Synthesis method and anticancer activity of 2-hydroxysuccinimide substituted indolones
A technique for the synthesis of hydroxysuccinimide, which is applied in the fields of organic chemistry, antineoplastic drugs, drug combinations, etc., can solve problems such as insufficient research, achieve high step/atom economy, wide application range, and easy raw materials The effect
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Embodiment 1
[0030]
[0031] Compound 1a, solvent and catalyst 1 were sequentially added to a 15 mL reaction tube, react at room temperature (2h), then compound 2a and catalyst 2 were added, the reaction tube was sealed under air conditions, and the temperature was stirred for reaction. After the reaction was completed, it was cooled to room temperature, quenched by adding water, filtered through celite, extracted with dichloromethane, the organic phase was dried, filtered with suction, spin-dried, and separated on a silica gel column (petroleum ether / ethyl acetate=2 / 1) to obtain Product 3a as a yellow solid.
[0032] By changing the reaction conditions such as the solvent of the reaction, the type of catalyst 1 and catalyst 2, the reaction temperature and the dosage ratio, the results are as follows:
[0033] Table 1 Synthesis of 3a under different conditions a
[0034]
[0035]
Embodiment 2
[0037]
[0038] 1a (133.9 mg, 0.6 mmol), 1,2-dichloroethane (2 mL) and gold chloride (4.5 mg, 0.015 mmol) were sequentially added to a 15 mL pressure-resistant tube, and reacted at room temperature for 2 h under air conditions, and then 2a (33.3 mg, 0.3 mmol) and anhydrous copper acetate (10.9 mg, 0.06 mmol) were added, the reaction tube was sealed, and placed in a 120° C. reaction module to stir for 8 h. After the reaction, the reaction system was cooled to room temperature, water was added to quench the reaction, filtered through celite, and the filtrate was extracted with dichloromethane. ethyl ester = 2 / 1) to give the product 3a as a yellow solid (66.6 mg, 66%).
[0039] The characterization data for this compound are: 1 H NMR (400MHz, DMSO-d 6 ):δ7.44-7.39(m,4H),7.35(d,J=7.6Hz,1H),7.30(t,J=8.0Hz,2H),7.22(t,J=7.6Hz,1H),7.10 (d, J=8.4Hz, 1H), 6.72-6.68 (m, 1H), 6.34 (d, J=5.6Hz, 1H), 4.47-4.43 (m, 1H), 4.40 (d, J=7.2Hz, 1H), 2.78(s, 3H). 13 C{ 1 H}NMR(100MHz,DMSO-d...
Embodiment 3
[0041] According to the method and steps of Example 2 a,b, by changing reactant 1 and reactant 2, various 2-hydroxysuccinimide-substituted indolinone compounds 3a-3z and 3aa-3kk were synthesized. The specific results are as follows:
[0042]
[0043]
[0044] a Reaction conditions: 1(0.6mmol), 2(0.3mmol), AuCl 3 (0.015mmol), Cu(OAc) 2 (0.03mmol), 1,2-dichloroethane (2mL), room temperature 2h, then 120 ℃ reaction 8h, air atmosphere; b Separation yield.
[0045] ____________________________________________________________________
[0046] Representative product characterization data are as follows:
[0047] 3-Hydroxy-4-(6-methoxy-3-oxo-2-phenylindolin-2-yl)-1-methylpyrrolidine-2,5-dione(3b)
[0048] Yellow solid (61.6 mg, 56%). 1 H NMR (400MHz, DMSO-d 6 ): δ7.42-7.38(m, 3H), 7.30(t, J=8.0Hz, 2H), 7.26-7.19(m, 2H), 6.62(d, J=2.0Hz, 1H), 6.33(d, J=5.6Hz,1H),6.28(dd,J 1 =8.8Hz,J 2 =2.4Hz,1H),4.45-4.41(m,1H),4.36(d,J=7.2Hz,1H),3.80(s,3H),2.78(s,3H). 13 C{ 1 H}NMR(...
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