method for the production of cannabinoids from types of industrial hemp

专利摘要:
The present invention describes a process for the production of (-) - cannabidiol (CBD) from industrial hemp, by means of an extraction followed by two alternative work processes: an A process, which provides the extraction with solvents, first at an alkaline pH and then at an acidic pH, to isolate the carboxyl form of the CBD, which is then subjected to decarboxylation, and a B process, which provides for the elimination of waxes and resins and then purification by chromatography. At the end of both alternative work processes, CBD is crystallized, obtained in high purity crystalline form.
公开号:BR112020001704A2
申请号:R112020001704-3
申请日:2018-07-26
公开日:2020-07-21
发明作者:Giovanni Cipolletti；Luana Vagnoli；Marina MATULLI；Barbara FEBBRUARI；Jacopo Chini
申请人:Inalco S.R.L.；
IPC主号:

专利说明:

[0001] [0001] The present invention relates to the field of cannabinoid extraction from a plant matrix; in particular, it refers to the extraction of (-) - cannabidiol (CBD) and to obtaining in the form of high purity crystal from the types of hemp. BACKGROUND
[0002] [0002] Cannabinoids or cannabinoids are chemicals of natural origin and biochemically classified as terpenophenols. They are compounds united by the ability to interact with cannabinoid receptors.
[0003] [0003] With the term cannabinoids, in general a family of chemical compounds present in Cannabis sativa is identified.
[0004] [0004] To date, about seventy of these compounds have been identified, among which the most important are: tetrahydrocannabinol (THC, Δ9-THC), cannabidiol (CBD), tetrahydrocannabivarin (THCV), cannabinol (CBN) , cannabichrome (CBC), cannabicyclol (CBL), cannabielsoin (CBE), cannabigerol (CBG), cannabinodiol (CBND), cannabitriol (CBT), cannabivarin (CBV), cannabidivarin (CBDV), cannabicromevarina (CBCV), cannabigerovarin (CBV)) and cannabigerol monoethyl ether (CBGM).
[0005] [0005] Recently, Sativex, a drug extracted from Cannabis Sativa, with a standardized cannabinoid content (THC and CBD), was placed on the market.
[0006] [0006] Cannabinoids are found in the hemp plant Cannabis sativa in the form of its carboxyl derivatives, cannabinoid carboxylic acids, from which the so-called "neutral cannabinoids" are derived by decarboxylation, that is, the elimination of CO2. Thus, for example, cannabidiol (CBD) is formed by the decarboxylation of cannabidiolic acid (CBDA).
[0007] [0007] (-) - Cannabidiol (CBD) can be found in the plant in both its acidic (CBDA) and decarboxylated (CBD) forms. The greater or lesser presence of one or another form of cannabinoid within the biomass can depend both on the growth conditions of the plant and, therefore, on the environmental parameters, as well as on the conditions used in the subsequent stages of processing and storage. In the treatment of industrial hemp, biomass can in fact undergo a drying phase that can, due to heating, lead to the decarboxylation of the cannabinoid acid form (CBDA) in its decarboxylated form (CBD). This decarboxylation process can occur even at low temperature (T.A.) if the biomass is stored for long periods before its use.
[0008] [0008] Isolation processes for neutral cannabinoids, particularly CBD, known in the state of the art (see, for example, the one described in US2015 / 0038567), prove to be quite laborious and it is not always possible to obtain them with high purity with processes that can be easily used on an industrial scale.
[0009] [0009] The objective of the present invention is to provide a process for the production from types of CBD industrial hemp, or other neutral cannabinoids, in high purity crystalline form. SUMMARY OF THE INVENTION
[0010] [0010] The present invention solves the problems previously mentioned by a process for the production of CBD or another neutral cannabinoid, said process comprising: i) contacting a biomass containing CBD and / or CBDA, or said other cannabinoid neutral or in the form of carboxylic acid, with an extraction solvent, for at least 10 minutes at a temperature of 0 ° C until the reflux temperature of the solvent, to obtain, after removal of the biomass, an extraction solution; said extraction solvent selected from the group consisting of pentane, hexane, heptane, octane, methylcyclohexane, acetone, propanol, ethanol, methanol, ethyl acetate, toluene, methylene chloride and mixtures thereof; continue according to a process (A) comprising: ii-a) contact the extraction solution with a hydroalcoholic solution and adjust the pH to 7.5-12.5 with a suitable alkaline solution, to obtain, after phase separation, a first hydroalcoholic phase and a first organic phase; if the extraction solvent is a water-miscible solvent, add also a first water-immiscible solvent selected from the group consisting of pentane, hexane, heptane, methylcyclohexane and mixtures thereof; iii-a) contacting the first hydroalcoholic phase with a second water-immiscible solvent and a suitable acid solution to bring the pH to 2.0-6.5, to obtain a second organic phase and a second hydroalcoholic phase; said second water-immiscible solvent selected from the group consisting of pentane, hexane, heptane, methylcyclohexane and mixtures thereof; iv-a) concentrate the second organic phase and subject the resulting oil to heating at a temperature between 65 ° C and 180 ° C, for a time of at least 10 minutes, to obtain the decarboxylation of CBDA to CBD; or continue according to a process (B) which comprises: ii-b) concentrating the extraction solution until an extraction oil is obtained and contacting the extraction oil with an alcohol, at a temperature below 20 ° C, for at least 10 minutes, to obtain a suspension of extract and waxes, said alcohol selected from the group consisting of methanol, ethanol, propanol and mixtures thereof; iii-b) filter and concentrate the suspension to obtain an extraction oil without wax and contact the extraction oil without wax with an organic solvent immiscible in water and a hydroalcoholic solution, to obtain an organic phase containing the extract without wax and resin and a hydroalcoholic phase containing resins;
[0011] [0011] Surprisingly, it was observed that the method of extraction and isolation of (-) - cannabidiol (CBD) described in the present invention can be applied to "biomass" having any ratio between the acid form (CBDA) and the decarboxylated one ( CBD) through any of the two processes defined in this document as: Process A and Process B.
[0012] [0012] It should be noted that, due to its specific simplicity, process A is indicated for processing in the pharmaceutical field, which is subject to more restrictive rules.
[0013] [0013] In addition to the CBD recovery, process B also applies to obtaining other cannabinoids (eg CBG, CBN etc.). DETAILED SPECIFICATION OF THE INVENTION
[0014] [0014] According to the invention, the solvents pentane, hexane, heptane and octane are intended as n-pentane, n-hexane, n-heptane, n-octane or mixtures of isomers thereof.
[0015] [0015] Preferably, according to the present invention, the raw material (ie biomass) used is industrial hemp (Cannabis Sativa species; Sativa subspecies). As an alternative, and also preferably, types of industrial hemp can be used, for example: Antal, Armanca, Beniko, Bialobrzeskie, Cannakomp, Karma, Carmagnola, Carmaleonte, Chamaeleon, Codimoro, CS, Dacia Sacuieni, Delta-Ilosa, Delta -405, Denise, Diana, Dioica 88, Eletta Campana, Epsilon 68, Fedora 17, Felina 32, Férimon, Fibranova, Fibrol, Finola, Futura 75, Ivory, KC Bonusz, KC Dora, KC Virtus, KC Zuzuna, Kompolti, KompoltiHibrid TC, Lipko, Lovrin 110, Marcello, Markant, Monica, Rajan, Ratza, Santhica 23, Santhica 27, Santhica 70, SecuieniJubilee, Silvana, Szarvasi, Tiborszallasi, Tisza, Tygra, Uniko B, Uso-31, Wielkopolkie, Wojko, Zenit .
[0016] [0016] The biomass is preferably micronized before being subjected to extraction with solvent, according to the process of the present invention. Process A:
[0017] [0017] Preferably, the extraction of CBDA and CBD occurs by keeping the hemp in contact with a solvent conveniently chosen from the group consisting of pentane, hexane, heptane, octane, methylcyclohexane and their mixtures; more preferably hexane (n-hexane or mixture of isomers) is used as the extraction solvent.
[0018] [0018] The extraction according to process A preferably takes place at a temperature between 0 ° C and 35 ° C, more preferably between 10 and 25 ° C, for a time of at least 10 minutes.
[0019] [0019] According to process A of the present invention, the acid form (CBDA) is separated from the decarboxylated form (CBD) and impurities by the addition of a hydroalcoholic solution, in which the alcohol is conveniently selected from the group consisting of in ethanol, methanol, preferably methanol. Separation occurs by adding, under stirring, a suitable alkaline solution, preferably a 30% NaOH solution, bringing the pH between 7.5 and 12.5, more preferably between 8.0 and 8.5, even more preferably between 8.2 and 8.3. It has been observed that pH 8.2-8.3 is particularly advantageous as it does not allow fatty acids such as omega-3 or omega-6 to be extracted in the hydroalcoholic phase, sometimes present, even in substantial quantities in the initial biomass.
[0020] [0020] The first hydroalcoholic phase is recovered and the CBDA is extracted by adding, with stirring, a second more or less non-polar water-immiscible solvent, preferably hexane (n-hexane or mixture of isomers) and a acid solution, preferably an acetic acid solution is used, bringing the pH between 6.5 and 2.0, preferably 4.5 and 5.5, even more preferably between 4.8 and 5.2.
[0021] [0021] The second organic phase is concentrated to an oil and the CBDA contained therein is decarboxylated to CBD, keeping the oil at a temperature between 65 ° C and 180 ° C, for a period of at least 10 minutes.
[0022] [0022] The CBD is then crystallized. Process B
[0023] [0023] The extraction of CBDA and CBD occurs by keeping the hemp in contact with a solvent preferably selected from the group consisting of acetone, propanol, ethanol, methanol, ethyl acetate, toluene, n-hexane or hexane-mixture of isomers; more preferably methanol, at the reflux temperature of the solvent, for a period of at least 10 minutes. If necessary, the suspension is kept under stirring until complete decarboxylation of CBDA to CBD.
[0024] [0024] The suspension can be kept at reflux for up to 60 hours or more.
[0025] [0025] The biomass is separated by filtration or centrifugation and the solution containing the CBD is concentrated to an oil.
[0026] [0026] The waxes present in the extraction solution are eliminated by the addition of an alcohol, preferably methanol is used, keeping the temperature below 20 ° C, preferably 4-10 ° C, even more preferably 4 ° C, for example. a period of at least 10 minutes. The suspension is filtered and the solution without wax is concentrated to an oil.
[0027] [0027] The resins are removed from the oil by adding, under stirring, a solvent suitably selected from the group consisting of toluene, pentane, hexane, heptane, octane and mixtures thereof; preferably hexane (n-hexane or mixture of isomers) is used; and a hydroalcoholic solution, in which alcohol is suitably selected from the group consisting of ethanol and methanol; preferably methanol is used.
[0028] [0028] The hexane phase is concentrated to an oil and loaded onto a silica gel column, using as an elution phase preferably a mixture of hexane (n-hexane or mixture of isomers) and ethyl acetate, preferably in a 20: 1 to 5: 1 ratio, even more preferably 10: 1.
[0029] [0029] The fractions containing the purified CBD are combined and concentrated in an oil and the CBD contained therein is crystallized. CRYSTALLIZATION
[0030] [0030] Crystallization of CBD, whether it comes from process A or process B, occurs by adding, with stirring, 0.3-3 volumes, preferably 0.5-1, even more preferably 0.6 volume of solvent in relation to to the weight of the oil. The solvent is conveniently selected from the group consisting of pentane, hexane, heptane, octane and methylcyclohexane, preferably hexane or heptane (or mixtures of their isomers) or methylcyclohexane is used as the crystallizing solvent , at a temperature of less than 30 ° C, for a period of at least 10 minutes. Crystallization is optionally caused by the addition of a minimal amount of crystal CBD.
[0031] [0031] This crystallization step can optionally be repeated a second time, to obtain a product with an even greater purity, adding, with stirring, 0.3-3 volumes, preferably 0.5-2.5, even more preferably 2 volumes of solvent in relation to the weight of the oil.
[0032] [0032] An advantageous aspect of the present invention is that processes A and B can be integrated, because process steps ii-b through iv-b can be applied to the first organic phase, obtained from step ii-a of process A to recover the CBD, or other neutral cannabinoid, contained therein.
[0033] [0033] The present invention can be better understood considering the following modalities. BRIEF DESCRIPTION OF THE FIGURES
[0034] [0034] FIG. 1 - shows the HPLC traces of two hemp extracts with different ratio between CBDA and CBD and related TR. EXPERIMENTAL PART MATERIALS AND METHODS
[0035] [0035] 132 kg of hexane and 40 kg of micronized hemp were introduced into a 250 liter steel jacketed reactor equipped with an agitator shaft while stirring at a temperature of 20 ° C for 4 hours.
[0036] [0036] After that time, the suspension was discharged from the reactor and filtered under vacuum in 2 aliquots. The biomass retained by the filter in each aliquot was washed with 10 liters of hexane.
[0037] [0037] The filtered solution was refilled in the reactor and concentrated under vacuum, at a temperature <35 ° C,
[0038] [0038] The concentrated solution was maintained at a temperature of <30 ° C for the subsequent phases. Separation of CBDA from CBD (Test Q207D / 396):
[0039] [0039] 1001.0 g (containing 77.7 g of CBDA + 16.8 g of CBD) of the concentrated solution, 540 ml of methanol, 810 ml of demineralized water and 5 g of sodium bisulfite were introduced into a flask. four-neck, 3-liter glass equipped with an agitator shaft. The pH was corrected to 12.0, with stirring, by adding a 30% NaOH solution (about 125 ml). The whole was transferred to a separating funnel for the separation of the upper hexane phase (1) from the aqueous lower phase with methanol (1).
[0040] [0040] The separating funnel was discharged keeping the two phases separated and transferring the upper hexane phase (1) back to the four-necked flask, in which 160 ml of methanol, 240 ml of demineralized water and 5 g were introduced of sodium bisulfite while stirring. The pH was adjusted to 12.5 by the addition of a 30% NaOH solution.
[0041] [0041] The whole was transferred to the separating funnel for the separation of the upper hexane phase (2) from the aqueous lower phase with methanol (2).
[0042] [0042] The two aqueous phases with methanol (1) and (2) were combined in the four-necked flask and 400 ml of hexane were added to it. The pH was reduced, with stirring, to 5.5 by the addition of glacial acetic acid and the whole was transferred to the separatory funnel to allow the separation of the upper hexane phase (3) from the aqueous lower phase with methanol (3).
[0043] [0043] The hexane phase (2) was transferred to the 4-neck flask and an equal volume of demineralized water was added to it. The pH was reduced to 5.5, under stirring, by the addition of glacial acetic acid and the whole was transferred to the separation funnel for the separation of the upper hexane phase (4) from the aqueous lower phase (4). Results (HPLC analysis): Sample Weight CBDA CBD (grams) (grams) (grams) Hexane phase (3) 89.7 75.1 1.80 Hexane phase (4) 1156.6 4.27 18.56 Decarboxylation of CBDA contained in the hexane phase (3):
[0044] [0044] The hexane phase (3) was placed in a 4-neck and 500 ml bottle, equipped with an agitator and condenser shaft for the recovery of the distilled hexane, and subjected to decarboxylation in a glycerin bath heated to a temperature of 120 ° C, under stirring, for about 7 hours. The concentrated solution to an oil was cooled to RT, diluted with 150 ml of hexane and filtered over a fossil flour panel, under vacuum.
[0045] [0045] The filtered solution was then reconcentrated by means of a rotary evaporator, at a temperature of 45 ° C, obtaining 77.7 g of oil (containing 65.9 g of CBD).
[0046] [0046] The 77.7 g of oil was transferred to a 4-neck, 250 ml glass bottle, equipped with a stirrer shaft, and 77 ml of hexane were added to it. The whole was stirred for 3 hours in a cold room at 4 ° C. After this period, the crystalline solid was filtered (always in a cold room, at 4 ° C) over a Gouch (G3) and washed with two 25 ml aliquots of cold hexane each. 46.5 g of crystal were obtained with 98.9% HPLC purity. CBD recovery from crystallization mother liquors:
[0047] [0047] The mother liquors obtained from the previous crystallization step were concentrated by means of a rotary evaporator, at a temperature of 45 ° C, obtaining 31 g of oil, which was transferred to a bottle with 4 necks and 100 ml ( equipped with a stirrer shaft), in a cold room, at 4 ° C. 15 ml of hexane was added to the oil. The whole was kept under agitation for 6 hours. After that time, the crystalline solid was filtered (always in a cold room, at 4 ° C) over a Gouch (G3) and washed with three 5 ml aliquots of cold hexane each. 6.0 g of crystal were obtained with 97.9% HPLC purity. Example 2: Recovery of CBD and CBDA present in the first hexane phase (process A) by chromatography (process B) Test No. Q207F / 594 Wax removal:
[0048] [0048] 87.7 g of the first hexane phase, obtained according to method (A), containing 1.98 g of CBD and 0.48 g of CBDA, were concentrated to an oil, by means of a rotary evaporator , under vacuum, at a temperature of 50 ° C. 50 ml of methanol was added to the oil and the whole was transferred to -20 ° C for one night.
[0049] [0049] The suspension was filtered under vacuum, over a Gouch filter funnel (G3), and the waxes retained by the filter were washed with two 50 ml aliquots of cold methanol. The filtered product was concentrated by means of a rotary evaporator, under vacuum, at a temperature of 50 ° C, obtaining 8.1 g of oil containing 1.60 g of CBD and 0.31 g of CBDA. Chromatography on silica gel:
[0050] [0050] 100 g of silica gel were placed in a glass column ( 5 cm x h 20 cm) and equilibrated in equicurrent with 250 ml of mobile phase (10: 1 hexane-ethyl acetate).
[0051] [0051] 8.1 g of oil from the previous step was loaded onto the column after its dilution with about 8 ml of mobile phase. Elution occurred by drop and 12 fractions of 22 g each were collected. In fractions 4 to 12, included, an HPLC analysis was performed to check the CBD content and relative purity. Results: Fraction N ° CBD content (g / 100 g) CBD purity (% of area) 4 0.11 77.68 5 1.16 92.52 6 1.96 91.97 7 1.53 88.50 8 1.06 81.99 9 0.62 73.69 10 0.36 63.93 11 0.18 54.17 12 0.08 37.48
[0052] [0052] A grouping of fractions 4 to 9 was included, included (high purity fractions), with a total CBD content of 1.41 g, and a grouping of fractions 10 to no. 12, included (fractions with medium purity), with a total CBD content of 0.138 g. Example 3: Obtaining CBD on a laboratory scale from hemp having a CBDA / CBD ratio of about 90/10 by extraction and separation of its acid form (CBDA) (Process A) (Test Q207E / 515). Hexane extraction from biomass:
[0053] [0053] 2 kg of micronized hemp and 10 liters of hexane (mixture of isomers) are placed in a 15 liter glass bottle, equipped with a stirrer shaft. The whole was kept under stirring at room temperature for 4 hours. After that time, the suspension was filtered on filter paper through the Buchner funnel, under vacuum, washing the biomass on the filter with 6 liters of hexane. The filtered product was concentrated by means of a rotary evaporator, under vacuum, at a temperature of 30 ° C, to a volume of 860 ml. Separation of CBDA from CBD:
[0054] [0054] The filtered solution containing 21.23 g of CBDA and 1.8 g of CBD (values obtained through HPLC analysis) was introduced into a 4-bottle, 3-liter glass flask, equipped with a stirrer shaft, and to it were added 478 ml of methanol and 360 ml of demineralized water.
[0055] [0055] The pH was increased to 8.2 by adding, with vigorous stirring, about 7 ml of a 30% NaOH solution.
[0056] [0056] The whole was transferred to a separating funnel, for the separation of the upper hexane phase (1) from the aqueous lower phase with methanol (1).
[0057] [0057] The aqueous phase with methanol (1) was transferred back to the 4-necked flask and 740 ml of hexane (mixture of isomers) was added, with stirring. The pH was adjusted to 5.0 by adding about 20 ml of glacial acetic acid.
[0058] [0058] The whole was transferred to a separating funnel, for the separation of the upper hexane phase (2) from the aqueous lower phase with methanol (2). Sample Weight CBDA CBD (grams) (grams) (grams) Hexane phase (1) 619.4 4.03 1.8 Hexane phase (2) 499.1 15.95 - Decarboxylation of CBDA contained in the hexane phase ( 2):
[0059] [0059] The hexane phase (2) was placed in a 4-bottle, 1-liter flask, equipped with a stirrer and condenser shaft, for the recovery of the distilled hexane, and subjected to decarboxylation in a glycerin bath heated to a temperature 120 ° C, under stirring, for about 4 hours. Crystallization of CBD:
[0060] [0060] The solution containing the CBD was concentrated by rotary evaporator, under vacuum, at a temperature of 50 ° C, obtaining 24.3 g of oil, which was diluted with 14.5 ml of hexane (mixture of isomers) and placed in a cold room at 4 ° C overnight. After that time, the suspension was filtered over a Gouch (G3) and the crystal was washed with 6 ml of cold hexane. 10.1 g of wet crystal CBD with a purity of 99.6% and 42.2 g of mother liquor containing 3.88 g of CBD were obtained. Example 4: Obtaining on a pilot scale of hemp CBD having a CBD / CBD ratio of about 90/10 by extraction and separation of its acid form (CBDA) (Process A) (Product P56 / 38/047). Hexane extraction from biomass:
[0061] [0061] 150 kg of micronized hemp and 700 liters of hexane (mixture of isomers) were introduced into a steel dryer filter, equipped with a stirring system. The whole was kept under stirring for 1 hour at room temperature. After this time, the stirring was stopped and the suspension was filtered by nitrogen pressure. The filtered product containing CBDA was collected in a cistern. The biomass retained by the filter was washed with two aliquots of 450 liters of hexane, each, while the whole was kept under agitation, at room temperature, for one hour, and the filtrate was discharged, each time, in the collection tank by pressure of nitrogen.
[0062] [0062] The exhausted biomass was discharged from the drying filter, in which an additional 150 kg of new micronized hemp were loaded for a second extraction. Pre-concentration:
[0063] [0063] The filtered solutions, obtained from two extractions of 150 kg of hemp each, were combined in a steel reactor, jacketed, equipped with a stirring and condenser system, and concentrated under vacuum, at a temperature of 30 ° C , up to a volume of about 180 liters.
[0064] [0064] 180 liters of pre-concentrated solution were loaded into a 250 liter steel jacketed reactor and equipped with an agitator shaft and a condenser, and concentrated under vacuum, at a temperature between 16 and 20 ° C, in a final volume of about 130 liters. 54 liters of drinking water were loaded into the reactor with 57 liters of methanol. The pH was brought to 8.2, under stirring, adding a 30% sodium hydroxide solution. The whole was kept static, at rest, for 60 minutes. The two phases were discharged separately and the hydroalcoholic phase was recharged in the reactor and 76.6 kg of hexane (mixture of isomers) were added to it. The pH was brought to 5.0 by adding 3.75 liters of glacial acetic acid and the whole was kept static, at rest, for one hour.
[0065] [0065] The lower hydroalcoholic phase (115 kg) was discharged into a tank for disposal, while the upper hexane phase was concentrated under vacuum, at a temperature of about 50 ° C, obtaining a final weight of about 27 kg , and recovered for the subsequent decarboxylation phase. Decarboxylation of CBDA contained in the hexane phase (2):
[0066] [0066] 4 hexane phases from the previous steps, containing 14.48 kg of CBDA (from HPLC analysis), were combined in a 250 liter steel jacketed reactor and equipped with an agitator shaft, and concentrated in a 50 ° C to an oil. The temperature was brought to about 120 ° C, while stirring for 4 hours. After that time, 13.6 kg of hexane (mixture of isomers) were added to the reactor and 30.3 kg of solution were discharged to the subsequent crystallization step. 1st Crystallization of the CDB:
[0067] [0067] 30.3 kg of CBD solution from the previous step were filtered on paper, under vacuum, through a Buchner filtration funnel and loaded into a 25 liter glass reactor, equipped with an agitator shaft. The solution was concentrated to an oil, under vacuum, at a temperature of 50 ° C and, after having been cooled to 35 ° C, 6 kg of hexane (n-hexane) were added. The solution was cooled to 20 ° C and crystallization was caused by the addition of 20 g of crystal CBD.
[0068] [0068] After 30 minutes, the temperature was brought to 4 ° C, keeping under stirring for 12 hours.
[0069] [0069] The suspension was filtered on paper, under vacuum, through a Buchner filter funnel and the crystal was washed with 6 liters of cold hexane (n-hexane). 8.16 kg of wet crystal CBD were obtained with an LOD of 0.33% and a purity of 98.6% and 12.65 kg of mother liquors containing 2.96 kg of CBD. 2nd crystallization of CBD:
[0070] [0070] 8.16 kg of CBD crystal from the previous step were loaded into a 25 liter glass reactor, equipped with an agitator shaft, and combined with 8.48 kg of hexane (n-hexane), at 35 ° C, under stirring, until complete solubilization. The temperature was brought to 4 ° C by making a descending ramp and maintained for 12 hours.
[0071] [0071] The suspension was filtered on paper, under vacuum, through a Buchner filter funnel, and the crystal was washed with 6.7 liters of cold hexane (n-hexane). 6.94 kg of wet crystal were obtained with a purity of 99.4% and 11.9 kg of mother liquor containing 625 g of CBD. Example 5: Obtaining CBD by silica gel chromatography on an industrial scale (Process B). Methanolic extraction of CBD from biomass (see FDL nº 2728PF_01_01):
[0072] [0072] In a 6,000 liter steel reactor, jacketed and equipped with an agitator shaft, 3,500 kg of methanol were introduced and, under agitation, 1000 kg of micronized biomass. The temperature was brought to 63-67 ° C, at reflux. The whole was kept under agitation until the percentage of CBDA was ≤ 7% in relation to CBD (about 60 hours). After reducing the internal temperature of the reactor by 15 - 25 ° C, the suspension was filtered by centrifugation on a screen, at 450 - 500 rpm, for 20-25 minutes, washing the biomass 3 times with about 20 kg of methanol, for 25-30 minutes. For the elimination of the wax component, the filtered solution was refilled in the reactor and concentrated under vacuum, at a temperature of 50 ° C, until obtaining an agitated oily residue to which 300 liters of methanol were added. The reactor temperature was brought to 63-67 ° C by vacuum distillation, under reflux, for 30 minutes. After this time, the temperature was lowered to -5 - -10 ° C and the suspension was kept under slow stirring for about 12 hours, at the end of which the temperature was increased to 5-10 ° C. 22 kg of fossil flour were added, with stirring, and the suspension was filtered by centrifugation on canvas, at 450-500 rpm, for 60 minutes, performing 3 washes with about 40 kg of cold methanol (5-10 ° C), each, for 35-40 minutes.
[0073] [0073] The filtered solution was loaded back into the reactor and concentrated under vacuum, at a temperature of 50 ° C, until obtaining an agitated oily residue, to which 400 liters of methanol were added. The reactor temperature was brought to 63-67 ° C by vacuum distillation, under reflux, for 30 minutes. After that time, the temperature was lowered to 15-25 ° C and 150 kg of hexane and 150 liters of demineralized water were loaded into the reactor. The mixture was kept under stirring, at a temperature of 15-25 ° C, for 30 minutes, and static, for another 30 minutes, to allow the separation of the lower aqueous phase with methanol (1) from the upper hexane phase (1) . The aqueous phase with methanol (1) was transferred to a second reactor, in which 75 kg of hexane were also introduced. The mixture was kept under stirring, at a temperature of 15-25 ° C, for 30 minutes, and static for another 30 minutes, to allow the separation of the lower aqueous phase with methanol (2) from the upper hexane phase (2). The aqueous phase with methanol (2) was discharged from the reactor into which the hexane phase (1) was introduced. The two hexane phases thus assembled were concentrated under vacuum, at a temperature of 50 ° C, obtaining 43 kg of concentrated solution. A sample of the concentrated product was obtained to determine the CBD content. Results: Dry weight = 43.9 kg Total CBD content = 16.0 kg CBD / dry weight ratio x 100 = 36.4% Chromatography on silica gel (see FLD nº 2728PF_03A_01):
[0074] [0074] A steel column ( 80 cm x h 200 cm)
[0075] [0075] 43.9 kg of extract without resins were diluted with hexane (mixture of isomers) to a total weight of 54 kg and loaded onto a column. The elution occurred in equicurrent with the mobile phase (10: 1 hexane-ethyl acetate), in a flow of 250-300 liters / hour. Eleven fractions of 100 kg each were collected, in which an HPLC analysis was performed to check the CBD content and relative purity. Results Fraction N ° CBD content (g / 100 g) CBD purity (% area) 1 0.003 9.5 2 0.059 26.3 3 2.800 91.7 4 4.077 91.0 5 2.803 88.3 6 1.974 86, 6 7 1,213 84.7 8 0.866 83.9 9 0.482 81.1 10 0.246 75.7 11 0.169 70.7
[0076] [0076] Fractions having a HPLC purity ranging from 86.6% to 91.7% (grouping of high purity fractions) were pooled for the subsequent crystallization step. Fractions having a purity of 81.1% to 84.7% were pooled (groupings of medium purity fractions) and purified again on column after being combined with other medium purity fractions from other chromatographies. 1st CBD Crystallization (see FDL nº 2728PF_01_02):
[0077] [0077] 69.5 kg of high purity fractions were collected from two different purifications on silica gel and containing 25.27 kg of CBD, vacuum filtered on canvas, loaded into a 250 liter steel jacketed reactor and equipped with a stirrer shaft and concentrated to an oil, under vacuum, at a temperature of 45 ° C. At the end of the concentration, the temperature was increased to 70 ° C, keeping the stirring for 3 hours. After that time, the temperature was lowered to 30 ° C and 18 liters of hexane (mixture of isomers) were added. The temperature was lowered to 15-21 ° C and crystallization was caused by the addition of 20 g of CBD crystal. The temperature was lowered further to 4 ° C and the whole was stirred for 12 hours. The suspension was discharged from the reactor and the "crude" CBD crystal was recovered by vacuum filtration on canvas, performing three washes of the crystals with a total of 12.6 liters of cold hexane. 20 kg of wet crystal CBD (with an HPLC purity of 99.22%) were obtained with an LOD of 7.9%, equivalent to 18.4 kg of dry product, and 32 kg of crystallization mother liquor. CBD recovery from crystallization mother liquors (see FDL nº 2728PF_01_02):
[0078] [0078] 23 kg of crystallization mother liquors were concentrated in a 25 liter reactor, jacketed, and equipped with a vacuum stirrer shaft, at a temperature of 50 ° C, up to a volume of 19 liters. 5 liters of hexane (mixture of isomers) were added and, after having brought the temperature to 4 ° C, crystallization was caused by the addition of 7 g of CBD crystal, keeping at 4 ° C, under stirring, overnight . The suspension was filtered under vacuum, on paper, and the crystal was washed with 2 liters of cold hexane (mixture of isomers).
[0079] [0079] 3.2 kg of wet crystal were obtained (with an HPLC purity of 95.94%). Example 6: Crystallization of CBD in methylcyclohexane (Test Q207F / 576B).
[0080] [0080] 25 g of CBD crystal, obtained by method A according to example 4, were dissolved at room temperature, under stirring, with 250 ml of hexane (mixture of isomers), in a 500 ml glass vial, equipped with magnetic stir bar, and left static overnight. The solution was filtered twice under vacuum, over a glass fiber filter with a porosity of 0.8 µm, and concentrated to an oil by a rotary evaporator, at a temperature of 50 ° C.
[0081] [0081] 50 ml of methylcyclohexane were added to the oil and the whole was placed at a temperature of 4 ° C, under stirring, for one night.
[0082] [0082] The suspension was filtered under vacuum, over a Gouch filter funnel (G3), and the crystal was washed with 20 ml of cold methylcyclohexane.
[0083] [0083] 16.9 g of moist crystal with HPLC purity of 99.05% and 24 g of mother liquor were obtained. Example 7: Crystallization of CBD from heptane (Test Q207F / 584).
[0084] [0084] 22.1 g of crystal CBD, obtained by method A according to example 4, were dissolved under stirring, at a temperature of 38 ° C, with 45 ml of heptane, in a 100 ml glass vial, equipped with a magnetic stir bar. The solution was brought to 4 ° C and crystallization was caused by the addition of a crystal CBD spatula tip, while keeping the whole stirred by the magnetic stir bar, for one night.
[0085] [0085] The suspension was filtered under vacuum, over a Gouch filter funnel (G3), and the crystal was washed with two 10 ml aliquots of cold heptane.
[0086] [0086] 20.1 g of moist crystal with HPLC purity of 99.2% and 36.4 g of mother liquor were obtained.

权利要求:
Claims (11)
[1]
1. A process for the production of cannabidiol (CBD) or another neutral cannabinoid, said process comprising: i) contacting a biomass containing CBD and / or CBDA, or said other neutral cannabinoid or in the form of carboxylic acid, with an extraction solvent for at least 10 minutes at a temperature between 0 ° C and the reflux temperature of the solvent, to obtain, after removal of the biomass, an extraction solution; said extraction solvent selected from the group consisting of pentane, hexane, heptane, octane, methylcyclohexane, acetone, propanol, ethanol, methanol, ethyl acetate, toluene, methylene chloride and mixtures thereof; continue according to a process (A) comprising: ii-a) contact the extraction solution with a hydroalcoholic solution and adjust the pH to 7.5-12.5 with a suitable alkaline solution, to obtain, after phase separation, a first hydroalcoholic phase and a first organic phase; if the extraction solvent is a water-miscible solvent, add also a first water-immiscible solvent selected from the group consisting of pentane, hexane, heptane, methylcyclohexane and mixtures thereof; iii-a) contacting the first hydroalcoholic phase with a second water-immiscible solvent and an acid solution adapted to bring the pH to 2.0-6.5 to obtain a second organic phase and a second hydroalcoholic phase; said second water-immiscible solvent selected from the group consisting of pentane, hexane, heptane, methylcyclohexane and mixtures thereof; iv-a) concentrate the second organic phase and subject the resulting oil to heating at a temperature between 65 ° C and 180 ° C for a period of at least 10 minutes to obtain the decarboxylation of CBDA to CBD; or continue according to a second process (B) which comprises: ii-b) concentrating the extraction solution until an extraction oil is obtained and contacting the extraction oil with an alcohol at a temperature below 20 ° C for at least 10 minutes to obtain a suspension of extract and waxes, said alcohol selected from the group consisting of methanol, ethanol, propanol and mixtures thereof; iii-b) filter and concentrate the suspension to obtain an extraction oil without wax and contact the extraction oil without wax with a water-immiscible organic solvent and a hydroalcoholic solution to obtain an organic phase containing the extract without wax and resin and a hydroalcoholic phase, containing resin; iv-b) concentrate the organic phase containing the extract without wax and resin and submit to chromatography on silica gel using a suitable eluent phase and collect the fractions containing CBD, or said other neutral cannabinoids; and conclude with v) crystallize the CBD, or said other neutral cannabinoid, from a third water-immiscible solvent selected from the group consisting of pentane, hexane, heptane, octane, methylcyclohexane and mixtures thereof.
[2]
2. A process according to claim 1 where the biomass is selected from the group consisting of Cannabis Sativa, Antal, Armanca, Beniko, Bialobrzeskie, Cannakomp, Carma, Carmagnola, Carmaleonte, Chamaeleon, Codimoro, CS, Dacia Sacuieni, Delta-Ilosa, Delta-405, Denise, Diana, Dioica 88, Eletta Campana, Epsilon 68, Fedora 17, Felina 32, Férimon, Fibranova, Fibrol, Finola, Futura 75, Ivory, KC Bonusz, KC Dora, KC Virtus, KC Zuzuna, Kompolti, KompoltiHibrid TC, Lipko, Lovrin 110, Marcello, Markant, Monica, Rajan, Ratza, Santhica 23, Santhica 27, Santhica 70, SecuieniJubileu, Silvana, Szarvasi, Tiborszallasi, Tisza, Tygra, Uniko B, Uso-31, Wielkopolkie, Wojko, Zenit.
[3]
A process according to claim 1 or 2, wherein the biomass is micronized before being subjected to solvent extraction.
[4]
A process according to any one of claims 1-3, where, when executing process A, the extraction in step (i) is carried out while keeping the cannabis in contact with an extraction solvent selected from the group that consists of pentane, hexane, heptane, octane, methylcyclohexane and mixtures thereof; hexane is preferably used as the extraction solvent and extraction is carried out at a temperature between 0 ° C and 35 ° C, preferably between 10 and 25 ° C, for a period of at least 10 minutes.
[5]
A process according to any one of claims 1-5, wherein, when carrying out process A, the hydroalcoholic solution of step (ii-a) is such that the alcohol is selected from the group consisting of ethanol, methanol , preferably methanol, the pH is adjusted,
preferably between 8.0 and 8.5, adding a suitable alkaline solution.
[6]
A process according to any one of claims 1-5, wherein, when carrying out process A, the pH of step (iii-a) is adjusted, preferably between 4.5 and 5.5, by adding a solution of acid acetic.
[7]
A process according to any one of claims 1-5, where, when executing process A, the first organic phase obtained at the end of step (ii-a) is subjected to steps (ii-b) - (iv- b) from process B and the CBD thus obtained is then subjected to crystallization.
[8]
A process according to any one of claims 1-3, where, when executing process B, extraction in step (i) is carried out while keeping the cannabis in contact with an extraction solvent selected from the group that consists of acetone, propanol, ethanol, methanol, ethyl acetate, toluene, n-hexane or hexane-mixture of isomers at the reflux temperature of the solvent for at least 10 minutes.
[9]
A process according to any one of claims 1-3 and 8, where, when carrying out process B, in step (ii-b), the alcohol used is methanol, while maintaining the temperature at 4-10 ° C, even more preferably at 4 ° C, for a period of at least 10 minutes.
[10]
A process according to any one of claims 1-3 and 8-9, where, when carrying out process B, in step (iii-b), the resins are removed from the extraction oil without wax by adding, with stirring, a solvent selected from the group consisting of toluene, pentane, hexane, heptane, octane and mixtures thereof; preferably hexane; and a hydroalcoholic solution in which the alcohol is conveniently selected from the group consisting of ethanol and methanol; preferably methanol.
[11]
A process according to any of claims 1-3 and 8-10, where, following process B, in step (iv-b), the eluent phase is a mixture of hexane (n-hexane or mixture isomers) and ethyl acetate, preferably in a 20: 1 to 5: 1 ratio.

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法律状态:
2021-11-03| B350| Update of information on the portal [chapter 15.35 patent gazette]|

优先权:

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申请号 | 申请日 | 专利标题

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IT102017000085508|2017-07-26|

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IT102017000085508A|IT201700085508A1|2017-07-26|2017-07-26|METHOD FOR THE PRODUCTION OF CANNABINOIDS FROM VARIETY OF INDUSTRIAL HEMP|

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PCT/EP2018/070275|WO2019020738A1|2017-07-26|2018-07-26|Method for the production of cannabinoids from types of industrial hemp|

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