CN110684003A - A simple and efficient total synthesis method of icariin and its derivatives - Google Patents

Abstract

The invention belongs to the field of natural medicine synthesis, and in particular relates to a total synthesis method of icariin and derivatives thereof. The specific technical scheme is as follows: using 2′-hydroxyacetophenone and benzaldehyde as raw materials, firstly, under the catalysis of organic polybasic acid metal ion complexes, isopentenyl is introduced into the aromatic ring of the raw materials, and then under mild and green conditions The flavonol skeleton was constructed under the following conditions, and then prenyl flavonoids including icariin and its derivatives were synthesized. The method effectively overcomes the limitations of poor substrate solubility and poor regioselectivity when the flavonoids are first constructed and the isopentenyl group is introduced later, and the problem of frequent introduction and removal of protective groups in the conventional prenylation method is avoided. The synthetic route is greatly simplified; meanwhile, the problems of complex products and many by-products in the isopentenyl rearrangement method are avoided. The total synthesis method provided by the invention has mild conditions, simple operation and high overall yield, and is suitable for large-scale production of isopentenyl flavonoids.

Description

A simple and efficient total synthesis method of icariin and its derivatives

technical field

The invention belongs to the field of natural medicine synthesis, in particular to a simple and efficient total synthesis method of icariin.

Background technique

Icariin is the aglycone of icariin, which is a flavonoid derivative of Epimedium, the genus Epimedium of the Berberaceae family. Traditional Chinese medicine believes that Epimedium has significant effects of lowering blood pressure, invigorating kidney and strengthening yang, and is widely used in the treatment of cardiovascular disease, amnesia, arthritis, fatigue, impotence, infertility and other diseases. The molecular structure of icariin is as follows:

Since icariin and noricariin were extracted, separated and identified in 1935, great progress has been made in the research on the pharmacological activities of icariin and its glycoside derivatives. In recent years, medical scientific research has shown that icariin has high anti-cancer activity in vitro and in vivo, and it may inhibit the malignant growth of hepatoma cell initiating cells by inhibiting sphingosine kinase I (Lu, P.H.etc.Oncotarget, 2017, 8, 22800-22810), icariin derivatives acoradine and flucoradine have entered Phase III clinical studies as class I new anti-cancer drugs (drug clinical trial registration number: CTR20170668). However, as the parent nucleus of icariin, the content of icariin in the plant Epimedium is extremely low, and it is usually necessary to extract and separate icariin first, and then hydrolyze the glycosidic bond by glycosidase to obtain the corresponding aglycone. Chinese patents CN1473938, CN101302548, CN107641621 and U.S. Patent US6399579 respectively report the methods for preparing icariin by enzymatic hydrolysis, which are complicated and expensive to obtain icariin. Using chemical methods to directly synthesize icariin is a simple and effective way.

Icariin is a flavonoid compound containing an isopentenyl group. It is a semi-synthetic method for obtaining icariin through the introduction of a isopentenyl group by using kaempferol or a flavonoid derivative as a raw material, or using a phloroglucinol derivative as a raw material. The total synthesis method of raw materials, the construction of flavonoid skeleton and the introduction of isopentenyl to obtain icariin are the two main methods currently used for chemical synthesis of icariin. The key step of its semi-synthetic method is the selective introduction of a prenyl group at the 8-position of the flavonoid skeleton. In the research at home and abroad, there have been many reports on the methods of semi-synthesizing icariin or isopentenyl flavonoids similar in structure to icariin, and the methods for introducing isopentenyl groups are mainly as follows: :

(1) with the coupling reaction of 2-methyl-3-butene-2-ol, the reaction formula is as follows:

Jain, AC et al. (August. J. Chem. 1975, ₂₈ , _607-619 ) used kaempferol as raw material, protected the phenolic hydroxyl group with methyl to obtain compound 1', and then reacted with 2-methyl- Coupling of 3-buten-2-ol to generate 8-prenyl flavone derivatives (compound 2'), 6-prenyl flavone derivatives (compound 3'), 6,8-diprenyl The mixture of flavonoid derivatives (compound 4'), the isolated compound (2') is the icariin derivative. The disadvantage of this method is that the reaction of introducing the isopentenyl group has no regioselectivity, the operation is complicated, and the product separation is difficult.

(2) with the nucleophilic substitution reaction of isopentenyl halide, the reaction formula is as follows:

(J.Chem.Soc., Perkin Trans. 1993, 1, 1153-1159) in the synthesis of licorice flavonoid E, under the action of strong base KOH, the flavonoid derivative (compound 5') is mixed with isotope Pentenyl bromide reacts to generate isopentenyl flavonoid derivatives at 8 and 6 positions, namely compound 6' and compound 7'. This method is similar to the method of Jain, A.C., etc., but its disadvantage is the reaction of introducing isopentenyl. The regioselectivity was poor, and the yield of icariin derivative (compound 6') was low, only 12%.

(3) the rearrangement reaction that isopentenyl participates in, the reaction formula is as follows:

In the early stage, Mei, QG et al. (Beilstein J.Org.Chem.2005, 11, 1220-1225) used kaempferol as raw material to synthesize 5-O-prenyl flavonoid (compound 8′), and then used metal europium Under the catalysis of the complex Eu(fod) ₃ , the Claisen-Cope rearrangement reaction occurs to obtain the 8-position isopentenyl flavonoid (compound 9′). The disadvantage of this method is that the rearrangement reaction produces multiple by-products (such as compound 10′). etc.), the separation operation of the target substance is complicated, and the catalyst is expensive.

The above methods for semi-synthesizing isopentenyl flavonoids and introducing isopentenyl groups generally have disadvantages such as limited raw materials, poor regioselectivity, and low yields. In recent years, the developed lanthanide metal europium or ytterbium complex Eu(fod) ₃ has been used as a catalyst for the rearrangement reaction of isopentenyl groups. Although the reaction yield has been improved to a certain extent, it still cannot improve the reaction regioselectivity. In poorer condition, in addition, rare earth metals are expensive and not suitable for large-scale industrial production.

There are few reports on the total synthesis of icariin, and its synthesis includes two key steps, one is the construction of the flavonoid skeleton, and the other is the selective introduction of the isopentenyl group. Chinese patent CN101205223 proposes a method for the total synthesis of icariin using phloroglucinol as raw material on the basis of summarizing the semi-synthetic method. The flavonol skeleton is constructed by the Baker-Venkataraman rearrangement reaction, and then the Claisen-Cope rearrangement reaction is carried out. Introducing isopentenyl group, 10 steps of reaction, the total yield is 11%, and icariin is obtained by total synthesis. The limitation is that the selectivity of isopentenyl group rearrangement reaction is poor, the synthesis steps are long, the operation is cumbersome, and the cost is relatively high. higher issues.

Similar to the above method, the previous research group Mou Guanmin et al. (Chin.J.Org.Chem.2013, 33, 1298-1303) used phloroglucinol as raw material, through HoubenHoesch reaction, one-pot Algar-Flynn-Oyamada reaction to construct Eight-step reactions including flavonoid skeleton and europium-promoted isopentenyl rearrangement achieved the total synthesis of icariin with a total yield of 4.2%. The disadvantage of this method is that the reaction selectivity of the step of introducing the isopentenyl group in the rearrangement reaction is poor, and the yield is not high.

To sum up, the current semi-synthetic methods of prenyl flavonoids generally have the disadvantages of poor reaction regioselectivity and low yield. Although the total synthesis method of icariin has been reported, the strategy of constructing the flavonol skeleton first and then introducing the isopentenyl group in the existing method cannot avoid the poor solubility of the flavonol and the introduction of the isopentenyl group. The incompatibility of each substrate in the reaction leads to the problem of low yield, and the overall synthesis route is long, the operation is tedious, and the cost is high. In addition, this method adopts the rearrangement reaction to introduce the isopentenyl group, which still does not solve the problem of poor reaction regioselectivity. Therefore, it is of great significance to provide a simple and efficient new method for the total synthesis of icariin.

SUMMARY OF THE INVENTION

The purpose of the present invention is to provide a simple and efficient new method for the total synthesis of icariin and its derivatives.

In order to achieve the above-mentioned purpose of the invention, the technical scheme adopted in the present invention is: a total synthesis method of isopentenyl flavonoids, firstly introducing isopentenyl under the catalysis of organic polybasic acid metal ion complex, and then constructing Flavonoid Skeleton.

Preferably, in the organic polybasic acid metal ion complex, the organic polybasic acid is a C2-C18 dibasic aliphatic carboxylic acid, a C3-C18 tribasic aliphatic carboxylic acid, a C4-C18 quaternary aliphatic carboxylic acid, One or more of C8-C18 polyvalent aromatic carboxylic acids; the metal ions are selected from Mg ²⁺ , Al ³⁺ , Zn ²⁺ , Cu ²⁺ , Ba ²⁺ , Fe ³⁺ , Co ²⁺ , One or more of Ni ²⁺ .

Preferably, the organic polybasic acid metal ion complex is magnesium succinate.

Preferably, the reaction equation that introduces isopentenyl under the catalysis of magnesium succinate is as follows:

Preferably, the isopentenyl flavonoid compound is icariin or a derivative thereof; the icariin or a derivative thereof is obtained from compound 6 by the following reaction equation:

Wherein, P ₁ and P ₂ are both selected from alkyl, alkoxyalkyl, alkylaminoalkyl, silyl ether, thioether, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, aryl , one or more of aromatic heterocyclic group, acyl group, sulfonic acid group, sulfinic acid group and phosphoric acid group; P ₃ is selected from H, alkyl group, alkoxyalkyl group, alkylamino alkyl group, silyl ether group , one or more of thioether group, cycloalkyl group, cycloheteroalkyl group, alkenyl group, alkynyl group, aryl group, aromatic hetero group, acyl group, sulfonic acid group, sulfinic acid group and phosphoric acid group; R ₃ Selected from H, alkyl, alkoxyalkyl, alkylaminoalkyl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, aryl, aromatic heterocyclyl, cyano, halogen, acyl, amido , ester group, sulfonic acid group, sulfonic acid amine group, sulfonic acid ester group, sulfinic acid group, sulfinic acid amine group, sulfinic acid ester group, amino group, amine group, thioether group, nitro group, phosphoric acid amine group , any one of phosphate groups; R ₁ ', R ₂ ', R ₃ ', R ₄ ' are selected from H, alkyl, alkoxyalkyl, alkylaminoalkyl, cycloalkyl, cycloheteroalkane group, alkenyl group, alkynyl group, aryl group, aromatic heterocyclic group, cyano group, halogen, acyl group, amide group, ester group, sulfonic acid group, sulfonic acid amino group, sulfonic acid ester group, sulfinic acid group, sulfinic acid group Any one of acid amine group, sulfinate group, phosphoric acid amine group, phosphoric acid ester group, amino group, amine group, thioether group and nitro group.

Preferably, the compound 6 is obtained from the compounds 4 and 5 by the following reaction equation:

Preferably, the compound 4 is obtained from the compound 3 by the following reaction equation:

Preferably, the total synthesis method of described icariin is:

Correspondingly, a compound synthesized by the total synthesis method of described isopentenyl flavonoids, the structural formula is:

Preferably, the synthetic method of the compound is:

The invention has the following beneficial effects: the method adopts the strategy of first introducing the isopentenyl group and then constructing the flavonoid skeleton, which effectively solves the problem that each substrate is incompatible due to poor solubility in the reaction of introducing the isopentenyl group in the existing method , compared with existing methods, the change of synthesis strategy avoids the steps of frequent introduction and removal of protecting groups, which greatly simplifies the reaction route. In addition, magnesium succinate is used as a catalyst when the isopentenyl group is introduced in this method, and the reaction shows good regioselectivity; when the flavonoid skeleton is constructed, the reaction medium is water or a mixed solvent of alcohol and water, the oxidant is the atmosphere or oxygen, and the green It is environmentally friendly, has good overall yield, is suitable for large-scale industrial production, and solves the problems of lengthy steps and low yield in the existing synthesis method of such compounds.

Detailed ways

The invention provides a method for fully synthesizing icariin and derivatives thereof. The chemical structures of the compounds involved in the following methods are shown in Table 1.

The corresponding structural formula of each compound in Table 1

The specific synthesis reaction formula is as follows:

Specifically include the following steps:

1. Compound 1 is reacted with compound 2 under the catalysis of an organic polybasic acid metal ion complex to generate compound 3.

Wherein, R ₃ of the compound 1 is selected from H, alkyl, alkoxyalkyl, alkylaminoalkyl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, aryl, aromatic heterocyclyl, cyano group, halogen, acyl group, amide group, ester group, sulfonic acid group, sulfonic acid amine group, sulfonic acid ester group, sulfinic acid group, sulfinic acid amine group, sulfinic acid ester group, amino group, amine group, sulfur Any one of ether group, nitro group, phosphoric acid amine group and phosphoric acid ester group, preferably, R ₃ is selected from H. Compound 1 can be obtained directly from the market, or can be synthesized by using phloroglucinol as a raw material and acetonitrile as an acetyl donor under the action of Lewis acid and hydrogen halide gas. The Lewis acid is selected from one or more of zinc salts, iron salts, copper salts, magnesium salts, and aluminum salts. A preferred solution is that the Lewis acid is selected from zinc chloride.

X of the compound 2 is selected from one or more of chlorine, bromine, iodine, mesylate, p-toluenesulfonate, and trifluoromethanesulfonate; preferably, X is selected from isopentane One or more of alkenyl chloride, isopentenyl bromide and isopentenyl iodide.

The preparation method of the organic polybasic acid metal ion complex is as follows: adding metal hydroxide and organic polybasic acid into water to react. Wherein, the organic polybasic acid is selected from C2 _{- C18} dibasic aliphatic carboxylic acid, C3 _{- C18} tribasic aliphatic carboxylic acid, _C4 - _{C18 tetrabasic} aliphatic carboxylic acid, C8- _C18 aliphatic carboxylic acid polyaromatic carboxylic acid. Preferably, the organic polybasic acid is selected from one or more of malonic acid, succinic acid and glutaric acid.

The metal ions are selected from one or more of Mg ²⁺ , Al ³⁺ , Zn ²⁺ , Cu ²⁺ , Ba ²⁺ , Fe ³⁺ , Co ²⁺ , and Ni ²⁺ . Preferably, the metal ions are selected from one or more of Mg ²⁺ , Al ³⁺ , and Zn ² .

2. The compound 3 is selectively protected at the 4- and 6-position phenolic hydroxyl groups to generate compound 4. The compound 4 is reacted with compound 5 in a one-pot reaction to generate compound 6.

The protective agents P ₁ and P ₂ of the phenolic hydroxyl group of the compound 4 are all selected from alkyl, alkoxyalkyl, alkylaminoalkyl, silyl ether, thioether, cycloalkyl, cycloheteroalkyl, One or more of alkenyl group, alkynyl group, aryl group, aromatic heterocyclic group, acyl group, sulfonic acid group, sulfinic acid group and phosphoric acid group. Preferably, P ₁ and P ₂ are selected from methoxymethyl, ethoxyethyl, 2-methoxyethoxymethyl, tetrahydropyran, benzyl, p-methoxybenzyl, acetyl , one or more of trifluoroacetyl and benzoyl.

R ₁ ', R ₂ ', R ₃ ', R ₄ ' in the compound 5 are selected from H, alkyl, alkoxyalkyl, alkylaminoalkyl, cycloalkyl, cycloheteroalkyl, alkenyl , alkynyl group, aryl group, aromatic heterocyclic group, cyano group, halogen group, acyl group, amide group, ester group, sulfonic acid group, sulfonic acid amino group, sulfonic acid ester group, sulfinic acid group, sulfinic acid amino group, Any of a sulfinate group, a phosphoric acid amine group, a phosphoric acid ester group, an amino group, an amine group, a thioether group, and a nitro group. Preferably, R ₁ ', R ₂ ', R ₃ ', R ₄ ' are selected from H; P ₃ is selected from H, alkyl, alkoxyalkyl, alkylaminoalkyl, silyl ether, thioether, One or more of cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, sulfonic acid, sulfinic, and phosphoric acid groups. Preferably, P ₃ is selected from alkyl.

P ₁ , P ₂ , R ₁ ′, R ₂ ′, R ₃ ′, R ₄ ′ and P ₃ in the compound 6 are the same as those in the compounds 4 and 5.

3. The compound 6 is further protected, and the desired icariin or its derivative, namely compound 7, is produced by the reaction. It should be understood that Compound 7 in Table 1 is a typical representative of icariin derivatives, and it is only an example in Table 1, and it is not limited that Compound 7 can only have the structure in Table 1.

In this step reaction, the reaction solvent is selected from one or more of water, alcohols, carboxylic acids, ethers, esters, ketones, cyanogens, and chlorine-containing solvents. Preferably, the reaction solvent is selected from one or more of water and alcohols. During the reaction in this step, a deprotection agent needs to be added, and the deprotection agent is selected from dealkylated ether protection agents. Preferably, the dealkylated ether protective agent is selected from protonic acid or Lewis acid. More preferably, the dealkylated ether protective agent is selected from one or more of hydrochloric acid and trifluoroacetic acid.

The present invention will be further explained below with reference to the examples of generating icariin.

Example

It should be noted that this example involves more compounds with complex structures. For the convenience of presentation, the form of "compound + Roman numerals" is used to represent a certain compound, for example: 2,4,6-trihydroxy-3 -Prenylacetophenone, which is compound ii.

The reaction equation for the total synthesis of icariin is as follows:

The compounds corresponding to each abbreviation are: (1) DMF: N,N-dimethylformamide; (2) MOMCl: chloromethyl methyl ether; (3) DIPEA: N,N-diisopropylethylamine.

The specific steps for the total synthesis of icariin are as follows:

1. Synthesis of magnesium succinate

At room temperature, the compound magnesium hydroxide (1.0 g, 17.2 mmol) and deionized water (20 mL) were added to the reaction flask, the temperature was raised to 100 ° C and stirred for 30 min, and 5 mL of succinic acid aqueous solution (3.4 mol/mL) was added to the above reaction solution. L), after adding, continue stirring at 100 °C for 1 h until the solid is completely dissolved, cool the reaction solution to room temperature, and concentrate the solvent to dryness to obtain a white solid, which is magnesium succinate (2.63 g), with a yield of 99.5%. The reaction formula is as follows:

2. Synthesis of 2,4,6-trihydroxy-3-isopentenylacetophenone (II)

The reaction equation for this step is as follows:

At room temperature, compound 2,4,6-trihydroxyacetophenone monohydrate (1.0 g, 5.37 mmol) was dissolved in 5 mL of dry DMF, followed by adding magnesium succinate (0.75 g, 5.37 mmol), Prenyl chloride (0.56 g, 5.37 mmol), potassium iodide (90 mg, 0.54 mmol). After the addition was completed, under the protection of argon, the temperature was raised to 40 °C and the reaction was stirred for 16 h. The reaction was performed until the TLC monitored the disappearance of the raw materials. The reaction solution was cooled to room temperature, and then poured into ice water to quench the reaction, extracted with 3×10 mL of ethyl acetate, and combined. The organic phase was successively washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The organic phase was concentrated under reduced pressure to dryness, and then subjected to silica gel column chromatography [V(petroleum ether):V(ethyl acetate)=6:1 ] was purified to obtain compound II as a white solid with a mass of 0.82 g and a yield of 65%. The H NMR and C NMR data are as follows:

¹ H NMR (400MHz, DMSO-d ₆ )δ14.01(s,1H), 10.52(s,1H), 10.29(s,1H), 6.00(s,1H), 5.23-5.03(m,1H), 3.08(d, J=7.1Hz, 2H), 2.56(s, 3H), 1.69(s, 3H), 1.61(s, 3H). ¹³ C NMR(101MHz, DMSO-d ₆ )δ202.94,163.63,162.83, 160.62, 130.01, 123.81, 106.14, 104.31, 94.45, 32.89, 25.95, 21.35, 18.09.m/z=237.1[M+H] ⁺ .

3. Synthesis of 2-hydroxy-3-prenyl-4,6-bis(methoxymethoxy)-acetophenone (ⅲ)

The reaction equation for this step is as follows:

Under an ice-water bath, compound ii (0.5 g, 2.11 mmol) was added to 5 mL of dry acetone, and N,N-diisopropylethylamine (0.82 g, 6.33 mmol) was added dropwise. After the addition was completed, the reaction was stirred for 10 min, and then chloromethyl methyl ether (0.51 g, 6.33 mmol) was added. After the addition was completed, the temperature was raised to 60° C. under the protection of argon, and the reaction was refluxed for 2 h. The reaction was performed until TLC monitored the disappearance of the raw materials. The reaction solution was then cooled to room temperature, poured into ice water to quench the reaction, and extracted with 3×10 mL of ethyl acetate. The organic phases were combined, washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated under reduced pressure to dryness, and then subjected to silica gel column chromatography [V(petroleum ether):V(ethyl acetate)=10: 1] Purified compound iii as yellow oil. The mass was 0.64 g, and the yield was 93%. The H NMR and C NMR data are as follows:

¹ H NMR (400MHz, DMSO-d ₆ )δ13.87(s, 1H), 6.37(s, 1H), 5.32(s, 2H), 5.30(s, 2H), 5.11(t, J=7.0Hz, 1H), 3.45(s, 3H), 3.40(s, 3H), 3.19(d, J=7.0Hz, 3H), 2.64(s, 3H), 1.72(s, 3H), 1.61(s, 3H). ¹³ C NMR (101MHz, DMSO-d ₆ )δ204.08,162.85,160.88,158.99,130.95,122.90,110.47,106.62,94.97,94.13,91.97,56.96,56.49,33.44,25.94,21.354,28=. [M+H] ⁺ .

4. Synthesis of 5,7-dimethoxymethyl-icariin (IV)

The reaction equation for this step is as follows:

At room temperature, compound iii (0.6 g, 1.85 mmol), 4-methoxybenzaldehyde (0.27 g, 1.95 mmol), MeOH (3 mL) and H ₂ O (9 mL) were added to a reaction flask, followed by pyrrole alkane (1.5 mL, 18.5 mmol). After the addition was completed, the temperature was raised to 50°C, and the reaction was stirred openly for 16 h. The reaction was performed until the TLC monitored the disappearance of the raw materials. The reaction solution was cooled to room temperature and poured into ice water to quench the reaction. Adjust pH=4.0 with 1N hydrochloric acid, extract with 3×10 mL of dichloromethane, combine the organic phases, wash with saturated sodium chloride solution in turn, dry with anhydrous sodium sulfate, concentrate the organic phase under reduced pressure to dryness, and then pass through a silica gel column layer. Analysis [V (petroleum ether): V (acetone) = 5: 1] was purified to obtain yellow oily compound IV, the mass was 0.48 g, and the yield was 57%. The H NMR and C NMR data are as follows:

¹ H NMR (400 MHz, CDCl ₃ ) δ 8.22 (d, J=9.0 Hz, 2H), 7.06 (d, J=8.9 Hz, 2H), 6.95 (s, 1H), 5.39 (s, 2H), 5.32 (s, 2H), 5.26(dd, J=13.2, 6.4Hz, 1H), 3.92(s, 3H), 3.65(d, J=6.7Hz, 2H), 3.60(s, 3H), 3.53(s, 3H), 1.86(s, 3H), 1.71(s, 3H). ¹³ C NMR (101MHz, CDCl ₃ )δ172.31, 161.73, 158.64, 155.92, 147.51, 145.66, 137.22, 137.14, 132.28, 129.05, 122.05, 114. 112.30, 111.52, 98.69, 95.76, 94.45, 56.65, 56.47, 55.41, 25.77, 22.24, 18.05.m/z=457.2[M+H] ⁺ ..

5. Synthetic icariin

The reaction equation for this step is as follows:

At room temperature, compound IV (0.6 g, 1.32 mmol), methanol (15 mL) and hydrochloric acid (3 mol/L, 5 mL) were added to the reaction flask. After TLC monitoring of the disappearance of the raw materials, the reaction solution was cooled to room temperature, concentrated under reduced pressure to remove methanol, the crude product was filtered and washed with water, and dried to obtain a yellow solid compound 7 with a mass of 0.46 g and a yield of 95%. The H NMR and C NMR data of the compound 7 are as follows:

¹ H NMR (400MHz, DMSO-d ₆ ) δ 12.39(s, 1H), 10.77(s, 1H), 9.51(s, 1H), 8.14(d, J=8.8Hz, 2H), 7.14(d, J=8.8Hz, 2H), 6.31(s, 1H), 5.19(t, J=6.2Hz, 1H), 3.86(s, 3H), 3.44(d, J=7.0Hz, 2H), 1.76(s, 2H),1.64(s,3H).m/z=369.1[M+H] ⁺ .

The above-mentioned H NMR and C NMR data are consistent with the data of icariin, so far, the desired icariin is produced by the reaction.

Claims (10)

1. A full synthesis method of isopentene flavonoid compounds is characterized in that: isopentene group is introduced under the catalytic action of organic polyacid metal ion complex, and then a flavone skeleton is constructed.

2. The total synthesis method of isopentenyl flavonoid compound according to claim 1, characterized in that: in the organic polybasic acid metal ion complex, the organic polybasic acid is one or more of C2-C18 dibasic aliphatic carboxylic acid, C3-C18 tribasic aliphatic carboxylic acid, C4-C18 tetrabasic aliphatic carboxylic acid and C8-C18 polybasic aromatic carboxylic acid; the metal ion is selected from Mg²⁺、Al³⁺、Zn²⁺、Cu²⁺、Ba²⁺、Fe³⁺、Co²⁺、Ni²⁺One or more of (a).

3. The total synthesis method of isopentenyl flavonoids according to claim 1, which is characterized in that: the organic polyacid metal ion complex is magnesium succinate.

4. The total synthesis method of isopentenyl flavonoids according to claim 3, which is characterized in that: the reaction equation for introducing isopentene under catalysis of magnesium succinate is as follows:

the R is₃Selected from H, alkyl, alkoxyalkyl, alkylaminoalkyl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, aryl, arylheterocyclyl, cyano, halogen, acyl, amido, ester, sulfonic acid amido, sulfonic acid, and the likeAny one of an ester group, a sulfinic acid amine group, a sulfinic acid ester group, an amino group, an amine group, a thioether group, a nitro group, an amine phosphate group and a phosphate ester group.

5. The total synthesis method of isopentenyl flavonoids according to any one of claims 1 to 4, wherein the total synthesis method comprises the following steps: the isopentene flavonoid compound is icaritin or a derivative thereof; the icaritin or the derivative thereof is obtained from the compound 6 through the following reaction equation:

wherein, P₁、P₂All selected from one or more of alkyl, alkoxyalkyl, alkylamino alkyl, silicon ether, thioether, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, aryl, aromatic heterocyclic group, acyl, sulfonic group, sulfinic group and phosphoric group; p₃One or more selected from H, alkyl, alkoxy alkyl, alkyl amino alkyl, silicon ether, thioether group, naphthenic group, cycloheteroalkyl, alkenyl, alkynyl, aryl, heteroaryl, acyl, sulfonic group, sulfinic group and phosphoric group; the R is₃Any one selected from H, alkyl, alkoxyalkyl, alkylaminoalkyl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, aryl, aromatic heterocyclic group, cyano, halogen, acyl, amide group, ester group, sulfonic acid amino group, sulfonic ester group, sulfinic acid amino group, sulfinic ester group, amino group, thioether group, nitro group, phosphoric acid amino group and phosphoric ester group; r₁′、R₂′、R₃′、R₄' is any one selected from the group consisting of H, alkyl, alkoxyalkyl, alkylaminoalkyl, cycloalkyl, cycloheteroalkyl, alkenyl, alkynyl, aryl, arylheterocyclyl, cyano, halogen, acyl, amide, ester, sulfonic acid amine, sulfonic acid ester, sulfinic acid amine, sulfinic acid ester, phosphoric acid amine, phosphoric acid ester, amino, amine, thioether, and nitro.

6. The total synthesis method of isopentenyl flavonoids according to claim 5, which is characterized in that: the compound 6 is obtained from the compounds 4 and 5 through the following reaction equation:

7. the total synthesis method of isopentenyl flavonoids according to claim 6, which comprises the following steps: the compound 4 is obtained from the compound 3 by the following reaction equation:

8. the total synthesis method of isopentenyl flavonoids according to any one of claims 5 to 7, which comprises the following steps: the total synthesis method of the icaritin comprises the following steps:

9. a compound synthesized by the total synthesis method of the isopentenyl flavonoid compound disclosed by claim 8, which is characterized in that: the structural formula is as follows:

10. the compound synthesized by the total synthesis method of isopentenyl flavonoid compound according to claim 9, wherein: the synthesis method of the compound comprises the following steps: