US20190276420A1 – September 12, 2019 – CONTINUOUS ISOLATION OF CANNABIDIOL AND CONVERSION OF CANNABIDIOL TO DELTA 8-TETRAHYDROCANNABINOL AND DELTA 9-TETRAHYDROCANNABINOL

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Inventors :

Mark G. TEGEN; Joon CHO

Owner :

SOCATI TECHNOLOGIES

Application Number :

US16388182

Document Number :

US20190276420A1

Priority Date :

April 18, 2019

Filing Date :

April 18, 2019

Date of Grant/ Publication :

September 12, 2019

Class :

C07D301 / 32; C07D311 / 86

Abstract

In alternative embodiments, provided are processes comprising the continuous isolation and purification of cannabinoids and further isomerization of the purified cannabidiol to ? 8 tetrahydrocannabinol (? 8 THC) and ? 9 tetrahydrocannabinol (? 9 THC). In alternative embodiments, provided are processes for converting ?8-THC into ? 9 -THC. In alternative embodiments, provided are processes for the industrial scale continuous isolation and purification of cannabinoids and further isomerization of the purified cannabidiol to ? 9 -THC.

Claim(s)

1 . A method or process for obtaining or purifying a substantially pure ? 9 THC from a natural or a synthetic source, wherein optionally the natural source comprises a plant or a microbial material, or a material derived from a plant source, comprising: (a) obtaining or being provided a first extract, aliquot or sample of the natural or synthetic source comprising a cannabidiol (CBD) and/or ? 9 THC and/or ? 8 THC and/or other cannabinoids from the natural or the synthetic source; (b) dissolving the first extract aliquot or sample in a first solvent, or diluting the first extract aliquot or sample in a first solvent; (c) loading the solvent-dissolved or diluted first extract aliquot or sample onto a first chromatography column, wherein optionally the chromatography column is a normal phase chromatography column, an ion exchange chromatography column, or a reverse phase chromatography column, wherein the ? 9 THC and/or ? 8 THC and/or other cannabinoids are reversibly bound to the first chromatography column, wherein optionally some of or substantially most of the extract aliquot or sample material not reversibly bound to the first column at the first station is removed with a first wash solution before the column is moved to a next or a second station; (d) eluting the ? 9 THC and/or ? 8 THC and/or other cannabinoids off the first chromatography column with an elution solvent mixture, wherein optionally the eluting is a gradient elution; (e) collecting or isolating the ? 9 THC and/or ? 8 THC and/or other cannabinoids from said elution solvent mixture, wherein optionally the elution is by a gradient elution process and the ? 9 THC and/or ? 8 THC and/or other cannabinoids are separately collected in different or separate gradient elution fractions, wherein optionally, if the elution is by a gradient elution process: in a first gradient solvent non-polar compounds and terpenes are eluted off the column; in a second gradient solvent cannabidiol (CBD) is eluted off the column; in a third gradient a CBD/tetrahydrocannabinol (THC) mix is first eluted and then remaining THC is eluted off the column; in a fourth gradient remaining cannabinoids are eluted off the column, wherein optionally the remaining cannabinoids comprise CBC, CBG, CBN; and, in a fifth gradient solvent all remaining polar compounds are eluted off the column, wherein the remaining polar compounds comprises cannabidiolic acid (CBDA) and tetrahydrocannabinolic acid (THCA), and optionally, if the elution is by a gradient elution process using reverse phase column chromatography, the gradient elution: begins with an 80:20 or a 70:30 methanol to water elution solution or equivalent, which elutes off the column some or substantially most of the polar compounds, wherein optionally the polar compounds comprise CBDA and/or TGCA; then the gradient elution moves to an 85:15 or an 80:20 methanol to water elution solvent or equivalent, which elutes off the column some or substantially most of the CBD; then the gradient elution moves to a 90:10 methanol to water elution solution or equivalent, which initially elutes off the column a mix of the remaining CBD and THC, and finally elutes off the column THC; and finally the gradient elution moves to a 100% methanol elution solution, which removes a mix of remaining cannabinoids comprising CBC, CBG, CBN; (f) adding a second solvent of opposite polarity (to the elution solvent mixture) to said elution solvent mixture; (g) removing all or substantially most of the second solvent, thereby leaving a first extract comprising a plurality of cannabinoids comprising the ? 9 THC and/or ? 8 THC and/or other cannabinoids, wherein optionally the other cannabinoids comprise CBC, CBG, CBN; (h) dissolving the first extract comprising the plurality of cannabinoids in a first reaction solvent; (i) adding a catalyst to the first extract comprising the plurality of cannabinoids and the first reaction solvent, wherein the catalyst can be added before, simultaneous with or after addition of the first reaction solvent to the extract comprising the plurality of cannabinoids; and (j) reacting the first extract comprising the plurality of cannabinoids, the catalyst and the first reaction solvent, wherein optionally the reaction converts ?8-THC to ? 9 -THC; (k) adding a neutralizing agent; (l) removal of the catalyst and the neutralizing agent to generate a first reaction product; (m) optionally adding a second reaction solvent to the first reaction product, wherein optionally the second reaction solvent comprises dimethyl sulfoxide, water, dimethylformamide, methanol, ethylene dichloride, chloroform, propanol, ethanol, isobutanol, formamide, methylene dichloride, butanol, isopropanol, tetrahydrofuran, dioxane, benzene, toluene, xylene, or combinations thereof; (n) optionally removing all or substantially most of the second reaction solvent, thereby leaving a second extract comprising a plurality of cannabinoids; (o) adding a stabilization agent to the second extract; (p) adding an elimination agent to the second extract; (q) removal (or removal of substantially all) of the stabilization agent and the elimination agent, thereby leaving a third extract; (r) and if the second reaction solvent is not removed in step (n), adding a third solvent of opposite polarity to the third extract; (s) removing the second reaction solvent, if present (if not removed in step (n)), and removing all or substantially most of the third solvent of opposite polarity, if added, thereby leaving a fourth extract; (t) dissolving third or the fourth extract in a second solvent, wherein optionally the second solvent is the same or substantially the same as the first solvent; (u) loading the dissolved third or the fourth extract onto a second chromatography column, wherein optionally the chromatography column is a normal phase chromatography column or a reverse phase chromatography column, wherein the plurality of cannabinoids are reversible bound to the second chromatography column, and optionally the second chromatography column is the same as the first chromatography column; and (v) eluting the dissolved third or the fourth extract from the second column with an elution solution, wherein optionally the elution is by a gradient elution process and the ? 9 THC and/or ? 8 THC and/or other cannabinoids are separately collected in different or separate gradient elution fractions; and (w) optionally collecting the plurality of cannabinoids from the elution solution, and/or removing all or substantially most of the elution solvent, thereby obtaining or purifying a substantially pure plurality of cannabinoids, wherein optionally the plurality of cannabinoids comprises ? 9 THC and/or ? 8 THC.;
10 . A method or process for purifying a cannabinoid to a substantially pure ? 9 tetrahydrocannabinol (? 9 -THC) from a natural or a synthetic source, wherein optionally the natural source comprises a plant or microbial material, or a material derived from a plant or a microbial source, comprising: (a) providing or having provided a first extract, aliquot or sample of the natural or synthetic source comprising at least one of cannabidiol (CBD), ? 9 THC, ? 8 THC, and other cannabinoids from the natural or the synthetic source, optionally a plant material; (b) providing or having provided a continuous chromatography apparatus or device comprising a plurality of stations and a plurality of chromatography columns, wherein optionally the plurality of stations and the plurality of chromatography columns comprise at least 2, 3, 4, 5, 6, 7, or 8 or more, or between about 3 and 30, stations and/or chromatography columns; (c) introducing or loading the first extract, aliquot or sample into a first column at a first station, wherein the CBD, ? 9 THC, and ? 8 THC and other cannabinoids reversibly bind to the first column, wherein optionally some of or substantially most of the first extract material not reversibly bound to the first column at the first station is removed with a first wash solution before the column is moved to a next or a second station; (d) moving the first column to a second station, wherein after the first column is moved to the second station a next or second column is introduced into the first station; (e) eluting the extract from the first chromatography column with a first elution solution at the second station, wherein optionally the eluting is a gradient elution; (f) collecting the first elution fractions from the first column at the second station; (g) removing all or substantially most of the first elution solution from the first elution fractions to produce a first purified extract substantially free of CBD, ? 9 THC, and ? 8 THC; (h) optionally repeating steps d to g on the first column with at least one additional elution solution, wherein the at least one additional elution solution produces a second purified extract substantially free of CBD, ? 9 THC, and ? 8 THC; (i) when the first column is moved to the next, or second, station, introducing a next or second column into the first station, and the extract, aliquot or sample is introduced or loading into the next or second column at the first station; (j) moving the second column to the next or second station after the first column is moved to a next or third station; (k) eluting the extract from the first column with a second elution solution at the next or second station, wherein optionally the elution is by a gradient elution process and the CBD, ? 9 THC, and ? 8 THC and other cannabinoids are separately collected in different or separate gradient elution fractions wherein optionally, if the elution is by a gradient elution process: in a first gradient solvent non-polar compounds and terpenes are eluted off the column; in a second gradient solvent cannabidiol (CBD) is eluted off the column; in a third gradient a CBD/tetrahydrocannabinol (THC) mix is first eluted and then remaining THC is eluted off the column; in a fourth gradient remaining cannabinoids are eluted off the column, wherein optionally the remaining cannabinoids comprise CBC, CBG, CBN; and, in a fifth gradient solvent all remaining polar compounds are eluted off the column, wherein the remaining polar compounds comprises cannabidiolic acid (CBDA) and tetrahydrocannabinolic acid (THCA); (l) collecting the second elution fractions from the first chromatography column at the second station; and (m) removing all or substantially most of the second elution solution from the second elution fractions to produce a second purified extract (or a third purified extract if step h is completed) comprising at least about 75% of the CBD, ? 9 THC, and ? 8 THC from the first extract, or between about 60% and 90% of CBD, ? 9 THC, and ? 8 THC, or between about 50% and 95% of CBD, ? 9 THC, and ? 8 THC, and optionally the gradient elution: begins with a 70:30 methanol to water elution solution or equivalent, which elutes off the column some or substantially most of the cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC) are eluted off the column; then the gradient elution moves to an 80:20 methanol to water elution solution or equivalent, which elutes off the column some or substantially most of the CBD; then the gradient elution moves to a 90:10 methanol to water elution solution or equivalent, which initially elutes off the column a mix of the remaining CBD and THC, and finally elutes off the column THC; and finally the gradient elution moves to a 100% methanol elution solution, which removes a mix of remaining cannabinoids comprising CBC, CBG, CBN; and (n) optionally repeating steps j to m on the first column with at least one second additional elution solution; (o) optionally repeating steps i to m with at least one additional column; (p) optionally mixing the second purified extract with a reaction mixture comprising a reaction solvent and a catalyst, wherein the reaction mixture comprises an aqueous phase and an organic phase; (q) optionally separating the mixture into an aqueous phase and an organic phase (separating the aqueous phase and the organic phase): and (r) optionally recovering the organic phase to obtain the substantially pure ? 9 -THC.

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