Preparation of ferulic acid dimer derivative and application of ferulic acid dimer derivative to treatment of Alzheimer's disease
A technology of ferulic acid dimer and derivatives, which is applied in the treatment of Alzheimer's disease. The field of preparation of ferulic acid dimer derivatives can solve the problem of ineffective treatment of AD and blood-brain barrier penetration. Low pass rate and other issues, to achieve the effect of improving blood-brain barrier pass rate, reducing cell apoptosis, and safe synthesis route
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Embodiment 1
[0021] Compound A
[0022] (1) Preparation of intermediate 2
[0023]
[0024] Add ferulic acid (300g, 1.54mol), 4-dimethylaminopyridine (15g, 0.12mol), acetic acid (2000mL) into a 5000mL four-necked flask, stir and heat to 45°C, and heat up to 60°C after the raw materials are completely dissolved. ℃ reaction, according to the molar ratio of ferulic acid and acetic anhydride 1:1.1, dropwise add acetic anhydride (170g, 2.04mol), monitor the liquid phase, stop the reaction after 1h of reaction, cool the reaction solution to room temperature, then pour the reaction solution into cold dilute hydrochloric acid aqueous solution, a white solid was precipitated, filtered by suction, and dried to obtain the crude compound 2. Add toluene (3000mL) into a 5000mL four-neck flask, reflux and stir for 0.5h, filter while hot, wash with petroleum ether three times, dry to obtain a white solid, weighing 330g, HPLC purity 98.89%, yield 91.67%.
[0025] m.p.194.6-196.7°C. 1 H NMR (300MHz, D...
Embodiment 2
[0036] Compound B
[0037] The preparation method is the same as that of Example 1. The ethylenediamine in the step (3) is replaced with propylenediamine to obtain the target product.
[0038]
[0039] Yellow oil (compound 4); 1 H NMR (400MHz, DMSO) δ8.16 (t, J = 5.3Hz, 2H), 7.43 (d, J = 15.7Hz, 2H), 7.34 (s, 2H), 7.14 (dd, J = 19.3, 8.2Hz ,4H),6.64(d,J=15.7Hz,2H),3.82(s,6H),3.28-3.20(m,4H),2.27(s,6H),1.74-1.61(m,2H).
[0040]
[0041] Yellow oil (target product 5); 1 H NMR (300MHz, DMSO) δ9.43(s, 2H), 8.00(t, J=5.6Hz, 2H), 7.32(d, J=15.7Hz, 2H), 7.13(d, J=1.8Hz, 2H ),6.99(dd,J=8.2,1.8Hz,2H),6.78(d,J=8.1Hz,2H),6.44(d,J=15.7Hz,2H),3.80(s,6H),3.27-3.13 (m,4H),1.71-1.56(m,2H).
Embodiment 3
[0043] Compound C
[0044] The preparation method is the same as that of Example 1. The ethylenediamine in the step (3) is replaced with 2,2-dimethylpropylenediamine to obtain the target product.
[0045]
[0046] Yellow powder (compound 4), m.p.87.6-89.5; 1 H NMR (300MHz, DMSO) δ8.11(s, 2H), 7.45(d, J=15.7Hz, 2H), 7.36(d, J=1.5Hz, 2H), 7.16(dt, J=16.9, 4.9Hz ,4H),6.74(d,J=15.7Hz,2H),3.82(s,6H),3.08(d,J=6.2Hz,4H),2.27(s,6H),0.86(s,6H).
[0047]
[0048] White powder (target product 5), m.p.135.5-136.1°C; 1 H NMR (300MHz, DMSO) δ9.46(s, 2H), 7.98(t, J=6.5Hz, 2H), 7.35(d, J=15.6Hz, 2H), 7.16(d, J=1.8Hz, 2H ),7.00(dd,J=8.2,1.8Hz,2H),6.79(d,J=8.1Hz,2H),6.54(d,J=15.7Hz,2H),3.81(s,6H),3.04(d ,J=6.3Hz,4H),0.84(s,6H).
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