CN110128385A - A kind of quercetin derivative and its synthetic method by lauroyl chloride chemical modification - Google Patents
A kind of quercetin derivative and its synthetic method by lauroyl chloride chemical modification Download PDFInfo
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- CN110128385A CN110128385A CN201910314568.3A CN201910314568A CN110128385A CN 110128385 A CN110128385 A CN 110128385A CN 201910314568 A CN201910314568 A CN 201910314568A CN 110128385 A CN110128385 A CN 110128385A
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- quercetin
- synthetic method
- quercetin derivative
- ethyl acetate
- water
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- 150000003244 quercetin derivatives Chemical class 0.000 title claims abstract description 34
- 238000010189 synthetic method Methods 0.000 title claims abstract description 20
- NQGIJDNPUZEBRU-UHFFFAOYSA-N dodecanoyl chloride Chemical compound CCCCCCCCCCCC(Cl)=O NQGIJDNPUZEBRU-UHFFFAOYSA-N 0.000 title claims abstract description 18
- 238000007385 chemical modification Methods 0.000 title claims abstract description 6
- 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 claims abstract description 66
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 claims abstract description 54
- 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 claims abstract description 33
- 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 claims abstract description 33
- MWDZOUNAPSSOEL-UHFFFAOYSA-N kaempferol Natural products OC1=C(C(=O)c2cc(O)cc(O)c2O1)c3ccc(O)cc3 MWDZOUNAPSSOEL-UHFFFAOYSA-N 0.000 claims abstract description 33
- 229960001285 quercetin Drugs 0.000 claims abstract description 33
- 235000005875 quercetin Nutrition 0.000 claims abstract description 33
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims abstract description 23
- 238000006243 chemical reaction Methods 0.000 claims abstract description 18
- 239000002253 acid Substances 0.000 claims abstract description 13
- 239000003054 catalyst Substances 0.000 claims abstract description 12
- 238000000034 method Methods 0.000 claims abstract description 12
- 239000005457 ice water Substances 0.000 claims abstract description 9
- 239000007791 liquid phase Substances 0.000 claims abstract description 9
- 238000002360 preparation method Methods 0.000 claims abstract description 9
- 238000010898 silica gel chromatography Methods 0.000 claims abstract description 9
- 239000002904 solvent Substances 0.000 claims abstract description 6
- 239000006096 absorbing agent Substances 0.000 claims abstract description 5
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 18
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 18
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 claims description 12
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 claims description 12
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 claims description 12
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 9
- NLKNQRATVPKPDG-UHFFFAOYSA-M potassium iodide Chemical compound [K+].[I-] NLKNQRATVPKPDG-UHFFFAOYSA-M 0.000 claims description 9
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 claims description 8
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 8
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 claims description 8
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 8
- 150000002148 esters Chemical class 0.000 claims description 7
- OZNMEZAXFKUCPN-UHFFFAOYSA-N 3,5,7-trihydroxychromen-4-one Chemical compound O1C=C(O)C(=O)C=2C1=CC(O)=CC=2O OZNMEZAXFKUCPN-UHFFFAOYSA-N 0.000 claims description 6
- VHYFNPMBLIVWCW-UHFFFAOYSA-N 4-Dimethylaminopyridine Chemical compound CN(C)C1=CC=NC=C1 VHYFNPMBLIVWCW-UHFFFAOYSA-N 0.000 claims description 6
- CSNNHWWHGAXBCP-UHFFFAOYSA-L Magnesium sulfate Chemical compound [Mg+2].[O-][S+2]([O-])([O-])[O-] CSNNHWWHGAXBCP-UHFFFAOYSA-L 0.000 claims description 6
- KWKXNDCHNDYVRT-UHFFFAOYSA-N dodecylbenzene Chemical compound CCCCCCCCCCCCC1=CC=CC=C1 KWKXNDCHNDYVRT-UHFFFAOYSA-N 0.000 claims description 6
- 239000012044 organic layer Substances 0.000 claims description 6
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 claims description 4
- PMZURENOXWZQFD-UHFFFAOYSA-L Sodium Sulfate Chemical compound [Na+].[Na+].[O-]S([O-])(=O)=O PMZURENOXWZQFD-UHFFFAOYSA-L 0.000 claims description 4
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 4
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 4
- 239000003208 petroleum Substances 0.000 claims description 3
- 229960001760 dimethyl sulfoxide Drugs 0.000 claims description 2
- 239000003480 eluent Substances 0.000 claims description 2
- 238000002156 mixing Methods 0.000 claims description 2
- 239000012071 phase Substances 0.000 claims description 2
- 238000000746 purification Methods 0.000 claims description 2
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 claims description 2
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 2
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 claims 3
- ZAMOUSCENKQFHK-UHFFFAOYSA-N Chlorine atom Chemical compound [Cl] ZAMOUSCENKQFHK-UHFFFAOYSA-N 0.000 claims 1
- LUJAXSNNYBCFEE-UHFFFAOYSA-N Quercetin 3,7-dimethyl ether Natural products C=1C(OC)=CC(O)=C(C(C=2OC)=O)C=1OC=2C1=CC=C(O)C(O)=C1 LUJAXSNNYBCFEE-UHFFFAOYSA-N 0.000 claims 1
- PUTDIROJWHRSJW-UHFFFAOYSA-N Quercitrin Natural products CC1OC(Oc2cc(cc(O)c2O)C3=CC(=O)c4c(O)cc(O)cc4O3)C(O)C(O)C1O PUTDIROJWHRSJW-UHFFFAOYSA-N 0.000 claims 1
- OXGUCUVFOIWWQJ-XIMSSLRFSA-N acanthophorin B Natural products O[C@H]1[C@H](O)[C@H](O)[C@H](C)O[C@H]1OC1=C(C=2C=C(O)C(O)=CC=2)OC2=CC(O)=CC(O)=C2C1=O OXGUCUVFOIWWQJ-XIMSSLRFSA-N 0.000 claims 1
- 239000012295 chemical reaction liquid Substances 0.000 claims 1
- 239000000460 chlorine Substances 0.000 claims 1
- 229910052801 chlorine Inorganic materials 0.000 claims 1
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 claims 1
- OEKUVLQNKPXSOY-UHFFFAOYSA-N quercetin 3-O-beta-D-glucopyranosyl(1->3)-alpha-L-rhamnopyranosyl(1->6)-beta-d-galactopyranoside Natural products OC1C(O)C(C(O)C)OC1OC1=C(C=2C=C(O)C(O)=CC=2)OC2=CC(O)=CC(O)=C2C1=O OEKUVLQNKPXSOY-UHFFFAOYSA-N 0.000 claims 1
- QPHXPNUXTNHJOF-UHFFFAOYSA-N quercetin-7-O-beta-L-rhamnopyranoside Natural products OC1C(O)C(O)C(C)OC1OC1=CC(O)=C2C(=O)C(O)=C(C=3C=C(O)C(O)=CC=3)OC2=C1 QPHXPNUXTNHJOF-UHFFFAOYSA-N 0.000 claims 1
- OXGUCUVFOIWWQJ-HQBVPOQASA-N quercitrin Chemical compound O[C@@H]1[C@H](O)[C@@H](O)[C@H](C)O[C@H]1OC1=C(C=2C=C(O)C(O)=CC=2)OC2=CC(O)=CC(O)=C2C1=O OXGUCUVFOIWWQJ-HQBVPOQASA-N 0.000 claims 1
- 150000003839 salts Chemical class 0.000 claims 1
- 239000007788 liquid Substances 0.000 abstract description 6
- 238000000926 separation method Methods 0.000 abstract description 5
- 206010028980 Neoplasm Diseases 0.000 abstract description 4
- 206010020772 Hypertension Diseases 0.000 abstract description 3
- 201000011510 cancer Diseases 0.000 abstract description 3
- 201000010099 disease Diseases 0.000 abstract description 3
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 abstract description 3
- 125000002887 hydroxy group Chemical group [H]O* 0.000 abstract description 3
- 208000031225 myocardial ischemia Diseases 0.000 abstract description 3
- 239000002994 raw material Substances 0.000 abstract description 2
- 238000006467 substitution reaction Methods 0.000 abstract description 2
- 230000015572 biosynthetic process Effects 0.000 abstract 1
- 239000012043 crude product Substances 0.000 abstract 1
- 238000004821 distillation Methods 0.000 abstract 1
- 238000003810 ethyl acetate extraction Methods 0.000 abstract 1
- 238000003786 synthesis reaction Methods 0.000 abstract 1
- IJGRMHOSHXDMSA-UHFFFAOYSA-N Atomic nitrogen Chemical compound N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 description 8
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 6
- 150000001875 compounds Chemical class 0.000 description 6
- 230000001093 anti-cancer Effects 0.000 description 5
- 238000000605 extraction Methods 0.000 description 4
- 239000010410 layer Substances 0.000 description 4
- 229910052757 nitrogen Inorganic materials 0.000 description 4
- HIXDQWDOVZUNNA-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-hydroxy-7-methoxychromen-4-one Chemical compound C=1C(OC)=CC(O)=C(C(C=2)=O)C=1OC=2C1=CC=C(OC)C(OC)=C1 HIXDQWDOVZUNNA-UHFFFAOYSA-N 0.000 description 3
- 208000024172 Cardiovascular disease Diseases 0.000 description 3
- 238000005086 pumping Methods 0.000 description 3
- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 2
- 208000026106 cerebrovascular disease Diseases 0.000 description 2
- 230000002526 effect on cardiovascular system Effects 0.000 description 2
- 230000000694 effects Effects 0.000 description 2
- 244000291564 Allium cepa Species 0.000 description 1
- 235000002732 Allium cepa var. cepa Nutrition 0.000 description 1
- 241000196324 Embryophyta Species 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 102100034343 Integrase Human genes 0.000 description 1
- 241000220225 Malus Species 0.000 description 1
- 235000011430 Malus pumila Nutrition 0.000 description 1
- 235000015103 Malus silvestris Nutrition 0.000 description 1
- 108010092799 RNA-directed DNA polymerase Proteins 0.000 description 1
- 244000269722 Thea sinensis Species 0.000 description 1
- GAMYVSCDDLXAQW-AOIWZFSPSA-N Thermopsosid Natural products O(C)c1c(O)ccc(C=2Oc3c(c(O)cc(O[C@H]4[C@H](O)[C@@H](O)[C@H](O)[C@H](CO)O4)c3)C(=O)C=2)c1 GAMYVSCDDLXAQW-AOIWZFSPSA-N 0.000 description 1
- 230000002378 acidificating effect Effects 0.000 description 1
- 150000001263 acyl chlorides Chemical class 0.000 description 1
- QVGXLLKOCUKJST-UHFFFAOYSA-N atomic oxygen Chemical compound [O] QVGXLLKOCUKJST-UHFFFAOYSA-N 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 235000021028 berry Nutrition 0.000 description 1
- 239000003795 chemical substances by application Substances 0.000 description 1
- 238000000354 decomposition reaction Methods 0.000 description 1
- 230000007812 deficiency Effects 0.000 description 1
- 239000006185 dispersion Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 235000013399 edible fruits Nutrition 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 229930003944 flavone Natural products 0.000 description 1
- -1 flavone compound Chemical class 0.000 description 1
- 235000011949 flavones Nutrition 0.000 description 1
- 239000012634 fragment Substances 0.000 description 1
- 238000001727 in vivo Methods 0.000 description 1
- 230000004060 metabolic process Effects 0.000 description 1
- 238000012986 modification Methods 0.000 description 1
- 230000004048 modification Effects 0.000 description 1
- 230000036457 multidrug resistance Effects 0.000 description 1
- 239000001301 oxygen Substances 0.000 description 1
- 229910052760 oxygen Inorganic materials 0.000 description 1
- 238000007634 remodeling Methods 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 235000013616 tea Nutrition 0.000 description 1
- 210000004881 tumor cell Anatomy 0.000 description 1
- 235000013311 vegetables Nutrition 0.000 description 1
- VHBFFQKBGNRLFZ-UHFFFAOYSA-N vitamin p Natural products O1C2=CC=CC=C2C(=O)C=C1C1=CC=CC=C1 VHBFFQKBGNRLFZ-UHFFFAOYSA-N 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- 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
- C07D311/22—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4
- C07D311/26—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3
- C07D311/28—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only
- C07D311/30—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 4 with aromatic rings attached in position 2 or 3 with aromatic rings attached in position 2 only not hydrogenated in the hetero ring, e.g. flavones
Abstract
The invention discloses a kind of quercetin derivatives and its synthetic method by lauroyl chloride chemical modification, belong to medical synthesis field, its method are as follows: raw material, that is, Quercetin and lauroyl chloride are added in a solvent, proper catalyst and acidity regulator is added, in ice-water bath under room temperature, reaction 8-10 hours, after reaction, pH value is adjusted with acid between 6-7, water is added, ethyl acetate extraction, liquid separation, water layer continues to be extracted with ethyl acetate 2-3 times, combined ethyl acetate layer, add water absorbing agent, overnight, it filters, distillation removal ethyl acetate, it obtains crude product and carries out the purifying of 200-300 mesh silica gel column chromatography, preparation liquid phase purifies again, the quercetin derivative of high-purity is made.The resulting quercetin derivative of the present invention is chemically modified Natural Quercetin, by the way that substitution reaction occurs in 4 '-OH hydroxyl positions, is conducive to improve its water-soluble and fat-soluble, improvement bioavilability.This quercetin derivative can be used for treating the diseases such as hypertension, myocardial ischemia and cancer.
Description
Technical field
The present invention relates to a kind of synthetic method of medicaments derivative for treating the diseases such as hypertension, myocardial ischemia and cancer,
More particularly to a kind of synthetic method of the quercetin derivative by lauroyl chloride chemical modification.
Background technique
Quercetin is a kind of flavone compound for being distributed widely in nature, is largely present in common plant and vegetables
In fruit, such as berry, tea, apple, onion.Quercetin not only cardiovascular disease, anti-cancer and in terms of have uniqueness
Effect, simultaneously, moreover it is possible to improve tumor microenvironment, including reduce tumour cell multidrug resistance generation related to Reverse transcriptase
Thank to enzyme.Therefore, it has also become the research hotspot of domestic and foreign scholars.
Quercetin (Quercetin), also known as quercetin, Quercetin are yellow, entitled 3,5,7,3', the 4'- pentahydroxyflavone of chemistry, tool
There are extensive pharmacology and bioactivity, chemical structural formula are as follows:
In quercetin molecule contain following structure fragment, 3-OH, 4-C=O, 5-OH, 7-OH and 3'-OH, 4'-OH, because
Ketonic oxygen and five hydroxyl oxygens can provide lone electron pair, have certain coordination ability.
The molecule of Quercetin is planarized structure, is piled up closely, and intermolecular attraction is big, is not easy by solvent or Dispersion of Solute Matter,
Thus, the water solubility of Quercetin is poor, inactivate into metabolism is absorbed rapidly in vivo, has strong first pass effect, biological
Availability is lower, is extremely limited the clinical application of Quercetin.Therefore, using Quercetin as raw material, by its structure
Modification, improve the water solubility of compound and fat-soluble, so that it obtains higher activity, be conducive to treat disease.
Summary of the invention
The present invention is and to provide one to solve the deficiencies such as Quercetin poorly water-soluble, bioavailability in the prior art be low
Kind of quercetin derivative, resulting quercetin derivative it is fat-soluble far better than Quercetin, bioavilability has biggish mention
Height can be used for treating cardiovascular and cerebrovascular disease, anticancer and anti-cancer.
It is a further object of the present invention to provide the method for synthesizing the quercetin derivative, the Quercetin for having obtained high-purity spreads out
Biology, the present invention are chemically modified Natural Quercetin, by the way that substitution reaction occurs in 4 '-OH hydroxyl positions, are conducive to improve
It is water-soluble and fat-soluble, improves bioavilability, and this method principle is simple, and product yield is high.
The technical solution adopted by the present invention to solve the technical problems is:
A kind of synthetic method of the quercetin derivative by lauroyl chloride chemical modification, route of the present invention is to use Quercetin
And lauroyl chloride, the target compound directly reacted under the action of catalyst, the method specifically include following step
It is rapid:
S1, Quercetin and lauroyl chloride are added in a solvent, add suitable catalyst and acidity tune after mixing
Agent is saved, 8~10h is reacted under the conditions of the temperature of ice-water bath to room temperature；
S2, with acid by the reaction solution of step S1 be adjusted to pH be 6~7, be added suitable quantity of water, be extracted with ethyl acetate 3~4
It is secondary；
Water absorbing agent is added thereto after S3, each resulting organic layer of merging to stand overnight, then successively takes out reaction solution
It filters, be spin-dried for, purify, finally prepare liquid phase and purify quercetin derivative up to high-purity again, product yield is 77%~
80%, purity reaches 96%~98%, Rf=0.2~0.5.
Its reaction equation are as follows:
It should be noted that the resulting product of the present invention can decompose under strongly acidic conditions, if in the process for being adjusted with acid pH
In, it is added dropwise excessively, reaction solution color can compile clear, product decomposition.
Preferably, the molar ratio of the Quercetin, lauroyl chloride and catalyst is 1:1.25:0.3~1:4:5.
Preferably, solvent described in step S1 is anhydrous dimethyl sulphoxide, N ' dinethylformamide, anhydrous tetrahydro furan
Mutter, pyridine or toluene, the catalyst is potassium iodide or 4-dimethylaminopyridine, the acidity regulator be sodium carbonate or/and
Potassium carbonate, the temperature of the ice-water bath to room temperature are 0~30 DEG C.
Preferably, the purity of the Quercetin is 98%, the purity of the lauroyl chloride is 98%.
Preferably, acid described in step S2 is hydrochloric acid, the concentration of the hydrochloric acid is that 0.1mol/L or 5% hydrochloric acid are water-soluble
Liquid.
Preferably, water absorbing agent described in step S3 is anhydrous sodium sulfate or/and anhydrous magnesium sulfate, the purification process is adopted
Mobile phase with silica gel column chromatography, the preparation liquid phase is acetonitrile and pure water, flow velocity are 3~5mL/s.
The anhydrous sodium sulfate is graininess, and anhydrous magnesium sulfate is powdered.
Preferably, the eluant, eluent of the silica gel column chromatography is petrol ether/ethyl acetate mixed liquor or methylene chloride/methanol
The volume ratio of mixed liquor, the acetonitrile and pure water is 2:1~4:1.
It is furthermore preferred that the volume ratio of the petroleum ether and ethyl acetate in the petrol ether/ethyl acetate mixed liquor is
10:1~4:1, the volume ratio of the methylene chloride and methanol in the methylene chloride/methanol mixed liquor are 10:1~4:1.
The invention also discloses the quercetin derivative of synthetic method preparation, the quercetin derivative is 2- hydroxyl
Base -4- (3,5,7- trihydroxy -4- oxo -4H- chromene -2- base) phenyl-dodecane acid esters, structural formula are as follows:
Quercetin derivative of the invention is for treating hypertension, myocardial ischemia and cancer.
The beneficial effects of the present invention are:
Quercetin derivative provided by the invention it is fat-soluble far better than Quercetin, bioavilability has biggish mention
Height can be used for treating cardiovascular and cerebrovascular disease, anticancer and anti-cancer；Synthetic method provided by the invention is simple and easy, and product yield is high,
It is with a wide range of applications.
Specific embodiment
Explanation is further described to technical solution of the present invention below by embodiment.
Embodiment 1:
A kind of synthetic method of quercetin derivative, synthetic route is to use Quercetin and lauroyl chloride, in catalyst action
The target compound directly reacted down, the method specifically comprise the following steps:
S1, the anhydrous DMSO of 10mL is added in 100mL three-necked flask, Quercetin 151mg is then added, by 163.5mg ten
Diacid chloride is dissolved in the anhydrous DMSO of 3mL, slowly instills in reaction solution, and 18.6mg potassium iodide and 25mg potassium carbonate is added；It is true with diaphragm
Empty pumping vacuum, whole nitrogen protection, ice-water bath to room temperature shading react, and revolving speed 650rpm/min reacts 10h；
S2, reaction terminates plus 0.1mol/L HCL, and tune pH value is 6-7, and 30mL ethyl acetate and 10ml pure water, extraction is added
It takes, liquid separation, water layer continues to be extracted 2 times with 30mL ethyl acetate；
S3, merge and anhydrous magnesium sulfate is added thereto after resulting organic layer every time stands overnight, then by reaction solution according to
It is secondary to filter, be spin-dried for Rotary Evaporators, it then carries out 200~300 mesh silica gel column chromatographies and preparation liquid phase purifies up to Quercetin
Derivative.
Products obtained therefrom is 2- hydroxyl -4- (3,5,7- trihydroxy -4- oxo -4H- chromene -2- base) phenyl-dodecane acid
Ester, yield 79%, purity is up to 98%, Rf=0.382.
Embodiment 2:
A kind of synthetic method of quercetin derivative, synthetic route is to use Quercetin and lauroyl chloride, in catalyst action
The target compound directly reacted down, the method specifically comprise the following steps:
S1,10mL anhydrous DMF is added in 100mL three-necked flask, Quercetin 151mg is then added, by 272.5mg 12
Acyl chlorides is dissolved in 10mL anhydrous DMF, and 25mg potassium carbonate and 15.18mg triethylamine is added, is vacuumized with vacuum diaphragm pump, whole nitrogen
Protection, ice-water bath to room temperature shading react, and revolving speed 650rpm/min reacts 10h；
S2, reaction terminates plus 0.1mol/L HCL, and tune pH value is 6-7, and 30mL ethyl acetate and 10ml pure water, extraction is added
It takes, liquid separation, water layer continues to be extracted 2 times with 30mL ethyl acetate；
S3, merge and anhydrous sodium sulfate is added thereto after resulting organic layer every time stands overnight, then by reaction solution according to
It is secondary to filter, be spin-dried for Rotary Evaporators, it then carries out 200~300 mesh silica gel column chromatographies and preparation liquid phase purifies up to Quercetin
Derivative.
Products obtained therefrom is 2- hydroxyl -4- (3,5,7- trihydroxy -4- oxo -4H- chromene -2- base) phenyl-dodecane acid
Ester, yield 77%, purity is up to 97%, Rf=0.332.
Embodiment 3:
A kind of synthetic method of quercetin derivative, synthetic route is to use Quercetin and lauroyl chloride, in catalyst action
The target compound directly reacted down, the method specifically comprise the following steps:
S1, the anhydrous THF of 10mL is added in 100mL three-necked flask, Quercetin 151mg is then added, by 136.25mg ten
Diacid chloride is dissolved in the anhydrous THF of 10mL, slowly instills in reaction solution, and 25mg sodium carbonate and 15.18mg triethylamine is added, true with diaphragm
Empty pumping vacuum, whole nitrogen protection, ice-water bath to room temperature shading react, and revolving speed 650rpm/min reacts 10h；
S2, reaction terminates plus 0.1mol/L HCL, and tune pH value is 6-7, and 30mL ethyl acetate and 10ml pure water, extraction is added
It takes, liquid separation, water layer continues to be extracted 2 times with 30mL ethyl acetate；
S3, merge and anhydrous magnesium sulfate is added thereto after resulting organic layer every time stands overnight, then by reaction solution according to
It is secondary to filter, be spin-dried for Rotary Evaporators, it then carries out 200~300 mesh silica gel column chromatographies and preparation liquid phase purifies up to Quercetin
Derivative.
Products obtained therefrom is 2- hydroxyl -4- (3,5,7- trihydroxy -4- oxo -4H- chromene -2- base) phenyl-dodecane acid
Ester, yield 80%, purity is up to 96%, Rf=0.382.
Embodiment 4:
A kind of synthetic method of quercetin derivative, synthetic route is to use Quercetin and lauroyl chloride, in catalyst action
The target compound directly reacted down, the method specifically comprise the following steps:
S1,20mL toluene is added in 100mL three-necked flask, Quercetin 453mg is then added, by 319mg lauroyl chloride
It is dissolved in 10mL toluene, is slowly instilled in reaction solution, 25mg sodium carbonate and 183.2mg 4-dimethylaminopyridine is added, it is true with diaphragm
Empty pumping vacuum, whole nitrogen protection, ice-water bath to room temperature shading react, and revolving speed 650rpm/min reacts 10h；
S2, reaction terminates plus 0.1mol/L HCL, and tune pH value is 6-7, and 30mL ethyl acetate and 10ml pure water, extraction is added
It takes, liquid separation, water layer continues to be extracted 2 times with 30mL ethyl acetate；
S3, merge and anhydrous magnesium sulfate is added thereto after resulting organic layer every time stands overnight, then by reaction solution according to
It is secondary to filter, be spin-dried for Rotary Evaporators, it then carries out 200~300 mesh silica gel column chromatographies and preparation liquid phase purifies up to Quercetin
Derivative.
Products obtained therefrom is 2- hydroxyl -4- (3,5,7- trihydroxy -4- oxo -4H- chromene -2- base) phenyl-dodecane acid
Ester, yield 79%, purity is up to 98%, Rf=0.406.
Embodiment described above is preferred version of the invention, is not intended to limit the present invention in any form,
There are also other variants and remodeling on the premise of not exceeding the technical scheme recorded in the claims.
Claims (9)
1. a kind of synthetic method of the quercetin derivative by lauroyl chloride chemical modification, which is characterized in that the method packet
Include following steps:
S1, Quercetin and lauroyl chloride are added in a solvent, add suitable catalyst and acidity regulator after mixing,
8~10h is reacted under the conditions of the temperature of ice-water bath to room temperature；
S2, with acid by the reaction solution of step S1 be adjusted to pH be 6~7, be added suitable quantity of water, be extracted with ethyl acetate 3~4 times；
S3, merge to extract every time in step S2 and water absorbing agent is added thereto after resulting organic layer stands overnight, it then will reaction
Liquid is successively filtered, is spin-dried for, is purified, and prepares liquid phase finally up to the quercetin derivative of high-purity.
2. the synthetic method of quercetin derivative according to claim 1, which is characterized in that the Quercetin, lauroyl
The molar ratio of chlorine and catalyst is 1:1.25:0.3~1:4:5.
3. the synthetic method of quercetin derivative according to claim 1, which is characterized in that solvent described in step S1 is
Anhydrous dimethyl sulphoxide, N ' dinethylformamide, anhydrous tetrahydro furan, pyridine or toluene, the catalyst be potassium iodide or
4-dimethylaminopyridine, the acidity regulator are sodium carbonate or/and potassium carbonate, the temperature of the ice-water bath to room temperature is 0~
30℃。
4. the synthetic method of quercetin derivative according to claim 1, which is characterized in that the purity of the Quercetin is
98%, the purity of the lauroyl chloride is 98%.
5. the synthetic method of quercetin derivative according to claim 1, which is characterized in that acid described in step S2 is salt
Acid, the aqueous hydrochloric acid solution that the hydrochloric acid solution or volume fraction that the hydrochloric acid is 0.1mol/L are 5%.
6. the synthetic method of quercetin derivative according to claim 1, which is characterized in that water absorbing agent described in step S3
For anhydrous sodium sulfate or/and anhydrous magnesium sulfate, the purification process uses silica gel column chromatography, the mobile phase of the preparation liquid phase
It is 3~5mL/s for acetonitrile and pure water, flow velocity.
7. the synthetic method of quercetin derivative according to claim 6, which is characterized in that in the silica gel column chromatography
Eluant, eluent be petrol ether/ethyl acetate mixed liquor or methylene chloride/methanol mixed liquor, the volume ratio of the acetonitrile and pure water
For 2:1~4:1.
8. the synthetic method of quercetin derivative according to claim 7, which is characterized in that the petroleum ether/acetic acid second
The volume ratio of the petroleum ether and ethyl acetate in ester mixed liquor is 10:1~4:1, in the methylene chloride/methanol mixed liquor
The methylene chloride and methanol volume ratio be 10:1~4:1.
9. a kind of quercetin derivative of method preparation according to any one of claims 1 to 8, which is characterized in that the quercitrin
Plain derivative is 2- hydroxyl -4- (3,5,7- trihydroxy -4- oxo -4H- chromene -2- base) phenyl-dodecane acid esters, knot
Structure formula are as follows:
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110742863A (en) * | 2019-11-22 | 2020-02-04 | 青海民族大学 | Quercetin derivative nano micelle and preparation method thereof |
| CN115819390A (en) * | 2022-10-28 | 2023-03-21 | 晨光生物科技集团股份有限公司 | Preparation method of quercetagetin fat-soluble derivative |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110742863A (en) * | 2019-11-22 | 2020-02-04 | 青海民族大学 | Quercetin derivative nano micelle and preparation method thereof |
| CN110742863B (en) * | 2019-11-22 | 2022-04-12 | 青海民族大学 | Quercetin derivative nano micelle and preparation method thereof |
| CN115819390A (en) * | 2022-10-28 | 2023-03-21 | 晨光生物科技集团股份有限公司 | Preparation method of quercetagetin fat-soluble derivative |
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