CN115010690B - Preparation method of high-purity cannabinol crystal - Google Patents
Preparation method of high-purity cannabinol crystal Download PDFInfo
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Abstract
The invention discloses a preparation method of high-purity cannabinol crystals, which adopts acetone as an extractant for extracting a cannabinol crude extract from cannabis sativa flower and leaf powder, removes organic compounds containing carboxylic acid and esters in the cannabinol crude extract in advance by adopting the processes of decarboxylation, saponification and the like, then adopts n-hexane for extraction to obtain a cannabinol refined extract, purifies the obtained cannabinol refined extract by sequentially passing through a low-pressure macroporous resin column and a low-pressure fine resin column, and finally adopts activated carbon and petroleum ether solvent for decoloring the cannabinol refined oil, so that the impurities in the cannabinol refined oil are further reduced, and as a large amount of impurities are removed in the early stage, the subsequent crystallization process times are reduced, and the cannabinol with the purity of about 99% can be obtained.
Description
Technical Field
The invention belongs to the technical field of phytochemical component extraction, and particularly relates to a preparation method of a high-purity cannabinol crystal.
Background
Cannabis sativa (Cannabis sativa L.), a genus of Cannabis of the family Cannabiaceae (Cannabis Linn.), also known as hemp, sisal, jute, and annual herbaceous plants, has important agricultural and medicinal values. The active substances in the cannabis are mainly cannabinoids, more than 60 cannabinoids are separated from the cannabis plant at present, and Tetrahydrocannabinol (THC) contained in the cannabis plant can cause hallucinogenic addiction, so that the cannabis is classified as 'narcotics' or 'drugs' by the convention of the United nations and the laws of many countries.
Because of the extremely high economic and medicinal values of the hemp, the hemp with the THC content less than three thousandths of the hemp flowers and leaves in the growth period is called as the industrial hemp for short, is used for industrial application, does not have the value of extracting toxic components THC or is directly taken as drugs, and can be legally planted in a large scale and industrially developed and utilized.
Cannabinol (CBN) is a non-addictive ingredient, CBN has the effects of relieving cough, relieving spasm, relieving pain, tranquilizing, improving sleep and the like, in a large amount of researches, tetrahydrocannabinol (THC) generates hallucinogenic addiction mainly through the coupling effect with cannabis receptor CB1, generates some negative effects of over-stimulating nerves, but has weaker association effect with cannabis receptor CB 2. Cannabinol (CBN) can selectively react with cannabinoid receptor CB2, and further has pharmacological actions of relieving pain, resisting inflammation, and inhibiting cancer cell spreading.
At present, the research on Cannabinol (CBN) has the difficulties that Cannabidiol (CBD) and Tetrahydrocannabinol (THC) are easy to enrich in the process of extracting and separating Cannabinol (CBN), the components are difficult to completely remove, or the pretreatment work of separating and purifying Cannabinol (CBN) by adopting traditional column chromatography is complex, the obtained crude product is unstable, so that the process is extremely complex, the production cost is high, the extraction rate is low, and the resource waste is easy to cause.
Removing components with hallucinogenic and addictive effects such as THC and the like as much as possible to obtain a high-purity product, which is a precondition for the development and application of Cannabinol (CBN); much work has been done on the related patents that have been filed for publications such as: chinese patent application publication No. CN11763189A discloses a method for separating and purifying cannabinol from industrial cannabis, which mainly adopts alcohol or supercritical extraction, water precipitation or molecular distillation, macroporous resin separation, and crystallization at-20 ℃ to obtain 95% Cannabinol (CBN), but the above method has certain disadvantages, for example, the used alcohol extraction can simultaneously extract a large amount of impurities, thus bringing a large amount of pressure to the back-end treatment, the use of supercritical extraction not only has a small treatment amount, but also has high equipment cost, and is not suitable for commercial mass production, the use of water precipitation has a poor effect when removing impurities, the molecular distillation equipment has high cost and a small treatment amount, and simultaneously, 95% cannabinol has problems when used for medicine; chinese patent application publication No. CN106860492A discloses a method for preparing cannabinol compounds, which adopts processes of adding weak acid into an organic solvent, ultrasonic extraction, dissolving and filtering the organic solvent, filtering an alkali solution, filtering an acid solution and the like, wherein Cannabinol (CBN) crystals with high purity are not obtained in the process, and the obtained substances cannot be directly used for medicine; chinese patent application publication No. CN109568389A discloses a preparation method of a high-purity cannabinol extract, which adopts the processes of solvent extraction, pH adjustment, column chromatography and the like, wherein Cannabinol (CBN) crystals are not obtained in the processes, the back-end treatment is relatively incomplete, and the obtained substances cannot be directly used for medicine; chinese patent application publication No. CN 111039914A discloses a cannabinol extraction and separation method, which mainly comprises the steps of extracting with an ethanol aqueous solution, enriching cannabinol by using an organic solvent, decoloring with activated carbon, purifying and enriching with a polyamide resin column, neutral alumina and a bonded silica gel column, and separating with a polyamide filler-containing chromatographic column to obtain a target section, and concentrating and crystallizing to obtain high-purity cannabinol, wherein the obtained cannabinol has higher purity than other methods, but the adopted process is more complex, and ethanol aqueous solution is adopted for crude extraction, and according to experiments, ethanol can carry a large amount of impurities at normal temperature, so that the cannabinol crude extract content is lower, the back-end treatment is difficult, and ethanol low-temperature extraction can not carry a large amount of impurities, but the low-temperature extraction energy consumption is higher, and the yield is lower; therefore, based on the above problem analysis, the present application designs a method for preparing high-purity cannabinol crystals.
Disclosure of Invention
The invention aims to provide a preparation method of high-purity cannabinol crystals, which solves the problems of high energy consumption, low yield, low treatment capacity and the like in the conventional method for obtaining high-purity cannabinol crystals.
The invention provides a preparation method of high-purity cannabinol crystals, which comprises the following steps:
s1: selecting industrial hemp flowers and leaves as raw materials, and drying and crushing the industrial hemp flowers and leaves;
s2: extracting the pulverized hemp flower and leaf powder with acetone solvent with volume concentration of 95% or more at normal temperature for 2-3 times, each time for 1.5-3.5h, mixing extractive solutions, and heating and concentrating to obtain cannabinol crude extract;
s3: performing decarboxylation treatment on the cannabinol crude extract obtained in the step S2 at the temperature of 110-120 ℃, wherein the decarboxylation treatment time is 1-1.5h;
s4: carrying out saponification treatment and extraction treatment on the cannabinol crude extract subjected to decarboxylation treatment in the step S3 in sequence, and concretely carrying out saponification treatment and extraction treatment on the cannabinol crude extract;
firstly, carrying out saponification reaction on the decarboxylated cannabinol crude extract by adopting a sodium hydroxide solution with the mass concentration of 0.5-1%, wherein the saponification reaction time is 2.5-3.5h, and after the saponification reaction is finished, adding a hydrochloric acid solution into a reaction solvent until the pH value of the reaction solvent is 6-8;
cooling to room temperature, adding n-hexane solution into the reaction solvent, stirring and standing to realize extraction for 2-3 times, wherein the extraction time is 40-50min each time, recovering the upper n-hexane solution of each extraction, combining the recovered upper n-hexane solutions, and concentrating to obtain cannabinol refined product;
s5: performing primary purification treatment on the refined cannabinol product obtained in the step S4 by using a low-pressure macroporous resin column, wherein the low-pressure macroporous resin column is an acetone water balance column with the volume concentration of 50-60%, eluting the foreigner in the refined cannabinol product by using acetone water with the volume concentration of 55-65% after sampling, eluting by using acetone water with the volume concentration of 60-70% and collecting the primary cannabinol pure eluent of the section, and finally eluting by using pure acetone to remove the rear-section impurities in the refined cannabinol product and regenerate the macroporous resin column; concentrating the collected cannabinol primary pure eluent at low pressure to obtain cannabinol oil;
s6: performing secondary purification treatment on the cannabinol oil obtained in the step S5 by adopting a low-pressure fine resin column, wherein the low-pressure fine resin column is an acetone water balance column with the volume concentration of 55-65%, eluting the foreigners in the cannabinol oil by using 60-70% acetone water after sample loading, eluting by using 60-70% acetone water, collecting the eluate of the cannabinol secondary pure oil, and finally eluting by using pure acetone to remove the rear-stage impurities in the cannabinol oil and regenerate the fine resin column; concentrating the collected cannabinol sub-pure oil eluent at low pressure to obtain cannabinol refined oil;
s7: adding a certain amount of activated carbon and petroleum ether solvent into the cannabinol refined grease obtained in the step S6, heating, stirring, standing, and finally filtering to remove a decolorant to obtain a decolored cannabinol refined solvent;
s8: and (4) carrying out low-temperature crystallization on the cannabinol refined solvent obtained in the step (S7) to obtain cannabinol crystals, wherein the crystallization time is 7-9h.
As a preferred scheme of the application, in step S2, acetone solvent with the mass 4-5 times that of the hemp flower and leaf powder is respectively added in each extraction.
As a preferable scheme of the application, in the step S4, in the saponification reaction process, the amount of the sodium hydroxide aqueous solution is 9.5-10.5 times of the weight of the crude extract, the saponification reaction temperature is 65-90 ℃, and the concentration of the hydrochloric acid solvent is more than or equal to 30%; in the extraction process, n-hexane solvent with the mass 10-13 times of that of the cannabinol crude extract is added in multiple extractions, or n-hexane solvent with the same volume as the sodium hydroxide solution is added in multiple extractions.
As a preferable embodiment of the present application, in the extraction process of step S4, specific conditions for concentrating the mixed upper n-hexane solution are as follows: heating the mixed upper n-hexane solution to 60-70 deg.C, and vacuumizing to 0.04-0.06Mpa.
In the preferable scheme of the application, in the step S5, acetone water with the volume concentration of 55-65% is used for eluting five to seven column volumes when the impurities in the refined cannabinol product are removed, acetone water with the volume concentration of 60-70% is used for eluting four to six column volumes when the cannabinol primary pure eluent is obtained, acetone water with the volume concentration of more than or equal to 95% is used for eluting four to five column volumes when the macroporous resin column is regenerated, the flow rate of each column volume is controlled to be 20-30min, and the column pressure is less than 0.2MPa.
As a preferred embodiment of the present application, the specific step of concentrating the cannabinol primary pure eluate at low pressure in step S5 comprises:
introducing the cannabinol primary pure eluate into a concentrator, heating the concentrator to 50-60 deg.C, adjusting vacuum degree to 0.04-0.06Mpa, and recovering acetone;
heating the concentrator to 85-95 deg.C, adjusting vacuum degree to 0.06-0.08Mpa, and removing water.
As a preferable scheme of the present application, in step S6, five to seven column volumes are eluted with acetone water having a volume concentration of 55 to 65% when the pre-impurity of the cannabinol oil is removed, four to six column volumes are eluted with acetone water having a volume concentration of 60 to 70% when the cannabinol sub-pure oil eluate is obtained, four to five column volumes are eluted with acetone water having a volume concentration of 95% or more when the fine resin column is regenerated, the flow rate of each column volume is controlled to be 20 to 30min, and the column pressure is 0.2 to 0.4Mpa.
As a preferable embodiment of the present application, the specific step of concentrating the cannabinol impure oleoresin eluate at low pressure in step S6 comprises:
introducing cannabinol sub-pure oil eluate into a concentrator, heating the concentrator to 50-60 deg.C, regulating vacuum degree to 0.04-0.06Mpa, and recovering acetone;
heating the concentrator to 85-95 deg.C, adjusting vacuum degree to 0.06-0.08Mpa, and removing water.
In a preferable scheme of the application, in the step S7, the using amount of the activated carbon is 10% of that of the cannabinol refined oil, the mass ratio of the volume of the low-boiling point petroleum ether solvent to the cannabinol refined oil lipid is 1.
As a preferred embodiment of the present application, in step S8, the crystallization temperature is in the range of-10 to-20 ℃.
Compared with the prior art, the preparation method of the high-purity cannabinol crystal has the advantages that: because the polarity of the ethanol is larger than that of the acetone, a large amount of impurities can be brought out during extraction, and the difficulty of subsequent treatment is increased, the acetone is used as an extracting agent for extracting the cannabinol crude extract from the cannabis flower and leaf powder, and the organic compounds containing carboxylic acid and esters in the cannabinol crude extract are removed in advance by adopting the processes of decarboxylation, saponification reaction and the like, so that a good impurity removal effect is realized, then the cannabinol refined product is extracted by adopting n-hexane, the main principle of extraction is to extract a target product into the n-hexane as much as possible, so that the target product is separated from water-soluble substances, and the purity of the cannabinol crude extract is greatly improved; the obtained cannabinol refined substance is purified by a low-pressure macroporous resin column after acetone water balance and a low-pressure fine resin column after acetone water balance, and the resin has the advantages of simple operation, low cost, low professional requirements on operators, high sample loading, long service life and the like compared with the existing supercritical and molecular distillation, so that the method is convenient to operate by adopting the macroporous resin column and the low-pressure fine resin column, can reduce the loss of samples, adopts organic solvent acetone with different volume concentrations as an elution solution to obtain the cannabinol refined grease with the purity of about 90 percent, and finally adopts active carbon and petroleum ether solvent to decolor the cannabinol refined grease, so that the impurities in the cannabinol refined grease are further reduced, and because a large amount of impurities are removed in the early stage, the subsequent crystallization process times are reduced, the cannabinol with the purity of about 99 percent can be obtained, namely compared with the existing process, the method has the advantages of simple process flow, small target material flow loss, thorough impurity removal and improvement on the yield and purity of the cannabinol.
Drawings
Fig. 1 is a state diagram showing the components contained in the crude cannabinol extract obtained after decarboxylation and the corresponding concentrations of the components on a chromatographic column after the retention time of the crude cannabinol extract is 8.979 min.
Fig. 2 is a state diagram showing the components and the corresponding concentrations of the components contained in the refined cannabinol product obtained after the extraction according to the second embodiment of the present invention on a chromatographic column after the retention time of the refined cannabinol product is 9.136 min.
Fig. 3 is a state diagram showing the substance components and the corresponding concentrations of the components on a chromatographic column after the retention time of the cannabinol oil and fat obtained after the primary purification is 9.018min according to the second embodiment of the invention.
FIG. 4 is a state diagram showing the substance components and the corresponding concentrations of the components on a column, after the retention time of cannabinol oil obtained after sub-purification according to example two of the present invention is 9.658 min.
Fig. 5 is a state diagram showing the substance components contained in the cannabinol crystal after the retention time of the cannabinol crystal is 9.449min and the corresponding concentrations of the components on a chromatographic column according to the second embodiment of the invention.
Fig. 6 is a state diagram of the cannabinol standard substance provided by the second embodiment of the invention on the chromatographic column after the retention time is 9.489 min.
Detailed Description
The present invention is described in further detail below with reference to specific embodiments and with reference to the attached drawings, it should be emphasized that the following description is merely exemplary and is not intended to limit the scope and application of the present invention.
Example 1: the embodiment provides a preparation method of high-purity cannabinol crystals, which comprises the following steps:
s1: selecting industrial hemp flowers and leaves as raw materials, and drying and crushing the industrial hemp flowers and leaves, in the embodiment, drying the industrial hemp flowers and leaves to enable the water content of the industrial hemp flowers and leaves to be lower than 12%, crushing the dried industrial hemp flowers and leaves, and sieving the crushed industrial hemp flowers and leaves with a 30-40-mesh sieve.
S2: extracting the crushed hemp flower and leaf powder for 2-3 times at normal temperature (25-30 ℃) by adopting an acetone solvent with the volume concentration of more than or equal to 95%, wherein the extraction time is 2h each time, mixing the extracting solution, heating and concentrating to obtain a crude cannabinol extract, in the embodiment, the acetone solvent with the mass 4-5 times that of the hemp flower and leaf powder is respectively added in multiple times of extraction, and the preferred mass ratio of the volume of the added acetone solvent to the hemp flower and leaf powder is 5:1.
s3: subjecting the crude cannabinol extract obtained in step S2 to decarboxylation at a temperature of 110-120 ℃ for a time period of 0.5-1.5h, preferably heating the crude cannabinol extract to 120 ℃ and stirring at that temperature for 1h.
S4: carrying out saponification treatment and extraction treatment on the decarboxylated cannabinol crude extract in the step S3 in sequence, specifically;
firstly, carrying out saponification reaction on a crude cannabinol extract subjected to decarboxylation treatment at the temperature of 65-90 ℃ by adopting a sodium hydroxide solution with the mass concentration of 0.5-1%, wherein the saponification reaction time is 2.5-3.5h, and after the saponification reaction is finished, adding a hydrochloric acid solution with the concentration of more than or equal to 30% into a reaction solvent until the pH of the reaction solvent is 6-8, wherein in the embodiment, the sodium hydroxide solution is 9.5-10.5 times of the weight of the crude extract;
when the temperature is reduced to room temperature (25-30 ℃), adding a normal hexane solution into the reaction solvent, stirring for 20min until the normal hexane and the aqueous solution are fully mixed, standing for 40-50min, and after the normal hexane and the aqueous solution are layered, recovering an upper-layer normal hexane solution, wherein the extraction times are 2-3 times, and the extraction time is 40-50min each time, combining the recovered upper-layer normal hexane solution and concentrating to obtain a cannabinol refined product, in the embodiment, the normal hexane solvent with the mass 10-13 times that of the cannabinol crude extract is added in multiple extractions, or the normal hexane solvent with the same volume as that of the sodium hydroxide solution is added in the multiple extractions; in this example, the specific conditions for concentrating the mixed upper n-hexane solution were as follows: heating the mixed upper n-hexane solution to 60-70 deg.C, and vacuumizing to 0.04-0.06Mpa.
S5: performing primary purification treatment on the cannabinol refined product obtained in the step S4 by using a low-pressure macroporous resin column, wherein the low-pressure macroporous resin column is an acetone water balance column with the volume concentration of 50-60%, in the embodiment, the preparation method of the acetone water balance column comprises the steps of filling the resin column, standing overnight, and eluting three column volumes by using 55% acetone water, namely, completing balance, in the embodiment, the macroporous resin does not need to be pretreated, and the type of the macroporous resin in the embodiment is preferably SP type;
eluting five to seven column volumes by using acetone water with volume concentration of 55 to 65 percent after sample loading to remove foreimpurities in the cannabinol refined product, eluting four to six column volumes by using acetone water with volume concentration of 60 to 70 percent and collecting the cannabinol eluate, and finally eluting by using pure acetone to remove rear-stage impurities in the cannabinol refined product and regenerate the macroporous resin column, wherein in the embodiment, the acetone water with volume concentration of more than or equal to 95 percent is used for eluting four to five column volumes when the macroporous resin column is regenerated, in the embodiment, the flow rate of each column volume is controlled to be 20 to 30min, and the preferable column pressure is less than 0.2MPa; concentrating the collected cannabinol eluate at low pressure to obtain cannabinol oil, in this example, the specific steps of concentrating the cannabinol eluate at low pressure include:
introducing cannabinol eluate into concentrator, heating to 50-60 deg.C, regulating vacuum degree to 0.04-0.06Mpa, and recovering acetone; heating the concentrator to 85-95 deg.C, adjusting vacuum degree to 0.06-0.08Mpa, and removing water.
S6: performing secondary purification treatment, also called secondary purification treatment, on the cannabinol oil obtained in the step S5 by using a low-pressure fine resin column, wherein the low-pressure fine resin column is an acetone water balance column with a volume concentration of 55-65%, in the embodiment, the manufacturing method of the acetone water balance column comprises the steps of filling the fine resin column, standing overnight, and eluting three column volumes by using 60% acetone water, namely, completing balance, wherein the fine resin does not need to be pretreated, and the type of the fine resin in the embodiment is preferably a polyRP type;
after sampling, eluting five to seven column volumes by 60 to 70 percent acetone water to remove foreimpurities in the cannabinol oil, eluting four to six column volumes by 60 to 70 percent acetone water and collecting the cannabinol oil eluent, and finally eluting by pure acetone to remove rear-stage impurities in the cannabinol oil and regenerate the fine resin column, wherein in the embodiment, the fine resin column is regenerated by eluting four to five column volumes by acetone water with the volume concentration of more than or equal to 95 percent, in the embodiment, the flow rate of each column volume is controlled to be 20 to 30min, and the column pressure is 0.2 to 0.4Mpa; concentrating the collected cannabinol oil eluate at low pressure to obtain cannabinol refined oil, wherein in the embodiment, the specific steps of concentrating the cannabinol sub-pure oil eluate at low pressure comprise:
introducing cannabinol sub-pure oil eluate into a concentrator, heating the concentrator to 50-60 deg.C, regulating vacuum degree to 0.04-0.06Mpa, and recovering acetone; heating the concentrator to 85-95 deg.C, adjusting vacuum degree to 0.06-0.08Mpa, and removing water.
S7: adding a certain amount of activated carbon and petroleum ether solvent into the cannabinol refined oil obtained in the step S6, in this embodiment, using the activated carbon as a decoloring agent, and using the low-boiling point petroleum ether as a solvent for decoloring, in this embodiment, the usage amount of the activated carbon is 10% of that of the cannabinol refined oil, the mass ratio of the volume of the low-boiling point petroleum ether solvent to the lipid of the cannabinol refined oil is 1.
S8: and (4) crystallizing the cannabinol refined solvent obtained in the step (S7) at a low temperature to obtain cannabinol crystals, wherein the crystallization time is 7-9 hours and the crystallization temperature is-10 to-20 ℃.
According to the steps, as the polarity of the ethanol is larger than that of the acetone, a large amount of impurities are brought out during extraction, and the difficulty of subsequent treatment is increased, the acetone is used as an extracting agent for extracting the cannabinol crude extract from the cannabis sativa flower leaf powder, and the organic compounds containing carboxylic acids and esters in the cannabinol crude extract are removed in advance by adopting the processes of decarboxylation, saponification reaction and the like, so that a good impurity removal effect is realized, then the cannabinol refined extract is extracted by adopting n-hexane, specifically, the target substance is extracted into the n-hexane as much as possible to be separated from the water-soluble substance, and thus, the purity of the cannabinol crude extract is greatly improved; the obtained cannabinol refined product is purified through a low-pressure macroporous resin column after acetone water balance and a low-pressure fine resin column after acetone water balance, and the resin has the advantages of simplicity in operation, low cost, low professional requirements on operators, high sample loading, long service life and the like compared with the existing supercritical and molecular distillation, so that the method is convenient to operate and can reduce the loss of samples by adopting the macroporous resin column and the low-pressure fine resin column, organic solvent acetone with different volume concentrations is used as an elution solution to obtain cannabinol refined oil with the purity of about 90%, and finally, the cannabinol refined oil is decolorized by adopting active carbon and petroleum ether solvent, so that the impurities in the cannabinol refined oil are further reduced, and a large amount of impurities are removed in the early stage, so that the subsequent crystallization process times are reduced, the cannabinol with the purity of about 99% can be obtained, that compared with the existing process, the process flow is simple, the target material flow loss is small, the impurities are thoroughly removed, and the yield and the purity of the cannabinol are improved.
Example 2: in this example, for better illustration, the following table is provided to illustrate the details of the CBN in this example, namely cannabinol;
TABLE 1
Table 1 shows data of the weight of extract, the content of CBN in the crude cannabinol extract obtained by selecting 10 groups of hemp leaf powder samples in step S2 according to this example, and using acetone, ethanol and n-hexane as the extracting agents respectively, and from table 1, it can be seen that the amount of extract in the crude cannabinol extract obtained when ethanol is used as the extracting agent at normal temperature or low temperature is very large, which indicates that the impurity content is very high, so that the subsequent impurity removal process is complicated, and the yield can be relatively low when n-hexane is used as the extracting agent at normal temperature, and the weight of extract obtained when acetone is used as the extracting agent is stabilized between 26.1g and 27.3 after the highest value and the lowest value are removed, and meanwhile, the content of CBN in the extract is stabilized at about 5.79%, and the average yield reaches more than 98.2%, therefore, based on the above test, this example preferably uses acetone as the extracting agent at normal temperature.
TABLE 2
Table 2 shows the data of the weight, CBN content and yield of the extract in the refined cannabinol product obtained by extracting 10 cannabis leaf powder samples in table 1 with acetone at normal temperature and then saponifying and extracting, as can be seen from the data in table 2, more than 60% of impurities in the original cannabinol crude extract are removed by the saponifying and extracting processes, so that the CBN content in the refined cannabinol product is increased, that is, the purity of CBN in the refined cannabinol product is further increased; meanwhile, as can be seen from table 2, the effect of removing impurities from the crude cannabinol extract is different when sodium hydroxide solutions with different mass concentrations and different temperatures are used, but the effect is not particularly remarkable, according to the data analysis, the saponification reaction temperature is preferably 75 ℃, the constant temperature reaction time is preferably 3 hours, and the volume ratio of n-hexane to sodium hydroxide aqueous solution is preferably 1.
TABLE 3
Table 3 shows values of the weight of the extract, the CBN content and the yield of cannabinol oil obtained by performing primary purification on 10 groups of cannabis leaf powder samples in table 1 in the manner shown in tables 1 and 2, and according to data in table 3, using a low-pressure macroporous resin column in combination with acetone can remove and purify a cannabinol refined product, so that the weight of the extract in the cannabinol oil is reduced to about 2.3, the CBN content is increased to about 61.5%, and meanwhile, according to data in table 3, not only the weight of the extract in the cannabinol oil obtained when ethanol water is used as an eluent is greater than the value obtained when acetone water is used as an eluent, but also the CBN content is reduced compared with acetone water used as an eluent, i.e., the problem of incomplete elution exists when ethanol is used as an eluent, and according to data in table 3, the problem of incomplete elution also exists when the type DA201 is used as a macroporous resin type; therefore, based on the analysis in table 3, it is preferable that the eluent is acetone, the type of macroporous resin is SP825L, and the acetone and the macroporous resin of this type are used as the eluent and the purification material to remove a large amount of impurities in the refined cannabinol product and rapidly improve the purity of CBN.
TABLE 4
Table 4 shows the values of the weight of the extract, the content of CBN, and the yield of the cannabinol refined oil obtained by repurifying the cannabinol oil primarily purified in table 3 in this embodiment, according to the data in table 4, it can be known that the cannabinol oil can be subjected to impurity removal and purification by using a low-pressure fine resin column in combination with acetone, so that the weight of the extract in the cannabinol refined oil is reduced to about 1.4, and the content of CBN is increased to about 89%.
TABLE 5
Table 5 shows the values of the extract weight, the CBN content and the yield of the crystallized cannabinol crystal provided in this example, and it can be seen from table 5 that the CBN content of the crystallized cannabinol crystal reaches about 99%, and meanwhile, from the total yield of the first group of samples in table 5 (the group is a reference group of 12 groups of samples, and the other groups of samples are all subject to parameter changes from tables 1 to 4), the total yield of CBN after the above preferred method of this example reaches 92.91%.
Based on the above analysis, the present embodiment provides a preferred method for preparing high-purity cannabinol crystals, which specifically includes:
s1: the industrial hemp flowers and leaves are selected as raw materials and are dried and crushed, in the embodiment, the industrial hemp flowers and leaves are dried to enable the moisture content to be lower than 12%, and the dried industrial hemp flowers and leaves are crushed and sieved by a 30-40 mesh sieve.
S2: extracting the crushed hemp flower and leaf powder for 2 times at normal temperature (25-30 ℃) by adopting an acetone solvent with the volume concentration of more than or equal to 95%, wherein the extraction time is 2h each time, mixing the extracting solution, heating and concentrating to obtain a crude cannabinol extract, in the embodiment, the acetone solvent with the mass 4-5 times that of the hemp flower and leaf powder is respectively added in the multiple extraction, and the preferable mass ratio of the added acetone solvent to the hemp flower and leaf powder is 5:1.
s3: subjecting the crude cannabinol extract obtained in step S2 to decarboxylation at a temperature of 110-120 ℃ for a time of 0.5-1.5h, preferably heating the crude cannabinol extract to 120 ℃ and stirring at that temperature for 1h in this example; referring to fig. 1, a state diagram of the components and their corresponding concentrations contained in the crude cannabinol extract obtained after decarboxylation provided in this example is shown on a chromatographic column, through which it can be seen that the crude cannabinol extract contains more impurities.
S4: carrying out saponification treatment and extraction treatment on the decarboxylated cannabinol crude extract in the step S3 in sequence, specifically;
firstly, carrying out saponification reaction on the decarboxylated cannabinol crude extract at the temperature of 75 ℃ by adopting a sodium hydroxide solution with the mass concentration of 0.5%, wherein the saponification reaction time is 3 hours, and after the saponification reaction is finished, adding a hydrochloric acid solution with the concentration of more than or equal to 30% into a reaction solvent until the pH of the reaction solvent is 6-8, wherein in the embodiment, the sodium hydroxide solution is 10 times of the weight of the cannabinol crude extract;
when the temperature is reduced to room temperature (25-30 ℃), adding a normal hexane solution into the reaction solvent, stirring for 20min until the normal hexane and the aqueous solution are fully mixed, standing for 40-50min, and waiting for the normal hexane and the aqueous solution to be layered, so that an upper-layer normal hexane solution can be recovered, wherein the extraction times are 2 times, the extraction time is 40-50min each time, combining the recovered upper-layer normal hexane solution, and concentrating to obtain a cannabinol refined product, in the embodiment, a normal hexane solvent with the same volume as that of the sodium hydroxide solution is added in multiple extractions, namely the volume ratio of the normal hexane to the sodium hydroxide solution is 1:1; in this example, the specific conditions for concentrating the mixed upper n-hexane solution were as follows: heating the mixed upper-layer n-hexane solution to 60-70 ℃, and vacuumizing to 0.04-0.06Mpa; referring to fig. 2, a state diagram of the components and their corresponding concentrations in the refined cannabinol extract obtained by the extraction process of this example on a chromatographic column is shown, and the chromatogram shows that the types and concentrations of impurities in the refined cannabinol extract are reduced, i.e., a large amount of impurities in the crude cannabinol extract are removed by the saponification and extraction processes.
S5: performing primary purification treatment on the cannabinol refined product obtained in the step S4 by using a low-pressure macroporous resin column, wherein the low-pressure macroporous resin column is an acetone water balance column with the volume concentration of 55%, in the embodiment, the preparation method of the acetone water balance column comprises the steps of filling the resin column, standing overnight, and eluting three column volumes by using 55% acetone water, namely, completing balance, in the embodiment, the macroporous resin does not need to be pretreated, and the type of the macroporous resin in the embodiment is preferably SP825L;
after sampling, firstly eluting five to seven column volumes by using acetone water with the volume concentration of 60 percent to remove foreimpurities in the cannabinol refined product, then eluting four to six column volumes by using acetone water with the volume concentration of 65 percent and collecting the cannabinol eluate, and finally eluting by using pure acetone to remove rear-stage impurities in the cannabinol refined product and regenerate the macroporous resin column, wherein in the embodiment, the macroporous resin column is regenerated by eluting four to five column volumes by using acetone water with the volume concentration of more than or equal to 95 percent, in the embodiment, the flow rate of each column volume is controlled to be 20-30min, and the preferable column pressure is less than 0.2Mpa; concentrating the collected cannabinol eluate at low pressure to obtain cannabinol oil, wherein the step of concentrating the cannabinol eluate at low pressure comprises:
introducing cannabinol eluate into concentrator, heating to 50-60 deg.C, regulating vacuum degree to 0.04-0.06Mpa, and recovering acetone; heating the concentrator to 90 deg.C, adjusting vacuum degree to 0.06-0.08Mpa, and removing water; referring to fig. 3, a state diagram of the substance components contained in the cannabinol oil and fat obtained after the primary purification and the corresponding concentrations thereof on the chromatographic column is shown.
S6: performing secondary purification treatment on the cannabinol oil obtained in the step S5 by using a low-pressure fine resin column, wherein the low-pressure fine resin column is an acetone water balance column with the volume concentration of 60%, in the embodiment, the manufacturing method of the acetone water balance column comprises the steps of filling the fine resin column, standing overnight, and eluting three column volumes by using 60% acetone water, namely, completing balance, wherein the fine resin does not need to be pretreated, and the type of the fine resin in the embodiment is preferably a PolyRP type;
after sampling, firstly eluting five to seven column volumes by 65 percent acetone water to remove foreimpurities in the cannabinol oil, then eluting four to six column volumes by 65 percent acetone water and collecting the cannabinol oil eluent of the section, and finally eluting by pure acetone to remove rear-section impurities in the cannabinol oil and regenerate a fine resin column, wherein in the embodiment, the fine resin column is regenerated by eluting four to five column volumes by 95 percent acetone water, in the embodiment, the flow rate of each column volume is controlled to be 20 to 30min, and the column pressure is 0.2 to 0.4Mpa; concentrating the collected cannabinol oil eluate at low pressure to obtain cannabinol refined oil, wherein in the embodiment, the specific steps of concentrating the cannabinol sub-pure oil eluate at low pressure comprise:
introducing cannabinol sub-pure oil eluate into a concentrator, heating the concentrator to 50-60 deg.C, regulating vacuum degree to 0.04-0.06Mpa, and recovering acetone; heating the concentrator to 85-95 deg.C, regulating vacuum degree to 0.06-0.08Mpa, and removing water; referring to fig. 4, a state diagram of the components contained in the cannabinol oil obtained after the secondary purification and the corresponding concentrations thereof on the chromatographic column is shown.
S7: adding a certain amount of activated carbon and petroleum ether solvent into the cannabinol refined grease obtained in the step S6, in this embodiment, using the activated carbon as a decoloring agent, and using the low-boiling point petroleum ether as a solvent for decoloring, in this embodiment, using the activated carbon in an amount of 10% of that of the cannabinol refined grease, wherein the mass ratio of the volume of the low-boiling point petroleum ether solvent to the lipid of the cannabinol refined grease is 1.
S8: carrying out low-temperature crystallization on the cannabinol refined solvent obtained in the step S7 to obtain cannabinol crystals with the CBN content being more than or equal to 99%, wherein the crystallization time is 8h, and the crystallization temperature is-15 ℃; referring to fig. 5, a state diagram of the cannabinol crystal and the corresponding concentration thereof displayed on the chromatographic column is provided in this embodiment, and referring to fig. 6, a state diagram of the cannabinol standard substance displayed on the chromatographic column is provided in this embodiment, and it can be seen from a comparison between fig. 5 and fig. 6 that the purity of the cannabinol crystal obtained by the above process in this embodiment is close to that of the cannabinol standard substance, that is, the high-purity cannabinol crystal can be obtained by the above process in this embodiment.
The foregoing is merely an example of the present invention and common general knowledge in the art of designing and describing specific structures and features has not been set forth herein in any greater detail. It should be noted that, for those skilled in the art, without departing from the present invention, several modifications can be made, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicability of the patent. The scope of protection claimed in the present application shall be subject to the contents of the claims, and the description of the embodiments and the like in the specification shall be used to explain the contents of the claims.
Claims (6)
1. The preparation method of the high-purity cannabinol crystal is characterized by comprising the following steps
S1: selecting industrial hemp flowers and leaves as raw materials, and drying and crushing the raw materials;
s2: extracting the pulverized hemp flower and leaf powder with acetone solvent with volume concentration of 95% or more at normal temperature for 2-3 times, each time for 1.5-3.5h, mixing extractive solutions, and heating and concentrating to obtain cannabinol crude extract;
s3: performing decarboxylation treatment on the cannabinol crude extract obtained in the step S2 at the temperature of 110-120 ℃, wherein the decarboxylation treatment time is 1-1.5h;
s4: carrying out saponification treatment and extraction treatment on the decarboxylated cannabinol crude extract in the step S3 in sequence, specifically;
firstly, carrying out saponification reaction on the decarboxylated cannabinol crude extract by adopting a sodium hydroxide solution with the mass concentration of 0.5-1%, wherein the saponification reaction time is 2.5-3.5h, and after the saponification reaction is finished, adding a hydrochloric acid solution into a reaction solvent until the pH value of the reaction solvent is 6-8;
cooling to room temperature, adding n-hexane solution into the reaction solvent, stirring and standing to realize extraction for 2-3 times, wherein the extraction time is 40-50min each time, recovering the upper n-hexane solution of each extraction, combining the recovered upper n-hexane solutions, and concentrating to obtain cannabinol refined product;
s5: performing primary purification treatment on the cannabinol refined product obtained in the step S4 by using a low-pressure macroporous resin column, wherein the low-pressure macroporous resin column is an acetone water balance column with the volume concentration of 50-60%, eluting the foreimpurities in the cannabinol refined product by using acetone water with the volume concentration of 55-65% after sample loading, eluting by using acetone water with the volume concentration of 60-70% and collecting the primary cannabinol eluate of the section, and finally eluting by using pure acetone to remove the impurities of the rear section in the cannabinol refined product and regenerate the macroporous resin column; concentrating the collected cannabinol primary pure eluent at low pressure to obtain cannabinol oil;
in the steps, acetone water with volume concentration of 55-65% is used for eluting five to seven column volumes when removing the foreigners of the refined cannabinol product, acetone water with volume concentration of 60-70% is used for eluting four to six column volumes when obtaining the primary pure cannabinol eluent, acetone water with volume concentration of more than or equal to 95% is used for eluting four to five column volumes when regenerating a macroporous resin column, the flow rate of each column volume is controlled to be 20-30min, and the column pressure is less than 0.2Mpa;
in the above step, the specific steps of low pressure concentrating the cannabinol primary pure eluent comprise:
introducing the cannabinol primary pure eluate into a concentrator, heating the concentrator to 50-60 deg.C, adjusting vacuum degree to 0.04-0.06Mpa, and recovering acetone;
heating the concentrator to 85-95 deg.C, adjusting vacuum degree to 0.06-0.08Mpa, and removing water;
the type of the low-pressure macroporous resin is SP type;
s6: performing secondary purification treatment on the cannabinol oil obtained in the step S5 by adopting a low-pressure fine resin column, wherein the low-pressure fine resin column is an acetone water balance column with the volume concentration of 55-65%, eluting the foreigners in the cannabinol oil by using 60-70% acetone water after sample loading, eluting by using 60-70% acetone water, collecting the eluate of the cannabinol secondary pure oil, and finally eluting by using pure acetone to remove the rear-stage impurities in the cannabinol oil and regenerate the fine resin column; concentrating the collected cannabinol sub-pure oil eluent at low pressure to obtain cannabinol refined oil;
in the steps, acetone water with volume concentration of 55-65% is used for eluting five to seven column volumes when removing the foreimpurity of the cannabinol oil, acetone water with volume concentration of 60-70% is used for eluting four to six column volumes when obtaining cannabinol sub-pure oil eluent, acetone water with volume concentration of more than or equal to 95% is used for eluting four to five column volumes when regenerating a fine resin column, the flow rate of each column volume is controlled to be 20-30min, and the column pressure is 0.2-0.4Mpa;
in the above steps, the specific steps of concentrating the cannabinol sub-pure oil eluate at low pressure comprise:
introducing cannabinol sub-pure oil eluate into a concentrator, heating the concentrator to 50-60 deg.C, regulating vacuum degree to 0.04-0.06Mpa, and recovering acetone;
heating the concentrator to 85-95 deg.C, adjusting vacuum degree to 0.06-0.08Mpa, and removing water;
the model of the low-pressure fine resin is a PolyRP model;
s7: adding a certain amount of activated carbon and petroleum ether solvent into the cannabinol refined grease obtained in the step S6, heating, stirring, standing, and finally filtering to remove a decolorant to obtain a decolored cannabinol refined solvent;
s8: and (4) carrying out low-temperature crystallization on the cannabinol refined solvent obtained in the step (S7) to obtain cannabinol crystals, wherein the crystallization time is 7-9h.
2. The method of claim 1, wherein acetone is added to the extraction of the cannabinol crystals in an amount of 4 to 5 times the weight of the cannabis sativa flower and leaf powder.
3. The method for preparing highly pure cannabinol crystals as claimed in claim 1, wherein in step S4, in the saponification reaction process, the amount of aqueous sodium hydroxide solution is 9.5-10.5 times the weight of the crude extract, the temperature of the saponification reaction is 65-90 ℃, and the concentration of hydrochloric acid solvent is 30% or more; in the extraction process, n-hexane solvent with the mass 10-13 times of that of the cannabinol crude extract is added in multiple extractions, or n-hexane solvent with the same volume as the sodium hydroxide solution is added in multiple extractions.
4. The method for preparing highly pure cannabinol crystals as claimed in claim 1, wherein in the extraction process of step S4, the specific conditions for concentrating the mixed upper n-hexane solution are as follows: heating the mixed upper n-hexane solution to 60-70 deg.C, and vacuumizing to 0.04-0.06Mpa.
5. The method for preparing highly pure cannabinol crystals as claimed in claim 1, wherein in step S7, the amount of activated carbon is 10% of that of the cannabinol refined oil, the mass ratio of the volume of the low boiling point petroleum ether solvent to the lipid content of the cannabinol refined oil is 1.
6. The method for preparing highly pure cannabinol crystals as claimed in claim 1, wherein in step S8, the crystallization temperature is between-10 ℃ and-20 ℃.
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| CN113683490A (en) * | 2021-08-02 | 2021-11-23 | 云南翰谷生物科技有限公司 | Preparation method of hypocannabidiol crystal |
| CN114539032A (en) * | 2022-03-07 | 2022-05-27 | 哈尔滨智慧工业大麻产业发展有限公司 | Method for preparing ultrapure cannabidiol monomer |
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