CN102079737B

CN102079737B - Method for preparing apigenin

Info

Publication number: CN102079737B
Application number: CN201010616467A
Authority: CN
Inventors: 杨健; 吴婷; 杨波; 吴远双
Original assignee: Kunming University of Science and Technology
Current assignee: Kunming University of Science and Technology
Priority date: 2010-12-31
Filing date: 2010-12-31
Publication date: 2012-09-05
Anticipated expiration: 2030-12-31
Also published as: CN102079737A

Abstract

The invention provides a method for preparing apigenin, which comprises the following steps: performing the condensation reaction of the raw material of 2,4-dimethoxy-6-hydroxyacetophenone with p-methoxybenzaldehyde with the catalysis of an alkali to obtain a compound II; performing the cyclization reaction with the presence of a catalyst to obtain a compound III; heating to remove the methoxy group at an oxygen-isolated and acidic condition so as to obtain apigenin. The invention prepares apigenin by chemical synthesis, and has the advantages of simple process, easy processing for product separation and purification, high yield, mass production potential, abundant raw material sources, and low cost.

Description

A kind of method for preparing apigenin

Technical field

The present invention relates to a kind of method for preparing apigenin, belong to the synthetic field of medicine.

Background technology

Apigenin, systematic naming method are 4 ˊ, 5,7-trihydroxyflavone, and its structural formula is suc as formula shown in the I.Apigenin is naturally occurring a kind of flavonoid compound, and the title of " phytoestrogen " is arranged, and extensively is present in multiple fruit, vegetables, beans and the tealeaves, and wherein content is the highest in the celery.Have multiple pharmacological effect, like: antitumor, anti-inflammatory, arteriosclerosis, antithrombotic, anxiety, effect such as antibiotic, antiviral, anti-oxidant, at present clinical be mainly used in antitumor.

Ⅰ

The anticancer scope of apigenin is wider, and in vitro tests proves that it all has restraining effect to kinds of tumor cells, as: breast cancer cell, stomach cancer cell, prostate cancer cell, liver cancer cell, ovarian cancer cell etc. all have restraining effect.

Apigenin can activate the pl4ARF-Mdm2-p53 approach through the expression of downward modulation Mdm2; Also can be through activating the p53/waf1 approach; Increase the stability of p53; P53 albumen in the tumour cell, P21/WAF1 protein level are raise, induce the cell retardance of multiple cancerous cell line, with cell-cycle arrest at G ₂/ M the phase, and through p53 approach inducing apoptosis of tumour cell.Nuclear Factor-Kappa B (NF-κ B), B cell lymphoma/white blood disease-2 (Bcl-2), Bax have also participated in the effect of apigenin inducing apoptosis of tumour cell.

Because the content of apigenin in crude drug is very low, all adopt the method for from plant, directly extracting to prepare apigenin usually.Prepare apigenin through chemical synthesis and can improve apigenin production efficiency, and can improve the quality of medicine greatly, therefore also received domestic and international pharmacy worker's attention.At present, the method report for preparing apigenin with chemical synthesis in a large number is few, and with 2,4-dimethoxy-6-hydroxy acetophenone is that raw material synthetic celery element does not appear in the newspapers yet.

Summary of the invention

Prepare apigenin for solving chemical synthesis, the present invention provides a kind of abundant raw material, productive rate height, technology simply to prepare the method for apigenin, and the present invention realizes through following technical scheme:

A kind of method for preparing apigenin, following each step of process:

(1) take by weighing 2,4-dimethoxy-6-hydroxy acetophenone is by 2; The mol ratio of 4-dimethoxy-6-hydroxy acetophenone and aubepine is that 1 ︰ 1 ~ 1.2 takes by weighing aubepine; Be that 1 ︰, 10 adding solvents dissolve by solid-to-liquid ratio again, add alkali again, making the concentration of alkali in solution is 10 ~ 25%; Stir 20 ~ 40h down at 20 ~ 40 ℃, and then get compound ii after handling;

Ⅱ

(2) getting compound ii, is that 1 ︰ 1 ~ 10 adds solvent by solid-to-liquid ratio, adds the catalyzer of raw materials quality 0.5 ~ 3%, is heated to 80 ~ 150 ℃, stirs 3 ~ 30h, handles obtaining the compound III after the cooling again;

Ⅲ

(3) take by weighing the compound III, by solid solid than or solid-to-liquid ratio be that 1 ︰ 5 ~ 20 adds an acidic catalysts, after mixing, under nitrogen protection, be heated to 100 ~ 180 ℃, reacted 6 ~ 10 hours, be cooled to room temperature then, obtain apigenin after the processing again, i.e. chemical compounds I.

Alkali in the said step (1) is Pottasium Hydroxide or sodium hydroxide.

Solvent in the said step (1) is methyl alcohol or ethanol.

Processing again in the said step (1) is to pass through with concentrated hydrochloric acid solution conditioned reaction liquid pH=3 ~ 4, and with the reaction solution suction filtration, filter cake is used distilled water wash, and filter cake carries out drying again.

Catalyzer in the said step (2) is iodine, iodized salt.

Solvent in the said step (2) is a DMSO 99.8MIN..

Handling again in the said step (2) is through taking by weighing the sodium sulfite anhy 96 with quality such as catalyzer; Add 5 ~ 10 times water of solvent volume, be made into sodium sulfite solution, cooling back solution in the step (2) is added in the sodium sulfite solution; Stir 0.5 ~ 1h; Hold over night, behind the suction filtration with filtration cakes torrefaction

An acidic catalyst in the said step (3) is solid pyridine hydrochloride, hydrobromic acid solution or hydroiodic acid HI acetum.

The mass concentration of the hydrobromic acid solution in the said step (3) is 48%.

The mass concentration of the hydroiodic acid HI acetum in the said step (3) is 56%.

Handling again in the said step (3) is that the volume ratio through by reactant and water is that 1 ︰ 10 ~ 20 adds in the entry, hold over night, suction filtration after drying.

Said reagent is commercial product, and wherein methyl alcohol, ethanol, methyl-sulphoxide are solution, and concentration is the concentration of conventional commercial product; Aubepine, Pottasium Hydroxide, sodium hydroxide, iodine, iodized salt, pyridine hydrochloride, sodium sulfite anhy 96 are solid, are the commercial product of routine.

The present invention utilizes chemical synthesis to prepare apigenin, and its advantage is:

1, technology is simple, and the product separation and purification treatment is easy;

2, productive rate is high; Reaction mole total recovery reaches more than 50%, possesses the potentiality of scale prodn.

3, raw material sources are abundant, and cost is low.

Embodiment

Below in conjunction with embodiment the present invention is done and to further describe.

Embodiment 1

(1) take by weighing 19.6g2,4-dimethoxy-6-hydroxy acetophenone is by 2; The mol ratio of 4-dimethoxy-6-hydroxy acetophenone and aubepine is that 1 ︰ 1.2 takes by weighing the 16.3g aubepine, is that 1 ︰, 10 adding 356mL methyl alcohol dissolve by solid-to-liquid ratio again, adds sodium hydroxide again; Making the concentration of alkali in solution is 15%; Stir 40h down at 20 ℃, use concentrated hydrochloric acid solution conditioned reaction liquid pH=3 then, the reaction solution suction filtration; Filter cake is used distilled water wash, gets compound ii behind the filtration cakes torrefaction; Yield 90%; M.p.:112 ~ 116; ¹HNMR (CDCl ₃) characterize: δ 3.82 (s, 3H), 3.85 (s, 3H), 3.92 (s, 3H), 5.97 (d, J=1.9Hz, 1H), 6.11 (d, J=1.9Hz, 1H), 6.93 (d, J=7.5Hz, 2H), 7.56 (d, J=7.5 Hz, 2H), 12.78 (s, 1H);

(2) getting the 15.7g compound ii, is that 1 ︰ 1 adds the 15.7mL DMSO 99.8MIN. by solid-to-liquid ratio, adds 0.0785g iodine, is heated to 150 ℃, stirs 3h, cooling; Take by weighing the sodium sulfite anhy 96 of 7.85g, add the water of 78.5mL, be made into sodium sulfite solution, will cool off back solution and add in the sodium sulfite solution, stir 1h, hold over night with filtration cakes torrefaction, obtains the compound III behind the suction filtration; Yield 84%; M.p.:158 ~ 160; ¹HNMR (CDCl ₃) characterize: δ 3.99 (s, 3H), 4.03 (s, 3H), 4.07 (s, 3H), 6.49 (d, J=2.2Hz, 1H); 6.68 (d, J=2.2Hz, 1H); 6.81 (s, 1H); 7.13 (d, J=7.5Hz, 2H); 7.95 (d, J=7.5Hz, 2H);

(3) take by weighing 3.1g compound III, by solid solid than being 1 ︰, 5 adding 15.5g pyridine hydrochlorides, after mixing; Under nitrogen protection, be heated to 150 ℃, reacted 6 hours, be cooled to room temperature then; Volume ratio by reactant and water is that 1 ︰ 15 adds in the entry, hold over night, suction filtration after drying; Obtain apigenin, i.e. chemical compounds I; Yield 82%; M.p.:345 ~ 350; ¹HNMR (DMSO) characterizes: δ 6.18 (s, 1H), 6.47 (s, 1H), 6.78 (s, 1H), 6.91 (d, J=7.8Hz, 2H), 7.91 (d, J=7.8Hz, 2H), 10.36 (s, 1H), 10.85 (s, 1H), 12.95 (s, 1H).

Embodiment 2

(1) take by weighing 19.6g2,4-dimethoxy-6-hydroxy acetophenone is by 2; The mol ratio of 4-dimethoxy-6-hydroxy acetophenone and aubepine is that 1 ︰ 1 takes by weighing the 13.6g aubepine, is that 1 ︰, 10 adding 332mL ethanol dissolve by solid-to-liquid ratio again, adds Pottasium Hydroxide again; Making the concentration of alkali in solution is 10%, stirs 20h down at 40 ℃, uses concentrated hydrochloric acid solution conditioned reaction liquid pH=4 then; With the reaction solution suction filtration, filter cake is used distilled water wash, gets compound ii behind the filtration cakes torrefaction; Yield 90%; M.p.:112 ~ 116; ¹HNMR (CDCl ₃) characterize: δ 3.82 (s, 3H), 3.85 (s, 3H), 3.92 (s, 3H), 5.97 (d, J=1.9Hz, 1H), 6.11 (d, J=1.9Hz, 1H), 6.93 (d, J=7.5Hz, 2H), 7.56 (d, J=7.5 Hz, 2H), 12.78 (s, 1H);

(2) getting the 15.7g compound ii, is that 1 ︰ 10 adds the 157mL DMSO 99.8MIN. by solid-to-liquid ratio, adds the 0.157g potassiumiodide, is heated to 80 ℃, stirs 30h, cooling; Take by weighing the sodium sulfite anhy 96 of 15.7g, add the water of 125.6mL, be made into sodium sulfite solution, will cool off back solution and add in the sodium sulfite solution, stir 0.5h, hold over night with filtration cakes torrefaction, obtains the compound III behind the suction filtration; Yield 80%; M.p.:158 ~ 160; ¹HNMR (CDCl ₃) characterize: δ 3.99 (s, 3H), 4.03 (s, 3H), 4.07 (s, 3H), 6.49 (d, J=2.2Hz, 1H); 6.68 (d, J=2.2Hz, 1H); 6.81 (s, 1H); 7.13 (d, J=7.5Hz, 2H); 7.95 (d, J=7.5Hz, 2H);

(3) taking by weighing 3.1g compound III, is that 1 ︰, 10 adding 31mL mass concentrations are 56% Hydrogen bromide acetum by solid-to-liquid ratio, after mixing; Under nitrogen protection, be heated to 100 ℃, reacted 10 hours, be cooled to room temperature then; Volume ratio by reaction solution and water is that 1 ︰ 10 adds in the 310mL water hold over night, suction filtration after drying; Obtain apigenin, i.e. chemical compounds I; Yield 70%; M.p.:345 ~ 350; ¹HNMR (DMSO) characterizes: δ 6.18 (s, 1H), 6.47 (s, 1H), 6.78 (s, 1H), 6.91 (d, J=7.8Hz, 2H), 7.91 (d, J=7.8Hz, 2H), 10.36 (s, 1H), 10.85 (s, 1H), 12.95 (s, 1H).

Embodiment 3

(1) take by weighing 19.6g2,4-dimethoxy-6-hydroxy acetophenone is by 2; The mol ratio of 4-dimethoxy-6-hydroxy acetophenone and aubepine is that 1 ︰ 1 takes by weighing the 13.6g aubepine, is that 1 ︰, 10 adding 332mL ethanol dissolve by solid-to-liquid ratio again, adds Pottasium Hydroxide again; Making the concentration of alkali in solution is 25%, stirs 30h down at 30 ℃, uses concentrated hydrochloric acid solution conditioned reaction liquid pH=3 then; With the reaction solution suction filtration, filter cake is used distilled water wash, gets compound ii behind the filtration cakes torrefaction; Yield 88%; M.p.:112 ~ 116; ¹HNMR (CDCl ₃) characterize: δ 3.82 (s, 3H), 3.85 (s, 3H), 3.92 (s, 3H), 5.97 (d, J=1.9Hz, 1H), 6.11 (d, J=1.9Hz, 1H), 6.93 (d, J=7.5Hz, 2H), 7.56 (d, J=7.5 Hz, 2H), 12.78 (s, 1H);

(2) getting the 15.7g compound ii, is that 1 ︰ 5 adds the 78.5mL DMSO 99.8MIN. by solid-to-liquid ratio, adds the 0.471g Soiodin, is heated to 100 ℃, stirs 20h, cooling; Take by weighing the sodium sulfite anhy 96 of 15.7g, add the water of 785mL, be made into sodium sulfite solution, will cool off back solution and add in the sodium sulfite solution, stir 0.5h, hold over night with filtration cakes torrefaction, obtains the compound III behind the suction filtration; Yield 83%; M.p.:158 ~ 160; ¹HNMR (CDCl ₃) characterize: δ 3.99 (s, 3H), 4.03 (s, 3H), 4.07 (s, 3H), 6.49 (d, J=2.2Hz, 1H); 6.68 (d, J=2.2Hz, 1H); 6.81 (s, 1H); 7.13 (d, J=7.5Hz, 2H); 7.95 (d, J=7.5Hz, 2H);

(3) taking by weighing 3.1g compound III, is that 1 ︰, 20 adding 62mL mass concentrations are 48% hydrobromic acid solution by solid-to-liquid ratio, after mixing; Under nitrogen protection, be heated to 180 ℃, reacted 8 hours, be cooled to room temperature then; Volume ratio by reaction solution and water is that 1 ︰ 20 adds in the 1240mL water hold over night, suction filtration after drying; Obtain apigenin, i.e. chemical compounds I; Yield 75%; M.p.:345 ~ 350; ¹HNMR (DMSO) characterizes: δ 6.18 (s, 1H), 6.47 (s, 1H), 6.78 (s, 1H), 6.91 (d, J=7.8Hz, 2H), 7.91 (d, J=7.8Hz, 2H), 10.36 (s, 1H), 10.85 (s, 1H), 12.95 (s, 1H).

The above only is a preferred implementation of the present invention; Should be pointed out that for those skilled in the art, under the prerequisite that does not break away from the principle of the invention; Can also make some improvement and retouching, these improvement and retouching also should be regarded as protection scope of the present invention.

Claims

1. A method for preparing apigenin, characterized in that through the following steps:

(1) Weigh 2,4-dimethoxy-6-hydroxyacetophenone, and the molar ratio of 2,4-dimethoxy-6-hydroxyacetophenone to p-methoxybenzaldehyde is 1: 1~1.2 Weigh p-methoxybenzaldehyde, then add methanol or ethanol to dissolve according to the solid-liquid ratio of 1:10, then add potassium hydroxide or sodium hydroxide, so that the concentration of alkali in the solution is 10~25% , stirred at 20~40°C for 20~40h, then adjusted the pH of the reaction solution to 3~4 with concentrated hydrochloric acid solution, filtered the reaction solution with suction, washed the filter cake with distilled water, and dried the filter cake to obtain compound II;

Figure 2010106164670100001DEST_PATH_IMAGE001

II

(2) Take compound II, add dimethyl sulfoxide according to the solid-liquid ratio of 1:1~10, add catalyst iodine or iodide salt with a mass of 0.5~3% of the raw material, heat to 80~150°C, and stir for 3~30h , after cooling, after weighing sodium bisulfite with the same quality as the catalyst, add water 5 to 10 times the volume of dimethyl sulfoxide to make a sodium bisulfite solution, and add the cooled solution in step (2) In sodium bisulfite solution, stir for 0.5~1h, let stand overnight, filter with suction and dry the filter cake to obtain compound III;

III

(3) Weigh compound III, and add solid pyridine hydrochloride, hydrobromic acid solution with a mass concentration of 48% or hydroiodic acid acetic acid solution with a mass concentration of 56% according to the solid-solid ratio or solid-liquid ratio of 1:5~20, After mixing evenly, heat to 100~180°C under the protection of nitrogen, react for 6~10 hours, then cool to room temperature, then add water according to the volume ratio of reactants and water at 1:10~20, let stand overnight, pump After filtering and drying, apigenin was obtained, that is, compound I.