SYNTHESIS OF PHYTOCANNABINOIDS INCLUDING A DECARBOXYLATION STEP
20200172459 ยท 2020-06-04
Inventors
- Tristan REEKIE (New South Wales, AU)
- Michael Scott (New South Wales, AU)
- Michael Kassiou (New South Wales, AU)
Cpc classification
C07C39/23
CHEMISTRY; METALLURGY
C07C37/50
CHEMISTRY; METALLURGY
C07C39/23
CHEMISTRY; METALLURGY
C07D311/94
CHEMISTRY; METALLURGY
C07C39/15
CHEMISTRY; METALLURGY
C07D311/58
CHEMISTRY; METALLURGY
C07C39/19
CHEMISTRY; METALLURGY
C07C39/19
CHEMISTRY; METALLURGY
C07C37/50
CHEMISTRY; METALLURGY
International classification
C07C37/50
CHEMISTRY; METALLURGY
C07C39/15
CHEMISTRY; METALLURGY
C07D311/58
CHEMISTRY; METALLURGY
Abstract
method for decarboxylating a carboxylated phytocannabinoid compound of Formula I to form a phytocannabinoid compound of Formula II: Formula I Formula II wherein: R1 is selected from the group consisting of: substituted or unsubstituted C.sub.1-C.sub.5 alkyl; R2 is selected from the group consisting of: OH or O, and R3 is selected from the group consisting of: a substituted or unsubstituted cyclohexene, a substituted or unsubstituted C.sub.2-C.sub.8 alkene, or a substituted or unsubstituted C.sub.2-C.sub.8 dialkene; or R2 is O, and R2 and R3 together form a ring structure in which R2 is an internal ring atom; wherein the method includes heating a reaction mixture comprising the carboxylated phytocannabinoid compound and a polar aprotic solvent in the presence of a LiCl for a time sufficient to decarboxylate at least a portion of the carboxylated phytocannabinoid compounds and form the phytocannabinoid compound.
##STR00001##
Claims
1. A method for decarboxylating a carboxylated phytocannabinoid compound of Formula I to form a phytocannabinoid compound of Formula II: ##STR00050## wherein: R1 is selected from the group consisting of: substituted or unsubstituted C.sub.1-C.sub.5 alkyl; R2 is selected from the group consisting of: OH or O, and R3 is selected from the group consisting of: a substituted or unsubstituted cyclohexene, a substituted or unsubstituted C.sub.2-C.sub.8 alkene, or a substituted or unsubstituted C.sub.2-C.sub.8 dialkene; or R2 is O, and R2 and R3 together form a ring structure in which R2 is an internal ring atom; wherein the method includes heating a reaction mixture comprising the carboxylated phytocannabinoid compound and a polar aprotic solvent in the presence of a LiCl for a time sufficient to decarboxylate at least a portion of the carboxylated phytocannabinoid compounds and form the phytocannabinoid compound.
2. A method for the preparation of a phytocannabinoid compound of Formula II comprising: subjecting a first reaction mixture comprising a compound of Formula A and a compound of Formula B in a solvent to reaction conditions such that the compound of Formula A and Formula B together undergo a condensation reaction according to Reaction Scheme I to form a carboxulated phytocannabinoid compound of Formula I: ##STR00051## wherein: R1 is selected from the group consisting of: unsubstituted C.sub.1-C.sub.5 alkyl; R2 is OH R3 is selected from the group consisting of: a substituted or unsubstituted cyclohexene, a substituted or unsubstituted C.sub.2-C.sub.8 alkene, or a substituted or unsubstituted C.sub.2-C.sub.8 dialkene R2 is R2 and R3 is R3; or R2 is O and R2 and R3 together form a ring structure in which R2 is an internal ring atom wherein the method further includes heating a second reaction mixture comprising the carboxylated phytocannabinoid compound and a polar aprotic solvent in the presence of LiCl for a time sufficient to decarboxylate at least a portion of the carboxylated phytocannabinoid compounds and form the phytocannabinoid compound according to Reaction Scheme II; ##STR00052##
3. The method of claim 1 or 2 wherein, the carboxylated phytocannabinoid compound is a compound of Formula IA and the phytocannabinoid compound is a compound of Formula IIA: ##STR00053## wherein: R2 is OH and R5 is C(CH.sub.3)CH.sub.2, or R2 is O and R5 is C(CH.sub.2).sub.2 and R2 and R5 are linked by a covalent bond; and R4 is selected from the group consisting of: substituted or unsubstituted C.sub.1-C.sub.4 alkyl, COOH, COOC.sub.1-C.sub.4 alkyl, OC.sub.1-C.sub.4 alkyl, COC.sub.1-C.sub.4 alkyl, tetrahydropyran, benzyl, para-methoxybenzyl, and OH.
4. The method of claim 3, wherein the carboxylated phytocannabinoid compound is a compound of Formula IB and the phytocannabinoid compound is a compound of Formula IIB: ##STR00054##
5. The method of claim 1 or 2, wherein the carboxylated phytocannabinoid compound is a compound of Formula IC and the phytocannabinoid compound is a compound of Formula IIC: ##STR00055## wherein: R6 and R7 together form a fused ring structure; R7 and R8 together form a fused ring structure; or R6, R7, and R8 together form a fused ring structure.
6. The method of claim 3 or 5, wherein the carboxylated phytocannabinoid compound is a compound of Formula ID and the phytocannabinoid compound is a compound of Formula IID: ##STR00056##
7. The method of claim 1 or 2, wherein the carboxylated phytocannabinoid compound is a compound of Formula IE and the phytocannabinoid compound is a compound of Formula IIE: ##STR00057## wherein: R9 is selected from the group consisting of: a substituted or unsubstituted C.sub.2-C.sub.8 alkene, or a substituted or unsubstituted C.sub.2-C.sub.8 dialkene.
8. The method of claim 2, wherein the first reaction mixture further comprises BF.sub.3.OEt.sub.2.
9. The method of any one of the preceding claims, wherein the polar aprotic solvent is selected from the group consisting of: N-methylpyrrolidone, tetrahydrofuran (THF), ethyl acetate (EtOAc), acetone, dimethylformamide (DMF), acetonitrile (MeCN), dimethyl sulfoxide (DMSO), propylene carbonate (PC), and combinations thereof.
10. The method of claim 1 or 2, wherein the phytocannabinoid compound is selected from the group consisting of: TABLE-US-00002
11. The method of any one of the preceding claims, wherein the step of heating the reaction mixture includes heating the reaction mixture to the boiling point of the polar aprotic solvent.
12. The method of claim 11, wherein the step of heating the reaction mixture is conducted under reflux.
13. The method of any one of the preceding claims, wherein the LiCl is present in an amount of from 1 to 3 molar equivalents relative to the compound of Formula I.
14. The method of claim 13, wherein the LiCl is present in an amount of from about 1.5 to about 2.5 molar equivalents.
15. The method of claim 14, wherein the LiCl is present in an amount of about 2 molar equivalents.
16. The method of any one of the preceding claims, wherein the polar aprotic solvent has a boiling point that is above 100 C.
17. The method of claim 16, wherein the polar aprotic solvent has a boiling point that is above 130 C.
Description
DETAILED DESCRIPTION OF THE EMBODIMENTS
[0056] The invention relates to methods of decarboxylating compounds of Formula I to form compounds of Formula II. The invention also more broadly relates to methods of synthesising compounds of Formula I from precursor compounds, and then decarboxylating the compounds of Formula I to form compounds of Formula II.
[0057] In view of the above, the invention relates to a method for the preparation of a phytocannabinoid compound of Formula II comprising:
[0058] subjecting a first reaction mixture comprising a compound of Formula A and a compound of Formula B in a solvent to reaction conditions such that the compound of Formula A and Formula B together undergo a condensation reaction according to Reaction Scheme I to form a carboxylated phytocannabinoid compound of Formula I:
##STR00011##
[0059] wherein the method further includes heating a second reaction mixture comprising the carboxylated phytocannabinoid compound and a polar aprotic solvent in the presence of LiCl for a time sufficient to decarboxylate at least a portion of the carboxylated phytocannabinoid compounds and form the phytocannabinoid compound according to Reaction Scheme II;
##STR00012##
[0060] As used herein, the term C.sub.1-C.sub.5 alkyl either used alone or in compound terms refers to straight chain or branched saturated hydrocarbon groups, having 1 to 4 carbon atoms. Suitable alkyl groups include, but are not limited to: methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl. The C.sub.1-C.sub.5 alkyl may be optionally substituted with one or more substituents. The substituents may replace one or more hydrogen atoms on any carbon atom or carbon atoms in the C.sub.1-C.sub.5 alkyl carbon atom chain. Preferred substituents include methyl or ethyl groups, and more preferably methyl groups.
[0061] As used herein, the term C.sub.2-C.sub.8 alkenyl either used alone or in compound terms refers to straight chain or branched unsaturated hydrocarbon groups, having 2 to 4 carbon atoms and including at least one carbon to carbon double bond, for example, the alkenyl group may be a monoalkenyl group, a diene group, or a triene group. Suitable alkenyl groups include, but are not limited to: ethenyl, propenyl, propadiene, butenyl, butadiene, pentenyl, pentadiene, hexenyl, hexadiene, heptenyl, heptadiene, octenyl, or octadiene groups. The carbon to carbon double bond may be between any two adjacent carbon atoms. The C.sub.2-C.sub.8 alkenyl may be optionally substituted with one or more substituents. The substituents may replace one or more hydrogen atoms on any carbon atom or carbon atoms in the C.sub.2-C.sub.8 alkenyl carbon atom chain. Preferred substituents include methyl or ethyl groups, and more preferably methyl groups.
[0062] The method thus provides a mechanism for preparing a large range of different carboxylated phytocannabinoid compounds from a large range of precursor compounds, which can then be easily decarboxylated to provide an active phytocannabinoid compound. By way of example, the method of invention can be applied to form the phytocannabinoids outlined in Table 1 below:
TABLE-US-00001 TABLE 1
[0063] Exemplary reaction schemes are provided below:
##STR00033##
##STR00034##
##STR00035##
##STR00036##
##STR00037##
##STR00038##
EXAMPLES
Example 1Forming Precursor Compounds of Formula B
Example 1A
[0064] ##STR00039##
[0065] A solution of methanol (250 mL) at 0 C. was treated with sodium (12.0 g, 0.52 mol) in portions and stirred until dissolved. Dimethyl malonate (67.7 mL, 0.59 mol) was then added followed by (E)-non-3-en-2-one (59 g, 0.42 mol) and the solution heated at reflux for 8 h. The methanol was removed then diluted with water (400 mL) and washed with CHCl.sub.3 (300 mL). The aqueous later was acidified and extracted with CHCl.sub.3 (3250 mL). The combined organic layers were dried (MgSO4) and concentrated to give a white solid.
[0066] The white solid (8.17 g, 34.0 mmol) was dissolved in DMF (20 ml) and cooled to 0 C. A solution of Br.sub.2 (1.75 mL, 34.0 mmol) in DMF (6.6 mL) was slowly added and the solution stirred at 20 C. for 1 h. The solution was then heated to 80 C. for 16 h before cooling and treatment with 5% Na.sub.2S.sub.2O.sub.3 aqueous solution (200 mL) and being extracted with ethyl acetate (3100 mL). The combined organic layers were dried (MgSO.sub.4) and concentrated. The crude material was recrystallized from DCM/hexane to give a white solid.
Example 1B
[0067] ##STR00040##
[0068] A solution of methanol (450 mL) at 0 C. was treated with sodium (25.5 g, 1.11 mol) in portions and stirred until dissolved. Dimethyl malonate (143 mL, 1.25 mol) was then added followed by (E)-hept-3-en-2-one (100 g, 0.89 mol) and the solution heated at reflux for 8 h. The methanol was removed then diluted with water (600 mL) and washed with CHCl.sub.3 (500 mL). The aqueous later was acidified and extracted with CHCl.sub.3 (3400 mL). The combined organic layers were dried (MgSO.sub.4) and concentrated to give a white solid.
[0069] The white solid (5.37 g, 25.3 mmol) was dissolved in DMF (12 ml) and cooled to 0 C. A solution of Br.sub.2 (1.30 mL, 25.4 mmol) in DMF (6.6 mL) was slowly added and the solution stirred at 20 C. for 1 h. The solution was then heated to 80 C. for 16 h before cooling and treatment with 5% Na.sub.2S.sub.2O.sub.3 aqueous solution (200 mL) and being extracted with ethyl acetate (3100 mL). The combined organic layers were dried (MgSO.sub.4) and concentrated. The crude material was recrystallized from DCM/hexane to give a white solid.
Example 2Forming Compounds of Formula I
Example 2A
[0070] ##STR00041##
[0071] R1 is propyl or pentyl.
[0072] A solution of (4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (1.1 equiv) and methyl 2,4-dihydroxy-6-pentylbenzoate (1 equiv) or methyl 2,4-dihydroxy-6-propylbenzoate (1 equiv) and MgSO.sub.4 (3 equiv) in DCM (0.1 M) at 20 C. was treated with BF.sub.3.OEt.sub.2 (0.1 equiv) in DCM (0.1 M) and stirred for 0.25 h. Water was added followed and extracted with DCM, dried (MgSO.sub.4) and concentrated. The residue was subjected to flash column chromatography (silica, 0 to 5% EtOAc/Hexane gradient elution) to give a colourless oil. Yields 30-40%.
Example 2B
[0073] ##STR00042##
[0074] R1 is propyl or pentyl.
[0075] A solution of (4R)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (1 equiv) and methyl 2,4-dihydroxy-6-pentylbenzoate (1 equiv) or methyl 2,4-dihydroxy-6-propylbenzoate (1 equiv) in chlorobenzene (0.1 M) at room temperature was treated with BF3.OEt.sub.2 (0.15 equiv) in chlorobenzene (0.05 M). The solution was stirred for 1 h then treated with aqueous NaHCO.sub.3 and extracted with DCM, dried (MgSO.sub.4) and concentrated. The residue was subjected to flash column chromatography (silica, 0 to 10% EtOAc/Hexane gradient elution) to give a colourless oil. Yields 60-70%
Example 2C
[0076] ##STR00043##
[0077] R1 is propyl or pentyl.
[0078] A solution of methyl (1R,2R)-2,6-dihydroxy-5-methyl-4-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1-biphenyl]-3-carboxylate (1 equiv) or methyl (1R,2R)-2,6-dihydroxy-5-methyl-4-pentyl-2-(prop-1-en-2-yl)-1,2,3,4-tetrahydro-[1,1-biphenyl]-3-carboxylate (1 equiv) in DCM (0.1 M) at 20 C. was treated with BF3.OEt.sub.2 (0.1 equiv) in DCM (0.05 M) and stirred for 1 h as it slowly warmed to 0 C. NaHCO.sub.3 in water was added and the aqueous phase extracted with DCM, dried (MgSO.sub.4) and concentrated. The residue was subjected to flash column chromatography (silica, 0 to 5% EtOAc/Hexane gradient elution) to give a colourless oil. Yields 50-55%
Example 2D
[0079] ##STR00044##
[0080] R1 is propyl or pentyl.
[0081] A solution of geraniol (1 equiv) and methyl 2,4-dihydroxy-6-pentylbenzoate (3 equiv) or methyl 2,4-dihydroxy-6-propylbenzoate (3 equiv) in CHC.sub.3 (0.1 M) at 20 C. was treated with BF.sub.3.OEt.sub.2 (0.1 equiv) in CHCl.sub.3 (0.1 M) and stirred for 0.25 h. Water was added followed and extracted with DCM, dried (MgSO.sub.4) and concentrated. The residue was subjected to flash column chromatography (silica, 0 to 5% EtOAc/Hexane gradient elution) to give a colourless oil. Yields 30-40%.
Example 2E
[0082] ##STR00045##
[0083] R1 is propyl or pentyl.
[0084] A solution of citral (3 equiv), 2,4-dihydroxy-6-pentylbenzoate (1 equiv) or methyl 2,4-dihydroxy-6-propylbenzoate (1 equiv) and Ca(OH).sub.2 (1 equiv) in methanol (0.5 M) in a sealed tube was heated at 140 C. for 1.5 h. The cooled solution was diluted with EtOAc and 1 M HCl. The separated aqueous phase was extracted with EtOAc and the combined organic layers were dried (MgSO.sub.4) and concentrated. The residue was subjected to flash column chromatography (silica, 30% DCM/Hexane elution) to give a colourless oil. Yields 75-85%.
Example 2F
[0085] ##STR00046##
[0086] R1 is propyl or pentyl.
Example 3Decarboxylation of Compounds of Formula I to Form Compound of Formula II According to Reaction Scheme II
[0087] ##STR00047##
[0088] A solution of the methyl ester (1 equiv) in DMSO/water (19:1) (0.2 M) was treated with LiCl (2 equiv) and stirred at reflux for 4 h. The cooled solution was diluted with water and extracted with Et.sub.2O (3 times). The combined organic phases were dried (MgSO.sub.4) and concentrated and the residue was subjected to flash column chromatography (silica, 0 to 5% EtOAc/Hexane gradient elution) to give the desired decarboxylated product. Yields 80-90%.
##STR00048## ##STR00049##
[0089] It will be understood that the invention disclosed and defined in this specification extends to all alternative combinations of two or more of the individual features mentioned or evident from the text or drawings. All of these different combinations constitute various alternative aspects of the invention.