CN110684003A - Simple and efficient total synthesis method of icaritin and derivatives thereof - Google Patents
Simple and efficient total synthesis method of icaritin and derivatives thereof Download PDFInfo
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Abstract
The invention belongs to the field of natural medicine synthesis, and particularly relates to a total synthesis method of icaritin and derivatives thereof. The specific technical scheme is as follows: 2' -hydroxyacetophenone and benzaldehyde are used as raw materials, isopentenyl is introduced to an aromatic ring of the raw materials under the catalysis of an organic polyacid metal ion complex, and a flavonol skeleton is constructed under mild and green conditions, so that isopentenyl flavonoid compounds including icaritin and derivatives thereof are synthesized. The method effectively overcomes the limitations of poor substrate solubility, poor regioselectivity and the like when the flavone is constructed firstly and the isopentenyl group is introduced later, avoids the problem that the conventional isopentenyl group conversion method needs to introduce and remove a protecting group frequently, and greatly simplifies the synthetic route; meanwhile, the problems of complex products and more byproducts in the isopentenyl rearrangement method are avoided. The total synthesis method provided by the invention has the advantages of mild conditions, simple and convenient operation and high overall yield, and is suitable for large-scale production of the isopentenyl flavonoid compound.
Description
Technical Field
The invention belongs to the field of natural medicine synthesis, and particularly relates to a simple and efficient total synthesis method of icaritin.
Background
Icaritin is aglycon of icariin, and icariin is a flavonoid derivative in epimedium of berberidaceae. Traditional Chinese medicine considers that epimedium plants have obvious effects of reducing blood pressure, tonifying kidney and strengthening yang, and are widely used for treating cardiovascular diseases, amnesia, arthritis, hypodynamia, impotence, infertility and other diseases. The molecular structural formula of the icaritin is as follows:
since the extraction, separation and structural identification of icariin and noricariin in 1935, research on the pharmacological activity of icariin and its glycoside derivatives has been greatly advanced. In recent years, medical science researches show that icaritin has high anti-liver cancer activity in vitro and in vivo, can inhibit malignant growth of liver cancer cell initiator cells by inhibiting sphingosine kinase I (Lu, P.H.etc. oncotarget,2017,8, 22800-. However, icaritin is used as the mother nucleus of icariin, the content of the icariin in the plant epimedium is extremely low, and the icariin is generally extracted and separated firstly, and then the glycosidic bond is hydrolyzed by glycosidase to obtain the corresponding aglycone. Chinese patents CN1473938, CN101302548, CN107641621 and US6399579 respectively report methods for preparing icariin by enzymatic hydrolysis, and the methods for obtaining icariin are complex in operation and high in cost. The direct synthesis of icaritin by chemical method is a simple and effective way.
Icaritin is a flavonoid compound containing isopentenyl, and a semisynthesis method for obtaining icaritin by taking kaempferol or a flavone derivative as a raw material through introducing isopentenyl or a total synthesis method for obtaining icaritin by taking a phloroglucinol derivative as a raw material through constructing a flavone skeleton and introducing isopentenyl are two main methods used for chemically synthesizing icaritin at present. The key step of the semi-synthesis method is to selectively introduce isopentenyl into the 8-position of the flavone skeleton. In the research at home and abroad, more reports have been made on methods for semi-synthesizing icaritin or isopentenyl flavonoid compounds with similar structures with the icaritin, and the methods for introducing isopentenyl are mainly as follows:
(1) coupling reaction with 2-methyl-3-buten-2-ol according to the following reaction formula:
jain, A.C. et al (August. J. chem.1975,28, 607-S619) used kaempferol as a raw material to obtain a compound 1' by protecting phenolic hydroxyl group with methyl group, and then BF3.Et2The O-catalyzed coupling with 2-methyl-3-butene-2-ol generates a mixture of 8-isopentenyl flavone derivatives (compound 2 '), 6-isopentenyl flavone derivatives (compound 3'), and 6, 8-diisopentenyl flavone derivatives (compound 4 '), and the separated compound (2') is the icaritin derivative.
(2) Nucleophilic substitution reaction with isopentenyl halide, the reaction formula is as follows:
lu, Z. et al (J.chem.Soc., Perkin Trans.1993,1,1153-1159) in the synthesis of licoflavone E, a flavone derivative (compound 5 ') is reacted with isopentenyl bromide under the action of strong base KOH to generate isopentenyl flavone derivatives at the 8-and 6-positions, i.e., compound 6' and compound 7 ', which is similar to the method of Jain, A.C. et al, and has disadvantages of poor regioselectivity of the reaction for introducing isopentenyl group, and low yield of icaritin derivative (compound 6'), which is only 12%.
(3) The rearrangement reaction in which isopentene group participates has the following reaction formula:
in the previous research group Mei, Q.G., et al (Beilstein J.org.chem.2005,11,1220-Compound 8'), followed by reaction with a europium metal complex Eu (fod)3The 8-site isopentenyl flavone (compound 9 ') is obtained by a Claisen-Cope rearrangement reaction under catalysis, and the method has the defects that a plurality of byproducts (such as compound 10' and the like) are generated by the rearrangement reaction, the separation operation of the target product is complex, and the catalyst is expensive.
The method for introducing isopentenyl into the semi-synthetic isopentenyl flavonoid compound generally has the defects of limited raw materials, poor regioselectivity, lower yield and the like. Recently, developed lanthanide europium or ytterbium complexes Eu (fod)3The catalyst is applied to the rearrangement reaction of isopentene group, although the reaction yield is improved to a certain extent, the condition of poor reaction area selectivity cannot be improved, and in addition, the rare earth metal is expensive and is not suitable for large-scale industrial production.
The method for completely synthesizing the icaritin has few reports, and the synthesis comprises two key steps, namely the construction of a flavone skeleton and the selective introduction of isopentenyl. Chinese patent CN101205223 proposes a method for fully synthesizing icaritin by using phloroglucinol as a raw material on the basis of summarizing a semi-synthesis method, wherein a flavonol skeleton is constructed through Baker-Venkataraman rearrangement reaction, then isopentenyl is introduced through Claisen-Cope rearrangement reaction, 10 steps of reaction are carried out, the total yield is 11%, the icaritin is obtained through full synthesis, and the method has the limitations that the isopentenyl rearrangement reaction selectivity is poor, the synthesis steps are long, the operation is complex, the cost is high, and the like.
Similar to the above method, the previous research group, the inventor, the. The method has the disadvantages that the step of introducing isopentene group in the rearrangement reaction has poor reaction selectivity and low yield.
In summary, the existing semi-synthesis method of the isopentenyl flavonoid compound generally has the defects of poor reaction regioselectivity and low yield. Although the total synthesis method of icaritin has been reported, the existing method adopts a strategy of firstly constructing a flavonol skeleton and then introducing isopentenyl, so that the problem of low yield caused by incompatibility of various substrates in the reaction of introducing the isopentenyl due to poor solubility of the flavonol can not be avoided, and the overall synthesis route is long, the operation is tedious and the cost is high. In addition, the method adopts rearrangement reaction to introduce isopentene group, and still does not solve the problem of poor selectivity of reaction region. Therefore, the novel simple and efficient total synthesis method of icaritin is of great significance.
Disclosure of Invention
The invention aims to provide a novel, simple and efficient total synthesis method of icaritin and derivatives thereof.
In order to achieve the purpose of the invention, the technical scheme adopted by the invention is as follows: a full synthesis method of isopentenyl flavonoid compounds comprises the steps of introducing isopentenyl under the catalytic action of an organic polyacid metal ion complex and then constructing a flavone skeleton.
Preferably, in the organic polyacid metal ion complex, the organic polyacid is one or more of a dibasic aliphatic carboxylic acid with C2-C18, a tribasic aliphatic carboxylic acid with C3-C18, a tetrabasic aliphatic carboxylic acid with C4-C18 and a polybasic aromatic carboxylic acid with C8-C18; the metal ion is selected from Mg2+、Al3+、Zn2+、Cu2+、Ba2+、Fe3+、Co2+、Ni2+One or more of (a).
Preferably, the organic polyacid metal ion complex is magnesium succinate.
Preferably, the reaction equation for introducing isopentene group under catalysis of magnesium succinate is as follows:
preferably, 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; r3Any 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.
Preferably, the compound 6 is obtained from the compounds 4 and 5 through 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 the icaritin comprises the following steps:
correspondingly, the compound synthesized by the total synthesis method of the isopentenyl flavonoid compound has the structural formula:
preferably, the synthesis method of the compound comprises the following steps:
the invention has the following beneficial effects: the method adopts a strategy of introducing the isopentenyl group first and then constructing the flavone skeleton, effectively solves the problem that substrates are incompatible due to poor solubility in the reaction of introducing the isopentenyl group in the existing method, and compared with the existing method, the change of the synthesis strategy avoids the steps of frequent introduction and removal of protecting groups, thereby greatly simplifying the reaction route. In addition, magnesium succinate is used as a catalyst when isopentene is introduced, and the reaction shows better regioselectivity; when the flavone skeleton is constructed, the reaction medium is water or an alcohol-water mixed solvent, the oxidant is air or oxygen, the method is green and environment-friendly, the total yield is good, the method is suitable for large-scale industrial production, and the problems of long steps and low yield of the existing synthetic method of the compounds are solved.
Detailed Description
The invention provides a method for fully synthesizing icaritin and derivatives thereof. The chemical structural formulas of the compounds involved in the following methods are shown in table 1.
TABLE 1 structural formulas corresponding to the respective compounds
The specific synthetic reaction formula is as follows:
the method specifically comprises the following steps:
1. reacting the compound 1 with the compound 2 under the catalysis of an organic polyacid metal ion complex to generate a compound 3.
Wherein R of the compound 13Any 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 ester, sulfinic acid amine, sulfinic ester, amino, amine, thioether, nitro, phosphoric acid amine, and phosphoric ester, preferably, R is selected from the group consisting of3Is selected from H. The compound 1 can be directly obtained from the market, and can also be synthesized by taking 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 salt, iron salt, copper salt, magnesium salt and aluminum salt, and the preferred scheme 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 one or more of isopentenyl chloride, isopentenyl bromide and isopentenyl iodide.
The preparation method of the organic polyacid metal ion complex comprises the following steps: adding metal hydroxide and organic polybasic acid into water to react to obtain the catalyst. Wherein, theC is selected from organic polybasic acid2～C18Of a dicarboxylic acid, C3～C18Of a tri-aliphatic carboxylic acid, C4～C18Tetra-aliphatic carboxylic acid of (2), C8～C18The polybasic aromatic carboxylic acid of (4). Preferably, the organic polybasic acid is selected from one or more of malonic acid, succinic acid and glutaric acid.
The metal ion is selected from Mg2+、Al3+、Zn2+、Cu2+、Ba2+、Fe3+、Co2+、Ni2+One or more of them. Preferably, the metal ion is selected from Mg2+、Al3+、Zn2One or more of them.
2. And selectively protecting the 4 and 6 phenolic hydroxyl groups of the compound 3 to generate a compound 4. And carrying out one-pot reaction on the compound 4 and the compound 5 to generate a compound 6.
A protective agent P for the phenolic hydroxyl group of said compound 41、P2Are selected from one or more of alkyl, alkoxyalkyl, alkylamino alkyl, silicon ether, thioether, naphthenic base, cycloheteroalkyl, alkenyl, alkynyl, aryl, aromatic heterocyclic group, acyl, sulfonic group, sulfinic group and phosphoric group. Preferably, P is1、P2Is selected from one or more of methoxymethyl, ethoxyethyl, 2-methoxyethoxymethyl, tetrahydropyran, benzyl, p-methoxybenzyl, acetyl, trifluoroacetyl and benzoyl.
R in said Compound 51′、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. Preferably, R1′、R2′、R3′、R4' is selected from H; p3Selected from H, alkyl, alkoxyalkyl, alkylaminoalkyl, siliconOne or more of ether group, thioether group, naphthenic group, cycloheteroalkyl group, alkenyl group, alkynyl group, aryl group, heteroaryl group, acyl group, sulfonic group, sulfinic acid group and phosphoric group. Preferably, P is3Selected from alkyl groups.
P in said Compound 61、P2、R1′、R2′、R3′、R4′、P3Same as in compounds 4, 5.
3. The compound 6 is further protected and reacted to produce the desired icaritin or its derivative, compound 7. It should be understood that compound 7 in table 1 is representative of icaritin derivatives, and is shown as an example in table 1, and compound 7 is not limited to the structure in table 1.
In the reaction, the reaction solvent is one or more selected from water, alcohols, carboxylic acids, ethers, esters, ketones, cyanides and chlorine-containing solvents. Preferably, the reaction solvent is one or more of water and alcohols. During the reaction, a deprotection agent is required to be added, and the deprotection agent is selected from dealkylation ether type protection agents. Preferably, the dealkylation ether type protecting agent is selected from protonic acid or Lewis acid. More preferably, the dealkylation ether protective agent is selected from one or more of hydrochloric acid and trifluoroacetic acid.
The present invention will be further explained with reference to examples below, taking the production of icaritin as an example.
Examples
It should be noted that in this embodiment, more complex compounds are involved, and for convenience of illustration, the form of "compound + roman numeral" is used to represent a compound, for example: 2,4, 6-trihydroxy-3-isopentenyl acetophenone, namely a compound ii.
The reaction equation of the total synthesis of icaritin 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 of the total synthesis of the icaritin are as follows:
1. synthesis of magnesium succinate
Adding a compound magnesium hydroxide (1.0g, 17.2mmol) and deionized water (20mL) into a reaction bottle at room temperature, heating to 100 ℃, stirring for 30min, adding 5mL succinic acid aqueous solution (3.4mol/L) into the reaction solution, continuing stirring at 100 ℃ for reaction for 1h after the addition is finished, cooling the reaction solution to room temperature, and concentrating the solvent to dryness to obtain a white solid, namely magnesium succinate (2.63g), wherein the yield is 99.5%. The reaction formula is shown as follows:
2. synthesis of 2,4, 6-trihydroxy-3-isopentenylacetophenone (ii)
The reaction equation in this step is as follows:
compound 2,4, 6-trihydroxyacetophenone monohydrate (1.0g, 5.37mmol) was dissolved in 5mL of dry DMF at room temperature, followed by the sequential addition of magnesium succinate (0.75g, 5.37mmol), isopentenyl chloride (0.56g, 5.37mmol), and potassium iodide (90mg, 0.54 mmol). After the addition, heating to 40 ℃ under the protection of argon, stirring for reaction for 16h, reacting until TLC monitors that raw materials disappear, cooling the reaction liquid to room temperature, pouring the reaction liquid into ice water to quench the reaction, extracting by using 3X 10mL ethyl acetate, combining organic phases, washing by using a saturated sodium chloride solution, drying by using anhydrous sodium sulfate, concentrating the organic phase under reduced pressure to dryness, and performing silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 6:1] purification gave compound ii as a white solid, with a mass of 0.82g and a yield of 65%. The nmr hydrogen and carbon spectra data are as follows:
1H NMR(400MHz,DMSO-d6)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).13C NMR(101MHz,DMSO-d6)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-isopentenyl-4, 6-bis (methoxymethoxy) -acetophenone (iii)
The reaction equation in this step is as follows:
compound ii (0.5g, 2.11mmol) was added to 5mL of dry acetone in an ice-water bath and N, N-diisopropylethylamine (0.82g, 6.33mmol) was added dropwise. After the addition, stirring and reacting for 10min, adding chloromethyl methyl ether (0.51g, 6.33mmol), heating to 60 ℃ under the protection of argon after the addition, refluxing and reacting for 2h until TLC monitors that the raw material disappears. The reaction was then cooled to room temperature, quenched into ice-water and extracted with 3X 10mL of ethyl acetate. The organic phases were combined and washed once with saturated sodium chloride solution, dried over anhydrous sodium sulfate, concentrated to dryness under reduced pressure and subjected to silica gel column chromatography [ V (petroleum ether): v (ethyl acetate) ═ 10:1] purified to give compound iii as a yellow oil. The mass was 0.64g, and the yield was 93%. The nmr hydrogen and carbon spectra data are as follows:
1H NMR(400MHz,DMSO-d6)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).13C NMR(101MHz,DMSO-d6)δ204.08,162.85,160.88,158.99,130.95,122.90,110.47,106.62,94.97,94.13,91.97,56.96,56.49,33.44,25.94,21.54,18.07.m/z＝325.2[M+H]+.
4. synthesis of 5, 7-dimethoxymethyl-icaritin (iv)
The reaction equation in this step is as follows:
compound iii (0.6g, 1.85 mm) was added under ambient temperatureol), 4-methoxybenzaldehyde (0.27g, 1.95mmol), MeOH (3mL) and H2O (9mL) was added to the reaction flask followed by pyrrolidine (1.5mL, 18.5 mmol). After the addition, the temperature is raised to 50 ℃, the reaction is carried out for 16h by open stirring, the reaction is carried out until the TLC monitors that the raw materials disappear, the reaction liquid is cooled to room temperature, and the reaction liquid is poured into ice water to quench the reaction. The pH was adjusted to 4.0 with 1N hydrochloric acid, extraction was performed using 3 × 10mL of dichloromethane, the organic phases were combined and washed successively with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the organic phase was concentrated to dryness under reduced pressure, and then subjected to silica gel column chromatography [ V (petroleum ether): v (acetone) ═ 5:1]Purification gave compound iv as a yellow oil in a mass of 0.48g and a yield of 57%. The nmr hydrogen and carbon spectra data are as follows:
1H NMR(400MHz,CDCl3)δ8.22(d,J＝9.0Hz,2H),7.06(d,J＝8.9Hz,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).13C NMR(101MHz,CDCl3)δ172.31,161.73,158.64,155.92,147.51,145.66,137.22,137.14,132.28,129.05,122.05,114.07,112.30,111.52,98.69,95.76,94.45,56.65,56.47,55.41,25.77,22.24,18.05.m/z＝457.2[M+H]+.。
5. synthesis of icaritin
The reaction equation in this step is as follows:
adding a compound iv (0.6g, 1.32mmol), methanol (15mL) and hydrochloric acid (3mol/L, 5mL) into a reaction bottle at room temperature, heating to 65 ℃ under the protection of argon, carrying out reflux reaction for 1h, reacting until a TLC (thin layer chromatography) monitoring raw material disappears, cooling the reaction liquid to room temperature, carrying out reduced pressure concentration to remove the methanol, filtering and washing a crude product, and drying to obtain a yellow solid compound 7 with the mass of 0.46g and the yield of 95%. The nmr hydrogen and carbon spectra data for compound 7 are as follows:
1H NMR(400MHz,DMSO-d6)δ12.39(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 nuclear magnetic resonance hydrogen spectrum data and the carbon spectrum data are consistent with the data of the icaritin, so that the required icaritin is generated through 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:
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