CN102351852A - Coumarone compound, its preparation method and its application - Google Patents
Coumarone compound, its preparation method and its application Download PDFInfo
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- CN102351852A CN102351852A CN2011102425479A CN201110242547A CN102351852A CN 102351852 A CN102351852 A CN 102351852A CN 2011102425479 A CN2011102425479 A CN 2011102425479A CN 201110242547 A CN201110242547 A CN 201110242547A CN 102351852 A CN102351852 A CN 102351852A
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Abstract
The invention provides a coumarone compound, a preparation method and an application in the medical and chemical field, the structural formula of the coumarone compound is shown as a following formula:; the invention also relates to the preparation method of the compound and the application of the compound in preparation of medicines used for inhibiting tumor cells biological activity. According to the invention, a traditional PPAR agonist hydrophobic tail hydrophobic tail and a flexible intermediate coupling chain are taken as a mother nucleus, a cis-structure of CombretastinA-4 is referred so that the good antineoplastic activity is presented, the coumarone structure is taken as an aromatic ring center between an acidic head and the flexible coupling chain in the PPAR agonist, the preparation method of compound is established and optimized, and the prepared novel compound is carried out an experiment for screening the tumor cells. The preliminary antineoplastic tests confirm that the prepared partial novel compound has specific and exclusive tumor inhibition activity aimed at human prostatic cancer cells, the coumarone compound can be used for preparing the antitumor medicines and medicines for treating and preventing tumor.
Description
Technical field
What the present invention relates to is compound in a kind of medicine and the chemical field and preparation method thereof, purposes, specifically is a kind of
Benzofuran compounds and preparation method thereof, purposes.
Background technology
Peroxidase growth factor activated receptor (Peroxisome Proliferator-Activated Receptors; PPARS) be a nuclear hormone receptor superfamily; Comprise PPAR α, PPAR β and three kinds of hypotypes of PPAR γ, these hypotypes at first are in African toad crowd, to be found.PPARS is one type of ligand-dependent type transcription factor, can regulate the target body expression of gene relevant with glucose metabolism with fat.Each PPAR acceptor can form a title complex with retinoic acid receptor X, and this title complex can combine the dna sequence dna with identification target body gene with specific peroxidase proliferator response factor (PPRE).PPAR is found to now from the nineties in 20th century, and the PPARS acceptor is regarded as the target spot of potential treatment and prevention of metabolic syndromes, and Pharmaceutical Chemist is primarily aimed at this point and studies related drugs with metabolism syndromess such as treatment cardiovascular disorder, type-II diabetes.At present the PPAR agonist mainly contains PPAR alfa agonists (chlorine special type), PPAR gamma agonist (thiazolidinediones) and three types of the two target spot agonists of PPAR α/γ, and is wherein maximum with the research of PPAR gamma agonist especially.This three excitomotor all has the medicine listing separately, and the representative of PPAR alfa agonists has fenofibrate and gemfibrozil; The representative of PPAR gamma agonist has pioglitazone and rosiglitazone; PPAR α/gamma agonist representative has muraglitazar and tesaglitazar.Although these medicines are all having significant curative effect aspect the treatment metabolic syndrome, this type Side effects of pharmaceutical drugs all compare seriously, liver toxicity, oedema, weight increase or the like.
The researchist finds that PPAR γ acceptor can suppress the propagation of cell when inducing the lipocyte differentiation, thereby has caused that the medicine scholar is for PPAR gamma agonist potential Antitumor Effects.If Christian? Hafner? Etc. In the 2005 "Current? Cancer? Drug? Targets" Volume 5 6 393's "New? Indications? For? Established? Drugs:? Combined? Tumor-Stroma-Targeted? Cancer? therapy? with? PPAR? γ? Agonists,? COX-2? Inhibitors,? mTOR? Antagonists? and? Metronomic? Chemotherapy "in that PPARγ may be used as a new target for anti-cancer therapy, the active data? PPARγ agonist inhibition of tumor cell proliferation, which may have two mechanisms: (1) PPARγ agonists may increase anti-tumor inhibitors of cyclin-dependent, resulting in cyclin / cdk mixture is passivated, while non-phosphorylated state can be stabilized the retinoblastoma protein; (2) PPARγ agonists can induce programmed cell death in tumor cells, partly due to increased pro-apoptotic proteins BAX and BAD, while stimulating several effector caspases expression.Although research has been carried out for some time to PPAR agonist antineoplastic action; But the emphasis of Pharmaceutical Chemist research at present all is that to utilize known antidiabetic medicine mainly be that thiazolidine dione compounds is studied its antitumor mechanism as template, and is fewer to the research of the brand-new PPAR agonist with antitumor action.
Summary of the invention
The present invention is directed to the deficiency that prior art exists; One type of novel benzofuran compounds and preparation method thereof, purposes are provided; Through preliminary antitumor test; Confirm that the novel benzofuran compounds of the present invention can suppress the activity of kinds of tumor cells, can be used to prepare the medicine of antineoplaston and prophylaxis of tumours.
The present invention realizes through following technical scheme, the benzofuran compounds that the present invention relates to, and its structural formula is:
(a) R
1Be the structure shown in formula I or the formula II:
Wherein, Z is any one among O, S, the NH; R
6, R
7Be hydrogen, C
1-C
5Alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, aromatic base, in the assorted aromatic base any one;
(b) R
2Be the structure shown in formula III, formula IV, formula (V) or the formula VI:
Wherein, n
2Be 1～3 integer, W is any one among O, S, the NH, R
8, R
9, R
10, R
11Be any substituted aromatic base of group or assorted aromatic base;
(c) R
3Be hydrogen, C
1-C
5Alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, aromatic base, in the assorted aromatic base any one; X, Y are O, any one among S, the NH; n
1It is 1～4 integer;
(d) R
4Be hydrogen or C
1-C
5The straight or branched alkyl;
(e) R
5Be hydrogen, C
1-C
5Alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, aromatic base, in the assorted aromatic base any one.
Preferably, its structural formula is:
Wherein, R
12, R
13Be hydrogen, C
1-C
5Alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, aromatic base, in the assorted aromatic base any one.
Preferably, its structural formula is:
Wherein, R
14, R
15Be hydrogen, C
1-C
5Alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, aromatic base, in the assorted aromatic base any one.
Second aspect the invention still further relates to the method for aforementioned benzofuran compounds, comprises the steps:
(1) get 2 of 1 molar equivalent, the Benzyl Chloride of 4-Dihydroxy benzaldehyde and 1.2 molar equivalents refluxes in acetonitrile and obtained 4-(benzyloxy)-2-hydroxy benzaldehyde in 12 hours;
(2) the replacement aldehyde of getting 4-(benzyloxy)-2-hydroxy benzaldehyde and 1.2 molar equivalents of 1 molar equivalent refluxes in zinc-titanium tetrachloride-tetrahydrofuran (THF) system and obtained (E)-5-(benzyloxy)-2-substituted ethylene base phenol in 2 hours;
(3) (E)-5-(benzyloxy)-2-substituted ethylene base phenol stirring at room in 6 molar equivalent salt of wormwood and 6 molar equivalent iodine of getting 1 molar equivalent obtained 6-(benzyloxy)-2-in 12 hours and replaces cumarone;
(4) get the 6-(benzyloxy) of 1 molar equivalent-2-and replace cumarone and be dissolved in the methylene dichloride, the titanium tetrachloride that adds 1.3 molar equivalents obtains 6-hydroxyl-2-and replaces cumarone;
(5) get the 6-hydroxyl of 1 molar equivalent-2-and replace cumarone and be dissolved in the acetonitrile, add 2-(5-methyl-2-benzene base oxazole-4-yl) ethyl methane sulfonate of 1 molar equivalent and the salt of wormwood backflow of 2 molar equivalents and obtained 5-methyl-2-phenyl-4-(2-(2-replaces cumarone-6-oxygen base) ethyl) oxazole in 12 hours;
(6) getting 5-methyl-2-phenyl-4-(2-(2-the replaces cumarone-6-oxygen base) ethyl) oxazole of 1 molar equivalent and the replacement acyl chlorides of 1.5 molar equivalents is dissolved in the methylene dichloride; The tin tetrachloride that adds 1.2 molar equivalents, stirring at room obtained 1-(2-replacement-6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group) cumarone-3-yl) in 12 hours and replace ketone;
(7) get 5-methyl-2-phenyl-4-(2-(2-replaces cumarone-6-oxygen base) ethyl) oxazole and the phosphorus oxychloride of 8 molar equivalents and the N of 8 molar equivalents of 1 molar equivalent; Dinethylformamide refluxes in the 2-ethylene dichloride and obtains 6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-formaldehyde 1;
(8) get 1 molar equivalent 6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-formaldehyde and 1 molar equivalent 3; 4; The 5-trimethoxy-aniline obtained (E)-3 in 12 hours in reflux in toluene; 4,5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-yl) methylene radical) aniline;
(9) get (E)-3 of 1 molar equivalent; 4; The sodium borohydride of 5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-yl) methylene radical) aniline and 1.5 molar equivalents stirs in methyl alcohol and obtains 3; 4,5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-yl) methyl) aniline.
The third aspect the invention still further relates to aforementioned benzofuran compounds is used for suppressing the tumour cell biologically active drug in preparation purposes.
Preferably, said tumour cell is human breast cancer cell, Human Prostate Cancer Cells, African green monkey kidney inoblast, human cervical carcinoma cell, mouse leukemia cell.
The present invention has following beneficial effect: the present invention with traditional P PAR activator hydrophobic tail with flexible in the middle of connection chain as parent nucleus; Cis-structure with reference to CombretastinA-4 has good antineoplastic activity; With the benzofuran structure as acid head in the PPAR activator and flexibly connect the aromatic ring center between the chain; Set up and optimize the preparation method of compound; And to the preparation new compound carry out the tumour cell screening experiment; Confirm that by preliminary antitumor test prepared part noval chemical compound has to the special narrow spectrum tumors inhibition activity of Human Prostate Cancer Cells, can be used to prepare the medicine of antineoplaston and prophylaxis of tumours.
Description of drawings
Fig. 1 is preparing method's synthetic route synoptic diagram of benzofuran compound.
Embodiment
Below in conjunction with specific embodiment the present invention is elaborated.Following examples will help those skilled in the art further to understand the present invention, but not limit the present invention in any form.Should be pointed out that to those skilled in the art, under the prerequisite that does not break away from the present invention's design, can also make some distortion and improvement.These all belong to protection scope of the present invention.
Embodiment 1
Synthetic (Fig. 1) of 4-(benzyloxy)-2-hydroxy benzaldehyde I: with 2; 4-Dihydroxy benzaldehyde (100mg; 0.72 mmol) be dissolved in the acetonitrile (15ml); Add then potassiumiodide (179.3mg, 1.08mmol) and sodium hydrogencarbonate (90.7 mg, 1.08mmol); After adding; (100 ul 0.87mmol), refluxed 12 hours slowly to drip Benzyl Chloride.After reaction is accomplished; Adding shrend goes out; Use ethyl acetate extraction; Merge organic phase; With saturated common salt water washing three times, behind the anhydrous sodium sulfate drying, concentrating under reduced pressure; (sherwood oil: ethyl acetate=10:1) obtains 4-(benzyloxy)-2-hydroxy benzaldehyde 110mg (colorless solid, yield 67%) through the silica gel chromatography column purification.
1HNMR?(CDCl
3；300MHz),?δ5.12(s,?2H,?O
CH 2 Ph)?6.40-6.64(m,?2H,?ArH),?7.41-7.43?(m,?6H,?ArH),?9.73(s,?1H,?CHO),?11.44(brs,?1H,?OH)。
(E)-5-(benzyloxy)-2-(4-methoxyl-styrene) phenol II
1Synthetic (Fig. 1): under nitrogen environment; With zinc powder (1.4g; 22mmol) be added in the anhydrous tetrahydro furan (20ml); Temperature with reaction system drops to-5～0 ℃ then; Under this temperature, drip titanium tetrachloride (1.2ml, 11mmol), the temperature with reaction system after adding rises to room temperature; Stir half an hour, and then refluxed 2.5 hours.After reflux finishing, the temperature of reaction system is dropped to-5～0 ℃ once more, (1g, 4.4mmol) (721mg, tetrahydrofuran solution 5.3mmol) drip off back backflow 2 hours with aubepine dropwise to add 4-(benzyloxy)-2-hydroxy benzaldehyde.After reaction finishes; Sodium bicarbonate aqueous solution cancellation reaction with 10%; Use dichloromethane extraction then; Merge organic phase; With saturated common salt water washing three times, behind the anhydrous sodium sulfate drying, concentrating under reduced pressure; Through the silica gel chromatography column purification (sherwood oil: ethyl acetate=5:1) obtain (E)-5-(benzyloxy)-2-(4-methoxyl-styrene) phenol 280 mg (colorless solid, yield 20%).
1HNMR (CDCl
3300MHz), and δ 3.84 (s, 3H, OCH3), 5.05 (s, 2H, O
CH 2 Ph), and 6.48-6.49 (d, 1H, Ar, J=2.4Hz); 6.58-6.62 (dd, 1H, ArH, J=8.7Hz, 2.7Hz); 6.988-6.934 (dd, 2H, ArH, J=3Hz, 8.7Hz); 6.951-6.989 (d, 1H, CH, J=11.4Hz); 7.133-7.155 (d, 1H, ArH, J=6.6Hz); 7.365-7.548 (m, 8H, ArH, CH).
Embodiment 3
6-(benzyloxy)-2-methoxyl group benzo furans III
1Synthetic (Fig. 1): will (E)-5-((280mg 0.84mmol) is dissolved in the tetrahydrofuran (THF) (15ml) benzyloxy-2-(4-methoxyl-styrene) phenol, adding Anhydrous potassium carbonate (695 mg; 5.04mmol), stir after 10 minutes, add iodine (1.28g; 5.04mmol), stirring at room 12 hours.After reaction finishes; With saturated sodium bicarbonate aqueous solution cancellation reaction; Drip saturated aqueous solution of sodium bisulfite then and remove residual iodine, use ethyl acetate extraction again, merge organic phase; With saturated common salt water washing three times; Behind the anhydrous sodium sulfate drying, concentrating under reduced pressure is through silica gel chromatography column purification (sherwood oil: ethyl acetate=5:1); Obtain 6-(benzyloxy)-2-methoxyl group benzo furans 150 mg (yellow solid, yield 54%).
1HNMR(CDCl
3；300MHz),?δ3.87(s,?3H,?OCH
3),?5.14(s,?2H,?O
CH 2 Ph),?6.826(s,?1H,?ArH),?6.889-6.918(d,?1H,?ArH,?J=8.7Hz),?6.968-6.991(d,?2H,?ArH,?J=6.9Hz),?7.132(s,?1H,?CH),?7.350-7.503(m,?6H,?ArH),?7.739-7.768(d,?2H,?ArH,?J=8.7Hz)。
Embodiment 4
2-methoxyl group-6-hydroxyl benzofuran IV
1Synthetic (Fig. 1): (50mg 0.15ml) is dissolved in the methylene dichloride (10ml), drips titanium tetrachloride (21.8ul, 0.20 mmol) under the room temperature, drips off back stirring at room half an hour with 6-(benzyloxy)-2-methoxyl group benzo furans.After reaction finishes, use the methyl alcohol cancellation, concentrating under reduced pressure after the silica gel chromatography column purification (sherwood oil: ethyl acetate=5:1) obtains 2-methoxyl group-6-hydroxyl benzofuran 23mg (colorless solid, yield 63%).
1HNMR (CDCl
3300MHz), δ 3.968 (s, 3H, OCH
3), 4.94 (brs, 1H, OH), 6.854-6.878 (d, 1H, ArH, J=7.2Hz); 6.914 (s, 1H, CH), 7.060-7.104 (m, 3H, ArH), 7.470-7.498 (d; 1H, ArH, J=8.4Hz), 7.836-7.864 (d, 2H, ArH, J=8.4Hz).
Embodiment 5
Synthetic (Fig. 1) of 2-(5-methyl-2-Ben Ji oxazole-4-yl) methyl acetate: (10g 45mmol) is dissolved in (200ml) in the toluene, and add benzamide then (5.45g 45mmol), adds the back and refluxed 12 hours in batches with 4-bromo-3-oxopentanoic acid methyl esters.After reaction is accomplished, filter concentrating under reduced pressure, silica gel chromatography column purification (sherwood oil: ethyl acetate=10:1), obtain 2-(5-methyl-2-benzene base oxazole-4-yl) methyl acetate 4.4g (yellow oil, yield 40%).
1HNMR((CD
3)
2CO；300MHz),?δ2.378(s,?3H,?CH
3),?3.587(s,?2H,?CH
2),?3.665(s,?3H,?OCH
3),?7.473-7.499(m,?3H,?ArH),?7.950-7.982(m,?2H,?ArH)。
Embodiment 6
2-(5-methyl-2-Ben Ji oxazole-4-yl) alcoholic acid synthesizes (Fig. 1): with Lithium Aluminium Hydride (207.1mg; 5.45 mmol) be dissolved in the anhydrous diethyl ether (20ml); In the time of-5 ℃, drip 2-(5-methyl-2-Ben Ji oxazole-4-yl) methyl acetate (890mg; 3.63mmol) diethyl ether solution; After drip finishing, stirring at normal temperature half an hour.After reaction is accomplished, in reaction system, drip saturated aqueous ammonium chloride solution cancellation, white floss occurs until reaction system.Filter, water washs with ethyl acetate, merges organic phase, with saturated salt solution washing three times, uses anhydrous sodium sulfate drying.Concentrating under reduced pressure obtains 2-(5-methyl-2-Ben Ji oxazole-4-yl) ethanol 710 mg (colorless solid, yield 96%).
1HNMR(CDCl
3；300MHz),?δ2.347(s,?3H,?CH
3),?2.754-2.792(t,?2H,?CH
2 CH 2 ,?J=5.7Hz),?3.924-3.963(t,?2H,?
CH 2 CH
2,?J=5.8Hz),?6.0-6.5(brs,?1H,?OH),?7.431-7.450(m,?3H,?ArH),?7.989-8.021(m,?2H,?ArH)。
Embodiment 7
Synthetic (Fig. 1) of 2-(5-methyl-2-Ben Ji oxazole-4-yl) ethyl methane sulfonate: with 2-(5-methyl-2-Ben Ji oxazole-4-yl) ethanol (630mg; 3.1mmol) be dissolved in the methylene dichloride (15ml); Drip triethylamine (0.64ml; 4.65 mmol); Then with methylsulfonyl chloride (0.37ml; 4.65mmol) in the time of 0 ℃, be added drop-wise in the reaction system, after dropping finishes, stirring at normal temperature 4 hours.After reaction is accomplished, in reaction system, drip saturated aqueous ammonium chloride solution cancellation, water washs with ethyl acetate, merges organic phase, with saturated salt solution washing three times, uses anhydrous sodium sulfate drying.(the sherwood oil: ethyl acetate=5:1), obtain 2-(5-methyl-2-benzene base oxazole-4-yl) ethyl methane sulfonate 700 mg (colorless solid, yield 80%) of silica gel chromatography column purification behind the concentrating under reduced pressure.
1H?NMR(CDCl
3；300?MHz),?δ2.365(s,?3H,?CH
3),?2.935-2.978(m,?5H,?CH
2 CH 2 ,?CH
3),?4.509-4.553(t,?2H,?
CH 2 CH
2,?J=6.6Hz),?7.423-7.446(m,?3H,?ArH),7.957-7.990(m,?2H,?ArH)。
Embodiment 8
4-(2-(2-(4-anisole) cumarone-6-oxygen base) ethyl)-5-methyl-2-Ben Ji oxazole V
1Synthetic (Fig. 1): with 2-(5-methyl-2-Ben Ji oxazole-4-yl) ethyl methane sulfonate (690mg; 2.45mmol), 2-methoxyl group-6-hydroxyl benzofuran (588.2mg; 2.45mmol) and salt of wormwood (675.8mg 4.9mmol) is dissolved in the acetonitrile (20ml), refluxes 12 hours.After reaction is accomplished, in reaction system, drip saturated aqueous ammonium chloride solution cancellation, water washs with ethyl acetate, merges organic phase, with saturated salt solution washing three times, uses anhydrous sodium sulfate drying.(the sherwood oil: ethyl acetate=5:1), obtain 4-(2-(2-(4-anisole) cumarone-6-oxygen base) ethyl)-5-methyl-2-benzene base oxazole 520mg (yellow solid, yield 50%) of silica gel chromatography column purification behind the concentrating under reduced pressure.
1H?NMR(CDCl
3；300?MHz),?δ?2.415(s,?3H,?CH
3),?3.065-3.021(t,?2H,?
CH 2 CH
2,?J=6.6Hz),?3.852(s,?3H,?OCH
3),?4.334-4.292(t,?2H,?CH
2 CH 2 ,?J=6.3Hz),?6.802(s,?1H,?CH),?6.830-6.859(d,?1H,?ArH,?J=8.7Hz),?6.951-6.980(d,?2H,?ArH,?J=8.7Hz),?7.065(s,?1H,?ArH),?7.353-7.447(m,?4H,?ArH),?7.723-7.748(d,?2H,?ArH,?J=7.5Hz),?8.001-8.025(m,?2H,?ArH)。
Embodiment 9
1-(2-(4-p-methoxy-phenyl)-6-(2-(5-methyl-2-phenyl-4-yl) oxyethyl group) cumarone-3-yl) ethyl ketone VI
1Synthetic (Fig. 1): with 4-(2-(2-(4-anisole) cumarone-6-oxygen base) ethyl)-5-methyl-2-Ben Ji oxazole (50mg; 0.12mmol) and Acetyl Chloride 98Min. (12.7ul; 0.18mmol) be dissolved in the methylene dichloride (10ml); Drip tin tetrachloride (17.1ul; 0.144mmol), stirring at room 12 hours.After reaction finished, ethyl acetate extraction was used in the water cancellation then, merged organic phase, with saturated salt solution washing three times, used anhydrous sodium sulfate drying.(the sherwood oil: ethyl acetate=3:1), obtain 1-(2-(4-p-methoxy-phenyl)-6-(2-(5-methyl-2-phenyl-4-yl) oxyethyl group) cumarone-3-yl) ethyl ketone 28mg (yellow solid, yield 51%) of silica gel chromatography column purification behind the concentrating under reduced pressure.
1H?NMR(CDCl
3；300?MHz),?δ2.051(s,?3H,?CH
3),?2.415(s,?3H,?CH
3),?3.065-3.021(t,?2H,?
CH 2 CH
2,?J=6.6Hz),?3.852(s,?3H,?OCH
3),?4.334-4.292(t,?2H,?CH
2 CH 2 ,?J=6.3Hz),?6.830-6.859(d,?1H,?ArH,?J=8.7Hz),?6.951-6.980(d,?2H,?ArH,?J=8.7Hz),?7.065(s,?1H,?ArH),?7.353-7.447(m,?4H,?ArH),?7.723-7.748(d,?2H,?ArH,?J=7.5Hz),?8.001-8.025(m,?2H,?ArH)。
Embodiment 10
(E)-1-(2-(4-p-methoxy-phenyl)-6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group) cumarone-3-yl)-3-(3,4, the 5-trimethoxyphenyl) third-2-alkene-1-ketone VI
2Synthetic (Fig. 1); With 1-(2-(4-p-methoxy-phenyl)-6-(2-(5-methyl-2-phenyl-4-yl) oxyethyl group) cumarone-3-yl) ethyl ketone (28mg; 0.059mmol) and 3; 4; 5-TMB (12mg; 0.059mmol) be dissolved in the methyl alcohol (15ml); (6.6mg 0.118mmol), refluxed 12 hours to add potassium hydroxide then.Reaction with the cancellation of 1N hydrochloric acid, is transferred to 1 with the pH value of solution after finishing.Use dichloromethane extraction then, merge organic phase,, use anhydrous sodium sulfate drying with saturated salt solution washing three times.Silica gel chromatography column purification behind the concentrating under reduced pressure (sherwood oil: ethyl acetate=3:1); Obtain (E)-1-(2-(4-p-methoxy-phenyl)-6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group) cumarone-3-yl)-3-(3; 4, the 5-trimethoxyphenyl) third-2-alkene-1-ketone 10mg (solid, 25%).
1H?NMR(CDCl
3；300MHz),?δ2.586(s,?3H,?CH
3),?3.035-3.079(d,?2H,?
CH 2 CH
2,?J=6.6Hz),?3.853(s,?12H,?4OCH
3),?4.428-0.472(d,?2H,?CH
2 CH 2 ,?J=6.6Hz),?6.510(s,?1H,?ArH),?6.809-6.861(d,?1H,?
CH=CH,?J=15.6Hz),?7.003-7.107(m,?5H,?ArH),?7.429-7.443(m,?2H,?ArH),?7.654-7.743(m,?4H,?ArH),7.992-8.021(m,?2H,?ArH)。
Embodiment 11
(E)-5-(benzyloxy)-2-(2-(5-methyl furan-2-yl) vinyl) phenol II
2Synthetic (Fig. 1): with reference to embodiment 2, yield 60%.
1HNMR(CDCl
3；300MHz),?δ2.355(s,?3H,?CH
3),?5.057(s,?2H,?CH
2),?6.149-6.177(d,?1H,?CH
CH,?J=8.4?Hz),?6.189-6.200(d,?1H,?
CHCH,?J=3.3?Hz),?6.472-6.480(d,?1H,?ArH,?J=2.4?Hz),?6.571-6.579(d,?1H,?ArH,?J=2.4?Hz),?6.688(s,?1H,?ArH),?6.765-6.819(d,?1H,?
CH=CH,?J=16.2?Hz),?7.073-7.128(d,?1H,?CH=
CH,?J=16.5?Hz),?7.372-7.426(m,?5H,?ArH),8.634-8.653(brs,?1H,?OH)。
Embodiment 12
(E)-5-(benzyloxy)-2-styryl phenol II
3Synthetic (Fig. 1): with reference to embodiment 2, yield 32%.
1H?NMR(CDCl
3；300?MHz),?δ5.079(s,?2H,?CH
2),?6.474-6.482(d,?1H,?ArH,?J=2.4Hz),?6.523-6.531(d,?1H,?ArH,?J=2.4Hz),?6.608-6.644(d,?1H,?CH=
CH,?J=10.8Hz),?6.993-7.048(d,?1H,?
CH=CH,?J=16.5Hz),?7.138(s,?1H,?ArH),?7.365-7.534(m,?5H,?ArH),?8.105-8.133(brs,?1H,?OH)。
Embodiment 13
6-(benzyloxy)-2-(5-methyl furan-2-yl) cumarone III
2Synthetic (Fig. 1); With reference to embodiment 3, yield 15%.
1HNMR(CDCl
3；300MHz),?δ2.385(s,?3H,?CH
3),?5.112(s,?2H,?CH
2),?6.085-6.093(d,?1H,?CHCH,?J=2.4Hz),?6.611-6.600(d,?1H,?CHCH,?J=3.3Hz),?6.754(s,?1H,?ArH),?6.923-6.931(d,?1H,?ArH,?J=2.4Hz),?6.952-6.959(d,?1H,?ArH,?J=2.1Hz),?7.256(s,?1H,?CH),?7.375-7.452(m,?5H,?ArH)。
Embodiment 14
6-(benzyloxy)-2-phenyl cumarone III
3Synthetic (Fig. 1); With reference to embodiment 3, yield 54%.
1H?NMR(CDCl
3；300?MHz),?δ5.134(s,?2H,?CH
2),?6.937-6.972(m,?2H,?ArH),?7.116-7.141(m,?1H,?ArH),?7.257-7.465(m,?10H,?ArH),?7.822(s,?1H,?CH)。
Embodiment 15
2-phenyl-6-hydroxyl benzofuran IV
2Synthetic (Fig. 1): with reference to embodiment 4, yield 90%.
1H?NMR(CDCl
3；?300?MHz),?δ4.5-5.0(brs,?1H,?OH),?6.957-7.025(m,?2H,?ArH),?7.269-7.302(m,?1H,?ArH),?7.405-7.441(m,?5H,?ArH),?7.839(s,?1H,?CH)。
Embodiment 16
2-(5-methyl furan-2-yl)-6-hydroxyl benzofuran IV
3Synthetic (Fig. 1): with reference to embodiment 4, yield 60%.
1HNMR(CDCl
3；300MHz),?δ2.478(s,?3H,?CH
3),?6.864-6.893(d,?1H,?CHCH,?J=8.7Hz),?6.955-6.984(d,?1H,?CHCH,?J=8.7Hz),?7.066(s,?1H,?CH),?7.523(s,?1H,?ArH),?7.872-7.892(m,?2H,?ArH),?9.843(brs,?1H,?OH)。
Embodiment 17
4-(2-(2-phenyl) cumarone-6-oxygen base) ethyl)-5-methyl-2-Ben Ji oxazole V
2(Fig. 1): with reference to embodiment 8, yield 48%.
1HNMR(CDCl
3；300MHz),?δ2.420(s,?3H,?CH
3),?3.010-3.054(t,?2H,?
CH 2 CH
2,?J=6.6Hz),?4.277-4.321(t,?3H,?CH
2 CH 2 ,?J=6.6Hz),?6.818(s,?1H,?ArH),?6.872-6.890(m,?2H,?ArH),?6.950(s,?1H,?CH),?7.088-7.433(m,?10H,?ArH)。
Embodiment 18
5-methyl-4-(2-(2-(5-methyl furan-2-yl) cumarone-6-oxygen base) ethyl)-2-Ben Ji oxazole V
3(Fig. 1): with reference to embodiment 8, yield 66%.
1HNMR(CDCl
3；300?MHz),?δ2.058(s,?3H,?CH
3),?2.389(s,?3H,?CH
3),?3.014-3.058(t,?2H,?
CH 2 CH
2,?J=6.6Hz),?4.283-4.327(t,?2H,?CH
2 CH 2 ,?J=6.6Hz),?6.089-6.097(d,?1H,?
CHCH,?J=2.4Hz),?6.602-6.613(d,?1H,?CH
CH,?J=3.3Hz),?6.749(s,?1H,?CH),?6.868-6.875(d,?1H,?ArH,?J=2.1Hz),?7.050-7.054(d,?1H,?ArH,?J=1.2Hz),?7.270-7.292(m,?2H,?ArH),?7.431-7.450(m,?3H,?ArH),?7.998-8.030(m,?2H,?ArH)。
Embodiment 19
(6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-(5-methyl furan-2-yl) cumarone-3-yl) (3,4, the 5-trimethoxyphenyl) ketone VI
3Synthetic (Fig. 1): with reference to embodiment 9, yield 35%.
1H?NMR(CDCl
3；?300?MHz),?δ2.056(s,?3H,?CH
3),?2.436(s,?3H,?CH
3),?3.075-3.119(t,?2H,?
CH 2 CH
2,?J=6.6?Hz),?3.993(s,?9H,?3OCH
3),?4.223-4.367(t,?2H,?CH
2 CH 2 ,?J=6.6Hz),?6.863-6.874(d,?1H,?
CHCH,?J=3.3Hz),?6.892-6.912(d,?1H,?CH
CH,?J=2.4Hz),?7.102-7.116(m,?3H,?ArH),?7.378-7.462(m,?3H,?ArH),7.463-7.472(m,?2H,?ArH)。
Embodiment 20
1-(6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-(5-methyl furan-2-yl) cumarone-3-yl) ethyl ketone VI
4Synthetic (Fig. 1): with reference to embodiment 9, yield 33%.
1HNMR(CDCl
3；300?MHz),?δ2.413(s,?3H,?CH
3),?2.453(s,?3H,?CH
3),?2.677(s,?3H,?CH
3),?3.029-3.073(t,?2H,?
CH 2 CH
2,?J=6.6Hz),?4.298-4.342(t,?2H,?CH
2 CH 2 ,?J=6.6Hz),?6.213-6.224(d,?1H,?
CHCH,?J=3.3Hz),?6.947-6.658(d,?1H,CH
CH,?J=3.3Hz),?7.137-7.144(d,?1H,?ArH,?J=2.1Hz),?7.147-7.159(d,?1H,?ArH,?J=3.6Hz),?7.430-7.485(m,?3H,?ArH),?7.834(s,?1H,?ArH),?8.003-8.024(m,?2H,?ArH)。
Embodiment 21
(6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-(5-methyl furan-2-yl) cumarone-3-yl) (4-(trifluoromethyl) phenyl) ketone VI
5Synthetic (Fig. 1): with reference to embodiment 9, yield 14%.
1H?NMR(CDCl
3；?300?MHz),?δ2.287(s,?3H,?CH
3),?2.265(s,?3H,?CH
3),?2.967-3.011(t,?2H,?
CH 2 CH
2,?J=6.6Hz),?4.253-4.297(t,?2H,?CH
2 CH 2 ,?J=6.6Hz),?6.213-6.224(d,?1H,?
CHCH,?J=3.3Hz),?6.947-6.658(d,?1H,?CH
CH,?J=3.3Hz),?7.039-7.061(d,?2H,?ArH,?J=6.6Hz),?7.137-7.144(d,?1H,?ArH,?J=2.1Hz),?7.147-7.159(d,?1H,?ArH,?J=3.6Hz),?7.393-7.402(m,?5H,?ArH),?7.834(s,?1H,?ArH),?7.997-8.010(m,?2H,?ArH)。
Embodiment 22
1-(6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-yl) ethyl ketone VI
6Synthetic (Fig. 1): with reference to embodiment 9, yield 61%.
1HNMR(CDCl
3；300?MHz),?δ2.223(s,?3H,?CH
3),?2.532(s,?3H,?CH
3),?3.006-3.050(t,?2H,?
CH 2 CH
2,?J=6.6Hz),?4.206-4.250(t,?2H,?CH
2 CH 2 ,?J=6.6Hz),?7.137-7.144(d,?1H,?ArH,?J=2.1Hz),?7.147-7.159(d,?1H,?ArH,?J=3.6Hz),?7.376-7.627(m,?10H,?ArH),?7.834(s,?1H,?ArH)。
Embodiment 23
(E)-1-(6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-yl)-3-(4-(trifluoromethyl) phenyl) third-2-alkene-1-ketone VI
7Synthetic (Fig. 1): with reference to embodiment 10, yield 35%.
1HNMR(CDCl
3；300MHz),?δ2.435(s,?3H,?CH
3),?3.011-3.055(t,?2H,?
CH 2 CH
2,?J=6.6Hz),?4.483-4.527(t,?2H,?CH
2 CH 2 ,?J=6.6Hz),?6.610-6.637(d,?2H,?ArH,?J=8.1Hz),?6.983-6.997(d,?1H,?ArH,?J=4.2Hz),?7.060-7.079(d,?1H,?ArH,?J=5.7Hz),?7.393-7.605(m,?13H,?ArH,?
CH=CH),?7.743(s,?1H,?ArH)。
Embodiment 24
6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-formaldehyde VI
8Synthetic (Fig. 1): in the time of 0～5 ℃ with phosphorus oxychloride (94.9ul; 1.04mmol) be added drop-wise to N; Dinethylformamide (80.8ul; 1.04 mmol) with 1; In the 2-ethylene dichloride (10ml), stir after 10 minutes, with 4-(2-(2-phenyl) cumarone-6-oxygen base) ethyl)-5-methyl-2-Ben Ji oxazole (50mg; 0.13mmol) join in the mixture solution, refluxed 12 hours.Reaction is poured reaction solution in the frozen water into after finishing, and uses dichloromethane extraction, and anhydrous sodium sulfate drying is used in water, saturated sodium bicarbonate aqueous solution and saturated common salt water washing more successively.(sherwood oil: ethyl acetate=5:1) obtains 6-(2-(5-methyl-2-benzene base oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-formaldehyde 20 mg (solid, yield 37%) to concentrating under reduced pressure after the silica gel chromatography column purification.
1HNMR(CDCl
3；300?MHz),?δ2.417(s,?3H,?CH
3),?3.020-3.064(t,?2H,?
CH 2 CH
2,?J=6.6Hz),?4.317-4.361(t,?2H,?CH
2 CH 2 ,?J=6.6Hz),?7.174-8.137(m,?13H,?ArH),?10.312(s,?1H,?CHO)。
Embodiment 25
(6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-yl) methyl alcohol VI
9Synthetic (Fig. 1): with 6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-formaldehyde (60mg 0.14mmol) is dissolved in the methyl alcohol (10ml), the adding sodium borohydride (8.1mg, 0.21mmol) after, stirring at room 45 minutes.Reaction is poured reaction solution in the frozen water into after finishing, and uses dichloromethane extraction, merges organic phase, with saturated common salt water washing three times, uses anhydrous sodium sulfate drying again.Concentrating under reduced pressure is after silica gel chromatography column purification (sherwood oil: ethyl acetate=3:1) obtain (6-(2-(5-methyl-2-benzene base oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-yl) methyl alcohol 12mg (yellow solid, yield 20%).
1HNMR(CDCl
3；300MHz),?δ2.390(s,?3H,?CH
3),?2.977-3.021(t,?2H,?
CH 2 CH
2,?J=6.6Hz),?4.234-4.278(t,?2H,?CH
2 CH 2 ,?J=6.6Hz),?4.936(s,?2H,?
CH 2 OH),?6.861-6.889(d,?2H,?ArH,?J=8.4Hz),?7.043(s,?1H,?ArH),?7.376-7.470(m,?10H,?ArH)。
Embodiment 26
(E)-3,4,5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-yl) methylene radical) aniline VI
10Synthetic (Fig. 1): (50mg, 0.118mmol) and 3,4, (21.6mg 0.118mmol) is dissolved in the toluene (10ml) the 5-trimethoxy-aniline, refluxes 12 hours with 6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-formaldehyde.After reaction finishes; Concentrating under reduced pressure is through silica gel chromatography column purification (sherwood oil: ethyl acetate=5:1) obtain (E)-3,4; 5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-yl) methylene radical) aniline 23mg (yellow solid, yield 33%).
1HNMR(CDCl
3；300MHz),?δ2.416(s,?3H,?CH
3),?3.022-3.067(t,?2H,?
CH 2 CH
2,?J=6.6Hz),?3.906(s,?9H,?3OCH
3),?4.327-4.371(t,?2H,?CH
2 CH 2 ,?J=6.6Hz),?6.462-6.497(d,?2H,?ArH,?J=10.5Hz),?6.982(s,?1H,?ArH),?6.989-7.145(m,?2H,?ArH),?7.425-7.505(m,?6H,?ArH),?7.751-7.769(m,?2H,?ArH),?7.990-8.011(m,?2H,?ArH),?8.784(s,?1H,?
CH=N)。
Embodiment 27
3,4,5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-yl) methyl) aniline VI
11Synthetic (Fig. 1): with (E)-3; 4; 5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-yl) methylene radical) aniline (17mg; 0.0289mmol) be dissolved in the methyl alcohol (5 ml); Add sodium borohydride (1.65mg; 0.0433mmol) and acetic acid (catalytic amount), stirring at room 12 hours.Reaction is poured reaction solution in the frozen water into after finishing, and uses dichloromethane extraction, merges organic phase, after saturated common salt water washing three times, uses anhydrous sodium sulfate drying again.Concentrating under reduced pressure is after silica gel chromatography column purification (sherwood oil: ethyl acetate=3:1) obtain 3; 4; 5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-yl) methyl) aniline 17mg (yellow solid, yield 100%).
1HNMR(CDCl
3；300?MHz),?δ2.411(s,?3H,?CH
3),?3.016-3.060(d,?2H,?
CH 2 CH
2,?J=6.6Hz),3.789(s,?9H,?3OCH
3),?4.299-4.343(d,?2H,?CH
2CH
2,?J=6.6Hz),?5.917(s,?2H,?CH),?7.094-7.172(m,?3H,?ArH),?7.421-7.476(m,?8H,?ArH),?7.774-7.800(m,?2H,?ArH),?7.979-7.994(m,?2H,?ArH)。
The anti-tumor activity of embodiment 28, compound
Adopt the tumor cell in vitro model, mtt assay carries out the screening active ingredients test, and the test operation step comprises:
(1) cell cultures
Cultivator breast cancer cell (MCF-7), Human Prostate Cancer Cells (DU-145) and African green monkey kidney inoblast (COS-7); All use the DMEM nutrient solution contain 10% foetal calf serum to cultivate, human cervical carcinoma cell (Hela), mouse leukemia cell (K562) use 1640 the nutrient solution that contains 10% foetal calf serum to cultivate.
Get each pipe of human breast cancer cell frozen in the liquid nitrogen (MCF-7), Human Prostate Cancer Cells (DU-145) and human cervical carcinoma cell (Hela); In 37 ℃ of water-bath recoveries; Add 6 ml nutrient solutions, centrifugal 5 min of 1000 rpm, supernatant liquor inclines; After repeating twice; Add after 10 ml contain the DMEM substratum piping and druming evenly of 10% foetal calf serum, be divided into two parts of kinds and go in the 10 ml culturing bottles, place 37 ℃, the cell culture incubator of 5%CO2 to hatch; Go down to posterity in good time, required in order to experiment.
(2) medicine preparation
All compounds are joined existing usefulness at present, and compound is prepared with DMSO, and maximum concentration is 100mM, prepare to be placed on-20 ℃ of preservations, supply repeatedly to use.Again according to desired concn, progressively dilute during administration with DMSO.
(3) MTT analytical method
The required cell of taking the logarithm vegetative period is adjusted into and plants 96 well culture plates behind the proper concn, every hole 100 μ l (about 2000～4000 cells), and place 37 ℃, 5%CO respectively
2Condition under hatch 24 h, the medicine for preparing is added successively cultivates in the plate hole, every hole 1 μ l, it is 100 μ M, 75 μ M, 50 μ M, 25 μ M, 10 μ M that its final concentration is respectively, each concentration is all established 3 multiple holes.Negative control is the equal-volume substratum, establishes the DMSO solvent control of respective concentration simultaneously.96 well culture plates after the administration are placed 37 ℃, 5%CO
2Condition under hatch 48 h.In every hole of 96 porocyte culture plates, add the 5.0 mg/ml MTT of 20 μ l, and place 37 ℃, 5%CO
2Condition under hatch 4 h, inhale then and remove nutrient solution, and add 150 μ l DMSO in every hole, use microplate reader to detect each hole A490 value or A470 value, calculating inhibiting rate, use SPSS computed in software inhibition concentration IC50 value.
Used positive control sample is classical Remedies for diabetes rosiglitazone (Rosiglitazone) and the classical antitumor drug taxol Taxol with anti-tumor activity in the table 1.The tumor cell in vitro inhibition test is the result show; Except the benzofuran compound with side chain not has certain cytotoxicity African green monkey kidney inoblast COS-7; Other compounds are equal to the cytotoxicity of African green monkey kidney inoblast COS-7>100uM, illustrate that this compounds toxicity is less.Compare the IC of compound (1,4,7) with positive control sample taxol (Taxol), rosiglitazone (Rosiglitazone)
50Basically all between 10～50 μ Μ; Compound 9 and 12 has narrow spectrum tumor inhibition effect to Human Prostate Cancer Cells (DU-145).
The test of table 1 benzofuran compounds anti-tumor biological
Claims (6)
1. a benzofuran compounds is characterized in that, its structural formula is:
R
1Be the structure shown in formula I or the formula II:
Wherein, Z is any one among O, S, the NH; R
6, R
7Be hydrogen, C
1-C
5Alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, aromatic base, in the assorted aromatic base any one;
(b) R
2Be the structure shown in formula III, formula IV, formula (V) or the formula VI:
(Ⅴ)、
(Ⅵ)；
Wherein, n
2Be 1～3 integer, W is any one among O, S, the NH, R
8, R
9, R
10, R
11Be any substituted aromatic base of group or assorted aromatic base;
(c) R
3Be hydrogen, C
1-C
5Alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, aromatic base, in the assorted aromatic base any one; X, Y are O, any one among S, the NH; n
1It is 1～4 integer;
(d) R
4Be hydrogen or C
1-C
5The straight or branched alkyl;
(e) R
5Be hydrogen, C
1-C
5Alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, aromatic base, in the assorted aromatic base any one.
2. benzofuran compounds according to claim 1 is characterized in that, its structural formula is:
Wherein, R
12, R
13Be hydrogen, C
1-C
5Alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, aromatic base, in the assorted aromatic base any one.
3. benzofuran compounds according to claim 1 is characterized in that, its structural formula is:
Wherein, R
14, R
15Be hydrogen, C
1-C
5Alkyl, nitro, carboxyl, fluorine, chlorine, bromine, ester group, hydroxyl, amino, amide group, alkoxyl group, aldehyde radical, aromatic base, in the assorted aromatic base any one.
4. a method for preparing the said benzofuran compounds of claim 1 is characterized in that, comprises the steps:
(1) get 2 of 1 molar equivalent, the Benzyl Chloride of 4-Dihydroxy benzaldehyde and 1.2 molar equivalents refluxes in acetonitrile and obtained 4-(benzyloxy)-2-hydroxy benzaldehyde in 12 hours;
(2) the replacement aldehyde of getting 4-(benzyloxy)-2-hydroxy benzaldehyde and 1.2 molar equivalents of 1 molar equivalent refluxes in zinc-titanium tetrachloride-tetrahydrofuran (THF) system and obtained (E)-5-(benzyloxy)-2-substituted ethylene base phenol in 2 hours;
(3) (E)-5-(benzyloxy)-2-substituted ethylene base phenol stirring at room in 6 molar equivalent salt of wormwood and 6 molar equivalent iodine of getting 1 molar equivalent obtained 6-(benzyloxy)-2-in 12 hours and replaces cumarone;
(4) get the 6-(benzyloxy) of 1 molar equivalent-2-and replace cumarone and be dissolved in the methylene dichloride, the titanium tetrachloride that adds 1.3 molar equivalents obtains 6-hydroxyl-2-and replaces cumarone;
(5) get the 6-hydroxyl of 1 molar equivalent-2-and replace cumarone and be dissolved in the acetonitrile, add 2-(5-methyl-2-benzene base oxazole-4-yl) ethyl methane sulfonate of 1 molar equivalent and the salt of wormwood backflow of 2 molar equivalents and obtained 5-methyl-2-phenyl-4-(2-(2-replaces cumarone-6-oxygen base) ethyl) oxazole in 12 hours;
(6) getting 5-methyl-2-phenyl-4-(2-(2-the replaces cumarone-6-oxygen base) ethyl) oxazole of 1 molar equivalent and the replacement acyl chlorides of 1.5 molar equivalents is dissolved in the methylene dichloride; The tin tetrachloride that adds 1.2 molar equivalents, stirring at room obtained 1-(2-replacement-6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group) cumarone-3-yl) in 12 hours and replace ketone;
(7) get 5-methyl-2-phenyl-4-(2-(2-replaces cumarone-6-oxygen base) ethyl) oxazole and the phosphorus oxychloride of 8 molar equivalents and the N of 8 molar equivalents of 1 molar equivalent; Dinethylformamide refluxes in the 2-ethylene dichloride and obtains 6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-formaldehyde 1;
(8) get 1 molar equivalent 6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-formaldehyde and 1 molar equivalent 3; 4; The 5-trimethoxy-aniline obtained (E)-3 in 12 hours in reflux in toluene; 4,5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-yl) methylene radical) aniline;
(9) get (E)-3 of 1 molar equivalent; 4; The sodium borohydride of 5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-yl) methylene radical) aniline and 1.5 molar equivalents stirs in methyl alcohol and obtains 3; 4,5-trimethoxy-N-((6-(2-(5-methyl-2-Ben Ji oxazole-4-yl) oxyethyl group)-2-phenyl cumarone-3-yl) methyl) aniline.
5. the said benzofuran compounds of claim 1 is used for suppressing the purposes of tumour cell biologically active drug in preparation.
6. purposes as claimed in claim 5 is characterized in that, said tumour cell is human breast cancer cell, Human Prostate Cancer Cells, African green monkey kidney inoblast, human cervical carcinoma cell, mouse leukemia cell.
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| CN102391260A (en) * | 2011-09-29 | 2012-03-28 | 上海交通大学 | 3-ketone-6-substituted-benzofuran compound as well as preparation method and application thereof |
| CN103588763B (en) * | 2011-09-29 | 2016-07-06 | 上海交通大学 | 2-replaces-3-aryl ketone-6-(5-methyl-2-phenyl-4-ethyoxyl oxazole) benzofuran compound |
| CN110746392A (en) * | 2019-10-31 | 2020-02-04 | 重庆医科大学 | Application of furan compound in preparation of antitumor drugs |
| CN113683769A (en) * | 2020-05-19 | 2021-11-23 | 上海交通大学 | Compound responding to endocytosis release and application thereof |
| CN114456136A (en) * | 2022-01-27 | 2022-05-10 | 广西中医药大学 | Double-target non-steroidal anti-inflammatory compound and preparation method and application thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102391260A (en) * | 2011-09-29 | 2012-03-28 | 上海交通大学 | 3-ketone-6-substituted-benzofuran compound as well as preparation method and application thereof |
| CN102391260B (en) * | 2011-09-29 | 2014-12-10 | 上海交通大学 | 3-ketone-6-substituted-benzofuran compound as well as preparation method and application thereof |
| CN103588763B (en) * | 2011-09-29 | 2016-07-06 | 上海交通大学 | 2-replaces-3-aryl ketone-6-(5-methyl-2-phenyl-4-ethyoxyl oxazole) benzofuran compound |
| CN110746392A (en) * | 2019-10-31 | 2020-02-04 | 重庆医科大学 | Application of furan compound in preparation of antitumor drugs |
| CN113683769A (en) * | 2020-05-19 | 2021-11-23 | 上海交通大学 | Compound responding to endocytosis release and application thereof |
| CN114456136A (en) * | 2022-01-27 | 2022-05-10 | 广西中医药大学 | Double-target non-steroidal anti-inflammatory compound and preparation method and application thereof |
| CN114456136B (en) * | 2022-01-27 | 2024-06-07 | 广西中医药大学 | Double-target non-steroidal anti-inflammatory compound, and preparation method and application thereof |
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| CN102351852B (en) | 2014-06-18 |
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