CN105801544A - 3-aryl-4-arylamine-coumarin derivative and preparing method and medical application thereof - Google Patents
3-aryl-4-arylamine-coumarin derivative and preparing method and medical application thereof Download PDFInfo
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- C07D311/00—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings
- C07D311/02—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only hetero atom, condensed with other rings ortho- or peri-condensed with carbocyclic rings or ring systems
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- C07D311/18—Benzo[b]pyrans, not hydrogenated in the carbocyclic ring with oxygen or sulfur atoms directly attached in position 2 not hydrogenated in the hetero ring substituted otherwise than in position 3 or 7
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- C07D407/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having oxygen atoms as the only ring hetero atoms, not provided for by group C07D405/00 containing two hetero rings
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Abstract
The invention relates to the field of medicinal chemistry, in particular to a series of 3-aryl-4-arylamine-coumarin derivatives and a preparing method and medical application thereof, especially medicine applied to curing cancer like breast cancer. A structural formula of a 3-aryl-4-arylamine-coumarin derivative compound is as follow, and definitions of all radical groups in the formula are shown in instructions in details. The structural formula is shown in the specification.
Description
Technical field
The present invention relates to medicinal chemistry art, be specifically related to a series of 3-aryl-4-aromatic amine-coumarin derivative, its
Preparation method and medical usage, especially for the application of anti-tumor aspect.
Background technology
Tumor is that malignant tumor is still current human health with abnormal cell hypertrophy out of control and the disease being diffused as feature
One threatens greatly.On February 4th, 2015, CA periodical " CA-Cancer J Clin " Online release " global cancer statistics in 2012 "
Full text.Estimating based on GLOBOCAN, in 2012, the whole world there are about 1.41 thousand ten thousand new cancer cases, and 8,200,000 patients die from cancer
Disease.Wherein the cancer patient of 57% and the cancer mortality patient of 65% come from developing country.For many years, cancer burden by
Gradually shifting to less developed country (less developed countries), the cancer in these areas is newly sent out number of cases and is accounted for the whole world
57%, cancer mortality number of cases accounts for the 65% of the whole world.Address prediction whole world cases of cancer will present swift and violent growing trend, by 2012
14,000,000 people, 19,000,000 people of cumulative year after year to 2025 year, be up to 24,000,000 people by 2035.Cancer has become as seriously
Harm human health and the major disease of life, so far still without very satisfied Therapeutic Method, therefore exploitation low toxicity is efficient
Antitumor drug is extremely urgent.
Coumarin kind compound is the class natural organic-compound that nature is important, is present in the plant of different genera
In, tool has been widely used, and experimental studies have found that coumarin has the multiple pharmacology such as AntiHIV1 RT activity, antitumor, antioxidation, antiinflammatory and lives
Property.Owing to coumarin kind compound has, molecular weight is little, synthesis is simple, bioavailability is high, pharmacological action is extensive, toxicity is little
Feature, has become as the research emphasis of much medicament research and development work in recent years.
Research finds, many coumarin kind compounds have cytotoxic effect to the cancerous cell line of mammal.Such as,
Coumarin and umbelliferone all have antitumor action with external in vivo, can lure by suppressing tubulin polymerization
It is right that guided cell cycle arrest can strengthen in G1 phase, the cell growth of suppression breast carcinoma system, and the drug combination of other anti-newborn tumor
The therapeutical effect of breast carcinoma.
Being based on the coumarin kind compound important value in field of cancer, the present inventor opens in recent years
The design having opened up a series of micromolecular compound with antitumor action with coumarin as parent nucleus works with study on the synthesis, closes
Become a series of new 3-aryl-4-aromatic amine-coumarin derivative.Pharmacological experiment shows, this compounds has well
Anti-human breast cancer cell (MCF-7) proliferation activity.
Summary of the invention
The invention discloses coumarin kind compound or its pharmaceutically acceptable salt with formula one structure.Through pharmacology
Experiment proves that this compounds has good anti-human breast cancer cell (MCF-7) proliferation activity.
Formula one:
Wherein R1Represent H, OH or OMe；
R2Representing substituted aroma ring, wherein the substituted radical on aromatic rings includes electron withdraw group or electron-donating group；
R3Represent OMe or H.
The part of compounds structure of the present invention is as follows:
I series:
II series:
III series:
In pharmacological evaluation and embodiment, the code name of compound is equal to the compound structure corresponding to above code name.
The compound of the present invention and the pharmaceutically acceptable salt of salt formation are also included in the present invention, formula one chemical combination
Thing can be with following salt formation pharmaceutical salts: example hydrochloric acid salt, sulfate, maleate etc..
The partial pharmacologic that the compounds of this invention is presented herein below is tested and result:
Mtt assay test MCF-7 Cells Proliferation of Human Breast Cancer test
Method of testing: MCF-7 breast cancer cell is cultivated with the RPMI1640 culture fluid containing 10% hyclone, life of taking the logarithm
Long-term cell is used for testing, and adjusting cell density is 2 × 104Individual/mL, is inoculated in 96 orifice plates, after cultivating 12 hours, adds 100 μ
The pastille culture medium in l/ hole, sample ultimate density is 2 × 10-4mol/L、1×10-4mol/L、1×10-5mol/L、1×10- 6Mol/L and 1 × 10-7Mol/L, the multiple hole of each concentration 3, replace testing drug as a control group with the culture medium of same volume,
Add 20 μ l/ hole MTT (concentration is 5mg/ml) after continuing to cultivate 48 hours, after cultivating 4h, abandon supernatant, add DMSO 150 μ
L/ hole, measures every hole absorbance (A) value with enzyme mark detector at 492nm wavelength, calculates cell proliferation inhibition rate by formula: press down
Rate processed=(control group A value-experimental group A value)/(control group A value-blank group A value) × 100%, and calculate IC50。
The MCF-7 Cells Proliferation of Human Breast Cancer experimental result of the compounds of this invention:
With Tamoxifen and Raloxifene as positive control, the 3-aryl-4-aromatic amine-coumarin of synthesis is derived
Thing has carried out MCF-7 cell experiment, and result of study shows, MCF-7 cells show is gone out preferably to suppress alive by majority of compounds
Property, wherein the activity of compound I-3 is preferably, its IC50It it is 12.08 μMs.
3-aryl-4-aromatic amine-coumarin derivative involved in the present invention is typically by reacting preparation as follows:
The compound of formula one of the present invention can be prepared by following methods:
I-1～I-10:
Reactant and reaction condition: a) POCl3, Pyridine, rt, 1h；B) KOH, Pyridine, rt, 2h；C) TsCl,
Et3N, dry DCM, rt, 0.5h；d)R2-NH2, Cs2CO3, EtOH, 75 DEG C, 3h.
II-1～II-10:
Reactant and reaction condition: a) BF3-Et2, 70 DEG C, 2h；B) BnOH, PPh3, DIAD, THF, 0 DEG C, 0.5h；c)
NaH, Diethyl carbonate, 125 DEG C, 1.5h；D) TsCl, Et3N, dry DCM, rt, 0.5h；e)R2-NH2, Cs2CO3,
EtOH, 75 DEG C, 3h；F) Pd-C, H2, THF, r.t, 12h.
III-1～III-10:
Reactant and reaction condition: a) BF3-Et2, 70 DEG C, 2h；B) MeOH, PPh3, DIAD, THF, 0 DEG C, 0.5h；c)
NaH, Diethyl carbonate, 125 DEG C, 1.5h；D) TsCl, Et3N, dry DCM, rt, 0.5h；e)R2-NH2, Cs2CO3,
EtOH, 75 DEG C, 3h.
Detailed description of the invention (described embodiment is used only to the present invention is described rather than for limiting the present invention)
Part of compounds to prepare example as follows:
Hydrogen nuclear magnetic resonance spectrometer is that (TMS is internal standard to Bruker AV 500 type, deuterated CDCl3Or deuterated DMSO is solvent)；
Mass spectrograph is Shimadzu GCMS-QP2010 type mass spectrograph or Mariner mass spectrograph；In experiment, column chromatography all uses Qingdao Haiyang chemical industry
100-200 mesh, 200-300 mesh or 300-400 mesh silica gel that company limited produces fix phase；Column chromatography silica gel is 100-
200 mesh, 200-300 mesh or 300-400 mesh silica gel (Haiyang Chemical Plant, Qingdao), eluant be petroleum ether-ethyl acetate system or
Methylene chloride-methanol system.Thin layer chromatography (TLC) GF254 thin layer chromatography board (Yantai Jiang You silica gel development corporation, Ltd.)；
It is petroleum ether-ethyl acetate system or methylene chloride-methanol system that TLC launches system；TLC is at ZF7 type ultraviolet analysis instrument for three purposed
Display is irradiated under (Gongyi, Henan Yu Hua Instrument Ltd.).Chemical reagent is commercially available chemical pure or analytical pure product, goes out spy
Outside different explanation, unprocessed direct use.
Embodiment 1
Preparation to methoxyl group base phenylacetic acid-2-(methoxycarbonyl base) phenyl ester (4)
3.04g methyl salicylate (20mmol) is dissolved in 25ml pyridine, and adds corresponding homoanisic acid
(3.3g, 20mmol), it is homogeneous for stirring under room temperature to reactant liquor.Under ice bath environment, be slowly added dropwise phosphorus oxychloride (2.2ml,
24mmol), 30min dropping is complete.At 0-10 DEG C, stirring reaction 3h, complete with TLC detection reaction.After having reacted, to instead
Answer and liquid adds dilute hydrochloric acid solution (2mol/L), the PH of mixed liquor is adjusted to 5-6, is extracted with ethyl acetate three times, merges organic
Phase, and wash three times with saturated common salt, anhydrous sodium sulfate is dried, and after 30min, decompression distillation, to dry, to thick product, passes through post
Chromatographic purification obtains white crystal 4.77g, and yield is 75%.ESI-MS m/z:323.4 [M+Na]+.
Embodiment 2
3,4-dimethoxyphenylacetic acids-2 '-the preparation of (methoxycarbonyl base) phenyl ester (5)
3.04g methyl salicylate (20mmol) is dissolved in 25ml pyridine, and adds 3,4-dimethoxyphenylacetic acid
(3.92g, 20mmol), it is homogeneous for stirring under room temperature to reactant liquor.Under ice bath environment, be slowly added dropwise phosphorus oxychloride (2.2ml,
24mmol), 30min dropping is complete.At 0-10 DEG C, stirring reaction 3h, complete with TLC detection reaction.After having reacted, to instead
Answer and liquid adds dilute hydrochloric acid solution (2mol/L), the PH of mixed liquor is adjusted to 5-6, is extracted with ethyl acetate three times, merges organic
Phase, and wash three times with saturated common salt, anhydrous sodium sulfate is dried, and after 30min, decompression distillation, to dry, to thick product, passes through post
Chromatographic purification obtains white crystal 5.22g, and yield is 75%.ESI-MS m/z:353.4 [M+Na]+.
Embodiment 3
The preparation of 4-hydroxyl-3-(4-methoxyphenyl)-coumarin (6)
1.5g intermediate 4 (5mmol) is dissolved in 5ml anhydrous pyridine, under room temperature, addition KOH powder (0.7g,
12.5mmol).Nitrogen ball is protected, stirring at normal temperature 5h, and decompression distills as reactor pyridine, addition 15ml in reaction bulb
NaOH solution (2N), aqueous phase ethyl acetate is washed twice, outwells organic facies, retains aqueous phase.Add dilute hydrochloric acid, aqueous phase is adjusted as PH
To about 4, placing cooling, be filtrated to get white powder product 0.67g, yield is 50%.ESI-MS m/z::267.1 [M-
H]-。
Embodiment 4
The preparation of 4-hydroxyl-3-(3,4-Dimethoxyphenyl)-coumarin (7)
1.65g intermediate 4 (5mmol) is dissolved in 5ml anhydrous pyridine, under room temperature, addition KOH powder (0.7g,
12.5mmol).Nitrogen ball is protected, stirring at normal temperature 5h, and decompression distills as reactor pyridine, addition 15ml in reaction bulb
NaOH solution (2N), aqueous phase ethyl acetate is washed twice, outwells organic facies, retains aqueous phase.Add dilute hydrochloric acid, aqueous phase PH is adjusted to
About 4, to place cooling, be filtrated to get white powder product 0.74g, yield is 50%.ESI-MS m/z::297.1 [M-
H]-。
Embodiment 5
The preparation of 3-(4-methoxyphenyl)-coumarin-4-p-toluenesulfonic esters (8)
0.5g intermediate 6 (1.87mmol) is dissolved in the dichloromethane that 10mL is dried, adds the triethylamine being dried
(0.56g, 5.60mmol), stirs under room temperature, and question response mixed liquor becomes homogeneous, is slowly added to Methyl benzenesulfonyl under ice bath
Chlorine (0.39g, 2.057mmol), stirs 10min, removes ice bath, continues stirring 30min under room temperature.TLC display reaction is completely.Subtract
Pressure distillation spins off dry unnecessary solvent and triethylamine, is purified by column chromatography, obtains yellow solid 0.68g, yield 76.4%.ESI-
MS m/z:445 [M+Na]+
Embodiment 6
The preparation of 3-(3,4-Dimethoxyphenyl)-coumarin-4-p-toluenesulfonic esters (9)
0.56g intermediate compound I-A (1.87mmol) is dissolved in the dichloromethane that 10mL is dried, adds the triethylamine being dried
(0.56g, 5.60mmol), stirs under room temperature, and question response mixed liquor becomes homogeneous, is slowly added to Methyl benzenesulfonyl under ice bath
Chlorine (0.39g, 2.057mmol), stirs 10min, removes ice bath, continues stirring 30min under room temperature.TLC display reaction is completely.Subtract
Pressure distillation spins off dry unnecessary solvent and triethylamine, is purified by column chromatography, obtains yellow solid 0.8g, yield 84.21%.ESI-
MS m/z:475 [M+Na]+
Embodiment 7
The preparation of 3-(4-methoxyphenyl)-4-(open-chain crown ether) coumarin (I-1)
0.2g intermediate 8 (0.47mmol) is dissolved in 6mL ethanol, adds 0.4g cesium carbonate (1.2mmol) and to methylbenzene
Amine (0.050g, 0.47mmol), 75 DEG C of backflow 2h, TLC display reactions are completely.Cooling, filters insoluble matter, filtrate is spin-dried for, logical
Cross column chromatography purification and obtain yellow crystals 0.2g, yield 80.00%.1H NMR(DMSO-d6, 300MHz) and δ: 8.4 (s, N-H),
7.9 (d, 1H, J=3), 7.57 (t, 1H), 7.4 (d, 1H), 7.29 (d, 1H), 7.08 (d, 2H), 6.8 (d, 2H), 6.6 (m,
4H), 3.6 (s, 3H), 2.1 (s, 3H) ppm；ESI-MS m/z:380.1 [M+Na]+
Embodiment 8
The preparation of 3-(4-methoxyphenyl)-4-(4-phenetidine) coumarin (I-2)
The synthesis of concrete operations reference compound (I-1), puts into 0.2g intermediate 8 (0.47mmol), p-ethoxyaniline
(0.064g, 0.47mmol), 0.4g cesium carbonate (1.2mmol), obtain 0.15g yellow solid, yield 56.81%.1H NMR
(DMSO-d6, 300MHz) and δ: 8.45 (s, 1H), 8.05 (d, 1H), 7.68 (t, 1H), 7.40 (d, 1H), 7.35 (t, 1H), 7.04
(d, 2H), 6.72 (m, 4H), 6.52 (d, 2H), 3.86 (m, 2H), 3.64 (s, 3H), 1.12 (t, 3H) ppm；ESI-MS
M/z:386.1 [M-H]+
Embodiment 9
The preparation of 3-(4-methoxyphenyl)-4-(3-hydroxy-4-methyl aniline) coumarin (I-3)
The synthesis of concrete operations reference compound (I-1), puts into 0.2g intermediate 8 (0.47mmol), 3-hydroxy-4-methyl
Aniline (0.057g, 0.47mmol), 0.4g cesium carbonate (1.2mmol), obtain 0.18g yellow solid, yield 70.04%.1H NMR
(DMSO-d6, 300MHz) and δ: 9.02 (s, 1H), 8.12 (s, 1H), 7.7 (d, 1H), 7.55 (t, 1H), 7.35 (d, 1H), 7.19
(t, 1H), 7.05 (d, 2H), 6.65 (m, 3H), 6.3 (d, 1H), 6.2 (d, 1H), 3.63 (s, 3H), 1.88 (s, 3H) ppm；
ESI-MS m/z:372.1 [M-H]+
Embodiment 10
The preparation of 3-(4-methoxyphenyl)-4-(3,4-methylene dioxo group aniline) coumarin (I-4)
The synthesis of concrete operations reference compound (I-1), puts into 0.2g intermediate 8 (0.47mmol), 3,4-(methylenedioxy)s
Base aniline (0.064g, 0.47mmol), 0.4g cesium carbonate (1.2mmol), obtain 0.15g black solid, yield 56.82%.1H
NMR(DMSO-d6, 300MHz) and δ: 8.47 (s, 1H), 8.00 (d, 1H), 7.55 (d, 1H), 7.55 (t, 1H), 7.35 (d, 1H),
7.28 (t, 1H), 7.01 (d, 2H), 6.67 (d, 2H), 6.30 (d, 2H), 5.82 (s, 2H), 3.66 (s, 3H) ppm；
ESI-MS m/z:386.1 [M-H]+
Embodiment 11
The preparation of 3-(4-methoxyphenyl)-4-(3-hydroxyl-4-aminoanisole) coumarin (I-5)
The synthesis of concrete operations reference compound (I-1), puts into 0.2g intermediate 8 (0.47mmol), 3-hydroxyl-4-methoxy
Base aniline (0.065g, 0.47mmol), 0.4g cesium carbonate (1.2mmol), obtain 0.20g yellow solid, yield 75.47%.1H
NMR(DMSO-d6, 300MHz) and δ: 8.0 (d, 1H), 7.72 (t, 1H), 7.48 (t, 1H), 7.40 (d, 3H), 7.35 (d, 1H),
6.9 (m, 3H), 6.4 (m, 2H), 4.9 (s, 2H), 3.7 (s, 3H), 3.6 (s, 3H) ppm；ESI-MS m/z:388 [M-H]+
Embodiment 12
The preparation of 3-(4-methoxyphenyl)-4-(3,4,5-trimethoxy-aniline) coumarin (I-6)
The synthesis of concrete operations reference compound (I-1), puts into 0.2g intermediate 8 (0.47mmol), 3,4,5-trimethoxies
Base aniline (0.086g, 0.47mmol), 0.4g cesium carbonate (1.2mmol), obtain 0.21g yellow solid, yield 73.43%.1H
NMR(DMSO-d6, 300MHz) and δ: 8.71 (s, 1H), 7.98 (d, 1H), 7.63 (d, 1H), 7.40 (d, 2H), 7.31 (d, 2H),
6.69 (s, 2H), 3.78 (s, 3H), 3.74 (s, 6H), 3.35 (s, 3H) ppm；ESI-MS m/z:456.2 [M+Na]+
Embodiment 13
The preparation of 3-(4-methoxyphenyl)-4-(4-acetylaminoaniline) coumarin (I-7)
The synthesis of concrete operations reference compound (I-1), puts into 0.2g intermediate 8 (0.47mmol), 4-acetyl amino phenyl
Amine (0.070g, 0.47mmol), 0.4g cesium carbonate (1.2mmol), obtain 0.22g yellow solid, yield 81.48%.1H NMR
(DMSO-d6, 300MHz) and δ: 9.94 (s, 1H), 8.72 (s, 1H), 7.98 (d, 1H), 7.62 (t, 1H), 7.52 (d, 2H), 7.33
(m, 6H), 6.97 (d, 2H), 3.78 (s, 3H), 2.03 (s, 3H) ppm；ESI-MS m/z:423.2 [M+Na]+
Embodiment 14
The preparation of 3-(4-methoxyphenyl)-4-(4-fluoroaniline) coumarin (I-8)
The synthesis of concrete operations reference compound (I-1), puts into 0.2g intermediate 8 (0.47mmol), 4-fluoroaniline
(0.052g, 0.47mmol), 0.4g cesium carbonate (1.2mmol), obtain 0.16g yellow solid, yield 63.49%.1H NMR
(DMSO-d6, 300MHz) and δ: 9.94 (s, 1H), 8.72 (s, 1H), 7.98 (d, 1H), 7.62 (t, 1H), 7.52 (d, 2H), 7.33
(m, 6H), 6.97 (d, 2H), 3.78 (s, 3H), 2.03 (s, 3H) ppm；ESI-MS m/z:360 [M-H]+
Embodiment 15
The preparation of 3-(4-methoxyphenyl)-4-(3-5-trifluoromethylaniline)-coumarin (I-9)
The synthesis of concrete operations reference compound (I-1), puts into 0.2g intermediate 8 (0.47mmol), m-trifluoromethyl benzene
Amine (0.075g, 0.47mmol), 0.4g cesium carbonate (1.2mmol), obtain 0.24g yellow solid, yield 87.27%.1H NMR
(DMSO-d6, 300MHz) and δ: 8.97 (s, 1H), 8.04 (d, 1H), 7.64 (d, 1H), 7.42 (t, 2H), 7.13 (d, 2H), 7.04
(m, 5H), 6.64 (d, 2H), 3.71 (s, 3H) ppm；ESI-MS m/z:434.1 [M+Na]+
Embodiment 16
The preparation of 3-(3,4-Dimethoxyphenyl)-4-(4-methyl-3-hydroxyl) aniline-coumarin (I-10)
The synthesis of concrete operations reference compound (I-1), puts into 0.2g intermediate 9 (0.44mmol), 3-hydroxyl-4 methyl
Aniline (0.054g, 0.44mmol), 0.4g cesium carbonate (1.2mmol), obtain 0.13g yellow solid, yield 51.18%.1H NMR
(DMSO-d6, 300MHz) and δ: 8.97 (s, 1H), 8.04 (d, 1H), 7.64 (d, 1H), 7.42 (t, 2H), 7.13 (d, 2H), 7.04
(m, 5H), 6.64 (d, 2H), 3.71 (s, 3H) ppm；ESI-MS m/z:402 [M-H]+
Embodiment 17
The preparation of 1-(2,4-dihydroxy phenyl)-2-(4-methoxyphenyl) ethyl ketone (11)
Dissolve resorcinol 3.60g (32.5mmol) with the new boron trifluoride ether solution 50ml steamed, add methoxy
Base phenylacetic acid 5.00g (30.0mmol).90 DEG C of reactions under nitrogen protection, determine terminal with TLC, instill saturated sodium bicarbonate molten
Liquid is released to bubble-free, and EA extracts three times, merges organic facies, and saturated sodium bicarbonate solution is washed three times, and saturated common salt is washed once,
Organic facies adds anhydrous sodium sulfate and is dried overnight.Concentrating under reduced pressure removes solvent, crude product dehydrated alcohol recrystallization, obtains off-white color
Powder 5.95g, productivity 77%, mp150-152 DEG C, EI-MS m/z:259 [M+H]+.
Embodiment 18
The preparation of 1-(2-hydroxyl-4-benzyloxy-phenyl)-2-(4-methoxyphenyl) ethyl ketone (12)
Waterless operation, adds to the anhydrous tetrahydrochysene of 100mL by 6.5g intermediate 11 (25.19mmol) and 3g benzylalcohol (27.7mmol)
In furan, stir to solution to become and clarify.Under ice bath, it is slowly added to triphenylphosphine (7.27g, 27.7mmol), drips 5.45ml
DIAD (27.7mmol), finishes rear TLC display reaction completely.It is spin-dried for excess of solvent, after being purified by column chromatography, obtains 7.9g white
Solid, yield 83.16%.ESI-MS m/z:347 [M-H]+
Embodiment 19
The preparation of 3-(4-methoxyphenyl)-4-hydroxyl-7-benzyloxy-coumarin (13)
Adding in 20ml diethyl carbonate by 1g intermediate 12 (2.87mmol) with 0.7gNaH (28.7mmol), strength is stirred
Mixing, nitrogen protects lower 120 DEG C of reactions, determines terminal with TLC.100ml frozen water is added in reactant liquor, destroy NaH, stir 2min
Rear separatory, organic facies discards, and aqueous phase is extracted with ethyl acetate three times, discards organic facies, is adjusted by aqueous phase pH with the hydrochloric acid of 1mol/L
To 3-4, a large amount of white solids separate out, and sucking filtration obtains crude product, obtain 0.8g white powder, productivity 80% after purification through column chromatography.ESI-
MS m/z:373 [M-H]
Embodiment 20
The preparation (14) of 3-(4-methoxyphenyl)-7-benzyloxy coumarin-4-p-toluenesulfonic esters
The synthesis of concrete operations reference compound (9), puts into 1.3g compound (13) (3.5mmol), paratoluensulfonyl chloride
(0.66g, 3.5mmol), triethylamine (1.46ml, 10.5mmol), obtain 1.8g faint yellow solid, yield 91.8%.ESI-MS m/
Z:529 [M+H]+
Embodiment 21
The preparation of 3-(4-methoxyphenyl)-4-(4-phenetidine)-7-benzyloxy coumarin (15-1)
The synthesis of concrete operations reference compound (I-1), puts into compound (14) 0.2g (0.38mmol), to ethoxybenzene
Amine 0.042g (0.38mmol), cesium carbonate (0.37g, 1.14mmol), obtain yellow solid 0.1g, yield 41.3%.ESI-MS m/
Z:494 [M+H]+
Embodiment 22
The preparation of 3-(4-methoxyphenyl)-4-(4-phenetidine)-umbelliferone (II-1)
0.08g compound 15-1 (0.16mmol) is added in the anhydrous THF of 4mL, add 0.01gPd-C, room temperature and adding
Under pressure hydrogen balloon, it is stirred overnight.After having reacted, sucking filtration removes unreacted palladium carbon, filtrate is spin-dried for, is carried by column chromatography
Pure, obtain yellow solid 0.03g, yield is 37.50%.1H NMR (DMSO, 300MHz) δ: 8.23 (s, 1H), 7.73 (d,
1H), 7.0 (d, 2H), 6.68 (m, 4H), 6.53 (d, 2H), 3.8 (t, 2H), 3.65 (s, 3H), 1.25 (t, 3H) ppm；ESI-MS
M/z:426.2 [M+Na]+
Embodiment 23
3-(4-methoxyphenyl)-4-(4-aminoanisole)-7-benzyloxy coumarin (15-2)
The synthesis of concrete operations reference compound (15-1), puts into compound (14) (0.2g, 0.38mmol), to methoxyl group
Aniline (0.046g, 0.38mmol), cesium carbonate (0.37g, 1.14mmol), obtain yellow sterling 0.2g, yield 81.30%.ppm；
ESI-MS m/z:480 [M+H]+
Embodiment 24
3-(4-methoxyphenyl)-4-(4-aminoanisole)-7-hydroxyl butylcoumariii (II-2)
The synthesis of concrete operations reference compound (II-1), puts into compound (15-2) (0.2g, 0.42mmol), Pd-C
(0.016g), yellow sterling 0.1g, yield 50.30% are obtained.1H NMR(DMSO-d6, 300MHz) and δ: 7.62 (d, 1H), 7.21 (d,
1H), 7.01 (d, 2H), 6.68 (d, 3H), 6.62 (d, 2H), 6.20 (d, 1H), 6.02 (d, 2H), 3.63 (s, 3H), 3.42 (s,
3H)ppm；ESI-MS m/z:412.2 [M+Na]+
Embodiment 25
3-(4-methoxyphenyl)-4-(3,4-bis-sub-aminoanisole)-7-benzyloxy coumarin (15-3)
The synthesis of concrete operations reference compound (15-1), puts into compound (14) (0.2g, 0.38mmol), 3,4-methylenes
Two epoxide aniline (0.052g, 0.38mmol), cesium carbonate (0.37g, 1.14mmol), obtain black sterling 0.12g, yield
47.62%.ESI-MS m/z:494 [M+H]+
Embodiment 26
3-(4-methoxyphenyl)-4-(3,4-bis-sub-aminoanisole)-umbelliferone (II-3)
The synthesis of concrete operations reference compound (II-1), puts into compound (15-3) 0.12g, Pd-C (0.01g) and obtains bright
Yellow solid 0.08g, yield 66.67%.1H NMR(DMSO-d6, 300MHz) and δ: 8.23 (s, 1H), 7.85 (d, 1H), 7.01
(d, 2H), 6.69 (m, 4H), 6.65 (d, 1H), 6.32 (d, 2H), 5.83 (s, 2H), 3.67 (s, 3H) ppm；ESI-MS m/z:
426.1[M+Na]+
Embodiment 27
3-(4-methoxyphenyl)-4-(3-hydroxy-4-methyl aniline)-7-benzyloxy coumarin (15-4)
The synthesis of concrete operations reference compound (15-1), input compound (14) (0.2g, 0.38mmol), 3-hydroxyl-
4-monomethylaniline. (0.046g, 0.38mmol), cesium carbonate (0.37g, 1.14mmol), obtain glassy yellow sterling 0.16g, yield
65.04%.ESI-MS m/z:480 [M+H]+
Embodiment 28
3-(4-methoxyphenyl)-4-(3-hydroxy-4-methyl aniline)-umbelliferone (II-4)
The synthesis of concrete operations reference compound (I-1), puts into compound (15-4) (0.16g, 0.33mmol), palladium carbon
(0.02g), glassy yellow sterling 0.098g, yield 61.25% are obtained.1H NMR(DMSO-d6, 300MHz) and δ: 7.84 (d, 1H), 7.36
(d, 1H), 7.01 (d, 2H), 6.77 (m, 3H), 6.52 (d, 1H), 6.46 (d, 1H), 6.38 (d, 1H), 6.29 (d, 1H), 3.64
(s, 3H), 1.95 (s, 3H) ppm；ESI-MS m/z:412.1 [M+Na]+
Embodiment 29
3-(4-methoxyphenyl)-4-(3,4,5-trimethoxy-aniline)-7-benzyloxy coumarin (15-5)
The synthesis of concrete operations reference compound (15-1), input compound (14) (0.2g, 0.38mmol), 3,4,5-tri-
Aminoanisole (0.069g, 0.38mmol), cesium carbonate (0.37g, 1.14mmol), obtain yellow green sterling 0.2g, yield
70.28%.ppm；ESI-MS m/z:540 [M+H]+
Embodiment 30
3-(4-methoxyphenyl)-4-(3,4,5-trimethoxy-aniline) coumarin (II-5)
The synthesis of concrete operations reference compound (I-1), puts into compound (15-5) (0.2g, mmol), palladium carbon
(0.02g), glassy yellow sterling 0.098g, yield 49.00% are obtained.1H NMR(DMSO-d6, 300MHz) and δ: 8.43 (s, 1H), 7.81
(d, 1H), 7.02 (d, 2H), 6.72 (d, 1H), 6.65 (m, 3H), 6.04 (s, 2H), 3.61 (s, 3H), 3.54 (s, 6H), 3.25
(s, 3H) ppm；ESI-MS m/z:472.1 [M+Na]+
Embodiment 31
3-(4-methoxyphenyl)-4-(3-hydroxyl-4-aminoanisole) coumarin-7-benzyloxy (15-6)
The synthesis of concrete operations reference compound (15-1), input compound (14) (0.2g, 0.38mmol), 3-hydroxyl-
4-aminoanisole (0.053g, 0.38mmol), cesium carbonate (0.37g, 1.14mmol), obtain yellow green sterling 0.18g, yield
71.14%.ppm；ESI-MS m/z:494 [M-H]+
Embodiment 32
3-(4-methoxyphenyl)-4-(3-hydroxyl-4-methoxyl group) aniline coumarin (II-6)
The synthesis of concrete operations reference compound (I-1), puts into compound (15-6) 0.18g, palladium carbon (0.02g), obtains bright
Yellow sterling 0.11g, yield 61.11%.1H NMR(DMSO-d6, 300MHz) and δ: 8.43 (s, 1H), 7.81 (d, 1H), 7.02
(d, 2H), 6.72 (d, 1H), 6.65 (m, 3H), 6.04 (s, 2H), 3.61 (s, 3H), 3.54 (s, 6H), 3.25 (s, 3H) ppm；
ESI-MS m/z:428.1 [M+Na]+
Embodiment 33
3-(4-methoxyphenyl)-4-(para-fluoroaniline) coumarin-7-benzyloxy (15-7)
The synthesis of concrete operations reference compound (15-1), puts into compound (14) (0.2g, 0.38mmol), para-fluoroaniline
(0.042g, 0.38mmol), obtains yellow green sterling 0.2g, cesium carbonate (0.37g, 1.14mmol), yield 82.64%.ppm；
ESI-MS m/z:468 [M+H]+
Embodiment 34
3-(4-methoxyphenyl)-4-(para-fluoroaniline)-umbelliferone (II-7)
The synthesis of concrete operations reference compound (I-1), puts into compound (15-7) 0.2g, palladium carbon (0.02g), obtains bright orange
Colour purity product 0.18g, yield 90.00%.1H NMR(DMSO-d6, 300MHz) δ: 10.48 (s, 1H), 8.48 (s, 1H), 7.79 (d,
1H), 6.9 (d, 2H), 6.73 (m, 6H), 6.63 (d, 2H), 3.64 (s, 3H) ppm；ESI-MS m/z:376 [M-H]+
Embodiment 35
3-(4-methoxyphenyl)-4-(3-Aminotrifluorotoluene)-7-benzyloxy coumarin (15-8)
The synthesis of concrete operations reference compound (15-1), puts into compound (14) (0.2g, 0.38mmol), a fluoroform
Base aniline (0.061g, 0.38mmol), cesium carbonate (0.37g, 1.14mmol), obtain yellow green sterling 0.15g, yield 57.47%.
ESI-MS m/z:518 [M+H]+
Embodiment 36
3-(4-methoxyphenyl)-4-(3-Aminotrifluorotoluene)-umbelliferone (II-8)
The synthesis of concrete operations reference compound (I-1), puts into compound (15-8) 0.15g, palladium carbon (0.02g), obtains bright
Yellow sterling 0.088g, yield 58.67%.1H NMR(DMSO-d6, 300MHz) and δ: 10.48 (s, 1H), 8.48 (s, 1H), 7.79
(d, 1H), 6.9 (d, 2H), 6.73 (m, 6H), 6.63 (d, 2H), 3.64 (s, 3H) ppm；ESI-MS m/z:376 [M-H]+
Embodiment 37
3-(4-methoxyphenyl)-4-(to sulfanoyl aniline)-7-benzyloxy coumarin (15-9)
The synthesis of concrete operations reference compound (15-1), puts into compound (14) (0.2g, 0.38mmol), to sulfonamides
Base aniline (0.065g, 0.38mmol), cesium carbonate (0.37g, 1.14mmol), obtain yellow green sterling 0.19g, yield 71.70%.
ESI-MS m/z:529 [M+H]+
Embodiment 38
3-(4-methoxyphenyl)-4-(to sulfanoyl aniline aniline)-umbelliferone (II-9)
The synthesis of concrete operations reference compound (I-1), puts into compound (15-9) 0.19g, palladium carbon (0.02g), obtains bright
Yellow sterling 0.17g, yield 89.47%.1H NMR(DMSO-d6, 300MHz) and δ: 8.59 (s, 1H), 7.46 (m, 3H), 7.15
(m, 4H), 6.91 (m, 4H), 6.56 (s, 2H), 3.67 (s, 3H) ppm；ESI-MS m/z:437.1 [M-H]+
Embodiment 39
3-(4-methoxyphenyl)-4-(acetparaminosalol aniline)-7-benzyloxy coumarin (15-10)
The synthesis of concrete operations reference compound (15-1), puts into compound (14) (0.2g, 0.38mmol), to acetyl ammonia
Base aniline (0.057g, 0.38mmol), cesium carbonate (0.37g, 1.14mmol), obtain yellow green sterling 0.16g, yield 62.26%.
ESI-MS m/z:507 [M+H]+
Embodiment 40
3-(4-methoxyphenyl)-4-(acetparaminosalol aniline)-umbelliferone (II-10)
The synthesis of concrete operations reference compound (I-1), puts into compound (15-9) 0.16g, palladium carbon (0.02g), obtains bright
Yellow sterling 0.11g, yield 68.75%.1H NMR(DMSO-d6, 300MHz) and δ: 8.59 (s, 1H), 7.46 (m, 3H), 7.15
(m, 4H), 6.91 (m, 4H), 6.56 (s, 2H), 3.67 (s, 3H) ppm；ESI-MS m/z:415 [M-H]+
Embodiment 41
The preparation of 1-(2-hydroxyl-4-methoxyphenyl)-2-(4-methoxyphenyl) ethyl ketone (16)
Waterless operation, adds to 40mL anhydrous four by 3g intermediate 11 (11.62mmol) and 0.37g methanol (11.62mmol)
In hydrogen furan, stir to solution to become and clarify.Under ice bath, it is slowly added to triphenylphosphine (3.59g, 12.78mmol), drips 2.6g
DIAD (12.78mmol), finishes rear TLC display reaction completely.It is spin-dried for excess of solvent, after being purified by column chromatography, obtains 2.8g white
Color solid, yield 83.08%.ESI-MS m/z:273 [M+H]+
Embodiment 42
The preparation of 1-(2-hydroxyl-4-methoxyphenyl)-2-(4-methoxyphenyl) ethyl ketone (17)
2.8g intermediate 16 (10.29mmol) is added in 40ml diethyl carbonate with 2.4gNaH (102.9mmol), by force
Power stirs, and nitrogen protects lower 120 DEG C of reactions, determines terminal with TLC.100ml frozen water is added in reactant liquor, destroy NaH, stirring
Separatory after 2min, organic facies discards, and aqueous phase is extracted with ethyl acetate three times, discards organic facies, with the hydrochloric acid of 1mol/L by aqueous phase
PH is adjusted to 3-4, and a large amount of white solids separate out, and sucking filtration obtains crude product, obtains 2.2g white powder, productivity after purification through column chromatography
78.57%, ESI-MS m/z:297 [M-H]
Embodiment 43
The preparation (18) of 3-(4-methoxyphenyl)-coumarin-4-p-toluenesulfonic esters
The synthesis of concrete operations reference compound (9), puts into 1.04g compound (13) (3.5mmol), paratoluensulfonyl chloride
(0.66g, 3.5mmol), triethylamine (1.46ml, 10.5mmol), obtain 1.3g faint yellow solid, yield 76.47%.ESI-MS
M/z:453 [M+H]+
Embodiment 44
The preparation of 3-(4-methoxyphenyl)-4-(3-hydroxyl-4-aminoanisole)-ayapanin (III-1)
0.2g intermediate 18 (0.44mmol) is dissolved in 6mL ethanol, adds 0.43g cesium carbonate (13.2mmol) and 3-hydroxyl
Base-4-aminoanisole (0.061g, 0.44mmol), 75 DEG C of backflow 2h, TLC display reactions are completely.Cooling, filters insoluble matter,
Filtrate is spin-dried for, is purified by column chromatography and obtain yellow crystals 0.2g, yield 76.63%.1H NMR(CDCl3, 300MHz) and δ:
7.30 (d, 2H), 7.20 (d, 1H), 7.00 (d, 2H), 6.82 (d, 1H), 6.73 (d, 2H), 6.60 (d, 1H), 6.55 (d, 1H),
6.44 (m, 1H), 6.04 (s, 1H), 5.66 (s, 1H), 3.87 (s, 3H), 3.82 (s, 3H) ppm；ESI-MS m/z:442.1 [M+
Na]+
Embodiment 45
The preparation of 3-(4-methoxyphenyl)-4-(3-hydroxy-4-methyl aniline) coumarin-7-methoxyl group (III-2)
The synthesis of concrete operations reference compound (III-1), input compound (18) (0.2g, 0.44mmol), 3-hydroxyl-
4-monomethylaniline. (0.054g, 0.44mmol), 0.43g cesium carbonate (13.2mmol), obtain yellow green sterling 0.2g, yield
78.74%.1H NMR(DMSO-d6, 300MHz) and δ: 9.08 (s, 1H), 7.46 (m, 3H), 8.05 (s, 1H), 7.64 (d, 1H),
7.11 (d, 2H), 6.96 (d, 1H), 6.87 (d, 1H), 6.84 (d, 1H), 6.78 (d, 2H), 6.72 (d, 1H) 6.28 (d, 1H),
6.19 (d, 1H), 3.88 (s, 3H), 3.69 (s, 3H), 1.96 (s, 3H), ppm；ESI-MS m/z:402.1 [M-H]+
Embodiment 46
The preparation of 3-(4-methoxyphenyl)-4-(3,4-methylene dioxo group aniline)-ayapanin (III-3)
The synthesis of concrete operations reference compound (III-1), puts into compound (18) (0.2g, 0.44mmol), and 3,4-is sub-
Methylenedioxy group aniline (0.060g, 0.44mmol), 0.43g cesium carbonate (13.2mmol), obtain black sterling 0.14g, yield
53.85%.1H NMR(DMSO-d6, 300MHz) and δ: 8.35 (s, 1H), 7.84 (d, 1H), 7.00 (t, 3H), 6.96 (d, 1H),
6.67 (d, 2H), 6.57 (d, 1H), 6.33 (d, 2H), 5.82 (s, 2H), 3.86 (s, 3H), 3.68 (s, 3H), ppm；ESI-MS
M/z:416.1 [M-H]+
Embodiment 47
The preparation of 3-(4-methoxyphenyl)-4-(acetylaminoaniline)-ayapanin (III-4)
The synthesis of concrete operations reference compound (III-1), puts into compound (18) (0.2g, 0.44mmol), to acetyl
Amino aniline (0.066g, 0.44mmol), 0.43g cesium carbonate (13.2mmol), obtain black sterling 0.19g, yield 71.43%.1H NMR(DMSO-d6, 300MHz) δ: 9.73 (s, 1H), 8.35 (s, 1H), 7.78 (d, 1H), 7.20 (d, 2H), 7.03 (d,
2H), 6.95 (d, 1H), 6.88 (d, 1H), 6.67 (m, 4H), 3.84 (s, 3H), 3.63 (s, 3H), 1.94 (s, 3H) ppm；ESI-
MS m/z:453.2 [M+Na]+
Embodiment 48
The preparation of 3-(4-methoxyphenyl)-4-(para-fluoroaniline)-ayapanin (III-5)
The synthesis of concrete operations reference compound (III-1), puts into compound (18) (0.2g, 0.44mmol), to fluorobenzene
Amine (0.049g, 0.44mmol), 0.43g cesium carbonate (13.2mmol), obtain black sterling 0.15g, yield 60.24%.1H 1H
NMR(DMSO-d6, 300MHz) and δ: 8.79 (s, 1H), 8.03 (s, 1H), 6.99 (m, 3H), 6.95 (d, 1H), 6.77 (d, 4H),
6.63 (d, 2H), 3.87 (s, 3H), 3.68 (s, 3H) ppm；ESI-MS m/z:414.1 [M+H]+
Embodiment 49
The preparation of 3-(4-methoxyphenyl)-4-(3-Aminotrifluorotoluene)-ayapanin (III-6)
The synthesis of concrete operations reference compound (III-1), puts into compound (18) (0.2g, 0.44mmol), a trifluoro
Monomethylaniline. (0.078g, 0.44mmol), 0.43g cesium carbonate (13.2mmol), obtain black sterling 0.21g, yield 75.54%.1H NMR(DMSO-d6, 300MHz) δ: 8.92 (s, 1H), 7.93 (d, 1H), 7.15 (d, 1H), 7.04 (m, 7H), 6.63 (d,
2H), 3.89 (s, 3H), 3.62 (s, 3H), 1.94 (s, 3H) ppm；ESI-MS m/z:440.1 [M-H]+
Embodiment 50
The preparation of 3-(4-methoxyphenyl)-4-(para hydroxybenzene amine)-ayapanin (III-7)
The synthesis of concrete operations reference compound (III-1), puts into compound (18) (0.2g, 0.44mmol), to hydroxyl
Aniline (0.048g, 0.44mmol), 0.43g cesium carbonate (13.2mmol), obtain black sterling 0.18g, yield 72.58%.1H
NMR(DMSO-d6, 300MHz) and δ: 9.10 (s, 1H), 8.20 (d, 1H), 7.82 (d, 1H), 7.01 (d, 2H), 6.95 (d, 1H),
6.85 (d, 1H), 6.65 (m, 4H), 6.42 (d, 2H), 3.85 (s, 3H), 3.67 (s, 3H), ppm；ESI-MS m/z:388.1
[M-H]+
Embodiment 51
The preparation of 3-(4-methoxyphenyl)-4-(P-nethoxyaniline)-ayapanin (III-8)
The synthesis of concrete operations reference compound (III-1), puts into compound (18) (0.2g, 0.44mmol), to methoxy
Base aniline (0.054g, 0.44mmol), 0.43g cesium carbonate (13.2mmol), obtain black sterling 0.19g, yield 74.80%.H1
NMR(DMSO-d6, 300MHz) and δ: 9.10 (s, 1H), 8.20 (d, 1H), 7.82 (d, 1H), 7.01 (d, 2H), 6.95 (d, 1H),
6.85 (d, 1H), 6.65 (m, 4H), 6.42 (d, 2H), 3.85 (s, 3H), 3.67 (s, 3H), ppm；ESI-MS m/z:404 [M+
H]+
Embodiment 52
The preparation of 3-(4-methoxyphenyl)-4-(to sulfanoyl aniline)-ayapanin (III-9)
The synthesis of concrete operations reference compound (III-1), puts into compound (18) (0.2g, 0.44mmol), to ammonia sulphur
Anilid (0.076g, 0.44mmol), 0.43g cesium carbonate (13.2mmol), obtain yellow sterling 0.1g, yield 36.36%.H1
NMR(DMSO-d6, 300MHz) and δ: 9.10 (s, 1H), 8.20 (d, 1H), 7.82 (d, 1H), 7.01 (d, 2H), 6.95 (d, 1H),
6.85 (d, 1H), 6.65 (m, 4H), 6.42 (d, 2H), 3.85 (s, 3H), 3.67 (s, 3H), ppm；ESI-MS m/z:431 [M+
H]+
Embodiment 53
The preparation of 3-(4-methoxyphenyl)-4-(3,4,5-trimethoxy-aniline)-ayapanin (III-10)
The synthesis of concrete operations reference compound (III-1), input compound (18) (0.2g, 0.44mmol), 3,4,5-
Trimethoxy-aniline (0.080g, 0.44mmol), 0.43g cesium carbonate (13.2mmol), obtain yellow sterling 0.2g, yield
71.43%.H1 NMR(DMSO-d6, 300MHz) and δ: 15.33 (s, 1H), 7.39 (d, 1H), 7.03 (d, 2H), 6.81 (d, 2H),
(6.51 s, 1H), 6.33 (d, 1H), 6.11 (s, 2H), 4.06 (s, 3H), 3.88 (s, 6H), 3.76 (s, 3H), 3.64 (s, 3H)
ppm；ESI-MS m/z:464 [M+H]+。
Claims (9)
1. the compound of general formula (1) or its pharmaceutically acceptable salt:
Wherein R1Represent H, OH or OMe；R2Representing substituted aroma ring, wherein the substituted radical on aromatic rings includes electron withdraw group
Or electron-donating group；R3Represent OMe or H.
Compound the most according to claim 1 or its pharmaceutically acceptable salt, it has a following structure:
I series:
Compound the most according to claim 2 or its pharmaceutically acceptable salt,
Wherein R2Represent:
R3Represent: H.
Compound the most according to claim 2 or its pharmaceutically acceptable salt,
Wherein R2Represent:
R3Represent: methoxyl group.
Compound the most according to claim 1 or its pharmaceutically acceptable salt, it has a following structure:
II series:
Wherein R2Represent:
Compound the most according to claim 1 or its pharmaceutically acceptable salt, it has following structure
III series:
Wherein R2Represent:
7. according to the compound described in claim 1 to 6 or its pharmaceutically acceptable salt, wherein pharmaceutically acceptable salt
For formula (1) with following acid formed acid-addition salts: hydrochloric acid, citric acid, succinic acid, sulphuric acid, maleic acid, tartaric acid, methanesulfonic acid,
Lactic acid, acetic acid, p-methyl benzenesulfonic acid or hydrobromic acid.
8. a pharmaceutical composition, wherein contains the compound any one of claim 1 to 6 or its pharmaceutically acceptable salt
Form with pharmaceutically acceptable carrier.
9. in claim 1 to 6, arbitrary compound and pharmaceutically acceptable salt thereof, in the application of anti-tumor aspect, especially exist
Application in terms of anti-breast cancer.
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