A synthetic method of daphnetin

Abstract

The present application relates to the technical fields of chemical medicine synthesis, and discloses a synthesis method of daphnetin. The method uses pyrogallic acid and malic acid as raw materials, uses concentrated sulfuric acid as a condensation catalyst, adds a water-removing agent and a phase transfer catalyst, and performs a reaction in an organic solvent, so that high-purity daphnetin crude products can be prepared, medicinal-grade daphnetin can be prepared by combining with a recrystallization technology, the yield of the product can reach more than 90%, and the purity of the product can reach 99%.

Description

Technical Field

[0001] The present invention relates to the field of medical technology, and in particular to a method for synthesizing daphnetin. Background Art

[0002] Daphnetin is a drug used in cardiovascular and cerebrovascular systems. Pharmacological evidence suggests it has anti-inflammatory, anti-platelet aggregation, anti-thrombotic, vasodilatory, coronary flow-increasing, anti-hypoxic, and myocardial metabolism-improving effects. It is clinically used to treat thromboangiitis obliterans and coronary heart disease, and has a strong analgesic effect. Its common name is Daphnetin, its chemical name is 7,8-dihydroxycoumarin, and its chemical structure is as follows:

[0003]

[0004] A document (Aust. J. Chem.) reports that the synthesis of daphnetin primarily involves Pechman condensation using pyrogallic acid and malic acid as raw materials in the presence of concentrated sulfuric acid as a catalyst and a dehydrator. This method suffers from low yield, intense heat release during the reaction, the generation of large amounts of toxic gases, the tendency for the raw materials to carbonize, and the resulting product, which is poor in appearance, sticky, and has small particles, a high water content, and difficulty drying. Furthermore, the concentrated sulfuric acid required for the reaction is highly corrosive, placing high demands on the quality of the equipment used in the synthesis process, resulting in significant losses and high production costs. Furthermore, patent CN1827612A discloses a new process for synthesizing daphnetin, using pyrogallic acid and malic acid as raw materials, concentrated sulfuric acid as a catalyst, and the addition of an appropriate amount of a dehydrating agent and an organic solvent to produce the product. This process offers advantages such as mild reaction conditions, easy operational control of the reaction process, and few by-products. However, the yield and purity of this method still need to be further improved. Summary of the Invention

[0005] The main purpose of the present invention is to provide a method for synthesizing daphnetin to solve the technical problems of low yield and low purity in the synthesis process of daphnetin in the prior art.

[0006] To achieve the above object, the present invention provides a method for synthesizing daphnetin, comprising the following steps:

[0007] Pyrogallol and malic acid are used as starting raw materials, and a first catalyst, a water scavenger, a second catalyst and an organic solvent are added to carry out a reaction to obtain daphnetin.

[0008] The equation for the above reaction is as follows:

[0009]

[0010] The first catalyst is concentrated sulfuric acid with a concentration of not less than 70%;

[0011] The second catalyst is a phase transfer catalyst selected from one or more of mercapto-terminated polyethylene glycol-2000, cyclodextrin and 15-crown-5. More preferably, the second catalyst is mercapto-terminated polyethylene glycol-2000.

[0012] The water-removing agent is one or more of molecular sieves, calcium oxide, phosphorus pentoxide, concentrated sulfuric acid, soda lime, anhydrous calcium sulfate, anhydrous magnesium sulfate and anhydrous sodium sulfate. More preferably, the water-removing agent is nanoscale anhydrous magnesium sulfate.

[0013] The organic solvent is one or more of dioxane, carbon tetrachloride, dimethylbenzene, ethyl acetate, butanone, isopropanol, butanol, acetone, methyl ethyl ketone, cyclohexanone, tetrahydrofuran, toluene, chlorobenzene, dichloromethane and dichloroethane. More preferably, the organic solvent is dimethylbenzene.

[0014] The present application uses pyrogallic acid and malic acid as raw materials, concentrated sulfuric acid as a condensation catalyst, adds a water-removing agent and a phase transfer catalyst, and performs a reaction in an organic solvent, so that a high-purity daphnetin crude product can be prepared, and a medicinal-grade daphnetin can be prepared by using a recrystallization technique. The product yield is 78-92%, and can be up to more than 90%, and the product purity can reach 99%.

[0015] In the reaction system, the molar ratio of the pyrogallic acid to the malic acid is 1:1-5. The molar ratio of the first catalyst to the pyrogallic acid is 1-10:1; the molar ratio of the water-removing agent to the pyrogallic acid is 0.01-0.05:1; the molar ratio of the second catalyst to the pyrogallic acid is 0.001-0.003:1; and the volume-mass ratio of the organic solvent to the pyrogallic acid is 1-20:1 (L / kg).

[0016] The reaction temperature is 90-140°C, and more preferably 100-140°C; and the reaction time is 10-100 min, and more preferably 10-60 min.

[0017] After the reaction is completed, a step of neutralizing the reaction system using a post-processing solvent and then performing extraction is further included. The post-processing solvent is one or more of ethanol, methanol, acetonitrile, dichloromethane, ethyl acetate and water. More preferably, the post-processing solvent is water.

[0018] Preferably, the present application provides a synthesis method of daphnetin, which includes the following steps:

[0019] The pyrogallic acid and malic acid are used as starting materials, the molar ratio of pyrogallic acid to malic acid is 1:1-5, and a first catalyst is added, wherein the molar ratio of the first catalyst to pyrogallic acid is 1-10:1; then a water-removing agent, a second catalyst and an organic solvent are added, wherein the molar ratio of the water-removing agent to pyrogallic acid is 0.01-0.05:1, the molar ratio of the second catalyst to pyrogallic acid is 0.001-0.003:1, and the volume-mass ratio of the organic solvent to pyrogallic acid is 1-20:1 (L / kg); the mixture is slowly stirred and heated to 100-140 DEG C for 10-60 min; after the reaction is completed, the mixture is poured into a post-treatment solvent, and then is left to stand for 48 h, precipitated, filtered, and washed with the post-treatment solvent until neutral, and dried at 105 DEG C, thereby obtaining daphnetin.

[0020] Compared with the prior art, the synthetic process of daphnetin provided by the application creatively uses the combined catalysis technology of phase transfer catalyst and water-removing agent, improves the regioselectivity of the reaction process, reduces by-products, overcomes the problems of heat release and material caking, and significantly improves the yield and purity, with a total yield of 78-92%, up to 92.75%, and a purity of up to 99%. The subsequent refining uses a non-organic solvent as a refining solvent, and the pharmaceutical-grade daphnetin meeting the composite ICH Guideline can be obtained. BRIEF DESCRIPTION OF DRAWINGS

[0021] In order to more clearly illustrate the technical solutions in the embodiments of the present application or the prior art, the drawings needed in the embodiments or the prior art description will be briefly introduced. Obviously, the drawings in the following description are only some embodiments of the present application, and other related drawings can be obtained by those skilled in the art without creative labor.

[0022] Figure 1 HPLC spectrum of the daphnetin product prepared in Example 1;

[0023] Figure 2 HPLC spectrum of the daphnetin product prepared in Example 6;

[0024] Figure 3 NMR hydrogen spectrum of the daphnetin product prepared in Example 6;

[0025] Figure 4 NMR carbon spectrum of the daphnetin product prepared in Example 6;

[0026] Figure 5 High-resolution mass spectrum of the daphnetin product prepared in Example 6.

[0027] The implementation, functional features and advantages of the present application will be further described with reference to the embodiments and the drawings. DETAILED DESCRIPTION

[0028] The technical solutions in the embodiments of the present application will be clearly and completely described below. Obviously, the described embodiments are only some of the embodiments of the present application, rather than all the embodiments. Based on the embodiments in the present application, all other embodiments obtained by those skilled in the art without creative work fall within the protection scope of the present application. It should be noted that the embodiments in the present application and the features in the embodiments can be combined with each other without conflict. Meanwhile, the raw materials mentioned below are not specifically described, which are all commercially available products. The process steps or preparation methods not specifically mentioned are all known to those skilled in the art.

[0029] The present application provides a synthetic method of daphnetin, comprising the following steps:

[0030] Pyrogallic acid and malic acid are used as starting materials, the molar ratio of pyrogallic acid to malic acid is 1:1-5, a first catalyst, a water-removing agent, a second catalyst and an organic solvent are added for reaction, after the reaction is completed, the reaction system is neutralized by using a post-treatment solvent and then extracted to obtain daphnetin.

[0031] The first catalyst is concentrated sulfuric acid, specifically, sulfuric acid with a concentration not less than 70%. The first catalyst includes but is not limited to commercially available conventional preparations of concentrated sulfuric acid. The molar ratio of the first catalyst to pyrogallic acid is 1-10:1.

[0032] The water-removing agent is one or more of molecular sieves, calcium oxide, diaphosphorus pentoxide, concentrated sulfuric acid, lime, anhydrous calcium sulfate, anhydrous magnesium sulfate and anhydrous sodium sulfate. More preferably, the water-removing agent is nanoscale anhydrous magnesium sulfate with an average particle size of 50-120 nm. The molar ratio of the water-removing agent to pyrogallic acid is 0.01-0.05:1.

[0033] The second catalyst is a phase transfer catalyst selected from one or more of mercapto-terminated polyethylene glycol-2000, cyclodextrin and 15-crown-5-ether-5. More preferably, the second catalyst is mercapto-terminated polyethylene glycol-2000. The molar ratio of the second catalyst to pyrogallic acid is 0.001-0.003:1.

[0034] The organic solvent is selected from one or more of dioxane, carbon tetrachloride, dimethylbenzene, ethyl acetate, butanone, isopropyl alcohol, butanol, acetone, methyl ethyl ketone, cyclohexanone, tetrahydrofuran, toluene, chlorobenzene, dichloromethane and dichloroethane. More preferably, the organic solvent is dimethylbenzene. The volume-mass ratio of the organic solvent to pyrogallic acid is 1-20:1 (L / kg). That is, when the addition amount of pyrogallic acid is 1 unit of mass (kg), the addition amount of the organic solvent is 1-20 units of volume (L).

[0035] The reaction temperature is 90-140°C, more preferably 100-140°C; and the reaction time is 10-100 min, more preferably 10-60 min.

[0036] The post-treatment solvent is selected from one or more of ethanol, methanol, acetonitrile, dichloromethane, ethyl acetate and water. More preferably, the post-treatment solvent is water.

[0037] The extraction after the neutralization reaction is not particularly limited and can be a recrystallization technique known to those skilled in the art. It includes but is not limited to: pouring the reaction mixture into a post-treatment solvent, standing for 48 h, filtering the precipitate, washing the filtered precipitate with the post-treatment solvent until neutral, and drying at 105°C to obtain refined daphnetin.

[0038] The following examples are further listed to illustrate the present application in detail. It should also be understood that the following examples are only used to further illustrate the present application and should not be construed as limiting the scope of the present application. Some non-essential improvements and adjustments made by those skilled in the art based on the above content of the present application are within the scope of the present application. The specific process parameters in the following examples are only one example in the appropriate range, i.e. those skilled in the art can select within the appropriate range according to the description herein, and are not limited to the specific values in the following examples. The specific conditions are not specified in the examples, which are carried out according to the conventional conditions or the conditions recommended by the manufacturer. The concentration of concentrated sulfuric acid used in the following examples and comparative examples is 98%. The average particle size of nanoscale anhydrous magnesium sulfate used in the following examples and comparative examples is 50-120 nm.

[0039] Example 1

[0040] The weighed 50.00 kg of xylene was vacuumed into the reaction tank, the stirring was started, and then 25.2 kg of pyrogallic acid, 45.1 kg of malic acid, 25.2 g of thiol-terminated polyethylene glycol-2000 and 252.0 g of nanoscale anhydrous magnesium sulfate were sequentially added into the tank. Then, 50 L of concentrated sulfuric acid was vacuumed into the reaction tank, and the mixture was slowly stirred and heated to 130°C. After 20 minutes of reaction, the mixture was poured into ice water, and then stood for 48 h. The precipitate was filtered, washed with ice water until neutral, and dried at 105°C to obtain 31.33 kg of white powder-like solid. The obtained product was tested by high performance liquid chromatography, and the test results are shown in Table 1 and Table 2, with a yield of 88.00% and a purity of 99.44%. Figure 1

[0041] Table 1

[0042]

[0043] Example 2

[0044] ​The weighed 50.00 kg of xylene was vacuumed into the reaction tank, and the stirring was started. Then 25.2 kg of pyrogallic acid, 45.1 kg of malic acid, 25.2 g of cyclodextrin, and 252.0 g of nano-anhydrous magnesium sulfate were sequentially added into the tank. Then 50 L of concentrated sulfuric acid was vacuumed into the reaction tank. Slowly stirred and heated to 130°C. After 20 minutes of reaction, it was poured into ice water, and then it was left to stand for 48 hours. The precipitate was filtered, washed with ice water until neutral, and dried at 105°C to obtain a light pink powder solid 29.01 kg, with a yield of 81.49% and a purity of 99.30%.

[0045] Example 3

[0046] The weighed 50.00 kg of xylene was vacuumed into the reaction tank, and the stirring was started. Then 25.2 kg of pyrogallic acid, 45.1 kg of malic acid, 25.2 g of cyclodextrin, and 252.0 g of nano-anhydrous magnesium sulfate were sequentially added into the tank. Then 50 L of concentrated sulfuric acid was vacuumed into the reaction tank. Slowly stirred and heated to 130°C. After 20 minutes of reaction, it was poured into ice water, and then it was left to stand for 48 hours. The precipitate was filtered, washed with ice water until neutral, and dried at 105°C to obtain a light pink powder solid 29.01 kg, with a yield of 81.49% and a purity of 99.30%.

[0047] Example 4

[0048] The weighed 50.00 kg of xylene was vacuumed into the reaction tank, and the stirring was started. Then 25.2 kg of pyrogallic acid, 45.1 kg of malic acid, 25.2 g of cyclodextrin, and 252.0 g of nano-anhydrous magnesium sulfate were sequentially added into the tank. Then 50 L of concentrated sulfuric acid was vacuumed into the reaction tank. Slowly stirred and heated to 130°C. After 20 minutes of reaction, it was poured into ice water, and then it was left to stand for 48 hours. The precipitate was filtered, washed with ice water until neutral, and dried at 105°C to obtain a light pink powder solid 29.01 kg, with a yield of 81.49% and a purity of 99.30%.

[0049] Example 5

[0050] The weighed 50.00 kg of xylene was vacuumed into the reaction tank, and the stirring was started. Then 25.2 kg of pyrogallic acid, 45.1 kg of malic acid, 25.2 g of cyclodextrin, and 252.0 g of nano-anhydrous magnesium sulfate were sequentially added into the tank. Then 50 L of concentrated sulfuric acid was vacuumed into the reaction tank. Slowly stirred and heated to 130°C. After 20 minutes of reaction, it was poured into ice water, and then it was left to stand for 48 hours. The precipitate was filtered, washed with ice water until neutral, and dried at 105°C to obtain a light pink powder solid 29.01 kg, with a yield of 81.49% and a purity of 99.30%.

[0051] Example 6

[0052] The weighed 50.00 kg of xylene was vacuumed into the reaction tank, the stirring was started, and then 25.2 kg of pyrogallic acid, 45.1 kg of malic acid, 50.4 g of thiol-terminated polyethylene glycol-2000 and 252.0 g of nano-anhydrous magnesium sulfate were sequentially added into the tank. Then, 50 L of concentrated sulfuric acid was vacuumed into the reaction tank. The mixture was slowly stirred and heated to 130℃, and reacted for 20 minutes. The reaction mixture was poured into ice water, and then was left to stand for 48 h. The precipitate was obtained by filtration, washed with ice water until neutral, and dried at 105℃ to obtain 33.02 kg of a white powder. The obtained product was tested by high performance liquid chromatography, and the test results are shown in Table 2 and Table 3. Figure 2 The yield was 92.75%, and the purity was 99.73%.

[0053] Table 2

[0054]

[0055] As shown in Table 3, the data of the nuclear magnetic resonance hydrogen spectrum of the obtained product are as follows: Figures 3-5 1 H NMR (600 MHz, DMSO): δ 10.10 (br, 1H), 9.34 (br, 1H), 7.88 (d, J = 9.6 Hz, 1H), 7.01 (d, J = 8.4 Hz, 1H), 6.79 (d, J = 8.4 Hz, 1H), 6.18 (d, J = 9.6 Hz, 1H).

[0056] The data of the nuclear magnetic resonance carbon spectrum of the obtained product are as follows: 13 C NMR (600 MHz, DMSO): δ 160.42, 149.69, 145.09, 143.72, 132.12, 118.84, 112.50, 112.08, 111.23.

[0057] The high resolution mass spectrum data of the obtained product are as follows: HRMS (ESI): calcd. for C9H6ONa [M+Na] + 201.0164, found 201.0171. The m / z 201.0171 in the high resolution mass spectrum is the [M+Na] peak of the sample, so the molecular weight of the sample is 178. +

[0058] Example 7

[0059] ​​50.00 kg of weighed xylene was vacuum pumped into the reaction tank, and stirring was started. 25.2 kg of pyrogallic acid, 45.1 kg of malic acid, 75.6 g of thiol-terminated polyethylene glycol-2000 and 252.0 g of nano-anhydrous magnesium sulfate were put into the tank in sequence. Then 50 L of concentrated sulfuric acid was vacuum pumped into the reaction tank, slowly stirred and heated to 130 ° C. After reacting for 20 minutes, poured into ice water, allowed to stand for 48 hours, precipitated, and filtered. The filtered precipitate was washed with ice water until neutral and dried at 105 ° C to obtain 31.66 kg of off-white powdery solid with a yield of 88.93% and a purity of 99.50%.

[0060] Comparative Example 1

[0061] 50.00 kg of weighed xylene was vacuum pumped into the reaction tank, and stirring was started. 25.2 kg of pyrogallic acid, 45.1 kg of malic acid and 252.0 g of nano-grade anhydrous magnesium sulfate were added to the tank in sequence. Then 50 L of concentrated sulfuric acid was vacuum pumped into the reaction tank, slowly stirred and heated to 130 ° C. After reacting for 20 minutes, poured into ice water, allowed to stand for 48 hours, precipitated, and filtered. The filtered precipitate was washed with ice water until neutral and dried at 105 ° C to obtain 19.58 kg of off-white powdery solid with a yield of 55% and a purity of 97.52%.

[0062] Example 8

[0063] The organic solvent was vacuum-pumped into the reaction tank, stirring was started, and pyrogallic acid, malic acid, 0.002 eq of thiol-terminated polyethylene glycol-2000 (pyrogallic acid was 1 eq) and a water scavenger were added to the tank in sequence. Then, 50 L of concentrated sulfuric acid was vacuum-pumped into the reaction tank, slowly stirred and heated, reacted for 20 minutes, poured into ice water, allowed to stand for 48 hours, precipitated, and filtered. The filtered precipitate was washed with ice water until neutral, and dried at 105°C to obtain a powdered solid.

[0064] The partial optimization of the reaction conditions for preparing daphnetin from pyrogallic acid and malic acid is shown in Table 3, where the molar ratio is the amount of pyrogallic acid and malic acid used.

[0065] Table 3

[0066]

[0067] Note: The amount of water remover added in Table 3 is based on pyrogallic acid as 1eq, and the equivalent value refers to the molar ratio; the amount of organic solvent added is the volume mass ratio to pyrogallic acid (L / kg).

[0068] From the above examples and comparative examples, the synthetic method provided by the present application adopts the combined catalysis technology of phase transfer catalyst and nanoscale water removing agent, optimizes the reaction process, realizes the preparation of daphnetin with high yield and high purity, and can reach the industrial production standard.

[0069] The above only describes the preferred embodiments of the present application, and does not limit the patent scope of the present application. Any equivalent structural transformation, direct / indirect application in other related technical fields, or the like made by using the content of the present application under the inventive concept of the present application is included in the patent protection scope of the present application.

Claims

1. A method for synthesizing daphnetin, characterized in that: The following steps are involved: Taking pyrogallic acid and malic acid as starting materials, adding a first catalyst, a water scavenger, a second catalyst and an organic solvent to react, thereby obtaining daphnetin; The first catalyst is concentrated sulfuric acid with a concentration of not less than 70%; The second catalyst is a phase transfer catalyst, specifically thiol-terminated polyethylene glycol-2000; The dehydrating agent is nano-scale anhydrous magnesium sulfate.

2. The method for synthesizing daphnetin according to claim 1, wherein: The organic solvent is one or more of dioxane, carbon tetrachloride, xylene, ethyl acetate, butanone, isopropyl alcohol, butanol, acetone, methyl ethyl ketone, cyclohexanone, tetrahydrofuran, toluene, chlorobenzene, dichloromethane and dichloroethane.

3. The method for synthesizing daphnetin according to claim 1, wherein The molar ratio of the pyrogallic acid to the malic acid is 1:1-5.

4. The method for synthesizing daphnetin according to claim 1, wherein: The molar ratio of the first catalyst to the pyrogallic acid is 1-10:1; the molar ratio of the water scavenger to the pyrogallic acid is 0.01-0.05:1; and the volume-to-mass ratio of the organic solvent to the pyrogallic acid is 1-20:1 L / kg.

5. The method for synthesizing daphnetin according to claim 1, wherein: The reaction temperature is 90~140℃, and the reaction time is 10~100min.

6. The method for synthesizing daphnetin according to claim 1, wherein: The steps include: The method comprises the following steps: using pyrogallic acid and malic acid as starting raw materials, wherein the molar ratio of pyrogallic acid to malic acid is 1:1-5, adding a first catalyst, wherein the molar ratio of the first catalyst to pyrogallic acid is 1-10:1; then adding a dehydrating agent, a second catalyst and an organic solvent, wherein the molar ratio of the dehydrating agent to pyrogallic acid is 0.01-0.05:1, and the volume mass ratio of the organic solvent to pyrogallic acid is 1-20:1 L / kg; slowly stirring and heating to 100-140°C, reacting for 10-60 minutes; after the reaction is completed, pouring into a post-treatment solvent, standing for 48 hours, precipitating, filtering, washing the filtered precipitate with a post-treatment solvent until it is neutral, and drying at 105°C to obtain daphnetin.

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