CN101508689A

CN101508689A - Synthesis of oroxylin

Info

Publication number: CN101508689A
Application number: CNA2009100298679A
Authority: CN
Inventors: 李志裕; 符伟; 杨博; 郭青龙; 尤启冬
Original assignee: China Pharmaceutical University
Current assignee: Nanjing Qinling Pharmaceutical Technology Co.,Ltd.
Priority date: 2009-03-26
Filing date: 2009-03-26
Publication date: 2009-08-19
Anticipated expiration: 2029-03-26
Also published as: CN101508689B

Abstract

The invention relates to the chemical synthesis field, in particular to a synthetic method of traditional Chinese herbal skullcap momoner oroxylin. The method is characterized by comprising the following steps: 5,6,7-trihydroxyflavone, benzyl bromide and benzyl chloride are subject to nucleophilic substitution reaction in the presence of an acid coating agent to generate 7-benzyl-5,6-dihydroxyflavone, the generated 7-benzyl-5,6-dihydroxyflavone reacts with dimethyl sulfate in the presence of the acid coating agent to generate 7-benzyl-6-methoxyl-5-hydroxylflavone; and the 7-benzyl-6-methoxyl-5-hydroxylflavone is subject to debenzylation in the presence of palladium-carbon under the reducing action of catalytic hydrogenation to obtain the oroxylin. The method has the advantages of simple steps, mild conditions, more than 65% of total reaction yield and high synthetic product purity of more than 99.0%.

Description

A kind of synthetic method of oroxylin

Technical field

The present invention relates to the field of chemical synthesis, particularly, the present invention relates to the synthetic of baikal skullcap root monomer oroxylin.

Background technology

Oroxylin is a contained chromocor compound in the labiate root of large-flowered skullcap (the Scutellaria baicalensis Georgi) root, has the structure of formula (I).

Formula (I)

Studies show that oroxylin has multiple pharmacological effect, comprise the memory impairment, mediation hepatoma cell line HepG2 apoptosis, the anti-inflammatory that improve eastern scopola alkali and big cerebral blood perfusion mediation, protect the liver and suppress effects such as sleep.

Because oroxylin has pharmacologically active widely, and extraction process is loaded down with trivial details from plant, purity is low, the cost height, and people explore its total synthesis method.

The method of complete synthesis oroxylin mainly contains following five kinds

(1) Allan-Robinson condensation method (Murti, V.V.Sreerama; Seshadri, T.R.Proceedings-Indian Academy of Sciences, Section A (1949), 29A1-8.) this method is with 2,4, and the 6-trihydroxy-acetophenone is a raw material, through part benzylization, part methylization, K ₂S ₂O ₈Oxidation obtains 2, and 5-dihydroxyl-4 benzyloxies-6-methoxyacetophenone is then at Bz ₂The Allan-Robinson condensation takes place down and obtains 7-benzyloxy-5-methoxy flavone in O and BzONa effect, and again through methylating, debenzylation and part demethylation obtain oroxylin under the HBr effect.This method technology is loaded down with trivial details, and yield is low, no practical value.

(2) with the scutellarin be synthetic method (Sarin, the P.S. of intermediate; Seshadri, T.R.Journal ofScientific ﹠amp; Industrial Research 1960), 19B117.) this method is raw material with the scutellarin, through the selectivity benzylization, and part methylization, debenzylation can obtain oroxylin.Document reports that in selectivity benzyl step yield is lower in this method.

(3) with 3,4,5-trimethoxy phenol is synthetic method (Shaw, the Jiajiu of raw material; Lee, An-Rong; Huang, Wen-Hsin.US 2004242907) this method second 3,4,5-trimethoxy phenol is raw material, through the Fries reaction, and dioxide giving, the part demethylation obtains oroxylin.

(4) pyrocondensation method (Rivaille, Pierre; Mentzner, Charles.Compt.Rend. (1965), 260 (8), 2243-5.) this method is with 2, the 6-2-methoxyhydroquinone for raw material directly and ethyl benzoylacetate condensation at high temperature obtain oroxylin.This method selectivity when pyrocondensation is bad, produces a large amount of methyl wogonins.

(5) isomerization method (Jozaef Varady Tetrahedron Letters; 196548; 4281-4282) this method is raw material with the wogonin; the part benzylization obtains 7-benzyl wogonin; isomerization reaction takes place under benzylalcohol and salt of wormwood effect then obtain 7-benzyl oroxylin, last debenzylation protection obtains oroxylin.The raw material wogonin that uses in this method needs polystep reaction synthetic, and the cost height only is fit to research and uses, and is not suitable for a large amount of synthetic oroxylins.

Summary of the invention

The invention discloses a kind of synthetic method of oroxylin, the present invention is the synthetic oroxylin of intermediate with the scutellarin, simple synthetic method, yield height, product purity height.

Synthetic method of the present invention is following reaction formula:

Comprise the following steps: successively

A. with 5 (compound 2) in the presence of acid-binding agent with cylite Benzyl Chloride generation nucleophilic substitution reaction, generate 7-benzyl-5,6-dihydroxyflavone (compound 3);

B. the compound 3 with above-mentioned generation reacts with methyl-sulfate in the presence of acid-binding agent, generates 7-benzyl-6-methoxyl group-5-flavonol (compound 4);

C. above-claimed cpd 4 debenzylation under the reductive action of catalytic hydrogenation in the presence of the palladium carbon is obtained oroxylin (compound 1).

Above-mentioned reaction a or b step are preferably reacted in following one or more organic solvent: acetone, DMF (N, dinethylformamide), acetonitrile, ethanol, chloroform, ethyl acetate.Further preferred acetone or alcohol.

The preferred yellow soda ash of acid-binding agent, salt of wormwood, saleratus or sodium bicarbonate.

Preferably in the reaction solvent of tetrahydrofuran (THF), ethanol, methyl alcohol, acetone, ethyl acetate or DMF, react in the c step.

In the above-mentioned reaction, preferred 10 ℃～150 ℃ of the temperature of reaction of a step or b step.Further preferred 30 ℃～60 ℃.

Preferred protective gas nitrogen or the argon gas of feeding in step a, b and the c reaction system.

Preferred 1:1～the 1:3 of mol ratio of 5 and cylite or Benzyl Chloride in a step wherein.Further preferred 1:1.4.

7-benzyl-5 in the b step, the preferred 1:4～1:10 of the mol ratio of 6-dihydroxyflavone and methyl-sulfate.Further preferred 1:6.6.

Preferred 1:0.05～the 1:1 of weight ratio of 5-hydroxyl-6-methoxyl group-7-benzyloxy flavones and palladium carbon in the c step.Further preferred 1:0.1.

Step of the present invention is simple, and mild condition, overall yield of reaction are greater than 65%, and synthetic product purity height is greater than 99.0%.

Embodiment

Embodiment 1

7-benzyl-5, the preparation of 6-dihydroxyflavone

Mechanical stirrer, thermometer are being housed, are adding scutellarin 16g in the 2000ml reaction flask of nitrogen ingress pipe, acetone 1600mL feeds N ₂Displaced air keeps logical nitrogen, is heated to 32 ℃, and scutellarin is dissolved fully, adds K ₂CO ₃59g, cylite 10mL, reaction 48h, cooling is evaporated to driedly, adds 200 ml waters and stirs, and filters, dry yellow solid 15.5g, yield 92%, Mp:195 ℃-196 ℃.10%FeCl ₃It is blackish green that ethanolic soln shows

¹H-NMR(DMSO-d ₆，300Hz)：δ?5.30(2H，s，CH ₂Ph)，7.01(1H，s，3H)，7.12(1H，S，8H)7.33-7.65(10H，m，ArH)，8.08-8.10(2H，d，ArH)，8.83(1H，s，6-OH)，12.55(1H，s，5-OH)MS(EI，m/z)360，269，241，139，91

Embodiment 2

7-benzyloxy-5, the preparation of 6-dihydroxyflavone

Mechanical stirrer, thermometer are being housed, are adding scutellarin 16g (59mmol) in the 2000ml reaction flask of nitrogen ingress pipe, ethanol 1500mL feeds N ₂Displaced air keeps logical nitrogen, is heated to 40 ℃, and scutellarin is dissolved fully, adds Na ₂CO ₃55g, cylite 15mL, reaction 24h, cooling is evaporated to driedly, adds 200 ml waters and stirs, and filters, dry yellow solid 14.0g, yield 77%, Mp:195 ℃-196 ℃.10%FeCl ₃It is blackish green that ethanolic soln shows.

Embodiment 3

7-benzyloxy-5, the preparation of 6-dihydroxyflavone

Mechanical stirrer, thermometer are being housed, are adding scutellarin 16g (59mmol) in the 2000ml reaction flask of nitrogen ingress pipe, acetone 1500mL feeds N ₂Displaced air is heated to 40 ℃, and scutellarin is dissolved fully, adds KHCO ₃59g, cylite 15mL, reaction 24h, cooling is evaporated to driedly, adds 200 ml waters and stirs, and filters, dry yellow solid 13.0g, yield 82%, Mp:195 ℃-196 ℃.10%FeCl ₃It is blackish green that ethanolic soln shows.

Embodiment 4

The preparation of 5-hydroxyl-6-methoxyl group-7-benzyloxy flavones

Mechanical stirring, thermometer are being housed, are adding 7-benzyl-5 in the 2000ml reaction flask of nitrogen ingress pipe, 6-dihydroxyflavone 8g (22mmol), ethanol 1600mL feeds N ₂Displaced air adds anhydrous K ₂CO ₃30g (0.22mol), methyl-sulfate 16mL finishes back flow reaction 6h, and TLC detects no raw material point, and cooling is evaporated to driedly, adds 100 ml waters and stirs, and filters, dry yellow solid 8g, yield 96%.Mp：165-166℃。

¹HNMR(CDCl ₃，300Hz)：δ?3.95(3H，s，OCH ₃)，5.25(2H，s，CH ₂Ph)，7.31-7.88(10H，m，Ar-H)，7.86-7.88(2H，d，Ar-H)，12.70(1H，s，5-OH)

MS(EI，m/z)374，359，283，153，91

Embodiment 5

The preparation of 5-hydroxyl-6-methoxyl group-7-benzyloxy flavones

Mechanical stirring, thermometer are being housed, are adding 7-benzyl-5 in the 2000ml reaction flask of nitrogen ingress pipe, 6-dihydroxyflavone 8g (22mmol), acetone 1500mL feeds N ₂Displaced air adds anhydrous Na ₂CO ₃28g, methyl-sulfate 25mL finishes back flow reaction 6h, and cooling is filtered, and filtrate decompression reclaims, and cooling is evaporated to driedly, adds 200 ml waters and stirs, and filters, dry yellow solid 7.2g, yield 87%.Mp：165-166℃。

Embodiment 6

The preparation of oroxylin

In being housed, the 1000mL single port bottle of magnetic agitation adds 5-hydroxyl-6-methoxyl group-7-benzyloxy flavones 8g (21mmol), 10% Pd/C 0.8g, tetrahydrofuran (THF) 500ml, reacted 5 hours, reaction is finished, and filters, and decompression and solvent recovery is to doing, re-crystallizing in ethyl acetate can get the oroxylin 4.5g of purity 99%.Yield 74%Mp:198 ℃-199 ℃ (195 ℃-197 ℃ in document) ¹HNMR (DMSO-d ₆, 300Hz): δ 3.85 (3H, s, OCH ₃), 6.63 (1H, s, 3H), 6.95 (1H, S, 8H), 7.56-7.59 (3H, m, ArH), 8.05-8.07 (2H, d, ArH), 10.78 (1H, s, 7-OH), 12.92 (1H, s, 5-OH) MS (EI, m/z), 284,269,241,139

IR?1653cm ^-1(v _C＝O)，3455cm ^-1(voH)。

Claims

1, a kind of synthetic method of oroxylin comprises the following steps: successively

A, with 5 in the presence of acid-binding agent with cylite or Benzyl Chloride generation nucleophilic substitution reaction, generate 7-benzyl-5, the 6-dihydroxyflavone;

B, with 7-benzyl-5, the 6-dihydroxyflavone in the presence of acid-binding agent with methyl-sulfate reaction, generate 7-benzyl-6-methoxyl group-5-flavonol;

C, 7-benzyl-6-methoxyl group-5-flavonol catalytic hydrogenation debenzylation in the presence of palladium carbon is obtained oroxylin.

2, the synthetic method of claim 1, wherein a or b step reaction solvent are selected from one or more in acetone, N.N-dimethyl formamide, acetonitrile, ethanol, chloroform, the ethyl acetate.

3, the synthetic method of claim 2, wherein a or b step reaction solvent are acetone or alcohols.

4, the synthetic method of claim 1, wherein acid-binding agent is salt of wormwood, saleratus, sodium bicarbonate or yellow soda ash.

5, the synthetic method of claim 1, wherein c step reaction solvent is selected from tetrahydrofuran (THF), ethanol, methyl alcohol, ethyl acetate or N.N-dimethyl formamide.

6, the synthetic method of claim 1, wherein a or b step reaction temperature are 10 ℃～150 ℃.

7, the synthetic method of claim 6, wherein a or b step reaction temperature are 30 ℃～60 ℃.

8, the synthetic method of claim 1 wherein feeds nitrogen or argon gas in a, b or the c step reaction.

9, the synthetic method of claim 1, wherein the mol ratio of 5 and cylite or Benzyl Chloride is 1:1～1:3 in a step; 7-benzyl-5 in the b step, the mol ratio of 6-dihydroxyflavone and methyl-sulfate are 1:4～1:10; The weight ratio of 5-hydroxyl-6-methoxyl group-7-benzyloxy flavones and palladium carbon is 1:0.05～1:1 in the c step.

10, the synthetic method of claim 9, wherein the mol ratio of 5 and cylite or Benzyl Chloride is 1:1.4 in a step; 7-benzyl-5 in the b step, the mol ratio of 6-dihydroxyflavone and methyl-sulfate are 1:6.6; The weight ratio of 5-hydroxyl-6-methoxyl group-7-benzyloxy flavones and palladium carbon is 1:0.1 in the c step.