CN102659735A - Quercetin-3-O-acyl ester and preparation method thereof - Google Patents
Quercetin-3-O-acyl ester and preparation method thereof Download PDFInfo
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Abstract
The invention relates to quercetin-3-O-acyl ester and a preparation method thereof and belongs to the technical field of pharmaceutical chemistry. The preparation method comprises the following steps: taking cheap rutin as a starting raw material and preparing a quercetin-3-O-acyl ester compound through benzylation, hydrolysis under the acidic conditions, esterification, catalytic hydrogenolysis and other reactions. The method has the characteristics of good selectivity, mild reaction condition, high yield, low cost, simplicity and convenience in operation, easiness in industrial production and the like. In addition, the inhibitory effect of the obtained quercetin-3-O-acyl ester on human esophageal squamous carcinoma cells EC9706, human prostatic cancer cells PC-3 and human gastric cancer cells MGC-803 is remarkably superior to that of quercetin; and the quercetin-3-O-acyl ester can be used in the field of foods and medicines and is possible to develop into a new candidate drug for treating tumor.
Description
Technical field
The invention belongs to the approximately materialization field that learns a skill, specifically, relate to the compound method of quercetin derivative.
Background technology
Quercetin (Quercetin) chemistry is by name 3,5,7,3 ', 4 '-pentahydroxyflavone, belong to the flavonols compound, be present in flower, leaf and the fruit of various plants.As be present in edible vegetables such as onion, capsicum, apple, grape and the fruit; The many herbal medicine such as the sophora bud, Wild Buckwheat Rhizome, taraxacum etc. all contain Quercetin (Agnes W.Boots, Guido R.M.M.Haenen, Aalt Bast., European Journal of Pharmacology, 2008,585:325-337; Bushra Sultana, Farooq Anwar., Food Chemistry, 2008,108:879-884.).Research shows, that Quercetin has is hypotensive, decreasing cholesterol, reducing blood-fat, effect such as anti-ageing, antiviral, antibiotic.And have stronger anti-oxidant and free radical scavenging function, it can stop effectively, and carcinogens becomes final carcinogens in the intravital activation of people in the environment, accelerates carcinogens in the intravital degraded of people, and promotes its discharge; Differentiation that can also inducing tumor cell; Promote apoptosis (Jan
Moskaug, Harald Carlsen, the Mari Myhrstad of tumour cell; Et al; Mechanisms of Ageing and Development, 2004,125:315-324; Trevor M.Kitson, Kathryn E.Kitson., Biochimica et Biophysica Acta, 2000,1481:247-254.).But because its lower bioavailability makes its application receive certain limitation.
In recent years, be lead compound with the Quercetin, it is done structural modification obtain various verivates, can obtain through screening active ingredients that some are active and approximately for all good than the Quercetin compound of kinetic property.She Ji etc. (Chinese pharmaceutical chemistry magazine, 1998,8:287-289.) prepared Quercetin-7-sodium sulfovinate and Quercetin-7,4 '-two kinds of water miscible compounds of di-sulfate disodium.Wu Xianxue etc. (Letters in Organic Chemistry, 2005,2:535-538.) from nonpolar hydrophobicity L-amino acid, 7 of Quercetins are done modification, prepared a series of 7-Quercetin amino amino manthanoate.(CN, 200810060140.2 [P] .2008-03-07 such as Peng You; The pharmaceutical Society of Japan; 2008,128:1845-1849.) 5 of Quercetins are done modification, synthesized 5-phenylsulfonyloxy Quercetin and in asked patent; The physiologically active that this method has improved compounds like quercetol has improved solvability.(J.Org.Chem.1992,57:5776-5778, Maria Teresa Gatto, Serena Falcocchio such as Maripaina Natoli; Eleonora Grippa, etal, Bioorganic&Medicinal Chemistry, 2002; 10:269-272.Lucia Montenegro, Claudia Carbone, Claudio Maniscalco; Et al, International Journal of Pharmaceutics, 2007; 2:257-262.) through enzyme catalysis method, selectivity has been synthesized a series of 3-O-Quercetin esters, and finds that they have good oxidization resistance and light-protection.But the enzyme that this method needs costs an arm and a leg, and is unfavorable for large-scale production, and reaction conditions requires harsh.He Huang etc. (European Journal of Medicinal Chemistry, 2009,44:1982-1988) synthesized Quercetin-3-O-amino acid ester, and found that it can become a kind of novel tyrosine kinase inhibitor.Yet these documents do not provide relevant antineoplastic activity.PJ.Mulholland etc. (Annals of Oncology, 2001,12:245-248.) synthesized 3 '-(N-ethyloic) formamyl-3; 4 ', 5,7-kaempferol (QC12); Though discover its water-soluble increase; Can be used as a kind of potential cancer therapy drug, but its stability is very poor, to such an extent as to the transformation period in blood is less than half a hour.And Mi Young Kim etc. (J.Med.Chem., 2010,53:8597-8607.) think that the oxidative degradation of Quercetin and metabolism are prone to occur in 3-OH and 7-OH, if connect the bioavailability that some suitable groups will help improving Quercetin in this site.
And the about thing of precursor can play good resistancing action for the secondary metabolism in the absorption process, thus help improving bioavailability of medicament (Lucia Biasutto, etal, J.Med.Chem.2007,50:241-253.).Therefore, selectivity is modified at Quercetin 3-OH, and synthetic 3-O-Quercetin ester might improve the bioavailability and the anti-tumor activity thereof of Quercetin.
Summary of the invention
The modifying method and the synthetic route that the purpose of this invention is to provide a kind of quercetin derivative.
These purposes of the present invention will further embody and set forth through following detailed description and explanation.
The invention provides the preparation of Quercetin-3-O-acyl ester, it is characterized in that, Quercetin-3-O-acyl ester has structure general formula (I):
Wherein, R is fatty acid acyl or aromatic acid acyl group or the 4-hetaroylpyrazol that contains 1～18 carbon atom.
Quercetin of the present invention-3-O-acyl ester, the preferred formyl radical of said fatty acid acyl, ethanoyl, propionyl group, butyryl radicals, oenanthyl, nonanoyl or octadecanoyl.
Quercetin of the present invention-3-O-acyl ester, the preferred benzoyl-of said aromatic acid acyl group, phenylacetyl, hydrocinnamoyl, to anisoyl, O-methoxy benzoyl-, adjacent acetoxy benzoyl, to acetoxy benzoyl, benzene oxygen ethanoyl, para hydroxybenzene formyl radical, p-benzoyl base, biphenyl ethanoyl, isobutyl-benzene propionyl group, to methyl benzoyl, asafoetide acyl group, o-methyl-benzene formyl radical or galloyl.
Quercetin of the present invention-3-O-acyl ester, the preferred furancarbonyl of said 4-hetaroylpyrazol, nicotinoyl, different nicotinoyl or tetrahydropyridine formyl radical.
Quercetin of the present invention-3-O-acyl ester can prepare according to the following steps:
The first step: with the rutin is raw material, adopt benzyl protection its 7,3`, 4` position hydroxyl, preparation tribenzyl rutin.
Second step: in ethanolic soln, use hydrochloric acid catalysis, rutinose is sloughed in hydrolysis, obtains the tribenzyl Quercetin.
The 3rd step: tribenzyl Quercetin and various acid prepare the Quercetin ester under DCC, DMAP condition.
The 4th step: under Pd-C catalysis, debenzylation obtains 3-Quercetin ester.
The preparation method of Quercetin of the present invention-3-O-acyl ester, described aprotic solvent is N, dinethylformamide or acetone.
The preparation method of Quercetin of the present invention-3-O-acyl ester, described alkali is NaOH, KOH, Na
2CO
3, K
2CO
3, among the NaH, pyridine, triethylamine one or more mix with arbitrary proportion.
The preparation method of Quercetin of the present invention-3-O-acyl ester, described mineral acid is a kind of in hydrochloric acid, sulfuric acid, phosphoric acid, the nitric acid.
Quercetin of the present invention-3-O-acyl ester; Through preliminary screening active ingredients; Its inhibition effect for people's esophageal squamous cell carcinoma cell EC9706, people's esophageal squamous cell carcinoma cell EC109, Human Prostate Cancer Cells PC-3, gastric carcinoma cells MGC-803 is superior to Quercetin; Can be used for field of medicaments, be expected to develop the medicine that becomes the treatment tumor disease.
Embodiment
1 laboratory apparatus and material
1.1 plant and instrument
Rotary Evaporators: RE-52AA, Shanghai Yarong Biochemical Instrument Plant; The circulation ability of swimming is used vacuum pump more: SHB-III, Zhengzhou Greatwall Scientific Industrial & Trading Co., Ltd.; Heat collecting type thermostatically heating magnetic stirring apparatus: DF-101S, the Ying Yu of Gongyi City gives magnificent instrument plant; Electric heating constant temperature air dry oven: 101-1, the Shanghai medical apparatus and instruments factory of making a leapleap forward.Ultraviolet-visible spectrophotometer: UV240, day island proper Tianjin company; IS10FT-IR type IR (U.S. Buddhist nun high-tensile strength); 400MHz NMR (Brucker); Esquire3000 mass spectrograph (Brucker).
1.2 medicine and reagent
Rutin: fragrant star Yongren, Henan is industry ltd approximately; Mono Chloro Acetic Acid, Anhydrous potassium carbonate, methylene dichloride: Tianjin chemical reagent three factories; Methyl alcohol, ethanol, trichloromethane, ETHYLE ACETATE, Glacial acetic acid min. 99.5, DMF, acetone: Tianjin Kermel Chemical Reagent Co., Ltd.; NSC 57182 (DCC), Dimethylamino pyridine (DMAP), Benzyl Chloride, cylite, palladium carbon: the brilliant pure Industrial Co., Ltd. in Shanghai.All the other reagent are analytical pure.
The preparation of 2 compounds
2.17,3`, 4`-O-tribenzyl Quercetin synthetic
Get rutin 2.44g (4.0mmol) and be dissolved among the 20mlDMF, add 1.93g (14.0mmol) Anhydrous potassium carbonate and stir, under the condition of ice bath; Slowly drip the fresh distillatory Benzyl Chloride of 1.6ml (14.0mmol); Slowly be warming up to room temperature, reaction stirred overnight (about 12h), the TLC detection reaction is complete.Add Glacial acetic acid min. 99.5 reaction solution transferred to pH6,, have a large amount of depositions to separate out again to wherein adding 200ml zero(ppm) water, after continuing to stir 1h, solids accumulation at the bottom of bottle, abandoning supernatant.In deposition, add 60ml 95% ethanol, heating in water bath to solid dissolves fully, disposable adding 10ml concentrated hydrochloric acid, and reflux begins to have yellow mercury oxide to produce behind the 15min, and the 1h afterreaction finishes.Cooling, refrigerator are placed and are spent the night, and filter, and oven dry gets bullion, and with trichloromethane/recrystallizing methanol, drying obtains yellow solid, productive rate 68%.M.p：188.3～190.1℃，
1HNMR(400MHz，DMSO)δ12.42(s，1H，5-OH)，9.72(s，1H，3-OH)，7.90(s，1H，2`-H)，7.85(d，J＝8.7Hz，1H，6`-H)，7.32～7.40(m，15H，3×OCH
2C
6H
5)，7.27(d，J＝8.8Hz，1H，5`-H)，6.87(d，J＝2.1Hz，1H，8-H)，6.46(d，J＝2.1Hz，1H，6-H)，5.25(s，4H，2×OCH
2C
6H
5)，5.21(s，2H，OCH
2C
6H
5).
IR(KBr)：3290，1651，1616，1593，1504，1455，1306，1258，997，749cm
-1
Embodiment 1: the preparation of Quercetin-3-O-acetic ester (3a)
7,3`, 4`-O-tribenzyl Quercetin-3-O-acetic ester synthetic
Take by weighing 1.144g (2mmol) tribenzyl Quercetin, be dissolved in the 40ml anhydrous methylene chloride, add 0.144g (2.4mmol) diacetyl oxide, stir adding DMAP 29mg (0.24mmol) down, stirring at room reaction 5h, the TLC detection reaction is complete.Reaction solution is used saturated sodium bicarbonate, Hydrogen chloride, saturated common salt water washing respectively 3 times, and anhydrous sodium sulfate drying reclaims solvent, obtains faint yellow solid, uses the chloroform-methanol recrystallization, and drying obtains faint yellow solid, productive rate 80%.
1H?NMR(400MHz，CDCl3)δ12.19(s，1H，5-OH)，7.48-7.30(m，17H，Ar-H)，7.01(d，J＝9.1Hz，1H，5`-H)，6.48(d，J＝2.2Hz，1H，8-H)，6.45(d，J＝2.2Hz，1H，6-H)，5.25(s，2H，OCH2C6H5)，5.21(s，2H，OCH2C6H5)，5.13(s，2H，OCH2C6H5)，2.25(s，3H，CH3CO-).
13C?NMR(101MHz，CDCl3)δ175.81，167.95，164.85，162.00，156.97，156.32，151.81，148.60，136.75，136.42，135.66，131.10，128.78，128.69，128.48，128.43，128.14，128.10，127.49，127.27，127.18，122.70，122.32，114.75，113.82，105.67，99.00，93.46，71.56，70.93，70.52，20.47.IR(KBr)：3440，3033，1758，1662，1610，1500，1454，1375，1254，1196，1009，739，697cm-1
The preparation of Quercetin-3-O-acetic ester
Get 7,3`, 4`-O-tribenzyl Quercetin-3-O-acetic ester 0.614g (1.0mmol) is dissolved in the methylene chloride mixed solvent, adds 5% Pd-C 0.213g, under the room temperature 0.4MPa pressure condition, hydrogenation reaction 6h, TLC monitoring reaction.After reaction finishes, filter, filtering Pd-C, the filtrate decompression distillating recovering solvent obtains solid, be eluent with chloroform-methanol (20: 1), and the mistake silicagel column obtains faint yellow solid, productive rate 36.0%, M.`p:196.6～198.2 ℃; ESI-MS:343 [M-H]
+ 1H NMR (400MHz, DMSO) δ 12.23 (s, 1H, 5-OH), 10.78 (s, 1H, 7-OH), 9.77 (s, 2H; 3`-OH, 4`-OH), 7.35 (d, J=2.2Hz, 1H, 2`-H), 7.29 (dd, J=8.4,2.2Hz; 1H, 6`-H), 6.93 (d, J=8.4Hz, 1H, 5`-H), 6.48 (d, J=1.9Hz, 1H; 8-H), 6.25 (d, J=1.9Hz, 1H, 6-H), 2.35 (s, 3H, CH3CO-).
13CNMR (101MHz, DMSO) δ 175.37,168.49, and 165.12,161.52,157.05,156.33; 149.78,145.95,130.05,120.98,120.06,116.49,115.39; 103.89,99.53,94.54,20.78.IR (KBr): 3327,1753,1651,1602; 1567,1489,1357,1306,1183,939,793cm
-1
Embodiment 2: the preparation of Quercetin-3-O-propionic ester (3b)
7,3`, 4`-O-tribenzyl Quercetin-3-O-propenoate synthetic
Take by weighing 1.144g (2mmol) tribenzyl Quercetin, be dissolved in the 40ml anhydrous methylene chloride, add 0.173g (2.4mmol) vinylformic acid; Stir and add DMAP 29mg (0.24mmol) down; Take by weighing 0.496g (2.4mmol) DCC and be dissolved in the anhydrous methylene chloride, slowly drip the dichloromethane solution of DCC under the condition of ice bath, slowly be warming up to room temperature after dropwising; Continue stirring reaction 5h, the TLC detection reaction is complete.Reaction solution is placed refrigerator cold-storage 1h, cross the DCU that filters out generation.Filtrating is used saturated sodium bicarbonate, Hydrogen chloride, saturated common salt water washing respectively 3 times, and anhydrous sodium sulfate drying reclaims solvent, obtains faint yellow solid, uses the chloroform-methanol recrystallization, and drying obtains faint yellow solid, productive rate 60%.
1H?NMR(400MHz，CDCl
3)δ12.21(s，1H，5-OH)，7.52-7.32(m，17H，Ar-H)，7.03(d，J＝8.9Hz，1H，5`-H)，6.68(d，J＝17.3Hz，1H，acrylic?acid?3-H)，6.53(d，J＝2.1Hz，1H，8-H)，6.48(d，J＝2.1Hz，1H，6-H)，6.37(d，J＝10.5Hz，1H，acrylic?acid?2-H)，6.09(d，J＝10.5Hz，1H，acrylic?acid?3-H)，5.26(s，2H，OCH
2C
6H
5)，5.22(s，2H，OCH
2C
6H
5)，5.16(s，2H，OCH
2C
6H
5).
13C?NMR(101MHz，CDCl
3)δ175.67，164.89，163.00，162.03，156.97，156.26，151.85，148.65，136.73，136.44，135.68，134.07，130.95，128.78，128.66，128.64，128.41，128.10，128.07，127.49，127.31，127.17，126.67，122.67，122.28，114.73，113.89，105.66，99.03，93.49，71.57，70.94，70.54.IR(KBr)：3386，3032，2931，1739，1661，1609，1499，1454，1376，1271，1195，1010，798，737，697cm
-1
Synthesizing of Quercetin-3-O-propionic ester
Get 7,3`, 4`-O-tribenzyl Quercetin-3-O-propenoate 0.627g (1.0mmol) is dissolved in the methylene chloride mixed solvent, adds 5% Pd-C 0.213g, under the room temperature 0.4MPa pressure condition, hydrogenation reaction 6h, TLC monitoring reaction.After reaction finishes, filter, filtering Pd-C, the filtrate decompression distillating recovering solvent obtains solid, be eluent with chloroform-methanol (20: 1), and mistake brick glue post obtains faint yellow solid, productive rate 38.0%, M.p:193.7～195.4 ℃; ESI-MS:357.0 [M-H]
+, 381.1 [M+Na]
+ 1H NMR (400MHz, DMSO) δ 12.22 (s, 1H, 5-OH), 11.04 (s, 1H, 7-OH), 9.96 (s, 1H, 3`-OH), 9.65 (s; 1H, 4`-OH), 7.33 (d, J=2.2Hz, 1H, 2`-H), 7.28 (dd, J=8.4,2.2Hz, 1H, 6`-H); 6.92 (d, J=8.4Hz, 1H, 5-H), 6.48 (d, J=2.0Hz, 1H, 8-H), 6.25 (d, J=2.0Hz; 1H, 6-H), 2.68 (q, J=7.5Hz, 2H, CH2COO), 1.15 (t, J=7.5Hz, 3H, CH3).
13C NMR (101MHz, MeOD) δ 175.78,172.06, and 164.84,161.58,157.19,156.88,148.95; 145.18,129.98,120.81,120.58,115.12,114.77,103.84,98.81; 93.73,26.68,7.85.IR (KBr): 3476,3127,1756,1654,1604; 1513,1454,13676,1286,1194,1086,792cm
-1
Embodiment 3: the preparation of Quercetin-3-O-benzoic ether (3c)
7,3`, 4`-O-tribenzyl Quercetin-3-O-benzoic ether synthetic
Take by weighing 1.144g (2mmol) tribenzyl Quercetin, be dissolved in the 40ml anhydrous methylene chloride, add 0.293g (2.4mmol) phenylformic acid; Stir and add DMAP 29mg (0.24mmol) down; Take by weighing 0.494g (2.4mmol) DCC and be dissolved in the anhydrous methylene chloride, slowly drip the dichloromethane solution of DCC under the condition of ice bath, slowly be warming up to room temperature after dropwising; Continue stirring reaction 7h, the TLC detection reaction is complete.Reaction solution is placed refrigerator cold-storage 1h, cross the DCU that filters out generation.Filtrating is used saturated sodium bicarbonate, Hydrogen chloride, saturated common salt water washing respectively 3 times, and anhydrous sodium sulfate drying reclaims solvent, obtains faint yellow solid; Use the chloroform-methanol recrystallization, drying, obtaining yellow solid is 7,3`; 4`-O-tribenzyl Quercetin-3-O-benzoic ether, productive rate 90%
1HNMR (400MHz, CDCl
3) δ 12.22 (s, 1H), 8.25 (d, 2H, Ar-H), 7.68 (d, J=7.5Hz, 1H, Ar-H), 7.57-7.33 (m; 19H, Ar-H), 6.99 (d, J=9.1Hz, 1H, 5`-H), 6.56 (d, J=2.2Hz, 1H; 8-H), 6.49 (d, J=2.2Hz, 1H, 6-H), 5.19 (d, J=14.8Hz, 4H, 2 * OCH
2C
6H
5), 5.01 (s, 2H, OCH
2C
6H
5).
13C NMR (101MHz, CDCl
3) δ 175.65,168.44,164.84,162.01,156.93,156.31,151.67,148.56,136.79,136.51; 135.67,132.78,131.20,129.54,128.77,128.71,128.69,128.61,128.42,128.12; 128.05,127.48,127.38,127.36,127.09,122.83,122.06,114.58,113.69; 105.64,98.99,93.46,71.51,70.88,70.53.IR (KBr): 3451,3033,2870,1742; 1661,1597,1500,1453,1377,1257,1194,735,697cm
-1
The preparation of Quercetin-3-O-benzoic ether
Get 7,3`, 4`-O-tribenzyl Quercetin-3-O-benzoic ether 0.677g (1mmol) is dissolved in the methylene chloride mixed solvent, adds 5% Pd-C 0.213g, hydrogenation reaction 6h under the normal temperature condition, TLC monitoring reaction.After reaction finishes, filter, filtering Pd-C, the filtrate decompression distillation obtains solid with receiving solvent, be eluent with chloroform-methanol (20: 1), silicagel column, obtain faint yellow solid, productive rate 81%, M.p:220.4～222.1 ℃; ESI-MS:407 [M+H]
+ 1H NMR (400MHz, DMSO) δ 12.17 (s, 1H, 5-OH), 11.00 (s, 1H, 7-OH), 9.88 (s, 1H, 3`-OH), 9.57 (s, 1H; 4`-OH), 8.20-8.11 (m, 2H, Ar-H), 7.78 (d, J=7.5Hz, 1H, Ar-H), 7.63 (t, J=7.8Hz, 2H; Ar-H), 7.38 (d, J=2.2Hz, 1H, 2`-H), 7.32 (dd, J=8.4,2.2Hz, 1H, 6`-H), 6.87 (d; J=8.4Hz, 1H, 5`-H), 6.52 (d, J=2.0Hz, 1H, 8-H), 6.28 (d, J=2.0Hz, 1H, 6-H).
13C NMR (101MHz, CDCl
3) δ 179.98,169.95,168.59,166.32,161.91,161.58,154.56,150.71; 139.74,135.29,135.05,134.40,133.08,125.75,124.81,121.10; 120.36,108.69,104.38,99.40.1R (KBr): 3327,1698,1656,1602,1506; 1443,1363,1275,1175,987,805,707cm
-1
Embodiment 4: the preparation of Quercetin-3-O-acetylsalicylate (3d)
7,3`, 4`-O-tribenzyl Quercetin-3-O-acetylsalicylate synthetic
Take by weighing Xaxa 0.44g (2.4mmol) and be dissolved in anhydrous methylene chloride; Stir and to add DCC 0.496g (2.4mmol) down, DMAP29mg (0.24mmol), the solution muddiness that is white in color; Add tribenzyl Quercetin 1.144g (2mmol) under the condition of ice bath; Slowly be warming up to room temperature, continue stirring reaction 5h, the TLC detection reaction is complete.Reaction solution is placed refrigerator cold-storage 1h, cross the DCU that filters out generation.Filtrating is used saturated sodium bicarbonate, Hydrogen chloride, saturated common salt water washing respectively 3 times, and anhydrous sodium sulfate drying reclaims solvent, obtains faint yellow solid; Use the chloroform-methanol recrystallization, drying, obtaining faint yellow solid is 7; 3`, 4`-O-tribenzyl Quercetin-3-O-acetylsalicylate, productive rate 66%.
1H?NMR(400MHz，DMSO)δ12.14(s，1H，5-OH)，7.59-7.32(m，21H，Ar-H)，7.29(d，J＝8.7Hz，1H，5`-H)，6.91(d，J＝2.1Hz，1H，8-H)，6.55(d，J＝2.1Hz，1H，6-H)，5.26(s，4H，2×OCH
2C
6H
5)，5.23(s，2H，OCH
2C
6H
5)，2.30(s，3H，OOCCH
3).
13C?NMR(101MHz，CDCl
3)δ175.81，167.95，164.85，162.00，156.97，156.32，151.81，148.60，136.75，136.42，135.66，131.10，128.78，128.69，128.48，128.43，128.14，128.10，127.49，127.27，127.18，122.70，122.32，114.75，113.82，105.67，99.00，93.46，71.56，70.93，70.52.IR(KBr)：3443，3033，2930，1753，1661，1608，1499，1453，1375，1272，1192，1011，811，737，696cm
-1
The preparation of Quercetin-3-O-acetylsalicylate
Get 7,3`, 4`-O-tribenzyl Quercetin-3-O-acetylsalicylate 0.440g (0.5mmol) is dissolved in the methylene chloride mixed solvent, adds 5% Pd-C 0.106g, hydrogenation reaction 6h under the normal temperature condition, TLC monitoring reaction.After reaction finishes, filter, filtering Pd-C, the filtrate decompression distillating recovering solvent obtains solid, is eluent with chloroform-methanol (20: 1), crosses brick glue post, obtains faint yellow solid, productive rate 80%.M.p：175.6～177.8℃；ESI-MS：463.0[M-H]
+，487.2[M+Na]
+；
1H?NMR(400MHz，DMSO)δ12.15(s，1H，5-OH)，11.06(s，1H，7-OH)，9.95(s，1H，3`-OH)，9.47(s，1H，4`-OH)，8.24(d，J＝7.8Hz，1H，Ar-H)，7.87-7.76(m，1H，Ar-H)，7.54(t，J＝7.6Hz，1H，Ar-H)，7.36(d，J＝4.2Hz，1H，Ar-H)，7.35(s，1H，2`-H)，7.26(dd，J＝8.4，2.1Hz，1H，6`-H)，6.86(d，J＝8.4Hz，1H，5`-H)，6.52(d，J＝1.9Hz，1H，8-H)，6.28(d，J＝1.9Hz，1H，6-H)，2.17(s，3H，COCH
3).
13C?NMR(101MHz，DMSO)δ175.06，169.49，165.19，161.53，161.48，157.13，156.85，151.51，149.85，146.02，136.10，132.52，130.05，127.19，125.16，121.47，121.04，119.96，116.29，115.58，103.91，99.63，94.64，21.05.IR(KBr)：3396，1743，1655，1606，1500，1450，1358，1250，1196，1036，754，696cm
-1
Embodiment 5: the preparation of Quercetin-3-O-butyric ester (3e)
7,3`, 4`-O-tribenzyl Quercetin-3-O-butyric ester synthetic, the preparation method is the same.Productive rate 88%.
1H?NMR(400MHz，CDCl
3)δ12.24(s，1H，5-OH)，7.57-7.31(m，17H，Ar-H)，7.02(d，J＝8.8Hz，1H，5`-H)，6.52(d，J＝2.1Hz，1H，8-H)，6.48(d，J＝2.1Hz，1H，6-H)，5.27(s，2H，OCH
2C
6H
5)，5.23(s，2H，OCH
2C
6H
5)，5.16(s，2H，OCH
2C
6H
5)，2.54(t，J＝7.4Hz，2H，CH3CH2*CH2COO)，1.78(q，2H，CH3*CH2CH2COO)，1.08-0.96(m，3H，*CH3CH2CH2COO).
13C?NMR(101MHz，CDCl
3)δ175.87，170.65，164.82，162.04，156.99，156.30，151.79，148.65，136.77，136.45，135.70，131.17，128.77，128.66，128.64，128.40，128.11，128.09，127.48，127.33，127.18，122.77，122.45，114.96，113.88，105.70，98.96，93.45，77.36，77.04，76.72，71.65，70.96，70.52，35.67，18.34，13.61.IR(KBr)：3446，2932，2874，1753，1663，1613，1514，1455，1378，1289，1197，996，811，699cm
-1
The preparation of Quercetin-3-O-butyric ester, the preparation method is the same.Productive rate 54%, M.p:206.6～208.5 ℃; ESI-MS:373.1 [M+H]
+, 395.1 [M+Na]
+ 1H NMR (400MHz, DMSO) δ 12.24 (s, 1H, 5-OH), 11.02 (s, 1H, 7-OH), 9.91 (s, 1H, 3`-OH); 9.55 (s, 1H, 4`-OH), 7.33 (d, J=1.3Hz, 1H, 2`-H), 7.27 (dd, J=8.4,2.2Hz; 1H, 6`-H), 6.91 (d, J=8.4Hz, 1H, 5`-H), 6.48 (d, J=2.0Hz, 1H; 8-H), 6.25 (d, J=2.0Hz, 1H, 6-H), 2.63 (t, J=7.2Hz, 2H, CH3CH2*CH2COO); 1.66 (dd, J=14.6,7.3Hz, 2H, CH3*CH2CH2COO), 0.95 (t, J=7.4Hz, 3H, * CH3CH2CH2COO).
13(101MHz, DMSO) δ 175.41,170.91,165.07,161.55,157.06,156.46,149.72,145.93,130.03,120.98,120.09,116.39,115.48,103.92,99.51,94.53,35.41,18.33,13.77. for C NMR
IR(KBr)：3372，3073，2968，2878，1750，1735，1597，1533，1449，1377，1295，1197，993，846，603cm
-1
Embodiment 6: the preparation of Quercetin-3-O-valerate (3f)
7,3`, 4`-O-tribenzyl Quercetin-3-O-valerate synthetic, the preparation method is the same.Productive rate 89%
1H NMR (400MHz, CDCl
3) δ 12.24 (s, 1H, 5-OH), 7.52-7.32 (m, 17H, Ar-H), 7.03 (d, J=9.0Hz, 1H, 5`-H), 6.51 (d, J=2.2Hz, 1H, 8-H), 6.47 (d, J=2.2Hz, 1H, 6-H), 5.27 (s, 2H, OCH
2C
6H
5), 5.23 (s, 2H, OCH
2C
6H
5), 5.16 (s, 2H, OCH
2C
6H
5), 2.57 (t, J=7.5Hz, 2H, CH2COO), 1.79-1.67 (m, 2H, CH2CH2COO), 1.41 (q, 2H, CH2CH2CH2COO), 0.95 (t, J=7.4Hz, 3H, CH3).
13C?NMR(101MHz，CDCl
3)δ175.87，170.84，164.80，162.01，156.98，156.30，151.75，148.61，136.74，136.44，135.68，131.16，128.78，128.67，128.65，128.42，128.12，128.10，127.50，127.33，127.17，122.76，122.41，114.86，113.78，105.69，98.96，93.44，71.61，70.93，70.51，33.55，26.81，22.18，13.74.
1R(KBr)：3442，2930，2870，1754，1661，1610，1515，1454，1377，1271，1197，1021，811，732，695cm
-1
Synthesizing of Quercetin-3-O-valerate, the preparation method is the same.Productive rate 62%, M.p:209.6～211.5 ℃; ESI-MS:385.0 [M-H]
+ 1H NMR (400MHz, DMSO) δ 12.23 (s, 1H, 5-OH), 11.03 (s, 1H, 7-OH), 9.91 (s, 1H.3`-OH), 9.54 (s; 1H, 4`-OH), 7.32 (d, J=2.2Hz, 1H, 2`-H), 7.26 (dd, J=8.4,2.2Hz, 1H; 6`-H), 6.91 (d, J=8.4Hz, 1H, 5`-H), 6.48 (d, J=2.0Hz, 1H, 8-H), 6.25 (d; J=2.0Hz, 1H, 6-H), 2.64 (t, J=7.3Hz, 2H CH3CH2CH2*CH2COO), 1.68-1.56 (m, 2H, CH3CH2*CH2CH2COO); 1.35 (dd, J=15.0,7.5Hz, 2H, CH3*CH2CH2CH2COO), 0.89 (t, J=7.3Hz, 3H, * CH3CH2CH2CH2COO).
13C?NMR(101MHz，DMSO)δ175.41，171.02，165.07，161.54，157.06，156.48，149.72，145.93，130.03，120.98，120.07，116.37，115.48，103.92，99.51，94.53，33.28，26.85，21.93，14.04.
IR(KBr)：3416，3301，2961，2864，1748，1659，1614，1513，1444，1358，1239，1196，1002，850，594cm
-1
Embodiment 7: the preparation of Quercetin-3-O-heptanoate (3g)
7,3`, 4`-O-tribenzyl Quercetin-3-O-heptanoate synthetic, the preparation method is the same.Productive rate 92%
1H NMR (400MHz, CDCl
3) δ 12.24 (s, 1H, 5-OH), 7.52-7.31 (m, 17H, Ar-H), 7.03 (d, J=8.9Hz, 1H, 5`-H), 6.51 (d, J=2.2Hz, 1H, 8-H), 6.47 (d, J=2.2Hz, 1H, 6-H), 5.27 (s, 2H, OCH
2C
6H
5), 5.23 (s, 2H, OCH
2C
6H
5), 5.16 (s, 2H, OCH
2C
6H
5), 2.55 (d, J=7.6Hz, 2H, CH2COO), 1.76-1.70 (m, 2H, CH2CH2COO), 1.39-1.29 (m, 6H, (CH2) 3), 0.90 (t, J=6.9Hz, 3H, CH3).
13C?NMR(101MHz，CDCl
3)δ175.87，170.86，164.80，162.01，156.97，156.30，151.76，148.61，136.74，136.44，135.68，131.16，128.78，128.67，128.65，128.42，128.12，128.10，127.50，127.33，127.17，122.76，122.41，114.84，?113.75，105.69，98.96，93.43，71.60，70.92，70.51，33.85，31.44，28.72，24.75，22.48，14.05.
IR(KBr)：3442，3032，2927，2853，1758，1662，1610，1514，1454，1377，1271，1196，995，733，696cm
-1
Synthesizing of Quercetin-3-O-heptanoate, the preparation method is the same.Productive rate 43%, M.p:195.9～197.1 ℃; ESI-MS:413.2 [M-H]
+, 437.1 [M+Na]
+ 1H NMR (400MHz, DMSO) δ 12.24 (s, 1H, 5-OH), 10.98 (s, 1H, 7-OH), 9.90 (s, 1H, 3`-OH); 9.56 (s, 1H, 4`-OH), 7.32 (d, J=2.1Hz, 1H, 2`-H), 7.26 (dd, J=8.4,2.1Hz; 1H, 6`-H), 6.91 (d, J=8.4Hz, 1H, 5`-H), 6.47 (d, J=1.9Hz, 1H, 8-H); 6.25 (d, J=1.9Hz, 1H, 6-H), 2.63 (t, J=7.3Hz, 2H, CH2COO), 1.70-1.56 (m; 2H, CH2CH2COO), 1.36-1.17 (m, 6H, (CH2) 3), 0.85 (t, J=6.6Hz, 3H, CH3).
13C?NMR(101MHz，DMSO)δ175.41，171.02，165.07，161.55，157.05，156.48，149.73，145.93，130.03，120.98，120.06，116.33，115.48，103.92，99.50，94.52，33.57，31.33，28.43，24.74，22.42，14.33.
IR(KBr)：3304，2930，2857，1745，1658，1612，1513，1443，1357，1275，1196，1002，850cm
-1
Embodiment 8: the preparation of Quercetin-3-O-pelargonic esternonate (3h)
7,3`, 4`-O-tribenzyl Quercetin-3-O-pelargonic esternonate synthetic, the preparation method is the same.Productive rate 85%
1H NMR (400MHz, CDCl
3) δ 12.24 (s, 1H, 5-OH), 7.58-7.32 (m, 17H, Ar-H), 7.03 (d, J=9.1Hz, 1H, 5`-H), 6.51 (d, J=2.2Hz, 1H, 8-H), 6.47 (d, J=2.2Hz, 1H, 6-H), 5.27 (s, 2H, OCH
2C
6H
5), 5.23 (s, 2H, OCH
2C
6H
5), 5.16 (s, 2H, OCH
2C
6H
5), 2.56 (t, J=7.5Hz, 2H, CH2COO), 1.81-1.67 (m, 2H, CH2CH2COO), 1.42-1.21 (m, 10H, (CH2) 5), 0.90 (t, J=6.8Hz, 3H, CH3).
13C?NMR(101MHz，CDCl
3)δ175.87，170.86，164.80，162.01，156.97，156.29，151.76，148.61，136.74，136.43，135.68，131.17，128.78，128.67，128.65，128.42，128.12，128.10，127.50，127.33，127.17，122.76，122.41，114.83，113.76，105.69，98.95，93.43，71.60，70.92，70.51，33.86，31.82，29.23，29.13，29.07，24.80，22.67，14.13.IR(KBr)：3449，2931，2853，1757，1663，1610，1509，1455，1377，1270，1195，994，814，696cm
-1
Synthesizing of Quercetin-3-O-pelargonic esternonate, the preparation method is the same.Productive rate 76%, M.p:197.3～198.7 ℃; 441 [M-H]
+, ESI-MS:443 [M+H]
+ 1H NMR (400MHz, DMSO) δ 12.25 (s, 1H, 5-OH), 10.95 (s, 1H, 7-OH), 9.96 (s, 1H, 3`-OH); 9.61 (s, 1H, 4`-OH), 7.33 (d, J=2.2Hz, 1H, 2`-H), 7.26 (dd, J=8.4,2.2Hz; 1H, 6`-H), 6.91 (d, J=8.4Hz, 1H, 5`-H), 6.47 (d, J=2.0Hz, 1H, 6-H); 6.25 (d, J=2.0Hz, 1H, 8-H), 2.63 (t, J=7.3Hz, 2H, CH2COO), 1.70-1.56 (m, 2H; CH2CH2COO), 1.27 (dd, J=20.9,9.8Hz, 10H, (CH2) 5), 0.84 (t, J=6.8Hz, 3H, CH3).
13C NMR (101MHz, DMSO) δ 175.41,171.00, and 165.08,161.56,157.05,156.45,149.74,145.93,130.04; 120.97,120.06,116.33,115.46,103.91,99.50,94.51,33.57,31.67,29.08; 29.02,28.76,24.78,22.55,14.42.IR (KBr): 3415,3302,2926,2855,1746,1659; 1614,1513,1444,1359,1240,1196,1002,851,668cm
-1
Embodiment 9: the preparation of Quercetin-3-O-stearate (3i)
7,3`, 4`-O-tribenzyl Quercetin-3-O-be synthesizing of resin acid ester just, and the preparation method is the same.Productive rate 81%.
1H?NMR(400MHz，CDCl
3)δ12.25(s，1H，5-OH)，7.51(s，1H，2`-H)，7.49(s，1H，6`-H)，7.49-7.33(m，15H，3×OCH
2C
6H
5)，7.03(d，J＝7.1Hz，1H，5`-H)，6.52(d，J＝2.2Hz，1H，8-H)，6.48(d，J＝2.2Hz，1H，6-H)，5.27(s，2H，OCH
2C
6H
5)，5.23(s，2H，OCH
2C
6H
5)，5.16(s，2H，OCH
2C
6H
5)，2.57(s，2H，-CH
2COO-)，1.82-1.68(m，2H，-CH
2CH
2COO-)，1.24-1.42(m，J＝19.3Hz，28H，14×CH
2)，0.92(t，J＝6.8Hz，3H，CH
3).
13C?NMR(101MHz，CDCl
3)δ175.86，170.83，164.82，162.04，156.98，156.26，151.82，148.67，136.78，136.47，135.73，131.21，128.76，128.66，128.64，128.39，128.11，128.08，127.48，127.35，127.19，122.77，122.47，114.93，113.84，105.70，98.96，93.44，71.65，70.96，70.51，33.87，31.95，29.73，29.49，29.39，29.30，29.10，24.82，22.72，14.14.IR(KBr)：3443，2921，2851，1758，1665，1611，1501，1453，1376，1271，1195，810，731，694cm
-1
The preparation method of Quercetin-3-O-stearate is the same, productive rate 70%.M.p：208.3～210.6℃；ESI-MS：600[M+H]
+；
1H?NMR(400MHz，DMSO)δ12.24(s，1H，5-OH)，10.98(s，1H，7-OH)，9.83(s，1H，3`-OH)，9.52(s，1H，4`-OH)，7.33(d，J＝2.1Hz，1H，2`-H)，7.26(dd，J＝8.4，2.1Hz，1H，6`-H)，6.90(d，J＝8.4Hz，1H，5`-H)，6.47(d，J＝1.8Hz，1H，8-H)，6.25(d，J＝1.8Hz，1H，6-H)，2.62(t，J＝7.2Hz，2H，-CH
2COO-)，1.62(d，J＝7.4Hz，2H，-CH
2CH
2COO-)，1.49-1.09(m，28H，14×CH
2)，0.83(t，J＝6.7Hz，3H，CH
3).
13C?NMR(101MHz，DMSO)δ175.41，170.93，165.08，161.60，157.05，156.42，149.74，145.95，130.08，120.93，120.10，116.32，115.47，103.93，99.49，94.48，33.60，31.77，29.54，29.50，29.41，29.32，29.20，24.78，22.56，14.36.IR(KBr)：3395，2981，2904，1719，1682，1606，1527，1440，1367，1288，1182，846，771，700cm
-1
Embodiment 10: the preparation of Quercetin-3-O-phenylacetate (3j)
7,3`, 4`-O-tribenzyl Quercetin-3-O-phenylacetate synthetic, the preparation method is the same.Productive rate 79%
1H?NMR(400MHz，CDCl
3)δ12.22(s，1H，5-OH)，7.48-7.30(m，21H，Ar-H)，7.15(d，J＝8.6Hz，1H，6`-H)，6.76(d，J＝8.6Hz，1H，5`-H)，6.50(d，J＝2.2Hz，1H，8-H)，6.48(d，J＝2.2Hz，1H，6-H)，5.24(s，2H，OCH
2C
6H
5)，5.15(s，2H，OCH
2C
6H
5)，5.12(s，2H，OCH
2C
6H
5)，3.91(s，2H，PhCH
2)
13C?NMR(101MHz，CDCl
3)δ175.80，164.90，163.80，162.04，157.00，156.23，151.79，148.60，136.58，136.40，135.69，134.17，131.28，130.58，128.80，128.78，128.62，128.53，128.42，128.36，128.07，127.99，127.51，127.26，127.14，122.61，122.32，114.59，113.89，105.71，99.03，93.51，71.38，70.87，70.55，30.93.IR(KBr)：3446，3033，2930，1761，1661，1608，1498，1454，1377，1271，1194，994，805，735，696cm
-1
The preparation of Quercetin-3-O-phenylacetate, the preparation method is the same.Productive rate 64%, M.p:197.3～199.6 ℃; ESI-MS:421 [M+H]
+ 1H NMR (400MHz, MeOD) δ 7.27 (m, 6H, Ar-H), 7.00 (dd, J=8.4,2.2Hz, 1H, 6`-H), 6.66 (d, J=8.4Hz, 1H, 5`-H), 6.37 (d, J=2.1Hz, 1H, 8-H), 6.19 (d, J=2.1Hz, 1H, 6-H), 3.92 (s, 2H, PhCH
2).
13C NMR (101MHz, MeOD) δ 175.63,169.22, and 164.88,161.66,157.20,156.95,148.90; 145.23,133.11,130.11,129.32,128.25,126.95,120.96; 120.37,115.06,114.59,103.84,98.80,93.69,39.99.
IR(KBr)：3488，3033，2870，1748，1654，1605，1514，1455，1368，1287，1194，790，735cm
-1
Embodiment 11: the preparation of Quercetin-3-O-Phenpropionate (3k)
7,3`, 4`-O-tribenzyl Quercetin-3-O-Phenpropionate synthetic, the preparation method is the same.Productive rate 81%
1H?NMR(400MHz，CDCl
3)δ12.23(s，1H，5-OH)，7.51-7.29(m，17H，Ar-H)，7.21-7.25(m，4H，Ar-H)，6.95(d，J＝8.6Hz，1H，5`-H)，6.52(d，J＝2.2Hz，1H，8-H)，6.48(d，J＝2.2Hz，1H，6-H)，5.27(s，2H，OCH
2C
6H
5)，5.19(s，2H，OCH
2C
6H
5)，5.16(s，2H，OCH
2C
6H
5)，3.05(d，J＝7.9Hz，2H，CH
2CH
2COOH)，2.89(s，2H，CH
2COOH).
13C?NMR(101MHz，DMSO)δ171.03，165.33，160.09，157.26，152.22，151.62，147.00，143.85，135.26，131.96，131.67，130.91，126.35，124.04，123.94，123.89，123.83，123.68，123.58，123.38，123.34，122.74，122.55，122.39，121.67，117.99，117.48，110.01，109.01，100.92，94.25，88.72，66.83，66.14，65.78，30.60，25.87.
IR(KBr)：3441，3031，2929，1759，1662，1611，1594，1512，1453，1377，1254，1198，809，736，695cm
-1
The preparation of Quercetin-3-O-Phenpropionate, the preparation method is the same.Productive rate 66%, M.p:187.1～189.5 ℃; ESI-MS:435 [M+H]
+ 1H NMR (400MHz, DMSO) δ 12.23 (s, 1H, 5-OH), 11.01 (s, 1H, 7-OH), 9.87 (s, 1H, 3`-OH), 9.58 (s, 1H; 4`-OH), 7.36 (d, J=2.2Hz, 1H, 2`-H), 7.29 (s, 1H, Ar-H), 7.28 (s, 3H, Ar-H), 7.23 (d; J=2.1Hz, 1H, Ar-H), 7.21 (d, J=2.2Hz, 1H, 6`-H), 6.88 (d, J=8.4Hz, 1H, 5`-H), 6.48 (d; J=2.0Hz, 1H, 8-H), 6.26 (d, J=2.0Hz, 1H, 6-H), 2.98 (dd, J=10.2,5.6Hz, 4H, PhCH
2CH
2COO).
13C?NMR(101MHz，DMSO)δ175.35，170.38，165.11，161.54，157.06，156.47，149.77，145.96，140.41，130.01，128.82，128.69，126.66，121.05，119.99，116.45，115.48，103.91，99.54，94.56，34.79，30.32.IR(KBr)：3373，1762，1654，1604，1497，1443，1356，1296，1196，993，736，697cm
-1
Embodiment 12: Quercetin-3-O-is to the preparation of acetoxy-benzoic acid ester (31)
7,3`, 4`-O-tribenzyl Quercetin-3-O-is synthetic to the acetoxy-benzoic acid ester, and the preparation method is the same.Productive rate 51%
1H?NMR(400MHz，CDCl
3)δ12.18(s，1H，5-OH)，8.26(d，J＝8.8Hz，2H，Ar-H，)，7.28～7.54(m，19H，Ar-H)，6.98(d，J＝9.2Hz，1H，5`-H)，6.54(d，J＝2.2Hz，1H，8-H)，6.48(d，J＝2.2Hz，1H，6-H)，5.21(s，2H，OCH
2C
6H
5)，5.16(s，2H，OCH
2C
6H
5)，5.07(s，2H，OCH
2C
6H
5)，2.36(s，3H，COCH
3).
13C?NMR(101MHz，CDCl
3)δ175.70，168.68，164.90，163.02，162.04，156.99，156.31，155.27，151.84，148.64，136.61，136.39，135.67，132.22，131.25，128.79，128.64，128.57，128.44，128.07，128.00，127.51，127.27，127.16，125.83，122.69，122.21，122.09，114.59，113.89，105.68，99.03，93.51，71.49，70.86，70.56，21.20.
IR(KBr)：3454，3032，2940，1739，1660，1599，1500，1454，1375，1255，1190，1012，818，750，695cm
-1
Quercetin-3-O-is synthetic to the acetoxy-benzoic acid ester, and the preparation method is the same.Productive rate 81%, M.p:178.5～180.1 ℃; ESI-MS:465.1 [M+H]
+, 463.3 [M-H]
+ 1H NMR (400MHz, DMSO) δ 12.16 (d, J=5.7Hz, 1H, 5-OH), 11.07 (s, 1H, 7-OH), 9.90 (s, 1H, 3`-OH), 9.53 (s; 1H, 4`-OH), 8.21 (d, J=8.7Hz, 2H, Ar-H), 7.41 (d, J=8.7Hz, 2H, Ar-H), 7.37 (d; J=2.0Hz, 1H, 2`-H), 7.32 (dd, J=8.4,2.1Hz, 1H, 6`-H), 6.88 (d, J=8.4Hz, 1H; 5`-H), 6.52 (d, J=2.0Hz, 1H, 6-H) 628 (d, J=2.0Hz, 1H, 8-H), 2.34 (s, 3H, OC*CH3).
13C?NMR(101MHz，DMSO)δ175.16，169.27，165.21，163.17，161.55，157.15，156.81，155.63，149.84，145.97，132.31，130.29，125.79，123.23，121.02，120.02，116.40，115.58，103.91，99.64，94.66，21.38.
1R(KBr)：3416，1740，1655，1604，1504，1444，1358，1266，1194，1015cm
-1
Embodiment 13: the preparation of Quercetin-3-O-o-methoxybenzoic acid ester (3m)
7,3`, 4`-O-tribenzyl Quercetin-3-O-o-methoxybenzoic acid ester synthetic, the preparation method is the same.Productive rate 73%
1H?NMR(400MHz，CDCl
3)δ12.29(s，1H，5-OH)，8.17(dd，J＝7.8，1.7Hz，1H，Ar-H)，7.65-7.31(m，18H，Ar-H)，7.13-7.02(m，2H，Ar-H)，7.00(d，J＝8.5Hz，1H，5`-H)，6.55(d，J＝2.1Hz，1H，8-H)，6.48(d，J＝2.1Hz，1H，6-H)，5.23(s，2H，OCH
2C
6H
5)，5.17(s，2H，OCH
2C
6H
5)，5.06(s，2H，OCH
2C
6H
5)，3.91(s，3H，OCH3).
13C?NMR(101MHz，CDCl
3)δ175.93，164.79，162.65，162.04，160.39，157.00，156.15，151.68，148.54，136.71，136.49，135.72，135.09，133.05，131.34，128.78，128.63，128.53，128.41，128.04，128.00，127.53，127.41，127.13，122.76，122.52，120.39，117.53，114.87，113.84，112.30，105.74，98.91，93.42，71.43，70.87，70.53，56.06.
IR(KBr)：3423，3033，2931，1746，1661，1598，1491，1454，1377，1255，1190，1008，751，695cm
-1
Synthesizing of Quercetin-3-O-o-methoxybenzoic acid ester, the preparation method is the same.Productive rate 41%, M.p:153.2～155.1 ℃; ESI-MS:435.1 [M-H]
+, 459.1 [M+Na]
+ 1H NMR (400MHz, DMSO) δ 12.24 (s, 1H, 5-OH), 11.06 (s, 1H, 7-OH), 9.93 (s, 1H, 3`-OH), 9.51 (s, 1H; 4`-OH), 7.98 (dd, J=7.8,1.7Hz, 1H, Ar-H), 7.75-7.64 (m, 1H, Ar-H), 7.47-7.34 (m, 2H, Ar-H); 7.25 (d, J=8.4Hz, 1H, 2`-H), 7.12 (t, J=7.5Hz, 1H, 6`-H), 6.90 (d, J=8.4Hz, 1H, 5`-H); 6.52 (d, J=2.0Hz, 1H, 8-H), 6.28 (d, J=2.0Hz, 1H, 6-H), 3.88 (s, 3H, OCH3).
13C?NMR(101MHz，DMSO)δ175.43，165.12，162.70，161.58，159.99，157.13，156.71，149.75，145.92，135.77，132.59，130.28，121.16，120.74，120.22，117.55，116.22，115.78，113.35，103.95，99.55，94.57，56.36.IR(KBr)：3362，1734，1654，1601，1490，1437，1358，1293，1191，1021，754，668cm
-1
Embodiment 14: the preparation of Quercetin-3-O-anisic acid ester (3n)
7,3`, 4`-O-tribenzyl Quercetin-3-O-anisic acid ester synthetic, the preparation method is the same.Productive rate 88%
1H?NMR(400MHz，CDCl
3)δ12.25(s，1H，5-OH)，8.15(d，J＝8.2Hz，2H，Ar-H)，7.55(s，2H，Ar-H)，7.49-7.30(m，17H，Ar-H)，6.99(d，J＝9.2Hz，1H，5`-H)，6.56(d，J＝2.2Hz，1H，8-H)，6.49(d，J＝2.2Hz，1H，6-H)，5.21(s，2H，OCH
2C
6H
5)，5.17(s，2H，OCH
2C
6H
5)，4.98(s，2H，OCH
2C
6H
5)，2.46(s，3H，OCH3).
13C?NMR(101MHz，CDCl
3)δ176.02，164.85，164.38，163.49，162.04，157.00，156.15，151.70，148.57，136.61，136.43，135.70，132.80，131.31，130.65，128.78，128.62，128.52，128.42，128.05，127.99，127.52，127.27，127.12，122.55，120.59，114.53，114.09，113.85，105.74，98.97，93.45，71.34，70.84，70.54，55.57.
1R(KBr)：3446，2933，2867，1731，1660，1604，1510，1454，1378，1255，1165，733，697cm
-1
Synthesizing of Quercetin-3-O-anisic acid ester, the preparation method is the same.Productive rate 58%, M.p:243.2～245.5 ℃; ESI-MS:435 [M-H]
+, 459.1 [M+Na]
+ 1H NMR (400MHz, DMSO) δ 12.19 (s, 1H, 5-OH), 10.99 (s, 1H, 7-OH), 9.88 (s, 1H, 3`-OH), 9.47 (s; 1H, 4`-OH), 8.08 (d, J=8.9Hz, 2H, Ar-H), 7.34 (d, J=2.2Hz, 1H, 2`-H), 7.28 (d; J=8.4Hz, 1H, 6`-H), 7.12 (d, J=8.9Hz, 2H, Ar-H), 6.83 (d, J=8.4Hz, 1H, 5`-H); 6.49 (d, J=2.0Hz, 1H, 8-H), 6.25 (d, J=2.0Hz, 1H, 6-H), 3.87 (s, 3H, OCH3).
13C?NMR(101MHz，DMSO)δ175.44，165.14，164.53，163.43，161.58，157.13，156.75，149.73，145.94，132.82，130.32，120.98，120.42，120.18，116.29，115.61，114.93，103.95，99.57，94.59，56.16.
1R(KBr)：3326，1720，1658，1604，1512，1444，1358，1270，1195，1166，847，762cm
-1
Embodiment 15: the preparation of Quercetin-3-O-isobutyl-benzene propionic ester (3o)
7,3`, 4`-O-tribenzyl Quercetin-3-O-isobutyl-benzene propionic ester synthetic, the preparation method is the same.Productive rate 90%.
1H?NMR(400MHz，CDCl
3)δ12.25(s，1H，5-OH)，7.50-7.31(m，17H，Ar-H)，7.25(d，J＝7.6Hz，2H，Ar-H)，7.09(d，J＝7.9Hz，2H，Ar-H)，6.70(s，1H，5`-H)，6.49(d，J＝2.2Hz，1H，8-H)，6.47(d，J＝2.2Hz，1H，6-H)，5.21(s，2H，OCH
2C
6H
5)，5.15(s，2H，OCH
2C
6H
5)，5.09(s，2H，OCH
2C
6H
5)，4.04(d，J＝7.0Hz，1H，OOC*CH(CH
3))，2.46(d，J＝7.2Hz，2H，*CH
2CH(CH
3)
2)，1.87(m，1H，CH
2*CH(CH
3))，1.64(d，J＝7.2Hz，3H，OOCCH(*CH
3))，0.93(d，J＝6.6Hz，6H，CH
2CH(*CH
3)
2).
13C?NMR(101MHz，CDCl
3)δ175.71，171.69，164.78，162.03，156.90，156.14，151.60，148.57，140.78，136.85，136.54，136.50，135.72，131.33，129.43，128.76，128.65，128.57，128.40，128.09，128.00，127.62，127.48，127.35，127.07，122.95，122.19，114.63，113.69，105.65，98.92，93.41，71.48，70.85，70.52，45.12，44.98，30.20，22.43，18.79.
1R(KBr)：3450，3033，2950，2865，1757，1660，1608，1513，1455，1375，1144，993，749，697cm
-1
The preparation method of Quercetin-3-O-isobutyl-benzene propionic ester is the same, productive rate 86%.M.p：244.4～246.6℃；ESI-MS：491.1[M+H]
+，489.1[M-H]
+；
1H?NMR(400MHz，DMSO)δ12.20(s，1H，5-OH)，10.99(s，1H，7-OH)，9.83(s，1H，3`-OH)，9.46(s，1H，4`-OH)，7.31(s，1H，2`-H)，7.29(s，2H，Ar-H)，7.15(d，J＝7.9Hz，2H，Ar-H)，6.94(s，1H，6`-H)，6.67(s，1H，5`-H)，6.46(d，J＝1.7Hz，1H，8-H)，6.26(d，J＝1.7Hz，1H，6-H)，4.12(q，J＝7.0Hz，1H，OOC*CH(CH
3))，2.45(d，J＝7.1Hz，2H，*CH
2CH(CH
3)
2)，1.92-1.76(m，1H，CH
2*CH(CH
3))，1.53(d，J＝7.1Hz，3H，OOCCH(*CH
3))，0.87(d，J＝6.6Hz，6H，CH
2CH(*CH
3)
2).
13C?NMR(101MHz，DMSO)δ175.23，171.94，165.08，161.56，157.02，149.68，145.96，140.64，136.92，130.17，129.56，128.03，121.14，119.88，116.16，115.33，103.90，99.54，94.50，79.63，44.74，44.38，40.39，40.18，39.98，39.77，39.56，30.03，22.66，18.87.IR(KBr)：3377，2956，2870，1741，1652，1610，1511，1464，1363，1142，992，849，796，699cm
-1
Embodiment 16: the preparation of Quercetin-3-O-phenoxy acetic acid ester (3p)
7,3`, 4`-O-tribenzyl Quercetin-3-O-phenoxy acetic acid ester synthetic, the preparation method is the same.Productive rate 78%
1H?NMR(400MHz，CDCl
3)δ12.11(s，1H，5-OH)，7.48-7.26(m，19H，Ar-H)，7.00(d，J＝7.4Hz，1H，Ar-H)，6.96(s，1H，Ar-H)，6.94(s，1H，Ar-H)，6.49(d，J＝2.2Hz，1H，8-H)，6.46(d，J＝2.2Hz，1H，6-H)，5.24(s，2H，OCH
2C
6H
5)，5.19(s，2H，OCH
2C
6H
5)，5.13(s，2H，OCH
2C
6H
5)，4.83(s，2H，OCH
2COO).
13C?NMR(101MHz，CDCl
3)δ175.28，166.46，164.94，161.98，157.66，156.96，156.57，151.92，148.66，136.70，136.39，135.61，130.70，129.65，128.79，128.70，128.65，128.44，128.15，128.08，127.49，127.31，127.14，122.78，122.00，114.79，113.82，105.59，99.10，93.58，71.54，70.93，70.56，65.08.
IR(KBr)：3422，3033，2933，1775，1651，1617，1599，1496，1455，1383，1269，1142，997，750，690cm
-1
Synthesizing of Quercetin-3-O-phenoxy acetic acid ester, the preparation method is the same.Productive rate 38%, M.p:156.5～158.3 ℃; ESI-MS:435.5 [M-H]
+, 437.1 [M+H]
+, 459.1 [M+Na]
+ 1H NMR (400MHz, MeOD) δ 7.37 (s, 1H, 2`-H), 7.29 (s, 1H, 6`-H), 7.23 (d, J=7.9Hz; 2H, Ar-H), 6.95 (s, 1H, 5`-H), 6.90 (t, J=6.7Hz, 3H, Ar-H); 6.41 (s, 1H, 8-H), 6.23 (s, 1H, 6-H), 5.03 (s, 2H, OCH2*COO).
13C?NMR(101MHz，MeOD)δ175.28，167.10，164.92，161.56，157.67，157.16，149.14，145.31，129.50，129.17，121.32，120.99，120.30，115.30，114.76，114.20，103.81，98.93，93.84，64.34.IR(KBr)：3373，1784，1655，1600，1496，1443，1383，1278，1167，993，752，689cm
-1
Embodiment 17: the preparation of Quercetin-3-O-isoguvacine ester (3q)
7,3`, 4`-O-tribenzyl Quercetin-3-O-nicotinate synthetic, the preparation method is the same.Productive rate 73%
1H?NMR(400MHz，CDCl
3)δ12.12(s，1H，5-OH)，9.44(s，1H，nicotinic?acid?2-H)，8.90(s，1H，nicotinic?acid?6-H)，8.47(d，J＝8.0Hz，1H，nicotinic?acid?4-H)，7.51(s，1H，nicotinic?acid?5-H)，7.50-7.30(m，17H，Ar-H)，7.00(d，J＝8.8Hz，1H，5`-H)，6.57(d，J＝1.9Hz，1H，8-H)，6.50(d，J＝1.9Hz，1H，6-H)，5.20(d，J＝16.7Hz，4H，2×OCH
2C
6H
5)，5.10(s，2H，OCH
2C
6H
5).
13C?NMR(101MHz，CDCl
3)δ175.44，165.01，162.58，162.04，157.01，156.51，154.43，152.00，151.57，148.71，137.92，136.54，136.32，135.63，131.05，128.79，128.64，128.57，128.45，128.11，128.04，127.49，127.22，127.14，125.00，123.62，122.72，122.07，114.72，113.90，105.63，99.14，93.62，71.55，70.90，70.59.
IR(KBr)：3423，3032，2929，1745，1660，1592，1499，1454，1376，1266，1193，1015，809，730，697cm
-1
The preparation of Quercetin-3-O-nicotinate, the preparation method is the same.Productive rate 50%, M.p:186.8～188.6 ℃; ESI-MS:41o [M-H]
+, 434.1 [M+Na]
+ 1H NMR (400MHz, DMSO) δ 12.47 (s, 1H, 5-OH), 10.91 (s, 1H, 7-OH), 9.84 (s, 1H, 3`-OH); 9.37 (s, 1H, 4`-OH), 7.66 (d, J=6.0Hz, 1H, 2 ¨-H), 7.34 (d, J=2.2Hz, 1H; 2`-H), 7.27 (dd, J=8.4,2.2Hz, 1H, 6`-H), 7.23 (d, J=4.8Hz, 1H), 6.87 (d; J=8.4Hz, 1H, 5-H), 6.45 (d, J=2.0Hz, 1H, 8-H), 6.22 (d, J=2.0Hz, 1H; 6-H), 3.17 (s, 2H), 2.27 (s, 2H), 1.79-1.67 (m, 2H).
13C NMR (101MHz, CDCl
3) δ 176.33,164.33,161.20,156.57,155.91,148.85,146.36,145.31,130.49,120.50,120.45,115.68,115.30,103.60,98.78,93.79,89.67,24.61,20.54,20.29.
3. pharmacological evaluation
Reason is implemented approximately: the anti tumor activity in vitro of Quercetin-3-O-acyl ester analog derivative
3.1 cell strain and reagent
Quercetin and ester compound thereof are mixed with the former medicine stock solution of 10mg/ml with aqua sterilisa; 4 ℃ of preservations are faced the time spent with the dilution of RPMI-1640 substratum, 0.22 μ m filtering with microporous membrane.EC109 (people's esophageal squamous cell carcinoma cell), EC9706 (people's esophageal squamous cell carcinoma cell), MGC-803 (gastric carcinoma cells), PC-3 (Human Prostate Cancer Cells) all buy in the Shanghai Inst. of Life Science, CAS cell bank.Each clone is all with the RPMI-1640 culture medium culturing that contains 10% top grade foetal calf serum, and culture condition is 5%CO
2, 37 ℃.
RPMI-1640 substratum (HyClone, the silent generation that biological chemistry Products Co., Ltd that flies of Beijing match), penicillium mould, Streptomycin sulphate (HyClone; SH40003-12), foetal calf serum (no phage, low endotoxin; Hangzhou Sijiqing Biological Engineering Material Co., Ltd.); The technological approximately ltd of the biological doctor of the lucky promise of trypsin), DMSO 99.8MIN. (dimethylsulfoxide, DMSO) (sigma company); Blue (MTT) (the sigma company) of tetramethyl-azo azoles.
3.2 instrument and equipment
CJ-2F Bechtop (Suzhou Feng Shi laboratory animal equipment ltd), CO2gas incubator (U.S. SIM company), inverted microscope (German Lycra company), the long ELIASA of Spectra Mr type all-wave (U.S. DYNEX company), 96 porocyte culture plates, 75cm
2Culturing bottle (U.S. Coming company).Blood counting chamber; BP211D electronic analytical balance (German sartorius company); The automatic dual pure water distiller of SZ-93 (Shanghai Yarong Biochemical Instrument Plant); General refrigerator (Qingdao HaiEr Co., Ltd), the portable stainless steel pressure steam sterilizer of SYQ-DSX-280B (go up marine peace medical apparatus and instruments factory).
3.3 experimental procedure
Detect Quercetin and the ester compound thereof of different concns restraining effect with mtt assay to EC109 cell, MGC-803 cell, EC9706 cell, PC-3 cell proliferation.The cell in vegetative period of taking the logarithm, the whole concentration of withering is 6 * 10
3Individual/every hole, be inoculated in 96 well culture plates every hole 200 μ l.Cultivate in 5%CO2,37 ℃ of incubators of saturated humidity.Treat cell attachment; Experimental group adds Quercetin germanium to final concentration difference 0.5,1,2,4,8,16,32,64, the 128 μ g/ml of RPMI 1640 substratum dilution; Solvent control group respectively adds perfect medium, and every hole final volume is 200 μ l, establishes 6 multiple holes for every group.Take out culture plate after cultivating 72h, morphological observation and taking pictures under the inverted microscope.Add 5mg/ml MTT (the every hole of 20 μ l/) again and continue to cultivate 4h; Clean every hole with PBS after outwelling original fluid; Add DMSO (150 μ l/ hole), rolling is even to make resolution of precipitate, behind the 20min under the room temperature (purplish red solution) 96 orifice plates is placed on the ELIASA; Survey at each hole OD value of 490nm wavelength (OD value) with ELIASA, calculate each class mean.By formula:
GI (growth inhibition ratio)=1-(about thing group OD value/control group OD value) * 100% calculates the growth inhibition ratio of each group.According to the result, adopt SPSS19.0 to calculate IC
50
Table 1MTT method detects the IC of each compound to different tumour cells
50Value
Can know from last table; The youngster of Quercetin plant ester derivative to the half-inhibition concentration of three kinds of tumour cells (people's esophageal squamous cell carcinoma cell EC9706, Human Prostate Cancer Cells PC-3, gastric carcinoma cells MGC-803) all less than Quercetin, show that the antitumor action of this analog derivative is stronger than Quercetin.Though and for its anti-tumor activity of people's esophageal squamous cell carcinoma cell EC109 less than Quercetin, it still has the effect of certain inhibition tumour cell.Therefore, this experiment has shown that the Quercetin ester derivative has the activity of stronger inhibition tumour cell to EC109, EC9706, PC-3, MGC-803 cell, might develop into the new medicine with these four kinds of cancers of treatment and related neoplasms.
Claims (9)
1. the preparation of Quercetin-3-O-acyl ester is characterized in that, Quercetin-3-O-acyl ester has structure general formula (I):
Wherein, R is fatty acid acyl or aromatic acid acyl group or the 4-hetaroylpyrazol that contains 1～18 carbon atom.
2. according to the said Quercetin of claim 1-3-O-acyl ester, it is characterized in that said fatty acid acyl is formyl radical, ethanoyl, propionyl group, butyryl radicals, oenanthyl, nonanoyl or octadecanoyl.
3. according to the said Quercetin of claim 1-3-O-acyl ester; It is characterized in that said aromatic acid acyl group is benzoyl-, phenylacetyl, hydrocinnamoyl, to anisoyl, O-methoxy benzoyl-, adjacent acetoxy benzoyl, to acetoxy benzoyl, benzene oxygen ethanoyl, para hydroxybenzene formyl radical, p-benzoyl base, biphenyl ethanoyl, isobutyl-benzene propionyl group, to methyl benzoyl, asafoetide acyl group, o-methyl-benzene formyl radical or galloyl.
4. according to the said Quercetin of claim 1-3-O-acyl ester, it is characterized in that said 4-hetaroylpyrazol is furancarbonyl, nicotinoyl, different nicotinoyl or tetrahydropyridine formyl radical.
5. according to the preparation method of the said compound of claim 1, form by following steps:
A. rutin is mixed than 1: 3～5 by amount of substance with Benzyl Chloride or cylite, be dissolved in the aprotic solvent, add 3～4 times alkali then, in room temperature reaction 10～18 hours; Using Glacial acetic acid min. 99.5 to transfer pH is 5～6, adds big water gaging, has deposition to separate out; Filter, drying obtains the thick product of solid-like;
B. the thick product of the solid-like that obtains among the step a is dissolved in the ethanolic soln, adds mineral acid then, refluxed 1～2 hour, filter, obtain yellow solid, recrystallization obtains faint yellow solid;
C. with the faint yellow solid among the step b, be dissolved in anhydrous methylene chloride, add dicyclohexylcarbodiimide; The 4-dimethylamino naphthyridine adds acid, stirring at room 6-8 hour under the condition of ice bath; Filter, after filtrating is used saturated sodium bicarbonate, watery hydrochloric acid, saturated common salt water washing, drying, the pressure reducing and steaming solvent; Get thick product,, obtain faint yellow solid through recrystallization;
D. with the faint yellow solid that obtains among the step c, be dissolved in the dichloromethane methanol mixed solvent, add palladium carbon, shortening under the room temperature condition through filtering palladium carbon, reclaims solvent, obtains target compound.
6. according to the preparation method of the said compound of claim 5, it is characterized in that aprotic solvent described in the step a is N, dinethylformamide or acetone.
7. according to the preparation method of the said compound of claim 5, it is characterized in that the alkali described in the step a is NaOH, KOH, Na
2CO
3, K
2CO
3, among the NaH, pyridine, triethylamine one or more mix with arbitrary proportion.
8. according to the preparation method of the said compound of claim 5, it is characterized in that the mineral acid described in the step b is a kind of in hydrochloric acid, sulfuric acid, phosphoric acid, the nitric acid.
9. compound according to claim 1, the application in the preparation antitumor drug.
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| CN113845504A (en) * | 2021-10-29 | 2021-12-28 | 晨光生物科技集团股份有限公司 | Esterification method of quercetagetin |
| CN115192621A (en) * | 2022-08-04 | 2022-10-18 | 宁波泉水生物科技有限公司 | Skin prebiotics, preparation method and application |
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| WO2021104416A1 (en) * | 2019-11-29 | 2021-06-03 | Medical And Pharmaceutical Industry Technology And Development Center | Compounds and methods for treating inflammatory bowel disease |
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| CN113845504B (en) * | 2021-10-29 | 2023-11-24 | 晨光生物科技集团股份有限公司 | Esterification method of quercitin |
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