Preparation method of erianin
Through the three-step reaction method of aldol condensation, decarboxylation and reduction under mild conditions, the yield and purity of malanin were successfully improved, and the problems of complex process, high environmental impact and high cost in the existing technology were solved, and the preparation of malanin suitable for industrial-scale production was achieved.
Patent Information
- Application Number
- CN202510226517.0
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2025-02-27
- Publication Date
- 2025-05-16
AI Technical Summary
The existing malanin chemical synthesis methods have low yields, complex processes, large environmental impacts, high costs, and difficult to adapt to large-scale production.
Malanin was successfully obtained by using a three-step reaction method of aldol condensation, decarboxylation and reduction under mild conditions, using aldol condensation reaction in acetic anhydride solution, microwave-assisted decarboxylation reaction, and reduction reaction in the presence of alkali.
The high yield (45.3%) and high purity preparation of umlanin is achieved, the process flow is simplified, the environmental impact and production costs are reduced, and it is suitable for industrial-scale production.
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Figure CN120004701A_ABST
Abstract
Description
Technical Field
[0001] The invention relates to the technical field of Erianin preparation, in particular to a method for preparing Erianin. Background Art
[0002] Cancer has become one of the leading causes of death in the world today. According to the latest data, there will be 19.96 million new cancer cases and 9.74 million cancer deaths worldwide in 2022. Lung cancer has surpassed breast cancer and has once again become the world's leading cancer. The traditional Chinese medicine Dendrobium has important functions such as antioxidant, anti-tumor, immune regulation, hypoglycemic, antipyretic, analgesic, anti-inflammatory, cardiovascular and neuroprotective. Erianin is the most active of its many active ingredients, and has good anti-cancer activity in vivo and in vitro, and is highly selective for tumor cells.
[0003] In addition to anti-cancer effects, the research results of Fang Lina et al. (Effects and mechanisms of Erianin on apoptosis of ovarian granulosa cells in rats with polycystic ovary syndrome, Chinese Pharmacy, 2024, 35 (11)) showed that Erianin (ERI) has a significant effect on promoting the proliferation of ovarian granulosa cells in rats with polycystic ovary syndrome (PCOS) and can effectively regulate the level of sex hormones. Its mechanism of action may be related to the inhibition of the Hippo-YSP signaling pathway. The research results of Fan Zengrong et al. (Effects of Erianin on regulating CCL2-CCR2 axis on inflammatory damage of articular chondrocytes, Chinese Journal of Osteoporosis. 2024, 30 03) showed that Erianin can inhibit LPS-induced apoptosis and inflammatory response of articular chondrocytes. Its mechanism may be related to the inhibition of CCL2 / CCR2 pathway. The CCL2 / CCR2 axis plays a key role in a variety of immune and inflammatory diseases, including cancer and non-malignant diseases. Erianin may play an important role in protecting articular chondrocytes and inhibiting inflammatory response by regulating this pathway.
[0004] As a potential clinical drug candidate or lead compound for drug development, Erianin has attracted widespread attention from the scientific community. The initial way to obtain Erianin was to extract and separate it directly from Dendrobium officinale. The principles of the extraction methods are generally the same. The processes involved include extraction, concentration, silica gel column chromatography, recrystallization and other steps, and they need to be repeated many times to obtain pure Erianin. In addition, the content of Erianin in Dendrobium officinale is relatively low, and the growth conditions of Dendrobium officinale are relatively harsh. Many Dendrobium officinale varieties, such as wild Dendrobium officinale, are rare and endangered plants under the national key second-level protection, and digging is prohibited. Therefore, it is very necessary to seek chemical synthesis methods to replace or complement natural plant extraction methods.
[0005] Erianin belongs to the bibenzyl class of compounds, its chemical name is 2-methoxy-5-[2-(3,4,5-trimethoxyphenyl)ethyl]-phenol, and its molecular formula is C 18 H 22 O5 , with a molecular weight of 318.36, mainly derived from Dendrobium officinale and Dendrobium chrysotoxum. Its chemical structure is as follows.
[0006]
[0007] Erianin structure The main chemical synthesis methods of Erianin at present include synthesis via alkyne intermediates, synthesis via olefin intermediates (Wittig reaction method), synthesis via olefin intermediates (aldol condensation method), etc. However, the yield of compounds in these methods does not exceed 40%, and there are problems such as cumbersome preparation process, adverse impact on the environment, high cost, and not conducive to large-scale production.
[0008] The present invention aims to solve the above problems existing in the prior art and provide a method for preparing Erianin which has the advantages of simple operation, high extraction efficiency, high purity and relatively mild reaction conditions. Summary of the invention
[0009] In view of the deficiencies of the prior art, the present invention provides a method for preparing Erianin, which solves the problems raised in the above background technology.
[0010] To achieve the above objectives, the present invention is implemented by the following technical scheme: a method for preparing Erianin, comprising the following steps: S1. Aldol condensation reaction: a compound of the general formula (I) is subjected to an aldol condensation reaction with a compound of the general formula (II) to prepare a compound of the formula (III), wherein the reaction is carried out in an organic solvent containing a catalyst; S2, decarboxylation reaction: reacting the compound of formula (III) obtained in S1 with the formed complex catalyst under microwave irradiation, separating and purifying to obtain the compound of formula (IV), the reaction is carried out in an organic solvent, and the catalyst is a composite catalyst; S3, reduction reaction: the compound of formula (IV) obtained in S2 is treated with a reducing agent to prepare Erianin, and the reaction is carried out in an inert solvent containing a base.
[0011] Preferably, the organic solvent used in S1 is an organic solvent selected from acid anhydrides, such as acetic anhydride, propionic anhydride, butyric anhydride, phthalic anhydride, etc., among which acetic anhydride is preferred.
[0012] Preferably, the reaction system of the aldol condensation reaction in S1 is as follows: triethylamine is added to an acetic anhydride solution containing compounds (I) and (II); the temperature is raised to 110°C, stirred for reaction for 6 hours, the reaction solution is poured into ice water to precipitate a solid, the obtained solid is completely dissolved in a 10% NaOH solution, and the solution is clarified; impurities are removed by extraction with ethyl acetate, and hydrochloric acid is slowly added dropwise under stirring to acidify the water layer to pH = 5 to obtain a light solid, which is then dried to obtain a crude product (III).
[0013] Preferably, the organic solvent in S2 is a solvent that is beneficial to the synthesis of metal complexes and microwave-assisted reactions, such as PEG-400, dimethylformamide, dimethyl sulfoxide, quinoline, etc., among which PEG-400 is preferred.
[0014] Preferably, the reaction system of the S2 separation and purification reaction is to add compound (III), CuI, 1,10-phenanthroline and PEG-400 into a round-bottom flask; then the flask is placed in a microwave synthesizer and irradiated (325W) for 4-12 min; after the reaction is completed, the mixture is cooled to room temperature, water and ethyl acetate are added, the resulting red crystalline powder is filtered out, washed with water and ethyl acetate, dried and stored for the next run; the filtrate is extracted with ethyl acetate; the combined organic phase is washed with water, dried over anhydrous magnesium sulfate, and then concentrated to obtain a crude product (IV), which is then purified by PTLC.
[0015] Preferably, in S3: the inert solvent in the reaction is one or more selected from dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, acetonitrile, hexamethylphosphoramide, carbon tetrachloride, among which dimethylformamide is preferred.
[0016] Preferably, the base used in the S3 reaction may generally include various organic bases and inorganic bases, such as sodium carbonate, potassium carbonate, sodium hydride, potassium hydride and other inorganic bases and similar bases; sodium acetate, pyrimidine, various dimethylpyridines, triethylamine, diisopropylethylamine and other organic bases and similar bases; among which organic bases such as sodium acetate, diisopropylethylamine, triethylamine, diisopropylethylamine and the like are preferred; in a preferred embodiment of the present invention, sodium acetate is selected as the base used in this reaction.
[0017] Preferably, in the S3 reduction reaction, compound (IV), DMF, p-toluenesulfonyl hydrazide and sodium acetate are added to a round bottom cup, and the mixture is heated at 95°C for 1 hour; the reaction is then cooled, the reactant is diluted with water and extracted three times with dichloromethane; the combined organic phase is washed with water and brine, and the organic layer is washed with Na 2 SO 4 Drying, filtration and concentration in vacuo gave a crude product; purification by column chromatography gave white crystals of Erianin.
[0018] The present invention provides a method for preparing Erianin, which has the following beneficial effects: 1. The preparation method of Erianin uses homovanillic acid and 3,4,5-trimethoxybenzaldehyde as raw materials, and successfully obtains Erianin in three steps through aldol condensation, decarboxylation and reduction of double bonds under mild conditions, with a total yield of 45.3%. At the same time, this route can synthesize the active intermediate Combretastatin A-4 (CA-4) with high selectivity. This scheme is convenient for obtaining biologically active natural products Erianin and CA-4, avoids harsh reaction conditions, and is suitable for industrial-scale production. BRIEF DESCRIPTION OF THE DRAWINGS
[0019] Figure 1 The nuclear magnetic resonance analysis spectrum (hydrogen spectrum) of the intermediate (III) prepared by the present invention; Figure 2 The nuclear magnetic resonance analysis spectrum (carbon spectrum) of the intermediate (III) prepared by the present invention; Figure 3 The mass spectrometry analysis spectrum of the intermediate (III) prepared by the present invention; Figure 4 The nuclear magnetic resonance analysis spectrum (hydrogen spectrum) of CA-4 prepared in the present invention; Figure 5 The nuclear magnetic resonance analysis spectrum (carbon spectrum) of CA-4 prepared in the present invention; Figure 6 The mass spectrometry analysis spectrum of CA-4 prepared by the present invention; Figure 7 The nuclear magnetic resonance analysis spectrum (hydrogen spectrum) of Erianin prepared by the present invention; Figure 8 The nuclear magnetic resonance analysis spectrum (carbon spectrum) of Erianin prepared by the present invention; Fig. 9 The mass spectrometry analysis spectrum of Erianin prepared by the present invention; Fig.10 The invention discloses a synthetic route of Erianin prepared by the invention. DETAILED DESCRIPTION
[0020] The technical solutions in the embodiments of the present invention will be described clearly and completely below in conjunction with the drawings in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, rather than all the embodiments.
[0021] Embodiment 1: See also Figures 1 to 10 The present invention provides a technical solution: a method for preparing Erianin, comprising the following steps: S1. Aldol condensation reaction: a compound of the general formula (I) is subjected to an aldol condensation reaction with a compound of the general formula (II) to prepare a compound of the formula (III), wherein the reaction is carried out in an organic solvent containing a catalyst; S2, decarboxylation reaction: reacting the compound of formula (III) obtained in S1 with the formed complex catalyst under microwave irradiation, separating and purifying to obtain the compound of formula (IV), the reaction is carried out in an organic solvent, and the catalyst is a composite catalyst; S3, reduction reaction: the compound of formula (IV) obtained in S2 is treated with a reducing agent to prepare Erianin, and the reaction is carried out in an inert solvent containing a base.
[0022] The organic solvent used in S1 is an organic solvent selected from acid anhydrides, such as acetic anhydride, propionic anhydride, butyric anhydride, phthalic anhydride, etc., among which acetic anhydride is preferred.
[0023] The reaction system of the aldol condensation reaction in S1 is as follows: triethylamine is added to an acetic anhydride solution containing compounds (I) and (II); the temperature is raised to 110°C, and the reaction is stirred for 6 hours, and then the reaction solution is poured into ice water to precipitate a solid. The obtained solid is completely dissolved in a 10% NaOH solution, and the solution becomes clear; impurities are removed by extraction with ethyl acetate, and hydrochloric acid is slowly added dropwise under stirring to acidify the water layer to pH = 5, to obtain a light solid, which is then dried to obtain a crude product (III).
[0024] The organic solvent in S2 is a solvent that is beneficial to the synthesis of metal complexes and microwave-assisted reactions, such as PEG-400, dimethylformamide, dimethyl sulfoxide, quinoline, etc., among which PEG-400 is preferred.
[0025] The reaction system of the S2 separation and purification reaction is as follows: Compound (III), CuI, 1,10-phenanthroline and PEG-400 are added to a round-bottom flask; the flask is then placed in a microwave synthesizer and irradiated (325W) for 4-12 min; after the reaction is completed, the mixture is cooled to room temperature, water and ethyl acetate are added, the resulting red crystalline powder is filtered out, washed with water and ethyl acetate, dried and stored for the next run; the filtrate is extracted with ethyl acetate; the combined organic phase is washed with water, dried over anhydrous magnesium sulfate, and then concentrated to obtain a crude product (IV), which is then purified by PTLC.
[0026] The inert solvent in the reaction is one or more selected from dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, acetonitrile, hexamethylphosphoramide, carbon tetrachloride, among which dimethylformamide is preferred.
[0027] Among them, the base used in the S3 reaction can generally include various organic bases and inorganic bases, such as sodium carbonate, potassium carbonate, sodium hydride, potassium hydride and other inorganic bases and similar bases; sodium acetate, pyrimidine, various dimethylpyridines, triethylamine, diisopropylethylamine and other organic bases and similar bases; among which organic bases such as sodium acetate, diisopropylethylamine, triethylamine, diisopropylethylamine and the like are preferred; in a preferred embodiment of the present invention, sodium acetate is selected as the base used in this reaction.
[0028] In the reduction reaction of S3, compound (IV), DMF, p-toluenesulfonyl hydrazide and sodium acetate were added to a round-bottomed cup, and the mixture was heated at 95°C for 1 h; the reaction was then cooled, the reactant was diluted with water and extracted three times with dichloromethane; the combined organic phase was washed with water and brine, and the organic layer was washed with Na 2 SO 4 Drying, filtration and concentration in vacuo gave a crude product; purification by column chromatography gave white crystals of Erianin.
[0029] Embodiment 2: See also Figures 1 to 9 The present invention provides a technical solution: a method for preparing Erianin, comprising the following steps: 1. Preparation of (E)-2-(3-hydroxy-4-methoxyphenyl)-3-(3,4,5-trimethoxyphenyl)acrylic acid (III) At room temperature, 3,4,5-trimethoxybenzaldehyde (6.14 g, 1 eq), 3-hydroxy-4-methoxyphenylacetic acid (6.41 g, 1.13 eq) and acetic anhydride solution (20 ml) were added to a 250 ml round-bottom flask in sequence, and triethylamine (20 ml) was added after stirring to dissolve. The mixture was refluxed at 120 °C and stirred vigorously for 6 h before the reaction was stopped. After the reaction system was cooled to room temperature, the reaction solution was poured into ice water to precipitate a solid, and the obtained solid was dissolved in 10% NaOH solution and stirred until clear. The impurities were removed by extraction with ethyl acetate, and the aqueous layer was acidified to pH = 5 to obtain a light yellow solid, which was filtered and dried to obtain a crude product. The crude product was purified by column chromatography to obtain intermediate (III), 8.46 g of white powder solid, with a yield of 75%.
[0030] 1 H NMR: (500 MHz, Chloroform-d) δ: 9.05 (s, 1H), 7.61 (s, 1H), 6.96 (d, J = 8.2 Hz, 1H), 6.60 (d, J = 2.1 Hz, 1H), 6.57 (dd, J = 8.1, 2.1 Hz, 1H), 6.47 (s, 2H), 3.77 (s, 3H), 3.61 (s, 3H), 3.50 (s, 6H).13 C NMR: (126MHz, Chloroform-d) δ: 168.58, 152.24, 147.23, 146.86, 138.62, 138.56, 132.26,129.83, 129.07, 120.27, 112.76, 108.04, 60.02, 55.82, 55.33, 54.93. MS:(LC-MS): calculated for C 19 H 20 O 7 [MH] - , 359.1136; found, 359.1128. 2. Preparation of Combretastatin A-4 At room temperature, compound (3) (8 g, 1 eq), CuI (0.423 g, 0.1 eq), 1, 10-phenanthroline (0.4 g, 0.1 eq) and PEG-400 (25 ml) were added to a 200 ml round-bottom flask in sequence and stirred to dissolve. The reaction flask was then placed in a microwave synthesizer and irradiated (325 W) for 6-12 min (1 min each time, 2 min interval) under stirring. After the reaction was completed, the mixture was cooled to room temperature, ice water was added to quench the reaction, and the resulting red crystalline powder [CuI (1, 10-phen)] was filtered through diatomaceous earth. 2 , washed with water and ethyl acetate, dried and stored for the next run. The filtrate was extracted three times with ethyl acetate. The combined organic phases were washed with water and purified by anhydrous Na 2 SO 4 The residue was dried, filtered and concentrated under reduced pressure to obtain a crude product, which was then purified by column chromatography to obtain Combretastatin A-4 as a white powder solid (6.11 g). The yield was 87%.
[0031] 1 H NMR (500 MHz, Chloroform-d) δ 7.14 (d, J = 2.1 Hz, 1H), 6.97 (dd,J = 8.3, 2.1 Hz, 1H), 6.90 (d, J = 4.3 Hz, 2H), 6.84 (d, J = 8.3 Hz, 1H), 6.71 (s, 1H), 5.63 (s, 1H), 3.91 (d, J = 1.8 Hz, 9H), 3.86 (d, J = 1.6 Hz, 3H). 13C NMR (126 MHz, Chloroform-d) δ 153.51, 146.55, 137.81, 133.46, 131.14,128.29, 127.20, 111.86, 103.48, 103.41, 61.11, 56.25, 56.14, 56.09, 56.05.MS:(LC-MS): calculated for C 18 H 20 O 5 [MH] - , 315.1238; found, 315.1230. 3. Preparation of Erianin CA-4 (0.81 g, 1 eq) was dissolved in DMF (2 ml) at room temperature, and then p-toluenesulfonyl hydrazide (1.43 g, 3 eq) and sodium acetate trihydrate (1.26 g, 6 eq) were added. The reaction was stirred and refluxed at 95 °C for 2 hours. The reaction was then cooled, diluted with water and extracted three times with dichloromethane. The combined organic phases were washed with water and brine, and the organic layer was washed with Na 2 SO 4 Dry, filter, and concentrate in vacuo to obtain a crude product, which was purified by column chromatography to obtain Erianin as a white powder solid, 0.70 g, with a yield of 85%.
[0032] 1 H NMR (500 MHz, Chloroform-d) δ 6.81 (d, J = 2.1 Hz, 1H), 6.77 (d, J= 8.1 Hz, 1H), 6.64 (dd, J = 8.2, 2.1 Hz, 1H), 6.38 (s, 2H), 5.59 (s, 1H), 3.87 (s, 3H), 3.83 (d, J = 1.5 Hz, 9H), 2.82 (s, 4H). 13 C NMR (126 MHz, Chloroform-d) δ 153.16, 145.61, 136.25, 135.15, 119.94, 114.78, 110.69,105.48, 61.01, 56.18, 56.16, 38.55, 37.45. MS:(LC-MS): calculated for C 18 H 22 O 5 [MH] -, 317.1394; found, 317.1384. The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.
Claims
1. A method for preparing Erianin, characterized in that: The following steps are involved: S1. Aldol condensation reaction: a compound of the general formula (I) is subjected to an aldol condensation reaction with a compound of the general formula (II) to prepare a compound of the formula (III), wherein the reaction is carried out in an organic solvent containing a catalyst; S2, decarboxylation reaction: reacting the compound of formula (III) obtained in S1 with the formed complex catalyst under microwave irradiation, separating and purifying to obtain the compound of formula (IV), the reaction is carried out in an organic solvent, and the catalyst is a composite catalyst; S3, reduction reaction: the compound of formula (IV) obtained in S2 is treated with a reducing agent to prepare Erianin, and the reaction is carried out in an inert solvent containing a base.
2. The method for preparing Erianin according to claim 1, characterized in that: The organic solvent used in S1 is an organic solvent selected from acid anhydrides, such as acetic anhydride, propionic anhydride, butyric anhydride, phthalic anhydride, etc., among which acetic anhydride is preferred.
3. The method for preparing Erianin according to claim 1, characterized in that: The reaction system of the aldol condensation reaction in S1 is as follows: triethylamine is added to the acetic anhydride solution of compounds (I) and (II); the temperature is raised to 110°C, and the reaction is stirred for 6 hours, and then the reaction solution is poured into ice water to precipitate a solid. The obtained solid is completely dissolved in a 10% NaOH solution, and the solution becomes clear; impurities are removed by extraction with ethyl acetate, and hydrochloric acid is slowly added dropwise under stirring to acidify the water layer to pH = 5 to obtain a light solid, which is then dried to obtain a crude product (III).
4. The method for preparing Erianin according to claim 1, characterized in that: The organic solvent in S2 is a solvent that is beneficial to the synthesis of metal complexes and microwave-assisted reactions, such as PEG-400, dimethylformamide, dimethyl sulfoxide, quinoline, etc., among which PEG-400 is preferred.
5. The method for preparing Erianin according to claim 1, characterized in that: The reaction system of the S2 separation and purification reaction is as follows: Compound (III), CuI, 1,10-phenanthroline and PEG-400 are added to a round-bottom flask; the flask is then placed in a microwave synthesizer and irradiated (325W) for 4-12 min; after the reaction is completed, the mixture is cooled to room temperature, water and ethyl acetate are added, the resulting red crystalline powder is filtered out, washed with water and ethyl acetate, dried and stored for the next run; the filtrate is extracted with ethyl acetate; the combined organic phase is washed with water, dried over anhydrous magnesium sulfate, and then concentrated to obtain a crude product (IV), which is then purified by PTLC.
6. The method for preparing Erianin according to claim 1, characterized in that: In said S3: the inert solvent in the reaction is one or more selected from dioxane, tetrahydrofuran, dimethylformamide, dimethyl sulfoxide, acetonitrile, hexamethylphosphoramide, carbon tetrachloride, among which dimethylformamide is preferred.
7. The method for preparing Erianin according to claim 1, characterized in that: The base used in the S3 reaction can generally include various organic bases and inorganic bases, such as sodium carbonate, potassium carbonate, sodium hydride, potassium hydride and other inorganic bases and similar bases in the S1; sodium acetate, pyrimidine, various dimethylpyridines, triethylamine, diisopropylethylamine and other organic bases and similar bases; among which organic bases such as sodium acetate, diisopropylethylamine, triethylamine, diisopropylethylamine and the like are preferred; in a preferred embodiment of the present invention, sodium acetate is selected as the base used in this reaction.
8. The method for preparing Erianin according to claim 1, characterized in that: In the S1: During the reduction reaction of S3, compound (IV), DMF, p-toluenesulfonyl hydrazide and sodium acetate are added to a round-bottomed cup, and the mixture is heated at 95°C for 1 hour; the reaction is then cooled, the reactant is diluted with water and extracted three times with dichloromethane; the combined organic phase is washed with water and brine, the organic layer is dried over Na2SO4, filtered and concentrated in vacuo to obtain a crude product; and purified by column chromatography to obtain white crystals of Erianin.