Preparation method of daphnetin

Abstract

The present invention relates to the technical field of organic synthesis, particularly to a daphnetin preparation method, which comprises: adopting 2, 3, 4-trihydroxybenzaldehyde and Meldrum's acid as starting raw materials, and carrying out a first-step reaction 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, and daphnetin is obtained. The method has the remarkable advantages that firstly, the reaction process is easy to control, the generation amount of byproducts is low, and the product is excellent in appearance quality and extremely high in purity; and secondly, the use of chemicals with high risk and high toxicity is avoided, meanwhile, a large amount of acid waste liquid is not generated, and the environmental pollution is effectively reduced. In addition, the recycling of the solvent and the catalyst further reduces the production cost. The yield and the purity are remarkably improved, the total yield can reach 90% or above, the purity exceeds 99%, and the method is very suitable for industrial large-scale production.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a method for preparing daphneline. Background Art

[0002] Daphnetin, also known as daphnetin, is a representative monomer component of coumarin compounds. The pure product appears as a white or off-white powder. It is one of the natural medicines independently developed by China and is mainly used in the treatment of cardiovascular diseases in clinical practice. Studies have shown that daphnetin has a wide range of pharmacological activities, including analgesia, anti-inflammatory, antioxidant and anti-tumor effects.

[0003] Daphnetin has a significant coumarin-like main chain. Unlike typical coumarin, it contains a hydroxyl group at 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 structure is as follows:

[0004]

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

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

[0007] In order to achieve sustainable and environmentally friendly chemical synthesis, more efficient, safe and economical synthetic strategies need to be further explored and developed 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 method for preparing daphnetoin, and the synthesis process is green and environmentally friendly.

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

[0010] 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;

[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 daphnetoside.

[0012] The equation for the above reaction is as follows:

[0013]

[0014] The present invention uses 2,3,4-trihydroxybenzaldehyde and Michaelis' acid as starting materials, and the molar ratio of the 2,3,4-trihydroxybenzaldehyde to Michaelis' acid is preferably 1:1-1:2, more preferably 1:1-1:1.5, 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-methylpyrrolidine trifluoromethanesulfonate, and polyethylene glycol 200. The above catalysts can accelerate the reaction speed 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 the 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 10-100°C, more preferably 25-70°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 filtered out to separate the intermediate 7,8-dihydroxycoumarin-3-carboxylic acid.

[0021] The present invention has no particular limitation on the filtering method, and it can be a filtering method well known to those skilled in the art, preferably reduced pressure filtration.

[0022] The reaction liquid containing the catalyst can be reused for the first step reaction. Test results show that after the reaction liquid containing the catalyst is reused 5 times, the yield is still maintained 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-methylimidazole acetate. The above catalysts can accelerate the reaction speed.

[0024] The amount of the second catalyst is 0.05 to 2 equivalents, more preferably 0.5 to 2 equivalents, and further preferably 1 to 2 equivalents, that is, the molar ratio of the second catalyst to the 2,3,4-trihydroxybenzaldehyde is preferably 0.05 to 2, more preferably 0.5 to 2, and further preferably 1 to 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 reaction time of the second step is preferably 2.5 to 12 h, more preferably 3 to 6 h.

[0027] The solvent for the second step reaction is preferably 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, 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, and the organic phase is daphnetoside.

[0029] The extraction solvent is preferably one or more of dichloromethane, ethyl acetate, butyl acetate, and methyl tert-butyl ether. The extraction can be performed once or multiple times, preferably 1 to 3 times.

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

[0031] 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.

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

[0033] Preferably, the aqueous phase obtained after extraction is neutralized to a pH value 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 for 5 times, the reaction yield remains above 91%.

[0035] Compared with the prior art, the present invention provides a method for preparing daphneline, comprising the following steps: using 2,3,4-trihydroxybenzaldehyde and Michaelis acid as starting materials, carrying out a first step reaction under the action of a first catalyst to obtain an 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 daphneline.

[0036] The synthesis process adopted by the present invention shows significant advantages over the traditional method: first, the reaction process is easy to control, the amount of by-products generated is low, the product appearance quality is excellent, and the purity is extremely high. Secondly, the process avoids the use of highly dangerous and toxic chemicals, and 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 synthesis process, the present invention achieves significant improvements in yield and purity, with a total yield of more than 90% and a purity of more than 99%. These characteristics make this process very suitable for industrial-scale production. BRIEF DESCRIPTION OF THE DRAWINGS

[0037] Figure 1 This is the HPLC standard curve of daphnetin;

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

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

[0040] Figure 4is a 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 the daphnetin product prepared in Example 2 of the present invention;

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

[0043] Figure 7 is the hydrogen nuclear magnetic resonance spectrum of the daphnetoside product prepared in Example 3 of the present invention;

[0044] Figure 8 is the carbon nuclear magnetic resonance spectrum of the daphnetoside product prepared in Example 3 of the present invention;

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

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

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

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

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

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

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

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

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

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

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

[0056] Fig. 20 is the HPLC spectrum of the daphnetin product prepared in Example 14 of the present invention;

[0057] Fig.21 is a graph showing the catalyst recycling yield in step 1 of Example 15 of the present invention;

[0058] Fig. 22 This is a graph showing the catalyst recycling yield in step 2 of Example 15 of the present invention;

[0059] Fig.23 This is a schematic diagram of the catalyst recycling in Example 15 of the present invention. DETAILED DESCRIPTION

[0060] In order to further illustrate the present invention, the following is a detailed description in conjunction with the embodiments. 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] All raw materials of the present invention have no particular limitation on their sources, and can be purchased from the market or prepared according to conventional methods known to those skilled in the art.

[0062] Example 1

[0063] In the reaction flask, add 2,3,4-trihydroxybenzaldehyde, Michaelis acid (the amount ratio of 2,3,4-trihydroxybenzaldehyde and Michaelis acid is shown in the first ratio column of Table 1), then add water (5 mL), add the first catalyst (as shown in Table 1) under slow stirring, adjust the speed to 500 rpm and gradually heat to the reaction temperature (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, the reaction liquid is removed by filtration under reduced pressure, and the filter cake is washed with water (3×5 mL). The filter cake is vacuum dried (35 ℃) to obtain a yellow solid.

[0064] Taking test number 12 as an example, 2,3,4-trihydroxybenzaldehyde (154 mg, 1 mmol) and Michaelis acid (144 mg, 1 mmol) were 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-d6) 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). 13C NMR (100 MHz, DMSO-d6)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 H7O6 [M + H] + 223.0237; found 223.0241.

[0065] The optimized reaction conditions for preparing 7,8-dihydroxycoumarin-3-carboxylic acid from 2,3,4-trihydroxybenzaldehyde and Michaelis acid (step 1) are shown in Table 1. All target compounds were characterized by H NMR ( 1 H NMR) to complete the structural confirmation, and its chemical purity was analyzed by integrated peak area comparison (such as Figure 2 The results showed that the purity of the products was ≥95%.

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

[0067]

[0068] a Molar ratio of 2,3,4-trihydroxybenzaldehyde to Michaelis acid

[0069] Comparative Example 1

[0070] The conditions of Example 1 were adopted, the catalyst type was replaced, and the test parameters and reaction results were shown in Table 2.

[0071] Table 2 Reaction conditions and yields of Comparative Example 1

[0072]

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

[0074] In the above control test, when the catalyst is replaced with SDS, hexadecyldimethyl (3-sulfopropyl) ammonium hydroxide, tetrabutylammonium chloride, triethylbenzylammonium chloride, and hexadecyltrimethylammonium bromide, a large amount of foam appears in the filtrate during the post-reaction treatment and the vacuum filtration process, which seriously affects the vacuum filtration, brings great inconvenience to the experimental operation, and is not conducive to large-scale production.

[0075] Embodiment 2:

[0076] In the reaction bottle, add 7,8-dihydroxycoumarin-3-carboxylic acid (222 mg, 1 mmol), then add the solvent (as shown in Table 3), add the second catalyst (as shown in Table 3) under slow stirring, adjust the speed to 500 rpm and gradually heat to the reaction temperature (reaction temperature and reaction time are shown in Table 3). After the reaction solution is cooled to room temperature, take 60 μL of the reaction solution, add 120 μL of 2NHCl, extract with ethyl acetate (3×120 μL), combine the organic phases, concentrate to dryness, and perform high performance liquid chromatography test. Taking the experiment No. 15 as an example, the yield calculated by the standard curve is 95.3% and the purity is 98.9%. HRMS (ESI-TOF):calcd. for C9H7O4 [M + H] + 179.0339; found 179.0342.

[0077] The optimized reaction conditions for preparing daphnetin from 7,8-dihydroxycoumarin-3-carboxylic acid (step 2) are shown in Table 3.

[0078] Table 3 Optimization table of reaction conditions for step 2

[0079]

[0080] a Determined by HPLC test;

[0081] Comparative Example 2

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

[0083] Table 4 Reaction conditions and yields of Comparative Example 2

[0084]

[0085] a Determined by HPLC test;

[0086] b Produces methyl ester;

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

[0088] Embodiment 3:

[0089] In the filter reactor, add 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Michaelis acid (28.8 g, 200 mmol), and then add water (1.0 L). Add 1-ethyl-3-methylimidazolium acetate (17.0 g, 100 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 50 ℃, and react for 30 h. After the reaction is cooled to room temperature, the reaction solution is removed by vacuum filtration using a filter reactor. Then add glycerol (1.0 L), add 1-(2-pyrimidinyl)piperazine (32.8 g, 200 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 150 ℃, and react 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 ethyl acetate was extracted (3 × 1.0 L). The organic phases were combined, washed with saturated brine (0.8 L), dried over anhydrous sodium sulfate (30.0 g), filtered to remove the desiccant, and concentrated under reduced pressure. The crude product was dissolved in ethanol (1.0 L), and then activated carbon (7.0 g) was added, decolorized at 80 ° C for 0.5 h, and filtered to remove the activated carbon after cooling slightly, and concentrated under reduced pressure to obtain 28.7 g of a milky yellow solid with a yield of 80.60% and a HPLC purity of 99.48%. 1 H NMR (400 MHz, DMSO-d6) 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-d6) δ 160.47, 149.72, 145.14, 143.75, 132.15, 118.89, 112.53, 112.11,111.27.

[0090] Embodiment 4:

[0091] In the filter reactor, add 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Michaelis acid (28.8 g, 200 mmol), and then add water (1.0 L). Add 1-ethyl-3-methylimidazolium acetate (17.0 g, 100 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 50 ℃, and react for 30 h. After the reaction is cooled to room temperature, the reaction solution is removed by vacuum filtration using a filter reactor. Then add propylene glycol (1.0 L), add 1,5-diazabicyclo[4.3.0]non-5-ene (24.8 g, 200 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 150 ℃, and react 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 ethyl acetate was extracted (3 × 1.0 L). The organic phases were combined, washed with saturated brine (0.8 L), dried over anhydrous sodium sulfate (30.0 g), filtered to remove the desiccant, and concentrated under reduced pressure. The crude product was dissolved in ethanol (1.0 L), and then activated carbon (7.0 g) was added, decolorized at 80 ° C for 0.5 h, and filtered to remove the activated carbon after cooling slightly, and concentrated under reduced pressure to obtain 29.4 g of gray-white solid, with a yield of 82.56% and an HPLC purity of 99.59%.

[0092] Embodiment 5:

[0093] In the filter reactor, add 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Michaelis acid (28.8 g, 200 mmol), and then add water (1.0 L). Add 1-ethyl-3-methylimidazolium acetate (17.0 g, 100 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 50 ℃, and react for 30 h. After the reaction is cooled to room temperature, the reaction solution is removed by vacuum filtration using a filter reactor. Then add glycerol (1.0 L), add 1-ethyl-3-methylimidazolium acetate (34.0 g, 200 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 150 ℃, and react 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 ethyl acetate was extracted (3 × 1.0 L). The organic phases were combined, washed with saturated brine (0.8 L), dried over anhydrous sodium sulfate (30.0 g), filtered to remove the desiccant, and concentrated under reduced pressure. The crude product was dissolved in ethanol (1.0 L), and then activated carbon (7.0 g) was added, decolorized at 80 ° C for 0.5 h, and filtered to remove the activated carbon after cooling slightly, and concentrated under reduced pressure to obtain 29.1 g of a milky yellow solid with a yield of 81.81% and an HPLC purity of 99.56%.

[0094] Embodiment 6:

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

[0096] Embodiment 7:

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

[0098] Embodiment 8:

[0099] In the filter reactor, add 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Michaelis acid (28.8 g, 200 mmol), and then add water (1.0 L). Add 1-ethyl-3-methylimidazolium trifluoroacetate (22.4 g, 100 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 50 ℃, and react for 30 h. After the reaction is cooled to room temperature, the reaction solution is removed by vacuum filtration using a filter reactor. Then add glycerol (1.0 L), add 1-ethyl-3-methylimidazolium acetate (34.0 g, 200 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 150 ℃, and react 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 ethyl acetate was extracted (3 × 1.0 L). The organic phases were combined, washed with saturated brine (0.8 L), dried over anhydrous sodium sulfate (30.0 g), filtered to remove the desiccant, and concentrated under reduced pressure. The crude product was dissolved in ethanol (1.0 L), and then activated carbon (7.0 g) was added, decolorized at 80 ° C for 0.5 h, and filtered to remove the activated carbon after cooling slightly, and concentrated under reduced pressure to obtain 30.0 g of a milky yellow solid with a yield of 84.28% and an HPLC purity of 99.87%.

[0100] Embodiment 9:

[0101] In the filter reactor, add 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Michaelis acid (28.8 g, 200 mmol), and then add water (1.0 L). Add N-butyl-N-methylpyrrolidine trifluoromethanesulfonate (29.1 g, 100 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 50 ℃, and react for 30 h. After the reaction is cooled to room temperature, the reaction solution is removed by vacuum filtration using a filter reactor. Then add glycerol (1.0 L), add 1-(2-pyrimidinyl)piperazine (32.8 g, 200 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 150 ℃, and react 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 ethyl acetate was extracted (3 × 1.0 L). The organic phases were combined, washed with saturated brine (0.8 L), dried over anhydrous sodium sulfate (30.0 g), filtered to remove the desiccant, and concentrated under reduced pressure. The crude product was dissolved in ethanol (1.0 L), and then activated carbon (7.0 g) was added, decolorized at 80 ° C for 0.5 h, and filtered to remove the activated carbon after cooling slightly, and concentrated under reduced pressure to obtain 32 g of off-white solid, with a yield of 89.96% and a HPLC purity of 99.25%.

[0102] Embodiment 10:

[0103] In the filter reactor, add 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Michaelis acid (28.8 g, 200 mmol), and then add water (1.0 L). Add N-butyl-N-methylpyrrolidine trifluoromethanesulfonate (29.1 g, 100 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 50 ° C, and react for 30 h. After the reaction is cooled to room temperature, the reaction solution is removed by vacuum filtration using a filter reactor. Then add propylene glycol (1.0 L), add 1,5-diazabicyclo[4.3.0]non-5-ene (24.8 g, 200 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 150 ° C, and react 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 ethyl acetate was extracted (3 × 1.0 L). The organic phases were combined, washed with saturated brine (0.8 L), dried over anhydrous sodium sulfate (30.0 g), filtered to remove the desiccant, and concentrated under reduced pressure. The crude product was dissolved in ethanol (1.0 L), and then activated carbon (7.0 g) was added, decolorized at 80 ° C for 0.5 h, and filtered to remove the activated carbon after cooling slightly, and concentrated under reduced pressure to obtain 32.25 g of gray-white solid, with a yield of 90.63% and an HPLC purity of 99.73%.

[0104] Embodiment 11:

[0105] In the filter reactor, add 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Michaelis acid (28.8 g, 200 mmol), and then add water (1.0 L). Add N-butyl-N-methylpyrrolidine trifluoromethanesulfonate (29.1 g, 100 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 50 ℃, and react for 30 h. After the reaction is cooled to room temperature, the reaction solution is removed by vacuum filtration using a filter reactor. Then add glycerol (1.0 L), add 1-ethyl-3-methylimidazolium acetate (34.0 g, 200 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 150 ℃, and react 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 ethyl acetate was used for extraction (3 × 1.0 L). The organic phases were combined, washed with saturated brine (0.8 L), dried over anhydrous sodium sulfate (30.0 g), filtered to remove the desiccant, and concentrated under reduced pressure. The crude product was dissolved in ethanol (1.0 L), and then activated carbon (7.0 g) was added, decolorized at 80 ° C for 0.5 h, and filtered to remove the activated carbon after cooling slightly, and concentrated under reduced pressure to obtain 30.2 g of a milky yellow solid with a yield of 84.73% and an HPLC purity of 99.71%.

[0106] Embodiment 12:

[0107] In the filter reactor, add 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Michaelis acid (28.8 g, 200 mmol), and then add water (1.0 L). Add polyethylene glycol 200 (20.0 g, 100 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 50 ℃, and react for 30 h. After the reaction is cooled to room temperature, the reaction solution is removed by vacuum filtration using a filter reactor. Then add glycerol (1.0 L), add 1-(2-pyrimidinyl)piperazine (32.8 g, 200 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 150 ℃, and react 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 ethyl acetate was used for extraction (3 × 1.0 L). The organic phases were combined, washed with saturated brine (0.8 L), dried over anhydrous sodium sulfate (30.0 g), filtered to remove the desiccant, and concentrated under reduced pressure. The crude product was dissolved in ethanol (1.0 L), and then activated carbon (7.0 g) was added, decolorized at 80 ° C for 0.5 h, and filtered to remove the activated carbon after cooling slightly, and concentrated under reduced pressure to obtain 30.5 g of off-white solid, with a yield of 85.77% and an HPLC purity of 99.84%.

[0108] Embodiment 13:

[0109] In the filter reactor, add 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Michaelis acid (28.8 g, 200 mmol), and then add water (1.0 L). Add polyethylene glycol 200 (20.0 g, 100 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 50 ℃, and react for 30 h. After the reaction is cooled to room temperature, the reaction solution is removed by vacuum filtration using a filter reactor. Then add propylene glycol (1.0 L), add 1,5-diazabicyclo[4.3.0]non-5-ene (24.8 g, 200 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 150 ℃, and react 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 ethyl acetate was extracted (3 × 1.0 L). The organic phases were combined, washed with saturated brine (0.8 L), dried over anhydrous sodium sulfate (30.0 g), filtered to remove the desiccant, and concentrated under reduced pressure. The crude product was dissolved in ethanol (1.0 L), and then activated carbon (7.0 g) was added, decolorized at 80 ° C for 0.5 h, and filtered to remove the activated carbon after cooling slightly, and concentrated under reduced pressure to obtain 31.4 g of gray-white solid, with a yield of 88.34% and an HPLC purity of 99.42%.

[0110] Embodiment 14:

[0111] In the filter reactor, add 2,3,4-trihydroxybenzaldehyde (30.8 g, 200 mmol), Michaelis acid (28.8 g, 200 mmol), and then add water (1.0 L). Add polyethylene glycol 200 (20.0 g, 100 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 50 ℃, and react for 30 h. After the reaction is cooled to room temperature, the reaction solution is removed by vacuum filtration using a filter reactor. Then add glycerol (1.0 L), add 1-ethyl-3-methylimidazolium acetate (34.0 g, 200 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 150 ℃, and react 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 ethyl acetate was extracted (3 × 1.0 L). The organic phases were combined, washed with saturated brine (0.8 L), dried over anhydrous sodium sulfate (30.0 g), filtered to remove the desiccant, and concentrated under reduced pressure. The crude product was dissolved in ethanol (1.0 L), and then activated carbon (7.0 g) was added, decolorized at 80 ° C for 0.5 h, and filtered to remove the activated carbon after cooling slightly, and concentrated under reduced pressure to obtain 30.2 g of a milky 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 by circulation method

[0113] Step 1: In a reaction flask, add 2,3,4-trihydroxybenzaldehyde (3.08 g, 20 mmol), Michaelis acid (2.88 g, 20 mmol), and then add water (100 mL). Add 1-ethyl-3-methylimidazolium trifluoroacetate (2.24 g, 10 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 50 °C for 20 h. After the reaction is cooled to room temperature, the reaction liquid is removed by vacuum filtration, and the filtered reaction liquid is used in the next reaction. The filter cake is washed with water (3 × 50 mL), and the filter cake is vacuum dried (35 °C) to obtain a yellow solid. After 5 cycles, the yield remains above 93%.

[0114] Step 2: In a reaction flask, add 7,8-dihydroxycoumarin-3-carboxylic acid (4.44 g, 20 mmol), then add propylene glycol (100 mL), add 1,5-diazabicyclo[4.3.0]non-5-ene (2.48 g, 20 mmol) under slow stirring, adjust the speed to 500 rpm and gradually heat to 150 °C for 3 h. After the reaction solution is cooled to room temperature, water (180 mL) and 2N HCl aqueous solution (20 mL) are added, extracted with ethyl acetate (3 × 100 mL), the organic phases are combined, washed with saturated brine (80 mL), dried over anhydrous sodium sulfate (3.0 g), filtered to remove the desiccant, and concentrated under reduced pressure. The crude product is dissolved in ethanol (100 mL), and then activated carbon (0.7 g) is added, decolorized at 80 °C for 0.5 h, filtered to remove the activated carbon after cooling slightly, and concentrated under reduced pressure to obtain off-white solid daphnetin. After ethyl acetate extraction, a saturated sodium bicarbonate solution was added to the aqueous phase, the pH was adjusted to 10, and ethyl acetate was used for further extraction (3× 100 mL), dried over anhydrous sodium sulfate (3.0 g), the desiccant was filtered out, and the product was concentrated under reduced pressure to obtain 1,5-diazabicyclo[4.3.0]non-5-ene. The catalyst will be used in subsequent cyclic reactions. If the quality is insufficient, new catalyst can be added to ensure the continuity of the reaction. Through this cyclic process, the yield can still be maintained above 91% even after 5 cycles.

[0115] The above examples show that the preparation process provided by the present invention adopts readily available and low-cost raw materials, emphasizes the green and environmentally friendly production concept, and the catalyst can be recycled, thereby achieving high-yield and high-purity preparation of daphnetoside, which is suitable for the high standards of industrial production.

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

2. The method for preparing daphnetoside according to claim 1, characterized in that: 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 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 temperature of the first step reaction is 10-100°C; the time of the first step reaction is 2-35 h.

5. The method for preparing daphnetoside according to claim 1, characterized in that: The solvent for the first step reaction is water.

6. 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.

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

8. The method for preparing daphnetoside according to claim 1, characterized in that: The temperature of the second step reaction is 120-180°C; the time of the second step reaction is 2.5-12 h.

9. The method for preparing daphnetoside according to claim 1, characterized in that: The solvent for 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.

10. 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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