Berberine derivative as well as preparation method and application thereof
A technology of compounds and mixtures, applied in the field of derivatives of natural product berberine, can solve problems such as limited anticancer activity
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[0061] The preparation of intermediates 1-4 has been reported and can be prepared by a relatively simple method.
[0062]
[0063] Specifically, the following steps are included:
[0064] (1) Commercial or self-made substituted pentadecyl acid 1 generates the corresponding acid chloride under the condition of oxalyl chloride;
[0065] (2) The intermediate acid chloride 6 is condensed with berbererythine to generate differently substituted compounds I-I;
[0066] (3) intermediate acid chloride 6 and intermediate 4 are condensed to generate amides compound I-II;
[0067] (4) condensation of different substituted pentadecyl halides and berberine to generate ether compounds I-III;
[0068] in,
[0069] In the step (1), the solvent used for the reaction with oxalyl chloride is selected from solvents such as dichloromethane; the reaction temperature is 0°C;
[0070] The solvent used for the condensation reaction described in step (2) is selected from acetonitrile; the reactio...
Embodiment 1
[0091]
[0092] Synthesis of Intermediate 5: The starting material ETC-1002 (1eq, 0.96mmol) was dissolved in dichloromethane, and Dess-Martin oxidant (2eq, 1.92mmol) was added at 0°C, stirred at room temperature for 1 hour, and the reaction was monitored by TLC completely. Quenched by saturated sodium thiosulfate solution, extracted with dichloromethane, washed with saturated brine, dried over anhydrous sodium sulfate, concentrated under reduced pressure, and purified by column chromatography (DCM:MeOH=25:1) to obtain the product intermediate 5 (0.82 mmol, 86%): 1 H NMR (300MHz, CDCl 3 )δ2.36 (t, J=6.0Hz, 4H), 1.61-1.44 (m, 8H), 1.27-1.23 (m, 8H), 1.16 (s, 12H). ESI-MS (m / z): [ M+Na] + ,365.2.
[0093] Synthesis of Intermediate 6: At 0°C, oxalyl chloride (2.46mmol, 3eq) was added dropwise to anhydrous dichloromethane solution of Intermediate 5 (0.82mmol, 1eq), and then a catalytic amount of DMF was added. The mixed solution was raised to room temperature and stirred fo...
Embodiment 2
[0101] The synthesis of embodiment 2 compound B3
[0102]
[0103] Reagent 13 (0.83mmol, 1eq) was dissolved in anhydrous dichloromethane, oxalyl chloride (1.65mmol, 2eq) and a catalytic amount of DMF were added dropwise at 0°C, and stirred at room temperature for 2h. The reaction solution was concentrated under reduced pressure, and the anhydrous acetonitrile solution of the crude product was added dropwise to the anhydrous acetonitrile solution of intermediate 1 (0.83 mmol, 1 eq), and the temperature was raised to reflux and stirred overnight. The reaction solution was concentrated under reduced pressure, and the crude product was purified by column chromatography (DCM:MeOH=15:1) to obtain compound B3 (0.50 mmol, 60%): 1 H NMR (400MHz, CD3OD) δ9.71(s, 1H), 8.82(s, 1H), 8.22(dd, J=13.6, 9.6Hz, 2H), 7.69(s, 1H), 6.97(s, 1H) ,6.12(s,2H),4.94(t,J=6.4Hz,2H),4.08(s,3H),3.27(d,J=6.4Hz,2H),2.86(t,J=7.2Hz,2H) ,1.88-1.80(m,2H),1.53(s,2H),1.33-1.30(m,20H),0.90(t,J=6.0Hz,3H). 13 C ...
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