Synthesis method and application of nitrogen heterocyclic compound with anti-tumor effect

A technology for a nitrogen heterocyclic compound and a synthesis method, which is applied in the field of biomedicine, can solve the problems of limited operation steps, difficulty in obtaining o-phenylenediamine substrates, and limited product diversity, and achieves single selectivity and high reaction yield. , the effect of excellent atom economy and step economy

Pending Publication Date: 2022-03-15
GUILIN UNIVERSITY OF TECHNOLOGY
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Problems solved by technology

[0003] In recent years, some research progress has been made in the synthesis of furo[2,3-b]quinoxaline derivatives ((a) T.Narender, et al.Org.Lett.2014, 16, 4528-4531;( b) M.Pal, etal.Org.Biomol.Chem.2013,11,4930–4934), as in 2017, the Verma research group developed a palladium / copper catalyzed coupling of bischloroquinoxaline compounds and alkynes Reaction (A.K. Verma, et al. Eur. J. Org. Chem. 2017, 3707–3715), the reaction yield is high and the selectivity is good, but the use of noble metal palladium and relatively complicated operation steps limit the application of the reaction ; In 2018, the Reddy group realized the copper-catalyzed coupling reaction of o-phenylenediamine, alkyd ester and aromatic alkyne. The reaction efficiency is high and the conversion can be completed in 20 minutes. Substrates are difficult to obtain and are only compatible with aromatic alkynes, which greatly limits the diversity of products (V.G.Reddy, et al..New J.Chem.2018,42,5972--5977)
In recent years, the development of inert C-H bond functionalization reactions has provided new ideas for the construction of furo[2,3-b]quinoxaline derivatives, but based on this The preparation of substances has not been studied

Method used

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  • Synthesis method and application of nitrogen heterocyclic compound with anti-tumor effect
  • Synthesis method and application of nitrogen heterocyclic compound with anti-tumor effect
  • Synthesis method and application of nitrogen heterocyclic compound with anti-tumor effect

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Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] (1) Weigh acetophenone (0.4mmol), 6-fluoroquinoxaline-2(1H)-one (0.2 mmol), copper trifluoromethanesulfonate (0.03mmol), K 2 S 2 o 8 (0.6mmol) and boric acid (0.4 mmol), transferred to a three-necked flask of 10 ml, added 2 ml of 1,2-dichloroethane, stirred magnetically at 80 degrees Celsius for 12 hours, cooled to room temperature after the reaction, filtered and collected The organic phase was rotary evaporated under reduced pressure to obtain the crude product 6-fluoro-2-phenylfuro[2,3-b]quinoxaline (A), and finally the pure target product was obtained by column chromatography. The eluent is petroleum ether: ethyl acetate = 3: 1, and the separation yield: 85%. Yellow solid; melting point 217.2-218.2°C; IR: ν=3432,1630, 819,757,730,681,658,614,429cm -1 ; 1 H NMR (500MHz, Chloroform-d) δ8.12(dd, J=9.2,5.7Hz,1H),8.05(d,J=9.6Hz,2H), 7.82(dd,J=9.5,2.8Hz,1H) ,7.56(t,J=6.8Hz,4H),7.30(s,1H); 13 C NMR (125MHz, Chloroform-d) δ164.6, 161.9 (q, J = 248.8Hz), 154.2, 145.2, ...

Embodiment 2

[0027] (2) Weigh 4-ethynyl acetophenone (0.4mmol), quinoxalin-2(1H)-one (0.2 mmol), copper trifluoromethanesulfonate (0.03mmol), K 2 S 2 o 8 (0.6mmol) and boric acid (0.4 mmol), transferred to a three-necked flask of 10 ml, added 2 ml of 1,2-dichloroethane, stirred magnetically at 80 degrees Celsius for 12 hours, cooled to room temperature after the reaction, filtered and collected The organic phase was rotary evaporated under reduced pressure to obtain the crude product 2-(4-ethynylphenyl)furo[2,3-b]quinoxaline (B), and finally the pure target product was obtained by column chromatography. The eluent is petroleum ether:ethyl acetate=3:1, and the separation yield: 87%. Brown solid; melting point 191.6-192.6°C; IR: ν = 3454, 1633, 750, 534cm -1 ; 1 H NMR (500MHz, Chloroform-d) δ8.20(d, J=9.8Hz, 1H), 8.13(s, 1H), 8.00(d, J=8.5Hz, 2H), 7.78(d, J=9.8Hz , 2H), 7.67(d, J=8.5Hz, 2H), 7.34(s, 1H), 3.28(s, 1H); 13 C NMR (125 MHz, Chloroform-d) δ162.9, 154.4, 144.3, 142.3, 139.0, ...

Embodiment 3

[0029] (3) Weigh cyclohexyl ethyl ketone (0.4mmol), quinoxalin-2(1H)-one (0.2mmol), copper trifluoromethanesulfonate (0.03mmol), K 2 S 2 o 8 (0.6mmol) and boric acid (0.4mmol), transferred to a three-necked flask of 10 ml, added 2 ml of 1,2-dichloroethane, magnetically stirred at 80 degrees Celsius for 12 hours, cooled to room temperature after the reaction, filtered and collected The organic phase was rotary evaporated under reduced pressure to obtain the crude product 2-cyclopropylfuro[2,3-b]quinoxaline (C), and finally the pure target product was obtained by column chromatography. The eluent is petroleum ether:ethyl acetate=3:1, and the separation yield: 75%. Dark black solid; melting point 90.1-91.1°C; IR: ν=3445,1632,1569,1385, 1311,941,806,760,599,454cm -1 ; 1 H NMR (500MHz, Chloroform-d) δ8.15(d, J=9.8Hz, 1H), 8.07(d, J=7.7Hz, 1H), 7.74–7.70(m, 2H), 6.73(s, 1H) ,2.24–2.20(m,1H),1.33(dd,J=4.8,2.5Hz,2H),1.25–1.22(m,2H); 13 C NMR (125MHz, Chloroform-d) δ170.9, 153.9,...

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Abstract

According to the synthetic method and application of the nitrogen heterocyclic compound with the anti-tumor effect, coupling reaction of a ketone compound and quinoxalinone is catalyzed through copper, the reaction yield is high, selectivity is good, operation is easy and convenient, and high practicability is achieved. According to the present invention, the synthesized nitrogen heterocyclic compound has good anti-tumor activity, and can significantly inhibit the proliferation of A549, HepG-2, Hela and MCF-7 cells, the activity of the 2-(4-ethynylphenyl) furo [2, 3-b] quinoxaline (B) on the four tumor cells exceeds the activity of the 5-fluorouracil, and the 2-(4-ethynylphenyl) furo [2, 3-b] quinoxaline (B) is expected to be developed into the broad-spectrum anti-tumor drug.

Description

technical field [0001] Belonging to the technical field of biomedicine, the invention relates to a synthesis method and application of nitrogen heterocyclic compounds with antitumor effects. Background technique [0002] Nitrogen heterocyclic compounds are an important class of organic compounds, which are widely used in the fields of medical science and material chemical industry. According to statistics, many of the top 200 best-selling drugs in the world in 2020 are nitrogen heterocyclic compounds, and four of the top ten drug molecules are nitrogen heterocyclic compounds. The annual sales of heterocyclic compounds (cardiovascular drugs) exceed 14 billion US dollars, which fully reflects the irreplaceability of nitrogen heterocyclic compounds. Based on this, in recent years, efficient synthesis methods of nitrogen heterocyclic compounds have attracted much attention, among which furo[2,3-b]quinoxaline derivatives have attracted more attention from medical researchers bec...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D491/048A61P35/00
CPCC07D491/048A61P35/00
Inventor 蒋光彬何美琴冯琼赖树玲凌彩萍刘翠宁及方华
Owner GUILIN UNIVERSITY OF TECHNOLOGY
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