US20100069651A1 - Process for production of delta-9-tetrahydrocannabinol - Google Patents

Process for production of delta-9-tetrahydrocannabinol Download PDF

Info

Publication number
US20100069651A1
US20100069651A1 US12/626,403 US62640309A US2010069651A1 US 20100069651 A1 US20100069651 A1 US 20100069651A1 US 62640309 A US62640309 A US 62640309A US 2010069651 A1 US2010069651 A1 US 2010069651A1
Authority
US
United States
Prior art keywords
compound
delta
substituted
tetrahydrocannabinol
solution
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Abandoned
Application number
US12/626,403
Inventor
David C. Burdick
Steven J. Collier
Frédéric Jos
Betina Biolatto
Bernhard J. Paul
Harold Meckler
Mark A. Helle
Alicia J. Habershaw
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Curia Global Inc
Original Assignee
Albany Molecular Research Inc
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Albany Molecular Research Inc filed Critical Albany Molecular Research Inc
Priority to US12/626,403 priority Critical patent/US20100069651A1/en
Publication of US20100069651A1 publication Critical patent/US20100069651A1/en
Priority to US13/108,651 priority patent/US8106244B2/en
Assigned to BANK OF AMERICA, N.A., AS ADMINISTRATIVE AGENT reassignment BANK OF AMERICA, N.A., AS ADMINISTRATIVE AGENT INTELLECTUAL PROPERTY SECURITY AGREEMENT Assignors: ALBANY MOLECULAR RESEARCH, INC., AMRI BOTHELL RESEARCH CENTER, INC., AMRI BURLINGTON, INC., AMRI RENSSELAER, INC.
Assigned to ALBANY MOLECULAR RESEARCH, INC., AMRI BURLINGTON, INC., AMRI BOTHELL RESEARCH CENTER, INC., AMRI RENESSELAER, INC. reassignment ALBANY MOLECULAR RESEARCH, INC. TERMINATION Assignors: BANK OF AMERICA, N.A.
Abandoned legal-status Critical Current

Links

Classifications

    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C29/00Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom not belonging to a six-membered aromatic ring
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07DHETEROCYCLIC COMPOUNDS
    • C07D311/00Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78Ring systems having three or more relevant rings
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C37/00Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/11Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms
    • C07C37/16Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions increasing the number of carbon atoms by condensation involving hydroxy groups of phenols or alcohols or the ether or mineral ester group derived therefrom
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00Preparation of carboxylic acid esters
    • C07C67/30Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07CACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00Systems containing only non-condensed rings
    • C07C2601/12Systems containing only non-condensed rings with a six-membered ring
    • C07C2601/16Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated

Definitions

  • the present invention relates to processes for preparation of (+trans-delta-9-tetrahydrocannabinol, intermediate compounds thereof, and derivative compounds thereof.
  • delta-9-tetrahydrocannabinol delta-9-THC
  • delta-9-THC delta-9-tetrahydrocannabinol
  • Cannabis sativa As an intoxicant makes it clear that the psychotropic properties of the producing plant were recognized since antiquity (Herodotus, The Histories , Book IV, pp. 295, Penguin Books, Ltd., Middlesex (1972)).
  • cannabinoids In addition to uses as anaesthetics, spasmolytics, and hypnotics, cannabinoids have been used to combat emesis and nausea induced by cancer chemotherapy, and also in the treatment of glaucoma.
  • cannabinoids have achieved a certain notoriety due to their abuse potential.
  • a significant portion of the synthetic effort has been directed toward the preparation of some of the oxygenated human urinary metabolites of delta-9-THC for use in forensic science as analytical standards for the detection of marijuana use.
  • CB1 cannabinoid receptor
  • CB2 cannabinoid receptor
  • the present invention is directed to overcoming the above-noted deficiencies in the art.
  • the present invention relates to a process for preparation of a product compound of the formula:
  • R 1 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl
  • R 2 is H, OH, protected hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, aryl, or heteroaryl
  • R 3 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl
  • R 4 is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl.
  • organoaluminum-based Lewis acid catalyst under conditions effective to produce the product compound.
  • Another aspect of the present invention relates to a process for preparation of a product compound of the formula:
  • R 1 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl
  • R 2 is H, OH, protected hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, aryl, or heteroaryl
  • R 3 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl
  • R 4 is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl
  • R 6 is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or ary
  • X H, alkyl, acyl, silyl, aryl, heteroaryl, sulfonyl, phosphoryl, or phosphinyl, in the presence of a metal triflate catalyst, under conditions effective to form the product compound.
  • Yet another aspect of the present invention relates to a process for preparation of a product compound of the formula:
  • R 1 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl
  • R 2 is H, OH, protected hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, aryl, or heteroaryl
  • R 3 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl
  • R 4 is SO 2 R 5 , wherein R 5 is substituted or unsubstituted alkyl.
  • R 4 ′ is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl
  • R 6 is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl, wherein at least one of R 4 ′ and R 6 must be H; with a first compound of the formula:
  • the second intermediate compound is treated with an organoaluminum-based Lewis acid catalyst, under conditions effective to produce a third intermediate compound of the formula:
  • the third intermediate compound is reacted with a substituted or unsubstituted alkylsulfonyl halide, alkylsulfonyl anhydride, alkylsulfonyl mixed anhydride, alkylsulfonyl ester, or alkylsulfonic acid, under conditions effective to produce the product compound.
  • the present invention also relates to a compound of the formula:
  • R 1 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl
  • R 2 is H, OH, protected hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, aryl, or heteroaryl
  • R 3 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl
  • R 8 , R 9 , and R 10 are the same or different and independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or halo
  • R 8 and R 9 ; R 8 and R 10 ; or R 9 and R 10 ; or R 8 , R 9 , and R 10 can together result in the formation of a cyclic moiety.
  • the reactions of the present invention proceed under mild conditions with practically no overreaction to cyclized products.
  • both the desired cannabidiol and an unwanted isomer, abn-cannabidiol are formed when BF 3 OEt 2 is used as catalyst.
  • the combination of a metal triflate catalyst, and the slow addition of menthadienol gives improved ratios of cannabidiol to abn-cannabidiol.
  • Running the reaction in dichloromethane (DCM) at temperatures above its boiling point further increases the selectivity.
  • the method of the present invention by the slow addition of a substoichiometric amount of menthadienol to a mixture of olivetol and a metal triflate catalyst in DCM at a temperature above its boiling point, gives vastly improved selectivities for cannabidiol over its unwanted regioisomer over the prior art, and also significantly reduces the transformation of the cannabidiol into cyclized products.
  • yields of delta-9-THC are approximately 50-60% at best, with ca. 20% iso-THC and the inherent problem of isomerization of the delta-9-THC to the delta-8 isomer by the strong Lewis acid.
  • AlCl 3 at very short reaction times, selectivities of ca. 10:1 delta-9-THC: iso-THC can be achieved, with little isomerization to delta-8 isomer. Extended reaction time favors the double bond isomerization.
  • the present invention relates to a process for preparation of a product compound of the formula:
  • R 1 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl
  • R 2 is H, OH, protected hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, aryl, or heteroaryl
  • R 3 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl
  • R 4 is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl.
  • organoaluminum-based Lewis acid catalyst under conditions effective to produce the product compound.
  • the organoaluminum-based Lewis acid catalyst used in the method of the present invention can be a trialkyl- or triarylaluminum, dialkyl- or diarylaluminum halide, alkylarylalurninum halide, dialkyl- or alkylaryl- or diarylaluminum alkoxide or aryloxide, dialkyl- or alkylaryl or diarylaluminum thioalkoxide or thioarylate, dialkyl- or alkylaryl or diarylaluminum carboxylate, alkyl- or arylaluminum dihalide, alkyl- or arylaluminum dialkoxide or diaryloxide or alkylaryloxide, alkyl- or aryl aluminum dithioalkoxide or dithioarylate, alkyl- or arylaluminum dicarboxylate, aluminum trialkoxide or triaryloxide or mixed alkylaryloxide, aluminum triacylcarboxylate or mixtures thereof.
  • organoaluminum-based Lewis acid catalysts include, but are not limited to, trimethylaluminum, triethylaluminum, triisopropylaluminum, triisobutylaluminum, trioctylaluminum, tridecylaluminum, diethylaluminum chloride, diisobutylaluminum chloride, diethylaluminum sesquichloride, ethyl aluminum dichloride, methylaluminum dichloride, isobutylaluminum dichloride, diethylaluminum ethoxide, diethylaluminum isopropoxide, diisobutylaluminum methoxide, diisobutylaluminum phenoxide, diphenylaluminum isoproproxide, tetraisobutylalumoxane, methylalumoxane, methylaluminum bis-(2,6-di-t-buty
  • the organoaluminum-based Lewis acid catalyst is a C 1 -C 30 alkylaluminum-based or C 6 -C 30 arylaluminum-based substance or mixture.
  • the organoaluminum-based Lewis acid catalyst contains one or more oxygenated substituents bonded to the aluminum which modify the physical properties or performance of the catalyst.
  • the organoaluminum-based Lewis acid catalyst may be made in situ before use by reaction of a precursor aluminum reagent with a modifying substituent.
  • the organoaluminum-based Lewis acid catalysts can be catalysts which provide high selectivity for delta-9-THC at lower levels of catalyst usage and at convenient rates for larger scale preparation.
  • the organoaluminum-based Lewis acid catalysts can be catalysts that produce delta-9-THC with very low levels of isomers (e.g., cis-delta-9-THC, delta-8-THC, and iso-THC), as these are difficult to remove from the product and render it difficult to achieve current standards of pharmaceutical purity.
  • isomers e.g., cis-delta-9-THC, delta-8-THC, and iso-THC
  • the step of treating is carried out with the organoaluminum-based Lewis acid catalyst in an amount from about 0.5 mol % to about 100 mol % with respect to the first intermediate compound. In yet another embodiment of the present invention, the step of treating is carried out with the organoaluminum-based Lewis acid catalyst in an amount from about 5 mol % to about 15 mol % with respect to the first intermediate compound.
  • the step of treating can be carried out in an organic solvent.
  • the solvent is aprotic.
  • organic solvent include, but are not limited to, hexane, heptane, toluene, xylene, dichloromethane, and mixtures thereof.
  • the step of treating can be carried out at a temperature of from about ⁇ 20° C. to about 100° C. In another embodiment of the present invention, the step of treating can be carried out at a temperature of from about ⁇ 20° C. to about 50° C. In yet another embodiment of the present invention, the step of treating can be carried out at a temperature of from about 0° C. to about 30° C.
  • the process of the present invention further involves reacting the product compound, where R 4 H, with a substituted or unsubstituted alkylsulfonyl halide, alkylsulfonyl anhydride, alkylsulfonyl mixed anhydride, alkylsulfonyl ester, or alkylsulfonic acid, under conditions effective to produce a second product compound of the formula:
  • R 1 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl
  • R 2 is H, OH, protected hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, aryl, or heteroaryl
  • R 3 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl
  • R 4 ′′′ is SO 2 R 5 , wherein R 5 is substituted or unsubstituted alkyl.
  • the product compound can be reacted with similar arylsulfonyl reagents to produce arylsulfonate compounds.
  • the above reaction is carried out with an alkylsulfonyl compound in an amount from about 1 to about 1.5 equivalents with respect to the product compound at atmospheric pressure at a temperature of from about ⁇ 20° C. to about 100° C. depending on the reagent.
  • the reaction is typically carried out at a temperature of from about ⁇ 10° C. to about 20° C.
  • the product compound can be a totally synthetic substance or a naturally derived substance.
  • the process of the present invention further involves carrying out a method selected from chromatography, countercurrent extraction, and distillation on the second product compound under conditions effective to produce a purified second product compound.
  • the process of the present invention further involves crystallizing the second product compound under conditions effective to produce a purified second product compound.
  • the purified second product compound can be hydrolyzed under conditions effective to produce the purified product compound in a desired isomer form.
  • the step of hydrolyzing is carried out in the presence of an organic or inorganic base in a solvent.
  • bases include, but are not limited to, sodium hydroxide, potassium t-butoxide, and mixtures thereof.
  • solvent include, but are not limited to, methanol, ethanol, isopropanol, t-butanol, acetonitrile, and mixtures thereof.
  • the second product compound is of the formula:
  • R 8 , R 9 , and R 10 are the same or different and independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or halo; and R 8 and R 9 ; R 8 and R 10 ; or R 9 and R 10 ; or R 8 , R 9 , and R 10 can together result in the formation of a cyclic moiety.
  • Alkyl is defined herein as C 1 -C n , wherein the carbon chains may be straight, branched, or containing or comprising rings. “Substituted alkyl” is defined as C 1X -C n X as described above, except that the carbons may bear one or more substituents X, such as functional groups containing oxygen, nitrogen, sulfur, halogen or aromatic or heteroaromatic rings. “Aryl” is defined as C 6 -C n aromatic rings or multiple rings. “Substituted aryl” is defined as C 6 -C n aromatic rings or multiple rings bearing substituents on one or more of these rings which may be functional groups of carbon, oxygen, nitrogen, sulfur or halogen.
  • Heteroaryl is defined as aromatic rings containing one or more heteroatom within the ring or rings. “Substituted heteroaryl” is defined as heteroaryl containing one or more substituents on one or more ring which may be functional groups of carbon, oxygen, nitrogen, sulfur or halogen. “Halo” is defined as chlorine, bromine, iodine or fluorine. Further, R 8 , R 9 , and R 10 may contain chiral centers or define a chiral center on the carbon bearing them.
  • the second product compound is a straight chain alkylsulfonate selected from methanesulfonate, ethanesulfonate, propanesulfonate, butanesulfonate, pentanesulfonate, hexanesulfonate, heptanesulfonate, octanesulfonate, nonanesulfonate, decanesulfonate, undecanesulfonate, dodecanesulfonate, tridecanesulfonate, tetradecanesulfonate, pentadecanesulfonate, hexadecanesulfonate, heptadecanesulfonate, octadecanesulfonate, nonadecanesulfonate, and icosanesulfonate.
  • the second product compound is a branched chain alkylsulfonate selected from cyclopropylsulfonate, isopropylsulfonate, isobutylsulfonate, tert-octylsulfonate, adamantly sulfonate, and 10-camphorsulfonate.
  • the second product compound is a substituted alkylsulfonate selected from chloromethylsulfonate, 2-chloroethylsulfonate, trifluoromethylsulfonate, trifluorethylsulfonate, perfluoroethylsulfonate, perfluorobutylsulfonate, perfluorooctanesulfonate, 2-aminoethylsulfonate, 2-dimethylaminoethylsulfonate, 2-phthalimidoethylsulfonate, 2-morpholinoethylsulfonate, 3-morpholinopropylsulfonate, 4-morpholinobutylsulfonate, 2-N-piperidinylethylsulfonate, 3-N-piperidylpropylsulfonate, 2-pyrrolidinylmethylsulfonate, 2-methoxyethy
  • the second product compound can have the following formula, where the camphorsulfonate group is in the S configuration:
  • the second product compound can have the following formula, where the camphorsulfonate group is in the R configuration:
  • the second product compound is a diastereomeric mixture of the following two formulae, where the camphorsulfonate group is in the S and R configurations, respectively:
  • the second product compound is an aryl or heteroaryl substituted alkylsulfonate selected from benzylsulfonate, 2-nitrobenzylsulfonate, 3-nitrobenzylsulfonate, 4-nitrobenzylsulfonate, 2-chlorobenzylsulfonate, 3-chlorobenzylsulfonate, 4-chlorobenzylsulfonate, 2-trifluoromethybenzylsulfonate, 3-trifluoromethylbenzylsulfonate, 4-trifluoromethylbenzylsulfonate, 3,5-dichlorobenzylsulfonate, 3,5-di-trifluoromethylbenzylsulfonate, 4-methylbenzylsulfonate, 4-t-butylbenzylsulfonate, 1-napthylethylsulfonate, 2-pyridylmethylsulfonate, 3-pyridyl
  • process of the present invention further involves reacting a second intermediate compound of the formula:
  • R 6 is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl; with a second compound of the formula:
  • X H, alkyl, acyl, silyl, aryl, heteroaryl, sulfinyl, sulfonyl, phosphoryl, or phosphinyl, in the presence of a metal triflate catalyst, under conditions effective to form the first intermediate compound.
  • the step of reacting is carried out under conditions effective to achieve preferential formation of the first intermediate compound over undesired stereochemical and regiochemical isomers as well as other impurities.
  • R 1 is H or COOR 7
  • R 2 is n-C 5 H 11
  • R 3 is H or COOR 7 , where R 7 is C 1 -C 20 alkyl.
  • R 1 is COOR 7 , where R 7 is ethyl
  • R 2 is n-C 5 H 11
  • R 2 n-C 5 H 11
  • the above reaction is carried out with the second intermediate compound in an amount of from about 1 to 1.2 equivalents with respect to the second compound.
  • the metal triflate catalyst can be a transition metal triflate or lanthanide triflate.
  • transition metal triflate include, but are not limited to, zinc triflate, ytterbium triflate, yttrium triflate, and scandium triflate.
  • the transition metal triflate is zinc triflate or scandium triflate.
  • the step of reacting is carried out with the metal triflate catalyst in an amount from about 0.5 mol % to about 100 mol % with respect to the second intermediate compound. In yet another embodiment of the present invention, the step of reacting is carried out with the metal triflate catalyst in an amount from about 0.5 mol % to about 10 mol % with respect to the second intermediate compound.
  • the step of reacting is carried out in an organic solvent.
  • organic solvent include, but are not limited to, a hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon, ether, ester, amide, nitrite, carbonate, alcohol, carbon dioxide, and mixtures thereof.
  • the organic solvent is dichloromethane.
  • the step of reacting is carried out at a temperature of from about ⁇ 20° C. to about 150° C.
  • the step of reacting can be carried out under pressure at a temperature above the normal atmospheric boiling point of the organic solvent or where temperatures are above boiling point and pressure is above atmosphere.
  • the step of reacting is carried out with a less than about one equivalent of the second compound to the second intermediate compound.
  • Ethyl olivetolate (25 g, 99 mmol) was dissolved in dichloromethane (250 mL) and MgSO 4 (25 g, 1 wt) and Sc(OTf) 3 (4.88 g, 9.9 mmol, 10 mol %) were added sequentially.
  • a solution of menthadienol (24.5 g, 161 mmol, 1.6 equiv, assuming purity of 100% but really approximately 80-85% AUC by GC) in dichloromethane (125 mL) was added over 1.5 h using a dropping funnel.
  • the ethyl cannabidiolate from Example 1 (31.3 g, 81 mmol) was dissolved in MeOH (10 vol, 310 mL) and degassed with argon. Separately, a solution of NaOH (64.8 g, 1.62 mol, 20 equiv) in deionized water (10 vol, 310 mL) was prepared and degassed with argon. The organic solution was added to the aqueous solution under a strict argon atmosphere, then the mixture heated to reflux and held there for 3.5 h, then cooled to room temperature. HPLC analysis indicated completion of reaction.
  • the reaction mixture was quenched with aqueous citric acid (129.6 g citric acid, 8.3 equiv, as a 30% solution in water). The addition was exothermic. Heptane (310 mL, 10 vol) was added to the mixture and the product extracted into the heptane phase. A second extraction using heptane (150 mL, ca. 5 vol) was then performed and HPLC analysis of the aqueous fractions indicated the absence of the cannabidiol. The combined organics were dried by azeotropic distillation of the water and concentrated to ca. 250 mL and then cooled to ⁇ 16 to ⁇ 17° C., and seeded with solid cannabidiol when the temperature reached ⁇ 1.5° C.
  • the cannabidiol from Example 2 (18.5 g, 58.8 mmol) was dissolved in dichloromethane (324 mL, 17.5 vol) and heated to 25° C. Triisobutylaluminum (5.9 mL of 1 M solution in hexane, 10 mol % catalyst) was then added via syringe and the reaction stirred at 20-25° C. for approx 20 h. After this time, HPLC analysis of the reaction mixture showed consumption of the cannabidiol and 94.8% trans-delta-9-THC. The reaction was quenched with water (1.6 mL, 15 equiv. based on moles of catalyst) and stirred for 1 h. After filtration through celite, the solvent was switched to toluene and the reaction mixture azeotroped to remove any remaining water. The solution of product in toluene (total volume ca. 92 mL) was used directly in the subsequent step.
  • Trans-delta-9-THC 3-nitrobenzenesulfonate (16.5 g) was dissolved in acetonitrile (330 mL, 20 vol) and 0.5 M NaOH (165 mL, 10 vol) was added. The mixture was heated to reflux and, after ca. 2 h, HPLC analysis indicated that the reaction was complete. After cooling, water (500 mL, 30 vol) was added followed by heptane (165 mL, 10 vol). The phases were mixed and the heptane layer was collected.
  • the aqueous phase was extracted again with heptane (165 mL, 10 vol) and the organic extracts were combined, washed with water (165 mL, 10 vol), dried over Na 2 SO 4 , filtered, and concentrated to a dark brown-purple oil.
  • the oil was reconstituted with EtOH and restripped to give the product as a light brown oil (10.79 g), containing ca. 6% EtOH by proton NMR analysis. HPLC analysis indicated a purity of 99.66% AUC.
  • the residual oil (30.9 kg) was fed to a 4 inch, wiped-film evaporator at 3 mm and 145° C. to remove the unreacted limonene oxide.
  • the non-volatile fraction (14.7 kg of thiophenyl ether) was dissolved in glacial acetic acid (26.0 L) and stirred while 35% hydrogen peroxide (6.0 kg) added over 6.5 hours.
  • the reaction temperature was maintained at 10-20° C.
  • the reaction was allowed to warm to room temperature overnight, then transferred into a mixture of warm water (89 L, 40-45° C.) and MTBE (34 L).
  • the organic phase was washed aqueous 5% sodium bicarbonate (4 washes, 18 L each) at 40-45° C., to achieve a final pH of ca. 8 and a negative starch-iodine test.
  • the organic phase was concentrated under reduced pressure at 60° C. to obtain a residue of crude sulfoxide mixture (14.8 kg, estimated 95% yield).
  • This residual was dissolved in tetraglyme (11.6 L) and stored until needed, during this time the product partially crystallized. The solution was gently warmed to redissolve the sulfoxide mixture. To a portion of this tetraglyme solution (containing ca.
  • the reaction was quenched by addition of solid anhydrous sodium carbonate (4.0 g) and stirred overnight at 25° C.
  • the reaction mixture was clarified by filtration through a bed of celite and the flask and filter cake was washed with dichloromethane (250 mL).
  • the combined filtrates were concentrated under reduced pressure to about 150 mL of volume.
  • Heptane (400 mL) was added and the mixture was again concentrated under reduced pressure to about 150 mL.
  • Heptane (400 mL) was added and the mixture extracted with aqueous sodium hydroxide solution (2 ⁇ 200 mL of a 20% aqueous solution) followed by water (2 ⁇ 200 mL). HPLC analysis showed the organic phase to be free of any residual ethyl olivetolate.
  • the reaction was quenched by addition of a degassed aqueous solution of citric acid (50 wt % solution, 400 g).
  • the mixture was extracted with heptane (400 mL) and the organic layer was washed with aqueous sodium bicarbonate solution (300 mL) and water (300 mL).
  • the heptane solution was concentrated under reduced pressure to ca. 100 mL, reconstituted with heptane (400 mL), concentrated again to ca. 50 mL and heptane (200 mL) was added.
  • the slowly stirred heptane solution was cooled to 10° C., seeded with cannabidiol crystals and stirred slowly at 10° C.
  • the reaction was quenched by addition of water (250 mL), stirred 30 minutes, combined with a slurry of celite in dichloromethane (10.0 g in 70 mL dichloromethane) and then clarified.
  • the reactor and filter cake were rinsed with dichloromethane (50 mL) and the combined filtrates distilled under reduced pressure (25° C. pot temperature, 22 inches of vacuum) to about 50 mL volume.
  • Toluene (106 mL) was added and the solvents again removed under reduced pressure. More toluene (106 mL) was added and removed under reduced pressure and then the dichloromethane-free residue was reconstituted in toluene (100 mL).
  • the organic phase was washed with 5% aqueous citric acid solution (100 mL), 5% aqueous sodium bicarbonate solution (100 mL) and 5% aqueous sodium chloride solution (100 mL).
  • the toluene layer was concentrated under reduced pressure to about 100 mL and additional toluene (100 mL) was added.
  • This drying sequence was repeated and then the solvent was replaced with isopropanol (200 mL).
  • the isopropanol was concentrated under reduced pressure and the residue was suspended in isopropanol (200 mL).
  • the slurry was warmed to 40° C. at which point the solids dissolved.
  • the stirred solution was cooled to 20° C. over 4 hours during which the product crystallized.
  • a stock solution of delta-9 THC in ethanol (6.90 g of 0.109 mg/mL tetrahydrocannabinol concentration) was mixed with Croda high purity sesame oil (29.25 g) from Croda, Inc. (Edison, N.J.). The resulting solution was warmed to 30° C., and sparged with filtered argon for 24 hours to afford ca. 30 g of 2.5% delta-9-tetrahydrocannabinol in sesame oil.
  • 1 H NMR 500 MHz (CDCl 3 ) showed no residual ethanol.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pyrane Compounds (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

The present invention relates to a process for preparation of a delta-9-tetrahydrocannabinol compound or derivative thereof involving treating a first intermediate compound with an organoaluminum-based Lewis acid catalyst, under conditions effective to produce the delta-9-tetrahydrocannabinol compound or derivative thereof. Another aspect of the present invention relates to a process for preparation of a cannabidiol or cannabidiolate compound involving reacting a first starting compound with a second starting compound in the presence of a metal triflate catalyst, under conditions effective to form the cannabidiol or cannabidiolate compound. The present invention also relates to a compound of the formula:
Figure US20100069651A1-20100318-C00001
where R8, R9, and R10 are the same or different and independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or halo, with R1, R2, and R3 defined herein.

Description

  • This application is a division of U.S. patent application Ser. No. 11/529,147, filed Sep. 28, 2006, which claims the benefit of U.S. Provisional Patent Application Ser. No. 60/722,031, filed Sep. 29, 2005, which are hereby incorporated by reference in their entirety.
  • FIELD OF THE INVENTION
  • The present invention relates to processes for preparation of (+trans-delta-9-tetrahydrocannabinol, intermediate compounds thereof, and derivative compounds thereof.
  • BACKGROUND OF THE INVENTION
  • In the years since the appearance of Razdan's ground-breaking review on the synthesis of cannabinoids, research activity has continued apace (Razdan, in ApSimon, ed., The Total Synthesis of Natural Products, Vol. 4, pp. 185-262, New York, N.Y.: Wiley and Sons (1981); Huffman et al., Current Med. Chem., 3:101-116 (1996)). The interest which this area engenders is due in part to the challenge which the structures pose to the synthetic organic chemist, and also because of the diverse and useful pharmacological activities which many of these materials express. The chemical structures of the naturally occurring tricyclic cannabinoids, typified by delta-9-tetrahydrocannabinol (delta-9-THC), are very simple: there are only two stereogenic carbon atoms, two carbocycles and the dihydrobenzopyran ring. The functionality is in most cases limited to the phenolic C1 hydroxyl and to one or two oxygen-bearing functional groups. One would be justified in questioning whether this class of compounds is of sufficient complexity to continue to interest the organic chemist. The difficulties of the synthesis belie the simplicity of the structure, and are due, at least in part, to the following: (a) the materials are typically non-crystalline, and are often quite difficult or impossible to separate and purify without recourse to HPLC; (b) the aromatic portion of the molecule is very sensitive to oxidation, particularly in the presence of base or transition metals (see Hodjat-Kashani et al., Heterocycles, 24:1973-1976 (1986)); and (c) the delta-9-unsaturation is thermodynamically disfavored relative to delta-8-unsaturation. There is also no general method by which to favor delta-9-unsaturation kinetically.
  • Interest in the pharmacology of these materials goes back many thousands of years (Abel, Marijuana: The First Twelve Thousand Years, pp. 11-12, New York and London: Plenum Press (1980)). Herodotus' account of the Scythians' use of Cannabis sativa as an intoxicant makes it clear that the psychotropic properties of the producing plant were recognized since antiquity (Herodotus, The Histories, Book IV, pp. 295, Penguin Books, Ltd., Middlesex (1972)). In addition to uses as anaesthetics, spasmolytics, and hypnotics, cannabinoids have been used to combat emesis and nausea induced by cancer chemotherapy, and also in the treatment of glaucoma. In recent times, cannabinoids have achieved a certain notoriety due to their abuse potential. A significant portion of the synthetic effort has been directed toward the preparation of some of the oxygenated human urinary metabolites of delta-9-THC for use in forensic science as analytical standards for the detection of marijuana use.
  • Several developments have contributed to the current resurgence in interest in this area. The identification of the first cannabinoid receptor (CB1) in rat brain (Devane et al., Mol. Pharmacol., 34:605-613 (1988)) was a major advance. The identification of a second, peripheral, receptor subtype in splenocytes (CB2) (Munro et al., Nature, 365:61-65 (1993)), as well as the discovery of arachidonylethanolamine (anandamide) as the endogenous ligand for CB1 (Devane et al., Science, 258:1946-1949 (1992)), has made the story much more interesting. Involvement of the pharmaceutical industry has resulted in synthesis and evaluation of large numbers of analogs, and in the discovery of the first receptor antagonist.
  • The present invention is directed to overcoming the above-noted deficiencies in the art.
  • SUMMARY OF THE INVENTION
  • The present invention relates to a process for preparation of a product compound of the formula:
  • Figure US20100069651A1-20100318-C00002
  • where:
    R1 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl;
    R2 is H, OH, protected hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, aryl, or heteroaryl;
    R3 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl; and
    R4 is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl.
    The process involves treating a first intermediate compound of the formula:
  • Figure US20100069651A1-20100318-C00003
  • with an organoaluminum-based Lewis acid catalyst, under conditions effective to produce the product compound.
  • Another aspect of the present invention relates to a process for preparation of a product compound of the formula:
  • Figure US20100069651A1-20100318-C00004
  • where:
    R1 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl;
    R2 is H, OH, protected hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, aryl, or heteroaryl;
    R3 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl;
    R4 is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl; and
    R6 is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl.
    The process involves reacting a first starting compound of the formula:
  • Figure US20100069651A1-20100318-C00005
  • with a second starting compound of the formula:
  • Figure US20100069651A1-20100318-C00006
  • where X=H, alkyl, acyl, silyl, aryl, heteroaryl, sulfonyl, phosphoryl, or phosphinyl, in the presence of a metal triflate catalyst, under conditions effective to form the product compound.
  • Yet another aspect of the present invention relates to a process for preparation of a product compound of the formula:
  • Figure US20100069651A1-20100318-C00007
  • where:
    R1 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl;
    R2 is H, OH, protected hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, aryl, or heteroaryl;
    R3 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl; and
    R4 is SO2R5, wherein R5 is substituted or unsubstituted alkyl.
    The process involves reacting a first intermediate compound of the formula:
  • Figure US20100069651A1-20100318-C00008
  • wherein:
    R4′ is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl,
    R6 is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl, wherein at least one of R4′ and R6 must be H;
    with a first compound of the formula:
  • Figure US20100069651A1-20100318-C00009
  • where X=H, alkyl, acyl, silyl, aryl, heteroaryl, sulfonyl, sulfonyl, phosphoryl, or phosphinyl, in the presence of a metal triflate catalyst, under conditions effective to form a second intermediate compound of the formula:
  • Figure US20100069651A1-20100318-C00010
  • Next, the second intermediate compound is treated with an organoaluminum-based Lewis acid catalyst, under conditions effective to produce a third intermediate compound of the formula:
  • Figure US20100069651A1-20100318-C00011
  • wherein R4″=H. Then, the third intermediate compound is reacted with a substituted or unsubstituted alkylsulfonyl halide, alkylsulfonyl anhydride, alkylsulfonyl mixed anhydride, alkylsulfonyl ester, or alkylsulfonic acid, under conditions effective to produce the product compound.
  • The present invention also relates to a compound of the formula:
  • Figure US20100069651A1-20100318-C00012
  • where:
    R1 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl;
    R2 is H, OH, protected hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, aryl, or heteroaryl;
    R3 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl;
    R8, R9, and R10 are the same or different and independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or halo; and
    R8 and R9; R8 and R10; or R9 and R10; or R8, R9, and R10 can together result in the formation of a cyclic moiety.
  • The condensation of olivetol or an olivetolate ester with menthadienol in the presence of Lewis acids has been known in the prior art. However, the reactions were plagued by problems with poor selectivity and subsequent conversion of the desired products to cyclized derivatives with little control. For example, boron trifluoride etherate (BF3OEt2) gives poor control over the reactions as it is difficult to stop at cannabidiol and the cyclization to delta-9-THC with further isomerization to delta-8-THCs is a common problem. The use of less reactive Lewis acids, such as MgBr2, is not favorable due to their poor reactivity. As the scale of these reactions increases, the control over the process becomes more difficult, due to the short reaction times needed. By using metal triflate catalysts, the reactions of the present invention proceed under mild conditions with practically no overreaction to cyclized products. In addition, in the case of olivetol, both the desired cannabidiol and an unwanted isomer, abn-cannabidiol, are formed when BF3OEt2 is used as catalyst. However, the combination of a metal triflate catalyst, and the slow addition of menthadienol (preferably less than one equivalent) gives improved ratios of cannabidiol to abn-cannabidiol. Running the reaction in dichloromethane (DCM) at temperatures above its boiling point further increases the selectivity. Hence, the method of the present invention, by the slow addition of a substoichiometric amount of menthadienol to a mixture of olivetol and a metal triflate catalyst in DCM at a temperature above its boiling point, gives vastly improved selectivities for cannabidiol over its unwanted regioisomer over the prior art, and also significantly reduces the transformation of the cannabidiol into cyclized products.
  • Further, the cyclization of cannabidiol to delta-9-THC is a notoriously difficult reaction to control and carry out selectively. Previously, catalysts, such as BF3OEt2, have been used. These can induce isomerization of the desired delta-9 isomer to the thermodynamically more stable delta-8 isomer, which is very difficult to separate from the product. Moreover, cyclization of the phenol unit can occur onto the endocyclic double bond to give significant levels of iso-THC derivatives, which are also very difficult to remove. The method of the present invention, by using organoaluminum-based Lewis acid catalysts, gives vastly superior selectivities in this cyclization. For example, with BF3OEt2, yields of delta-9-THC are approximately 50-60% at best, with ca. 20% iso-THC and the inherent problem of isomerization of the delta-9-THC to the delta-8 isomer by the strong Lewis acid. Using AlCl3 at very short reaction times, selectivities of ca. 10:1 delta-9-THC: iso-THC can be achieved, with little isomerization to delta-8 isomer. Extended reaction time favors the double bond isomerization. In contrast, when the method of the present invention is used as described herein, e.g., when iBu3Al is used, yields of delta-9-THC are >92% with <2% iso-THC with practically no isomerization of the desired product to delta-8-THC.
  • DETAILED DESCRIPTION OF THE INVENTION
  • The present invention relates to a process for preparation of a product compound of the formula:
  • Figure US20100069651A1-20100318-C00013
  • where:
    R1 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl;
    R2 is H, OH, protected hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, aryl, or heteroaryl;
    R3 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl; and
    R4 is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl.
    The process involves treating a first intermediate compound of the formula:
  • Figure US20100069651A1-20100318-C00014
  • with an organoaluminum-based Lewis acid catalyst, under conditions effective to produce the product compound.
  • The organoaluminum-based Lewis acid catalyst used in the method of the present invention can be a trialkyl- or triarylaluminum, dialkyl- or diarylaluminum halide, alkylarylalurninum halide, dialkyl- or alkylaryl- or diarylaluminum alkoxide or aryloxide, dialkyl- or alkylaryl or diarylaluminum thioalkoxide or thioarylate, dialkyl- or alkylaryl or diarylaluminum carboxylate, alkyl- or arylaluminum dihalide, alkyl- or arylaluminum dialkoxide or diaryloxide or alkylaryloxide, alkyl- or aryl aluminum dithioalkoxide or dithioarylate, alkyl- or arylaluminum dicarboxylate, aluminum trialkoxide or triaryloxide or mixed alkylaryloxide, aluminum triacylcarboxylate or mixtures thereof. Suitable examples of organoaluminum-based Lewis acid catalysts include, but are not limited to, trimethylaluminum, triethylaluminum, triisopropylaluminum, triisobutylaluminum, trioctylaluminum, tridecylaluminum, diethylaluminum chloride, diisobutylaluminum chloride, diethylaluminum sesquichloride, ethyl aluminum dichloride, methylaluminum dichloride, isobutylaluminum dichloride, diethylaluminum ethoxide, diethylaluminum isopropoxide, diisobutylaluminum methoxide, diisobutylaluminum phenoxide, diphenylaluminum isoproproxide, tetraisobutylalumoxane, methylalumoxane, methylaluminum bis-(2,6-di-t-butyl-4-methylphenoxide), diisobutylaluminum acetate, diisobutylaluminum benzoate, diisobutylaluminum trifluoroacetate, diisobutylaluminum isopropoxide, diisobutylaluminum 2,6-di-t-butyl-4-methylphenoxide, isobutylaluminum bis-(2,6-di-t-butyl-4-methylphenoxide), isobutylaluminum diacetate, aluminum trimethoxide, aluminum triisopropoxide, aluminum tri-tert-butoxide, and aluminum trifluoroacetate. Several such catalysts are commercially available or can be prepared from commercially available aluminum reagents, using methods known in the literature, such as described by Ooi and Maruoka, Science of Synthesis, Vol. 7, pp. 131-195, Stuttgart, Germany: Thieme (2000), which is hereby incorporated by reference in its entirety.
  • In one embodiment of the present invention, the organoaluminum-based Lewis acid catalyst is a C1-C30 alkylaluminum-based or C6-C30 arylaluminum-based substance or mixture. In another embodiment of the present invention, the organoaluminum-based Lewis acid catalyst contains one or more oxygenated substituents bonded to the aluminum which modify the physical properties or performance of the catalyst. In another embodiment of the present invention, the organoaluminum-based Lewis acid catalyst may be made in situ before use by reaction of a precursor aluminum reagent with a modifying substituent. Specifically, the organoaluminum-based Lewis acid catalysts can be catalysts which provide high selectivity for delta-9-THC at lower levels of catalyst usage and at convenient rates for larger scale preparation. More specifically, the organoaluminum-based Lewis acid catalysts can be catalysts that produce delta-9-THC with very low levels of isomers (e.g., cis-delta-9-THC, delta-8-THC, and iso-THC), as these are difficult to remove from the product and render it difficult to achieve current standards of pharmaceutical purity.
  • In another embodiment of the present invention, the step of treating is carried out with the organoaluminum-based Lewis acid catalyst in an amount from about 0.5 mol % to about 100 mol % with respect to the first intermediate compound. In yet another embodiment of the present invention, the step of treating is carried out with the organoaluminum-based Lewis acid catalyst in an amount from about 5 mol % to about 15 mol % with respect to the first intermediate compound.
  • The step of treating can be carried out in an organic solvent. In one embodiment of the present invention, the solvent is aprotic. Examples of organic solvent include, but are not limited to, hexane, heptane, toluene, xylene, dichloromethane, and mixtures thereof.
  • The step of treating can be carried out at a temperature of from about −20° C. to about 100° C. In another embodiment of the present invention, the step of treating can be carried out at a temperature of from about −20° C. to about 50° C. In yet another embodiment of the present invention, the step of treating can be carried out at a temperature of from about 0° C. to about 30° C.
  • In another embodiment of the present invention, R2 is n-C5H11 and R1=R3=R4=H.
  • In another embodiment, the process of the present invention further involves reacting the product compound, where R4H, with a substituted or unsubstituted alkylsulfonyl halide, alkylsulfonyl anhydride, alkylsulfonyl mixed anhydride, alkylsulfonyl ester, or alkylsulfonic acid, under conditions effective to produce a second product compound of the formula:
  • Figure US20100069651A1-20100318-C00015
  • where:
    R1 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl;
    R2 is H, OH, protected hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, aryl, or heteroaryl;
    R3 is H, substituted or unsubstituted alkyl, carboxylic ester, or acyl; and
    R4′″ is SO2R5, wherein R5 is substituted or unsubstituted alkyl.
    Alternatively, the product compound can be reacted with similar arylsulfonyl reagents to produce arylsulfonate compounds.
  • In one embodiment, the above reaction is carried out with an alkylsulfonyl compound in an amount from about 1 to about 1.5 equivalents with respect to the product compound at atmospheric pressure at a temperature of from about −20° C. to about 100° C. depending on the reagent. When alkylsulfonyl chloride is used, for example, the reaction is typically carried out at a temperature of from about −10° C. to about 20° C.
  • The product compound can be a totally synthetic substance or a naturally derived substance.
  • In another embodiment, the process of the present invention further involves carrying out a method selected from chromatography, countercurrent extraction, and distillation on the second product compound under conditions effective to produce a purified second product compound. In another embodiment, the process of the present invention further involves crystallizing the second product compound under conditions effective to produce a purified second product compound.
  • The purified second product compound can be hydrolyzed under conditions effective to produce the purified product compound in a desired isomer form. In another embodiment of the present invention, the step of hydrolyzing is carried out in the presence of an organic or inorganic base in a solvent. Examples of base include, but are not limited to, sodium hydroxide, potassium t-butoxide, and mixtures thereof. Examples of solvent include, but are not limited to, methanol, ethanol, isopropanol, t-butanol, acetonitrile, and mixtures thereof.
  • In another embodiment of the present invention, R1=R3=H and R2 is H, OH, protected hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, aryl, or heteroaryl. In yet another embodiment of the present invention, R1=R3=H and R2 is n-C5H11.
  • In another embodiment of the present invention, the second product compound is of the formula:
  • Figure US20100069651A1-20100318-C00016
  • where:
    R8, R9, and R10 are the same or different and independently selected from the group consisting of H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or halo; and
    R8 and R9; R8 and R10; or R9 and R10; or R8, R9, and R10 can together result in the formation of a cyclic moiety.
  • “Alkyl” is defined herein as C1-Cn, wherein the carbon chains may be straight, branched, or containing or comprising rings. “Substituted alkyl” is defined as C1X-CnX as described above, except that the carbons may bear one or more substituents X, such as functional groups containing oxygen, nitrogen, sulfur, halogen or aromatic or heteroaromatic rings. “Aryl” is defined as C6-Cn aromatic rings or multiple rings. “Substituted aryl” is defined as C6-Cn aromatic rings or multiple rings bearing substituents on one or more of these rings which may be functional groups of carbon, oxygen, nitrogen, sulfur or halogen. “Heteroaryl” is defined as aromatic rings containing one or more heteroatom within the ring or rings. “Substituted heteroaryl” is defined as heteroaryl containing one or more substituents on one or more ring which may be functional groups of carbon, oxygen, nitrogen, sulfur or halogen. “Halo” is defined as chlorine, bromine, iodine or fluorine. Further, R8, R9, and R10 may contain chiral centers or define a chiral center on the carbon bearing them.
  • In another embodiment of the present invention, the second product compound is a straight chain alkylsulfonate selected from methanesulfonate, ethanesulfonate, propanesulfonate, butanesulfonate, pentanesulfonate, hexanesulfonate, heptanesulfonate, octanesulfonate, nonanesulfonate, decanesulfonate, undecanesulfonate, dodecanesulfonate, tridecanesulfonate, tetradecanesulfonate, pentadecanesulfonate, hexadecanesulfonate, heptadecanesulfonate, octadecanesulfonate, nonadecanesulfonate, and icosanesulfonate.
  • In another embodiment of the present invention, the second product compound is a branched chain alkylsulfonate selected from cyclopropylsulfonate, isopropylsulfonate, isobutylsulfonate, tert-octylsulfonate, adamantly sulfonate, and 10-camphorsulfonate.
  • In another embodiment of the present invention, the second product compound is a substituted alkylsulfonate selected from chloromethylsulfonate, 2-chloroethylsulfonate, trifluoromethylsulfonate, trifluorethylsulfonate, perfluoroethylsulfonate, perfluorobutylsulfonate, perfluorooctanesulfonate, 2-aminoethylsulfonate, 2-dimethylaminoethylsulfonate, 2-phthalimidoethylsulfonate, 2-morpholinoethylsulfonate, 3-morpholinopropylsulfonate, 4-morpholinobutylsulfonate, 2-N-piperidinylethylsulfonate, 3-N-piperidylpropylsulfonate, 2-pyrrolidinylmethylsulfonate, 2-methoxyethylsulfonate, (1R)-3-bromocamphor-8-sulfonate, (1S)-3-bromocamphor-8-sulfonate, (1S)-3-bromo-camphor-10-sulfonate, (1R)-10-camphorsulfonate, and (1S)-10-camphorsulfonate.
  • Specifically, the second product compound can have the following formula, where the camphorsulfonate group is in the S configuration:
  • Figure US20100069651A1-20100318-C00017
  • Alternatively, the second product compound can have the following formula, where the camphorsulfonate group is in the R configuration:
  • Figure US20100069651A1-20100318-C00018
  • In another embodiment of the present invention, the second product compound is a diastereomeric mixture of the following two formulae, where the camphorsulfonate group is in the S and R configurations, respectively:
  • Figure US20100069651A1-20100318-C00019
  • In another embodiment of the present invention, the second product compound is an aryl or heteroaryl substituted alkylsulfonate selected from benzylsulfonate, 2-nitrobenzylsulfonate, 3-nitrobenzylsulfonate, 4-nitrobenzylsulfonate, 2-chlorobenzylsulfonate, 3-chlorobenzylsulfonate, 4-chlorobenzylsulfonate, 2-trifluoromethybenzylsulfonate, 3-trifluoromethylbenzylsulfonate, 4-trifluoromethylbenzylsulfonate, 3,5-dichlorobenzylsulfonate, 3,5-di-trifluoromethylbenzylsulfonate, 4-methylbenzylsulfonate, 4-t-butylbenzylsulfonate, 1-napthylethylsulfonate, 2-pyridylmethylsulfonate, 3-pyridylmethylsulfonate, 4-pyridylmethylsulfonate, 2-(2-pyridyl)ethylsulfonate, and diphenylmethanesulfonate.
  • In another embodiment, the process of the present invention further involves reacting a second intermediate compound of the formula:
  • Figure US20100069651A1-20100318-C00020
  • where:
    R6 is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl;
    with a second compound of the formula:
  • Figure US20100069651A1-20100318-C00021
  • where X=H, alkyl, acyl, silyl, aryl, heteroaryl, sulfinyl, sulfonyl, phosphoryl, or phosphinyl, in the presence of a metal triflate catalyst, under conditions effective to form the first intermediate compound.
  • In one embodiment of the present invention, the step of reacting is carried out under conditions effective to achieve preferential formation of the first intermediate compound over undesired stereochemical and regiochemical isomers as well as other impurities.
  • In another embodiment of the present invention, R1 is H or COOR7, R2 is n-C5H11, and R3 is H or COOR7, where R7 is C1-C20 alkyl. In another embodiment of the present invention, R1 is COOR7, where R7 is ethyl, R2 is n-C5H11, and R3 is H or COOR7, where R7 is C1-C20 alkyl, R4=H, and X=H. In yet another embodiment of the present invention, R1=R3=R4=H, R2=n-C5H11, and X=H.
  • In another embodiment, the above reaction is carried out with the second intermediate compound in an amount of from about 1 to 1.2 equivalents with respect to the second compound.
  • The metal triflate catalyst can be a transition metal triflate or lanthanide triflate. Examples of transition metal triflate include, but are not limited to, zinc triflate, ytterbium triflate, yttrium triflate, and scandium triflate. Specifically, the transition metal triflate is zinc triflate or scandium triflate.
  • In another embodiment of the present invention, the step of reacting is carried out with the metal triflate catalyst in an amount from about 0.5 mol % to about 100 mol % with respect to the second intermediate compound. In yet another embodiment of the present invention, the step of reacting is carried out with the metal triflate catalyst in an amount from about 0.5 mol % to about 10 mol % with respect to the second intermediate compound.
  • In another embodiment of the present invention, the step of reacting is carried out in an organic solvent. Examples of organic solvent include, but are not limited to, a hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon, ether, ester, amide, nitrite, carbonate, alcohol, carbon dioxide, and mixtures thereof. Specifically, the organic solvent is dichloromethane.
  • In another embodiment of the present invention, the step of reacting is carried out at a temperature of from about −20° C. to about 150° C. Specifically, the step of reacting can be carried out under pressure at a temperature above the normal atmospheric boiling point of the organic solvent or where temperatures are above boiling point and pressure is above atmosphere.
  • In another embodiment of the present invention, the step of reacting is carried out with a less than about one equivalent of the second compound to the second intermediate compound.
  • EXAMPLES
  • The following examples are provided to illustrate embodiments of the present invention but are by no means intended to limit its scope.
  • Example 1 Preparation of Ethyl Cannabidiolate by Condensation of Ethyl Olivetolate with Menthadienol
  • Ethyl olivetolate (25 g, 99 mmol) was dissolved in dichloromethane (250 mL) and MgSO4 (25 g, 1 wt) and Sc(OTf)3 (4.88 g, 9.9 mmol, 10 mol %) were added sequentially. A solution of menthadienol (24.5 g, 161 mmol, 1.6 equiv, assuming purity of 100% but really approximately 80-85% AUC by GC) in dichloromethane (125 mL) was added over 1.5 h using a dropping funnel. The reaction was monitored by HPLC analysis and after approximately 3 h the reaction was filtered through celite, the solids washed with dichloromethane (125 mL), and the combined organics were evaporated under reduced pressure. The residue was dissolved in heptane and applied to 5 wt silica, then eluted with heptane (1×500 mL), 10% dichloromethane/heptane (6×500 mL), 15% dichloromethane/heptane (2×500 mL) and 20% dichloromethane/heptane (2×500 mL). Fractions containing ethyl cannabidiolate were combined and concentrated to give the product (31.3 g, 82% yield, with a purity of 93.3% AUC by HPLC).
  • Example 2 Preparation of Cannabidiol
  • The ethyl cannabidiolate from Example 1 (31.3 g, 81 mmol) was dissolved in MeOH (10 vol, 310 mL) and degassed with argon. Separately, a solution of NaOH (64.8 g, 1.62 mol, 20 equiv) in deionized water (10 vol, 310 mL) was prepared and degassed with argon. The organic solution was added to the aqueous solution under a strict argon atmosphere, then the mixture heated to reflux and held there for 3.5 h, then cooled to room temperature. HPLC analysis indicated completion of reaction. The reaction mixture was quenched with aqueous citric acid (129.6 g citric acid, 8.3 equiv, as a 30% solution in water). The addition was exothermic. Heptane (310 mL, 10 vol) was added to the mixture and the product extracted into the heptane phase. A second extraction using heptane (150 mL, ca. 5 vol) was then performed and HPLC analysis of the aqueous fractions indicated the absence of the cannabidiol. The combined organics were dried by azeotropic distillation of the water and concentrated to ca. 250 mL and then cooled to −16 to −17° C., and seeded with solid cannabidiol when the temperature reached −1.5° C. After 20 h, the resulting solids were filtered off, washed with cold heptane and dried on the filter, then under high vacuum. This ultimately gave 17.9 g cannabidiol (57.5% yield over two steps from ethyl olivetolate) with a purity of >99.8% AUC by HPLC.
  • Example 3 Preparation of trans-delta-9-THC
  • The cannabidiol from Example 2 (18.5 g, 58.8 mmol) was dissolved in dichloromethane (324 mL, 17.5 vol) and heated to 25° C. Triisobutylaluminum (5.9 mL of 1 M solution in hexane, 10 mol % catalyst) was then added via syringe and the reaction stirred at 20-25° C. for approx 20 h. After this time, HPLC analysis of the reaction mixture showed consumption of the cannabidiol and 94.8% trans-delta-9-THC. The reaction was quenched with water (1.6 mL, 15 equiv. based on moles of catalyst) and stirred for 1 h. After filtration through celite, the solvent was switched to toluene and the reaction mixture azeotroped to remove any remaining water. The solution of product in toluene (total volume ca. 92 mL) was used directly in the subsequent step.
  • Example 4 Preparation of trans-delta-9-THC 3-nitrobenzenesulfonate
  • The crude toluene solution of trans-delta-9-THC (assumed to be quantitative yield, 58.8 mmol) from Example 3 was treated with triethylamine (24.6 mL, 3 equiv) and then a solution of 3-nitrobenzenesulfonyl chloride (13.04 g, 1 equiv) in toluene (92.5 mL) was added to the reaction at room temperature over approximately 30 min. The addition funnel was washed with toluene (10 mL) which was added to the reaction. After 2 h, the starting material was consumed (by HPLC analysis) and the reaction was quenched with water (185 mL) and stirred for 20 min. The organic phase was collected and then washed with 10% citric acid (95 mL), saturated NaHCO3 solution (95 mL) and water (185 mL) then azeotropically dried. The solvent was replaced with isopropanol (147 mL, 5 vol based on 100% yield of sulfonate), seeded with crystalline trans-delta-9-THC 3-nitrobenzenesulfonate and stirred at room temperature for 24 h. The resulting solids were isolated by filtration to give 19.4 g trans-delta-9-THC 3-nitrobenzenesulfonate with an HPLC purity of 99.2% (AUC). A second crystallization from isopropanol (5 vol) was performed to give 16.7 g product with a purity of 99.6% AUC by HPLC. Yield from cannabidiol: 57.4%.
  • Example 5 Preparation of (−)-trans-delta-9-THC
  • Trans-delta-9-THC 3-nitrobenzenesulfonate (16.5 g) was dissolved in acetonitrile (330 mL, 20 vol) and 0.5 M NaOH (165 mL, 10 vol) was added. The mixture was heated to reflux and, after ca. 2 h, HPLC analysis indicated that the reaction was complete. After cooling, water (500 mL, 30 vol) was added followed by heptane (165 mL, 10 vol). The phases were mixed and the heptane layer was collected. The aqueous phase was extracted again with heptane (165 mL, 10 vol) and the organic extracts were combined, washed with water (165 mL, 10 vol), dried over Na2SO4, filtered, and concentrated to a dark brown-purple oil. The oil was reconstituted with EtOH and restripped to give the product as a light brown oil (10.79 g), containing ca. 6% EtOH by proton NMR analysis. HPLC analysis indicated a purity of 99.66% AUC.
  • Example 6 Preparation of Cannabidiol by Condensation of Olivetol with Menthadienol
  • A solution of olivetol (1 g, 5.56 mmol) in dichloromethane (15 mL) was treated with Zn(OTf)2 (10 mg, 0.5 mol %) and heated to 60° C. in a modified pressure tube equipped with a septum for additions. A solution of menthadienol (0.63 g, 0.75 equiv, 4.14 mmol) in dichloromethane (5 mL) was added via syringe over 5.5 h. HPLC analysis of the reaction after a total of 6 h showed a 2.6:1 ratio of cannabidiol to abn-cannabidiol (47.0%:17.9%) with 23.3% unreacted olivetol and 4.3% of a double addition product. Only trace levels of cyclized degradants (delta-8- and delta-9-THC) were observed, even after continuation of the heating for a total of 20 h.
  • Example 7 Preparation of (+)-Menthadienol
  • To a stirred mixture of potassium carbonate (2.98 kg) in ethanol (16.7 L) was added (+)-limonene oxide (25.0 kg) and the mixture heated to 60° C. Thiophenol (8.86 kg) was added over 11 hours at 70-80° C. Ethanol was distilled out at atmospheric pressure over the course of four hours until the pot temperature reached 105° C., the batch cooled to 80° C. then cold water (16 L) added. After cooling to 40° C., methyl t-butyl ether (MTBE, 16 L) was added. The organic phase was separated, washed with water (4.5 L), and the solvents removed under reduced pressure at 60° C. The residual oil (30.9 kg) was fed to a 4 inch, wiped-film evaporator at 3 mm and 145° C. to remove the unreacted limonene oxide. The non-volatile fraction (14.7 kg of thiophenyl ether) was dissolved in glacial acetic acid (26.0 L) and stirred while 35% hydrogen peroxide (6.0 kg) added over 6.5 hours. The reaction temperature was maintained at 10-20° C. The reaction was allowed to warm to room temperature overnight, then transferred into a mixture of warm water (89 L, 40-45° C.) and MTBE (34 L). The organic phase was washed aqueous 5% sodium bicarbonate (4 washes, 18 L each) at 40-45° C., to achieve a final pH of ca. 8 and a negative starch-iodine test. The organic phase was concentrated under reduced pressure at 60° C. to obtain a residue of crude sulfoxide mixture (14.8 kg, estimated 95% yield). This residual was dissolved in tetraglyme (11.6 L) and stored until needed, during this time the product partially crystallized. The solution was gently warmed to redissolve the sulfoxide mixture. To a portion of this tetraglyme solution (containing ca. 8.3 kg of sulfoxide mixture) was added potassium carbonate (2.7 kg) and tetraglyme (5 L) and the stirred mixture was heated to 180° C. with application of vacuum (75-80 mm), distilling the volatiles over the course of nine hours. The strong smelling distillate (ca. 2.8 kg) was dissolved in heptane (2.5 L) and washed with water (4.5 L+1 L), then concentrated under reduced pressure at 60° C. to crude (+)-menthadienol (1.76 kg) of approximately 83% purity by GC. Several batches of crude (+)-menthadienol (totaling ca. 6.68 kg) were combined with hexadecane (1.00 kg) and solid potassium carbonate (67 grams) in a stirred round bottom flask fitted with a 5 plate 2 inch diameter Oldershaw column fitted with a reflux return splitter. Distillation was effected at pot temperature of ca. 105-110° C. with vacuum of ca. 1-5 mm. After the initial low boiling fractions were removed (bp: 45-75° C.), main fractions of boiling point: 75-80° C. were collected totaling 4.0 kg of (+)-menthadienol (assayed at 95-98% by gas chromatography (AUC)). Optical rotation of a sample prepared by this procedure was +75.4° (c=1.074 in chloroform at 25° C.). The literature value is +67.9° at 20° C. (Ohloff et al., Helvetica Chimica Acta, 63:76 (1980), which is hereby incorporated by reference in its entirety).
  • Example 8 Representative Lab Procedures for Ethyl Olivetolate Preparation of Sodium Ethyl Dihydroolivetolate
  • To a stirred mixture of anhydrous ethanol (10.5 L) and diethylmalonate (1.90 kg) at 20° C. was added, over 35 minutes, a sodium ethoxide solution (21% in ethanol, 4.2 L). The reaction temperature was allowed to rise to 27° C. To the resulting slurry was added 3-nonene-2-one (1.50 kg), over the course of three hours, allowing the temperature to rise to 45-50° C. The reaction mixture heated to 70° C. over two hours and held for an additional two hours. The reaction mixture was then cooled to 0° C. and held overnight. The solid product was then collected by filtration through a polypropylene filter. The solid cake was rinsed with MTBE (5.0 L) then dried under reduced pressure at 20-25° C. to constant weight affording 2.38 kg (99% yield) of sodium ethyl dihydroolivetolate as an off-white solid. 1H NMR 500 MHz (DMSO-d6) δ 0.85 (t, 3H), 1.1-1.5 (m, 11H), 1.7 (dd, 1H), 2.05, dd, 1H), 2.4 (m, 1H), 2.7 (d, 1H), 4.05 (q, 2H) and 4.4 ppm (s, 1H). HPLC analysis showed 100% product (Phenomenex (Houston, Tex.) HyperClone 5 u BDS C18 column, 4.6×150 mm, 1 mL/min, gradient 100% water/0.1% TFA to 100% acetonitrile/0.1% TFA over 15 minutes, rt=8.0 min).
  • Preparation of Ethyl Dibromoolivetolate
  • To a stirred suspension of sodium ethyl dihydroolivetolate (200.8 g, 0.727 mol) and anhydrous sodium acetate (238.5 g, 2.91 mol) in acetic acid (1010 mL) at 50° C. was dropwise added bromine (655.5 g, 2.29 mol) over the course of three hours while maintaining the batch temperature at 50-55° C. After stirring an additional hour at 50-55° C., the slurry was cooled over three hours to 20° C. Water (925 mL) was added over 1 h during which the product crystallized. The slurry was cooled to 10° C., held overnight, and then filtered through filter paper. The solid cake was washed with water (3×400 mL, to achieve a final rinse pH of 4) and then air dried overnight to obtain 310 g (86% yield) of crude ethyl dibromoolivetolate, containing ca. 11.7% by weight of water. 1H NMR, 500 MHz (CDCl3) δ 0.9 (t, 3H), 1.4 (m, 8H), 1.6 (t, 3H), 3.1 (m, 2H), 4.4 (m, 2H), 6.4 (s, 1H) and 12.3 ppm s, 1H). HPLC analysis showed 98.5% product (AUC, Sunfire reversed phase C18 column from Waters Corporation (Milford, Mass.), 4.6×150 mm, 1 mL/min, gradient 80% 0.1% TFA in water with 20% 0.5% TFA in acetonitrile to 100% of 0.5% TFA in acetonitrile over 15 minutes, rt=13.8 min).
  • Preparation of Ethyl Olivetolate
  • A 2 L Parr reactor charged with ethyl dibromoolivetolate (160.3 g of water wet material, 0.345 mol), ethanol (290 mL), water (440 mL), sodium citrate (220 g, 0.747 mol) and 5% palladium-on-charcoal catalyst (7.4 g) was degassed with nitrogen and then pressurized to 50 psig with hydrogen gas. The stirrer was started and the reaction mixture was heated to 60° C. and maintained at that pressure and temperature for six hours after which the heat was turned off. After cooling to ambient temperature, the mixture was filtered through celite (100 g) and the reactor and solid filter cake was rinsed with water (600 mL), then toluene (300 mL). The layers were separated and the organic phase was evaporated under reduced pressure to a semisolid residue. Heptane (260 mL) was added and the mixture was warmed to 45° C. at which point the solids dissolved. The stirred mixture was allowed to cool slowly to ambient temperature overnight, during which crystallization occurred. The slurry was cooled to 5° C., held 4 hours, and the solid product was collected by filtration. The filter cake was rinsed with cold heptane (150 mL) then dried to a constant weight under reduced pressure at 20° C. to afford 63.0 g (72% yield) of yellow crystals of ethyl olivetolate. HPLC analysis indicated that the product was 99.6% pure (AUC, Sunfire reversed phase C18 column, 4.6×150 mm, 1 mL/min flow rate, gradient 80% 0.1% TFA in water with 20% 0.5% TFA in acetonitrile to 100% of 0.5% TFA in acetonitrile over 15 minutes, rt=10.3 min). This product was identified by melting point (mp: 66-67° C., literature: 68° C., Anker et al., J. Chem. Soc. pp. 311 (1945)) and NMR analysis. 1H NMR, 500 MHz (CDCl3) δ 0.9 (t, 3H), 1.4 (m, 8H), 1.6 (t, 3H), 2.8 (m, 2H), 4.4 (m, 2H), 5.4 (br s, 1H), 6.2 (s, 1H), 6.3 (s, 1H) and 11.8 ppm (s, 1H).
  • Example 9 Preparation of Ethyl Cannabidiolate
  • To a stirred solution of ethyl olivetolate (40.1 g, 155 mmol) in dichloromethane (360 mL) was added anhydrous magnesium sulfate (10.4 g) and scandium triflate (3.93 g, 8 mmol). The mixture was cooled to 10° C. To this slurry was added a cold solution of (+)-menthadienol (25.1 g, 155 mmol) in dichloromethane (160 mL) over three minutes, followed by a dichloromethane rinse (120 mL). A slight exotherm was observed. After stirring at 10° C. for three hours, HPLC analysis showed the reaction was complete by no further decrease in the olivetolate ester concentration. The reaction was quenched by addition of solid anhydrous sodium carbonate (4.0 g) and stirred overnight at 25° C. The reaction mixture was clarified by filtration through a bed of celite and the flask and filter cake was washed with dichloromethane (250 mL). The combined filtrates were concentrated under reduced pressure to about 150 mL of volume. Heptane (400 mL) was added and the mixture was again concentrated under reduced pressure to about 150 mL. Heptane (400 mL) was added and the mixture extracted with aqueous sodium hydroxide solution (2×200 mL of a 20% aqueous solution) followed by water (2×200 mL). HPLC analysis showed the organic phase to be free of any residual ethyl olivetolate. The heptane phase was concentrated under reduced pressure to 58.6 g (87% yield after correcting for the HPLC purity of 90%) of a dark colored oil, primarily ethyl cannabidiolate as determined by HPLC analysis. This crude material is used directly in the next step described in Example 9.
  • Example 10 Preparation of Cannabidiol
  • Crude ethyl cannabidiolate (58.6 g, ca. 90% pure by HPLC) was dissolved in methanol (390 mL) and the stirred solution was degassed by refluxing under nitrogen for 1 hour. Aqueous sodium hydroxide solution (80.8 g of NaOH in 390 mL of water) was degassed by refluxing under nitrogen for one hour. The hydroxide solution was transferred under nitrogen pressure, through a steel cannula to the hot ethyl cannabidiolate/methanol solution over 20 minutes while maintaining the reaction at 70° C. After five hours at 70-80° C., the hydrolysis was found complete by HPLC analysis and the reaction cooled to 20° C. The reaction was quenched by addition of a degassed aqueous solution of citric acid (50 wt % solution, 400 g). The mixture was extracted with heptane (400 mL) and the organic layer was washed with aqueous sodium bicarbonate solution (300 mL) and water (300 mL). The heptane solution was concentrated under reduced pressure to ca. 100 mL, reconstituted with heptane (400 mL), concentrated again to ca. 50 mL and heptane (200 mL) was added. The slowly stirred heptane solution was cooled to 10° C., seeded with cannabidiol crystals and stirred slowly at 10° C. for three hours to develop a crop of crystals. The slurry was stored overnight at −5° C. The solid product was collected by filtration on cold sintered glass and the reactor and cake rinsed with cold heptane (150 mL). The solids were dried under nitrogen stream for two hours then under reduced pressure at 20° C. for 15 hours to afford 21 g (44% yield) of solid cannabidiol. HPLC analysis showed 99.6% (AUC) product (Sunfire C18 5 u column, 4.6 mm×150 mm, 1 ml/min flow rate, gradient 80% of 0.1% TFA/water and 20% 0.05% TFA/acetonitrile to 100% 0.05% TFA/acetonitrile over 15 minutes, rt=11.9 min).
  • Example 11 Preparation of Crude Delta-9-Tetrahydrocannabinol
  • To a nitrogen inerted, stirred solution of cannabidiol (21.2 g, 67.1 mmol) in dichloromethane (370 mL) was added, by syringe pump, commercial tri-isobutylaluminum solution (1 Min hexanes, 6.7 mL, 10 mol %) over 4.5 hours. The temperature of the reaction mixture was maintained at 20-25° C. and the mixture was stirred overnight. Additional charges of triisobutylaluminum solution (1 M in hexanes, 2.67 mL added, 4 mol %) were made over the next day to drive the reaction to >99% conversion by HPLC analysis. The reaction was quenched by addition of water (250 mL), stirred 30 minutes, combined with a slurry of celite in dichloromethane (10.0 g in 70 mL dichloromethane) and then clarified. The reactor and filter cake were rinsed with dichloromethane (50 mL) and the combined filtrates distilled under reduced pressure (25° C. pot temperature, 22 inches of vacuum) to about 50 mL volume. Toluene (106 mL) was added and the solvents again removed under reduced pressure. More toluene (106 mL) was added and removed under reduced pressure and then the dichloromethane-free residue was reconstituted in toluene (100 mL). HPLC analysis showed 95.6% delta-9-tetrahydrocannabinol, 1.1% cis-tetrahydrocannabinol, and no cannabinol. (Sunfire C18 5 u, 4.6 mm×150 mm, 1 ml/min, gradient 80% 0.1% TFA/water and 20% 0.05% TFA/acetonitrile to 100% 0.05% TFA/acetonitrile over 15 minutes, delta-9 tetrahydrocannabinol: rt=15.1 min). The yield was estimated at 95%. The solution was stored under nitrogen until needed for preparation of the camphorsulfonate derivative.
  • Example 12 Preparation of Delta-9-Tetrahydrocannabinol (1S)-10-camphorsulfonate
  • To a solution of crude delta-9-tetrahydrocannabinol in toluene (containing 21.1 g of delta-9-tetrahydrocannabinol, 67.1 mmol on 100 mL of toluene) was added a solution of 4-dimethylaminopyridine (0.83 g) and diisopropylethylamine (35.2 mL, 3 equiv) in toluene (106 mL). The stirred reaction mixture was cooled to 0° C. and a slurry of (1S)-10-camphorsulfonyl chloride (19.8 g, 74.8 mmol, 1.1 equiv.) in toluene (150 mL) at 0° C. was added over 30 minutes. The addition funnel rinsed with toluene (50 mL) and this rinse was added to the stirred reaction mixture, and the mixture held overnight at 0° C. Additional (1S)-10-camphorsulfonyl chloride (total of 10.75 g in toluene (55 mL)) was added over six hours to achieve 99% conversion. Water (200 mL) was added over 15 minutes and the mixture stirred overnight. The organic phase was washed with 5% aqueous citric acid solution (100 mL), 5% aqueous sodium bicarbonate solution (100 mL) and 5% aqueous sodium chloride solution (100 mL). The toluene layer was concentrated under reduced pressure to about 100 mL and additional toluene (100 mL) was added. This drying sequence was repeated and then the solvent was replaced with isopropanol (200 mL). The isopropanol was concentrated under reduced pressure and the residue was suspended in isopropanol (200 mL). The slurry was warmed to 40° C. at which point the solids dissolved. The stirred solution was cooled to 20° C. over 4 hours during which the product crystallized. After stirring for 2 h at 15-20° C., the product was collected by filtration, rinsed with cold isopropanol (90 mL), and the solid crystalline product was dried under reduced pressure at 50° C. overnight to afford 19.67 g (56% yield) of delta-9-tetrahydrocannabinol (1S)-10-camphorsulfonate. HPLC analysis showed 98.5% delta-9-tetrahydrocannabinol (1S)-10-camphorsulfonate, 0.86% delta-8-tetrahydrocannabinol (1S)-10-camphorsulfonate, and 0.35% cis-tetrahydrocannabinol (1S)-10-camphorsulfonate. mp 94-95° C. 1H NMR 500 MHz (CDCl3) δ 0.9 (s, 3H), 1.1 (s, 3H), 1.2 (s, 3H), 1.35 (m, 4H), 1.4-1.5 (m, 5H), 1.45-1.55 (m, 5H), 1.95 (s, 1H), 2.0 (s, 1H), 2.05-2.2 (m, 4H), 2.40 and 2.45 (d of t, 1H), 2.45-2.60 (m, 3H), 3.25 (d, 1H), 3.42 (d, 1H), 3.88 (d, 1H), 6.17 (s, 1H), 6.6 (s, 1H) and 6.68 ppm (s, 1H).
  • Example 13 Purified Delta-9-Tetrahydrocannabinol
  • To a mechanically stirred slurry of crystalline purified delta-9-tetrahydrocannabinol (1S)-10-camphorsulfonate (1.1 g, 2.1 mmol) in water (3.6 mL) and t-butanol (7.4 mL) under argon, was added a mixture of sodium hydroxide (0.83 g, 21 mmol) in water (7.4 mL) and t-butanol (15 mL). The slurry was heated to 70° C. over 2 h, at which point the HPLC analysis showed the hydrolysis to be complete. The reaction mixture was cooled to ambient temperature and diluted with water (11 mL) and extracted with heptane (11 mL). The heptane solution was washed with water (2×6 mL). The heptane solution was concentrated under reduced pressure and the residue was dissolved in ethanol (5 mL). The ethanol solution was filtered through a 0.45 micron filter. HPLC analysis showed 99.2% delta-9-tetrahydrocannabinol and 0.49% cis-delta-9-tetrahydrocannabinol. (Agilent Technologies (Wilmington, Del.) Hypersil Gold, 4.6 mm×150 mm, isocratic MeOH/H2O/THF (71:24:5) mixture at 1 mL/min flow rate, 228 nm, delta-9-tetrahydrocannabinol rt=18.9 min, cis-delta-9-tetrahydrocannabinol rt=17.7 min). This solution was stored under an argon atmosphere and in the freezer until it was carried into the next step.
  • Example 14 Preparation of Delta-9-Tetrahydrocannabinol in Sesame Oil
  • A stock solution of delta-9 THC in ethanol (6.90 g of 0.109 mg/mL tetrahydrocannabinol concentration) was mixed with Croda high purity sesame oil (29.25 g) from Croda, Inc. (Edison, N.J.). The resulting solution was warmed to 30° C., and sparged with filtered argon for 24 hours to afford ca. 30 g of 2.5% delta-9-tetrahydrocannabinol in sesame oil. 1H NMR 500 MHz (CDCl3) showed no residual ethanol.
  • Example 15 Preparation of Crude Delta-9-Tetrahydrocannabinol
  • To a solution of cannabidiol (500 mg) in dichloromethane (8.75 mL) at 20° C., was added a solution of an organoaluminum-based Lewis acid catalyst in dichloromethane (1.0 mL) over five minutes and the reaction mixtures stirred under nitrogen and monitored by HPLC. Table 1 below shows the relative HPLC quantitation of the different product compounds in area percent at the time specified, using different organoaluminum-based Lewis acid catalysts.
  • TABLE 1
    Relative HPLC Quantitation of Product Compounds
    (in area percent)
    Organoaluminum-based Lewis Acid Catalyst Reaction Time Cannabidiol cis-THC 9-THC 8-THC iso-THC
    20 mol % triisobutylaluminum 21 h 9.8 1.8 87.6 0.3 0.5
    20 mol % isobutylaluminum-bis-(2,6- 22 h 3.3 3.4 91.5 0.5 0.7
    di-t-butyl-4-methylphenoxide)
    20 mol % diisobutylaluminum thiophenoxide 69 h 3.5 3.7 89.6 1.2 1
    20 mol % diisobutylaluminum benzoate 22 h 6.3 2.7 92.5 0.5 0.7
    20 mol % diisobutylaluminum acetate 22 h 5.1 2.6 91.3 0.4 0.6
    20 mol % aluminum tri-t-butoxide 22 h 70.5 0.3 29 0.0 0.1
  • Although the invention has been described in detail, for the purpose of illustration, it is understood that such detail is for that purpose and variations can be made therein by those skilled in the art without departing from the spirit and scope of the invention which is defined by the following claims.

Claims (5)

1. A process for preparation of a product compound of the formula:
Figure US20100069651A1-20100318-C00022
wherein X=H, alkyl, acyl, silyl, aryl, heteroaryl, sulfinyl, sulfonyl, phosphoryl, or phosphinyl;
said process comprising:
treating a first intermediate compound of the formula:
Figure US20100069651A1-20100318-C00023
with a carbonate base under conditions effective to produce the product compound.
2. The process according to claim 1, wherein the carbonate base is K2CO3.
3. The process according to claim 1, wherein X is hydrogen.
4. The process according to claim 1 further comprising:
reacting a starting material compound of the formula:
Figure US20100069651A1-20100318-C00024
 under conditions effective to form a second intermediate compound of the formula:
Figure US20100069651A1-20100318-C00025
and,
reacting the second intermediate compound under conditions effective to form the first intermediate compound.
5. The process according to claim 4, wherein the conditions effective to form the second intermediate compound include reacting the starting material compound with thiophenol.
US12/626,403 2005-09-29 2009-11-25 Process for production of delta-9-tetrahydrocannabinol Abandoned US20100069651A1 (en)

Priority Applications (2)

Application Number Priority Date Filing Date Title
US12/626,403 US20100069651A1 (en) 2005-09-29 2009-11-25 Process for production of delta-9-tetrahydrocannabinol
US13/108,651 US8106244B2 (en) 2005-09-29 2011-05-16 Process for production of delta-9-tetrahydrocannabinol

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
US72203105P 2005-09-29 2005-09-29
US11/529,147 US7674922B2 (en) 2005-09-29 2006-09-28 Process for production of delta-9-tetrahydrocannabinol
US12/626,403 US20100069651A1 (en) 2005-09-29 2009-11-25 Process for production of delta-9-tetrahydrocannabinol

Related Parent Applications (1)

Application Number Title Priority Date Filing Date
US11/529,147 Division US7674922B2 (en) 2005-09-29 2006-09-28 Process for production of delta-9-tetrahydrocannabinol

Related Child Applications (1)

Application Number Title Priority Date Filing Date
US13/108,651 Continuation US8106244B2 (en) 2005-09-29 2011-05-16 Process for production of delta-9-tetrahydrocannabinol

Publications (1)

Publication Number Publication Date
US20100069651A1 true US20100069651A1 (en) 2010-03-18

Family

ID=37906689

Family Applications (3)

Application Number Title Priority Date Filing Date
US11/529,147 Expired - Fee Related US7674922B2 (en) 2005-09-29 2006-09-28 Process for production of delta-9-tetrahydrocannabinol
US12/626,403 Abandoned US20100069651A1 (en) 2005-09-29 2009-11-25 Process for production of delta-9-tetrahydrocannabinol
US13/108,651 Active US8106244B2 (en) 2005-09-29 2011-05-16 Process for production of delta-9-tetrahydrocannabinol

Family Applications Before (1)

Application Number Title Priority Date Filing Date
US11/529,147 Expired - Fee Related US7674922B2 (en) 2005-09-29 2006-09-28 Process for production of delta-9-tetrahydrocannabinol

Family Applications After (1)

Application Number Title Priority Date Filing Date
US13/108,651 Active US8106244B2 (en) 2005-09-29 2011-05-16 Process for production of delta-9-tetrahydrocannabinol

Country Status (11)

Country Link
US (3) US7674922B2 (en)
EP (3) EP2578561A1 (en)
JP (1) JP2009510078A (en)
KR (1) KR20080063800A (en)
CN (2) CN102766128A (en)
AU (1) AU2006297300B2 (en)
CA (1) CA2623723A1 (en)
IL (1) IL190388A0 (en)
NZ (3) NZ567029A (en)
WO (1) WO2007041167A2 (en)
ZA (1) ZA200802767B (en)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109734554A (en) * 2019-02-25 2019-05-10 江苏暨明医药科技有限公司 A kind of synthesis technology of trans--menthyl -2,8- diene -1- alcohol
US12029718B2 (en) 2021-11-09 2024-07-09 Cct Sciences, Llc Process for production of essentially pure delta-9-tetrahydrocannabinol

Families Citing this family (72)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8039509B2 (en) * 2006-11-10 2011-10-18 Johnson Matthey Public Limited Company Composition comprising (−)-Δ9-trans-tetrahydrocannabinol
US8980940B2 (en) 2006-11-10 2015-03-17 Johnson Matthey Public Limited Company Stable cannabinoid compositions and methods for making and storing them
GB0702895D0 (en) * 2007-02-14 2007-03-28 Resolution Chemicals Ltd Delta 9 tetrahydrocannabinol derivatives
GB0703284D0 (en) 2007-02-20 2007-03-28 Resolution Chemicals Ltd Delta 9 - tetrahydrocannabinol processing
JP5551604B2 (en) 2007-11-30 2014-07-16 オールトランツ インコーポレイティド Tetrahydrocannabinol prodrug, composition comprising tetrahydrocannabinol prodrug, and method of using the same
WO2009099868A1 (en) * 2008-02-06 2009-08-13 Mallinckrodt Inc. Process for the preparation of (-) -delta 9-tetrahydrocannabinol
GB0807915D0 (en) * 2008-05-01 2008-06-04 Resolution Chemicals Ltd Production of delta 9 tetrahydrocannabinol
US8445034B1 (en) 2010-11-02 2013-05-21 Albert L Coles, Jr. Systems and methods for producing organic cannabis tincture
ES2547354T3 (en) * 2013-09-03 2015-10-05 Symrise Ag Mixtures of cannabinoid compounds, their preparation and use
US9380813B2 (en) 2014-02-11 2016-07-05 Timothy McCullough Drug delivery system and method
US9220294B2 (en) 2014-02-11 2015-12-29 Timothy McCullough Methods and devices using cannabis vapors
US10821240B2 (en) 2014-02-11 2020-11-03 Vapor Cartridge Technology Llc Methods and drug delivery devices using cannabis
US10045540B2 (en) 2014-04-01 2018-08-14 Fayetteville State University Pest control composition
JP6659933B2 (en) * 2014-05-29 2020-03-04 フレッシュ・カット・ディベロップメント・エル・エル・シー Stable cannabinoid preparation
GB2530001B (en) 2014-06-17 2019-01-16 Gw Pharma Ltd Use of cannabidiol in the reduction of convulsive seizure frequency in treatment-resistant epilepsy
GB2531281A (en) 2014-10-14 2016-04-20 Gw Pharma Ltd Use of cannabidiol in the treatment of intractable epilepsy
EP3253727A4 (en) * 2015-02-05 2018-08-08 Colorado Can LLC Purified cbd and cbda, and methods, compositions and products employing cbd or cbda
EP3061450A1 (en) 2015-02-26 2016-08-31 Symrise AG Mixtures of cannabinoid compounds, their preparation and use
US10059683B2 (en) 2015-07-10 2018-08-28 Noramco, Inc. Process for the production of cannabidiol and delta-9-tetrahydrocannabinol
EP3455213B1 (en) * 2016-05-13 2021-11-24 Symrise AG Method for purifying cannabinoid compounds via simulated moving bed chromatography
US10399920B2 (en) 2016-06-01 2019-09-03 S&B Pharma, Inc. Crystalline form of cannabidiol
US10239808B1 (en) 2016-12-07 2019-03-26 Canopy Holdings, LLC Cannabis extracts
CN106632214B (en) * 2016-12-28 2019-01-25 西北大学 A kind of synthetic method of cannabinol compounds
US10702495B2 (en) 2017-02-20 2020-07-07 Nexien Biopharma, Inc. Method and compositions for treating dystrophies and myotonia
AU2018287018B2 (en) 2017-06-20 2022-04-28 University Of Guelph Cannabidiolic acid esters compositions and uses thereof
US10640482B2 (en) 2017-07-21 2020-05-05 University Of South Florida Synthesis of cannabinoids
US10272360B2 (en) 2017-08-05 2019-04-30 Priya Naturals, Inc. Phytochemical extraction system and methods to extract phytochemicals from plants including plants of the family Cannabaceae sensu stricto
CA3107566A1 (en) 2017-08-07 2019-02-14 Enantia, S.L. A cocrystal of 2-[(1r,6r)-6-isopropenyl-3-methylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol
CN111183135A (en) * 2017-08-16 2020-05-19 悉尼大学 Synthesis of phytocannabinoids comprising a decarboxylation step
EP3676238A1 (en) * 2017-09-01 2020-07-08 Pureform Global, Inc. Synthetic cannabidiol compositions and methods of making the same
US11202771B2 (en) 2018-01-31 2021-12-21 Treehouse Biotech, Inc. Hemp powder
US11851415B2 (en) 2018-03-07 2023-12-26 Cleen Technology Inc. Continuous isolation of cannabidiol and cannabinoids and conversion of cannabidiol to delta 8-tetrahydrocannabinol and delta 9-tetrahydrocannabinol
US11192870B2 (en) 2018-03-07 2021-12-07 Socati Technologies—Oregon, Llc Continuous isolation of cannabidiol and conversion of cannabidiol to delta 8-tetrahydrocannabinol and delta 9-tetrahydrocannabinol
EP3539637A1 (en) * 2018-03-13 2019-09-18 CLS Labs, Inc. Cannabidiol extraction and conversion process
CA3073093A1 (en) 2018-08-03 2020-02-06 Biomass Oil Separation Solutions, Llc Processes and apparatus for extraction of substances and enriched extracts from plant material
WO2020031179A1 (en) 2018-08-06 2020-02-13 Beetlebung Pharma Ltd. Methods for synthesis of cannabinoid compounds
US10822320B2 (en) * 2018-08-10 2020-11-03 Natural Extraction Systems, LLC Methods to purify cannabinoids
AU2019335372A1 (en) 2018-09-05 2021-05-06 Purisys Llc Cannabidiol compositions having modified cannabinoid profiles
CA3119729A1 (en) 2018-10-10 2020-04-16 Treehouse Biotech, Inc. Synthesis of cannabigerol
WO2020089424A1 (en) 2018-10-31 2020-05-07 Enantia, S.L. Solid compositions of cocrystals of cannabinoids
CA3135650A1 (en) * 2019-04-05 2020-10-08 Rapid Dose Therapeutics Corp. Apparatus for and method of converting cbd and/or cbd derivatives to at least one other type of cannabinoid and/or cannabinoid derivative such as thc
US11370767B2 (en) 2019-04-23 2022-06-28 Soma Oil Llc Cannabis processing systems and methods
US10569189B1 (en) * 2019-05-17 2020-02-25 NextLeaf Solutions Ltd. Method for acetylation of cannabinoids
CN111943813B (en) * 2019-05-17 2023-04-14 上海特化医药科技有限公司 Preparation method of cannabidiol compound
BR112021023512A2 (en) * 2019-05-23 2022-02-01 Kare Chemical Tech Inc Catalytic cannabinoid precursors and processes
WO2020248061A1 (en) * 2019-06-11 2020-12-17 Canopy Growth Corporation Improved methods for converting cannabidiol into delta9-tetrahydrocannabinol under neat or aprotic reaction conditions
CA3142957A1 (en) * 2019-06-11 2020-12-17 Canopy Growth Corporation Improved methods for converting cannabidiol into delta8-tetrahydrocannabinol
WO2020248060A1 (en) * 2019-06-11 2020-12-17 Canopy Growth Corporation Improved methods for converting cannabidiol into delta9-tetrahydrocannabinol under protic reaction conditions
EP3750528A1 (en) 2019-06-11 2020-12-16 Nexien Biopharma, Inc. Compositions for treating dystrophies and myotonia
WO2021012044A1 (en) 2019-07-22 2021-01-28 Canopy Growth Corporation Continuous crystallization of cannabinoids in a stirred-tank reactor
US10799546B1 (en) 2019-07-26 2020-10-13 Biomass Oil Separation Solutions, Llc Modular, integrated process and apparatus for extracting, refining and remediating active substances from plant material
US10954209B1 (en) * 2019-09-15 2021-03-23 NextLeaf Solutions Ltd. Acetylation of cannabinoids using sulfuric acid catalyst
MX2022003189A (en) 2019-09-16 2022-06-08 Vapor Cartridge Tech Llc Drug delivery system with stackable substrates.
US11542243B1 (en) * 2019-09-26 2023-01-03 FusionFarms, LLC Method of converting delta9-THC to delta10-THC and the purification of the delta10-THC by crystallization
EP4069215A4 (en) 2019-12-06 2024-01-17 Jlabs Beauty LLC Topical compositions containing rose oil and cannabidiol and methods of making and using the same
US20230002425A1 (en) * 2020-01-08 2023-01-05 Chengdu Baiyu Pharmaceutical Co., Ltd. Cannabidiol derivatives, preparation method thereof and use thereof
EP4089081A4 (en) * 2020-01-08 2024-02-21 Chengdu Baiyu Pharmaceutical Co., Ltd. Tetrahydrocannabinol derivative, and preparation method therefor and medical use thereof
US11767306B2 (en) * 2020-01-17 2023-09-26 Cannacraft, Inc Methods for converting CBD to tetrahydrocannabinols
US10981849B1 (en) * 2020-02-20 2021-04-20 Sci Pharmtech Inc. Method for preparing cannabinoids
EP3868736B1 (en) 2020-02-21 2022-11-30 SCI Pharmtech Inc Solvent-free method for preparing cannabinoids
GB202002754D0 (en) 2020-02-27 2020-04-15 Gw Res Ltd Methods of treating tuberous sclerosis complex with cannabidiol and everolimus
AU2021235467A1 (en) 2020-03-12 2021-10-07 Council Of Scientific And Industrial Research Process for the synthesis of cannabidiol and intermediates thereof
US11786838B2 (en) 2020-03-23 2023-10-17 Cannacraft, Inc. Methods for removing pesticides from Cannabis products
CN116194431A (en) 2020-03-31 2023-05-30 植物疗法有限公司 Terpene phenol compound and application thereof
EP4153306A4 (en) 2020-05-22 2024-06-26 Ilera Derm LLC Compositions for treating acne and dermatological conditions
CN113896616A (en) * 2020-07-06 2022-01-07 复旦大学 Preparation method of cannabidiol
CN112094257B (en) * 2020-08-19 2023-08-22 公安部禁毒情报技术中心 Preparation method of delta-9 tetrahydrocannabinol
CN114644547A (en) * 2020-12-21 2022-06-21 云南汉盟制药有限公司 Preparation method of cannabidiol and/or hypocannabidiol
CN115504864A (en) * 2021-06-07 2022-12-23 南通新世元生物科技有限公司 Method for obtaining high-purity cannabidiol from industrial cannabis sativa
CN113979836B (en) * 2021-10-13 2023-05-30 上海应用技术大学 Preparation method of 4-isopropenyl-1-methyl-2-cyclohexene-1-ol
WO2024028516A1 (en) 2022-08-05 2024-02-08 Salud & Semillas, S.L. CANNABINOID SYNTHESIS STARTING OUT FROM OLIVETOL AND TERPENE IN DICHLOROMETHANE WITH FeCl3 * 6H2O AS CATALYST
CN115583933B (en) * 2022-10-31 2024-02-06 暨明医药科技(苏州)有限公司 Preparation method of high-purity tetrahydrocannabinoid homolog

Citations (62)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2304669A (en) * 1940-08-16 1942-12-08 Adams Roger Isolation of cannabidiol
US2419935A (en) * 1941-07-09 1947-05-06 Adams Roger Marihuana active compounds
US2419936A (en) * 1942-04-29 1947-05-06 Adams Roger Preparation of compounds with marihuana activity
US2419934A (en) * 1941-07-09 1947-05-06 Adams Roger Optically active tetrahydrodibenzopyrans having marihuana activity and process for making same
US2509387A (en) * 1950-05-30 Dibenzopyran marihuana-like
US3507885A (en) * 1966-03-25 1970-04-21 Hoffmann La Roche 3-alkyl-6h-dibenzo(b,d)pyrans
US3562312A (en) * 1966-11-04 1971-02-09 Albert Eschenmoser Manufacture of 2-substituted resorcinol derivatives
US3636058A (en) * 1966-03-25 1972-01-18 Hoffmann La Roche 7 10 - dihydro - 3 - alkyl - 6h - dibenzo(b d) pyran-6 9(8h)-diones and 5-hydroxy-7-alkyl-4-chromanones
US3734930A (en) * 1971-09-22 1973-05-22 R Razdan Direct synthesis of ({31 )-trans-{66 {11 tetrahydrocannabinol from olivetol and ({30 )-trans-{66 {11 -carene oxide
US3833616A (en) * 1968-09-16 1974-09-03 T Petrzilka 6a,10a-trans-6a,7,8,10a-tetrahydrodibenzo(b,d)-pyrans
US3919322A (en) * 1969-01-22 1975-11-11 Hoffmann La Roche 3-Substituted -5-alkyl-2-cyclohexen-1-ones
US3920705A (en) * 1967-05-19 1975-11-18 Theodore Petrzilka 6a,10a-trans-6a,10,10a-tetrahydrodibenzo(b,d)-pyrans
US4025516A (en) * 1975-06-23 1977-05-24 The John C. Sheehan Institute For Research, Inc. Process for the preparation of (-)-6a,10a-trans-6a,7,8,10a-tetrahydrodibenzo[b,d]-pyrans
US4054582A (en) * 1976-07-06 1977-10-18 Eli Lilly And Company Process for converting cis-hexahydrodibenzo[b,d]pyran-9-ones to trans-hexahydrodibenzo[b,d]-pyran-9-ones
US4075230A (en) * 1976-11-10 1978-02-21 Eli Lilly And Company Preparation of optically active trans-hexahydrodibenzopyranones
US4102902A (en) * 1976-11-10 1978-07-25 Eli Lilly And Company Stereoselective preparation of hexahydro dibenzopyranones and intermediates therefor
US4116979A (en) * 1975-06-23 1978-09-26 Sheehan Institute For Research, Inc. Process for the preparation of (-)-6a,10a-trans-6a,7,8,10a-tetrahydrodibenzo[b,d]-pyrans
US4131614A (en) * 1976-07-06 1978-12-26 Eli Lilly And Company Process for preparing cis-hexahydrodibenzopyranones
US4148809A (en) * 1976-07-06 1979-04-10 Eli Lilly And Company Process for preparing dl-cis-1-hydroxy-3-substituted-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-ones
US4171315A (en) * 1978-03-31 1979-10-16 Eli Lilly And Company Preparation of cis-hexahydrodibenzopyranones
US4179517A (en) * 1976-01-12 1979-12-18 Yissum Research Development Company Of The Hebrew University Of Jerusalem Novel tetrahydrocannabinol type compounds
US4278603A (en) * 1973-11-05 1981-07-14 Eli Lilly And Company Novel polymorphic crystalline form of dibenzopyranone
US4381399A (en) * 1981-12-21 1983-04-26 Aerojet-General Corporation Purification of tetrahydrodibenzo[b,d]pyrans from crude synthetic mixtures
US4433183A (en) * 1981-05-04 1984-02-21 Firmenich Sa Process for the preparation of (+)-p-mentha-2,8-dien-1-ol
US4876276A (en) * 1986-10-24 1989-10-24 Yissum Research Development Co. Of The Hebrew University Of Jerusalem (3S-4S)-7-hydroxy-Δ6 -tetrahydrocannabinols
US4933363A (en) * 1988-08-16 1990-06-12 Elsohly Mahmoud A Method for effecting systemic delivery of delta-9-tetrahydrocannabinol
US5227537A (en) * 1991-01-09 1993-07-13 Heinrich Mack Nachf. Method for the production of 6,12-dihydro-6-hydroxy-cannabidiol and the use thereof for the production of trans-delta-9-tetrahydrocannabinol
US5338753A (en) * 1992-07-14 1994-08-16 Sumner H. Burstein (3R,4R)-Δ6 -tetrahydrocannabinol-7-oic acids useful as antiinflammatory agents and analgesics
US5342971A (en) * 1992-12-29 1994-08-30 The Australian National University Process for the preparation of dibenzo[b,d]pyrans
US5389375A (en) * 1993-05-21 1995-02-14 University Of Mississippi Stable suppository formulations effecting bioavailability of Δ9 -thc
US5440052A (en) * 1993-08-06 1995-08-08 University Of Connecticut Compositions useful as a cannabinoid receptor probe
US5521215A (en) * 1989-11-07 1996-05-28 Ramot University Authority For Applied Research And Industrial Development Ltd. NMDA-blocking pharmaceuticals
US5538993A (en) * 1991-09-12 1996-07-23 Yissum Research Development Company Certain tetrahydrocannabinol-7-oic acid derivatives
US5605928A (en) * 1992-06-02 1997-02-25 Yissum Research Development Company Of The Hebrew University In Jerusalem Antiemetic compositions
US5635530A (en) * 1991-09-12 1997-06-03 Yissum Research Development Company Of The Hebrew University Of Jerusalem (3S,4S)-delta-6-tetrahydrocannabinol-7-oic acids and derivatives thereof, processors for their preparation and pharmaceutical compositions containing them
US5932610A (en) * 1995-09-11 1999-08-03 Yissum Research Development Co. Of The Hebrew University Tumor necrosis factor α (TNF-α) inhibiting pharmaceuticals
US6008383A (en) * 1998-10-26 1999-12-28 University Of Mississippi Method of preparing delta-9-tetrahydrocannabinol esters
US6274635B1 (en) * 1999-03-22 2001-08-14 Immugen Pharmaceuticals Inc. Alkylated resorcinol derivatives for the treatment of immune diseases
US6355650B1 (en) * 1997-10-17 2002-03-12 Atlantic Technology Ventures, Inc. (3R,4R)-Δ8-tetrahydrocannabinol-11-oic acids useful as antiinflammatory agents and analgesics
US20020037923A1 (en) * 1999-03-22 2002-03-28 Travis Craig R. Resorcinolic compounds
US20020111377A1 (en) * 2000-12-22 2002-08-15 Albany College Of Pharmacy Transdermal delivery of cannabinoids
US20030017216A1 (en) * 2001-07-23 2003-01-23 Schmidt Robert Gustav Isolation of herbal and cannabinoid medicinal extracts
US6563009B1 (en) * 1999-07-12 2003-05-13 Virginia Commonwealth University Vasodilator cannabinoid analogs
US6610737B1 (en) * 2000-06-22 2003-08-26 Pharmos Corporation Non-psychotropic cannabinoids
US6630507B1 (en) * 1998-04-21 2003-10-07 The United States Of America As Represented By The Department Of Health And Human Services Cannabinoids as antioxidants and neuroprotectants
US6689881B1 (en) * 1999-07-02 2004-02-10 Warner-Lambert Llc Method for preparing substituted [1,4]diazepino[6,7,1-hi]indol-4-ones
US20040043946A1 (en) * 2002-09-03 2004-03-04 Popp Karl F. Topical formulations for treatment of skin disorders
US20040054007A1 (en) * 2000-05-17 2004-03-18 Burstein Summer H Methods for decreasing cell proliferation based on (3r,4r)-delta8-tetrahydrocannabinol-11-oic acids
US6730519B2 (en) * 1998-10-26 2004-05-04 The University Of Mississippi Method of preparing delta-9-tetrahydrocannabinol
US20040110827A1 (en) * 2002-12-04 2004-06-10 Haim Aviv High enantiomeric purity dexanabinol for pharmaceutical compositions
US20040143126A1 (en) * 2001-03-07 2004-07-22 Webster G. R. Barrie Conversion of cbd to delta8-thc and delta9-thc
US20040225011A1 (en) * 2000-05-17 2004-11-11 Summer Burstein Cannabinoid drugs
US20040242593A1 (en) * 2003-05-20 2004-12-02 Moore Bob M. Cannabinoid derivatives, methods of making, and use thereof
US20040248970A1 (en) * 2003-04-10 2004-12-09 Webster G.R. Barrie CBD-delta8-THC composition
US20040249174A1 (en) * 2001-05-25 2004-12-09 Silverberg Lee Jonathan Synthesis of cannabinoids
US20050032881A1 (en) * 2000-06-22 2005-02-10 Aaron Garzon Novel non-psychotropic cannabinoids
US20050049298A1 (en) * 2002-02-01 2005-03-03 Goodwin Neil John Production of Delta 9 tetrahydrocannabinol
US6867335B2 (en) * 2001-05-25 2005-03-15 Johnson Matthey Public Limited Company Uncatalysed addition reactions
US6946150B2 (en) * 2002-08-14 2005-09-20 Gw Pharma Limited Pharmaceutical formulation
US6949582B1 (en) * 1999-05-27 2005-09-27 Wallace Walter H Method of relieving analgesia and reducing inflamation using a cannabinoid delivery topical liniment
US20050266108A1 (en) * 2002-09-23 2005-12-01 Gw Pharma Limited Methods of purifying cannabinoids from plant material
US20060074252A1 (en) * 2004-10-01 2006-04-06 Souza Fabio E Synthetic route to dronabinol

Family Cites Families (24)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB558418A (en) 1940-08-16 1944-01-05 Roger Adams Process for securing pharmacologically useful products from cannabidiol
US4202902A (en) * 1979-03-05 1980-05-13 Shell Oil Company Lipogenesis control by cyclopropane-carboxylic acids, esters and amides
IL92238A (en) 1989-11-07 1995-07-31 Yissum Res Dev Co Nmda blocking composition containing tetrahydro-cannabinol derivatives some novel tetrahydro-cannabinol derivatives and process for their preparation
US5292899A (en) * 1991-11-27 1994-03-08 Synthetic Technology Corporation Synthesis of 11-nor-Δ-9-tetrahydrocannabinol-9-carboxylic acid glucuronide
JPH07196565A (en) * 1993-12-28 1995-08-01 Idemitsu Petrochem Co Ltd 4-alkyl-2-fluorocyclohexanol, its production and optical resolution method
US6328992B1 (en) 1997-03-03 2001-12-11 Lawrence L. Brooke Cannabinoid patch and method for cannabis transdermal delivery
US6148261A (en) * 1997-06-20 2000-11-14 American Calcar, Inc. Personal communication system to send and receive voice data positioning information
WO2000020472A1 (en) * 1998-10-05 2000-04-13 The B.F. Goodrich Company Catalyst and methods for polymerizing cycloolefins
WO2001013886A1 (en) 1999-08-20 2001-03-01 Roxane Laboratories, Inc. Composition for inhalation comprising delta-9-tetrahydrocannabinol in a semiaqueous solvent
US6949648B2 (en) * 2000-03-27 2005-09-27 Takeda Pharmaceutical Company Limited Condensed pyrazole derivatives, process for producing the same and use thereof
IL136839A (en) 2000-06-16 2006-12-10 Yissum Res Dev Co Pharmaceutical compositions comprising cannabidiol derivatives, and processes for the preparation of same
DE10051427C1 (en) 2000-10-17 2002-06-13 Adam Mueller Process for the production of an extract containing tetrahydrocannabinol and cannabidiol from cannabis plant material and cannabis extracts
DE10106024B4 (en) 2001-02-09 2004-10-14 Thc Pharm Gmbh Process for the preparation of dronabinol
GB2377218A (en) 2001-05-04 2003-01-08 Gw Pharmaceuticals Ltd Process and apparatus for extraction of active substances and enriched extracts from natural products
GB2381450B (en) 2001-10-31 2006-05-31 Gw Pharma Ltd Compositions for administration of natural or synthetic cannabinoids by vaporisation
WO2003091189A1 (en) 2002-04-25 2003-11-06 Virginia Commonwealth University Cannabinoids
GB2393182B (en) 2002-09-23 2007-03-14 Gw Pharma Ltd Method of preparing cannabidiol from plant material
DK1560819T3 (en) * 2002-11-12 2009-02-09 Mallinckrodt Inc Crystalline cannabinoid derivatives and method of cannabinoid purification
EP1613578A2 (en) 2003-04-10 2006-01-11 Mallinckrodt Inc. Olivetol-cyclodextrin complexes and regio-selective process for preparing delta 9-tetrahydrocannabinol
US20070287843A1 (en) 2004-04-07 2007-12-13 Cabaj John E Methods and Intermediates for the Synthesis of Delta-9 Tetrahydrocannabinol
GB2414933B (en) 2004-06-08 2009-07-15 Gw Pharma Ltd Cannabinoid compositions for the treatment of disease and/or symptoms in arthritis
EP1773801A1 (en) 2004-07-19 2007-04-18 Cilag Ltd. Method for obtaining pure tetrahydrocannabinol
TWI436991B (en) 2004-11-22 2014-05-11 Euro Celtique Sa Methods for purifying trans-(-)-△9-tetrahydrocannabinol and trans-(+)-△9-tetrahydrocannabinol
EP1827393A4 (en) 2004-12-09 2012-04-18 Insys Therapeutics Inc Room-temperature stable dronabinol formulations

Patent Citations (69)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US2509387A (en) * 1950-05-30 Dibenzopyran marihuana-like
US2304669A (en) * 1940-08-16 1942-12-08 Adams Roger Isolation of cannabidiol
US2419935A (en) * 1941-07-09 1947-05-06 Adams Roger Marihuana active compounds
US2419934A (en) * 1941-07-09 1947-05-06 Adams Roger Optically active tetrahydrodibenzopyrans having marihuana activity and process for making same
US2419936A (en) * 1942-04-29 1947-05-06 Adams Roger Preparation of compounds with marihuana activity
US3507885A (en) * 1966-03-25 1970-04-21 Hoffmann La Roche 3-alkyl-6h-dibenzo(b,d)pyrans
US3636058A (en) * 1966-03-25 1972-01-18 Hoffmann La Roche 7 10 - dihydro - 3 - alkyl - 6h - dibenzo(b d) pyran-6 9(8h)-diones and 5-hydroxy-7-alkyl-4-chromanones
US3562312A (en) * 1966-11-04 1971-02-09 Albert Eschenmoser Manufacture of 2-substituted resorcinol derivatives
US3920705A (en) * 1967-05-19 1975-11-18 Theodore Petrzilka 6a,10a-trans-6a,10,10a-tetrahydrodibenzo(b,d)-pyrans
US3833616A (en) * 1968-09-16 1974-09-03 T Petrzilka 6a,10a-trans-6a,7,8,10a-tetrahydrodibenzo(b,d)-pyrans
US3919322A (en) * 1969-01-22 1975-11-11 Hoffmann La Roche 3-Substituted -5-alkyl-2-cyclohexen-1-ones
US3734930A (en) * 1971-09-22 1973-05-22 R Razdan Direct synthesis of ({31 )-trans-{66 {11 tetrahydrocannabinol from olivetol and ({30 )-trans-{66 {11 -carene oxide
US4278603A (en) * 1973-11-05 1981-07-14 Eli Lilly And Company Novel polymorphic crystalline form of dibenzopyranone
US4116979A (en) * 1975-06-23 1978-09-26 Sheehan Institute For Research, Inc. Process for the preparation of (-)-6a,10a-trans-6a,7,8,10a-tetrahydrodibenzo[b,d]-pyrans
US4025516A (en) * 1975-06-23 1977-05-24 The John C. Sheehan Institute For Research, Inc. Process for the preparation of (-)-6a,10a-trans-6a,7,8,10a-tetrahydrodibenzo[b,d]-pyrans
US4179517A (en) * 1976-01-12 1979-12-18 Yissum Research Development Company Of The Hebrew University Of Jerusalem Novel tetrahydrocannabinol type compounds
US4054582A (en) * 1976-07-06 1977-10-18 Eli Lilly And Company Process for converting cis-hexahydrodibenzo[b,d]pyran-9-ones to trans-hexahydrodibenzo[b,d]-pyran-9-ones
US4131614A (en) * 1976-07-06 1978-12-26 Eli Lilly And Company Process for preparing cis-hexahydrodibenzopyranones
US4148809A (en) * 1976-07-06 1979-04-10 Eli Lilly And Company Process for preparing dl-cis-1-hydroxy-3-substituted-6,6-dimethyl-6,6a,7,8,10,10a-hexahydro-9H-dibenzo[b,d]pyran-9-ones
US4075230A (en) * 1976-11-10 1978-02-21 Eli Lilly And Company Preparation of optically active trans-hexahydrodibenzopyranones
US4102902A (en) * 1976-11-10 1978-07-25 Eli Lilly And Company Stereoselective preparation of hexahydro dibenzopyranones and intermediates therefor
US4171315A (en) * 1978-03-31 1979-10-16 Eli Lilly And Company Preparation of cis-hexahydrodibenzopyranones
US4433183A (en) * 1981-05-04 1984-02-21 Firmenich Sa Process for the preparation of (+)-p-mentha-2,8-dien-1-ol
US4381399A (en) * 1981-12-21 1983-04-26 Aerojet-General Corporation Purification of tetrahydrodibenzo[b,d]pyrans from crude synthetic mixtures
US4876276A (en) * 1986-10-24 1989-10-24 Yissum Research Development Co. Of The Hebrew University Of Jerusalem (3S-4S)-7-hydroxy-Δ6 -tetrahydrocannabinols
US4933363A (en) * 1988-08-16 1990-06-12 Elsohly Mahmoud A Method for effecting systemic delivery of delta-9-tetrahydrocannabinol
US5521215A (en) * 1989-11-07 1996-05-28 Ramot University Authority For Applied Research And Industrial Development Ltd. NMDA-blocking pharmaceuticals
US5227537A (en) * 1991-01-09 1993-07-13 Heinrich Mack Nachf. Method for the production of 6,12-dihydro-6-hydroxy-cannabidiol and the use thereof for the production of trans-delta-9-tetrahydrocannabinol
US5635530A (en) * 1991-09-12 1997-06-03 Yissum Research Development Company Of The Hebrew University Of Jerusalem (3S,4S)-delta-6-tetrahydrocannabinol-7-oic acids and derivatives thereof, processors for their preparation and pharmaceutical compositions containing them
US5538993A (en) * 1991-09-12 1996-07-23 Yissum Research Development Company Certain tetrahydrocannabinol-7-oic acid derivatives
US5605928A (en) * 1992-06-02 1997-02-25 Yissum Research Development Company Of The Hebrew University In Jerusalem Antiemetic compositions
US5338753A (en) * 1992-07-14 1994-08-16 Sumner H. Burstein (3R,4R)-Δ6 -tetrahydrocannabinol-7-oic acids useful as antiinflammatory agents and analgesics
US5342971A (en) * 1992-12-29 1994-08-30 The Australian National University Process for the preparation of dibenzo[b,d]pyrans
US5389375A (en) * 1993-05-21 1995-02-14 University Of Mississippi Stable suppository formulations effecting bioavailability of Δ9 -thc
US5872148A (en) * 1993-08-06 1999-02-16 University Of Connecticut Compositions useful as a cannabinoid receptor probe
US5440052A (en) * 1993-08-06 1995-08-08 University Of Connecticut Compositions useful as a cannabinoid receptor probe
US6545041B2 (en) * 1995-09-11 2003-04-08 Yessum Research Development Co. Of The Hebrew University Of Jerusalem Tumor necrosis factor alpha (TNF-α) inhibiting pharmaceuticals
US5932610A (en) * 1995-09-11 1999-08-03 Yissum Research Development Co. Of The Hebrew University Tumor necrosis factor α (TNF-α) inhibiting pharmaceuticals
US20020049245A1 (en) * 1995-09-11 2002-04-25 Yissum Research Development Co. Tumor necrosis factor alpha (TNF-alpha) inhibiting pharmaceuticals
US6331560B1 (en) * 1995-09-11 2001-12-18 Yissum Research Development Co. Of The Hebrew University Of Jerusalem Tumor necrosis factor alpha (TNF-α) inhibiting pharmaceuticals
US6355650B1 (en) * 1997-10-17 2002-03-12 Atlantic Technology Ventures, Inc. (3R,4R)-Δ8-tetrahydrocannabinol-11-oic acids useful as antiinflammatory agents and analgesics
US6630507B1 (en) * 1998-04-21 2003-10-07 The United States Of America As Represented By The Department Of Health And Human Services Cannabinoids as antioxidants and neuroprotectants
US6730519B2 (en) * 1998-10-26 2004-05-04 The University Of Mississippi Method of preparing delta-9-tetrahydrocannabinol
US6008383A (en) * 1998-10-26 1999-12-28 University Of Mississippi Method of preparing delta-9-tetrahydrocannabinol esters
US20020037923A1 (en) * 1999-03-22 2002-03-28 Travis Craig R. Resorcinolic compounds
US6566560B2 (en) * 1999-03-22 2003-05-20 Immugen Pharmaceuticals, Inc. Resorcinolic compounds
US20030158191A1 (en) * 1999-03-22 2003-08-21 Travis Craig R. Cannabinol derivatives
US6274635B1 (en) * 1999-03-22 2001-08-14 Immugen Pharmaceuticals Inc. Alkylated resorcinol derivatives for the treatment of immune diseases
US6949582B1 (en) * 1999-05-27 2005-09-27 Wallace Walter H Method of relieving analgesia and reducing inflamation using a cannabinoid delivery topical liniment
US6689881B1 (en) * 1999-07-02 2004-02-10 Warner-Lambert Llc Method for preparing substituted [1,4]diazepino[6,7,1-hi]indol-4-ones
US6563009B1 (en) * 1999-07-12 2003-05-13 Virginia Commonwealth University Vasodilator cannabinoid analogs
US20040225011A1 (en) * 2000-05-17 2004-11-11 Summer Burstein Cannabinoid drugs
US20040054007A1 (en) * 2000-05-17 2004-03-18 Burstein Summer H Methods for decreasing cell proliferation based on (3r,4r)-delta8-tetrahydrocannabinol-11-oic acids
US6610737B1 (en) * 2000-06-22 2003-08-26 Pharmos Corporation Non-psychotropic cannabinoids
US20050032881A1 (en) * 2000-06-22 2005-02-10 Aaron Garzon Novel non-psychotropic cannabinoids
US20020111377A1 (en) * 2000-12-22 2002-08-15 Albany College Of Pharmacy Transdermal delivery of cannabinoids
US20040143126A1 (en) * 2001-03-07 2004-07-22 Webster G. R. Barrie Conversion of cbd to delta8-thc and delta9-thc
US6867335B2 (en) * 2001-05-25 2005-03-15 Johnson Matthey Public Limited Company Uncatalysed addition reactions
US20040249174A1 (en) * 2001-05-25 2004-12-09 Silverberg Lee Jonathan Synthesis of cannabinoids
US20030017216A1 (en) * 2001-07-23 2003-01-23 Schmidt Robert Gustav Isolation of herbal and cannabinoid medicinal extracts
US20050049298A1 (en) * 2002-02-01 2005-03-03 Goodwin Neil John Production of Delta 9 tetrahydrocannabinol
US20050171361A1 (en) * 2002-02-01 2005-08-04 Goodwin Neil J. Production of delta 9 tetrahydrocannabinol
US6946150B2 (en) * 2002-08-14 2005-09-20 Gw Pharma Limited Pharmaceutical formulation
US20040043946A1 (en) * 2002-09-03 2004-03-04 Popp Karl F. Topical formulations for treatment of skin disorders
US20050266108A1 (en) * 2002-09-23 2005-12-01 Gw Pharma Limited Methods of purifying cannabinoids from plant material
US20040110827A1 (en) * 2002-12-04 2004-06-10 Haim Aviv High enantiomeric purity dexanabinol for pharmaceutical compositions
US20040248970A1 (en) * 2003-04-10 2004-12-09 Webster G.R. Barrie CBD-delta8-THC composition
US20040242593A1 (en) * 2003-05-20 2004-12-02 Moore Bob M. Cannabinoid derivatives, methods of making, and use thereof
US20060074252A1 (en) * 2004-10-01 2006-04-06 Souza Fabio E Synthetic route to dronabinol

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109734554A (en) * 2019-02-25 2019-05-10 江苏暨明医药科技有限公司 A kind of synthesis technology of trans--menthyl -2,8- diene -1- alcohol
US12029718B2 (en) 2021-11-09 2024-07-09 Cct Sciences, Llc Process for production of essentially pure delta-9-tetrahydrocannabinol

Also Published As

Publication number Publication date
KR20080063800A (en) 2008-07-07
WO2007041167A3 (en) 2007-11-22
EP2578577A1 (en) 2013-04-10
IL190388A0 (en) 2008-11-03
AU2006297300B2 (en) 2012-05-10
EP1928853A2 (en) 2008-06-11
US7674922B2 (en) 2010-03-09
CN101316832A (en) 2008-12-03
JP2009510078A (en) 2009-03-12
WO2007041167A2 (en) 2007-04-12
AU2006297300A1 (en) 2007-04-12
US8106244B2 (en) 2012-01-31
NZ601567A (en) 2013-03-28
NZ567029A (en) 2011-09-30
CA2623723A1 (en) 2007-04-12
US20110263878A1 (en) 2011-10-27
CN102766128A (en) 2012-11-07
ZA200802767B (en) 2009-09-30
EP1928853A4 (en) 2011-02-16
EP2578561A1 (en) 2013-04-10
US20070093665A1 (en) 2007-04-26
NZ594077A (en) 2013-02-22

Similar Documents

Publication Publication Date Title
US8106244B2 (en) Process for production of delta-9-tetrahydrocannabinol
CA2751741C (en) Process for the preparation of (-) -delta 9-tetrahydrocannabinol
CN114269717A (en) Catalytic cannabinoid processes and precursors
CN112592260A (en) Method for synthesizing cannabidiol
AU2012201041B2 (en) Process for production of delta-9-tetrahydrocannabinol
CN102001979A (en) Preparation method of 2-(2&#39;, 2&#39;-difluoroethoxyl)-6-trifluoromethyl phenyl propyl sulfide
US20070287843A1 (en) Methods and Intermediates for the Synthesis of Delta-9 Tetrahydrocannabinol
US20110275872A1 (en) Process for the synthesis of ethynylcyclopropane
CN112645863B (en) Dipyrromethene-1-ketone compound and preparation method thereof
CN112479967B (en) Biliverdin compound, and preparation method and application thereof
US7153994B2 (en) Manufacture of trimethylhydroquinone diacylates
CN114394884A (en) Preparation method of allyl phenol compound
US20130267717A1 (en) Process for the preparation of atovaquone
CN107188786B (en) Preparation method of optically pure cyclopentenol as medical intermediate
KR0150292B1 (en) A novel process for the preparation of propenoic ester derivatives containing pyrazole
US8258322B2 (en) Synthesis of hexahydrodibenzopyranones
WO2023122754A1 (en) Processes and intermediates for preparing gb13, gb22 and himgaline
CN116199607A (en) Preparation method of pilocarpine and intermediate compound thereof
CN114805168A (en) Pyrrolinone compound and synthetic method thereof
EP2003112A1 (en) Method for producing carboxylic acid compound
JPH0211585A (en) Production of chroman derivative
JPH07242572A (en) Production of dimethylheptatriacontane and its analog
HU203090B (en) New process for producing chromone derivative

Legal Events

Date Code Title Description
STCB Information on status: application discontinuation

Free format text: ABANDONED -- FAILURE TO PAY ISSUE FEE

AS Assignment

Owner name: BANK OF AMERICA, N.A., AS ADMINISTRATIVE AGENT, MA

Free format text: INTELLECTUAL PROPERTY SECURITY AGREEMENT;ASSIGNORS:ALBANY MOLECULAR RESEARCH, INC.;AMRI RENSSELAER, INC.;AMRI BOTHELL RESEARCH CENTER, INC.;AND OTHERS;REEL/FRAME:026397/0001

Effective date: 20110603

AS Assignment

Owner name: AMRI BURLINGTON, INC., NEW YORK

Free format text: TERMINATION;ASSIGNOR:BANK OF AMERICA, N.A.;REEL/FRAME:028072/0335

Effective date: 20120411

Owner name: ALBANY MOLECULAR RESEARCH, INC., NEW YORK

Free format text: TERMINATION;ASSIGNOR:BANK OF AMERICA, N.A.;REEL/FRAME:028072/0335

Effective date: 20120411

Owner name: AMRI RENESSELAER, INC., NEW YORK

Free format text: TERMINATION;ASSIGNOR:BANK OF AMERICA, N.A.;REEL/FRAME:028072/0335

Effective date: 20120411

Owner name: AMRI BOTHELL RESEARCH CENTER, INC., NEW YORK

Free format text: TERMINATION;ASSIGNOR:BANK OF AMERICA, N.A.;REEL/FRAME:028072/0335

Effective date: 20120411