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WO2009099868A1 - Procédé pour la préparation du (-)-delta 9-tétrahydrocannabinol - Google Patents

Procédé pour la préparation du (-)-delta 9-tétrahydrocannabinol Download PDF

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WO2009099868A1
WO2009099868A1 PCT/US2009/032361 US2009032361W WO2009099868A1 WO 2009099868 A1 WO2009099868 A1 WO 2009099868A1 US 2009032361 W US2009032361 W US 2009032361W WO 2009099868 A1 WO2009099868 A1 WO 2009099868A1
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aryl
reaction mixture
group
substituted
alkyl
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Bobby N. Trawick
Mark H. Owens
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Mallinckrodt Inc
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Mallinckrodt Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
    • C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
    • C07D311/78—Ring systems having three or more relevant rings
    • C07D311/80—Dibenzopyrans; Hydrogenated dibenzopyrans

Definitions

  • the present disclosure is generally directed to a process for the chemical synthesis of (-)- ⁇ 9 -tetrahydrocannabinol ( ⁇ 9 -THC) and/or structurally related compounds.
  • the process comprises a one-pot condensation and sulfonylation reaction sequence that produces crude ⁇ 9 -THC aryi sulfonate ester or related compounds. Sulfonylation of ⁇ 9 -THC, or structurally related compounds, immediately upon their formation imparts stability to the cannabinoids, and prevents formation of the thermodynamicaliy more stable corresponding ⁇ 8 -isomer.
  • ⁇ 9 -THC aryl sulfonate ester or structurally related compounds may also be readily separated from the corresponding ⁇ 8 -THC isomer using reverse phase chromatography. Hydrolysis of the ⁇ 9 -THC aryl sulfonate ester or related compounds after separation produces ⁇ 9 -THC or related compounds containing relatively low amounts of the corresponding ⁇ 8 -isomer.
  • Cannabis preparations in the form of marijuana, hashish, etc. have been known and used for many years for their psychoactive and therapeutic properties
  • the major active constituent of the resin which is extruded from the female plants of Cannabis sativa L is (- ⁇ -tetrahydrocannabinol ( ⁇ 9 -THC).
  • the FDA has approved ⁇ 9 -THC for several therapeutic applications.
  • the antiemetic and appetite stimulating properties of ⁇ 9 -THC have proven therapeutically beneficial. Consequently, research has been directed towards the preparation of ⁇ 9 -THC via a synthetic method, in order to eliminate the need to obtain the material by extraction from natural sources.
  • ⁇ 9 -THC presents several unique challenges for its synthetic production on a commercial scale, the primary challenge being the instability of the double bond in the cyclohexane ring.
  • ⁇ 9 -THC readily undergoes double-bond isomerization to its more thermodynamicaliy stable regioisomer, ⁇ 8 -THC.
  • Such an inherent propensity to isomerize means that precautions are to be taken when manipulating ⁇ 9 -THC in both its crude and pure forms to minimize formation of ⁇ 8 -THC.
  • ⁇ 8 -THC formation is particularly desirable when the ⁇ 9 -THC is to be used therapeutically, as USP guidelines limit ⁇ 8 -THC levels in ⁇ 9 -THC preparations to 2 weight% or less for the dronabinol API. Additionally, separation of ⁇ 8 -THC from ⁇ 9 - THC is challenging and typically requires multiple chromatographic purifications or the use of expensive silver-impregnated substrates for its removal. Such extensive handling and purification requirements tend to make commercial-scale production of ⁇ 9 -THC economically unattractive.
  • the present disclosure is generally directed to a process for the chemical synthesis of (-)- ⁇ 9 -tetrahydrocan ⁇ abinol ⁇ 9 -THC), or alternatively a structurally related compound.
  • the process comprises a "one-pot" condensation and sulfonylation reaction sequence that produces crude ⁇ 9 -THC aryl sulfonate ester, or alternatively a structurally related compound.
  • the process comprises the preparation of a crude reaction mixture comprising, for example, ⁇ 9 -THC, followed by the direct sulfonylation (e.g., tosyiation) of that reaction mixture (i.e., sulfonylation without an intervening separation or purification step to isolate the ⁇ 9 -THC reaction product, or other structurally related compound reaction product), in order to obtain the corresponding aryl sulfonate ester.
  • direct sulfonylation e.g., tosyiation
  • the present disclosure is further directed to a process for the synthesis of a cannabinoid having general Formula I:
  • R 1 to R 3 are independently selected from the group consisting of H, alkyl, substituted alky!, OH, aryl, acyl, halide, nitrate, sulphonate, phosphate, and OR', wherein R 1 is alkyi, aryl, substituted alkyl, substituted aryl, silyl, acyl, or phosphonate; and R c , R d , and R e are independently selected from the group consisting of H, alkyl, or substituted alkyl.
  • the process comprises reacting a substituted resorcinol having general Formula II:
  • R 1 , R 2 , and R 3 are as defined above, with a compound having general Formula III:
  • R a is H, alkyl, aryl, acyl, or silyl
  • R b is H, alkyl aryl, or acyl
  • R c , R d , and R e are as defined above, in the presence of an acid catalyst and a non-alkaline dehydrating agent to form a first reaction mixture comprising a cannabinoid having general Formula I.
  • the first reaction mixture which contains the cannabinoid having general Formula I, is then contacted with an aryl sulfonyl halide and a base to produce a second reaction mixture comprising an aryl sulfonate having general Formula IV:
  • R 1 , R 2 , R 3 , R c , R d , and R e are as defined above, and Y is selected from the group consisting of a substituted aryl group, an uns ⁇ bstituted aryl group, a substituted alkyl group, and an unsubstituted alkyl group.
  • the aryl sulfonate is isolated from the second reaction mixture, and is then hydrolyzed to produce the cannabinoid having general Formula I.
  • R 1 to R 3 are independently selected from the group consisting of H 1 atkyl, substituted alkyl, OH 1 aryl, acyl, halide, nitrate, sulphonate, phosphate, and OR', wherein R' is alkyl, aryl, substituted alky!, substituted aryl, silyl, acyl, or phosphonate; R c , R d , and R e are independently selected from the group consisting of H, alkyi, or substituted alkyl; and Y is selected from the group consisting of a substituted aryi group, an unsubstituted aryl group, a substituted alkyl group, and an unsubstituted alky] group.
  • the process comprises reacting a substituted resorcinol having general Formula Ii:
  • R 1 , R 2 , and R 3 are as defined above, with a compound having general Formula III:
  • R a is H, alkyl, aryl, acyl, or silyl
  • R b is H 1 alkyl aryl, or acyl
  • R c , R d , and R e are as defined above, in the presence of an acid catalyst and a non-alkaline dehydrating agent to form a first reaction mixture comprising a cannabinoid having general Formula I:
  • the first reaction mixture containing the cannabinoid having general Formula ! is then contacted with an aryl sulfonyi halide and a base to produce a second reaction mixture comprising the aryl sulfonate.
  • R 1 to R 3 are independently selected from the group consisting of H, alkyl, substituted alkyl, OH 1 aryl, acyl, halide, nitrate, sulphonate, phosphate, and OR', wherein R' is alkyl, aryl, substituted alkyl, substituted aryl, silyl, acyl, or phosphonate; R c , R d , and R e are independently selected from the group consisting of H, alkyl, or substituted alkyl; and
  • Y is selected from the group consisting of a substituted aryl group, an unsubstituted aryl group, a substituted alky! group, and an unsubstituted alky! group.
  • the process comprises reacting a substituted resorcinol having genera! Formula !l:
  • R 1 , R 2 , R 3 , and R c are as defined above, and R d and R e are as defined above.
  • the first reaction mixture, and in particular the cannabinoid having general Formula I present therein is then reacted with an aryl sulfonyt haiide in the presence of a base to produce a second reaction mixture comprising the aryl sulfonate.
  • the present disclosure is still further directed to a process for the preparation of (-)- ⁇ 9 - tetrahydrocannabinol aryl sulfonate.
  • the process comprises reacting olivetol with a compound selected from the group consisting of p-mentha-2-en-1 ,8-diol and p-mentha-2,8-dien-1-ol in the presence of an acid catalyst and an excess of a non-alkaline dehydrating agent to form a first reaction mixture comprising (- ⁇ -tetrahydrocannabinol.
  • the first reaction mixture and in particular the (-)- ⁇ 9 - tetrahydrocannabinol therein, is then reacted with an aryl sulfonyl haiide in the presence of a base to produce a second reaction mixture comprising an aryl sulfonate having general Formula IV:
  • R 1 is C 5 Hn; R 2 and R 3 are H; R c , R d , and R e are -CH 3 ; and Y is a substituted or unsubstituted aryi group.
  • the present disclosure is generally directed to a process for the chemical synthesis of (-)- ⁇ 9 -tetrahydrocannabinol ( ⁇ 9 -THC), or alternatively a structurally similar or related compound.
  • the process comprises a one-pot condensation and sulfonylation reaction sequence that produces crude sulfonated reaction product (e.g., a ⁇ 9 -THC aryl sulfonate, or alternatively a structurally similar or related sulfonate compound), which may then be converted (e.g., hydrolyzed) to the desired product.
  • a desired threshold e.g., the ratio of the desired isomer, such as ⁇ 9 -THC, to the undesired isomer, such as ⁇ B -THC, being about 49:1 or more
  • ⁇ 9 -THC aryl sulfonate may also be readily separated from ⁇ 8 -THC aryl sulfonate isomer, using for example reverse phase chromatography. Subsequent conversion (e.g., hydrolysis) of the ⁇ 9 -THC aryl sulfonate, or other structurally related compound, produces the desired product (e.g., ⁇ 9 -THC, or other structurally related compound) containing relatively low amounts of the corresponding ⁇ 8 -isomer.
  • desired product e.g., ⁇ 9 -THC, or other structurally related compound
  • the phrase "structurally similar or related" compound generally refers to a compound that has the same 3-ring core structure of THC, but that differs in terms of the substituent(s) and/or location of the substituent(s) on the 3-ring core structure. It is therefore to be understood that reference to the preparation of ⁇ 9 -THC is also generally intended to refer to the preparation of other structurally similar or related compounds.
  • a "one-pot" reaction process generally refers to a process wherein (i) the condensation reaction to initially prepare a reaction product mixture that includes ⁇ 9 - THC, or alternatively a structurally similar or related compound, and (ii) the subsequent sulfonylation (e.g., tosylation) reaction, are performed without an intervening step involving isolation or purification of the reaction product from the condensation reaction mixture (e.g., a filtration or washing step, a recrystaliization step, chromatography step, etc.). Accordingly, the sulfonylation reaction may be performed in the same container or reaction vessel in which the condensation reaction was performed.
  • the contents of that reaction container or vessel may be transferred to a new container or vessel without departing from the scope of the invention, provide this transfer does not involve some act of purification, as noted above (e.g., filtration, recrystaliization, chromatography, etc.). Accordingly, the present process involves the "direct" sulfonylation of the first (or condensation) reaction mixture formed.
  • USP guidelines limit ⁇ 8 -THC levels in a ⁇ 9 - THC preparation to about 2 weight% or less, as compared to the sum of the weight of ⁇ 9 -THC and ⁇ 8 - THC; stated another way, USP guidelines call for the weight ratio of the ⁇ 9 -THC to ⁇ 8 -THC to be less than or equal to about 98:2 (or 49:1) or less. If the ⁇ 8 -THC level exceeded this amount, further separation of the ⁇ 9 -THC from ⁇ 8 -THC contaminant will typically be needed. Separation of ⁇ 9 -THC from its ⁇ 8 regioisomer has, however, proven to be challenging, and typically requires multiple chromatographic purifications or the use of expensive equipment
  • cannabinoids such as ⁇ 9 -THC and structurally similar related compounds, having general Formula I:
  • R 1 to R 3 are independently selected from the group consisting of H, alky], substituted alky] ⁇ e.g., substituted or unsubstituted C1-C10, including for example methyl, ethyl, propyl, butyl, pentyl, etc.,), -OH, aryl, acyl, halide, nitrate, sulphonate, phosphate, and -OR 1 , wherein R 1 is alky], aryi, substituted alky I or aryl, si IyI 1 acyl, or phosphonate; and
  • R c , R d , and R e are independently selected from the group consisting of H 1 alkyl, or substituted alkyl; can be synthesized by condensing a substituted resorcinol compound having general Formula
  • R 1 to R 3 are as defined above, with a compound having general formula III (or a stereoisomer thereof, such as wherein the confirmation of the C1 chiral carbon is "S" rather than “R”, as shown here, the combination of chiral carbons thus being S 1 R rather than R 1 R):
  • R a is H, alkyl, aryl, acyl, or silyl
  • R b is H, alkyl, aryl, oracyl
  • Rc 1 Rd, and Re are as defined above, in the presence of an acid catalyst and a non-alkaline dehydrating agent.
  • the reaction is optimized, and/or the progress of the reaction is monitored (e.g., by performing repeated analyses on the reaction over a period of time, using means generally known in the art, such as HPLC) such that the ratio of the ⁇ 9 -THC isomer, relative to the ⁇ 8 -THC isomer, is about 49:1 or greater (e.g., about 50:1 , about 55:1 , about 60:1 , about 75:1 , about 85:1 , about 95:1 , about 99:1 , etc.).
  • Such ratios may be achieved, for example, by monitoring the concentration of the ⁇ 8 -THC isomer, relative to the ⁇ 9 -THC, or both, during the reaction, and/or by monitoring first the appearance and then disappearance of a reaction intermediate (as further detailed herein below).
  • the reaction may then be quenched once the presence of the intermediate is sufficiently low, or no longer detectable, and/or before the concentration of the ⁇ 8 -THC isomer is too high (by, for example, introduction of a base, such as triethylamine, to the reaction mixture), in this way, the formation of the desired product (e.g., ⁇ 9 -THC) is maximized, while the formation of the undesired product (e.g., ⁇ a -THC) is minimized.
  • a base such as triethylamine
  • the ratio of the ⁇ 9 -THC isomer, relative to the ⁇ 8 -THC isomer may in an alternative embodiment be less than about 49:1 without departing from the intended scope of the invention (the ratio, for example, being about 45:1 , about 40:1 , about 35:1 or less).
  • the reaction produces a first reaction mixture comprising a cannabinoid having general Formula I 1 which includes ⁇ 9 -THC, as well as various impurities, including for example ⁇ 8 -THC,
  • the cannabinoids of Formula I present in the first reaction mixture are then sulfonated, and in one particular embodiment are immediately sulfonated (i.e., as soon as the desired ratio of isomers is achieved, sulfonylation is initiated by addition of the aryl sulfonyl halide reagent to the first reaction mixture), by treating the first reaction mixture with an aryl sulfonyl halide in the presence of a base (such as, for example, the base noted above added to quench the initial condensation reaction), to produce a second reaction mixture comprising an aryl sulfonate having general Formula IV: Formula IV wherein R 1 , R 2 , R 3 , R c , R d , and R
  • the process of the present disclosure is a one-pot reaction, and therefore does not involve any isolation or purification of the ⁇ 9 -THC (or structurally similar or related compound) between the condensation reaction and the subsequent sulfonylation (e.g., tosylation) reaction. Rather, the aryl sulfonyl halide and base are added to the first reaction mixture after completion of the condensation reaction, and in one particular embodiment immediately after the reaction (the base being added to quench the condensation reaction, for example, when the desired isomeric ratio is reached), to sulfonate the compound of Formula I present therein. In this way, further isomerization of the Formula I compound may be limited, and desirably is substantially prevented.
  • Sulfonylation of the Formula I compound present in the first reaction mixture also improves the ease with which the ⁇ 8 -isomer impurity can be removed.
  • separation of, for example, the ⁇ 9 -THC (or structurally related compounds) from the corresponding ⁇ 8 -isomer is typically inefficient, requiring multiple chromatographic separations or use of expensive equipment.
  • the Formula IV aryl sulfonate synthesized during the process of the present disclosure can be readily separated from the corresponding sulfonated ⁇ 8 -isomer using reverse phase chromatography.
  • the Formula IV aryl sulfonates may be hydrolyzed to re-form the compound having genera! Formula I 1 such as ⁇ 9 -THC.
  • the Formula IV ary! sulfonates may be recrystallized, using means generally known in the art, following chromatographic purification to further purify the compounds prior to hydrolysis.
  • the process of the present disclosure advantageously produces compounds of Formula I 1 such as ⁇ 9 -THC, that are at least 90% pure, at least about 92% pure, at least about 94% pure, at least about 95% pure, at least about 96% pure, at least about 98% pure or more (e.g., about 99%, or even about 100%).
  • the compounds of Formula I produced using the process of the present disclosure are at least about 95% pure, or even at least about 98% pure.
  • the concentration of the corresponding ⁇ 8 -isomer is, in one particular embodiment, not more than about 2%, and may be not more than about 1%, or even about 0.5%, relative to the amount of the desired isomer of Formula I.
  • R a , R b , R c , R d and R e are as defined above, in the presence of an acid catalyst and a non- alkaline dehydrating agent (and in a particular embodiment in the presence of a molar excess of the agent relative to the Formula III compound).
  • alkyl group may contain substituents such as halide, hydroxyl, amine, and thiol.
  • alkyl as used in various embodiments herein, may desirably refer to Ci to C10 alkyl. Additionally, the alkyl group may optionally be saturated or unsaturated, acyclic or cyclic.
  • the compound of Formula Il is a substituted resorcinol.
  • R 2 and R 3 are H.
  • R 1 may suitably be an alkyl group or substituted alkyi group, In a particular embodiment, R 1 is an alky! having from about 1 to about 10 carbon atoms, or an alkyl having from 1 to 5 carbon atoms, and still more preferably is CsHn.
  • R 1 may contain groups (e.g., as a substituent or within the chain itself) that promote water solubility (e.g., ketone, ester, hydroxyl, or amine groups).
  • the substituted resorcinol of Formula Il is olivetol, wherein R 2 and R 3 are H, and R 1 is C 5 Hn.
  • Olivetol has the following structure:
  • R b is acyl and 0R b is an ester group. Suitable ester groups include acetate, propionate, butyrate, trimethylacetate, phenylacetate, phenoxyacetate, diphenylacetate, benzoate, p-nitrobenzoate, phthalate, and succinate.
  • both R a and R b are acyl groups so that the compound of Formula III is a diester
  • the two ester groups are suitably chosen independently from acetate, propionate, butyrate, trimethylacetate, phenylacetate, phenoxyacetate, diphenylacetate, benzoate, p- nitrobenzoate, phthalate, and succinate.
  • both R a and R b are diphenylacetate.
  • both R a and R b are H .
  • R°, R d , and R e can be varied independently of R a and R b .
  • R 0 is selected from the group consisting of — CH3 or H.
  • R d and R e are independently selected from the group consisting of — CH 3 or — CH2OH.
  • one or more of R c , R d , and R e is — CH3.
  • the compound of Formula 111 is p-mentha-2- en-1,8-diol, wherein R c , R d , and R e are — CH3, and R a and R b are both H.
  • p-mentha-2-en-1 ,8-dioi has the following structure (with the stereochemical conformation noted parenthetically):
  • the first reaction mixture may be prepared by reacting a substituted resorcino! of Formula Il with a compound of general Formula Vl:
  • R a , R b , and R c are as defined above, in the presence of an acid catalyst and an excess of a non-alkaline dehydrating agent (and in a particular embodiment in the presence of a molar excess of the agent relative to the Formula Vl compound).
  • the compound of Formula Vl is p-mentha- 2,8-dien-1-ol, wherein R b and R c are -CH3, and R a is -H.
  • p-Mentha-2,8-dien-1-ol has the following structure (with the stereochemical conformation noted parenthetically):
  • the condensation reaction is typically carried out by combining about equal molar amounts of a compound of Formula It with a compound of Formula III or Formula Vl 1 in order to obtain a reaction mixture that includes the compound of Formula I, plus impurities (including, for example, the ⁇ 8 -isomer of the compound of Formula I).
  • the compound of Formula I may be prepared by combining a compound of Formula Il with a compound of Formula III or V! in a moiar ratio of from about 2:1 to about 0.75:1 , or from about 1.5:1 to about 0.85:1.
  • oiivetol is reacted with about an equal molar amount of p-mentha-2-en-1 ,8-diol or p- mentha-2,8-dien-1-ol.
  • the condensation reaction does not exclusively yield the compound of Formula I, under optimal conditions (e.g., proper selection of reagents, concentration of reagents, reaction conditions, etc.), it is possible to obtain the compound of Formula I where the amount thereof, as compared to other products (such as the ⁇ 8 -isomer), is maximized.
  • the yield of Formula ! compound may be from about 15 wt.% to about 40 wt.%, or about 20 wt.% to about 35 wt.%, of the reaction product mixture.
  • any conventional inert organic solvent such as petroleum ether, diethyl benzene, toluene, tetrahydrofuran, dioxane, heptane, and halogenated aliphatic or aromatic hydrocarbons such as methylene chloride, chloroform, carbon tetrachloride, bromobenzene, and 2-methyl-THF can be used.
  • ethers such as diethyl ether, dioxane, and tetrahydrofuran are used, a higher concentration of acid catalyst may be needed.
  • Use of chlorinated hydrocarbons, and in particular methylene chloride may be particularly advantageous in one or more embodiments herein.
  • a quantity of solvent will be used which acts to optimize the overall yield of the reaction.
  • a quantity of solvent is used that is sufficient to dissolve (e.g., the compounds of Formula Ii 1 HI and/or IV) and/or thorough suspend (e.g., the dehydrating agent) all the condensation reaction reagents therein.
  • a quantity of solvent will typically be used which ensure the concentration of the compound of Formula II, III and/or IV is within the range of about 15 g/L and about 200 g/L, or about 17 g/L to about 180 g/L, or about 18 g/L to about 170 g/L.
  • the reaction between the substituted resorcinol of Formula H and the compound of Formula III or Vl is carried out in the presence of an acid catalyst.
  • boron trifluoride may be advantageous, in one or more embodiments, although other Lewis acids such as aluminum chloride, zinc chloride, stannic chloride, iron chloride, and antimony pentafluoride can also be used.
  • a convenient form for use of boron trifluoride is boron trifluoride complexed with diethyl ether, also known as boron trifluoride etherate. Boron trifluoride can also be dissolved in inert anhydrous solvents, and the use of such solutions would also be suitable.
  • Protonic acids such as p- toluenesulfonic, methanesuifonic, and trifluoracetic acid can also be used, but the yields are generally lower.
  • Other suitable catalysts include metal Inflates, such as indium (III) triflate, scandium (III) triflate, ytterbium (III) triflate, bismuth (111) triflate, and the like. [0041 ] A quantity of acid catalyst will be used which acts to optimize the overall yield of the reaction.
  • the quantity of catalyst used is within the range of about 1 g/L to about 5 g/L, or about 1.2 g/L to about 4.8 g/L, or about 1.5 g/L to about 4.5 g/L, or about 1.75 g/L to about 4 g/L, relative to the volume of solvent used.
  • the quantity of acid catalyst may be expressed in terms molar equivalents relative to the motes of the compound of Formula I to be formed.
  • the molar ratio of the acid catalyst to the motes of compound Formula I may be in the range of from about 0.1:1 to about 0.4:1 , or from about 0.2:1 to about 0.3:1.
  • a non-alkaline dehydrating agent is used in the preparation of the compound of Formula I.
  • Any conventional materia! which has the ability to readily combine with a molecule of water, and is non-alkaline and otherwise chemically inert can be used.
  • Agents useful in the practice of this disclosure include cafcium sulfate, magnesium sulfate, sodium sulfate, calcium chloride, aluminum oxide, silica, and molecular sieves such as those formed from potassium aluminum silicate.
  • the reaction is advantageously carried out by thoroughly mixing an excess of the non-alkaline dehydrating agent with the reactants so as to efficiently remove water as it is formed during the reaction.
  • excess is meant a quantity which is sufficient to react with the water formed during the condensation and any water which is present in the solvent. Typically, however, a quantity may be used within the range of the range of about 30 g/L to about 360 g/L, or about 60 g/L to about 330 g/L, or about 90 g/L to about 300 g/L, relative to the volume of solvent used.
  • a compound of Formula Il e.g., olivetol
  • of Formula III e.g., p-mentha-2-en-1,8-diol
  • Formula Vl e.g., p-mentha-2,8-dien-1-ol
  • a solvent e.g., dicholoromethane
  • a dehydrating agent e.g., magnesium sulfate
  • the resulting solution or suspension is then optionally chilled or cooled (e.g., to a temperature of less than about 15 0 C, about 10 0 C or even 5°C), and then a catalyst (e.g., boron trifluoride etherate) is added, optionally in a solution of the same solvent (such as for example dichloromethane), and also optionally over a period of time (e.g., 5 minutes, 10 minutes, 20 minutes or more, depending on the quantity to be added, the quantity of the reaction mixture, and/or the ability to control the temperature adequately if an exothermic reaction occurs).
  • a catalyst e.g., boron trifluoride etherate
  • the temperature of the resulting solution or suspension may then be heated, as necessary, in order to ensure the reaction proceeds within an acceptable period of time and to an acceptable end point ⁇ i.e., yield of the compound of Formula I).
  • the condensation reaction is carried out within a temperature range of from about 5°C to about 20 0 C, and more typically from about 8 0 C to about 15°C, for a period of time sufficient to optimize the yield of the compound of Formula I, and furthermore to minimize the formation of the ⁇ 8 - isomer thereof.
  • the reaction is carried out for about 1 to about 10 hours, or more typically about 3 to about 8 hours, with lower reaction temperatures requiring longer reaction times and vice versa.
  • the acid catalyst concentration impacts the rate of reaction and/or yield of the desired product, this impact varying with the temperature at which the reaction is carried out.
  • the type of acid used may also impact the process conditions used. For example, Lewis acids, such as BF3, allow the reaction to be carried out at a lower temperature than that needed for protic acids. When protic acids are used, the reaction is typically carried out under refluxing conditions, or extended reaction times (and may be more prone to yielding the ⁇ 8 isomer).
  • the reaction is optionally quenched and the product compound I is sulfonated to prevent further conversion of this product compound to the ⁇ Msomer.
  • at least one aryl sulfonyl halide in the presence of at least one base is added to the first reaction mixture to sulfonate the compound of Formula I, and ⁇ 8 -isomer thereof, that is present in the first reaction mixture.
  • the ary! sulfonyl halide reacts with the compound of Formula I (and the ⁇ 8 -isomer thereof) at the phenyl hydroxyl group, thereby producing aryl sulfonates.
  • Sulfonylation desirably occurs immediately upon completion of the condensation reaction to prevent further formation of ⁇ 8 -isomers, and facilitates the separation of ⁇ 9 - and ⁇ 8 -isomers (using techniques generally known in the art, including for example reverse phase chromatography).
  • "immediate" sulfonylation generally means the sulfonylation reagents (i.e., aryl sulfonyl halide and base) are added to the first reaction (i.e., condensation reaction) mixture as soon as conversion of the Formula Il and Formula 111 or Vl compounds to the product compound of Formula I is deemed to be sufficiently complete.
  • Completion of the condensation reaction may be monitored through use of techniques known in the art, including for example high performance liquid chromatography (HPLC). Specifically, the condensation reaction produces an intermediate product having the following general Formula V:
  • the sulfonylation reagents i.e., aryl sulfonyl halide and base
  • the aryl sulfonyl halide forms a sulfonate of both the compound of Formula I present in the first reaction mixture, as well as any ⁇ 8 -isomers that may have formed during the condensation reaction.
  • the base used in the sulfonylation reaction is added, at least in part, to neutralize the halide acid produced as a by-product during the reaction. Therefore, any suitable base that does not interfere with the sulfonylation reaction may be used.
  • Exemplary bases include lower alkyl amines, especially tertiary amines such as triethyl amine, which provide inexpensive bases that are suitable for the present invention.
  • Primary and secondary amines may also be used, but may result in unwanted reactions with the sulfonyl halide.
  • amines of the formula R 5 R 6 R 7 N may be used, wherein R 5 , R s , and R 7 may typically be lower alkyl substituents having from about one to about six carbon atoms.
  • the aryi group of the sulfonyl halide may be any aromatic system, substituted (including multiply substituted) or unsubstituted, that does not interfere with the sulfonylation reaction.
  • Suitable aromatic systems include but are not limited to benzene, alkyl substituted benzene, halogen substituted benzene, nitrobenzene, alkyloxy substituted benzene and substituted and unsubstituted napthyl compounds.
  • Particularly suitable alkyl substituents include an alkyl group directly attached to an aromatic ring carbon where the alky! substituent may typically be from about one to about six carbon atoms.
  • the aryl sulfonyl halide is p-toluenesulfonyl chloride.
  • the aryl sulfonyl halide and base are added to the first reaction mixture, and allowed to react at about room temperature (e.g., about 2O 0 C to about 25 C C) until sulfonylation is complete, forming a second reaction mixture.
  • room temperature e.g., about 2O 0 C to about 25 C C
  • the sulfonylation reaction will be complete after from about 2 hours to about 16 hours, more typically after from about 4 hours to about 12 hours, and still more typically after about 6 or about 8 hours.
  • the reaction may be run at increased temperatures, although doing so may result in minimal increase in reaction rate. Reaction temperatures in the range of from about room temperature to about 75°C, or about 35°C to about 55 0 C, may therefore alternatively be used.
  • the reaction product may be separated or isolated from the second reaction mixture using essentially any means generally known in the art.
  • the drying agent is removed from the second reaction mixture, such as by means of filtration, and then the filtrate is subject to a solvent extraction step (using for example sodium bicarbonate and brine solutions).
  • the solvent is then removed from the second reaction mixture by any suitable method, such as evaporation (e.g., rotary evaporation), supercritical fluid chromatography, normal phase liquid chromatography, and the like, yielding an oily residue that contains the aryl sulfonates present in the second reaction mixture (including compounds of Formula IV).
  • the crude aryl sulfonates may then be subjected to additional separation and purification steps generally known in the art, including for example reverse-phase chromatography, to remove sulfonated ⁇ 8 -THC or related compounds, as well as additional reaction by-products.
  • the crude aryl sulfonates are purified using reverse-phase chromatography using a Prodigy ODS-Prep 250 x 21 ,2 mm ID column; and an eluant comprising 77 volume percent methanol, 10 volume percent tetrahydrofuran, and 13 volume percent water, at a flow rate of 20 mL/minute, and UV detection at 255 nm.
  • the isolated fractions containing the aryl sulfates of Formula IV obtained from chromatographic purification may optionally comprise not more than about 2 wt.%, or not more than about 1 wt.%, or even not more than about 0.5 wt.%, of the sulfonated ⁇ 8-isomers. If desired, however, isolated fractions of the Formula IV aryl sulfonates containing these amounts of sulfonated ⁇ 8 -isomers may be further purified, alone or in combination, using recrystallization techniques generally known in the art to remove other impurities from the isolated fractions.
  • Suitable solvents for recrystallization include, but are not limited to, heptane, hexane, t-butyl methyl ether, n-pentanol, n-butanol, isopropanol, isobutanol, ethanol, acetone, aceto ⁇ itrile, and isopropyl acetate, In particular, alcohols, including methanol, may be used.
  • the purity of the aryl sulfonates obtained, after separation and optional recrystallization is typically greater than about 90 weight%, and more typically is great than about 95 weight%, and still more typically is greater than about 99 weight%.
  • the resulting aryl sulfonates having Formula IV are highly crystalline and stable at room temperature.
  • the crystalline Formula IV aryl sulfonates can then be hydrolyzed to recover the purified compound of Formula i by, for example, base hydrolysis, as illustrated in the reaction below:
  • the base comprises at least one metal salt of an alkyl oxide in at least one alkyl alcohol.
  • Suitable bases include but are not limited to potassium methoxide, ethoxide, propoxide, isopropoxide, t- butoxide, and t-pentanoxide, with tertiary alkoxides being used in one or more embodiments.
  • Suitable alcohols include, but are not limited to, methanol, ethanol, n-propanol, isopropa ⁇ ol, t-butanot, and t- pentanol, with tertiary alcohols being used in one or more embodiments.
  • the use of the same alkyl group for both the oxide and the alcohol, such as for example potassium t-butoxide in t-butanol, optionally with several equivalents of water, may be desirably to, for example, prevent exchange of the aikyl groups present therein.
  • the reaction may include about 2, about 3 or more equivalents of base, and about 3, about 4 or more equivalents of water, per equivalent of the sulfonated compound (i.e., the compound of Formula IV).
  • the reaction is typically carried out at a temperature in excess of room temperature (e.g., a temperature in excess of about 20 0 C or about 25°C), and may optionally be carried out at a temperature of about 50 0 C, about 65
  • a suitable method of hydrolysis comprises placing the crystalline Formula IV aryl sulfonates in a flask, or some other type of vessel, under an inert atmosphere.
  • the flask is typically equipped for or with (i) magnetic stirring, or some other type of agitation, (ii) electronic temperature control, (iii) a condenser, (iv) an inert gas bubbler, and/or (v) a heating mantle.
  • Deionized water and an alkyl oxide in alcohol are added to the flask. All solvents utilized are optionally deoxygenated by bubbling with an inert gas.
  • the resulting slurry is then heated (to for example about 65 0 C or more), to increase the reaction rate and to force the reaction to completion. While the reaction will proceed at lower temperatures, the reaction may optionally be heated to a temperature between about 40 0 C to about 80 0 C, with about 50 0 C to about 70 0 C being used in one or more embodiments, the maximum temperature being determined by the boiling point of the solvent being used, The reaction mixture is maintained at the desired temperature until the reaction is substantially complete, which is typically between about 2 to about 12 hours, more typically between about 2.5 to about 8 hours, and more typically about 3 hours. The reaction mixture is then cooled to room temperature.
  • the purity of the recovered cannabinoid product typically is about 90 weight%, about 95 weight%, about 98 weight% or more. Additionally, the overall yield of the reaction sequence used to obtain this highly pure cannabinoid product is at least about 15 wt.%, about 20 wt.%, about 25 wt.%, about 30 wt.% or more.
  • the synthetic cannabinoid produced using the process of the present disclosure will, in at least one embodiment, advantageously comprise not more than about 2 wt.%, more typically not more than about 1 wt.%, and more typically not more than about 0.5 wt.% of the corresponding ⁇ 8 - isomer, which is within the 2% USP limit for ⁇ 8 -isomer levels for ⁇ 9 -THC preparations.
  • the process of the present disclosure is applicable to both small scale and large, commercial scale production of synthetic ⁇ 9 -THC or related compounds.
  • the process of the present disclosure is effective for the production of ⁇ 9 -THC, or structurally similar or related compounds, using as little as about 1 g up to about 50 g, about 100 g, about 250 g, about 500 g, or more, of a Formula Il compound as the starting material.
  • the resulting reaction mixture was filtered using vacuum filtration through Whatman 541 filter paper to remove the magnesium sulfate. Evaporation of the solvent produced an oily residue containing crude ⁇ 9 -THC tosylate.
  • the crude tosylate was purified using a single pass through of a reverse-phase preparative chromatography column under the following conditions: Column: 250 x 10 mm, packed with Develosil RP-Aqueous Phase; Eiua ⁇ t: 3/3/2/2 acetonitrile/methanol/THF/water isocratic; Flow Rate 4.7 mL/min.
  • Example 1 the ⁇ 9 -THC tosylate prepared in Example 1 was hydrolyzed to obtain ⁇ 9 -THC.
  • ⁇ 9 -tetrahydrocannabivarin (3-propyl-THC) is synthesized.
  • the oi! was purified using reversed phase preparative chromatography, as described in Example 1. Column fractions were combined and concentrated to give an oily residue.
  • the 3-propyl- THC tosylate was obtained by dissolving the oil in a heated solution of 10:1 methanol :acetone, allowing the solution to cool to room temperature, and recovering the 3-propyl-THC tosylate crystals by vacuum filtration.
  • the reaction flask was then charged with 55 mL t-butanol and 0.95 mL of degassed water. 6.90 g of potassium t-butoxide was then added, and the reaction mixture was heated at 65°C for 4.5 hours. After 4.5 hours, the heat was removed, and the reaction was allowed to cool to 5O 0 C.
  • the reaction mixture was then charged with 95 mL of degassed water, and the resulting mixture was allowed to cool to room temperature with stirring for 1 hour.

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  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

La présente invention concerne un procédé de synthèse chimique du (-)-Δ9- tétrahydrocannabinol (Δ9-THC) et autres composés apparentés de formule (I). En particulier, le procédé comprend une séquence de réaction monotope de condensation et de sulfonylation qui produit un arylsulfonate de Δ9-THC brut ou autres composés apparentés. Immédiatement lors de leur formation, la sulfonylation du Δ9-THC ou autres composés apparentés confère la stabilité aux cannabinoïdes, et empêche la formation de l'isomère Δ8 correspondant. Les arylsulfonates de Δ9THC peuvent être facilement séparés des arylsulfonates de Δ6THC par chromatographie en phases inversées. L'hydrolyse des arylsulphonates de Δ9-THC ou autres composés apparentés donne un Δ9-THC ou autres composés apparentés contenant des quantités relativement basses de l'isomère Δ8 correspondant. (Formule I).
PCT/US2009/032361 2008-02-06 2009-01-29 Procédé pour la préparation du (-)-delta 9-tétrahydrocannabinol Ceased WO2009099868A1 (fr)

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CN107405327A (zh) * 2015-02-26 2017-11-28 西姆莱斯有限公司 大麻素化合物的混合物、其制备和应用
EP3061450A1 (fr) * 2015-02-26 2016-08-31 Symrise AG Mélanges de composés cannabinoïdes, leur fabrication et leur utilisation
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CN108137526A (zh) * 2015-07-10 2018-06-08 诺拉姆科有限公司 用于生产大麻二酚和△-9-四氢大麻酚的方法
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JP7651458B2 (ja) 2018-08-20 2025-03-26 ベッソール ファルマ、エルエルシー カンナビノイドの作成のためのプロセス
WO2020041321A1 (fr) * 2018-08-20 2020-02-27 Berkowitz Barry A Procédé de production de cannabinoïdes
JP2021535201A (ja) * 2018-08-20 2021-12-16 ベッソール ファルマ、エルエルシー カンナビノイドの作成のためのプロセス
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US12252477B2 (en) 2018-08-20 2025-03-18 Bessor Pharma, Llc Applications of known and novel cannabinoids
JP2022507668A (ja) * 2018-11-14 2022-01-18 エンバイオ リミテッド カンナビノイドを調製するための方法および化合物
WO2020099942A1 (fr) * 2018-11-14 2020-05-22 Embio Limited Procédé et composés pour la préparation de cannabinoïdes
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