Process for the Production of Cannabinoids and Cannabinoid Acids

Abstract

The present invention relates to a process for the preparation of diverse known and novel cannabinoids 5, which include cannabigerol (CBG, 1), cannabigerolic acid (CBGA, 2), cannabigerovarin (CBGV, 3), cannabigerovarinic acid (CBGVA, 4) and other naturally occurring monocyclic cannabinoids and other analogues from simple inexpensive starting materials using a cascade sequence of allylic rearrangement and aromatization. Novel cannabinoids of series 5 are also claimed as part of the invention. These synthesized cannabinoids, unlike the minor cannabinoids isolated from Cannabis saliva or synthesized from the condensation reactions such as the reactions of substituted resorcinols with monoterpenes, are much easier to obtain at high purity levels. In particular, these cannabinoids, including but not limited to cannabigerol (CBG, 1), cannabigerolic acid (CBGA, 2), cannabigerovarin (CBGV, 3) and cannabigerovarinic acid (CBGVA, 4) are obtained without contamination with impurities with variation in RA and RB (e.g. contamination of CBG with CBGV).

##STR00001##

Claims

1. A process for the preparation of a product compound of the formula 5: ##STR00013## wherein: R.sup.A is selected from the group consisting of H, CO.sub.2H and its pharmaceutically acceptable salts, CO.sub.2R.sup.C, CONHR.sup.D, and CONR.sup.DR.sup.E; R.sup.B is selected from the group consisting of H, C.sub.1 to C.sub.2 alkyl, linear or branched C.sub.3 to C.sub.10 alkyl, and double branched C.sub.4 to C.sub.10 alkyl, in each case optionally substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro-groups, or is selected from the group consisting of (CH.sub.2).sub.oC.sub.3 to C.sub.6 cycloalkyl, (CH.sub.2).sub.pOR.sup.F, and C.sub.3 to C.sub.6 cycloalkyl optionally substituted by a C.sub.1 to C.sub.8 alkyl; o is an integer from 0-6; p is an integer from 1-6; R.sup.C is selected from the group consisting of C.sub.1 to C.sub.6 alkyl, (CH.sub.2).sub.qC.sub.3 to C.sub.6 cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; q is an integer from 0-6; R.sup.D is selected from the group consisting of C.sub.1 to C.sub.6 alkyl, (CH.sub.2).sub.rC.sub.3 to C.sub.6 cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; and R.sup.E is selected from the group consisting of C.sub.1 to C.sub.6 alkyl, (CH.sub.2).sub.rC.sub.3 to C.sub.6 cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; or NR.sup.DR.sup.E is selected from the group consisting of azetidinyl, pyrrolidinyl, morpholinyl and piperidinyl, each optionally substituted by one or two hydroxyl groups or hydroxymethyl groups with the exception that the hydroxyl groups cannot be on the carbon bearing the heterocyclic ring nitrogen or the heterocyclic ring oxygen with morpholine; R.sup.F is C.sub.1 to C.sub.6 alkyl or (CH.sub.2).sub.rC.sub.3 to C.sub.6 cycloalkyl; each r is an integer independently selected from 0-6; R? and R? are independently C.sub.1 to C.sub.6 alkyl or optionally substituted aryl, or R? and R? in combination are (CH.sub.2).sub.s, wherein s is 4, 5 or 6, said process comprising the steps of: providing a first intermediate of the formula 6: ##STR00014## wherein R? and R? are independently C.sub.1 to C.sub.6 alkyl or optionally substituted aryl, or R? and R? in combination are (CH.sub.2).sub.s, wherein s is 4, 5 or 6; treating the first intermediate of the formula 6 with an electrophilic acylating reagent R.sup.BCOZ in which any hydroxyl group or groups in R.sup.1 or R.sup.2 is protected in the presence of a first base 8 and also in the presence of a first Lewis acid 9, a palladium catalyst 10 with optional additional ligands 11, and silica or an alternative equivalent solid reagent or a second base 12 followed by a Br?nsted or second Lewis acid 13 or a base alone and optional deprotection to provide a second intermediate 7: ##STR00015## wherein: R? and R? are independently C.sub.1 to C.sub.6 alkyl or optionally substituted aryl, or R? and R? in combination are (CH.sub.2).sub.s, s is 4, 5 or 6; and hydrolyzing the second intermediate 7 with optional decarboxylation or by transesterification or by amide formation with optional deprotection to provide the product of formula 5.

2. The process according to claim 1, wherein Z is a halide.

3. The process according to claim 1, wherein R? and R.sup.? are both methyl.

4. The process according to claim 1, wherein the first base 8 is an amine or heterocyclic amine.

5. The process according to claim 1, wherein the first base 8 is pyridine.

6. The process according to claim 1, wherein the first Lewis acid 9 is magnesium chloride.

7. The process according to claim 1, wherein the palladium catalyst 10 is derived from a palladium(II) complex in the presence of a phosphine 11 as ligand.

8. The process according to claim 1, wherein the palladium catalyst 10 is a palladium(0) complex in the presence of a phosphine 11 as ligand.

9. The process according to claim 1, wherein the palladium catalyst 10 is derived from a palladium(II) complex which contains one or more phosphine ligands.

10. The process according to claim 1, wherein the palladium catalyst 10 is a palladium(0) complex which contains one or more phosphine ligands.

11. The process according to claim 1, wherein the palladium catalyst 10 is tris(dibenzylideneacetone)dipalladium(0) [Pd.sub.2(dba).sub.3] in the presence of a triarylphosphine or triheteroarylphosphine as ligand 11.

12. The process according to claim 1, wherein the second base 12 is cesium acetate, cesium carbonate or potassium carbonate.

13. The process according to claim 1, wherein the Br?nsted or second Lewis acid 13, if used, is acetic acid or hydrogen chloride.

14. The process according to claim 1, wherein the hydroxyl-protecting group or groups are silyl protecting groups.

15. The process according to claim 1, wherein the hydroxyl-protecting group or groups are independently selected from the group consisting of t-butyldimethylsilyl, thexyldimethylsilyl, t-butyldiphenylsilyl or tri-iso-propylsilyl protecting groups.

16. A compound having the structure of formula 5: ##STR00016## wherein: R.sup.A is selected from the group consisting of H, CO.sub.2H and its pharmaceutically acceptable salts, CO.sub.2R.sup.C, CONHR.sup.D, and CONR.sup.DR.sup.E; R.sup.B is selected from the group consisting of H, C.sub.1 to C.sub.2 alkyl, linear or branched C.sub.3 to C.sub.10 alkyl, and double branched C.sub.4 to C.sub.10 alkyl in each case optionally substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro-groups, or is selected from the group consisting of (CH.sub.2).sub.oC.sub.3 to C.sub.6 cycloalkyl, (CH.sub.2).sub.pOR.sup.F, and C.sub.3 to C.sub.6 cycloalkyl optionally substituted by a C.sub.1 to C.sub.8 alkyl; o is an integer from 0-6; p is an integer from 1-6; R.sup.C is selected from the group consisting of C.sub.1 to C.sub.6 alkyl, (CH.sub.2).sub.qC.sub.3 to C.sub.6 cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; q is an integer from 0-6; R.sup.D is selected from the group consisting of C.sub.1 to C.sub.6 alkyl, (CH.sub.2).sub.rC.sub.3 to C.sub.6 cycloalkyl, C.sub.3 to C.sub.6 cycloalkyl, allyl, benzyl, substituted benzyl and 2-phenylethyl; and R.sup.E is selected from the group consisting of C.sub.1 to C.sub.6 alkyl, (CH.sub.2).sub.rC.sub.3 to C.sub.6 cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl; or NR.sup.DR.sup.E is azetidinyl, pyrrolidinyl, morpholinyl and piperidinyl, each optionally substituted by one or two hydroxyl groups or hydroxymethyl groups with the exception that the hydroxyl groups cannot be on the carbon bearing the heterocyclic ring nitrogen or the heterocyclic ring oxygen with morpholine; R.sup.F is C.sub.1 to C.sub.6 alkyl or (CH.sub.2).sub.rC.sub.3 to C.sub.6 cycloalkyl; each r is an integer independently selected from 0-6; with the exception that the compound of formula 5 cannot be cannabigerol (CBG, 1), cannabigerolic acid (CBGA, 2), cannabigerovarin (CBGV, 3) and cannabigerovarinic acid (CBGVA, 4).

17. An intermediate compound having the structure of formula 7: ##STR00017## wherein: R.sup.B is selected from the group consisting of H or C.sub.1 to C.sub.2 alkyl, linear or branched C.sub.3 to C.sub.10 alkyl, and double branched C.sub.4 to C.sub.10 alkyl in each case optionally substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro-groups, or is selected from the group consisting of (CH.sub.2).sub.oC.sub.3 to C.sub.6 cycloalkyl, (CH.sub.2).sub.pOR.sup.F, and C.sub.3 to C.sub.6 cycloalkyl optionally substituted by a C.sub.1 to C.sub.8 alkyl; o is an integer from 0-6; p is an integer from 1-6; R? and R? are independently C.sub.1 to C.sub.6 alkyl or optionally substituted aryl, or R? and R? in combination are (CH.sub.2).sub.s, and is 4, 5 or 6, with exception to when each of R.sup.B, R? and R? is Me.

18. The process according to claim 1, wherein the compound of formula 5 is cannabigerol (CBG, 1) or cannabigerolic acid (CBGA, 2).

19. The process according to claim 1, wherein the compound of formula 5 is cannabigerovarin (CBGV, 3) or cannabigerovarinic acid (CBGVA, 4).

20-23. (canceled)

Description

DETAILED DESCRIPTION OF THE INVENTION

[0050] Large Scale-Synthesis of Cannabigerol (CBG, 1), Cannabigerolic Acid (CBGA, 2), Cannabigerovarin (CBGV, 3), Cannabigerovarinic Acid (CBGVA, 4) and Analogs

[0051] The present invention relates to a large-scale process for the preparation of diverse known and novel cannabinoids 5 including cannabigerol (CBG, 1), cannabigerolic acid (CBGA, 2), cannabigerovarin (CBGV, 3) and cannabigerovarinic acid (CBGVA, 4) and other naturally occurring monocyclic cannabinoids from simple inexpensive starting materials using a cascade sequence of allylic rearrangement and aromatization. The invention includes synthesis of the target cannabinoids as oils or crystalline derivatives, as appropriate, including solvates, hydrates and polymorphs. The process involves the large-scale syntheses of cannabinoids 5:

##STR00005##

where: [0052] R.sup.A is H, CO.sub.2H and its pharmaceutically acceptable salts, CO.sub.2R.sup.C, CONHR.sup.D, CONR.sup.DR.sup.E; [0053] R.sup.B is H or C.sub.1 to C.sub.2 alkyl, linear or branched C.sub.3 to C.sub.10 alkyl or double branched C.sub.4 to C.sub.10 alkyl in each case optionally substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro-groups, (CH.sub.2).sub.oC.sub.3 to C.sub.6 cycloalkyl, (CH.sub.2).sub.pOR.sup.F, or C.sub.3 to C.sub.6 cycloalkyl optionally substituted by a C.sub.1 to C.sub.8 alkyl; [0054] o is 0, 1, 2, 3, 4, 5 or 6; [0055] p is 1, 2, 3, 4, 5 or 6; [0056] R.sup.C is C.sub.1 to C.sub.6 alkyl, (CH.sub.2).sub.qC.sub.3 to C.sub.6 cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl; [0057] q is 0, 1, 2, 3, 4, 5 or 6; [0058] R.sup.D is C.sub.1 to C.sub.6 alkyl, (CH.sub.2).sub.rC.sub.3 to C.sub.6 cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl; R.sup.E is C.sub.1 to C.sub.6 alkyl, (CH.sub.2).sub.rC.sub.3 to C.sub.6 cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl; or NR.sup.DR.sup.E is azetidinyl, pyrrolidinyl, morpholinyl or piperidinyl each optionally substituted by one or two hydroxyl groups or hydroxymethyl groups with the exception that the hydroxyl groups cannot be on the carbon bearing the heterocyclic ring nitrogen or the heterocyclic ring oxygen with morpholine; [0059] R.sup.F is C.sub.1 to C.sub.6 alkyl, (CH.sub.2).sub.rC.sub.3 to C.sub.6 cycloalkyl; [0060] each r is independently 0, 1, 2, 3, 4, 5 or 6; [0061] said process comprising: [0062] treating a first intermediate of the formula 6 with (1) an acylating reagent R.sup.BCOZ in which any hydroxyl group or groups in R.sup.B are protected in the presence of a first base 8 and also in the presence of a first Lewis acid 9, (2) a palladium catalyst 10 with optional additional ligands 11 and (3) silica or an alternative equivalent solid reagent or a second mild base 12 followed by a Br?nsted or second Lewis acid 13 or a mild base alone such as cesium acetate and optional deprotection to provide the second intermediate 7 and secondly hydrolysis of said 6 with optional decarboxylation or by transesterification or by amide formation with optional deprotection as appropriate to provide 5;

##STR00006##

wherein: [0063] Z is a halogen preferably chlorine or R.sup.BCOZ is an alternative reactive electrophilic acylating agent; [0064] R? and R? are independently C.sub.1 to C.sub.6 alkyl or optionally substituted aryl or R? and R? in combination are (CH.sub.2).sub.s (s is 4, 5 or 6) with R? and R? being preferably both methyl; [0065] the first base 8 is an amine or a heterocyclic amine such as pyridine; [0066] the first Lewis acid 9 is preferably magnesium chloride; [0067] the palladium catalyst 10 is either derived from a palladium(II) precatalyst or is itself a palladium(0) catalyst and the optional additional ligands 11 include but are not limited to one or more phosphines or diphosphines or their equivalents, preferably the palladium catalyst 10 and ligands 11 are specifically but not limited to phosphine complexes of palladium(0) such as tetrakis(triphenylphosphine)palladium(0) or tris(dibenzylideneacetone)dipalladium(0) [Pd.sub.2(dba).sub.3] in the presence of a triarylphosphine or triheteroarylphosphine particularly tri-2-furylphosphine; [0068] the second base 12 is cesium acetate or cesium carbonate or potassium carbonate; [0069] the Br?nsted or second Lewis acid 13, if used, is acetic acid or hydrogen chloride;
wherein: [0070] the optional hydroxyl-protecting group or groups are silyl protecting groups; [0071] the optional hydroxyl-protecting group or groups are preferably independently t-butyldimethylsilyl, thexyldimethylsilyl, t-butyldiphenylsilyl or tri-iso-propylsilyl protecting groups.

[0072] It should be noted that several of the intermediates in these syntheses can exist as keto- and enol tautomers. The depiction of a structure as a keto-form also includes the corresponding enol-form including mixtures containing both keto- and enol forms. Additionally, the depiction of a structure as an enol-form also includes the corresponding keto-form including mixtures containing both keto- and enol forms. By way of example, intermediates 6 exist as mixtures of both keto- and enol forms although the structures, for reasons of simplicity, are drawn as the keto-forms.

[0073] The small-scale syntheses of intermediates 6 and 7 have previously been published (R? and R? are both methyl; R.sup.B is Me, AcOCH.sub.2, trans-PhCH?CH) and are known [Ma, T. K.; White, A. J. P.; Barrett, A. G. M., Meroterpenoid Total Synthesis: Conversion of Geraniol and Farnesol into Amorphastilbol, Grifolin and Grifolic acid by Dioxinone-?-keto-Acylation, Palladium Catalyzed Decarboxylative Allylic Rearrangement and Aromatization, Tetrahedron Letters, 2017, 58, 2765-2767. Elliott, D. C.; Ma, T. K.; Selmani, A.; Cookson, R.; Parsons, P. J.; Barrett, A. G. M., Sequential Ketene Generation from Dioxane-4,6-dione-Keto-Dioxinones for the Synthesis of Terpenoid Resorcylates, Organic Letters 2016, 18, 1800-1803. Cordes, J.; Calo, F.; Anderson, K.; Pfaffeneder, T.; Laclef, S.; White, A. J. P.; Barrett, A. G. M., Total Syntheses of Angelicoin A, Hericenone J, and Hericenol A via Migratory Prenyl- and Geranylation-Aromatization Sequences, Journal of Organic Chemistry 2012, 77, 652-657]. However, methods for the large-scale synthesis of the novel cannabinoids 5 listed above have not been hitherto published.

[0074] Protecting groups are well known to persons skilled in the art and are described in textbooks such as Greene and Wuts, (P. G. M. Wuts, T. W. Greene, Greene's Protective Groups in Organic Synthesis, 2006, Fourth Edition, John Wiley, New York).

[0075] Cleavage of the dioxinone rings of intermediate 7 by saponification or an equivalent process to produce the cannabinoid carboxylic acids 5 (R.sup.A?CO.sub.2H) is carried out as described in R.

[0076] Cookson, T. N. Barrett and A. G. M. Barrett, ?-Keto-dioxinones and ?,?-Diketo-dioxinones in Biomimetic Resorcylate Total Synthesis, Accounts of Chemical Research, 2015, volume 48, pages 628-642 and references therein.

[0077] Decarboxylation of the cannabinoid carboxylic acids 5 (R.sup.A?CO.sub.2H) is carried out as described in H. Perrotin-Brunel, W. Buijs, J. van Spronsen, M. J. E. van Roosmalen, C. J. Peters, R. Verpoorte and G.-J. Witkamp, Decarboxylation of ?.sup.9-tetrahydrocannabinol: Kinetics and molecular modeling, Journal of Molecular Structure, 2011, volume 987, pages 67-73 and references therein.

[0078] Amide formation is carried out by activation of the carboxylic acid for example by formation of the N-hydroxysuccinimide ester and coupling with the corresponding amine, for example see Goto (Y. Goto, Y. Shima, S. Morimoto, Y. Shoyama, H. Murakami, A. Kusai and K. Nojima, Determination of tetrahydrocannabinolic acid-carrier protein conjugate by matrix-assisted laser desorption/ionization mass spectrometry and antibody formation, Organic Mass Spectrometry, 1994, volume 29, pages 668-671). Alternative amide coupling reagents include but are not limited to dicyclohexyl carbodiimide (DCC), di-iso-propyl carbodiimide (DIC), 0-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), 0-(benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and bromotri(pyrrolidino)phosphonium hexafluorophosphate (PyBrop) (E. Valeur and M. Bradley, Amide bond formation: beyond the myth of coupling reagents, Chemical Society Reviews, 2009, volume 38, pages 606-631).

[0079] The aforementioned novel cannabinoids with formulae 5 above may be used as active compounds either alone or admixed in combination with known cannabinoids such as but not limited to ?.sup.9-tetrahydrocannabinol (THC), tetrahydrocannabivarin (THBV), cannabidiol (CBD) or cannabidivarin (CBDV) or other drugs for the treatment of pain, multiple sclerosis-related spasticity, nausea, epilepsy, Alzheimer's brain injury/concussion, cancer, infection, glaucoma and retinal degeneration, disorders of immune-inflammation, lung injury or disease, liver injury or disease, kidney injury or disease, eye injury or disease, amongst other pathologies. In some embodiments, the said novel cannabinoids with formulae 5 above either alone or admixed in combination with known cannabinoids such as but not limited to ?.sup.9-tetrahydrocannabinol (THC), tetrahydrocannabivarin (THBV), cannabidiol (CBD) or cannabidivarin (CBDV) or other drugs are formulated into pharmaceutical compositions in a suitable form for administration to a patient. Such formulations, in addition to the active cannabinoid or cannabinoids in a combination therapeutic agent, contain pharmaceutically acceptable diluents and excipients, which may include binders such as lactose, starches, cellulose, sorbitol, polyethylene glycol or polyvinyl alcohol or other pharmaceutically acceptable oligosaccharides or polymers, disintegrants such as polyvinylpyrrolidone, carboxymethylcellulose or other pharmaceutically acceptable disintegrants, vehicles such as petrolatum, dimethyl sulfoxide, mineral oil, or in omega-3 oil-in-water nanoemulsions, or as complexes with cyclodextrins such as hydroxypropyl-beta-cyclodextrin, preservatives including antioxidants such as vitamin A, vitamin E, vitamin C, retinyl palmitate, cysteine, methionine, sodium citrate, citric acid, parabens or alternative pharmaceutically acceptable preservatives, antiadherents, lubricants and glidants such as magnesium stearate, stearic acid, talc, silica, pharmaceutically acceptable fats or oils, coatings such as cellulose ether hydroxypropyl methylcellulose, gelatin or other pharmaceutically acceptable coatings, flavors and fragrances such as but not limited to the volatile terpenes of Cannabis and citrus fruits and other pharmaceutically acceptable diluents or excipients. The aforementioned pharmaceutical compositions may be administrated to a patient by enteral administration for example as a pill, tablet or capsule, by sublingual administration for example as a tablet, strip, drops, spray, lozenge, effervescent tablet, intranasal administration for example as a spray or micronized powder, inhalation administration for example as a spray or micronized powder, rectal administration for example as a suppository or solution, by parenteral drug administration by intramuscular, subcutaneous or intravenous injection for example of a solution or by other known methods of clinical administration.

[0080] The aromatization reaction is suitable for the synthesis of novel cannabinoids 5 and these compounds are also part of the invention. The invention includes synthesis of the target cannabinoids as oils or crystalline derivatives, as appropriate, including solvates, hydrates and polymorphs. These novel cannabinoids 5 have the formula:

##STR00007## [0081] wherein: [0082] R.sup.A is H, CO.sub.2H and its pharmaceutically acceptable salts, CO.sub.2R.sup.C, CONHR.sup.D, CONR.sup.DR.sup.E; [0083] R.sup.B is H or C.sub.1 to C.sub.2 alkyl, linear or branched C.sub.3 to C.sub.10 alkyl or double branched C.sub.4 to C.sub.10 alkyl in each case optionally substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro-groups, (CH.sub.2).sub.oC.sub.3 to C.sub.6 cycloalkyl, (CH.sub.2).sub.pOR.sup.F, or C.sub.3 to C.sub.6 cycloalkyl optionally substituted by a C.sub.1 to C.sub.8 alkyl; [0084] o is 0, 1, 2, 3, 4, 5 or 6; [0085] p is 1, 2, 3, 4, 5 or 6; [0086] R.sup.C is C.sub.1 to C.sub.6 alkyl, (CH.sub.2).sub.qC.sub.3 to C.sub.6 cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl; [0087] q is 0, 1, 2, 3, 4, 5 or 6; [0088] R.sup.D is C.sub.1 to C.sub.6 alkyl, (CH.sub.2).sub.rC.sub.3 to C.sub.6 cycloalkyl, C.sub.3 to C.sub.6 cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl; R.sup.E is C.sub.1 to C.sub.6 alkyl, (CH.sub.2).sub.rC.sub.3 to C.sub.6 cycloalkyl, allyl, benzyl, substituted benzyl or 2-phenylethyl; or NR.sup.DR.sup.E is azetidinyl, pyrrolidinyl, morpholinyl or piperidinyl each optionally substituted by one or two hydroxyl groups or hydroxymethyl groups with the exception that the hydroxyl groups cannot be on the carbon bearing the heterocyclic ring nitrogen or the heterocyclic ring oxygen with morpholine; [0089] R.sup.F is C.sub.1 to C.sub.6 alkyl, (CH.sub.2).sub.rC.sub.3 to C.sub.6 cycloalkyl; [0090] each r is independently 0, 1, 2, 3, 4, 5 or 6;
with the exception of cannabinoids cannabigerol (CBG, 1), cannabigerolic acid (CBGA, 2), cannabigerovarin (CBGV, 3) cannabigerovarinic acid (CBGVA, 4), and cannabinoids 5 [R.sup.A?H with R.sup.B?H, R.sup.B?CH.sub.3, R.sup.B=n-C.sub.3H.sub.7, R.sup.B?CH.sub.2OH, R.sup.B=n-C.sub.5H.sub.11, R.sup.B=n-C.sub.7H.sub.15, R.sup.B?CH.sub.2OCH.sub.3, R.sup.B?CH.sub.2CH.sub.2 CH.sub.2CH.sub.2CH.sub.2OH, R.sup.B?C(CH.sub.3).sub.2(CH.sub.2).sub.5CH.sub.3, R.sup.B?CH.sub.2(CHOH)-n-C.sub.3H.sub.7, R.sup.B?C.sub.2H.sub.4(CHOH)-n-C.sub.2H.sub.5, R.sup.B?C.sub.3H.sub.6(CHOH)CH.sub.3], 5 [R.sup.A?CO.sub.2H with R.sup.B=n-C.sub.3H.sub.7, R.sup.B=n-C.sub.5H.sub.11], 5 [R.sup.A?CO.sub.2CH.sub.3 with R.sup.B?CH.sub.3, R.sup.B=n-C.sub.3H.sub.7, R.sup.B=n-C.sub.5H.sub.11], and 5 [R.sup.A?CO.sub.2CH.sub.2CH.sub.3 with R.sup.B=n-C.sub.5H.sub.11].

[0091] The dioxinone resorcylate derivatives 7 below, which are intermediates for the synthesis of cannabinoids, are also available by the synthetic routes herein described and are part of the invention. These novel dioxinone derivatives 7 have the formula:

##STR00008## [0092] wherein: [0093] R.sup.B is H or C.sub.1 to C.sub.2 alkyl, linear or branched C.sub.3 to C.sub.10 alkyl or double branched C.sub.4 to C.sub.10 alkyl in each case optionally substituted by one or two hydroxyl groups or optionally substituted by one or more fluoro-groups, (CH.sub.2).sub.oC.sub.3 to C.sub.6 cycloalkyl, (CH.sub.2).sub.pOR.sup.F, or C.sub.3 to C.sub.6 cycloalkyl optionally substituted by a C.sub.1 to C.sub.8 alkyl; [0094] o is 0, 1, 2, 3, 4, 5 or 6; [0095] p is 1, 2, 3, 4, 5 or 6; [0096] R? and R? are independently C.sub.1 to C.sub.6 alkyl or optionally substituted aryl or R? and R? in combination are (CH.sub.2).sub.s; [0097] s is 4, 5 or 6.
with the exception of 7 (R.sup.B=Me; R?=R?=Me).

EXAMPLES

Example 1

(E)-3,7-Dimethylocta-2,6-dien-1-yl 4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate (6, R.SUP.?.?R.SUP.?.=Me)

[0098] ##STR00009##

[0099] N-(3-Dimethylaminopropyl)-N-ethyl carbodiimide hydrochloride (16) (2.6 g, 12.5 mmol) and 4-dimethylaminopyridine (DMAP) (1.5 g, 12.5 mmol) were sequentially added to a solution of 2-phenyl-1,3-dioxane-4,6-dione (14, R.sup.?=Ph, R.sup.??H) (2.4 g, 12.5 mmol) in anhydrous dichloromethane (125 mL). After 5 minutes, 2-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)acetic acid (15, R.sup.??R.sup.?=Me) (2.3 g, 12.5 mmol) was added with stirring in one portion. After 16 hours at room temperature, water (100 mL) was added and the organic fraction separated. The organic fraction was washed with 1M hydrochloric acid (2?100 mL) and brine (100 mL). The washed organic layer was dried over MgSO.sub.4, filtered, and concentrated under reduced pressure. The crude product was immediately dissolved in anhydrous toluene (100 mL), and geraniol (18) (1.1 mL, 6.3 mmol) was added dropwise with stirring. The solution was heated to 55? C. and maintained at this temperature for 4 hours. Once the starting material had been consumed, the solution concentrated under reduced pressure. The crude reaction product was purified by flash column chromatography (EtOAc:pentane; 4:20), providing the title compound 6 (R.sup.??R.sup.?=Me) as a colorless oil (1.9 g, 5.3 mmol, 84%): .sup.1H NMR (400 MHz, CDCl.sub.3) ? 5.43-5.27 (m, 2H), 5.11-5.04 (m, 1H), 4.71-4.63 (m, 2H), 3.51 (s, 2H), 3.50 (d, J=0.5 Hz, 2H), 2.15-2.00 (m, 4H), 1.71 (s, 6H), 1.69 (s, 1H), 1.68 (d, J=1.3 Hz, 4H), 1.60 (d, J=1.4 Hz, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 195.8, 166.5, 163.7, 143.8, 132.1, 123.7, 117.4, 107.5, 97.3, 62.8, 49.3, 47.1, 39.7, 26.4, 25.8, 25.2, 17.9, 16.7; IR (neat) 2966, 2917, 2856, 1718, 1636, 1388, 1270, 1200, 1014, 900 cm.sup.?1; HRMS (ES+) m/z calculated for C.sub.20H.sub.29O.sub.6[M+H].sup.+ 365.1959, found 365.1968; Rf 0.14 (EtOAc:pentane; 4:20) UV/Vanillin.

Example 2

(E)-8-(3,7-Dimethylocta-2,6-dien-1-yl)-7-hydroxy-2,2-dimethyl-5-pentyl-4H-benzo[d][1,3]dioxin-4-one (7, R.SUP.?.?R.SUP.?.=Me, R.SUP.B.=n-pentyl)

[0100] ##STR00010##

[0101] (E)-3,7-Dimethylocta-2,6-dien-1-yl 4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-oxobutanoate 6 (R.sup.??R.sup.?=Me) (1.5 g, 4.1 mmol) was dissolved in dichloromethane (30 mL) cooled to 0? C. and pyridine (0.66 mL, 8.2 mmol) and MgCl.sub.2 (0.4 g, 4.1 mmol) were added sequentially with stirring. After 5 minutes, n-hexanoyl chloride (R.sup.BCOZ, R.sup.B=n-pentyl, Z=Cl) (0.75 g, 6.2 mmol) was added dropwise with stirring. After stirring for 1 hour at 0? C. and 2 hours at room temperature, saturated aqueous NH.sub.4Cl (50 mL) was added and the biphasic mixture was subsequently acidified to pH 1 using 1M hydrochloric acid. The biphasic mixture was separated, and the aqueous partition was extracted with dichloromethane (2?50 mL). The combined organic fractions were washed with brine (100 mL), dried with MgSO.sub.4, filtered, and concentrated under reduced pressure. The resultant oil was dissolved in THF (20 mL) and tri(2-furyl)phosphine (190 mg, 0.8 mmol) and tris(dibenzylideneacetone)dipalladium(0) (180 mg, 0.2 mmol) were added sequentially. After 1 hour, CsOAc in iso-propanol (0.5 M, 24 mL, 12 mmol) was added dropwise with stirring, and the reaction mixture was stirred for a further 1 hour. The reaction was quenched with 10% aqueous citric acid (100 mL), the biphasic solution was separated, and the aqueous layer was extracted with dichloromethane (3?40 mL). The organic extracts were combined and washed with brine (100 mL), dried over MgSO.sub.4, filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography (dichloromethane:pentane; 1:1) to provide the title compound 7 (R.sup.??R.sup.?=Me, R.sup.B=n-pentyl) as a white solid (0.77 mg, 1.9 mmol, 47%): .sup.1H NMR (400 MHz, CDCl.sub.3) ? 6.42 (s, 1H), 6.10 (s, 1H), 5.24-5.14 (m, 1H), 5.04 (dddd, J=7, 5.5, 3.5, 1.5 Hz, 1H), 3.32 (dd, J=7, 1 Hz, 2H), 3.04-2.94 (m, 2H), 2.16-1.99 (m, 5H), 1.79 (d, J=1.3 Hz, 3H), 1.67 (s, 7H), 1.75-1.52 (m, 6H), 1.66 (d, J=1.5 Hz, 3H), 1.58 (d, J=1.5 Hz, 3H), 1.34 (tq, J=5, 3 Hz, 5H), 0.93-0.82 (m, 3H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 160.6, 160.1, 156.1, 147.8, 138.6, 132.0, 123.7, 120.9, 112.9, 112.7, 105.0, 104.6, 39.7, 34.3, 31.9, 30.6, 26.4, 25.7, 22.6, 22.0, 17.7, 16.2, 14.1; IR (neat) 3291 (br), 2956, 2924, 2855, 1690, 1605, 1590, 1293, 1276, 1208, 1165, 1113, 1047 cm.sup.?1; HRMS (ES+) m/z calculated for C.sub.25H.sub.37O.sub.4[M+H].sup.+ 401.2686, found 401.2686; Rf 0.28 (dichloromethane:pentane; 1:1) UV/Vanillin.

Example 3

[0102] Cannabigerolic Acid (2)

##STR00011##

[0103] Potassium tert-butoxide (450 mg, 4 mmol) was suspended in Et.sub.2O (5 mL) and (E)-8-(3,7-dimethylocta-2,6-dien-1-yl)-7-hydroxy-2,2-dimethyl-5-pentyl-4H-benzo[d][1,3]dioxin-4-one 7 (R.sup.??R.sup.?=Me, R.sup.B=n-pentyl) (200 mg, 0.5 mmol) and water (30 ?L, 2 mmol) were added to the suspension. After 72 hours stirring, water (10 mL) and Et.sub.2O (10 mL) were added and the biphasic mixture was phase separated. The organic layer was extracted with water (3?10 mL). The collected aqueous fraction was acidified with 4M hydrochloric acid (10 mL) until pH 1 was reached. The acidic solution was extracted with dichloromethane (3?10 mL) and the combined organic extracts were dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (AcOH:EtOAc:pentane; 0.01:1:20) to give cannabigerolic acid (2) as a white powder (120 mg, 0.34 mmol, 68%): .sup.1H NMR (400 MHz, CD.sub.3OD) a 6.20 (s, 1H), 5.21 (tq, J=7, 1.5 Hz, 1H), 5.05 (ddq, J=8.5, 6, 1.5 Hz, 1H), 3.27 (d, J=7 Hz, 2H), 2.91-2.76 (m, 2H), 2.09-2.00 (m, 2H), 1.95 (dd, J=8.5, 6.5 Hz, 2H), 1.76 (d, J=1.5 Hz, 3H), 1.59 (t, J=1.5 Hz, 4H), 1.58-1.48 (m, 4H), 1.41-1.27 (m, 4H), 0.96-0.87 (m, 3H); .sup.13C NMR (101 MHz, CD.sub.3OD) a 175.4, 164.7, 161.1, 146.8, 135, 132, 125.5, 124.2, 114.0, 110.9, 104.5, 40.9, 37.6, 33.2, 33.0, 27.7, 25.8, 23.6, 22.8, 17.7, 16.2, 14.4; IR (neat) 3534, 3400, 2959, 2911, 1635, 1610 1457, 1271, 1245, 1169, 754 cm.sup.?1; H RMS (ES+) m/z calculated for C.sub.22H.sub.33O.sub.4[M+H].sup.+ 361.2373, found 361.2372; Rf 0.32 (AcOH:EtOAc:pentane; 0.01:1:20) UV/Vanillin.

Example 4

[0104] Cannabigerol (1)

##STR00012##

[0105] In a sealable reaction vial, (E)-8-(3,7-Dimethylocta-2,6-dien-1-yl)-7-hydroxy-2,2-dimethyl-5-pentyl-4H-benzo[d][1,3]dioxin-4-one 7 (R.sup.??R.sup.?=Me, R.sup.B=n-pentyl) (100 mg, 0.25 mmol) was dissolved in 1,4-dioxane (2.5 mL). Aqueous 5M KOH was (1.25 mL) was added and the biphasic mixture was sparged with nitrogen for 10 minutes. The reaction vial was sealed and heated to 120? C. for 18 hours. After cooling to room temperature, the reaction mixture was acidified with 4M hydrochloric acid (10 mL) with cooling, and the aqueous layer was extracted with EtOAc (3?20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO.sub.4, filtered, and concentrated under reduced pressure. The crude product was purified by column chromatography (Et.sub.2O:pentane; 2:20) to provide cannabigerol (1) as a white powder (50 mg, 0.16 mmol, 64%): .sup.1H NMR (400 MHz, CDCl.sub.3) ? 6.41 (s, 1H), 5.91 (s, 1H), 5.20 (tq, J=7.3, 1.3 Hz, 1H), 5.08-4.99 (m, 1H), 3.33 (d, J=7.2 Hz, 2H), 3.05-2.93 (m, 2H), 2.06 (tq, J=9.5, 5, 3.5 Hz, 4H), 1.79 (d, J=1.5 Hz, 3H), 1.67 (d, J=3 Hz, 9H), 1.59 (d, J=1.5 Hz, 6H), 1.45-1.24 (m, 5H), 0.94-0.82 (m, 5H); .sup.13C NMR (101 MHz, CDCl.sub.3) ? 160.6, 160.2, 156.2, 148.0, 139.0, 132.2, 123.8, 120.9, 113.0, 112.7, 110.1, 105.2, 104.7, 39.8, 34.4, 32.0, 30.8, 26.5, 25.9, 22.7, 22.1, 17.9, 16.4, 14.2; IR (neat) 3215, 2956, 2912, 2854, 1689, 1591, 1420, 1297, 912, 863 cm.sup.?1; HRMS (ES+) m/z calculated for C.sub.21H.sub.32O.sub.2[M+H].sup.+ 316.2402, found 316.2402; Rf 0.22 (Et.sub.2O:pentane; 2:20) UV/Vanillin.