CN101302194B - Synthetic method of polysubstituted chinoline compound - Google Patents

Synthetic method of polysubstituted chinoline compound Download PDF

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CN101302194B
CN101302194B CN2008100508846A CN200810050884A CN101302194B CN 101302194 B CN101302194 B CN 101302194B CN 2008100508846 A CN2008100508846 A CN 2008100508846A CN 200810050884 A CN200810050884 A CN 200810050884A CN 101302194 B CN101302194 B CN 101302194B
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CN101302194A (en
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董德文
梁永久
张睿
周扬
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Changzhou Institute Of Energy Storage Materials & Devices
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Changchun Institute of Applied Chemistry of CAS
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Abstract

The invention belongs to an organic synthesis method, in particular to a synthesis method for polysubstituted quinoline compound. Aiming at the problems of narrow application range, hard reaction conditions, complex process, low yield rate, etc. in the prior synthesis method of the polysubstituted quinoline, the invention provides a novel synthesis method which is to use a 1-aryl-2-arylamino butanone compound to synthesize the polysubstituted quinoline compound in one step under Vilsemeier reaction conditions. The method has the advantages of wide application range, ready availability of the 1-aryl-2-arylamino butanone compound, one step synthesis, simple operation, reaction at a temperature of between 80 and 140 DEG C and normal pressure, high yield rate up to 95 percent.

Description

A kind of synthetic method of polysubstituted chinoline compound
Technical field
The present invention relates to a kind of synthetic method of polysubstituted chinoline compound, particularly a kind of by the synthetic method of 1-aryl-2-aryl amine ethyl ketone compounds at next step synthetic polysubstituted chinoline compound of Vilsmeier reaction conditions.
Background technology
Quinolines is the hexa-atomic nitrogen-containing heterocycle compound of the important benzo of a class, extensively is present in the natural product, has important biology, pharmaceutical activity; As the multi-functional organic synthesis intermediate of a class, quinolines has obtained in fields such as Synthetic Organic Chemistry, medicine synthetic chemistry, materials chemistries to use widely simultaneously.Pharmaceutical active compounds that some are important such as intra-arterial growth factor-2/thrombocyte is derived the growth factor receptors combined depressant, insulin-like growth factor-1 acceptor inhibitor, multiple pharmaceutical active compounds such as hiv reverse transcriptase inhibitor, its main active ingredient is quinolines.(Bioorganic ﹠amp; Medicinal Chemistry Letters 2001,11,1943-1945; Bioorganic ﹠amp; Medicinal Chemistry 2008,16 is 4242-4251) from present existing document, the existing synthetic method of this compounds mainly is divided into two classes: a class is to adopt the female ring structure of existing quinoline to carry out chemically modified (Tetrahedron Lett., 2002,43,3547-3549); Another kind of is synthetic through annulation by chain compound, comprise Skraup reaction (Ber.1880,13,2086), Doebner-Von Miller reacts (Ber.1883,16,2464.), (Bull.Soc.Chim.France 1888 in the Combes reaction, 49,89), Friedlander reacts (Ber.1882,15,2572), Pfitzinger reacts (J.Prakt.Chem.1886,33 (2), 100), Meth-Cohn reaction or the like, wherein the Meth-Cohn reaction is a kind of synthetic method (J.Chem.Soc., the Perkin Trans 2 that adopts acetyl aromatic amine compounds synthesizing halogen quinolines under the Vilsmeier reaction conditions, 1981,1520-1530).Although the existing a lot of reports of the synthetic method of relevant quinolines, existing quinolines synthetic method exists problems such as narrow application range, severe reaction conditions, step complexity or productive rate are low.Therefore, the acquisition of the exploitation of the novel synthesis of quinolines and novel quinoline compounds is organic chemistry and pharmaceutical chemical hot research field always.
Summary of the invention:
The objective of the invention is provides a kind of novel synthesis of polysubstituted chinoline compound at problem such as narrow application range in the existing quinolines synthetic method, severe reaction conditions, step complexity, productive rate be low.
Polysubstituted chinoline compound involved in the present invention, its structural formula are that II-1 is as follows:
Figure DEST_PATH_GSB00000114884800021
In the formula, Ar is Ph-, xenyl, 4-CH 3Ph-, 4-(CH 3CH 2) Ph-, 4-[CH 3(CH 2) 2] Ph-, 4-[(CH 3) 2CH] Ph-, 4-(PhCH 2O) Ph-, 4-CH 3OPh-, 4-(CH 3CH 2O) Ph-, 4-(CH 3(CH 2) 2O) Ph-, 4-[(CH 3) 2CHO] Ph-, 4-ClPh-, 4-BrPh-, 4-FPh-, 4-NO 2Ph-, 4-CNPh-, 4-[(CH 3) 2N] Ph-, 4-(CH 3O 2C) Ph-, 4-(CH 3CH 2O 2C) Ph-, 3-CH 3Ph-, 3-(CH 3CH 2) Ph-, 3-[CH 3(CH 2) 2] Ph-, 3-[(CH 3) 2CH] Ph-, 3-(PhCH 2O) Ph-, 3-CH 3OPh-, 3-(CH 3CH 2O) Ph-, 3-(CH 3(CH 2) 2O) Ph-, 3-[(CH 3) 2CHO] Ph-, 3-ClPh-, 3-BrPh-, 3-FPh-, 3-NO 2Ph-, 3-CNPh-, 3-[(CH 3) 2N] Ph-, 3-(CH 3O 2C) Ph-, 3-(CH 3CH 2O 2C) Ph-, 2-CH 3Ph-, 2-(CH 3CH 2) Ph-, 2-[CH 3(CH 2) 2] Ph-, 2-[(CH 3) 2CH] Ph-, 2-(PhCH 2O) Ph-, 2-CH 3OPh-, 2-(CH 3CH 2O) Ph-, 2-(CH 3(CH 2) 2O) Ph-, 2-[(CH 3) 2CHO] Ph-, 2-ClPh-, 2-BrPh-, 2-FPh-, 2-NO 2Ph-, 2-CNPh-, 2-[(CH 3) 2N] Ph-, 2-(CH 3O 2C) Ph-, 2-(CH 3CH 2O 2C) Ph-, 2,4-(CH 3) 2Ph-, 3,4-(CH 3) 2Ph-, 3,5-(CH 3) 2Ph-, 3,4,5-(CH 3) 3Ph-, 2,4-(CH 3O) 2Ph-, 3,4-(CH 3O) 2Ph-, 3,5-(CH 3O) 2Ph-, 3,4,5-(CH 3O) 3Ph-, 2-CH 3-4-ClPh-, 2-CH 3O-4-ClPh-, 2-CH 3-4-BrPh-, 2-CH 3O-4-BrPh-, 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl;
R is-H, Ph-,-CH 3,-CH 2CH 3,-(CH 2) 2CH 3,-CH (CH 3) 2,-(CH 2) 3CH 3,-CH 2CH (CH 3) 2,-(CH 2) 4CH 3,-CH 2C (CH 3) 3,-(CH 2) 5CH 3,-(CH 2) 6CH 3,-(CH 2) 7CH 3,-(CH 2) 8CH 3,-(CH 2) 9CH 3,-(CH 2) 10CH 3,-(CH 2) 11CH 3, PhCH 2-,-OCH 3,-OCH 2CH 3,-O (CH 2) 2CH 3,-OCH (CH 3) 2,-O (CH 2) 3CH 3,-OCH 2CH (CH 3) 2,-O (CH 2) 4CH 3,-OCH 2C (CH 3) 3,-O (CH 2) 5CH 3,-O (CH 2) 6CH 3,-O (CH 2) 7CH 3,-O (CH 2) 8CH 3,-O (CH 2) 9CH 3,-O (CH 2) 10CH 3,-O (CH 2) 11CH 3, CH 2=CHCH 2O-, PhCH 2O-, 4-CH 3PhCH 2O-, 4-(CH 3O) PhCH 2O-, 4-ClPhCH 2O-, 4-BrPhCH 2O-, 3-CH 3PhCH 2O-, 3-(CH 3O) PhCH 2O-, 3-ClPhCH 2O-, 3-BrPhCH 2O-, 2-CH 3PhCH 2O-, 2-(CH 3O) PhCH 2O-, 2-ClPhCH 2O-or 2-BrPhCH 2O-; Wherein the R group is at 6 or 8 of quinolines.
Polysubstituted chinoline compound involved in the present invention, synthetic under the Vilsmeier reaction conditions by 1-aryl-2-aryl amine ethyl ketone compounds I-1, reaction equation is expressed as follows:
Figure S2008100508846D00031
The preparation method's of polysubstituted chinoline compound involved in the present invention step and condition are as follows:
Used Vilsmeier reagent is: phosphorus tribromide (PBr 3) and N, dinethylformamide (DMF) mixes by 1: 3 molar ratio down at 0～10 ℃, stirs the reagent that obtained in 15-45 minute;
Under the room temperature, Vilsmeier reagent with above-mentioned new preparation, by it is that 3.0～10.0 multiples of the mole of raw material 1-aryl-2-aryl amine ethyl ketone compounds I-1 or I-2 add and to be equipped with in the reactor of reflux condensing tube and agitator, be cooled to 0 ℃ under stirring, in 20～60 minutes, adding concentration in reaction system respectively is the raw material 1-aryl-2-aryl amine ethyl ketone compounds I-1 of 0.01～0.5 mol or the N of 1-aryl-2-aryl amine ethyl ketone compounds I-2, dinethylformamide solution, wherein the R substituting group is identical with R substituting group in the product, be warming up to 80～140 ℃ then, continue to stir stopped reaction 1～10 hour, use organic solvent extraction, washing, after the drying, filter, steam and remove organic solvent, separate through silica gel column chromatography, obtain corresponding polysubstituted chinoline compound II-1 or II-2 respectively.
Productive rate is looked differential responses between 50～95%, sees the embodiment in the embodiment for details.
Beneficial effect of the present invention is: the novel method for synthesizing that a kind of polysubstituted chinoline compound is provided.This method of this method is applied widely, and raw material 1-aryl-2-aryl amine ethyl ketone compounds is easy to get, one-step synthesis, and synthesis step is few; The reaction conditions gentleness, temperature of reaction is at 80～140 ℃; Normal pressure; Productive rate is up to 95%.
Embodiment:
Below in each embodiment reaction used Vilsmeier reagent be: phosphorus tribromide (PBr 3) and N, dinethylformamide (DMF) mixes by 1: 3 molar ratio down at 0～10 ℃, stirs the reagent that obtained in 15-45 minute;
Embodiment 1
Under the room temperature, in 100 milliliters of round-bottomed flasks of reflux condensing tube and agitator are housed, the Vilsmeier reagent that contains phosphorus tribromide 4.0 mmoles that adds new preparation, after being cooled to 0 ℃ under stirring, in 30 minutes, in reaction system, add concentration and be the N of reaction raw materials 1-phenyl-2-anilino ethyl ketone compounds I-1 that the structure of 0.04 mol is shown below, 25 milliliters of dinethylformamide solution, be warming up to 80 ℃ then, continue to stir 10 hours, stopped reaction, reaction solution are poured in 100 milliliters of saturated aqueous common salts, use twice of 50 milliliters of dichloromethane extraction respectively, merge organic phase, respectively with 50 milliliters of washings, twice, 10 gram anhydrous sodium sulfate drying, filter, steam to remove organic solvent, through silica gel column chromatography separate corresponding quinoline product II-1, productive rate 61%.Reaction equation is expressed as follows:
Figure S2008100508846D00041
Embodiment 2
Under the room temperature, in 100 milliliters of round-bottomed flasks of reflux condensing tube and agitator are housed, the Vilsmeier reagent that contains phosphorus tribromide 4.0 mmoles that adds new preparation, after being cooled to 0 ℃, in 20 minutes, in reaction system, add concentration and be the N of reaction raw materials 1-phenyl-2-(4-methyl-phenyl)-amido ethyl ketone compounds I-1 that the structure of 0.02 mol is shown below, 50 milliliters of dinethylformamide solution, be warming up to 120 ℃ then, continue to stir 3 hours, stopped reaction, reaction solution are poured in 100 milliliters of saturated aqueous common salts, use twice of 50 milliliters of dichloromethane extraction respectively, merge organic phase, respectively with 50 milliliters of washings, twice, 10 gram anhydrous sodium sulfate drying, filter, steam to remove organic solvent, through silica gel column chromatography separate corresponding quinoline product H-1, productive rate 65%.Reaction equation is expressed as follows:
Figure S2008100508846D00042
Embodiment 3
Under the room temperature, in 50 milliliters of round-bottomed flasks of reflux condensing tube and agitator are housed, the Vilsmeier reagent that contains phosphorus tribromide 5.0 mmoles that adds new preparation, after being cooled to 0 ℃, in 40 minutes, in reaction system, add concentration and be the N of reaction raw materials 1-(4-methyl-phenyl)-2-(4-methyl-phenyl)-amido ethyl ketone compounds I-1 that the structure of 0.5 mol is shown below, 2 milliliters of dinethylformamide solution, be warming up to 120 ℃ then, continue to stir 3 hours, stopped reaction, reaction solution are poured in 100 milliliters of saturated aqueous common salts, use twice of 50 milliliters of dichloromethane extraction respectively, merge organic phase, respectively with 50 milliliters of washings, twice, 10 gram anhydrous sodium sulfate drying, filter, steam to remove organic solvent, through silica gel column chromatography separate corresponding quinoline product II-1, productive rate 84%.Reaction equation is expressed as follows:
Figure S2008100508846D00051
Embodiment 4
Under the room temperature, in 250 milliliters of round-bottomed flasks of reflux condensing tube and agitator are housed, the Vilsmeier reagent that contains phosphorus tribromide 10.0 mmoles that adds new preparation, after being cooled to 0 ℃, in 60 minutes, in reaction system, add concentration and be the N of reaction raw materials 1-(4-methyl-phenyl)-2-(4-methoxyl group-phenyl) amido ethyl ketone compounds I-1 that the structure of 0.01 mol is shown below, 100 milliliters of dinethylformamide solution, be warming up to 120 ℃ then, continue to stir 4 hours, stopped reaction, reaction solution are poured in 100 milliliters of saturated aqueous common salts, use twice of 50 milliliters of dichloromethane extraction respectively, merge organic phase, respectively with 50 milliliters of washings, twice, 10 gram anhydrous sodium sulfate drying, filter, steam to remove organic solvent, through silica gel column chromatography separate corresponding quinoline product II-1, productive rate 78%.Reaction equation is expressed as follows:
Figure S2008100508846D00052
Embodiment 5
Under the room temperature, in 100 milliliters of round-bottomed flasks of reflux condensing tube and agitator are housed, the Vilsmeier reagent that contains phosphorus tribromide 7.5 mmoles that adds new preparation, after being cooled to 0 ℃, in 20 minutes, in reaction system, add concentration and be the N of reaction raw materials 1-(4-chloro-phenyl)-2-(2-methyl-phenyl) amido ethyl ketone compounds I-1 that the structure of 0.04 mol is shown below, 25 milliliters of dinethylformamide solution, be warming up to 120 ℃ then, continue to stir 4 hours, stopped reaction, reaction solution are poured in 100 milliliters of saturated aqueous common salts, use twice of 20 milliliters of dichloromethane extraction respectively, merge organic phase, respectively with 50 milliliters of washings, twice, 10 gram anhydrous sodium sulfate drying, filter, steam to remove organic solvent, through silica gel column chromatography separate corresponding quinoline product II-1, productive rate 50%.Reaction equation is expressed as follows:
Figure S2008100508846D00053
Embodiment 6
Under the room temperature, in 100 milliliters of round-bottomed flasks of reflux condensing tube and agitator are housed, the Vilsmeier reagent that contains phosphorus tribromide 6.0 mmoles that adds new preparation, after being cooled to 0 ℃, in 30 minutes, in reaction system, add concentration and be the N of reaction raw materials 1-(4-chloro-phenyl)-2-(4-methoxyl group-phenyl) amido ethyl ketone compounds I-1 that the structure of 0.05 mol is shown below, 20 milliliters of dinethylformamide solution, be warming up to 140 ℃ then, continue to stir 3 hours, stopped reaction, reaction solution are poured in 100 milliliters of saturated aqueous common salts, use twice of 30 milliliters of dichloromethane extraction respectively, merge organic phase, respectively with 50 milliliters of washings, twice, 10 gram anhydrous sodium sulfate drying, filter, steam to remove organic solvent, through silica gel column chromatography separate corresponding quinoline product II-1, productive rate 85%.Reaction equation is expressed as follows:
Figure S2008100508846D00061
Embodiment 7
Under the room temperature, in 100 milliliters of round-bottomed flasks of reflux condensing tube and agitator are housed, the Vilsmeier reagent that contains phosphorus tribromide 4.0 mmoles that adds new preparation, after being cooled to 0 ℃, in 30 minutes, in reaction system, add concentration and be the N of reaction raw materials 1-(4-methoxyl group-phenyl)-2-(4-methoxyl group-phenyl) amido ethyl ketone compounds I-1 that the structure of 0.02 mol is shown below, 50 milliliters of dinethylformamide solution, be warming up to 120 ℃ then, continue to stir 5 hours, stopped reaction, reaction solution are poured in 100 milliliters of saturated aqueous common salts, use twice of 50 milliliters of dichloromethane extraction respectively, merge organic phase, respectively with 50 milliliters of washings, twice, 10 gram anhydrous sodium sulfate drying, filter, steam to remove organic solvent, through silica gel column chromatography separate corresponding quinoline product II-1, productive rate 83%.Reaction equation is expressed as follows:
Embodiment 8
Under the room temperature, in 50 milliliters of round-bottomed flasks of reflux condensing tube and agitator are housed, the Vilsmeier reagent that contains phosphorus tribromide 4.0 mmoles that adds new preparation, after being cooled to 0 ℃, in 30 minutes, in reaction system, add concentration and be the N of reaction raw materials 1-(4-phenyl-phenyl)-2-anilino ethyl ketone compounds I-1 that the structure of 0.1 mol is shown below, 10 milliliters of dinethylformamide solution, be warming up to 120 ℃ then, continue to stir 6 hours, stopped reaction, reaction solution are poured in 100 milliliters of saturated aqueous common salts, use twice of 50 milliliters of dichloromethane extraction respectively, merge organic phase, respectively with 50 milliliters of washings, twice, 10 gram anhydrous sodium sulfate drying, filter, steam to remove organic solvent, through silica gel column chromatography separate corresponding quinoline product II-1, productive rate 76%.Reaction equation is expressed as follows:
Figure S2008100508846D00071
Embodiment 9
Under the room temperature, in 100 milliliters of round-bottomed flasks of reflux condensing tube and agitator are housed, the Vilsmeier reagent that contains phosphorus tribromide 8.0 mmoles that adds new preparation, after being cooled to 0 ℃, in 40 minutes, in reaction system, add concentration and be the N of reaction raw materials 1-(4-phenyl-phenyl)-2-(4-methoxyl group-phenyl) amido ethyl ketone compounds I-1 that the structure of 0.04 mol is shown below, 25 milliliters of dinethylformamide solution, be warming up to 120 ℃ then, continue to stir 5 hours, stopped reaction, reaction solution are poured in 100 milliliters of saturated aqueous common salts, use twice of 50 milliliters of dichloromethane extraction respectively, merge organic phase, respectively with 50 milliliters of washings, twice, 10 gram anhydrous sodium sulfate drying, filter, steam to remove organic solvent, through silica gel column chromatography separate corresponding quinoline product II-1, productive rate 82%.Reaction equation is expressed as follows:
Figure S2008100508846D00072
Embodiment 10
Under the room temperature, in 100 milliliters of round-bottomed flasks of reflux condensing tube and agitator are housed, the Vilsmeier reagent that contains phosphorus tribromide 6.0 mmoles that adds new preparation, after being cooled to 0 ℃, in 30 minutes, in reaction system, add concentration and be the N of reaction raw materials 1-(4-chloro-phenyl)-2-(naphthalidine base) ethyl ketone compounds I-2 that the structure of 0.02 mol is shown below, 50 milliliters of dinethylformamide solution, be warming up to 130 ℃ then, continue to stir 4 hours, stopped reaction, reaction solution are poured in 100 milliliters of saturated aqueous common salts, use twice of 50 milliliters of dichloromethane extraction respectively, merge organic phase, respectively with 50 milliliters of washings, twice, 10 gram anhydrous sodium sulfate drying, filter, steam to remove organic solvent, through silica gel column chromatography separate corresponding quinoline product II-2, productive rate 87%.Reaction equation is expressed as follows:
Figure S2008100508846D00073
Embodiment 11
Under the room temperature, in 100 milliliters of round-bottomed flasks of reflux condensing tube and agitator are housed, the Vilsmeier reagent that contains phosphorus tribromide 8.0 mmoles that adds new preparation, after being cooled to 0 ℃, in system, in 60 minutes, in reaction system, add concentration and be the N of reaction raw materials 1-phenyl-2-(naphthalidine base) ethyl ketone compounds I-2 that the structure of 0.05 mol is shown below, 20 milliliters of dinethylformamide solution, be warming up to 120 ℃ then, continue to stir 6 hours, stopped reaction, reaction solution are poured in 100 milliliters of saturated aqueous common salts, use twice of 50 milliliters of dichloromethane extraction respectively, merge organic phase, respectively with 50 milliliters of washings, twice, 10 gram anhydrous sodium sulfate drying, filter, steam to remove organic solvent, through silica gel column chromatography separate corresponding quinoline product II-2, productive rate 89%.Reaction equation is expressed as follows:
Figure S2008100508846D00081
Embodiment 12
Under the room temperature, in 100 milliliters of round-bottomed flasks of reflux condensing tube and agitator are housed, the Vilsmeier reagent that contains phosphorus tribromide 4.0 mmoles that adds new preparation, after being cooled to 0 ℃, in 25 minutes, in reaction system, add concentration and be the N of reaction raw materials 1-(4-methyl-phenyl)-2-(naphthalidine base) ethyl ketone compounds I-2 that the structure of 0.04 mol is shown below, 25 milliliters of dinethylformamide solution, be warming up to 120 ℃ then, continue to stir 7 hours, stopped reaction, reaction solution are poured in 100 milliliters of saturated aqueous common salts, use twice of 50 milliliters of dichloromethane extraction respectively, merge organic phase, respectively with 50 milliliters of washings, twice, 10 gram anhydrous sodium sulfate drying, filter, steam to remove organic solvent, through silica gel column chromatography separate corresponding quinoline product II-2, productive rate 91%.Reaction equation is expressed as follows:
Embodiment 13
Under the room temperature, in 50 milliliters of round-bottomed flasks of reflux condensing tube and agitator are housed, the Vilsmeier reagent that contains phosphorus tribromide 5.0 mmoles that adds new preparation, after being cooled to 0 ℃, in 20 minutes, in reaction system, add concentration and be the N of reaction raw materials 1-phenyl-2-(4-phenyl-phenyl) amido ethyl ketone compounds I-1 that the structure of 0.2 mol is shown below, 5 milliliters of dinethylformamide solution, be warming up to 130 ℃ then, continue to stir 4 hours, stopped reaction, reaction solution are poured in 100 milliliters of saturated aqueous common salts, use twice of 50 milliliters of dichloromethane extraction respectively, merge organic phase, respectively with 50 milliliters of washings, twice, 10 gram anhydrous sodium sulfate drying, filter, steam to remove organic solvent, through silica gel column chromatography separate corresponding quinoline product II-1, productive rate 95%.Reaction equation is expressed as follows:
Figure S2008100508846D00091
Embodiment 14
Under the room temperature, in 100 milliliters of round-bottomed flasks of reflux condensing tube and agitator are housed, the Vilsmeier reagent that contains phosphorus tribromide 7.0 mmoles that adds new preparation, after being cooled to 0 ℃, in 50 minutes, in reaction system, add concentration and be the N of reaction raw materials 1-(4-methyl-phenyl)-2-(4-phenyl-phenyl) amido ethyl ketone compounds I-1 that the structure of 0.02 mol is shown below, 50 milliliters of dinethylformamide solution, be warming up to 120 ℃ then, continue to stir 5 hours, stopped reaction, reaction solution are poured in 100 milliliters of saturated aqueous common salts, use twice of 50 milliliters of dichloromethane extraction respectively, merge organic phase, respectively with 50 milliliters of washings, twice, 10 gram anhydrous sodium sulfate drying, filter, steam to remove organic solvent, through silica gel column chromatography separate corresponding quinoline product II-1, productive rate 79%.Reaction equation is expressed as follows:
Figure S2008100508846D00092
Embodiment 15
Under the room temperature, in 100 milliliters of round-bottomed flasks of reflux condensing tube and agitator are housed, the Vilsmeier reagent that contains phosphorus tribromide 6.0 mmoles that adds new preparation, after being cooled to 0 ℃, in 45 minutes, in reaction system, add concentration and be the N of reaction raw materials 1-(2-thienyl)-2-anilino ethyl ketone compounds I-1 that the structure of 0.04 mol is shown below, 25 milliliters of dinethylformamide solution, be warming up to 120 ℃ then, continue to stir 6 hours, stopped reaction, reaction solution are poured in 100 milliliters of saturated aqueous common salts, use twice of 50 milliliters of dichloromethane extraction respectively, merge organic phase, respectively with 50 milliliters of washings, twice, 10 gram anhydrous sodium sulfate drying, filter, steam to remove organic solvent, through silica gel column chromatography separate corresponding quinoline product II-1, productive rate 67%.Reaction equation is expressed as follows:
Figure S2008100508846D00101
Embodiment 16
Under the room temperature, in 100 milliliters of round-bottomed flasks of reflux condensing tube and agitator are housed, the Vilsmeier reagent that contains phosphorus tribromide 4.0 mmoles that adds new preparation, after being cooled to 0 ℃, in 30 minutes, in reaction system, add concentration and be the N of reaction raw materials 1-(4-pyridyl)-2-anilino ethyl ketone compounds I-1 that the structure of 0.05 mol is shown below, 20 milliliters of dinethylformamide solution, be warming up to 130 ℃ then, continue to stir 4 hours, stopped reaction, reaction solution are poured in 100 milliliters of saturated aqueous common salts, use twice of 50 milliliters of dichloromethane extraction respectively, merge organic phase, respectively with 50 milliliters of washings, twice, 10 gram anhydrous sodium sulfate drying, filter, steam to remove organic solvent, through silica gel column chromatography separate corresponding quinoline product II-1, productive rate 73%.Reaction equation is expressed as follows:

Claims (1)

1. the synthetic method of a polysubstituted chinoline compound is characterized in that, the structural formula of described polysubstituted chinoline compound is that II-1 is as follows:
Figure DEST_PATH_RE-FSB00000114884700011
In the formula, Ar is Ph-, xenyl, 4-CH 3Ph-, 4-(CH 3CH 2) Ph-, 4-[CH 3(CH 2) 2] Ph-, 4-[(CH 3) 2CH] Ph-, 4-(PhCH 2O) Ph-, 4-CH 3OPh-, 4-(CH 3CH 2O) Ph-, 4-(CH 3(CH 2) 2O) Ph-, 4-[(CH 3) 2CHO] Ph-, 4-ClPh-, 4-BrPh-, 4-FPh-, 4-NO 2Ph-, 4-CNPh-, 4-[(CH 3) 2N] Ph-, 4-(CH 3O 2C) Ph-, 4-(CH 3CH 2O 2C) Ph-, 3-CH 3Ph-, 3-(CH 3CH 2) Ph-, 3-[CH 3(CH 2) 2] Ph-, 3-[(CH 3) 2CH] Ph-, 3-(PhCH 2O) Ph-, 3-CH 3OPh-, 3-(CH 3CH 2O) Ph-, 3-(CH 3(CH 2) 2O) Ph-, 3-[(CH 3) 2CHO] Ph-, 3-ClPh-, 3-BrPh-, 3-FPh-, 3-NO 2Ph-, 3-CNPh-, 3-[(CH 3) 2N] Ph-, 3-(CH 3O 2C) Ph-, 3-(CH 3CH 2O 2C) Ph-, 2-CH 3Ph-, 2-(CH 3CH 2) Ph-, 2-[CH 3(CH 2) 2] Ph-, 2-[(CH 3) 2CH] Ph-, 2-(PhCH 2O) Ph-, 2-CH 3OPh-, 2-(CH 3CH 2O) Ph-, 2-(CH 3(CH 2) 2O) Ph-, 2-[(CH 3) 2CHO] Ph-, 2-ClPh-, 2-BrPh-, 2-FPh-, 2-NO 2Ph-, 2-CNPh-, 2-[(CH 3) 2N] Ph-, 2-(CH 3O 2C) Ph-, 2-(CH 3CH 2O 2C) Ph-, 2,4-(CH 3) 2Ph-, 3,4-(CH 3) 2Ph-, 3,5-(CH 3) 2Ph-, 3,4,5-(CH 3) 3Ph-, 2,4-(CH 3O) 2Ph-, 3,4-(CH 3O) 2Ph-, 3,5-(CH 3O) 2Ph-, 3,4,5-(CH 3O) 3Ph-, 2-CH 3-4-ClPh-, 2-CH 3O-4-ClPh-, 2-CH 3-4-BrPh-, 2-CH 3O-4-BrPh-, 2-furyl, 2-thienyl, 2-pyridyl, 3-pyridyl or 4-pyridyl;
R is-H, Ph-,-CH 3,-CH 2CH 3,-(CH 2) 2CH 3,-CH (CH 3) 2,-(CH 2) 3CH 3,-CH 2CH (CH 3) 2,-(CH 2) 4CH 3,-CH 2C (CH 3) 3,-(CH 2) 5CH 3,-(CH 2) 6CH 3,-(CH 2) 7CH 3,-(CH 2) 8CH 3,-(CH 2) 9CH 3,-(CH 2) 10CH 3,-(CH 2) 11CH 3, PhCH 2-,-OCH 3,-OCH 2CH 3,-O (CH 2) 2CH 3,-OCH (CH 3) 2,-O (CH 2) 3CH 3,-OCH 2CH (CH 3) 2,-O (CH 2) 4CH 3,-OCH 2C (CH 3) 3,-O (CH 2) 5CH 3,-O (CH 2) 6CH 3,-O (CH 2) 7CH 3,-O (CH 2) 8CH 3,-O (CH 2) 9CH 3,-O (CH 2) 10CH 3,-O (CH 2) 11CH 3, CH 2=CHCH 2O-, PhCH 2O-, 4-CH 3PhCH 2O-, 4-(CH 3O) PhCH 2O-, 4-ClPhCH 2O-, 4-BrPhCH 2O-, 3-CH 3PhCH 2O-, 3-(CH 3O) PhCH 2O-, 3-ClPhCH 2O-, 3-BrPhCH 2O-, 2-CH 3PhCH 2O-, 2-(CH 3O) PhCH 2O-, 2-ClPhCH 2O-or 2-BrPhCH 2O-; Wherein the R group is at 6 or 8 of quinolines;
Related polysubstituted chinoline compound, synthetic under the Vilsmeier reaction conditions by 1-aryl-2-aryl amine ethyl ketone compounds I-1, reaction equation is expressed as follows:
Figure RE-FSB00000059057300021
The preparation method's of related polysubstituted chinoline compound step and condition are as follows:
Used Vilsmeier reagent is: phosphorus tribromide (PBr 3) and N, dinethylformamide (DMF) mixes by 1: 3 molar ratio down at 0～10 ℃, stirs the reagent that obtained in 15-45 minute;
Under the room temperature, Vilsmeier reagent with above-mentioned new preparation, by it is that 3.0～10.0 multiples of the mole of raw material 1-aryl-2-aryl amine ethyl ketone compounds I-1 add and to be equipped with in the reactor of reflux condensing tube and agitator, be cooled to 0 ℃ under stirring, in 20～60 minutes, adding concentration in reaction system is the N of the raw material 1-aryl-2-aryl amine ethyl ketone compounds I-1 of 0.01～0.5 mol, dinethylformamide solution, wherein the R substituting group is identical with R substituting group in the product, be warming up to 80～140 ℃ then, continue to stir stopped reaction 1～10 hour, use organic solvent extraction, washing, after the drying, filter, steam and remove organic solvent, separate through silica gel column chromatography, obtain corresponding polysubstituted chinoline compound II-1.
CN2008100508846A 2008-06-26 2008-06-26 Synthetic method of polysubstituted chinoline compound Expired - Fee Related CN101302194B (en)

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