Preparation method for cannflavin compounds
Disclosed is a preparation method for cannflavin compounds. The preparation method has the advantages of cheap and easily available raw materials, few reaction steps, short production period, simple operation, etc. The method comprises: firstly, condensing 4′-hydroxy-3′-methoxyacetophenone and diethyl carbonate (DEC) under an alkaline condition to obtain 4′-hydroxy-3′-methoxybenzoyl acetate; reacting 1,3,5-trihydroxybenzene with bromo-isoamylene under an alkaline condition to obtain 2-isopentenyl-1,3,5-trihydroxybenzene; and finally, condensing 4′-hydroxy-3′-methoxybenzoyl acetate and 2-isopentenyl-1,3,5-trihydroxybenzene at a high temperature to produce cannflavin B and/or isocannflavin B, and then subjecting same to separation and purification to obtain pure cannflavin B and pure isocannflavin B.
1 . A preparation method for a cannflavin compound, comprising the following steps:
step (1): condensing 4′-hydroxy-3′-methoxyacetophenone and diethyl carbonate under an alkaline condition to obtain ethyl 4′-hydroxy-3′-methoxybenzoylacetate;
step (2): reacting 1,3,5-trihydroxybenzene with bromo-isoamylene under an alkaline condition to obtain 2-isopentenyl-1,3,5-trihydroxybenzene; and
step (3): reacting ethyl 4′-hydroxy-3′-methoxybenzoylacetate with 2-isopentenyl-1,3,5-trihydroxybenzene to obtain cannflavin B and/or isocannflavin B;
wherein the step (2) comprises the following steps: adding water and potassium hydroxide into a reaction vessel, stirring, then adding 1,3,5-trihydroxybenzene, cooling, adding dropwise bromo-isoamylene, stirring, reacting, and then performing post-treatment on the resulting reaction liquid to obtain 2-isopentenyl-1,3,5-trihydroxybenzene;
for the step (2): a molar ratio of 1,3,5-trihydroxybenzene to bromo-isoamylene is 1:1 to 2:1;
the reaction temperature is 0-15° C.;
the post-treatment comprises a quenching step, and the quenching step comprises: adding ethyl acetate to the reaction vessel, and adding an acid to adjust pH of the mixture to 4.0-7.0;
the post-treatment further comprises an extraction step after the quenching step, and the extraction step comprises: adding ethyl acetate to the reaction liquid, and layering; adding ethyl acetate to the aqueous layer for extraction, and layering; combining the organic layers, washing, layering, and then combining the organic layers.
2 . The preparation method according to claim 1 , wherein for the step (1), the reaction is performed under an oxygen-free environment; and the reaction system further comprises a solvent selected from the group consisting of: toluene, benzene, and a combination thereof.
3 . The preparation method according to claim 2 , wherein the oxygen-free environment in the step (1) is an inert gas protected reaction environment;
the alkali is an inorganic alkali;
a mass molar ratio of the inorganic alkali to 4′-hydroxy-3′-methoxyacetophenone is 50-1000 g/mol;
a molar ratio of 4′-hydroxy-3′-methoxyacetophenone to diethyl carbonate is 1:3 to 3:1;
the reaction temperature is 80-130° C.;
the reaction time is 2-12 h; and
4′-hydroxy-3′-methoxyacetophenone is added dropwise to diethyl carbonate.
4 . The preparation method according to claim 1 , wherein the step (1) comprises the following steps: under inert gas protection, adding NaH and toluene into a reaction vessel, stirring, adding diethyl carbonate, heating, adding dropwise a mixture of 4′-hydroxy-3′-methoxyacetophenone and toluene, stirring, reacting, and then performing post-treatment on the resulting reaction liquid to obtain ethyl 4′-hydroxy-3′-methoxybenzoylacetate.
5 . The preparation method according to claim 1 , wherein for the step (2), the reaction system further comprises a solvent selected from the group consisting of: water, methanol, and a combination thereof.
6 . The preparation method according to claim 5 , wherein in step (2),
a mass molar ratio of the potassium hydroxide to bromo-isoamylene is 50-1000 g/mol;
a molar ratio of 1,3,5-trihydroxybenzene to bromo-isoamylene is 1.9:1;
the reaction temperature is 0-10° C.;
the reaction time is 8-24 h.
7 . The preparation method according to claim 1 , wherein for the step (3), the reaction is performed under an oxygen-free environment.
8 . The preparation method according to claim 7 , wherein the oxygen-free environment in the step (3) is an inert gas protected reaction environment;
the reaction temperature is 150-230° C.;
the reaction time is 2-8 h; and
a molar ratio of ethyl 4′-hydroxy-3′-methoxybenzoylacetate to 2-isopentenyl-1,3,5-trihydroxybenzene is 1:2 to 3:1.
9 . The preparation method according to claim 1 , wherein the step (3) comprises the following steps: under inert gas protection, adding ethyl 4′-hydroxy-3′-methoxybenzoylacetate and 2-isopentenyl-1,3,5-trihydroxybenzene into a reaction vessel, stirring, heating, reacting, and then performing post-treatment on the resulting reaction liquid to obtain cannflavin B and/or isocannflavin B.
10 . The preparation method according to claim 4 , wherein the post-treatment comprises a quenching step; and
the quenching step comprises: adding an acid to the reaction vessel to adjust pH of the mixture to 4.0-7.0.