CN104098535A - Preparation method for 4-(3-fluorine phenyl)-2,2-phenyl-5-(4-(methylmercapto-)phenyl) furan-3(2H)-ketone - Google Patents
Preparation method for 4-(3-fluorine phenyl)-2,2-phenyl-5-(4-(methylmercapto-)phenyl) furan-3(2H)-ketone Download PDFInfo
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- CN104098535A CN104098535A CN201410364152.XA CN201410364152A CN104098535A CN 104098535 A CN104098535 A CN 104098535A CN 201410364152 A CN201410364152 A CN 201410364152A CN 104098535 A CN104098535 A CN 104098535A
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- JECUZQLBQKNEMW-UHFFFAOYSA-N CC(c(cc1)ccc1SC)=O Chemical compound CC(c(cc1)ccc1SC)=O JECUZQLBQKNEMW-UHFFFAOYSA-N 0.000 description 1
- SKOMBKMLOHIBTF-UHFFFAOYSA-N O=C(Cc1cccc(F)c1)Cl Chemical compound O=C(Cc1cccc(F)c1)Cl SKOMBKMLOHIBTF-UHFFFAOYSA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
- C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
- C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
- C07D307/58—One oxygen atom, e.g. butenolide
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Abstract
The invention discloses a preparation method for 4-(3-fluorine phenyl)-2,2-phenyl-5-(4-(methylmercapto-)phenyl)furan-3(2H)-ketone. The preparation method comprises the following steps: m-fluorobenzene acetylchloride is generated under the existence of fluorobenzene acetic acid and thionyl chloride; 2-bromine-2-methyl propionyl-bromine is reacted with trimethyl cyanogen silane to generate 3-bromine-3-methyl-2-oxo butyl cyanide; m-fluorobenzene acetylchloride is reacted with thioanisole to generate 2-(3-fluorine phenyl)-1-(4-(methylmercapto-)phenyl) acetone under the existence of aluminium trichloride and dichloromethane; the 4-(3-fluorine phenyl)-2,2-phenyl-5-(4-(methylmercapto-)phenyl)furan-3(2H)-ketone is generated by the 2-(3-fluorine phenyl)-1-(4-( methylmercapto-)phenyl)acetone and the 3-bromine-3-methyl-2-oxo butyl cyanide; a best product is obtained through separation, crystallization, filtering and drying.
Description
Technical field
The present invention relates to a kind of methodology of organic synthesis, relate in particular to a kind of 4-(3-fluorophenyl)-2, the preparation method of 2-dimethyl-5-(4-(methylthio group) phenyl) furans-3 (2H)-one.
Background technology
4-(3-fluorophenyl)-2,2-dimethyl-5-(4-(methylthio group) phenyl) furans-3 (2H)-one has stronger restraining effect, and anti-inflammatory activity is good, can be used for the fields such as medical treatment, biology, chemical industry.4-in prior art (3-fluorophenyl)-2, the production method of 2-dimethyl-5-(4-(methylthio group) phenyl) furans-3 (2H)-one is complicated, and production cost is high, and yield is low, and product purity is not high simultaneously.
Therefore,, for addressing the above problem, spy provides a kind of new technical scheme.
Summary of the invention
The object of this invention is to provide a kind of technique simple, the 4-that product yield is high (3-fluorophenyl)-2, the method for 2-dimethyl-5-(4-(methylthio group) phenyl) furans-3 (2H)-one.
The present invention is achieved through the following technical solutions:
A kind of 4-(3-fluorophenyl)-2, the preparation method of 2-dimethyl-5-(4-(methylthio group) phenyl) furans-3 (2H)-one, comprises the following steps:
A, in clean there-necked flask, add successively a fluorophenylacetic acid, sulfur oxychloride and dimethyl formamide, stirring is warming up to backflow, temperature is at 110 ℃, reaction 3～5h, reaction finishes rear air distillation and removes sulfur oxychloride, the product of collecting 64 ℃/5mmHg burgundy, obtains a fluorophenylacetyl chloride, and reaction equation is as follows:
B, at clean there-necked flask, add 2-bromo-2-methylpropionyl bromine and trimethylsilyl cyanide; temperature is cooled to room temperature after being controlled at 80～90 ℃ of stirring reaction 2～3h; the bromo-3-methyl-2-of the product 3-oxo fourth cyanogen of collecting 66～75 ℃/79mmHg, reaction equation is as follows:
C, in clean there-necked flask, add successively methylene dichloride and aluminum trichloride (anhydrous) to stir to be cooled to below 5 ℃, add again a fluorophenylacetyl chloride to stir 5～10min, temperature is controlled at 5 ℃ and starts below to drip thioanisole, time for adding is controlled 1～2h, dropwise nature and rise again to room temperature and stir 2～3h again, reaction equation is as follows:
D, the reactant in step c is poured in 36% the hydrochloric acid soln preparing, stratification after stirring 30min, extract saturated sodium bicarbonate solution and salt water washing for organic layer, washing is steamed solvent to the greatest extent by distillation, then add n-hexane dissolution dilution, be cooled to 10 ℃ of following stirred crystallization 1～3h, filtration, vacuum-drying obtain 2-(3-fluorophenyl)-1-(4-(methylthio group) phenyl) ethyl ketone;
E, in clean there-necked flask, add successively tetrahydrofuran (THF) and 2-(3-fluorophenyl)-1-(4-(methylthio group) phenyl) ethyl ketone to stir 30min, control temperature and add below sodium hydride at 30 ℃, after stirring 30min, be cooled to below 5 ℃, start to drip the bromo-3-methyl-2-of 3-oxo fourth cyanogen, time for adding is controlled at 1～1.5h, and reaction equation is as follows:
F, step e are warming up to stirring at room 5h after completion of the reaction, being cooled to 5 ℃ neutralizes with acetic acid again, distillation desolventizing, residuum adds methylene dichloride and water agitator treating 1～1.5h, after stratification 30min, extract organism saturated common salt water washing, organic layer distillation desolventizing, residue is warming up to 55～60 ℃ of dissolvings with methyl alcohol, be cooled to 5 ℃ of stirred crystallization 2～3h, filter to obtain wet product, vacuum-drying obtains product 4-(3-fluorophenyl)-2,2-dimethyl-5-(4-(methylthio group) phenyl) furans-3 (2H)-one.
Described vacuum drying condition is: at 50 ℃, and-0.095MPa vacuum-drying 2～6h.
The mass ratio of described chlorobenzene acetic acid, the bromo-2-methylpropionyl of 2-bromine, trimethylsilyl cyanide and thioanisole is: 3: 5.5: 2.8: 2.4.
The invention has the beneficial effects as follows: technique of the present invention is simple, easy to operate, product yield is high, and purity essence has reduced production cost simultaneously, has improved production efficiency.
Embodiment
Below in conjunction with embodiment, to a kind of 4-of the present invention (3-fluorophenyl)-2, the preparation method of 2-dimethyl-5-(4-(methylthio group) phenyl) furans-3 (2H)-one further illustrates.
Embodiment
1) preparation of fluorophenylacetyl chloride (FPAC) between
In the there-necked flask of 1L, add successively fluorophenylacetic acid between 305g.The DMF of sulfur oxychloride 500ml and 2ml, stirs and is warming up to backflow, and temperature is at 110 ℃, and the time is 4h, and reaction finishes, and sulfur oxychloride is removed in air distillation, collects 64 ℃/5mmHg product, the product of 320g burgundy, yield 82.3%.
2) synthetic (BBC) of the bromo-3-methyl-2-of 3-oxo fourth cyanogen
In the there-necked flask of 1L, add the BBB (the bromo-2-methylpropionyl of 2-bromine) of 557g and the trimethylsilyl cyanide of 283g, temperature is controlled at 85 ℃ of stirring reactions 3 hours, after be cooled to room temperature, collect the product 384g of 70 ℃/79mmHg, yield 90.04%.
3) 2-(3-fluorophenyl)-1-(4-(methylthio group) phenyl) ethyl ketone (FME)
In the there-necked flask of 3L, add methylene dichloride 2500ml, add rapidly (255g, 1.91mol) aluminum trichloride (anhydrous) stirs and to be cooled to below 5 ℃, then add (305g, 1.77mol) between fluorophenylacetyl chloride, stir after 5min, temperature is controlled at 5 ℃ of < and starts to drip (237g, 1.91mol) thioanisole, and time for adding is controlled 1～2h.Dropwise, naturally rise again to room temperature, then stir 3h.Reactant is poured in previously prepared good hydrochloric acid soln (water of hydrochloric acid+2000g of 36% of 660ml) into, stir 30min, stratification, saturated sodium bicarbonate solution 660ml and salt solution (1000ml * 2) washing for the organic layer of getting, organic layer steams solvent to the greatest extent through distillation, add normal hexane 1000ml dissolved dilution, be cooled to 10 ℃ of following stirred crystallization 2h.Filter filter cake at 50 ℃, the product 2-of-0.095MPa vacuum-drying 4h (3-fluorophenyl)-1-(4-(methylthio group) phenyl) ethyl ketone 406g, yield 88.2%.
4) 4-(3-fluorophenyl)-2,2-dimethyl-5-(4-(methylthio group) phenyl) furans-3 (2H)-one
In the there-necked flask of 5L, add tetrahydrofuran (THF) 3900ml, the FME of (512g, 1.97mol), stirs 30min, controls 20 ℃ of temperature and adds below sodium hydride (60%, 180g, 7.5mol), finishes, and stirs 0.5h.Reaction solution is cooled to 5 ℃ of <, starts to drip BBC (403g, 2.29mol), and time for adding is controlled at 1h.Reinforced complete, be warming up to room temperature, stir 5h.Being cooled to 5 ℃ neutralizes with acetic acid (122g) again.Distillation desolventizing, residue adds methylene dichloride 2500ml and water 2000ml agitator treating 1h, after stratification 30min, saturated aqueous common salt for organic layer (1000ml * 2) washing of getting.Organic layer distillation desolventizing, methyl alcohol for residue (700ml) is warming up to 55 ℃ of dissolvings, is cooled to 5 ℃ of stirred crystallization 2h, filters to obtain wet product, and at 50 ℃ ,-0.095MPa vacuum-drying 4h obtains product 535g, yield 83%
The above, be only a wherein embodiment of invention, is not the present invention to be done to the restriction of any other form, and according to any modification or equivalent variations that technical spirit of the present invention is done, still belong to invention scope required for protection.
Claims (3)
1. a 4-(3-fluorophenyl)-2, the preparation method of 2-dimethyl-5-(4-(methylthio group) phenyl) furans-3 (2H)-one, is characterized in that: comprise the following steps:
A, in clean there-necked flask, add successively a fluorophenylacetic acid, sulfur oxychloride and dimethyl formamide, stirring is warming up to backflow, temperature is at 110 ℃, reaction 3～5h, reaction finishes rear air distillation and removes sulfur oxychloride, the product of collecting 64 ℃/5mmHg burgundy, obtains a fluorophenylacetyl chloride, and reaction equation is as follows:
B, at clean there-necked flask, add 2-bromo-2-methylpropionyl bromine and trimethylsilyl cyanide; temperature is cooled to room temperature after being controlled at 80～90 ℃ of stirring reaction 2～3h; the bromo-3-methyl-2-of the product 3-oxo fourth cyanogen of collecting 66～75 ℃/79mmHg, reaction equation is as follows:
C, in clean there-necked flask, add successively methylene dichloride and aluminum trichloride (anhydrous) to stir to be cooled to below 5 ℃, add again a fluorophenylacetyl chloride to stir 5～10min, temperature is controlled at 5 ℃ and starts below to drip thioanisole, time for adding is controlled 1～2h, dropwise nature and rise again to room temperature and stir 2～3h again, reaction equation is as follows:
D, the reactant in step c is poured in 36% the hydrochloric acid soln preparing, stratification after stirring 30min, extract saturated sodium bicarbonate solution and salt water washing for organic layer, washing is steamed solvent to the greatest extent by distillation, then add n-hexane dissolution dilution, be cooled to 10 ℃ of following stirred crystallization 1～3h, filtration, vacuum-drying obtain 2-(3-fluorophenyl)-1-(4-(methylthio group) phenyl) ethyl ketone;
E, in clean there-necked flask, add successively tetrahydrofuran (THF) and 2-(3-fluorophenyl)-1-(4-(methylthio group) phenyl) ethyl ketone to stir 30min, control temperature and add below sodium hydride at 30 ℃, after stirring 30min, be cooled to below 5 ℃, start to drip the bromo-3-methyl-2-of 3-oxo fourth cyanogen, time for adding is controlled at 1～1.5h, and reaction equation is as follows:
F, step e are warming up to stirring at room 5h after completion of the reaction, being cooled to 5 ℃ neutralizes with acetic acid again, distillation desolventizing, residuum adds methylene dichloride and water agitator treating 1～1.5h, after stratification 30min, extract organism saturated common salt water washing, organic layer distillation desolventizing, residue is warming up to 55～60 ℃ of dissolvings with methyl alcohol, be cooled to 5 ℃ of stirred crystallization 2～3h, filter to obtain wet product, vacuum-drying obtains product 4-(3-fluorophenyl)-2,2-dimethyl-5-(4-(methylthio group) phenyl) furans-3 (2H)-one.
2. a kind of 4-(3-fluorophenyl)-2 according to claim 1, the preparation method of 2-dimethyl-5-(4-(methylthio group) phenyl) furans-3 (2H)-one, it is characterized in that: described vacuum drying condition is: at 50 ℃ ,-0.095MPa vacuum-drying 2～6h.
3. a kind of 4-(3-fluorophenyl)-2 according to claim 1; the preparation method of 2-dimethyl-5-(4-(methylthio group) phenyl) furans-3 (2H)-one, is characterized in that: the mass ratio of described chlorobenzene acetic acid, the bromo-2-methylpropionyl of 2-bromine, trimethylsilyl cyanide and thioanisole is: 3: 5.5: 2.8: 2.4.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866558A (en) * | 2015-08-21 | 2017-06-20 | 宁波百思佳医药科技有限公司 | Acyl group triazole compound and its preparation method and application |
| CN106977475A (en) * | 2017-06-09 | 2017-07-25 | 康化（上海）新药研发有限公司 | A kind of NSAIDs moors the synthetic method of horse former times cloth key intermediate |
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| CN1348447A (en) * | 1999-04-14 | 2002-05-08 | 株式会社太平洋 | 4,5-diaryl-3(i(2H))-furanone derivatives as cyclooxygenase-2 inhibitors |
| CN1865249A (en) * | 2005-05-17 | 2006-11-22 | 北京上地新世纪生物医药研究所有限公司 | Oxazole analog derivative and its preparation method and its anti-inflammatory and analgesic uses |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1348447A (en) * | 1999-04-14 | 2002-05-08 | 株式会社太平洋 | 4,5-diaryl-3(i(2H))-furanone derivatives as cyclooxygenase-2 inhibitors |
| CN1865249A (en) * | 2005-05-17 | 2006-11-22 | 北京上地新世纪生物医药研究所有限公司 | Oxazole analog derivative and its preparation method and its anti-inflammatory and analgesic uses |
| CN102947262A (en) * | 2010-06-22 | 2013-02-27 | 捷恩智株式会社 | Compound having branched alkyl or branched alkenyl, optically isotropic liquid crystal medium and optical element |
Non-Patent Citations (2)
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| FRANCISCO CATURLA ET AL.: "Synthesis and Biological Evaluation of 2-Phenylpyran-4-ones: A New Class of Orally Active Cyclooxygenase-2 Inhibitors", 《J.MED.CHEM.》 * |
| KLAUS HERRMANN ET AL.: "Synthese von Acylcyaniden (a-Oxonitrilen)mit Cyano-trimethylsilan", 《SYNTHESIS》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106866558A (en) * | 2015-08-21 | 2017-06-20 | 宁波百思佳医药科技有限公司 | Acyl group triazole compound and its preparation method and application |
| CN106866558B (en) * | 2015-08-21 | 2019-07-30 | 宁波百思佳医药科技有限公司 | Acyl group triazole compound and its preparation method and application |
| CN106977475A (en) * | 2017-06-09 | 2017-07-25 | 康化（上海）新药研发有限公司 | A kind of NSAIDs moors the synthetic method of horse former times cloth key intermediate |
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Application publication date: 20141015 |