CN116903570A - Preparation method of 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin - Google Patents
Preparation method of 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin Download PDFInfo
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- CN116903570A CN116903570A CN202310872426.5A CN202310872426A CN116903570A CN 116903570 A CN116903570 A CN 116903570A CN 202310872426 A CN202310872426 A CN 202310872426A CN 116903570 A CN116903570 A CN 116903570A
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- Prior art keywords
- methoxy
- reaction
- formula
- allyl
- coumarin
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- 238000002360 preparation method Methods 0.000 title claims abstract description 10
- 238000006243 chemical reaction Methods 0.000 claims abstract description 47
- 239000001301 oxygen Substances 0.000 claims abstract description 28
- 229910052760 oxygen Inorganic materials 0.000 claims abstract description 28
- WFDIJRYMOXRFFG-UHFFFAOYSA-N Acetic anhydride Chemical compound CC(=O)OC(C)=O WFDIJRYMOXRFFG-UHFFFAOYSA-N 0.000 claims abstract description 27
- 239000002904 solvent Substances 0.000 claims abstract description 20
- 150000001336 alkenes Chemical group 0.000 claims abstract description 19
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 19
- BTQAJGSMXCDDAJ-UHFFFAOYSA-N 2,4,6-trihydroxybenzaldehyde Chemical compound OC1=CC(O)=C(C=O)C(O)=C1 BTQAJGSMXCDDAJ-UHFFFAOYSA-N 0.000 claims abstract description 18
- FSQDURCMBCGCIK-UHFFFAOYSA-N 2-(2,4-dihydroxyphenyl)acetic acid Chemical compound OC(=O)CC1=CC=C(O)C=C1O FSQDURCMBCGCIK-UHFFFAOYSA-N 0.000 claims abstract description 18
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N benzo-alpha-pyrone Natural products C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 claims abstract description 18
- NROAVOJZSXMULV-UHFFFAOYSA-N 3-(3-methylbut-3-enyl)chromen-2-one Chemical compound C(CC(=C)C)C=1C(OC2=CC=CC=C2C=1)=O NROAVOJZSXMULV-UHFFFAOYSA-N 0.000 claims abstract description 17
- -1 allyl coumarin Chemical compound 0.000 claims abstract description 17
- 229960000956 coumarin Drugs 0.000 claims abstract description 16
- 235000001671 coumarin Nutrition 0.000 claims abstract description 16
- 238000005804 alkylation reaction Methods 0.000 claims abstract description 11
- 238000007069 methylation reaction Methods 0.000 claims abstract description 11
- 238000006482 condensation reaction Methods 0.000 claims abstract description 8
- 238000003381 deacetylation reaction Methods 0.000 claims abstract description 8
- 125000006239 protecting group Chemical group 0.000 claims abstract description 6
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims description 84
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 39
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 38
- 238000000034 method Methods 0.000 claims description 35
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 34
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 claims description 33
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 30
- 230000008569 process Effects 0.000 claims description 30
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 27
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 27
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims description 27
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 24
- 239000000741 silica gel Substances 0.000 claims description 24
- 229910002027 silica gel Inorganic materials 0.000 claims description 24
- 239000003513 alkali Substances 0.000 claims description 23
- 238000001035 drying Methods 0.000 claims description 23
- 239000003054 catalyst Substances 0.000 claims description 21
- 230000035484 reaction time Effects 0.000 claims description 21
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 18
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 17
- 235000011181 potassium carbonates Nutrition 0.000 claims description 17
- DKGAVHZHDRPRBM-UHFFFAOYSA-N Tert-Butanol Chemical compound CC(C)(C)O DKGAVHZHDRPRBM-UHFFFAOYSA-N 0.000 claims description 14
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 claims description 13
- 239000002585 base Substances 0.000 claims description 13
- JNGQZZUZGAWLRX-UHFFFAOYSA-N 2-(methoxymethoxy)benzaldehyde Chemical compound COCOC1=CC=CC=C1C=O JNGQZZUZGAWLRX-UHFFFAOYSA-N 0.000 claims description 12
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 claims description 12
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 12
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 12
- 239000005457 ice water Substances 0.000 claims description 12
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims description 9
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 9
- KEAYESYHFKHZAL-UHFFFAOYSA-N Sodium Chemical compound [Na] KEAYESYHFKHZAL-UHFFFAOYSA-N 0.000 claims description 9
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 claims description 9
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 claims description 9
- 239000002253 acid Substances 0.000 claims description 9
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 claims description 9
- 229910000024 caesium carbonate Inorganic materials 0.000 claims description 9
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 claims description 9
- 239000012312 sodium hydride Substances 0.000 claims description 9
- 229910000104 sodium hydride Inorganic materials 0.000 claims description 9
- 238000003756 stirring Methods 0.000 claims description 9
- BKOOMYPCSUNDGP-UHFFFAOYSA-N 2-methylbut-2-ene Chemical compound CC=C(C)C BKOOMYPCSUNDGP-UHFFFAOYSA-N 0.000 claims description 8
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 claims description 8
- BHELZAPQIKSEDF-UHFFFAOYSA-N allyl bromide Chemical compound BrCC=C BHELZAPQIKSEDF-UHFFFAOYSA-N 0.000 claims description 7
- JAMFGQBENKSWOF-UHFFFAOYSA-N bromo(methoxy)methane Chemical compound COCBr JAMFGQBENKSWOF-UHFFFAOYSA-N 0.000 claims description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 7
- SCYULBFZEHDVBN-UHFFFAOYSA-N 1,1-Dichloroethane Chemical compound CC(Cl)Cl SCYULBFZEHDVBN-UHFFFAOYSA-N 0.000 claims description 6
- GQHTUMJGOHRCHB-UHFFFAOYSA-N 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine Chemical compound C1CCCCN2CCCN=C21 GQHTUMJGOHRCHB-UHFFFAOYSA-N 0.000 claims description 6
- LCGLNKUTAGEVQW-UHFFFAOYSA-N Dimethyl ether Chemical group COC LCGLNKUTAGEVQW-UHFFFAOYSA-N 0.000 claims description 6
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 claims description 6
- BZLVMXJERCGZMT-UHFFFAOYSA-N Methyl tert-butyl ether Chemical compound COC(C)(C)C BZLVMXJERCGZMT-UHFFFAOYSA-N 0.000 claims description 6
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 claims description 6
- NBIIXXVUZAFLBC-UHFFFAOYSA-N Phosphoric acid Chemical compound OP(O)(O)=O NBIIXXVUZAFLBC-UHFFFAOYSA-N 0.000 claims description 6
- WQDUMFSSJAZKTM-UHFFFAOYSA-N Sodium methoxide Chemical compound [Na+].[O-]C WQDUMFSSJAZKTM-UHFFFAOYSA-N 0.000 claims description 6
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 claims description 6
- 230000009471 action Effects 0.000 claims description 6
- 239000007810 chemical reaction solvent Substances 0.000 claims description 6
- 239000012022 methylating agents Substances 0.000 claims description 6
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 claims description 6
- 239000011736 potassium bicarbonate Substances 0.000 claims description 6
- 229910000028 potassium bicarbonate Inorganic materials 0.000 claims description 6
- 235000015497 potassium bicarbonate Nutrition 0.000 claims description 6
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical compound [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 claims description 6
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 6
- 235000017550 sodium carbonate Nutrition 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 claims description 6
- FCDPQMAOJARMTG-UHFFFAOYSA-M benzylidene-[1,3-bis(2,4,6-trimethylphenyl)imidazolidin-2-ylidene]-dichlororuthenium;tricyclohexylphosphanium Chemical compound C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.CC1=CC(C)=CC(C)=C1N(CCN1C=2C(=CC(C)=CC=2C)C)C1=[Ru](Cl)(Cl)=CC1=CC=CC=C1 FCDPQMAOJARMTG-UHFFFAOYSA-M 0.000 claims description 5
- INQOMBQAUSQDDS-UHFFFAOYSA-N iodomethane Chemical group IC INQOMBQAUSQDDS-UHFFFAOYSA-N 0.000 claims description 5
- 239000011986 second-generation catalyst Substances 0.000 claims description 5
- TVZPLCNGKSPOJA-UHFFFAOYSA-N copper zinc Chemical compound [Cu].[Zn] TVZPLCNGKSPOJA-UHFFFAOYSA-N 0.000 claims description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N dimethyl sulfoxide Natural products CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 4
- 239000012074 organic phase Substances 0.000 claims description 4
- 229910000030 sodium bicarbonate Inorganic materials 0.000 claims description 4
- 235000017557 sodium bicarbonate Nutrition 0.000 claims description 4
- 125000004810 2-methylpropylene group Chemical group [H]C([H])([H])C([H])(C([H])([H])[*:2])C([H])([H])[*:1] 0.000 claims description 3
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 claims description 3
- GRYLNZFGIOXLOG-UHFFFAOYSA-N Nitric acid Chemical compound O[N+]([O-])=O GRYLNZFGIOXLOG-UHFFFAOYSA-N 0.000 claims description 3
- VMHLLURERBWHNL-UHFFFAOYSA-M Sodium acetate Chemical compound [Na+].CC([O-])=O VMHLLURERBWHNL-UHFFFAOYSA-M 0.000 claims description 3
- HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 3
- 125000003668 acetyloxy group Chemical group [H]C([H])([H])C(=O)O[*] 0.000 claims description 3
- 229910000147 aluminium phosphate Inorganic materials 0.000 claims description 3
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 claims description 3
- PNPBGYBHLCEVMK-UHFFFAOYSA-N benzylidene(dichloro)ruthenium;tricyclohexylphosphanium Chemical compound Cl[Ru](Cl)=CC1=CC=CC=C1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1.C1CCCCC1[PH+](C1CCCCC1)C1CCCCC1 PNPBGYBHLCEVMK-UHFFFAOYSA-N 0.000 claims description 3
- 239000012295 chemical reaction liquid Substances 0.000 claims description 3
- 239000003153 chemical reaction reagent Substances 0.000 claims description 3
- 239000007822 coupling agent Substances 0.000 claims description 3
- 230000017858 demethylation Effects 0.000 claims description 3
- 238000010520 demethylation reaction Methods 0.000 claims description 3
- IEJIGPNLZYLLBP-UHFFFAOYSA-N dimethyl carbonate Chemical compound COC(=O)OC IEJIGPNLZYLLBP-UHFFFAOYSA-N 0.000 claims description 3
- VAYGXNSJCAHWJZ-UHFFFAOYSA-N dimethyl sulfate Chemical compound COS(=O)(=O)OC VAYGXNSJCAHWJZ-UHFFFAOYSA-N 0.000 claims description 3
- 238000001914 filtration Methods 0.000 claims description 3
- 239000011985 first-generation catalyst Substances 0.000 claims description 3
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 3
- 230000011987 methylation Effects 0.000 claims description 3
- 229910017604 nitric acid Inorganic materials 0.000 claims description 3
- 235000011056 potassium acetate Nutrition 0.000 claims description 3
- 238000004537 pulping Methods 0.000 claims description 3
- 239000001632 sodium acetate Substances 0.000 claims description 3
- 235000017281 sodium acetate Nutrition 0.000 claims description 3
- 239000000126 substance Substances 0.000 claims description 3
- 125000001424 substituent group Chemical group 0.000 claims description 3
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 claims description 3
- ITMCEJHCFYSIIV-UHFFFAOYSA-N triflic acid Chemical compound OS(=O)(=O)C(F)(F)F ITMCEJHCFYSIIV-UHFFFAOYSA-N 0.000 claims description 3
- IAZDPXIOMUYVGZ-WFGJKAKNSA-N Dimethyl sulfoxide Chemical group [2H]C([2H])([2H])S(=O)C([2H])([2H])[2H] IAZDPXIOMUYVGZ-WFGJKAKNSA-N 0.000 claims description 2
- 230000029936 alkylation Effects 0.000 abstract description 2
- 239000007858 starting material Substances 0.000 abstract description 2
- 238000004895 liquid chromatography mass spectrometry Methods 0.000 description 7
- 235000006200 Glycyrrhiza glabra Nutrition 0.000 description 4
- 239000003814 drug Substances 0.000 description 4
- LPLVUJXQOOQHMX-QWBHMCJMSA-N glycyrrhizinic acid Chemical compound O([C@@H]1[C@@H](O)[C@H](O)[C@H](O[C@@H]1O[C@@H]1C([C@H]2[C@]([C@@H]3[C@@]([C@@]4(CC[C@@]5(C)CC[C@@](C)(C[C@H]5C4=CC3=O)C(O)=O)C)(C)CC2)(C)CC1)(C)C)C(O)=O)[C@@H]1O[C@H](C(O)=O)[C@@H](O)[C@H](O)[C@H]1O LPLVUJXQOOQHMX-QWBHMCJMSA-N 0.000 description 4
- 238000003786 synthesis reaction Methods 0.000 description 4
- 244000303040 Glycyrrhiza glabra Species 0.000 description 3
- 235000011477 liquorice Nutrition 0.000 description 3
- 239000000203 mixture Substances 0.000 description 3
- 229930014626 natural product Natural products 0.000 description 3
- 241000196324 Embryophyta Species 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 239000002537 cosmetic Substances 0.000 description 2
- 238000010586 diagram Methods 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 235000013305 food Nutrition 0.000 description 2
- 239000000463 material Substances 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000002633 protecting effect Effects 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000011541 reaction mixture Substances 0.000 description 2
- 239000011734 sodium Substances 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 241000202807 Glycyrrhiza Species 0.000 description 1
- 235000001453 Glycyrrhiza echinata Nutrition 0.000 description 1
- 235000017382 Glycyrrhiza lepidota Nutrition 0.000 description 1
- 239000004378 Glycyrrhizin Substances 0.000 description 1
- 125000002777 acetyl group Chemical group [H]C([H])([H])C(*)=O 0.000 description 1
- 238000005865 alkene metathesis reaction Methods 0.000 description 1
- 230000000844 anti-bacterial effect Effects 0.000 description 1
- 230000001093 anti-cancer Effects 0.000 description 1
- 230000003110 anti-inflammatory effect Effects 0.000 description 1
- 230000002921 anti-spasmodic effect Effects 0.000 description 1
- 230000000840 anti-viral effect Effects 0.000 description 1
- 239000003963 antioxidant agent Substances 0.000 description 1
- 230000003078 antioxidant effect Effects 0.000 description 1
- 230000000975 bioactive effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- DEZRYPDIMOWBDS-UHFFFAOYSA-N dcm dichloromethane Chemical compound ClCCl.ClCCl DEZRYPDIMOWBDS-UHFFFAOYSA-N 0.000 description 1
- 238000010511 deprotection reaction Methods 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 238000003912 environmental pollution Methods 0.000 description 1
- 238000000605 extraction Methods 0.000 description 1
- LPLVUJXQOOQHMX-UHFFFAOYSA-N glycyrrhetinic acid glycoside Natural products C1CC(C2C(C3(CCC4(C)CCC(C)(CC4C3=CC2=O)C(O)=O)C)(C)CC2)(C)C2C(C)(C)C1OC1OC(C(O)=O)C(O)C(O)C1OC1OC(C(O)=O)C(O)C(O)C1O LPLVUJXQOOQHMX-UHFFFAOYSA-N 0.000 description 1
- UYRUBYNTXSDKQT-UHFFFAOYSA-N glycyrrhizic acid Natural products CC1(C)C(CCC2(C)C1CCC3(C)C2C(=O)C=C4C5CC(C)(CCC5(C)CCC34C)C(=O)O)OC6OC(C(O)C(O)C6OC7OC(O)C(O)C(O)C7C(=O)O)C(=O)O UYRUBYNTXSDKQT-UHFFFAOYSA-N 0.000 description 1
- 229960004949 glycyrrhizic acid Drugs 0.000 description 1
- 235000019410 glycyrrhizin Nutrition 0.000 description 1
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 1
- 150000002611 lead compounds Chemical class 0.000 description 1
- 229940010454 licorice Drugs 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- WOOWBQQQJXZGIE-UHFFFAOYSA-N n-ethyl-n-propan-2-ylpropan-2-amine Chemical compound CCN(C(C)C)C(C)C.CCN(C(C)C)C(C)C WOOWBQQQJXZGIE-UHFFFAOYSA-N 0.000 description 1
- 230000007935 neutral effect Effects 0.000 description 1
- 229910052757 nitrogen Inorganic materials 0.000 description 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 1
- 239000012299 nitrogen atmosphere Substances 0.000 description 1
- QJGQUHMNIGDVPM-UHFFFAOYSA-N nitrogen group Chemical group [N] QJGQUHMNIGDVPM-UHFFFAOYSA-N 0.000 description 1
- 238000001308 synthesis method Methods 0.000 description 1
- 239000011345 viscous material Substances 0.000 description 1
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
- C07D311/04—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring
- C07D311/06—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2
- C07D311/08—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring
- C07D311/18—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted otherwise than in position 3 or 7
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
Landscapes
- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
The invention relates to a preparation method of 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin. The preparation method comprises the following steps: 2,4, 6-trihydroxybenzaldehyde is taken as a starting material, and 4, 6-dihydroxyl-2-methoxy-3-allylbenzaldehyde is generated through alkylation, protective group loading, methylation reaction and protective group removal reaction; then carrying out condensation reaction with 2, 4-dihydroxyphenylacetic acid in acetic anhydride solvent to obtain 7,3 (2 ', 4') -tri-oxygen substituent-5-methoxy-6 allyl coumarin; then carrying out olefin exchange with olefin to obtain 7,3 (2 ', 4') -tri-oxygen substituent-5-methoxy-6 isopentenyl coumarin; finally, 7,3 (2 ', 4') -trihydroxy-5-methoxy-6 isopentenyl coumarin is obtained through deacetylation reaction.
Description
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to a preparation method of 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin.
Background
7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin, also called Glycyrrhizin (GCM), belongs to 3-aryl coumarin compounds, and was first reported in 1986 as a natural product mainly existing in licorice, and the molecular structure is shown in formula-1 below. The liquorice coumarin is used as the most representative bioactive coumarin compound in liquorice, has various biological activities such as antiviral activity, antibacterial activity, antispasmodic activity, antioxidant and anti-inflammatory activity, liver protecting activity, anticancer activity and the like, and is an important natural product, a medicine active molecule and a medicine lead compound. The existing research on 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin is mainly related to the biological activity, and the synthesis method of the coumarin has not been reported.
7,3 (2 ', 4') -trihydroxy-5-methoxy-6 isopentenyl coumarin is taken as an important natural product, is mainly extracted from plants such as liquorice, has a low extraction yield of only 0.023 percent (w/w), is unfavorable for industrialized implementation, and is easy to cause vegetation damage and environmental pollution due to excessive exploitation of natural resources, so that further application research on biological medicines, cosmetics, foods, luminescent materials and the like is limited.
Disclosure of Invention
The present invention aims to provide a novel chemical synthesis method of 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin.
In particular, the invention provides a preparation method of 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin, which comprises the following steps:
(1) 2,4, 6-trihydroxybenzaldehyde (formula-2) and 3-bromopropene are subjected to alkylation reaction in alkali 1 to obtain 3-allyl-2, 4, 6-trihydroxybenzaldehyde (formula-3);
(2) 3-allyl-2, 4, 6-trihydroxybenzaldehyde (formula-3) and bromomethyl methyl ether undergo methyl methylation reaction in alkali 2 to form a protecting group, thereby obtaining 3-allyl-2-hydroxy-4, 6-bis (methoxymethoxy) benzaldehyde (formula-4);
(3) Methylation reaction of 3-allyl-2-hydroxy-4, 6-di (methoxymethoxy) benzaldehyde (formula-4) and a methylation reagent in alkali 3 to obtain 3-allyl-2-methoxy-4, 6-di (methoxymethoxy) benzaldehyde (formula-5);
(4) The 3-allyl-2-methoxy-4, 6-bis (methoxymethoxy) benzaldehyde (formula-5) undergoes a demethylation methyl ether protecting group reaction in acid 1 to obtain 4, 6-dihydroxy-2-methoxy-3-allyl benzaldehyde (formula-6);
(5) 4, 6-dihydroxyl-2-methoxy-3-allylbenzaldehyde (formula-6) and 2, 4-dihydroxyphenylacetic acid are subjected to condensation reaction in acetic anhydride solution of alkali 4 to obtain 7,3 (2 ', 4') -tri-oxygen-containing substituent-5-methoxy-6 allylcoumarin (formula-7); the oxygen-containing substituent is an acetoxy group;
(6) Carrying out olefin exchange reaction on 7,3 (2 ', 4') -tri-oxygen-containing substituent-5-methoxy-6 allyl coumarin (formula-7) and olefin under the action of a catalyst 1 to obtain 7,3 (2 ', 4') -tri-oxygen-containing substituent-5-methoxy-6 isopentenyl coumarin (formula-8);
(7) Deacetylation reaction of 7,3 (2 ', 4') -tri-oxygen substituent-5-methoxy-6 isopentenyl coumarin (formula-8) under the action of catalyst 2 to obtain 7,3 (2 ', 4') -trihydroxy-5-methoxy-6 isopentenyl coumarin (formula-1);
preferably, in the step (1), the reaction solvent is water, methanol or ethanol, and the base 1 is sodium hydride, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate or cesium carbonate; wherein, the molar concentration ratio of the 2,4, 6-trihydroxybenzaldehyde (formula-2), the 3-bromopropene and the alkali 1 is 1: (1.0-2.0): (2-4); the temperature of the alkylation reaction is-10-80 ℃; the alkylation reaction time is 1-10 h;
in the step (1), the post-treatment process is as follows: acidifying the reaction solution with hydrochloric acid to pH 4-5, extracting with ethyl acetate, drying, concentrating, pulping with dichloromethane, collecting organic phase, and concentrating to obtain 3-allyl-2, 4, 6-trihydroxybenzaldehyde (formula-3).
Preferably, in the step (2), the reaction solvent is dichloromethane, dichloroethane, chloroform, tetrahydrofuran or methyl tert-butyl ether; the base 2 is triethylamine, N, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 4-diazabicyclo [2.2.2] octane or sodium hydride;
the molar concentration ratio of 3-allyl-2, 4, 6-trihydroxybenzaldehyde, bromomethyl methyl ether and alkali 2 is 1 (1.5-4.0): (2.0 to 4.0);
the reaction temperature of the step (2) is 20-80 ℃; the reaction time is 1-6 h;
in the step (2), the post-treatment process comprises the following steps: concentrating the reaction solution, acidifying with hydrochloric acid to pH 4-5, extracting with ethyl acetate, drying, concentrating, and separating with silica gel column to obtain 3-allyl-2-hydroxy-4, 6-di (methoxymethoxy) benzaldehyde (formula-4).
Preferably, in the step (3), the solvent is dimethyl sulfoxide, dimethylformamide, methylpyrrolidone, acetonitrile or tetrahydrofuran; the methylating agent is methyl iodide, dimethyl carbonate and dimethyl sulfate; the base 3 is sodium hydride, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, and cesium carbonate; the molar concentration ratio of the 3-allyl-2-hydroxy-4, 6-di (methoxymethoxy) benzaldehyde (formula-4) and the methylating agent to the alkali 3 is 1 (1.5-4.0): (2.0 to 4.0);
the reaction temperature is 20-50 ℃; the reaction time is 4-10 h;
in the step (3), the post-treatment process is as follows: pouring the reaction solution into ice water, stirring, extracting with ethyl acetate, drying, concentrating, and separating with silica gel column to obtain 3-allyl-2-methoxy-4, 6-bis (methoxymethoxy) benzaldehyde (formula-5).
Preferably, in step (4), acid 1 is sulfuric acid, hydrochloric acid, nitric acid, trifluoroacetic acid, phosphoric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, citric acid or acetic acid; the solvent is methanol, ethanol, isopropanol or tert-butanol; the molar concentration ratio of 3-allyl-2-methoxy-4, 6-bis (methoxymethoxy) benzaldehyde to acid 1 is 1: (0.1 to 1);
the reaction temperature of the demethylated methyl ether protecting group is 30-90 ℃; the reaction time is 2-24 hours;
in the step (4), the post-treatment process is as follows: pouring the reaction solution into ice water, stirring, adjusting pH to neutrality with sodium bicarbonate, extracting with ethyl acetate, drying, concentrating, and separating with silica gel column to obtain 4, 6-dihydroxy-2-methoxy-3-allylbenzaldehyde (formula-6).
Preferably, in the step (5), the solvent is acetic anhydride; the base 4 is triethylamine, sodium acetate, potassium acetate or potassium carbonate; the molar ratio of 4, 6-dihydroxyl-2-methoxyl-3-allylbenzaldehyde, 2, 4-dihydroxyphenylacetic acid, alkali 4 and solvent is 1: (1.0-1.2): (2-4): (4-7);
the temperature of the condensation reaction is 100-140 ℃; the reaction time is 2-8 h;
in the step (5), the post-treatment process is as follows: adding ice water into the reaction liquid, stirring vigorously, dissolving the obtained sticky substance by adopting ethyl acetate, drying and concentrating, and separating by a silica gel column to obtain the 7,3 (2 ', 4') -tri-oxygen substituent-5-methoxy-6 allyl coumarin.
Preferably, in the step (6), the solvent is dichloromethane, dichloroethane or chloroform; the olefin is 2-methyl propylene, 2-methyl-2-butene; catalyst 1 is a Grubbs first generation catalyst, grubbs second generation catalyst, schrock catalyst; the molar concentration ratio of the 7,3 (2 ', 4') -tri-oxo substituent-5-methoxy-6 allyl coumarin (formula-7), the catalyst 1 and the olefin is 1: (0.05-0.2): (10-100);
the temperature of the olefin exchange reaction is 0-40 ℃; the reaction time is 8-24 hours;
in the step (6), the post-treatment process is as follows: concentrating the reaction solution, adjusting the pH to 4-5 with hydrochloric acid, extracting with ethyl acetate, drying, concentrating, and separating with reverse silica gel column to obtain 7,3 (2 ', 4') -tri-oxygen substituent-5-methoxy-6 isopentenyl coumarin.
Preferably, in the step (7), the solvent is ethanol, methanol or water; the catalyst 2 is copper-zinc coupling agent, zinc powder, potassium carbonate, cesium carbonate, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium bicarbonate or sodium methoxide; the molar concentration ratio of the 7,3 (2 ', 4') -tri-oxygen substituent-5-methoxy-6 isopentenyl coumarin to the catalyst 2 is 1: (1-40);
the temperature of the deacetylation reaction is 20-40 ℃; the reaction time is 4-24 hours;
in the step (7), the post-treatment process is as follows: filtering the reaction solution, concentrating the solution, adjusting the pH to 4-5 by hydrochloric acid, extracting by ethyl acetate, drying, concentrating, and separating by a reverse silica gel column to obtain the 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin.
Advantageous effects
Compared with the method for extracting plants, the method has the advantages of low cost and easy obtainment of raw materials, lower cost, simple operation, simple steps, higher yield and higher efficiency, can be used for rapid and massive synthesis, fills the blank of research on synthesizing the 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin by using a chemical synthesis method, and provides more choices for raw material sources of further application research on aspects of biological medicines, cosmetics, foods, luminescent materials and the like.
Drawings
FIG. 1 is a diagram of 4, 6-dihydroxy-2-methoxy-3-allylbenzaldehyde 1 HNMR profile;
FIG. 2 is 7,3 (2 ', 4') -triacetoxy-5-methoxy-6 allyl coumarin 1 HNMR profile;
FIG. 3 is 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin 1 HNMR profile.
Detailed Description
The present invention is further illustrated by the following embodiments, which are to be understood as merely illustrative of the invention and not limiting thereof.
The preparation method of the 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin provided by the invention adopts the following synthetic route: 2,4, 6-trihydroxybenzaldehyde (formula-2) is used as a starting material, and 3-allyl-2, 4, 6-trihydroxybenzaldehyde (formula-3) is obtained through alkylation; then adding a protecting group to obtain 3-allyl-2-hydroxy-4, 6-di (methoxymethoxy) benzaldehyde (formula-4); then carrying out methylation reaction to obtain 3-allyl-2-methoxy-4, 6-bis (methoxymethoxy) benzaldehyde (formula-5); then carrying out deprotection reaction to obtain 4, 6-dihydroxyl-2-methoxyl-3-allylbenzaldehyde (formula-6); then carrying out condensation reaction with 2, 4-dihydroxyphenylacetic acid in acetic anhydride solvent to obtain 7,3 (2 ', 4') -tri-oxygen substituent-5-methoxy-6 allyl coumarin (formula-7); then carrying out olefin exchange with olefin to obtain 7,3 (2 ', 4') -tri-oxygen substituent-5-methoxy-6 isopentenyl coumarin (formula-8); finally, 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin (formula-1) is obtained through deacetylation reaction.
Specifically, the preparation method of the 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin provided by the invention can comprise the following steps:
(1) 2,4, 6-trihydroxybenzaldehyde (formula-2) and 3-bromopropene are subjected to alkylation reaction in alkali 1 to obtain 3-allyl-2, 4, 6-trihydroxybenzaldehyde (formula-3);
(2) 3-allyl-2, 4, 6-trihydroxybenzaldehyde (formula-3) and bromomethyl methyl ether undergo methyl methylation reaction in alkali 2 to form a protecting group, thereby obtaining 3-allyl-2-hydroxy-4, 6-bis (methoxymethoxy) benzaldehyde (formula-4);
(3) Methylation reaction of 3-allyl-2-hydroxy-4, 6-di (methoxymethoxy) benzaldehyde (formula-4) and a methylation reagent in alkali 3 to obtain 3-allyl-2-methoxy-4, 6-di (methoxymethoxy) benzaldehyde (formula-5);
(4) The 3-allyl-2-methoxy-4, 6-bis (methoxymethoxy) benzaldehyde (formula-5) undergoes a demethylation methyl ether protecting group reaction in acid 1 to obtain 4, 6-dihydroxy-2-methoxy-3-allyl benzaldehyde (formula-6);
(5) 4, 6-dihydroxyl-2-methoxy-3-allylbenzaldehyde (formula-6) and 2, 4-dihydroxyphenylacetic acid are subjected to condensation reaction in acetic anhydride solution of alkali 4 to obtain 7,3 (2 ', 4') -tri-oxygen-containing substituent-5-methoxy-6 allylcoumarin (formula-7); the oxygen-containing substituent (RO-) at the 3, 2',4' positions is acetoxy; the acetyl group can play a role in protecting hydroxyl;
(6) Carrying out olefin exchange reaction (olefin metathesis reaction) on 7,3 (2 ', 4') -tri-oxygen substituent-5-methoxy-6 allyl coumarin (formula-7) and olefin under the action of a catalyst 1 to obtain 7,3 (2 ', 4') -tri-oxygen substituent-5-methoxy-6 isopentenyl coumarin (formula-8);
(7) The 7,3 (2 ', 4') -tri-oxygen substituent-5-methoxy-6-isopentenyl coumarin (formula-8) is subjected to deacetylation reaction under the action of a catalyst 2 to obtain 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin (formula-1).
In some embodiments, in step (1), the reaction solvent may be water, methanol or ethanol, preferably water. The base 1 may be sodium hydride, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate or cesium carbonate, preferably potassium hydroxide. Wherein, the molar concentration ratio of the 2,4, 6-trihydroxybenzaldehyde (formula-2), the 3-bromopropene and the alkali 1 is 1: (1.0-2.0): (2 to 4), preferably 1:1.2:3.
the alkylation reaction temperature may be-10 to 80 ℃, preferably 25 ℃; the alkylation reaction time is 1 to 10 hours, preferably 4 hours.
In the step (1), the post-treatment process may be: acidifying the reaction solution with hydrochloric acid to pH 4-5, extracting with ethyl acetate, drying, concentrating, pulping with dichloromethane, collecting organic phase, and concentrating to obtain 3-allyl-2, 4, 6-trihydroxybenzaldehyde (formula-3).
In some embodiments, in step (2), the reaction solvent may be dichloromethane, dichloroethane, chloroform, tetrahydrofuran or methyl tert-butyl ether, preferably dichloromethane. The base 2 may be triethylamine, N, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 4-diazabicyclo [2.2.2] octane or sodium hydride, preferably triethylamine. The molar concentration ratio of 3-allyl-2, 4, 6-trihydroxybenzaldehyde (formula-3) to bromomethyl methyl ether to alkali 2 is 1 (1.5-4.0): (2.0 to 4.0), preferably 1:4:2.2.
the reaction temperature in step (2) may be 20 to 80 ℃, preferably 30 ℃; the reaction time may be 1 to 6 hours, preferably 4 hours.
In the step (2), the post-treatment process may be: concentrating the reaction solution, acidifying with hydrochloric acid to pH 4-5, extracting with ethyl acetate, drying, concentrating, and separating with silica gel column to obtain 3-allyl-2-hydroxy-4, 6-di (methoxymethoxy) benzaldehyde (formula-4).
In some embodiments, in step (3), the solvent may be dimethyl sulfoxide, dimethylformamide, methylpyrrolidone, acetonitrile or tetrahydrofuran, preferably DMF. The methylating agent may be methyl iodide, dimethyl carbonate, dimethyl sulfate, preferably methyl iodide. The base 3 may be sodium hydride, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, and cesium carbonate, preferably potassium carbonate. The molar concentration ratio of 3-allyl-2-hydroxy-4, 6-bis (methoxymethoxy) benzaldehyde (formula-4), methylating agent and base 3 may be 1 (1.5-4.0): (2.0 to 4.0), preferably 1:3:2.
the reaction temperature may be 20 to 50 ℃, preferably 25 ℃; the reaction time may be from 4 to 10 hours, preferably 6 hours.
In some embodiments, in step (3), the post-treatment process may be: pouring the reaction solution into ice water, stirring, extracting with ethyl acetate, drying, concentrating, and separating with silica gel column to obtain 3-allyl-2-methoxy-4, 6-bis (methoxymethoxy) benzaldehyde (formula-5).
In some embodiments, in step (4), the acid 1 may be sulfuric acid, hydrochloric acid, nitric acid, trifluoroacetic acid, phosphoric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, citric acid or acetic acid, preferably sulfuric acid. The solvent may be methanol, ethanol, isopropanol or tert-butanol, preferably tert-butanol. The molar concentration ratio of 3-allyl-2-methoxy-4, 6-bis (methoxymethoxy) benzaldehyde (formula-5) to acid 1 may be 1: (0.1 to 1), preferably 1:0.1.
the temperature for the reaction of removing the methyl ether protecting group can be 30-90 ℃, and is preferably 80 ℃; the reaction time may be 2 to 24 hours, preferably 8 hours.
In some embodiments, in step (4), the post-treatment process may be: pouring the reaction solution into ice water, stirring, adjusting pH to neutrality with sodium bicarbonate, extracting with ethyl acetate, drying, concentrating, and separating with silica gel column to obtain 4, 6-dihydroxy-2-methoxy-3-allylbenzaldehyde (formula-6).
In some embodiments, in step (5), the solvent may be acetic anhydride; the base 4 may be triethylamine, sodium acetate, potassium acetate or potassium carbonate, preferably triethylamine. The molar ratio of 4, 6-dihydroxyl-2-methoxyl-3-allylbenzaldehyde, 2, 4-dihydroxyphenylacetic acid, alkali 4 and solvent is 1: (1.0-1.2): (2-4): (4-7), preferably 1:1.1:2.5:6.
the temperature of the condensation reaction may be from 100 to 140 ℃, preferably 110 ℃; the reaction time may be 2 to 8 hours, preferably 6 hours.
In some embodiments, in step (5), the post-treatment process may be: adding ice water into the reaction liquid, stirring vigorously, dissolving the obtained sticky substance by adopting ethyl acetate, drying and concentrating, and separating by a silica gel column to obtain the 7,3 (2 ', 4') -tri-oxygen substituent-5-methoxy-6 allyl coumarin.
In some embodiments, in step (6), the solvent may be dichloromethane, dichloroethane or chloroform, preferably dichloromethane. The olefin may be 2-methyl propylene, 2-methyl-2-butene; catalyst 1 may be a Grubbs first generation catalyst, grubbs second generation catalyst, schrock catalyst, preferably Grubbs second generation catalyst. The molar concentration ratio of the 7,3 (2 ', 4') -tri-oxo substituent-5-methoxy-6 allyl coumarin (formula-7), the catalyst 1 and the olefin is 1: (0.05-0.2): (10 to 100), preferably 1:0.05:23.5.
the temperature of the olefin exchange reaction may be from 0 to 40 ℃, preferably 30 ℃; the reaction time may be 8 to 24 hours, preferably 12 hours.
In some embodiments, in step (6), the post-treatment process may be: concentrating the reaction solution, adjusting the pH to 4-5 with hydrochloric acid, extracting with ethyl acetate, drying, concentrating, and separating with reverse silica gel column to obtain 7,3 (2 ', 4') -tri-oxygen substituent-5-methoxy-6 isopentenyl coumarin.
In some embodiments, in step (7), the solvent may be ethanol, methanol, water; the catalyst 2 can be a copper-zinc coupling agent, zinc powder, potassium carbonate, cesium carbonate, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium bicarbonate or sodium methoxide. The molar concentration ratio of the 7,3 (2 ', 4') -tri-oxygen substituent-5-methoxy-6 isopentenyl coumarin to the catalyst 2 is 1: (1 to 40), preferably 1:38.
the temperature of the deacetylation reaction may be 20 to 40 ℃, preferably 40 ℃; the reaction time may be from 4 to 24 hours, preferably 16 hours.
In some embodiments, in step (7), the post-treatment process may be: filtering the reaction solution, concentrating the solution, adjusting the pH to 4-5 by hydrochloric acid, extracting by ethyl acetate, drying, concentrating, and separating by a reverse silica gel column to obtain the 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin.
The present invention will be described in more detail by way of examples. It is also to be understood that the following examples are given solely for the purpose of illustration and are not to be construed as limitations upon the scope of the invention, since numerous insubstantial modifications and variations will now occur to those skilled in the art in light of the foregoing disclosure. The specific process parameters and the like described below are also merely examples of suitable ranges, i.e., one skilled in the art can make a suitable selection from the description herein and are not intended to be limited to the specific values described below.
Example 1
A method for synthesizing 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin, which comprises the following steps:
(1) KOH (54.5 g,974.2 mmol) was dissolved in H 2 O (400 mL) was then added to the round bottom flask, ice-bath, followed by 2,4, 6-trihydroxybenzaldehyde (50 g,324.6 mmol) and 3-bromopropene (47.13 g,389.52 mmol) and stirred at 25℃for 4h. After the reaction, the reaction solution was acidified to pH 4 to 5 with hydrochloric acid, extracted with ethyl acetate, dried, concentrated, slurried with methylene chloride, and the organic phase was collected and concentrated to give 3-allyl-2, 4, 6-trihydroxybenzaldehyde (39.9 g,205.6mmol, LCMS: m/z (ESI) 194.7[ M+H)] + )。
(2) To a solution of the resulting 3-allyl-2, 4, 6-trihydroxybenzaldehyde (39.9 g,205.6 mmol) in methylene chloride (350 mL) were added N, N-diisopropylethylamine DIPEA (106.72 g,822.62 mmol) and MOMBr (51.4 g,451.3 mmol), and the mixture was stirred at 30℃for 4 hours. After the reaction, the reaction solution was concentrated, acidified to pH 4 to 5 with hydrochloric acid, extracted with ethyl acetate, dried, concentrated, and separated on a silica gel column to give 3-allyl-2-hydroxy-4, 6-bis (methoxymethoxy) benzaldehyde (50 g, 178 mmol, LCMS: m/z (ESI) 282.9[ M+H)] + )。
(3) To a solution of 3-allyl-2-hydroxy-4, 6-bis (methoxymethoxy) benzaldehyde (50 g, 178 mmol) in DMF (400 mL) was added potassium carbonate (74 g,537 mmol) and methyl iodide (50.8 g, 356 mmol) under ice bath, and the mixture was reacted at 25℃for 6h. After the reaction, the reaction mixture was poured into ice water and stirred, extracted with ethyl acetate, dried and concentrated, and separated by a silica gel column to give 3-allyl-2-methoxy-4, 6-bis (methoxymethoxy) benzaldehyde (40.0 g,135.1mmol, LCMS: m/z (ESI) 296.9[ M+H)] + )。
(4) Chamber3-allyl-2-methoxy-4, 6-bis (methoxymethoxy) benzaldehyde (10 g,37.16 mmol) was dissolved in t-BuOH (200 mL) of t-butanol at room temperature, and a solution of concentrated sulfuric acid (0.37 g,3.7 mmol) in t-BuOH was added thereto at room temperature and stirred at 80℃for 8h. After the reaction, the reaction mixture was poured into ice water and stirred, sodium bicarbonate was adjusted to neutral, extracted with ethyl acetate, dried, concentrated, and separated on a silica gel column to give 4, 6-dihydroxy-2-methoxy-3-allylbenzaldehyde (5.7 g,27.4mmol, LCMS: m/z (ESI) 208.7[ M+H)] + )。 1 HNMR(400MHz,DMSO-d 6 )δ11.91(s,1H),11.02(s,1H),9.91(s,1H),6.17(s,1H),5.94-5.87(m,1H),4.97-4.93(m,2H),3.87(s,3H),3.21(d,J＝6,2H)。
(5) 4, 6-dihydroxy-2-methoxy-3-allylbenzaldehyde (5.7 g,27.4 mmol) and 2, 4-dihydroxyphenylacetic acid (5 g,30.14 mmol) were dissolved in acetic anhydride (19.5 g,191.8 mmol) at room temperature, triethylamine (6.9 g,68.5 mmol) was added and the reaction stirred at 110℃for 6h. After the reaction, ice water was added to the reaction solution, and the mixture was stirred vigorously to give a viscous material, which was dissolved with ethyl acetate, dried and concentrated, and separated on a silica gel column to give 7,3 (2 ', 4') -triacetoxy-5-methoxy-6 allyl coumarin (8.4 g,18.0mmol, LCMS: m/z (ESI) 489.1[ M+Na)] + )。 1 HNMR(400MHz,DMSO-d 6 )δ7.96(s,1H),7.59(d,J＝8,1H),7.19-7.15(m,3H),5.89-5.82(m,1H),5.04-4.99(m,2H),3.86(s,3H),3.35(d,J＝6.4,2H),2.31(d,J＝3.2,6H),2.13(s,3H)。
(6) 7,3 (2 ',4 ') -triacetoxy-5-methoxy-6 allyl coumarin (5.6 g,12.01 mmol) was dissolved in dichloromethane DCM (500 mL) at room temperature, grubbs ' second generation catalyst (500 mg,0.6 mmol) was added, after nitrogen substitution 2-methyl-2-butene (30 mL) was added and stirred at 30℃for 16h. The post-treatment process comprises the following steps: concentrating the reaction solution, adjusting pH to 4-5 with hydrochloric acid, extracting with ethyl acetate, drying, concentrating, and separating with reverse silica gel column to obtain 7,3 (2 ', 4') -triacetoxy-5-methoxy-6-isopentenyl coumarin (5 g,10.1mmol, LCMS: m/z (ESI) 517.2[ M+Na ]] + )。
(7) 7,3 (2 ', 4') -triacetoxy-5-methoxy-6-isopentenyl coumarin (500 mg,1.01 mmol) was dissolved in MeOH (50 ml) at room temperature, and then copper-zinc couplant (5 g) was added thereto and stirred at 40℃for 16 hours under a shielding nitrogen atmosphere. The rear partFiltering, concentrating the solution, adjusting pH to 4-5 with hydrochloric acid, extracting with ethyl acetate, drying, concentrating, and separating with reverse silica gel column to obtain 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin (300.2 mg,0.82mmol, LCMS: m/z (ESI) 369.1[ M+H ])] + )。 1 HNMR(400MHz,DMSO-d 6 )δ10.58(s,1H),9.39(s,2H),7.81(s,1H),7.11(d,J＝8.4,1H),6.60(s,1H),6.36(d,J＝1.6,1H),6.28-6.25(m,1H),5.15(t,J＝7.2,1H),3.76(s,3H),3.26(d,J＝6.4,2H),1.73(s,3H),1.64(s,3H)。
FIG. 1 is a diagram of 4, 6-dihydroxy-2-methoxy-3-allylbenzaldehyde 1 HNMR profile; FIG. 2 is 7,3 (2 ', 4') -triacetoxy-5-methoxy-6 allyl coumarin 1 HNMR profile; FIG. 3 is 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin 1 HNMR profile.
While the present invention has been described in detail through the foregoing description of the preferred embodiment, it should be understood that the foregoing description is not to be considered as limiting the invention. Many modifications and substitutions of the present invention will become apparent to those of ordinary skill in the art upon reading the foregoing. Accordingly, the scope of the invention should be limited only by the attached claims.
Claims (8)
1. A process for the preparation of 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin, characterized in that it comprises the following steps:
(1) 2,4, 6-trihydroxybenzaldehyde (formula-2) and 3-bromopropene are subjected to alkylation reaction in alkali 1 to obtain 3-allyl-2, 4, 6-trihydroxybenzaldehyde (formula-3);
(2) 3-allyl-2, 4, 6-trihydroxybenzaldehyde (formula-3) and bromomethyl methyl ether undergo methyl methylation reaction in alkali 2 to form a protecting group, thereby obtaining 3-allyl-2-hydroxy-4, 6-bis (methoxymethoxy) benzaldehyde (formula-4);
(3) Methylation reaction of 3-allyl-2-hydroxy-4, 6-di (methoxymethoxy) benzaldehyde (formula-4) and a methylation reagent in alkali 3 to obtain 3-allyl-2-methoxy-4, 6-di (methoxymethoxy) benzaldehyde (formula-5);
(4) The 3-allyl-2-methoxy-4, 6-bis (methoxymethoxy) benzaldehyde (formula-5) undergoes a demethylation methyl ether protecting group reaction in acid 1 to obtain 4, 6-dihydroxy-2-methoxy-3-allyl benzaldehyde (formula-6);
(5) 4, 6-dihydroxyl-2-methoxy-3-allylbenzaldehyde (formula-6) and 2, 4-dihydroxyphenylacetic acid are subjected to condensation reaction in acetic anhydride solution of alkali 4 to obtain 7,3 (2 ', 4') -tri-oxygen-containing substituent-5-methoxy-6 allylcoumarin (formula-7); the oxygen-containing substituent is an acetoxy group;
(6) Carrying out olefin exchange reaction on 7,3 (2 ', 4') -tri-oxygen-containing substituent-5-methoxy-6 allyl coumarin (formula-7) and olefin under the action of a catalyst 1 to obtain 7,3 (2 ', 4') -tri-oxygen-containing substituent-5-methoxy-6 isopentenyl coumarin (formula-8);
(7) Deacetylation reaction of 7,3 (2 ', 4') -tri-oxygen substituent-5-methoxy-6 isopentenyl coumarin (formula-8) under the action of catalyst 2 to obtain 7,3 (2 ', 4') -trihydroxy-5-methoxy-6 isopentenyl coumarin (formula-1);
2. the preparation method according to claim 1, wherein in the step (1), the reaction solvent is water, methanol or ethanol, and the base 1 is sodium hydride, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate or cesium carbonate; wherein, the molar concentration ratio of the 2,4, 6-trihydroxybenzaldehyde (formula-2), the 3-bromopropene and the alkali 1 is 1: (1.0-2.0): (2-4);
the temperature of the alkylation reaction is-10-80 ℃; the alkylation reaction time is 1-10 h;
in the step (1), the post-treatment process is as follows: acidifying the reaction solution with hydrochloric acid to pH 4-5, extracting with ethyl acetate, drying, concentrating, pulping with dichloromethane, collecting organic phase, and concentrating to obtain 3-allyl-2, 4, 6-trihydroxybenzaldehyde (formula-3).
3. The process according to claim 1 or 2, wherein in step (2), the reaction solvent is methylene chloride, dichloroethane, chloroform, tetrahydrofuran or methyl tert-butyl ether; the base 2 is triethylamine, N, N-diisopropylethylamine, 1, 8-diazabicyclo [5.4.0] undec-7-ene, 1, 4-diazabicyclo [2.2.2] octane or sodium hydride;
the molar concentration ratio of 3-allyl-2, 4, 6-trihydroxybenzaldehyde, bromomethyl methyl ether and alkali 2 is 1 (1.5-4.0): (2.0 to 4.0);
the reaction temperature of the step (2) is 20-80 ℃; the reaction time is 1-6 h;
in the step (2), the post-treatment process comprises the following steps: concentrating the reaction solution, acidifying with hydrochloric acid to pH 4-5, extracting with ethyl acetate, drying, concentrating, and separating with silica gel column to obtain 3-allyl-2-hydroxy-4, 6-di (methoxymethoxy) benzaldehyde (formula-4).
4. A process according to any one of claims 1 to 3, wherein in step (3) the solvent is dimethyl sulfoxide, dimethylformamide, methylpyrrolidone, acetonitrile or tetrahydrofuran; the methylating agent is methyl iodide, dimethyl carbonate and dimethyl sulfate; the base 3 is sodium hydride, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, and cesium carbonate; the molar concentration ratio of the 3-allyl-2-hydroxy-4, 6-di (methoxymethoxy) benzaldehyde (formula-4) and the methylating agent to the alkali 3 is 1 (1.5-4.0): (2.0 to 4.0);
the reaction temperature is 20-50 ℃; the reaction time is 4-10 h;
in the step (3), the post-treatment process is as follows: pouring the reaction solution into ice water, stirring, extracting with ethyl acetate, drying, concentrating, and separating with silica gel column to obtain 3-allyl-2-methoxy-4, 6-bis (methoxymethoxy) benzaldehyde (formula-5).
5. The process according to any one of claims 1 to 4, wherein in step (4), acid 1 is sulfuric acid, hydrochloric acid, nitric acid, trifluoroacetic acid, phosphoric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, citric acid or acetic acid; the solvent is methanol, ethanol, isopropanol or tert-butanol; the molar concentration ratio of 3-allyl-2-methoxy-4, 6-bis (methoxymethoxy) benzaldehyde to acid 1 is 1: (0.1 to 1);
the reaction temperature of the demethylated methyl ether protecting group is 30-90 ℃; the reaction time is 2-24 hours;
in the step (4), the post-treatment process is as follows: pouring the reaction solution into ice water, stirring, adjusting pH to neutrality with sodium bicarbonate, extracting with ethyl acetate, drying, concentrating, and separating with silica gel column to obtain 4, 6-dihydroxy-2-methoxy-3-allylbenzaldehyde (formula-6).
6. The process according to any one of claims 1 to 5, wherein in step (5), the solvent is acetic anhydride; the base 4 is triethylamine, sodium acetate, potassium acetate or potassium carbonate; the molar ratio of 4, 6-dihydroxyl-2-methoxyl-3-allylbenzaldehyde, 2, 4-dihydroxyphenylacetic acid, alkali 4 and solvent is 1: (1.0-1.2): (2-4): (4-7);
the temperature of the condensation reaction is 100-140 ℃; the reaction time is 2-8 h;
in the step (5), the post-treatment process is as follows: adding ice water into the reaction liquid, stirring vigorously, dissolving the obtained sticky substance by adopting ethyl acetate, drying and concentrating, and separating by a silica gel column to obtain the 7,3 (2 ', 4') -tri-oxygen substituent-5-methoxy-6 allyl coumarin.
7. The process according to any one of claims 1 to 6, wherein in step (6), the solvent is dichloromethane, dichloroethane or chloroform; the olefin is 2-methyl propylene, 2-methyl-2-butene; catalyst 1 is a Grubbs first generation catalyst, grubbs second generation catalyst, schrock catalyst; the molar concentration ratio of the 7,3 (2 ', 4') -tri-oxo substituent-5-methoxy-6 allyl coumarin (formula-7), the catalyst 1 and the olefin is 1: (0.05-0.2): (10-100);
the temperature of the olefin exchange reaction is 0-40 ℃; the reaction time is 8-24 hours;
in the step (6), the post-treatment process is as follows: concentrating the reaction solution, adjusting the pH to 4-5 with hydrochloric acid, extracting with ethyl acetate, drying, concentrating, and separating with reverse silica gel column to obtain 7,3 (2 ', 4') -tri-oxygen substituent-5-methoxy-6 isopentenyl coumarin.
8. The process according to any one of claims 1 to 7, wherein in step (7), the solvent is ethanol, methanol, water; the catalyst 2 is copper-zinc coupling agent, zinc powder, potassium carbonate, cesium carbonate, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium bicarbonate or sodium methoxide; the molar concentration ratio of the 7,3 (2 ', 4') -tri-oxygen substituent-5-methoxy-6 isopentenyl coumarin to the catalyst 2 is 1: (1-40);
the temperature of the deacetylation reaction is 20-40 ℃; the reaction time is 4-24 hours;
in the step (7), the post-treatment process is as follows: filtering the reaction solution, concentrating the solution, adjusting the pH to 4-5 by hydrochloric acid, extracting by ethyl acetate, drying, concentrating, and separating by a reverse silica gel column to obtain the 7,3 (2 ', 4') -trihydroxy-5-methoxy-6-isopentenyl coumarin.
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