Synthesis of cannabinoids and cannabinoid precursors, and related compounds, formulations, and methods of use
Methods are provided for the synthesis of cannabinoids, including cannabidiol (CBD), cannabinol (CBN), cannabichromene (CBC), cannabidiolic acid (CBDA), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabidivarin (CBDV), cannabidibutol (CBD-C4), dihydrocannabidiol (DCBD), tetrahydrocannabivarin (THCV), analogs thereof, and precursors to the foregoing. One method employs phloroglucinol or a phloroglucinol analog as a starting material. The syntheses are stereospecific, efficient, selective, and cost-effective, with little or no potential for generation of THC ((−)-trans-Δ 9 -tetrahydro-cannabinol) or any other psychoactive side product. Telescoped syntheses are also provided, as are new cannabinoids, pharmaceutical formulations, and methods of use.
1. A method for synthesizing a cannabinoid, wherein the method comprises:
(a) reacting an optionally substituted phloroglucinol reactant having the structure
with an electron-withdrawing hydroxyl-protecting reagent under conditions effective to provide a first intermediate comprising a hydroxyl-protected compound having the structure
wherein n is zero, 1 or 2; R 2 is selected from C 1 -C 12 alkyl, C 1 -C 12 alkoxy, C 2 -C 12 alkoxyalkyl, C 1 -C 12 alkylsulfanyl, C 2 -C 12 acyl, C 2 -C 12 acyloxy, C 2 -C 12 alkoxycarbonyl, C 6 -C 18 aryloxycarbonyl, carboxyl, and halo; and PR is a hydroxyl-protecting group;
(b) effecting a cross-coupling reaction between the first intermediate and a reactant R 1 -M in a solvent in the presence of a cross-coupling catalyst, wherein:
R 1 is selected from C 1 -C 12 alkyl; (C 1 -C 8 alkoxy)-substituted C 1 -C 12 alkyl; C 1 -C 12 alkyl substituted with N (C 1 -C 8 alkyl) 2 ; C 1 -C 12 alkyl substituted with C 1 -C 8 alkylsulfonyl (—SO 2 -alkyl); and C 1 -C 12 alkyl substituted with oxanyl, morpholino, or diazinanyl, and
M is selected from —Zn—X, —B(OH) 2 , —B(OR) 2 , —MgX and —CuLi in which X is halo and R is alkyl, thereby providing a second intermediate in which a protected hydroxyl group has been replaced with R 1 , the second intermediate having the structure
(c) hydrolyzing the second intermediate to remove the hydroxyl-protecting groups, thereby providing an R 1 -substituted deprotected compound as a third intermediate having the
(d) contacting the R 1 -substituted deprotected compound with a substituted cyclohexene reactant having the structure
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 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 coupling of the R 1 -substituted deprotected intermediate and the substituted cyclohexene reactant to provide a reaction product composition comprising a cannabinoid having the structure
2. The method of claim 1 , wherein R 1 -M is R 1 —MgBr, the cross-coupling catalyst is an iron-based catalyst, and the cross-coupling reaction is a Fürstner reaction carried out at a reaction temperature in the range of −25° C. to 25° C.
3. The method of claim 2 , wherein about 1 equivalent to about 1.5 equivalents of R 1 —MgBr are used and the reaction temperature in the range of −15° C. to −5° C.
4. The method of claim 1 , wherein the first intermediate is not isolated or purified prior to the cross-coupling reaction of step (b).
5. The method of claim 1 , wherein the third intermediate is not isolated or purified prior to step (d).
6. The method of claim 1 , wherein R 5 and R 8 are methyl, so that the cannabinoid in the reaction product composition has the structure
7. The method of claim 6 , wherein n is zero.
8. The method of claim 7 , wherein R 1 is n-pentyl, such that the R 1 -substituted deprotected compound is olivetol and the cannabinoid is cannabidiol (CBD).
9. The method of claim 7 , wherein R 1 is n-propyl, such that the R 1 -substituted deprotected compound is divarinol.
10. The method of claim 8 , wherein R 1 is n-pentyl and the method further comprises subjecting the cannabinoid to cyclization conditions.
11. The method of claim 6 , wherein the electron-withdrawing hydroxyl-protecting reagent converts hydroxyl groups to sulfonate esters.
12. The method of claim 11 , wherein the sulfonate esters are selected from tosylate, mesylate, triflate, benzyl sulfonate, 2-[(4-nitrophenyl) ethyl] sulfonate, and fluorosulfonate.