PREPARATION METHOD FOR CANNFLAVIN COMPOUNDS

Abstract

Disclosed in the present invention is a preparation method for cannflavin compounds. The preparation method has advantages such as cheap and easily available raw materials, few reaction steps, short production period, and easy operation. The method comprises: first, condensing 4-hydroxy-3-methoxyacetophenone and diethyl carbonate (DEC) under an alkaline condition to obtain ethyl 4-hydroxy-3-methoxybenzoylacetate, next, reacting 1,3,5-trihydroxybenzene with geraniol to obtain (E)-2-(3,7-dimethyloct-2,6-dien-1-yl)benzene-1,3,5-triphenol; and finally, condensing ethyl 4-hydroxy-3-methoxybenzoylacetate and (E)-2-(3,7-dimethyloct-2,6-dien-1-yl)benzene-1,3,5-triphenol at high temperature to produce cannflavin A and/or cannflavin C, and then carrying out separation and purification to obtain pure cannflavin A and cannflavin C.

Claims

1. A preparation method for a cannflavin compound, comprising the following steps: condensing ##STR00021## and diethyl carbonate under an alkaline condition to obtain ##STR00022## reacting ##STR00023## with an alcohol compound (R.sub.3OH) to obtain ##STR00024## and reacting ##STR00025## with ##STR00026## to obtain the cannflavin compound; wherein the cannflavin compound has a structure of general formula I: ##STR00027## R.sub.5, R.sub.6, R.sub.7, R.sub.5, and R.sub.9 are independently selected from the group consisting of: H, C.sub.1-14 alkyl, C.sub.3-14 alkenyl, hydroxy, C.sub.1-5 alkoxy, carboxyl, amino, and halogen; R.sub.2 and R.sub.4 are independently selected from the group consisting of: H, C.sub.1-14 alkyl, C.sub.3-14 alkenyl, hydroxy, C.sub.1-5 alkoxy, carboxyl, and halogen; and R.sub.3 and R.sub.1 are independently selected from the group consisting of: H, C.sub.1-14 alkyl, C.sub.3-14 alkenyl, and C.sub.1-5 alkoxy.

2. The preparation method according to claim 1, comprising the following steps: condensing ##STR00028## and diethyl carbonate under an alkaline condition to obtain ##STR00029## reacting ##STR00030## with an alcohol compound (R.sub.3OH) to obtain ##STR00031## and reacting ##STR00032## with ##STR00033## to obtain the cannflavin compound; wherein the cannflavin compound has a structure of general formula II: ##STR00034## R.sub.5, R.sub.8, and R.sub.9 are independently selected from the group consisting of: H, C.sub.1-14 alkyl, C.sub.3-14 alkenyl, hydroxy, C.sub.1-5 alkoxy, carboxyl, amino, and halogen; R.sub.3 and R.sub.1 are independently selected from the group consisting of: H, C.sub.1-14 alkyl, C.sub.3-14 alkenyl, and C.sub.1-5 alkoxy.

3. The preparation method according to claim 1, 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): subjecting 1,3,5-trihydroxybenzene and geraniol to a C-alkylation reaction to obtain (E)-2-(3,7-dimethyloct-2,6-dien-1-yl)benzene-1,3,5-triphenol; and step (3): condensing ethyl 4-hydroxy-3-methoxybenzoylacetate and (E)-2-(3,7-dimethyloct-2,6-dien-1-yl)benzene-1,3,5-triphenol at high temperature to produce cannflavin A and/or cannflavin C.

4. The preparation method according to claim 3, wherein the step (1) comprises a step of reacting 4-hydroxy-3-methoxyacetophenone with diethyl carbonate; the reaction is performed under an oxygen-free environment; the reaction is performed under an alkaline condition; the reaction system further comprises a solvent selected from the group consisting of: toluene and/or benzene.

5. The preparation method according to claim 4, 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.

6. The preparation method according to claim 3, 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.

7. The preparation method according to claim 3, wherein the step (2) comprises a step of subjecting 1,3,5-trihydroxybenzene and geraniol to the C-alkylation reaction, wherein the reaction is performed under an oxygen-free environment; and the reaction system further comprises a solvent selected from the group consisting of: acetonitrile and/or diethyl ether.

8. The preparation method according to claim 7, wherein the oxygen-free environment in the step (2) is an inert gas protected reaction environment, and further, the inert gas is nitrogen; a molar ratio of 1,3,5-trihydroxybenzene to geraniol is 1:3 to 3:1; the reaction temperature is 0-25 C.; the reaction time is 8-24 h; and the step (2) further comprises dropwise addition of a solution of boron trifluoride in diethyl ether.

9. The preparation method according to claim 3, wherein the step (2) comprises the following steps: adding acetonitrile saturated with silver nitrate into a reaction vessel, then adding 1,3,5-trihydroxybenzene and geraniol, cooling under inert gas protection, adding dropwise a solution of boron trifluoride in diethyl ether, stirring, reacting, and then performing post-treatment on the resulting reaction liquid to obtain (E)-2-(3,7-dimethyloct-2,6-dien-1-yl)benzene-1,3,5-triphenol.

10. The preparation method according to claim 3, wherein the step (3) comprises a step of reacting ethyl 4-hydroxy-3-methoxybenzoylacetate with (E)-2-(3,7-dimethyloct-2,6-dien-1-yl)benzene-1,3,5-triphenol, wherein the reaction is performed under an oxygen-free environment.

11. The preparation method according to claim 10, 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 (E)-2-(3,7-dimethyloct-2,6-dien-1-yl)benzene-1,3,5-triphenol is 1:3 to 3:1.

12. The preparation method according to claim 3, wherein the step (3) comprises the following steps: under inert gas protection, adding ethyl 4-hydroxy-3-methoxybenzoylacetate and (E)-2-(3,7-dimethyloct-2,6-dien-1-yl)benzene-1,3,5-triphenol into a reaction vessel, stirring, heating, reacting, and then performing post-treatment on the resulting reaction liquid to obtain cannflavin A and/or cannflavin C.

13. The preparation method according to claim 3, comprising the following steps: condensing 4-hydroxy-3-methoxyacetophenone and diethyl carbonate under an alkaline condition to obtain ethyl 4-hydroxy-3-methoxybenzoylacetate; adding acetonitrile saturated with silver nitrate into a reaction vessel, then adding 1,3,5-trihydroxybenzene and geraniol, cooling under inert gas protection, adding dropwise a solution of boron trifluoride in diethyl ether, stirring, reacting, and then performing post-treatment on the resulting reaction liquid to obtain (E)-2-(3,7-dimethyloct-2,6-dien-1-yl)benzene-1,3,5-triphenol; under inert gas protection, adding ethyl 4-hydroxy-3-methoxybenzoylacetate and (E)-2-(3,7-dimethyloct-2,6-dien-1-yl)benzene-1,3,5-triphenol into a reaction vessel, stirring, heating, reacting, and then performing post-treatment on the resulting reaction liquid to obtain cannflavin A and/or cannflavin C.

14. Use of ethyl 4-hydroxy-3-methoxybenzoylacetate in preparing a compound, wherein the compound is a cannflavin compound.

15. The preparation method according to claim 2, wherein R.sub.5 is H, R.sub.8 is H, and R.sub.9 is H.

16. The preparation method according to claim 15, wherein R.sub.1 is H, and R.sub.3 is geranyl.

17. The preparation method according to claim 15, wherein R.sub.1 is geranyl, and R.sub.3 is H.

18. The preparation method according to claim 6, 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.

19. The preparation method according to claim 9, wherein the post-treatment comprises a quenching step; and the quenching step comprises: adding a quenching solvent to the reaction vessel.

20. The use according to claim 14, wherein the cannflavin compound is cannflavin A and/or cannflavin C.

Description

DETAILED DESCRIPTION

[0114] It should be noted that the detailed description as follows is exemplary and is intended to provide further explanation of the present application. Unless otherwise stated, all technical and scientific terms used herein have the same meaning as that commonly understood by those of ordinary skill in the art to which the present application belongs.

Example 1: Synthesis of Ethyl 4-hydroxy-3-methoxybenzoylacetate

[0115] ##STR00018##

[0116] To a reaction flask, 60% NaH (6.00 g, 150 mmol) was added, under nitrogen protection, toluene (60 mL) and DEC (11.82 g, 100 mmol) were added, and the resulting mixture was stirred, and heated to reflux. A solution of 4-hydroxy-3-methoxyacetophenone (12.82 g, 50 mmol) in toluene (60 mL) was added dropwise. After the addition was completed, the resulting mixture was refluxed for 4 h, then cooled to room temperature, adjusted to pH neutral with acetic acid, and added with a saturated ammonium chloride aqueous solution (150 mL). The aqueous phase was extracted with ethyl acetate (100 mL3). The organic phases were combined, and washed successively with a saturated ammonium chloride aqueous solution (100 mL2) and saturated brine (100 mL2). The resulting organic phase was dried over anhydrous sodium sulfate, and filtered under vacuum. The filtrate was concentrated to dryness, added with n-hexane (50 mL), stirred overnight, and filtered to obtain ethyl 4-hydroxy-3-methoxybenzoylacetate (15.43 g, 93.9%) as an orange-yellow solid. MS (ESI): 238.9 [M+H].sup.+.

Example 2: Synthesis of (E)-2-(3,7-dimethyloct-2,6-dien-1-yl)benzene-1,3,5-triphenol

[0117] ##STR00019##

[0118] To a reaction flask, 50 mL of acetonitrile saturated with silver nitrate was added and stirred. 1,3,5-trihydroxybenzene (3.33 g, 26.41 mmol) and geraniol (4.08 g, 26.45 mmol) were added. Under nitrogen protection, the resulting mixture was cooled in an ice-water bath, followed by dropwise addition of a solution of boron trifluoride in diethyl ether (1.23 g, 8.85 mmol). After the addition was completed, the resulting mixture was stirred at room temperature overnight. The reaction liquid was poured into 50 mL of ice-water mixture, and extracted with ethyl acetate (30 mL3). The organic phases were combined, washed successively with 5% aqueous sodium bicarbonate solution and water (20 mL3), dried over anhydrous sodium sulfate, and filtered under vacuum. The filtrate was concentrated to dryness, and the resulting oil was subjected to column chromatography (silica gel 200-300 mesh, petroleum ether:ethyl acetate=8:1.fwdarw.4:1.fwdarw.2:1) to obtain (E)-2-(3,7-dimethyloct-2,6-dien-1-yl)benzene-1,3,5-triphenol as an oil (0.6 g). MS (ESI): 263.2 [M+H].sup.+.

Example 3: Synthesis of Cannflavin A and/or Cannflavin C

[0119] ##STR00020##

[0120] To a reaction flask, (E)-2-(3,7-dimethyloct-2,6-dien-1-yl)benzene-1,3,5-triphenol (3.8 g, mmol) and ethyl 4-hydroxy-3-methoxybenzoylacetate (2.8 g, 10.67 mmol) were added and stirred. Under nitrogen protection, the resulting mixture was heated to 200 C., and maintained at this temperature for 3 h. The reaction mixture was cooled to room temperature, and the resulting product was purified by normal-phase silica gel column chromatography (silica gel 200-300 mesh, petroleum ether:ethyl acetate=10:1.fwdarw.2:1) multiple times and then purified by reverse-phase silica gel column chromatography (reverse-phase silica gel 200-300 mesh, water:methanol=50:50.fwdarw.40:90) multiple times to obtain cannflavin A (0.3227 g) and cannflavin C (0.2048 g) as yellow solids.

[0121] Cannflavin A: MS (ESI): MS (ESI): 437.0[M+H]+, .sup.1H-NMR (Acetone-d.sub.6, 400 MHz), : 1.56 (3H, s), 1.61 (3H, s), 1.81 (3H, s), 1.96 (2H, m), 2.04 (2H, m), 3.37 (2H, d), 4.00 (3H, s), 5.06 (1H, t), 5.29 (1H, t), 6.62 (1H, s), 6.70 (1H, s), 7.00 (1H, d), 7.58 (1H, dd), 7.60 (1H, d), 8.49 (1H, s), 9.56 (1H, s), 13.05. (1H, s).

[0122] Cannflavin C: MS (ESI): 437.0[M+H]+, .sup.1H-NMR (Acetone-d.sub.6, 400 MHz), : 1.50 (3H, s), 1.52 (3H, s), 1.84 (3H, s), 1.97 (2H, m), 2.03 (2H, m), 359(2H, d), 4.01 (3H, s), 5.04 (1H, t), (1H, t), 6.35 (1H, s), 6.72 (1H, s), 7.03 (1H, d), 7.63 (1H, dd), 7.64 (1H, d), 8.54 (1H, s), 9.63 (1H, s), 12.98. (1H, s).

[0123] The above descriptions are only preferred examples of the present application and are not intended to limit the present invention, and various modifications and changes may be made by those skilled in the art. Any modifications, equivalent replacements, improvements, and the like that are made within the spirit and principle of the present application shall all fall within the protection scope of the present application.