CN115504864A - Method for obtaining high-purity cannabidiol from industrial cannabis sativa - Google Patents
Method for obtaining high-purity cannabidiol from industrial cannabis sativa Download PDFInfo
- Publication number
- CN115504864A CN115504864A CN202110629569.4A CN202110629569A CN115504864A CN 115504864 A CN115504864 A CN 115504864A CN 202110629569 A CN202110629569 A CN 202110629569A CN 115504864 A CN115504864 A CN 115504864A
- Authority
- CN
- China
- Prior art keywords
- cannabidiol
- obtaining
- crude oil
- high purity
- industrial
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 title claims abstract description 72
- 229950011318 cannabidiol Drugs 0.000 title claims abstract description 72
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 title claims abstract description 72
- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 title claims abstract description 72
- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 title claims abstract description 62
- 244000025254 Cannabis sativa Species 0.000 title claims abstract description 34
- 238000000034 method Methods 0.000 title claims abstract description 30
- 235000008697 Cannabis sativa Nutrition 0.000 title claims description 11
- 239000010779 crude oil Substances 0.000 claims abstract description 27
- 235000012766 Cannabis sativa ssp. sativa var. sativa Nutrition 0.000 claims abstract description 23
- 235000012765 Cannabis sativa ssp. sativa var. spontanea Nutrition 0.000 claims abstract description 23
- 235000009120 camo Nutrition 0.000 claims abstract description 23
- 235000005607 chanvre indien Nutrition 0.000 claims abstract description 23
- 239000011487 hemp Substances 0.000 claims abstract description 23
- 239000007787 solid Substances 0.000 claims abstract description 18
- 238000005917 acylation reaction Methods 0.000 claims abstract description 11
- -1 cannabidiol diester Chemical class 0.000 claims abstract description 11
- 230000010933 acylation Effects 0.000 claims abstract description 7
- 239000003153 chemical reaction reagent Substances 0.000 claims abstract description 6
- 238000001914 filtration Methods 0.000 claims abstract description 3
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 36
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 claims description 24
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 15
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 14
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 12
- 238000006243 chemical reaction Methods 0.000 claims description 12
- 238000001816 cooling Methods 0.000 claims description 12
- 239000002904 solvent Substances 0.000 claims description 11
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 10
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical group CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 8
- 239000003208 petroleum Substances 0.000 claims description 8
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 7
- 238000001953 recrystallisation Methods 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 6
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
- 239000003795 chemical substances by application Substances 0.000 claims description 6
- 239000012046 mixed solvent Substances 0.000 claims description 5
- 229910052757 nitrogen Inorganic materials 0.000 claims description 5
- 238000003756 stirring Methods 0.000 claims description 5
- 238000000967 suction filtration Methods 0.000 claims description 5
- 241000218236 Cannabis Species 0.000 claims description 4
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 4
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims description 4
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 4
- 239000002585 base Substances 0.000 claims description 4
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 claims description 4
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 4
- 238000006460 hydrolysis reaction Methods 0.000 claims description 3
- 150000007529 inorganic bases Chemical class 0.000 claims description 3
- 238000002386 leaching Methods 0.000 claims description 3
- 150000007530 organic bases Chemical class 0.000 claims description 3
- 125000003837 (C1-C20) alkyl group Chemical group 0.000 claims description 2
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- DKPFZGUDAPQIHT-UHFFFAOYSA-N Butyl acetate Natural products CCCCOC(C)=O DKPFZGUDAPQIHT-UHFFFAOYSA-N 0.000 claims description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 239000003513 alkali Substances 0.000 claims description 2
- 150000008064 anhydrides Chemical class 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 2
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 2
- 150000002148 esters Chemical class 0.000 claims description 2
- 239000012065 filter cake Substances 0.000 claims description 2
- 150000004820 halides Chemical class 0.000 claims description 2
- 238000010438 heat treatment Methods 0.000 claims description 2
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 2
- 229930195733 hydrocarbon Natural products 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- VSTXCZGEEVFJES-UHFFFAOYSA-N 1-cycloundecyl-1,5-diazacycloundec-5-ene Chemical compound C1CCCCCC(CCCC1)N1CCCCCC=NCCC1 VSTXCZGEEVFJES-UHFFFAOYSA-N 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- CYQFCXCEBYINGO-UHFFFAOYSA-N THC Natural products C1=C(C)CCC2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3C21 CYQFCXCEBYINGO-UHFFFAOYSA-N 0.000 abstract description 11
- CYQFCXCEBYINGO-IAGOWNOFSA-N delta1-THC Chemical compound C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 CYQFCXCEBYINGO-IAGOWNOFSA-N 0.000 abstract description 11
- 229960004242 dronabinol Drugs 0.000 abstract description 11
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 230000003301 hydrolyzing effect Effects 0.000 abstract description 2
- 238000000926 separation method Methods 0.000 abstract 1
- 238000004440 column chromatography Methods 0.000 description 6
- 238000004128 high performance liquid chromatography Methods 0.000 description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 3
- 239000013078 crystal Substances 0.000 description 3
- 229940079593 drug Drugs 0.000 description 3
- 239000003814 drug Substances 0.000 description 3
- 238000000605 extraction Methods 0.000 description 3
- 238000010813 internal standard method Methods 0.000 description 3
- 239000011259 mixed solution Substances 0.000 description 3
- 230000001376 precipitating effect Effects 0.000 description 3
- 238000000746 purification Methods 0.000 description 3
- 239000000243 solution Substances 0.000 description 3
- YYROPELSRYBVMQ-UHFFFAOYSA-N 4-toluenesulfonyl chloride Chemical compound CC1=CC=C(S(Cl)(=O)=O)C=C1 YYROPELSRYBVMQ-UHFFFAOYSA-N 0.000 description 2
- CURLTUGMZLYLDI-UHFFFAOYSA-N Carbon dioxide Chemical compound O=C=O CURLTUGMZLYLDI-UHFFFAOYSA-N 0.000 description 2
- 239000000287 crude extract Substances 0.000 description 2
- 238000010828 elution Methods 0.000 description 2
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 239000003921 oil Substances 0.000 description 2
- 239000003960 organic solvent Substances 0.000 description 2
- 239000012071 phase Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- SSNHGLKFJISNTR-DYSNNVSPSA-N (6ar,10ar)-6,6,9-trimethyl-3-pentyl-6a,7,8,10a-tetrahydrobenzo[c]chromen-1-ol;2-[(1r,6r)-3-methyl-6-prop-1-en-2-ylcyclohex-2-en-1-yl]-5-pentylbenzene-1,3-diol Chemical compound OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1.C1=C(C)CC[C@H]2C(C)(C)OC3=CC(CCCCC)=CC(O)=C3[C@@H]21 SSNHGLKFJISNTR-DYSNNVSPSA-N 0.000 description 1
- HCSBTDBGTNZOAB-UHFFFAOYSA-N 2,3-dinitrobenzoic acid Chemical compound OC(=O)C1=CC=CC([N+]([O-])=O)=C1[N+]([O-])=O HCSBTDBGTNZOAB-UHFFFAOYSA-N 0.000 description 1
- SKDHHIUENRGTHK-UHFFFAOYSA-N 4-nitrobenzoyl chloride Chemical compound [O-][N+](=O)C1=CC=C(C(Cl)=O)C=C1 SKDHHIUENRGTHK-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 206010012335 Dependence Diseases 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 150000001335 aliphatic alkanes Chemical class 0.000 description 1
- 239000012670 alkaline solution Substances 0.000 description 1
- PNEYBMLMFCGWSK-UHFFFAOYSA-N aluminium oxide Inorganic materials [O-2].[O-2].[O-2].[Al+3].[Al+3] PNEYBMLMFCGWSK-UHFFFAOYSA-N 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 238000004458 analytical method Methods 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 239000001569 carbon dioxide Substances 0.000 description 1
- 229910002092 carbon dioxide Inorganic materials 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 239000000284 extract Substances 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 150000002632 lipids Chemical class 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920006122 polyamide resin Polymers 0.000 description 1
- 239000000047 product Substances 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 230000002936 tranquilizing effect Effects 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
- C07C37/68—Purification; separation; Use of additives, e.g. for stabilisation
- C07C37/86—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
- 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
Abstract
The invention discloses a method for obtaining high-purity cannabidiol from industrial hemp, which comprises the steps of adding an acylation reagent into crude oil extracted from the industrial hemp, converting the cannabidiol in the crude oil into cannabidiol diester which is easy to crystallize, filtering solid, recrystallizing, and hydrolyzing the recrystallized cannabidiol diester to obtain the high-purity cannabidiol. Compared with the prior art, the method solves the problems of difficult separation of cannabidiol and difficult removal of tetrahydrocannabinol in the prior art, and has the advantages of low production cost, good reproducibility and high cannabidiol purity.
Description
Technical Field
The invention belongs to the technical field of medicines, and particularly relates to a method for obtaining high-purity cannabidiol from industrial cannabis sativa.
Background
The content of Tetrahydrocannabinol (THC) in industrial hemp is less than 0.3%, and the THC is not extracted, so that the industrial hemp can be planted and processed according to the law in Yunnan and Heilongjiang provinces in China at present. Cannabidiol (CBD) contained in industrial cannabis sativa has no mental activity and addiction, and has good pharmacological activities of resisting inflammation, resisting depression, resisting epilepsy, tranquilizing, resisting tumor, etc. Currently, there are drugs containing CBD that have been used clinically, such as Sativex, epidiolex, etc. In addition, there are dozens of CBD drugs in clinical trials. Thus, efficient CBD acquisition from industrial cannabis is of great importance.
Since CBD and THC are always present in concomitant form, the extraction of CBD from industrial cannabis also means that THC is continuously enriched and its content is continuously increased. How to improve the content of CBD and ensure that the content of THC in the product does not exceed the standard (less than 0.3 percent) is very critical. On the other hand, because of the low melting point, strong lipid solubility and poor crystallinity of CBD, it is very difficult to directly crystallize CBD from industrial hemp crude extract.
Some prior art references methods for obtaining CBD crystals from industrial cannabis. After obtaining hemp crude oil (with a CBD content of generally 20 to 70%) by supercritical or subcritical extraction with an organic solvent (such as ethanol or an alkane solvent) or carbon dioxide, further purification is required to increase the CBD content and crystallize the hemp crude oil. Concentrating the extract, sequentially separating and purifying by using a normal phase column and a reverse phase column, and then recrystallizing to finally obtain the CBD with the purity of 92 to 98 percent as in the patent application with the application number of 201811468947.X; the patent application with the application number of 201810950247.8 adopts a chromatographic column for gradient elution, and the concentrated solution is recrystallized to obtain CBD; the patent application with the application number of 201810111141.9 adopts alcohol extraction, adopts alkaline solution to enhance the water solubility of CBD, adopts organic solvent to extract and enrich CBD, purifies and enriches the CBD through a polyamide resin column, neutral alumina and a bonded silica gel column, and then recrystallizes to obtain CBD; in the application No. 201610674119.6, crude extract is extracted with water, concentrated, chromatographed, and recrystallized to obtain CBD crystal.
Analysis of the prior art has shown that in order to achieve the precipitation of CBD crystals, further treatment of the hemp crude oil is required to increase the CBD content (and at the same time reduce the THC content) to facilitate the precipitation from the oil. These methods, without exception, employ column chromatography techniques. In industrial production, the reproducibility and economy of column chromatography are poor, and thus the production cost of CBD is high.
Disclosure of Invention
The invention aims to: in order to solve the problems, the method provided by the invention has the advantages of low production cost and good reproducibility, and the method for obtaining high-purity cannabidiol from industrial cannabis sativa.
The technical scheme of the invention is as follows:
a process for preparing high-purity cannabidiol from industrial hemp includes such steps as adding acylating agent to the coarse oil of industrial hemp, acylating (converting cannabidiol to easily crystallized cannabidiol diester), filtering, recrystallizing, and hydrolyzing. Further, the acylation reaction comprises the following processes: dissolving the hemp crude oil in a solvent, adding an acylation reagent, stirring at room temperature for 12-36 hours, then cooling to-30 to-10 ℃, keeping for 2 to 20 hours, carrying out suction filtration at low temperature, and leaching a filter cake with the solvent to obtain the hemp crude oil.
Furthermore, the cannabidiol content in the industrial hemp crude oil is 20 to 90 percent.
Further, the acylating agent is selected from one or more of benzoic acid, p-toluenesulfonic acid, p-nitrobenzoic acid, and carboxylic acid activated forms of anhydrides, acid halides, or activated esters formed therefrom.
Furthermore, the dosage of the acylating agent is 1.2 to 5.0 times of the molar weight of the pure cannabidiol contained in the crude oil according to the conversion of the pure cannabidiol contained in the crude oil.
Further, the solvent used in the acylation reaction is one or more selected from C1-C20 hydrocarbons, C1-C20 alkyl halides, C1-C20 ethers, acetonitrile, N-dimethylformamide, acetone, pyridine, triethylamine and ethyl acetate.
Further, the solvent used in the acylation reaction is n-hexane, dichloromethane or tetrahydrofuran.
Further, the solvent used in the recrystallization process of the cannabidiol diester is one or more selected from ethyl ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, petroleum ether, n-heptane and n-hexane.
Further, the hydrolysis reaction comprises the following processes: dissolving a solid (cannabidiol diester) obtained by recrystallization in a mixed solvent consisting of water and ethanol, adding alkali, heating the reaction solution to 45-55 ℃ under the protection of nitrogen, keeping the temperature for 8-12 hours, cooling the reaction solution to room temperature, adjusting the pH value to 3-5, extracting, concentrating an organic phase, cooling to precipitate a solid, and recrystallizing the obtained solid to obtain the high-purity cannabidiol.
Further, the base is an inorganic base or an organic base, the inorganic base is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate and ammonia water, the organic base is selected from one or more of triethylamine, pyridine, piperidine and 1, 8-diazabicycloundecen-7-ene, and the dosage of the base is 2 to 10 times of the mole number of the cannabidiol diester to be hydrolyzed.
Has the advantages that:
compared with the prior art, the method does not need column chromatography purification on the extracted crude oil, but adds an acylation reagent to convert the crude oil into the cannabidiol diester which is easier to crystallize, so that the cannabidiol diester is separated out from the crude oil, recrystallized and hydrolyzed to obtain the high-purity cannabidiol. The method avoids the column chromatography operation with poor reproducibility and economy, has low requirement on equipment, and has good application prospect.
Detailed Description
The present invention is described in detail below with reference to specific examples, but the present invention is not limited thereto in any way. The relevant reagents used in the following examples are all commercially available.
Example 1
Extracting pulverized industrial hemp dried flower and leaf with ethanol according to known method, concentrating, and distilling under reduced pressure to obtain industrial hemp crude oil. The CBD content was 57% by HPLC. 100g of the crude oil was dissolved in 1L of anhydrous dichloromethane, and 50g of anhydrous pyridine, 6.5g of N, N-dimethyl-4-aminopyridine and 76g of benzoyl chloride were added thereto, followed by stirring at room temperature for 24 hours. Cooling to-30 deg.C and keeping the temperature for 5h. Suction filtration is carried out at low temperature, and cooled petroleum ether is used for leaching to obtain an earthy yellow solid. The mixed solution of ethyl acetate-petroleum ether (volume ratio is 1. mp 100 to 102 ℃ [ alpha ]] D 25 ＝-76.0 (c＝0.1，EtOH)； 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.06 (d, J = 8.0Hz, 4H), 7.70 (t, J = 7.9 Hz, 2H), 7.57 (t, J = 8.0 Hz, 4H), 6.93 (s, 2H), 4.99 (s, 1H), 4.51 (s, 1H), 4.43 (s, 1H), 3.42 (m, 1H), 2.65 (m, 1H), 2.46 (m, 2H), 1.55-1.46 (m, 9H), 1.24 (m, 4H), 1.04 (s, 3H), 0.81 (t, J = 6.8 Hz, 3H); 13 C NMR (151 MHz, DMSO-d 6 ) δ 164.52, 149.59, 147.24, 141.95, 134.13, 133.05, 129.81, 129.01, 126.24, 123.62, 111.29, 45.46, 38.05, 34.29, 30.86, 30.02, 29.47, 28.01, 22.79, 21.95, 19.41, 13.95.
52g of cannabidiol bisbenzoate is taken and dissolved in a mixed solvent of 250 mL of water and 250 mL of ethanol. 20 g of sodium hydroxide are added and the reaction is heated to 50 ℃ under nitrogen. After 10 hours, the reaction was cooled to room temperature and the pH was adjusted to 3-5 with dilute hydrochloric acid. Extracting with 200 mL of n-heptane, concentrating, cooling to-5 deg.C, and precipitating a large amount of pale yellow solid; recrystallizing with n-heptane to obtain 27 g white solid; the content of cannabidiol detected by HPLC internal standard method is 98.7%, the purity is 99.9%, and tetrahydrocannabinol is not detected. mp 67-68 deg.C, [ alpha ]] D 25 ＝-131.9 (c＝0.1，EtOH)； 1 H NMR(400 MHz, DMSO-d 6 ): δ 8.68 (s, 2H), 6.01 (s, 2H), 5.08 (s, 1H), 4.48 (s, 1H), 4.40 (s, 1H), 3.81 (d, J = 8.9 Hz, 1H), 2.99 (m, 1H), 2.29 (t, J = 7.6 Hz, 2H), 2.13 (m, 1H), 1.94 (m, 1H), 1.69-1.50 (m, 8H), 1.42 (m, 2H), 1.18 (m, 4H), 0.85 (t, J = 6.9 Hz, 3H); 13 C NMR (151 MHz, DMSO-d 6 ) δ 156.25, 149.12, 140.16, 130.02, 126.86, 114.11, 109.65, 106.58, 43.64, 35.52, 34.89, 31.00, 30.28, 29.47, 23.28, 21.99, 19.22, 13.92。
Example 2
Extracting pulverized industrial hemp dried flower and leaf with ethanol according to known method, concentrating, and distilling under reduced pressure to obtain industrial hemp crude oil. The CBD content was 50% by HPLC. 100g of the crude oil was dissolved in 1L of anhydrous dichloromethane, and 50g of anhydrous pyridine, 6.5g of N, N-dimethyl-4-aminopyridine, and 91g of p-toluenesulfonyl chloride were added thereto, followed by stirring at room temperature for 24 hours. Cooling to-20 deg.CAnd keeping the temperature for 10 hours. Suction filtration at low temperature and elution with cooled petroleum ether to obtain a tan solid. The mixed solution of ethyl acetate-petroleum ether (volume ratio is 1. mp 80-82 deg.C, [ alpha ]] D 25 ＝-98.2 (c＝0.1，EtOH)； 1 H NMR (400 MHz, DMSO-d 6 ): δ 7.73 (m, 4H), 7.50 (m, 4H), 6.84 (m, 2H), 4.40 (s, 1H), 4.37 (s, 1H), 4.24 (s, 1H), 3.45 (d, J = 9.6Hz, 1H), 2.42 (m, 9H), 1.70 (m, 1H), 1.47-1.14 (m, 15H), 0.84 (t, J = 6.8 Hz, 3H); 13 C NMR (151 MHz, DMSO-d 6 ) δ 148.61, 146.86, 145.95, 142.49, 132.06, 130.28, 128.03, 126.93, 122.29, 111.29, 45.23, 37.36, 34.03, 30.40, 29.63, 29.19, 28.08, 23.15, 21.82, 21.17, 18.28, 13.85。
62 g of cannabidiol ditoluonate was dissolved in a mixed solvent of 300 mL of water and 300 mL of ethanol. 20 g of sodium hydroxide are added and the reaction is heated to 50 ℃ under nitrogen. After 10 hours, the reaction was cooled to room temperature and the pH was adjusted to 3-5 with dilute hydrochloric acid. Extracting with 200 mL of n-heptane, concentrating, cooling to-5 ℃, and precipitating a large amount of light yellow solid; recrystallization from n-heptane gave 25 g of a white solid. The content of cannabidiol detected by HPLC internal standard method is 98.2%, the purity is 99.7%, and tetrahydrocannabinol is not detected.
Example 3
Extracting pulverized industrial hemp dried flower and leaf with ethanol according to known method, concentrating, and distilling under reduced pressure to obtain industrial hemp crude oil. The CBD content was found to be 48% by HPLC. 100g of the crude oil was dissolved in 1L of anhydrous dichloromethane, and 50g of anhydrous pyridine, 6.5g of N, N-dimethyl-4-aminopyridine and 85g of p-nitrobenzoyl chloride were added thereto, followed by stirring at room temperature for 24 hours. Cooling to-15 deg.C and holding for 10h. Suction filtration at low temperature and rinsing with cooled petroleum ether gave a tan solid. And recrystallizing the mixed solution of ethyl acetate and petroleum ether (the volume ratio is 1). mp 57 to 59 ℃ [ alpha ]] D 25 ＝-68.9 (c＝0.1，EtOH)； 1 H NMR (400 MHz, DMSO-d 6 ): δ 8.44 (d, J = 8.2 Hz, 4H), 8.34 (d, J = 8.6 Hz, 4H), 7.10 (s, 2H), 5.03 (s, 1H), 4.57 (s, 1H), 4.47 (s, 1H), 3.49 (d, J = 9.0 Hz, 1H), 2.69-2.59 (m, 3H), 1.62 (m, 2H), 1.59 (m, 2H), 1.49 (s, 3H), 1.29 (m, 4H), 1.05 (s, 3H), 0.86 (t, J = 6.6 Hz, 3H); 13 C NMR (151 MHz, DMSO-d 6 ) δ 170.40, 163.17, 150.68, 149.34, 147.23, 142.24, 134.05, 133.24, 131.33, 125.99, 124.10, 123.70, 111.40, 59.81, 45.55, 38.17, 34.28, 30.81, 29.96, 29.44, 27.85, 22.87, 21.94, 19.67, 13.94。
62 g of cannabidiol dinitrobenzoate is taken and dissolved in a mixed solvent of 300 mL of water and 300 mL of ethanol. 20 g of sodium hydroxide are added and the reaction is heated to 50 ℃ under nitrogen. After 10 hours, the reaction was cooled to room temperature and the pH was adjusted to 3-5 with dilute hydrochloric acid. Extracting with 200 mL of n-heptane, concentrating, cooling to-5 deg.C, and precipitating a large amount of pale yellow solid; recrystallization from n-heptane gave 29 g of a white solid. The content of cannabidiol detected by HPLC internal standard method is 98.0%, the purity is 99.9%, and tetrahydrocannabinol is not detected.
The above examples show that the present invention does not require column chromatography purification of the crude oil, but rather, converts the crude oil into cannabidiol diester which is more easily crystallized by adding an acylating agent, so that the cannabidiol diester is separated out from the crude oil, recrystallized, and then hydrolyzed to obtain high purity cannabidiol. The method avoids the operation of column chromatography with poor reproducibility and economy, has low requirement on equipment and has good application prospect.
The embodiments described above are intended to facilitate a person of ordinary skill in the art in understanding and using the invention. It will be readily apparent to those skilled in the art that various modifications to these embodiments may be made, and the generic principles described herein may be applied to other embodiments without the use of the inventive faculty. Therefore, the present invention is not limited to the above embodiments, and those skilled in the art should make improvements and modifications within the scope of the present invention based on the disclosure of the present invention.
Claims (10)
1. A method for obtaining high-purity cannabidiol from industrial hemp is characterized in that an acylation reagent is added into crude oil extracted from the industrial hemp for acylation reaction, the crude oil is filtered after the reaction is finished, the solid obtained by filtering is recrystallized, and then the solid obtained by recrystallization is subjected to hydrolysis reaction to obtain the high-purity cannabidiol.
2. The method for obtaining cannabidiol in high purity from industrial cannabis sativa according to claim 1, wherein the acylation comprises the following steps: dissolving the hemp crude oil in a solvent, adding an acylation reagent, stirring at room temperature for 12-36 hours, cooling to-30 to-10 ℃, keeping for 2 to 20 hours, carrying out suction filtration at low temperature, and leaching a filter cake with the solvent to obtain the hemp crude oil.
3. A method of obtaining cannabidiol in high purity from industrial cannabis as claimed in claim 2, wherein the acylating agent is selected from one or more of benzoic acid, p-toluene sulfonic acid, p-nitrobenzoic acid, and carboxylic acid activated forms of anhydrides, acid halides or activated esters formed therefrom.
4. The method of claim 2, wherein the amount of the acylation agent is 1.2 to 5.0 times the molar amount of the cannabidiol contained in the crude oil, in terms of the amount of the cannabidiol.
5. The method for obtaining cannabidiol with high purity from industrial cannabis sativa as claimed in claim 2, wherein the solvent is one or more selected from C1-C20 hydrocarbons, C1-C20 alkyl halides, C1-C20 ethers, acetonitrile, N-dimethylformamide, acetone, pyridine, triethylamine and ethyl acetate.
6. The method for obtaining cannabidiol in high purity from industrial cannabis sativa as claimed in claim 5, wherein the solvent is n-hexane, dichloromethane or tetrahydrofuran.
7. The method for obtaining cannabidiol with high purity from industrial cannabis sativa according to claim 1, wherein the solvent used in the recrystallization process is selected from one or more of ethyl ether, methyl tert-butyl ether, ethyl acetate, butyl acetate, petroleum ether, n-heptane and n-hexane.
8. The method for obtaining cannabidiol with high purity from industrial cannabis sativa as claimed in claim 1, wherein the hydrolysis reaction comprises the steps of dissolving a solid obtained by recrystallization in a mixed solvent of water and ethanol, adding an alkali, heating the reaction solution to 45 to 55 ℃ under the protection of nitrogen, keeping for 8 to 12 hours, cooling the reaction solution to room temperature, adjusting the pH value to 3 to 5, extracting, concentrating an organic phase, cooling to precipitate a solid, and recrystallizing the obtained solid to obtain cannabidiol with high purity.
9. The method of claim 8, wherein the base is one or more of an inorganic base selected from sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and ammonia, or an organic base selected from one or more of triethylamine, pyridine, piperidine, and 1, 8-diazabicycloundec-7-ene.
10. The method for obtaining cannabidiol of high purity from industrial cannabis sativa as claimed in claim 9, wherein the amount of the base is 2 to 10 times the molar number of the cannabidiol diester to be hydrolyzed.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110629569.4A CN115504864A (en) | 2021-06-07 | 2021-06-07 | Method for obtaining high-purity cannabidiol from industrial cannabis sativa |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202110629569.4A CN115504864A (en) | 2021-06-07 | 2021-06-07 | Method for obtaining high-purity cannabidiol from industrial cannabis sativa |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN115504864A true CN115504864A (en) | 2022-12-23 |
Family
ID=84499001
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202110629569.4A Pending CN115504864A (en) | 2021-06-07 | 2021-06-07 | Method for obtaining high-purity cannabidiol from industrial cannabis sativa |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN115504864A (en) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116983264A (en) * | 2023-09-28 | 2023-11-03 | 中国农业科学院农产品加工研究所 | Embedding system of dihydrocannabidiol dibenzoate as well as preparation method and application thereof |
Citations (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101316832A (en) * | 2005-09-29 | 2008-12-03 | Amr科技公司 | Process for production of delta-9-tetrahydrocannabinol |
| CN104277917A (en) * | 2014-10-24 | 2015-01-14 | 汉康(云南)生物科技有限公司 | Extraction method and extraction device for cannabidiol-enriched industrial hemp essential oil |
| CN105008400A (en) * | 2013-03-14 | 2015-10-28 | 塞拉尼斯醋酸纤维有限公司 | Naturally derived mixed cellulose esters and methods relating thereto |
| CN106278828A (en) * | 2016-08-16 | 2017-01-04 | 云南汉素生物科技有限公司 | A kind of method extracting cannabidiol from industrial hemp floral leaf |
| CN106810426A (en) * | 2016-12-29 | 2017-06-09 | 暨明医药科技（苏州）有限公司 | A kind of synthetic method of cannabidiol |
| CN109646992A (en) * | 2019-01-28 | 2019-04-19 | 周继铭 | The method of cannabidiol enriched substance is extracted from industrial hemp |
| CN109678675A (en) * | 2019-02-25 | 2019-04-26 | 中国农业科学院麻类研究所 | A method of separation cannabidiol |
| CN110041172A (en) * | 2019-06-05 | 2019-07-23 | 云南绿新生物药业有限公司 | A kind of technique improving cannabidiol recovery rate using microbiological treatment hemp floral leaf |
| CN110041171A (en) * | 2019-05-31 | 2019-07-23 | 黑龙江阳光工业大麻研究院 | A method of extracting cannabidiol from industrial hemp leaf |
| CN110143855A (en) * | 2019-07-02 | 2019-08-20 | 黑龙江康源生物科技有限公司 | The isolation and purification method of cannabidiol in a kind of industrial hemp |
| CN110935191A (en) * | 2019-12-10 | 2020-03-31 | 中国农业科学院麻类研究所 | Method for extracting and purifying industrial hemp wax |
| CN111039761A (en) * | 2019-12-31 | 2020-04-21 | 江苏汉邦科技有限公司 | Method for purifying cannabidiol |
| CN111718243A (en) * | 2019-03-21 | 2020-09-29 | 大连博迈科技发展有限公司 | Device and method for preparing high-purity cannabidiol from industrial cannabis sativa |
| CN111718242A (en) * | 2019-03-21 | 2020-09-29 | 大连博迈科技发展有限公司 | CBD extraction device and method |
| CN111792981A (en) * | 2020-06-24 | 2020-10-20 | 云南麻省健康科学有限公司 | Method for purifying cannabidiol |
| CN111808670A (en) * | 2020-03-20 | 2020-10-23 | 浙江双子智能装备有限公司 | Method for extracting and purifying broad-spectrum hemp oil from hemp |
| CN111960930A (en) * | 2020-08-27 | 2020-11-20 | 哈尔滨工业大学 | Method for separating and purifying cannabidiol from industrial cannabis sativa leaves |
| CN111978157A (en) * | 2020-08-21 | 2020-11-24 | 滇麻生物科技(曲靖)有限公司 | Method for extracting and purifying cannabidiol from industrial cannabis sativa |
-
2021
- 2021-06-07 CN CN202110629569.4A patent/CN115504864A/en active Pending
Patent Citations (18)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101316832A (en) * | 2005-09-29 | 2008-12-03 | Amr科技公司 | Process for production of delta-9-tetrahydrocannabinol |
| CN105008400A (en) * | 2013-03-14 | 2015-10-28 | 塞拉尼斯醋酸纤维有限公司 | Naturally derived mixed cellulose esters and methods relating thereto |
| CN104277917A (en) * | 2014-10-24 | 2015-01-14 | 汉康(云南)生物科技有限公司 | Extraction method and extraction device for cannabidiol-enriched industrial hemp essential oil |
| CN106278828A (en) * | 2016-08-16 | 2017-01-04 | 云南汉素生物科技有限公司 | A kind of method extracting cannabidiol from industrial hemp floral leaf |
| CN106810426A (en) * | 2016-12-29 | 2017-06-09 | 暨明医药科技（苏州）有限公司 | A kind of synthetic method of cannabidiol |
| CN109646992A (en) * | 2019-01-28 | 2019-04-19 | 周继铭 | The method of cannabidiol enriched substance is extracted from industrial hemp |
| CN109678675A (en) * | 2019-02-25 | 2019-04-26 | 中国农业科学院麻类研究所 | A method of separation cannabidiol |
| CN111718243A (en) * | 2019-03-21 | 2020-09-29 | 大连博迈科技发展有限公司 | Device and method for preparing high-purity cannabidiol from industrial cannabis sativa |
| CN111718242A (en) * | 2019-03-21 | 2020-09-29 | 大连博迈科技发展有限公司 | CBD extraction device and method |
| CN110041171A (en) * | 2019-05-31 | 2019-07-23 | 黑龙江阳光工业大麻研究院 | A method of extracting cannabidiol from industrial hemp leaf |
| CN110041172A (en) * | 2019-06-05 | 2019-07-23 | 云南绿新生物药业有限公司 | A kind of technique improving cannabidiol recovery rate using microbiological treatment hemp floral leaf |
| CN110143855A (en) * | 2019-07-02 | 2019-08-20 | 黑龙江康源生物科技有限公司 | The isolation and purification method of cannabidiol in a kind of industrial hemp |
| CN110935191A (en) * | 2019-12-10 | 2020-03-31 | 中国农业科学院麻类研究所 | Method for extracting and purifying industrial hemp wax |
| CN111039761A (en) * | 2019-12-31 | 2020-04-21 | 江苏汉邦科技有限公司 | Method for purifying cannabidiol |
| CN111808670A (en) * | 2020-03-20 | 2020-10-23 | 浙江双子智能装备有限公司 | Method for extracting and purifying broad-spectrum hemp oil from hemp |
| CN111792981A (en) * | 2020-06-24 | 2020-10-20 | 云南麻省健康科学有限公司 | Method for purifying cannabidiol |
| CN111978157A (en) * | 2020-08-21 | 2020-11-24 | 滇麻生物科技(曲靖)有限公司 | Method for extracting and purifying cannabidiol from industrial cannabis sativa |
| CN111960930A (en) * | 2020-08-27 | 2020-11-20 | 哈尔滨工业大学 | Method for separating and purifying cannabidiol from industrial cannabis sativa leaves |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN116983264A (en) * | 2023-09-28 | 2023-11-03 | 中国农业科学院农产品加工研究所 | Embedding system of dihydrocannabidiol dibenzoate as well as preparation method and application thereof |
| CN116983264B (en) * | 2023-09-28 | 2023-12-22 | 中国农业科学院农产品加工研究所 | Embedding system of dihydrocannabidiol dibenzoate as well as preparation method and application thereof |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN106810426B (en) | Method for synthesizing cannabidiol | |
| CN102702220B (en) | Method for extracting arteannuic acid from artemisinin crystallization mother liquor | |
| CN106256824B (en) | Preparation method of high-purity delafloxacin meglumine salt | |
| CN115504864A (en) | Method for obtaining high-purity cannabidiol from industrial cannabis sativa | |
| CN116640088A (en) | Preparation method of high-purity Lei Fen narasin | |
| CN102453011A (en) | Preparation method of high-purity naringenin | |
| CN102050848A (en) | Method for preparing secoisolariciresinol diglucoside | |
| CN103897025A (en) | Preparation method of pidotimod | |
| CN111792981B (en) | Method for purifying cannabidiol | |
| CN102993135B (en) | A kind of purification process of orlistat | |
| CN107033114B (en) | Method for separating and purifying dihydromyricetin | |
| CN106588888B (en) | Method for preparing high-purity L-sunitinib malate | |
| CN114853593A (en) | Method for extracting high-purity nervonic acid from acer truncatum buge oil | |
| CN114989091A (en) | Preparation method of glutamyl ethyl imidazole | |
| CN105503986A (en) | Prednisolone acetate preparation method | |
| CN101805380B (en) | Method for preparing (3S, 5S)-2, 3-dihydroxyl-5-hydroxymethyl tetrahydrofuran triacetate | |
| CN107746408B (en) | Purification method of vinblastine sulfate | |
| CN105732547A (en) | Preparation method of dehydrated andrographolide diacid half ester basic salt | |
| CN105753820B (en) | A kind of method of purification of dehydroandrographolide succinate | |
| CN110759933A (en) | Preparation method of cefdinir impurity G | |
| CN104529908A (en) | Method for preparing rosuvastatin calcium | |
| EP3026047A1 (en) | Method for producing heterocyclic compound | |
| CN110183368A (en) | The synthetic method of (3R, 4S) -1- fluorenylmethyloxycarbonyl -4- N-ethyl pyrrole N -3- carboxylic acid suitable for industrialization | |
| CN111484460B (en) | Synthetic method of olanzapine related substance compound I and compound II | |
| CN111440173B (en) | Preparation method of PI3K inhibitor |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination |