US20230357177A1 - Synthesis of cannabidiol and analogs thereof, and related compounds, formulations, and methods of use - Google Patents

Synthesis of cannabidiol and analogs thereof, and related compounds, formulations, and methods of use Download PDF

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US20230357177A1
US20230357177A1 US18/212,061 US202318212061A US2023357177A1 US 20230357177 A1 US20230357177 A1 US 20230357177A1 US 202318212061 A US202318212061 A US 202318212061A US 2023357177 A1 US2023357177 A1 US 2023357177A1
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hydrocarbyl
substituted
alkyl
heteroatom
functional group
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Glenn M. SAMMIS
Markus ROGGEN
Matthew Roberts
Caitlyn KREBS
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Nalu Bio Inc
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    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans
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    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
    • C07C37/0555—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group being esterified hydroxy groups
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    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/658—Medicinal preparations containing organic active ingredients o-phenolic cannabinoids, e.g. cannabidiol, cannabigerolic acid, cannabichromene or tetrahydrocannabinol
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    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/50—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/52—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having two carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
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    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
    • C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
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    • C07C309/00—Sulfonic acids; Halides, esters, or anhydrides thereof
    • C07C309/63—Esters of sulfonic acids
    • C07C309/72—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C309/73—Esters of sulfonic acids having sulfur atoms of esterified sulfo groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton to carbon atoms of non-condensed six-membered aromatic rings
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    • C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
    • C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
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    • C07C37/11—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
    • C07C37/16—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms by condensation involving hydroxy groups of phenols or alcohols or the ether or mineral ester group derived therefrom
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    • C07C39/02—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with no unsaturation outside the aromatic ring
    • C07C39/08—Dihydroxy benzenes; Alkylated derivatives thereof
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    • C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
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    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
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    • C07C43/00—Ethers; Compounds having groups, groups or groups
    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/205—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring
    • C07C43/2055—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring the aromatic ring being a non-condensed ring containing more than one ether bond
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    • C07C43/02—Ethers
    • C07C43/20—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring
    • C07C43/215—Ethers having an ether-oxygen atom bound to a carbon atom of a six-membered aromatic ring having unsaturation outside the six-membered aromatic rings
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    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/56—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds
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    • C07C47/56—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups
    • C07C47/57—Compounds having —CHO groups bound to carbon atoms of six—membered aromatic rings containing hydroxy groups polycyclic
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    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/29—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by introduction of oxygen-containing functional groups
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    • C07C67/293—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
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    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/02—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen
    • C07C69/22—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety
    • C07C69/28—Esters of acyclic saturated monocarboxylic acids having the carboxyl group bound to an acyclic carbon atom or to hydrogen having three or more carbon atoms in the acid moiety esterified with dihydroxylic compounds
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    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates generally to methods for chemically synthesizing cannabinoids, including cannabidiol (CBD) and analogs thereof, to compounds and compositions employed in and generated by the synthetic methods, to methods for synthesizing the reactants used, and to methods for using the synthesized compounds.
  • CBD cannabidiol
  • the invention has utility in the fields of medicine, medicinal chemistry, therapeutics, and chemical and pharmaceutical manufacturing.
  • CBD cannabinoids
  • THC ((-)-trans- ⁇ 9 -tetrahydro-cannabinol)
  • CBD cannabinoids
  • CBD is a chiral 21-carbon terpenophenolic cannabinoid that is biosynthesized in the plant by decarboxylation of its immediate precursor, cannabidiolic acid.
  • cannabidiolic acid cannabidiolic acid
  • CBD and other naturally occurring cannabinoids have been obtained primarily by extraction, isolation, and purification from C. Sativa and industrial hemps, cultivars that are used to manufacture fiber and oilseed. This has proven difficult primarily because of the chemical and physical similarities among the many phytocannabinoids present in the natural source, making isolation of CBD from C. Sativa and hemp a complex process, leading to quality control challenges in commercial manufacturing. See Lo et al. (2019) Nature 567: 123-126.
  • the present invention is addressed to the above needs in the art and, in one embodiment, provides a method for synthesizing a plurality of cannabinoids, including, without limitation, CBD, cannabinol (CBN), cannabichromene (CBC), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidibutol (CBD-C4), dihydrocannabidiol (DCBD), tetrahydrocannabivarin (THCV), analogs thereof, and synthetic precursors to the aforementioned compounds.
  • CBD cannabinol
  • CBD cannabichromene
  • CBD cannabidiolic acid
  • CBD cannabigerol
  • CBD cannabigerolic acid
  • CBD cannabidivarin
  • CBD-C4 cannabidivarin
  • DCBD dihydrocannabidiol
  • THCV
  • the methods are stereospecific, efficient, cost-effective, and readily adapted to produce cannabinoids such as CBD and CBD precursors, as well as a host of other cannabinoids, cannabinoid precursors, and cannabinoid analogs, with little or no incidental generation of THC or other psychoactive side-products.
  • the synthetic method can be carried out as a “one pot” reaction, i.e., without isolation of intermediates between reaction steps.
  • the invention provides novel cannabinoids.
  • pharmaceutical formulations are provided that comprise a cannabinoid that can be synthesized using the presently disclosed methods.
  • the invention provides methods of using the cannabinoids or pharmaceutical formulations thereof, wherein the methods involve administration of a cannabinoid or formulation thereof to a subject to provide a beneficial effect.
  • the invention provides a method for synthesizing olivetol or an analog thereof from a suitably substituted phloroglucinol reactant.
  • Olivetol and olivetol analogs that are produced using the method can be used as reactants in a number of chemical syntheses (including in methods for synthesizing cannabinoids as described in detail elsewhere herein) and have the structure of formula (AA) wherein:
  • a method for synthesizing a cannabinoid comprising:
  • R 1 when R 1 is n-pentyl, when the cannabinoid product (CC) is CBD or analog thereof. In some embodiments, when R 1 is n-propyl, cannabinoid (CC) is CBDV or an analog thereof. In some embodiments, when R 1 is methyl, cannabinoid (CC) is CBD-C1 or an analog thereof. In some embodiments, when R 1 is n-butyl, cannabinoid (CC) is cannabidibutol, i.e., CBD-C4, or an analog thereof.
  • a method for synthesizing tetrahydrocannabivarin (THCV) or an analog thereof.
  • the method proceeds as above with the proviso that R 1 is n-propyl, such that compound (AA) is optionally substituted divarinol, such that the resulting cannabinoid is CBDV or an analog thereof.
  • the reaction product can then be cyclized using conventional means to provide THCV or a substituted analog thereof.
  • methods for synthesizing other cannabinoids including, without limitation, CBN, CBDA, CBG, CBGA, and analogs of any of the foregoing are also provided.
  • cannabinoids including CBD analogs
  • EE formula (EE)
  • CBN analogs having the structure of formula (FF) are provided (FF)
  • CBC analogs having the structure (GG)
  • THCV analogs are provided having the structure (HH)
  • compositions comprising a cannabinoid synthesized using a method of the invention in combination with a pharmaceutical excipient appropriate to the selected mode of administration, where the cannabinoid is present in an effective amount for the intended purpose.
  • the formulations may comprise an amount of an additional active agent, such that the amount of the cannabinoid and the additional active agent together represent an effective beneficial amount.
  • Any additional active agent will typically, although not necessarily, be used for the same purpose as the selected cannabinoid analog, and any additional active agent in the formulation may or may not be an additional cannabinoid.
  • Formulations are typically provided as unit dosage forms for administration of the active agent(s) to a subject.
  • a method for administering a cannabinoid synthesized using a method of the invention to a subject to achieve a beneficial effect, e.g., to treat a subject affected by a condition, disorder, or disease responsive to administration of a cannabinoid.
  • the method comprises administering to the subject an effective amount of the cannabinoid to achieve the intended effect. Administration may be carried out once, on an as needed basis, or within the context of an ongoing dosage regimen. Indications for which the cannabinoids of the invention have utility are described in detail in the next section.
  • a catalyst refers not only to a single catalyst but also to a combination of two or more different catalysts
  • a reagent refers to a single reagent or to a combination of reagents, and the like.
  • hydrocarbyl refers to hydrocarbyl groups or linkages containing 1 to about 18 carbon atoms, typically 1 to 12 carbon atoms, including linear, branched, cyclic, saturated, and unsaturated species, such as alkyl groups, alkenyl groups, aryl groups, and the like. “Substituted hydrocarbyl” refers to hydrocarbyl substituted with one or more substituent groups, and the term “heteroatom-containing hydrocarbyl” refers to hydrocarbyl in which at least one carbon atom is replaced with a heteroatom. Unless otherwise indicated, the term “hydrocarbyl” is to be interpreted as including substituted and/or heteroatom-containing hydrocarbyl moieties.
  • alkyl refers to a branched or unbranched saturated hydrocarbon group typically although not necessarily containing 1 to about 18 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, octyl, decyl, and the like, as well as cycloalkyl groups such as cyclopentyl, cyclohexyl, and the like.
  • alkyl groups herein contain 1 to 12 carbon atoms, e.g., 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, 1 to 6 carbon atoms or 1 to 3 carbon atoms.
  • “Substituted alkyl” refers to alkyl substituted with one or more substituent groups
  • the terms “heteroatom-containing alkyl” and “heteroalkyl” refer to alkyl in which at least one carbon atom is replaced with a heteroatom, as described in further detail infra. If not otherwise indicated, the term “alkyl” includes linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkyl.
  • alkenyl refers to a linear, branched, or cyclic hydrocarbon group of 2 to about 18 carbon atoms containing at least one double bond, such as ethenyl, n-propenyl, isopropenyl, n-butenyl, isobutenyl, octenyl, decenyl, tetradecenyl, hexadecenyl, eicosenyl, tetracosenyl, and the like.
  • Alkenyl groups herein typically contain 2 to 12 carbon atoms, e.g., 2 to 12 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms or 2 to 3 carbon atoms.
  • cycloalkenyl intends a cyclic alkenyl group, typically having 5 to 8 carbon atoms.
  • substituted alkenyl refers to alkenyl substituted with one or more substituent groups
  • heteroatom-containing alkenyl and “heteroalkenyl” refer to alkenyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the term “alkenyl” includes linear, branched, cyclic, unsubstituted, substituted, and/or heteroatom-containing alkenyl.
  • alkynyl refers to a linear or branched hydrocarbon group of 2 to 18 carbon atoms containing at least one triple bond, such as ethynyl, n-propynyl, and the like.
  • alkynyl groups herein contain 2 to 12 carbon atoms, e.g., 2 to 12 carbon atoms, 2 to 10 carbon atoms, 2 to 8 carbon atoms, 2 to 6 carbon atoms or 2 to 3 carbon atoms.
  • substituted alkynyl refers to alkynyl substituted with one or more substituent groups
  • heteroatom-containing alkynyl and heteroalkynyl refer to alkynyl in which at least one carbon atom is replaced with a heteroatom. If not otherwise indicated, the term “alkynyl” includes linear, branched, unsubstituted, substituted, and/or heteroatom-containing alkynyl.
  • alkoxy refers to an alkyl group bound through a single, terminal ether linkage; that is, an “alkoxy” group may be represented as -O-alkyl where alkyl is as defined above. Alkoxy groups thus include C 1 -C 6 alkoxy groups such as methoxy, ethoxy, n-propoxy, isopropoxy, t-butyloxy, etc.
  • alkenyloxy and “alkynyloxy” are defined in an analogous manner.
  • aryl refers to an aromatic substituent containing a single aromatic ring or multiple aromatic rings that are fused together, directly linked, or indirectly linked (such that the different aromatic rings are bound to a common group such as a methylene or ethylene moiety).
  • Preferred aryl groups contain 5 to 18 carbon atoms, and particularly preferred aryl groups contain 5 to 14 carbon atoms.
  • Exemplary aryl groups contain one aromatic ring or two fused or linked aromatic rings, e.g., phenyl, naphthyl, biphenyl, diphenylether, diphenylamine, benzophenone, and the like.
  • Substituted aryl refers to an aryl moiety substituted with one or more substituent groups
  • heteroatom-containing aryl and “heteroaryl” refer to aryl substituent, in which at least one carbon atom is replaced with a heteroatom, as will be described in further detail infra. If not otherwise indicated, the term “aryl” includes unsubstituted, substituted, and/or heteroatom-containing aromatic substituents.
  • aryloxy refers to an aryl group bound through a single, terminal ether linkage, wherein “aryl” is as defined above.
  • An “aryloxy” group may be represented as -O-aryl where aryl is as defined above.
  • Preferred aryloxy groups contain 5 to 18 carbon atoms, and particularly preferred aryloxy groups contain 5 to 14 carbon atoms.
  • aryloxy groups include, without limitation, phenoxy, o-halo-phenoxy, m-halo-phenoxy, p-halo-phenoxy, o-methoxy-phenoxy, m-methoxy-phenoxy, p-methoxy-phenoxy, 2,4-dimethoxy-phenoxy, 3,4,5-trimethoxy-phenoxy, and the like.
  • alkaryl refers to an aryl substituent that is substituted with an alkyl group
  • aralkyl refers to an alkyl substituent that is substituted with an aryl group, wherein “aryl” and “alkyl” are as defined above.
  • Preferred alkaryl and aralkyl groups contain 6 to 18 carbon atoms, and particularly preferred aralkyl groups contain 6 to 16 carbon atoms.
  • alkaryl groups include, for example, p-methylphenyl, 2,4-dimethylphenyl, p-cyclohexylphenyl, 2,7-dimethylnaphthyl, 7-cyclooctyinaphthyl, 3-ethyl-cyclopenta-1,4-diene, and the like.
  • Aralkyl groups include, without limitation, benzyl, 2-phenyl-ethyl, 3-phenyl-propyl, 4-phenyl-butyl, 5-phenyl-pentyl, 4-phenylcyclohexyl, 4-benzylcyclohexyl, 4-phenylcyclohexylmethyl, 4-benzylcyclohexylmethyl, and the like.
  • alkaryloxy and aralkyloxy refer to substituents of the formula -OR wherein R is alkaryl or aralkyl, respectively, as just defined.
  • acyl refers to substituents having the formula -(CO)-alkyl, -(CO)-aryl, or -(CO)-aralkyl
  • acyloxy refers to substituents having the formula -O(CO)-alkyl, -O(CO)-aryl, or -O(CO)-aralkyl, wherein “alkyl,” “aryl, and “aralkyl” are as defined above.
  • cyclic refers to alicyclic or aromatic substituents that may or may not be substituted and/or heteroatom containing, and that may be monocyclic, bicyclic, or polycyclic.
  • alicyclic is used in the conventional sense to refer to an aliphatic cyclic moiety, as opposed to an aromatic cyclic moiety, and may be monocyclic, bicyclic, polycyclic, and may be bridged.
  • halo and “halogen” are used in the conventional sense to refer to a chloro, bromo, fluoro, or iodo substituent.
  • heteroatom-containing refers to a molecule, linkage, or substituent in which one or more carbon atoms are replaced with an atom other than carbon, e.g., nitrogen, oxygen, sulfur, phosphorus, or silicon, typically nitrogen, oxygen, or sulfur, preferably nitrogen or oxygen.
  • heteroalkyl refers to an alkyl substituent that is heteroatom-containing
  • heterocyclic refers to a cyclic substituent that is heteroatom-containing
  • heteroaryl and heteroaromatic respectively refer to “aryl” and “aromatic” substituents that are heteroatom-containing, and the like.
  • heteroalkyl groups include alkoxyaryl, alkylsulfanyl-substituted alkyl, N-alkylated amino alkyl, and the like.
  • heteroaryl substituents include pyrrolyl, pyrrolidinyl, pyridinyl, quinolinyl, indolyl, pyrimidinyl, imidazolyl, 1,2,4-triazolyl, tetrazolyl, etc., and examples of heteroatom-containing alicyclic groups are pyrrolidino, morpholino, piperazino, piperidino, etc.
  • substituted as in “substituted alkyl,” “substituted aryl,” and the like, as alluded to in some of the aforementioned definitions, is meant that in the alkyl, aryl, or other moiety, at least one hydrogen atom bound to a carbon (or other) atom is replaced with one or more non-hydrogen substituents. Examples of such substituents include functional groups and hydrocarbyl moieties.
  • Functional groups that may represent substituents in the substituted molecular structures and segments thereof include, without limitation: halo, hydroxyl, sulfhydryl, C 1 -C 18 alkoxy, C 2 -C 18 alkoxyalkyl, C 2 -C 18 alkenyloxy, C 2 -C 18 alkynyloxy, C 5 -C 18 aryloxy, acyl (including C 2 -C 18 alkylcarbonyl (-CO-alkyl) and C 6 -C 18 arylcarbonyl (-CO-aryl)), acyloxy (-O-acyl), C 2 -C 18 alkoxycarbonyl (-(CO)-O-alkyl), C 6 -C 18 aryloxycarbonyl (-(CO)-O-aryl), halocarbonyl (-CO)-X where X is halo), C 2 -C 18 alkylcarbonato (-O-(CO)-O-alkyl), C 6 -
  • the aforementioned functional groups may, if a particular group permits, be further substituted with one or more additional functional groups or with one or more hydrocarbyl moieties such as those specifically enumerated above, and the term “functional group” encompasses all such instances.
  • substituted When the term “substituted” appears prior to a list of possible substituted groups, it is intended that the term apply to every member of that group.
  • substituted alkyl, alkenyl, and aryl is to be interpreted as “substituted alkyl, substituted alkenyl, and substituted aryl.”
  • heteroatom-containing when the term “heteroatom-containing” appears prior to a list of possible heteroatom-containing groups, it is intended that the term apply to every member of that group.
  • heteroatom-containing alkyl, alkenyl, and aryl is to be interpreted as “heteroatom-containing alkyl, substituted alkenyl, and substituted aryl.”
  • Some of the compounds described herein may contain one or more asymmetric centers and give rise to enantiomers, diastereomers, or other stereoisomeric forms.
  • Such a compound may be in the form of a single stereoisomer, i.e., be “stereoisomerically pure,” or contained in a mixture of two or more stereoisomers, e.g., two diastereomers, two enantiomers, or a mixture of two diastereomers and two enantiomers.
  • cannabidiol and analogs thereof are in (-)-configuration rather than in the (+)-configuration or in a ( ⁇ ) racemic mixture (numbering convention included):
  • a “pharmacologically active agent,” sometimes referred to herein as simply an “active agent,” encompasses not only the specified cannabinoid or other molecular entity but also its pharmaceutically acceptable analogs and derivatives, including, but not limited to, salts, esters, prodrugs, conjugates, active metabolites, crystalline forms, enantiomers, stereoisomers, and other such derivatives, analogs, and related compounds.
  • pharmaceutically acceptable is meant a material that is not biologically or otherwise undesirable, i.e., the material may be incorporated into a pharmaceutical formulation or dosage form administered to a subject without causing any undesirable biological effects or interacting in a deleterious manner with any of the other components of the composition in which it is contained.
  • pharmaceutically acceptable refers to a pharmaceutical carrier or excipient, it is implied that the carrier or excipient has met the required standards of toxicological and manufacturing testing and/or that it is included on the Inactive Ingredient Guide prepared by the U.S. Food and Drug administration.
  • treating and “treatment” as used herein refer to reduction in severity and/or frequency of symptoms, elimination of symptoms and/or underlying cause, and improvement or remediation of damage, e.g., reduction in the number and/or extent of menopausal symptoms with a patient being given hormone replacement therapy using the drug delivery system of the invention. Unless otherwise indicated, the terms “treating” and “treatment” as used herein encompass prevention of symptoms as well.
  • an “effective amount” of a cannabinoid or pharmaceutical formulation containing the cannabinoid refers to an amount that is nontoxic and sufficient for producing an intended beneficial effect.
  • the beneficial effect is typically, although not necessarily, a therapeutic effect, wherein administration involves “treatment” as defined above.
  • An “effective dosage” and a “unit dosage” provide an “effective amount” of an active agent.
  • subject or “individual” or “patient” refers to any living individual for whom therapy is desired, and refers to the recipient of the therapy to be practiced according to the invention.
  • the subject is generally a mammalian individual and most typically is human.
  • “Optional” or “optionally” means that the subsequently described circumstance may or may not occur, so that the description includes instances where the circumstance occurs and instances where it does not.
  • the phrase “optionally co-administered with” when referring to the administration of an active agent to a subject encompasses administration of the active agent in the context of a monotherapy as well as co-administration of the active agent with a second compound.
  • the phrase “optionally substituted” means that a non-hydrogen substituent may or may not be present on a given atom, and, thus, the description includes structures wherein a non-hydrogen substituent is present and structures wherein a non-hydrogen substituent is not present.
  • the invention provides a method for synthesizing a compound useful as a synthetic precursor to the cannabinoids described herein, including, without limitation CBD and CBD analogs.
  • the compound synthesized is olivetol or an olivetol analog that has the structure of formula (AA) wherein:
  • R 1 Some examples of R 1 include, without limitation:
  • R 1 substituents may be further substituted with one or more additional substituents that may or may not be the same as the substituents identified above.
  • R 1 substituents include a C 1 -C 18 alkyl group (e.g., a C 1 -C 12 alkyl group, a C 1 -C 10 alkyl, or C 1 -C 8 alkyl group) disubstituted with Cl or F; a C 2 -C 18 alkoxyalkyl group substituted with one or more C 2 -C 18 alkoxyalkyl groups, e.g., a C 2 -C 12 alkoxyalkyl group having the structure (C 1 -C 8 alkoxy)-substitituted C 1 -C 12 alkyl, wherein the C 1 -C 12 alkyl is substituted with an additional C 2 -C 12 alkoxyalkyl group, and the like.
  • R 1 substituents (sometimes referred to hereafter as the “representative R 1 substituents”) are as follows:
  • the starting material (AA-1) can be obtained commercially or synthesized using procedures known or readily available to one of ordinary skill in the art.
  • the electron-withdrawing protecting group PR can be one of any number of electron-withdrawing protecting groups.
  • —O—PR represents a sulfonate ester.
  • —O—PR may be represented as —O—(SO 2 )—R 3 wherein R 3 is selected from: C 1 -C 12 hydrocarbyl optionally substituted with one or more nonhydrogen substituents and optionally containing at least one heteroatom; C 1 -C 12 perfluorocarbyl; and fluoro.
  • examples of such protecting groups include tosylate, mesylate, triflate (trifluoromethanesulfonate), benzyl sulfonate, 2-[(4-nitrophenyl)ethyl) sulfonate, and fluorosulfate, corresponding to the following —O—PR moieties:
  • Suitable electron-withdrawing hydroxyl-protecting reagents for effecting protection of the hydroxyl groups as —O—PR will be known to those in the art or found in the pertinent texts and literature, as are the reaction conditions normally employed.
  • the hydroxyl groups of compound (AA-1) can be protected by treatment of (AA-1) using electron-withdrawing hydroxyl-protecting reagents as follows:
  • the hydroxyl-protected compound (AA-2) may or may not be isolated and purified at this point. It may be preferred, in some instances, that the reaction proceed as a “one pot” reaction without isolation of (AA-2) before continuing.
  • the synthesis of (AA) might be carried out in a flow reactor, where the starting material is introduced at an initial inlet and the final product is obtained downstream without isolation of any intermediates therebetween.
  • a cross-coupling reaction is carried out between the hydroxyl-protected intermediate (AA-2) and a reactant R 1 -M in the presence of a catalyst that facilitates the cross-coupling reaction, wherein R 1 is as defined earlier and M comprises a metallic element, to provide a compound having the structure of formula (AA-3)
  • reaction involves the coupling of R 1 -M to the aromatic ring of compound (AA-2), it will be appreciated that the reaction is an sp2-sp3 cross-coupling reaction.
  • cross-coupling reactions traditionally involve the metal-catalyzed coupling of an sp2-hybridized substituted aryl electrophile with an organometallic nucleophile, wherein the aryl electrophile may be a phenol derivative or an aryl halide. Numerous techniques are suitable for carrying out this step and have been described in the literature. Among these cross-coupling techniques are:
  • Preferred cross-coupling reactions herein are carried out at a reaction temperature lower than about 25° C., e.g., lower than about 15° C., lower than about 5° C., lower than about -5°, etc.
  • the cross-coupling reaction temperature may be in the range of about -25 C to about 25° C., such as about -20° C. to about 20° C., about -15° C. to about 15° C., about -10° C. to about 10° C., about -15° C. to about 5° C., about -15° C. to about 0° C., about -15° C. to about -10° C., about -5° C. to about 5° C., about -25° C. to about 5° C., about -25° C. to about -5° C., or at approximately -10° C.
  • Negishi, Suzuki-Miyaura and Mostner cross-coupling are generally preferred herein, with the iron-catalyzed Erasmusstner coupling particularly preferred, insofar as the reaction can be carried out under relatively mild conditions and iron catalysts tend to be low in cost, non-toxic, and selective.
  • introduction of the R 1 substituent is carried out using the Harrisonstner reaction, using about 1 equivalent to about 1.5 equivalents of the Grignard reagent R 1 -MgBr.
  • the reaction temperature is maintained in the range of about -15° C. to about -5° C., preferably in the range of about -15° C.
  • ferric chloride or ferric acetylacetonate Fe(acac) 3
  • catalyst load is in the range of about 5 mol% to about 10 mol%
  • the reaction is carried out in a solvent such as THF or a THF/toluene mixture in the presence of an additive that facilitates cross-coupling with iron salts (see, e.g., Nomme et al.
  • NMP N-methyl pyrrolidone
  • TEDA tetramethylethylenediamine
  • DMEU N, N′-dimethylethylene urea
  • DMPU N,N′-dimethylpropyleneurea
  • R 1 -M reagents can be selected to provide (AA-3) intermediates having a variety of R 1 substituents, wherein R 1 is as defined earlier in this section.
  • Compound (AA-3) can be isolated and purified at this point, although, if desired, the next step of the synthesis, deprotection, can instead proceed without isolation and purification, in the same reaction vessel, as explained with respect to the initial reaction step and the intermediate (AA-2).
  • AA-3 The compound having the structure of formula (AA-3) is believed to be a new chemical entity and is claimed as such herein.
  • m is 1, n is zero, R 1 is n-pentyl, and the ring is 1,3,5-trisubstituted, such the compound has the structure (AA-4):
  • compound (AA-3) is deprotected to give the desired end product, compound (AA).
  • Deprotecting reagents and reaction conditions for removal of hydroxyl protecting groups are known to those of ordinary skill in the art, and are described throughout the pertinent texts. See, e.g., Greene et al., “Protective Groups in Organic Synthesis,” 3rd Ed. (New York: John Wiley & Sons, 1999). Greene states, for example, that tosyl groups can be removed by reductive cleavage with Na/NH 3 or by treatment with sodium borohydride or lithium aluminum hydride.
  • tosyl groups are preferably removed by potassium hydroxide, sodium hydroxide, isobutyl alcohol, or t-butyl alcohol.
  • Benzyl sulfonate can be cleaved with sodium amide, while mesylate groups can be removed by photolysis in the presence of potassium iodide, triflate groups can be removed by acid and hydrogenolysis, and fluorosulfate protecting groups can be removed by a strong aqueous base or under hydridic conditions.
  • the reaction product can be isolated and then purified by any suitable means or combination thereof, e.g., by filtration, extraction, crystallization or recrystallization, use of chromatographic means, or the like.
  • the reaction product can be used without purification in a subsequent synthesis, i.e., in a “one-pot” reaction.
  • the reaction product can be immediately used in synthesizing a cannabinoid such as CBD or an analog thereof as described herein. Also see Example 28, pertaining to the synthesis of olivetol via a telescoped reaction.
  • n is zero, such that the starting compound of formula (AA-1) is dihydroxy- or trihydroxybenzene.
  • m is also zero, it will be appreciated that compound (AA-1) is a dihydroxybenzene, i.e., 1,2-dihydroxybenzene, 1,3-dihydroxybenzene, or 1,4-dihydroxybenzene.
  • compound (AA-1) is a trihydroxybenzene, typically 1,2,4-trihydroxybenzene or 1,3,5-trihydroxybenzene. The latter compound is also known as phloroglucinol.
  • reaction product (AA) is olivetol:
  • the invention provides, in one embodiment, a method for synthesizing olivetol and analogs thereof, where the method can be scaled up to an efficient and economical process that provides a high purity reaction product and no harmful by-products.
  • the purified reaction product may be a composition that comprises, in addition to compound (AA), an additional compound in which cross-coupling has occurred at two ring hydroxyl sites instead of one, such that the reaction product comprises a compound having the structure of formula (AA-5) and a compound having the structure of formula (AA-6) wherein:
  • the molar ratio of (AA-5) to (AA-6) in the purified reaction product can vary.
  • (AA-6) represents at most about 2 mol% of the combination of (AA-5) and (AA-6), while (AA-5) correspondingly represents greater than about 98 mol% of (AA-5) plus (AA-6), such that the mol ratio of (AA-5) to (AA-6) is at least about 49:1.
  • (AA-6) represents at most about 0.1 mol% of the combination of (AA-5) and (AA-6), while (AA-5) correspondingly represents greater than about 99.9 mol% of (AA-5) plus (AA-6).
  • (AA-6) represents at most about 0.01 mol% of the combination of (AA-5) and (AA-6), while (AA-5) correspondingly represents greater than about 99.99 mol% of (AA-5) plus (AA-6).
  • (AA-6) represents in the range of about 0.001 mol% to about 2 mol% of the combination of (AA-5) and (AA-6), with (AA-5) correspondingly represents about 98 mol% to about 99.999 mol% of the (AA-5) plus (AA-6) combination.
  • the substituent R 1 is as defined previously for compounds having structure (AA).
  • (AA)-type compounds include the following compounds collectively referred to herein as “(AA)-type compounds”.
  • a method for the synthesis of cannabidiol or analogs thereof from the compound synthesized in the preceding section i.e., compound (AA), which may, as noted previously, be olivetol per se.
  • Compound (AA) may be isolated and purified prior to use in this synthesis, using conventional means or methods readily apparent to those of ordinary skill in the art. However, compound (AA) can be used in this synthesis as prepared, without isolation and purification.
  • the method results in the synthesis of a compound having the structure of formula (CC)
  • any of the foregoing representative R 1 substituents may be further substituted with one or more additional substituents that may or may not be the same as the substituents identified above.
  • R 1 substituents include a C 1 -C 18 alkyl group (e.g., a C 1 -C 12 alkyl group C 1 -C 10 alkyl, or C 1 -C 8 alkyl group) disubstituted with Cl or F; a C 2 -C 18 alkoxyalkyl group substituted with one or more C 2 -C 18 alkoxyalkyl groups, e.g., a C 2 -C 12 alkoxyalkyl group having the structure (C 1 -C 6 alkoxy)-substitituted C 1 -C 12 alkyl, wherein the C 1 -C 12 alkyl is substituted with an additional C 2 -C 12 alkoxyalkyl group; a C 2 -C 18 alkoxyalkyl group substituted with one or
  • R 1 is selected from the representative R 1 substituents as defined and exemplified in Section II, above.
  • compound (AA) which may be obtained commercially or used as synthesized as described in Section II, undergoes a Lewis acid-catalyzed coupling reaction with a second reactant having the structure of formula (CC-1)
  • reaction product (CC) then has the structure (CC-2)
  • reaction product with (AA-9) then has the structure (CC-3)
  • reaction product has the structure of formula (CC-4)
  • R 1 in reactant (AA) can be varied to provide many different cannabinoids, e.g., CBD analogs, substituted at the 4′ position (the location of the R 1 substituent). It will be understood that when R 1 is n-pentyl, the compound of formula (CC-4) is CBD, and when R 1 is n-propyl, the compound of formula (CC-4) is CBDV. Cyclization of CBDV, the penultimate intermediate in the synthesis of THCV, can be carried out using methods known to those of ordinary skill in the art and/or described in the pertinent texts and literature with respect to synthesis of either THCV or THC.
  • the reaction between reactant (AA) and reactant (CC-1) to provide compound (CC) is essentially an electrophilic aromatic substitution reaction and requires a Lewis acid catalyst.
  • Lewis acid catalysts are based on metals such as aluminum, boron, nickel, silicon, tin, titanium, iron, copper, zinc, and palladium, with aluminum and boron catalysts being most common and generally preferred herein for the reaction of (AA) with (CC-1).
  • Lewis acid catalysts that can be advantageously employed for the reaction include, without limitation, boron trichloride, boron trifluoride, boron trifluoride ethyl etherate, iron (III) bromide, iron (III) chloride, aluminum chloride, and aluminum bromide.
  • An exemplary Lewis acid catalyst for the reaction is boron trifluoride (BF 3 ), which may be in the form of an organic complex, e.g., BF 3 etherate (BF 3 •Et 2 O), optionally used in conjunction with a metal oxide support such as zeolite or alumina.
  • the coupling of the two reactants is carried out in a suitable organic solvent, e.g., heptane, dichloroethane (DCE), dichloromethane (DCM), N-methylpyrrolidone (NMP), chlorobenzene, or the like, in an inert atmosphere (e.g., under argon), at an elevated temperature in the range of about 30° C. to about 140° C., or about 30° C. to about 130° C., or about 35° C. to about 100° C., such as 35° C., 40° C., 65° C., 80° C., 85° C., or 90° C., typically although not necessarily at reflux.
  • a suitable organic solvent e.g., heptane, dichloroethane (DCE), dichloromethane (DCM), N-methylpyrrolidone (NMP), chlorobenzene, or the like
  • an inert atmosphere e.g., under argon
  • the reaction is quenched with sodium bisulfate or another suitable base, and the product is extracted with diethyl ether or another organic solvent effective to extract the desired product. See Examples 4 and 5.
  • An excess of the (AA) reactant may, in some cases, be desired in order to reduce the presence of one or more contaminants such as abn-CBD and tetrahydrocannabinol (THC) in the synthesis of CBD.
  • the yield of the reaction is in the range of about 30% to about 60%, with the desired reaction product (CC) obtained as at least about 95% pure.
  • reaction product obtained may be modified to provide other desired analogs as explained in Part III of this section.
  • the selected solvent, reaction temperature, catalyst loading, and stoichiometry may be varied to optimize the composition of the reaction product, e.g., by reducing the presence of contaminants, and to maximize yield.
  • Use of a molecular sieve is also advantageous in minimizing incidental formation of contaminants, particularly THC.
  • reaction product comprises a mixture of two regioisomers having the structures of formula (CC-4A) and (CC-4B):
  • the reaction product composition generally comprises at least about 98 mol% compound (CC-5), such as at least about 99.9 mol% compound (CC-5), or at least about 99.999 mol% compound (CC-5).
  • the at least one additional compound selected from (CC-5A) and (CC-5B), and (CC-5C) represents in the range of about 0.001 mol% to about 2 mol% of the composition.
  • menthadienol ring of the CBD analog (CC-1) synthesized as just described may be substituted in different ways and the substituents having different possible configurations, depending on the particular (AA)-type reactant selected. See “Representative (AA) Reactants” in Section II.
  • 8,9-dehydro analogs of structure (CC) including 8,9-dihydrocannabidiol (H 2 CBD) and variations thereof, may be prepared from ⁇ -phellandrene or via the Friedel-Crafts reaction described in Millimaci et al. (Jun. 8, 2023, Version 1) ChemRxiv, doi 10.26434/chemrxiv-2023-7wtzg, the disclosure of which is incorporated by reference herein.
  • the starting material that reacts with reactant (CC-4) is the compound (AB-1)
  • n, R 1 , and R 2 are as previously defined, and R A is generally C 1 -C 4 alkyl, e.g., methyl or ethyl.
  • Suitable solvents, reaction temperatures, and Lewis acid catalysts are as described in part A. The coupling reaction results in the product (AB-2)
  • Example 20 A representative reaction is included herein in Example 20. As with the cross-coupling reaction described in part A, a variety of analogs can be synthesized in this way by selection of appropriately substituted reactants. For example, analogs of CBD having modifications at the 4′ position may be prepared by starting with a reactant (AB-1) having the desired R 1 substituent.
  • an alternative method for synthesizing a cannabinoid such as CBD, the cannabinoid having the structure of formula (DD)
  • DD-1 3,5-dihydroxybenzoic acid
  • the starting material may be obtained commercially, e.g., as benzyloxy-protected 3,5-dihydroxybenzoic acid, and modified to include one or more R 2 substituents, or a desired R 2 -substituted analog of may be purchased and used without modification,
  • the initial step of the synthesis involves reacting (DD-1) with R 9 -Li under reducing conditions to provide a hydroxyl-protected ketone intermediate having the structure (DD-2)
  • intermediate (DD-3) undergoes an electrophilic addition reaction with compound (CC-1), i.e., the menthadienol reactant as defined earlier herein
  • compound (CC-1) is added at the 4-position of (DD-3) in the presence of a Lewis Acid catalyst, to form the immediate precursor to compound (DD), i.e., compound (DD-4):
  • this method is efficient and economical, enables the use of mild reaction conditions without need for harsh reagents or special precautions, is readily adapted to produce a variety of cannabinoids, including, but not limited to, CBD analogs as well as CBD per se, and has little or no potential for incidental production of THC.
  • the method comprises:
  • Suitable electron-withdrawing hydroxyl-protecting reagents, PR moieties, hydroxyl-protecting techniques, deprotection techniques, cross-coupling reaction techniques, cross-coupling catalysts, and cross-coupling reaction conditions are as set forth with respect to the synthesis of compound (AA) in Section II.
  • the method comprises:
  • Reagents, reactants, techniques, and reaction conditions appropriate for carrying out steps (a) through (b) in the synthesis of compound (CC) are analogous to, and for the most part, the same as, those described in Section II with respect to synthesis of the CBD precursor, the olivetol analog having the structure of formula (AA).
  • R 1 can be C 1 -C 12 hydrocarbyl, including C 1 -C 10 hydrocarbyl, e.g., C 1 -C 10 alkyl, C 2 -C 10 alkenyl, C 2 -C 10 alkynyl, and C 5 -C 10 aryl, including cycloalkyl, branched alkyl, cycloalkenyl, branched cycloalkenyl, etc., any of which is optionally substituted, e.g., substituted with zero to 3 functional groups typically selected from hydroxyl, halo, carboxyl, C 2 -C 6 acyloxy, C 2 -C 6 alkoxycarbonyl, C 2 -C 6 alkylamido, and combinations thereof, and containing zero to 3 heteroatoms such as O, S, or N (including NH, NR where is C 1 -C 12 hydrocarbyl, and N-heterocycles such as pyrrole, pyrrolidine, pyridine
  • R 2 may be any of the groups and substituents identified above with respect to R 1 , and may, in addition, be a functional group selected from those set forth in part (I) of this Detailed Description.
  • Examples of functional groups that may serve as R 2 substituents thus include, without limitation, halo, carboxyl, C 1 -C 12 alkoxy, C 1 -C 12 alkylsulfanyl, C 2 -C 12 acyl, C 2 -C 12 acyloxy, C 2 -C 12 alkoxycarbonyl, and C 6 -C 18 aryloxycarbonyl (-(CO)-O-aryl).
  • reaction product may be modified to provide desired analogs of the compound obtained, e.g., by: hydrogenation of the isopropenyl substituent to an isopropyl group (see, e.g., Ben-Shabat et al. (2005) J. Med. Chem.
  • Table 1 illustrates various CBD analogs that may be prepared using the methods of Section III, using different R 1 -M reactants to produce variants at the 4′ position of the CBD molecule:
  • Additional CBD analogs can be prepared using the present syntheses by selection of different R 2 groups when n is nonzero, optionally combined with selection of different R 1 moieties in the R 1 -M reactant and/or different placement of the substituents on the phenyl ring.
  • reaction product has the structure of formula (CC-8)
  • R 10 Compound n-Pentyl 2-Hydroxyethyl n-Pentyl 2-Hydroxypentyl n-Pentyl 2,3-Dihydroxypropyl N-Pentyl Cyclohexyl N-Pentyl N-Hexyl N-Pentyl 2-(Methylsulfonamido)ethyl N-Propyl 2-Hydroxyethyl N-Propyl Cyclohexyl N-Propyl N-Hexyl See, e.g., Götz et al. (2019), “Structure-Effect Relationships of Novel Semi-Synthetic Cannabinoid Derivatives,” Frontiers in Pharmacology 10: 1284.
  • analogs such as H2CBD, having an isopropyl group instead of an isopropenyl substituent at the 4-position which again can be accomplished by using a modified (+)-menthadienol analog as a reactant, i.e., a compound having a 4-isopropyl substituent (ibid.); analogs having a substituted alkyl group such as hydroxyethyl or hydroxypropyl instead of an isopropenyl group at the 4-position, which can be accomplished in the same way, by using a modified (+)-menthadienol analog as a reactant; other analogs classified by Jung et al.
  • the compound or compounds ultimately synthesized may be further modified, if desired, to produce an additional type of analog, e.g., partial hydrogenation of a reaction product to convert the isopropenyl group of the (+)-menthadienol ring to an isopropyl group, or full hydrogenation to additionally convert the (+)-menthadienol ring to a cyclohexyl group.
  • an additional type of analog e.g., partial hydrogenation of a reaction product to convert the isopropenyl group of the (+)-menthadienol ring to an isopropyl group, or full hydrogenation to additionally convert the (+)-menthadienol ring to a cyclohexyl group.
  • the present method can, accordingly, be used to make not only CBD but also naturally occurring CBD analogs as well as known and unknown synthetic analogs, including metabolites, prodrugs, salts, esters, crystalline forms, stereoisomers, and the like.
  • CBD analogs include, without limitation,
  • the invention provides new cannabinoids, including, without limitation, analogs of CBD, analogs of CBN, analogs of CBC, and analogs of THCV.
  • the analogs can be synthesized using any of the methods described in Section III, or other methods as will be described infra.
  • the new compounds share not only certain aspects of molecular structure with known and/or naturally occurring cannabinoids, but also pharmacological properties and uses.
  • novel analogs include CBD analogs having the structure of formula (EE)
  • q1 is 1, q2 is zero, and the two hydroxyl groups are located meta to R 16 .
  • q1 is 1, q2 is zero, and the two hydroxyl groups are located meta to R 16 , R 12 and R 15 are C 1 -C 6 alkyl, e.g., methyl, R 13 and R 14 are H, and R 16 is C 1 -C 12 alkyl or C 2 -C 12 alkyl substituted with:
  • the compound of formula (EE) is a CBD analog having the structure of formula (EE-1)
  • R 16 is as defined above.
  • q3 and q4 are zero, and the hydroxyl group is located meta to R 22 , R 18 and R 21 are C 1 -C 6 alkyl, e.g., methyl, R 19 and R 20 are H, and R 22 is C 1 -C 12 alkyl or C 2 -C 12 alkenyl substituted with:
  • the compound of formula (FF) is a CBN analog having the structure of formula (FF-1)
  • R 22 is as defined above.
  • q5 and q6 are zero and the remaining hydroxyl group is located meta to R 27 , R 24 and R 25 are H, R 26 is C 1 -C 6 alkyl, and R 27 is C 2 -C 12 alkyl substituted with:
  • compound (GG) is a CBC analog having the structure of formula (GG-1) when R 26 is methyl:
  • R 27 is as defined above.
  • q7 is zero, R 49 and R 52 are methyl, and R 50 and R 51 are H, so that the THCV analog having the structure (HH) is (HH-1)
  • R 54 is C 1 -C 12 alkyl or C 2 -C 12 alkenyl (preferably C 1 -C 3 alkyl) substituted with:
  • CBD, CBN, CBC, and THCV analogs include, without limitation, compounds having the structures of formula (EE-1), (FF-1), (GG-1), and (HH-1) wherein R 16 , R 22 , R 27 , and R 54 are selected from the following:
  • cannabinoids having the aforementioned structures, i.e. any of the structures (EE), (EE-1), (FF), (FF-1), (GG), (GG-1), (HH), and (HH-1) wherein R 16 , R 22 , R 27 , and R 54 are selected from the “representative R 1 substituents” defined and exemplified in Section (II) of this Detailed Description.
  • CBD analogs having the structure of formula (EE) can be synthesized using the methods described in Section III and/or in the Examples herein, or by implementing other synthetic methods that will be apparent to those of ordinary skill in the art from the present disclosure.
  • CBN analogs having the structure of formula (FF) are typically prepared from a starting material having the structure of formula (FF-P)
  • the starting material may be prepared in substituted form or substituted after synthesis, depending on the desired CBN analog.
  • the CBN analogs herein can also be synthesized using the methods of Examples 24-27, optionally modified using techniques known to those of ordinary skill in the art and/or described in the literature.
  • CBC and CBC analogs having the structure (GG) may be synthesized according to either of the following reactions (a) or (b):
  • CBC analogs can be provided as reaction products by starting with a suitably substituted olivetol analog, i.e., compound (AA). Also see Pollastro et al. (2016) Nat. Prod. Comm. 13(9): 1189-1194, which describes cannabichromene synthesis.
  • Additional cannabinoid compounds that can be synthesized using the present methods thus include, without limitation, the following:
  • compositions suitable for administration of a cannabinoid synthesized as described herein are compositions wherein the cannabinoid, as a pharmacologically active agent, is contained in a “therapeutically effective” amount, i.e., in an amount effective to achieve its intended purpose.
  • the cannabinoid may be in the form of a reaction product composition, but more typically it will be in isolated, purified form.
  • toxicity and therapeutic efficacy of a compound or composition described herein can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., procedures used for determining the maximum tolerated dose (MTD), the ED50, which is the effective dose to achieve 50% of maximal response, and the therapeutic index (TI), which is the ratio of the MTD to the ED50.
  • MTD maximum tolerated dose
  • ED50 the effective dose to achieve 50% of maximal response
  • TI therapeutic index
  • Compounds and compositions with high Tls are the more preferred compounds and compositions herein, and preferred dosage regimens are those that maintain plasma levels of the active agents at or above a minimum concentration to maintain the desired therapeutic effect. Dosage will, of course, also depend on a number of factors, including the particular compound or composition, the site of intended delivery, the route of administration, and other pertinent factors known to the prescribing physician.
  • Administration of a cannabinoid of the invention may be carried out using any appropriate mode of administration.
  • administration can be, for example, oral, parenteral, transdermal, transmucosal (including rectal and vaginal), sublingual, by inhalation, or via an implanted reservoir in a dosage form.
  • parenteral as used herein is intended to include subcutaneous, intravenous, and intramuscular injection.
  • the pharmaceutical formulation containing the cannabinoid may be a solid, semi-solid or liquid, such as, for example, a tablet, a capsule, a caplet, a liquid, a suspension, an emulsion, a suppository, granules, pellets, beads, a powder, or the like, preferably in unit dosage form suitable for single administration of a precise dosage.
  • suitable pharmaceutical compositions and dosage forms may be prepared using conventional methods known to those in the field of pharmaceutical formulation and described in the pertinent texts and literature, e.g., in Remington: The Science and Practice of Pharmacy (Easton, Pa.: Mack Publishing Co., 1995).
  • oral dosage forms are generally preferred, and include tablets, capsules, caplets, solutions, suspensions, and syrups, and may also comprise a plurality of granules, beads, powders, or pellets that may or may not be encapsulated.
  • Preferred oral dosage forms are tablets and capsules.
  • Tablets may be manufactured using standard tablet processing procedures and equipment. Direct compression and granulation techniques are preferred.
  • tablets will generally contain inactive, pharmaceutically acceptable carrier materials such as binders, lubricants, disintegrants, fillers, stabilizers, surfactants, coloring agents, and the like.
  • Capsules are also preferred oral dosage forms for those cannabinoids that are orally active, in which case the cannabinoid-containing formulation may be encapsulated in the form of a liquid or solid (including particulates such as granules, beads, powders or pellets).
  • Suitable capsules may be either hard or soft, and are generally made of gelatin, starch, or a cellulosic material, with gelatin capsules preferred.
  • Two-piece hard gelatin capsules are preferably sealed, such as with gelatin bands or the like. See, for example, Remington: The Science and Practice of Pharmacy, cited supra, which describes materials and methods for preparing encapsulated pharmaceuticals.
  • Oral dosage forms may, if desired, be formulated so as to provide for gradual, sustained release of the cannabinoid over an extended time period.
  • sustained release dosage forms are formulated by dispersing the cannabinoid within a matrix of a gradually hydrolyzable material such as a hydrophilic polymer, or by coating a solid, drug-containing dosage form with such a material.
  • Hydrophilic polymers useful for providing a sustained release coating or matrix include, by way of example: cellulosic polymers such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, methyl cellulose, ethyl cellulose, cellulose acetate, and carboxymethylcellulose sodium; acrylic acid polymers and copolymers, preferably formed from acrylic acid, methacrylic acid, acrylic acid alkyl esters, methacrylic acid alkyl esters, and the like, e.g.
  • Preparations for parenteral administration of the cannabinoid include sterile aqueous and nonaqueous solutions, suspensions, and emulsions.
  • Injectable aqueous solutions contain the cannabinoid in water-soluble form.
  • nonaqueous solvents or vehicles include fatty oils, such as olive oil and corn oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, low molecular weight alcohols such as propylene glycol, synthetic hydrophilic polymers such as polyethylene glycol, liposomes, and the like.
  • Parenteral formulations may also contain adjuvants such as solubilizers, preservatives, wetting agents, emulsifiers, dispersants, and stabilizers, and aqueous suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, and dextran.
  • Injectable formulations are rendered sterile by incorporation of a sterilizing agent, filtration through a bacteria-retaining filter, irradiation, or heat. They can also be manufactured using a sterile injectable medium.
  • the active agent may also be in dried, e.g., lyophilized, form that may be rehydrated with a suitable vehicle immediately prior to administration via injection.
  • the cannabinoid may also be administered through the skin using conventional transdermal drug delivery systems, wherein the active agent is contained within a laminated structure that serves as a drug delivery device to be affixed to the skin.
  • the drug composition is contained in a layer, or “reservoir,” underlying an upper backing layer.
  • the laminated structure may contain a single reservoir, or it may contain multiple reservoirs.
  • the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery.
  • the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, may be either a polymeric matrix as described above, or it may be a liquid or hydrogel reservoir, or may take some other form.
  • Transdermal drug delivery systems may in addition contain a skin permeation enhancer.
  • the cannabinoid may be formulated in a depot preparation for controlled release of the active agent, preferably sustained release over an extended time period.
  • sustained release dosage forms are generally administered by implantation (e.g., subcutaneously or by intramuscular injection).
  • the cannabinoid can also be formulated for inhalation, e.g., as a solution in saline, as a dry powder, or as an aerosol. Administration may be via the intranasal route or via oral inhalation.
  • a pharmaceutical formulation for delivery to the lungs via oral inhalation can also be a dry powder formulation, such as may comprise nanoparticle-sized solid particles containing the cannabinoid and suitable dry powder excipients, for example, lactose monohydrate, magnesium stearate, mannitol, or the like. Suitable dry powder composition components and inhaler types are described, inter alia, by de Boer (2017) Expert Opin Drug Deliv. 14(4): 499-512, and U.S. Pat. Publication No. 2009/00004279 to Hofmann et al., both incorporated by reference herein.
  • Phytocannabinoids and structurally related exo-cannabinoids as a class have highly selective agonist and antagonist activity for the G protein-coupled receptors (GPCRs), CB(1) and CB(2), and individually may have activity at other receptors (such as the opiate mu- and kappa-receptors) that regulate a wide variety of metabolic and neurochemical processes.
  • GPCRs G protein-coupled receptors
  • CB(1) and CB(2) individually may have activity at other receptors (such as the opiate mu- and kappa-receptors) that regulate a wide variety of metabolic and neurochemical processes.
  • GPCRs G protein-coupled receptors
  • CB(1) and CB(2) individually may have activity at other receptors (such as the opiate mu- and kappa-receptors) that regulate a wide variety of metabolic and neurochemical processes.
  • These receptors have been implicated in the progression of numerous diseases such as anorexia, emesis, pain, inflammation, multiple sclerosis,
  • the cannabinoids prepared using the present methods including, but not limited to, CBD analogs, CBN analogs, CBC analogs, THCV, and THCV analogs, are compounds that, like CBD and other known cannabinoids, exhibit at least one of:
  • a therapeutic utility of particular interest is in the treatment of opioid withdrawal symptoms, wherein a cannabinoid of the invention is administered to an individual who has stopped opioid use or is in the process of reducing the regular dosage of an opioid.
  • a cannabinoid as described herein may be co-administered with at least one additional active agent, either simultaneously (in the same formulation or in different formulations) or separately.
  • An additional active agent may have utility against the primary indication of interest.
  • administration to treat inflammation may involve co-administration of the cannabinoid with a nonsteroidal anti-inflammatory agent (NSAID) or a steroidal anti-inflammatory agent.
  • administration to treat pain may involve co-administration of the cannabinoid with an additional analgesic agent, e.g., an opioid analgesic or a non-opioid analgesic.
  • Co-administration of a cannabinoid as provided herein with an opioid analgesic agent is of interest insofar as a combination formulation, or separate co-administration, will reduce the therapeutic dosage of the opioid required and eliminate or at least minimize many of the undesirable side effects associated with opioid use, such as sedation, dizziness, tolerance, physical dependence, and the like. See Nielsen et al. (2017), “Opioid-Sparing Effect of Cannabinoids′′ A Systematic Review and Meta-Analysis,” Neuropsychopharmacology 42(9): 1752-1765, which indicates that the median effective dose (ED50) of morphine administered in combination with ⁇ 9-THC is 3.6 times lower than the ED50 of morphine alone.
  • Co-administration of a cannabinoid with an opioid analgesic may also exhibit synergistic activity, with increased analgesic efficacy and/or reduced side effects seen relative to either drug administered as a monotherapy.
  • the cannabinoid may also be co-administered with olivetol or olivetol analog having the structure of formula (AA), as an anti-inflammatory formulation.
  • a combination formulation can be readily synthesized using the present methods, particularly the method of Part A of Section III, by using an excess of compound (AA).
  • the initial reaction would be carried out with an excess of phloroglucinol or a phloroglucinol analog having the structure (AA-1).
  • Active agents that may be beneficial to co-administer with the cannabinoid are, therefore, as follows:
  • compositions of the invention thus include, without limitation, any of the novel cannabinoids of the invention, including those of formulae (EE), (EE-1), (FF), (FF-1), (GG), (GG-1), (HH), and (HH-1), present in an effective amount and in combination with at least one pharmaceutically acceptable excipient appropriate for a particular formulation type or dosage form.
  • Phloroglucinol 100 g was dissolved in a THF/water mixture (4 V/14 V) in a flask equipped with a mechanical stirrer and under a nitrogen blanket. Nitrogen gas was bubbled through the solution for 30 minutes to degas. Next, NaHCO 3 (3.2 equiv), p-TsCl (3.05 equiv), and DMAP (0.1 equiv) were added while stirring, creating a clear yellow solution with white solids. The reaction mixture was brought to 35° C. and maintained at that temperature. The reaction was monitored using TLC (70:30 hexane/EtOAc) and HPLC. Additional NaHCO 3 was added as the pH decreased (total 3.4 equiv. of NaHCO 3 ).
  • 1,3,5-tritosylate benzene (75 g) and dry/degassed THF (7.75 V) were added to a jacketed flask which was equipped with a mechanical stirrer and an addition funnel (3x vac/N 2 cycles applied) to form a clear solution.
  • FeCl 3 (0.05 equiv) and dry NMP (4.75 equiv) were added under nitrogen, forming a red solution.
  • the solution was cooled to -13° C./-15° C. and sparged with nitrogen. 2 M n-pentyl-MgBr (1.4 equiv.) was slowly charged through the addition funnel. The reaction solution was stirred for 1 hr at -10° C.
  • reaction completion was monitored by HPLC; the solution was then stirred overnight at -10° C. Then, the reaction solution was diluted with MTBE (5 V) and quenched with 1N HCl (1.3 equiv.) at 0° C. The jacket temperature was then gradually increased to ambient temperature and stirred for about 30 min. The organic layer was separated out from the aqueous layer. Both layers were checked by HPLC, and since the aqueous layer did not contain any product, the aqueous layer was not further extracted. The organic product solution was successively washed with 10 % NaHCO 3 (8 V), H 2 O (8 V), and brine (8 V). The washed organic layer was concentrated on a rotary evaporator at 35° C.
  • 5-pentyl-1,3-phenylene bis(4-methylbenzenesulfonate) (ditosylated olivetol, 190 g) was dissolved in toluene (8.5 V) and t-butanol (1.5 V). in a three-necked round bottom flask equipped with a mechanical stirrer, a 12-inch condenser, and under a nitrogen atmosphere. Solid NaOH (9 equiv.) were added, forming a slurry. The solution was then refluxed at 100° C. with a condenser set up at -8° C.
  • the layers were separated, and the combined organic product layer was concentrated using a rotary evaporator while co-stripping with heptane twice (approximately 2 V) to produce crude olivetol oil in solution.
  • the olivetol oil (68 g) was provided at a purity level of 97.5%.
  • reaction mixture was removed from the heat and the remainder of the linoleyl bromide solution was added dropwise over approximately one hour, at which point the reaction mixture had taken on a brownish grey color and a significant portion of the Mg turnings had been consumed. Upon completion of the addition, the reaction mixture was stirred for a further hour resulting in 1 M solution of 1-pentylmagnesium bromide.
  • 1,3,5-tritosylatebenzene (1.30 g, 2.21 mmol. 1equiv.) was dissolved in 5 mL of dry THF and 0.5 mL of dry NMP.
  • Fe(acac) 3 (0.04 g, 0.11 mmol, 0.05 equiv.) was added resulting in a homogenous orange solution.
  • Reaction was placed under argon and cooled to 0° C. with an ice bath.
  • Solution of the prepared 1 M 1-pentylmagnesium bromide (6.63 mL, 6.63 mmol, 3 equiv.) was added to the reaction mixture via syringe dropwise.
  • reaction was stirred for further 30 minutes at 0° C. TLC (70:30 Hexanes/EtOAc) showed the complete consumption of starting material. Reaction was stopped and diluted with Et 2 O (15 mL) then carefully quenched with 0.5 M HCl. (20 mL). Reaction mixture was extracted with Et 2 O (3 ⁇ 20 mL).
  • the resulting product is 5-propyl-1,3-phenylene bis(4-methylbenzenesulfonate), expected at a yield of greater than 90% and substantially free of contaminants.
  • the compound may be isolated and purified or used as is in the next step.
  • the final reaction product is divarinol, as indicated in the scheme.
  • the ratio of CBD to olivetol in the final product was approximately 1: 0.62. Washing with hot water to dissolve the remaining olivetol resulted in a CBD-to-olivetol ratio of 1: 0.32, and washing an additional time resulted in a CBD-to-olivetol ratio of 1: 0.
  • Example 4 The reaction of Example 4 was repeated using different reaction temperatures and solvents as indicated in Table 4 below, and the relative amounts of CBD, abn-CBD, and bis obtained are provided, as is the ratio of CBD to THC in the final product:
  • reaction product composition can be obtained with a mol ratio of CBD to abn-CBD of greater than 1:0.20 and a mol ratio of CBD to bis greater than 1:0.10.
  • Example 13 The process of Example 13 was repeated using different solvents, different concentrations, different reaction temperatures, and different quantities of BF 3 •OEt 2 , as indicated in Table 5 along with the results obtained (“Conc” refers to the amount solvent compared to 1 equivalent of CBD in the reaction, at a 100% theoretical yield):
  • dimethoxy-CBD 0.051 g, 0.15 mmol
  • NaOH 0.072 g, 1.8 mmol
  • NMP 0.6 mL
  • the reaction was heated to 130° C. and stirred overnight.
  • the reaction was quenched with 1.0 M HCl (10 mL), extracted with ethyl acetate, washed with water and brine, dried over Na 2 SO 4 , and concentrated under reduced pressure.
  • Example 4 (b) Then, the method of Example 4 was followed in which divarinol was substituted for olivetol as the co-reactant in the cross-coupling reaction with (1S,4R)-p-mentha-2,8-dien-1-ol (0.023 g, 0.15 mmol, 1 eq.).
  • reaction conditions 500 mg scale: 500 mg of the pivaloyl-protected intermediate (1.1 equiv.), Na 2 CO 3 (2.0 equiv.), PdCl2(dppf)•dcm (0.05 equiv.), 1,4-dioxane, 110° C., 1 h.
  • the reaction product 140 mg, 33%) was characterized by 1 H NMR and MS.
  • a reductive amination reaction using ethylamine was then used to transform the aldehyde intermediate to the 4-(2-ethylaminoethyl) compound, followed by removal of the pivaloyl protecting groups using conventional means to provide the desired reaction product.
  • the reactions are illustrated below:
  • Reagents and reaction conditions first step: Starting material (1.5 equiv.), Pd(OAc) 2 (0.05 equiv.), dppf (0.075), triethylsilane (1.3 equiv.), Na 2 CO 3 (1.5 equiv.), ACN, 80° C., 16 hr. Product characterized by 1 H NMR and MS, yield 400 mg (30%).
  • step (1) starting material (1.5 equiv.), Na 2 CO 3 (2.0 equiv.) PdCl2(dppf)•DCM (0.03 equiv.), 1,4-dioxane, H 2 O, 0° C., 16 h, sealed tube.
  • Product characterized by UPLC and 1 H NMR, yield 200 mg (46%).
  • step (2) Pd(C), hydrogen, ethanol, room temperature.
  • Product characterized by 1 H NMR, MS, HPLC, 2D NMR, yield 80 mg (80%).
  • Phloroglucinol 50 g, 396 mmol, 1 equiv. was dissolved in THF (700 mL, 14 V) and water (200 mL, 4 V) in a three-neck jacketed flask equipped with a mechanical stirrer under a nitrogen atmosphere.
  • 1,3,5-tritosylate benzene (230 g, 391 mmol, 1 equiv.) and dry/degassed THF (1265 mL, 5.5 V) were charged into an RB flask. KF and contain of the solution were checked. Then solution was transferred into a jacketed flask (3 times vac/N 2 cycles applied) through a cannula which was equipped with a mechanical stirrer under a nitrogen atmosphere to form a light-yellow solution.
  • FeCl 3 (3.17 g, 19.5 mmol, 0.05 equiv.) and DMPU (126.5 mL, 0.55 V) were charged under N 2 atm forming a colored solution. Solution was purged with nitrogen again. The solution was cooled down to -10 to -13° C. internal temperature with the glycol chiller set to -15° C.
  • n-PentylMgBr 244 mL, 488 mmol, 1.25 equiv. was slowly charged through an addition funnel over approximately 7.5 hours). More n-PentylMgBr was charged after the first reaction check since starting material was still present (12 mL, 0.061 equiv). Once the reaction was deemed complete, MTBE (575 mL, 2.5 V) and 1 M HCl (586 mL, 586 mmol, 1.5 equiv.) were charged and allowed to stir for 30 minutes. Layers were separated and aqueous layer were washed with MTBE (575 mL, 2.5 V).
  • Ditosylated olivetol (5-pentyl-1,3-phenylene bis(4-methylbenzenesulfonate)) from Step 2 (190.0 g, 388 mmol, 1 equiv.)(estimated crude Step 2 qty) was dissolved in toluene (1615 mL, 8.5 V) and t-BuOH (285 mL, 1.5 V) in a three necked round bottom flask equipped with a mechanical stirrer, a 12-inch condenser and under a nitrogen atmosphere.
  • the layers were separated, and the organic layer was washed with water four times to remove all water-soluble impurities (190 mL, 1 V).
  • the layers were separated, and the combined organic product layer was concentrated using a rotary evaporator while co-stripping with Heptane twice (110 mL, ⁇ 2 V) to produce crude olivetol oil in solution.

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