CN105237504B - Nitrogenous analog derivative of myricetin and its preparation method and application - Google Patents

Nitrogenous analog derivative of myricetin and its preparation method and application Download PDF

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CN105237504B
CN105237504B CN201510621302.5A CN201510621302A CN105237504B CN 105237504 B CN105237504 B CN 105237504B CN 201510621302 A CN201510621302 A CN 201510621302A CN 105237504 B CN105237504 B CN 105237504B
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myricetin
reaction
preparation
chromene
trimethoxyphenyls
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CN105237504A (en
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薛伟
赵洪菊
黄银久
王忠波
胡小梅
张贤
陈玉
夏丽娟
龚华玉
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Guizhou University
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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
    • 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
    • C07D311/32—2,3-Dihydro derivatives, e.g. flavanones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/12—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D407/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00
    • C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
    • C07D407/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links

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Abstract

The present invention relates to nitrogenous analog derivative of a kind of myricetin and its preparation method and application, compound structure has general formula (III) expression.Invention describes using myricetrin, halogenated alkane, secondary amine, piperazine hexahydrate, aromatic acid, substituted aroma acid, bromoacetate, hydrazine hydrate, aromatic aldehyde and substituted aroma aldehyde as raw material, be substituted, hydrolyze and condensation reaction synthesizes a series of nitrogenous analog derivatives of myricetin.Such compound has cancer cell good inhibiting effect, and toxicity is smaller, available for preparing anticancer drug.

Description

Nitrogenous analog derivative of myricetin and its preparation method and application
Technical field
The present invention relates to the analog derivative of nitrogen containing myricetin with antitumaous effect and preparation methods and purposes.
Background technology
Myricetin (3', 4', 5', 3,5,7- quercetagetin alcohol, Myricetin), myricetin widely exists in acorn-cup Section (Fagaceae), pulse family (Leguminosae), herald spring (Pfimulaceae), Vitaceae (Vitaceae), composite family (Compositae) etc. in plants, myricetin is typically found in the fruit of our daily consumptions, vegetables and in beverage, such as： Tea and red wine etc..Some researches show that：Myricetin has anticancer, anti-oxidant (Ong, K.C.；Khoo, H.E.Biologicaleffectsofmyricetin[J].GeneralPharmacology:TheVascularSystem, 1997,29(2):121-126), antiviral (Ono, K.；Nakane,H.；Fukushima,M.； etal.Differentialinhibitoryeffectsofvariousflavonoidsontheactivitiesofreverse transcriptaseandcellularDNAandRNApolymerases[J] .EuropeanJournalofBiochemistry,1990,190(3):469-476), anti-inflammatory (Lee, Y.S.；Choi, E.M.MyricetininhibitsIL-1β- inducedinflammatorymediatorsinSW982humansynovialsarcomacells[J] .InternationalImmunopharmacology,2010,10(7):812-814), antibacterial (El-Gammal, A.A.； Mansour,R.Antimicrobialactivitiesofsomeflavonoidcompounds[J].Zentralblattfü rMikrobiologie,1986,141(7):A variety of pharmacological activity such as 561-565).
Its research in terms of active anticancer is more at present, has apparent inhibiting effect (to open to mankind's kinds of tumor cells Beautiful, the Huang Qingling of show, pharmacology activity research progress [J] the Tianjin pharmacy of Ji Yubin myricetins, 2008,20 (5):57-60).It is existing There is effect for multiple stages of the medical evidence myricetin in tumor development, the proliferation including tumour cell, induction tumour The differentiation of cell and apoptosis and the generation and transfer for inhibiting tumour.Since myricetin has, Antitumor test is extensive, to normal thin Cellular toxicity is low, while the effect of energy strengthen immunity, therefore is developing novel field of antineoplastic medicaments, myricetin and red bayberry The derivative of element has obtained more and more concerns.
2007, Lee (K.W.；Kang,N.J.；Rogozin,E.A.； etal.MyricetinisanovelnaturalinhibitorofneoplasticcelltransformationandMEK1 [J].Carcinogenesis,2007,28(9):1918-1927) find myricetin under a concentration of 10 μm of ol/L to JP6P+It is small The malignant transformation and proliferation of mouse epidermal cell have obvious inhibiting effect, and mechanism is to block MEK/ERK/AP-1 signals road Diameter；Myricetin may also suppress methionine and the activity of Akt, influences the recombination of medulloblastoma actin cytoskeleton, contains into Myeloma cells morphological change as caused by hepatocyte growth factor in transfer process, so as to inhibit its transfer, IC50It is worth and is 6μmol/L(Labbé,D.；Provencal,M.；Lamy,S.；etal.Theflavonolsquercetin,kaempferol, andmyricetininhibithepatocytegrowthfactor-inducedmedulloblastomacellmigration [J].TheJournalofnutrition,2009,139(4)：646-652).
2009, Zhang Li waited that (Zhang Lijing, Liu Zhiguo, Meng great Li, summer bright treasure Chinese waxmyrtle barks extract and myricetin resist quietly Tumor promotion [J] Shenyang Pharmaceutical Universities journal, 2009,26 (4):307-311) myricetin monomeric compound is resisted in vitro Tumor research, research shows that：Myricetin is to HeLa Cells, human melanoma A375-S2 cell, human breast carcinoma MCF- 7 cells and human hepatoma HepG2 cell are respectively provided with apparent cytotoxicity, and myricetin significantly inhibits the proliferation of HeLa cells, lures Lead HeLa natural death of cerebral cells.
2010, (Zhang Xiujuan's Zhang Xiujuan etc. reached the clouds, Yu Hua, and Ji Yubin myricetins induction human liver cancer HepG-2 is thin Research [J] CHINA JOURNAL OF CHINESE MATERIA MEDICAs of born of the same parents' Apoptosis mechanism, 2010,35 (8):Myricetin 1046-1050) has been inquired into human liver cancer HepG-2 inhibits growth and apoptosis-induced Function and its mechanisms, research shows that：Myricetin has human liver cancer HepG-2 cell growths There is apparent inhibiting effect, and with dose dependent, IC50For 58.6617mg/L；After myricetin effect 72h, HepG-2 cells Typical cells apoptosis feature is presented, for cell-cycle arrest in the G2/M phases, apoptosis rate is up to 64.73%.2011, Zhang etc. (Zhang,X.；Zou,Z.；Xu,C.；etal.MyricetininducesG2/ MphasearrestinHepG2cellsbyinhibitingtheactivityofthecyclinB/Cdc2complex[J] .MolMedReport,2011,4:Mechanism of action of the myricetin to liver cancer cells 273-277) is further studied, finds red bayberry Element is by reducing the level of Cdc2 and Cyclin B1 in liver cancer cells, so as to inhibit the growth and breeding of liver cancer cells.
2010, (Wei, W., the Effectsofmyricetinontheapoptosisofbladdercancerc such as Wei Wei ellBIU-87[J].JournalofChongqingMedicalUniversity,2010,35(12):1791-1793) have studied Myricetin induces the mechanism of bladder cancer cell line BIU-87 apoptosis, by cultivating human bladder cancer cell strain BIU-87, adds in different Concentration myricetin interferes, and cytomorphology variation is observed under inverted microscope；And utilize MTT and Hoechst33258 decoration methods Detect influence of the myricetin to bladder cancer cell line BIU-87 apoptosis；Afterwards gene participating in apoptosis is detected with RT-PCR The change of survivin and caspase-3 transcriptional levels, Western blot detect the expression feelings of survivin and caspase-3 Condition, the results showed that：Myricetin can induce transitional cell bladder carcinoma cell line BIU-87 Apoptosis, and significantly inhibit transcription and the table of survivin It reaches, while has up-regulation effect to caspase-3.
2011, (Phillips, the P. such as Phillips；Sangwan,V.；Borja-Cacho,D.； etal.Myricetininducespancreaticcancercelldeathviatheinductionofapoptosisandin hibitionofthephosphatidylinositol3-kinase(PI3K)signalingpathway[J] .Cancerletters,2011,308(2):181-188) have studied myricetin to pancreatic cancer cell in vivo with external work With.The study found that myricetin inhibits AktL phosphorylations in 25 μm of ol/L~200 μm ol/L in dosage accordance with tolerance, PI3 can be reduced The activity of kinases, the outer apoptosis of pancreatic cancer cell of inductor are dead；In vivo, myricetin passes through the abatement to tumour and cancer cell It shifts to treat pancreatic neoplasm.
2011, (Kang, the N.J. such as Kang；Jung,S.K.；Lee,K.W.；etal.Myricetinisapotentche mopreventivephytochemicalinskincarcinogenesis[J].AnnalsoftheNewYorkAcademyofS ciences,2011,1229(1):Inhibiting effect of the myricetin to mouse skin cancer cell 124-132) is had studied, research is found： Myricetin is by weakening Ultraviolet B, inducing the expression of COX-2, so as to inhibit cutaneum carcinoma apoptosis；Pass through the antibacterial work of action target The angiogenesis induced with PI3-K, therefore, myricetin are a promising chemopreventive agents for inhibiting growth of cancer cells.
Invention content
It is an object of the invention to design to synthesize the nitrogenous analog derivatives of myricetin of structure novels a series of, such compound Based on natural products myricetrin, a series of myricetin derivatives have been synthesized by structural modification, table is tested through active anticancer Bright, it is bright that myricetin derivative with myricetin and existing commercial medicament EpirubicinHydrochloride compares active anticancer It is aobvious to improve, and myricetin derivative is smaller to the cytotoxicity of breast cancer cell (MDA-MB-231), and such compound can be made To inhibit the drug of cancer cell.The nitrogenous analog derivative structure of prepared myricetin is represented by general formula (III)：
R3For (1) phenyl or substituted-phenyl；(2) heterocycle includes pyridyl group, furyl, thienyl, pyrrole radicals；
Substituted-phenyl on phenyl ring containing one or more methyl, ethyl, methoxyl group, ethyoxyl, n-propyl, isopropyl, Trifluoromethyl, nitro, amido.
In the content of present invention, substituted-phenyl can be on phenyl ring containing one or more methyl, ethyl, methoxyl group, ethyoxyl,
N-propyl, isopropyl, trifluoromethyl, nitro, amido.
In the content of present invention, compound has antitumor activity, is characterized in having to human breast cancer cell (MDA-MB-231) Good activity, purposes is the application in anticancer drug is prepared.
The preparation method of the logical formula (III) compound of the present invention be with myricetrin, halogenated alkane, bromoacetate, hydrazine hydrate, Aromatic aldehyde and substituted aroma aldehyde are raw material, are substituted, hydrolyze and condensation reaction synthesis target product, synthetic route are：
Synthetic method is as follows：
The first step：The preparation of 3- hydroxyl -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone
Myricetrin and K are added in round-bottomed flask2CO3It is dissolved in DMF, after stirring evenly, iodomethane is slowly added dropwise,
A few hours are stirred at room temperature, it is water-dispersible after stopping reaction, it is extracted with ethyl acetate, merging filtrate, merges organic Phase is concentrated under reduced pressure, concentrate then is dissolved in absolute ethyl alcohol, is warming up to reflux, and after solution clarification, flow back lower addition concentrated hydrochloric acid, Slowly have yellow solid precipitation, the reaction was continued 2h, cooling, refrigerator stands overnight, filters, obtain crude product, do not need to purify, The reaction of next step is directly used in,
Second step：3- fluoroacetic acid ethyl ester -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone Preparation
The product of the first step, K are sequentially added in there-necked flask2CO3And anhydrous propanone, after being stirred at room temperature uniformly, bromine second is added dropwise Acetoacetic ester, drop finish, and back flow reaction a few hours after stopping reaction, are cooled to room temperature, are poured into ice water after concentration, and crystallization filters, Filter cake is recrystallized to give target product with chloroform/water,
Third walks：2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromene -3- bases) oxygen Base) acethydrazide preparation
The product of second step, 80% hydrazine hydrate and absolute ethyl alcohol, back flow reaction, TCL contact plates are sequentially added in there-necked flask Tracking until the reaction is complete, is concentrated under reduced pressure after removing a large amount of solvents, and cooling has precipitation to generate precipitation, filters, and filter cake is with anhydrous Ethyl alcohol recrystallization obtains target product,
4th step：The preparation of myricetin acylhydrazone
The product and aromatic aldehyde of third step are sequentially added in there-necked flask, is dissolved with absolute ethyl alcohol, instills the vinegar of catalytic amount Acid, agitating and heating reflux, the tracking of TLC contact plates, until the reaction is complete, concentration of reaction solution, cooling have a large amount of Precipitation, take out Filter, filter cake are recrystallized to give target product with absolute ethyl alcohol.
This step is suitable for the synthesis of all above-mentioned nitrogenous analog derivatives of target compound myricetin.
Route of the present invention and preparation method have synthesized and have proved that the compound of antitumaous effect is as follows：
Compound 22:2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromene -3- bases) Oxygroup)-N'- (2- fluorine benzal) acethydrazide
Compound 23:2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromene -3- bases) Oxygroup)-N'- (4- methylbenzilidenes) acethydrazide
Compound 24:2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromene -3- bases) Oxygroup)-N'- (pyridine -2- methylenes) acethydrazide
Compound 25:2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromene -3- bases) Oxygroup)-N'- (furans -2- methylenes) acethydrazide
Compound 26:2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromene -3- bases) Oxygroup)-N'- ((3 methyl thiophene -2- bases) methylene) acethydrazide
Compound 27:N'- ((1H- pyrroles -2- bases) methylene) -2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- Trimethoxyphenyl) -4H- chromene -3- bases) oxygroup) acethydrazide
The nitrogenous analog derivative of myricetin that the present invention synthesizes has preferable active anticancer, available for preparing anticancer drug.
Description of the drawings
Fig. 1：Compound (9-18) acts on breast cancer cell MDA-MB-231 24,48,72 hours in the case where setting concentration Morphology Effects.
Fig. 2：Compound (19-27) acts on breast cancer cell MDA-MB-231 24,48,72 hours in the case where setting concentration Morphology Effects.
The present invention relates to 27 nitrogenous analog derivatives of myricetin all have good inhibitory activity to target tumor, it is positive Medicine is significantly too big (so that cell all broken cracking) to the toxicity of tumour cell, and the compound of this experiment synthesis is substantially to mesh Mark cellular damage very little, this inhibitory activity be mainly reflected in inhibit cell proliferation (cell quantity significantly becomes compared with the control It is few) or Cell differentiation inducing activity (it being obtained from morphological observation, cell is deformed cell simultaneously reduced number of, but It is that damage be not apparent), so these medicines have target tumor unusual inhibitory activity, it is worth further deeply being ground Study carefully.
Specific embodiment
This specific implementation example is only explanation of the invention, but does not limit the present invention, and the timely personnel in this field are readding Can as needed this embodiment be made the modification of no creative contribution after this specification by running through, but as long as in the present invention Right in all protected by Patent Law.
Embodiment one, 3- (3- (diethyl amino -1- bases) propoxyl group) -5,7- dimethoxys -2- (3,4,5- trimethoxies Phenyl) -4H- chromene -4- ketone (compound 1)
(1) synthesis of 3- hydroxyls -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone
Myricetrin 2.32g (5mmol) is added in round-bottomed flask and is dissolved in 11.06g in 60mLDMF (16mmol) K2CO3
After stirring 10min, 10mL (32mmol) iodomethane is slowly added in, 60h, filtering precipitation is stirred at room temperature, and use second Acetoacetic ester washs, and merging filtrate pours into filtrate in 100mL water, is extracted with ethyl acetate three times, merges organic phase, and decompression is dense Then concentrate is dissolved in the absolute ethyl alcohol of 30mL by contracting, be warming up to reflux, and after solution clarification, flow back lower addition 8mL concentrated hydrochloric acids, Slowly have yellow solid precipitation, the reaction was continued 2h, cooling, refrigerator stands overnight, filters, obtain crude product A, crude product A is not It needs to purify, is directly used in the reaction of next step.
(2) 3- (3- bromines propoxyl group) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone Synthesis
The product A1.17g (3mmol) of previous step and 1.66g (12mmol) K is added in round-bottomed flask2CO3, with 30mL's After DMF dissolvings, 2.42g (12mmol) 1,3- dibromopropanes are added in, react 12h at room temperature, ethyl acetate is solvent contact plate Tracking reaction, after stopping reaction, is dissipated with the moisture of 50mL, is extracted 3 times with ethyl acetate, each 25ml obtains organic phase successively With the HCl of 1N, saturation NaHCO3, after saturation NaCl aqueous solutions wash 2 times respectively, combined ethyl acetate layer uses anhydrous sodium sulfate Solvent is boiled off after drying, with reduced pressure chromatography (petroleum ether：Ethyl acetate=2:1, V/V) intermediate B 1, is obtained.
(3) target compound 3- (3- (diethyl amino -1- bases) propoxyl group) -5,7- dimethoxys -2- (3,4,5- trimethoxies Base phenyl) -4H- chromene -4- ketone synthesis：
The product B10.25g (0.5mmol) of previous step, anhydrous K are added in round-bottomed flask2CO30.14g (1mmol) and 25mLDMF adds in 0.70g (1mmol) diethylamine after stirring 10min, is reacted at room temperature for 24 hours, with (chloroform：Methanol=5:1, V/V it is) the tracking reaction of solvent contact plate, after stopping reaction, adds in 50mL moisture and dissipate, be extracted with ethyl acetate three times, every time 25ml merges the HCl, saturation NaHCO of organic phase 1N3, after saturation NaCl aqueous solutions wash 2 times respectively, combined ethyl acetate layer, Solvent is boiled off after being dried with anhydrous sodium sulfate, with reduced pressure chromatography (chloroform：Methanol=10:1, V/V) target product, is obtained.
Embodiment two, 5,7- dimethoxys -3- (4- (pyrrolidin-1-yl) butoxy) -2- (3,4,5- trimethoxy-benzenes Base) -4H- chromene -4- ketone (compound 7)
(1) synthesis of 3- hydroxyls -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone
As embodiment one (1) condition and method synthesize.
(2) 3- (4- bromines butoxy) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone Synthesis
If embodiment one (2) condition and method synthesize, difference lies in the Isosorbide-5-Nitrae-dibromobutanes for adding in 2.56g.
(3) 5,7- dimethoxys -3- (4- (pyrrolidin-1-yl) butoxy) -2- (3,4,5- trimethoxyphenyls) -4H- The synthesis of chromene -4- ketone：
If embodiment one (3) condition and method synthesize, difference lies in the pyrrolidines for adding in 0.68g.
Using similar synthetic method, the following institute of structure of the part myricetin derivative of class containing Heterocyclylalkyl synthesized Show：
Embodiment three, 5,7- dimethoxys -3- (4- (piperazine -1- bases) butoxy) -2- (3,4,5- trimethoxy-benzenes Base) -4H- chromenes -4-
(1) synthesis of 3- hydroxyls -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone
As embodiment one (1) condition and method synthesize.
(2) 3- (4- bromines butoxy) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone Synthesis
As embodiment two (2) condition and method synthesize.
(3) 5,7- dimethoxys -3- (4- (piperazine -1- bases) butoxy) -2- (3,4,5- trimethoxyphenyls) -4H- colors The synthesis of alkene -4- ketone：
The product 1.05g (2mmol) of previous step, anhydrous K are added in round-bottomed flask2CO31.38g (10mmol) and 50mLDMF adds in 1.94g (10mmol) piperazine hexahydrate piperazine after stirring 10min, is reacted at room temperature for 24 hours, with (chloroform：First Alcohol=5:1, V/V) it is the tracking reaction of solvent contact plate, after stopping reaction, adds in 50mL moisture and dissipate, be extracted with ethyl acetate three It is secondary, merge the HCl, saturation NaHCO of organic phase 1N3, after saturation NaCl aqueous solutions wash 2 times respectively, combined ethyl acetate layer is used Solvent is boiled off after anhydrous sodium sulfate drying, with reduced pressure chromatography (chloroform：Methanol=15:1, V/V) target product, is obtained.
Embodiment four, 3- (4- (4- (4- fluoro benzoyls) piperazine -1- bases) butoxy) -5,7- dimethoxys -2- (3, 4,5- trimethoxyphenyls) -4H- chromene -4- ketone (compound 12)
(1) synthesis of 3- hydroxyls -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone
As embodiment one (1) condition and method synthesize.
(2) 3- (4- bromines butoxy) -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone It prepares
As embodiment two (2) condition and method synthesize.
(3) 5,7- dimethoxys -3- (4- (piperazine -1- bases) butoxy) -2- (3,4,5- trimethoxyphenyls) -4H- colors The synthesis of alkene -4- ketone
As embodiment three (3) condition and method synthesize.
(4) 3- (4- (4- (4- fluoro benzoyls) piperazine -1- bases) butoxy) -5,7- dimethoxys -2- (3,4,5- front threes Phenyl) -4H- chromene -4- ketone synthesis：
In round-bottomed flask, under condition of ice bath, add in parafluorobenzoic acid 0.046g (0.33mmoL) and HATU0.137g (0.36mmoL) is stirred under ice bath together with the triethylamine that 1mL is added in after the drying DCM dissolvings of 10mL Then 30min removes ice bath, the product 0.159g (0.3mmoL) for adding in third step reacts 12h, TLC tracking reactions at room temperature To no significant change (solvent:Chloroform:Methanol=5:1, V/V) after, stopping reaction, reaction solution is washed with water 3 times, every time DCM is removed under reduced pressure after anhydrous sodium sulfate drying in 20mL, then reduced pressure chromatography separation (chloroform:Methanol=10:1, V/V) it, obtains Target product.
Embodiment five, 3- (4- (4- (4- chlorobenzene formacyls) piperazine -1- bases) butoxy) -5,7- dimethoxys -2- (3, 4,5- trimethoxyphenyls) -4H- chromene -4- ketone (compound 13)
(1) synthesis of 3- hydroxyls -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone
As embodiment one (1) condition and method synthesize.
(2) 3- oxygen (4- bromobutyls) -3 ', the preparation of 4 ', 5,5 ', 7- pentamethoxyl myricetins
As embodiment two (2) condition and method synthesize.
(3) 5,7- dimethoxys -3- (4- (piperazine -1- bases) butoxy) -2- (3,4,5- trimethoxyphenyls) -4H- colors The synthesis of alkene -4- ketone
As embodiment three (3) condition and method synthesize.
(4) 3- (4- (4- (4- chlorobenzene formacyls) piperazine -1- bases) butoxy) -5,7- dimethoxys -2- (3,4,5- front threes Phenyl) -4H- chromene -4- ketone synthesis：
If embodiment three (4) condition and method synthesize, difference lies in the parachlorobenzoic-acids for adding in 0.052g.
Using similar synthetic method, the following institute of the structure of the derivative of part piperazine acidamide myricetin synthesized Show：
Embodiment six, 2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromenes -3- Base) oxygroup)-N'- (2- fluorine benzal) acethydrazide (compound 22)
(1) synthesis of 3- hydroxyls -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone
As embodiment one (1) condition and method synthesize.
(2) system of 3- fluoroacetic acid ethyl ester -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone It is standby
The product 1.17g (3mmol) of the first step, anhydrous K are sequentially added in there-necked flask2CO30.5g (3.6mmol) and nothing After 30min is stirred at room temperature, bromoacetate 0.4mL (3.6mmol) is added dropwise in water acetone 30mL, and drop finishes, and back flow reaction for 24 hours, cools down It to room temperature, pours into ice water, crystallization, filters after reduced pressure, filter cake is recrystallized to give target product with chloroform/water.
(3) 2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromene -3- bases) oxygroup) The preparation of acethydrazide
Sequentially add the product 1.42g (3mmol) of second step in there-necked flask, 80% hydrazine hydrate 0.66mL (10mmol) and Absolute ethyl alcohol 30mL stirs lower back flow reaction 2h, TCL contact plate tracking, until the reaction is complete, a large amount of solvents is removed under reduced pressure, cools down, Crystallization, filters, and filter cake is recrystallized to give target product with absolute ethyl alcohol.
(4) 2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromene -3- bases) oxygroup) - The synthesis of N'- (2- fluorine benzal) acethydrazide：
The product 0.15g (0.33mmol), o fluorobenzaldehyde 0.045g of third step are sequentially added in there-necked flask (0.36mmol), 25mL absolute ethyl alcohols and catalytic amount acetic acid, agitating and heating reflux 2h, the tracking of TLC contact plates, until the reaction is complete, Concentration of reaction solution, cooling, crystallization filter, and filter cake is recrystallized to give target product with absolute ethyl alcohol.
Embodiment seven, 2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromenes -3- Base) oxygroup)-N'- (4- methylbenzilidenes) acethydrazide (compound 23)
(1) synthesis of 3- hydroxyls -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone
As embodiment one (1) condition and method synthesize.
(2) system of 3- fluoroacetic acid ethyl ester -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone It is standby
As embodiment six (2) condition and method synthesize.
(3) 2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromene -3- bases) oxygroup) The preparation of acethydrazide
As embodiment six (3) condition and method synthesize.
(4) 2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromene -3- bases) oxygroup) - The synthesis of N'- (4- methylbenzilidenes) acethydrazide：
If embodiment six (4) condition and method synthesize, difference lies in the p-tolyl aldehydes for adding in 0.044g.
Using similar synthetic method, the structure of part myricetin acylhydrazone synthesized is as follows：
The spectral data of the nitrogenous analog derivative of myricetin of synthesis is as follows：
2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromene -3- bases) oxygroup)-N'- (2- luorobenzyls) acethydrazide (compound 22)
Yellow solid, yield：78.4%, m.p.136~138 DEG C；IR(KBr,cm-1):νmax1699,1683,1620, 1604,1558,1417,1361,1246,1207,1124,1109,1012,819；1HNMR(500MHz,CDCl3)δ:3.92- 3.99(m,15H,5×OCH3),4.35(s,2H,CH2), 6.40 (d, J=2.3Hz, 1H, H-6), 6.54 (d, J=2.3Hz, 1H, ), H-8 7.07 (J=18.9Hz, 1H), 7.16 (t, J=14.9Hz, 1H), 7.22 (overlappings, 2H, H-2 ', H-6 '), 7.35 (q, J=20.6Hz, 1H), 8.15 (t, J=13.7Hz, 1H), 9.65 (s, 1H, NH), 12.35 (s, 1H, N=CH)；13CNMR(125MHz,CDCl3)δ:174.7 (C-4), 165.6 (C=O), 164.7 (C-7), 161.1 (C-9), 160.6 (C), 159.1(C-2),154.2(C-5),153.6(C-3’,C-5’),142.6(CH),141.3(C-4’),140.8(C-3),132.0 (CH),127.6(CH),124.8(C-1’),124.4(CH),121.8(C),115.7(CH),108.8(C-10),105.7(C- 6’,C-2’),96.5(C-6),92.7(C-8),73.2(OCH2),61.2(4’-OCH3),56.6(7-OCH3),56.5(3’,5’- OCH3),56.0(8-OCH3)；MS(ESI,m/z):567.3[M+H]+,589.2[M+Na]+.
2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromene -3- bases) oxygroup)-N'- (4- methylbenzilidenes) acethydrazide (compound 23)
Pale solid, yield：82.3%, m.p.152~154 DEG C；IR(KBr,cm-1):νmax1699,1683,1620, 1604,1558,1506,1417,1354,1247,1219,1124,1109,1011,819；1HNMR(500MHz,CDCl3)δ: 2.36(s,3H,CH3),3.92-3.99(m,15H,5×OCH3),4.35(s,2H,CH2), 6.40 (d, J=2.3Hz, 1H, H- 6), 6.54 (d, J=2.3Hz, 1H, H-8), 7.19 (d, J=8Hz, 2H, 2CH), 7.21 (overlappings, 2H, H-2 ', H- 6 '), 7.71 (d, J=8Hz, 2H, CH), 8.35 (s, 1H, NH), 12.10 (s, 1H, N=CH)；13CNMR(125MHz,CDCl3) δ:174.7 (C-4), 165.2 (C=O), 164.9 (C-7), 161.1 (C-9), 159.1 (C-2), 154.2 (C-5), 153.6 (C- 3’,C-5’),149.5(C),141.5(C-4’),140.8(C-3),131.1(C),129.6(CH),129.4(CH),128.5 (CH),127.9(CH),124.8(C-1’),108.8(C-10),105.7(C-6’,C-2’),96.5(C-6),92.8(C-8), 73.3(OCH2),61.2(4’-OCH3),56.7(7-OCH3),56.5(3’,5’-OCH3),56.0(8-OCH3),21.7(CH3)； MS(ESI,m/z):563.3[M+H]+,585.3[M+Na]+.
2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromene -3- bases) oxygroup)-N'- (pyridine -2- ylmethyls) acethydrazide (compound 24)
Faint yellow solid, yield：55.6%, m.p.176~178 DEG C；IR(KBr,cm-1):νmax1699,1683,1602, 1588,1506,1417,1361,1244,1211,1126,1012,819；1HNMR(500MHz,CDCl3)δ:3.92-3.99(m, 15H,5×OCH3),4.36(s,2H,CH2), 6.40 (d, J=2.3Hz, 1H, H-6), 6.53 (d, J=2.3Hz, 1H, H-8), 7.22 (overlappings, 2H, H-2 ', H-6 '), 7.27 (t, J=13.3Hz, 1H), 7.71 (t, J=15.4Hz, 1H), 8.20 (d, J=8Hz, 1H), 8.53 (s, 1H, NH), 8.62 (d, J=4.6Hz, 1H), 12.53 (s, 1H, N=CH)；13CNMR (125MHz,CDCl3)δ:174.7 (C-4), 165.9 (C=O), 164.8 (C-7), 161.2 (C-9), 159.1 (C-2), 154.1 (C-5),153.6(C-3’,C-5’),153.3(C),149.6(CH),149.4(CH),141.4(C-4’),140.8(C-3), 136.4(CH),127.6(CH),124.8(C-1’),121.3(CH),108.8(C-10),105.7(C-6’,C-2’),96.5 (C-6),92.7(C-8),73.2(OCH2),61.2(4’-OCH3),56.6(7-OCH3),56.5(3’,5’-OCH3),56.0(8- OCH3)；MS(ESI,m/z):550.3[M+H]+,572.2[M+Na]+.
2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromene -3- bases) oxygroup)-N'- (furans -2- methylenes) acethydrazide (compound 25)
Pale solid, yield：73.2%, m.p.172~174 DEG C；IR(KBr,cm-1):νmax1699,1683,1608, 1558,1506,1417,1359,1246,1217,1126,1066,1014,819；1HNMR(500MHz,CDCl3)δ:3.92- 3.99(m,15H,5×OCH3),4.32(s,2H,CH2), 6.41 (d, J=2.3Hz, 1H, H-6), 6.48 (q, J=5.1Hz, 1H, ), CH 6.54 (d, J=2.3Hz, 1H, H-8), 6.86 (d, J=3.4Hz, 1H, CH), 7.20 (overlappings, 2H, H-2 ', H-6 '), 7.51 (d, J=1.15Hz, 1H, CH), 8.30 (s, 1H, NH), 12.25 (s, 1H, N=CH)；13CNMR(125MHz, CDCl3)δ:174.8 (C-4), 165.2 (C=O), 164.9 (C-7), 161.1 (C-9), 159.1 (C-2), 154.2 (C-5), 153.6(C-3’,C-5’),149.5(C),144.7(CH),141.5(C-4’),140.8(C-3),138.8(CH),124.8(C- 1’),113.3(CH),111.9(CH),108.8(C-10),105.7(C-6’,C-2’),96.6(C-6),92.8(C-8),73.3 (OCH2),61.2(4’-OCH3),56.7(7-OCH3),56.5(3’,5’-OCH3),56.0(8-OCH3)；MS(ESI,m/z): 539.3[M+H]+,561.2[M+Na]+.
2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromene -3- bases) oxygroup)-N'- ((3 methyl thiophene -2- bases) methylene) acethydrazide (compound 26)
Pale solid, yield：65.9%, m.p.132~134 DEG C；IR(KBr,cm-1):νmax1699,1681,1620, 1606,1558,1506,1417,1354,1246,1217,1126,1107,1064,1010,816；1HNMR(500MHz,CDCl3) δ:2.42(s,3H,CH3),3.92-3.99(m,15H,5×OCH3),4.32(s,2H,CH2), 6.41 (d, J=2.3Hz, 1H, H- 6), 6.54 (d, J=2.3Hz, 1H, H-8), 6.84 (d, J=5.15Hz, 1H, CH), 7.21 (overlappings, 2H, H-2 ', H-6 '), 7.28 (d, J=5.15Hz, 1H, CH), 8.63 (s, 1H, NH), 12.08 (s, 1H, N=CH)；13CNMR(125MHz, CDCl3)δ:174.7 (C-4), 164.9 (C=O), 164.9 (C-7), 161.1 (C-9), 159.1 (C-2), 154.1 (C-5), 153.6(C-3’,C-5’),144.1(C),141.4(C-4’),140.8(C-3),140.5(C),132.5(CH),130.5 (CH),128.0(CH),124.8(C-1’),108.8(C-10),105.7(C-6’,C-2’),96.5(C-6),92.8(C-8), 73.3(OCH2),61.2(4’-OCH3),56.7(7-OCH3),56.5(3’,5’-OCH3),56.0(8-OCH3),14.2(CH3)； MS(ESI,m/z):569.2[M+H]+,591.2[M+Na]+
N'- ((1H- pyrroles -2- bases) methylene) -2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxy-benzenes Base) -4H- chromene -3- bases) oxygroup) acethydrazide (compound 27)
Pale solid, yield：72.4%, m.p.135~137 DEG C；IR(KBr,cm-1):νmax1699,1681,1620, 1602,1558,1506,1417,1354,1244,1213,1126,1107,1039,1006,815；1HNMR(500MHz,CDCl3) δ:3.92-4.00(m,15H,5×OCH3),4.32(s,2H,CH2), 6.25 (d, J=2.3Hz, 1H, H-6), 6.41 (d, J= 2.3Hz,1H,H-8),6.54(m,2H,2CH),6.91(s,1H,CH),7.21(overlappings,2H,H-2’,H-6’), 8.23 (s, 1H, NH), 9.54 (s, 1H, NH), 12.11 (s, 1H, N=CH)；13CNMR(125MHz,CDCl3)δ:174.8(C- 4), 165.2 (C=O), 164.9 (C-7), 161.0 (C-9), 159.1 (C-2), 154.1 (C-5), 153.6 (C-3 ', C-5 '), 141.4(C-4’),140.8(C-3),140.8(CH),127.2(C),124.8(C-1’),124.3(CH),114.8(CH), 109.8(CH),108.8(C-10),105.7(C-6’,C-2’),96.5(C-6),92.8(C-8),73.2(OCH2),61.2 (4’-OCH3),56.7(7-OCH3),56.5(3’,5’-OCH3),56.0(8-OCH3)；MS(ESI,m/z):538.3[M+H]+, 560.2[M+Na]+The external increasing of embodiment eight, compound to cancer cell MDA-MB-231, A549, PC-3, HeLa and SiHa Grow inhibitory activity test
Human breast cancer cell MDA-MB-231 is cultivated with the DMEM of 10%FBS, human lung cancer cell A549, human prostata cancer PC-3, proliferating epidermal cancer cell HeLa and human cervical cancer 1 squamous cell carcinoma SiHa are cultivated with the RPMI1640 of 10%FBS, 37 DEG C, 5% CO2Saturated humidity incubator in cultivate, change within 2 days a culture solution, pass a second generation within 4-6 days.Growth period cell of taking the logarithm is real Test object.Cell 0.025% trypsase (containing 0.5mMEDTA) digestion process.20mM compounds are dissolved in DMSO as storage Standby liquid.Before use, directly required concentration is diluted to culture medium.Negative control group adds in and drug same volume DMSO, positive controls add in and are tested Farmorubine Hydrochloride and Gefitinib of the drug with concentration.DMSO in treatment agent Ultimate density is no more than 0.1% (v/v).
Take the logarithm growth period cell, after 0.025% trypsin digestion, be resuspended in DMEM containing 10%FBS or In RPMI1640 culture mediums, with 4.5 × 104The final concentration of a/mL is inoculated on 96 well culture plates, per 100 μ L of hole, the rightmost side one Be classified as blank control group, add it is acellular have serum DMEM or RPMI1640 culture medium, be placed in 37 DEG C, 5%CO2Saturated humidity It is cultivated in incubator.Sop up culture medium afterwards for 24 hours, add in the drug containing various concentration has blood serum medium, per 200 μ L of hole, blank Control group adds 200 μ L complete mediums to handle the requirement of experiment time respectively per hole, removes supernatant, adds 100 μ L/well concentration The MTT of 0.5mg/mL.10% SDS of 100 μ L/well is added after culture 4h again.After 10h makes crystal fully dissolve at 37 DEG C It takes out, 5min is swung in microseism, places 30min at room temperature, OD values is surveyed under A595 wavelength, and calculate cell activity, inhibiting rate and P Value.
Using the concentration of drug or processing time as horizontal axis, OD values or inhibiting rate are the longitudinal axis, draw curve.Per concentration of specimens Six holes are repeated, each experiment in triplicate, is averaged as final result.
Experimental result carries out variance analysis, P with SPSS softwares<It is significant difference when 0.05, p<It is extremely aobvious for difference when 0.01 It writes.The inhibiting rate calculation formula of cell Proliferation is as follows：
1 myricetin nitrogen containing derivative of table is to the in-vitro multiplication inhibitory activity of breast cancer cell MDA-MB-231
Note：* compound in the case where setting concentration to MDA-MB-231 inhibiting rates and negative control group (DMSO) inhibiting rate difference Property the significant difference (P ＜ 0.05) of analysis.
2 myricetin nitrogen containing derivative of table is to in-vitro multiplication inhibitory activity (10 μ of A549, PC-3, HeLa and SiHa cancer cell M)
Note：* compound under a concentration of 10 μM to cancer cell A549, PC-3, HeLa and SiHa inhibiting rate and negative control The significant difference of group (DMSO) inhibiting rate difference analysis (P ＜ 0.05).
Show that more than compound all has good suppression to target tumor MDA-MB-231 from the data and attached drawing of table 1 System activity, the wherein inhibitory activity of compound 25 is compared with positive drug Farmorubine Hydrochloride, in same dosage and action time It is higher than positive drug, most it is worth mentioning that positive drug is significantly too big (so that cell whole is crushed and split to the toxicity of tumour cell Solution), the noval chemical compound synthesized by this patent substantially damages target cell very little, and it is thin that this inhibitory activity is mainly reflected in inhibition (from morphological observation, we are not difficult to send out the proliferation (cell quantity significantly tails off compared with the control) or Cell differentiation inducing activity of born of the same parents Existing, cell is deformed cell simultaneously reduced number of, but it is not apparent to damage)；It can be seen that from the data of table 2, The nitrogenous analog derivative of synthesized myricetin also has good inhibition to cancer cells such as A549, PC-3, HeLa and SiHa, The inhibition of part of compounds is better than positive control medicament, shows that this series compound can be used as anticancer drug into traveling one The research of step.

Claims (4)

1. the nitrogenous analog derivative of myricetin, it is characterized in that structure is represented by general formula (III)：
R3For furyl.
2. application of the nitrogenous analog derivative of myricetin described in claim 1 in anticancer drug is prepared.
3. according to the preparation method of the nitrogenous analog derivative of myricetin described in claim 1, it is characterised in that logical formula (III) compound Preparation method be using myricetrin, iodomethane, bromoacetate, hydrazine hydrate, aldehyde R-CHO as raw material, be substituted and condensation reaction Target product is synthesized, synthetic reaction route is:
Wherein R, R3For furyl.
4. the preparation method of the nitrogenous analog derivative of myricetin according to claim 3, it is characterized in that being substituted and being condensed conjunction Into the synthetic method of logical formula (III) is：
The first step：The preparation of 3- hydroxyl -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone
Myricetrin and K are added in round-bottomed flask2CO3It is dissolved in DMF, after stirring evenly, iodomethane is slowly added dropwise,
It is stirred at room temperature 60 hours, it is water-dispersible after stopping reaction, it is extracted with ethyl acetate, merges organic phase, be concentrated under reduced pressure, so Concentrate is dissolved in absolute ethyl alcohol afterwards, is warming up to reflux, after solution clarification, flow back it is lower add in concentrated hydrochloric acid, slowly there is yellow to consolidate Body is precipitated, the reaction was continued 2h, and cooling, refrigerator is stood overnight, and filters, obtains crude product, do not need to purify, and is directly used in next step Reaction,
Second step：The system of 3- fluoroacetic acid ethyl ester -5,7- dimethoxys -2- (3,4,5- trimethoxyphenyls) -4H- chromene -4- ketone It is standby
The product of the first step, K are sequentially added in there-necked flask2CO3And anhydrous propanone, after being stirred at room temperature uniformly, bromoacetic acid second is added dropwise Ester, drop finish, and back flow reaction 24 hours after stopping reaction, is cooled to room temperature, is poured into ice water after concentration, and crystallization filters, filter cake Target product is recrystallized to give with chloroform/water,
Third walks：2- ((5,7- dimethoxy-4 's-oxo -2- (3,4,5- trimethoxyphenyls) -4H- chromene -3- bases) oxygroup) The preparation of acethydrazide sequentially adds the product of second step, 80% hydrazine hydrate and absolute ethyl alcohol in there-necked flask, back flow reaction 2h, TCL contact plates track, and until the reaction is complete, are concentrated under reduced pressure after removing a large amount of solvents, and cooling has precipitation to generate precipitation, filters, filter cake Target product is recrystallized to give with absolute ethyl alcohol,
4th step：The preparation of the nitrogenous analog derivative of myricetin
The product and aldehyde R-CHO of third step are sequentially added in there-necked flask, is dissolved with absolute ethyl alcohol, instills the acetic acid of catalytic amount, Agitating and heating reflux 2h, the tracking of TLC contact plates, until the reaction is complete, concentration of reaction solution, cooling have a large amount of Precipitation, take out Filter, filter cake are recrystallized to give formula (III) compound with absolute ethyl alcohol
Wherein, R, R3For furyl.
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