Catalytic Cannabinoid Processes and Precursors

Abstract

The present disclosure relates to novel cannabinoid sulfonate esters and processes for their use for the preparation of cannabinoids. The disclosure also relates to the use of catalysts and catalytic processes for the preparation of cannabinoids from cannabinoid sulfonate esters.

Description

[Technical field]

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS This application claims the benefit of priority to U.S. Provisional Application No. 62 / 851,837, filed May 23, 2019, and U.S. Provisional Application No. 62 / 890,661, filed August 23, 2019, the contents of which are incorporated by reference herein in their entireties.

[0002] Field of Disclosure The present disclosure relates to cannabinoid sulfonate compounds and the use of said compounds for the preparation of cannabinoids. The present disclosure also relates to the use of catalysts and catalytic processes for the preparation of cannabinoids using cannabinoid sulfonate esters as precursors. [Background technology]

[0003] Cannabidiol (CBD) is the non-psychotropic main medicinal component of the cannabis plant. Therefore, the medicinal benefits of CBD are great. CBD has been shown to counteract the psychoactive effects of tetrahydrocannabinol (THC), the other main component of cannabis. Hence, over the years, various CBD-rich cannabis strains have been developed and used medically to treat inflammation, AIDS, ALS, Alzheimer's disease, anorexia, anxiety, arthritis, asthma, cancer, depression, diabetes, epilepsy, glaucoma, migraine headaches, nausea, neuropathic pain, and Parkinson's disease, to name a few. Furthermore, numerous clinical trials are being conducted worldwide for the medicinal use of CBD, THC, Cannabidivarin (CBDV), Tetrahydrocannabivarin (THV) and other cannabinoids for these and numerous other diseases.

[0004] The demand for pure, single-ingredient CBD and other cannabinoids is growing rapidly, and as the demand for medical cannabis and legal recreational cannabis continues to grow, the amount of cannabis plants grown and harvested specifically for the extraction of cannabinoids will decrease. The advantages of synthetic cannabinoids compared to products extracted from medical cannabis or hemp plants are the stability of supply, as well as quality control and scalability. The production volume can be constantly adjusted according to demand. Extracted cannabis resin contains more than 150 cannabinoid products in addition to other compounds present in the plant. Even in the case of cannabis plants with high CBD or THC content, the process of extracting and purifying those products is laborious and time-consuming, and only small amounts of the desired components are achieved compared to the amount of plant material. Furthermore, the yield and quality of cannabis or hemp can be affected by drought, pests, pesticides, and adverse weather conditions.

[0005] Therefore, researchers have developed or are actively developing processes for biologically derived (Luo et al. Nature 2019, 567, 123-126) or chemically synthesized cannabinoid products. A variety of synthetic approaches for single component cannabinoid products are described in the prior art, each reflecting the expertise of the researcher or the objectives of the company or sponsor.

[0006] Several groups have reported the acid catalyzed alkylation of olivetol with menthadienol (US2007 / 0072939), but this procedure leads to a mixture of products that require lengthy separation and purification using chromatography.

[0007] One group reported the preparation of cannabidiol acid esters from carboxylic acid ester derivatives of olivetol and menthadienol by Lewis acid catalysis (EP2578561; US7674922). Cannabidiol was then obtained after hydrolysis and decarboxylation. The yields were low compared to the starting materials, and the use of expensive noble metal catalysts makes the process expensive.

[0008] Another group reported the use of acid-catalyzed alkylation of dihalide derivatives of olivetol and related compounds with menthadienol (Srebnik et al. J. Chem. Soc. Perkin Trans. 1987, 1423-1427; US 10,059,683). However, this procedure is laborious and tedious, as it requires time-consuming steps for halogenation of the precursor and dehalogenation of the product.

[0009] Other researchers have explored the use of chiral total synthetic procedures (Kobayashi et al. Org.Lett. 2006, 8, 2699-2702; Carreira et al. J.Am.Chem.Soc. 2017, 139, 18206-18212), but these are limited in scope due to the difficulty in obtaining the desired chiral precursors and products in high yields and purity.

[0010] The prior art reflects the difficulties associated with developing a reliable, commercially viable route to synthetic cannabinoids. This is due in part to the nature of the products, which are difficult to crystallize and separate from one another. Better processes for developing synthetic cannabinoids are needed. Summary of the Invention

[0011] The present invention describes, in some embodiments, an approach to developing synthetic cannabinoids that focuses on the use of inexpensive, commercially available chemicals and their use to prepare stable precursors that can be converted to the desired cannabinoid products as needed. Such commercially available chemicals include, but are not limited to, limonene, resorcinol, and their derivatives.

[0012] In various aspects, the present invention relates to the preparation of novel cannabinoid sulfonate compounds and the use of such sulfonate compounds for the preparation of cannabinoid products using catalysts and catalytic processes to replace sulfonate groups.Cannabinoid sulfonate esters may be prepared and purified prior to conversion to desired individual cannabinoid products.Cannabinoid sulfonate esters are air-stable and shelf-stable compounds that can be stored, transported, and converted to desired cannabinoid products as needed.

[0013] Thus, in some embodiments, the present invention provides a compound of formula (I): [ka] wherein R1 is a hydrogen atom, an optionally substituted linear or branched alkyl group of any length, or an optionally substituted alkenyl group of any length, or an optionally substituted alkynyl group, or an optionally substituted cycloalkyl group, or an optionally substituted aryl group, or an optionally substituted heteroaryl group, or an optionally substituted OR c group or NR c 2 groups, possible non-limiting R1 substituents are halogen atoms, OR c , or N.R. c 2 groups, where R cis a hydrogen atom or a cyclic, linear or branched alkyl, aryl or alkenyl group. Generally, the compounds of formula (I) may be prepared and isolated prior to use.

[0014] In some other embodiments, the present disclosure also provides a compound of formula (II): [ka] The invention also relates to cannabinoid sulfonate esters of the formula R1 is a hydrogen atom, an optionally substituted linear or branched alkyl group of any length, or an optionally substituted alkenyl group of any length, or an optionally substituted alkynyl group, or an optionally substituted cycloalkyl group, or an optionally substituted aryl group, or an optionally substituted heteroaryl group, or an optionally substituted OR group. c group or NR c 2 groups, possible non-limiting R1 substituents are halogen atoms, OR c , or N.R. c 2 groups, where R c is a hydrogen atom or a cyclic, linear or branched alkyl, aryl or alkenyl group; R2 and R3 represent an optionally substituted linear or branched alkyl group of any length, or an optionally substituted alkenyl group of any length, or an optionally substituted alkynyl group, or an optionally substituted cycloalkyl group, or an optionally substituted aryl group, or an optionally substituted heteroaryl group, or an optionally substituted acyl group, where one or more of the carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl groups of R2 and / or R3 may be replaced with a heteroatom selected from the group consisting of O, S, N, P and Si, which may be substituted with one or more groups, if possible. In general, the compound of formula (II) may be prepared and isolated before use.

[0015] In various embodiments of the present invention, transformations to which the compounds of the present invention can be applied include, but are not limited to, catalytic and non-catalytic carbon-carbon bond forming reactions, including the Ullmann reaction, the Suzuki-Miyaura reaction, the Negishi reaction, the Kumada reaction, the Sonogashira reaction, and the Stille reaction. Such carbon-carbon bond forming reactions include: [ka] wherein R2 and R3 represent a linear or branched alkyl group of any length, which may be substituted, or an alkenyl group of any length, which may be substituted, or an alkynyl group, which may be substituted, or a cycloalkyl group, which may be substituted, or an aryl group, which may be substituted, or a heteroaryl group, which may be substituted, or an acyl group, where one or more of the carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl groups of R2 and / or R3 may be replaced with a heteroatom selected from the group consisting of O, S, N, P and Si, which may be substituted with one or more groups, where possible; and R4 represents a hydrogen atom, a linear or branched alkyl group of any length, which may be substituted, or an alkenyl group of any length, which may be substituted, or an alkynyl group, which may be substituted, or a cycloalkyl group, which may be substituted, or an aryl group, where possible.

[0016] In some other aspects of the invention, the present invention provides the following cannabinoid products: [ka] The present invention provides a method for the synthesis of one or more of:

[0017] In some aspects, the present invention provides a process for the preparation of a compound of formula (III), formula (IV), formula (V) or formula (VI) from a compound of formula (I) or formula (II) by a catalyst. In some other aspects, the present invention provides a process for the preparation of a compound of formula (III), formula (IV), formula (V) or formula (VI) from a compound of formula (I) or formula (II) without a catalyst. In various embodiments, the process for the preparation of a compound of formula (III), formula (IV), formula (V) or formula (VI) from a compound of formula (I) or formula (II) according to the present invention uses a boron-containing compound such as R4-B(OH)2, R4-B(OR)2 or R4-BF3K. In some other aspects of the process of the present invention, a Grignard compound such as R4-MgX is used to prepare the compound of formula (III), formula (IV), formula (V) or formula (VI). In yet another embodiment of the process of the present invention, an organozinc compound such as R4-ZnX is used to prepare Formula (III), Formula (IV), Formula (V) or Formula (VI).

[0018] In some embodiments, the present invention provides compounds or compositions comprising Formula (III), Formula (IV), Formula (V) or Formula (VI), where the compound, or composition as the case may be, may be a pure isomer or a mixture of isomers.

[0019] In some other aspects, the compounds and compositions of the invention include all isomers of the compounds of formula (I) and formula (II). In some other embodiments, it provides a mixture of isomers of the compounds of formula (I) and formula (II). In yet some other embodiments, it provides a single isomer of the compounds of formula (I) and formula (II). In some other aspects, the invention provides processes and methods for making any of the foregoing.

[0020] The invention also encompasses methods of making compositions, compounds and compositions comprising the compounds of the invention, kits comprising any one or more of the foregoing components (which may include instructions for making or using any one or more of the foregoing components), and uses of any of the foregoing.

[0021] Other features and advantages of the present disclosure will become apparent from the following detailed description, but it should be understood that the detailed description and specific examples, while indicating preferred embodiments of the present disclosure, are given by way of illustration only, since various changes and modifications within the spirit and scope of the disclosure will become apparent to those skilled in the art from this detailed description.

[0022] The present invention will be described in more detail with reference to the following drawings, which are intended to be illustrative of certain embodiments of the invention and are not intended to limit the scope of the invention. [Brief description of the drawings]

[0023] [Figure 1] FIG. 1 shows a scheme for the preparation of cannabidiol (CBD). [Diagram 2] FIG. 2 shows the X-ray crystal structure of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3,5-triol. [Diagram 3] FIG. 3 shows the X-ray crystal structure of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate. [Figure 4] FIG. 4 shows the X-ray crystal structure of cannabidiol. [Diagram 5] FIG. 5 shows the H NMR spectrum of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3,5-triol. [Figure 6] FIG. 6 shows the H NMR spectrum of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate. [Figure 7]FIG. 7 shows the H NMR spectrum of 4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate. [Figure 8] FIG. 8 shows the 1H NMR spectrum of cannabidiol (CBD). [Figure 9] FIG. 9 shows the 1H NMR spectrum of tetrahydrocannabinol (THC). [Figure 10] FIG. 10 shows the H NMR spectrum of (5-heptyl-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-1,3-phenylene)bis(oxy)bis(trimethylsilane). [Figure 11] FIG. 11 shows the 1H NMR spectrum of Cannabidiphorol (CBDP). [Figure 12] FIG. 12 shows the 1H NMR spectrum of Tetrahydrocannabiphorol (THCP). [Figure 13] FIG. 13 shows the X-ray crystal structure of 2-((1S,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3,5-triol. [Figure 14] FIG. 14 shows the H NMR spectrum of 2-((1S,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3,5-triol. [Figure 15] FIG. 15 shows the H NMR spectrum of 4-((1S,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0024] (I) Definition The term "alkyl," as used herein, means straight-chain and / or branched-chain saturated alkyl radicals containing one or more carbon atoms, and includes (depending on identity) methyl, ethyl, propyl, isopropyl, n-butyl, s-butyl, isobutyl, t-butyl, 2,2-dimethylbutyl, n-pentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, n-hexyl, and the like.

[0025] The term "alkenyl," as used herein, means a straight- and / or branched-chain unsaturated alkyl radical containing two or more carbon atoms and one to three double bonds, and includes (depending on identity) vinyl, allyl, 2-methylprop-1-enyl, but-1-enyl, but-2-enyl, but-3-enyl, 2-methylbut-1-enyl, 2-methylpent-1-enyl, 4-methylpent-1-enyl, 4-methylpent-2-enyl, 2-methylpent-2-enyl, 4-methylpent-1,3-dienyl, hexen-1-yl, and the like.

[0026] The term "alkynyl," as used herein, means a straight-chain and / or branched, unsaturated alkyl radical containing two or more carbon atoms and one to three triple bonds, and includes (depending on identity) acetylinyl, propynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, 3-methylbut-1-enyl, 3-methylpent-1-ynyl, 4-methylpent-1-ynyl, 4-methylpent-2-ynyl, pent-1,3-di-ynyl, hexyn-1-yl, and the like.

[0027] The term "alkoxy," as used herein, means straight and / or branched chain alkoxy groups containing one or more carbon atoms and includes (depending on identity) methoxy, ethoxy, propyloxy, isopropyloxy, t-butoxy, heptoxy, and the like.

[0028] The term "cycloalkyl," as used herein, means a mono-, bi- or tricyclic saturated carbocyclic group containing three or more carbon atoms and includes (depending on identity) cyclopropyl, cyclobutyl, cyclopentyl, cyclodecyl, and the like.

[0029] The term "aryl," as used herein, means a monocyclic, bicyclic, or tricyclic aromatic ring system containing at least one aromatic ring and six or more carbon atoms, and includes phenyl, naphthyl, anthracenyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl, and the like.

[0030] The term "heteroaryl," as used herein, means a monocyclic, bicyclic, or tricyclic ring system containing one or two aromatic rings and, unless otherwise stated, five or more atoms, one, two, three, four, or five of which are heteromoieties independently selected from N, NH, N(alkyl), O, and S, and includes thienyl, furyl, pyrrolyl, pyridyl, indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuryl, benzothienyl, and the like.

[0031] The term "halo" or "halogen" as used herein, means chloro, fluoro, bromo or iodo.

[0032] The term "fluoro-substituted," as used herein, means that at least one (including all) of the hydrogens of the referenced group have been replaced with a fluorine.

[0033] The suffix "ene" added to any of the above groups means that the group is divalent, i.e., inserted between two other groups.

[0034] The term "ring system" as used herein refers to a carbon-containing ring system, including monocyclic, fused bicyclic and polycyclic rings, bridged rings and metallocenes. Where specified, carbons in the ring may be substituted or replaced with heteroatoms.

[0035] In understanding the scope of the present disclosure, the term "comprising" and its derivatives, as used herein, are intended to be open-ended terms that specify the presence of the described features, elements, components, groups, integers, and / or steps, but do not exclude the presence of other features, elements, components, groups, integers, and / or steps that are not described. The above also applies to words with similar meanings, such as "including," "having," and their derivatives. For example, "including" also encompasses "including but not limited to." Finally, terms of degree, such as "substantially," "about," and "approximately," as used herein, refer to a reasonable amount of deviation from the modified term such that the end result is not significantly altered. These terms of degree should be interpreted to encompass deviations of at least ±5% of the modified term, if such deviations do not negate the meaning of the modified word.

[0036] (II) Compounds of the Disclosure The present disclosure provides a compound of formula (I): [ka] and any stereoisomer or acceptable salt thereof, wherein R1 is a hydrogen atom, an optionally substituted linear or branched alkyl group of any length, or an optionally substituted alkenyl group of any length, or an optionally substituted alkynyl group, or an optionally substituted cycloalkyl group, or an optionally substituted aryl group, or an optionally substituted heteroaryl group, or an optionally substituted OR c group or NR c 2 groups, possible non-limiting R1 substituents are halogen atoms, OR c , or N.R. c 2 groups, where R c is a hydrogen atom or a cyclic, linear or branched alkyl, aryl or alkenyl group. Generally, the compounds of formula (I) may be prepared and isolated prior to use.

[0037] In one embodiment, R1 is a hydrogen atom, -OR c , -NR c 2. Fluoro-substituted (C1-C 20 ) Alkyl, (C1-C 20 ) alkyl group, (C2-C 20 ) alkenyl group, (C2-C 20 ) alkynyl group, (C3-C 20 ) Cycloalkyl group, (C6-C 14 ) an aryl group, or (C5-C 14 ) heteroaryl groups, each of the latter six groups being selected from one or more halogen atoms (F, Cl, Br or I), -(C1-C 20 ) Alkyl, (C2-C 20 ) alkenyl group, (C2-C 20 ) alkynyl group, -OR d , or -NR d 2, R c and R d independently or simultaneously, hydrogen, (C1-C 20 ) Alkyl, (C2-C 20 ) alkenyl, or (C2-C20 ) alkynyl.

[0038] In another embodiment, R1 is a hydrogen atom, a fluoro-substituted (C1-C 20 ) Alkyl, (C1-C 20 ) alkyl group, (C2-C 20 ) alkenyl group, (C2-C 20 ) alkynyl group, (C3-C 20 ) Cycloalkyl group, (C6-C 14 ) aryl group, (C5-C 14 ) heteroaryl groups, each of the latter six groups being selected from one or more halogen atoms (F, Cl, Br or I), -(C1-C 20 ) Alkyl, (C2-C 20 ) alkenyl group, (C2-C 20 ) alkynyl group, -OR d , or -NR d 2, R c and R d independently or simultaneously, hydrogen, (C1-C 20 ) Alkyl, (C2-C 20 ) alkenyl, or (C2-C 20 ) alkynyl.

[0039] In another embodiment, R1 is a hydrogen atom, a fluoro-substituted (C1-C 10 ) Alkyl, (C1-C 10 ) alkyl group, (C2-C 10 ) alkenyl group, (C2-C 10 ) alkynyl group, (C3-C 10 ) Cycloalkyl group, (C6-C 10 ) aryl group, (C5-C 10 ) heteroaryl groups, each of the latter six groups being selected from one or more halogen atoms (F, Cl, Br or I), -(C1-C 20 ) Alkyl, (C2-C 20 ) alkenyl group, or (C2-C 20 ) may be substituted with an alkynyl group.

[0040] In another embodiment, R1 represents a hydrogen atom, a fluoro-substituted (C1-C6) alkyl, a (C1-C6) alkyl group, a (C2-C6) alkenyl group, a (C2-C6) alkynyl group, a (C3-C6) cycloalkyl group, a (C6) aryl group, a (C5-C6) heteroaryl group, each of the latter six groups being selected from the group consisting of one or more halogen atoms (F, Cl, Br or I), or -(C1-C6) 20 ) may be substituted with alkyl.

[0041] In another embodiment, R1 represents a hydrogen atom, a fluoro-substituted (C1-C6) alkyl, a (C1-C6) alkyl group, or a phenyl group, each of the latter two groups being optionally substituted with one or more halogen atoms (F, Cl, Br, or I), or -(C1-C 10 ) may be substituted with alkyl.

[0042] In another embodiment, R1 is a hydrogen atom, -CF3, [ka] Represents.

[0043] In one embodiment, the compound of formula (I) is [ka] , TIFF0007654642000008.tif1431 or TIFF0007654642000009.tif1431 It is.

[0044] In one embodiment, the compound of formula (I) has the formula (IA): [ka] wherein LG is any suitable leaving group, such as a halo group, a sulfonate, or a boronate. In another embodiment, the boronate leaving group is -B(OR)2, where R is H, (C1-C 20 ) alkyl group, (C2-C 20 ) alkenyl group, (C2-C 20 )-alkynyl group, (C 20 )-cycloalkyl group, or (C6-C 14 In another embodiment, the boronate leaving group is -B(OR)2, where R is H, (C1-C 20 )Alkyl group ((C1-C 10 ) alkyl group, etc.) or (C6-C 14 ) Aryl group ((C6-C 10 ) an aryl group). In another embodiment, the boronate leaving group is -BF3K. In another embodiment, the leaving group is a triflate, mesylate, or tosylate group.

[0045] The present disclosure also provides a compound of formula (II): [ka] and any stereoisomer or acceptable salt thereof, wherein R1 is a hydrogen atom, an optionally substituted linear or branched alkyl group of any length, or an optionally substituted alkenyl group of any length, or an optionally substituted alkynyl group, or an optionally substituted cycloalkyl group, or an optionally substituted aryl group, or an optionally substituted heteroaryl group, or an optionally substituted OR group. c group or NR c 2 groups, possible non-limiting R1 substituents are halogen atoms, OR c , or N.R. c 2 groups, where R c is a hydrogen atom or a cyclic, linear or branched alkyl, aryl or alkenyl group; R2 and R3 represent an optionally substituted linear or branched alkyl group of any length, or an optionally substituted alkenyl group of any length, or an optionally substituted alkynyl group, or an optionally substituted cycloalkyl group, or an optionally substituted aryl group, or an optionally substituted heteroaryl group, or an optionally substituted acyl group, where one or more of the carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl groups of R2 and / or R3 may be replaced with a heteroatom selected from the group consisting of O, S, N, P and Si, which may be substituted with one or more groups, if possible. In general, the compound of formula (II) may be prepared and isolated before use.

[0046] In another embodiment, R1 in the compound of formula (II) is as defined in the embodiments for all compounds of formula (I).

[0047] In one embodiment, R2 and R3 are independently or simultaneously selected from the group consisting of (C1 to C 20 ) alkyl group, (C2-C 20 ) alkenyl group, (C2-C 20 ) alkynyl group, (C3-C 20 ) cycloalkyl group, -Si[(C1-C 20 ) alkyl]3 groups, (C6-C 14 ) an aryl group, or (C5-C 14 ) heteroaryl group, or acyl group -C(=O)-R', where R' is (C1-C 20 ) alkyl groups, each of which is independently one or more halogen atoms (F, Cl, Br or I), -(C1-C 20 ) alkyl group, (C2-C 20 ) alkenyl group, (C2-C 20 ) alkynyl group, -OR d , or -NR d 2, R c and R dindependently or simultaneously, hydrogen, (C1-C 20 ) Alkyl, (C2-C 20 ) alkenyl, or (C2-C 20 ) alkynyl, One or more of the carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl groups of R2 and / or R3 may be optionally substituted with one or more halogens (F, Cl, Br or I), or -(C1-C 20 ) may be substituted with an alkyl group, or may be substituted with a heteroatom selected from the group consisting of O, S, N, P and Si.

[0048] In one embodiment, R2 and R3 are independently or simultaneously selected from the group consisting of (C1 to C 10 ) alkyl group, (C2-C 10 ) alkenyl group, (C2-C 10 ) alkynyl group, (C3-C 10 ) cycloalkyl group, -Si[(C1-C 10 ) alkyl]3 groups, (C6-C 10 ) an aryl group, or (C5-C 10 ) heteroaryl group, or acyl group -C(=O)-R', where R' is (C1-C 10 ) alkyl groups, each of which is independently one or more halogen atoms (F, Cl, Br or I), -(C1-C 10 ) alkyl group, (C2-C 10 ) alkenyl group, (C2-C 10 ) alkynyl group, -OR d , or -NR d 2, R c and R d independently or simultaneously, hydrogen, (C1-C 10 ) Alkyl, (C2-C 10 ) alkenyl, or (C2-C 10 ) alkynyl, One or more of the carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl groups of R2 and / or R3 may be optionally substituted with one or more halogens (F, Cl, Br or I), or -(C1-C 10 ) may be substituted with an alkyl group, or may be substituted with a heteroatom selected from the group consisting of O, S, N, P and Si.

[0049] In one embodiment, R2 and R3 independently or simultaneously represent a (C1-C6) alkyl group, a (C2-C6) alkenyl group, a (C2-C6) alkynyl group, a (C3-C6) cycloalkyl group, a -Si[(C1-C6) alkyl] group, a phenyl group, or a (C5-C6) heteroaryl group, or an acyl group -C(=O)-R', where R' is a (C1-C6) alkyl group, each of which is independently one or more halogen atoms (F, Cl, Br, or I), a -(C1-C6) alkyl group, a (C2-C6) alkenyl group, a (C2-C6) alkynyl group, -OR d , or -NR d 2, R c and R d are independently or simultaneously hydrogen, (C1-C6) alkyl, (C2-C6) alkenyl, or (C2-C6) alkynyl; One or more of the carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl groups of R2 and / or R3 may be optionally substituted with one or more halogens (F, Cl, Br or I), or -(C1-C 106 ) may be substituted with an alkyl group, or may be substituted with a heteroatom selected from the group consisting of O, S, N, P and Si.

[0050] In one embodiment, R2 and R3 independently or simultaneously represent a (C1-C6)alkyl group, a -Si[(C1-C6)alkyl]3 group, or a phenyl group.

[0051] In one embodiment, R2 and R3, independently or simultaneously, represent a -Si[(C1-C6)alkyl]3 group. In one embodiment, R2 and R3, independently or simultaneously, represent a -Si[(C1-C3)alkyl]3 group. In one embodiment, R2 and R3, independently or simultaneously, represent a -Si(CH3)3 group.

[0052] In one embodiment, the compound of formula (II) has the formula (IIA): [ka] wherein LG is any suitable leaving group. In one embodiment, LG is (i) anionic groups such as sulfonates, halides or boronates; (ii)MX n Groups (M = Li, Mg, Zn, Sn, B, Si; X = halide, OH, OR, (C1-C 20 ) Alkyl, (C1-C 20 )aryl, etc.; n = 0 to 3); It is.

[0053] In another embodiment, the boronate leaving group is -B(OR)2, where R is H, (C1-C 20 ) alkyl group, (C2-C 20 ) alkenyl group, (C2-C 20 )-alkynyl group, (C 20 )-cycloalkyl group, or (C6-C 14 In another embodiment, the boronate leaving group is -B(OR)2, where R is H, (C1-C 20 )Alkyl group ((C1-C 10 ) alkyl group, etc.) or (C6-C 14 ) Aryl group ((C6-C 10 ) an aryl group, etc. In another embodiment, the boronate leaving group is -BF3K.

[0054] In one embodiment, for example, a compound of formula (IIA), and then a compound of formula (II), are prepared as in the following scheme: [ka] TIFF0007654642000014.tif77162

[0055] Transformations to which the compounds of the present disclosure can be applied include, but are not limited to, catalytic and non-catalytic carbon-carbon bond forming reactions, including the Ullmann reaction, the Suzuki-Miyaura reaction, the Negishi reaction, the Kumada reaction, the Sonogashira reaction, and the Stille reaction. Such carbon-carbon bond forming reactions include: [ka] wherein R2 and R3 represent a linear or branched alkyl group of any length, which may be substituted, or an alkenyl group of any length, which may be substituted, or an alkynyl group, which may be substituted, or a cycloalkyl group, which may be substituted, or an aryl group, which may be substituted, or a heteroaryl group, which may be substituted, or an acyl group, where one or more of the carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl groups of R2 and / or R3 may be replaced by a heteroatom selected from the group consisting of O, S, N, P and Si, which may be substituted with one or more groups, where possible; and R4 represents a hydrogen atom, a linear or branched alkyl group of any length, which may be substituted, or an alkenyl group of any length, which may be substituted, or an alkynyl group, which may be substituted, or a cycloalkyl group, or an aryl group, which may be substituted.

[0056] In one embodiment, R2 and R3 in the compounds of formula (III), (IV), (V) and (VI) are as defined in each of the embodiments for the compound of formula (II).

[0057] In one embodiment, R4 is a hydrogen atom, 20 ) alkyl group, (C2-C 20 ) alkenyl group, (C2-C 20 ) alkynyl group, (C3-C 20 ) Cycloalkyl group, (C6-C 14 ) aryl groups, each of the latter five groups being one or more halogen atoms (F, Cl, Br or I), -(C1-C 20 ) Alkyl, (C2-C 20 ) alkenyl group, (C2-C 20 ) alkynyl group, (C6-C 14 ) aryl group, -OR d , or -NR d 2, R c and R d independently or simultaneously, hydrogen, (C1-C 20 ) Alkyl, (C2-C 20 ) alkenyl, or (C2-C 20 ) alkynyl.

[0058] In one embodiment, R4 is a hydrogen atom, 20 ) alkyl group, (C2-C 20 ) alkenyl group, (C6-C 14 ) aryl groups, each of the latter three groups being selected from one or more halogen atoms (F, Cl, Br or I), -(C1-C 10 ) Alkyl, (C2-C 10 ) alkenyl group, (C2-C 10 ) alkynyl group, or (C6-C 10 ) may be substituted with an aryl group.

[0059] In one embodiment, R4 is a hydrogen atom, 20 ) alkyl group, (C6-C 10) aryl groups, each of the latter two groups being optionally substituted with one or more phenyl groups.

[0060] In one embodiment, R4 represents a hydrogen atom or may be substituted with a phenyl group (C1-C 20 ) represents an alkyl group.

[0061] (III) The process of the present disclosure The present disclosure also first provides a method for producing a compound of formula (VII): [ka] and a compound of formula (VIII): [ka] by contacting a compound of formula (IX): [ka] The present invention also relates to a process for the preparation of a compound of formula (I), comprising forming a compound of formula (I).

[0062] Compound (IX) is then converted to a compound of formula (I) by contacting the compound of formula (IX) with the requisite sulfonylating reagent in the presence of a base.

[0063] Compound (I) is then converted to a compound of formula (II) by contacting the compound of formula (I) with a suitable reagent in the presence of a base.

[0064] In some embodiments, the conversion of compound (VII) and compound (VIII) to compound (IX) requires a suitable acid catalyst. Suitable acid catalysts include, but are not limited to, Lewis acids, organic acids, and inorganic acids.

[0065] The present disclosure also provides [ka] The present invention also relates to a process for the catalytic and non-catalytic use of compounds of formula (I) and formula (II) for the preparation of cannabinoid compounds of the formula (I), wherein R2 and R3 represent a linear or branched alkyl group of any length, which may be substituted, or an alkenyl group of any length, which may be substituted, or an alkynyl group, which may be substituted, or a cycloalkyl group, which may be substituted, or an aryl group, which may be substituted, or a heteroaryl group, which may be substituted, or an acyl group, where one or more of the carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl groups of R2 and / or R3 may be replaced by a heteroatom selected from the group consisting of O, S, N, P and Si, which may be substituted with one or more groups, where possible, and R4 represents a hydrogen atom, a linear or branched alkyl group of any length, which may be substituted, or an alkenyl group of any length, which may be substituted, or an alkynyl group, which may be substituted, or a cycloalkyl group, or a aryl group, which may be substituted.

[0066] In one embodiment, R2, R3 and R4 are as defined above.

[0067] Carbon-carbon bond forming reactions for the preparation of cannabinoid compounds of formula (III), formula (IV), formula (V) or formula (VI) include, but are not limited to, the Ullmann reaction, the Suzuki-Miyaura reaction, the Negishi reaction, the Kumada reaction, the Sonogashira reaction and the Stille reaction.

[0068] In some embodiments of the invention, a compound of formula (I) or formula (II) is contacted with a nucleophilic R group R-W in the presence or absence of a catalyst to make a compound of formula (III), formula (IV), formula (V) or formula (VI), where R is as defined above and is nucleophilic and W is an electrophilic group such as a boron-containing compound (such as R-B(OH), R-B(OR) or R-BFK); or a Grignard compound (such as R-MgX); or an organozinc compound (such as R-ZnX).

[0069] In some embodiments of the present invention, the catalytic system characterizing the process of the present invention may include a base. In some aspects, the base may be any conventional base. In some embodiments, non-limiting examples include organic non-coordinating bases such as DBU; alkali metal carbonates or alkaline earth metal carbonates; carboxylates such as sodium acetate or potassium acetate; or alcoholates or hydroxide salts. A preferred base is an alcoholate or hydroxide salt selected from the group consisting of compounds of formula (RO)2M' and ROM'', where M' is an alkaline earth metal, M'' is an alkali metal, and R represents hydrogen or a linear or branched alkyl group.

[0070] The catalyst may be added to the reaction medium in a wide range of concentrations. As non-limiting examples, values ​​ranging from 0.001% to 50% relative to the amount of substrate (thus representing a substrate / catalyst (S / cat) ratio of 100,000 to 2, respectively) can be cited as catalyst concentrations. Preferably, the complex concentration will be comprised between 0.01% and 10% (i.e. an S / cat ratio of 10,000 to 10, respectively). In some preferred embodiments, concentrations in the range of 0.1 to 5% will be used, corresponding to an S / cat ratio of 1000 to 20, respectively.

[0071] If necessary, the useful amount of base added to the reaction mixture may fall within a relatively wide range. In some embodiments, non-limiting examples include a range of 1-100 molar equivalents relative to the substrate. However, it should be noted that it is also possible to add a small amount of base (e.g., base / substrate=1-3) to achieve a high yield.

[0072] In the process of the present invention, the catalytic reaction may be carried out in the presence or absence of a solvent. If a solvent is necessary or used for practical reasons, any solvent currently used in catalytic reactions may be used for the purposes of the present invention. Non-limiting examples include aromatic solvents such as benzene, toluene or xylene; hydrocarbon solvents such as hexane or cyclohexane; ethers such as tetrahydrofuran; or even primary or secondary alcohols, or water; or mixtures thereof. Those skilled in the art can well select the most convenient solvent in each case to optimize the catalytic reaction.

[0073] The temperature at which the catalytic reaction can be carried out is comprised between −30° C. and 200° C., more preferably within the range of 0° C. and 100° C. Of course, the person skilled in the art is also able to select the preferred temperature.

[0074] Standard catalytic conditions, as used herein, typically refer to a mixture of substrate and catalyst, possibly in the presence of a solvent, with or without a base, and treating such mixture with the desired reactants at a selected temperature in air or under an inert atmosphere of nitrogen or argon gas. It will be within the ordinary skill of the art to vary the reaction conditions (including, for example, catalyst, temperature, solvent, and reagents) to optimize the yield of the desired product.

[0075] The present invention is illustrated in the following examples, which are set forth to aid in the understanding of the invention and should not be construed as in any way limiting the scope of the invention as defined in the claims which follow thereafter.

[0076] (IV) Compound of formula (X) - benzylcannabidiol The present disclosure also provides a method for producing a compound having the following structure: [ka] Also included is the compound of formula (X) which is benzylcannabidiol having the formula: R2 and R3 are as defined above in any paragraph for compounds of formula (II); R5 and R6 are hydrogen, halo, -OR c , -NR c 2. Carboxylate (-COOR; where R is H or (C1-C6) alkyl), phosphate, sulfate, (C1-C 20 ) alkyl group, (C2-C 20 ) alkenyl group, (C2-C 20 ) alkynyl group, (C3-C 20 ) Cycloalkyl group, (C6-C 14 ) an aryl group, or (C5-C 14 ) one or more substituents that are heteroaryl groups, where R c and R d independently or simultaneously, hydrogen, (C1-C 20 ) Alkyl, (C2-C 20 ) alkenyl, or (C2-C 20 ) alkynyl; X is (C1~C 10 alkylene) or (C2-C 10 alkenylene).

[0077] In one embodiment, R5 and R6 are hydrogen, halo, (C1-C 10 ) alkyl group, or (C6-C 10 ) one or more substituents that are aryl groups. In one embodiment, R5 and R6 are one or more substituents that are hydrogen, halo, (C1-C6) alkyl groups, or phenyl groups.

[0078] In one embodiment, X is (C1-C6 alkylene) or (C2-C6 alkenylene). In another embodiment, X is (C1-C2 alkylene) or (C2 alkenylene).

[0079] In one embodiment, the compound of formula (X) is [ka] It is. EXAMPLES

[0080] The present disclosure is further illustrated by the following examples, in which temperatures are given in degrees Celsius and abbreviations have their usual meaning in the art.

[0081] All procedures described below have been carried out under an inert atmosphere unless otherwise noted. All preparations and manipulations under air-free conditions were carried out under N2 or Ar atmosphere using standard Schlenk, vacuum line, and glove box techniques in dry, oxygen-free solvents. Deuterated solvents were degassed and dried over activated molecular sieves. NMR spectra were obtained using a 300 MHz spectrometer ( 1 H is 300MHz, 13 75MHz for C, and 31 121.5MHz for P) or 400MHz spectrometer ( 1 H is 400MHz, 13 100MHz for C, and 31 P was recorded at 162 MHz. 31 All P chemical shifts were measured relative to 85% H3PO4 as an external reference. 1 H and 13 C chemical shifts were measured relative to the peaks of partially deuterated solvents but are reported relative to tetramethylsilane.

[0082] Example 1: Preparation of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3,5-triol [ka]

[0083] Absolute ethanol (400 ml) and dichloromethane (800 ml) were added to a mixture of 1,3,5-trihydroxybenzene (91.1 g, 722 mmol) and anhydrous magnesium sulfate (100 g, 834 mmol) and the suspension was cooled to 0° C. Tetrafluoroborate diethyl etherate (7.0 g, 43 mmol) was added slowly with stirring. A solution of (1S,4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-enol (100.0 g, 656 mmol) in dichloromethane (800 ml) was added slowly with stirring at 0° C. over 2 hours and 45 minutes. The mixture was allowed to warm to room temperature and stirred for 1.5 hours. The reaction mixture was filtered and the residue was washed with dichloromethane. The filtrate was washed with water (600 ml) containing NaHCO3 (15 grams). The aqueous portion was extracted with dichloromethane and the combined organic layers were washed with brine (300 ml) and then dried (MgSO4). It was filtered and the solvent removed under reduced pressure to give a viscous, sticky residue. Yield of crude product=168 grams.

[0084] Dichloromethane (470 ml) was added to the crude product and the mixture was stirred for 2 hours. It was filtered and the white crystalline solid was washed with dichloromethane (3×135 ml). The solid was dried under vacuum to give the first crop of product. Yield=70.30 g.

[0085] The mother liquor and washings were combined, the solvent removed and the residue dried under vacuum. Dichloromethane (240 ml) was added and the mixture was stirred for 90 minutes. It was filtered and the white crystalline solid was washed with dichloromethane (3×35 ml). The solid was dried under vacuum to give a second crop of product. Yield=18.0 g.

[0086] The mother liquor and washings were combined, the solvent was removed and the residue was dried under vacuum. Dichloromethane (125 ml) was added and the mixture was stirred for 2 hours. It was filtered and the white crystalline solid was washed with dichloromethane (3 x 12 ml). The solid was dried under vacuum to give a third crop of product. Yield = 5.2 g. Total yield = 93.5g.

[0087] Example 2: Preparation of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate [ka]

[0088] Triethylamine (108.3 g, 1.07 mol) was added to a mixture of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3,5-triol (93.5 g, 308.8 mmol) in dichloromethane (900 ml) with stirring at room temperature. Solid N-phenyl-bis(trifluoromethanesulfonimide) (118.61 g, 332 mmol) was added over 1.5 hours and the mixture was kept at room temperature using a water bath. The mixture was stirred overnight at room temperature before being quenched with water (350 ml) and the phases separated. The aqueous layer was extracted with dichloromethane (3×100 ml) and the combined organic layers were dried (MgSO4). It was filtered through a short pad of silica gel and the solvent was removed under reduced pressure. The residue was dissolved in hexane / CH2Cl2 (100 ml of a 1:3 mixture) and filtered through a short pad of silica gel, eluting with hexane / CH2Cl2 (1:3) until no product was detected in the eluent (TLC). The filtrate was evaporated to give the crude product. Yield of crude product=118 g.

[0089] Hexane (120 ml) was added to the crude product and the mixture was stirred for 2 hours. It was filtered and the white crystalline solid was washed with hexane and dried under vacuum to give the first crop of product. Yield=72.5 g.

[0090] The mother liquor and washings were combined and evaporated to dryness. It was dissolved in EA / Hexane (70 ml of a 3:4 mixture) and filtered through a short pad of silica gel, eluting with EA / Hexane (1:5). The filtrate was evaporated to dryness and to the residue (36 g) was added hexane (40 ml) and the mixture was stirred for 1 h. It was filtered and the white crystalline solid was washed with hexane and dried under vacuum to give a second crop of product. Yield=25.0 g.

[0091] The remaining residue was chromatographed with hexane / EA (6:1) to give a third crop of product. Yield = 7.0 grams. Total yield = 104.5g.

[0092] Example 3: Preparation of 4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate [ka]

[0093] TMSCl (144 g, 1.32 mol) was added to a mixture of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate (104 g, 265 mmol) and NEt3 (134 g, 1.33 mol) in CHCl2 (600 ml) at 0°C. The mixture was stirred at room temperature overnight. It was filtered and the solid was washed with dichloromethane. The combined filtrate was stripped of volatiles under reduced pressure. The residue was suspended in hexane (800 ml) and stirred at room temperature for 2 h. The mixture was filtered, the solvent was removed under reduced pressure and the residue was dried under vacuum to give the product as a pale yellow oil. Yield=135 g.

[0094] Example 4: Preparation of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentylbenzene-1,3-diol (cannabidiol) [ka]

[0095] A solution of n-pentylmagnesium bromide (14 ml of a 2.0 M solution in diethyl ether; 28 mmol) was added to a mixture of ZnBr2 (6.3 g, 28 mmol) and LiBr (3.0 g, 34 mmol) in THF (40 ml) and the suspension was stirred under argon for 30 min. A solution of 4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate (10.0 g, 18.6 mmol) and PdCl2(dppf) (140 mg, 0.19 mmol) in THF (40 ml) was added and the mixture was stirred at room temperature under argon for 2 h. Water (20 ml) was added followed by 2M H2SO4 (10 ml) and the mixture was stirred at room temperature for 1 h. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was dissolved in hexane and filtered through a short pad of silica gel. The silica was washed with hexane and the combined filtrates were evaporated to dryness to give a pale yellow oil which crystallized on standing at room temperature. Yield = 5.25g.

[0096] Example 5: Preparation of (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (tetrahydrocannabinol) [ka]

[0097] A solution of triisobutylaluminium (0.6 ml of a 1.0 M solution in hexane; 0.6 mmol) was added to a solution of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentylbenzene-1,3-diol (2.0 g, 6.36 mmol) in dichloromethane (35 ml) and the mixture was stirred at room temperature for 24 hours. The reaction was quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness to give the product as a pale yellow resin. Yield=1.65 g.

[0098] Example 6: Preparation of 5-methyl-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol (cannabidiorcol) [ka]

[0099] A solution of methylmagnesium bromide (1.4 ml of a 2.0 M solution in diethyl ether; 2.8 mmol) was added to a mixture of ZnBr2 (0.63 g, 2.8 mmol) and LiBr (0.3 g, 3.4 mmol) in THF (4 ml) and the suspension was stirred under argon for 30 min. A solution of 4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate (1.0 g, 1.86 mmol) and PdCl2(dppf) (14 mg, 0.019 mmol) in THF (4 ml) was added and the mixture was stirred at 40° C. under argon for 24 h. Water (2 ml) was added followed by 2M H2SO4 (1.0 ml) and the mixture was stirred at room temperature for 1 h. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was dissolved in hexane and filtered through a short pad of silica gel. The silica was washed with hexane and the combined filtrates were evaporated to dryness to give a pale yellow oil. Yield = 0.46g.

[0100] Example 7: Preparation of 5-ethyl-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol [ka]

[0101] A solution of ethylmagnesium bromide (1.4 ml of a 2.0 M solution in diethyl ether; 2.8 mmol) was added to a mixture of ZnBr2 (0.63 g, 2.8 mmol) and LiBr (0.3 g, 3.4 mmol) in THF (4 ml) and the suspension was stirred under argon for 30 min. A solution of 4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate (1.0 g, 1.86 mmol) and PdCl2(dppf) (14 mg, 0.019 mmol) in THF (4 ml) was added and the mixture was stirred at room temperature under argon for 12 h. Water (2 ml) was added followed by 2M H2SO4 (1.0 ml) and the mixture was stirred at room temperature for 1 h. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was dissolved in hexane and filtered through a short pad of silica gel. The silica was washed with hexane and the combined filtrate was evaporated to dryness to give a pale yellow oil. Yield = 0.48g.

[0102] Example 8: Preparation of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-propylbenzene-1,3-diol (cannabidivarin) [ka]

[0103] A solution of propylmagnesium bromide (1.4 ml of a 2.0 M solution in diethyl ether; 2.8 mmol) was added to a mixture of ZnBr2 (0.63 g, 2.8 mmol) and LiBr (0.3 g, 3.4 mmol) in THF (4 ml) and the suspension was stirred under argon for 30 min. A solution of 4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate (1.0 g, 1.86 mmol) and PdCl2(dppf) (14 mg, 0.019 mmol) in THF (4 ml) was added and the mixture was stirred at room temperature under argon for 6 h. Water (2 ml) was added followed by 2M H2SO4 (1.0 ml) and the mixture was stirred at room temperature for 1 h. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was dissolved in hexane and filtered through a short pad of silica gel. The silica was washed with hexane and the combined filtrate was evaporated to dryness to give a pale yellow oil. Yield = 0.52 g.

[0104] Example 9: Preparation of 5-butyl-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol (cannabidibutol) [ka]

[0105] A solution of butylmagnesium bromide (1.4 ml of a 2.0 M solution in diethyl ether; 2.8 mmol) was added to a mixture of ZnBr2 (0.63 g, 2.8 mmol) and LiBr (0.3 g, 3.4 mmol) in THF (4 ml) and the suspension was stirred under argon for 30 min. A solution of 4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate (1.0 g, 1.86 mmol) and PdCl2(dppf) (14 mg, 0.019 mmol) in THF (4 ml) was added and the mixture was stirred at room temperature under argon for 12 h. Water (2 ml) was added followed by 2M H2SO4 (1.0 ml) and the mixture was stirred at room temperature for 1 h. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was dissolved in hexane and filtered through a short pad of silica gel. The silica was washed with hexane and the combined filtrate was evaporated to dryness to give a pale yellow oil. Yield = 0.54g.

[0106] Example 10: Preparation of 5-hexyl-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol [ka]

[0107] This was prepared using hexylmagnesium bromide following the procedure outlined in Example 9. The product was isolated as a pale yellow oil. Yield = 0.59g.

[0108] Example 11: Preparation of 5-heptyl-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol (cannabidiphorol) [ka]

[0109] This was prepared using heptylmagnesium bromide following the procedure outlined in Example 9. The product was isolated as a pale yellow oil. Yield = 0.62g.

[0110] Example 12: Preparation of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-octylbenzene-1,3-diol [ka]

[0111] This was prepared using octylmagnesium bromide following the procedure outlined in Example 9. The product was isolated as a pale yellow oil. Yield = 0.65g.

[0112] Example 13: Preparation of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-nonylbenzene-1,3-diol [ka]

[0113] This was prepared using nonylmagnesium bromide following the procedure outlined in Example 9. The product was isolated as a pale yellow oil. Yield = 0.68g.

[0114] Example 14: Preparation of 5-decyl-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol [ka]

[0115] This was prepared using decylmagnesium bromide following the procedure outlined in Example 9. The product was isolated as a pale yellow oil. Yield = 0.70g.

[0116] Example 15: Preparation of 5-icosyl-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol [ka]

[0117] This was prepared using icosylmagnesium bromide following the procedure outlined in Example 9. The product was isolated as a white solid. Yield = 0.95g.

[0118] Example 16: Preparation of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-phenethylbenzene-1,3-diol [ka]

[0119] A solution of phenethylmagnesium bromide (1.4 ml of a 2.0 M solution in diethyl ether; 2.8 mmol) was added to a mixture of ZnBr2 (0.63 g, 2.8 mmol) and LiBr (0.3 g, 3.4 mmol) in THF (4 ml) and the suspension was stirred under argon for 30 min. A solution of 4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate (1.0 g, 1.86 mmol) and PdCl2(dppf) (14 mg, 0.019 mmol) in THF (4 ml) was added and the mixture was stirred at 50° C. under argon for 24 h. Water (2 ml) was added followed by 2M H2SO4 (1.0 ml) and the mixture was stirred at room temperature for 1 h. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was dissolved in hexane and filtered through a short pad of silica gel. The silica was washed with hexane and the combined filtrates were evaporated to dryness to give a pale yellow oil which was purified by chromatography. Yield = 0.61 g.

[0120] Example 17: Preparation of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-styrylbenzene-1,3-diol [ka]

[0121] This was prepared using styrylmagnesium bromide following the procedure outlined in Example 16. The product was isolated as a pale yellow oil. Yield = 0.58g.

[0122] Example 18: Preparation of 5-(4-methoxystyryl)-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol [ka]

[0123] This was prepared using 4-methoxystyrylmagnesium bromide following the procedure outlined in Example 16. The product was isolated as a yellow oil which was purified by chromatography. Yield = 0.63g.

[0124] Example 19: Preparation of (6aR,10aR)-3,6,6,9-tetramethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (tetrahydrocannabiorcol) [ka]

[0125] A solution of triisobutylaluminium (0.15 ml of a 1.0 M solution in hexane; 0.15 mmol) was added to a solution of 5-methyl-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol (413 mg, 1.6 mmol) in dichloromethane (10 ml) and the mixture was stirred at room temperature for 24 h. The reaction was quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness to give the product as a pale yellow resin. Yield=340 mg.

[0126] Example 20: Preparation of (6aR,10aR)-3-ethyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol [ka]

[0127] This was prepared using 5-ethyl-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol (436 mg, 1.6 mmol) following the procedure outlined in Example 19. The product was isolated as a pale yellow oil. Yield = 346 mg.

[0128] Example 21: Preparation of (6aR,10aR)-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (tetrahydrocannabivarin) [ka]

[0129] This was prepared using 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-propylbenzene-1,3-diol (458 mg, 1.6 mmol) following the procedure outlined in Example 19. The product was isolated as a pale yellow oil. Yield = 362 mg.

[0130] Example 22: Preparation of (6aR,10aR)-3-butyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (tetrahydrocannabutol) [ka]

[0131] This was prepared using 5-butyl-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol (481 mg, 1.6 mmol) following the procedure outlined in Example 19. The product was isolated as a pale yellow oil. Yield = 367 mg.

[0132] Example 23: Preparation of (6aR,10aR)-3-hexyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol [ka]

[0133] This was prepared using 5-hexyl-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol (526 mg, 1.6 mmol) following the procedure outlined in Example 19. The product was isolated as a pale yellow resin. Yield = 452 mg.

[0134] Example 24: Preparation of (6aR,10aR)-3-heptyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (tetrahydrocannabiphorol) [ka]

[0135] This was prepared using 5-heptyl-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol (548 mg, 1.6 mmol) following the procedure outlined in Example 19. The product was isolated as a pale yellow resin. Yield = 475 mg.

[0136] Example 25: Preparation of (6aR,10aR)-6,6,9-trimethyl-3-octyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol [ka]

[0137] This was prepared using 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-octylbenzene-1,3-diol (570 mg, 1.6 mmol) following the procedure outlined in Example 19. The product was isolated as a pale yellow resin. Yield = 494 mg.

[0138] Example 26: Preparation of (6aR,10aR)-6,6,9-trimethyl-3-nonyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol [ka]

[0139] This was prepared using 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-nonylbenzene-1,3-diol (593 mg, 1.6 mmol) following the procedure outlined in Example 19. The product was isolated as a pale yellow resin. Yield = 532 mg.

[0140] Example 27: Preparation of (6aR,10aR)-3-decyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol [ka]

[0141] This was prepared using 5-decyl-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol (615 mg, 1.6 mmol) following the procedure outlined in Example 19. The product was isolated as a pale yellow resin. Yield = 565 mg.

[0142] Example 28: Preparation of (6aR,10aR)-3-icosyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol [ka]

[0143] This was prepared using 5-icosyl-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol (840 mg, 1.6 mmol) following the procedure outlined in Example 19. The product was isolated as a white solid. Yield = 802 mg.

[0144] Example 29: Preparation of (6aR,10aR)-6,6,9-trimethyl-3-phenethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol [ka]

[0145] This was prepared using 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-phenethylbenzene-1,3-diol (558 mg, 1.6 mmol) following the procedure outlined in Example 19. The product was isolated as a pale yellow resin. Yield = 492 mg.

[0146] Example 30: Preparation of 2-((1S,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3,5-triol [ka]

[0147] The mother liquor from Example 1 contained about 5% 2-((1S,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3,5-triol, which was isolated by silica gel chromatography. Yield=2.5 g.

[0148] Example 31: Preparation of 3,5-dihydroxy-4-((1S,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate [ka]

[0149] Triethylamine (10.8 g, 107 mmol) was added to a mixture of 2-((1S,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3,5-triol (9.35 g, 30.9 mmol) in dichloromethane (100 ml) with stirring at room temperature. Solid N-phenyl-bis(trifluoromethanesulfonimide) (12.0 g, 33.6 mmol) was added over 1.5 hours and the mixture was kept at room temperature using a water bath. The mixture was stirred overnight at room temperature before being quenched with water (40 ml) and the phases separated. The aqueous layer was extracted with dichloromethane (3×25 ml) and the combined organic layers were dried (MgSO4). It was filtered through a short pad of silica gel and the solvent was removed under reduced pressure. The residue was dissolved in hexane / CH2Cl2 (100 ml of a 1:3 mixture) and filtered through a short pad of silica gel, eluting with hexane / CH2Cl2 (1:3) until no product was detected in the eluent (TLC). The filtrate was evaporated to dryness and the residue was chromatographed to give the product as a white solid. Yield=9.6 grams.

[0150] Example 32: Preparation of 4-((1S,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate [ka]

[0151] TMSCl (14 g, 128 mol) was added to a mixture of 3,5-dihydroxy-4-((1S,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate (9.5 g, 24 mmol) and NEt3 (12 g, 120 mmol) in CHCl2 (60 ml) at 0° C. The mixture was stirred at room temperature overnight. It was filtered and the solid was washed with dichloromethane. The combined filtrate was stripped of volatiles under reduced pressure. The residue was suspended in hexane (100 ml) and stirred at room temperature for 2 h. The mixture was filtered, the solvent was removed under reduced pressure and the residue was dried under vacuum to give the product as a pale yellow oil. Yield=12.3 g.

[0152] Example 33: Preparation of 2-((1S,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentylbenzene-1,3-diol [ka]

[0153] A solution of pentylmagnesium bromide (1.4 ml of a 2.0 M solution in diethyl ether; 2.8 mmol) was added to a mixture of ZnBr2 (0.63 g, 2.8 mmol) and LiBr (0.3 g, 3.4 mmol) in THF (4 ml) and the suspension was stirred under argon for 30 min. A solution of 4-((1S,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate (1.0 g, 1.86 mmol) and PdCl2(dppf) (14 mg, 0.019 mmol) in THF (4 ml) was added and the mixture was stirred at room temperature under argon for 12 h. Water (2 ml) was added followed by 2M H2SO4 (1.0 ml) and the mixture was stirred at room temperature for 1 h. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was dissolved in hexane and filtered through a short pad of silica gel. The silica was washed with hexane and the combined filtrate was evaporated to dryness to give a pale yellow oil. Yield = 0.55g.

[0154] Example 34: Preparation of (6aR,10aS)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol [ka]

[0155] A solution of triisobutylaluminium (0.15 ml of a 1.0 M solution in hexane; 0.15 mmol) was added to a solution of 2-((1S,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentylbenzene-1,3-diol (503 mg, 1.6 mmol) in dichloromethane (10 ml) and the mixture was stirred at room temperature for 24 h. The reaction was quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness to give the product as a pale yellow resin. Yield=432 mg.

[0156] Example 35: Preparation of 5-icosyl-2-((1S,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol [ka]

[0157] This was prepared using icosylmagnesium bromide following the procedure outlined in Example 33. The product was isolated as a pale yellow solid. Yield = 0.86g.

[0158] Example 36: Preparation of 2-((1S,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-phenethylbenzene-1,3-diol [ka]

[0159] A solution of phenethylmagnesium bromide (1.4 ml of a 2.0 M solution in diethyl ether; 2.8 mmol) was added to a mixture of ZnBr2 (0.63 g, 2.8 mmol) and LiBr (0.3 g, 3.4 mmol) in THF (4 ml) and the suspension was stirred under argon for 30 min. A solution of 4-((1S,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate (1.0 g, 1.86 mmol) and PdCl2(dppf) (14 mg, 0.019 mmol) in THF (4 ml) was added and the mixture was stirred at 50° C. under argon for 24 h. Water (2 ml) was added followed by 2M H2SO4 (1.0 ml) and the mixture was stirred at room temperature for 1 h. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was dissolved in hexane and filtered through a short pad of silica gel. The silica was washed with hexane and the combined filtrates were evaporated to dryness to give a pale yellow oil which was purified by chromatography. Yield = 0.54g.

[0160] Example 37: Preparation of (6aR,10aS)-3-icosyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol [ka]

[0161] This was prepared using 5-icosyl-2-((1S,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol (840 mg, 1.6 mmol) following the procedure outlined in Example 34. The product was isolated as a white solid. Yield = 735 mg.

[0162] Example 38: Preparation of (6aR,10aS)-6,6,9-trimethyl-3-phenethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol [ka]

[0163] This was prepared using 2-((1S,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-phenethylbenzene-1,3-diol (558 mg, 1.6 mmol) following the procedure outlined in Example 34. The product was isolated as a pale yellow resin. Yield = 450 mg.

[0164] Example 39: Preparation of 2-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3,5-triol [ka]

[0165] This was prepared according to the procedure described in Example 1 using 1,3,5-trihydroxybenzene and (1R,4S)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-enol.

[0166] Example 40: Preparation of 3,5-dihydroxy-4-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate [ka]

[0167] This was prepared according to the procedure described in Example 2 using 2-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3,5-triol.

[0168] Example 41: Preparation of 4-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate [ka]

[0169] This was prepared according to the procedure described in Example 3 using 3,5-dihydroxy-4-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate.

[0170] Example 42: Preparation of 2-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentylbenzene-1,3-diol (S,S-cannabidiol) [ka]

[0171] This was prepared according to the procedure described in Example 4 using 4-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate.

[0172] Example 43: Preparation of 2-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-propylbenzene-1,3-diol (S,S-cannabidivarin) [ka]

[0173] This was prepared according to the procedure described in Example 8 using 4-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate.

[0174] Example 44: Preparation of 5-butyl-2-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol (S,S-cannabidibutol) [ka]

[0175] This was prepared according to the procedure described in Example 43 using butylmagnesium bromide.

[0176] Example 45: Preparation of 5-hexyl-2-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol [ka]

[0177] This was prepared following the procedure outlined in Example 43 using hexylmagnesium bromide.

[0178] Example 46: Preparation of 5-heptyl-2-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol (S,S-cannabidiphorol) [ka]

[0179] This was prepared following the procedure outlined in Example 43 using heptylmagnesium bromide.

[0180] Example 47: Preparation of 2-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-phenethylbenzene-1,3-diol [ka]

[0181] This was prepared following the procedure outlined in Example 43 using phenethylmagnesium bromide.

[0182] Example 48: Preparation of (6aS,10aS)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (S,S-tetrahydrocannabinol) [ka]

[0183] This was prepared following the procedure outlined in Example 5 using 2-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentylbenzene-1,3-diol.

[0184] Example 49: Preparation of (6aS,10aS)-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (S,S-tetrahydrocannabivarin) [ka]

[0185] This was prepared following the procedure outlined in Example 21 using 2-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-propylbenzene-1,3-diol.

[0186] Example 50: Preparation of (6aS,10aS)-3-butyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (S,S-tetrahydrocannabutol) [ka]

[0187] This was prepared following the procedure outlined in Example 22 using 5-butyl-2-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol.

[0188] Example 51: Preparation of (6aS,10aS)-3-hexyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol [ka]

[0189] This was prepared following the procedure outlined in Example 23 using 5-hexyl-2-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol.

[0190] Example 52: Preparation of (6aS,10aS)-3-heptyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (S,S-tetrahydrocannabiphorol) [ka]

[0191] This was prepared following the procedure outlined in Example 24 using 5-heptyl-2-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol.

[0192] Example 53: Preparation of (6aS,10aS)-6,6,9-trimethyl-3-phenethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol [ka]

[0193] This was prepared following the procedure outlined in Example 29 using 2-((1S,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-phenethylbenzene-1,3-diol.

[0194] Example 54: Preparation of 2-((1R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3,5-triol [ka]

[0195] The mother liquor from Example 39 contained approximately 5% 2-((1R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3,5-triol, which was isolated using the procedure described in Example 30.

[0196] Example 55: Preparation of 3,5-dihydroxy-4-((1R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate [ka]

[0197] It was prepared from 2-((1R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3,5-triol using the procedure described in Example 31.

[0198] Example 56: Preparation of 4-((1R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate [ka]

[0199] It was prepared from 3,5-dihydroxy-4-((1R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate using the procedure described in Example 32.

[0200] Example 57: Preparation of 2-((1R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentylbenzene-1,3-diol [ka]

[0201] This was prepared from 4-((1R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate using the procedure described in Example 33.

[0202] Example 58: Preparation of (6aS,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol [ka]

[0203] It was prepared from 2-((1R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentylbenzene-1,3-diol using the procedure described in Example 34.

[0204] Example 59: Preparation of 5-icosyl-2-((1R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol [ka]

[0205] This was prepared from 4-((1R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate using the procedure described in Example 35.

[0206] Example 60: Preparation of 2-((1R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-phenethylbenzene-1,3-diol [ka]

[0207] This was prepared from 4-((1R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate using the procedure described in Example 36.

[0208] Example 61: Preparation of (6aS,10aR)-3-icosyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol [ka]

[0209] This was prepared following the procedure outlined in Example 37 using 5-icosyl-2-((1R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol.

[0210] Example 62: Preparation of (6aS,10aR)-6,6,9-trimethyl-3-phenethyl-6a,7,8,10a-tetrahydro-6H-benzo[c]chromen-1-ol (Perrottetinene) [ka]

[0211] This was prepared following the procedure outlined in Example 38 using 2-((1R,6S)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-phenethylbenzene-1,3-diol.

[0212] Example 63: Preparation of 3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate [ka]

[0213] Anhydrous DMF (25 ml) was added to a mixture of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate (5.0 g, 12.7 mmol), methyl iodide (3.77 g, 26.5 mmol), and potassium carbonate (4.2 g, 30.4 mmol) in a Schlenk flask and the suspension was vigorously stirred at room temperature under argon for 12 hours. Water (100 ml) was added and the mixture was extracted with ethyl acetate (3×25 ml). The organic layer was washed with water, brine, and dried (MgSO4). It was filtered and the solvent was removed under reduced pressure. The residue was chromatographed using hexane / CH2Cl2 and the pure product was isolated as a yellow oil. Yield=4.3 grams.

[0214] Example 64: Reaction of 3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate with n-pentylzinc bromide [ka]

[0215] A solution of n-pentylzinc bromide (5.0 ml of a 0.5 M solution in THF; 2.50 mmol) was added to a mixture of 3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate (1.0 g, 2.38 mmol) and PdCl2(dppf) (40 mg, 0.06 mmol, 2.5%) and the mixture was stirred at room temperature under argon for 1 h. It was quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The NMR spectrum of the residue shows 100% conversion of substrate to product. The product was obtained as a pale yellow oil by flash chromatography with hexane / ethyl acetate. Yield=0.70 g.

[0216] Example 65: Reaction of 3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate with n-propylzinc bromide [ka]

[0217] A solution of n-propylzinc bromide (12.0 ml of a 0.5 M solution in THF; 6.0 mmol) was added to a mixture of 3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate (1.68 g, 4.0 mmol) and PdCl2(dppf) (30 mg, 0.04 mmol, 1.0%) and the mixture was stirred at room temperature under argon for 3 h. It was quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The NMR spectrum of the residue shows 100% conversion of substrate to product. The product was obtained as a pale yellow oil by flash chromatography with hexane / ethyl acetate. Yield=1.20 g.

[0218] Example 66: Reaction of 3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate with phenethylzinc bromide [ka]

[0219] A solution of phenethylzinc bromide (12.0 ml of a 0.5 M solution in THF; 6.0 mmol) was added to a mixture of 3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate (1.68 g, 4.0 mmol) and PdCl2(dppf) (30 mg, 0.04 mmol, 1.0%) and the mixture was stirred at 50° C. under argon for 24 h. It was quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The NMR spectrum of the residue shows 100% conversion of substrate to product. The product was obtained as a pale yellow oil by flash chromatography with hexane / ethyl acetate. Yield=1.42 g.

[0220] Example 67: Preparation of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl 4-methylbenzenesulfonate [ka]

[0221] Triethylamine (31 ml, 222 mmol) was added to a solution of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3,5-triol (38.5 g, 148 mmol) in dichloromethane (200 ml) and the mixture was cooled to 0° C. A solution of toluenesulfonyl chloride (29.6 g, 155 mmol) was added slowly and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution and the phases were separated. The aqueous layer was extracted with dichloromethane (3×50 ml) and the combined organic layers were dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was chromatographed using hexane / CH2Cl2 and the pure product was isolated as a white crystalline solid. Yield=40.2 grams.

[0222] Example 68: Preparation of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate [ka]

[0223] Triethylamine (3.1 ml, 22.2 mmol) was added to a solution of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3,5-triol (3.85 g, 14.8 mmol) in dichloromethane (50 ml) and the mixture was cooled to 0° C. A solution of trifluoromethanesulfonyl anhydride (4.51 g, 16.0 mmol) was added slowly and the mixture was allowed to warm to room temperature and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution and the phases separated. The aqueous layer was extracted with dichloromethane (3×25 ml) and the combined organic layers were dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was chromatographed using hexane / CHCl2 and the pure product was isolated as an orange-red oil. Yield = 4.2 grams.

[0224] Example 69: Preparation of 3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl 4-methylbenzenesulfonate [ka]

[0225] Anhydrous DMF (25 ml) was added to a mixture of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl 4-methylbenzenesulfonate (5.0 g, 12.1 mmol), methyl iodide (3.77 g, 26.5 mmol), and potassium carbonate (4.2 g, 30.4 mmol) in a Schlenk flask and the suspension was vigorously stirred at room temperature under argon for 12 hours. Water (100 ml) was added and the mixture was extracted with ethyl acetate (3×25 ml). The organic layer was washed with water, brine, and dried (MgSO4). It was filtered and the solvent was removed under reduced pressure. The residue was chromatographed using hexane / CH2Cl2 and the pure product was isolated as a viscous pale yellow oil. Yield=4.8 grams.

[0226] Example 70: Preparation of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-(tosyloxy)-1,3-phenylene diacetate [ka]

[0227] Acetyl chloride (0.39 g, 4.94 mmol) was added to a mixture of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl 4-methylbenzene-sulfonate (1.0 g, 2.41 mmol) and NEt3 (0.73 g, 7.24 mmol) in CHCl2 (10 ml) under argon at 0° C. The mixture was stirred at room temperature for 4 h. The reaction was quenched with water and the phases were separated. The aqueous layer was extracted with dichloromethane (3×10 ml) and the combined organic layers were washed with dilute sodium bicarbonate solution, then dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was chromatographed using hexane / CHCl2 and the pure product was isolated as a pale yellow oil. Yield=1.12 grams.

[0228] Example 71: Preparation of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-(trifluoromethylsulfonyloxy)-1,3-phenylene diacetate [ka]

[0229] Acetyl chloride (2.05 g, 26.1 mmol) was added to a mixture of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate (5.0 g, 12.7 mmol) and NEt3 (3.86 g, 38.2 mmol) in CHCl2 (50 ml) under argon at 0°C. The mixture was stirred at room temperature for 15 h. An additional portion of acetyl chloride (2.0 g) was added and stirred at room temperature until the reaction was complete (TLC). The reaction was quenched with sodium bicarbonate solution and the phases were separated. The aqueous layer was extracted with dichloromethane (3 x 25 ml) and the combined organic layers were washed with brine before being dried (MgSO4), filtered and the solvent removed under reduced pressure. The residue was chromatographed using hexane / CHCl2 and the pure product was isolated as a pale yellow oil. Yield = 5.51 grams.

[0230] Example 72: Preparation of 4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl 4-methylbenzenesulfonate [ka]

[0231] Trimethylsilyl chloride (2.5 g, 23.0 mmol) was added to a mixture of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl 4-methylbenzenesulfonate (3.0 g, 7.2 mmol) and NEt3 (2.8 g, 27.7 mmol) in CHCl (25 ml) under argon at 0° C. The mixture was stirred at room temperature for 12 h. It was filtered and the filtrate was stripped of solvent. It was then suspended in hexane (25 ml) and stirred for 4 h. It was filtered, the solvent was removed under reduced pressure and the product was dried under vacuum to give a tan oil. Yield=4.00 g.

[0232] Example 73: Reaction of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate with n-pentylzinc bromide [ka]

[0233] A solution of n-pentylzinc bromide (2.1 ml of a 0.5 M solution in THF; 1.04 mmol) was added to a mixture of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate (100 mg, 0.26 mmol), ZnBr2 (117 mg, 0.52 mmol) and PdCl2(dppf) (10 mg, 0.03 mmol, 5%) and the mixture was stirred at 60 °C under argon for 12 h. It was cooled to room temperature, quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. NMR spectrum of the residue shows 15% conversion of substrate to product.

[0234] Example 74: Reaction of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate with n-propylzinc bromide [ka]

[0235] A solution of n-propylzinc bromide (2.1 ml of a 0.5 M solution in THF; 1.04 mmol) was added to a mixture of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate (100 mg, 0.26 mmol), ZnBr2 (117 mg, 0.52 mmol) and PdCl2(dppf) (10 mg, 0.03 mmol, 5%) and the mixture was stirred at 60 °C under argon for 12 h. It was cooled to room temperature, quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. NMR spectrum of the residue shows 12% conversion of substrate to product.

[0236] Example 75: Reaction of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-(trifluoromethylsulfonyloxy)-1,3-phenylene diacetate with n-pentylzinc bromide [ka]

[0237] A solution of n-pentylzinc bromide (6.3 ml of a 0.5 M solution in THF; 3.15 mmol) was added to a mixture of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-(trifluoromethylsulfonyloxy)-1,3-phenylene diacetate (1.0 g, 2.10 mmol) and PdCl2(dppf) (35 mg, 0.05 mmol, 2.3%) and the mixture was stirred at 60° C. under argon for 12 h. It was cooled to room temperature, quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The NMR spectrum of the residue shows 100% conversion of substrate to product. The product was obtained as a pale yellow oil by flash chromatography with hexane / ethyl acetate. Yield=0.67 g.

[0238] Example 76: Reaction of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-(trifluoromethylsulfonyloxy)-1,3-phenylene diacetate with n-propylzinc bromide [ka]

[0239] A solution of n-propylzinc bromide (6.3 ml of a 0.5 M solution in THF; 3.15 mmol) was added to a mixture of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-(trifluoromethylsulfonyloxy)-1,3-phenylene diacetate (1.0 g, 2.10 mmol) and PdCl2(dppf) (35 mg, 0.05 mmol, 2.3%) and the mixture was stirred at 60° C. under argon for 12 h. It was cooled to room temperature, quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The NMR spectrum of the residue shows 100% conversion of substrate to product. The product was obtained as a pale yellow oil by flash chromatography with hexane / ethyl acetate. Yield=0.65 g.

[0240] Example 77: Preparation of (2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentyl-1,3-phenylene)bis(oxy)bis(trimethylsilane) [ka]

[0241] A solution of n-pentylzinc bromide (5.6 ml of a 0.5 M solution in THF; 2.80 mmol) was added to a mixture of 4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate (1.0 g, 1.87 mmol) and PdCl2(dppf) (34 mg, 0.047 mmol, 2.5%) and the mixture was stirred at room temperature under argon for 1 h. It was quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The NMR spectrum of the residue shows 100% conversion of substrate to product. Yield=0.83 g.

[0242] Example 78: Preparation of (2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-propyl-1,3-phenylene)bis(oxy)bis(trimethylsilane) [ka]

[0243] A solution of n-propylzinc bromide (5.6 ml of a 0.5 M solution in THF; 2.80 mmol) was added to a mixture of 4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate (1.0 g, 1.87 mmol) and PdCl2(dppf) (34 mg, 0.047 mmol, 2.5%) and the mixture was stirred at room temperature under argon for 2 h. It was quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The NMR spectrum of the residue shows 100% conversion of substrate to product. Yield=0.79 g.

[0244] Example 79: Hydrolysis of (2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentyl-1,3-phenylene)bis(oxy)bis(trimethylsilane) [ka]

[0245] Ethanol (10 ml) and dilute H2SO4 (5 ml of a 2M solution) were added to a solution of (2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentyl-1,3-phenylene)bis(oxy)bis(trimethylsilane) (0.83 g) in THF (5 ml) and the mixture was stirred at room temperature for 1 h. It was extracted with ether (3 x 10 ml) and the combined extracts were dried (MgSO4) and then evaporated to dryness. The product was purified by flash chromatography with hexane / ethyl acetate. Yield = 0.55 g.

[0246] Example 80: Hydrolysis of (2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-propyl-1,3-phenylene)bis(oxy)bis(trimethylsilane) [ka]

[0247] Ethanol (10 ml) and dilute H2SO4 (5 ml of a 2M solution) were added to a solution of (2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentyl-1,3-phenylene)bis(oxy)bis(trimethylsilane) (0.79 g) in THF (5 ml) and the mixture was stirred at room temperature for 1 h. It was extracted with ether (3 x 10 ml) and the combined extracts were dried (MgSO4) and then evaporated to dryness. The product was purified by flash chromatography with hexane / ethyl acetate. Yield = 0.53 g.

[0248] Example 81: Preparation of (2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentyl-1,3-phenylene)bis(oxy)bis(trimethylsilane) [ka]

[0249] A solution of n-pentylmagnesium bromide (2.0 ml of a 1.0 M solution in diethyl ether; 2.0 mmol) was added to a mixture of 4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate (200 mg, 0.37 mmol) and PdCl2(dppf) (10 mg, 0.014 mmol) and the mixture was stirred at room temperature under argon for 1 h. It was quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. NMR spectrum of the residue shows 80% conversion of substrate to product.

[0250] Example 82: Preparation of (2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-propyl-1,3-phenylene)bis(oxy)bis(trimethylsilane) [ka]

[0251] A solution of n-propylmagnesium bromide (2.0 ml of a 1.0 M solution in diethyl ether; 2.0 mmol) was added to a mixture of 4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate (200 mg, 0.37 mmol) and PdCl2(dppf) (10 mg, 0.014 mmol) and the mixture was stirred at room temperature under argon for 2 h. It was quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. NMR spectrum of the residue shows 85% conversion of substrate to product.

[0252] Example 83: Reaction of 3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl 4-methylbenzenesulfonate with n-pentylzinc bromide using [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) chloride and zinc bromide as catalyst [ka]

[0253] A solution of n-pentylzinc bromide (1.8 ml of a 0.5 M solution in THF; 0.90 mmol) was added to a mixture of 3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl 4-methylbenzenesulfonate (200 mg, 0.45 mmol), ZnBr2 (102 mg, 0.45 mmol) and PdCl2(dppf) (16 mg, 0.022 mmol, 5%) and the mixture was stirred at 60 °C under argon for 15 h. It was cooled to room temperature, quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. NMR spectrum of the residue shows 12% conversion of substrate to product.

[0254] Example 84: Reaction of 3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl 4-methylbenzenesulfonate with n-pentylzinc bromide using [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) chloride and zinc triflate as catalyst [ka]

[0255] A solution of n-pentylzinc bromide (1.8 ml of a 0.5 M solution in THF; 0.90 mmol) was added to a mixture of 3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl 4-methylbenzenesulfonate (200 mg, 0.45 mmol), Zn(OTf)2 (164 mg, 0.45 mmol) and PdCl2(dppf) (16 mg, 0.022 mmol, 5%) and the mixture was stirred at 60° C. under argon for 15 h. It was cooled to room temperature, quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The NMR spectrum of the residue shows 15% conversion of substrate to product.

[0256] Example 85: Reaction of 3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl 4-methylbenzenesulfonate with n-pentylzinc bromide using [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) chloride and copper(II) bromide as catalysts [ka]

[0257] A solution of n-pentylzinc bromide (1.8 ml of a 0.5 M solution in THF; 0.90 mmol) was added to a mixture of 3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl 4-methylbenzenesulfonate (200 mg, 0.45 mmol), CuBr2 (101 mg, 0.45 mmol) and PdCl2(dppf) (16 mg, 0.022 mmol, 5%) and the mixture was stirred at 60° C. under argon for 15 h. It was cooled to room temperature, quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The NMR spectrum of the residue shows 26% conversion of substrate to product.

[0258] Example 86: Reaction of 3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl 4-methylbenzenesulfonate with n-propylzinc bromide using [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(II) chloride and zinc bromide as catalyst [ka]

[0259] A solution of n-propylzinc bromide (1.8 ml of a 0.5 M solution in THF; 0.90 mmol) was added to a mixture of 3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl 4-methylbenzenesulfonate (200 mg, 0.45 mmol), ZnBr2 (102 mg, 0.45 mmol) and PdCl2(dppf) (16 mg, 0.022 mmol, 5%) and the mixture was stirred at 60 °C under argon for 15 h. It was cooled to room temperature, quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. NMR spectrum of the residue shows 15% conversion of substrate to product.

[0260] Example 87: Reaction of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate with n-pentylmagnesium bromide using [1,1'-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) as catalyst [ka]

[0261] A solution of n-pentylmagnesium bromide (2.0 ml of a 1.0 M solution in diethyl ether; 2.0 mmol) was added to a mixture of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate (200 mg, 0.45 mmol) and PdCl2(dppf) (10 mg, 0.014 mmol, 3%) and the mixture was stirred at 60° C. under argon for 15 h. It was cooled to room temperature, quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. NMR spectrum of the residue indicates 20% conversion of substrate to product.

[0262] Example 88: Reaction of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate with n-propylmagnesium bromide using [1,1'-bis(diphenylphosphino)ferrocene]dichloro-palladium(II) as catalyst [ka]

[0263] A solution of n-propylmagnesium bromide (2.0 ml of a 1.0 M solution in diethyl ether; 2.0 mmol) was added to a mixture of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate (200 mg, 0.45 mmol) and PdCl2(dppf) (10 mg, 0.014 mmol, 3%) and the mixture was stirred at 60° C. under argon for 15 h. It was cooled to room temperature, quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. NMR spectrum of the residue shows 18% conversion of substrate to product.

[0264] Example 89: Reaction of 1,3-dimethoxy-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentylbenzene with sodium ethylthiolate [ka]

[0265] Sodium ethylthiolate (1.33 g, 15.8 mmol) was added to a solution of 1,3-dimethoxy-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentyl-benzene (1.35 g, 3.94 mmol) in DMF (10 ml) and the mixture was heated at 150° C. under argon for 5 h. It was cooled to room temperature, quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was purified by flash chromatography. Yield=1.02 g.

[0266] Example 90: Reaction of 1,3-dimethoxy-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentylbenzene with sodium ethyl thiolate [ka]

[0267] Sodium ethylthiolate (133 mg, 1.6 mmol) was added to a solution of 1,3-dimethoxy-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentyl-benzene (135 mg, 0.40 mmol) in DMF (5 ml) and the mixture was heated at 120° C. under argon for 3 h. It was cooled to room temperature, quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was purified by flash chromatography. Yield=95 mg.

[0268] Example 91: Reaction of 1,3-dimethoxy-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentylbenzene with sodium dodecylthiolate [ka]

[0269] Sodium dodecylthiolate (494 mg, 2.2 mmol) was added to a solution of 1,3-dimethoxy-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentyl-benzene (250 mg, 0.73 mmol) in NMP (5 ml) and the mixture was heated at 160° C. under argon for 6 h. It was cooled to room temperature and neutralized with dilute sulfuric acid. The mixture was extracted with ethyl acetate (3×10 ml) and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. The residue was purified by flash chromatography. Yield=195 mg.

[0270] Example 92: Reaction of 1,3-dimethoxy-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-propylbenzene with sodium dodecylthiolate [ka]

[0271] Sodium dodecylthiolate (494 mg, 2.2 mmol) was added to a solution of 1,3-dimethoxy-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentyl-benzene (250 mg, 0.79 mmol) in NMP (5 ml) and the mixture was heated at 160° C. under argon for 6 h. It was cooled to room temperature and neutralized with dilute sulfuric acid. The mixture was extracted with ethyl acetate (3×10 ml) and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. The residue was purified by flash chromatography. Yield=182 mg.

[0272] Example 93: Reaction of 1,3-dimethoxy-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentylbenzene with methylmagnesium iodide [ka]

[0273] A solution of methylmagnesium iodide (5.25 ml of a 3.0 M solution in diethyl ether; 15.8 mmol) was added to 1,3-dimethoxy-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentylbenzene (1.35 g, 3.94 mmol) and the mixture was stirred at room temperature under argon for 30 min. It was then heated slowly to 160° C. under reduced pressure. It was heated at 160° C. under vacuum for 3 h. The reaction was cooled to room temperature and ether was added followed by ammonium chloride solution (slowly). The phases were separated and the aqueous layer was extracted with ether. The combined organic layers were dried (MgSO4), filtered and evaporated to dryness. The residue was purified by flash chromatography. Yield=0.94 g.

[0274] Example 94: Reaction of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate with n-pentylmagnesium bromide using bis(diphenylphosphino)ethane]nickel(II) chloride as catalyst [ka]

[0275] A solution of n-pentylmagnesium bromide (1.0 ml of a 1.0 M solution in diethyl ether; 1.0 mmol) was added to a mixture of 3,5-dihydroxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate (100 mg, 0.25 mmol), NiCl2(dppe) (13 mg, 0.025 mmol, 10%) and K3PO4 (54 mg, 0.24 mmol) and the mixture was stirred at room temperature under argon for 20 h. It was cooled to room temperature, quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. NMR spectrum of the residue shows 22% conversion of substrate to product.

[0276] Example 95: (6aR,10aR)-6,6,9-trimethyl-3-pentyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol (Δ 8 Preparation of -tetrahydrocannabinol [ka]

[0277] A solution of HBF4.Et2O (40 mg, 0.25 mmol) was added to a solution of 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-pentylbenzene-1,3-diol (1.0 g, 3.18 mmol) in dichloromethane (10 ml) and the mixture was stirred at room temperature for 16 h. The reaction was quenched with water and the phases were separated. The organic layer was washed with NaHCO3 solution, dried (MgSO4), filtered and evaporated to dryness to give the product as a yellow resin. Yield=0.84 g.

[0278] Example 96: (6aR,10aR)-3-heptyl-6,6,9-trimethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol (Δ 8 -Tetrahydrocannabiphorol) [ka]

[0279] This was prepared using 5-heptyl-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene-1,3-diol following the procedure outlined in Example 95. The product was isolated as a yellow resin.

[0280] Example 97: Preparation of (6aR,10aR)-6,6,9-trimethyl-3-phenethyl-6a,7,10,10a-tetrahydro-6H-benzo[c]chromen-1-ol [ka]

[0281] This was prepared using 2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-5-phenethylbenzene-1,3-diol following the procedure outlined in Example 95. The product was isolated as a yellow resin.

[0282] Example 98: Preparation of 5-bromo-1,3-dimethoxy-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene [ka]

[0283] A solution of tBuBrettPhos (4.8 mg, 0.01 mmol) and Pd2(dba)3 (4.6 mg, 0.005 mmol) in dioxane (5 ml) was added to a mixture of 3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl trifluoromethanesulfonate (210 mg, 0.5 mmol), KBr (120 mg, 1.0 mmol) and KF (15 mg, 0.25 mmol) under argon and the mixture was vigorously stirred at 120° C. for 16 h. It was cooled to room temperature, filtered through a pad of silica gel and concentrated under reduced pressure. The product was purified by silica gel chromatography. Yield=105 mg.

[0284] Example 99: Preparation of (5-bromo-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-1,3-phenylene)bis(oxy)bis(trimethylsilane) [ka]

[0285] A solution of tBuBrettPhos (19 mg, 0.04 mmol) and Pd2(dba)3 (18 mg, 0.02 mmol) in dioxane (5 ml) was added to a mixture of 4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)-3,5-bis(trimethylsilyloxy)phenyl trifluoromethanesulfonate (540 mg, 1.0 mmol) and KBr (240 mg, 2.0 mmol) under argon and the mixture was vigorously stirred at 120° C. for 20 h. It was cooled to room temperature, filtered through a pad of silica gel and concentrated under reduced pressure. The product was purified by silica gel chromatography. Yield=182 mg.

[0286] Example 100: Reaction of 5-bromo-1,3-dimethoxy-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene with n-pentylzinc bromide [ka]

[0287] A solution of n-pentylzinc bromide (0.67 ml of a 0.5 M solution in THF; 0.34 mmol) was added to a mixture of 5-bromo-1,3-dimethoxy-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene (100 mg, 0.28 mmol) and PdCl2(dppf) (5 mg, 0.007 mmol) and the mixture was stirred under argon at room temperature for 6 h. It was quenched with ammonium chloride solution and diethyl ether was added. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The NMR spectrum of the residue shows 100% conversion of substrate to product. The product was obtained as a pale yellow oil by flash chromatography with hexane / ethyl acetate. Yield=92 mg.

[0288] Example 101: Preparation of 3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenylboronic acid [ka]

[0289] A solution of 5-bromo-1,3-dimethoxy-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene (100 mg, 0.28 mmol) in THF (5 ml) was cooled to -70°C and butyllithium (0.2 ml of a 1.6 M solution in hexane; 0.32 mmol) was added. The mixture was stirred for 1 h under argon and trimethylborate (35 mg, 0.34 mmol) was added. The mixture was then allowed to warm to room temperature and stirred for 4 h under argon. It was quenched with ammonium chloride solution and stirred overnight. Ethyl acetate was added and the phases were separated. The organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was recrystallized from ethyl acetate and hexane. Yield = 82 mg.

[0290] Example 102: Preparation of (3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl)magnesium bromide [ka]

[0291] A solution of 5-bromo-1,3-dimethoxy-2-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)benzene (485 mg, 1.38 mmol) in THF (5 ml) was added to magnesium turnings (40 mg, 1.7 mmol) and the mixture was heated at 60° C. for 2 h.

[0292] Example 103: Reaction of (3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl)magnesium bromide with n-pentyl bromide [ka]

[0293] A solution of (3,5-dimethoxy-4-((1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl)phenyl)magnesium bromide (1.38 mmol) from Example 102 was added to a mixture of ZnBr2 (622 mg, 2.76 mmol) and LiBr (240 mg, 2.76 mmol) in THF (40 ml) and the suspension was stirred under argon for 30 min. A solution of n-pentyl bromide (250 mg, 1.66 mmol) and PdCl2(dppf) (14 mg, 0.019 mmol) in THF (5 ml) was added and the mixture was stirred at room temperature under argon for 4 h. Water (10 ml) was added followed by dilute H2SO4 (1.0 ml) and the mixture was stirred at room temperature for 1 h. The phases were separated and the organic layer was dried (MgSO4), filtered and evaporated to dryness. The residue was dissolved in hexane and filtered through a short pad of silica gel. The silica was washed with hexane and the combined filtrates were evaporated to dryness to give a pale yellow oil. Yield=435 mg.

[0294] Example 104: Purification of Cannabidiol Crude cannabidiol (10.0 g) was dissolved in isooctane (40 ml) and heated to 40° C. The solution was cooled to 32° C., seeded with cannabidiol crystals and stirred at 32° C. for 1 h. The suspension was slowly cooled to −20° C. and stirred for 2 h. The crystals were filtered and washed with cold (−20° C.) isooctane (40 ml). The product was dried under vacuum to give pure, crystalline cannabidiol. Yield=9.4 g.

[0295] Although the foregoing invention has been described in some detail for purposes of clarity and understanding, those skilled in the art will appreciate upon reading this disclosure that various changes in form and detail can be made therein without departing from the true scope of the invention as set forth in the appended claims.

[0296] All publications, patents, and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference in its entirety.

Claims

1. Formula (I): 【Chemistry 1】 A compound of the formula: R １ is a hydrogen atom, -OR ｃ , -NR ｃ ２ , fluoro-substituted (C １ ~C ２０ ) alkyl, (C １ ~C ２０ ) alkyl group, (C ２ ~C ２０ ) an alkenyl group, (C ２ ~C ２０ ) an alkynyl group, (C ３ ~C ２０ ) a cycloalkyl group, (C ６ ~C １４ ) an aryl group, or (C ５ ~C １４ ) heteroaryl groups, each of the latter six groups being selected from one or more halogen atoms, -(C １ ~C ２０ ) alkyl, (C ２ ~C ２０ ) an alkenyl group, (C ２ ~C ２０ ) an alkynyl group, -OR ｄ or -NR ｄ ２ and R ｃ and R ｄ are independently or simultaneously hydrogen, (C １ ~C ２０ ) alkyl, (C ２ ~C ２０ ) alkenyl, or (C ２ ~C ２０ ) alkynyl; The compound, or any stereoisomer or acceptable salt thereof.

2. R １ is a hydrogen atom, a fluoro-substituted (C １ ~C ２０ ) alkyl, (C １ ~C ２０ ) alkyl group, (C ２ ~C ２０ ) an alkenyl group, (C ２ ~C ２０ ) an alkynyl group, (C ３ ~C ２０ ) a cycloalkyl group, (C ６ ~C １４ ) an aryl group, (C ５ ~C １４ ) heteroaryl groups, each of the latter six groups being selected from one or more halogen atoms, -(C １ ~C ２０ ) alkyl group, (C ２ ~C ２０ ) an alkenyl group, (C ２ ~C ２０ ) an alkynyl group, -OR ｄ or -NR ｄ ２ and R ｃ and R ｄ are independently or simultaneously hydrogen, (C １ ~C ２０ ) alkyl, (C ２ ~C ２０ ) alkenyl, or (C ２ ~C ２０ 2. The compound of formula (I) according to claim 1, wherein R is 1 or 2;

3. R １ is a hydrogen atom, a fluoro-substituted (C １ ~C １０ ) alkyl, (C １ ~C １０ ) alkyl group, (C ２ ~C １０ ) an alkenyl group, (C ２ ~C １０ ) an alkynyl group, (C ３ ~C １０ ) a cycloalkyl group, (C ６ ~C １０ ) an aryl group, (C ５ ~C １０ ) heteroaryl groups, each of the latter six groups being selected from one or more halogen atoms (F, Cl, Br or I), -(C １ ~C ２０ ) alkyl, (C ２ ~C ２０ ) an alkenyl group, or (C ２ ~C ２０ 3. A compound of formula (I) according to claim 1 or 2, which may be substituted with an alkynyl group.

4. R １ is a hydrogen atom, a fluoro-substituted (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkyl group, (C ２ ~C ６ ) an alkenyl group, (C ２ ~C ６ ) an alkynyl group, (C ３ ~C ６ ) a cycloalkyl group, (C ６ ) an aryl group, (C ５ ~C ６ ) heteroaryl groups, each of the latter six groups being selected from one or more halogen atoms, or -(C １ ~C ２０ 4. A compound of formula (I) according to any one of claims 1 to 3, which is optionally substituted with alkyl.

5. R １ is a hydrogen atom, a fluoro-substituted (C １ ~C ６ ) alkyl, (C １ ~C ６ ) alkyl group, or a phenyl group, each of the latter two groups being selected from one or more halogen atoms (F, Cl, Br or I), or -(C １ ~C １０ 5. A compound of formula (I) according to any one of claims 1 to 4, which is optionally substituted with alkyl.

6. R １ is a hydrogen atom, -CF ３ , a group represented by the following formula: 【Chemistry 2】 A compound of formula (I) according to any one of claims 1 to 5, which represents

7. A compound represented by the following formula: 【Chemistry 3】 The compound of formula (I) according to any one of claims 1 to 6,

8. Formula (II): 【Chemistry 4】 A compound of the formula: R １ is as defined in any one of claims 1 to 7, R ２ and R ３ independently or simultaneously, (C １ ~C ２０ ) alkyl group, (C ２ ~C ２０ ) an alkenyl group, (C ２ ~C ２０ ) an alkynyl group, (C ３ ~C ２０ ) cycloalkyl group, —Si[(C １ ~C ２０ ) alkyl] ３ Group, (C ６ ~C １４ ) an aryl group, or (C ５ ~C １４ ) a heteroaryl group, or an acyl group, —C(═O)—R′, where R′ is (C １ ~C ２０ ) alkyl groups, each of which may be one or more halogen atoms (F, Cl, Br or I), -(C １ ~C ２０ ) alkyl group, (C ２ ~C ２０ ) an alkenyl group, (C ２ ~C ２０ ) an alkynyl group, -OR ｄ or -NR ｄ ２ and R ｄ are independently or simultaneously hydrogen, (C １ ~C ２０ ) alkyl, (C ２ ~C ２０ ) alkenyl, or (C ２ ~C ２０ ) alkynyl; R ２ and / or R ３ One or more of the carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl groups of the formula (I) may be selected from the group consisting of one or more halogens (F, Cl, Br or I), or -(C １ ~C ２０ ) optionally substituted with an alkyl group, optionally substituted with a heteroatom selected from the group consisting of O, S, N, P and Si; The compound, or any stereoisomer or acceptable salt thereof.

9. R ２ and R ３ independently or simultaneously, (C １ ~C １０ ) alkyl group, (C ２ ~C １０ ) an alkenyl group, (C ２ ~C １０ ) an alkynyl group, (C ３ ~C １０ ) cycloalkyl group, —Si[(C １ ~C １０ ) alkyl] ３ Group, (C ６ ~C １０ ) an aryl group, or (C ５ ~C １０ ) a heteroaryl group, or an acyl group, —C(═O)—R′, where R′ is (C １ ~C １０ ) alkyl groups, each of which may be one or more halogen atoms (F, Cl, Br or I), -(C １ ~C １０ ) alkyl group, (C ２ ~C １０ ) an alkenyl group, (C ２ ~C １０ ) an alkynyl group, -OR ｄ or -NR ｄ ２ and R ｄ are independently or simultaneously hydrogen, (C １ ~C １０ ) alkyl, (C ２ ~C １０ ) alkenyl, or (C ２ ~C １０ ) alkynyl; R ２ and / or R ３ One or more of the carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl groups of the formula (I) may be selected from the group consisting of one or more halogens (F, Cl, Br or I), or -(C １ ~C １０ ) optionally substituted with an alkyl group, optionally substituted with a heteroatom selected from the group consisting of O, S, N, P and Si; A compound of formula (II) according to claim 8.

10. R ２ and R ３ independently or simultaneously, (C １ ~C ６ ) alkyl group, (C ２ ~C ６ ) an alkenyl group, (C ２ ~C ６ ) an alkynyl group, (C ３ ~C ６ ) cycloalkyl group, —Si[(C １ ~C ６ ) alkyl] ３ group, a phenyl group, or (C ５ ~C ６ ) a heteroaryl group, or an acyl group, —C(═O)—R′, where R′ is (C １ ~C ６ ) alkyl groups, each of which may be one or more halogen atoms (F, Cl, Br or I), -(C １ ~C ６ ) alkyl group, (C ２ ~C ６ ) an alkenyl group, (C ２ ~C ６ ) an alkynyl group, -OR ｄ or -NR ｄ ２ and R ｄ are independently or simultaneously hydrogen, (C １ ~C ６ ) alkyl, (C ２ ~C ６ ) alkenyl, or (C ２ ~C ６ ) alkynyl; R ２ and / or R ３ One or more of the carbon atoms in the alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl or acyl groups of the formula (I) may be selected from the group consisting of one or more halogens (F, Cl, Br or I), or -(C １ ~C ６ ) optionally substituted with an alkyl group, optionally substituted with a heteroatom selected from the group consisting of O, S, N, P and Si; 10. A compound of formula (II) according to claim 8 or 9.

11. R ２ and R ３ independently or simultaneously, (C １ ~C ６ ) alkyl group, —Si[(C １ ~C ６ ) alkyl] ３ A compound of formula (II) according to any one of claims 8 to 10, wherein R represents a group, or a phenyl group.

12. R ２ and R ３ independently or simultaneously, -Si[(C １ ~C ６ ) alkyl] ３ A compound of formula (II) according to any one of claims 8 to 11, wherein R represents a group.

13. R ２ and R ３ independently or simultaneously, -Si[(C １ ~C ３ ) alkyl] ３ A compound of formula (II) according to any one of claims 8 to 12, wherein R represents a group.

14. R ２ and R ３ is -Si(CH ３ ) ３ A compound of formula (II) according to any one of claims 8 to 13, wherein R represents a group.

15. Formula (III), Formula (IV), Formula (V) or Formula (VI): 【Chemistry 5】 1. A process for the preparation of a compound of the formula In the formula, R ２ and R ３ is as defined in any one of claims 8 to 14, The process comprises reacting a compound of formula (I) as defined in any one of claims 1 to 7 or a compound of formula (II) as defined in any one of claims 8 to 14 (i) R ４ -B(OH) ２ , R ４ -B(OR) ２ Or R ４ -BF ３ K (where R is H, (C １ ~C ２０ ) alkyl group, (C ２ ~C ２０ ) an alkenyl group, (C ２ ~C ２０ ) an alkynyl group, (C ３ ~C ２０ ) a cycloalkyl group, or (C ６ ~C １４ ) an aryl group; (ii) R ４ Grignard compounds of MgX; or (iii) R ４ -ZnX zinc compounds; reacting with X is a halogen atom; R ４ is a hydrogen atom, (C １ ~C ２０ ) alkyl group, (C ２ ~C ２０ ) an alkenyl group, (C ２ ~C ２０ ) an alkynyl group, (C ３ ~C ２０ ) a cycloalkyl group, (C ６ ~C １４ ) aryl groups, each of the latter five groups being one or more halogen atoms (F, Cl, Br or I), -(C １ ~C ２０ ) alkyl, (C ２ ~C ２０ ) an alkenyl group, (C ２ ~C ２０ ) an alkynyl group, (C ６ ~C １４ ) an aryl group, —OR ｄ or -NR ｄ ２ and R ｄ are independently or simultaneously hydrogen, (C １ ~C ２０ ) alkyl, (C ２ ~C ２０ ) alkenyl, or (C ２ ~C ２０ ) alkynyl; process.

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