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

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 Formula (IV) is the abnormal-CBD, having the formula (V′);

18. The process according to claim 3 , wherein the compound of Formula (IA) is the compound of Formula (IV-H 2 );

19. The process according to claim 18 , where R 3 is X 2 R K .

20. The process according to claim 18 , wherein R 3 is alkyl.

21. The process according to claim 18 , wherein the compound of formula (IV-H 2 ) is hydrogenated CBD (H 2 CBD) having formula (V-H 2 );

22. The process according to claim 18 , wherein the compound of formula (IV-H 2 ) is abnormal hydrogenated CBD (Abnormal H 2 CBD) having formula (V′-H 2 );

23. The process according to claim 1 , wherein the compound of Formula (IIA) is olivetol having the structure of Formula (VI), or olivetolic acid having the structure of Formula (VII):

24. The process according to claim 2 , wherein the compound of Formula (IIIB) is the compound having the structure (VIII)

25. The process according to claim 24 , wherein the compound of Formula (VIII) is (+)-p-mentha-2,8-dien-1-ol having the structure of Formula (IX),

26. The process according to claim 2 , wherein the compound of Formula (IIC) is α-phellandrene having the structure of Formula (XII);

27. The process according to claim 24 , wherein the compound of Formula (XII) is 2-methyl-5-isopropenyl-1,3-cyclohexadiene having the structure of Formula (XIII);

28. A plurality of processes according to claim 1 , wherein said processes operate in parallel with the process outputs collected synchronously.

29. An automated, scalable, continuous flow reactor system for preparation of CBD or derivative thereof, the system comprising: one or more modular flow chemistry assembly lines; each assembly line comprising (1) controlled input from one or more source pumps for reagents; (2) at least one packed bed reactor (PBR); (3) optionally, at least one heated reactor incorporating one or more membrane separators for waste CO 2 ; (4) optionally, at least one back pressure regulator; (5) optionally, at least one auxiliary pump; (6) optionally, at least one membrane separator for waste water; and (7) one or more collection tanks for the CBD or derivative thereof.

30. The system according to claim 29 , wherein the at least one packed bed reactor comprises an acid selected from the group consisting of large- and medium-pore zeolites, aluminosilicates, sulfonated tetrafluoroethylene fluoropolymer-copolymer, sulfated zirconia, silica gel, polyaniline sulfate, graphene oxide (GO), carboxylic acid functionalized GO (GO-CO 2 H), polymer-supported boronic acids, heteropolyacids, tungstated zirconia, heterogeneous sulfonic acids, supported AlCl 3 , supported SnCl 4 , supported TiCl 4 , protic acids on solid supports, a sulfonic acid-substituted calix[x]arene derivative, β-cyclodextrin, and β-cyclodextrin-derivatives.