CN101967135B - 4-aryl coumarin compound and preparation method and application thereof - Google Patents
4-aryl coumarin compound and preparation method and application thereof Download PDFInfo
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Abstract
The invention discloses a 4-aryl coumarin compound and a preparation method and application thereof. The 4-aryl coumarin compound has a structure shown in a formula (I). The preparation method comprises the following steps: taking substituted benzaldehyde and propandioic acid as raw materials, heating under condition of existing pyridine and piperidine, and generating Perkin reaction and decarboxylic reaction to obtain a series of substituted phenylacrylic acid compounds; carrying out bromination and elimination reaction on the substituted phenylacrylic acid compounds or acetylation to protect a phenolic hydroxyl group, and then carrying out bromination and elimination reaction to obtain substituted phenylpropiolic acid compounds; and enabling the substituted phenyl propargylic acid compounds and phenolic compounds to react under the catalysis of boron trifluoride etherate and phosphorus oxychloride or trifluoroacetic acid to obtain a series of 4-aryl coumarin compounds. The compounds can be used for preparing antineoplastic medicine, anti-abnormal-angiogenesis medicine, antimicrobial medicine, antioxidation medicine and antimalarial medicine.
Description
Technical field
The invention belongs to the pharmaceutical chemistry field, particularly a kind of 4-aryl-coumarin compounds and its production and use.
Background technology
Aryl-coumarin (arylcoumarin, aryl-2H-1-chromen-2-one) is the basic structure of some natural products, extensively is present in nature.Aryl-coumarin mainly contains 3-aryl-coumarin and 4-aryl-coumarin two large classes.Because it has similar skeleton structure to natural products such as isoflavones and diphenylethylenes, thereby receives researchist's concern.Studies show that the aryl-coumarin compounds has the physiologically active of multiple beneficial, such 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, the people such as the Minpei Kuroda of Tokyo Univ Japan have just found the 3-aryl-coumarin of a plurality of PPAR-of having γ ligand-binding activities, these 3-aryl-coumarins can by with PPAR-γ ligand binding peroxide activator enzyme body proliferation activated receptor, thereby reduce the glucose level (Bioorg.Med.Chem.Lett.2003,13:4267) of diabetic mice.In the same year, the people such as Christian Bailly confirm that 4-aryl-coumarin compounds has obvious cytotoxicity to tumour cell, can suppress the assembling of tubulin, cause death of neoplastic cells (J.Med.Chem.2003,46:5437).As seen, may find to have the compound of good biological activity in the aryl-coumarin compounds, be to have compound structure type researching value, that merit attention.
4-aryl-coumarin compounds is as the important class in the aryl-coumarin, and its chemosynthesis and bioactivity research are coming into one's own in recent years gradually, but that correlative study still belongs to is at the early-stage.4-aryl-coumarin compounds structurally has certain similarity with CombretastatinA-4, podophyllotoxin, thereby its bioactivity research merits attention with further structural modification work very much.
Combretastatin A-4 podophyllotoxin 4-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-5,6,7-trimethoxy tonka bean camphor
Summary of the invention
The shortcoming and defect that exists in order to solve above-mentioned prior art, primary and foremost purpose of the present invention is to provide a kind of 4-aryl-coumarin compounds.
Another object of the present invention is to provide the preparation method of above-mentioned 4-aryl-coumarin compounds.
A further object of the present invention is to provide the application of above-mentioned 4-aryl-coumarin compounds.
Purpose of the present invention is achieved through the following technical solutions: a kind of 4-aryl-coumarin compounds, this 4-aryl-coumarin compounds have suc as formula the structure shown in (I):
(I)
R wherein
1, R
2, R
3, R
5Or R
7Be H, OCH
3Or OH; R
4Be H or OH; R
6Be H or OCH
3
The preparation method of above-mentioned 4-aryl-coumarin compounds comprises following operation steps (preparation technology's flow process is as shown in Figure 1):
(1) take propanedioic acid and substituted benzaldehyde as raw material, under pyridine and hexahydropyridine existence condition, heats, Perkin condensation and decarboxylic reaction occur, obtain the substituted phenyl acrylic acid compounds through separation and purification; Described substituted benzaldehyde has suc as formula structure, wherein R shown in (II)
5Be H, OCH
3Or OH, R
7Be H, OCH
3Or OH, R
6Be H or OCH
3
(II)
(2) the substituted phenyl acrylic acid compounds is dissolved in the dehydrated alcohol, adds sulfur oxychloride (SOCl
2) be heated to backflow, reaction 1～4h, concentration of reaction solution adds entry, and product is separated out naturally, and placement is spent the night, and suction filtration obtains the substituted phenyl acrylic acid ethyl ester;
(3) the substituted phenyl acrylic acid ethyl ester is dissolved in the methylene dichloride, drips Br under the condition of ice bath
2, in 5～30min, add, stir 0.5～3h, washed reaction liquid is spin-dried for solvent, and hold over night obtains 2,3-dibromo-benzene base ethyl propionate compounds;
(4) with 2,3-dibromo-benzene base ethyl propionate compounds, potassium hydroxide and ethanol mixing and stirring, be heated to backflow, reaction 8～12h adds concentrated hydrochloric acid to acid after the cooling, and extracted with diethyl ether is spin-dried for behind the solvent to get phenyl propynoic acid compounds crude product;
(5) phenyl propynoic acid compounds crude product and aldehydes matter are dissolved in boron trifluoride ether solution (BF
3-Et
2O) in, stir, add again phosphorus oxychloride (POCl
3), stirring at normal temperature 2～12h after ring-closure reaction is complete, through separation and purification, obtains suc as formula the 4-aryl-coumarin compounds shown in (I); Perhaps with phenyl propynoic acid compounds crude product, aldehydes matter and trifluoroacetic acid (CF
3COOH) mix, stir under the normal temperature condition until react completely, through separation and purification, obtain the 4-aryl-coumarin compounds suc as formula (I).
The mol ratio of the described propanedioic acid of step (1) and substituted benzaldehyde is 1: 1～1.5: 1; The mol ratio of described pyridine and hexahydropyridine is 20: 1～20: 6; The mol ratio of described pyridine and propanedioic acid is 1: 1～1: 5.
The described separation and purification of step (1) is that reaction is complete, cooling 10～60min, and the hydrochloric acid soln of adding 1～10M is placed 2～10h, and suction filtration washes precipitation with water, obtains substituted phenyl acrylic acid compounds crude product; With substituted phenyl acrylic acid compounds crude product dehydrated alcohol recrystallization, obtain sterling substituted phenyl acrylic acid compounds, yield is 85%～95%.
When the described substituted phenyl acrylic acid ethyl ester compound of step (2) contains free phenolic hydroxyl group, the substituted phenyl acrylic acid ethyl ester is dissolved in the acetic acid, adds sulfur oxychloride (SOCl
2) being heated to backflow, reaction 1～4h adds entry, and product is separated out naturally, leaves standstill, and suction filtration obtains the substituted phenyl acrylic acid ethyl ester compound that phenolic hydroxyl group is protected by ethanoyl.
The mol ratio of the described substituted phenyl acrylic acid compounds of step (2), sulfur oxychloride and ethanol is 1: (1～2): (3～10).
The temperature of the described ice bath of step (3) is 0～4 ℃.
The described substituted phenyl acrylic acid ethyl ester of step (3), Br
2With the mol ratio of methylene dichloride be 1: (1～1.5): (10～50).
The mol ratio of the described potassium hydroxide of step (4) and ethanol is 1: 1.2～1: 5; Described 2, the mol ratio of 3-dibromo-benzene base ethyl propionate compounds and potassium hydroxide is 1: 3～1: 30.
The described separation and purification of step (5) is that reaction solution is poured in the frozen water, uses extracted with diethyl ether, is spin-dried for and removes ether, obtains 4-aryl-coumarin compounds crude product; 4-aryl-coumarin compounds crude product is separated with silica gel column chromatography, elutriant is sherwood oil again: ethyl acetate=1: 1 obtains 4-aryl-coumarin compounds sterling; The temperature of described ring-closure reaction is 0～40 ℃; The mol ratio of described phenyl propynoic acid compounds crude product and aldehydes matter is 1: 1～1: 1.2; Described phenolic compound is Resorcinol, pyrogallol or meta-methoxy phenol.
Above-mentioned 4-aryl-coumarin compounds can be applicable to prepare antitumor drug, anti-angiogenic paraplasm medicine, anti-oxidation medicine, antibacterials or anti-malaria medicaments.
The present invention compared with prior art has following advantage and effect:
(1) the invention provides a kind of 4-aryl-coumarin compounds of novelty, have and cis-stilbene compounds, podophyllotoxin etc. similarly chemical structure and associated biomolecule are active.
(2) provide a kind of synthetic method of 4-aryl-coumarin compounds, have yield height, the advantage such as easy and simple to handle.
(3) 4-aryl-coumarin compounds provided by the invention can be used for preparing antitumor, anti-angiogenic paraplasm, antibiotic, anti-oxidant, anti-malaria medicaments.
Description of drawings
Fig. 1 is 4-aryl-coumarin compounds preparation technology schema of the present invention.
Embodiment
The present invention is described in further detail below in conjunction with embodiment, but embodiments of the present invention are not limited to this.
Embodiment 1:
The acrylic acid preparation of 3,4-Dimethoxyphenyl
In the twoport reaction flask of 100mL, add 2.08g (0.02mol) propanedioic acid, 2.8g (0.017mol) Veratraldehyde, the 3mL pyridine, the 0.3mL hexahydropyridine, 3h refluxes after being heated to 95 ℃, react complete, cooling 10min adds 50mL 10mol/L hydrochloric acid soln, places 2h, suction filtration, with 200mL water washing precipitation, obtain 3,4-Dimethoxyphenyl vinylformic acid crude product.Use again the dehydrated alcohol recrystallization, get 3,4-Dimethoxyphenyl vinylformic acid sterling 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 pyridine, 0.5mL hexahydropyridine, 3h refluxes after being heated to 95 ℃, react complete, cooling 60min adds 50mL 3mol/L hydrochloric acid soln, place 10h, suction filtration washs solid with clear water, obtains 3-hydroxyl-4-p-methoxy-phenyl vinylformic acid crude product.Use again the dehydrated alcohol recrystallization, get 3-hydroxyl-4-p-methoxy-phenyl vinylformic acid sterling 14.63g, yield 90.6%.
Embodiment 3:
The preparation of 3-hydroxyl-4-p-methoxy-phenyl propynoic acid
1.94g (10mmol) embodiment 2 gained 3-hydroxyls-4-p-methoxy-phenyl vinylformic acid is dissolved in the 30mL dehydrated alcohol, adds 1mL SOCl
2Be heated to back flow reaction 2h, stopped heating, concentration of reaction solution adds entry, and product is separated out, and places, and suction filtration gets 3-hydroxyl-4-p-methoxy-phenyl ethyl propenoate crude product.3-hydroxyl-4-methoxy acrylic acid ethyl ester crude product is dissolved in the 30mL acetic acid, adds 1mL SOCl
2Be heated to backflow.Reaction 2h, stopped heating adds entry, and product is separated out naturally, places night after product curing suction filtration and gets 3-hydroxyl-4-acetoxyl group phenyl ethyl propenoate crude product.3-hydroxyl-4-acetoxyl group phenyl ethyl propenoate is dissolved in the 20mL methylene dichloride, and ice bath drips 0.5mL Br
2(9.8mmol), 5min adds, and stirs 3h, and washed reaction liquid is spin-dried for, and places night after product curing and gets final product to get 3-(3-acetoxyl group-4-p-methoxy-phenyl)-2,3-dibromo ethyl propionate crude product.Again with 3-(3-acetyl oxygen-4-p-methoxy-phenyl)-2,3-dibromo ethyl propionate, 5gKOH, 20mL C
2H
5OH adds in the 25mL reaction flask, stirs, and is heated to backflow, keeps 8h, adds concentrated hydrochloric acid after the cooling to acid, and extracted with diethyl ether is spin-dried for rear placement 24h after product and solidifies to get 3-hydroxyl-4-p-methoxy-phenyl propynoic acid crude product 0.71g.Total recovery 37%.Product need not purifying, can be directly used in next step reaction.
Embodiment 4:
The preparation of 3,4-Dimethoxyphenyl propynoic acid
With 2.08g (10mmol) embodiment 1 gained 3,4-Dimethoxyphenyl vinylformic acid is dissolved in the 30mL dehydrated alcohol, adds 1mL SOCl
2Be heated to backflow. reaction 4h, stopped heating, concentration of reaction solution adds entry, and product is separated out, and places, and suction filtration gets 3,4-Dimethoxyphenyl ethyl propenoate crude product.3,4-Dimethoxyphenyl ethyl propenoate is dissolved in the 20mL methylene dichloride, ice bath drips 0.4mL Br again
2, 30min adds, and stirs 0.5h, and washed reaction liquid is spin-dried for, and places night after product curing and gets final product to get 3-(3,4-Dimethoxyphenyl)-2,3-dibromo ethyl propionate.With 3-(3,4-Dimethoxyphenyl)-2,3-dibromo ethyl propionate, 5gKOH, 20mL C
2H
5OH adds in the 25mL reaction flask, stirs, and is heated to backflow, keeps 12h, adds concentrated hydrochloric acid after the cooling to strongly-acid, extracted with diethyl ether, be spin-dried for rear placement 24h after product solidify 3,4-Dimethoxyphenyl propynoic acid crude product 0.9g.Overall yield 44%.Product need not purifying, can be directly used in next step reaction.
Embodiment 5
The preparation of 4-(3 ', 4 '-Dimethoxyphenyl)-umbelliferone
The twoport reaction flask of 100mL is placed ice bath, then add 2.06g (10mmol) embodiment 4 gained 3,4-Dimethoxyphenyl propynoic acid, 1.1g (10mmol) Resorcinol, 5.6g (0.04mol) boron trifluoride diethyl etherate, stir, add 3g (0.02mol) phosphorus oxychloride again, 10min recession deicing is bathed, stirring at normal temperature, TLC monitoring reaction process (chromatographic solution: sherwood oil: ethyl acetate=2: 1), pour in the frozen water by stopped reaction behind the 12h, use extracted with diethyl ether, be spin-dried for and remove ether, get 4-(3 ', 4 '-Dimethoxyphenyl)-umbelliferone crude product.Crude product separates with silica gel column chromatography, and elutriant is sherwood oil: ethyl acetate=1: 1 gets 4-(3 ', 4 '-Dimethoxyphenyl)-umbelliferone sterling 1.60g, productive rate 54.0%.Spectral data is as follows:
mp：239-241℃
IR：3194(OH)，1695(CO)，1624，1599，1518，1263and 1140cm-1
1HNMR(400MHz，CD
3COCD
3)δ3.90and 3.94(6H，s，3H and 3H，2×OCH
3)，6.20(1H，s，C-3H)，6.74(1H，s，J＝2.4Hz and 8Hz，C-6’H)，6.91(1H，s，J＝2.4Hz，C-2’H)，6.97(1H，d，J＝8Hz，C-5’H)，6.98(1H，d，J＝2Hz，C-8H)，7.02(1H，dd，J＝2Hz and 8.8Hz，C-6’H)，7.45(1H，d，J＝8.8Hz，C-5’H)
Ms：m/Z：298(M
+)，283(M
+-CH
3)，270，255，227，199，184，113
Embodiment 6
The preparation of 4-(3 ', 4 '-Dimethoxyphenyl)-umbelliferone
In the twoport reaction flask of 100mL, add 2.06g (10mmol) embodiment 4 gained 3,4-Dimethoxyphenyl propynoic acid, 1.1g (10mmol) Resorcinol, 4mL trifluoroacetic acid, stirring at normal temperature, TLC monitoring reaction process (chromatographic solution: sherwood oil: ethyl acetate=2: 1), pour in the frozen water by stopped reaction behind the 2h, use extracted with diethyl ether, be spin-dried for and remove ether, get 4-(3 ', 4 '-Dimethoxyphenyl)-umbelliferone crude product.Crude product separates with silica gel column chromatography, the elutriant sherwood oil: ethyl acetate=1: 1 gets 4-(3 ', 4 '-Dimethoxyphenyl)-umbelliferone sterling 1.68g, productive rate 56.4%.Spectral data is with embodiment 5.
Embodiment 7
The preparation of 4-(3 ', 4 '-Dimethoxyphenyl)-Daphnelin
In the twoport reaction flask of 100mL, add 1.03g (5mmol) embodiment 4 gained 3,4-Dimethoxyphenyl propynoic acid, 0.63g (5mmol) pyrogallol, the 4mL trifluoroacetic acid, stirring at normal temperature, and TLC monitoring reaction process (chromatographic solution: sherwood oil: ethyl acetate=2: 1), stopped reaction behind the 7h, pour in the frozen water, use extracted with diethyl ether, be spin-dried for and remove ether, get 4-(3 ', 4 '-Dimethoxyphenyl)-the Daphnelin crude product.Crude product separates with silica gel column chromatography, and elutriant is sherwood oil: ethyl acetate=1: 1 gets 4-(3 ', 4 '-Dimethoxyphenyl)-Daphnelin sterling 0.91g, productive rate 58.0%.Spectral data is as follows:
mp：125-128℃
IR：2987，1726(CO)，1618，1518，1379，1255，1147and 814cm-1
1HNMR(400MHz，CD
3COCD
3)δ：3.87and 3.88(6H，s，3H and 3H，2×OCH
3)，6.07(1H，s，C-3H)，6.83and 7.00(2H，2×d，J＝8.8Hz，C-5H and C-6H)7.06(1H，dd，J＝2Hz and 8.4Hz，C-5’H)，7.10(1H，d，J＝2Hz，C-2’H)，7.11(1H，d，J＝8.4Hz，C-6’H)
Ms：m/Z：314(M
+)，286(M
+-CO)，271(M
+-CO-CH3)，161，133，115，103
Embodiment 8
The preparation of 4-(3 ', 4 '-Dimethoxyphenyl)-ayapanin
In the twoport reaction flask of 100mL, add 1.76g embodiment 4 gained 3,4-Dimethoxyphenyl propynoic acid, 1.1g meta-methoxy phenol, 5mL trifluoroacetic acid, stirring at normal temperature, TLC monitoring reaction process (chromatographic solution: sherwood oil: ethyl acetate=2: 1), pour in the frozen water by stopped reaction behind the 6h, use extracted with diethyl ether, be spin-dried for and remove ether, get 4-(3 ', 4 '-Dimethoxyphenyl)-ayapanin crude product.Crude product separates with silica gel column chromatography, the elutriant sherwood oil: ethyl acetate=1: 1 gets 4-(3 ', 4 '-Dimethoxyphenyl)-ayapanin sterling 1.44g, productive rate 53.8%.Spectral data is as follows:
mp：157-158℃
IR：3411(CO)，1695(OH)，1606，1518，1448，1173and 1140cm-1
1HNMR(400MHz，CD
3COCD
3)δ：3.88，3.89and 3.93(9H，s，3H，3H and 3H，3×OCH
3)，6.14(1H，s，C-3H)，6.90and 7.08(2H，2×dd，J＝8.8Hz，2.4Hz andJ＝8.4Hz，2Hz C-6H and C-6’H)6.94and 7.12(2H，2×d，J＝2.4Hz，C-8H andC-2’H)，7.12and 7.55(2H，2×d，J＝8.4Hz and 8.8Hz，C-5H and C-5’H)
Ms：m/Z：312(M
+)，297(M
+CH
3)，284(M
+-CO-CH
3)，269，213，183，139
Embodiment 9
The preparation of 4-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-Daphnelin
In the twoport reaction flask of 100mL, add 0.6g (0.003mol) embodiment 3 gained 3-hydroxyls-4-p-methoxy-phenyl propynoic acid, 0.4g (0.003mol) pyrogallol, the 3mL trifluoroacetic acid, stirring at normal temperature, TLC monitoring reaction process (chromatographic solution: sherwood oil: ethyl acetate=2: 1), 6.5h rear stopped reaction, pour in the frozen water, use extracted with diethyl ether, be spin-dried for and remove ether, get 4-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-Daphnelin crude product.Crude product separates with silica gel column chromatography, the elutriant sherwood oil: ethyl acetate=1: 1 gets 4-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-Daphnelin sterling 0.51g, productive rate 53.7%.Spectral data is as follows:
mp：123-125℃
IR：3371(OH)，1695(CO)，1653，1599，1448，1240，1178and 1130cm-1
1HNMR(400MHz，CD
3COCD
3)δ：3.91(3H，s，OCH
3)6.03(1H，s，C-3H)，6.83(1H，d，J＝8.8Hz，C-6H)，6.95-6.99(3H，m，C-5H，C-2’H and C-6’H)7.10(1H，d，J＝8Hz，C-5’H)
Ms：m/Z：300(M
+)，272(M
+-CO)，257(M
+-CO-CH
3)，229，115
Embodiment 10
The mensuration of synthetic new compound anti-tumor activity among the present invention
With above-described embodiment 8 products therefroms as sample, after the DMSO dissolving, with the two anti-RPMI-1640 nutrient solution dilutions of 10% (mass percent concentration, as follows) calf serum and 1% (mass percent concentration), 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 (BGC823 stomach cancer cell) in every hole, at 37 ℃ of 5%CO
2The saturation vapour CO2gas incubator in cultivate and to allow cell note wall in 12 hours.Every hole adds the sample that 50 μ L concentration are 1mg/L, 100 μ g/L, 50 μ g/L, 10 μ g/L, 5 μ g/L and 1 μ g/L, and the sample of each concentration is established 3 repeating holes.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 LMTT (5mg/mL) dye liquors.At 37 ℃ of 5%CO
2The saturation vapour CO2gas incubator in add 100 μ L 10% (W/V) sodium lauryl sulphate (SDS) after cultivating 4h, incubated overnight is surveyed its absorbance under 570 nm.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:
The measurement result of table 1 anti-tumor activity
4-aryl-coumarin compounds has obvious killing activity to stomach cancer cell as can be seen from Table 1.The IC of 4-(3 ', 4 '-Dimethoxyphenyl)-umbelliferone wherein
50Reach 36 ± 3 μ g/m L.
Embodiment 11
The mensuration of synthetic new compound anti-oxidant activity among the present invention:
Weighing 1,1-phenylbenzene-2-trinitrophenyl-hydrazine (DPPH) (production of WaKo company) 5mg, constant volume is in the 50mL dehydrated alcohol, be diluted to 10mg/L during experiment, and with equal-volume be the sample mix of 1mg/L, 100 μ g/L, 50 μ g/L, 10 μ g/L, 5 μ g/L and 1 μ g/L with dehydrated alcohol dilution, drawing 100 μ L adds in 96 orifice plates, in microplate reader, measure the absorbance under the 517nm wavelength one time every 1min, negative control adds 100 μ L dehydrated alcohols, and three repetitions are done in every group of experiment.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 is removed the activity of DPPH free radical
Table 2 data presentation 4-aryl-coumarin compounds has removing free radical ability in various degree.4-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-Daphnelin wherein, it is the strongest that 4-(3 ', 4 '-Dimethoxyphenyl)-Daphnelin is removed the free radical ability.
Embodiment 12
The mensuration of synthetic new compound anti-microbial activity among the present invention:
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-1, 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 Bacillusdysenteriae, and Candida albicans Candida albicans (ATCC43300).Measurement result is as shown in table 3:
The measurement result of the antibacterial living-article of table 3
Table 3 data declaration sample has anti-microbial activity, chooses its minimal inhibitory concentration of sample determination and minimal bactericidal concentration that inhibition zone is arranged in the table.
In the LB nutrient solution, after 37 ℃ of incubated overnight, be diluted to 10 with aseptic LB liquid for the examination bacterium
5The CUF/ml cell concentration is got 190 μ L kinds in 96 orifice plates, adds the sample (concentration is in 48～25000 μ g/mL scopes) that 10 μ L use the DMSO doubling dilution.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 only have 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, positive control is for adding 10 μ L with penbritin and the paraxin (Amresco) of 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 that sample concentration corresponding to fungistatic effect hole and adjacent invalid hole arranged MICs and MBCs the results are shown in Table 4.
The bacteriostatic activity of table 4 compound
4-aryl-coumarin compounds has in various degree anti-microbial activity as can be seen from Table 4.Wherein 4-(3 '-hydroxyl-4 '-p-methoxy-phenyl)-Daphnelin has very strong restraining effect to subtilis, particularly merits attention.
Embodiment 13 pharmaceutical compositions
Prepare every prescription that contains 100 tablets of tablets of 10mg active ingredient:
4-(3 ', 4 '-Dimethoxyphenyl)-umbelliferone ... 1.0g
Hydroxypropylcellulose ... 0.2g
Wheat starch ... 1.0g
Lactose ... 10.0g
Magnesium Stearate ... 0.3g
Talcum powder ... 0.3g
Embodiment 14
Powder is distributed into 1000 bags (200 milligrams of every bags contain 100 milligrams of active substances) with 4-(3 ', 4 '-Dimethoxyphenyl)-umbelliferone 100 grams and lactose 100 grams after grinding, 100 orders sieve, mix.
Above-described embodiment is the better embodiment of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and the principle, substitutes, combination, simplify; all should be the substitute mode of equivalence, be included within protection scope of the present invention.
Claims (7)
1. the preparation method of a 4-aryl-coumarin compounds is characterized in that comprising following operation steps:
(1) take propanedioic acid and substituted benzaldehyde as raw material, under pyridine and hexahydropyridine existence condition, heats, Perkin condensation and decarboxylic reaction occur, obtain the substituted phenyl acrylic acid compounds through separation and purification; Described substituted benzaldehyde has structure shown in formula II, wherein R
5Be H, OCH
3Or OH, R
7Be H, OCH
3Or OH, R
6Be H or OCH
3
(2) the substituted phenyl acrylic acid compounds is dissolved in the dehydrated alcohol, add sulfur oxychloride and be heated to backflow, reaction 1～4h, concentration of reaction solution, add entry, product is separated out naturally, and placement is spent the night, suction filtration obtains the substituted phenyl acrylic acid ethyl ester, and the mol ratio of described substituted phenyl acrylic acid compounds, sulfur oxychloride and ethanol is 1:(1～2): (3～10);
Described substituted phenyl acrylic acid ethyl ester is when not containing the substituted phenyl acrylic acid ethyl ester of free phenolic hydroxyl group, directly enters step (3) reaction;
When described substituted phenyl acrylic acid ethyl ester contains free phenolic hydroxyl group, the substituted phenyl acrylic acid ethyl ester is dissolved in the acetic acid, add sulfur oxychloride and be heated to backflow, reaction 1～4h, add entry, product is separated out naturally, leaves standstill, suction filtration obtains the substituted phenyl acrylic acid ethyl ester compound that phenolic hydroxyl group is protected by ethanoyl;
(3) will not contain the substituted phenyl acrylic acid ethyl ester of free phenolic hydroxyl group or substituted phenyl acrylic acid ethyl ester compound that phenolic hydroxyl group is protected by ethanoyl and be dissolved in the methylene dichloride, drip Br under the condition of ice bath
2, in 5～30min, add, stir 0.5～3h, washed reaction liquid is spin-dried for solvent, and hold over night obtains 2,3-dibromo-benzene base ethyl propionate compounds;
(4) with 2,3-dibromo-benzene base ethyl propionate compounds, potassium hydroxide and ethanol mixing and stirring, be heated to backflow, reaction 8～12h adds concentrated hydrochloric acid to acid after the cooling, and extracted with diethyl ether is spin-dried for behind the solvent to get phenyl propynoic acid compounds crude product;
(5) phenyl propynoic acid compounds crude product and aldehydes matter are dissolved in the boron trifluoride ether solution, stir, add phosphorus oxychloride again, stirring at normal temperature 2～12h after ring-closure reaction is complete, through separation and purification, obtains 4-aryl-coumarin compounds; Perhaps phenyl propynoic acid compounds crude product, aldehydes matter are mixed with trifluoroacetic acid, stir under the normal temperature condition until react completely, through separation and purification, obtain 4-aryl-coumarin compounds;
Described 4-aryl-coumarin compounds has structure as shown in the formula (I):
R wherein
1, R
2, R
3, R
5Or R
7Be H, OCH
3Or OH; R
4Be H or OH; R
6Be H or OCH
3
2. the preparation method of 4-aryl-coumarin compounds according to claim 1, it is characterized in that: the mol ratio of the described propanedioic acid of step (1) and substituted benzaldehyde is 1:1～1.5:1; The mol ratio of described pyridine and hexahydropyridine is 20:1～20:6; The mol ratio of described pyridine and propanedioic acid is 1:1～1:5.
3. the preparation method of 4-aryl-coumarin compounds according to claim 2, it is characterized in that: the mol ratio of described propanedioic acid and substituted benzaldehyde is 1.2:1.
4. the preparation method of 4-aryl-coumarin compounds according to claim 1, it is characterized in that: the described separation and purification of step (1) is that reaction is complete, cooling 10～60min, the hydrochloric acid soln that adds 1～10M, place 2～10h, suction filtration washes precipitation with water, obtains substituted phenyl acrylic acid compounds crude product; With substituted phenyl acrylic acid compounds crude product dehydrated alcohol recrystallization, obtain sterling substituted phenyl acrylic acid compounds, yield is 85%～95%.
5. the preparation method of 4-aryl-coumarin compounds according to claim 1, it is characterized in that: the temperature of the described ice bath of step (3) is 0～4 ℃; Described substituted phenyl acrylic acid ethyl ester, Br
2With the mol ratio of methylene dichloride be 1:(1～1.5): (10～50).
6. the preparation method of 4-aryl-coumarin compounds according to claim 1, it is characterized in that: the mol ratio of the described potassium hydroxide of step (4) and ethanol is 1:1.2～1:5; Described 2, the mol ratio of 3-dibromo-benzene base ethyl propionate compounds and potassium hydroxide is 1:3～1:30.
7. the preparation method of 4-aryl-coumarin compounds according to claim 1, it is characterized in that: the described separation and purification of step (5) is that reaction solution is poured in the frozen water, use extracted with diethyl ether, be spin-dried for and remove ether, obtain 4-aryl-coumarin compounds crude product; 4-aryl-coumarin compounds crude product is separated with silica gel column chromatography, elutriant is sherwood oil: ethyl acetate=1:1 again, obtains 4-aryl-coumarin compounds sterling; The temperature of described ring-closure reaction is 0～40 ℃; The mol ratio of described phenyl propynoic acid compounds crude product and aldehydes matter is 1:1～1:1.2; Described phenolic compound is Resorcinol, Resorcinol, pyrocatechol, pyrogallol or meta-methoxy phenol.
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| CN102796085B (en) * | 2012-09-04 | 2015-04-15 | 西南大学 | Coumarin triazole, and preparation method and application thereof |
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| CN106187969B (en) * | 2016-06-29 | 2019-03-26 | 山东省医学科学院药物研究所 | A kind of preparation method of 4- aryl-coumarin class compound |
| 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 |
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| CN110256390B (en) * | 2019-06-21 | 2020-11-24 | 中国人民解放军第四军医大学 | Coumarin compound, preparation method and application of coumarin compound in preparation of medicine for treating cerebral apoplexy |
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