CN101891728B

CN101891728B - Scutellarein derivative as well as preparation method and application thereof

Info

Publication number: CN101891728B
Application number: CN2010101772025A
Authority: CN
Inventors: 唐于平; 李念光; 段金廒
Original assignee: Nanjing University of Chinese Medicine
Current assignee: Nanjing University of Chinese Medicine
Priority date: 2010-05-20
Filing date: 2010-05-20
Publication date: 2012-05-23
Anticipated expiration: 2030-05-20
Also published as: CN101891728A

Abstract

The invention relates to the research field of medicinal chemistry, in particular to a novel scutellarein-6-site derivative (I), as well as a preparation method and an application thereof to medicines for preventing and treating thrombus. Pharmacological test results show that compared with scutellarin and scutellarein, the compound has better function of inhibiting platelet aggregation. The scutellarein-6-site derivative (I) provided by the invention can be used for treating a series of diseases caused by the thrombus, such as myocardial infarction, ischemia injury and so on.

Description

Scutellarin aglycone derivative and preparation method thereof and its application

Technical field

The present invention relates to the pharmaceutical chemistry research field, be specifically related to one type of novel Scutellarein-6-bit derivant (I), and its preparation method and the application in control thrombus medicine.

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 from the natural phant Herba Erigerontis, extracts, and the mixture of breviscapine, scutellarin etc. is arranged, and is mainly scutellarin (content occupies more than 95%) (Chen Yiyue; Wang Shengtao, Ceng Wenshan, Zhu Yinghong; Fu Yongmei; The river great waves. Breviscarpine is to the relexation of rat aorta flesh ring. new Chinese medicine and clinical pharmacology .1994,5 (2), 15-19).Last century since the seventies, Breviscapine just was applied to clinical; Through 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 research proof, 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 is merely 0.16mgmL ^-1(Zhang Haiyan, flat its ability, Guo Jianxin, behaviour's cutting edge of a knife or a sword. Breviscarpine and Benexate Hydrochloride thereof are in pharmacokinetics in rats. Acta Pharmaceutica Sinica; 2005,40 (6), 563-567), secondly Breviscarpine is fat-soluble also very poor in the PBS of pH4.2 solution; LogP is-2.56 (behaviour's cutting edge of a knife or a sword, Guo Jianxin, flat its ability, Shao Yun; Liang Jing. synthetic, the physico-chemical property of scutellarin class prodrug and Study on degradation. Acta Pharmaceutica Sinica, 2006,41 (7), 595-602).Research is also found in addition, and the lower reason of Breviscarpine bioavailability is except poorly soluble, and beyond being difficult to absorb, also having an important reasons is that its staple 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) % (Ge Qinghua, Zhou Zhen only; Zhi Xiaojin, Ma Lili, Chen Xiuhua. Breviscarpine is in intravital pharmacokinetics of dog and absolute bioavailability research. Chinese Journal of Pharmaceuticals, 2003; 34 (12), 618-621), and the quiet notes of domesticated dog are eliminated the transformation period weak point, are (52 ± 29) min (Jiang Xuehua; Li Suhua, Lan Ke, Yang Junyi; Week is quiet. and Breviscarpine is in the intravital pharmacokinetics of domesticated dog. Acta Pharmaceutica Sinica .2003,38 (5), 371-373).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; Be merely biological half-life (2.27 ± 0.58) min (Feng Fang, Shen Yulan. foundation and the pharmacokinetic studies of trace scutellarin SPE-HPLC/MS/MS in the human plasma. Chinese Pharmaceutical Journal .2006,41 (6); 457), scutellarin because of the low big limitations of its poorly soluble and bioavailability its clinical application.

More domestic scientific research personnel hope 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, the invention disclosed patent was nearly 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 through 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 it to pass through the major reason that 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 is 1,3,5,8h gets blood and survey scutellarin, but only when 5h, detect 20ngmL ^-1And in blood plasma and urine, find a large amount of aglycons, the prompting scutellarin possibly be to arrive colon to be hydrolyzed to aglycon and to absorb, infer oral scutellarin in vivo real onset possibly be aglycon (LiuY; HuM.Absorption andmetabolism of flavonoids in the Caco-2 cell culture model and a perfused rat intestinal model.DrugMetab Dispos; 2002,30 (4), 370-377).Oral being easy to of researchs such as Che Qingming report Scutellarein absorbs, and compares with scutellarin, and internal metabolism is stable; Its relative bioavailability is 301.8% (Che Qingming; Pan Liyi, Chen Ying, He Hong. the pharmacokinetic studies of Scutellarein. Chinese Pharmaceutical Journal .2007; 42 (18), 1418-1421).Because Scutellarein has better pharmacological action and bioavailability than scutellarin; Therefore; Solubleness and the higher relatively Scutellarein of bioavailability are carried out structural modification, aspect cardiovascular and cerebrovascular diseases medicament research, will have very significant meaning.

Summary of the invention:

Goal of the invention: technical problem to be solved by this invention is; Overcome the deficiency of prior art; Be raw material through alkylation, glycosides hydrolysis, selectivity methyl-etherified, hydrogenation debenzylation, 6 alkylations or acidylates, slough that thereby methyl ether blocking group synthesizing series has pharmaceutical use and solvability is good with the lamp-dish flower acetic glycosides; Bioavailability is high, untoward reaction is low; Lamp-dish flower acetic aglycon-6-the bit derivant of drug safety, another object of the present invention provide the preparation method and its application in preparation control thrombus disease medicine of lamp-dish flower acetic aglycon-6-bit derivant.

Technical scheme: in order to realize above purpose, the general formula (I) of lamp-dish flower acetic aglycon provided by the invention-6-bit derivant as follows:

Wherein the R representative replaces ether, and substituting group can be hydrogen, alkyl, halogen, carbonyl, cyanic acid, nitro, amino, substituted-amino, hydroxyl, ether, carboxyl, ester group or amido;

As preferred version, above-described substituted-amino is R ₁NH or R ₁R ₂N, wherein R ₁Or R ₂Alkyl, R for C1～6 ₁, R ₂Connect into ring-type or connect into ring-type through 1～3 heteroatoms.

As preferred version, above-described alkyl is the aliphatic hydrocarbon substituting group of aromatic hydrocarbon or C1～15.

As preferred version, above-described ether can be the ether of C1～10, and described carboxyl is the fat or the alicyclic ring carboxyl of aromatic carboxylic or C1～8, and described ester group is the fat or the alicyclic ring ester group of aromatic ester groups or C1～8; Or as another preferred version, wherein said carboxamido-group can be the fat or the alicyclic ring amido of fragrant amido or C1～8.

As another preferred version, wherein above-described halogen can be F, Cl, Br or I.

Perhaps R also can represent substituted acyl, and substituting group is hydrogen, halogen, carbonyl, cyanic acid, nitro, amino, substituted-amino, hydroxyl, ether, carboxyl, ester group, amido, C1～C10 alkyl, C1～C10 alkoxyl group, C1～C10 aminoalkyl group, C1～C10 alkyl amine group, C1～C10 alkylthio, C1～C10 perfluoroalkyl, C1～C10 perfluoro alkoxy, C1～C10 alkoxy carbonyl, nitro or amino.

As preferred version, described substituted-amino is R ₁NH or R ₁R ₂N, wherein R ₁Or R ₂Alkyl, R for C1～6 ₁, R ₂Connect into ring-type or connect into ring-type through 1～3 heteroatoms.

As preferred version, described ether can be the ether of C1～10, and described carboxyl is the fat or the alicyclic ring carboxyl of aromatic carboxylic or C1～10, and described ester group is the fat or the alicyclic ring ester group of aromatic ester groups or C1～10; Or as another preferred version, wherein said amido can be the fat or the alicyclic ring amido of fragrant amido or C1～10.

As preferred version, wherein above-described halogen can be F, Cl, Br or I

The preparation method of Scutellarein provided by the invention-6-bit derivant specifically may further comprise the steps:

A, to get scutellarin (1) be starting raw material, at K ₂CO ₃Effect under, obtain 4 ' with the bromobenzyl alkylated reaction, the scutellarin compound (2) of 6 benzylizations, subsequent use;

B, get benzyl scutellarin compound (2) that step a obtains under the catalysis of the vitriol oil, heating hydrolysis in 95% ethanolic soln obtains the Scutellarein compound (3) of 6 substituted benzylizations of selectivity;

C, get the Scutellarein compound (3) of 6 benzylizations that step b obtains, under alkaline condition, in acetone soln, obtain 4 ', 7 substituted scutellarin aglycone derivatives of methoxyl group methylene radical (4) with the chloromethyl ether reaction;

D, get scutellarin aglycone derivative (4) that step c obtains under the palladium/carbon catalyst condition, the hydrogenation debenzylation obtains scutellarin aglycone derivative (5);

E, get scutellarin aglycone derivative (5) that steps d obtains under alkaline condition with bromoalkane or replace acyl chloride reaction and obtain compound (6), compound (6) catalysis under acidic conditions generates has the described Scutellarein of general formula (I)-6-bit derivant.

As preferred version, the preparation method of above-described Scutellarein-6-bit derivant, scutellarin among the step a (1) and K ₂CO ₃The mole dosage ratio be 1: 2～2.5, as more excellent scheme, scutellarin (1) and K ₂CO ₃The mole dosage ratio be 1: 2.5; And scutellarin is 1: 2～2.3 with the mole dosage ratio of bromobenzyl, and as more excellent scheme, scutellarin is 1: 2.3 with the mole dosage ratio of bromobenzyl; And step a reaction solvent is 2; 5-dimethyl furan, temperature of reaction are 25～30 ℃, and the reaction times is 6～8 hours.

As preferred version; The preparation method of above-described Scutellarein-6-bit derivant; The volumetric molar concentration of the used vitriol oil is 0～3mol/L among the step b, and compound (2) is 5g/100ml～10g/100ml with 95% consumption of ethanol ratio, and temperature of reaction is 70～90 ℃; Reaction times is 3～6 hours.

As preferred version, used alkali is salt of wormwood among the step c, and compound (3) is 1: 2～2.4 with the mole dosage ratio of salt of wormwood, and the mole dosage ratio of compound (3) and chloromethyl ether is 1: 2～2.2, and temperature of reaction is 60～70 ℃; Reaction times is 8～12 hours, and as more excellent scheme, compound (3) is 1: 2.4 with the mole dosage ratio of salt of wormwood, and the mole dosage ratio of compound (3) and chloromethyl ether is 1: 2.2.

As preferred version; The preparation method of Scutellarein of the present invention-6-bit derivant, the described palladium/carbon catalyst concentration of steps d is 5% or 10%, reaction solvent is methyl alcohol, ethanol or THF; Temperature of reaction is 25～30 ℃, and the reaction times is 3～12 hours.

As preferred version; The preparation method of Scutellarein of the present invention-6-bit derivant; Scutellarin aglycone derivative among the step e (5) is 1: 1～3 with the mole dosage ratio of bromo alkane or replacement acyl chlorides, and scutellarin aglycone derivative (5) is basic metal, alkalimetal hydride, alkalimetal oxide, earth alkali metal, alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate or alkali metal bicarbonates with the used alkali of bromoalkane hydrocarbon reaction; Scutellarin aglycone derivative (5) can be triethylamine, Tributylamine, trioctylamine, pyridine, N with replacing the used alkali of acyl chloride reaction, quaternary ammonium alkali such as trimethylamine class alkali such as N-dimethyl--α-Ben Yian, 4-methylmorpholine or TBAH; And scutellarin aglycone derivative among the step e (5) is 1: 1～4 with the consumption mol ratio of alkali, and reaction solvent is methylene dichloride, chloroform, THF, N, dinethylformamide or toluene, and temperature of reaction is 20～30 ℃, the reaction times is 2～48 hours.As another preferred version; Compound among the step e (6) catalysis under acidic conditions generates Scutellarein-6-bit derivant; Used catalyzer is the concentrated hydrochloric acid or the vitriol oil; The catalyzed reaction solvent is methyl alcohol, ethanol, methylene dichloride, THF or their mixture, and temperature of reaction is 0 ℃～25 ℃.

Scutellarein provided by the invention-6-bit derivant is prevented and treated

claim

1 or 2 described Scutellarein-6-bit derivants are prevented and treated the application in the thrombotic diseases medicines such as myocardial infarction, ischemia injury in preparation in preparation; As preferred version; There are a plurality of hydroxyls in Scutellarein-6-bit derivant molecular structure; Thereby show certain acidity, can form salt to Scutellarein-6-bit derivant and basic metal, alkaline earth metal hydroxides, alkaline carbonate or alkaline earth metal carbonate, alkali metal hydrocarbonate or alkali metal bicarbonates reaction.As further preferred version, Scutellarein-6-bit derivant salt and pharmaceutically acceptable carrier are processed the medicine of tablet, capsule, granule, sprays, injection, micro-capsule, ointment or skin-permeable and control-released plaster formulation.

Scutellarein provided by the invention-when 6-bit derivant salt is processed tablet, Scutellarein-6-bit derivant salt and carrier lactose or W-Gum, add magnesium stearate lubricant when needing mixes, and compressing tablet is processed tablet then.Scutellarein provided by the invention-when 6-bit derivant salt is processed capsule mixes whole grain, the encapsulated then capsule of processing to Scutellarein-6-bit derivant salt and carrier lactose or W-Gum.Scutellarein provided by the invention-when 6-bit derivant salt is processed granule mixes compsn and thinner lactose or W-Gum, whole grain, and drying is processed granule.As Scutellarein provided by the invention-when 6-bit derivant salt is processed injection liquid, get Scutellarein-6-bit derivant salt and add solubilizing agent, stir; 80 ℃ were heated 30 minutes; Filter, regulate pH value, be filtered to clear and bright with sintered glass funnel or other filter; Can was processed injection liquid in 30 minutes 100 to 115 ℃ of sterilizations.

Beneficial effect: Scutellarein provided by the invention-6-bit derivant and prior art are at present than having the following advantages:

1, serial scutellarin aglycon provided by the invention-6-bit derivant, through optionally connecting ester dissolubility and water-soluble functional group in Scutellarein-6-position, the Scutellarein that obtains-6-bit derivant solvability is good; Can improve human body and take the artifact availability, it is active to strengthen the antithrombotic pharmacology, and untoward reaction is low; Medication is safer; And Scutellarein-6-bit derivant can prepare salt with multiple alkali reaction, and can be made into multiple pharmaceutical dosage form, makes things convenient for clinical application.

2, the preparation method of Scutellarein provided by the invention-6-bit derivant; Be raw material through alkylation, glycosides hydrolysis, selectivity methyl-etherified, hydrogenation debenzylation, 6-position selective alkylation or selective acylation, slough that thereby methyl ether blocking group synthesizing series has pharmaceutical use and solvability is good with the scutellarin glycosides; The new compound of the Scutellarein that bioavailability is high-6-bit derivant; Preparing method provided by the invention, workable, production efficiency is high; Cost is low, and the finished product yield is high, purity is high.

Description of drawings

Fig. 1 is the structural representation of Scutellarein of the present invention-6-bit derivant general formula (I).

Fig. 2 is Scutellarein of the present invention-6-bit derivant preparing method's a reacting flow chart.

Embodiment

According to following embodiment, can understand the present invention better.Yet, those skilled in the art will readily understand that the described concrete material proportion of embodiment, processing condition and result thereof only are used to explain the present invention, and the present invention that should also can not limit in claims to be described in detail.

Embodiment 14 ', the preparation of 6-benzyloxy-5-hydroxyl-7-glucal acyloxy flavones (2)

In reaction flask, add scutellarin 2.4g, DMF, K successively ₂CO ₃(2.5equiv), under the inert nitrogen gas protection, add cylite (2.3equiv), 25 ℃ were reacted 8 hours, after reaction finishes, added frozen water, and solid is separated out in control PH≤6, suction filtration, dry yellow solid 2.7 grams that get.Yield 81%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：627.01[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，7.20(10H，Ar-H)，5.22(2H，s，H-CHAr)，5.16(2H，s，H-CHAr)，5.51(1H，d，J＝12，1”-H).

Embodiment 24 ', 5, the preparation of 7-trihydroxy--6-benzyloxy flavones (3)

Get the compound 23.2g that instance 1 makes, add in the ethanol solution of sulfuric acid of 1mol/L, under the protection of rare gas element; 80 ℃ were reacted 12 hours, after reaction finishes, added frozen water; PH is at 5-6 in control; Separate out yellow solid, suction filtration, the gained bullion gets yellow solid 0.9g (elutriant: methylene dichloride: methyl alcohol) with column chromatography purification.Yield 48%.

Gained compound spectroscopic data is:

[0050]?MS(TOF，m/z)：375.01[M-H] ^-.

[0051]? ¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，7.20(5H，Ar-H)，5.18(2H，s，1”-H).

Embodiment 34 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-benzyloxy flavones (4)

K with 1.65g ₂CO ₃, 1.9g midbody 3, drop into successively in the 30ml acetone, stirring at room adds MOMCl (1.5equiv) after 30 minutes, be warming up to the 70 ℃ of stirring reactions in chamber 12 hours.Reaction finishes the back and adds an amount of frozen water, control PH4-7, and suction filtration, filter cake is washed with small amount of ice water.The gained bullion gets yellow solid 1.7g (solvent: ether) through recrystallization.Productive rate: 72.6%

Gained compound spectroscopic data is:

MS(TOF，m/z)：463.15[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，7.20(5H，m，Ar-H)，5.22(2H，s，1”-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃).

Embodiment 44 ', 7-dimethoxy methylene radical oxygen-5, the preparation of 6-dihydroxyflavone (5)

1.7g midbody 4,0.085g catalyst P d-C are joined in ether/methanol mixed solution, logical H2,25 ℃ were reacted 12 hours, and suction filtration is removed catalyzer, boils off solvent, gets yellow bullion, and bullion is with the yellow powder shape solid 1.05g of ether recrystallization.Yield 77%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：373.01[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，8.48(1H，s，6-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃).

Embodiment 54 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-methoxy flavone (6a)

With the midbody 5 of 750mg, the K of 415mg ₂CO ₃Join successively among the DMF of 30mL, stirring at room added CH after 30 minutes ₃I 0.15mL, stirring at room 24 hours.Reaction finishes the back with the ethyl acetate extraction reaction solution, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion gets yellow powder 624mg with column chromatography purification.Productive rate: 80%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：387.11[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，3.36(3H，s，-OCH ₃).

Embodiment 64 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-oxyethyl group flavones (6b)

With the midbody 5 of 750mg, the K of 415mg ₂CO ₃Join successively among the DMF of 30mL, stirring at room added CH after 30 minutes ₃CH ₂I 0.19mL, stirring at room 24 hours.Reaction finishes the back with the ethyl acetate extraction reaction solution, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion gets yellow powder 660mg with column chromatography purification.Productive rate: 82.5%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：401.05[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，3.42(2H，t，-OCH ₂)，1.33(3H，t，-CH ₃)

Embodiment 74 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-propoxy-flavones (6c)

With the midbody 5 of 750mg, the K of 415mg ₂CO ₃Join successively among the DMF of 30mL, stirring at room added CH after 30 minutes ₃CH ₂CH ₂I 0.24mL, stirring at room 24 hours.Reaction finishes the back with the ethyl acetate extraction reaction solution, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion gets yellow powder 640mg with column chromatography purification.Productive rate: 77%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：415.09[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，3.42(2H，t，-OCH ₂)，1.53(2H，m，-CH ₂-)，1.03(3H，t，-CH ₃)

Embodiment 84 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-butoxy flavones (6d)

With the midbody 5 of 750mg, the K of 415mg ₂CO ₃Join successively among the DMF of 30mL, stirring at room added CH after 30 minutes ₃CH ₂CH ₂CH ₂I 0.45mL, stirring at room 24 hours.Reaction finishes the back with the ethyl acetate extraction reaction solution, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion gets yellow powder 730mg with column chromatography purification.Productive rate: 86%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：429.11[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，3.42(2H，t，-OCH ₂)，1.53(2H，m，-CH ₂-)，1.23(2H，m，-CH ₂-)，1.03(3H，t，-CH ₃).

Embodiment 94 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-acetoxyl group flavones (6e)

Midbody 5, the 4ml anhydrous pyridine of getting 750mg join among the DMF of 30ml successively, and the stirring at room reaction adds the chloracetyl of 2.4mmol, room temperature reaction 24 hours after 30 minutes.Reaction finishes afterreaction liquid and pours in the frozen water with ethyl acetate extraction anhydrous sodium sulfate drying into.Revolve and desolvate, the gained bullion gets pale yellow powder 526mg with column chromatography purification.Productive rate: 63%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：415.01[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，?3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，2.23(3H，s，-COCH ₃)

Embodiment 10 4 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-propionyloxy flavones (6f)

Midbody 5, the 4ml anhydrous pyridine of getting 750mg join among the DMF of 30ml successively, and the stirring at room reaction adds the chlorine propionyl of 2.4mmol, room temperature reaction 24 hours after 30 minutes.Reaction finishes afterreaction liquid and pours in the frozen water with ethyl acetate extraction anhydrous sodium sulfate drying into.Revolve and desolvate, the gained bullion gets pale yellow powder 569mg with column chromatography purification.Productive rate: 66%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：429.03[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，2.27(2H，s，-COCH ₂)，1.03(3H，t，-CH ₃).

Embodiment 11 4 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-butyryl acyloxy flavones (6g)

Midbody 5, the 4ml anhydrous pyridine of getting 750mg join among the DMF of 30ml successively, and the stirring at room reaction adds the butyryl chloride of 2.4mmol, room temperature reaction 24 hours after 30 minutes.Reaction finishes afterreaction liquid and pours in the frozen water with ethyl acetate extraction anhydrous sodium sulfate drying into.Revolve and desolvate, the gained bullion gets pale yellow powder 632mg with column chromatography purification.Productive rate: 71%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：443.11[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，2.27(2H，s，-COCH ₂)，1.43(2H，m，-CH ₂-)，1.03(3H，t，-CH ₃).

Embodiment 12 4 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-benzoyloxy flavones (6h)

Midbody 5, the 4ml anhydrous pyridine of getting 750mg join among the DMF of 30ml successively, and the stirring at room reaction adds the Benzoyl chloride 99min. of 2.4mmol, room temperature reaction 24 hours after 30 minutes.Reaction finishes afterreaction liquid and pours in the frozen water with ethyl acetate extraction anhydrous sodium sulfate drying into.Revolve and desolvate, the gained bullion gets yellow powder 613mg with column chromatography purification.Productive rate: 64%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：477.05[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，7.31-8.11(5H，m，-ArH).

Embodiment 13 4 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-(N-Pyrrolidine methanoyl)-flavones (6i)

Midbody 5, the 4ml anhydrous pyridine of getting 750mg join among the DMF of 30ml successively, and the stirring at room reaction adds the Pyrrolidine formyl chloride of 2.4mmol, room temperature reaction 24 hours after 30 minutes.Reaction finishes afterreaction liquid and pours in the frozen water with ethyl acetate extraction anhydrous sodium sulfate drying into.Revolve and desolvate, the gained bullion gets faint yellow crystallization 727mg with column chromatography purification.Productive rate: 77%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：470.13[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，2.79(4H，t，-N(CH ₂) ₂-)，1.48(4H，t，-CH ₂-CH ₂-).

Embodiment 14 4 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-(N, N-dimethylamino methanoyl)-flavones (6j)

Midbody 5, the 4ml anhydrous pyridine of getting 750mg join among the DMF of 30ml successively, and the stirring at room reaction adds the N of 2.4mmol, N-dimethylcarbamyl chloride, room temperature reaction 24 hours after 30 minutes.Reaction finishes afterreaction liquid and pours in the frozen water with ethyl acetate extraction anhydrous sodium sulfate drying into.Revolve and desolvate, the gained bullion gets faint yellow crystallization 678mg with column chromatography purification.Productive rate: 76%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：444.12[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，2.69(6H，s，-NCH ₃).

Embodiment 15 4 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-(N, N-diethylamino methanoyl)-flavones (6k)

Midbody 5, the 4ml anhydrous pyridine of getting 750mg join among the DMF of 30ml successively, and the stirring at room reaction adds the N of 2.4mmol, N-diethylamino formyl chloride, room temperature reaction 24 hours after 30 minutes.Reaction finishes afterreaction liquid and pours in the frozen water with ethyl acetate extraction anhydrous sodium sulfate drying into.Revolve and desolvate, the gained bullion gets faint yellow crystallization 768mg with column chromatography purification.Productive rate: 81%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：472.13[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，2.89(4H，q，-NCH ₂-)，1.38(6H，t，-CH ₃).

Embodiment 16 4 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-(N, N-diisopropylaminoethyl methanoyl)-flavones (6l)

Midbody 5, the 4ml anhydrous pyridine of getting 750mg join among the DMF of 30ml successively, and the stirring at room reaction adds the N of 2.4mmol, N-diisopropylaminoethyl formyl chloride, room temperature reaction 24 hours after 30 minutes.Reaction finishes afterreaction liquid and pours in the frozen water with ethyl acetate extraction anhydrous sodium sulfate drying into.Revolve and desolvate, the gained bullion gets faint yellow crystallization 623mg with column chromatography purification.Productive rate: 63%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：500.01[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，?j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，2.92(2H，q，-NCH-)，1.18(12H，d，-CH ₃)

Embodiment 17 4 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-(N-morpholine methanoyl)-flavones (6m)

Midbody 5, the 4ml anhydrous pyridine of getting 750mg join among the DMF of 30ml successively, and the stirring at room reaction adds the N-morpholine formyl chloride of 2.4mmol, room temperature reaction 24 hours after 30 minutes.Reaction finishes afterreaction liquid and pours in the frozen water with ethyl acetate extraction anhydrous sodium sulfate drying into.Revolve and desolvate, the gained bullion gets yellow crystal 828mg with column chromatography purification.Productive rate: 85%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：486.01[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，2.79(4H，t，-NCH ₂-)，2.98(4H，t，-OCH ₂-).

Embodiment 18 4 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-(N-methyl-N-ethylamino methanoyl)-flavones (6n)

Midbody 5, the 4ml anhydrous pyridine of getting 750mg join among the DMF of 30ml successively, and the stirring at room reaction adds N-methyl-N-ethylamino formyl chloride of 2.4mmol, room temperature reaction 24 hours after 30 minutes.Reaction finishes afterreaction liquid and pours in the frozen water with ethyl acetate extraction anhydrous sodium sulfate drying into.Revolve and desolvate, the gained bullion gets faint yellow crystallization 571mg with column chromatography purification.Productive rate: 62%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：458.02[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，2.77(2H，q，-NCH ₂-)，2.45(3H，s，-NCH ₃)，1.18(3H，T，-CH ₃).

Embodiment 19 4 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-(N-piperidine formyl oxygen base)-flavones (6o)

Midbody 5, the 4ml anhydrous pyridine of getting 750mg join among the DMF of 30ml successively, and the stirring at room reaction adds the N-piperidine formyl chlorine of 2.4mmol, room temperature reaction 24 hours after 30 minutes.Reaction finishes afterreaction liquid and pours in the frozen water with ethyl acetate extraction anhydrous sodium sulfate drying into.Revolve and desolvate, the gained bullion gets yellow crystal 836mg with column chromatography purification.Productive rate: 86%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：484.11[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，2.79(4H，t，-NCH ₂-)，1.68(4H，dd，-CH ₂-)，1.44(2H，dd，-CH ₂-)

Embodiment 20 4 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-[N-(4-benzyl) piperidine formyl oxygen base]-flavones (6p)

Midbody 5, the 4ml anhydrous pyridine of getting 750mg join among the DMF of 30ml successively, and the stirring at room reaction adds N-(4-benzyl) the piperidine formyl chlorine of 2.4mmol, room temperature reaction 24 hours after 30 minutes.Reaction finishes afterreaction liquid and pours in the frozen water with ethyl acetate extraction anhydrous sodium sulfate drying into.Revolve and desolvate, the gained bullion gets pale yellow powder 645mg with column chromatography purification.Productive rate: 56%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：574.10[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，2.79(4H，t，-NCH ₂-)，1.48(4H，m，-CH ₂-)，1.54(2H，m，-CH ₂-)，2.20(2H，d，-ArCH ₂)，7.35-8.21(5H，m，-ArH)

Embodiment 21 4 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-[N-(4-methyl) piperidine formyl oxygen base]-flavones (6q)

Midbody 5, the 4ml anhydrous pyridine of getting 750mg join among the DMF of 30ml successively, and the stirring at room reaction adds N-(4-methyl) the piperidine formyl chlorine of 2.4mmol, room temperature reaction 24 hours after 30 minutes.Reaction finishes afterreaction liquid and pours in the frozen water with ethyl acetate extraction anhydrous sodium sulfate drying into.Revolve and desolvate, the gained bullion gets yellow crystal 629mg with column chromatography purification.Productive rate: 63%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：498.02[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，2.79(4H，t，-NCH ₂-)，1.48(4H，m，-CH ₂-)，1.54(2H，m，-CH ₂-)，1.20(3H，d，-CH ₃).

Embodiment 22 4 ', the preparation of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-(third carbamoyloxy)-flavones (6r)

Midbody 5, the 4ml anhydrous pyridine of getting 750mg join among the DMF of 30ml successively, and the stirring at room reaction adds third urea chloride of 2.4mmol, room temperature reaction 24 hours after 30 minutes.Reaction finishes afterreaction liquid and pours in the frozen water with ethyl acetate extraction anhydrous sodium sulfate drying into.Revolve and desolvate, the gained bullion gets faint yellow crystallization 667mg with column chromatography purification.Productive rate: 75%

Gained compound spectroscopic data is:

MS(TOF，m/z)：444.02[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，2.39(2H，t，-COCH ₂-)，2.48(2H，t，-NCH ₂-)，5.71(2H，s，-NH ₂)

Embodiment 23 4 ', 5, the preparation of 7-trihydroxy--6-methoxy flavone (Ia)

Get 620mg midbody 6a, join in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate yellow solid product 364mg.Productive rate: 76%

Gained compound spectroscopic data is:

MS(TOF，m/z)：299.01[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，4.18(3H，s，-OCH ₃).

Embodiment 24 4 ', 5, the preparation of 7-trihydroxy--6-oxyethyl group flavones (Ib)

Get 500mg midbody 6b, join in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate yellow solid product 355mg.Productive rate: 916%

Gained compound spectroscopic data is:

MS(TOF，m/z)：313.02[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，3.42(2H，t，-OCH ₂)，1.33(3H，t，-CH ₃)

Embodiment 25 4 ', 5, the preparation of 7-trihydroxy--6-propoxy-flavones (Ic)

Get 500mg midbody 6c, join in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate yellow solid product 3mg.Productive rate: 85%

Gained compound spectroscopic data is:

MS(TOF，m/z)：327.03[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，3.42(2H，t，-OCH ₂)，1.53(2H，m，-CH ₂-)，1.03(3H，t，-CH ₃)

Embodiment 26 4 ', 5, the preparation of 7-trihydroxy--6-butoxy flavones (Id)

Get 500mg midbody 6d, join in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate yellow solid product 350mg.Productive rate: 88%

Gained compound spectroscopic data is:

MS(TOF，m/z)：341.00[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，3.42(2H，t，-OCH ₂)，1.53(2H，m，-CH ₂-)，1.23(2H，m，-CH ₂-)，1.03(3H，t，-CH ₃).

Embodiment 27 4 ', 5, the preparation of 7-trihydroxy--6-acetoxyl group flavones (Ie)

Get 500mg midbody 6e, join in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate faint yellow solid product 339mg.Productive rate: 86%

Gained compound spectroscopic data is:

MS(TOF，m/z)：315.00[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，2.23(3H，s，-COCH ₃).

Embodiment 28 4 ', 5, the preparation of 7-trihydroxy--6-propionyloxy flavones (If)

Get 500mg midbody 6f, join in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate faint yellow solid product 350mg.Productive rate: 88%

Gained compound spectroscopic data is:

MS(TOF，m/z)：329.13[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，2.27(2H，s，-COCH ₂)，1.03(3H，t，-CH ₃).

Embodiment 29 4 ', 5, the preparation of 7-trihydroxy--6-butyryl acyloxy flavones (Ig)

Get 500mg midbody 6g, join in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate faint yellow solid product 325mg.Productive rate: 81%

Gained compound spectroscopic data is:

MS(TOF，m/z)：355.0[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，2.27(2H，s，-COCH ₂)，1.43(2H，m，-CH ₂-)，1.03(3H，t，-CH ₃)。

Embodiment 30 4 ', 5, the preparation of 7-trihydroxy--6-benzoyloxy flavones (Ih)

Get 500mg midbody 6h, join in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate faint yellow solid product 326mg.Productive rate: 80%

Gained compound spectroscopic data is:

MS(TOF，m/z)：389.08[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，7.31-8.11(5H，m，-ArH).

Embodiment 31 4 ', 5, the preparation of 7-trihydroxy--6-(N-Pyrrolidine methanoyl)-flavones (Ii)

Get 500mg midbody 6i, join in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate faint yellow solid crystallization 341mg.Productive rate: 84%

Gained compound spectroscopic data is:

MS(TOF，m/z)：381.11[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，2.79(4H，t，-N(CH ₂) ₂-)，1.48(4H，t，-CH ₂-CH ₂-).

Embodiment 32 4 ', 5, the preparation of 7-trihydroxy--6-(N, N-dimethylamino methanoyl)-flavones (Ij)

Get 500mg midbody 6j, join in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate yellow solid crystallization 345mg.Productive rate: 86%

Gained compound spectroscopic data is:

MS(TOF，m/z)：356.12[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，2.69(6H，s，-NCH ₃).

Embodiment 33 4 ', 5, the preparation of 7-trihydroxy--6-(N, N-diethylamino methanoyl)-flavones (Ik)

Get 500mg midbody 6k, join in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate yellow solid crystallization 326mg.Productive rate: 80%

Gained compound spectroscopic data is:

MS(TOF，m/z)：384.07[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，2.89(4H，q，-NCH ₂-)，1.38(6H，t，-CH ₃).

Embodiment 34 4 ', 5, the preparation of 7-trihydroxy--6-(N, N-diisopropylaminoethyl methanoyl)-flavones (Il)

Get 500mg midbody 6l, join in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate yellow solid crystallization 330mg.Productive rate: 80%

Gained compound spectroscopic data is:

MS(TOF，m/z)：412.03[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，2.92(2H，q，-NCH-)，1.18(12H，d，-CH ₃)

Embodiment 35 4 ', 5, the preparation of 7-trihydroxy--6-(N-morpholine methanoyl)-flavones (Im)

Get 500mg midbody 6m, join in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate yellow solid crystallization 324mg.Productive rate: 79%

Gained compound spectroscopic data is:

MS(TOF，m/z)：398.11[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，2.79(4H，t，-NCH ₂-)，2.98(4H，t，-OCH ₂-)。

Embodiment 36 4 ', 5, the preparation of 7-trihydroxy--6-(N-methyl-N-ethylamino methanoyl)-flavones (In)

Get 500mg midbody 6n, join in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate yellow solid crystallization 320mg.Productive rate: 79%

Gained compound spectroscopic data is:

MS(TOF，m/z)：370.09[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，2.77(2H，q，-NCH ₂-)，2.45(3H，s，-NCH ₃)，1.18(3H，T，-CH ₃).

Embodiment 37 4 ', 5, the preparation of 7-trihydroxy--6-(N-piperidine formyl oxygen base)-flavones (Io)

Get 500mg midbody 6o, join in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate yellow solid product 315mg.Productive rate: 77%

Gained compound spectroscopic data is:

MS(TOF，m/z)：396.01[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，2.79(4H，t，-NCH ₂-)，1.68(4H，dd，-CH ₂-)，1.44(2H，dd，-CH ₂-)

Embodiment 38 4 ', 5, the preparation of 7-trihydroxy--6-[N-(4-benzyl) piperidine formyl oxygen base]-flavones (Ip)

Get 500mg midbody 6p, join in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate yellow solid product 343mg.Productive rate: 81%

Embodiment 39 4 ', 5, the preparation of 7-trihydroxy--6-[N-(4-methyl) piperidine formyl oxygen base]-flavones (Iq)

Get 620mg midbody 6q, join in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate yellow solid product 362mg.Productive rate: 88%

Gained compound spectroscopic data is:

MS(TOF，m/z)：410.15[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，2.79(4H，t，-NCH ₂-)，1.48(4H，m，-CH ₂-)，1.54(2H，m，-CH ₂-)，2.20(2H，d，-ArCH ₂)，7.35-8.21(5H，m，-ArH)

Embodiment 40 4 ', 5, the preparation of 7-trihydroxy--6-(third carbamoyloxy)-flavones (Ir)

Get 500mg midbody 6r, join in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate yellow solid crystallization 277mg.Productive rate: 69%

Gained compound spectroscopic data is:

MS(TOF，m/z)：356.12[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，2.79(4H，t，-NCH ₂-)，1.48(4H，m，-CH ₂-)，1.54(2H，m，-CH ₂-)，1.20(3H，d，-CH ₃).

Embodiment 41 4 ', 5, the preparation (Is) of 7-trihydroxy--6-methanoyl-flavones

Midbody 5, the 4ml anhydrous pyridine of getting 750mg join among the DMF of 30ml successively, and the stirring at room reaction adds the formyl chloride of 2.4mmol, room temperature reaction 24 hours after 30 minutes.Reaction finishes afterreaction liquid and pours in the frozen water with ethyl acetate extraction anhydrous sodium sulfate drying into.Revolve and desolvate, the gained bullion is with column chromatography purification, pale yellow powder, promptly 4 ', 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-methanoyl flavones 526mg.Productive rate: 63%.

Gained compound spectroscopic data is:

MS(TOF，m/z)：415.01[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，5.16(2H，s，-OCH ₂O-)，5.23(2H，s，-OCH ₂O-)，3.21(3H，s，-OCH ₃)，3.48(3H，s，-OCH ₃)，9.13(1H，s，-COH)

Get 4 ', 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-methanoyl flavones 500mg joins in the mixing solutions (1: 1) of 20ml methylene dichloride and ether, and ice bath adds the concentrated hydrochloric acid of 2ml down, slowly is warming up to room temperature, stirs 6 hours.Reaction finishes the back with ethyl acetate extraction, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate the faint yellow solid product, promptly 4 ', 5,7-trihydroxy--6-methanoyl-flavones 339mg.Productive rate: 86%

Gained compound spectroscopic data is:

MS(TOF，m/z)：315.00[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，9.14(3H，s，-COH).

Embodiment 42 4 ', 5, the preparation of 7-three-hydroxyl-6-iodo methoxy flavone

With the midbody 5 of 750mg, the K of 415mg ₂CO ₃Join successively among the DMF of 30mL, stirring at room added CH after 30 minutes ₂I ₂0.58mL, stirring at room 24 hours.Reaction finishes the back with the ethyl acetate extraction reaction solution, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion gets yellow powder 740mg with column chromatography purification, productive rate: 87%.Get 500mg 4 ', 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-iodo methoxy flavone joins in 20ml methylene dichloride and the alcoholic acid mixing solutions (1: 1); Ice bath adds the concentrated hydrochloric acid of 2ml down; Slowly be warming up to room temperature, stirred 6 hours, reaction finishes the back with ethyl acetate extraction; Water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate yellow solid product, promptly 4 ', 5,7-trihydroxy--6-iodo methoxy flavone 349mg, productive rate: 87%, purity 99%

Gained compound spectroscopic data is:

MS(TOF，m/z)：425.00[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，3.82(2H，t，-OCH ₂I)。

Embodiment 434 ', 5, the amino inferior methoxy flavone of 7-trihydroxy--6-N-methyl-N-propyl group

With the midbody 5 of 750mg, the K of 415mg ₂CO ₃Join successively among the DMF of 30mL, stirring at room added CH after 30 minutes ₃NC ₃H ₇CH ₂I 0.65mL, stirring at room 24 hours.Reaction finishes the back with the ethyl acetate extraction reaction solution, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion gets yellow powder 760mg with column chromatography purification, productive rate: 88%.Get 500mg 4 ', the amino inferior methoxy flavone of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-N-methyl N-propyl group joins in 20ml trichloromethane and the alcoholic acid mixing solutions (1: 1); Ice bath adds the concentrated hydrochloric acid of 2ml down; Slowly be warming up to room temperature, stirred 6 hours, reaction finishes the back with ethyl acetate extraction; Water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate yellow solid product, promptly 4 ', 5, the amino inferior methoxy flavone 353mg of 7-trihydroxy--6-N-methyl-N-propyl group, productive rate: 88.5%, purity 99.5%

Gained compound spectroscopic data is:

MS(TOF，m/z)：370.00[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，3.42(2H，t，-OCH ₂)，3.72(3H，c，-NCH ₃)，3.75(2H，t，-NCH ₂)，1.23(2H，m，-CH ₂-)，1.03(3H，t，-CH ₃)。

Embodiment 44 4 ', 5, the preparation of the inferior methoxy flavone of 7-trihydroxy--6-carboxyl

With the midbody 5 of 750mg, the K of 415mg ₂CO ₃Join successively among the DMF of 30mL, stirring at room added HOOCCH after 30 minutes ₂I 0.71mL, stirring at room 24 hours.Reaction finishes the back with the ethyl acetate extraction reaction solution, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion gets yellow powder 729mg with column chromatography purification, productive rate: 86%.Get 500mg 4 ', the inferior methoxy flavone of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-carboxyl joins in 20ml trichloromethane and the alcoholic acid mixing solutions (1: 1); Ice bath adds the concentrated hydrochloric acid of 2ml down; Slowly be warming up to room temperature, stirred 6 hours, reaction finishes the back with ethyl acetate extraction; Water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate yellow solid product, promptly 4 ', 5, the inferior methoxy flavone 370mg of 7-trihydroxy--6-carboxyl, productive rate: 86%, purity 99.8%

Gained compound spectroscopic data is:

MS(TOF，m/z)：343.00[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，3.62(2H，t，-OCH ₂)，12.54(1H，s，-COOH)。

Implement 45 4 ', 5, the preparation of the inferior methoxy flavone of 7-trihydroxy--6-hydroxyl

With the midbody 5 of 750mg, the K of 415mg ₂CO ₃Join successively among the DMF of 30mL, stirring at room added HOCH after 30 minutes ₂I 0.65mL, stirring at room 24 hours.Reaction finishes the back with the ethyl acetate extraction reaction solution, and water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion gets yellow powder 734mg with column chromatography purification, productive rate: 87%.Get 500mg 4 ', the inferior methoxy flavone of 7-dimethoxy methylene radical oxygen-5-hydroxyl-6-hydroxyl joins in 20ml trichloromethane and the alcoholic acid mixing solutions (1: 1); Ice bath adds the concentrated hydrochloric acid of 2ml down; Slowly be warming up to room temperature, stirred 6 hours, reaction finishes the back with ethyl acetate extraction; Water and saturated aqueous common salt respectively wash twice, anhydrous magnesium sulfate drying.Revolve and desolvate, the gained bullion with silica gel column chromatography separate yellow solid product, promptly 4 ', 5, the inferior methoxy flavone 388mg of 7-trihydroxy--6-hydroxyl, productive rate: 89%, purity 99.9%

Gained compound spectroscopic data is:

MS(TOF，m/z)：343.00[M-H] ^-.

¹HNMR(DMSO-d ₆，300MHz)：12.97(5-OH)，10.44(1H，s，7-OH)，10.30(1H，s，4’-OH)，7.91(2H，d，j＝8.58，2’，6’-ArH)，6.92(2H，d，j＝8.58，3’，5’-ArH)，6.74(1H，s，3-H)，6.57(1H，s，8-H)，3.68(2H，t，-OCH ₂)，5.6(1H，s，-OH)。

Embodiment 46 lamp-dish flower acetics aglycon-6-bit derivant is to the influence of rat thrombin time

At present, the screening ordinary method of antithrombotic compound is to investigate the active of compound anticoagulant and to the influence of thrombin time, the present invention investigates each compound antithrombotic acitivity through measuring compound to the influence of thrombin time.

Concrete grammar: get the healthy male rabbit; The vetanarcol physiological salt soln auricular vein injecting anesthetic of 30mg/kg rabbit body weight; Operation separates carotid atery and gets blood, is collected in the plastic centrifuge tube 3.8% Sodium Citrate aqueous solution anti-freezing (blood and antithrombotics volume ratio are 9: 1).The centrifugal 10min of 800r/min, and the preparation platelet rich plasma (Platelet-rich plasma, PRP), the centrifugal 10min of 3000r/min, the preparation platelet poor plasma (Platelet-poor plasma, PPP).

With lamp-dish flower acetic glycosides and lamp-dish flower acetic aglycon as control group; Lamp-dish flower acetic aglycon-6-bit derivant is as experimental group; Sample is dissolved in 80% ethanol, is made into the solution that starting point concentration is about 1.2mg/ml, 0.6mg/ml, 0.3mg/ml, 0.15mg/ml, 0.075mg/ml respectively.

The mensuration of PT (prothrombin time):

Principle: thrombokinase and calcium ion mixture can make thrombogen change zymoplasm into, and zymoplasm makes Fibrinogen change fibrin clot into, and time that grumeleuse forms and the extrinsic soagulation factor content in the blood plasma are negative correlation.

Method: add solvent or given the test agent 10 μ L, PPP 50 μ L in the test cup, preparatory temperature 3min in 37 ℃ of preparatory temperature holes will test cup and change TCH test channel over to, add 37 ℃ of inductor PT reagent 100 μ L of temperature in advance, the time that record PPP solidifies.

The mensuration of APTT (activated partial thromboplastin time):

Principle: blood plasma to be measured adds the activated partial thromboplastin solution, and Fibrinogen changes scleroproein into, measures and solidifies the required time, is blood plasma activated partial thromboplastin time to be measured (APTT).If the intrinsic pathway defectiveness, setting time promptly prolongs, and is directly proportional with the degree of single-factor shortage.Equally also lack and be directly proportional with the accumulation of the required factor of intrinsic pathway.

Method: solvent or given the test agent 10 μ L, adding PPP 50 μ L and warm in advance APTT reagent 50 μ L in the test cup, preparatory temperature 5min in 37 ℃ of preparatory temperature holes will test cup and change TCH test channel over to, add 37 ℃ of warm in advance inductor CaCl ₂Reagent 50 μ L, the time that record PPP solidifies.

The mensuration of TT (thrombin time):

Principle: blood plasma to be measured adds the thrombin solution of demarcating, and Fibrinogen changes scleroproein into, measures and solidifies the required time, is thrombin time of blood plasma to be measured (TT).

Method: add solvent or given the test agent 10 μ L, PPP 50 μ L in the test cup, preparatory temperature 3min in 37 ℃ of preparatory temperature holes will test cup and change TCH test channel over to, add the inductor TT reagent 50 μ L of room temperature, the time that record PPP solidifies.

The mensuration of FIB (Fibrinogen):

Principle: the quantitatively determined Fibrinogen is the classical way that generally uses, and this method is after adding zymoplasm, to measure the aggegation time of diluting plasma.

Method: 1.: the preparation of typical curve: the definite value blood plasma after will redissolving is processed 1: 5,1: 10,1: 15,1: 20,1: 30 diluting plasma respectively.Get each 200 μ L of diluting plasma of different concns, 37 ℃ of temperature 3 minutes in advance add FIB reagent 100 μ L then respectively, measure setting time, by the automatic formation curve of coagulo meter and preserve.2.: add solvent or given the test agent 10 μ L, PPP 50 μ L in the test cup, preparatory temperature 3min in 37 ℃ of preparatory temperature holes will test cup and change TCH test channel over to, add zymoplasm (FIB) the 50 μ L of room temperature, time or concentration that record PPP solidifies.

More than all experimental datas represent with

; Mean relatively adopts the t check between group, and concrete experimental result is as shown in table 1.

Embodiment 46 lamp-dish flower acetics aglycon-6-bit derivant is active to the inhibition of platelet aggregation

This mensuration adopts ADP inductive platelet aggregation test method by routine, promptly carries out platelet aggregation test with turbidimetry.Get the healthy male rabbit; The vetanarcol physiological salt soln auricular vein injecting anesthetic of 30mg/kg rabbit body weight; Operation separates carotid atery and gets blood, is collected in the plastic centrifuge tube 3.8% Sodium Citrate aqueous solution anti-freezing (blood and antithrombotics volume ratio are 9: 1).The centrifugal 10min of 800r/min, and the preparation platelet rich plasma (Platelet-rich plasma, PRP), the centrifugal 10min of 3000r/min, the preparation platelet poor plasma (Platelet-poor plasma, PPP).Sample is dissolved in the absolute ethyl alcohol, is made into the solution that starting point concentration is respectively 150mmol/L, 100mmol/L, 50mmol/L, 25mmol/L, 12.5mmol/L, be numbered compound number .1～compound number .5 respectively.Add 280 μ LPRP, solvent or given the test agent 10 μ L in the test cup; Preparatory temperature 1min in 37 ℃ of preparatory temperature holes will test cup and change TCH test channel over to, add inductor ADP (final concentration 5umol/L) 10 μ L; MA in the observed and recorded 6min (Maximum aggregation rate, MAR).Make blank (Control) with absolute ethyl alcohol, FLA (FA) is made positive control, calculate the anticoagulant rate (Aggregation inhibition rate, AIR) and sample segment 50% assemble inhibition concentration (IC50), the result sees table 1.

Table 1 part of compounds is to the situation that influences of thrombin time and platelet aggregation activity

Factions

Concentration (mg/ml)

PT(s)

APTT(s)

TT(s)

FIB(s)

?ADP(IC ₅₀)?(mmol/L)

Control

80％EtOH

8.3±0.45

26.3±2.92

23.2±1.88

0.51±0.08

?

Scutellarin

1.17

9.2±0.17

31.6±7.79

34.5±2.45

0.61±0.01

34.7

Scutellarein

1.20

9.1±0.98

45.8±4.06

36.6±2.81

0.64±0.04

11.4

Ia

1.13

9.8±0.76

43.0±4.78

48.3±2.59

0.79±0.08

1.5

Ib

1.14

9.5±0.10

38.2±3.96

42.5±3.25

0.86±0.03

1.4

Ic

1.10

10.9±1.12

35.6±2.58

39.7±2.78

0.89±0.01

1.2

Id

1.24

9.5±0.59

37.7±2.15

42.3±0.65

0.82±0.09

1.6

Ie

1.25

9.7±0.41

45.7±1.66

37.9±2.03

0.94±0.11

2.5

If

1.35

10.1±0.56

36.5±1.84

37.6±3.41

0.90±0.10

3.7

Ig

1.04

10.2±0.19

37.9±4.06

39.4±2.83

0.94±0.008

6.9

Ih

1.16

9.6±0.42

39.7±4.13

38.2±1.56

0.97±0.52

1.4

Ii

1.16

9.8±0.42

39.7±4.13

48.2±1.56

0.84±0.02

1.9

Ij

1.24

9.3±0.17

38.3±1.71

49.2±1.60

0.88±0.03

0.9

Ik

1.16

10.3±0.28

54.7±3.75

42.5±5.51

0.83±0.05

3.5

Il

1.35

10.8±0.23

50.2±4.45

42.9±4.00

0.87±0.04

2.8

Im

1.25

10.0±0.28

41.7±3.47

44.9±2.56

0.93±0.07

0.2

In

1.10

9.4±0.76

46.2±3.37

44.8±4.02

0.89±0.04

0.9

Io

1.16

9.9±0.27

49.8±2.66

46.6±2.62

0.95±0.08

2.4

Ip

1.25

9.8±0.22

52.2±1.65

47.4±0.67

0.91±0.01

3.2

Iq

1.10

9.4±0.27

62.4±5.06

39.2±7.81

0.94±0.04

1.6

Ir

1.16

9.2±0.60

60.3±7.37

40.6±4.88

0.99±0.08

1.3

Is

1.16

9.6±0.31

36.3±3.62

39.2±6.43

0.85±0.04

6.3

The result is: MV ± S.D. (n=4). ^*: P＜0.05, ^*: P＜0.01, ^{* *}: P＜0.001.

Show by above table 1 experimental result; Compare with control group; Scutellarein-6-bit derivant with general formula I provided by the invention can improve the value of activated partial thromboplastin time (APTT) and thrombin time (TT); And has obvious suppression platelet aggregation (ADP) activity; Explain that Scutellarein provided by the invention-6-bit derivant has significant inhibitory effect to zymoplasm, experimental result shows that part Scutellarein-6-bit derivant has stronger inhibition active than scutellarin glycosides and Scutellarein simultaneously.And show that through the anticoagulant experimental result compare with scutellarin glycosides and Scutellarein, Scutellarein provided by the invention-6-bit derivant has the activity of better anticoagulant.Therefore; Provided by the invention Scutellarein is carried out structural modification after; Can more obviously increase antithrombotic pharmacologically active, and can prepare serial salt to Scutellarein-6-bit derivant and alkali reaction, improve water-soluble; Thereby be prepared into different dosage form, therefore Scutellarein provided by the invention-6-bit derivant and salt thereof are expected to be developed further into the medicine into thrombotic diseases such as treatment myocardial infarction, ischemia injury, apoplexy.

Above embodiment only is explanation technical conceive of the present invention and characteristics; Its purpose is to let the people that is familiar with this technology understand content of the present invention and implements; Can not limit protection scope of the present invention with this; All equivalences that spirit is done according to the present invention change or modify, and all should be encompassed in protection scope of the present invention.

Claims

1. Scutellarein-6-bit derivant is characterized in that, they are to have the compound shown in the general formula (I):

R represents substituted acyl; Substituting group is C1～C10 alkyl, C1～C10 aminoalkyl group, C1～C10 alkylamino, C1～C10 alkylthio, C1～Ci0 perfluoroalkyl, hydrogen, phenyl, N-Pyrrolidine base, N; N-dimethylamino, N; N-diethylamino, N, N-diisopropylaminoethyl, N-morpholinyl, N-methyl-N-ethylamino, N-piperidyl, N-(4-methyl) piperidyl.

2. method for preparing the described Scutellarein of claim 1-6-bit derivant is characterized in that may further comprise the steps:

E, get the scutellarin aglycone derivative (5) that steps d obtains and under alkaline condition, obtain compound (6) with replacing acyl chloride reaction, compound (6) catalysis under acidic conditions generates Scutellarein-6-bit derivant.

3. the preparation method of Scutellarein according to claim 2-6-bit derivant is characterized in that, scutellarin among the step a (1) and K ₂CO ₃The mole dosage ratio be 1: 2～2.5, scutellarin is 1: 2～2.3 with the mole dosage ratio of bromobenzyl, reaction solvent is 2, the 5-dimethyl furan, temperature of reaction is 25～30 ℃, the reaction times is 6～8 hours.

4. the preparation method of Scutellarein according to claim 2-6-bit derivant; It is characterized in that; Used alkali is salt of wormwood among the step c; Compound (3) is 1: 2～2.4 with the mole dosage ratio of salt of wormwood, and the mole dosage ratio of compound (3) and chloromethyl ether is 1: 2～2.2, and temperature of reaction is 60～70 ℃; Reaction times is 8～12 hours.

5. the preparation method of Scutellarein according to claim 2-6-bit derivant; It is characterized in that; Scutellarin aglycone derivative among the step e (5) is 1: 1～3 with the mole dosage ratio that replaces acyl chlorides; Scutellarin aglycone derivative (5) is trimethylamine class alkali or quaternary ammonium hydroxide with replacing the used alkali of acyl chloride reaction, and the consumption mol ratio of scutellarin aglycone derivative (5) and alkali is 1: 1～4, and reaction solvent is methylene dichloride, chloroform, THF, N; Dinethylformamide or toluene, temperature of reaction are 20～30 ℃; Reaction times is 2～48 hours.

6. the salt of the described Scutellarein of claim 1-6-bit derivant; It is characterized in that said salt is that said Scutellarein-6-bit derivant and alkali metal hydroxide, alkaline earth metal hydroxides, alkaline carbonate, alkaline earth metal carbonate, alkali metal hydrocarbonate or alkali metal bicarbonates prepared in reaction obtain.

7. the described Scutellarein of claim 1-6-bit derivant is in the application in preparation control thrombotic diseases medicine, and said thrombotic diseases is myocardial infarction, ischemia injury.