Chemistry process for the production of cannabinoid compounds

Abstract

This invention relates to a novel process for the synthesis of CBD- and THC-related natural cannabinoids using natural eccalite clay as a green catalyst, and has been optimised to produce CBDV and Δ9-THCV. Starting from resorcinol derivatives and chiral terpenes, the method first yields intermediate carboxylic acids or esters, which are hydrolyzed to intermediate target CBD-related cannabinoids. These are then further cyclized to form the target THC-related cannabinoids. The process emphasizes environmental sustainability, efficiency, and regioselectivity, avoiding toxic or corrosive reagents requiring specialist handling and environments, and enabling simpler, high-purity production of these cannabinoid classes.

Description

[0001] 2 CHEMISTRY PROCESS FOR THE PRODUCTION OF CANNABINOID COMPOUNDS FIELD OF THE INVENTION The field of the invention pertains to pharmaceutical chemistry, specifically focusing on the synthesis of cannabinoid compounds using environmentally friendly or "green" chemistry methods. It involves the innovative use of a natural eccalite (a form of bentonite clay) as a primary catalyst in a two-step synthesis process to produce cannabinoids, such as cannabidivarin (CBDV) and Δ9-tetrahydrocannabivarin (Δ9-THCV) among others, for pharmaceutical applications. This field encompasses the development of novel synthetic pathways, catalysis, and the optimization of these processes for higher yield, selectivity, and environmental sustainability in the production of minor cannabinoids.

[0002] 3 BACKGROUND OF THE INVENTION Exploration into the constituents of cannabis, including natural and synthetic cannabinoids, has expanded the understanding and identification of compounds with therapeutic potential. Among these, CBDV and Δ9-THCV are noted for their unique properties, offering potential treatments for a variety of medical conditions without the psychoactive effects of THC. Identified initially in hashish1, these compounds are distinct due to their propyl side chain, differentiating them from the more common pentyl chain found in cannabinoids like CBD and THC. This variation is critical, given that certain cannabis strains, particularly African landrace strains, show higher concentrations of these minor cannabinoids. The clinical interest in cannabinoids has fuelled extensive research into their effects on the human body, specifically their interaction with the endocannabinoid system (ECS) and transient receptor potential (TRP) ion channels. The therapeutic implications of CBDV and Δ9-THCV, especially in the treatment of neuropathic pain, epilepsy, osteoarthritis, autism spectrum disorder (ASD), and muscular dystrophy, are significant. These effects can be attributed to their chemical structure and interaction with physiological systems, including modulation of the ECS and impact on TRP ion channels2,3. Given the therapeutic potential, there is a pressing need for efficient, sustainable, and economically viable production methods for CBDV and Δ9-THCV. Traditional isolation of these materials from cannabis extracts is hindered by low yields and high cost, driving the development of synthetic and semi-synthetic methods for large-scale production. The current invention introduces a novel two-step synthesis pathway employing "green" chemistry principles with eccalite clay as a catalyst, focussing on environmental sustainability while optimizing yield and purity. The synthesis method employs eccalite, a type of bentonite clay, to catalyse the synthesis of both CBDV and Δ9-THCV and aligning with sustainable practices. Beginning with specific resorcinol derivatives, the process culminates in the efficient production of the target cannabinoids, overcoming the limitations of natural abundance 4 and previous synthetic methods4. This advancement in cannabinoid research and production draws from a rich foundation of existing research, including the pharmacology of cannabinoids and their production methods. Notably, this invention parallels and expands upon previous patents focused on cannabinoid conversion and purification processes. For instance, patents WO2020198876A15, WO2021207605A16, and US 11352337 B17describe methods and apparatuses for converting CBD or its derivatives into other cannabinoids or for preparing cannabinoids using specific catalysts such as zeolites. Moreover, WO2006136273A18and WO2020146907A19detail processes for converting CBD to THC, utilizing molecular sieves or other novel methods. These patents, along with WO2017194173A110which focuses on purifying cannabinoid compounds, underscore the ongoing efforts and innovations in cannabinoid synthesis and processing. The current invention contributes to this evolving landscape by offering a greener, efficient synthesis method for CBDV and Δ9-THCV, further enriching the field with a sustainable production approach. References 1. Merkus, F. W. H. M. " Cannabivarin and Tetrahydrocannabivarin, Two New Constituents of Hashish." Nature, 1971, 232, 579–580. 2. De Petrocellis, L.; Ligresti, A.; Moriello, A. S.; Allarà, M.; Bisogno, T.; Petrosino, S.; Stott, C. G.; Di Marzo, V. " Effects of cannabinoids and cannabinoid- enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes." British Journal of Pharmacology, 2011, 163, 7, 1479-1494. 3. González-Ramírez, R.; Chen, Y.; Liedtke, W. B. et al. “TRP Channels and Pain.” In “Neurobiology of TRP Channels” (Emir, T. L. R. ed.); Boca Raton (FL): CRC Press / Taylor & Francis; 2017. Chapter 8. Available from: https: / / www.ncbi.nlm.nih.gov / books / NBK476120 / doi: 10.4324 / 9781315152837-8. 4. Bloemendal, V. R. L. J.; van Hest, J. C. M.; Rutjes, F. P. J. T. “Synthetic pathways to tetrahydrocannabinol (THC): an overview.” Org. Biomol. Chem., 2020,18, 3203-3215. 5 Lewis, J. et al. "Apparatus for and method of converting CBD and / or CBD derivatives to at least one other type of cannabinoid and / or cannabinoid derivative such as THC." WO2020198876A1, 2020. Sotzing, G. A. "Methods for preparing cannabinoids and related instruments." WO2021207605A1, 3Bc, Llc, 2021. Gindelberger, D. "Zeolite catalyst and method for preparation of aromatic tricyclic pyrans." US 11352337 B1, 2022. Erler, J.; Heitner, S. "Method for the production of dronabinol from cannabidiol, using a molecular sieve." WO2006136273A1, 2005. Nivorozhkin, A. "Novel methods and related tools for CBD conversion to THC." WO2020146907A1, 2020. H. Erfurt, M. Weber, H.-J. Niemeyer, M. R. Götz, M. Winkler. “Method for purifying cannabinoid compounds.” WO2017194173A1, Symrise Ag, 2016.

[0003] 6 SUMMARY OF THE INVENTION According to a first aspect of the invention, there may be provided a process for the production of cannabinoid compounds of general formula III and IV wherein R is independently chosen from H, OH, alkyl, alkenyl, alkynyl, or cycloalkyl; R1 – R4 are independently chosen from H, halogen, nitrile, nitro, hydroxy, alkyl, O-alkyl, carboxylate, acyl, branched alkyl, ester, S-alkyl, alkylsulphonyl, alkylsulphoxide, alkylsulphonamide, S-(hetero)aryl, (hetero)arylsulphonyl, (hetero)arylsulphoxide, (hetero)arylsulphonamide, alkenyl, alkynyl, (hetero)cycloalkyl, acyloxy, (hetero)aryl; where the alkyl or (hetero)aryl moieties are optionally further substituted with one or more groups independently selected from halogen, hydroxy, alkyl, O-alkyl, carboxylate, acyl, amino or, amino alkyl; wherein the alkyl, alkenyl, alkynyl, (hetero)cycloalkyl, acyl, acyloxy, (hetero)aryl or (hetero)arylalkyl moieties are independently further substituted with one or more groups selected from cyano, halogen, nitro; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-14 arylalkyl, heteroaryl or heterocycloalkyl, each optionally substituted with further group(s) Y; and C(O)Ra, C(O)ORa, C(O)NRbRc, C(=NRa)NRbRc, OR, OC(O)Ra, OC(O)ORa, OC(O)NRbRc, OC(=NRa)NRbRc, OS(O)Ra, OS(O)2Ra, OS(O)NRbRc, NRbRc, NRbC(O)Rd, NRbC(O)ORd, NRa(O)NRbRc, NRaC(=NRb)NRcRd, NRaS(O)Rb, NRaS(O)2Rb, NRaS(O)NRbRc, NRaS(O)2NRbRc, SRa, S(O)Ra, S(O)NRaRb, S(O)2NRaRb, and (CH2)nNRaRb, where Ra, Rb, Rc and Rd are independently selected from 7 hydrogen, cyano, halogen, nitro; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-14 arylalkyl, heteroaryl or heterocycloalkyl; Further, the process may comprise treating compound of formula I having R1 = OH and blocking group R2 with a chiral terpene formula II with X = OR in the presence of an acidic clay to form a product with formula III; Still further converting intermediate formula III having with R1 = OH and blocking group R2 to deprotected compound formula III having R1 = OH and R2 = H to under basic conditions; and Taking compound formula III having R1 = OH and R2 = H and treating it with the same acid catalyst to form the final product formula IV having R1 = OH and R2 = H. In an ideal embodiment, the process as described above for the preparation of compound formula V or pharmaceutical acceptable salt or ester thereof; the process may comprise treating a resorcinol compound of formula VI where X = CO2R (R = alkyl, alkenyl, alkynyl, or cycloalkyl) with a chiral terpene compound of formula VII in the presence of an acidic clay as catalyst to form a compound of formula VIII. Further, the process above where treating compound of formula VIII (X = CO2R) with a hydrolysing agent forms a compound of formula VIII (X = H), Still further, the process above where cyclising the compound of formula VIII (X = H) by reacting with an acidic clay forms compound formula V. 8 Moreover, the process as claimed above where the compound with formula VIII may be selected from any one or more of the following compounds: 2,4-Dihydroxy-3-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6- propylbenzoic acid and its alkyl or cycloalkyl esters 6-Butyl-2,4-dihydroxy-3-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en- 1-yl]benzoic acid and its alkyl or cycloalkyl esters 2,4-Dihydroxy-3-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6- pentylbenzoic acid and its alkyl or cycloalkyl esters 2,4-Dihydroxy-6-hexyl-3-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en- 1-yl]benzoic acid and its alkyl or cycloalkyl esters 2,4-Dihydroxy-6-heptyl-3-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2- en-1-yl]benzoic acid and its alkyl or cycloalkyl esters 2,4-Dihydroxy-3-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6- octylbenzoic acid and its alkyl or cycloalkyl esters 2,4-Dihydroxy-3-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6- phenylbenzoic acid 2-[(6R)-3-Methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-propylbenzene- 1,3-diol and esters thereof 5-Butyl-2-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]benzene- 1,3-diol and esters thereof 2-[(6R)-3-Methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene- 1,3-diol and esters thereof 5-Hexyl-2-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]benzene- 1,3-diol and esters thereof 5-Heptyl-2-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5- benzene-1,3-diol and esters thereof 2-[(6R)-3-Methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-phenylbenzene- 1,3-diol and esters thereof The process as claimed above, where the compound with formula V is selected from any one or more of the following compounds: (6aR,10aR)-3-Propyl-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydrobenzo[c]- chromen-1-ol and esters thereof 9 (6aR,10aR)-3-Butyl-6,6,9-trimethyl-3-butyl-6a,7,8,10a-tetrahydrobenzo[c]- chromen-1-ol and esters thereof (6aR,10aR)-3-Pentyl-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]- chromen-1-ol and esters thereof (6aR,10aR)-3-Hexyl-6,6,9-trimethyl-3-hexyl-6a,7,8,10a-tetrahydrobenzo[c]- chromen-1-ol and esters thereof (6aR,10aR)-3-Heptyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydrobenzo[c]chromen- 1-ol and esters thereof (6aR,10aR)-3-Phenyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydrobenzo[c]chromen- 1-ol and esters thereof Coupling compound formula VI (X = CO2R) and compound formula VII (Y = OH) The process as described above to produce compound of formula VIII (X = CO2R) where the acid catalyst may be an acidic clay, comprising of any one or more of mordenite, zeolite and bentonites. More specifically, the acidic clay may be a natural zeolite or eccalite that is activated with aqueous acid and dried before use. The process as described above wherein the solvent used with the acidic clay may be chosen from any one or more of hydrocarbons, cyclic hydrocarbons, halogenated hydrocarbons, aromatics, ketones, alcohols, carbonates and esters, preferably wherein the solvent used with the acidic clay may be chosen from chlorinated aliphatic solvents. Most preferably, the chlorinated aliphatic solvent may be dichloromethane. The process for the preparation of compound formula VIII (X = CO2R), wherein the reaction may be performed between 0 and 50 °C, preferably between 15 and 30 °C and most preferably at 25°C. 10 The process as described above, wherein the mole ratio of resorcinol to chiral terpene may be between 1:1 and 10:1, preferably 1:1 to 1:3, and most preferably 1:2. The process as described above wherein the concentration of the resorcinol in solvent may be between 2 – 15% m / v, most preferably 10% m / v. The process as described above wherein the ratio of resorcinol to eccalite is in the range 1:1 – 1:3 m / m, most preferably 1:1 m / m. The process as described above where a drying agent, such as anhydrous sodium sulphate or magnesium sulphate, may be present in a 1:1 m / m ratio with the resorcinol. The process as described above where the unreacted resorcinol of formula VI (X = CO2R) may be reclaimed from the reaction mixture with aqueous base, preferably an alkaline hydroxide, most preferably 2% (m / v) aqueous potassium hydroxide, and then isolated acidification and extraction to produce the unchanged starting material. The process as described above where the compound formula VIII (X = CO2R, R4 = H) may be formed exclusively, free of cannabinoid regioisomers. The process as described above wherein the crude product of formula VIII (X = CO2R) may be used as-is in the hydrolysis reaction, or the terpenoid by- products may be distilled off under vacuum before use and the residue used in the next step. Hydrolysis of 11 The process as described above to produce compound of formula VIII (X = H) wherein the solvent used may be a C1 – C4 alcohol, most preferably methanol, and the hydrolysing agent is an alkaline hydroxide, most preferably sodium hydroxide. The process as described above wherein the hydrolysis of compound formula VIII (X = CO2R) to compound formula VIII (X = H) may be accomplished in boiling aqueous hydroxide / alcohol solution, and wherein the base is most preferably 5M sodium hydroxide and the alcohol is methanol; and the final ratio of these may be 7:3 v / v alcohol: hydroxide solution. The process as described above where the concentration of the compound formula VIII (X = CO2R) may be 2 -15% m / v, most preferably 10% m / v. The process as described above wherein the product may be isolated by acidification using mineral or organic acids, most preferably ascorbic or citric acid, then extracted and dried to a crude material. The process as described above wherein the crude material may be purified by recrystallisation from hydrocarbon solvents selected from C1 - C10 alkanes, cycloalkanes, or branched alkanes, most preferably heptane or decane at -10°C - 0°C to afford pure crystalline compound formula VIII (X = H). Ring-closure of compound formula VIII (X = H) The process as described above to produce compound of formula VIII (X = H) where the acid catalyst may be an acidic clay, comprising of any one or more of mordenite, zeolite and bentonites. Most preferably, the acidic clay may be a natural eccalite that is activated with aqueous acid and dried before use. 12 The process as described above wherein the solvent used with the acidic clay may be chosen from any one or more of hydrocarbons, cyclic hydrocarbons, halogenated hydrocarbons, aromatics, ketones, alcohols, carbonates and esters. More preferably, the solvent used with the acidic clay may be chosen from chlorinated aliphatic solvents, most preferably, the chlorinated aliphatic solvent may be dichloromethane. The process as described above wherein the cyclisation may be performed between –20°C to 30°C, preferably –15°C to 0°C and most preferably at -2°C to -10°C. The process as described above wherein the reaction may be performed in flow chemistry / plug flow mode. The process as described above wherein the eccalite may be placed in a flow column reactor in 1:1 to 1:20 m / m ratio of eccalite compound, most preferably a 1:10 m / m ratio. The process as described above wherein the substrate concentration may be between 1 – 20% m / v to solvent, preferably 5 – 15% m / v, and most preferably 10% m / v. The process as described above wherein the flow rate of the prepared solution through the acidic clay packed in the column reactor may be between 0.5 – 5 ml / min, most preferably 0.5-1.0 ml / min. The process as described above wherein the ratio of the desired product formula V may be formed in ~85% preference to its regioisomer X. 13 Process as described above, wherein the crude material may be purified by precipitation as a derivative by analogy to CN115583933B.

[0004] 14 EXPERIMENTAL The invention will now be described with reference to the following non-limiting examples. 1. Synthesis of resorcinols A stirred (500rpm) solution of sodium (40.758g, 1.773mol) in anhydrous absolute ethanol (750ml, 2.36M) at 25°C under nitrogen atmosphere was treated with a blend of ethyl acetoacetate (103.712g, 0.767mol) and ethyl hexanoate (94.671g, 0.667mol) dropwise over 1h. The resultant solution was boiled for 18h, forming a dense yellow suspension. The reaction was cooled to 25°C and filtered to produce a yellow mass. The retentate was resuspended in ethyl acetate (500ml), filtered and dried to form a pale yellow salt. Water (250ml) was added to the mass and the solution cooled to 0°C before adjusting the pH < 2 using concentrated hydrochloric acid. The organic components separated as a yellow oil that was separated from the aqueous layer, dried with magnesium sulphate and concentrated to a yellow oil, ethyl 2,4-dioxo-6- propylcyclohexanecarboxylate (96.012g, 63.7%).1H NMR indicated that this was a complex mixture of the four possible diastereomers and was sufficiently pure to carry through to the next step. In a similar fashion, the following materials were prepared: A solution of sodium (1.234g, 53.54mmol), anhydrous absolute ethanol (20ml), ethyl acetoacetate (3.266g, 25.09mmol) and ethyl pentenoate (2.75g, 21.42mmol) was treated as above to afford a yellow oil, ethyl 2,4-dioxo-6-ethylcyclohexanecarboxylate 15 (1.878g, 42%). Analysis of isolated salt:1H NMR (D2O): 5.19 (s, 1H, H-3), 4.32 (q, 2H, OCH2Me, J 6.37Hz), 3.31 (d, 1H, H-1, J 9.31Hz), 2.51 (dd, 1H, H-5a, J 16.87 and 4.07Hz), 2.41 (m, 1H, H-6), 2.21 (dd, 1H, H-5b, J 16.30 and 10.18Hz), 1.53 (m, 1H, -CHCHaHb), 1.45 (m, 1H, -CHCHaHb), 1.37 (t, 3H, OCH2Me, J 6.41Hz), 0.99 (t, 3H, -CH2Me, J 6.68Hz);13C NMR (D2O): 198.59 (CO), 192.89 (C-2), 175.17 (CO2), 101.96 (C-3), 62.22 (OCH2Me), 57.32 (C-1), 38.41 (C-5), 37.81 (C-6), 26.24 (-CHCH2), 13.30 (OCH2Me), 10.03 (-CH2Me); UPLC-HRMS (ESI+): found 235.0935, C11H16O4Na requires 235.0946.1H NMR indicated that this was a complex mixture of the four possible diastereomers and was sufficiently pure to carry through to the next step. Analysis of the neutral oil: UPLC-HRMS (ESI-): found 211.0954; C11H15O4 requires 211.0970. A solution of sodium (1.445g, 62.85mmol), anhydrous absolute ethanol (24ml), ethyl acetoacetate (4.094g, 31.44mmol) and ethyl octenoate (3.53g, 24.16mmol) was treated as above to afford a yellow oil, ethyl 2,4-dioxo-6-pentylcyclohexanecarboxylate (2.715g, 44%). Analysis of isolated salt:1H NMR (D2O): 5.18 (s, 1H, H-3), 4.32 (q, 2H, OCH2Me, J 7.01Hz), 3.30 (d, 1H, H-1, J 9.90Hz), 2.51 (dd, 1H, H-5a, J 16.27 and 4.68Hz), 2.48 (m, 1H, H-6), 2.20 (dd, 1H, H-5b, J 16.59 and 10.09Hz), 1.46 and 1.35 (2 x m, 8H, -CH(CH2)4-), 1.37 (t, 3H, OCH2Me, J 7.10Hz), 0.95 (t, 3H, -CH2Me, J 7.09Hz);13C NMR (D2O): 198.50 (CO), 192.87 (C-2), 175.18 (CO2), 101.94 (C-3), 62.18 (OCH2Me), 57.80 (C-1), 38.43 (C-5), 36.79 (C-6), 33.26 (-CHCH2-), 30.95 (CH2CH2Me), 25.06 (-CH2(CH2)2Me), 21.78 (-CH2Me), 13.37 (OCH2Me), 13.30 (-CH2Me). UPLC-HRMS (ESI+): found 277.1400, C14H22O4Na requires 277.1416.1H NMR indicated that this was a complex mixture of the four possible diastereomers and was sufficiently pure to carry through to the next step. Analysis of the neutral oil: UPLC- HRMS (ESI-): found 253.1435; C14H21O4 requires 253.1440. 16 d. Ethyl 2,4-dioxo-6-phenylcyclohexanecarboxylate1 A solution of sodium (2.392g, 104.45mmol), anhydrous absolute ethanol (40ml), ethyl acetoacetate (6.473g, 49.74mmol) and ethyl cinnamate (6.645g, 37.71mmol) was treated as above to afford a beige powder, ethyl 2,4-dioxo-6- phenylcyclohexanecarboxylate (4.113g, 42%). Analysis of isolated salt:1H NMR (D2O): 7.47 (m, 5H, aryl H), 5.27 (s, 1H, H-3), 4.10 (q, 2H, OCH2Me, J 7.63Hz), 3.84 (d, 1H, H-1, J 11.95Hz), 3.68 (ddd, 1H, H-6, J 12.97, 12.26 and 4.56Hz), 2.76 (dd, 1H, H-5a, J 16.84 and 12.50Hz), 2.54 (dd, 1H, H-5b, J 16.88 and 4.48Hz), 1.11 (t, 3H, OCH2Me, J 7.17Hz);13C NMR (D2O): 197.33 (CO), 192.23 (C-2), 174.19 (CO2), 140.70 (quat. aryl C), 128.92 and 127.41 (aryl C), 101.78 (C-3), 62.03 (OCH2Me), 58.40 (C-1), 43.87 (C-5), 41.17 (C-6), 13.13 (OCH2Me). UPLC-HRMS (ESI+): found 283.0931, C15H16O4Na requires 283.0946.1H NMR indicated that this was a complex mixture of the four possible diastereomers and was sufficiently pure to carry through to the next step. Analysis of the neutral oil: UPLC-HRMS (ESI-): found 259.0951; C15H15O4 requires 259.0970. 2. Synthesis of resorcinols: dehydroaromatisation A stirred (500rpm) solution of ethyl 2,4-dioxo-6-propylcyclohexanecarboxylate (93.836g, 0.415mol) was dissolved in dry dimethylsulphoxide (750ml, 0.55M) at 80°C under nitrogen atmosphere was treated with iodine crystals (10.059g, 39.63mmol, 9.6%mol) in one portion and left to stir for 24h. The resultant brown / black solution was cooled to 25°C, portioned between ethyl acetate (750ml) and brine (750ml), then washed with saturated aqueous sodium dithionite (500ml) and brine (500ml). The organic extract was dried with magnesium sulphate under stirring, treated with DARCO activated carbon for 20 minutes and then filtered through celite before being 17 concentrated to an orange oil. Ethyl acetate was recycled for future use. The solid that resulted on standing was recrystallised from ~2% (v / v) ethyl acetate in hexane to afford a beige powder, ethyl divarinate (55.157g, 59.1%).1H NMR (CDCl3): 6.28 (d, 1H, H-3, J 2.68Hz), 6.23 (d, 1H, H-5, J 2.54Hz), 5.51 (br s, 1H, OH), 4.40 (q, 2H, OCH2Me, 7.20Hz), 2.84 (m, 2H, ArCH2-), 1.84 (br s, 1H, OH), 1.58 (m, 2H, -CH2Me), 1.42 (t, 3H, OCH2Me, J 7.29), 0.96 (t, 3H, -CH2Me, J 7.38Hz);13C NMR (CDCl3): 171.52 (CO), 165.37 (C-2), 160.21 (C-4), 148.63 (C-6), 110.86 (C-5), 105.22 (C-1), 101.45 (C-3), 61.30 (OCH2Me), 38.91 (ArCH2-), 24.98 (-CH2Me), 14.15 (-CH2Me), 14.08 (OCH2Me); UPLC-HRMS (ESI+): found 225.1114; C12H17O4 requires 225.1127; (ESI-): found 223.0952; C12H15O4 requires 223.0970. In a similar fashion, the following materials were prepared: b. Ethyl 2,4-dihydroxy-6-ethylbenzoate (VI, R1, R4 = H, R3 = ethyl, X = CO2Et)2 Ethyl 2,4-dioxo-6-ethylcyclohexanecarboxylate (1.878g, 8.846mol) in dry dimethylsulphoxide (9.4ml, 0.55M) containing iodine crystals (0.452g, 1.770mmol, 20%mol) as above, to afford a pale orange oil, ethyl 2,4-dihydroxy-6-ethylbenzoate (0.760g, 17%) after column chromatography (10-20% ethyl acetate:hexane).1H NMR (CDCl3): 11.81 (s, 1H, C-2 -OH), 6.28 (d, 1H, H-3, J 2.63Hz), 6.25 (d, 1H, H-5, J 2.67Hz), 5.68 (s, 1H, C-4 -OH), 4.41 (q, 2H, OCH2Me, 7.13Hz), 2.90 (q, 2H, ArCH2- , J 7.43), 1.42 (t, 3H, OCH2Me, 7.13Hz), 1.19 (t, 3H, CH2Me, J 7.45);13C NMR (CDCl3): 171.49 (CO), 165.26 (C-2), 160.49 (C-4), 150.27 (C-6), 110.04 (C-5), 105.11 (C-1), 101.37 (C-3), 61.34 (CO2CH2-), 29.75 (ArCH2-), 15.90 (CH2Me), 14.03 (OCH2Me); UPLC-HRMS (ESI+): found 209.0794; C11H13O4 requires 209.0814; (ESI-): found 211.0959; C11H15O4 requires 211.0970. c. Ethyl olivetate (VI, R1, R4 = H, R3 = pentyl, X = CO2Et)2 18 Ethyl 2,4-dioxo-6-pentylcyclohexanecarboxylate (2.715g, 10.68mol) in dry dimethylsulphoxide (13.6ml, 0.55M) containing iodine crystals (0.547g, 2.138mmol, 20%mol) as above, to afford a pale orange oil, ethyl olivetate (1.252g, 20.5%) after column chromatography (10-20% ethyl acetate:hexane).1H NMR (CDCl3): 11.81 (s, 1H, C-2 -OH), 6.28 (d, 1H, H-3, J 2.68Hz), 6.23 (d, 1H, H-5, J 2.63Hz), 5.80 (br s, 1H, C-4 -OH), 4.41 (q, 2H, OCH2Me, 7.20Hz), 2.85 (m, 2H, ArCH2-), 1.55 (m, 2H, ArCH2CH2-), 1.41 (t, 3H, OCH2Me, 7.23Hz), 1.33 (m, 4H, -(CH2)2Me), 0.90 (t, 3H, CH2Me, J 7.14);13C NMR (CDCl3): 171.55 (CO), 165.29 (C-2), 160.34 (C-4), 148.91 (C-6), 110.81 (C-5), 105.17 (C-1), 101.40 (C-3), 61.31 (CO2CH2-), 36.91 (ArCH2-), 32.05 (-CH2CH2Me), 31.62 (ArCH2CH2-), 22.61 (CH2Me), 14.11 (OCH2Me), 14.03 (CH2Me); UPLC-HRMS (ESI+): found 253.1426; C14H21O4 requires 253.1440; (ESI-): found 251.1265; C14H19O4 requires 251.1283. d. Ethyl 2,4-dihydroxy-6-phenylbenzoate (VI, R1, R4 = H, R3 = phenyl, X = CO2Et)2 Ethyl 2,4-dioxo-6-phenylcyclohexanecarboxylate (4.113g, 15.08mol) in dry dimethylsulphoxide (20.5ml, 0.55M) containing iodine crystals (0.828g, 3.61mmol, 20%mol) as above, to afford a pale yellow solid, ethyl 2,4-dihydroxy-6-phenylbenzoate (1.016g, 10.4%) after column chromatography (10-20% ethyl acetate:hexane).1H NMR (CDCl3): 11.34 (s, 1H, C-2 -OH), 7.31 (m, 3H, aryl H), 7.20 (m, 2H, aryl H), 6.44 (d, 1H, H-3, J 2.59Hz), 6.28 (d, 1H, H-5, J 2.61Hz), 5.86 (br s, 1H, C-4 -OH), 3.94 (q, 2H, OCH2Me, 7.20Hz), 0.73 (t, 3H, OCH2Me, 7.17Hz);13C NMR (CDCl3): 170.88 (CO), 164.11 (C-2), 159.85 (C-4), 147.45 (C-6), 142.88 (quaternary aryl C), 127.95, 127.47 and 126.78 (aryl C), 111.24 (C-5), 105.42 (C-1), 102.35 (C-3), 60.70 (CO2CH2-), 12.95 (OCH2Me); UPLC-HRMS (ESI+): found 259.0956; C15H15O4 requires 259.0970; (ESI- ): found 257.0803; C15H13O4 requires 257.0814. 19 3. Synthesis of cannabidiol derivatives: couplings a. 2,4-Dihydroxy-3-[(1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl]- 6-propyl-benzoate (VIII, R1, R4, R6, R7 = H, R3 = n-propyl, R5 = Me, X = A mechanically stirred (500rpm) solution of ethyl divarinate (38.576g, 0.172mol) and (1S,4R)-4-isopropenyl-1-methylcyclohex-2-en-1-ol (VII, R6, R7 = H, R, R5 = Me, Y = OH) (first portion: 34.140g, 0.224mol; second portion (18h): 15.676g, 0.103mmol) in anhydrous dichloromethane (390ml, 10% m / v) at 25°C was treated with magnesium sulphate (first portion: 41.671g; second portion (18h): 21.139g) and activated eccalite powder (first portion: 39.462g; second portion (18h): 22.650g). The resultant beige suspension was stirred for 18h between terpene doses. The solids were filtered off and washed with dichloromethane (100ml) and the filtrate concentrated to a brown gum. Dichloromethane was recycled for future use. 10% (v / v) Ethyl acetate:hexane solution (500ml) was added, and the solution was washed with 2% aqueous potassium hydroxide (2 x 100ml) and brine (100ml). The aqueous phase is acidified with concentrated hydrochloric acid, extracted with ethyl acetate (2 x 150ml), dried with magnesium sulphate and concentrated to a brown oil, unreacted ethyl divarinate, which can be used for repeat reactions. Ethyl acetate was recycled for future use. The existing ethyl acetate / hexane solution was dried with magnesium sulphate, decolourised with activated charcoal, filtered through celite and concentrated to a brown oil, crude 2,4-dihydroxy-3-[(1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2- enyl]-6-propyl-benzoate. The material was contaminated with terpenoid byproducts that may be distilled off before use, but is in general sufficiently pure to carry through to the next step. In a similar manner, the following were synthesised: 20 b. 2,4-Dihydroxy-3-[(1R,6R)-6-ethyl-3-methyl-6-(prop-1-en-2-yl)cyclohex- 2-enyl]benzoate (VIII, R1, R4, R6, R7 = H, R3 = ethyl, R5 = Me, X = CO2Et) A solution of the resorcinol (0.760g, 3.615mmol), cis-isolimonenol (0.851g, 5.588mmol), eccalite (0.773g), magnesium sulphate (0.783g) in dichloromethane (3ml) treated as above afforded, after column chromatography (5% ethyl acetate:hexane), 2,4-dihydroxy-3-[(1R,6R)-6-ethyl-3-methyl-6-(prop-1-en-2- yl)cyclohex-2-enyl]-benzoate (0.665g, 53%) as a clear viscous oil.1H NMR (CDCl3): 12.08 (s, 1H, C-2 OH), 6.48 (br s, 1H, C-4 OH), 6.23 (s, 1H, H-5), 5.55 (br s, 1H, H-2’), 4.53 (m, 1H, trans-H-1’’), 4.40 (m, 1H, cis-H-1’’), 4.39 and 4.38 (2 x q, 2H, CO2CH2Me, J 7.20Hz), 4.10 (br d, 1H, H-1’, J 7.41Hz), 2.92 (dq, 1H, ArCHaHbMe, J 13.85 and 7.42Hz), 2.80 (dq, 1H, ArCHaHbMe, J 13.83 and 7.34Hz), 2.39 (br m, 1H, H-6’), 2.22 (br m, 1H, H-4a’), 2.09 (br m, 1H, H-4b’), 1.82 – 1.78 (obscured m, 2H, H-5’), 1.78 (br m, 3H, C-3’ Me), 1.71 (br m, 3H, C-3’’ Me), 1.41 (t, 3H, CO2CH2Me, J 7.16Hz), 1.18 (t, 3H, ArCH2Me, J 7.42Hz);13C NMR (CDCl3): 172.18 (CO2), 163.16 (C-2), 160.00 (C-4), 147.27 (C-6), 140.11 (C-2’’), 124.13 (C-2’), 114.40 (C-3), 111.19 (C-1’’), 110.67 (C-5), 104.01 (C-1), 61.12 (CO2CH2Me), 46.64 (C-6’), 35.40 (C-1’), 30.23 (C-4’), 29.69 (ArCH2Me), 27.87 (C-5’), 23.66 (C-3’ Me), 18.85 (C-3’’ Me), 15.86 (ArCH2Me), 14.04 (CO2CH2Me); UPLC-HRMS (ESI+): found 345.2050; C21H29O4 requires 345.2066; (ESI-): found 343.1896; C21H27O4 requires 343.1909. c. 2,4-Dihydroxy-3-[(1R,6R)-3-methyl-6-pentyl-6-(prop-1-en-2- yl)cyclohex-2-enyl]benzoate (VIII, R1, R4, R6, R7 = H, R3 = pentyl, R5 = Me, A solution of (1.196g, 7.857mmol), eccalite (1.251g), magnesium sulphate (1.255g) in dichloromethane (6.2ml) treated as above afforded, after column chromatography (5% ethyl 21 acetate:hexane), 2,4-dihydroxy-3-[(1R,6R)-3-methyl-6-pentyl-6-(prop-1-en-2- yl)cyclohex-2-enyl]benzoate (0.891g, 47%) as a clear viscous oil.1H NMR (CDCl3): 12.07 (s, 1H, C-2 OH), 6.47 (br s, 1H, C-4 OH), 6.21 (s, 1H, H-5), 5.55 (br s, 1H, H-2’), 4.52 (dq, 1H, trans-H-1’’, J 2.29, 1.42Hz), 4.39 (m, 1H, cis-H-1’’), 4.38 and 4.37 (2 x q, 2H, CO2CH2Me, J 7.30Hz), 4.10 (br d, 1H, H-1’, J 7.18Hz), 2.86 (ddd, 1H, ArCHaHbCH2-, J 12.91, 9.28 and 6.39Hz), 2.76 (ddd, 1H, ArCHaHbCH2-, J 12.92, 9.26 and 6.66Hz), 2.39 (br m, 1H, H-6’), 2.21 (br m, 1H, H-4a’), 2.09 (br m, 1H, H-4b’), 1.82 – 1.78 (obscured m, 2H, H-5’), 1.78 (br m, 3H, C-3’ Me), 1.71 (br m, 3H, C-3’’ Me), 1.53 (br m, 2H, ArCH2CH2-), 1.40 (t, 3H, CO2CH2Me, J 7.18Hz), 1.32 (m, 4H, -(CH2)2Me), 0.89 (t, 3H, ArCH2Me, J 7.08Hz);13C NMR (CDCl3): 172.24 (CO2), 163.18 (C-2), 159.82 (C-4), 145.92 (C-6), 140.09 (C-2’’), 124.13 (C-2’), 114.41 (C-3), 111.48 (C-5), 111.18 (C-1’’), 104.07 (C-1), 61.09 (CO2CH2Me), 46.64 (C-6’), 36.91 (ArCH2-), 35.42 (C-1’), 32.07 (-CH2CH2Me), 31.55 (ArCH2CH2-), 30.24 (C-4’), 27.87 (C-5’), 23.66 (C-3’ Me), 22.64 (-CH2CH2Me), 18.85 (C-3’’ Me), 14.12 (CO2CH2Me), 14.04 (-CH2Me); UPLC-HRMS (ESI+): found 387.2528; C24H35O4 requires 387.2535; (ESI-): found 385.2363; C24H33O4 requires 385.2379. d. 2,4-Dihydroxy-3-[(1R,6R)-3-methyl-6-phenyl-6-(prop-1-en-2- yl)cyclohex-2-enyl]benzoate (VIII, R1, R4, R6, R7 = H, R3 = phenyl, R5 = A solution of the resorcinol (1.016g, 3.937mmol), cis-isolimonenol (2 x 0.982g, 6.449mmol), eccalite (1.024g), magnesium sulphate (1.034g) in dichloromethane (5.0ml) treated as above afforded, after column chromatography (5% ethyl acetate:hexane), 2,4-dihydroxy-3-[(1R,6R)-3-methyl-6-pentyl-6-(prop-1-en-2- yl)cyclohex-2-enyl]benzoate (0.250g, 16%) as a clear viscous oil.1H NMR (CDCl3): 11.61 (s, 1H, C-2 OH), 7.31 – 7.27 (m, 3H, aryl H), 7.20 – 7.18 (m, 2H, aryl H), 6.58 (br s, 1H, C-4 OH), 6.27 (s, 1H, H-5), 5.59 (br s, 1H, H-2’), 4.58 (dq, 1H, trans-H-1’’, J 2.31 and 1.46Hz), 4.46 (br s, 1H, cis-H-1’’), 4.16 (br d, 1H, H-1’, J 8.09Hz), 3.93 and 3.92 (2 x q, 2H, CO2CH2Me, J 7.17Hz), 2.46 (br m, 1H, H-6’), 2.23 (br m, 1H, H-4a’), 2.12 (br m, 1H, H-4b’), 1.82 – 1.78 (obscured m, 2H, H-5’), 1.80 (br m, 3H, C-3’ Me), 22 1.74 (br m, 3H, C-3’’ Me), 0.71 (t, 3H, CO2CH2Me, J 7.21Hz);13C NMR (CDCl3): 171.54 (CO2), 162.00 (C-2), 159.36 (C-4), 147.13 (C-2’’), 144.70 (C-6), 143.33 (quat. aryl C), 140.46 (C-3’), 128.06, 127.35 and 126.47 (aryl C), 123.79 (C-2’),115.65 (C-3), 111.96 (C-5), 111.41 (C-1’’), 104.20 (C-1), 60.51 (CO2CH2Me), 46.57 (C-6’), 35.46 (C-1’), 30.25 (C-4’), 27.89 (C-5’), 23.70 (C-3’ Me), 18.86 (C-3’’), 12.93 (CO2CH2Me); UPLC- HRMS (ESI+): found 393.2056; C25H29O4 requires 393.2066; (ESI-): found 391.1905; C25H27O4 requires 391.1909. 4. Synthesis of cannabidiol derivatives: decarboxylations a. 2-[(1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl]-5- A stirred (500rpm) solution of the crude 2,4-dihydroxy-3-[(1R,6R)-3-methyl-6-(prop-1- en-2-yl)-cyclohex-2-enyl]-6-propylbenzoate isolated above in methanol (161ml) was purged under a stream of nitrogen gas for 10 minutes. Sodium hydroxide (13.760g, 0.344mol) in 68ml water was similarly purged with nitrogen, then added to the methanolic solution and the mixture was boiled for 18h under nitrogen atmosphere. The purple solution was cooled to 25°C, diluted with water (70ml), extracted with ethyl acetate (2 x 60ml) to remove excess terpenes and byproducts and the organic phase discarded. The aqueous phase is acidified with solid citric acid, extracted with ethyl acetate (3 x 60ml), dried with magnesium sulphate and concentrated to a brown oil that solidified on standing. Ethyl acetate was recycled for future use. Crystallisation as a 1:1 (v / v) mixture in heptane at 0°C was accomplished in three successive crops using seed crystals to afford beige needles of 2-[(1R,6R)-3-methyl-6-(prop-1-en-2- yl)cyclohex-2-enyl]-5-propylbenzene-1,3-diol (CBDV, VIII, X, R1, R4, R6, R7 = H, R3 = n-propyl, R5 = Me) (14.669g, 62% conversion, 48.1% over two steps based on conversion).1H NMR (CDCl3): 6.25 (br s, 1H, H-4), 6.18 (br s, 1H, H-6), 5.96 (br s, 1H, OH), 5.57 (s, 1H, H-2’), 4.75 (br s, 1H, OH), 4.65 (br m, 1H, trans-H-1”), 4.55 (br m, 1H, cis-H-1”), 3.85 (m, 1H, H-1’), 2.42 (dd, 2H, ArCH2-, J 7.45 and 6.77Hz), 2.40 (m, 1H, H-6’), 2.23 (m, 1H, H-4’a), 2.09 (dm, 1H, H-4’b, J 17.88Hz), 1.86 – 1.73 (m, 2H, 23 H-5’), 1.79 (br s, 3H, C-3’ Me), 1.65 (m, 3H, C-3”), 1.58 (m, 2H, -CH2Me), 0.90 (t, 3H, -CH2Me);13C NMR (CDCl3): 156.09 (br, C-1), 153.92 (br, C-3), 149.30 (C-2”), 142.73 (C-5), 139.96 (C-3’), 124.17 (C-2’), 113.82 (C-1), 110.81 (C-1”), 109.82 (br, C-4), 108.06 (br, C-6), 46.16 (C-1’), 37.56 (ArCH2-), 37.23 (C-6’), 30.40 (C-4’), 28.41 (C-5’), 23.98 (-CH2Me), 23.62 (C-3’ Me), 20.45 (C-2” Me), 13.75 (-CH2Me). In a similar way, the following were synthesised: b. 2-[(1R,6R)-5-ethyl-3-methyl-6-(prop-1-en-2-yl)cyclohex-2- enyl]benzene-1,3-diol (CBDV, VIII, X, R1, R4, R6, R7 = H, R3 = ethyl, R5 = Me) A solution of 2,4-dihydroxy-3-[(1R,6R)-6-ethyl-3-methyl-6-(prop-1-en-2-yl)-cyclohex- 2-enyl]benzoate (0.665g, 1.931mmol), 5M aqueous NaOH (0.83ml) and methanol (1.93ml) under nitrogen gas treated as above afforded, after column chromatography (5% ethyl acetate:hexane), 2-[(1R,6R)-5-ethyl-3-methyl-6-(prop-1-en-2-yl)cyclohex-2- enyl]benzene-1,3-diol (0.237g, 45%) as an orange oil.1H NMR (CDCl3): 6.26 (br s, 1H, H-4), 6.21 (br s, 1H, H-6), 5.96 (br s, 1H, OH), 5.56 (br m, 1H, H-2’), 4.89 (br s, 1H, OH), 4.65 (br dq, 1H, trans-H-1’’, J 1.95 and 1.64Hz), 4.56 (br m, 1H, cis-H-1’’), 3.87 (m, 1H, H-1’), 2.49 (q, 2H, ArCH2-, J 7.57Hz), 2.41 (ddd, 1H, H-6’, J 11.72, 10.53 and 3.26Hz), 2.23 (m, 1H, H-4a’), 2.09 (dm, 1H, H-4b’), 1.85 – 1.75 (m, 2H, H-5’), 1.79 (br m, 3H, C-3’ Me), 1.66 (m, 3H, C-3’’), 1.17 (t, 3H, -CH2Me, J 7.81Hz);13C NMR (CDCl3): 156.09 (br, C-1), 154.06 (br, C-3), 149.21 (C-2’’), 144.26 (C-5), 139.89 (C-3’), 124.18 (C-2’), 113.80 (C-2), 110.82 (C-1’’), 109.10 (br, C-4), 107.39 (br, C-6), 46.17 (C-6’), 37.11 (C-1’), 30.86 (C-4’), 28.42 (C-5’), 28.34 (ArCH2-), 23.61 (C-3’ Me), 20.36 (C-3’’), 14.99 (-CH2Me). c. 2-[(1R,6R)-3-methyl-5-pentyl-6-(prop-1-en-2-yl)cyclohex-2- enyl]benzene-1,3-diol (CBDV, VIII, X, R1, R4, R6, R7 = H, R3 = pentyl, R5 = Me) 24 A solution of 2,4-dihydroxy-3-[(1R,6R)-3-methyl-6-pentyl-6-(prop-1-en-2-yl)-cyclohex- 2-enyl]benzoate (0.891g, 2.306mmol), 5M aqueous NaOH (0.99ml) and methanol (2.31ml) under nitrogen gas treated as above afforded, after column chromatography (5% ethyl acetate:hexane), 2-[(1R,6R)-3-methyl-5-pentyl-6-(prop-1-en-2-yl)cyclohex- 2-enyl]benzene-1,3-diol (0.292g, 40%) as an orange oil.1H NMR (CDCl3): 6.24 (br s, 1H, H-4), 6.19 (br s, 1H, H-6), 5.95 (br s, 1H, OH), 5.57 (br m, 1H, H-2’), 4.76 (br s, 1H, OH), 4.65 (br dq, 1H, trans-H-1’’, J 1.98 and 1.50Hz), 4.56 (br m, 1H, cis-H-1’’), 3.85 (m, 1H, H-1’), 2.44 (br dd, 2H, ArCH2-, J 7.30 and 7.84Hz), 2.40 (ddd, 1H, H-6’, J 11.73, 10.53 and 3.17Hz), 2.23 (m, 1H, H-4a’), 2.09 (dm, 1H, H-4b’), 1.86 – 1.73 (m, 2H, H-5’), 1.79 (br m, 3H, C-3’ Me), 1.65 (m, 3H, H-3’’), 1.56 (br quin, 2H, ArCH2CH2- , J 7.49Hz), 1.31 and 1.29 (2 x br m, 4H, -(CH2)2Me), 0.87 (t, 3H, -CH2Me, J 7.31Hz);13C NMR (CDCl3): 156.11 (br, C-1), 153.91 (br, C-3), 149.30 (C-2’’), 143.02 (C-5), 139.93 (C-3’), 124.18 (C-2’), 113.77 (C-2), 110.80 (C-1’’), 109.73 (br, C-4), 108.01 (br, C-6), 46.16 (C-6’), 37.23 (C-1’), 35.46 (ArCH2-), 31.48 and 22.51 (-(CH2)2Me), 30.60 (ArCH2CH2-), 30.40 (C-4’), 28.42 (C-5’), 23.61 (C-3’ Me), 20.45 (C-3’’), 13.99 (-CH2Me). d. 2-[(1R,6R)-3-methyl-5-phenyl-6-(prop-1-en-2-yl)cyclohex-2- enyl]benzene-1,3-diol (CBDV, VIII, X, R1, R4, R6, R7 = H, R3 = phenyl, R5 = Me) A solution of 2,4-dihydroxy-3-[(1R,6R)-3-methyl-6-phenyl-6-(prop-1-en-2-yl)- cyclohex-2-enyl]benzoate (0.250g, 0.637mmol), 5M aqueous NaOH (0.43ml) and methanol (1.0ml) under nitrogen gas treated as above afforded, after column chromatography (5% ethyl acetate:hexane), 2-[(1R,6R)-3-methyl-5-phenyl-6-(prop-1- en-2-yl)cyclohex-2-enyl]benzene-1,3-diol (0.102g, 50%) as a brown oil.1H NMR (CDCl3): 7.54 (m, 2H, aryl H), 7.38 (m, 2H, aryl H), 7.30 (m, 1H, aryl H), 6.70 (br s, 1H, H-4), 6.60 (br s, 1H, H-6), 6.09 (br s, 1H, OH), 5.61 (br m, 1H, H-2’), 4.93 (br s, 1H, OH), 4.68 (br dq, 1H, trans-H-1’’, J 1.98 and 1.44Hz), 4.59 (br m, 1H, cis-H-1’’), 3.93 (m, 1H, H-1’), 2.46 (ddd, 1H, H-6’, J 11.79, 10.56 and 3.19Hz), 2.26 (m, 1H, H-4a’), 25 2.12 (dm, 1H, H-4b’), 1.89 – 1.79 (m, 2H, H-5’), 1.82 (br m, 3H, C-3’ Me), 1.69 (m, 3H, H-3’’);13C NMR (CDCl3): 156.62 (br, C-1), 154.52 (br, C-3), 149.09 (C-2’’), 140.82 (C-5), 140.37 (quat. aryl C), 140.36 (C-3’), 128.61, 127.32 and 126.76 (aryl C), 123.79 (C-2’), 115.77 (C-2), 110.07 (C-1’’), 108.64 (br, C-4), 106.63 (br, C-6), 46.14 (C-6’), 37.28 (C-1’), 30.42 (C-4’), 28.40 (C-5’), 23.68 (C-3’ Me), 20.41 (C-3’’). 5. Synthesis of THC-type cannabinoid systems a. (6aR,10aR)-3-propyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H- benzo[c]chromen-1-ol (Δ9-THCV, V, R1, R4, R6, R7 = H, R3 = n-propyl, R, Activated eccalite powder (2 x 120g) was packed into two borosilicate glass Uniqsis pressure column reactors (10mm x 100mm) and plumbed into a Uniqsis FlowSyn Maxi reactor equipped with two 10ml / min pumps and 20 bar backpressure regulators. The columns were fixed to a column stand on a Uniqsis Polar BearTMPlus Flow heating / cooling module, and the entire system equilibrated with neat dichloromethane for 30 minutes at 1 ml / min flow rate before cooling the columns to -10°C. A stirred (100rpm) solution of 2-[(1R,6R)-3-methyl-6-(prop-1-en-2-yl)cyclohex-2-enyl]-5- propylbenzene-1,3-diol (12.402g, 43.301mmol) in dichloromethane (125ml, 10% m / v) at 10°C was plumbed into the loop on a closed recycling path back into the reservoir. The solution was pumped through the column at 1ml / min for 3 – 5 days until the starting material was consumed, affording a mixture of Δ9-THCV : Δ8-THCV : iso-Δ8- THCV in an 81 : 5 : 14 ratio, with 92% conversion of starting material. The columns were sluiced with fresh dichloromethane (120ml), and the pooled organic solution was concentrated to afford a brown gum that turns purple on exposure to air and light. Dichloromethane was recycled for later reuse. Purification was demonstrated below using a derivatization / precipitation / deprotection protocol. In a similar fashion, the following reactions were performed: 26 b. (6aR,10aR)-3-ethyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H- benzo[c]chromen-1-ol (Δ9-EtTHC, V, R1, R4, R6, R7 = H, R3 = ethyl, R, R5 = Me) Activated eccalite powder (2.021g), 2-[(1R,6R)-5-ethyl-3-methyl-6-(prop-1-en-2- yl)cyclohex-2-enyl]benzene-1,3-diol (0.236g) and dichloromethane (2.5ml, ~10% m / v) were treated as above at –2°C using a flowrate of 0.5ml / min 24h to yield a mixture of Δ9-EtTHC : Δ8-EtTHC : iso-Δ8-EtTHC in a 71.9 : 12.7 : 15.3 ratio, with 88.6% conversion of starting material. No purification attempted. c. (6aR,10aR)-3-pentyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H- benzo[c]chromen-1-ol (Δ9-THC, V, R1, R4, R6, R7 = H, R3 = pentyl, R, R5 Activated eccalite powder (2.905g), 2-[(1R,6R)-3-methyl-5-pentyl-6-(prop-1-en-2- yl)cyclohex-2-enyl]benzene-1,3-diol (0.292g) and dichloromethane (3.0ml, ~10% m / v) were treated as above at –2°C using a flowrate of 0.5ml / min for 24h to yield a mixture of Δ9-THC : Δ8-THC : iso-Δ8-THC in a 72.4 : 13.9 : 8.2 ratio, with 92.4% conversion of starting material. No purification attempted. d. (6aR,10aR)-3-Phenyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydro-6H- benzo[c]chromen-1-ol (Δ9-PhTHC, V, R1, R4, R6, R7 = H, R3 = phenyl, R, Activated eccalite powder (1.117g), 2-[(1R,6R)-3-methyl-5-phenyl-6-(prop-1-en-2- yl)cyclohex-2-enyl]benzene-1,3-diol (0.102g) and dichloromethane (2.2ml, ~10% m / v) were treated as above at –2°C using a flowrate of 0.5ml / min for 24h to yield a mixture 27 of Δ9-PhTHC : Δ8-PhTHC : iso-Δ8-PhTHC in a 55.2 : 16.2 : 28.6 ratio, with 55.1% conversion of starting material occurred. No purification attempted. 6. Purification of Δ9-THCV a. (6aS,10aR)-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydro-6H- benzo[c]chromen-1-yl 2-(2-nitrophenyl)acetate A portion of the crude material (3.985g, 13.906mmol) in dichloromethane (50ml, 0.27M) was treated with triethylamine (3.87ml, 27.81mmol, 2eq.) and cooled to 0°C. Fresh 2-(2-nitrophenyl)acetyl chloride (3.33g, 16.688mmol, 1.2eq.) was added carefully, and the solution stirred for 24h under nitrogen atmosphere. The solution was washed with 10% aqueous potassium bicarbonate solution, dried with magnesium sulphate and concentrated to an orange gum. The mixture was boiled in 5% ethyl acetate / hexane (50ml) until dissolved, then cooled to 0°C over an hour to afford a fine white precipitate, (6aS,10aR)-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydro-6H- benzo[c]chromen-1-yl 2-(2-nitrophenyl)acetate (1.798g).1H NMR indicated that the material had a Δ9-THCV : Δ8-THCV ratio of 92:8, with no other isomers in the mixture. 1H NMR (CDCl3): 8.17 (dd, 1H, aryl H-3, J 8.21 and 1.13Hz), 7.63 (~td, 1H, aryl H-5, J 7.48 and 1.09Hz), 7.50 (~ddd, 1H, aryl H-4, J 8.80, 7.62 and 1.25Hz), 7.46 (dd, 1H, aryl H-6, J 7.61 and 0.90Hz), 6.53 (br d, 1H, H-4, J 1.38Hz), 6.44 (br d, 1H, H-2, J 1.49Hz), 5.79 (m, 1H, H-10), 4.27 (d, 1H, CO2CHaHb, J 17.11Hz), 4.22 (d, 1H, CO2CHaHb, J 17.11Hz), 3.06 (br d, 1H, H-10a, J 11.05Hz), 2.47 (dd, 2H, ArCH2-, J 8.00 and 6.83Hz), 2.13 (m, 2H, H-8), 1.88 (m, 1H, H-7a), 1.62 (br m, 3H, C-9 Me), 1.58 (~br q, 2H, ArCH2CH2, J 7.48Hz), 1.39 (br m, 3H, C-6 Mea), 1.35 (m, 1H, H-7b), 1.06 (br s, 3H, C-6 Meb), 0.91 (t, 3H, CH2Me, J 7.41Hz);13C NMR (CDCl3): 167.67 (CO), 154.44 (C-4a), 149.27 (C-1), 148.72 (aryl C-2), 142.55 (C-3), 134.60 (C-9), 133.65 (aryl C-5), 133.54 (aryl C-6), 129.46 (aryl C-1), 128.81 (aryl C-4), 125.47 (aryl C-3), 123.52 (C-10), 115.42 (C-4), 115.02 (C-10b), 114.01 (C-2), 77.46 (C-6), 45.67 (C-6a), 40.17 (CO2CH2), 37.49 (ArCH2-), 34.01 (C-10a), 31.02 (C-8), 27.39 (C-6 Mea), 24.88 (C-7), 23.94 (ArCH2CH2), 23.40 (C-9 Me), 19.26 (C-6 Meb), 13.81 (CH2Me); UPLC-HRMS (ESI+): found 450.2281; C27H32NO5 requires 450.2280. 28 b. Deprotection and isolation of Δ9-THCV A solution of the protected species (1.725g, 3.837mmol) in absolute ethanol (8.9ml, 0.43M) was treated with ammonium chloride (0.697g, 13.03mmol, 3eq.) and zinc powder (1.081g, 16.54mmol, 4 eq.) and stirred for 36h. The mixture was filtered, the solids washed with further ethanol, and the filtrate concentrated to an orange gum. This was dissolved and partitioned between hexane and sodium bicarbonate solution, the organics dried with magnesium sulphate and concentrated to an orange oil. Column chromatography (5- 10% ethyl acetate:hexane afforded a pale orange oil, Δ9-THCV (0.808g, 73.5%, 92:8 Δ9: Δ8ratio).1H NMR (CDCl3): 6.31 (~quin, 1H, H-10, J 1.69), 6.26 (d, 1H, H-4, J 1.66Hz), 6.13 (br d, 1H, H-2, J 1.62Hz), 4.85 (s, 1H, C-1 OH), 3.20 (m, 1H, H-10a), 2.42 (td, 2H, ArCH2-, J 7.51 and 3.20Hz), 2.16 (m, 2H, H-8), 1.91 (m, 1H, H-7a), 1.68 (br m, 3H, C-9 Me), 1.58 (dq, 2H, ArCH2CH2, J 15.29 and 7.38Hz), 1.41 (s, 3H, C-6 Mea), 1.44-1.35 (m, 1H, H-7b), 1.09 (s, 3H, C-6 Meb), 0.91 (t, 3H, CH2Me, J 7.39Hz);13C NMR (CDCl3): 154.78 (C-4a), 154.19 (C-1), 142.53 (C-3), 134.35 (C-9), 123.78 (C-10), 110.16 (C-4), 109.11 (C-10b), 107.61 (C-2), 77.19 (C-6), 45.84 (C-6a), 37.61 (ArCH2-), 33.60 (C-10a), 31.17 (C-8), 27.56 (C-6 Mea), 25.02 (C-7), 24.00 (ArCH2CH2), 23.33 (C-9 Me), 19.26 (C-6 Meb), 13.87 (CH2Me); UPLC-HRMS (ESI+): found 287.1996; C19H27O2 requires 287.2011.

[0005] 29 References 1. Focella, A.; Teitel, S.; Brossi, A. “A simple and practical synthesis of olivetol.” J. Org. Chem.1977, 42, 21, 3456–3457. 2. Hurem, D.; Macphail, B. J.; Carlini, R.; Lewis, J., McNulty, J. “Catalytic, Oxidative Synthesis of Olivetol, Methyl Olivetolate and Orthogonally Protected Methyl Ether Derivatives.” SynOpen 2021, 5, 86–90. 3. Mitchell Jr., J. P.; Prince, P. “Methods of manufacturing cannabidiol or cannabidivarin and intermediates of manufacturing cannabidiol or cannabidivarin.” WO2020229891A1, Fresh Cut Development, Llc, 2020.

Claims

30 CLAIMS 1. A process for the production of cannabinoid compounds of general formula III and IVwherein R is independently chosen from H, OH, alkyl, alkenyl, alkynyl, or cycloalkyl; R1 – R4 are independently chosen from H, halogen, nitrile, nitro, hydroxy, alkyl, O-alkyl, carboxylate, acyl, branched alkyl, ester, S-alkyl, alkylsulphonyl, alkylsulphoxide, alkylsulphonamide, S-(hetero)aryl, (hetero)arylsulphonyl, (hetero)arylsulphoxide, (hetero)arylsulphonamide, alkenyl, alkynyl, (hetero)cycloalkyl, acyloxy, (hetero)aryl; where the alkyl or (hetero)aryl moieties are optionally further substituted with one or more groups independently selected from halogen, hydroxy, alkyl, O-alkyl, carboxylate, acyl, amino or, amino alkyl; wherein the alkyl, alkenyl, alkynyl, (hetero)cycloalkyl, acyl, acyloxy, (hetero)aryl or (hetero)arylalkyl moieties are independently further substituted with one or more groups selected from cyano, halogen, nitro; C1-6 alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-14 arylalkyl, heteroaryl or heterocycloalkyl, each optionally substituted with further group(s) Y; and C(O)Ra, C(O)ORa, C(O)NRbRc, C(=NRa)NRbRc, OR, OC(O)Ra, OC(O)ORa, OC(O)NRbRc, OC(=NRa)NRbRc, OS(O)Ra, OS(O)2Ra, OS(O)NRbRc, NRbRc, NRbC(O)Rd, NRbC(O)ORd, NRa(O)NRbRc, NRaC(=NRb)NRcRd, NRaS(O)Rb, NRaS(O)2Rb, NRaS(O)NRbRc, NRaS(O)2NRbRc, SRa, S(O)Ra, S(O)NRaRb, S(O)2NRaRb, and (CH2)nNRaRb, where Ra, Rb, Rc and Rd are independently selected from hydrogen, cyano, halogen, nitro; C1-6 alkyl, C2-6 alkenyl, C2-631 alkynyl, C3-7 cycloalkyl, C6-14 aryl, C7-14 arylalkyl, heteroaryl or heterocycloalkyl; 2. The process of claim 1, wherein the process comprises of treating compound of formula I having R1 = OH and blocking group R2 with a chiral terpene formula II with X = OR in the presence of an acidic clay to form a product with formula III.

3. The process of claim 2, wherein converting intermediate formula III having with R1 = OH and blocking group R2 to deprotected compound formula III having R1 = OH and R2 = H to under basic conditions.

4. The process of claim 3, with compound formula III having R1 = OH and R2 = H and treating it with the acidic clay to form the final product formula IV having R1 = OH and R2 = H.

5. The process of claim 4, for the preparation of compound formula Vor pharmaceutical acceptable salt or ester thereof; the process may comprise treating a resorcinol compound of formula VI where X = CO2R (R = alkyl, alkenyl, alkynyl, or cycloalkyl) with a chiral terpene compound of formula VII in the presence of an as catalyst to form a compound of formula VIII.

6. The process of claim 5, wherein treating compound of formula VIII (X = CO2R) with a hydrolysing agent forms a compound of formula VIII (X = H),32 7. The process of claim 6, wherein cyclising the compound of formula VIII (X = H) by reacting with an acidic clay forms compound formula V.

8. The process of claim 5, wherein the compound with formula VIII is selected from, but not limited to, any one or more of the following compounds; 2,4-Dihydroxy-3-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6- propylbenzoic acid and its alkyl or cycloalkyl esters, 6-Butyl-2,4-dihydroxy-3-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en- 1-yl]benzoic acid and its alkyl or cycloalkyl esters, 2,4-Dihydroxy-3-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6- pentylbenzoic acid and its alkyl or cycloalkyl esters, 2,4-Dihydroxy-6-hexyl-3-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en- 1-yl]benzoic acid and its alkyl or cycloalkyl esters, 2,4-Dihydroxy-6-heptyl-3-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2- en-1-yl]benzoic acid and its alkyl or cycloalkyl esters, 2,4-Dihydroxy-3-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6- octylbenzoic acid and its alkyl or cycloalkyl esters, 2,4-Dihydroxy-3-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-6- phenylbenzoic acid, 2-[(6R)-3-Methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-propylbenzene- 1,3-diol and esters thereof, 5-Butyl-2-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]benzene- 1,3-diol and esters thereof, 2-[(6R)-3-Methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene- 1,3-diol and esters thereof, 5-Hexyl-2-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]benzene- 1,3-diol and esters thereof, 5-Heptyl-2-[(6R)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5- benzene-1,3-diol and esters thereof, and 2-[(6R)-3-Methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-phenylbenzene- 1,3-diol and esters thereof33 9. The process of claim 5, wherein the compound with formula V is selected from, but not limited to, any one or more of the following compounds; (6aR,10aR)-3-Propyl-6,6,9-trimethyl-3-propyl-6a,7,8,10a-tetrahydrobenzo[c]- chromen-1-ol and esters thereof, (6aR,10aR)-3-Butyl-6,6,9-trimethyl-3-butyl-6a,7,8,10a-tetrahydrobenzo[c]- chromen-1-ol and esters thereof, (6aR,10aR)-3-Pentyl-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]- chromen-1-ol and esters thereof, (6aR,10aR)-3-Hexyl-6,6,9-trimethyl-3-hexyl-6a,7,8,10a-tetrahydrobenzo[c]- chromen-1-ol and esters thereof, (6aR,10aR)-3-Heptyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydrobenzo[c]chromen- 1-ol and esters thereof, and (6aR,10aR)-3-Phenyl-6,6,9-trimethyl-6a,7,8,10a-tetrahydrobenzo[c]chromen- 1-ol and esters thereof 10. The process of any one of the above claims, to produce compound of formula VIII (X = CO2R) wherein the acid catalyst is an acidic clay, comprising of any one or more of mordenite, zeolite and bentonites11. The process of claim 10, to produce compound of formula VIII (X = CO2R) wherein the acid catalyst is an acidic clay, comprising of any one or more of mordenite, zeolite and bentonites.

12. The process of claim 11, wherein the acidic clay is a natural zeolite or eccalite that is activated with aqueous acid and dried before use.34 13. The process of any one of the above claims, wherein the solvent used with the acidic clay is chosen from any one or more of hydrocarbons, cyclic hydrocarbons, halogenated hydrocarbons, aromatics, ketones, alcohols, carbonates and esters.

14. The process of claim 13, wherein the solvent used with the acidic clay is chosen from chlorinated aliphatic solvents.

15. The process of claim 14, wherein the chlorinated aliphatic solvent is dichloromethane.

16. The process of claim 10 for the preparation of compound formula VIII (X = CO2R), wherein the reaction is performed between 0 and 50 °C 17. The process of claim 16, wherein the reaction is performed between 15 and 30 °C.

18. The process of claim 16, wherein the reaction is performed at 25°C.

19. The process of claim 10, wherein the mole ratio of resorcinol to chiral terpene is between 1:1 and 10:

1.

20. The process of claim 19, wherein the mole ration of resorcinol to chiral terpene is between 1:1 to 1:

3.

21. The process of claim 19, wherein the mole ration of resorcinol to chiral terpene is 1:2.35 22. The process of claim 10, wherein the concentration of the resorcinol in solvent is between 2 – 15% m / v.

23. The process of claim 22, wherein the concentration of the resorcinol in solvent is 10% m / v.

24. The process of claim 10, wherein the ratio of resorcinol to eccalite is in the range 1:1 – 1:3 m / m.

25. The process of claim 24, wherein the ratio of resorcinol to eccalite is 1:1 m / m.

26. The process of claim 10, wherein a drying agent, such as anhydrous sodium sulphate or magnesium sulphate, is present in a 1:1 m / m ratio with the resorcinol.

27. The process of claim 5, wherein the unreacted resorcinol of formula VI (X = CO2R) is reclaimed from the reaction mixture with aqueous base, preferably an alkaline hydroxide.

28. The process of claim 27, wherein the alkaline hydroxide is a 2% (m / v) aqueous potassium hydroxide.

29. The process of claim 27, wherein the unreacted resorcinol of formula VI (X = CO2R), wherein isolated acidification and extraction is applied to produce the unchanged starting material.

30. The process of claim 10, wherein the compound formula VIII (X = CO2R, R4 = H) is formed exclusively, free of cannabinoid regioisomers.36 31. The process of claim 10, wherein the crude product of formula VIII (X = CO2R) is used as-is in the hydrolysis reaction.

32. The process of claim 10, wherein the product of formula VIII (X = CO2R), is only used after the terpenoid by-products is distilled off under vacuum.

33. The process of any claim above, to produce compound of formula VIII (X = H)34. The process of claim 33, wherein the solvent used is a C1 – C4 alcohol.

35. The process of claim 34, wherein the solvent used is methanol.

36. The process of claim 33, wherein the hydrolysing agent is an alkaline hydroxide.

37. The process of claim 36, wherein the hydrolysing agent is sodium hydroxide.

38. The process of claim 33 wherein the hydrolysis of compound formula VIII (X = CO2R) to compound formula VIII (X = H) is accomplished in boiling aqueous hydroxide / alcohol solution.

39. The process of claim 38, wherein the base is most preferably 5M sodium hydroxide.

40. The process of claim 38 wherein the alcohol is methanol.37 41. The process of claim 38, wherein the final ratio is 7:3 v / v alcohol: hydroxide solution.

42. The process of claim 33, wherein the concentration of the compound formula VIII (X = CO2R) is 2 -15% m / v.

43. The process of claim 42, wherein the concentration of the compound formula VIII (X = CO2R) is 10% m / v.

44. The process of claim 33, wherein the product is isolated by acidification using mineral or organic acids.

45. The process of claim 44, wherein the product is isolated by acidification using ascorbic or citric acid and extracted and dried to a crude material.

46. The process of claim 45, wherein the crude material is purified by recrystallisation from hydrocarbon solvents selected from C1 - C10 alkanes, cycloalkanes, or branched alkanes.

47. The process of claim 46, wherein the hydrocarbon solvents is heptane or decane.

48. The process of claim 44, wherein the product is isolated by acidification at -10°C - 0°C to afford pure crystalline compound formula VIII (X = H).

49. The process of claim 48, to produce compound of formula VIII (X = H) where the acid catalyst is an acidic clay, comprising of any one or more of mordenite, zeolite and bentonites.38 50. The process of claim 49, wherein the acidic clay is a natural eccalite that is activated with aqueous acid and dried before use.

51. The process of claim 49, wherein the solvent used with the acidic clay is chosen from any one or more of hydrocarbons, cyclic hydrocarbons, halogenated hydrocarbons, aromatics, ketones, alcohols, carbonates and esters.

52. The process of claim 51, wherein the solvent used with the acidic clay is chosen from chlorinated aliphatic solvents.

53. The process of claim 52, wherein the chlorinated aliphatic solvent is dichloromethane.

54. The process of claim 33, wherein cyclisation is performed between –20°C - 30°C55. The process of claim 54, wherein cyclisation is performed between –15°C – 0°C.

56. The process of claim 54, wherein cyclisation is performed between -2°C to 10°C.

57. The process of claim 54 wherein the reaction is performed in flow chemistry / plug flow mode.39 58. The process of claim 57 wherein eccalite is placed in a flow column reactor in 1:1 to 1:20 m / m ratio of eccalite compound.

59. The process of claim 57 wherein eccalite is placed in a flow column reactor in a 1:10 m / m ratio.

60. The process of claim 57 wherein the substrate concentration is between 1 – 20% m / v to solvent.

61. The process of claim 60 wherein the substrate concentration is between 5 – 15% m / v.

62. The process of claim 61 wherein the substrate concentration is 10% m / v.

63. The process of claim 57 wherein the flow rate of the prepared solution through the acidic clay packed in the column reactor is between 0.5 – 5 ml / min.

64. The process of claim 63 wherein the flow rate of the prepared solution through the acidic clay packed in the column reactor is 0.5-1.0 ml / min.

65. The process of claim 54 wherein the ratio of the desired product formula V may be formed in ~85% preference to its regioisomer X66. The process of claim 54, wherein the crude material is purified by precipitation, followed by deprotection under reducing conditions.

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