TECHNICAL FIELD

[0001] 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.

[0002] Abbreviations: 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; LC-MS, liquid chromatography-mass spectrometry; MSA, methanesulfonic acid; MTBE, methyl / _{<? /7} -butyl ether; 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.

BACKGROUND ART

[0003] Phytocannabinoids are naturally occurring cannabinoids present in the cannabis plant, and synthetic cannabinoids are derivatives of phytocannabinoids synthesized from non natural sources. Currently, 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.

[0004] US 3,562,312 describes the synthesis of CBD ethyl ester. The product was obtained from ethyl olivetolate and dementhanediol. The reaction provided 42% of CBD-carboxylic acid ethyl ester, and CBD was then obtained by NaOH mediated decarboxylation reaction.

[0005] Crombie et ah, J. Chem. Research (S), 1977, 114, 1301-1345, describes a method for the synthesis of CBD methyl ester from methyl olivetolate and menthadienol in the presence of p-toluene sulfonic acid. The reaction provided 39-56% of methyl cannabidiolate. The methyl ester was then hydrolyzed, and the corresponding carboxylic acid was further decarboxylated to introduce the proton to make CBD. A similar method is disclosed in US 7,674,922 for CBD. The coupling reaction of menthadienol and ethyl olivetolate using MgS0 ₄ and Sc(0S0 ₂ CF ₃ ) ₃ provided ethyl cannabidiolate in 87% yield, and further hydrolysis and decarboxylation of the ethyl cannabidiolate provided CBD in 44% yield. Similarly, US 20170349518 discloses the synthesis CBD using Na ₂ S0 ₄ and boron trifluoride diethyl etherate (BF ₃ OEt ₂ ). The conversion step gave 48% of CBD.

[0006] There are limited methods reported for the synthesis of CBG and CBN. US 20170283837 reports the synthesis of CBG from olivetol and geraniol using -TSA. Similar method has been reported by Futoshi et al, Phytochemistry , 1995, 39, 457-458 and by Seung-Hwa et al. in Bulletin of the Korean Chemical Society, 1995, 16(3), 293-296. Synthesis of CBC has been reported from olivetol and citral in Luo et al, Synthesis 2015, 47(18), 2713-2720 and by Yong-Rok and Xue in Bulletin of the Korean Chemical Society, 2005, 26(12), 1933-1936. The yield of CBG and CBN from olivetol is 40-50%.

[0007] The prior art reveals difficulties in manufacturing CBD, CBG and CBC from olivetol, halogenated olivetols, and olivetol ethyl or methyl esters. The yields are low, and in case of olivetol, the reaction is not stereoselective. The multi-step synthesis is required for the preparation of halogenated olivetols and olivetol esters, and the overall yield from these syntheses is poor.

SUMMARY OF INVENTION

[0008] Disclosed herein are simple synthetic routes for the preparation of cannabinoid compounds such as CBD, delta-9 (A ⁹ )-THC, delta-8 (A ⁸ )-THC, CBN, HU-308, CBDA, THCA, CBNA, CBGA, CBG, CBCA, and CBC (herein referred to as 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 reactions are stereoselective and provide the desired cannabinoid compound in high yield. [0009] In one aspect, 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”:

wherein

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,

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:

(1) removal of the R ₃ group to obtain said compound of the formula I, and optionally conversion of said compound to said compound of the formula IV; or

(2) 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

(3) conversion of the R ₃ group to carboxylic acid group, to obtain said compound of the formula VI; and optionally either (i) CBD-to-THC cyclization under acidic conditions to obtain said compound of the formula VII; or (ii) conversion to said compound of the formula VIII, and optionally removal of said carboxylic acid group to obtain said compound of the formula IV,

characterized in that said R ₃ group is an electron- withdrawing group (EWG) selected from -CN, -CHO, or -CONMe(OMe).

[0010] In another aspect, 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

“Method B” .

wherein

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).

[0011] In still another aspect, 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”:

wherein 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).

[0012] In yet another aspect, 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” .

wherein 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).

[0013] The synthetic procedures disclosed herein, including full chemical structures of all compounds involved, are shown in the Appendix hereinafter, Schemes 1-15, wherein the starting compounds, intermediates and products referred to are identified by the Arabic numbers 1-35. Certain intermediate compounds used or obtained in the procedures disclosed are identified as compounds In-1 to In-10. The present invention therefore further provides particular compounds used/obtained in the syntheses disclosed herein.

[0014] In a further aspect, the invention provides a compound of the formula In-3:

wherein

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; and

R ₃ is an EWG selected from -CN, -CHO, or -CONMe(OMe); and

Rs is H, or a linear or branched (Ci-Ci ₂ )alkyl.

[0015] In still a further aspect, the invention provides a compound of the formula In-4:

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. [0016] In yet a further aspect, the invention provides a compound of the formula In-9 or In-10:

wherein

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); and

R ₆ is -H, or -C(0)CH .

DETAILED DESCRIPTION

[0017] In one aspect, 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:

(1) removal of the R ₃ group to obtain said compound of the formula I, and optionally conversion of said compound to said compound of the formula IV ; or

(2) 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

(3) conversion of the R ₃ group to carboxylic acid group, to obtain said compound of the formula VI; and optionally either (i) CBD-to-THC cyclization under acidic conditions to obtain said compound of the formula VII; or (ii) conversion to said compound of the formula VIII, and optionally removal of said carboxylic acid group to obtain said compound of the formula IV, characterized in that said R ₃ group is an EWG selected from -CN, -CHO, or - CONMe(OMe).

[0018] The term "alkyl" as used herein 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,l,2-trimethylbutyl, «-octyl, 2- methylheptyl, l,l-dimethylhexyl, l,2-dimethylhexyl, l,l,2-trimethylpentyl, «-nonyl, 1,1- dimethylheptyl, l,2-dimethylheptyl, l,l,2-trimethylhexyl, «-decyl, l,l,2-trimethylheptyl, «- undecyl, «-dodecyl, and the like. Preferred are (Ci-C9)alkyl groups, more 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. Examples of 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.

[0019] The term "halogen" as used herein refers to a halogen and includes fluoro, chloro, bromo, and iodo, but it is preferably chloro or bromo.

[0020] The term "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.

[0021] The term "alkoxy" as used herein refers a radical of the formula -OR, wherein R is alkyl as defined above, preferably (Ci-C ₆ )alkyl. Non-limiting examples of alkoxy groups include methoxy, ethoxy, and propoxy.

[0022] The term "amino acid" as used herein 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-ethynyl-tryptophan, 3-(6- chloroindolyl)alanine, 3-(6-bromoindolyl)alanine, 3-(5-bromoindolyl)alanine, azidohomoalanine, -chlorophenyl alanine, a-aminocaprylic acid, O-methyl-L-tyrosine, N- acetylgalactosamine-a-threonine, and N-acetylgalactosamine-a-serine.

[0023] The term "amino acid residue" as used herein 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.

[0024] The term“electron-withdrawing group” (EWG) as used herein refers to any group capable pf drawing electrons away from a reaction center. Particular such groups used according to the methods disclosed herein are -CN, -CHO, and -CONMe(OMe).

[0025] The term "hydroxyl-protecting group" as used herein 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. Examples of 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. In preferred embodiments, the hydroxyl-protecting group is acetic anhydride in pyridine.

[0026] According to Method A, 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 ) . [0027] 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.

[0028] In one particular such aspect, 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). Particular such compounds are those wherein 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.

[0029] In another particular such aspect, 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). Particular such compounds are those wherein 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.

[0030] In still another particular such aspect, 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. Particular such compounds are those wherein 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. [0031] In yet another particular such aspect, 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. Particular such compounds are those wherein 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.

[0032] In a further particular such aspect, 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). In particular such compounds, Rs is H; Ri is H, -OH, or -O-amino acid; 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.

[0033] In still a further particular such aspect, the cannabinoid compound prepared by

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). In particular such compounds, R ₅ is H; Ri is H, -OH, or -O-amino acid; 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.

[0034] In yet a further particular such aspect, the cannabinoid compound prepared by

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). In particular such compounds, Rs is H; Ri is H, -OH, or -O-amino acid; 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.

[0035] In another particular such aspect, 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). In particular such compounds, Rs is H; Ri is H, -OH, or -O-amino acid; 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.

[0036] In certain embodiments, said EWG is -CN. In some particular embodiments, 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. In other particular embodiments, 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.

[0037] In other embodiments, said EWG is -CHO. In some particular embodiments, 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. In other particular embodiments, 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. In particular embodiments, the aldehyde group is oxidized with NaOCh in sulfamic acid, KMn0 ₄ , chromic acid or a salt thereof, or TEMPO with BAIB (TEMPO/BAIB).

[0038] In certain embodiments, 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. In other embodiments, 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. In some particular embodiments, said EWG is -CN, and 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. In other particular embodiments, 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.

[0039] In certain embodiments, 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. In other embodiments, 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. In some particular embodiments, said EWG is -CN, and 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. In other particular embodiments, 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.

[0040] In certain embodiments, 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. In other embodiments, 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 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 (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. In some particular embodiments, said EWG is -CN, and 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. In other particular embodiments, 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.

[0041] In certain embodiments, 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. In other embodiments, 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. In some particular embodiments, said EWG is -CN, and 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. In other particular embodiments, 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.

[0042] In certain embodiments, 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). In particular such embodiments, 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.

[0043] Yet, and although not schematically shown, it should be understood that 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.

[0044] In certain embodiments, 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. In some particular embodiments, said EWG is -CN, and 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. In other particular embodiments, said EWG is -CHO, and 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.

[0045] In certain embodiments, 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. In some particular embodiments, said EWG is -CN, and 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. In other particular embodiments, said EWG is -CHO, and 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.

[0046] In certain embodiments, 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. In some particular embodiments, said EWG is -CN, and 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. In other particular embodiments, said EWG is -CHO, and 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.

[0047] In certain embodiments, 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. In some particular embodiments, said EWG is -CN, and 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. In other particular embodiments, said EWG is -CHO, and 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.

[0048] In another aspect, 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).

[0049] According to Method B, 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.

[0050] In one particular such aspect, 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). In particular such compounds, Ri is H, -OH, or -O-amino acid; R ₅ is H; 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.

[0051] In certain embodiments, said EWG is -CN, and 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.

[0052] In certain embodiments, 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. In particular embodiments, 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).

[0053] In certain embodiments, 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. In other embodiments, 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. In some particular embodiments, 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. In other particular embodiments, 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.

[0054] In certain embodiments, 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. As described above (see Method A), 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. As further described above, in some embodiments, 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).

[0055] In still another aspect, 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).

[0056] According to Method C, 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.

[0057] In one particular such aspect, 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).

[0058] In another particular such aspect, 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).

[0059] In certain embodiments, said EWG is -CN, and 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.

[0060] In certain embodiments, 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. In particular embodiments, the aldehyde group is oxidized with NaOCh in sulfamic acid, KMn0 ₄ , chromic acid or a salt thereof, or TEMPO with BAIB (TEMPO/BAIB).

[0061] In certain embodiments, 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. In some particular embodiments, said EWG is -CN, and 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. In other particular embodiments, said EWG is -CHO, and 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.

[0062] In certain embodiments, 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. In some particular embodiments, said EWG is -CN, and 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. In other particular embodiments, said EWG is -CHO, and 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.

[0063] An alternative method for the preparation of a cannabinoid compound of the formula IX or X, wherein R ₂ and R ₅ are each as defined above, starting from a resorcinol derivative of the formula In-l wherein R ₃ is an EWG as defined above, is illustrated in Scheme 11, where the phenolic allyl group is transformed to aromatic carbon atom by Claisen rearrangement.

[0064] In yet another aspect, 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). [0065] According to Method D, 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.

[0066] In one particular such aspect, 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).

[0067] In another particular such aspect, 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).

[0068] In certain embodiments, said EWG is -CN, and 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.

[0069] In certain embodiments, 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. In particular embodiments, the aldehyde group is oxidized with NaOCh in sulfamic acid, KMn0 ₄ , chromic acid or a salt thereof, or TEMPO with BAIB (TEMPO/BAIB).

[0070] In certain embodiments, 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. In some particular embodiments, said EWG is -CN, and 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. In other particular embodiments, said EWG is - CHO, and 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.

[0071] In certain embodiments, 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. In some particular embodiments, said EWG is -CN, and 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. In other particular embodiments, said EWG is -CHO, and 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.

[0072] In a further aspect, 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.

[0073] In still a further aspect, 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.

[0074] In yet a further aspect, 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 .

[0075] 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. In certain more particular such compounds, Ri is H. In other more particular such compounds, Ri is -OH.

[0076] A compound of the formula In- 10 (representing a A ⁸ -THC derivative) 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.

[0077] The invention will be now illustrated by the following non-limiting Examples.

EXAMPLES

Example 1. Synthesis of cannabidiol (CBD)

[0078] CBD was prepared as depicted in Scheme 1, according to the procedure described hereinbelow.

Preparation of olivetol dimethyl ether (1)

[0079] To a stirred slurry of magnesium turnings (60 gr) in THF (l50ml) was added dropwise a solution of 3,5-dimethoxy-bromo-benzene (500 gr) in 800 ml THF, keeping the temperature between 30 and 40°C. After completion the addition, the solution was refluxed until full dissolving of the magnesium turnings. The reaction mixture then was cooled down to 35°C. A solution of bromopentane (398.5 gr), lithium bromide (1.08 gr) and CuCl ₂ (3gr) in

1 lit THF was added dropwise, then the solution was refluxed and held overnight.

[0080] The solution was cooled down to 5°C and 20% acetic acid (700 gr) was added dropwise. The mixture was extracted with three times with MTBE and the organic layer was washed with 5% sodium bicarbonate to achieve final pH of ca. 8. The organic phase was concentrated under reduced pressure and distilled affording 300 gr of olivetol dimethyl ether (purity>97%). (GC-FID retention time=l6.l min).

Preparation of bromo-dimethoxy olivetol (2)

[0081] To a stirred solution of olivetol dimethyl ether (500 gr) in DCM (1.2 L) was added NBS (417 gr) in small portions while maintaining the temperature below l0°C. After completion of the addition, the reaction mixture held for 30 min at RT. Then, the reaction mixture was filtered, and the filtrate was washed with 5% sodium bicarbonate (1.5 lit) and extracted with DCM. The organic phase was extracted with saturated brine and concentrated under reduced pressure. The crude was distilled under high vacuum to give 500 gr of bromo- dimethoxyolivetol (purity>96%). (GC-FID retention time=l8.4 min).

Preparation of dimethoxy olivetol aldehyde (3)

[0082] To a stirred slurry of magnesium turnings (8.4 gr) in THF (30 ml) was added dropwise a solution of bromo-dimethoxy-olivetol (100 gr) in THF (160 ml), keeping the temperature between 30 and 40°C. after completion the addition, the solution was refluxed until full dissolving of the magnesium turnings. The reaction mixture then was cooled down to 35°C. A solution of dimethylformamide (40 ml) was added dropwise, and then the solution was refluxed for 1 hr.

[0083] The solution was cooled down to 5°C and 1M HC1 (300 gr) was added dropwise. The mixture was extracted with three times with MTBE and the organic layer was washed with 5% sodium bicarbonate at pH 8. The organic phase was concentrated under reduced pressure and distilled to yield 65 gr of dimethoxyolivetol aldehyde (purity>96%). (GC-FID retention time=l8.7 min).

Preparation of olivetol aldehyde (4)

[0084] To a slurry of AlCb (84 g) in DCM (150 ml) was added a solution of dimethoxyolivetol aldehyde (50 g) in DCM (50 ml) in dropwise while maintaining the temperature below 40°C. The reaction mixture was stirred at room temperature for overnight. The reaction was quenched with 1M HC1 in ice (300 g) and extracted three times with ethyl acetate. The organic phase washed with 5% sodium bicarbonate and concentrated under reduced pressure and distilled affording 30 g of olivetol aldehyde (GC-FID retention time=l9 min; HPLC retention time=l l.7 min, MS m/z=209 (M ⁺ ), ' HNMR (CDCI3): 12.4 (s, 1H), 10.07 (s, 1H), 6.23 (d, 1H), 6.22 (d, 1H), 5.7 (bs, 1H), 2.81 (t, 2H), 1.63 (m, 2H), 1.35 (m, 4H), 0.92 (t, 3H). Preparation of cannabidiol-aldehyde (5)

[0085] To a stirred solution of olivetol aldehyde (50 g) in DCM (200 ml) was added -TSA (10 mg). The mixture cooled to 5°C. To this solution was added a cold solution of (+)- menthadienol (36.5 g) in DCM (150 ml). After stirring for 2 hr at this temperature, the reaction mixture quenched with saturated sodium bicarbonate and extracted 3 times in methylene chloride. The organic phase washed with 1 N sodium hydroxide followed by washing with 1 N HC1. The organic phase was concentrated under reduced pressure to give 46 g of cannabidiol-aldehyde. The product was identified by LC-MS, GC and NMR analysis. (HPLC retention time=l5.84 min; MS m/z= 343 (M ⁺ )). 1HNMR (DMSO-d ₆ ): 12.92 (1H, s), 10.52 (1H, s), 9.97 (lH,s), 6.24 (lH,s), 5.10 (lH,s), 4.85 (1H, m), 4.44 (1H, m), 3.86 (1H, m), 2.81 (2H, t), 2.16 (1H, m), 2.02 (2H, m), 1.73 (2H, m), 1.67 (3H, s), 1.64 (3H, s), 1.58 (2H, m), 1.35 (4H, m), 0.92 (3H, t).

Preparation of cannabidiol diacetate aldehyde (6)

[0086] Compound 5 (46 g) was dissolved in DCM (250 ml), and pyridine (52 ml), acetic anhydride (63 ml) and catalytic amount of DMAP were added. The reaction mixture was stirred at room temperature for overnight. Then the solution was poured onto 1 M HC1 and extracted with DCM. The combined organic extract was washed with 5% sodium bicarbonate and brine. The organic phase was concentrated under reduced pressure to give quantitative yield, and continued to the next step without further purifications. (HPLC retention time=l6.l min; MS m/z=427 [M ⁺ ]).

Preparation of cannabidiol carboxylate (7)

[0087] To a stirred solution of cannabidiol diacetate aldehyde 6 (2.4 g) in DMSO/THF/H ₂ 0 (2: 1:0.5) was added sulfamic acid (2.48 g). The reaction mixture was then cooled to 5°C. Then, a solution of NaClCh (2.5 gr) in water was added dropwise to the cold solution. The reaction mixture was quenched with sodium bicarbonate and extracted with ethyl acetate. The organic phase was concentrated under reduced pressure affording compound 7 as white solid. The product was identified by LC-MS and NMR analysis. (HPLC retention time=l4.08 min; MS m/z= 465 [M+Na]). 1HNMR (DMSO-d ₆ ): 13.49 (1H, bs), 6.80 (1H, s), 4.97 (1H, s), 4.50 (1H, m), 4.40 (1H, m), 3.35 (1H, m), 2.68 (2H, t), 2.16 (1H, m), 2.02 (2H, m), 1.71 (2H, m), 1.62 (3H, s), 1.58 (3H, s), 1.51 (2H, m), 1.35 (4H, m), 0.92 (3H, t). Preparation of CBD

[0088] Cannabidiol-carboxylate (500 mg) was dissolved in methanol (3 ml) and 20% NaOH (3 ml) was added. The reaction mixture was heated to 70°C for 2 hours under nitrogen. The reaction mixture was quenched with aqueous citric acid solution and extracted with ethyl acetate. The organic phase was purified on silica gel column to give CBD (310 mg, 88%). The crude product was also distilled under vacuum at 200-220°C. The isolated product was identical by HPLC and LC-MS relative to a reference standard solution of cannabidiol [HPLC retention time=l4.8 min; MS m/z= 315 (M ⁺ )].

[0089] Alternatively, CBD was synthesized as depicted in Scheme 2, according to the following procedure.

Preparation of cyano-dimethoxyolivetol (8)

[0090] To a stirred solution of bromo-dimethoxyolivetol (30 gr) in DMF (150 ml) was added copper cyanide (18 gr). The reaction mixture was heated up to l50°C for overnight. The reaction was quenched with water and extracted with Ethyl acetate. The organic phase was concentrated under reduced pressure to give the desired product (70%). The product was identified by GC-MS (GC retention time=l9 min, MS m/z=233, HPLC retention time=l3.6 min).

Preparation of cyano-olivetol (9)

[0091] A 1M solution of BBr ₃ (17 ml) in DCM was slowly added to a solution of cyano- dimethoxy-olivetol (0.5 gr) in methylene chloride (20 ml) with cooling by ice-bath. After the addition, the ice bath was removed, and the reaction mixture was stirred for overnight. The reaction mixture was quenched with 1.0 M HC1 and extracted with DCM. The organic phase was washed with 5% sodium bicarbonate and then concentrated under reduced pressure to give the desired product as a white solid. The product was identified by LC-MS and NMR analysis. (HPLC retention time=l0.3 min; MS m/z=206 [M ⁺ ]). 1HNMR (DMSO-d ₆ ): 10.76 (bs, 1H), 10.30 (bs, 1H), 6.31 (d, 1H), 6.27 (d, 1H), 2.62 (t, 2H), 1.60 (m, 2H), 1.36 (m, 4H), 0.92 (t, 3H).

Preparation of cyano-cannabidiol (10)

[0092] To a stirred solution of cyano-olivetol (300 mg) in DCM (20 ml) was added BF ₃ etherate (0.20 ml). The mixture cooled to 5°C. To this solution was added a cold solution of

(-i-)-menthadienol (370 mg) in DCM (10 ml). After stirring for 2 hours at this temperature, the reaction mixture was quenched with saturated sodium bicarbonate and extracted (3 times). The organic phase washed with 1.0 N sodium hydroxide followed by washing with 1N HC1. The organic phase was concentrated under reduced pressure. The product was identified by LC-MS and NMR analysis. (HPLC retention time=l4.8 min; MS m/z=340 [M ⁺ ]). ¹ H-NMR (DMSO-de): 9.99 (bs, 1H), 9.45 (bs, 1H), 6.29 (s, 1H), 5.11 (s, 1H), 4.45 (m, 2H), 3.87 (d, 1H), 2.96 (t, 2H), 2.16 (m, 1H), 1.98 (m, 1H), 1.73 (m, 2H), 1.63 (s, 3H), 1.58 (s, 3H), 1.54 (m, 2H), 1.35 (m, 4H), 0.92 (t, 3H).

Example 2. Pilot scale preparation of cannabidivarin (CBDV)

[0093] CBDV was prepared following the procedure used for the preparation of CBD (Scheme 1), starting from 5-propylresorcinol (replacing compound 4 in said scheme).

Preparation of cannabidivarin-aldehyde

[0094] In a 20-liter reactor equipped with mechanical stirrer, thermometer, cooling coil and bottom drain. Lauda or Huber cooling/heating chilling system, 2,4-dihydroxy-6- propylbenzaldehyde (1 kg) in DCM (5 kg) was added, followed by -TSA (50 g). The reactor was cooled to 0-5°C. A cold solution of (-i-)-menthadienol (0.84 kg) in DCM (3 kg) was added over 7-8 hours at 0-5°C. The mixture was stirred at 0-5°C for 1 hour. When the GC showed <20% of starting material, a solution of KOH (85%) in cold distilled water (1.5 L) was added and stirred for 10-20 minutes at 25°C. The organic phase was separated, and the aqueous phase was extracted with another round of KOH (1M, 0.5 kg). The combined organic phase was treated with dilute HC1 (0.5 kg, 1M) and stirred for 10-20 minutes at 25°C. The organic phase was further treated with sodium bicarbonate (0.475 kg) and washed with brine. It was then concentrated on rotary evaporator and passed through a plug of silica gel (1 kg) with 5% EtO Ac -hexane (~8 liter eluent). The solvent was concentrated to produce 1.7 kg of crude product. The water phase from KOH extraction provided C3 olivetol aldehyde (0.133 kg) after adjusting pH and extraction in DCM.

Preparation of cannabidivarin diacetate aldehyde

[0095] In a 20-liter reactor equipped with mechanical stirrer, thermometer, cooling coil and bottom drain. Lauda or Huber cooling/heating chilling system was added 2, 6 -dihydroxy- 5'- methyl-4-propyl-2'-(prop-l-en-2-yl)-r,2',3',4'-tetrahydro-[l ,r-biphenyl]-3-carbaldehyde (1 kg) in dry toluene (3.6 kg), followed by DMAP (3.8 g) and triethylamine (0.49 kg). Acetic anhydride (0.65 kg) was added at room temperature and stirred at 25°C for 1.5 hour. When the GC showed the complete conversion of starting material, dilute HC1 was added and stirred for 5-10 minutes at 25°C. The organic phase was washed with water, NaHC0 ₃ and brine and concentrated on rotary evaporator to give the desired product (1.2 kg) as liquid.

Preparation of CBDVA diacetate

[0096] In a 20-liter reactor equipped with mechanical stirrer, thermometer, cooling coil and bottom drain. Lauda or Huber cooling/heating chilling system was added 3 -formyl-5 '-methyl- 4-propyl-2'-(prop-l-en-2-yl)-r,2',3',4'-tetrahydro-[l,r-biph enyl]-2,6-diyl diacetate (1 kg), DMSO (2.75 kg), THF (1.25 kg) and water (0.7 kg). Sulfamic acid (0.45 kg) was then added and stirred for 25°C to get a homogeneous solution. The mixture was cooled to 0-5°C and a solution of sodium chlorite (0.4 kg of NaCl0 ₂ in 2 kg H ₂ 0) was added dropwise over 2.5 hours, while keeping the temperature below l0°C. When the HPLC showed the complete conversion of starting material, the reaction was slowly warmed to 25 °C and stirred for 1 hour. Ethyl acetate (2 kg) was added. The organic phase was separated and washed with NaHC0 ₃ , water and brine. It was concentrated on rotary evaporator to give CBDVA diacetate (0.750 kg).

Preparation of CBDV

[0097] In a 20-liter reactor equipped with mechanical stirrer, thermometer, cooling coil and bottom drain. Lauda or Huber cooling/heating chilling system was added 2,6-diacetoxy-5'- methyl-4-propyl-2'-(prop-l-en-2-yl)-r,2',3',4'-tetrahydro-[l ,r-biphenyl]-3-carboxylic acid (1 kg), and methanol (1.6 kg) in presence of nitrogen stream inside the reaction, then 20% sodium hydroxide in deionized water (2 kg) was added. The reaction was heated at 75°C for 1 hour. When the HPLC showed the complete conversion of starting material, it was cooled to 25°C. A solution of citric acid (0.64 kg in 1 kg H ₂ 0) was added and stirred for 10 minutes. Ethyl acetate (2 kg) was added and stirred for 10 minutes. Organic phase was washed with NaHC0 ₃ , water and brine. It was concentrated on rotary evaporator. Crude CBDV was distilled under vacuum (0.1-10 mmHg) at 200-250°C. It provided 220 g of liquid, which was recrystallized in hexane to provide CBDV (200 g) as pale brown colored solid. Structure of the product was confirmed by comparing with a reference standard of CBDV.

Example 3. Synthesis of cannabichromene (CBC) aldehyde (29)

[0098] CBC aldehyde was prepared as depicted in Scheme 12, step 1, according to the procedure described hereinbelow.

[0099] To a solution of citral ((CH ) ₂ -C=CH-(CH ₂ ) ₂ -C(CH )=CH-CHO; 0.54 gr, 3.6 mmol) in toluene (20 ml) was added piperidine (0.3 gr, 3.6 mmol). The solution was heated to 50- 55°C for 30 min. Then, the solution of olivetol aldehyde (0.5 gr, 2.4 mmol) in toluene (5 ml) was added and the reaction mixture was refluxed for overnight. The reaction mixture was quenched with water and extracted with ethyl acetate. The combined organic layers were washed with sat. NaCl, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure. The crude residue was purified using silica gel flash column chromatography (gradient eluent: 3- 5% EtOAc: hexane). The product was characterized by GC-MS, LC-MS and NMR analysis. (MS m/z: 343 (M+); GC-MS: 342).

[00100] In an alternative procedure, to solution of citral (0.32 ml, 1.85 mmol) and piperidine (0.40 ml, 4.07 mmol) in EtOAc (3.5 ml) was added dropwise Ac ₂ 0 (0.40 ml, 4.26 mmol) at 0°C. After addition, the flask was sealed and heated in a 90°C oil bath for 1 h. This iminium salt solution was then added to a solution of olivetol-aldehyde (0.57 gr, 2.75 mmol). The resulting mixture was stirred at 130°C for 2 days. Then, the reaction mixture was cooled to room temperature and quenched with sat. NaHC0 ₃ , and extracted with EtOAc. The combined organic phases were washed with sat. NaCl, dried over Na ₂ S0 ₄ , and concentrated under reduced pressure.

Example 4. Synthesis of cannabinol (CBN)

[00101] CBN was prepared directly from CBD as illustrated in Scheme 7.

[00102] In particular, CBD (1 gr, 3.18 mmol) was dissolved in 15 ml toluene. To this solution was added iodine (1.2 gr, 4.77 mmol), and then the reaction mixture was refluxed for 1 hr. 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).

APPENDIX

Scheme 1: Synthesis of CBD (procedure A)

Scheme 2: Synthesis of CBD (procedure B)

Scheme 3: Synthesis of A ⁹ -THC (procedure A)

Scheme 4: Synthesis of A ⁹ -THC (procedure B)

Scheme 5: Synthesis of HU-308 and analogs thereof

Scheme 6: Synthesis of desoxy A ⁹ -THC and analogs thereof

Scheme 7: Synthesis of CBDA, CBNA and CBN Scheme 8: Synthesis of THCA and THCVA acetylation and

oxidation (for CHO) mineral or or organic or hydrolysis (for OAc/CN) Lewis acid

Scheme 9: Synthesis of CBG and CBGA from olivetol aldehyde

CBGA

Scheme 10: Synthesis of CBG and CBGA from olivetol nitrile

CBGA Scheme 11: Synthesis of CBG and CBGA from olivetol aldehyde

CBGA

Scheme 12: Synthesis of CBC and CBCA from olivetol aldehyde

Scheme 13: Synthesis of olivetol acid and olivetol esters from olivetol aldehyde

Scheme 14: Synthesis of olivetol acid and olivetol esters from olivetol nitrile

Scheme 15: Synthesis of olivetol acid and olivetol esters from dimethoxy olivetol acid