Summary of the invention
The object of the invention is to provide a kind of compound stability better, have good anti-tumor activity containing Isosorbide-5-Nitrae-pentadiene-3-ketone compounds of sulfonate ester group.
Another object of the present invention is to provide the preparation method of this Isosorbide-5-Nitrae-pentadiene that contains sulfonate ester group-3-ketone compounds.
Another object of the present invention is to provide the purposes in antitumor inhibitor of this Isosorbide-5-Nitrae-pentadiene that contains sulfonate ester group-3-ketone compounds.
A kind of Isosorbide-5-Nitrae-pentadiene-3-ketone compounds containing sulfonate ester group of the present invention, (I) is as follows for its general structure:
(I)
Wherein: the substituted sulfonic acid ester group on phenyl ring is ortho position, a position, contraposition;
R
1for C
1-6alkyl, phenyl, neighbour,, contraposition monosubstituted or polysubstituted phenyl or heterocycle;
R
2for C
1-6alkyl, phenyl, neighbour,, contraposition monosubstituted or polysubstituted phenyl or heterocycle.
Above-mentioned a kind of Isosorbide-5-Nitrae-pentadiene-3-ketone compounds containing sulfonate ester group, wherein: R
1, R
2in each group all can be replaced by least one or more halogen atom, itrile group, nitro, hydroxyl substituent.
Above-mentioned a kind of Isosorbide-5-Nitrae-pentadiene-3-ketone compounds containing sulfonate ester group, wherein: halogen atom is fluorine, chlorine, bromine, iodine atom.
Above-mentioned a kind of Isosorbide-5-Nitrae-pentadiene-3-ketone compounds containing sulfonate ester group, wherein: heterocycle is to contain 4-12 carbon atom and contain 1-3 heteroatomic monocycle or bicyclic heterocyclic group that is selected from nitrogen, oxygen or sulphur.Preferably pyrazolyl, furyl, tetrahydrofuran base, thienyl, thiazolyl, isothiazolyl, imidazolyl, pyrryl, oxazolyl, isoxazolyl, triazolyl, tetrazyl, thiadiazolyl group, pyridyl, morpholinyl, piperazinyl, triazinyl, piperidyl, pyridazinyl, pyrimidyl.
Above-mentioned a kind of Isosorbide-5-Nitrae-pentadiene-3-ketone compounds containing sulfonate ester group, wherein: heterocyclic group is replaced by one or more groups that are independently selected from halogen atom, itrile group or nitro.
Above-mentioned a kind of Isosorbide-5-Nitrae-pentadiene-3-ketone compounds containing sulfonate ester group, wherein: C
1-6alkyl preferable methyl, ethyl, n-propyl, sec.-propyl, normal-butyl, isobutyl-, the tertiary butyl, n-pentyl, isopentyl, tert-pentyl, neo-pentyl, n-hexyl, isohexyl, tertiary hexyl, new hexyl.
Above-mentioned a kind of Isosorbide-5-Nitrae-pentadiene-3-ketone compounds containing sulfonate ester group, wherein preferably synthetic compound is:
(1E, 4E)-1-(2-fluorophenyl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-phenyl-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(2-nitro-4-chloro-phenyl-)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(4-aminomethyl phenyl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(4-chloro-phenyl-)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(5-chloro-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(5-chloro-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl)-5-(4-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(2,3-dichlorophenyl)-5-(4-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(4-fluorophenyl)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(the chloro-5-nitrophenyl of 2-)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(2-nitro-4-chloro-phenyl-)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(5-chloro-1,3-dimethyl-1H-pyrazoles-4 base)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(2-p-methoxy-phenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(4-p-methoxy-phenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(4-chloro-phenyl-)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(2,3-dichlorophenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(3-nitrophenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(2,4 dichloro benzene base)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
(1E, 4E)-1-(4-aminomethyl phenyl)-5-(4-(Phenylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone;
Or (1E, 4E)-1-(2-p-methoxy-phenyl)-5-(4-(Phenylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone.
Of the present invention a kind of containing 1 of sulfonate ester group, the preparation method of 4-pentadiene-3-ketone compounds, be taking monosubstituted hydroxy benzaldehyde, acetone, replacement SULPHURYL CHLORIDE, replace aldehyde, sodium hydroxide, salt of wormwood as raw material, synthetic through three steps taking acetone, dehydrated alcohol, acetonitrile as solvent, synthetic route is as follows:
(1) synthesizing of (E)-4-(monosubstituted hydroxy phenyl)-3-butene-2-one:
10.0 parts of monosubstituted hydroxy aldehydes are joined in the mixing solutions of 150.0 parts, 150.0 parts, acetone and water, be stirred to solid and all dissolve, be added drop-wise in reaction system room temperature reaction 11 ~ 15 h after 12.0 parts, sodium hydroxide being formulated as to 10% the aqueous solution.After reaction finishes, rotary evaporation is removed acetone, in raffinate, adds hot water to solid all to dissolve, and passes into carbonic acid gas to no longer variable color of reaction solution, has solid to produce, and suction filtration, washing, oven dry, separate to obtain product with silica gel column chromatography.
This step is applicable to the synthetic of all above-mentioned (E)-4-(monosubstituted hydroxy phenyl)-3-butene-2-one.
(2) synthesizing of (E)-4-(substituted sulfonic acid ester group phenyl)-3-butene-2-one:
Taking acetonitrile as solvent, add successively 20.0 parts, salt of wormwood, (E)-4-(monosubstituted hydroxy phenyl)-10.0 parts of 3-butene-2-one, after dissolution of solid, slowly drip and replace room temperature reaction 1-3 h after 10.0 parts of SULPHURYL CHLORIDE.After reaction finishes, decompression is sloughed solvent after washing, suction filtration, is dried to obtain solid, separates to obtain product with silica gel column chromatography.
This step is applicable to the synthetic of all above-mentioned (E)-4-(substituted sulfonic acid ester group phenyl)-3-butene-2-one.
(3) target compound is synthetic:
By (E)-4-(substituted sulfonic acid ester group phenyl)-1.0 parts of 3-butene-2-one, replace in the mixing solutions that 1.0 parts, aldehyde joins second alcohol and water (V (ethanol): V (water)=2:1), after NaOH1.2 part being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system room temperature reaction 1-10h.Reaction finishes rear suction filtration, washing, oven dry gained solid, and dehydrated alcohol/DMF recrystallization obtains target compound.
The present invention compared with prior art, there is obvious beneficial effect, as can be known from the above technical solutions: the present invention will have extensive bioactive curcumin derivate 1, the sulfonate ester group of 4-pentadiene-3-ketone and active structure splices, synthesize Isosorbide-5-Nitrae-pentadiene-3-ketone compounds of a class formation novelty.The synthetic route of this compounds is simple, reaction conditions gentleness, and reaction at room temperature just can be carried out; Isosorbide-5-Nitrae-pentadiene-3-ketone compounds stability of synthesized is better, has good anti-tumor activity.
Further illustrate beneficial effect of the present invention by embodiment below.
Embodiment
embodiment 1:synthesizing of compound (1E, 4E)-1-(2-fluorophenyl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
In 100 mL there-necked flasks, add successively 4-hydroxy benzaldehyde (10.0 mmol), 11 mL acetone and 11 mL water, being stirred to solid all dissolves, after sodium hydroxide (12.0 mmol) being formulated as to 10% the aqueous solution, be added drop-wise in reaction system, after room temperature reaction 11.0 h, stop reaction.Rotary evaporation is removed acetone, in raffinate, add 50 mL hot water to red solid all to dissolve, pass into carbonic acid gas to no longer variable color of reaction solution, there is faint yellow solid to produce, suction filtration, washing, oven dry, separate [V (ethyl acetate): V (sherwood oil)=2:1] with silica gel column chromatography and obtain faint yellow solid, yield: 74.3%, fusing point: 101-103 ° C.
(2) synthesizing of (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one:
In 50mL there-necked flask, add (E)-4-(4-hydroxy phenyl)-3-butene-2-one (10.0 mmol), salt of wormwood (20.0 mmol), 15mL acetonitrile, under stirring at room temperature, drip the Tosyl chloride (10.0 mmol) that is dissolved in acetonitrile, after 2h, stop reaction.Be spin-dried for solvent after washing, the yellow solid of oven dry, separates [V (ethyl acetate): V (sherwood oil)=3:1] with silica gel thin-layer chromatography and obtains faint yellow solid, fusing point: 58-60 С.
(3) synthesizing of (1E, 4E)-1-(2-fluorophenyl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 2-fluorobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 8h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol/DMF recrystallization.
embodiment 2:synthesizing of (1E, 4E)-1-phenyl-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
With embodiment 1 (1) step;
(2) synthesizing of (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one:
With embodiment 1 (2) step;
(3) synthesizing of (1E, 4E)-1-phenyl-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), phenyl aldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 10h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol/DMF recrystallization.
embodiment 3:synthesizing of (1E, 4E)-1-(2-nitro-4-chloro-phenyl-)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
With embodiment 1 (1) step;
(2) synthesizing of (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one:
With embodiment 1 (2) step;
(3) synthesizing of (1E, 4E)-1-(2-nitro-4-chloro-phenyl-)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 2-nitro-4-chlorobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 1h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol/DMF recrystallization.
embodiment 4:synthesizing of (1E, 4E)-1-(4-aminomethyl phenyl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
With embodiment 1 (1) step;
(2) synthesizing of (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one:
With embodiment 1 (2) step;
(3) synthesizing of (1E, 4E)-1-(4-aminomethyl phenyl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 4-tolyl aldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 5h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol/DMF recrystallization.
embodiment 5:synthesizing of (1E, 4E)-1-(4-chloro-phenyl-)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
With embodiment 1 (1) step;
(2) synthesizing of (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one:
With embodiment 1 (2) step;
(3) synthesizing of (1E, 4E)-1-(4-chloro-phenyl-)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 4-chlorobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 8h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 6:synthesizing of (1E, 4E)-1-(5-chloro-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
With embodiment 1 (1) step;
(2) synthesizing of (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one:
With embodiment 1 (2) step;
(3) synthesizing of (1E, 4E)-1-(5-chloro-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl)-5-(4-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(4-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), the chloro-3-methyl isophthalic acid-phenyl-1H-of 5-pyrazoles formaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 5h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 7:synthesizing of (1E, 4E)-1-(5-chloro-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl)-5-(4-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
With embodiment 1 (1) step;
(2) synthesizing of (E)-4-(4-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
In 50mL there-necked flask, add (E)-4-(4-hydroxy phenyl)-3-butene-2-one (10.0 mmol), salt of wormwood (20.0 mmol), 15mL acetonitrile, under stirring at room temperature, drip the methylsulfonyl chloride (10.0 mmol) that is dissolved in acetonitrile, after 1h, stop reaction.Be spin-dried for solvent after washing, dry to obtain yellow solid, separate [V (ethyl acetate): V (sherwood oil)=3:1] with silica gel thin-layer chromatography and obtain faint yellow solid, fusing point: 136-138 С.
(3) synthesizing of (1E, 4E)-1-(5-chloro-3-methyl isophthalic acid-phenyl-1H-pyrazoles-4-yl)-5-(4-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(4-(methylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), the chloro-3-methyl isophthalic acid-phenyl-1H-of 5-pyrazoles formaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 7h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 8:synthesizing of (1E, 4E)-1-(2,3-dichlorophenyl)-5-(4-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
With embodiment 1 (1) step;
(2) synthesizing of (E)-4-(4-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
With embodiment 7 (2) step;
(3) synthesizing of (1E, 4E)-1-(2,3-dichlorophenyl)-5-(4-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(4-(methylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 2,3-dichlorobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 5h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 9:synthesizing of (1E, 4E)-1-(4-fluorophenyl)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
In 100 mL there-necked flasks, add successively salicylic aldehyde (10.0 mmol), 11 mL acetone and 11 mL water, being stirred to solid all dissolves, after sodium hydroxide (12 mmol) being formulated as to 10% the aqueous solution, be added drop-wise in reaction system, after room temperature reaction 15 h, stop reaction.Rotary evaporation is removed acetone, in raffinate, add 75 mL hot water to red solid all to dissolve, pass into carbonic acid gas to no longer variable color of reaction solution, there is faint yellow solid to produce, suction filtration, washing, oven dry, separate [V (ethyl acetate): V (sherwood oil)=2:1] with silica gel column chromatography and obtain faint yellow solid, yield: 78.8%, fusing point: 139-141 ° C.
(2) synthesizing of (E)-4-(2-(tosic acid ester group) phenyl)-3-butene-2-one
In 50mL there-necked flask, add (E)-4-(2-hydroxy phenyl)-3-butene-2-one (10.0 mmol), salt of wormwood (20.0 mmol), 15mL acetonitrile, under stirring at room temperature, drip the Tosyl chloride (10.0 mmol) that is dissolved in acetonitrile, after 3h, stop reaction.Be spin-dried for solvent after washing, suction filtration, dry to obtain faint yellow solid, separate [V (ethyl acetate): V (sherwood oil)=3:1] with silica gel thin-layer chromatography and obtain product, fusing point: 77-79 С.
(3) synthesizing of (1E, 4E)-1-(4-fluorophenyl)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone
In 50mL there-necked flask, add (E)-4-(2-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 4-fluorobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 6h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 10:synthesizing of (1E, 4E)-1-(the chloro-5-nitrophenyl of 2-)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
With embodiment 9 (1) step;
(2) synthesizing of (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
With embodiment 9 (2) step;
(3) synthesizing of (1E, 4E)-1-(the chloro-5-nitrophenyl of 2-)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(2-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), the chloro-5-nitrobenzaldehyde of 2-(1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 1h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 11:synthesizing of (1E, 4E)-1-(2-nitro-4-chloro-phenyl-)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
With embodiment 9 (1) step;
(2) synthesizing of (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
With embodiment 9 (2) step;
(3) synthesizing of (1E, 4E)-1-(2-nitro-4-chloro-phenyl-)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(2-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 2-nitro-4-chlorobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 1h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 12:(1E, 4E)-1-(5-chloro-1,3-dimethyl-1H-pyrazoles-4 base)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone synthetic, comprises the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
With embodiment 9 (1) step;
(2) synthesizing of (E)-4-(2-(tosic acid ester group) phenyl)-3-butene-2-one:
With embodiment 9 (2) step;
(3) (1E, 4E)-1-(5-chloro-1,3-dimethyl-1H-pyrazoles-4 base)-5-(2-(tosic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone synthetic:
In 50mL there-necked flask, add (E)-4-(2-(tosic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 5-chloro-1,3-dimethyl-1H-pyrazoles formaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 1h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 13:synthesizing of compound (1E, 4E)-1-(2-p-methoxy-phenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
With embodiment 7 (1) step;
(2) synthesizing of (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
In 50mL there-necked flask, add (E)-4-(2-hydroxy phenyl)-3-butene-2-one (10.0 mmol), salt of wormwood (20.0 mmol), 15mL acetonitrile, drips methylsulfonyl chloride (10.0 mmol) under stirring at room temperature, stop reaction after 1h.Be spin-dried for solvent after washing, suction filtration, oven dry gained solid, silica gel thin-layer chromatography separates [V (ethyl acetate): V (sherwood oil)=3:1] and obtains light yellow crystal, fusing point: 100-103 С.
(3) synthesizing of (1E, 4E)-1-(2-p-methoxy-phenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), Benzaldehyde,2-methoxy (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 6h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellowish brown solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 14:synthesizing of (1E, 4E)-1-(4-p-methoxy-phenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
With embodiment 7 (1) step;
(2) synthesizing of (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
With embodiment 13 (2) step;
(3) synthesizing of (1E, 4E)-1-(2-p-methoxy-phenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), Benzaldehyde,2-methoxy (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 6h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellowish brown solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 15:synthesizing of (1E, 4E)-1-(4-chloro-phenyl-)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
With embodiment 7 (1) step;
(2) synthesizing of (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
With embodiment 13 (2) step;
(3) synthesizing of (1E, 4E)-1-(4-chloro-phenyl-)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone
In 50mL there-necked flask, add (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 4-chlorobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 6h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 16:synthesizing of (1E, 4E)-1-(2,3-dichlorophenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
With embodiment 7 (1) step;
(2) synthesizing of (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
With embodiment 13 (2) step;
(3) synthesizing of (1E, 4E)-1-(2,3-dichlorophenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 2,3-dichlorobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 6h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 17:synthesizing of compound (1E, 4E)-1-(3-nitrophenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
With embodiment 7 (1) step;
(2) synthesizing of (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
With embodiment 13 (2) step;
(3) synthesizing of (1E, 4E)-1-(3-nitrophenyl)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 3-nitrobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 6h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellowish brown solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 18:synthesizing of (1E, 4E)-1-(2,4 dichloro benzene base)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(2-hydroxy phenyl)-3-butene-2-one:
With embodiment 7 (1) step;
(2) synthesizing of (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one:
With embodiment 13 (2) step;
(3) synthesizing of (1E, 4E)-1-(2,4 dichloro benzene base)-5-(2-(methylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(2-(methylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 2,4-dichlorobenzaldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 6h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 19:synthesizing of (1E, 4E)-1-(4-aminomethyl phenyl)-5-(4-(Phenylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
With embodiment 1 (1) step;
(2) synthesizing of (E)-4-(4-(Phenylsulfonic acid ester group) phenyl)-3-butene-2-one:
In 50mL there-necked flask, add (E)-4-(4-hydroxy phenyl)-3-butene-2-one (10.0 mmol), salt of wormwood (20.0 mmol), 15mL acetonitrile, drips benzene sulfonyl chloride (10.0 mmol) under stirring at room temperature, stop reaction after 2h.Be spin-dried for solvent after washing, suction filtration, oven dry gained solid, silica gel thin-layer chromatography separates [V (ethyl acetate): V (sherwood oil)=3:1] and obtains yellow crystals, fusing point: 58-61 С.
(3) synthesizing of (1E, 4E)-1-(4-aminomethyl phenyl)-5-(4-(Phenylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone:
In 50mL there-necked flask, add (E)-4-(4-(Phenylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), 2-tolyl aldehyde (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 8h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
embodiment 20:synthesizing of compound (1E, 4E)-1-(2-p-methoxy-phenyl)-5-(4-(Phenylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone, comprise the following steps:
(1) synthesizing of (E)-4-(4-hydroxy phenyl)-3-butene-2-one:
With embodiment 7 (1) step;
(2) synthesizing of (E)-4-(4-(Phenylsulfonic acid ester group) phenyl)-3-butene-2-one:
With embodiment 19 (2) step;
(3) (1E, 4E)-1-(5-chloro-1,3-dimethyl-1H-pyrazoles-4 base)-5-(4-(Phenylsulfonic acid ester group) phenyl)-Isosorbide-5-Nitrae-pentadiene-3-ketone synthetic:
In 50mL there-necked flask, add (E)-4-(4-(Phenylsulfonic acid ester group) phenyl)-3-butene-2-one (1.0 mmol), Benzaldehyde,2-methoxy (1.0 mmol), 6mL ethanol and 3mL water, after NaOH (1.2 mmol) being mixed with to 4% the aqueous solution, be slowly added drop-wise in reaction system, after stirring at room temperature 8h, stop reaction.Have solid to separate out, suction filtration, washing, oven dry obtain yellow solid, obtain target compound with dehydrated alcohol recrystallization.
qualitative data is as follows:
Proton nmr spectra (1H NMR) data to above-described embodiment 1-20 gained compound are as shown in table 1, physico-chemical property and ultimate analysis data are as shown in table 2, infrared spectra (IR) data are as shown in table 3, and carbon-13 nmr spectra (13C NMR) data are as shown in table 4.
The proton nmr spectra data of table 1 compound
The physico-chemical property of table 2 compound and ultimate analysis
The IR data of table 3 compound
Embodiment |
IR,
ν max(cm
-1)
|
1
|
IR (KBr):
n max:3037, 1670, 1575, 1502, 1458, 1415, 1375, 1199
|
2
|
IR (KBr):
n max:3053, 1653, 1591, 1573, 1500, 1448, 1375, 1176
|
3
|
IR (KBr):
n max:3068, 1653, 1595, 1527, 1498, 1473, 1369, 1172,
|
4
|
IR (KBr):
n max:3099, 1649, 1595, 1568, 1456, 1369, 1155
|
5
|
IR (KBr):
n max:3051, 1653, 1558, 1521, 1456, 1375, 1195
|
6
|
IR (KBr):
n max:3062, 1651, 1591, 1500, 1456, 1373, 1197
|
7
|
IR (KBr):
n max:3005, 1666, 1593, 1579, 1527, 1473, 1359, 1176
|
8
|
IR (KBr):
n max:3066, 1668, 1587, 1577, 1554, 1454, 1569, 1195
|
9
|
IR (KBr):
n max:2999, 1685, 1624, 1593, 1500, 1473, 1365, 1193
|
10
|
IR (KBr):
n max:3101, 1672, 1618, 1589, 1519, 1452, 1373, 1182
|
11
|
IR (KBr):
n max:3072, 1680, 1625, 1595, 1529, 1479, 1375, 1193
|
12
|
IR (KBr):
n max:3062, 1670, 1616, 1595, 1523, 1481, 1369, 1192
|
13
|
IR (KBr):
n max:3020, 1649, 1616, 1581, 1489, 1438, 1342, 1182
|
14
|
IR (KBr):
n max:3022, 1668, 1622, 1583, 1508, 1452, 1363, 1182
|
15
|
IR (KBr):
n max:3018, 1668, 1622, 1587, 1489, 1355, 1186
|
16
|
IR (KBr):
n max:3020, 1649, 1612, 1587, 1477, 1342, 1197
|
17
|
IR (KBr):
n max:3034, 1676, 1625, 1595, 1525, 1481, 1350, 1186
|
18
|
IR (KBr):
n max:3022, 1651, 1616, 1585, 1471, 1340, 1182
|
19
|
IR (KBr):
n max:3024, 1649, 1624, 1581, 1500, 1448, 1330, 1170
|
20
|
IR (KBr):
n max:3010, 1668, 1616, 1575, 1504, 1448, 1338, 1195
|
Table 4 compound
13c NMR data
biological activity test test is as follows:
test example 1:to PC 3 cell 72 h vitro inhibition screening active ingredients tests
The Anticancer Activity in vitro of target compound is tested using DMSO as object of reference, adopt MTT colorimetry through three replications the inhibiting rate of compound to Human Prostate Cancer Cells PC3.
MTT test method: by sterilizing intermediate water edge sealing for the uplink and downlink of 96 orifice plates, every hole 200
μl(peripheral hole moisture easily evaporates).The cell in vegetative period of taking the logarithm, with after 0.25% trypsinase rule digestion, is resuspended in containing in RPMI 1640 substratum of 10% FBS, with 2 × 10
4the final concentration of individual/mL is inoculated in 96 well culture plates, every hole 100
μl, the rightmost side one is classified blank group as, adds acellular serum RPMI 1640 substratum that have.Be placed in 37 DEG C, 5% CO
2saturated humidity incubator in cultivate 24 h and make cell attachment.Sop up substratum, add the blood serum medium that has containing different pharmaceutical concentration, every hole 200
μl, notices that in substratum, DMSO final concentration can not exceed 0.1%, and the every hole of blank group adds 200
μl perfect medium.Process respectively the requirement of experiment time, remove supernatant, add 100
μthe MTT of L/well concentration 0.5 mg/mL.After cultivating 4 h, add again 100
μ10% the SDS of L/well.At 37 DEG C, 12 h make crystallisate fully dissolve rear taking-up, and 5 min are swung in microseism, place 30 min under room temperature, survey OD value, and calculate inhibiting rate and P value under A595 wavelength.Compound is as shown in table 5 to PC 3 cell 72 h vitro inhibition activity test results.
Taking drug level or treatment time as transverse axis, OD value or inhibiting rate are the longitudinal axis, curve plotting.Every concentration of specimens repeats six holes, and each experiment in triplicate, is averaged as net result.
Experimental result is carried out variance analysis with SPSS software, when P<0.05, is significant difference, is that difference is extremely remarkable when P<0.01.The inhibiting rate calculation formula of cell proliferation is as follows:
Table 5 embodiment 1-20 compound is to PC3 cell 72 h vitro inhibition activity test results
test example 2:to the 72 h vitro inhibition screening active ingredients tests of Bcap-37 cell
Test method is identical with test example 1 with the calculation formula of inhibiting rate, and acquired results is in table 6.
Table 6: embodiment 1-20 compound is to Bcap-37 cell 72 h vitro inhibition activity test results
The above, it is only preferred embodiment of the present invention, not the present invention is done to any pro forma restriction, any technical solution of the present invention content that do not depart from, any simple modification, equivalent variations and the modification above embodiment done according to technical spirit of the present invention, all still belong in the scope of technical solution of the present invention.