# US 2021/0276936 A1 · Synthesis of Cannabigerol

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- Number: US 2021/0276936 A1
- Document ID: US20210276936A1
- Status: Published application
- Kind: A1
- Application number: 17/324,419
- Filed: 2021-05-19
- Published: 2021-09-09
- Earliest claimed: 2018-10-10
- Assignees: c/o Treehouse Biotech, Inc.
- Applicants: c/o Treehouse Biotech, Inc.
- Inventors: Thomas Smeltzer; Robert Davis; Sean Colvin; Jacob Black
- Web page: https://patentgrep.com/patent/US20210276936A1

## CPC

- C07C 39/19: containing carbon-to-carbon double bonds but no carbon-to-carbon triple bonds
- C07C 43/215: having unsaturation outside the six-membered aromatic rings
- B01J 21/16: Clays or other mineral silicates
- B01J 27/053: Sulfates
- B01J 27/055: with alkali metals, copper, gold or silver
- B01J 27/08: Halides
- B01J 27/10: Chlorides
- B01J 27/12: Fluorides
- B01J 27/128: with iron group metals or platinum group metals
- B01J 27/138: with alkaline earth metals, magnesium, beryllium, zinc, cadmium or mercury
- B01J 27/232: Carbonates
- B01J 27/25: Nitrates
- B01J 31/0225: {comprising sulfonic acid groups or the corresponding salts}
- C07C 37/055: the substituted group being bound to oxygen, e.g. ether group
- C07C 37/11: by reactions increasing the number of carbon atoms
- C07C 37/16: by condensation involving hydroxy groups of phenols or alcohols or the ether or mineral ester group derived therefrom
- C07C 37/18: by condensation involving halogen atoms of halogenated compounds
- C07C 37/685: {Processes comprising at least two steps in series}
- C07C 41/30: by increasing the number of carbon atoms, e.g. by oligomerisation
- C07C 43/285: having unsaturation outside the six-membered aromatic rings
- C07F 7/081: {comprising at least one atom selected from the elements N, O, halogen, S, Se or Te}
- C07F 7/1804: {Compounds having Si-O-C linkages (Si-O-acyl linkages C07F7/1896)}
- B01J 31/1805: {the ligands containing nitrogen}
- B01J 31/2404: {Cyclic ligands, including e.g. non-condensed polycyclic ligands, the phosphine-P atom being a ring member or a substituent on the ring}
- B01J 2231/4205: C-C cross-coupling, e.g. metal catalyzed or Friedel-Crafts type
- B01J 2531/824: Palladium
- C07C: ACYCLIC OR CARBOCYCLIC COMPOUNDS
- B01J: CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- C07F: ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM (metal-containing porphyrins C07D487/22)

## 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.

## Claims

### Claim 1

A compound having the formula:

### Claim 2

A compound having the formula:

### Claim 3

A compound having the formula:

### Claim 4

A compound having the formula:

### Claim 5

A compound having the formula:

### Claim 6

A compound having the formula:

### Claim 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.

### Claim 8 (depends on 7)

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.

### Claim 9 (depends on 7)

The method of claim 7, wherein the acidic catalyst is pTSA.

### Claim 10 (depends on 7)

The method of claim 7, wherein the acidic catalyst is one of CSA, MsOH, FeCl3, or AcCl.

### Claim 11 (depends on 7)

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.

### Claim 12 (depends on 11)

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%.

### Claim 13 (depends on 12)

The method of claim 12, wherein the period of time is no greater than about 1.5 hours.

### Claim 14 (depends on 7)

The method of claim 7, wherein the olivetol and the geraniol is added in a molar ratio of about 1:1.

### Claim 15 (depends on 7)

The method of claim 7, further comprising:
separating CBG from the reactant solution using at least one separation technique.

### Claim 16 (depends on 15)

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.

### Claim 17 (depends on 16)

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.

### Claim 18 (depends on 16)

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.

### Claim 19 (depends on 16)

The method of claim 16, wherein the desiccant is magnesium sulfate.

### Claim 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 R1 and R2 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.

### Claim 21 (depends on 20)

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.

### Claim 22 (depends on 20)

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)).

### Claim 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 R1 and R2 each are selected from the group consisting of: SEM, MOM, Me, Bn, TBS, and hydrogen,
wherein Z2 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.

### Claim 24 (depends on 22)

The method of claim 22, wherein the solvent is selected from the group consisting of: N,N-dimethylacetamide, toluene, 1-butanol, and tetrahydrofuran.

### Claim 25 (depends on 23)

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)).