CN114057551B - Method for preparing cannabidiol - Google Patents

Method for preparing cannabidiol Download PDF

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CN114057551B
CN114057551B CN202010778740.3A CN202010778740A CN114057551B CN 114057551 B CN114057551 B CN 114057551B CN 202010778740 A CN202010778740 A CN 202010778740A CN 114057551 B CN114057551 B CN 114057551B
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solution
cannabidiol
adsorbent
concentrating
extraction
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CN114057551A (en
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柳旭
高伟博
李惠龙
赵丽梅
常坦然
李如彦
李庆中
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Yunnan Hanmeng Pharmaceutical Co ltd
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Yunnan Hanmeng Pharmaceutical Co ltd
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    • 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 cannabidiol, which at least comprises the following steps: a) Pretreating raw materials containing industrial hemp to obtain pretreated materials; b) Extracting the pretreated material with alcohol, concentrating the extract to obtain a concentrated solution, adding water for decarboxylation, and concentrating II to obtain a dry extract; c) Mixing the dry extract with the adsorbent I to form a solid dispersion system, and performing solid phase extraction to obtain a primary cannabidiol solution; d) Concentrating III, decolorizing and crystallizing the cannabidiol primary product solution to obtain the cannabidiol. The preparation method has the advantages of simple process, high product transfer rate, time and labor saving, large treatment capacity and high product purity, and is suitable for industrial scale-up production.

Description

Method for preparing cannabidiol
Technical Field
The application relates to a method for preparing cannabidiol, belonging to the field of chemical industry.
Background
Industrial Cannabis (academic name: cannabis sativa L.) is a plant of Cannabiaceae and Cannabis, and Tetrahydrocannabinol (THC) content in flowers and leaves in growth period is less than three thousandths, so that large-scale planting and industrialized development and utilization can be legally performed. With the continued development of Cannabidiol (CBD), the medicinal value of other related cannabinoids, particularly sub-Cannabidiol (CBDV), is also increasingly being recognized. For example, patent US20190160023A1 proposes that high purity CBDV is useful 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.
Currently, "Yun Ma No. 7" planted in Yunnan on a large scale has relatively high CBDV content, and the CBDV content is about 0.2% after complete decarboxylation conversion; in the commercial extract, the content of CBD is about 40-70%, while the content of CBDV is close to 13-30%, and the content of CBDV in the European and American hemp raw material is very low, so that the commercial extract has a considerable market price. However, at present, no high-purity CBDV technology suitable for industrial production exists.
Patent CN110655453a discloses a method for extracting and separating cannabidiol, which adopts ethanol aqueous solution for extraction, then uses organic solvent for extraction and enrichment of cannabidiol, and uses polyamide resin column, neutral alumina and bonded silica gel column for purification and enrichment after active carbon decolorization, and then obtains high-purity cannabidiol by crystallization, however, the process link is complex and the cost is higher. Patent CN110143854a discloses a method for simultaneously extracting CBD and CBDV, which combines subsequent gradient solution crystallization through the treatment process of pretreatment in an oxygen-enriched environment, and gradient crystallization is performed by ethanol-water solution with the volume ratio of 0:1-1:0, wherein the CBDV is crystallized first, and then the CBD is crystallized. However, the pretreatment in the method is not easy to realize industrialization, and has hidden troubles of yield and pigment.
In view of the above, we have developed a preparation method which is simple in process, low in cost and stable in product quality.
Disclosure of Invention
The present invention provides a method for preparing Cannabidiol (CBDV). The method adopts specific lower ethanol concentration for extraction, and the lipid and pigment impurities in the extracting solution are the least, so that a large amount of post-treatment work is reduced; in the aspect of decarboxylation conversion, the step and concentration are carried out simultaneously, so that complete conversion from CBDVA to CBDV can be achieved, batch difference of baking of flowers and leaves is reduced, and dependence on equipment and sites is reduced; in the aspect of separation and purification, the special adsorbent and the solid phase extraction technology are adopted, so that column chromatography can be completely avoided, time and labor are saved, special crystallization conditions are finally controlled, one-step crystallization is carried out, and the finished product with the purity of more than 99% is obtained, the process is simple, time and labor are saved, and the method is suitable for industrial scale-up production.
According to one aspect of the present application, there is provided a process for preparing cannabidiol, comprising at least the steps of:
a) Pretreating raw materials containing industrial hemp to obtain pretreated materials;
b) Extracting the pretreated material with alcohol, concentrating the extract to obtain a concentrated solution, adding water for decarboxylation, and concentrating II to obtain a dry extract;
c) Mixing the dry extract with the adsorbent I to form a solid dispersion system, and performing solid phase extraction to obtain a primary cannabidiol solution;
d) Concentrating III, decolorizing and crystallizing the primary cannabidiol solution to obtain the cannabidiol.
Optionally, in step a), the preprocessing includes: pulverizing the raw materials containing industrial hemp to 250-1700 μm.
Optionally, the raw material containing industrial hemp is one or a combination of more than two of industrial hemp flowers, leaves, roots, stalk cores or seed shells.
In the application, the feeding amount of the industrial hemp raw material is industrial grade amount, and in the embodiment, a case of 100kg is specifically given, and in practical application, the scale can be correspondingly enlarged by 2-10 times according to the production requirement.
Optionally, in step b), the alcohol extraction is performed as an aqueous ethanol solution; the concentration of the ethanol water solution is 60-80 wt%.
Preferably, the concentration of the ethanol aqueous solution is 65-75wt%.
Optionally, the upper limit of the concentration of the aqueous ethanol solution is selected from 65wt%, 70wt%, 75wt% or 80wt%; the lower limit is selected from 60wt%, 65wt%, 70wt% or 75wt%.
Optionally, the conditions of the extraction are: the mass volume ratio (M/V) of the pretreatment material to the ethanol water solution is 1Kg: 5-30L, the extraction time is 1-3 h, and the extraction is 1-3 times.
Preferably, the mass volume ratio of the pretreatment material to the ethanol water solution is 1Kg: 7-15L.
Optionally, the upper limit of the mass-to-volume ratio of the pretreatment material and the ethanol aqueous solution is selected from 1: 7. 1: 10. 1: 7. 1: 7. 1: 15. 1: 20. 1:25 or 1:30; 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 conventional alkane or ether solvents, even alcohol, the specific ethanol water solution has the concentration of 60-75wt% and has the least lipid and pigment impurities, thereby reducing a large amount of post-treatment.
Optionally, in step b), the conditions of concentration I are:
the temperature is 50-65 ℃, the pressure is-0.065 to-0.10 MPa, and the extract is concentrated to a relative density of 1.05-1.15.
Optionally, in step b), the conditions for decarboxylation by adding water are:
the mass ratio of water to pretreated materials 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 pretreatment material is selected from 1: 20. 1: 30. 1: 40. 1: 50. 1: 60. 1: 70. 1: 80. 1:90 or 1:100; 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 of concentration II are:
concentrating at 60-100deg.C under-0.065 to-0.10 MPa to obtain dry extract.
The decarboxylation and concentration are carried out simultaneously, so that complete conversion from CBDVA to CBDV can be achieved, and batch difference of baking of flowers and leaves and dependence on equipment and sites are 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, a step of; 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 system into a solid phase extraction column, flushing the column with a nonpolar solvent, and eluting with a polar solvent.
Optionally, the nonpolar solvent is selected from at least one of nonpolar alkane, halogenated alkane, ester and medium chain fatty alcohol.
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 at least one selected from n-octanol, sec-octanol and heptanol.
And (3) flushing the column by adopting a nonpolar solvent until the effluent liquid is nearly colorless, pressing the effluent liquid to be dry by nitrogen, and eluting by changing the polar solvent.
Optionally, the polar solvent is selected from at least one of short-chain alcohols and ketones.
Preferably, the short-chain alcohol is at least one selected from methanol, ethanol and isopropanol.
Preferably, the ketone is selected from at least one of acetone and butanone.
Preferably, the polar solvent is at least one selected from methanol, ethanol, isopropanol, acetone and butanone.
Optionally, in step d), the conditions for concentrating III are:
the temperature is 50-65 ℃, the pressure is minus 0.065-minus 0.10MPa, and the concentration of the secondary cannabidiol is 100-300 g/L.
Optionally, in step d), the decoloring is: adding water into the concentrated substance III until the volume fraction of the organic phase is 40-70%, obtaining a diluent, and adding an adsorbent II for decoloring.
Optionally, the adsorbent II is at least one selected from diatomite, activated carbon, calcium phosphate, calcium carbonate, macroporous resin and MCI resin powder.
Optionally, the macroporous resin is at least one selected from 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 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 and the adsorbent II is selected from 1L:0.8kg, 1L:1kg, 1L:2kg, 1L:3kg, 1L:4kg or 1L:5kg; the lower limit is selected from 1L:0.6kg, 1L:0.8kg, 1L:1kg, 1L:2kg, 1L:3kg or 1L:4kg.
Optionally, the method further comprises a step of filtering after the decoloring.
Optionally, the filtering is filter pressing or suction filtration, and the pore diameter of a filter screen adopted by the filtering is not less than 400 meshes.
The specific adsorbent and the solid phase extraction technology can completely avoid column chromatography, and save time and labor.
Optionally, in step d), the crystallization at least includes:
adding water to 15-25% of the volume fraction of the organic phase while stirring at the temperature of-10-20 ℃ until the crystal nucleus amount is no longer increased, stopping stirring, and incubating and crystallizing for 2-12 h at constant temperature;
the water adding rate is that the volume fraction of the organic phase is reduced by 0.25-2% per minute.
The water adding rate can influence the size and purity of the crystal form, and better crystal form can be obtained by controlling the water adding rate in the range, so that pigment packages are reduced, and the purity is improved.
The finished product with the purity of more than 99 percent is obtained through one-step crystallization, the process is simple, and the purity of the product is high.
Optionally, after crystallization, washing and drying to obtain the finished product of the Cannabidiol (CBDV).
Optionally, the washing is: -20-10 ℃ and 15-25% (V/V) of solvent leaching.
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.
Still further, an organic phase solvent in the crystallization step may be used.
Optionally, the drying includes one of vacuum drying, freeze drying, near infrared drying, air drying, or microwave drying.
Optionally, the drying temperature is 30 ℃ to 65 ℃.
In this application, "CBDV" refers to cannabidiol.
In this application, "CBD" refers to cannabidiol.
In this application, "CBDVA" refers to "cannabidiol".
As used herein, "room temperature" means "room temperature 25.+ -. 5 ℃ C.).
As used herein, "relative density" refers to "weight per liter of solution in kg/L" at 50 ℃.
As used herein, "alcohol" refers to "the volume fraction of an alcohol vehicle in water".
As used herein, "medium chain fatty alcohol" refers to a fatty alcohol having 6 to 12 carbon atoms.
As used herein, the term "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) means the ratio of the mass (kg) of a substance to the volume (L) of another substance, whereas the volume-to-mass ratio (V/M) is also understood as such.
In this application, unless otherwise indicated, the data ranges given are selected from any of the values in the ranges and include the endpoints of the ranges.
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 specific ethanol aqueous solution extraction, has high extraction rate of the CBDV, has fewer impurities, and can achieve complete conversion from CBDVA to CBDV by simultaneous decarboxylation and concentration; the batch difference of the baking of the flowers and leaves is reduced, and the dependence on equipment and places 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 conditions are controlled, and the crystallization efficiency and the product quality are improved; the whole preparation process condition is easy to control, the treatment capacity is large, the industrial production is easy to realize, and the preparation method has excellent industrial preparation prospect.
2) The separation and purification process of the high-purity CBDV provided by the application has higher transfer rate and the purity can reach more than 99 percent.
3) The adsorbent used in the method can be recycled after being dried (the activated carbon can be recycled after being coked for 1-5 hours at 300-500 ℃), and the theoretical time can reach more than 100 times, and basically no production waste is generated.
Drawings
FIG. 1 is a liquid chromatogram of an extraction stock solution of industrial hemp flowers and leaves of example 1;
FIG. 2 is a liquid chromatogram of the final product of cannabidiol prepared in example 1;
FIG. 3 is a liquid chromatogram of the final product of cannabidiol prepared in example 2;
FIG. 4 is a liquid chromatogram of the final product of cannabidiol prepared in example 3.
Detailed Description
The present application is described in detail below with reference to examples, but the present application is not limited to these examples.
Unless otherwise indicated, all starting materials in the examples of the present application were purchased commercially.
The industrial hemp raw material is mature industrial hemp leaves of 7-9 months, and is primarily dried by farmers, and the content of Tetrahydrocannabinol (THC) is below 0.3%.
The product analysis method in the examples of the present application is as follows:
the high performance liquid chromatography is utilized to analyze the extracting stock solution of industrial hemp raw materials and the finished product of the cannabidiol, the analysis instrument is Agilent liquid 1260, and the analysis conditions are as follows:
chromatographic conditions and system suitability test: octadecylsilane chemically bonded silica is used as a filler; acetonitrile is taken as a mobile phase A, water is taken as a mobile phase B, and isocratic elution is carried out according to the volume ratio of A (%):B (%) of=70:30; the detection wavelength was 210nm. The theoretical plate number is not lower than 2500 calculated as CBDV peak.
Preparation of a control solution: precisely weighing CBDV reference substance, adding methanol-water (1:1, V/V) to obtain reference substance solution containing 0.1mg per ml.
Preparation of CBDV test solution: taking about 25mg of CBDV finished product, precisely weighing, placing into a 250ml measuring flask, adding 20ml of acetonitrile-water (1:1, V/V), performing ultrasonic treatment for 10 minutes, adding acetonitrile-water (1:1, V/V) to dilute to a scale, shaking uniformly, filtering with a microporous filter membrane (0.45 pm), and taking a subsequent filtrate to obtain the finished product.
The industrial hemp leaf raw material sample solution is prepared by precisely weighing 500mg of the fine powder of the hemp leaf crushed to 75-150 micrometers, placing the fine powder into a 50ml conical flask, precisely adding 50ml of 75% methanol solution (vol%) into the conical flask, weighing the fine powder, performing ultrasonic treatment for 20 minutes at ultrasonic frequency of 40KHZ, standing for 30 minutes, weighing the fine powder, supplementing the loss weight with 75% methanol solution, shaking the fine powder, and taking the subsequent filtrate.
Assay: respectively precisely sucking 10 μl of the reference solution and the above sample solution, and injecting into liquid chromatograph for measurement.
The content of sub-cannabidiol in the industrial cannabis sativa leaf raw material used in the present application is calculated by the following method:
flower leaf raw material CBDV content= (sample CBDV peak area x 0.1 x 50)/(reference peak area x 500) x100%
FIG. 1 is a liquid chromatogram of a leaf extract stock solution, with a retention time of 4.754min for CBDV.
The CBDV content of the industrial cannabis sativa leaf material used in this application was found to be 0.18% by mass.
The transfer rate of the CBDV finished product is calculated as follows:
CBDV transfer rate = (CBDV finished product mass purity)/(flower and leaf raw material water-knot drier mass 0.0018) 100%
Example 1 CBDV was prepared according to the following method
1) Crushing industrial hemp leaves into 10-mesh coarse powder, wherein the measured value of moisture is 14.6wt%, so as to obtain a pretreated material;
2) Soaking the pretreated materials with 100Kg of 60wt% ethanol water solution (each time 5 times of volume (W/V, 1Kg corresponds to 5L)) for 1 hr at room temperature, extracting for 3 times, and mixing to obtain extractive solution;
3) Concentrating the above extractive solution at 50deg.C and-0.10 Mpa until no alcohol smell exists, and adding purified water with a pretreatment material content of 1/100 (w/w), heating to 110deg.C for 1 hr in oil bath, introducing 110deg.C steam, and decocting under normal pressure to remove residual water to obtain dry extract.
4) The dry extract was weighed, and 4 times (W/W) of diatomaceous earth and calcium phosphate (mass ratio 3: 1) Mixing, transferring to a short extraction column (d: L=1:2), flushing 2.5BV with n-heptane, drying the effluent almost colorless, replacing the air and bubbles in the column with methanol until the effluent is stable, flushing 1.5BV after soaking for 1h, and collecting methanol eluent to obtain CBDV primary product solution.
5) Concentrating the CBDV primary product solution at 65 ℃ and minus 0.85MPa to fluid extract, measuring the concentration of the cannabidiol by HPLC to about 200g/L, adding water while the solution is hot to adjust the volume fraction of the methanol to 70%, adding 0.6% active carbon (W/V, namely, 0.6kg of active carbon is added to 1L of solution), stirring for 30min at 65 ℃, and carrying out filter pressing by a titanium rod filter to obtain the clear CBDV primary product color-removing liquid.
6) And (3) 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 0.5% per minute until the solution starts to have obvious milky turbidity, starting to measure the alcohol content, and reducing the pump speed to 2-5 drops/second until crystals are not increased any more, stopping pumping the water by the methanol volume fraction of about 15%, and taking 6.8 hours. And (3) filter-pressing with 400-mesh filter cloth, finally, leaching the obtained crystal with 10ml of 20% methanol-water (Vol%) surface at-20 ℃, and drying to obtain the CBDV crystal semi-finished product.
7) And (3) placing the CBDV crystal semi-finished product in a vacuum drying condition (-0.10 MPa,16 h) at 50 ℃ until the moisture is measured to be below 2wt%, thus obtaining the CBDV finished product, sampling, and detecting the purity by HPLC. FIG. 2 is an HPLC chromatogram of a pure product, with a retention time of 4.978min for CBDV of 99.25% purity as determined by HPLC. The process flow takes 36.3 hours in total from the extraction of the flowers and leaves to the harvesting of the final product.
Example 2 CBDV was prepared according to the following method
1) Crushing industrial hemp leaves into 40 mesh powder, wherein the measured value of moisture is 13.5wt%, so as to obtain a pretreated material;
2) Soaking the pretreated material with 100kg of 75% ethanol (vol%) 7 times of the volume (W/V) at room temperature for 2 hr, extracting for 2 times, and mixing to obtain extractive solution;
3) Concentrating the above extractive solution at 60deg.C under-0.080 Mpa to relative density of 1.15 without alcohol smell, adding purified water with pretreatment amount of 1/10 (w/w), boiling at normal pressure (94 deg.C) for 2 hr, and steaming under reduced pressure at 65deg.C under-0.095 Mpa to obtain dry extract.
4) The dry extract was weighed, added with 0.25 times (W/W) of silica gel, mixed well to form a solid dispersion, and transferred to a dwarf extraction column (d: l=1:2) with n-heptane: ethyl acetate (95:5, V:V) is used for flushing 1.5BV, effluent liquid is almost colorless, nitrogen is used for drying, ethanol is used for replacing air holes and bubbles in the column until the effluent liquid is stable, after the effluent liquid is soaked for 1h, the column is flushed for 1.5BV, and ethanol eluent is collected to obtain a CBDV primary product solution.
5) Concentrating the CBDV primary product solution at 55 ℃ under-0.10 Mpa under reduced pressure to obtain fluid extract, measuring the concentration of the cannabidiol by HPLC to about 100g/L, adding water to adjust the volume fraction of ethanol to 40% while the solution is hot, adding 5% macroporous resin HP20 (W/V), stirring for 1h at room temperature, and filtering by a 300-mesh sieve to obtain clear CBDV primary product depigmenting liquid.
6) And (3) 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 starts to have obvious milky turbidity, starting to measure the alcohol content, and reducing the pump speed to 2-5 drops/second until crystals are not increased any more, stopping pumping the water by the ethanol volume fraction of about 22%, and taking 2.5 hours. And (3) filter-pressing with 400-mesh filter cloth, and finally, leaching the obtained crystal with 20ml of 20% ethanol-water (V/V) surface at the temperature of minus 20 ℃ and drying to obtain a CBDV crystal semi-finished product.
7) And (3) placing the CBDV crystal semi-finished product in a vacuum drying condition (-0.10 MPa,16 h) at 50 ℃ until the moisture is measured to be below 2wt%, thus obtaining the CBDV finished product, sampling, and detecting the purity by HPLC. FIG. 3 is an HPLC chromatogram of a pure product with a retention time of 4.724min for CBDV with a purity of 99.72% as determined by HPLC. The process flow takes 34.5 hours in total from the extraction of the flowers and leaves to the harvesting of the final product.
EXAMPLE 3 preparation of CBDV according to the following procedure
1) Crushing industrial hemp leaves into 60-mesh coarse powder, wherein the measured value of moisture is 16.6wt% to obtain a pretreated material;
2) Soaking the pretreated material with 100kg of 80wt% ethanol 30 times of the pretreated material for 1h at room temperature, extracting for 1 time, and filtering to obtain an extract;
3) Concentrating the above extractive solution at 65deg.C under-0.75 Mpa until no alcohol smell exists, and adding purified water with a relative density of 1.11/10 (w/w) of the pretreated material at 75deg.C for 3 hr, and removing the residual water at 75deg.C under-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 uniformly to form a solid dispersion, transferring to a dwarf extraction column (d: l=1:2), and mixing with petroleum ether: and (3) flushing the dichloromethane (85:15 volume ratio) for 3BV, wherein the effluent is almost colorless, pressing the nitrogen to dry, replacing the air holes and the air bubbles in the column with acetone until the effluent is stable, flushing the column for 2BV after soaking for 1h, and collecting the acetone eluent to obtain a CBDV primary product solution.
5) Concentrating the CBDV primary product solution to fluid extract at 50 ℃ below zero and 0.10MPa, measuring the concentration of the cannabidiol to about 300g/L by HPLC, adding water to adjust the volume fraction of acetone to 60% while the solution is hot, adding 2% MCI resin powder (W/V) at 40 ℃ and stirring for 1h, and filtering by a 400-mesh sieve to obtain clear CBDV primary product depigmentation liquid.
6) And (3) 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% per minute until the solution starts to have obvious milky turbidity, 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 for 3.4 hours. Press-filtering with 400 mesh filter cloth, and finally, eluting with 10ml of 25% acetone-water (V/V) surface at-20deg.C, and press-drying to obtain semi-finished product of CBDV crystal.
7) And (3) placing the CBDV crystal semi-finished product in a vacuum drying condition (-0.10 MPa,16 h) at 50 ℃ until the moisture is measured to be below 2wt%, thus obtaining the CBDV finished product, sampling, and detecting the purity by HPLC. FIG. 4 is an HPLC chromatogram of a pure product, with a retention time of 4.858min for CBDV with a purity of 99.65% as determined by HPLC. The process flow takes 36.4 hours in total from the extraction of the flowers and leaves to the harvesting of the final product.
Comparative example 1 CBDV was prepared according to the following method
1) Crushing industrial hemp leaf raw material (10 kg) into coarse powder of 40-60 meshes, baking at 105 ℃ for 2 hours, wherein the water content is 5.8wt% to obtain a pretreated material;
2) Stirring and leaching the pretreated material with 15 times of butane for 2 hours, extracting for 2 times, and combining to obtain an extracting solution;
3) Concentrating the extractive solution at 40deg.C under reduced pressure to obtain dry extract, dissolving with 70wt% ethanol, and discarding insoluble substances;
4) The transfer solution is passed through D101 macroporous resin, and is washed by purified water for 2BV, ethanol with 55wt% is washed for 4BV, and the collection is stopped from the liquid phase inspection to the beginning of the CBDV until the concentration of the CBDV is detected to be lower than 0.5g/L, and the rest is used as a waste liquid recovery solvent;
5) Concentrating the collected liquid until the alcohol content is 55wt%, feeding the concentrated liquid to a medium-pressure chromatographic column DAC50, wherein the filler is C18, removing impurities by using 55wt% alcohol for 2.5BV, and eluting by using 70wt% alcohol to obtain CBDV eluent;
7) Concentrating the CBDV eluent under reduced pressure at 60 ℃ and minus 0.10MPa until a large amount of crystals are precipitated in the concentrated solution, stopping, and placing the concentrated solution in a cold storage at 4-10 ℃ for crystallization for 12 hours;
8) Discharging and recovering the crystallization mother liquor, crushing the crystals, filtering the crystals to dryness, leaching the crystals 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 measured to be below 2wt%, and obtaining a finished product, wherein the purity of CBDV is 99.35 percent by HPLC. The process flow takes 49.5 hours in total from the extraction of the flowers and leaves to the harvesting of the final product.
The above examples are summarized in table 1 below.
TABLE 1
In summary, it can be seen that by adopting the preparation method of the cannabidiol provided by the application, the product transfer rate is kept above 50%, the time and the labor are saved, the purity of the cannabidiol can reach above 99%, the single treatment capacity is large, and the industrialized preparation can be realized.
The foregoing description is only a few examples of the present application and is not intended to limit the present application in any way, and although the present application is disclosed in the preferred examples, it is not intended to limit the present application, and any person skilled in the art may make some changes or modifications to the disclosed technology without departing from the scope of the technical solution of the present application, and the technical solution is equivalent to the equivalent embodiments.

Claims (20)

1. A process for the preparation of cannabidiol comprising at least the steps of:
a) Pretreating raw materials containing industrial hemp to obtain pretreated materials;
b) Extracting the pretreated material with alcohol, concentrating the extract to obtain a concentrated solution, adding water for decarboxylation, and concentrating II to obtain a dry extract;
c) Mixing the dry extract with the adsorbent I to form a solid dispersion system, and performing solid phase extraction to obtain a primary cannabidiol solution;
d) Concentrating III, decoloring and crystallizing the primary cannabidiol solution to obtain the secondary cannabidiol;
in the step b), the alcohol extraction is ethanol water solution for extraction; the concentration of the ethanol water solution is 60-80 wt%;
in step b), the conditions for decarboxylation by adding water are:
the mass of the water and the pretreated material is as follows: 1:10-100;
the temperature is 75-110 ℃ and the time is 1-3 h;
in the step c), the adsorbent I is at least one selected from diatomite, calcium phosphate, calcium carbonate and silica gel;
in step c), the solid phase extraction comprises: transferring the solid dispersion system into a solid phase extraction column, flushing the column with a nonpolar solvent, and eluting with a polar solvent.
2. The method according to claim 1, wherein in step a), the pre-treatment comprises: pulverizing the raw materials containing industrial hemp to 250-1700 μm.
3. The method according to claim 1, wherein the concentration of the aqueous ethanol solution is 65-75 wt%.
4. The method according to claim 1, wherein the conditions of the extraction are: the mass volume ratio of the pretreatment material to the ethanol water solution is 1Kg: 5-30L, the extraction time is 1-3 h, and the extraction is 1-3 times.
5. The method according to claim 4, wherein the mass-to-volume ratio of the pretreatment material to the aqueous ethanol solution is 1Kg: 7-15L.
6. 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 to-0.10 MPa, and the extract is concentrated to a relative density of 1.05-1.15.
7. The method according to claim 1, wherein in step b), the conditions of concentration II are: the temperature is 60-100 ℃, the pressure is minus 0.065-minus 0.10MPa, and the dry extract is obtained by concentration.
8. The method according to claim 1, wherein in step c), the mass ratio of the dry extract to the adsorbent I is: 1:0.25 to 5.
9. The method according to claim 8, wherein the mass ratio of the dry extract to the adsorbent I is 1:0.5 to 2.
10. The method of claim 1, wherein the non-polar solvent is selected from at least one of a non-polar alkane, an alkane halide, an ester, and a medium chain fatty alcohol.
11. The method according to claim 10, wherein the non-polar alkane is selected from at least one of petroleum ether, diethyl ether, n-hexane, n-heptane;
the halogenated alkane is at least one selected from dichloromethane and chloroform;
the ester is at least one of ethyl acetate and butyl acetate;
the medium-chain fatty alcohol is at least one selected from n-octanol, sec-octanol and heptanol.
12. The method of claim 1, wherein the polar solvent is selected from at least one of short chain alcohols, ketones.
13. The method according to claim 12, wherein the polar solvent is selected from at least one of methanol, ethanol, isopropanol, acetone, butanone.
14. The method according to claim 1, wherein in step d), the conditions for concentrating III are:
the temperature is 50-65 ℃, the pressure is minus 0.065-minus 0.10MPa, and the concentration of the secondary cannabidiol is 100-300 g/L.
15. The method according to claim 1, wherein in step d), the decolorization is: adding water into the concentrated substance III until the volume fraction of the organic phase is 40-70%, obtaining a diluent, and adding an adsorbent II for decoloring.
16. The method of claim 15, wherein the adsorbent II is selected from at least one of diatomaceous earth, activated carbon, calcium phosphate, calcium carbonate, macroporous resin, MCI resin powder.
17. The method of claim 16, wherein 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.
18. The method according to claim 15, wherein the volume to mass ratio of the diluent to the adsorbent II is: 1L: 0.6-5 kg.
19. The method according to claim 18, wherein the volume to mass ratio of the diluent to the adsorbent II is: 1L: 0.8-2.0 kg.
20. The method according to claim 1, wherein in step d), the crystallization comprises at least: adding water to 15-25% of the volume fraction of the organic phase while stirring at the temperature of-10-20 ℃ until the crystal nucleus amount is no longer increased, stopping stirring, and incubating and crystallizing for 2-12 h at constant temperature;
the rate of adding water is that the volume fraction of the organic phase is reduced by 0.5-2.5% per minute.
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US8445034B1 (en) * 2010-11-02 2013-05-21 Albert L Coles, Jr. Systems and methods for producing organic cannabis tincture
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
CN111978158A (en) * 2020-08-21 2020-11-24 滇麻生物科技(曲靖)有限公司 Method for extracting purified hypocannabidiol from industrial cannabis sativa

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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
CN111978158A (en) * 2020-08-21 2020-11-24 滇麻生物科技(曲靖)有限公司 Method for extracting purified hypocannabidiol from industrial cannabis sativa

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