CN102964233A - Synthetic method of 3,5-2-fluoro-(trifluoromethyl)benzophenone - Google Patents
Synthetic method of 3,5-2-fluoro-(trifluoromethyl)benzophenone Download PDFInfo
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- CN102964233A CN102964233A CN2012104638173A CN201210463817A CN102964233A CN 102964233 A CN102964233 A CN 102964233A CN 2012104638173 A CN2012104638173 A CN 2012104638173A CN 201210463817 A CN201210463817 A CN 201210463817A CN 102964233 A CN102964233 A CN 102964233A
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Abstract
The invention discloses a synthetic method of a compound, which belongs to the technical field of organic synthesis. A synthetic method of 3,5-2-fluoro-(trifluoromethyl)benzophenone comprises the following steps: putting solvents and iodine into a four-port reaction kettle, and under the protection of nitrogen, putting magnesium chips and a small amount of bromoethane into the reaction kettle to carry out initiation reaction, wherein the reaction time is controlled in 15min; dropwise adding 3,5-difluorobromobenzene into the reaction kettle at 30-40 DEG C; after the adding step is completed, stirring the obtained mixture for 2h at 35 DEG C so as to obtain a Grignard reagent; slowly dropwise adding the obtained Grignard reagent into a trifluoroacetic anhydride solvent solution at 20-30 DEG C; and after the adding step is completed, carrying out thermal reaction for 1-1.5h at 25 DEG C; slowly adding the obtained reaction liquid into ice water, separating out an organic layer, extracting a water layer by using ethyl acetate, combining with the organic layer, carrying out water washing, drying and solvent recovery on the organic layer so as to obtain a coarse product, and carrying out rectification on the coarse product so as to obtain a pure product. The synthetic method disclosed by the invention is low in raw material cost, simple in process condition, easy to operate, moderate to the environment, and high in product yield.
Description
Technical field
The present invention relates to the synthetic method of compound, the synthetic method especially for the compound of medicine intermediate belongs to the organic synthesis field.
Background technology
3,5-two fluoro trifluoromethyl benzene ketone are a kind of important medicine and organic chemical industry's intermediate, the research and development of this compound can be made material storage for synthesizing some compounds with physiologically active and pharmacologically active, but the domestic and international synthetic pertinent literature report that has no to this compound.
Summary of the invention
The deficiency that exists in order to overcome prior art, the present invention seeks to supply raw materials that cost is low, processing condition are simple to operation, gentle to environment, that product yield is higher is a kind of 3, the synthetic method of 5-two fluoro trifluoromethyl benzene ketone
In order to realize the foregoing invention purpose, solve the problem that prior art exists, the technical scheme that the present invention takes is: a kind of 3, the synthetic method of 5-two fluoro trifluoromethyl benzene ketone, may further comprise the steps: (a), drop into solvent, iodine in the four-hole reactor that mechanical stirring, thermowell and reflux condensing tube are housed, under nitrogen protection, drop into magnesium chips in the reactor and a small amount of monobromethane carries out initiation reaction, the time is controlled at 15min; (b), in reactor, drip 3,5-difluoro bromobenzene, drip process temperature and be controlled at 30～40 ℃, after dripping, temperature is controlled at 35 ℃ and stirs 2h, makes Grignard reagent; (c), the Grignard reagent of making is slowly splashed in the solvent solution of trifluoroacetic anhydride, splash into process temperature and be controlled at 20～30 ℃, splashed into rear temperature and be controlled at 25 ℃ of insulation reaction 1～1.5h; (d), with reaction solution, slowly add in the frozen water, tell organic layer, water layer adopts ethyl acetate extraction, merges organic layer, organic layer through washing, dry, reclaim solvent, obtain crude product, carry out rectifying and make sterling.
Described solvent is selected from a kind of in tetrahydrofuran (THF) or the methyltetrahydrofuran.
Beneficial effect of the present invention is: a kind of 3, the synthetic method of 5-two fluoro trifluoromethyl benzene ketone, may further comprise the steps: (a), drop into solvent, iodine in the four-hole reactor that mechanical stirring, thermowell and reflux condensing tube are housed, under nitrogen protection, drop into magnesium chips in the reactor and a small amount of monobromethane carries out initiation reaction, the time is controlled at 15min; (b), in reactor, drip 3,5-difluoro bromobenzene, drip process temperature and be controlled at 30～40 ℃, after dripping, temperature is controlled at 35 ℃ and stirs 2h, makes Grignard reagent; (c), the Grignard reagent of making is slowly splashed in the solvent solution of trifluoroacetic anhydride, splash into process temperature and be controlled at 20～30 ℃, splashed into rear temperature and be controlled at 25 ℃ of insulation reaction 1～1.5h; (d), with reaction solution, slowly add in the frozen water, tell organic layer, water layer adopts ethyl acetate extraction, merges organic layer, organic layer through washing, dry, reclaim solvent, obtain crude product, carry out rectifying and make sterling.Compared with the prior art, the invention provides that raw materials cost is low, processing condition are simple to operation, gentle to environment, product yield is high.
Embodiment
The invention will be further described below in conjunction with embodiment:
Embodiment 1
Add tetrahydrofuran (THF) 140g in the four-hole reactor that mechanical stirring, thermowell, reflux condensing tube are housed, iodine 0.2g under nitrogen protection, adds magnesium chips 20.3g, monobromethane 1.5g, and initiation reaction keeps 15min.Room temperature drips 3,5-difluoro bromobenzene 124.8g, drips process temperature and is controlled at 30～40 ℃.After dripping, temperature is controlled at 35 ℃ and stirs 2h, makes Grignard reagent.With 200ml tetrahydrofuran (THF) dilution Grignard reagent, and slowly above-mentioned Grignard reagent is added drop-wise in the tetrahydrofuran solution (100ml) of trifluoroacetic anhydride (177.5g), drip process temperature and be controlled at 20～30 ℃, drip rear temperature and be controlled at 25 ℃ of insulation reaction 1～1.5h.With reaction solution, slowly add in the frozen water.Tell organic layer, the water layer ethyl acetate extraction merges organic layer, and organic layer obtains crude product 146g through washing, drying, filtration, recovery solvent, and gas phase content 51.5%, yield are 55.1%.This crude product is carried out rectifying, and obtaining the sterling quality is 56.6g, and purity is 98.1%, is separated into yield 41.5% after the rectifying.
Embodiment 2
Add methyltetrahydrofuran 14g in the four-hole reactor that mechanical stirring, thermowell, reflux condensing tube are housed, iodine 0.02g under nitrogen protection, adds magnesium chips 2g, monobromethane 0.15g, and initiation reaction keeps 15min.Room temperature drips 3,5-difluoro bromobenzene 12.5g, drips process temperature and is controlled at 30～40 ℃.After dripping, temperature is controlled at 35 ℃ and stirs 2h, makes Grignard reagent.With 20ml methyltetrahydrofuran dilution Grignard reagent, and slowly above-mentioned Grignard reagent is added drop-wise in methyltetrahydrofuran (20ml) solution of trifluoroacetic anhydride (17.8g), drip process temperature and be controlled at 20～30 ℃, drip rear temperature and be controlled at 25 ℃ of insulation reaction 1～1.5h.With reaction solution, slowly add in the frozen water.Tell organic layer, the water layer ethyl acetate extraction merges organic layer, and organic layer obtains crude product 15.2g through washing, drying, filtration, recovery solvent, and gas phase content 49.2%, yield are 54.8%.This crude product is carried out rectifying, and obtaining the sterling quality is 5.2g, and purity is 98.7%, and product finally is separated into yield 37.6%.
Embodiment 3
Add tetrahydrofuran (THF) 14g in the four-hole reactor that mechanical stirring, thermowell, reflux condensing tube are housed, iodine 0.02g under nitrogen protection, adds magnesium chips 2g, monobromethane 0.15g, and initiation reaction keeps 15min.Room temperature drips 3,5-difluoro bromobenzene 12.5g, drips process temperature and is controlled at 30～40 ℃.After dripping, temperature is controlled at 35 ℃ and stirs 2h, makes Grignard reagent.With 20ml tetrahydrofuran (THF) dilution Grignard reagent, and slowly above-mentioned Grignard reagent is added drop-wise in methyltetrahydrofuran (20ml) solution of trifluoroacetic anhydride (17.8g), drip process temperature and be controlled at 20～30 ℃, drip rear temperature and be controlled at 25 ℃ of insulation reaction 1～1.5h.With reaction solution, slowly add in the frozen water.Tell organic layer, the water layer ethyl acetate extraction merges organic layer, and organic layer obtains crude product 17.9g through washing, drying, filtration, recovery solvent, and gas phase content 41.8%, yield are 54.8%.This crude product is carried out rectifying, and obtaining the sterling quality is 6.3g, and purity is 98.5%, and product finally is separated into yield 45.8%.
Embodiment 4
Add tetrahydrofuran (THF) 14g in the four-hole reactor that mechanical stirring, thermowell, reflux condensing tube are housed, iodine 0.02g under nitrogen protection, adds magnesium chips 2g, methyl iodide 0.1g, and initiation reaction keeps 15min.Room temperature drips 3,5-difluoro bromobenzene 12.5g, drips process temperature and is controlled at 30～40 ℃.After dripping, temperature is controlled at 35 ℃ and stirs 2h, makes Grignard reagent.With 20ml tetrahydrofuran (THF) dilution Grignard reagent, and slowly above-mentioned Grignard reagent is added drop-wise in methyltetrahydrofuran (20ml) solution of trifluoroacetic anhydride (17.8g), drip process temperature and be controlled at 20～30 ℃, drip rear temperature and be controlled at 25 ℃ of insulation reaction 1～1.5h.With reaction solution, slowly add in the frozen water.Tell organic layer, the water layer ethyl acetate extraction merges organic layer, and organic layer obtains crude product 17.6g through washing, drying, filtration, recovery solvent, and gas phase content 40.8%, yield are 52.6%.This crude product is carried out rectifying, and obtaining the sterling quality is 6.2g, and purity is 97.7%, and product finally is separated into yield 45.1%.
Embodiment 5
Add tetrahydrofuran (THF) 14g in the four-hole reactor that mechanical stirring, thermowell, reflux condensing tube are housed, iodine 0.02g under nitrogen protection, adds magnesium chips 2g, methyl iodide 0.1g, and initiation reaction keeps 15min.Room temperature drips 3,5-difluoro bromobenzene 12.5g, drips process temperature and is controlled at 30～40 ℃.After dripping, temperature is controlled at 35 ℃ and stirs 2h, makes Grignard reagent.With 20ml tetrahydrofuran (THF) dilution Grignard reagent, and slowly above-mentioned Grignard reagent is added drop-wise in methyltetrahydrofuran (20ml) solution of trifluoroacetic anhydride (17.8g), drip process temperature and be controlled at 20～30 ℃, drip rear temperature and be controlled at 25 ℃ of insulation reaction 1～1.5h.With reaction solution, slowly add in the frozen water.Tell organic layer, the water layer ethyl acetate extraction merges organic layer, and organic layer obtains crude product 17.8g through washing, drying, filtration, recovery solvent, and gas phase content 37.4%, yield are 48.9%.This crude product is carried out rectifying, and obtaining the sterling quality is 6.0g, and purity is 97.2%, and product finally is separated into yield 43.4%.
Embodiment 6
Add methyltetrahydrofuran 14g in the four-hole reactor that mechanical stirring, thermowell, reflux condensing tube are housed, iodine 0.02g under nitrogen protection, adds magnesium chips 2g, methyl iodide 0.15g, and initiation reaction keeps 15min.Room temperature drips 3,5-difluoro bromobenzene 12.5g, drips process temperature and is controlled at 30～40 ℃.After dripping, temperature is controlled at 35 ℃ and stirs 2h, makes Grignard reagent.With 20ml methyltetrahydrofuran dilution Grignard reagent, and slowly above-mentioned Grignard reagent is added drop-wise in methyltetrahydrofuran (20ml) solution of trifluoroacetic anhydride (17.8g), drip process temperature and be controlled at 20～30 ℃, drip rear temperature and be controlled at 25 ℃ of insulation reaction 1～1.5h.With reaction solution, slowly add in the frozen water.Tell organic layer, the water layer ethyl acetate extraction merges organic layer, and organic layer obtains crude product 15.3g through washing, drying, filtration, recovery solvent, and gas phase content 45.4%, yield are 50.8%.This crude product is carried out rectifying, and obtaining the sterling quality is 5.5g, and purity is 98.7%, and product finally is separated into yield 41.2%.
Claims (2)
1. one kind 3, the synthetic method of 5-two fluoro trifluoromethyl benzene ketone is characterized in that may further comprise the steps:
(a), drop into solvent, iodine in the four-hole reactor that mechanical stirring, thermowell and reflux condensing tube are housed, under nitrogen protection, drop into magnesium chips in the reactor and a small amount of monobromethane carries out initiation reaction, the time is controlled at 15min;
(b), in reactor, drip 3,5-difluoro bromobenzene, drip process temperature and be controlled at 30～40 ℃, after dripping, temperature is controlled at 35 ℃ and stirs 2h, makes Grignard reagent;
(c), the Grignard reagent of making is slowly splashed in the solvent solution of trifluoroacetic anhydride, splash into process temperature and be controlled at 20～30 ℃, splashed into rear temperature and be controlled at 25 ℃ of insulation reaction 1～1.5h;
(d), with reaction solution, slowly add in the frozen water, tell organic layer, water layer adopts ethyl acetate extraction, merges organic layer, organic layer through washing, dry, reclaim solvent, obtain crude product, carry out rectifying and make sterling.
2. described a kind of 3 according to claim 1, the synthetic method of 5-two fluoro trifluoromethyl benzene ketone is characterized in that: described solvent is selected from a kind of in tetrahydrofuran (THF) or the methyltetrahydrofuran.
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Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106029620A (en) * | 2014-09-19 | 2016-10-12 | 东丽精细化工株式会社 | Method for producing 2'-trifluoromethyl group-substituted aromatic ketone |
| CN108047019A (en) * | 2017-12-29 | 2018-05-18 | 广西万德药业有限公司 | 2,2,2- trifluoroacetophenones clean the preparation method of high conversion |
| CN112500517A (en) * | 2020-12-01 | 2021-03-16 | 山东德仕化工有限公司 | Oil-soluble super-heavy oil viscosity reducer and preparation method and application thereof |
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| TW200911778A (en) * | 2007-07-16 | 2009-03-16 | Wyeth Corp | Process for the preparation of trifluoroalkyl-phenyl and heterocyclic sulfonamides |
| CN101693720A (en) * | 2009-09-15 | 2010-04-14 | 杭州师范大学 | Method for utilizing silicon chloride to prepare phenyl-trichloro-silicane and diphenyl dichlorosilane through Gerber method |
| CN101712603A (en) * | 2009-12-04 | 2010-05-26 | 江苏工业学院 | Method for preparing halogenated methyl-benzaldehyde by Grignard reaction |
| CN101990530A (en) * | 2008-04-09 | 2011-03-23 | 杜邦公司 | Method for preparing 3-trifluoromethyl chalcones |
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- 2012-11-18 CN CN2012104638173A patent/CN102964233A/en active Pending
Patent Citations (4)
| Publication number | Priority date | Publication date | Assignee | Title |
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| TW200911778A (en) * | 2007-07-16 | 2009-03-16 | Wyeth Corp | Process for the preparation of trifluoroalkyl-phenyl and heterocyclic sulfonamides |
| CN101990530A (en) * | 2008-04-09 | 2011-03-23 | 杜邦公司 | Method for preparing 3-trifluoromethyl chalcones |
| CN101693720A (en) * | 2009-09-15 | 2010-04-14 | 杭州师范大学 | Method for utilizing silicon chloride to prepare phenyl-trichloro-silicane and diphenyl dichlorosilane through Gerber method |
| CN101712603A (en) * | 2009-12-04 | 2010-05-26 | 江苏工业学院 | Method for preparing halogenated methyl-benzaldehyde by Grignard reaction |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106029620A (en) * | 2014-09-19 | 2016-10-12 | 东丽精细化工株式会社 | Method for producing 2'-trifluoromethyl group-substituted aromatic ketone |
| US9783476B2 (en) | 2014-09-19 | 2017-10-10 | Toray Fine Chemicals Co., Ltd. | Method of producing 2′-trifluoromethyl group-substituted aromatic ketone |
| CN106029620B (en) * | 2014-09-19 | 2018-01-30 | 东丽精细化工株式会社 | The manufacture method of 2 ' trifluoromethyl substituted aroma race ketone |
| CN108047019A (en) * | 2017-12-29 | 2018-05-18 | 广西万德药业有限公司 | 2,2,2- trifluoroacetophenones clean the preparation method of high conversion |
| CN112500517A (en) * | 2020-12-01 | 2021-03-16 | 山东德仕化工有限公司 | Oil-soluble super-heavy oil viscosity reducer and preparation method and application thereof |
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Application publication date: 20130313 |