Total synthesis method of salvianolic acid F

Abstract

The invention relates to a total synthesis method of salvianolic acid F. The method comprises the following steps: brominating 2, 3-dimethoxybenzaldehyde to obtain 2-bromine-5, 6-dimethoxybenzaldehyde, carrying out Wittig reaction to obtain (E)-1-bromine-2-(3, 4-dimethoxystyryl)-3, 4-dimethoxybenzene, and carrying out reaction on (E)-1-bromine-2-(3, 4-dimethoxystyryl)-3, 4-dimethoxybenzene to obtain the salvianolic acid F. The preparation method comprises the following steps: taking salvianolic acid as a raw material, reacting with acrylate under the action of alkali and a palladium catalyst to obtain tetramethyl salvianolic acid F, and obtaining salvianolic acid F from the tetramethyl salvianolic acid F and a demethylation reagent. The preparation method is short in route and reasonable in process, the adopted reagent is safe, low in cost and free of environmental pollution, meanwhile, the preparation method has the advantages of simplicity in operation, easiness in separation and the like, and the obtained product is high in yield.

Description

Technical Field

[0001] The present invention relates to a total synthesis method of salvianolic acid F, belonging to the technical field of biomedicine. Background Art

[0002] Salvianolic acid F (CAS: 158732-59-3), chemical name: (2E)-3-[2-[(1E)-2-(3,4-Dihydroxyphenyl)ethenyl]-3,4-dihydroxyphenyl]-2-propenoic acid.

[0003] Structural formula:

[0004]

[0005] Salvianolic acid F has significant effects on the cardiovascular system.

[0006] However, the content of salvianolic acid F in Salvia miltiorrhiza is low, and only trace amounts of salvianolic acid F can be obtained by extraction. Due to the high cost of direct extraction from plants, large quantities of salvianolic acid F are difficult to obtain. Therefore, realizing the artificial synthesis and industrialization of salvianolic acid F and its derivatives has important practical significance for the pharmacological activity research and industrialization of salvianolic acid F.

[0007] Currently, only two literatures have reported the synthesis of salvianolic acid F. The earliest one was used by Vincent Dalla (Tetrahedron, 1999, 55, 6923-6930). 3,4-Dimethoxybenzyl alcohol was brominated with bromine, followed by a Wittig reaction, deprotonation of bromine with n-BuLi at -78 °C to introduce an aldehyde group, a Knovengel reaction, base hydrolysis to remove the methyl group of the methyl ester, and finally the four methyl groups of the aryl methyl ether were removed by BBr3 to obtain salvianolic acid F. This route is classical and short, but it has the following disadvantages: using dangerous n-BuLi that requires a low-temperature environment, the yield of the Knovengel reaction is as low as 20%, and the yield of demethylation with BBr3 is as low as 26%, etc.

[0008] The invention patent (CN108689829B) applied by Zhang Wanbin et al. reported a preparation method of salvianolic acid F. Tetramethyl salvianolic acid F reacts in a solvent under the action of an aluminum salt and a base to obtain salvianolic acid F. This invention has the advantages of mild reaction conditions, few side reactions, high yield, and convenient post-treatment. This route successfully prepared salvianolic acid F and solved the disadvantages of using BBr3 reagent. However, this patent only reported the demethylation step.

[0009] In addition, there are also some deficiencies in the methods reported in other literatures for salvianolic acid F analogues. For example, Xuan Lijiang (Tetrahedron, 2016, 72, 5047-5055.) used 2,3-disubstituted benzaldehyde as the starting material and obtained the important intermediate methyl (E)-3-(2-((E)-3,4-disubstituted styryl)-3,4-disubstituted phenyl)acrylate mainly through C-H activation reaction and Wittig reaction. Among them, the C-H activation reaction requires the addition of additives AgSbF6 and CuOAc2 and is carried out at a high temperature of 110 °C, and the reaction yield is relatively low. In the Wittig reaction, an olefin with a mixed cis-trans configuration is obtained, and it is necessary to further transform to obtain a compound with a pure trans configuration. The reaction conditions are relatively harsh, the operation is relatively complex, and AgSbF6 has certain toxicity and corrosiveness, which is not conducive to industrialization.

[0010] In summary, the existing synthesis methods related to salvianolic acid F have disadvantages such as high cost of starting materials, harsh reaction conditions, complex operations, and the use of toxic, harmful and expensive reagents, resulting in high costs, low total yields, and being not conducive to environmental protection and large-scale industrial production. Summary of the Invention

[0011] The purpose of the present invention is to overcome the defects of the above-mentioned existing technologies and provide a total synthesis method of salvianolic acid F with reasonable process, simple operation and easy industrialization.

[0012] The present invention is achieved through the following technical solutions: A preparation method of salvianolic acid F, the reaction route of the method is as follows:

[0013] The reaction steps are as follows:

[0014] Step 1: 2,3-Dimethoxybenzaldehyde reacts with a halogenating reagent to obtain 2-bromo-5,6-dimethoxybenzaldehyde;

[0015] Step 2: 3,4-Dimethoxybenzyl bromide reacts with phenylphosphine to obtain (3,4-dimethoxybenzyl)triphenylphosphonium salt;

[0016] Step 3: 2-Bromo-5,6-dimethoxybenzaldehyde reacts with (3,4-dimethoxybenzyl)triphenylphosphonium salt under the catalysis of a base to obtain (E)-1-bromo-2-(3,4-dimethoxystyryl)-3,4-dimethoxybenzene;

[0017] Step 4: (E)-1-Bromo-2-(3,4-dimethoxystyryl)-3,4-dimethoxybenzene reacts with an acrylate under the action of a base and a catalyst to obtain tetramethyl salvianolic acid F;

[0018] Step 5: Tetramethyl salvianolic acid F is demethylated to obtain salvianolic acid F.

[0019] The method according to the present invention, wherein in step one, 2,3-dimethoxybenzaldehyde reacts with a halogenating reagent at a temperature of room temperature to 50 °C to obtain 2-bromo-5,6-dimethoxybenzaldehyde. In step one, the molar ratio of 2,3-dimethoxybenzaldehyde to the halogenating reagent is 1:(0.5 to 10), and the halogenating reagent is selected from one of N-halosuccinimide (NXS), 1,3-dihalo-5,5-dimethylhydantoin (DXDMH), and trihaloisocyanuric acid (TXCA), and the X element is selected from one of iodine, bromine, and chlorine.

[0020] The method according to the present invention, wherein in step two, 3,4-dimethoxybenzyl bromide reacts with phenylphosphine at a temperature of 80 to 120 °C to obtain (3,4-dimethoxybenzyl)triphenylphosphonium salt. In step two, the molar ratio of 3,4-dimethoxybenzyl bromide to phenylphosphine is 1:(1 to 10), and the phenylphosphine is tetraphenylphosphonium.

[0021] The method according to the present invention, wherein in step three, 2-bromo-5,6-dimethoxybenzaldehyde and (3,4-dimethoxybenzyl)triphenylphosphonium salt react under base catalysis at a temperature of room temperature to 100 °C to obtain (E)-1-bromo-2-(3,4-dimethoxystyryl)-3,4-dimethoxybenzene. In step three, the molar ratio of 2-bromo-5,6-dimethoxybenzaldehyde to (3,4-dimethoxybenzyl)triphenylphosphonium salt is 1:(1 to 30), and the molar ratio of 2-bromo-5,6-dimethoxybenzaldehyde to the base is 1:(1 to 10), and the base is selected from one or a combination of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-pentoxide, sodium tert-pentoxide, potassium tert-pentoxide, lithium hydroxide, sodium hydroxide, and potassium hydroxide.

[0022] The method according to the present invention, wherein in step four, (E)-1-bromo-2-(3,4-dimethoxystyryl)-3,4-dimethoxybenzene reacts with an acrylate at a temperature of 80 to 120 °C under the action of a base and a catalyst to obtain tetramethyl salvianolic acid F. In step four, the molar ratio of (E)-1-bromo-2-(3,4-dimethoxystyryl)-3,4-dimethoxybenzene to the catalyst is 1:(1 to 10); the molar ratio of (E)-1-bromo-2-(3,4-dimethoxystyryl)-3,4-dimethoxybenzene to the base is 1:(1 to 10), and the catalyst is selected from one or a combination of palladium acetate, bis(triphenylphosphine)palladium dichloride, palladium chloride, palladium di(acetylacetonate), diphenylphosphinoferrocene dichloride, palladium trifluoroacetate, and palladium pivalate, and the base is selected from one or a combination of triethylamine, diethylamine, ammonia water, piperidine, and carbonate.

[0023] The method according to the present invention, wherein, in step five, tetramethyl salvianolic acid F is demethylated at 80-120°C to obtain salvianolic acid F; the molar ratio of tetramethyl salvianolic acid F to the demethylating reagent is 1:(1-30), and the demethylating reagent is one or a combination of BBr3, AlX3 (X = Cl, Br or F).

[0024] Compared with the prior art, the present invention has the following beneficial effects:

[0025] (1) The bromination uses a novel halogenating reagent that is easy to obtain as the bromine source to replace bromine, which is easy to be toxic and has strong oxidizing properties.

[0026] (2) The starting material is replaced from 2-hydroxy-3-methoxybenzaldehyde to 2,3-dimethoxybenzaldehyde. The raw material is cheaper and easier to obtain, eliminating the use of acetic anhydride and subsequent corresponding group conversions. After the reaction, the pure product can be obtained by slurrying.

[0027] (3) During the Wittig reaction, t-KOBu is used instead of K2CO3 / 18-crown-6. The yield is increased from 78% to 85%, and the catalytic system is simplified. There is no cis product in the reaction, the reaction operation is simple, and the solvent is easier to handle.

[0028] (4) The preparation method of the present invention has a short route, a reasonable process, uses safe and low-cost reagents, does not pollute the environment, and has the advantages of simple operation and easy separation. The yield of the obtained product is high. BRIEF DESCRIPTION OF THE DRAWINGS

[0029] By reading the detailed description of the non-limiting embodiments with reference to the following drawings, other features,

[0030] objects and advantages of the present invention will become more apparent:

[0031] Figure 1 is the 1H NMR spectrum of salvianolic acid F in the present invention;

[0032] Figure 2 is the 13C NMR spectrum of salvianolic acid F in the present invention. DETAILED DESCRIPTION OF THE EMBODIMENTS

[0033] The present invention will be described in detail below with reference to specific embodiments. The following embodiments will help those skilled in the art to further understand the present invention, but do not limit the present invention in any form. It should be noted that those of ordinary skill in the art can make several modifications and improvements without departing from the concept of the present invention. These all belong to the protection scope of the present invention.

[0034] Example 1

[0035] I. Synthesis of 2-bromo-5,6-dimethoxybenzaldehyde

[0036] Weigh 2,3-dimethoxybenzaldehyde (100 g, 600 mmol) and put it into a round-bottom flask. Add 750 mL of DMF, and finally add NBS (128.2 g, 720 mmol). Stir the reaction at room temperature for 48 h. After the reaction is completed, add 2-fold amount of water to the reaction solution. After solid precipitation, filter by suction. Pulverize the solid for 3 h, filter by suction and dry to obtain 117.6 g of white solid 2-bromo-5,6-dimethoxybenzaldehyde in total.

[0037] II. Synthesis of (3,4-dimethoxybenzyl)triphenylphosphonium salt

[0038] Place 3,4-dimethoxybenzyl bromide (60 g, 260.9 mmol) in a round-bottom flask, add 360 mL of toluene, add triphenylphosphine (91.3 g, 350.6 mmol), and reflux the reaction at 110 °C for 5 h. After the reaction is completed, white solid is produced. Filter the reaction solution, and dry to obtain 133.7 g of white powdery solid (3,4-dimethoxybenzyl)triphenylphosphonium salt in total.

[0039] III. Synthesis of (E)-1-bromo-2-(3,4-dimethoxystyryl)-3,4-dimethoxybenzene

[0040] Weigh 2-bromo-5,6-dimethoxybenzaldehyde (18.4 g, 74.9 mmol) and place it in a round-bottom flask. Add 450 mL of acetonitrile, add (3,4-dimethoxybenzyl)triphenylphosphonium salt (39.0 g, 79.365 mmol), add t-BuONa (21.9 g, 224.6 mmol), and react at 78 °C for 16 h under nitrogen protection. After the reaction is completed, filter the reaction, and perform column chromatography for rough separation on the filtrate by making sand. After recrystallization, obtain 20.2 g of white solid (3,4-dimethoxybenzyl)triphenylphosphonium salt in total.

[0041] IV. Synthesis of methyl (E)-3-[2-[(E)-3,4-dimethoxystyryl]-3,4-dimethoxyphenyl]acrylate

[0042] Weigh (E)-1-bromo-2-(3,4-dimethoxystyryl)-3,4-dimethoxybenzene (30 g, 83.2 mmol), add 300 mL of DMF, add triphenylphosphine (19 g, 32.8 mmol), add triethylamine (20.1 g, 208.3 mmol), and add palladium acetate (7.0 g, 32.8 mmol). Stir vigorously at room temperature for 15 min, transfer the reaction to 110 °C, and dropwise add a methyl acrylate / DMF solution (methyl acrylate: 183.5 mmol) under a nitrogen atmosphere. After the addition is complete, react at 110 °C under a nitrogen atmosphere for 18 h. After the reaction is completed, add 3 times the amount of purified water to the reaction solution, extract the aqueous layer with ethyl acetate 3 times, combine the ethyl acetate layers, wash the ethyl acetate layer with saturated brine 3 times to remove DMF in the ethyl acetate layer, dry the ethyl acetate layer with anhydrous sodium sulfate, perform rough column chromatography separation, and obtain 29.1 g of a pale yellow solid AB-2 after recrystallization.

[0043] V. Synthesis of Salvianolic Acid F

[0044] Dissolve toluene (125 mL) in N,N-dimethylaniline (40.2 mL, 250 mmol) and AlCl3 (31.8 g, 250 mmol), stir for 30 min, then dropwise add to the reaction flask containing (E)-methyl 3-[2-[(E)-3,4-dimethoxystyryl]-3,4-dimethoxyphenyl]acrylate (9.6 g, 25 mmol), react at 100 °C for 12 h. After the reaction is completed, cool the reaction to room temperature, then slowly add twice the amount of water, stir, separate the toluene phase, add 150 mL of 3 mmol hydrochloric acid, add sodium chloride to the aqueous phase until the aqueous layer is saturated, extract the mixture with ethyl acetate, dry over anhydrous sodium sulfate, and perform column chromatography separation to obtain 6.12 g of a pale yellow solid, which is salvianolic acid F. 1 H NMR (400 MHz, Acetone-d6) δ 8.19 (s, 1H, HCOOH), 8.03 (d, J = 15.8 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 16.3 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 6.91 (dd, J = 8.2, 2.0 Hz, 1H), 6.84 (t, J = 8.0 Hz, 2H), 6.73 (d, J = 16.4 Hz, 1H), 6.28 (d, J = 15.8 Hz, 1H). 13CNMR (101 MHz, Acetone) δ 168.28, 163.26, 147.09, 146.24, 145.98, 145.12, 143.86, 137.13, 130.82, 127.20, 126.07, 120.13, 120.00, 119.85, 117.11, 116.13, 114.69, 113.62.

[0045] Example 2

[0046] I. Synthesis of 2 - bromo - 5,6 - dimethoxybenzaldehyde

[0047] Weigh 2,3 - dimethoxybenzaldehyde (100 g, 600 mmol) and put it into a round - bottom flask, add 750 mL of DMF, and finally add 1,3 - dihalo - 5,5 - dimethylhydantoin (205.9 g, 720 mmol). Stir and react at 45 °C for 36 h. After the reaction is completed, add 2 times the amount of water to the reaction solution. After solid precipitation, filter by suction. Pulverize the solid for 3 h, filter by suction and dry to obtain 123.5 g of white solid 2 - bromo - 5,6 - dimethoxybenzaldehyde in total.

[0048] II. Synthesis of (3,4 - dimethoxybenzyl)triphenylphosphonium salt

[0049] Place 3,4 - dimethoxybenzyl bromide (60 g, 260.9 mmol) in a round - bottom flask, add 360 mL of mesitylene, add triphenylphosphine (91.3 g, 350.6 mmol), and reflux and react at 110 °C for 5 h. After the reaction is completed, white solid is produced. Filter the reaction solution, and after drying, obtain 120.8 g of white powdery solid (3,4 - dimethoxybenzyl)triphenylphosphonium salt. III. Synthesis of (E) - 1 - bromo - 2 - (3,4 - dimethoxystyryl) - 3,4 - dimethoxybenzene

[0050] Weigh 2 - bromo - 5,6 - dimethoxybenzaldehyde (18.4 g, 74.9 mmol) and put it into a round - bottom flask, add 450 mL of acetonitrile, add (3,4 - dimethoxybenzyl)triphenylphosphonium salt (39.0 g, 79.365 mmol), add t - BuOK (25.2 g, 224.6 mmol), and react at 75 °C for 18 h under nitrogen protection. After the reaction is completed, filter the reaction, and perform column chromatography and rough fractionation on the filtrate with silica gel. After recrystallization, obtain 21.1 g of white solid (3,4 - dimethoxybenzyl)triphenylphosphonium salt in total.

[0051] IV. Synthesis of methyl (E) - 3 - [2 - [(E) - 3,4 - dimethoxystyryl] - 3,4 - dimethoxyphenyl]acrylate

[0052] Weigh (E)-1-bromo-2-(3,4-dimethoxystyryl)-3,4-dimethoxybenzene (30 g, 83.2 mmol), add 300 mL of DMF, add triphenylphosphine (19 g, 32.8 mmol), add diethylamine (15.2 g, 208.3 mmol), and add palladium chloride (5.8 g, 32.8 mmol). Stir vigorously at room temperature for 30 min, transfer the reaction to 115 °C, and dropwise add methyl acrylate / DMF solution (methyl acrylate: 183.5 mmol) under a nitrogen atmosphere. After the addition is complete, react at 110 °C under a nitrogen atmosphere for 18 h. After the reaction is completed, add 3 times the amount of purified water to the reaction solution, extract the aqueous layer with ethyl acetate 3 times. After combining the ethyl acetate layers, wash the ethyl acetate layer with saturated brine 3 times to remove DMF in the ethyl acetate layer. After drying the ethyl acetate layer with anhydrous sodium sulfate, perform a preliminary column chromatography separation, and obtain 22.0 g of light yellow solid AB-2 after recrystallization.

[0053] V. Synthesis of Salvianolic Acid F

[0054] Dissolve xylene (125 mL) in N,N-dimethylaniline (40.2 mL, 250 mmol) and AlBr3 (66.7 g, 250 mmol), stir for 30 min, then dropwise add it into the reaction flask containing methyl (E)-3-[2-[(E)-3,4-dimethoxystyryl]-3,4-dimethoxyphenyl]acrylate (9.6 g, 25 mmol). React at 100 °C for 12 h. After the reaction is completed, cool the reaction to room temperature, then slowly add twice the amount of water, stir, separate the organic phase, add 150 mL of 3 mmol hydrochloric acid, add sodium chloride to the aqueous phase until the aqueous layer is saturated, extract the mixture with ethyl acetate, dry with anhydrous sodium sulfate, and perform column chromatography separation to obtain 5.95 g of light yellow solid, which is salvianolic acid F. 1 H NMR (400 MHz, Acetone-d6) δ 8.19 (s, 1H, HCOOH), 8.03 (d, J = 15.8 Hz, 1H), 7.18 (d, J = 8.4 Hz, 1H), 7.17 (d, J = 16.3 Hz, 1H), 7.12 (d, J = 2.0 Hz, 1H), 6.91 (dd, J = 8.2, 2.0 Hz, 1H), 6.84 (t, J = 8.0 Hz, 2H), 6.73 (d, J = 16.4 Hz, 1H), 6.28 (d, J = 15.8 Hz, 1H). 1313C NMR (101 MHz, Acetone) δ 168.28, 163.26, 147.09, 146.24, 145.98, 145.12, 143.86, 137.13, 130.82, 127.20, 126.07, 120.13, 120.00, 119.85, 117.11, 116.13, 114.69, 113.62.

Claims

1. A preparation method of salvianolic acid F, characterized in that, The reaction route is as follows: The reaction steps are as follows: Step 1: 2,3-Dimethoxybenzaldehyde reacts with a halogenating reagent to obtain 2-bromo-5,6-dimethoxybenzaldehyde; Step 2: 3,4-Dimethoxybenzyl bromide reacts with phenylphosphine to obtain (3,4-dimethoxybenzyl)triphenylphosphonium salt; Step 3: 2-Bromo-5,6-dimethoxybenzaldehyde reacts with (3,4-dimethoxybenzyl)triphenylphosphonium salt under base catalysis to obtain (E)-1-bromo-2-(3,4-dimethoxystyryl)-3,4-dimethoxybenzene; Step 4: (E)-1-Bromo-2-(3,4-dimethoxystyryl)-3,4-dimethoxybenzene reacts with an acrylate under the action of a base and a catalyst to obtain tetramethyl salvianolic acid F; Step 5: Tetramethyl salvianolic acid F is demethylated to obtain salvianolic acid F.

2. The method according to claim 1, characterized in that, In Step 1, 2,3-dimethoxybenzaldehyde reacts with a halogenating reagent at room temperature to 50 °C to obtain 2-bromo-5,6-dimethoxybenzaldehyde.

3. The method according to claim 1, characterized in that In Step 1, the molar ratio of 2,3-dimethoxybenzaldehyde to the halogenating reagent is 1:(0.5 - 10), and the halogenating reagent is selected from one of N-halosuccinimide (NXS), 1,3-dihalo-5,5-dimethylhydantoin (DXDMH), and trihaloisocyanuric acid (TXCA), where the X element is selected from one of iodine, bromine, and chlorine.

4. The method according to claim 1, characterized in that In Step 2, 3,4-dimethoxybenzyl bromide reacts with phenylphosphine at 80 - 120 °C to obtain (3,4-dimethoxybenzyl)triphenylphosphonium salt.

5. The method according to claim 4, wherein In Step 2, the molar ratio of 3,4-dimethoxybenzyl bromide to phenylphosphine is 1:(1 - 10), and the phenylphosphine is tetraphenylphosphine.

6. The method according to claim 1, characterized in that In Step 3, 2-bromo-5,6-dimethoxybenzaldehyde reacts with (3,4-dimethoxybenzyl)triphenylphosphonium salt under base catalysis at room temperature to 100 °C to obtain (E)-1-bromo-2-(3,4-dimethoxystyryl)-3,4-dimethoxybenzene.

7. The method according to claim 6, wherein In Step 3, the molar ratio of 2-bromo-5,6-dimethoxybenzaldehyde to (3,4-dimethoxybenzyl)triphenylphosphonium salt is 1:(1 - 30), and the molar ratio of 2-bromo-5,6-dimethoxybenzaldehyde to the base is 1:(1 - 10), where the base is selected from one of lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, lithium tert-pentoxide, sodium tert-pentoxide, potassium tert-pentoxide, lithium hydroxide, sodium hydroxide, and potassium hydroxide or a combination thereof.

8. The method according to claim 1, wherein In Step 4, (E)-1-bromo-2-(3,4-dimethoxystyryl)-3,4-dimethoxybenzene reacts with an acrylate under the action of a base and a catalyst at 80 - 120 °C to obtain tetramethyl salvianolic acid F.

9. The method according to claim 8, wherein In Step 4, the molar ratio of (E)-1-bromo-2-(3,4-dimethoxystyryl)-3,4-dimethoxybenzene to the catalyst is 1:(1 to 10); the molar ratio of (E)-1-bromo-2-(3,4-dimethoxystyryl)-3,4-dimethoxybenzene to the base is 1:(1 to 10), where the catalyst is selected from one or a combination of palladium acetate, bis(triphenylphosphine)palladium dichloride, palladium chloride, palladium di(acetylacetonate), diphenylphosphinoferrocene dichloride, palladium trifluoroacetate, palladium pivalate; and the base is selected from one or a combination of triethylamine, diethylamine, ammonia water, piperidine, carbonate salts.

10. The method according to claim 1, characterized in that, In Step 5, tetramethyl salvianolic acid F undergoes demethylation at 80 to 120 °C to obtain salvianolic acid F; the molar ratio of tetramethyl salvianolic acid F to the demethylation reagent is 1:(1 to 30), and the demethylation reagent is selected from one or a combination of BBr3, AlX3 (X = Cl, Br or F).

Images