A kind of coumarin derivative with 1,2,4-oxadiazole-structural fragment and its application
A technology of coumarin derivatives and structural fragments, which is applied in the field of medicine and can solve problems such as poor therapeutic effect
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Embodiment 1
[0027] Embodiment 1: the preparation of formula 3 compound
[0028]
[0029] Dissolve 880 mg of powdered 7-hydroxy-4-methylcoumarin (formula 1) in 50 ml of acetone, add 828 mg of potassium carbonate, stir for 0.5 h, then add 1.5 g of p-cyanobenzyl bromide (formula 2), 83 mg of potassium iodide and 156 mg of tetrabutylammonium bromide, stirred at 50° C. for 5 h, the reaction was complete as detected by TLC, and the reaction solution was concentrated. Recrystallization from 50% ethanol gave 1.426 g of compound formula 3, a yellow solid, with a yield of 98%. 1 H NMR (400MHz, CDCl 3 )δ7.73(d, J=8.3Hz, 2H), 7.57(dd, J=11.6, 8.5Hz, 3H), 6.95(dd, J=8.8, 2.5Hz, 1H), 6.88(d, J=2.5 Hz,1H),6.18(s,1H),5.21(s,2H),2.43(s,3H).ESI-MS m / z:292.4[M+H]+.
Embodiment 2
[0030] Embodiment 2: the preparation of formula 4 compound
[0031]
[0032] Dissolve 582mg of the compound of formula 3 in 10ml of absolute ethanol, cool to 0°C in ice bath, add 751mg of triethylamine and 308mg of hydroxylamine hydrochloride, stir for 0.5h, then heat to reflux (80°C) overnight. Extracted with ethyl acetate (25ml*3), the combined organic layers were washed 3 times with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography to obtain 395 mg of the compound of formula 4 as a yellow solid with a yield of 85%. 1 H NMR (400MHz, CDCl 3 )δ7.88(d,J=8.4Hz,1H),7.69(d,J=8.4Hz,1H),7.58–7.47(m,3H),6.99–6.93(m,1H),6.90(d,J =2.3Hz,1H),6.17(d,J=1.2Hz,1H),5.28–5.15(m,2H),4.89(s,2H),2.43(s,3H).ESI-MS m / z:325.2 [M+H]+.
Embodiment 3
[0033]Embodiment 3: the preparation of general formula I compound
[0034]
[0035] Dissolve 0.5mmol of the compound of formula 5 in 5ml of dichloromethane, add 0.55mmol of N,N-diisopropylethylamine and 0.55mmol of 2-(7-azobenzotriazole)-tetramethyluronium hexafluorophosphate (HATU ), stirred at room temperature for 3h, and TLC detected that the reaction was complete. Add 0.5 mmol of the compound of formula 4 dissolved in dichloromethane to the above reaction solution, stir at room temperature for three hours, TLC detects that the reaction is complete, and concentrate the reaction solution. Extracted with ethyl acetate (15ml*3), the combined organic layer was washed 3 times with saturated sodium chloride solution, dried over anhydrous sodium sulfate and concentrated under reduced pressure to obtain a residue. The above residue was dissolved in 10 ml of ethanol, 4 mmol of anhydrous sodium acetate was added, and heated to reflux (80° C.) overnight, TLC detected that the reac...
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