CN101824017A - Method for preparing scutellarin aglycone - Google Patents
Method for preparing scutellarin aglycone Download PDFInfo
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Abstract
The invention discloses a method for preparing scutellarin aglycone. In the method, 95 percent ethanol is used as reaction solution; and scutellarin undergoes hydrolysis reaction in 3 to 8 mol/L organic acid alcohol solution under the protection of an inert gas to prepare high-purity scutellarin aglycone. Due to the adoption of the method for preparing the scutellarin aglycone provided by the invention, an optimal preparation process for the scutellarin aglycone is determined; the overall preparation method has the characteristics of fast reaction speed and high efficiency; the obtained scutellarin aglycone has the characteristics of high yield and high purity; and the method for preparing the scutellarin aglycone provided by the invention has high operability and can realize industrialized mass production.
Description
Technical field
The present invention relates to a kind of preparation method of compound, being specifically related to a kind of is raw material prepares Scutellarein by acid hydrolysis method with flavonoid compound scutellarin glycosides.
Background technology
Scutellarein is a flavonoid compound in the short booth bitter fleabane of the composite family class plant Herba Erigerontis, Herba Erigerontis has another name called Herba Erigerontis, another name oil lamp chrysanthemum, TUXIXIN, push up grass, root of Chinese wild ginger grass, eastern chrysanthemum etc., Herba Erigerontis hardship cold in nature, little, Gan Wenxin have expelling cold and relieving exterior syndrome, dispel rheumatism, the effect of promoting blood circulation and removing blood stasis, clearing and activating the channels and collaterals, anti-inflammatory analgetic.Breviscarpine is the flavonoid active ingredient that extracts from the natural phant Herba Erigerontis, and the mixture of breviscapine, scutellarin etc. is arranged, and is mainly scutellarin (content occupies more than 95%).Last century since the seventies, Breviscapine just was applied to clinical, by nearly 30 years clinical application and wide deep pharmacological research, the curative effect that it is unique and the characteristics of safety and low toxicity have obtained social recognition, modern medicines studies have shown that, Breviscarpine has blood flow increasing, effects such as microcirculation improvement, vasodilation, reduction blood viscosity, reducing blood-fat, short fibrinolytic, antithrombotic, platelet aggregation-against, its injection and tablet have become clinical common drug, at aspects such as treatment cardiovascular and cerebrovascular diseases, rheumatic arthritis and apoplexy sequelas significant curative effect are arranged.
Modern clinical research finds that bioavailability is lower in the Breviscarpine process of clinical application, is poorly soluble on the one hand, and the solubleness of bibliographical information Breviscarpine in water only is 0.16mgmL
-1, secondly Breviscarpine is fat-soluble also very poor in the PBS of pH4.2 solution, and logP is-2.56.
Research is also found in addition, the lower reason of Breviscarpine bioavailability is except poorly soluble, beyond being difficult to absorb, also having an important reasons is that its main component scutellarin is easy to metabolism in vivo, no matter people such as Ge Qinghua discover oral or intravenously administrable, scutellarin metabolism elimination speed in animal body is fast, and the oral absolute bioavailability of Beagle dog is (0.40 ± 0.19) % only, and the quiet notes of domesticated dog are eliminated the transformation period weak point, are (52 ± 29) min.People such as Feng Fang have studied the pharmacokinetic parameters behind the low dose of scutellarin dripping pill of the oral 60mg of human body, the discovery scutellarin is eliminated very fast in vivo, only be (2.27 ± 0.58) min biological half-life, and scutellarin hangs down with bioavailability because of it is poorly soluble and limited its clinical application greatly.
More domestic scientific research personnel wish by means of exploitation Breviscarpine novel form, to improve its oral administration biaavailability or to prolong the transformation period in its body.In recent years, Breviscarpine novel form invention disclosed patent reached 59, related to injection, liposome, phospholipid complex, oral cavity quick disintegrating slice, Sublingual tablet, sustained release pellet, controlled releasing penetrant pump, cyclodextrin inclusion compound, dripping pill, self-emulsifier etc.But at present the novel form of listing is few, and this shows, and change by formulation can not improve well that Breviscarpine is poorly soluble, absorption difference, problem that bioavailability is low.The rigid structure of scutellarin is to limit the major reason that its saturating film absorbs, and the glucal acidic group is fallen in hydrolysis, and molecular structure diminishes, and rigidity reduces, and helps its oral absorption,
Occupy people such as Wen Zheng and measure scutellarin Plasma Concentration and clinical pharmacokinetics thereof, experimenter's oral administration 360mg scutellarin, 1,3,5,8h gets blood and survey scutellarin, but only the 5h time point detects 20ngmL
-1, and in blood plasma and urine, find a large amount of aglycons, the prompting scutellarin may be to arrive colon to be hydrolyzed to aglycon and to absorb, infer oral scutellarin in vivo real onset may be aglycon.Oral being easy to of researchs such as Che Qingming report Scutellarein absorbs, and compares with scutellarin, and internal metabolism is stable, and its relative bioavailability is 301.8%.Because Scutellarein has better pharmacological action and bioavailability than scutellarin, but the content of Scutellarein is lower in the plant amedica Herba Erigerontis, and the content of scutellarin is higher, and therefore by chemical reaction scutellarin being converted into Scutellarein has very important researching value.Chinese invention patent CN 1683357A discloses a kind of method for preparing Scutellarein., but because the solubleness of scutellarin in the aqueous solution is lower, limited the productive rate of Scutellarein.
Summary of the invention:
Goal of the invention: technical problem to be solved by this invention is, overcomes the deficiencies in the prior art, provides that a kind of speed of response is fast, productive rate is high, is raw material prepares Scutellarein by acid hydrolysis method with the scutellarin glycosides.
Technical scheme: in order to realize above purpose, the preparation method of Scutellarein provided by the invention specifically may further comprise the steps,
(1) get mineral acid, join in the ethanol, be made into volumetric molar concentration and be the mineral acid alcoholic solution of 3mol/L～8mol/L, standby;
(2) scutellarin is joined the mineral acid alcoholic solution that step (1) is prepared, making the concentration of scutellarin in the mineral acid alcoholic solution is 0.05g/ml～0.1g/ml, and reaction 2～6 hours then is hydrolyzed under protection of inert gas;
(3) after reaction finishes, extract reaction solution to steam and remove part ethanol, then with frozen water in reaction solution, cooling crystallization, crystallization be the back suction filtration fully, gets solid organic solvent recrystallization, use rare pure liquid recrystallization again after the crystallization, get Scutellarein.
As preferred version, the mineral acid described in the step (1) can be a kind of in the vitriol oil, concentrated hydrochloric acid, the concentrated nitric acid or their mixture.
As preferred version, the ethanol described in the step (1) is the ethanol of concentration 95%.Water-soluble experiment by scutellarin, scutellarin water-soluble and fat-soluble all very poor, therefore selecting the big solvent of scutellarin solubleness is to carry out the acid hydrolytic reaction The key factor, screening by experiment, scutellarin has solubleness preferably in concentration is 95% ethanol, so the present invention selects for use 95% ethanol can increase substantially reaction yield as the acid hydrolytic reaction solvent.
As preferred version, wherein the concentration of the mineral acid alcoholic solution that obtains of step (1) preparation is 4～6mol/L, and scutellarin issues unboiled water at acidic conditions and separates, and the glycosidic link fracture generates Scutellarein and glucuronic acid.The concentration of acid can not be too little in the hydrolytic process, and the too little hydrolysis reaction speed of concentration is too slow, and efficient is low, but the concentration of acid also should not be too high, too high as acid concentration, react too violent, even acid can form melt salt with the carbonyl in the flavones structure, thereby reaction yield is reduced, screening by experiment, the concentration of acid is 3mol/L～8mol/L during scutellarin acid hydrolysis of the present invention, as more excellent, hydrolysis reaction speed was fast when the concentration of acid was 4～6mol/L, the productive rate height.
As preferred version, in the step (2) scutellarin joined the reaction that is hydrolyzed in the mineral acid alcoholic solution, and the concentration of control scutellarin in the mineral acid alcoholic solution is 0.06g/ml～0.08g/ml, and control reaction temperature is 70～110 ℃, hydrolysis time is 3～4 hours, the concentration of scutellarin wherein, temperature of reaction all has material impact to speed of response and productive rate, screening determines that the concentration of reactant scutellarin is 0.06g/ml～0.08g/ml by experiment, speed of response was fast when temperature of reaction was 70～110 ℃, can finish reaction in 3～4 hours, efficient height and productive rate are also higher.
As preferred version; under the protection of nitrogen or argon gas rare gas element, carry out during step (2) acid hydrolytic reaction; because Scutellarein is the polyphenol hydroxyl flavonoid compound; in air, be oxidized to the quinoid structure easily; thereby active the reduction; and the present invention reacts under acid hot conditions; Scutellarein is easier to be oxidized; therefore in order to guarantee reaction product purity and yield; the present invention carries out under the protection of nitrogen or argon gas rare gas element, can well prevent the Scutellarein oxidation.
As preferred version, the used organic solvent of recrystallization is acetone, ethyl acetate or ethanol in the step (3), impure by cooling crystallization afterreaction product, in order to improve the purity of reaction product, get product and carry out recrystallization with acetone, ethyl acetate or ethanol, can improve degree of purity of production, in order further to improve degree of purity of production, the present invention to the first time recrystallized product carry out secondary recrystallization with the methyl alcohol of the ethanol of concentration 70～90% or concentration 50～80% once more and can make the purity of Scutellarein reach 99%～99.9%.
Beneficial effect: the preparation method of Scutellarein provided by the invention and prior art are now than having the following advantages:
1, the preparation method of Scutellarein provided by the invention, to reaction conditions, carry out screening system as the factors such as concentration, temperature of reaction and time of the kind of reaction solvent, acid and concentration, reactant scutellarin and determine best preparation technology, it is poorly soluble to have solved scutellarin, the easy oxidation of structure in the reaction process, problem such as speed of response is slow, product purity is low.
2, the preparation method of Scutellarein provided by the invention, speed of response is fast, efficient is high, gained Scutellarein productive rate height, purity height, and the preparation method of Scutellarein provided by the invention workable, can realize industrialized production.
Description of drawings
Accompanying drawing is a Scutellarein preparation method's of the present invention reacting flow chart.
Embodiment
The manufacturer and the specification of following examples 1 to 9 used chemical reaction reagent are as follows:
Reagent name manufacturer rank specification
The vitriol oil, the analytical pure 500ml of concentrated hydrochloric acid Shanghai chemical reagent company limited
The analytical pure 500ml of concentrated nitric acid Shanghai chemical reagent company limited
The 95% analytical pure 500ml of ethanol Shanghai chemical reagent company limited
Scutellarin Chengdu Mianning outstanding person resembles medicine material company limited＞95%
Ethyl acetate, the analytical pure 500ml of acetone Shanghai chemical reagent company limited
Methyl alcohol, the analytical pure 500ml of ethanol Shanghai chemical reagent company limited
The preparation of embodiment 1 Scutellarein
(1) get concentrated hydrochloric acid, joining concentration is to be configured to the concentrated hydrochloric acid ethanolic soln that volumetric molar concentration is 4mol/L in 95% ethanol, standby;
(2) scutellarin is joined in the hydrochloric acid alcoholic solution of step (1) preparation, making the concentration of scutellarin in the hydrochloric acid alcoholic solution is 0.05g/ml, 80 ℃ of back flow reaction 5 hours under nitrogen protection then, and reaction is stirred simultaneously;
(3) after reaction finishes, extract reaction solution to steam and remove half volume of ethanol, the frozen water that adds 5 times of amounts of reaction solution volume then, cooling crystallization, crystallization be the back suction filtration fully, gets the solid re-crystallizing in ethyl acetate, be 80% methanol solution recrystallization again with concentration after the crystallization, get Scutellarein, productive rate is 82%, and it is 99% that high performance liquid phase detects its purity.
The preparation of embodiment 2 Scutellareins
(1) get concentrated hydrochloric acid, joining concentration is to be configured to the concentrated hydrochloric acid ethanolic soln that volumetric molar concentration is 6mol/L in 95% ethanol, standby;
(2) scutellarin is joined in the hydrochloric acid alcoholic solution of step (1) preparation, making the concentration of scutellarin in the hydrochloric acid alcoholic solution is 0.05g/ml, 85 ℃ of back flow reaction 5 hours under nitrogen protection then, and reaction is stirred simultaneously;
(3) after reaction finishes, extract reaction solution to steam and remove half volume of ethanol, the frozen water that adds 5 times of amounts of reaction solution volume then, cooling crystallization, crystallization be the back suction filtration fully, gets the solid acetone recrystallization, be 80% ethanol liquid recrystallization again with concentration after the crystallization, get Scutellarein, productive rate is 93%, and it is 99% that high performance liquid phase detects its purity.
The preparation of embodiment 3 Scutellareins
(1) get concentrated hydrochloric acid, joining concentration is to be configured to the concentrated hydrochloric acid ethanolic soln that volumetric molar concentration is 8mol/L in 95% ethanol, standby;
(2) scutellarin is joined in the hydrochloric acid alcoholic solution of step (1) preparation, making the concentration of scutellarin in the hydrochloric acid alcoholic solution is 0.08g/ml, 90 ℃ of back flow reaction 4 hours under nitrogen protection then, and reaction is stirred simultaneously;
(3) after reaction finishes, extract reaction solution to steam and remove half volume of ethanol, the frozen water that adds 5 times of amounts of reaction solution volume then, cooling crystallization, crystallization be the back suction filtration fully, gets the solid re-crystallizing in ethyl acetate, be 90% ethanol liquid recrystallization again with concentration after the crystallization, get Scutellarein, productive rate is 88%, and it is 99% that high performance liquid phase detects its purity.
The preparation of embodiment 4 Scutellareins
(1) get the vitriol oil, joining concentration is to be configured to the vitriol oil ethanolic soln that volumetric molar concentration is 4mol/L in 95% ethanol, standby;
(2) scutellarin is joined in the alcohol sulfate solution of step (1) preparation, making the concentration of scutellarin in alcohol sulfate solution is 0.05g/ml, 80 ℃ of back flow reaction 4 hours under argon shield then, and reaction is stirred simultaneously;
(3) after reaction finishes, extract reaction solution to steam and remove half volume of ethanol, the frozen water that adds 5 times of amounts of reaction solution volume then, cooling crystallization, crystallization be the back suction filtration fully, gets the solid re-crystallizing in ethyl acetate, must be the methanol solution recrystallization with concentration again after the crystallization, get Scutellarein, productive rate is 84%, and it is 99.9% that high performance liquid phase detects its purity.
The preparation of embodiment 5 Scutellareins
(1) get the vitriol oil, joining concentration is to be configured to the vitriol oil ethanolic soln that volumetric molar concentration is 6mol/L in 95% ethanol, standby;
(2) scutellarin is joined in the alcohol sulfate solution of step (1) preparation, making the concentration of scutellarin in alcohol sulfate solution is 0.03g/ml, 90 ℃ of back flow reaction 5 hours under argon shield then, and reaction is stirred simultaneously;
(3) after reaction finishes, extract reaction solution to steam and remove half volume of ethanol, the frozen water that adds 5 times of amounts of reaction solution volume then, cooling crystallization, crystallization be the back suction filtration fully, gets the solid re-crystallizing in ethyl acetate, must be the methanol solution recrystallization with concentration again after the crystallization, get Scutellarein, productive rate is 95%, and it is 99% that high performance liquid phase detects its purity.
The preparation of embodiment 6 Scutellareins
(1) get the vitriol oil, joining concentration is to be configured to the vitriol oil ethanolic soln that volumetric molar concentration is 8mol/L in 95% ethanol, standby;
(2) scutellarin is joined in the alcohol sulfate solution of step (1) preparation, making the concentration of scutellarin in alcohol sulfate solution is 0.08g/ml, 75 ℃ of back flow reaction 5 hours under argon shield then, and reaction is stirred simultaneously;
(3) after reaction finishes, extract reaction solution to steam and remove half volume of ethanol, the frozen water that adds 5 times of amounts of reaction solution volume then, cooling crystallization, crystallization be the back suction filtration fully, gets the solid re-crystallizing in ethyl acetate, must be the methanol solution recrystallization with concentration again after the crystallization, get Scutellarein, productive rate is 90%, and it is 99.5% that high performance liquid phase detects its purity.
The preparation of embodiment 7 Scutellareins
(1) get concentrated nitric acid, joining concentration is to be configured to the concentrated nitric acid ethanolic soln that volumetric molar concentration is 6mol/L in 95% ethanol, standby;
(2) scutellarin is joined in the salpeter solution of step (1) preparation, making the concentration of scutellarin in the nitric acid alcoholic solution is 0.06g/ml, 85 ℃ of back flow reaction 5 hours under the nitrogen gas shiled then, and reaction is stirred simultaneously;
(3) after reaction finishes, extract reaction solution to steam and remove half volume of ethanol, the frozen water that adds 5 times of amounts of reaction solution volume then, cooling crystallization, crystallization be the back suction filtration fully, gets the solid re-crystallizing in ethyl acetate, must be the methanol solution recrystallization with concentration again after the crystallization, get Scutellarein, productive rate is 88%, and it is 99.5% that high performance liquid phase detects its purity.
The preparation of embodiment 8 Scutellareins
(1) get the concentrated hydrochloric acid and the vitriol oil, joining concentration is to be configured to concentrated hydrochloric acid and the vitriol oil ethanolic soln that volumetric molar concentration is 6mol/L in 95% ethanol, standby;
(2) scutellarin is joined in the concentrated hydrochloric acid and concentrated sulfuric acid solution of step (1) preparation, making the concentration of scutellarin in the mixing acid alcoholic solution is 0.08g/ml, 80 ℃ of back flow reaction 4 hours under the nitrogen gas shiled then, and reaction is stirred simultaneously;
(3) after reaction finishes, extract reaction solution to steam and remove half volume of ethanol, the frozen water that adds 5 times of amounts of reaction solution volume then, cooling crystallization, crystallization be the back suction filtration fully, gets the solid ethyl alcohol recrystallization, must be the methanol solution recrystallization with concentration again after the crystallization, get Scutellarein, productive rate is 90%, and it is 99.6% that high performance liquid phase detects its purity.
The POP and the mass-spectrometric data of above embodiment 1 to 8 gained Scutellarein are as follows:
1H-NMR(DMSO，300M)：12.79(1H，s，5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，8.71(1H，s，6-OH)，7.91(2H，d，J＝8.6，2’，6’-ArH)，6.91(2H，d，J＝8.6，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H).
MS(TOF，m/z)：284.9474[M-H]
-.
The result is consistent with reported in literature to determine that preparation method provided by the invention can obtain the high Scutellarein of purity.
Claims (9)
1. the preparation method of a Scutellarein is characterized in that may further comprise the steps,
(1) get mineral acid, join in the ethanol, be made into volumetric molar concentration and be the mineral acid alcoholic solution of 3mol/L～8mol/L, standby;
(2) scutellarin is joined the mineral acid alcoholic solution that step (1) is prepared, making the concentration of scutellarin in the mineral acid alcoholic solution is 0.05g/ml～0.1g/ml, and reaction 2～6 hours then is hydrolyzed under protection of inert gas;
(3) after reaction finishes, extract reaction solution to steam and remove part ethanol, then with frozen water in reaction solution, cooling crystallization, crystallization be the back suction filtration fully, gets solid organic solvent recrystallization, use rare pure liquid recrystallization again after the crystallization, get Scutellarein.
2. the preparation method of Scutellarein according to claim 1 is characterized in that, the mineral acid described in the step (1) is a kind of in the vitriol oil, concentrated hydrochloric acid, the concentrated nitric acid or their mixture.
3. the preparation method of Scutellarein according to claim 1 is characterized in that, the ethanol described in the step (1) is the ethanol of concentration 95%.
4. according to the preparation method of each described Scutellarein of claim 1 to 3, it is characterized in that the concentration of the mineral acid alcoholic solution that step (1) preparation obtains is 4～6mol/L.
5. the preparation method of Scutellarein according to claim 1, it is characterized in that, step joins the mineral acid alcoholic solution with scutellarin in (2), and making the concentration of scutellarin in the mineral acid alcoholic solution is 0.06g/ml～0.08g/ml, and 70～110 ℃ of hydrolysis reaction 3～4 hours.
6. the preparation method of Scutellarein according to claim 1 is characterized in that, the rare gas element described in the step (2) is nitrogen or argon gas.
7. the preparation method of Scutellarein according to claim 1 is characterized in that, the used organic solvent of recrystallization is acetone, ethyl acetate or ethanol in the step (3).
8. the preparation method of Scutellarein according to claim 1 is characterized in that, the used rare pure liquid of recrystallization is the ethanol of concentration 70～90% or the methyl alcohol of concentration 50～80% in the step (3).
9. the preparation method of Scutellarein according to claim 1 is characterized in that, the purity of the Scutellarein that step (3) obtains is 99%～99.9%.
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| CN102690308A (en) * | 2012-06-15 | 2012-09-26 | 南京中医药大学 | Scutellarin-7-glycosyl derivatives, and preparation method and application thereof |
| CN102702155A (en) * | 2012-06-15 | 2012-10-03 | 南京中医药大学 | Scutellarin aglycone methylate product based on in-vivo metabolic mechanism as well as preparation method and application of scutellarin aglycone methylate product |
| CN102731459A (en) * | 2012-06-15 | 2012-10-17 | 南京中医药大学 | Scutellarin aglycone Mannich derivatives, and preparation method and application thereof |
| CN103570660A (en) * | 2012-07-23 | 2014-02-12 | 昆明制药集团股份有限公司 | Method for preparing high-purity scutellarein |
| CN104311518A (en) * | 2014-11-18 | 2015-01-28 | 南京中医药大学 | Preparation method for 6-methoxyscutellarin |
| CN104693163A (en) * | 2015-03-24 | 2015-06-10 | 中国药科大学 | Method for preparing corresponding aglycon with glucuronide as raw material |
| WO2016095702A1 (en) * | 2014-12-15 | 2016-06-23 | 云南省药物研究所 | Scutellarin aglycone crystal form and preparation method thereof |
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| CN102731459A (en) * | 2012-06-15 | 2012-10-17 | 南京中医药大学 | Scutellarin aglycone Mannich derivatives, and preparation method and application thereof |
| CN102702155B (en) * | 2012-06-15 | 2014-05-07 | 南京中医药大学 | Scutellarin aglycone methylate product based on in-vivo metabolic mechanism as well as preparation method and application of scutellarin aglycone methylate product |
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| CN104311518A (en) * | 2014-11-18 | 2015-01-28 | 南京中医药大学 | Preparation method for 6-methoxyscutellarin |
| WO2016095702A1 (en) * | 2014-12-15 | 2016-06-23 | 云南省药物研究所 | Scutellarin aglycone crystal form and preparation method thereof |
| CN104592184B (en) * | 2014-12-15 | 2017-09-29 | 云南省药物研究所 | Scutellarein crystal formation and preparation method thereof |
| CN107501223A (en) * | 2014-12-15 | 2017-12-22 | 云南省药物研究所 | Scutellarein crystal formation and preparation method thereof |
| US10172824B2 (en) | 2014-12-15 | 2019-01-08 | Yunnan Institute Of Materia Medica | Crystal forms of scutellarin aglycone and preparation thereof |
| CN104693163A (en) * | 2015-03-24 | 2015-06-10 | 中国药科大学 | Method for preparing corresponding aglycon with glucuronide as raw material |
| CN104693163B (en) * | 2015-03-24 | 2017-01-18 | 中国药科大学 | Method for preparing corresponding aglycon with glucuronide as raw material |
| CN106214698A (en) * | 2016-09-28 | 2016-12-14 | 昆明医科大学 | A kind of pharmaceutical composition containing inorganic arsenic chemicals and application thereof |
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