CN101544658A - (3R)-3-benzyl-7a-(difluoromethyl)tetrahydropyrrolo[2,1-b]oxazole-5(6H)-ketone and synthesis method thereof - Google Patents
(3R)-3-benzyl-7a-(difluoromethyl)tetrahydropyrrolo[2,1-b]oxazole-5(6H)-ketone and synthesis method thereof Download PDFInfo
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- CN101544658A CN101544658A CN200910048354A CN200910048354A CN101544658A CN 101544658 A CN101544658 A CN 101544658A CN 200910048354 A CN200910048354 A CN 200910048354A CN 200910048354 A CN200910048354 A CN 200910048354A CN 101544658 A CN101544658 A CN 101544658A
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- difluoromethyl
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Abstract
The invention relates to (3R)-3-benzyl-7a-(difluoromethyl)tetrahydropyrrolo[2,1-b]oxazole-5(6H)-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, catalytic dosage of paratoluenesulfonic acid and anhydrous magnesium sulfate into toluene, refluxing the mixture for half an hour with stirring, then adding (D)-phenylpropanolamine, and adding the catalytic dosage of paratoluenesulfonic acid after continuously reacting for 10 to 15 hours, wherein the mol ratio of the difluoro gamma-methyl keto ester to the (D)-phenylpropanolamine is (1-1.2):1; performing reflux reaction for 10 to 15 hours, and ending the reaction; and performing suction filtration, filtrate condensation, separation and purification to obtain a light yellow needled solid, namely the (3R)-3-benzyl-7a-(difluoromethyl)tetrahydropyrrolo[2,1-b]oxazole-5(6H)-ketone. The (3R)-3-benzyl-7a-(difluoromethyl)tetrahydropyrrolo[2,1-b]oxazole-5(6H)-ketone and the synthesis method thereof have prominent characteristics and marked advantages that: raw materials are easy to obtain, the operation is simple, the product is synthesized by a one-pot method, the productivity is up to 74 percent, and the product is suitable to be produced on a large scale.
Description
Technical field:
The present invention relates to a kind of new compound (3R)-3-benzyl-7a-(difluoromethyl) Pyrrolidine also [2,1-b] oxazole-5 (6H)-ketone and synthetic method thereof.
Background technology:
Fluorine chemistry is as a vitochemical branch, from finding vitality abrim all the time till now in beginning.In industrial and agricultural production, fluorochemicals is used widely.
Up to now, in thousands of organic compound of synthetic, have only the organic compound of minority to have physiologically active, and have in the organic compound of physiologically active at these, great majority contain heterocycle.Therefore, design has caused the attention of synthetic chemistry man with synthetic heterogeneous ring compound with physiologically active.Heterocyclic chemistry and life science, Materials science has confidential relation.Some components of life entity have heterocycle structure, as amino acid, nucleic acid etc.Oxazole member ring systems compound is the important heterogeneous ring compound of a class, has a wide range of applications.The oxazole compounds has certain property of medicine, is present in minority agricultural chemicals and the medicine.
Document (Aicher, T.D. were arranged in 1998; Balkan, B.; Bell, P.A.; Brand, L.J.; Cheon, S.H.; Deems, R.O.; Fell, J.B.; Fillers, W.S.; Fraser, J.D.; Gao, J.; Knorr, D.C.; Kahle, G.G.; Leone, C.L.; Nadelson, J.; Simpson, R.; Smith, H.C.J.Med.Chem.1998,41,4556-4566.) reported that a kind of nafoxidine Bing oxazole Hete rocyclic derivatives has lowering blood glucose concentration, the physiologically active of treatment diabetes.Calendar year 2001 has document (Ranjit C. again; Desai.; J.Org.Chem.2001,66,4939-4940) this compounds has been done further research, find to strengthen the electron-withdrawing power of above-claimed cpd 7a bit substituent, can strengthen its physiologically active.
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 be to provide a kind of new compound (3R)-3-benzyl-7a-(difluoromethyl) Pyrrolidine also [2,1-b] oxazole-5 (6H)-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 (3R)-3-benzyl-7a-(difluoromethyl) Pyrrolidine also [2,1-b] oxazole-5 (6H)-ketone is characterized in that the structure of this compound is:
(3R)-3-benzyl-7a-(difluoromethyl) Pyrrolidine also [2,1-b] oxazole-5 (6H)-ketone
The physical parameter of this compound:
Molecular formula: C
14H
15F
2NO
2
Structural formula:
Chinese named: (3R)-3-benzyl-7a-(difluoromethyl) Pyrrolidine also [2,1-b] oxazole-5 (6H)-ketone
English name:
(3R)-3-benzyl-7a-(difluoromethyl)tetrahydropyrrolo[2，1-b]oxazol-5(6H)-one
Molecular weight: 267.27
Outward appearance: faint yellow needle-like solid
Fusing point: 80.1～80.8 degrees centigrade
Infrared spectra (adopting the Perkin-Elmer983G infrared spectrometer, liquid-film method):
Vmax(cm
-1)：3084，3029，2941，2908，1958，1887，1821，1704，1604，1584，1498，1454，1346，1137，1078，1031，735，702
Proton nmr spectra (500MHz, CDCl
3): 7.372～7.207 (m, 5H, ArH); 5.569,5.458,5.348 (t, J=55Hz, 1H, CF
2H); 4.435～4.379 (m, 1H, CH); 4.183～4.144 (m, 1H, CH
2); 4.007～3.976 (m, 1H, CH
2); 3.126,3.115,3.098,3.088 (dd, J
1=14Hz, J
2=5.5Hz, 1H, CH
2); 2.848～2.773 (m, 2H, CH
2); 2.552～2.468 (m, 2H, CH
2); 2.043～1.952 (m, 1H, CH
2)
Nucleus magnetic resonance fluorine spectrum (470MHz, CDCl
3, interior mark: C
6F
6) :-129.67 ,-129.78 (d, J=51.7Hz, 0.3);-130.19 ,-130.31 (d, J=56.4Hz, 1);-130.84 ,-130.96 (d, J=51.7Hz, 1);-131.96 ,-132.07d, J=51.7Hz, 0.3)
Carbon-13 nmr spectra (125MHz, CDCl
3): 178.44; 136.41; 129.09; 128.32; 126.55; 115.17,113.19,111.21 (J=247.5Hz); 98.75,98.54,98.35 (J=26.25Hz); 72.99; 56.20; 39.17; 32.95; 27.42
A kind of above-mentioned (3R)-3-benzyl-7a-(difluoromethyl) Pyrrolidine also [2 for preparing, the method of 1-b] oxazole-5 (6H)-ketone, it is characterized in that this method has following steps: difluoro gamma-keto acid ethyl ester and catalytic dosage of paratoluenesulfonic acid and anhydrous magnesium sulfate are dissolved in the toluene, add (D)-amphetamine alcohol after stirring the half an hour of refluxing down; React and add catalytic dosage of paratoluenesulfonic acid again after 10～15 hours; Wherein difluoro gamma-keto acid ethyl ester with (D)-mol ratio of amphetamine alcohol is: (1～1.2): 1; Back flow reaction 10～15 hours, reaction finishes; Suction filtration, concentrated filtrate; Separation and purification get faint yellow needle-like solid be (3R)-3-benzyl-7a-(difluoromethyl) Pyrrolidine also [2,1-b] oxazole-5 (6H)-ketone.
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.The invention to the fluoro-containing group difluoromethyl with strong electrophilic function being incorporated into the 7a position of nafoxidine Bing oxazole Hete rocyclic derivatives, replace the phenyl ring that has the electrophilic function originally, make (3R)-3-benzyl-7a-of the present invention (difluoromethyl) Pyrrolidine also [2,1-b] oxazole-5 (6H)-ketone should have stronger activity, more helps absorbing.
The present invention has following conspicuous high-lighting characteristics and significance advantage: raw material of the present invention is easy to get, and operates very simply, and one kettle way is synthetic, and productive rate 74% is fit to scale operation.
Embodiment:
Embodiment one: preparation (3R)-3-benzyl-7a-(difluoromethyl) Pyrrolidine also [2,1-b] oxazole-5 (6H)-ketone adopts following steps: 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 (D)-amphetamine alcohol 0.302 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 after reaction finished, and filtrate concentrates.3. the concentrated solution that obtains is separated with silica gel column chromatography, developping agent is that volume ratio is the sherwood oil of 4:1 and the mixed solvent of ethyl acetate, gets faint yellow needle-like solid 0.39 gram, and productive rate is 74%.
Embodiment two: preparation (3R)-3-benzyl-7a-(difluoromethyl) Pyrrolidine also [2,1-b] oxazole-5 (6H)-ketone adopts following steps: 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 (D)-amphetamine alcohol 7.55 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 after reaction finished, and filtrate concentrates.3. the concentrated solution that obtains is separated with silica gel column chromatography, developping agent is that volume ratio is the sherwood oil of 4:1 and the mixed solvent of ethyl acetate, gets faint yellow needle-like solid 9.48 grams, and productive rate is 71%.
Embodiment three: preparation (3R)-3-benzyl-7a-(difluoromethyl) Pyrrolidine also [2,1-b] oxazole-5 (6H)-ketone adopts following steps: 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 20 grams.Said mixture stirring and refluxing in oil bath adds (D)-amphetamine alcohol 75.5 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 after reaction finished, and filtrate concentrates.3. the concentrated solution that obtains is separated with silica gel column chromatography, developping agent is that volume ratio is the sherwood oil of 4:1 and the mixed solvent of ethyl acetate, gets faint yellow needle-like solid 90.78 grams, and productive rate is 68%.
Claims (2)
1. (3R)-3-benzyl-7a-(difluoromethyl) Pyrrolidine [2,1-b] oxazoles-5 (6H)-ketone also is characterized in that the structure of this compound is:
2. one kind is synthesized the also method of [2,1-b] oxazoles-5 (6H)-ketone of (3R)-3-benzyl-7a-according to claim 1 (difluoromethyl) Pyrrolidine, it is characterized in that this method has following steps:
A. difluoro gamma-keto acid ethyl ester and catalytic dosage of paratoluenesulfonic acid and anhydrous magnesium sulfate are dissolved in the toluene, add (D)-amphetamine alcohol after stirring the half an hour of refluxing down; React and add catalytic dosage of paratoluenesulfonic acid again after 10～15 hours; Wherein difluoro gamma-keto acid ethyl ester with (D)-mol ratio of amphetamine alcohol is: (1～1.2): 1;
B. back flow reaction is 10～15 hours, and reaction finishes; Suction filtration, concentrated filtrate; Separation and purification get faint yellow needle-like solid be (3R)-3-benzyl-7a-(difluoromethyl) Pyrrolidine also [2,1-b] oxazole-5 (6H)-ketone.
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