HK1127033A

HK1127033A - Process for production of delta-9-tetrahydrocannabinol

Info

Publication number: HK1127033A
Application number: HK09104951.0A
Authority: HK
Inventors: David C. Burdick; Steven J. Collier; Frederic Jos; Betina Biolatto; Bernhard J. Paul; Harold Meckler; Mark A. Helle; Alicia J. Habershaw
Original assignee: Albany Molecular Research, Inc.
Priority date: 2005-09-29
Filing date: 2006-09-28
Publication date: 2009-09-18

Description

Method for producing delta-9-tetrahydrocannabinol

[0001] This application claims the benefit of U.S. provisional patent application serial No. 60/722,031, filed 2005-9-29, which is incorporated herein by reference in its entirety.

Technical Field

[0002] The present invention relates to processes for the preparation of (-) -trans-delta-9-tetrahydrocannabinol, intermediate compounds thereof, and compounds derived therefrom.

Background

[0003] Research activities have been rapidly continuing since The year in which a breakthrough review on The Synthesis of cannabinoids (cannabinoids) by Razdan has been published (Razdan, edited by ApSimon, The Total Synthesis of Natural Products, Vol. 4, pp. 185 & 262, New York: Wiley and Sons (1981); Huffman et al, Current Med. chem., 3: 101 & 116 (1996)). The reason for this area of interest is partly due to the fact that the (cannabis) structure is a challenge for synthetic organic chemists and also due to the diverse and useful pharmacological activities expressed by many of these substances. The chemical structure of tricyclic cannabinoids of natural origin, represented by delta-9-tetrahydrocannabinol (delta-9-THC), is very simple: there are only two stereogenic carbon atoms, two carbocyclic rings and a dihydrobenzopyran ring. In most cases the functional groups are limited to the phenolic C1 hydroxyl group and one or two oxygen-carrying functional groups. It is reasonable for anyone to suspect whether such compounds are of sufficient complexity to continue to interest organic chemists. The difficulty of synthesis masks the simplicity of construction and is due, at least in part, to the reason: (a) this material is generally non-crystalline and is often quite difficult or impossible to isolate or purify without the aid of HPLC; (b) the aromatic portion of the molecule is very sensitive to oxidation, particularly in the presence of bases or transition metals (see Hodjat-Kashani et al, Heterocycles, 24: 1973-1976 (1986)); and (c) delta-9-unsaturation is thermodynamically unfavorable relative to delta-8-unsaturation. There is no general method to make the delta-9-unsaturation kinetically favored.

[0004] The pharmacological interest in these substances dates back several Thousand Years (Abel, Cannabis: The First ten Thousand Years (Marijuana: The First Twill Thousand Years), pages 11-12, New York and London: Plenum (1980)). The use of Cannabis sativa (Cannabis sativa) of Scytalans (Scythians ') recorded by Hirododus (Herodotus') as anaesthetic is clearly recognised as a psychologically recognised trait of plants produced from ancient times (Herodotus, Histories, Book IV, p.295, Penguin Books GmbH, Middlesex (1972)). In addition to use as anesthetics, spasmolytics, and hypnotics, cannabinoids have been used to combat cancer chemotherapy-induced emesis and nausea, and also to treat glaucoma. Recently, cannabinoids have become somewhat notorious for their potential for abuse. A significant portion of the integrated efforts have been directed to the preparation of certain oxidized human urine metabolites of delta-9-THC as analytical standards for use in the forensic science (forcenic science) for the detection of cannabis use.

[0005] Several developments have contributed to the resurgence of current interest in the field. The identification of the first cannabinoid receptor (CB1) in the brain of rats was a major advance (Deven et al, mol. Pharmacol., 34: 605-. The identification of the second, peripheral receptor subtype (CB2) within splenocytes (Munro et al, Nature, 365: 61-65(1993)) and the discovery of anandamide as an endogenous ligand for CB1 (Deven et al, Science, 258: 1946-1949(1992)) have led to a more interesting story. The involvement of pharmaceutical companies has led to the synthesis and evaluation of a large number of analogs and to the discovery of the first receptor antagonists.

[0006] The present invention is directed to overcoming the above-mentioned deficiencies in the art.

Summary of The Invention

[0007] The present invention relates to a process for preparing a product of a compound of the formula:

wherein:

R₁is H, substituted or unsubstituted alkyl, carboxylate, or acyl;

R₂h, OH, protected hydroxy, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, aryl, or heteroaryl;

R₃is H, substituted or unsubstituted alkyl, carboxylate, or acyl; and

R₄is H, substituted or unsubstituted alkyl, silyl, hetero-substituted (hetero-substituted) or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl or arylphosphoryl.

The process comprises treating a first intermediate compound of the formula:

[0008] in another aspect, the invention relates to a process for preparing a product of a compound of the formula:

wherein:

R₁is H, substituted or unsubstituted alkaneA group, a carboxylic acid ester or an acyl group;

R₃is H, substituted or unsubstituted alkyl, carboxylate, or acyl;

R₄is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl; and

R₆is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl.

The process comprises reacting a first starting compound of the formula:

with a second starting compound of the formula:

wherein X ═ H, alkyl, acyl, silyl, aryl, heteroaryl, sulfonyl, phosphoryl, or phosphinyl.

[0009] Yet another aspect of the invention relates to a process for preparing a product of a compound of the formula:

wherein:

R₁is H, substituted or unsubstituted alkyl, carboxylate, or acyl;

R₃is H, substituted or unsubstituted alkyl, carboxylate, or acyl; and R₄Is SO₂R₅Wherein R is₅Is a substituted or unsubstituted alkyl group.

The process comprises reacting a first intermediate compound of the formula:

wherein:

R₄' is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl or arylphosphoryl,

R₆is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl or arylphosphoryl,

wherein R is₄' and R₆Must be H;

with a first compound of the formula:

wherein 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 a second intermediate compound of the formula:

then, treating the second intermediate compound with an organoaluminum-based lewis acid catalyst under conditions effective to produce a third intermediate compound of the formula:

wherein R is₄And ═ H. The third intermediate compound is then reacted with a substituted or unsubstituted alkyl sulfonyl halide, alkyl sulfonic anhydride, mixed anhydride of alkyl sulfonic acids, alkyl sulfonate ester, or alkyl sulfonic acid under conditions effective to produce the compound product.

[0010] The invention also relates to compounds of the formula:

wherein:

R₁is H, substituted or unsubstituted alkyl, carboxylate, or acyl;

R₃is H, substituted or unsubstituted alkyl, carboxylate, or acyl;

R₈、R₉and R₁₀Are the same or different and are independently selected from H, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or halo; and

R₈and R₉；R₈And R₁₀(ii) a Or R₉And R₁₀(ii) a Or R₈、R₉And R₁₀May together form a ring-shaped portion.

[0011]The condensation of Oleyl alcohol or Oleyl ester (olivolate ester) with menthadiene alcohol (menthodienol) in the presence of Lewis acids is known from the prior art. However, the reaction suffers from poor selectivity problems and results in the subsequent conversion of the desired product to the cyclic derivative with little control. For example, boron trifluoride etherate (BF) is a common problem₃OEt₂) The control of the reaction is poor because it is difficult to stop at the cannabidiol and the ring closure to delta-9-THC is accompanied by further isomerization to delta-8-THCs. Use of less reactive Lewis acids such as MgBr₂Are disadvantageous because they have poor reactivity. As the scale of these reactions increases, control of the process becomes more difficult because of the short reaction times required. By using a metal triflate catalyst, the reaction of the present invention proceeds under mild conditions and virtually without over-reaction to the ring closure product. In addition, in the case of Oleyl alcohol, when BF is to be applied₃OEt₂When used as a catalyst, both the desired cannabidiol and the undesired isomer, abn-cannabidiol, are formed. However, combining the metal triflate catalyst with the slow addition of mendienol (preferably less than 1 equivalent) increases the ratio of cannabidiol to abn-cannabidiol. The reaction was carried out in Dichloromethane (DCM) at a temperature above its boiling point to further increase the selectivity. Thus, by slowly adding a substoichiometric amount of menthadiene alcohol to a mixture of Oleyl alcohol and a metal triflate catalyst in DCM at a temperature above its boiling point, the present invention compares to the prior art with respect to the undesired regioisomers (regiooisomers)The method greatly improves the selectivity of cannabidiol, and remarkably reduces the transformation of cannabidiol into cyclization products.

[0012]Furthermore, cannabidiol cyclisation to delta-9-THC is a reaction which is recognized as being difficult to control and carry out selectively. Previously, catalysts such as BF have been used₃OEt₂. These can cause isomerization of the desired delta-9 isomer to the thermodynamically more stable delta-8 isomer, which is difficult to separate from the product. In addition, the phenol unit cyclization can occur at the endocyclic double bond to give significant levels of iso-THC derivatives that are also very difficult to remove. The process of the present invention exhibits a greatly superior selectivity in this ring closure by using an organoaluminum-based lewis acid catalyst. For example, using BF₃OEt₂Yields of delta-9-THC of up to about 50-60% with about 20% iso-THC are inherent problems with the isomerization of delta-9-THC to the delta-8 isomer via strong Lewis acids. Use of AlCl in very short reaction times₃Selectivity of about 10: 1 delta-9-THC to iso-THC can be achieved with little isomerization to the delta-8 isomer. The double bond isomerization is facilitated by prolonging the reaction time. In contrast, when the process of the invention is employed as described herein, for example when iBu is used₃For Al, the yield of delta-9-THC is > 92%, with < 2% iso-THC, and virtually no isomerization of the desired product to delta-8-THC takes place.

Detailed Description

[0013] The present invention relates to a process for preparing a product of a compound of the formula:

wherein:

R₁is H, substituted or unsubstituted alkyl, carboxylate, or acyl;

R₂h, OH, protected hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, arylOr a heteroaryl group;

R₃is H, substituted or unsubstituted alkyl, carboxylate, or acyl; and

R₄is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl.

The process comprises treating a first intermediate compound of the formula:

[0014] the organoaluminum-based Lewis acid catalysts used in the process of the present invention may be trialkyl-or triaryl-aluminum, dialkyl-or diarylaluminum halides, alkylarylaluminum halides, dialkyl-or alkylaryl-or diarylaluminum alkoxides or aryloxides (aryloxides), dialkyl-or alkylaryl-or diarylaluminum thioalkoxides (thioalkoxides) or thioarylates, dialkyl-or alkylaryl-or diarylaluminum carboxylates, alkyl-or arylaluminum dihalides, alkyl-or arylaluminum dialkoxides or diaryloxides or alkylaryloxy compounds, alkyl-or arylaluminum dithioalkoxides or dithioarylates, alkyl-or arylaluminum dicarboxylates, aluminum trialkoxide or aluminum triaryloxide compounds or aluminum mixed alkylaryloxy compounds, Aluminum triacyl carboxylates 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, ethylaluminum dichloride, methylaluminum dichloride, isobutylaluminum dichloride, diethylaluminum ethoxide, diethylaluminum isopropoxide, diisobutylaluminum methoxide, diisobutylaluminum phenoxide, diphenylaluminum isopropoxide, tetraisobutylaluminoxane (alumoxane), methylaluminoxane, bis- (2, 6-di-tert-butyl-4-methylphenol) methylaluminum, diisobutylaluminum acetate, diisobutylaluminum benzoate, diisobutylaluminum trifluoroacetate, diisobutylaluminum isopropoxide, diisobutyl 2, 6-di-tert-butyl-4-methylphenol aluminum, bis- (2, 6-di-t-butyl-4-methylphenol), isobutylaluminum diacetate, trimethoxyaluminum, triisoaluminum propoxide, tri-t-butoxyaluminum, and aluminum trifluoroacetate. Several such catalysts are commercially available or may be prepared by methods known in the literature, for example those described by Ooi and Maruoka, Science of Synthesis, Vol.7, p.131-: the method described by Thieme (2000), which is hereby incorporated by reference in its entirety, was prepared from commercially available aluminum reagents.

[0015]In one embodiment of the present invention, the organoaluminum-based Lewis acid catalyst is C₁-C₃₀Alkylaluminium base or C₆-C₃₀An aryl aluminum based species or mixture. In another embodiment of the present invention, the organoaluminum-based lewis acid catalyst comprises one or more oxygen-containing substituents bonded to aluminum that improve the physical properties or performance of the catalyst. In another embodiment of the present invention, the organoaluminum-based lewis acid catalyst may be prepared in situ by reacting a precursor aluminum reagent with a modifying surrogate prior to use. In particular, organoaluminum-based lewis acid catalysts can be catalysts that provide high selectivity to delta-9-THC when used at low levels and at convenient rates for large-scale production. More specifically, the organoaluminum-based Lewis acid catalyst may be one that produces delta-9-THC containing very low levels of isomers (e.g., cis-delta-9-THC, delta-8-THC, and iso-THC) because these isomers are difficult to remove from the product and thus become difficult to meet current pharmaceutical purity standards

[0016] In another embodiment of the present invention, the treating step is carried out with an organoaluminum-based Lewis acid catalyst in an amount of from about 0.5 mol% to about 100 mol% relative to the first intermediate compound. In yet another embodiment of the present invention, the treating step is carried out with the organoaluminum-based Lewis acid catalyst in an amount of from about 5 mol% to about 15 mol% relative to the first intermediate compound.

[0017] The treating step may be carried out in an organic solvent. In one embodiment of the invention, the solvent is aprotic. Examples of organic solvents include, but are not limited to, hexane, heptane, toluene, xylene, methylene chloride, and mixtures thereof.

[0018] The treating step may be carried out at a temperature of from about-20 ℃ to about 100 ℃. In another embodiment of the present invention, the treating step may be carried out at a temperature of from about-20 ℃ to about 50 ℃. In yet another embodiment of the present invention, the treating step may be carried out at a temperature of from about 0 ℃ to about 30 ℃.

[0019]In another embodiment of the invention, R₂Is n-C₅H₁₁And R₁＝R₃＝R₄＝H。

[0020] In another embodiment, the process of the present invention further comprises contacting the second compound of the formula,

wherein: r₁Is H, substituted or unsubstituted alkyl, carboxylate, or acyl;

R₃is H, substituted or unsubstituted alkyl, carboxylate, or acyl; and

R₄is SO₂R₅Wherein R is₅Is a substituted or unsubstituted alkyl group, and is,

in which R is₄Product of a compound of formula (i) H, with substituted or unsubstitutedThe alkyl sulfonyl halide, alkyl sulfonic anhydride (alkyl sulfonic anhydride), alkyl sulfonic mixed anhydride (alkyl sulfonic anhydride), alkyl sulfonate (alkyl sulfonate) or alkyl sulfonic acid.

Alternatively, the product compound can be reacted with a similar arylsulfonyl reagent to produce an arylsulfonate compound.

[0021] In one embodiment, the above reaction is carried out with an alkyl sulfonyl compound in an amount of about 1 to 1.5 equivalents relative to the compound product at a temperature of about-20 ℃ to about 100 ℃, depending on the reagents, at standard atmospheric pressure. When alkylsulfonyl chlorides are used, for example, the reaction is typically carried out at a temperature of from about-10 ℃ to about 20 ℃.

[0022] The compound product may be a wholly synthetic material or a naturally derived material.

[0023] In another embodiment, the process of the invention further comprises subjecting the second compound product to a process selected from the group consisting of chromatography, countercurrent extraction, and distillation under conditions effective to produce a purified second compound product. In another embodiment, the process of the invention further comprises crystallizing the second compound product under conditions effective to produce a purified second compound product.

[0024] The purified second compound product can be hydrolyzed under conditions effective to produce a purified compound product in the desired isomeric form. In another embodiment of the present invention, the hydrolysis step is carried out in a solvent in the presence of an organic or inorganic base. Examples of bases include, but are not limited to, sodium hydroxide, potassium tert-butoxide, and mixtures thereof. Examples of solvents include, but are not limited to, methanol, ethanol, isopropanol, tert-butanol, acetonitrile, and mixtures thereof.

[0025]In another embodiment of the invention, R₁＝R₃H and R₂H, OH, protected hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, aryl, or heteroaryl. In yet another embodiment of the present invention, R₁＝R₃H and R₂Is n-C₅H₁₁。

[0026] In another embodiment of the invention, the second compound product has the formula:

wherein:

[0027]"alkyl" is defined herein as C₁-C_nWherein the carbon chain may be straight, branched or contain or include rings. "substituted alkyl" is defined as C as described above_1X-C_nX, apart from carbon, may carry one or more substituents X, for example functional groups containing oxygen, nitrogen, sulfur, halogen or aromatic or heteroaromatic rings. "aryl" is defined as C₆-C_nAromatic or polycyclic. "substituted aryl" is defined as a C with a substituent on one or more of these rings that can be a carbon, oxygen, nitrogen, sulfur, or halogen functional group₆-C_nAromatic or polycyclic. "heteroaryl" is defined as an aromatic ring containing one or more heteroatoms in one or more rings. "substituted heteroaryl" is defined as heteroaryl containing one or more substituents on one or more rings that can be carbon, oxygen, nitrogen, sulfur, or halogen functional groups. "halo" is defined as chloro, bromo, iodo or fluoro. In addition, R₈、R₉And R₁₀May contain chiral centers or define a chiral center on the carbon bearing them.

[0028] In another embodiment of the invention, the second compound product is a linear alkyl sulfonate selected from the group consisting of methanesulfonate, ethanesulfonate, propanesulfonate, butanesulfonate, pentanesulfonate, hexanesulfonate, heptanesulfonate, octanesulfonate, nonanesulfonate, decanesulfonate, undecanesulfonate, dodecanesulfonate, tridecanesulfonate, tetradecanesulfonate, pentadecanesulfonate, hexadecanesulfonate, heptadecanesulfonate, octadecanesulfonate, nonadecanosulfonate, and eicosanesulfonate (icosanesulfonate).

[0029] In another embodiment of the invention, the second compound product is a branched alkyl sulfonate selected from the group consisting of cyclopropyl sulfonate, isopropyl sulfonate, isobutyl sulfonate, tert-octyl sulfonate, adamantyl sulfonate, and 10-camphorsulfonate.

[0030] In another embodiment of the invention, the second compound product is a substituted alkyl sulfonate selected from chloromethylsulfonate, 2-chloroethylsulfonate, trifluoromethylsulfonate, trifluoroethylsulfonate, perfluoroethylsulfonate, perfluorobutylsulfonate, perfluorooctylsulfonate, 2-aminoethylsulfonate, 2-dimethylaminoethylsulfonate, 2-phthalimidoethylsulfonate, 2-morpholinoethylsulfonate, 3-morpholinopropylsulfonate, 4-morpholinobutylsulfonate, 2-N-piperidinylethylsulfonate, 3-N-piperidinylpropylsulfonate, 2-pyrrolidinylmethylsulfonate, 2-methoxyethylsulfonate, (1R) -3-bromocamphor-8-sulfonate, bromo-camphor-8-sulfonate, bromo-2-piperidinylethanesulfonate, bromo-3-piperidinopropylsulfonate, bromo-2-pyrrolidinomethylsulfonate, bromo-2-piperidinoethylsulfonate, bromo-, (1S) -3-bromocamphor-8-sulfonic acid ester, (1S) -3-bromo-camphor-10-sulfonic acid ester, (1R) -10-camphorsulfonic acid ester, and (1S) -10-camphorsulfonic acid ester.

[0031] In particular, the second compound product can have the formula wherein the camphorsulfonate group is present in the S configuration:

[0032] alternatively, the second compound product can have the formula wherein the camphorsulfonate group is present in the R configuration:

[0033] in another embodiment of the invention, the second compound product is a diastereomeric mixture of the following two formulae wherein the camphorsulfonate groups are present in the S and R configurations, respectively:

[0034] in another embodiment of the invention, the second compound product is an aryl or heteroaryl substituted alkyl sulfonate selected from the group consisting of benzyl sulfonate, 2-nitrobenzyl sulfonate, 3-nitrobenzyl sulfonate, 4-nitrobenzyl sulfonate, 2-chlorobenzyl sulfonate, 3-chlorobenzyl sulfonate, 4-chlorobenzyl sulfonate, 2-trifluoromethylbenzyl sulfonate, 3-trifluoromethylbenzyl sulfonate, 4-trifluoromethylbenzyl sulfonate, 3, 5-dichlorobenzyl sulfonate, 3, 5-bistrifluoromethylbenzyl sulfonate, 4-methylbenzyl sulfonate, 4-tert-butylbenzyl sulfonate, 1-naphthylethyl sulfonate, 2-pyridylmethylsulfonate, 3-pyridylmethylsulfonate, 2-nitrobenzyl sulfonate, 4-nitrobenzyl sulfonate, and mixtures thereof, 4-pyridylmethylsulfonate, 2- (2-pyridyl) ethylsulfonate and diphenylmethanesulfonate.

[0035] In another embodiment, the process of the present invention further comprises reacting a second intermediate compound of the formula:

wherein:

R₆is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl;

with a second compound of the formula:

wherein X ═ H, alkyl, acyl, silyl, aryl, heteroaryl, sulfinyl, sulfonyl, phosphoryl, or phosphinyl.

[0036] In one embodiment of the invention, the reacting step is carried out under conditions effective to effect formation of the first intermediate compound in preference to the undesired stereochemical and regiochemical isomers and other impurities.

[0037]In another embodiment of the invention, R₁Is H or COOR₇，R₂Is n-C₅H₁₁And R₃Is H or COOR₇Wherein R is₇Is C₁-C₂₀An alkyl group. In another embodiment of the invention, R₁Is COOR₇Wherein R is₇Is ethyl, R₂Is n-C₅H₁₁And R₃Is H or COOR₇Wherein R is₇Is C₁-C₂₀Alkyl radical, R₄H and X H. In yet another embodiment of the invention, R₁＝R₃＝R₄＝H，R₂＝n-C₅H₁₁And X ═ H.

[0038] In another embodiment, the above reaction is carried out with the second intermediate compound in an amount of about 1 to about 1.2 equivalents relative to the second compound.

[0039] The metal triflate catalyst may be a transition metal triflate or a lanthanide triflate. Examples of transition metal triflates include, but are not limited to, zinc triflate, ytterbium triflate, yttrium triflate, and scandium triflate. In particular, the transition metal triflate is zinc triflate or scandium triflate.

[0040] In another embodiment of the present invention, the reacting step is carried out with the metal triflate catalyst in an amount of from about 0.5 mol% to about 100 mol% relative to the second intermediate compound. In yet another embodiment of the present invention, the reacting step is carried out with the metal triflate catalyst in an amount of from about 0.5 mol% to about 10 mol% relative to the second intermediate compound.

[0041] In another embodiment of the present invention, the reacting step is carried out in an organic solvent. Examples of organic solvents include, but are not limited to, hydrocarbons, aromatic hydrocarbons, halogenated hydrocarbons, ethers, esters, amides, nitriles, carbonates, alcohols, carbon dioxide, and mixtures thereof. Specifically, the organic solvent is dichloromethane.

[0042] In another embodiment of the present invention, the reacting step is carried out at a temperature of from about-20 ℃ to about 150 ℃. In particular, the reaction step may be carried out under pressure, at a temperature above the atmospheric boiling point of the organic solvent or wherein the temperature is above the boiling point and the pressure is greater than atmospheric pressure.

[0043] In another embodiment of the present invention, the reacting step is carried out with less than about one equivalent of the second compound relative to the second intermediate compound.

Examples

[0044] The following examples are provided to illustrate embodiments of the present invention but are in no way intended to limit its scope.

Example 1 preparation of Cannabis diolate Ethyl ester by condensation of Oleanolic acid Ethyl ester (ethyl oleate) with Mendienol

[0045]Oleanolic acid ethyl ester (25g, 99mmol) was dissolved in dichloromethane (250mL) and MgSO was added sequentially₄(25g, 1wt) and Sc (OTf)₃(4.88g, 9.9mmol, 10 mol%). Using a dropping funnel, a solution of menthadiene alcohol (24.5g, 161mmol, 1.6 equiv., assumed 100% pure but actually about 80-85% AUC by GC) in dichloromethane (125mL) was added over 1.5 hours. The reaction was monitored by HPLC analysis and after about 3 hours the reaction was filtered through celite, the solid was washed with dichloromethane (125mL) and the combined organics evaporated under reduced pressure. The residue was dissolved in heptane and applied to 5wt silica, then eluted with heptane (1X 500mL), 10% dichloromethane/heptane (6X 500mL), 15% dichloromethane/heptane (2X 500mL), and 20% dichloromethane/heptane (2X 500 mL). The fractions containing cannabidiolic acid ethyl ester were combined and concentrated to give the product (31.3g, 82% yield, 93.3% AUC by HPLC purity).

EXAMPLE 2 preparation of cannabidiol

[0046] Cannabidiolic acid ethyl ester from example 1 (31.3g, 81mmol) was dissolved in MeOH (10 volumes, 310mL) and degassed with argon. Separately, a solution of NaOH (64.8g, 1.62mol, 20 equivalents) in deionized water (10 volumes, 310mL) was prepared and degassed with argon. To this aqueous solution was added an organic solution under a strict argon atmosphere, and then the mixture was heated to reflux and held for 3.5 hours, after which it was cooled to room temperature. HPLC analysis showed the reaction was complete. The reaction mixture was quenched with aqueous citric acid (129.6g citric acid, 8.3 equivalents as a 30% aqueous solution). The addition process is exothermic. Heptane (310mL, 10 volumes) was added to the mixture and the product was extracted into the heptane phase. A second extraction with heptane (150mL, about 5 volumes) was then performed and HPLC analysis of the aqueous fraction showed no cannabidiol present. The combined organics were dried by azeotropic distillation with water and concentrated to about 250mL, then cooled to-16 to-17 ℃ and inoculated with solid cannabidiol when the temperature reached-1.5 ℃. After 20 hours, the solid formed is filtered off, washed with cold heptane and dried successively on a filter and under high vacuum. This finally gives 17.9g of cannabidiol (57.5% yield in two steps from ethyl oleurolate) in an HPLC purity of > 99.8% AUC.

EXAMPLE 3 preparation of trans-delta-9-THC

[0047] Cannabidiol (18.5g, 58.8mmol) from example 2 was dissolved in dichloromethane (324mL, 17.5 volumes) and heated to 25 ℃. Triisobutylaluminum (5.9mL of 1M hexane solution, 10 mol% catalyst) was then added via syringe and the reaction was stirred at 20-25 ℃ for about 20 hours. Thereafter, HPLC analysis of the reaction mixture showed cannabidiol consumption and 94.8% trans- δ -9-THC. The reaction was quenched with water (1.6mL, 15 equivalents based on moles of catalyst) and stirred for 1 hour. After filtration through celite, the solvent was switched to toluene and the reaction mixture was azeotroped to remove any remaining water. The toluene solution of the product (total volume about 92mL) was used directly in the subsequent step.

EXAMPLE 4 preparation of trans-delta-9-THC 3-Nitrobenzenesulfonate

[0048]A solution of the crude toluene of trans-delta-9-THC from example 3 (58.8 mmol, assuming quantitative yield) was treated with triethylamine (24.6mL, 3 equivalents), then a solution of 3-nitrobenzenesulfonyl chloride (13.04g, 1 equivalent) in toluene (92.5mL) was added to the reaction over about 30 minutes at room temperature. The addition funnel was washed with toluene (10mL) added to the reaction. After 2 hours, the starting material was consumed (by HPLC analysis), the reaction was quenched with water (185mL) and stirred for 20 minutes. The organic phase was collected and then treated with 10% citric acid (95mL), saturated NaHCO₃The solution (95mL) and water (185mL) were washed and then azeotropically dried. The solvent was replaced with isopropanol (147mL, 5 volumes, 100% yield based on sulfonate), seeded with crystalline trans-delta-9-THC 3-nitrobenzenesulfonate and stirred at room temperature for 24 hours. Separating the resulting solids by filtration19.4g of trans-delta-9-THC 3-nitrobenzenesulfonate are obtained, which is 99.2% pure by HPLC (AUC). A second crystallization from isopropanol (5 volumes) gave 16.7g of product with an HPLC purity of 99.6% AUC. The yield from cannabidiol was 57.4%.

EXAMPLE 5 preparation of- (-) -trans-delta-9-THC

[0049]trans-delta-9-THC 3-nitrobenzenesulfonate (16.5g) was dissolved in acetonitrile (330mL, 20 volumes) and 0.5M NaOH (165mL, 10 volumes) was added. The mixture was heated to reflux and after about 2 hours, HPLC analysis showed the reaction was complete. After cooling, water (500mL, 30 volumes) and heptane (165mL, 10 volumes) were added. The phases were mixed and the heptane layer was collected. The aqueous phase was re-extracted with heptane (165mL, 10 volumes) and the organic extracts combined, washed with water (165mL, 10 volumes), and Na₂SO₄Dried, filtered and concentrated to a dark purple brown oil. The oil was reconstituted with EtOH and desorbed again to give the product as a light brown oil (10.79g) which by proton NMR analysis showed about 6% EtOH. HPLC analysis showed 99.66% purity AUC.

Example 6 preparation of cannabidiol by condensation of Oleanolic with Mendienol

[0050]With Zn (OTf)₂(10mg, 0.5 mol%) A solution of Oleyl-alcohol (1g, 5.56mmol) in dichloromethane (15mL) was treated and heated to 60 ℃ in a modified pressure tube equipped with a septum for addition. A solution of menthadiene alcohol (0.63g, 0.75 eq., 4.14mmol) in dichloromethane (5mL) was added via syringe over 5.5 h. After a total of 6 hours, HPLC analysis of the reaction showed a 2.6: 1 ratio of cannabidiol to abn-cannabidiol (47.0%: 17.9%) with 23.3% unreacted Oleanolic alcohol to 4.3% double bond addition product. Only trace levels of ring degradation (delta-8-and delta-9-THC) were observed even after a total of 20 hours of continuous heating.

EXAMPLE 7 preparation of- (+) -Mendienol

[0051] To a stirred mixture of potassium carbonate (2.98kg) in ethanol (16.7L) was added (+) -limonene oxide (25.0kg) and the mixture was heated to 60 ℃. Thiophenol (Thiophenol) (8.86kg) was added at 70-80 ℃ over 11 hours. Ethanol was distilled off at atmospheric pressure over a 4 hour period until the pot temperature reached 105 ℃, the batch was cooled to 80 ℃, and then cold water (16L) was added. After cooling to 40 ℃, methyl tert-butyl ether (MTBE, 16L) was added. The organic phase was separated, washed with water (4.5L) and the solvent removed under reduced pressure at 60 ℃. The residual oil (30.9kg) was sent to a 4 inch wiped film evaporator at 3mm and 145 ℃ to remove unreacted limonene oxide. The nonvolatile fraction (14.7kg of thiophenyl ether) was dissolved in glacial acetic acid (26.0L) and stirred while 35% hydrogen peroxide (6.0kg) was added over 6.5 hours. The reaction temperature was maintained at 10-20 ℃. The reaction was allowed to warm to room temperature overnight and then transferred to a mixture of warm water (89L, 40-45 ℃) and MTBE (34L). The organic phase was washed with 5% aqueous sodium bicarbonate at 40-45 deg.C (4 washes of 18L each) to a final pH of about 8 and was negative in the starch-iodine experiment. The organic phase was concentrated at 60 ℃ under reduced pressure to give a residue of crude sulfoxide mixture (14.8kg, estimated 95% yield). The residue was dissolved in tetraglyme (11.6L) and stored until needed, during which time the product partially crystallized. The solution was warmed gradually to dissolve the sulfoxide mixture again. To a portion of this tetraglyme solution (containing about 8.3kg of sulfoxide mixture) was added potassium carbonate (2.7kg) and tetraglyme (5L) and the stirred mixture was heated to 180 ℃ with the application of vacuum (75-80mm) and the volatiles were distilled over a period of 9 hours. The strongly smelling distillate (ca. 2.8kg) was dissolved in heptane (2.5L) and washed with water (4.5L +1L) and then concentrated under reduced pressure at 60 ℃ to crude (+) -menthadiene alcohol (1.76kg) with a purity of about 83% by GC analysis. In a stirred round bottom flask equipped with 5 pieces of an Oldershaw column with a 2 inch diameter fitted with a reflux return splitter, several batches of crude (+) -menthadiene alcohol (about 6.68kg total) were combined with hexadecane (1.00kg) and solid potassium carbonate (67 g). Distillation was effected at a pot temperature of about 105 ℃ and 110 ℃ with a vacuum of about 1-5 mm. After removal of the initial low-boiling fraction (bp: 45-75 ℃), a total of 4.0kg of (+) -menthadieneol were collected as the main fraction boiling between 75 and 80 ℃ (95-98% (AUC) by gas chromatography). The optical rotation of the sample prepared by this method was +75.4 ° (c ═ 1.074 at 25 ℃ in chloroform). The literature value is +67.9 ℃ at 20 ℃ (Ohloff et al, Helvetica ChimicaActa, 63: 76(1980), which is hereby incorporated by reference in its entirety).

Example 7 representative laboratory procedure for Ethyl Oleanolate

Preparation of Ethyl dihydroolivetol Ether Sodium salt (Sodium Ethyl Dihydroolivetolate)

[0052]To a stirred mixture of absolute ethanol (10.5L) and diethyl malonate (1.90kg) was added sodium ethoxide solution (21% in ethanol, 4.2L) over 35 minutes at 20 ℃. The reaction temperature was raised to 27 ℃. 3-nonen-2-one (1.50kg) was added to the resulting slurry over a period of 3 hours, and the temperature was raised to 45-50 ℃. The reaction mixture was heated to 70 ℃ over 2 hours and held for an additional 2 hours. The reaction mixture was then allowed to cool to 0 ℃ and held overnight. The solid product was then collected by filtration through a polypropylene filter. The solid filter cake was rinsed with MTBE (5.0L) and then dried to constant weight at 20-25 deg.C under reduced pressure to give 2.38kg (99% yield) of ethyl dihydroolivil ether sodium salt as an off-white solid.¹H NMR 500MHz(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 4.4ppm (s, 1H). HPLC analysis showed 100% product (Phenomenex (Houston, TX) hypercone 5u BDS C18 column, 4.6 × 150mm, 1 mL/min, gradient 100% water/0.1% TFA to 100% acetonitrile/0.1% TFA over 15 min, rt 8.0 min).

Preparation of ethyl dibromo oleurol ether

[0053]To a stirred suspension of ethyl dihydroolivetol ether sodium salt (200.8g, 0.727mol) and anhydrous sodium acetate (238.5g, 2.91mol) in acetic acid (1010mL) was added bromine (655.5g, 2.29mol) dropwise over a period of 3 hours at 50 ℃ while maintaining the batch temperature at 50-55 ℃. After stirring at 50-55 ℃ for a further 1 hour, the slurry was cooled to 20 ℃ over 3 hours. Water (9) was added over 1 hour25mL) during which the product crystallized. The slurry was allowed to cool to 10 ℃, left overnight, and then filtered through filter paper. The solid filter cake was washed with water (3X 400mL to achieve a final rinse pH of 4) and then air dried overnight to give 310g (86% yield) of crude ethyl dibromoolivil ether containing about 11.7% by weight water.¹H NMR，500MHz(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 12.3ppm s, 1H). HPLC analysis showed 98.5% product (AUC, Sunfire reverse phase C18 column from Waters Corporation (Milford, MA), 4.6 × 150mm, 1 mL/min, gradient 80% 0.1% TFA in water with 20% 0.5% TFA in acetonitrile to 100% 0.5% TFA in acetonitrile over 15 min, rt 13.8 min).

Preparation of ethyl oleurol ether

[0054]A2L Parr reactor to which was added ethyl dibromoOleanolic ether (160.3g of a water-wet mass, 0.345mol), ethanol (290mL), water (440mL), sodium citrate (220g, 0.747mol) and 5% palladium on charcoal catalyst (7.4g) was degassed with nitrogen and then pressurized to 50 psig with hydrogen. Stirring was started and the reaction mixture was heated to 60 ℃ and kept at that pressure and temperature for 6 hours, after which the heating was stopped. After cooling to ambient temperature, the mixture was filtered through celite (100g), and the reactor and solid filter cake were rinsed with water (600mL) followed by toluene (300 mL). The layers were separated and the organic phase was evaporated under reduced pressure to give a semi-solid residue. Heptane (260mL) was added and the mixture was warmed to 45 ℃ at which time the solid dissolved. The stirred mixture was allowed to slowly cool to ambient temperature over night during which time crystallization occurred. The slurry was cooled to 5 ℃, left for 4 hours, and the solid product was collected by filtration. The filter cake was rinsed with cold heptane (150mL) and then dried at 20 ℃ under reduced pressure to constant weight to give 63.0g (72% yield) of yellow crystalline ethyl oleurolate. HPLC analysis showed the product to be 99.6% pure (AUC, Sunfire reverse phase C18 column, 4.6 × 150mm, 1 mL/min flow rate, gradient 80% 0.1% TFA in water with 20% 0.5% TFA in acetonitrile to 100% 0.5% TFA in acetonitrile over 15 min, rt 10.3 min). The product is obtained by meltingPoints (mp: 66-67 ℃, literature: 68 ℃, Anker et al, J.chem.Soc. p. 311 (1945)) and NMR analysis.¹H NMR，500MHz(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 11.8ppm (s, 1H).

EXAMPLE 8 preparation of Cannabis diphenolic acid ethyl ester

[0055] To a stirred solution of ethyl oleurolate (40.1g, 155mmol) in dichloromethane (360mL) was added anhydrous magnesium sulfate (10.4g) and scandium triflate (3.93g, 8 mmol). The mixture was cooled to 10 ℃. To this slurry was added over 3 minutes a cold solution of (+) -menthadiene alcohol (25.1g, 155mmol) in dichloromethane (160mL) followed by a dichloromethane (120mL) rinse. A slight exotherm was observed. After stirring for 3 hours at 10 ℃, HPLC analysis showed the reaction was complete and there was no further decrease in the oleurol ester concentration. The reaction was quenched by the addition of solid anhydrous sodium carbonate (4.0g) and stirred at 25 ℃ overnight. The reaction mixture was clarified by filtration through a celite bed and the filter cake was washed with dichloromethane (250 mL). The combined filtrates were concentrated under reduced pressure to a volume of about 150 mL. Heptane (400mL) was added and the mixture was again concentrated under reduced pressure to about 150 mL. Heptane (400mL) was added and the mixture was extracted with sodium hydroxide solution (2X 200mL of 20% aqueous solution) followed by water (2X 200 mL). HPLC analysis showed the organic phase to be free of any residual ethyl oleurolate. The heptane phase was concentrated under reduced pressure to 58.6g (87% yield after calibration for 90% HPLC purity) of a dark oil, mainly cannabidiolic acid ethyl ester, as determined by HPLC analysis. The crude material was used directly in the next step described in example 9.

EXAMPLE 9 preparation of cannabidiol

[0056] Crude cannabidiolic acid ethyl ester (58.6g, approx. 90% purity by HPLC) was dissolved in methanol (390mL) and the stirred solution was degassed by refluxing under nitrogen for 1 hour. An aqueous solution of sodium hydroxide (80.8g of NaOH in 390mL of water) was degassed by refluxing under nitrogen for 1 hour. The hydroxide solution was transferred through a steel tube to a hot cannabidiolic acid ethyl ester/methanol solution under nitrogen pressure over 20 minutes while maintaining the reaction at 70 ℃. After 5 hours at 70-80 ℃, the hydrolysis was found to be complete by HPLC analysis and the reaction was cooled to 20 ℃. The reaction was quenched by the addition of degassed aqueous citric acid (50 wt% solution, 400 g). The mixture was extracted with heptane (400mL) and the organic layer was washed with aqueous sodium bicarbonate (300mL) and water (300 mL). The heptane solution was concentrated to about 100mL under reduced pressure, reconstituted with heptane (400mL), again concentrated to about 50mL and heptane (200mL) was added. The slowly stirred heptane solution was allowed to cool to 10 ℃, seeded with cannabidiol crystals and stirred slowly at 10 ℃ for 3 hours to allow the first crop of crystals to appear. The slurry was stored overnight at-5 ℃. The solid product was collected by filtration on cold sintered glass (filter) and the reactor and filter cake were rinsed with cold heptane (150 mL). The solid was dried under a stream of nitrogen for 2 hours and then decompressed at 20 ℃ for 15 hours to give 21g (44% yield) of solid cannabidiol. HPLC analysis showed 99.6% (AUC) product (Sunfire C185u column, 4.6mm × 150mm, 1 ml/min flow rate, gradient 80% 0.1% TFA/water and 20% 0.05% TFA acetonitrile to 100% 0.05% TFA/acetonitrile over 15 min, rt 11.9 min).

EXAMPLE 10 preparation of crude delta-9-tetrahydrocannabinol

[0057] To a nitrogen-inerted, stirred solution of cannabidiol (21.2g, 67.1mmol) in dichloromethane (370mL) was added a commercial solution of triisobutylaluminum (1M in hexane, 6.7mL, 10 mol%) via a syringe pump over 4.5 hours. The temperature of the reaction mixture was maintained at 20-25 ℃ and the mixture was stirred overnight. The next day triisobutylaluminum solution (1M in hexanes, 2.67mL, 4 mol%) was added to drive the reaction to > 99% conversion of the reaction as analyzed by HPLC. The reaction was quenched by the addition of water (250mL), stirred for 30 minutes, combined with a slurry of celite in methylene chloride (10.0g in 70mL of methylene chloride), and then clarified. The reactor and filter cake were rinsed with dichloromethane (50mL) and the combined filtrates were distilled under reduced pressure (25 ℃ pot temperature, 22 inches vacuum) to a volume of about 50 mL. Toluene (106mL) was added and the solvent removed again under reduced pressure. Additional toluene (106mL) was added and removed under reduced pressure, and the residue, which contained no dichloromethane, was reconstituted with toluene (100 mL). HPLC analysis showed 95.6% delta-9-tetrahydrocannabinol, 1.1% cis-tetrahydrocannabinol and no cannabinol. (Sunfire C185u, 4.6mm × 150mm, 1 ml/min, gradient 80% 0.1% TFA/water and 20% 0.05% TFA/acetonitrile to 100% 0.05% TFA/acetonitrile over 15 min, delta-9 tetrahydrocannabinol: rt 15.1 min). The yield was estimated to be 95%. The solution was stored under nitrogen until needed for the preparation of camphorsulfonate derivatives.

EXAMPLE 11 preparation of delta-9-tetrahydrocannabinol (1S) -10-camphorsulfonate

[0058]To a solution of crude delta-9-tetrahydrocannabinol in toluene (containing 21.1g delta-9-tetrahydrocannabinol,. delta.7.1 mmol, in 100mL toluene) was added a solution of 4-dimethylaminopyridine (0.83g) and diisopropylethylamine (35.2mL, 3 equivalents) in toluene (106 mL). The stirred reaction mixture was cooled to 0 ℃ and a slurry of (1S) -10-camphorsulfonyl chloride (19.8g, 74.8mmol, 1.1 equiv.) in toluene (150mL) was added at 0 ℃ over 30 minutes. The addition funnel was rinsed with toluene (50mL) and the rinse was added to the stirred reaction mixture, which was allowed to stand overnight at 0 ℃. Additional (1S) -10-camphorsulfonyl chloride (10.75 g total in toluene (55 mL)) was added over 6 hours to achieve 99% conversion. Water (200mL) was added over 15 minutes and the mixture was stirred overnight. The organic phase was washed with 5% aqueous citric acid (100mL), 5% aqueous sodium bicarbonate (100mL) and 5% aqueous sodium chloride (100 mL). The toluene layer was concentrated to about 100mL under reduced pressure and additional toluene (100mL) was added. The 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 allowed to warm to 40 ℃ at which time the solids dissolved. The stirred solution was allowed to cool to 20 ℃ over 4 hours, during which time the product crystallized. After stirring for 2 hours at 15-20 ℃, the product was collected by filtration, rinsed with cold isopropanol (90mL) and the solid crystalline product was dried under reduced pressure at 50 ℃ to give 19.67g (56% yield) of delta-9-tetrahydrocannabinol (1S) -10-camphorsulfonate. HPLC analysis showed 98.5% delta-9-tetrahydrocannabinol (1S) -10-camphorsulfonic acidEster, 0.86% delta-8-tetrahydrocannabinol (1S) -10-camphorsulfonate and 0.35% cis-tetrahydrocannabinol (1S) -10-camphorsulfonate. mp 94-95 ℃.¹H NMR 500MHz(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 (doublet of triplets, 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 6.68ppm (s, 1H).

Example 12 purified delta-9-tetrahydrocannabinol

[0059]To a mechanically stirred slurry of crystalline purified delta-9-tetrahydrocannabinol (1S) -10-camphorsulfonate (1.1g, 2.1mmol) in water (3.6mL) and t-butanol (7.4mL) was added a mixture of sodium hydroxide (0.83g, 21mmol) in water (7.4mL) and t-butanol (15mL) under argon. The slurry was heated to 70 ℃ over 2 hours at which time HPLC analysis indicated complete hydrolysis. The reaction mixture was cooled to ambient temperature and diluted with water (11mL) and extracted with heptane (11 mL). The heptane solution was washed with water (2X 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, DE) Hypersil Gold, 4.6 mm. times.150 mm, isocratic MeOH/H₂O/THF (71: 24: 5) mixture at 1 mL/min flow rate, 228nm, δ -9-tetrahydrocannabinol rt 18.9 min, cis- δ -9-tetrahydrocannabinol rt 17.7 min. The solution was stored under argon atmosphere and in a refrigerator until the next step was carried out.

Example 13 preparation of delta-9-tetrahydrocannabinol in sesame oil

[0060]Stock solutions of delta-9 THC in ethanol (6.90g, 0.109mg/mL tetrahydrocannabinol concentration) were mixed with Croda high purity sesame oil (29.25g) from Croda corporation (Edison, NJ). The resulting solution was warmed to 30 ℃ and sprayed with filtered argon for 24 hours to give about 30g of 2.5% delta-9-tetrahydrocannabinol in sesame oil.¹H NMR 500MHz(CDCl₃) Showing no residual ethanol.

Example 14 preparation of crude delta-9-tetrahydrocannabinol

[0061] To a solution of cannabidiol (500mg) in dichloromethane (8.75mL) was added a solution of an organoaluminium based lewis acid catalyst in dichloromethane (1.0mL) over 5 minutes at 20 ℃ and the reaction mixture was stirred under nitrogen and monitored by HPLC. Table 1 below shows the relative HPLC quantification of area percent of the different compound products at specific times with different organo-aluminum based lewis acid catalysts.

TABLE 1

[0062] Although the present invention has been described in detail for the purpose of illustration, it is to be understood that such detail can be readily made by those skilled in the art for that purpose without departing from the spirit and scope of the invention as defined by the following claims.

Claims

1. A process for preparing a product of a compound of the formula:

wherein:

R₁is H, substituted or unsubstituted alkyl, carboxylate, or acyl;

R₂h, OH, protected hydroxy, substituted or unsubstituted alkyl, alkenyl, alkynyl,Acyl, aryl or heteroaryl;

R₃is H, substituted or unsubstituted alkyl, carboxylate, or acyl; and

R₄is H, substituted or unsubstituted alkyl, silyl, hetero-substituted or unsubstituted acyl, alkylsulfonyl, arylsulfonyl, alkylphosphoryl, or arylphosphoryl;

the method comprises the following steps:

treating a first intermediate compound of the formula with an organoaluminum-based lewis acid catalyst under conditions effective to produce a product of the compound:

2. the process according to claim 1, wherein the organo-aluminum based Lewis acid catalyst is selected from the group consisting of trialkyl-or triaryl aluminum, dialkyl-or diarylaluminum halide, alkylaryl aluminum halide, dialkyl-or alkylaryl-or diarylaluminum alkoxide or aryloxide, dialkyl-or alkylaryl-or diarylaluminum thioalkoxide or thioarylide, dialkyl-or alkylaryl-or diarylaluminum carboxylate, alkyl-or arylaluminum dihalide, alkyl-or arylaluminum dialkoxide or diaryloxide or alkylaryloxy oxide, alkyl-or arylaluminum dithioalkoxide or dithioarylate, alkyl-or arylaluminum dicarboxylate, aluminum trialkoxide or aluminum triaryloxide or aluminum mixed alkylaryl oxide, aluminum mixed alkylaryl oxide, Aluminum triacyl carboxylates and mixtures thereof.

3. The process according to claim 2, wherein the organo-aluminum based lewis acid catalyst is C₁-C₃₀An alkylaluminum-based catalyst.

4. The process according to claim 2, wherein the organo-aluminum based lewis acid catalyst is ethylaluminum dichloride, diethylaluminum chloride, diethylaluminum sesquichloride, isobutylaluminum dichloride, diisobutylaluminum chloride or a mixture thereof.

5. The process according to claim 2, wherein the trialkylaluminum is trimethylaluminum, triethylaluminum, triisopropylaluminum, triisobutylaluminum, trioctylaluminum or tridecylaluminum.

6. The process according to claim 2, wherein the organoaluminium-based lewis acid catalyst is diisobutylaluminium acetate, diisobutylbenzoate, diisobutyltrifluoroacetate, diisobutylaluminium isopropoxide, diisobutylaluminium 2, 6-di-tert-butyl-4-methylphenolate or isobutylaluminum bis- (2, 6-di-tert-butyl-4-methylphenolate).

7. The process according to claim 1, wherein the treatment is carried out with the organoaluminum-based lewis acid catalyst in an amount ranging from about 0.5 mol% to about 100 mol% relative to the first intermediate compound.

8. The process according to claim 7, wherein the treatment is carried out with the organoaluminum-based Lewis acid catalyst in an amount ranging from about 5 mol% to about 15 mol% relative to the first intermediate compound.

9. The process according to claim 1, wherein the treatment is carried out in an organic solvent.

10. The process according to claim 9, wherein the solvent is an aprotic solvent.

11. The process according to claim 9, wherein the organic solvent is hexane, heptane, toluene, xylene, dichloromethane or mixtures thereof.

12. The method according to claim 1, wherein the treatment is carried out at a temperature of about-20 ℃ to about 100 ℃.

13. The method according to claim 12, wherein the treatment is carried out at a temperature of about-20 ℃ to about 50 ℃.

14. The method according to claim 13, wherein the treatment is carried out at a temperature of about 0 ℃ to about 30 ℃.

15. The method according to claim 1, wherein R₂Is n-C₅H₁₁And R is₁＝R₃＝R₄＝H。

16. The method according to claim 1, further comprising:

under conditions effective to produce a product of a second compound of the formula,

wherein:

R₁is H, substituted or unsubstituted alkyl, carboxylate, or acyl;

R₃is H, substituted or unsubstituted alkyl, carboxylate, or acyl; and

in which R is₄The product of the compound ═ H, reacted with substituted or unsubstituted alkyl sulfonyl halides, alkyl sulfonic anhydrides, mixed anhydrides of alkyl sulfonic acids, alkyl sulfonates, or alkyl sulfonic acids.

17. The method according to claim 16, wherein the compound product is a fully synthetic or naturally derived material.

18. The method according to claim 16, further comprising:

subjecting the second compound product to a method selected from the group consisting of chromatography, countercurrent extraction, and distillation under conditions effective to produce a purified second compound product.

19. The method according to claim 16, further comprising:

crystallizing the second compound product under conditions effective to produce a purified second compound product.

20. The method according to claim 19, further comprising:

hydrolyzing the purified second compound product under conditions effective to produce the purified compound product in the desired isomeric form.

21. The process according to claim 20, wherein the hydrolysis is carried out in a solvent in the presence of an organic or inorganic base.

22. The process according to claim 21, wherein the base is sodium hydroxide, potassium tert-butoxide or a mixture thereof.

23. The method according to claim 21, wherein the solvent is methanol, ethanol, isopropanol, tert-butanol, acetonitrile or a mixture thereof.

24. The method according to claim 16, wherein R₁＝R₃H and R₂H, OH, protected hydroxyl, substituted or unsubstituted alkyl, alkenyl, alkynyl, acyl, aryl, or heteroaryl.

25. The method according to claim 24, wherein,wherein R is₁＝R₃H and R₂Is n-C₅H₁₁。

26. A method according to claim 16, wherein the second compound product has the formula:

wherein:

27. The compound according to claim 26, wherein said compound is a linear alkyl sulfonate selected from the group consisting of mesylate, esylate, propanesulfonate, butanesulfonate, pentanesulfonate, hexanesulfonate, heptanesulfonate, octanesulfonate, nonanesulfonate, decanesulfonate, undecanesulfonate, dodecanesulfonate, tridecanesulfonate, tetradecanesulfonate, pentadecanesulfonate, hexadecanesulfonate, heptadecanesulfonate, octadecanesulfonate, nonadecanosulfonate, and eicosanesulfonate.

28. The compound according to claim 26, wherein the compound is a branched alkyl sulfonate selected from the group consisting of cyclopropyl sulfonate, isopropyl sulfonate, isobutyl sulfonate, tert-octyl sulfonate, adamantyl sulfonate, and 10-camphorsulfonate.

29. The compound according to claim 26, wherein the compound is a substituted alkyl sulfonate selected from chloromethylsulfonate, 2-chloroethylsulfonate, trifluoromethylsulfonate, trifluoroethylsulfonate, perfluoroethylsulfonate, perfluorobutylsulfonate, perfluorooctylsulfonate, 2-aminoethylsulfonate, 2-dimethylaminoethylsulfonate, 2-phthalimidoethylsulfonate, 2-morpholinoethylsulfonate, 3-morpholinopropylsulfonate, 4-morpholinobutylsulfonate, 2-N-piperidinylethylsulfonate, 3-N-piperidinylpropylsulfonate, 2-pyrrolidinylmethylsulfonate, 2-methoxyethylsulfonate, (1R) -3-bromocamphor-8-sulfonate, a, (1S) -3-bromocamphor-8-sulfonic acid ester, (1S) -3-bromo-camphor-10-sulfonic acid ester, (1R) -10-camphorsulfonic acid ester, and (1S) -10-camphorsulfonic acid ester.

30. A compound according to claim 26, wherein the compound has the formula:

31. a compound according to claim 26, wherein the compound has the formula:

32. the compound according to claim 26, wherein said compound is a diastereomeric mixture of a compound of the following two structural formulae:

33. the compound according to claim 26, wherein said compound is an aryl or heteroaryl substituted alkyl sulfonate selected from the group consisting of benzyl sulfonate, 2-nitrobenzyl sulfonate, 3-nitrobenzyl sulfonate, 4-nitrobenzyl sulfonate, 2-chlorobenzyl sulfonate, 3-chlorobenzyl sulfonate, 4-chlorobenzyl sulfonate, 2-trifluoromethylbenzyl sulfonate, 3-trifluoromethylbenzyl sulfonate, 4-trifluoromethylbenzyl sulfonate, 3, 5-dichlorobenzyl sulfonate, 3, 5-bis-trifluoromethylbenzyl sulfonate, 4-methylbenzyl sulfonate, 4-tert-butylbenzyl sulfonate, 1-naphthylethyl sulfonate, 2-pyridylmethylsulfonate, 3-pyridylmethylsulfonate, and mixtures thereof, 4-pyridylmethylsulfonate, 2- (2-pyridyl) ethylsulfonate and diphenylmethanesulfonate.

34. The method according to claim 26, further comprising:

35. The method according to claim 26, further comprising:

36. The method according to claim 35, further comprising:

37. The method according to claim 1, further comprising:

reacting a second intermediate compound of the formula:

wherein:

with a second compound of the formula:

38. The method according to claim 37, wherein said reaction is carried out under conditions effective to achieve preferential formation of the first intermediate compound as compared to the undesired stereochemical and regiochemical isomers as well as the undesired compound.

39. The method according to claim 37, wherein R₁Is H or COOR₇，R₂Is n-C₅H₁₁And R₃Is H or COOR₇Wherein R is₇Is C₁-C₂₀An alkyl group.

40. The method according to claim 39, wherein R₁Is COOR₇Wherein R is₇Is ethyl, R₄H and X H.

41. The method according to claim 39, wherein R₁＝R₃＝R₄H and X H.

42. The method according to claim 37, wherein the metal triflate catalyst is a transition metal triflate or a lanthanide triflate.

43. The method according to claim 42, wherein the transition metal triflate is selected from the group consisting of zinc triflate, ytterbium triflate, yttrium triflate and scandium triflate.

44. The method according to claim 43, wherein the transition metal triflate is zinc triflate or scandium triflate.

45. The process according to claim 37, wherein the reaction is carried out with the metal triflate salt catalyst in an amount of from about 0.5 mol% to about 100 mol% relative to the second intermediate compound.

46. The process according to claim 45, wherein the reaction is carried out with the metal triflate catalyst in an amount from about 0.5 mol% to about 10 mol% relative to the second intermediate compound.

47. The process according to claim 37, wherein the reaction is carried out in an organic solvent.

48. The method according to claim 47, wherein the organic solvent is a hydrocarbon, aromatic hydrocarbon, halogenated hydrocarbon, ether, ester, amide, nitrile, carbonate, alcohol, carbon dioxide, or a mixture thereof.

49. The method according to claim 48, wherein the organic solvent is dichloromethane.

50. The process according to claim 37, wherein the reaction is carried out at a temperature of from about-20 ℃ to about 150 ℃.

51. The process according to claim 50, wherein the reaction is carried out under pressure, at a temperature above the atmospheric boiling point of the organic solvent or wherein the temperature is above the boiling point and the pressure is greater than atmospheric pressure.

52. The method according to claim 37, wherein the reaction is carried out with about one equivalent less of the second compound than the second intermediate compound.

53. A process for preparing a product of a compound of the formula:

wherein:

R₁is H, substituted or unsubstituted alkyl, carboxylate, or acyl;

R₃is H, substituted or unsubstituted alkyl, carboxylate, or acyl;

the method comprises the following steps: reacting a first starting compound of the formula:

with a second starting compound of the formula:

54. The method according to claim 53, wherein the reaction is carried out under conditions effective to achieve preferential formation of the first intermediate compound as compared to the undesired isomer.

55. The method according to claim 53, wherein R₁Is H or COOR₇，R₂Is n-C₅H₁₁And R₃Is H or COOR₇Wherein R is₇Is C₁-C₂₀An alkyl group.

56. The method according to claim 55, wherein R₁Is COOR₇Wherein R is₇Is ethyl, R₄H and X H.

57. The method according to claim 55, wherein R₁＝R₃＝R₄H and X H.

58. A process according to claim 53 wherein the metal triflate catalyst is a transition metal triflate or a lanthanide triflate.

59. The method according to claim 58, wherein the transition metal triflate is selected from the group consisting of zinc triflate, ytterbium triflate, yttrium triflate, and scandium triflate.

60. The method according to claim 59, wherein the transition metal triflate is zinc triflate or scandium triflate.

61. The method according to claim 60, wherein the reaction is carried out with the metal triflate salt catalyst in an amount of from about 0.5 mol% to about 100 mol% relative to the second intermediate compound.

62. The method according to claim 61, wherein the reaction is carried out with the metal triflate salt catalyst in an amount of from about 0.5 mol% to about 10 mol% relative to the second intermediate compound.

63. The method according to claim 53, wherein the reaction is carried out in an organic solvent.

64. The method according to claim 63, wherein the organic solvent is a hydrocarbon, an aromatic hydrocarbon, a halogenated hydrocarbon, an ether, an ester, an amide, a nitrile, a carbonate, an alcohol, carbon dioxide, or a mixture thereof.

65. The method according to claim 64, wherein the organic solvent is dichloromethane.

66. The method according to claim 53, wherein the reaction is carried out at a temperature of from about-20 ℃ to about 150 ℃.

67. The process according to claim 66, wherein the reaction is carried out under pressure, at a temperature above the atmospheric boiling point of the organic solvent or wherein the temperature is above the boiling point and the pressure is greater than atmospheric pressure.

68. The method according to claim 53, wherein the reaction is carried out with about one equivalent less of the second compound than the second intermediate compound.

69. A process for preparing a product of a compound of the formula:

wherein:

R₁is H, substituted or unsubstituted alkyl, carboxylate, or acyl;

R₃is H, substituted or unsubstituted alkyl, carboxylate, or acyl; and

R₄is SO₂R₅Wherein R is₅Is a substituted or unsubstituted alkyl group, the method comprising:

reacting a first intermediate compound of the formula:

wherein:

wherein R is₄' and R₆Must be H;

with a first compound of the formula:

wherein R is₄H; the third intermediate compound is then reacted with a substituted or unsubstituted alkyl sulfonyl halide, alkyl sulfonic anhydride, mixed anhydride of alkyl sulfonic acids, alkyl sulfonate ester, or alkyl sulfonic acid under conditions effective to produce the compound product.

70. A compound of the formula:

wherein:

R₁is H, substituted or unsubstituted alkyl, carboxylate, or acyl;

R₃is H, substituted or unsubstituted alkyl, carboxylate, or acyl;

R₈、R₉and R₁₀Are the same or different and are independently selected from H, substituted or unsubstituted alkylSubstituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, or halo; and

71. The compound according to claim 70, wherein the compound is a linear alkyl sulfonate selected from the group consisting of mesylate, esylate, propanesulfonate, butanesulfonate, pentanesulfonate, hexanesulfonate, heptanesulfonate, octanesulfonate, nonanesulfonate, decanesulfonate, undecanesulfonate, dodecanesulfonate, tridecanesulfonate, tetradecanesulfonate, pentadecanesulfonate, hexadecanesulfonate, heptadecanesulfonate, octadecanesulfonate, nonadecanosulfonate, and eicosanesulfonate.

72. The compound according to claim 70, wherein the compound is a branched alkyl sulfonate selected from the group consisting of cyclopropyl sulfonate, isopropyl sulfonate, isobutyl sulfonate, tert-octyl sulfonate, adamantyl sulfonate, and 10-camphorsulfonate.

73. The compound according to claim 70, wherein the compound is a substituted alkyl sulfonate selected from chloromethylsulfonate, 2-chloroethylsulfonate, trifluoromethylsulfonate, trifluoroethylsulfonate, perfluoroethylsulfonate, perfluorobutylsulfonate, perfluorooctylsulfonate, 2-aminoethylsulfonate, 2-dimethylaminoethylsulfonate, 2-phthalimidoethylsulfonate, 2-morpholinoethylsulfonate, 3-morpholinopropylsulfonate, 4-morpholinobutylsulfonate, 2-N-piperidinylethylsulfonate, 3-N-piperidinylpropylsulfonate, 2-pyrrolidinylmethylsulfonate, 2-methoxyethylsulfonate, (1R) -3-bromocamphor-8-sulfonate, a, (1S) -3-bromocamphor-8-sulfonic acid ester, (1S) -3-bromo-camphor-10-sulfonic acid ester, (1R) -10-camphorsulfonic acid ester, and (1S) -10-camphorsulfonic acid ester.

74. A compound according to claim 73, wherein the compound has the formula:

75. a compound according to claim 73, wherein the compound has the formula:

76. the compound according to claim 73, wherein said compound is a diastereomeric mixture of two structural formulae:

77. the compound according to claim 70, wherein the compound is an aryl-or heteroaryl-substituted alkyl sulfonate selected from the group consisting of benzyl sulfonate, 2-nitrobenzyl sulfonate, 3-nitrobenzyl sulfonate, 4-nitrobenzyl sulfonate, 2-chlorobenzyl sulfonate, 3-chlorobenzyl sulfonate, 4-chlorobenzyl sulfonate, 2-trifluoromethylbenzyl sulfonate, 3-trifluoromethylbenzyl sulfonate, 4-trifluoromethylbenzyl sulfonate, 3, 5-dichlorobenzyl sulfonate, 3, 5-bis-trifluoromethylbenzyl sulfonate, 4-methylbenzyl sulfonate, 4-tert-butylbenzyl sulfonate, 1-naphthylethyl sulfonate, 2-pyridylmethylsulfonate, 3-pyridylmethylsulfonate, and mixtures thereof, 4-pyridylmethylsulfonate, 2- (2-pyridyl) ethylsulfonate and diphenylmethanesulfonate.