CN109678832A - One pot synthesis is synthesized the method and its product and application of Quercetin ester by rutin - Google Patents
One pot synthesis is synthesized the method and its product and application of Quercetin ester by rutin Download PDFInfo
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- CN109678832A CN109678832A CN201910058087.0A CN201910058087A CN109678832A CN 109678832 A CN109678832 A CN 109678832A CN 201910058087 A CN201910058087 A CN 201910058087A CN 109678832 A CN109678832 A CN 109678832A
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- quercetin
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- 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
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
Abstract
The invention belongs to compound synthesis technical field, in particular to one pot synthesis method and its product and application that Quercetin ester is synthesized by rutin.Rutin and acid anhydrides or acyl chloride reaction are treated different things alike under the action of acid or alkali and directly prepare Quercetin ester.The present invention provides multiple new Quercetin ester compounds, and are synthesized by one kettle way.The method reagent is easy to get, and mild condition, operating procedure is few, saving of work and time, saves raw material, and reduction exhaust emission is few, and yield is high, lays a good foundation for the effective use of quercetin derivative, has promotional value.
Description
Technical field
The invention belongs to technical field of chemical synthesis, in particular to one pot synthesis by rutin synthesize Quercetin ester method and
Its product and application.
Background technique
Quercetin (Quercetin, 3,4 ', 3 ', 5,7- pentahydroxyflavones) is a kind of typical flavonoids, is present in many
Food such as apple, onion, broccoli, grape, ginkgo, in tealeaves.Quercetin has various physiological activity, anticancer, drop
Blood, antiviral, prevention and treatment cardiovascular and cerebrovascular disease, anti-inflammatory, anti-oxidant etc..Epidemiology and nutritionist think, Quercetin
It is a kind of native compound for being most hopeful the prevention and treatment applied to disease.The molecular structure of Quercetin makes the water-soluble of it
It is poor, bioavilability is lower, in order to improve such case, people be made it is many it is water-soluble preferably, bioavilabilities
High Study on Quercetin-Metal Complexes, Quercetin esters etc..Such as Tahsin has synthesized Quercetin glutamic acid and Quercetin alanine
Ester can be used as cytostatic most effective conjugate, have good inhibiting effect " TAHSIN F to prostate gland cancer cell
K, MARIA V C, MIN-SUNG L E, et al.Rational design and structure-activity
relationship studies of quercetin–amino acid hybrids targeting the anti-
Apoptotic protein Bcl-xL [J] .Org.Biomol.Chem., 2017,15 (37): 7956-7976. ".Ye Bin etc. is closed
At Quercetin -3-O- phenyl isocyanate, to human body chronic myelogenous leukemia cell K562 (IC50=1.852 μm of ol/L) and
Mouse colonic cell CT26 (IC50=1.177 μm of ol/L) have good inhibiting effect, be respectively 73 times of Quercetin and
308 times of " YE Bin, YANG Jin-liang, CHEN Li-juan, et al.Induction of apoptosis by
phenylisocyanate derivative of quercetin:involvement of heat shock protein
[J] .Anti-Cancer Drugs, 2007,18 (10): 1165-1171. ".Hirpara, Ketan V. studies have shown that plant come
The molecule in source has played important function in cancer chemotherapy.Flavone compound Quercetin, a kind of molecule of plant origin
It has shown that adjusting proliferation and leads to cancer cell death.Some flavone compounds come into clinical test, wherein Mongolian oak
Pi Su occurs as perspective anticancer drug candidate, and prodrug Quercetin -3- amino-acid ester (QC12) has entered I phase clinical research
"Hirpara,Ketan V.；Aggarwal,Pawan；Mukherjee,Amrita J.；et al.Quercetin and Its
Derivatives:Synthesis,Pharmacological Uses with Special Emphasis on Anti-
Tumor Properties and Prodrug with Enhanced Bio-Availability,Anti-Cancer
Agents in Medicinal Chemistry(Formerly Current Medicinal Chemistry-Anti-
Cancer Agents),2009,9(2):138-161.".The experiments such as Ekta Kohli find that Quercetin pentaacetate (QPA) can
To inhibit the genetoxic of aflatoxin B1 (AFB1).The microsome transacetylase that acts through of QPA causes to adjust certain enzymes
(such as P-450 enzyme, the catalytic activity of NADPH) cytochrome C-reductase and glutathione S-transferase may pass through protein
Acetylation.It is different from Quercetin, it can be observed that QPA inhibits the combination of AFB1 and DNA.Illustrate that QPA is preventing caused by AFB1
Effect " Ekta Kohli, Hanumantharao G.Raj, Ranju Kumari, et al.Comparison in genetoxic
of the Prevention of Aflatoxin B1-Induced Genotoxicity by Quercetin and
Quercetin Pentaacetate,Bioorganic&Medicinal Chemistry Letters 2002,12:2579–
2582".Zhang Yihua etc. has synthesized the acylated Quercetin of 3,3 ', 4 ', 5-, tetra--O-, has been respectively synthesized 3,3 ', 4 ', 5-, tetra--O- acetylation
Quercetin and 3, the propionating Quercetin of 3 ', 4 ', 5-, tetra--O- " CN 105693677A date of application: 2016.03.01 ".
Quercetin ester has preferable pharmacological activity, and some has significant inhibiting effect to cancer cell, and some is to freedom
Base Scavenging activity is stronger, provides important clue for the effective use of native compound.One acyl group ester compounds text of Quercetin
Offer report it is more, Quercetin diacyl ester compounds, three acyl ester compound of Quercetin are less, four acyl group ester compounds of Quercetin
Less, the only Quercetin pentaacetate that five acyl group ester compounds of Quercetin are reported at present.In addition, being conventionally synthesized Quercetin ester
Method is as follows: rutin hydrolyzes in the hydrochloric acid solution of methanol, isolated Quercetin.Quercetin and acid anhydrides or acyl chlorides are in dense sulphur
Quercetin ester is esterified to obtain under acid effect.
The drawbacks of this method is, rutin hydrolysis needs to consume a large amount of methanol, and methanol and water form azeotrope and is difficult point
From acid-bearing wastewater emission of serious pollution of environment.The product cost that rutin hydrolysis, Quercetin are esterified is relatively high.
Summary of the invention
The object of the present invention is to provide a kind of one pot synthesis to be synthesized the method and its product and application of Quercetin ester by rutin.
In order to solve the above technical problems, The technical solution adopted by the invention is as follows:
The method that one pot synthesis synthesizes Quercetin ester by rutin, by rutin and acid anhydrides or acyl chloride reaction, in acid or the work of alkali
Under, treats different things alike and directly prepare Quercetin ester；The general structure of the Quercetin ester is as follows:
R substituent therein can it is same or different be selected from following substituent group: methyl, ethyl, propyl, butyl,
Isopropyl, isobutyl group, tert-butyl, phenyl, benzyl, o-methyl-phenyl, aminomethyl phenyl, p-methylphenyl, adjacent ethylphenyl,
Ethylphenyl, to ethylphenyl, O-Nitrophenylfluorone, hydroxy phenyl, rubigan, p-bromophenyl, 2,3- dichlorophenyl, 3,5-
Dichlorophenyl.
The acid anhydrides is aliphatic anhydride or aromatic anhydride.
Acetic anhydride, propionic andydride, butyric anhydride, succinic anhydride or anhydride maleique may be selected in the aliphatic anhydride；It is described
Aromatic anhydride be benzoyl oxide, phenylacetic anhydride, o-toluic acid acid anhydride, p-methylbenzoic acid acid anhydride, 0-chloro-benzoic acid acid anhydride or
Parachlorobenzoic-acid acid anhydride.
The acyl chlorides preferably is selected from one of following: chloroacetic chloride, propionyl chloride, butyl chloride, chlorobenzoyl chloride, phenyllacetyl chloride, adjacent first
Base chlorobenzoyl chloride, m-methyl benzoyl formyl chloride, to methyl benzoyl chloride, o-chlorobenzoyl chloride.
The acid is sulfuric acid, hydrochloric acid, and the alkali is aniline, piperidines or pyridine.General rutin and anhydride reaction use
Acid makees catalyst, and rutin and acyl chloride reaction make catalyst using alkali.
Feed ratio are as follows: rutin: acid anhydrides or acyl chlorides: acid or alkali=1mol:1-10ml:0.05-1ml.
Temperature control is stirred in 25-98 DEG C, reaction process when reaction.Electric jacket heating can be used in heating, micro-
Wave heating, can be with water-bath, also with oil bath etc..
Rutin is reacted again after can first being dissolved with solvent, and solvent has no special requirements, and can dissolve rutin.
Quercetin ester is usually to be prepared by Quercetin and acid anhydrides or acyl chloride reaction, and Quercetin is hydrolyzed by rutin and prepared.This hair
It is bright by rutin and acid anhydrides or acyl chloride reaction, treat different things alike and directly prepare Quercetin ester.In this method, rutin exists with acid anhydrides or acyl chlorides
Acid or the lower reaction of alkali (piperidines) effect, firstly generate four acid esters of rutin, while reaction, rutin acts in byproduct hydrogen chloride
Lower glycosidic bond fracture, exposed Quercetin 3- hydroxyl are further reacted with acid anhydrides or acyl chlorides, generate five acid esters of Quercetin.
Method for the treatment of different things alike of the invention, reagent are easy to get, and mild condition, operating procedure is few, saving of work and time, save raw material, subtract
Few discharge, pollution is few, and yield is high, lays a good foundation for the effective use of quercetin derivative, is the method for having very much promotional value,
According to the principle of atom economy, meet continuable development principle.
It is different according to the raw material of use, a variety of different compounds can be synthesized, 2-13 below is never reported before being
The noval chemical compound crossed:
Anti-tumor activity experiment has been carried out to above compound, all there is preferable anti-tumor activity.
Compared with the prior art, the invention has the following advantages:
The present invention provides multiple new Quercetin ester compounds, and are synthesized by one kettle way.The method reagent
It is easy to get, mild condition, operating procedure is few, saving of work and time, saves raw material, reduces discharge, and pollution is few, and yield is high, spreads out for Quercetin
The effective use of biology is laid a good foundation, and is that the method for having very much promotional value according to the principle of atom economy meets sustainable development
Open up principle.
Specific embodiment
Below the technical scheme of the invention is illustrated by a specific example, but the scope of the present invention is not limited thereto:
The amount of acid or base catalyst is indicated with drop in following embodiment, and the volume of 20 drops is calculated as 1ml.
Embodiment 1
The synthesis of Quercetin pentaacetate (1)
610mg (1mmol) rutin is weighed, 5ml acetic anhydride, which is added, dissolves it sufficiently with magnetic stirrer 0.5h
Afterwards, the 5 drop concentrated sulfuric acids are added, control 65 DEG C of temperature, flow back 6h, and TLC plate monitoring reaction process ensures fully reacting.80ml is added to steam
Distilled water stirs 2h, has a large amount of solids to be precipitated.It is precipitated to solid and water becomes clarification abandon water layer, precipitating is washed to neutrality, and acetic acid is added
Ethyl ester 80mL dissolution, crosses silicagel column, acetone: petroleum ether (3:2) elution is collected eluent revolving, is recrystallized through chloroform/methanol,
Yield 58.2%.
Clear crystal, m.p.194.5~195.1 DEG C (literature value: 195~196 DEG C).IR (KBr), v, cm-1: 2946.2,
1776.3 1264.6,1199.82.1HNMR (DMSO, 600MHz), δ: the 7.86 (- H of m, 1H, 2 ')；The 7.84 (- H of m, 1H, 6 ')；
7.65 (H of s, 1H, 5 ')；7.55 (s, 1H, 8H)；6.17 (s, 1H, 6H)；2.34 (m, 15H, CH3).MS, m/z:513.1 [M+1]+。
Embodiment 2
The synthesis of five propionic ester of Quercetin (2)
610mg (1mmol) rutin is weighed, 5ml propionic andydride, which is added, dissolves it sufficiently with magnetic stirrer 0.5h
Afterwards, the 5 drop concentrated sulfuric acids are added, control 65 DEG C of temperature, flow back 6h, and TLC plate monitoring reaction process ensures fully reacting.80ml is added to steam
Distilled water stirs 2h, has a large amount of solids to be precipitated.It is precipitated to solid and water becomes clarification abandon water layer, precipitating is washed to neutrality, and acetic acid is added
Ethyl ester 80mL dissolution, crosses silicagel column, acetone: petroleum ether (3:2) elution is collected eluent revolving, is recrystallized through chloroform/methanol,
Yield is 57.3%, m.p.136.1~138.4 DEG C.IR (KBr), v, cm-1: 2936,1769.2,1244.6,1108.8.1HNMR
(CDCl3, 600MHz), δ: the 7.86 (- H of m, 1H, 2 ')；The 7.64 (- H of m, 1H, 6 ')；7.60 (H of s, 1H, 5 ')；7.54 (s, 1H,
8H)；7.16 (s, 1H, 6H)；2.63~2.78 (d, 10H, CH2)；1.16 (m, 15H, CH3).MS, m/z:583.18 [M+1]+。
Embodiment 3
The synthesis of five benzoic ether of Quercetin (3)
610mg (1mmol) rutin is weighed, is dissolved in 20ml dimethylformamide (DMF), 5ml chlorobenzoyl chloride is added, uses magnetic
Power blender stirs 0.5h, makes it after completely dissolution, and 10 drop piperidines are added, control 65 DEG C of temperature, and flow back 6h, and the monitoring of TLC plate is anti-
Process is answered to ensure fully reacting.80ml distilled water is added, stirs 2h, there are a large amount of solids to be precipitated.It is precipitated to solid and water becomes clarification
Abandon water layer, precipitating are washed to neutrality, and ethyl acetate 80mL dissolution is added, crosses silicagel column, acetone: petroleum ether (3:2) elution is collected
Eluent revolving, recrystallizes, yield 57.3%, m.p.112.3~1114.5 DEG C through chloroform/methanol.IR (KBr), v, cm-1:
3406.0,2926.1,1745.3,1259.6,1129.8.1HNMR(CDCl3, 600MHz), δ: the 7.78 (- H of m, 1H, 2 ')；7.72
(- the H of m, 1H, 6 ')；7.70 (H of s, 1H, 5 ')；7.66 (s, 1H, 6H)；6.17 (s, 1H, 8H)；7.62~8.04 (m, 25H, ph-
H).MS, m/z:823.18 [M+1]+。
Embodiment 4
The synthesis of five o-toluic acid ester (4) of Quercetin
610mg (1mmol) rutin is weighed, is dissolved in 20ml dimethylformamide (DMF), 5ml o-methyl-benzene formyl is added
Chlorine makes it after completely dissolution with magnetic stirrer 0.5h, and 6 drop piperidines are added, control 55 DEG C of temperature, flow back 5h, TLC plate
Monitoring reaction process ensures fully reacting.80ml distilled water is added, stirs 2h, there are a large amount of solids to be precipitated.To solid precipitation and water
Become clarification abandon water layer, precipitating is washed to neutrality, and methyl acetate 80mL dissolution is added, crosses silicagel column, acetone: petroleum ether (3:1) is washed
It is de-, eluent revolving is collected, is recrystallized through chloroform/methanol, white solid, yield 68.1%.M.p.118.6~119.8 DEG C.
IR (KBr), v, cm-1: 3406.4,2840.2,1668.0,1246.7,1139.7.1HNMR(CDCl3, 600MHz), δ: 8.20
(- the H of s, 1H, 2 ')；The 7.87 (- H of m, 1H, 6 ')；7.76 (H of m, 1H, 5 ')；7.62 (s, 1H, 6H)；7.35 (m, 1H, 8H)；7.18~
7.40 (m, 20H, ph-H)；2.20~2.84 (s, 15H, CH3).MS, m/z:893.4 [M+1]+。
Embodiment 5
The synthesis of five m-methyl benzoic acid ester (5) of Quercetin
610mg (1mmol) rutin is weighed, is dissolved in 20ml dimethylformamide (DMF), toluyl between 5ml is added
Chlorine makes it after completely dissolution with magnetic stirrer 0.5h, and 8 drop piperidines are added, control temperature 60 C, flow back 6h, TLC plate
Monitoring reaction process ensures fully reacting.80ml distilled water is added, stirs 2h, there are a large amount of solids to be precipitated.To solid precipitation and water
Become clarification abandon water layer, precipitating is washed to neutrality, and propyl acetate 80mL dissolution is added, crosses silicagel column, acetone: petroleum ether (2:2) is washed
It is de-, eluent revolving is collected, is recrystallized through chloroform/methanol, white solid, yield 54.4%, m.p.121.1~123.6 DEG C.
IR (KBr), v, cm-1: 3414.8,2907.3,1775.4,1286.8,1068.7.1HNMR(CDCl3, 600MHz), 8.27 (s,
1H, 2 '-H, ph-H)；8.17 (m, 1H, 6 '-H, ph-H)；8.03 (H of s, 1H, 5 ')；7.61 (s, 1H, 6H)；7.45 (s, 1H,
8H)；7.36~7.79 (m, 20H, ph-H)；2.07~2.83 (s, 15H, CH3).MS, m/z:893.3 [M+1]+。
Embodiment 6
The synthesis of five p-methylbenzoic acid ester (6) of Quercetin
610mg (1mmol) rutin is weighed, is dissolved in 20ml dimethylformamide (DMF), 5ml is added to toluyl
Chlorine makes it after completely dissolution with magnetic stirrer 0.5h, and 7 drop piperidines are added, control temperature 50 C, flow back 5h, TLC plate
Monitoring reaction process ensures fully reacting.80ml distilled water is added, stirs 2h, there are a large amount of solids to be precipitated.To solid precipitation and water
Become clarification abandon water layer, precipitating is washed to neutrality, and methyl acetate 70mL dissolution is added, crosses silicagel column, acetone: petroleum ether (3:2.5)
Elution is collected eluent revolving, is recrystallized through chloroform/methanol, white solid, yield 43.8%, m.p.126.3~127.5
℃.IR (KBr), v, cm-1: 3308.2,2897.3,1738.9,1328.4,1029.6.1HNMR(CDCl3, 600MHz), δ:
The 7.86 (- H of m, 1H, 2 ')；The 7.65 (- H of m, 1H, 6 ')；7.55 (H of s, 1H, 5 ')；7.52 (s, 1H, 6H)；7.17 (s, 1H, 8H)；
7.14~7.83 (m, 20H, ph-H)；2.39~2.65 (s, 15H, CH3).MS, m/z:893.3 [M+1]+。
Embodiment 7
The synthesis of (3,5- dimethyl) benzoic ether of Quercetin five (7)
610mg (1mmol) rutin is weighed, is dissolved in 20ml dimethylformamide (DMF), 5ml 3,5- dimethyl benzene is added
Formyl chloride makes it after completely dissolution with magnetic stirrer 0.5h, and 10 drop piperidines are added, control 58 DEG C of temperature, and flow back 4h,
TLC plate monitoring reaction process ensures fully reacting.80ml distilled water is added, stirs 2h, there are a large amount of solids to be precipitated.It is precipitated to solid
And water becomes clarification abandon water layer, precipitating is washed to neutrality, and methyl acetate 65mL dissolution is added, crosses silicagel column, ethyl acetate: dichloromethane
Alkane (3:2) elution is collected eluent revolving, is recrystallized through chloroform/methanol, white solid, yield 61.1%, m.p.132.6
~133.1 DEG C.IR (KBr), v, cm-1: 3518.2,2802.6,1721.8,1259.7,1129.6.1HNMR(CDCl3,
600MHz), δ: the 7.91 (- H of s, 1H, 2 ')；The 7.78 (- H of m, 1H, 6 ')；7.58 (H of s, 1H, 5 ')；7.43 (s, 1H, 6H)；7.26
(s, 1H, 8H)；7.25~7.67 (m, 15H, ph-H)；2.17~2.35 (s, 30H, CH3).MS, m/z:963.5 [M+1]+。
Embodiment 8
The synthesis of five p-ethylbenzoic acid ester (8) of Quercetin
610mg (1mmol) rutin is weighed, is dissolved in 20ml dimethylformamide (DMF), 5ml is added to ethylbenzoyl
Chlorine makes it after completely dissolution with magnetic stirrer 0.5h, and 12 drop piperidines are added, control 62 DEG C of temperature, flow back 4h, TLC plate
Monitoring reaction process ensures fully reacting.80ml distilled water is added, stirs 2h, there are a large amount of solids to be precipitated.To solid precipitation and water
Become clarification abandon water layer, precipitating is washed to neutrality, and ethyl acetate 82mL dissolution is added, crosses silicagel column, ethyl acetate: methylene chloride
(3:1) elution is collected eluent revolving, is recrystallized through chloroform/methanol, white solid, yield 63.4%, and m.p.130.1~
131.6℃.IR (KBr), v, cm-1: 3416.3,2901.2,1725.3,1248.8,1069.8.1HNMR(CDCl3, 600MHz),
δ: the 7.79 (- H of m, 1H, 2 ')；The 7.76 (- H of m, 1H, 6 ')；7.74 (H of s, 1H, 5 ')；7.66 (s, 1H, 6H)；6.17 (s, 1H, 8H)；
7.25~7.67 (m, 20H, ph-H)；2.27~2.52 (s, 15H, CH3)；0.97~1.08 (m, 10H, CH2).MS, m/z:
963.2[M+1]+。
Embodiment 9
The synthesis of five phenylacetate of Quercetin (9)
610mg (1mmol) rutin is weighed, is dissolved in 20ml dimethylformamide (DMF), 5ml phenyllacetyl chloride is added, uses magnetic
Power blender stirs 0.5h, makes it after completely dissolution, and 9 drop piperidines are added, control 57 DEG C of temperature, and flow back 4h, the monitoring reaction of TLC plate
Process ensures fully reacting.80ml distilled water is added, stirs 2h, there are a large amount of solids to be precipitated.It is precipitated to solid and water becomes clarification and abandons
Water layer, precipitating are washed to neutrality, and methyl acetate 68mL dissolution is added, crosses silicagel column, ethyl acetate: methylene chloride (2:3) elution,
Eluent revolving is collected, is recrystallized through chloroform/methanol, white solid, yield 60.5%, m.p.129.5~130.2 DEG C.IR
(KBr), v, cm-1: 3446.8,2922.8,1725.3,1237.4,1057.6.1HNMR(CDCl3, 600MHz), δ: 7.78 (m,
1H, 2 '-H)；The 7.75 (- H of m, 1H, 6 ')；7.74 (H of s, 1H, 5 ')；7.61 (s, 1H, 6H)；6.19 (s, 1H, 8H)；7.26~
7.69 (m, 25H, ph-H)；0.98~1.09 (m, 10H, CH2).MS, m/z:893.4 [M+1]+。
Embodiment 10
The synthesis of five 0-chloro-benzoic acid ester (10) of Quercetin
610mg (1mmol) rutin is weighed, is dissolved in 20ml dimethylformamide (DMF), 5ml o-chlorobenzoyl chloride is added,
With magnetic stirrer 0.5h, make it after completely dissolution, 12 drop piperidines are added, control 75 DEG C of temperature, flow back 4h, TLC plate prison
Surveying reaction process ensures fully reacting.80ml distilled water is added, stirs 2h, there are a large amount of solids to be precipitated.It is precipitated to solid and water becomes
Abandon water layer is clarified, precipitating is washed to neutrality, and ethyl acetate 68mL dissolution is added, crosses silicagel column, methyl acetate: methylene chloride (3:
2) it elutes, collects eluent revolving, recrystallized through chloroform/methanol, white solid, yield 58.8%, m.p.132.6~
133.1℃.IR (KBr), v, cm-1: 3408.7,1663.1,1168.9,1014.7.1HNMR(CDCl3, 600MHz), δ: 8.25
(- the H of m, 1H, 2 ')；The 8.15 (- H of m, 1H, 6 ')；8.08 (H of s, 1H, 5 ')；8.01 (s, 1H, 6H)；7.50 (s, 1H, 8H)；7.01~
7.90 (m, 20H, ph-H).MS, m/z:995.1 [M+1]+。
Embodiment 11
The synthesis of five parachlorobenzoic-acid ester (11) of Quercetin
610mg (1mmol) rutin is weighed, is dissolved in 20ml dimethylformamide (DMF), 5ml parachlorobenzoyl chloride is added,
With magnetic stirrer 0.5h, make it after completely dissolution, 11 drop piperidines are added, control 74 DEG C of temperature, flow back 4h, TLC plate prison
Surveying reaction process ensures fully reacting.80ml distilled water is added, stirs 2h, there are a large amount of solids to be precipitated.It is precipitated to solid and water becomes
Abandon water layer is clarified, precipitating is washed to neutrality, and ethyl acetate 78mL dissolution is added, crosses silicagel column, methyl acetate: methylene chloride (3:
1) it elutes, collects eluent revolving, recrystallized through chloroform/methanol, white solid, yield 61.3%, m.p.132.6~
134.1℃.IR (KBr), v, cm-1: 3436.2,1785.2,1247.9,1019.4.1HNMR(CDCl3, 600MHz), δ: 8.19
(- the H of m, 1H, 2 ')；The 7.84 (- H of s, 1H, 6 ')；7.52 (H of m, 1H, 5 ')；7.47 (s, 1H, 6H)；7.25 (s, 1H, 8H)；7.18~
7.90 (m, 20H, ph-H).MS, m/z:955.2 [M+1]+。
Embodiment 12
The synthesis of (2, the 3- dichlorobenzoic acid) ester of Quercetin five (12)
610mg (1mmol) rutin is weighed, is dissolved in 20ml dimethylformamide (DMF), 5ml 2,3- dichloro-benzenes first is added
Acyl chlorides makes it after completely dissolution with magnetic stirrer 0.5h, and 15 drop piperidines are added, control 78 DEG C of temperature, flow back 4h, TLC
Plate monitoring reaction process ensures fully reacting.80ml distilled water is added, stirs 2h, there are a large amount of solids to be precipitated.To solid be precipitated and
Water becomes clarification abandon water layer, and precipitating is washed to neutrality, and ethyl acetate 70mL dissolution is added, crosses silicagel column, methyl acetate: methylene chloride
(2:3) elution is collected eluent revolving, is recrystallized through chloroform/methanol, white solid, yield 52.4%, m.p.137.6 DEG C.
IR (KBr), v, cm-1: 3466.1,1794.2,1347.6,1121.6.1HNMR(CDCl3, 600MHz), δ: 8.33 (m, 1H, 2 '-
H)；The 8.17 (- H of m, 1H, 6 ')；7.83 (H of s, 1H, 5 ')；7.55 (s, 1H, 6H)；7.20 (s, 1H, 8H)；7.30~7.93 (m,
15H, ph-H).MS, m/z:1169.0 [M+1]+。
Embodiment 13
The synthesis of (3, the 4- dichlorobenzoic acid) ester of Quercetin five (13)
610mg (1mmol) rutin is weighed, is dissolved in 20ml dimethylformamide (DMF), 5ml3,4- dichloro-benzenes first is added
Acyl chlorides makes it after completely dissolution with magnetic stirrer 0.5h, and 14 drop piperidines are added, control 77 DEG C of temperature, flow back 4h, TLC
Plate monitoring reaction process ensures fully reacting.80ml distilled water is added, stirs 2h, there are a large amount of solids to be precipitated.To solid be precipitated and
Water becomes clarification abandon water layer, and precipitating is washed to neutrality, and ethyl acetate 70mL dissolution is added, crosses silicagel column, methyl acetate: methylene chloride
(3:1.5) elution is collected eluent revolving, is recrystallized through chloroform/methanol, white solid, yield 51.6%, m.p.132.6
~133.1 DEG C.IR (KBr), v, cm-1: 3370.2,1791.7,1233.9,1011.3.1HNMR(CDCl3, 600MHz), δ:
The 7.79 (- H of m, 1H, 2 ')；The 7.76 (- H of m, 1H, 6 ')；7.74 (H of s, 1H, 5 ')；7.66 (s, 1H, 6H)；6.17 (s, 1H, 8H)；
7.25~7.67 (m, 15H, ph-H).MS, m/z:1166.9 [M+1]+。
Anti-tumor activity experiment
Various concentration Quercetin and its ester type compound are detected to EC109 cell, EC9706 cell, B16-F10 with mtt assay
The inhibiting effect of cell, SGC-7901 cell Proliferation.Logarithmic growth phase cell, adjustment concentration are 6 × 103A/hole, is inoculated in
In 96 well culture plates, every 200 μ L of hole.5%CO2, saturated humidity, cultivate in 37 DEG C of incubators.Adherent to cell, experimental group is added
The diluted Quercetin ester of RPMI1640 culture medium to final concentration is respectively 0.5,1,2,4,8,16,32,64,128 μ g/mL, solvent
Complete medium is respectively added in control group, and every hole final volume is 200 μ L, and every group sets 6 multiple holes.Culture plate is taken out after culture 72h,
It sets microscopically observation form and takes pictures.It adds 5mg/mL MTT (20 hole μ L/) to continue to cultivate 4h, be used after outwelling original fluid
PBS cleans every hole, is added in DMSO (150 hole μ L/), and shaking up dissolves precipitating, at room temperature by 96 holes after 20min (purplish red solution)
Plate detects each hole absorbance value (A value) at 570nm in enzyme linked immunological microplate reader.Experiment is independently repeated 3 times, and is averaged.And
Growth inhibition ratio is calculated by formula (1).According to acquired results, IC is calculated using SPPS19.050Value.
GI (growth inhibition ratio)=1- (medicine group A value/control group A value) × 100%
Using 13 Quercetin esters of mtt assay preliminary assessment and the anti-tumor activity of Quercetin.With anti-tumor drug fluorine urine
Pyrimidine is positive control, has investigated target compound respectively to Human esophageal squamous cell cancer cell (EC109), Human esophageal squamous cell cancer cell
(EC9706), the inhibiting effect of gastric carcinoma cells (SGC7901) and mouse melanin tumor cell (B16-F10) 4 plants of tumour cells.
As it can be seen from table 1 Quercetin is relatively preferable to the inhibiting effect of EC109 and EC9706 cell, and to other two
The IC of kind cell50Value is all larger than 128 μm of ol/L, and 13 kinds of Quercetin ester derivatives of synthesis have not this 4 kinds of cancer cells
With the inhibiting effect of degree, five parachlorobenzoic-acid ester of Quercetin is to Human esophageal squamous cell cancer cell (EC109) and Human esophageal squamous cell cancer cell
(EC9706) there is good inhibiting effect.
Proliferation inhibition rate of the 1 Quercetin ester of table to different tumour cells
IC of the five parachlorobenzoic-acid ester of compound Quercetin to Human esophageal squamous cell cancer (EC109)50Value has respectively reached 28.446 μ
Mol/L is much smaller than parent Quercetin (31.924 μm of ol/L), is better than currently used anticarcinogen 5-FU (41.738 μm of ol/L), has
Further research is hoped to become the drug candidate of anti-esophageal squamous cell carcinoma.In addition, other compounds all show centainly 4 kinds of cancer cells
Inhibiting effect.
Claims (9)
1. the method that one pot synthesis synthesizes Quercetin ester by rutin, which is characterized in that by rutin and acid anhydrides or acyl chloride reaction, in acid
Or under the action of alkali, treats different things alike and directly prepare Quercetin ester；The general structure of the Quercetin ester is as follows:
R substituent therein same or different can be selected from following substituent group: methyl, ethyl, propyl, butyl, isopropyl
Base, isobutyl group, tert-butyl, phenyl, benzyl, o-methyl-phenyl, aminomethyl phenyl, p-methylphenyl, adjacent ethylphenyl, ethyl
Phenyl, to ethylphenyl, O-Nitrophenylfluorone, hydroxy phenyl, rubigan, p-bromophenyl, 2,3- dichlorophenyl, 3,5- dichloro
Phenyl.
2. the method that one pot synthesis as described in claim 1 synthesizes Quercetin ester by rutin, which is characterized in that the acid anhydrides
For aliphatic anhydride or aromatic anhydride.
3. the method that one pot synthesis as claimed in claim 2 synthesizes Quercetin ester by rutin, which is characterized in that the fat
Race's acid anhydrides is acetic anhydride, propionic andydride, butyric anhydride, succinic anhydride or anhydride maleique；The aromatic anhydride be benzoyl oxide,
Phenylacetic anhydride, o-toluic acid acid anhydride, p-methylbenzoic acid acid anhydride, 0-chloro-benzoic acid acid anhydride or parachlorobenzoic-acid acid anhydride.
4. the method that one pot synthesis as described in claim 1 synthesizes Quercetin ester by rutin, which is characterized in that the acyl chlorides
Selected from one of following: chloroacetic chloride, propionyl chloride, butyl chloride, chlorobenzoyl chloride, phenyllacetyl chloride, o-methyl-benzene formyl chloride, methylbenzene first
Acyl chlorides, to methyl benzoyl chloride, o-chlorobenzoyl chloride.
5. the method that one pot synthesis as described in claim 1 synthesizes Quercetin ester by rutin, which is characterized in that inventory ratio
Are as follows: rutin: acid anhydrides or acyl chlorides: acid or alkali=1mol:1-10ml:0.05-1ml.
6. the method that one pot synthesis as described in claim 1 synthesizes Quercetin ester by rutin, which is characterized in that the acid is
Sulfuric acid, hydrochloric acid, the alkali are aniline, piperidines or pyridine.
7. the method that one pot synthesis as described in claim 1 synthesizes Quercetin ester by rutin, which is characterized in that temperature when reaction
Control is stirred in 25-98 DEG C, reaction process.
8. one pot synthesis is synthesized the product of the method for Quercetin ester by rutin, the structural formula of the Quercetin ester is as follows:
9. application of the Quercetin ester in anti-tumor drug.
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