A preparation method of 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenyl coumarin

Abstract

The present invention relates to a preparation method of 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenyl coumarin. The preparation method includes: using 2,4,6-trihydroxybenzaldehyde as the starting material, through alkylation, protection group introduction, methylation reaction, and deprotection group reaction to generate 4,6-dihydroxy-2-methoxy-3-allylbenzaldehyde; then carrying out a condensation reaction with 2,4-dihydroxyphenylacetic acid in acetic anhydride solvent to obtain 7,3(2’,4’)-trioxo-substituted-5-methoxy-6-allyl coumarin; subsequently carrying out olefin metathesis with an olefin to obtain 7,3(2’,4’)-trioxo-substituted-5-methoxy-6-isopentenyl coumarin; and finally obtaining 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenyl coumarin through deacetylation reaction.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic chemical synthesis, and particularly relates to a preparation method of 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenylcoumarin. Background Art

[0002] 7,3(2’,4’)-Trihydroxy-5-methoxy-6-isopentenylcoumarin, also known as Glycycoumarin (GCM), belongs to 3-arylcoumarin compounds. It was first reported as a natural product mainly existing in licorice in 1986, and its molecular structure is shown in Formula -1 below. As the most representative bioactive coumarin compound in licorice, Glycycoumarin has various biological activities such as antiviral activity, antibacterial activity, antispasmodic activity, antioxidant and anti-inflammatory activity, liver protection activity, and anticancer activity. It is an important natural product, drug active molecule, and drug lead compound. The existing research on 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenylcoumarin mainly focuses on its biological activity-related aspects, and there is no relevant report on its synthesis method.

[0003]

[0004] As an important class of natural products, 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenylcoumarin is mainly obtained by extraction from plants such as licorice. The extraction yield is relatively low, only 0.023% (w / w), which is not conducive to industrial implementation. Moreover, excessive exploitation of natural resources is likely to cause vegetation damage and environmental pollution, restricting its further application research in biomedicine, cosmetics, food, and luminescent materials, etc. Summary of the Invention

[0005] In view of the above problems, the present invention aims to provide a new chemical synthesis method of 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenylcoumarin.

[0006] Specifically, the present invention provides a preparation method of 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenylcoumarin, and the preparation method includes the following steps:

[0007] (1) 2,4,6-Trihydroxybenzaldehyde (Formula -2) reacts with 3-bromopropene in Base 1 to undergo an alkylation reaction to obtain 3-allyl-2,4,6-trihydroxybenzaldehyde (Formula -3);

[0008]

[0009] (2) 3 - allyl - 2,4,6 - trihydroxybenzaldehyde (Formula - 3) reacts with bromomethyl methyl ether in base 2 to undergo methyl methoxylation to protect the groups, yielding 3 - allyl - 2 - hydroxy - 4,6 - bis(methoxymethoxy)benzaldehyde (Formula - 4);

[0010]

[0011] (3) 3 - allyl - 2 - hydroxy - 4,6 - bis(methoxymethoxy)benzaldehyde (Formula - 4) reacts with a methylation reagent in base 3 to undergo methylation, yielding 3 - allyl - 2 - methoxy - 4,6 - bis(methoxymethoxy)benzaldehyde (Formula - 5);

[0012]

[0013] (4) 3 - allyl - 2 - methoxy - 4,6 - bis(methoxymethoxy)benzaldehyde (Formula - 5) undergoes demethyl methoxy protection group reaction in acid 1, yielding 4,6 - dihydroxy - 2 - methoxy - 3 - allylbenzaldehyde (Formula - 6);

[0014]

[0015] (5) 4,6 - dihydroxy - 2 - methoxy - 3 - allylbenzaldehyde (Formula - 6) reacts with 2,4 - dihydroxyphenylacetic acid in an acetic anhydride solution of base 4 to undergo a condensation reaction to obtain 7,3(2’,4’)-tri - oxygen - substituted - 5 - methoxy - 6 - allylcoumarin (Formula - 7); The oxygen - substituted group is an acetoxy group;

[0016]

[0017] (6) 7,3(2’,4’)-tri - oxygen - substituted - 5 - methoxy - 6 - allylcoumarin (Formula - 7) reacts with an alkene under the action of catalyst 1 to undergo an olefin metathesis reaction to obtain 7,3(2’,4’)-tri - oxygen - substituted - 5 - methoxy - 6 - isopentenylcoumarin (Formula - 8);

[0018]

[0019] (7) 7,3(2’,4’)-tri - oxygen - substituted - 5 - methoxy - 6 - isopentenylcoumarin (Formula - 8) undergoes a deacetylation reaction under the action of catalyst 2 to obtain 7,3(2’,4’)-tri - hydroxy - 5 - methoxy - 6 - isopentenylcoumarin (Formula - 1);

[0020]

[0021] Preferably, in step (1), the reaction solvent is water, methanol or ethanol, and the base 1 is sodium hydride, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate or cesium carbonate; wherein, the molar concentration ratio of 2,4,6-trihydroxybenzaldehyde (Formula-2), 3-bromopropene and base 1 is 1:(1.0-2.0):(2-4); the temperature of the alkylation reaction is -10 to 80 °C; the alkylation reaction time is 1 to 10 h;

[0022] In step (1), the post-treatment process is: acidify the reaction solution with hydrochloric acid to pH 4-5, then extract with ethyl acetate, dry, concentrate, slurry with dichloromethane, collect the organic phase, concentrate to obtain 3-allyl-2,4,6-trihydroxybenzaldehyde (Formula-3).

[0023] Preferably, in step (2), the reaction solvent is dichloromethane, dichloroethane, chloroform, tetrahydrofuran or methyl tert-butyl ether; the base 2 is triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane or sodium hydride;

[0024] The molar concentration ratio of 3-allyl-2,4,6-trihydroxybenzaldehyde, bromomethyl methyl ether and base 2 is 1:(1.5-4.0):(2.0-4.0);

[0025] The reaction temperature of step (2) is 20-80 °C; the reaction time is 1-6 h;

[0026] In step (2), the post-treatment process is: concentrate the reaction solution, acidify with hydrochloric acid to pH 4-5, extract with ethyl acetate, dry, concentrate, and separate by silica gel column to obtain 3-allyl-2-hydroxy-4,6-bis(methoxymethoxy)benzaldehyde (Formula-4).

[0027] Preferably, in step (3), the solvent is dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, acetonitrile or tetrahydrofuran; the methylation reagent is methyl iodide, dimethyl carbonate, dimethyl sulfate; the base 3 is sodium hydride, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate; the molar concentration ratio of 3-allyl-2-hydroxy-4,6-bis(methoxymethoxy)benzaldehyde (Formula-4), the methylation reagent and base 3 is 1:(1.5-4.0):(2.0-4.0);

[0028] The reaction temperature is 20-50 °C; the reaction time is 4-10 h;

[0029] In step (3), the post-treatment process is as follows: pour the reaction solution into ice water, stir, extract with ethyl acetate, dry, concentrate, and separate by silica gel column to obtain 3-allyl-2-methoxy-4,6-bis(methoxymethoxy)benzaldehyde (Formula-5).

[0030] Preferably, in step (4), Acid 1 is sulfuric acid, hydrochloric acid, nitric acid, trifluoroacetic acid, phosphoric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, citric acid or acetic acid; the solvent is methanol, ethanol, isopropanol or tert-butanol; the molar concentration ratio of 3-allyl-2-methoxy-4,6-bis(methoxymethoxy)benzaldehyde to Acid 1 is 1:(0.1 - 1);

[0031] The temperature for the demethyl methyl ether protecting group removal reaction is 30 - 90 °C; the reaction time is 2 - 24 h;

[0032] In step (4), the post-treatment process is as follows: pour the reaction solution into ice water, stir, adjust the pH to neutral with sodium bicarbonate, extract with ethyl acetate, dry, concentrate, and separate by silica gel column to obtain 4,6-dihydroxy-2-methoxy-3-allylbenzaldehyde (Formula-6).

[0033] Preferably, in step (5), the solvent is acetic anhydride; Base 4 is triethylamine, sodium acetate, potassium acetate or potassium carbonate; the molar ratio of 4,6-dihydroxy-2-methoxy-3-allylbenzaldehyde, 2,4-dihydroxybenzeneacetic acid, Base 4 and the solvent is 1:(1.0 - 1.2):(2 - 4):(4 - 7);

[0034] The temperature for the condensation reaction is 100 - 140 °C; the reaction time is 2 - 8 h;

[0035] In step (5), the post-treatment process is as follows: add ice water to the reaction solution, stir vigorously, dissolve the obtained viscous substance with ethyl acetate, dry and concentrate, and separate by silica gel column to obtain 7,3(2’,4’)-tri-oxygen-substituted-5-methoxy-6-allyl coumarin.

[0036] Preferably, in step (6), the solvent is dichloromethane, dichloroethane or chloroform; the alkene is 2-methylpropene, 2-methyl-2-butene; the catalyst 1 is Grubbs first-generation catalyst, Grubbs second-generation catalyst, Schrock catalyst; the molar concentration ratio of 7,3(2’,4’)-tri-oxygen-substituted-5-methoxy-6-allyl coumarin (Formula-7), catalyst 1 and the alkene is 1:(0.05 - 0.2):(10 - 100);

[0037] The temperature for the olefin metathesis reaction is 0 - 40 °C; the reaction time is 8 - 24 h;

[0038] In step (6), the post-treatment process is as follows: concentrating the reaction solution, adjusting the pH to 4-5 with hydrochloric acid, extracting with ethyl acetate, drying, concentrating, and separating through a reverse silica gel column to obtain 7,3(2’,4’)-trioxo-substituted-5-methoxy-6-isopentenyl coumarin.

[0039] Preferably, in step (7), the solvent is ethanol, methanol, or water; the catalyst 2 is a copper-zinc coupling agent, zinc powder, potassium carbonate, cesium carbonate, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, or sodium methoxide; the molar concentration ratio of 7,3(2’,4’)-trioxo-substituted-5-methoxy-6-isopentenyl coumarin to the catalyst 2 is 1:(1-40);

[0040] The temperature of the deacetylation reaction is 20-40°C; the reaction time is 4-24 h;

[0041] In step (7), the post-treatment process is as follows: filtering the reaction solution, concentrating the solution, adjusting the pH to 4-5 with hydrochloric acid, extracting with ethyl acetate, drying, concentrating, and separating through a reverse silica gel column to obtain 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenyl coumarin.

[0042] Beneficial effects

[0043] Compared with the method of plant extraction, the raw materials of this method are cheap and easily available, the cost is lower, the operation is simple, the steps are concise, the yield is higher, it is more efficient, can be synthesized quickly and in large quantities, fills the research gap in synthesizing 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenyl coumarin by chemical synthesis method, and provides more choices for the raw material sources of further applied research of 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenyl coumarin in biomedicine, cosmetics, food, and luminescent materials, etc. Description of the drawings

[0044] Figure 1 It is the 1 HNMR spectrum of 4,6-dihydroxy-2-methoxy-3-allylbenzaldehyde;

[0045] Figure 2 It is the 1 HNMR spectrum of 7,3(2’,4’)-triacetoxy-5-methoxy-6-allyl coumarin;

[0046] Figure 3 It is the 1 HNMR spectrum of 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenyl coumarin. Specific embodiments

[0047] The present invention will be further described by way of embodiments. It should be understood that the following embodiments are only for illustrating the present invention and not for limiting the present invention.

[0048] The preparation method of 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenylcoumarin provided by the present invention adopts the following synthetic route: Using 2,4,6-trihydroxybenzaldehyde (Formula-2) as the starting material, it is alkylated to obtain 3-allyl-2,4,6-trihydroxybenzaldehyde (Formula-3); then a protecting group is introduced to obtain 3-allyl-2-hydroxy-4,6-bis(methoxymethoxy)benzaldehyde (Formula-4); then it undergoes a methylation reaction to obtain 3-allyl-2-methoxy-4,6-bis(methoxymethoxy)benzaldehyde (Formula-5); subsequently, a deprotection reaction is carried out to generate 4,6-dihydroxy-2-methoxy-3-allylbenzaldehyde (Formula-6); then it undergoes a condensation reaction with 2,4-dihydroxyphenylacetic acid in acetic anhydride solvent to obtain 7,3(2’,4’)-trioxo-substituted-5-methoxy-6-allylcoumarin (Formula-7); subsequently, it undergoes olefin metathesis with an olefin to obtain 7,3(2’,4’)-trioxo-substituted-5-methoxy-6-isopentenylcoumarin (Formula-8); finally, a deacetylation reaction is carried out to obtain 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenylcoumarin (Formula-1).

[0049]

[0050]

[0051] Specifically, the preparation method of 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenylcoumarin provided by the present invention may include the steps:

[0052] (1) 2,4,6-Trihydroxybenzaldehyde (Formula-2) undergoes an alkylation reaction with 3-bromopropene in Base 1 to obtain 3-allyl-2,4,6-trihydroxybenzaldehyde (Formula-3);

[0053] (2) 3-Allyl-2,4,6-trihydroxybenzaldehyde (Formula-3) undergoes a methyl methoxylation reaction with bromomethyl methyl ether in Base 2 to introduce a protecting group, obtaining 3-allyl-2-hydroxy-4,6-bis(methoxymethoxy)benzaldehyde (Formula-4);

[0054] (3) 3-Allyl-2-hydroxy-4,6-bis(methoxymethoxy)benzaldehyde (Formula-4) undergoes a methylation reaction with a methylation reagent in Base 3 to obtain 3-allyl-2-methoxy-4,6-bis(methoxymethoxy)benzaldehyde (Formula-5);

[0055] (4) 3-Allyl-2-methoxy-4,6-bis(methoxymethoxy)benzaldehyde (Formula-5) undergoes a demethyl methyl ether protecting group reaction in Acid 1 to obtain 4,6-dihydroxy-2-methoxy-3-allylbenzaldehyde (Formula-6);

[0056] (5) 4,6-Dihydroxy-2-methoxy-3-allylbenzaldehyde (Formula-6) undergoes a condensation reaction with 2,4-dihydroxy phenylacetic acid in an acetic anhydride solution of Base 4 to obtain 7,3(2’,4’)-tri-oxygen-substituted-5-methoxy-6-allyl coumarin (Formula-7); the oxygen substituents (RO-) at the 3, 2’, and 4’ positions are acetoxy groups; the acetyl group can play a role in protecting the hydroxyl group;

[0057] (6) 7,3(2’,4’)-Tri-oxygen-substituted-5-methoxy-6-allyl coumarin (Formula-7) undergoes an olefin metathesis reaction (olefin cross-metathesis reaction) with an olefin under the action of Catalyst 1 to obtain 7,3(2’,4’)-tri-oxygen-substituted-5-methoxy-6-isopentenyl coumarin (Formula-8);

[0058] (7) 7,3(2’,4’)-Tri-oxygen-substituted-5-methoxy-6-isopentenyl coumarin (Formula-8) undergoes a deacetylation reaction under the action of Catalyst 2 to obtain 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenyl coumarin (Formula-1).

[0059] In some embodiments, in step (1), the reaction solvent can be water, methanol, or ethanol, preferably water. The Base 1 can be sodium hydride, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, or cesium carbonate, preferably potassium hydroxide. Among them, the molar concentration ratio of 2,4,6-trihydroxybenzaldehyde (Formula-2), 3-bromopropene, and Base 1 is 1:(1.0 - 2.0):(2 - 4), preferably 1:1.2:3.

[0060] The temperature of the alkylation reaction can be -10 to 80°C, preferably 25°C; the alkylation reaction time is 1 to 10 h, preferably 4 h.

[0061] In step (1), the post-treatment process can be: acidifying the reaction solution with hydrochloric acid to a pH of 4 - 5, then extracting with ethyl acetate, drying, concentrating, slurrying with dichloromethane, collecting the organic phase, and concentrating to obtain 3-allyl-2,4,6-trihydroxybenzaldehyde (Formula-3).

[0062] In some embodiments, in step (2), the reaction solvent can be dichloromethane, dichloroethane, chloroform, tetrahydrofuran or methyl tert-butyl ether, preferably dichloromethane. The base 2 can be triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane or sodium hydride, preferably triethylamine. The molar concentration ratio of 3-allyl-2,4,6-trihydroxybenzaldehyde (Formula-3), bromomethyl methyl ether and base 2 is 1:(1.5 - 4.0):(2.0 - 4.0), preferably 1:4:2.2.

[0063] The reaction temperature of step (2) can be 20 - 80 °C, and the preferred temperature is 30 °C; the reaction time can be 1 - 6 h, preferably 4 h.

[0064] In step (2), the post-treatment process can be: concentrating the reaction solution, acidifying with hydrochloric acid to a pH of 4 - 5, extracting with ethyl acetate, drying, concentrating, and separating by silica gel column to obtain 3-allyl-2-hydroxy-4,6-bis(methoxymethoxy)benzaldehyde (Formula-4).

[0065] In some embodiments, in step (3), the solvent can be dimethyl sulfoxide, dimethylformamide, N-methylpyrrolidone, acetonitrile or tetrahydrofuran, preferably DMF. The methylation reagent can be methyl iodide, dimethyl carbonate, dimethyl sulfate, preferably methyl iodide. The base 3 can be sodium hydride, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate, preferably potassium carbonate. The molar concentration ratio of 3-allyl-2-hydroxy-4,6-bis(methoxymethoxy)benzaldehyde (Formula-4), methylation reagent and base 3 can be 1:(1.5 - 4.0):(2.0 - 4.0), preferably 1:3:2.

[0066] The reaction temperature can be 20 - 50 °C, preferably 25 °C; the reaction time can be 4 - 10 h, preferably 6 h.

[0067] In some embodiments, in step (3), the post-treatment process can be: pouring the reaction solution into ice water and stirring, extracting with ethyl acetate, drying, concentrating, and separating by silica gel column to obtain 3-allyl-2-methoxy-4,6-bis(methoxymethoxy)benzaldehyde (Formula-5).

[0068] In some embodiments, in step (4), the acid 1 can be sulfuric acid, hydrochloric acid, nitric acid, trifluoroacetic acid, phosphoric acid, p-toluenesulfonic acid, trifluoromethanesulfonic acid, citric acid or acetic acid, preferably sulfuric acid. The solvent can be methanol, ethanol, isopropanol or tert-butanol, preferably tert-butanol. The molar concentration ratio of 3-allyl-2-methoxy-4,6-bis(methoxymethoxy)benzaldehyde (Formula-5) to acid 1 can be 1:(0.1-1), preferably 1:0.1.

[0069] The temperature of the demethyl methyl ether protecting group reaction can be 30-90 °C, preferably 80 °C; the reaction time can be 2-24 h, preferably 8 h.

[0070] In some embodiments, in step (4), the post-treatment process can be: pouring the reaction solution into ice water, stirring, adjusting the pH to neutral with sodium bicarbonate, extracting with ethyl acetate, drying, concentrating, and separating by silica gel column to obtain 4,6-dihydroxy-2-methoxy-3-allylbenzaldehyde (Formula-6).

[0071] In some embodiments, in step (5), the solvent can be acetic anhydride; the base 4 can be triethylamine, sodium acetate, potassium acetate or potassium carbonate, preferably triethylamine. The molar ratio of 4,6-dihydroxy-2-methoxy-3-allylbenzaldehyde, 2,4-dihydroxybenzeneacetic acid, base 4 and the solvent is 1:(1.0-1.2):(2-4):(4-7), preferably 1:1.1:2.5:6.

[0072] The temperature of the condensation reaction can be 100-140 °C, preferably 110 °C; the reaction time can be 2-8 h, preferably 6 h.

[0073] In some embodiments, in step (5), the post-treatment process can be: adding ice water to the reaction solution, stirring vigorously, dissolving the obtained viscous substance with ethyl acetate, drying and concentrating, and separating by silica gel column to obtain 7,3(2’,4’)-trioxo-substituted-5-methoxy-6-allylcoumarin.

[0074] In some embodiments, in step (6), the solvent can be dichloromethane, dichloroethane or chloroform, preferably dichloromethane. The alkene can be 2-methylpropene, 2-methyl-2-butene; the catalyst 1 can be Grubbs first-generation catalyst, Grubbs second-generation catalyst, Schrock catalyst, preferably Grubbs second-generation catalyst. The molar concentration ratio of 7,3(2’,4’)-trioxo-substituted-5-methoxy-6-allylcoumarin (Formula-7), catalyst 1 and the alkene is 1:(0.05-0.2):(10-100), preferably 1:0.05:23.5.

[0075] The temperature of the metathesis reaction can be 0 to 40 °C, preferably 30 °C; the reaction time can be 8 to 24 h, preferably 12 h.

[0076] In some embodiments, in step (6), the post-treatment process can be: concentrating the reaction solution, adjusting the pH to 4 - 5 with hydrochloric acid, extracting with ethyl acetate, drying, concentrating, and separating by passing through a reverse silica gel column to obtain 7,3(2’,4’)-trioxo-substituted-5-methoxy-6-isopentenylcoumarin.

[0077] In some embodiments, in step (7), the solvent can be ethanol, methanol, water; catalyst 2 can be a copper-zinc coupling agent, zinc powder, potassium carbonate, cesium carbonate, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, or sodium methoxide. The molar concentration ratio of 7,3(2’,4’)-trioxo-substituted-5-methoxy-6-isopentenylcoumarin to catalyst 2 is 1:(1 - 40), preferably 1:38.

[0078] The temperature of the deacetylation reaction can be 20 to 40 °C, preferably 40 °C; the reaction time can be 4 to 24 h, preferably 16 h.

[0079] In some embodiments, in step (7), the post-treatment process can be: filtering the reaction solution, concentrating the solution, adjusting the pH to 4 - 5 with hydrochloric acid, extracting with ethyl acetate, drying, concentrating, and separating by passing through a reverse silica gel column to obtain 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenylcoumarin.

[0080] The following further lists examples to illustrate the present invention in detail. Similarly, it should be understood that the following examples are only used to further illustrate the present invention and cannot be construed as limiting the protection scope of the present invention. Those skilled in the art's non-essential improvements and adjustments made based on the above content of the present invention all fall within the protection scope of the present invention. The specific process parameters and the like in the following examples are also only an example within a suitable range, that is, those skilled in the art can make selections within a suitable range through the description herein, rather than being limited to the specific values in the following examples.

[0081] Example 1

[0082] A method for synthesizing 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenylcoumarin, comprising the following steps:

[0083] (1) Dissolve KOH (54.5 g, 974.2 mmol) in H2O (400 mL), then add it to a round-bottom flask, cool it in an ice bath, and then add 2,4,6-trihydroxybenzaldehyde (50 g, 324.6 mmol) and 3-bromopropene (47.13 g, 389.52 mmol). Stir at 25 °C for 4 h. After the reaction is completed, acidify the reaction solution with hydrochloric acid to pH 4 - 5, extract with ethyl acetate, dry, concentrate, slurry with dichloromethane, collect the organic phase, and concentrate to obtain 3-allyl-2,4,6-trihydroxybenzaldehyde (39.9 g, 205.6 mmol, LCMS: m / z(ESI) 194.7 [M+H] + ).

[0084] (2) Add N,N-diisopropylethylamine DIPEA (106.72 g, 822.62 mmol) and MOMBr (51.4 g, 451.3 mmol) to a dichloromethane (350 mL) solution of the obtained 3-allyl-2,4,6-trihydroxybenzaldehyde (39.9 g, 205.6 mmol). Stir at 30 °C for 4 h. After the reaction is completed, concentrate the reaction solution, acidify it with hydrochloric acid to pH 4 - 5, extract with ethyl acetate, dry, concentrate, and separate by silica gel column chromatography to obtain 3-allyl-2-hydroxy-4,6-bis(methoxymethoxy)benzaldehyde (50 g, 179 mmol, LCMS: m / z(ESI) 282.9 [M+H] + ).

[0085] (3) Under an ice bath, add potassium carbonate (74 g, 537 mmol) and methyl iodide (50.8 g, 358 mmol) to a DMF (400 mL) solution of 3-allyl-2-hydroxy-4,6-bis(methoxymethoxy)benzaldehyde (50 g, 179 mmol). React at 25 °C for 6 h. After the reaction is completed, pour the reaction solution into ice water and stir, extract with ethyl acetate, dry, concentrate, and separate by silica gel column chromatography to obtain 3-allyl-2-methoxy-4,6-bis(methoxymethoxy)benzaldehyde (40.0 g, 135.1 mmol, LCMS: m / z(ESI) 296.9 [M+H] + ).

[0086] (4) At room temperature, dissolve 3-allyl-2-methoxy-4,6-bis(methoxymethoxy)benzaldehyde (10 g, 37.16 mmol) in tert-butanol t-BuOH (200 mL). Add a solution of concentrated sulfuric acid (0.37 g, 3.7 mmol) in t-BuOH at room temperature and stir at 80 °C for 8 h. After the reaction is completed, pour the reaction solution into ice water, stir, adjust the pH to neutral with sodium bicarbonate, extract with ethyl acetate, dry, concentrate, and separate by silica gel column chromatography to obtain 4,6-dihydroxy-2-methoxy-3-allylbenzaldehyde (5.7 g, 27.4 mmol, LCMS: m / z (ESI) 208.7 [M+H] + ). 1 1H NMR (400 MHz, DMSO-d6) δ 11.91 (s, 1H), 11.02 (s, 1H), 9.91 (s, 1H), 6.17 (s, 1H), 5.94 - 5.87 (m, 1H), 4.97 - 4.93 (m, 2H), 3.87 (s, 3H), 3.21 (d, J = 6, 2H).

[0087] (5) At room temperature, dissolve 4,6-dihydroxy-2-methoxy-3-allylbenzaldehyde (5.7 g, 27.4 mmol) and 2,4-dihydroxybenzeneacetic acid (5 g, 30.14 mmol) in acetic anhydride (19.5 g, 191.8 mmol), add triethylamine (6.9 g, 68.5 mmol), and stir at 110 °C for 6 h. After the reaction is completed, add ice water to the reaction solution and stir vigorously. The viscous substance is dissolved in ethyl acetate, dried and concentrated, and separated by silica gel column chromatography to obtain 7,3(2’,4’)-triacetoxy-5-methoxy-6-allylcoumarin (8.4 g, 18.0 mmol, LCMS: m / z (ESI) 489.1 [M+Na] + ) 1 1H NMR (400 MHz, DMSO-d6) δ 7.96 (s, 1H), 7.59 (d, J = 8, 1H), 7.19 - 7.15 (m, 3H), 5.89 - 5.82 (m, 1H), 5.04 - 4.99 (m, 2H), 3.86 (s, 3H), 3.35 (d, J = 6.4, 2H), 2.31 (d, J = 3.2, 6H), 2.13 (s, 3H).

[0088] (6) At room temperature, dissolve 7,3(2’,4’)-triacetoxy-5-methoxy-6-allylcoumarin (5.6 g, 12.01 mmol) in dichloromethane DCM (500 mL), add Grubbs second-generation catalyst (500 mg, 0.6 mmol), after purging with nitrogen, add 2-methyl-2-butene (30 mL), and stir at 30 °C for 16 h. The post-treatment process is as follows: concentrate the reaction solution, adjust the pH to 4 - 5 with hydrochloric acid, extract with ethyl acetate, dry, concentrate, and separate by reverse silica gel column to obtain 7,3(2’,4’)-triacetoxy-5-methoxy-6-isopentenylcoumarin (5 g, 10.1 mmol, LCMS: m / z(ESI) 517.2 [M+Na] + ).

[0089] (7) At room temperature, dissolve 7,3(2’,4’)-triacetoxy-5-methoxy-6-isopentenylcoumarin (500 mg, 1.01 mmol) in MeOH (50 ml), then add copper-zinc coupling agent (5 g), stir at 40 °C for 16 hours under nitrogen protection in the dark. The post-treatment is filtration, concentrate the solution, adjust the pH to 4 - 5 with hydrochloric acid, extract with ethyl acetate, dry, concentrate, and separate by reverse silica gel column to obtain 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenylcoumarin (300.2 mg, 0.82 mmol, LCMS: m / z(ESI) 369.1 [M+H] + ). 1 HNMR(400MHz, DMSO-d6) δ10.58(s, 1H), 9.39(s, 2H), 7.81(s, 1H), 7.11(d, J = 8.4, 1H), 6.60(s, 1H), 6.36(d, J = 1.6, 1H), 6.28 - 6.25(m, 1H), 5.15(t, J = 7.2, 1H), 3.76(s, 3H), 3.26(d, J = 6.4, 2H), 1.73(s, 3H), 1.64(s, 3H).

[0090] Figure 1 is the 1 HNMR spectrum of 4,6-dihydroxy-2-methoxy-3-allylbenzaldehyde; Figure 2 is the 1 HNMR spectrum of 7,3(2’,4’)-triacetoxy-5-methoxy-6-allylcoumarin; Figure 3 is the 1 HNMR spectrum of 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenylcoumarin.

[0091] Although the content of the present invention has been described in detail through the above preferred embodiments, it should be recognized that the above description should not be considered as a limitation of the present invention. After those skilled in the art have read the above content, various modifications and alternatives to the present invention will be obvious. Therefore, the protection scope of the present invention should be defined by the appended claims.

Claims

1. A preparation method of 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenyl coumarin, characterized in that, The preparation method comprises the following steps: (1) 2,4,6-trihydroxybenzaldehyde (Formula-2) undergoes an alkylation reaction with 3-bromopropene in Base 1 to obtain 3-allyl-2,4,6-trihydroxybenzaldehyde (Formula-3); (2) 3-allyl-2,4,6-trihydroxybenzaldehyde (Formula-3) undergoes a methyl methoxylation reaction with bromomethyl methyl ether in Base 2 to protect the groups, obtaining 3-allyl-2-hydroxy-4,6-bis(methoxymethoxy)benzaldehyde (Formula-4); (3) 3-allyl-2-hydroxy-4,6-bis(methoxymethoxy)benzaldehyde (Formula-4) undergoes a methylation reaction with a methylation reagent in Base 3 to obtain 3-allyl-2-methoxy-4,6-bis(methoxymethoxy)benzaldehyde (Formula-5); (4) 3-allyl-2-methoxy-4,6-bis(methoxymethoxy)benzaldehyde (Formula-5) undergoes a demethyl methoxy protecting group reaction in Acid 1 to obtain 4,6-dihydroxy-2-methoxy-3-allylbenzaldehyde (Formula-6); (5) 4,6-dihydroxy-2-methoxy-3-allylbenzaldehyde (Formula-6) undergoes a condensation reaction with 2,4-dihydroxy phenylacetic acid in an acetic anhydride solution of Base 4 to obtain 7,3(2’,4’)-trioxo-substituted-5-methoxy-6-allyl coumarin (Formula-7); the oxo-substituent is an acetoxy group; (6) 7,3(2’,4’)-trioxo-substituted-5-methoxy-6-allyl coumarin (Formula-7) undergoes a metathesis reaction with an olefin under the action of Catalyst 1 to obtain 7,3(2’,4’)-trioxo-substituted-5-methoxy-6-isopentenyl coumarin (Formula-8); (7) 7,3(2’,4’)-trioxo-substituted-5-methoxy-6-isopentenyl coumarin (Formula-8) undergoes a deacetylation reaction under the action of Catalyst 2 to obtain 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenyl coumarin (Formula-1); 2. The preparation method according to claim 1, wherein In step (1), the reaction solvent is water, methanol or ethanol, and the Base 1 is sodium hydride, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate or cesium carbonate; wherein, the molar concentration ratio of 2,4,6-trihydroxybenzaldehyde (Formula-2), 3-bromopropene and Base 1 is 1:(1.0 - 2.0):(2 - 4); The temperature of the alkylation reaction is -10 to 80 °C; the alkylation reaction time is 1 to 10 h; In step (1), the post-treatment process is: acidifying the reaction solution with hydrochloric acid to a pH of 4 - 5, then extracting with ethyl acetate, drying, concentrating, slurrying with dichloromethane, collecting the organic phase, and concentrating to obtain 3-allyl-2,4,6-trihydroxybenzaldehyde (Formula-3).

3. The preparation method according to claim 1, characterized in that, In step (2), the reaction solvent is dichloromethane, dichloroethane, chloroform, tetrahydrofuran or methyl tert-butyl ether; the Base 2 is triethylamine, N,N-diisopropylethylamine, 1,8-diazabicyclo[5.4.0]undec-7-ene, 1,4-diazabicyclo[2.2.2]octane or sodium hydride; The molar concentration ratio of 3 - allyl - 2,4,6 - trihydroxybenzaldehyde, bromomethyl methyl ether to base 2 is 1:(1.5 - 4.0):(2.0 - 4.0); The reaction temperature in step (2) is 20 - 80 °C; the reaction time is 1 - 6 h; In step (2), the post - treatment process is: concentrating the reaction solution, acidifying with hydrochloric acid to a pH of 4 - 5, extracting with ethyl acetate, drying, concentrating, and separating by silica gel column to obtain 3 - allyl - 2 - hydroxy - 4,6 - bis(methoxymethoxy)benzaldehyde (Formula - 4).

4. The preparation method according to claim 1, wherein In step (3), the solvent is dimethyl sulfoxide, dimethylformamide, N - methylpyrrolidone, acetonitrile or tetrahydrofuran; the methylation reagent is methyl iodide, dimethyl carbonate, dimethyl sulfate; base 3 is sodium hydride, potassium hydroxide, sodium hydroxide, lithium hydroxide, sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate and cesium carbonate; the molar concentration ratio of 3 - allyl - 2 - hydroxy - 4,6 - bis(methoxymethoxy)benzaldehyde (Formula - 4), methylation reagent to base 3 is 1:(1.5 - 4.0):(2.0 - 4.0); The reaction temperature is 20 - 50 °C; the reaction time is 4 - 10 h; In step (3), the post - treatment process is: pouring the reaction solution into ice water and stirring, extracting with ethyl acetate, drying, concentrating, and separating by silica gel column to obtain 3 - allyl - 2 - methoxy - 4,6 - bis(methoxymethoxy)benzaldehyde (Formula - 5).

5. The preparation method according to claim 1, characterized in that, In step (4), acid 1 is sulfuric acid, hydrochloric acid, nitric acid, trifluoroacetic acid, phosphoric acid, p - toluenesulfonic acid, trifluoromethanesulfonic acid, citric acid or acetic acid; the solvent is methanol, ethanol, isopropanol or tert - butanol; the molar concentration ratio of 3 - allyl - 2 - methoxy - 4,6 - bis(methoxymethoxy)benzaldehyde to acid 1 is 1:(0.1 - 1); The temperature for the reaction of removing the methoxymethyl ether protecting group is 30 - 90 °C; the reaction time is 2 - 24 h; In step (4), the post - treatment process is: pouring the reaction solution into ice water and stirring, adjusting the pH to neutral with sodium bicarbonate, extracting with ethyl acetate, drying, concentrating, and separating by silica gel column to obtain 4,6 - dihydroxy - 2 - methoxy - 3 - allylbenzaldehyde (Formula - 6).

6. The preparation method according to claim 1, wherein In step (5), the solvent is acetic anhydride; base 4 is triethylamine, sodium acetate, potassium acetate or potassium carbonate; the molar ratio of 4,6 - dihydroxy - 2 - methoxy - 3 - allylbenzaldehyde, 2,4 - dihydroxybenzeneacetic acid, base 4 and the solvent is 1:(1.0 - 1.2):(2 - 4):(4 - 7); The temperature for the condensation reaction is 100 - 140 °C; the reaction time is 2 - 8 h; In step (5), the post - treatment process is: adding ice water to the reaction solution, stirring vigorously, dissolving the obtained viscous substance with ethyl acetate, drying and concentrating, and separating by silica gel column to obtain 7,3(2’,4’)-tri - oxygen - substituted - 5 - methoxy - 6 - allylcoumarin.

7. The preparation method according to claim 1, characterized in that, In step (6), the solvent is dichloromethane, dichloroethane or chloroform; the alkene is 2-methylpropene or 2-methyl-2-butene; the catalyst 1 is Grubbs first-generation catalyst, Grubbs second-generation catalyst or Schrock catalyst; the molar concentration ratio of 7,3(2’,4’)-trioxo-substituted-5-methoxy-6-allyl coumarin (Formula-7), catalyst 1 and the alkene is 1:(0.05 - 0.2):(10 - 100); The temperature of the olefin metathesis reaction is 0 - 40 °C; the reaction time is 8 - 24 h; In step (6), the post-treatment process is as follows: concentrate the reaction solution, adjust the pH to 4 - 5 with hydrochloric acid, extract with ethyl acetate, dry, concentrate, and separate by reverse silica gel column to obtain 7,3(2’,4’)-trioxo-substituted-5-methoxy-6-isopentenyl coumarin.

8. The preparation method according to any one of claims 1-7, characterized in that, In step (7), the solvent is ethanol, methanol or water; the catalyst 2 is copper-zinc coupling agent, zinc powder, potassium carbonate, cesium carbonate, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate or sodium methoxide; the molar concentration ratio of 7,3(2’,4’)-trioxo-substituted-5-methoxy-6-isopentenyl coumarin and catalyst 2 is 1:(1 - 40); The temperature of the deacetylation reaction is 20 - 40 °C; the reaction time is 4 - 24 h; In step (7), the post-treatment process is as follows: filter the reaction solution, concentrate the solution, adjust the pH to 4 - 5 with hydrochloric acid, extract with ethyl acetate, dry, concentrate, and separate by reverse silica gel column to obtain 7,3(2’,4’)-trihydroxy-5-methoxy-6-isopentenyl coumarin.

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