A method for synthesizing bergamottin

Abstract

The application discloses a synthesis method of bergamottin, which comprises the following steps: (1) taking m-benzene triol as raw material, and synthesizing 5-methoxy-1,3-benzene diol through a selective etherification reaction; (2) preparing 5-methoxy-7-hydroxycoumarin through a Pechmann condensation reaction; (3) obtaining 5-methoxy-7-allyloxy coumarin through an etherification reaction; (4) preparing 5-methoxy-6-allyl-7-hydroxycoumarin through a Claisen rearrangement reaction; and (5) synthesizing the natural compound bergamottin through an oxidation ring formation reaction. The synthesis method has the advantages of simple reaction process, cheap and easily obtained raw materials, simple product separation and purification, and high yield (all higher than 69%), and the purity of the bergamottin reaches more than 99%, so that the method can be used for large-scale production and has a wide application prospect.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of organic synthesis, in particular to a synthesis method of xanthotoxin. BACKGROUND

[0002] Xanthotoxin, also known as 5-methoxypsoralen, is a natural furanocoumarin compound, which exists in the stems and leaves of Petroselinum crispum, the roots and rhizomes of Notopterygium incisum, the leaves, roots and root barks of Ficus plants, and has the effects of antibacterial, antiviral, anti-cell proliferation, anti-tumor, and enhancing immunity. In addition, adding xanthotoxin to cigarettes can reveal elegant bean fragrance, which can significantly improve the internal quality of cigarettes and has important application value. However, there are few reports on the synthesis method of xanthotoxin, which is mainly obtained by separation from natural plants, resulting in high price of xanthotoxin and limiting its application in cigarettes and medicines.

[0003] At present, the synthesis methods mainly include: 1) using m-benzenetriol as raw material, through etherification, Pechmann condensation, iodination, etherification, oxidation, cyclization and substitution, xanthotoxin is synthesized through 9 steps, which has long steps and low yield, and expensive Pd(OAc)2 is used as catalyst in the process; 2) using m-benzenetriol as raw material, through etherification, condensation cyclization, reduction, cyclization and catalytic dehydrogenation, xanthotoxin is synthesized through 5 steps, which has short steps, but low yield, and the first four steps need to be reacted under anhydrous conditions, HCl gas is used in the first and third steps, and expensive Pd-C is used as catalyst in the fifth step of catalytic dehydrogenation.

[0004] Therefore, it is particularly important to develop a new synthesis method of xanthotoxin. SUMMARY

[0005] The technical problem to be solved by the present application is to provide a synthesis method of xanthotoxin, which synthesizes xanthotoxin through 5 steps of etherification, Pechmann condensation, etherification, Claisen rearrangement and oxidation ring formation by analyzing the structure of xanthotoxin and using inexpensive m-benzenetriol as raw material, and the synthesis method is simple in operation, high in yield and easy to scale up.

[0006] The technical problem to be solved by the present application is solved by the following technical scheme:

[0007] A synthesis method of bergamottin, comprising the following steps: (1) taking m-hydroxybenzoic acid as raw material, synthesizing 5-methoxy-1, 3-benzenediol through selective etherification reaction; (2) preparing 5-methoxy-7-hydroxycoumarin through Pechmann condensation reaction; (3) obtaining 5-methoxy-7-allyloxy coumarin through etherification reaction; (4) preparing 5-methoxy-6-allyl-7-hydroxycoumarin through Claisen rearrangement reaction; and (5) synthesizing natural compound bergamottin through oxidation ring formation reaction.

[0008] The reaction formula is as follows:

[0009]

[0010] Preferably, the method comprises the following steps:

[0011] (1) Preparation of 5-methoxy-1, 3-benzenediol: in a round-bottom flask, m-hydroxybenzoic acid, a solvent and a catalyst are added, and the system is cooled to 0-5 DEG C in an ice bath, then methyl iodide is added, and stirring is continued for 0.5-2 h, and then the reaction is carried out at room temperature for 8-12 h; after the reaction is completed, the solid is filtered, washed with ethyl acetate, and the organic phases are combined, and the solvent is removed under reduced pressure; the crude product is separated by silica gel column chromatography to obtain 5-methoxy-1, 3-benzenediol.

[0012] (2) Preparation of 5-methoxy-7-hydroxycoumarin: in a round-bottom flask, concentrated H2SO4 is added, and the system is cooled to 0-25 DEG C in a low-temperature reactor; then 5-methoxy-1, 3-benzenediol and malic acid are slowly added to the concentrated H2SO4 under stirring; after the addition of 5-methoxy-1, 3-benzenediol and malic acid, stirring is continued at low temperature for 0.5-2 h, and then the reaction is carried out at room temperature for 12-30 h; after the reaction is completed, the reaction mixture is slowly added to ice water, and the precipitate is collected by suction filtration, washed with ice water and dried; the crude product is separated by silica gel column chromatography to obtain 5-methoxy-7-hydroxycoumarin.

[0013] (3) Preparation of 5-methoxy-7-allyloxy coumarin: in a round-bottom flask, an organic solvent, 5-methoxy-7-hydroxycoumarin and a catalyst are added, and an organic solution containing allyl bromide is slowly added dropwise to the reaction system under stirring; after the dropwise addition is completed, heating is carried out at reflux for 5-12 h; after the reaction is completed, the solvent is removed under reduced pressure, and distilled water is added for stirring; the solid is collected by suction filtration, washed with water and dried; the crude product is recrystallized from 95% ethanol to obtain 5-methoxy-7-allyloxy coumarin.

[0014] (4) Preparation of 5-methoxy-6-allyl-7-hydroxycoumarin: in a round bottom flask, 5-methoxy-7-allyloxy coumarin and an organic base are added, heated to reflux for 2-6 hours, after the reaction is completed, the solvent is removed by evaporation under reduced pressure, ice water is added, and the solid is collected by suction filtration, washed with water and dried, and the crude product is separated by silica gel column chromatography to obtain 5-methoxy-6-allyl-7-hydroxycoumarin;

[0015] (5) Preparation of bergamottin: in a round bottom flask, 5-methoxy-6-allyl-7-hydroxycoumarin, an oxidizing agent and a solvent are added, and the reaction is carried out at room temperature for 12-24 hours, after the reaction is completed, an inorganic acid is added and stirred for 0.5-2 hours, the reaction mixture is poured into ice water, the solid is collected by suction filtration, washed with water and dried, and the crude product is recrystallized from 95% ethanol to obtain bergamottin.

[0016] Preferably, in step (1), the solvent is one of acetone, dichloromethane or trichloromethane; the catalyst is one of potassium carbonate, sodium carbonate or potassium hydroxide; and the molar ratio of m-hydroxybenzoic acid, iodomethane and catalyst is 1:(1-1.1):(1-1.2).

[0017] Preferably, in step (2), the mass fraction of concentrated H2SO4 is 70%-98%; and the molar ratio of 5-methoxy-1,3-benzenediol and malic acid is 1:(1-1.3).

[0018] Preferably, in step (3), the organic solvent is one of acetone, dichloromethane or trichloromethane; the catalyst is one of potassium carbonate, sodium carbonate or potassium hydroxide; and the molar ratio of 5-methoxy-7-hydroxycoumarin, catalyst and allyl bromide is 1:(1-1.2):(1-1.3).

[0019] Preferably, in step (4), the organic base is one of triethylamine, N,N-dimethylaniline or N,N-diethylaniline; and the organic base is both a solvent and a catalyst.

[0020] Preferably, in step (5), the oxidizing agent is one or more of osmium tetroxide, potassium periodate or potassium perchlorate; the solvent is one or more of methanol, ethanol or distilled water; and the inorganic acid is one of 98% H2SO4, 37% HCl or 85% H3PO4.

[0021] The above technical solution of the present application has the following beneficial effects:

[0022] The synthesis method of bergamottin of the present application has the advantages of simple process, cheap and readily available raw materials, simple product separation and purification, high yield of more than 69%, purity of more than 99% of the final bergamottin, and wide application prospect. BRIEF DESCRIPTION OF DRAWINGS

[0023] The accompanying drawings, which are incorporated in and constitute a part of this specification, illustrate embodiments of the application and, together with the description, serve to explain the principles of the application.

[0024] Figure 1 NMR hydrogen spectrum of bergamottin;

[0025] Figure 2 NMR carbon spectrum of bergamottin;

[0026] Figure 3 Mass spectrum of bergamottin. DETAILED DESCRIPTION

[0027] Various exemplary embodiments of the present application will now be described in detail with reference to the accompanying drawings. It should be noted that the relative arrangements, numerical expressions, and numerical values of the components and steps set forth in these embodiments do not limit the scope of the present application unless otherwise specifically stated.

[0028] A synthesis method of bergamottin, comprising the following steps:

[0029] (1) 5-methoxy-1,3-benzenediol is synthesized by selective etherification reaction with m-benzenetriol as raw material; (2) 5-methoxy-7-hydroxycoumarin is prepared by Pechmann condensation reaction; (3) 5-methoxy-7-allyloxy coumarin is obtained by etherification reaction; (4) 5-methoxy-6-allyl-7-hydroxycoumarin is prepared by Claisen rearrangement reaction; (5) natural compound bergamottin is synthesized by oxidation ring formation reaction;

[0030] The reaction formula is as follows:

[0031]

[0032] wherein, formula (1) is 5-methoxy-1,3-benzenediol, formula (2) is 5-methoxy-7-hydroxycoumarin, formula (3) is 5-methoxy-7-allyloxy coumarin, formula (4) is 5-methoxy-6-allyl-7-hydroxycoumarin, and formula (5) is bergamottin. The following will be described in detail by way of examples:

[0033] Example 1

[0034] A synthesis method of bergamottin, comprising the following steps:

[0035] (1) Preparation of 5-methoxy-1,3-benzene-diol (1): In a 250 mL round bottom flask, add phloroglucinol (12.60 g, 100 mmol), acetone (150 mL) and potassium carbonate (13.80 g), cool to 5 °C in an ice bath, add 14.20 g of methyl iodide to the system, after the end of the drop, react at room temperature for 12 h, after the reaction is completed, filter the potassium carbonate, wash twice with 40 mL of ethyl acetate, combine the organic phase, dry and evaporate the solvent under reduced pressure, separate the crude product by silica gel column chromatography to obtain 10.20 g of white 5-methoxy-1,3-benzene-diol with a yield of 72.86%.

[0036] (2) Preparation of 5-methoxy-7-hydroxycoumarin (2): In a 100 mL round bottom flask, add 60 mL of H2SO4 (98%), cool to below -20 °C in a low-temperature reactor, under stirring conditions, slowly add 5-methoxy-1,3-benzene-diol (7.00 g, 50 mmol) and malic acid (7.40 g, 55 mmol) mixed solids to concentrated H2SO4, maintain the reaction temperature at -20 °C. After the reactants are added, continue to stir at -20 °C for 1 h, then raise the temperature to room temperature and react for 24 h, after the reaction is completed, slowly add the reaction mixture to ice water, precipitate is separated out, collect the precipitate by suction filtration, wash with ice water, dry, recrystallize the crude product with 95% ethanol to obtain 6.63 g of white flaky 5-methoxy-7-hydroxycoumarin with a yield of 69.06%.

[0037] (3) Preparation of 5-methoxy-7-allyloxy coumarin (3): In a 100 mL round bottom flask, add acetone (70 mL), 5-methoxy-7-hydroxycoumarin (5.76 g, 30 mmol) and potassium carbonate (4.14 g, 30 mmol), under stirring conditions, slowly drop an allyl bromide (4.02 g, 33 mmol) acetone solution into the reaction system. After the drop is completed, heat to reflux for 10 h, after the reaction is completed, evaporate most of the solvent under reduced pressure, add water to precipitate white solids. Collect the solids by suction filtration, wash with water, dry, recrystallize the crude product with 95% ethanol to obtain 5.87 g of white 5-methoxy-7-allyloxy coumarin with a yield of 84.34%.

[0038] (4) Preparation of 5-methoxy-6-allyl-7-hydroxycoumarin (4): In a 100 mL round bottom flask, add 5-methoxy-7-allyloxy coumarin (4.64 g, 20 mmol) and N,N-diethyl aniline (50 mL), heat to reflux for 4 h, after the reaction is completed, evaporate the solvent under reduced pressure, separate the crude product by silica gel column chromatography to obtain 3.21 g of white 5-methoxy-6-allyl-7-hydroxycoumarin with a yield of 69.18%.

[0039] (5) Preparation of bergamottin (5): In a 50 mL round bottom flask, 5-methoxy-6-allyl-7-hydroxycoumarin (2.32 g, 10 mmol), osmium tetroxide (0.25 g, 1 mmol), potassium periodate (1.00 g), methanol (20 mL) and distilled water (10 mL) were added, and the reaction was carried out at room temperature for 20 h. After the reaction was completed, 85% H3PO4(8 mL) was added and stirring was continued for 1 h. The reaction mixture was poured into ice water, and a white solid was precipitated. The solid was collected by suction filtration, washed with water, and dried. The crude product was recrystallized from 95% ethanol to obtain 1.58 g of white needle-shaped bergamottin at a yield of 73.15%.

[0040] Example 2

[0041] A method for synthesizing bergamottin, comprising the steps of:

[0042] (1) Preparation of 5-methoxy-1,3-benzenediol (1): In a 250 mL round bottom flask, m- trihydroxybenzene (12.60 g, 100 mmol), dichloromethane (150 mL), and sodium carbonate (11.66 g) were added, and the system was cooled to 5°C in an ice bath. Then, 14.20 g of methyl iodide was added dropwise, and the reaction was carried out at room temperature for 10 h after the dropwise addition was completed. After the reaction was completed, the potassium carbonate was filtered, and the organic phase was collected by washing the potassium carbonate twice with 40 mL of ethyl acetate. After drying, the solvent was removed under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain 8.54 g of white 5-methoxy-1,3-benzenediol at a yield of 61.00%.

[0043] (2) Preparation of 5-methoxy-7-hydroxycoumarin (2): In a 100 mL round bottom flask, 60 mL of H2SO4(90%) was added, and the system was cooled to below -15°C in a low-temperature reactor. Then, 5-methoxy-1,3-benzenediol (7.00 g, 50 mmol) and malic acid (8.04 g, 60 mmol) were slowly added to the concentrated H2SO4under stirring, and the reaction temperature was maintained at -15°C. After the reactants were added, stirring was continued at -15°C for 2 h, and then the temperature was increased to room temperature and the reaction was carried out for 30 h. After the reaction was completed, the reaction mixture was slowly added to ice water, and a precipitate was precipitated. The precipitate was collected by suction filtration, washed with ice water, and dried. The crude product was recrystallized from 95% ethanol to obtain 6.22 g of white flaky 5-methoxy-7-hydroxycoumarin at a yield of 64.79%.

[0044] (3) Preparation of 5-methoxy-7-allyloxy coumarin (3): In a 100 mL round bottom flask, dichloromethane (70 mL), 5-methoxy-7-hydroxy coumarin (5.76 g, 30 mmol) and sodium carbonate (3.50 g, 33 mmol) were added, and an allyl bromide (4.02 g, 33 mmol) solution in dichloromethane was slowly added dropwise to the reaction system under stirring. After the addition was completed, it was heated to reflux for 10 h. After the reaction was completed, most of the solvent was removed by evaporation under reduced pressure, and water was added to precipitate white solids. The solids were collected by suction filtration, washed with water, dried, and the crude product was recrystallized from 95% ethanol to obtain 4.98 g of white 5-methoxy-7-allyloxy coumarin with a yield of 71.55%.

[0045] (4) Preparation of 5-methoxy-6-allyl-7-hydroxy coumarin (4): In a 100 mL round bottom flask, 5-methoxy-7-allyloxy coumarin (4.64 g, 20 mmol) and triethylamine (50 mL) were added, and it was heated to reflux for 6 h. After the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain 1.56 g of white 5-methoxy-6-allyl-7-hydroxy coumarin with a yield of 33.62%.

[0046] (5) Preparation of aurapten (5): In a 50 mL round bottom flask, 5-methoxy-6-allyl-7-hydroxy coumarin (2.32 g, 10 mmol), osmium tetroxide (0.25 g, 1 mmol), potassium perchlorate (1.00 g), methanol (20 mL), and distilled water (10 mL) were added, and it was reacted at room temperature for 20 h. After the reaction was completed, 37% HCl (8 mL) was added and stirred for 1 h, and the reaction mixture was poured into ice water to precipitate white solids. The solids were collected by suction filtration, washed with water, dried, and the crude product was recrystallized from 95% ethanol to obtain 1.12 g of white needle-shaped aurapten with a yield of 51.85%.

[0047] Example 3

[0048] A method for synthesizing aurapten, comprising the steps of:

[0049] (1) Preparation of 5-methoxy-1,3-benzene-diol (1): In a 250 mL round bottom flask, m-hydroxybenzoic acid (12.60 g, 100 mmol), chloroform (150 mL), and potassium hydroxide (6.11 g) were added, and it was cooled to 5°C in an ice bath. Then, 14.20 g of methyl iodide was added dropwise to the system. After the addition was completed, it was reacted at room temperature for 10 h. After the reaction was completed, it was filtered, and the potassium carbonate was washed with 40 mL of ethyl acetate twice. The organic phases were combined, dried, and the solvent was removed by evaporation under reduced pressure. The crude product was separated by silica gel column chromatography to obtain 7.63 g of white 5-methoxy-1,3-benzene-diol with a yield of 54.50%.

[0050] (2) Preparation of 5-methoxy-7-hydroxycoumarin (2): In a 100 mL round bottom flask, 60 mL of H2SO4 (80%) was added and cooled to below -10 °C in a low temperature reactor. 5-methoxy-1,3-benzenediol (7.00 g, 50 mmol) and malic acid (7.40 g, 55 mmol) were mixed and added slowly into the concentrated H2SO4 under stirring at -10 °C. After the addition of the reactants, the reaction was continued to stir at -10 °C for 0.5 h and then was raised to room temperature for 20 h. After the reaction was completed, the reaction mixture was slowly added into ice water and the precipitate was collected by suction filtration. The precipitate was washed with ice water and dried. The crude product was recrystallized from 95% ethanol to obtain 6.09 g of white flaky 5-methoxy-7-hydroxycoumarin with a yield of 63.44%.

[0051] (3) Preparation of 5-methoxy-7-allyloxycoumarin (3): In a 100 mL round bottom flask, chloroform (70 mL), 5-methoxy-7-hydroxycoumarin (5.76 g, 30 mmol) and potassium hydroxide (1.85 g, 33 mmol) were added and an allyl bromide (4.02 g, 33 mmol) solution in chloroform was slowly added dropwise into the reaction system under stirring. After the addition was completed, the reaction was heated to reflux for 12 h. After the reaction was completed, most of the solvent was removed by evaporation under reduced pressure and water was added to precipitate a white solid. The solid was collected by suction filtration, washed with water and dried. The crude product was recrystallized from 95% ethanol to obtain 5.46 g of white 5-methoxy-7-allyloxycoumarin with a yield of 78.45%.

[0052] (4) Preparation of 5-methoxy-6-allyl-7-hydroxycoumarin (4): In a 100 mL round bottom flask, 5-methoxy-7-allyloxycoumarin (4.64 g, 20 mmol) and N,N-dimethylaniline (50 mL) were added and heated to reflux for 5 h. After the reaction was completed, the solvent was removed by evaporation under reduced pressure. The crude product was separated by silica gel column chromatography to obtain 2.77 g of white 5-methoxy-6-allyl-7-hydroxycoumarin with a yield of 59.70%.

[0053] (5) Preparation of aurapten (5): In a 50 mL round bottom flask, 5-methoxy-6-allyl-7-hydroxycoumarin (2.32 g, 10 mmol), osmium tetroxide (0.25 g, 1 mmol), potassium periodate (1.00 g), ethanol (20 mL) and distilled water (10 mL) were added and the reaction was continued to stir at room temperature for 24 h. After the reaction was completed, 98% H2SO4 (8 mL) was added and the stirring was continued for 2 h. The reaction mixture was poured into ice water to precipitate a white solid. The solid was collected by suction filtration, washed with water and dried. The crude product was recrystallized from 95% ethanol to obtain 1.42 g of white needle-like aurapten with a yield of 65.74%.

[0054] Structural characterization data of the compounds:

[0055] Ambrox: 1 H NMR (600 MHz), δ: 8.18 (d, J = 9.6 Hz, 1H), 8.04 (d, J = 2.4 Hz, 1H), 7.42-7.39 (m), 7.33 (s, 1H), 6.31 (d, J = 9.6 Hz, 1H), 4.26 (s, 1H); 13 C NMR (150 MHz,), δ: 160.59, 158.25, 152.59, 149.91, 146.32, 139.92, 112.77, 112.72, 106.16, 106.03, 93.55, 60.69. HRMS m / z calcd for C 12 H8O4[M+H] + 217.0495, found 217.0508.

[0056] Although the present application has been disclosed with reference to examples as above, it is not intended to limit the present application, and any person skilled in the art can make various modifications and changes without departing from the spirit and scope of the present application, and the scope of protection of the present application is defined by the claims and their equivalents.

Claims

1. A method of synthesizing bergapten, characterized by, Comprising the following steps: (1) 5-Methoxy-1,3-benzenediol ( 1 Preparation of 5-methoxy-1,3-benzenediol: In a 250 mL round-bottom flask, 12.60 g of phloroglucinol, 150 mL of acetone, and 13.80 g of potassium carbonate were added. The mixture was cooled to 5 °C in an ice bath. 14.20 g of iodomethane was added to the system. After the addition was complete, the mixture was reacted at room temperature for 12 h. After the reaction was complete, the mixture was filtered, and the potassium carbonate was washed twice with 40 mL of ethyl acetate. The organic phases were combined, dried, and the solvent was removed by vacuum distillation. The crude product was separated by silica gel column chromatography to give white 5-methoxy-1,3-benzenediol with a yield of 72.86%. (2) Preparation of 5-methoxy-7-hydroxycoumarin: 2 In a 100 mL round-bottom flask, 60 mL of 98% H2SO4 was added, and the low-temperature reactor was cooled to below -20 °C. Under stirring, 5-methoxy-1,3-benzenediol 7.00 g and malic acid 7.40 g were mixed and slowly added to the concentrated H2SO4, keeping the reaction temperature below -20 °C. After the reactants were added, stirring was continued at -20 °C for 1 h, and then the temperature was raised to room temperature for 24 h. After the reaction was completed, the reaction mixture was slowly added to ice water, and a precipitate was separated out. The precipitate was collected by suction filtration, washed with ice water, and dried. The crude product was recrystallized from 95% ethanol to obtain 6.63 g of white flaky 5-methoxy-7-hydroxycoumarin with a yield of 69.06%. (3) Preparation of 5-methoxy-7-allyloxy coumarin: 3 In a 100 mL round-bottom flask, 70 mL of acetone, 5-methoxy-7-hydroxy coumarin 5.76 g and potassium carbonate 4.14 g were added, and under stirring, an allyl bromide 4.02 g solution in acetone was slowly added dropwise into the reaction system; after the addition was completed, it was heated to reflux for 10 h, after the reaction was completed, most of the solvent was distilled off under reduced pressure, and water was added to precipitate white solids; the solids were collected by suction filtration, washed with water and dried, and the crude product was recrystallized with 95% ethanol to obtain 5.87 g of white 5-methoxy-7-allyloxy coumarin, with a yield of 84.34%. (4) Preparation of 5-methoxy-6-allyl-7-hydroxycoumarin: 4 In a 100 mL round-bottom flask, 5-methoxy-7-allyloxy coumarin 4.64 g and N , N diethyl aniline 50 mL were added, heated to reflux for 4 h, after the reaction was completed, the solvent was removed by evaporation under reduced pressure, and the crude product was separated by silica gel column chromatography to obtain 3.21 g of white 5-methoxy-6-allyl-7-hydroxycoumarin, with a yield of 69.18%; (5) Bergamot lactone ( 5 Preparation of 5-methoxy-6-allyl-7-hydroxycoumarin: In a 50 mL round-bottom flask, 2.32 g of 5-methoxy-6-allyl-7-hydroxycoumarin, 0.25 g of osmium tetroxide, 1.00 g of potassium periodate, 20 mL of methanol, and 10 mL of distilled water were added. The mixture was reacted at room temperature for 20 h. After the reaction was completed, 8 mL of 85% H3PO4 was added and the mixture was stirred for another 1 h. The reaction mixture was then poured into ice water, and a white solid precipitated. The solid was collected by suction filtration, washed with water, and dried. The crude product was recrystallized from 95% ethanol to give 1.58 g of white needle-like bergamot lactone, with a yield of 73.15%.

2. The method of synthesis of bergamottin according to claim 1, characterized in that, In step (1), phloroglucinol was 100 mmol.

3. The method of synthesis of bergamottin according to claim 1, characterized in that, In step (2), 5-methoxy-1,3-benzenediol was 50 mmol, and malic acid was 55 mmol.

4. The method of synthesis of bergamottin according to claim 1, characterized in that, In step (3), 5-methoxy-7-hydroxycoumarin was 30 mmol, potassium carbonate was 30 mmol, and allyl bromide was 33 mmol.

5. The method of synthesis of bergamottin according to claim 1, characterized in that, In step (4), 5-methoxy-7-allyloxy coumarin was 20 mmol.

6. The method of synthesis of bergamottin according to claim 1, characterized in that, In step (5), 5-methoxy-6-allyl-7-hydroxycoumarin was 10 mmol.

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