CN101544664A - 3a-(difluoromethyl)-3,3a-dihydrobenzene[d]pyrrole[2,1-b]thiazole-1(2H)-ketone and synthesis method thereof - Google Patents
3a-(difluoromethyl)-3,3a-dihydrobenzene[d]pyrrole[2,1-b]thiazole-1(2H)-ketone and synthesis method thereof Download PDFInfo
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- CN101544664A CN101544664A CN200910048347A CN200910048347A CN101544664A CN 101544664 A CN101544664 A CN 101544664A CN 200910048347 A CN200910048347 A CN 200910048347A CN 200910048347 A CN200910048347 A CN 200910048347A CN 101544664 A CN101544664 A CN 101544664A
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- difluoromethyl
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- thiazole
- dihydrobenzene
- pyrrole
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Abstract
The invention relates to 3a-(difluoromethyl)-3,3a-dihydrobenzene[d]pyrrole[2,1-b]thiazole-1(2H)-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, stirring the mixture to reflux for 20 to 60 minutes, and then adding ortho-aminophenol; adding the catalytic dosage of paratoluenesulfonic acid after continuously reacting 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 sticky liquid, namely the 3a-(difluoromethyl)-3,3a-dihydrobenzene[d]pyrrole[2,1-b]thiazole-1(2H)-ketone, wherein the mol ratio of the difluoro gamma-methyl keto ester to the ortho-aminophenol is (1-1.2):1. The 3a-(difluoromethyl)-3,3a-dihydrobenzene[d]pyrrole[2,1-b]thiazole-1(2H)-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 67 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-benzothiazole pyrrolidinone derivatives and synthetic method thereof, particularly a kind of 3a-(difluoromethyl)-3,3a-dihydrobenzo [d] pyrroles [2,1-b] thiazoles-1 (2H)-ketone and synthetic method thereof.
Background technology:
Organic fluorine chemistry is a vitochemical important branch.Fluorinated organic compound is used widely in pharmaceutical industries, and up to the present, the fluorine-containing medicine of listing has nearly 2000, is used for the treatment of various diseases.And in some agricultural chemicals of latest developments, much all be fluorochemicals.For example, the broad-spectrum herbicide JV-485 that is used for winter wheat is compounds that contain four fluorine atoms.In addition, fluorinated organic compound also can be used for the dyestuff of excellent property, polymer-function material and fluorinated liquid crystal material.
Heterogeneous ring compound almost account for three of known organic compound/, and of many uses, be the very important material of a class.Nitrogenous thia ring benzothiazole compound is the important heterogeneous ring compound of a class, has a wide range of applications in pharmaceutical chemistry and materials chemistry.Therefore, the synthetic of benzothiazole heterocyclic compound caused that people pay attention to widely.As the 2-aminobenzothiazole is exactly the important dyestuff intermediate of a class.Being used to produce cationic violet 3RL, also being used to produce cationic violet 2RL etc. with synthetic 3-methylbenzothiazole hydrazone, also is the raw material of other organic syntheses.
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)-3,3a-dihydrobenzo [d] pyrroles [2,1-b] thiazoles-1 (2H)-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 3a-(difluoromethyl)-3,3a-dihydrobenzo [d] pyrroles [2,1-b] thiazoles-1 (2H)-ketone is characterized in that, the structure of this compound is:
3a-(difluoromethyl)-3,3a-dihydrobenzo [d] pyrroles [2,1-b] thiazoles-1 (2H)-ketone
The physical parameter of this compound:
Molecular formula: C
11H
9F
2NOS
Structural formula:
Chinese named: 3a-(difluoromethyl)-3,3a-dihydrobenzo [d] pyrroles [2,1-b] thiazoles-1 (2H)-ketone
English name: 3a-(difluoromethyl)-3,3a-dihydrobenzo[d] pyrrolo[2,1-b] thiazol-1 (2H)-one
Molecular weight: 241.26
Outward appearance: yellow thick liquid
Infrared spectra (adopting the Perkin-Elmer983G infrared spectrometer, liquid-film method):
νmax(cm
-1)：3010，2936，2865，1942，1856，1732，1602，1498，1436，1357，1220，1062，1017，968，746
Proton nmr spectra (500MHz, CDCl
3): 7.657,7.642 (d, J=7.5Hz, 1H, ArH); 7.145,7.130,7.116 (d, J=7.5Hz, 2H, ArH); 7.083～7.050 (m, 1H, ArH); 5.878,5.766,5.655 (t, J=56Hz, 1H, CF
2H); 2.961～2.870 (m, 1H, CH
2); 2.820,2.800,2.778 (t, J=10Hz, 1H, CH
2); 2.672～2.587 (m, 2H, CH
2)
Nucleus magnetic resonance fluorine spectrum (470MHz, CDCl
3, interior mark: C
6F
6) :-127.81 ,-127.93 (d, J=56.4Hz, 0.8);-128.39 ,-128.51 (d, J=56.4Hz, 1);-131.91 ,-132.02 (d, J=51.7Hz, 1);-132.49 ,-132.61 (d, J=56.4Hz, 0.8)
Carbon-13 nmr spectra (125MHz, CDCl
3): 173.58; 134.95; 130.32; 126.05; 125.82; 122.33; 117.24; 115.99,113.99,112.00 (J=250Hz); 80.47,80.265,80.06 (J=25.6Hz); 33.23; 26.76
A kind of synthetic above-mentioned 3a-(difluoromethyl)-3,3a-dihydrobenzo [d] pyrroles [2,1-b] method of thiazole-1 (2H)-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, the anhydrous magnesium sulfate that adds catalyst levels again, stir down back flow reaction adds adjacent amino thiophene phenol 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, and through separation and purification, gets yellow thick liquid and is 3a-(difluoromethyl)-3,3a-dihydrobenzo [d] pyrroles [2,1-b] thiazoles-1 (2H)-ketone; The mol ratio of described difluoro gamma-keto acid ethyl ester and adjacent amino thiophene phenol 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, and increase heteroatomic electronegativity and also generally can increase original heterocyclic physiologically active.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 invention is modified to the benzothiazole ring to the benzoglyoxaline ring, and the fluoro-containing group difluoromethyl with electrophilic function is incorporated into the 3a position of benzothiazole pyrrolones derivative, replace the phenyl ring that has the electrophilic function originally, make 3a-of the present invention (difluoromethyl)-3,3a-dihydrobenzo [d] pyrroles [2,1-b] thiazole-1 (2H)-ketone should have the activity that more increases, 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 67% is fit to scale operation.
Embodiment:
Embodiment 1: 1. add difluoro gamma-keto acid ethyl ester 0.40 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 adjacent amino thiophene phenol 0.25 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 yellow thick liquid 0.32 gram, and productive rate is 67%.
Embodiment 2: 1. add difluoro gamma-keto acid ethyl ester 10 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 adjacent amino thiophene phenol 6.25 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 18 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 yellow thick liquid 7.71 grams, and productive rate is 64%.
Embodiment 3: 1. add difluoro gamma-keto acid ethyl ester 100 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 adjacent amino thiophene phenol 62.5 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 yellow thick liquid 74.7 grams, and productive rate is 62%.
Claims (2)
1. a 3a-(difluoromethyl)-3,3a-dihydrobenzo [d] pyrroles [2,1-b] thiazoles-1 (2H)-ketone is characterized in that the structure of this compound is:
2. one kind is synthesized 3a-according to claim 1 (difluoromethyl)-3,3a-dihydrobenzo [d] pyrroles [2,1-b] method of thiazole-1 (2H)-ketone, it is characterized in that this method has following steps: difluoro gamma-keto acid ethyl ester and catalytic dosage of paratoluenesulfonic acid are dissolved in the toluene, the anhydrous magnesium sulfate that adds catalyst levels again, stir down back flow reaction adds adjacent amino thiophene phenol 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, and through separation and purification, gets yellow thick liquid and is 3a-(difluoromethyl)-3,3a-dihydrobenzo [d] pyrroles [2,1-b] thiazoles-1 (2H)-ketone; The mol ratio of described difluoro gamma-keto acid ethyl ester and adjacent amino thiophene phenol is: (1～1.2): 1.
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| CN200910048347A CN101544664A (en) | 2009-03-26 | 2009-03-26 | 3a-(difluoromethyl)-3,3a-dihydrobenzene[d]pyrrole[2,1-b]thiazole-1(2H)-ketone and synthesis method thereof |
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