CN112111025B - 一种大麻二酚环糊精偶合物及其制备方法 - Google Patents
一种大麻二酚环糊精偶合物及其制备方法 Download PDFInfo
- Publication number
- CN112111025B CN112111025B CN202011045913.7A CN202011045913A CN112111025B CN 112111025 B CN112111025 B CN 112111025B CN 202011045913 A CN202011045913 A CN 202011045913A CN 112111025 B CN112111025 B CN 112111025B
- Authority
- CN
- China
- Prior art keywords
- cyclodextrin
- cannabidiol
- mono
- deoxy
- conjugate
- 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.)
- Active
Links
- 229950011318 cannabidiol Drugs 0.000 title claims abstract description 145
- 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 141
- 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 141
- 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 141
- 229920000858 Cyclodextrin Polymers 0.000 title claims abstract description 118
- 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 115
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical compound O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 title claims abstract description 76
- 238000002360 preparation method Methods 0.000 title claims abstract description 36
- 239000003795 chemical substances by application Substances 0.000 claims abstract description 12
- 239000003960 organic solvent Substances 0.000 claims abstract description 12
- 150000001732 carboxylic acid derivatives Chemical class 0.000 claims abstract description 10
- 239000003513 alkali Substances 0.000 claims abstract description 9
- 238000006243 chemical reaction Methods 0.000 claims abstract description 9
- 230000009471 action Effects 0.000 claims abstract description 4
- 238000007112 amidation reaction Methods 0.000 claims abstract description 3
- 239000001116 FEMA 4028 Substances 0.000 claims description 38
- 229960004853 betadex Drugs 0.000 claims description 38
- -1 hexafluorophosphate Chemical compound 0.000 claims description 35
- 238000001035 drying Methods 0.000 claims description 33
- 239000002244 precipitate Substances 0.000 claims description 23
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 17
- 238000003756 stirring Methods 0.000 claims description 17
- 238000001914 filtration Methods 0.000 claims description 16
- 238000005406 washing Methods 0.000 claims description 15
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 14
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 9
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 9
- ZCSHNCUQKCANBX-UHFFFAOYSA-N lithium diisopropylamide Chemical compound [Li+].CC(C)[N-]C(C)C ZCSHNCUQKCANBX-UHFFFAOYSA-N 0.000 claims description 8
- HTZCNXWZYVXIMZ-UHFFFAOYSA-M benzyl(triethyl)azanium;chloride Chemical compound [Cl-].CC[N+](CC)(CC)CC1=CC=CC=C1 HTZCNXWZYVXIMZ-UHFFFAOYSA-M 0.000 claims description 7
- 239000002904 solvent Substances 0.000 claims description 7
- QOSSAOTZNIDXMA-UHFFFAOYSA-N Dicylcohexylcarbodiimide Chemical group C1CCCCC1N=C=NC1CCCCC1 QOSSAOTZNIDXMA-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- 239000003054 catalyst Substances 0.000 claims description 6
- 239000012043 crude product Substances 0.000 claims description 6
- 229920001450 Alpha-Cyclodextrin Polymers 0.000 claims description 5
- 150000008065 acid anhydrides Chemical class 0.000 claims description 5
- 229940043377 alpha-cyclodextrin Drugs 0.000 claims description 5
- WHGYBXFWUBPSRW-FOUAGVGXSA-N beta-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO WHGYBXFWUBPSRW-FOUAGVGXSA-N 0.000 claims description 5
- 235000011175 beta-cyclodextrine Nutrition 0.000 claims description 5
- 229940080345 gamma-cyclodextrin Drugs 0.000 claims description 5
- BDNKZNFMNDZQMI-UHFFFAOYSA-N 1,3-diisopropylcarbodiimide Chemical compound CC(C)N=C=NC(C)C BDNKZNFMNDZQMI-UHFFFAOYSA-N 0.000 claims description 3
- FALRKNHUBBKYCC-UHFFFAOYSA-N 2-(chloromethyl)pyridine-3-carbonitrile Chemical compound ClCC1=NC=CC=C1C#N FALRKNHUBBKYCC-UHFFFAOYSA-N 0.000 claims description 3
- BGRWYRAHAFMIBJ-UHFFFAOYSA-N diisopropylcarbodiimide Natural products CC(C)NC(=O)NC(C)C BGRWYRAHAFMIBJ-UHFFFAOYSA-N 0.000 claims description 3
- KWYUFKZDYYNOTN-UHFFFAOYSA-M potassium hydroxide Substances [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 3
- 239000011734 sodium Substances 0.000 claims description 3
- QDRKDTQENPPHOJ-UHFFFAOYSA-N sodium ethoxide Chemical compound [Na+].CC[O-] QDRKDTQENPPHOJ-UHFFFAOYSA-N 0.000 claims description 3
- 229940014800 succinic anhydride Drugs 0.000 claims description 3
- ASOKPJOREAFHNY-UHFFFAOYSA-N 1-Hydroxybenzotriazole Chemical compound C1=CC=C2N(O)N=NC2=C1 ASOKPJOREAFHNY-UHFFFAOYSA-N 0.000 claims description 2
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 claims description 2
- JPSKCQCQZUGWNM-UHFFFAOYSA-N 2,7-Oxepanedione Chemical compound O=C1CCCCC(=O)O1 JPSKCQCQZUGWNM-UHFFFAOYSA-N 0.000 claims description 2
- OFNISBHGPNMTMS-UHFFFAOYSA-N 3-methylideneoxolane-2,5-dione Chemical compound C=C1CC(=O)OC1=O OFNISBHGPNMTMS-UHFFFAOYSA-N 0.000 claims description 2
- DFATXMYLKPCSCX-UHFFFAOYSA-N 3-methylsuccinic anhydride Chemical compound CC1CC(=O)OC1=O DFATXMYLKPCSCX-UHFFFAOYSA-N 0.000 claims description 2
- WUMMIJWEUDHZCL-UHFFFAOYSA-N 3-prop-2-enyloxolane-2,5-dione Chemical compound C=CCC1CC(=O)OC1=O WUMMIJWEUDHZCL-UHFFFAOYSA-N 0.000 claims description 2
- XLSGYCWYKZCYCK-UHFFFAOYSA-N 4-(2-methylpropyl)oxane-2,6-dione Chemical compound CC(C)CC1CC(=O)OC(=O)C1 XLSGYCWYKZCYCK-UHFFFAOYSA-N 0.000 claims description 2
- MGICRVTUCPFQQZ-UHFFFAOYSA-N 4-methyloxane-2,6-dione Chemical compound CC1CC(=O)OC(=O)C1 MGICRVTUCPFQQZ-UHFFFAOYSA-N 0.000 claims description 2
- 239000005977 Ethylene Substances 0.000 claims description 2
- 238000004440 column chromatography Methods 0.000 claims description 2
- VANNPISTIUFMLH-UHFFFAOYSA-N glutaric anhydride Chemical compound O=C1CCCC(=O)O1 VANNPISTIUFMLH-UHFFFAOYSA-N 0.000 claims description 2
- KKHUSADXXDNRPW-UHFFFAOYSA-N malonic anhydride Chemical compound O=C1CC(=O)O1 KKHUSADXXDNRPW-UHFFFAOYSA-N 0.000 claims description 2
- 239000012528 membrane Substances 0.000 claims description 2
- 239000012074 organic phase Substances 0.000 claims description 2
- 238000000926 separation method Methods 0.000 claims description 2
- 150000001718 carbodiimides Chemical group 0.000 claims 2
- 150000003839 salts Chemical class 0.000 claims 2
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical compound C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 claims 1
- 238000001212 derivatisation Methods 0.000 claims 1
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 46
- 238000009776 industrial production Methods 0.000 abstract description 2
- 239000002994 raw material Substances 0.000 abstract 1
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 45
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 24
- 239000000243 solution Substances 0.000 description 17
- PIICEJLVQHRZGT-UHFFFAOYSA-N Ethylenediamine Chemical compound NCCN PIICEJLVQHRZGT-UHFFFAOYSA-N 0.000 description 16
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 16
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 description 13
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 12
- 238000005481 NMR spectroscopy Methods 0.000 description 11
- 239000000047 product Substances 0.000 description 11
- 239000000706 filtrate Substances 0.000 description 10
- 238000000034 method Methods 0.000 description 9
- 239000002808 molecular sieve Substances 0.000 description 8
- URGAHOPLAPQHLN-UHFFFAOYSA-N sodium aluminosilicate Chemical compound [Na+].[Al+3].[O-][Si]([O-])=O.[O-][Si]([O-])=O URGAHOPLAPQHLN-UHFFFAOYSA-N 0.000 description 8
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 7
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 7
- 150000001875 compounds Chemical class 0.000 description 7
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000010521 absorption reaction Methods 0.000 description 6
- 125000003368 amide group Chemical group 0.000 description 6
- 230000008878 coupling Effects 0.000 description 5
- 238000010168 coupling process Methods 0.000 description 5
- 238000005859 coupling reaction Methods 0.000 description 5
- 229940097362 cyclodextrins Drugs 0.000 description 5
- 238000000502 dialysis Methods 0.000 description 5
- 238000002156 mixing Methods 0.000 description 5
- 238000001291 vacuum drying Methods 0.000 description 5
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 229960001701 chloroform Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 125000002924 primary amino group Chemical group [H]N([H])* 0.000 description 4
- 238000000967 suction filtration Methods 0.000 description 4
- FAGUFWYHJQFNRV-UHFFFAOYSA-N tetraethylenepentamine Chemical compound NCCNCCNCCNCCN FAGUFWYHJQFNRV-UHFFFAOYSA-N 0.000 description 4
- 229960000549 4-dimethylaminophenol Drugs 0.000 description 3
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 description 3
- 239000003153 chemical reaction reagent Substances 0.000 description 3
- 238000001514 detection method Methods 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 238000000655 nuclear magnetic resonance spectrum Methods 0.000 description 3
- 238000001228 spectrum Methods 0.000 description 3
- 239000007821 HATU Substances 0.000 description 2
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 description 2
- PXIPVTKHYLBLMZ-UHFFFAOYSA-N Sodium azide Chemical compound [Na+].[N-]=[N+]=[N-] PXIPVTKHYLBLMZ-UHFFFAOYSA-N 0.000 description 2
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 description 2
- GSEJCLTVZPLZKY-UHFFFAOYSA-N Triethanolamine Chemical compound OCCN(CCO)CCO GSEJCLTVZPLZKY-UHFFFAOYSA-N 0.000 description 2
- 150000001408 amides Chemical class 0.000 description 2
- 230000000903 blocking effect Effects 0.000 description 2
- KIZFHUJKFSNWKO-UHFFFAOYSA-M calcium monohydroxide Chemical compound [Ca]O KIZFHUJKFSNWKO-UHFFFAOYSA-M 0.000 description 2
- NEHMKBQYUWJMIP-UHFFFAOYSA-N chloromethane Chemical compound ClC NEHMKBQYUWJMIP-UHFFFAOYSA-N 0.000 description 2
- 238000009833 condensation Methods 0.000 description 2
- 230000005494 condensation Effects 0.000 description 2
- 238000007796 conventional method Methods 0.000 description 2
- 235000019441 ethanol Nutrition 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 230000006872 improvement Effects 0.000 description 2
- 238000002329 infrared spectrum Methods 0.000 description 2
- FBBDOOHMGLLEGJ-UHFFFAOYSA-N methane;hydrochloride Chemical compound C.Cl FBBDOOHMGLLEGJ-UHFFFAOYSA-N 0.000 description 2
- 239000002088 nanocapsule Substances 0.000 description 2
- 239000003208 petroleum Substances 0.000 description 2
- 238000001556 precipitation Methods 0.000 description 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 238000001953 recrystallisation Methods 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 2
- VILCJCGEZXAXTO-UHFFFAOYSA-N 2,2,2-tetramine Chemical compound NCCNCCNCCN VILCJCGEZXAXTO-UHFFFAOYSA-N 0.000 description 1
- FPQQSJJWHUJYPU-UHFFFAOYSA-N 3-(dimethylamino)propyliminomethylidene-ethylazanium;chloride Chemical compound Cl.CCN=C=NCCCN(C)C FPQQSJJWHUJYPU-UHFFFAOYSA-N 0.000 description 1
- NLXLAEXVIDQMFP-UHFFFAOYSA-N Ammonia chloride Chemical class [NH4+].[Cl-] NLXLAEXVIDQMFP-UHFFFAOYSA-N 0.000 description 1
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical compound [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 1
- 229920000856 Amylose Polymers 0.000 description 1
- 208000019901 Anxiety disease Diseases 0.000 description 1
- 241000193830 Bacillus <bacterium> Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- 206010006187 Breast cancer Diseases 0.000 description 1
- 208000026310 Breast neoplasm Diseases 0.000 description 1
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- RPNUMPOLZDHAAY-UHFFFAOYSA-N Diethylenetriamine Chemical compound NCCNCCN RPNUMPOLZDHAAY-UHFFFAOYSA-N 0.000 description 1
- WQZGKKKJIJFFOK-GASJEMHNSA-N Glucose Natural products OC[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O WQZGKKKJIJFFOK-GASJEMHNSA-N 0.000 description 1
- 102000000340 Glucosyltransferases Human genes 0.000 description 1
- 108010055629 Glucosyltransferases Proteins 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 206010027476 Metastases Diseases 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 208000013738 Sleep Initiation and Maintenance disease Diseases 0.000 description 1
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 1
- 208000005392 Spasm Diseases 0.000 description 1
- KDYFGRWQOYBRFD-UHFFFAOYSA-N Succinic acid Natural products OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 description 1
- RSWGJHLUYNHPMX-ONCXSQPRSA-N abietic acid Chemical compound C([C@@H]12)CC(C(C)C)=CC1=CC[C@@H]1[C@]2(C)CCC[C@@]1(C)C(O)=O RSWGJHLUYNHPMX-ONCXSQPRSA-N 0.000 description 1
- 230000002411 adverse Effects 0.000 description 1
- HFHDHCJBZVLPGP-RWMJIURBSA-N alpha-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO HFHDHCJBZVLPGP-RWMJIURBSA-N 0.000 description 1
- 125000003277 amino group Chemical group 0.000 description 1
- 235000011114 ammonium hydroxide Nutrition 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000036506 anxiety Effects 0.000 description 1
- 239000007864 aqueous solution Substances 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- WVOLTBSCXRRQFR-DLBZAZTESA-N cannabidiolic acid Chemical class OC1=C(C(O)=O)C(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 WVOLTBSCXRRQFR-DLBZAZTESA-N 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- 210000001072 colon Anatomy 0.000 description 1
- 239000002131 composite material Substances 0.000 description 1
- 238000001816 cooling Methods 0.000 description 1
- 239000002537 cosmetic Substances 0.000 description 1
- 239000013078 crystal Substances 0.000 description 1
- 239000008367 deionised water Substances 0.000 description 1
- 229910021641 deionized water Inorganic materials 0.000 description 1
- AQEFLFZSWDEAIP-UHFFFAOYSA-N di-tert-butyl ether Chemical compound CC(C)(C)OC(C)(C)C AQEFLFZSWDEAIP-UHFFFAOYSA-N 0.000 description 1
- 229910000071 diazene Inorganic materials 0.000 description 1
- WGLUMOCWFMKWIL-UHFFFAOYSA-N dichloromethane;methanol Chemical compound OC.ClCCl WGLUMOCWFMKWIL-UHFFFAOYSA-N 0.000 description 1
- 150000002016 disaccharides Chemical class 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 239000003480 eluent Substances 0.000 description 1
- 239000000839 emulsion Substances 0.000 description 1
- 206010015037 epilepsy Diseases 0.000 description 1
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- GDSRMADSINPKSL-HSEONFRVSA-N gamma-cyclodextrin Chemical compound OC[C@H]([C@H]([C@@H]([C@H]1O)O)O[C@H]2O[C@@H]([C@@H](O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O[C@H]3O[C@H](CO)[C@H]([C@@H]([C@H]3O)O)O3)[C@H](O)[C@H]2O)CO)O[C@@H]1O[C@H]1[C@H](O)[C@@H](O)[C@@H]3O[C@@H]1CO GDSRMADSINPKSL-HSEONFRVSA-N 0.000 description 1
- 239000008103 glucose Substances 0.000 description 1
- 230000036541 health Effects 0.000 description 1
- 238000004896 high resolution mass spectrometry Methods 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 239000001257 hydrogen Substances 0.000 description 1
- 239000012535 impurity Substances 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 206010022437 insomnia Diseases 0.000 description 1
- 210000002429 large intestine Anatomy 0.000 description 1
- 240000004308 marijuana Species 0.000 description 1
- 238000001819 mass spectrum Methods 0.000 description 1
- 238000002844 melting Methods 0.000 description 1
- 230000008018 melting Effects 0.000 description 1
- 230000009401 metastasis Effects 0.000 description 1
- 244000005700 microbiome Species 0.000 description 1
- 239000011259 mixed solution Substances 0.000 description 1
- 150000002772 monosaccharides Chemical class 0.000 description 1
- LSHROXHEILXKHM-UHFFFAOYSA-N n'-[2-[2-[2-(2-aminoethylamino)ethylamino]ethylamino]ethyl]ethane-1,2-diamine Chemical compound NCCNCCNCCNCCNCCN LSHROXHEILXKHM-UHFFFAOYSA-N 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 229920001542 oligosaccharide Polymers 0.000 description 1
- 239000012044 organic layer Substances 0.000 description 1
- 238000000643 oven drying Methods 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 150000008442 polyphenolic compounds Chemical class 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 206010039073 rheumatoid arthritis Diseases 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000001384 succinic acid Substances 0.000 description 1
- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 229960001124 trientine Drugs 0.000 description 1
- 238000002211 ultraviolet spectrum Methods 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Images
Classifications
-
- C—CHEMISTRY; METALLURGY
- C08—ORGANIC MACROMOLECULAR COMPOUNDS; THEIR PREPARATION OR CHEMICAL WORKING-UP; COMPOSITIONS BASED THEREON
- C08B—POLYSACCHARIDES; DERIVATIVES THEREOF
- C08B37/00—Preparation of polysaccharides not provided for in groups C08B1/00 - C08B35/00; Derivatives thereof
- C08B37/0006—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid
- C08B37/0009—Homoglycans, i.e. polysaccharides having a main chain consisting of one single sugar, e.g. colominic acid alpha-D-Glucans, e.g. polydextrose, alternan, glycogen; (alpha-1,4)(alpha-1,6)-D-Glucans; (alpha-1,3)(alpha-1,4)-D-Glucans, e.g. isolichenan or nigeran; (alpha-1,4)-D-Glucans; (alpha-1,3)-D-Glucans, e.g. pseudonigeran; Derivatives thereof
- C08B37/0012—Cyclodextrin [CD], e.g. cycle with 6 units (alpha), with 7 units (beta) and with 8 units (gamma), large-ring cyclodextrin or cycloamylose with 9 units or more; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L29/00—Foods or foodstuffs containing additives; Preparation or treatment thereof
- A23L29/30—Foods or foodstuffs containing additives; Preparation or treatment thereof containing carbohydrate syrups; containing sugars; containing sugar alcohols, e.g. xylitol; containing starch hydrolysates, e.g. dextrin
- A23L29/35—Degradation products of starch, e.g. hydrolysates, dextrins; Enzymatically modified starches
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
- A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
- A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
- A23L33/105—Plant extracts, their artificial duplicates or their derivatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/69—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit
- A61K47/6949—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes
- A61K47/6951—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the conjugate being characterised by physical or galenical forms, e.g. emulsion, particle, inclusion complex, stent or kit inclusion complexes, e.g. clathrates, cavitates or fullerenes using cyclodextrin
-
- A—HUMAN NECESSITIES
- A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
- A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
- A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Polymers & Plastics (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Animal Behavior & Ethology (AREA)
- Food Science & Technology (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Molecular Biology (AREA)
- Nutrition Science (AREA)
- Botany (AREA)
- Mycology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Biochemistry (AREA)
- Materials Engineering (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Organic Chemistry (AREA)
- Polysaccharides And Polysaccharide Derivatives (AREA)
- Medicinal Preparation (AREA)
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
Abstract
本发明公开了一种大麻二酚环糊精偶合物及其制备方法;本发明偶合物是在碱和缩合剂的作用下,羧酸衍生化大麻二酚和胺基修饰的环糊精在有机溶剂中发生酰胺化反应制得;与大麻二酚相比,本发明大麻二酚环糊精偶合物具有更多亲水活性基团,生物相溶性好,具有更好的水溶性;且本发明大麻二酚环糊精偶合物的制备方法简单,原料易得,反应条件温和,适于工业化生产和市场推广应用。
Description
技术领域
本发明属于药物、食品和保健品制备领域,具体涉及一类大麻二酚环糊精偶合物及其制备方法。
背景技术
大麻二酚(cannabidiol,CBD)是从大麻植物中提取纯天然成分,一般为白色或淡黄色树脂或结晶,熔点为66℃-67℃,几乎不溶于水。大麻二酚具有阻断某些多酚对人体神经系统不利的影响,并且具有阻断乳腺癌转移、止痛、治疗癫痫、抗类风湿性关节炎、抗痉挛、抗失眠、抗焦虑、抗菌消炎等生理功能;另外,近年来研究发现,大麻二酚在食品、保健品、化妆品等领域也具有较大的应用潜力。
但是,大麻二酚几乎不溶于水且见光易分解见氧易氧化,不稳定,极大地限制了大麻二酚在现实中的商业应用。
环糊精(cyclodextrins,CDs)是直链淀粉在芽孢杆菌产生的环糊精葡萄糖基转移酶作用下生成的一系列天然环状低聚糖,研究较多且具有实际意义的是含有6-8个葡萄糖组成的α-环糊精、β-环糊精、γ-环糊精。环糊精几乎不能水解,通过人体胃和小肠部位时仅有少量的吸收。然而,环糊精可被结肠内部的微生物发酵,降解成为单糖或双糖,这样能被大肠所吸收。
类比于通过非键接引入水溶性胺基环糊精基团来增加大麻二酚的水溶性,对提高大麻二酚水溶性已经有一些报道(具体制备方法参见:[1]肖丰坤,李琳婧,陈黎飞,雷鹏,施豪,姚国凯,赵红敏.大麻二酚制剂及其制备方法[P].云南省:CN111184690A,2020-05-22.[2]吕品,郭孟璧,郭鸿彦,杨明,郭蓉,许艳萍,陈璇,张庆滢,潘宗兵.基于环糊精载体的水溶性大麻二酚纳米制剂及制备方法[P].云南省:CN111000827A,2020-04-14.[3]栾云鹏,郑双庆,李志朋,李襄,毛德昌.一种大麻二酚与碱性环糊精的包合物及其制备方法[P].云南省:CN109833312A,2019-06-04.[4]刘胜贵,王钲霖,李智高,付彬彬,孔令羽.一种水溶性大麻二酚包合物(纳米胶囊)的制备方法[P].云南省:CN110179862A,2019-08-30.)。这些报道中多用分子间形成包合物形式来增加大麻二酚的水溶性,但对于通过共价键键接的方式提高大麻二酚水溶性未有报道。
发明内容
针对大麻二酚几乎不溶于水而严重制约了大麻二酚的应用问题,本发明通过共价键引入胺基环糊精基团来提高大麻二酚的水溶性,提供一类水溶性较好、稳定性极佳、没有毒副作用的大麻二酚胺基环糊精偶合物。
本发明大麻二酚环糊精偶合物是大麻二酚类化合物通过其衍生化的羧基与胺基修饰的环糊精的胺基形成酰胺键连接而制得。
大麻二酚环糊精偶合物的结构式如下:
其中m=0、1、2、3、4;n=0、1、2、3、4、5;x=0、1、2。
在本发明中,大麻二酚环糊精偶合物是指羧酸衍生化大麻二酚化合物与胺基修饰的环糊精通过酰胺键连接而形成的化合物;更具体地,是指将不同链长的胺基环糊精中的胺基与不同链长的大麻二酚羧酸衍生物中的羧基通过形成酰胺键进行键接,制备了一系列新型一类大麻二酚环糊精偶合物。
上述大麻二酚环糊精偶合物的制备方法是在有机溶剂中,在碱和缩合剂的作用下,羧酸衍生化大麻二酚和胺基修饰的环糊精在0℃~100℃下发生酰胺化反应,反应1~30h后,加入溶剂产生沉淀,过滤后,洗涤沉淀,干燥即得大麻二酚环糊精偶合物。
具体方法如下:
(1)羧酸衍生化大麻二酚的制备:
将大麻二酚与酸酐溶于有机溶剂中,加入催化剂和碱,在0~100℃下搅拌反应0.1~24h后,用溶剂萃取后,洗涤,收集有机相,干燥后得粗品,粗品经过柱层析或膜分离纯化,浓缩干燥后制得,产率可高达90%;其中大麻二酚与酸酐的摩尔量比为1:1~4,催化剂的添加量为大麻二酚摩尔量的1~50%;
所述有机溶剂为一氯甲烷、二氯甲烷、三氯甲烷、N,N-二甲基甲酰胺、甲醇、乙醇、丙醇、二甲基亚砜、丙酮、乙醚、叔丁基甲基醚、三乙醇胺、石油醚、乙酸乙酯、四氢呋喃、吡啶、甲苯中的一种;
所述催化剂为DCC(二环己基碳二亚胺)、DMAP(4-二甲氨基吡啶)、TEBAC(三乙基苄基氯化铵)中的一种;
所述碱为NaOH、KOH、Na2CO3、NaHCO3、CaOH、乙二胺、三乙胺、N,N-二异丙基乙胺(DIPEA)、二异丙基胺基锂、甲醇钠、乙醇钠中的一种;
所述酸酐为丙二酸酐、丁二酸酐、甲基丁二酸酐、衣康酸酐、烯丙基丁二酸酐、戊二酸酐、3-甲基戊二酸酐、3-异丁基戊二酸酐、2,2-二甲基戊二酸酐、己二酸酐中的一种。
萃取用的溶剂为乙酸乙酯、乙醚、叔丁基醚、一氯甲烷、二氯甲烷、三氯甲烷中的一种;
洗涤使用饱和食盐水、饱和氯化铵溶液或水洗涤;
(2)羧酸衍生化大麻二酚与胺基环糊精的酰胺缩合
将羧酸衍生化大麻二酚溶解在有机溶剂中,然后加入缩合剂和碱,搅拌1~60min,再加入胺基修饰的环糊精,在0~100℃下搅拌反应0.1~30h;加入溶剂沉淀,过滤,滤渣洗涤烘干即得大麻二酚环糊精偶合物;滤液也可通过透析分离得部分产物,其中羧酸衍生化大麻二酚和胺基修饰的环糊精的摩尔量比为1:1~4;
所述有机溶剂为一氯甲烷、二氯甲烷、三氯甲烷、N,N-二甲基甲酰胺、甲醇、乙醇、丙醇、二甲基亚砜、丙酮、乙醚、叔丁基甲基醚、三乙醇胺、石油醚、乙酸乙酯、四氢呋喃、吡啶、甲苯中的一种;
所述缩合剂为DCC(二环己基碳二亚胺)、EDCI(1-乙基-(3-二甲基氨基丙基)碳酰二亚胺)、DIC(二异丙基碳二亚胺)、复合缩合剂DMAP(4-二甲氨基吡啶)、TEBAC(三乙基苄基氯化铵)、1-羟基苯并三唑、HATU(2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯)、HBTU(O-苯并三氮唑-四甲基脲六氟磷酸酯)、PyBOP(六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷)等;
所述碱NaOH、KOH、Na2CO3、NaHCO3、CaOH、乙二胺、三乙胺、N,N-二异丙基乙胺(DIPEA)、二异丙基胺基锂、甲醇钠、乙醇钠中的一种。
本发明的优点和效果如下:
本发明针对大麻二酚难溶和不稳定的现状,通过大麻二酚类化合物衍生化的羧基与胺基修饰的环糊精的胺基形成酰胺键连接,得到大麻二酚环糊精偶合物,从而提高大麻二酚的溶解性和稳定性;
本发明提供的大麻二酚环糊精偶合物是以共价键连接大麻二酚和胺基环糊精,该偶合物能显著提高大麻二酚的水溶性,相较于已报道过的以纳米胶囊、包合物、乳浊液等非共价键形式提高大麻二酚的水溶性来说,稳定性更佳、水溶性更好。另一方面,本发明所述的一类大麻二酚环糊精偶合物的制备方法,操作简单,反应条件温和,所得产品收率高,纯度高,适用于工业化生产和市场推广应用。
附图说明
图1是大麻二酚丁二酸衍生物核磁共振氢谱(1H NMR)图;
图2是大麻二酚丁二酸衍生物核磁共振碳谱(13C NMR)图;
图3是单-[6-(乙二胺基)-6-脱氧]-β-环糊精核磁共振氢谱(1H NMR)图;
图4是大麻二酚和大麻二酚丁二酸衍生物核磁共振氢谱(1H NMR)的比较图;
图5是单-[6-(乙二胺基)-6-脱氧]-β-环糊精-大麻二酚偶合物的核磁共振氢谱(1H NMR)图;
图6是单-[6-(乙二胺基)-6-脱氧]-β-环糊精-大麻二酚偶合物的核磁共振碳谱(13C NMR)图;
图7是大麻二酚和单-[6-(乙二胺基)-6-脱氧]-β-环糊精-大麻二酚偶合物的红外波谱图;
图8是单-[6-(乙二胺基)-6-脱氧]-β-环糊精-大麻二酚偶合物的质谱图;
图9是大麻二酚与大麻二酚环糊精偶合物的紫外波谱图。
具体实施方式
下面通过实施例进一步对本发明中所述方法进行描述,但本发明保护范围不受实施例限制,本实施例中使用的试剂如无特殊说明均为常规市售试剂或按常规方法配制的试剂,使用的方法如无特殊说明均为常规方法;
实施例1:本实施例大麻二酚环糊精偶合物结构式如下:
上述大麻二酚环糊精偶合物的制备方法如下:
1、大麻二酚丁二酸衍生物的制备
取1g大麻二酚溶于10mL三氯甲烷,然后加入3.6mg DMAP、296mg的丁二酸酐、145μL的乙二胺,100℃下搅拌反应0.1h,用乙酸乙酯萃取,饱和食盐水洗涤,水洗涤后,有机层用无水硫酸钠干燥,过滤,旋干,得粗品;粗品随后过硅胶柱,采用二氯甲烷-甲醇混合液(体积比20:1)洗脱,收集洗脱液旋干即得羧酸衍生化大麻二酚;
核磁共振检测如图1、2、4所示,在2.6-2.9ppm处出现了乙基峰,而大麻二酚在此处没有特征峰,而其他核磁峰的积分比例均与理论值相同,说明大麻二酚丁二酸衍生物成功制备;
2、单-[6-(乙二胺基)-6-脱氧]-β-环糊精的制备
参照文献[B.L.May,S.D.Kean,C.J.Easton,and S.F.Lincoln:J.Chem.Soc.,Perkin Trans.13157–3160(1997)];取单6-对甲苯磺酰-β-环糊精(3g,2.329mmol)加入20mL乙二胺溶液中,在80℃下反应8h,冷却后将反应液滴入丙酮中,收集沉淀即可得到单-[6-(乙二胺基)-6-脱氧]-β-环糊精(2.3g,1.956mmol),产率84%。
核磁共振检测如图3所示,在D2O条件下,单-[6-(乙二胺基)-6-脱氧]-β-环糊精的积分比例和化学位移均与参照的文献一致,说明了成功制备了单-[6-(乙二胺基)-6-脱氧]-β-环糊精。
3、单-[5-(乙二胺基)-6-脱氧]-β-环糊精与大麻二酚丁二酸衍生物的酰胺缩合
将1.2g,2.9mmol的大麻二酚丁二酸衍生物溶解到40mL的DMF中,加入1.10g,2.9mmol的HATU、400μL的DIPEA,搅拌2min,再加入3.4g,2.89mmol的单-[6-(乙二胺基)-6-脱氧]-β-环糊精,在10℃下反应30h,旋干去除大部分有机溶剂,加入水,溶液变浑浊,抽滤;滤渣用二氯甲烷洗涤,烘干;滤液用透析袋分离纯化,旋干水,干燥,合并产物,即得大麻二酚环糊精偶合物;
核磁共振检测结果如图5,6所示,大麻二酚的特征峰a,b,c和β-环糊精上的特征峰均同时出现了;红外波谱检测如图7所示,大麻二酚的两个羟基吸收峰分别在3520.75cm-1、3412.15cm-1,偶合物的羟基峰在3418.23cm-1,可明显地表明一个羟基被取代,且指纹区也出现了明显的不同;这些都充分地说明了单-[6-(乙二胺基)-6-脱氧]-β-环糊精与大麻二酚丁二酸衍生物偶合物的成功制备;高分辨率质谱结果如图8所示,m/z:1573.6671。
4、大麻二酚环糊精偶合物水溶性的测定
用紫外分光光度计对大麻二酚和大麻二酚环糊精偶合物吸收波长进行检测,结果如图9所示,大麻二酚在无水乙醇中的最大吸收波长为272nm,而大麻二酚环糊精偶合物的最大吸收波长为280nm,发生了红移,且吸收强度有明显的增强;因大麻二酚和大麻二酚环糊精偶合物最大吸收波长不一致,无法采用标准曲线法测大麻二酚环糊精偶合物的水溶性;因此,我们采取称重法测量大麻二酚环糊精偶合物的水溶性。
在25℃下,向1mL去离子水中加入过量大麻二酚环糊精偶合物使溶液达到饱和,过滤,滤液旋干,称重为1.8mg;因此,该偶合物(CBD-2NBCD)的水溶性为1.8mg/mL;
表1:大麻二酚和大麻二酚β环糊精偶合物的水溶性[(25.0±0.1)℃]
实施例2:本实施例大麻二酚环糊精偶合物结构式如下:
上述大麻二酚环糊精偶合物的制备方法如下:
1、大麻二酚丁二酸衍生物的制备方法同实施例1步骤1;
2、单-[6-(二乙烯三胺基)-6-脱氧]-β-环糊精的制备
参照文献[B.L.May,S.D.Kean,C.J.Easton,and S.F.Lincoln:J.Chem.Soc.,Perkin Trans.13157–3160(1997)];取单6-对甲苯磺酰-β-环糊精(3g,2.329mmol)加入20mL无水的二乙烯三胺溶液中,加入分子筛,在80℃反应12h,反应完成后过滤除去分子筛,然后将澄清溶液逐滴加入到丙酮中,搅拌30min,抽滤得到白色沉淀,真空干燥24h,然后用5-10mL水将沉淀溶解,再滴到丙酮中,得到白色沉淀(2.27g,1.863mmol),产率80%;
3、单-[6-(二乙烯三胺基)-6-脱氧]-β-环糊精与大麻二酚丁二酸衍生物偶合物的制备
将1.2g,2.9mmol的大麻二酚丁二酸衍生物溶解到40mL的DMF中,加入11.03g,29mmol的HBTU、490μL的DIPEA,搅拌1min,再加入5.31g,4.35mmol的单-[6-(二乙烯三胺基)-6-脱氧]-β-环糊精,在25℃下反应10h;旋干去除大部分有机溶剂,加入水,溶液变浑浊,抽滤;滤渣用二氯甲烷洗涤,烘干;滤液用透析袋分离纯化,旋干水,干燥,合并产物,即得大麻二酚环糊精偶合物;
4、大麻二酚环糊精偶合物水溶性的测定同实施例1步骤4,结果如表1所示,该大麻二酚环糊精偶合物(CBD-3NBCD)水溶性为5.1mg/mL。
实施例3:本实施例大麻二酚环糊精偶合物结构式如下:
上述大麻二酚环糊精偶合物的制备方法如下:
1、大麻二酚丁二酸衍生物的制备方法同实施例1步骤1;
2、单-[6-(胺基)-6-脱氧]-β-环糊精的制备
取单6-对甲苯磺酰-β-环糊精(3.25g,2.5mmol)和叠氮钠(0.2g,3.075mmol)溶在25mL的DMF中,N2保护,80℃反应12h。随后冷却至室温,撤去N2保护,过滤得黄色滤液,随后将滤液滴入丙酮中重结晶;重复以上操作至无杂质点,真空干燥得产物2.6g,产率为86%;
取单6-叠氮-β-环糊精(2.0g,1.76mmol)加入到10mL的DMF中,随后加入三苯基膦(2.27g,8.7mmol),在室温下搅拌2h,然后缓慢加入5mL氨水,继续搅拌24h后,过滤,滤液缓慢滴加到丙酮里重结晶,重复以上操作数次,收集沉淀干燥得白色纯品1.83g,产率为85%。
3、单-[6-(胺基)-6-脱氧]-β-环糊精与大麻二酚丁二酸羧酸衍生物偶合物的制备
将1.24g,3mmol的大麻二酚戊二酸衍生物溶解到40mL的DMSO中,加入1.57g,4.13mmol HBTU、4mmol二异丙基氨基锂,搅拌1h,再加入3.54g,3mmol单-[6-(胺基)-6-脱氧]-β-环糊精,在100℃下反应0.1h;旋干去除大部分溶剂,加入丙酮沉淀,沉淀用丙酮洗涤,再用水快速洗涤,然后烘箱干燥,即得大麻二酚环糊精偶合物。
4、大麻二酚环糊精偶合物水溶性的测定同实施例1步骤4,结果如表1所示,该大麻二酚环糊精偶合物(CBD-1NBCD)水溶性为0.4mg/mL。
实施例4:本实施例大麻二酚环糊精偶合物结构式如下:
1、大麻二酚丁二酸衍生物的制备方法同实施例1步骤1;
2、单-[6-(三乙烯四胺基)-6-脱氧]-β-环糊精的制备
参照文献[B.L.May,S.D.Kean,C.J.Easton,and S.F.Lincoln:J.Chem.Soc.,Perkin Trans.13157–3160(1997)]。取单6-对甲苯磺酰-β-环糊精(3g,2.329mmol)加入20mL无水的三乙烯四胺溶液中,加入分子筛,在80℃反应12h,反应完成后过滤除去分子筛,然后将澄清溶液逐滴加入到丙酮中,搅拌30min,抽滤得到白色沉淀,真空干燥24h,然后用5-10mL水将沉淀溶解,再滴到丙酮中,得到白色沉淀(2.411g,1.91mmol),产率82%;
3、单-[6-(三乙烯四胺基)-6-脱氧]-β-环糊精与大麻二酚丁二酸衍生物偶合物的制备
将1.2g,2.9mmol的大麻二酚丁二酸衍生物溶解到40mL的DMF中,加入22.64g,43.5mmol的PyBOP、490μL的DIPEA,搅拌1min,再加入5.05g,4.0mmol的单-[6-(三乙烯四胺基)-6-脱氧]-β-环糊精,在25℃下反应10h;旋干去除大部分有机溶剂,加入水,溶液变浑浊,抽滤;滤渣用二氯甲烷洗涤,烘干;滤液用透析袋分离纯化,旋干水,干燥,合并产物,即得大麻二酚环糊精偶合物;
4、大麻二酚环糊精偶合物水溶性的测定方法同实施例1步骤4,结果如表1所示,该大麻二酚环糊精偶合物(CBD-4NBCD)水溶性为9.0mg/mL。
实施例5:本实施例大麻二酚环糊精偶合物结构式如下:
上述大麻二酚环糊精偶合物的制备方法如下:
1、大麻二酚丁二酸衍生物的制备方法同实施例1步骤1;
2、单-[6-(四乙烯五胺基)-6-脱氧]-β-环糊精的制备
参照文献[B.L.May,S.D.Kean,C.J.Easton,and S.F.Lincoln:J.Chem.Soc.,Perkin Trans.13157–3160(1997)];取单6-对甲苯磺酰-β-环糊精(3g,2.329mmol)加入20mL无水的四乙烯五胺溶液中,加入分子筛,在80℃反应12h,反应完成后过滤除去分子筛,然后将澄清溶液逐滴加入到丙酮中,搅拌30min,抽滤得到白色沉淀,真空干燥24h,然后用5-10mL水将沉淀溶解,再滴到丙酮中,得到白色沉淀(2.58g,1.98mmol),产率85%;
3、单-[6-(四乙烯五胺基)-6-脱氧]-β-环糊精与大麻二酚丁二酸衍生物偶合物的制备
将1.2g,2.9mmol的大麻二酚丁二酸衍生物溶解到40mL的DMF中,加入22.05g,58mmol的HBTU、700μL的DIPEA,搅拌1min,再加入11.36g,8.7mmol的单-[6-(四乙烯五胺基)-6-脱氧]-β-环糊精,在25℃下反应10h;旋干去除大部分有机溶剂,加入水,溶液变浑浊,抽滤;滤渣用二氯甲烷洗涤,烘干;滤液用透析袋分离纯化,旋干水,干燥,合并产物,即得大麻二酚环糊精偶合物;
4、大麻二酚环糊精偶合物水溶性的测定方法同实施例1步骤4,结果如表1所示,该大麻二酚环糊精偶合物(CBD-5NBCD)水溶性为13.5mg/mL。
实施例6:本实施例大麻二酚环糊精偶合物结构式如下:
上述大麻二酚环糊精偶合物的制备方法如下:
1、大麻二酚丁二酸衍生物的制备方法同实施例1步骤1;
2、单-[6-(五乙烯六胺基)-6-脱氧]-β-环糊精的制备
参照文献[B.L.May,S.D.Kean,C.J.Easton,and S.F.Lincoln:J.Chem.Soc.,Perkin Trans.13157–3160(1997)];取单6-对甲苯磺酰-β-环糊精(3g)加入20mL无水的五乙烯六胺溶液中,加入分子筛,在80℃反应12h,反应完成后过滤除去分子筛,然后将澄清溶液逐滴加入到丙酮中,搅拌30min,抽滤得到白色沉淀,真空干燥24h,然后用10mL水将沉淀溶解,再滴到丙酮中,得到白色沉淀(2.64g,1.96mmol),产率为84%;
3、单-[6-(五乙烯六胺基)-6-脱氧]-β-环糊精与大麻二酚丁二酸衍生物偶合物的制备
将1.2g,2.9mmol的大麻二酚丁二酸衍生物溶解到40mL的DMF中,加入45.27g,87mmol的ByBOP、1000μL的DIPEA,搅拌1min,再加入15.32g,11.36mmol的单-[6-(五乙烯六胺基)-6-脱氧]-β-环糊精,在25℃下反应10h;旋干去除大部分有机溶剂,加入水,溶液变浑浊,抽滤;滤渣用二氯甲烷洗涤,烘干;滤液用透析袋分离纯化,旋干水,干燥,合并产物,即得大麻二酚环糊精偶合物;
4、大麻二酚环糊精偶合物水溶性的测定方法同实施例1步骤4,结果如表1所示,该大麻二酚环糊精偶合物(CBD-6NBCD)水溶性为17.4mg/mL。
Claims (8)
1.结构式如下式所示的大麻二酚环糊精偶合物:
其中m=0、1、2、3、4;n= 2、3、4、5;x= 0、1、2;
上述大麻二酚环糊精偶合物的制备方法是在碱和缩合剂的作用下,羧酸衍生化大麻二酚和胺基修饰的环糊精在10℃~25℃下发生酰胺化反应,反应 10~30h后,加入溶剂产生沉淀,过滤后,洗涤沉淀,干燥即得大麻二酚环糊精偶合物;其中羧酸衍生化大麻二酚和胺基修饰的环糊精的摩尔量比为1:1~4;
胺基修饰的环糊精为单-[6-(二乙烯三胺基)-6-脱氧]-β-环糊精、单-[6-(三乙烯四胺基)-6-脱氧]-β-环糊精、单-[6-(四乙烯五胺基)-6-脱氧]-β-环糊精、单-[6-(五乙烯六胺基)-6-脱氧]-β-环糊精、单-[6-(二乙烯三胺基)-6-脱氧]-α-环糊精、单-[6-(三乙烯四胺基)-6-脱氧]-α-环糊精、单-[6-(四乙烯五胺基)-6-脱氧]-α-环糊精、单-[6-(五乙烯六胺基)-6-脱氧]-α-环糊精、单-[6-(二乙烯三胺基)-6-脱氧]-γ-环糊精、单-[6-(三乙烯四胺基)-6-脱氧]-γ-环糊精、单-[6-(四乙烯五胺基)-6-脱氧]-γ-环糊精、单-[6-(五乙烯六胺基)-6-脱氧]-γ-环糊精中的一种。
2.根据权利要求1所述的大麻二酚环糊精偶合物,其特征在于:缩合剂为碳二亚胺类缩合剂和鎓盐类缩合剂;其中羧酸衍生化大麻二酚与缩合剂的摩尔比为1:25~35。
3.根据权利要求2所述的大麻二酚环糊精偶合物,其特征在于:碳二亚胺类缩合剂为二环己基碳二亚胺、1-乙基-(3-二甲基氨基丙基)碳酰二亚胺、二异丙基碳二亚胺、4-二甲氨基吡啶、三乙基苄基氯化铵或1-羟基苯并三唑。
4.根据权利要求2所述的大麻二酚环糊精偶合物,其特征在于:鎓盐类缩合剂为2-(7-氮杂苯并三氮唑)-N,N,N',N'-四甲基脲六氟磷酸酯、O-苯并三氮唑-四甲基脲六氟磷酸酯或六氟磷酸苯并三唑-1-基-氧基三吡咯烷基磷。
5.据权利要求1所述的大麻二酚环糊精偶合物,其特征在于:羧酸衍生化大麻二酚是将大麻二酚与酸酐溶解在有机溶剂中,加入催化剂和碱,在0~100℃下搅拌反应0.1~24h后,用溶剂萃取后,洗涤,收集有机相干燥后得粗品,粗品经过柱层析或膜分离纯化,浓缩干燥后制得,其中酸酐与大麻二酚的摩尔量之比为1:1~4,催化剂的添加量为大麻二酚摩尔量的1~50%。
6.据权利要求5所述的大麻二酚环糊精偶合物,其特征在于:酸酐为丙二酸酐、丁二酸酐、甲基丁二酸酐、衣康酸酐、烯丙基丁二酸酐、戊二酸酐、3-甲基戊二酸酐、3-异丁基戊二酸酐、2,2-二甲基戊二酸酐、己二酸酐中的一种。
7.据权利要求5所述的大麻二酚环糊精偶合物,其特征在于:催化剂为二环己基碳二亚胺、4-二甲氨基吡啶、TEBAC三乙基苄基氯化铵中的一种。
8.据权利要求1或5所述的大麻二酚环糊精偶合物,其特征在于:碱为NaOH、KOH、Na2CO3、NaHCO3、Ca(OH)2、乙二胺、三乙胺、N,N-二异丙基乙胺,二异丙基胺基锂、甲醇钠、乙醇钠中的一种。
Priority Applications (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011045913.7A CN112111025B (zh) | 2020-09-28 | 2020-09-28 | 一种大麻二酚环糊精偶合物及其制备方法 |
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
CN202011045913.7A CN112111025B (zh) | 2020-09-28 | 2020-09-28 | 一种大麻二酚环糊精偶合物及其制备方法 |
Publications (2)
Publication Number | Publication Date |
---|---|
CN112111025A CN112111025A (zh) | 2020-12-22 |
CN112111025B true CN112111025B (zh) | 2022-08-16 |
Family
ID=73798442
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
CN202011045913.7A Active CN112111025B (zh) | 2020-09-28 | 2020-09-28 | 一种大麻二酚环糊精偶合物及其制备方法 |
Country Status (1)
Country | Link |
---|---|
CN (1) | CN112111025B (zh) |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN113087661B (zh) * | 2021-03-24 | 2022-09-06 | 福建省中科生物股份有限公司 | 一种2’,6’-双吡啶取代大麻二酚醚类化合物及其制备方法和用途 |
CN114409712B (zh) * | 2022-03-02 | 2024-01-30 | 昆明理工大学 | 一种含大麻二酚Pt(Ⅳ)配合物及其制备方法和应用 |
CN116041183A (zh) * | 2023-01-03 | 2023-05-02 | 中国农业科学院农产品加工研究所 | 一种大麻二酚半抗原、人工抗原以及单克隆抗体和应用 |
Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103483592A (zh) * | 2013-09-24 | 2014-01-01 | 昆明理工大学 | 环糊精接枝聚赖氨酸聚合物及其制备方法 |
WO2014090128A1 (zh) * | 2012-12-14 | 2014-06-19 | 昆明制药集团股份有限公司 | 一种青蒿素环糊精缀合物及其制备方法 |
CN109833312A (zh) * | 2019-04-09 | 2019-06-04 | 栾云鹏 | 一种大麻二酚与碱性环糊精的包合物及其制备方法 |
CN109867734A (zh) * | 2017-12-05 | 2019-06-11 | 天津工业大学 | 一类咖啡酸修饰的环糊精衍生物及其制备方法 |
CN109867733A (zh) * | 2017-12-05 | 2019-06-11 | 天津工业大学 | 一类阿魏酸修饰的环糊精衍生物及其制备方法 |
WO2020028897A1 (en) * | 2018-08-03 | 2020-02-06 | Lilu's Garden, Ltd. | CONSTRUCT OF β-CYCLODEXTRIN AND CANNABINOID GUEST COMPLEX AND PROCESSES FOR PRODUCING A PASTE COMPRISING THE SAME |
CN111000827A (zh) * | 2019-12-31 | 2020-04-14 | 云南省农业科学院经济作物研究所 | 基于环糊精载体的水溶性大麻二酚纳米制剂及制备方法 |
-
2020
- 2020-09-28 CN CN202011045913.7A patent/CN112111025B/zh active Active
Patent Citations (7)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2014090128A1 (zh) * | 2012-12-14 | 2014-06-19 | 昆明制药集团股份有限公司 | 一种青蒿素环糊精缀合物及其制备方法 |
CN103483592A (zh) * | 2013-09-24 | 2014-01-01 | 昆明理工大学 | 环糊精接枝聚赖氨酸聚合物及其制备方法 |
CN109867734A (zh) * | 2017-12-05 | 2019-06-11 | 天津工业大学 | 一类咖啡酸修饰的环糊精衍生物及其制备方法 |
CN109867733A (zh) * | 2017-12-05 | 2019-06-11 | 天津工业大学 | 一类阿魏酸修饰的环糊精衍生物及其制备方法 |
WO2020028897A1 (en) * | 2018-08-03 | 2020-02-06 | Lilu's Garden, Ltd. | CONSTRUCT OF β-CYCLODEXTRIN AND CANNABINOID GUEST COMPLEX AND PROCESSES FOR PRODUCING A PASTE COMPRISING THE SAME |
CN109833312A (zh) * | 2019-04-09 | 2019-06-04 | 栾云鹏 | 一种大麻二酚与碱性环糊精的包合物及其制备方法 |
CN111000827A (zh) * | 2019-12-31 | 2020-04-14 | 云南省农业科学院经济作物研究所 | 基于环糊精载体的水溶性大麻二酚纳米制剂及制备方法 |
Non-Patent Citations (1)
Title |
---|
Scutellarin-cyclodextrin conjugates: Synthesis, characterization and anticancer activity;Bo Yang等;《Carbohydrate Polymers》;20121012;第92卷;第1308-1314页 * |
Also Published As
Publication number | Publication date |
---|---|
CN112111025A (zh) | 2020-12-22 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CN112111025B (zh) | 一种大麻二酚环糊精偶合物及其制备方法 | |
KR100948143B1 (ko) | 쿠커비투릴이 결합된 실리카겔을 이용한 정지상 및 컬럼,그리고 상기 컬럼을 이용한 탁산의 분리 방법 | |
CN111298132B (zh) | 一种树状分子吉西他滨自组装纳米前药及其制备方法和应用 | |
CN114516871B (zh) | 一种苝酰亚胺衍生物纳米材料及其制备方法和应用 | |
CN106916236B (zh) | 一种环糊精-喜树碱类超分子化疗药物及其制备和应用 | |
JP6453761B2 (ja) | アルテアンヌイン−シクロデキストリン結合体及びその製造方法 | |
CN115057797B (zh) | 一种水溶性联苯芳烃的合成及生物毒素解毒的应用 | |
Sashiwa et al. | Chemical modification of chitosan 8: preparation of chitosan–dendrimer hybrids via short spacer | |
CN107281498B (zh) | 一种聚乙二醇修饰的铁离子螯合剂 | |
CN108623711B (zh) | 阿魏酸-环糊精共价偶联化合物及其制备方法和应用 | |
CN111253505B (zh) | 具有细胞靶向性的水溶性环糊精药物载体及其制备方法 | |
CN110201182B (zh) | 一种紫杉醇-dha-右旋糖酐偶联聚合物及其合成方法和应用 | |
CN102093403B (zh) | 含偶氮苯基团的复合脂质及其中间体,制备方法与用途 | |
JP2010006763A (ja) | ポルフィリン誘導体 | |
CN114437171A (zh) | 一种含偶氮苯基团的二肽表面活性剂及其制备方法 | |
CN118406174B (zh) | 含甘露糖聚合物、联用raft聚合和点击化学制备含甘露糖聚合物的方法及其应用 | |
CN114075136B (zh) | 水溶性含偶氮苯吡啶的三叉手性分子及其制备方法与应用 | |
CN118420882B (zh) | 侧链含四苯乙烯和甘露糖的聚合物及其制备方法和应用 | |
CN114315956B (zh) | 一种利用氧化型谷胱甘肽衍生物制备多重响应型凝胶的方法 | |
Longo et al. | Synthesis of a new substituted zinc phthalocyanine as functional monomer in the preparation of MIPs | |
CN113980671B (zh) | 多胺衍生物修饰的量子点、制备方法和作为纳米药物载体的应用 | |
CN116675786A (zh) | 一种靶向传递喜树碱的环糊精超分子药物及其制备方法和应用 | |
CN118791649A (zh) | 一种端羟基硫代烷基β-环糊精硫酸酯衍生物的合成方法 | |
CN117964532A (zh) | 一种富含硒补充剂的特膳食品 | |
Na et al. | First Hydrogelation of Discrete Metal Complexes. Structures and Fluxional Behavior of Cyclopalladium (II) Complexes |
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 | ||
TA01 | Transfer of patent application right | ||
TA01 | Transfer of patent application right |
Effective date of registration: 20220728 Address after: No. 4404, floor 44, plot A2, dianjing Mingzhu community, Huangtupo District, Fengning sub district office, Wuhua District, Kunming, Yunnan 650000 Applicant after: YUNNAN PEILIN TECHNOLOGY Co.,Ltd. Address before: No.z060, 2 / F, building 14, Yunnan Ziyun Qingniao jewelry processing and trading base, 39 Shuntong Avenue, economic development zone, Kunming area, Kunming City, Yunnan Province Applicant before: Muhe Yongkang Biotechnology (Yunnan) Co.,Ltd. |
|
GR01 | Patent grant | ||
GR01 | Patent grant |