CN101906090A - 3,4-dihydro-4-aryl coumarin compounds as well as preparation method and application thereof - Google Patents
3,4-dihydro-4-aryl coumarin compounds as well as preparation method and application thereof Download PDFInfo
- Publication number
- CN101906090A CN101906090A CN 201010195208 CN201010195208A CN101906090A CN 101906090 A CN101906090 A CN 101906090A CN 201010195208 CN201010195208 CN 201010195208 CN 201010195208 A CN201010195208 A CN 201010195208A CN 101906090 A CN101906090 A CN 101906090A
- Authority
- CN
- China
- Prior art keywords
- dihydro
- aryl
- compounds
- coumarin compounds
- preparation
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Abstract
The invention discloses 3,4-dihydro-4-aryl coumarin derivatives as well as a preparation method and application thereof. The preparation method comprises the following steps of: with substituted benzaldehyde and malonic acid as raw materials, heating in the presence of pyridine and piperidine and generating a Perkin reaction and a decarboxylic reaction to obtain substituted phenylacrylic acid derivatives; and then subjecting the substituted phenylacrylic acid derivatives and phenol compounds to a reaction in the presence of the catalysis of boron trifluoride diethyl ether and phosphorus oxychloride to obtain the 3,4-dihydro-4-aryl coumarin compounds. The compounds can be used for preparing medicaments for resisting tumors, abnormal vascular proliferation, bacterial and oxidation.
Description
Technical field
The present invention relates to chemical field, particularly a kind of 3,4-dihydro-4-aryl-coumarin compounds and its production and use.
Background technology
Aryl-coumarin (arylcoumarin, aryl-2H-1-chromen-2-one) mainly comprises 3-aryl-coumarin and 4-aryl-coumarin two big classes, is the basic structure of some natural products.Because it has similar skeleton structure to numerous bioactive natural products such as isoflavones, diphenylethylene compounds etc., thereby receives researchist's concern.Studies show that the aryl-coumarin compounds has the physiologically active of multiple beneficial, as leukemia (Leuk.Res.2008,32:1914; J.Med.Chem, 2003,46:5437; Exp.Hema, 2008,36:1625), antimycotic (Life.Sci.2002,71:1449; Microbiology, 2005,151:1691), anticoagulation (Bioorg.Med.Chem.Lett, 2006,16:257), anti-oxidant (Bioorg.Med.Chem, 2007,91), anti-inflammatory (Nat.Prod.Res 15:1516), antiviral (Nat.Prod.Res.2002,17 (2):, 2007,21 (12): 1104; Immu.Inve.2007,36:203) and anti-diabetic activity (Phytochemistry, 2007,68:2087) etc.2003, people such as the Minpei Kuroda of Tokyo Univ Japan have found the 3-aryl-coumarin of a plurality of PPAR-of having γ ligand-binding activities, thereby these 3-aryl-coumarins can by activate the glucose level that ppar gamma receptor reduces diabetic mice (Bioorg.Med.Chem.Lett.2003,13:4267).In the same year, people such as Christian Bailly confirm that 4-aryl-coumarin compounds has significant cytotoxicity, can suppress the assembling of tubulin, thereby make death of neoplastic cells (J.Med.Chem.2003.46:5437).
Yet, 3,4-dihydro-4-aryl-coumarin compounds is as a kind of hydrogenant 4-aryl-coumarin derivatives, and is less about its bioactive research report.2005, Ajit Kumar found to mention 3 when the 4-aryl-coumarin can be used as albumen Transacetylase substrate, 4-dihydro-4-aryl-coumarin compounds effect similar to the 4-aryl-coumarin (Bioorg.Med.Chem.2005,13:4300).The same year, people such as Frederik Roelens found 4-(4 '-hydroxy phenyl)-5,7-dihydroxyl-8-alkyl-3,4-melilotine have estrogenic activity (Eur.J.Med.Chem.2005,40:1042).3,4-dihydro-4-aryl-coumarin compounds structurally has certain similarity with Combretastatin A-4, podophyllotoxin, thereby its bioactivity research merits attention with further structural modification work very much.Existing 3, preparation method's majority of 4-dihydro-4-aryl-coumarin compounds all exists reaction conditions violent, the not high shortcoming of productive rate, and this quasi-molecule is under violent condition and unstable, this makes existing most method be restricted in the use.
Summary of the invention
The objective of the invention is to overcome the shortcoming that exists in the prior art, provide a kind of 3,4-dihydro-4-aryl-coumarin compounds.
Another object of the present invention is to provide a kind of above-mentioned 3, the preparation method of 4-dihydro-4-aryl-coumarin compounds.
It is a kind of above-mentioned 3 that a further object of the present invention is to provide, the purposes of 4-dihydro-4-aryl-coumarin compounds.
Purpose of the present invention is achieved through the following technical solutions:
A kind of 3,4-dihydro-4-aryl-coumarin compounds, its structural formula is a formula 1:
In the formula 1, R
1, R
2, R
3, R
4, R
5, R
7Be H, OCH
3Or OH, R
1, R
2, R
3, R
4, R
5, R
7Can be the same or different; R
6Be OCH
3
Above-mentioned 3, the preparation method of 4-dihydro-4-aryl-coumarin compounds comprises the steps:
(1) under pyridine and hexahydropyridine existence condition, Perkin condensation and decarboxylic reaction take place in propanedioic acid and substituted benzaldehyde, again through separation and purification, obtain the substituted phenyl acrylic acid compounds;
(2) at phosphorus oxychloride (POCl
3) and boron trifluoride diethyl etherate (BF
3-Et
2O) under the existence condition, described substituted phenyl acrylic acid compounds and phenolic compound generation ring-closure reaction again through separation and purification, obtain 3,4-dihydro-4-aryl-coumarin compounds.
In the step 1, the mol ratio of propanedioic acid and substituted benzaldehyde is (1～1.5): 1, be preferably 1.2: 1; The mol ratio of pyridine and hexahydropyridine is 20: (1～6); The mol ratio of pyridine and propanedioic acid is (1～5): 1; Temperature of reaction is 70～90 ℃, and the reaction times is 4～12 hours.
In the step 1, described separation and purification is with the reaction product cooling 10min～30min of step 1, adds 1～5M hydrochloric acid soln, is no less than 2 hours storage period, and suction filtration washes precipitation with water, obtains substituted phenyl acrylic acid compounds crude product; Use the dehydrated alcohol recrystallization again, obtain the substituted phenyl acrylic acid compounds behind the purifying.
In the step 2, substituted phenyl acrylic acid compounds: phenolic compound: phosphorus oxychloride: the mol ratio of boron trifluoride diethyl etherate is 1: (1～1.2): (2～3): (3～6); The temperature of described ring-closure reaction is 0～40 ℃, and the reaction times is 4～18 hours.
In the step 2, described separation and purification is that the reaction solution of step 2 is poured in the frozen water, uses extracted with diethyl ether, is spin-dried for and removes ether, gets 3,4-dihydro-4-aryl-coumarin compounds crude product; Again with acetone-water or ethyl acetate-sherwood oil recrystallization crude product, obtain 3 behind the purifying, 4-dihydro-4-aryl-coumarin compounds; Also can separate crude product with silica gel column chromatography, elutriant is a sherwood oil: ethyl acetate=1: 1 obtains 3 behind the purifying, 4-dihydro-4-aryl-coumarin compounds.
Described 3, the preparation method of 4-dihydro-4-aryl-coumarin compounds, can adopt following reaction formula to represent:
A kind of pharmaceutical composition, active ingredient are above-mentioned 3, and 4-dihydro-4-aryl-coumarin compounds also contains the pharmaceutically useful carrier of one or more inert non-toxic.
Above-mentioned 3, the purposes of 4-dihydro-4-aryl-coumarin compounds is the application in antitumor, the anti-angiogenic paraplasm of preparation, anti-oxidant, antibacterials.
The present invention compared with prior art has following advantage and effect:
(1) provided by the invention 3,4-dihydro-4-aryl-coumarin compounds has and similarly chemical structure and associated biomolecule activity such as cis-stilbene compounds, podophyllotoxin.
(2) preparation method of the present invention is simple to operate, the yield height.
(3) provided by the invention 3,4-dihydro-4-aryl-coumarin compounds can be used for preparing antitumor, anti-angiogenic paraplasm, antibiotic, anti-oxidation medicine.
Embodiment
Below in conjunction with embodiment the present invention is done further detailed description, but embodiments of the present invention are not limited thereto.
Embodiment 1
3, the acrylic acid preparation of 4-Dimethoxyphenyl:
In the twoport reaction flask of 100ml, add 2.08g (0.02mol) propanedioic acid, 2.8g (0.017mol) 3,4-dimethoxy benzaldehyde, 3ml (0.037mol) pyridine, 0.3ml (0.003mol) hexahydropyridine, the 3h that refluxes after being heated to 95 ℃, reaction finishes, cooling 10min, add the 50ml3mol/L hydrochloric acid soln, place 2h, suction filtration, with 200ml water washing precipitation, obtain crude product; Crude product dehydrated alcohol recrystallization gets pure product 3,4-Dimethoxyphenyl vinylformic acid 3.1g, yield 88.3%.
Embodiment 2
3-hydroxyl-acrylic acid the preparation of 4-p-methoxy-phenyl:
In the twoport reaction flask of 100ml, add 12.98g (0.125mol) propanedioic acid, 12.65g (0.083mol) 3-hydroxyl-4-methoxybenzaldehyde, 15ml (0.168mol) pyridine, 1.5ml (0.015mol) hexahydropyridine, 3h refluxes after being heated to 95 ℃, reaction finishes, and cooling 10min adds the 50ml3mol/L hydrochloric acid soln, place 2h, suction filtration with 1000ml water washing precipitation, obtains crude product; Crude product dehydrated alcohol recrystallization gets pure product 3-hydroxyl-4-p-methoxy-phenyl vinylformic acid 14.63g, yield 90.6%.
Embodiment 3
4-(3 ', 4 '-Dimethoxyphenyl)-7-hydroxyl-3, the preparation of 4-melilotine:
The twoport reaction flask of 100ml is placed ice bath, add 2.08g (0.01mol) 3 then, 4-Dimethoxyphenyl vinylformic acid, 1.1g (0.01mol) Resorcinol, 3g (0.02mol) phosphorus oxychloride, 5.6g (0.04mol) boron trifluoride diethyl etherate, stir, 10min recession deicing is bathed stirring at normal temperature (15-30 ℃), TLC monitoring reaction process (developping agent: sherwood oil: ethyl acetate=2: 1), stopped reaction behind the 12h is poured in the frozen water, uses extracted with diethyl ether, be spin-dried for and remove ether, get crude product; Get pure product 4-(3 ', 4 '-Dimethoxyphenyl)-7-hydroxyl-3 with acetone and water recrystallization, 4-melilotine 1.82g, productive rate 60.7%.
IR：3429(OH)，1761(CO)，1626，1597，1516，1462，1419，1335，1271，1244，1159，1103，1024，991，847and?812cm
-1
1HNMR(400MHz，CDCl
3)δ：2.98(2H，m，C-3H)，3.79and?3.84(6H，2s，3H?and?3H?each，2×OCH
3)，4.20(1H，t，J＝6.0Hz，C-4H)，6.56(1H，dd，2.4and?8.4Hz，C-6H)6.63-6.67(3H，m，C-6’H，C-5’H，C-5H)，6.80and?6.82(2H，2×d，J＝2.4Hz，C-8H?and?C-2’H).
Ms：m/Z：300(M
+)，282(M
+-H
2O)，267(M
+-CH
3-H
2O)，257，243，227，190，163，129.
Embodiment 4
4-(3 ', 4 ', 5 '-trimethoxyphenyl)-6-hydroxyl-3, the preparation of 4-melilotine:
The twoport reaction flask of 100ml is placed ice bath, add 4.76g (0.02mol) 3 then, 4,5-trimethoxyphenyl vinylformic acid, 2.2g (0.02mol) Resorcinol, 6g (0.04mol) phosphorus oxychloride, 11.2g (0.08mol) boron trifluoride diethyl etherate stirs, 10min recession deicing is bathed, stirring at normal temperature (15-30 ℃), and TLC monitoring reaction process (developping agent: sherwood oil: ethyl acetate=2: 1), stopped reaction behind the 18h, pour in the frozen water, use extracted with diethyl ether, be spin-dried for and remove ether, get crude product; Get pure product 4-(3 ', 4 ', 5 '-trimethoxyphenyl)-6-hydroxyl-3,4-melilotine 4.71g, productive rate 71.4% with acetone and water recrystallization.
IR：3421(OH)，1757(CO)，1504，1454，1232，1195and?1122cm
-1
1HNMR(400MHz，CDCl
3)δ：2.98(2H，m，C-3H)，3.77and?3.80(9H，2s，6H?and?3H?each，3×OCH
3)，4.17(1H，t，J＝6.4Hz，C-4H)，6.33(2H，s，C-2’H?and?C-6’H)，6.55(1H，dd，J＝2.4Hz?and?8.6Hz，C-6H)，6.64(1H，d，J＝2.4Hz，C-8H)，6.85(1H，d，J＝8.6Hz，C-5H)
Ms：m/Z：330(M
+)，312(M
+-H
2O)，297(M
+-H
2O-CH
3)，257，213，181，128.
Embodiment 5
4-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-7-hydroxyl-3, the preparation of 4-melilotine:
The twoport reaction flask of 100ml is placed ice bath, add 1.94g (0.01mol) 3-hydroxyl-4-p-methoxy-phenyl vinylformic acid then, 1.1g (0.01mo) Resorcinol, 3g (0.02mol) phosphorus oxychloride, 5.6g (0.04mol) boron trifluoride diethyl etherate stirs, 10min recession deicing is bathed, stirring at normal temperature (15-30 ℃), and TLC monitoring reaction process (developping agent: sherwood oil: ethyl acetate=2: 1), stopped reaction behind the 12h, pour in the frozen water, use extracted with diethyl ether, be spin-dried for and remove ether, get crude product; Crude product separates with silica gel column chromatography, the elutriant sherwood oil: ethyl acetate=1: 1 gets pure product 4-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-7-hydroxyl-3,4-melilotine 1.58g, productive rate 55.2%.
IR：3513(OH)，3334，1733(CO)，1627，1597，1513，1450，1300，1273，1223，1151，815cm
-1
1HNMR(400MHz，CDCl
3)δ：2.98(2H，m，C-3H)，3.86(3H，s，OCH
3)，4.16(1H，t，J＝6.4Hz，C-4H)，6.54and?6.59(2H，2×dd，J＝2.4Hz?and?8.4HzC-6’H?and?C-6H)，6.61and?6.69(2H，2×d，J＝2.4Hz，C-2’H?and?C-8H)，6.77-6.83(2H，2×d，J＝8.4Hz，C-5’H?and?C-5H)
Ms：m/Z：286(M
+)，268(M
+-H
2O)，253(M
+-CH
3-H
2O)，243，227，213，176.115.
Embodiment 6
4-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-7,8-dihydroxyl-3, the preparation of 4-melilotine:
The twoport reaction flask of 100ml is placed ice bath, add 1.94g (0.01mol) 3-hydroxyl-4-p-methoxy-phenyl vinylformic acid then, 1.26g (0.01mol) pyrogallol, 4g (0.026mol) phosphorus oxychloride, 5.6g (0.04mol) boron trifluoride diethyl etherate stirs, 10min recession deicing is bathed, stirring at normal temperature (15-30 ℃), TLC monitoring reaction process (developping agent: sherwood oil: ethyl acetate=2: 1), pour in the frozen water by stopped reaction behind the 12h, direct suction filtration gets crude product behind the ageing 4h; Get pure product 4-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-7,8-dihydroxyl-3,4-melilotine 2.1g, productive rate 69.5% with sherwood oil and re-crystallizing in ethyl acetate again.
IR：3498(OH)，3417，1753(CO)，1516，1468，1271，1198，1174?and?1126cm
-1
1HNMR(400MHz，CDCl
3)δ：2.99(2H，m，C-3H)，3.86(3H，s，OCH
3)，4.19(1H，t，J＝6.4Hz，C-4H)，6.43and?6.65(2H，2×d，J＝8.4Hz，C-6’H?andC-5’H)，6.59and?6.78(2H，2×d，J＝8Hz，C-6H?and?C-5H)，6.69(1H，s，C-2H)，
Ms：m/Z：302(M
+)，284(M
+-H
2O)，269(M+-CH
3-H
2O)，259，243，229，194.179.
Embodiment 7
4-(3 ', 4 '-Dimethoxyphenyl)-7,8-dihydroxyl-3, the preparation of 4-melilotine:
The twoport reaction flask of 100ml is placed ice bath, add 2.08g (0.01mol) 3 then, 4-Dimethoxyphenyl vinylformic acid, 1.26g (0.01mol) pyrogallol, 4g (0.026mol) phosphorus oxychloride, 5.6g (0.04mol) boron trifluoride diethyl etherate, stir, 10min recession deicing is bathed stirring at normal temperature (15-30 ℃), TLC monitoring reaction process (developping agent: sherwood oil: ethyl acetate=2: 1), stopped reaction behind the 12h, pour in the frozen water, direct suction filtration gets crude product behind the ageing 4h; Get pure product 4-(3 ', 4 '-Dimethoxyphenyl)-7 with sherwood oil and re-crystallizing in ethyl acetate again, 8-dihydroxyl-3,4-melilotine 2.3g, productive rate 72.8%.
IR：3423(OH)，1755(CO)，1516，1468，1275，1238，1192，1169and?1020cm
-1
1HNMR(400MHz，CDCl
3)δ：3.03(2H，m，C-3H)，3.81and?3.85(6H，s，3H?and?3H?each，2×OCH
3)，4.24(1H，dd，J＝7.6Hz?and?6.4Hz，C-4H)，6.41，6.66and?6.80(4H，4×d，J＝8.4Hz，C-6’H，C-5’H，C-6H?and?C-5H)，6.64(1H，s，C-2H)
Ms：m/Z：316(M
+)，298(M
+-H
2O)，283(M+-CH
3-H
2O)，273，259，243，190.
Embodiment 8
4-(3 ', 4 ', 5 '-trimethoxyphenyl)-7,8-dihydroxyl-3, the preparation of 4-melilotine:
The twoport reaction flask of 100ml is placed ice bath, add 1.19g (0.005mol) 3,4 then, 5-trimethoxyphenyl methoxy acrylic acid, 0.63g (0.005mol) pyrogallol, 2.3g (0.015mol) phosphorus oxychloride, 2.8g (0.02mol) boron trifluoride diethyl etherate stirs, 10min recession deicing is bathed, stirring at normal temperature, TLC monitoring reaction process (developping agent: sherwood oil: ethyl acetate=2: 1), pour in the frozen water by stopped reaction behind the 12h, direct suction filtration gets crude product behind the ageing 4h; Get pure product 4-(3 ', 4 ', 5 '-trimethoxyphenyl)-7,8-dihydroxyl-3,4-melilotine 0.91g, productive rate 52.6% with sherwood oil and re-crystallizing in ethyl acetate again.
IR：3471(OH)，1751(CO)，1597，1512，1466，1311，1246，1122and?1007cm
-1
1HNMR(400MHz，CDCl
3)δ：3.03(2H，m，C-3H)，3.78(6H，s，2×OCH
3)，3.82(3H，s，OCH
3)，4.22(2H，dd，J＝6Hz?and?7.6Hz)，6.33(2H，s，2’H?and6’H)，6.45and?6.67(2H，2×d，J＝8.8Hz，C-5H?and?C-6H).
Ms：m/Z：346(M
+)，328(M
+-H
2O)，313(M
+-CH
3-H
2O)，273，257，243，229，181，115.
Embodiment 9
4-(4 '-p-methoxy-phenyl)-7,8-dihydroxyl-3, the preparation of 4-melilotine:
The twoport reaction flask of 100ml is placed ice bath, add 0.89g (0.005mol) 4-p-methoxy-phenyl vinylformic acid then, 0.63g (0.05mol) pyrogallol, 2.3g (0.015mol) phosphorus oxychloride, 2.8g (0.02mol) boron trifluoride diethyl etherate stirs, 10min recession deicing is bathed, stirring at normal temperature, TLC monitoring reaction process (developping agent: sherwood oil: ethyl acetate=2: 1), pour in the frozen water by stopped reaction behind the 12h, direct suction filtration gets crude product behind the ageing 4h; Get pure product 4-(4 '-p-methoxy-phenyl)-7 with sherwood oil and re-crystallizing in ethyl acetate again, 8-dihydroxyl-3,4-melilotine 0.89g, productive rate 62.2%.
IR：3413(OH)，1751(CO)，1612，1514，1311，1284，1247，1180，1144and1007cm
-1
1HNMR(400MHz，CDCl
3)δ：3.01(2H，m，C-3H)，3.78(3H，s，OCH
3)，4.24(1H，t，J＝6.8Hz，C-4H)，6.39(2H，2×d，J＝8.4Hz，C-5H?and?C-6H)，6.85and?7.04(4H，2×d，J＝8.8Hz，C-2’H，C-6’H，C-3’H?and?C-5’H).
Ms：m/Z：286(M
+)，268(M
+-H
2O)，243，229，200，115.
Embodiment 10
Synthetic 3 of the present invention, the mensuration of the anti-tumor activity of 4-dihydro-4-aryl-coumarin compounds
Sample is pressed the finite concentration dilution with nutrient solution (containing 10% calf serum and 1% pair of anti-RPMI-1640 nutrient solution) after dissolving with DMSO, and the concentration of experiment DMSO is controlled within 1.5% (V/V).Get 96 porocyte culture plates, add the nutrient solution that 50 μ l contain about 5000 tumour cells (stomach cancer cell BGC823) in every hole, at 37 ℃ of 5%CO
2The saturation vapour CO2gas incubator in cultivate and to allow cell card wall in 2 hours.Every hole adds the certain density sample of 50 μ l, 3 repeating holes of each sample.6 of control wells: 3 positive control holes, every hole add 50 μ l cisplatins (10 μ g/ml), and 3 every holes of negative control hole add 50 μ l nutrient solutions.At 37 ℃ of 5%CO
2The saturation vapour CO2gas incubator in cultivated 48 hours.Every hole adds 10 μ l MTT (5mg/ml) dye liquors.At 37 ℃ of 5%CO
2The saturation vapour CO2gas incubator in add 100 μ l 10% (W/V) SDS after cultivating 4h, incubated overnight is surveyed its absorbance under 570nm.Calculate the inhibiting rate (IR) of sample on cell proliferation according to following formula: IR=1-ODr/ODc (ODr: experimental group; ODc: negative control group) according to the IC of typical curve calculation sample
50, measurement result is used
Expression, as shown in table 1:
Table 1: the measurement result of anti-tumor activity
As can be seen from Table 1,3,4-dihydro-4-aryl-coumarin compounds has in various degree killing activity to stomach cancer cell.4-(4 '-p-methoxy-phenyl)-7 wherein, 8-dihydroxyl-3, the 4-melilotine, 4-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-7,8-dihydroxyl-3, antitumor activity of compound such as 4-melilotine are stronger.
Embodiment 11
Synthetic 3 of the present invention, the mensuration of the anti-oxidant activity of 4-dihydro-4-aryl-coumarin compounds:
Weighing DPPH (production of WaKo company) 5mg, constant volume is in the 50ml dehydrated alcohol, be diluted to 10 μ g/mL during experiment, drawing 100 μ l adds in 96 orifice plates, and press the sample mix of finite concentration preparation with dehydrated alcohol with equal-volume, and in microplate reader, measure the absorbance under the 517nm wavelength one time every 1min, negative control adds 100 μ l dehydrated alcohols, three repetitions are done in every group of experiment, and sodium ascorbate (Vc) is set to positive controls.Sample at a time is calculated as follows the clearance rate (Y) of DPPH free radical: (ODc: negative control is at the absorbance at 517nm place in Y (%)=[(ODc-ODs)/ODc] * 100; ODs: sample is at the absorbance at 517nm place), per sample in the clearance rate at 30min place, the 50 3nhibitory dose EC of calculation sample
50, measurement result is with using
Expression, as shown in table 2:
Table 2: the activity of removing the DPPH free radical
Table 2 data presentation, 3,4-dihydro-4-aryl-coumarin compounds has removing free radical ability in various degree.Wherein with 4-(3 ', 4 ', 5 '-trimethoxyphenyl)-7,8-dihydroxyl-3, the activity of 4-melilotine is for the strongest.
Embodiment 12
Synthetic 3 of the present invention, the mensuration of the anti-microbial activity of 4-dihydro-4-aryl-coumarin compounds:
Contain 10 with every milliliter
6The bacterium liquid of bacterium or spore is evenly coated the solid bacteria media surface, to place media surface through the filter paper of 0.5cm diameter of sterilization, drip the testing sample solution of 2.5 μ l, 100 μ g/ μ l, cultivate 18-20h in 37 ℃, observe inhibition zone and whether form, what inhibition zone formation was arranged shows that anti-microbial activity is arranged.Comprise for the examination bacterium: intestinal bacteria Escherichia coli (ATCC25922), streptococcus aureus Staphylococcus aureus (ATCC2592), subtilis Bacillus dysenteriae, and Candida albicans Candida albicans (ATCC43300).Measurement result is as shown in table 3:
Table 3: the measurement result of bacteriostatic activity
Annotate: "-" expression does not have inhibition zone; Within "+" expression inhibition zone size 0～0.2cm; " ++ " expression inhibition zone size is in 0.2～0.5cm scope; " +++" represent that inhibition zone is greater than 0.5cm.
Table 3 data declaration, 3,4-dihydro-4-aryl-coumarin compounds has anti-microbial activity in various degree.Choose its minimal inhibitory concentration of sample determination and minimal bactericidal concentration that inhibition zone is arranged in the table 3.
In the LB nutrient solution, after 37 ℃ of incubated overnight, be diluted to the 105CUF/ml cell concentration for the examination bacterium, get 190 μ l kinds in 96 orifice plates, add the sample (concentration is in 48～25000 μ g/ml scopes) of 10 μ l usefulness DMSO doubling dilution with aseptic LB liquid.Cultivate 24h for 37 ℃, producing obviously to microorganism growth, inhibiting minimum sample concentration is designated as minimal inhibitory concentration MIC (MinimumInhibitory Concentration), draw the bacterium liquid after the 10 μ l sample preparation, dropping is on the LB flat board, whether have bacterium colony form, cultivate the minimum sample concentration that does not have bacterium colony formation or have only a bacterium colony to form behind the 48h for 37 ℃ and be designated as minimum bactericidal concentration MBC (Minimum BactericidalConcentration) if observing.Negative control is 5% (v/v) DMSO, and positive control is for adding penbritin and the paraxin (Amresco) of 10 μ l with the DMSO preparation, tests at every turn and respectively designs an aseptic checking hole (the LB substratum of 200 μ l) at four angles of 96 orifice plates.MICs result shows that with the average of the sample concentration that fungistatic effect hole and adjacent invalid hole correspondence are arranged MICs and MBCs the results are shown in Table 4.
The bacteriostatic test of table 4. sample
As can be seen from Table 4,3,4-dihydro-4-aryl-coumarin compounds has anti-microbial activity in various degree.4-(4 '-p-methoxy-phenyl)-6-hydroxyl-3 wherein, compounds such as 4-melilotine have very strong restraining effect to subtilis, particularly merit attention.
Embodiment 13: pharmaceutical composition
Prepare every prescription that contains 100 tablets of tablets of 10mg active ingredient:
(1) 4-(3 ', 4 '-Dimethoxyphenyl)-7,8-dihydroxyl-3,4-melilotine 1.0g
(2) hydroxypropylcellulose 0.2g
(3) wheat starch 1.0g
(4) lactose 10.0g
(5) Magnesium Stearate 0.3g
(6) talcum powder 0.3g
Embodiment 14
Formulation is a powder: with 4-(3 ', 4 '-Dimethoxyphenyl)-7, and 8-dihydroxyl-3,4-melilotine 100 grams and lactose 100 grams are distributed into 1000 bags (200 milligrams of every bags contain 100 milligrams of active substances) after grinding, 100 orders sieve, mix.
Claims (8)
1. one kind 3,4-dihydro-4-aryl-coumarin compounds, its structural formula is:
Wherein, R
1, R
2, R
3, R
4, R
5, R
7Be H, OCH
3Or OH, R
1, R
2, R
3, R
4, R
5, R
7Can be the same or different; R
6Be OCH
3
2. a claim 1 is described 3, and the preparation method of 4-dihydro-4-aryl-coumarin compounds is characterized in that comprising the steps:
(1) under pyridine and hexahydropyridine existence condition, Perkin condensation and decarboxylic reaction take place in propanedioic acid and substituted benzaldehyde, again through separation and purification, obtain the substituted phenyl acrylic acid compounds;
(2) under phosphorus oxychloride and boron trifluoride diethyl etherate existence condition, described substituted phenyl acrylic acid compounds and phenolic compound generation ring-closure reaction again through separation and purification, obtain 3,4-dihydro-4-aryl-coumarin compounds.
3. according to claim 23, the preparation method of 4-dihydro-4-aryl-coumarin compounds is characterized in that: in the step 1, the mol ratio of propanedioic acid and substituted benzaldehyde is (1～1.5): 1; The mol ratio of pyridine and hexahydropyridine is 20: (1～6); The mol ratio of pyridine and propanedioic acid is (1～5): 1; Temperature of reaction is 70～90 ℃, and the reaction times is 4～12 hours.
4. according to claim 23, the preparation method of 4-dihydro-4-aryl-coumarin compounds, it is characterized in that: in the step 1, described separation and purification is the reaction product cooling 10min～30min with step 1, add 1～5M hydrochloric acid soln, be no less than 2 hours storage period, suction filtration, wash precipitation with water, obtain substituted phenyl acrylic acid compounds crude product; Use the dehydrated alcohol recrystallization again, obtain the substituted phenyl acrylic acid compounds behind the purifying.
5. according to claim 23, the preparation method of 4-dihydro-4-aryl-coumarin compounds, it is characterized in that: in the step 2, substituted phenyl acrylic acid compounds: phenolic compound: phosphorus oxychloride: the mol ratio of boron trifluoride diethyl etherate is 1: (1～1.2): (2～3): (3～6); The temperature of described ring-closure reaction is 0～40 ℃, and the reaction times is 4～18 hours.
6. according to claim 23, the preparation method of 4-dihydro-4-aryl-coumarin compounds, it is characterized in that: in the step 2, described separation and purification is that the reaction solution of step 2 is poured in the frozen water, use extracted with diethyl ether, be spin-dried for and remove ether, get 3,4-dihydro-4-aryl-coumarin compounds crude product; Again with acetone-water or ethyl acetate-sherwood oil recrystallization crude product, obtain 3 behind the purifying, 4-dihydro-4-aryl-coumarin compounds; Or separating crude product with silica gel column chromatography, elutriant is a sherwood oil: ethyl acetate=1: 1 obtains 3 behind the purifying, 4-dihydro-4-aryl-coumarin compounds.
7. pharmaceutical composition is characterized in that: active ingredient is that claim 1 is described 3,4-dihydro-4-aryl-coumarin compounds, and the pharmaceutically useful carrier of one or more inert non-toxic.
8. a claim 1 is described 3, and the purposes of 4-dihydro-4-aryl-coumarin compounds is characterized in that: be the application in antitumor, the anti-angiogenic paraplasm of preparation, anti-oxidant, antibacterials.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010195208 CN101906090A (en) | 2010-06-04 | 2010-06-04 | 3,4-dihydro-4-aryl coumarin compounds as well as preparation method and application thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201010195208 CN101906090A (en) | 2010-06-04 | 2010-06-04 | 3,4-dihydro-4-aryl coumarin compounds as well as preparation method and application thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101906090A true CN101906090A (en) | 2010-12-08 |
Family
ID=43261700
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN 201010195208 Pending CN101906090A (en) | 2010-06-04 | 2010-06-04 | 3,4-dihydro-4-aryl coumarin compounds as well as preparation method and application thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101906090A (en) |
Cited By (10)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102260236A (en) * | 2011-06-24 | 2011-11-30 | 上海应用技术学院 | Preparation method of coumarin compounds |
| EP2570035A1 (en) | 2011-09-15 | 2013-03-20 | Symrise AG | Use of neoflavanoids for modifying taste |
| CN105541773A (en) * | 2015-12-14 | 2016-05-04 | 山东省医学科学院药物研究所 | Preparation method of 3,4-dihydro-4-arylcoumarin compounds |
| CN106317030A (en) * | 2016-08-24 | 2017-01-11 | 国家烟草质量监督检验中心 | 4-indolyl coumarin derivative, and preparing method and application thereof |
| CN106974907A (en) * | 2017-03-22 | 2017-07-25 | 山东省医学科学院药物研究所 | A kind of application of 4 aryl-coumarin class compound |
| CN110016031A (en) * | 2019-01-30 | 2019-07-16 | 浙江工业大学 | Imidazoles [1,3,5] compound in triazine class and its preparation method and application that amide groups replaces |
| CN110016033A (en) * | 2019-01-30 | 2019-07-16 | 浙江工业大学 | A kind of imidazo heterocyclic nitrogen compound and the preparation method and application thereof |
| CN110016034A (en) * | 2019-01-30 | 2019-07-16 | 浙江工业大学 | Imidazoles [1,2-a] [1,3,5] triazine formic ether compounds and the preparation method and application thereof |
| CN112168817A (en) * | 2020-10-21 | 2021-01-05 | 山东省医学科学院药物研究所（山东省抗衰老研究中心、山东省新技术制药研究所） | Application of 3-aryl coumarin compound |
| WO2022256480A1 (en) * | 2021-06-03 | 2022-12-08 | Conagen Inc. | Arylcoumarin synthesis with azeotropic removal of water |
-
2010
- 2010-06-04 CN CN 201010195208 patent/CN101906090A/en active Pending
Non-Patent Citations (5)
| Title |
|---|
| 《Bioorganic & Medicinal Chemistry》 20031231 Ishwar Singh,et al Synthetic and Novel Biocatalytic Resolution Studies on (±)-5/6/7-Acetoxy-4-aryl-3,4-dihydrocoumarins 529-538 第11卷, * |
| 《J. Chem. Research (S)》 20001231 Biswanath Das，et al Condensation of phenols with alkylcinnamates in the presence of FeCl3 556-557 , * |
| 《J. Indian Chem. Soc.》 20011231 P. L. Majumder,et al The reactions of phenols with alpha,beta-unsaturated aromatic acids in presence of polyphosphoric acid:synthetic and mechanistic studies 743-755 第78卷, * |
| 《Tetrahedron Letters》 20070505 Cláudio E. Rodrigues-Santos and Aurea Echevarria An efficient and fast synthesis of 4-aryl-3,4-dihydrocoumarins by (CF3SO3)3Y catalysis under microwave irradiation 4505-4508 第48卷, * |
| 《染料与染色》 20030228 张彦英等 芳基取代香豆素合成方法的研究进展 35，39-41 1-9 第40卷, 第1期 * |
Cited By (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102260236A (en) * | 2011-06-24 | 2011-11-30 | 上海应用技术学院 | Preparation method of coumarin compounds |
| CN102260236B (en) * | 2011-06-24 | 2014-08-20 | 上海应用技术学院 | Preparation method of coumarin compounds |
| EP2570035A1 (en) | 2011-09-15 | 2013-03-20 | Symrise AG | Use of neoflavanoids for modifying taste |
| CN105541773B (en) * | 2015-12-14 | 2018-06-29 | 山东省医学科学院药物研究所 | A kind of preparation method of 3,4- dihydros -4- aryl-coumarin class compounds |
| CN105541773A (en) * | 2015-12-14 | 2016-05-04 | 山东省医学科学院药物研究所 | Preparation method of 3,4-dihydro-4-arylcoumarin compounds |
| CN106317030A (en) * | 2016-08-24 | 2017-01-11 | 国家烟草质量监督检验中心 | 4-indolyl coumarin derivative, and preparing method and application thereof |
| CN106317030B (en) * | 2016-08-24 | 2018-11-30 | 国家烟草质量监督检验中心 | A kind of 4- indyl coumarin derivative and its preparation method and application |
| CN106974907A (en) * | 2017-03-22 | 2017-07-25 | 山东省医学科学院药物研究所 | A kind of application of 4 aryl-coumarin class compound |
| CN110016031A (en) * | 2019-01-30 | 2019-07-16 | 浙江工业大学 | Imidazoles [1,3,5] compound in triazine class and its preparation method and application that amide groups replaces |
| CN110016033A (en) * | 2019-01-30 | 2019-07-16 | 浙江工业大学 | A kind of imidazo heterocyclic nitrogen compound and the preparation method and application thereof |
| CN110016034A (en) * | 2019-01-30 | 2019-07-16 | 浙江工业大学 | Imidazoles [1,2-a] [1,3,5] triazine formic ether compounds and the preparation method and application thereof |
| CN110016031B (en) * | 2019-01-30 | 2021-05-11 | 浙江工业大学 | Amido substituted imidazole [1,3,5] triazine compound, preparation method and application thereof |
| CN112168817A (en) * | 2020-10-21 | 2021-01-05 | 山东省医学科学院药物研究所（山东省抗衰老研究中心、山东省新技术制药研究所） | Application of 3-aryl coumarin compound |
| WO2022256480A1 (en) * | 2021-06-03 | 2022-12-08 | Conagen Inc. | Arylcoumarin synthesis with azeotropic removal of water |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN101906090A (en) | 3,4-dihydro-4-aryl coumarin compounds as well as preparation method and application thereof | |
| CN101967135B (en) | 4-aryl coumarin compound and preparation method and application thereof | |
| CN102659735B (en) | quercetin-3-O-acyl ester and preparation method thereof | |
| Prachayasittikul et al. | Synthesis and structure–activity relationship of 2-thiopyrimidine-4-one analogs as antimicrobial and anticancer agents | |
| Konidala et al. | Design, multistep synthesis and in-vitro antimicrobial and antioxidant screening of coumarin clubbed chalcone hybrids through molecular hybridization approach | |
| CN101580477A (en) | Dehydroabietylamine derivatives and application thereof in bactericidal and antineoplastic medicaments | |
| CN101723907B (en) | O-dicyano-acenaphtho pyrazine compound and anti-tumor application thereof | |
| Patel et al. | Cu (II) and Ni (II) complexes of coumarin derivatives with fourth generation flouroquinolone: synthesis, characterization, microbicidal and antioxidant assay | |
| Nassar et al. | Synthesis of new uracil derivatives and their sugar hydrazones with potent antimicrobial, antioxidant and anticancer activities | |
| Patel et al. | Spectral, thermal, biological and multi‐heating rate kinetic properties of Cu (II) complexes containing N2O2 donor ligands: 1, 10‐phenanthroline and acyl coumarins | |
| Kumar et al. | Synthesis and biological evaluation of novel 4-(hetero) aryl-2-piperazino quinazolines as anti-leishmanial and anti-proliferative agents | |
| CN102702155B (en) | Scutellarin aglycone methylate product based on in-vivo metabolic mechanism as well as preparation method and application of scutellarin aglycone methylate product | |
| CN101792401B (en) | Biphenyl compound with anti-tumor activity and preparation method thereof | |
| CN103833719B (en) | Epigallo-catechin gallate (EGCG) alkyl derivative and antitumor application thereof | |
| CN109134487B (en) | Compound and its preparation method and application of the one kind containing benzoic acid nitrogen mustard segment | |
| Thakor et al. | Synthesis and cell line study of pyrazole substituted coumarin derivatives | |
| CN109988197B (en) | Ferrocene coumarin compound and preparation method and application thereof | |
| Tehrani et al. | Synthesis and Biological examination of novel tetra pyranopyrimidine heterocycles contained lipophilic spacers | |
| CN107445970B (en) | DMXAA-pyraloxanthone hybrid compound and preparation method and application thereof | |
| CN106928292B (en) | A kind of nitrate NO donator type scutellarin derivative and its preparation method and application | |
| CN101050179B (en) | 2,3,4,5-tetrasubstituted derivatives of benzyl ethylene class, preparation method and application | |
| CN113788822B (en) | Novel naringenin pyrimidine hydrazone derivative and preparation method and application thereof | |
| CN101602653B (en) | Halogenated hydroxyl aromatic methane compounds, preparation method and use thereof | |
| CN103301102A (en) | Method for extracting antioxidant from myricaria laxiflora and application thereof | |
| CN108276394A (en) | Daidzein derivative, preparation method and application |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C02 | Deemed withdrawal of patent application after publication (patent law 2001) | ||
| WD01 | Invention patent application deemed withdrawn after publication |
Application publication date: 20101208 |