CN101684112A - Preparation method of 5,6,7,4'-tetramethoxy flavones of scutellarin and aglucone key intermediate thereof - Google Patents

Abstract

The invention relates to a preparation method of 5,6,7,4'-tetramethoxy flavone of scutellarin and aglucone key intermediate thereof. The 5,6,7,4'-tetramethoxy flavones is prepared by utilizing 2-hydroxyl-4,5,6-trimethoxy hypnone as the raw material and comprising a reaction a step and a reaction b step, wherein in the reaction a, 2-hydroxyl-4,5,6-trimethoxy hypnone and p-methoxybenzaldehyde are condensed to prepare a chalcone derivative; and in the reaction b, the chalcone derivative is processed in a oxidative cyclization mode to prepare the 5,6,7,4'-tetramethoxy flavone. The method has the advantages of simple operation steps and high product yield.

Description

Preparation method of scutellarin and its aglycone key intermediate 5,6,7,4'-tetramethoxyflavone

technical field

The invention relates to a compound preparation process, in particular to a preparation method of scutellarin and its aglycone key intermediate 5,6,7,4'-tetramethoxyflavone.

Background technique

Erigeron breviscapus, also known as Erigeron breviscapus, belongs to the genus Fabaceae. The scutellarin is isolated and extracted from the whole plant of breviscapine, mainly containing scutellarin (>90%), and also contains a small amount of scutellarin, which is also called scutellarin. Breviscapine has the effects of promoting blood circulation and removing blood stasis, dispelling cold and relieving the surface, relaxing tendons and activating collaterals, expelling wind and dampness, and is often used clinically to treat cardiovascular and cerebrovascular diseases.

5,6,7,4'-tetramethoxyflavone is an important intermediate for the preparation of cardiovascular drugs scutellarin and scutellarin aglycone (Cui Jianmei et al., "Natural Product Research and Development", 2003, 15( 3): 255-258), the preparation method reported at present has following two kinds:

1) It is prepared by condensation of 3,4,5-trimethoxyphenol and p-methoxybenzoic acid under the action of phosphorus pentoxide and methanesulfonic acid. Although the method only has one-step reaction, the reaction raw material p-methoxyphenynoic acid is difficult to obtain and difficult to prepare. Simultaneously, the yield of this step condensation reaction is extremely low, only about 5%, does not have application value.

2) 2-Hydroxy-4,5,6-trimethoxyacetophenone is used as raw material, first reacts with p-methoxybenzoyl chloride to generate phenolic ester, and then the phenolic ester undergoes Baker-Venkatamah rearrangement under alkaline conditions The reaction yields phenol aryl diketone, which is heated under the condition of HOAc-NaOAc to obtain 5,6,7,4'-tetramethoxyflavone through cyclization. The method is operated through three steps of reaction, and the yield of each reaction step is also good, but the operation requirement is more loaded down with trivial details.

Contents of the invention

The object of the present invention is to provide a new method for preparing 5,6,7,4'-tetramethoxyflavone, the key intermediate of scutellarin and its aglycone, the method has simple operation steps and high product yield.

The preparation method of scutellarin and its aglycone key intermediate 5,6,7,4'-tetramethoxyflavone of the present invention is based on the 2-hydroxyl-4,5,6-trimethyl Oxyacetophenone is used as a raw material and prepared in two steps through reaction a and reaction b, wherein reaction a is prepared by condensation of 2-hydroxy-4,5,6-trimethoxyacetophenone and p-methoxybenzaldehyde To obtain the chalcone derivative shown in compound 3, reaction b is to prepare the 5,6,7,4'-tetramethoxyflavone shown in compound 1 after the oxidative cyclization of the chalcone derivative, the chemical reaction The formula is as follows:

       

Compound 2 Compound 3 Compound 1

Wherein, the reaction solvent in reaction a is selected from lower alcohols, ethers or hydrocarbon solvents, and may be one or any combination thereof.

Lower alcohols include primary alcohols below C6, secondary alcohols or tertiary alcohols, such as methanol, ethanol, etc.; ether solvents can be simple ethers or mixed ethers, such as tetrahydrofuran, dioxane, etc.; common hydrocarbon solvents From alkanes, alkenes, alkynes, cycloalkanes, cycloalkenes or aromatics.

Wherein, the reaction temperature of reaction a is 20-100 DEG C; Catalyst comprises inorganic acid (such as hydrochloric acid, sulfuric acid etc.), organic acid (such as p-toluenesulfonic acid etc.) or inorganic base (such as potassium hydroxide, sodium hydroxide etc.) or Organic bases (such as pyridine, triethylamine, etc.).

Wherein, the dosage ratio of p-methoxybenzaldehyde and 2-hydroxyl-4,5,6-trimethoxyacetophenone is 1-2.5:1.

Wherein, the reaction solvent in reaction b can be dimethyl sulfoxide, alcohols (ethylene glycol, propylene glycol, etc.), hydrocarbons (toluene, xylene, etc.), ethers (dioxane, etc.) or N, N - other common solvents such as dimethylformamide (DMF); the reaction reagent is a mixture of dimethyl sulfoxide and inorganic iodine or its metal salt; the reaction temperature is 80-200°C.

The invention provides a new method for synthesizing scutellarin and its aglycone key intermediate 5,6,7,4'-tetramethoxyflavone, which is prepared by two-step reaction, and the operation steps are simple. The product yield is high and has good application value. The reaction yields of Example 1 and Example 2 of the present invention are both about 85%, and the total reaction yield of the two-step reaction is about 72%, which is the same as that in the prior art for preparing scutellarin and its aglycon key intermediates Compared with the method of 5,6,7,4'-tetramethoxyflavone, it not only significantly exceeds the one-step reaction method (about 5%), but also is obviously higher than the total yield of the three-step reaction method reported in the literature (about 5%). around 60%).

Detailed ways

The preparation method of scutellarin and its aglycone key intermediate 5,6,7,4'-tetramethoxyflavone described in the present invention will be specifically illustrated by the following examples. The raw material (2-hydroxy-4,5,6-trimethoxyacetophenone) in the present invention is prepared according to the method reported in the literature (Duan Xinfang et al., "Organic Chemistry", 2003, 23(4): 353-355).

Embodiment 1: the preparation of chalcone (compound 3)

Weigh 11.3g (0.05mol) of the compound 2,2-hydroxy-4,5,6-trimethoxyacetophenone and 7.4g (0.06mol) of p-methoxybenzaldehyde in a 250ml round bottom flask, add 150ml of methanol and 22.5 g of solid KOH, stirred and reacted at room temperature for 36 hours. After most of the methanol was distilled off under reduced pressure, 200ml of water was added, and then the pH was adjusted to 3-4 with concentrated hydrochloric acid. Precipitate a red precipitate, put it well and filter it, wash the precipitate with a little water, press dry, and dry at 60°C. Example 1 is the first step reaction of the present invention to prepare scutellarin and its aglycone key intermediate 5,6,7,4'-tetramethoxyflavone, which is obtained from 2-hydroxy-4,5,6- The chalcone derivative (compound 3) was prepared by condensation of trimethoxyacetophenone and p-methoxybenzaldehyde. The first step reacted to obtain 14.5 g of compound 3 dry product, and the reaction yield was about 85%. 1HNMR (CDCl3): δ13.80 (s, 1H), δ7.87 (s, 1H), δ7.86 (s, 1H), δ7.62 (d, J=8.5Hz, 2H), δ6.96 ( d, J=8.5Hz, 2H), δ6.31(s, 1H), δ3.94(s, 3H), δ3.92(s, 3H), δ3.88(s, 3H), δ3.86( s, 3H). MS (m/e): 344.

Embodiment 2: the preparation of 5,6,7,4'-tetramethoxyflavone (compound 1)

Weigh 17.2g (0.05mol) of compound A9 into a 250ml round bottom flask, add 50ml of DMSO and a little iodine, heat to reflux for 30min, then let the reaction solution cool down, add 100ml of cold water, stir well, and filter to obtain the compound A7 is off-white crystal. Example 2 is the second step reaction of the present invention to prepare scutellarin and its aglycone key intermediate 5,6,7,4'-tetramethoxyflavone, which is derived from the chalcone prepared in Example 1 5,6,7,4'-tetramethoxyflavone was obtained after oxidative cyclization of compound (compound 3). In the second step, 14.6 g of dry product of compound 1 was obtained, and the reaction yield was about 85%. ¹ HNMR (CDCl ₃ ): δ7.83(d, J=9.0Hz, 2H), δ7.01(d, J=9.0Hz, 2H), δ6.81(s, 1H), δ6.59(s, 1H), δ4.00(s, 3H), δ3.99(s, 3H), δ3.93(s, 3H), δ3.89(s, 3H). MS (m/e): 342.

The above two examples illustrate the two-step reaction of the present invention for preparing scutellarin and its aglycone key intermediate 5,6,7,4'-tetramethoxyflavone, and the operation steps are simple. Among them, the yield of the two-step reaction is about 85%, so the total reaction yield is 85% × 85% ≈ 72%, and the preparation of scutellarin and its aglycon key intermediates in the prior art 5,6 , compared with the method of 7,4'-tetramethoxyflavone, it not only significantly exceeds the one-step reaction (about 5%), but also obviously higher than the total yield of the three-step reaction method reported in the literature (about 60%) .

The preparation method of scutellarin and its aglycon key intermediate 5,6,7,4'-tetramethoxyflavone provided by the present invention has been described in detail above. It should be pointed out that the content described in the specific embodiments is a preferred embodiment for better implementing the present invention, and the protection scope of the present invention is not limited to the technical solutions described in the above embodiments, but should be described in the claims. The essential content of the present invention shall prevail, and any possible changes in composition, content and process shall fall within the protection scope of the present invention as long as they do not deviate from the essential content of the claims of the present invention.

Claims (10)

1, lamp-dish flower acetic and glucoside thereof unit key intermediate 5,6,7, the preparation method of 4 '-tetramethoxy flavones, it is characterized in that, be with the 2-hydroxyl-4,5 shown in the compound 2,6-trimethoxy methyl phenyl ketone is a raw material, be prepared from two steps of reaction b by reaction a, wherein reacting a is by 2-hydroxyl-4,5,6-trimethoxy methyl phenyl ketone and aubepine condensation make the chalcone derivative shown in the compound 3, reaction b will make 5,6,7 shown in the compound 1 behind this chalcone derivative dioxide giving, 4 '-tetramethoxy flavones, chemical equation is as follows:

Compound 2 compounds 3 compounds 1

2, preparation method according to claim 1 is characterized in that, the reaction solvent of reaction a is selected from lower alcohols, ethers or varsol.

3, preparation method according to claim 2 is characterized in that, the lower alcohols solvent comprises primary alcohol, secondary alcohol or the tertiary alcohol that C6 is following.

4, preparation method according to claim 2 is characterized in that, ether solvent is tetrahydrofuran (THF) or dioxane.

5, preparation method according to claim 1 is characterized in that, the temperature of reaction of reaction a is 20-100 ℃.

6, preparation method according to claim 1 is characterized in that, the catalyzer of reaction a comprises mineral acid, organic acid, mineral alkali or organic bases.

7, preparation method according to claim 1 is characterized in that, aubepine and 2-hydroxyl-4,5 among the reaction a, and 6-trimethoxy methyl phenyl ketone amount ratio is 1-2.5: 1.

8, preparation method according to claim 1 is characterized in that, the reaction solvent of reaction b comprises dimethyl sulfoxide (DMSO), alcohols, hydro carbons, ethers or N, dinethylformamide.

9, preparation method according to claim 1 is characterized in that, the reaction reagent of reaction b is the mixture of dimethyl sulfoxide (DMSO) and inorganic iodine or its metal-salt.

10, preparation method according to claim 1 is characterized in that, the temperature of reaction of reaction b is 80-200 ℃.