CN109265424A - A kind of flavone derivative and preparation method thereof and identification method - Google Patents
A kind of flavone derivative and preparation method thereof and identification method Download PDFInfo
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Abstract
The invention discloses a kind of flavone derivative, the derivant structure formula includes as shown in general formula (I) and general formula (II):Wherein, R1For alkyl or cycloalkyl, R2For alkyl or cycloalkyl, R1、R2Cycloaliphatic ring or heterocycle, R are formed with nitrogen-atoms3For alkyl, aryl or aralkyl, n value is 1~10.The invention also discloses a kind of preparation method of flavone derivative and identification methods.
Description
Technical field
The present invention relates to the researchs of flavone derivative, and in particular to a kind of flavone derivative and preparation method thereof and mirror
Determine method.
Background technique
It is out of control that malignant tumour is that cell caused by gene mutation is adjusted, and cell is free, unconfined proliferation.Cell cycle
Protein dependent kinase 1 (CDK1) and cell periodic protein B (Cyclin B), which are combined, forms compound, in other CDK/Cyclin
In the case where missing, catalysis substrate phosphorylation is remained to, cell is pushed to complete division process.Thus, CDK1 becomes anti-tumor drug
The potential target spot of research, the research of CDK1 inhibitor become the new direction of anti-tumor drug exploitation.
The CDKs inhibitor developed at present is mainly the emulative inhibitor of ATP.Although different CDKs are in the cell cycle
Effect played in process is different, but since their structures in ATP-binding domain domain are closely similar, so the CDKs of early development
Inhibitor is often non-selective.Non-selective CDKs inhibitor tends to cause nausea over the course for the treatment of, vomiting, tired
The side effects such as exhausted and liver dysfunction, therefore the CDKs inhibitor for developing selectivity is extremely urgent.
The crystal structure of CDK1 has not been reported.But the crystal structure based on kinases such as known CDK2, can with CDK1 into
Row Blast search obtains its crystal structure.The ATP binding site of CDK1 is analyzed, finds it mainly by hydrophobic pocket 1
(Pocket1) it can be formed with the amino acid residue of substrate interaction with hydrophobic pocket 2 (Pocket2) and sack.
Summary of the invention
For above-mentioned problems of the prior art, goal of the invention of the invention first is that having designed and developed a kind of flavones
Analog derivative.
Goal of the invention of the invention second is that having designed and developed the preparation method of above-mentioned flavone derivative.
Goal of the invention of the invention third is that having designed and developed the identification method of above-mentioned flavone derivative.
Technical solution provided by the invention are as follows:
A kind of flavone derivative, the derivant structure formula include as shown in general formula (I) and general formula (II):
Wherein, R1For alkyl or cycloalkyl, R2For alkyl or cycloalkyl, R1、R2Cycloaliphatic ring or miscellaneous is formed with nitrogen-atoms
Ring, R3For alkyl, aryl or aralkyl, n value is 1~10.
Preferably, R1、R2Nafoxidine ring is formed with nitrogen-atoms；
R1、R2Morpholine ring is formed with nitrogen-atoms；Or
R1、R2N methyl piperazine ring is formed with nitrogen-atoms.
Preferably, R1、R2It is propyl.
Preferably, R3For aryl.
The preparation method of the flavone derivative comprising take off grape alditol using the compound with general formula (III)
The compound with general formula (IV) is obtained after acid, replaces to obtain the compound with general formula (V) using amine methyl；
Esterification is carried out to the compound with general formula (V) and obtains the compound with general formula (I)；
Etherification reaction is carried out to the compound with general formula (V) and obtains the compound with general formula (II)；
Wherein, the compound with general formula (III), general formula (IV) and general formula (V) are as follows:
Wherein, R1For alkyl or cycloalkyl, R2For alkyl or cycloalkyl, R1、R2Cycloaliphatic ring or miscellaneous is formed with nitrogen-atoms
Ring.
Preferably, the chemical combination with general formula (IV) is obtained after taking off glucuronic acid using the compound with general formula (III)
Object, the process for replacing to obtain the compound with general formula (V) using amine methyl are as follows:
It takes the compound with general formula (III) to be dissolved in the pasty state with water, is slowly added to 50% sulfuric acid, 90 DEG C of water-bath machinery stir
It mixes to clarification, after the reaction was continued, is poured into when stirring in ready ice water, decompression suction filtration then is carried out to it, filter cake is washed with water
To weakly acidic pH, filtrate is discarded, filter cake is dried in vacuo, appropriate ethyl acetate is taken to be dispersed into uniform suspension, decompression filters, filter cake
It is washed with ethyl acetate, filter cake is dried in vacuo, obtain the compound with general formula (IV)；
It takes the compound with general formula (IV) appropriate, a certain amount of methanol dissolution is added, weighs the amine reagent and first of equivalent
Aldehyde is added in reaction flask, is reacted at 20-65 DEG C, and thin-layered chromatography detects reaction process, until the reaction is complete, a large amount of solid wait have
Body filters after being precipitated, and collects solid, washs solid in three times with a small amount of methanol, solid is dried in a vacuum drying oven, is obtained
Compound with general formula (V).
Preferably, esterification is carried out to the compound with general formula (V) and obtains the compound with general formula (I)
Process is as follows:
It is appropriate to weigh corresponding organic acid, a certain amount of anhydrous tetrahydro furan is added, N- hydroxy benzenes is added under agitation
And triazole, dicyclohexylcarbodiimide is then weighed, being dissolved in a certain amount of anhydrous tetrahydro furan then will with dropping funel
It is added drop-wise in above-mentioned reaction solution and stirs under the conditions of -5 DEG C, and reaction solution is filtered, and obtains white solid and clear filtrate, and filtrate is standby
With；
The compound with general formula (V) is taken, certain anhydrous tetrahydro furan is added, under agitation, is sequentially added to two
Methylamino pyridine, triethylamine, are stirred at room temperature, and active ester filtrate is then slowly dropped to this reaction with dropping funel
The reaction was continued in liquid, and thin-layered chromatography detects reaction process, reaches balance wait react, reaction solution is concentrated to dryness, silicagel column is used
Chromatography, polyamide column separation, thin layer preparation, the purifying of the methods of recrystallization obtain the compound with general formula (I).
Preferably, etherification reaction is carried out to the compound with general formula (V) and obtains the compound with general formula (II)
Process is as follows:
Take the compound with general formula (V), a certain amount of n,N-Dimethylformamide be added, under agitation, successively plus
Enter Isosorbide-5-Nitrae-dibromobutane, potassium carbonate, potassium iodide is stirred to react under the conditions of 60 DEG C~70 DEG C under nitrogen protection；It then will be above-mentioned
Reaction solution filters away extra potassium carbonate and potassium iodide, and a few drop formic acid are added in reaction solution, then depressurizes reaction solution dense
Be reduced to it is dry, concentrate cool after be added ice water compound is dispersed in water to form suspension, adjust pH to neutrality, then filter
Obtain filter cake；Filter cake is separated with silica gel column chromatography after vacuum drying, and purifying obtains the compound with general formula (II).
The identification method of the flavone derivative, which is characterized in that the compound identification process with general formula (I)
Include:
There to be the compound of general formula (I) to carry out after preliminary structure determines by nuclear magnetic resonance spectroscopy and carbon spectrum, and have
The quantity and displacement of the compound of general formula (IV) and the compound progress hydrogen atom with general formula (V) compare, and determine amine methylene
Response location and primary esterification position；
There to be the compound of general formula (I) to react with strontium chloride, and generate green to brown or even black precipitate, it is determined that raw
At the compound with general formula (I).
Preferably, will there is the compound of general formula (I) to include: with strontium chloride reaction process
It takes the compound with general formula (I) to set in small test tube, methanol dissolution is added, the methanol solution of strontium chloride is added, then
Add the methanol solution for having used ammonia saturated with vapor, paying attention to observation, whether there is or not precipitatings to generate.
The present invention compared with prior art possessed by the utility model has the advantages that
1, using CDK1 as target, target spot is clear, Computer-Aided Drug Design is combined with Rational drug design, with Huang
A kind of reed mentioned in ancient books element designs a kind of selective novel C DK1 inhibitor of synthesis for lead compound；
2,7 of baicalein and 8 are modified for the first time simultaneously, improves the selective inhibitory to CDK1；
3, using spectroscopy parsing and the method that combines of chemical identification, it was demonstrated that the esterification to baicalein mannich alkali
Occur on 7 phenolic hydroxyl groups with etherificate, it is determined that the accurate structural of target compound.
Detailed description of the invention
Fig. 1 is experimental design thinking of the invention.
Fig. 2 is the compound esterification schematic diagram of the present invention with general formula (V).
Specific embodiment
Present invention will be described in further detail below with reference to the accompanying drawings, to enable those skilled in the art referring to specification text
Word can be implemented accordingly.
Using baicalein as lead compound in the present invention, retain and amino acid knot on the outside of the hydrophobic pocket of the active region CDK1
Group necessary to closing, while hydrophobic group can be being introduced with the position in conjunction with CDK1 catalytic center Pocket1, to develop
The high novel flavonoids CDK1 inhibitor of high-efficiency low-toxicity, selectivity out.
As shown in Figure 1, the present invention with CDK1 (cell cycle protein dependent kinase 1) be target spot, set using rational drug
The Principle Method of meter, using baicalein as lead compound, retain can with the functional group that Pocket 2 be combined with each other in CDK1, to Huang
6 (7) hydroxyls of a kind of reed mentioned in ancient books element, 8 hydrogen atoms carry out selective modification, in 8 introducing amine methyl chains, the amino of enhancing and sack
The interaction of sour residue；Primary study introduces different substituents on 6 (7) hydroxyls, investigates itself and CDK1 catalytic center
The mosaic status of Pocket 1 illustrates its influence to anti-tumor activity, according to the difference of 6 connect substituents, by design
Compound is divided into A, two series of B, the i.e. ester derivant and ether derivant of baicalein；
Wherein, the synthetic route of A class compound is as follows:
The synthetic route of B class compound is as follows:
The present invention provides the flavone compounds with general formula (I) and general formula (II):
Wherein, R1For alkyl or cycloalkyl, R2For alkyl or cycloalkyl, R1、R2Cycloaliphatic ring or miscellaneous is formed with nitrogen-atoms
Ring, R3For alkyl, aryl or aralkyl, n value is 1~10.
In another embodiment, R1、R2Nafoxidine ring is formed with nitrogen-atoms.
In another embodiment, R1、R2Morpholine ring is formed with nitrogen-atoms.
In another embodiment, R1、R2N methyl piperazine ring is formed with nitrogen-atoms.
In another embodiment, R1、R2It is propyl.
In another embodiment, R3For aryl.
The present invention also provides a kind of preparation methods of flavone derivative, take off Portugal using the compound with general formula (III)
The compound with general formula (IV) is obtained after grape uronic acid, replaces to obtain the compound with general formula (V) using amine methyl；
Esterification is carried out to the compound with general formula (V) and obtains the compound with general formula (I)；
Etherification reaction is carried out to the compound with general formula (V) and obtains the compound with general formula (II)；
Wherein, the compound with general formula (III), general formula (IV) and general formula (V) are as follows:
Wherein, R1For alkyl or cycloalkyl, R2For alkyl or cycloalkyl, R1、R2Cycloaliphatic ring or miscellaneous is formed with nitrogen-atoms
Ring.
In another embodiment, R1、R2Nafoxidine ring is formed with nitrogen-atoms.
In another embodiment, R1、R2Morpholine ring is formed with nitrogen-atoms.
In another embodiment, R1、R2N methyl piperazine ring is formed with nitrogen-atoms.
In another embodiment, R1、R2It is propyl.
In another embodiment, R3For aryl.
In another embodiment, it obtains after taking off glucuronic acid using the compound with general formula (III) with general formula
(IV) compound, the process for replacing to obtain the compound with general formula (V) using amine methyl are as follows:
It takes the compound with general formula (III) to be dissolved in the pasty state with water, is slowly added to 50% sulfuric acid, 90 DEG C of water-bath machinery stir
It mixes to clarification, after the reaction was continued, is poured into when stirring in ready ice water, decompression suction filtration then is carried out to it, filter cake is washed with water
To weakly acidic pH, filtrate is discarded, filter cake is dried in vacuo, appropriate ethyl acetate is taken to be dispersed into uniform suspension, decompression filters, filter cake
It is washed with ethyl acetate, filter cake is dried in vacuo, obtain the compound with general formula (IV)；
It takes the compound with general formula (IV) appropriate, a certain amount of methanol dissolution is added, weighs the amine reagent and first of equivalent
Aldehyde is added in reaction flask, is reacted at 20-65 DEG C, and thin-layered chromatography detects reaction process, until the reaction is complete, a large amount of solid wait have
Body filters after being precipitated, and collects solid, washs solid in three times with a small amount of methanol, solid is dried in a vacuum drying oven, is obtained
Compound with general formula (V).
In another embodiment, esterification is carried out to the compound with general formula (V) and obtains that there is general formula (I)
The process of compound is as follows:
It is appropriate to weigh corresponding organic acid, a certain amount of anhydrous tetrahydro furan is added, N- hydroxy benzenes is added under agitation
And triazole, dicyclohexylcarbodiimide is then weighed, being dissolved in a certain amount of anhydrous tetrahydro furan then will with dropping funel
It is added drop-wise in above-mentioned reaction solution stirs 12 hours under the conditions of -5 DEG C, and reaction solution is filtered, white solid and clear filtrate are obtained,
Filtrate is spare；
The compound with general formula (V) is taken, certain anhydrous tetrahydro furan is added, under agitation, is sequentially added to two
Methylamino pyridine, triethylamine, are stirred at room temperature, and active ester filtrate is then slowly dropped to this reaction with dropping funel
The reaction was continued in liquid, and thin-layered chromatography detects reaction process, reaches balance wait react, reaction solution is concentrated to dryness, silicagel column is used
Chromatography, polyamide column separation, thin layer preparation, the purifying of the methods of recrystallization obtain the compound with general formula (I).
In another embodiment, etherification reaction is carried out to the compound with general formula (V) and obtains that there is general formula (II)
The process of compound is as follows:
Take the compound with general formula (V), a certain amount of n,N-Dimethylformamide be added, under agitation, successively plus
Enter Isosorbide-5-Nitrae dibromobutane, potassium carbonate, potassium iodide is stirred to react under the conditions of 60 DEG C~70 DEG C under nitrogen protection；It then will be above-mentioned
Reaction solution filters away extra potassium carbonate and potassium iodide, and a few drop formic acid are added in reaction solution, then depressurizes reaction solution dense
Be reduced to it is dry, concentrate cool after be added ice water compound is dispersed in water to form suspension, adjust pH to neutrality, then filter
Obtain filter cake；Filter cake is separated with silica gel column chromatography after vacuum drying, and purifying obtains the compound with general formula (II).
The present invention is further illustrated below with reference to specific embodiment.
Embodiment 1
It weighs scutelloside (such as formula (III) compound represented) 4g 20mL water to dissolve in the pasty state, is slowly added to 50% sulfuric acid
100mL, 90 DEG C of water-bath mechanical stirrings after the reaction was continued 5min, are poured into ready 500mL ice water, so to clarifying when stirring
Decompression suction filtration is carried out to it afterwards, filter cake is washed with water to weakly acidic pH, discards filtrate and takes appropriate acetic acid second after filter cake vacuum drying for 24 hours
Ester is dispersed into uniform suspension, and decompression filters, and filter cake is washed 3 times with ethyl acetate, for 24 hours by filter cake vacuum drying, obtains radix scutellariae
Element (such as formula (IV) compound represented) 1.74g, yield 71.9%.
Baicalein (such as formula (IV) compound represented) 1.08g (0.004mol) is weighed in 150mL reaction flask, first is added
Alcohol 30mL makees solvent, under agitation, sequentially adds 37% formalin 0.486mL (0.006mol), morpholine 0.696mL
(0.008mol) reacts reaction flask under the conditions of 55 DEG C, and thin-layered chromatography monitors reaction process, until the reaction is complete, has big
Yellow solid is measured to be precipitated；Yellow solid is filtered, filter cake (such as formula (V -1) compound represented) is washed with a small amount of methanol, will filter
Cake is dried in a vacuum drying oven, weighing: 1.38g, yield 93.5%.
Hydrogen nuclear magnetic resonance spectrum analysis:1H-NMR(DMSO-d6 600MHz)δ:8.09(m,2H,H-2′,6′),7.58-7.63
(m,3H,H-3′,4′,5′),6.96(s,1H,H-3),3.95(s,2H,H-9),3.62(s,4H,H-11,12),2.61(s,4H,
H-10,13).
Carbon-13 nmr spectra analysis:13C-NMR(DMSO-d6,151MHz)δ:182.7(C-4),163.0(C-2),154.7
(C-8a),148.5(C-5),146.4(C-7),132.3(C-4′),131.6(C-1′),129.7(2C-3′,5′),129.4(C-
6),126.7(2C-2′,6′),104.9(C-3),104.1(C-5a),100.6(C-8),66.5(2C-11,12),53.1(2C-
10,13),52.0(C-9).
It weighs benzoic acid 0.226g (0.0018mol), 30mL anhydrous tetrahydro furan is added, HOBT is added under agitation
(I-hydroxybenzotriazole) 0.354g (0.00262mol) then weighs DCC (N, N'- dicyclohexylcarbodiimide) 0.541g
(0.00262mol) is dissolved in 20mL tetrahydrofuran, is then added dropwise in above-mentioned reaction solution with dropping funel in -5 DEG C of items
It is stirred to react 12h under part, reaction solution is filtered, obtains white solid and clear filtrate, filtrate is spare.
8- morpholine methylene baicalein (such as formula (V -1) compound represented) 1.0g (0.00271mol) is weighed, nothing is added
Water tetrahydrofuran 50mL sequentially adds DMAP (4-dimethylaminopyridine) 0.066g (0.00054mol) under agitation, and three
Then above-mentioned spare filtrate is slowly dropped in this reaction solution with dropping funel, reaction is stirred at room temperature by ethamine 1mL
For 24 hours, reaction solution is concentrated to dryness, obtains yellow product, separate (eluant, eluent is methylene chloride: methanol 80:1) with silica gel column chromatography,
Target compound is further purified to obtain in recrystallization (such as formula (I -1) compound represented).
Hydrogen nuclear magnetic resonance spectrum analysis:1H-NMR(DMSO-d6,600MHz)δ:13.17(s,1H,5-OH),8.13(m,4H,H-
2′,6′,2″,6″),7.72-7.79(m,1H,H-4″),7.57-7.65(m,5H,H-3′,4′,5′,3″,5″),7.01(s,1H,
H-3),4.17(s,2H,H-9),3.68(s,4H,H-12,13),2.81(s,4H,H-11,14).
Carbon-13 nmr spectra analysis:13C-NMR(DMSO-d6,151MHz)δ:182.3(C-4),164.1(C-10),163.2
(C-2),160.7(C-8a),152.8(C-5),152.1(C-7),134.4(C-4″),132.5(C-1′),131.4(C-4′),
130.3(2C-2″,6″),129.7(2C-3′,5′),129.4(2C-3″,5″),129.2(C-1″),126.9(2C-2′,6′),
123.1(C-6),105.2(C-3),102.7(C-5a),99.5(C-8),65.8(2C-12,13),52.7(C-9),52.4(2C-
11,14).
Embodiment 2
It weighs scutelloside (such as formula (III) compound represented) 4g 20mL water to dissolve in the pasty state, is slowly added to 50% sulfuric acid
100mL, 90 DEG C of water-bath mechanical stirrings after the reaction was continued 5min, are poured into ready 500mL ice water, so to clarifying when stirring
Decompression suction filtration is carried out to it afterwards, filter cake is washed with water to weakly acidic pH, discards filtrate and takes appropriate acetic acid second after filter cake vacuum drying for 24 hours
Ester is dispersed into uniform suspension, and decompression filters, and filter cake is washed 3 times with ethyl acetate, for 24 hours by filter cake vacuum drying, obtains radix scutellariae
Element (such as formula (IV) compound represented) 1.74g, yield 71.9%.
Baicalein (such as formula (IV) compound represented) 1.08g (0.004mol) is weighed in 150mL reaction flask, first is added
Alcohol 30mL makees solvent, under agitation, sequentially adds 37% formalin 0.486mL (0.006mol), nafoxidine
0.496mL (0.006mol) reacts reaction flask under the conditions of 45 DEG C, and thin-layered chromatography monitors reaction process, until having reacted
Entirely, a large amount of yellow solids are precipitated；Yellow solid is filtered, washs the filter cake (chemical combination as shown in formula (V -2) with a small amount of methanol
Object), filter cake is dried in a vacuum drying oven, is weighed: 1.31g, yield 92.5%.
Hydrogen nuclear magnetic resonance spectrum analysis:1H-NMR(DMSO-d6,600MHz)δ:8.05-8.06(m,2H,H-2′,6′),7.57-
7.58(m,3H,H-3′,4′,5′),6.81(s,1H,H-3),4.35(s,2H,H-9),3.12(s,4H,H-10,13),1.90
(s,4H,H-11,12).
Carbon-13 nmr spectra analysis:13C-NMR(DMSO-d6,151MHz)δ:180.9(C-4),163.8(C-2),161.0
(C-8a),150.1(C-5),143.7(C-7),132.0(C-4′),131.7(C-1′),130.7(C-6),129.6(2C-3′,
5′),126.5(2C-2′,6′),104.9(C-3),101.0(C-5a),97.2(C-8),53.2(2C-10,13),49.7(C-
9),23.4(C-11,12).
It weighs P-methoxybenzoic acid 0.387g (0.00255mol), 30mL anhydrous tetrahydro furan is added, in stirring condition
Lower addition HOBT (I-hydroxybenzotriazole) 0.378g (0.0028mol), then weighing DCC, (N, N'- dicyclohexyl carbon two is sub-
Amine) 0.525g (0.00255mol), it is dissolved in 20mL tetrahydrofuran, is then added dropwise in above-mentioned reaction solution with dropping funel
It is stirred to react 12h under the conditions of -5 DEG C, reaction solution is filtered, obtains white solid and clear filtrate, filtrate is spare.
8- nafoxidine methylene baicalein (such as formula (V -2) compound represented) 1.0g (0.0028mol) is weighed, is added
Enter anhydrous tetrahydro furan 50mL, under agitation, sequentially adds DMAP (4-dimethylaminopyridine) 0.066g
Then above-mentioned spare filtrate is slowly dropped to this reaction solution with dropping funel by (0.00054mol), triethylamine 0.8mL
In, reaction is stirred at room temperature for 24 hours, reaction solution is concentrated to dryness, yellow product is obtained, (eluant, eluent is with silica gel column chromatography separation
Methylene chloride: methanol 70:1), target compound is further purified to obtain in recrystallization (such as formula (I -2) compound represented).
Hydrogen nuclear magnetic resonance spectrum analysis:1H-NMR(CDCl3, 600MHz) and δ: 12.89 (s, 1H, 5-OH), 8.24 (d, J=
12.0Hz, 2H, H-2 ", 6 "), 7.83 (d, J=6Hz, 2H, H-2 ', 6 '), 7.54 (m, 3H, H-3 ', 4 ', 5 '), 6.97 (d, J=
12.0Hz,2H,H-3″,5″),6.63(s,1H,H-3),4.28(s,2H,H-9),3.88(s,3H,H-15),2.87(s,4H,H-
11,14),1.92(s,4H,12,13).
Carbon-13 nmr spectra analysis:13C-NMR(CDCl3,151MHz)δ:182.4(C-4),164.2(C-10),163.8
(C-4″),162.9(C-2),160.5(C-8a),152.8(C-5),151.5(C-7),132.7(2C-2″,6″),131.7(C-
4′),131.6(C-1′),129.2(2C-3′,5′),126.1(2C-2′,6′),123.1(C-6),121.4(C-1″),113.7
(C-3″,5″),105.6(C-3),103.7(C-5a),98.8(C-8),55.5(C-15),53.6(2C-11,14),51.9(C-
9),23.7(2C-12,13).
Embodiment 3
It weighs scutelloside (such as formula (III) compound represented) 4g 20mL water to dissolve in the pasty state, is slowly added to 50% sulfuric acid
100mL, 90 DEG C of water-bath mechanical stirrings after the reaction was continued 5min, are poured into ready 500mL ice water, so to clarifying when stirring
Decompression suction filtration is carried out to it afterwards, filter cake is washed with water to weakly acidic pH, discards filtrate and takes appropriate acetic acid second after filter cake vacuum drying for 24 hours
Ester is dispersed into uniform suspension, and decompression filters, and filter cake is washed 3 times with ethyl acetate, for 24 hours by filter cake vacuum drying, obtains radix scutellariae
Element (such as formula (IV) compound represented) 1.74g, yield 71.9%.
Baicalein (such as formula (IV) compound represented) 1.08g (0.004mol) is weighed in 150mL reaction flask, first is added
Alcohol 30mL makees solvent, under agitation, sequentially adds 37% formalin 0.486mL (0.006mol), di-n-propylamine
0.656mL (0.0048mol) reacts reaction flask under the conditions of 45 DEG C, and thin-layered chromatography monitors reaction process, until having reacted
Entirely, a large amount of yellow solids are precipitated；Yellow solid is filtered, washs the filter cake (chemical combination as shown in formula (V -3) with a small amount of methanol
Object), filter cake is dried in a vacuum drying oven, is weighed: 1.41g, yield 92.5%.
Hydrogen nuclear magnetic resonance spectrum analysis:1H-NMR(DMSO-d6,600MHz)δ:12.57(s,1H,5-OH),8.04-8.06(m,
2H,H-2′,6′),7.56-7.61(m,3H,H-3′,4′,5′),6.85(s,1H,H-3),4.27(s,2H,H-9),2.77(t,J
=6Hz, 4H, H-10,13), 1.64 (m, 4H, H-11,14), 0.88 (t, J=6Hz, 6H, H-12,15)
Carbon-13 nmr spectra analysis:13C-NMR(DMSO-d6,151MHz)δ:181.7(C-4),161.8(C-2),160.7
(C-8a),148.8(C-5),144.9(C-7),132.0(C-1′),131.8(C-4′),130.3(C-6),129.6(2C-3′,
5),126.6(2C-2′,6′),105.0(C-3),102.3(C-5a),97.7(C-8),54.8(2C-10,13),50.4(C-9),
18.7(2C-11,14),11.8(2C-12,15).
It measures α-methacrylic acid 0.185mL (0.00217mol), 30mL anhydrous tetrahydro furan is added, under agitation
HOBT (I-hydroxybenzotriazole) 0.323g (0.00239mol) is added, then weighs DCC (N, N'- dicyclohexylcarbodiimide)
0.493g (0.00239mol), is dissolved in 20mL tetrahydrofuran, then with dropping funel be added dropwise in above-mentioned reaction solution in-
It is stirred to react 12h under the conditions of 5 DEG C, reaction solution is filtered, obtains white solid and clear filtrate, filtrate is spare.
8- di-n-propylamine methylene baicalein (such as formula (V -3) compound represented) 1.0g (0.00261mol) is weighed, is added
Anhydrous tetrahydro furan 50mL sequentially adds DMAP (4-dimethylaminopyridine) 0.066g (0.00054mol) under agitation,
Then above-mentioned spare filtrate is slowly dropped in this reaction solution by triethylamine 1mL with dropping funel, be stirred at room temperature anti-
For 24 hours reaction solution should be concentrated to dryness, yellow product is obtained, with silica gel column chromatography separation (eluant, eluent is methylene chloride: methanol 100:
1), target compound is further purified to obtain in recrystallization (such as formula (I -3) compound represented).
Hydrogen nuclear magnetic resonance spectrum analysis:1H-NMR(DMSO-d6,600MHz)δ:13.10(s,1H,5-OH),8.05-8.07(m,
2H,H-2′,6′),7.56-7.62(m,3H,H-3′,4′,5′),6.83(s,1H,H-3),6.23(s,1H,H-12E),5.84
(s, 1H, H-12Z), 4.35 (s, 2H, H-9), 2.92 (t, J=6Hz, 4H, H-11,14), 1.99 (s, 3H, H-19), 1.68 (m,
4H, H-12,15), 0.87 (t, J=6Hz, 6H, H-13,16)
Carbon-13 nmr spectra analysis:13C-NMR(DMSO-d6,151MHz)δ:181.0(C-4),167.4(C-10),164.8
(C-2),161.8(C-8a),153.3(C-5),152.1(C-7),135.9(C-17),132.0(C-4′),131.7(C-1′),
129.6(2C-3′,5′),127.4(C-6),126.7(2C-2′,6′),124.3(C-18),105.0(C-3),99.6(C-5a),
97.2(C-8),54.4(2C-11,14),50.1(C-9),18.7(C-19),17.9(2C-12,15),11.6(2C-13,16).
Embodiment 4
It weighs scutelloside (such as formula (III) compound represented) 4g 20mL water to dissolve in the pasty state, is slowly added to 50% sulfuric acid
100mL, 90 DEG C of water-bath mechanical stirrings after the reaction was continued 5min, are poured into ready 500mL ice water, so to clarifying when stirring
Decompression suction filtration is carried out to it afterwards, filter cake is washed with water to weakly acidic pH, discards filtrate and takes appropriate acetic acid second after filter cake vacuum drying for 24 hours
Ester is dispersed into uniform suspension, and decompression filters, and filter cake is washed 3 times with ethyl acetate, for 24 hours by filter cake vacuum drying, obtains radix scutellariae
Element (such as formula (IV) compound represented) 1.74g, yield 71.9%.
Baicalein (such as formula (IV) compound represented) 1.08g (0.004mol) is weighed in 150mL reaction flask, first is added
Alcohol 30mL makees solvent, under agitation, sequentially adds 37% formalin 0.486mL (0.006mol), N methyl piperazine
0.443mL (0.0048mol) reacts reaction flask under the conditions of 50 DEG C, and thin-layered chromatography monitors reaction process, until having reacted
Entirely, a large amount of yellow solids are precipitated；Yellow solid is filtered, washs the filter cake (chemical combination as shown in formula (V -4) with a small amount of methanol
Object), filter cake is dried in a vacuum drying oven, is weighed: 1.37g, yield 89.5%.
Hydrogen nuclear magnetic resonance spectrum analysis:1H-NMR(DMSO-d6,600MHz)δ:8.07-8.08(m,2H,H-2′,6′),7.57-
7.61(m,3H,H-3′,4′,5′),6.93(s,1H,H-3),4.02(s,2H,H-9),2.69(s,4H,H-10,13),2.51
(s,4H,H-11,12),2.20(s,3H,H-14).
Carbon-13 nmr spectra analysis:13C-NMR(DMSO-d6,151MHz)δ:182.4(C-4),162.6(C-2),156.2
(C-8a),148.4(C-5),146.0(C-7),132.2(C-4′),131.6(C-1′),129.6(2C-3′,5′),126.7
(2C-2′,6′),104.9(C-3),103.7(C-5a),100.0(C-8),54.7(2C-10,13),52.2(2C-11,12),
45.9(C-9).
It measures α-methacrylic acid (0.0018mol), 30mL anhydrous tetrahydro furan is added, HOBT is added under agitation
(I-hydroxybenzotriazole) 0.323g (0.00239mol) then weighs DCC (N, N'- dicyclohexylcarbodiimide) 0.493g
(0.00239mol) is dissolved in 20mL tetrahydrofuran, is then added dropwise in above-mentioned reaction solution with dropping funel in -5 DEG C of items
It is stirred to react 12h under part, reaction solution is filtered, obtains white solid and clear filtrate, filtrate is spare.
8-N- methyl piperazine methylene baicalein (such as formula (V -4) compound represented) 1.0g (0.00261mol) is weighed,
Anhydrous tetrahydro furan 50mL is added and sequentially adds DMAP (4-dimethylaminopyridine) 0.066g under agitation
Then above-mentioned spare filtrate is slowly dropped in this reaction solution by (0.00054mol), triethylamine 1mL with dropping funel,
Reaction is stirred at room temperature for 24 hours, reaction solution is concentrated to dryness, yellow product is obtained, (eluant, eluent is dichloro with silica gel column chromatography separation
Methane: methanol 80:1), target compound is further purified to obtain in recrystallization (such as formula (I -4) compound represented).
Hydrogen nuclear magnetic resonance spectrum analysis:1H-NMR(DMSO-d6,600MHz)δ:13.06(s,1H,5-OH),7.08-7.10(m,
2H,H-2′,6′),7.57-7.63(m,3H,H-3′,4′,5′),6.93(s,1H,H-3),6.26(s,1H,H-12E),5.87
(s,1H,H-12Z),4.20(s,2H,H-9),2.89(s,4H,H-14,17),2.51(s,4H,H-15,16),2.23(s,3H,
H-18),2.00(s,H,H-13).
Carbon-13 nmr spectra analysis:13C-NMR(DMSO-d6,151MHz)δ:181.8(C-4),164.8(C-10),163.0
(C-2),162.6(C-8a),152.9(C-5),152.0(C-7),135.6(C-11),132.3(C-4′),131.5(C-1′),
129.6(2C-3′,5′),127.9(C-6),126.8(2C-2′,6′),123.5(C-12),105.1(C-3),101.6(C-
5a),98.7(C-8),53.7(2C-14,17),52.4(C-9),51.5(2C-15,16),45.6(C-18),18.7(C-13).
Embodiment 5
It weighs scutelloside (such as formula (III) compound represented) 4g 20mL water to dissolve in the pasty state, is slowly added to 50% sulfuric acid
100mL, 90 DEG C of water-bath mechanical stirrings after the reaction was continued 5min, are poured into ready 500mL ice water, so to clarifying when stirring
Decompression suction filtration is carried out to it afterwards, filter cake is washed with water to weakly acidic pH, discards filtrate and takes appropriate acetic acid second after filter cake vacuum drying for 24 hours
Ester is dispersed into uniform suspension, and decompression filters, and filter cake is washed 3 times with ethyl acetate, for 24 hours by filter cake vacuum drying, obtains radix scutellariae
Element (such as formula (IV) compound represented) 1.74g, yield 71.9%.
Baicalein (such as formula (IV) compound represented) 1.08g (0.004mol) is weighed in 150mL reaction flask, first is added
Alcohol 30mL makees solvent, under agitation, sequentially adds 37% formalin 0.486mL (0.006mol), morpholine 0.696mL
(0.008mol) reacts reaction flask under the conditions of 55 DEG C, and thin-layered chromatography monitors reaction process, until the reaction is complete, has big
Yellow solid is measured to be precipitated；Yellow solid is filtered, filter cake (such as formula (V -1) compound represented) is washed with a small amount of methanol, will filter
Cake is dried in a vacuum drying oven, weighing: 1.38g, yield 93.5%.
Hydrogen nuclear magnetic resonance spectrum analysis:1H-NMR(DMSO-d6,600MHz)δ:8.09(m,2H,H-2′,6′),7.58-7.63
(m,3H,H-3′,4′,5′),6.96(s,1H,H-3),3.95(s,2H,H-9),3.62(s,4H,H-11,12),2.61(s,4H,
H-10,13).
Carbon-13 nmr spectra analysis:13C-NMR(DMSO-d6,151MHz)δ:182.7(C-4),163.0(C-2),154.7
(C-8a),148.5(C-5),146.4(C-7),132.3(C-4′),131.6(C-1′),129.7(2C-3′,5′),129.4(C-
6),126.7(2C-2′,6′),104.9(C-3),104.1(C-5a),100.6(C-8),66.5(2C-11,12),53.1(2C-
10,13),52.0(C-9).
8- morpholine methylene baicalein (such as formula (V -1) compound represented) 1g (0.0031mol) is weighed, DMF is added
(n,N-Dimethylformamide) 30mL sequentially adds Isosorbide-5-Nitrae-dibromobutane 0.478mL (0.0040mol), carbon under agitation
Sour potassium 1.28g, potassium iodide 1.54g are stirred to react 7h under the conditions of 60 DEG C~70 DEG C under nitrogen protection, then by above-mentioned reaction
Liquid filters away extra potassium carbonate and potassium iodide, and a few drop formic acid are added in reaction solution, are then concentrated under reduced pressure into reaction solution
It is dry, ice water is added after cooling and is dispersed in water compound to form suspension, adjusts pH to neutrality, filter cake is then obtained by filtration.
Filter cake separates (eluant, eluent is methylene chloride: methanol=100:1) with silica gel column chromatography after vacuum drying, and recrystallization is further pure
Change to obtain target compound (such as formula (II -1) compound represented).
Hydrogen nuclear magnetic resonance spectrum analysis:1H-NMR(CDCl3,600MHz)δ:12.89(s,1H,5-OH),7.92-7.94(m,
2H,H-2′,6′),7.52-7.58(m,3H,H-3′,4′,5′),6.68(s,1H,H-3),4.74(s,2H,H-9),4.30(t,J
=5.4Hz, 2H, H-10), 3.83 (s, 2H, H-13), 3.70 (s, 4H, H-15,16), 2.58 (s, 4H, H-14,17), 2.07
(m,2H,H-11),1.86(m,2H,H-12).
Carbon-13 nmr spectra analysis:13C-NMR(CDCl3,151MHz)δ:183.0(C-4),164.0(2C-2,8a),
157.7(C-5),151.4(C-7),131.9(C-6),129.2(2C-1′,4′),126.3(4C-2′,3′,5′,6′),106.2
(2C-3,5a),105.1(C-8),73.6(2C-10,13),71.5(2C-15,16),67.2(C-9),53.3(C-17),50.2
(C-14),28.8(2C-11,12).
Embodiment 6
It weighs scutelloside (such as formula (III) compound represented) 4g 20mL water to dissolve in the pasty state, is slowly added to 50% sulfuric acid
100mL, 90 DEG C of water-bath mechanical stirrings after the reaction was continued 5min, are poured into ready 500mL ice water, so to clarifying when stirring
Decompression suction filtration is carried out to it afterwards, filter cake is washed with water to weakly acidic pH, discards filtrate and takes appropriate acetic acid second after filter cake vacuum drying for 24 hours
Ester is dispersed into uniform suspension, and decompression filters, and filter cake is washed 3 times with ethyl acetate, for 24 hours by filter cake vacuum drying, obtains radix scutellariae
Element (such as formula (IV) compound represented) 1.74g, yield 71.9%.
Baicalein (such as formula (IV) compound represented) 1.08g (0.004mol) is weighed in 150mL reaction flask, first is added
Alcohol 30mL makees solvent, under agitation, sequentially adds 37% formalin 0.486mL (0.006mol), nafoxidine
0.496mL(0.006mol).Reaction flask is reacted under the conditions of 45 DEG C, thin-layered chromatography monitors reaction process, until having reacted
Entirely, there are a large amount of yellow solids to be precipitated, yellow solid is filtered, washs the filter cake (chemical combination as shown in formula (V -2) with a small amount of methanol
Object), filter cake is dried in a vacuum drying oven, is weighed: 1.31g, yield 92.5%.
Hydrogen nuclear magnetic resonance spectrum analysis:1H-NMR(DMSO-d6,600MHz)δ:8.05-8.06(m,2H,H-2′,6′),7.57-
7.58(m,3H,H-3′,4′,5′),6.81(s,1H,H-3),4.35(s,2H,H-9),3.12(s,4H,H-10,13),1.90
(s,4H,H-11,12).
Carbon-13 nmr spectra analysis:13C-NMR(DMSO-d6,151MHz)δ:180.9(C-4),163.8(C-2),161.0
(C-8a),150.1(C-5),143.7(C-7),132.0(C-4′),131.7(C-1′),130.7(C-6),129.6(2C-3′,
5′),126.5(2C-2′,6′),104.9(C-3),101.0(C-5a),97.2(C-8),53.2(2C-10,13),49.7(C-
9),23.4(C-11,12).
8- nafoxidine methylene baicalein (such as formula (V -2) compound represented) 1g (0.0028mol) is weighed, is added
DMF (n,N-Dimethylformamide) 30mL sequentially adds Isosorbide-5-Nitrae-dibromobutane 0.478mL under agitation
(0.0040mol), potassium carbonate 1.28g, potassium iodide 1.54g are stirred to react 7h under the conditions of 60 DEG C~70 DEG C under nitrogen protection,
Then above-mentioned reaction solution is filtered away to extra potassium carbonate and potassium iodide, a few drop formic acid are added in reaction solution, it then will be anti-
It answers liquid to be concentrated to dryness, ice water is added after cooling and is dispersed in water compound to form suspension, adjusting pH to neutrality, then
Filter cake is obtained by filtration.Filter cake separates (eluant, eluent is methylene chloride: methanol=200:1) with silica gel column chromatography after vacuum drying,
Target compound is further purified to obtain in recrystallization (such as formula (II -2) compound represented).
Hydrogen nuclear magnetic resonance spectrum analysis:1H-NMR(DMSO-d6, 600MHz) and δ: 12.94 (s, 1H, 5-OH), 8.11 (d, J=
7.2Hz, 2H, H-2 ', 6 '), 7.59-7.64 (m, 3H, 3 ', 4 ', 5 '), 7.04 (s, 1H, H-3), 4.64 (t, J=5.6Hz, 1H,
), H-10 4.15 (t, J=5.1Hz, 1H, H-13), 3.71 (s, 2H, H-9), 3.53 (s, 4H, H-14,17), 2.46 (s, 4H, H-
11,12), 1.96 (t, J=5.6Hz, 2H, H-15), 1.73 (t, J=5.6Hz, 2H, H-16)
Carbon-13 nmr spectra analysis:13C-NMR(DMSO-d6,151MHz)δ:183.1(C-4),163.9(C-2),158.0
(C-8a),153.6(C-5),151.2(C-7),132.6(C-6),131.4(C-4′),131.1(C-1′),129.7(2C-3′,
5′),126.9(2C-2′,6′),106.9(C-3),106.1(C-5a),105.0(C-8),73.5(C-10),72.2(C-13),
66.8(2C-14,17),53.6(2C-11,12),50.2(C-9),28.7(C-15),24.7(C-16).
The present invention also provides the identifications to the compound with general formula (I) to comprise the following processes:
Three phenolic hydroxyl group activity sequences in baicalein (compound with general formula (IV)) are as follows: 7 hydroxyl > 6 hydroxyl > 5
Position hydroxyl, esterification preferentially occur at 7, it is contemplated that 8 bit substituent space bits in the compound with general formula (V)
The influence of resistance, esterification are likely to occur in 6 (as shown in Figure 1).
1, spectroscopic method certification process:
There is the compound of general formula (I) to carry out preliminary structure by nuclear magnetic resonance spectroscopy, carbon spectrum, mass spectrum and determine gained,
Compared with baicalein (compound with general formula (IV)), series compound hydrogen spectrum unimodal 2 hydrogen of chemical shift 4.3 or so is
9 methylene and be more corresponding hydrogen atoms between 1~5 in hydrogen spectrum chemical shift, meet amine methyl nitrogen-atoms institute by 8
The even hydrogen on carbon atom introduces amine methylene at 8 thus, it is possible to determine, the esterification of chemical shift more than 7.28 or so
The hydrogen of the fragrant organic acid corresponding number of introducing can prove the graceful of organic acid and baicalein (compound with general formula (IV))
Buddhist nun wishes alkali into ester, chemical shift 12.8 or so have it is more blunt it is unimodal be hydrogen on 5 phenolic hydroxyl groups, illustrate that 5 phenolic hydroxyl groups do not have
It is substituted.
1 carbon of the chemical shift 50 or so of carbon spectrum is carbon on 9 methylene and 10~50 or so is corresponding secondary
The carbon of amine may further prove to introduce amine methylene at 8, be 10 in the carbon atom that 160~180 or so have more
Carbonyl carbon, and in more than 128 or so corresponding carbon atoms of fragrant area's phenyl ring, can also further prove ester bond shape
At.
Confirmed compared with the relative molecular mass of expecting compound by mass spectrographic molecular ion peak, in 6 (7) phenol hydroxyls
Base be it is monosubstituted, synthesized esterification products have only connect an one's share of expenses for a joint undertaking carboxylic acid, by above-mentioned spectral data analyze structure may for tool
There are the compound of general formula (I) and the compound with general formula (Ⅹ):
It not can confirm that ester bond is formed in 6 still at 7, due to general formula (I) by above-mentioned hydrogen spectrum, carbon spectrum, mass spectrometric data
Compound structure particularity, two-dimentional nuclear-magnetism also have no idea well confirm ester bond specific generation position, therefore, this hair
Specific structure bright and that the compound with general formula (I) is confirmed in conjunction with chemical method.
2, chemical method determination process
Determination basis are as follows: have the flavone compound of adjacent two phenolic hydroxyl structures in ammonia methanol solution in molecule, it can
With strontium chloride (SrCl2) green is generated to brown or even black precipitate, synthesized compound point can be determined that by this method
Whether there are adjacent two phenolic hydroxyl groups in son, and then determine the position of substituent group, determination basis is as follows:
(1) if, 7 phenolic hydroxyl groups of Mannich base be substituted into ester, compound 6 form adjacent diphenol hydroxyl with 5 phenolic hydroxyl groups
Base, will be at positive reaction with the method.
(2) if, 6 phenolic hydroxyl groups of Mannich base be substituted into ester, will with the method without adjacent two phenolic hydroxyl groups in compound molecule
At negative reaction.
Reaction equation:
Specific experiment method: it takes about 1.0mg inspection product (compound with general formula (I)) to set in small test tube, 1.0ml first is added
Alcohol dissolve (can be heated in water-bath when necessary), be added 3 drop 0.01mol/L strontium chlorides methanol solutions, then plus 3 drop steamed with ammonia
The methanol solution of gas saturation, paying attention to observation, whether there is or not precipitatings to generate.
Experimental result: the compound with general formula (I) generates black precipitate at positive reaction.
Experiment conclusion: there are adjacent two phenolic hydroxyl groups, it is known that 6 and 5 phenolic hydroxyl groups in 4 molecule of compound that this project is combined into
Adjacent two phenolic hydroxyl groups are formed, i.e., 6 do not have substituent group, and acyl group has been connected to 7 of molecule.
Comprehensive spectral data and chemical method can be confirmed that the compound with general formula (I) that the present invention synthesizes is 7 phenol
Hydroxyl forms ester bond, the series compound of 8 amine methylene；In the present embodiment, with the knot of such as formula (I -2) compound represented
It is illustrated for structure:
The compound is yellow powder, MS (ESI, negative) m/z:486.1580 [M-H]+；
Hydrogen nuclear magnetic resonance spectrum analysis:1H–NMR(CDCl3, 600MHz) and δ: 12.89 (1H, s, 5-OH), 8.24 (2H, d, J=
12.0Hz, H-2 ', 6 '), 7.83 (2H, d, J=6Hz, H-3 ", 5 "), 7.54 (3H, m, H-3 ', 4 ', 5 '), 6.97 (2H, d, J=
6Hz,H-2″,6″),6.63(1H,s,H-3),4.28(2H,s,H-9),3.88(3H,s,H-15),2.87(4H,s,H-11,
14),1.92(4H,s,H-12,13)；
Carbon-13 nmr spectra analysis:13C-NMR(CDCl3,151MHz)δ:182.4(4),164.2(10),163.8(2),
162.9(4″),160.5(8a),152.8(5),151.5(7),132.7(2″,6″),131.7(6),131.6(1′),129.2
(3′,5′),126.1(2′,6′),123.1(4′),121.4(1″),113.7(3″,5″),105.6(5a),103.7(3),98.8
(8),55.5(15),53.6(11,14),51.9(9),23.7(12,13).
Test example
Anticancer activity reality is carried out to such as formula (II -1~4) compound represented and such as formula (II -1~2) compound represented
It tests, using CCK8 method to the compound and lead compound baicalein, positive control CPG74514A carries out anti-MCF-7 tumour
Cell-proliferation activity experiment；Experimental result is as shown in table 1.
The experiment of 1 MCF-7 anticancer activity of table
The experimental results showed that as formula (II -1), (II -2), (I -3), (I -4) compound represented inhibit MCF-7 tumour thin
The activity of the proliferation of born of the same parents is better than lead compound baicalein, such as formula (II -2) compound represented activity and CDK1 selective depression
Agent CPG74514A is suitable, illustrates with general structure (II) and part there is the compound of general formula (I) can obviously inhibit MCF-7
The proliferation of tumour cell, can develop into anti-tumor drug.
Although the embodiments of the present invention have been disclosed as above, but its is not only in the description and the implementation listed
With it can be fully applied to various fields suitable for the present invention, for those skilled in the art, can be easily
Realize other modification, therefore without departing from the general concept defined in the claims and the equivalent scope, the present invention is simultaneously unlimited
In specific details and legend shown and described herein.
Claims (10)
1. a kind of flavone derivative, which is characterized in that the derivant structure formula includes such as general formula (I) and general formula (II) institute
Show:
Wherein, R1For alkyl or cycloalkyl, R2For alkyl or cycloalkyl, R1、R2Cycloaliphatic ring or heterocycle, R are formed with nitrogen-atoms3For
Alkyl, aryl or aralkyl, n value are 1~10.
2. flavone derivative as described in claim 1, which is characterized in that R1、R2Nafoxidine ring is formed with nitrogen-atoms；
R1、R2Morpholine ring is formed with nitrogen-atoms；Or
R1、R2N methyl piperazine ring is formed with nitrogen-atoms.
3. flavone derivative as described in claim 1, which is characterized in that R1、R2It is propyl.
4. flavone derivative as claimed in any one of claims 1-3, which is characterized in that R3For aryl.
5. the preparation method of flavone derivative of any of claims 1-4 comprising using with general formula (III)
Compound take off glucuronic acid after obtain the compound with general formula (IV), replace to obtain with general formula using amine methyl
(V) compound；
Esterification is carried out to the compound with general formula (V) and obtains the compound with general formula (I)；
Etherification reaction is carried out to the compound with general formula (V) and obtains the compound with general formula (II)；
Wherein, the compound with general formula (III), general formula (IV) and general formula (V) are as follows:
Wherein, R1For alkyl or cycloalkyl, R2For alkyl or cycloalkyl, R1、R2Cycloaliphatic ring or heterocycle are formed with nitrogen-atoms.
6. the preparation method of flavone derivative as claimed in claim 5, which is characterized in that use the change with general formula (III)
It closes after object takes off glucuronic acid and obtains the compound with general formula (IV), replacing to obtain using amine methyl has general formula (V)
The process of compound is as follows:
It takes the compound with general formula (III) to be dissolved in the pasty state with water, is slowly added to 50% sulfuric acid, 90 DEG C of water-bath mechanical stirrings are extremely
Clarification, after the reaction was continued, pours into ready ice water when stirring, decompression suction filtration is then carried out to it, filter cake is washed with water to close
Neutrality discards filtrate, and filter cake is dried in vacuo, and appropriate ethyl acetate is taken to be dispersed into uniform suspension, and decompression filters, filter cake second
Acetoacetic ester washing, filter cake is dried in vacuo, the compound with general formula (IV) is obtained；
It takes the compound with general formula (IV) appropriate, a certain amount of methanol dissolution is added, the amine reagent and formaldehyde for weighing equivalent add
Enter into reaction flask, reacted at 20-65 DEG C, thin-layered chromatography detects reaction process, until the reaction is complete, wait there are a large amount of solids to analyse
It is filtered after out, collects solid, wash solid in three times with a small amount of methanol, solid is dried in a vacuum drying oven, is had
The compound of general formula (V).
7. the preparation method of flavone derivative as claimed in claim 6, which is characterized in that the chemical combination with general formula (V)
Object carries out esterification and obtains having the process of the compound of general formula (I) as follows:
It is appropriate to weigh corresponding organic acid, a certain amount of anhydrous tetrahydro furan is added, N- hydroxy benzo three is added under agitation
Nitrogen azoles, then weighs dicyclohexylcarbodiimide, is dissolved in a certain amount of anhydrous tetrahydro furan and then is dripped with dropping funel
It is added in above-mentioned reaction solution and is stirred under the conditions of -5 DEG C, reaction solution is filtered, obtain white solid and clear filtrate, filtrate is spare；
The compound with general formula (V) is taken, certain anhydrous tetrahydro furan is added, under agitation, is sequentially added to diformazan ammonia
Yl pyridines, triethylamine, are stirred at room temperature, and are then slowly dropped to active ester filtrate in this reaction solution with dropping funel
The reaction was continued, and thin-layered chromatography detects reaction process, reaches balance wait react, reaction solution is concentrated to dryness, silica gel column chromatography is used
Separation, polyamide column separation, thin layer preparation, the purifying of the methods of recrystallization obtain the compound with general formula (I).
8. the preparation method of flavone derivative as claimed in claim 6, which is characterized in that the chemical combination with general formula (V)
Object carries out etherification reaction and obtains having the process of the compound of general formula (II) as follows:
The compound with general formula (V) is taken, a certain amount of n,N-Dimethylformamide is added, under agitation, sequentially adds 1,
4- dibromobutane, potassium carbonate, potassium iodide are stirred to react under the conditions of 60 DEG C~70 DEG C under nitrogen protection；Then by above-mentioned reaction
Liquid filters away extra potassium carbonate and potassium iodide, and a few drop formic acid are added in reaction solution, are then concentrated under reduced pressure into reaction solution
Dry, concentrate is added ice water after cooling and is dispersed in water compound to form suspension, adjusts pH to neutrality, is then obtained by filtration
Filter cake；Filter cake is separated with silica gel column chromatography after vacuum drying, and purifying obtains the compound with general formula (II).
9. the identification method of flavone derivative of any of claims 1-4, which is characterized in that with general formula
(I) compound identification process includes:
There to be the compound of general formula (I) to carry out after preliminary structure determines by nuclear magnetic resonance spectroscopy and carbon spectrum, and with general formula
(IV) compound and the compound with general formula (V) carry out the quantity of hydrogen atom and displacement is compared, and determines the anti-of amine methylene
Answer position and primary esterification position；
There to be the compound of general formula (I) to react with strontium chloride, and generate green to brown or even black precipitate, it is determined that generate
Compound with general formula (I).
10. the identification method of flavone derivative as claimed in claim 9, which is characterized in that will have the chemical combination of general formula (I)
Object includes: with strontium chloride reaction process
It takes the compound with general formula (I) to set in small test tube, methanol dissolution is added, the methanol solution of strontium chloride is added, then plus
With the methanol solution of ammonia saturated with vapor, paying attention to observation, whether there is or not precipitatings to generate.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110028474A (en) * | 2019-04-24 | 2019-07-19 | 四川省中医药科学院 | A method of preparing flavone aglycone or isoflavone |
| CN114920755A (en) * | 2022-02-07 | 2022-08-19 | 天津中医药大学 | Compound with flavone parent nucleus and application thereof in preparation of CDK1 inhibitor |
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| WO1996031206A2 (en) * | 1995-04-07 | 1996-10-10 | Warner-Lambert Company | Flavones and coumarins as agents for the treatment of atherosclerosis |
| CN1668287A (en) * | 2001-09-06 | 2005-09-14 | 赛诺克思公司 | Inhibition by 3-deoxyflavonoids of t-lymphocyte activation and therapies related thereto |
| CN1750825A (en) * | 2003-02-24 | 2006-03-22 | 北卡罗来纳查佩尔山大学 | Flavone acetic acid analogs and methods of use thereof |
| CN106220600A (en) * | 2016-08-05 | 2016-12-14 | 厦门大学 | Flavone derivatives and its production and use |
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2018
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Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1996031206A2 (en) * | 1995-04-07 | 1996-10-10 | Warner-Lambert Company | Flavones and coumarins as agents for the treatment of atherosclerosis |
| CN1668287A (en) * | 2001-09-06 | 2005-09-14 | 赛诺克思公司 | Inhibition by 3-deoxyflavonoids of t-lymphocyte activation and therapies related thereto |
| CN1750825A (en) * | 2003-02-24 | 2006-03-22 | 北卡罗来纳查佩尔山大学 | Flavone acetic acid analogs and methods of use thereof |
| CN106220600A (en) * | 2016-08-05 | 2016-12-14 | 厦门大学 | Flavone derivatives and its production and use |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110028474A (en) * | 2019-04-24 | 2019-07-19 | 四川省中医药科学院 | A method of preparing flavone aglycone or isoflavone |
| CN114920755A (en) * | 2022-02-07 | 2022-08-19 | 天津中医药大学 | Compound with flavone parent nucleus and application thereof in preparation of CDK1 inhibitor |
| CN114920755B (en) * | 2022-02-07 | 2023-11-17 | 天津中医药大学 | Compounds with flavone parent nucleus and use thereof in preparation of CDK1 inhibitors |
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