Preparation method of hylurogan A

Abstract

The application belongs to the technical field of medicine synthesis, and particularly relates to a preparation method of hancolide A. The preparation method provided by the application comprises the following steps: Michael addition reaction of a compound of formula II with a cinnamic acid derivative or a phenylpropynic acid derivative to obtain a compound of formula III or a compound of formula III-1; FC acylation reaction of the compound of formula III or the compound of formula III-1 to obtain a compound of formula IV or a compound of formula V; oxidation of the compound of formula IV to obtain the compound of formula V; methylation of the compound of formula V to obtain a compound of formula VI; and deprotection of the compound of formula VI to obtain the compound of formula I. The application is a low-cost, full-synthesis route of hancolide A suitable for industrial production.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of drug synthesis, and particularly relates to a preparation method of quercetagetin A. BACKGROUND

[0002] Quercetagetin A is one of the main active ingredients extracted from Scutellaria baicalensis Georgi. It has been proven that quercetagetin A has a wide range of pharmacological effects, including strong anticancer effect, anti-inflammatory, neuroprotective, anticoagulant, anti-itching and the like. The pharmacological activity of quercetagetin A has been studied in vivo and in vitro, which reflects its potential in disease treatment. Therefore, quercetagetin A has become one of the hotspots in the research of flavonoid innovative drugs in recent years.

[0003] The currently reported synthesis methods of quercetagetin A are all semi-synthetic methods: taking baicalein (structure as shown in formula VII) as a raw material, quercetagetin A is obtained through several steps of synthesis (for example, Chinese patent CN 108456190B).

[0004]

[0005] The main disadvantage of the scheme is that the starting material baicalein is currently mainly obtained by extraction. Due to its relatively low natural content, the extraction cost is high, the period is long, and the cost of quercetagetin A is greatly increased. The present application is a total synthesis method of quercetagetin A. The compound of formula II is used as a starting material, and quercetagetin A is obtained through several conventional reactions. The compound of formula II is simple and easy to obtain, and the price is low. Many literatures have reported its synthesis method. Therefore, it is urgent to develop a total synthesis method with low cost, simple operation, short period and easy industrial production. SUMMARY

[0006] In order to solve the problems existing in the prior art, the purpose of the present application is to provide a preparation method of quercetagetin A. The present application takes 2,6-bis(benzyloxy)benzene-1,4-diol as a starting material. The compound is simple and easy to obtain, and the cost is low. Compared with the existing semi-synthetic method of quercetagetin A using baicalein as a starting material, the present application is a total synthesis method, which can greatly reduce the synthesis cost of quercetagetin, and the reaction operation involved in the present application is simple, short in period and easy to industrial production.

[0007] The technical scheme of the present application is as follows:

[0008] A preparation method of quercetagetin A, comprising the following steps:

[0009] S1: Michael addition reaction of the compound of formula II to obtain the compound of formula III or formula III-1:

[0010]

[0011] S2: the compound of formula III is subjected to FC acylation ring closure to obtain a compound of formula IV; or the compound of formula III-1 is subjected to FC acylation ring closure to obtain a compound of formula V:

[0012]

[0013] S3: the compound of formula IV is subjected to oxidation to obtain a compound of formula V:

[0014]

[0015] S4: the compound of formula V is subjected to methylation to obtain a compound of formula VI:

[0016]

[0017] S5: the compound of formula VI is subjected to removal of R1 to obtain a compound of formula I:

[0018]

[0019] wherein, the R1 is a hydroxyl protecting group; the R2 is alkoxy or hydroxyl.

[0020] Preferably, the hydroxyl protecting group is MOM, benzyl, trimethylsilyl, acetyl or sulfonyl; and / or, the alkoxy is methoxy or ethoxy.

[0021] Preferably, in the step S1, the compound of formula II is subjected to Michael addition reaction with a cinnamic acid derivative or a phenylpropynic acid derivative.

[0022] Preferably, the cinnamic acid derivative or the phenylpropynic acid derivative is added in a molar ratio of 1.0-1.5 times of the compound of formula II.

[0023] Preferably, the cinnamic acid derivative is methyl cinnamate, ethyl cinnamate or cinnamic acid; and / or, the phenylpropynic acid derivative is methyl phenylpropynate, ethyl phenylpropynate or phenylpropynic acid.

[0024] Preferably, the step S2 is carried out in the presence of a Lewis acid or a protonic acid catalyst; the Lewis acid or the protonic acid catalyst is added in a molar ratio or mass ratio of 1.0-5.0 times of the compound of formula III or the compound of formula III-1.

[0025] Preferably, the Lewis acid or the protonic acid catalyst is aluminum trichloride, zinc chloride, boron trifluoride etherate, polyphosphoric acid or sulfuric acid.

[0026] Preferably, the step S3 uses manganese dioxide, DMSO-iodine system, Jones reagent or Dess-Martin reagent as the oxidant.

[0027] Preferably, the step S4 uses dimethyl sulfate, methyl iodide or dimethyl carbonate as the methylation reagent.

[0028] Preferably, the reaction temperature of the step S1 is 50-150℃; the reaction temperature of the step S2 is 50-150℃; the reaction temperature of the step S2 is 50-150℃;

[0029] Preferably, the step S5 removes R1 by hydrogenation, acid hydrolysis or base hydrolysis.

[0030] Preferably, the step S2 uses one or more of chloroform, toluene, DMSO, chlorobenzene, nitrobenzene, polyphosphoric acid as the solvent.

[0031] The step S4 uses one or more of methanol, dichloromethane, tetrahydrofuran, acetone, acetonitrile as the solvent.

[0032] The step S5 uses one or more of methanol, ethanol, tetrahydrofuran, ethyl acetate as the solvent.

[0033] Compared with the prior art, the preparation method of the invention has the following advantages:

[0034] The compound of formula II 2,6-bis(benzyloxy)benzene-1,4-diol is simple to obtain and low in cost; compared with the prior art method of semi-synthesizing baiyunoside A using baicalein as the starting material, the invention is a total synthesis method, which can greatly reduce the synthesis cost of baiyunoside A, and the reaction operation involved in the invention is simple and easy to industrialize. BRIEF DESCRIPTION OF DRAWINGS

[0035] Figure 1 The synthesis route of the invention (synthesis route of the compound of formula III obtained in step S1);

[0036] Figure 2 Another synthesis route of the invention (synthesis route of the compound of formula III-1 obtained in step S1);

[0037] Figure 3 Mass spectrum of the synthetic Qianliaosu A of the present application;

[0038] Figure 4 NMR spectrum of the synthetic Qianliaosu A of the present application. DETAILED DESCRIPTION

[0039] The present application is further described below by way of specific embodiments, but this is not a limitation of the present application. Those skilled in the art can make various modifications or improvements according to the basic idea of the present application, as long as they do not deviate from the basic idea of the present application, and they are within the protection scope of the present application.

[0040] In the following examples and comparative examples, the reagents not specifically mentioned are conventional reagents, which can be purchased from conventional reagent production and sales companies.

[0041] Example 1

[0042] Preparation of compound 3-(3,5-bis(benzyloxy)-4-hydroxyphenoxy)-3-phenylpropionic acid of formula III

[0043] Into a reaction flask, toluene (3.2 L) was added, 2,6-bis(benzyloxy)benzene-1,4-diol (322 g, 1.00 mol, 1.00 eq) was added, cinnamic acid (156 g, 1.05 mol, 1.05 eq) was added, nitrogen was replaced for 3 times, under nitrogen protection, the temperature was raised to 110°C to reflux, the reaction was carried out for 8 h, the temperature was cooled to 50-60°C, toluene was removed by distillation under reduced pressure, the remaining material was 3-(3,5-bis(benzyloxy)-4-hydroxyphenoxy)-3-phenylpropionic acid crude product, which was directly used in the next step.

[0044] Mass spectrum: [M+1] + = 471.2.

[0045] Preparation of compound 5,7-bis(benzyloxy)-6-hydroxy-2-phenylchromen-4-one of formula IV

[0046] Polyphosphoric acid (966 g) was heated to 60°C to become mobile, and was added to the 3-(3,5-bis(benzyloxy)-4-hydroxyphenoxy)-3-phenylpropionic acid crude product obtained in the previous step, and was stirred at 60°C. After the system became uniform, nitrogen was replaced for 3 times, the temperature was raised to 80°C under nitrogen protection, and was kept for 5 h. The temperature was cooled to 50°C, and the system was slowly added to an ice-water mixture to precipitate a large amount of sticky solid. Dichloromethane was used for extraction, and the organic phase was separated. The organic phase was concentrated under reduced pressure to a paste, methanol was added for distillation, and methanol-water system was used for recrystallization. 5,7-bis(benzyloxy)-6-hydroxy-2-phenylchromen-4-one (334 g, two-step yield 74%) was obtained.

[0047] Mass spectrum: [M+1] += 453.2.

[0048] Preparation of compound of formula V, 5,7-bis(benzyloxy)-6-hydroxy-2-phenyl-4H- chromen-4-one

[0049] Dimethyl sulfoxide (0.9 L) was added to the reaction flask, iodine (17 g, 0.066 mol, 0.10 eq) was added, 5,7-bis(benzyloxy)-6-hydroxy-2-phenylbenzo pyran-4-one (300 g, 0.66 mol, 1.00 eq) was added, nitrogen was replaced for 3 times, and the temperature was raised to 100-110 °C under nitrogen protection, the reaction was carried out for 2 h, and the reaction solution was cooled to room temperature. A large amount of solid oil mixture was precipitated after water was added. Ethyl acetate was used for extraction, and the organic phase was concentrated under reduced pressure to a paste. Methyl tert-butyl ether was added for dispersion, filtration was carried out, and the filter cake was dried to obtain 5,7-bis(benzyloxy)-6-hydroxy-2-phenyl-4H-chromen-4-one (212 g, yield 71%).

[0050] Mass spectrum: [M+1] + = 451.2.

[0051] Preparation of compound of formula VI, 5,7-bis(benzyloxy)-6-methoxy-2-phenyl-4H- chromen-4-one

[0052] Tetrahydrofuran (0.8 L) was added to the reaction flask, potassium carbonate (79 g, 0.572 mol, 1.30 eq) was added, dimethyl sulfate (61 g, 0.484 mol, 1.10 eq) was slowly added, 5,7-bis(benzyloxy)-6-hydroxy-2-phenyl-4H-chromen-4-one (200 g, 0.44 mol, 1.00 eq) was added, and the temperature was raised to 50-60 °C. The reaction was carried out for 8 h, and the temperature was lowered to 40 °C. Concentration was carried out under reduced pressure to obtain an oil. Water was added for dilution, ethyl acetate was added for extraction, and the organic phase was separated. Basic activated carbon (20 g) was added to the organic phase, the temperature was raised to 40 °C, and the mixture was stirred for 4 h. Filtration was carried out while hot, the filter cake was washed with a small amount of ethyl acetate, and the filtrate was combined to obtain an ethyl acetate solution of 5,7-bis(benzyloxy)-6-methoxy-2-phenyl-4H-chromen-4-one, which was directly used in the next step.

[0053] Mass spectrum: [M+1] + = 465.2.

[0054] Preparation of compound of formula I, 5,7-dihydroxy-6-methoxy-2-phenyl-4H-chromen-4- one (Fissidensic Acid A)

[0055] The ethyl acetate solution of 5,7-bis(benzyloxy)-6-methoxy-2-phenyl-4H- chromen-4-one obtained in the above step was added into a hydrogenation kettle, palladium on carbon (10 g) was added, hydrogenation reaction was carried out at 60 °C for 4 h, the temperature was decreased to room temperature, filtration was carried out, activated carbon (20 g) was added into the filtrate, stirring was carried out at 40 °C for 4 h, filtration was carried out through a pad of filter paper, the filtrate was concentrated under reduced pressure, a large amount of solid was precipitated, methyl tert-butyl ether was added for dilution, filtration was carried out, and the filter cake was 5,7-dihydroxy-6-methoxy-2-phenyl-4H-chromen-4-one crude product with a purity of 98.2%, which was recrystallized to obtain refined product with a purity of 99%.

[0056] Mass: [M+1] + = 285.1.

[0057] NMR 1 HNMR (DMSO-d6, 400 MHz): 12.92 (1H, s), 8.04-8.08 (2H, m), 7.53-7.64 (3H, m), 6.96 (1H, s), 6.63 (1H, s), 3.76 (3H, s).

[0058] Example 2

[0059] Preparation of compound 3-(3,5-bis(benzyloxy)-4-hydroxyphenoxy)-3-phenylacrylic acid of formula III-1

[0060] Toluene (1.6 L) was added into a reaction bottle, 2,6-bis(benzyloxy)benzene-1,4-diol (161 g, 0.50 mol, 1.00 eq) was added, propargyl acid (77 g, 0.525 mol, 1.05 eq) was added, nitrogen replacement was carried out for 3 times, the temperature was increased to 90 °C under nitrogen protection, reaction was carried out for 3 h, the temperature was cooled to 50-60 °C, toluene was removed by distillation under reduced pressure, and the remaining material was 3-(3,5-bis(benzyloxy)-4-hydroxyphenoxy)-3-phenylacrylic acid crude product, which was directly used in the next step.

[0061] Mass: [M+1] + = 469.2.

[0062] Preparation of compound 5,7-bis(benzyloxy)-6-hydroxy-2-phenyl-4H-chromen-4-one of formula V

[0063] The polyphosphoric acid (400 g) was heated to 60 °C to become fluid, and was added to the crude 3-(3,5-bis(benzyloxy)-4-hydroxyphenoxy)-3-phenylacrylic acid obtained in the previous step. The system was stirred at 60 °C, and after it became homogeneous, it was replaced with nitrogen three times. The system was heated to 95 °C under nitrogen protection, and was kept at this temperature for 2 h. The system was cooled to 50 °C, and was slowly added to an ice-water mixture. A large amount of viscous oily substance was precipitated. The oily substance was extracted with dichloromethane, and the organic phase was separated. The organic phase was concentrated under reduced pressure, and was purified by silica gel column separation to obtain 5,7-bis(benzyloxy)-6-hydroxy-2-phenyl-4H-chromen-4-one (70 g, two-step yield 31%).

[0064] Mass spectrum: [M+1] + = 451.2.

[0065] The above examples are only illustrative of the principles of the present application and its efficacy, and are not intended to limit the present application. Any person skilled in the art can modify or change the above examples without departing from the spirit and scope of the present application. Therefore, all equivalent modifications or changes completed by those skilled in the art without departing from the spirit and technical thought disclosed by the present application should be covered by the claims of the present application.

Claims

1. A method for preparing gypenoside A, characterized in that, The method comprises the following steps: S1: Michael addition reaction of the compound of formula II to obtain a compound of formula III or a compound of formula III-1: ； S2: FC acylation reaction of the compound of formula III to obtain a compound of formula IV, or FC acylation reaction of the compound of formula III-1 to obtain a compound of formula V: ； S3: oxidation of the compound of formula IV to obtain a compound of formula V: ； S4: methylation of the compound of formula V to obtain a compound of formula VI: ； S5: removal of R1 from the compound of formula VI to obtain a compound of formula I: ； wherein the R1 is a hydroxyl protecting group; the R2 is alkoxy or hydroxyl; the alkoxy is methoxy or ethoxy.

2. The method for preparing the multilayer paper pigment A as described in claim 1, characterized in that, The hydroxyl protecting group is MOM, benzyl, trimethylsilyl, acetyl or sulfonyl.

3. The method for preparing the multilayer paper pigment A as described in claim 1, characterized in that, In the step S1, the compound of formula II is subjected to Michael addition reaction with cinnamic acid or a cinnamic acid derivative or phenylpropargylic acid or a phenylpropargylic acid derivative; the cinnamic acid derivative is methyl cinnamate or ethyl cinnamate; the phenylpropargylic acid derivative is methyl phenylpropargylic acid or ethyl phenylpropargylic acid.

4. The method for preparing the multilayer paper pigment A as described in claim 3, characterized in that, In the step S1, the addition amount of the cinnamic acid or the cinnamic acid derivative or the phenylpropargylic acid or the phenylpropargylic acid derivative is 1.0-1.5 times the molar ratio of the compound of formula II.

5. The method for preparing the multilayer paper pigment A as described in claim 1, characterized in that, The step S2 is carried out in the presence of a Lewis acid or a protonic acid catalyst; the Lewis acid or the protonic acid catalyst is added in an amount of 1.0-5.0 times the molar ratio or mass ratio of the compound of formula III or the compound of formula III-1.

6. The method for preparing the multilayer paper pigment A as described in claim 5, characterized in that, The Lewis acid or the protonic acid catalyst is aluminum trichloride, zinc chloride, boron trifluoride etherate, polyphosphoric acid or sulfuric acid.

7. The method for preparing the multilayer paper pigment A as described in claim 1, characterized in that, In the step S3, manganese dioxide, DMSO-iodine system, Jones reagent or Dess-Martin reagent is used as the oxidant.

8. The method for preparing the multilayer paper pigment A as described in claim 1, characterized in that, In the step S4, dimethyl sulfate, iodomethane or dimethyl carbonate is used as the methylation reagent.

9. The method for preparing the multilayer paper pigment A as described in claim 1, characterized in that, The reaction temperature in the step S1 is 50-150 DEG C; the reaction temperature in the step S2 is 50-150 DEG C; In the step S2, one or more of chloroform, toluene, DMSO, chlorobenzene, nitrobenzene and polyphosphoric acid is used as the solvent; In the step S4, one or more of methanol, dichloromethane, tetrahydrofuran, acetone and acetonitrile is used as the solvent; In the step S5, the removal of R1 is carried out by hydrogenation, acid hydrolysis or base hydrolysis; And / or, in the step S5, one or more of methanol, ethanol, tetrahydrofuran and ethyl acetate is used as the solvent.

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