Synthesis of Cannabigerol

Abstract

Multiple methods of synthesizing cannabigerol are presented. Combining olivetol with geraniol derivatives are provided. Cross-coupling methods of combing functionalized resorcinols are provided. Useful intermediates are formed during such cross-coupling steps.

What is claimed: 
     
         1 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         2 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         3 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         4 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         5 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         6 . A compound having the formula: 
       
         
           
           
               
               
           
         
       
     
     
         7 . A method of making CBG, the method comprising:
 providing a solvent;   adding olivetol to the solvent;   adding geraniol-derivative to the solvent, wherein the generiol-derivative has the formula:   
       
         
           
           
               
               
           
         
       
       where X is OH or bromide;
 and adding an acidic catalyst to the solvent to form a solution; 
 reacting the solution to form a reactant solution comprising CBG. 
 
     
     
         8 . The method of  claim 7 , wherein the solvent is at least one of methyl tert-butyl ether (“MTBE”), acetonitrile, toluene, ethanol, heptane, hexane, pentane, acetone, ethyl acetate, butyl acetate, isobutyl acetate, t-butyl acetate, tetrahydrofuran, 2-methyl tetrahydrofuran, tetrahydrofuran, 1,4-dioxane, chloroform, or dichloromethane. 
     
     
         9 . The method of  claim 7 , wherein the acidic catalyst is pTSA. 
     
     
         10 . The method of  claim 7 , wherein the acidic catalyst is one of CSA, MsOH, FeCl 3 , or AcCl. 
     
     
         11 . The method of  claim 7 , wherein reacting the solution comprises reacting the solution at a temperature for a period of time between about 20 minutes and 24 hours. 
     
     
         12 . The method of  claim 11 , wherein the temperature is between about 55° C. and 100° C., and the percent of conversion of olivetol to CBG is at least about 45%. 
     
     
         13 . The method of  claim 12 , wherein the period of time is no greater than about 1.5 hours. 
     
     
         14 . The method of  claim 7 , wherein the olivetol and the geraniol is added in a molar ratio of about 1:1. 
     
     
         15 . The method of  claim 7 , further comprising:
 separating CBG from the reactant solution using at least one separation technique.   
     
     
         16 . The method of  claim 15 , wherein the separation technique comprises a method having the steps of:
 neutralizing the reactant solution and adding a desiccant to form a neutralized solution;   filtering the neutralized solution and evaporating the solvent to form a concentrated oil;   adding lipophilic solvent to the concentrated oil to form a reactant oil; and   precipitating CBG.   
     
     
         17 . The method of  claim 16 , wherein precipitating the CBG comprises reducing the temperature of the reactant oil to about negative twenty degrees Celsius or less. 
     
     
         18 . The method of  claim 16 , wherein the lipophilic solvent is selected from the group consisting of: benzene, heptane, acetic acid, acetone, isobutyl acetate, anisole, isopropyl acetate, 1-butanol, methyl acetate, 2-butanol, 3-methyl-1-butanol, butyl acetate, methylethylketone, tert-butylmethyl ether, methylisobutylketone, cumene, 2-methyl-1-propanol, dimethyl sulfoxide, pentane, ethanol, 1-pentanol, ethyl acetate, 1-propanol, ethyl ether, 2-propanol, ethyl formate, propyl acetate, and mixtures thereof. 
     
     
         19 . The method of  claim 16 , wherein the desiccant is magnesium sulfate. 
     
     
         20 . A method comprising:
 providing a first compound having the structure   
       
         
           
           
               
               
           
         
         combining the first compound with a second compound having the structure: 
       
       
         
           
           
               
               
           
         
       
       in a solvent to form a solution;
 adding a catalyst to the solution to form an active mixture; and reacting the active mixture to form a reacting mixture, wherein the reacting mixture contains a detectable amount of a third compound having the structure: 
 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  each are selected from the group consisting of: SEM, MOM, Me, Bn, TBS, and hydrogen; 
         wherein Z is selected from the group consisting of: boronate group, boronic acid, iodide, and bromide; and 
         wherein Y is selected from the group consisting of: iodide, bromide, Bpin, a boronate group and boronic acid group. 
       
     
     
         21 . The method of  claim 20 , wherein the solvent is selected from the group consisting of: N,N-dimethylacetamide, toluene, 1-butanol, tetrahydrofuran, and mixtures thereof. 
     
     
         22 . The method of  claim 20 , wherein the catalyst is selected from the group consisting of: XPhos-Pd-G3 ((2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate); SPhos-Pd-G2 (Chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)); cataCXium-A-Pd-G3-(Mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II)); APhos-Pd-G3 ([4-(Di-tert-butylphosphino)-N,N-dimethylaniline-2-(2′-aminobiphenyl)]palladium(II) methanesulfonate); P(Cy)3-Pd-G3 ([(Tricyclohexylphosphine)-2-(2′-aminobiphenyl)]palladium(II) methanesulfonate); PEPPSI-IPent (Dichloro[1,3-bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)); and Pd(PPh3) 4  (Palladium-tetrakis(triphenylphosphine)). 
     
     
         23 . A method comprising:
 providing a first compound having the structure   
       
         
           
           
               
               
           
         
         combining the first compound with a second compound having the structure: 
       
       
         
           
           
               
               
           
         
       
       in a solvent to form a solution;
 adding a catalyst to the solution to form an active mixture; and reacting the active mixture to form a reacting mixture, wherein the reacting mixture contains a detectable amount of a third compound having the structure: 
 
       
         
           
           
               
               
           
         
         wherein R 1  and R 2  each are selected from the group consisting of: SEM, MOM, Me, Bn, TBS, and hydrogen, 
         wherein Z 2  is selected from the group consisting of: boronate group, boronic acid, iodide, bromide; and 
         wherein Y is selected from the group consisting of: iodide, bromide, Bpin, a boronate group and boronic acid group. 
       
     
     
         24 . The method of  claim 22 , wherein the solvent is selected from the group consisting of: N,N-dimethylacetamide, toluene, 1-butanol, and tetrahydrofuran. 
     
     
         25 . The method of  claim 23 , wherein the catalyst is selected from the group consisting of: XPhos-Pd-G3 ((2-Dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) methanesulfonate); SPhos-Pd-G2 (Chloro(2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)); cataCXium-A-Pd-G3-(Mesylate[(di(1-adamantyl)-n-butylphosphine)-2-(2′-amino-1,1′-biphenyl)]palladium(II)); APhos-Pd-G3 ([4-(Di-tert-butylphosphino)-N,N-dimethylaniline-2-(2′-aminobiphenyl)]palladium(II) methanesulfonate); P(Cy)3-Pd-G3 ([(Tricyclohexylphosphine)-2-(2′-aminobiphenyl)]palladium(II) methanesulfonate); PEPPSI-IPent (Dichloro[1,3-bis(2,6-Di-3-pentylphenyl)imidazol-2-ylidene](3-chloropyridyl)palladium(II)); and Pd(PPh3) 4  (Palladium-tetrakis(triphenylphosphine)).