CN103408537A - 5-substituted dihydrobenzofuran-imidazolium salt compound and preparation method thereof - Google Patents

5-substituted dihydrobenzofuran-imidazolium salt compound and preparation method thereof Download PDF

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CN103408537A
CN103408537A CN2012104654778A CN201210465477A CN103408537A CN 103408537 A CN103408537 A CN 103408537A CN 2012104654778 A CN2012104654778 A CN 2012104654778A CN 201210465477 A CN201210465477 A CN 201210465477A CN 103408537 A CN103408537 A CN 103408537A
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substituted
cumarone
dihydro
methyl
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张洪彬
羊晓东
李艳
徐晓亮
李莹超
闫居明
周宏宇
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Kunming Institute of Botany of CAS
Yunnan University YNU
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Kunming Institute of Botany of CAS
Yunnan University YNU
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Abstract

The invention discloses a 5-substituted dihydrobenzofuran-imidazolium salt compound and a preparation method thereof. The preparation method comprises the following steps of: performing Vilsmeier reaction by taking 2,3-dihydrobenzofuran as a raw material, thereby synthesizing 5-carboxaldehyde dihydrobenzofuran, reducing the 5-carboxaldehyde dihydrobenzofuran into 5-benzyl alcohol substituted dihydrobenzofuran in an alcohol by using sodiumborohydride, and then converting the 5-benzyl alcohol substituted dihydrobenzofuran into methanesulfonate, next, carrying out a reflux reaction between the methanesulfonate and imidazolium or benzimidazole in a solvent, thereby synthesizing 1-(substituted dihydrobenzofuran) imidazolium, and finally, on the basis, reacting the 1-(substituted dihydrobenzofuran) imidazolium with a halide to synthesize the 5-substituted dihydrobenzofuran-imidazolium salt compound. According to the invention, a pharmacophore with remarkable anti-tumor activity in a natural product is used as a precursor and then design and synthesis of anti-tumor medicine molecules are carried out, and consequently, the synthesized compound has excellent in-vitro anti-tumorous cytotoxin activity. Researches show that the compound has excellent in-vitro anti-cancer biological activity when the imidazolium structure unit is 5,6-dimethyl benzimidazole and the substituent group thereof on the site of 3 is 2-bromobenzyl, naphthoyl methyl or 4-bromophenacyl.

Description

5-substituted-dihydro cumarone-imidazole salt compound and preparation method thereof
Technical field
The present invention relates to a kind of 5-substituted-dihydro cumarone-imidazole salt compound and preparation method thereof, and this compound is the application of the pharmaceutical composition of activeconstituents at anticancer aspect.
Background technology
Cancer is a class disease of serious threat human health.The Main Means that is used for the treatment of at present cancer is chemotherapy.The chemotherapeutics overwhelming majority of clinical application makes the toxic side effect such as the patient feels sick, vomiting, leukopenia, bone marrow depression.Therefore, find high reactivity, nontoxic or hypotoxic anticancer compound becomes an important topic of new drug research.Natural product and correlative study thereof are the sources of medicine innovation.From natural product, finding physiologically active compound, according to its molecular structure information, design and synthesize class natural product storehouse, the lead compound that therefrom screens and find high-level efficiency, highly selective, low toxic side effect carries out studying before clinical drug, has become the effective way that obtains the drug candidate molecule.
The substituted-dihydro cumarone extensively is present in the natural product molecule as important bio-active group; also as bioactive important feature unit, be present in the molecule of medicine simultaneously, at antitumor, antiviral, antibiotic, anti-inflammatory, anti-oxidant and the aspects such as provide protection of cardiovascular systems are shown to good physiologically active.
Imidazoles extensively is present in the natural product molecule as the important five member ring heterocyclic compound of a class.Imidazole ring also is present in the molecule of synthetic mycocide, weedkiller, plant-growth regulator and medicine as the important feature unit of physiologically active.Particularly, synthetic imidazole salt compound on the imidazo ring systems basis, due to the attention that has multiple biological activity and be subject to domestic and international organic synthesis and pharmaceutical chemistry research worker.Up to now, research shows that imidazole salt compound has anti-tumor activity, antibacterium and antimycotic activity, anti-inflammatory activity, anti-arrhythmia activity, the synthetic enzyme inhibition activity of thrombocyte, and as oral hypoglycemia agent.
As shown in Figure 1, the representative natural product pharmacophore that has anti-tumor activity.
In recent years, between pharmacophore or active compound, carry out rational molecular hybridization (Molecular hybridization), as a kind of New Policy of drug discovery, be subject to synthetic chemistry and Pharmaceutical Chemist is paid attention to greatly.Domestic and international a series of result of study is pointed out us, and the design of natural product and class natural product-imidazoles composition, heterocomplex, the synthetic Study on Physiological Activity that reaches have larger potentiality in the anti-cancer agent research field.So far, also lack and utilize 5-substituted-dihydro cumarone to produce the 5-substituted-dihydro cumarone-imidazole salt compound in the application of anticancer aspect, also lack manufacture method effectively.
Summary of the invention
The purpose of the embodiment of the present invention is to provide a kind of 5-substituted-dihydro cumarone-imidazole salt compound and preparation method thereof, the pharmacophore (5-substituted-dihydro cumarone and imidazole structure unit) with remarkable anti-tumor activity of take in natural product is the guide, carries out the design of antitumor drug molecule and synthetic.
The purpose of the embodiment of the present invention is to provide a kind of 5-substituted-dihydro cumarone-imidazole salt compound, its general structure (I) or (II) expression:
Figure BSA00000807136800022
General structure (I):
When X=Br, R 1=phenacyl, 4-methoxybenzoyl methyl, 4-bromobenzene formyl methyl, naphthoyl methyl, 2-bromobenzyl;
When X=I, R 1=normal-butyl;
General structure (II):
Work as X=Br, R 2=H, R 3During=H, R 1=phenacyl, 4-methoxybenzoyl methyl, 4-bromobenzene formyl methyl, naphthoyl methyl, 2-bromobenzyl, 4-nitrobenzyl, allyl group;
Work as X=Br, R 2=CH 3, R 3During=H, R 1=phenacyl, 4-methoxybenzoyl methyl, naphthoyl methyl;
Work as X=Br, R 2=H, R 3=CH 3The time, R 1=phenacyl, 4-methoxybenzoyl methyl, 4-(2-hydroxybenzoyl) methyl, 4-bromobenzene formyl methyl, naphthoyl methyl, 2-bromobenzyl, 4-nitrobenzyl;
Work as X=I, R 2=H, R 3=H, CH 3The time, R 1=normal-butyl;
Work as X=I, R 2=CH 3, R 3During=H, R 1=normal-butyl.
The purpose of the embodiment of the present invention is to provide a kind of preparation method of 5-substituted-dihydro cumarone-imidazole salt compound, and this preparation method comprises the following steps:
Figure BSA00000807136800031
With 2, the 3-Dihydrobenzofuranes is raw material, with phosphorus oxychloride and N, the synthetic 5-aldehyde radical Dihydrobenzofuranes (Vilsmeier reaction) of dinethylformamide reaction, by it, with sodium borohydride reduction, be 5-benzylalcohol substituted-dihydro cumarone in alcoholic solution, with methylsulfonyl chloride, form methanesulfonates under dichloromethane solvent and triethylamine condition again, then with imidazoles or benzoglyoxaline or 2-tolimidazole or 5, synthetic 1-(the 5-substituted-dihydro cumarone) imidazoles of 6-dimethylbenzimidazole back flow reaction in acetonitrile or toluene solvant, on this basis with halides in acetone or toluene or 1, the synthetic 5-substituted-dihydro cumarone-imidazole salt compound of back flow reaction in 4-dioxane solvent.
Further, this preparation method is further comprising the steps:
A, compound 2 (molecular formula C 9H 8O 2) the preparation method:
With 2, the 3-Dihydrobenzofuranes is raw material, with phosphorus oxychloride and N, the synthetic 5-aldehyde radical Dihydrobenzofuranes of dinethylformamide reaction: under ice-water bath, to N, in dinethylformamide, slowly drip phosphorus oxychloride, react after 10 minutes, slowly drip 2, 3-Dihydrobenzofuranes (1), consumption is 2 by mole ratio, 3-Dihydrobenzofuranes: N, dinethylformamide: phosphorus oxychloride=1: 2.2: 2, remove ice-water bath, 85 ℃ of lower heated and stirred were reacted 12 hours, reaction system is poured in frozen water, add sodium hydroxide solution, regulating pH value is 8～9, use ethyl acetate extraction, organic phase is washed with saturated common salt, anhydrous Na 2SO4 drying, filter, after the solvent concentrating under reduced pressure, through silica gel column chromatography, petroleum ether-ethyl acetate is eluent, prepare 5-aldehyde radical Dihydrobenzofuranes (2),
B, compound 3 (molecular formula C 9H 10O 2) preparation:
The 5-aldehyde radical Dihydrobenzofuranes of take is raw material, the synthetic 5-benzylalcohol substituted-dihydro cumarone of reduction in alcoholic solvent: the 5-aldehyde radical substituted-dihydro cumarone (2) that upper step is obtained is dissolved in methyl alcohol or alcohol solvent, under 0 ℃ of condition, stir after 5 minutes, slowly add SODIUM BOROHYDRIDE POWDER, consumption is 5-aldehyde radical Dihydrobenzofuranes by mole ratio: sodium borohydride=1: 1.1, the consumption of methyl alcohol or ethanol is 20-50ml: 1g5-aldehyde radical Dihydrobenzofuranes, under room temperature, stirring reaction is 2 hours, after the solvent concentrating under reduced pressure, through silica gel column chromatography, petroleum ether-ethyl acetate is eluent, prepare 5-benzylalcohol substituted-dihydro cumarone (3),
The preparation of C, compound 5a-5d:
The 5-benzylalcohol substituted-dihydro cumarone of take is raw material, with methylsulfonyl chloride, form methanesulfonates under dichloromethane solvent and triethylamine condition, again with imidazoles or benzoglyoxaline or 2-tolimidazole or 5, the synthetic 5-substituted-dihydro cumarone of 6-dimethylbenzimidazole back flow reaction in acetonitrile or toluene solvant-imidazoles composition: during the 5-benzylalcohol substituted-dihydro cumarone (3) that upper step is obtained is dissolved in dichloromethane solvent, add triethylamine, under 0 ℃ of condition, stir after 5 minutes, dropwise add methylsulfonyl chloride, consumption is 5-benzylalcohol substituted-dihydro cumarone by mole ratio: triethylamine: methylsulfonyl chloride=1: 3: 1.5, the consumption of methylene dichloride is 50-100ml: 1g5-benzylalcohol substituted-dihydro cumarone, under room temperature, stirring reaction is after 12 hours, add methylene dichloride dilution (50ml: the g substrate), water and saturated common salt washing respectively, organic phase anhydrous Na SO 4drying, filter, and after the solvent concentrating under reduced pressure, prepares methanesulfonates product (4),
Methanesulfonates product (4) is dissolved in acetonitrile or toluene solvant, add imidazoles or benzoglyoxaline or 2-tolimidazole or 5, the 6-dimethylbenzimidazole, consumption is the methanesulfonates product by mole ratio: imidazoles, benzoglyoxaline, 2-tolimidazole or 5, 6-dimethylbenzimidazole=1: 3, the consumption of acetonitrile or toluene is 50-100ml: 1g methanesulfonates product, stirring and refluxing reaction 24-48 hour, after the solvent concentrating under reduced pressure, through silica gel column chromatography, petroleum ether-ethyl acetate is eluent, prepare 4 5-substituted-dihydro cumarone-imidazoles composition: 1-(5-methyl substituted Dihydrobenzofuranes) imidazoles (5a, molecular formula C 12H 12N 2O) or 1-(5-methyl substituted Dihydrobenzofuranes) benzoglyoxaline (5b, molecular formula C 16H 14N 2O) or 1-(5-methyl substituted Dihydrobenzofuranes) 2-tolimidazole (5c, molecular formula C 17H 16N 2O) or 1-(5-methyl substituted Dihydrobenzofuranes) 5,6-dimethylbenzimidazole (5d, molecular formula C 18H 18N 2O),
The preparation of D, compound 6-36:
The 5-substituted-dihydro cumarone-imidazoles composition of take is raw material, in acetone or toluene or 1, synthetic 5-substituted-dihydro cumarone-imidazole salts in 4-dioxane solvent: the 5-substituted-dihydro cumarone that upper step is obtained-imidazoles composition (5a-5d) is dissolved in acetone or toluene or 1, in 4-dioxane solvent, under stirring, add halogenated alkane, consumption by mole ratio is: 5-substituted-dihydro cumarone-imidazoles composition: halogenated alkane=1: 1.2, acetone or toluene or 1, 4-dioxane consumption is 50-200ml: 1g5-substituted-dihydro cumarone-imidazoles composition, reaction stirring and refluxing 24-48 hour, after the silica gel thin-layer chromatography detection reaction is complete, be cooled to room temperature, if solid precipitation is arranged separates out, filter, precipitation with washing with acetone for several times, dry, prepare 5-substituted-dihydro cumarone-imidazole salts, if do not have the removal of solvent under reduced pressure that solid is separated out to obtain oily liquids, with the ether washing for several times, drying, prepare 5-substituted-dihydro cumarone-imidazole salts.
Further, the 5-substituted-dihydro cumarone-imidazole salts prepared is:
The purpose of the embodiment of the present invention is to provide a kind of curing cancer drug that comprises above-mentioned 5-substituted-dihydro cumarone-imidazole salt compound.
The present invention be take in natural product the pharmacophore (substituted-dihydro cumarone and imidazole structure unit) with remarkable anti-tumor activity and is the guide, carries out the design of antitumor drug molecule and synthetic.Compound after synthetic has extraordinary extracorporeal anti-tumor cytotoxic activity.Structure activity study shows, find that working as imidazole structure unit is 5, the 6-dimethylbenzimidazole, and when its 3-bit substituent is 2-bromobenzyl, naphthoyl methyl or 4-bromobenzene formyl methyl, 5-substituted-dihydro cumarone-imidazole salt compound and commercial cancer therapy drug---cis-platinum (DDP) is compared, and has extraordinary external anticancer physiologically active.
The accompanying drawing explanation
Fig. 1 is the representative natural product pharmacophore with anti-tumor activity that prior art provides.
Fig. 2 is 5-substituted-dihydro cumarone-imidazole salt compound that the embodiment of the present invention provides.
Fig. 3 is the preparation method of 5-substituted-dihydro cumarone-imidazole salt compound provided by the invention.
Embodiment
In order to make purpose of the present invention, technical scheme and advantage clearer, below in conjunction with drawings and Examples, the present invention is further elaborated.Should be appreciated that specific embodiment described herein, only in order to explain the present invention, is not intended to limit the present invention.
Embodiment 11-(5-methyl substituted Dihydrobenzofuranes)-3-(phenacyl) imidazoles bromine salt
Figure BSA00000807136800071
Preparation process is as follows:
1.5-the preparation of aldehyde radical Dihydrobenzofuranes (2):
Under ice-water bath, to DMF (28.4ml, 0.366mol) in slowly drip phosphorus oxychloride (31.0ml, 0.333mol), react after 10 minutes, slowly drip 2,3-Dihydrobenzofuranes (1,20.0g, 0.166mol), removing ice-water bath, 85 ℃ of lower heated and stirred were reacted 12 hours, reaction system is poured in frozen water, adds sodium hydroxide solution, and regulating pH value is 8～9, use ethyl acetate extraction, organic phase is washed with saturated common salt, anhydrous Na 2SO 4Drying, filter, and after the solvent concentrating under reduced pressure, through silica gel column chromatography (100-200 order), petroleum ether-ethyl acetate (5: 1) is eluent, prepare 5-aldehyde radical Dihydrobenzofuranes (2,22.8g), yield 93%;
2.5-the preparation of benzylalcohol substituted-dihydro cumarone (3):
5-aldehyde radical Dihydrobenzofuranes (2,2.96g, 20mmol) is dissolved in to methyl alcohol or ethanol (100ml), under 0 ℃ of condition, stir after 5 minutes, slowly add sodium borohydride (836mg, 20mmol), under room temperature, stirring reaction is 2 hours, after the solvent concentrating under reduced pressure, through silica gel column chromatography (100-200 order), petroleum ether-ethyl acetate (1: 1) is eluent, prepares 5-benzylalcohol substituted-dihydro cumarone (3,2.70g), yield 90%;
The preparation of (3.1-5-methyl substituted Dihydrobenzofuranes) imidazoles (5a):
By 5-benzylalcohol substituted-dihydro cumarone (3,530mg, 3.53mmol) be dissolved in methylene dichloride (80ml), add triethylamine (1.51ml, 10.58mmol), under 0 ℃ of condition, stir after 5 minutes, dropwise add methylsulfonyl chloride (0.35ml, 4.24mmol), under room temperature, stirring reaction is after 12 hours, add methylene dichloride dilution (40ml), water and saturated common salt washing respectively, organic phase anhydrous Na SO 4Drying, filter, and after the solvent concentrating under reduced pressure, prepares methanesulfonates product (4); Methanesulfonates product (4) is dissolved in to acetonitrile (80ml), add imidazoles (720mg, 10.58mmol), stirring and refluxing reaction 36 hours, after the solvent concentrating under reduced pressure, through silica gel column chromatography (100-200 order), petroleum ether-ethyl acetate (3: 1 → 1: 1) is eluent, obtain white amorphous powder (5a, 529mg), yield 75%;
The preparation of (4.1-5-methyl substituted Dihydrobenzofuranes)-3-(phenacyl) imidazoles bromine salt (6):
1-(5-methyl substituted Dihydrobenzofuranes) imidazoles (5a, 200mg, 1mmol) is dissolved in to toluene (20ml), under stirring, add phenacyl bromide (238mg, 1.2mmol), reaction stirring and refluxing 24 hours, be cooled to room temperature, removal of solvent under reduced pressure obtains oily liquids, with the ether washing for several times, drying, prepare brown oily liquids (6,346mg), yield 87%.
Brown oily liquids, molecular formula C 20H 19BrN 2O 2.
1H-NMR(300MHz，CDCl 3)δ：9.93(s，1H)，7.95(d，2H，J＝7.5Hz)，7.53-7.50(m，2H)，7.38(dd，1H，J＝14.7，7.2Hz)，7.23(d，2H，J＝6.0Hz)，7.11(d，2H，J＝8.1Hz)，6.67(d，1H，J＝8.1Hz)，6.23(s，2H)，5.29(s，2H)，4.49(2H，t，J＝8.4Hz)，3.10(2H，t，J＝8.4Hz).
13C?NMR(75MHz，CDCl 3)：δ190.62，161.22，137.44，134.72，133.45，?129.43，129.13，128.82，128.57，126.08，124.28，120.86，109.87，71.68，55.88，53.48，29.42.
IRv max(cm -1)：3399，3060，2966，1697，1559，1491，1444，1352，1237，1155，1031，985，936，823，756，688，630.
ESI-MS(70eV)m/z：320[M+1-Br] +，319[M-Br] +.
Embodiment 21-(5-methyl substituted substituted-dihydro cumarone)-3-(4-methoxybenzoyl methyl) imidazoles bromine salt
Figure BSA00000807136800091
Preparation process is as follows:
1.5-the preparation of aldehyde radical Dihydrobenzofuranes (2): method is with embodiment 1.
2.5-the preparation of benzylalcohol substituted-dihydro cumarone (3): method is with embodiment 1.
3.1-the preparation of (5-methyl substituted Dihydrobenzofuranes) imidazoles (5a): method is with embodiment 1.
The preparation of (4.1-5-methyl substituted Dihydrobenzofuranes)-3-(4-methoxybenzoyl methyl) imidazoles bromine salt (7):
1-(5-methyl substituted Dihydrobenzofuranes) imidazoles (5a, 200mg, 1mmol) is dissolved in to toluene (20ml), under stirring, add 4-methoxybenzoyl monobromomethane (274mg, 1.2mmol), reaction stirring and refluxing 20 hours, be cooled to room temperature, have solid precipitation to separate out, filter, precipitation with washing with acetone for several times, dry, prepare white amorphous powder (7,346mg), yield 80%.
The white amorphous powder, molecular formula C 21H 21BrN 2O 3.
1H-NMR(300MHz，CDCl 3)δ：8.14(d，2H，J＝9.0Hz)，7.61-7.69(m，3H)，7.36(s，1H)，7.25(d，1H，J＝8.1Hz)，7.05(d，2H，J＝9.0Hz)，6.80(d，1H，J＝8.1Hz)，6.35(s，2H)，5.66(s，2H)，4.59(2H，t，J＝8.7Hz)，3.93(s，3H)，3.22(2H，t，J＝8.7Hz).
13C-NMR(75MHz，CDCl 3)：δ188.46，165.03，161.05，142.93，132.55，131.06，130.90，128.90，128.77，127.30，127.06，126.34，125.39，123.86，114.46，113.54，113.39，109.80，71.67，55.62，53.08，51.47，49.53，49.25，48.96，48.69，48.42，29.37.
IRv max(cm -1)：3417，3059，1687，1602，1495，1442，1353，1243，1170，986，830，634.
ESI-MS(70eV)m/z：350[M+1-Br] +，349[M-Br] +.
Embodiment 31-(5-methyl substituted Dihydrobenzofuranes)-3-(4-bromobenzene formyl methyl) imidazoles bromine salt
Figure BSA00000807136800101
Preparation process is as follows:
1.5-the preparation of aldehyde radical Dihydrobenzofuranes (2): method is with embodiment 1.
2.5-the preparation of benzylalcohol substituted-dihydro cumarone (3): method is with embodiment 1.
3.1-the preparation of (5-methyl substituted Dihydrobenzofuranes) imidazoles (5a): method is with embodiment 1.
The preparation of (4.1-5-methyl substituted Dihydrobenzofuranes)-3-(4-bromobenzene formyl methyl) imidazoles bromine salt (8):
1-(5-methyl substituted Dihydrobenzofuranes) imidazoles (5a, 200mg, 1mmol) is dissolved in to toluene (20ml), under stirring, add 4-bromobenzene formyl monobromomethane (331mg, 1.2mmol), reaction stirring and refluxing 24 hours, be cooled to room temperature, have solid precipitation to separate out, filter, precipitation with washing with acetone for several times, dry, prepare white amorphous powder (8,390mg), yield 82%.
The white amorphous powder, molecular formula C 20H 18Br 2N 2O 2.
1H-NMR(300MHz，CDCl 3)δ：9.48(s，1H)，7.94(d，2H，J＝8.7Hz)，7.66(d，2H，J＝8.7Hz)，7.57(s，1H)，7.35(s，1H)，7.30(s，1H)，7.19(d，1H，J＝8.1Hz)，6.19(d，1H，J＝8.1Hz)，6.14(s，2H)，5.36(s，?2H)，4.60(2H，t，J＝8.7Hz)，3.22(2H，t，J＝8.7Hz).
13C-NMR(75MHz，CDCl 3)：δ189.77，161.10，137.06，132.34，132.13，130.00，129.85，129.25，128.75，125.83，124.30，121.03，109.80，71.61，55.55，53.35，49.42，49.13，48.85，48.57，48.28，29.27.
IR?v max(cm -1)：3137，2969，1701，1582，1493，1237，1164，1113，1071，988，942，823，740664.
ESI-MS(70eV)m/z：398[M+1-Br] +，397[M-Br] +.
Embodiment 41-(5-methyl substituted Dihydrobenzofuranes)-3-(naphthoyl methyl) imidazoles bromine salt
Figure BSA00000807136800111
Preparation process is as follows:
1.5-the preparation of aldehyde radical Dihydrobenzofuranes (2): method is with embodiment 1.
2.5-the preparation of benzylalcohol substituted-dihydro cumarone (3): method is with embodiment 1.
3.1-the preparation of (5-methyl substituted Dihydrobenzofuranes) imidazoles (5a): method is with embodiment 1.
The preparation of (4.1-5-methyl substituted Dihydrobenzofuranes)-3-(naphthoyl methyl) imidazoles bromine salt (9):
1-(5-methyl substituted Dihydrobenzofuranes) imidazoles (5a, 200mg, 1mmol) is dissolved in to toluene (20ml), under stirring, add naphthoyl monobromomethane (298mg, 1.2mmol), reaction stirring and refluxing 18 hours, be cooled to room temperature, have solid precipitation to separate out, filter, precipitation with washing with acetone for several times, dry, prepare white amorphous powder (9,269mg), yield 60%.
Yellow amorphous powder, molecular formula C 24H 21BrN 2O 2.
1H-NMR(300MHz，CDCl 3)δ：9.68(s，1H)，8.68(s，1H)，7.99(d，1H，J＝7.5Hz)，7.92(d，1H，J＝8.1Hz)，7.81(d，2H，J＝8.4Hz)，7.59(s，2H)，7.52(d，1H，J＝8.1Hz)，7.30(s，1H)，7.26(s，1H)，7.15(d，1H，J＝7.5Hz)，6.72(d，1H，J＝8.1Hz)，6.27(s，2H)，5.29(s，2H)，?4.53(2H，t，J＝8.7Hz)，3.14(2H，t，J＝8.7Hz).
13C-NMR(75MHz，CDCl 3)：δ190.48，161.03，137.14，135.99，132.27，131.08，130.63，129.93，129.28，128.85，128.65，127.67，127.08，125.93，124.42，124.29，123.13，120.94，109.73，71.60，55.69，53.19，29.29.
IR?v max(cm -1)：3415，3031，1689，1493，1365，1239，1170，939，815，752.
ESI-MS(70eV)m/z：370[M+1-Br] +，369[M-Br] +.
Embodiment 51-(5-methyl substituted Dihydrobenzofuranes)-3-(2-bromobenzyl) imidazoles bromine salt
Figure BSA00000807136800121
Preparation process is as follows:
1.5-the preparation of aldehyde radical Dihydrobenzofuranes (2): method is with embodiment 1.
2.5-the preparation of benzylalcohol substituted-dihydro cumarone (3): method is with embodiment 1.
3.1-the preparation of (5-methyl substituted Dihydrobenzofuranes) imidazoles (5a): method is with embodiment 1.
The preparation of (4.1-5-methyl substituted Dihydrobenzofuranes)-3-(naphthoyl methyl) imidazoles bromine salt (9):
1-(5-methyl substituted Dihydrobenzofuranes) imidazoles (5a, 200mg, 1mmol) is dissolved in to toluene (20ml), under stirring, add 2-bromine bromobenzyl (298mg, 1.2mmol), reaction stirring and refluxing 18 hours, be cooled to room temperature, removal of solvent under reduced pressure obtains oily liquids, with the ether washing for several times, drying, prepare brown oily liquids (10,408mg), yield 91%.
Brown oily liquids, molecular formula C 19H 18Br 2N 2O.
1H-NMR(300MHz，CDCl 3)δ：10.64(s，1H)，7.83(d，1H，J＝7.8Hz)，7.66(d，1H，J＝7.8Hz)，7.41-7.38(m，2H)，7.29-7.26(m，3H)，7.21(d，1H，J＝8.1Hz)，6.74(d，1H，J＝8.1Hz)，5.69(s，2H)，5.48(s，2H)，4.57(2H，t，J＝8.4Hz)，3.19(2H，t，J＝8.4Hz).
13C-NMR(75MHz，CDCl 3)：δ160.76，136.35，133.24，132.30，132.03，131.25，129.35，128.53，128.34，126.04，124.96，124.19，122.27，121.98，109.49，71.48，63.62，52.94，52.84，29.26.
IRv max(cm -1)：3399，3055，2966，1612，1557，1489，1443，1356，1242，1148，1029，981，938，826，752，633.
ES?I-MS(70eV)m/z：370[M+1-Br] +，369[M-Br] +.
Embodiment 61-(5-substituted-dihydro cumarone)-3-(normal-butyl) iodonium imidazolide salts
Figure BSA00000807136800131
Preparation process is as follows:
1.5-the preparation of aldehyde radical Dihydrobenzofuranes (2): method is with embodiment 1.
2.5-the preparation of benzylalcohol substituted-dihydro cumarone (3): method is with embodiment 1.
3.1-the preparation of (5-methyl substituted Dihydrobenzofuranes) imidazoles (5a): method is with embodiment 1.
The preparation of (4.1-5-methyl substituted Dihydrobenzofuranes)-3-(normal-butyl) iodonium imidazolide salts (11):
1-(5-methyl substituted Dihydrobenzofuranes) imidazoles (5a, 200mg, 1mmol) is dissolved in to toluene (20ml), under stirring, add 1-iodo-n-butane (221mg, 1.2mmol), reaction stirring and refluxing 18 hours, be cooled to room temperature, removal of solvent under reduced pressure obtains oily liquids, with the ether washing for several times, drying, prepare brown oily liquids (11,307mg), yield 80%.
Brown oily liquids, molecular formula C 16H 21IN 2O.
1H-NMR(300MHz，CDCl 3)δ：9.90(1H，s)，7.50(1H，s)，7.37(1H，d，J＝9.9Hz)，7.22(1H，d，J＝9.3Hz)，7.11(1H，d，J＝8.1Hz)，6.72(1H，d，J＝8.1Hz)，5.26(2H，s)，4.55(2H，t，J＝8.4Hz)，4.35-4.25(m，2H)，4.19(2H，t，J＝7.2Hz)，3.18(2H，t，J＝8.4Hz)，1.83-1.76(m，2H)，0.93(t，3H，J＝7.2Hz).
13C-NMR(75MHz，CDCl 3)：δ161.22，135.84，129.74，129.26，128.78，?126.45，125.81，124.53，123.91，123.51，122.35，122.11，113.57，109.94，71.78，55.52，52.19，32.14，29.57，19.63，13.64.
IR?v max(cm -1)：3419，3072，2955，1614，1557，1489，1446，1360，1242，1156，981，937，819，754，649.
ESI-MS(70eV)m/z：258[M+1-I] +，257[M-I] +.
Embodiment 71-(5-methyl substituted Dihydrobenzofuranes)-3-(phenacyl) benzoglyoxaline bromine salt
Preparation process is as follows:
1.2-the preparation of benzoyl substituted-dihydro cumarone: method is with embodiment 1.
2.2-the preparation of benzylalcohol substituted-dihydro cumarone: method is with embodiment 1.
The preparation of (3.1-5-methyl substituted Dihydrobenzofuranes) benzoglyoxaline (5b):
By 5-benzylalcohol substituted-dihydro cumarone (3,530mg, 3.53mmol) be dissolved in methylene dichloride (80ml), add triethylamine (1.51ml, 10.58mmol), under 0 ℃ of condition, stir after 5 minutes, dropwise add methylsulfonyl chloride (0.35ml, 4.24mmol), under room temperature, stirring reaction is after 12 hours, add methylene dichloride dilution (40ml), water and saturated common salt washing respectively, organic phase anhydrous Na SO 4Drying, filter, and after the solvent concentrating under reduced pressure, prepares methanesulfonates product (4); Methanesulfonates product (4) is dissolved in to toluene (80ml), add benzoglyoxaline (1.25g, 10.58mmol), stirring and refluxing reaction 48 hours, after the solvent concentrating under reduced pressure, through silica gel column chromatography (100-200 order), petroleum ether-ethyl acetate (3: 1 → 1: 1) is eluent, obtain white amorphous powder (5b, 794mg), yield 90%;
The preparation of (4.1-5-methyl substituted Dihydrobenzofuranes)-3-(phenacyl) benzoglyoxaline bromine salt (12):
1-(5-methyl substituted Dihydrobenzofuranes) benzoglyoxaline (5b, 250mg, 1mmol) is dissolved in to 1,4-dioxane (20ml), add phenacyl bromide (238mg, 1.2mmol) under stirring, reaction stirring and refluxing 24 hours, be cooled to room temperature, has solid precipitation to separate out, filter, with washing with acetone for several times, drying, prepare white amorphous powder (12 to precipitation, 367mg), yield 82%.
The white amorphous powder, molecular formula C 24H 21BrN 2O 2.
1H-NMR(300MHz，CDCl 3)δ：10.29(1H，s)，8.09(2H，d，J＝7.2Hz)，7.66-7.61(2H，m)，7.54-7.49(5H，m)，7.32(1H，s)，7.19(1H，d，J＝7.8Hz)，7.73(1H，d，J＝8.4Hz)，6.40(2H，s)，5.60(2H，s)，4.51(2H，t，J＝8.7Hz)，3.15(2H，t，J＝8.7Hz).
13C?NMR(75MHz，CDCl 3)：δ190.32，161.14，143.15，135.0，133.50，132.55，130.96，129.26，128.99，128.84，128.64，127.36，127.13，125.49，123.87，113.65，113.38，109.86，71.73，53.60，51.61，49.82，49.54，49.25，48.97，48.68，29.45.
IRv max(cm -1)：3418，3037，1607，1558，1490，1444，1349，1235，1187，1106，983，936，757，686.
ESI-MS(70eV)m/z：370[M+1-Br] +，369[M-Br] +.
Embodiment 81-(5-methyl substituted Dihydrobenzofuranes)-3-(4-methoxybenzoyl methyl) benzoglyoxaline bromine salt
Figure BSA00000807136800151
Preparation process is as follows:
1.2-the preparation of benzoyl substituted-dihydro cumarone: method is with embodiment 1.
2.2-the preparation of benzylalcohol substituted-dihydro cumarone: method is with embodiment 1.
3.1-the preparation of (5-methyl substituted Dihydrobenzofuranes) benzoglyoxaline: method is with embodiment 7.
The preparation of (4.1-5-methyl substituted Dihydrobenzofuranes)-3-(4-methoxybenzoyl methyl) benzoglyoxaline bromine salt (13):
1-(5-methyl substituted Dihydrobenzofuranes) benzoglyoxaline (5b, 250mg, 1mmol) is dissolved in to 1,4-dioxane (20ml), add 4-methoxybenzoyl monobromomethane (275mg, 1.2mmol) under stirring, reaction stirring and refluxing 24 hours, be cooled to room temperature, has solid precipitation to separate out, filter, with washing with acetone for several times, drying, prepare white amorphous powder (13 to precipitation, 411mg), yield 86%.
The white amorphous powder, molecular formula C 25H 23BrN 2O 3.
1H-NMR(300MHz，CDCl 3)δ：10.19(1H，s)，8.14(2H，d，J＝8.7Hz)，7.69(1H，dd，J＝9.0，3.0Hz)，7.61-7.56(3H，m)，7.36(1H，d，J＝6.0Hz)，7.26(1H，d，J＝8.1Hz)，7.04(2H，d，J＝8.7Hz)，6.79(1H，d，J＝8.1Hz)，6.36(2H，s)，5.66(2H，s)，4.58(2H，t，J＝8.7Hz)，3.92(3H，s)，3.24(2H，t，J＝8.7Hz).
13C?NMR(75MHz，CDCl 3)：δ188.42，164.94，161.02，143.04，131.10，130.82，128.87，128.77，127.21，126.99，126.36，125.44，123.85，114.43，113.46，109.74，71.65，55.64，53.23，51.49，49.52，49.23，29.38.
IR?v max(cm -1)：3419，2958，1682，1602，1492，1431，1347，1242，1179，1114，1027，982，938，834，763.
ESI-MS(70eV)m/z：400[M+1-Br] +，399[M-Br] +.
Embodiment 91-(5-methyl substituted Dihydrobenzofuranes)-3-(4-bromobenzene formyl methyl) benzoglyoxaline bromine salt
Figure BSA00000807136800161
Preparation process is as follows:
1.2-the preparation of benzoyl substituted-dihydro cumarone: method is with embodiment 1.
2.2-the preparation of benzylalcohol substituted-dihydro cumarone: method is with embodiment 1.
3.1-the preparation of (5-methyl substituted Dihydrobenzofuranes) benzoglyoxaline: method is with embodiment 7.
The preparation of (4.1-5-methyl substituted Dihydrobenzofuranes)-3-(4-bromobenzene formyl methyl) benzoglyoxaline bromine salt (14):
1-(5-methyl substituted Dihydrobenzofuranes) benzoglyoxaline (5b, 250mg, 1mmol) is dissolved in to 1,4-dioxane (20ml), add 4-bromobenzene formyl monobromomethane (331mg, 1.2mmol) under stirring, reaction stirring and refluxing 24 hours, be cooled to room temperature, has solid precipitation to separate out, filter, with washing with acetone for several times, drying, prepare white amorphous powder (14 to precipitation, 405mg), yield 77%.
The white amorphous powder, molecular formula C 24H 20Br 2N 2O 2.
1H-NMR(300MHz，CDCl 3)δ：10.25(1H，s)，8.05(2H，d，J＝8.1Hz)，7.71-7.67(4H，m)，7.61-7.59(2H，m)，7.37(1H，s)，7.26(1H，d，J＝7.8Hz)，6.78(1H，d，J＝8.1Hz)，6.49(2H，s)，5.66(2H，s)，4.57(2H，t，J＝8.4Hz)，3.21(2H，t，J＝8.4Hz).
13C?NMR(75MHz，CDCl 3)：δ189.6，161.01，142.84，132.43，132.17，130.77，130.10，128.85，128.74，127.36，127.12，125.34，123.79，113.55，113.46，109.77，71.62，53.53，51.45，49.55，49.26，48.97，48.69，48.41，29.33.
IR?v max(cm -1)：3428，3008，1686，1586，1489，1435，1383，1235，1116，984，934，815，746.
ESI-MS(70eV)m/z：448[M+1-Br] +，447[M-Br] +.
Embodiment 101-(5-methyl substituted Dihydrobenzofuranes)-3-(naphthoyl methyl) benzoglyoxaline bromine salt
Figure BSA00000807136800171
Preparation process is as follows:
1.2-the preparation of benzoyl substituted-dihydro cumarone: method is with embodiment 1.
2.2-the preparation of benzylalcohol substituted-dihydro cumarone: method is with embodiment 1.
3.1-the preparation of (5-methyl substituted Dihydrobenzofuranes) benzoglyoxaline: method is with embodiment 7.
The preparation of (4.1-5-methyl substituted Dihydrobenzofuranes)-3-(naphthoyl methyl) benzoglyoxaline bromine salt (15):
1-(5-methyl substituted Dihydrobenzofuranes) benzoglyoxaline (5b, 250mg, 1mmol) is dissolved in to 1,4-dioxane (20ml), add naphthoyl monobromomethane (298mg, 1.2mmol) under stirring, reaction stirring and refluxing 24 hours, be cooled to room temperature, has solid precipitation to separate out, filter, with washing with acetone for several times, drying, prepare yellow amorphous powder (15 to precipitation, 438mg), yield 88%.
Yellow amorphous powder, molecular formula C 28H 23BrN 2O 2.
1H-NMR(300MHz，DMSO)δ：9.83(1H，s)，8.92(1H，s)，8.23(2H，d，J＝7.5Hz)，8.17-8.05(4H，m)，7.79-7.71(4H，m)，7.48(1H，s)，7.36(1H，d，J＝8.1Hz)，6.83(1H，d，J＝8.1Hz)，6.55(2H，s)，5.80(2H，s)，4.54(2H，t，J＝8.4Hz)，3.18(2H，t，J＝8.4Hz).
13C?NMR(75MHz，DMSO)：δ191.14，160.24，142.23，135.55，132.21，131.05，130.82，130.52，129.67，129.36，128.92，128.69，128.37，127.86，127.40，126.86，126.67，125.73，125.27，123.31，123.05，114.03，109.22，71.24，53.27，49.94，28.84.
IR?v max(cm -1)：3424，3034，2954，1689，1621，1561，1490，1439，1362，1242，1188，1122，984，940，819，760.
ESI-MS(70eV)m/z：420[M+1-Br] +，419[M-Br] +.
Embodiment 111-(5-methyl substituted Dihydrobenzofuranes)-3-(2-bromobenzyl) benzoglyoxaline bromine salt
Figure BSA00000807136800181
Preparation process is as follows:
1.2-the preparation of benzoyl substituted-dihydro cumarone: method is with embodiment 1.
2.2-the preparation of benzylalcohol substituted-dihydro cumarone: method is with embodiment 1.
3.1-the preparation of (5-methyl substituted Dihydrobenzofuranes) benzoglyoxaline: method is with embodiment 7.
The preparation of (4.1-5-methyl substituted Dihydrobenzofuranes)-3-(2-bromobenzyl) benzoglyoxaline bromine salt (16):
1-(5-methyl substituted Dihydrobenzofuranes) benzoglyoxaline (5b, 250mg, 1mmol) is dissolved in to 1,4-dioxane (20ml), add 2-bromine bromobenzyl (298mg, 1.2mmol) under stirring, reaction stirring and refluxing 24 hours, be cooled to room temperature, has solid precipitation to separate out, filter, with washing with acetone for several times, drying, prepare white amorphous powder (16 to precipitation, 453mg), yield 91%.
The white amorphous powder, molecular formula C 23H 20Br 2N 2O.
1H-NMR(300MHz，DMSO)δ：10.11(1H，s)，8.07(1H，d，J＝6.9Hz)，7.91(1H，d，J＝6.9Hz)，7.74(1H，d，J＝7.8Hz)，7.67-7.65(2H，m)，7.53-7.47(3H，m)，7.38(2H，t，J＝7.8Hz)，6.77(1H，d，J＝8.1Hz)，5.89(2H，s)，5.75(2H，s)，4.50(2H，t，J＝8.4Hz)，3.14(2H，t，J＝8.4Hz).
13C?NMR(75MHz，DMSO)：δ160.07，142.94，133.32，132.49，131.23，131.04，130.82，128.74，128.45，128.23，126.91，126.79，125.55，123.14，114.29，113.87，109.04，71.21，50.61，49.90，28.82.
IR?v max(cm -1)：3456，3016，1614，1557，1489，1438，1370，1240，1111，1024，939，841，756，658.
ESI-MS(70eV)m/z：420[M+1-Br] +，419[M-Br] +.
Embodiment 121-(5-methyl substituted Dihydrobenzofuranes)-3-(4-nitrobenzyl) benzoglyoxaline bromine salt
Figure BSA00000807136800191
Preparation process is as follows:
1.2-the preparation of benzoyl substituted-dihydro cumarone: method is with embodiment 1.
2.2-the preparation of benzylalcohol substituted-dihydro cumarone: method is with embodiment 1.
3.1-the preparation of (5-methyl substituted Dihydrobenzofuranes) benzoglyoxaline: method is with embodiment 7.
The preparation of (4.1-5-methyl substituted Dihydrobenzofuranes)-3-(4-nitrobenzyl) benzoglyoxaline bromine salt (17):
1-(5-methyl substituted Dihydrobenzofuranes) benzoglyoxaline (5b, 250mg, 1mmol) is dissolved in to 1,4-dioxane (20ml), add 4-nitro bromobenzyl (254mg, 1.2mmol) under stirring, reaction stirring and refluxing 24 hours, be cooled to room temperature, has solid precipitation to separate out, filter, with washing with acetone for several times, drying, prepare white amorphous powder (17 to precipitation, 414mg), yield 89%.
The white amorphous powder, molecular formula C 23H 20BrN 3O 3.
1H-NMR(300MHz，DMSO)δ：10.13(1H，s)，8.26(2H，d，J＝7.8Hz)，8.05(1H，d，J＝6.9Hz)，7.91(1H，d，J＝6.9Hz)，7.79(2H，d，J＝7.8Hz)，7.65-7.63(2H，m)，7.48(1H，s)，7.37(1H，d，J＝7.8Hz)，6.80(1H，d，J＝8.1Hz)，6.00(2H，s)，5.71(2H，s)，4.53(2H，t，J＝8.4Hz)，3.17(2H，t，J＝8.4Hz).
13C?NMR(75MHz，DMSO)：δ160.14，147.56，142.78，141.28，131.01，129.45，128.91，128.30，126.89，125.73，125.25，123.94，114.21，113.82，109.11，71.22，50.07，49.16，28.83.
IRv max(cm -1)：3446，3387，3020，1610，1559，1517，1443，1346，1243，1110，943，760，714，613.
ESI-MS(70eV)m/z：387[M+1-Br] +，386[M-Br] +.
Embodiment 131-(5-methyl substituted Dihydrobenzofuranes)-3-(allyl group) benzoglyoxaline bromine salt
Figure BSA00000807136800211
Preparation process is as follows:
1.2-the preparation of benzoyl substituted-dihydro cumarone: method is with embodiment 1.
2.2-the preparation of benzylalcohol substituted-dihydro cumarone: method is with embodiment 1.
3.1-the preparation of (5-methyl substituted Dihydrobenzofuranes) benzoglyoxaline: method is with embodiment 7.
The preparation of (4.1-5-methyl substituted Dihydrobenzofuranes)-3-(allyl group) benzoglyoxaline bromine salt (18):
1-(5-methyl substituted Dihydrobenzofuranes) benzoglyoxaline (5b, 250mg, 1mmol) is dissolved in to 1,4-dioxane (20ml), add allyl bromide 98 (144mg, 1.2mmol) under stirring, reaction stirring and refluxing 24 hours, be cooled to room temperature, has solid precipitation to separate out, filter, with washing with acetone for several times, drying, prepare white amorphous powder (18 to precipitation, 329mg), yield 89%.
The white amorphous powder, molecular formula C 19H 19BrN 2O.
1H-NMR(300MHz，DMSO)δ：9.98(1H，s)，8.03-8.00(2H，m)，7.66(2H，s)，7.46(1H，s)，7.35(1H，d，J＝8.1Hz)，6.78(1H，d，J＝7.8Hz)，6.21-6.10(1H，m)，5.69(2H，s)，5.43(2H，dd，J＝15.3，7.5Hz)，5.21(1H，d，J＝3.9Hz)，4.51(2H，t，J＝8.1Hz)，3.15(2H，t，J＝8.1Hz).
13C?NMR(75MHz，DMSO)：δ160.08，142.20，131.17，130.99，128.78，128.24，126.63，125.61，120.57，114.02，109.05，71.20，49.85，48.95，28.82.
IRv max(cm -1)：3418，3105，2926，2761，1609，1555，1491，1436，1370，1290，1241，1114，1004，940，841，758，650，604.
ESI-MS(70eV)m/z：292[M+1-Br] +，291[M-Br] +.
Embodiment 14 1-(5-methyl substituted Dihydrobenzofuranes)-3-(normal-butyl) benzoglyoxaline salt compounded of iodine
Figure BSA00000807136800221
Preparation process is as follows:
1.2-the preparation of benzoyl substituted-dihydro cumarone: method is with embodiment 1.
2.2-the preparation of benzylalcohol substituted-dihydro cumarone: method is with embodiment 1.
3.1-the preparation of (5-methyl substituted Dihydrobenzofuranes) benzoglyoxaline: method is with embodiment 7.
The preparation of (4.1-5-methyl substituted Dihydrobenzofuranes)-3-(normal-butyl) benzoglyoxaline salt compounded of iodine (19):
1-(5-methyl substituted Dihydrobenzofuranes) benzoglyoxaline (5b, 250mg, 1mmol) is dissolved in to 1,4-dioxane (20ml), add 1-iodo-n-butane (221mg, 1.2mmol) under stirring, reaction stirring and refluxing 24 hours, be cooled to room temperature, has solid precipitation to separate out, filter, with washing with acetone for several times, drying, prepare white amorphous powder (19 to precipitation, 321mg), yield 74%.
The white amorphous powder, molecular formula C 20H 23IN 2O.
1H-NMR(300MHz，DMSO)δ：9.90(1H，s)，8.10(1H，dd，J＝7.8，3.3Hz)，8.02(1H，d，J＝5.1Hz)，7.68-6.65(2H，m)，7.44(1H，s)，7.33(2H，d，J＝8.1Hz)，6.78(1H，d，J＝8.1Hz)，5.65(2H，s)，4.54-4.48(4H，m)，3.15(2H，t，J＝8.7Hz)，1.94-1.88(2H，m)，1.40-1.32(2H，m)，0.93(3H，t，J＝7.2Hz).
13C?NMR(75MHz，DMSO)：δ160.08，141.97，131.31，130.77，128.69，128.25，126.60，125.52，113.93，113.81，109.06，71.20，49.83，46.56，30.45，28.82，19.08，13.35.
IR?v max(cm -1)：3438，3124，3031，2952，1613，1554，1491，1377，1243，1193，1109，982，933，769.
ESI-MS(70eV)m/z：308[M+1-I] +，307[M-I] +.
Embodiment 15 1-(5-methyl substituted Dihydrobenzofuranes)-3-(phenacyl)-2-tolimidazole bromine salt
Figure BSA00000807136800231
Preparation process is as follows:
1.5-the preparation of aldehyde radical Dihydrobenzofuranes (2): method is with embodiment 1.
2.5-the preparation of benzylalcohol substituted-dihydro cumarone (3): method is with embodiment 1.
The preparation of (3.1-5-methyl substituted Dihydrobenzofuranes)-2-tolimidazole (5c):
By 5-benzylalcohol substituted-dihydro cumarone (3,530mg, 3.53mmol) be dissolved in methylene dichloride (80ml), add triethylamine (1.51ml, 10.58mmol), under 0 ℃ of condition, stir after 5 minutes, dropwise add methylsulfonyl chloride (0.35ml, 4.24mmol), under room temperature, stirring reaction is after 12 hours, add methylene dichloride dilution (40ml), water and saturated common salt washing respectively, organic phase anhydrous Na SO 4Drying, filter, and after the solvent concentrating under reduced pressure, prepares methanesulfonates product (4); Methanesulfonates product (4) is dissolved in to acetonitrile (80ml), add 2-tolimidazole (1.40g, 10.58mmol), stirring and refluxing reaction 36 hours, after the solvent concentrating under reduced pressure, through silica gel column chromatography (100-200 order), petroleum ether-ethyl acetate (3: 1 → 1: 1) is eluent, obtain white amorphous powder (5c, 885mg), yield 95%;
The preparation of (4.1-5-methyl substituted Dihydrobenzofuranes)-3-(phenacyl)-2-tolimidazole bromine salt (20):
1-(5-methyl substituted Dihydrobenzofuranes)-2-tolimidazole (5c, 264mg, 1mmol) is dissolved in to acetone (20ml), under stirring, add phenacyl bromide (238mg, 1.2mmol), reaction stirring and refluxing 24 hours, be cooled to room temperature, have solid precipitation to separate out, filter, precipitation with washing with acetone for several times, dry, prepare white amorphous powder (20,397mg), yield 86%.
The white amorphous powder, molecular formula C 25H 23BrN 2O 2.
1H-NMR(300MHz，DMSO)δ：8.15(2H，t，J＝7.2Hz)，8.07-8.01(2H，m)，7.81(1H，d，J＝7.2Hz)，7.70-7.63(4H，m)，7.27(1H，s)，7.16(1H，d，J＝8.1Hz)，6.79(1H，d，J＝8.1Hz)，6.45(2H，s)，5.79(2H，s)，?4.52(2H，t，J＝8.4Hz)，3.15(2H，t，J＝8.4Hz)，2.92(3H，s).
13C?NMR(75MHz，DMSO)：δ191.06，153.06，134.66，128.93，128.67，127.54，126.35，125.73，124.46，113.31，109.15，71.18，51.91，48.15，28.88，10.76.
IRv max(cm -1)：3424，3032，2958，2905，1690，1614，1532，1485，1353，1234，1103，984，757，685.
ESI-MS(70eV)m/z：384[M+1-Br] +，383[M-Br] +.
Embodiment 161-(5-methyl substituted Dihydrobenzofuranes)-3-(4-methoxybenzoyl methyl)-2-tolimidazole bromine salt
Figure BSA00000807136800241
Preparation process is as follows:
1.5-the preparation of aldehyde radical Dihydrobenzofuranes (2): method is with embodiment 1.
2.5-the preparation of benzylalcohol substituted-dihydro cumarone (3): method is with embodiment 1.
3.1-the preparation of (5-methyl substituted Dihydrobenzofuranes)-2-tolimidazole (5c): method is with embodiment 15.
The preparation of (4.1-5-methyl substituted Dihydrobenzofuranes)-3-(4-methoxybenzoyl methyl)-2-tolimidazole bromine salt (21):
1-(5-methyl substituted Dihydrobenzofuranes)-2-tolimidazole (5c, 264mg, 1mmol) is dissolved in to acetone (20ml), under stirring, add 4-methoxybenzoyl monobromomethane (275mg, 1.2mmol), reaction stirring and refluxing 24 hours, be cooled to room temperature, have solid precipitation to separate out, filter, precipitation with washing with acetone for several times, dry, prepare white amorphous powder (21,453mg), yield 92%.
The white amorphous powder, molecular formula C 26H 25BrN 2O 3.
1H-NMR(300MHz，DMSO)δ：8.28(2H，d，J＝8.7Hz)，7.62-7.54(4H，?m)，7.08(2H，s)，7.04(2H，d，J＝6.3Hz)，6.79(1H，d，J＝8.1Hz)，6.69(2H，s)，5.56(2H，s)，4.58(2H，t，J＝8.4Hz)，3.92(3H，s)，3.31(2H，t，J＝8.4Hz)，3.13(3H，s).
13C?NMR(75MHz，DMSO)：δ189.23，164.32，159.86，153.07，131.55，131.18，130.69，128.40，127，53，126.34，125.77，124.46，114.22，113.34，109.14，71.18，55.82，51.58，48.12，28.88，10.83.
IR?v max(cm -1)：3411，3021，2956，2844，1679，1599，1478，1349，1242，1176，1112，982，938，829，764.
ESI-MS(70eV)m/z：414[M+1-Br] +，413[M-Br] +.
Embodiment 171-(5-methyl substituted Dihydrobenzofuranes)-3-(naphthoyl methyl)-2-tolimidazole bromine salt
Figure BSA00000807136800251
Preparation process is as follows:
1.5-the preparation of aldehyde radical Dihydrobenzofuranes (2): method is with embodiment 1.
2.5-the preparation of benzylalcohol substituted-dihydro cumarone (3): method is with embodiment 1.
3.1-the preparation of (5-methyl substituted Dihydrobenzofuranes)-2-tolimidazole (5c): method is with embodiment 15.
The preparation of (4.1-5-methyl substituted Dihydrobenzofuranes)-3-(naphthoyl methyl)-2-tolimidazole bromine salt (22):
1-(5-methyl substituted Dihydrobenzofuranes)-2-tolimidazole (5c, 264mg, 1mmol) is dissolved in to acetone (20ml), under stirring, add naphthoyl monobromomethane (298mg, 1.2mmol), reaction stirring and refluxing 24 hours, be cooled to room temperature, have solid precipitation to separate out, filter, precipitation with washing with acetone for several times, dry, prepare white amorphous powder (22,461mg), yield 90%.
Yellow amorphous powder, molecular formula C 29H 25BrN 2O 2.
1H-NMR(300MHz，CDCl 3)δ：9.00(1H，s)，8.23(1H，d，J＝7.8Hz)，8.15(1H，d，J＝8.7Hz)，8.11-8.07(4H，m)，7.79-7.74(2H，m)，7.69-7.62(2H，m)，7.31(1H，s)，7.20(1H，d，J＝7.8Hz)，6.81(1H，d，J＝8.1Hz)，6.64(2H，s)，5.83(2H，s)，4.53(2H，t，J＝8.4Hz)，3.17(2H，t，J＝8.4Hz)，2.99(3H，s).
13C?NMR(75MHz，DMSO)：δ191.04，159.88，153.15，135.61，131.95，131.58，131.38，131.01，130.74，129.68，129.40，128.55，128.42，127.87，127.59，127.39，126.38，125.79，124.51，123.50，113.38，113.25，109.16，71.20，66.32，52.10，48.20，28.90，10.92.
IRv max(cm -1)：3412，3026，2954，2902，1685，1620，1528，1481，1359，1236，1120，981，938，820，758.
ESI-MS(70eV)m/z：434[M+1-Br] +，433[M-Br] +.
Embodiment 181-(5-methyl substituted Dihydrobenzofuranes)-3-(normal-butyl)-2-tolimidazole salt compounded of iodine
Preparation process is as follows:
1.5-the preparation of aldehyde radical Dihydrobenzofuranes (2): method is with embodiment 1.
2.5-the preparation of benzylalcohol substituted-dihydro cumarone (3): method is with embodiment 1.
3.1-the preparation of (5-methyl substituted Dihydrobenzofuranes)-2-tolimidazole (5c): method is with embodiment 15.
The preparation of (4.1-5-methyl substituted Dihydrobenzofuranes)-3-(normal-butyl)-2-tolimidazole salt compounded of iodine (23):
1-(5-methyl substituted Dihydrobenzofuranes)-2-tolimidazole (5c, 264mg, 1mmol) is dissolved in to acetone (20ml), under stirring, add 1-iodo-n-butane (221mg, 1.2mmol), reaction stirring and refluxing 24 hours, be cooled to room temperature, have solid precipitation to separate out, filter, precipitation with washing with acetone for several times, dry, prepare white amorphous powder (23,399mg), yield 89%.
The white amorphous powder, molecular formula C 21H 25IN 2O.
1H-NMR(300MHz，CDCl 3)δ：8.06(1H，d，J＝7.2Hz)，7.96(1H，d，J＝6.9Hz)，7.64-7.60(2H，m)，7.26(1H，s)，7.16(1H，d，J＝8.1Hz)，6.75(1H，d，J＝8.1Hz)，5.67(2H，s)，4.50(4H，m)，3.13(2H，t，J＝8.4Hz)，2.99(3H，s)，1.82-1.77(2H，m)，1.42-1.35(2H，m)，0.92(3H，t，J＝7.2Hz).
13C?NMR(75MHz，DMSO)：δ160.01，151.40，130.82，128.27，127.65，126.12，125.84，124.53，113.24，113.09，109.00，71.15，48.03，45.11，30.52，28.88，19.23，13.52，10.88.
IR?v max(cm -1)：3427，3029，2950，1614，1480，1364，1241，1110，983，937，774.
ESI-MS(70eV)m/z：322[M+1-I] +，321[M-I] +.
Embodiment 191-(5-methyl substituted Dihydrobenzofuranes)-3-(phenacyl)-5,6-dimethylbenzimidazole bromine salt
Figure BSA00000807136800271
Preparation process is as follows:
1.5-the preparation of aldehyde radical Dihydrobenzofuranes (2): method is with embodiment 1.
2.5-the preparation of benzylalcohol substituted-dihydro cumarone (3): method is with embodiment 1.
(3.1-5-methyl substituted Dihydrobenzofuranes)-5, the preparation of 6-dimethylbenzimidazole (5d):
By 5-benzylalcohol substituted-dihydro cumarone (3,530mg, 3.53mmol) be dissolved in methylene dichloride (80ml), add triethylamine (1.51ml, 10.58mmol), under 0 ℃ of condition, stir after 5 minutes, dropwise add methylsulfonyl chloride (0.35ml, 4.24mmol), under room temperature, stirring reaction is after 12 hours, add methylene dichloride dilution (40ml), water and saturated common salt washing respectively, organic phase anhydrous Na SO 4Drying, filter, and after the solvent concentrating under reduced pressure, prepares methanesulfonates product (4); Methanesulfonates product (4) is dissolved in to toluene (80ml), add 5,6-dimethylbenzimidazole (1.54g, 10.58mmo l), stirring and refluxing reaction 36 hours, after the solvent concentrating under reduced pressure, through silica gel column chromatography (100-200 order), petroleum ether-ethyl acetate (3: 1 → 1: 1) is eluent, obtains white amorphous powder (5d, 834mg), yield 85%;
(4.1-5-methyl substituted Dihydrobenzofuranes)-3-(phenacyl)-5, the preparation of 6-dimethylbenzimidazole bromine salt (24):
By 1-(5-methyl substituted Dihydrobenzofuranes)-5,6-dimethylbenzimidazole (5d, 278mg, 1mmol) be dissolved in Isosorbide-5-Nitrae-dioxane (20ml), under stirring, add phenacyl bromide (238mg, 1.2mmol), reaction stirring and refluxing 24 hours, be cooled to room temperature, have solid precipitation to separate out, filter, precipitation with washing with acetone for several times, dry, prepare white amorphous powder (24,424mg), yield 89%.
The white amorphous powder, molecular formula C 26H 25BrN 2O 2.
1H-NMR(300MHz，CDCl 3)δ：10.86(s，1H)，8.15(d，2H，J＝7.5Hz)，7.65(dd，1H，J＝14.1，7.2Hz)，7.52(dd，2H，J＝15.0，7.5Hz)，7.39(d，2H，J＝6.9Hz)，7.29(s，1H)，7.22(d，1H，J＝7.8Hz)，6.76(d，1H，J＝8.1Hz)，6.56(s，2H)，5.57(s，2H)，4.55(2H，t，J＝8.8Hz)，3.19(2H，t，J＝8.8Hz)，2.39(s，3H)，2.36(s，3H).
13C?NMR(75MHz，CDCl 3)δ：190.23，161.06，142.02，137.60，137.31，134.78，133.53，131.00，129.31，129.17，128.94，128.67，125.40，123.86，113.15，113.03，109.72，71.67，53.64，51.37，29.46，20.67，20.56.
IRv max(cm -1)：3378，2976，2161，1826，1687，1555，1489，1348，1234，1112，994，940，856，758，687，639.
ESI-MS(70eV)m/z：398[M+1-Br] +，397[M-Br] +.
Embodiment 201-(5-methyl substituted Dihydrobenzofuranes)-3-(4-methoxybenzoyl methyl)-5,6-dimethylbenzimidazole bromine salt
Figure BSA00000807136800291
Preparation process is as follows:
1.5-the preparation of aldehyde radical Dihydrobenzofuranes (2): method is with embodiment 1.
2.5-the preparation of benzylalcohol substituted-dihydro cumarone (3): method is with embodiment 1.
(3.1-5-methyl substituted Dihydrobenzofuranes)-5, the preparation of 6-dimethylbenzimidazole (5d): method is with embodiment 19.
(4.1-5-methyl substituted Dihydrobenzofuranes)-3-(4-methoxybenzoyl methyl)-5, the preparation of 6-dimethylbenzimidazole bromine salt (25):
By 1-(5-methyl substituted Dihydrobenzofuranes)-5,6-dimethylbenzimidazole (5d, 278mg, 1mmol) be dissolved in Isosorbide-5-Nitrae-dioxane (20ml), under stirring, add 4-methoxybenzoyl monobromomethane (275mg, 1.2mmol), reaction stirring and refluxing 24 hours, be cooled to room temperature, have solid precipitation to separate out, filter, precipitation with washing with acetone for several times, dry, prepare white amorphous powder (25,476mg), yield 94%.
The white amorphous powder, molecular formula C 27H 27BrN 2O 3.
1H-NMR(300MHz，CDCl 3)δ：10.82(s，1H)，8.13(d，2H，J＝8.7Hz)，7.73(s，2H)，7.29(d，1H，J＝2.7Hz)，7.36(s，1H)，7.22(d，1H，J＝7.8Hz)，6.99(d，2H，J＝8.7Hz)，6.77(d，1H，J＝8.7Hz)，6.46(s，2H)，5.56(s，2H)，4.55(2H，t，J＝8.8Hz)，3.89(s，3H)，3.20(2H，t，J＝8.8Hz)，2.39(s，3H)，2.36(s，3H).
13C?NMR(75MHz，CDCl 3)δ：188.41，164.88，161.08，142.05，137.52，?137.23，131.17，129.31，128.97，128.63，126.50，125.42，123.83，114.45，113.15，113.05，109.72，71.68，55.66，53.24，51.36，29.47，20.67，20.56.
IRv max(cm -1)：3408，3130，2963，1680，1494，1441，1349，1242，1179，1122，1015，951，833，603.
ESI-MS(70eV)m/z：428[M+1-Br] +，427[M-Br] +.
Embodiment 211-(5-methyl substituted Dihydrobenzofuranes)-3-(4-(2-hydroxybenzoyl) methyl)-5,6-dimethylbenzimidazole bromine salt
Figure BSA00000807136800301
Preparation process is as follows:
1.5-the preparation of aldehyde radical Dihydrobenzofuranes (2): method is with embodiment 1.
2.5-the preparation of benzylalcohol substituted-dihydro cumarone (3): method is with embodiment 1.
(3.1-5-methyl substituted Dihydrobenzofuranes)-5, the preparation of 6-dimethylbenzimidazole (5d): method is with embodiment 19.
(4.1-5-methyl substituted Dihydrobenzofuranes)-3-(4-(2-hydroxybenzoyl) methyl)-5, the preparation of 6-dimethylbenzimidazole bromine salt (26):
By 1-(5-methyl substituted Dihydrobenzofuranes)-5,6-dimethylbenzimidazole (5d, 278mg, 1mmol) be dissolved in Isosorbide-5-Nitrae-dioxane (20ml), under stirring, add 4-(2-hydroxybenzoyl) monobromomethane (257mg, 1.2mmol), reaction stirring and refluxing 24 hours, be cooled to room temperature, have solid precipitation to separate out, filter, precipitation with washing with acetone for several times, dry, prepare white amorphous powder (26,433mg), yield 88%.
The white amorphous powder, molecular formula C 26H 25BrN 2O 3.
1H-NMR(300MHz，CDCl 3)δ：9.34(s，1H)，8.00(d，2H，J＝7.2Hz)，7.44(s，1H)，7.37(s，1H)，7.32(s，1H)，7.23(d，1H，J＝7.2Hz)，6.95?(d，2H，J＝8.4Hz)，6.78(d，1H，J＝7.2Hz)，6.18(s，2H)，5.58(s，2H)，4.57(2H，t，J＝8.8Hz)，3.21(2H，t，J＝8.8Hz)，2.41(s，3H)，2.38(s，3H).
13C?NMR(75MHz，CDCl 3)δ：191.80，167.32，164.48，144.93，141.30，140.98，134.72，132.96，132.36，132.14，128.72，127.70，119.52，116.51，113.29，75.18，56.21，54.65，33.90，24.03，23.90.
IR?v max(cm -1)：3397，3066，1680，1597，1491，1355，1235，1170，1110，938，837，727，593.
ESI-MS(70eV)m/z：414[M+1-Br] +，413[M-Br] +.
Embodiment 221-(5-methyl substituted Dihydrobenzofuranes)-3-(4-bromobenzene formyl methyl)-5,6-dimethylbenzimidazole bromine salt
Figure BSA00000807136800311
Preparation process is as follows:
1.5-the preparation of aldehyde radical Dihydrobenzofuranes (2): method is with embodiment 1.
2.5-the preparation of benzylalcohol substituted-dihydro cumarone (3): method is with embodiment 1.
(3.1-5-methyl substituted Dihydrobenzofuranes)-5, the preparation of 6-dimethylbenzimidazole (5d): method is with embodiment 19.
(4.1-5-methyl substituted Dihydrobenzofuranes)-3-(4-bromobenzene formyl methyl)-5, the preparation of 6-dimethylbenzimidazole bromine salt (27):
By 1-(5-methyl substituted Dihydrobenzofuranes)-5,6-dimethylbenzimidazole (5d, 278mg, 1mmol) be dissolved in Isosorbide-5-Nitrae-dioxane (20ml), under stirring, add 4-bromobenzene formyl monobromomethane (331mg, 1.2mmol), reaction stirring and refluxing 24 hours, be cooled to room temperature, have solid precipitation to separate out, filter, precipitation with washing with acetone for several times, dry, prepare white amorphous powder (27,482mg), yield 87%.
The white amorphous powder, molecular formula C 26H 24Br 2N 2O 2.
1H-NMR(300MHz，CDCl 3)δ：9.68(s，1H)，8.05(d，2H，J＝8.7Hz)，7.75(d，2H，J＝8.7Hz)，7.54(s，1H)，7.50(s，1H)，7.34(s，1H)，7.25(d，1H，J＝8.1Hz)，6.80(d，1H，J＝8.4Hz)，6.63(s，2H)，5.61(s，2H)，4.59(2H，t，J＝8.8Hz)，3.23(2H，t，J＝8.8Hz)，2.45(s，3H)，2.42(s，3H).
13C?NMR(75MHz，CDCl 3)δ：189.51，160.79，137.73，137.40，132.23，132.08，130.70，129.79，129.22，128.62，128.40，124.95，123.94，112.91，109.52，71.36，52.65，50.82，29.08，20.04，19.92.
IRv max(cm -1)：3117，2966，1690，1582，1489，1411，1393，1237，1113，1067，993，938，813，724.
ESI-MS(70eV)m/z：476[M+1-Br] +，475[M-Br] +.
Embodiment 231-(5-methyl substituted Dihydrobenzofuranes)-3-(naphthoyl methyl)-5,6-dimethylbenzimidazole bromine salt
Figure BSA00000807136800321
Preparation process is as follows:
1.5-the preparation of aldehyde radical Dihydrobenzofuranes (2): method is with embodiment 1.
2.5-the preparation of benzylalcohol substituted-dihydro cumarone (3): method is with embodiment 1.
(3.1-5-methyl substituted Dihydrobenzofuranes)-5, the preparation of 6-dimethylbenzimidazole (5d): method is with embodiment 19.
(4.1-5-methyl substituted Dihydrobenzofuranes)-3-(naphthoyl methyl)-5, the preparation of 6-dimethylbenzimidazole bromine salt (28):
By 1-(5-methyl substituted Dihydrobenzofuranes)-5,6-dimethylbenzimidazole (5d, 278mg, 1mmol) be dissolved in Isosorbide-5-Nitrae-dioxane (20ml), under stirring, add naphthoyl monobromomethane (298mg, 1.2mmol), reaction stirring and refluxing 24 hours, be cooled to room temperature, have solid precipitation to separate out, filter, precipitation with washing with acetone for several times, dry, prepare yellow amorphous powder (28,473mg), yield 90%.
Yellow amorphous powder, molecular formula C 30H 27BrN 2O 2.
1H-NMR(300MHz，DMSO)δ：9.73(s，1H)，8.05(s，1H)，8.23(d，1H，J＝6.6Hz)，8.14(d，1H，J＝7.8Hz)，8.08(s，2H)，7.93(s，2H)，7.75-7.71(m，2H)，7.46(s，1H)，7.35(d，1H，J＝7.5Hz)，6.83(d，1H，J＝7.5Hz)，6.51(s，2H)，5.74(s，2H)，4.54(2H，t，J＝7.5Hz)，3.21(2H，t，J＝7.5Hz)，2.42(s，3H)，2.36(s，3H).
13C?NMR(75MHz，DMSO)δ：191.17，160.16，141.97，136.63，136.39，135.55，132.01，131.05，130.83，130.67，129.67，129.33，128.74，128.33，127.85，127.36，125.54，123.31，113.49，113.33，109.18，71.23，53.21，49.72，40.36，40.09，38.97，38.70，28.86，19.92.
IR?v max(cm -1)：3411，3121，2959，1688，1580，1489，1359，1237，1186，1123，938，824，754，683，599.
ESI-MS(70eV)m/z：448[M+1-Br] +，447[M-Br] +.
Embodiment 241-(5-methyl substituted Dihydrobenzofuranes)-3-(2-bromobenzyl)-5,6-dimethylbenzimidazole bromine salt
Figure BSA00000807136800331
Preparation process is as follows:
1.5-the preparation of aldehyde radical Dihydrobenzofuranes (2): method is with embodiment 1.
2.5-the preparation of benzylalcohol substituted-dihydro cumarone (3): method is with embodiment 1.
(3.1-5-methyl substituted Dihydrobenzofuranes)-5, the preparation of 6-dimethylbenzimidazole (5d): method is with embodiment 19.
(4.1-5-methyl substituted Dihydrobenzofuranes)-3-(2-bromobenzyl)-5, the preparation of 6-dimethylbenzimidazole bromine salt (29):
By 1-(5-methyl substituted Dihydrobenzofuranes)-5,6-dimethylbenzimidazole (5d, 278mg, 1mmol) be dissolved in Isosorbide-5-Nitrae-dioxane (20ml), under stirring, add 2-bromine bromobenzyl (298mg, 1.2mmol), reaction stirring and refluxing 24 hours, be cooled to room temperature, have solid precipitation to separate out, filter, precipitation with washing with acetone for several times, dry, prepare yellow amorphous powder (29,442mg), yield 84%.
Yellow amorphous powder, molecular formula C 25H 24Br 2N 2O.
1H-NMR(300MHz，CDCl 3)δ：11.30(s，1H)，7.59(d，1H，J＝7.5Hz)，7.58(t，1H，J＝7.5Hz)，7.46(d，1H，J＝5.4Hz)，7.21-7.36(m，4H)，6.72(d，1H，J＝8.1Hz)，5.89(s，2H)，5.76(s，2H)，4.53(2H，t，J＝8.8Hz)，3.16(2H，t，J＝8.8Hz)，2.36(s，3H)，2.33(s，3H).
13C?NMR(75MHz，CDCl 3)δ：160.79，141.98，137.44，133.43，131.82，130.96，129.86，129.71，128.68，128.55，125.51，124.72，123.58，113.52，113.32，109.52，71.59，51.16，51.09，29.45，20.64.
IRv max(cm -1)：3412，3096，2957，2745，1834，1612，1552，1489，1439，1351，1237，1120，982，939，853，760，667，617.
ESI-MS(70eV)m/z：448[M+1-Br] +，447[M-Br] +.
Embodiment 251-(5-methyl substituted Dihydrobenzofuranes)-3-(4-nitrobenzyl)-5,6-dimethylbenzimidazole bromine salt
Preparation process is as follows:
1.5-the preparation of aldehyde radical Dihydrobenzofuranes (2): method is with embodiment 1.
2.5-the preparation of benzylalcohol substituted-dihydro cumarone (3): method is with embodiment 1.
(3.1-5-methyl substituted Dihydrobenzofuranes)-5, the preparation of 6-dimethylbenzimidazole (5d): method is with embodiment 19.
(4.1-5-methyl substituted Dihydrobenzofuranes)-3-(4-nitrobenzyl)-5, the preparation of 6-dimethylbenzimidazole bromine salt (30):
By 1-(5-methyl substituted Dihydrobenzofuranes)-5,6-dimethylbenzimidazole (5d, 278mg, 1mmol) be dissolved in Isosorbide-5-Nitrae-dioxane (20ml), under stirring, add 4-nitro bromobenzyl (254mg, 1.2mmol), reaction stirring and refluxing 24 hours, be cooled to room temperature, have solid precipitation to separate out, filter, precipitation with washing with acetone for several times, dry, prepare white amorphous powder (30,419mg), yield 85%.
The white amorphous powder, molecular formula C 26H 24BrN 3O 4.
1H-NMR(300MHz，CDCl 3)δ：10.56(s，1H)，8.21(d，2H，J＝8.4Hz)，7.69(d，2H，J＝8.4Hz)，7.46(s，1H)，7.39(s，1H)，7.34(s，1H)，7.26(d，1H，J＝8.1Hz)，6.78(d，1H，J＝8.1Hz)，5.98(s，2H)，5.64(s，2H)，4.58(2H，t，J＝8.8Hz)，3.21(2H，t，J＝8.8Hz)，2.39(s，3H)，2.37(s，3H).
13C?NMR(75MHz，CDCl 3)δ：164.90，152.06，144.90，144.12，142.00，133.77，132.96，132.72，132.62，129.28，128.25，117.43，116.89，113.65，75.57，55.21，53.91，33.29，24.45.
IRv max(cm -1)：3402，2953，1606，1524，1442，1346，1241，1110，855，807，713，610.
ESI-MS(70eV)m/z：443[M+1-Br] +，442[M-Br] +.
Embodiment 261-(5-methyl substituted Dihydrobenzofuranes)-3-(normal-butyl)-5,6-dimethylbenzimidazole salt compounded of iodine
Figure BSA00000807136800361
Preparation process is as follows:
1.5-the preparation of aldehyde radical Dihydrobenzofuranes (2): method is with embodiment 1.
2.5-the preparation of benzylalcohol substituted-dihydro cumarone (3): method is with embodiment 1.
(3.1-5-methyl substituted Dihydrobenzofuranes)-5, the preparation of 6-dimethylbenzimidazole (5d): method is with embodiment 19.
(4.1-5-methyl substituted Dihydrobenzofuranes)-3-(normal-butyl)-5, the preparation of 6-dimethylbenzimidazole salt compounded of iodine (31):
By 1-(5-methyl substituted Dihydrobenzofuranes)-5,6-dimethylbenzimidazole (5d, 278mg, 1mmol) be dissolved in Isosorbide-5-Nitrae-dioxane (20ml), under stirring, add 1-iodo-n-butane (221mg, 1.2mmol), reaction stirring and refluxing 24 hours, be cooled to room temperature, have solid precipitation to separate out, filter, precipitation with washing with acetone for several times, dry, prepare white amorphous powder (31,379mg), yield 82%.
The white amorphous powder, molecular formula C 22H 27IN 2O.
The Antitumor CTL activity experimental result of part of compounds:
Part of compounds has been carried out the Antitumor CTL activity screening of leukemia, liver cancer, lung cancer, mammary cancer and 5 kinds of cell strains of colorectal carcinoma, its 50 3nhibitory dose (IC according to the MTT method 50The value, μ M) measurement result with commercial cancer therapy drug---cis-platinum (DDP) is compared in following table 2.
Antitumor CTL activity data (the IC of table 2 part 5-substituted-dihydro cumarone-imidazole salts 50, μ M)
Figure BSA00000807136800371
Above data presentation, 5-substituted-dihydro cumarone-imidazole salt compound 14,15,16,22,27,28,29 has extraordinary extracorporeal anti-tumor cytotoxic activity; 17 couples of lung cancer cell line A-549 of compound have selecting cell cytotoxic activity preferably.Structure activity study shows, find that working as imidazole structure unit is 5, the 6-dimethylbenzimidazole, and when its 3-bit substituent is 2-bromobenzyl, naphthoyl methyl or 4-bromobenzene formyl methyl, imidazole salt compound and commercial cancer therapy drug---cis-platinum (DDP) is compared, and has extraordinary external anticancer physiologically active.
The foregoing is only preferred embodiment of the present invention, not in order to limit the present invention, all any modifications of doing within the spirit and principles in the present invention, be equal to and replace and improvement etc., within all should being included in protection scope of the present invention.

Claims (5)

1. a 5-substituted-dihydro cumarone-imidazole salt compound, is characterized in that, its general structure (I) or (II) expression:
Figure FSA00000807136700011
General structure (I):
When X=Br, R 1=phenacyl, 4-methoxybenzoyl methyl, 4-bromobenzene formyl methyl, naphthoyl methyl, 2-bromobenzyl;
When X=I, R 1=normal-butyl;
General structure (II):
Work as X=Br, R 2=H, R 3During=H, R 1=phenacyl, 4-methoxybenzoyl methyl, 4-bromobenzene formyl methyl, naphthoyl methyl, 2-bromobenzyl, 4-nitrobenzyl, allyl group;
Work as X=Br, R 2=CH 3, R 3During=H, R 1=phenacyl, 4-methoxybenzoyl methyl, naphthoyl methyl;
Work as X=Br, R 2=H, R 3=CH 3The time, R 1=phenacyl, 4-methoxybenzoyl methyl, 4-(2-hydroxybenzoyl) methyl, 4-bromobenzene formyl methyl, naphthoyl methyl, 2-bromobenzyl, 4-nitrobenzyl;
Work as X=I, R 2=H, R 3=H, CH 3The time, R 1=normal-butyl;
Work as X=I, R 2=CH 3, R 3During=H, R 1=normal-butyl.
2. the preparation method of a 5-substituted-dihydro cumarone-imidazole salt compound, is characterized in that, this preparation method comprises the following steps:
With 2, the 3-Dihydrobenzofuranes is raw material, with phosphorus oxychloride and N, the synthetic 5-aldehyde radical Dihydrobenzofuranes (Vilsmeier reaction) of dinethylformamide reaction, by it, with sodium borohydride reduction, be 5-benzylalcohol substituted-dihydro cumarone in alcoholic solution, with methylsulfonyl chloride, form methanesulfonates under dichloromethane solvent and triethylamine condition again, then with imidazoles or benzoglyoxaline or 2-tolimidazole or 5, synthetic 1-(the 5-substituted-dihydro cumarone) imidazoles of 6-dimethylbenzimidazole back flow reaction in acetonitrile or toluene solvant, on this basis with halides in acetone or toluene or 1, the synthetic 5-substituted-dihydro cumarone-imidazole salt compound of back flow reaction in 4-dioxane solvent.
3. preparation method as claimed in claim 2, is characterized in that, this preparation method further comprises:
The preparation of A, compound 5a-5d:
With 2,3-Dihydrobenzofuranes (1) is raw material, with phosphorus oxychloride and N, the dinethylformamide reaction prepares 5-aldehyde radical Dihydrobenzofuranes (2), it is prepared to 5-benzylalcohol substituted-dihydro cumarone (3) with sodium borohydride reduction in alcoholic solution, then under dichloromethane solvent and triethylamine condition, prepare methanesulfonates product (4) with methylsulfonyl chloride;
The methanesulfonates product of take is raw material, with imidazoles or benzoglyoxaline or 2-tolimidazole or 5, the synthetic 5-substituted-dihydro cumarone of 6-dimethylbenzimidazole back flow reaction in acetonitrile or toluene solvant-imidazoles composition: methanesulfonates product (4) is dissolved in acetonitrile or toluene solvant, add imidazoles or benzoglyoxaline or 2-tolimidazole or 5, the 6-dimethylbenzimidazole, consumption is the methanesulfonates product by mole ratio: imidazoles, benzoglyoxaline, 2-tolimidazole or 5, 6-dimethylbenzimidazole=1: 3, the consumption of acetonitrile or toluene is 50-100ml: 1g methanesulfonates product, stirring and refluxing reaction 24-48 hour, prepare 4 5-substituted-dihydro cumarone-imidazoles composition: 1-(5-methyl substituted Dihydrobenzofuranes) imidazoles (5a, molecular formula C 12H 12N 2O) or 1-(5-methyl substituted Dihydrobenzofuranes) benzoglyoxaline (5b, molecular formula C 16H 14N 2O) or 1-(5-methyl substituted Dihydrobenzofuranes)-2-tolimidazole (5c, molecular formula C 17H 16N 2O) or 1-(5-methyl substituted Dihydrobenzofuranes)-5,6-dimethylbenzimidazole (5d, molecular formula C 18H 18N 2O),
The preparation of B, compound 6-36:
The 5-substituted-dihydro cumarone-imidazoles composition of take is raw material, in acetone or toluene or 1, synthetic 5-substituted-dihydro cumarone-imidazole salts in 4-dioxane solvent: 5-substituted-dihydro cumarone-imidazoles composition (5a-5d) is dissolved in to acetone or toluene or 1, in 4-dioxane solvent, under stirring, add halogenated alkane, consumption by mole ratio is: 5-substituted-dihydro cumarone-imidazoles composition: halogenated alkane=1: 1.2, acetone or toluene or 1, 4-dioxane consumption is 50-200ml: 1g5-substituted-dihydro cumarone-imidazoles composition, reaction stirring and refluxing 24-48 hour, prepare 5-substituted-dihydro cumarone-imidazole salts (6-36).
4. preparation method as claimed in claim 3, is characterized in that, the 5-substituted-dihydro cumarone-imidazole salts prepared is: (molecular formula) C 20H 19BrN 2O 2, C 21H 21BrN 2O 3, C 20H 18Br 2N 2O 2, C 24H 21BrN 2O 2, C 19H 18Br 2N 2O, C 16H 21IN 2O, C 24H 21BrN 2O 2, C 25H 23BrN 2O 3, C 24H 29Br 2N 2O 2, C 28H 23BrN 2O 2, C 23H 20Br 2N 2O, C 23H 20BrN 3O 3, C 19H 19BrN 2O, C 20H 23IN 2O, C 25H 23BrN 2O 2, C 26H 25BrN 2O 3, C 29H 25BrN 2O 2, C 21H 25IN 2O, C 26H 25BrN 2O 2, C 27H 27BrN 2O 3, C 26H 25BrN 2O 3, C 26H 24Br 2N 2O 2, C 30H 27BrN 2O 2, C 25H 24Br 2N 2O, C 26H 24BrN 3O 4, C 22H 27IN 2O.
5. curing cancer drug that comprises 5-substituted-dihydro cumarone-imidazole salt compound claimed in claim 1.
CN2012104654778A 2012-11-19 2012-11-19 5-substituted dihydrobenzofuran-imidazolium salt compound and preparation method thereof Pending CN103408537A (en)

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