13956-29-1

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Here, we report a three-step concise and stereoselective synthesis route to one of the most important phytocannabinoids, namely, (-)-cannabidiol (-CBD), from inexpensive and readily available starting material R-(+)-limonene. The synthesis involved the diastereoselective bifunctionalization of limonene, followed by effective elimination leading to the generation of key chiral p-mentha-2,8-dien-1-ol. The chiral p-mentha-2,8-dien-1-ol on coupling with olivetol under silver catalysis provided regiospecific (-)-CBD, contrary to reported ones which gave a mixture. The newly developed approach was further extended to its structural analogues cannabidiorcin and other tail/terpenyl-modified analogues. Moreover, its opposite isomer (+)-cannabidiol was also successfully synthesized from S-(-)-limonene.

The present disclosure concerns a group of cannabinoid compounds defined by formulas (I) to (IV), wherein R1 is —H or —COOH, for the first time isolated and fully characterized in structure, absolute stereochemistry by the present applicant. Methods of isolation, characterization, stereoselective synthesis, biological activity, pharmaceutical compositions and therapeutic applications of the present compounds as modulators of the cannabinoid CB1 receptor are also object of the disclosure.

Provided is a method for preparing synthetic cannabidiol, including hydrolysis-decarboxylation of a compound represented by formula (II) in a solvent-free state under atmospheric pressure. The method further includes preparation of the compound represented by formula (II). The method provides a safe, economical, environmentally friendly and scalable method for synthetic preparation of cannabidiol.

The invention provides a method for continuously preparing a cannabidiol intermediate compound (4R)-1-methyl-4-(2-(1-propylene))-2-cyclohexene-2-ol (formula III) through photooxidation, which comprises the following steps: taking (R)-(+)-limonene (formula I-a) as an initial raw material, carrying out continuous photooxidation reaction in a photoreactor to obtain peroxide, and then carrying out reduction reaction to obtain an intermediate III. The technical route is simple and easy to implement, conditions are mild, column separation and purification are not needed, the production cost is greatly reduced, and industrial production is convenient to implement. The cannabidiol intermediate compound III is prepared by using a simple synthesis route, and the method has the advantages of simple process, less pollution, easiness in purification and the like.

Cannabidiol (CBD), the second most abundant of the active compounds found in the Cannabis sativa plant, is of increasing interest because it is approved for human use and is neither euphorizing nor addictive. Here, we design and synthesize novel compounds taking into account that CBD is both a partial agonist, when it binds to the orthosteric site, and a negative allosteric modulator, when it binds to the allosteric site of the cannabinoid CB2 receptor. Molecular dynamic simulations and site-directed mutagenesis studies have identified the allosteric site near the receptor entrance. This knowledge has permitted to perform structure-guided design of negative and positive allosteric modulators of the CB2 receptor with potential therapeutic utility.

The present application discloses powder and aqueous formulations. These include but are not limited to water dispersible cannabinoid formulations, especially those comprising cannabidiol (CBD), cannabigerol (CBG), and cannabinol (CBN) as well as other cannabinoids. Generally, these embodiments do not include major amounts of Tetrahydrocannabinol (THC), but certain embodiments are envisioned that do contain measurable concentrations of THC. Embodiments may include one or more emulsifiers selected from the group consisting of Tween (polysorbate) 20, Tween 60, Tween 80, Span 20, Span 60, Span 80, Poloxamer 188, Vit E-TPGS (TPGS), TPGS-1000, TPGS-750-M, Solutol HS 15, PEG-40 hydrogenated castor oil, PEG-35 Castor oil, PEG-8-glyceryl capylate/caprate, PEG-32-glyceryl laurate, PEG-32-glyceryl palmitostearate, Polysorbate 85, polyglyceryl-6-dioleate, sorbitan monooleate, Capmul MCM, Maisine 35-1, glyceryl monooleate, glyceryl monolinoleate, PEG-6-glyceryl oleate, PEG-6-glyceryl linoleate, oleic acid, linoleic acid, propylene glycol monocaprylate, propylene glycol monolaurate, polyglyceryl-3 dioleate, polyglyceryl-3 diisostearate and lecithin.

The invention provides an isolated material, or a phenolate form of at least one phenol- containing active material, wherein the isolated material comprises one or more phenolate species and a counter ion (a cation) in the form of a metal salt, a phosphonium or an ammonium.

The invention discloses a preparation method of cannabidiol. To the method, malonate type compounds and hexanal serve as starting materials, Knoevenagel condensation reaction is carried out under basic conditions to obtain compound (3). The obtained compound (3) and the acetoacetate compound undergo Michael addition and intramolecular Aldol condensation reaction under basic conditions to obtain compound (5). Compound (5) is subjected to oxidative aromatization to give compound (6). Compound (6) and (+) - trans - are subjected to -2-8 - alkylation to give compound (-1 -) under acidic conditions to mint Friedel, Crafts diene 8 alcohol. The finally obtained compound (8) is subjected to high-temperature hydrolysis decarboxylation to obtain the target compound cannabidiol (CBD) under an alkaline condition, and has the CBD) high reaction selectivity, no isomer formation, high total yield, less byproducts, easy purification of the product, low process cost and easy realization of industrial production.

The invention discloses a synthetic method of cannabidiol, wherein the synthetic method specifically comprises the steps: carrying out a coupling reaction on a raw material A and (1S,4R)-1-methyl-4-(1-methyl vinyl)-2-cyclohexene-1-ol under the catalysis of an acid catalyst to obtain an intermediate I or an intermediate II; converting hydroxyl in the intermediate II into a halide-like compound to obtain an intermediate III; and carrying out Suzuki coupling on the intermediate I or the intermediate III and pentyl boride to obtain the final product cannabidiol. The reaction system is simple, thereaction temperature is within 100 DEG C, the reaction conditions are easy to control, and large-scale production is easy; the cannabidiol intermediate prepared by the method disclosed by the invention can be recrystallized and purified by a conventional method, the yield is up to 86.5%, the purity is up to 98.7%, and the chemical purity and single impurity index requirements of the cannabidiol intermediate serving as a key intermediate of a crude drug can be met; the yield of the cannabidiol prepared by the method is as high as 80.7%, the purity is as high as 97%, the raw material indexes arecompletely met, and a new method and thought are provided for industrial production of the cannabidiol.

Cannabidiol is one of the main non-psychoactive cannabinoids present in Cannabis sativa and, in the last decade, it is gaining great interest among the scientific community for its pharmaceutical, nutraceutical, and cosmetic applications. Herein, we report the first continuous flow chemical synthesis of cannabidiol (CBD) and its analogues cannabidivarin (CBDV) and cannabidibutol (CBDB). This approach permits to synthesize products in very good yields (55–59 %), limiting the formation of psychoactive and illegal cannabinoids such as tetrahydrocannabinol (THC).

The present invention provides simple synthetic routes for the preparation of cannabinoid compounds such as CBD, CBDV, THC, THCV, CBN, HU-308, CBG, CBC, and derivatives thereof, which are stereoselective and provide the desired cannabinoid compound in high yield.

The present invention relates to compositions, and methods of use thereof, related to the endocannabinoid system and includes therapeutic compositions including an agent and an enhancer thereof, optionally, formulated for administration of the therapeutic compositions, preferably in a measured amount.

Cannabidiol (CBD) formulation comprising a mixture of full spectrum cannabidiol oil (FSO) and cannabidiol isolate (CBD isolate) is disclosed. The formulation contains a total amount of CBD derived from a combination of an amount of CBD in the FSO and an amount of CBD from the CBD isolate. The formulation of FSO and CBD isolate in used for medicinal and health benefits in a wide range of products, such as tinctures, capsules, creams or lotions, bath salts or bombs, soaps, pet or animal tinctures, and pet or animal edible chews.

The invention discloses a preparation method of a compound with a general formula I or pharmaceutically acceptable salts, stereoisomers, esters, prodrugs and solvates thereof, which comprises the following steps: (1) by using a compound A and (1S, 4R) 1methyl 4 (1methyl vinyl) 2cyclohexene 1alcohol as raw materials, carrying out coupling under the action of a chiral imidazolone salt catalyst to obtain a compound B; carrying out sodium sulfite dehalogenation and alkali washing to obtain an intermediate 1; (2) heating the intermediate 1 to 80100 DEG C under the action of DMSO, lithium chloride and an antioxidant, reacting, and recrystallizing to obtain a compound with a general formula I;.

The invention relates to a resorcinol derivative and a preparation method thereof. According to the invention, the synthesis method can be very simply and conveniently expanded and applied to synthesis and preparation of other derivatives and analogues of cannabidiol, so that the selectivity is greatly improved, the generation of regioisomers and disubstituted byproducts is avoided to the greatestextent, and the yield is remarkably improved; the method has the advantages of low material cost, few pollutants, simplicity and convenience in operation, easiness in expanded application of a synthetic route and the like; and the method specifically designed by the invention can reduce byproducts, so that the method can be carried out by using a one-pot method so as to greatly reduce the productand energy consumption during purification by using a step-by-step method and greatly reduce pollutants.

The present disclosure relates to new cannabinoid sulfonate esters and processes for their use to prepare cannabinoids. The disclosure also relates to the use of catalysts and catalytic processes for the preparation of cannabinoids from the cannabinoid sulfonate esters.

The invention belongs to the field of chemical pharmacy, and particularly discloses a synthetic method of cannabidiol. The synthetic method comprises the following steps: S1, adopting 2, 4-dimethoxy-6-amyl methyl benzoate as a raw material, and carrying out a coupling reaction on the raw material and (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-ol under a Lewis acid catalysis condition to obtain an intermediate (I); S2, performing high-temperature decarboxylation on the prepared intermediate (I) under the action of strong alkali to prepare an intermediate (II); and S3, removing methyl from the prepared intermediate (II) under the action of boron tribromide to obtain the final product cannabidiol. The purity of the cannabidiol obtained by the preparation method disclosed by the invention is 99.90-99.99%; the total yield of the finally prepared bulk drug with qualified purity can reach 60-80% at most, the process is obviously improved, and the method has a good industrial application prospect.

Herein are described apparatus and processes for the preparation of cannabinoids, such as cannabidiol (CBD) and derivatives thereof. The apparatus and processes described can be used for the one-step, flow-mediated synthesis of cannabidiol and derivatives with improved overall yield, material throughput, and product purity relative to batch processes.

Described is a method of selectively isolating non-rigid structure meroterpenes (for example, cannabidiolic acid) from a complex matrix that may also contain rigid structure meroterpenes (for example, THCa), comprising selectively precipitating the non-rigid structure meroterpenes in the form of a triethylamine salt complex by adding triethylamine; isolating the triethylamine salt complex from the mother liquor; then heating the triethylamine salt complex to vaporize the triethylamine, leaving an isolated neutral non-rigid structure meroterpene. In certain embodiments, the starting product is a cannabis resin that has been solubilized in, for example, d-limonene.

A process for the synthesis of Cannabidiol of formula (1): (1) is herein disclosed. The process comprises contacting a solution [solution (S1)] of (+)-p-mentha-diene-3-ol of formula (4) (4) or an ester thereof and olivetol of formula (3): (3) with a solution [solution (S2)] of a non-supported Lewis acid in a continuous flow reactor and treatment of the resulting mixture with a basic solution. The process offers the advantage that it can be conveniently carried out on an industrialscale while avoiding the formation of abnormal CBD and THC (Δ9-tetrahydrocannabinol).

The present disclosure relates to the preparation of a highly pure cannabidiol compound by a novel synthesis route. The cannabidiol compound can be prepared by an acid-catalyzed reaction of a di-halo olivetol with menthadienol, followed by two crystallization steps. The highly pure cannabidiol compound is produced in high yield, stereospecificity, or both, and shows exceedingly low levels of Δ-9-tetrahydrocannabinol at the time of preparation and after storage.

A process for the preparation of substantially pure diverse known and novel cannabinoids 1 and 2, which include Δ9-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), cannabidiol (11), cannabidivarin (12) and other naturally occurring tetracyclic and tricyclic cannabinoids and other synthetic tetracyclic and tricyclic analogues, via intermediates 3, 6, 4 and 5, using a cascade sequence of allylic rearrangement, aromatization and, for the tetracyclic cannabinoids, further highly stereoselective and regioselective cyclization. These synthesized cannabinoids can more easily be obtained at high purity levels than cannabinoids isolated or synthesized via known methods. The cannabinoids 2, including Δ9-tetrahydrocannabinol (7), tetrahydrocannabivarin (9), are obtained containing very low levels of isomeric cannabinoids such as the undesirable Δ8- tetrahydrocannabinol. The known and novel analogues with variation in aromatic ring substituents, whilst easily synthesized with the new methodology, would be much more difficult to make from any of the components of cannabis or cannabis oil.

A novel synthetic route for making (-)-CBD and its derivatives bearing various C4′-side chains is developed by a late-stage diversification method. Starting from commercially available phloroglucinol, the key intermediate (-)-CBD-2OPiv-OTf is efficiently and regioselectively prepared and further undergoes Negishi cross-coupling to furnish (-)-CBD. This approach allowed an efficient synthesis of (-)-CBD in a five-step total 52% yield on a 10 g scale. Furthermore, diversification on the C4′-side chain with this method can be realized in a wide range.

The present invention relates to a highly economic process for the purification of a cannabinoid acid, more specifically THCA or CBDA, from either a crude cannabis plant material or a cell culture of said cannabis plant, using ion exchange resins. The purified cannabinoid acid obtained may then be decarboxylated to yield the corresponding cannabinoid, i.e., THC or CBD, respectively.

The monocyclic 1,4-benzoquinone, HU-331, the direct oxidation product of cannabidiol, inhibits the catalytic activity of topoisomerase II but without inducing DNA strand breaks or generating free radicals, and unlike many fused-ring quinones exhibits minimal cardiotoxicity. Thus, monocyclic quinones have potential as anticancer agents, and investigation of the structural origins of their biological activity is warranted. New syntheses of cannabidiol and (±)-HU-331 are here reported. Integrated synthetic protocols afforded a wide range of polysubstituted resorcinol derivatives; many of the corresponding novel 2-hydroxy-1,4-benzoquinone derivatives are potent inhibitors of the catalytic activity of topoisomerase II, some more so than HU-331, whose monoterpene unit replaced by a 3-cycloalkyl unit conferred increased antiproliferative properties in cell lines with IC50 values extending below 1 mM, and greater stability in solution than HU-331. The principal pharmacophore of quinones related to HU-331 was identified. Selected monocyclic quinones show potential for the development of new anticancer agents.

Provided are synthesis processes and intermediates for preparing cannabinoids and analogs.

Crystalline Cannabidiol of a novel form, including (R,R)-(?)-crystalline Cannabidiol, as well as methods of making such novel form of Cannabidiol, pharmaceutical formulations comprising such novel form of Cannabidiol, and methods of treating diseases with such novel form of Cannabidiol.

The invention provides a method for 2, 4 - dihydroxy - 6 - amyl methyl benzoate as raw materials, with the potassium hydroxide under the catalysis of the N, N - dialkyl amine ester interchange, then with the (1S, 4R) - 1 - methyl - 4 - (1 - methyl vinyl) - 2 - cyclohexene - 1 - ol in place under Lewis acid-catalyzed coupling reaction, acid and alkali extraction and recrystallized to obtain the high purity of the key intermediate product, obtained through hydrolysis of the crude hemp diphenol decarboxylation, crude a times of re-crystallization can be obtained in accordance with the requirements of the quality of the raw material medicine hemp diphenol. The method of the invention in low cost raw materials and reagents, commercial is easy to obtain, prepare the qualified when the purity of the total yield of the raw material can be as high as 35 - 40%, the process is obviously improved, it has very good industrial application prospects. (by machine translation)

A food additive comprising cannabinoids but lacking at least in part the taste and aroma associated with cannabis while retaining the psychoactive and medicinal properties thereof is provided for as well as methods of making.

The present disclosure relates to the preparation of a cannabidiol compound or a derivative thereof. The cannabidiol compound or derivatives thereof can be prepared by an acid-catalyzed reaction of a suitably selected and substituted di-halo-olivetol or derivative thereof with a suitably selected and substituted cyclic alkene to produce a dihalo-cannabidiol compound or derivative thereof. The dihalo-cannabidiol compound or derivative thereof can be produced in high yield, high stereospecificity, or both. It can then be converted under reducing conditions to a cannabidiol compound or derivatives thereof.

The present invention relates to methods for purifying one or two cannabinoid compounds using simulated moving bed chromatography, wherein the cannabinoid compound(s) is/are obtained in the extract and/or the raffinate with the total amount of isomeric impurities being below detection level. In particular, the present invention relates to methods for the purification of cannabidiol, trans-(-)-delta-9-tetrahydrocannabinol, cannabidivarin, trans-(-)-delta-9-tetrahydrocannabivarin and cannabigerol which have been obtained by enantiopure synthesis.

Cannabidiol is the nonpsychoactive natural component of C. sativa that has been shown to be neuroprotective in multiple animal models. Our interest is to advance a therapeutic candidate for the orphan indication hepatic encephalopathy (HE). HE is a serious neurological disorder that occurs in patients with cirrhosis or liver failure. Although cannabidiol is effective in models of HE, it has limitations in terms of safety and oral bioavailability. Herein, we describe a series of side chain modified resorcinols that were designed for greater hydrophilicity and "drug likeness", while varying hydrogen bond donors, acceptors, architecture, basicity, neutrality, acidity, and polar surface area within the pendent group. Our primary screen evaluated the ability of the test agents to prevent damage to hippocampal neurons induced by ammonium acetate and ethanol at clinically relevant concentrations. Notably, KLS-13019 was 50-fold more potent and >400-fold safer than cannabidiol and exhibited an in vitro profile consistent with improved oral bioavailability.

Specific compositions comprising one or multiple (cannabinoid) compound(s) of formula (A) and/or one or multiple salt(s) thereof are described as well as methods for their manufacture. A compound of formula (A), a salt of formula (A) and a respective composition for use as medicine and for use in a method for the therapeutic treatment of the human or animal body, respectively, are also described. Furthermore, corresponding pharmaceutical formulations, cosmetic preparations and foodstuff and/or gourmet or snack preparations fit for consumption as well as a method for the manufacture of delta-9-tetrahydrocannabinol are described.

The field of the invention is organic synthesis, more particularly a process for preparing cannabinoids. The process described is applicable to all stereoisomers and homologues of cannabinoids. For this purpose, the present patent application provides a process for preparing the abovementioned compounds in two or three chemical synthesis steps.

Described herein are cannabidiol prodrugs, methods of making cannabidiol prodrugs, formulations comprising cannabidiol prodrugs and methods of using cannabidiols. One embodiment described herein relates to the transdermal or topical administration of a cannabidiol prodrug for treating and preventing diseases and/or disorders.

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: 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.

Pharmaceutical compositions comprising the cannabinoid active pharmaceutical ingredient, crystalline trans-(±)-Δ9-tetrahydrocannabinol, and formulations thereof are disclosed. The invention also relates to methods for treating or preventing a condition such as pain comprising administering to a patient in need thereof an effective amount of crystalline trans-(±)-Δ9-tetrahydrocannabinol. In specific embodiments, the crystalline trans-(±)-Δ9-tetrahydrocannabinol administered according to the methods for treating or preventing a condition such as pain can have a purity of at least about 98% based on the total weight of cannabinoids.

Methods for making trans-(-)-Δ9-tetrahydrocannabinoI and trans-(+)-Δ9-tetrahydrocannabinol are disclosed herein. In one embodiment, a trans-(-)-Δ9-tetrahydrocannabinoI composition is prepared by allowing a composition comprising (±)-Δ9-tetrahydrocannabinol to separate on a chiral stationary phase to provide a trans-(-)-Δ9-tetrahydrocannabinoI composition comprising at least about 99% by weight of trans-(-)-Δ9-tetrahydrocannabinol based on the total amount of trans-(-)-Δ9-tetrahydrocannabinol and trans-(+)-Δ9-tetrahydrocannabinol. The invention also relates to methods for treating or preventing a condition such as pain comprising administering to a patient in need thereof an effective amount of a trans-(-)-Δ9-tetrahydrocannabinoI having a purity of at least about 98% based on the total weight of cannabinoids.

The invention relates to the extraction of pharmaceutically active components from plant materials, and more particularly to the preparation of a botanical drug substance (BDS) for incorporation in to a medicament. It also relates to a BDS of given purity, for use in pharmaceutical formulations. In particular it relates to BDS comprising cannabinoids obtained by extraction from cannabis.

The invention relates to pharmaceutical formulations, and more particularly to formulations containing cannabinoids for administration via a pump action spray. In particular, the invention relates to pharmaceutical formulations, for use in administration of lipophilic medicaments via mucosal surfaces, comprising: at least one lipophilic medicament, a solvent and a co-solvent, wherein the total amount of solvent and co-solvent present in the formulation is greater than 55% wt/wt of the formulation and the formulation is absent of a self emulsifying agent and/or a fluorinated propellant.

Δ9-Tetrahydrocannabinol 1 and its isomers were synthesized via domino-type methodology. The first approach, leading to (±)-1, relies on the Mo(IV)-catalyzed, one-pot cascade reaction of citral (4) with olivetol (15), affording (±)-Δ9-tetrahydrocannabinol as a 69 : 31 mixture of the trans-(natural) and cis-isomers in 20% yield. The alternative approach, leading to natural (-)-1, commenced with epoxidation of (+)-limonene (R)-(+)-16; opening of the resulting cis-epoxide 17 with PhSeNa, followed by elimination, afforded tertiary alcohol 21, whose acetate 22 was treated with olivetol 15 in the presence of Mo(II) catalyst IV to afford (-)-1 in 52% yield.

The syntheses of (-)-cannabidiol and (-)-cannabidiol dimethyl ether were accomplished via fragmentation of an appropriately substituted 9-bromocamphor derivative.A new method of α-arylation of 3,9-dibromocamphor was shown to provide a variety of α-arylated camphor derivatives in good yields.

Examination of the toluene-p-sulphonic acid-catalysed reaction of (1S,2S,3R,6R)-(+)-trans-car-2-ene epoxide with olivetol shows that, inconsistently with the accepted mechanism, (3R,4R)-(-)-o- and -p-cannabidiols are produced as well as (3R,4R)-(-)-Δ1- and Δ6-tetrahydrocannabinols.Evidence is now presented that, as in Petrzilka's reaction employing chiral p-mentha-2,8-dien-1-ols, the reacting species is the delocalised (4R)-p-mentha-2,8-dien-1-yl cation (9).Similar terpenylation using (1S,3S,4R,6R)-(+)-trans-car-3-ene epoxide shows that besides the reported (-)-Δ6-THC, o- and p-cannabidiols, Δ1-THC and Δ4,8-iso-THC can also be produced.The nature of the products, the chirality, and the characteristics of the reaction implicate again the delocalised cation (9).Its formation via Kropp-type rearrangement is excluded and a pathway leading to (4R)-p-mentha-2,6,8-triene, which on protonation gives (9), is proposed.Protonated on C-8, the triene can be trapped and isolated as (4R)-p-mentha-2,6-dien-8-ol.The latter, made in (+/-)-form from citral, proved to be an excellent terpenylating agent for producing cannabinoids.Terpenylation of olivetol by the pinanes (1S,4S,5S)-(-)-cis-verbenol and (1R,5S,7R)-(+)-cis-chrysanthenol is compared.A major drawback of the latter is partial racemisation which occurs in the verbenone-chrysanthenone isomerisation during its photochemical preparation.Whilst Δ1-THC cannot be directly obtained from verbenol, its tertiary allylic cation permits a much higher yielding terpenylation than the secondary cation from chrysanthenol.

Boron trifluoride etherate on alumina catalyses the condensation of resorcinols and monomethyl resorcinols with several monoterpenoid allylic alcohols: in contrast to paralell reactions with boron trifluoride etherate in solution the products obtained do not undergo further cyclisations.

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