Continuous isolation of cannabidiol and conversion of cannabidiol to delta 8-tetrahydrocannabinol and delta 9-tetrahydrocannabinol

Abstract

In alternative embodiments, provided are processes comprising the continuous isolation and purification of cannabinoids and further isomerization of the purified cannabidiol to Δ 8 tetrahydrocannabinol (Δ 8 THC) and Δ 9 tetrahydrocannabinol (Δ 9 THC). In alternative embodiments, provided are processes for converting Δ8-THC into Δ 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 Δ 9 -THC.

We claim: 
     
         1 . A method or process for obtaining or purifying a substantially pure Δ 9  THC from a natural or a synthetic 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 Δ 9  THC and/or Δ 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 the Δ 9  THC and/or Δ 8  THC and/or other cannabinoids are reversibly bound to the first chromatography column; 
 (d) eluting the Δ 9  THC and/or Δ 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 Δ 9  THC and/or Δ 8  THC and/or other cannabinoids from said elution solvent mixture; 
 (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 Δ 9  THC and/or Δ 8  THC and/or other cannabinoids; 
 (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 Δ 8  THC to Δ 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; 
 (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 and 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 Δ 9  THC and/or Δ 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 Δ 9  THC and/or Δ 8  THC. 
 
     
     
         2 . The method or process of  claim 1 , wherein the CBD content of the first extract, aliquot or sample material is greater than about 25%, 50%, 75%, 90% or 95% by weight, or is between about 5% and 95% by weight, by weight of the material. 
     
     
         3 . The method or process of  claim 1 , wherein the first solvent and/or the second solvent comprises methanol, propanol, ethanol, isobutanol, butanol, isopropanol, tetrahydrofuran, chloroform, acetone, hexane, methylene dichloride, and/or dichloroethane; and optionally the first solvent and/or the second solvent comprises chloroform, methylene dichloride and methanol, propanol and/or ethanol. 
     
     
         4 . The method or process of  claim 1 , wherein the chromatography column comprises a silica gel, an alumina or an ion exchange material, and optionally the ion exchange column comprises an anion exchange material; and optionally the chromatography column is a normal phase chromatography column, ion exchange column or reverse phase column. 
     
     
         5 . The method or process of  claim 1 , wherein the elution solution comprises a solvent, and the solvent comprises a one or a mixture of: ethylene dichloride; chloroform; or, methylene dichloride; and an alcohol comprising methanol, ethanol, propanol or butanol or a mixture thereof; an acid comprising acetic acid, formic acid, oxalic acid, glycolic acid or a mixture thereof; and/or, ammonium hydroxide, or the elution solvent is or comprises a dichloromethane, dichloroethane, or chloroform and methanol or ethanol. 
     
     
         6 . The method or process of  claim 1 , wherein the first reaction solvent comprises ethylene dichloride, chloroform, methylene dichloride, toluene, xylene, benzene, hexane and/or pentane, or mixtures thereof. 
     
     
         7 . The method or process of  claim 1 , wherein the catalyst is or comprises a Lewis acid or a non-oxidizing acid catalyst, and optionally the catalyst comprises p-toluenesulfonic acid. 
     
     
         8 . The method or process of  claim 1 , wherein:
 (a) the neutralizing agent is or comprises an alkali, or the neutralizing agent is or comprises sodium bicarbonate, sodium carbonate, calcium hydroxide or ammonium hydroxide;   (b) the stabilization agent is or comprises zinc chloride or methylene chloride;   (c) the second reaction solvent comprises dimethyl sulfoxide, water, dimethylformamide, methanol, saline, chloroform, propanol, ethanol, isobutanol, formamide, butanol, isopropanol, tetrahydrofuran, dioxane, benzene, toluene and/or xylene or a mixture thereof, and optionally the second reaction solvent comprises chloroform, hexane, dichloromethane, dichloroethane, benzene or toluene or a mixture thereof;   (d) the elimination agent is or comprises a strong base, and optionally the strong base comprises: lithium hydroxide (LiOH), sodium hydroxide (NaOH), potassium hydroxide (KOH), rubidium hydroxide (RbOH), cesium hydroxide (CsOH), magnesium hydroxide (Mg(OH)2), calcium hydroxide (Ca(OH)2), strontium hydroxide Sr(OH)2), barium hydroxide Ba(OH)2), potassium hydride and/or sodium hydride, potassium tert-pentoxide, organic superbases, bispidines, multicyclic polyamines, organometallic compounds of reactive metals, wherein optionally the reactive metals comprise organolithium, organo-magnesium, lithium diisopropylamide, n-butyl lithium and potassium tert-butoxide, sodium methoxide, or sodium ethoxide; and optionally the elimination agent is or comprises potassium tert- pentoxide, lithium diisopropylamide and/or potassium tert-butoxide;   (e) the elution solution is or comprises a solvent or mixture of solvents; or   (f) the extract is filtered before being loaded on to the column, and optionally the extract is mixed with silica, diatomaceous earth (DE), bentonite clay (BC), or equivalents, or mixtures thereof, before filtering, and optionally the extract is chilled before being mixed with the silica, DE, BC or equivalents or is chilled before being filtered.   
     
     
         9 . The method or process of  claim 1 , wherein:
 (a) the microbial material comprises or is derived from a bacterium, an algal cell, a lichen or a yeast, or a recombinant bacterium, lichen, algal cell or yeast cell;   (b) the plant or starting material comprises or is derived from a botanical drug substance, including hemp or a cannabis plant, wherein optionally the cannabis plant is a  Cannabis sativa , a  Cannabis chemovar,  or variants thereof, or a decarboxylated  Cannabis  plant material;   and optionally the plant or starting material comprises oils or extracts from a trichome or a trichome fraction of a pubescent plant, or an algae or a lichen;   and optionally the oils or extracts are from the plant or microbial material by: washing, contacting or exposing the trichome or trichome fraction, or the pubescent plant, algae or lichen, with: at least one non-polar, organic solvent; at least one polar, organic solvent; or, a mix of at least one non-polar, organic solvent with (and) at least one polar, organic solvent.   
     
     
         10 . The method or process of  claim 1 , wherein:
 (a) the microbial material comprises or is derived from a bacterium, an algal cell, a lichen or a yeast, or a recombinant bacterium, lichen, algal cell or yeast cell;   (b) the plant or starting material comprises or is derived from a botanical drug substance, including hemp or a cannabis plant, wherein optionally the cannabis plant is a  Cannabis sativa , a  Cannabis  chemovar, or variants thereof, or herbal  Cannabis  or dried  Cannabis  biomass, or a decarboxylated  Cannabis  plant material;   and optionally the plant material comprises or is derived from any plant part, wherein any plant part comprises bark, wood, leaves, stems, roots, flowers, fruits, seeds, berries or parts thereof, and exudate;   and optionally the plant or starting material comprises oils or extracts from a trichome or a trichome fraction of a pubescent plant, or an algae or a lichen;   and optionally the oils or extracts are from the plant or microbial material by:   washing, contacting or exposing the trichome or trichome fraction, or the pubescent plant, algae or lichen, with: at least one non-polar, organic solvent; at least one polar, organic solvent; or, a mix of at least one non-polar, organic solvent with (and) at least one polar, organic solvent.   
     
     
         11 . The method of  claim 1 , wherein the natural source comprises a plant or a microbial material, or a material derived from a plant source. 
     
     
         12 . The method of  claim 1 , wherein the chromatography column is a normal phase chromatography column, an ion exchange chromatography column, or a reverse phase chromatography column. 
     
     
         13 . The method of  claim 1 , wherein the 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. 
     
     
         14 . The method of  claim 1 , wherein the elution comprises use of a gradient elution process and the Δ 9  THC and/or Δ 8  THC and/or other cannabinoids are separately collected in different or separate gradient elution fractions. 
     
     
         15 . The method of  claim 14 , wherein if the elution comprises use of 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).   
     
     
         16 . The method of  claim 1 , wherein the elution comprises use of a gradient elution process comprising use of a reverse phase column chromatography, and 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.   
     
     
         17 . The method of  claim 1 , wherein the elution comprises use of a gradient elution process and the Δ 9  THC and/or Δ 8  THC and/or other cannabinoids are separately collected in different or separate gradient elution fractions. 
     
     
         18 . The method of  claim 1 , wherein 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. 
   
     
     
         19 . The method of  claim 1 , wherein in step (g) the other cannabinoids comprise CBC, CBG, CBN. 
     
     
         20 . The method of  claim 1 , wherein 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.