PROCESS FOR THE SYNTHESIS OF CANNABIDIOL AND INTERMEDIATES THEREOF

Abstract

The present invention relates to process for the preparation of cannabidiol (A) from the coupling of (D) and (E) through the intermediates (C) and (D) starting from compound (B). The invention further relates to the novel compounds (B), (C), (D) and (E) and reagents used in this process. More specifically, this invention provides the manufacturing of Cannabidiol (A) in milligram to gram or kilogram scale.

##STR00001##

Claims

1. A process for the preparation of cannabidiol compound of formula (A) ##STR00037## wherein R is independently selected from H, OH, alkyl, alkenyl, alkynyl, or cycloalkyl; R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are independently selected from H, OH, alkyl, alkenyl, alkynyl, acyl, acyloxy, or cycloalkyl; X is independently selected from OH, H, heteroaryl, Cl, Br, I, OTf, OTs, or phosphinyl; Y is independently selected from S, SO, Se, SeO, Cl, Br, I, N-dialkyl, N-aryl, or A-heteroaryl; R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 are independently selected from H, halogen, —CN, —NO.sub.2, —OH, alkyl, —O-alkyl, —COOH, —C(O), —C alkyl, —C(O)OC, S-alkyl, —SO-alkyl, —SO.sub.2-alkyl, S-aryl, —SO-aryl, —SO.sub.2-aryl, SO-heteroaryl, —SO.sub.2—N-aryl, —N—SO.sub.2-aryl NR′R″, alkenyl, alkynyl, acyl, acyloxy, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein the alkyl, aryl or heteroaryl, are optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, alkyl, —O-alkyl, —COOH, —C(O), —C alkyl, —C(O)OC, alkyl, NR′R″, or —(CH.sub.2).sub.nNR′R″; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, acyl, acyloxy, aryl, arylalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more groups, each independently selected from (a) cyano, halo, and nitro; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 arylalkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.sup.1; and (c) —C(O)R.sup.a, —C(O)OR.sup.a, —C(O)NR.sup.bR.sup.c, —C(N R.sup.a) NR.sup.bR.sup.c, —OR.sup.a, —OC(O)R.sup.a, —OC(O)OR.sup.a, OC(O)NR.sup.bR.sup.c, —OC(═N R.sup.a)NR.sup.bR.sup.c, —OS(O)R.sup.a, —OS(O)2R.sup.a, —OS(O)NR.sup.bR.sup.c, —OS(O)2NR.sup.bR.sup.c, —NR.sup.bR.sup.c, —NR.sup.aC(O)R.sup.d, —N R.sup.a C(O)OR.sup.d, —NR.sup.a (O)NR.sup.bR.sup.c, —NR.sup.aC(═NR.sup.d)NR.sup.bR.sup.c, —N R.sup.aS(O)R.sup.d, —NR.sup.aS(O)2R.sup.d, —NR.sup.aS(O)NR.sup.bR.sup.c, —NR.sup.a S(O).sub.2NR.sup.bR.sup.c, —SR.sup.a, —S(O)R.sup.a, —S(O).sub.2R.sup.a, —S(O)NR.sup.bR.sup.c, —S(O).sub.2NR.sup.bR.sup.c, or —(CH.sub.2).sub.nNR′R″; wherein, R.sup.a, R.sup.b, R.sup.c, and R.sup.d are independently selected from (i) hydrogen; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15arylalkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.sup.1; or (iii) R.sup.b and R.sup.c together with the N atom to which they are attached from heterocyclyl, optionally substituted with one or more substituents Q.sup.1; wherein, Q.sup.1 is independently selected from the group consisting of (a) cyano, halo, or nitro; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15arylalkyl, heteroaryl, or heterocyclyl; and (c) —C(O)R.sup.e, —C(O)OR.sup.e, —C(O)NR.sup.fR.sup.g, —C(NR.sup.e) NR.sup.fR.sup.g, —OR.sup.e, —OC(O) R.sup.e, —OC(O)OR.sup.e, OC(O)NR.sup.fR.sup.g, —OC(═NR.sup.e)NR.sup.fR.sup.g, —OS(O) R.sup.e, —OS(O).sub.2R.sup.e, —OS(O)NR.sup.fR.sup.g, —OS(O)2NR.sup.fR.sup.g, —NR.sup.fR.sup.g, —N R.sup.e C(O)R.sup.h, —N R.sup.e C(O)OR.sup.h, —N R.sup.e (O)NR.sup.fR.sup.g, —NR.sup.eC(═NR.sup.h)NR.sup.fR.sup.g, —N R.sup.e S(O)R.sup.h, —N R.sup.e S(O).sub.2R.sup.h, —N R.sup.e S(O)NR.sup.fR.sup.g, —N R.sup.e S(O).sub.2NR.sup.fR.sup.g, —SR.sup.e, —S(O) R.sup.e, —S(O).sub.2R.sup.e, —S(O)NR.sup.fR.sup.g, or —S(O).sub.2NR.sup.fR.sup.g; wherein R.sup.e, R.sup.f, R.sup.g, and R.sup.h is independently selected from (i) hydrogen; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15arylalkyl, heteroaryl, or heterocyclyl; (iii) R.sup.f and R.sup.g together with the N atom to which they are attached from heterocyclyl; wherein each represents a single or double bond; provided that both groups are not double bonds, and wherein denoted, dash marks indicate the points of attachment; wherein, represents a single bond, above the plane or below the plane or both above the plane or both below the plane or one is above the plane and one is below the plane.

2. The process as claimed in claim 1, wherein the compounds are selected from: a) (+)-1-methyl-2-(phenylselanyl)-4-(prop-1-en-2-yl)cyclohexan-1-ol b) (−)-1-methyl-2-(phenylselanyl)-4-(prop-1-en-2-yl)cyclohexan-1-ol c) 4-(2-hydroxypropan-2-yl)-1-methyl-2-(phenylselanyl)cyclohexan-1-ol d) (+)-2-(4-hydroxy-4-methyl-3-(phenylselanyl)cyclohexyl)propan-2-yl 2,2,2-trifluoroacetate e) 4-isopropyl-1-methyl-2-(phenylselanyl)cyclohexan-1-ol f) (+)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol g) (+)-1-methyl-2-(phenylselanyl)-4-(prop-1-en-2-yl)cyclohexan-1-ol (D2) h) (+)2-(4-hydroxy-4-methylcyclohex-2-en-1-yl)propan-2-yl 2,2,2-trifluoroacetate i) (+)-4-isopropyl-1-methylcyclohex-2-en-1-ol j) (−)-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol k) (+Z)-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol l) (−)-2-((1R,2R)-2′,6′-dihydroxy-5-methyl-4′-pentyl-1,2,3,4-tetrahydro-[1,1′-biphenyl]-2-yl)propan-2-yl 2,2,2-trifluoroacetate m) (−)-(1′S,2′S)-2′-isopropyl-5′-methyl-4-pentyl-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol n) (−)-5′-methyl-2′-(prop-1-en-2-yl)-4-propoxy-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol o) (−)-4-(dodecyloxy)-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol p) (−)-4,5′-dimethyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol

3. The process for preparation of cannabidiol compound of formula (A) as claimed in claim 1, the preparation of formula (A) by coupling of compound of formula (D) and compound of formula (E) comprising the step of: ##STR00038## wherein the coupling reaction occurs with metal triflates selected from AgOTf, Ni(OTf).sub.2, Hg(OTf).sub.2, LiOTf, Bi(OTf).sub.3, Ln(OTf).sub.3, or Ac(OTf).sub.x, preferably AgOTf or along with ligands selected from bipyridyl, substituted bipyridyl phenanthrolene, substituted phenanthrolene, pyridine, substituted pyridine, BINAP, QINAP PINAP, Ph.sub.3P or like phosphines or with heterogeneous acids selected from mixed metal oxides, SiO.sub.2—SO.sub.3H/COFe.sub.2O.sub.4, SiO.sub.2—Pr—SO.sub.3H, zeolites, zeotype materials, OMR-[C4HMTA][SO.sub.3H], MPD-SO.sub.3H-IL, MeAPSO, MeAPO, SAPO, ALPO.sub.4, Natrolite, ZSM-5, H-ZSM-5, periodic mesoporous organosilicas (PMOs), mesoporous silicas (PMSs), H.sub.3PW.sub.12O.sub.40, H.sub.4SiW.sub.12O.sub.40, Cs.sub.2HPW.sub.12O.sub.40, HPW/ZrO.sub.2, HPW/Nb.sub.2O.sub.5, Montmorillonite, pyrophyllite, Talc, Vermiculite, Sauconite, Saponite, Nontronite, Kaolnite, Chlorite, Illite, SAPO-34, Zirconium phosphates or sulphates, cation/anion exchange resins amberlyst, or amberlite, likewise preferably montmorillonite clay; the coupling reaction is carried out in the presence of a solvent or mixture of solvents selected from tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroethane, acetone, hexane, dichloromethane, chloroform, ethyl acetate, or toluene, preferably dichloroethane; and with stirring the reaction mixture for time period in the range of 0.1 to 48 hours at a temperature in the range of −40° C. to 60° C.

4. The process for preparation of cannabidiol compound of the formula (A) as claimed in claim 1, conversion of compound of formula (B) to compound of formula (C) via bi-functionalization of double bond: ##STR00039## wherein the bi-functionalization of double bond is carried out in the presence of reagent selected from PhSeSePh, ZPhSeSePhZ, HetArSeSeHetAr, PhSSPh, ZPhSSPhZ, HetArSSHetAr, PhSeBr, ZPhSeBr, HetArSeBr, PhSeCl, ZPhSeCl, HetArSeCl, PhSCl, ZPhSCl, HetArSCl, PhSBr, ZPhSBr, HetArSBr, NBS, NIS, or NCS, optionally with oxidants selected from mCPBA, Oxone, DDQ, CAN, N-Hydroxy succinamide, t-Butylhydroperoxide, Selectfluor, Hydrogen peroxide, BIAB, NFSI, TMSOTf, PyF-BF.sub.4, PyF-OTf, TMPyF-OTf preferably with PhSeBr, PhSeCl, PhSCl, PhSBr, PhSSPh/AgOTf, PhSSPh/Selectfluor, PhSeSePh/AgOTf, or PhSeSePh/Selectfluor; wherein Z is independently selected from halogen, —CN, —N(Me).sub.2, —NO.sub.2, —OH, alkyl, —O-alkyl, —COOH, —C(O), or —C alkyl; the bi-functionalization is carried out in the presence of a solvent or a mixture of solvents selected from H.sub.2O, tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroethane, acetone, hexane, dichloromethane, chloroform, ethyl acetate, or toluene; and with stirring the reaction mixture for time period in the range of 0.1 h-48 h and at a temperature in the range of −80° C. to 60° C.

5. The process for preparation of cannabidiol compound of the formula (A) as claimed in claim 1, the conversion of compound of formula (C) to compound of formula (D) comprising the step of: ##STR00040## regenerating double bond by elimination of group (Y) of compound of formula (C) and conversion to compound formula (D) in the presence of oxidants selected from mCPBA, Oxone, DDQ, CAN, N-hydroxy succinamide, t-Butylhydroperoxide, Selectfluor, Hydrogen peroxide, BIAB, NFSI, TMSOTf, PyF-BF.sub.4, PyF-OTf, TMPyF-OTf, or PIFA, preferably Selectfluor, and Hydrogen peroxide; wherein the regenerating double bond by elimination is carried out in the presence of a solvent or a mixture of solvents selected from H.sub.2O, tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroethane, acetone, hexane, dichloromethane, chloroform, ethyl acetate, or toluene; and with stirring the reaction mixture for a time period in the range of 0.1 to 48 hours at a temperature in the range of −40° C. to 60° C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0008] The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.

Definitions

[0009] For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are delineated here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have the meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.

[0010] The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.

[0011] The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.

[0012] Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.

[0013] The term “alkyl” refers to straight or branched aliphatic hydrocarbon groups having the specified number of carbon atoms, which are attached to the rest of the molecule by a single atom, which may be optionally substituted by one or more substituents. Preferred alkyl groups 1 to 6 carbon atoms include, without limitation, methyl, ethyl, n-propyl, isopropyl, butyl, isobutyl, t-butyl, pentyl, hexyl, and the like.

[0014] The term “aryl” refers to aromatic radicals having 6 to 14 carbon atoms, which may be optionally substituted by one or more substituents. Preferred aryl groups include, without limitation, phenyl, naphthyl, indanyl, biphenyl, and the like.

[0015] The term “arylalkyl” refers to an aryl group directly bonded to an alkyl group, which may be optionally substituted by one or more substituents and have 7 to 15 carbon atoms. Preferred arylalkyl groups include, without limitation, —CH.sub.2C.sub.6H.sub.5, —C.sub.2H.sub.4C.sub.6H.sub.5, and the like. The terms arylalkyl and aralkyl may be used interchangeably.

[0016] The term “heterocyclyl” refers to a heterocyclic ring radical which may be optionally substituted by one or more substituents. The heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

[0017] Furthermore, the term “heterocyclyl” refers to a stable 3 to 15 membered rings radical, which consists of carbon atoms and from one to five heteroatoms selected from nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention the heterocyclic ring radical may be monocyclic, bicyclic or tricyclic ring systems, and the nitrogen, phosphorus, carbon, or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states.

[0018] The term “heteroaryl” refers to an aromatic heterocyclic ring radical as defined above. The heteroaryl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of stable structure.

[0019] The term “fused heterocyclyl” refers to monocyclic or polycyclic ring, polycyclic ring system refers to a ring system containing 2 or more rings, preferably bicyclic or tricyclic rings, in which rings can be fused, bridged or spiro rings or any combinations thereof. A fused ring as used herein means that the two rings are linked to each other through two adjacent ring atoms common to both rings. The fused ring can contain 1-4 hetero atoms independently selected from N, O, and S. The rings can be either fused by nitrogen or —CH— group.

[0020] The term “cycloalkyl” refers to non-aromatic mono or polycyclic ring system of about 3 to 7 carbon atoms, which may be optionally substituted by one or more substituents. The polycyclic ring denotes hydrocarbon systems containing two or more ring systems with one or more ring carbon atoms in common i.e. a spiro, fused or bridged structures. Preferred cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0021] The term “alkenyl” refers to an aliphatic hydrocarbon group containing a carbon-carbon double bond, and which may be straight or branched chain having about 2 to 6 carbon atoms, which may be optionally substituted by one or more substituents. Preferred alkenyl groups include, without limitation, ethenyl, 1-propenyl, 2-propenyl, iso-propenyl, 2-methyl-1-propenyl, 1-butenyl, 2-butenyl and the like.

[0022] The term “alkynyl” refers to a straight or branched hydrocarbyl radicals having at least one carbon-carbon triple bond and having in the range of 2-6 carbon atoms, which may be optionally substituted by one or more substituents. Preferred alkynyl groups include, without limitation, ethynyl, propynyl, butynyl and the like.

[0023] The term “acyl” refers to a group derived by the removal of one or more hydroxyl groups from an oxoacid, including inorganic acids and it has a double-bonded oxygen atom and R group (R—C═O). R group of the acyl includes but not limited to alkyl, alkenyl, alkynyl, aryl, cycloalkyl, haloalkyl, arylalkyl, heteroaryl, heterocyclyl and the like.

[0024] The term “acyloxy” refers to the acyl group bonded to oxygen: R—C(═O)—O— wherein R—C(═O) is the acyl group. R group includes but not limited to alkyl, alkenyl, alkynyl, aryl, cycloalkyl, haloalkyl, arylalkyl, heteroaryl, heterocyclyl and the like.

[0025] Ratios, concentrations, amounts, and other numerical data may be presented herein in a range format. It is to be understood that such range format is used merely for convenience and brevity and should be interpreted flexibly to include not only the numerical values explicitly recited as the limits of the range, but also to include all the individual numerical values or sub-ranges encompassed within that range as if each numerical value and sub-range is explicitly recited. For example, a temperature in the range of −40° C. to 60° C. should be interpreted to include not only the explicitly recited limits of −40° C. to 60° C. but also to include sub-ranges, such as −30° C. to 50° C., −10° C. to 40° C., 0° C. to 35° C. and so forth, as well as individual amounts, within the specified ranges, such as 19.6° C., and 27.3° C.

[0026] The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally-equivalent products, compositions, and methods are clearly within the scope of the disclosure, as described herein.

[0027] In an embodiment of the present disclosure, there is provided a process for the preparation of the compound of Formula (A)

##STR00004##

wherein R is independently selected from H, OH, alkyl, alkenyl, alkynyl, or cycloalkyl; R.sub.1, R.sub.2, R.sub.3 and R.sub.4 are independently selected from H, OH, alkyl, alkenyl, alkynyl, acyl, acyloxy, or cycloalkyl; X is independently selected from OH, H, heteroaryl, Cl, Br, I, OTf, OTs, or phosphinyl; Y is independently selected from S, SO, Se, SeO, Cl, Br, I, N-dialkyl, N-aryl, or N-heteroaryl; R.sub.5, R.sub.6, R.sub.7, R.sub.8, R.sub.9 are independently selected from H, halogen, —CN, —NO.sub.2, —OH, alkyl, —O-alkyl, —COOH, —C(O), —C alkyl, —C(O)OC, S-alkyl, —SO-alkyl, —SO.sub.2-alkyl, S-aryl, —SO-aryl, —SO.sub.2-aryl, SO-heteroaryl, —SO.sub.2—N-aryl, —N—SO.sub.2-aryl NR′R″, alkenyl, alkynyl, acyl, acyloxy, aryl, heteroaryl, cycloalkyl, or heterocyclyl; wherein the alkyl, aryl or heteroaryl, are optionally substituted with one or more substituents independently selected from the group consisting of halogen, OH, alkyl, —O-alkyl, —COOH, —C(O), —C alkyl, —C(O)OC, alkyl, NR′R″, and —(CH.sub.2).sub.nNR′R″; wherein the alkyl, alkenyl, alkynyl, cycloalkyl, acyl, acyloxy, aryl, arylalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or more groups, each independently selected from (a) cyano, halo, or nitro; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15 arylalkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more in one embodiment, one, two, three, or four substituents Q.sup.1; and (c) —C(O)R.sup.a, —C(O)OR.sup.a, —C(O)NR.sup.bR.sup.c, —C(N R.sup.a) NR.sup.bR.sup.c, —OR.sup.a, —OC(O) R.sup.a, —OC(O)OR.sup.a, OC(O)NR.sup.bR.sup.c, —OC(═N R.sup.a)NR.sup.bR.sup.c, —OS(O)R.sup.a, —OS(O)2R.sup.a, —OS(O)NR.sup.bR.sup.c, —OS(O)2NR.sup.bR.sup.c, —NR.sup.bR.sup.c, —NR.sup.aC(O)R.sup.d, —N R.sup.a C(O)OR.sup.d, —NR.sup.a(O)NR.sup.bR.sup.c, —NR.sup.aC(═NR.sup.d)NR.sup.bR.sup.c, —N R.sup.aS(O)R.sup.d, —NR.sup.aS(O)2R.sup.d, —NR.sup.aS(O)NR.sup.bR.sup.c, —NR.sup.a S(O).sub.2NR.sup.bR.sup.c, —SR.sup.a, —S(O)R.sup.a, —S(O).sub.2R.sup.a, —S(O)NR.sup.bR.sup.c, —S(O).sub.2NR.sup.bR.sup.c, or —(CH.sub.2).sub.nNR′R″; wherein, R.sup.a, R.sup.b, R.sup.e, and R.sup.d are independently selected from (i) hydrogen; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15arylalkyl, heteroaryl, or heterocyclyl, each optionally substituted with one or more substituents Q.sup.1; or (iii) R.sup.b and R.sup.c together with the N atom to which they are attached from heterocyclyl, optionally substituted with one or more substituents Q.sup.1; wherein, Q.sup.1 is independently selected from the group consisting of (a) cyano, halo, or nitro; (b) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15arylalkyl, heteroaryl, and heterocyclyl; and (c) —C(O)R.sup.e, —C(O)OR.sup.e, —C(O)NR.sup.fR.sup.g, —C(NR.sup.e) NR.sup.fR.sup.g, —OR.sup.e, —OC(O) R.sup.e, —OC(O)OR.sup.e, OC(O)NR.sup.fR.sup.g, —OC(═NR.sup.e)NR.sup.fR.sup.g, —OS(O) R.sup.e, —OS(O).sub.2R.sup.e, —OS(O)NR.sup.fR.sup.g, —OS(O)2NR.sup.fR.sup.g, —NR.sup.fR.sup.g, —N R.sup.eC(O)R.sup.h, —N R.sup.eC(O)OR.sup.h, —N R.sup.e(O)NR.sup.fR.sup.g, —NR.sup.eC(═NR.sup.h)NR.sup.fR.sup.g, —N R.sup.e S(O)R.sup.h, —N R.sup.e S(O).sub.2R.sup.h, —N R.sup.e S(O)NR.sup.fR.sup.g, —N R.sup.e S(O).sub.2NR.sup.fR.sup.g, —SR.sup.e, —S(O) R.sup.e, —S(O).sub.2R.sup.e, —S(O)NR.sup.fR.sup.g, or —S(O).sub.2NR.sup.fR.sup.g; wherein R.sup.e, R.sup.f, R.sup.g, and R.sup.h is independently selected from (i) hydrogen; (ii) C.sub.1-6 alkyl, C.sub.2-6 alkenyl, C.sub.2-6 alkynyl, C.sub.3-7 cycloalkyl, C.sub.6-14 aryl, C.sub.7-15arylalkyl, heteroaryl, or heterocyclyl; (iii) R.sup.f and R.sup.g together with the N atom to which they are attached from heterocyclyl; wherein, each represents a single or double bond; provided that both groups are not double bonds, and wherein denoted, dash marks indicate the points of attachment; wherein, represents a single bond, above the plane or below the plane or both above the plane or both below the plane or one is above the plane and one is below the plane.

[0028] In an embodiment of the present invention there is provided the process as disclosed herein, wherein the compounds are selected from [0029] a) (+)-1-methyl-2-(phenylselanyl)-4-(prop-1-en-2-yl)cyclohexan-1-ol [0030] b) (−)-1-methyl-2-(phenylselanyl)-4-(prop-1-en-2-yl)cyclohexan-1-ol [0031] c) 4-(2-hydroxypropan-2-yl)-1-methyl-2-(phenylselanyl)cyclohexan-1-ol [0032] d) (+)-2-(4-hydroxy-4-methyl-3-(phenylselanyl)cyclohexyl)propan-2-yl 2,2,2-trifluoroacetate [0033] e) 4-isopropyl-1-methyl-2-(phenylselanyl)cyclohexan-1-ol [0034] f) (+)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol [0035] g) (+)-1-methyl-2-(phenylselanyl)-4-(prop-1-en-2-yl)cyclohexan-1-ol (D2) [0036] h) (+)-2-(4-hydroxy-4-methylcyclohex-2-en-1-yl)propan-2-yl 2,2,2-trifluoroacetate [0037] i) (+)-4-isopropyl-1-methylcyclohex-2-en-1-ol [0038] j) (−)-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol [0039] k) (+Z)-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol [0040] l) (−)-2-((1R,2R)-2′,6′-dihydroxy-5-methyl-4′-pentyl-1,2,3,4-tetrahydro-[1,1′-biphenyl]-2-yl)propan-2-yl 2,2,2-trifluoroacetate [0041] m) (−)-(1′S,2′S)-2′-isopropyl-5′-methyl-4-pentyl-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol [0042] n) (−)-5′-methyl-2′-(prop-1-en-2-yl)-4-propoxy-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol [0043] o) (−)-4-(dodecyloxy)-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1-biphenyl]-2,6-diol [0044] p) (−)-4,5′-dimethyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol

[0045] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (A) by coupling of compounds of formula (D) and compound of formula (E):

##STR00005##

wherein the coupling reaction occurs with metal triflates selected from AgOTf, Ni(OTf).sub.2, Hg(OTf).sub.2, LiOTf, Bi(OTf).sub.3, Ln(OTf).sub.3, or Ac(OTf).sub.x, preferably AgOTf or along with ligands selected from bipyridyl, substituted bipyridyl phenanthrolene, substituted phenanthrolene, pyridine, substituted pyridine, BINAP, QINAP, PINAP, Ph.sub.3P or like phosphines or with heterogeneous acids selected from mixed metal oxides, SiO.sub.2—SO.sub.3H/COFe.sub.2O.sub.4, SiO.sub.2—Pr—SO.sub.3H, zeolites, zeotype materials, OMR-[C4HMTA][SO.sub.3H], MPD-SO.sub.3H-IL, MeAPSO, MeAPO, SAPO, ALPO.sub.4, Natrolite, ZSM-5, H-ZSM-5, periodic mesoporous organosilicas (PMOs), mesoporous silicas (PMSs), H.sub.3PW.sub.12O.sub.40, H.sub.4SiW.sub.12O.sub.40, Cs.sub.2HPW.sub.12O.sub.40, HPW/ZrO.sub.2, HPW/Nb.sub.2O.sub.5, Montmorillonite, pyrophyllite, Talc, Vermiculite, Sauconite, Saponite, Nontronite, Kaolinite, Chlorite, Illite, SAPO-34, Zirconium phosphates or sulphates, cation/anion exchange resins amberlyst, amberlite, preferably montmorillonite clay; the coupling reaction is carried out in the presence of a solvent or mixture of solvents selected from tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroethane, acetone, hexane, dichloromethane, chloroform, ethyl acetate, or toluene, preferably dichloroethane; and the coupling reaction is carried out with stirring the reaction mixture for time period in the range of 0.1 to 48 hours at a temperature in the range of −40° C. to 60° C.

[0046] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (A) by coupling of compounds of formula (D) and compound of formula (E) as disclosed herein, wherein the coupling reaction can occur alone with metal triflates (AgOTf, Ni(OTf).sub.2, Hg(OTf).sub.2, LiOTf, Bi(OTf).sub.3, Ln(OTf).sub.3, or Ac(OTf).sub.x) preferably AgOTf, or along with ligands selected from bipyridyl, substituted bipyridyl phenanthrolene, substituted phenanthrolene, pyridine, substituted pyridine, BINAP, QINAP, PINAP, Ph.sub.3P or like phosphines or with heterogeneous acids, mixed metal oxides, SiO.sub.2—SO.sub.3H/COFe.sub.2O.sub.4, SiO.sub.2—Pr—SO.sub.3H, Zeolites, zeotype materials (OMR-[C4HMTA][SO.sub.3H], MPD-SO.sub.3H-IL, MeAPSO, MeAPO, SAPO, ALPO.sub.4, Natrolite, ZSM-5, H-ZSM-5, periodic mesoporous organosilicas (PMOs), mesoporous silicas (PMSs), H.sub.3PW.sub.12O.sub.40, H.sub.4SiW.sub.12O.sub.40, Cs.sub.2HPW.sub.12O.sub.40, HPW/ZrO.sub.2, HPW/Nb.sub.2O.sub.5), Mantmorillonite, pyrophyllite, Talc, Vermiculite, Sauconite, Saponite, Nontronite, Kaolinite, Chlorite, Illite, SAPO-34, Zirconium phosphates or sulphates, cation/anion exchange resins amberlyst, or amberlite, preferably montmorillonite clay.

[0047] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (A) by coupling of compounds of formula (D) and compound of formula (E) as disclosed herein, wherein the coupling reaction occur in a solvent or mixture of solvents selected from tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroethane, acetone, Hexane, dichloromethane, chloroform, ethyl acetate, or toluene, and the like, preferably dichloroethane.

[0048] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (A) by coupling of compounds of formula (D) and compound of formula (E) as disclosed herein, wherein the coupling reaction is carried out with stirring the reaction mixture for time period in the range of 0.1 to 48 hours. In another embodiment of the present invention, there is provided a process as disclosed herein wherein the coupling reaction is carried out with stirring the reaction mixture for time period in the range of 1 to about 3 hours, or about 6 to about 48 hours, or about 12 to about 24 hours, or about 14 to about 18 hours, preferably for 5-10 h.

[0049] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (A) by coupling of compounds of formula (D) and compound of formula (E) as disclosed herein, wherein the coupling reaction is carried out at a temperature in the range of −40° C. to 60° C. In another embodiment of the present invention, there is provided a process for the preparation of compound of formula (A) by coupling of compounds of formula (D) and compound of formula (E) as disclosed herein, wherein the coupling reaction is carried out at a temperature in the range of −40° C. to 40° C., or −35° C. to −25° C., or −0° C. to 50° C., preferably at 10° C. to 35° C.

[0050] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (D) from compound of formula (C) comprising the steps of:

##STR00006##

regenerating of double bond by elimination of group (Y) of compound formula (C) and conversion to compound formula (D) in the presence of oxidants selected from mCPBA, Oxone, DDQ, CAN, N-hydroxy succinamide, t-Butylhydroperoxide, Selectfluor, Hydrogen peroxide, BIAB, NFSI, TMSOTf, PyF-BF.sub.4, PyF-OTf, TMPyF-OTf, or PIFA, preferably Selectfluor, and Hydrogen peroxide.

[0051] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (D) from compound of formula (C) as disclosed herein, wherein elimination is carried out in the presence of a solvent or a mixture of solvents, selected from H.sub.2O, tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroethane, acetone, hexane, dichloromethane, chloroform, ethyl acetate, or toluene, and the like.

[0052] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (D) from compound of formula (C) as disclosed herein, wherein regenerating of double bond by elimination is carried out by stirring the reaction mixture for a time period in the range of 0.1 to 48 hours. In another embodiment of the present invention, there is provided a process for the preparation of compound of formula (D) from compound of formula (C) as disclosed herein, wherein regenerating of double bond by elimination is carried out by stirring the reaction mixture for a time period in the range of 1 to 3 hours, or 6 to 48 hours, or 12 to 24 hours, or 14 to 18 hours.

[0053] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (D) from compound of formula (C) as disclosed herein, wherein regenerating of double bond by elimination is carried out at a temperature in the range of −40° C. to 60° C. In another embodiment of the present invention, there is provided a process for the preparation of compound of formula (D) from compound of formula (C) as disclosed herein, wherein regenerating of double bond by elimination is carried out at a temperature in the range of −40° C. to 40° C., or −35° C. to −25° C., or −0° C. to 5, preferably at −10° C. to 35° C.

[0054] In an embodiment of the present invention there is provided process for the preparation of compound of formula (C) by the bi-functionalization of double bond of compound of formula (B):

##STR00007##

wherein the bi-functionalization of double bond is carried out in the presence of by a reagent selected from PhSeSePh, ZPhSeSePhZ, HetArSeSeHetAr, PhSSPh, ZPhSSPhZ, HetArSSHetAr, PhSeBr, ZPhSeBr HetArSeBr, PhSeCl, ZPhSeCl, HetArSeCl, PhSCl, ZPhSCl, HetArSCl, PhSBr, ZPhSBr HetArSBr, NBS, NIS, or NCS, along with oxidants or without oxidants, for example mCPBA, Oxone, DDQ, CAN, N-Hydroxy succinamide, t-Butylhydroperoxide, Selectfluor, Hydrogen peroxide, BIAB, NFSI, TMSOTf, PyF-BF.sub.4, PyF-OTf, TMPyF-OTf preferably with PhSeBr, PhSeCl, PhSCl, PhSBr, PhSSPh/AgOTf, PhSSPh/Selectfluor, PhSeSePh/AgOTf, PhSeSePh/Selectfluor, or the like and wherein Z is independently halogen, —CN, —N(Me).sub.2, —NO.sub.2, —OH, alkyl, —O-alkyl, —COOH, —C(O), —C alkyl.

[0055] In an embodiment of the present invention there is provided process for the preparation of compound of formula (C) by the bi-functionalization of double bond of compound of formula (B) as disclosed herein, wherein the bi-functionalization is carried out in the presence of a solvent or a mixture of solvents, selected from H.sub.2O, tetrahydrofuran, dioxane, acetonitrile, chlorobenzene, dichloroethane, acetone, hexane, dichloromethane, chloroform, ethyl acetate, or toluene, and the like.

[0056] In an embodiment of the present invention there is provided process for the preparation of compound of formula (C) by the bi-functionalization of double bond of compound of formula (B) as disclosed herein, wherein the bi-functionalization is carried out by stirring the reaction mixture for a time period in the range of 0.1 h-48 h. In another embodiment of the present invention there is provided process for the preparation of compound of formula (C) by the bi-functionalization of double bond of compound of formula (B) as disclosed herein, wherein the bi-functionalization is carried out by stirring the reaction mixture for a time period in the range of 1 to 3 hours, or 6 to 48 hours, or 12 to 24 hours, or 14 to 18 hours, preferably 12-24 h.

[0057] In an embodiment of the present invention there is provided process for the preparation of compound of formula (C) by the bi-functionalization of double bond of compound of formula (B) as disclosed herein, wherein the bi-functionalization is carried out at a temperature in the range of −80° C. to 60° C., preferably −40° C. to −10° C.

[0058] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (A) by coupling of compound of formula (D) and compound of formula (E):

##STR00008##

[0059] In an embodiment of the present invention, there is provided a process for the preparation of compound of formula (D) from compound of formula (C):

##STR00009##

[0060] In an embodiment the present invention, there is provided a process for the preparation of compound of formula (C) by the bi-functionalization of double bond of compound of formula (B):

##STR00010##

[0061] In an embodiment of the present invention, there is provided a compound of formula (C):

##STR00011##

[0062] In an embodiment of the present invention, there is provided a compound of following formula (D):

##STR00012##

[0063] In an embodiment of the present invention, there is provided a compound of following formula (A):

##STR00013##

[0064] In an embodiment of the present invention, there is provided a compound of following formula (C):

##STR00014##

[0065] In an embodiment of the present invention, there is provided a compound of following formula (D):

##STR00015##

[0066] In an embodiment of the present invention, there is provided a compound of following formula (A):

##STR00016##

[0067] In an embodiment of the present invention, there is provided a compounds of following formula:

##STR00017##

List of Abbreviations

THC—Tetrahydrocannabinol

CBD—Cannabidiol

[0068] BINAP—(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl)

DCE—Dichloroethane

[0069] m-CPBA—meta chloroperbenzoic acid
DDQ—2,3-Dichloro-5,6-dicyano-1,4-benzoquinone
CAN—Cerric ammonium nitrate

BIAB—(Diacetoxyiodo)benzene

NFSI—N-Fluorobenzenesulfonimide

[0070] OTf—trifluoromethanesulfonate
CDCl.sub.3—Deuterated chloroform
CD.sub.3OD—Deuterated methanol

NMR—Nuclear Magnetic Resonance

PPM—Parts Per Million

TLC—Thin Layer Chromatography

HRMS—High Resolution Mass Spectrometry

THF—Tetrahydrofuran

DCM—Dichloromethane

ACN—Acetonitrile

DEPT—Distortionless Enhancement of Polarization Transfer

UV—Ultraviolet

[0071] ESI-MS—Electrospray ionization mass specrometry
LC-MS—Liquid chromatography-mass spectrometry

MS—Mass Spectrometry

MHz—Megahertz

TOF—Turnover Frequency

OCOCF.SUB.3−.—Trifluoroacetoxy

[0072] EtOAc—Ethyl acetate

AgOTf—Silver Trifluoromethanesulfonate

[0073] ESI—Electronspray ionisation
Ni(OTf).sub.2—Nickel (II) trifluoromethanesulfonate
Hg(OTf).sub.2—Mercury triflate
LiOTf—Lithium trifluoromethanesulfonate
Bi(OTf).sub.2—Bismuth(III) trifluoromethanesulfonate
Ln(OTf).sub.2—Lanthanide trifluoromethanesulfonate
Ac(OTf).sub.2—Actanide trifluoromethanesulfonate

PMO—Polarized Molecular Orbital

ZSM—Zeolite Socony Mobil-5

SAPO—Silicoaluminophosphate

[0074] PyF-BF.sub.4—N-Fluoropyridinium triflate
TMSOTf—Trimethylsilyl trifluoromethanesulfonate

NBS—N—Bromosuccinimide

NIS—N—Iodosuccinimide

NCS—N—Chlorosuccinimide

Material and Method Used in Experiments:

[0075] All the product mixtures were analysed by thin layer chromatography. UV inactive compounds were visualized in staining solution and UV active compounds were detected with UV lamp (λ=254 nm). All the reactions were performed under inert atmosphere wherever required. Anhydrous solvents like THF, toluene, dichloroethane were dried in standard way. NMR spectra (.sup.1HNMR, .sup.13C, DEPT) were recorded in 400 MHz spectrometer using CDCl.sub.3 and CD.sub.3OD solvent. ES1-MS and HRMS spectra were recorded on LC-MS/MS and HRMS-6540-UHD machines. Optical rotations were measured on a Perkin Elmer polarimeter. Column chromatography was carried out with silica gel (60-120, 230-400 mesh)

EXAMPLES

[0076] The present invention is further defined in the following Examples. It should be understood that these Examples, while indicating preferred embodiments of the invention, are given by way of illustration only.

Step 1: Bi-Functionalization of (+) or (−) Limonene or Limonene Derivatives

[0077] ##STR00018##

Preparation of (+)-1-methyl-2-(phenylselanyl)-4-(prop-1-en-2-yl)cyclohexan-1-ol (C1)

[0078] ##STR00019##

[0079] Example 1: To a stirred solution of (R)-(+)-limonene (B1) (1.2 g, 7.0 mmol) in ACN:H.sub.2O (98:2, 6 ml) at −30 to −35° C. was added a solution of phenylselenyl bromide (1 g, 4.5 mmol) in ACN and allowed to stir at the same temperature. After the initiation of reaction, hydrogen peroxide (2.1 mmol) as an activator was added to the reaction mixture The progress of the reaction was monitored by TLC. After completion of the reaction (approximately 24 h), the reaction mixture was poured in hypo solution and extracted with ethyl acetate (3 times). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated in vacuum. The crude material was subjected to silica gel column chromatography R.sub.f=0.4 EtOAc:Hexane (0.3-9.7) as an eluent to afford the title compound (+) 1-methyl-2-(phenylselanyl)-4-(prop-1-en-2-yl)cyclohexan-1-ol (C1) (638 mg, 49%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): δ(ppm)=7.58 (dd, J=4 Hz, 2H), 7.27 (m, 3H), 4.71 (d, J=13.6 Hz, 2H), 3.44 (t, J=4 Hz, 1H), 2.33 (m, 1H), 2.21 (m, 1H), 1.85 (m, 2H), 1.68 (s, 3H), 1.64 (m, 3H), 1.41 (s, 3H), 1.26 (bs, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): δ(ppm)=149.03, 134.41, 130.55, 129.13, 127.39, 109.29, 72.59, 54.62, 39.54, 35.24, 33.70, 29.55, 26.24, 21.35; [α].sub.D.sup.20=+129 (c=1.0, CHCl.sub.3); LC-MS: (ESI+): m/z calcd for C.sub.16H.sub.22OSe 310.084; found 327.25.

TABLE-US-00001 TABLE 1 Reaction conditions for synthesis of compound formula (+)-C1 from R-(+)-B1 REAGENTS EXAMPLE REACTANT AND CONDITIONS YIELD (%)  2 R-(+)-B1 PhSeSePh, Oxone, (+)-C1 ACN:H.sub.2O, rt, 7-8 h (24%)  3 R-(+)-B1 PhSeSePh, DDQ, (+)-C1 ACN:H.sub.2O, rt, 7-8 h (12%)  4 R-(+)-B1 PhSeSePh, tBuOOH, (+)-C1 ACN:H.sub.2O, rt, 7-8 h (8%)  5 R-(+)-B1 PhSeSePh, Selectfluor, (+)-C1 ACN:H.sub.2O, rt, 7-8 h (34%)  6 R-(+)-B1 PhSeSePh, Selectfluor, — ACN:H.sub.2O, 0°, 7-8 h  7 R-(+)-B1 PhSeSePh, Selectfluor, — ACN:H.sub.2O, 10°, 7-8 h  8 R-(+)-B1 PhSeSePh, Selectfluor, (+)-C1 DCM:H.sub.2O, rt, 7-8 h (18%)  9 R-(+)-B1 PhSeSePh, Selectfluor, (+)-C1 Acetone:H.sub.2O, rt, 7-8 h, (18%) 10 R-(+)-B1 PhSeSePh, Selectfluor, (+)-C1 Hexane:H.sub.2O, rt, 7-8 h (22%) 11 R-(+)-B1 PhSeSePh, K.sub.2S.sub.2O.sub.8, (+)-C1 ACN:H.sub.2O, rt, 7-8 h (11%) 12 R-(+)-B1 PhSeSePh, AgOTf, (+)-C1 ACN:H.sub.2O, rt, 7-8 h (13%) 13 R-(+)-B1 PhSeBr, −30 to −35° C., (+)-C1 ACN:H.sub.2O, 24 h (41%) 14 R-(+)-B1 PhSeBr, 0° C., THF:H.sub.2O, (+)-C1 24 h (38%) 15 R-(+)-B1 PhSeBr, Selectfluor −30 (+)-C1 to −35° C., ACN:H.sub.2O, 24 h (42%) 16 R-(+)-B1 PhSeBr, AgOTf, −30 (+)-C1 to −35° C., ACN:H.sub.2O, 24 h (41%) 17 R-(+)-B1 PhSeBr, −30 to −35° C., (+)-C1 DCM:H.sub.2O, 24 h (13%) 18 R-(+)-B1 PhSeBr, −78° C., (+)-C1 DCM:H.sub.2O, 24 h, (6%) 19 R-(+)-B1 PhSCl, −30° C., ACN:H.sub.2O (+)-C1 (19%)

Preparation of (−)-1-methyl-2-(phenylselanyl)-4-(prop-1-en-2-yl)cyclohexan-1-ol (C2)

[0080] ##STR00020##

[0081] Example 20: To a stirred solution of (S)-(−)-limonene (B2) (544 mg, 4.0 mmol) in ACN:H.sub.2O (98:2, 6 ml) at −30 to −35° C. was added a solution of phenylselenyl bromide (256 mg, 1.0 mmol) in ACN and allowed to stir at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction (approximately 24 h), the reaction mixture was poured in hypo solution and extracted with ethyl acetate (3 times). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated in vacuum. The crude material was subjected to silica gel column chromatography R.sub.f=0.4 EtOAc:Hexane (0.3-9.7) as an eluent to afford the title compound (−)-1-methyl-2-(phenylselanyl)-4-(prop-1-en-2-yl)cyclohexan-1-ol (C2) (39%) as a yellow oil. 1H NMR (400 MHz, CDCl.sub.3): δ(ppm)=7.58 (dd, j=4 Hz, 2H), 7.27 (m, 3H), 4.71 (d, j=13.6 Hz, 2H), 3.44 (t, j=4 Hz, 1H), 2.33 (m, 1H), 2.21 (m, 1H), 1.85 (m, 2H), 1.68 (s, 3H), 1.64 (m, 3H), 1.41 (s, 3H), 1.26 (bs, 1H); .sup.13C NMR (100 MHz, CDCl.sub.3): δ(ppm)=149.03, 134.41, 130.55, 129.13, 127.39, 109.29, 72.59, 54.62, 39.54, 35.24, 33.70, 29.55, 26.24, 21.35; [α].sub.D.sup.20=−138 (c=1.0, CHCl.sub.3); LC-MS: (ESI+): m/z calcd for C.sub.16H.sub.22OSe 310.084; found 327.25.

TABLE-US-00002 TABLE 2 Reaction conditions for synthesis of compound formula (−)-C2 from S-(−)-B2 REAGENTS AND EXAMPLE REACTANT CONDITIONS YIELD (%) 21 S-(−)-B2 PhSeSePh, Selectfluor, (−)-C2 (35%) rt ACN:H.sub.2O, 7-8 h

Preparation of (+) 4-(2-hydroxypropan-2-yl)-1-methyl-2-(phenylselanyl)cyclohexan-1-ol (C3)

[0082] ##STR00021##

[0083] Example 22: To a stirred solution of (+) α-terpineol (B3) (616 mg, 4.0 mmol) in ACN:H.sub.2O (98:2, 6 ml) at −30 to −35° C. was added a solution of phenylselenyl bromide (256 mg, 1.0 mmol) in ACN and allowed to stir at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction (approximately 24 h), the reaction mixture was poured in hypo solution and extracted with ethyl acetate (3 times). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated in vacuum. The crude material was subjected to silica gel column chromatography R.sub.f=0.5 EtOAc:Hexane (0.2-9.8) as a eluent to afford title compound (+) 4-(2-hydroxypropan-2-yl)-1-methyl-2-(phenylselanyl)cyclohexan-1-ol (C3) (268 mg, 82%) as a dark yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): δ(ppm)=7.55 (dd, J=4 Hz, 2H), 7.25 (m, 3H), 3.54 (t, J=4 Hz, 1H), 2.63 (m, 1H), 2.24 (m, 1H), 1.65 (m, 2H), 1.55 (m, 3H), 1.25 (s, 3H), 1.23 (s, 3H), 1.12 (s, 3H). [α].sub.D.sup.20=+79 (c=1.0, CHCl.sub.3); LC-MS: (ESI+): m/z calcd for calcd C.sub.16H.sub.24O.sub.2Se 327.094; found 293.25

TABLE-US-00003 TABLE 3 Reaction conditions for synthesis of compound formula (+)-C3 from (+)-B3 REAGENTS AND EXAMPLE REACTANT CONDITIONS YIELD (%) 23 (+)-B3 PhSeSePh, Selectfluor, (+)-C3 (71%) ACN:H.sub.2O, rt, 7-8 h 24 (+)-B3 PhSeBr, −30 to −35° C., (+)-C3 (76%) THF:H.sub.2O, 24 h

Preparation of (+)-2-(4-hydroxy-4-methyl-3-(phenylselanyl)cyclohexyl)propan-2-yl 2,2,2-trifluoroacetate (C4)

[0084] ##STR00022##

[0085] Example 25: To a stirred solution of 2-(4-methylcyclohex-3-en-1-yl)propan-2-yl 2,2,2-trifluoroacetate (B4) (1 g, 4.0 mmol) in ACN:H.sub.2O (98:2, 6 ml) at −30 to −35° C. was added a solution of phenylselenyl bromide (256 mg, 1.0 mmol) in ACN and allowed to stir at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction (approximately 24 h), the reaction mixture was poured in hypo solution and extracted with ethyl acetate (3 times). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated in 3 vacuum. The crude material was subjected to silica gel column chromatography R.sub.f=0.3 EtOAc:Hexane (0.4-9.6) as an eluent to afford the title compound (+)-2-(4-hydroxy-4-methyl-3-(phenylselanyl)cyclohexyl)propan-2-yl 2,2,2-trifluoroacetate (C4) (138.24 mg, 59%) as a yellow oil; .sup.1H NMR (400 MHz, CDCl.sub.3): δ(ppm)=7.58 (dd, J=4 Hz, 2H), 7.27 (m, 3H), 3.45 (d, J=4 Hz, 1H), 2.39 (m, 1H), 2.11 (m, 1H), 1.73 (m, 2H), 1.67 (m, 3H) 1.52 (s, 3H), 1.48 (s, 3H), 1.45 (s, 3H); [α].sub.D.sup.20=+111 (c=1.0, CHCl.sub.3); .sup.19F NMR (376 MHz, CDCl.sub.3): δ(ppm)=−75.65

TABLE-US-00004 TABLE 4 Reaction conditions for synthesis of compound formula (+)-C4 from (+)-B4 REAGENTS AND EXAMPLE REACTANT CONDITIONS YIELD (%) 26 (+)-B4 PhSeSePh, Selectfluor, (+)-C4 (37%) ACN:H.sub.2O, rt, 7-8 h

Preparation of 4-isopropyl-1-methyl-2-(phenylselanyl)cyclohexan-1-ol (C5)

[0086] ##STR00023##

[0087] Example 27: To a stirred solution of (+)-4-isopropyl-1-methylcyclohex-1-ene (B5) (552 mg, 4.0 mmol) in ACN:H.sub.2O (98:2, 6 ml) at −30 to −35° C. was added a solution of phenylselenyl bromide (256 mg, 1.0 mmol) in ACN and allowed to stir at the same temperature. The progress of the reaction was monitored by TLC. After completion of the reaction (approximately 24 h), the reaction mixture was poured in hypo solution and extracted with ethyl acetate (3 times). The organic layer was dried over Na.sub.2SO.sub.4 and concentrated in vacuum. The crude material was subjected to silica gel column chromatography R.sub.f=0.5 EtOAc:Hexane (0.4-9.6) as an eluent to afford the title compound (+)-4-isopropyl-1-methyl-2-(phenylselanyl)cyclohexan-1-ol (C5) (138.24 mg, 86%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): δ(ppm)=7.60 (dd, J=4 Hz, 2H), 7.28 (m, 3H), 3.44 (t, J=4 Hz, 1H), 2.03 (m, 1H), 1.81 (m, 3H), 1.57 (m, 3H), 1.40 (s, 3H), 0.88 (d, j=4 Hz, 3H), 0.83 (d, j=4 Hz, 3H).sup.13C NMR (100 MHz, CDCl.sub.3): δ 134.53, 130.94, 129.31, 127.31, 72.68, 55.14, 39.22, 35.25, 32.37, 30.72, 29.10, 24.82, 20.14, 20.05; [α].sub.D.sup.20=−101 (c=1.0, CHCl.sub.3); LC-MS: (ESI+): m/z calcd for C.sub.16H.sub.24OSe; 295 [M-OH].sup.+.

TABLE-US-00005 TABLE 5 Reaction conditions for synthesis of compound formula (+)-C5 from (+)-B5 REAGENTS EXAMPLE REACTANT AND CONDITIONS YIELD (%) 28 (+)-B5 PhSeBr, −30 to −35° C., (+)-C5 ACN:H.sub.2O, 24 h (86%)

Step 2: Regeneration of the Double Bond by Elimination (C-D)

[0088] ##STR00024##

Preparation of (+)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (D1)

[0089] ##STR00025##

[0090] Example 29: The solution of (+)-1-methyl-2-(phenylselenyl)-4-(prop-1-en-2-yl)cyclohexan-1-ol (C1) (155 mg, 0.5 mmol) in THF (5 ml) was allowed to stir for 10 min. Then, Selectfluor (531 mg, 1.5 mmol) was added to the reaction. The reaction mixture was stirred for 9-10 h or until reactant gets consumed. The progress of reaction was monitored by TLC. The reaction mixture was poured in water and extracted with ethyl acetate. The crude material was subjected to silica gel column chromatography R.sub.f=0.4 EtOAc:hexane (0.3-9.7) as an eluent to afford the title compound (+)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (D1) (64.9 mg, 85%) as light yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): δ(ppm)=5.71 (dd, 1H), 5.66 (dd, 1H), 4.78 (d, J=16 Hz, 1H), 4.75 (d, J=8 Hz, 1H), 2.66 (m, 1H), 1.80 (m, 2H), 1.74 (s, 3H), 1.59 (m, 1H), 1.49 (br, OH, 1H), 1.30 (s, 3H). .sup.13C NMR (100 MHz, CDCl.sub.3): δ(ppm)=148.125 (C-8), 134.13 (C-2), 132.20 (C-1), 110.74 (C-9), 67.41 (C-3), 43.34 (C-6), 36.77 (C-4), 29.70 (C-5), 27.10 (C-10), 20.81 (C-7); [α].sub.D.sup.20Experimental=+146 (c=1.0, CHCl.sub.3); literature=+53.8 (CHCl.sub.3);

[0091] HRMS (ESI-TOF) m/z: [M-OH]-calcd for C.sub.10H.sub.16O; 152.120; found 135.15.

TABLE-US-00006 TABLE 6 Reaction conditions for synthesis of compound formula (+)-D1 from (+)-C1 REAGENTS EXAMPLE REACTANT AND CONDITIONS YIELD(%) 30 (+)-C1 H.sub.2O.sub.2, THF, 0° to rt 7-8 h (+)-D1(76%) 31 (+)-C1 Oxone, THF, rt 14 h (+)-D1(69%) 32 (+)-C1 Selectfluor(1.5 mmol), (+)-D1(82%) THF, rt 10 h 33 (+)-C1 Selectfluor(0.5 mmol), (+)-D1(76%) THF, rt, 28 h 34 (+)-C1 Selectfluor(1.5 mmol), (+)-D1(76%) ACN, rt, 28 h 35 (+)-C1 N-fluorobenzenesulfonamide, (+)-D1(53%) THF, 9-10 h 36 (+)-C1 (Bis(trifluoroacetoxy)iodo- (+)-D1(24%) benzene), THF, 9-10 h

Preparation of (+)-1-methyl-2-(phenylselanyl)-4-(prop-1-en-2-yl)cyclohexan-1-ol (D2)

[0092] ##STR00026##

[0093] Example 37: The solution of (−)-1-methyl-2-(phenylselenyl)-4-(prop-1-en-2-yl)cyclohexan-1-ol (C2) (155 mg, 0.5 mmol) in THF (5 mL) was allowed to stir for 10 min. Then, (531 mg, 1.5 mmol) Selectfluor was added to the reaction. The reaction mixture was stirred for 9-10 h or until reactant gets consumed. The progress of reaction was monitored by TLC. The reaction mixture was poured in water and extracted with ethyl acetate. The crude material was subjected to silica gel column chromatography, R.sub.f=0.4 EtOAc:hexane (0.3-9.7) as an eluent to afford the title compound (−)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (D2) (81%) as light yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): δ(ppm)=5.71 (dd, 1H), 5.66 (dd, 1H), 4.78 (d, J=16 Hz, 1H), 4.75 (d, J=8 Hz, 1H), 2.66 (m, 1H), 1.80 (m, 2H), 1.74 (s, 3H), 1.59 (m, 1H), 1.49 (br, OH, 1H), 1.30 (s, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3): δ(ppm)=148.125 (C-8), 134.13 (C-2), 132.20 (C-1), 110.74 (C-9), 67.41 (C-3), 43.34 (C-6), 36.77 (C-4), 29.70 (C-5), 27.10 (C-10), 20.81 (C-7); [α].sub.D.sup.20Experimental=−92 (c=1.0, CHCl.sub.3); LC-MS: (ESI+): m/z calcd for C.sub.10H.sub.16O; 152.120; found 135.15.

Preparation of (+)-2-(4-hydroxy-4-methylcyclohex-2-en-1-yl)propan-2-yl 2,2,2-trifluoroacetate (D3)

[0094] ##STR00027##

[0095] Example 38: The solution of (+)-2-(4-hydroxy-4-methyl-3-(phenylselanyl)cyclohexyl)propan-2-yl 2,2,2-trifluoroacetate (C3) (212 mg, 0.5 mmol) in THF (5 mL) was allowed to stir for 10 min. Then, (531 mg, 1.5 mmol) Selectfluor was added to the reaction. The reaction mixture was stirred for 9-10 h or until reactant gets consumed. The progress of reaction was monitored by TLC. The reaction mixture was poured in water and extracted with ethyl acetate. The crude material was subjected to silica gel column chromatography R.sub.f=0.3 EtOAc:hexane (0.3-9.7) as an eluent to afford the title compound (+)-2-(4-hydroxy-4-methylcyclohex-2-en-1-yl)propan-2-yl 2,2,2-trifluoroacetate (D3) (79 mg, 59.3%) as light yellow oil. .sup.1HNMR (400 MHz, CDCl.sub.3): δ(ppm)=5.79 (m, 111), 5.67 (m, 111), 2.72 (s, 111), 2.49 (s, 111) 1.80 (m, 311), 1.57 (d, J=12 Hz, 3H), 1.52 (d, J=8 Hz, 3H) 1.29 (d, J=8 Hz, 3H). .sup.19F NMR (376 MHz, CDCl.sub.3): δ(ppm)=−75.65; [α].sub.D.sup.20=+51 (c=1.0, CHCl.sub.3)

TABLE-US-00007 TABLE 7 Reaction conditions for synthesis of compound formula (+)-D3 from (+)-C3 REAGENTS EXAMPLE REACTANT AND CONDITIONS YIELD (%) 39 (+)-C3 H.sub.2O.sub.2, THF, 7-8 h (+)-D3 (51.1%)

Preparation of (+)-4-isopropyl-1-methylcyclohex-2-en-1-ol (D4)

[0096] ##STR00028##

[0097] Example 40: The solution of (+)-4-isopropyl-1-methyl-2-(phenylselanyl)cyclohexan-1-ol (C4) (156 mg, 0.5 mmol) in THF (5 mL) was allowed to stir for 10 min. Then, (531 mg, 1.5 mmol) Selectfluor was added to the reaction. The reaction mixture was stirred for 9-10 h or until reactant gets consumed. The progress of reaction was monitored by TLC. The reaction mixture was poured in water and extracted with ethyl acetate. The crude material was subjected to silica gel column chromatography R.sub.f=0.5 EtOAc:hexane (0.3-9.7) as an eluent to afford the title compound (+)-4-isopropyl-1-methylcyclohex-2-en-1-ol (D4) (63%) as light yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): δ(ppm)=.sup.1H NMR (400 MHz, CDCl.sub.3): δ 5.66 (m, 2H), 1.84 (m, 2H), 1.62 (m, 2H), 1.47 (m, 2H), 1.26 (s, 3H), 0.89 (m, 6H); .sup.13C NMR (100 MHz, CDCl.sub.3):133.64, 133.08, 67.59, 42.23, 37.36, 31.74, 29.74, 21.67, 19.65, 19.31; [α].sub.D.sup.20Experimental=+48 (c=1.0, CHCl.sub.3); LC-MS: (ESI+): m/z calcd for C.sub.10H.sub.18O; 154.136; found 137.136

TABLE-US-00008 TABLE 8 Reaction conditions for synthesis of compound formula (+)-D4 from (+)-C4 REAGENTS AND EXAMPLE REACTANT CONDITIONS YIELD (%) 41 (+)-C4 H.sub.2O.sub.2, THF, 7-8 h (+)-D4 (61%) 42 (+)-C4 Selectfluor, toluene, 9-10 h (+)-D4 (59%)

Step 3: Condensation of Olivetol or Derivatives with Menthadienol or Derivatives to Prepare Cannabidiol or Derivatives

[0098] ##STR00029##

Preparation of (−)-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (A1)

[0099] ##STR00030##

[0100] Example 43: To a solution of Silver bis(trifluoromethanesulfonyl)imide (AgNTf.sub.2) (20 mol %) in anhydrous DCE was added (+)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (D1) (76 mg, 0.5 mmol) in solution form using syringe. Then, olivetol (E1) (72 mg, 0.4 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC.

[0101] Reaction mixture was poured in water and extracted with EtOAc. The crude material was subjected to silica gel column chromatography R.sub.f 0.5 EtOAc/hexane (0.1:9.9) as an eluent to afford the title compound (−) 5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (A1) (67.18 mg, 43%) as a yellow oil .sup.1H NMR (400 MHz, CDCl.sub.3): δ(ppm)=6.22 (bs, 2H), 5.98 (bs, 1H, OH), 5.57 (s, 1H), 4.78 (bs, 1H, OH), 4.66 (s, 1H), 4.56 (s, 1H), 3.86 (dd, J=8 Hz, 1H), 2.43 (t, 2H), 2.38 (m, 1H), 2.22 (m, 1H), 2.10 (m, 1H), 1.83 (m, 2H), 1.79 (s, 3H), 1.66 (s, 3H), 1.56 (t, 3H), 1.30 (m, 4H), 0.88 (t, 3H); .sup.13C NMR (100 MHz, CD.sub.3OD): δ(ppm)=156.13, 148.90, 141.36, 133.20, 125.86, 114.61, 109.23, 107.02, 45.06, 36.13, 35.19, 31.23, 30.64, 30.31, 29.30, 22.29, 22.17, 18.17, 12.97; [α].sub.D.sup.20=−43 (c=1.0, CHCl.sub.3); LC-MS: (ESI+): m/z calcd for C.sub.21H.sub.31O.sub.2; 314.225; found 315.2317.

[0102] Example 44: To a solution of silver triflate (20 mol %) in anhydrous DCE was added (+)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (D1) (76 mg, 0.5 mmol) in solution form using syringe. Then, olivetol (E1) (72 mg, 0.4 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc. The crude material was subjected to silica gel column chromatography R.sub.f0.5 EtOAc/hexane (0.1:9.9) as an eluent to afford the title compound (−) 5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (A1) (62.5 mg, 36%) as a yellow oil.

TABLE-US-00009 TABLE 9 Reaction conditions for synthesis of compound formula (−)-A1 from (+)-D1. REAGENTS EXAMPLE REACTANT AND CONDITIONS YIELD (%) 45 (+)-D1 Montmorillonite clay, (−)-A1 (34%) dry DCE, rt, 8 h 46 (+)-D1 AgOTf, dry DCE, (−)-A1 (22%) phenanthrolene, rt, 8 h 47 (+)-D1 AgOTf, dry DCE, pyridine, (−)-A1 (31%) rt, 8 h 48 (+)-D1 AgOTf, dry DCE, (−)-A1 (18%) BINAP, rt, 8 h 49 (+)-D1 AgOTf, dry DCE, (−)-A1 (18%) phosphine, rt, 8 h 50 (+)-D1 AgOTf, dry toluene, (−)-A1 (40%) rt, 8 h 51 (+)-D1 AgOTf, dry Benzene, (−)-A1 (40%) rt, 8 h

Preparation of (+Z)-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (A2)

[0103] ##STR00031##

[0104] Example 52 To a solution of silver triflate (20 mol %) in anhydrous DCE was added (−)-1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (D2) (76 mg, 0.5 mmol) in solution form using syringe. Then, olivetol (72 mg, 0.4 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc. The crude material was subjected to silica gel column chromatography R.sub.f=0.5 EtOAc/hexane (0.1:9.9) as an eluent to afford the title compound (+)-5′-methyl-4-pentyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (A2) (56.25 mg, 36%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): δ(ppm)=6.22 (bs, 2H), 5.98 (bs, 1H, OH), 5.57 (s, 1H), 4.78 (bs, 1H, OH), 4.66 (s, 1H), 4.56 (s, 1H), 3.86 (dd, J=8 Hz, 1H), 2.43 (t, 2H), 2.38 (m, 1H), 2.22 (m, 1H), 2.10 (m, 1H), 1.83 (m, 2H), 1.79 (s, 3H), 1.66 (s, 3H), 1.56 (t, 3H), 1.30 (m, 4H), 0.88 (t, 3H); .sup.13C NMR (100 MHz, CDCl.sub.3): δ(ppm)=161.11 (2′C and 6′C), 149.37 (8 C), 142.99 (4-′C), 140.00 (3-C), 124.08 (2C), 113.87 (1′C), 110.92 (3′C and 5′C), 46.20 (6 C), 37.24 (1C), 35.50 (1″ C), 32.51 (4 C), 30.61 (3″ C), 30.42 (2″ C), 28.44 (5C), 23.66 (7C), 22.55 (4″ C), 20.47 (9 C), 14.03 (5″ C); [α].sub.D.sup.20=+21 (c=1.0, CHCl.sub.3); LC-MS: (ESI+): m/z calcd for C.sub.21H.sub.31O.sub.2; 314.225; found 315.2317.

TABLE-US-00010 TABLE 10 Reaction conditions for synthesis of compound formula (+)-A1 from (−)-D1. REAGENTS EXAMPLE REACTANT CONDITIONS AND YIELD (%) 53 (−)-D2 AgOTf, dry toluene (+)-A2 (34%)

Preparation of (−)-2-((1R,2R)-2′,6′-dihydroxy-5-methyl-4′-pentyl-1,2,3,4-tetrahydro-[1,1′-biphenyl]-2-yl)propan-2-yl 2,2,2-trifluoroacetate (A3)

[0105] ##STR00032##

[0106] Example 54: To a solution of silver triflate (20 mol %) in anhydrous DCE was added 2-(4-hydroxy-4-methylcyclohex-2-en-1-yl)propan-2-yl 2,2,2-trifluoroacetate (D3) (133 mg, 0.5 mmol) in solution form using syringe. Then, olivetol (180 mg, 1 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc. The crude material was subjected to silica gel column chromatography R.sub.f 0.4 EtOAc/hexane (0.2:9.9) as an eluent to afford the title compound (−)-2-((1R,2R)-2′,6′-dihydroxy-5-methyl-4′-pentyl-1,2,3,4-tetrahydro-[1,1′-biphenyl]-2-yl)propan-2-yl 2,2,2-trifluoroacetate (A3) (81 mg, 41%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): δ(ppm)=6.22 (bs, 2H), 5.98 (bs, 1H, OH), 5.57 (s, 1H), 4.78 (bs, 1H, OH), 4.66 (s, 1H), 4.56 (s, 1H), 3.86 (dd, J=8 Hz, 1H), 2.43 (t, 2H), 2.38 (m, 1H), 2.22 (m, 1H), 2.10 (m, 1H), 1.83 (m, 2H), 1.79 (s, 3H), 1.66 (s, 3H), 1.56 (t, 3H), 1.30 (m, 4H), 0.88 (t, 3H); .sup.19F NMR (376 MHz, CDCl.sub.3): δ(ppm)=−75.65; .sup.13C NMR (100 MHz, CD.sub.3OD): δ(ppm)=156.13, 148.90, 141.36, 133.20, 125.86, 114.61, 109.23, 107.02, 45.06, 36.13, 35.19, 31.23, 30.64, 30.31, 29.30, 22.29, 22.17, 18.17, 12.97; [α].sub.D.sup.20=−43 (c=1.0, CHCl.sub.3).

TABLE-US-00011 TABLE 11 Reaction conditions for synthesis of compound formula (−)-A3 from (+)-D3 REAGENTS EXAMPLE REACTANT AND CONDITIONS YIELD (%) 55 (+)-D3 AgOTf, dry toluene (−)-A3 (40%)

Preparation of (−)-(1′S,2′S)-2′-isopropyl-5′-methyl-4-pentyl-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (A4)

[0107] ##STR00033##

[0108] Example 56: To a solution of silver triflate (20 mol %) in anhydrous DCE was added (+) 4-isopropyl-1-methylcyclohex-2-en-1-ol (D4) (76 mg, 0.5 mmol) in solution form using syringe. Then, olivetol (E1) (72 mg, 0.4 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc. The crude material was subjected to silica gel column chromatography R.sub.f 0.5 EtOAc/hexane (0.1:9.9) as an eluent to afford the title compound (−)-(1′S,2′S)-2′-isopropyl-5′-methyl-4-pentyl-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (A4) (39%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): δ(ppm)=6.22 (bs, 2H), 5.98 (bs, 1H, OH), 5.57 (s, 1H), 4.78 (bs, 1H, OH), 3.86 (dd, J=8 Hz, 1H), 2.43 (t, 2H), 2.38 (m, 1H), 2.22 (m, 1H), 2.10 (m, 1H), 1.83 (m, 2H), 1.79 (s, 3H), 1.66 (s, 6H), 1.56 (t, 3H), 1.30 (m, 4H), 0.88 (t, 3H); [α].sub.D.sup.20=−48 (c=1.0, CHCl.sub.3); LC-MS: (ESI+): m/z for C.sub.19H.sub.26O.sub.3; 317.240 [M+H].sup.+.

TABLE-US-00012 TABLE 12 Reaction conditions for synthesis of compound formula (−)-A4 form (+)-D4 REAGENTS EXAMPLE REACTANT AND CONDITIONS YIELD (%) 57 (+)-D4 AgOTf, dry toluene (−)-A4 (38%)

Preparation of (−)-5′-methyl-2′-(prop-1-en-2-yl)-4-propoxy-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (A5)

[0109] ##STR00034##

[0110] Example 58—To a solution of silver triflate (20 mol %) in anhydrous DCE was added (+) 1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (D1) (76 mg, 0.5 mmol) in solution form using syringe. Then, 5-propoxybenzene-1,3-diol (E2) (100 mg, 0.6 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc. The crude material was subjected to silica gel column chromatography R.sub.f 0.4 EtOAc/hexane (0.1:9.9) as an eluent to afford the title compound (−)-5′-methyl-2′-(prop-1-en-2-yl)-4-propoxy-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (A5) (62.2 mg, 41.05%) as a yellow oil. .sup.1H NMR (400 MHz, CDCl.sub.3): δ(ppm)=6.04 (bs, 2H), 5.59 (s, 1H), 4.74 (s, 1H), 4.62 (s, 1H), 3.86 (t, 2H), 3.69 (m. 1H), 2.38 (m, 1H), 2.22 (m, 1H), 2.10 (m, 1H), 1.83 (m, 2H), 1.79 (s, 3H), 1.66 (s, 3H), 1.30 (m, 2H), 1.06 (t, 3H); [α].sub.D.sup.20=−21 (c=1.0, CHCl.sub.3); LC-MS: (ESI+): m/z calcd for C.sub.19H.sub.26O.sub.3; 303.40.

Preparation of (−)-4-(dodecyloxy)-5′-methyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol

[0111] ##STR00035##

[0112] Example 59—To a solution of silver triflate (20 mol %) in anhydrous DCE was added (+) 1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (D1) (76 mg, 0.5 mmol) in solution form using syringe. Then, 5-(dodecyloxy)benzene-1,3-diol (E3) (118 mg, 0.4 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc. The crude material was subjected to silica gel column chromatography R.sub.f 0.4 EtOAc/hexane (0.1:9.9) as an eluent to afford the title compound (−)-5′-methyl-2′-(prop-1-en-2-yl)-4-propoxy-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (A6) (78 mg, 36.4%) as a yellow oil. .sup.1HNMR (400 MHz, CDCl.sub.3) δ(ppm)=5.96 (s, 2H), 5.48 (s, 1H), 4.61 (s, 1H), 4.51 (s, 1H), 3.78 (t, 3H), 3.71 (m, 1H), 2.28 (m, 1H), 2.21-1.95 (m, 2H), 1.72 (s, 3H), 1.68-1.62 (m, 2H), 1.58 (s, 3H), 1.19 (s, 20H), 0.81 (s, 3H). .sup.13C NMR (101 MHz, CDCl.sub.3) δ(ppm)=159.03, 149.54, 140.21, 111.17, 108.98, 67.78, 46.35, 31.93, 30.41, 29.62, 29.30 12.4 28.44, 26.05, 23.04, 20.76, 14.44. LC-MS: (ESI+): m/z calcd for C.sub.21H.sub.31O.sub.2; 428.33; found 429.40.

Preparation of (−)-4,5′-dimethyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (Cannabidiorcinol) (A7)

[0113] ##STR00036##

[0114] Example 60—To a solution of silver triflate (20 mol %) in anhydrous DCE was added (+) 1-methyl-4-(prop-1-en-2-yl)cyclohex-2-en-1-ol (D1) (76 mg, 0.5 mmol) in solution form using syringe. Then, Orcinol (E4) (50 mg, 0.4 mmol) in solution form was added slowly to the reaction mixture. Then reaction was allowed to stir at room temperature under dark conditions until the completion of the reactant. The progress of reaction was monitored by TLC. Reaction mixture was poured in water and extracted with EtOAc. The crude material was subjected to silica gel column chromatography R.sub.f0.4 EtOAc/hexane (0.1:9.9) as an eluent to afford the title compound (−)-4,5′-dimethyl-2′-(prop-1-en-2-yl)-1′,2′,3′,4′-tetrahydro-[1,1′-biphenyl]-2,6-diol (Cannabidiorcinol) (A7) (41 mg, 39%)) as a yellow oil. 1H NMR (400 MHz, CDCl.sub.3) δ(ppm)=6.15 (d, 2H), 5.89 (bs, OH), 5.48 (s, 1H), 4.59 (s, 1H), 4.49 (s, 1H), 3.78 (d, 1H), 2.33 (m, 1H), 2.14 (s, 1H), 2.01 (m, 1H), 1.72-1.67 (m, 3H), 1.59 (s, 3H), 1.51 (s, 3H). 13C NMR (101 MHz, CDCl.sub.3) δ(ppm)=149.32, 137.95, 113.89, 110.90, 46.02, 30.27, 21.35, 20.31.

Advantages of the Present Invention:

[0115] The present invention deals with a novel process development for the production of a (+) or (−) Cannabidiol and related compounds thereof. The (+) or (−) cannabidiol and related compounds thereof can be prepared via three steps sequence bi-functionalization of (+) or (−) limonene or limonene derivative thereof, elimination to (+) or (−) menthadienol or derivatives thereof, and metal triflate or acid or heteroacid catalyzed condensation of (+) or (−) menthadienol or menthadienol derivatives with olivetol or olivetol derivatives thereof. The processes of the present disclosure provide a number of advantages over current methods. The main advantage of the present disclosure are i) inexpensive and commercially available starting materials, ii) accessibility of the (+) or (−) cannabidiol or derivatives, iii) high selectivity in condensation reaction, and iv) high overall yield.