CN114057551A - Method for preparing hypocannabidiol - Google Patents
Method for preparing hypocannabidiol Download PDFInfo
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- CN114057551A CN114057551A CN202010778740.3A CN202010778740A CN114057551A CN 114057551 A CN114057551 A CN 114057551A CN 202010778740 A CN202010778740 A CN 202010778740A CN 114057551 A CN114057551 A CN 114057551A
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- 238000000034 method Methods 0.000 title claims abstract description 33
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- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 48
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 claims abstract description 28
- 239000000463 material Substances 0.000 claims abstract description 25
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 claims abstract description 23
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- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 claims abstract description 23
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Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/685—Processes comprising at least two steps in series
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
- C07C37/82—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by solid-liquid treatment; by chemisorption
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/70—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment
- C07C37/84—Purification; separation; Use of additives, e.g. for stabilisation by physical treatment by crystallisation
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/86—Purification; separation; Use of additives, e.g. for stabilisation by treatment giving rise to a chemical modification
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Crystallography & Structural Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The application discloses a method for preparing hypocannabidiol, which at least comprises the following steps: a) pretreating a raw material containing industrial hemp to obtain a pretreated material; b) extracting the pretreated material with alcohol, concentrating the extract I to obtain a concentrated solution, adding water for decarboxylation, and concentrating the extract II to obtain a dry extract; c) mixing the dry extract with an adsorbent I to form a solid dispersion system, and performing solid-phase extraction to obtain a primary cannabidiol solution; d) and concentrating III, decoloring and crystallizing the cannabidiol primary solution to obtain the hypocannabidiol. The preparation method has the advantages of simple process, high product transfer rate, time and labor saving, large processing capacity and high product purity, and is suitable for industrial scale-up production.
Description
Technical Field
The application relates to a method for preparing hypocannabidiol, belonging to the field of chemical industry.
Background
Industrial hemp (Cannabis sativa L.) is a plant of Cannabis of Cannabaceae, the content of Tetrahydrocannabinol (THC) in the flower and leaf in the growth period is less than three per thousand, and the industrial hemp can be legally planted in large scale and industrially developed and utilized. With the continued development of Cannabidiol (CBD), the medicinal value of other related cannabinoids, especially Cannabidivarin (CBDV), has also become increasingly recognized. For example, patent US20190160023a1 suggests high purity CBDV in the treatment of Autism Spectrum Disorders (ASD) and ASD-related disorders such as Fragile X Syndrome (FXS); rett Syndrome (RS); or Angelman Syndrome (AS); and in the treatment of schizophrenia. CBDV has been shown to be particularly effective in improving cognitive dysfunction in rodent models of ASD, FXS, RS, AS and schizophrenia.
At present, the content of CBDV of the large-scale planted Yunnan hemp No. 7 is relatively high and is about 0.2 percent after complete decarboxylation conversion; in the commercially available extract, the content of CBD accounts for about 40-70%, the content of CBDV is close to 13-30%, and the content of CBDV of European and American hemp raw materials is very low, so that the extract has considerable market price. However, at present, no high-purity CBDV process suitable for industrial production exists.
Patent CN110655453A discloses a method for extracting and separating hypocannabidiol, which comprises extracting with ethanol aqueous solution, extracting with organic solvent to enrich hypocannabidiol, decolorizing with activated carbon, purifying with polyamide resin column, neutral alumina and bonded silica gel column, and crystallizing to obtain high-purity hypocannabidiol, but the process is complicated and the cost is high. Patent CN110143854A discloses a method for simultaneously extracting CBD and CBDV, which comprises the steps of carrying out pretreatment in an oxygen-enriched environment, combining with subsequent gradient solution crystallization, carrying out gradient crystallization on ethanol-water solution with the volume ratio of 0: 1-1: 0, crystallizing CBDV, and then crystallizing CBD. However, the pretreatment described in this method is not easy to be industrialized, and there are concerns about yield and coloring matter.
In view of this, we have developed a preparation method with simple process, low cost and stable product quality.
Disclosure of Invention
The invention provides a method for preparing Cannabidiol (CBDV). The method adopts specific low ethanol concentration for extraction, has minimum lipid and pigment impurities in the extractive solution, and reduces a large amount of post-treatment work; in the aspect of decarboxylation transformation, the link and concentration are carried out simultaneously, so that the complete transformation from the CBDVA to the CBDV can be realized, the batch difference of the flower and leaf roasting is reduced, and the dependence on equipment and a field is reduced; in the aspect of separation and purification, a specific adsorbent and a solid phase extraction technology are adopted, column chromatography can be completely avoided, time and labor are saved, specific crystallization conditions are finally controlled, and a finished product with the purity of more than 99% is obtained through one-step crystallization.
According to one aspect of the present application, there is provided a method for preparing cannabidiol, characterized in that it comprises at least the following steps:
a) pretreating a raw material containing industrial hemp to obtain a pretreated material;
b) extracting the pretreated material with alcohol, concentrating the extract I to obtain a concentrated solution, adding water for decarboxylation, and concentrating the extract II to obtain a dry extract;
c) mixing the dry extract with an adsorbent I to form a solid dispersion system, and performing solid-phase extraction to obtain a primary cannabidiol solution;
d) and concentrating III, decoloring and crystallizing the primary cannabidiol solution to obtain the cannabidiol.
Optionally, in step a), the pre-processing includes: a raw material containing industrial hemp is pulverized to 250 to 1700 μm.
Optionally, the raw material containing industrial hemp is one or a combination of more than two of industrial hemp flowers, leaves, roots, stem cores or seed shells.
In the application, the feeding amount of the industrial hemp raw material is the industrial-grade amount, a case of 100kg is specifically given in the embodiment, and in practical application, the scale can be correspondingly enlarged by 2-10 times according to production requirements.
Optionally, in step b), the alcohol is extracted as an ethanol aqueous solution; the concentration of the ethanol water solution is 60-80 wt%.
Preferably, the concentration of the ethanol water solution is 65-75 wt%.
Alternatively, the upper limit of the concentration of the aqueous ethanol solution is selected from 65 wt%, 70 wt%, 75 wt%, or 80 wt%; the lower limit is selected from 60 wt%, 65 wt%, 70 wt% or 75 wt%.
Optionally, the extraction conditions are: the mass-to-volume ratio (M/V) of the pretreatment material to the ethanol aqueous solution is 1 Kg: 5-30L, the extraction time is 1-3 h, and the extraction is carried out for 1-3 times.
Preferably, the mass volume ratio of the pretreatment material to the ethanol aqueous solution is 1 Kg: 7-15L.
Optionally, the upper limit of the mass to volume ratio of the pretreatment feed to the aqueous ethanol solution is selected from 1: 7. 1: 10. 1: 7. 1: 7. 1: 15. 1: 20. 1: 25 or 1: 30, of a nitrogen-containing gas; the lower limit is selected from 1: 5. 1: 7. 1: 10. 1: 7. 1: 7. 1: 15. 1: 20 or 1: 25.
compared with the conventional alkane or ether solvent, even alcohol, the specific ethanol aqueous solution with the concentration of 60-75 wt% is extracted, so that the lipid and pigment impurities are minimum, and a large amount of post-treatment is reduced.
Optionally, in step b), the conditions for concentrating I are:
the temperature is 50-65 ℃, the pressure is-0.065-0.10 MPa, and the extracting solution is concentrated to the relative density of 1.05-1.15.
Alternatively, in step b), the decarboxylation by adding water is carried out under the following conditions:
the mass ratio of the water to the pretreated material is as follows: 1: 10-100;
the temperature is 75-110 ℃, and the time is 1-3 h.
Optionally, the upper limit of the mass ratio of water to pretreated feedstock is selected from 1: 20. 1: 30. 1: 40. 1: 50. 1: 60. 1: 70. 1: 80. 1: 90 or 1: 100, respectively; the lower limit is selected from 1: 10. 1: 20. 1: 30. 1: 40. 1: 50. 1: 60. 1: 70. 1: 80 or 1: 90.
optionally, in step b), the conditions for concentrating II are:
the temperature is 60-100 ℃, the pressure is-0.065 to-0.10 MPa, and the dry extract is obtained by concentration.
Decarboxylation and concentration are carried out simultaneously, so that complete conversion from CBDVA to CBDV can be achieved, batch difference of mosaic baking is reduced, and dependence on equipment and fields is reduced.
Optionally, in step c), the adsorbent I is selected from at least one of diatomaceous earth, calcium phosphate, calcium carbonate, and silica gel.
Optionally, in step c), the mass ratio of the dry extract to the adsorbent I is: 1: 0.25 to 5.
Preferably, the mass ratio of the dry extract to the adsorbent I is 1: 0.5 to 2.
Optionally, the upper limit of the mass ratio of the dry extract to the adsorbent I is selected from 1: 0.3, 1: 0.4, 1: 0.5, 1: 1. 1: 2. 1: 3. 1: 4 or 1: 5; the lower limit is selected from 1: 0.25, 1: 0.3, 1: 0.4, 1: 0.5, 1: 1. 1: 2. 1: 3 or 1: 4.
optionally, in step c), the solid phase extraction comprises: transferring the solid dispersion to a solid phase extraction column, washing the column with a non-polar solvent, and eluting with a polar solvent.
Optionally, the non-polar solvent is selected from at least one of non-polar alkanes, halogenated alkanes, esters, medium-chain fatty alcohols.
Preferably, the nonpolar alkane is selected from at least one of petroleum ether, diethyl ether, n-hexane and n-heptane.
Preferably, the alkyl halide is at least one selected from dichloromethane and chloroform.
Preferably, the ester is selected from at least one of ethyl acetate and butyl acetate.
Preferably, the medium-chain fatty alcohol is selected from at least one of n-octanol, sec-octanol and heptanol.
And (4) flushing the column by using a non-polar solvent until the effluent is nearly colorless, drying by using nitrogen, and eluting by using a polar solvent.
Optionally, the polar solvent is selected from at least one of short chain alcohols, ketones.
Preferably, the short-chain alcohol is selected from at least one of methanol, ethanol, isopropanol.
Preferably, the ketone is selected from at least one of acetone and butanone.
Preferably, the polar solvent is selected from at least one of methanol, ethanol, isopropanol, acetone, and butanone.
Optionally, in step d), the conditions for concentrating III are:
the temperature is 50-65 ℃, the pressure is-0.065-0.10 MPa, and the concentration of the concentrated cannabidiol is 100-300 g/L.
Optionally, in step d), the decoloring is: and adding water into the concentrated substance III until the volume fraction of the organic phase is 40-70% to obtain a diluent, and adding an adsorbent II for decolorization.
Optionally, the adsorbent II is selected from at least one of diatomite, activated carbon, calcium phosphate, calcium carbonate, macroporous resin and MCI resin powder.
Optionally, the macroporous resin is selected from at least one of AB-8, D-101, HPD700, XAD2, XDA-8, LSA-7, D-941, DM-130, ADS600, ADS-17, SP-825, HPD-600.
Optionally, the volume-to-mass ratio of the diluent to the adsorbent II is: 1L: 0.6-5 kg.
Preferably, the volume-to-mass ratio of the diluent to the adsorbent II is: 1L: 0.8-2.0 kg.
Optionally, the upper limit of the volume-to-mass ratio of the diluent to the adsorbent II is selected from 1L: 0.8kg, 1L: 1kg, 1L: 2kg, 1L: 3kg, 1L: 4kg or 1L: 5 kg; the lower limit is selected from 1L: 0.6kg, 1L: 0.8kg, 1L: 1kg, 1L: 2kg, 1L: 3kg or 1L: 4 kg.
Optionally, a filtration step is included after the decolorization.
Optionally, the filtration is filter pressing or suction filtration, and the aperture of the filter screen adopted by the filtration is not less than 400 meshes.
The specific adsorbent and the solid phase extraction technology can completely avoid column chromatography, thereby saving time and labor.
Optionally, in step d), the crystallization comprises at least:
adding water while stirring at the temperature of-10-20 ℃ until the volume fraction of the organic phase is 15-25% until the crystal nucleus amount is not increased any more, stopping stirring, and incubating and crystallizing at constant temperature for 2-12 h;
the rate of addition of water is such as to reduce the volume fraction of the organic phase by 0.25% to 2% per minute.
The water adding speed can affect the size and purity of the crystal form, a better crystal form can be obtained by controlling the water adding speed within the range, pigment coating is reduced, and the purity is improved.
The finished product with the purity of more than 99 percent can be obtained by one-step crystallization, the process is simple, and the product purity is high.
Optionally, after crystallization, washing and drying, the finished product of the Cannabidiol (CBDV) is obtained.
Optionally, the washing is: eluting with a solvent at a temperature of between 20 ℃ below zero and 10 ℃ below zero and between 15 and 25 percent (V/V).
The solvent may be water or a mixture of water and an organic solvent.
Specifically, the organic solvent may be methanol, ethanol, isopropanol, acetone, butanone, etc.
Further, an organic phase solvent in the crystallization step may be used.
Optionally, the drying comprises one of vacuum drying, freeze drying, near infrared drying, forced air drying or microwave drying.
Optionally, the temperature of the drying is 30 ℃ to 65 ℃.
In this application, "CBDV" refers to cannabidivarin.
In this application, "CBD" refers to cannabidiol.
In this application, "CBDVA" refers to "cannabinoids".
In the present application, "room temperature" means "room temperature 25. + -. 5 ℃ C".
As used herein, "relative density" refers to "the weight of the solution at 50 ℃ per liter of solution in kg/L".
In the present application, "alcoholic degree" means "volume fraction of alcoholic medium in water".
In the application, the term "medium-chain fatty alcohol" refers to a fatty alcohol having 6 to 12 carbon atoms.
In the present application, "short-chain alcohol" refers to an alcohol having 1 to 3 carbon atoms.
In the present application, unless otherwise specified, the mass-to-volume ratio (M/V) represents the ratio of the mass (kg) of a substance to the volume (L) of another substance, and vice versa, the volume-to-mass ratio (V/M) can be understood as such.
In this application, unless otherwise indicated, the data ranges given are selected from any value within the range, and include the endpoints of the range.
The beneficial effects that this application can produce include:
1) the separation and purification process of the high-purity CBDV provided by the application adopts a preparation method of alcohol extraction, solid phase extraction and solvent crystallization, adopts a specific ethanol aqueous solution for extraction, has high CBDV extraction rate and less impurities, and can achieve complete conversion from CBDVA to CBDV by simultaneously performing decarboxylation and concentration; the batch difference of the leaf roasting is reduced, and the dependence on equipment and a field is insufficient; the solid phase extraction is adopted for further purification, and compared with the traditional column chromatography, the method is simple and convenient to operate, large in treatment capacity and high in efficiency; the crystallization condition is controlled, and the crystallization efficiency and the product quality are improved; the whole preparation process has the advantages of easy control of conditions, large treatment capacity, easy industrial production and good industrial preparation prospect.
2) The separation and purification process of the high-purity CBDV has high transfer rate and the highest purity of more than 99 percent.
3) The adsorbent used in the application can be regenerated properly and dried for repeated use (the active carbon can be repeatedly used after being coked at 500 ℃ for 1-5 h) for more than 100 times theoretically, and basically has no production waste.
Drawings
FIG. 1 is a liquid chromatogram of an extraction stock solution of industrial hemp leaves raw material in example 1;
FIG. 2 is a liquid chromatogram of the finished cannabidiol product obtained in example 1;
FIG. 3 is a liquid chromatogram of the finished cannabidiol product obtained in example 2;
FIG. 4 is a liquid chromatogram of the finished cannabidiol product obtained in example 3.
Detailed Description
The present application will be described in detail with reference to examples, but the present application is not limited to these examples.
The raw materials in the examples of the present application were all purchased commercially, unless otherwise specified.
The industrial hemp raw material is 7-9 months of mature industrial hemp flowers and leaves, and after primary drying by farmers, the content of Tetrahydrocannabinol (THC) is below 0.3%.
The product analysis method in the examples of the present application is as follows:
analyzing the raw material extract of industrial hemp and the finished product of cannabidiol by high performance liquid chromatography, wherein an analyzer is an Agilent liquid phase 1260, and the analysis conditions are as follows:
chromatographic conditions and system applicability test: octadecylsilane chemically bonded silica is used as a filling agent; taking acetonitrile as a mobile phase A, taking water as a mobile phase B, and carrying out isocratic elution according to the volume ratio of A (%): B (%) being 70: 30; the detection wavelength was 210 nm. The number of theoretical plates should not be less than 2500 calculated from CBDV peaks.
Preparation of control solutions: precisely weighing CBDV, and adding methanol-water (1:1, V/V) to obtain control solution containing 0.1 mg/l ml.
Preparation of CBDV test solution: taking about 25mg of CBDV finished product, precisely weighing, placing in a 250ml measuring flask, adding 20ml of acetonitrile-water (1:1, V/V), carrying out ultrasonic treatment for 10 minutes, adding acetonitrile-water (1:1, V/V) to dilute to a scale, shaking up, filtering with a microporous filter membrane (0.45pm), and taking a subsequent filtrate to obtain the CBDV.
A test solution of industrial folium Cannabis is prepared by precisely weighing and pulverizing to 75-150 μm folium Cannabis fine powder 500mg, placing in 50ml conical flask, precisely adding 75% methanol solution (Vol%) 50ml, weighing, ultrasonic treating for 20 min, ultrasonic treating at 40KHZ frequency, standing for 30min, weighing again, supplementing with 75% methanol solution, reducing weight loss, shaking, and collecting filtrate.
The determination method comprises the following steps: precisely sucking 10 μ l of each of the reference solution and the sample solution, injecting into liquid chromatograph, and measuring.
The content of the hypocannabinol in the industrial cannabis sativa leaf raw material used in the present application is calculated by the following method:
the content of the mosaic material CBDV (peak area of the sample CBDV 0.1 x 50)/(peak area of the control 500) 100%
FIG. 1 is a liquid chromatogram of a raw liquid of a flower and leaf extract, and a peak with a retention time of 4.754min represents CBDV.
The actual mass fraction of the CBDV content in the industrial hemp flower and leaf raw material used in the application is 0.18%.
The transfer rate of the finished CBDV product is calculated as follows:
the transfer rate of CBDV is (the quality of finished CBDV product is purity)/(the weight of the water-retaining dried flower and leaf material is 0.0018) 100%
Example 1 CBDV was prepared as follows
1) Crushing industrial hemp leaves raw materials into 10-mesh coarse powder, wherein the water content is 14.6 wt%, so as to obtain a pretreatment material;
2) soaking the above pretreated materials in 5 times volume (W/V, 1Kg corresponds to 5L) of 60 wt% ethanol water solution at room temperature for 1 hr for 3 times, and mixing to obtain extractive solution;
3) concentrating the above extractive solution at 50 deg.C and-0.10 Mpa until no alcohol smell exists and the relative density is 1.05, adding purified water of 1/100(w/w) as pretreatment material, heating to 110 deg.C, oil bathing for 1h, introducing 110 deg.C steam, and decocting under normal pressure to remove residual water to obtain dry extract.
4) Weighing the dry extract, adding 4 times (W/W) of diatomite and calcium phosphate (mass ratio of 3: 1) mixing, transferring to a dwarf extraction column (d: L is 1:2), flushing with n-heptane for 2.5BV until the effluent is almost colorless, drying with nitrogen, replacing the air gaps and air bubbles in the column with methanol until the effluent is stable, flushing the column for 1.5BV after soaking for 1h, and collecting methanol eluent to obtain CBDV primary product solution.
5) Concentrating the CBDV primary product solution to a fluid extract at 65 ℃ and-0.85 MPa, measuring the concentration of the cannabidiol by HPLC (high performance liquid chromatography), adding water to adjust the volume fraction of the methanol to 70% when the solution is hot, adding 0.6% of active carbon (W/V, namely adding 0.6kg of active carbon into every 1L of solution), stirring for 30min at 65 ℃, and performing filter pressing by using a titanium rod filter to obtain a clear CBDV primary product decoloration solution.
6) Standing the CBDV primary decolorized solution to room temperature, stirring on an ice-water bath, slowly injecting purified water by a peristaltic pump, controlling the water adding rate to reduce the volume fraction of the organic phase by about 0.5% per minute until the solution is obviously milky turbid, starting to measure the alcohol degree, reducing the pump speed to 2-5 drops/second until crystals are not increased any more and the volume fraction of methanol is about 15%, stopping pumping water, and consuming 6.8 hours. Filter pressing with 400 mesh filter cloth, finally obtaining the crystal, carrying out surface leaching with 10ml of 20% methanol-water (Vol%) at minus 20 ℃, and drying by pressing to obtain a CBDV crystal semi-finished product.
7) And (3) placing the semi-finished CBDV crystal at 50 ℃ for vacuum drying (-0.10MPa, 16h) until the water content is measured below 2 wt% to obtain a CBDV finished product, sampling, and detecting the purity by HPLC. FIG. 2 is an HPLC chromatogram of a pure product, and the peak with a retention time of 4.978min represents CBDV, and the purity of CBDV is 99.25% by HPLC. The process flow is from the extraction of the flower leaves to the harvest of the final finished product, and the total time is 36.3 h.
Example 2 CBDV was prepared as follows
1) Crushing industrial hemp leaves raw materials into 40-mesh powder, wherein the measured water content is 13.5 wt%, so as to obtain a pretreatment material;
2) soaking the above pretreated materials in 7 times volume (W/V) of 75% ethanol (Vol%) at room temperature for 2 hr, extracting for 2 times, and mixing to obtain extractive solution;
3) concentrating the above extractive solution at 60 deg.C and-0.080 Mpa until no alcohol smell exists and the relative density is 1.15, adding purified water of 1/10(w/w) of pretreatment material, boiling at normal pressure (94 deg.C) for 2 hr, and evaporating residual water at 65 deg.C and-0.095 Mpa under reduced pressure to obtain dry extract.
4) Weighing the dry extract, adding 0.25 times (W/W) of silica gel, mixing well to obtain a solid dispersion, transferring to a dwarf extraction column (d: L is 1:2), adding n-heptane: washing with ethyl acetate (95: 5, V: V) for 1.5BV, removing almost colorless effluent, drying with nitrogen, replacing air gaps and bubbles in the column with ethanol until the effluent is stable, soaking for 1h, washing the column for 1.5BV, and collecting ethanol eluate to obtain CBDV primary product solution.
5) And (3) concentrating the CBDV primary product solution at 55 ℃ and-0.10 Mpa under reduced pressure to obtain a fluid extract, measuring the concentration of cannabidiol by HPLC (high performance liquid chromatography) to be about 100g/L, adding water while the solution is hot to adjust the volume fraction of ethanol to be 40%, adding 5% macroporous resin HP20(W/V), stirring for 1h at room temperature, and filtering by a 300-mesh sieve to obtain a clear CBDV primary product decoloration solution.
6) Standing the CBDV primary decolorized solution to room temperature, stirring on an ice-water bath, slowly injecting purified water by a peristaltic pump, controlling the water adding rate to reduce the volume fraction of an organic phase by about 1.5% per minute until the solution is obviously milky turbid, starting to measure the alcohol degree, reducing the pump speed to 2-5 drops/second until crystals are not increased any more and the volume fraction of ethanol is about 22%, stopping pumping water, and consuming 2.5 hours. Filter pressing with 400 mesh filter cloth, finally obtaining the crystal, then carrying out surface leaching with 20ml of 20% ethanol-water (V/V) at minus 20 ℃, and carrying out press drying to obtain the CBDV crystal semi-finished product.
7) And (3) placing the semi-finished CBDV crystal at 50 ℃ for vacuum drying (-0.10MPa, 16h) until the water content is measured below 2 wt% to obtain a CBDV finished product, sampling, and detecting the purity by HPLC. FIG. 3 is an HPLC chromatogram of a pure product, wherein the peak with a retention time of 4.724min represents CBDV, and the purity of CBDV is 99.72% as determined by HPLC. The process flow is from the extraction of the flower leaves to the harvest of the final finished product, and the total time is 34.5 h.
Example 3 CBDV was prepared as follows
1) Crushing industrial hemp leaves raw materials into coarse powder of 60 meshes, wherein the measured water content is 16.6 wt%, so as to obtain a pretreatment material;
2) soaking the pretreated materials in 30 times of 80 wt% ethanol at room temperature for 1 hr, extracting for 1 time, and filtering to obtain extractive solution;
3) concentrating the above extractive solution at 65 deg.C and-0.75 Mpa until no alcohol smell exists and the relative density is 1.11, adding purified water of 1/10(w/w) as pretreatment material, heating at 75 deg.C for 3 hr, and removing residual water at 75 deg.C and-0.085 Mpa to obtain dry extract.
4) The dry extract was weighed and equal amounts of (W/W) silica gel and calcium carbonate (1: 2, mass ratio), mixing to obtain a solid dispersion, transferring to a dwarf extraction column (d: L ═ 1:2), mixing with petroleum ether: washing with dichloromethane (85: 15 volume ratio) for 3BV, eluting the eluate with almost colorless nitrogen gas, replacing air gap and bubble in the column with acetone until the eluate is stable, soaking for 1h, washing the column for 2BV, and collecting acetone eluate to obtain CBDV primary product solution.
5) Concentrating the CBDV primary product solution to a fluid extract at 50 ℃ and-0.10 MPa, measuring the concentration of cannabidiol by HPLC (high performance liquid chromatography) to be about 300g/L, adding water while the solution is hot to adjust the volume fraction of acetone to be 60%, adding 2% MCI resin powder (W/V), stirring for 1h at 40 ℃, and filtering by a 400-mesh sieve to obtain clear CBDV primary product decolored solution.
6) Standing the CBDV primary decolorized solution to room temperature, stirring on an ice-water bath, slowly injecting purified water by a peristaltic pump, controlling the water adding rate to reduce the volume fraction of the organic phase by about 1% per minute until the solution is obviously milky turbid, reducing the pump speed to 2-5 drops/second until crystals are not increased any more and the volume fraction of acetone is about 25%, and stopping pumping water, wherein the time is 3.4 hours. Filter pressing with 400 mesh filter cloth, finally obtaining the crystal, carrying out surface leaching with 10ml of 25% acetone-water (V/V) at minus 20 ℃, and drying by pressing to obtain a CBDV crystal semi-finished product.
7) And (3) placing the semi-finished CBDV crystal at 50 ℃ for vacuum drying (-0.10MPa, 16h) until the water content is measured below 2 wt% to obtain a CBDV finished product, sampling, and detecting the purity by HPLC. FIG. 4 is an HPLC chromatogram of a pure product, wherein the peak with a retention time of 4.858min represents CBDV, and the purity of CBDV is 99.65% by HPLC. The process flow is from the extraction of the flower leaves to the harvest of the final finished product, and the total time is 36.4 h.
Comparative example 1 CBDV was prepared as follows
1) Crushing industrial hemp leaves (10kg) into coarse powder of 40-60 meshes, baking for 2 hours at 105 ℃ until the water content is 5.8 wt% to obtain a pretreatment material;
2) stirring and leaching the pretreated materials for 2 hours by 15 times of volume of butane, extracting for 2 times, and mixing to obtain an extracting solution;
3) concentrating the above extractive solution at 40 deg.C under reduced pressure to obtain dry extract, dissolving with 70 wt% ethanol, and removing insoluble substances;
4) passing the converted solution through D101 macroporous resin, sequentially washing with purified water for 2BV and 55 wt% ethanol for 4BV, starting to collect CBDV from liquid phase detection, stopping collecting until the detected CBDV concentration is lower than 0.5g/L, and taking the rest as waste liquid recovery solvent;
5) concentrating the collected liquid to 55 wt% of alcohol content, feeding the collected liquid to a medium-pressure chromatographic column DAC50 with a filler of C18, removing impurities by 55 wt% of alcohol for 2.5BV, and eluting by 70 wt% of alcohol to obtain CBDV eluent;
7) concentrating the CBDV eluate at 60 deg.C under-0.10 MPa until a large amount of crystals are precipitated, stopping crystallizing at 4-10 deg.C for 12 hr;
8) discharging the crystallization mother liquor, recovering, shoveling the crystals, performing suction filtration till the crystals are dry, then leaching with a small amount of purified water, taking out the crystals, placing the crystals at 50 ℃ for vacuum drying under-0.10 MPa for 16 hours until the water content is below 2 wt%, thus obtaining the finished product, wherein the purity of the CBDV is 99.35% by HPLC. The process flow is from the flower leaves to the harvest of the final finished product, and the total time is 49.5 h.
The above examples are summarized in table 1 below.
TABLE 1
In conclusion, the method for preparing the hypocannabinol provided by the application has the advantages that the product transfer rate is kept above 50%, the time and the labor are saved, the purity of the hypocannabinol can reach above 99%, the single treatment capacity is large, and the industrial preparation can be realized.
Although the present application has been described with reference to a few embodiments, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the application as defined by the appended claims.
Claims (10)
1. A method for preparing cannabidiol, comprising at least the steps of:
a) pretreating a raw material containing industrial hemp to obtain a pretreated material;
b) extracting the pretreated material with alcohol, concentrating the extract I to obtain a concentrated solution, adding water for decarboxylation, and concentrating the extract II to obtain a dry extract;
c) mixing the dry extract with an adsorbent I to form a solid dispersion system, and performing solid-phase extraction to obtain a primary cannabidiol solution;
d) and concentrating III, decoloring and crystallizing the primary cannabidiol solution to obtain the cannabidiol.
2. The method according to claim 1, wherein in step a), the pre-processing comprises: a raw material containing industrial hemp is pulverized to 250 to 1700 μm.
3. The method according to claim 1, wherein in step b), the alcohol extraction is an ethanol aqueous solution for extraction; the concentration of the ethanol water solution is 60-80 wt%;
preferably, the concentration of the ethanol water solution is 65-75 wt%;
preferably, the extraction conditions are: the mass volume ratio of the pretreatment material to the ethanol aqueous solution is 1 Kg: 5-30L, the extraction time is 1-3 h, and the extraction is carried out for 1-3 times;
preferably, the mass volume ratio of the pretreatment material to the ethanol aqueous solution is 1 Kg: 7-15L.
4. The method according to claim 1, wherein in step b), the conditions for concentrating I are:
the temperature is 50-65 ℃, the pressure is-0.065-0.10 MPa, and the extracting solution is concentrated to the relative density of 1.05-1.15;
preferably, in step b), the decarboxylation by adding water is carried out under the following conditions:
the water and pretreated materials were: 1: 10-100;
the temperature is 75-110 ℃, and the time is 1-3 h;
preferably, in step b), the conditions for the concentration II are: the temperature is 60-100 ℃, the pressure is-0.065-0.10 MPa, and dry extract is obtained by concentration.
5. The method according to claim 1, wherein in step c), the adsorbent I is selected from at least one of diatomaceous earth, calcium phosphate, calcium carbonate and silica gel;
preferably, in step c), the mass ratio of the dry extract to the adsorbent I is: 1: 0.25 to 5;
preferably, the mass ratio of the dry extract to the adsorbent I is 1: 0.5 to 2.
6. The method according to claim 1, wherein in step c), the solid phase extraction comprises: transferring the solid dispersion system into a solid phase extraction column, firstly washing the column with a non-polar solvent, and then eluting with a polar solvent;
preferably, the nonpolar solvent is selected from at least one of nonpolar alkanes, halogenated alkanes, esters, medium-chain fatty alcohols;
preferably, the nonpolar alkane is selected from at least one of petroleum ether, diethyl ether, n-hexane and n-heptane;
the alkyl halide is at least one of dichloromethane and chloroform;
the ester is selected from at least one of ethyl acetate and butyl acetate;
the medium-chain fatty alcohol is selected from at least one of n-octanol, sec-octanol and heptanol;
preferably, the polar solvent is selected from at least one of short-chain alcohols, ketones;
preferably, the polar solvent is selected from at least one of methanol, ethanol, isopropanol, acetone, and butanone.
7. The process according to claim 1, wherein in step d) the conditions for concentration of III are:
the temperature is 50-65 ℃, the pressure is-0.065-0.10 MPa, and the concentration of the concentrated cannabidiol is 100-300 g/L.
8. The method according to claim 1, wherein in step d), the decolorization is: and adding water into the concentrated substance III until the volume fraction of the organic phase is 40-70% to obtain a diluent, and adding an adsorbent II for decolorization.
9. The method of claim 8, wherein the adsorbent II is selected from at least one of diatomaceous earth, activated carbon, calcium phosphate, calcium carbonate, macroporous resin, MCI resin powder;
preferably, the macroporous resin is selected from at least one of AB-8, D-101, HPD700, XAD2, XDA-8, LSA-7, D-941, DM-130, ADS600, ADS-17, SP-825, HPD-600;
preferably, the volume-to-mass ratio of the diluent to the adsorbent II is: 1L: 0.6-5 kg;
preferably, the volume-to-mass ratio of the diluent to the adsorbent II is: 1L: 0.8-2.0 kg.
10. The process according to claim 1, characterized in that in step d), said crystallization comprises at least: adding water while stirring at the temperature of-10-20 ℃ until the volume fraction of the organic phase is 15-25% until the crystal nucleus amount is not increased any more, stopping stirring, and incubating and crystallizing at constant temperature for 2-12 h;
the rate of addition of water is such as to reduce the volume fraction of the organic phase by 0.5% to 2.5% per minute.
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| CN110655453A (en) * | 2019-11-26 | 2020-01-07 | 云南绿新生物药业有限公司 | Extraction and separation method of hypocannabidiol |
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