One-step flow-mediated synthesis of cannabidiol (CBD) and derivatives

Patent metadata

Field	Value
Publication number	US-10981850-B2
Application number	US-202016848215-A
Country	US
Kind code	B2
Filing date	Apr 14, 2020
Priority date	Apr 15, 2019
Publication date	Apr 20, 2021
Grant date	Apr 20, 2021

Abstract

Herein are described apparatus and processes for the preparation of cannabinoids, such as cannabidiol (CBD) and derivatives thereof. The apparatus and processes described can be used for the one-step, flow-mediated synthesis of cannabidiol and derivatives with improved overall yield, material throughput, and product purity relative to batch processes.

First claim

What is claimed is:

1. A process for the preparation of a cannabidiol (CBD) or a derivative thereof, the process comprising:
(a) providing a solution comprising of a first compound that is a 1,3-diene, an allylic alcohol or an allylic ether and a second compound of Formula (IIA) or (IIB) into a packed-bed reactor (PBR) comprising a solid or heterogeneous catalyst;
(b) circulating the first and second compound through the PBR to react the first compound with the second compound;
(c) collecting from the PBR a solution comprising the CBD or a derivative thereof;
wherein the structures of (IIA) and (IIB) are:

wherein: Z 1 is CR 2 or N;
Z 2 is CR 4 or N;
wherein R 1 , R 3 , R 5 , are each independently selected from the group consisting of H, OH, —CO 2 H, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, heterocycle, —X 2 R K , or halides,
wherein R 2 , and R 4 , are each independently selected from the group consisting of H, OH, —CO 2 H, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, heterocycle, —X 2 R K and not selected from halides,
wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, alkyl, O-alkyl, —NR A R B , —S-alkyl, —SO-alkyl, —SO 2 -alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocycle; and the alkenyl, alkynyl, or acyl group optionally includes —O—, —S—, —SO 2 —, —N(R G )— substituting one or more carbons in the carbon chain,
wherein the aryl or heteroaryl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, alkyl, O-alkyl, —COOH, —C(O)—C 1-4 alkyl, —C(O)O—C 1-4 alkyl, —NR C R D , —S-alkyl, —SO-alkyl and —SO 2 -alkyl;
wherein X 1 is selected from —O—, —S—, —SO 2 —, —N(R E )—;
wherein X 2 is selected from —O—, —S—, —SO 2 —, —N(R F )—;
wherein R A , R B , R C , R D , R E , R F , R K R G are each independently selected from hydrogen and C 1-4 alkyl;
or a pharmaceutically acceptable salt or ester thereof.

2. The process according to claim 1 , wherein the first compound has a structure selected from the group consisting of:

wherein R 6 , R 7 , R 8 , R 9 , R 10 and R 11 are each independently selected from the group consisting of H, OH, —CO 2 H, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, heterocycle, —X 2 R K , or halides,
wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, alkyl, O-alkyl, —NR A R B , —S-alkyl, —SO-alkyl, —SO 2 -alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocycle; and the alkenyl, alkynyl, or acyl group optionally includes —O—, —S—, —SO 2 —, —N(R G )— substituting one or more carbons in the carbon chain,
wherein the aryl or heteroaryl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, alkyl, O-alkyl, —COOH, —C(O)—C 1-4 alkyl, —C(O)O—C 1-4 alkyl, —NR C R D , —S-alkyl, —SO-alkyl and —SO 2 -alkyl;
wherein X 1 is selected from —O—, —S—, —SO 2 —, —N(R E )—;
wherein X 2 is selected from —O—, —S—, —SO 2 —, —N(R F )—;
wherein is absent or a C 1-3 alkylene linker, which links the carbon bonded to R 9 and the carbon bonded to R 10 ;
wherein R A , R B , R C , R D , R E , R F , R K , and R G are each independently selected from hydrogen and C 1-4 alkyl;
or a pharmaceutically acceptable salt or ester thereof.

3. The process of claim 1 , wherein the CBD or the derivative thereof has a structure selected from the group consisting of:

wherein R 6 , R 7 , R 8 , R 9 , and R 10 are each independently selected from the group consisting of H, OH, —CO 2 H, protected hydroxyl, alkyl, alkenyl, alkynyl, acyl, aryl, heteroaryl, cycloalkyl, heterocycle, —X 2 R K , or halides,
wherein the alkyl, alkenyl, alkynyl or acyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, —OH, alkyl, O— alkyl, —NR A R B , —S-alkyl, —SO-alkyl, —SO 2 -alkyl, alkenyl, alkynyl, aryl, heteroaryl, cycloalkyl or heterocycle;
wherein the aryl or heteroaryl, whether alone or as part of a substituent group, is optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, alkyl, O-alkyl, —COOH, —C(O)—C 1-4 alkyl, —C(O)O—C 1-4 alkyl, —NR C R D , —S-alkyl, —SO-alkyl and —SO 2 -alkyl;
wherein X 1 is selected from —O—, —S—, —SO 2 —, —N(R E )—;
wherein X 2 is selected from —O—, —S—, —SO 2 —, —N(R F )—;
wherein is absent or a C 1-3 alkylene linker, which links the carbon bonded to R 9 and the carbon bonded to R 10 ;
wherein R A , R B , R C , R D , R E , R F and R K are each independently selected from hydrogen and C 1-4 alkyl.

4. The process according to claim 1 , wherein the second compound is (IIA) and Z 1 is CR 2 or the second compound is (IIB), and R 2 in (IIA) and (IIB) is —CO 2 H, and wherein the process further comprises a decarboxylation step.

5. The process according to claim 4 , wherein the decarboxylation step comprises continuous flow thermolysis.

6. The process according to claim 1 , further comprising diluting the solution comprising CBD or the derivative thereof.

7. The process according to claim 6 , wherein said diluting produces a two phase solution, having a first and second phase, wherein the first phase has a higher concentration of CBD or the derivative thereof.

8. The process according to claim 7 , further comprising separating the first phase from the second phase.

9. The process according to claim 8 , wherein said separating comprises a membrane separation step.

10. The process according to claim 1 , further comprising separating CBD or the derivative thereof from the solution comprising the CBD or derivative thereof.

11. The process according to claim 10 , wherein separating comprises a membrane separation step.

12. The process according to claim 1 , further comprising isolating the CBD or derivative thereof using a method selected from crystallization, concentration, distillation, drying, spray drying, precipitation, chromatographic separation, extraction, filtering or combinations thereof.

13. The process according to claim 3 , wherein the compound of Formula (IA) is the compound of Formula (IV)

14. The process according to claim 13 , wherein R 3 is X 2 R K .

15. The process according to claim 13 , wherein R 3 is alkyl.

16. The process according to claim 13 , wherein the compound of Formula (IV) is (−)-cannabidiol (CBD) having the Formula (V)

17. The process according to claim 16 , wherein the compound of Formul

Assignees

• Univ Boston

Inventors

• Porco John A
• Beeler Aaron B
• Brown Lauren E
• Trilles Richard V

Classifications

• B01J8/067

  Heating or cooling the reactor (B01J8/062 takes precedence) · CPC title

• B01J2208/00893

  Feeding means for the reactants · CPC title

• B01J2208/00141

  Coils · CPC title

• B01J2208/00539

  Pressure · CPC title

• B01J2208/00017

  Controlling the temperature · CPC title