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A kind of 4-fluoropyridine derivative and its preparation method and application

A technology for fluoropyridine and derivatives, which is applied in the field of 4-fluoropyridine derivatives and their preparation, can solve the problems of limited efficient synthesis methods of fluorine-containing pyridine compounds, and achieve simple and easy-to-obtain raw materials and reagents, and efficient and efficient preparation methods. Simple operation effect

Active Publication Date: 2022-07-22
SHANDONG NORMAL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, the inventors have found that currently available efficient synthetic methods for fluorine-containing pyridine compounds are very limited

Method used

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  • A kind of 4-fluoropyridine derivative and its preparation method and application
  • A kind of 4-fluoropyridine derivative and its preparation method and application
  • A kind of 4-fluoropyridine derivative and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0062] Preparation of 4-Fluoropyridine Derivatives 3aa

[0063]

[0064] Into a 15mL pressure-resistant tube was added (3,3-difluorocycloprop-1-en-1-yl)benzene 1a (0.2 mmol), p-toluenesulfonylmethylisonitrile 2a (0.4 mmol), and 2 mL of 1,4 - Dioxane was dissolved, a stirrer was added, the pressure-resistant tube cock was tightened, and then placed at room temperature for stirring. The reaction time was 5h. At this time, TLC detected that the substrate 2a completely disappeared, and the solvent was evaporated under reduced pressure. The final product was isolated to obtain the final product, which was confirmed to be the 4-fluoropyridine derivative 3aa by H NMR, C and MS, and the yield was 93%.

[0065] figure 1 is the hydrogen nuclear magnetic spectrum of the 4-fluoropyridine derivative obtained in Example 1 of the present invention, figure 2 For its nuclear magnetic fluoride spectrum, image 3 Its carbon NMR spectrum.

[0066] Spectrogram analysis data:

[0067] 1 H...

Embodiment 2

[0069] Preparation of 4-fluoropyridine derivative 3ba:

[0070]

[0071] Substitute 1-chloro-4-(3,3-difluorocycloprop-1-en-1-yl)benzene 1b for (3,3-difluorocycloprop-1-en-1-yl in Example 1) ) Benzene 1a, other conditions were the same as in Example 1, to obtain 4-fluoropyridine derivative 3ba with a yield of 85%.

[0072] Figure 4 is the hydrogen nuclear magnetic spectrum of the 4-fluoropyridine derivative obtained in Example 2 of the present invention, Figure 5 For its nuclear magnetic fluoride spectrum, Image 6 Its carbon NMR spectrum.

[0073] Spectrogram analysis data:

[0074] 1 H NMR (400MHz, CDCl 3 )δ8.68(d,J=9.2Hz,1H),8.00(d,J=8.4Hz,1H),7.97(d,J=8.4Hz,2H),7.49-7.42(m,4H),7.36( d, J=8.0Hz, 2H), 2.43(s, 3H). 19 FNMR (376MHz, CDCl 3 )δ-103.0. 13 C NMR (100MHz, CDCl 3 )δ165.9(d,J=268Hz),160.3(d,J=6Hz),152.5(d,J=4Hz),145.3,135.8,135.2,130.2(d,J=3Hz),129.9,129.3,129.1 ,128.8,127.3(d,J=10Hz),111.1(d,J=22Hz),21.6.HRMS(ESI-TOF)m / z calculated for C 18 H 13 Cl...

Embodiment 3

[0076] Preparation of 4-fluoropyridine derivative 3ca:

[0077]

[0078] Substitute 1-chloro-3-(3,3-difluorocycloprop-1-en-1-yl)benzene 1c for (3,3-difluorocycloprop-1-en-1-yl in Example 1) ) Benzene 1a, other conditions are the same as in Example 1, 4-fluoropyridine derivative 3ca, the yield is 93%.

[0079] Spectrogram analysis data:

[0080] 1 H NMR (400MHz, CDCl 3 )δ8.68(d,J=9.2Hz,1H),8.01(d,J=9.2Hz,1H),7.97(d,J=8.0Hz,2H),7.48(s,1H),7.46-7.41( m,2H),7.39-7.35(m,3H),2.43(s,3H). 19 F NMR (376MHz, CDCl 3 )δ-102.7. 13 C NMR (100MHz, CDCl 3 )δ165.8(d,J=268Hz),160.5(d,J=6Hz),152.5(d,J=3Hz),145.3,135.1,134.9,132.0,130.3,129.9,129.6,129.1,128.9(d, J=3Hz),127.1(d,J=3Hz),127.0,111.0(d,J=22Hz),21.6.HRMS(ESI-TOF)m / z calculated for C 18 H 13 ClFNO 2 NaS + ([M+Na] + )384.0232, found 384.0245.

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Abstract

The present invention relates to a 4-fluoropyridine derivative and its preparation method and application. 4-Fluoropyridine derivative, is the compound shown in formula I or its isomer or pharmaceutically acceptable salt: wherein, R 1 One selected from aryl, heteroaryl, alkyl, ester or condensed aryl; R 2 One of aryl groups or hydrogen atoms; R 3 One selected from ester group, sulfonyl group and heteroaryl group. The preparation method is the cyclization reaction of geminal difluorocyclopropene and methylene isocyanide to obtain the compound represented by formula I. The preparation method has mild conditions and simple operation, and the obtained 4-fluoropyridine derivative has application prospects in the fields of medicine, pesticide, material and the like.

Description

technical field [0001] The invention belongs to the technical field of organic synthesis chemistry, and in particular relates to a 4-fluoropyridine derivative and a preparation method and application thereof. Background technique [0002] The disclosure of information in this Background section is only for enhancement of understanding of the general background of the invention and should not necessarily be taken as an acknowledgement or any form of suggestion that this information forms the prior art already known to a person of ordinary skill in the art. [0003] The fluorine atom has four effects: electronic effect, pseudo-mimicking effect, blocking effect and permeation effect. Fluorine-containing compounds have little impact on the environment, and have the advantages of high selectivity, high added value, low toxicity, and environmental friendliness. Therefore, organic fluorides have been widely used in medicine, pesticides, materials and other fields. According to st...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D213/71C07D409/04C07D401/06C07D213/79C07D213/803A61K31/44A61K31/4436A61K31/4439A01N43/40A01P7/04A61P29/00A61P31/18
CPCC07D213/71C07D409/04C07D401/06C07D213/79C07D213/803A01N43/40A61P29/00A61P19/02A61P31/18
Inventor 董金环冯万忠朱韵洁徐显秀
Owner SHANDONG NORMAL UNIV