CN106749302A - E‑3‑（苯基衍生物‑次甲基）‑吡喃并二氢黄酮衍生物及制备及应用 - Google Patents
E‑3‑（苯基衍生物‑次甲基）‑吡喃并二氢黄酮衍生物及制备及应用 Download PDFInfo
- Publication number
- CN106749302A CN106749302A CN201611105678.1A CN201611105678A CN106749302A CN 106749302 A CN106749302 A CN 106749302A CN 201611105678 A CN201611105678 A CN 201611105678A CN 106749302 A CN106749302 A CN 106749302A
- Authority
- CN
- China
- Prior art keywords
- pyrans
- acid
- och
- flavanone
- methine
- 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.)
- Granted
Links
- 238000002360 preparation method Methods 0.000 title claims abstract description 23
- 150000002207 flavanone derivatives Chemical class 0.000 title claims abstract description 21
- 150000004880 oxines Chemical class 0.000 title claims abstract description 9
- 125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims abstract description 50
- 238000006243 chemical reaction Methods 0.000 claims abstract description 39
- 150000003935 benzaldehydes Chemical class 0.000 claims abstract description 7
- 229930003949 flavanone Natural products 0.000 claims abstract description 7
- 235000011981 flavanones Nutrition 0.000 claims abstract description 7
- ZONYXWQDUYMKFB-UHFFFAOYSA-N SJ000286395 Natural products O1C2=CC=CC=C2C(=O)CC1C1=CC=CC=C1 ZONYXWQDUYMKFB-UHFFFAOYSA-N 0.000 claims abstract description 6
- 230000003110 anti-inflammatory effect Effects 0.000 claims abstract description 6
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims abstract description 5
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 claims abstract description 3
- 239000000203 mixture Substances 0.000 claims abstract 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 78
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 34
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 22
- 125000001997 phenyl group Chemical class [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 12
- JEYWNNAZDLFBFF-UHFFFAOYSA-N Nafoxidine Chemical compound C1CC2=CC(OC)=CC=C2C(C=2C=CC(OCCN3CCCC3)=CC=2)=C1C1=CC=CC=C1 JEYWNNAZDLFBFF-UHFFFAOYSA-N 0.000 claims description 12
- 229950002366 nafoxidine Drugs 0.000 claims description 12
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 9
- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims description 6
- 239000003963 antioxidant agent Substances 0.000 claims description 6
- 230000003078 antioxidant effect Effects 0.000 claims description 6
- 235000006708 antioxidants Nutrition 0.000 claims description 6
- 239000003814 drug Substances 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 5
- FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 4
- ROSDSFDQCJNGOL-UHFFFAOYSA-N Dimethylamine Chemical compound CNC ROSDSFDQCJNGOL-UHFFFAOYSA-N 0.000 claims description 4
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 4
- YNAVUWVOSKDBBP-UHFFFAOYSA-N Morpholine Chemical compound C1COCCN1 YNAVUWVOSKDBBP-UHFFFAOYSA-N 0.000 claims description 4
- 150000001298 alcohols Chemical class 0.000 claims description 4
- 230000000844 anti-bacterial effect Effects 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
- 125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 4
- 230000008859 change Effects 0.000 claims description 4
- 239000002537 cosmetic Substances 0.000 claims description 4
- XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
- FUZZWVXGSFPDMH-UHFFFAOYSA-N hexanoic acid Chemical compound CCCCCC(O)=O FUZZWVXGSFPDMH-UHFFFAOYSA-N 0.000 claims description 4
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 4
- 150000007524 organic acids Chemical class 0.000 claims description 4
- 150000007530 organic bases Chemical class 0.000 claims description 4
- 239000002798 polar solvent Substances 0.000 claims description 4
- KDYFGRWQOYBRFD-UHFFFAOYSA-N succinic acid Chemical compound OC(=O)CCC(O)=O KDYFGRWQOYBRFD-UHFFFAOYSA-N 0.000 claims description 4
- NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 4
- 230000002526 effect on cardiovascular system Effects 0.000 claims description 3
- WLJVXDMOQOGPHL-PPJXEINESA-N 2-phenylacetic acid Chemical compound O[14C](=O)CC1=CC=CC=C1 WLJVXDMOQOGPHL-PPJXEINESA-N 0.000 claims description 2
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 2
- 239000005711 Benzoic acid Substances 0.000 claims description 2
- FEWJPZIEWOKRBE-JCYAYHJZSA-N Dextrotartaric acid Chemical compound OC(=O)[C@H](O)[C@@H](O)C(O)=O FEWJPZIEWOKRBE-JCYAYHJZSA-N 0.000 claims description 2
- FEWJPZIEWOKRBE-UHFFFAOYSA-N Tartaric acid Natural products [H+].[H+].[O-]C(=O)C(O)C(O)C([O-])=O FEWJPZIEWOKRBE-UHFFFAOYSA-N 0.000 claims description 2
- 235000011054 acetic acid Nutrition 0.000 claims description 2
- 239000002253 acid Substances 0.000 claims description 2
- 230000000259 anti-tumor effect Effects 0.000 claims description 2
- 235000010233 benzoic acid Nutrition 0.000 claims description 2
- 239000003054 catalyst Substances 0.000 claims description 2
- HPNMFZURTQLUMO-UHFFFAOYSA-N diethylamine Chemical compound CCNCC HPNMFZURTQLUMO-UHFFFAOYSA-N 0.000 claims description 2
- 235000019253 formic acid Nutrition 0.000 claims description 2
- 235000011187 glycerol Nutrition 0.000 claims description 2
- 150000003053 piperidines Chemical class 0.000 claims description 2
- ULWHHBHJGPPBCO-UHFFFAOYSA-N propane-1,1-diol Chemical class CCC(O)O ULWHHBHJGPPBCO-UHFFFAOYSA-N 0.000 claims description 2
- 235000019260 propionic acid Nutrition 0.000 claims description 2
- IUVKMZGDUIUOCP-BTNSXGMBSA-N quinbolone Chemical compound O([C@H]1CC[C@H]2[C@H]3[C@@H]([C@]4(C=CC(=O)C=C4CC3)C)CC[C@@]21C)C1=CCCC1 IUVKMZGDUIUOCP-BTNSXGMBSA-N 0.000 claims description 2
- 230000035484 reaction time Effects 0.000 claims description 2
- 229960005137 succinic acid Drugs 0.000 claims description 2
- 235000002906 tartaric acid Nutrition 0.000 claims description 2
- 239000011975 tartaric acid Substances 0.000 claims description 2
- 229940005605 valeric acid Drugs 0.000 claims description 2
- HSJKGGMUJITCBW-UHFFFAOYSA-N 3-hydroxybutanal Chemical compound CC(O)CC=O HSJKGGMUJITCBW-UHFFFAOYSA-N 0.000 claims 2
- BDERNNFJNOPAEC-UHFFFAOYSA-N propan-1-ol Chemical compound CCCO BDERNNFJNOPAEC-UHFFFAOYSA-N 0.000 claims 2
- XMIIGOLPHOKFCH-UHFFFAOYSA-N 3-phenylpropionic acid Chemical compound OC(=O)CCC1=CC=CC=C1 XMIIGOLPHOKFCH-UHFFFAOYSA-N 0.000 claims 1
- 210000000481 breast Anatomy 0.000 claims 1
- 238000006482 condensation reaction Methods 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 4
- 238000004519 manufacturing process Methods 0.000 abstract description 2
- 125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 abstract 2
- 150000001412 amines Chemical class 0.000 abstract 1
- 230000003064 anti-oxidating effect Effects 0.000 abstract 1
- 230000009286 beneficial effect Effects 0.000 abstract 1
- 125000000896 monocarboxylic acid group Chemical group 0.000 abstract 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 47
- 239000001100 (2S)-5,7-dihydroxy-2-(3-hydroxy-4-methoxyphenyl)chroman-4-one Substances 0.000 description 32
- AIONOLUJZLIMTK-AWEZNQCLSA-N hesperetin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O)=CC(O)=C2C(=O)C1 AIONOLUJZLIMTK-AWEZNQCLSA-N 0.000 description 31
- AIONOLUJZLIMTK-UHFFFAOYSA-N hesperetin Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(O)=CC(O)=C2C(=O)C1 AIONOLUJZLIMTK-UHFFFAOYSA-N 0.000 description 31
- 235000010209 hesperetin Nutrition 0.000 description 31
- 229960001587 hesperetin Drugs 0.000 description 31
- FTODBIPDTXRIGS-UHFFFAOYSA-N homoeriodictyol Natural products C1=C(O)C(OC)=CC(C2OC3=CC(O)=CC(O)=C3C(=O)C2)=C1 FTODBIPDTXRIGS-UHFFFAOYSA-N 0.000 description 31
- HUMNYLRZRPPJDN-UHFFFAOYSA-N benzaldehyde Chemical compound O=CC1=CC=CC=C1 HUMNYLRZRPPJDN-UHFFFAOYSA-N 0.000 description 19
- 229960000583 acetic acid Drugs 0.000 description 15
- -1 Flavone compound Chemical class 0.000 description 14
- 239000012362 glacial acetic acid Substances 0.000 description 14
- FTVWIRXFELQLPI-ZDUSSCGKSA-N (S)-naringenin Chemical compound C1=CC(O)=CC=C1[C@H]1OC2=CC(O)=CC(O)=C2C(=O)C1 FTVWIRXFELQLPI-ZDUSSCGKSA-N 0.000 description 13
- 239000003480 eluent Substances 0.000 description 13
- SRCZQMGIVIYBBJ-UHFFFAOYSA-N ethoxyethane;ethyl acetate Chemical compound CCOCC.CCOC(C)=O SRCZQMGIVIYBBJ-UHFFFAOYSA-N 0.000 description 13
- 229930003944 flavone Natural products 0.000 description 13
- 235000011949 flavones Nutrition 0.000 description 13
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 12
- 238000005160 1H NMR spectroscopy Methods 0.000 description 12
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 12
- 238000013461 design Methods 0.000 description 12
- WGEYAGZBLYNDFV-UHFFFAOYSA-N naringenin Natural products C1(=O)C2=C(O)C=C(O)C=C2OC(C1)C1=CC=C(CC1)O WGEYAGZBLYNDFV-UHFFFAOYSA-N 0.000 description 12
- 235000007625 naringenin Nutrition 0.000 description 12
- 229940117954 naringenin Drugs 0.000 description 12
- 239000003208 petroleum Substances 0.000 description 12
- 238000004064 recycling Methods 0.000 description 12
- 239000000741 silica gel Substances 0.000 description 12
- 229910002027 silica gel Inorganic materials 0.000 description 12
- 239000007787 solid Substances 0.000 description 12
- 235000019441 ethanol Nutrition 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- 150000001875 compounds Chemical class 0.000 description 8
- HHEAADYXPMHMCT-UHFFFAOYSA-N dpph Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC([N+]([O-])=O)=C1[N]N(C=1C=CC=CC=1)C1=CC=CC=C1 HHEAADYXPMHMCT-UHFFFAOYSA-N 0.000 description 8
- 230000000694 effects Effects 0.000 description 8
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 8
- 150000002213 flavones Chemical class 0.000 description 7
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 7
- QNGNSVIICDLXHT-UHFFFAOYSA-N para-ethylbenzaldehyde Natural products CCC1=CC=C(C=O)C=C1 QNGNSVIICDLXHT-UHFFFAOYSA-N 0.000 description 7
- 235000004237 Crocus Nutrition 0.000 description 6
- 241000596148 Crocus Species 0.000 description 6
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 6
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 6
- 230000003647 oxidation Effects 0.000 description 6
- 238000007254 oxidation reaction Methods 0.000 description 6
- 238000003756 stirring Methods 0.000 description 6
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 6
- 229930182470 glycoside Natural products 0.000 description 5
- 235000013824 polyphenols Nutrition 0.000 description 5
- 238000005882 aldol condensation reaction Methods 0.000 description 4
- 150000002338 glycosides Chemical class 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000002904 solvent Substances 0.000 description 4
- 238000006467 substitution reaction Methods 0.000 description 4
- 206010014025 Ear swelling Diseases 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 3
- 240000001307 Myosotis scorpioides Species 0.000 description 3
- 125000003368 amide group Chemical group 0.000 description 3
- 230000000840 anti-viral effect Effects 0.000 description 3
- QUQPHWDTPGMPEX-UTWYECKDSA-N aurantiamarin Natural products COc1ccc(cc1O)[C@H]1CC(=O)c2c(O)cc(O[C@@H]3O[C@H](CO[C@@H]4O[C@@H](C)[C@H](O)[C@@H](O)[C@H]4O)[C@@H](O)[C@H](O)[C@H]3O)cc2O1 QUQPHWDTPGMPEX-UTWYECKDSA-N 0.000 description 3
- 230000008901 benefit Effects 0.000 description 3
- 229910052739 hydrogen Inorganic materials 0.000 description 3
- 230000001965 increasing effect Effects 0.000 description 3
- 230000001939 inductive effect Effects 0.000 description 3
- LGZXYFMMLRYXLK-UHFFFAOYSA-N mercury(2+);sulfide Chemical compound [S-2].[Hg+2] LGZXYFMMLRYXLK-UHFFFAOYSA-N 0.000 description 3
- 150000003233 pyrroles Chemical class 0.000 description 3
- 150000003254 radicals Chemical class 0.000 description 3
- 230000008961 swelling Effects 0.000 description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 3
- QAGGICSUEVNSGH-UHFFFAOYSA-N Diosmetin Natural products C1=C(O)C(OC)=CC=C1C1=CC(=O)C2=CC=C(O)C=C2O1 QAGGICSUEVNSGH-UHFFFAOYSA-N 0.000 description 2
- URLKBWYHVLBVBO-UHFFFAOYSA-N Para-Xylene Chemical group CC1=CC=C(C)C=C1 URLKBWYHVLBVBO-UHFFFAOYSA-N 0.000 description 2
- 238000002835 absorbance Methods 0.000 description 2
- 230000001476 alcoholic effect Effects 0.000 description 2
- 230000033228 biological regulation Effects 0.000 description 2
- 125000002915 carbonyl group Chemical group [*:2]C([*:1])=O 0.000 description 2
- MBNGWHIJMBWFHU-UHFFFAOYSA-N diosmetin Chemical compound C1=C(O)C(OC)=CC=C1C1=CC(=O)C2=C(O)C=C(O)C=C2O1 MBNGWHIJMBWFHU-UHFFFAOYSA-N 0.000 description 2
- 235000015428 diosmetin Nutrition 0.000 description 2
- 229960001876 diosmetin Drugs 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 238000002474 experimental method Methods 0.000 description 2
- 238000000605 extraction Methods 0.000 description 2
- 150000002212 flavone derivatives Chemical class 0.000 description 2
- 150000002240 furans Chemical class 0.000 description 2
- VUYDGVRIQRPHFX-UHFFFAOYSA-N hesperidin Natural products COc1cc(ccc1O)C2CC(=O)c3c(O)cc(OC4OC(COC5OC(O)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2 VUYDGVRIQRPHFX-UHFFFAOYSA-N 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- JVTAAEKCZFNVCJ-UHFFFAOYSA-N lactic acid Chemical compound CC(O)C(O)=O JVTAAEKCZFNVCJ-UHFFFAOYSA-N 0.000 description 2
- ARGKVCXINMKCAZ-UHFFFAOYSA-N neohesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(CO)O3)OC3C(C(O)C(O)C(C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UHFFFAOYSA-N 0.000 description 2
- XKZQKPRCPNGNFR-UHFFFAOYSA-N 2-(3-hydroxyphenyl)phenol Chemical group OC1=CC=CC(C=2C(=CC=CC=2)O)=C1 XKZQKPRCPNGNFR-UHFFFAOYSA-N 0.000 description 1
- DGPBVJWCIDNDPN-UHFFFAOYSA-N 2-(dimethylamino)benzaldehyde Chemical compound CN(C)C1=CC=CC=C1C=O DGPBVJWCIDNDPN-UHFFFAOYSA-N 0.000 description 1
- VAJVDSVGBWFCLW-UHFFFAOYSA-N 3-Phenyl-1-propanol Chemical compound OCCCC1=CC=CC=C1 VAJVDSVGBWFCLW-UHFFFAOYSA-N 0.000 description 1
- GZSOSUNBTXMUFQ-NJGQXECBSA-N 5,7,3'-Trihydroxy-4'-methoxyflavone 7-O-rutinoside Natural products O(C[C@@H]1[C@@H](O)[C@H](O)[C@@H](O)[C@H](Oc2cc(O)c3C(=O)C=C(c4cc(O)c(OC)cc4)Oc3c2)O1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](C)O1 GZSOSUNBTXMUFQ-NJGQXECBSA-N 0.000 description 1
- 240000006409 Acacia auriculiformis Species 0.000 description 1
- 241000894006 Bacteria Species 0.000 description 1
- JMGZEFIQIZZSBH-UHFFFAOYSA-N Bioquercetin Natural products CC1OC(OCC(O)C2OC(OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5)C(O)C2O)C(O)C(O)C1O JMGZEFIQIZZSBH-UHFFFAOYSA-N 0.000 description 1
- 0 CC=Cc(c(O)cc(O)c1C(C2)=O)c1OC2*(cc1*)ccc1OC Chemical compound CC=Cc(c(O)cc(O)c1C(C2)=O)c1OC2*(cc1*)ccc1OC 0.000 description 1
- 241000675108 Citrus tangerina Species 0.000 description 1
- 229940123457 Free radical scavenger Drugs 0.000 description 1
- QUQPHWDTPGMPEX-UHFFFAOYSA-N Hesperidine Natural products C1=C(O)C(OC)=CC=C1C1OC2=CC(OC3C(C(O)C(O)C(COC4C(C(O)C(O)C(C)O4)O)O3)O)=CC(O)=C2C(=O)C1 QUQPHWDTPGMPEX-UHFFFAOYSA-N 0.000 description 1
- 206010061218 Inflammation Diseases 0.000 description 1
- 238000012449 Kunming mouse Methods 0.000 description 1
- 101100108853 Mus musculus Anp32e gene Proteins 0.000 description 1
- CMWTZPSULFXXJA-UHFFFAOYSA-N Naproxen Natural products C1=C(C(C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-UHFFFAOYSA-N 0.000 description 1
- 101100221809 Neurospora crassa (strain ATCC 24698 / 74-OR23-1A / CBS 708.71 / DSM 1257 / FGSC 987) cpd-7 gene Proteins 0.000 description 1
- DYUQAZSOFZSPHD-UHFFFAOYSA-N Phenylpropyl alcohol Natural products CCC(O)C1=CC=CC=C1 DYUQAZSOFZSPHD-UHFFFAOYSA-N 0.000 description 1
- XUIMIQQOPSSXEZ-UHFFFAOYSA-N Silicon Chemical compound [Si] XUIMIQQOPSSXEZ-UHFFFAOYSA-N 0.000 description 1
- 241001464837 Viridiplantae Species 0.000 description 1
- 238000010521 absorption reaction Methods 0.000 description 1
- 150000008065 acid anhydrides Chemical class 0.000 description 1
- 230000004913 activation Effects 0.000 description 1
- PYKYMHQGRFAEBM-UHFFFAOYSA-N anthraquinone Natural products CCC(=O)c1c(O)c2C(=O)C3C(C=CC=C3O)C(=O)c2cc1CC(=O)OC PYKYMHQGRFAEBM-UHFFFAOYSA-N 0.000 description 1
- 150000004056 anthraquinones Chemical class 0.000 description 1
- RPMNUQRUHXIGHK-PYXJVEIZSA-N apigenin 7-O-neohesperidoside Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)O[C@H]1OC1=CC(O)=C2C(=O)C=C(C=3C=CC(O)=CC=3)OC2=C1 RPMNUQRUHXIGHK-PYXJVEIZSA-N 0.000 description 1
- 229930034861 apigenin-7-O-neohesperidoside Natural products 0.000 description 1
- 125000003118 aryl group Chemical group 0.000 description 1
- 238000005815 base catalysis Methods 0.000 description 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- 230000037396 body weight Effects 0.000 description 1
- 210000000170 cell membrane Anatomy 0.000 description 1
- 239000012295 chemical reaction liquid Substances 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- APSNPMVGBGZYAJ-GLOOOPAXSA-N clematine Natural products COc1cc(ccc1O)[C@@H]2CC(=O)c3c(O)cc(O[C@@H]4O[C@H](CO[C@H]5O[C@@H](C)[C@H](O)[C@@H](O)[C@H]5O)[C@@H](O)[C@H](O)[C@H]4O)cc3O2 APSNPMVGBGZYAJ-GLOOOPAXSA-N 0.000 description 1
- 239000003086 colorant Substances 0.000 description 1
- 230000000052 comparative effect Effects 0.000 description 1
- 238000002425 crystallisation Methods 0.000 description 1
- 230000008025 crystallization Effects 0.000 description 1
- 150000001923 cyclic compounds Chemical class 0.000 description 1
- 238000005034 decoration Methods 0.000 description 1
- 238000006356 dehydrogenation reaction Methods 0.000 description 1
- GZSOSUNBTXMUFQ-YFAPSIMESA-N diosmin Chemical compound C1=C(O)C(OC)=CC=C1C(OC1=C2)=CC(=O)C1=C(O)C=C2O[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO[C@H]2[C@@H]([C@H](O)[C@@H](O)[C@H](C)O2)O)O1 GZSOSUNBTXMUFQ-YFAPSIMESA-N 0.000 description 1
- 229960004352 diosmin Drugs 0.000 description 1
- IGBKNLGEMMEWKD-UHFFFAOYSA-N diosmin Natural products COc1ccc(cc1)C2=C(O)C(=O)c3c(O)cc(OC4OC(COC5OC(C)C(O)C(O)C5O)C(O)C(O)C4O)cc3O2 IGBKNLGEMMEWKD-UHFFFAOYSA-N 0.000 description 1
- 238000004090 dissolution Methods 0.000 description 1
- 238000009826 distribution Methods 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000005069 ears Anatomy 0.000 description 1
- IVTMALDHFAHOGL-UHFFFAOYSA-N eriodictyol 7-O-rutinoside Natural products OC1C(O)C(O)C(C)OC1OCC1C(O)C(O)C(O)C(OC=2C=C3C(C(C(O)=C(O3)C=3C=C(O)C(O)=CC=3)=O)=C(O)C=2)O1 IVTMALDHFAHOGL-UHFFFAOYSA-N 0.000 description 1
- 150000002208 flavanones Chemical class 0.000 description 1
- 229930182486 flavonoid glycoside Natural products 0.000 description 1
- 150000007955 flavonoid glycosides Chemical class 0.000 description 1
- 230000007760 free radical scavenging Effects 0.000 description 1
- 239000003292 glue Substances 0.000 description 1
- 238000010438 heat treatment Methods 0.000 description 1
- 229940025878 hesperidin Drugs 0.000 description 1
- 230000004054 inflammatory process Effects 0.000 description 1
- 230000002401 inhibitory effect Effects 0.000 description 1
- 150000002576 ketones Chemical class 0.000 description 1
- 239000004310 lactic acid Substances 0.000 description 1
- 235000014655 lactic acid Nutrition 0.000 description 1
- 229960000448 lactic acid Drugs 0.000 description 1
- 230000031700 light absorption Effects 0.000 description 1
- 239000007788 liquid Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- CMWTZPSULFXXJA-VIFPVBQESA-N naproxen Chemical compound C1=C([C@H](C)C(O)=O)C=CC2=CC(OC)=CC=C21 CMWTZPSULFXXJA-VIFPVBQESA-N 0.000 description 1
- 229960002009 naproxen Drugs 0.000 description 1
- DFPMSGMNTNDNHN-ZPHOTFPESA-N naringin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1O[C@H]1[C@H](OC=2C=C3O[C@@H](CC(=O)C3=C(O)C=2)C=2C=CC(O)=CC=2)O[C@H](CO)[C@@H](O)[C@@H]1O DFPMSGMNTNDNHN-ZPHOTFPESA-N 0.000 description 1
- ARGKVCXINMKCAZ-UZRWAPQLSA-N neohesperidin Chemical compound C1=C(O)C(OC)=CC=C1[C@H]1OC2=CC(O[C@H]3[C@@H]([C@@H](O)[C@H](O)[C@@H](CO)O3)O[C@H]3[C@@H]([C@H](O)[C@@H](O)[C@H](C)O3)O)=CC(O)=C2C(=O)C1 ARGKVCXINMKCAZ-UZRWAPQLSA-N 0.000 description 1
- 239000003921 oil Substances 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- FDRQPMVGJOQVTL-UHFFFAOYSA-N quercetin rutinoside Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 FDRQPMVGJOQVTL-UHFFFAOYSA-N 0.000 description 1
- 239000002516 radical scavenger Substances 0.000 description 1
- 239000002994 raw material Substances 0.000 description 1
- 238000011084 recovery Methods 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- RPMNUQRUHXIGHK-SBDOOABHSA-N rhoifolin Natural products O([C@@H]1[C@@H](O)[C@H](O)[C@H](CO)O[C@H]1Oc1cc(O)c2C(=O)C=C(c3ccc(O)cc3)Oc2c1)[C@H]1[C@H](O)[C@@H](O)[C@@H](O)[C@H](C)O1 RPMNUQRUHXIGHK-SBDOOABHSA-N 0.000 description 1
- IKGXIBQEEMLURG-BKUODXTLSA-N rutin Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@@H]1OC[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-BKUODXTLSA-N 0.000 description 1
- ALABRVAAKCSLSC-UHFFFAOYSA-N rutin Natural products CC1OC(OCC2OC(O)C(O)C(O)C2O)C(O)C(O)C1OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5 ALABRVAAKCSLSC-UHFFFAOYSA-N 0.000 description 1
- 235000005493 rutin Nutrition 0.000 description 1
- 229960004555 rutoside Drugs 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- XDQITMCFPPPMBC-TUANDBMESA-N scutelloside Natural products OC[C@H]1O[C@@H](O[C@@H]2O[C@@H]3C[C@H]4[C@H](O)[C@@H](O)[C@@](O)(CO3)[C@@H]24)[C@H](O)[C@@H](O)[C@@H]1O XDQITMCFPPPMBC-TUANDBMESA-N 0.000 description 1
- 229930000044 secondary metabolite Natural products 0.000 description 1
- 229910052710 silicon Inorganic materials 0.000 description 1
- 239000010703 silicon Substances 0.000 description 1
- 239000000344 soap Substances 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 230000006641 stabilisation Effects 0.000 description 1
- 238000011105 stabilization Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 229960001367 tartaric acid Drugs 0.000 description 1
- DKVBOUDTNWVDEP-NJCHZNEYSA-N teicoplanin aglycone Chemical compound N([C@H](C(N[C@@H](C1=CC(O)=CC(O)=C1C=1C(O)=CC=C2C=1)C(O)=O)=O)[C@H](O)C1=CC=C(C(=C1)Cl)OC=1C=C3C=C(C=1O)OC1=CC=C(C=C1Cl)C[C@H](C(=O)N1)NC([C@H](N)C=4C=C(O5)C(O)=CC=4)=O)C(=O)[C@@H]2NC(=O)[C@@H]3NC(=O)[C@@H]1C1=CC5=CC(O)=C1 DKVBOUDTNWVDEP-NJCHZNEYSA-N 0.000 description 1
- 238000012360 testing method Methods 0.000 description 1
- 229930182493 triterpene saponin Natural products 0.000 description 1
- 150000003648 triterpenes Chemical class 0.000 description 1
- 238000005303 weighing Methods 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D493/00—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system
- C07D493/02—Heterocyclic compounds containing oxygen atoms as the only ring hetero atoms in the condensed system in which the condensed system contains two hetero rings
- C07D493/04—Ortho-condensed systems
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K8/00—Cosmetics or similar toiletry preparations
- A61K8/18—Cosmetics or similar toiletry preparations characterised by the composition
- A61K8/30—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds
- A61K8/49—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds
- A61K8/4973—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom
- A61K8/498—Cosmetics or similar toiletry preparations characterised by the composition containing organic compounds containing heterocyclic compounds with oxygen as the only hetero atom having 6-membered rings or their condensed derivatives, e.g. coumarin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61Q—SPECIFIC USE OF COSMETICS OR SIMILAR TOILETRY PREPARATIONS
- A61Q17/00—Barrier preparations; Preparations brought into direct contact with the skin for affording protection against external influences, e.g. sunlight, X-rays or other harmful rays, corrosive materials, bacteria or insect stings
-
- 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)
- Organic Chemistry (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- Dermatology (AREA)
- Birds (AREA)
- Epidemiology (AREA)
- Cosmetics (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明公开了一种E‑3‑(苯基衍生物‑次甲基)‑吡喃并二氢黄酮衍生物及制备及应用，其结构通式如(Ⅰ)所示，其中：R1可为‑H、‑CH3、‑CH2CH3、‑CH2CH2CH3、‑CH＝C(CH3)2、‑CH＝C(CH3)CH2CH2CH＝C(CH3)2；R2可为‑H、‑CH3；R3可为‑H、‑OH；R4可为‑H、‑OH、‑OCH3、‑N(CH3)2、‑F、‑Cl中单基团或多基团；R5可为‑OH、‑OCH3、‑N(CH3)2‑F、‑Cl、‑COOH中单基团或多基团；X可为‑CH或‑CH2。以吡喃并二氢黄酮类化合物经有机胺催化，与苯甲醛衍生物一步反应制得。工艺简单，利于工业化生产。且具有较好的抗炎、抗氧化作用，具有潜在的临床应用前景。
Description
技术领域：
本发明领域属于化学、化妆品和医药，涉及一种E-3-(苯基衍生物-次甲基)-吡喃并二氢黄酮衍生物及制备及应用。
背景技术
黄酮类化合物在自然界中种类繁多，含量丰富，提取制备工艺简单，价格低廉。由于天然黄酮系植物酶的次生代谢产物，多含有酚羟基。由于酚羟基分布不均匀，分占两个苯环，未形成邻二酚OH，抗氧化性作用较弱，代表性的化合物如橙皮苷、柚皮苷、新橙皮苷、地奥司明、野漆树苷、芹菜素、橙皮素、柚皮素、甲基橙皮苷。即使含有邻二酚羟基，由于两个苯环具有较好的共平面性，分子与分子易于层层排列，形成结晶，水溶性低。
绿色植物合成黄酮类化合物，主要在植物体内发挥抗氧化、抗菌、抗病毒、抗炎的功效，用于保护植物。黄酮类化合物水溶性较低，为了发挥功效，在植物体内常合成苷类化合物。由于苷类化合物极性较大，难以通过动物体内的细胞膜，生物利用度角度。在动物体内吸收，大多数是利用肠道细菌，对苷类的降解，产生苷元被吸收，吸收量有限，导致黄酮苷类化合物生物利用度低下，代表性的化合物，如橙皮苷、地奥司明、黄芩苷。
在黄酮3-位引入取代基，与黄酮-2-苯基存在空间位阻，发生扭曲，水溶性增加，代表性化合物如芦丁。由于天然黄酮多存在5,7-二OH，对黄酮的A环有显著的活化作用，当在在黄酮-3位引入取代基，导致A环上也能发生反应，副产物较多，且性质相近，难以分离，产率不高，其研究受限。因此，对5,7-二OH二氢黄酮的3位进行取代，一直受到制约。
当对7-OH进行苄基、甲氧基等保护，容易开环，生成査尔酮，具有较好的惰性，无法再进行羟醛缩合。因此，对于含有7-OH的二氢黄酮，在其3-位和苯甲醛及其衍生物缩合，有着及其严重的困难。
用酸酐保护7-OH，形成酯键，由于羟醛缩合，需要酸碱催化，酯键容易水解，导致副反应较多，产率不高，因此酯键保护同样受到明显限制。
多环类化合物，具有较好的活性：由饱和环构成的，如四环三萜皂苷、五环三萜皂苷、强行苷等甾环；由芳香环构成的如木脂素、黄酮、蒽醌虽也有一定活性，分子中环的个数还是过于单薄，继续增加其环状化合物，有利于增大其比表面积，进而增加和靶标的结合力，有利于提高活性。
发明内容
本发明提供一种E-3-(苯基衍生物-次甲基)-吡喃并二氢黄酮衍生物及制备及应用，其调节二氢黄酮7,8-吡喃吡喃环上的取代基、3-次甲基苯基上的取代基，构建有着不同极性的新型黄酮，提升二氢黄酮中双键、酚羟基、形成较大的共轭结构，以及合适的脂水分配系数，以期在抗炎、抗氧化、抗菌、抗病毒、抗肿瘤、扩张心脑血管等作用具有更好的活性。
本发明一种E-3-(苯基衍生物-次甲基)-吡喃并二氢黄酮衍生物，其结构通式如(Ⅰ)所示，
其中：R1可为-H、-CH3、-CH2CH3、-CH2CH2CH3、-CH＝C(CH3)2、-CH＝C(CH3)CH2CH2CH＝C(CH3)2；R2可为-H、-CH3；R3可为-H、-OH；R4可为-H、-OH、-OCH3、-N(CH3)2、-F、-Cl中单基团或多基团；R5可为-OH、-OCH3、-N(CH3)2-F、-Cl、-COOH中单基团或多基团；X可为-CH或-CH2。
本发明另一目的是公开一种E-3-(苯基衍生物-次甲基)-吡喃并二氢黄酮衍生物制备，其是以吡喃并(7,8)-二氢黄酮，在极性溶剂中，以有机碱+有机酸为催化剂，与苯甲醛衍生物通过aldol condensation反应制得，其中吡喃并(7,8)-二氢黄酮与苯甲醛衍生物的质量mol比例为3:1-1:3，控制反应温度在室温-100℃，控制反应时间为1h-72h。
本发明所述的吡喃并(7,8)-二氢黄酮，其结构式见(II)，
其中：R1、R2、R3与结构(I)中的R1、R2、R3、X基团含义相同，R1可为-H、-CH3、-CH2CH3、-CH2CH2CH3、-CH＝C(CH3)2、-CH＝C(CH3)CH2CH2CH＝C(CH3)2；R2可为-H、-CH3；R3可为-H、-OH；R4可为-H、-OH、-OCH3、-N(CH3)2、-F、-Cl中单基团或多基团；X可为-CH或-CH2。
本发明所述的苯甲醛衍生物，结构式见(III)
其中：R5与结构(I)中的R4基团含义相同：可为-OH、-OCH3、-N(CH3)2-F、-Cl、-COOH中单基团或多基团。
本发明所述的极性溶剂为DMSO、THF、醇类任意一种，所述的醇类为甲醇、乙醇、丙醇、异丙醇、乙二醇、丙二醇、丙三醇任意一种。
本发明所述的有机碱为二甲胺、二乙胺、四氢吡咯、哌啶、吗啉任意一种，优选为四氢吡咯。
本发明所述的有机酸，为甲酸、乙酸、丙酸、丁酸、戊酸、己酸、苯甲酸、苯乙酸、苯丙酸，乳酸、琥珀酸、酒石酸，优选为冰醋酸。
本发明反应条件温和，可在醇、THF、DMSO中进行，aldol condensation反应部位单一，产物易于提纯，整个制备工艺简单，有利于工业化生产。
本发明的原理是：
5,7-二OH二氢黄酮化合物，易于制备5-OH-吡喃并(7,8)-二氢黄酮。本发明利用天然界含量丰富，提取工艺简单，价格低廉的橙皮素、柚皮素为原料。通过制环，增加3-次甲基-苯基衍生物，增加了环数目、并可增加酚OH、-OCH3、胺基，显著扩大了共轭性，脂水分配系数易于调节，得到颜色丰富多彩的E-3-(苯基衍生物-次甲基)-吡喃并二氢黄酮衍生物，在水溶性、醇溶性、抗氧化能增加，在抗菌、抗炎、抗氧化、抗病毒、心脑血管保护等方面作用，较原有的黄酮具有先天优势，更易制备成合适的制剂，使其具有进一步应用在食品、药品、化妆品领域，潜在的临床应用前景及潜在的经济效益和社会效益。
具体实施方式：下面结合本发明实施例对本发明进一步的详细说明。本发明实施例公开了E-3-(苯基衍生物-次甲基)-吡喃并二氢黄酮衍生物的制备的方法。本领域技术人员可以借鉴本文内容，适当改进工艺参数实现。特别需要指出的是，所有类似的替换和改动对本领域技术人员来说是显而易见的，它们都被视为包括在本发明。本发明的应用已经通过较佳实施例进行了描述，相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的应用进行改动或适当变更与组合，来实现和应用本发明技术。
为了进一步理解本发明，下面结合实施例对本发明进行详细说明。
实施例1：E-3-(3,4,5-三OCH3苯次甲基)-8,8-二甲基吡喃并橙皮素的制备：取8,8-二甲基吡喃并橙皮素0.404g，3,4,5-三OCH3苯甲醛0.223g，四氢呋喃5.0mL，吡咯140μL，冰醋酸130μL，70℃密闭反应24h。回收反应液至体积1/2，硅胶拌样，以石油醚-乙酸乙酯＝3/1为洗脱剂，收集橘黄棕色色带，回收溶剂，得橙黄色固体412mg(Cpd1)。1H NMR(400MHz,CDCl3)δ12.92(s,1H:5-OH),7.97(s,1H:1”-H),7.10(d,J＝2.1Hz,1H:2'-H),6.90(dd,J＝8.3,1.9Hz,1H:6'-H),6.78(d,J＝8.3Hz,1H:5'-H),6.57(d,J＝10.1Hz,1H:10-H),6.48(d,3H:3”-H+7”-H+H-2),5.83(s,1H:6-H),5.62(s,1H:3'-OH),5.44(d,J＝10.1Hz,1H:9-H),3.86(s,6H:4'-OCH3+5”-OCH3),3.65(s,6H:6”-OCH3+4”-OCH3),1.39(d,J＝10.2Hz,6H:(8-CH3)2；13C NMR(101MHz,CDCl3)δ185.01(C-4),162.33(C-6a),159.72(C-5),159.21(C-10aa),153.18(C-4”+C-6”),147.00(C-4'),146.03(C-3'),139.54(C-1”),138.81(C-5”),131.25(C-1'),130.54(C-3),129.37(C-9),125.84(C-2”),119.60(C-6'),115.26(C-10),114.01(C-2'),110.41(C-5'),107.53(C-3”+C-7”),103.27(C-4a),103.01(C-10a),96.89(C-6),78.35(C-8),77.74(C-2),60.97(5”-OCH3),55.94(4”-OCH3+6”-OCH3+4'-OCH3),28.63(8-CH3),28.59(8-CH3)；ES-,1.02e6，[M-H]-555.45(100％),[M]-556.41,[M+H]-557.49；ES+,1.88e6，[M+H]+547.42(100％),[M+H]+548.37,[M+Na]+569.41,[M+Na+H]+570.36,[M+K]+585.33,[M+K+H]+586.32；calcalc.for：C31H30O9，反应式如下：
实施例2：E-3-(3,4-二OCH3苯次甲基)-8,8-二甲基吡喃并橙皮素的制备：取,8-二甲基吡喃并橙皮素0.368g，3,4-二OCH3苯甲醛0.180g，四氢呋喃5.0mL，吡咯120μL，冰醋酸100μL，70℃密闭反应24h。回收反应液至体积1/2，硅胶拌样，以石油醚-乙酸乙酯＝3.5/1为洗脱剂，收集橘黄棕色色带，回收溶剂，得橙黄色382mg(Cpd2)。1H NMR(400MHz,CDCl3)δ12.97(s,1H:5-OH),7.99(s,1H:1”-H),7.11(d,J＝2.1Hz,1H:2'-H),6.90(dd,J＝8.3,1.8Hz,2H:H-6'+7”-H),6.84(d,J＝8.4Hz,1H:5'-H),6.77(d,J＝8.0Hz,2H:6”-H+3”-H),6.57(d,J＝10.0Hz,1H:10-H),6.49(s,1H:H-2),5.83(s,1H:H-6),5.63(s,1H:3'-OH),5.43(d,J＝10.0Hz,1H:9-H),3.87(d,6H:4'-OCH3+5”-OCH3),3.67(s,3H:4”-OCH3),1.39(d,6H:(8-CH3)2；13C NMR(101MHz,CDCl3)δ185.25(C-4),162.16(C-7),159.67(C-5),159.18(C-10aa),150.63(C-5”),148.90(C-4”),146.98(C-4'),146.02(C-3'),138.83(C-1”),131.18(C-1'),129.33(C-3),126.86(C-9),125.77(C-2”),124.17(C-6'),119.46(C-7”),115.31(C-10),114.00(C-2'),113.07(C-5'),111.15(C-6”),110.43(C-3”),102.99(C-10a),103.28(C-4a),96.84(C-6),78.28(C-8),77.65(C-2),55.71(4”-OCH3),55.93(5”-OCH3),55.91(4”-OCH3),28.62(8-CH3),28.53(8-CH3)；ES-,5.66e5，[M-H]-515.37(100％),[M]-516.28,[M+H]-517.44,[M+K]-555.45；ES+,2.59e6，[M+H]+517.44(100％),[M+H]+517.15,[M+2H]+518.86,[M+Na]+539.52,[M+Na+H]+540.45,[M+K]+555.26；cal calc.for：C30H28O8，反应式如下：
实施例3：E-3-(3,4,5-三OCH3苯次甲基)-8,8-二甲基二氢吡喃并橙皮素的制备：
称取8,8-二甲基二氢吡喃并橙皮素0.154g，三OCH3苯甲醛0.084g，四氢呋喃4.0mL，四氢吡咯40ul，冰醋酸30μL，75℃搅拌反应24h，回收反应液至体积1/2，硅胶拌样，以石油醚-乙酸乙酯＝3/1为洗脱剂，收集橘黄棕色色带，回收溶剂，得黄色固体161mg(Cpd3)。
1H NMR(400MHz,CDCl3)δ13.00(s,1H:5-OH),7.96(s,1H:1”-H),7.10(d,J＝1.8Hz,1H:2'-H),6.90(dd,J＝8.3,1.8Hz,1H:6'-H),6.78(d,J＝8.3Hz,1H:5'-H),6.5(s,2H:3”-H+7”-H),6.46(s,H:2-H),5.82(s,1H:6-H),5.60(s,1H:3'-OH),3.85(6H:4'-OCH3+5”-OCH3),3.65(s,6H:6”-OCH3+4”-OCH3),2.14-2.69(M,2H:10-CH2),1.56-1.79(M,2H:9-CH2),1.29-1.31(s,6Hz,(8-CH3)2)；13C NMR(101MHz,CDCl3)δA环：163.10(C-6a),97.06(C-6),162.21(C-5),102.19(C-4a),157.57(C-10aa),102.82(C-10a)；B环：131.45(C-1'),114.03(C-2'),145.96(C-3'),146.88(C-4'),110.37(C-5'),119.61(C-6'),55.94(4'-OCH3),C环：77.45(C-2),130.99(C-3),184.93(C-4)；D环：27.01(8-CH3),26.63(8-CH3),76.29(C-8),31.87(C-9),15.67(10-CH2)；E环：139.44(C-1”),129.50(C-2”),107.49(C-3”+C-7”),153.16(C-4”+C-6”),138.49(C-5”),60.96(5”-OCH3),55.90(4”-OCH3+6”-OCH3)；ES-,1.46e5，[M-H]-547.41(100％),[M]-548.35；ES+,2.20e6，[M+H]+549.4,[M+Na]+571.441(100％),[M+Na+H]+572.36,[M+K]+587.46,[M+K+H]+588.49；cal calc.for：C31H32O9，反应式如下：
实施例4：E-3-(3,4-二OH苯次甲基)-8-CH3-8-(4-CH3-戊-3-烯)-吡喃并橙皮素的制备：称取8-CH3-8-(4-CH3-戊-3-烯)-吡喃并橙皮素0.622g，3，4-二OH苯甲醛0.200g，四氢呋喃5.0mL，四氢吡咯70μL，冰醋酸60μL，60℃搅拌反应48h，回收反应液至体积1/2，硅胶拌样，以石油醚-乙酸乙酯＝2/1为洗脱剂，收集橘黄棕色色带，回收溶剂，以10％乙醇加热洗涤，弃去乙醇液，旋干，得深橘黄色固体418mg(Cpd4)。1H NMR(400MHz,CDCl3)δ12.85(d,J＝2.5Hz,1H：5-OH),7.84(1H：1"-H),7.06(d,J＝1.7Hz,1H：2'-H),6.85(dd,J＝8.3,1.9Hz,2H:6'-H+3"-H),6.79–6.68(m,3H：5'-H+7”-H+6”-H),6.60(d,J＝10.2Hz,1H：10-H),6.45(s,1H:H-2),5.6-6.2(4H:6-H+3'-OH+4”-OH+5”-OH),5.38(dd,J＝10.2,6.9Hz,1H:9-H),5.05(m,1H:13-H),3.83(s,3H:4-OCH3),2.03(td,J＝15.1,7.6Hz,2H：12-CH2),1.78–1.67(m,2H：11-CH2),1.58(dd,6H：14-(CH3)2),1.36(d,J＝8.3Hz,3H:8-CH3)；13C NMR(101MHz,CDCl3)δA环：162.81(C-7),96.82(C-6),159.78(C-5),103.18(C-4a),159.03(C-10aa),102.93(C-10a)；B环130.93(C-1'),113.93(C-2'),146.24(C-3'),146.93(C-4'),110.60(C-5'),119.50(C-6')；C环：185.69(C-4),129.08(C-3),80.93(C-2)；D环：77.23(C-8),27.48(8-CH3),124.77(C-9),115.87(C-10),41.86(C-11),22.65(C-12),123.80(C-13),131.92(C-14),25.66(14-CH3),17.64(14-CH3)；E环139.11(C-1”),126.76(C-2”),115.65(C-3”),143.61(C-4”),145.72(C-5”),116.99(C-6”),124.53(C-7”)。ES-,1.02e6，[M-H]-555.45(100％),[M]-556.41,[M+H]-557.49；ES+,9.39e5，[M+H]+557.36(100％),[M+Na]+579.34,[M+Na+H]+580.17；cal calc.for：C33H32O8，反应式如下：
实施例5：E-3-(4-OH苯次甲基)-8-CH3-8-(4-CH3-戊-3-烯)-吡喃并橙皮素的制备：称取8-CH3-8-(4-CH3-戊-3-烯)-吡喃并橙皮素0.440g，4-OH苯甲醛0.123g，四氢呋喃5.0mL，四氢吡咯60μL，冰醋酸50μL，60℃搅拌反应48h，回收反应液至体积1/2，硅胶拌样，以石油醚-乙酸乙酯＝2.5/1为洗脱剂，收集橘黄棕色色带，回收溶剂，得深橘黄色固体396mg(Cpd5)。1H NMR(400MHz,CDCl3)δ12.93(s,1H:5-OH),7.95(s,1H:1”-H),7.17(d,8.4Hz,2H:3”-H+7”-H),7.09(d,1.9Hz,1H:2'-H),6.89(1H:6'-H),6.84-6.74(q,3H:5'-H+6”-H+4”-H),6.60(dd,J＝10.2Hz,7.3Hz,1H:10-H),6.45(s,1H:2-H),5.84(s,1H:6-H),5.37(dd,J＝10.2,1H:9-H),5.05(m,1H:13-H),3.86(s,3H:4'-OCH3),2.02(m,2H:12-CH2),1.76–1.49(m,8H:11-CH2+(14-CH3)2),1.36(d,3H:8-CH3)。13C NMR(101MHz,CDCl3)δ：A环：162.56(C-6a),96.71(C-6),159.72(C-5),103.20(C-4a),159.08(C-10aa),102.77(C-10a)；B环：131.06(C-1'),113.91(C-2'),145.96(C-3'),146.95(C-4'),110.47(C-5'),119.41(C-6'),55.89(4”-OCH3),C环：80.71(C-2),128.84(C-3),185.54(C-4)；D环：29.72(8-CH3),77.24(C-8),124.67(C-9),115.96(C-10),41.84(C-11),22.58(12-CH2),123.84(C-13),131.88(C-14),25.63(14-CH3),17.65(14-CH3)(D环及侧链受手性影响，峰分裂)；E环：138.83(C-1”),126.21(C-2”),132.42(C-3”+C-7”),116.04(C-4”+C-6”),158.12(C-5”)。ES-,3.75e6，[M-H]-539.44(100％),[M]-540.41,[M]-541.39；ES+,5.24e6，[M+H]+541.47(100％),[M+H]+542.43,[M+Na]+563.33。cal calc.for：C33H32O7，反应式如下：
实施例6：E-3-(3-OH-4-OCH3苯次甲基)-8-CH3-8-(4-CH3-戊-3-烯)-吡喃并橙皮素的制备：称取CH3-8-(4-CH3-戊-3-烯)-吡喃并橙皮素0.424g，3-OH-4-OCH3-苯甲醛0.148g，四氢呋喃5.0mL，四氢吡咯60μL，冰醋酸50μL，60℃密闭搅拌反应48h，回收反应液至体积1/2，硅胶拌样，以石油醚-乙酸乙酯＝2.5/1为洗脱剂，收集橘黄棕色色带，回收溶剂，得橘黄色固体252mg(Cpd 6)。1H NMR(400MHz,CDCl3)δ12.93(s,1H:5-OH),7.92(s,1H:1”-H),7.08(s,1H:2'-H),6.87(d,2H:7”-H+6'-H),6.82(2H:3”-H+5'-H),6.77(d,J＝8.4Hz,1H:6”-H),6.60(dd,J＝10.2Hz,7.3Hz,1H:10-H),6.49(s,1H:2-H),5.84(s,1H:6-H),5.60(d,J＝3.4Hz,2H:3'-OH+4”-OH),5.37(dd,J＝10.2,1H:9-H),5.05(d,J＝6.5Hz,1H:13-H),3.90(s,3H:5”-OCH3),3.86(s,3H:4'-OCH3),2.02(dd,J＝19.3,7.9Hz,2H:12-CH2),1.76–1.49(m,8H:11-CH2+(14-CH3)2),1.36(d,J＝6.3Hz,3H:8-CH3)；13C NMR(101MHz,CDCl3)δA环:162.58(C-6a),96.71(C-6),159.76(C-5),103.23(C-4a),159.11(C-10aa),102.89(C-10a)；B环:131.08(C-1'),113.87(C-2'),145.67(C-3'),146.92(C-4'),110.46(C-5'),119.30(C-6'),55.89(4”-OCH3)；C环:185.43(C-4),129.79(C-3),80.76(C-2)；D环:138.58(C-1”),127.48(C-2”),116.11(C-3”),145.99(C-4”),148.11(C-5”),110.64(C-6”),123.44(C-7”),55.99(5”-OCH3)；E环:77.30(C-8),27.47(8-CH3),124.65(C-9),115.97(C-10),41.85(C-11),22.58(C-12),23.85(C-13),131.86(C-14),25.62(14-CH3),17.64(14-CH3)。ES-,6.27e5，[M-H]-569.46(100％),[M]-570.49,[M+H]-571.33；ES+,2.23e6，[M+H]+571.49(100％),[M+2H]+572.53,[M+Na]+593.46,[M+Na+H]+594.43。cal calc.for：C34H34O8，反应式如下：
实施例7：E-3-(3,4,5-三OCH3苯次甲基)-8-CH3-8-(4-CH3-戊-3-烯)-吡喃并橙皮素的制备：称取CH3-8-(4-CH3-戊-3-烯)-吡喃并橙皮素0.268g，3,4,5-三OCH3苯甲醛0.121g，四氢呋喃5.0mL，四氢吡咯50μL，冰醋酸40μL，70℃密闭搅拌回流反应48h，回收反应液至体积1/2，硅胶拌样，以石油醚-乙酸乙酯＝3/1为洗脱剂，收集橘黄棕色色带，回收溶剂，得橘黄色固体200mg(Cpd 7)。1H NMR(400MHz,CDCl3)δ12.92(s,1H:5-OH),7.96(s,1H:1”-H),7.10(d,J＝1.8Hz,1H:2'-H),6.90(dd,J＝8.3,1.8Hz,1H:6'-H),6.78(d,J＝8.3Hz,1H:5'-H),6.61(d,J＝10.2Hz,1H:10-H),6.48(3H:3”-H+7”-H+H-2),5.81(s,1H:6-H),5.66(s,1H:3'-OH),5.38(d,J＝10.2,1H:9-H),5.05(m,1H:13-H),3.85(6H:4'-OCH3+5”-OCH3),3.65(s,6H:6”-OCH3+4”-OCH3),2.03(m,2H:12-CH2),1.72-1.62(M,8H:11-CH2+8-CH3+14-CH3),1.36(d,3H:14-CH3)。13C NMR
(101MHz,CDCl3)δA环：162.77(C-6a),159.75(C-5),159.15(C-10aa),107.52(C-4a),103.19(C-10a),96.74(C-6)；B环：131.28(C-1'),115.90(C-2'),146.03(C-3'),147.00(C-4'),114.04(C-5'),119.61(C-6'),55.95(4'-OCH3)；C环：80.79(C-2),130.56(C-3),184.94(C-4)；D环：77.75(C-8),27.19(8-CH3),124.75(C-9),115.90(C-10),41.65(C-11),22.58(C-12),123.80(C-13),131.83(C-14),25.60(14-CH3),17.55(14-CH3)；E环：139.52(C-1”),129.39(C-2”),110.41(C-3”+C-7”),153.18(C-4”+C-6”),138.74(C-5”),60.97(5”-OCH3),55.95(4”-OCH3+6”-OCH3)。ES-,5.18e5，[M-H]-613.52,[M]-614.45,[M+K]-653.37,[M+H-CH3]-600.61；ES+,5.93e6,[M+H]+615.53,[M+Na]+637.50(100％),[M+Na+H]+638.50,[M+K]+653.47,[M+K+H]+654.43。cal calc.for：C34H34O8，反应式如下：
实施例8：E-3-(N,N-二CH3苯次甲基)-8-CH3-8-(4-CH3-戊-3-烯)-吡喃并橙皮素的制备：称取CH3-8-(4-CH3-戊-3-烯)-吡喃并橙皮素0.268g，N,N-二CH3苯甲醛0.121g，四氢呋喃5.0mL，四氢吡咯50μL，冰醋酸40μL，70℃密闭搅拌回流反应48h，回收反应液至体积1/2，硅胶拌样，以石油醚-乙酸乙酯＝4.5/1为洗脱剂，收集橘红色色色带，回收溶剂，得橘红色固体250mg(Cpd 8)。1H NMR(400MHz,CDCl3)δ13.19(s,1H:5-OH),7.98(s,1H:1”-H),7.21(d,J＝8.7Hz,2H:3”-H+7”-H),7.13(d,J＝2.1Hz,1H:2'-H),6.94–6.86(m,1H:6'-H),6.75(d,J＝8.4Hz,1H:5'-H),6.62(dd,3H:10-H+4”-H+6”-H),6.54(s,1H:H-2),5.83(s,1H:6-H),5.60(s,1H:3'-OH),5.36(dd,J＝10.1,7.3Hz,1H:9-H),5.06(m,J＝6.9Hz,1H:13-H),3.85(s,3H:4'-OCH3),3.00(s,6H:5”-N(CH3)2),2.14–1.93(m,2H:12-CH2),1.76–1.53(m,8H:11-CH2+8-CH3+14-CH3),1.35(d,J＝7.4Hz,3H:14-CH3)。13C NMR(101MHz,CDCl3)δA环：162.09(C-6a),96.56(C-6),159.67(C-5),103.25(C-4a),159.11(C-10aa),102.72(C-10a)；B环：131.43(C-1'),114.03(C-2'),145.92(C-3'),146.83(C-4'),110.36(C-5'),119.40(C-6'),55.89(4”-OCH3)；C环：80.56(C-2),126.01(C-3),185.43(C-4)；D环：27.43(8-CH3),77.73(C-8),124.51(C-9),116.13(C-10),41.83(C-11),22.68(12-CH2),123.92(C-13),131.84(C-14),25.69(14-CH3),17.66(14-CH3)(D环及侧链受手性影响，峰分裂)；E环：139.66(C-1”),121.66(C-2”),132.77(C-3”+C-7”),111.80(C-4”+C-6”),151.37(C-5”),40.02(N-CH3)2。ES+,1.55e6,[M+H]+568.50,[M+2H]+569.45,[M+3H]+570.40,[M+Na]+590.46,[M+Na+H]+591.45,[M+Na+2H]+592.41,cal calc.for：C35H37NO6，反应式如下：
实施例9：E-3-(4-OH苯次甲基)-8-CH3-8-(4-CH3-戊-3-烯)-吡喃吡喃并柚皮素的制备：称取8-CH3-8-(4-CH3-戊-3-烯)-吡喃并橙皮素0.311g，4-OH苯甲醛0.094g，四氢呋喃5.0mL，四氢吡咯45μL，冰醋酸40μL，70℃密闭搅拌回流反应48h，回收反应液至体积1/2，硅胶拌样，以石油醚-乙酸乙酯＝2.5/1为洗脱剂，收集橘黄色色带，回收溶剂，得橘黄色固体288mg(Cpd 9)。1H NMR(400MHz,CDCl3)δ12.91(1H:5-OH),7.95(s,1H:1”-H),7.30(t,J＝7.7Hz,2H:3”-H+7”-H),7.15(t,J＝7.7Hz,2H:2'-H+6'-H),6.79(dd,J＝7.77,2.2Hz,4H:3'-H+5'-H+4”-H+6”-H),6.60(d,J＝10.2Hz,1H:10-H),6.47(s,1H:H-2),5.83(s,1H:6-H),5.38(dd,J＝10.2Hz,1H:9-H),5.04(m,1H:13-H)),2.03(td,J＝15.5,8.0Hz,2H:12-CH2),1.77–1.52(m,8H:11-CH2+8-CH3+14-CH3),1.36(3H:14-CH3)；13C NMR(101MHz,CDCl3)δA环：162.96(C-6a),96.81(C-6),159.83(C-5),103.22(C-4a),159.02(C-10aa),102.98(C-10a)；B环：129.81(C-1'),129.04(C-2'+C-6'),116.03(C-3'+C-5'),157.65(C-4')；C环：81.05(C-2),129.07(C-3),185.81(C-4)；D环：27.47(8-CH3),77.24(C-8),124.86(C-9),115.72(C-10),41.85(C-11),22.58(12-CH2),123.77(C-13),131.94(C-14),25.66(14-CH3),17.64(14-CH3)(D环及侧链受手性影响，峰分裂)；E环：138.89(C-1”),126.45(C-2”),132.45(C-3”+C-7”),115.83(C-4”+C-6”),156.12(C-5”)；ES-,2.21e6，[M-H]-509.40(100％),[M]-510.37,[M+H]-511.37；ES+,2.62e6,[M+H]+511.42(100％),[M+2H]+512.34.cal calc.for：C32H30O6，反应式如下：
实施例10：E-3-(3,4-二OH苯次甲基)-8-CH3-8-(4-CH3-戊-3-烯)-吡喃并柚皮素的制备：称取8-CH3-8-(4-CH3-戊-3-烯)-吡喃并橙皮素0.326g，3,4-二OH苯甲醛0.110g，四氢呋喃5.0mL，四氢吡咯50μL，冰醋酸45μL，70℃密闭搅拌回流反应48h，回收反应液至体积1/2，硅胶拌样，以石油醚-乙酸乙酯＝2/1为洗脱剂，收集橙红色色带，回收溶剂，得橙红色固体246mg(Cpd 10)。1H NMR(400MHz,CDCl3)δ12.86(d,J＝1.8Hz,1H:5-OH),7.87(s,1H:1”-H),7.26(d,J＝6.8Hz,2H:2'-H+6'-H),6.82(d,J＝8.0Hz,1H:3”-H),6.74(d,J＝9.1Hz,4H:3'-H+5'-H+3”-H+6”-H),6.61(d,J＝10.1Hz,1H:10-H),6.49(s,1H:H-2),5.86(s,1H:6-H),5.41(dd,J＝10.1,6.6Hz,1H:9-H),5.12–5.00(m,1H:13-H),2.05(dd,J＝17.3,8.4Hz,2H:12-CH2),1.82–1.55(m,8H:11-CH2+8-CH3+14-CH3),1.38(d,J＝12.9Hz,3H:14-CH3).13C NMR(101MHz,CDCl3)δA环：162.33(C-6a),96.97(C-6),159.71(C-5),103.30(C-4a),159.09(C-10aa),103.03(C-10a)；B环：130.91(C-1'),129.00(C-2'+C-6'),115.99(C-3'+C-5'),157.59(C-4')；C环：81.02(C-2),125.88(C-3),185.74(C-4)；D环：28.54(8-CH3),78.41(C-8),126.47(C-9),115.78(C-10),41.64(C-11),22.65(12-CH2),123.47(C-13),132.42(C-14),25.68(14-CH3),17.58(14-CH3)(D环及侧链受手性影响，峰分裂)；E环：138.95(C-1”),119.46(C-2”),145.83(C-4”),110.58(C-3”),146.97(C-5”),113.87(C-6”),115.25(C-7”)。ES-,4.72e6，[M-H]-525.41(100％),[M]-526.40,[M+H]-527.32；ES+,3.00e6，[M+H]+527.41(100％),[M+H]+528.40,[M+2H]+528.86,[M+Na]+549.43。cal calc.for：C32H30O7，反应式如下：
实施例11：
E-3-(3-OH-4-OCH3-苯次甲基)-8-CH3-8-(4-CH3-戊-3-烯)-吡喃并柚皮素的制备：称取CH3-8-(4-CH3-戊-3-烯)-吡喃并橙皮素0.322g，3-OH-4-OCH3苯甲醛0.120g，无水乙醇5.0mL，四氢吡咯50μL，冰醋酸45μL，70℃密闭搅拌反应48h，回收反应液至体积1/2，硅胶拌样，以石油醚-乙酸乙酯＝2.5/1为洗脱剂，收集橙黄色色带，回收溶剂，得橘黄色固体298mg(Cpd11)。1H NMR(400MHz,CDCl3)δ12.95(s,1H:5-OH),7.95(s,1H:1”-H),7.33(t,J＝7.1Hz,2H:H+3”-H+7”-H),6.89-6.78(m,5H:6”-H+6'-H+2'-H+3'-H+5'-H),6.63(d,J＝10.2Hz,1H:10-H),6.54(s,1H:H-2),5.85(s,1H:6-H),5.47–5.37(m,1H:9-H),5.13–5.00(m,1H:13-H),3.93(s,3H:5”-OCH3),2.06(m,2H:12-CH2),1.81–1.56(m,8H:11-CH2+8-CH3+14-CH3),1.38(d,3H:14-CH3)。13C NMR(101MHz,CDCl3)δA环：162.76(C-6a),96.72(C-6),159.83(C-5),103.26(C-4a),159.02(C-10aa),102.81(C-10a)；B环：129.90(C-1'),129.05(C-2'+C-6'),115.77(C-3'+C-5'),156.14(C-4')；C环：80.91(C-2),128.85(C-3),185.65(C-4)；D环：27.45(8-CH3),77.24(C-8),124.73(C-9),115.89(C-10),41.85(C-11),22.58(12-CH2),123.80(C-13),131.90(C-14),25.63(14-CH3),17.64(14-CH3)(D环及侧链受手性影响，峰分裂)；E环：138.74(C-1”),127.39(C-2”),116.08(C-3”),145.64(C-4”),148.20(C-5”),110.68(C-6”),123.58(C-7”)；ES-,7.06e5，[M-H]-539.23(100％),[M]-540.06；ES+,2.05e6，[M+H]+541.39(100％),[M+H]+542.43,[M+2H]+528.86,[M+Na]+563.36,[M+Na+H]+563.36。cal calc.for：C32H30O7，反应式如下：
实施例12：
E-3-(4-(N,N-二甲基)-苯次甲基)-8-CH3-8-(4-CH3-戊-3-烯)-吡喃并柚皮素的制备：称取CH3-8-(4-CH3-戊-3-烯)-吡喃并柚皮素0.355g，对二甲胺基苯甲醛0.133g，无水乙醇5.0mL，四氢吡咯45μL，冰醋酸40μL，70℃密闭搅拌反应48h，回收反应液至体积1/2，硅胶拌样，以石油醚-乙酸乙酯＝2.5/1为洗脱剂，收集橘红色色带，回收溶剂，得红棕色色固体342mg(Cpd12)。1H NMR(400MHz,CDCl3)δ13.17(s,1H:5-OH),7.98(s,1H:1”-H),7.32(d,J＝7.8Hz,2H:3”-H+7”-H),7.19(d,J＝8.7Hz,2H:2'-H+6'-H),6.75(d,J＝8.1Hz,2H:3'-H+5'-H),6.60(m,3H:4”-H+6”-H+10-H),6.57(s,1H:H-2),5.83(s,1H:6-H),5.36(m,1H:9-H),5.05(d,J＝6.0Hz,1H:13-H),2.98(d,J＝11.8Hz,6H:5”-N(CH3)2,2.04(dt,J＝19.7,7.8Hz,2H:12-CH2),1.76–1.52(m,8H:11-CH2+8-CH3+14-CH3),1.35(d,J＝9.9Hz,3H:14-CH3)。13CNMR(101MHz,CDCl3)δA环：162.29(C-6a),96.50(C-6),159.06(C-5),103.25(C-4a),159.77(C-10aa),102.88(C-10a)；B环：129.99(C-1'),129.12(C-2'+C-6'),115.66(C-3'+C-5'),156.29(C-4')；C环：80.71(C-2),128.94(C-3),185.64(C-4)；D环：27.41(8-CH3),80.71(C-8),124.57(C-9),116.06(C-10),41.84(C-11),22.60(12-CH2),123.88(C-13),131.86(C-14),25.64(14-CH3),17.64(14-CH3)(D环及侧链受手性影响，峰分裂)；E环：139.85(C-1”),126.05(C-2”),132.83(C-3”+C-7”),111.83(C-4”+C-6”),151.44(C-5”),40.01(N-CH3)2。ES+,1.02e6，[M+H]+538.50,[M+H]+539.62。cal calc.for：C34H35NO5，反应式如下：
实施例13：
E-3-(3,4-二OH苯次甲基)-8,8-二甲基吡喃并柚皮素的制备：取8,8-二甲基吡喃并柚皮素0.325g，3,4-二OH苯甲醛0.132g，四氢呋喃5.0mL，吡咯60ul，冰醋酸55ul，70℃密闭反应48h。回收反应液至体积1/2，硅胶拌样，以石油醚-乙酸乙酯＝2/1为洗脱剂，收集橘黄棕色色带，回收溶剂，得橙红色固体251mg(Cpd13)。ES-,1.73e6，[M-H]-457.35(100％),[M]-458.34,[M+H]-459.25；ES+,2.54e6，[M+H]+459.40(100％),[M+2H]+460.33,[M+Na]+481.35,[M+Na+H]+482.18,cal calc.for：C27H22O7，反应式如下：
实施例14
目的：测定其结构修饰产物后溶解度的变化，以橙皮素、柚皮素的脱氢修饰产物为对照，根据药典对极易溶解、易溶、溶解、略溶、微溶、难溶的规定。取供实验化合物10mg，用移液枪或移液管加入不同溶剂，密闭超声20s，密闭放置1h后观察溶解现象，如果不溶，继续增加溶剂体积用量，重复上述操作记录溶液体积用量。根据药典规定，判断化合物溶解性能，见表1，
表1香叶木素、芹菜素及橙皮素、柚皮素结构修饰产物在不同溶剂中溶解度对照
表1表明吡喃环并橙皮素、吡喃环并柚皮素经过结构3-次甲基苯衍生物的结构修饰，新引入的E环，含有极性基团，如羟基、胺基，甲氧基等，增大了同溶剂的作用力；此外，因空间位阻作用，B、E环发生发生扭曲，共平面变差，显著增加了溶解性，溶解性能优良。比橙皮素、柚皮素、香叶木素、芹菜素等黄酮类化合物，溶解度好很多。
实施例15
目的：初步评价结构修饰产物对抗氧化能力的影响：采用DPPH法，以橙皮素作为对照，进行说明。
对DPPH·清除试验：DPPH·是一种稳定的自由基，其醇溶液呈深紫色，在517nm处有一吸收峰。反应系统中的自由基清除剂可以和DPPH的单电子配对而使A517nm降低，因此，根据A517nm的变化来检测自由基的清除情况，评价样品的抗氧化能力。橙皮素设置6个梯度的浓度，为5、10、15、20、25、30、60μg/mL的样品85％乙醇溶液，取2.0mL样品，加人1.0mL，DPPH甲醇溶液(3.0×10-4mol/L)，混合30min后在520nm处测定各样品吸光值(Ai)，每份样品平行操作3次，最后取其平均值。DPPH·自由基清除率K按公式计算：K(％)＝[1-(Ai-Aj)/Ac]×100式中：Ac为2.0mL50％乙醇加入1.0mL DPPH甲醇溶液(3.0×10-4mol/L)混合后的吸光度，Aj为2.0mL样品加入1.0mL，甲醇混合后的吸光度，结果见表2：
表2橙皮素及其结构修饰产物的抗DPPH·的能力
清除DPPH·自由基的剂量主要和供电子有关，增加双键，对抗氧化能力略有增加，增加能够和羰基共轭的羟基，胺基，可以显著提升抗氧化能力。橙皮素分子中含有3个酚羟基，其中两个形成分子内氢键，4-OH中O的孤对电子向羰基转移，电子云密度显著降低，而其结构改造产物cpd4比橙皮素多了3个双键，一个邻二酚羟基，其抗氧化能力显著飙升。同理，cp8也比hespertin抗氧化能力好很多。可以代替后者，可作为食品、药品、化妆品中抗氧剂。
实施例16
目的：初步评价结构修饰产物对抗炎化能力的影响：采用二甲苯诱导小鼠耳肿胀实验法，以橙皮素及其结构修饰产物为例说明。
二甲苯诱导小鼠耳肿胀：取昆明种小鼠132只,按体重随机分为22组,每组6只,雌雄各半,即模型组(灌服0.5％CMC液0.4mL/20g)，阳性药组(萘普生45mg/kg)，橙皮素、cpd1-8化合物各为两组(分别灌服0.6％及0.3％药品)。以上各组小鼠每日给药1次/d,连续5d,于末次给药后30min,于小鼠右耳前后两面均匀涂抹二甲苯50μL,右耳作对照,致炎后30min脱颈椎处死小鼠,以7mm直径打孔器取下耳缘左、右片,分别用电子天平称重,以左、右耳片重量差表示肿胀度,并计算抑制率(％)＝(模型组平均肿胀度-给药组平均肿胀度)/模型组平均肿胀度×100％。进行组间显著差比较实验结果见表3：
表3橙皮素及其衍生物对二甲苯诱导小鼠耳肿胀的影响
与阴性组比*P<0.05,**P<0.01,***P<0.001。
Claims (8)
1.一种E-3-(苯基衍生物-次甲基)-吡喃并二氢黄酮衍生物，其结构通式如(Ⅰ)所示，
其中：R1可为-H、-CH3、-CH2CH3、-CH2CH2CH3、-CH＝C(CH3)2、-CH＝C(CH3)CH2CH2CH＝C(CH3)2；R2可为-H、-CH3；R3可为-H、-OH；R4可为-H、-OH、-OCH3、-N(CH3)2、-F、-Cl中单基团或多基团；R5可为-OH、-OCH3、-N(CH3)2-F、-Cl、-COOH中单基团或多基团；X可为-CH或-CH2。
2.一种E-3-(苯基衍生物-次甲基)-吡喃并二氢黄酮衍生物的制备，是以吡喃并(7,8)-二氢黄酮，在极性溶剂中，以有机碱+有机酸为催化剂，与苯甲醛衍生物通过aldolcondensation反应制得，其中吡喃并(7,8)-二氢黄酮与苯甲醛衍生物的质量mol比例为3:1-1:3，控制反应温度在室温-100℃，控制反应时间为1h-72h。
3.根据权利要求2所述的E-3-(苯基衍生物-次甲基)-吡喃并二氢黄酮衍生物的制备，其特征是所述的吡喃并(7,8)-二氢黄酮，其结构式见(II)，
其中：R1、R2、R3与结构(I)中的R1、R2、R3、X基团含义相同，R1可为-H、-CH3、-CH2CH3、-CH2CH2CH3、-CH＝C(CH3)2、-CH＝C(CH3)CH2CH2CH＝C(CH3)2；R2可为-H、-CH3；R3可为-H、-OH、-OCH3、-N(CH3)2、-F、-Cl中单基团或多基团；X可为-CH或-CH2。
4.根据权利要求2所述的E-3-(苯基衍生物-次甲基)-吡喃并二氢黄酮衍生物的制备，其特征是所述的苯甲醛衍生物，其结构式见(III)，
其中：R4与结构(I)中的R4基团含义相同：可为-OH、-OCH3、-N(CH3)2-F、-Cl、-COOH中单基团或多基团。
5.根据权利要求2所述的E-3-(苯基衍生物-次甲基)-吡喃并二氢黄酮衍生物的制备，其特征是所述的极性溶剂为DMSO、THF、醇类任意一种，所述的醇类为甲醇、乙醇、丙醇、异丙醇、乙二醇、丙二醇、丙三醇任意一种。
6.根据权利要求2所述的E-3-(苯基衍生物-次甲基)-吡喃并二氢黄酮衍生物的制备，其特征是所述的有机碱为二甲胺、二乙胺、四氢吡咯、哌啶、吗啉任意一种。
7.根据权利要求2所述的E-3-(苯基衍生物-次甲基)-吡喃并二氢黄酮衍生物的制备，其特征是所述的有机酸为甲酸、乙酸、丙酸、丁酸、戊酸、己酸、苯甲酸、苯乙酸、苯丙酸，乳酸、琥珀酸、酒石酸任意一种或几种。
8.一种E-3-(苯基衍生物-次甲基)-吡喃并二氢黄酮衍生物，用于抗炎、抗氧化食品、化妆品组合物，抗菌、抗肿瘤、心脑血管保护的药物的组合物。
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611105678.1A CN106749302B (zh) | 2016-12-05 | 2016-12-05 | E-3-(苯基衍生物-次甲基)-吡喃并二氢黄酮衍生物及制备及应用 |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201611105678.1A CN106749302B (zh) | 2016-12-05 | 2016-12-05 | E-3-(苯基衍生物-次甲基)-吡喃并二氢黄酮衍生物及制备及应用 |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN106749302A true CN106749302A (zh) | 2017-05-31 |
| CN106749302B CN106749302B (zh) | 2018-10-19 |
Family
ID=58878381
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201611105678.1A Active CN106749302B (zh) | 2016-12-05 | 2016-12-05 | E-3-(苯基衍生物-次甲基)-吡喃并二氢黄酮衍生物及制备及应用 |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN106749302B (zh) |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111978330A (zh) * | 2020-09-03 | 2020-11-24 | 中国科学院昆明植物研究所 | 黄烷醇-脂肪醇杂合体及其药物组合物与其制备方法和应用 |
Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104004037A (zh) * | 2014-06-12 | 2014-08-27 | 宜春学院 | 黄芩苷及其酯的8-位甲胺类衍生物及其制备方法 |
-
2016
- 2016-12-05 CN CN201611105678.1A patent/CN106749302B/zh active Active
Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104004037A (zh) * | 2014-06-12 | 2014-08-27 | 宜春学院 | 黄芩苷及其酯的8-位甲胺类衍生物及其制备方法 |
Non-Patent Citations (3)
| Title |
|---|
| HA MOHAMMED ET AL.: "Facile synthesis of chrysin-derivatives with promising activities as aromatase inhibitors", 《NATURAL PRODUCT COMMUNICATIONS》 * |
| 刘成伦等: "黄酮类化合物抗氧化性质的研究进展", 《食品研究与开发》 * |
| 宋成英等: "对生物黄酮生物活性的综述", 《化学工程与装备》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111978330A (zh) * | 2020-09-03 | 2020-11-24 | 中国科学院昆明植物研究所 | 黄烷醇-脂肪醇杂合体及其药物组合物与其制备方法和应用 |
| CN111978330B (zh) * | 2020-09-03 | 2023-08-22 | 中国科学院昆明植物研究所 | 黄烷醇-脂肪醇杂合体及其药物组合物与其制备方法和应用 |
Also Published As
| Publication number | Publication date |
|---|---|
| CN106749302B (zh) | 2018-10-19 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Lee et al. | Antioxidative phenolic compounds from the roots of Rhodiola sachalinensis A. Bor | |
| Güvenç et al. | Investigations of anti-inflammatory, antinociceptive, antioxidant and aldose reductase inhibitory activities of phenolic compounds from Sideritis brevibracteata | |
| Salama | Alkaloids and flavonoids from the air dried aerial parts of Citrullus colocynthis | |
| Ali et al. | Anti-ulcer xanthones from the roots of Hypericum oblongifolium Wall | |
| Bangani et al. | Homoisoflavanones and stilbenoids from Scilla nervosa | |
| Ming et al. | Investigation on Flos Trollii: constituents and bioactivities | |
| CN104761526A (zh) | 一种具有抗病毒活性的异黄酮类化合物及其制备方法和应用 | |
| CN106749302B (zh) | E-3-(苯基衍生物-次甲基)-吡喃并二氢黄酮衍生物及制备及应用 | |
| CN105646621B (zh) | 漾濞核桃青皮中一种异黄酮苷及其制备方法和抗炎用途 | |
| CN105503778A (zh) | 一种木藜芦烷型二萜化合物及其制备方法和医药用途 | |
| CN103288614B (zh) | 具有抗肿瘤活性的间苯三酚类化合物及其药物组合物 | |
| CN106397380B (zh) | 7-oh-8-[(1-胺基-1-苯基衍生物)-次甲基]-黄酮化合物及其制备方法及其应用 | |
| CN107383129B (zh) | 一种香豆素苷类化合物及其制备方法和应用 | |
| Abd El-kader et al. | Xanthone and lignan glycosides from the aerial parts of Polygonum bellardii all growing in Egypt | |
| CN112961137B (zh) | 一种黄烷-3,4-二醇衍生物及其提取方法和用途 | |
| CN112920151B (zh) | 异戊烯基黄酮类化合物及其制备方法和应用 | |
| CN106632545B (zh) | (z，e)5-oh-3-(苯基衍生物-次甲基)-二氢黄酮-7-o-糖苷及其制备及其应用 | |
| Chokchaichamnankit et al. | Prenylated flavonoids from the leaves of Derris malaccensis and their cytotoxicity | |
| CN105726656A (zh) | 一种治疗妇科炎症用组合物、制备方法与栓制剂 | |
| Lee et al. | Anti-neutrophilic inflammatory secondary metabolites from the traditional Chinese medicine, Tiankuizi | |
| CN105348272A (zh) | 一种新的柠檬苦素类化合物及其制备方法和医药用途 | |
| El-Sherbeni et al. | Anti-oxidant and cytotoxic activities of Cassia nodosa Buch.-Ham. Ex Roxb. and some of its pure constituents | |
| CN104610396B (zh) | 一种氧化吡咯里西啶生物碱苷类化合物及其用途 | |
| CN103665090B (zh) | 枸骨皂苷化合物、其制备方法及应用 | |
| CN103374051A (zh) | 一种葛花鸢尾苷的制备方法与应用 |
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 | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |