CN105622574A - 3-benzimidazole-2(1H)-quinolinone derivative and preparation method and application thereof - Google Patents

3-benzimidazole-2(1H)-quinolinone derivative and preparation method and application thereof Download PDF

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CN105622574A
CN105622574A CN201610078898.3A CN201610078898A CN105622574A CN 105622574 A CN105622574 A CN 105622574A CN 201610078898 A CN201610078898 A CN 201610078898A CN 105622574 A CN105622574 A CN 105622574A
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compound
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methyl
hydrogen
chloro
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CN105622574B (en
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张业
邝文彬
余砚成
黄日镇
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Guilin Medical University
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Guilin Normal College
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/04—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/04—Ortho-condensed systems
    • C07D491/056—Ortho-condensed systems with two or more oxygen atoms as ring hetero atoms in the oxygen-containing ring

Abstract

The invention discloses a 3-benzimidazole-2(1H)-quinolinone derivative and a preparation method and application thereof. The preparation method of the derivative includes: dissolving a 2(1H)-quinolinone derivative and an o-phenylenediamine derivative in an organic solvent, and reacting under the condition of heating to obtain the 3-benzimidazole-2(1H)-quinolinone derivative. Compared with common antitumor drug 5-FU and cisplatin, the derivative has the advantages that some derivatives in the derivative have more efficient activity, and have low toxicity on normal hepatocytes HL-7702. The 3-benzimidazole-2(1H)-quinolinone derivative is shown as in the following structural formula, wherein R1 is hydrogen, methyl and methoxyl, or forms 1,2-methylenedioxy with R2; R2 is hydrogen, or forms 1,2-methylenedioxy with the R1; R3 is hydrogen, methyl, methoxyl, fluoro, chloro, bromo, nitro or trifluoromethyl; R4 is hydrogen, methyl, methoxyl or chloro.

Description

3-benzimidazolyl-2 radicals (1H)-(E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide and its preparation method and application
Technical field
The present invention relates to pharmaceutical technology field, be specifically related to 3-benzimidazolyl-2 radicals (1H)-(E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide and its preparation method and application.
Background technology
Malignant tumor, also known as cancer, is one of the intractable diseases of serious harm people life in the world. It is reported have about 7,000,000 people to die from cancer every year in the world, and China has about 1,500,000 people to die from cancer every year. Simultaneously because antitumor drug exists the shortcomings such as toxic and side effects is big, drug resistance is strong, therefore the research and development of new type antineoplastic medicine are subject to showing great attention to of people.
Existing research shows, the antioxidant of good activity is candidate compound (Tyagi, the Y.K. of antitumor drug; Kumar, A.; Raj, H.G.; Vohra, P.; Gupta, G.; Kumari, R.; Kumar, P.; Gupta, R.K.Eur.J.Med.Chem.2005,40,413.). Finding in research at us early stage, 3-schiff bases-2 (1H)-(E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide has good oxidation activity (Zhang, Y.; Fang, Y.L.; Liang, H.; Wang, H.S.; Hu, K.; Liu, X.X.; Yi, X.H.; Peng, Y.Bioorg.Med.Chem.2013,23,107.). Additionally, research is it is also shown that 2 (1H)-(E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide have biological activity (DeRuiter, J.Brubaker, the A.N. such as anticancer, antioxidation, antiinflammatory; Whitmer, W.L.; Stein, J.L.; J.Med.Chem.1986,29,2024.; Zhang, Y.; Fang, Y.L.; Liang, H.; Wang, H.S.; Hu, K.; Liu, X.X.; Yi, X.H.; Peng, Y.Bioorg.Med.Chem.2013,23,107.; Hewawasam, P.; Fan, W.; Knipe, J.; Moon, L.S.; Boissard, G.C.; Gribkoff, K.V.; Starett, E.J.Bioorg.Med.Chem.Lett.2002,12,1779.). But at present still and there are no 3 upper functional groups benzimidazoles that introduce at 2 (1H)-quinolinones to prepare the open report of 2 (1H)-(E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide and application thereof.
Summary of the invention
The technical problem to be solved in the present invention is to provide 3-benzimidazolyl-2 radicals (the 1H)-(E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide of a series of novel structure and their preparation method and application.
The present invention relates to compound or its pharmaceutically acceptable salt shown in following formula (I):
Wherein,
R1For hydrogen (H), methyl (CH3), methoxyl group (OCH3) or and R2Form 1,2-methylene-dioxy (CH2-O-CH2);
R2For hydrogen (H) or and R1Form 1,2-methylene-dioxy (CH2-O-CH2);
R3For hydrogen (H), methyl (CH3), methoxyl group (OCH3), fluorine-based (F), chloro (Cl), bromo (Br), nitro (NO2) or trifluoromethyl (CF3);
R4For hydrogen (H), methyl (CH3), methoxyl group (OCH3) or chloro (Cl).
Shown in above-mentioned formula (I), the preparation method of compound is: compound shown in modus ponens (II) and compound shown in formula (III) are dissolved in organic solvent, react, namely obtain target product under heating condition;
Wherein,
R1For hydrogen (H), methyl (CH3), methoxyl group (OCH3) or and R2Form 1,2-methylene-dioxy (CH2-O-CH2);
R2For hydrogen (H) or and R1Form 1,2-methylene-dioxy (CH2-O-CH2);
R3For hydrogen (H), methyl (CH3), methoxyl group (OCH3), fluorine-based (F), chloro (Cl), bromo (Br), nitro (NO2) or trifluoromethyl (CF3);
R4For hydrogen (H), methyl (CH3), methoxyl group (OCH3) or chloro (Cl).
In preparation method of the present invention, the ratio of the amount of substance of compound shown in described formula (II) and compound shown in formula (III) is preferably 1:0.9��1.1. When the consumption of compound shown in formula (III) exceedes above-mentioned scope, reaction can also generate target product equally, simply can cause that the separating difficulty of postorder increases, also can reduce the product of target product.
In preparation method of the present invention, compound shown in described formula (II) can be specifically 3-carboxaldehyde radicals-2 (1H)-quinolinone, 3-carboxaldehyde radicals-6-methyl-2 (1H)-quinolinone, 3-carboxaldehyde radicals-6-methoxyl group-2 (1H)-quinolinone or 3-carboxaldehyde radicals-6,7-methylene-dioxy-2 (1H)-quinolinone. Shown in above-mentioned formula (II), compound can designed, designed synthetic route synthesize, it is also possible to reference to the paper (Zhang, the Y. that deliver before the present inventor; Fang, Y.L.; Liang, H.; Wang, H.S.; Hu, K.; Liu, X.X.; Yi, X.H.; Peng, Y.Bioorg.Med.Chem.2013,23,107) it is prepared, concrete synthetic route is:
Wherein, R is worked as1For H, R2During for H, product is 3-carboxaldehyde radicals-2 (1H)-quinolinone; Work as R1For methyl, R2During for H, product is 3-carboxaldehyde radicals-6 methyl-2 (1H)-quinolinone; Work as R1For methoxyl group, R2During for H, product is 3-carboxaldehyde radicals-6 methoxyl group-2 (1H)-quinolinone; And work as R1With R2When forming 1,2-methylene-dioxy, product is 3-carboxaldehyde radicals-6,7-methylene-dioxy-2 (1H)-quinolinone.
In preparation method of the present invention, compound shown in described formula (III) can be without the O-phenylene diamine derivatives replaced, 4 mono-substituted O-phenylene diamine derivatives or 4,5 disubstituted O-phenylene diamine derivatives. Specifically, can be o-phenylenediamine, 4-fluorine o-phenylenediamine, 4-chlorine o-phenylenediamine, 4-bromine o-phenylenediamine, NPD, 4-trifluoromethyl o-phenylenediamine, 4,5-dimethyl o-phenylenediamine, 4,5-dimethoxy o-phenylenediamines or 4,5-dichloride base o-phenylenediamines etc.
In preparation method of the present invention, described organic solvent can be alcohols solvent and/or aprotic polar solvent. Wherein, one or more the combination in described alcohols solvent can be chosen from methanol that volumetric concentration is 80��100%, volumetric concentration is 80��100% ethanol, normal propyl alcohol, n-butyl alcohol and ethylene glycol monomethyl ether; Described aprotic polar solvent can be one or more the combination in N,N-dimethylformamide, DMAC N,N' dimethyl acetamide, dimethyl sulfoxide, oxolane and toluene. Combination more than be chosen as in above-mentioned alcohols solvent two kinds of materials of organic solvent, or be the combination of more than two kinds of materials in above-mentioned aprotic polar solvent, or be one or more in alcohols solvent with one or more combination in aprotic polar solvent time, the proportioning between them can be any proportioning.
In preparation method of the present invention, the consumption of polar solvent can be determined as required, under normal circumstances, shown in the formula (II) of 1mmol, the compound organic solvent of 5��15mL shown in the formula (III) of compound and 0.9��1.1mmol dissolves. In concrete dissolving step, compound shown in formula (II) and compound shown in formula (III) can be dissolved with partial solvent respectively, remix and react together; Also organic solvent dissolution is added again after compound shown in formula (II) and compound shown in formula (III) can be mixed.
In preparation method of the present invention, described reaction generally carries out in conventional reactor, and whether reaction can adopt thin layer chromatography tracing detection completely. In order to accelerate response speed, reaction preferably is in 50 DEG C and carries out (time that reaction extremely typically requires 5��10h completely with this understanding) to the boiling point temperature range of organic solvent, carries out and more preferably in the boiling point temperature range of 70 DEG C to organic solvent. After completion of the reaction, gained reactant filters, collect solid, washing (washing typically by dehydrated alcohol, absolute methanol or water etc.), dry and (can naturally dry or dry, when adopting drying mode, dry temperature to be advisable less than 50 DEG C), it is final target product.
The especially preferred described reaction of speed in order to further speed up reaction is to carry out when heating and being ultrasonic. Described ultrasonic frequency is preferably 40��65kHz, and power is preferably 240��600W, more preferably 420��600W; When reaction is under above-mentioned ultrasound condition and when temperature carries out at the boiling point temperature range of 50 DEG C to organic solvent, reaction is to completely about needing 1��1.5h.
Present invention additionally comprises compound shown in above-mentioned formula (I) or the application in preparing antitumor drug of its pharmaceutically acceptable salt.
The present invention farther includes the antitumor drug prepared with compound or its pharmaceutically acceptable salt shown in above-mentioned formula (I) for effective ingredient.
Compared with prior art, the invention provides 3-benzimidazolyl-2 radicals (the 1H)-(E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide of a series of novel structure, its manufacturing cycle is short, and post processing is simple, and cost is low, and gained derivant purity is high, steady quality; Applicant further found that, derivant of the present invention can improve the anti-tumor activity of 3-carboxaldehyde radicals-2 (1H)-quinolinone skeleton, compared with conventional antitumor drug 5-FU and cisplatin, the activity of some derivant is higher and the toxicity of people normal cell lines of human liver HL-7702 is lower, there is good potential medical value, be expected to the preparation for various antitumor drug.
Detailed description of the invention
Below in conjunction with specific embodiment, the present invention is described in further detail, and to be more fully understood that present disclosure, but the present invention is not limited to following example.
In following embodiment, involved raw material 3-carboxaldehyde radicals-2 (1H)-quinolinone compound 1a represents, raw material 3-carboxaldehyde radicals-6-methyl-2 (1H)-quinolinone compound 2a represents, raw material 3-carboxaldehyde radicals-6-methoxyl group-2 (1H)-quinolinone compound 3a represents, raw material 3-carboxaldehyde radicals-6,7-methylene-dioxy-2 (1H)-quinolinone is (also referred to as 3-carboxaldehyde radicals-[1,3] dioxolanes also [6,7-g]-2 (1H)-quinolinones) represent with compound 4a, their preparation method is as follows respectively:
1, the preparation of 1a: by the POCl of 3.5mLDMF and 17mL3Mixing, after stirring, adds 2.03g acetanilide, is warming up to 90 DEG C, is heated to reflux 16h, pour in a large amount of frozen water after cooling, filter, obtain yellow powder. Being mixed with 70% acetum of 200mL by the yellow powder obtained, reflux 8h at 95 DEG C, and cooling obtains compound 1a yellow needles solid, and 91%.
Compound 1a:1HNMR(500MHz,DMSO-d6) ��: 12.22 (s, 1H, NH), 10.23 (s, 1H, CHO), 8.49 (s, 1H, C=CH), 7.91 (d, J=7.9Hz, 1H, Ar H), 7.65 (t, J=7.8Hz, 1H, Ar H), 7.35 (d, J=8.3Hz, 1H, Ar H), 7.25 (t, J=8.0Hz, 1H, Ar H);13CNMR(126MHz,DMSO-d6)��:190.24,161.90,142.92,141.60,134.16,131.38,126.07,123.14,118.60,115.89.MSm/z:174[M+H]+.
2, the preparation of 2a: the preparation process of reference compound 1a, so that the first and second anilides are replaced acetanilide, can prepare compound 2a, productivity 87%, and crystal structure is such as shown in formula:
Compound 2a:1HNMR (500MHz, DMSO) ��: 12.13 (s, 1H, NH), (10.22 s, 1H, CHO), 8.37 (s, 1H, C=CH), 7.65 (s, 1H, Ar H), 7.47 (d, J=8.5Hz, 1H, Ar H), 7.24 (d, J=8.4Hz, 1H, Ar H), 2.32 (s, 3H, CH3);13CNMR(126MHz,DMSO-d6)��:190.27,161.81,142.51,139.72,135.58,132.23,130.47,125.98,118.53,115.81,20.73.MSm/z:188[M+H]+.
3, the preparation of 3a: the preparation process of reference compound 1a, replaces acetanilide with methacetin, can prepare compound 3a, productivity 85%.
Compound 3a:1HNMR (500MHz, DMSO) ��: 12.15 (s, 1H, NH), (10.23 s, 1H, CHO), 8.38 (s, 1H, C=CH), 7.66 (s, 1H, Ar H), 7.48 (d, J=8.5Hz, 1H, Ar H), 7.25 (d, J=8.4Hz, 1H, Ar H), 3.77 (s, 3H, CH3);13CNMR(126MHz,DMSO-d6)��:189.25,161.80,143.51,138.98,135.58,132.23,130.47,125.98,118.53,116.78,55.72.MSm/z:204[M+H]+.
4, the preparation of 4a: the preparation process of reference compound 1a, replaces acetanilide with 3,4-methylene-dioxy acetanilide, can prepare compound 4a, productivity 82%.
Compound 4a:1HNMR(500MHz,d6-DMSO) ��: 12.13 (s, 1H, NH), 10.22 (s, 1H, CHO), 8.37 (s, 1H, C=CH), 7.65 (s, 1H, Ar H), 7.47 (d, J=8.5Hz, 1H, Ar H), 5.98 (s, 2H, OCH2O);13CNMR(126MHz,DMSO-d6)��190.27,161.81,142.51,139.72,135.58,132.23,130.47,125.98,118.53,115.81,20.73.MSm/z:218[M+H]+.
Embodiment 1:3-(5,6-dimethyl-1H-benzimidazolyl-2 radicals-Ji)-2 (1H)-quinolinone (compound 1a1) preparation
Weigh Compound 1a0.1g (0.58mmol), 4,5-dimethyl-1,2-neighbour's benzene two 0.09g (0.64mmol), 6mL absolute methanol are placed in pressure tube (tube sealing), temperature be 85 DEG C, supersonic frequency be 40kHz, ultrasonic power be 540W when reaction to (TLC tracing detection completely, about 1h), sucking filtration after cooling, with absolute ethanol washing, obtains compound 1a10.148g, productivity 88.3%.
Compound 1a1: Yields88.3%,1HNMR(500MHz,DMSO-d6) �� 12.42 (s, 2H, NH), 9.05 (s, 1H, H-Ar), 7.94 (d, J=7.2Hz, 1H, H-Ar), 7.60 (s, 1H, H-Ar), 7.43 (s, 3H, H-Ar), 7.28 (d, J=7.5Hz, 1H, H-Ar), 2.30 (s, 6H, 2CH3-);13CNMR(126MHz,DMSO-d6)��161.28,147.31,138.99,138.83,131.80,129.38,123.07,120.75,119.70,115.68,20.59.MSm/z:290[M+H]+.
Accordingly, it can be determined that above-claimed cpd 1a1For 3-(5,6-dimethyl-1H-benzimidazolyl-2 radicals-Ji)-2 (1H)-quinolinones, its structural formula is shown below:
Embodiment 2:3-(the chloro-1H-benzimidazolyl-2 radicals-Ji of 5,6-bis-)-2 (1H)-quinolinone (compound 1a2) preparation
Weigh Compound 1a0.1g (0.58mmol), 4,5-bis-chloro-1,2-o-phenylenediamine 0.11g (0.64mmol), 6mL absolute methanol are placed in pressure tube (tube sealing), stirring reaction (TLC tracing detection extremely completely under 80 DEG C of conditions, about 6h), sucking filtration after cooling, with absolute ethanol washing, obtains compound 1a20.136g, productivity 71.4%.
Compound 1a2: Yields71.4%,1HNMR(500MHz,DMSO-d6) �� 12.89 (s, 1H, NH), 12.53 (s, 1H, NH), 9.12 (s, 1H, H-Ar), 7.97 (d, J=7.1Hz, 1H, H-Ar), 7.93 (s, 2H, H-Ar), 7.64 (s, 1H, H-Ar), 7.45 (s, 1H, H-Ar), 7.30 (d, J=7.5Hz, 1H, H-Ar);13CNMR(126MHz,DMSO-d6)��161.26,161.10,153.43,150.77,140.59,139.42,132.54,129.75,124.91,123.23,119.61,119.48,115.81,115.31.MSm/z:330[M+H]+.
Accordingly, it can be determined that above-claimed cpd 1a2For 3-(5,6-bis-chloro-1H-benzimidazolyl-2 radicals-Ji)-2 (1H)-quinolinones, its structural formula is shown below:
Embodiment 3:3-(the fluoro-1H-benzimidazolyl-2 radicals-Ji of 5-)-2 (1H)-quinolinone (compound 1a3) preparation
Method with reference to embodiment 2, Weigh Compound 1a0.1g (0.58mmol), 5-fluoro-1,2-o-phenylenediamine 0.08g (0.64mmol), 10mL dehydrated alcohol are placed in pressure tube (tube sealing), stirring reaction (TLC tracing detection extremely completely under 80 DEG C of conditions, about 6h), sucking filtration after cooling, with absolute ethanol washing, obtains compound 1a30.116g, productivity 71.7%.
Compound 1a3: Yields71.7%,1HNMR(500MHz,DMSO-d6) �� 12.75 (s, 1H, NH), 12.49 (s, 1H, NH), 9.10 (s, 1H, H-Ar), 7.96 (d, J=7.9Hz, 1H, H-Ar), 7.58 (s, 5H, H-Ar), 7.30 (d, J=7.5Hz, 1H, H-Ar), 7.07 (s, 1H, H-Ar);13CNMR(126MHz,DMSO-d6)��161.23,161.15,139.96,139.47,139.24,135.08,134.96,132.23,131.67,129.60,129.55,123.15,120.25,115.75,110.56,103.89.MSm/z:280[M+H]+.
Accordingly, it can be determined that above-claimed cpd 1a3For 3-(the fluoro-1H-benzimidazolyl-2 radicals-Ji of 5-)-2 (1H)-quinolinones, its structural formula is shown below:
Embodiment 4:3-(the chloro-1H-benzimidazolyl-2 radicals-Ji of 5-)-2 (1H)-quinolinone (compound 1a4) preparation
Method with reference to embodiment 1, Weigh Compound 1a0.1g (0.58mmol), 5-chloro-1,2-o-phenylenediamine 0.09g (0.64mmol), 6mL normal propyl alcohol are placed in pressure tube (tube sealing), temperature be 85 DEG C, supersonic frequency be 40kHz, ultrasonic power be 540W when reaction to (TLC tracing detection completely, about 1.5h), sucking filtration after cooling, with absolute ethanol washing, obtains compound 1a40.150g, productivity 87.7%.
Compound 1a4: Yields87.7%,1HNMR(500MHz,DMSO-d6) �� 12.80 (s, 1H, NH), 12.50 (s, 1H, NH), 9.12 (s, 1H, H-Ar), 7.98 (s, 1H, H-Ar), 7.75 (d, J=7.2Hz, 1H, H-Ar), 7.68 (s, 1H, H-Ar), 7.63 (s, 1H, H-Ar), 7.46 (s, 1H, H-Ar), 7.30 (d, J=7.5Hz, 1H, H-Ar), 7.23 (s, 1H, H-Ar);13CNMR(126MHz,DMSO-d6)��161.16,142.05,140.15,140.00,139.31,135.64,133.78,132.32,129.65,126.98,126.85,122.89,120.02,119.55,118.05,115.77.MSm/z:296[M+H]+.
Accordingly, it can be determined that above-claimed cpd 1a4For 3-(the chloro-1H-benzimidazolyl-2 radicals-Ji of 5-)-2 (1H)-quinolinones, its structural formula is shown below:
Embodiment 5:3-(the bromo-1H-benzimidazolyl-2 radicals-Ji of 5-)-2 (1H)-quinolinone (compound 1a5) preparation
Method with reference to embodiment 2, Weigh Compound 1a0.1g (0.58mmol), 5-bromo-1,2-o-phenylenediamine 0.12g (0.64mmol), 6mL dimethyl sulfoxide are placed in pressure tube (tube sealing), stirring reaction (TLC tracing detection extremely completely under 80 DEG C of conditions, about 7h), sucking filtration after cooling, uses anhydrous absolute ethanol washing, obtains compound 1a50.145g, productivity 73.5%.
Compound 1a5: Yields73.5%,1HNMR(500MHz,DMSO-d6) �� 12.80 (s, 1H, NH), 12.50 (s, 1H, NH), 9.12 (s, 1H, H-Ar), 7.96 (d, J=7.9Hz, 1H, H-Ar), 7.87 (s, 1H, H-Ar), 7.69 (d, J=8.5Hz, 1H, H-Ar), 7.63 (s, 1H, H-Ar), 7.44 (d, J=9.3Hz, 1H, H-Ar), 7.34 (s, 1H, H-Ar), 7.30 (t, J=7.5Hz, 1H, H-Ar);13CNMR(126MHz,DMSO-d6)��161.17,142.33,140.18,140.09,139.30,136.17,134.07,132.33,129.66,125.45,125.34,123.18,121.05,120.46,119.56,119.54.MSm/z:340[M+H]+.
Accordingly, it can be determined that above-claimed cpd 1a5For 3-(the bromo-1H-benzimidazolyl-2 radicals-Ji of 5-)-2 (1H)-quinolinones, its structural formula is shown below:
Embodiment 6:3-(5-nitro-1H-benzimidazolyl-2 radicals-Ji)-2 (1H)-quinolinone (compound 1a6) preparation
Method with reference to embodiment 2, Weigh Compound 1a0.1g (0.58mmol), 5-nitro-1,2-o-phenylenediamine 0.1g (0.64mmol), 5mLN, dinethylformamide is placed in pressure tube (tube sealing), under 70 DEG C of conditions, stirring reaction is extremely completely (TLC tracing detection, about 7h), sucking filtration after cooling, with absolute ethanol washing, obtain compound 1a60.123g, productivity 69.1%.
Compound 1a6: Yields69.1%,1HNMR(500MHz,DMSO-d6) �� 13.24 (s, 1H, NH), 12.56 (s, 1H, NH), 9.19 (s, 1H, H-Ar), 8.94 (s, 1H, H-Ar), 8.15 (s, 1H, H-Ar), 8.00 (s, 1H, H-Ar), 7.95 (d, J=7.9Hz, 1H, H-Ar), 7.66 (s, 1H, H-Ar), 7.46 (s, 1H, H-Ar), 7.31 (d, J=7.5Hz, 1H, H-Ar);13CNMR(126MHz,DMSO-d6)��161.06,154.37,147.17,141.38,139.63,134.78,132.82,129.92,129.28,128.06,127.35,123.28,122.37,119.44,118.27,115.86.MSm/z:307[M+H]+.
Accordingly, it can be determined that above-claimed cpd 1a6For 3-(5-nitro-1H-benzimidazolyl-2 radicals-Ji)-2 (1H)-quinolinones, its structural formula is shown below:
Embodiment 7:3-(5,6-dimethyl-1H-benzimidazolyl-2 radicals-Ji)-6 methyl-2 (1H)-quinolinone (compound 2a1) preparation
Method with reference to embodiment 2, Weigh Compound 2a0.1g (0.54mmol), 4,5-dimethyl-1,2-o-phenylenediamine 0.08g (0.59mmol), 6mLN, N-dimethyl acetylamide are placed in pressure tube (tube sealing), stirring reaction (TLC tracing detection extremely completely under 80 DEG C of conditions, about 7h), sucking filtration after cooling, with absolute ethanol washing, obtains compound 2a10.118g, productivity 72.1%.
Compound 2a1: Yields72.1%,1HNMR(500MHz,DMSO-d6) �� 12.40 (s, 1H, NH), 12.35 (s, 1H, NH), 8.96 (s, 1H, H-Ar), 7.71 (s, 1H, H-Ar), 7.49 (s, 1H, H-Ar), 7.43 (d, J=8.4Hz, 2H, H-Ar), 7.34 (d, J=8.4Hz, 1H, H-Ar), 2.35 (s, 9H, 3CH3-);13CNMR(126MHz,DMSO-d6)��161.17,147.44,142.05,138.52,137.07,133.21,132.14,128.62,120.65,119.66,118.79,115.62,113.05,20.94,20.62.MSm/z:304[M+H]+.
Accordingly, it can be determined that above-claimed cpd 2a1For 3-(5,6-dimethyl-1H-benzimidazolyl-2 radicals-Ji)-6 methyl-2 (1H)-quinolinones, its structural formula is shown below:
Embodiment 8:3-(the chloro-1H-benzimidazolyl-2 radicals-Ji of 5,6-bis-)-6 methyl-2 (1H)-quinolinone (compound 2a2) preparation
Method with reference to embodiment 2, Weigh Compound 2a0.1g (0.54mmol), 4,5-bis-chloro-1,2-o-phenylenediamine 0.1g (0.59mmol), 6mL volumetric concentration be 80% methanol be placed in pressure tube (tube sealing), under 50 DEG C of conditions, stirring reaction is extremely completely (TLC tracing detection, about 9h), sucking filtration after cooling, use anhydrous absolute ethanol washing, obtain compound 2a20.117g, productivity 63.4%.
Compound 2a2: Yields63.4%,1HNMR(500MHz,DMSO-d6)��12.47(s,1H,NH),12.20(s,1H,NH),9.03(s,1H,H-Ar),7.93(s,1H,H-Ar),7.75(s,1H,H-Ar),7.46(s,2H,H-Ar),7.12(s,1H,H-Ar),2.36(s,3H,CH3-);13CNMR(126MHz,DMSO-d6)��161.12,142.57,140.32,137.97,134.01,133.69,132.36,128.95,128.54,128.06,125.69,123.32,118.97,118.89,20.91.MSm/z:344[M+H]+.
Accordingly, it can be determined that above-claimed cpd 2a2For 3-(5,6-bis-chloro-1H-benzimidazolyl-2 radicals-Ji)-6 methyl-2 (1H)-quinolinones, its structural formula is shown below:
Embodiment 9:3-(the fluoro-1H-benzimidazolyl-2 radicals-Ji of 5-)-6 methyl-2 (1H)-quinolinone (compound 2a3) preparation
Method with reference to embodiment 2, Weigh Compound 2a0.1g (0.54mmol), 5-fluoro-1,2-o-phenylenediamine 0.07g (0.59mmol), 8mL toluene are placed in pressure tube (tube sealing), stirring reaction (TLC tracing detection extremely completely under 80 DEG C of conditions, about 8h), sucking filtration after cooling, with absolute ethanol washing, obtains compound 2a30.114g, productivity 71.9%.
Compound 2a3: Yields71.9%,1HNMR(500MHz,DMSO-d6) �� 12.74 (s, 1H, NH), 12.42 (s, 1H, NH), 9.00 (s, 1H, H-Ar), 7.75 (s, 1H, H-Ar), 7.65 (s, 1H, H-Ar), 7.50 (s, 1H, H-Ar), 7.45 (d, J=8.4Hz, 1H, H-Ar), 7.35 (d, J=8.4Hz, 1H, H-Ar), 7.07 (s, 1H, H-Ar), 2.38 (s, 3H, CH3-);13CNMR(126MHz,DMSO-d6)��161.03,158.24,139.97,139.56,139.14,134.93,133.64,133.55,132.24,131.64,128.80,128.76,120.13,115.68,110.51,103.89,20.91.MSm/z:294[M+H]+.
Accordingly, it can be determined that above-claimed cpd 2a3For 3-(the fluoro-1H-benzimidazolyl-2 radicals-Ji of 5-)-6 methyl-2 (1H)-quinolinones, its structural formula is shown below:
Embodiment 10:3-(the chloro-1H-benzimidazolyl-2 radicals-Ji of 5-)-6 methyl-2 (1H)-quinolinone (compound 2a4) preparation
Method with reference to embodiment 2, Weigh Compound 2a0.1g (0.54mmol), 5-chloro-1,2-o-phenylenediamine 0.08g (0.59mmol), 6mL volumetric concentration be 90% ethanol be placed in pressure tube (tube sealing), stirring reaction (TLC tracing detection extremely completely under 45 DEG C of conditions, about 10h), sucking filtration after cooling, with absolute ethanol washing, obtains compound 2a40.115g, productivity 68.7%.
Compound 2a4: Yields68.7%,1HNMR(500MHz,DMSO-d6) �� 12.79 (s, 1H, NH), 12.43 (s, 1H, NH), 9.02 (s, 1H, H-Ar), 7.79 (s, 1H, H-Ar), 7.73 (s, 1H, H-Ar), 7.67 (s, 1H, H-Ar), 7.46 (d, J=8.4Hz, 1H, H-Ar), 7.35 (d, J=8.4Hz, 1H, H-Ar), 7.22 (s, 1H, H-Ar), 2.38 (s, 3H, CH3-);13CNMR(126MHz,DMSO-d6)��161.04,142.06,139.82,139.67,137.37,133.74,132.27,128.86,126.94,126.82,122.83,122.71,120.00,118.04,115.70,20.92.MSm/z:310[M+H]+.
Accordingly, it can be determined that above-claimed cpd 2a4For 3-(the chloro-1H-benzimidazolyl-2 radicals-Ji of 5-)-6 methyl-2 (1H)-quinolinones, its structural formula is shown below:
Embodiment 11:3-(the bromo-1H-benzimidazolyl-2 radicals-Ji of 5-)-6 methyl-2 (1H)-quinolinone (compound 2a5) preparation
Method with reference to embodiment 2, Weigh Compound 2a0.1g (0.54mmol), 5-bromo-1,2-o-phenylenediamine 0.11g (0.59mmol), 6mL volumetric concentration be 95% methanol be placed in pressure tube (tube sealing), stirring reaction (TLC tracing detection extremely completely under 85 DEG C of conditions, about 6h), sucking filtration after cooling, with absolute ethanol washing, obtains compound 2a50.137g, productivity 71.8%.
Compound 2a5: Yields71.8%,1HNMR(500MHz,DMSO-d6) �� 12.80 (s, 1H, NH), 12.43 (s, 1H, NH), 9.02 (s, 1H, H-Ar), 7.90 (s, 1H, H-Ar), 7.72 (s, 1H, H-Ar), 7.70 (s, 1H, H-Ar), 7.47 (d, J=8.4Hz, 1H, H-Ar), 7.36 (d, J=8.4Hz, 1H, H-Ar), 7.33 (s, 1H, H-Ar), 2.38 (s, 3H, CH3-);13CNMR(126MHz,DMSO-d6)��161.05,142.33,139.86,139.76,137.40,134.04,133.75,132.29,128.87,128.83,125.40,125.31,121.04,119.51,115.87,115.71,20.92.MSm/z:354[M+H]+.
Accordingly, it can be determined that above-claimed cpd 2a5For 3-(the bromo-1H-benzimidazolyl-2 radicals-Ji of 5-)-6 methyl-2 (1H)-quinolinones, its structural formula is shown below:
Embodiment 12:3-(5-nitro-1H-benzimidazolyl-2 radicals-Ji)-6 methyl-2 (1H)-quinolinone (compound 2a6) preparation
Method with reference to embodiment 2, Weigh Compound 2a0.1g (0.54mmol), 5-nitro-1,2-o-phenylenediamine 0.09g (0.59mmol), 15mL normal propyl alcohol are placed in pressure tube (tube sealing), reaction is (TLC tracing detection extremely completely, about 6h), sucking filtration after cooling, washes with water, obtains compound 2a60.114g, productivity 66.2%.
Compound 2a6: Yields66.2%,1HNMR(500MHz,DMSO-d6) �� 12.41 (s, 1H, NH), 12.09 (s, 1H, NH), 8.91 (s, 1H, H-Ar), 7.93 (s, 1H, H-Ar), 7.57 (s, 1H, H-Ar), 7.42 (d, J=8.4Hz, 1H, H-Ar), 7.27 (d, J=8.4Hz, 1H, H-Ar), 6.87 (s, 1H, H-Ar), 6.79 (s, 1H, H-Ar), 2.38 (s, 3H, CH3-);13CNMR(126MHz,DMSO-d6)��161.87,154.43,151.54,138.98,138.44,136.47,134.45,133.87,131.95,129.18,126.76,124.94,119.42,115.72,113.34,113.17,20.85.MSm/z:321[M+H]+.
Accordingly, it can be determined that above-claimed cpd 2a6For 3-(5-nitro-1H-benzimidazolyl-2 radicals-Ji)-6 methyl-2 (1H)-quinolinones, its structural formula is shown below:
Embodiment 13:3-(5,6-dimethyl-1H-benzimidazolyl-2 radicals-Ji)-6 methoxyl group-2 (1H)-quinolinone (compound 3a1) preparation
Method with reference to embodiment 2, Weigh Compound 3a0.1g (0.49mmol), 4,5-bis-chloro-1,2-neighbour's benzene two 0.1g (0.73mmol), 6mL absolute methanol are placed in pressure tube (tube sealing), under 85 DEG C of conditions, stirring reaction is extremely completely (TLC tracing detection, about 7h), sucking filtration after cooling, with absolute ethanol washing, obtain compound 3a10.141g, productivity 80.3%.
Compound 3a2: Yields80.3%,1HNMR(500MHz,DMSO-d6) �� 12.31 (s, 1H, NH), 11.74 (s, 1H, NH), 9.08 (s, 1H, H-Ar), 8.22 (s, 1H, H-Ar), 7.85 (s, 1H, H-Ar), 7.62 (s, 1H, H-Ar), 7.38 (d, J=9.0Hz, 1H, H-Ar), 7.28 (d, J=8.9Hz, 1H, H-Ar), 3.76 (s, 3H, CH3-),2.36(s,6H,CH3-);13CNMR(126MHz,DMSO-d6)��160.61,155.22,142.63,140.07,136.07,135.82,134.14,132.96,128.54,125.72,125.10,122.31,117.16,117.08,113.32,110.44,56.04,21.90.MSm/z:321[M+H]+.
Accordingly, it can be determined that above-claimed cpd 3a1For 3-(5,6-dimethyl-1H-benzimidazolyl-2 radicals-Ji)-6 methoxyl group-2 (1H)-quinolinones, its structural formula is shown below:
Embodiment 14:3-(the chloro-1H-benzimidazolyl-2 radicals-Ji of 5,6-bis-)-6-methoxyl group-2 (1H)-quinolinone (compound 3a2) preparation
Method with reference to embodiment 2, Weigh Compound 3a0.1g (0.49mmol), 4,5-bis-chloro-1,2-o-phenylenediamine 0.1g (0.54mmol), 6mL dimethyl sulfoxide and 2mLN, dinethylformamide is placed in pressure tube (tube sealing), reaction (TLC tracing detection extremely completely under 80 DEG C of conditions, about 6h), sucking filtration after cooling, with absolute ethanol washing, obtains compound 3a20.124g, productivity 70.3%.
Compound 3a2: Yields70.3%,1HNMR(500MHz,DMSO-d6) �� 12.31 (s, 1H, NH), 11.74 (s, 1H, NH), 9.08 (s, 1H, H-Ar), 8.22 (s, 1H, H-Ar), 7.85 (s, 1H, H-Ar), 7.62 (s, 1H, H-Ar), 7.38 (d, J=9.0Hz, 1H, H-Ar), 7.28 (d, J=8.9Hz, 1H, H-Ar), 3.76 (s, 3H, CH3-);13CNMR(126MHz,DMSO-d6)��160.61,155.22,142.63,140.07,136.07,135.82,134.14,132.96,128.54,125.72,125.10,122.31,117.16,117.08,113.32,110.44,56.04.MSm/z:360[M+H]+.
Accordingly, it can be determined that above-claimed cpd 3a2For 3-(5,6-bis-chloro-1H-benzimidazolyl-2 radicals-Ji)-6 methoxyl group-2 (1H)-quinolinones, its structural formula is shown below:
Embodiment 15:3-(the fluoro-1H-benzimidazolyl-2 radicals-Ji of 5-)-6 methoxyl group-2 (1H)-quinolinone (compound 3a3) preparation
Method with reference to embodiment 2, Weigh Compound 3a0.1g (0.49mmol), 5-fluoro-1,2-o-phenylenediamine 0.07g (0.54mmol), 2mL dimethyl sulfoxide, 2mL dehydrated alcohol and 2mL absolute methanol are placed in pressure tube (tube sealing), stirring reaction (TLC tracing detection extremely completely under 80 DEG C of conditions, about 8h), sucking filtration after cooling, with absolute ethanol washing, obtains compound 3a30.110g, productivity 72.6%.
Compound 3a3: Yields72.6%,1HNMR(500MHz,DMSO-d6) �� 12.76 (s, 1H, NH), 12.40 (s, 1H, NH), 9.06 (s, 1H, H-Ar), 7.68 (s, 1H, H-Ar), 7.51 (s, 1H, H-Ar), 7.45 (s, 1H, H-Ar), 7.38 (d, J=9.0Hz, 1H, H-Ar), 7.26 (d, J=8.6Hz, 1H, H-Ar), 7.07 (s, 1H, H-Ar), 3.83 (s, 3H, CH3-);13CNMR(126MHz,DMSO-d6)��160.75,155.18,143.59,139.38,138.95,133.92,131.63,121.92,121.83,120.40,120.20,117.09,110.36,103.89,56.03.MSm/z:310[M+H]+.
Accordingly, it can be determined that above-claimed cpd 3a3For 3-(the fluoro-1H-benzimidazolyl-2 radicals-Ji of 5-)-6-methoxyl group-2 (1H)-quinolinone, its structural formula is shown below:
Embodiment 16:3-(the chloro-1H-benzimidazolyl-2 radicals-Ji of 5-)-6 methoxyl group-2 (1H)-quinolinone (compound 3a4) preparation
Method with reference to embodiment 2, Weigh Compound 3a0.1g (0.49mmol), 5-chloro-1,2-o-phenylenediamine 0.08g (0.54mmol), 5mL volumetric concentration be 85% methanol and 5mL normal propyl alcohol be placed in pressure tube (tube sealing), reaction (TLC tracing detection extremely completely under 75 DEG C of conditions, about 7h), sucking filtration after cooling, with absolute ethanol washing, obtains compound 3a40.108g, productivity 67.7%.
Compound 3a4: Yields67.7%,1HNMR(500MHz,DMSO-d6) �� 12.81 (s, 1H, NH), 12.42 (s, 1H, NH), 9.08 (s, 1H, H-Ar), 7.68 (s, 2H, H-Ar), 7.52 (s, 1H, H-Ar), 7.36 (d, J=8.9Hz, 1H, H-Ar), 7.29 (d, J=9.0Hz, 1H, H-Ar), 7.22 (s, 1H, H-Ar), 3.83 (s, 3H, CH3-);13CNMR(126MHz,DMSO-d6)��160.69,155.19,139.56,134.00,126.89,122.78,122.02,120.18,117.11,110.40,56.03.MSm/z:326[M+H]+.
Accordingly, it can be determined that above-claimed cpd 3a4For 3-(the chloro-1H-benzimidazolyl-2 radicals-Ji of 5-)-6 methoxyl group-2 (1H)-quinolinones, its structural formula is shown below:
Embodiment 17:3-(the bromo-1H-benzimidazolyl-2 radicals-Ji of 5-)-6 methoxyl group-2 (1H)-quinolinone (compound 3a5) preparation
Method with reference to embodiment 2, Weigh Compound 3a0.1g (0.49mmol), 5-bromo-1,2-o-phenylenediamine 0.1g (0.54mmol), 5mL toluene and 5mLN, dinethylformamide is placed in pressure tube (tube sealing), under 100 DEG C of conditions, stirring reaction is extremely completely (TLC tracing detection, about 5h), sucking filtration after cooling, with absolute ethanol washing, obtain compound 3a50.133g, productivity 73.3%.
Compound 3a5: Yields73.3%,1HNMR(500MHz,DMSO-d6) �� 12.82 (s, 1H, NH), 12.41 (s, 1H, NH), 9.08 (s, 1H, H-Ar), 7.87 (s, 1H, H-Ar), 7.65 (s, 1H, H-Ar), 7.51 (s, 1H, H-Ar), 7.38 (d, J=8.9Hz, 1H, H-Ar), 7.34 (d, J=8.5Hz, 1H, H-Ar), 7.27 (s, 1H, H-Ar), 3.82 (s, 3H, CH3-);13CNMR(126MHz,DMSO-d6)��160.68,155.19,139.61,134.01,125.36,122.03,120.17,120.13,117.11,114.81,110.39,56.03.MSm/z:370[M+H]+.
Accordingly, it can be determined that above-claimed cpd 3a5For 3-(the bromo-1H-benzimidazolyl-2 radicals-Ji of 5-)-6-methoxyl group-2 (1H)-quinolinone, its structural formula is shown below:
Embodiment 18:3-(5-nitro-1H-benzimidazolyl-2 radicals-Ji)-6 methoxyl group-2 (1H)-quinolinone (compound 3a6) preparation
Method with reference to embodiment 2, Weigh Compound 3a0.1g (0.49mmol), 5-nitro-1,2-o-phenylenediamine 0.1g (0.54mmol), 1mL absolute methanol, 2mL dimethyl sulfoxide and 3mL toluene are placed in pressure tube (tube sealing), stirring reaction (TLC tracing detection extremely completely under 60 DEG C of conditions, about 7h), sucking filtration after cooling, with absolute ethanol washing, obtains compound 3a60.111g, productivity 67.7%.
Compound 3a6: Yields67.7%,1HNMR(500MHz,DMSO-d6) �� 12.07 (s, 1H, NH), 8.93 (s, 1H, NH), 8.91 (s, 1H, H-Ar), 7.93 (s, 1H, H-Ar), 7.31 (d, J=8.9Hz, 2H, H-Ar), 7.25 (d, J=8.8Hz, 1H, H-Ar), 6.86 (s, 1H, H-Ar), 6.79 (s, 1H, H-Ar), 3.82 (s, 3H, CH3-);13CNMR(126MHz,DMSO-d6)��161.56,154.94,154.40,151.56,138.77,136.51,135.12,134.40,127.08,124.96,122.21,120.01,117.15,113.37,113.16,110.46,55.94.MSm/z:337[M+H]+.
Accordingly, it can be determined that above-claimed cpd 3a6For 3-(5-nitro-1H-benzimidazolyl-2 radicals-Ji)-6-methoxyl group-2 (1H)-quinolinone, its structural formula is shown below:
Embodiment 19:3-(5,6-dimethyl-1H-benzimidazolyl-2 radicals-Ji)-[1,3] dioxolanes also [6,7-g]-2 (1H)-quinolinone (compound 4a1) preparation
Method with reference to embodiment 2, Weigh Compound 4a0.1g (0.46mmol), 4,5-dimethyl-1,2-o-phenylenediamine 0.07g (0.51mmol), 7mL ethylene glycol monomethyl ether are placed in pressure tube (tube sealing), under 85 DEG C of conditions, stirring reaction is extremely completely (TLC tracing detection, about 7h), sucking filtration after cooling, with absolute ethanol washing, obtain compound 4a10.113g, productivity 73.9%.
Compound 4a1: Yields73.9%,1HNMR(500MHz,DMSO-d6) �� 12.33 (s, 1H, NH), 11.93 (s, 1H, NH), 8.92 (s, 1H, H-Ar), 7.45 (s, 1H, H-Ar), 7.38 (s, 2H, H-Ar), 6.92 (d, J=9.0Hz, 1H, H-Ar), 6.13 (s, 2H ,-CH2-),2.30(s,6H,2CH3-);13CNMR(126MHz,DMSO-d6)��161.00,151.67,147.83,144.44,138.55,136.61,130.77,117.50,114.31,106.12,102.57,95.42,20.56.MSm/z:334[M+H]+.
Accordingly, it can be determined that above-claimed cpd 4a1For 3-(5,6-dimethyl-1H-benzimidazolyl-2 radicals-Ji)-[1,3] dioxolanes also [6,7-g]-2 (1H)-quinolinone, its structural formula is shown below:
Embodiment 20:3-(the chloro-1H-benzimidazolyl-2 radicals-Ji of 5,6-bis-)-[1,3] dioxolanes also [6,7-g]-2 (1H)-quinolinone (compound 4a2) preparation
Method with reference to embodiment 2, Weigh Compound 4a0.1g (0.46mmol), 4,5-bis-chloro-1,2-o-phenylenediamine 0.09g (0.51mmol), 6mL dehydrated alcohol are placed in pressure tube (tube sealing), under 65 DEG C of conditions, stirring reaction is extremely completely (TLC tracing detection, about 8h), sucking filtration after cooling, wash with anhydrous absolute methanol, obtain compound 4a20.119g, productivity 69.1%.
Compound 4a2: Yields69.1%,1HNMR(500MHz,DMSO-d6) �� 12.44 (s, 1H, NH), 11.71 (s1H, NH), 8.97 (s, 1H, H-Ar), 7.77 (s, 2H, H-Ar), 6.92 (d, J=9.0Hz, 1H, H-Ar), 6.66 (s, 1H, H-Ar), 6.14 (s, 1H ,-CH2-),6.05(s,1H,-CH2-);13CNMR(126MHz,DMSO-d6)��160.82,152.30,144.59,140.08,137.32,127.46,114.18,106.28,105.59,102.73,102.08,95.42.MSm/z:375[M+H]+.
Accordingly, it can be determined that above-claimed cpd 4a2For 3-(5,6-bis-chloro-1H-benzimidazolyl-2 radicals-Ji)-[1,3] dioxolanes also [6,7-g]-2 (1H)-quinolinone, its structural formula is shown below:
Embodiment 21:3-(the fluoro-1H-benzimidazolyl-2 radicals-Ji of 5-)-[1,3] dioxolanes also [6,7-g]-2 (1H)-quinolinone (compound 4a3) preparation
Method with reference to embodiment 2, Weigh Compound 4a0.1g (0.46mmol), 5-fluoro-1,2-o-phenylenediamine 0.06g (0.51mmol), 6mL absolute methanol are placed in pressure tube (tube sealing), stirring reaction (TLC tracing detection extremely completely under 85 DEG C of conditions, about 8h), sucking filtration after cooling, with absolute ethanol washing, obtains compound 4a30.109g, productivity 73.1%.
Compound 4a3: Yields73.1%,1HNMR(500MHz,DMSO-d6) �� 12.66 (s, 1H, NH), 12.29 (s, 1H, NH), 8.96 (s, 1H, H-Ar), 7.68 (s, 1H, H-Ar), 7.46 (s, 1H, H-Ar), 7.05 (s, 1H, H-Ar), 6.92 (d, J=9.0Hz, 1H, H-Ar), 6.84 (s, 1H, H-Ar), 6.10 (s, 2H ,-CH2-);13CNMR(126MHz,DMSO-d6)��160.89,152.01,144.52,143.65,139.49,137.00,127.74,114.22,106.21,105.58,102.65,95.43.MSm/z:324[M+H]+.
Accordingly, it can be determined that above-claimed cpd 4a3For 3-(the fluoro-1H-benzimidazolyl-2 radicals-Ji of 5-)-[1,3] dioxolanes also [6,7-g]-2 (1H)-quinolinone, its structural formula is shown below:
Embodiment 22:3-(the chloro-1H-benzimidazolyl-2 radicals-Ji of 5-)-[1,3] dioxolanes also [6,7-g]-2 (1H)-quinolinone (compound 4a4) preparation
Method with reference to embodiment 2, Weigh Compound 4a0.1g (0.46mmol), 5-chloro-1,2-o-phenylenediamine 0.07g (0.51mmol), 6mL absolute methanol are placed in pressure tube (tube sealing), reaction (TLC tracing detection extremely completely under 85 DEG C of conditions, about 8h), sucking filtration after cooling, with absolute ethanol washing, obtains compound 4a40.107g, productivity 68.3%.
Compound 4a4: Yields68.3%,1HNMR(500MHz,DMSO-d6) �� 12.70 (s, 1H, NH), 12.41 (s, 1H, NH), 8.98 (s, 1H, H-Ar), 7.72 (s, 1H, H-Ar), 7.61 (s, 1H, H-Ar), 7.45 (s, 1H, H-Ar), 7.20 (d, J=8.7Hz, 1H, H-Ar), 6.92 (d, J=8.9Hz, 1H, H-Ar), 6.12 (s, 2H ,-CH2-);13CNMR(126MHz,DMSO-d6)��160.89,152.10,144.54,142.14,139.71,137.10,126.65,122.51,119.72,117.80,114.22,106.24,102.68,95.42.MSm/z:340[M+H]+.
Accordingly, it can be determined that above-claimed cpd 4a4For 3-(the chloro-1H-benzimidazolyl-2 radicals-Ji of 5-)-[1,3] dioxolanes also [6,7-g]-2 (1H)-quinolinone, its structural formula is shown below:
Embodiment 23:3-(the bromo-1H-benzimidazolyl-2 radicals-Ji of 5-)-[1,3] dioxolanes also [6,7-g]-2 (1H)-quinolinone (compound 4a5) preparation
Method with reference to embodiment 2, Weigh Compound 4a0.1g (0.46mmol), 5-bromo-1,2-o-phenylenediamine 0.09g (0.51mmol), 6mL absolute methanol are placed in pressure tube (tube sealing), stirring reaction (TLC tracing detection extremely completely under 80 DEG C of conditions, about 8h), sucking filtration after cooling, with absolute ethanol washing, obtains compound 4a50.130g, productivity 73.8%.
Compound 4a5: Yields73.8%,1HNMR(500MHz,DMSO-d6) �� 12.71 (s, 1H, NH), 12.42 (s, 1H, NH), 8.99 (s, 1H, H-Ar), 7.86 (s, 1H, H-Ar), 7.64 (s, 1H, H-Ar), 7.46 (s, 1H, H-Ar), 7.31 (d, J=8.5Hz, 1H, H-Ar), 6.93 (d, J=9.0Hz, 1H, H-Ar), 6.16 (s, 2H ,-CH2-);13CNMR(126MHz,DMSO-d6)��160.89,152.12,144.55,139.72,137.12,125.12,116.66,114.56,114.22,106.25,102.69,95.43.MSm/z:384[M+H]+.
Accordingly, it can be determined that above-claimed cpd 4a5For 3-(the bromo-1H-benzimidazolyl-2 radicals-Ji of 5-)-[1,3] dioxolanes also [6,7-g]-2 (1H)-quinolinone, its structural formula is shown below:
Embodiment 24:3-(5-nitro-1H-benzimidazolyl-2 radicals-Ji)-[1,3] dioxolanes also [6,7-g]-2 (1H)-quinolinone (compound 4a6) preparation
Method with reference to embodiment 2, Weigh Compound 4a0.1g (0.46mmol), 5-nitro-1,2-o-phenylenediamine 0.08g (0.51mmol), 6mL absolute methanol are placed in pressure tube (tube sealing), stirring reaction (TLC tracing detection extremely completely under 60 DEG C of conditions, about 9h), sucking filtration after cooling, with absolute ethanol washing, obtains compound 4a60.109g, productivity 67.9%.
Compound 4a6: Yields67.9%,1HNMR(500MHz,DMSO-d6) �� 12.47 (s, 1H, NH), 11.82 (s, 1H, NH), 9.01 (s, 1H, H-Ar), 8.57 (s, 1H, H-Ar), 8.10 (d, J=8.9Hz, 1H, H-Ar), 7.82 (s, 1H, H-Ar), 7.47 (s, 1H, H-Ar), 6.91 (d, J=8.9Hz, 1H, H-Ar), 6.15 (s, 2H ,-CH2-);13CNMR(126MHz,DMSO-d6)��160.78,152.56,144.64,140.80,137.65,118.09,115.92,114.16,106.36,102.80,95.42.MSm/z:351[M+H]+.
Accordingly, it can be determined that above-claimed cpd 4a6For 3-(5-nitro-1H-benzimidazolyl-2 radicals-Ji)-[1,3] dioxolanes also [6,7-g]-2 (1H)-quinolinone, its structural formula is shown below:
For the antitumor action of 3-benzimidazolyl-2 radicals (1H)-(E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide of the present invention is described, anti-tumor activity experiment that the compound that above-claimed cpd 1a, 2a, 3a and 4a and above-described embodiment 1��24 are prepared by applicant has all carried out (with conventional antitumor drug 5-fluorouracil (5-FU) and cisplatin (Cis-platin) for reference), and the chemical combination that above-described embodiment is prepared is carried out Normocellular toxicity test. One, the anti tumor activity in vitro test of compound
1. the inoculation of cell and cultivation
Selected cell strain is placed in 37 DEG C, 5%CO2In incubator when abundant humidifying, it is inoculated in and cultivates containing in the 10% PPMI1640 culture fluid inactivateing new-born calf serum. With inverted microscope observation of cell growing state, change weekly 2��3 subcultures, within 6��7 days, go down to posterity once, go down to posterity with 0.25% trypsinization during inoculation, generally take and go down to posterity 3��4 times, be in exponential phase cell for testing.
2. the active primary dcreening operation of Compound cellular level
This tests the compound used, purity >=95%, all compounds are configured to 100 �� g/mL, cosolvent DMSO final concentration is less than 1%, test each compound suppression ratio to cancerous cell under this concentration, all suppression ratio are more than 50% and meet (such as cell shrinkage, broken, floating etc.) of cell under light microscopic suppressed (or impaired) metamorphosis, and to the less of compound of normal cytotoxicity, then preliminary judgement is that this compound primary dcreening operation is effective, namely enters next step and asks for IC50Stage.
3. cell growth inhibition test (mtt assay)
MTT colorimetry, is a kind of method detecting Growth of Cells and survival. Cleaning Principle: different from dead cell, exogenous MTT can be reduced to water-insoluble bluish violet crystallization first a ceremonial jade-ladle, used in libation (Formazan) by the succinate dehydrogenase in living cells mitochondrion and be deposited in cell. Dimethyl sulfoxide (DMSO) can dissolve the first a ceremonial jade-ladle, used in libation in cell, measures its absorbance value with enzyme-linked immunosorbent assay instrument at 490nm wavelength place, can indirectly reflect living cells quantity. Within the scope of certain cell number, the amount that MTT crystallization is formed is directly proportional to cell number. The method is widely used in the Activity determination of some bioactie agents, large-scale screening anti-tumor medicine, cell toxicity test and tumor radiosensitivity mensuration etc., has highly sensitive, economic dispatch feature.
Taking the cell being in exponential phase, every hole 180 �� L (about 4500-5000 cell) celliferous culture medium inoculated is in 96 well culture plates, in 37 DEG C, 5%CO224h is cultivated when abundant humidifying. After cell attachment, adding sample by the amount of every hole 20 �� L, each sample sets 6 multiple holes, concurrently sets corresponding blank. Continuing to cultivate after 48h, every hole adds 10 �� LMTT reagent (concentration is 5mg/mL), after continuing to hatch 4h, inhales and abandons supernatant, and every hole adds 150 �� LDMSO, slight concussion reaction 5��8min, makes crystalline particle fully dissolve. Blank group returns to zero, and measures the absorbance after removing bias light absorption value by microplate reader with 490nm wavelengthCalculate cell proliferation inhibition rate, the test-compound that primary dcreening operation antitumous effect is good, continue to continue to be the IC of corresponding cell strain with 5 Concentraton gradient50Value, all experiments are averaged after all repeating 3 times. Experimental result refers to table 1 below.
The table 1. compound semi-inhibit rate concentration (IC to different tumor cell lines50, ��M).
By data in table 1 it can be seen that in the inhibitory activity test experiments to human liver cancer cell HepG2, compound 1a3��1a4��1a5��2a4��4a1��4a2��4a3��4a4Showing good inhibitory activity, activity is significantly better than tumor Drugs 5-FU, wherein compound 1a4��1a5��4a3��4a4Activity and clinical anti-cancer drugs Cisplatin suitable, and the toxicity of people normal cell lines of human liver HL-7702 is significantly smaller than cisplatin and 5-FU by them; In the inhibitory activity test experiments to Proliferation of Human Ovarian Cell SKOV-3, compound 1a3��1a4��1a5��2a4��4a1��4a2��4a4Show good inhibitory activity, except compound 2a4Outward, the activity of these compounds is significantly better than tumor Drugs 5-FU, wherein compound 1a4��1a5��4a1Activity even better than clinical anti-cancer drugs Cisplatin, and the toxicity of people normal cell lines of human liver HL-7702 is significantly smaller than cisplatin and 5-FU by them; In the inhibitory activity test experiments to National People's Congress cell lung cancer cell NCI-H460, compound 1a3��1a4��1a5��2a4��4a1��4a2��4a4Showing good inhibitory activity, activity is significantly better than tumor Drugs 5-FU, wherein compound 1a4��1a5Activity even better than clinical anti-cancer drugs Cisplatin, and the toxicity of people normal cell lines of human liver HL-7702 is significantly smaller than cisplatin and 5-FU by them; In the inhibitory activity test experiments to human liver cancer cell BEL-7404, compound 1a3��1a4��1a5��2a4��4a1��4a2��4a3��4a4Showing good inhibitory activity, activity is significantly better than tumor Drugs 5-FU, wherein compound 4a2��4a3��4a4Activity even better than clinical anti-cancer drugs Cisplatin, and the toxicity of people normal cell lines of human liver HL-7702 is significantly smaller than cisplatin and 5-FU by them. Result above shows, it is feasible by benzimidazole functional group introducing 2 (1H)-quinolinone skeletons are prepared novel 3-o-phenylenediamine-2 (1H)-quinolinone antitumoral compounds, it is expected to filter out the new antitumoral compounds of high-efficiency low-toxicity, compared with conventional antitumor drug 5-FU and cisplatin, the activity of some 3-o-phenylenediamine-2 (1H)-(E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide is more efficient, and the toxicity of people normal cell lines of human liver HL-7702 is lower.

Claims (9)

1. compound or its pharmaceutically acceptable salt shown in following formula (I):
Wherein,
R1For hydrogen, methyl, methoxyl group or and R2Form 1,2-methylene-dioxy;
R2For hydrogen or and R1Form 1,2-methylene-dioxy;
R3For hydrogen, methyl, methoxyl group, fluorine-based, chloro, bromo, nitro or trifluoromethyl;
R4For hydrogen, methyl, methoxyl group or chloro.
2. the preparation method of compound described in claim 1, it is characterised in that: compound shown in modus ponens (II) and compound shown in formula (III) are dissolved in organic solvent, react, namely obtain target product under heating condition;
Wherein,
R1For hydrogen, methyl, methoxyl group or and R2Form 1,2-methylene-dioxy;
R2For hydrogen or and R1Form 1,2-methylene-dioxy;
R3For hydrogen, methyl, methoxyl group, fluorine-based, chloro, bromo, nitro or trifluoromethyl;
R4For hydrogen, methyl, methoxyl group or chloro.
3. preparation method according to claim 2, it is characterised in that: described organic solvent is alcohols solvent and/or aprotic polar solvent.
4. preparation method according to claim 3, it is characterised in that: one or more the combination in described alcohols solvent can be chosen from methanol that volumetric concentration is 80��100%, volumetric concentration is 80��100% ethanol, normal propyl alcohol, n-butyl alcohol and ethylene glycol monomethyl ether.
5. preparation method according to claim 3, it is characterised in that: described aprotic polar solvent is one or more the combination in DMF, N,N-dimethylacetamide, dimethyl sulfoxide, oxolane and toluene.
6. preparation method according to claims 2 to 5, it is characterised in that: described reaction carries out in the boiling point temperature range of 50 DEG C to organic solvent.
7. preparation method according to claims 2 to 5, it is characterised in that: described reaction carries out under ultrasound condition.
8. compound described in claim 1 or the application in preparing antitumor drug of its pharmaceutically acceptable salt.
9. the antitumor drug prepared with compound described in claim 1 or its pharmaceutically acceptable salt for effective ingredient.
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018042096A1 (en) * 2016-08-31 2018-03-08 Adpuerivitam 2-quinolin-2-one derivatives as modulators of nmda receptors, compositions comprising same and use of these compounds in the treatment of diseases involving the central nervous system
CN108003150A (en) * 2016-10-31 2018-05-08 河南工业大学 The preparation method and applications of 4- heteroaryl qualone derivatives
CN109020997A (en) * 2018-07-05 2018-12-18 桂林医学院 3- benzimidazole -6,7- piperonyl cyclonene -2 (1H)-quinolinone-Zn complex and its preparation method and application
CN112608252A (en) * 2020-12-15 2021-04-06 广西师范大学 4-nitroaniline derivative and synthesis method and application thereof

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6479512B1 (en) * 1999-10-19 2002-11-12 Merck & Co., Inc. Tyrosine kinase inhibitors
CN104817535A (en) * 2015-03-19 2015-08-05 广西师范大学 Quinolinone derivative, and synthetic method and application thereof

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6479512B1 (en) * 1999-10-19 2002-11-12 Merck & Co., Inc. Tyrosine kinase inhibitors
CN104817535A (en) * 2015-03-19 2015-08-05 广西师范大学 Quinolinone derivative, and synthetic method and application thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RODRIGO ABONIA ET AL.: "A Simple One-Pot Synthesis of New Imidazol-2-yl-1H-quinolin-2-ones from the Direct Reaction of 2-Chloroquinolin-3-carbaldehyde with Aromatic o-Diamines", 《EUROPEAN JOURNAL OF ORGANIC CHEMISTRY》 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2018042096A1 (en) * 2016-08-31 2018-03-08 Adpuerivitam 2-quinolin-2-one derivatives as modulators of nmda receptors, compositions comprising same and use of these compounds in the treatment of diseases involving the central nervous system
CN108003150A (en) * 2016-10-31 2018-05-08 河南工业大学 The preparation method and applications of 4- heteroaryl qualone derivatives
CN109020997A (en) * 2018-07-05 2018-12-18 桂林医学院 3- benzimidazole -6,7- piperonyl cyclonene -2 (1H)-quinolinone-Zn complex and its preparation method and application
CN109020997B (en) * 2018-07-05 2021-03-02 桂林医学院 3-benzimidazole-6, 7-piperonyl-2 (1H) -quinolinone-zinc complex and preparation method and application thereof
CN112608252A (en) * 2020-12-15 2021-04-06 广西师范大学 4-nitroaniline derivative and synthesis method and application thereof

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