[go: up one dir, main page]

WO2020031179A1 - Procédés de synthèse de composés cannabinoïdes - Google Patents

Procédés de synthèse de composés cannabinoïdes Download PDF

Info

Publication number
WO2020031179A1
WO2020031179A1 PCT/IL2019/050887 IL2019050887W WO2020031179A1 WO 2020031179 A1 WO2020031179 A1 WO 2020031179A1 IL 2019050887 W IL2019050887 W IL 2019050887W WO 2020031179 A1 WO2020031179 A1 WO 2020031179A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
compound
group
carboxylic acid
ewg
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/IL2019/050887
Other languages
English (en)
Inventor
Prakash Jagtap
Sanaa MUSA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Beetlebung Pharma Ltd
Original Assignee
Beetlebung Pharma Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Beetlebung Pharma Ltd filed Critical Beetlebung Pharma Ltd
Publication of WO2020031179A1 publication Critical patent/WO2020031179A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C255/00—Carboxylic acid nitriles
    • C07C255/49—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton
    • C07C255/53—Carboxylic acid nitriles having cyano groups bound to carbon atoms of six-membered aromatic rings of a carbon skeleton containing cyano groups and hydroxy groups bound to the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C07C45/57—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom
    • C07C45/58—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds from heterocyclic compounds with oxygen as the only heteroatom in three-membered rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • 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
    • C07C67/297—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • 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
    • C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
    • C07D311/58—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4
    • C07D311/70—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring other than with oxygen or sulphur atoms in position 2 or 4 with two hydrocarbon radicals attached in position 2 and elements other than carbon and hydrogen in position 6
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • 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

Definitions

  • the present invention provides methods for chemical synthesis of cannabinoid compounds such as CBD, CBDV, THC, THCV, CBN, HU-308, CBG, CBC, and derivatives thereof.
  • BAIB bis(acetoxy)iodobenzene
  • CBC cannabichromene
  • CBCA cannabichromenic acid
  • CBD cannabidiol
  • CBDA cannabidiolic acid
  • CBDV cannabidivarin
  • CBDVA cannabidivarinic acid
  • CBG cannabigerol
  • CBGA cannabigerol acid
  • CBN cannabinol
  • CBNA cannabinol acid
  • CSA camphorsulfonic acid
  • DCM dichloromethane
  • DMAP 4-dimethylaminopyridine
  • DMF dimethylformamide
  • DMSO dimethyl sulfoxide
  • EA ethyl acetate
  • EWG electron-withdrawing group
  • GC-FID gas chromatography-flame ionization detector
  • GC-MS gas chromatography- mass spectrometry
  • HPLC high pressure liquid chromatography
  • NBS N- bromosuccinimide
  • p- TSA p-toluenesulfonic acid
  • py pyridine
  • TBDMS tert- butyldimethylsilyl
  • TBDPS ieri-butyldiphenylsilyl
  • TBS /£77-butyldi methyl si lyl
  • TEMPO (2,2,6,6-tetramethylpiperidin-l-yl)oxyl
  • THC A 9 -tetrahydrocannabinol
  • THCA tetrahydrocannabinolic acid
  • THF tetrahydrofuran
  • TMS trimethylsilyl.
  • Phytocannabinoids are naturally occurring cannabinoids present in the cannabis plant, and synthetic cannabinoids are derivatives of phytocannabinoids synthesized from non natural sources.
  • cannabinoids there are several FDA-approved cannabinoid-based products and other cannabinoids are under clinical investigation. So far, various synthetic routes for the synthesis of cannabinoids, in particular CBD and THC, have been reported.
  • Lewis acid catalyzed alkylation of olivetol with trans-menthadienol has been reported in US 5,227,537. The reaction using -tolucnc sulfonic acid provided 44% of CBD.
  • CBD cannabinoid compounds
  • delta-9 (A 9 )-THC delta-8 (A 8 )-THC
  • CBN HU-308
  • CBDA THCA
  • CBNA CBGA
  • CBG CBG
  • CBCA CBC
  • CBC CBC
  • compounds of the formulae I, II, III, IV, V, VI, VII, VIII, IX, X, XI and XII, respectively and derivatives thereof, as well as enantiomers of the aforesaid, starting from, e.g., 2,4-dihydroxy-6- pentylbenzaldehyde (olivetol aldehyde) and 2,4-dihydroxy-6-pentylbenzonitrile (olivetol nitrile).
  • the present invention provides a method for the preparation of a cannabinoid compound of the formula I, II, III, IV, VI, VII, or VIII, or an enantiomer thereof, herein referred to as“ Method A”:
  • Ri is H, -OH, -OC(0)-(Ci-C 6 )alkyl, preferably -OC(0)CH 3 , -0C(0)(CH 2 ) n N(Ci-C 6 alkyl) 2 , -0C(0)(CH 2 ) n N + (Ci-C 6 alkyl) 3 , or -O-amino acid wherein said amino acid is linked through a carboxyl group thereof;
  • R 2 is a linear or branched (Ci-Ci 2 )alkyl optionally substituted with one or more halogen atoms;
  • R 5 is H, or a linear or branched (Ci-Ci 2 )alkyl; and n is an integer of 1 to 6, e.g., 1, 2 or 3,
  • CBD-to-THC cyclization under acidic conditions followed by removal of the R 3 group to obtain said compound of the formula II, and optionally further followed by D 9 - to A 8 -THC transformation in the presence of a Lewis acid or an acid such as -TSA and MSA, to obtain said compound of the formula III; or
  • R 3 group is an electron- withdrawing group (EWG) selected from -CN, -CHO, or -CONMe(OMe).
  • EWG electron- withdrawing group
  • the present invention provides a method for the preparation of a cannabinoid compound of the formula V or II, or an enantiomer thereof, herein referred to as
  • Ri is H, -OH, -OC(0)-(Ci-C 6 )alkyl, preferably -OC(0)CH 3 , -0C(0)(CH 2 ) n N(Ci-C 6 alkyl) 2 , -0C(0)(CH 2 ) n N + (Ci-C 6 alkyl) 3 , or -O-amino acid wherein said amino acid is linked through a carboxyl group thereof;
  • R 2 is a linear or branched (Ci-Ci 2 )alkyl optionally substituted with one or more halogen atoms;
  • R5 is H, or a linear or branched (Ci-Ci 2 )alkyl, preferably CH 3 ; and n is an integer of 1 to 6, e.g., 1, 2 or 3,
  • said method comprising electrophilic addition reaction of a resorcinol derivative of the formula In-l with a compound of the formula In-5, in the presence of a Lewis acid, e.g., in a batch reactor or in a continuous flow reactor, to obtain a compound of the formula In-6, followed by either (i) removal of the R 3 group to obtain said compound of the formula V ; or (ii) cyclization under acidic conditions or in the presence of a Lewis acid, and then removal of the R 3 group to obtain said compound of the formula II, characterized in that said R 3 group is an EWG selected from -CN, -CHO, or -CONMe(OMe).
  • the present invention provides a method for the preparation of a cannabinoid compound of the formula IX or X, or an enantiomer thereof, herein referred to as“ Method C”:
  • R 2 is a linear or branched (Ci-Ci 2 )alkyl optionally substituted with one or more halogen atoms; and R5 is H, or a linear or branched (Ci-Ci 2 )alkyl,
  • said method comprising electrophilic addition reaction of a resorcinol derivative of the formula In-l with geraniol or linalool, in the presence of a Lewis acid, e.g., in a batch reactor or in a continuous flow reactor, to obtain a compound of the formula In-7, followed by conversion of the R 3 group to carboxylic acid group to obtain said compound of the formula IX, and optionally removal of said carboxylic acid group to obtain said compound of the formula X, characterized in that said R 3 group is an EWG selected from -CN, -CHO, or - CONMe(OMe).
  • the present invention provides a method for the preparation of a cannabinoid compound of the formula XI or XII, or an enantiomer thereof, herein referred to as“Method D” .
  • R 2 is a linear or branched (Ci-Ci 2 )alkyl optionally substituted with one or more halogen atoms; and R5 is H, or a linear or branched (Ci-Ci 2 )alkyl,
  • said method comprising electrophilic addition reaction of a resorcinol derivative of the formula In-l with citral while heating, e.g., in a batch reactor or in a continuous flow reactor, to obtain a compound of the formula In-8, followed by conversion of the R 3 group to carboxylic acid group to obtain said compound of the formula XI, and optionally removal of said carboxylic acid group to obtain said compound of the formula XII, characterized in that said R 3 group is an EWG selected from -CN, -CHO, or -CONMe(OMe).
  • the invention provides a compound of the formula In-3:
  • Ri is H, -OH, -OC(0)-(Ci-C 6 )alkyl, preferably -OC(0)CH 3 , -0C(0)(CH 2 ) n N(Ci-C 6 alkyl) 2 , -0C(0)(CH 2 ) n N + (Ci-C 6 alkyl) 3 , or -O-amino acid wherein said amino acid is linked through a carboxyl group thereof;
  • R 2 is a linear or branched (Ci-Ci 2 )alkyl optionally substituted with one or more halogen atoms;
  • R 3 is an EWG selected from -CN, -CHO, or -CONMe(OMe);
  • Rs is H, or a linear or branched (Ci-Ci 2 )alkyl.
  • the invention provides a compound of the formula In-4:
  • R 2 is a linear or branched (Ci-Ci 2 )alkyl optionally substituted with one or more halogen atoms;
  • R 3 is an EWG selected from -CN, -CHO, or -CONMe(OMe);
  • R 4 each independently is a protecting group selected from (C 2 -C 6 )alkyl, (Ci- C 6 )alkoxy(Ci-C 6 )alkylene, trimethylsilyl, triethylsilyl, ieri-butyldimethylsilyl, tert- butyldiphenylsilyl, benzyl, phenylcarbonyl, -CHO, or acetyl.
  • the invention provides a compound of the formula In-9 or In-10:
  • Ri is H, -OH, -OC(0)-(Ci-C 6 )alkyl, preferably -OC(0)CH , -0C(0)(CH 2 ) n N(Ci-C 6 alkyl) 2 , -0C(0)(CH 2 ) n N + (Ci-C 6 alkyl) 3 , or -O-amino acid wherein said amino acid is linked through a carboxyl group thereof;
  • R 2 is a linear or branched (Ci-Ci 2 )alkyl optionally substituted with one or more halogen atoms;
  • R 3 is an EWG selected from -CN, -CHO, or -CONMe(OMe);
  • R 6 is -H, or -C(0)CH .
  • the present invention provides a method, herein referred to as Method A, for the preparation of a cannabinoid compound of the formula I, II, III, IV, VI, VII, or VIII, wherein Ri, R 2 and R5 are each as defined above, or an enantiomer thereof, said method comprising electrophilic addition reaction of a resorcinol derivative of the formula In-l with a compound of the formula In-2, in the presence of a Lewis acid, to obtain a compound of the formula In-3, followed by:
  • CBD-to-THC cyclization under acidic conditions followed by removal of the R 3 group to obtain said compound of the formula II, and optionally further followed by D 9 - to A 8 -THC transformation in the presence of a Lewis acid or an acid such as -TSA and MSA, to obtain said compound of the formula III; or
  • alkyl typically means a linear or branched saturated hydrocarbon radical having 1-12 carbon atoms and includes, e.g., methyl, ethyl, «-propyl, isopropyl, «-butyl, sec-butyl, isobutyl, /c/7- butyl, 2-methylpropyl, «-pentyl, isopentyl, neopentyl, 2-methylbutyl, l,l-dimethylpropyl, 2,2-dimethylpropyl, «-hexyl, isohexyl, 2- methylpentyl, 3-methylpentyl, l,l-dimethylbutyl, 2,2-dimethylbutyl, 2-ethylbutyl, «-heptyl, 2-methylhexyl, l,l-dimethylpentyl, l,2-dimethylpentyl, l,2-trimethylbutyl
  • (Ci-C9)alkyl groups are preferably (Ci- Cejalkyl groups, most preferably pentyl.
  • the alkyl may optionally be haloalkyl, i.e., substituted with one or more, e.g., one, two or three, halogen atoms.
  • haloalkyls include, without limiting, each one of the specific alkyls listed above, substituted at any position thereof with one or more identical or different halogen atoms.
  • Preferred haloalkyls are alkyls such as those specifically listed above substituted with one halogen atom at any position thereof.
  • halogen refers to a halogen and includes fluoro, chloro, bromo, and iodo, but it is preferably chloro or bromo.
  • alkylene typically means a divalent straight or branched hydrocarbon radical having 1-6 carbon atoms and includes, e.g., methylene, ethylene, propylene, butylene, 2-methylpropylene, pentylene, 2-methylbutylene, hexylene, 2-methylpentylene, 3- methylpentylene, 2,3-dimethylbutylene, and the like.
  • Preferred are (Ci-C 4 )alkylene, most preferably methylene or ethylene.
  • alkoxy refers a radical of the formula -OR, wherein R is alkyl as defined above, preferably (Ci-C 6 )alkyl.
  • alkoxy groups include methoxy, ethoxy, and propoxy.
  • amino acid refers to an organic compound comprising both amine and carboxylic acid functional groups, which may be either a natural or non natural amino acid.
  • the twenty-two amino acids naturally occurring in proteins are aspartic acid, tyrosine, leucine, tryptophan, arginine, valine, glutamic acid, methionine, phenylalanine, serine, alanine, glutamine, glycine, proline, threonine, asparagine, lysine, histidine, isoleucine, cysteine, selenocysteine, and pyrrolysine.
  • Non-limiting examples of other amino acids include dimethylglycine, trimethylglycine, citrulline, diaminopropionic acid, diaminobutyric acid, ornithine, aminoadipic acid, b-alanine, l-naphthylalanine, 3-(l- naphthyl)alanine, 3-(2-naphthyl)alanine, g-aminobutiric acid, 3-(aminomethyl) benzoic acid, p-ethynyl-phenylalanine, p-propargly-oxy-phenylalanine, m-ethynyl-phenylalanine, p- bromophenylalanine, p-iodophenylalanine, p-azidophenylalanine, p-acetylphenylalanine, norleucine, azidonorleucine, 6-ethynyl-tryptophan, 5-ethy
  • amino acid residue refers to a residue of an amino acid after removal of the -OH group from a carboxyl group thereof, e.g., its a-carboxyl group or side chain carboxyl group, if present.
  • EWG electron-withdrawing group
  • hydroxyl-protecting group denotes a group capable of masking hydroxyl groups during chemical group transformations elsewhere in the molecule, i.e., to a group capable of replacing the hydrogen atom of a hydroxyl group on a molecule that is stable and non-reactive to reaction conditions to which the protected molecule is to be exposed.
  • hydroxyl-protecting groups include, without limiting, acetic anhydride in pyridine or K 2 CO 3 ; and trialkyl silyl halides, formyl chloride, or di-ieri-butyl-dicarbonate, in imidazole, triethylamine, or DMAP.
  • the hydroxyl-protecting group is acetic anhydride in pyridine.
  • the cannabinoid compound of the formula I, II, III, IV, VI, VII, or VIII is prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l, wherein R 3 is a particular EWG, with a compound of the formula In-2, in the presence of a Lewis acid, to obtain a compound of the formula In-3.
  • Non-limiting examples of Lewis acids that can be used according to the methods of the present invention include BF OEt 2 , ZnCl 2 , Si0 2 , p-TSA, CSA, AlCl 3 , BBr , FeCl 3 , FeBr , SnCL, TiCL, AlBr , and MgS0 4 together with a triflate catalyst such as Sc(0S0 2 CF 3 ) 3 , Yb(0S0 2 CF 3 ) 3 or Sm(0S0 2 CF ) .
  • a triflate catalyst such as Sc(0S0 2 CF 3 ) 3 , Yb(0S0 2 CF 3 ) 3 or Sm(0S0 2 CF ) .
  • the resorcinol derivative of the formula In-l, wherein Rs is H, used inter alia in Method A may be prepared from a compound of the formula In-4, wherein R 2 , R3 and R 4 are each as defined above, by removal of said protecting groups.
  • the cannabinoid compound prepared by Method A is a compound of the formula I, i.e., CBD, a derivative thereof, or an enantiomer thereof, and the method further comprises removal of said EWG from the compound of the formula In-3 (see Schemes 1-2).
  • R5 is H
  • Ri is H (e.g., CBD and CBDV), -OH (e.g., 7-OH CBD and 7-OH CBDV), or -O-amino acid (an amino acid ester of CBD or CBDV, or a derivative thereof); and said amino acid is, e.g., valine, cysteine, arginine, glutamine, dimethylglycine, or trimethylglycine, linked through either its a- carboxyl group or side chain carboxyl group, if present.
  • the cannabinoid compound prepared by Method A is a compound of the formula II, i.e., A 9 -THC, a derivative thereof, or an enantiomer thereof, and the method further comprises CBD-to-THC cyclization of the compound of the formula In-3, under acidic conditions, followed by removal of said EWG from the intermediate compound thus obtained (see Schemes 3-4).
  • R5 is H
  • Ri is H (e.g., A 9 -THC), -OH (e.g., l l-OH THC), or -O-amino acid (an amino acid ester of A 9 -THC or a derivative thereof); and said amino acid is, e.g., valine, cysteine, arginine, glutamine, dimethylglycine, or trimethylglycine, linked through either its a-carboxyl group or side chain carboxyl group, if present.
  • the cannabinoid compound prepared by Method A is a compound of the formula III, i.e., A 8 -THC, a derivative thereof, or an enantiomer thereof, and the method further comprises CBD-to-THC cyclization of the compound of the formula In-3, under acidic conditions, followed by removal of said EWG from the intermediate compound thus obtained, to thereby obtain a compound of the formula II, and then A 9 -THC to A 8 -THC transformation in the presence of a Lewis acid as defined above or an acid such as -TSA and MSA to thereby obtain the compound of the formula III.
  • a Lewis acid as defined above or an acid such as -TSA and MSA
  • R5 is H
  • Ri is H (e.g., A 8 -THC), -OH (e.g., l l- OH A 8 -THC), or -O-amino acid (an amino acid ester of A 8 -THC or a derivative thereof); and said amino acid is, e.g., valine, cysteine, arginine, glutamine, dimethylglycine, or trimethylglycine, linked through either its a-carboxyl group or side chain carboxyl group, if present.
  • the cannabinoid compound prepared by Method A is a compound of the formula IV, i.e., CBN, a derivative thereof, or an enantiomer thereof, and the method further comprises removal of said EWG from the compound of the formula In-3 to thereby obtain a compound of the formula I (see Schemes 1-2), and conversion of said compound of the formula I to said compound of the formula IV.
  • R 5 is H
  • Ri is H (e.g., CBN), -OH (e.g., 7-OH CBN), or - O-amino acid (an amino acid ester of CBN or a derivative thereof); and said amino acid is, e.g., valine, cysteine, arginine, glutamine, dimethylglycine, or trimethylglycine, linked through either its a-carboxyl group or side chain carboxyl group, if present.
  • Ri is H (e.g., CBN), -OH (e.g., 7-OH CBN), or - O-amino acid (an amino acid ester of CBN or a derivative thereof)
  • said amino acid is, e.g., valine, cysteine, arginine, glutamine, dimethylglycine, or trimethylglycine, linked through either its a-carboxyl group or side chain carboxyl group, if present.
  • the cannabinoid compound prepared by Method A is a compound of the formula VI, i.e., CBDA, a derivative thereof, or an enantiomer thereof, and the method further comprises conversion of said EWG to carboxylic acid group (see Schemes 7-8).
  • Rs is H
  • Ri is H, -OH, or -O-amino acid
  • said amino acid is, e.g., valine, cysteine, arginine, glutamine, dimethylglycine, or trimethylglycine, linked through either its a-carboxyl group or side chain carboxyl group, if present.
  • Method A is a compound of the formula VII, i.e., THCA, a derivative thereof, or an enantiomer thereof, and the method further comprises conversion of said EWG to carboxylic acid group, and then CBD-to-THC cyclization under acidic conditions (see Scheme 8).
  • R 5 is H
  • Ri is H, -OH, or -O-amino acid
  • said amino acid is, e.g., valine, cysteine, arginine, glutamine, dimethylglycine, or trimethylglycine, linked through either its a-carboxyl group or side chain carboxyl group, if present.
  • Method A is a compound of the formula VIII, i.e., CBNA, a derivative thereof, or an enantiomer thereof, and the method further comprises conversion of said EWG to carboxylic acid group, and then conversion to said compound of the formula VIII (see Scheme 7).
  • Rs is H
  • Ri is H, -OH, or -O-amino acid
  • said amino acid is, e.g., valine, cysteine, arginine, glutamine, dimethylglycine, or trimethylglycine, linked through either its a-carboxyl group or side chain carboxyl group, if present.
  • the cannabinoid compound prepared by Method A is a compound of the formula IV, i.e., CBN, a derivative thereof, or an enantiomer thereof, and the method further comprises conversion of said EWG to carboxylic acid group, conversion to said compound of the formula VIII, and subsequent decarboxylation (see Scheme 7).
  • Rs is H
  • Ri is H, -OH, or -O-amino acid
  • said amino acid is, e.g., valine, cysteine, arginine, glutamine, dimethylglycine, or trimethylglycine, linked through either its a-carboxyl group or side chain carboxyl group, if present.
  • said EWG is -CN.
  • removal of said -CN group is carried out by (i) hydrolysis with a strong base such as KOH or NaOH, in a suitable solvent, e.g., aqueous ethylene glycol solution, isopropanol, methanol, diglyme, propylene glycol, or THF; or (ii) reduction to aldehyde group, followed by oxidation of said aldehyde group to carboxylic acid group, and subsequent removal of said carboxylic acid group, i.e., decarboxylation.
  • a strong base such as KOH or NaOH
  • conversion of said -CN group to carboxylic acid group is carried out by (iii) hydrolysis with a strong base such as KOH or NaOH, in a suitable solvent, e.g., aqueous ethylene glycol solution, isopropanol, methanol, diglyme, propylene glycol, or THF; or (iv) reduction to aldehyde group, followed by oxidation of said aldehyde group to carboxylic acid group.
  • a strong base such as KOH or NaOH
  • said EWG is -CHO.
  • removal of said -CHO group is carried out by protection of the hydroxyl groups, if present (depending whether Rs is H or not) with a hydroxyl protecting group as defined above, followed by oxidation of the aldehyde group to carboxylic acid group and then hydrolysis with a strong base such as KOH or NaOH, e.g., in aqueous methanol solution.
  • conversion of said -CHO group to carboxylic acid group is carried out by protection of the hydroxyl groups, if present, with a hydroxyl protecting group as defined above, followed by oxidation of the aldehyde group to carboxylic acid group.
  • the aldehyde group is oxidized with NaOCh in sulfamic acid, KMn0 4 , chromic acid or a salt thereof, or TEMPO with BAIB (TEMPO/BAIB).
  • the compound prepared by Method A is a compound of the formula I wherein Ri is H; and R 5 is H, i.e., CBD (R 2 is «-pentyl), CBDV (R 2 is «-propyl), a CBD derivative (R 2 is an alkyl other than «-pentyl or «-propyl), or an enantiomer thereof, according to any one of the embodiments above.
  • Such compounds are prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In- 1 wherein R 3 is an EWG as defined above, with a compound of the formula In-2 wherein Ri is H, i.e., (+)-trans- mentha-2,8-dien-l-ol, in the presence of a Lewis acid such as BF 3 OEt 2 , so as to obtain the compound of the formula In-3, followed by removal of said EWG to obtain said compound of the formula I.
  • a Lewis acid such as BF 3 OEt 2
  • the compound prepared by this method is a compound of the formula I wherein Ri is -OH; and R 5 is H, i.e., 7-OH-CBD (R 2 is tz-pentyl), 7-OH- CBDV (R 2 is 77-propyl), a 7-OH-CBD derivative (R 2 is an alkyl other than 77-pentyl or 77- propyl), or an enantiomer thereof, according to any one of the embodiments above.
  • Such compounds are prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is an EWG as defined above, with a compound of the formula In-2 wherein Ri is -OH or -OAc (-0C(0)CH 3 ), i.e., (+)-trans-mentha-2,8-diene-l,7-diol or (+)-trans-mentha-2,8-diene-l-ol-7-yl acetate, respectively, in the presence of a Lewis acid such as BF 3 OEt 2 , so as to obtain the compound of the formula In-3, followed by removal of said EWG to obtain said compound of the formula I.
  • a Lewis acid such as BF 3 OEt 2
  • said EWG is -CN
  • removal of said -CN group is carried out by either (i) hydrolysis with a strong base, e.g., KOH or NaOH, in a suitable solvent as defined above (e.g., KOH in aqueous ethylene glycol solution); or (ii) reduction to aldehyde group, followed by oxidation of said aldehyde group to carboxylic acid group, and subsequent decarboxylation.
  • a strong base e.g., KOH or NaOH
  • said EWG is -CHO, and removal of said -CHO is carried out by protection of the hydroxyl groups, e.g., with acetic anhydride in pyridine or K 2 C0 3 , followed by oxidation of the aldehyde group, e.g., with NaOCl 2 in sulfamic acid, to carboxylic acid group, and then hydrolysis with a strong base, e.g., with KOH in aqueous methanol solution.
  • a strong base e.g., with KOH in aqueous methanol solution.
  • the compound prepared by Method A is a compound of the formula II wherein Ri is H; and R 5 is H, i.e., A 9 -THC (R 2 is 77-pentyl), A 9 -THCV (R 2 is 77- propyl), a A 9 -THC derivative (R 2 is an alkyl other than 77-pentyl or 77-propyl, e.g., 1,1- dimethylheptyl), or an enantiomer thereof, according to any one of the embodiments above.
  • Such compounds are prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is an EWG as defined above, with (+)-trans- mentha-2,8-dien-l-ol, in the presence of a Lewis acid such as BF 3 OEt 2 , so as to obtain the compound of the formula In-3, followed by CBD-to-THC cyclization under acidic conditions, and then removal of said EWG to obtain said compound of the formula II.
  • a Lewis acid such as BF 3 OEt 2
  • the compound prepared by this method is a compound of the formula II wherein Ri is -OH; and R 5 is H, i.e., l l-OH THC (R 2 is 77-pentyl), l l-OH THCV (R 2 is 77- propyl), a l l-OH THC derivative (R 2 is an alkyl other than 77-pentyl or 77-propyl, e.g., 1,1- dimethylheptyl), or an enantiomer thereof, according to any one of the embodiments above.
  • Such compounds are prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is an EWG as defined above, with (+)-trans- mentha-2,8-diene-l,7-diol or (+)-trans-mentha-2,8-diene-l-ol-7-yl acetate, in the presence of a Lewis acid such as BF 3 OEt 2 , so as to obtain the compound of the formula In-3, followed by CBD-to-THC cyclization under acidic conditions, and then removal of said EWG to obtain said compound of the formula II.
  • a Lewis acid such as BF 3 OEt 2
  • said EWG is -CN
  • removal of said -CN group is carried out by either (i) hydrolysis with a strong base, e.g., KOH or NaOH, in a suitable solvent as defined above (e.g., KOH in aqueous ethylene glycol solution); or (ii) reduction to aldehyde group, followed by oxidation of said aldehyde group to carboxylic acid group, and subsequent decarboxylation.
  • a strong base e.g., KOH or NaOH
  • said EWG is -CHO, and removal of said -CHO is carried out by protection of the hydroxyl groups, e.g., with acetic anhydride in pyridine or K2CO3, followed by oxidation of the aldehyde group, e.g., with NaOCE in sulfamic acid, to carboxylic acid group, and then hydrolysis with a strong base, e.g., with KOH in aqueous methanol solution.
  • a strong base e.g., with KOH in aqueous methanol solution.
  • the compound prepared by Method A is a compound of the formula III wherein Ri is H; and R5 is H, i.e., A 8 -THC (R 2 is «-pentyl), A 8 -THCV (R 2 is «- propyl), a A 8 -THC derivative (R 2 is an alkyl other than «-pentyl or «-propyl, e.g., 1,1- dimethylheptyl, l,l-dimethylhexyl, l,l-dimethylpentyl, l,l-dimethylbutyl, 1,1- dimethylpropyl, 2-methylheptyl, 2-methylhexyl, 2-methylpentyl, 3-methylpentyl, 2- methylbutyl, 2-methylpropyl, or «77-butyl), or an enantiomer thereof, according to any one of the embodiments above.
  • Such compounds are prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is an EWG as defined above, with (+)-trans-mentha-2,8-dien-l-ol, in the presence of a Lewis acid such as BF 3 OEt 2 , so as to obtain the compound of the formula In-3, followed by (a) CBD-to-THC cyclization under acidic conditions; (b) removal of said EWG; and (c) D 9 - to A 8 -THC transformation in the presence of said Lewis acid or acid to obtain said compound of the formula III.
  • a Lewis acid such as BF 3 OEt 2
  • the compound prepared by this method is a compound of the formula III wherein Ri is -OH; and R 5 is H, i.e., l l-OH-A 8 -THC (R 2 is «-pentyl), l l-OH-A 8 -THCV (R 2 is «-propyl), a l l-OH-A 8 -THC derivative (R 2 is an alkyl other than «-pentyl or «-propyl, e.g., l,l-dimethylheptyl, l,l-dimethylhexyl, l,l-dimethylpentyl, l,l-dimethylbutyl, 1,1- dimethylpropyl, 2-methylheptyl, 2-methylhexyl, 2-methylpentyl, 3-methylpentyl, 2- methylbutyl, 2-methylpropyl, or «77-butyl), or an enantiomer thereof, according to any one of the
  • Such compounds are prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is an EWG as defined above, with (+)-trans-mentha-2,8-diene-l,7-diol or (+)-trans-mentha-2,8-diene-l-ol-7-yl acetate, in the presence of a Lewis acid such as BF 3 OEt 2 , so as to obtain the compound of the formula In-3, followed by (a) CBD-to-THC cyclization under acidic conditions; (b) removal of said EWG; and (c) D 9 - to A 8 -THC transformation in the presence of said Lewis acid or acid to obtain said compound of the formula III.
  • a Lewis acid such as BF 3 OEt 2
  • said EWG is -CN
  • removal of said -CN group is carried out by either (i) hydrolysis with a strong base, e.g., KOH or NaOH, in a suitable solvent as defined above (e.g., KOH in aqueous ethylene glycol solution); or (ii) reduction to aldehyde group, followed by oxidation of said aldehyde group to carboxylic acid group, and subsequent decarboxylation.
  • a strong base e.g., KOH or NaOH
  • said EWG is -CHO, and removal of said -CHO is carried out by protection of the hydroxyl groups, e.g., with acetic anhydride in pyridine or K2CO3, followed by oxidation of the aldehyde group, e.g., with NaOCE in sulfamic acid, to carboxylic acid group, and then hydrolysis with a strong base, e.g., with KOH in aqueous methanol solution.
  • a strong base e.g., with KOH in aqueous methanol solution.
  • the compound prepared by Method A is a compound of the formula IV wherein Ri is H; and R5 is H, i.e., CBN (R 2 is «-pentyl), a CBN derivative (R 2 is an alkyl other than «-pentyl), or an enantiomer thereof, according to any one of the embodiments above.
  • Such compounds are prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is an EWG as defined above, with (+)- trans-mentha-2,8-dien-l-ol, in the presence of a Lewis acid such as BF 3 OEt 2 , so as to obtain the compound of the formula In-3, followed by removal of said EWG to obtain said compound of the formula I, and then conversion to said compound of the formula IV.
  • a Lewis acid such as BF 3 OEt 2
  • the compound prepared by this method is a compound of the formula IV wherein Ri is -OH; and R5 is H, i.e., 7-OH-CBN (R 2 is «-pentyl), a 7-OH-CBN derivative (R 2 is an alkyl other than «-pentyl), or an enantiomer thereof, according to any one of the embodiments above.
  • Such compounds are prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is an EWG as defined above, with (+)- trans-mentha-2,8-diene-l,7-diol or (+)-trans-mentha-2, 8-diene- l-ol-7-yl acetate, in the presence of a Lewis acid such as BF 3 OEt 2 , so as to obtain the compound of the formula In-3, followed by removal of said EWG to obtain said compound of the formula I, and then conversion to said compound of the formula IV.
  • a Lewis acid such as BF 3 OEt 2
  • said EWG is -CN
  • removal of said -CN group is carried out by either (i) hydrolysis with a strong base, e.g., KOH or NaOH, in a suitable solvent as defined above (e.g., KOH in aqueous ethylene glycol solution); or (ii) reduction to aldehyde group, followed by oxidation of said aldehyde group to carboxylic acid group, and subsequent decarboxylation.
  • a strong base e.g., KOH or NaOH
  • said EWG is -CHO, and removal of said -CHO is carried out by protection of the hydroxyl groups, e.g., with acetic anhydride in pyridine or K 2 CO 3 , followed by oxidation of the aldehyde group, e.g., with NaOCh in sulfamic acid, to carboxylic acid group, and then hydrolysis with a strong base, e.g., with KOH in aqueous methanol solution.
  • a strong base e.g., with KOH in aqueous methanol solution.
  • the compound prepared by Method A is a compound of the formula II or III, wherein R 5 is H, or an enantiomer thereof, according to any one of the embodiments above, and once obtained, the hydroxyl group of said compound is phosphorylated, and the intermediate compound thus obtained is then dephosphorylated to obtain a desoxy A 9 -THC compound or desoxy A 8 -THC compound of the formula Ila or Ilia, respectively (see Scheme 6).
  • the phosphorylation step is carried out with diethyl chlorophosphate (ClPO(OEt) 2 ) or dimethyl chlorophosphate (ClPO(OMe) 2 ) in the presence of a base such as pyridine or triethylamine in THF or DCM, and the phosphorylated compound thus obtained is then dephosphorylated in the presence of Li/NH 3 , Na/NH 3 , or K/NH3.
  • a base such as pyridine or triethylamine in THF or DCM
  • a compound of the formula II wherein R 5 is H can be first phosphorylated and then dephosphorylated as described above to obtain a desoxy A 9 -THC compound of the formula Ila, followed by D 9 - to A 8 -THC transformation, in the presence of a Lewis acid or an acid such as p-TSA and MSA, to obtain a desoxy A 8 -THC compound of the formula Ilia.
  • the compound prepared by Method A is a compound of the formula VI wherein Ri is H; and R 5 is H, i.e., CBDA (R 2 is «-pentyl), CBDVA (R 2 is «- propyl), a derivative thereof (R 2 is an alkyl other than «-pentyl or «-propyl), or an enantiomer thereof, according to any one of the embodiments above.
  • Such compounds are prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is an EWG as defined above, with (+)-trans-mentha-2,8-dien-l-ol, in the presence of a Lewis acid such as BF 3 0Et 2 , so as to obtain the compound of the formula In-3, followed by conversion of said EWG to carboxylic acid group.
  • said EWG is -CN
  • conversion of said -CN group to carboxylic acid group is carried out by either (i) hydrolysis with a strong base, e.g., KOH or NaOH, in a suitable solvent as defined above (e.g., KOH in aqueous ethylene glycol solution); or (ii) reduction to aldehyde group, followed by oxidation of said aldehyde group to carboxylic acid group.
  • a strong base e.g., KOH or NaOH
  • said EWG is -CHO
  • conversion of said -CHO group to carboxylic acid group is carried out by protection of the hydroxyl groups, e.g., with acetic anhydride in pyridine or K2CO3, followed by oxidation of the aldehyde group, e.g., with NaOCh in sulfamic acid, to carboxylic acid group.
  • the compound prepared by Method A is a compound of the formula VII wherein Ri is H; and R5 is H, i.e., THCA (R 2 is «-pentyl), THCVA (R 2 is «- propyl), a derivative thereof (R 2 is an alkyl other than «-pentyl or «-propyl), or an enantiomer thereof, according to any one of the embodiments above.
  • Such compounds are prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is an EWG as defined above, with (+)-trans-mentha-2,8-dien-l-ol, in the presence of a Lewis acid such as BF 3 OEt 2 , so as to obtain the compound of the formula In-3, followed by conversion of said EWG to carboxylic acid group and then CBD-to-THC cyclization under acidic conditions, e.g., HC1, H 2 S0 4 , p-TSA, CSA, or Al, B, Fe, Sn or Ti-based Lewis acids.
  • a Lewis acid such as BF 3 OEt 2
  • said EWG is -CN
  • conversion of said -CN group to carboxylic acid group is carried out by either (i) hydrolysis with a strong base, e.g., KOH or NaOH, in a suitable solvent as defined above (e.g., KOH in aqueous ethylene glycol solution); or (ii) reduction to aldehyde group, followed by oxidation of said aldehyde group to carboxylic acid group.
  • a strong base e.g., KOH or NaOH
  • said EWG is -CHO
  • conversion of said -CHO group to carboxylic acid group is carried out by protection of the hydroxyl groups, e.g., with acetic anhydride in pyridine or K 2 C0 3 , followed by oxidation of the aldehyde group, e.g., with NaOCh in sulfamic acid, to carboxylic acid group.
  • the compound prepared by Method A is a compound of the formula VIII wherein Ri is H; and R5 is H, i.e., CBNA (R 2 is «-pentyl), a derivative thereof (R 2 is an alkyl other than «-pentyl), or an enantiomer thereof, according to any one of the embodiments above.
  • Such compounds are prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is an EWG as defined above, with (+)- trans-mentha-2,8-dien-l-ol, in the presence of a Lewis acid such as BF 3 OEt 2 , so as to obtain the compound of the formula In-3, followed by conversion of said EWG to carboxylic acid group, and then conversion of the compound obtained (a compound of the formula VI) to said compound of the formula VIII.
  • a Lewis acid such as BF 3 OEt 2
  • said EWG is -CN
  • conversion of said -CN group to carboxylic acid group is carried out by either (i) hydrolysis with a strong base, e.g., KOH or NaOH, in a suitable solvent as defined above (e.g., KOH in aqueous ethylene glycol solution); or (ii) reduction to aldehyde group, followed by oxidation of said aldehyde group to carboxylic acid group.
  • a strong base e.g., KOH or NaOH
  • said EWG is -CHO
  • conversion of said -CHO group to carboxylic acid group is carried out by protection of the hydroxyl groups, e.g., with acetic anhydride in pyridine or K2CO3, followed by oxidation of the aldehyde group, e.g., with NaOCh in sulfamic acid, to carboxylic acid group.
  • Conversion of the compound of the formula VI to said compound of the formula VIII may be carried out by dehydrogenation reaction using bromine or iodine in toluene, in the presence of triethylamine or Pd in toluene.
  • the compound prepared by Method A is a compound of the formula IV wherein Ri is H; and R5 is H, i.e., CBN (R 2 is «-pentyl), a derivative thereof (R 2 is an alkyl other than «-pentyl), or an enantiomer thereof, according to any one of the embodiments above.
  • Such compounds are prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is an EWG as defined above, with (+)- trans-mentha-2,8-dien-l-ol, in the presence of a Lewis acid such as BF 3 OEt 2 , so as to obtain the compound of the formula In-3, followed by conversion of said EWG to carboxylic acid group, and then conversion of the compound obtained to a compound of the formula VIII, and subsequent decarboxylation.
  • a Lewis acid such as BF 3 OEt 2
  • said EWG is -CN
  • conversion of said -CN group to carboxylic acid group is carried out by either (i) hydrolysis with a strong base, e.g., KOH or NaOH, in a suitable solvent as defined above (e.g., KOH in aqueous ethylene glycol solution); or (ii) reduction to aldehyde group, followed by oxidation of said aldehyde group to carboxylic acid group.
  • a strong base e.g., KOH or NaOH
  • said EWG is -CHO
  • conversion of said -CHO group to carboxylic acid group is carried out by protection of the hydroxyl groups, e.g., with acetic anhydride in pyridine or K 2 C0 3 , followed by oxidation of the aldehyde group, e.g., with NaOCh in sulfamic acid, to carboxylic acid group.
  • Decarboxylation of the compound of the formula VIII to said compound of the formula IV may be carried out by heating in KOH or NaOH in methanol.
  • the present invention provides a method, herein referred to as Method B, for the preparation of a cannabinoid compound of the formula V or II, wherein Ri, R 2 and R5 are each as defined above, or an enantiomer thereof, said method comprising electrophilic addition reaction of a resorcinol derivative of the formula In- 1 with a compound of the formula In-5, in the presence of a Lewis acid, to obtain a compound of the formula In- 6, followed by either (i) removal of the R 3 group to obtain said compound of the formula V; or (ii) cyclization under acidic conditions, followed by removal of the R 3 group to obtain said compound of the formula II, characterized in that said R 3 group is an EWG selected from - CN, -CHO, or -CONMe(OMe).
  • the cannabinoid compound of the formula V or II is prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is a particular EWG, with a compound of the formula In-5, in the presence of a Lewis acid as defined above, to obtain a compound of the formula In-6.
  • the cannabinoid compound prepared by Method B is a compound of the formula V, i.e., HU-308, a derivative thereof, or an enantiomer thereof such as HU-433, and the method further comprises removal of said EWG from the compound of the formula In-7 (see Scheme 5).
  • Ri is H, -OH, or -O-amino acid
  • R 5 is H
  • said amino acid is, e.g., valine, cysteine, arginine, glutamine, dimethylglycine, or trimethylglycine, linked through either its a-carboxyl group or side chain carboxyl group, if present.
  • said EWG is -CN
  • removal of said -CN group is carried out, e.g., by reduction to aldehyde group, followed by oxidation of said aldehyde group to carboxylic acid group and subsequent decarboxylation.
  • said EWG is -CHO, and removal of said -CHO group is carried out, e.g., by protection of the hydroxyl groups, if present, with a hydroxyl protecting group as defined above, followed by oxidation of the aldehyde group to carboxylic acid group and subsequent decarboxylation.
  • the aldehyde group is oxidized with NaOCl 2 in sulfamic acid, KMn0 4 , chromic acid or a salt thereof, or TEMPO with BAIB (TEMPO/BAIB).
  • the compound prepared by Method B is a compound of the formula V wherein Ri is H; R 2 is an alkyl such as l,l-dimethylheptyl; and Rs is H or CH 3 , or an enantiomer thereof, according to any one of the embodiments above.
  • Such compounds are prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is an EWG as defined above, with a compound of the formula In-5 wherein Ri is H, i.e., verbenol, in the presence of a Lewis acid such as BF 3 OEt 2 , so as to obtain the compound of the formula In-6, followed by removal of said EWG to obtain said compound of the formula V.
  • the compound prepared by this method is a compound of the formula V wherein Ri is -OH; R 2 is an alkyl such as l,l-dimethylheptyl; and R 5 is H or CH 3 , or an enantiomer thereof, according to any one of the embodiments above.
  • Such compounds are prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is an EWG as defined above, with a compound of the formula In-5 wherein Ri is -OH, i.e., pina-2-ene-4,l0-diol, in the presence of a Lewis acid such as BF 3 OEt 2 , so as to obtain the compound of the formula In-6, followed by removal of said EWG to obtain said compound of the formula V.
  • said EWG is -CN, and removal of said -CN group is carried out by reduction to aldehyde group, followed by oxidation of said aldehyde group to carboxylic acid group and subsequent decarboxylation.
  • said EWG is -CHO, and removal of said - CHO is carried out by protection of the hydroxyl groups, e.g., with acetic anhydride in pyridine or K 2 C0 3 , followed by oxidation of the aldehyde group, e.g., with NaOCh in sulfamic acid, to carboxylic acid group, and subsequent decarboxylation.
  • the compound prepared by Method B is a compound of the formula II wherein Rs is H, or an enantiomer thereof, according to any one of the embodiments above.
  • the compound of the formula II may be subjected to A 9 - to A 8 -THC transformation in the presence of a Lewis acid or an acid such as -TSA and MSA, to obtain the corresponding compound of the formula III.
  • the hydroxyl group of the compound of the formula II or III is phosphorylated, and the intermediate compound thus obtained is then dephosphorylated to obtain a desoxy A 9 -THC compound or desoxy A 8 -THC compound of the formula Ila or Ilia, respectively (see Scheme 6).
  • the present invention provides a method, herein referred to as Method C, for the preparation of a cannabinoid compound of the formula IX or X, wherein R 2 and Rs are each as defined above, or an enantiomer thereof, said method comprising electrophilic addition reaction of a resorcinol derivative of the formula In- 1 with geraniol or linalool, in the presence of a Lewis acid, to obtain a compound of the formula In-7, followed by conversion of the R 3 group to carboxylic acid group to obtain said compound of the formula IX, and optionally removal of said carboxylic acid group to obtain said compound of the formula X, characterized in that said R 3 group is an EWG selected from -CN, -CHO, or - CONMe(OMe).
  • the cannabinoid compound of the formula IX or X is prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l, wherein R 3 is a particular EWG, with geraniol or linalool, in the presence of a Lewis acid as defined above, to obtain a compound of the formula In-7.
  • the cannabinoid compound prepared by Method C is a compound of the formula IX, i.e., CBGA, a derivative thereof, or an enantiomer thereof, and the method further comprises conversion of said EWG to carboxylic acid group to obtain said compound of the formula IX (see Schemes 9-10).
  • the cannabinoid compound prepared by Method C is a compound of the formula X, i.e., CBG, a derivative thereof, or an enantiomer thereof, and the method further comprises conversion of said EWG to carboxylic acid group to obtain said compound of the formula IX and subsequent decarboxylation (see Schemes 9-10).
  • said EWG is -CN
  • conversion of said -CN group to carboxylic acid group is carried out, e.g., by (i) hydrolysis with a strong base such as KOH or NaOH, in a suitable solvent, e.g., aqueous ethylene glycol solution, isopropanol, methanol, diglyme, propylene glycol, or THF; or (ii) reduction to aldehyde group, followed by oxidation of said aldehyde group to carboxylic acid group.
  • a strong base such as KOH or NaOH
  • said EWG is -CHO, and conversion of said -CHO group to carboxylic acid group is carried out, e.g., by protection of the hydroxyl groups, if present, with a hydroxyl protecting group as defined above, followed by oxidation of the aldehyde group to carboxylic acid group.
  • the aldehyde group is oxidized with NaOCh in sulfamic acid, KMn0 4 , chromic acid or a salt thereof, or TEMPO with BAIB (TEMPO/BAIB).
  • the compound prepared by Method C is a compound of the formula IX wherein Rs is H, i.e., CBGA (R 2 is /7-pentyl ), a derivative thereof (R 2 is an alkyl other than //-pentyl), or an enantiomer thereof, according to any one of the embodiments above.
  • Such compounds are prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is an EWG as defined above, with geraniol or linalool, in the presence of a Lewis acid such as BF 3 OEt 2 , so as to obtain the compound of the formula In-7, followed by conversion of said EWG to carboxylic acid group.
  • said EWG is -CN
  • conversion of said -CN group to carboxylic acid group is carried out by either (i) hydrolysis with a strong base, e.g., KOH or NaOH, in a suitable solvent as defined above (e.g., KOH in aqueous ethylene glycol solution); or (ii) reduction to aldehyde group, followed by oxidation of said aldehyde group to carboxylic acid group.
  • a strong base e.g., KOH or NaOH
  • said EWG is -CHO
  • conversion of said -CHO group to carboxylic acid group is carried out by protection of the hydroxyl groups, e.g., with acetic anhydride in pyridine or K 2 CO 3 , followed by oxidation of the aldehyde group, e.g., with NaOCh in sulfamic acid, to carboxylic acid group.
  • the compound prepared by Method C is a compound of the formula X wherein R 5 is H, i.e., CBG (R 2 is «-pentyl), a derivative thereof (R 2 is an alkyl other than «-pentyl), or an enantiomer thereof, according to any one of the embodiments above.
  • Such compounds are prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is an EWG as defined above, with geraniol or linalool, in the presence of a Lewis acid such as BF 3 OEt 2 , so as to obtain the compound of the formula In-7, followed by conversion of said EWG to carboxylic acid group and subsequent decarboxylation.
  • said EWG is -CN
  • conversion of said - CN group to carboxylic acid group is carried out by either (i) hydrolysis with a strong base, e.g., KOH or NaOH, in a suitable solvent as defined above (e.g., KOH in aqueous ethylene glycol solution); or (ii) reduction to aldehyde group, followed by oxidation of said aldehyde group to carboxylic acid group.
  • a strong base e.g., KOH or NaOH
  • said EWG is -CHO
  • conversion of said -CHO group to carboxylic acid group is carried out by protection of the hydroxyl groups, e.g., with acetic anhydride in pyridine or K 2 C0 3 , followed by oxidation of the aldehyde group, e.g., with NaOCh in sulfamic acid, to carboxylic acid group.
  • Decarboxylation of the compound of the formula IX to said compound of the formula X may be carried out by heating in methanol in the presence of KOH or NaOH.
  • the present invention provides a method, herein referred to as Method D, for the preparation of a cannabinoid compound of the formula XI or XII, wherein R 2 and R 5 are each as defined above, or an enantiomer thereof, said method comprising electrophilic addition reaction of a resorcinol derivative of the formula In- 1 with citral while heating, to obtain a compound of the formula In- 8, followed by conversion of the R 3 group to carboxylic acid group to obtain said compound of the formula XI, and optionally removal of said carboxylic acid group to obtain said compound of the formula XII, characterized in that said R 3 group is an EWG selected from -CN, -CHO, or -CONMe(OMe).
  • the cannabinoid compound of the formula XI or XII is prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is a particular EWG, with citral while heating, to obtain the compound of the formula In- 8.
  • the cannabinoid compound prepared by Method D is a compound of the formula XI, i.e., CBCA, a derivative thereof, or an enantiomer thereof, and the method further comprises conversion of said EWG to carboxylic acid group (see Scheme 12).
  • the cannabinoid compound prepared by Method D is a compound of the formula XII, i.e., CBC, a derivative thereof, or an enantiomer thereof, and the method further comprises conversion of said EWG to carboxylic acid group, and subsequent decarboxylation (see Scheme 12).
  • said EWG is -CN
  • conversion of said -CN group to carboxylic acid group is carried out, e.g., by (i) hydrolysis with a strong base such as KOH or NaOH, in a suitable solvent, e.g., aqueous ethylene glycol solution, isopropanol, methanol, diglyme, propylene glycol, or THF; or (ii) reduction to aldehyde group, followed by oxidation of said aldehyde group to carboxylic acid group.
  • a strong base such as KOH or NaOH
  • said EWG is -CHO, and conversion of said -CHO group to carboxylic acid group is carried out, e.g., by protection of the hydroxyl groups, if present, with a hydroxyl protecting group as defined above, followed by oxidation of the aldehyde group to carboxylic acid group.
  • the aldehyde group is oxidized with NaOCh in sulfamic acid, KMn0 4 , chromic acid or a salt thereof, or TEMPO with BAIB (TEMPO/BAIB).
  • the compound prepared by Method D is a compound of the formula XI wherein Rs is H, i.e., CBCA (R 2 is /7-pentyl), a derivative thereof (R 2 is an alkyl other than //-pentyl), or an enantiomer thereof, according to any one of the embodiments above.
  • Such compounds are prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is an EWG as defined above, with citral while heating, to obtain the compound of the formula In-8, followed by conversion of said EWG to carboxylic acid group.
  • said EWG is -CN
  • conversion of said -CN group to carboxylic acid group is carried out by either (i) hydrolysis with a strong base, e.g., KOH or NaOH, in a suitable solvent as defined above (e.g., KOH in aqueous ethylene glycol solution); or (ii) reduction to aldehyde group, followed by oxidation of said aldehyde group to carboxylic acid group.
  • a strong base e.g., KOH or NaOH
  • said EWG is - CHO
  • conversion of said -CHO group to carboxylic acid group is carried out by protection of the hydroxyl groups, e.g., with acetic anhydride in pyridine or K2CO3, followed by oxidation of the aldehyde group, e.g., with NaOCh in sulfamic acid, to carboxylic acid group.
  • the compound prepared by Method D is a compound of the formula XII wherein R5 is H, i.e., CBC (R 2 is /7-pentyl ), a derivative thereof (R 2 is an alkyl other than //-pentyl), or an enantiomer thereof, according to any one of the embodiments above.
  • Such compounds are prepared by first electrophilic addition reaction of a resorcinol derivative of the formula In-l wherein R 3 is an EWG as defined above, with citral while heating, to obtain the compound of the formula In-8, followed by conversion of said EWG to carboxylic acid group and subsequent decarboxylation.
  • said EWG is -CN
  • conversion of said -CN group to carboxylic acid group is carried out by either (i) hydrolysis with a strong base, e.g., KOH or NaOH, in a suitable solvent as defined above (e.g., KOH in aqueous ethylene glycol solution); or (ii) reduction to aldehyde group, followed by oxidation of said aldehyde group to carboxylic acid group.
  • a strong base e.g., KOH or NaOH
  • said EWG is -CHO
  • conversion of said -CHO group to carboxylic acid group is carried out by protection of the hydroxyl groups, e.g., with acetic anhydride in pyridine or K 2 C0 3 , followed by oxidation of the aldehyde group, e.g., with NaOCh in sulfamic acid, to carboxylic acid group.
  • Decarboxylation of the compound of the formula XI to said compound of the formula XII may be carried out by heating in KOH or NaOH in methanol.
  • the invention provides a compound of the formula In-3 as defined above, wherein Ri is H, -OH, -OC(0)-(Ci-C 6 )alkyl, preferably -OC(0)CH 3 , - 0C(0)(CH 2 ) n N(Ci-C6 alkyl) 2 , -0C(0)(CH 2 ) n N + (Ci-C6 alkyl) 3 , or -O-amino acid wherein said amino acid is linked through either its a-carboxyl group or side chain carboxyl group, if present; R 2 is a linear or branched (Ci-Ci 2 )alkyl optionally substituted with one or more halogen atoms; R 3 is an EWG selected from -CN, -CHO, or -CONMe(OMe); and R5 is H, or a linear or branched (Ci-Ci 2 )alkyl.
  • the invention provides a compound of the formula In-4 as defined above, wherein R 2 is a linear or branched (Ci-Ci 2 )alkyl optionally substituted with one or more halogen atoms; R 3 is an EWG selected from -CN, -CHO, or -CONMe(OMe); and R 4 each independently is a protecting group selected from (C 2 -C 6 )alkyl, (Ci- C 6 )alkoxy(Ci-C 6 )alkylene, trimethylsilyl, triethylsilyl, ieri-butyldimethylsilyl, tert- butyldiphenylsilyl, benzyl, phenylcarbonyl, -CHO, or acetyl.
  • R 2 is a linear or branched (Ci-Ci 2 )alkyl optionally substituted with one or more halogen atoms
  • R 3 is an EWG selected from -CN, -CHO, or -
  • the invention provides a compound of the formula In-9 or In- 10, as defined above, wherein Ri is H, -OH, -OC(0)-(Ci-C 6 )alkyl, preferably -OC(0)CH 3 , - 0C(0)(CH 2 ) n N(Ci-C6 alkyl) 2 , -0C(0)(CH 2 ) n N + (Ci-C6 alkyl) 3 , or -O-amino acid wherein said amino acid is linked through either its a-carboxyl group or side chain carboxyl group, if present; R 2 is a linear or branched (Ci-Ci 2 )alkyl optionally substituted with one or more halogen atoms; R 3 is an EWG selected from -CN, -CHO, or -CONMe(OMe); and R 6 is -H, or -C(0)CH .
  • Particular compounds of the formula In- 10 or In- 11 disclosed herein are those wherein (i) R is -CHO; and R 6 is -H or -C(0)CH ; (ii) R is -CN; and R 6 is -H or -C(0)CH ; or (iii) R 3 is -CONMe(OMe); and R 6 is -H.
  • Ri is H.
  • Ri is -OH.
  • a compound of the formula In- 10 may be obtained from a compound of the formula la-9 (representing a A 9 -THC derivative) by D 9 - to A 8 -THC transformation in the presence of a Lewis acid such as BF 3 OEt 2 or an acid such as p- TSA in DCM.
  • CBD was prepared as depicted in Scheme 1, according to the procedure described hereinbelow.
  • CBD was synthesized as depicted in Scheme 2, according to the following procedure.
  • CBDV was prepared following the procedure used for the preparation of CBD (Scheme 1), starting from 5-propylresorcinol (replacing compound 4 in said scheme).
  • CBC aldehyde was prepared as depicted in Scheme 12, step 1, according to the procedure described hereinbelow.
  • CBN was prepared directly from CBD as illustrated in Scheme 7.
  • CBD (1 gr, 3.18 mmol) was dissolved in 15 ml toluene.
  • iodine 1.2 gr, 4.77 mmol
  • the reaction mixture was cooled to room temperature and then quenched with 10% sodium thiosulfate solution.
  • the organic phase was separated, and the water phase was extracted with ethyl acetate (or toluene) two more times.
  • the combined organic phase was dried over Na 2 S0 4 , filtered and concentrated under reduced pressure, then purified by silica gel chromatography to give 0.54 gr from the desired product.
  • the product was characterized by GC-MS, LC-MS and NMR analysis. (MS m/z: 311 (M+); GC-MS: 310).

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne des voies synthétiques simples pour la préparation de composés cannabinoïdes tels que CBD, CBDV, THC, THCV, CBN, HU-308, CBG, CBC, et leurs dérivés, qui sont stéréosélectifs et fournissent le composé cannabinoïde souhaité avec un rendement élevé.
PCT/IL2019/050887 2018-08-06 2019-08-05 Procédés de synthèse de composés cannabinoïdes Ceased WO2020031179A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
US201862714906P 2018-08-06 2018-08-06
US62/714,906 2018-08-06
US201862767705P 2018-11-15 2018-11-15
US62/767,705 2018-11-15

Publications (1)

Publication Number Publication Date
WO2020031179A1 true WO2020031179A1 (fr) 2020-02-13

Family

ID=67874485

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IL2019/050887 Ceased WO2020031179A1 (fr) 2018-08-06 2019-08-05 Procédés de synthèse de composés cannabinoïdes

Country Status (1)

Country Link
WO (1) WO2020031179A1 (fr)

Cited By (13)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2021245672A1 (fr) * 2020-06-03 2021-12-09 Epm (Ip), Inc. Dérivés d'acide cannabigérolique (cbga) et leurs utilisations
WO2021245671A1 (fr) * 2020-06-03 2021-12-09 Epm (Ip), Inc. Dérivés d'acide cannabidiolique (cbda) et leurs utilisations
WO2021243468A1 (fr) 2020-06-04 2021-12-09 London Pharmaceuticals And Research Corporation Analogues de cannabidiol rigide utilisés en tant que modulateurs puissants de récepteurs cannabinoïdes et leurs utilisations
CN113896616A (zh) * 2020-07-06 2022-01-07 复旦大学 一种大麻二酚的制备方法
CN114507153A (zh) * 2020-11-17 2022-05-17 中国科学院上海药物研究所 一类间苯二酚化合物及其制备方法以及在神经系统疾病中的应用
CN114853711A (zh) * 2022-04-15 2022-08-05 上海锐康生物技术研发有限公司 一种铜催化一锅法制备大麻酚的方法
WO2022133332A3 (fr) * 2020-12-17 2022-08-18 Nalu Bio, Inc. Synthèse de cannabidiol et d'analogues de celui-ci, et composés, formulations et procédés d'utilisation associés
US20220306598A1 (en) * 2021-03-25 2022-09-29 Precision Extraction Corporation Method for highly selective conversion of cbd to delta-8 thc
WO2022213120A1 (fr) * 2021-04-02 2022-10-06 Lygos, Inc. Cannabinoïdes obtenus à partir d'acides carboxyliques de résorcinol substitués
WO2022240430A1 (fr) * 2020-05-12 2022-11-17 FinChemica, Inc. Conversion catalytique de cannabidiol et procédés associés
CN115504862A (zh) * 2021-06-07 2022-12-23 南通新世元生物科技有限公司 一种大麻萜酚的制备方法
WO2023207460A1 (fr) * 2022-04-29 2023-11-02 汉义生物科技（北京）有限公司 Dérivé de cannabidiol, son procédé de préparation et son utilisation
EP4222260A4 (fr) * 2020-10-02 2025-01-15 Bessor Pharma, LLC Procédé de production de cannabinol, d'acide cannabinolique, de cannabivarine, d'acide cannabivarinique et de cannabinoïdes apparentés

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3562312A (en) 1966-11-04 1971-02-09 Albert Eschenmoser Manufacture of 2-substituted resorcinol derivatives
US5227537A (en) 1991-01-09 1993-07-13 Heinrich Mack Nachf. Method for the production of 6,12-dihydro-6-hydroxy-cannabidiol and the use thereof for the production of trans-delta-9-tetrahydrocannabinol
US20090221712A1 (en) * 2006-02-14 2009-09-03 Rolf Gericke Mandelic hydrazides
US7674922B2 (en) 2005-09-29 2010-03-09 Albany Molecular Research, Inc. Process for production of delta-9-tetrahydrocannabinol
EP2883866A1 (fr) * 2012-08-13 2015-06-17 FUJIFILM Corporation INTERMÉDIAIRE POUR LA SYNTHÈSE DE 1-(2-DÉSOXY-2-FLUORO-4-THIO-beta-D-ARABINOFURANOSYL)CYTOSINE, INTERMÉDIAIRE POUR LA SYNTHÈSE D'UN THIONUCLÉOSIDE ET PROCÉDÉS POUR LA PRODUCTION DE CES INTERMÉDIAIRES
US20170283837A1 (en) 2016-04-04 2017-10-05 Full Spectrum Laboratories Ltd BIOENZYMATIC SYNTHESIS OF THC-v, CBV AND CBN AND THEIR USE AS THERAPEUTIC AGENTS
US20170349518A1 (en) 2016-06-01 2017-12-07 Daniel Dickman Crystalline Form of Cannabidiol

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3562312A (en) 1966-11-04 1971-02-09 Albert Eschenmoser Manufacture of 2-substituted resorcinol derivatives
US5227537A (en) 1991-01-09 1993-07-13 Heinrich Mack Nachf. Method for the production of 6,12-dihydro-6-hydroxy-cannabidiol and the use thereof for the production of trans-delta-9-tetrahydrocannabinol
US7674922B2 (en) 2005-09-29 2010-03-09 Albany Molecular Research, Inc. Process for production of delta-9-tetrahydrocannabinol
US20090221712A1 (en) * 2006-02-14 2009-09-03 Rolf Gericke Mandelic hydrazides
EP2883866A1 (fr) * 2012-08-13 2015-06-17 FUJIFILM Corporation INTERMÉDIAIRE POUR LA SYNTHÈSE DE 1-(2-DÉSOXY-2-FLUORO-4-THIO-beta-D-ARABINOFURANOSYL)CYTOSINE, INTERMÉDIAIRE POUR LA SYNTHÈSE D'UN THIONUCLÉOSIDE ET PROCÉDÉS POUR LA PRODUCTION DE CES INTERMÉDIAIRES
US20170283837A1 (en) 2016-04-04 2017-10-05 Full Spectrum Laboratories Ltd BIOENZYMATIC SYNTHESIS OF THC-v, CBV AND CBN AND THEIR USE AS THERAPEUTIC AGENTS
US20170349518A1 (en) 2016-06-01 2017-12-07 Daniel Dickman Crystalline Form of Cannabidiol

Non-Patent Citations (16)

* Cited by examiner, † Cited by third party
Title
ALFRED RUSSELL ET AL: "[CONTRIBUTION FROM THE DEPARTMENT OF CHEMISTRY, THE UNIVERSITY OF NORTH CAROLINA ] The Constitution of Natural Tannins. VI.' Coloring Matters Derived from 2,s", 1 January 1939 (1939-01-01), pages 421, XP055265896, Retrieved from the Internet <URL:http://pubs.acs.org/doi/pdf/10.1021/ja01265a021> *
BARLUENGA S ET AL: "Solution- and solid-phase synthesis of radicicol (monorden) and pochonin C", CHEMISTRY - A EUROPEAN JOURNAL, WILEY - V C H VERLAG GMBH & CO. KGAA, DE, vol. 11, no. 17, 19 August 2005 (2005-08-19), pages 4935 - 4952, XP002739242, ISSN: 0947-6539, [retrieved on 20050607], DOI: 10.1002/CHEM.200500160 *
BISWAJIT PANDA ET AL: "Gold Catalysis: Regio- and Stereoselective Total Synthesis of Xyloketals D and G and the Related Natural Product Alboatrin", JOURNAL OF ORGANIC CHEMISTRY, vol. 78, no. 6, 15 March 2013 (2013-03-15), US, pages 2413 - 2421, XP055630305, ISSN: 0022-3263, DOI: 10.1021/jo302545n *
CROMBIE ET AL., J. CHEM. RESEARCH (S, vol. 114, 1977, pages 1301 - 1345
EIDEN FRITZ ET AL: "Darstellung und Reaktionen von Formyl-tetrahydrocannabinol-Derivaten", ARCHIV DER PHARMAZIE, WILEY VERLAG, WEINHEIM, vol. 315, no. 6, 1 January 1982 (1982-01-01), pages 551 - 561, XP009516542, ISSN: 0365-6233, [retrieved on 20060923], DOI: 10.1002/ARDP.19823150613 *
FUTOSHI ET AL., PHYTOCHEMISTRY, vol. 39, 1995, pages 457 - 458
KRISTIAN M. JACOBSEN ET AL: "The natural product brartemicin is a high affinity ligand for the carbohydrate-recognition domain of the macrophage receptor mincle", MEDCHEMCOMM, vol. 6, no. 4, 1 January 2015 (2015-01-01), United Kingdom, pages 647 - 652, XP055630868, ISSN: 2040-2503, DOI: 10.1039/C4MD00512K *
LUO ET AL., SYNTHESIS, vol. 47, no. 18, 2015, pages 2713 - 2720
RAPHAËL RODRIGUEZ ET AL: "A new and efficient method for o-quinone methide intermediate generation: application to the biomimetic synthesis of the benzopyran derived natural products ( )-lucidene and ( )-alboatrin", ORGANIC & BIOMOLECULAR CHEMISTRY, vol. 3, no. 19, 1 January 2005 (2005-01-01), pages 3488, XP055630301, ISSN: 1477-0520, DOI: 10.1039/b508972g *
SAFWAT A. AHMED ET AL: "Minor oxygenated cannabinoids from high potency Cannabis sativa L.", PHYTOCHEMISTRY, vol. 117, 1 September 2015 (2015-09-01), GB, pages 194 - 199, XP055630314, ISSN: 0031-9422, DOI: 10.1016/j.phytochem.2015.04.007 *
SEUNG-HWA ET AL., BULLETIN OF THE KOREAN CHEMICAL SOCIETY, vol. 16, no. 3, 1995, pages 293 - 296
TAI KYOUNG KIM ET AL: "Total Syntheses of Lobaric Acid and Its Derivatives from the Antarctic Lichen Stereocaulon alpinum", JOURNAL OF NATURAL PRODUCTS., vol. 81, no. 6, 22 June 2018 (2018-06-22), US, pages 1460 - 1467, XP055630288, ISSN: 0163-3864, DOI: 10.1021/acs.jnatprod.8b00227 *
WANG ZENGTAO ET AL: "Concise synthesis of licochalcone C and its regioisomer, licochalcone H", ARCHIVES OF PHARMACAL RESEARCH, NATL. FISHERIES UNIVERSITY, PUSAN, KR, vol. 36, no. 12, 30 July 2013 (2013-07-30), pages 1432 - 1436, XP035312459, ISSN: 0253-6269, [retrieved on 20130730], DOI: 10.1007/S12272-013-0222-3 *
YONG ROK LEE ET AL: "Concise Synthesis of Biologically Interesting ( )-Cannabichromene, ( )-Cannabichromenic Acid, and ( )-Daurichromenic Acid", BULLETIN OF THE KOREAN CHEMICAL SOCIETY, vol. 26, no. 12, 20 December 2005 (2005-12-20), KR, pages 1933 - 1936, XP055630569, ISSN: 0253-2964, DOI: 10.5012/bkcs.2005.26.12.1933 *
YONG-ROKXUE, BULLETIN OF THE KOREAN CHEMICAL SOCIETY, vol. 26, no. 12, 2005, pages 1933 - 1936
YU CHUNHUI ET AL: "Total synthesis of dysidavarone A", TETRAHEDRON, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 72, no. 29, 31 May 2016 (2016-05-31), pages 4337 - 4345, XP029620683, ISSN: 0040-4020, DOI: 10.1016/J.TET.2016.05.073 *

Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022240430A1 (fr) * 2020-05-12 2022-11-17 FinChemica, Inc. Conversion catalytique de cannabidiol et procédés associés
WO2021245671A1 (fr) * 2020-06-03 2021-12-09 Epm (Ip), Inc. Dérivés d'acide cannabidiolique (cbda) et leurs utilisations
WO2021245672A1 (fr) * 2020-06-03 2021-12-09 Epm (Ip), Inc. Dérivés d'acide cannabigérolique (cbga) et leurs utilisations
WO2021243468A1 (fr) 2020-06-04 2021-12-09 London Pharmaceuticals And Research Corporation Analogues de cannabidiol rigide utilisés en tant que modulateurs puissants de récepteurs cannabinoïdes et leurs utilisations
CN113896616A (zh) * 2020-07-06 2022-01-07 复旦大学 一种大麻二酚的制备方法
EP4222260A4 (fr) * 2020-10-02 2025-01-15 Bessor Pharma, LLC Procédé de production de cannabinol, d'acide cannabinolique, de cannabivarine, d'acide cannabivarinique et de cannabinoïdes apparentés
CN114507153A (zh) * 2020-11-17 2022-05-17 中国科学院上海药物研究所 一类间苯二酚化合物及其制备方法以及在神经系统疾病中的应用
CN117043147A (zh) * 2020-12-17 2023-11-10 纳鲁生物股份有限公司 大麻二酚及其类似物的合成以及相关化合物、制剂和使用方法
US12264143B2 (en) 2020-12-17 2025-04-01 Nalu Bio, Inc. Synthesis of cannabinoids and cannabinoid precursors, and related compounds, formulations, and methods of use
WO2022133332A3 (fr) * 2020-12-17 2022-08-18 Nalu Bio, Inc. Synthèse de cannabidiol et d'analogues de celui-ci, et composés, formulations et procédés d'utilisation associés
JP2024502751A (ja) * 2020-12-17 2024-01-23 ナル バイオ， インコーポレイテッド カンナビジオールおよびそのアナログの合成、ならびに関連化合物、製剤、および使用の方法
US20220306598A1 (en) * 2021-03-25 2022-09-29 Precision Extraction Corporation Method for highly selective conversion of cbd to delta-8 thc
WO2022213120A1 (fr) * 2021-04-02 2022-10-06 Lygos, Inc. Cannabinoïdes obtenus à partir d'acides carboxyliques de résorcinol substitués
CN115504862A (zh) * 2021-06-07 2022-12-23 南通新世元生物科技有限公司 一种大麻萜酚的制备方法
CN114853711B (zh) * 2022-04-15 2024-01-23 上海锐康生物技术研发有限公司 一种铜催化一锅法制备大麻酚的方法
WO2023197384A1 (fr) * 2022-04-15 2023-10-19 上海锐康生物技术研发有限公司 Procédé de préparation de cannabinol dans un procédé monotope catalysé par du cuivre
CN114853711A (zh) * 2022-04-15 2022-08-05 上海锐康生物技术研发有限公司 一种铜催化一锅法制备大麻酚的方法
WO2023207460A1 (fr) * 2022-04-29 2023-11-02 汉义生物科技（北京）有限公司 Dérivé de cannabidiol, son procédé de préparation et son utilisation

Similar Documents

Publication Publication Date Title
WO2020031179A1 (fr) Procédés de synthèse de composés cannabinoïdes
EP2861554B1 (fr) Procédé amélioré pour la préparation du trépostinil et de ses dérivés
KR101658855B1 (ko) 벤진덴 프로스타글란딘의 합성을 위한 중간체 및 그 제조
US7186850B2 (en) Synthesis of cannabinoids
AP385A (en) Benzopyrans and related LTB4 antagonists.
CN105985306B (zh) 天然产物黄酮类化合物的全合成制备方法
JP2009292824A (ja) エストロゲン関連治療用のノンステロイド系四環式化合物
CA2147263C (fr) Derives du 4-alcoxy-2,6-di-tert-butylphenol
US4395560A (en) Preparation of 6a,10a-trans-hexahydrodibenzopyranones
TW201309662A (zh) 多酚新合成方法
Menting et al. Quinones. Part 9. Stability of quinones toward water. Synthesis of a 1, 7-naphthoquinone
JP3050733B2 (ja) ４−アルコキシ−２，６−ジ−ｔ−ブチルフェノール誘導体
Fryatt et al. The synthesis of multiply 13C‐labelled plant and mammalian lignans as internal standards for LC‐MS and GC‐MS analysis
US20060094886A1 (en) Manufacture of tocopheryl acetate
CN110143857B (zh) 一种半棉酚、棉酚及它们的类似物的合成方法
EP3233776B1 (fr) Formation de chromanes fondée sur une réaction intermoléculaire d&#39;alcynes avec du diméthylfurane en présence de complexes d&#39;or (i)
US10532991B2 (en) Method for preparing hispidulin and its derivatives
Joubert et al. Synthesis of labelled [13C6] testosterone and [13C5] 19‐nortestosterone
Dinnar et al. Sustainable Synthesis of Cannabinoids via Metal-Free Aromatic Deformylation
KR20110012105A (ko) 도미노 알돌형 반응 및 6π―전자고리화 반응을 이용한 피라노스틸벤 화합물의 합성방법
Clive Synthesis of the aromatic unit of calicheamicin γ 1 I
Achilonu et al. Research Article Bioactive Phytochemicals: Efficient Synthesis of Optically Active Substituted Flav-3-enes and Flav-3-en-3-oR Derivatives
Wawrzeńczyk et al. Insect growth regulators. XXI. Synthesis of Juvenoids with the 5, 5‐dimethylcyclohex‐3‐en‐1‐yl system
US7763740B2 (en) Method for the production of mumbaistatin derivatives
Sabol et al. Conformationally restricted leukotriene antagonists. Stereoselective synthesis of some leukotriene D4 analogs

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19765331

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 19765331

Country of ref document: EP

Kind code of ref document: A1