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Preparation method of [(phenyl sulfonyl) difluoro methyl] trimethyl silane

A technology of trimethylsilane and trimethylchlorosilane, which is applied in the field of preparation of high-efficiency difluoromethylation reagent-[difluoromethyl]trimethylsilane, can solve the problems of lower utilization rate, excessive carbonyl substrate, Does not meet environmental protection and other issues, and achieves the effect of easy condition control and high yield

Inactive Publication Date: 2006-01-25
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Claims
  • Application Information

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Problems solved by technology

Although this method can carry out nucleophilic addition reaction to many carbonyl compounds, and then reduce the sulfone group to obtain difluoromethyl alcohol, there are the following disadvantages: (a) the reaction conditions are harsh (need to strictly control the low temperature -78 ° C); ( b) excess carbonyl substrate is required; (c) excess base is required, which makes substrates (especially aliphatic aldehydes) susceptible to enolization and thus reduces utilization; (d) the removal of sulfone groups involves environmental unfriendliness The reagent (sodium amalgam) does not meet the requirements of environmental protection
[0004] [(Benzenesulfonyl)difluoromethyl]trimethylsilane (TMSCF 2 SO 2 Although the preparation of Ph) has been reported, due to the use of mCPBA to oxidize PhSCF 2 SiMe 3 The method, the operation of alkali neutralization will be used in post-treatment, this step makes product a large amount of hydrolysis, so this preparation method has very big limitation (Prakash, G.K.S.; Hu, J.; Olah, G.A.J.Org.Chem.2003 , 68, 4457)

Method used

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  • Preparation method of [(phenyl sulfonyl) difluoro methyl] trimethyl silane
  • Preparation method of [(phenyl sulfonyl) difluoro methyl] trimethyl silane
  • Preparation method of [(phenyl sulfonyl) difluoro methyl] trimethyl silane

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Embodiment 1

[0020] [(Benzenesulfonyl)difluoromethyl]trimethylsilane (TMS-CF 2 SO 2 A typical preparation method of Ph): Cool a solution of tetrahydrofuran (50mL) containing difluorobromomethylphenyl sulfone (5.0g, 18.4mmol) and trimethylchlorosilane (3.8mL, 27.7mmol) to -78°C, then A solution of n-butyllithium in hexane (1.6M, 20.7 mL, 33.2 mmol) was added slowly. The reaction mixture was stirred at -78°C for 1 hour, then quenched by the addition of cold saturated aqueous ammonium chloride. The mixed solution was extracted three times with diethyl ether (50 mL each time), and then the combined organic phases were washed with cold saturated aqueous sodium chloride solution and water respectively, and dried over anhydrous sodium sulfate. After removing the solvent on a rotary evaporator, the crude product was distilled under reduced pressure to obtain 3.8 g of [(benzenesulfonyl)difluoromethyl]trimethylsilane, yield: 78%. Boiling point 102-104 ° C 1mmHg. NMR Characterization: 1 H NMR (C...

Embodiment 2

[0022] Difluoromethylphenyl sulfone (PhSO 2 CF 2 H) Preparation of [(benzenesulfonyl)difluoromethyl]trimethylsilane as starting material: THF containing difluoromethylphenyl sulfone (5.0 g, 26 mmol) and trimethylchlorosilane (4.2 g, 39 mmol) (50 mL) solution was cooled to -78°C, then n-butyllithium hexane solution (1.6M, 29.2 mL, 46.8 mmol) was added slowly. The reaction mixture was stirred at -78°C for 3 hours, then quenched by the addition of cold saturated aqueous ammonium chloride. The mixed solution was extracted three times with diethyl ether (50 mL each time), and then the combined organic phases were washed with cold saturated aqueous sodium chloride solution and water respectively, and dried over anhydrous sodium sulfate. After removing the solvent on a rotary evaporator, the crude product was distilled under reduced pressure to obtain 3.9 g of [(benzenesulfonyl)difluoromethyl]trimethylsilane, yield: 57%. The NMR characterization data is the same as in Example 1. ...

Embodiment 3

[0024] Utilize difluorobromomethylphenyl sulfone, trimethylchlorosilane, tetradimethylaminoethylene to prepare [(benzenesulfonyl) difluoromethyl] trimethylsilane: difluorobromomethylphenyl sulfone ( 30mmol), trimethylchlorosilane (45mmol), tetradimethylaminoethylene to prepare [(benzenesulfonyl) difluoromethyl] (60mmol) dissolved in dry dimethylformamide (60ml), and Stir for 8 hours between -30°C and room temperature. Aftertreatment method is identical with embodiment 1-2. The product [(benzenesulfonyl)difluoromethyl]trimethylsilane can be observed to have a conversion yield greater than 60% using nuclear magnetic resonance spectroscopy. Characterization data as above.

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Abstract

The invention provides a process for preparing [(phenylsulfonyl) difluoromethyl] trimethyl silane (TMS-CF2SO2Ph) which comprises, in organic solvent at -78 deg. C to room temperature and at the presence of C1-C4 lithium alkyl or 4-dimethylamino, using difluoromethyl phenyl sulfone or difluoro halogenated methylbenzene sulfone as raw material, and reacting with trimethylchlorosilane. The invention realizes easy operation, and the prepared [(phenylsulfonyl) difluoromethyl] trimethyl silane can catalyze carbonyl compounds for difluoro methylation reaction.

Description

technical field [0001] The invention relates to a high-efficiency difluoromethylation reagent-[(benzenesulfonyl)difluoromethyl]trimethylsilane (TMSCF 2 SO 2 Ph) preparation method. The reagent is an important difluoromethylation reagent for the synthesis of fluorine-containing drugs and fluorine-containing materials. Background technique [0002] Fluorochemicals are widely used in drug design and new material development. The selective introduction of fluorine atoms or fluorine-containing building blocks into organic molecules can greatly enhance the biological activity of these molecules. Therefore, the research on selective fluorination and fluoroalkylation has been paid more and more attention in the fields of medicine, pesticide, materials and so on. Although fluorination and trifluoromethylation reactions have been extensively studied, studies on difluoromethylation reactions are relatively much less. Since difluoromethyl (CF 2 H) and hydroxymethyl (CH 2 OH) has ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07F7/08C07F7/12
Inventor 胡金波倪传法
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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