Title of Invention

SYNTHESIS OF CANNABINOIDS

Abstract

. A process for the production of a cannabinoids compound of general formula A: Compound A wherein Rc, Rd and Rc are independently H, alkyl, or substituted alkyl; and R1 to R4 are independently H, OH, OR' (R' is alkyl, aryl, substituted alkyl or aryl, silyl, acyl, or phosphonate), alkyl, substituted alkyl, aryl, acyl, halide, amine, nitrate, sulphonate or phosphonate; comprising reacting compound B with compound C: Rc 0Ra Rl R2 Compound B R3 HO Compound C wherein R3 is H, alkyl. aryl, acyl or silyl; Rb is alkyl, aryl or acyl; Rc, Rd , Rc and R1 to R4 are as hereinbefore denned; and comprising, when necessary, a ring closure reaction

Full Text

FORM 2 THE PATENTS ACT 1970 [39 OF 1970] COMPLETE SPECIFICATION [See Section 10; rule 13] "SYNTHESIS OF CANNABINOIDS" JOHNSON MATTHEY PUBLIC LIMITED COMPANY, a British body corporate of 2-4 Cockspur Street, Trafalgar Square, London SWIY 5BQ, United Kingdom, The following specification particularly describes the nature of the invention and the manner in which it is to be performed:- The present invention relates to a novel process that can be used to produce (-)-A -tetxahydrocannibinol and related cannibinoid compounds. The invention further 5 relates to novel compounds used in the process. (-)-A9-TetrahydrocannibinoI (A9-THC) is the active ingredient in marijuana. It is used therapeutically as an inhalant or an "oral drug for stimulation of appetite among AIDS and cancer chemotherapy patients. Related carmibinoid compounds that show llo pharmacological activity are also known. In particular, there have been attempts to produce water soluble analogues of A9-THC ('The Total synthesis of Cannibinoids' in The Total Synthesis of Natural Products, Vol 4, John ApSirnon, Wiley, 1981, pp 239-243). A9-THC The chemical synthesis and isolation of A9-THC are both challenging. A9-THC is a very high boiling, viscous liquid. It is very prone to acid-catalysed isomerization to the thermodynamically more stable A* isomer, it is easily oxidized by oxygen to inactive cannibinol, and it is sensitive to light and heat. All of these factors make purification difficult, especially on an industrial scale, and chromatography has 2i generally been used. 29 2 WO 0 W6S99 Previous syntheses of A9-THC have tended to be either lengthy or low-yielding. Most involve coupling of a chira! terpene to a resorcinol derivative. The primary difficulty has been lack of selectivity in the coupling. Acid catalysed couplings have generally led to mixtures of products (Crombie et al, J Chem Soc. Perkin Trans. I 1988 k 1243). Attempts to avoid the selectivity problem by using base-catalysed coupling reactions have involved lengthier syntheses overall (Rickards et al, J. Org. Chem. 1984 49 572). Syntheses not using chiral terpenes have yielded racemic product (Childers et al, J: Org. Chem. 1984 49 5276), In seemingly the best known method (US 5,227,537), Stoss claims that acid- catalysed coupling of (+)-/?-menth-2-ene-l,8-diol (1) with olivetol (2) can be stopped at the intermediate Friedel-Crafts product (3), and then the intermediate (3) can be isolated and converted in good yield to A9-THC using ZnBr2 (24 hours, reflaxing CH2CI2). The present inventors have encountered several problems with this scheme. lfc The initial /Holuenesulfonic acid catalysed Friedel-Crafts reaction was difficult to stop cleanly at the intermediate (3) under Stoss' conditions and gave mixtures of the intermediate (3) and A9-THC, the ring-closed product. Any A9-THC formed is likely to isomerize to A8-THC under the disclosed conditions. The use of a heavy metal such as ZnBr2 in the last step of an industrial process is highly undesirable as it may lead to traces of metal in the product, and this is especially undesirable for pharmaceuticals. Stoss' method therefore appears to offer no real advantage in yield or purity of A -THC over a one-pot coupling that goes directly to A9-THC. Razdan has published a one-pot method for coupling of (+)-p-menth-2-ene-l,8-diol (1) with olivetol (2) to produce A -THC (Razdan et al, Tet. Lett. 1983 24 3129). This also suffers from several problems: it uses nearly 14 equivalents of ZnC2 as the acid, and uses six equivalents of olivetol (2). Even under these conditions, the yield is still only 28% from (+)-p-menth-2-ene-1,8-diol (1). OH (1) 3 Thus there is a need for a short, practical, high-yielding synthesis of A9-THC that can be practised on an industrial scale. This is the problem that the present inventors have set out to address. fi Accordingly the present invention provides a process for the production of a compound of general formula A: 3 Compound A wherein Rc, Rd and Rc are independently H, alkyl, or substituted alkyl; and RL to R4 are independently H, OH, OR' (R' is alkyl, aryl, substituted alkyl or aryl, silyl, acyl, or iui phosphonate), alkyl, substituted alkyl, aryl, acyl, halide, amine, nitrate, sulphonate or phosphonate; comprising reacting compound B with compound C: 5j wherein Ra is H, alkyl, aryl, acyl or silyl; Rb is alkyl, aryl or acyl; Rc, Rd, Rc and R1 to R4 are as hereinbefore defined; and comprising, when necessary, a ring closure reaction. 4 : : Preferably the reaction of compound B with compound C is carried out in the presence of an acid catalyst. A substituted alkyl group may contain substituents such as halide, hydroxy!, amine and thiol. Alkyl groups may be saturated or unsaturated, acyclic or cyclic. Compound B is similar to the (+)-P-menth-2-ene-l,8-diol used in the Stoss method. However, compound B is not a diol, and contains one or more ether or ester groups. R is alkyl, aryl or acyl, and preferably Ra is independently alkyl, aryl or acyl. 10 In a preferred embodiment, Rb is acyl, and ORb is an ester group. Suitable ester groups include . acetate, propionate, butyrate, trimethylacetate, phenyl acetate, phenoxyacetate, diphenylacetate, beazoate, p-nitrobenzoate, phthalate and succinate. 15 In an especially preferred embodiment both Ra and Rb are acyl groups so that compound B is a diester. The two ester groups are suitably chosen independently from acetate, propionate, butyrate, trimethylacetate, pheny (acetate, phenoxyacetate, diphenylacetate, benzoate, p-nitrobenzoate, phthalate and succinate. An especially preferred compound has ORa = ORb = diphenylacetate: Rc, Rd and Rc can be varied independently of Rs and Rb and will affect the structure of the product, compound A. Rc is suitably Me or H, preferably Me. R and Rc are suitably Me or CH2OH, preferably Me. - $- 25-NOV-2333 21 = 25 2115 9242327 97% Compound C is a phenolic compound and is preferably a resorcinol derivative such as olivetol (3). R is preferably OR" wherein R" is H, alky], substituted aikyl, acy] or silyl $ Most preferably R' is OH. Preferably, R2 and R4 are H. R is suitably an alkyl group or substituted alky! group. In a preferred embodiment, R3 is CsH11- R3 may contain groups that promote water solubility, eg ketone, ester, hydroxyl or amine groups. In one embodiment of the invention, RJ contains a thioketa] (this can be further converted to an aldehyde). Most preferably, compound C is olivetol (3), wherein R1 is OH, R2 is H, R3 is « C5H11 and R4 is H. Suitably, one equivalent of compound B is reacted with approximately one equivalent of compound C. In a preferred embodiment of the invention compound B is an ether or ester of (+)-Jp-menth-2-ene-l,8-diol (Rc = Me, Rd = Me, Re = Me), compound C is olivetol (R1 = OH, R2 = H, R3 = CsH11, H4 = H) and the product, compound A, is 69-THC. The present invention therefore provides a novel synthesis of A'-THC. The present invention provides both a one-step and a two-step process for the production of compound A. In the one-step process the reaction of compound B and compound C produces compound A directly. In the one-step process, suitably about one equivalent of acid catalyst is used, eg between 0.8 to 1.5 equivalents. Preferably the reaction is carried out below 0CC, most preferably from -20°C to 0°C. In the two-step process the reaction of compound B and compound C produces a ring-opened product, compound D: B C Compound D For the two-step process, suitably less than one equivalent of acid is used, preferably from 0.1 to 0.5 equivalents. Preferably the reaction is carried out below 0°C, more preferably below -10°C. A ring closure step is then carried out. Suitable reagents for the ring closure step include acids such as BF3.(OEt)2 or TsOH. One possible advantage of the two-step process is that if compound D is a crystalline solid, purification of the intermediate is straightforward and this may lead to higher purity in the final product, compound A. The present invention provides one-step and two-step syntheses that can be used to produce A9-THC. The syntheses show improved selectivity and yield compared to prior art methods. The amount of isomers generated is small and purification is simple. The phenolic reactant (compound C) is not used in excess. The process is suitable for scale-up to an industrial process. Preferably the yield of the synthesis of A9-THC is greater than 50%, more preferably the yield is greater than 75%. The process also provides high purity A - THC. Preferably A9-THC is obtained in greater than 70% purity, more preferably 35 greater than 90% purity. Methods known in the art can be used to further purify the products of the reaction. The process of the present invention is suitably carried out in a polar aprotic solvent, preferably methylene chloride. Suitable acid catalysts include most Lewis acids. Non-metallic catalysts such as BF3.0Et2 and toluenesulfonic acid are preferred. Non-metallic catalysts offer advantages over the zinc catalysts used in the Stoss and Razdan methods because there is no possibility of a metal residue in the product. BF3.0Et2 is preferred because it is easily removed from the reaction mixture, and is less prone to causing isomerisation of A -THC to A -THC than p-TsOH. Suitably about one equivalent of catalyst or less is used, eg 0.1 to 1.5 equivalents. This offers a clear improvement over Ra2dan's method where 14 equivalents of acid are used. Procedures for isolating the product, compound A, from the reaction mixture are well known to those in the art. Chromatography can be used to purify the product. 5 Certain compounds of structure B are novel and are particularly advantageous when used in the presenr invention. Compounds wherein both ORa and ORb are chosen independently from acetate, propionate, butyrate, trimethylacetate, phenylacetate, phenoxyacetate, diphenylacetate, benzoate,P-nitrobenzoate, phthalate and succinate (provided that only one of OR3 and OR is acetate) represent a further aspect of this invention. Preferably the groups are chosen so that compound B is a solid. Preferably both OR1 and ORb are diphenylacetate. Preferably, R; Rd and Rc are Me. Compound B can be produced by a variety of methods. Compounds wherein R3 2|5 - H or silyl can be prepared by the ring-opening of epoxides (5) with an alcohoI, a carboxylic acid or silylated derivatives of alcohols and carboxylic acids. Reactions of this type are described in a co-pending patent application by the present inventors. Compounds wherein Ra and R6 are both the same can be produced by base catalysed reaction of the corresponding diol (6) with anhydrides or chlorides. Re OH Re ORa 5 Compounds wherein R3 is not H or silyl and wherein Ra and Rb are different can be produced by base-catalysed reaction of mono-ethers or mono-esters (7) with ethers or chlorides. RC OH (Ra)20 or RaCl Re ORa i0 The following examples are illustrative but not limiting of the invention. General Experimental Details Anhydrous solvents were purchased from Aldrich Chemical Company (Milwaukee, WI, USA). Samples of A9-THC and A8-THC were obtained from ik RBI/Sigma (Natick, MA, USA). (+)-p-Menth-2-ene-l,8-diol was prepared as described in a co-pending patent application by the present inventors. TLC plates (silica gel GF, 250micron, 10 x 20cm) were purchased from Analtech (Newark, DE, USA). TLCs were visualized under short wave UV, and then by spraying with eerie ammonium nitrate/suifuric acid and heating. Column chromatography was carried out using TLC grade silica gel purchased from Aldrich Chemical Company, NMR spectra were obtained on a Bruker 300 MHz instrument. HPLC area percentages reported here are not corrected. HPLCs were run on Shimadzu LC-10AD. 9 ; EXAMPLE la: One-step reaction of bis(diphenylacetate) compound (4) witb oliveto) (3) to produce A9-THC Preparation of bis(diphenylacetate) compound (4) f A 25ml three-necked roundbottom flask with a stir bar was oven-dried, fitted with septa, and cooled under N2 Pyridine (12ml) was added and the pale yellow solution was stirred. Diphenylacetyl chloride (5.69g, 4.2eq.) was added. The solution aimed brown. N,N-dimethylaminopyridine (0.1435g, 0.2eq.) was added. The mixture 1|0 was stirred for 1 hour. (+)-p-Menth-2-ene-l,8-diol (1-OOg) was added. The mixture became a lighter colour and solids precipitated. The slurry was allowed to stir overnight at room temperature. The reaction was quenched with water. The mixture was extracted three times with ethyl acetate. The organics were combined and washed with 2M HC1, saturated NaHC03, and saturated NaCl (aq.), dried over Na2S04, filtered and concentrated in vacuo to orange oil. The oil was dissolved in hot methanol and cooled to crystallize. The white solid was collected and washed twice with cold methanol. After drying under vacuum, the yield was 3.282g (76.8% yield). HNMR (CDC13): 5 (ppm) 7.4-7.2 (m, 20H), 5.89-5.84 (dd, IH), 5.51-5.47 (dd, 1H)S 4.90 (s, 2H), 2.1-2.6 (m, JH), 2.0-1.9 (m, 2H), 1.7-].6 (m, IH), 1.43 (s, 3H), 1.42 (s, 3H), 1.40 2d (s, 3H), 1.35-IJ2 (m, IH). l3C NMR: 5 (ppm) 171.47, 171.44, 139.06, 138.84, 132.38, 128.64, 128.56, 128.51, 128.46, 128.28, 127.11, 127.07, 127,02, 85.12, 80.91, 58.32, 57.86, 44.22, 33.81, 25.41, 23.32, 22.81, 21.41. M.p. lll°C. Elemental Analysis: 81.66% C, 6.59% H. Rf (20% EtOAc/hexane): 0.54. [a]D25 = +61.5° (c=1.00, CHCl3). IR(KBr,cm"'): 3061,3028, 1720.5 (caibonyl stretch). One-step reaction A 25ml roundbottom flask with a stir bar was oven-dried, fitted with septa, and cooled under N2. The bis(diphenylacetate) (4) (279mg, 0A99mmol) and olivetol (90mg) were added. Anhydrous CH2CI2 (8ml) was added and stirred. The solution i was cooled to -5°C internal temperature. BF3'(OEt)2 (64µl, 1.0 eq.) was added. The solution gradually darkened to orange. After 30 minutes, the reaction was quenched with 10% Na2CO3 (10ml). The layers were separated and the organic layer was washed with 2 x 5ml 10% Na2CO3. The aqueous washes were combined and extracted rwice with CH2CI2. The organics were combined and washed with water and saturated NaCl solution, then dried over Na2SO4, filtered, and concentrated in vacuo to light yellow oil. The oil was chromatographed on 5g TLC mesh silica to yield 135.2mg (86.1%) of A9-THC. NMR did show a small amount of solvent present. HPLC showed 96.6 area percent A9 -THC. H NMR agreed with published reports and commercial samples. 13C NMR(CDCl3):a(ppm) 154.81, 154.16, 142.82, 134.41, 123.74, 110.11, 107.54,77.18, 15 45.83, 35.47, 33.58, 31.52, 31.17, 30.63, 27.58, 25.03, 23.34, 22.53, 19.28, 13.99. HPLC R.T.: 28.34min. Rf (10% MTBE/hexane): 0.30. [a]D25 - -174.2° (c=1.16, EtOH). EXAMPLE lb: Reaction of bis(diphenvlacetate) (4) compound with olivetol to produce ring-open intermediate Bis(diphenylacetate) (4) was prepared as for example la A 25ml 2-neck roundbottom flask with a stir bar was oven-dried, fitted with 2|s septa, and cooled under N2 Bis(diphenylactetate) (4) (279mg, 0.499mmol) and olivetol (90mg) were added. Anhydrous CH2CI2 (8ml) was added. The solution was stirred to dissolve the solids and then cooled to -20°C internal temperature. BF3(OEt)2 (16µl, 0.25eq.) was added. The solution was stirred for 12 minutes and then quenched with 10% Na2C03 (aq.) (6ml). The mixture was extracted twice with CH2C12. The 30 combined organics were washed with water and saturated NaCl, dried over Na2so4 filtered, and concentrated in vacuo to oil. Chromatography on lOg TLC mesh silica gel (2% MTBE/hexane - 15%) yielded A9-THC (fractions 16-22, 31.4 mg, 20.0% yield), but the predominant product was the diphenylacetate triol (the ring open product corresponding to compound D) (fr. 24-37, 160 mg, 60.7% yield). 'H NMR (CDC13): 8 (ppm) 7.26-71.8 (m, I OH), 6.26 (br s. IH), 6.04 (br s, IH), 5.35 (s, IH), 4.51 (s, IH), 3.92 (brd, IH), 2.43-2.36 (m, 3H), 2.1-1.9 (m, 2H), 1.79 (m,1H) 1.71 (s, 3H), 1.6-1.4 5f (m, 2H), 1.44 (S2 3H), 1.42 (s, 3H), 1.3-1.2 (m, 4H), 0.85 (t, 3H). l3C NMR (CDC13) 6 ppm 171.56, 142.87, 139.24, 139.08, 128.64, 128.36, 128.31, 126.92; 126,89, 124.93, '115.43, 87.27, 57.53, 45.94, 35.43, 33.46, 31.51, 30.60, 29.96, 24.04, 23.34, 23.20, 123.17, 22.48, 13.97. R, (20% EtOAc/hexane): 0.48. [a]D25 = -45.9° (c=1.298, CHC13). Elemental Analysis: 78.69% C, 8.93% H. EXAMPLE 2a: One-step reaction of moooacetate compound (81 with olivetol to produce A9THC A 25ml roundbottom flask with a stir bar was oven-dried, fitted with septa, and cooled under N2. The monoacetate (8) (I09mg) and oJiveto) (92.5mg) were added. Anhydrous CH2CI2 (8ml) was added and stirred. The solution was cooled to -5°C internal temperature. BF3.(OEt)2 (65ul, l.Oeq.) was added. The solution gradually io darkened to orange. After 24 minutes, the reaction was quenched with 10% Na2CO3. The layers were separated and the aqueous layer was extracted twice with CH2'CI2. The organics were combined and washed with water and saturated NaCl solution, then dried over Na2SO4, filtered, and concentrated in vacuo to oil. HPLC showed 64.0 area percent A9-THC The oiL was chromatographed on 20g TLC mesh silica to yield 2)5 5S.7mg (36.3%) of A9-THC. !H NMR agreed with published reports and commercial samples. EXAMPLE 2b: Reaction of monoacetate compound (8) with olivetol to produce ring-open intermediate A 25ml 2-neck roundbottom flask with a stir bar was oven-dried, fitted with septa, and cooled under N2. The monoacetate (8) (109mg, 0.5l4mmol) and olivetol (92.5mg) were added. Anhydrous CH2CI2 (8mi) was added. The solution was stirred to dissolve the solids and then cooled to -20°C internal temperature. BF3'(OEt)2 (16ul, 0.25eq.) was added. The solution was stirred for 45 minutes and then quenched with 10% Na2C03 (aq.) (4ml). The mixture was extracted twice with CH2G2. The combined organics were washed with water, dried over Na1-SO4 filtered, and concentrated in vacuo to a colourless oil. Chromatography on silica gel yielded 90.5mg (47.0% yield) of acetyl triol (the ring open product corresponding to compound D). 'H NMR (CDCL3): S (ppm) 6.22 (br m, 2H,), 5.76 (be s, 2H), 5.36 (s, 1H), 4.00 (be d, 1H), 2.67 (dt 1H), 2.40 (t, 2H), 2.26-2.16 (m, 1H), 2.07-1.90 (m, 2H), 1.73 (s, 3H), 1.51 (s, 15 3H), 1.49 (s, 3H), 1.42 (s, 3H), 1.32-1.24 (m, 4H), 0.85 (t, 3H). 13C NMR (CDCI3): 8 (ppm) 170.83, 142.69, 138.03, 124.99, 115.42, 85.90, 44.29, 35.38, 33.47, 31.49, 30.66, 30.09, 25.16, 24.65, 23.17, 22.57, 22.43, 21.84, 13.95. Rt-(20% EtOAc/hexane): 0.37. EXAMPLE 3a: 30 One-step reaction of monomethoxy compound (9) with olivetol to produce A -THC A 25ml roundbottom flask with a stir bar was oven-dried, fitted with septa, and -OMe cooled under N2. The monomethoxy compound (9) (91.9mg) and olivetol (90mg) were added. .Anhydrous CH2CL2 (8ml) was added and stirred. The solution was cooled to - 5°C internal temperature. BF3.(OEt)2 (16ul, 0.25eq.) was added. After 1 hour another 16µl was added. Two hours later, another 32µl was added. The solution gradually darkened to orange. TLC showed a mixture of A9-THC and the ring open product, and major spots. The reaction was quenched with 10% Na2C03- The layers were separated and the organic was washed with water and sat. NaCI, then dried over Na2S04, filtered, and concentrated in vacuo to oil. EXAMPLE 3b: Reaction of monomethoxy compound with olivetol to produce ring-open intermediate A 5ml roundbottom flask with a stir bar was oven-dried, fitted with a septum, and cooled under N2. The monomethoxy compound (9) (33.5mg) in 1.5ml of anhydrous methylene chloride was added. Olivetol (32.7mg) and magnesium sulfate (134mg) were added. P-Toluenesulfonic acid monohydrate (34.6mg) was added. The slurry was stirred at room temperature for 30 minutes. Solid NaHCOi (100 mg) was added and stirred. The solids were removed by filtration. The solution was washed once with 5% NaHC03 (aq.). The aqueous wash was extracted once with CH2CI2- The organics were combined, washed with water, and dried over Na2SO4. The solution was concentrated in vacuo and chromatographed on silica gel. Colourless oil of the methoxy triol (the ring open product corresponding to compound D) (35.3 mg, 56.0% yield) was obtained. ]H NMR (CDC13): 5 (ppm) 7.90 (br s, IH), 6.68 (br s? IH), 6.33-6.21 (br d, 2H) 5.75 (s, IH), 3.74 (s, IH), 3.20 (s, 3H), 2.44 (t, 2H), 2.07 (br s, 2H), 2.00-1.77 (m, 3H), 1.80 (s, 3H), 1.54 (m, 2H), 1.31 (m, 3H), 1.14 (s, 3H, 1.13 (s, 3H), 0.87 (t, 3H). i3C NMR (CDC13): 5 (ppm) 186.50, 169.63, 166.85,143,41, 140.11, 123.58, 79.32, 48.63, 48.05, 35.51, 32.62, 31.52, 30.63, 27.76, 23.74, 23.01, 22.53, 21.95, 20.39, 13.99. Elemental Analysis: 73.3% C, 8.80% H. Rf (10% EtOAc/hexane): 0.25. [aJD25 = -22.7° (c-0.088, CHCI3). EXAMPLE 4: One step reaction of diacetate (10) witb olivetol to produce A9-THC preparation of diacetate (10) OAc OAc (10) A 100ml three-necked roundbottom flask with a stir bar was oven-dried, fined with septa, and cooled under N2 (+)-P-menth-2-ene-l,8-diol (lO.OOg) was added. Triethylamine (68.7ml, 8.4eq.) was added and the slurry was stirred. N,N-dimethylaminopyridine (1.435g, 0.2eq.) was added. Acetic anhydride (23.3ml) was placed in an addition funnel and added slowly over 15 minutes. The yellow solution no became homogeneous. The solution was warmed to 35°C internal temperature and stirred for 2.5 hours, then raised to 400C for another three hours, then allowed to stir for 13 hours at room temperature. The reaction was quenched with water while cooling in ice. The mixture was extracted three times with hexane and once with ethyl acetate. The organics were combined and washed with saturated NaCl (aq.), dried over Na2S04, filtered and concentrated in vacuo to an orange oil. Chromatography on 50g TLC mesh silica yielded the diacetate (10) as a colourless oil (12.3g, 82.3%). The oil was cooled in dry ice to freeze the oil and then the solid was broken up with a spatula. It was allowed to warm to room temperature and it remained a white solid. H NMR (CDCI3): 6 (ppm): 5.S4 (dd, IH), 5.54 (dd, 1H), 2.70 (m, 1H), 2.05-1.8 (m, 3H), 1.85 (s, 6H), 1.68 (m, IH), 1.40 (s, 3H), 1.30 (s, 3H), 1.29 (s, 3H). ,3C NMR (CDCb): & (ppm) 169.95, 169.89, 132.40, 127.88, 83.79, 79.73, 43.62, 33.85, 25.26, 23.10, 22.74, 22.05, 21.49. m.p. 28-31°C. Elemental Analysis: 65.26% C, 8.61% H. Rf (20% EtOAc/hexane): 0.52. [a]02S = ^73.5° (c=0.99, CHC13). Onerstep Reaction A 25ml roundbonom flask with a stir bar was oven-dried, fitted with septa, and cooled under N2. The diacetate (10) (126.9mg, 0.499mmol) and olivetol (90mg, 0.499mmol) were added. Anhydrous CH2CI2 (8ml) was added and stirred. 15 The solution was cooled to -5°C internal temperature. BF3.(OEt)2 (64µ1, l.Oeq.) was added. The solution gradually darkened to red. After 15 minutes, the reaction was quenched with 10% Na2C03. The layers were separated and the organic layer was washed with 10% Na2CO3. The combined aqueous were extracted once with CH2Cl2 (5 The organics were combined and washed with water and saturated NaCl solution, then dried over Na2SO4 filtered, and concentrated in vacuo to a tannish oil (0.132mg). HPLC showed 88.8 area percent A9-THC. Chromatography on silica gel yielded 95.9mg (61.0% yield) of A9-THC. HPLC showed 94.9 area percent A9-THC. EXAMPLE 5: One-step reaction of dibenzoate (11) with oljvetol to produce A -THC Preparation of dibenzoate (11) 01) A 25ml three-necked roundbottom flask with a stir bar was oven-dried, fitted with septa, and cooled under N2. (+)-p-Menth-2-ene-l,8-diol (l.OOg) was added. Pyridine (6ml, 12.6eq.) was added and the pale yellow solution was stirred. N,N-dimethylaminopyridine (0.1435g, 0.2eq.) was added. Benzoyl chloride (2.73ml, 4eq.) was added. After 10 minutes, a solid precipitated. The slurry was allowed to stir overnight at room temperature. The reaction was quenched with water. The mixture was extracted three times with CH2C12. The organics were combined and washed with water and saturated NaCl (aq.), dried over Na2SO4 filtered and concentrated in vacuo. The oil was chromato graphed on 25g TLC mesh silica to yield a colourless oil. The oil was cooled in dry ice and froze, but melted on warming to room temperature. H P5 NMR( CDC13) S (ppro): 8.0 (dt, 4H), 7.51 (m, 2H), 7.40 (dt, 4H), 6.16 (dd, 1H), 5.88 (dd, 1H), 3.00 (m, 1H), 2.29 (m, 2H), 2.02 (m, 1H), 1.70 (s, 3H), 1.62 (s, 3H), 1.60 (s, 3H), 1.25 ( m, 1H), 13C NMR (CDC13) 5 (ppm): 165.53, 132. 80, 132.53, 132.50, 131.77, 131.63, 129.40, 129.36, 128.39, 128.22, 128.16, 80.64, 44.55, 34.09, 25.81, 16 : 23.50,23.10,22.59,21.99,14.14,14.05. Elemental Analysis: 76.21% C, 6.97% H. Rf (20% EtOAc/hexane): 0.57. One-step Reaction A 25ml roundbottom flask with a stir bar was oven-dried, fitted with septa, and cooled under N2 The dibenzoate (11) (189mg, 0.499mmol) and olivetol (90mg) were added. Anhydrous CH2CI2 (Sml) was added and stirred. The solution was cooled to -5°C internal temperature. BF3.(OEt)2 (64µl, l.Oeq.) was added. The solution gradually darkened to red. After 15 minutes, the reaction was quenched with 10% Na2CO3. The layers were separated and the organic layer was washed with water and saturated NaCl solution, then dried over Na2S04, filtered, and concentrated in vacuo to oil. HPLC showed 78.8 area percent A9-THC. EXAMPLE 6 One-step reaction of di-p-nitrobenzoate (12) with olivetol to produce A9-THC -.. 0 Preparation of di-p-nitrobenzoate (12) (12) A 25ml three-necked roundbottom flask with a stir bar was oven-dried, fitted with septa, and cooled under N2. (+)-P-Menth-2-ene-l,8-diol (l.OOg) was added. Pyridine (6ml, 12.6eq.) was added and the pale yellow solution was stirred. N,N-dimethylaminopyridine (0.1435g, 0.2eq.) was added. p-Nitrobenzoyl chloride (4.58ml, 4.2eq.) was added. After a few minutes, tan solid precipitated. More pyridine (12ml) was added. The slurry was allowed to stir overnight at room temperature. The reaction was quenched with water. The mixture was extracted three times with ethyl acetate. The organics were combined and washed twice with saturated NaCl (aq-), dried over Na2S04, filtered and concentrated in vacuo to light yellow solid. The solid was 7 recystaJlized from isopropyl alcohol and dried under vacuum. The yield was 3.303g (120% yield), which clearly still contained pyridine and isopropyl alcohol by NMR. It was dried more and then recrystallized from ethyl acetate/hex an e to give a lightly coloured solid (1.89 g, 63.7%). lH NMR (d6-acerone) still seemed to have too many 5 aryl protons. 'H NMR (CD2C12) 6 (ppm): 8.3-8.2 (m, 4H), 8.2-8.1 (m, 4H), 6.14 (dd, 1H), 5.88 (d, 1H), 3.04 (m,IH), 2.29 (m, 2H)7 2.00 (m, 1H), 1.70 (s. 3H), 1.62 (s, 3H), 1.60 (s, 3H0, 1.67-1.65 (m, 2H). 13C NMR (CD2CL2) 8 (ppm): 164.275, 164.244, 151.00, 133.00, 131.46, 131.09, 131.04, 129.29, 124.00, 123.96, 87.04, 82.75, 45.00, 34.55, 26.10. 23.83, 23.45, 22.64. m.p >2000C (decomposition). Elemental Analysis: 10 59.68% C, 4.71% H, 6.07% N. Rf (20% EtOAc/hexane): 0.41. (a]D2S = +38.0° (c=0.21,CHCI3). One step Reaction A 10ml roundbottom flask with a stir bar was oven-dried, fitted with septa, and cooled under NY The di-p-nitrobenzoate (12) (116.5mg) and olivetol (45mg) were added. Anhydrous CH2CL2 (4ml) was added and stirred. The solution was cooled to -5°C internal temperature. BF3.(OEt)2 (32ul, l.Oeq.) was added. The cloudy solution gradually darkened to orange. After 2 hours, the reaction was quenched with 10% Na2C03- The layers were separated and the organic layer was washed with water and 20 sat. NaCl, then dried over Na2S04, filtered, and concentrated in vacuo to yellow oil. HPLC showed 71.5 area percent A9-THC. We Claim: 1. A process for the production of a cannabinoids compound of general formula A: Compound A wherein Rc, Rd and Rc are independently H, alkyl, or substituted alkyl; and R1 to R4 are independently H, OH, OR' (R' is alkyl, aryl, substituted alkyl or aryl, silyl, acyl, or phosphonate), alkyl, substituted alkyl, aryl, acyl, halide, amine, nitrate, sulphonate or phosphonate; comprising reacting compound B with compound C: Rc 0Ra Rl R2 Compound B R3 HO Compound C wherein R3 is H, alkyl. aryl, acyl or silyl; Rb is alkyl, aryl or acyl; Rc, Rd , Rc and R1 to R4 are as hereinbefore denned; and comprising, when necessary, a ring closure reaction. 2. A process as claimed in claim 1, wherein Ra is alkyl, aryl or acyl. 3. A process as claimed in claim 1 or claim 2, wherein Rb is an acyl group. 4. A process as claimed in claim 3, wherein ORb is an ester group selected from acetate, propionate, butyrate, trimethylacetate, phenylacetate, 9 phenoxyacetate, diphenylacetate, benzoate, p-nitrobenzoate. phthalate or succinate. 5. A process as claimed in claim 1, wherein both Ra and Rb are acyl group. 6. A process as claimed in claim 5, wherein ORa and ORb are ester groups independently selected from acetate, propionate, butyrate, trimethylacetate, phenylacetate, phenoxyacetate, diphenylacetate, benzoate, p-nitrobenzoate, phthalate or succinate. 7. A process as claimed in claim 6, wherein ORa and ORb are diphenylacetate. 8. A process as claimed in any one of the preceding claims, wherein Rc, Rd and Re are methyl. 9. A process as claimed in any one of the preceding claims, wherein R1 is ORa wherein Rb is alkyl, substituted alkyl, acyl or silyl. 10. A process as claimed in claim 9, wherein R1 is OH. 11. A process as claimed in any one of the preceding claims, wherein R2 and R4 are H. 12. A process as claimed in any one of the preceding claims, wherein R3 is C5H11. 13. A process as claimed in any of the preceding claims, wherein compound A is A9-THC, compound B is an ether or ester of (+)-p-menth-2-ene-l, 8-diol and compound C is olivetol. 14. A process as claimed in any one of the preceding claims, wherein the reaction of compound B with compound C is carried out in the presence of an acid catalyst. 15. A process as claimed in claim 14, wherein the acid catalyst is nonmetallic. 16. A process as claimed in claim 14 or 13, wherein 0.1-0.5 equivalents of acid are used. 17. A compound, represented by structure B, Compound B wherein ORa and ORb are independently chosen from acetate, propionate, butyrate trimethylacetate, phenylacetate, phenoxyacetate, diphenylacetate, benzoate, p-nitrobenzoate, phthalate and succinate (provided that only one of ORa and ORb is acetate), and Rc, Rd and Rc are independently H, alkyl, or substituted alkyl. 18. A compound as claimed in claim 17, wherein ORa and ORb are diphenylacetate. Dated this 12th day of November, 2003. (RICHA PANDEY) OF REMFRY AND SAGAR ATTORNEY FOR THE APPLICANTS 21

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