CN101544646A - 3a-(difluoromethyl)-2,3,3a-tetrahydro-1H-benzene[d]pyrrole[1,2-a]thiazole-1-ketone and synthesis method thereof - Google Patents
3a-(difluoromethyl)-2,3,3a-tetrahydro-1H-benzene[d]pyrrole[1,2-a]thiazole-1-ketone and synthesis method thereof Download PDFInfo
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- CN101544646A CN101544646A CN200910048348A CN200910048348A CN101544646A CN 101544646 A CN101544646 A CN 101544646A CN 200910048348 A CN200910048348 A CN 200910048348A CN 200910048348 A CN200910048348 A CN 200910048348A CN 101544646 A CN101544646 A CN 101544646A
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Abstract
The invention relates to 3a-(difluoromethyl)-2,3,3a-tetrahydro-1H-benzene[d]pyrrole[1,2-a]thiazole-1-ketone and a synthesis method thereof. The structural formula of the compound is shown as right. The method comprises the following steps: dissolving difluoro gamma-methyl keto ester and catalytic dosage of paratoluenesulfonic acid into toluene, adding catalytic dosage of anhydrous magnesium sulfate, performing reflux reaction on the mixture for 20 to 60 minutes with stirring, and then adding o-phenylenediamine; adding the catalytic dosage of paratoluenesulfonic acid after continuously reacting for 10 to 15 hours, performing reflux reaction for 10 to 15 hours, performing reflux reaction for 10 to 15 hours, and ending the reaction; and performing separation and purification to obtain a yellow-white solid, namely the 3a-(difluoromethyl)-2,3,3a-dihydro-1H-benzene[d]pyrrole[1,2-a]thiazole-1-ketone, wherein the mol ratio of the difluoro gamma-methyl keto ester to the o-phenylenediamine is (1-1.2):1. The 3a-(difluoromethyl)-2,3,3a-dihydro-1H-benzene[d]pyrrole[1,2-a]thiazole-ketone has stronger activity and is more favorable for absorption. In the invention, raw materials are easy to obtain, the operation is simple, the product is synthesized by a one-pot method, the productivity is high up to 85 percent, and the product is suitable to be produced on a large scale.
Description
Technical field:
The present invention relates to a kind of is 3 '-difluoromethyl-1-benzoglyoxaline pyrrolidinone derivatives and synthetic method thereof, particularly a kind of 3a-(difluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone and synthetic method thereof.
Background technology:
Heterocyclic chemistry is very important in an organic chemistry branch.Heterogeneous ring compound almost accounts for 1/3rd of known organic compound, and of many uses, is the very important material of a class.Some of many important materials such as chlorophyll, protoheme, nucleic acid and clinical application have the natural drug of significant curative effect and synthetic drugs etc., all contain the structure of heterogeneous ring compound.Mostly alkaloid is the medium-height grass the effective elements of the medicine, and the overwhelming majority is nitrogenous heterogeneous ring compound.Nitrogen-containing heterocycle compound is a part important in the organic compound, and it has almost accounted for the overwhelming majority of heterogeneous ring compound.Nitrogen-containing heterocycle compound has a wide range of applications in field of fine chemical such as agricultural chemicals, medicine, dyestuff, is the focus that people study all the time.
The benzoglyoxaline member ring systems has certain property of medicine, is present in the minority medicine.The benzimidazoles insect repellent be a kind of insect repellent benzimidazoles medicine commonly used in edible animal (pig, ox, sheep, horse, poultry etc.) aquaculture to animal body in various parasitic nematodes, tapeworm the strong effect of killing is arranged, part benzimidazoles medicine is also effective to liver fluke.The benzimidazoles medicine is to the mammal low toxicity, so be suitable as the medicine of the enteron parasite disease of livestock such as pig, ox, sheep, horse and poultry animal, is the antiparasitic of efficient, wide spectrum, low toxicity.
Document (Chimirri, A. were arranged in 1989; Sarro, A.D.; Sarro, G.D.; Grasso, S.; Trimarchi, G.R.J.Med.Chem.1989,32,93-95.) reported that benzoglyoxaline pyrrolones derivative has anti-epileptic, anticonvulsant biological activity, can be applicable in the medicine.There is phenyl ring the benzoglyoxaline pyrrolones derivative 3a position of being reported in this piece article, and on the phenyl ring electron-withdrawing group is arranged.
The synthetic method of this compound does not have report at present as yet.
Summary of the invention:
One of purpose of the present invention is to provide a kind of new compound 3a-(difluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone.
Two of purpose of the present invention is to provide the synthetic method of this compound.
For achieving the above object, the reaction mechanism of the inventive method is:
According to above-mentioned reaction mechanism, the present invention adopts following technical scheme:
A kind of 3 ' difluoromethyl-1-benzoglyoxaline pyrrolidinone derivatives is characterized in that the structure of this compound is:
3a-(difluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone
The physical parameter of this compound:
Molecular formula: C
11H
10F
2N
2O
Structural formula:
Chinese named: 3a-(difluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone
English name: 3a-(difluoromethyl)-2,3,3a, 4-tetrahydro-1H-benzo[d] pyrrolo[1,2-a] imidazol-1-one
Molecular weight: 224.08
Outward appearance: white-yellowish solid
Fusing point: 79.4～81.8 degrees centigrade
Infrared spectra (adopting the Perkin-Elmer983G infrared spectrometer, liquid-film method):
νmax(cm
-1)：3273，3065，2933，289，1918，1878，1713，1606，1492，1429，1362，1216，1068，1018，974，740
Proton nmr spectra (500MHz, CDCl
3): 7.460,7.445, (d, J
1=7.5Hz, 1H, ArH); 7.017,7.015,7.001,7.000,6.986,6.984 (t, d, J
1=7.75Hz, J
2=1.25Hz, 1H, ArH); 6.875,6.860,6.845 (t, J=7.5Hz, 1H, ArH); 6.723,6.708 (d, J=7.5Hz, 1H, ArH); 5.804,5.692,5.580 (t, J=56Hz, 1H, CF
2H); 4.576 (s, 1H, NH); 2.921～2.804 (m, 2H, CH
2); 2.602～2.548 (m, 1H, CH
2); 2.357～2.292 (m, 1H, CH
2)
Nucleus magnetic resonance fluorine spectrum (470MHz, CDCl
3, interior mark: C
6F
6) :-133.23 ,-133.34 (d, J=51.7Hz, 0.5);-133.83 ,-133.95 (d, J=56.4Hz, 1);-135.18 ,-135.30 (d, J=56.4Hz, 1);-135.79 ,-135.91 (d, J=56.4Hz, 0.5)
Carbon-13 nmr spectra (125MHz, CDCl
3): 176.06; 141.70; 129.45; 125.96,120.58,115.53; 110.53; 115.53,113.54,111.55 (t, J=248.75Hz); 85.51,85.31,85.10 (t, J=25.625Hz); 33.36; 29.23
A kind of synthetic above-mentioned 3a-(difluoromethyl)-2,3,3a, the method for 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone, its feature in the concrete steps of this method of fourth is; Difluoro gamma-keto acid ethyl ester and catalytic dosage of paratoluenesulfonic acid are dissolved in the toluene, add the anhydrous magnesium sulfate of catalyst levels again, stir down back flow reaction adds O-Phenylene Diamine after 20～60 minutes; Continue reaction and add catalytic dosage of paratoluenesulfonic acid again after 10～15 hours, back flow reaction 10～15 hours, reaction finishes; Through separation and purification, get white-yellowish solid and be 3a-(difluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone; The mol ratio of described difluoro gamma-keto acid ethyl ester and O-Phenylene Diamine is: (1～1.2): 1.
In the pharmaceutical chemistry field, fluorine atom or one contain fluoroalkyl and are incorporated into and are considered to one of most effectual way that host compound is modified in the host molecule.Because the fluorine atom radius is little, has bigger electronegativity again, its formed C-F key bond energy is than big many of C-H key bond energy, the stability and the physiologically active of organofluorine compound have been increased significantly, fluorinated organic compound also has higher fat-soluble and hydrophobicity in addition, promote it to absorb in vivo and transmission speed, physiological action is changed.Have characteristics such as consumption is few, toxicity is low, drug effect is high, metabolic capacity is strong so a lot of fluorine-containing medicines and agricultural chemicals are relative on performance, this makes its proportion in the new pharmaceutical pesticide species more and more higher.Therefore the fluoro-containing group difluoromethyl of the handle of the invention with electrophilic function is incorporated into the 3a position of benzoglyoxaline pyrrolones derivative, replace the phenyl ring that has the electrophilic function originally, make 3a-of the present invention (difluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone should have stronger activity, more helps absorbing.The inventive method raw material is easy to get, and operates very simply, and one kettle way is synthetic, and productive rate is fit to scale operation up to 85%.
Embodiment:
Embodiment 1: 1. add difluoro gamma-keto acid ethyl ester 0.43 gram in 50 milliliters the round-bottomed flask that reflux condensing tube is housed, p-methyl benzenesulfonic acid 0.019 gram, 25 milliliters of toluene, anhydrous magnesium sulfate 0.2 gram.Said mixture stirring and refluxing in oil bath adds O-Phenylene Diamine 0.216 gram after half an hour; 2. reactant reaction solution under refluxing becomes redness gradually.React and add 0.019 gram p-methyl benzenesulfonic acid after 12 hours again.Continue reaction 12 hours, then stopped reaction.Suction filtration was removed anhydrous magnesium sulfate, concentrated filtrate after reaction finished.3. the concentrated solution that obtains is separated with silica gel column chromatography, developping agent is that volume ratio is the sherwood oil of 6:1 and the mixed solvent of ethyl acetate, gets white-yellowish solid 3a-(difluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone 0.38 gram, productive rate is 85%.
Embodiment 2: 1. add difluoro gamma-keto acid ethyl ester 10.8 grams in 250 milliliters the round-bottomed flask that reflux condensing tube is housed, p-methyl benzenesulfonic acid 0.475 gram, 150 milliliters of toluene, anhydrous magnesium sulfate 5 grams.Said mixture stirring and refluxing in oil bath adds O-Phenylene Diamine 5.4 grams after half an hour; 2. reactant reaction solution under refluxing becomes redness gradually.React and add 0.475 gram p-methyl benzenesulfonic acid after 12 hours again.Continue reaction 16 hours, then stopped reaction.Suction filtration was removed anhydrous magnesium sulfate, concentrated filtrate after reaction finished.3. the concentrated solution that obtains is separated with silica gel column chromatography, developping agent is that volume ratio is the sherwood oil of 6:1 and the mixed solvent of ethyl acetate, gets white-yellowish solid 3a-(difluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone 9.3 grams, productive rate is 83%.
Embodiment 3: 1. add difluoro gamma-keto acid ethyl ester 108 grams in 2 liters the round-bottomed flask that reflux condensing tube is housed, p-methyl benzenesulfonic acid 4.75 grams, 1000 milliliters of toluene, anhydrous magnesium sulfate 25 grams.Said mixture stirring and refluxing in oil bath adds O-Phenylene Diamine 54 and restrains 2. reactant reaction solution under refluxing and become redness gradually after half an hour.React and add 4.75 gram p-methyl benzenesulfonic acids after 12 hours again.Continue reaction 20 hours, then stopped reaction.Suction filtration was removed anhydrous magnesium sulfate, concentrated filtrate after reaction finished.3. the concentrated solution that obtains is separated with silica gel column chromatography, developping agent is that volume ratio is the sherwood oil of 6:1 and the mixed solvent of ethyl acetate, gets white-yellowish solid 3a-(difluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone 90.7 grams, productive rate is 81%.
Claims (2)
1. a 3a-(difluoromethyl) 2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone is characterized in that the structure of this compound is:
2. one kind is synthesized 3a-according to claim 1 (difluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] method of imidazoles-1-ketone, the concrete steps that it is characterized in that this method are: difluoro gamma-keto acid ethyl ester and catalytic dosage of paratoluenesulfonic acid are dissolved in the toluene, add the anhydrous magnesium sulfate of catalyst levels again, stir down back flow reaction adds O-Phenylene Diamine after 20～60 minutes; Continue reaction and add catalytic dosage of paratoluenesulfonic acid again after 10～15 hours, back flow reaction 10～15 hours, reaction finishes; Through separation and purification, get white-yellowish solid and be 3a-(difluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone; The mol ratio of described difluoro gamma-keto acid ethyl ester and O-Phenylene Diamine is: (1～1.2): 1.
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| CN200910048348A CN101544646A (en) | 2009-03-26 | 2009-03-26 | 3a-(difluoromethyl)-2,3,3a-tetrahydro-1H-benzene[d]pyrrole[1,2-a]thiazole-1-ketone and synthesis method thereof |
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