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Difluoroethyl-containing nitrosamine compounds and preparation method thereof

A technology of difluoroethylnitrosamine and difluoroethylamine, which is applied in the field of chemistry, can solve problems that have not been reported, and achieve the effects of good substrate universality, easy product, and mild reaction conditions

Inactive Publication Date: 2018-03-23
ZUNYI MEDICAL UNIVERSITY
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0003] In view of the potential biological activity of nitrosamine compounds and the important role of difluoroethyl in medicinal chemistry, and the synthesis of such compounds has not been reported so far, it is necessary to develop an efficient, high-yield, and simple method to The synthesis of such compounds is of great significance, and their synthesis can establish a material basis for the application of difluoroethyl-containing nitrosamine compounds in drug discovery and drugability evaluation

Method used

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  • Difluoroethyl-containing nitrosamine compounds and preparation method thereof
  • Difluoroethyl-containing nitrosamine compounds and preparation method thereof
  • Difluoroethyl-containing nitrosamine compounds and preparation method thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Synthesis of Compound 4a

[0026]

[0027] Add difluoroethylamine (1,352.3μL, 5.0mmol), tert-butyl nitrite (2,1.9mL, 16.0mmol), 1-phenyl-2-nitroethylene shown in the formula (II) successively into a 5mL reaction flask (3a, 149.0 mg, 1.0 mmol) and acetic acid (2.9 μL, 0.05 mmol), stirred at room temperature for 6 hours. After the reaction was detected by thin-layer chromatography, it was separated by silica gel column chromatography (300-400 mesh) (petroleum ether: ethyl acetate = 5:1) to obtain 246.1 mg of a yellow oil with a yield of 95%. NMR and high-resolution Mass spectrometry analysis results are as follows: 1 H NMR (400MHz, CDCl 3 )δ7.45–7.43(m,3H),7.32(t,J=3.4Hz,2H),6.01(dd,J=5.2,9.8Hz,1H),5.75(tt,J=4.0,55.8Hz,1H ),5.56(dd,J=9.8,18.0Hz,1H),4.99(dd,J=5.2,14.8Hz,1H),4.19–4.07(m,1H),3.40(qd,J=12.8,5.2Hz, 1H); 13 C NMR (100MHz, CDCl 3 )δ132.9, 130.2, 129.9, 127.5, 111.3 (t, J=242.2Hz, 1C), 76.1, 64.8, 35.8 (dd, J=26.8, 30.4Hz, 1C); 19 F NMR (376MHz, CDCl 3...

Embodiment 2

[0029] Synthesis of compound 4b

[0030]

[0031] Add difluoroethylamine (1,352.3μL, 5.0mmol), tert-butyl nitrite (2,1.9mL, 16.0mmol), 1-(2-methoxyphenyl )-2-nitroethylene (3b, 179.2 mg, 1.0 mmol) and acetic acid (2.9 μL, 0.05 mmol), stirred at room temperature for 6 hours. After the reaction was detected by thin-layer chromatography, it was separated by silica gel column chromatography (300-400 mesh) (petroleum ether: ethyl acetate = 5:1) to obtain 260.2 mg of a yellow solid with a yield of 90% and a melting point of 76.9-78.6°C. NMR and high-resolution mass spectrometry test analysis results are as follows: 1 H NMR (400MHz, CDCl 3 )δ7.40(t, J=7.8Hz, 1H), 7.07(d, J=7.8Hz, 1H), 7.01–6.98(m, 2H), 6.38(dd, J=4.4, 10.2Hz, 1H), 5.77(tdd, J=3.0, 4.8, 55.6Hz, 1H), 5.54(dd, J=10.2, 14.8Hz, 1H), 4.96(dd, J=4.4, 14.8Hz, 1H), 4.22–4.11(m, 1H), 3.90(s, 3H), 3.50–3.39(m, 1H); 13 C NMR (100MHz, CDCl 3 )δ156.9, 131.4, 128.0, 121.5, 120.9, 111.5, 111.3 (t, J = 243.6Hz, 1C), 74.7, 59...

Embodiment 3

[0033] Synthesis of compound 4c

[0034]

[0035] Add difluoroethylamine (1,352.3 μL, 5.0 mmol), tert-butyl nitrite (2, 1.9 mL, 16.0 mmol), 1-(2-fluorophenyl)- 2-Nitroethylene (3c, 167.0 mg, 1.0 mmol) and acetic acid (2.9 μL, 0.05 mmol) were stirred at room temperature for 6 hours. After the reaction was detected by thin-layer chromatography, it was separated by silica gel column chromatography (300-400 mesh) (petroleum ether: ethyl acetate = 5:1) to obtain 274.3 mg of a yellow oil with a yield of 99%. NMR and high-resolution Mass spectrometry analysis results are as follows: 1 H NMR (400MHz, CDCl 3 )δ7.48–7.42(m,1H),7.28–7.23(m,2H),7.21–7.16(m,1H),6.32(dd,J=4.8,9.8Hz,1H),5.91–5.75(m, 1H), 5.60(dd, J=9.8, 14.8Hz, 1H), 5.02(dd, J=4.8, 14.8Hz, 1H), 4.16–4.04(m, 1H), 3.61–3.49(m, 1H); 13 C NMR (100MHz, CDCl 3 )δ160.39(d, J=249.2Hz, 1C), 132.19(d, J=8.5Hz, 1C), 128.75(d, J=2.6Hz, 1C), 125.59(d, J=3.7Hz, 1C) ,120.38(d,J=13.2Hz,1C),116.76(d,J=21.4Hz,1C),111.17(t,J=243.7Hz,1...

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Abstract

The invention discloses difluoroethyl-containing nitrosamine compounds and a preparation method thereof. A series of difluoroethyl-containing nitrosamine derivatives are obtained by taking carboxylicacid as a catalyst and carrying out an aza-Michael addition / nitrosation tandem reaction on three components, i.e., difluoroethylamine, tert-butyl nitrite and 1-aryl 2-nitroethylene at room temperaturein absence of other organic solvents. Molecular skeletons of the compounds contain potentially bioactive difluoroethyl and nitrosamine groups, thus establishing a material basis for drug discovery and druggability evaluation, and having an important application value. The preparation method provided by the invention adopts the easy-to-obtain raw materials, does not need an additional organic solvent, and has the advantages of mild reaction conditions, simple operation, high yield and good substrate universality.

Description

technical field [0001] The invention relates to the technical field of chemistry, in particular to a difluoroethyl-containing nitrosamine compound and a preparation method thereof. Background technique [0002] The small atomic radius, low orbital energy and maximum electronegativity make fluorine exhibit some very unique properties. After introducing fluorine atoms or fluorine-containing groups into organic molecules, the physical, chemical, and biological properties of the parent molecules will change significantly due to their inductive effects, pseudomimetic effects, blocking effects, lipophilic effects, and hydrogen bonding effects. Among them, difluoroethyl (-CH 2 CF 2 H), as an important fluorine-containing group, contains a weakly acidified C-H bond, which can regulate the biological activity, metabolic stability and lipophilicity of the molecule, and plays an equally important role in the fields of medicine and pesticides as other fluoroalkyl groups role. Theref...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07C243/06C07C241/00C07C255/65C07C253/30C07D307/52C07D333/20
CPCC07C243/06C07C241/00C07C253/30C07C255/65C07D307/52C07D333/20
Inventor 韩文勇陈永正汪建树崔宝东万南微
Owner ZUNYI MEDICAL UNIVERSITY
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