CN115477630B - 一类香豆素衍生物及其制备方法 - Google Patents
一类香豆素衍生物及其制备方法 Download PDFInfo
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- CN115477630B CN115477630B CN202211215996.9A CN202211215996A CN115477630B CN 115477630 B CN115477630 B CN 115477630B CN 202211215996 A CN202211215996 A CN 202211215996A CN 115477630 B CN115477630 B CN 115477630B
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- ethyl acetate
- minutes
- bromosubstrate
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- 238000002360 preparation method Methods 0.000 title claims abstract description 33
- 150000001893 coumarin derivatives Chemical class 0.000 title 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 126
- 238000006243 chemical reaction Methods 0.000 claims abstract description 49
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims abstract description 45
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims abstract description 44
- MXQOYLRVSVOCQT-UHFFFAOYSA-N palladium;tritert-butylphosphane Chemical compound [Pd].CC(C)(C)P(C(C)(C)C)C(C)(C)C.CC(C)(C)P(C(C)(C)C)C(C)(C)C MXQOYLRVSVOCQT-UHFFFAOYSA-N 0.000 claims abstract description 36
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 claims abstract description 24
- 229910052757 nitrogen Inorganic materials 0.000 claims abstract description 24
- 150000001875 compounds Chemical class 0.000 claims abstract description 22
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims abstract description 19
- 239000000706 filtrate Substances 0.000 claims abstract description 19
- 238000000746 purification Methods 0.000 claims abstract description 19
- 239000011541 reaction mixture Substances 0.000 claims abstract description 19
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 19
- 150000004775 coumarins Chemical class 0.000 claims abstract description 17
- JRZJOMJEPLMPRA-UHFFFAOYSA-N olefin Natural products CCCCCCCC=C JRZJOMJEPLMPRA-UHFFFAOYSA-N 0.000 claims abstract description 6
- 229940125782 compound 2 Drugs 0.000 claims abstract description 5
- CFNMUZCFSDMZPQ-GHXNOFRVSA-N 7-[(z)-3-methyl-4-(4-methyl-5-oxo-2h-furan-2-yl)but-2-enoxy]chromen-2-one Chemical compound C=1C=C2C=CC(=O)OC2=CC=1OC/C=C(/C)CC1OC(=O)C(C)=C1 CFNMUZCFSDMZPQ-GHXNOFRVSA-N 0.000 claims abstract description 4
- FAPWRFPIFSIZLT-UHFFFAOYSA-M Sodium chloride Chemical class [Na+].[Cl-] FAPWRFPIFSIZLT-UHFFFAOYSA-M 0.000 claims abstract description 4
- 238000004440 column chromatography Methods 0.000 claims abstract description 4
- 239000012044 organic layer Substances 0.000 claims abstract description 4
- 239000000741 silica gel Substances 0.000 claims abstract description 4
- 229910002027 silica gel Inorganic materials 0.000 claims abstract description 4
- 239000007787 solid Substances 0.000 claims abstract description 4
- 150000001336 alkenes Chemical class 0.000 claims abstract description 3
- 238000011068 loading method Methods 0.000 claims abstract description 3
- 239000012074 organic phase Substances 0.000 claims description 33
- 239000012043 crude product Substances 0.000 claims description 18
- 239000012267 brine Substances 0.000 claims description 15
- 238000003818 flash chromatography Methods 0.000 claims description 15
- 229920006395 saturated elastomer Polymers 0.000 claims description 15
- HPALAKNZSZLMCH-UHFFFAOYSA-M sodium;chloride;hydrate Chemical compound O.[Na+].[Cl-] HPALAKNZSZLMCH-UHFFFAOYSA-M 0.000 claims description 15
- -1 et 3 N Chemical compound 0.000 claims description 13
- 239000007795 chemical reaction product Substances 0.000 claims description 9
- 239000011734 sodium Substances 0.000 claims description 7
- BWHDROKFUHTORW-UHFFFAOYSA-N tritert-butylphosphane Chemical compound CC(C)(C)P(C(C)(C)C)C(C)(C)C BWHDROKFUHTORW-UHFFFAOYSA-N 0.000 claims description 6
- LNFVZUMSDAIQDQ-UHFFFAOYSA-N E-Suberenol Natural products O1C(=O)C=CC2=C1C=C(OC)C(C=CC(C)(C)O)=C2 LNFVZUMSDAIQDQ-UHFFFAOYSA-N 0.000 claims description 4
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 4
- 239000000758 substrate Substances 0.000 claims description 4
- PPBRXRYQALVLMV-UHFFFAOYSA-N Styrene Chemical compound C=CC1=CC=CC=C1 PPBRXRYQALVLMV-UHFFFAOYSA-N 0.000 claims description 3
- GCTPMLUUWLLESL-UHFFFAOYSA-N benzyl prop-2-enoate Chemical compound C=CC(=O)OCC1=CC=CC=C1 GCTPMLUUWLLESL-UHFFFAOYSA-N 0.000 claims description 3
- SUPCQIBBMFXVTL-UHFFFAOYSA-N ethyl 2-methylprop-2-enoate Chemical compound CCOC(=O)C(C)=C SUPCQIBBMFXVTL-UHFFFAOYSA-N 0.000 claims description 3
- HVAMZGADVCBITI-UHFFFAOYSA-M pent-4-enoate Chemical compound [O-]C(=O)CCC=C HVAMZGADVCBITI-UHFFFAOYSA-M 0.000 claims description 3
- 239000007864 aqueous solution Substances 0.000 claims 6
- 238000001035 drying Methods 0.000 claims 5
- 238000001914 filtration Methods 0.000 claims 5
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 abstract description 30
- 229910000030 sodium bicarbonate Inorganic materials 0.000 abstract description 15
- 235000017557 sodium bicarbonate Nutrition 0.000 abstract description 15
- 238000004519 manufacturing process Methods 0.000 abstract description 4
- 238000005481 NMR spectroscopy Methods 0.000 description 21
- 239000007832 Na2SO4 Substances 0.000 description 12
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 description 12
- 229910052938 sodium sulfate Inorganic materials 0.000 description 12
- 235000011152 sodium sulphate Nutrition 0.000 description 12
- 239000000243 solution Substances 0.000 description 11
- 238000001228 spectrum Methods 0.000 description 11
- 238000003756 stirring Methods 0.000 description 10
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical group [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical group [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical group [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 description 8
- LWIHDJKSTIGBAC-UHFFFAOYSA-K tripotassium phosphate Chemical group [K+].[K+].[K+].[O-]P([O-])([O-])=O LWIHDJKSTIGBAC-UHFFFAOYSA-K 0.000 description 8
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 6
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 6
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 6
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 6
- 239000004698 Polyethylene Substances 0.000 description 6
- 229910052799 carbon Inorganic materials 0.000 description 6
- 238000012512 characterization method Methods 0.000 description 6
- 238000010586 diagram Methods 0.000 description 6
- GPAYUJZHTULNBE-UHFFFAOYSA-N diphenylphosphine Chemical compound C=1C=CC=CC=1PC1=CC=CC=C1 GPAYUJZHTULNBE-UHFFFAOYSA-N 0.000 description 6
- 239000001257 hydrogen Substances 0.000 description 6
- 229910052739 hydrogen Inorganic materials 0.000 description 6
- 239000007858 starting material Substances 0.000 description 6
- JRMUNVKIHCOMHV-UHFFFAOYSA-M tetrabutylammonium bromide Chemical compound [Br-].CCCC[N+](CCCC)(CCCC)CCCC JRMUNVKIHCOMHV-UHFFFAOYSA-M 0.000 description 6
- IMNIMPAHZVJRPE-UHFFFAOYSA-N triethylenediamine Chemical compound C1CN2CCN1CC2 IMNIMPAHZVJRPE-UHFFFAOYSA-N 0.000 description 6
- JUQWLDVJWGCWHN-UHFFFAOYSA-N 6-bromo-7-methoxychromen-2-one Chemical compound O1C(=O)C=CC2=C1C=C(OC)C(Br)=C2 JUQWLDVJWGCWHN-UHFFFAOYSA-N 0.000 description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-M Acrylate Chemical compound [O-]C(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-M 0.000 description 5
- ARJOQCYCJMAIFR-UHFFFAOYSA-N prop-2-enoyl prop-2-enoate Chemical compound C=CC(=O)OC(=O)C=C ARJOQCYCJMAIFR-UHFFFAOYSA-N 0.000 description 5
- CEUWWRFKARIADH-UHFFFAOYSA-N 1,1'-biphenyl;diphenylphosphane Chemical group C1=CC=CC=C1C1=CC=CC=C1.C=1C=CC=CC=1PC1=CC=CC=C1 CEUWWRFKARIADH-UHFFFAOYSA-N 0.000 description 4
- 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 description 4
- HNVRRHSXBLFLIG-UHFFFAOYSA-N 3-hydroxy-3-methylbut-1-ene Chemical compound CC(C)(O)C=C HNVRRHSXBLFLIG-UHFFFAOYSA-N 0.000 description 4
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 description 4
- ATRRKUHOCOJYRX-UHFFFAOYSA-N Ammonium bicarbonate Chemical compound [NH4+].OC([O-])=O ATRRKUHOCOJYRX-UHFFFAOYSA-N 0.000 description 4
- XTHFKEDIFFGKHM-UHFFFAOYSA-N Dimethoxyethane Chemical compound COCCOC XTHFKEDIFFGKHM-UHFFFAOYSA-N 0.000 description 4
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 4
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 4
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 4
- 239000001099 ammonium carbonate Substances 0.000 description 4
- 229910000019 calcium carbonate Inorganic materials 0.000 description 4
- 235000010216 calcium carbonate Nutrition 0.000 description 4
- 239000001506 calcium phosphate Chemical group 0.000 description 4
- 235000011010 calcium phosphates Nutrition 0.000 description 4
- MVPPADPHJFYWMZ-UHFFFAOYSA-N chlorobenzene Chemical compound ClC1=CC=CC=C1 MVPPADPHJFYWMZ-UHFFFAOYSA-N 0.000 description 4
- KTWOOEGAPBSYNW-UHFFFAOYSA-N ferrocene Chemical compound [Fe+2].C=1C=C[CH-]C=1.C=1C=C[CH-]C=1 KTWOOEGAPBSYNW-UHFFFAOYSA-N 0.000 description 4
- 238000000034 method Methods 0.000 description 4
- PIBWKRNGBLPSSY-UHFFFAOYSA-L palladium(II) chloride Chemical compound Cl[Pd]Cl PIBWKRNGBLPSSY-UHFFFAOYSA-L 0.000 description 4
- SCVFZCLFOSHCOH-UHFFFAOYSA-M potassium acetate Chemical compound [K+].CC([O-])=O SCVFZCLFOSHCOH-UHFFFAOYSA-M 0.000 description 4
- 239000011736 potassium bicarbonate Substances 0.000 description 4
- 229910000028 potassium bicarbonate Inorganic materials 0.000 description 4
- 235000015497 potassium bicarbonate Nutrition 0.000 description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 description 4
- 235000011181 potassium carbonates Nutrition 0.000 description 4
- TYJJADVDDVDEDZ-UHFFFAOYSA-M potassium hydrogencarbonate Chemical group [K+].OC([O-])=O TYJJADVDDVDEDZ-UHFFFAOYSA-M 0.000 description 4
- 229910000160 potassium phosphate Inorganic materials 0.000 description 4
- 235000011009 potassium phosphates Nutrition 0.000 description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 description 4
- 235000017550 sodium carbonate Nutrition 0.000 description 4
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical group [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 description 4
- 239000001488 sodium phosphate Chemical group 0.000 description 4
- 229910000162 sodium phosphate Inorganic materials 0.000 description 4
- 235000011008 sodium phosphates Nutrition 0.000 description 4
- NHGXDBSUJJNIRV-UHFFFAOYSA-M tetrabutylammonium chloride Chemical compound [Cl-].CCCC[N+](CCCC)(CCCC)CCCC NHGXDBSUJJNIRV-UHFFFAOYSA-M 0.000 description 4
- VDZOOKBUILJEDG-UHFFFAOYSA-M tetrabutylammonium hydroxide Chemical compound [OH-].CCCC[N+](CCCC)(CCCC)CCCC VDZOOKBUILJEDG-UHFFFAOYSA-M 0.000 description 4
- QORWJWZARLRLPR-UHFFFAOYSA-H tricalcium bis(phosphate) Chemical group [Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O QORWJWZARLRLPR-UHFFFAOYSA-H 0.000 description 4
- YWWDBCBWQNCYNR-UHFFFAOYSA-N trimethylphosphine Chemical group CP(C)C YWWDBCBWQNCYNR-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical group C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- RYFMWSXOAZQYPI-UHFFFAOYSA-K trisodium phosphate Chemical group [Na+].[Na+].[Na+].[O-]P([O-])([O-])=O RYFMWSXOAZQYPI-UHFFFAOYSA-K 0.000 description 4
- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N benzo-alpha-pyrone Natural products C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 description 3
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 description 3
- 230000015572 biosynthetic process Effects 0.000 description 3
- 229960000956 coumarin Drugs 0.000 description 3
- 235000001671 coumarin Nutrition 0.000 description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 description 3
- 150000004694 iodide salts Chemical class 0.000 description 3
- 238000003786 synthesis reaction Methods 0.000 description 3
- 230000002194 synthesizing effect Effects 0.000 description 3
- XKXIQBVKMABYQJ-UHFFFAOYSA-N tert-butyl hydrogen carbonate Chemical compound CC(C)(C)OC(O)=O XKXIQBVKMABYQJ-UHFFFAOYSA-N 0.000 description 3
- WSLDOOZREJYCGB-UHFFFAOYSA-N 1,2-Dichloroethane Chemical compound ClCCCl WSLDOOZREJYCGB-UHFFFAOYSA-N 0.000 description 2
- QFMZQPDHXULLKC-UHFFFAOYSA-N 1,2-bis(diphenylphosphino)ethane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCP(C=1C=CC=CC=1)C1=CC=CC=C1 QFMZQPDHXULLKC-UHFFFAOYSA-N 0.000 description 2
- LZDKZFUFMNSQCJ-UHFFFAOYSA-N 1,2-diethoxyethane Chemical compound CCOCCOCC LZDKZFUFMNSQCJ-UHFFFAOYSA-N 0.000 description 2
- LVEYOSJUKRVCCF-UHFFFAOYSA-N 1,3-bis(diphenylphosphino)propane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCP(C=1C=CC=CC=1)C1=CC=CC=C1 LVEYOSJUKRVCCF-UHFFFAOYSA-N 0.000 description 2
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 2
- 125000003903 2-propenyl group Chemical group [H]C([*])([H])C([H])=C([H])[H] 0.000 description 2
- BCJVBDBJSMFBRW-UHFFFAOYSA-N 4-diphenylphosphanylbutyl(diphenyl)phosphane Chemical compound C=1C=CC=CC=1P(C=1C=CC=CC=1)CCCCP(C=1C=CC=CC=1)C1=CC=CC=C1 BCJVBDBJSMFBRW-UHFFFAOYSA-N 0.000 description 2
- 229910000013 Ammonium bicarbonate Inorganic materials 0.000 description 2
- 238000007341 Heck reaction Methods 0.000 description 2
- FXHOOIRPVKKKFG-UHFFFAOYSA-N N,N-Dimethylacetamide Chemical compound CN(C)C(C)=O FXHOOIRPVKKKFG-UHFFFAOYSA-N 0.000 description 2
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 2
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-diisopropylethylamine Substances CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 2
- GSCCALZHGUWNJW-UHFFFAOYSA-N N-Cyclohexyl-N-methylcyclohexanamine Chemical compound C1CCCCC1N(C)C1CCCCC1 GSCCALZHGUWNJW-UHFFFAOYSA-N 0.000 description 2
- SECXISVLQFMRJM-UHFFFAOYSA-N N-Methylpyrrolidone Chemical compound CN1CCCC1=O SECXISVLQFMRJM-UHFFFAOYSA-N 0.000 description 2
- XTUVJUMINZSXGF-UHFFFAOYSA-N N-methylcyclohexylamine Chemical compound CNC1CCCCC1 XTUVJUMINZSXGF-UHFFFAOYSA-N 0.000 description 2
- CTQNGGLPUBDAKN-UHFFFAOYSA-N O-Xylene Chemical compound CC1=CC=CC=C1C CTQNGGLPUBDAKN-UHFFFAOYSA-N 0.000 description 2
- 239000002202 Polyethylene glycol Substances 0.000 description 2
- UIIMBOGNXHQVGW-DEQYMQKBSA-M Sodium bicarbonate-14C Chemical compound [Na+].O[14C]([O-])=O UIIMBOGNXHQVGW-DEQYMQKBSA-M 0.000 description 2
- RYXZOQOZERSHHQ-UHFFFAOYSA-N [2-(2-diphenylphosphanylphenoxy)phenyl]-diphenylphosphane Chemical compound C=1C=CC=C(P(C=2C=CC=CC=2)C=2C=CC=CC=2)C=1OC1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RYXZOQOZERSHHQ-UHFFFAOYSA-N 0.000 description 2
- 235000012538 ammonium bicarbonate Nutrition 0.000 description 2
- 235000012501 ammonium carbonate Nutrition 0.000 description 2
- 125000004429 atom Chemical group 0.000 description 2
- 239000002585 base Substances 0.000 description 2
- 125000001246 bromo group Chemical group Br* 0.000 description 2
- FJDQFPXHSGXQBY-UHFFFAOYSA-L caesium carbonate Chemical compound [Cs+].[Cs+].[O-]C([O-])=O FJDQFPXHSGXQBY-UHFFFAOYSA-L 0.000 description 2
- 229910000024 caesium carbonate Inorganic materials 0.000 description 2
- 229910000389 calcium phosphate Inorganic materials 0.000 description 2
- 239000003153 chemical reaction reagent Substances 0.000 description 2
- WDIIYWASEVHBBT-UHFFFAOYSA-N di(propan-2-yl)phosphane Chemical compound CC(C)PC(C)C WDIIYWASEVHBBT-UHFFFAOYSA-N 0.000 description 2
- LCSNDSFWVKMJCT-UHFFFAOYSA-N dicyclohexyl-(2-phenylphenyl)phosphane Chemical group C1CCCCC1P(C=1C(=CC=CC=1)C=1C=CC=CC=1)C1CCCCC1 LCSNDSFWVKMJCT-UHFFFAOYSA-N 0.000 description 2
- ZPWVASYFFYYZEW-UHFFFAOYSA-L dipotassium hydrogen phosphate Chemical compound [K+].[K+].OP([O-])([O-])=O ZPWVASYFFYYZEW-UHFFFAOYSA-L 0.000 description 2
- 235000019797 dipotassium phosphate Nutrition 0.000 description 2
- 229910000396 dipotassium phosphate Inorganic materials 0.000 description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 description 2
- CRHWEIDCXNDTMO-UHFFFAOYSA-N ditert-butylphosphane Chemical compound CC(C)(C)PC(C)(C)C CRHWEIDCXNDTMO-UHFFFAOYSA-N 0.000 description 2
- 239000003446 ligand Substances 0.000 description 2
- 229910000402 monopotassium phosphate Inorganic materials 0.000 description 2
- 235000019796 monopotassium phosphate Nutrition 0.000 description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 description 2
- 235000019799 monosodium phosphate Nutrition 0.000 description 2
- XTAZYLNFDRKIHJ-UHFFFAOYSA-N n,n-dioctyloctan-1-amine Chemical compound CCCCCCCCN(CCCCCCCC)CCCCCCCC XTAZYLNFDRKIHJ-UHFFFAOYSA-N 0.000 description 2
- PJNZPQUBCPKICU-UHFFFAOYSA-N phosphoric acid;potassium Chemical compound [K].OP(O)(O)=O PJNZPQUBCPKICU-UHFFFAOYSA-N 0.000 description 2
- 229920001223 polyethylene glycol Polymers 0.000 description 2
- 235000011056 potassium acetate Nutrition 0.000 description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 2
- 239000002994 raw material Substances 0.000 description 2
- 239000012047 saturated solution Substances 0.000 description 2
- 229910001467 sodium calcium phosphate Inorganic materials 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- VNFWTIYUKDMAOP-UHFFFAOYSA-N sphos Chemical compound COC1=CC=CC(OC)=C1C1=CC=CC=C1P(C1CCCCC1)C1CCCCC1 VNFWTIYUKDMAOP-UHFFFAOYSA-N 0.000 description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 2
- USFPINLPPFWTJW-UHFFFAOYSA-N tetraphenylphosphonium Chemical compound C1=CC=CC=C1[P+](C=1C=CC=CC=1)(C=1C=CC=CC=1)C1=CC=CC=C1 USFPINLPPFWTJW-UHFFFAOYSA-N 0.000 description 2
- TUQOTMZNTHZOKS-UHFFFAOYSA-N tributylphosphine Chemical compound CCCCP(CCCC)CCCC TUQOTMZNTHZOKS-UHFFFAOYSA-N 0.000 description 2
- WLPUWLXVBWGYMZ-UHFFFAOYSA-N tricyclohexylphosphine Chemical group C1CCCCC1P(C1CCCCC1)C1CCCCC1 WLPUWLXVBWGYMZ-UHFFFAOYSA-N 0.000 description 2
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 2
- COIOYMYWGDAQPM-UHFFFAOYSA-N tris(2-methylphenyl)phosphane Chemical group CC1=CC=CC=C1P(C=1C(=CC=CC=1)C)C1=CC=CC=C1C COIOYMYWGDAQPM-UHFFFAOYSA-N 0.000 description 2
- DLQYXUGCCKQSRJ-UHFFFAOYSA-N tris(furan-2-yl)phosphane Chemical compound C1=COC(P(C=2OC=CC=2)C=2OC=CC=2)=C1 DLQYXUGCCKQSRJ-UHFFFAOYSA-N 0.000 description 2
- 239000008096 xylene Substances 0.000 description 2
- SMZOUWXMTYCWNB-UHFFFAOYSA-N 2-(2-methoxy-5-methylphenyl)ethanamine Chemical compound COC1=CC=C(C)C=C1CCN SMZOUWXMTYCWNB-UHFFFAOYSA-N 0.000 description 1
- NIXOWILDQLNWCW-UHFFFAOYSA-N 2-Propenoic acid Natural products OC(=O)C=C NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 150000007513 acids Chemical class 0.000 description 1
- 150000008064 anhydrides Chemical class 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 239000003054 catalyst Substances 0.000 description 1
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Abstract
本发明公开了香豆素衍生物技术领域的一类香豆素衍生物及其制备方法在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管,加入溴代底物1、双(三叔丁基膦)钯(0)、甲苯、三乙胺、烯烃类化合物2;然后将反应瓶密封并置于90℃油浴中;反应完成后(通过TLC监测,约12分钟),将反应混合物冷却至室温,加入NaHCO3水溶液,然后搅拌5分钟;用乙酸乙酯转移通过硅胶短柱除去不溶性固体,并用乙酸乙酯洗涤;滤液用乙酸乙酯稀释并用水萃取3遍,饱和氯化钠萃取1遍;合并的有机层用无水Na2SO4干燥;湿法上样柱层析纯化后,得到化合物E‑suberenol;解决了现有技术纯度不高,操作复杂,产率偏低,不能大量生产的问题;提高反应的原子经济性。
Description
技术领域
本发明涉及香豆素衍生物技术领域,具体为一类香豆素衍生物及其制备方法。
背景技术
目前以简单原料温和高效地合成烯烃类香豆素类化合物报道仍然较少。例如要求苛刻的反应条件强酸等、毒性试剂(TBAB等)、以及高活性碘代物的使用。并且现有路线步骤繁琐,起始原料不通用,反应时间长,原子经济性不好,制备成本高,总产率低;并且Heck偶联过程中用到过量的TBAB,不仅后处理困难,而且对于环境也有一定的污染;鉴于此,发展简易经济的合成方法以合成多样的烯烃类香豆素类化合物是非常重要的。
基于此,本发明设计了一类香豆素衍生物及其制备方法,以解决上述问题。
发明内容
本发明的目的在于提供一类香豆素衍生物及其制备方法,以解决上述背景技术中提出的问题。
为实现上述目的,本发明提供如下技术方案:一类香豆素衍生物及其制备方法,其特征在于:所述香豆素衍生物的制备方法如下:步骤一:制备E-suberenol(3)
在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管,加入溴代底物1、双(三叔丁基膦)钯(0)、甲苯、三乙胺、烯烃类化合物2;然后将反应瓶密封并置于90℃油浴中;反应完成后(通过TLC监测,约12分钟),将反应混合物冷却至室温,加入NaHCO3水溶液,然后搅拌5分钟;用乙酸乙酯转移通过硅胶短柱除去不溶性固体,并用乙酸乙酯洗涤;滤液用乙酸乙酯稀释并用水萃取3遍,饱和氯化钠萃取1遍;合并的有机层用无水Na2SO4干燥,过滤有机相,浓缩得到粗产物;湿法上样柱层析纯化后,得到化合物E-suberenol:
步骤二:(E)-3-(7-甲氧基-2-氧代-2H-铬-6-基)乙酸烯丙酯(3-1)的制备:
在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管,加入溴代底物16-溴-7-甲氧基香豆素、双(三叔丁基膦)钯(0),Et3N,乙酸烯丙酯;然后将反应瓶密封并置于100℃油浴中;反应完成后(由TLC监测,约30分钟),将反应混合物冷却至室温,并添加1mL饱和NaHCO3水溶液,然后搅拌5分钟;然后通过硅藻土过滤反应粗品,并用乙酸乙酯洗涤。用乙酸乙酯稀释滤液,并用水和盐水萃取。合并有机相用无水Na2SO4干燥,过滤有机相,并在30℃的真空中浓缩,以提供粗产品。通过快速柱色谱纯化后,获得目标化合物。
步骤三:(叔丁基碳酸)(E)-3-(7-甲氧基-2-氧代-2H-铬-6-基)丙烯酸酐(3-2)的制备:
在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管,加入溴代底物1、双(三叔丁基膦)钯(0),甲苯、Et3N、丙烯酸(叔丁基碳酸)酐;然后将反应瓶密封并置于100℃油浴中;反应30分钟后,将反应混合物冷却至室温并添加饱和NaHCO3水溶液,然后搅拌5分钟;然后通过硅藻土过滤反应粗品,并用乙酸乙酯洗涤。用乙酸乙酯稀释滤液,并用水和盐水萃取;合并有机相用无水Na2SO4干燥,过滤有机相,并在30℃的真空中浓缩,以提供粗产品。通过快速柱色谱纯化后,获得目标化合物。
步骤四:苄基(E)-3-(7-甲氧基-2-氧代-2H-铬-6-基)丙烯酸酯(3-3)的制备:
在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管、溴代底物1、双(三叔丁基膦)钯(0),Et3N(82μL,0.6mmol,1.5eq.),丙烯酸苄酯。然后将反应瓶密封并置于100℃油浴中;反应完成后,将反应混合物冷却至室温,并添加1mL饱和NaHCO3水溶液,然后搅拌5分钟。然后通过硅藻土过滤反应粗品,并用乙酸乙酯洗涤。用乙酸乙酯稀释滤液,并用水和盐水萃取。合并有机相用无水Na2SO4干燥,过滤有机相,并在30℃的真空中浓缩,以提供粗产品。通过快速柱色谱纯化后,获得目标化合物。
步骤五::(E)-7-甲氧基-6-苯乙烯基-2H-色酮-2-酮(3-4)的制备:
在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管、溴代底物1、双(三叔丁基膦)钯(0)、甲苯、Et3N、乙烯苯;然后将反应瓶密封并置于100℃油浴中。反应30分钟后,将反应混合物冷却至室温并添加饱和NaHCO3水溶液,然后搅拌5分钟。然后通过硅藻土过滤反应粗品,并用乙酸乙酯洗涤;用乙酸乙酯稀释滤液,并用水和盐水萃取。合并有机相用无水Na2SO4干燥,过滤有机相,并在30℃的真空中浓缩,以提供粗产品。通过快速柱色谱纯化后,获得目标化合物。
步骤六:乙基(E)-3-(7-甲氧基-2-氧代-2H-铬-6-基)-2-甲基丙烯酸酯(3-5)的制备:
在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管、溴代底物1、双(三叔丁基膦)钯(0),甲苯、Et3N、甲基丙烯酸乙酯;然后将反应瓶密封并置于100℃油浴中。反应30分钟后,将反应混合物冷却至室温并添加饱和NaHCO3水溶液,然后搅拌5分钟。然后通过硅藻土过滤反应粗品,并用乙酸乙酯洗涤。用乙酸乙酯稀释滤液,并用水和盐水萃取;合并有机相用无水Na2SO4干燥,过滤有机相,并在30℃的真空中浓缩,以提供粗产品;通过快速柱色谱纯化后,获得目标化合物。
作为本发明的进一步方案,碳酸氢钠饱和溶液可以替换为碳酸氢钾、碳酸钠、碳酸钾、碳酸钙、磷酸一氢钠、磷酸二氢钠、磷酸一氢钾、磷酸二氢钾、磷酸钾、磷酸钠、磷酸钙。
作为本发明的进一步方案,所述三叔丁基膦可替换为三苯基膦、三甲基膦、三(邻甲基苯基)磷、三环己基膦、三环己基膦氟硼酸盐、三正丁基磷、4,5-双二苯基膦-9,9-二甲基氧杂蒽、双(2-二苯基磷苯基)醚、三(2-呋喃基)膦、四氟硼酸三叔丁基膦、1,2-双(二苯基膦)乙烷、1,3-双(二苯基膦)丙烷、1,4-双(二苯基膦)丁烷、2-(二叔丁基膦)联苯、2-(二环己基膦基)联苯、2-双环己基膦-2',6'-二甲氧基联苯、2-二环己膦基-2'-(N,N-二甲胺)-联苯、2-二环己基膦-2',4',6'-三异丙基联苯、正丁基二(1-金刚烷基)膦、1,1'-双(二异丙基膦)二茂铁、R-(+)-1,1'-联萘-2.2'-双二苯膦、1.1'-联-2-萘酚、5,5'-双(二苯基磷酰)-4,4'-二-1,3-联苯、双二苯基磷酰联萘、双(2-二苯基磷苯基)醚、1,1-二(二-叔丁基膦基)-二茂铁、2-二叔丁基膦-2',4',6'-三异丙基联苯、四三苯基膦氯化钯、二(三叔丁基膦)钯、[1,1'-双(二叔丁基膦)二茂铁]二氯化钯(II)或者不添加配体。
作为本发明的进一步方案,所述三乙胺可替换为三正丙胺、N,N-二异丙基乙胺、N,N-二乙基苯胺、三正辛胺、N,N-环己基甲胺、吡啶、4-二甲氨基吡啶、1,8-二氮杂双环[5.4.0]十一碳-7-烯、1,4-二氮杂二环[2.2.2]辛烷、四丁基氯化铵、四丁基溴化铵、三乙烯二胺、N-甲基二环己基胺、四丁基氢氧化铵、醋酸钾、醋酸钠、碳酸氢钠、碳酸氢钾、碳酸氢铵、碳酸钠、碳酸钾、碳酸铵、碳酸钙、碳酸铯、磷酸一氢钠、磷酸二氢钠、磷酸一氢钾、磷酸二氢钾、磷酸钾、磷酸钠、磷酸钙或者不添加碱。
作为本发明的进一步方案,所述甲苯可替换四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、苯、二甲苯、1,4-二氧六环、乙二醇二甲醚、乙二醇二乙醚、1,2-二氯乙烷,聚乙二醇、乙腈、氯代苯,二甲基亚砜或者不添加溶剂。
作为本发明的进一步方案,所述合成过程中反应温度在40℃-145℃之间。
作为本发明的进一步方案,所述溴代底物1为:
或其他类似的溴代底物。
作为本发明的进一步方案,所述烯烃类化合物2为:
或其他烯烃类化合物。
与现有技术相比,本发明的有益效果是:
1.本专利合成路线以简单易制备的6-溴-7-甲氧基香豆素为起始原料,通过钯催化的Heck反应,与烯烃类化合物进行偶联,以较高的产率得到香豆素类衍生物。同时使用不同取代基的溴代底物与2-甲基丁烯-2-醇进行Heck反应时,同样以中等到高产率得到烯醇类化合物。本专利路线克服了对环境有危害、操作复杂、产率低等问题,同时避免了高毒性试剂(TBAB等)以及高活性碘代物的使用。总体来说,该专利合成路线简捷,原料简单易得,操作简便,催化剂使用量少且廉价易得,衍生物产率较好,不但为香豆素类衍生物的合成提供了一种新方法,也为产品规模化生产及提高生产效率提供了更多可能。
2.避免毒性试剂(TBAB等)以及难以制备的高活性碘化物的使用;解决了现有技术纯度不高,操作复杂,产率偏低,不能大量生产的问题;提高反应的原子经济性;提供一种工艺稳定,操作简便,合成效率高的烯烃类香豆素类化合物的制备方法。
附图说明
图1为本发明E-suberenol的核磁共振氢谱示意图;
图2为本发明E-suberenol的核磁共振碳谱示意图;
图3为本发明E-suberenol衍生物1的核磁共振氢谱示意图;
图4为本发明E-suberenol衍生物1的核磁共振碳谱示意图;
图5为本发明E-suberenol衍生物2的核磁共振氢谱示意图;
图6为本发明E-suberenol衍生物2的核磁共振碳谱示意图;
图7为本发明E-suberenol衍生物3的核磁共振氢谱示意图;
图8为本发明E-suberenol衍生物3的核磁共振碳谱示意图;
图9为本发明E-suberenol衍生物4的核磁共振氢谱示意图;
图10为本发明E-suberenol衍生物4的核磁共振碳谱示意图;
图11为本发明E-suberenol衍生物5的核磁共振氢谱示意图;
图12为本发明E-suberenol衍生物5的核磁共振碳谱示意图。
具体实施方式
请参阅图1-12,本发明提供一种技术方案:一类香豆素衍生物及其制备方法,所述香豆素衍生物的制备方法如下:
步骤一:制备E-suberenol(3)
在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管,加入溴代底物1(6-溴-7-甲氧基香豆素)6-溴-7-甲氧基香豆素(1.02g,4.0mmol,1.0eq.)、双(三叔丁基膦)钯(0)(164mg,0.032mmol,0.08eq.)、甲苯(15mL)、三乙胺(834μL,6.0mmol,1.5eq.)、烯烃类化合物2(1,1-二甲基烯丙醇)1,1-二甲基烯丙醇(1.88mL,18.0mmol,4.5eq.)。然后将反应瓶密封并置于90℃油浴中。反应完成后(通过TLC监测,约12分钟),将反应混合物冷却至室温,加入NaHCO3水溶液,然后搅拌5分钟。用乙酸乙酯转移通过硅胶短柱除去不溶性固体,并用乙酸乙酯(100mL)洗涤。滤液用乙酸乙酯稀释并用水萃取3遍,饱和氯化钠萃取1遍。合并的有机层用无水Na2SO4干燥,过滤有机相,浓缩得到粗产物。湿法上样柱层析(洗脱剂,PE:EA=8:1至2:1)纯化后,得到化合物E-suberenol:(1.02g,98%yield)
化合物E-suberenol结构表征数据:
1H NMR(400MHz,CDCl3)δ7.63(d,1H,J=9.4Hz),7.48(s,1H),6.85(d,1H,J=16.2Hz),6.78(s,1H),6.36(d,1H,J=16.2Hz),6.26(d,1H,J=9.4Hz),3.90(s,3H),1.44(s,6H);
13C NMR(100MHz,CDCl3)δ161.20,159.93,155.11,143.49,139.20,125.33,123.78,119.74,113.39,112.20,98.94,71.26,56.00,29.91;
IR(KBr):3838.15,3732.92,3433.47,2932.10,2345.14,1728.08,1611.93,1356.06,1210.07,1020.71,830.13,675.92cm-1;
HRMS(EI)calcdforC15H16O4[M+Na]+283.0940,found283.0941.
步骤二:(E)-3-(7-甲氧基-2-氧代-2H-铬-6-基)乙酸烯丙酯(3-1)的制备:
在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管,加入溴代底物1(6-溴-7-甲氧基香豆素)(100.0mg,0.4mmol,1.0eq.)、双(三叔丁基膦)钯(0)(16.4mg,0.032mmol,0.08eq.),Et3N(82μL,0.6mmol,1.5eq.),乙酸烯丙酯(197μL,1.8mmol,4.5eq.)。然后将反应瓶密封并置于100℃油浴中。反应完成后(由TLC监测,约30分钟),将反应混合物冷却至室温,并添加1mL饱和NaHCO3水溶液,然后搅拌5分钟。然后通过硅藻土过滤反应粗品,并用乙酸乙酯(30mL)洗涤。用乙酸乙酯(50mL)稀释滤液,并用水(2 10mL)和盐水(10mL)萃取。合并有机相用无水Na2SO4干燥,过滤有机相,并在30℃的真空中浓缩,以提供粗产品。通过快速柱色谱纯化后(PE:EA=20:1至2:1),获得目标化合物(62.3mg,收率58%,回收的起始原料,28mg,28%;基于回收的起始原料,收率96%)。
(E)-3-(7-甲氧基-2-氧代-2H-铬-6-基)乙酸烯丙酯结构数据表征:
1HNMR(400MHz,CDCl3)δ7.63(d,J=9.4Hz,1H),7.50(s,1H),6.91(dt,J=16.2,1.4Hz,1H),6.79(s,1H),6.37–6.29(m,1H),6.27(d,J=9.4Hz,1H),4.74(dd,J=6.5,1.4Hz,2H),3.92(s,3H),2.11(s,3H);
13C NMR(100MHz,CDCl3)δ170.85,160.96,160.01,155.49,143.33,127.62,125.95,124.98,123.00,113.57,112.24,99.07,77.23,65.28,56.06,29.40,29.35,21.02;
IR(KBr):3377.89,3151.08,1716.08,1627.91,1360.89,1303.77,1234.40,1105.11,980.03,887.18,785.53,561.11,485.83cm-1.
步骤三:(叔丁基碳酸)(E)-3-(7-甲氧基-2-氧代-2H-铬-6-基)丙烯酸酐(3-2)的制备:
在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管,加入溴代底物1(6-溴-7-甲氧基香豆素)(100.0mg,0.4mmol,1.0eq.)、双(三叔丁基膦)钯(0)(16.4mg,0.032mmol,0.08eq.),甲苯(3mL,在添加之前用氮气鼓泡10分钟)、Et3N(82μL,0.6mmol,1.5eq.)、丙烯酸(叔丁基碳酸)酐(256μL,1.8mmol,4.5eq.)。然后将反应瓶密封并置于100℃油浴中。反应30分钟后,将反应混合物冷却至室温并添加1mL饱和NaHCO3水溶液,然后搅拌5分钟。然后通过硅藻土过滤反应粗品,并用乙酸乙酯(30mL)洗涤。用乙酸乙酯(50mL)稀释滤液,并用水(210mL)和盐水(10mL)萃取。合并有机相用无水Na2SO4干燥,过滤有机相,并在30℃的真空中浓缩,以提供粗产品。通过快速柱色谱纯化后(PE:EA=20:1至2:1),获得目标化合物(134mg,99%产率)。
(叔丁基碳酸)(E)-3-(7-甲氧基-2-氧代-2H-铬-6-基)丙烯酸酐结构数据表征:
1H NMR(400MHz,CDCl3)δ7.83(d,J=16.1Hz,1H),7.64(d,J=9.5Hz,1H),7.58(s,1H),6.82(s,1H),6.45(d,J=16.1Hz,1H),6.29(d,J=9.5Hz,1H),3.95(s,3H),1.53(s,9H);
13C NMR(100MHz,CDCl3)δ166.35,161.10,160.59,156.60,143.14,137.12,127.80,121.67,121.38,113.89,112.35,99.44,80.63,77.22,56.18,28.21;
IR(KBr):3864.28,3616.88,3432.95,33370.99,3279.80,3221.79,2844.13,2778.31,2705.77,2358.27,1719.46,1612.29,1527.40,1202.16,933.12,740.13,593.93,505.01cm-1.
步骤四:苄基(E)-3-(7-甲氧基-2-氧代-2H-铬-6-基)丙烯酸酯(3-3)的制备:
在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管、溴代底物1(6-溴-7-甲氧基香豆素)(100.0mg,0.4mmol,1.0eq.)、双(三叔丁基膦)钯(0)(16.4mg,0.032mmol,0.08eq.),Et3N(82μL,0.6mmol,1.5eq.),丙烯酸苄酯(277μL,1.8mmol,4.5eq.)。然后将反应瓶密封并置于100℃油浴中。反应完成后(由TLC监测,约30分钟),将反应混合物冷却至室温,并添加1mL饱和NaHCO3水溶液,然后搅拌5分钟。然后通过硅藻土过滤反应粗品,并用乙酸乙酯(30mL)洗涤。用乙酸乙酯(50mL)稀释滤液,并用水(2 10mL)和盐水(10mL)萃取;合并有机相用无水Na2SO4干燥,过滤有机相,并在30℃的真空中浓缩,以提供粗产品。通过快速柱色谱纯化后(PE:EA=20:1至2:1),获得目标化合物(108.1,82%产率,回收起始原料,10mg,10%;92%产率,基于回收起始原料)。
苄基(E)-3-(7-甲氧基-2-氧代-2H-铬-6-基)丙烯酸酯结构数据表征:
1H NMR(400MHz,CDCl3)δ7.95(d,J=16.2Hz,1H),7.63(d,J=9.5Hz,1H),7.58(s,1H),7.44–7.34(m,5H),6.82(s,1H),6.59(d,J=16.1Hz,1H),6.29(d,J=9.5Hz,1H),5.26(s,2H),3.95(s,3H);
13C NMR(100MHz,CDCl3)δ166.93,161.26,160.54,156.80,143.13,138.91,136.02,128.61,128.34,128.31,121.00,119.35,113.98,112.37,99.53,66.44,56.23;
IR(KBr):3051.76,2955.51,1717.38,1618.34,1459.89,1370.05,1278.25,993.34,806.11,685.04,588.96,525.77cm-1.
步骤五:(E)-7-甲氧基-6-苯乙烯基-2H-色酮-2-酮(3-4)的制备:
在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管、溴代底物1(6-溴-7-甲氧基香豆素)(100.0mg,0.4mmol,1.0eq.)、双(三叔丁基膦)钯(0)(16.4mg,0.032mmol,0.08eq.)、甲苯(3mL,在添加之前用氮气鼓泡10min)、,Et3N(82μL,0.6mmol,1.5eq.),乙烯苯(208μL,1.8mmol,4.5eq.)。然后将反应瓶密封并置于100℃油浴中;反应30分钟后,将反应混合物冷却至室温并添加1mL饱和NaHCO3水溶液,然后搅拌5分钟。然后通过硅藻土过滤反应粗品,并用乙酸乙酯(30mL)洗涤。用乙酸乙酯(50mL)稀释滤液,并用水(2 10mL)和盐水(10mL)萃取。合并有机相用无水Na2SO4干燥,过滤有机相,并在30℃的真空中浓缩,以提供粗产品。通过快速柱色谱纯化后(PE:EA=20:1至2:1),获得目标化合物(101.4mg,93%产率)。
(E)-7-甲氧基-6-苯乙烯基-2H-色酮-2-酮结构数据表征:
1HNMR(400MHz,CDCl3)δ7.69(d,J=9.5Hz,1H),7.65(s,1H),7.55(d,J=1.6Hz,1H),7.53(d,J=1.6Hz,1H),7.41(d,J=12.6Hz,1H),7.39–7.34(m,2H),7.31–7.27(m,1H),7.10(d,J=16.5Hz,1H),6.83(s,1H),6.29(d,J=9.5Hz,1H),3.96(s,3H);
13C NMR(100MHz,CDCl3)δ161.06,160.07,155.24,143.44,137.36,130.14,128.71,127.82,126.61,124.96,124.28,121.82,113.51,112.37,99.09,77.22,56.09;
IR(KBr):3734.51,3065.12,2961.85,1734.40,1616.27,1482.04,1362.57,1109.49,1014.14,873.31,767.40,702.21,486.38cm-1.
步骤六::乙基(E)-3-(7-甲氧基-2-氧代-2H-铬-6-基)-2-甲基丙烯酸酯(3-5)的制备:
在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管、溴代底物1(6-溴-7-甲氧基香豆素)(100.0mg,0.4mmol,1.0eq.)、双(三叔丁基膦)钯(0)(16.4mg,0.032mmol,0.08eq.),甲苯(3mL,在添加之前用氮气鼓泡10分钟)、Et3N(82μL,0.6mmol,1.5eq.)、甲基丙烯酸乙酯(226μL,1.8mmol,4.5eq.)。然后将反应瓶密封并置于100℃油浴中。反应30分钟后,将反应混合物冷却至室温并添加1mL饱和NaHCO3水溶液,然后搅拌5分钟。然后通过硅藻土过滤反应粗品,并用乙酸乙酯(30mL)洗涤。用乙酸乙酯(50mL)稀释滤液,并用水(2 10mL)和盐水(10mL)萃取。合并有机相用无水Na2SO4干燥,过滤有机相,并在30℃的真空中浓缩,以提供粗产品。通过快速柱色谱纯化后(PE:EA=20:1至2:1),获得目标化合物:(101.1mg,90%产率)。
乙基(E)-3-(7-甲氧基-2-氧代-2H-铬-6-基)-2-甲基丙烯酸酯结构数据表征:
1H NMR(400MHz,CDCl3)δ7.80–7.70(m,1H),7.67(d,J=9.5Hz,1H),7.36(s,1H),6.84(s,1H),6.30(d,J=9.5Hz,1H),4.29(q,J=7.1Hz,2H),3.93(s,3H),2.06(d,J=1.5Hz,3H),1.36(t,J=7.1Hz,3H);
13C NMR(100MHz,CDCl3)δ168.22,160.89,160.78,155.85,143.34,132.69,129.74,128.92,122.40,113.56,111.84,99.05,61.01,56.19,14.35,14.30;
IR(KBr):2976.89,1728.10,1620.70,1490.48,1373.29,1264.36,1115.96,1015.77,910.89,732.44,480.06cm-1.
作为本发明的进一步方案,碳酸氢钠饱和溶液可以替换为碳酸氢钾、碳酸钠、碳酸钾、碳酸钙、磷酸一氢钠、磷酸二氢钠、磷酸一氢钾、磷酸二氢钾、磷酸钾、磷酸钠、磷酸钙。
作为本发明的进一步方案,所述三叔丁基膦可替换为三苯基膦、三甲基膦、三(邻甲基苯基)磷、三环己基膦、三环己基膦氟硼酸盐、三正丁基磷、4,5-双二苯基膦-9,9-二甲基氧杂蒽、双(2-二苯基磷苯基)醚、三(2-呋喃基)膦、四氟硼酸三叔丁基膦、1,2-双(二苯基膦)乙烷、1,3-双(二苯基膦)丙烷、1,4-双(二苯基膦)丁烷、2-(二叔丁基膦)联苯、2-(二环己基膦基)联苯、2-双环己基膦-2',6'-二甲氧基联苯、2-二环己膦基-2'-(N,N-二甲胺)-联苯、2-二环己基膦-2',4',6'-三异丙基联苯、正丁基二(1-金刚烷基)膦、1,1'-双(二异丙基膦)二茂铁、R-(+)-1,1'-联萘-2.2'-双二苯膦、1.1'-联-2-萘酚、5,5'-双(二苯基磷酰)-4,4'-二-1,3-联苯、双二苯基磷酰联萘、双(2-二苯基磷苯基)醚、1,1-二(二-叔丁基膦基)-二茂铁、2-二叔丁基膦-2',4',6'-三异丙基联苯、四三苯基膦氯化钯、二(三叔丁基膦)钯、[1,1'-双(二叔丁基膦)二茂铁]二氯化钯(II)或者不添加配体。
作为本发明的进一步方案,所述三乙胺可替换为三正丙胺、N,N-二异丙基乙胺、N,N-二乙基苯胺、三正辛胺、N,N-环己基甲胺、吡啶、4-二甲氨基吡啶、1,8-二氮杂双环[5.4.0]十一碳-7-烯、1,4-二氮杂二环[2.2.2]辛烷、四丁基氯化铵、四丁基溴化铵、三乙烯二胺、N-甲基二环己基胺、四丁基氢氧化铵、醋酸钾、醋酸钠、碳酸氢钠、碳酸氢钾、碳酸氢铵、碳酸钠、碳酸钾、碳酸铵、碳酸钙、碳酸铯、磷酸一氢钠、磷酸二氢钠、磷酸一氢钾、磷酸二氢钾、磷酸钾、磷酸钠、磷酸钙或者不添加碱。
作为本发明的进一步方案,所述甲苯可替换四氢呋喃、N,N-二甲基甲酰胺、N,N-二甲基乙酰胺、N-甲基吡咯烷酮、苯、二甲苯、1,4-二氧六环、乙二醇二甲醚、乙二醇二乙醚、1,2-二氯乙烷,聚乙二醇、乙腈、氯代苯,二甲基亚砜或者不添加溶剂。
作为本发明的进一步方案,所述合成过程中反应温度在40℃-145℃之间
作为本发明的进一步方案,溴代底物为:
或其他类似的溴代底物。
作为本发明的进一步方案,烯烃类化合物为:
或其他烯烃类化合物。
Claims (6)
1.一类香豆素衍生物的制备方法,其特征在于:所述香豆素衍生物的制备方法如下:
制备E-suberenol (3)在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管,加入溴代底物1、双(三叔丁基膦)钯(0)、甲苯、三乙胺、烯烃类化合物2;然后将反应瓶密封并置于90℃油浴中;反应完成后,将反应混合物冷却至室温,加入NaHCO3水溶液,然后搅拌5分钟;用乙酸乙酯转移通过硅胶短柱除去不溶性固体,并用乙酸乙酯洗涤;滤液用乙酸乙酯稀释并用水萃取3遍,饱和氯化钠萃取1遍;合并的有机层用无水Na2SO4干燥,过滤有机相,浓缩得到粗产物;湿法上样柱层析纯化后,得到化合物E-suberenol。
2.一类香豆素衍生物的制备方法,其特征在于:
在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管,加入溴代底物1、双(三叔丁基膦)钯(0),Et3N,乙酸烯丙酯;然后将反应瓶密封并置于100℃油浴中;反应完成后,将反应混合物冷却至室温,并添加1 mL饱和NaHCO3水溶液,然后搅拌5分钟;然后通过硅藻土过滤反应粗品,并用乙酸乙酯洗涤,用乙酸乙酯稀释滤液,并用水和盐水萃取;合并有机相用无水Na2SO4干燥,过滤有机相,并在30℃的真空中浓缩,以提供粗产品,通过快速柱色谱纯化后,获得目标化合物;
其中溴代底物1的结构如下:。
3.一类香豆素衍生物的制备方法,其特征在于:
在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管,加入溴代底物1、双(三叔丁基膦)钯(0),甲苯、Et3N、丙烯酸(叔丁基碳酸)酐;然后将反应瓶密封并置于100℃油浴中;反应30分钟后,将反应混合物冷却至室温并添加饱和NaHCO3水溶液,然后搅拌5分钟;然后通过硅藻土过滤反应粗品,并用乙酸乙酯洗涤,用乙酸乙酯稀释滤液,并用水和盐水萃取;合并有机相用无水Na2SO4干燥,过滤有机相,并在30℃的真空中浓缩,以提供粗产品,通过快速柱色谱纯化后,获得目标化合物;
其中溴代底物1的结构如下:。
4.一类香豆素衍生物的制备方法,其特征在于:
在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管、溴代底物1、双(三叔丁基膦)钯(0),Et3N(82 μL,0.6 mmol,1.5 eq.),丙烯酸苄酯,然后将反应瓶密封并置于100℃油浴中;反应完成后,将反应混合物冷却至室温,并添加1 mL饱和NaHCO3水溶液,然后搅拌5分钟,然后通过硅藻土过滤反应粗品,并用乙酸乙酯洗涤,用乙酸乙酯稀释滤液,并用水和盐水萃取;合并有机相用无水Na2SO4干燥,过滤有机相,并在30℃的真空中浓缩,以提供粗产品,通过快速柱色谱纯化后,获得目标化合物;
其中溴代底物1的结构如下:。
5.一类香豆素衍生物的制备方法,其特征在于:
在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管、溴代底物1、双(三叔丁基膦)钯(0)、甲苯、Et3N,乙烯苯;然后将反应瓶密封并置于100℃油浴中,反应30分钟后,将反应混合物冷却至室温并添加饱和NaHCO3水溶液,然后搅拌5分钟,然后通过硅藻土过滤反应粗品,并用乙酸乙酯洗涤,用乙酸乙酯稀释滤液,并用水和盐水萃取,合并有机相用无水Na2SO4干燥,过滤有机相,并在30℃的真空中浓缩,以提供粗产品,通过快速柱色谱纯化后,获得目标化合物;
其中溴代底物1的结构如下:。
6.一类香豆素衍生物的制备方法,其特征在于:
在氮气保护下,向双颈圆底烧瓶中加入磁子并加冷凝管、溴代底物1、双(三叔丁基膦)钯(0),甲苯、Et3N、甲基丙烯酸乙酯;然后将反应瓶密封并置于100℃油浴中;反应30分钟后,将反应混合物冷却至室温并添加饱和NaHCO3水溶液,然后搅拌5分钟,然后通过硅藻土过滤反应粗品,并用乙酸乙酯洗涤;用乙酸乙酯稀释滤液,并用水和盐水萃取;合并有机相用无水Na2SO4干燥,过滤有机相,并在30℃的真空中浓缩,以提供粗产品;通过快速柱色谱纯化后,获得目标化合物;
其中溴代底物1的结构如下:。
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Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102746124A (zh) * | 2012-07-24 | 2012-10-24 | 苏州大学 | 制备取代烯烃的方法 |
WO2019170163A1 (zh) * | 2018-03-07 | 2019-09-12 | 东莞市均成高新材料有限公司 | 三联芳单膦配体、它们的制备方法和在催化偶联反应中的用途 |
CN111662264A (zh) * | 2020-05-15 | 2020-09-15 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | 一种香豆素类衍生物的合成方法 |
CN114805174A (zh) * | 2022-02-24 | 2022-07-29 | 大理大学 | 一种tmc-205、一锅合成方法以及应用 |
-
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Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN102746124A (zh) * | 2012-07-24 | 2012-10-24 | 苏州大学 | 制备取代烯烃的方法 |
WO2019170163A1 (zh) * | 2018-03-07 | 2019-09-12 | 东莞市均成高新材料有限公司 | 三联芳单膦配体、它们的制备方法和在催化偶联反应中的用途 |
CN111662264A (zh) * | 2020-05-15 | 2020-09-15 | 贵州省中国科学院天然产物化学重点实验室(贵州医科大学天然产物化学重点实验室) | 一种香豆素类衍生物的合成方法 |
CN114805174A (zh) * | 2022-02-24 | 2022-07-29 | 大理大学 | 一种tmc-205、一锅合成方法以及应用 |
Non-Patent Citations (2)
Title |
---|
Coumarin-3-carboxylic acid derivatives as potentiators and inhibitors of recombinant and native N-methyl-D-aspartate receptors;Mark W. Irvine et al;《Neurochemistry International 》;第61卷;第593–600页 * |
Half-Sandwich Ruthenium Carbene Complexes Link trans-Hydrogenation and gem-Hydrogenation of Internal Alkynes;Alexandre Guthertz et al;《J. Am. Chem. Soc. 》;第140卷;第3156−3169页 * |
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