A method for preparing daphnetin

Abstract

The present invention relates to the technical field of organic synthesis, and particularly to a preparation method of daphnetin, which comprises the following steps: using 2,3,4-trihydroxybenzaldehyde and Meldrum's acid as starting materials, carrying out a first-step reaction under the action of a first catalyst to obtain the intermediate 7,8-dihydroxycoumarin-3-carboxylic acid; carrying out a second-step reaction on the intermediate 7,8-dihydroxycoumarin-3-carboxylic acid under the action of a second catalyst to obtain daphnetin. This method shows significant advantages: Firstly, the reaction process is easy to control, the amount of by-products generated is low, the appearance quality of the product is excellent, and the purity is extremely high. Secondly, the use of highly dangerous and toxic chemicals is avoided, and at the same time, a large amount of acidic waste liquid is not generated, effectively reducing environmental pollution. In addition, the recycling of solvents and catalysts further reduces the production cost. A significant improvement has been achieved in terms of yield and purity, with the total yield reaching over 90% and the purity exceeding 99%, making it very suitable for industrial-scale production.

Description

Technical Field

[0001] The present invention relates to the technical field of organic synthesis, and particularly relates to a preparation method of daphnetin. Background Art

[0002] Daphnetin, also known as daphnetin A, is a representative monomer component in coumarin compounds. The pure product appears as a white or off-white powdery substance. It is one of the natural drugs independently developed in China and is mainly used for the treatment of cardiovascular diseases in clinical practice. Research shows that daphnetin has a wide range of pharmacological activities, including analgesic, anti-inflammatory, antioxidant, and anti-tumor effects.

[0003] Daphnetin has a significant coumarin backbone. Different from typical coumarins, it contains a hydroxyl group at each of the C-7 and C-8 positions. Therefore, the chemical name of daphnetin is also called 7,8-dihydroxycoumarin, and its English name is 7,8-dihydroxycoumarin. The molecular structural formula is as follows:

[0004]

[0005] As a precious natural product, daphnetin was initially mainly extracted from Daphne giraldii Nitsche. Traditional extraction methods include alcohol extraction, ether extraction, and multiple recrystallizations with ethanol. The extraction process is complex and time-consuming. According to research, only about 2-3 grams of daphnetin can be obtained from every kilogram of Daphne giraldii Nitsche. The extraction efficiency is low, and a large amount of waste residue and waste liquid are generated during the extraction process, imposing a burden on the environment. These factors not only limit the extraction efficiency of daphnetin but also affect its potential in large-scale applications. In addition, the complex extraction process and low extraction rate result in a high production cost of daphnetin, further limiting its wide application and popularization in the market.

[0006] Therefore, in the past few decades, organic chemists and pharmaceutical chemists around the world have devoted a lot of energy to developing efficient synthesis methods of daphnetin to meet its wide demand in drug research and clinical applications. However, there are still problems such as low yield, the use of hazardous chemicals, the generation of a large amount of acidic waste liquid, and poor appearance quality of the product.

[0007] In order to achieve sustainable and environmentally friendly chemical synthesis, it is necessary to further explore and develop more efficient, safe, and economical synthesis strategies to meet the requirements of green chemistry and adapt to the needs of industrial production. Summary of the Invention

[0008] In view of this, the technical problem to be solved by the present invention is to provide a preparation method of daphnetin with a green and environmentally friendly synthesis process.

[0009] The present invention provides a method for preparing daphnetin, comprising the following steps:

[0010] Using 2,3,4-trihydroxybenzaldehyde and Meldrum's acid as starting materials, a first-step reaction is carried out under the action of a first catalyst to obtain the intermediate 7,8-dihydroxycoumarin-3-carboxylic acid;

[0011] The intermediate 7,8-dihydroxycoumarin-3-carboxylic acid is subjected to a second-step reaction under the action of a second catalyst to obtain daphnetin.

[0012] The reaction equations for the above reactions are as follows:

[0013]

[0014] In the present invention, 2,3,4-trihydroxybenzaldehyde and Meldrum's acid are used as starting materials, and the molar ratio of 2,3,4-trihydroxybenzaldehyde to Meldrum's acid is preferably 1:1 to 1:2, more preferably 1:1 to 1:1.5, and further preferably 1:1.

[0015] The first catalyst is preferably one or more of 1-ethyl-3-methylimidazolium trifluoroacetate, 1-ethyl-3-methylimidazolium acetate, 1-ethyl-3-methylimidazolium trifluoromethanesulfonate, N-butyl-N-methylpyrrolidinium trifluoromethanesulfonate, and polyethylene glycol 200. The above catalysts can accelerate the reaction rate and ensure the smooth progress of the subsequent filtration step.

[0016] The amount of the first catalyst is preferably 0.05 to 2 equivalents, more preferably 0.1 to 1.0 equivalents, and further preferably 0.5 equivalents. That is, the molar ratio of the first catalyst to 2,3,4-trihydroxybenzaldehyde is preferably 0.05 to 2, more preferably 0.1 to 1.0, and further preferably 0.5. In some specific embodiments of the present invention, the amount of the first catalyst is 0.05, 0.1, 0.2, 0.5, 1.0, 1.5, or 2.0 equivalents, or a range value with any of the above values as the upper or lower limit.

[0017] The temperature of the first-step reaction is preferably 10 to 100 °C, more preferably 25 to 70 °C, and further preferably 50 °C.

[0018] The time of the first-step reaction is preferably 2 to 35 h, more preferably 2 to 30 h. In some specific embodiments of the present invention, the time of the first-step reaction is 2, 2.5, 3, 3.5, 4, 4.5, 5 h, 10, 20, or 30 h, or a range value with any of the above values as the upper or lower limit.

[0019] The solvent for the first-step reaction is preferably water.

[0020] After the first-step reaction is completed, the reaction solution containing the catalyst is removed by filtration, and the intermediate 7,8-dihydroxycoumarin-3-carboxylic acid is separated.

[0021] The present invention has no special limitation on the filtration method, which can be a filtration method well-known to those skilled in the art, and preferably vacuum filtration.

[0022] The reaction solution containing the catalyst can be recycled to the first-step reaction. The test results show that after the reaction solution containing the catalyst is reused 5 times, the yield still remains above 93%.

[0023] The catalyst for the second-step reaction is preferably one or more of 1,5-diazabicyclo[4.3.0]non-5-ene, 1-(2-pyrimidinyl)piperazine, and 1-ethyl-3-methylimidazolium acetate. The above catalysts can accelerate the reaction rate.

[0024] The amount of the second catalyst is 0.05 - 2 equivalents, more preferably 0.5 - 2 equivalents, and further preferably 1 - 2 equivalents. That is, the molar ratio of the second catalyst to 2,3,4-trihydroxybenzaldehyde is preferably 0.05 - 2, more preferably 0.5 - 2, and further preferably 1 - 2. In some specific embodiments of the present invention, the amount of the second catalyst is 0.05, 0.1, 0.2, 0.3, 0.4, 0.5, 1.0, 1.5, 2.0 equivalents, or a range value with any of the above values as the upper or lower limit.

[0025] The temperature of the second-step reaction is preferably 120 - 180 °C, more preferably 150 - 170 °C, and further preferably 150 °C.

[0026] The time of the second-step reaction is preferably 2.5 - 12 h, more preferably 3 - 6 h.

[0027] The solvent for the second-step reaction is preferably one or more of ethylene glycol, 1,2-propanediol, 1,3-propanediol, glycerol, diethylene glycol, and PEG-200, or a mixed solution selected from glycerol and water, and more preferably glycerol.

[0028] When the second catalyst is selected from 1,5-diazabicyclo[4.3.0]non-5-ene and / or 1-(2-pyrimidinyl)piperazine, after the second-step reaction is completed, the system is neutralized with an acidic aqueous solution and then extracted. The organic phase is daphnetin.

[0029] The solvent for the extraction is preferably one or more of dichloromethane, ethyl acetate, butyl acetate, and methyl tert-butyl ether. The number of extractions can be one or more times, and preferably 1 - 3 times.

[0030] Preferably, the organic phase is purified. Preferably, the organic phases are combined, concentrated to dryness, and the crude product is decolorized with activated carbon. The solvent for decolorization is preferably ethanol.

[0031] The aqueous phase obtained after extraction is neutralized to alkaline, and the second catalyst is recovered by extraction and recycled to the second-step reaction.

[0032] The extraction solvent is preferably one or more of dichloromethane, ethyl acetate, butyl acetate, and methyl tert-butyl ether. The number of extraction times can be one or more, preferably 1 to 3 times.

[0033] Preferably, the aqueous phase obtained after extraction is neutralized to a pH of about 10, and the recovered second catalyst is obtained after extraction, drying, and concentration.

[0034] The test results show that after the recovered second catalyst is recycled 5 times, the reaction yield remains above 91%.

[0035] Compared with the prior art, the present invention provides a method for preparing daphnetin, comprising the following steps: using 2,3,4-trihydroxybenzaldehyde and Meldrum's acid as starting materials, performing a first-step reaction under the action of a first catalyst to obtain the intermediate 7,8-dihydroxycoumarin-3-carboxylic acid; and performing a second-step reaction on the intermediate 7,8-dihydroxycoumarin-3-carboxylic acid under the action of a second catalyst to obtain daphnetin.

[0036] The synthetic process adopted by the present invention shows significant advantages compared with the traditional method: First, its reaction process is easy to control, the amount of by-products generated is low, the appearance quality of the product is excellent, and the purity is extremely high. Second, this process avoids the use of highly dangerous and toxic chemicals, and at the same time does not produce a large amount of acidic waste liquid, effectively reducing environmental pollution. In addition, the recycling of solvents and catalysts further reduces production costs. Compared with the traditional synthetic process, the present invention has achieved significant improvements in yield and purity. The total yield can reach more than 90%, and the purity exceeds 99%. These characteristics make this process very suitable for industrial-scale production. Description of the Drawings

[0037] Figure 1 is the high performance liquid chromatography standard curve of daphnetin;

[0038] Figure 2 is the nuclear magnetic resonance hydrogen spectrum of 7,8-dihydroxycoumarin-3-carboxylic acid prepared in Example 1 of the present invention;

[0039] Figure 3 is the nuclear magnetic resonance carbon spectrum of 7,8-dihydroxycoumarin-3-carboxylic acid prepared in Example 1 of the present invention;

[0040] Figure 4is the high-resolution mass spectrum of 7,8-dihydroxycoumarin-3-carboxylic acid prepared in Example 1 of the present invention;

[0041] Figure 5 is the HPLC spectrum of daphnetin product prepared in Example 2 of the present invention;

[0042] Figure 6 is the high-resolution mass spectrum of daphnetin product prepared in Example 2 of the present invention;

[0043] Figure 7 is the 1H NMR spectrum of daphnetin product prepared in Example 3 of the present invention;

[0044] Figure 8 is the 13C NMR spectrum of daphnetin product prepared in Example 3 of the present invention;

[0045] Figure 9 is the HPLC spectrum of daphnetin product prepared in Example 3 of the present invention;

[0046] Figure 10 is the HPLC spectrum of daphnetin product prepared in Example 4 of the present invention;

[0047] Figure 11 is the HPLC spectrum of daphnetin product prepared in Example 5 of the present invention;

[0048] Figure 12 is the HPLC spectrum of daphnetin product prepared in Example 6 of the present invention;

[0049] Figure 13 is the HPLC spectrum of daphnetin product prepared in Example 7 of the present invention;

[0050] Figure 14 is the HPLC spectrum of daphnetin product prepared in Example 8 of the present invention;

[0051] Figure 15 is the HPLC spectrum of daphnetin product prepared in Example 9 of the present invention;

[0052] Figure 16 is the HPLC spectrum of daphnetin product prepared in Example 10 of the present invention;

[0053] Figure 17 is the HPLC spectrum of daphnetin product prepared in Example 11 of the present invention;

[0054] Figure 18 is the HPLC spectrum of daphnetin product prepared in Example 12 of the present invention;

[0055] Figure 19 is the HPLC spectrum of daphnetin product prepared in Example 13 of the present invention;

[0056] Figure 20 It is the HPLC chromatogram of the daphnetin product prepared in Example 14 of the present invention;

[0057] Figure 21 It is the yield graph of the catalyst recycling in Step 1 of Example 15 of the present invention;

[0058] Figure 22 It is the yield graph of the catalyst recycling in Step 2 of Example 15 of the present invention;

[0059] Figure 23 It is the schematic diagram of the catalyst recycling in Example 15 of the present invention. Detailed implementation manners

[0060] To further illustrate the present invention, the following will be described in detail in combination with examples. However, it should be understood that these descriptions are only for further illustrating the features and advantages of the present invention, rather than limiting the claims of the invention.

[0061] For all raw materials of the present invention, there is no particular limitation on their sources, and they can be purchased on the market or prepared according to the conventional methods well-known to those skilled in the art.

[0062] Example 1

[0063] In a reaction flask, add 2,3,4-trihydroxybenzaldehyde and mesoxalic acid (the dosage ratio of 2,3,4-trihydroxybenzaldehyde to mesoxalic acid is shown in the "Ratio" column of Table 1), then add water (5 mL), and slowly add the first catalyst (as shown in Table 1) under stirring. Adjust the rotation speed to 500 rpm and gradually heat up to the reaction temperature (the reaction temperature and reaction time are shown in Table 1) to carry out the first-step reaction. After the reaction is cooled to room temperature, filter the reaction solution under reduced pressure, and then wash the filter cake with water (3×5 mL). After the filter cake is dried in vacuo (35 °C), a yellow solid is obtained.

[0064] Taking Test Serial Number 12 as an example, 2,3,4-trihydroxybenzaldehyde (154 mg, 1 mmol) and mesoxalic acid (144 mg, 1 mmol) are added to obtain 214.3 mg of a yellow solid, with a melting point of 260.1 - 261.7 °C and a yield of 95.1%. 1 H NMR (400MHz, DMSO-d 6 ) δ 12.88 (s, 1H), 10.65 (s, 1H), 9.59 (s, 1H), 8.66 (s, 1H),7.27 (d, J = 8.4 Hz, 1H), 6.87 (d, J = 8.8 Hz, 1H). 13 C NMR (100 MHz, DMSO-d 6) δ 164.41, 157.80, 152.52, 150.17, 144.84, 131.89, 121.68, 113.40, 112.22, 111.48. HRMS (ESI-TOF): calcd. for C 10 H 7 O 6 [M + H] + 223.0237; found 223.0241.

[0065] Optimization of the reaction conditions for the preparation of 7,8-dihydroxycoumarin-3-carboxylic acid (step 1) from 2,3,4-trihydroxybenzaldehyde and Meldrum's acid is shown in Table 1. The structures of all target compounds were confirmed by 1H NMR ( 1 H NMR), and their chemical purities were analyzed by comparing the integral peak areas (as Figure 2 shown), and the results showed that the product purities were all ≥95%.

[0066] Table 1 Optimization table of reaction conditions for step 1

[0067]

[0068] a Molar ratio of 2,3,4-trihydroxybenzaldehyde to Meldrum's acid

[0069] Comparative Example 1

[0070] Using the conditions of Example 1 and replacing the catalyst type, the test parameters and reaction results are shown in Table 2.

[0071] Table 2 Reaction condition parameters and yields for Comparative Example 1

[0072]

[0073] In Table 2, SDS is sodium dodecyl sulfate.

[0074] In the above control experiments, when the catalyst was replaced with SDS, cetyl dimethyl(3-sulfopropyl) ammonium hydroxide, tetrabutyl ammonium chloride, triethyl benzyl ammonium chloride, or cetyl trimethyl ammonium bromide, during the post-reaction treatment and the vacuum filtration process, a large amount of foam appeared in the filtrate, seriously affecting the vacuum filtration, bringing great inconvenience to the experimental operation, and being even less conducive to large-scale production.

[0075] Example 2:

[0076] In a reaction flask, 7,8-dihydroxycoumarin-3-carboxylic acid (222 mg, 1 mmol) was added, followed by the addition of a solvent (as shown in Table 3). The second catalyst (as shown in Table 3) was added under slow stirring, the rotation speed was adjusted to 500 rpm, and the temperature was gradually raised to the reaction temperature (the reaction temperature and reaction time are shown in Table 3). After the reaction solution was cooled to room temperature, 60 μL of the reaction solution was taken, 120 μL of 2N HCl was added, and extraction was carried out with ethyl acetate (3×120 μL). The organic phases were combined, concentrated to dryness, and subjected to high performance liquid chromatography test. Taking the experiment No. 15 as an example, the yield was calculated to be 95.3% and the purity was 98.9% using the standard curve. HRMS (ESI-TOF): calcd. for C 9 H 7 O 4 [M + H] + 179.0339; found 179.0342.

[0077] The optimization of the reaction conditions for the preparation of daphnetin from 7,8-dihydroxycoumarin-3-carboxylic acid (Step 2) is shown in Table 3.

[0078] Table 3 Optimization of reaction conditions for Step 2

[0079]

[0080] a Determined by HPLC test;

[0081] Comparative Example 2

[0082] Using the conditions of Example 2, the catalyst type was replaced, and the test parameters and reaction results are shown in Table 4.

[0083] Table 4 Reaction condition parameters and yields for Comparative Example 2

[0084]

[0085] a Determined by HPLC test;

[0086] b Methyl ester was formed;

[0087] In Table 4, DABCO is triethylenediamine; CDI is N,N'-carbonyldiimidazole.

[0088] Example 3:

[0089] In a filtration reactor, 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol) and Meldrum's acid (28.8 g, 200 mmol) were added. Then water (1.0 L) was added, and 1-ethyl-3-methylimidazolium acetate (17.0 g, 100 mmol) was added under slow stirring. The rotation speed was adjusted to 500 rpm and the temperature was gradually increased to 50 °C, and the reaction was carried out for 30 h. After the reaction was cooled to room temperature, the reaction solution was removed by vacuum filtration using a filtration kettle. Subsequently, glycerol (1.0 L) was added, and 1-(2-pyrimidinyl)piperazine (32.8 g, 200 mmol) was added under slow stirring. The rotation speed was adjusted to 500 rpm and the temperature was gradually increased to 150 °C, and the reaction was carried out for 10 h. After the reaction solution was cooled to room temperature, water (1.8 L) and 2N HCl aqueous solution (0.2 L) were added, and extraction was carried out with ethyl acetate (3 × 1.0 L). The organic phases were combined, washed with saturated brine (0.8 L), dried over anhydrous sodium sulfate (30.0 g), the desiccant was filtered off, and concentrated under reduced pressure. The crude product was dissolved in ethanol (1.0 L), and then activated carbon (7.0 g) was added. Decolorization was carried out at 80 °C for 0.5 h. After slightly cooling, the activated carbon was filtered off, and concentrated under reduced pressure to obtain 28.7 g of a cream-yellow solid with a yield of 80.60% and an HPLC purity of 99.48%. 1 H NMR (400 MHz, DMSO-d 6 ) δ10.09 (s, 1H), 9.33 (s, 1H), 7.90 (d, J = 9.2 Hz, 1H), 7.02 (d, J = 8.4 Hz,1H), 6.80 (d, J = 8.8 Hz, 1H), 6.18 (d, J = 9.6 Hz, 1H). 13 C NMR (100 MHz,DMSO-d 6 ) δ 160.47, 149.72, 145.14, 143.75, 132.15, 118.89, 112.53, 112.11,111.27.

[0090] Example 4:

[0091] In a filtration reactor, 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Meldrum's acid (28.8 g, 200 mmol) were added, then water (1.0 L) was added. 1-Ethyl-3-methylimidazolium acetate (17.0 g, 100 mmol) was added under slow stirring, the rotation speed was adjusted to 500 rpm and the temperature was gradually raised to 50 °C, and the reaction was carried out for 30 h. After the reaction was cooled to room temperature, the reaction solution was removed by vacuum filtration using a filtration kettle. Subsequently, glycerol (1.0 L) was added, 1,5-diazabicyclo[4.3.0]non-5-ene (24.8 g, 200 mmol) was added under slow stirring, the rotation speed was adjusted to 500 rpm and the temperature was gradually raised to 150 °C, and the reaction was carried out for 10 h. After the reaction solution was cooled to room temperature, water (1.8 L) and 2N HCl aqueous solution (0.2 L) were added, and extraction was carried out with ethyl acetate (3 × 1.0 L). The organic phases were combined, washed with saturated brine (0.8 L), dried over anhydrous sodium sulfate (30.0 g), the desiccant was filtered off, and concentrated under reduced pressure. The crude product was dissolved in ethanol (1.0 L), then activated carbon (7.0 g) was added, and decolorization was carried out at 80 °C for 0.5 h. After slightly cooling, the activated carbon was filtered off, and concentrated under reduced pressure to obtain 29.4 g of an off-white solid, with a yield of 82.56% and an HPLC purity of 99.59%.

[0092] Example 5:

[0093] In a filtration reactor, 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Meldrum's acid (28.8 g, 200 mmol) were added, then water (1.0 L) was added. 1-Ethyl-3-methylimidazolium acetate (17.0 g, 100 mmol) was added under slow stirring, the rotation speed was adjusted to 500 rpm and the temperature was gradually raised to 50 °C, and the reaction was carried out for 30 h. After the reaction was cooled to room temperature, the reaction solution was removed by vacuum filtration using a filtration kettle. Subsequently, glycerol (1.0 L) was added, 1-Ethyl-3-methylimidazolium acetate (34.0 g, 200 mmol) was added under slow stirring, the rotation speed was adjusted to 500 rpm and the temperature was gradually raised to 150 °C, and the reaction was carried out for 10 h. After the reaction solution was cooled to room temperature, water (1.8 L) and 2N HCl aqueous solution (0.2 L) were added, and extraction was carried out with ethyl acetate (3 × 1.0 L). The organic phases were combined, washed with saturated brine (0.8 L), dried over anhydrous sodium sulfate (30.0 g), the desiccant was filtered off, and concentrated under reduced pressure. The crude product was dissolved in ethanol (1.0 L), then activated carbon (7.0 g) was added, and decolorization was carried out at 80 °C for 0.5 h. After slightly cooling, the activated carbon was filtered off, and concentrated under reduced pressure to obtain 29.1 g of a cream solid, with a yield of 81.81% and an HPLC purity of 99.56%.

[0094] Example 6:

[0095] In a filtration reactor, 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Meldrum's acid (28.8 g, 200 mmol) were added, then water (1.0 L) was added. 1-Ethyl-3-methylimidazolium trifluoroacetate (22.4 g, 100 mmol) was added under slow stirring, the rotation speed was adjusted to 500 rpm and the temperature was gradually raised to 50 °C, and the reaction was carried out for 30 h. After the reaction was cooled to room temperature, the reaction solution was removed by vacuum filtration using the filtration reactor. Subsequently, glycerol (1.0 L) was added, 1-(2-pyrimidinyl)piperazine (32.8 g, 200 mmol) was added under slow stirring, the rotation speed was adjusted to 500 rpm and the temperature was gradually raised to 150 °C, and the reaction was carried out for 10 h. After the reaction solution was cooled to room temperature, water (1.8 L) and 2N HCl aqueous solution (0.2 L) were added, extracted with ethyl acetate (3 × 1.0 L), the organic phases were combined, washed with saturated brine (0.8 L), dried over anhydrous sodium sulfate (30.0 g), the desiccant was filtered off, and concentrated under reduced pressure. The crude product was dissolved in ethanol (1.0 L), then activated carbon (7.0 g) was added, decolorized at 80 °C for 0.5 h, filtered off the activated carbon after slightly cooling, and concentrated under reduced pressure to obtain 31.9 g of an off-white solid, with a yield of 89.78% and an HPLC purity of 99.73%.

[0096] Example 7:

[0097] In a filtration reactor, 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Meldrum's acid (28.8 g, 200 mmol) were added, then water (1.0 L) was added. 1-Ethyl-3-methylimidazolium trifluoroacetate (22.4 g, 100 mmol) was added under slow stirring, the rotation speed was adjusted to 500 rpm and the temperature was gradually raised to 50 °C, and the reaction was carried out for 30 h. After the reaction was cooled to room temperature, the reaction solution was removed by vacuum filtration using the filtration reactor. Subsequently, glycerol (1.0 L) was added, 1,5-diazabicyclo[4.3.0]non-5-ene (24.8 g, 200 mmol) was added under slow stirring, the rotation speed was adjusted to 500 rpm and the temperature was gradually raised to 150 °C, and the reaction was carried out for 10 h. After the reaction solution was cooled to room temperature, water (1.8 L) and 2N HCl aqueous solution (0.2 L) were added, extracted with ethyl acetate (3 × 1.0 L), the organic phases were combined, washed with saturated brine (0.8 L), dried over anhydrous sodium sulfate (30.0 g), the desiccant was filtered off, and concentrated under reduced pressure. The crude product was dissolved in ethanol (1.0 L), then activated carbon (7.0 g) was added, decolorized at 80 °C for 0.5 h, filtered off the activated carbon after slightly cooling, and concentrated under reduced pressure to obtain 31.8 g of an off-white solid, with a yield of 89.40% and an HPLC purity of 99.40%.

[0098] Example 8:

[0099] In a filtration reactor, add 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Meldrum's acid (28.8 g, 200 mmol), then add water (1.0 L), and slowly add 1-ethyl-3-methylimidazolium trifluoroacetate (22.4 g, 100 mmol) under stirring. Adjust the rotation speed to 500 rpm and gradually heat up to 50 °C, and react for 30 h. After the reaction is cooled to room temperature, use the filtration kettle to filter under reduced pressure to remove the reaction solution. Subsequently, add glycerol (1.0 L), slowly add 1-ethyl-3-methylimidazolium acetate (34.0 g, 200 mmol) under stirring, adjust the rotation speed to 500 rpm and gradually heat up to 150 °C, and react for 10 h. After the reaction solution is cooled to room temperature, add water (1.8 L) and 2N HCl aqueous solution (0.2 L), extract with ethyl acetate (3 × 1.0 L), combine the organic phases, wash with saturated brine (0.8 L), dry with anhydrous sodium sulfate (30.0 g), filter off the desiccant, and concentrate under reduced pressure. The crude product is dissolved in ethanol (1.0 L), then add activated carbon (7.0 g), decolorize at 80 °C for 0.5 h, filter off the activated carbon after slightly cooling, and concentrate under reduced pressure to obtain 30.0 g of a pale yellow solid, with a yield of 84.28% and an HPLC purity of 99.87%.

[0100] Example 9:

[0101] In a filtration reactor, add 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Meldrum's acid (28.8 g, 200 mmol), then add water (1.0 L). While stirring slowly, add N-butyl-N-methylpyrrolidinium trifluoromethanesulfonate (29.1 g, 100 mmol). Adjust the rotation speed to 500 rpm and gradually heat up to 50 °C, and react for 30 h. After the reaction is cooled to room temperature, use the filtration reactor to filter off the reaction solution under reduced pressure. Subsequently, add glycerol (1.0 L). While stirring slowly, add 1-(2-pyrimidinyl)piperazine (32.8 g, 200 mmol). Adjust the rotation speed to 500 rpm and gradually heat up to 150 °C, and react for 10 h. After the reaction solution is cooled to room temperature, add water (1.8 L) and 2N HCl aqueous solution (0.2 L), extract with ethyl acetate (3 × 1.0 L), combine the organic phases, wash with saturated brine (0.8 L), dry with anhydrous sodium sulfate (30.0 g), filter off the desiccant, and concentrate under reduced pressure. The crude product is dissolved in ethanol (1.0 L), then add activated carbon (7.0 g), decolorize at 80 °C for 0.5 h, filter off the activated carbon after slightly cooling, and concentrate under reduced pressure to obtain 32 g of an off-white solid, with a yield of 89.96% and an HPLC purity of 99.25%.

[0102] Example 10:

[0103] In a filtration reactor, add 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Meldrum's acid (28.8 g, 200 mmol), then add water (1.0 L). While stirring slowly, add 1,5-diazabicyclo[4.3.0]non-5-ene (24.8 g, 200 mmol). Adjust the rotation speed to 500 rpm and gradually heat up to 150 °C, and react for 10 h. After the reaction is cooled to room temperature, add water (1.8 L) and 2N HCl aqueous solution (0.2 L), extract with ethyl acetate (3 × 1.0 L), combine the organic phases, wash with saturated brine (0.8 L), dry with anhydrous sodium sulfate (30.0 g), filter off the desiccant, and concentrate under reduced pressure. The crude product is dissolved in ethanol (1.0 L), then add activated carbon (7.0 g), decolorize at 80 °C for 0.5 h, filter off the activated carbon after slightly cooling, and concentrate under reduced pressure to obtain 32.25 g of an off-white solid, with a yield of 90.63% and an HPLC purity of 99.73%.

[0104] Example 11:

[0105] In a filtration reactor, add 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Meldrum's acid (28.8 g, 200 mmol), then add water (1.0 L). While stirring slowly, add N-butyl-N-methylpyrrolidinium trifluoromethanesulfonate (29.1 g, 100 mmol). Adjust the rotation speed to 500 rpm and gradually heat up to 50 °C, and react for 30 h. After the reaction is cooled to room temperature, use the filtration reactor to filter off the reaction solution under reduced pressure. Subsequently, add glycerol (1.0 L). While stirring slowly, add 1-ethyl-3-methylimidazolium acetate (34.0 g, 200 mmol). Adjust the rotation speed to 500 rpm and gradually heat up to 150 °C, and react for 10 h. After the reaction solution is cooled to room temperature, add water (1.8 L) and 2N HCl aqueous solution (0.2 L), extract with ethyl acetate (3 × 1.0 L), combine the organic phases, wash with saturated brine (0.8 L), dry with anhydrous sodium sulfate (30.0 g), filter off the desiccant, and concentrate under reduced pressure. The crude product is dissolved in ethanol (1.0 L), then add activated carbon (7.0 g), decolorize at 80 °C for 0.5 h, filter off the activated carbon after slightly cooling, and concentrate under reduced pressure to obtain 30.2 g of a creamy yellow solid, with a yield of 84.73% and an HPLC purity of 99.71%.

[0106] Example 12:

[0107] In a filtration reactor, add 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Meldrum's acid (28.8 g, 200 mmol), then add water (1.0 L). While stirring slowly, add polyethylene glycol 200 (20.0 g, 100 mmol). Adjust the rotation speed to 500 rpm and gradually heat up to 50 °C, and react for 30 h. After the reaction is cooled to room temperature, use the filtration reactor to filter off the reaction solution under reduced pressure. Subsequently, add glycerol (1.0 L). While stirring slowly, add 1-(2-pyrimidinyl)piperazine (32.8 g, 200 mmol). Adjust the rotation speed to 500 rpm and gradually heat up to 150 °C, and react for 10 h. After the reaction solution is cooled to room temperature, add water (1.8 L) and 2N HCl aqueous solution (0.2 L), extract with ethyl acetate (3 × 1.0 L), combine the organic phases, wash with saturated brine (0.8 L), dry with anhydrous sodium sulfate (30.0 g), filter off the desiccant, and concentrate under reduced pressure. The crude product is dissolved in ethanol (1.0 L), then add activated carbon (7.0 g), decolorize at 80 °C for 0.5 h, filter off the activated carbon after slightly cooling, and concentrate under reduced pressure to obtain 30.5 g of an off-white solid, with a yield of 85.77% and an HPLC purity of 99.84%.

[0108] Example 13:

[0109] In a filtration reactor, add 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Meldrum's acid (28.8 g, 200 mmol), then add water (1.0 L). Slowly stir and add polyethylene glycol 200 (20.0 g, 100 mmol). Adjust the rotation speed to 500 rpm and gradually heat up to 50 °C, and react for 30 h. After the reaction is cooled to room temperature, use the filtration kettle to filter under reduced pressure to remove the reaction solution. Subsequently, add glycerol (1.0 L). Slowly stir and add 1,5-diazabicyclo[4.3.0]non-5-ene (24.8 g, 200 mmol). Adjust the rotation speed to 500 rpm and gradually heat up to 150 °C, and react for 10 h. After the reaction solution is cooled to room temperature, add water (1.8 L) and 2N HCl aqueous solution (0.2 L), extract with ethyl acetate (3 × 1.0 L), combine the organic phases, wash with saturated brine (0.8 L), dry with anhydrous sodium sulfate (30.0 g), filter off the desiccant, and concentrate under reduced pressure. The crude product is dissolved in ethanol (1.0 L), then add activated carbon (7.0 g), decolorize at 80 °C for 0.5 h, filter off the activated carbon after slightly cooling, and concentrate under reduced pressure to obtain 31.4 g of off-white solid, with a yield of 88.34% and an HPLC purity of 99.42%.

[0110] Example 14:

[0111] In a filtration reactor, add 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Meldrum's acid (28.8 g, 200 mmol), then add water (1.0 L). Slowly stir and add polyethylene glycol 200 (20.0 g, 100 mmol). Adjust the rotation speed to 500 rpm and gradually heat up to 50 °C, and react for 30 h. After the reaction is cooled to room temperature, use the filtration kettle to filter under reduced pressure to remove the reaction solution. Subsequently, add glycerol (1.0 L). Slowly stir and add 1-ethyl-3-methylimidazolium acetate (34.0 g, 200 mmol). Adjust the rotation speed to 500 rpm and gradually heat up to 150 °C, and react for 10 h. After the reaction solution is cooled to room temperature, add water (1.8 L) and 2N HCl aqueous solution (0.2 L), extract with ethyl acetate (3 × 1.0 L), combine the organic phases, wash with saturated brine (0.8 L), dry with anhydrous sodium sulfate (30.0 g), filter off the desiccant, and concentrate under reduced pressure. The crude product is dissolved in ethanol (1.0 L), then add activated carbon (7.0 g), decolorize at 80 °C for 0.5 h, filter off the activated carbon after slightly cooling, and concentrate under reduced pressure to obtain 30.2 g of cream-yellow solid, with a yield of 84.82% and an HPLC purity of 99.35%.

[0112] Example 15: Specific Methods and Steps for Improving Catalyst Utilization Rate by Recycling Method

[0113] Step 1: In a reaction flask, add 2,3,4-trihydroxybenzaldehyde (3.08 g, 20 mmol), Meldrum's acid (2.88 g, 20 mmol), then add water (100 mL). Slowly stir and add 1-ethyl-3-methylimidazolium trifluoroacetate (2.24 g, 10 mmol). Adjust the rotation speed to 500 rpm and gradually heat up to 50 °C, and react for 20 h. After the reaction is cooled to room temperature, filter under reduced pressure to remove the reaction solution, and the filtered reaction solution is put into the next reaction for use. Wash the filter cake with water (3 × 50 mL), and after vacuum drying the filter cake at 35 °C, a yellow solid is obtained. After recycling 5 times, the yield still remains above 93%.

[0114] Step 2: In a reaction flask, add 7,8-dihydroxycoumarin-3-carboxylic acid (4.44 g, 20 mmol), then add glycerol (100 mL). Slowly stir and add 1,5-diazabicyclo[4.3.0]non-5-ene (2.48 g, 20 mmol). Adjust the rotation speed to 500 rpm and gradually heat up to 150 °C, and react for 3 h. After the reaction solution is cooled to room temperature, add water (180 mL) and 2N HCl aqueous solution (20 mL), extract with ethyl acetate (3 × 100 mL), combine the organic phases, wash with saturated brine (80 mL), dry with anhydrous sodium sulfate (3.0 g), filter off the desiccant, and concentrate under reduced pressure. The crude product is dissolved in ethanol (100 mL), then add activated carbon (0.7 g), decolorize at 80 °C for 0.5 h, filter off the activated carbon after slightly cooling, and concentrate under reduced pressure to obtain daphnetin as an off-white solid. Add saturated sodium bicarbonate solution to the aqueous phase after ethyl acetate extraction, adjust the pH to 10, continue to extract with ethyl acetate (3 × 100 mL), dry with anhydrous sodium sulfate (3.0 g), filter off the desiccant, and concentrate under reduced pressure to obtain 1,5-diazabicyclo[4.3.0]non-5-ene. This catalyst will be used in subsequent recycling reactions. If the quality is insufficient, new catalyst can be supplemented to ensure the continuity of the reaction. Through this recycling process, even after 5 cycles, the yield can still remain above 91%.

[0115] The above examples show that the preparation process provided by the present invention uses easily available and low-cost raw materials, emphasizes the production concept of green environmental protection, the catalyst can be recycled, realizes the preparation of daphnetin with high yield and high purity, and meets the high-standard requirements of industrial production.

[0116] The description of the above embodiments is only used to help understand the method and its core idea of the present invention. It should be noted that for those of ordinary skill in the art, without departing from the principle of the present invention, several improvements and modifications can be made to the present invention, and these improvements and modifications also fall within the protection scope of the claims of the present invention.

Claims

1. A method for preparing daphneline, comprising the following steps: Using 2,3,4-trihydroxybenzaldehyde and Michaelis acid as starting materials, a first step reaction is carried out under the action of a first catalyst to obtain an intermediate 7,8-dihydroxycoumarin-3-carboxylic acid; The intermediate 7,8-dihydroxycoumarin-3-carboxylic acid is subjected to a second step reaction under the action of a second catalyst to obtain daphnetoside; The first catalyst is selected from 1-ethyl-3-methylimidazolium trifluoroacetate, 1-ethyl-3-methylimidazolium acetate, 1-ethyl-3-methylimidazolium trifluoromethanesulfonate, N -Butyl- N - one or more of methylpyrrolidine trifluoromethanesulfonate and polyethylene glycol 200; The solvent of the first step reaction is water; The second catalyst is selected from one or more of 1,5-diazabicyclo[4.3.0]non-5-ene, 1-(2-pyrimidinyl)piperazine and 1-ethyl-3-methylimidazolium acetate; The solvent of the second step reaction is selected from one or more of ethylene glycol, 1,2-propylene glycol, 1,3-propylene glycol, glycerol, diethylene glycol, PEG-200, or a mixed solution of glycerol and water; The temperature of the first step reaction is 25-70°C; The temperature of the second step reaction is 150°C~170°C.

2. The method for preparing daphnetoside according to claim 1, characterized in that: The amount of the first catalyst is 0.05 to 2 equivalents.

3. The method for preparing daphnetoside according to claim 1, characterized in that: The molar ratio of the 2,3,4-trihydroxybenzaldehyde to Michaelis acid is 1:1-1:

2.

4. The method for preparing daphnetoside according to claim 1, characterized in that: The first step reaction time is 2 to 35 h.

5. The method for preparing daphnetoside according to claim 1, characterized in that: After the first step of the reaction is completed, the reaction solution containing the catalyst is filtered out to separate the intermediate 7,8-dihydroxycoumarin-3-carboxylic acid; The reaction liquid containing the catalyst is recycled to the first step reaction.

6. The method for preparing daphnetoside according to claim 1, characterized in that: The amount of the second catalyst is 0.05 to 2 equivalents.

7. The method for preparing daphnetoside according to claim 1, characterized in that: The reaction time of the second step is 2.5~12 h.

8. The method for preparing daphnetoside according to claim 1, characterized in that: When the second catalyst is selected from 1,5-diazabicyclo[4.3.0]non-5-ene and / or 1-(2-pyrimidinyl)piperazine, after the second step reaction is completed, the system is neutralized with an acidic aqueous solution and then extracted, and the organic phase is daphnetolide; The aqueous phase obtained after the extraction is neutralized to alkalinity, and the second catalyst is extracted and recovered and reused in the second step reaction.

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