Compound containing difluromethylation and preparation method therefor

A difluoromethyl compound technology, applied in the field of difluoromethyl-containing compounds, can solve problems such as high production costs, unsuitable for industrial production, and long routes

Active Publication Date: 2015-11-25
SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] The technical problem to be solved by the present invention is to overcome the drawbacks of the prior art, such as cumbersome steps, long route, low conversion rate, high raw material price, high production cost, and unsuitability for industrialized production, in the synthesis method of compounds with difluoromethyl groups. And provide a kind of compound containing difluoromethyl and preparation method thereof

Method used

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  • Compound containing difluromethylation and preparation method therefor
  • Compound containing difluromethylation and preparation method therefor
  • Compound containing difluromethylation and preparation method therefor

Examples

Experimental program
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Effect test

Embodiment 1

[0071] The difluoromethylation reaction research of the iodoarene (RI) that palladium participates in embodiment 1

[0072]Under the condition of argon, 4-phenyliodobenzene (0.1mmol), trimethyldifluoromethylsilane, palladium catalyst, additives, ligands and bases were dissolved in a dry deoxygenated solvent in the corresponding proportions in the table , heated to the temperature listed in the table, and after reacting for the time listed in the table, an equal proportion of trifluorotoluene was added as an internal standard, and the yield was determined by fluorine spectrum. See Table 1 for the screening of palladium catalysts, see Table 2 for the screening of additives, see Table 3 for the screening of bases, see Table 4 for the screening of solvents, see Table 5 for the screening of ligands, and see Table 6 for the screening of reaction temperature , see Table 7 for the screening of reaction time, see Table 8 for the screening of palladium catalyst dosage, see Table 9 for t...

Embodiment 2

[0121] The experiment of the difluoromethylation of the iodoarene (RI) of embodiment 2 palladium catalysis

[0122]Under argon atmosphere, iodoarene (0.5mmol), bis(dibenzylideneacetone)palladium (14.5mg, 0.025mmol), 1,1'-bis(diphenylphosphino)ferrocene (28mg, 0.05 mmol), additive SIPrAgCl (53.5 mg, 0.1 mmol), sodium tert-butoxide (96.1 mg, 1.0 mmol) were dissolved in 5 mL of dioxane, and 150 uL of trimethyldifluorosilane was added to the system. After reacting at 80°C for 4 hours, cool to room temperature, add 10 mL of distilled water to quench the reaction, filter through celite and extract the filtrate with dichloromethane (25ml×3), combine the organic phases, dry over anhydrous sodium sulfate, concentrate, and After separation, the corresponding difluoromethylated products 1a-1l were obtained, and the specific yields are shown in Table 12.

[0123] Table 12 Study on the suitability of substrates for difluoromethylated arenes with iodine bands

[0124]

[0125]

[01...

Embodiment 3

[0151] The difluoromethylation reaction research of the brominated arene (RBr) that embodiment 3 palladium participates in

[0152] Under the condition of argon, 4-phenylbromobenzene (0.1mmol), trimethyldifluoromethylsilane, palladium catalyst, additives, ligands and bases were dissolved in the dry deoxygenated solvent in the corresponding proportions in the table , heated to the temperature listed in the table, and after reacting for the time listed in the table, an equal proportion of trifluorotoluene was added as an internal standard, and the yield was determined by fluorine spectrum. See Table 13 for the screening of palladium catalysts, see Table 14 for the screening of additives, see Table 15 for the screening of bases, see Table 16 for the screening of solvents, see Table 17 for the screening of ligands, and see Table 18 for the screening of reaction temperature , see Table 19 for the screening of reaction time, see Table 20 for the screening of palladium catalyst dosag...

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Abstract

The invention discloses a compound containing difluromethylation and a preparation method therefor. The invention provides a preparation method of a compound RCF2H containing the difluromethylation. The preparation method comprises the following steps of: under the protection of inert gas, performing a coupling reaction on a compound RX and trimethyl difluromethylation silicon in an organic solvent under the existing conditions of a palladium catalyst, a ligand and alkali so as to obtain the compound RCF2H containing the difluromethylation. Through the adoption of the difluromethylation reaction of the compound disclosed by the invention, the difluromethylation of the compound with various aryl halogen compounds such as aryl iodide, aryl bromide and natural products (such as estrone or vitamin E) can be realized, the conditions of the type of reactions are mild, raw materials are cheap and easy to obtain, the conversion rate of the reaction is high, the compatibility of base groups is good, and the compound has a good market application prospect. RX+TMSCF2H -> RCF2H

Description

technical field [0001] The present invention relates to compounds containing difluoromethyl groups and their preparation methods. Background technique [0002] By introducing fluorine atoms and fluoroalkyl groups into drug molecules, its fat solubility and metabolic stability can be well enhanced. In recent years, the introduction of fluorine atoms and fluoroalkyl groups into molecules has become the development direction in the synthesis and design of drug molecules. . Among the numerous fluoroalkyl groups, difluoromethyl groups have become an important class of fluoroalkyl groups in the design of drug molecules because they can mimic hydroxyl or sulfhydryl groups in terms of physiological activity. Therefore, the introduction of difluoromethyl groups into molecules has become an important topic in medicinal chemistry and organic fluorine chemistry. However, there are relatively few reported direct difluoromethylation methods involving transition metals (background docume...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07B39/00C07C17/263C07C22/08C07C67/343C07C69/76C07C41/30C07C43/225C07C231/12C07C233/65C07C209/68C07C211/29C07C25/18C07C43/247C07C211/56C07C235/46C07D207/325C07D295/088C07D317/16C07D213/65C07D209/86C07D277/66C07D311/58C07J21/00
Inventor 沈其龙古阳
Owner SHANGHAI INST OF ORGANIC CHEM CHINESE ACAD OF SCI
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