CN100586937C - Ligustrazine stilbenoids derivatives, preparation method thereof, medicament composition and use - Google Patents
Ligustrazine stilbenoids derivatives, preparation method thereof, medicament composition and use Download PDFInfo
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- CN100586937C CN100586937C CN200710014906A CN200710014906A CN100586937C CN 100586937 C CN100586937 C CN 100586937C CN 200710014906 A CN200710014906 A CN 200710014906A CN 200710014906 A CN200710014906 A CN 200710014906A CN 100586937 C CN100586937 C CN 100586937C
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- China
- Prior art keywords
- trimethylpyrazine
- ligustrazine
- preparation
- ethyl acetate
- anhydrous
- Prior art date
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- FINHMKGKINIASC-UHFFFAOYSA-N tetramethyl-pyrazine Natural products CC1=NC(C)=C(C)N=C1C FINHMKGKINIASC-UHFFFAOYSA-N 0.000 title claims abstract description 66
- 238000002360 preparation method Methods 0.000 title claims abstract description 48
- -1 Ligustrazine stilbenoids Chemical class 0.000 title claims abstract description 42
- 239000003814 drug Substances 0.000 title claims abstract description 18
- 239000000203 mixture Substances 0.000 title claims description 34
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims abstract description 76
- YLQBMQCUIZJEEH-UHFFFAOYSA-N Furan Chemical group C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims abstract description 39
- 238000003756 stirring Methods 0.000 claims abstract description 17
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims abstract description 15
- 238000001035 drying Methods 0.000 claims abstract description 13
- 238000010025 steaming Methods 0.000 claims abstract description 11
- 238000004440 column chromatography Methods 0.000 claims abstract description 10
- BDZBKCUKTQZUTL-UHFFFAOYSA-N triethyl phosphite Chemical compound CCOP(OCC)OCC BDZBKCUKTQZUTL-UHFFFAOYSA-N 0.000 claims abstract description 10
- NNXBZTOMYBIUGR-UHFFFAOYSA-N 2-(chloromethyl)-3,5,6-trimethylpyrazine Chemical compound CC1=NC(C)=C(CCl)N=C1C NNXBZTOMYBIUGR-UHFFFAOYSA-N 0.000 claims abstract description 6
- 201000001320 Atherosclerosis Diseases 0.000 claims abstract description 3
- 208000029078 coronary artery disease Diseases 0.000 claims abstract description 3
- 238000010438 heat treatment Methods 0.000 claims abstract description 3
- 238000010992 reflux Methods 0.000 claims abstract description 3
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 102
- XDTMQSROBMDMFD-UHFFFAOYSA-N Cyclohexane Chemical compound C1CCCCC1 XDTMQSROBMDMFD-UHFFFAOYSA-N 0.000 claims description 32
- 239000013078 crystal Substances 0.000 claims description 27
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 20
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims description 12
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 12
- 239000011259 mixed solution Substances 0.000 claims description 12
- 238000012544 monitoring process Methods 0.000 claims description 12
- 239000000243 solution Substances 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 10
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 10
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 9
- MHAJPDPJQMAIIY-UHFFFAOYSA-N Hydrogen peroxide Chemical compound OO MHAJPDPJQMAIIY-UHFFFAOYSA-N 0.000 claims description 8
- 238000003810 ethyl acetate extraction Methods 0.000 claims description 8
- SMQUZDBALVYZAC-UHFFFAOYSA-N salicylaldehyde Chemical compound OC1=CC=CC=C1C=O SMQUZDBALVYZAC-UHFFFAOYSA-N 0.000 claims description 8
- 239000011734 sodium Substances 0.000 claims description 8
- 239000007787 solid Substances 0.000 claims description 8
- 239000002904 solvent Substances 0.000 claims description 7
- PKZJLOCLABXVMC-UHFFFAOYSA-N 2-Methoxybenzaldehyde Chemical compound COC1=CC=CC=C1C=O PKZJLOCLABXVMC-UHFFFAOYSA-N 0.000 claims description 6
- HSGOLPGJARMUOX-UHFFFAOYSA-N 3,5,6-trimethylpyrazine-2-carbaldehyde Chemical compound CC1=NC(C)=C(C=O)N=C1C HSGOLPGJARMUOX-UHFFFAOYSA-N 0.000 claims description 6
- WMPDAIZRQDCGFH-UHFFFAOYSA-N 3-methoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1 WMPDAIZRQDCGFH-UHFFFAOYSA-N 0.000 claims description 6
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 6
- KCXMKQUNVWSEMD-UHFFFAOYSA-N benzyl chloride Chemical compound ClCC1=CC=CC=C1 KCXMKQUNVWSEMD-UHFFFAOYSA-N 0.000 claims description 6
- 229940073608 benzyl chloride Drugs 0.000 claims description 6
- 238000009835 boiling Methods 0.000 claims description 6
- 229960001701 chloroform Drugs 0.000 claims description 6
- ZRSNZINYAWTAHE-UHFFFAOYSA-N p-methoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C=C1 ZRSNZINYAWTAHE-UHFFFAOYSA-N 0.000 claims description 6
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 6
- LAXOCXPBJXIBHO-UHFFFAOYSA-N (3,5,6-trimethylpyrazin-2-yl)methanol Chemical compound CC1=NC(C)=C(CO)N=C1C LAXOCXPBJXIBHO-UHFFFAOYSA-N 0.000 claims description 5
- 150000003934 aromatic aldehydes Chemical class 0.000 claims description 5
- WSFSSNUMVMOOMR-UHFFFAOYSA-N formaldehyde Substances O=C WSFSSNUMVMOOMR-UHFFFAOYSA-N 0.000 claims description 5
- GTLWADFFABIGAE-UHFFFAOYSA-N 1-chloroethylbenzene Chemical group CC(Cl)C1=CC=CC=C1 GTLWADFFABIGAE-UHFFFAOYSA-N 0.000 claims description 4
- IAVREABSGIHHMO-UHFFFAOYSA-N 3-hydroxybenzaldehyde Chemical compound OC1=CC=CC(C=O)=C1 IAVREABSGIHHMO-UHFFFAOYSA-N 0.000 claims description 4
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 4
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 239000012043 crude product Substances 0.000 claims description 4
- 238000000605 extraction Methods 0.000 claims description 4
- 125000006277 halobenzyl group Chemical group 0.000 claims description 4
- 239000010410 layer Substances 0.000 claims description 4
- 239000012044 organic layer Substances 0.000 claims description 4
- 238000001953 recrystallisation Methods 0.000 claims description 4
- FPYUJUBAXZAQNL-UHFFFAOYSA-N 2-chlorobenzaldehyde Chemical compound ClC1=CC=CC=C1C=O FPYUJUBAXZAQNL-UHFFFAOYSA-N 0.000 claims description 3
- ZWDVQMVZZYIAHO-UHFFFAOYSA-N 2-fluorobenzaldehyde Chemical compound FC1=CC=CC=C1C=O ZWDVQMVZZYIAHO-UHFFFAOYSA-N 0.000 claims description 3
- SRWILAKSARHZPR-UHFFFAOYSA-N 3-chlorobenzaldehyde Chemical compound ClC1=CC=CC(C=O)=C1 SRWILAKSARHZPR-UHFFFAOYSA-N 0.000 claims description 3
- UOQXIWFBQSVDPP-UHFFFAOYSA-N 4-fluorobenzaldehyde Chemical compound FC1=CC=C(C=O)C=C1 UOQXIWFBQSVDPP-UHFFFAOYSA-N 0.000 claims description 3
- BXRFQSNOROATLV-UHFFFAOYSA-N 4-nitrobenzaldehyde Chemical compound [O-][N+](=O)C1=CC=C(C=O)C=C1 BXRFQSNOROATLV-UHFFFAOYSA-N 0.000 claims description 3
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 3
- TUBUGIPAUYMXPQ-UHFFFAOYSA-N formaldehyde;2-methoxyphenol Chemical compound O=C.COC1=CC=CC=C1O TUBUGIPAUYMXPQ-UHFFFAOYSA-N 0.000 claims description 3
- CNUDBTRUORMMPA-UHFFFAOYSA-N formylthiophene Chemical compound O=CC1=CC=CS1 CNUDBTRUORMMPA-UHFFFAOYSA-N 0.000 claims description 3
- OVWYEQOVUDKZNU-UHFFFAOYSA-N m-tolualdehyde Chemical compound CC1=CC=CC(C=O)=C1 OVWYEQOVUDKZNU-UHFFFAOYSA-N 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- MAAZDFZETNADTQ-UHFFFAOYSA-N 2,3,5,6-tetramethylpyrazine;trihydrate Chemical compound O.O.O.CC1=NC(C)=C(C)N=C1C MAAZDFZETNADTQ-UHFFFAOYSA-N 0.000 claims description 2
- 229960000583 acetic acid Drugs 0.000 claims description 2
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 2
- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 238000001816 cooling Methods 0.000 claims description 2
- 239000012362 glacial acetic acid Substances 0.000 claims description 2
- 208000028867 ischemia Diseases 0.000 claims description 2
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 claims description 2
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 2
- 125000003107 substituted aryl group Chemical group 0.000 claims 1
- 238000000034 method Methods 0.000 abstract description 9
- 208000026106 cerebrovascular disease Diseases 0.000 abstract description 8
- 150000001875 compounds Chemical class 0.000 abstract description 6
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N Phenol Chemical group OC1=CC=CC=C1 ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 abstract description 4
- 125000001207 fluorophenyl group Chemical group 0.000 abstract description 2
- 241001597008 Nomeidae Species 0.000 abstract 3
- YTPLMLYBLZKORZ-UHFFFAOYSA-N Thiophene Chemical compound C=1C=CSC=1 YTPLMLYBLZKORZ-UHFFFAOYSA-N 0.000 abstract 2
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 abstract 2
- RDOXTESZEPMUJZ-UHFFFAOYSA-N anisole Chemical compound COC1=CC=CC=C1 RDOXTESZEPMUJZ-UHFFFAOYSA-N 0.000 abstract 2
- 238000002156 mixing Methods 0.000 abstract 2
- LQNUZADURLCDLV-UHFFFAOYSA-N nitrobenzene Chemical compound [O-][N+](=O)C1=CC=CC=C1 LQNUZADURLCDLV-UHFFFAOYSA-N 0.000 abstract 2
- 125000003118 aryl group Chemical group 0.000 abstract 1
- JFDZBHWFFUWGJE-UHFFFAOYSA-N benzonitrile Chemical compound N#CC1=CC=CC=C1 JFDZBHWFFUWGJE-UHFFFAOYSA-N 0.000 abstract 1
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 abstract 1
- 238000001914 filtration Methods 0.000 abstract 1
- 208000023589 ischemic disease Diseases 0.000 abstract 1
- UZKWTJUDCOPSNM-UHFFFAOYSA-N methoxybenzene Substances CCCCOC=C UZKWTJUDCOPSNM-UHFFFAOYSA-N 0.000 abstract 1
- 229960003742 phenol Drugs 0.000 abstract 1
- 238000005160 1H NMR spectroscopy Methods 0.000 description 28
- 238000002330 electrospray ionisation mass spectrometry Methods 0.000 description 28
- 239000003480 eluent Substances 0.000 description 28
- 238000010183 spectrum analysis Methods 0.000 description 26
- 238000001644 13C nuclear magnetic resonance spectroscopy Methods 0.000 description 18
- 239000002585 base Substances 0.000 description 16
- 230000002526 effect on cardiovascular system Effects 0.000 description 8
- 208000024172 Cardiovascular disease Diseases 0.000 description 7
- 241000112528 Ligusticum striatum Species 0.000 description 5
- 239000008194 pharmaceutical composition Substances 0.000 description 5
- 238000011160 research Methods 0.000 description 5
- 210000003556 vascular endothelial cell Anatomy 0.000 description 5
- VGGSQFUCUMXWEO-UHFFFAOYSA-N Ethene Chemical class C=C VGGSQFUCUMXWEO-UHFFFAOYSA-N 0.000 description 4
- 239000005977 Ethylene Substances 0.000 description 4
- 230000006378 damage Effects 0.000 description 4
- 238000013461 design Methods 0.000 description 4
- 229940079593 drug Drugs 0.000 description 4
- 230000000694 effects Effects 0.000 description 4
- 239000012980 RPMI-1640 medium Substances 0.000 description 3
- LUKBXSAWLPMMSZ-OWOJBTEDSA-N Trans-resveratrol Chemical compound C1=CC(O)=CC=C1\C=C\C1=CC(O)=CC(O)=C1 LUKBXSAWLPMMSZ-OWOJBTEDSA-N 0.000 description 3
- 244000309466 calf Species 0.000 description 3
- 239000000460 chlorine Substances 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 229910052731 fluorine Inorganic materials 0.000 description 3
- 230000036541 health Effects 0.000 description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 3
- 235000015097 nutrients Nutrition 0.000 description 3
- 238000005502 peroxidation Methods 0.000 description 3
- 210000002966 serum Anatomy 0.000 description 3
- 235000018991 trans-resveratrol Nutrition 0.000 description 3
- JIVGSHFYXPRRSZ-UHFFFAOYSA-N 2,3-dimethoxybenzaldehyde Chemical compound COC1=CC=CC(C=O)=C1OC JIVGSHFYXPRRSZ-UHFFFAOYSA-N 0.000 description 2
- LWRSYTXEQUUTKW-UHFFFAOYSA-N 2,4-dimethoxybenzaldehyde Chemical compound COC1=CC=C(C=O)C(OC)=C1 LWRSYTXEQUUTKW-UHFFFAOYSA-N 0.000 description 2
- AVPYQKSLYISFPO-UHFFFAOYSA-N 4-chlorobenzaldehyde Chemical compound ClC1=CC=C(C=O)C=C1 AVPYQKSLYISFPO-UHFFFAOYSA-N 0.000 description 2
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical group [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 description 2
- 208000027418 Wounds and injury Diseases 0.000 description 2
- 230000002785 anti-thrombosis Effects 0.000 description 2
- 239000003146 anticoagulant agent Substances 0.000 description 2
- 239000011737 fluorine Substances 0.000 description 2
- 208000014674 injury Diseases 0.000 description 2
- 231100000053 low toxicity Toxicity 0.000 description 2
- 125000000449 nitro group Chemical group [O-][N+](*)=O 0.000 description 2
- 230000008520 organization Effects 0.000 description 2
- 150000002978 peroxides Chemical class 0.000 description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 2
- 235000013824 polyphenols Nutrition 0.000 description 2
- 125000003373 pyrazinyl group Chemical group 0.000 description 2
- 238000000926 separation method Methods 0.000 description 2
- 230000009466 transformation Effects 0.000 description 2
- WJUFSDZVCOTFON-UHFFFAOYSA-N veratraldehyde Chemical compound COC1=CC=C(C=O)C=C1OC WJUFSDZVCOTFON-UHFFFAOYSA-N 0.000 description 2
- VQRBXYBBGHOGFT-UHFFFAOYSA-N 1-(chloromethyl)-2-methylbenzene Chemical compound CC1=CC=CC=C1CCl VQRBXYBBGHOGFT-UHFFFAOYSA-N 0.000 description 1
- DMHZDOTYAVHSEH-UHFFFAOYSA-N 1-(chloromethyl)-4-methylbenzene Chemical compound CC1=CC=C(CCl)C=C1 DMHZDOTYAVHSEH-UHFFFAOYSA-N 0.000 description 1
- OJFDIGNMEQRUNF-UHFFFAOYSA-N 2,3,5-trimethyl-6-(2-phenylethenyl)pyrazine Chemical compound N1=C(C)C(C)=NC(C)=C1C=CC1=CC=CC=C1 OJFDIGNMEQRUNF-UHFFFAOYSA-N 0.000 description 1
- AFUKNJHPZAVHGQ-UHFFFAOYSA-N 2,5-dimethoxy-Benzaldehyde Chemical compound COC1=CC=C(OC)C(C=O)=C1 AFUKNJHPZAVHGQ-UHFFFAOYSA-N 0.000 description 1
- 125000004172 4-methoxyphenyl group Chemical group [H]C1=C([H])C(OC([H])([H])[H])=C([H])C([H])=C1* 0.000 description 1
- 201000006474 Brain Ischemia Diseases 0.000 description 1
- 101150041968 CDC13 gene Proteins 0.000 description 1
- 206010008120 Cerebral ischaemia Diseases 0.000 description 1
- 241000125183 Crithmum maritimum Species 0.000 description 1
- 235000014375 Curcuma Nutrition 0.000 description 1
- 244000164480 Curcuma aromatica Species 0.000 description 1
- 240000009138 Curcuma zedoaria Species 0.000 description 1
- 235000003405 Curcuma zedoaria Nutrition 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 241001465251 Ephedra sinica Species 0.000 description 1
- PXGOKWXKJXAPGV-UHFFFAOYSA-N Fluorine Chemical group FF PXGOKWXKJXAPGV-UHFFFAOYSA-N 0.000 description 1
- 241000244365 Ligusticum sinense Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
- PJANXHGTPQOBST-VAWYXSNFSA-N Stilbene Natural products C=1C=CC=CC=1/C=C/C1=CC=CC=C1 PJANXHGTPQOBST-VAWYXSNFSA-N 0.000 description 1
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical group C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 description 1
- 208000007536 Thrombosis Diseases 0.000 description 1
- HEDRZPFGACZZDS-MICDWDOJSA-N Trichloro(2H)methane Chemical compound [2H]C(Cl)(Cl)Cl HEDRZPFGACZZDS-MICDWDOJSA-N 0.000 description 1
- 239000004480 active ingredient Substances 0.000 description 1
- 239000003513 alkali Substances 0.000 description 1
- 229930013930 alkaloid Natural products 0.000 description 1
- 230000000489 anti-atherogenic effect Effects 0.000 description 1
- 229940127219 anticoagulant drug Drugs 0.000 description 1
- UHOVQNZJYSORNB-UHFFFAOYSA-N benzene Substances C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 1
- 150000001555 benzenes Chemical group 0.000 description 1
- 210000004027 cell Anatomy 0.000 description 1
- 206010008118 cerebral infarction Diseases 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 239000001812 curcuma zedoaria berg. rosc. Substances 0.000 description 1
- VFLDPWHFBUODDF-FCXRPNKRSA-N curcumin Chemical compound C1=C(O)C(OC)=CC(\C=C\C(=O)CC(=O)\C=C\C=2C=C(OC)C(O)=CC=2)=C1 VFLDPWHFBUODDF-FCXRPNKRSA-N 0.000 description 1
- 125000004802 cyanophenyl group Chemical group 0.000 description 1
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- 201000010099 disease Diseases 0.000 description 1
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 1
- 239000002552 dosage form Substances 0.000 description 1
- 238000001647 drug administration Methods 0.000 description 1
- 210000003725 endotheliocyte Anatomy 0.000 description 1
- 239000002532 enzyme inhibitor Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 150000002240 furans Chemical group 0.000 description 1
- HYBBIBNJHNGZAN-UHFFFAOYSA-N furfural Chemical compound O=CC1=CC=CO1 HYBBIBNJHNGZAN-UHFFFAOYSA-N 0.000 description 1
- 125000002541 furyl group Chemical group 0.000 description 1
- 125000000623 heterocyclic group Chemical group 0.000 description 1
- 229910052739 hydrogen Inorganic materials 0.000 description 1
- 125000004464 hydroxyphenyl group Chemical group 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 231100000225 lethality Toxicity 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- JESXATFQYMPTNL-UHFFFAOYSA-N mono-hydroxyphenyl-ethylene Natural products OC1=CC=CC=C1C=C JESXATFQYMPTNL-UHFFFAOYSA-N 0.000 description 1
- 125000006501 nitrophenyl group Chemical group 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
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- 238000012827 research and development Methods 0.000 description 1
- 235000021286 stilbenes Nutrition 0.000 description 1
- 150000003436 stilbenoids Chemical class 0.000 description 1
- QTENRWWVYAAPBI-YCRXJPFRSA-N streptomycin sulfate Chemical compound OS(O)(=O)=O.OS(O)(=O)=O.OS(O)(=O)=O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O.CN[C@H]1[C@H](O)[C@@H](O)[C@H](CO)O[C@H]1O[C@@H]1[C@](C=O)(O)[C@H](C)O[C@H]1O[C@@H]1[C@@H](N=C(N)N)[C@H](O)[C@@H](N=C(N)N)[C@H](O)[C@H]1O QTENRWWVYAAPBI-YCRXJPFRSA-N 0.000 description 1
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- 125000001544 thienyl group Chemical group 0.000 description 1
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- 231100000331 toxic Toxicity 0.000 description 1
- 230000002588 toxic effect Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000024883 vasodilation Effects 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 239000000341 volatile oil Substances 0.000 description 1
- 235000019509 white turmeric Nutrition 0.000 description 1
Landscapes
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention relates to a kind of ligustrazine derivant, preparation method and medicinal compound and its application, belonging to chuanxiong rhizome derivant medicine technique. The structure general formula is as that: Ar is hydroxybenzene, fluorophenyl, chlorphenyl, methylbenzene, methoxybenzene, nitrobenzene, cyanobenzene, furan group, ligustrazine or thiofuran. Said preparation method comprises following steps: mixing intermediate 2- chloromethyl- 3, 5, 6- trimethyl pyrazine and halogenated benzyl, triethyl phosphite; heating and refluxing, adding waterless tetrahydrofuran and NaH at tetrahydrofuran bath condition, dropping mixing solution of aromatic aldchyde and waterless tetrahydrofuran, stirring, extracting, drying, filtering, steaming to remove disslovant, separating residueswith fast column chromatography, recrystallizing with methanol, and getting ligustrazine derivant. Said product and medical findings can be used to produce medicinal compound, and medicine for preventing angiocardiopathy and cerebrovascular diseases such as ischemic disease, atherosclerosis and coronary disease.
Description
(1) technical field
The present invention relates to a kind of derivative and preparation method thereof, be specifically related to ligustrazine stilbenoids derivatives and preparation method thereof, and relate to, belong to the derivative drugs technical field this derivative and assistant agent composition pharmaceutical composition.
(2) background technology
Cardiovascular and cerebrovascular diseases is lethality rate and disability rate the highest common clinical and frequently-occurring disease, is " the No.1 killer " of the harm humans health of The World Health Organization's identification.The data presentation of World Health Organization's announcement in 2006, the whole world has 1,500 ten thousand people to die from cardiovascular and cerebrovascular disease every year approximately, accounts for 30% of total dead population.The medicine for the treatment of at present cardiovascular and cerebrovascular diseases clinically is numerous, but shortcoming such as ubiquity poor selectivity, toxic side effect be bigger.Therefore, research and development cardiovascular and cerebrovascular diseases medicine efficient, low toxicity is still one of emphasis of drug research.
Ligusticum wallichii is the dry rhizome of samphire Ligusticum wallichii (Ligusticum chuanxiong Hort), is widely used in Chinese patent medicine as tcm clinical practice blood-activating and qi-promoting, wind-expelling pain-stopping medicine, the treatment cardiovascular and cerebrovascular diseases.Its main active ingredient is Ligusticum wallichii alkaloids such as Ligustrazine.
Ligustrazine (Ligustrazine) different name Ligusticum wallichii I alkali, the chemical name 2, the abbreviation tetramethylpyrazine (Tetramethylyrazine, TMP), the structure See Figure:
China at first gets TMP from conventional Chinese medicine Ligusticum wallichii rhizome, also find the existence of TMP then in the volatile oil component of zingiberaceous plant temperature curcuma zedoary rhizome and ephedra sinica.Pharmaceutical research shows: Ligustrazine has vasodilation, anticoagulant, prevents thrombosis, improves multiple effects such as cerebral ischemia.
Because the Ligustrazine internal metabolism is fast, the transformation period is short, be the pharmacological agent concentration of remaining valid, clinically must frequent drug administration, poison so easily cause savings, make its application be subjected to certain limitation, referring to Xu Rui, Li Yuan, Huang Xi, Ligustrazine pharmacokinetics progress, the Anhui Chinese Medicine College journal, 2002,21 (1): 58-61.Therefore, be that lead compound carries out structural modification and transformation with the Ligustrazine, reduce its toxicity, improve its pharmacokinetic property, research and develop Ligustrazine class cardiovascular and cerebrovascular diseases medicine tool new and effective, low toxicity and have very important significance.
(3) summary of the invention
The present invention is directed to the deficiencies in the prior art, a kind of ligustrazine stilbenoids derivatives and preparation method thereof and the pharmaceutical composition and the application that contain ligustrazine stilbenoids derivatives are provided.
Technical scheme of the present invention is as follows:
1. ligustrazine stilbenoids derivatives
Ligustrazine stilbenoids derivatives of the present invention is 2-(substituted ethylene base)-3,5, and 6-trimethylpyrazine analog derivative has following general structure:
Wherein Ar is hydroxy phenyl, fluorophenyl, chloro-phenyl-, aminomethyl phenyl, p-methoxy-phenyl, nitrophenyl, cyano-phenyl, furyl, Ligustrazine base or thienyl.
The code name and the concrete structure of target compound of the present invention see Table 1.
The structural formula of table 1 target compound A1-A28
The present invention is structural models with the trans-resveratrol, keeping under the constant prerequisite of its basic framework, substitute one of them phenyl ring with the pyrazine ring, promptly on the Ligustrazine side chain, introduce the substituted phenylethylene base, 28 ligustrazine stilbenoids derivatives have been synthesized in design: (1) studies show that, the trans-resveratrol activity of transconfiguration is apparently higher than cis, so be the synthetic target compound with Ligustrazine trans-stilben analog derivative; Discover that (2) close relationship of phenolic hydroxyl group has been synthesized hydroxyl stilbenoids derivatives A2, A7 etc. so design on the cardiovascular and cerebrovascular of trans-resveratrol active as study of anti-atherogenic effect, anti thrombotic action etc. and its structure; (3) according to the bioisostere principle, with OH with isostere F, Cl, CH
3Substitute, fluorine, chlorine, methyl substituted derivative A4, A3, A18 etc. have been synthesized in design; (4) research report, the Stilbene prostanoid enzyme inhibitors with antithrombotic acitivity contains in molecule the phenolic hydroxyl group, also contains methoxyl group etc., thereby has designed class stilbenoids derivatives A5, A10, A17 etc. that a series of methoxyl group replaces; (5) in order further to inquire into the structure activity relationship between ligustrazine stilbenoids derivatives different substituents and the different fragrant heterocycle, the present invention has also introduced group such as A9, A26 such as nitro, cyano group at phenyl ring, while, with furan nucleus, thiphene ring, pyrazine ring substituted benzene ring etc., A15, A22, A24 etc. were synthesized in design in the ligustrazine stilbenoids structure.
2. the synthetic route of ligustrazine stilbenoids derivatives is as follows:
Method 1:
Method 2:
R is fluorine, chlorine, hydroxyl, methoxyl group, methyl, cyano group or nitro in the above reaction formula,
The title of intermediate 4,5,6 is respectively: intermediate 4 is 2-methylol-3,5, and 6-trimethylpyrazine, intermediate 5 are 2-chloromethyl-3,5, and 6-trimethylpyrazine, intermediate 6 are 3,5,6-trimethylpyrazine-2-formaldehyde.
Among the following preparation method except that specifying used reagent concentration be mass volume ratio.
3. intermediate 2-methylol-3,5, the preparation method of 6-trimethylpyrazine 4
With Tetramethylpyrazine trihydrate (30.4g, 160mmol), Glacial acetic acid (40ml) and 30% hydrogen peroxide (18ml, mixture 160mmol) is in 70 ℃ of reacting by heating 4h, (18ml 160mmol), continues reaction 4h to replenish adding 30% hydrogen peroxide, the TLC monitoring is to reacting completely, be cooled to room temperature, regulate pH=10, chloroform extraction with 50% sodium hydroxide solution, anhydrous sodium sulfate drying, filter, boil off trichloromethane, obtain Ligustrazine list oxynitrides crude product.Add aceticanhydride (15.1ml then; 160mmol), reflux 2.5h, TLC monitoring is after react completely; remove excessive aceticanhydride under reduced pressure; obtain black pulpous state Ligustrazine acetylate, the cooling back adds 20% sodium hydroxide solution (155ml), and placement is spent the night; chloroform extraction (150ml; 30ml * 5 time), anhydrous sodium sulfate drying filters; remove solvent under reduced pressure; obtain 2-methylol-3,5,6-trimethylpyrazine 4 crude products; with the normal hexane recrystallization; yellow needle crystal intermediate 4 (15.5g, yield 64%), mp:88～89 ℃.
4. intermediate 2-chloromethyl-3,5, the preparation method of 6-trimethylpyrazine 5
With above-mentioned gained 2-methylol-3,5,6-trimethylpyrazine 4 (15.5g, 102mmol) with methylene dichloride 300ml dissolving, (7.4ml 102mmol), dropwise adds dichloromethane solution under condition of ice bath to get sulfur oxychloride, ice bath reaction 30min, room temperature reaction 2.5h again, the TLC monitoring reaction is complete, removes solvent under reduced pressure, the residue dissolve with ethanol, add 5%KOH ethanolic soln 100ml, stir a moment, filter, steaming desolventizes, get yellow solid 2-chloromethyl-3,5,6-trimethylpyrazine 5 (21.1g, yield 100%), mp:102～105 ℃.
5. intermediate 3,5, the preparation method of 6-trimethylpyrazine-2-formaldehyde 6
With above-mentioned gained 2-methylol-3,5, and 6-trimethylpyrazine 4 (1.52g, 10mmol), DCC (4.25g, 20mmol) mix mutually with anhydrous dimethyl sulphoxide (10ml), stir slowly drip down phosphoric acid (0.51g, 5mmol), exothermic heat of reaction, interior temperature slowly raises, and separates out solid, is chilled to room temperature, wash solid with ethyl acetate, filter, water gagings such as adding mix, jolting, water layer are alkalized to pH9～10, separate organic layer, the ethyl acetate extraction water layer merges organic layer, anhydrous Na for several times
2SO
4Drying, steaming desolventizes, faint yellow solid, fast post separate (ethyl acetate: hexanaphthene 1: 3), white crystal 3,5,6-trimethylpyrazine-2-formaldehyde 6 (0.75g, yield 50%), mp:79～80 ℃.
6. target product 2-(substituted ethylene base)-3,5, the preparation method of 6-trimethylpyrazine analog derivative
(1) 2-(substituted ethylene base)-3,5, synthetic (method 1) of 6-trimethylpyrazine analog derivative
Get 2-chloromethyl-3,5,6-trimethylpyrazine 5 (1.65g, 9.7mmol) in two neck bottles, add new distillatory triethyl-phosphite (1.92ml, 9.7mmol), mixed solution is heated to little boiling, the TLC monitoring reaction is complete, is cooled to room temperature.Bathe condition (below 5 ℃) at cryosel, add anhydrous tetrahydro furan (10ml) and 60%NaH (mass ratio, 0.78g, 19.4mmol), fully stir 40min, slowly splash into aromatic aldehyde (9.7mmol) and anhydrous tetrahydro furan (25ml) mixed solution again, stirring at room 12h, the TLC monitoring reaction is complete, ethyl acetate extraction, anhydrous Na
2SO
4Drying, steaming desolventizes, and residue separates with rapid column chromatography, and recrystallizing methanol gets A1～A17, A20～A24, A27～A28.
(2) 2-(substituted ethylene base)-3,5, synthetic (method 2) of 6-trimethylpyrazine analog derivative
Get halo benzyl (9.7mmol) in two neck bottles, add new distillatory triethyl-phosphite (1.92ml, 9.7mmol), mixed solution is heated to little boiling, the TLC monitoring reaction is complete, is cooled to room temperature.Bathe condition (below 5 ℃) at cryosel, add anhydrous tetrahydro furan (10ml) and 60%NaH (mass ratio, 0.78g, 19.4mmol), fully stir 40min, slowly splash into intermediate 3,5 again, 6-trimethylpyrazine-2-formaldehyde 6 (1.46g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixed solution, stirring at room 12h, the TLC monitoring reaction is complete, ethyl acetate extraction, anhydrous Na
2SO
4Drying, steaming desolventizes, and residue is purified with rapid column chromatography or recrystallization, gets A18～A19, A25～A26.
The isolating eluting solvent of above-mentioned rapid column chromatography system is: ethyl acetate/hexanaphthene.
Above-mentioned aromatic aldehyde is: phenyl aldehyde, the 2-hydroxy benzaldehyde, the 3-chlorobenzaldehyde, the 4-fluorobenzaldehyde, 2, the 5-dimethoxy benzaldehyde, 2-hydroxy 3-methoxybenzene formaldehyde, the 2-hydroxy benzaldehyde, 2, the 3-dimethoxy benzaldehyde, the 4-nitrobenzaldehyde, the 4-methoxybenzaldehyde, (E)-phenylacrolein, the 3-methoxybenzaldehyde, 2, the 4-dimethoxy benzaldehyde, furtural, the 2-fluorobenzaldehyde, 3, the 4-dimethoxy benzaldehyde, 2,3, the 4-TMB, the 4-chlorobenzaldehyde, 3,4, the 5-TMB, thiophenecarboxaldehyde, the 3-tolyl aldehyde, 3,5,6-trimethylpyrazine-2-formaldehyde, 2-methoxybenzaldehyde or 2-chlorobenzaldehyde.
Above-mentioned halo benzyl is: adjacent methyl benzyl chloride, to methyl benzyl chloride, adjacent cyano group benzyl chloride or a cyano group benzyl chloride.
7. ligustrazine stilbenoids derivatives pharmaceutical composition
Ligustrazine stilbenoids derivatives pharmaceutical composition of the present invention contains above-mentioned ligustrazine stilbenoids derivatives, and ligustrazine stilbenoids derivatives and pharmaceutical excipient are made the medicine of different dosage form.
8. the application of ligustrazine stilbenoids derivatives
Ligustrazine stilbenoids derivatives of the present invention can be used for preparing cardiovascular and cerebrovascular diseases medicines such as ischemia resisting, atherosclerosis and coronary heart disease.
Ligustrazine stilbenoids derivatives is as follows to the protection test of the vascular endothelial cell of peroxidation loss:
(1) the used cell of experiment is vascular endothelial cell (ECV-304), available from Shandong University immune Research chamber.During use with containing the RPMI-1640 substratum of 10% newborn calf serum, penicillin (100U/L) and Streptomycin sulphate (100U/L), under 37 ℃ at 5%CO
2Cultivate in the incubator, passed for 2～3 generations, in stable condition.In 96 orifice plates, every hole adds 4 * 103 ECV-304, adds the RPMI-1640 nutrient solution that contains 10% calf serum, puts 5%CO
2Under 37 ℃ of conditions, cultivate 24h in the incubator.
(2) after ECV-304 cultivates 24h in containing the RPMI-1640 nutrient solution of 10% calf serum, in normal group, add and do not contain H
2O
2With the normal nutrient solution of medicine, adding concentration in model group is 150 μ mol.L-1H
2O
2Nutrient solution, add in the protection group that to contain the different concns medicine and contain final concentration be 150 μ mol.L-1H
2O
2Nutrient solution, continue to cultivate 12h, every then hole adds 10 μ l MTT solution (5mg/ml), cultivates 4h for 37 ℃, the supernatant liquor that inclines, every hole adds dimethyl sulfoxide (DMSO) 100 μ l, places 10min, on the inherent full-automatic microplate reader of 30min in the mensuration OD of 570nm place value (OD
570nm).The record result, the computerized compound is to the propagation percentage P (%) of the ECV-304 of peroxide injury.
Table 2 ligustrazine stilbenoids derivatives is to the propagation percentage and the EC of the vascular endothelial cell of peroxidation loss
50Value
Experimental result shows: the activity of newly-designed part ligustrazine stilbenoids derivatives is better than positive control medicine Ligustrazine (EC
50=0.79mmol.L
-1), the vascular endothelial cell of peroxide injury is all had good provide protection, its EC as A2, A3, A6, A9, A11, A12, A15, A16, A21, A24, A28
50Be worth lower.Wherein, derivative A6 (EC
50=0.03mmol.L
-1), A9 (EC
50=0.09mmol.L
-1), A11 (EC
50=0.06mmol.L
-1) the strongest to the provide protection of endotheliocyte of damage, their EC
50Value all is lower than 0.10mmol.L
-1Derivative A15 (EC
50=0.29mmol.L
-1), 24 (EC
50=0.16mmol.L
-1), 28 (EC
50=0.14mmol.L
-1) also can promote the propagation of the vascular endothelial cell of peroxidation loss, its EC well
50Value all is lower than 0.30mmol.L
-1
(4) embodiment
Embodiment 1:2-styryl-3,5, the preparation of 6-trimethylpyrazine (A1)
Get 2-chloromethyl-3,5,6-trimethylpyrazine 5 (1.65g, 9.7mmol) in two neck bottles, add new distillatory triethyl-phosphite (1.92ml, 9.7mmol), mixed solution is heated to little boiling, the TLC monitoring reaction is complete, is cooled to room temperature.Bathe condition (below 5 ℃) at cryosel, add anhydrous tetrahydro furan (10ml) and 60%NaH (mass ratio, 0.78g, 19.4mmol), fully stir 40min, slowly splash into phenyl aldehyde (1.03g again, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixed solution, stirring at room 12h, the TLC monitoring reaction is complete, ethyl acetate extraction, anhydrous Na
2SO
4Drying, steaming desolventizes, and residue separates with rapid column chromatography, and eluent is an ethyl acetate: hexanaphthene (1: 10 volume ratio), recrystallizing methanol gets yellow crystals 2-styryl-3,5,6-trimethylpyrazine 1.1g, productive rate 49%, mp:60-62 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3058 (v
=CH), 1626 (v
CH=CH), 1595,1574,1491,1450, (v
CH=CH, Ar), 1405,1395 (v
C=N), 746,691 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 7.78 (1H, d ,=CH-, J=15.7Hz), 7.28 (each 1H, d ,=CH-, J=15.4Hz,), 7.60 (2H, d, Ar-H, J=7.3Hz), 7.38 (2H, t, Ar-H, J=7.5Hz), 7.30 (1H, t, Ar-H, J=7.3Hz), 2.62 (3H, s ,-CH
3), 2.54 (3H, s ,-CH
3), 2.51 (3H, s ,-CH
3);
13C-NMR (CDCl
3, δ ppm): 149.53,149.22,147.04,145.38 (pyrazine-C), 136.88,134.03,128.71,128.37,127.19,122.89 (CH=CH-Ar-C); 21.83 (CH
3), 21.75 (CH
3), 20.99 (CH
3) .ESI-MS:m/z225.3 (M+1).
Embodiment 2:2-(3-hydroxystyrene based)-3,5,6-trimethylpyrazine (A2)
As method as described in the embodiment 1, different is slowly splash into the 3-hydroxy benzaldehyde (1.78g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 5 volume ratio), get white crystal 0.9g, productive rate 40%, mp:202-204 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3055 (v
=CH), 1631 (v
CH=CH), 1607,1578,1489,1468 (v
CH=CH, Ar), 1407 (v
C=N), 872,778,687 (γ
=CHFace is outer);
1H-NMR (DMSO, δ ppm): 9.49 (1H, s ,-OH), 7.59 (1H, d ,=CH-, J=15.6Hz), 7.32 (1H, d,=CH-, J=15.6Hz), 7.20 (1H, t, Ar-H, J=7.8Hz), 7.13 (1H, d, Ar-H, J=7.7Hz), 7.10 (1H, s, Ar-H), 6.72 (1H, d, Ar-H, J=7.3Hz), 2.56 (3H, s ,-CH
3), 2.50 (3H, s ,-CH
3), 2.44 (3H, s ,-CH
3);
13C-NMR (DMSO, δ ppm): 149.41,178.67,146.25,137.63 (pyrazine-C), 157.54,137.63,133.02,129.62,122.77,118.26,115.51,113.41 (CH=CH-Ar-C), 21.31 (CH
3), 21.25 (CH
3), 20.40 (CH
3); ESI-MS:m/z 241.4 (M+1).
Embodiment 3:2-(3-chloro-styrene base)-3,5, the preparation of 6-trimethylpyrazine (A3)
As method as described in the embodiment 1, different is slowly splash into the 3-chlorobenzaldehyde (1.46g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 5 volume ratio), get yellow crystals 0.7g, productive rate 27%, mp:92-94 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3054 (v
=CH), 1631 (v
CH=CH), 1589,1559,1473 (v
CH=CH, Ar), 1424,1405 (v
C=N), 872,799,685 (γ
=CHFace is outer); 1H-NMR (CDCl
3, δ ppm): 7.73 (1H, d ,=CH-, J=15.6Hz), 7.29 (1H, d ,=CH-, J=15.7Hz), 7.60 (1H, s, Ar-H), 7.47 (1H, d, Ar-H, J=7.6Hz), 7.32 (1H, t, Ar-H, J=7.9Hz), 7.29 (1H, d, Ar-H, J=7.4Hz), 2.64 (3H, s ,-CH
3), 2.56 (3H, s ,-CH
3), 2.54 (3H, s ,-CH
3);
13C-NMR (CDCl
3, δ ppm): 150.62,149.27,147.29,144.85 (pyrazine-C), 138.91,134.72,132.52,129.93,128.19,126.84,1125.50,124.39 (CH=CH-Ar-C); 21.78,20.96 (3-CH
3); ESI-MS:m/z259.2 (M+1).
Embodiment 4:2-(4-fluorophenethyl thiazolinyl)-3,5, the preparation of 6-trimethylpyrazine (A4)
As method as described in the embodiment 1, different is slowly splash into the 4-fluorobenzaldehyde (1.21g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 5 volume ratio), get faint yellow platelet 1.1g, productive rate 43%, mp:88-90 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3058 (v
=CH), 1635 (v
CH=CH), 1599,1508 (v
CH=CH, Ar), 1447,1416 (v
C=N), 824 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 7.77 (1H, d ,=CH-, J=15.5Hz), 7.20 (1H, d ,=CH-, J=15.4Hz), 7.58 (2H, t, Ar-H, J=8.3Hz), 7.08, (2H, t, Ar-H, J=8.4Hz), 2.66 (3H, s ,-CH
3), 2.57 (3H, s ,-CH
3), 2.56 (3H, s ,-CH
3);
13C-NMR (CDCl
3, δ ppm): 149.31,148.83,146.70,144.90 (pyrazine-C), 132.49,130.23,128.46,122.46,115.46,115.31 (CH
2=CH
2-Ar-C), 21.44 (CH
3), 21.41 (CH
3), 20.79 (CH
3); ESI-MS:m/z 243.4 (M+1).
Embodiment 5:2-(2, the 5-dimethoxy-styryl)-3,5, the preparation of 6-trimethylpyrazine (A5)
As method as described in the embodiment 1, different is slowly to splash into 2,5-dimethoxy benzaldehyde (1.61g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 3 volume ratio) gets orange-yellow platelet 1.1g, productive rate 40%, mp:124-126 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3036 (v
=CH), 1619 (v
CH=CH), 1604,1495,1462 (v
CH=CH, Ar), 1443,1417 (v
C=N), 839,810,708 (γ
=CFace is outer);
1H-NMR (CDCl
3, δ ppm): 8.03 (1H, d ,=CH-, J=15.8Hz), 7.34 (1H, d ,=CH-, J=15.8Hz), 7.18 (1H, sd Ar-H, J=2.8Hz), 6.87 (2H, m, Ar-H), 3.88 (3H, s ,-OCH
3), 3.84 (3H, s ,-OCH
3), 2.62 (3H, s ,-CH
3), 2.56 (3H, s ,-CH
3), 2.52 (3H, s ,-CH
3); ESI-MS:m/z 285.3 (M+1).
Embodiment 6:2-(2-hydroxy 3-methoxybenzene vinyl)-3,5, the preparation of 6-trimethylpyrazine (A6)
As described in embodiment 1, different is slowly splash into 2-hydroxy 3-methoxybenzene formaldehyde (1.47g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 3), get yellow platelet 0.9g, productive rate 35%, mp:187-188 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3052 (v
=CH), 1625 (v
CH=CH), 1602,1581,1477 (v
CH=CH, Ar), 1441,1399 (v
C=N), 717 (γ
=CHFace is outer);
1H-NMR (DMSO, δ ppm): 9.02 (1H, s ,-OH), 8.02 (1H, d ,=CH-, J=15.8Hz), 7.35 (1H, d,=CH-, J=15.8Hz), 7.32 (1H, d, Ar-H, J=7.7Hz), 6.92 (1H, d, Ar-H, J=7.8Hz), 6.80 (1H, t, Ar-H, J=7.8Hz), 3.83 (3H, s ,-OCH
3), 2.54 (3H, s ,-CH
3), 2.50 (3H, s ,-CH
3), 2.49 (3H, s ,-CH
3);
13C-NMR (DMSO, δ ppm): 148.89,148.03,146.80,145.14 (pyrazine-C), 149.21,144.88,128.37,123.73,122.36,119.12,118.81,111.54 (CH=CH-Ar-C), 56.02 (OCH
3), 21.59 (CH
3), 21.49 (CH
3), 20.71 (CH
3); ESI-MS:m/z 271.4 (M+1).
Embodiment 7:2-(2-hydroxystyrene based)-3,5, the preparation of 6-trimethylpyrazine (A7)
As described in embodiment 1, different is slowly splash into the 2-hydroxy benzaldehyde (1.18g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 3), yellow crystals 0.8g, productive rate 35%, mp:221-222 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3068 (v
=CH), 1620 (v
CH=CH), 1601,1539,1498,1458 (v
CH=CH, Ar), 1408 (v
C=N), 742 (γ
=CHFace is outer);
1H-NMR (DMSO, δ ppm): 9.90 (1H, s ,-OH), 7.97 (1H, d,=CH-, J=15.8Hz), 7.39 (1H, d ,=CH-, J=15.8Hz), 7.69 (1H, d, Ar-H, J=7.8Hz), 7.13 (1H, t, Ar-H, J=8.3Hz), 6.89 (1H, d, Ar-H, J=8.1Hz), 6.83 (1H, t, Ar-H, J=7.6Hz), 2.54 (3H, s ,-CH
3), 2.47 (3H, s ,-CH
3), 2.43 (3H, s ,-CH
3);
13C-NMR (DMSO, δ ppm): 149.10,148.73,146.79,145.40 (pyrazine-C), 153.67,129.05,128.77,127.82,124.11,120.66,120.20,115.93 (CH=CH-Ar-C), 21.28 (CH
3), 21.25 (CH
3), 20.55 (CH
3); ESI-MS:m/z 241.2 (M+1).
Embodiment 8:2-(2, the 3-dimethoxy-styryl)-3,5, the preparation of 6-trimethylpyrazine (A8)
As described in embodiment 1, different is slowly to splash into 2,3-dimethoxy benzaldehyde (1.61g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 5) gets yellow crystals 0.7g, productive rate 25%, mp:87-88 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3069 (v
=CH), 1634 (v
CH=CH), 1576,1559,1477 (v
CH=CH, Ar), 1455,1429 (v
C=N), 787 (γ
=CHFace is outer);
1H-NMR (DMSO, δ ppm): 7.92 (1H, d ,=CH-, J=15.9Hz), 7.43 (1H, d ,=CH-, J=15.8Hz), 7.44 (1H, d, Ar-H, J=7.9Hz), 7.11 (1H, t, Ar-H, J=7.8Hz), 7.03 (1H, d, Ar-H, J=8.2Hz), 3.83 (3H, s ,-OCH
3), 3.76 (3H, s ,-OCH
3), 2.56 (3H, s ,-CH
3), 2.48 (3H, s ,-CH
3), 2.44 (3H, s ,-CH
3); ESI-MS:m/z 285.4 (M+1).
Embodiment 9:2-(4-nitrostyrolene base)-3,5, the preparation of 6-trimethylpyrazine (A9)
As described in embodiment 1, different is slowly splash into the 4-nitrobenzaldehyde (1.46g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 5), yellow needle 0.9g, productive rate 35%, mp:175-177 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3073 (v
=CH), 1694 (v
CH=CH), 1591,1490,1447 (v
CH=CH, Ar), 1413 (v
C=N), 1339 (v
NO2), 818 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 8.27 (2H, d, Ar-H, J=8.7Hz), 7.87 (1H, d ,=CH-, J=15.6Hz), 7.44 (1H, d ,=CH-, J=15.6Hz), 7.75 (2H, Ar-H, J=8.7Hz), 2.69 (3H, s ,-CH
3), 2.59 (3H, s ,-CH
3), 2.57 (3H, s ,-CH
3); ESI-MS:m/z 270.6 (M+1).
Embodiment 10:2-(4-methoxyl-styrene)-3,5, the preparation of 6-trimethylpyrazine (A10)
As described in embodiment 1, different is slowly splash into the 4-methoxybenzaldehyde (1.32g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 5), yellow needle 1.1g, productive rate 45%, mp:101-102 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3058 (v
=CH), 1625 (v
CH=CH), 1602,1510,1447 (v
CH=CH, Ar), 1418 (v
C=N), 808 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 7.77 (1H, d ,=CH-, J=15.5Hz), 7.15 (1H, d ,=CH-, J=15.6Hz), 7.57 (1H, d, Ar-H, J=8.7Hz), 6.94 (1H, d, Ar-H, J=8.7Hz), 3.86 (3H, s ,-OCH
3), 2.64 (3H, s ,-CH
3), 2.56 (3H, s ,-CH
3), 2.54 (3H, s ,-CH
3); ESI-MS:m/z 255.4 (M+1).
Embodiment 11:2-(3, the 4-dimethoxy-styryl)-3,5, the preparation of 6-trimethylpyrazine (A11)
As described in embodiment 1, different is slowly to splash into 3,4-dimethoxy benzaldehyde (1.61g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 5) gets yellow crystals 1.0g, productive rate 36%, mp:121-123 ℃.
Quick post separation condition: IR (KBr, cm
-1): 3060 (v
=CH), 1629 (v
CH=CH), 1598,1515,1459 (v
CH=CH, Ar), 1417 (v
C=N), 841,811,766 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 7.74 (1H, d ,=CH-, J=15.6Hz), 7.14 (1H, d ,=CH-, J=15.6Hz), 7.20 (1H, dd, Ar-H, J=8.2Hz), 7.13 (1H, s, Ar-H), 6.90 (1H, d, Ar-H, J=8.3Hz), 3.97 (3H, s ,-OCH
3), 3.93 (3H, s ,-OCH
3), 2.64 (3H, s ,-CH
3), 2.55 (3H, s ,-CH
3), 2.52 (3H, s ,-CH
3);
13C-NMR (CDCl
3, δ ppm): 149.28,148.72,146.50,145.31 (pyrazine-C), 148.80,133.59,129.81,121.87,120.79,120.30,110.96,109.46 (CH=CH-Ar-C), 55.65 (OCH
3), 55.49 (OCH
3), 21.47 (CH
3), 21.39 (CH
3), 20.91 (CH
3); ESI-MS:m/z 285.5 (M+1).
Embodiment 12:2-(4-benzene butenyl)-3,5, the preparation of 6-trimethylpyrazine (A12)
As described in embodiment 1, different is slowly splash into the phenyl allyl aldehyde (1.28g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 10), yellow crystals 0.7g, productive rate 28%, mp:118-120 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3023 (v
=CH), 1615 (v
CH=CH), 1607,1533,1487,1450 (v
CH=CH, Ar), 1403 (v
C=N), 749 (γ
=CFace is outer);
1H-NMR (CDCl
3, δ ppm): 7.61,7.05,6.85 (4H ,-CH=CH-CH=CH-, J=14.4Hz), 7.49 (2H, d, Ar-H, J=7.6Hz), 7.36 (2H, t, Ar-H, J=7.5Hz), 7.27 (1H, Ar-H);
13C-NMR (CDCl
3, δ ppm): 148.98,148.84,146.66,145.17 (pyrazine-C), 136.86,135.20,134.13,128.43,127.64,126.62,126.34 (CH=CH-CH=CH-Ar-C), 21.47 (CH
3), 21.39 (CH
3), 20.91 (CH
3); ESI-MS:m/z 251.6 (M+1).
Embodiment 13:2-(3-methoxyl-styrene)-3,5, the preparation of 6-trimethylpyrazine (A13)
As described in embodiment 1, different is slowly splash into the 3-methoxybenzaldehyde (1.32g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 5), yellow crystals 1.0g, productive rate 41%, mp:87-89 ℃.
Spectral analysis data: IR (KBr, cm-1): 3051 (v=CH), 1629 (vCH=CH), 1602,1577,1485,1455 (vCH=CH, Ar), 1436,1401 (vC=N), 873,778,686 (γ=C face is outer); 1H-NMR (CDC13, δ ppm): 7.80 (1H, d ,=CH-, J=15.6Hz), 7.27 (1H, d ,=CH-, J=15.6Hz), 7.32 (1H, t, Ar-H, J=7.8Hz), 7.23 (1H, d, Ar-H, J=7.7Hz), 6.90 (1H, dd, Ar-H, J=8.1Hz), 3.88 (3H, s ,-OCH
3), 2.68 (3H, s ,-CH
3), 2.58 (6H, s, 2-CH
3);
13C-NMR (CDCl
3, δ ppm): 149.63,149.17,147.14,145.32 (pyrazine-C), 159.94,138.47,133.98,129.68,123.40,119.83,113.97,112.63 (CH=CH-Ar-C), 55.32 (OCH
3), 21.79 (CH
3), 21.75 (CH
3), 21.01 (CH
3); ESI-MS:m/z 255.8 (M+1).
Embodiment 14:2-(2, the 4-dimethoxy-styryl)-3,5, the preparation of 6-trimethylpyrazine (A14)
As described in embodiment 1, different is slowly to splash into 2,4-dimethoxy benzaldehyde (1.61g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 5) gets yellow crystals 1.3g, productive rate 48%, mp:142-144 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3069 (v
=CH), 1604,1574,1499,1453 (v
CH=CH, Ar), 1438,1399 (v
C=N), 879,831 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 7.99 (1H, d ,=CH-, J=15.8Hz), 7.26 (1H, d ,=CH-, J=15.7Hz), 7.56 (1H, d, Ar-H, J=8.5Hz), 6.55 (1H, d, Ar-H, J=8.5Hz), 6.50 (1H, s, Ar-H), 3.91 (3H, s ,-OCH
3), 3.86 (3H, s ,-OCH
3), 2.61 (3H, s ,-CH
3), 2.55 (3H, s ,-CH
3), 2.52 (3H, s ,-CH
3);
13C-NMR (CDCl
3, δ ppm): 160.81,158.60,148.28,146.09 (pyrazine-C), 129.79,128.96,128.52,124.63,121.46,119.04,104.71,98.23 (CH=CH-Ar-C), 55.19 (OCH
3), 55.10 (OCH
3), 21.46 (CH
3), 21.36 (CH
3), 20.74 (CH
3); ESI-MS:m/z 285.3 (M+1).
Embodiment 15:2-(2-furyl)-3,5, the preparation of 6-trimethylpyrazine (A15)
As described in embodiment 1, different is slowly splash into 2 furan carboxyaldehyde (0.93g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 20), yellowish brown crystal 1.0g, productive rate 50%, mp:56-58 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3112 (v
=CH), 1636 (v
CH=CH), 1565,1486,1443 (v
CH=CH, Ar), 1398 (v
C=N), 745 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 7.58 (1H, d ,=CH-, J=15.4Hz), 7.18 (1H, d ,=CH-, J=15.4Hz), 7.44 (1H, s, furan-H), 6.46-6.44 (2H, m, furan-H, J=Hz), 2.60 (3H, s ,-CH
3), 2.53 (3H, s ,-CH
3), 2.51 (3H, s ,-CH
3);
13C-NMR (CDCl
3, δ ppm): 149.35,149.12,147.08,145.14 (pyrazine-C), 153.16,142.82,121.07,120.95,111.94,111.03 (CH=CH-thiophene-C), 21.80 (CH
3), 21.73 (CH
3), 20.88 (CH
3); ESI-MS:m/z 215.2 (M+1).
Embodiment 16:2-(2-fluorophenethyl thiazolinyl)-3,5, the preparation of 6-trimethylpyrazine (A16)
As described in embodiment 1, different is slowly splash into the 2-fluorobenzaldehyde (1.20g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 10), yellow crystals 0.4g, productive rate 18%, mp:77-80 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3057 (v
=CH), 1629 (v
CH=CH), 1577,1487,1456 (v
CH=CH, Ar), 1404,1391 (v
C=N), 743 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 7.90 (1H, d ,=CH-, J=15.8Hz), 7.39 (1H, d ,=CH-, J=15.8Hz), 7.63 (1H, t, Ar-H, J=7.7Hz), 7.27 (1H, Ar-H), 7.17 (1H, t, Ar-H, J=7.6Hz), 7.10,7.27 (1H, Ar-H), 2.64 (3H, s ,-CH
3), 2.56 (3H, s ,-CH
3), 2.54 (3H, s ,-CH
3);
13C-NMR (CDCl
3, δ ppm): 161.52,159.85 (pyrazine-C), 129.37,128.17,126.75,125.08,123.98,115.79,115.64 (CH=CH-Ar-C); 21.51 (CH
3); ESI-MS:m/z 243.5 (M+1).
Embodiment 17:2-(2,3,4-trimethoxy styryl)-3,5, the preparation of 6-trimethylpyrazine (A17)
As described in embodiment 1, different is slowly to splash into 2,3, the 4-TMB (1.90g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 10), get yellow crystals 0.7g, productive rate 24%, mp:64-67 ℃.
Spectral analysis data: IR (KBr, cm
-1): 1624 (v
CH=CH), 1592,1493,1463 (v
CH=CH, Ar), 1415 (v
C=N), 792 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 7.92 (1H, d ,=CH-, J=15.8Hz), 7.30 (1H, d ,=CH-, J=15.8Hz), 7.35 (1H, d, Ar-H, J=8.7Hz), 6.73 (1H, d, Ar-H, J=8.7Hz), 3.96 (3H, s ,-OCH
3), 3.92 (3H, s ,-OCH
3), 3.91 (3H, s ,-OCH
3), 2.62 (3H, s ,-CH
3), 2.56 (3H, s ,-CH
3), 2.52 (3H, s ,-CH
3); ESI-MS:m/z 315.3 (M+1).
Embodiment 18:2-(2-methyl styrene base)-3,5, the preparation of 6-trimethylpyrazine (A18)
Get 2-methyl benzyl chloride (1.36g, 9.7mmol) in two neck bottles, add new distillatory triethyl-phosphite (1.92ml, 9.7mmol), mixed solution is heated to little boiling, the TLC monitoring reaction is complete, is cooled to room temperature.Bathe condition (below 5 ℃) at cryosel, add anhydrous tetrahydro furan (10ml) and 60%NaH (mass ratio, 0.78g, 19.4mmol), fully stir 40min, slowly splash into 3,5 again, 6-trimethylpyrazine-2-formaldehyde (1.46g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixed solution, stirring at room 12h, the TLC monitoring reaction is complete, ethyl acetate extraction, anhydrous Na
2SO
4Drying, steaming desolventizes, and residue separates with rapid column chromatography, and eluent is an ethyl acetate: hexanaphthene (1: 5), recrystallizing methanol gets yellow crystals 1.0g, productive rate 46%, mp:142-144 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3058 (v
=CH), 1629 (v
CH=CH), 1598,1571,1484,1445 (v
CH=CH, Ar), 1404 (v
C=N), 745 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 8.02 (1H, d ,=CH-, J=15.5Hz), 7.18 (1H, d ,=CH-, J=15.5Hz), 7.66 (1H, Ar-H), 7.23 (3H, m, Ar-H), 2.62 (3H, s ,-CH
3), 2.56 (3H, s ,-CH
3), 2.53 (3H, s ,-CH
3); ESI-MS:m/z 239.1 (M+1).
Embodiment 19:2-(4-vinyl toluene base)-3,5, the preparation of 6-trimethylpyrazine (A19)
As described in embodiment 18, different is get 4-methyl benzyl chloride (1.36g, 9.7mmol) and new distillatory triethyl-phosphite (1.92ml, 9.7mmol) mix, eluent is an ethyl acetate: hexanaphthene (1: 5) gets orange-yellow crystal 0.5g, productive rate 23%, mp:76-79 ℃.
Quick post separation condition: IR (KBr, cm
-1): 3058 (v
=CH), 1629 (v
CH=CH), 1571,1510,1484,1446 (vC
H=CH, Ar), 1404 (v
C=N), 808 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 8.03 (1H, d ,=CH-, J=15.5Hz), 7.18 (1H, d ,=CH-, J=15.5Hz), 7.66 (1H, Ar-H), 7.23 (3H, m, Ar-H), 2.62 (3H, s ,-CH
3), 2.57 (3H, s ,-CH
3), 2.53 (3H, s ,-CH
3), 2.50 (3H, s ,-CH
3); ESI-MS:m/z 239.4 (M+1).
Embodiment 20:2-(4-chloro-styrene base)-3,5, the preparation of 6-trimethylpyrazine (A20)
As described in embodiment 1, different is slowly splash into the 4-chlorobenzaldehyde (1.45g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 10), orange crystal 0.7g, productive rate 29%, mp:79-81 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3061 (v
=CH), 1633 (v
CH=CH), 1591,1566,1490,1443 (v
CH=CH, Ar), 1409 (v
C=N), 810 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 7.75 (1H, d ,=CH-, J=15.7Hz), 7.26 (1H, d ,=CH-, J=15.7Hz), 7.54 (2H, d, Ar-H, J=8.2Hz), 7.37 (2H, d, Ar-H, J=8.5Hz), 2.63 (3H, s ,-CH
3), 2.56 (3H, s ,-CH
3), 2.53 (3H, s ,-CH
3);
13C-NMR (CDCl
3, δ ppm): 149.83,149.21,147.14,145.05 (pyrazine-C), 135.51,133.99,132.68,128.9,128.32,123.57 (CH=CH-Ar-C); 21.73 (CH
3), 21.71 (CH
3), 20.91 (CH
3); ESI-MS:m/z 259.2 (M+1).
Embodiment 21:2-(3,4,5-trimethoxy styryl)-3,5, the preparation of 6-trimethylpyrazine (A21)
As described in embodiment 1, different is slowly to splash into 3,4, the 5-TMB (1.90g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 10), get yellow crystals 0.7g, productive rate 22%, mp:132-134 ℃.
Spectral analysis data: IR (KBr, cm
-1): 1628 (v
CH=CH), 1578,1504,1454 (v
CH=CH, Ar), 1419 (v
C=N), 810 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 7.73 (1H, d ,=CH-, J=15.6Hz), 7.17 (1H, d ,=CH-, J=15.6Hz), 6.83 (2H, s, Ar-H), 3.94 (6H, s ,-OCH
3), 3.90 (3H, s ,-OCH
3), 2.65 (3H, s ,-CH
3), 2.56 (3H, s ,-CH
3), 2.53 (3H, s ,-CH
3);
13C-NMR (CDCl
3, δ ppm): 149.12,148.77,146.63,144.99 (pyrazine-C), 153.12,133.78,132.33,122.12,104.18 (CH=CH-Ar-C); 60.63,55.90 (OCH
3), 21.43 (CH
3), 21.38 (CH
3), 20.74 (CH
3); ESI-MS:m/z 315.3 (M+1).
Embodiment 22:2-(2-thienyl)-3,5, the preparation of 6-trimethylpyrazine (A22)
As described in embodiment 1, different is slowly splash into 2 thiophene carboxaldehyde (1.09g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 5), yellow crystals 1.0g, productive rate 48%, mp:142-144 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3065 (v
=CH), 1625 (v
CH=CH), 1540,1517,1444, (v
CH=CH, Ar), 1402 (v
C=N), 726 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 7.92 (1H, d ,=CH-, J=15.4Hz), 7.08 (1H, d ,=CH-, J=15.4Hz), 7.27 (1H, d, thiophene-H, J=2.2Hz), 7.21 (1H, d, thiophene-H, J=3.4Hz), 7.05 (1H, thiophene-H, J=3.6Hz), 2.61 (3H, s ,-CH
3), 2.54 (3H, s ,-CH
3), 2.52 (3H, s ,-CH
3);
13C-NMR (CDCl
3, δ ppm): 149.09,148.80,146.59,144.76 (pyrazine-C), 142.24,127.48,127.44,126.54,125.08,122.07 (CH=CH-thiophene-C), 21.43 (CH
3), 21.40 (CH
3), 20.52 (CH
3); ESI-MS:m/z231.2 (M+1).
Embodiment 23:2-(3-vinyl toluene base)-3,5, the preparation of 6-trimethylpyrazine (A23)
As described in embodiment 1, different is slowly splash into the 3-tolyl aldehyde (1.16g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 10), yellow crystals 0.2g, productive rate 10%, mp:67-68 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3032 (v
=CH), 1630 (v
CH=CH), 1601,1580,1483,1443 (v
CH=CH, Ar), 1400 (v
C=N), 852,788,686 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 7.77 (1H, d ,=CH-, J=15.7Hz), 7.26 (1H, d ,=CH-, J=17.5Hz), 7.41 (1H, s, Ar-H), 7.40 (1H, d, Ar-H, J=7.9Hz), 7.28 (1H, t, Ar-H, J=7.5Hz), 7.14 (1H, d, Ar-H, J=7.4Hz), 2.65 (3H, s ,-CH
3), 2.56 (3H, s ,-CH
3), 2.54 (3H, s ,-CH
3), 2.40 (3H, s ,-CH
3);
13C-NMR (CDCl
3, δ ppm): 149.12,148.77,146.72,145.16 (pyrazine-C), 137.93,136.63,133.89,128.86,127.49,128.27,124.11,122.50 (CH=CH-Ar-C), 21.45 (CH
3), 21.40 (CH
3), 20.70 (CH
3), 21.10 (CH
3); ESI-MS:m/z 239.3 (M+1).
Embodiment 24:2-[2-(3,5,6-trimethylpyrazine base)]-3,5, the preparation of 6-trimethylpyrazine (A24)
As described in embodiment 1, different is slowly to splash into 3,5,6-trimethylpyrazine-2-formaldehyde (1.46g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 5), get yellow crystals 0.2g, productive rate 10%, mp:182-184 ℃.
Spectral analysis data: IR (KBr, cm
-1): 1629 (v
CH=CH), 1444,1408 (v
C=N), 826 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 7.96 (2H, s ,-CH=CH-), 2.70 (6H, s ,-CH
3), 2.57 (6H, s ,-CH
3), 2.54 (6H, s ,-CH
3); ESI-MS:m/z 269.5 (M+1).
Embodiment 25:2-(2-cyano-styrene base)-3,5, the preparation of 6-trimethylpyrazine (A25)
As described in embodiment 18, different is get 2-cyano group benzyl chloride (1.36g, 9.7mmol) and new distillatory triethyl-phosphite (1.92ml, 9.7mmol) mix, eluent is an ethyl acetate: hexanaphthene (1: 10) gets light yellow crystal 0.9g, productive rate 38%, mp:171-174 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3056 (v
=CH), 2222 (v
-CN), 1632 (v
CH=CH), 1595,1564,1481,1449 (v
CH=C H, Ar), 1404 (v
C=N), 777 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 8.09 (1H, d ,=CH-, J=15.6Hz), 7.52 (1H, d ,=CH-, J=15.7Hz), 7.82 (1H, d, Ar-H, J=8.0Hz), 7.71 (1H, d, Ar-H, J=7.7Hz), 7.62 (1H, t, Ar-H, J=7.7Hz), 7.40 (1H, t, Ar-H, J=7.6Hz), 2.66 (3H, s ,-CH
3), 2.58 (3H, s ,-CH
3), 2.55 (3H, s ,-CH
3);
13C-NMR (CDCl
3, δ ppm): 144.07,139.91,131.74,128.30 (pyrazine-C), 133.17,132.43,129.27,127.80,127.69,126.40,117.70,111.29 (CH=CH-Ar-C); 21.45 (CH
3), 21.07 (CH
3), 20.54 (CH
3), 21.10 (CH
3); ESI-MS:m/z 250.4 (M+1).
Embodiment 26:2-(3-cyano-styrene base)-3,5, the preparation of 6-trimethylpyrazine (A26)
As described in embodiment 18, different is get 3-cyano group benzyl chloride (1.36g, 9.7mmol) and new distillatory triethyl-phosphite (1.92ml, 9.7mmol) mix, eluent is an ethyl acetate: hexanaphthene (1: 10) gets yellow crystals 1.2g, productive rate 50%, mp:149-151 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3056 (v
=CH), 2225 (v
-CN), 1635 (v
CH=CH), 1596,1576,1479,1443 (v
CH=CH, Ar), 1412,1391 (v
C=N), 856,797,681 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 7.77 (1H, d ,=CH-, J=15.6Hz), 7.33 (1H, d ,=CH-, J=15.6Hz), 7.88 (1H, s, Ar-H), 7.81 (1H, d, Ar-H, J=7.9Hz), 7.59 (1H, d, Ar-H, J=7.7Hz), 7.50 (1H, t, Ar-H, J=7.8Hz), 2.65 (3H, s ,-CH
3), 2.56 (3H, s ,-CH
3), 2.54 (3H, s ,-CH
3);
13C-NMR (CDCl
3, δ ppm): 150.27,149.12,147.16,144.06 (pyrazine-C), 137.94,130.99,130.11,131.09,129.23,125.19,118.37,112.75 (CH=CH-Ar-C), 118.37 (CN), 21.62 (CH
3), 21.46 (CH
3), 20.60 (CH
3); ESI-MS:m/z 250.4 (M+1).
Embodiment 27:2-(2-methoxyl-styrene)-3,5, the preparation of 6-trimethylpyrazine (A27)
As described in embodiment 1, different is slowly splash into the 2-methoxybenzaldehyde (1.34g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 10), get white crystal 0.25g, productive rate 10%, mp:91-93 ℃.
Spectral analysis data: IR (KBr, cm-1): 3051 (v=CH), 1629 (vCH=CH), 1602,1577,1485,1455 (vCH=
CH, Ar), 1436,1401 (v
C=N), 758 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 8.09 (1H, d ,=CH-, J=15.8Hz), 7.36 (1H, d ,=CH-, J=15.8Hz), 7.63 (1H, d, Ar-H, J=6.7Hz), 6.99 (1H, t, Ar-H, J=7.4Hz), 6.95 (1H, t, Ar-H, J=7.4Hz), 6.89 (1H, d, Ar-H, J=8.2Hz), 3.91 (3H, s ,-OCH
3), 2.61,2.55,2.50 (each3H, s, 3-CH
3); ESI-MS:m/z 255.4 (M+1).
Embodiment 28:2-(2-chloro-styrene base)-3,5, the preparation of 6-trimethylpyrazine (A28)
As described in embodiment 1, different is slowly splash into the 2-chlorobenzaldehyde (1.45g, 9.7mmol) and anhydrous tetrahydro furan (25ml) mixture, eluent is an ethyl acetate: hexanaphthene (1: 10), white crystal 0.6g, productive rate 23%, mp:56-59 ℃.
Spectral analysis data: IR (KBr, cm
-1): 3054 (v
=CH), 1623 (v
CH=CH), 1561,1471,1447 (v
CH=CH, Ar), 1406 (v
C=N), 758 (γ
=CHFace is outer);
1H-NMR (CDCl
3, δ ppm): 8.15 (1H, d ,=CH-, J=15.6Hz), 7.29 (1H, d ,=CH-, J=15.1Hz), 7.73 (1H, d, Ar-H, J=7.7Hz), 7.51 (1H, Ar-H), 7.43 (1H, Ar-H), 7.37 (1H, Ar-H), 2.61 (3H, s ,-CH
3), 2.55 (3H, s ,-CH
3), 2.51 (3H, s ,-CH
3); ESI-MS:m/z 259.2 (M+1).
Claims (6)
1. the ligustrazine stilbenoids derivatives that has following structure:
2. the preparation method of the described ligustrazine stilbenoids derivatives of claim 1 is characterized in that, the preparation of described compd A 1～A17, A21～A24, A27～A28, and step is as follows:
Get intermediate 2-chloromethyl-3,5,6-trimethylpyrazine 9.7mmol is in two neck bottles, add new distillatory triethyl-phosphite 9.7mmol, mixed solution is heated to little boiling, and reacts completely, below cryosel is bathed condition-5 ℃, add anhydrous tetrahydro furan 10ml and 60%NaH19.4mmol, fully stir 40min, slowly splash into aromatic aldehyde 9.7mmol and anhydrous tetrahydro furan 25ml mixed solution again, stirring at room 12h, ethyl acetate extraction, anhydrous Na
2SO
4Drying, steaming desolventizes, and residue separates with rapid column chromatography, and recrystallizing methanol gets A1～A17, A21～A24, A27～A28, and reaction formula is as follows:
The isolating eluting solvent of above-mentioned rapid column chromatography system is: ethyl acetate/hexanaphthene;
Above-mentioned aromatic aldehyde is: phenyl aldehyde, the 2-hydroxy benzaldehyde, the 3-chlorobenzaldehyde, the 4-fluorobenzaldehyde, 2, the 5-dimethoxy benzaldehyde, 2-hydroxy 3-methoxybenzene formaldehyde, the 3-hydroxy benzaldehyde, 2, the 3-dimethoxy benzaldehyde, the 4-nitrobenzaldehyde, the 4-methoxybenzaldehyde, (E)-phenylacrolein, the 3-methoxybenzaldehyde, 2, the 4-dimethoxy benzaldehyde, furtural, the 2-fluorobenzaldehyde, 3, the 4-dimethoxy benzaldehyde, 2,3, the 4-TMB, 3,4, the 5-TMB, thiophenecarboxaldehyde, the 3-tolyl aldehyde, 3,5,6-trimethylpyrazine-2-formaldehyde, 2-methoxybenzaldehyde or 2-chlorobenzaldehyde;
Ar is the corresponding substituted aryl after above-mentioned aromatic aldehyde removes aldehyde radical.
3. the preparation method of the described ligustrazine stilbenoids derivatives of claim 1 is characterized in that, the preparation of described compd A 18～A19, A25～A26, and step is as follows:
Get halo benzyl 9.7mmol in two neck bottles, add new distillatory triethyl-phosphite 9.7mmol, mixed solution is heated to little boiling, react completely, below cryosel is bathed condition-5 ℃, add anhydrous tetrahydro furan 10ml and 60%NaH19.4mmol, fully stir 40min, slowly splash into intermediate 3 again, 5,6-trimethylpyrazine-2-formaldehyde 6 9.7mmol and anhydrous tetrahydro furan 25ml mixed solution, stirring at room 12h, ethyl acetate extraction, anhydrous Na
2SO
4Drying, steaming desolventizes, and residue is purified with rapid column chromatography or recrystallization, gets A18～A19, A25～A26, and reaction formula is as follows:
R is methyl or cyano group in the formula,
The isolating eluting solvent of above-mentioned rapid column chromatography system is: ethyl acetate/hexanaphthene;
Above-mentioned halo benzyl is: adjacent methyl benzyl chloride, to methyl benzyl chloride, adjacent cyano group benzyl chloride or a cyano group benzyl chloride.
4. the preparation method of ligustrazine stilbenoids derivatives as claimed in claim 2 is characterized in that, described intermediate 2-chloromethyl-3,5, and 6-trimethylpyrazine 5 prepares as follows:
(1) intermediate 2-methylol-3,5, the preparation method of 6-trimethylpyrazine 4
With Tetramethylpyrazine trihydrate 160mmol, the mixture of Glacial acetic acid 40ml and 30% hydrogen peroxide 160mmol replenishes adding 30% hydrogen peroxide 160mmol in 70 ℃ of reacting by heating 4h, continues reaction 4h, be cooled to room temperature, regulate pH to 10, chloroform extraction with 50% sodium hydroxide solution, anhydrous sodium sulfate drying, filter, boil off trichloromethane, obtain Ligustrazine list oxynitrides crude product, add aceticanhydride 160mmol then, reflux 2.5h removes excessive aceticanhydride under reduced pressure, obtains black pulpous state Ligustrazine acetylate, the cooling back adds 20% sodium hydroxide solution 155ml, placement is spent the night, chloroform extraction, anhydrous sodium sulfate drying, filter, remove solvent under reduced pressure, obtain 2-methylol-3,5,6-trimethylpyrazine 4 crude products, with the normal hexane recrystallization, yellow needle crystal 4 15.5g, mp:88～89 ℃;
(2) intermediate 2-chloromethyl-3,5, the preparation method of 6-trimethylpyrazine 5
With gained 2-methylol-3,5,6-trimethylpyrazine 102mmol dissolves with methylene dichloride 300ml, get sulfur oxychloride 102mmol, under condition of ice bath, dropwise add dichloromethane solution, ice bath reaction 30min, room temperature reaction 2.5h again, the TLC monitoring reaction is complete, removes solvent under reduced pressure, the residue dissolve with ethanol adds 5%KOH ethanolic soln 100ml, stirs a moment, filter, steaming desolventizes, and gets yellow solid 2-chloromethyl-3,5,6-trimethylpyrazine 5 21.1g, mp:102～105 ℃;
Above reagent concentration is mass volume ratio.
5. the preparation method of ligustrazine stilbenoids derivatives as claimed in claim 3 is characterized in that, described intermediate 3,5, and 6-trimethylpyrazine-2-formaldehyde 6 prepares as follows:
With 2-methylol-3,5,6-trimethylpyrazine 10mmol, DCC20mmol mix mutually with anhydrous dimethyl sulphoxide 10ml, stir down and slowly drip anhydrous phosphoric acid 5mmol, exothermic heat of reaction, interior temperature slowly raises, separate out solid, be chilled to room temperature, wash solid with ethyl acetate, filter, water gagings such as adding mix, jolting, water layer alkalizes to pH9～10, separates organic layer, and the ethyl acetate extraction water layer for several times, merge organic layer, anhydrous Na
2SO
4Drying, steaming desolventizes, faint yellow solid, fast post separates, white crystal 3,5,6-trimethylpyrazine-2-formaldehyde 60.75g, mp:79～80 ℃.
6. the application of the described ligustrazine stilbenoids derivatives of claim 1 in preparation ischemia resisting, atherosclerosis and medicaments for coronary disease.
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Non-Patent Citations (6)
| Title |
|---|
| Chemistry of Pyrazine and its Derivatives. V. Acylation andAlkylation of 2,6-Dimethylpyrazine and Certain Other PyrazineDerivatives. Marwan R. Kamal et al.J. Org. Chem.,Vol.27 No.4. 1962 |
| Chemistry of Pyrazine and its Derivatives.V.Acylation andAlkylation of 2,6-Dimethylpyrazine and Certain Other Pyrazine Derivatives.Marwan R.Kamal et al.J.Org.Chem,Vol.27 No.4. 1962 * |
| Synthesis and antiplatelet activity of derivativesof Ligustrazine(tetramethylpyrazine). Mark L. Nelson et al.Med. Chem. Res.,Vol.2 No.7. 1992 |
| Synthesis and antiplatelet activity of derivativesof Ligustrazine(tetramethylpyrazine). Mark L.Nelson et al.Med.Chem.Res,Vol.2 No.7. 1992 * |
| 川芎嗪的结构修饰及生物活性. 杨杰等.化学通报，第7期. 2003 |
| 川芎嗪的结构修饰及生物活性. 杨杰等.化学通报，第7期. 2003 * |
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