In another embodiment of the present invention, the structure of formula (BB) [ka] [In the formula,

[0220] m is either zero or 1.

[0221] n is zero, 1, or 2.

[0222] R 1 and R 2 It is defined similarly to the compound of formula (AA),

[0223] R 4 is H, C2-C6 alkenyl, or C1-C6 alkyl, and if it is a C2-C6 alkenyl or C1-C6 alkyl, it is optionally substituted with a non-hydrogen substituent selected from hydroxyl, carboxyl, and halo.

[0224] A method is provided for synthesizing compounds having Cy which is either substituted or unsubstituted and is a 4-7 membered cyclic group containing 1-3 heteroatoms as needed. In a preferred embodiment, Cy is a 5-7 membered hydrocarbyl ring, e.g., cyclohexyl, cyclohexenyl, or phenyl, and C1-C 12 They are substituted with hydrocarbyl groups or functional groups as needed.

[0225] In one embodiment,

[0226] R 4 These are selected from isopropyl, isopropenyl, hydroxyethyl, and hydroxypropyl.

[0227] Cy is selected from cyclohexyl, cyclohexenyl, and phenyl and is optionally substituted with one or two C1-C6 alkyl, C1-C6 alkoxy, carboxyl, or halo substituents.

[0228] The method is,

[0229] (a) Structure of formula (BB-1) [ka] A compound having the structure of formula (BB-2) is used as an electron-withdrawing hydroxyl protecting reagent. [ka]

[0230] The step of reacting under conditions effective for obtaining a hydroxyl-protected intermediate having (wherein PR represents an electron-withdrawing hydroxyl protecting group), (b) In the presence of a catalyst that promotes the cross-coupling reaction, the hydroxyl-protected intermediate (BB-2) and reactant R 1 A cross-coupling reaction is carried out with -M (where M contains a metallic element) to form the structure of formula (BB-3). [ka] A step to obtain a compound having,

[0231] (c) The step of treating compound (BB-3) with a reagent composition effective in removing the hydroxyl protecting group to obtain compound (BB) and Includes.

[0232] Appropriate electron-withdrawing hydroxyl protecting reagents, PR moieties, hydroxyl protection techniques, deprotection techniques, cross-coupling reaction techniques, cross-coupling catalysts, and cross-coupling reaction conditions are described for the synthesis of compound (AA) in Section II.

[0233] In a related embodiment of this present invention, the structure of formula (CC) [ka] (In the formula, m, n, R 1 , R 2、 and R 5 ~R 8 A method is provided for synthesizing compounds having (as previously defined).

[0234] The method is,

[0235] (a) Structure of equation (BA-1) [ka] A compound having the structure of formula (BA-2) as shown above, with an electron-withdrawing hydroxyl protecting reagent. [ka] The step of reacting under conditions effective for obtaining a hydroxyl-protected intermediate having (wherein PR represents an electron-withdrawing hydroxyl protecting group as previously defined),

[0236] (b) In the presence of a catalyst that promotes the cross-coupling reaction, the hydroxyl-protected intermediate (BA-2) and reactant R 1 -M(here, R 1 -M is defined as in Section II) and a cross-coupling reaction is performed with the structure of formula (BA-3). [ka] A step to obtain a compound having,

[0237] (c) A step of treating compound (BA-3) with a deprotection reagent effective in removing the hydroxyl protecting group to obtain compound (CC), wherein compound (CC) can be isolated and purified using standard techniques, or can be used directly in subsequent reactions after preparation. Includes.

[0238] The appropriate reagents, reactants, techniques, and reaction conditions for carrying out steps (a) and (b) in the synthesis of compound (CC) are similar to, and in most respects identical to, those described in Section II for the synthesis of the olivetol analog having the structure of formula (AA), which is a CBD precursor.

[0239] In one embodiment,

[0240] R 1 C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C12 Hydrocarbyl and substituted heteroatom-containing C1-C 12 Selected from hydrocarbil,

[0241] R 2 C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Hydrocarbyl and selected from functional groups, if n is 2, R 2 They can be the same or different.

[0242] R 5 This is a C1-C6 alkyl substituted with H, carboxyl, C2-C6 acyloxy, C2-C6 alkoxycarbonyl, C1-C6 alkyl, or a C1-C6 alkyl substituted with hydroxyl, carboxyl, or halo, for example, a C1-C3 alkyl or a C1-C3 alkyl substituted with hydroxyl, carboxyl, or halo.

[0243] R 6 and R 7 H is H,

[0244] R 8 H is H,

[0245] -O-PR is a sulfonic acid ester, such as a tosylate ester or a mesylate ester.

[0246] Therefore, R 1 C1~C 10 C1-C including hydrocarbil 12 Hydrocarbyls, such as cycloalkyl, branched alkyl, cycloalkenyl, branched cycloalkenyl, etc., C1-C 10 Alkyl, C2~C 10 Alkenyl, C2~C 10 Alkinyl, and C5~C 10It may also be an aryl group, one of which may be substituted as needed, for example, with zero to three functional groups usually selected from hydroxyl, halo, carboxyl, C2-C6 acyloxy, C2-C6 alkoxycarbonyl, C2-C6 alkylamide, and combinations thereof, and zero to three heteroatoms, for example, O, S, or N(NH, NR(wherein C1-C 12 It contains hydrocarbyl, and N-heterocyclic compounds (including pyrrole, pyrrolidine, pyridine, imidazole, pyrazole, pyrazolidine, pyrazine, piperidine, azetidine, etc.).

[0247] As previously explained with respect to compound (AA), R 2 R 1 With respect to this, it may be any of the groups and substituents identified above, and in addition, a functional group selected from those shown in Part (I) of this detailed description. Therefore, R 2 Examples of functional groups that can function as substituents include, without limitation, halos, carboxyls, and C1-C12 12 Alkoxy, C1-C 12 Alkyl sulfanyl, C2~C 12 Ashiru, C2~C 12 Acyloxy, C2~C 12 Alkoxycarbonyl, and C6~C 18 Examples include aryloxycarbonyl (-(CO)-O-aryl).

[0248] In another embodiment, a method for synthesizing compound (CC) involves, prior to step (a), the structure of formula (AA-1) in the presence of a Lewis acid catalyst. [ka] The first reactant having the structure of formula (CC-1) [ka] (In the formula, m, n, L, R 2 , R 5 , R 6 , R7 , and R 8 The step further involves reacting a second reactant having (as previously defined) with the reactant as described in Part A of this section. When m is 2, n is zero, and the aromatic ring is 1,3,5-trisubstituted, the reactant of formula (AA-1) is phloroglucinol. Thus, the final product obtained using phloroglucinol as a reactant has the structure of formula (BA-4). [ka] It has, and in the reactant of formula (CC-1), when L is hydroxyl, R 5 and R 8 is methyl, and R 6 and R 7 Since is H, the reactants of formula (CC-1) have structure (3), and therefore the final product, i.e., the compound of formula (CC), has structure (CC-3). [ka] It has.

[0249] R 1 If n-pentyl is present, the compound of formula (CC-3) is CBD.

[0250] E. Modification of reaction products:

[0251] After the synthesis is complete, the reaction product can be modified as described in Parts A, B, C, or D to obtain desired analogs of the compound obtained by, for example,: hydrogenation of the isopropenyl substituent to the isopropyl group (see, e.g., Ben-Shabat et al. (2005) J.Med. Chem. 49:1113-17), substitution of the double bond of the isopropenyl group to obtain a substituted alkyl group at that position, reaction of a free hydroxyl group on the phenyl ring of the CBD structure to obtain an ether or ester substituent, etc., conversion to a tricyclic compound by performing a linkage between the isopropenyl group and the nearest hydroxyl group on the phenyl ring, aromatization of the mentadienol ring, hydrogenation of the cyclohexyl moiety of the mentadienol ring, or by a combination of two or more of the above.

[0252] IV. Cannabinoid Analogs:

[0253] It will be recognized that the synthetic methods in Section III are useful for producing a variety of cannabinoids and their analogs, including naturally occurring analogs as well as semi-synthetic or synthetic analogs not found in nature. In another embodiment, the present invention also provides cannabinoid analogs having novel molecular structures, thus representing new compositions of the substances discussed below in Part B of this Section.

[0254] A. Naturally occurring or other known CBD analogs:

[0255] Table 1 shows different R values ​​for generating variants at the 4' position of the CBD molecule. 1 -This illustrates various CBD analogs that can be prepared using the M reactant and the method in Section III:

[0256] [Table 1-1] [Table 1-2]

[0257] For example, see Morales (2017), "An Overview on Medicinal Chemistry of Synthetic and Natural Derivatives of Cannabidiol," Frontiers in Pharmacology 8: 1-18, and Jung et al. (2019), see above.

[0258] The list above is by no means limited to the compounds in the table, but merely illustrates some representative 4' analogs of CBD that can be prepared using the synthesis described above.

[0259] Additional CBD analogs are added using this synthesis, if n is non-zero, R as needed. 1 - Different R in M ​​reactants 1 Different R in combination with the selection of different arrangements of substituents on the partial and / or phenyl ring. 2 It can be prepared by selecting the base material.

[0260] For example, equation (AA-1) [ka] When the reactant of formula (where m is equal to 1 and n is equal to 1) is tetrasubstituted and the ring is 1,3,5-trihydroxylated, the compound has the structure of formula (CC-7). [ka] It has.

[0261] Reaction with (+)-mentadienol or its analogue, previously described hydroxyl protection, co-reactant R 1 After cross-coupling with -M and deprotection, the reaction product has the structure of formula (CC-8). [ka] It has.

[0262] R 1 - Different R in M 1 Select the portion and the m, n, and R in the reactant (AA-1). 2 Table 2 shows examples of analogs that can be prepared by changing the following:

[0263] [Table 2-1] [Table 2-2]

[0264] Another example of an analog base (where R 2 is morphologically -(CO)-OR 10 Table 3 shows the substituted or unsubstituted alkoxycarbonyls.

[0265] [Table 3-1] [Table 3-2]

[0266] For example, see Gotz et al. (2019), "Structure-Effect Relationships of Novel Semi-Synthetic Cannabinoid Derivatives," Frontiers in Pharmacology 10: 1284.

[0267] Other CBD analogs that can be prepared using this synthesis method include, without limitation, those having modified hydroxyl groups, such as alkoxy groups, or sometimes acyloxy groups. Analogs that can be converted before or after the reaction of (+)-mentadienol or (+)-mentadienol analog (BA-4) or (CC-3) with phloroglucinol or phloroglucinol analog (AA-1) (for examples of such compounds, see Haj et al. (2015) J. Pharmacol. Exper. Ther. 355: 66-75, e.g., compounds HU-444 and HU-445; as previously cited Jung et al. (See Chem. Asian J. 14: 3749-62, 2019); analogs having a carboxyl or ester group at position 1, which can be introduced by using appropriately substituted (+)-mentadienol analogs (BA-4) or (CC-3) (Haj et al. (2015)); analogs such as H2CBD having an isopropyl group instead of an isopropenyl substituent at position 4, which can also be achieved by using a modified (+)-mentadienol analog as a reactant, i.e., a compound having a 4-isopropyl substituent (ibid.); analogs having a substituted alkyl group, e.g., hydroxyethyl or hydroxypropyl, instead of an isopropenyl group at position 4, which can also be achieved by using a modified (+)-mentadienol analog as a reactant; "Limonene portion modified" by Jung et al. (2019) Other analogs classified as "decorated analogs"; aryl-oxidized compounds, these are also described in Jung et al. (2019); as in the case of H4CBD, (+)-methyl Analogues in which the antadienol ring is hydrogenated; Jung et al.'s "double-modified" or multiple-modified analogues having two or more types of modifications compared to CBD itself; and analogues having a larger alkenyl group than the isopropenyl group of CBD (see Kobayashi et al. (2006) Org. Lett. 8: 2699-702, William et al. (2002) J. Org. Chem. 67: 8771-82 and William et al. (2001) Org. Lett. 3: (Cited from 2017-20) is an example. The aforementioned list is not intended to be complete. This is intended to be an example of a typical CBD analog that can be prepared using this method.

[0268] As described above, the final synthesized compound(s) can be further modified, if desired, to produce additional types of analogs, for example, by partially hydrogenating the reaction product to convert the isopropenyl group of the (+)-mentadienol ring to an isopropyl group, or by completely hydrogenating the (+)-mentadienol ring to further convert it to a cyclohexyl group.

[0269] Therefore, this method can be used to produce not only CBD, but also naturally occurring CBD analogs, as well as known and unknown synthetic analogs, including metabolites, prodrugs, salts, esters, crystalline forms, and stereoisomers. Examples of these analogs, without limitation, include:

[0270] Cannabichromanone (CBCN),

[0271] Cannabichromanone-C3 (CBCN-C3),

[0272] Cannabis chromium (CBC),

[0273] Cannabichromenic acid (CBCA),

[0274] Cannabiclomevalin (CBCV),

[0275] Cannabiclomevalic acid (CBCVA)

[0276] Cannabicitran (CBCT),

[0277] Cannabis coumaronone (CBCON),

[0278] Cannabicyclol (CBL),

[0279] Cannabicycloalic acid (CBLA),

[0280] Cannabicyclovaline (CBLV),

[0281] Cannabidiol monomethyl ether (CBDM)

[0282] Cannabidiol dimethyl ether (CBDD),

[0283] Cannabidiol dimethylheptyl (CBD-DMH),

[0284] Cannabidiol dimethylheptyl-7-euic acid (HU-320),

[0285] Dimethylheptylpentylcannabidiol (DMHP-CBD),

[0286] Cannabidiolic acid (CBDA),

[0287] Cannabidiol (CBD-C1),

[0288] Cannabidiphorol (CBDP),

[0289] Cannabidivarin (CBDV),

[0290] Cannabidivaric acid (CBDVA)

[0291] Cannabis (CBE),

[0292] Cannabiellsonic acid A (CBEA-C5A),

[0293] Cannabiellsonic acid B (CBEA-C5B)

[0294] Cannabis franc (CBF),

[0295] Cannabigerosin (CBGO),

[0296] Cannabigerol (CBG),

[0297] Cannabigerol monomethyl ether (CBGM),

[0298] Cannabigerol acid A (CBGA),

[0299] Cannabigerol A monomethyl ether (CBGAM-C5A),

[0300] Cannabigerolsin (CBGO),

[0301] Cannabigerovaline (CBGV),

[0302] Cannabigerovalic acid (CBGVA),

[0303] Cannabiglendall-C3,

[0304] Cannabis mobone (CBM),

[0305] Cannabinidiol (CBND),

[0306] Cannabinodiolic (CBND-C5),

[0307] Cannabinodivarin (CBV)

[0308] Cannabinol (CBN),

[0309] Cannabinolic acid (CBNA),

[0310] Cannabinol methyl ether (CBNM),

[0311] Cannabi All Call (CBN-C1),

[0312] Cannabis xepan (CBX),

[0313] Cannabis Lipsol (CBR),

[0314] Cannabitetrol (CBTT),

[0315] Cannabitriol (CBT),

[0316] Cannabitriol-C3 (CBT-C3),

[0317] Cannabis biliary chromium,

[0318] Cannabivarin (CBV),

[0319] 7-Carboxyl-CBD,

[0320] Dehydrocannabifuran (DCBF),

[0321] 8,9-Dihydrocannabidiol (H2CBD) and H4CBD,

[0322] 10-O-ethyl-cannabitriol,

[0323] 7-Hydroxyl-CBD,

[0324] Isotetrahydrocannabinol,

[0325] Isotetrahydrocannabivarin, and

[0326] Tetrahydrocannabivarin (THCV).

[0327] B. New cannabinoids:

[0328] In another embodiment, the present invention provides novel cannabinoids, without limitation, including analogues of CBD, CBN, CBC, and THCV. The analogues can be synthesized using the methods described in Section III or any other methods described below. The novel compounds share pharmacological properties and uses, as well as certain aspects of their molecular structure, with known and / or naturally occurring cannabinoids.

[0329] The new analog has the structure of equation (EE). [ka] A CBD analog having the structure of formula (FF). [ka] A CBN analog having the structure of formula (GG) [ka] A CBC analog having, and the structure of formula (HH) [ka] Includes THCV analogs.

[0330] In a CBD analog having the structure of formula (EE), q1 is zero or 1, and q2 is zero, 1, or 2, and the substituents are as follows:

[0331] R 11 C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12Hydrocarbyl and functional groups (e.g., halo, carboxyl, C1-C) 12 Alkoxy, C1-C 12 Alkyl sulfanyl, C2~C 12 Ashiru, C2~C 12 Acyloxy, C2~C 12 Alkoxycarbonyl, and C6~C 18 Selected from aryloxycarbonyl (-(CO)-O-aryl)), if n is 2, R 11 The R atoms may be the same or different, and any two R atoms bonded to adjacent carbon atoms. 11 They may combine to form a cyclic structure selected from 5-membered and 6-membered rings, which may be condensed as needed into an additional 5-membered or 6-membered ring, and the ring may be aromatic, alicyclic, heteroaromatic, or heteroalicyclic, having zero to 4 nonhydrogen substituents and zero to 3 heteroatoms.

[0332] R 12 This is H, carboxyl, C2-C6 acyloxy, C2-C6 alkoxycarbonyl, C1-C6 alkyl, or a C1-C6 alkyl substituted with hydroxyl, carboxyl, or halo.

[0333] R 13 and R 14 These are H, C1~C independently. 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Selected from hydrocarbyl and functional groups,

[0334] R 15 These are methyl, hydroxymethyl, or halomethyl,

[0335] R 16 (a)-(CO)-NR 28 -R 29 (In the formula, R 28 is H or C1~C 12 Hydrocarbil, R 29 is C1~C12 (b)-NR (hydrocarbyl) 30 -R 31 (In the formula, R 30 is H or C1~C 12 Hydrocarbil, R 31 is C6~C 12 Hydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbil, C1-C 12 Heterohydrocarbyl, or C1-C1 substituted with at least one functional group 12 (It is a heterohydrocarbyl), (c)-(SO2)-R 32 (In the formula, R 32 is H or C1~C 12 Heterohydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbyl, or C1-C1 substituted with at least one functional group 12 (It is a heterohydrocarbyl), (d)-(SO2)-NR 33 R 34 (In the formula, R 33 is H or C1~C 12 Hydrocarbil, R 34 is H or C1~C 12 (It is hydrocarbyl.) [ka] (In the formula, L 1 (where C1-C6 alkyl is substituted with C1-C6 18 Alkyl, C2~C 18 Alkenyl, or C2~C 18 It is either alkinyl or R 16 C1~C 12 C1-C substituted with hydrocarbyl oxy 12 Hydrocarbyl oxy, as described in Section I, refers to unsubstituted hydrocarbyl, substituted hydrocarbyl, and / or heteroatom-containing hydrocarbyl.

[0336] In one embodiment, q1 is 1, q2 is zero, and the two hydroxyl groups are R 16It is positioned in a meta position relative to that.

[0337] In another embodiment, q1 is 1, q2 is zero, and the two hydroxyl groups are R 16 In relation to R, 12 and R 15 These are C1-C6 alkyl groups, for example, methyl And R 13 and R 14 H is R 16 teeth

[0338] (a)-(CO)-NR 28 -R 29 (In the formula, R 28 is H or C1-C8 alkyl, R 29 (These are C1-C8 alkyl groups.)

[0339] (b)-NR 30 R 31 (In the formula, R 30 is H or C1-C8 alkyl, R 31 is C6~C 12 Alkyl, C1-C8 alkyl substituted with at least one functional group, C1-C8 heteroalkyl, or C1-C8 heteroalkyl substituted with at least one functional group),

[0340] (c)-(SO2)-R 32 (In the formula, R 32 (This is a C1-C8 heteroalkyl group, a C1-C8 alkyl group substituted with at least one functional group, or a C1-C8 heteroalkyl group substituted with at least one functional group),

[0341] (d)-(SO2)-NR 33 R 34 (In the formula, R 33 is H or C1-C8 alkyl, R 34 (wherein H is either H or C1-C8 alkyl, and the C1-C8 alkyl group is either substituted or unsubstituted), [ka] C1~C replaced by 12 Alkyl or C2-C 12 It is alkyl.

[0342] R 12 and R 15 If is methyl, the compound of formula (EE) has the structure of formula (EE-1). [ka] (In the formula, R 16 It is a CBD analog that has the properties defined above.

[0343] Structure of equation (FF) [ka] In a CBN analog having,

[0344] q3 is zero or 1, q4 is zero, 1 or 2, and the substituents are as follows:

[0345] R 17 C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Hydrocarbyl and functional groups (e.g., halo, carboxyl, C1-C) 12 Alkoxy, C1-C 12 Alkyl sulfanyl, C2~C 12 Ashiru, C2~C 12 Acyloxy, C2~C 12 Alkoxycarbonyl, and C6~C 18 Selected from aryloxycarbonyl (-(CO)-O-aryl)), if n is 2, R 17 The R atoms may be the same or different, and any two R atoms bonded to adjacent carbon atoms. 17They may combine to form a cyclic structure selected from 5-membered and 6-membered rings, which may be condensed as needed into an additional 5-membered or 6-membered ring, and the ring may be aromatic, alicyclic, heteroaromatic, or heteroalicyclic, having zero to 4 nonhydrogen substituents and zero to 3 heteroatoms.

[0346] R 18 This is H, carboxyl, C2-C6 acyloxy, C2-C6 alkoxycarbonyl, C1-C6 alkyl, or a C1-C6 alkyl substituted with hydroxyl, carboxyl, or halo.

[0347] R 19 and R 20 These are H, C1~C independently. 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Selected from hydrocarbyl and functional groups,

[0348] R 21 These are methyl, hydroxymethyl, or halomethyl,

[0349] R 22 (a)-(CO)-NR 35 -R 36 (In the formula, R 35 is H or C1~C 12 Hydrocarbil, R 36 is C1~C 12 (b)-NR (hydrocarbyl) 37 -R 38 (In the formula, R 37 is H or C1~C 12 Hydrocarbil, R 38 is C6~C 12 Hydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbil, C1-C 12 Heterohydrocarbyl, or C1-C1 substituted with at least one functional group 12(It is a heterohydrocarbyl), (c)-(SO2)-R 39 (In the formula, R 39 is H or C1~C 12 Heterohydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbyl, or C1-C1 substituted with at least one functional group 12 (It is a heterohydrocarbyl), (d)-(SO2)-NR 40 R 41 (In the formula, R 42 is H or C1~C 12 Hydrocarbil, R 43 is H or C1~C 12 (It is hydrocarbyl.) [ka] (In the formula, L 1 is C 1 ~C 6 C1-C (which are alkyl) 18 Alkyl, C2~C 18 Alkenyl, or C2~C 18 It is either alkinyl or R 22 C1~C 12 C1-C substituted with hydrocarbyl oxy 12 Hydrocarbyl oxy, and as used in Section I, “hydrocarbyl” refers to unsubstituted hydrocarbyl, substituted hydrocarbyl, and / or heteroatom-containing hydrocarbyl.

[0350] In one embodiment, q3 and q4 are zero, and the hydroxyl group is R 22 In relation to R, 18 and R 21 R is a C1-C6 alkyl group, for example, methyl. 19 and R 20 H is R 22 teeth,

[0351] (a)-(CO)-NR 35 R 36 (In the formula, R 35 is H or C1-C8 alkyl, R36 (These are C1-C8 alkyl groups.)

[0352] (b)-NR 37 R 38 (In the formula, R 37 is H or C1-C8 alkyl, R 38 is C6~C 12 Alkyl, C1-C8 alkyl substituted with at least one functional group, C1-C8 heteroalkyl, or C1-C8 heteroalkyl substituted with at least one functional group),

[0353] (c)-(SO2)-R 39 (In the formula, R 39 (This is a C1-C8 heteroalkyl group, a C1-C8 alkyl group substituted with at least one functional group, or a C1-C8 heteroalkyl group substituted with at least one functional group),

[0354] (d)-(SO2)-NR 40 R 41 (In the formula, R 40 is H or C1-C8 alkyl, R 41 (where H is either H or a C1-C8 alkyl group, and the C1-C8 alkyl group can be either substituted or unsubstituted.) [ka] C1~C replaced by 12 Alkyl or C2-C 12 It is Alkenil.

[0355] In this embodiment, R 18 and R 21 If is methyl, the compound of formula (FF) has the structure of formula (FF-1). [ka] (In the formula, R 22 It is a CBN analog having the characteristics defined above.

[0356] In a CBC analog having the structure of formula (GG), the reactant (AA) can, in this case as well, be appropriately substituted to produce the desired CBC analog. (GG) [ka] Then q5 is zero or 1, q6 is zero, 1, or 2, the sum of q5 and q6 is not greater than 2, and the substituents are as follows:

[0357] R 23 C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Hydrocarbyl and functional groups (e.g., halo, carboxyl, C1-C) 12 Alkoxy, C1-C 12 Alkyl sulfanyl, C2~C 12 Ashiru, C2~C 12 Acyloxy, C2~C 12 Alkoxycarbonyl, and C6~C 18 Selected from aryloxycarbonyl (-(CO)-O-aryl)), if n is 2, R 23 The R atoms may be the same or different, and any two R atoms bonded to adjacent carbon atoms. 23 They joined together, and the additional 5 members It may form a cyclic structure selected from 5-membered and 6-membered rings, which is optionally condensed into a 6-membered ring, and the ring is aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and has zero to 4n3on-hydrogen substituents and zero to 3 heteroatoms.

[0358] R 24 is a C1-C6 alkyl group substituted with H, C1-C6 alkyl, or hydroxyl, carboxyl, or halo.

[0359] R 25 H, C1~C 12 Hydrocarbyl, substitution C1-C 12Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Hydrocarbyl, or a functional group,

[0360] R 26 These are methyl, hydroxymethyl, or halomethyl,

[0361] R 27 (a)-(CO)-NR 42 R 43 (In the formula, R 42 is H or C1~C 12 Hydrocarbil, R 43 is C1~C 12 (b)-NR (hydrocarbyl) 44 R 45 (In the formula, R 44 is H or C1~C 12 Hydrocarbil, R 45 is C6~C 12 Hydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbil, C1-C 12 Heterohydrocarbyl, or C1-C1 substituted with at least one functional group 12 (It is a heterohydrocarbyl), (c)-(SO2)-R 46 (In the formula, R 46 is H or C1~C 12 Heterohydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbyl, or C1-C1 substituted with at least one functional group 12 (It is a heterohydrocarbyl), (d)-(SO2)-NR 47 R 48 (In the formula, R 47 is H or C1~C 12 Hydrocarbil, R 48 is H or C1~C 12 (It is hydrocarbyl.) [ka] (In the formula, L 1 is C1 ~C 6 C1-C (which are alkyl) 18 Alkyl or C2-C 18 It is an alkenyl, or R 27 C1~C 12 C1-C substituted with hydrocarbyl oxy 12 Hydrocarbyl oxy, and as previously stated, "hydrocarbyl" refers to unsubstituted hydrocarbyl, substituted hydrocarbyl, and / or heteroatom-containing hydrocarbyl.

[0362] In one embodiment, q5 and q6 are zero, and the residual hydroxyl group is R 27 In relation to R, 24 and R 25 H is R 26 R is a C1-C6 alkyl group, 27 teeth,

[0363] (a)-(CO)-NR 42 R 43 (In the formula, R 28 is H or C1-C8 alkyl, R 43 (These are C1-C8 alkyl groups.)

[0364] (b)-NR 44 R 45 (In the formula, R 44 is H or C1-C8 alkyl, R 45 is C6~C 12 Alkyl, C1-C8 alkyl substituted with at least one functional group, C1-C8 heteroalkyl, or C1-C8 heteroalkyl substituted with at least one functional group),

[0365] (c)-(SO2)-R 46 (In the formula, R 46 (This is a C1-C8 heteroalkyl group, a C1-C8 alkyl group substituted with at least one functional group, or a C1-C8 heteroalkyl group substituted with at least one functional group),

[0366] (d)-(SO2)-NR47 R 48 (In the formula, R 47 is H or C1-C8 alkyl, R 48 (wherein H is either H or C1-C8 alkyl, and the C1-C8 alkyl group is either substituted or unsubstituted), [ka] C2~C replaced by 12 It is alkyl. In the above embodiment, compound (GG) is R 26 If it is methyl, the structure of formula (GG-1) is: [ka] (In the formula, R 27 It is a CBC analog having the characteristics defined above.

[0367] Structure of formula (HH) [ka] In the THCV analog represented by , q7 is either zero or 1, and the substituents are as follows:

[0368] R 53 C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Hydrocarbyl and functional groups (e.g., halo, carboxyl, C1-C) 12 Alkoxy, C1-C 12 Alkyl sulfanyl, C2~C 12 Ashiru, C2~C 12 Acyloxy, C2~C 12 Alkoxycarbonyl, and C6~C 18 Selected from aryloxycarbonyl (-(CO)-O-aryl),

[0369] R 49is H, carboxyl, C2-C6 acyloxy, C2-C6 alkoxycarbonyl, C1-C6 alkyl, or C1-C6 alkyl substituted with hydroxyl, carboxyl, or halo,

[0370] R 50 and R 51 are independently selected from H, C1-C 12 hydrocarbyl, substituted C1-C 12 hydrocarbyl, heteroatom-containing C1-C 12 hydrocarbyl, substituted heteroatom-containing C1-C 12 hydrocarbyl, and functional groups,

[0371] R 52 is methyl, hydroxymethyl, or halomethyl,

[0372] R 54 is (a) -(CO)-NR 55 R 56 (wherein R 55 is H or C1-C 12 hydrocarbyl, and R 56 is C1-C 12 [[ID=]](b) -NR 57 R 58 (wherein R 57 is H or C1-C 12 hydrocarbyl, and R 58 is C6-C 12 hydrocarbyl, C1-C 12 hydrocarbyl substituted with at least one functional group, C1-C 12 heterohydrocarbyl, or C1-C 12 heterohydrocarbyl substituted with at least one functional group), (c) -(SO2)-R 59 (wherein R 59 is H or C1-C 12 heterohydrocarbyl, C1-C 12 hydrocarbyl substituted with at least one functional group, or C1-C 12(heterohydrocarbyl), (d)-(SO2)-NR 60 R 61 (wherein R 60 is H or C1-C 12 hydrocarbyl, and R 61 is H or C1-C 12 hydrocarbyl), [Chemical Formula] (wherein L 1 is C1-C6 alkyl) substituted C1-C 18 alkyl, C2-C 18 alkenyl, or C2-C 18 alkynyl, or R 16 [[ID=2 )hydrocarbyloxy.

[0373] In one embodiment, q7 is zero, and R 49 and R 52 are methyl, and R 50 and R 51 are H, whereby the THCV analog having the structure (HH) is (HH-1) [Chemical Formula] (wherein R 54 is C1-C 12 alkyl or C2-C 12 alkenyl (preferably C1-C3 alkyl) substituted with:

[0374] (a)-(CO)-NR 55 R 56 (wherein R 55 is H or C1-C8 alkyl, and R 56 is C1-C8 alkyl),

[0375] (b)-NR 57 R 58 (wherein R 57 is H or C1-C8 alkyl, and R​​​​58 is C6~C 12 Alkyl, C1-C8 alkyl substituted with at least one functional group, C1-C8 heteroalkyl, or C1-C8 heteroalkyl substituted with at least one functional group),

[0376] (c)-(SO2)-R 59 (In the formula, R 32 (is a C1-C8 heteroalkyl group, a C1-C8 alkyl group substituted with at least one functional group, or a C1-C8 heteroalkyl group substituted with at least one functional group),

[0377] (d)-(SO2)-NR 60 R 61 (In the formula, R 60 is H or C1-C8 alkyl, R 61 (wherein H is either H or a C1-C8 alkyl group, and the C1-C8 alkyl group can be either substituted or unsubstituted.)

[0378] As examples of specific CBD, CBN, CBC, and THCV analogs, without limitation, the structure of formulas (EE-1), (FF-1), (GG-1), and (HH-1) (formula) is used. Medium, R 16 , R 22 , R 27 , and R 54 Examples of compounds having the following (selected from the following):

[0379] -(CO)-NHCH3;

[0380] -(CO)-NHCH2CH3;

[0381] -(CO)-NH-(CH2)2CH3;

[0382] -(CO)-NH-(CH2)3CH3;

[0383] -(CO)-NH-(CH2)4CH3;

[0384] -(CH2)-(CO)-NHCH3;

[0385] -(CH2)-(CO)-NHCH2CH3;

[0386] -(CH2)-(CO)-NH-(CH2)2CH3;

[0387] -(CH2)-(CO)-NH-(CH2)3CH3;

[0388] -(CH2)-(CO)-NH-(CH2)4CH3;

[0389] -(CH2)2-(CO)-NHCH3;

[0390] -(CH2)2-(CO)-NHCH2CH3;

[0391] -(CH2)2-(CO)-NH-(CH2)2CH3;

[0392] -(CH2)2-(CO)-NH-(CH2)3CH3;

[0393] -(CH2)2-(CO)-NH-(CH2)4CH3;

[0394] -(CH2)3-(CO)-NHCH3;

[0395] -(CH2)3-(CO)-NHCH2CH3;

[0396] -(CH2)3-(CO)-NH-(CH2)2CH3;

[0397] -(CH2)3-(CO)-NH-(CH2)3CH3;

[0398] -(CH2)3-(CO)-NH-(CH2)3CH3

[0399] -NHCH3;

[0400] -NHCH2CH3;

[0401] -NH-(CH2)3CH3;

[0402] -NH-(CH2)4CH3;

[0403] -(CH2)-NHCH3;

[0404] -(CH2)-NHCH2CH3;

[0405] -(CH2)-NH-(CH2)2CH3;

[0406] -(CH2)-NH-(CH2)3CH3;

[0407] -(CH2)2-NHCH3;

[0408] -(CH2)2-NHCH2CH3;

[0409] -(CH2)2-NH-(CH2)2CH3;

[0410] -(CH2)2-NH-(CH2)3CH3;

[0411] -(CH2)3-NHCH3;

[0412] -(CH2)3-NHCH2CH3;

[0413] -(CH2)3-NH-(CH2)2CH3;

[0414] -(CH2)3-NH-(CH2)3CH3;

[0415] -(CH2)3-NH-(CH2)4CH3;

[0416] -(SO2)-CH3;

[0417] -(SO2)-CH2CH3;

[0418] -(SO2)-(CH2)3CH3;

[0419] -(SO2)-(CH2)4CH3;

[0420] -(CH2)-(SO2)-CH3;

[0421] -(CH2)-(SO2)-CH2CH3;

[0422] -(CH2)-(SO)2-(CH2)3CH3;

[0423] -(CH2)-(SO2)-(CH2)4CH3;

[0424] -(CH2)2-(SO2)-CH3;

[0425] -(CH2)2-(SO2)-CH2CH3;

[0426] -(CH2)2-(SO2)-(CH2)3CH3;

[0427] -(CH2)2-(SO2)-(CH2)4CH3;

[0428] -(CH2)3-(SO2)-CH3;

[0429] -(CH2)3-(SO2)-CH2CH3;

[0430] -(CH2)3-(SO2)-(CH2)3CH3;

[0431] -(CH2)3-(SO2)-(CH2)4CH3;

[0432] -(SO2)-NHCH3;

[0433] -(SO2)-NH-CH2CH3;

[0434] -(SO2)-NH-(CH2)3CH3;

[0435] -(SO2)-NH-(CH2)4CH3;

[0436] -(CH2)-(SO2)-NH-CH3;

[0437] -(CH2)-(SO2)-NH-CH2CH3;

[0438] -(CH2)-(SO2)-NH-(CH2)2CH3;

[0439] -(CH2)-(SO2)-NH-(CH2)4CH3;

[0440] -(CH2)2-(SO2)-NH-CH3;

[0441] -(CH2)2-(SO2)-NH-CH2CH3;

[0442] -(CH2)2-(SO2)-NH-(CH2)2CH3;

[0443] -(CH2)2-(SO2)-NH-(CH2)4CH3;

[0444] -(CH2)3-(SO2)-NH-CH3;

[0445] -(CH2)3-(SO2)-NH-CH2CH3;

[0446] -(CH2)3-(SO2)-NH-(CH2)2CH3; and

[0447] -(CH2)3-(SO2)-NH-(CH2)4CH3.

[0448] CBD analogs having the structure of formula (EE) can be synthesized using the methods described in Section III and / or the examples of this specification, or by performing other synthesis methods that will be apparent to those skilled in the art from this disclosure. CBN analogs having the structure of formula (FF) are typically of the structure of formula (FF-P). [ka] Prepared from starting materials having the following characteristics: Rigby (1971) J. Chem. Soc. Section C: It can be readily synthesized using the methods of Organic (4):765-768. The starting material (FF-P) may be prepared in a substituted form or substituted after synthesis, depending on the desired CBN analog. The synthesis of CBN analogs is described in Examples 24-27. Generally, CBC and CBC analogs having structure (GG) are synthesized by the following reaction (a) or (b): [ka] Cannabichromene can be synthesized according to either of the following methods, and the CBC analog can be obtained as a reaction product by starting with a appropriately substituted olivetol analog, i.e., compound (AA). See also Polllastro et al. (2018) Nat. Prod. Comm. 13(9): 1189-1194, which describes the synthesis of cannabichromene. THCV as used herein Typical synthesis methods of THCV that are readily adaptable to the preparation of analogs (in this case as well, by selecting appropriately substituted phloroglucinol, which then reacts to yield appropriately substituted divalinol intermediates) are described in Examples 3 and 21.

[0449] V. Pharmaceutical preparations and methods of use:

[0450] A pharmaceutical formulation suitable for the administration of cannabinoids synthesized as described herein is a composition in which the cannabinoid is contained as a pharmacological activator in a "therapeutably effective" amount, i.e., an amount effective in achieving its intended purpose. The cannabinoid may be in the form of a reaction product composition, but more typically in an isolated and purified form.

[0451] Determining the therapeutically effective dose for any particular cannabinoid is within the scope of the skills of those skilled in the art. Generally, the toxicity and therapeutic efficacy of the compounds or compositions described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., procedures used to determine the maximum tolerated dose (MTD), ED50 (effective dose for achieving 50% of the maximum response), and therapeutic index (TI) (ratio of MTD to ED50). Compounds and compositions with high TI are more preferred herein, and preferred dosing regimens are those that maintain plasma levels of the lowest or higher concentration of the active ingredient to maintain the desired therapeutic effect. Dosage naturally also depends on several factors, including the specific compound or composition, the intended site of delivery, the route of administration, and other relevant factors known to the prescribing physician.

[0452] The cannabinoids of the present invention can be administered using any suitable mode of administration. Therefore, administration may be, for example, orally, parenterally, percutaneously, transmucosally (including rectally and transvaginally), sublingually, by inhalation, or via an embedded reservoir within the dosage form. The term "parenterally," as used herein, is intended to include subcutaneous, intravenous, and intramuscular injection. Depending on the intended mode of administration, the pharmaceutical formulation containing the cannabinoid may be solid, semi-solid, or liquid, for example, in unit dosage forms suitable for a single dose of a precise amount, such as tablets, capsules, caplets, solutions, suspensions, emulsions, suppositories, granules, pellets, beads, or powders. Suitable pharmaceutical compositions and dosage forms are known to those skilled in the art of pharmaceutical formulation, as well as described in relevant texts and literature, e.g., Remington: The Science and Practice of Pharmacy (Easton, Pa.: Mack Publishing Co., 1995). It can be prepared using conventional methods. For orally active compounds, oral dosage forms are generally preferred, which include tablets, capsules, caplets, solutions, suspensions, and syrups, and may also include multiple granules, beads, powders, or pellets, which may or may not be encapsulated. Preferred oral dosage forms are tablets and capsules.

[0453] Tablets can be manufactured using standard tablet processing procedures and equipment. Direct compression and granulation techniques are preferred. In addition to activators, tablets generally contain inert, pharmaceutically acceptable carrier materials, such as binders, lubricants, disintegrants, fillers, stabilizers, surfactants, and colorants.

[0454] Capsules are also a preferred oral dosage form for orally active cannabinoids, in which case the cannabinoid-containing preparation may be encapsulated in liquid or solid form (including fine particles, e.g., granules, beads, powders, or pellets). Suitable capsules may be either rigid or flexible and are generally made from gelatin, starch, or cellulosic materials, with gelatin capsules being preferred. Two-piece rigid gelatin capsules are preferably sealed, for example, with a gelatin band. See, for example, Remington: The Science and Practice of Pharmacy cited above, which describes materials and methods for preparing encapsulated pharmaceuticals.

[0455] Whether in the form of tablets, capsules, caplets, or microparticles, oral dosage forms can be formulated to provide a slow, sustained release of cannabinoids over a long period of time, if desired. Generally, as is recognized by those skilled in the art, sustained-release dosage forms are formulated by dispersing cannabinoids in a matrix of gradually hydrolyzable materials, such as hydrophilic polymers, or by coating solid drug-containing dosage forms with such materials. Examples of hydrophilic polymers useful for obtaining sustained-release coatings or matrices include: cellulosic polymers, e.g., hydroxypropylcellulose, hydroxyethylcellulose, hydroxypropylmethylcellulose, methylcellulose, ethylcellulose, cellulose acetate, and sodium carboxymethylcellulose; acrylic polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, alkyl acrylates, alkyl methacrylates, etc., e.g., copolymers of acrylic acid, methacrylic acid, methyl acrylate, ethyl acrylate, methyl methacrylate and / or ethyl methacrylate; and vinyl polymers and copolymers, e.g., polyvinylpyrrolidone, polyvinyl acetate, and ethylene-vinyl acetate copolymers.

[0456] Preparations for parenteral administration of cannabinoids include sterile aqueous and non-aqueous solutions, suspensions, and emulsions. Aqueous solutions for injection contain cannabinoids in a water-soluble form. Examples of non-aqueous solvents or vehicles include fatty oils, such as olive oil and corn oil. Examples include koshi oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, low molecular weight alcohols, such as propylene glycol, synthetic hydrophilic polymers, such as polyethylene glycol, and liposomes. Parenteral formulations may also contain adjuvants, such as solubilizers, preservatives, wetting agents, emulsifiers, dispersants, and stabilizers, and aqueous suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, and dextran. Injectable formulations are sterilized by incorporating a sterilizing agent, filtration through a bacterial retention filter, irradiation, or heating. Injectable formulations may also be manufactured using sterile media for injection. The activators may also be in a dry, e.g., lyophilized form, which can be rehydrated in a suitable vehicle immediately before administration by injection.

[0457] Cannabinoids may also be administered via the skin using conventional transdermal drug delivery systems, where the activator is contained within a laminated structure that functions as a drug delivery device attached to the skin. In such a structure, the drug composition is contained within a layer or "reservoir" located beneath an upper backing layer. The laminated structure may contain a single reservoir or multiple reservoirs. In one embodiment, the reservoir contains a polymer matrix of a pharmaceutically acceptable contact adhesive material that serves to adhere the system to the skin during drug delivery. Alternatively, the drug-containing reservoir and the skin-contact adhesive may exist as separate and distinct layers, with the adhesive located beneath the reservoir, in which case the reservoir may be the polymer matrix described above, a liquid or hydrogel reservoir, or take some other form. The transdermal drug delivery system may also contain a skin penetration enhancer.

[0458] In addition, cannabinoids can also be formulated in depot preparations for controlled release of the activator, preferably for sustained release over a long period. These sustained-release dosage forms are generally administered by implantation (e.g., by subcutaneous or intramuscular injection).

[0459] Cannabinoids can also be formulated for inhalation, for example, as a solution in saline, as a dry powder, or as an aerosol. Administration may be via the intranasal route or via oral inhalation. Pharmaceutical formulations for delivery to the lungs via oral inhalation may also be dry powder formulations and may include, for example, nanoparticle-sized solid particles containing cannabinoids and suitable dry powder additives, such as lactose monohydrate, magnesium stearate, mannitol, etc. Suitable components of dry powder compositions and types of inhalers are, among others, both incorporated herein by reference, de Boer (2017) Expert Opin Drug Deliv. 14(4): 499-512 and the U.S. Patent of Hofmann et al. It is described in publication no. 2009 / 00004279.

[0460] Plant-derived cannabinoids and structurally related exocannabinoids, as one class, possess highly selective agonist and antagonist activity towards G protein-coupled receptors (GPCRs), CB(1) and CB(2), and can individually exhibit activity at other receptors (e.g., opiate mu receptors and kappa receptors) that regulate a wide variety of metabolic and neurochemical processes. These receptors have been involved in the progression of many diseases, such as eating disorders, vomiting, pain, inflammation, multiple sclerosis, neurodegenerative disorders (Parkinson's disease, Huntington's disease, Tourette's syndrome, Alzheimer's disease), epilepsy, glaucoma, osteoporosis, schizophrenia, cardiovascular disorders, cancer, obesity, and metabolic syndrome-related disorders. For all of these, cannabis (Cannabis sativa) Plant-derived cannabinoids extracted from L.) show promise as a potential treatment.

[0461] Therefore, cannabinoids prepared using this method, including but not limited to CBD analogs, CBN analogs, CBC analogs, THCV, and THCV analogs, D is a compound that exhibits at least one of the following, like CBD and other known cannabinoids:

[0462] Neuroprotective effects in neurodegenerative disorders (e.g., Fernandez-Ruiz et al. (2013) Br. J. Clin. Pharmacol. 75: 323-33, regarding the treatment of Alzheimer's disease); Scuderi et al. (2014) Phyther. Res. 28: 1007-13; Ibeas Bih (2015) Neurotherapeutics 12: 699-730; Martin-Moreno et al. (2011) Mol. Pharmacol. 79(6): See 964-73),

[0463] Recovery of progressive degeneration of nigrostriatal dopamine neurons in Parkinson's disease (see Lastres-Becker et ala. (2005) Neurobiol. Dis. 19(1-2): 96-107),

[0464] Beneficial effects in cerebral ischemia (see Braida et al. (2003) Neurosci. Lett. 345: 61-64),

[0465] Antiepileptic activity (see Devinsky et al. (2015) Lancet Neurol. 15: 270-78; Wright et al. (2015) Epilepsy Res. 111: 111-113),

[0466] Antipsychotic activity (see Bhattacharyya et al. (2010) Neuropsychopharmacology 35: 764-74),

[0467] Anti-inflammatory activity (see Ruiz-Valdepena et al. (2015) Bioorgan. Med. Chem. 23: 1377-85 and Burstein et al. (2015) Bioorgan. Med. Chem. 23: 1377-85),

[0468] Analgesic activity, either by directly reducing pain or by reducing the perception of pain (see, for example, Maione et al. (2015) Br. J. Pharmacol. 162: 584-96),

[0469] Antiasthmatic activity (see Ribeiro et al. (2015) Immunopharmacol. Immunotoxicol. 37: 35-41, and Vuolo et al. (2015) Mediators Inflamm. 2015:538670),

[0470] anxiolytic activity,

[0471] Antitumor activity (McAllister et al. (2011) Breast Cancer Res. Treat. 129: 37-47, and Massi et al. (2013) Br. J. Clin. Pharmacol. 75: 303-12) (See reference)

[0472] Antiarthritis activity (see, for example, Lowin et al. (2020) Cell Death Dis. 11(8): 714),

[0473] Antipsychotic activity, including anti-schizophrenic activity (see Leweke (2016) Front Pharmacol. 7: 422),

[0474] Antidiabetic activity (for the treatment of type 1 diabetes, see Weiss et al. (2008) Neuropharmacology 54(1): 244-249), and

[0475] Effectiveness in treating post-traumatic stress disorder (PTSD).

[0476] Additional information relating to the potential use of CBD, regulatory approvals, and clinical trials can be found in Fasino et al. (2016) Pharmacotherapy 36: 781-96 and White (2019) J. Clin. Pharm. 59(7): 923-34, the disclosures of which are incorporated herein by reference. It is possible.

[0477] A particularly interesting therapeutic benefit lies in the treatment of opioid withdrawal symptoms, where the cannabinoids of the present invention are administered to individuals who have discontinued opioid use or are in the process of reducing their standard opioid dosage.

[0478] Depending on the indication, the cannabinoids described herein may be co-administered with at least one additional activator, either simultaneously (in the same formulation or different formulations) or separately. The additional activator may be useful for the primary indication of interest. For example, an administration to treat inflammation may include co-administration of cannabinoids with nonsteroidal anti-inflammatory drugs (NSAIDs) or steroidal anti-inflammatory drugs. As another example, an administration to treat pain may include co-administration of cannabinoids with additional analgesics, such as opioid analgesics or non-opioid analgesics.

[0479] The co-administration of cannabinoids provided herein with opioid analgesics is interesting insofar as combination formulations or separate co-administrations reduce the required therapeutic dose of opioids and eliminate or at least minimize many of the undesirable side effects associated with opioid use, such as sedation, dizziness, tolerance, and physical dependence. See Nielsen et al. (2017), "Opioid-Sparing Effect of Cannabinoids," A Systematic Review and Meta-Analysis, Neuropsychopharmacology 42(9): 1752-1765, which shows that the half-effective dose (ED50) of morphine administered in combination with Δ9-THC is 1 / 3.6 of the ED50 of morphine alone. Co-administration of cannabinoids with opioid analgesics can also show synergistic activity, resulting in increased analgesic efficacy and / or reduced side effects compared to when either drug is administered as monotherapy.

[0480] Cannabinoids may also be co-administered as anti-inflammatory preparations with olivetol or olivetol analogs having the structure of formula (AA). Such combination preparations can be readily synthesized by using an excess amount of compound (AA) using the present method, particularly the method of Part A of Section III. In a shortened reaction in which cannabinoid synthesis follows immediately after the synthesis of (AA), the first reaction is carried out using an excess amount of phloroglucinol or phloroglucinol analog having the structure (AA-1).

[0481] Therefore, the following activators may be beneficial when co-administered with cannabinoids:

[0482] Opioid analgesics, such as alfentanil, buprenorphine, butorphanol, codeine, drocode, fentanil, hydrocodone, hydromorphone, levorphanol, meperidine, methadone, morphine, nalbufine, oxycodone, oxymorphone, pentazocine, propoxyfen, sufentanil, and tramadol; and non-opioid analgesics, such as apazon, etodolac, difenpyramide, indomethacin, meclofenamete, mefenamic acid, oxaprozin, phenylbutazone, piroxicam, and tolmetine.

[0483] Propionic acid derivatives, for example, ketoprofen, flurbiprofen, ibuprofen, naproxen, fenoprofen, benoxaprofen, indoprofen, pirprofen, carprofen, oxaprozin, pranoprofen, suprofen, aluminop Lofen, butibufen, fenbufen and tiaprofenic acid; acetylsalicylic acid; Apazon; diclofenac; diphenpyramid; diflunisal; etodolac; flufenamic acid; indomethacin; ketrolac; meclofenamete; mefenamic acid; nabumetone; phenylbutazone; piroxicam; salicylic acid; sulindac; tolmetin; oxicam, e.g., meloxicam and piroxicam; nabumetone; phenylbutazone; piroxicam; salicylate, e.g., salsalate and acetylsalicylic acid; sulfasalazine; sulindac; tolmetin; and COX-2 inhibitors, e.g., NSAIDs including celecoxib, lofecoxib, and valdecoxib.

[0484] Corticosteroids of varying strengths, such as hydrocortisone, hydrocortisone-21-monoesters (e.g., hydrocortisone-21-acetate, hydrocortisone-21-butyrate, hydrocortisone-21-propionate, hydrocortisone-21-valerate, etc.), hydrocortisone-17,21-diesters (e.g., hydrocortisone-17,21-diaacetate, hydrocortisone-17-acetate-21-butyrate, hydrocortisone-17,21-dibutyrate, etc.), alclometasone, dexamethasone, flumethasone, prednisolone, and methylprednisolone, are steroidal anti-inflammatory agents.

[0485] Activating agents for the treatment of drug withdrawal symptoms, such as buprenorphine, methadone, and alpha-2 adrenergic agonists, such as rofexidine and clonidine, as well as

[0486] Activating agents for the treatment of PTSD, such as antidepressants, benzodiazepines, prazosin, psilocybin, and glucocorticoids.

[0487] Therefore, the pharmaceutical formulations of the present invention include, without limitation, any of the following novel cannabinoids of formulas (EE), (EE-1), (FF), (FF-1), (GG), (GG-1), (HH), and (HH-1) present in an effective amount in combination with at least one pharmaceutically acceptable excipient suitable for a particular type of formulation or dosage form.

[0488] Although the present invention is described in conjunction with several specific embodiments, it should be understood that the foregoing description and the following embodiments are illustrative and not limit the scope of the invention.

[0489] All patents, patent publications, documentary references, and other materials cited herein are incorporated by reference in their entirety.

[0490] Abbreviations used in the following examples: ACE: Acetone DCE: Dichloroethane DCM: Dichloromethane DMAP: Dimethylaminopyridine æ:ethyl acetate Fe(acac)3: Acetylacetone ferric ester HPLC: High-Performance Liquid Chromatography NTBE: Methyl tributyl ether NaHCO3: Sodium bicarbonate NMP: N-methylpyrrolidone THF: Tetrahydrofuran TLC: Thin-layer chromatography p-TsCl:p-toluenesulfonyl chloride [Examples]

[0491] (Example 1) Synthesis of oliveitol (a) Synthesis of 1,3,5-tris-p-toluenesulfonylbenzene: [ka]

[0492] Phloroglucinol (7) (100 g) was dissolved in a THF / water mixture (4V / 14V) in a flask equipped with a mechanical stirrer and under a nitrogen blanket. The solution was degassed by blowing nitrogen gas into it for 30 minutes. Next, NaHCO3 (3.2 equivalents), p-TsCl (3.05 equivalents), and DMAP (0.1 equivalent) were added with stirring to create a clear yellow solution with a white solid. The reaction mixture was brought to 35°C and maintained at that temperature. The reaction was monitored using TLC (70:30 hexane / Â) and HPLC. Additional NaHCO3 (3.4 equivalents in total) was added to reduce the pH. After about 4 hours, when the reaction was considered complete, the aqueous layer was separated by washing the organic layer twice with 5V (1:1) water / brine solution and the product loss was checked (0.15%). The filtrate was also checked for product loss (0.03%). The organic solution was stripped until a thick slurry was formed, and 3V heptane was added while stirring for 1 hour to further precipitate the product. The mixture was then vacuum filtered and washed with 1V heptane. The resulting white crude solid was dried for 24 hours to produce 392.8 g of the final product, 1,3,5-tritosylatebenzene(8) (i.e., completely tosylated phloroglucinol). NMR and HPLC showed a purity of 98.6% and a yield of 84.2% of the desired product.

[0493] (b) Alkylation of 1,3,5-tritosylatebenzene: [ka]

[0494] 1,3,5-Tritosylbenzene (8) (75 g) and dried / degassed THF (7.75 V) were added to a jacketed flask equipped with a mechanical stirrer and an addition funnel (3 × vac / N2 cycle applied) to form a clear solution. FeCl3 (0.05 equivalent) and dried NMP (4.75 equivalent) were added to the solution under nitrogen to form a red solution. The solution was cooled to -13°C / -15°C and sparged with nitrogen. 2 M n-pentyl-MgBr (1.4 equivalent) was slowly added through the addition funnel. The reaction solution was stirred at -10°C for 1 hour, and the completion of the reaction was monitored by HPLC. The solution was then stirred overnight at -10°C. The reaction solution was then diluted with MTBE (5 V) and quenched with 1 N HCl (1.3 equivalent) at 0°C. The jacket temperature was then gradually increased to ambient temperature. The mixture was stirred for approximately 30 minutes. The organic layer was separated from the aqueous layer. Both layers were checked by HPLC, and since the aqueous layer contained no product, it was not further extracted. The organic product solution was sequentially washed with 10% NaHCO3 (8V), H2O (8V), and brine (8V). The washed organic layer was concentrated at 35°C using a rotary evaporator to obtain crude 5-pentyl-1,3-phenylenebis(4-methylbenzenesulfonate) as an orange oil. Crystallization of the oil was attempted using THF / heptane, but a mixture of two layers was obtained. The solution was stripped and co-stripping with heptane (1.6V) yielded an orange-red solid. The solid was dried under high vacuum at room temperature to obtain approximately 52 g of solid product, ditosylated oliveitol (9). HPLC showed a conversion rate of approximately 86.3% of the product.

[0495] (c) Detosylation of ditosylated oliveitol: [ka]

[0496] 5-pentyl-1,3-phenylenebis(4-methylbenzenesulfonate) (dicosylated oliveitol, 190 g) was dissolved in toluene (8.5V) and t-butanol (1.5V) in a three-necked round-bottom flask equipped with a mechanical stirrer and a 12-inch condenser, under a nitrogen atmosphere. Solid NaOH (9 equivalents) was added to form a slurry. The solution was then refluxed to 100°C using a condenser set to -8°C and stirred for approximately 1 hour until the reaction was considered complete by TLC (50:50 hexane / RINKAN) and HPLC. The solution was then cooled to ambient temperature, water (4V) was added, and the solution was stirred for approximately 1 hour. The layers were separated, and the aqueous product layer was washed with 300 mL of toluene. Isopropyl acetate (3V) and 32% HCl (10 equivalents) were added to the aqueous solution of the product in an ice bath and stirred for 30 minutes. The layers were separated, and the organic layer was washed four times with water to remove all water-soluble impurities (1V). The layers were separated again, and the combined organic product layers were concentrated using a rotary evaporator while stripping both layers twice with heptane (approximately 2V) to produce crude olivetol oil in solution. Olivetol oil (68g) was obtained with a purity level of 97.5%. (Example 2) Alternative synthesis of oliveitol

[0497] (a) Synthesis of 1,3,5-tris-p-toluenesulfonylbenzene: [ka]

[0498] In a round-bottom flask, phloroglucinol (1.30 g, 10.3 mmol) and triethylamine (5.4 mL, 39 mmol, 3 equivalents) were stirred in 45 mL of DCM for 10 minutes. The mixture was stirred. The flask was placed in a cold water bath, and tosyl chloride (7.44 g, 39 mmol, 3 equivalents) was added little by little, followed by DMAP (0.159 g, 1.3 mmol, 0.1 equivalent). The flask was left stirred for two days, then washed with brine, dehydrated with Na2SO4, and concentrated in a rotary evaporator (water bath 30°C) to obtain a brown oily substance (6.06 g). The oily substance was subjected to liquid column chromatography (70:30~50:50 hexane:siRNA) to obtain a colorless oily substance, which was crystallized as a white powder (4.9 g).

[0499] (b) Synthesis of 5-pentyl-1,3-phenylenebis(4-methylbenzenesulfonate): [ka]

[0500] In a dry 50 mL three-necked flask fitted with a condenser, two small crystals of I2 were added to a suspension of Mg turning at room temperature in THF (5 mL) (0.303 g, 12.61 mmol, 1.2 equivalents). The reaction mixture was placed under argon. A syringe containing a solution of 1-bromopentane (1.52 g, 10.08 mmol, 1 equivalent) in THF (3.75 mL) was prepared for addition to the reaction mixture. A 10-15% solution of 1-bromopentane was added, and the mixture was heated under reflux to initiate the reaction (<5 minutes). After initiation, the reaction mixture was removed from the heat, and the remaining linoleyl bromide solution was added dropwise over approximately 1 hour. At this point, the reaction mixture had turned brownish-gray, indicating that a significant portion of the Mg turning had been consumed. Upon completion of the addition, the reaction mixture was stirred for a further 1 hour to obtain a 1 M solution of 1-pentylmagnesium bromide.

[0501] In an oven-dried 50 mL round-bottom flask, 1,3,5-tritosylatebenzene (1.30 g, 2.21 mmol, 1 equivalent) was dissolved in 5 mL of dry THF and 0.5 mL of dry NMP. Fe(acac)3 (0.04 g, 0.11 mmol, 0.05 equivalent) was added to the reaction mixture to obtain a homogeneous orange solution. The reaction mixture was placed under argon and cooled to 0°C using an ice bath. The prepared 1 M 1-pentylmagnesium bromide solution (6.63 mL, 6.63 mmol, 3 equivalents) was added to the reaction mixture dropwise using a syringe. Upon completion of the addition (15 minutes), the reaction mixture was stirred for a further 30 minutes at 0°C. TLC (70:30 hexane / siRNA) showed complete consumption of the starting materials. The reaction was stopped, diluted with Et2O (15 mL), and then carefully quenched with 0.5 M HCl (20 mL). The reaction mixture was extracted with Et2O (3 × 20 mL). The combined organic layer was washed with NaHCO3 (1 × 50 mL), H2O (1 × 50 mL), and brine (1 × 50 mL), dehydrated with Na2SO4, and concentrated using a rotary evaporator (water bath 35°C) to obtain crude 5-pentyl-1,3-phenylenebis(4-methylbenzenesulfonate) as a pale yellow mixture of solid and oily substances. This crude product was subjected to liquid column chromatography (85:15 hexane / Depositphotos) to obtain 0.823 g of the desired product.

[0502] (c) Synthesis of olivetor: [ka]

[0503] In a 25 mL round-bottom flask, 5-pentyl-1,3-phenylenebis(4-methylbenzenesulfonate) (0.094 g, 0.192 mmol, 1 equivalent) was dissolved in toluene (2.0 mL). t-BuOH (0.5 mL, 0.355 g, 3.85 mmol, 20 equivalents) and pulverized KOH (0.107 g, 1.92 mmol, 10 equivalents) were added to the reaction flask. A condenser was attached to the reaction flask, and the reactants were placed under argon. When the reactants were heated to 100 °C (reflux), a brown solid appeared in the reaction flask. After 20 minutes of reflux, TLC (1:1 hexane / Depositphotos) showed consumption of the starting materials. The reaction was stopped, and the solvent was removed by rotary evaporation. The reaction residue was then redissolved in Depositphotos (5 mL) and washed with 1 M HCl (5 mL). The reaction mixture was extracted with Depositphotos (3 × 5 mL). The combined organic layers were dehydrated with Na2SO4 and concentrated using a rotary evaporator (water bath 35°C) to obtain crude 5-pentylbenzene-1,3-diol as a black oily substance. The crude product was subjected to liquid column chromatography (70:30 hexane / siRNA) to obtain 0.033 g of the desired product. (Example 3) Synthesis of divalinol from phloroglucinol

[0504] (a) Example 1, 1,3,5-tritosylatebenzene was synthesized from phloroglucinol by repeating the method of part (a).

[0505] (b) Repeat the method of Example 1, part (b), using n-propyl-MgBr instead of N-pentyl-MgBr: [ka]

[0506] The resulting product is 5-propyl-1,3-phenylenebis(4-methylbenzenesulfonate)(10), with a yield greater than 90% and expected to be substantially free of impurities. The compound may be isolated and purified, or it may be used directly in the next step.

[0507] (c) Repeat the method of Example 1, part (c), except that the reaction product of the preceding step is used instead of ditosylated olivetol: [ka] The final reaction product is divalinol, as shown in the scheme. (Example 4) CBD synthesis from oliveitol using alumina [ka]

[0508] In a flame-dried 20 mL vial, basic alumina (0.375 g, 3.68 mmol, 24.5 equivalents), dried 1,2-dichloroethane (5.6 mL), and dried heptane (1.9 mL) were added, and the solution was placed under argon. BF3·Et2O (0.056 mL, 0.45 mmol, 3 equivalents) was added, and the suspension was stirred for 15 minutes, then boiled for 1 minute. The mixture of oliveitol (2) (0.0811 g, 0.45 mmol, 3 equivalents) and (1S,4R)-p-menta-2,8-dien-1-ol (3) (0.023 g, 0.15 mmol, 1 equivalent) in dried 1,2-dichloroethane (1.5 mL) and dried heptane (0.5 mL) was added to the boiling suspension, and the reaction was rapidly quenched with aqueous saturated NaHCO3 (4 mL) within 10 seconds. Et2O (20 mL) and an additional saturated NaHCO3 (20 mL) were added. The organic layer was washed with brine, dehydrated with Na2SO4, and concentrated under vacuum. The product was purified by column chromatography (10:88:2 siRNA / hexane / Et3N) to obtain 0.0285 g of the desired product.

[0509] The ratio of CBD to oliveitol in the final product was approximately 1:0.62. Washing with warm water to dissolve the remaining oliveitol resulted in a CBD-to-oliveitol ratio of 1:0.32, and further washing yielded a CBD-to-oliveitol ratio of 1:0. (Examples 5-12) Additional synthesis of CBD from oliveitol using alumina

[0510] As shown in Table 4 below, the reaction of Example 4 was repeated using different reaction temperatures and solvents, and the relative amounts of CBD, abn-CBD, and bis obtained are provided, as well as the ratio of CBD to THC in the final product: [Table 4] The results indicate that reaction product compositions can be obtained with molar ratios of CBD to abn-CBD greater than 1:0.20 and molar ratios of CBD to bis greater than 1:0.10. (Example 13) CBD synthesis from oliveitol using only boron trifluoride. [ka]

[0511] In a flame-dried 20 mL vial, olivetol (2) (54 mg, 0.45 mmol, 1 equivalent) and (1S,4R)-p-menta-2,8-dien-1-ol (3) (45 mg, 0.3 mmol, 1 equivalent) were added to dried 1,2-dichloroethane (0.75 mL), and the reaction mixture was heated to 80°C. Then, BF3·OEt2 (2 mol%) in 1,2-dichloroethane (0.05 mL) was added over 10 minutes. The reaction mixture was quenched with aqueous saturated NaHCO3 (0.5 mL). The organic layer was separated, dehydrated with Na2SO4, and concentrated under vacuum. The product was then... 1 Analysis was performed by 1H NMR spectroscopy. The yield of CBD obtained was 31%, and the composition of the reaction product was determined to be 1:1:0.5 CBD / abn CBD / bis. (Examples 14-18) Synthesis of CBD from oliveitol using only boron trifluoride.

[0512] As shown in Table 5 along with the obtained results, the process of Example 13 was repeated using different solvents, different concentrations, different reaction temperatures, and different amounts of BF3·OEt2 (where "Conc" refers to the amount of solvent compared to one equivalent of CBD in the reactant at a theoretical yield of 100%): [Table 5] (Example 19) Synthesis of CBD from oliveitol using alumina and MgSO4

[0513] In an oven-dried 10 mL three-necked round-bottom flask fitted with an oven-dried condenser, olivetol (2) (0.541 g, 3 mmol, 2 equivalents), anhydrous alumina (0.091 g, 0.9 mmol, 0.6 equivalents), anhydrous MgSO4 (0.361 g, 3 mmol, 2 equivalents), and anhydrous dichloroethane (4.5 mL) were added. The mixture was placed under argon and BF3·Et2O (0.019 mL, 0.15 mmol, 0.1 equivalent) was added. The suspension was stirred at room temperature for 15 minutes, then heated to 90°C for 2 minutes. A solution of (1S,4R)-p-menta-2,8-dien-1-ol (3) (0.228 g, 1.5 mmol, 1 equivalent) in dichloroethane (0.5 mL) was added to the mixture, boiling for 2.5 minutes. Next, the reaction mixture was refluxed for 15 minutes, then quenched with saturated aqueous solution (NaHCO3), and diluted with DCM. The organic layer was washed with brine, dehydrated with Na2SO4, and concentrated under vacuum. The reaction mixture was refluxed for 30 minutes, then quenched. 1 1H NMR showed the absence of olivetol. (Example 20) Synthesis of CBD from oliveitol via protecting group method

[0514] Synthesis of dimethoxyolibethol: [ka]

[0515] In a flame-dried 100 mL round-bottom flask, NaH (1.00 g, 25 mmol) and anhydrous DMF (30 mL) were added, and the mixture was placed under argon and cooled to 0°C. Olivetol (2) (1.80 g, 1.0 mmol) was added to anhydrous DMF (10 mL), and the mixture was stirred for 5 minutes. Methyl iodide (1.9 mL, 30 mmol) was added dropwise, and the ice bath was removed. The reaction mixture was stirred for 20 minutes, and then quenched with 3.0 M HCl (30 mL). The mixture was extracted with ethyl acetate, the organic layer was washed with water and brine, dehydrated with Na2SO4, and concentrated under reduced pressure to obtain a dark brown oil. Product (11) was obtained by column chromatography (5% HCl / Hex) in 79% yield as a clear, yellow oil. It was purified.

[0516] (b) Synthesis of dimethoxy-CBD on a 0.3 mmol scale: [ka]

[0517] Basic alumina (0.749 g, 7.35 mmol) and anhydrous DCM (5.5 mL) were added to a flame-dried 100 mL round-bottom flask. The mixture was placed under argon and BF3-Et2O (0.11 mL, 0.9 mmol) was added. The suspension was stirred for 15 minutes, then heated to 40°C and stirred for 1 minute. Dimethoxyoliveitol (11) (0.0625 g, 0.3 mmol) was added to anhydrous DCM (2 mL) and the mixture was stirred for 1 minute. (1S,4R)-p-menta-2,8-dien-1-ol (3) (0.0457 g, 0.3 mmol) was added dropwise over 10 minutes to anhydrous DCM (2 mL), and the reaction mixture was stirred for 1 minute. The reaction mixture was quenched with 4 mL of saturated NaHCO3, extracted with diethyl ether, washed with brine, dehydrated with Na2SO4, and concentrated under reduced pressure. Product (12) was purified by column chromatography (5% siRNA / hexane) in 62% yield as a clear, colorless oil.

[0518] (b) Synthesis of dimethoxyCBD, 1.0 mmol scale:

[0519] Basic alumina (2.50 g, 24.5 mmol) and anhydrous DCM (18 mL) were added to a flame-dried 100 mL round-bottom flask. The mixture was placed under argon and BF3-Et2O (0.37 mL, 3 mmol) was added. The suspension was stirred for 15 minutes, then heated to 40°C and stirred for 1 minute. Dimethoxyoliveitol (11) (0.208 g, 1.0 mmol) was added to anhydrous DCM (6.5 mL) and the mixture was stirred for 1 minute. (1S,4R)-p-menta-2,8-dien-1-ol (3) (0.152 g, 1 mmol) was added dropwise over 10 minutes to anhydrous DCM (6.5 mL), and the reaction mixture was stirred for 1 minute. The reaction mixture was quenched with 30 mL of saturated NaHCO3, extracted with 30 mL of diethyl ether, washed with brine, dehydrated with Na2SO4, and concentrated under reduced pressure. Product (12) was purified by column chromatography (100% hexane) in 34% yield as a clear, colorless oil.

[0520] (c) CBD synthesis: [ka]

[0521] Dimethoxy-CBD(11) (0.051 g, 0.15 mmol), NaOH (0.072 g, 1.8 mmol), and NMP (0.6 mL) were added to a flame-dried 4 mL vial. The mixture was placed under nitrogen and decanethiol (0.16 mL, 0.75 mmol) was added. The reaction mixture was heated to 130 °C and stirred overnight. The reaction mixture was quenched with 1.0 M HCl (10 mL), extracted with ethyl acetate, washed with water and brine, dehydrated with Na2SO4, and concentrated under reduced pressure. (Example 21) Synthesis of THCV from phloroglucinol via divalinol [ka]

[0522] (a) Divalinol (6) was prepared from phloroglucinol (7) according to the method of Example 3.

[0523] (b) Next, following the method of Example 4, in the cross-coupling reaction with (1S,4R)-p-menta-2,8-dien-1-ol (0.023 g, 0.15 mmol, 1 equivalent), divarinol (6) was used as the co-reactant instead of olivetol.

[0524] (c) Cyclization of the intermediate obtained in (b) is carried out using a Lewis acid and molecular sieve or other means that are obvious to those skilled in the art and / or described in the literature. (Example 22) Synthesis of CBD analogs having a 4'-(2-ethylaminoethyl) substituent [ka]

[0525] (a) The pivaloyl protection of the hydroxyl group of the reactant was obtained by the following reaction: [ka] The reaction conditions were as follows: pivaloyl chloride (2.5 equivalents), DMAP, 3.0 (equivalents), MeCN, 0°C, 16 hours. The identity of the product (2.10 g, 73%). of 1 The data was characterized by 1H NMR and MS.

[0526] (b) Next, the C-4' site of the synthesized pivaloyl-protected intermediate (17) was modified using the reaction in the following scheme to obtain the 4'-ethoxyethenyl group: [ka] Reaction conditions (500 mg scale): 500 mg 1, 2 (1.1 equivalents), Na2CO3 (2.0 equivalents), PdCl2 (dppf)·dcm (0.05 equivalents), 1,4-dioxane, 110°C, 1 hour. Reaction product (18) (140 mg, 33%) 1 The data was characterized by 1H NMR and MS.

[0527] Next, compound (18) was converted to aldehyde (20) as shown: [ka] Reaction conditions: 4M HCl (5 equivalents), 1,4-dioxane, toluene, 50°C, 1 hour.

[0528] Next, the aldehyde intermediate (20) was transformed into a 4-(2-ethylaminoethyl) intermediate (21) using a reductive amination reaction with ethylamine, and subsequently, the desired reaction product (22) was obtained by removing the pivaloyl protecting group using conventional means. The reaction is illustrated below: [ka] Reaction conditions: Ethylamine (5) (1.1 equivalents), NaCNBH3 (2.0 equivalents), MeOH, room temperature, 16 hours. (Example 23) Synthesis of CBD analogs having a 4'-(2-(n-propyl)aminoethyl) substituent [ka]

[0529] Reagents and reaction conditions for the conversion of (16) to (23): (16) (1.5 equivalents), Pd(OAc)2 (0.05 equivalents), dppf (0.075), triethylsilane (1.3 equivalents), Na2CO3 (1.5 equivalents), ACN, 80°C, 16 hours. The product was 1 Characterized by 1H NMR and MS, yield 400 mg (30%).

[0530] Reagents and reaction conditions for the conversion of (23) to (24): (23) (1.1 equivalents), NaCNBH3 (2.0 equivalents), MeOH, room temperature, 16 hours. The product 1 Yield of 40 mg (purity 97% determined by HPLC), characterized by 1H NMR and MS. (Example 24) Synthesis of CBN analogs having a 4'-(2-ethoxyethyl) substituent [ka]

[0531] Reagents and reaction conditions for the conversion of (24) to (25): (24) (1.5 equivalents), Na2CO3 (2.0 equivalents), PdCl2 (dppf)·DCM (0.03 equivalents), 1,4-dioxane, H2O, 90°C, 16 hours, sealed tube. The product was analyzed by UPLC and 1 Characterized by 1H NMR, yield 200 mg (46%).

[0532] Reagents and reaction conditions for the conversion of (25) to (27): Pd(C), hydrogen, ethanol, room temperature. The product 1 Characterized by H NMR, MS, HPLC, and 2D NMR, Rate 80mg (80%). (Example 25) Synthesis of CBN analogs having a 4'-(2-morpholinoethyl) substituent

[0533] Compound (26) targets CBN 3 [ka] Convert to the following:

[0534] Reagents and reaction conditions: (26) 1.5 equivalents, dioxane, HCl, toluene, 50°C, 30 minutes. (Example 26) Shortened oliveitol synthesis

[0535] Step 1:

[0536] In a three-necked jacketed flask equipped with a mechanical stirring device, phloroglucinol (50 g, 396 mmol, 1 equivalent) was dissolved in THF (700 mL, 14V) and water (200 mL, 4V) under a nitrogen atmosphere.

[0537] Next, NaHCO3 (119.91 g, 1.43 mol, 3.2-3.6 equivalents), DMAP (4.84 g, 39.6 mmol, 0.1 equivalent), and p-TsCl (230.55 g, 1.21 mol, 3.05 equivalents) were added to create a clear yellow solution with a white solid. The reaction mixture was heated to 35°C and maintained at that temperature, stirring continuously overnight, for 4 hours until it was considered complete by TLC and HPLC.

[0538] After the reaction was deemed complete, the aqueous layer was separated and checked for product loss by HPLC. The organic product layer was washed twice with a 1:1 water / brine solution (250 mL, 5V). The aqueous wash was also checked for product loss. The organic layer was stripped until a thick slurry / semi-solid was formed, to which THF (200 mL, 4V) was added and co-stripping was performed until a water content of less than 0.02% KF was measured. Solvent exchange was then required to remove toluene (toluene to THF). After removing water from the solution, the reaction product in THF, fully tosylated phloroglucinol, was carried over to the next step.

[0539] Step 2:

[0540] 1,3,5-Tritosylbenzene (230 g, 391 mmol, 1 equivalent) and dried / degassed THF (1265 mL, 5.5V) were placed in an RB flask. KF and the contents of the solution were checked. The solution was then transferred to a jacketed flask (applying 3 vac / N2 cycles) under a nitrogen atmosphere via a cannula equipped with a mechanical stirrer to form a pale yellow solution.

[0541] FeCl3 (3.17g, 19.5 mmol, 0.05 equivalents) and DMPU (126 A 0.5 mL (0.55V) solution was added under an N2 atmosphere to form a colored solution. The solution was purged again with nitrogen. The solution was cooled to an internal temperature of -10 to -13°C using a glycol condenser set to -15°C.

[0542] 2M n-pentyl MgBr (244 mL, 488 mmol, 1.25 equivalents) was slowly added via an addition funnel over approximately 7.5 hours. After checking the first reactant, since the starting material was still present (12 mL, 0.061 equivalents), additional n-pentyl MgBr was added. Once the reaction was considered complete, MTBE (575 mL, 2.5V) and 1M HCl (586 mL, 586 mmol, 1.5 equivalents) were added and stirred for 30 minutes. The layers were separated, and the aqueous layer was washed with MTBE (575 mL, 2.5V). The organic layers were combined and then washed twice with 10% w / w NaHCO3, water, and brine (575 mL, 2.5V for each wash). The organic solution was then stripped to form a high-viscosity oily substance, which was co-stripped with toluene (285 mL, 1.25V).

[0543] The crude oil was carried over to the next reaction, step 3.

[0544] Step 3:

[0545] In a three-necked round-bottom flask equipped with a mechanical stirrer and a 12-inch condenser, under a nitrogen atmosphere, ditosylated olivetol (5-pentyl-1,3-phenylenebis(4-methylbenzenesulfonate)) (190.0 g, 388 mmol, 1 equivalent) from Step 2 was dissolved in toluene (1615 mL, 8.5 V) and t-BuOH (285 mL, 1.5 V).

[0546] Next, NaOH (139.9 g, 3.49 mol, 9 equivalents) was added to form a slurry. Then, using a condenser set to -8°C, the slurry was refluxed to 100°C and stirred for approximately 1 hour until it was considered complete. The reaction mixture was then cooled to ambient temperature.

[0547] Next, water (563 mL, 4V) was added and the mixture was stirred for approximately 1 hour. The layers were separated, and the aqueous product layer was washed with 300 mL of toluene.

[0548] Isopropyl acetate (570 mL, 3V) and 32% HCl (349.9 mL, 3.49 mol, 10 equivalents) were added to the aqueous solution of the product in the ice bath, and the mixture was then stirred for 30 minutes.

[0549] The layers were separated, and the organic layer was washed four times with water to remove all water-soluble impurities (190 mL, 1V). The layers were separated again, and the combined organic product layers were concentrated using a rotary evaporator while co-stripping twice with heptane (110 mL, approximately 2V) to produce crude olivetol oil in solution. In one embodiment, for example, the following items are provided. (Item 1) Structure of formula (AA) [ka] [In the formula, m is either zero or 1. n is zero, 1, or 2. R 1 C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl and substituted heteroatom-containing C1-C 12 Selected from hydrocarbil, R 2 C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C12 Hydrocarbyl and selected from functional groups, if n is 2, the R 2 They may be the same or different, and any R on adjacent carbon atoms 2 A method for synthesizing a compound having [which may be linked together to form a cyclic structure], (a) Structure of equation (AA-1) [ka] A compound having the structure of formula (AA-2) is used with an electron-withdrawing hydroxyl protecting reagent. [ka] The step of reacting under conditions effective for obtaining a hydroxyl-protected intermediate having (wherein PR represents an electron-withdrawing hydroxyl protecting group), (b) In the presence of a catalyst that promotes the cross-coupling reaction, the hydroxyl-protected intermediate (AA-2) and reactant R 1 The cross-coupling reaction is carried out with -M (where M contains a metallic element) to obtain the structure of formula (AA-3). [ka] A step to obtain a compound having, (c) Hydrolyzing the compound of (AA-3) to remove the hydroxyl protecting group to obtain a reaction product composition containing compound (AA), Methods that include... (Item 2) The reactant has structure R 1 The method described in item 1, which is a Grignard reagent containing -MgBr. (Item 3) The method according to item 2, wherein the catalyst is iron-based. (Item 4) R 1is a C1-C alkyl substituted with zero to 3 functional groups selected from halo, hydroxyl, carboxyl, C1-C8 alkoxy, C2-C8 acyloxy, C2-C8 alkoxycarbonyl, amino, mono-(C1-C8 alkyl)-substituted amino, di-(C1-C8 alkyl) substituted amino, C2-C8 alkylamide, mono-(C1-C8 alkyl)-substituted carbamoyl, di-(C1-C8 alkyl)-substituted carbamoyl, and combinations thereof 18 alkyl, C2-C 18 alkenyl, and C2-C 18 alkynyl, and the method according to any one of items 1 to 3. (Item 5) The method according to any one of items 1 to 4, wherein n is zero, m is 1, and the compound (AA-1) is phloroglucinol. (Item 6) R 1 is n-pentyl, and the compound (AA) contains olivetol, and the method according to item 5. ​​​​​​​​​​​​​​​​​​​​​​​​​Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Hydrocarbyl and selected from functional groups, R 8 A second reactant having methyl, hydroxymethyl, or halomethyl (where L is a leaving group) is brought into contact with the reactant (AA) and (CC-1) under reaction conditions effective in bringing about a cross-coupling of the reactant (CC) in the presence of a Lewis acid catalyst, thereby forming the structure of formula (CC). [ka] The steps include obtaining a composition of a reaction product containing a cannabidiol (CBD) analog having Methods that include... (Item 9) m is 1, n is zero, and (AA-1) is phloroglucinol. R 5 and R 8 It is methyl, R 6 and R 7 H is, As a result, the CBD analog in the reaction product composition has the structure of formula (CC-3). [ka] The method described in item 8, having the characteristics of item 8. (Item 9) The method according to item 7 or item 8, wherein the reaction conditions include contacting the first reactant with the second reactant in a solvent at a high temperature in the presence of anhydrous alumina and MgSO4. (Item 10) The method according to item 7, 8, or 9, wherein the Lewis acid catalyst comprises BF3. (Item 11) R 1 The method according to item 7, 8, 9, or 10, wherein (CC-3) is n-pentyl and (CC-3) contains CBD. (Item 12) R 1The method according to item 7, 8, 9, or 10, wherein is n-propyl. (Item 13) The method according to item 12, further comprising subjecting (CC-3) to cyclization conditions to obtain a reaction product composition containing tetrahydrocannabivarin. (Item 14) The method described in any of items 7 to 13, wherein (AA) is neither isolated nor purified prior to step (b). (Item 15) The composition of the reaction product is compound (4) and (5) [ka] The method described in item 11, further including the method described in item 11. (Item 16) The method according to item 15, wherein the molar ratio of CBD to (4) in the composition of the reaction product is at least 1:0.2 and the molar ratio of CBD to (5) is at least 1:0.10. (Item 17) The composition of the reaction product is 1 When evaluated using 1H NMR analysis, the method described in item 11 does not contain THC. (Item 18) Structure of formula (EE) [ka] [In the formula, q1 is zero or 1, and q2 is zero, 1, or 2. R 11 C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Hydrocarbyl and selected from functional groups, if n is 2, the R 11 The R atoms may be the same or different, and any two R atoms bonded to adjacent carbon atoms. 11They may combine to form a cyclic structure selected from 5-membered and 6-membered rings, which may be condensed as needed into an additional 5-membered or 6-membered ring, wherein the ring is aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and has zero to 4 nonhydrogen substituents and zero to 3 heteroatoms. R 12 This is H, carboxyl, C2-C6 acyloxy, C2-C6 alkoxycarbonyl, C1-C6 alkyl, or a C1-C6 alkyl substituted with hydroxyl, carboxyl, or halo. R 13 and R 14 These are H, C1~C independently. 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Selected from hydrocarbyl and functional groups, R 15 These are methyl, hydroxymethyl, or halomethyl, R 16 (a)-(CO)-NR 28 -R 29 (In the formula, R 28 is H or C1~C 12 Hydrocarbil, R 29 is C1~C 12 (b)-NR (hydrocarbyl) 30 -R 31 (In the formula, R 30 is H or C1~C 12 Hydrocarbil, R 31 is C6~C 12 Hydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbil, C1-C 12 Heterohydrocarbyl, or C1-C1 substituted with at least one functional group 12 (It is a heterohydrocarbyl), (c)-(SO2)-R 32 (In the formula, R 32 is H or C1~C 12 Heterohydrocarbyl, C1-C1 substituted with at least one functional group 12Hydrocarbyl, or C1-C1 substituted with at least one functional group 12 (It is a heterohydrocarbyl), (d)-(SO2)-NR 33 R 34 (In the formula, R 33 is H or C1~C 12 Hydrocarbil, R 34 is H or C1~C 12 (It is hydrocarbyl.) [ka] (L in the formula 1 (where C1-C6 alkyl is substituted with C1-C6 18 Alkyl, C2~C 18 Alkenyl, or C2~C 18 It is either alkinyl or R 16 This is an additional C1~C 12 C1-C substituted with hydrocarbyl oxy 12 A CBD analog containing hydrocarbyl oxy. (Item 19) q1 is 1, q2 is zero, and the two hydroxyl groups are R 16 In relation to R, 12 and R 15 The C1-C6 alkyl group is R 13 and R 14 H is R 16 (a)-(CO)-NR 28 -R 29 (In the formula, R 28 is H or C1-C8 alkyl, R 29 (These are C1-C8 alkyl groups.) (b)-NR 30 R 31 (In the formula, R 30 is H or C1-C8 alkyl, R 31 is C6~C 12 Alkyl, C1-C8 alkyl substituted with at least one functional group, C1-C8 heteroalkyl, or C1-C8 heteroalkyl substituted with at least one functional group), (c)-(SO2)-R 32(In the formula, R 32 (This is a C1-C8 heteroalkyl group, a C1-C8 alkyl group substituted with at least one functional group, or a C1-C8 heteroalkyl group substituted with at least one functional group), (d)-(SO2)-NR 33 R 34 (In the formula, R 33 is H or C1-C8 alkyl, R 34 (wherein H is H or C1-C8 alkyl, and the C1-C8 alkyl group is either substituted or unsubstituted), [ka] C1~C replaced by 12 Alkyl or C2-C 12 CBD analogs that are alkyl, as listed in item 18. (Item 20) R 12 and R 15 It is methyl, and as a result, the compound has the structure of formula (EE-1). [ka] A CBD analog as described in item 19, having the properties of: (Item 21) Structure of equation (FF) [ka] [In the formula, q3 is zero or 1, and q4 is zero, 1 or 2. R 17 C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Hydrocarbyl and selected from functional groups, if n is 2, the R 17 The R atoms may be the same or different, and any two R atoms bonded to adjacent carbon atoms. 17These may combine to form a cyclic structure selected from five-membered and six-membered rings, which may be condensed as needed into an additional five-membered or six-membered ring, wherein the ring is aromatic, alicyclic, heteroaromatic, or heteroalicyclic. It has zero to four nonhydrogen substituents and zero to three heteroatoms, R 18 This is H, carboxyl, C2-C6 acyloxy, C2-C6 alkoxycarbonyl, C1-C6 alkyl, or a C1-C6 alkyl substituted with hydroxyl, carboxyl, or halo. R 19 and R 20 These are H, C1~C independently. 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Selected from hydrocarbyl and functional groups, R 21 These are methyl, hydroxymethyl, or halomethyl, R 22 (a)-(CO)-NR 35 -R 36 (In the formula, R 35 is H or C1~C 12 Hydrocarbil, R 36 is C1~C 12 (b)-NR (hydrocarbyl) 37 -R 38 (In the formula, R 37 is H or C1~C 12 Hydrocarbil, R 38 C6~C 12 Hydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbil, C1-C 12 Heterohydrocarbyl, or C1-C1 substituted with at least one functional group 12 (It is a heterohydrocarbyl), (c)-(SO2)-R 39 (In the formula, R 39 is H or C1~C 12Heterohydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbyl, or C1-C1 substituted with at least one functional group 12 (It is a heterohydrocarbyl), (d)-(SO2)-NR 40 R 41 (In the formula, R 42 is H or C1~C 12 Hydrocarbil, R 43 is H or C1~C 12 (It is hydrocarbyl.) [ka] (In the formula, L 1 is C 1 ~C 6 C1-C (which are alkyl) 18 Alkyl, C2~C 18 Alkenyl, or C2~C 18 It is either alkinyl or R 22 Additional C1~C 12 C1-C substituted with hydrocarbyl oxy 12 Cannabinol (CBN) analogs containing hydrocarbyl oxy. (Item 22) q3 and q4 are zero, and the hydroxyl group is R 22 In relation to R, 18 and R 21 The C1-C6 alkyl group is R 19 and R 20 H is R 22 teeth, (a)-(CO)-NR 35 R 36 (In the formula, R 35 is H or C1-C8 alkyl, R 36 (These are C1-C8 alkyl groups.) (b)-NR 37 R 38 (In the formula, R 37 is H or C1-C8 alkyl, R 38 is C6~C 12Alkyl, C1-C8 alkyl substituted with at least one functional group, C1-C8 heteroalkyl, or C1-C8 heteroalkyl substituted with at least one functional group), (c)-(SO2)-R 39 (In the formula, R 39 (This is a C1-C8 heteroalkyl group, a C1-C8 alkyl group substituted with at least one functional group, or a C1-C8 heteroalkyl group substituted with at least one functional group.) (d)-(SO2)-NR 40 R 41 (In the formula, R 40 is H or C1-C8 alkyl, R 41 (wherein H is H or C1-C8 alkyl, and the C1-C8 alkyl group is either substituted or unsubstituted), [ka] C1~C replaced by 12 Alkyl or C2-C 12 A CBN analog, which is an alkenyl, as described in item 21. (Item 24) R 18 and R 21 It is methyl, and as a result, the compound has the structure of formula (FF-1). [ka] A CBN analog as described in item 23, having the characteristics of the analog. (Item 25) Structure of formula (GG) [ka] [In the formula, q5 is zero or 1, q6 is zero, 1 or 2, and the sum of q5 and q6 is not greater than 2. R 23 C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12Hydrocarbyl and selected from functional groups, if n is 2, the R 23 The R atoms may be the same or different, and any two R atoms bonded to adjacent carbon atoms. 23 They may combine to form a cyclic structure selected from 5-membered and 6-membered rings, which may be condensed as needed into an additional 5-membered or 6-membered ring, wherein the ring is aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and has zero to 4n3on-hydrogen substituents and zero to 3 heteroatoms. R 24 is a C1-C6 alkyl group substituted with H, C1-C6 alkyl, or hydroxyl, carboxyl, or halo. R 25 H, C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Hydrocarbyl, or a functional group, R 26 These are methyl, hydroxymethyl, or halomethyl, R 27 (a)-(CO)-NR 42 R 43 (In the formula, R 42 is H or C1~C 12 Hydrocarbil, R 43 is C1~C 12 (b)-NR (hydrocarbyl) 44 R 45 (In the formula, R 44 is H or C1~C 12 Hydrocarbil, R 45 is C6~C 12 Hydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbil, C1-C 12 Heterohydrocarbyl, or C1-C1 substituted with at least one functional group 12 (It is a heterohydrocarbyl), (c)-(SO2)-R 46 (In the formula, R 46 is H or C1~C 12Heterohydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbyl, or C1-C1 substituted with at least one functional group 12 (It is a heterohydrocarbyl), (d)-(SO2)-NR 47 R 48 (In the formula, R 47 is H or C1~C 12 Hydrocarbil, R 48 is H or C1~C 12 (It is hydrocarbyl.) [ka] (In the formula, L 1 is C 1 ~C 6 C1-C (which are alkyl) 18 Alkyl or C2-C 18 It is an alkenyl, or R 27 Additional C1~C 12 C1-C substituted with hydrocarbyl oxy 12 A cannabichromene (CBC) analog containing hydrocarbyl oxy. (Item 26) q5 and q6 are zero, and the remaining hydroxyl group is R 27 In relation to R, 24 and R 25 H is R 26 The C1-C6 alkyl group is R 27 but, (a)-(CO)-NR 42 R 43 (In the formula, R 28 is H or C1-C8 alkyl, R 43 (These are C1-C8 alkyl groups.) (b)-NR 44 R 45 (In the formula, R 44 is H or C1-C8 alkyl, R 45 is C6~C 12Alkyl, C1-C8 alkyl substituted with at least one functional group, C1-C8 heteroalkyl, or C1-C8 heteroalkyl substituted with at least one functional group), (c)-(SO2)-R 46 (In the formula, R 46 (This is a C1-C8 heteroalkyl group, a C1-C8 alkyl group substituted with at least one functional group, or a C1-C8 heteroalkyl group substituted with at least one functional group.) (d)-(SO2)-NR 47 R 48 (In the formula, R 47 is H or C1-C8 alkyl, R 48 (wherein H is H or C1-C8 alkyl, and the C1-C8 alkyl group is either substituted or unsubstituted), [ka] C2~C replaced by 12 CBC analogs that are alkyl, as listed in item 25. (Item 27) R 26 The compound is methyl, and the structure of formula (GG-1) [ka] A CBC analog as described in item 26, having the characteristics of the analog. (Item 28) Structure of formula (HH) [ka] [In the formula, q7 is either zero or 1. R 53 C1~C 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Selected from hydrocarbyl and functional groups, R 49This is H, carboxyl, C2-C6 acyloxy, C2-C6 alkoxycarbonyl, C1-C6 alkyl, or a C1-C6 alkyl substituted with hydroxyl, carboxyl, or halo. R 50 and R 51 These are H, C1~C independently. 12 Hydrocarbyl, substitution C1-C 12 Hydrocarbyl, heteroatom-containing C1-C 12 Hydrocarbyl, substituted heteroatom-containing C1-C 12 Selected from hydrocarbyl and functional groups, R 52 These are methyl, hydroxymethyl, or halomethyl, R 54 (a)-(CO)-NR 55 R 56 (In the formula, R 55 is H or C1~C 12 Hydrocarbil, R 56 is C1~C 12 (b)-NR (hydrocarbyl) 57 R 58 (In the formula, R 57 is H or C1~C 12 Hydrocarbil, R 58 is C6~C 12 Hydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbil, C1-C 12 Heterohydrocarbyl, or C1-C1 substituted with at least one functional group 12 (It is a heterohydrocarbyl), (c)-(SO2)-R 59 (In the formula, R 59 is H or C1~C 12 Heterohydrocarbyl, C1-C1 substituted with at least one functional group 12 Hydrocarbyl, or C1-C1 substituted with at least one functional group 12 (It is a heterohydrocarbyl), (d)-(SO2)-NR 60 R 61 (In the formula, R 60 is H or C1~C 12 Hydrocarbil, R61 is H or C1~C 12 (It is hydrocarbyl.) [ka] (In the formula, L 1 (where C1-C6 alkyl is substituted with C1-C6 18 Alkyl, C2~C 18 Alkenyl, or C2~C 18 It is either alkinyl or R 16 is C1~C 12 C1-C substituted with hydrocarbyl oxy 12 It is hydrocarbyloxy. A tetrahydrocannabivarin (THCV) analog containing [unclear]. (Item 29) A pharmaceutical preparation comprising a compound described in any one of items 18 to 28 of the effective quantity section, in combination with a pharmaceutical additive. (Item 30) A method for treating a subject affected by a condition, disorder, or disease in response to cannabinoid administration, comprising administering to the subject, if necessary, an effective amount of any one of items 18 to 28 in relation to an ongoing dosage regimen. (Item 31) The method according to item 30, wherein the compound is further present in a pharmaceutical formulation containing an additive.

Claims

[Claim 1] The invention described in the specification.

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