SYNTHESIS OF CANNABIDIOL AND ANALOGS THEREOF, AND RELATED COMPOUNDS, FORMULATIONS, AND METHODS OF USE

1 . A method for synthesizing a compound having the structure of formula (AA)

wherein:

m is zero or 1;

n is zero, 1, or 2;

R 1 is selected from C 1 -C 12 hydrocarbyl, substituted C 1 -C 12 hydrocarbyl, heteroatom-containing C 1 -C 12 hydrocarbyl, and substituted heteroatom-containing C 1 -C 12 hydrocarbyl; and

R 2 is selected from C 1 -C 12 hydrocarbyl, substituted C 1 -C 12 hydrocarbyl, heteroatom-containing C 1 -C 12 hydrocarbyl, substituted heteroatom-containing C 1 -C 12 hydrocarbyl, and functional groups, and when n is 2, the R 2 may be the same or different, and any R 2 on adjacent carbon atoms may be linked to form a cyclic structure, the method comprising:

(a) reacting a compound having the structure of formula (AA-1)

with an electron-withdrawing hydroxyl-protecting reagent under conditions effective to provide a hydroxyl-protected intermediate having the structure of formula (AA-2)

in which PR represents an electron-withdrawing hydroxyl protecting group;

(b) effecting a cross-coupling reaction between the hydroxyl-protected intermediate (AA-2) and a reactant R 1 -M in the presence of a catalyst that facilitates the cross-coupling reaction, wherein M comprises a metallic element, to provide a compound having the structure of formula (AA-3)

(c) hydrolyzing the compound of (AA-3) to remove the hydroxyl protecting groups and provide a reaction product composition comprising compound (AA).

2 . The method of claim 1 , wherein the reactant is a Grignard reagent having the structure R 1 —MgBr.

3 . The method of claim 2 , wherein the catalyst is iron-based.

4 . The method of any one of claims 1-3 , wherein R 1 is selected from C 1 -C 18 alkyl, C 2 -C 18 alkenyl, and C 2 -C 18 alkynyl, substituted with zero to 3 functional groups selected from halo, hydroxyl, carboxyl, C 1 -C 8 alkoxy, C 2 -C 8 acyloxy, C 2 -C 8 alkoxycarbonyl, amino, mono-(C 1 -C 8 alkyl)-substituted amino, di-(C 1 -C 8 alkyl) substituted amino, C 2 -C 8 alkylamido, mono-(C 1 -C 8 alkyl)-substituted carbamoyl, di-(C 1 -C 8 alkyl)-substituted carbamoyl, and combinations thereof.

5 . The method of any one of claims 1-4 , wherein n is zero, m is 1, and compound (AA-1) is phloroglucinol.

6 . The method of claim 5 , wherein R 1 is n-pentyl, and compound (AA) comprises olivetol.

7 . The method of any one of claims 1-6 , wherein the hydroxyl-protected intermediate (AA-2) is not isolated or purified prior to the cross-coupling reaction of step (b).

8 . A method for synthesizing a cannabinoid, wherein the method comprises:

(a) synthesizing a compound having the structure of formula (AA) to serve as a first reactant, said synthesizing being conducted according to the method of claim 1 ;

(b) contacting (AA) with a second reactant having the structure of formula (CC-1)

wherein R 5 is H, carboxyl, C 2 -C 6 acyloxy, C 2 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted with hydroxyl, carboxyl, or halo; R 6 and R 7 are independently selected from C 1 -C 12 hydrocarbyl, substituted C 1 -C 12 hydrocarbyl, heteroatom-containing C 1 -C 12 hydrocarbyl, substituted heteroatom-containing C 1 -C 12 hydrocarbyl, and functional groups; R 7 is methyl, hydroxymethyl, or halomethyl;

and L is a leaving group, in the presence of a Lewis acid catalyst under reaction conditions effective to result in cross-coupling of reactants (AA) and (CC-1) and thereby provide a reaction product composition comprising a cannabidiol (CBD) analog having the structure of formula (CC)

9 . The method of claim 8 , wherein:

m is 1, n is zero, and (AA-1) is phloroglucinol;

R 5 and R 7 are methyl;

R 6 and R 7 are H,

so that the CBD analog in the reaction product composition has the structure of formula (CC-3)

9 . The method of claim 7 or claim 8 , wherein the reaction conditions comprise contacting the first reactant with the second reactant in a solvent at an elevated temperature in the presence anhydrous alumina and MgSO 4 .

10 . The method of claim 7, 8, or 9 , wherein the Lewis acid catalyst comprises BF 3 .

11 . The method of claim 7, 8, 9, or 10 , wherein R 1 is n-pentyl, and (CC-3) comprises CBD.

12 . The method of claim 7, 8, 9, or 10 , wherein R 1 is n-propyl.

13 . The method of claim 12 , further including subjecting (CC-3) to cyclization conditions, thereby providing a reaction product composition comprising tetrahydrocannabivarin.

14 . The method of any of claims 7 through 13 , wherein (AA) is not isolated or purified prior to step (b).

15 . The method of claim 11 , wherein the reaction product composition further comprises compounds (4) and (5)

16 . The method of claim 15 , wherein the mol ratio of CBD to (4) in the reaction product composition is at least 1:0.2 and the mol ratio of CBD to (5) is at least 1:0.10.

17 . The method of claim 11 , wherein the reaction product composition is free of THC as evaluated using 1 H NMR analysis.

18 . A CBD analog having the structure of formula (EE)

wherein:

q1 is zero or 1, and q2 is zero, 1, or 2;

R 11 is selected from C 1 -C 12 hydrocarbyl, substituted C 1 -C 12 hydrocarbyl, heteroatom-containing C 1 -C 12 hydrocarbyl, substituted heteroatom-containing C 1 -C 12 hydrocarbyl, and functional groups, and wherein when n is 2, the R 11 may be the same or different and any two R 11 bound to adjacent carbon atoms may be taken together to form a cyclic structure selected from a five-membered ring and a six-membered ring, optionally fused to an additional five-membered or six-membered ring, wherein the rings are aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and have zero to 4 non-hydrogen substituents and zero to 3 heteroatoms;

R 12 is H, carboxyl, C 2 -C 6 acyloxy, C 2 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted with hydroxyl, carboxyl, or halo;

R 13 and R 14 are independently selected from H, C 1 -C 12 hydrocarbyl, substituted C 1 -C 12 hydrocarbyl, heteroatom-containing C 1 -C 12 hydrocarbyl, substituted heteroatom-containing C 1 -C 12 hydrocarbyl, and functional groups;

R 15 is methyl, hydroxymethyl, or halomethyl; and

R 16 is C 1 -C 18 alkyl, C 2 -C 18 alkenyl, or C 2 -C 18 alkynyl, substituted with (a) —(CO)—NR 28 —R 29 wherein R 28 is H or C 1 -C 12 hydrocarbyl and R 29 is C 1 -C 12 hydrocarbyl, (b) —NR 30 —R 31 wherein R 30 is H or C 1 -C 12 hydrocarbyl and R 31 is C 6 -C 12 hydrocarbyl, C 1 -C 12 hydrocarbyl substituted with at least one functional group, C 1 -C 12 heterohydrocarbyl, or C 1 -C 12 heterohydrocarbyl substituted with at least one functional group, (c) —(SO 2 )—R 32 wherein R 32 is H or C 1 -C 12 heterohydrocarbyl, C 1 -C 12 hydrocarbyl substituted with at least one functional group, or C 1 -C 12 heterohydrocarbyl substituted with at least one functional group, (d) —(SO 2 )—NR 33 R 34 wherein R 33 is H or C 1 -C 12 hydrocarbyl and R 34 is H or C 1 -C 12 hydrocarbyl,

wherein L 1 is C 1 -C 6 alkyl, or wherein R 16 is C 1 -C 12 hydrocarbyloxy substituted with an additional C 1 -C 12 hydrocarbyloxy.

19 . The CBD analog of claim 18 , wherein:

q1 is 1, q2 is zero, and the two hydroxyl groups are located meta to R 16 , R 12 and R 15 are C 1 -C 6 alkyl, R 13 and R 14 are H, and R 16 is C 1 -C 12 alkyl or C 2 -C 12 alkyl substituted with:

(a) —(CO)—NR 28 —R 29 wherein R 28 is H or C 1 -C 8 alkyl and R 29 is C 1 -C 8 alkyl;

(b) —NR 30 R 31 wherein R 30 is H or C 1 -C 8 alkyl and R 31 is C 6 -C 12 alkyl, C 1 -C 8 alkyl substituted with at least one functional group, C 1 -C 8 heteroalkyl, or C 1 -C 8 heteroalkyl substituted with at least one functional group;

(c) —(SO 2 )—R 32 wherein R 32 is C 1 -C 8 heteroalkyl, C 1 -C 8 alkyl substituted with at least one functional group, or C 1 -C 8 heteroalkyl substituted with at least one functional group;

(d) —(SO 2 )—NR 33 R 34 wherein R 33 is H or C 1 -C 8 alkyl and R 34 is H or C 1 -C 8 alkyl, wherein the C 1 -C 8 alkyl groups are either substituted or unsubstituted;

20 . The CBD analog of claim 19 , wherein R 12 and R 15 are methyl, such that the compound has the structure of formula (EE-1)

21 . A cannabinol (CBN) analog having the structure of formula (FF)

wherein:

q3 is zero or 1, and q4 is zero, 1 or 2;

R 17 is selected from C 1 -C 12 hydrocarbyl, substituted C 1 -C 12 hydrocarbyl, heteroatom-containing C 1 -C 12 hydrocarbyl, substituted heteroatom-containing C 1 -C 12 hydrocarbyl, and functional groups, and wherein when n is 2, the R 17 may be the same or different and any two R 17 bound to adjacent carbon atoms may be taken together to form a cyclic structure selected from a five-membered ring and a six-membered ring, optionally fused to an additional five-membered or six-membered ring, wherein the rings are aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and have zero to 4 non-hydrogen substituents and zero to 3 heteroatoms;

R 18 is H, carboxyl, C 2 -C 6 acyloxy, C 2 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted with hydroxyl, carboxyl, or halo;

R 19 and R 20 are independently selected from H, C 1 -C 12 hydrocarbyl, substituted C 1 -C 12 hydrocarbyl, heteroatom-containing C 1 -C 12 hydrocarbyl, substituted heteroatom-containing C 1 -C 12 hydrocarbyl, and functional groups;

R 21 is methyl, hydroxymethyl, or halomethyl; and

R 22 is C 1 -C 18 alkyl, C 2 -C 18 alkenyl, or C 2 -C 18 alkynyl, substituted with (a) —(CO)—NR 35 —R 36 wherein R 35 is H or C 1 -C 12 hydrocarbyl and R 36 is C 1 -C 12 hydrocarbyl, (b) —NR 37 —R 38 wherein R 37 is H or C 1 -C 12 hydrocarbyl and R 38 is C 6 -C 12 hydrocarbyl, C 1 -C 12 hydrocarbyl substituted with at least one functional group, C 1 -C 12 heterohydrocarbyl, or C 1 -C 12 heterohydrocarbyl substituted with at least one functional group, (c) —(SO 2 )—R 39 wherein R 39 is H or C 1 -C 12 heterohydrocarbyl, C 1 -C 12 hydrocarbyl substituted with at least one functional group, or C 1 -C 12 heterohydrocarbyl substituted with at least one functional group, (d) —(SO 2 )—NR 40 R 41 wherein R 42 is H or C 1 -C 12 hydrocarbyl and R 43 is H or C 1 -C 12 hydrocarbyl,

wherein L 1 is C 1 -C 6 alkyl, or wherein R 22 is C 1 -C 12 hydrocarbyloxy substituted with an additional C 1 -C 12 hydrocarbyloxy.

22 . The CBN analog of claim 21 , wherein:

q3 and q4 are zero, and the hydroxyl group is located meta to R 22 ;

R 18 and R 21 are C 1 -C 6 alkyl, R 19 and R 20 are H, and R 22 is C 1 -C 12 alkyl or C 2 -C 12 alkenyl substituted with:

(a) —(CO)—NR 35 R 36 wherein R 35 is H or C 1 -C 8 alkyl and R 36 is C 1 -C 8 alkyl;

(b) —NR 37 R 38 wherein R 37 is H or C 1 -C 8 alkyl and R 38 is C 6 -C 12 alkyl, C 1 -C 8 alkyl substituted with at least one functional group, C 1 -C 8 heteroalkyl, or C 1 -C 8 heteroalkyl substituted with at least one functional group;

(c) —(SO 2 )—R 39 wherein R 39 is C 1 -C 8 heteroalkyl, C 1 -C 8 alkyl substituted with at least one functional group, or C 1 -C 8 heteroalkyl substituted with at least one functional group;

(d) —(SO 2 )—NR 40 R 41 wherein R 40 is H or C 1 -C 8 alkyl and R 41 is H or C 1 -C 8 alkyl, wherein the C 1 -C 8 alkyl groups are either substituted or unsubstituted;

24 . The CBN analog of claim 23 , wherein R 18 and R 21 are methyl, such that the compound has the structure of formula (FF-1)

25 . A cannabichromene (CBC) analog having the structure of formula (GG)

wherein:

q5 is zero or 1, q6 is zero 1, or 2, and the sum of q5 and q6 does not exceed 2;

R 23 is selected from C 1 -C 12 hydrocarbyl, substituted C 1 -C 12 hydrocarbyl, heteroatom-containing C 1 -C 12 hydrocarbyl, substituted heteroatom-containing C 1 -C 12 hydrocarbyl, and functional groups, and wherein when n is 2, the R 23 may be the same or different and any two R 23 bound to adjacent carbon atoms may be taken together to form a cyclic structure selected from a five-membered ring and a six-membered ring, optionally fused to an additional five-membered or six-membered ring, wherein the rings are aromatic, alicyclic, heteroaromatic, or heteroalicyclic, and have zero to 4 non-hydrogen substituents and zero to 3 heteroatoms;

R 24 is H, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted with hydroxyl, carboxyl, or halo;

R 25 is H, C 1 -C 12 hydrocarbyl, substituted C 1 -C 12 hydrocarbyl, heteroatom-containing C 1 -C 12 hydrocarbyl, substituted heteroatom-containing C 1 -C 12 hydrocarbyl, or a functional group;

R 26 is methyl, hydroxymethyl, or halomethyl; and

R 27 is C 1 -C 18 alkyl or C 2 -C 18 alkenyl substituted with (a) —(CO)—NR 42 R 43 wherein R 42 is H or C 1 -C 12 hydrocarbyl and R 43 is C 1 -C 12 hydrocarbyl, (b) —NR 44 R 45 wherein R 44 is H or C 1 -C 12 hydrocarbyl and R 45 is C 6 -C 12 hydrocarbyl, C 1 -C 12 hydrocarbyl substituted with at least one functional group, C 1 -C 12 heterohydrocarbyl, or C 1 -C 12 heterohydrocarbyl substituted with at least one functional group, (c) —(SO 2 )—R 46 wherein R 46 is H or C 1 -C 12 heterohydrocarbyl, C 1 -C 12 hydrocarbyl substituted with at least one functional group, or C 1 -C 12 heterohydrocarbyl substituted with at least one functional group, (d), —(SO 2 )—NR 47 R 48 wherein R 47 is H or C 1 -C 12 hydrocarbyl and R 48 is H or C 1 -C 12 hydrocarbyl,

wherein L 1 is C 1 -C 6 alkyl, or wherein R 27 is C 1 -C 12 hydrocarbyloxy substituted with an additional C 1 -C 12 hydrocarbyloxy.

26 . The CBC analog of claim 25 , wherein:

q5 and q6 are zero and the remaining hydroxyl group is located meta to R 27 , R 24 and R 25 are H, R 26 is C 1 -C 6 alkyl, and R 27 is C 2 -C 12 alkyl substituted with:

(a) —(CO)—NR 42 R 43 wherein R 28 is H or C 1 -C 8 alkyl and R 43 is C 1 -C 8 alkyl;

(b) —NR 44 R 45 wherein R 44 is H or C 1 -C 8 alkyl and R 45 is C 6 -C 12 alkyl, C 1 -C 8 alkyl substituted with at least one functional group, C 1 -C 8 heteroalkyl, or C 1 -C 8 heteroalkyl substituted with at least one functional group;

(c) —(SO 2 )—R 46 wherein R 46 is C 1 -C 8 heteroalkyl, C 1 -C 8 alkyl substituted with at least one functional group, or C 1 -C 8 heteroalkyl substituted with at least one functional group;

(d) —(SO 2 )—NR 47 R 48 wherein R 47 is H or C 1 -C 8 alkyl and R 48 is H or C 1 -C 8 alkyl, wherein the C 1 -C 8 alkyl groups are either substituted or unsubstituted;

27 . The CBC analog of claim 26 , wherein R 26 is methyl and the compound has the structure of formula (GG-1)

28 . A tetrahydrocannabivarin (THCV) analog having the structure of formula (HH)

wherein:

q7 is zero or 1;

R 53 is selected from C 1 -C 12 hydrocarbyl, substituted C 1 -C 12 hydrocarbyl, heteroatom-containing C 1 -C 12 hydrocarbyl, substituted heteroatom-containing C 1 -C 12 hydrocarbyl, and functional groups;

R 49 is H, carboxyl, C 2 -C 6 acyloxy, C 2 -C 6 alkoxycarbonyl, C 1 -C 6 alkyl, or C 1 -C 6 alkyl substituted with hydroxyl, carboxyl, or halo;

R 50 and R 51 are independently selected from H, C 1 -C 12 hydrocarbyl, substituted C 1 -C 12 hydrocarbyl, heteroatom-containing C 1 -C 12 hydrocarbyl, substituted heteroatom-containing C 1 -C 12 hydrocarbyl, and functional groups;

R 52 is methyl, hydroxymethyl, or halomethyl; and

R 54 is C 1 -C 18 alkyl, C 2 -C 18 alkenyl, or C 2 -C 18 alkynyl, substituted with (a) —(CO)—NR 5 R 56 wherein R 55 is H or C 1 -C 12 hydrocarbyl and R 16 is C 1 -C 12 hydrocarbyl, (b) —NR 57 R 58 wherein R 57 is H or C 1 -C 12 hydrocarbyl and R 58 is C 6 -C 12 hydrocarbyl, C 1 -C 12 hydrocarbyl substituted with at least one functional group, C 1 -C 12 heterohydrocarbyl, or C 1 -C 12 heterohydrocarbyl substituted with at least one functional group, (c) —(SO 2 )—R 59 wherein R 59 is H or C 1 -C 12 heterohydrocarbyl, C 1 -C 12 hydrocarbyl substituted with at least one functional group, or C 1 -C 12 heterohydrocarbyl substituted with at least one functional group, (d) —(SO 2 )—NR 60 R 61 wherein R 60 is H or C 1 -C 12 hydrocarbyl and R 61 is H or C 1 -C 12 hydrocarbyl,

wherein L 1 is C 1 -C 6 alkyl, or wherein R 16 is C 1 -C 12 hydrocarbyloxy substituted with C 1 -C 12 hydrocarbyloxy.

29 . A pharmaceutical formulation comprising an effective amount of a compound of any one of claims 18 through 28 , in combination with a pharmaceutical excipient.

30 . A method for treating a subject affected by a condition, disorder, or disease responsive to administration of a cannabinoid, comprising administering to the subject, optionally within the context of an ongoing dosage regimen, an effective amount of the compound of any one of claims 18 through 28 .

31 . The method of claim 30 , wherein the compound is in a pharmaceutical formulation additionally comprising an excipient.