CN113896616A - 一种大麻二酚的制备方法 - Google Patents
一种大麻二酚的制备方法 Download PDFInfo
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- CN113896616A CN113896616A CN202011218149.9A CN202011218149A CN113896616A CN 113896616 A CN113896616 A CN 113896616A CN 202011218149 A CN202011218149 A CN 202011218149A CN 113896616 A CN113896616 A CN 113896616A
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- cannabidiol
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- bis
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- 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 67
- 229950011318 cannabidiol Drugs 0.000 title claims abstract description 67
- 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 67
- 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 64
- 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 55
- 238000002360 preparation method Methods 0.000 title abstract description 9
- -1 olive alcohol diester Chemical class 0.000 claims abstract description 41
- 238000000034 method Methods 0.000 claims abstract description 22
- 238000005859 coupling reaction Methods 0.000 claims abstract description 13
- ALSTYHKOOCGGFT-KTKRTIGZSA-N (9Z)-octadecen-1-ol Chemical compound CCCCCCCC\C=C/CCCCCCCCO ALSTYHKOOCGGFT-KTKRTIGZSA-N 0.000 claims abstract description 9
- 125000004185 ester group Chemical group 0.000 claims abstract description 7
- 230000003301 hydrolyzing effect Effects 0.000 claims abstract description 4
- 238000006243 chemical reaction Methods 0.000 claims description 27
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 20
- IRMPFYJSHJGOPE-UHFFFAOYSA-N olivetol Chemical compound CCCCCC1=CC(O)=CC(O)=C1 IRMPFYJSHJGOPE-UHFFFAOYSA-N 0.000 claims description 20
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- MKPMHJQMNACGDI-VHSXEESVSA-N (1S,4R)-p-Mentha-2,8-dien-1-ol Chemical compound CC(=C)[C@@H]1CC[C@](C)(O)C=C1 MKPMHJQMNACGDI-VHSXEESVSA-N 0.000 claims description 17
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 15
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 9
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- 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 9
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- 238000010168 coupling process Methods 0.000 claims description 7
- 239000002841 Lewis acid Substances 0.000 claims description 6
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 claims description 6
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 6
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- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 6
- 230000008878 coupling Effects 0.000 claims description 6
- 150000007517 lewis acids Chemical class 0.000 claims description 6
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 5
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-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
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 4
- 238000004440 column chromatography Methods 0.000 claims description 4
- 238000004821 distillation Methods 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
- 238000001953 recrystallisation Methods 0.000 claims description 4
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 4
- KZMGYPLQYOPHEL-UHFFFAOYSA-N Boron trifluoride etherate Chemical compound FB(F)F.CCOCC KZMGYPLQYOPHEL-UHFFFAOYSA-N 0.000 claims description 3
- 150000005690 diesters Chemical class 0.000 claims description 3
- 229940098779 methanesulfonic acid Drugs 0.000 claims description 3
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- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 2
- XBDQKXXYIPTUBI-UHFFFAOYSA-M Propionate Chemical compound CCC([O-])=O XBDQKXXYIPTUBI-UHFFFAOYSA-M 0.000 claims description 2
- 125000001931 aliphatic group Chemical group 0.000 claims description 2
- 150000008378 aryl ethers Chemical class 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
- 239000012043 crude product Substances 0.000 claims description 2
- 235000014113 dietary fatty acids Nutrition 0.000 claims description 2
- 239000000194 fatty acid Substances 0.000 claims description 2
- 229930195729 fatty acid Natural products 0.000 claims description 2
- 150000004665 fatty acids Chemical class 0.000 claims description 2
- 230000003100 immobilizing effect Effects 0.000 claims description 2
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 2
- 238000011403 purification operation Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- 239000011973 solid acid Substances 0.000 claims description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 claims 3
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 3
- QGZKDVFQNNGYKY-UHFFFAOYSA-N Ammonia Chemical compound N QGZKDVFQNNGYKY-UHFFFAOYSA-N 0.000 claims 2
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims 2
- NQRYJNQNLNOLGT-UHFFFAOYSA-N Piperidine Chemical compound C1CCNCC1 NQRYJNQNLNOLGT-UHFFFAOYSA-N 0.000 claims 2
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 claims 2
- 150000007529 inorganic bases Chemical class 0.000 claims 2
- 150000007530 organic bases Chemical class 0.000 claims 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims 1
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 claims 1
- 239000002202 Polyethylene glycol Substances 0.000 claims 1
- 229910021529 ammonia Inorganic materials 0.000 claims 1
- 150000001875 compounds Chemical class 0.000 claims 1
- 230000007062 hydrolysis Effects 0.000 claims 1
- 238000006460 hydrolysis reaction Methods 0.000 claims 1
- 239000002608 ionic liquid Substances 0.000 claims 1
- 229920001223 polyethylene glycol Polymers 0.000 claims 1
- 238000006116 polymerization reaction Methods 0.000 claims 1
- 239000008096 xylene Substances 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 12
- 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 12
- 229960004242 dronabinol Drugs 0.000 abstract description 12
- 239000003814 drug Substances 0.000 abstract description 7
- 229940079593 drug Drugs 0.000 abstract description 6
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical compound [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 description 36
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 27
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 16
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical class [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 12
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 12
- KJIFKLIQANRMOU-UHFFFAOYSA-N oxidanium;4-methylbenzenesulfonate Chemical compound O.CC1=CC=C(S(O)(=O)=O)C=C1 KJIFKLIQANRMOU-UHFFFAOYSA-N 0.000 description 10
- 239000007787 solid Substances 0.000 description 10
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 9
- 238000005160 1H NMR spectroscopy Methods 0.000 description 9
- 239000012044 organic layer Substances 0.000 description 8
- 239000000243 solution Substances 0.000 description 8
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 description 6
- IMNFDUFMRHMDMM-UHFFFAOYSA-N N-Heptane Chemical compound CCCCCCC IMNFDUFMRHMDMM-UHFFFAOYSA-N 0.000 description 6
- 239000005711 Benzoic acid Substances 0.000 description 5
- 235000010233 benzoic acid Nutrition 0.000 description 5
- OTLNPYWUJOZPPA-UHFFFAOYSA-N 4-nitrobenzoic acid Chemical compound OC(=O)C1=CC=C([N+]([O-])=O)C=C1 OTLNPYWUJOZPPA-UHFFFAOYSA-N 0.000 description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-M Acetate Chemical compound CC([O-])=O QTBSBXVTEAMEQO-UHFFFAOYSA-M 0.000 description 4
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical compound COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 4
- 229920006395 saturated elastomer Polymers 0.000 description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 description 4
- 238000003756 stirring Methods 0.000 description 4
- 230000002378 acidificating effect Effects 0.000 description 3
- 239000007864 aqueous solution Substances 0.000 description 3
- 239000012230 colorless oil Substances 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 239000003208 petroleum Substances 0.000 description 3
- 238000003786 synthesis reaction Methods 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
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 2
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- 230000015572 biosynthetic process Effects 0.000 description 2
- WTEOIRVLGSZEPR-UHFFFAOYSA-N boron trifluoride Chemical compound FB(F)F WTEOIRVLGSZEPR-UHFFFAOYSA-N 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 239000012535 impurity Substances 0.000 description 2
- 125000001160 methoxycarbonyl group Chemical group [H]C([H])([H])OC(*)=O 0.000 description 2
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- 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
- 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
- 229910015900 BF3 Inorganic materials 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010039897 Sedation Diseases 0.000 description 1
- 230000000259 anti-tumor effect Effects 0.000 description 1
- PASDCCFISLVPSO-UHFFFAOYSA-N benzoyl chloride Chemical compound ClC(=O)C1=CC=CC=C1 PASDCCFISLVPSO-UHFFFAOYSA-N 0.000 description 1
- 239000006227 byproduct Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
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- 238000000605 extraction Methods 0.000 description 1
- 238000001914 filtration Methods 0.000 description 1
- 235000013305 food Nutrition 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000009776 industrial production Methods 0.000 description 1
- 240000004308 marijuana Species 0.000 description 1
- 230000003340 mental effect Effects 0.000 description 1
- 239000012046 mixed solvent Substances 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 150000002989 phenols Chemical class 0.000 description 1
- 230000001376 precipitating effect Effects 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 239000011541 reaction mixture Substances 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000036280 sedation Effects 0.000 description 1
- 238000000926 separation method Methods 0.000 description 1
- 238000010898 silica gel chromatography Methods 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
- C07C37/01—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis
- C07C37/055—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group
- C07C37/0555—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by replacing functional groups bound to a six-membered aromatic ring by hydroxy groups, e.g. by hydrolysis the substituted group being bound to oxygen, e.g. ether group being esterified hydroxy groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C201/00—Preparation of esters of nitric or nitrous acid or of compounds containing nitro or nitroso groups bound to a carbon skeleton
- C07C201/06—Preparation of nitro compounds
- C07C201/12—Preparation of nitro compounds by reactions not involving the formation of nitro groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/28—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reaction of hydroxy compounds with sulfonic acids or derivatives thereof
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
- C07C303/26—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids
- C07C303/30—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of esters of sulfonic acids by reactions not involving the formation of esterified sulfo groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C67/00—Preparation of carboxylic acid esters
- C07C67/28—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group
- C07C67/297—Preparation of carboxylic acid esters by modifying the hydroxylic moiety of the ester, such modification not being an introduction of an ester group by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/12—Systems containing only non-condensed rings with a six-membered ring
- C07C2601/16—Systems containing only non-condensed rings with a six-membered ring the ring being unsaturated
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- Organic Chemistry (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
本发明属于医药技术领域,具体涉及一种大麻二酚的制备方法。本发明方法包括,将橄榄醇转化成橄榄醇双酯,然后再经偶合反应得到大麻二酚双酯,大麻二酚双酯经过纯化后,水解去除两个酯基,得到高纯度的大麻二酚。本发明的方法条件温和、易于操作,制得的大麻二酚纯度高,且能完全避免四氢大麻酚的生成,具有良好的应用前景。
Description
技术领域
本发明属于医药技术领域,具体涉及一种大麻二酚的制备方法。
背景技术
现有技术公开了大麻二酚(CBD)最初是从大麻中分离得到的一种亲脂性的酚类化合物。近年的研究表明,CBD无精神活性,在医药、化妆品及保健食品中有很大的应用潜力;以医药领域为例,CBD显示了较好的抗炎、抗抑郁、抗癫痫、镇静、抗肿瘤等药理活性。目前,临床上使用的含CBD的药物有Sativex、Epidiolex等,此外,处于临床实验阶段的CBD类药物达数十种之多。
CBD的获取途径有植物提取、生物合成及化学合成;实践显示,前述两种途径得到的CBD杂质比较多,较难进行质量控制,相比而言,化学合成方法获得的产物较为单一且杂质可控,在原料药的供应上有很大优势。
化学合成CBD主要有以下方法:
1)早期的文献(Petrzilka等,Helv.Chim.Acta 1967,50,719;Baek等,Tetrahedron Lett.1985,26,1083)使用橄榄醇(反应式I中A1)与(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇(反应式I中B1)在酸催化下直接偶合,可以得到CBD(如“反应式I”所示);该种方法的优点是路线简短,但缺点也非常明显,如:偶合中会生成大量二取代副产物及错位取代的异构体、从而造成偶合收率过低;更严重的是,生成的CBD在正常偶合反应所需的酸性条件下,会不可避免地继续环化生成四氢大麻酚(THC)(如“副反应I”所示)。
2)如下式“反应式II”所示,专利US 20100298579(反应式II中R1=CO2Me,R2=H)、US 20150336874(反应式I中R1=CO2Me,R2=H)、US 2017008868A1(反应式II中R1=R2=Cl,Br,I)及US 20070093665(反应式II中R1=CO2Et,R2=H)等,使用取代的橄榄醇(反应式I中A2)与B1在酸性条件下反应,偶合生成中间体C1,然后再将C1中的R1(或R1+R2)脱除,可以得到CBD;采用该类方法,其优点是偶合收率较反应式I的方法有所提高;实践显示,虽然该种方法不会在偶合步骤中生成THC,但仍会生成少量取代的THC(如“副反应II”所示的C2);实践表明,如果不能将混在主产物C1中的C2彻底去除,在将C1脱除R1(或R1+R2)的过程中,C2又会转化成THC;由于C1和C2的性质非常接近,二者要实现完全分离非常困难,因此,使用上述策略也很难完全避免THC的生成。
通过分析以上现有的技术路线,可以看出,生成THC的根本原因是橄榄醇中游离的羟基在酸性条件下对分子内的环外双键进攻所致。因此,如果将两个酚羟基封闭起来,就可以完全避免THC的生成。
基于现有技术的基础与现状,本申请的发明人拟提供一种新的制备大麻二酚的方法,以解决现有技术难以完全避免THC生成的问题。
发明内容
本发明的目的在于基于现有技术的基础与现状,提供一种新的制备大麻二酚的方法,本发明方法可以方便进行工业化生产,解决现有技术很难完全避免THC生成的问题。
本发明的技术方案是通过以下方式施现。
具体的,本发明的一种大麻二酚的制备方法,其包括:首先将橄榄醇转化成橄榄醇双酯,然后再经偶合反应得到大麻二酚双酯;大麻二酚双酯经纯化后,水解去除两个酯基,制得大麻二酚;所述的大麻二酚双酯纯化操作中,包括重结晶、柱层析或蒸馏。
更具体的,本发明的制备大麻二酚的方法包括S1、S2、S3三个步骤。
首先,步骤S1,橄榄醇A1转化成橄榄醇双酯A3;所述的双酯可以是双-乙酸酯、双-苯甲酸酯、双-对甲苯磺酸酯、双-对硝基苯甲酸酯;
继而,步骤S2,橄榄醇双酯A3与(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇(B1)或B1的衍生物(S2中以B2表示),包括B1的甲基醚、乙基醚、C3-C10的脂肪醚或芳香醚,乙酸酯、丙酸酯、C4-C15的脂肪酸或芳香酸酯,在酸催化下进行偶合得到CBD的双酯C3;所述的酸催化可以使用质子酸或路易斯酸,其中质子酸优选盐酸、硫酸、对甲苯磺酸、甲磺酸,路易斯酸优选三氟化硼乙醚、氯化铝,或者将质子酸、路易斯酸固载而成的固体酸;得到的C3粗品通过柱层析、重结晶或蒸馏进行纯化;
第三步S3,经过纯化的CBD双酯(C3)水解去除酯基得到CBD。
本发明提供了一种新的制备大麻二酚的方法,该方法条件温和、易于操作,制得的大麻二酚纯度高,且能完全避免四氢大麻酚的生成,本发明方法可以方便进行工业化生产,解决现有技术很难完全避免THC生成的问题,具有良好的应用前景。
具体实施方式
为了更好地理解本发明,下面结合具体实施例对本发明做进一步说明。
第一步(S1),橄榄醇双酯的制备:
实施例1:橄榄醇双-(乙酸)-酯
橄榄醇18.03g(0.1mol)溶于300mL无水吡啶,并降温至0度。通过滴液漏斗缓缓加入30.63g醋酸酐,控制反应体系温度不超过10度。加完醋酸酐后,控制反应体系温度在20-30度并继续搅拌20小时。减压浓缩,然后将残余物溶解于500mL乙酸乙酯,依次以水、稀盐酸、饱和碳酸氢钠溶液洗涤。以无水硫酸钠干燥有机层,过滤并减压浓缩后,得到23.26g无色油状物。以橄榄醇计,收率为88%;1H NMR(400MHz,DMSO-d6):δ6.87(s,2H),6.79(s,1H),2.57(t,J=7.2Hz,2H),2.45(s,6H),1.55(m,2H),1.28(m,4H),0.86(t,J=6.9Hz,3H);13CNMR(150MHz,DMSO-d6):δ168.95,150.73,144.91,119.03,113.16,34.63,30.77,30.16,21.92,20.79,13.86.。
实施例2:橄榄醇双-(苯甲酸)-酯
橄榄醇18.03g(0.1mol)溶于300mL无水吡啶,并降温至0度。通过滴液漏斗缓缓加入42.17g苯甲酰氯,控制反应体系温度不超过10度。滴加完成后,控制反应体系温度在20-30度并继续搅拌20小时。减压浓缩,然后将残余物溶解于500mL乙酸乙酯,依次以水、稀盐酸、饱和碳酸氢钠溶液洗涤。以无水硫酸钠干燥有机层,过滤并减压浓缩后,得到34.96g无色油状物。以橄榄醇计,收率90%;1H NMR(400MHz,DMSO-d6):δ8.11(d,J=7.2Hz,4H),7.73(t,J=6.7Hz,2H),7.59(t,J=7.5Hz,4H),7.12(s,1H),7.08(s,2H),2.62(t,J=7.1Hz,2H),1.58(m,2H),1.28(m,4H),0.84(t,J=6.9Hz,3H);13C NMR(150MHz,DMSO-d6):δ164.40,150.92,145.26,134.13,129.82,129.00,128.80,119.44,113.45,34.71,30.81,30.18,21.94,13.90.。
实施例3:橄榄醇双-(对甲苯磺酸)-酯
橄榄醇18.03g(0.1mol)溶于300mL无水吡啶,并降温至0度。分批加入对甲苯磺酰氯57.20g,并控制反应体系温度不超过10度。加料完成后,控制反应体系温度在20-30度并继续搅拌20小时。减压浓缩,然后将残余物溶解于500mL乙酸乙酯,依次以水、稀盐酸、饱和碳酸氢钠溶液洗涤。以无水硫酸钠干燥有机层,过滤并减压浓缩后,得到45.44g白色固体。以橄榄醇计,收率93%;mp 67~69℃;1H NMR(400MHz,DMSO-d6):δ7.65-7.63(m,4H),7.46-7.43(m,4H),6.71-6.65(m,3H),2.40-2.36(m,8H),1.20-1.17(m,4H),0.80(m,2H),0.80(t,J=6.9Hz,3H);13C NMR(151MHz,DMSO-d6)δ148.92,146.19,146.04,130.72,130.19,128.30,121.05,113.56,34.13,30.15,29.81,21.75,21.16,13.76.。
实施例4:橄榄醇双-(对硝基苯甲酸)-酯
橄榄醇18.03g(0.1mol)溶于300mL无水吡啶,并降温至0度。分批加入55.67g对硝基苯甲酰氯,并控制反应体系温度不超过10度。加料完成后,控制反应体系温度在20-30度并继续搅拌20小时。减压浓缩,然后将残余物溶解于500mL乙酸乙酯,依次以水、稀盐酸、饱和碳酸氢钠溶液洗涤。以无水硫酸钠干燥有机层,过滤并减压浓缩后,得到43.06g白色固体。以橄榄醇计,收率90%;mp 112~114℃;1H NMR(400MHz,DMSO-d6):δ8.43-8.40(m,4H),8.37-8.35(m,4H),7.25(m,1H),7.20(m,1H),2.66(t,J=7.3Hz,2H),1.61(m,2H),1.30(m,4H),0.87(t,J=6.9Hz,3H);13C NMR(151MHz,DMSO-d6)δ163.03,150.65,145.53,134.32,131.35,124.05,119.66,113.28,34.71,30.80,30.14,21.94,13.92.。
第二步(S2),大麻二酚双酯的制备:
实施例5:大麻二酚双-(乙酸)-酯
将26.43g橄榄醇双-(乙酸)-酯溶于500mL二氯甲烷并降温到-10度。加入一水合对甲苯磺酸1.90g,然后在4小时内缓缓滴加18.27g(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇并保持反应体系温度不高于-5度。滴加结束后,使其自然升温,在反应体系不高于20度的情况下,继续搅拌10小时。依次以饱和碳酸氢钠水溶液、水洗涤反应液,有机层干燥浓缩,所得残余物进行硅胶柱层析,得到25.9g无色油状物,收率65%。[α]D 25=-96.1(c=0.1,EtOH);1HNMR(400MHz,DMSO-d6):δ6.75(s,2H),4.95(s,1H),4.46(s,1H),4.37(s,1H),3.41(m,1H),2.61(m,1H),2.18(m,7H),1.98(m,1H),1.68-1.55(m,10H),1.26(m,4H),0.85(t,J=6.9Hz,3H);13C NMR(151MHz,DMSO-d6)δ169.05,149.44,147.38,141.43,132.49,125.90,124.06,111.00,45.23,37.44,34.20,30.79,29.99,29.79,28.07,23.20,21.91,20.63,18.94,13.91.
其它条件不变,将(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇替换为相同摩尔数的(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇甲醚、(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇乙酸酯、(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇苄基醚、(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇苯甲酸酯,同样得到大麻二酚双-(乙酸)-酯,收率依次为:61%、69%、53%、48%;
其它条件不变,将溶剂二氯甲烷替换为二氯乙烷、甲苯、乙腈、乙醚、四氢呋喃,同样得到大麻二酚双-(乙酸)-酯,收率依次为43%、68%、51%、55%、59%;
其它条件不变,将一水合对甲苯磺酸替换为等摩尔数的甲磺酸、三氟化硼乙醚、氯化铝,同样得到大麻二酚双-(乙酸)-酯,收率依次为66%、47%、44%。
实施例6:大麻二酚双-(苯甲酸)-酯
将38.85g橄榄醇双-(苯甲酸)-酯溶于700mL二氯甲烷并降温到-10度。加入一水合对甲苯磺酸1.90g,然后在4小时内缓缓滴加18.27g(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇并保持反应体系温度不高于-5度。滴加结束后,使其自然升温,在反应体系不高于20度的情况下,继续搅拌10小时。依次以饱和碳酸氢钠水溶液、水洗涤反应液,有机层干燥浓缩,得白色固体。以乙酸乙酯-石油醚重结晶,得37.11g白色固体,收率71%;mp100~102℃;[α]D 25=-76.0(c=0.1,EtOH);1HNMR(400MHz,DMSO-d6):δ8.06(d,J=8.0Hz,4H),7.70(t,J=7.9Hz,2H),7.57(t,J=8.0Hz,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=6.8Hz,3H);13C NMR(151MHz,DMSO-d6)δ164.52,149.59,147.24,141.95,134.13,133.05,129.81,129.01,126.24,123.62,111.29,45.46,38.05,34.29,30.86,30.02,29.47,28.01,22.79,21.95,19.41,13.95.
其它条件不变,将(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇替换为(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇甲醚(用量为19.95g),同样得到大麻二酚双-(苯甲酸)-酯,收率为51%;
其它条件不变,将(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇替换为(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇乙酸酯(用量为23.31g),同样得到大麻二酚双-(乙酸)-酯,收率为59%。
实施例7:大麻二酚双-(对甲苯磺酸)-酯
将48.86g橄榄醇双-(对甲苯磺酸)-酯溶于1L二氯甲烷并降温到-10度。加入一水合对甲苯磺酸1.90g,然后在4小时内缓缓滴加18.27g(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇并保持反应体系温度不高于-5度。滴加结束后,使其自然升温,在反应体系不高于20度的情况下,继续搅拌10小时。依次以饱和碳酸氢钠水溶液、水洗涤反应液,有机层干燥浓缩得白色固体。以乙酸乙酯-石油醚重结晶,得37.37g白色固体,收率60%;mp 80~82℃;[α]D 25=-98.2(c=0.1,EtOH);1H NMR(400MHz,DMSO-d6):δ7.73(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=6.8Hz,3H);13C NMR(151MHz,DMSO-d6)δ148.61,146.86,145.95,142.49,132.06,130.28,128.03,126.93,122.29,111.29,45.23,37.36,34.03,30.40,29.63,29.19,28.08,23.15,21.82,21.17,18.28,13.85.
其它条件不变,将(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇替换为(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇甲醚(用量为19.95g),同样得到大麻二酚双-(苯甲酸)-酯,收率为48%;
其它条件不变,将(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇替换为(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇乙酸酯(用量为23.31g),同样得到大麻二酚双-(乙酸)-酯,收率为57%。
实施例8:大麻二酚双-(对硝基苯甲酸)-酯
将47.85g橄榄醇双-(对硝基苯甲酸)-酯溶于1L二氯甲烷并降温到-10度。加入一水合对甲苯磺酸1.90g,然后在4小时内缓缓滴加18.27g(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇并保持反应体系温度不高于-5度。滴加结束后,使其自然升温,在反应体系不高于20度的情况下,继续搅拌10小时。依次以饱和碳酸氢钠水溶液、水洗涤反应液,有机层干燥浓缩得白色固体。以乙酸乙酯-石油醚重结晶,得38.6g白色固体,收率63%;mp57~59℃;[α]D 25=-68.9(c=0.1,EtOH);1H NMR(400MHz,DMSO-d6):δ8.44(d,J=8.2Hz,4H),8.34(d,J=8.6Hz,4H),7.10(s,2H),5.03(s,1H),4.57(s,1H),4.47(s,1H),3.49(d,J=9.0Hz,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=6.6Hz,3H);13C NMR(151MHz,DMSO-d6)δ170.40,163.17,150.68,149.34,147.23,142.24,134.05,133.24,131.33,125.99,124.10,123.70,111.40,59.81,45.55,38.17,34.28,30.81,29.96,29.44,27.85,22.87,21.94,19.67,13.94.
其它条件不变,将(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇替换为(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇甲醚(用量为19.95g),同样得到大麻二酚双-(苯甲酸)-酯,收率为60%;
其它条件不变,将(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇替换为(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇乙酸酯(用量为23.31g),同样得到大麻二酚双-(乙酸)-酯,收率为66%。
第三步(S3),大麻二酚的制备:
实施例9:由大麻二酚双-(乙酸)-酯制备大麻二酚
取大麻二酚双-(乙酸)-酯39.85g,溶于200mL水和200mL乙醇的混合溶剂。加入20g氢氧化钠,并在氮气保护下将反应液加热至50度。10小时后,将反应液冷却至室温,并以稀盐酸调节pH值至3-5。以200mL正庚烷进行萃取,并浓缩至100mL左右,降温至-5度,析出大量浅黄色固体;以正庚烷重结晶,得22g白色固体,收率70%;HPLC纯度99.9%;mp 67~68℃;[α]D 25=-131.9(c=0.1,EtOH);1H NMR(400MHz,DMSO-d6):δ8.68(s,2H),6.01(s,2H),5.08(s,1H),4.48(s,1H),4.40(s,1H),3.81(d,J=8.9Hz,1H),2.99(m,1H),2.29(t,J=7.6Hz,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=6.9Hz,3H);13C NMR(151MHz,DMSO-d6)δ156.25,149.12,140.16,130.02,126.86,114.11,109.65,106.58,43.64,35.52,34.89,31.00,30.28,29.47,23.28,21.99,19.22,13.92.
将实施例9中的大麻二酚双-(乙酸)-酯替换为等摩尔数的大麻二酚双-(苯甲酸)-酯、大麻二酚双-(对甲苯磺酸)-酯或大麻二酚双-(对硝基苯甲酸)-酯,其它条件不变,同样可得大麻二酚。
将实施例9中的乙醇替换为等体积数的异丙醇、乙腈、乙二醇、乙二醇二甲醚、四氢呋喃、丙酮,其它条件不变,同样可得到大麻二酚。
将实施例9中的氢氧化钠替换为等摩尔数氢氧化钾、碳酸钠、碳酸钾、碳酸铯、三乙胺、1,8-二氮杂二环十一碳-7-烯,其它条件不变,同样可得到大麻二酚。
Claims (7)
2.如权利要求1所述的制备方法,其特征在于,所述的橄榄醇双酯选自双-乙酸酯、双-苯甲酸酯、双-对甲苯磺酸酯、双-对硝基苯甲酸酯。
3.如权利要求1或2所述的制备方法,其特征在于,所述的偶合反应中使用所述的橄榄醇双酯,与选自如下的化合物进行偶合:(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇,(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇的甲基醚、乙基醚、C3-C10的脂肪醚或芳香醚,(1S,4R)-1-甲基-4-(1-甲基乙烯基)-2-环己烯-1-醇的乙酸酯、丙酸酯、C4-C15的脂肪酸或芳香酸酯。
4.如权利要求1所述的制备方法,其特征在于,所述的偶合反应在如下溶剂或其组合中施现:二氯甲烷、氯仿、二氯乙烷、乙醚、叔丁基甲基醚、苯、甲苯、二甲苯、氯苯、乙腈、N,N-二甲基甲酰胺、四氢呋喃、丙酮、乙酸乙酯。
5.如权利要求1所述的制备方法,其特征在于,所述的偶合反应中使用质子酸或路易斯酸催化;其中质子酸选自盐酸、硫酸、对甲苯磺酸、甲磺酸,所述的路易斯酸选自三氟化硼乙醚、氯化铝;或者将质子酸、路易斯酸固载而成的固体酸。
6.如权利要求1所述的制备方法,其特征在于,其中大麻二酚双酯水解去除酯基采用的溶剂是水、C1-C10的醇、乙二醇、聚合度为2-10的聚乙二醇、乙二醇二甲醚、乙腈、N,N-二甲基甲酰胺、四氢呋喃、丙酮、离子液体或其组合。
7.如权利要求1所述的制备方法,其特征在于,其中大麻二酚双酯水解去除酯基采用的碱为无机碱或有机碱,其中无机碱选自氢氧化钠、氢氧化钾、碳酸钠、碳酸钾、碳酸铯、氨水;有机碱选自三乙胺、吡啶、哌啶、1,8-二氮杂二环十一碳-7-烯。
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