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Aromatic sulfonyl modified difluoromethyl reaction block and synthesis method thereof

A technology of difluoromethyl reaction and aromatic sulfonyl group, which is applied in the field of synthesis and development of difluoromethyl reaction building blocks, can solve the problems of unstable reagent properties, harsh reaction conditions, and difficult availability of raw materials, etc., and achieve good universality Sex, stable and safe, easy to store

Active Publication Date: 2022-05-27
PINGDINGSHAN UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0003] At present, the development of difluoromethyl reaction building blocks is still in the initial stage of development. Although some difluoromethyl reaction building blocks have been developed, there are problems such as unstable reagent properties, harsh reaction conditions, cumbersome operation, and unavailable raw materials. shortcoming

Method used

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  • Aromatic sulfonyl modified difluoromethyl reaction block and synthesis method thereof
  • Aromatic sulfonyl modified difluoromethyl reaction block and synthesis method thereof
  • Aromatic sulfonyl modified difluoromethyl reaction block and synthesis method thereof

Examples

Experimental program
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Effect test

Embodiment 1

[0048]

[0049] (4-1)

[0050] 1) Dissolve 20 mmol of p-methylthiophenol in 20 mL of dimethyl sulfoxide, add 2.0 equivalents of sodium hydride (40 mmol), stir at room temperature for 1 hour, and then add 48 mmol of ethyl bromodifluoroacetate , stirred at room temperature for 12 hours, then washed, extracted, concentrated, and directly put into the next reaction without further purification; 2) The above product was dissolved in 20 mL of ethanol, and then 2.0 equivalent of sodium borohydride (40 mmol) was added, at 0 °C The reaction was carried out for 0.5 hours, washed, extracted and concentrated to obtain primary alcohol derivatives substituted with difluorosulfide, which was directly put into the next reaction without purification; 3) The above product was dissolved in a mixed solution of 40 mL of water and acetic acid (volume ratio 1 : 1), add 4.0 equivalents of hydrogen peroxide, heat under reflux for 2 hours, wash, extract, and concentrate to obtain a crude product, wh...

Embodiment 2

[0053]

[0054] (4-2)

[0055] 1) Dissolve 20 mmol of 2,4-dimethylthiophenol in 40 mL of dimethyl sulfoxide, add 1.5 equivalents of sodium hydride (30 mmol), stir at room temperature for 1 hour, and then add 50 mmol of bromine Ethyl difluoroacetate was stirred at room temperature for 12 hours, followed by washing, extraction, and concentration. It was directly used in the next reaction without further purification; 2) The above product was dissolved in 20 mL of ethanol, and then 2.0 equivalent of sodium borohydride (40 mmol) was added. , reacted at 0 °C for 0.5 hours, washed, extracted and concentrated to obtain difluorosulfide-substituted primary alcohol derivatives, which were directly put into the next step without purification; 3) The above product was dissolved in a mixture of 40 mL of water and acetic acid To the solution (volume ratio 1:1), add 4.0 equivalents of hydrogen peroxide, heat under reflux for 2 hours, wash, extract, and concentrate to obtain a crude produc...

Embodiment 3

[0058]

[0059] (4-3)

[0060] 1) Dissolve 20 mmol of 3-bromothiophenol in 40 mL of dimethyl sulfoxide, add 2.0 equivalents of sodium hydride (40 mmol), stir at room temperature for 1 hour, and then add 60 mmol of ethyl bromodifluoroacetate , stirred at room temperature for 12 hours, then washed, extracted, concentrated, and directly put into the next reaction without further purification; 2) The above product was dissolved in 20 mL of ethanol, and then 3.0 equivalent of sodium borohydride (60 mmol) was added, and the reaction was carried out at 0 °C. The reaction was carried out for 0.5 hours, washed, extracted and concentrated to obtain primary alcohol derivatives substituted with difluorosulfide, which was directly put into the next reaction without purification; 3) The above product was dissolved in a mixed solution of 40 mL of water and acetic acid (volume ratio 1 : 1), add 4.0 equivalents of hydrogen peroxide, heat under reflux for 2 hours, wash, extract, and concentr...

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Abstract

The invention relates to an aromatic sulfonyl modified difluoromethyl reaction block and a synthesis method thereof. The structural formula of the aromatic sulfonyl modified difluoromethyl reaction block is shown in the specification, in the structural formula, R1 is phenyl, phenyl substituted by C1-C5 alkyl or phenyl substituted by halogen; r1 is phenyl, phenyl substituted by C1-C5 alkyl, phenyl substituted by halogen, phenyl substituted by C1-C7 alkoxy or phenyl substituted by trifluoromethyl, and R2 is phenyl, phenyl substituted by C1-C5 alkyl, phenyl substituted by halogen, phenyl substituted by C1-C7 alkoxy or phenyl substituted by trifluoromethyl. According to the synthesis method, aryl thiophenol, brominated ethyl difluoroacetate and aryl sulfonyl hydrazide are used as raw materials, and the aromatic sulfonyl modified difluoromethyl reaction block is obtained through simple operation and mild reaction conditions. The synthesis method of the aromatic sulfonyl modified difluoromethyl reaction block has the advantages of cheap and easily available raw materials, mild reaction conditions, simple and safe operation and the like, develops the difluoromethyl reaction block with a brand new skeleton structure, and is an important synthesis intermediate.

Description

technical field [0001] The invention belongs to the fields of synthetic chemistry and reagent development, and mainly relates to the synthesis and development of an aromatic sulfonyl-modified difluoromethyl reaction building block. Background technique [0002] As an important functional group, difluoromethyl can be regarded as an isostere of carbonyl, amide, alcohol and hydroxamic acid. It not only has good lipophilicity, but also can be used as a carrier for hydrogen bonds. in drug molecules. For example, Lubiprostone, a special drug for female constipation developed by Takeda Pharmaceutical, and Gemcitabine, a broad-spectrum anticancer drug developed by Eli Lilly, both contain difluoromethyl functional groups. The development and application of new difluoromethyl reaction building blocks is an important way to construct difluoromethyl-containing drug molecules. Therefore, the development and application of new difluoromethyl reaction building blocks has always been a re...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C311/49C07C303/40
CPCC07C311/49C07C303/40
Inventor 李玖零郑新华刘丹丹赵爽杨玉洁章晓敏陈明慧覃洁冰朱琳琳
Owner PINGDINGSHAN UNIVERSITY
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