Quinolone derivative as well as preparation method and application thereof
A derivative and quinolone technology, applied in the fields of medicinal chemistry and pharmacotherapeutics, can solve the problems of insufficient activity and no statistical difference, and achieve the effect of inhibiting tumor cell proliferation, inducing cell apoptosis, and low toxicity
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Embodiment 1
[0043] Synthesis of Diethyl 2-(((4-Hydroxyphenyl)amino)methylene)malonate (Compound 3)
[0044] Add 4-aminophenol (compound 1, 0.5 g, 4.5 mmol) to 2.5 mL of ethanol, then add ethoxymethylene malonate (compound 2, 925 μL, 4.5 mmol), and react at room temperature for 2 hours , until the reaction is complete, spin off ethanol under low pressure, and wash with methyl tert-butyl ether to obtain diethyl 2-(((4-hydroxyphenyl)amino)methylene)malonate (compound 3), white Solid (1.26 g, 98% yield).
[0045] 1 H NMR (500MHz, CDCl 3 )δ10.95(d,J=13.9Hz,1H,NH),8.41(d,J=13.9Hz,1H,CH),7.07–6.95(m,2H,Ar-H),6.92–6.82(m, 2H, Ar-H), 6.62(s, 1H, OH), 4.3(q, J=7.0, 2H, CH 2 ), 4.29 (q, J=7.0, 2H, CH 2 ), 1.35(t, J=7.0Hz, 3H, CH 3 ), 1.32(t, J=7.0Hz, 3H, CH 3 ).
[0046] Synthesis of 2-[(4-acetoxy-phenylamino)-methylene]-diethyl malonate (compound 4)
[0047] Diethyl 2-(((4-hydroxyphenyl)amino)methylene)malonate (compound 3, 0.5 g, 1.7 mmol) and triethylamine (374 μL, 2.6 mmol) were added t...
Embodiment 2
[0059] Synthesis of 6-((4-methylbenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 7b)
[0060] Referring to the synthesis of compound 7a in Example 1, only 4-(trifluoromethoxy)benzyl bromide was replaced with 4-(methyl)benzyl bromide to obtain compound 7b as a white solid with a yield of 85.2%.
[0061] mp>250℃.IR(KBr):3451,2894,1685,1626,1490,1383cm -1 . 1 H NMR (500MHz, DMSO) δ15.47(s, 1H, COOH), 13.52(s, 1H, NH), 8.81(d, J=5.5Hz, 1H, CH), 7.82(d, J=9.1Hz, 1H,Ar-H),7.74(s,1H,Ar-H),7.64(d,J=8.4Hz,2H,Ar-H),7.61(dd,J=9.1,1.6Hz,1H,Ar-H ), 7.41(d, J=8.2Hz, 2H, Ar-H), 5.31(s, 2H, CH 2 ). 13 C NMR (126MHz, DMSO) δ177.42(s), 166.49(s), 156.44(s), 143.32(s), 137.19(s), 134.13(s), 133.35(s), 128.96(s), 127.75 (s), 125.59(s), 124.77(s), 121.40(s), 106.86(s), 105.51(s), 69.66(s), 20.71(s). MS(ESI) m / z 308.1[M-H] - ; HRMS (ESI) calcd for C 18 h 14 NO 4 [M-H] - 308.0928,found 308.0931.
Embodiment 3
[0063] Synthesis of 6-((2-fluorobenzyl)oxy)-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Compound 7c)
[0064] Referring to the synthesis of compound 7a in Example 1, only 4-(trifluoromethoxy)benzyl bromide was replaced by 2-fluorobenzyl bromide to obtain compound 7c as a white solid with a yield of 88.6%.
[0065] mp>250℃.IR(KBr):3439,2901,1694,1622,1492,1387cm -1 . 1 H NMR (500MHz, DMSO) δ15.50(s, 1H, COOH), 13.57(s, 1H, NH), 8.81(d, J=6.3Hz, 1H, CH), 7.83(d, J=9.1Hz, 1H,Ar-H),7.78(d,J=2.8Hz,1H,Ar-H),7.63–7.55(m,2H,Ar-H),7.44(dd,J=9.1,2.8Hz,1H,Ar -H),7.32–7.20(m,2H,Ar-H),5.30(s,2H,CH 2 ). 13 C NMR (126MHz, DMSO) δ177.98(s), 167.01(s), 161.93(s), 159.97(s), 156.78(s), 143.96(s), 134.86(s), 131.17(dd, J= 21.6, 6.1Hz), 126.14(s), 124.82–124.31(m), 123.76(d, J=14.6Hz), 122.06(s), 116.02(s), 115.86(s), 107.46(s), 105.98( s),64.70(d).MS(ESI)m / z 336.0[M+Na] + ; HRMS (ESI) calcd for C 17 h 12 FNO 4 [M+Na] + 336.0643,found 336.0641.
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