Claims:We claim:

1. A method (200) for preparation of cannabidiol, the method comprising the steps of:
a. preparing an activated mentha-2,8-diene-1-ol (201);
b. coupling the activated mentha-2,8-diene-1-ol with 5 substituted resorcinol to obtain cannabidiol (202), wherein the substituted resorcinol is preferably 5-n-alkyl resorcinol , more preferably 5-pentyl resorcinol (olivetol);
c. coupling the activated mentha-2,8-diene-1-ol with 5,6 disubstituted resorcinol, to obtain cannabidiolate (203) wherein the disubstituted resorcinol is preferably methyl olivetolate;
d. decarboxylating the cannabidiolate to obtain cannabidiol (204);
e. purifying the cannabidiol obtained in step (202) or (204) to obtain purified cannabidiol (205); and
f. crystallizing the purified cannabidiol to obtain white crystalline cannabidiol with 99-100% purity (206); wherein the tetrahydrocannabinol is below detection limit.

2. The method as claimed in claim 1, wherein preparing activated mentha-2,8-diene-1-ol further comprises preparing any one of the intermediate compounds selected from a group comprising mentha-2,8-diene-1-yl ester (Formula IV) (201 A), mentha-2,8-diene-1-arylsulfonyl carbamate (Formula V) (201 B), mentha-2,8-diene-1-arylsulfonyl thiocarbamate (Formula VI) (201 C).

3. The method as claimed in claim 2, wherein preparing mentha-2,8-diene-1-yl ester (201 A) further comprises of the steps of:
a. dissolving mentha-2,8-diene-1-ol in an organic solvent to obtain a solution (201 A a), wherein the organic solvent is selected from a group comprising tetrahydrofuran, methyl tetrahydrofuran, dioxane, halogenated, pyridine, pyrrolidine, morpholine, preferably pyridine;
b. adding a non-nucleophillic organic base to the resulting solution in step (201 A a) to form reaction mass (201Ab1).
c. adding carboxylic acid chloride to the solution (201 Ab1) to form a reaction mass (201 A c1), wherein the carboxylic acid chloride is selected from a group comprising n-alkyl, branched alkyl, substituted or un-substituted aryl, substituted or un-substituted alkyl aryl, heteroaryl, preferably substituted or unsubstituted arylacetyl chloride, more preferably diphenyl acetyl chloride;
d. quenching reaction mass (201 A c1) using mineral acid. Mineral acid used for this step can be hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid or mixture thereof;
e. adding water immiscible organic solvent to extract the product from the resulting solution (201Ad1) as define as step (201Ae1);
f. separating organic layer and isolating menthe-2,8diene-1-yl ester diester (201A f).
4. The method as claimed in claim 2, wherein preparing menthe-2,8-diene-1-yl ester (201 A) further comprises following steps of:
a. dissolving menthadiene-1-ol in inert solvent to obtain a solution (step 201 A a), wherein the inert solvent is selected from tetrahydrofuran, methyl tetrahydrofuran, dioxane, halogenated solvent preferably tetrahydrofuran;
b. adding coupling agent to the solution in the presence of a non-nucleophilic organic base to form a reaction mass (201 A b2), wherein the coupling agent is selected from a group comprising carbodiimides, phosphonium based coupling agent, uronium based coupling agents;
c. adding carboxylic acids to the reaction mass (201 A c2), wherein the carboxylic acid is selected from a group comprising n-alkyl, branched alkyl, substituted or un-substituted aryl, substituted or un-substituted alkyl aryl, heteroaryl, preferably substituted or unsubstituted aryl acetic acid , more preferably diphenyl acetic acid ;
d. optionally filtration of reaction mass (201 A d1);
e. concentration followed by dissolution in water immiscible organic solvent followed by washing with mineral acid and subsequently with water (201 A e2).
f. Separating organic layer and isolating menthe-2,8diene-1-yl ester diester (201A f).

5. The method as claimed in claim 3 and 4, wherein the non-nucleophilic organic base is a base selected from a group comprising pyridine, methyl pyridine, pyrrolidine, trimethyl amine, triethyl amine, tripropyl amine, diisopropyl ethyl amine, N-methyl morpholine, 1,2-Bis(methylamino)ethane (DAMEDA), 1,2-Bis (dimethylamino) ethane (TAMEDA), lutidine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo [2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), butyl alcohol (HOBt), 4-(dimethylamino) pyridine (DMAP) and combination thereof, preferably one of the group comprising lutidine, HOBt, DMAP and more preferably DMAP or hydroxy benzotriazole.

6 The method as claimed in claim 2, wherein preparing mentha-2,8-diene-1-arylsulfonyl carbamate (201 B) further comprises the steps of:
a. dissolving mentha-2,8-diene-1-ol in an aprotic solvent to obtain a solution (201B a), wherein the aprotic solvent is selected from a group comprising tetrahydrofuran, dioxane, toluene, xylene, chloroform, methylene chloride, dimethyl formamide, cyclohexane, hexane, heptane and ether, preferably methylene chloride;
b. cooling the solution between -10oC to 10oC, preferably between -5oC to 0oC (201B b);
c. adding an arylsulfonyl isocyanate to the precool solution (201B b), to obtain a reaction mass (201 B c);
d. maintaining the temperature of the reaction mass between -10oC to 10oC (201 B d); and
e. isolating or in-situ use of reaction mass of mentha-2,8-diene-1-arylsulfonyl carbamate (201 B e).
7. The method as claimed in claim 2, wherein preparing mentha-2,8-diene-1-arylsulfonyl thiocarbamate (201 C) further comprises the steps of:
a. dissolving mentha-2,8-diene-1-ol in an inert solvent to obtain a solution (201 C a), wherein the solvent is selected from a group comprising toluene, methylene chloride, tetrahydrofuran, dioxane, dimethyl formamide, cyclohexane, hexane, heptane and ether, preferably in methylene chloride;
b. cooling the obtained solution between -10oC to 10oC, preferably -5oC to 0oC (201 C b);
c. adding a substituted aryl sulfonyl isothiocyanate, within 5 minutes of formation of solution to obtain a reaction mass (201 C c), wherein the substituted aryl sulfonyl thiocarbamate is preferably p-toluene sulphonyl thiocarbamate;
d. maintaining the temperature of the reaction mass between -5oC and 0oC (201 C d); and
e. isolating or in-situ use of reaction mass of mentha-2,8-diene-1-arylsulfonyl thiocarbamate (201 C e).

8. The method as claimed in claim 1, wherein coupling the activated mentha-2,8-diene-1-ol with 5-substituted resorcinol (202) further comprises the steps of:
a. preparing a first solution of activated mentha-2,8-diene-1-ol in aprotic solvent (202 a), wherein the aprotic solvent is selected from a group comprising n-alkane, halogenated alkane and aromatic solvents, preferably halogenated alkane, more preferably methylene chloride;
b. dissolving the 5-substituted resorcinol in aprotic solvent to obtain second solution (202 b), wherein the aprotic solvent is selected from a group comprising n-alkane, halogenated alkane and aromatic solvents, preferably halogenated solvent, more preferably methylene chloride;
c. adding a Lewis acid to the second solution to obtain a reaction mixture (202 c), wherein the Lewis acid is selected from a group comprising d-block transition metal triflate including boron trifluoride etherate, acetic acid and ethyl acetate, preferably boron trifluoride etherate, and wherein the temperature of second solution is maintained between -5oC and 0oC during the addition;
d. adding the first solution to the reaction mixture to obtain a reaction mass (202 d), wherein the temperature of reaction mass is maintained between -25oC and 0oC;
e. quenching the reaction mass after completion of the reaction with sodium carbonate to obtain a heterogeneous reaction mass (202 e);
f. filtering the heterogeneous reaction mass (202 f);
g. washing the filtered reaction mass with 1% sodium hydroxide and water (202 g);
h. separating the organic layer (202 h);
i. drying the organic layer over sodium sulfate (202 i); and
j. concentrating the dried layer under reduced pressure to obtain cannabidiol (202 j).

9. The method as claimed in claim 1, wherein reacting the activated mentha-2,8-diene-1-ol with 5,6 disubstituted resorcinol (203) further comprises the steps of:
a. preparing a first solution of activated mentha-2,8-diene-1-ol and magnesium sulfate in aprotic solvent (203 a), wherein the aprotic solvent is selected from a group comprising n-alkane, halogenated alkane and aromatic solvents, preferably halogenated solvent, more preferably methylene chloride;
b. dissolving the 5,6-disubstituted resorcinol in aprotic solvent to obtain second solution and cooling to temperature between -5 oC and 0 oC (203 b), wherein the aprotic solvent is selected from a group comprising n-alkane, halogenated alkane and aromatic solvents, preferably halogenated solvent, more preferably methylene chloride;
c. adding a Lewis acid to the second solution to obtain a reaction mixture (203 c), wherein the Lewis acid is selected from a group comprising d-block transition metal triflate including boron trifluoride etherate, acetic acid and ethyl acetate, preferably boron trifluoride etherate, and wherein the temperature of second solution is maintained between -5oC and 0oC during the addition;
d. adding the first solution to the reaction mixture to obtain a reaction mass (203 d), wherein the temperature is maintained between -5oC and 0oC during the addition;
e. quenching the reaction mass after completion of the reaction with sodium carbonate to obtain a heterogeneous reaction mass (203 e);
f. filtering the heterogeneous reaction mass (203 f);
g. washing the filtered reaction mass with 1% sodium hydroxide and water (203 g);
h. separating the organic layer (203 h);
i. drying the organic layer over sodium sulfate (203 i); and
j. concentrating the dried layer under reduced pressure to obtain cannabidiolate (203 j).

10. The method as claimed in claim 1, wherein decarboxylating the cannabidiolate (204) further comprises the steps of:
a. dissolving the cannabidiolate in a solvent to obtain a solution (204 a), wherein the solvent is selected from a group comprising alcohol, water or mixture thereof, preferably alcohol and water, wherein the alcohol is selected from a group comprising methanol, ethanol, 2-propanol, 1-butanol, and glycol, more preferably methanol in combination with water.
b. combining the solution with a base to obtain a reaction mixture (204 b), wherein the base is selected from a group comprising lithium hydroxide, sodium hydroxide and potassium hydroxide;
c. heating the reaction mixture between 55oC and 65oC for 14 hours (204 c);
d. cooling the reaction mixture to ambient temperature (204 d);
e. adding an organic solvent to the reaction mixture and separating the organic layer (204 e), wherein the organic solvent is preferably toluene; and
f. concentrating the separated organic layer under reduced pressure to obtain cannabidiol (204 f).

11. The method as claimed in claim 1, wherein purifying the obtained cannabidiol (205) further comprises the steps of:
a. dissolving the cannabidiol in lower alkanes to obtain a solution (205 a), wherein the lower alkane is selected from a group comprising pentane, hexane, heptane or mixture there of;
b. passing the solution through a bed of silica (205 b), wherein the size of silica mesh is selected from a group comprising 60-120, 100-200, 240-400, preferably a 60-120 mesh;
c. eluting the bed of silica with a mixture of nonpolar solvent and polar solvent to obtain the eluate (205 c), wherein the mixture of solvent is selected from a group comprising lower alkane and di-isopropyl ether, lower alkane and ethyl acetate, lower alkane and methylene chloride, preferably the non-polar lower alkane solvent is hexane and polar solvent is ethyl acetate; and
d. concentrating the eluent to obtain purified cannabidiol (205 d).

12. The method as claimed in claim 1, wherein crystallizing the purified cannabidiol (206) further comprises the steps of:
a. dissolving the purified cannabidiol in an organic solvent to obtain a solution, wherein the organic solvent is selected from a group comprising n-alkane, preferably n-pentane, n-hexane and n-heptane more preferably n-heptane; and
b. crystallizing the solution at a temperature between of -10oC and 10oC, preferably between -10oC and 0oC to obtain pure cannabidiol with purity 99% -100%.

13. A mentha-2,8-diene-1-yl ester (Formula IV) obtained using the method claimed in claim 3, wherein R1 is n-alkyl, branched alkyl, substituted or un-substituted aryl, alkyl aryl or heterocyclic derivative.

14. The mentha-2,8-diene-1-yl ester as claimed in claim 13, wherein the R1 group in is an aryl substituted alkyl group forming compound of (Formula XII), wherein R4 is selected from a group comprising H, NO2, halo, substituted or un-substituted alkyl, substituted or un-substituted aryl, heteroaryl, and wherein R5 is ortho, meta or para substituted and is selected from a group comprising H, NO2, halo, substituted or un-substituted alkyl and substituted and unsubstituted aryl.

15. The compound as claimed in claim 14, wherein R4 and R5 in Formula XII is phenyl group and –H respectively, forming compound of (Formula XIII), wherein the purity of the mentha-2,8-diene-1-yl ester (Formula XIII) is between 97% and 98%.

16. A mentha-2,8-diene-1-arylsulfonyl carbamate of Formula V obtained using method claimed in claim6, wherein R2 is selected from a group comprising H, NO2, halo, substituted or un-substituted alkoxy, substituted or un-substituted alkyl moiety.

17. The mentha-2,8-diene-1-arylsulfonyl carbamate as claimed in claim 16, wherein R2 is a p-methyl group forming compound of (Formula XV) wherein the purity of mentha-2,8-diene-1-(4-methyl) phenylsulfonyl carbamate (Formula XV) is between 78% and 79%.

18. A mentha-2,8-diene-1-arylsulfonyl thiocarbamate of (Formula VI) obtained using method claimed in claim 7, wherein R2 is selected from a group comprising H, NO2, halo, substituted or un-substituted alkoxy, substituted or un-substituted alkyl moiety.

19. The mentha-2,8-diene-1-arylsulfonyl thiocarbamate as claimed in claim 18, wherein R2 is a p-methyl group forming compound of (Formula XVI), wherein the purity of mentha-2,8-diene-1-arylsulfonyl thiocarbamate (Formula XVI) is between 78% and 79%.

, Description:Preamble to the Description
[0001] The following specification describes the invention and the manner in which it is to be performed:
DESCRIPTION OF THE INVENTION
Technical field of the invention
[0002] The present invention relates to a method for preparation of cannabidiol. More particularly, the invention relates to a method comprising the activation of mentha-2,8-diene-1-ol and condensation of activated mentha-2,8-diene-1-ol with substituted phenol to obtain cannabinoid.
Background of the invention
[0003] Cannabidiol (CBD) is one of the important phyto-cannabinoid, which is naturally occurring in Cannabis sativa plant and forms about 40% of the plant’s extract. The other important cannabinoids found in the plant extract includes delta-9-tetrahydrocannabinol (?9-THC), cannabinol (CBN), cannabigerol (CBG), Cannabidivarin (CBDV), Tetrahydrocannabivarin (THCV) and terpenes. Cannabidiol exhibits multiple pharmacological actions and is found to be effective as an analgesic, anticonvulsant, muscle relaxant, anxiolytic, antipsychotic etc. It also exhibits neuroprotective, anti-inflammatory, and antioxidant activity. Cannabidiol is found to be very effective in treating health disorders such as epilepsy, acne, arthritis, anxiety due to insomnia, chronic pain and it may also alleviate cancer-related symptoms. Cannabidiol is very useful in curing childhood epilepsy syndromes such as Dravet syndrome and Lennox-Gastaut syndrome (LGS), which generally do not respond to antiseizure medications. Further, CBD does not cause intoxication or euphoria that is associated with the use of tetrahydrocannabinol. The oral bioavailability of CBD is 13% to 19%, while its bioavailability via inhalation is 11% to 45% (mean 31%). The elimination half-life of cannabidiol is nine hours.
[0004] The structure of CBD is composed of three major parts namely limonene moiety, resorcinol moiety and 5-carbon-alkyl side chain. A number of homologues of cannabidiol have been synthesized that comprise the analogs of the three structural parts. Cannabidiol is a crystalline solid, which is insoluble in water but soluble in organic solvents. The synthesis of CBD through a number of metabolic pathways and its chemistry has been extensively studied for more than thirty years.
[0005] The Swiss Chemical society journal, Helvetica Chimica Acta, in its publication 719 (1967) entitled “Synthese und Chiralität des (-)-Cannabidiols Vorläufige Mitteilung” discloses a method of formation of (-)-CBD by the acid catalyzed condensation of (+)-cis--p-mentha-2,8-diene-1-ol and olivetol through the formation of an intermediate namely N,N-dimethylformamide-dienopentyl acetal. However, the method is very complex and results in formation of a mixture of three products including 25?% of (-)-CBD, 35?% of abnormal CBD, 5?% of (-)-2,4-disubstituted olivetol and 30?% unreacted olivetol.
[0006] The publication in Tetrahedron Letters volume 26, Issue 8, 1985, pages 1083-1086 titled “Boron triflouride etherate on alimina - a modified Lewis acid reagent: An improved synthesis of cannabidiol” discloses the use of boron trifluoride etherate on alumina as a modified catalyst for condensation of resorcinol and monomethyl resorcinol with several monoterpenoid allylic alcohols. The article discloses the condensation of (+)-p-mentha-diene-ol with olivetol in the presence of the modified catalyst. The method results in producing good yield of pure cannabidiol and does not lead to formation of cyclized cannabinoids. However, significant amount of abnormal CBD is a major bye-product.
[0007] The publication in Journal of the Chemical Society, Perkin Transactions 1 Issue 5, 1988, page 1243 titled “Acid-catalysed terpenylations of olivetol in the synthesis of cannabinoids” discloses a method of condensation of car-2-ene epoxide with olivetol at 50oC in the presence of p-toluene-sulfonic acid to give cannabinoids. However, the product obtained is a mixture of 64% CBD, 28% abnormal CBD, 6% delta-9 THC and 2% Delta -8 THC.
[0008] The research article in Journal of Organic Chemistry 1992, pages 3627-3631, titled “A one-step method for the .alpha.-arylation of camphor. Synthesis of (-)-cannabidiol and (-)-cannabidiol dimethyl ether” relates to a method for synthesis of (-)-cannabidiol and (-)-cannabidiol dimethyl ether. According to the method, in the first step, 3,9-dibromocamphor is treated with cuprate of olivetol dimethyl ether to obtain endo selective a-aryl ketone. In the second step the a-aryl ketone is reduced to alcohol by Di-isobutyl Aluminum Hydride (DIBAL-H) and the resulting hydroxyl functionality was protected with methanesulphonyl chloride to obtain endo mesylate. In third step, the endo mesylate undergoes dehydrohalogenation to cannabidiol dimethyl ether by treating with sodium in presence of naphthalene at 0oC. The method results in production of cannabidiol dimethyl ether with 71% yield. However, the article does not disclose the procedure for preparation of cannabidiol.
[0009] The patent document WO2004/092101 titled “Olivetol-cyclodextrin complexes and regio-selective process for preparing delta 9-tetrahydrocannabinol” discloses a process for preparation of cannabidiol through the formation of an intermediate complex of cyclodextrine with olivetol. According to the process mentioned in the document, the cyclodextrin-olivetol complex is made to react with (+)-mentha-2,8-diene-1-ol in presence of p-toluenesulfonic acid in tetrahydrofuran as solvent media. However, the document does not disclose the yield and purity of cannabidiol obtained by the process.
[0010] The report in Organic Letters 2699-2702 (2006), titled “Synthesis of Cannabidiols via Alkenylation of Cyclohexenyl Monoacetate” mentions another method for synthesis of cannabidiol and its analogues by nickel-catalyzed allylation of 2-cyclohexene-1,4-diol monoacetate with (alkenyl)ZnCl or Tetramethylethylenediamine (TMEDA). The method comprises the reaction of cuprate of olivetol dimethyl ether with 2-Iodo-4-isopropenylcyclohex-2-ene-1-one as the first step. The second step is conversion of ketone functionality of the intermediate to diethyl phosphonate. In the third step, the phosphonate functionality is further converted to methyl group using methyl magnesium bromide in presence of nickel acetoacetate. This is followed by ortho demethylation of the product to form cannabidiol. However, the method involves a series of steps which complicates the process.
[0011] The patent document WO 2007041167 entitled “Process for production of delta-9-tetrahydrocannabinol” discloses a process for preparation of cannabidiol. The method involves the preparation of ethyl cannabidiolate by reaction of menthadiene-1-ol with ethyl olivetolate in presence of scandium triflate in methylene chloride in the first step. The product obtained in initial step undergoes hydrolysis to form cannabidiol. The purity of product is >99.8%. The process involves purification of ethyl cannabidiolate by column chromatography and distillation. This is followed by seeding with cannabidiol at cannabidiol stage. Though the process results in product with purity of 99.8%, the overall yield is low (57.5%) and hence the process is not economical.
[0012] The patent document WO 2009/018389 titled “Prodrugs of cannabidiol, compositions comprising prodrugs of cannabidiol and methods of using the same” describes a method for making cannabidiol prodrug and formulation containing the same and its administration. The method comprises the condensation of olivetol with menthadiene-1-ol in presence of p-toluene sulfonic acid as catalyst in benzene. The method results in the formation of cannabidiol with 24% yield after purification by column chromatography. However, there is no mention of the interference due to formation of other undesirable impurities during the process.
[0013] The US patent application US 2017/0008868 titled “Process for the production of cannabidiol and delta-9-tetrahydrocannabinol” relates to the preparation of cannabidiol or its derivative by acid-catalysed reaction of di-halo-olivetol with cyclic alkene followed by reduction. According to the process, 4,6-dihalo olivetol is made to react with menthadiene-1-ol to obtain dihalo cannabidiol. The dihalo-cannabidiol obtained with 99% yield and 93% purity. This is followed by reduction of the dihalo derivative using sodium sulfite in-presence of L-ascorbic acid to give cannabidiol with 55% yield and purity 99.3%. Since the process uses dihalo olivetol the formation of abnormal CBD is reduced substantially. However, the condensation temperature required for preparation of dihalo cannabidiol is very low and the process requires usage of large quantities of halogenating agent both of which become important disadvantages of the process.
[0014] The US patent application US 2017/0349518 titled “Crystalline Form of Cannabidiol” describes a method of preparing new forms of crystalline cannabidiol in which the cannabidiol is dissolved in a solvent such as methyl tert-butyl ether (MTBE) followed by crystallisation after adding an anti-solvent in which the cannabidiol has lower solubility. After removal of MTBE, the temperature of the reaction mass is reduced and it is then seeded with new form of crystals in the presence of cannabidivarin to obtain new crystalline form of cannabidiol. The patent document also discloses the preparation of methyl cannabidiolate by condensation of methyl olivetolate with mentha-2,8-diene-1-ol in presence of boron trifluoride etherate. The methyl cannabidiolate obtained is hydrolysed in situ to form cannabidiol. However, the solid cannabidiol isolated from methyl olivetolate using the method gave low yield of 48%.
[0015] A recent publication in Organic Letters 381 (2018) titled “Enantioselective Total Synthesis of Cannabinoids—A Route for Analogue Development” reported a synthetic strategy for a scalable production of (-)-CBD by combining three well-recognized reactions Corey–Bakshi–Shibata (CBS) reduction of ketones, stereospecific Ireland–Claisen rearrangement and Ru-catalyzed ring-closing metathesis. However, the mentioned procedure may not be feasible on a commercial scale.
[0016] The patent application WO2019/046806 entitled “Synthetic cannabidiol compositions and methods of making the same” discloses the process for preparation of synthetic cannabidiol composition. The method involves the steps of combining (+)-menthadienol and olivetol with a Lewis Acid catalyst to form a first reaction mixture which is added to a terpene-containing component to form a second reaction mixture. The second reaction mixture is washed with water and the organic phase is separated. The separated organic phase is further purified by complexation procedure to form insoluble CBD-1,4-diazabicyclo[2.2.2]octane (DABCO) complex. The complex is isolated, washed and dissolved in solvent and hydrolysed in the presence of acid to form crystals of substantially pure cannabidiol. However, the method is very cumbersome and tedious.
[0017] The patent application WO2019/033168 entitled “Synthesis of phytocannabinoids including a decarboxylation step” relates to a method for decarboxylation of a carboxylated phytocannabinoid compound. The patent document discloses the condensation of methyl olivetolate with menthadiene-1-ol in presence of 0.1 equivalent of boron trifluoride etherate with chlorobenzene as solvent to yield the carboxylated phyto-cannabinoid. The decarboxylation of the carboxylated phyto-cannabinoid compound dissolved in a polar aprotic solvent in the presence of a lithium chloride results in the formation of cannabidiol. However, the method results in low yield of (60%-70%) of the cannabidiol.
[0018] The US patent application US2019/0023680 titled “Synthesis of cannabinoids” relates to synthesis processes and intermediates for preparing cannabinoids and its analogues. The patent document discloses a new methodology, which uses olivetol as starting compound and the sequential reactions on olivetol to produce cannabidiol. The chemical reaction involved in the process includes protection of hydroxyl functionalities of olivetol, formylation, condensation with acetone, stereoselective reduction of ketone, esterification of chiral hydroxyl functionality with 4-methylpent-4-enoic acid. This is followed by rearrangement using Ireland-Claisen reaction, esterification, Ring-closing metathesis (RCM) reaction and lastly Grignard reaction to give cannabidiol. However, the disclosed method is very complex and involves number of steps and hence is difficult to adopt on commercial scale.
[0019] It is obvious from the above-mentioned prior arts that there is no single method to obtain cannabidiol in appreciable yield and good purity, which have negligible quantity of abnormal CBD. Further, the methods mentioned in the prior arts require multiple steps for the preparation of cannabidiols and purification which are associated with practical problems in adopting them on large scale.
[0020] Therefore, there is need for a method for preparation of cannabidiol involving simple steps and using easily available reagents which produces cannabidiol with high purity and with commercial feasibility.
Summary of the invention

[0021] The invention relates to a method for preparation of cannabidiol by reacting activated p-mentha-2,8-diene-1-ol with a substituted resorcinol. The method comprises preparation of activated p-mentha-2,8-diene-1-ol followed by its reaction with mono or disubstituted resorcinol resulting in the formation of cannabidiol or cannabidiolate respectively. The method also includes the decarboxylation of the obtained cannabidiolate to form cannabidiol. The method also includes the purification of cannabidiol by filtration through a bed of silica followed by crystallization from solvent at low temperature to obtain white solid crystals of cannabidiol with purity between 99% and 100% wherein amount of tetrahydrocannabidiol is below the detection limit.

[0022] The method for preparation of cannabidiol comprises preparing an activated mentha-2,8-diene-1-ol, coupling the activated mentha-2,8-diene-1-ol with 5 substituted resorcinol to obtain cannabidiol, coupling the activated mentha-2,8-diene-1-ol with 5,6 disubstituted resorcinol to obtain cannabidiolate, decarboxylating the cannabidiolate to obtain cannabidiol, purifying the cannabidiol and crystallizing the purified cannabidiol to obtain white crystalline cannabidiol with 99%-100% purity.

[0023] The invention is a method for preparation of cannabidiol by preparing activated p-mentha-2,8-diene-1-ol. The activated p-mentha-2,8-diene-1-ol (Formula II), prepared by activating the hydroxyl group in the said compound by reacting with activating group there by resulting any one of the compound shown as, mentha-2,8-diene-1-yl ester (Formula IV), mentha-2,8-diene-1-arylsulfonyl carbamate (Formula V) or mentha-2,8-diene-1-arylsulfonyl thiocarbamate (Formula VI).

[0024] The substituted resorcinol (Formula III) used in the method is either a 5-substituted resorcinol (wherein R” is H) with Formula VII. R’ in Formula VII is H, OH, protected hydroxyl, substituted or un-substituted alkyl, alkenyl, alkynyl, acyl, aryl or heteroaryl or a 5,6-disubstituted resorcinol of Formula III wherein R’ is H, OH, protected hydroxyl, substituted or un-substituted alkyl, alkenyl, alkynyl, acyl, aryl or heteroaryl and R” is COOR3 where, R3 is substituted or un-substituted alkyl, aryl, hetero aryl. The more preferred 5-substituted resorcinol is olivetol and 5,6-disubstituted resorcinol is olivitolate (Formula VIII).

[0025] The method for preparation of cannabidiol (Formula IX) comprises preparing mentha-2,8-diene-1-yl ester with general Formula IV wherein R1 is n-alkyl, branched alkyl, substituted or un-substituted aryl, alkyl aryl or heterocyclic derivative. This is followed by coupling the ester obtained with 5-substituted resorcinol (Formula VII) or 5,6-disubstituted resorcinol (Formula VIII) to obtain the cannabidiol or cannabidiolate respectively.

[0026] The preparation of mentha-2,8-diene-1-yl ester further comprises reacting mentha-2,8-diene-1-ol with carboxylic acid or carboxylic acid chloride. Reacting the mentha-2,8-diene-1-yl ester obtained with 5-substituted resorcinol (Formula VII) in aprotic solvent, in the presence of Lewis acid gives cannabidiol (Formula IX).

[0027] The method for preparing cannabidiol further comprises reacting the activated mentha-2,8-diene-1-yl ester obtained (Formula IV) with 5,6-disubstituted resorcinol of Formula VIII in the presence of an Lewis acid to obtain cannabidiolate (Formula X) followed by decarboxylation of cannabidiolate in a protic solvent in presence of acids or base to give cannabidiol (Formula IX).

[0028] The preparation of mentha-2,8-diene-1-arylsulfonyl carbamate (Formula V) further comprises reacting mentha-2,8-diene-1-ol with substituted or un-substituted aryl sulfonyl isocyanate, substituted or un-substituted heteroaryl sulfonyl isocyanate, followed by coupling of the obtained mentha-2,8-diene-1-arylsulfonyl carbamate (Formula V) with either 5-substituted resorcinol with Formula VII in aprotic solvent, in the presence of Lewis acid to obtain cannabidiol (Formula IX) or with 5,6-disubstituted resorcinol with Formula VIII in aprotic solvent, in the presence of acid to obtain cannabidiolate (Formula X). The method further includes the decarboxylation of obtained cannabidiolate in a protic solvent in presence of acids or base to obtain cannabidiol (Formula IX).

[0029] The preparation of mentha-2,8-diene-1-arylsulfonyl thiocarbamate (Formula VI) further comprises reacting mentha-2,8-diene-1-ol with substituted or un-substituted aryl sulfonyl isothiocyanate, substituted or un-substituted heteroaryl sulfonyl isothiocyanate followed by coupling the obtained mentha-2,8-diene-1-arylsulfonyl thiocarbamate (Formula VI) with either 5-substituted resorcinol with Formula VII in aprotic solvent, in the presence of Lewis acid to obtain cannabidiol or with 5,6-disubstituted resorcinol with Formula VIII in aprotic solvent, in the presence of acid to obtain cannabidiolate. The method further includes the decarboxylation of obtained cannabidiolate in a protic solvent in presence of acids or base to obtain cannabidiol.

[0030] The method for preparation of cannabidiol includes the purification of cannabidiol obtained from the reaction of activated mentha-2,8-diene-1-ol with substituted resorcinol which further comprises filtering the obtained cannabidiol through a bed of silica followed by crystallization using organic solvent to obtain cannabidiol with purity between 99% and 100% and wherein tetrahydrocannabinol is below detection limit.

[0031] The invention is a method for preparation of cannabidiol by preparation of activated mentha2,8-diene-1-ol with of the representative structures as depicted as formula XIII, XV or XVI.

Brief description of the drawings

[0032] The foregoing and other features of embodiments will become more apparent from the following detailed description of embodiments when read in conjunction with the accompanying drawings.

[0033] Figure 1 is a schematic representation of the examples of preparation of cannabidiol. Figure 1a and Figure 1b represent one of the examples for preparation of cannabidiol from mentha-2,8-diene-1-yl ester. Figure 1c represents one of the examples for preparation of cannabidiol from mentha-2,8-diene-1-arylsulfonyl carbamate and Figure 1d represents one of the examples for preparation of cannabidiol from mentha-2,8-diene-1-arylsulfonyl thiocarbamate.

[0034] Figure 2 illustrates a flowchart representing the method for preparation of cannabidiol.

[0035] Figure 3 illustrates the preparation of activated p-mentha-2,8-diene-1-ol.

[0036] Figure 4 illustrates the method for preparing mentha-2,8-diene-1-yl ester.

[0037] Figure 5 illustrates a flowchart for the preparation of mentha-2,8-diene-1-arylsulfonyl carbamate.

[0038] Figure 6 illustrates the preparation of mentha-2,8-diene-1-arylsulfonyl thiocarbamate.

[0039] Figure 7 is a flowchart representing the coupling of the activated mentha-2,8-diene-1-ol with 5-substituted resorcinol.

[0040] Figure 8 illustrates the coupling of activated mentha-2,8-diene-1-ol with 5,6-disubstituted resorcinol.

[0041] Figure 9 illustrates the decarboxylation of cannabidiolate.

[0042] Figure 10 illustrates a flowchart representing the purification of cannabidiol.

Detailed description of the invention

[0043] Reference will now be made in detail to the description of the present subject matter, one or more examples of which are shown in figures. Each example is provided to explain the subject matter and not a limitation. Various changes and modifications obvious to one skilled in the art to which the invention pertains are deemed to be within the spirit, scope and contemplation of the invention.

[0044] The invention relates to a method for preparation of cannabidiol (Formula I) by activating p-mentha-2,8-diene-1-ol, coupling the activated mentha-2,8-diene-1-ol (Formula II) with mono or disubstituted resorcinol (Formula III), obtaining the crude cannabidiol or the cannabidiolate, decarboxylating cannabidiolate to obtain crude cannabidiol and purification of the crude cannabidiol to obtain cannabidiol with purity between 99% and 100% in which tetrahydrocannabinol is below the detection limit.

[0045] Figure 1 is a schematic representation of the examples for preparation of cannabidiol. As represented in Figure 1a, mentha-2,8-diene-1-ol is activated with diphenyl acetyl chloride in the presence of pyridine and 4-(dimethylamino) pyridine (DMAP) to obtain mentha-2,8-diene-1-diphenyl ester, which on condensation with olivetol in the presence of boron trifluoride diethyl etherate results in cannabidiol. As shown in Figure 1b, mentha-2,8-diene-1-ol is activated with diphenyl acetyl chloride in the presence of pyridine and (DMAP) to obtain mentha-2,8-diene-1-diphenyl ester, which on condensation with disubstituted resorcinol results in methyl olivetolate that is decarboxylated in the presence of aqueous sodium hydroxide and methanol to obtain cannabidiol. The Figure 1c represents the reaction of mentha-2,8-diene-1-ol dissolved in methylene chloride with p-toluene sulfonyl isocyanate to produce the mentha-2,8-diene-1-p-toluenesulfonyl carbamate which on reaction with 5,6-disubstituted resorcinol produces the methyl cannabidiolate. The decarboxylation of the methyl cannabidiolate in the presence of aqueous sodium hydroxide and methanol produces cannabidiol. Figure 1d represents the reaction of mentha-2,8-diene-1-ol dissolved in methylene chloride with p-toluene sulfonyl isothiocyanate to produce the mentha-2,8-diene-1-p-toluenesulfonyl thiocarbamate, which on reaction with 5,6-disubstituted resorcinol produces methyl cannabidiolate. The decarboxylation of the methyl cannabidiolate in the presence of aqueous sodium hydroxide and methanol produces cannabidiol.

[0046] Figure 2 illustrates a flowchart representing the method for preparation of cannabidiol. The method for preparation of cannabidiol (200) comprises the steps of preparing an activated mentha-2,8-diene-1-ol (201). At step (202), the activated mentha-2,8-diene-1-ol is coupled with 5 substituted resorcinol to obtain cannabidiol. Alternatively, the activated mentha-2,8-diene-1-ol is coupled with 5,6 disubstituted resorcinol to obtain cannabidiolate at step (203). At step (204), the cannabidiolate is decarboxylated to obtain cannabidiol. At step (205), cannabidiol obtained in step (202) or (204) is subjected to purification. At step (205), the purified cannabidiol is crystallized from organic solvent to obtain white crystalline cannabidiol, which exhibits purity between 99% and 100%.

[0047] The method for preparation of cannabidiol includes preparation of activated mentha-2,8-diene-1-ol with Formula II, wherein R is substituted or un-substituted alkyl, aryl, benzyl, acyl, substituted or un-substituted alkyl carbamoyl, substituted or un-substituted aryl carbamoyl, substituted or un-substituted alkyl sulfonyl carbamoyl, substituted or un-substituted aryl sulfonyl carbamoyl, substituted or un-substituted alkyl thiocarbamoyl, substituted or un-substituted aryl thiocarbamoyl, substituted of un-substituted alkyl sulfonyl thiocarbamoyl, substituted or un-substituted aryl sulfonyl thiocarbamoyl.

[0048] The preparation of activated p-mentha-2,8-diene-1-ol further comprises the step of preparing an intermediate compound as depicted in Figure 3. The intermediate compound prepared is mentha-2,8-diene-1-yl ester (Formula IV) in which R1 is n-alkyl, branched alkyl, substituted or un-substituted aryl, alkyl aryl or heterocyclic derivative at step (201 A), or mentha-2,8-diene-1-arylsulfonyl carbamate (Formula V) in which R2 is selected from a group comprising H, NO2, halo, substituted or un-substituted alkoxy, substituted or un-substituted alkyl moiety and the position of R2 is ortho, meta or para at step (201 B), or mentha-2,8-diene-1-arylsulfonyl thiocarbamate (Formula VI) in which R2 is selected from a group comprising H, NO2, halo, substituted or un-substituted alkoxy, substituted or un-substituted alkyl moiety and the position of said moiety at ortho, meta or para at step (201 C).

[0049] The substituted resorcinol used in the method is either a 5-substituted resorcinol (Formula VII) wherein R’ is H, OH, protected hydroxyl, substituted or un-substituted alkyl, alkenyl, alkynyl, acyl, aryl or heteroaryl or a 5,6-disubstituted resorcinol (Formula VIII) wherein R’ is H, OH, protected hydroxyl, substituted or un-substituted alkyl, alkenyl, alkynyl, acyl, aryl or heteroaryl and R3 is substituted or un-substituted alkyl, aryl, hetero aryl. The preferred 5-substituted resorcinol is olivetol and the preferred 5,6-disubstituted resorcinol is methyl olivetolate (Formula XI)

[0050] Figure 4 illustrates the method for preparation of mentha-2,8-diene-1-yl ester. The method (201 A) of preparation of mentha-2,8-diene-1-yl ester comprises the step (201 A a) of dissolving mentha-2,8-diene-1-ol in an inert organic solvent to obtain a solution at step The organic solvent for the esterification is selected from a group comprising tetrahydrofuran, methyl tetrahydrofuran, dioxane, halogenated solvent such as methylene chloride, ethylene chloride, chloroform, carbon tetrachloride or non-nucleophillic base. The non-nucleophilic organic base is selected from a group comprising pyridine, methyl pyridine, pyrrolidine, trimethyl amine, triethyl amine, tripropyl amine, diisopropyl ethyl amine, N-methyl morpholine, 1,2-Bis(methylamino)ethane (DAMEDA), 1,2-Bis(dimethylamino)ethane (TAMEDA), lutidine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo [2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), preferably tetrahydrofuran or pyridine and its derivatives. At step (201 A b1), a non-nucleophillic organic base is added to the solution to obtain a reaction mass. Non-nucleophillic organic base in this step is Dimethyl amino pyridine (DMAP), Hydroxybenzotriazole (HOBt), Hydroxy azotriazole (HOAt), preferably dimethyl amino pyridine. At step (201 A b2), a coupling agent is added to the solution in the presence of a non-nucleophilic organic base to obtain a reaction mass. The inert organic solvent used in the reaction is selected from a tetrahydrofuran, methyl tetrahydrofuran, dioxane, halogenated solvent, preferably tetrahydrofuran. The coupling agent is selected from a group comprising carbodiimides [e.g N,N'-Dicyclohexylcarbodiimide(DCC), 1-Ethyl-3-(3-imethylaminopropyl) carbodiimide (EDC)], Phosphonium based coupling agent [e.g. (7-Azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), Bromo tris(dimethylamino) phosphonium hexafluorophosphate (BrOP), Chlorotripyrrolidinophosphonium hexafluorophosphate (PyClop), Pentafluorophenyl diphenylphosphinate (FDPP), bisphenol A diphosphate (BDP)], Uronium [e.g. O-(Benzotriazol-1-yl)-N N N'N'-bis(tetramethylene)uronium hexafluorophosphate (BCC), N,N,N',N'-Tetramethyl-O-(3,4-dihydro-4-oxo-1,2,3-benzotriazin-3-yl)uranium tetrafluoroborate (TDBTU), 1,1,3,3-Tetramethylurea (TNU), O-(1,2-Dihydro-2-oxo-pyridyl]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TPTU), N,N,N',N'-Tetramethyl-O-(N-succinimidyl)uronium tetrafluoroborate (TSTU), HAPyu, O-(7-azabenzotriazol-1-yl)-1,1,3,3-pentamethylenuronium (TAPipU), 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-Oxide Hexafluorophosphate (HATU), 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium tetrafluoroborate (TBTU)], iminium based [e.g.benzyloxymethyl (BOM)].The non-nucleophilic organic base is selected from a group comprising pyridine, methyl pyridine, pyrrolidine, trimethyl amine, triethyl amine, tripropyl amine, diisopropyl ethyl amine, N-methyl morpholine, 1,2-Bis(methylamino)ethane (DAMEDA), 1,2-Bis(dimethylamino)ethane (TAMEDA), lutidine, 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU), 1,4-diazabicyclo [2.2.2]octane (DABCO), 1,5-diazabicyclo[4.3.0]non-5-ene (DBN), Hydroxybenzotriazole (HOBt), 4-(dimethylamino) pyridine (DMAP) and combination thereof, preferably one of the group comprising lutidine, HOBt, DMAP and more preferably DMAP and/or hydroxybenzotriazole. Carboxylic acid or carboxylic acid chloride is added to the reaction mass at step 201 A c2 and 201 A c1 respectively. The carboxylic acid or carboxylic acid chloride used in the preparation of the ester is selected from a group comprising n-alkyl, branched alkyl, substituted or un-substituted aryl, substituted or un-substituted alkyl aryl, heteroaryl. The preferable carboxylic acid/ acid chloride is a substituted or unsubstituted arylacetic acid or substituted/unsubstituted aryl acetyl chloride, more preferably the carboxylic acid is diphenyl acetic acid or the carboxylic acid chloride is diphenyl acetyl chloride. At step (201 A d1), the reaction mass is quench by addition of mineral acid. The mineral acid can be hydrochloric acid, hydrobromic acid, phosphoric acid or sulfuric acid and mixture thereof, preferably dilute hydrochloric acid. Whereas at step (201 A d2) the solid byproduct formed is filter off (in case of use of dicylclohexylcarbodimide is used as coupling agent). At step (201A e1 and 201 A e2) is subjected optionally dissolving in water immiscible organic solvent and washing with aqueous solution of alkali/alkaline earth metal salt as there carbonates, bicarbonate or hydroxide. At step (201 A f) organic layer is separated and concentrated. Obtained ester is dried to obtain pure mentha-2,8-diene-1-yl-ester (Formula XII).

[0051] The method for the preparation of cannabidiol comprises the reaction of the activated mentha-2,8-diene-1-yl ester (Formula XII) with substituted resorcinol (Formula VII) in presence of Lewis acid, preferably in presence of dehydrating agent to obtain cannabinoid. The reaction can be depicted as follows-

[0052] The method for the preparation of cannabidiol comprises the reaction of the activated mentha-2,8-diene-1-yl ester (Formula XII) with 5,6-disubstituted resorcinol (Formula VIII) to obtain cannabinoids (Formula X), wherein R’ is selected from a group comprising substituted or un-substituted alkyl, substituted or un-substituted aryl, heteroaryl and R3 is substituted or un-substituted alkyl, substituted or un-substituted aryl. Preferably R’ and R3 are substituted or un-substituted alkyl, most preferably R’ is n-pentyl and R3 is lower alkyl from methyl to n-propyl or iso-propyl, followed by decarboxylation of cannabinoids (Formula X) in aqueous or organic solvent in the presence of a base to obtain cannabidiol (Formula IX). The reaction is depicted as follows:

[0053] Figure 5 illustrates a flowchart for the method of preparation of mentha-2,8-diene-1-arylsulfonyl carbamate. The method (201 B) of preparation of mentha-2,8-diene-1-arylsulfonyl carbamate (Formula V) comprises the step (201B a) of dissolving mentha-2,8-diene-1-ol in an aprotic solvent to obtain a solution. The aprotic solvent for the reaction is selected from a tetrahydrofuran, dioxane, toluene, xylene, chloroform, methylene chloride, dimethylformamide, cyclohexane, hexane, heptane and ether. The solvent is preferably methylene chloride. At step (201 B b), the solution obtained is cooled between -10oC to 10oC, preferably between -5oC to 0oC. At step (201 B c), arylsulfonyl isocyanate is added to the above precooled solution within five minutes to 60 minutes. At step (201 B d) the temperature of reaction mass is maintained between -10oC to 10oC followed by a step (201 B e) of optionally isolating mentha-2,8-diene-1-arylsulfonyl carbamate.

[0054] Figure 6 illustrates the method of preparation of mentha-2,8-diene-1-arylsulfonyl thiocarbamate. The method (201 C) of preparation of mentha-2,8-diene-1-arylsulfonyl thiocarbamate (Formula VI) comprises a step (201 C a) of dissolving mentha-2,8-diene-1-ol in an inert solvent to obtain a solution. The inert solvent for the reaction is selected from a group comprising is selected from a group comprising toluene, methylene chloride, tetrahydrofurn, dioxane, dimethyl formamide, cyclohexane, hexane, heptane and ether, preferably in methylene chloride. At step (201 C b), the solution obtained is cooled between -10oC to 10oC, preferably between -5oC to 0oC. At step (201 C c), substituted arylsulphonyl isothiocyanate is added to the above precooled solution within five to sixty minutes. At step (201 C d), the temperature of reaction mass is maintained between -10oC to 10oC followed by a step (201 C e) of optionally isolation of mentha-2,8-diene-1-arylsulfonyl thiocarbamate.

[0055] The invention is a method for preparation of cannabidiol in which the activated mentha-2,8-diene-1-ol is coupled with 5-substituted resorcinol. Figure 7 illustrates a flowchart representing the step (202) of coupling of the activated mentha-2,8-diene-1-ol with 5-substituted resorcinol comprising preparing a first solution of activated mentha-2,8-diene-1-ol in aprotic solvent or use of activated methandiene-1-ol from step (201) at step (202 a). The aprotic solvent for the reaction is selected from a group comprising n-alkane, halogenated alkane, aromatic solvents, preferably halogenated alkane, more preferably methylene chloride. At step (202 b), the 5-substituted resorcinol is dissolved in aprotic solvent to obtain a second solution. The aprotic solvent used for dissolution in step (202 b) is selected from a group comprising n-alkane, halogenated alkane and aromatic solvents, preferably halogenated solvent, more preferably methylene chloride. At step (202 c), a Lewis acid is added to the second solution maintaining the temperature between -5oC to 5oC to obtain a reaction mixture. The Lewis acid used for the reaction is selected from a group comprising d-block transition metal triflate including boron trifluoride etherate complex, boron trifluoride acetic acid complex, boron trifluoride ethyl acetate complex, preferably boron trifluoride etherate complex. The quantity of Lewis acid added is in the range of 0.1 to 1 equivalent, preferably 0.25 to 0.75 equivalents and more preferably 0.5 equivalents. This is followed by addition of the first solution to the reaction mixture to obtain a reaction mass at step (202 d), maintaining the temperature between -25oC to 0oC. After the completion of the reaction, the reaction mass is quenched with alkaline or alkaline earth metal carbonate preferably sodium carbonate at step (202 e) to obtain a heterogeneous reaction mass which is filtered at step (202 f). At step (202 g), the filtered reaction mass is washed with dilute sodium hydroxide solution and water, at step (202 h), the organic layer is separated. At step (202 i), the separated layer is subjected to drying over drying agent, preferably sodium or magnesium sulfate. At step (202 j), organic layer is concentrated under reduced pressure to obtain cannabidiol.

[0056] The invention is a method for preparation of cannabidiol in which the activated mentha-2,8-diene-1-ol is coupled with 5,6-disubstituted resorcinol. Figure 8 illustrates the step (203) of coupling of activated mentha-2,8-diene-1-ol with 5,6-disubstituted resorcinol comprising the step (203 a) of preparing a first solution of activated mentha-2,8-diene-1-ol and magnesium sulfate in aprotic solvent. The aprotic solvent for the dissolution is selected from a group comprising n-alkane, halogenated alkane and aromatic solvents, preferably halogenated solvent, more preferably methylene chloride. At step (203 b), 5,6-disubstituted resorcinol is dissolved in aprotic solvent to obtain a second solution maintaining the temperature between -10oC to 10oC. The aprotic solvent is selected from a group comprising n-alkane, halogenated alkane and aromatic solvents, preferably halogenated solvent, more preferably methylene chloride. At step (203 c), a Lewis acid is added to the second solution maintaining the temperature between -10oC to 10oC during the addition to obtain a reaction mixture. The Lewis acid used in the reaction is selected from a group comprising d-block transition metal triflate including boron trifluoride etherate complex, boron trifluoride acetic acid complex, borontrifluoride ethyl acetate complex, preferably boron trifluoride etherate. At step (203 d), the first solution is added to the reaction mixture, maintaining the temperature between-10oC to 10oC during the addition and a reaction mass is obtained. After the completion of the reaction, at step (203 e), the reaction mass is quenched with base preferably alkali metal carbonate, bicarbonate, hydroxide more preferably sodium carbonate to obtain a heterogeneous reaction mass and subjected to filtration at step (203 f). At step (203 g), the filtered reaction mass is washed with aqueous solution of alkali metal hydroxide, alkaline earth metal hydroxide preferably alkali metal hydroxide and more preferably dilute solution of sodium hydroxide and subsequently with water. At step (203 h), the organic layer is separated. At step (203 i), the separated organic layer is dried over drying agent, preferably sodium sulfate and obtained organic layer is concentrated at step (203 j) under reduced pressure to obtain cannabidiolate.

[0057] The method for preparation of cannabidiol includes decarboxylation of cannabidiolate obtained (204). Figure 9 illustrates the decarboxylation of cannabidiolate, which further comprises a step (204 a) of dissolving the cannabidiolate in a solvent to obtain a solution. The solvent is selected from a group comprising alcohol, water or mixture thereof. The alcohol is selected from a group comprising methanol, ethanol, 2-propanol, 1-butanol, and glycol, more preferably methanol. At step (204 b), the solution is combined with a base to obtain a reaction mixture. The base used in the reaction is selected from a group comprising lithium hydroxide, sodium hydroxide and potassium hydroxide. At step (204 c), the reaction mixture is heated between 55oC to 65oC followed by a step (204 d) of cooling it to ambient temperature. At step (204 e), an organic solvent is added to the reaction mixture and the organic layer is separated. The preferable organic solvent used at this step is toluene. At step (204 f), the separated organic layer is concentrated under reduced pressure to obtain cannabidiol.

[0058] In one embodiment, the invention is a method of preparing cannabidiol by esterification of mentha-2,8-diene-1-ol using diphenyl acetyl chloride in organic solvent in the presence of catalytic amount of non nucleophilic base. The preferred solvent is pyridine and the catalyst is dimethyl aminopyridine and /or hydroxy benzotriazole to obtain mentha-2,8-diene-1-diphenyl acetyl ester (Formula XIII) followed by reacting the diphenyl acetyl ester with 5-pentyl resorcinol (olivetol) in the presence of a catalyst preferably Lewis acid to obtain cannabidiol, wherein the reaction is carried out from low temperature to ambient temperature, preferably at -10oC to 10oC and most preferably at -5 to 5oC. The aprotic solvent for the reaction includes n-alkane, halogenated or aromatic solvents, preferably halogenated solvent. The Lewis acid used in the reaction is selected from a group comprising d-block transition metal triflate, boron trifluoride coordinated as etherate, acetic acid, ethyl acetate and most preferably it is boron trifluoride diethyletherate complex. The reaction can be depicted as figure 1a

[0059] In another embodiment, the invention is a method of preparing cannabidiol by esterification of mentha-2,8-diene-1-ol using diphenyl acetyl chloride in the presence of dimethylaminopyridine (DMAP) in pyridine to obtain mentha-2,8-diene-1-diphenyl acetyl ester (Formula XIII) followed by reacting the diphenyl ester with 5,6 disubstituted resorcinol in the presence of a Lewis acid to obtain methyl cannabidiolate of Formula XIV which on decarboxylation in the presence of aqueous sodium hydroxide and methanol gives cannabidiol. The reaction can be depicted as figure 1b.

[0060] In one embodiment, the invention is method for preparation of the above said intermediate with Formula XIII is prepared by dissolving menthe-2,8-diene-1-ol in aprotic solvent followed by addition of diphenylacetic acid, coupling agent and non-nucleophilic base. The preferred solvent media is ethyl acetate, Tetrahydrofuran, whereas the coupling agent is from the family of carbodiimides, onium (uronium) based and phosphonium based, preferably dicyclohexyl carbodiimide. The non-nucleophilic base is aryl triazoles, dimethyl aminopyridine or mixture thereof, preferably dimethylaminopyridine.

[0061] In another embodiment, the invention is a method of preparing cannabidiol by reacting mentha-2,8-diene-1-ol with arylsulfonyl isocyanate in aprotic solvent to obtain mentha-2,8-diene-1-arylsulfonyl carbamate (Formula V) followed by reacting the mentha-2,8-diene-1-arylsulfonyl carbamate with 5-substituted resorcinol (Formula VII) in the presence of a catalyst preferably Lewis acid to obtain cannabidiol, wherein the reaction is carried out from low temperature to ambient temperature, preferably at -10oC to 10oC and most preferably at -5oC to 5oC. The aprotic solvent for the reaction includes n-alkane, halogenated or aromatic solvents, preferably halogenated solvent, most preferably methylene dichloride. The Lewis acid used in the reaction is selected from a group comprising d-block transition metal triflate, boron trifluoride coordinated as etherate, acetic acid complex, ethyl acetate complex, acetonitrile complex and most preferably it is boron trifluoride diethyletherate. The reaction can be depicted as follows-

[0062] In another embodiment, the invention is a method of preparing cannabidiol by reacting mentha-2,8-diene-1-ol with p-toluene sulfonyl isocyanate in aprotic solvent to obtain mentha-2,8-diene-1-(4-methyl)phenylsulfonyl carbamate (Formula XV). Reacting mentha-2,8-diene-1-(4-methyl)phenylsulfonyl carbamate with 5,6-disubstituted resorcinol (Formula XI) in the presence of a Lewis acid to obtain methyl olivetolate of Formula XIV which on decarboxylation in the presence of aqueous sodium hydroxide and methanol gives cannabidiol. The reaction can be depicted as figure 1c.

[0063] In another embodiment, the invention is a method of preparing cannabidiol by reacting mentha-2,8-diene-1-ol with arylsulfonyl thioisocyanate in aprotic solvent to obtain mentha-2,8-diene-1-arylsulfonyl thiocarbamate (Formula VI) followed by reacting obtained mentha-2,8-diene-1-arylsulfonyl thiocarbamate with 5-substituted resorcinol (Formula VII) in the presence of a catalyst preferably Lewis acid to obtain cannabidiol, wherein the reaction is carried out from low temperature to ambient temperature, preferably at -10oC to 10oC and most preferably at -5oC to 5oC. The aprotic solvent for the reaction includes n-alkane, halogenated or aromatic solvents, preferably halogenated solvent, most preferably methylene dichloride (MDC). The Lewis acid used in the reaction is selected from a group comprising d-block transition metal triflate, boron trifluoride coordinated as etherate complex, acetic acid complex, ethyl acetate complex and most preferably it is boron trifluoride diethyletherate complex. The reaction can be depicted as follows-

[0064] In another embodiment, the invention is a method of preparing cannabidiol by reacting mentha-2,8-diene-1-ol with p-toluene sulfonyl isothiocyanate in aprotic solvent to obtain mentha-2,8-diene-1-(4-methyl)phenylsulfonyl thiocarbamate (Formula XVI) followed by reacting the mentha-2,8-diene-1-(4-methyl)phenylsulfonyl thiocarbamate with 5,6 disubstituted resorcinol (Formula XI) in the presence of a Lewis acid to obtain methyl olivetolate of Formula XIV which on decarboxylation in the presence of aqueous sodium hydroxide and methanol gives cannabidiol. The reaction can be depicted as Figure 1d

[0065] The method for preparation of cannabidiol comprises purification of cannabidiol (205). Figure 10 is a flowchart representing the purification of cannabidiol obtained in step (202) or (204) which further comprises of dissolving the cannabidiol in lower alkanes to obtain a solution at step (205 a). The lower alkanes used for dissolving the cannabidiol is selected from a group comprising pentane, hexane, heptane or mixture thereof. At step (205 b), the solution obtained at step (205a) is passed through a bed of silica. The particle size of the silica used for preparation of bed of silica is selected from a 60-120, 100-200, 240-400 mesh, preferably the mesh size is 60-120. At step (205 c), the absorbed cannabidiol on bed of silica is eluted with a mixture of nonpolar and polar solvent to obtain the eluate. The mixture of nonpolar solvent and polar solvent used for elusion is selected from a group comprising lower alkane and diisopropyl ether, lower alkane and ethyl acetate, lower alkane and methylene chloride, preferably the non-polar solvent is lower alkane and is n-heptane and polar solvent is ethyl acetate. Finally, at step (205 d), the eluent is concentrated to obtain purified cannabidiol.

[0066] The crystallization of purified cannabidiol (206) comprises dissolving the purified cannabidiol in an organic solvent to obtain a solution followed by crystallizing the solution the solution at a temperature between of -10oC and 10oC, preferably between -10oC and 0oC, to obtain pure cannabidiol with purity 99% -100%. The organic solvent used for dissolution of purified cannabidiol is selected from a group comprising n-alkane, preferably n-pentane, n-hexane and n-heptane more preferably n-heptane. The white crystalline solid of cannabidiol obtained. Liquid chromatography of the said compound shows purity of the compound is more than 99% whereas abnormal cannabidiol and tetrahydrocannabidiol is not detected.

[0067] The invention relates to an activated mentha-2,8-diene-1-ol intermediate compound namely mentha-2,8-diene-1-yl ester (Formula IV), wherein R1 is n-alkyl, branched alkyl, substituted or un-substituted aryl, alkyl aryl or heterocyclic derivative, preferably the R1 group is an aryl substituted alkyl group to form intermediate of (Formula XII). In (Formula XII) R4 is selected from a group comprising H, NO2, halo, substituted or un-substituted alkyl, substituted or un-substituted aryl, heteroaryl, and R5 is ortho, meta or para substituted moiety and includes H, NO2, halo, substituted or un-substituted alkyl and substituted and unsubstituted aryl. R4 and R5 are most preferably phenyl and H group and the intermediate compound is (Formula XIII). The reaction can be depicted as follows:

[0068] The invention relates to an activated mentha-2,8-diene-1-ol intermediate compound namely mentha-2,8-diene-1-arylsulfonyl carbamate of Formula V, wherein R2 is selected from a group comprising H, NO2, halo, substituted or un-substituted alkoxy, substituted or un-substituted alkyl moiety, more preferably R2 is a p-methyl group and the intermediate compound is (Formula XV) which has a purity between 78% and 79%. The reaction can be depicted as follows:

[0069] The invention relates to an activated mentha-2,8-diene-1-ol intermediate compound namely mentha-2,8-diene-1-arylsulfonyl thiocarbamate of Formula VI, wherein R2 is selected from a group comprising H, NO2, halo, substituted or un-substituted alkoxy, substituted or un-substituted alkyl moiety, more preferably R2 is a p-methyl group and the intermediate compound is (Formula XVI) which has a purity between 78% and 79%. The reaction can be depicted as follows

[0070] The following examples are offered to illustrate various aspects of the invention. However, the examples are not intended to limit or define the scope of the invention in any manner.

Example 1: Method for preparation of mentha-2,8-diene-1-diphenylacetyl ester [(4R)-4-isopropenyl-1-methylcyclohex-2-en-1-yl diphenylacetate]

[0071] 11 g of mentha-2,8-diene-1-ol (72.26mmol) is dissolved in 132 mL of pyridine. 1.76 g of dimethyl aminopyridine (14.4mmol) is added to the clear solution with stirring. To the resulting clear solution of menthadiene-1-ol, 25.08 g of diphenyl acetyl chloride (108.76 mmol) is added. After completion of reaction, the reaction mass is cooled below 10oC and is quenched by addition of 330 mL of 10% hydrochloric acid. The resulting mentha-2,8-diene-1-diphenylacetyl ester formed is filtered off. The filtered mentha-2,8-diene-1-diphenylacetyl ester is washed with water (2 X 220mL) and dried at 40oC to obtain 15g of mentha-2,8-diene-1-diphenylacetyl ester. The purity of the ester is 97.39%. The mentha-2,8-diene-1-diphenylacetyl ester formed has a melting point between 50oC-52oC. The IR spectrum for the ester showed bands at 3648, 3440, 3057, 2940, 1948, 1731, 1598, 1092 cm-1.

Example 2: Method for preparation of methyl cannabidiolate

[0072] 4.83 g of methyl olivetolate (20.27mmol) and 2.8 g of magnesium sulfate (23.26 mmol) are added to 70 mL of methylene chloride to form the reaction mass. The reaction mass is cooled to 0oC-5oC. To the reaction mass 0.19 g of boron trifluoride etherate (1.33mmmol) is added maintaining the temperature between 0oC -5oC. 7 g of metha-2,8-diene-1-diphenyl acetyl ester (20.27mmol) is dissolved in 70 mL of methylene chloride and this is added to the reaction mass maintaining the reaction temperature 0oC -5oC. After completion of reaction, reaction mass is quenched by addition of 3.5 g of sodium bicarbonate and filtered off. The mother liquor is washed with 1% sodium hydroxide (2X70mL) and water (2x70mL) and the organic layer is separated. The organic layer is dried over sodium sulfate and concentrated under reduced pressure to obtain 6.85 g of methyl cannabidiolate which has a purity of 94.79%.

Example 3: Method for preparation of cannabidiol from methyl cannabidiolate

[0073] 10 g of methyl cannabidiolate (26.85mmol) is combined with 30 mL of 25%w/v of caustic lye and the obtained reaction mass is heated between 90oC and 100oC for 14 hours. After completion of reaction, the reaction mass was cooled at ambient temperature. To the cooled reaction mass 50 mL of toluene is added and the organic layer is separated. The separated organic layer is concentrated under reduced pressure to obtain 6.12g of cannabidiol. HPLC Purity by area % is 90.81%.

Example 4: Method for preparation of cannabidiol from mentha-2,8-diene-1-diphenylacetyl ester

[0074] O.52 g of olivetol (2.9mmmol) is dissolved in 10 mL of methylene chloride. To the clear solution 0.024 mL of boron trifluoride etherate (0.01mmol) is added at 0oC -5oC. To the activated olivetol solution 1 g of methadiene-1-diphenyl acetyl ester (2.9mmol) as a solution in 10 mL of methylene chloride is added maintaining the temperature between 0oC -5oC. After completion of reaction, resulting reaction mass was quenched with 0.5 g of sodium bicarbonate to form a heterogeneous reaction mass which is filtered off. The filtrate is washed with 20mL of 1% sodium hydroxide and 20 mL of water and the organic layer is separated. The separated organic layer is dried over sodium sulfate and concentrated under reduced pressure to obtain 0.75g of cannabidiol with HPLC purity of 88.35%.

Example 5: Method for preparation of methyl cannabidiolate from mentha-2,8-diene-1-arylsulfonyl carbamate

[0075] 3 g of mentha-2,8-diene-1-ol (19.7mmol) was dissolved in 30 mL of methylene chloride and the resulting clear solution was cooled to -5oC to 0oC. 4.85 g of p-toluene sulfonyl isocyanate (24.6 mmol) is added maintaining the temperature of the reaction mass between -5oC to 0oC. The mentha-2,8-diene-1-arylsulfonyl carbamate is formed in situ. In another flask, 4.67 g of methyl olivetolate (19.5mmmol) is dissolved in 30 mL of methylene chloride. The clear solution was cooled to -15oC to -20oC. The mentha-2,8-diene-1-arylsulfonyl carbamate formed in situ is added to the olivetolate solution at -15oC to -20oC. After completion of reaction, resulting reaction mass is quenched by addition of 60 mL of water and the organic layer is separated. The separated organic layer is concentrated under reduced pressure to obtain thick oily liquid. To the oily liquid 60 mL of heptane is added and the precipitate obtained is filtered off. The filtrate is concentrated to produce 7.15g of yellow viscous oil of methyl cannabidiolate with HPLC purity of 78.8%

Example 6: Method for preparation of cannabidiol from mentha-2,8-diene-1-arylsulfonyl carbamate

[0076] 1g of mentha-2,8-diene-1-ol (6.57mmol) is dissolved in 10 mL of methylene chloride. The resulting clear solution is cooled to a temperature of 0oC -5oC. 1.61 g of p-toluene sulfonyl isocyanate (8.21mmol) is added within 5 minutes of forming the solution maintaining reaction temperature 0oC -5oC under nitrogen atmosphere to obtain mentha-2,8-diene-1-arylsulfonyl carbamate in situ. In another flask a solution of 1.18 g of olivetol (6.57mmol) in 10 mL of methylene chloride is prepared. To olivetol solution 0.055g of boron trifluoride (0.44mmol) is added at a temperature between -5oC to 0oC. To the olivetol solution, the solution of mentha-2,8-diene-1-arylsulfonyl carbamate formed in situ is added at -15oC and the reaction mass was stirred at -15oC for 10 minutes. After completion of the reaction, 20 mL of water (20mL) is added to quench the reaction mass. The organic layer is separated and washed with aqueous 1% sodium hydroxide (2x50mL) followed by 50 mL of water. The separated organic layer is dried over sodium sulfate and concentrated under reduced pressure to obtain 0.55 g of the oily cannabidiol with HPLC purity of 78%.

Example 7: Purification of cannabidiol

[0077] The cannabidiol obtained from example 3, 4 and 6 is purified by column chromatography using diisopropyl ether and hexane as mobile phase. The cannabidiol after column purification is stirred in heptane to obtained white crystalline solid. The Liquid Chromatography analysis of cannabidiol obtained showed purity >99.5% a/a in which the tetrahydrocannabinol is below detection limit.

[0078] The method of the invention results in obtaining intermediate compounds which undergo coupling with substituted resorcinol to give cannabidiol which exhibits high degree of purity in the range between 99% and 100%. The greatest advantage of the method is that there is negligible amount of tetrahydrocannabinol which is below the detection limit. Further, the coupling agents, bases and organic solvents used in the method are easily available and are of low cost.