CONVERSION OF THC, CBD AND THEIR DERIVATIVES TO CANNABINOL

Abstract

In a method for aromatizing an alicyclic region of a cannabinoid, especially in enantiopure, scalemic and/or racemic form, in particular for aromatizing the cyclohexene group in Δ.sup.9-THC-C.sub.5, Δ.sup.9-THCA-C.sub.5 A, Δ.sup.9-THCV-C.sub.3, Δ.sup.9-THCVA-C.sub.5 A, and/or scalemic or racemic mixtures of these substances, wherein an oxidizing agent is added to the cannabinoid, sulfur is used as the oxidizing agent.

Claims

1-12. (canceled)

13. Method for aromatizing an alicyclic region of a cannabinoid, wherein an oxidizing agent is added to the cannabinoid, wherein sulfur is used as the oxidizing agent.

14. Method according to claim 13, wherein the cannabinoid is present in enantiopure, scalemic and/or racemic form.

15. Method according to claim 13, wherein the alicyclic region of the cannabinoid is the cyclohexene group in Δ.sup.9-THC-C.sub.5, Δ.sup.9-THCA-C.sub.5 A, Δ.sup.9-THCV-C.sub.3, Δ.sup.9-THCVA-C.sub.5 A, and/or scalemic or racemic mixtures of these substances.

16. Method according to claim 13, wherein the cannabinoid is converted to a cannabinol.

17. Method according to claim 16, wherein the cannabinol is CBN-C.sub.5 and/or CBN-C.sub.3.

18. Method according to claim 13, wherein cyclooctasulfur is used as oxidizing agent.

19. Method according to claim 13, wherein between 1.5 and 2.5 equivalents of sulfur are added to one equivalent of cannabinoid.

20. Method according to claim 13, wherein the cannabinoid is heated with the sulfur to a temperature between 150° C. and 350° C.

21. Method for the conversion of a cannabidiol to a cannabinol and/or a cannabinolic acid, respectively, wherein an acid- or base-promoted cyclization is carried out in a first step and the method according to claim 13 is carried out in a second step.

22. Method according to claim 21, wherein the cannabidiol is CBD-C.sub.5 and/or CBD-C.sub.3, and/or a cannabidiolic acid and/or scalemic or racemic mixtures of these substances.

23. Method according to claim 22, wherein the cannabidiolic acid is CBDA-C.sub.5 and/or CBDA-C.sub.3 and/or scalemic or racemic mixtures of these substances.

24. Method according to claim 22, wherein in the first step cannabidiol or the cannabidiolic acid, respectively, is dissolved in an organic solvent and is mixed with an acid to achieve the cyclization.

25. Method according to claim 24, wherein the organic solvent is toluene and/or the acid is p-toluenesulfonic acid.

26. Method according to claim 25, wherein in the first step between 0.05 and 0.15 equivalent of p-toluenesulfonic acid is added to one equivalent of cannabidiol or cannabidiolic acid, respectively.

27. Method according to claim 24, wherein in the first step the cannabidiol and/or the cannabidiolic acid dissolved in the organic solvent is heated to a temperature between 80° C. and 250° C.

28. Method according to claim 22, wherein CBD-C.sub.5 is subjected to an acid-based cyclization in a first step and is subsequently reacted with sulfur as oxidant to form CBN-C.sub.5.

29. Use of sulfur as an oxidizing agent for aromatizing an alicyclic region of a cannabinoid.

30. Use according to claim 29, whereby the cannabinoid is obtained by acid- or base-promoted cyclization of a cannabidiol.

Description

PREFERRED EMBODIMENTS

[0030] In a first step, CBD (0.010 kg, 0.032 mol, 1.0 equiv) was dissolved in toluene (320 mL) in a 500 mL three-necked round-bottomed flask equipped with reflux condenser and pTsOH.H.sub.2O (0.61 g, 3.2 mmol, 0.1 equiv) was added in one portion. The resulting colorless solution was heated to 140° C. and stirred at reflux for 1.5 h, after which TLC analysis (1:1 CH.sub.2Cl.sub.2/hexanes) showed full consumption of CBD. The reaction mixture was cooled to ambient temperature and deionized water (50 mL) was added. After separation of the organic layer, the aqueous phase was extracted with EtOAc (2×120 mL). The combined organic extracts were washed with sat. aq. NaHCO.sub.3 (75 mL), water (80 mL) and brine (80 mL), dried over MgSO.sub.4 and concentrated under reduced pressure.

[0031] In a second step, to the unpurified, reddish oil obtained in step 1 was added sulfur (2.0 g, 8.0 mmol Ss, 0.25 equiv) in a 50 mL round-bottomed flask, and the mixture was heated neat to 250° C. in an aluminium heating block. After separation of the organic layer, the aqueous phase was extracted with EtOAc (2×80 mL). The combined organic extracts were washed with water (80 mL) and brine (80 mL), dried over MgSO.sub.4 and concentrated under reduced pressure.

[0032] The unpurified product was purified by flash column chromatography (SiO.sub.2, eluting in hexanes to 2% to 3% EtOAc/hexanes, using a total of 15 L of technical grade solvent) to obtain CBN as an orange oil (7.3 g, 74% yield).

[0033] In this preferred embodiment of the inventive method as shown in the following reaction scheme, CBD-C.sub.5 is converted in the first step to Δ.sup.9-THC-C.sub.5 by an electrophile addition to the double binding resulting in an acid-based cyclisation using p-toulenesulfonic acid. In the second step, Δ.sup.9-THC-C.sub.5 is aromatized and converted by sulfur to CBN-C.sub.5:

##STR00001##

[0034] Attempts indicate that purification of crude CBN by vacuum distillation is feasible and could be a preferred method for purification on larger scale (200° C., 0.01 mbar, see Justus Liebigs Annalen der Chemie, 1960, 630, 71-83). However, in several fields of application, the purification is not necessary or can be done more efficiently by methods well known by the skilled in the art.

[0035] Further experiments showed the following yields depending on the size of the batch:

TABLE-US-00001 TABLE 1 Yield of CBN depending on the batch size Amount of CBD Yield of CBN 500 mg 67% 1 g 70% 5 g 68% 10 g 74%

[0036] Comparing with the state of the art according to J. Nat. Prod. 2018, 81, 630-630, where a yield of only 60% of a 1 g scale has been achieved, the inventive method is significantly better, as for the 1 g scale of the invention an yield of 70% could be achieved.

[0037] In summary, it is to be noted that a method for aromatizing an alicyclic region of a cannabinoid is established, wherewith a particularly high yield can be achieved at low cost.