CN102775374A - Coumarin compound, and preparation method and application thereof - Google Patents
Coumarin compound, and preparation method and application thereof Download PDFInfo
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- CN102775374A CN102775374A CN2012102735516A CN201210273551A CN102775374A CN 102775374 A CN102775374 A CN 102775374A CN 2012102735516 A CN2012102735516 A CN 2012102735516A CN 201210273551 A CN201210273551 A CN 201210273551A CN 102775374 A CN102775374 A CN 102775374A
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- coumarin
- methyl
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- hydroxy
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- ZYGHJZDHTFUPRJ-UHFFFAOYSA-N benzo-alpha-pyrone Natural products C1=CC=C2OC(=O)C=CC2=C1 ZYGHJZDHTFUPRJ-UHFFFAOYSA-N 0.000 title claims abstract description 107
- 235000001671 coumarin Nutrition 0.000 title claims abstract description 35
- 229960000956 coumarin Drugs 0.000 title claims abstract description 34
- 238000002360 preparation method Methods 0.000 title claims abstract description 20
- -1 Coumarin compound Chemical class 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 74
- HSHNITRMYYLLCV-UHFFFAOYSA-N 4-methylumbelliferone Chemical compound C1=C(O)C=CC2=C1OC(=O)C=C2C HSHNITRMYYLLCV-UHFFFAOYSA-N 0.000 claims abstract description 26
- 230000003078 antioxidant effect Effects 0.000 claims abstract description 11
- 239000003814 drug Substances 0.000 claims abstract description 7
- 239000003963 antioxidant agent Substances 0.000 claims abstract description 3
- 229940079593 drug Drugs 0.000 claims abstract description 3
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 15
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 10
- VSCWAEJMTAWNJL-UHFFFAOYSA-K aluminium trichloride Chemical compound Cl[Al](Cl)Cl VSCWAEJMTAWNJL-UHFFFAOYSA-K 0.000 claims description 9
- CSKNSYBAZOQPLR-UHFFFAOYSA-N benzenesulfonyl chloride Chemical compound ClS(=O)(=O)C1=CC=CC=C1 CSKNSYBAZOQPLR-UHFFFAOYSA-N 0.000 claims description 9
- MXNBDFWNYRNIBH-UHFFFAOYSA-N 3-fluorobenzoic acid Chemical compound OC(=O)C1=CC=CC(F)=C1 MXNBDFWNYRNIBH-UHFFFAOYSA-N 0.000 claims description 7
- BBYDXOIZLAWGSL-UHFFFAOYSA-N 4-fluorobenzoic acid Chemical compound OC(=O)C1=CC=C(F)C=C1 BBYDXOIZLAWGSL-UHFFFAOYSA-N 0.000 claims description 7
- 229910052731 fluorine Inorganic materials 0.000 claims description 7
- UXTMROKLAAOEQO-UHFFFAOYSA-N chloroform;ethanol Chemical compound CCO.ClC(Cl)Cl UXTMROKLAAOEQO-UHFFFAOYSA-N 0.000 claims description 6
- 229910052739 hydrogen Inorganic materials 0.000 claims description 5
- 239000013078 crystal Substances 0.000 claims description 4
- 238000005618 Fries rearrangement reaction Methods 0.000 claims description 3
- 239000007791 liquid phase Substances 0.000 claims description 3
- 238000005809 transesterification reaction Methods 0.000 claims description 3
- 239000004480 active ingredient Substances 0.000 claims description 2
- 239000007790 solid phase Substances 0.000 claims description 2
- KRQLKZZASJQSLH-UHFFFAOYSA-N (4-methyl-2-oxochromen-7-yl) 4-fluorobenzoate Chemical compound C1=CC=2C(C)=CC(=O)OC=2C=C1OC(=O)C1=CC=C(F)C=C1 KRQLKZZASJQSLH-UHFFFAOYSA-N 0.000 claims 2
- 125000001231 benzoyloxy group Chemical group C(C1=CC=CC=C1)(=O)O* 0.000 claims 1
- 150000003254 radicals Chemical class 0.000 abstract description 6
- 238000012360 testing method Methods 0.000 abstract description 5
- 229960001396 hymecromone Drugs 0.000 abstract description 4
- HHEAADYXPMHMCT-UHFFFAOYSA-N dpph Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC([N+]([O-])=O)=C1[N]N(C=1C=CC=CC=1)C1=CC=CC=C1 HHEAADYXPMHMCT-UHFFFAOYSA-N 0.000 abstract 1
- 108091003079 Bovine Serum Albumin Chemical class 0.000 description 15
- 229940098773 bovine serum albumin Drugs 0.000 description 15
- 238000006243 chemical reaction Methods 0.000 description 15
- 239000001301 oxygen Substances 0.000 description 13
- 229910052760 oxygen Inorganic materials 0.000 description 13
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 238000010438 heat treatment Methods 0.000 description 8
- 238000001953 recrystallisation Methods 0.000 description 8
- 238000005406 washing Methods 0.000 description 8
- 230000000694 effects Effects 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- REFJWTPEDVJJIY-UHFFFAOYSA-N Quercetin Chemical compound C=1C(O)=CC(O)=C(C(C=2O)=O)C=1OC=2C1=CC=C(O)C(O)=C1 REFJWTPEDVJJIY-UHFFFAOYSA-N 0.000 description 6
- 238000004458 analytical method Methods 0.000 description 6
- 238000002474 experimental method Methods 0.000 description 6
- 239000000523 sample Substances 0.000 description 6
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 5
- MGJZITXUQXWAKY-UHFFFAOYSA-N diphenyl-(2,4,6-trinitrophenyl)iminoazanium Chemical compound [O-][N+](=O)C1=CC([N+](=O)[O-])=CC([N+]([O-])=O)=C1N=[N+](C=1C=CC=CC=1)C1=CC=CC=C1 MGJZITXUQXWAKY-UHFFFAOYSA-N 0.000 description 5
- 239000011737 fluorine Chemical group 0.000 description 5
- 238000002386 leaching Methods 0.000 description 5
- 239000013558 reference substance Substances 0.000 description 5
- 238000000967 suction filtration Methods 0.000 description 5
- XVZWWNMZVZWQKU-UHFFFAOYSA-N 3-acetyl-7-hydroxy-5-(hydroxymethyl)chromen-2-one Chemical compound C1=C(O)C=C2OC(=O)C(C(=O)C)=CC2=C1CO XVZWWNMZVZWQKU-UHFFFAOYSA-N 0.000 description 4
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 description 4
- 238000000862 absorption spectrum Methods 0.000 description 4
- 239000001110 calcium chloride Substances 0.000 description 4
- 229910001628 calcium chloride Inorganic materials 0.000 description 4
- 238000001816 cooling Methods 0.000 description 4
- 238000002189 fluorescence spectrum Methods 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- WQGWDDDVZFFDIG-UHFFFAOYSA-N pyrogallol Chemical compound OC1=CC=CC(O)=C1O WQGWDDDVZFFDIG-UHFFFAOYSA-N 0.000 description 4
- 239000007787 solid Substances 0.000 description 4
- JMGZEFIQIZZSBH-UHFFFAOYSA-N Bioquercetin Natural products CC1OC(OCC(O)C2OC(OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5)C(O)C2O)C(O)C(O)C1O JMGZEFIQIZZSBH-UHFFFAOYSA-N 0.000 description 3
- 238000005481 NMR spectroscopy Methods 0.000 description 3
- ZVOLCUVKHLEPEV-UHFFFAOYSA-N Quercetagetin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=C(O)C(O)=C(O)C=C2O1 ZVOLCUVKHLEPEV-UHFFFAOYSA-N 0.000 description 3
- HWTZYBCRDDUBJY-UHFFFAOYSA-N Rhynchosin Natural products C1=C(O)C(O)=CC=C1C1=C(O)C(=O)C2=CC(O)=C(O)C=C2O1 HWTZYBCRDDUBJY-UHFFFAOYSA-N 0.000 description 3
- 230000009471 action Effects 0.000 description 3
- 230000003110 anti-inflammatory effect Effects 0.000 description 3
- 230000000259 anti-tumor effect Effects 0.000 description 3
- 238000011161 development Methods 0.000 description 3
- 230000018109 developmental process Effects 0.000 description 3
- 201000010099 disease Diseases 0.000 description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 3
- IVTMALDHFAHOGL-UHFFFAOYSA-N eriodictyol 7-O-rutinoside Natural products OC1C(O)C(O)C(C)OC1OCC1C(O)C(O)C(O)C(OC=2C=C3C(C(C(O)=C(O3)C=3C=C(O)C(O)=CC=3)=O)=C(O)C=2)O1 IVTMALDHFAHOGL-UHFFFAOYSA-N 0.000 description 3
- 230000007062 hydrolysis Effects 0.000 description 3
- 238000006460 hydrolysis reaction Methods 0.000 description 3
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 description 3
- 238000007254 oxidation reaction Methods 0.000 description 3
- 235000005875 quercetin Nutrition 0.000 description 3
- 229960001285 quercetin Drugs 0.000 description 3
- FDRQPMVGJOQVTL-UHFFFAOYSA-N quercetin rutinoside Natural products OC1C(O)C(O)C(CO)OC1OCC1C(O)C(O)C(O)C(OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 FDRQPMVGJOQVTL-UHFFFAOYSA-N 0.000 description 3
- IKGXIBQEEMLURG-BKUODXTLSA-N rutin Chemical compound O[C@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@@H]1OC[C@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](OC=2C(C3=C(O)C=C(O)C=C3OC=2C=2C=C(O)C(O)=CC=2)=O)O1 IKGXIBQEEMLURG-BKUODXTLSA-N 0.000 description 3
- ALABRVAAKCSLSC-UHFFFAOYSA-N rutin Natural products CC1OC(OCC2OC(O)C(O)C(O)C2O)C(O)C(O)C1OC3=C(Oc4cc(O)cc(O)c4C3=O)c5ccc(O)c(O)c5 ALABRVAAKCSLSC-UHFFFAOYSA-N 0.000 description 3
- 235000005493 rutin Nutrition 0.000 description 3
- 229960004555 rutoside Drugs 0.000 description 3
- 238000005160 1H NMR spectroscopy Methods 0.000 description 2
- QKNYBSVHEMOAJP-UHFFFAOYSA-N 2-amino-2-(hydroxymethyl)propane-1,3-diol;hydron;chloride Chemical compound Cl.OCC(N)(CO)CO QKNYBSVHEMOAJP-UHFFFAOYSA-N 0.000 description 2
- 208000030507 AIDS Diseases 0.000 description 2
- UHOVQNZJYSORNB-UHFFFAOYSA-N Benzene Chemical compound C1=CC=CC=C1 UHOVQNZJYSORNB-UHFFFAOYSA-N 0.000 description 2
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 2
- 208000001953 Hypotension Diseases 0.000 description 2
- 230000010100 anticoagulation Effects 0.000 description 2
- KLOIYEQEVSIOOO-UHFFFAOYSA-N carbocromen Chemical compound CC1=C(CCN(CC)CC)C(=O)OC2=CC(OCC(=O)OCC)=CC=C21 KLOIYEQEVSIOOO-UHFFFAOYSA-N 0.000 description 2
- 229960005003 carbocromen Drugs 0.000 description 2
- 229960001261 cloridarol Drugs 0.000 description 2
- KBFBRIPYVVGWRS-UHFFFAOYSA-N cloridarol Chemical compound C=1C2=CC=CC=C2OC=1C(O)C1=CC=C(Cl)C=C1 KBFBRIPYVVGWRS-UHFFFAOYSA-N 0.000 description 2
- 150000004775 coumarins Chemical class 0.000 description 2
- 238000002447 crystallographic data Methods 0.000 description 2
- 238000013016 damping Methods 0.000 description 2
- 238000005516 engineering process Methods 0.000 description 2
- 239000012530 fluid Substances 0.000 description 2
- 239000001257 hydrogen Substances 0.000 description 2
- 125000002887 hydroxy group Chemical group [H]O* 0.000 description 2
- 208000021822 hypotensive Diseases 0.000 description 2
- 230000001077 hypotensive effect Effects 0.000 description 2
- 230000003993 interaction Effects 0.000 description 2
- 230000004060 metabolic process Effects 0.000 description 2
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 230000003647 oxidation Effects 0.000 description 2
- 230000008569 process Effects 0.000 description 2
- 229940079877 pyrogallol Drugs 0.000 description 2
- 230000004223 radioprotective effect Effects 0.000 description 2
- 239000000376 reactant Substances 0.000 description 2
- 238000010992 reflux Methods 0.000 description 2
- 238000011160 research Methods 0.000 description 2
- GHMLBKRAJCXXBS-UHFFFAOYSA-N resorcinol Chemical compound OC1=CC=CC(O)=C1 GHMLBKRAJCXXBS-UHFFFAOYSA-N 0.000 description 2
- 239000002904 solvent Substances 0.000 description 2
- 238000002211 ultraviolet spectrum Methods 0.000 description 2
- ORHBXUUXSCNDEV-UHFFFAOYSA-N umbelliferone Chemical class C1=CC(=O)OC2=CC(O)=CC=C21 ORHBXUUXSCNDEV-UHFFFAOYSA-N 0.000 description 2
- PJVWKTKQMONHTI-UHFFFAOYSA-N warfarin Chemical compound OC=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 PJVWKTKQMONHTI-UHFFFAOYSA-N 0.000 description 2
- 229960005080 warfarin Drugs 0.000 description 2
- OCZVHBZNPVABKX-UHFFFAOYSA-N 1,1-diphenyl-2-(2,4,6-trinitrophenyl)hydrazine;ethanol Chemical compound CCO.[O-][N+](=O)C1=CC([N+](=O)[O-])=CC([N+]([O-])=O)=C1NN(C=1C=CC=CC=1)C1=CC=CC=C1 OCZVHBZNPVABKX-UHFFFAOYSA-N 0.000 description 1
- CJIJXIFQYOPWTF-UHFFFAOYSA-N 7-hydroxycoumarin Natural products O1C(=O)C=CC2=CC(O)=CC=C21 CJIJXIFQYOPWTF-UHFFFAOYSA-N 0.000 description 1
- 208000024172 Cardiovascular disease Diseases 0.000 description 1
- MYMOFIZGZYHOMD-UHFFFAOYSA-N Dioxygen Chemical compound O=O MYMOFIZGZYHOMD-UHFFFAOYSA-N 0.000 description 1
- WRQNANDWMGAFTP-UHFFFAOYSA-N Methylacetoacetic acid Chemical compound COC(=O)CC(C)=O WRQNANDWMGAFTP-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 208000019155 Radiation injury Diseases 0.000 description 1
- 230000002292 Radical scavenging effect Effects 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 230000032683 aging Effects 0.000 description 1
- 125000000217 alkyl group Chemical group 0.000 description 1
- 230000002790 anti-mutagenic effect Effects 0.000 description 1
- 230000003064 anti-oxidating effect Effects 0.000 description 1
- 235000006708 antioxidants Nutrition 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 238000006701 autoxidation reaction Methods 0.000 description 1
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- 125000001153 fluoro group Chemical group F* 0.000 description 1
- 125000000524 functional group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
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- 230000003859 lipid peroxidation Effects 0.000 description 1
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- 230000001404 mediated effect Effects 0.000 description 1
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- 230000000144 pharmacologic effect Effects 0.000 description 1
- ISWSIDIOOBJBQZ-UHFFFAOYSA-N phenol group Chemical group C1(=CC=CC=C1)O ISWSIDIOOBJBQZ-UHFFFAOYSA-N 0.000 description 1
- 235000013824 polyphenols Nutrition 0.000 description 1
- 239000000843 powder Substances 0.000 description 1
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- HFTAFOQKODTIJY-UHFFFAOYSA-N umbelliferone Natural products Cc1cc2C=CC(=O)Oc2cc1OCC=CC(C)(C)O HFTAFOQKODTIJY-UHFFFAOYSA-N 0.000 description 1
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Abstract
The invention belongs to the technical field of medicines and in particular relates to a coumarin compound represented by a general formula I, wherein the compound is 4-methyl-7-hydroxy-8-(3-fluorobenzenzoyl) coumarin or 4-methyl-7-hydroxy-8-(4-fluorobenzenzoyl) coumarin. The invention further relates to the coumarin compound represented by the general formula I, a preparation method of the coumarin compound and an application of the coumarin compound as an antioxidant. The compound is obtained by modifying on the basis of the structure of the hymecromone; the antioxidant activity tests prove that the compound represented by the formula I has significant functions in removing superoxide anion free radical O2<->. and DPPH. (1,1-diphenyl-2-picrylhydrazyl radical 2,2-Diphenyl-1-(2,4,6-trinitrophenyl)hydrazyl) free radical.
Description
Technical field
The invention belongs to medical technical field, the purposes of particularly a kind of coumarin kind compound and preparation method thereof and inhibitor with anti-oxidant activity.
Background technology
The active oxygen radical that body produces in metabolic processes (ROS), like ultra-oxygen anion free radical (O
2 -), hydroxyl radical free radical (HO), lipid peroxidation radical (ROO) and singlet oxygen (
1O
2) organism old and feeble with processes such as disease, normal immune metabolism, cell signaling in all play an important role.Research shows; Superfluous radical can cause the damage of human normal cell and tissue in the human body; Thereby cause the generation of many dysfunctions of body and various diseases; Like aging, rheumatic arthritis, cancer, cardiovascular and cerebrovascular diseases, Alzheimer, mellitus and radiation injury etc., oxidation-resistant active ingredient can be removed radical, reduction-oxidation material, plays the effect of protection body.Seek and develop the important subject that the antioxidant that can remove oxyradical has become fields such as current biology, medical science, chemistry, pharmaceutics.
That coumarin kind compound has is antitumor, pharmacologically active widely such as anti-AIDS, Alzheimer, antibiotic, anticoagulation, anti-inflammatory, hypotensive, radioprotective, is widely used in biology, medicine, especially at field of medicaments.Some coumarin kind compounds such as warfarin (warfarin), Armillarisin A (armillarisin A), Hymecromone (hymecromone), cloridarol (chloridarol), Chromonar (carbochromen) etc. have been widely used in clinical.The increasing coumarin kind compound of what is more important demonstrates has huge development potentiality to the multiclass treatment of diseases, and correlative study becomes increasingly active, and development very rapidly.
Coumarins is the fragrant oxygen helerocyclics that contains benzo α-pyrone structure, has good thermodynamics and photochemical stability, is easy to carry out structural modification and can introduces various functional groups easily.Most have hydroxyl or alkyl in the C-7 position.And the umbelliferone class has multiple pharmacological effect; Like neuroprotective, antitumor, antimutagenic and anti-inflammatory action etc.; These effects all with the tonka bean camphor molecular structure in contained phenolic hydroxyl group can influence formation and the removing of ROS, thereby the oxidative damage that influences free radical mediated is relevant.Therefore the structural chemistry of umbelliferone is modified or structure of modification; Can obtain having the compound of higher pharmacologically active; To help to seek and have new drug efficient, low toxicity, application all has important and practical meanings with clinical medicine in the development of biomedicine field to coumarin kind compound for this.
Summary of the invention
Technical problem to be solved by this invention is the deficiency to prior art, and a kind of coumarin kind compound new, that have anti-oxidant activity is provided.
Another technical problem to be solved by this invention has provided the preparation method of aforesaid coumarin kind compound.
Further purpose of the present invention is to provide said application with anti-oxidant activity of coumarin kind compound.The anti-oxidant activity that this coumarin kind compound shows can be used in the preparation of medicines such as antitumor, anti-AIDS, Alzheimer, anticoagulation, anti-inflammatory, hypotensive, radioprotective.
Technical problem to be solved by this invention is to realize through following technical scheme.The present invention is a kind of coumarin kind compound, representes with following general formula I, and this compound is on the 7-hydroxy-4-methylcoumarin architecture basics of (having another name called Hymecromone), to modify to obtain:
I
Wherein, R
1, R
2For H or be F, and R
1And R
2Can not be H or for F simultaneously.
In the compound of the present invention, work as R
1=F, R
2During=H, this compound is 4-methyl-7-hydroxyl-8-(3-fluoro benzoyl) tonka bean camphor shown in the formula I-a; Work as R
1=H, R
2During=F, this compound is 4-methyl-7-hydroxyl-8-(4-fluoro benzoyl) tonka bean camphor shown in formula I-b.
I-a I?-b
The compounds of this invention can be according to the reactions path of preparing:
This method mainly may further comprise the steps:
⑴ 7-hydroxy-4-methylcoumarin and fluorine substituted benzoyl acid compounds and benzene sulfonyl chloride through transesterification reaction, obtain 4-methyl-7-(fluorine substituted benzoyl acyl-oxygen base) coumarin kind compound II-a or II-b in liquid phase.
⑵ pass through the Fries rearrangement reaction with resulting 4-methyl-7-(fluorine substituted benzoyl acyl-oxygen base) tonka bean camphor and aluminum trichloride (anhydrous) 200 ℃ of processes, obtains coumarin kind compound I-a and I-b.
Coumarin kind compound of the present invention is worked as R
1=H, R
2During=F, the unit cell parameters of compound monocrystal is: oblique system, spacer
P 21/c, a=13.3771 (15),
b=7.5521 (10),
c=19.3917 (17), α=90o, β=118.996 (6) o, γ=90o, pile up for three-dimensional netted in the space.
Preparing method's of the present invention preferred concrete steps are following: the benzene sulfonyl chloride of 3-fluorobenzoic acid or 4-fluorobenzoic acid and equimolar amount was reacted 0.5～1.0 hour in 10～18 ℃; The 7-hydroxy-4-methylcoumarin holding temperature that adds equimolar amount again obtains 4-methyl-7-(3-fluorobenzoyl oxygen base) tonka bean camphor or 4-methyl-7-(4-fluorobenzoyl oxygen base) tonka bean camphor 20～25 ℃ of reactions 20～48 hours; Then with resultant 4-methyl-7-(3-fluorobenzoyl oxygen base) tonka bean camphor or 4-methyl-7-(4-fluorobenzoyl oxygen base) tonka bean camphor and aluminum trichloride (anhydrous) 1:3 reacting by heating 1.5～2.5 hours in 200～210 ℃ of oil baths in molar ratio; Then through the dilute hydrochloric acid solution hydrolysis; Water washing; Purify with volume ratio 2:1 ethanol-chloroform recrystallization, obtain 4-methyl-7-hydroxyl-8-(3-fluoro benzoyl) tonka bean camphor or 4-methyl-7-hydroxyl-8-(4-fluoro benzoyl) tonka bean camphor.
Synthetic compound of the present invention is through ir spectra, ultimate analysis, H
1Means such as NMR and the analysis of X-single crystal diffraction characterize new compound, have confirmed the structure of compound.
Initial compounds is commercially available or those skilled in the art can be easy to obtain by conventional chemical reaction or the said chemical reaction of document among the present invention.
The preparation method of compound provided by the invention, technology is simple, and is low for the experimental installation requirement, only needs common heating device and reflux, is convenient to produce in enormous quantities.
The contriver has carried out the anti-oxidant activity test to compound according to the invention, and compound of the present invention can effectively be removed ultra-oxygen anion free radical (O
2 -) and the DPPH radical, clearance rate is with medium effective concentration IC
50Weigh, data are listed in table 1.Its resistance of oxidation is better than the reference substance rutin slightly, and is weaker than the reference substance Quercetin, and said compound can be used for the preparation of anti-oxidation medicine.
The contriver has proved that through UV spectrum among the embodiment and fluorescence spectrum research this compounds and bovine serum albumin (BSA) have stronger interaction, has the potential medicinal application and is worth.
Description of drawings
Fig. 1 is 4-methyl-7-hydroxyl-8-(4-fluoro benzoyl) tonka bean camphor (crystalline structure synoptic diagram of compound I-b);
Fig. 2 is 4-methyl-7-hydroxyl-8-(3-fluoro benzoyl) tonka bean camphor (infrared spectrogram of compound I-a);
Fig. 3 is 4-methyl-7-hydroxyl-8-(4-fluoro benzoyl) tonka bean camphor (infrared spectrogram of compound I-b);
Fig. 4 is 4-methyl-7-hydroxyl-8-(3-fluoro benzoyl) tonka bean camphor (uv absorption spectra of compound I-a);
Fig. 5 is 4-methyl-7-hydroxyl-8-(4-fluoro benzoyl) tonka bean camphor (uv absorption spectra of compound I-b);
Fig. 6 is 4-methyl-7-hydroxyl-8-(3-fluoro benzoyl) tonka bean camphor (hydrogen nuclear magnetic resonance spectrogram of compound I-a);
Fig. 7 is 4-methyl-7-hydroxyl-8-(4-fluoro benzoyl) tonka bean camphor (hydrogen nuclear magnetic resonance spectrogram of compound I-b);
Fig. 8 is 4-methyl-7-hydroxyl-8-(3-fluoro benzoyl) tonka bean camphor (uv absorption spectra of compound I-a) and BSA effect;
Fig. 9 is 4-methyl-7-hydroxyl-8-(4-fluoro benzoyl) tonka bean camphor (uv absorption spectra of compound I-b) and BSA effect;
Figure 10 is 4-methyl-7-hydroxyl-8-(3-fluoro benzoyl) tonka bean camphor (fluorescence spectrum figure of compound I-a) and BSA effect;
Figure 11 is 4-methyl-7-hydroxyl-8-(4-fluoro benzoyl) tonka bean camphor (fluorescence spectrum figure of compound I-b) and BSA effect.
Embodiment
Through embodiment the present invention is further specified below, should be noted that these embodiment only are used for the present invention is illustrated, should not be construed limitation of the present invention.Used initial compounds is that commercial prod maybe can be from known compound method preparation in compound synthetic, and these methods are basic with conspicuous to synthetic chemist.Therefore, the description of following compound method can be thought detailed in concrete.
(1) at first 3-fluorobenzoic acid or 4-fluorobenzoic acid, benzene sulfonyl chloride and 7-hydroxy-4-methylcoumarin are passed through transesterification reaction in liquid phase, obtain 4-methyl-7-(fluorine substituted benzoyl acyl-oxygen base) tonka bean camphor;
(2) then resultant 4-methyl-7-(fluorine substituted benzoyl acyl-oxygen base) tonka bean camphor and aluminum trichloride (anhydrous) are obtained the coumarin kind compound that corresponding general formula is I through the Fries rearrangement reaction in solid phase.
Embodiment 3; A kind of preparation method suc as formula the described coumarin kind compound of I; Its concrete steps are following: the benzene sulfonyl chloride of 3-fluorobenzoic acid or 4-fluorobenzoic acid and equimolar amount was reacted 1.0 hours in 18 ℃; The 7-hydroxy-4-methylcoumarin holding temperature that adds equimolar amount again obtains 4-methyl-7-(3-fluorobenzoyl oxygen base) tonka bean camphor or 4-methyl-7-(4-fluorobenzoyl oxygen base) tonka bean camphor 25 ℃ of reactions 48 hours; Then with resultant 4-methyl-7-(3-fluorobenzoyl oxygen base) tonka bean camphor or 4-methyl-7-(4-fluorobenzoyl oxygen base) tonka bean camphor and aluminum trichloride (anhydrous) 1:3 reacting by heating 2.5 hours in 210 ℃ of oil baths in molar ratio; Then through the dilute hydrochloric acid solution hydrolysis; Water washing; Purify with volume ratio 2:1 ethanol-chloroform recrystallization, obtain 4-methyl-7-hydroxyl-8-(3-fluoro benzoyl) tonka bean camphor or 4-methyl-7-hydroxyl-8-(4-fluoro benzoyl) tonka bean camphor.
Embodiment 4,7-hydroxy-4-methylcoumarin (III) preparation experiment.
, the 500mL round-bottomed flask of reflux condensing tube adds Resorcinol 11g (100mmol), methyl aceto acetate 13mL (102.5mmol), 85% SPA 52mL in being housed; Heated and stirred 6h in 70 ℃ of water-baths; Reaction is finished, and is cooled to room temperature, gets yellow solid; Suction filtration, water washing leaching cake, the dry bullion that gets.Bullion recrystallization in ethanol gets 7-hydroxy-4-methyl first tonka bean camphor, white solid, and fusing point: 188～191 ℃, yield 96%.
In the there-necked flask of the 100ml that constant pressure funnel, calcium chloride tube and TM are housed, add 3-fluorobenzoic acid 2.01g (10mmol), add an amount of pyridine and make solvent; Put in the cooling bath, drip benzene sulfonyl chloride 1.5mL (12mmol), room temperature reaction is after 30 minutes; Place cooling bath again, drip the pyridine solution that contains 7-hydroxy-4-methylcoumarin 1.76g (10mmol), drip and finish; Holding temperature was 20～25 ℃ of reactions 24 hours, and reaction is finished, and reactant is poured in the frozen water; Suction filtration, water washing leaching cake, the dry bullion that gets.Bullion recrystallization in ethanol gets 4-methyl-7-(3-fluorobenzoyl oxygen base) tonka bean camphor, white solid, and fusing point: 175～178 ℃, yield 90%.IR (KBr, cm
-1): 3420,1722,1703,1577,1280,1259,1130; Ultimate analysis, C
17H
11FO
4: calculated value C 65.87, H 7.56; Measured value C 65.48, H 7.59.
Embodiment 6, the preparation experiment of 4-methyl-7-(4-fluorobenzoyl oxygen base) tonka bean camphor (II-b).
In the there-necked flask of the 100ml that constant pressure funnel, calcium chloride tube and TM are housed, add 4-fluorobenzoic acid 2.01g (10mmol), add an amount of pyridine and make solvent; Put in the cooling bath, drip benzene sulfonyl chloride 1.5mL (12mmol), room temperature reaction is after 30 minutes; Place cooling bath again, drip the pyridine solution that contains 7-hydroxy-4-methylcoumarin 1.76g (10mmol), drip and finish; Holding temperature was 20-25 ℃ of reaction 24 hours, and reaction is finished, and reactant is poured in the frozen water; Suction filtration, water washing leaching cake, the dry bullion that gets.Bullion recrystallization in ethanol gets 4-methyl-7-(4-fluorobenzoyl oxygen base) tonka bean camphor, white solid, 166～168 ℃ of fusing points, yield 92%.IR (KBr, cm
-1): 1739,1640,1561,1256,1248,1120,1017; Ultimate analysis, C
17H
11FO
4: calculated value C 65.87, H 7.56; Measured value C 65.39, H 7.33.
Embodiment 7, with reference to Fig. 2, and 4,6, the preparation experiment of 4-methyl-8-(3-fluoro benzoyl) tonka bean camphor (I-a).
With 4-methyl-7-(3-fluorobenzoyl oxygen base) tonka bean camphor and aluminum trichloride (anhydrous) 1:3 feed ratio in molar ratio, place round-bottomed flask with calcium chloride tube, reacting by heating is 2 hours in 200～210 ℃ of oil baths; Be chilled to room temperature, add mass concentration 10% hydrochloric acid soln 20mL, heating is 1 hour on thermostat water bath; Be chilled to room temperature; Suction filtration, water washing leaching cake, the dry bullion that gets.Bullion recrystallization in ethanol-chloroform (2:1) gets compound 4-methyl-7-hydroxyl-8-(3-fluoro benzoyl) tonka bean camphor (I-a), white powder, and fusing point: 226～228 ℃, productive rate 65%.
1H NMR (400 MHz, CDCl
3, δ): 1.23～1.26 (3H, m, CH
3), 2.426 (1H, s, OH), 2.429 (3H, s, 4-CH
3), 6.09 (1H, s, 3-H), 7.04 (1H, d,
J=9.2Hz, 6-H), 7.27 ~ 7.45 (4H, m, Ph-H), 7.73 (1H, d,
J=9.2Hz, 5-H), 10.87 (1H, s, 7-OH); IR (KBr, cm
-1): 3286,1737,1704,1679,1581,1441,1385,1259,1062; Ultimate analysis, C
17H
11FO
4C
2H
5OH: calculated value C 66.27, H 4.98; Measured value C 66.55, H 5.01.
Embodiment 8, with reference to Fig. 1,3,5,7, and the preparation experiment of 4-methyl-8-(4-fluoro benzoyl) tonka bean camphor (I-b).
With 4-methyl-7-(3-fluorobenzoyl oxygen base) tonka bean camphor and aluminum trichloride (anhydrous) 1:3 feed ratio in molar ratio, place round-bottomed flask with calcium chloride tube, reacting by heating is 2 hours in 200～210 ℃ of oil baths; Be chilled to room temperature, add mass concentration 10% hydrochloric acid soln 20mL, heating is 1 hour on thermostat water bath; Be chilled to room temperature; Suction filtration, water washing leaching cake, the dry bullion that gets.Bullion recrystallization in ethanol-chloroform (2:1) gets compound 4-methyl-7-hydroxyl-8-(4-fluoro benzoyl) tonka bean camphor (I-b), white crystal, 244～248 ℃ of fusing points, yield 61%.
1H NMR (400 MHz, CDCl
3, δ): 2.29 (3H, s, 4-CH
3), 4.88 (1H, s, 7-OH), 6.19 (1H, s, 3-H), 6.98 (1H, s, 6-H), 7.27 ~ 7.71 (4H, m, Ph-H), 7.82 (1H, s, 5-H); IR (KBr, cm
-1): 3322,1737,1703,1676,1599,1568,1311,1241,1062; Ultimate analysis, C
17H
11FO
4: calculated value C 68.46, H 3.72; Measured value C 68.19, H3.69; Figure is as shown in Figure 1 for X-diffraction single crystal structure, and crystallographic data is seen table 1.
Table 1 compound (I-
b ) crystallographic data
In 10mL tool plug test tube, add the sample of 0.8 mg/L DPPH ethanol solution 1.0 mL and different volumes respectively, constant volume shakes up, under the dark room conditions behind reaction 30 min in 518 nm places mensuration absorbancy (A
i), the absorbancy (A that replaces sample to record with ethanol
0), the absorbancy (A of corresponding concentration sample
j) be that the result sees table 2 with reference to solution.
Clearance rate=[1 (A
iA
j)/A
0] * 100%
The ultra-oxygen anion free radical clearance test adopts the autoxidation of pyrogallol under the alkaline condition to produce O
2 -Free radical system.In 10mL tool plug test tube, add the sample solution of pH 8.2,0.05 mol/L Tris-HCl damping fluid 4.5 mL and different volumes respectively; Shake up, place 25 ℃ of water-bath preheating 30 min, add 3 mmol/L pyrogallol solution 1mL of 25 ℃ of preheatings; In 25 ℃ of water-baths, react 5 min behind the mixing; Add the hydrochloric acid 1 mL termination reaction of 8 mol/L, use the zero(ppm) water constant volume, measure absorbancy (A immediately at 318 nm places
i), blank group (A
0) replace sample, the absorbancy (A of corresponding concentration sample with the zero(ppm) water of equal volume
j) be that the result sees table 2 with reference to solution.
Clearance rate=[1 (A
iA
j)/A
0] * 100%
The anti-oxidant activity of table 2 compound
This shows that two compounds (I-a and I-b) are to ultra-oxygen anion free radical (O
2 -) and the DPPH radical scavenging(action) is in various degree arranged.Under same experimental conditions, compound (I-a and I-b) obviously is weaker than reference substance rutin and the Quercetin removing ability to the DPPH radical to the removing ability of DPPH radical; Compound (I-a and I-b) is to ultra-oxygen anion free radical (O
2 -) scavenging(action) be better than the reference substance rutin to ultra-oxygen anion free radical (O
2 -) the removing ability, and be weaker than the reference substance Quercetin to ultra-oxygen anion free radical (O
2 -) the removing ability.
The interactional binding constant of compound and bovine serum albumin (BSA)
K aAnd binding site number
nBe through following Equation for Calculating:
log［（
F 0 -
F）/
F］=log
K a+?nlog［
Q］
Wherein
F 0 The fluorescence intensity of expression bovine serum albumin,
FFluorescence intensity when expression adds compound,
QThe expression compound concentrations,
nBe the binding site number of trying to achieve,
K aThe expression binding constant, calculation result is seen table 3, explains that two compounds and BSA have strong keying action.
Table 3Compound to the binding constant of BSA (
K a) and binding site number (
n) (T=293K)
| Sample | K a | n |
| Compound (I- a） | 2.4797×10 5 | 0.978 |
| Compound (I- b） | 3.4906×10 5 | 1.0301 |
Claims (6)
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| CN110386998A (en) * | 2019-07-22 | 2019-10-29 | 中国科学院烟台海岸带研究所 | A kind of coumarin-like inulin derivative and its preparation and application |
| CN116535373A (en) * | 2023-05-06 | 2023-08-04 | 波顿香料股份有限公司 | Nut aroma compound, preparation method thereof and nut-flavored coffee aroma base |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN104974123A (en) * | 2015-07-13 | 2015-10-14 | 渤海大学 | Coumarin compound with antioxidant activity, and preparation method and application thereof |
| CN104974123B (en) * | 2015-07-13 | 2017-09-22 | 渤海大学 | Coumarin kind compound with antioxidation activity and preparation method and application |
| CN110386998A (en) * | 2019-07-22 | 2019-10-29 | 中国科学院烟台海岸带研究所 | A kind of coumarin-like inulin derivative and its preparation and application |
| CN116535373A (en) * | 2023-05-06 | 2023-08-04 | 波顿香料股份有限公司 | Nut aroma compound, preparation method thereof and nut-flavored coffee aroma base |
| CN116535373B (en) * | 2023-05-06 | 2025-03-11 | 波顿香料股份有限公司 | Nut aroma compound, preparation method thereof and nut-flavored coffee aroma base |
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