CN101544648A - 3a-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-benzene[d]pyrrole[1,2-a]imidazole-1-ketone and synthesis method thereof - Google Patents
3a-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-benzene[d]pyrrole[1,2-a]imidazole-1-ketone and synthesis method thereof Download PDFInfo
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- CN101544648A CN101544648A CN200910048353A CN200910048353A CN101544648A CN 101544648 A CN101544648 A CN 101544648A CN 200910048353 A CN200910048353 A CN 200910048353A CN 200910048353 A CN200910048353 A CN 200910048353A CN 101544648 A CN101544648 A CN 101544648A
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Abstract
The invention relates to 3a-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-benzene[d]pyrrole[1,2-a]imidazole-1-ketone and a synthesis method thereof. The structural formula of the compound is shown as right. The method comprises the following steps: dissolving trifluoro gamma-methyl keto ester and catalytic dosage of paratoluenesulfonic acid into toluene, adding catalytic dosage of anhydrous magnesium sulfate, carrying out reflux reaction on the mixture to reflux 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, and continuously reacting for 10 to 15 hours, wherein the mol ratio of the trifluoro gamma-methyl keto ester to the o-phenylenediamin is (1-1.2):1; and after the reaction is finished, performing separation and purification to obtain a white solid, namely the 3a-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-benzene[d]pyrrole[1,2-a]imidazole-1-ketone. The 3a-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-benzene[d]pyrrole[1,2-a]imidazole-1-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 93 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 '-Trifluoromethyl-1-benzoglyoxaline pyrrolidinone derivatives and synthetic method thereof, particularly a kind of 3a-(trifluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone and synthetic method thereof.
Background technology:
Heterogeneous ring compound is very wide in distributed in nature, and its quantity almost accounts for 1/3rd of known organic compound, and purposes is also a lot.Some of many important materials such as chlorophyll and clinical application have the natural drug of significant curative effect and synthetic drugs etc., all contain the structure of heterogeneous ring compound.And in the structure of these heterogeneous ring compounds, mostly contain nitrogen heteroatom, therefore the research to nitrogen-containing heterocycle compound was once becoming focus.
Benzimidazoles compound has excellent structure and performance characteristics and uses very extensive.It has good biological activity such as anticancer, antimycotic, anti-inflammatory, treatment hypoglycemia and physiologic derangement etc.; Also have multiple medical active such as proton pump inhibition, parasiticide, antiviral property, atherogenic activity etc.Pyrrolidone compound also is the very high compound of a class using value, is important medicine intermediate, in order to produce piracetam, Myelosan etc., also is the raw material of producing Polyvinylpyrolidone (PVP).The benzoglyoxaline pyrrolidone compound is the bis-heterocyclic compounds that contains two nitrogen heteroatoms, and structure is special, and their polymkeric substance is widely used as heat-resisting gas separation membrane material (as: poly-pyrrole throat) usually.
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.
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-(trifluoromethyl)-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 that the inventive method has adopted is:
According to above-mentioned reaction mechanism, the present invention adopts following technical scheme:
A kind of 3 '-Trifluoromethyl-1-benzoglyoxaline pyrrolidinone derivatives is characterized in that, the structure of this compound is:
3a-(trifluoromethyl)-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
9F
3N
2O
Structural formula:
Chinese named: 3a-(trifluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone
English name: 3a-(trifluoromethyl)-2,3,3a, 4-tetrahydro-1H-benzo[d] pyrrolo[1,2-a] imidazol-1-one
Molecular weight: 242.07
Outward appearance: white solid
Fusing point: 143.5～146.3 degrees centigrade
Infrared spectra (adopting the Perkin-Elmer983G infrared spectrometer, liquid-film method):
νmax(cm
-1)：3259，3039，2940，1714，1606，1490，1434，1365，1325，1201，1172，1153，1054，1017，971，762，745
Proton nmr spectra (500MHz, Acetone): 7.373,7.372,7.358,7.357 (dd, J
1=7.5Hz, J
2=0.5Hz, 1H, ArH); 6.999,6.997,6.984,6.982,6.968,6.966 (td, J
1=7.75Hz, J
2=1Hz, 1H, ArH); 6.815～6.750 (m, 2H, ArH); 6.479 (s, 1H, NH); 2.914～2.841 (m, 2H, CH
2); 2.675～2.541 (m, 2H, CH
2)
Nucleus magnetic resonance fluorine spectrum (470MHz, Acetone, interior mark: C
6F
6): δ=-86.43 (s)
Carbon-13 nmr spectra (125MHz, Acetone): 177.51; 143.55; 131.71; 129.60,127.31,125.02,122.73 (J=286.25Hz); 126.67; 120.69; 115.86; 111.21; 86.52,86.27,86.02,, 85.77 (J=31.25Hz); 33.39; 31.75
A kind of synthetic above-mentioned 3a-(trifluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] method of imidazoles-1-ketone, it is characterized in that the concrete steps of this method are: trifluoro γ-ketone acid methyl esters and catalytic dosage of paratoluenesulfonic acid are dissolved in the toluene, add the anhydrous magnesium sulfate of catalyst levels again, back flow reaction is 20～60 minutes under stirring, and adds O-Phenylene Diamine; Continue reaction and add catalytic dosage of paratoluenesulfonic acid again after 10～15 hours, continue reaction 10～15 hours; The mol ratio of described trifluoro γ-ketone acid methyl esters and O-Phenylene Diamine is: (1～1.2): 1; Reaction gets white solid through separation and purification and is 3a-(trifluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone after finishing.
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 wants big many than 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.The fluoro-containing group trifluoromethyl that the handle of the invention has an electrophilic function is incorporated into the 3a position of benzoglyoxaline pyrrolones derivative, replace the phenyl ring that has the electrophilic function originally, thereby 3a-of the present invention (trifluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone should have stronger activity, more helps absorbing.
Raw material of the present invention is easy to get, and operates very simply, and one kettle way is synthetic, and productive rate is fit to scale operation up to 93%.
Embodiment:
Embodiment one: 1. add trifluoro γ-ketone acid methyl esters 0.44 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 yellowing gradually under refluxing.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 solid 3a-(trifluoromethyl) 2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone 0.45 gram, productive rate is 93%.
Embodiment two: 1. add trifluoro γ-ketone acid methyl esters 11 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 8 grams.Said mixture stirring and refluxing in oil bath adds O-Phenylene Diamine 5.4 grams after half an hour; 2. reactant reaction solution yellowing gradually under refluxing.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 solid 3a-(trifluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone 10.91 grams, productive rate is 90%.
Embodiment three: 1. add trifluoro γ-ketone acid methyl esters 110 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 yellowing gradually under refluxing 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 solid 3a-(trifluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone 104.10 grams, productive rate is 86%.
Claims (2)
1. a 3a-(trifluoromethyl)-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 (trifluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] method of imidazoles-1-ketone, it is characterized in that this method has following steps: trifluoro γ-ketone acid methyl esters and catalytic dosage of paratoluenesulfonic acid are dissolved in the toluene, add the anhydrous magnesium sulfate of catalyst levels again, back flow reaction is 20～60 minutes under stirring, and adds O-Phenylene Diamine; Continue reaction and add catalytic dosage of paratoluenesulfonic acid again after 10～15 hours, continue reaction 10～15 hours; The mol ratio of described trifluoro γ-ketone acid methyl esters and O-Phenylene Diamine is: (1～1.2): 1; Reaction gets white solid through separation and purification and is 3a-(trifluoromethyl)-2,3,3a, 4-tetrahydrochysene-1H-benzo [d] pyrroles [1,2-a] imidazoles-1-ketone after finishing.
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| CN200910048353A CN101544648A (en) | 2009-03-26 | 2009-03-26 | 3a-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-benzene[d]pyrrole[1,2-a]imidazole-1-ketone and synthesis method thereof |
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| CN200910048353A CN101544648A (en) | 2009-03-26 | 2009-03-26 | 3a-(trifluoromethyl)-2,3,3a,4-tetrahydro-1H-benzene[d]pyrrole[1,2-a]imidazole-1-ketone and synthesis method thereof |
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