CN102126942A - Method for synthesizing hypericin - Google Patents

Abstract

The present invention relates to a synthetic method of hypericin, which comprises the following steps: (1) dissolving emodin and SnCl ₂ ·2H ₂ O in glacial acetic acid, adding 36-40% of Concentrated hydrochloric acid, reacted for 1-3 hours, cooled to obtain emodin anthrone; (2) dissolve emodin anthrone and potassium tert-butoxide in DMF, react in a microwave solid-liquid phase synthesis/extractor, and react 30-90 minutes, cooling to obtain protohypericin; (3) dissolving protohypericin in acetone, irradiating with halogen lamp for 15-24 hours, concentrating and precipitating to obtain hypericin. The method has the advantages of simple operation, low cost, less pollution, high yield and purity.

Description

Synthetic method of hypericin

technical field

The invention belongs to the field of medicine synthesis and relates to a synthesis method of hypericin.

Background technique

Hypericin, that is, 4,4,5,5,7,7-hexahydroxy-2,2-dimethyl-middle-naphthodianthrone, is the belt of Hypericum perforatum of Garciniaceae The whole flower is processed and extracted, and it has a highly targeted and effective effect on viruses such as influenza. Hypericin has various pharmacological effects such as antiviral, antidepressant, sedative, antibacterial and anti-inflammatory, and wound astringent. It can inhibit DNA and RNA viruses, and also has a certain inhibitory effect on tumor cells. The multiple pharmacological effects of hypericin make its market demand increasing day by day. Since the content of hypericin in the whole plant of Hypericum perforatum is only about 4/10,000, at present, the content of hypericin extracted from Hypericum perforatum in its extracts at home and abroad does not exceed 1%. Extraction process, the content of hypericin extracted and separated is not very high, and it will destroy a large amount of natural vegetation or occupy a large amount of cultivated land. In order to expand the drug source of hypericin and increase the content of hypericin, this goal can only be achieved through effective chemical synthesis methods.

Chinese patent application CN1827574A discloses a chemical synthesis method of hypericin and its derivatives. The method comprises the following steps: 1) dissolving 1,3,8-trihydroxy-6-methylanthraquinone in analytically pure glacial acetic acid, then adding 36-40% concentrated hydrochloric acid containing SnCl ₂ ·2H ₂ O, in React at no higher than 125°C for 1-4 hours, cool to obtain 1,3,8-trihydroxy-6-methylanthrone; 2) combine 1,3,8-trihydroxy-6-methylanthrone with Pyridine, piperidine, nitridine and FeSO ₄ 7H ₂ O reacted at 100-130°C in the dark for 0.5-3 hours, then dissolved the reaction product in acetone, irradiated with a halogen lamp for 12-24 hours, concentrated, and washed with n-hexane The alkane was dissolved, and the precipitate was filtered to obtain hypericin. The synthetic route disclosed in this document belongs to the traditional synthetic reaction process, which has the disadvantages of long reaction time, complex reaction components, large environmental pollution, cumbersome operation and difficult purification of products.

Contents of the invention

In view of the shortcomings of the prior art of synthesizing hypericin, the purpose of the present invention is to provide a hypericin synthesis method with low cost, high relative yield and yield, and less environmental pollution.

In order to realize the purpose of the present invention, the contriver improves reaction conditions and method through a large number of tests, has explored a kind of method of effective synthetic hypericin, and concrete technical scheme is as follows:

A kind of synthetic method of hypericin, comprises the following steps:

(1) Convert emodin into emodin anthrone

(2) Convert emodin anthrone into protohypericin

(3) Convert the original hypericin into hypericin

The step (2) is to carry out the catalyzed condensation reaction of emodin anthrone with potassium tert-butoxide as a catalyst under microwave conditions.

The above-mentioned synthetic method of hypericin, wherein the preferred step (2) is: dissolving emodin anthrone and potassium tert-butoxide in DMF, reacting in a microwave solid-liquid phase synthesis/extractor, cooling, and separating to obtain the original Hypericin, wherein the molar ratio of emodin anthrone to potassium tert-butoxide is 3-5:0.5-0.7. Further preferred step (2) is: dissolving emodin anthrone and potassium tert-butoxide in DMF, reacting in a microwave solid-liquid phase synthesis/extraction apparatus, cooling, and separating to obtain protohypericin, wherein emodin anthracene The molar ratio of ketone to potassium tert-butoxide is 3-5:0.5-0.7; and the catalyzed condensation reaction of emodin anthrone is protected by Ar ₂ , the microwave reaction power is kept at 250-550W, the reaction temperature is 130-150°C, and the reaction time for 30-90 minutes.

In the above-mentioned synthetic method of hypericin, the product obtained by the catalytic condensation reaction in the step (2) needs to be purified by silica gel column chromatography, and the eluent is petroleum ether with a volume ratio of 4:8:2-0.3: ethyl acetate : Methanol.

In any one of the hypericin synthesis methods above, the step (1) is: dissolving emodin and SnCl ₂ ·2H ₂ O in glacial acetic acid, raising the temperature to 100-125°C, and then adding concentrated hydrochloric acid in batches, Keep the reaction temperature at 100-125°C, react for 1-3 hours, cool, and separate emodin anthrone; wherein the molar ratio of emodin to SnCl ₂ 2H ₂ O is 1:3.5-5, and the volume of glacial acetic acid and concentrated hydrochloric acid The ratio is 5:1-3. A further preferred step (2) is: dissolve emodin and SnCl ₂ ·2H ₂ O in glacial acetic acid, raise the temperature to 100-125°C, then add concentrated hydrochloric acid in batches, keep the reaction temperature at 100-125°C, and react 1-3 Hours, cooled, and separated to obtain emodin anthrone; wherein the molar ratio of emodin to SnCl ₂ 2H ₂ O was 1:1.5-3.5, and the volume ratio of glacial acetic acid to concentrated hydrochloric acid was 5:1-3; and the whole reaction process Protected by Ar ₂ in the middle, when the reaction temperature reaches 100-125°C and reflux occurs, concentrated hydrochloric acid is slowly added in batches.

Any one of the above hypericin synthesis methods, the step (3) is: after dissolving the original hypericin in acetone, irradiating with a halogen lamp for 15-24 hours, and concentrating to obtain hypericin; wherein the The molar ratio of protohypericin and acetone is 0.5-0.7: 3-10. Further preferred step (2) is: after the original hypericin is dissolved in acetone, Ar ₂ is protected, and Ar ₂ is introduced below the liquid level, irradiated by a halogen lamp for 15-24 hours, and concentrated to obtain hypericin; wherein The molar ratio of protohypericin to acetone is 0.5-0.7:3-10.

Compared with the prior art, the hypericin synthesis method of the present invention has the following beneficial technical effects: the inventor creatively uses potassium tert-butoxide as a strong base catalyst to catalyze the condensation reaction of emodin anthrone, making the preparation of hypericin The operation of the element is simple, the preparation cost is low, the relative yield and purity are higher, the environmental pollution is less, and a relatively ideal effect has been obtained.

Detailed ways

The following are specific examples of the present invention, and further describe the technical solution of the present invention, but the protection scope of the present invention is not limited to these examples. All changes or equivalent substitutions that do not depart from the concept of the present invention are included in the protection scope of the present invention.

The methods used in the following examples are conventional methods unless otherwise specified.

Now use the method artificial synthesis hypericin of the present invention, concrete example comprises the following steps:

(1) Convert emodin into emodin anthrone

Take 2 g (7.4 mmol) of emodin, add it to 120 mL of glacial acetic acid, protect it with Ar ₂ , add SnCl ₂ 2H ₂ O 2.8 g (12.4 mmol) under stirring, start heating the mixture, the reaction temperature reaches 115 °C, and reflux begins to appear . At about 110°C, 48 mL of concentrated hydrochloric acid was added dropwise, and after the addition was complete, the reaction was refluxed for 2 h (TLC tracking). After standing to cool, filter with a Buchner funnel, wash the residue with deionized water until neutral, vacuum dry and weigh to obtain 1.766 mg of emodin anthrone with a yield of 93%.

When tracking the reaction process by TLC, draw 20 μL of the reaction solution every half hour, add an appropriate amount of absolute ethanol to dissolve it completely, and prepare a sample solution. Then accurately weigh 1mg of emodin anthrone and add absolute ethanol to dissolve it, suck it out with a pipette, transfer it to a 25mL volumetric flask, wash with absolute ethanol several times, add absolute ethanol to dilute to 25mL, and prepare a raw material solution. Spot the prepared reaction solution and emodin anthrone ethanol solution on a thin-layer chromatography plate, choose chloroform:methanol with a volume ratio of 3:1 as the developer, and observe the yellow spots of the reactants and the fluorescent spots of the products in the reaction system The change is used as an indicator to judge the extent of the reaction.

(2) Convert emodin anthrone into protohypericin

Get 1.024g (4mmol) of emodin anthrone and 0.062g (0.55mmol) of potassium tert-butoxide dissolved in 40mL of DMF (N,N-dimethylformamide), magnetic stirring, in the microwave solid-liquid phase synthesis/extraction apparatus The reaction was carried out in , and Ar ₂ was passed through before the reaction, and the air in the reaction bottle was exhausted. Set the reaction temperature to 145°C, the reaction power to 450W, and the reaction time to 40mim to start the reaction. After the reaction, it was cooled to room temperature, and deionized water was added. Add 2 mol hydrochloric acid to adjust the pH value of the solution to 2, filter it with a Buchner funnel, wash the precipitate with cold water until neutral, and dry it in vacuum. After elution on a silica gel column chromatography column, the eluent (petroleum ether: ethyl acetate: methanol = 4:8:0.9) obtained 0.544 mg of prohypericin, with a yield of 53.9%

(3) Convert the original hypericin into hypericin

Protohypericin 170 mg (0.33 mmol) was dissolved in 500 mL of acetone, protected by Ar ₂ and irradiated under a 500-watt halogen lamp for 24 hours. After the reaction was complete, the solvent was rotovapped to 5 mL. After vacuum drying, the product was weighed. The product obtained above was eluted on a silica gel column chromatography, and the eluent (petroleum ether: ethyl acetate: methanol = 4:8:0.5) was used to obtain 150 mg of hypericin with a yield of 95%. (content is ≥ 98.5%).

Claims (8)

1. hypericin synthetic method, comprise that step (1) is converted into emodin anthrone with Schuttgelb, (2) emodin anthrone is converted into former hypericin, (3) former hypericin is converted into hypericin, it is characterized in that: described step (2) is under the condition of microwave, carries out the reaction of emodin anthrone catalyzing and condensing with potassium tert.-butoxide as catalyzer.

2. hypericin synthetic method as claimed in claim 1, it is characterized in that: described step (2) is that emodin anthrone and potassium tert.-butoxide are dissolved among the DMF, be combined at the microwave solid-liquid/react in the abstraction instrument, cooling, separate obtaining former hypericin, wherein the mol ratio of emodin anthrone and potassium tert.-butoxide is 3-5: 0.5-0.7.

3. hypericin synthetic method as claimed in claim 2 is characterized in that: the reaction of emodin anthrone catalyzing and condensing is with Ar in the described step (2) ₂Protection, microwave reaction power remains on 250-550W, and temperature of reaction is 130-150 ℃, and the reaction times is 30-90 minute.

4. hypericin synthetic method as claimed in claim 3 is characterized in that: the product that the reaction of described step (2) catalyzing and condensing obtains is through purification by silica gel column chromatography, and elutriant is that volume ratio is 4: 8: the sherwood oil of 2-0.3: ethyl acetate: methyl alcohol.

5. as the arbitrary described hypericin synthetic method of claim 1-4, it is characterized in that: described step (1) is with Schuttgelb and SnCl ₂2H ₂O is dissolved in the glacial acetic acid, is warming up to 100-125 ℃, adds concentrated hydrochloric acid then in batches, keeps 100-125 ℃ of temperature of reaction, reaction 1-3 hour, and cooling separates obtaining emodin anthrone; Wherein Schuttgelb and SnCl ₂2H ₂The mol ratio of O is 1: 3.5-5, glacial acetic acid and concentrated hydrochloric acid volume ratio are 5: 1-3.

6. hypericin synthetic method as claimed in claim 5 is characterized in that: in the reaction process of described step (1) with Ar ₂Protection reaches 100-125 ℃ in temperature of reaction, and slowly adds concentrated hydrochloric acid when backflow phenomenon occurring in batches.

7. as the arbitrary described hypericin synthetic method of claim 1-4, it is characterized in that: described step (3) is after former hypericin is dissolved in acetone, and halogen lamp irradiation 15-24 hour concentrates, and obtains hypericin; Wherein said former hypericin and acetone mol ratio are 0.5-0.7: 3-10.

8. hypericin synthetic method as claimed in claim 7 is characterized in that: after former hypericin is dissolved in acetone, and Ar ₂Protection, and with Ar ₂Below the feeding liquid level.