Coumarins derivative used as caspase-3 activator and application thereof
A technology of coumarins and derivatives, which is applied in drug combination, organic chemistry, anti-tumor drugs, etc., and can solve the problems that anti-tumor drugs cannot inhibit the growth of tumor cells and cannot be delivered correctly
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Embodiment 1
[0081] Preparation of Step A, 8-hydroxyl-2-oxo-2H-chromene-3-carboxylic acid:
[0082] Add 0.1mol of 2,3-dihydroxybenzaldehyde and 0.11mol of McFarlandic acid into 80ml of water, react and stir at 80°C for 2h, cool after the reaction, and filter with suction to obtain the product intermediate A with a yield of 92.5%, MS (ESI)m / z(%):205.1[M-H] - ; 1 H NMR (400 MHz, DMSO) δ 10.35 (s, 1H), 8.68 (s, 1H), 7.35–7.29 (m, 1H), 7.24–7.18 (m, 2H).
[0083] The preparation of step B, N-ethyl-N-(4-nitrobenzyl) ethylamine (1)
[0084] 20g of p-nitrobenzyl bromide (0.092mol) and 14.14g of diethylamine (0.19mol) were added to 80ml of acetonitrile, stirred at room temperature for 5h, after the reaction was complete, 200ml of water and 200ml of dichloromethane were added to the reaction solution, Extracted to obtain an organic layer, dried over anhydrous sodium sulfate, evaporated to dryness, yield 73.1%, MS (ESI) m / z (%): 208.4 [M+H] + ;1H NMR (400MHz, CDCl3) δ8.21–8.13(d, J=8.6Hz, 2H), 7...
Embodiment 2
[0092] With reference to step A in Example 1, 2-hydroxyl 3-methoxybenzaldehyde was used as raw material to prepare 8-methoxy-2-oxo-2H-chromene-3-carboxylic acid, yield 88.7%, MS (ESI) m / z (%): 219.1 [M-H] - ; 1 H NMR (400 MHz, DMSO) δ 8.71 (s, 1H), 7.46–7.43 (m, 1H), 7.43–7.39 (m, 1H), 7.37–7.30 (m, 1H), 3.93 (s, 3H).
[0093] With reference to step B, step C, and step D in Example 1, 6-(diethylaminomethyl) benzo[d]thiazol-2-amine (B-2) is prepared, and finally with reference to Example 1 Step E, with 8-methoxy-2-oxo-2H-chromene-3-carboxylic acid and 6–(diethylaminomethyl) benzo[d]thiazol-2-amine (B- 2) As a raw material, N-[2-(6-(diethylaminomethyl)benzo[d]thiazolyl)]-8-methoxy-2-oxo-2H-benzopyran was prepared -3-Carboxamide, the structure is shown in Table 1, yield: 46.2%; MS (ESI) m / z (%): 437.0 [M+H] + ; 1 H NMR (400MHz,DMSO)δ9.02(s,1H),8.20(s,1H),7.98–7.85(m,1H),7.65–7.53(m,2H),7.53–7.47(m,1H), 7.46–7.37 (m, 1H), 4.41 (s, 2H), 3.97 (s, 3H), 3.22–3.02 (d, J=7.0Hz, 4H...
Embodiment 3
[0095] Referring to Step A in Example 1, 8-hydroxy-2-oxo-2H-chromene-3-carboxylic acid was prepared.
[0096] Referring to step B in Example 1, using p-nitrobenzyl bromide and 4-methylpiperidine as raw materials, prepare 4-methyl-1-(4-nitrophenyl)piperidine (1), refer to the implementation Step C of Example 1, using 4-methyl-1-(4-nitrophenyl)piperidine as raw material, prepares 4-(4-methylpiperidinylmethyl)aniline (B-1), refer to The method of step D in the embodiment one, use 4-(4-methylpiperidylmethyl)aniline as raw material, prepare 6-(4-methylpiperidylmethyl)benzo[d]thiazole- 2-amine (B-2), yield: 85.3%; MS (ESI) m / z (%): 262.1 [M+H] + ; 1 H NMR (400MHz, DMSO) δ7.75(s, 1H), 7.65(s, 2H), 7.38(d, J=8.0Hz, 1H), 7.30(d, J=8.0Hz, 1H), 4.22(s ,2H),3.33(m,2H),2.77(m,2H),1.77(m,2H),1.56(m,1H),1.29(m,2H),0.90(d,J=5.4Hz,3H) .
[0097] Finally, with reference to step E in Example 1, 8-hydroxy-2-oxo-2H-benzopyran-3-carboxylic acid and 6-(4-methylpiperidinylmethyl)benzo[d] Thiazo...
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