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

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

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)

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

(d) 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 8 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 cannabinoid having the structure of formula (CC)

.

2 . The method of claim 1 , wherein:

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

R 5 and R 8 are methyl; and

R 6 and R 7 are H,

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

.

3 . The method of claim 1 , 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 .

4 . The method of claim 1 , wherein the Lewis acid catalyst comprises BF 3 .

5 . The method of claim 1 , wherein R 1 is n-pentyl, and (CC-3) comprises CBD.

6 . The method of claim 1 , wherein R 1 is n-propyl.

7 . The method of claim 6 , further including subjecting (CC-3) to cyclization conditions, thereby providing a reaction product composition comprising tetrahydrocannabivarin.

8 . The method of claim 1 , wherein (AA) is not isolated or purified prior to step (d).

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

10 . A cannabinoid having the structure of formula (EE)

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.

11 . The cannabinoid of claim 10 , 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 6 alkyl substituted with at least one functional group, C 1 -C 6 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 6 alkyl substituted with at least one functional group, or C 1 -C 6 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;

.

12 . The cannabinoid of claim 11 , wherein R 12 and R 15 are methyl, such that the compound has the structure of formula (EE-1)

.

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

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.

14 . The CBN analog of claim 13 , 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 6 alkyl substituted with at least one functional group, C 1 -C 6 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 6 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;

.

15 . The CBN analog of claim 13 , wherein R 18 and R 21 are methyl, such that the compound has the structure of formula (FF-1)

.

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

wherein:

q5 is zero or 1, q6 is zero1, 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 n3on-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.

17 . A pharmaceutical formulation comprising an effective amount of the compound of claim 10 in combination with a pharmaceutical excipient.

18 . 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 claim 10 .

19 . The method of claim 18 , wherein the compound is in a pharmaceutical formulation additionally comprising an excipient.